Crystal form and salt form of benzoindole derivative, and preparation method therefor

Abstract

The present application relates to the field of pharmaceutical crystal forms, and in particular to a crystal form and salt form of a benzoindole derivative compound (formula I), a preparation method therefor, and a use thereof. Crystal form I of the obtained compound of formula I exhibits good physical and chemical stability and crystal form stability; and a preparation process thereof is simple, has good repeatability, has a high yield, is environmentally friendly and easy to operate, allows for convenient recovery, and is suitable for large-scale production.

Description

A crystal form of a benzindole derivative, a salt form and a preparation method thereof TECHNICAL FIELD

[0001] The present application belongs to the field of drug crystal forms, and particularly relates to a crystal form and a salt form of a benzindole derivative compound, and a preparation method and use thereof. BACKGROUND

[0002] Multiple myeloma (MM) is a hematological tumor caused by abnormal proliferation of plasma cells. Its main characteristics are the significant and active proliferation of plasma cells in bone marrow, accompanied by excessive secretion of monoclonal immunoglobulin, and a small number of patients are non-secretory MM without M protein production. At present, the treatment of MM has made a major breakthrough, and multiple drugs such as proteasome inhibitors (bortezomib), immunomodulatory drugs (lenalidomide, pomalidomide), CD38 monoclonal antibodies (daratumumab and Elotuzumab) and histone deacetylase inhibitors (panobinostat) have been approved by FDA for the treatment of MM. Among them, the immunomodulatory agent of molecular glue is the focus of current drug development.

[0003] Molecular glue degraders are a class of small molecules that can induce and stabilize the binding of E3 ubiquitin ligase and target protein, resulting in ubiquitination and proteasome degradation of the target protein. Compared with bifunctional molecular degraders (protac), molecular glue has lower affinity for target proteins, but can bind E3 ubiquitin ligase and mediate contact with target proteins through it. Therefore, molecular glue can degrade target proteins that do not have small molecule binding pockets. In addition, the target protein of the molecular glue itself needs to have a non-functional weak affinity with the E3 ligase. Molecular glue can bind to the gap of the interaction interface of the two, increase the binding interface of the two and promote it to a functional strong interaction. At present, the molecular glue of MM such as lenalidomide, pomalidomide, etc. can recruit CRBN ubiquitin ligase, promote the binding of CRBN and zinc finger protein transcription factor IKZF1 / 3, and then cause the ubiquitination and degradation of IKZF1 / 3. Since IKZF1 / 3 can promote the proliferation of MM cells by regulating the expression of proto-oncogenes IRF4 and c-myc, therefore, the degradation of IKZF1 / 3 induced by molecular glue can significantly inhibit the growth of MM cells. Although lenalidomide has good efficacy on multiple myeloma, most patients will develop drug resistance after 2 years of treatment. Pomalidomide is the preferred drug for multiple myeloma patients who have developed resistance to lenalidomide, and studies have shown that its combination with dexamethasone can inhibit the growth of lenalidomide-resistant tumor cells and induce apoptosis. Although pomalidomide can improve the efficacy of lenalidomide-resistant patients, however, about 1 / 3 of patients will develop point mutations in the CRBN gene after continuous administration, leading to pomalidomide resistance. In addition, although lenalidomide and pomalidomide can inhibit the proliferation of multiple myeloma, the incidence of G3 / G4 neutropenia can be as high as 35% and about 50%, respectively. The objective response rate (ORR) of the molecular glue CC-92480 developed by Bristol-Myers Squibb in the clinical phase 1 experiment reached 54.4%, but the incidence of neutropenia was as high as 53%. Therefore, the development of molecular glue that is effective for lenalidomide and pomalidomide-resistant patients, while having lower hematologic toxicity, especially neutropenia, is of great significance for the treatment of multiple myeloma. SUMMARY

[0004] The applicant provides a brand-new structure of benzindole derivative in patent application PCT / CN2024 / 082990 (application date 2024.03.21), which is (S)-3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-4-yl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione, the chemical name is shown in the following formula I; it has excellent tumor cell inhibition activity, specific selectivity to target protein IKZF1 / 3, excellent degradation activity, lower liver microsomal toxicity, and good in vivo bioavailability, and has good clinical application prospect. The entire content of this patent is incorporated herein by reference.

[0005] It is well known that the crystal form of a drug has an impact on the quality of the preparation and the production process, and the study of the crystal form of a drug can provide a reference for formulation workers in prescription development, new drug dosage form design, optimization of production process, quality control of drugs, and clinical efficacy. Therefore, it is of great significance to find and obtain a stable crystal form and a pharmaceutically acceptable crystal form of a compound of formula I, as well as a salt form.

[0006] When the inventors of the present application studied the crystal form of the compound of formula I, they obtained a new crystal form, a salt form of the compound of formula I, especially a new crystalline solid form of the compound of formula I, which has excellent physical and chemical stability, is not easy to absorb moisture, has good solubility, and has good bioavailability, and its preparation method is green and environmentally friendly, suitable for industrial production.

[0007] Therefore, one aspect of the present application provides a crystal form I of a compound of formula I, wherein the X-ray powder diffraction pattern of the crystal form I has characteristic peaks at 2θ angles of 5.9±0.2°, 7.7±0.2°, 10.0±0.2°, 13.7±0.2°, 17.1±0.2°, 18.3±0.2°, 19.1±0.2° and 21.3±0.2° using Cu-Kα radiation.

[0008] In some preferred embodiments, the crystal form I further has one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) peaks at 2θ angles selected from the following positions: 7.9±0.2°, 11.2±0.2°, 12.9±0.2°, 16.1±0.2°, 16.6±0.2°, 17.4±0.2°, 18.6±0.2°, 20.4±0.2°, 23.4±0.2° and 25.5±0.2° in the X-ray powder diffraction pattern using Cu-Kα radiation.

[0009] In some more preferred embodiments, the Form I has characteristic peaks in its X-ray powder diffraction pattern at 5.9 ± 0.2°, 7.7 ± 0.2°, 7.9 ± 0.2°, 10.0 ± 0.2°, 12.9 ± 0.2°, 13.7 ± 0.2°, 16.1 ± 0.2°, 16.6 ± 0.2°, 17.1 ± 0.2°, 17.4 ± 0.2°, 18.3 ± 0.2°, 18.6 ± 0.2°, 19.1 ± 0.2°, 20.4 ± 0.2°, 21.3 ± 0.2°, 23.4 ± 0.2°, and 25.5 ± 0.2°, using Cu-Kalpharadiation.

[0010] In some preferred embodiments, the Form I further has one or more peaks in its X-ray powder diffraction pattern at 2-theta angles selected from the group consisting of 11.6 ± 0.2°, 11.9 ± 0.2°, 13.2 ± 0.2°, 14.2 ± 0.2°, 15.1 ± 0.2°, 17.7 ± 0.2°, 19.8 ± 0.2°, 21.6 ± 0.2°, 21.9 ± 0.2°, 22.2 ± 0.2°, 22.8 ± 0.2°, 24.0 ± 0.2°, 24.9 ± 0.2°, 25.8 ± 0.2°, 26.2 ± 0.2°, 26.8 ± 0.2°, and 28.7 ± 0.2°, using Cu-Kalpharadiation.

[0011] In some preferred embodiments, the Form I has an X-ray powder diffraction pattern substantially as shown in Figure 1.

[0012] In some preferred embodiments, the Form I has a DSC pattern with endothermic peaks at about 236.2 °C and 244.5 °C.

[0013] In some preferred embodiments, the Form I has a DSC pattern substantially as shown in Figure 2.

[0014] In some preferred embodiments, the Form I has a weight loss of about 0.54% at 30-150 °C in a thermogravimetric analysis curve.

[0015] In some preferred embodiments, the Form I is an anhydrous form, i.e., substantially free of crystallization water or solvent.

[0016] In some preferred embodiments, the Form I has a TGA pattern substantially as shown in Figure 3.

[0017] In some preferred embodiments, the Form I has a DVS pattern substantially as shown in Figure 4. As can be seen from the figure, the Form I is only slightly hygroscopic.

[0018] In another aspect, the present application provides a preparation method of the crystalline form I, comprising: suspending the compound of formula I in a mixture of isopropyl alcohol and water, then cooling and crystallizing, and drying to obtain the crystalline form I.

[0019] In some preferred embodiments, in the preparation method of the crystalline form I, the suspension temperature is 40-60°C, and the suspension time is 1-3 hours.

[0020] In some preferred embodiments, in the preparation method of the crystalline form I, the cooling and crystallizing temperature is 0-5°C, and the crystallizing time is 3-5 hours.

[0021] In some preferred embodiments, in the preparation method of the crystalline form I, the volume ratio of isopropyl alcohol to water is 9:1.

