A crystalline form of a sulfur-containing isoindoline derivative

Abstract

The present disclosure relates to a crystalline form of a sulfur-containing isoindoline derivative. In particular, the present disclosure relates to a crystalline form of a compound as shown in Formula (I) and methods of making the same.

Description

[0001] This application claims priority to Chinese patent application 202210060175.6, filed on January 19, 2022. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This disclosure relates to a crystal form of a sulfur-containing isoindoline derivative and a method for preparing the same. Specifically, it provides the crystal form of a compound as shown in Formula I and a method for preparing the same. Background Technology

[0003] Multiple myeloma (MM) is a malignant tumor with main symptoms including hypercalcemia, kidney damage, anemia, and bone disease. MM is the second most common hematologic malignancy after non-Hodgkin's lymphoma, and current treatments primarily involve drug therapy and autologous stem cell transplantation.

[0004] Currently, there are four main classes of drugs widely used in clinical practice: lenalidomide immunomodulators, proteasome inhibitors, hormones, and monoclonal antibodies. Drugs in clinical research stages include bispecific antibodies, ADCs, and CAR-T therapy. These drugs have different mechanisms of action, and combination therapy often achieves better efficacy. Clinically, dual, triple, or even quadruple therapy is commonly used, typically combining immunomodulators, proteasome inhibitors, and hormones, sometimes with the addition of antibodies. Lenalidomide is the most commonly used immunomodulator, used in first-line treatment, maintenance therapy after stem cell transplantation, and second- and third-line treatment after relapse. Its sales reached $9.7 billion in 2018 / 2019. The entire MM market is also considerable and growing rapidly, due to continuous improvements in the diagnosis and treatment of MM, leading to longer patient survival and extended treatment durations. The MM market is projected to reach $33 billion by 2022, with immunomodulators, represented by lenalidomide, still accounting for the largest share.

[0005] The mechanism of action of immunomodulators (IMiDs) in treating multiple myeloma (MM) is primarily based on the fact that IMiD drugs bind to the Cerebrolysin B (CRBN) protein, activating the E3 ligase activity of CRBN, which then selectively binds to the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). This leads to the rapid ubiquitination and degradation of Ikaros and Aiolos. Downregulation of Ikaros / Aiolos results in downregulation of c-Myc, followed by downregulation of IRF4, ultimately inhibiting myeloma cell growth and inducing apoptosis. Furthermore, IKZF3 can inhibit the transcription of IL-2 and TNF cytokines in T / NK cells. IKZF3 degradation relieves this inhibition, promoting the release of these cytokines and thus exerting an immunomodulatory effect. Clinical trials have also shown a correlation between the clinical benefits of IMiD drugs and the level of CRBN expression. Knocking down CRBN in lenalidomide-sensitive cell lines (OPM2 and KMS18) revealed the loss of lenalidomide's inhibitory activity on cell growth, leading to drug resistance. The level of CRBN knockdown was correlated with the degree of drug resistance. In cell proliferation experiments, reducing the expression level of CRBN in cells (U266-CRBN60 and U266-CRBN75) reduced the inhibitory activity of both lenalidomide and pomalidomide on cell growth.

[0006] Currently approved IMiD drugs include thalidomide, lenalidomide, and pomalidomide, all from Celgene (now merged with BMS). The binding affinity of the three compounds to CRBN increases sequentially, hence the clinical dosage decreases accordingly. The primary indication for all three compounds is multidisciplinary disease (MM). Thalidomide and lenalidomide also have other indications, especially lenalidomide, which can be used to treat myelodysplastic syndromes (MDS). Regarding side effects, lenalidomide and pomalidomide exhibit similar effects, with significant myelosuppression, a target-related toxicity. Thalidomide has some other side effects, such as sedation, constipation, and neurological side effects.

[0007] All IMiDs' adipicimide moieties bind to a hydrophobic bag defined by three tryptophan residues in CRBN (called the "thalidomide binding bag"). Conversely, the phthalimide / isoindolone ring is exposed to the solvent and alters the molecular surface of CRBN, thereby modulating substrate recognition. Different IMiDs lead to significant modifications on the CRBN molecular surface and different substrate recognition preferences. Therefore, modifications to IMiDs may lead to the degradation of other transcription factors, causing unwanted toxic side effects. This mode of action of IMiDs is also known as molecular glue, vividly describing the binding effect of this small molecule on two protein substrates.