[0022] In another aspect, the present application provides a crystalline form II of the compound of formula I, wherein the X-ray powder diffraction pattern has characteristic peaks at 5.3±0.2°, 7.1±0.2°, 7.9±0.2°, 8.6±0.2°, 12.3±0.2°, 15.2±0.2°, 16.2±0.2°, 22.4±0.2° and 25.1±0.2° in terms of 2θ angle using Cu-Kα radiation; preferably, the X-ray powder diffraction pattern has characteristic peaks at 5.3±0.2°, 7.1±0.2°, 7.9±0.2°, 8.1±0.2°, 8.6±0.2°, 12.3±0.2°, 13.7±0.2°, 14.7±0.2°, 15.2±0.2°, 16.2±0.2°, 17.7±0.2°, 19.4±0.2°, 20.0±0.2°, 22.4±0.2°, 23.6±0.2°, 25.1±0.2° and 26.5±0.2° in terms of 2θ angle.

[0023] In some preferred embodiments, the X-ray powder diffraction pattern of the crystalline form II is substantially as shown in Figure 7.

[0024] In another aspect, the present application provides a crystalline form III of the compound of formula I, wherein the X-ray powder diffraction pattern has characteristic peaks at 2-theta angles of 4.5±0.2°, 5.2±0.2°, 9.0±0.2°, 10.2±0.2°, 14.4±0.2° and 16.5±0.2° using Cu-Ka radiation; preferably, the X-ray powder diffraction pattern has characteristic peaks at 2-theta angles of 4.5±0.2°, 5.2±0.2°, 6.8±0.2°, 8.2±0.2°, 9.0±0.2°, 9.6±0.2°, 10.2±0.2°, 11.5±0.2°, 12.2±0.2°, 13.0±0.2°, 13.6±0.2°, 14.4±0.2°, 14.7±0.2°, 15.9±0.2°, 16.5±0.2°, 18.2±0.2° and 20.4±0.2°.

[0025] In some preferred embodiments, the X-ray powder diffraction pattern of the crystalline form III is substantially as shown in Figure 8.

[0026] In another aspect, the present application provides a crystalline form IV of the compound of formula I, wherein the X-ray powder diffraction pattern has characteristic peaks at 2-theta angles of 5.1±0.2°, 5.9±0.2°, 7.4±0.2°, 9.4±0.2°, 10.3±0.2°, 13.2±0.2°, 14.9±0.2° and 17.4±0.2° using Cu-Ka radiation; preferably, the X-ray powder diffraction pattern has characteristic peaks at 2-theta angles of 5.1±0.2°, 5.9±0.2°, 7.4±0.2°, 9.4±0.2°, 10.3±0.2°, 11.0±0.2°, 13.2±0.2°, 14.9±0.2°, 16.0±0.2°, 16.8±0.2°, 17.4±0.2°, 18.7±0.2°, 19.0±0.2°, 20.9±0.2°, 21.2±0.2°, 21.5±0.2°, 23.0±0.2°, 26.1±0.2° and 26.7±0.2°.

[0027] In some preferred embodiments, the X-ray powder diffraction pattern of the crystalline form IV is substantially as shown in Figure 9.

[0028] In another aspect, the present application provides a crystalline form V of the compound of formula I, wherein the X-ray powder diffraction pattern has characteristic peaks at 5.5±0.2°, 7.1±0.2°, 9.0±0.2°, 11.0±0.2°, 13.1±0.2°, 15.2±0.2°, 15.9±0.2° and 25.4±0.2° in terms of 2θ angle using Cu-Kα radiation; preferably, the X-ray powder diffraction pattern has characteristic peaks at 4.5±0.2°, 5.5±0.2°, 7.1±0.2°, 9.0±0.2°, 11.0±0.2°, 13.1±0.2°, 14.3±0.2°, 15.2±0.2°, 15.9±0.2°, 16.7±0.2°, 18.1±0.2°, 18.6±0.2°, 19.7±0.2°, 21.5±0.2°, 22.2±0.2°, 25.4±0.2° and 26.4±0.2° in terms of 2θ angle.

[0029] In some preferred embodiments, the X-ray powder diffraction pattern of the crystalline form V is substantially as shown in Figure 10.

[0030] In another aspect, the present application provides a crystalline form VI of the compound of formula I, wherein the X-ray powder diffraction pattern has characteristic peaks at 5.2±0.2°, 5.9±0.2°, 7.4±0.2°, 9.4±0.2°, 10.4±0.2°, 13.3±0.2°, 15.0±0.2° and 17.5±0.2° in terms of 2θ angle using Cu-Kα radiation; preferably, the X-ray powder diffraction pattern has characteristic peaks at 5.2±0.2°, 5.9±0.2°, 7.4±0.2°, 9.4±0.2°, 10.4±0.2°, 13.3±0.2°, 15.0±0.2°, 16.9±0.2°, 17.5±0.2°, 19.0±0.2°, 20.7±0.2°, 20.9±0.2°, 21.3±0.2°, 21.6±0.2° and 23.1±0.2° in terms of 2θ angle.

[0031] In some preferred embodiments, the X-ray powder diffraction pattern of the crystalline form VI is substantially as shown in Figure 11.

[0032] In another aspect, the present application provides a crystalline form VII of the compound of formula I, wherein the X-ray powder diffraction pattern has characteristic peaks at 5.9±0.2°, 12.1±0.2°, 15.1±0.2°, 16.0±0.2°, 16.8±0.2°, 18.1±0.2°, 22.2±0.2°, 23.3±0.2° and 25.5±0.2° in terms of 2θ angle; preferably, the X-ray powder diffraction pattern has characteristic peaks at 5.9±0.2°, 8.4±0.2°, 8.8±0.2°, 9.8±0.2°, 11.3±0.2°, 12.1±0.2°, 15.1±0.2°, 16.0±0.2°, 16.8±0.2°, 17.7±0.2°, 18.1±0.2°, 18.3±0.2°, 19.9±0.2°, 20.7±0.2°, 21.6±0.2°, 22.2±0.2°, 22.6±0.2°, 23.3±0.2°, 24.1±0.2° and 25.5±0.2° in terms of 2θ angle using Cu-Ka radiation.

[0033] In some preferred embodiments, the X-ray powder diffraction pattern of the crystalline form VII is substantially as shown in Figure 12.

[0034] In another aspect, the present application provides a crystalline form VIII of the compound of formula I, wherein the X-ray powder diffraction pattern has characteristic peaks at 3.7±0.2°, 5.2±0.2°, 7.2±0.2°, 8.1±0.2°, 11.5±0.2°, 13.5±0.2°, 14.6±0.2°, 15.1±0.2°, 16.3±0.2° and 18.3±0.2° in terms of 2θ angle; preferably, the X-ray powder diffraction pattern has characteristic peaks at 3.7±0.2°, 5.2±0.2°, 7.2±0.2°, 8.1±0.2°, 10.3±0.2°, 11.5±0.2°, 13.5±0.2°, 14.6±0.2°, 15.1±0.2°, 15.4±0.2°, 16.3±0.2°, 18.3±0.2°, 22.0±0.2°, 24.9±0.2°, 25.2±0.2° and 26.1±0.2° in terms of 2θ angle using Cu-Ka radiation.

[0035] In some preferred embodiments, the X-ray powder diffraction pattern of the crystalline form VIII is substantially as shown in Figure 13.

[0036] In another aspect, the present application provides a compound of Formula I in crystalline Form IX, wherein the X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 4.8±0.2°, 7.2±0.2°, 9.6±0.2°, 11.0±0.2°, 11.8±0.2°, 15.4±0.2°, and 19.3±0.2° using Cu-Ka radiation; preferably, the X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 4.8±0.2°, 7.2±0.2°, 9.6±0.2°, 11.0±0.2°, 11.8±0.2°, 15.4±0.2°, 16.2±0.2°, 18.0±0.2°, 18.8±0.2°, 19.3±0.2°, 20.0±0.2°, 21.7±0.2°, and 24.8±0.2°.

[0037] In some preferred embodiments, the X-ray powder diffraction pattern of the crystalline Form IX is substantially as shown in FIG. 14.

[0038] In another aspect, the present application provides a compound of Formula I in crystalline Form X, wherein the X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 6.0±0.2°, 9.0±0.2°, 9.6±0.2°, 12.0±0.2°, 15.1±0.2°, 21.1±0.2°, and 25.0±0.2° using Cu-Ka radiation; preferably, the X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 6.0±0.2°, 9.0±0.2°, 9.6±0.2°, 12.0±0.2°, 15.1±0.2°, 16.9±0.2°, 17.6±0.2°, 21.1±0.2°, 22.0±0.2°, 22.4±0.2°, 25.0±0.2°, and 25.3±0.2°.

[0039] In some preferred embodiments, the X-ray powder diffraction pattern of the crystalline Form X is substantially as shown in FIG. 15.

[0040] In another aspect, the present application provides a compound of Formula I in crystalline Form XI, wherein the X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 6.8±0.2°, 10.2±0.2°, 14.2±0.2°, 17.1±0.2°, 18.4±0.2°, and 22.1±0.2° using Cu-Ka radiation; preferably, the X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 6.6±0.2°, 6.8±0.2°, 10.2±0.2°, 14.2±0.2°, 15.1±0.2°, 16.1±0.2°, 17.1±0.2°, 18.4±0.2°, 20.7±0.2°, 21.7±0.2°, 22.1±0.2°, 24.1±0.2°, and 25.2±0.2°.

[0041] In some preferred embodiments, the crystalline Form XI has an X-ray powder diffraction pattern substantially as shown in FIG. 16.

[0042] In another aspect, the present application provides a compound of Formula I in crystalline Form XII, wherein the X-ray powder diffraction pattern has characteristic peaks at 2-theta angles of 4.9±0.2°, 7.3±0.2°, 9.7±0.2°, 11.9±0.2°, 16.3±0.2°, 17.7±0.2°, 19.4±0.2° and 23.0±0.2°, using Cu-Kalpharadiation; preferably, at 2-theta angles of 4.9±0.2°, 5.5±0.2°, 7.3±0.2°, 9.7±0.2°, 11.1±0.2°, 11.9±0.2°, 13.9±0.2°, 14.9±0.2°, 15.5±0.2°, 16.3±0.2°, 17.2±0.2°, 17.7±0.2°, 18.2±0.2°, 19.0±0.2°, 19.4±0.2°, 19.6±0.2°, 20.2±0.2°, 20.9±0.2°, 21.5±0.2°, 22.2±0.2°, 23.0±0.2°, 25.4±0.2°, 25.8±0.2°, 26.8±0.2° and 27.3±0.2°.

[0043] In some preferred embodiments, the crystalline Form XII has an X-ray powder diffraction pattern substantially as shown in FIG. 17.

[0044] In another aspect, the present application provides a compound of Formula I in crystalline Form XIII, wherein the X-ray powder diffraction pattern has characteristic peaks at 2-theta angles of 5.2±0.2°, 6.1±0.2°, 7.5±0.2°, 9.6±0.2°, 10.6±0.2°, 13.4±0.2°, 17.6±0.2° and 19.1±0.2°, using Cu-Kalpharadiation; preferably, at 2-theta angles of 5.2±0.2°, 6.1±0.2°, 7.5±0.2°, 8.6±0.2°, 9.6±0.2°, 10.6±0.2°, 11.1±0.2°, 13.4±0.2°, 14.1±0.2°, 15.0±0.2°, 17.0±0.2°, 17.6±0.2°, 19.1±0.2°, 20.9±0.2°, 21.4±0.2°, 21.8±0.2°, 23.2±0.2°, 23.3±0.2°, 25.9±0.2°, 26.9±0.2°, 27.8±0.2° and 28.4±0.2°.

[0045] In some preferred embodiments, the crystalline Form XIII has an X-ray powder diffraction pattern substantially as shown in FIG. 18.

[0046] In another aspect, the present application provides a crystalline form XIV of the compound of formula I, wherein the X-ray powder diffraction pattern has characteristic peaks at 5.2±0.2°, 7.0±0.2°, 9.2±0.2°, 12.6±0.2°, 13.5±0.2°, 15.8±0.2°, 19.3±0.2°, and 23.9±0.2° in terms of 2θ angle using Cu-Kα radiation; preferably, the X-ray powder diffraction pattern has characteristic peaks at 5.2±0.2°, 7.0±0.2°, 7.9±0.2°, 9.2±0.2°, 9.7±0.2°, 11.4±0.2°, 12.6±0.2°, 13.5±0.2°, 14.2±0.2°, 15.8±0.2°, 17.0±0.2°, 18.2±0.2°, 19.3±0.2°, 20.3±0.2°, 20.9±0.2°, 22.7±0.2°, 23.1±0.2°, 23.9±0.2°, 24.5±0.2°, 25.6±0.2°, 26.6±0.2°, 27.3±0.2°, 28.7±0.2° and 29.3±0.2° in terms of 2θ angle using Cu-Kα radiation.

[0047] In some preferred embodiments, the X-ray powder diffraction pattern of the crystalline form XIV is substantially as shown in FIG. 19.

[0048] In another aspect, the present application provides a crystalline form XV of the compound of formula I, wherein the X-ray powder diffraction pattern has characteristic peaks at 5.3±0.2°, 6.1±0.2°, 7.0±0.2°, 9.2±0.2°, 11.3±0.2°, 12.4±0.2°, 13.3±0.2°, 13.9±0.2°, 14.1±0.2°, 15.7±0.2°, 16.0±0.2°, 16.9±0.2°, 17.3±0.2°, 18.2±0.2°, 18.7±0.2°, 19.0±0.2°, 19.4±0.2°, 20.7±0.2°, 22.6±0.2°, 23.3±0.2°, 23.7±0.2°, 24.1±0.2°, 24.5±0.2°, 26.4±0.2° and 27.1±0.2° in terms of 2θ angle using Cu-Kα radiation.

[0049] In some preferred embodiments, the X-ray powder diffraction pattern of the crystalline form XV is substantially as shown in FIG. 20.

[0050] In another aspect, the present application provides an amorphous form of the compound of formula I, wherein the X-ray powder diffraction pattern is substantially as shown in FIG. 21.

[0051] In another aspect, the present application provides a salt of the compound of Formula I, wherein the salt is selected from p-toluenesulfonic acid salt, benzenesulfonic acid salt, methanesulfonic acid salt, hydrochloric acid salt, fumaric acid salt, succinic acid salt, citric acid salt, citric acid salt, acetic acid salt, formic acid salt, benzoic acid salt, propionic acid salt, oxalic acid salt, salicylic acid salt, ascorbic acid salt, phthalic acid salt, butyric acid salt, camphorsulfonic acid salt, camphoric acid salt, cinnamic acid salt, ethanesulfonic acid salt, hippuric acid salt, glycolic acid salt, hydrobromic acid salt, hydroiodic acid salt, lactic acid salt, maleic acid salt, malonic acid salt, glutamic acid salt, nitric acid salt, or phosphoric acid salt.

[0052] In some preferred embodiments, the salt of the compound of Formula I is in crystalline form. In another aspect, the present application provides a p-toluenesulfonic acid salt crystalline form of the compound of Formula I, which has an X-ray powder diffraction pattern with characteristic peaks at 5.9±0.2°, 7.5±0.2°, 8.6±0.2°, 10.8±0.2°, 12.2±0.2°, 14.6±0.2°, 16.4±0.2°, 17.9±0.2°, 20.1±0.2°, 21.3±0.2°, 22.8±0.2°, and 25.4±0.2° in terms of 2θ angle. The molar ratio of the compound of Formula I to p-toluenesulfonic acid is 1:1.

[0053] In some preferred embodiments, the X-ray powder diffraction pattern of the p-toluenesulfonic acid salt crystalline form is substantially as shown in FIG. 24.

[0054] In some preferred embodiments, the DSC pattern of the p-toluenesulfonic acid salt crystalline form is substantially as shown in FIG. 25.

[0055] In some preferred embodiments, the TGA pattern of the p-toluenesulfonic acid salt crystalline form is substantially as shown in FIG. 26.

[0056] In some preferred embodiments, the p-toluenesulfonic acid salt crystalline form is prepared by suspending the compound of Formula I and p-toluenesulfonic acid in ethanol at room temperature.

[0057] In another aspect, the present application provides a succinic acid co-crystal of the compound of Formula I, which has an X-ray powder diffraction pattern with characteristic peaks at 5.8±0.2°, 9.8±0.2°, 12.0±0.2°, 15.2±0.2°, 16.1±0.2°, 17.7±0.2°, 23.2±0.2°, and 25.3±0.2° in terms of 2θ angle using Cu-Kα radiation.

[0058] In some preferred embodiments, the X-ray powder diffraction pattern of the succinic acid co-crystal has characteristic peaks at 2 theta angles of 5.8±0.2°, 9.8±0.2°, 11.3±0.2°, 12.0±0.2°, 15.2±0.2°, 16.1±0.2°, 16.8±0.2°, 17.7±0.2°, 18.2±0.2°, 20.6±0.2°, 22.2±0.2°, 22.6±0.2°, 23.2±0.2°, 24.0±0.2° and 25.3±0.2°.

[0059] In some preferred embodiments, the X-ray powder diffraction pattern of the succinic acid co-crystal is substantially as shown in Figure 27.