[0008] Because the median survival for multiple myeloma is currently over five years, this prolonged survival has led to a high proportion of patients developing resistance to currently marketed drugs such as lenalidomide and pomalidomide, severely reducing the effectiveness of these treatments. Therefore, we envision developing more active drug molecules to overcome drug resistance while minimizing the toxic side effects of these compounds.

[0009] Published patent applications for Cereblon modifiers include WO2008115516A2, WO2011100380A1, WO2019226770A1, WO2019014100A1 and WO2020064002A1, etc.

[0010] The applicant's patent application WO2022017365 provides a compound as shown in Formula I, with the chemical name (S)-4-(4-((5-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)pyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile, which has good Cereblon regulating effect.

[0011]

[0012] Generally speaking, the crystal structure of a drug's active ingredient and its salts not only affects the drug's physical and chemical stability but also the ease of subsequent drug preparation and production costs. Different crystallization and storage conditions can lead to changes in the crystal structure of the compound and its salts, sometimes even resulting in other crystal forms. Therefore, considering stability, ease of drug preparation, and production costs, in-depth research on the crystal form of the compound shown in formula (I) is essential. Summary of the Invention

[0013] This disclosure provides the crystal form of the compound shown in formula (I) and its preparation method, wherein the chemical name of the compound shown in formula (I) is (S)-4-(4-((5-(((2-(2,6-dioxoperidin-3-yl)-1-oxoisoindol-4-yl)oxy)methyl)pyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile,

[0014]

[0015] This disclosure provides an amorphous form of the compound shown in formula (I), whose X-ray powder diffraction pattern has no obvious characteristic peaks in the range of 2-48° at a diffraction angle of 2θ.

[0016] This disclosure further provides a method for preparing the amorphous form of the compound shown in formula (I), comprising: method 1: a) mixing the compound shown in formula (I) with propylene glycol methyl ether, n-heptane or petroleum ether, b) slurrying and crystallizing;

[0017] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200. In some embodiments, the method for preparing the amorphous compound shown in (I) according to this disclosure further includes filtration, washing, or drying steps.

[0018] This disclosure provides the A-phase of the compound shown in formula (I), with an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, exhibiting characteristic peaks at 5.765, 8.061, 9.925, 16.632, 17.900, 19.469, and 21.115. In some embodiments, the A-phase of the compound shown in formula (I) exhibits characteristic peaks at 5.765, 7.465, 8.061, 9.925, 12.890, 15.085, 16.632, 17.900, 19.469, and 21.115. In some embodiments, the A-phase of the compound shown in formula (I) exhibits characteristic peaks at 5.765, 7.465, 8.061, 9.925, 11.674, 12.890, 14.270, 15.085, 16.632, 17.900, 18.715, 19.469, and 21.115. In some embodiments, the X-ray powder diffraction pattern of the A-phase of the compound shown in formula (I), expressed as a diffraction angle 2θ, is as follows: Figure 2 As shown.

[0019] This disclosure further provides a method for preparing the A crystal form of the compound shown in formula (I), comprising: method 1: a) mixing the compound shown in formula (I) with tetrahydrofuran and dissolving it, b) adding n-heptane to crystallize;

[0020] Alternatively, method 2: a) mix the compound shown in formula (I) with dichloromethane and dissolve it; b) add ethyl acetate to crystallize.

[0021] Or method 3: a) mix the compound shown in formula (I) with water, isopropyl acetate, acetone, ethyl acetate / ethanol or ethyl acetate / n-heptane, b) slurry and crystallize;

[0022] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing crystal form A of the compound of formula (I) described in this disclosure further includes steps such as filtration, washing, or drying.

[0023] This disclosure provides the B-crystal form of the compound shown in formula (I), and its X-ray powder diffraction pattern, expressed in diffraction angles of 2θ, with characteristic peaks at 4.977, 6.788, 10.047, 14.143, 15.684, 18.547, and 20.840. In some embodiments, the B-crystal form of the compound shown in formula (I) has characteristic peaks at 4.977, 6.788, 10.047, 14.143, 15.684, 18.547, 20.840, 24.096, and 25.505. In some embodiments, the X-ray powder diffraction pattern of the B-crystal form of the compound shown in formula (I), expressed in diffraction angles of 2θ, is as follows: Figure 3 As shown.

[0024] This disclosure further provides a method for preparing the crystal form of compound B shown in formula (I), comprising: a) mixing the compound shown in formula (I) with ethyl acetate or acetonitrile / methanol, b) slurrying and crystallizing, and drying at 30°C;

[0025] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing the B crystal form of the compound of formula (I) described in this disclosure further includes steps such as filtration, washing, or drying.

[0026] This disclosure provides the C-crystal form of the compound shown in formula (I), and its X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 5.653, 7.974, 9.989, 16.143, 17.860, 18.992, and 20.972. In some embodiments, the C-crystal form of the compound shown in formula (I) has characteristic peaks at 5.653, 7.974, 9.989, 11.505, 12.798, 14.265, 16.143, 17.860, 18.992, and 20.972. In some embodiments, the C-crystal form of the compound shown in formula (I) exhibits characteristic peaks at 3.533, 5.653, 7.974, 8.790, 9.989, 11.505, 12.798, 14.265, 15.277, 16.143, 17.860, 18.992, and 20.972. In some embodiments, the X-ray powder diffraction pattern of the C-crystal form of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is as follows: Figure 4 As shown.

[0027] This disclosure further provides a method for preparing the C crystal form of the compound shown in formula (I), comprising: method 1: a) mixing the compound shown in formula I with ethanol, isopropanol, methyl tert-butyl ether, methyl isobutyl ketone, water / ethanol, water / isopropanol, water / methanol (1:1), cyclohexane, and isopropyl ether; b) slurrying and crystallizing.

[0028] Alternatively, method 2: a) the compound shown in formula (I) is mixed with dichloromethane, water / acetone, and tetrahydrofuran / ethanol, dissolved, b) volatilized and crystallized;

[0029] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing the C-crystal form of the compound of formula (I) described in this disclosure further includes steps such as filtration, washing, or drying.

[0030] This disclosure provides the D-crystal form of the compound shown in formula (I), and its X-ray powder diffraction pattern, expressed in diffraction angles of 2θ, with characteristic peaks at 6.831, 9.845, 13.453, 18.225, 20.117, 20.891, and 23.006. In some embodiments, the D-crystal form of the compound shown in formula (I) has characteristic peaks at 6.831, 9.845, 10.927, 13.453, 16.096, 18.225, 20.117, 20.891, 23.006, and 26.132. In some embodiments, the X-ray powder diffraction pattern of the D-crystal form of the compound shown in formula (I), expressed in diffraction angles of 2θ, is as follows: Figure 5 As shown.

[0031] This disclosure further provides a method for preparing the D crystal form of the compound shown in formula (I), including:

[0032] Method 1: a) Mix the compound shown in formula (I) with acetonitrile, b) Pulping and crystallization.

[0033] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing the D crystal form of the compound of formula (I) described in this disclosure further includes steps such as filtration, washing, or drying.

[0034] This disclosure provides the E-crystal form of the compound shown in formula (I), and its X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 5.864, 7.573, 8.087, 10.003, 16.444, 19.349, and 20.553. In some embodiments, the E-crystal form of the compound shown in formula (I) has characteristic peaks at 5.864, 7.573, 8.087, 10.003, 12.471, 15.165, 16.444, 17.432, 19.349, and 20.553. In some embodiments, the E-crystal form of the compound shown in formula (I) has characteristic peaks at 5.864, 7.573, 8.087, 10.003, 11.701, 12.471, 15.165, 16.444, 17.432, 19.349, 20.553, 21.067, and 21.709. In some embodiments, the X-ray powder diffraction pattern of the E-crystal form of the compound shown in formula (I), expressed as a diffraction angle 2θ, is as follows: Figure 6 As shown.

[0035] This disclosure further provides a method for preparing the E crystal form of the compound shown in formula (I), comprising: method 1: a) mixing the compound shown in formula I with 2-butanone or 10% water / methanol, b) slurrying and crystallizing;

[0036] Alternatively, method 2: a) mix the compound shown in formula I with DCM and dissolve it; b) add n-heptane to induce crystallization.