[0060] In some preferred embodiments, the DSC pattern of the succinic acid co-crystal is substantially as shown in Figure 28.

[0061] In some preferred embodiments, the TGA pattern of the succinic acid co-crystal is substantially as shown in Figure 29.

[0062] In some preferred embodiments, the method for preparing the succinic acid co-crystal is by suspending the compound of Formula I and succinic acid in ethanol at room temperature.

[0063] The application brings the following beneficial effects:

[0064] 1. The crystal form of the compound of Formula I provided by the application has excellent effects in drugs for preventing and / or treating diseases mediated by cereblon.

[0065] 2. The crystal form of the compound of Formula I provided by the application has good physical and chemical stability, and low hygroscopicity. The comprehensive performance of the crystal form I is excellent in all aspects, has excellent bioavailability in vivo, and is beneficial to clinical use.

[0066] 3. The preparation process of the crystal form of the compound of Formula I provided by the application is simple, reproducible, high-yield, green and environmentally friendly, easy to operate, convenient for recovery, and easy to realize large-scale production. BRIEF DESCRIPTION OF DRAWINGS

[0067] Figure 1 is the XRPD pattern of the crystal form I of the compound of Formula I.

[0068] Figure 2 is the DSC pattern of the crystal form I of the compound of Formula I.

[0069] Figure 3 is the TGA pattern of the crystal form I of the compound of Formula I.

[0070] Figure 4 is the DVS pattern of the crystal form I of the compound of Formula I.

[0071] Figure 5 is the comparison chart of the stability influencing factors of the crystal form I of the compound of Formula I for 30 days.

[0072] Figure 6 is a long-term and accelerated stability study 6 month crystal form comparison plot for the compound of Formula I Form I.

[0073] Figure 7 is an XRPD plot of the compound of Formula I Form II.

[0074] Figure 8 is an XRPD plot of the compound of Formula I Form III.

[0075] Figure 9 is an XRPD plot of the compound of Formula I Form IV.

[0076] Figure 10 is an XRPD plot of the compound of Formula I Form V.

[0077] Figure 11 is an XRPD plot of the compound of Formula I Form VI.

[0078] Figure 12 is an XRPD plot of the compound of Formula I Form VII.

[0079] Figure 13 is an XRPD plot of the compound of Formula I Form VIII.

[0080] Figure 14 is an XRPD plot of the compound of Formula I Form IX.

[0081] Figure 15 is an XRPD plot of the compound of Formula I Form X.

[0082] Figure 16 is an XRPD plot of the compound of Formula I Form XI.

[0083] Figure 17 is an XRPD plot of the compound of Formula I Form XII.

[0084] Figure 18 is an XRPD plot of the compound of Formula I Form XIII.

[0085] Figure 19 is an XRPD plot of the compound of Formula I Form XIV.

[0086] Figure 20 is an XRPD plot of the compound of Formula I Form XV.

[0087] Figure 21 is an XRPD plot of the compound of Formula I amorphous.

[0088] Figure 22 is an influence factor stability study 30 day crystal form comparison plot for the compound of Formula I amorphous.

[0089] Figure 23 is a long-term and accelerated stability study 6 month crystal form comparison plot for the compound of Formula I amorphous.

[0090] Figure 24 is an XRPD plot of the compound of Formula I p-toluenesulfonic acid salt Form.

[0091] Figure 25 is a DSC plot of the compound of Formula I p-toluenesulfonic acid salt Form.

[0092] Figure 26 is a TGA plot of the p-toluenesulfonic acid salt of the compound of Formula I.

[0093] Figure 27 is an XRPD plot of the succinic acid co-crystal of the compound of Formula I.

[0094] Figure 28 is a DSC plot of the succinic acid co-crystal of the compound of Formula I.

[0095] Figure 29 is a TGA plot of the succinic acid co-crystal of the compound of Formula I.

[0096] Figure 30 is a 30-day stability study of the succinic acid co-crystal of the compound of Formula I.

[0097] Figure 31 is a 6-month stability study of the succinic acid co-crystal of the compound of Formula I. DETAILED DESCRIPTION

[0098] The present application is further described in connection with the following examples, which are not intended to limit the application. Any patentable scope of equivalents thereto following in the art is intended to be within the scope of the present application.

[0099] The compound of Formula I in the present application also includes its tautomers. Tautomers refer to isomeric forms of a compound that are in equilibrium with each other.

[0100] The terms such as "Form I of the compound of Formula I", "Form I"; "Form of the p-toluenesulfonic acid salt of the compound of Formula I", "Form of the p-toluenesulfonic acid salt" and the like used in the present application can be used interchangeably, and the interchangeability of the above does not affect the meaning thereof.

[0101] The abbreviations used in the present application are explained as follows:

[0102] XRPD: X-ray powder diffraction

[0103] The X-ray powder diffraction (XRPD) measurement described in the present application is performed using a Malvern-Panalytical Empyrean X-ray powder diffractometer, and the specific parameters are as follows:

[0104] In the X-ray powder diffraction pattern of the present application, the error of the 2θ diffraction angle is ±0.20°. In the present application, "the X-ray powder diffraction pattern is substantially as shown in Figure 1" means that the X-ray powder diffraction pattern is substantially the same as Figure 1, and the term "substantially the same" of the X-ray powder diffraction pattern means that the representative peak position and intensity change are taken into account.

[0105] DSC: differential scanning calorimeter

[0106] Differential scanning calorimetry (DSC) measurements described herein were collected using a METTLER TOLEDO model DSC-1 at a heating rate of 10 °C / min over a temperature range of 25-300 °C with a nitrogen purge rate of 60 mL / min during the test.

[0107] TGA: thermogravimetric analyzer

[0108] Thermogravimetric analysis (TGA) measurements described herein were collected using a METTLER TOLEDO model TGA-2 at a heating rate of 10 °C / min over a temperature range of 30-300 °C with a nitrogen purge rate of 20 mL / min during the test.

[0109] The error for TGA can be within about ±0.5 mass %. Herein, “the TGA pattern is substantially as shown in FIG. 3” means that the TGA pattern is substantially the same as FIG. 3, and the term “substantially the same” for the TGA pattern means that such an error variation is taken into account.

[0110] DVS: dynamic vapor sorption analyzer

[0111] Dynamic vapor sorption analyzer Intrinsic (SMS Instruments, UK) was used to detect the change of sample weight with humidity at 25 °C. The specific parameters: start equilibrium at 25 °C, 0% relative humidity, weight change less than 0.002% within 2 min, jump 10% relative humidity, enter the next stage, the maximum equilibrium time of each stage is 360 min. After reaching 98% relative humidity and completing the equilibrium, a reverse relative humidity jump was performed. The relative humidity changes as follows: 0%—10%—20%—30%—40%—50%—60%—70%—80%—90%—98%—90%—80%—70%—60%—50%—40%—30%—20%—10%—0%. Data analysis software DVS Control (SMS Instruments, UK).

[0112] Preparation Example 1: Preparation of the compound shown in Formula I (prepared according to Examples 29-31 of PCT / CN2024 / 082990, the compound of Formula I is the compound of Example 30 of this patent application):

[0113] (1) Synthesis of intermediate 3 (3-(2-oxo-6-(4-(piperazin-1-ylmethyl)benzyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione):

[0114] Intermediate 3 was synthesized according to the method provided in patent application WO2020210630A1.

[0115] (2) Synthesis of Intermediate 5 (2-(lH-imidazol-l-yl)-4-(methylsulfonyl)pyrimidine) and Intermediate 36 (2-methyl-4-(methylsulfonyl)-6-(4-(trifluoromethyl)-lH-imidazol-l- yl)pyrimidine):

[0116] Step a. Synthesis of 2-(lH-imidazol-l-yl)-4-(methylthio)pyrimidine

[0117] To a 50 mL two-necked flask was added 2-chloro-4-methylthiopyrimidine (805 mg, 5 mmol, CAS: 49844-93-1), imidazole (510 mg, 7.5 mmol), cuprous iodide (181 mg, 1.0 mmol) and cesium carbonate (3.26 g, 10 mmol), followed by anhydrous N,N-dimethylacetamide (20 mL) under nitrogen atmosphere, and the mixture was stirred at 80 °C overnight. To the reaction mixture was added saturated brine solution (100 mL), and extracted with ethyl acetate (30 mL) for 3 times. The organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (682 mg, yield 71%) as a white solid. LC-MS: m / z [M+H] + = 193.

[0118] Step b. Synthesis of Intermediate 5 (2-(lH-imidazol-l-yl)-4-(methylsulfonyl)pyrimidine)

[0119] To a 50 mL two-necked flask was added 2-chloro-4-methylthiopyrimidine (805 mg, 5 mmol, CAS: 49844-93-1), imidazole (510 mg, 7.5 mmol), cuprous iodide (181 mg, 1.0 mmol) and cesium carbonate (3.26 g, 10 mmol), followed by anhydrous N,N-dimethylacetamide (20 mL) under nitrogen atmosphere, and the mixture was stirred at 80 °C overnight. To the reaction mixture was added saturated brine solution (100 mL), and extracted with ethyl acetate (30 mL) for 3 times. The organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (682 mg, yield 71%) as a white solid. LC-MS: m / z [M+H] + = 225.

[0120] Reference to the following table, Intermediate 36 was prepared according to the preparation method of Intermediate 5 except that the starting material described in the column of “Starting Material” was used to replace the corresponding starting material:

[0121] PCT / CN2024 / 082990 Example 293-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-4-yl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione

[0122] To a 50 mL vial was added 3-(2-oxo-6-(4-(piperazin-1-ylmethyl)benzyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (150 mg, 0.32 mmol, Intermediate 3), 2-methyl-4-(methylsulfonyl)-6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidine (147 mg, 0.48 mmol, Intermediate 36) and N,N-diisopropylethylamine (0.265 mL, 1.6 mmol, d = 0.782 g / mL) followed by dimethyl sulfoxide (3 mL) and the mixture stirred at 120 °C for 5 hours. The reaction was purified by preparative liquid chromatography (acetonitrile and water with 0.1% formic acid) to give the yellow title compound (95 mg, 43% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.71 (s, 1H), 8.63 (t, J = 1.5 Hz, 1H), 8.33 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 7.0 Hz, 1H), 7.81 (dd, J = 8.3, 7.0 Hz, 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.25 (q, J = 8.0 Hz, 4H), 7.12 (d, J = 7.3 Hz, 1H), 7.04 (s, 1H), 5.45 (dd, J = 13.0, 5.4 Hz, 1H), 4.39 (s, 2H), 3.70 (s, 4H), 3.46 (s, 2H), 3.02 - 2.89 (m, 1H), 2.85 - 2.60 (m, 2H), 2.41 (m, 7H), 2.13 - 2.06 (m, 1H); LC-MS: m / z [M+H] = 695. + = 695.

[0123] PCT / CN2024 / 082990 Example 30 (S)-3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-4-yl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione

[0124] (R)-3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-4-yl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione of PCT / CN2024 / 082990

[0125] Chiral separation: 27 g of 3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-4-yl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Example 29) was separated into enantiomers by chiral normal phase preparative HPLC method. The preparative fractions were first evaporated individually under reduced pressure to obtain solid material. The solid material was then suspended in a mixture of acetonitrile and water (2:3) and kept in dry ice / acetone bath until the acetonitrile-water mixture solidified. The frozen mixture was then freeze-dried under a lyophilizer for 20 hours to obtain (S)-3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-4-yl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Example 30) (first eluted peak, RT = 1.659 min, tentatively assigned as “S” ABS) (11.5 g, 99.37% ee) and (R)-3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-4-yl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Example 31) (second eluted peak, RT = 2.133 min, tentatively assigned as ‘R’ ABS) (12.5 g, 100% ee).

[0126] Analytical separation method:

[0127] Instrument: Shimadzu LC-20AB with PDA detector

[0128] Column: Chiralpak IC-3 100 x 4.6 mm I.D., 3 μm

[0129] Mobile phase: A: Hexane (0.1% DEA), B: IPA: MeCN = 2:1

[0130] Isocratic: B: 60%

[0131] Flow rate: 1.0 mL / min

[0132] Column temperature: 35 °C

[0133] Wavelength: 254 nm

[0134] Preparative separation method:

[0135] Instrument: Shimadzu LC-A HPLC

[0136] Column: Chiralpak IC, 250 x 30 mm, 10 pm

[0137] Mobile phase: A: DCM, B: IPA

[0138] Isocratic: B: 50%

[0139] Flow rate: 150 mL / min

[0140] Column temperature: R.T.

[0141] Wavelength: 220 nm, 254 nm

[0142] Sample preparation: Dissolve sample in ~2000 mL DCM / IPA

[0143] Injection: 200 mL

[0144] Cycle time: 35 min

[0145] Example 30 of PCT / CN2024 / 082990 (i.e. a compound of Formula I): 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.71 (s, 1H), 8.62 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 6.8 Hz, 1H), 7.81 (dd, J = 8.4, 7.2 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 7.2 Hz, 1H), 7.03 (s, 1H), 5.45 (dd, J = 12.8, 5.2 Hz, 1H), 4.39 (s, 2H), 3.69 (s, 4H), 3.46 (s, 2H), 3.02 - 2.89 (m, 1H), 2.81 - 2.70 (m, 1H), 2.67 - 2.63 (m, 1H), 2.43 - 2.38 (m, 7H), 2.15 - 2.04 (m, 1H); LC-MS: m / z [M+H] + = 695.

[0146] Test Example 1. NCI-H929 cell proliferation Cell Titer-GLO (CTG) assay

[0147] Purpose of the experiment: to detect the inhibitory activity of the compound of formula I on the proliferation of NCI-H929 cells.

[0148] Experimental method:

[0149] NCI-H929 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd. The cells were cultured in RPMI1640 (Viva; C3010-0500) medium containing 10% fetal bovine serum (Viva, C04002-500) and 1% penicillin-streptomycin, and the cells were cultured in a cell incubator at 37°C, 5% CO2 and saturated humidity.

[0150] Cells growing to the logarithmic growth phase were seeded into 96-well plates (5000 cells / well), and after overnight culture, 0.00512 nM, 0.0256 nM, 0.128 nM, 0.64 nM, 3.2 nM, 16 nM, 80 nM, 400 nM of the compound of formula I, 0.1% DMSO and the complete medium were added as the solvent and blank control, respectively, and each test had 2 replicate wells. The 96-well plates were incubated in a 37°C, 5% CO2 incubator for 72 h. After incubation, the 96-well plates were placed at room temperature for half an hour in advance, and then 50 μL The mixture was placed on a shaker for 2 min, then incubated at room temperature for 10 min in the dark before measuring the Luminance signal using a SpectraMax Paradigm (Molecular Devices).

[0151] Cell viability inhibition rate (%) = 100 - (RLU compound -RLU blank ) / (RLU control -RLU blank )*100%, Control is 0.1% DMSO treatment group, blank is medium control. Compound IC 50 The IC50and maximum inhibition rate were calculated by the non-linear regression function "Dose-Response-Inhibition" in Graphpad Prism 7.0.

[0152] Conclusion: The compound of formula I of the present application shows excellent cell proliferation inhibition activity on NCI-H929 cells.

[0153] The present application is described in detail by the following examples, but this does not mean that the protection scope of the present application is limited. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application. Unless otherwise specified, the reagents, materials, etc. mentioned in the following examples are those commercially available in the art.

[0154] The present application is described in detail by the following examples, but this does not mean that the protection scope of the present application is limited. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application. Unless otherwise specified, the reagents, materials, etc. mentioned in the following examples are those commercially available in the art.

[0155] Example 1: Preparation of the compound of formula I in crystalline form I

[0156] The compound of formula I 2.0 g was weighed into 36 mL of isopropyl alcohol and 4 mL of water, stirred and suspended at 50°C for 1 h, cooled to 5°C and continued to be suspended for 5 h, the obtained solid was collected and dried to obtain 1.75 g of solid, which was named as crystalline form I.

[0157] The obtained compound of formula I in crystalline form I was subjected to X-ray powder determination using Cu-ka rays, and the XRPD pattern thereof had diffraction angles and relative intensities as shown in Table 1; the XRPD pattern thereof is shown in Figure 1, the DSC pattern is shown in Figure 2, and the TGA pattern is shown in Figure 3.

[0158] Table 1 Diffraction angles and relative intensities of the compound of formula I in crystalline form I

[0159] Example 2: Preparation of the compound of formula I in crystalline form I

[0160] The compound of formula I 15.0 g was weighed into 270 mL of isopropanol and 30 mL of water, stirred at 50 °C for 1 h, cooled to 5 °C and stirred for 5 h. The obtained solid was collected and dried to give the compound of formula I Form I 12.9 g, whose XRPD pattern was consistent with that of Figure 1.

[0161] Example 3: Preparation of the compound of formula I Form II

[0162] The compound of formula I 0.5 g was weighed into 2 mL of isopropanol and 2 mL of water, stirred at 50 °C for 15 h, and the obtained solid was collected and dried to give the compound of formula I Form II 0.35 g, whose XRPD pattern was shown in Figure 7.