[0037] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing the E crystal form of the compound of formula (I) described in this disclosure further includes steps such as filtration, washing, or drying.

[0038] This disclosure provides the F-crystal form of the compound shown in formula (I), with X-ray powder diffraction patterns expressed as diffraction angles of 2θ, exhibiting characteristic peaks at 5.062, 7.820, 10.077, 14.231, 16.672, 18.586, and 20.435. In some embodiments, the F-crystal form of the compound shown in formula (I) exhibits characteristic peaks at 5.062, 7.820, 10.077, 14.231, 15.192, 16.672, 18.586, 20.435, 21.868, and 25.442. In some embodiments, the F-crystal form of the compound shown in formula (I) exhibits characteristic peaks at 5.062, 7.820, 10.077, 14.231, 15.192, 16.672, 18.586, 20.435, 21.868, 24.193, 25.442, 26.303, and 28.629. In some embodiments, the X-ray powder diffraction pattern of the F-crystal form of the compound shown in formula (I), expressed as a diffraction angle 2θ, is shown below. Figure 7 As shown.

[0039] This disclosure further provides a method for preparing the F crystal form of the compound shown in formula (I), including:

[0040] Method 1: a) Mix the compound shown in formula (I) with solvent II, wherein solvent II is selected from p-xylene, methanol, 2-methyltetrahydrofuran, o-xylene or toluene; b) Pulping and crystallization.

[0041] Alternatively, method 2: a) mix the compound shown in formula (I) with dichloromethane or tetrahydrofuran and dissolve it; b) add isopropyl acetate, methyl tert-butyl ether or methyl isobutyl ketone to crystallize.

[0042] Alternatively, method 3: a) mix the compound shown in formula (I) with 1,4-dioxane, dissolve, b) volatilize and crystallize.

[0043] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing the F crystal form of the compound of formula (I) described in this disclosure further includes steps such as filtration, washing, or drying.

[0044] This disclosure provides the G-phase of the compound shown in formula (I), with an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, exhibiting characteristic peaks at 5.999, 7.972, 9.951, 11.388, 17.812, 20.975, and 25.819. In some embodiments, the G-phase of the compound shown in formula (I) exhibits characteristic peaks at 5.999, 7.396, 7.972, 8.637, 9.951, 11.388, 15.291, 17.812, 20.975, and 25.819. In some embodiments, the G crystal form of the compound shown in formula (I) has characteristic peaks at 5.999, 7.396, 7.972, 8.637, 9.951, 11.388, 12.763, 15.291, 17.812, 20.975, 23.408, 25.819, and 27.400. In some embodiments, the X-ray powder diffraction pattern of the G crystal form of the compound shown in formula (I), expressed as a diffraction angle 2θ, is as follows: Figure 8 As shown.

[0045] This disclosure further provides a method for preparing the G crystal form of the compound shown in formula (I), including:

[0046] Method 1: a) Mix the compound shown in formula (I) with chloroform and dissolve it, b) volatilize and crystallize.

[0047] Alternatively, method 2: a) mix the compound shown in formula (I) with 1,2-dichloroethane, b) slurry and crystallize.

[0048] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing the G crystal form of the compound shown in formula (I) according to this disclosure further includes steps such as filtration, washing, or drying.

[0049] This disclosure provides the H-crystal form of the compound shown in formula (I), with an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, showing characteristic peaks at 5.758, 7.533, 9.901, 14.267, 16.420, 18.103, and 26.356. In some embodiments, the H-crystal form of the compound shown in formula (I) has characteristic peaks at 5.758, 7.533, 9.901, 14.267, 16.420, 18.103, 18.917, 20.489, 24.049, and 26.356. In some embodiments, the H-crystal form of the compound shown in formula (I) has characteristic peaks at 5.758, 7.533, 9.901, 14.267, 16.420, 18.103, 18.917, 20.489, 24.049, and 26.356. In some embodiments, the X-ray powder diffraction pattern of the H-crystal form of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is as follows: Figure 9 As shown.