[0163] Example 4: Preparation of the compound of formula I Form III

[0164] The compound of formula I 0.5 g was weighed into 2 mL of isopropanol and 2 mL of water, stirred at 50 °C for 15 h, and the obtained solid was collected and dried to give the compound of formula I Form II 0.35 g, whose XRPD pattern was shown in Figure 7.

[0165] Example 5: Preparation of the compound of formula I Form IV

[0166] The compound of formula I 0.5 g was weighed into 2 mL of isopropanol and 2 mL of water, stirred at 50 °C for 15 h, and the obtained solid was collected and dried to give the compound of formula I Form II 0.35 g, whose XRPD pattern was shown in Figure 7.

[0167] Example 6: Preparation of the compound of formula I Form V

[0168] The compound of formula I 0.5 g was weighed into 2 mL of isopropanol and 2 mL of water, stirred at 50 °C for 15 h, and the obtained solid was collected and dried to give the compound of formula I Form II 0.35 g, whose XRPD pattern was shown in Figure 7.

[0169] Example 7: Preparation of the compound of formula I Form VI

[0170] The compound of formula I 0.5 g was weighed into 2 mL of isopropanol and 2 mL of water, stirred at 50 °C for 15 h, and the obtained solid was collected and dried to give the compound of formula I Form II 0.35 g, whose XRPD pattern was shown in Figure 7.

[0171] Example 8: Preparation of the compound of formula I Form VII

[0172] The compound of formula I 0.5 g was weighed into 2 mL of isopropanol and 2 mL of water, stirred at 50 °C for 15 h, and the obtained solid was collected and dried to give the compound of formula I Form II 0.35 g, whose XRPD pattern was shown in Figure 7.

[0173] Example 9: Preparation of Form VIII of the compound of Formula I

[0174] Example 9: Preparation of Form VIII of the compound of Formula I

[0175] Example 10: Preparation of Form IX of the compound of Formula I

[0176] Example 10: Preparation of Form IX of the compound of Formula I

[0177] Example 11 : Preparation of Form X of the compound of Formula I

[0178] Example 11 : Preparation of Form X of the compound of Formula I

[0179] Example 12: Preparation of Form XI of the compound of Formula I

[0180] Example 12: Preparation of Form XI of the compound of Formula I

[0181] Example 13: Preparation of Form XII of the compound of Formula I

[0182] Example 13: Preparation of Form XII of the compound of Formula I

[0183] Example 14: Preparation of Form XIII of the compound of Formula I

[0184] Example 14: Preparation of Form XIII of the compound of Formula I

[0185] Example 15: Preparation of Form XIV of the compound of Formula I

[0186] A 0.2 g sample of the compound of Formula I was added to 2.0 mL of MIBK and the solution was added dropwise to 20.0 mL of water. The resulting solid was collected after 16 h of suspension and dried to obtain 0.15 g of the compound of Formula I, Form XV, which had an XRPD pattern as shown in Figure 20.

[0187] Example 16: Preparation of the compound of Formula I, Form XV

[0188] A 0.2 g sample of the compound of Formula I was added to 2.0 mL of MIBK and the solution was added dropwise to 20.0 mL of water. The resulting solid was collected after 16 h of suspension and dried to obtain 0.15 g of the compound of Formula I, Form XV, which had an XRPD pattern as shown in Figure 20.

[0189] Example 17: Preparation of the compound of Formula I, amorphous

[0190] A 10 g sample of the compound of Formula I was added to 50.0 mL of dichloromethane and the solution was rotary evaporated. The resulting solid was collected and dried to obtain 9.9 g of the compound of Formula I, amorphous, which had an XRPD pattern as shown in Figure 21.

[0191] Example 18: Preparation of the compound of Formula I, p-toluenesulfonic acid salt, Form

[0192] A 0.2 g sample of the compound of Formula I and 0.15 g of p-toluenesulfonic acid were added to 5.0 mL of ethanol and the mixture was suspended at room temperature for 24 h. The resulting solid was collected and dried to obtain 0.25 g of the compound of Formula I, p-toluenesulfonic acid salt, Form, which had an XRPD pattern as shown in Figure 24, a DSC pattern as shown in Figure 25, and a TGA pattern as shown in Figure 26.

[0193] Example 19: Preparation of the compound of Formula I, succinic acid co-crystal

[0194] A 2.0 g sample of the compound of Formula I and 1.0 g of succinic acid were added to 50.0 mL of ethanol and the mixture was suspended at room temperature for 24 h. The resulting solid was collected and dried to obtain 2.5 g of the compound of Formula I, succinic acid co-crystal, which had an XRPD pattern as shown in Figure 27, a DSC pattern as shown in Figure 28, and a TGA pattern as shown in Figure 29.

[0195] Test Example 1: Influence factor stability investigation experiment

[0196] The compound of Formula I, Form I (prepared according to Reference Example 1), amorphous (prepared according to Reference Example 17), and succinic acid co-crystal (prepared according to Reference Example 19) were placed at high temperature (60 °C), high humidity (RH 92.5%), and light (4500 lx ± 500 lx) for 30 days to investigate the stability of the crystal forms. The results are shown in Table 2 and Figures 5, 22, and 30.

[0197] Table 2: Influence factor stability experiment of the compound of Formula I, Form I, amorphous, and succinic acid co-crystal

[0198] The stability test results show that the compound of formula I crystal form I, amorphous and succinic acid co-crystal remain unchanged in crystal form under the influence of factors, have excellent crystal form stability, which can ensure the quality stability during the drug storage process, and avoid the transformation of crystal form due to factors such as pressure, heating, solvent, moisture (or humidity), excipients, mechanical force, etc. during the drug preparation process, so as to affect the effectiveness and safety of the drug.

[0199] Test Example 2: Long-term and accelerated stability investigation experiment

[0200] The compound of formula I crystal form I (prepared according to Reference Example 1), amorphous (prepared according to Reference Example 17) and succinic acid co-crystal (prepared according to Reference Example 19) were placed under long-term and accelerated stability conditions at 25℃ / RH 60% and 40℃ / RH 75% for 6 months to investigate the crystal form stability and chemical stability thereof, and the results are shown in Table 3 and Figures 6, 23 and 31:

[0201] Table 3 Long-term and accelerated stability experiment of the compound of formula I crystal form I, amorphous and succinic acid co-crystal

[0202] The results show that the compound of formula I crystal form I, amorphous and succinic acid co-crystal also have good crystal form stability under long-term and accelerated conditions, which can meet the requirements of drug production and storage.

[0203] Test Example 3: Solubility test experiment

[0204] The compound of formula I crystal form I (prepared according to Reference Example 1), amorphous (prepared according to Reference Example 17) and succinic acid co-crystal (prepared according to Reference Example 19) were respectively subjected to solubility test determination in different media, and the results are shown in Table 4:

[0205] Table 4 Solubility data of the compound of formula I crystal form I, amorphous and succinic acid co-crystal

[0206] “-” means not determined

[0207] The test results show that the compound of formula I crystal form I, amorphous and succinic acid co-crystal can meet the solubility requirements of the bulk drug, and can be used for drug development.

[0208] Test Example 4: Hygroscopicity investigation experiment

[0209] The compound of formula I crystal form I (prepared according to Reference Example 1) was placed in a dynamic moisture adsorption instrument to investigate the weight change of the sample in the range of 0-98%-0 humidity. The hygroscopicity results are shown in Table 5 and Figure 4:

[0210] Table 5 Hygroscopicity of the compound of formula I crystal form I

[0211] As can be seen from Table 5 and Figure 4, the compound of formula I crystal form I is only slightly hygroscopic, which indicates that the crystal form I has better controllability of quality during storage of the drug substance and the preparation.

[0212] Test Example 5: Pharmacokinetic test

[0213] The compound of formula I crystal form I (prepared in Reference Example 1) was subjected to animal experiments, i.e. a certain amount of the test drug was accurately weighed, added to 0.5% methyl cellulose solution and mixed to obtain a suspension of 0.5 mg / ml, which was used for gavage administration. Rhesus monkeys (n = 2, half male and half female) were administered with 1 mg / kg of the test product by gavage, and whole blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 h before and after administration, respectively, to obtain plasma after centrifugation. The concentration of the drug in the monkey plasma samples was quantitatively detected by LC-MS / MS method, and the pharmacokinetic parameters were calculated by WinNonlin software according to the non-compartment model method. The main pharmacokinetic parameters are shown in Table 4 below:

[0214] Table 6 Pharmacokinetic parameters of the compound of formula I crystal form I

[0215] It is obvious to those skilled in the art that various modifications and changes can be made to the compounds and the preparation method thereof without departing from the spirit or scope of the present application, and therefore the scope of protection of the present application covers all the modifications and changes made to the present application, as long as they are within the scope of the claims and the equivalent embodiments.

Claims

1. Form I of a compound of Formula I ###0001### Formula I wherein, the X-ray powder diffraction pattern of the crystalline form I has characteristic peaks at 2-theta angles of 5.9±0.2°, 7.7±0.2°, 10.0±0.2°, 13.7±0.2°, 17.1±0.2°, 18.3±0.2°, 19.1±0.2° and 21.3±0.2°, 2. The crystalline Form I of claim 1, wherein, the X-ray powder diffraction pattern of said crystalline Form I further has one or more peaks selected from the positions 7.9±0.2°, 11.2±0.2°, 12.9±0.2°, 16.1±0.2°, 16.6±0.2°, 17.4±0.2°, 18.6±0.2°, 20.4±0.2°, 23.4±0.2° and 25.5±0.2°; Preferably, the X-ray powder diffraction pattern of said crystalline Form I further has one or more peaks selected from the positions 11.6±0.2°, 11.9±0.2°, 13.2±0.2°, 14.2±0.2°, 15.1±0.2°, 17.7±0.2°, 19.8±0.2°, 21.6±0.2°, 21.9±0.2°, 22.2±0.2°, 22.8±0.2°, 24.0±0.2°, 24.9±0.2°, 25.8±0.2°, 26.2±0.2°, 26.8±0.2° and 28.7±0.2°; More preferably, the X-ray powder diffraction pattern of said crystalline Form I is substantially as shown in Figure 1.

3. The crystalline Form I of claim 1, wherein, Said crystalline Form I optionally has one or more characteristics selected from the group consisting of: (1) the DSC pattern of said crystalline Form I has endothermic peaks at about 236.2°C and 244.5°C; (2) said crystalline Form I has a DSC pattern substantially as shown in Figure 2; (3) the thermogravimetric analysis curve of said crystalline Form I has a weight loss of about 0.54% at 30-150°C; (4) said crystalline Form I has a TGA pattern substantially as shown in Figure 3; (5) the DVS pattern of said crystalline Form I is substantially as shown in Figure 4.

4. A process for preparing crystalline Form I according to any one of claims 1 to 3, wherein, The method comprises: suspending the compound of Formula I in a mixture of isopropanol and water, cooling to crystallize, and drying to obtain said crystalline Form I; Preferably, the suspension temperature is 40-60°C, and the suspension time is 1-3 hours; and / or, Preferably, the cooling crystallization temperature is 0-5°C, and the crystallization time is 3-5 hours; and / or, Preferably, the volume ratio of isopropanol to water is 9:

1.

5. A crystalline form of a compound of Formula I ###0002### wherein, the crystalline form is selected from one or more of: Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, or Form XV, wherein: The X-ray powder diffraction pattern of said crystalline Form II has characteristic peaks at 2θ angles of 5.3±0.2°, 7.1±0.2°, 7.9±0.2°, 8.6±0.2°, 12.3±0.2°, 15.2±0.2°, 16.2±0.2°, 22.4±0.2° and 25.1±0.2°; preferably, at 2θ angles of 5.3±0.2°, 7.1±0.2°, 7.9±0.2°, 8.1±0.2°, 8.6±0.2°, 12.3±0.2°, 13.7±0.2°, 14.7±0.2°, 15.2±0.2°, 16.2±0.2°, 17.7±0.2°, 19.4±0.2°, 20.0±0.2°, 22.4±0.2°, 23.6±0.2°, 25.1±0.2° and 26.5±0.2°; more preferably, the X-ray powder diffraction pattern of said crystalline Form II is substantially as shown in Figure 7. the X-ray powder diffraction pattern of the crystalline form III has characteristic peaks at 2-theta angles of 4.5±0.2°, 5.2±0.2°, 9.0±0.2°, 10.2±0.2°, 14.4±0.2° and 16.5±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form III has characteristic peaks at 2-theta angles of 4.5±0.2°, 5.2±0.2°, 6.8±0.2°, 8.2±0.2°, 9.0±0.2°, 9.6±0.2°, 10.2±0.2°, 11.5±0.2°, 12.2±0.2°, 13.0±0.2°, 13.6±0.2°, 14.4±0.2°, 14.7±0.2°, 15.9±0.2°, 16.5±0.2°, 18.2±0.2° and 20.4±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form III is substantially as shown in Figure 8; the X-ray powder diffraction pattern of the crystalline form IV has characteristic peaks at 2-theta angles of 5.1±0.2°, 5.9±0.2°, 7.4±0.2°, 9.4±0.2°, 10.3±0.2°, 13.2±0.2°, 14.9±0.2° and 17.4±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form IV has characteristic peaks at 2-theta angles of 5.1±0.2°, 5.9±0.2°, 7.4±0.2°, 9.4±0.2°, 10.3±0.2°, 11.0±0.2°, 13.2±0.2°, 14.9±0.2°, 16.0±0.2°, 16.8±0.2°, 17.4±0.2°, 18.7±0.2°, 19.0±0.2°, 20.9±0.2°, 21.2±0.2°, 21.5±0.2°, 23.0±0.2°, 26.1±0.2° and 26.7±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form IV is substantially as shown in Figure 9; the X-ray powder diffraction pattern of the crystalline form V has characteristic peaks at 2-theta angles of 5.5±0.2°, 7.1±0.2°, 9.0±0.2°, 11.0±0.2°, 13.1±0.2°, 15.2±0.2°, 15.9±0.2° and 25.4±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form V has characteristic peaks at 2-theta angles of 4.5±0.2°, 5.5±0.2°, 7.1±0.2°, 9.0±0.2°, 11.0±0.2°, 13.1±0.2°, 14.3±0.2°, 15.2±0.2°, 15.9±0.2°, 16.7±0.2°, 18.1±0.2°, 18.6±0.2°, 19.7±0.2°, 21.5±0.2°, 22.2±0.2°, 25.4±0.2° and 26.4±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form V is substantially as shown in Figure 10; the X-ray powder diffraction pattern of the crystalline form VI has characteristic peaks at 2-theta angles of 5.2±0.2°, 5.9±0.2°, 7.4±0.2°, 9.4±0.2°, 10.4±0.2°, 13.3±0.2°, 15.0±0.2° and 17.5±0.2°; preferably, at 2-theta angles of 5.2±0.2°, 5.9±0.2°, 7.4±0.2°, 9.4±0.2°, 10.4±0.2°, 13.3±0.2°, 15.0±0.2°, 16.9±0.2°, 17.5±0.2°, 19.0±0.2°, 20.7±0.2°, 20.9±0.2°, 21.3±0.2°, 21.6±0.2° and 23.1±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form VI is substantially as shown in Figure 11; the X-ray powder diffraction pattern of the crystalline form VII has characteristic peaks at 2-theta angles of 5.9±0.2°, 12.1±0.2°, 15.1±0.2°, 16.0±0.2°, 16.8±0.2°, 18.1±0.2°, 22.2±0.2°, 23.3±0.2° and 25.5±0.2°; preferably, at 2-theta angles of 5.9±0.2°, 8.4±0.2°, 8.8±0.2°, 9.8±0.2°, 11.3±0.2°, 12.1±0.2°, 15.1±0.2°, 16.0±0.2°, 16.8±0.2°, 17.7±0.2°, 18.1±0.2°, 18.3±0.2°, 19.9±0.2°, 20.7±0.2°, 21.6±0.2°, 22.2±0.2°, 22.6±0.2°, 23.3±0.2°, 24.1±0.2° and 25.5±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form VII is substantially as shown in Figure 12; the X-ray powder diffraction pattern of the crystalline form VIII has characteristic peaks at 2-theta angles of 3.7±0.2°, 5.2±0.2°, 7.2±0.2°, 8.1±0.2°, 11.5±0.2°, 13.5±0.2°, 14.6±0.2°, 15.1±0.2°, 16.3±0.2° and 18.3±0.2°; preferably, at 2-theta angles of 3.7±0.2°, 5.2±0.2°, 7.2±0.2°, 8.1±0.2°, 10.3±0.2°, 11.5±0.2°, 13.5±0.2°, 14.6±0.2°, 15.1±0.2°, 15.4±0.2°, 16.3±0.2°, 18.3±0.2°, 22.0±0.2°, 24.9±0.2°, 25.2±0.2° and 26.1±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form VIII is substantially as shown in Figure 13; the X-ray powder diffraction pattern of the crystalline Form IX has characteristic peaks at 2-theta angles of 4.8±0.2°, 7.2±0.2°, 9.6±0.2°, 11.0±0.2°, 11.8±0.2°, 15.4±0.2°, and 19.3±0.2°; preferably, at 2-theta angles of 4.8±0.2°, 7.2±0.2°, 9.6±0.2°, 11.0±0.2°, 11.8±0.2°, 15.4±0.2°, 16.2±0.2°, 18.0±0.2°, 18.8±0.2°, 19.3±0.2°, 20.0±0.2°, 21.7±0.2°, and 24.8±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline Form IX is substantially as shown in FIG. 14; the X-ray powder diffraction pattern of the crystalline Form X has characteristic peaks at 2-theta angles of 6.0±0.2°, 9.0±0.2°, 9.6±0.2°, 12.0±0.2°, 15.1±0.2°, 21.1±0.2°, and 25.0±0.2°; preferably, at 2-theta angles of 6.0±0.2°, 9.0±0.2°, 9.6±0.2°, 12.0±0.2°, 15.1±0.2°, 16.9±0.2°, 17.6±0.2°, 21.1±0.2°, 22.0±0.2°, 22.4±0.2°, 25.0±0.2°, and 25.3±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline Form X is substantially as shown in FIG. 15; the X-ray powder diffraction pattern of the crystalline Form XI has characteristic peaks at 2-theta angles of 6.8±0.2°, 10.2±0.2°, 14.2±0.2°, 17.1±0.2°, 18.4±0.2°, and 22.1±0.2°; preferably, at 2-theta angles of 6.6±0.2°, 6.8±0.2°, 10.2±0.2°, 14.2±0.2°, 15.1±0.2°, 16.1±0.2°, 17.1±0.2°, 18.4±0.2°, 20.7±0.2°, 21.7±0.2°, 22.1±0.2°, 24.1±0.2°, and 25.2±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline Form XI is substantially as shown in FIG. 16; the X-ray powder diffraction pattern of the crystalline Form XII has characteristic peaks at 2-theta angles of 4.9±0.2°, 7.3±0.2°, 9.7±0.2°, 11.9±0.2°, 16.3±0.2°, 17.7±0.2°, 19.4±0.2° and 23.0±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline Form XII has characteristic peaks at 2-theta angles of 4.9±0.2°, 5.5±0.2°, 7.3±0.2°, 9.7±0.2°, 11.1±0.2°, 11.9±0.2°, 13.9±0.2°, 14.9±0.2°, 15.5±0.2°, 16.3±0.2°, 17.2±0.2°, 17.7±0.2°, 18.2±0.2°, 19.0±0.2°, 19.4±0.2°, 19.6±0.2°, 20.2±0.2°, 20.9±0.2°, 21.5±0.2°, 22.2±0.2°, 23.0±0.2°, 25.4±0.2°, 25.8±0.2°, 26.8±0.2° and 27.3±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline Form XII is substantially as shown in Figure 17; the X-ray powder diffraction pattern of the crystalline Form XIII has characteristic peaks at 2-theta angles of 5.2±0.2°, 6.1±0.2°, 7.5±0.2°, 9.6±0.2°, 10.6±0.2°, 13.4±0.2°, 17.6±0.2° and 19.1±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline Form XIII has characteristic peaks at 2-theta angles of 5.2±0.2°, 6.1±0.2°, 7.5±0.2°, 8.6±0.2°, 9.6±0.2°, 10.6±0.2°, 11.1±0.2°, 13.4±0.2°, 14.1±0.2°, 15.0±0.2°, 17.0±0.2°, 17.6±0.2°, 19.1±0.2°, 20.9±0.2°, 21.4±0.2°, 21.8±0.2°, 23.2±0.2°, 23.3±0.2°, 25.9±0.2°, 26.9±0.2°, 27.8±0.2° and 28.4±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline Form XIII is substantially as shown in Figure 18; the X-ray powder diffraction pattern of said crystalline Form XIV has characteristic peaks at 2Theta angles of 5.2±0.2°, 7.0±0.2°, 9.2±0.2°, 12.6±0.2°, 13.5±0.2°, 15.8±0.2°, 19.3±0.2°, and 23.9±0.2°; preferably, the X-ray powder diffraction pattern of said crystalline Form XIV has characteristic peaks at 2Theta angles of 5.2±0.2°, 7.0±0.2°, 7.9±0.2°, 9.2±0.2°, 9.7±0.2°, 11.4±0.2°, 12.6±0.2°, 13.5±0.2°, 14.2±0.2°, 15.8±0.2°, 17.0±0.2°, 18.2±0.2°, 19.3±0.2°, 20.3±0.2°, 20.9±0.2°, 22.7±0.2°, 23.1±0.2°, 23.9±0.2°, 24.5±0.2°, 25.6±0.2°, 26.6±0.2°, 27.3±0.2°, 28.7±0.2° and 29.3±0.2°; more preferably, the X-ray powder diffraction pattern of said crystalline Form XIV is substantially as shown in Figure 19; the X-ray powder diffraction pattern of said crystalline Form XV has characteristic peaks at 2Theta angles of 5.3±0.2°, 6.1±0.2°, 7.0±0.2°, 9.2±0.2°, 11.3±0.2°, 12.4±0.2°, 13.3±0.2°, 13.9±0.2°, 14.1±0.2°, 15.7±0.2°, 16.0±0.2°, 16.9±0.2°, 17.3±0.2°, 18.2±0.2°, 18.7±0.2°, 19.0±0.2°, 19.4±0.2°, 20.7±0.2°, 22.6±0.2°, 23.3±0.2°, 23.7±0.2°, 24.1±0.2°, 24.5±0.2°, 26.4±0.2° and 27.1±0.2°; preferably, the X-ray powder diffraction pattern of said crystalline Form XV is substantially as shown in Figure 20.