[0050] This disclosure further provides a method for preparing the H crystal form of the compound shown in formula (I), including:

[0051] Method 1: a) Mix the compound shown in formula (I) with n-octane or n-hexane, b) Pulping and crystallization;

[0052] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing the H crystal form of the compound shown in formula (I) according to this disclosure further includes steps such as filtration, washing, or drying.

[0053] This disclosure provides the X-ray powder diffraction pattern of crystal form I of the compound shown in formula (I), expressed in diffraction angle 2θ, with characteristic peaks at 5.294, 6.826, 7.564, 10.739, 13.699, 16.812, and 20.709. In some embodiments, the X-ray powder diffraction pattern of crystal form I of the compound shown in formula (I), expressed in diffraction angle 2θ, is as follows: Figure 10 As shown.

[0054] This disclosure further provides a method for preparing the crystal form of compound I shown in formula (I), including:

[0055] Method 1: a) Mix the compound shown in formula (I) with tetrahydrofuran, dissolve, b) volatilize and crystallize.

[0056] Alternatively, method 2: a) mix the compound shown in formula (I) with tetrahydrofuran, dissolve it, b) add water to crystallize.

[0057] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing crystal form I of the compound of formula (I) according to this disclosure further includes steps such as filtration, washing, or drying.

[0058] This disclosure provides the J-crystal form of the compound shown in formula (I), with an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, exhibiting characteristic peaks at 5.041, 10.068, 16.424, 20.544, 21.190, 24.077, and 25.433. In some embodiments, the J-crystal form of the compound shown in formula (I) exhibits characteristic peaks at 5.041, 8.212, 10.068, 14.101, 15.167, 16.424, 20.544, 21.190, 24.077, and 25.433. In some embodiments, the J-crystal form of the compound shown in formula (I) exhibits characteristic peaks at 5.041, 8.212, 10.068, 14.101, 15.167, 16.424, 20.544, 21.190, 22.036, 22.679, 24.077, 25.433, and 26.454. In some embodiments, the X-ray powder diffraction pattern of the J-crystal form of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is as follows: Figure 11 As shown.

[0059] This disclosure further provides a method for preparing the J crystal form of the compound shown in formula (I), comprising: a) mixing the compound shown in formula (I) with dimethyl sulfoxide and dissolving it; b) adding water, isopropyl acetate or methyl tert-butyl ether and crystallizing.

[0060] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing the J-crystal form of the compound shown in formula (I) according to this disclosure further includes steps such as filtration, washing, or drying.

[0061] This disclosure provides the K-crystal form of the compound shown in formula (I) and its X-ray powder diffraction pattern expressed in diffraction angles of 2θ, showing characteristic peaks at 5.156, 7.699, 10.339, 14.334, 16.203, 18.327, and 23.418. In some embodiments, the K-crystal form of the compound shown in formula (I) has characteristic peaks at 5.156, 7.699, 10.339, 14.334, 16.203, 18.327, 23.418, 25.348, 25.919, and 26.446. In some embodiments, the X-ray powder diffraction pattern of the K-crystal form of the compound shown in formula (I) expressed in diffraction angles of 2θ is as follows: Figure 12 As shown.

[0062] This disclosure further provides a method for preparing the K crystal form of the compound shown in formula (I), comprising: a) mixing the compound shown in formula (I) with N-methylpyrrolidone and dissolving it, b) evaporating and crystallizing it.

[0063] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing the K crystal form of the compound shown in formula (I) according to this disclosure further includes steps such as filtration, washing, or drying.

[0064] This disclosure provides the L-crystal form of the compound shown in formula (I), and its X-ray powder diffraction pattern, expressed in diffraction angles of 2θ, with characteristic peaks at 4.932, 5.360, 9.831, 14.844, 18.244, 20.104, and 24.914. In some embodiments, the L-crystal form of the compound shown in formula (I) has characteristic peaks at 4.932, 5.360, 9.831, 10.753, 14.844, 16.369, 18.244, 20.104, 23.129, and 24.914. In some embodiments, the X-ray powder diffraction pattern of the L-crystal form of the compound shown in formula (I), expressed in diffraction angles of 2θ, is as follows: Figure 13 As shown.