6. An amorphous form of a compound of formula I, wherein, the X-ray powder diffraction pattern of said amorphous form is substantially as shown in Figure 21.

7. A salt of a compound of formula I ###0002### wherein the salt is selected from a p-toluenesulfonate, a benzenesulfonate, a methanesulfonate, a hydrochloride, a fumarate, a succinate, a citrate, a citrate, an acetate, a formate, a benzoate, a propionate, an oxalate, a salicylate, an ascorbate, a phthalate, a butyrate, a camphorsulfonate, a camphorate, a cinnamate, an ethanesulfonate, a hippurate, a glycolate, a hydrobromide, a hydroiodide, a lactate, a maleate, a malonate, a glutamate, a nitrate or a phosphate; preferably, the salt is in crystalline form.

8. The salt of claim 6, wherein, the salt is a p-toluenesulfonate crystalline form having an X-ray powder diffraction pattern with characteristic peaks at 2Theta angles of 5.9±0.2°, 7.7±0.2°, 10.0±0.2°, 13.7±0.2°, 17.1±0.2°, 18.3±0.2°, 19.1±0.2° and 21.3±0.2°; Preferably, the p-toluenesulfonate salt crystalline form has an X-ray powder diffraction pattern substantially as shown in Figure 24.

9. A succinic acid co-crystal of a compound of Formula I, wherein, The X-ray powder diffraction pattern of the succinic acid co-crystal has characteristic peaks at 2Θ angles of 5.8±0.2°, 9.8±0.2°, 12.0±0.2°, 15.2±0.2°, 16.1±0.2°, 17.7±0.2°, 23.2±0.2° and 25.3±0.2°; Preferably, the succinic acid co-crystal has an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles of 5.8±0.2°, 9.8±0.2°, 11.3±0.2°, 12.0±0.2°, 15.2±0.2°, 16.1±0.2°, 16.8±0.2°, 17.7±0.2°, 18.2±0.2°, 20.6±0.2°, 22.2±0.2°, 22.6±0.2°, 23.2±0.2°, 24.0±0.2° and 25.3±0.2°; More preferably, the succinic acid co-crystal has an X-ray powder diffraction pattern substantially as shown in Figure 27.

10. A pharmaceutical composition consisting of one or more of the crystalline Form I of any one of claims 1-3, the crystalline form of claim 5, the amorphous of claim 6, the salt of any one of claims 7-8, the succinic acid co-crystal of claim 9, and a pharmaceutically acceptable carrier.

11. Use of the crystalline Form I of any one of claims 1-3, the crystalline form of claim 5, the amorphous of claim 6, the salt of any one of claims 7-8, the succinic acid co-crystal of claim 9, the pharmaceutical composition of claim 10, in the manufacture of a medicament for the prevention and / or treatment of a disease mediated by cereblon; Preferably, the disease is mediated by IKZF1 and / or IKZF3; Preferably, the disease is a cancer, a tumor, an immune disease or an inflammatory disease; Preferably, the immune disease is an autoimmune disease; Preferably, the disease is a hematological malignancy; Preferably, the disease is multiple myeloma, leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma.

12. Use of the crystalline Form I of any one of claims 1-3, the crystalline form of claim 5, the amorphous of claim 6, the salt of any one of claims 7-8, the succinic acid co-crystal of claim 9, the pharmaceutical composition of claim 10, in the manufacture of an immunomodulator of IKZF1 and IKZF3 dual targets.

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