[0065] This disclosure further provides a method for preparing the L-crystal form of the compound shown in formula (I), comprising: a) mixing the compound shown in formula (I) with N,N-dimethylacetamide and dissolving it, b) evaporating and crystallizing it.

[0066] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing the L-crystal form of the compound of formula (I) described in this disclosure further includes steps such as filtration, washing, or drying.

[0067] This disclosure provides the M-crystal form of the compound shown in formula (I), with an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, exhibiting characteristic peaks at 14.959, 16.322, 18.410, 20.748, 22.067, 23.670, and 26.863. In some embodiments, the M-crystal form of the compound shown in formula (I) exhibits characteristic peaks at 14.959, 16.322, 18.410, 20.748, 22.067, 23.670, 24.839, 25.873, 26.863, and 27.811. In some embodiments, the M-crystal form of the compound shown in formula (I) exhibits characteristic peaks at 14.959, 16.322, 18.410, 20.748, 22.067, 23.670, 24.322, 24.839, 25.873, 26.863, and 27.811. In some embodiments, the X-ray powder diffraction pattern of the M-crystal form of the compound shown in formula (I), expressed as a diffraction angle 2θ, is shown below. Figure 14 As shown.

[0068] This disclosure further provides a method for preparing the crystal form M of the compound shown in formula (I), comprising: a) heating the crystal form A, crystal form B, crystal form C, crystal form E, crystal form H or crystal form I of the compound shown in formula I to 225°C.

[0069] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing the M crystal form of the compound shown in formula (I) according to this disclosure further includes steps such as filtration, washing, or drying.

[0070] This disclosure provides the N-crystal form of the compound shown in formula (I), with X-ray powder diffraction patterns expressed as diffraction angles of 2θ, exhibiting characteristic peaks at 5.028, 9.942, 10.900, 15.428, 18.410, 20.274, and 25.252. In some embodiments, the N-crystal form of the compound shown in formula (I) exhibits characteristic peaks at 5.028, 7.671, 9.942, 10.900, 15.428, 16.560, 18.410, 20.274, 24.036, and 25.252. In some embodiments, the N-crystal form of the compound shown in formula (I) exhibits characteristic peaks at 5.028, 7.671, 9.942, 10.900, 12.677, 15.428, 16.560, 18.410, 20.274, 24.036, 25.252, and 26.385. In some embodiments, the X-ray powder diffraction pattern of the N-crystal form of the compound shown in formula (I), expressed as a diffraction angle 2θ, is shown below. Figure 15 As shown.

[0071] This disclosure further provides a method for preparing the N-crystal form of the compound shown in formula (I), comprising: a) mixing the compound shown in formula I with ethyl acetate / tetrahydrofuran (1:1) heating to dissolve, and b) cooling to crystallize.

[0072] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing the N-crystal form of the compound of formula (I) described in this disclosure further includes steps such as filtration, washing, or drying.

[0073] This disclosure provides the O-form of the compound shown in formula (I), with an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, showing characteristic peaks at 11.796, 17.423, 18.081, 19.136, 21.707, 22.165, and 25.719. In some embodiments, the O-form of the compound shown in formula (I) has characteristic peaks at 7.843, 11.796, 17.423, 18.081, 19.136, 21.707, 22.165, 24.412, 25.719, and 28.521. In some embodiments, the O crystal form of the compound shown in formula (I) has characteristic peaks at 7.843, 11.796, 15.455, 17.423, 18.081, 19.136, 21.055, 21.707, 22.165, 24.412, 25.719, 27.538, and 28.521. In some embodiments, the X-ray powder diffraction pattern of the O crystal form of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is as follows: Figure 16 As shown.

[0074] This disclosure further provides a method for preparing the O crystal form of the compound shown in formula (I), comprising: a) mixing the compound shown in formula I with acetonitrile and benzenesulfonic acid, heating, and b) cooling to crystallize.

[0075] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200. In some embodiments, the method for preparing the O-crystal form of the compound of formula (I) described in this disclosure further includes steps such as filtration, washing, or drying.

[0076] This disclosure provides the P-crystal form of the compound shown in formula (I), with X-ray powder diffraction patterns expressed as diffraction angles 2θ, exhibiting characteristic peaks at 5.359, 7.491, 10.786, 14.249, 16.527, 17.729, and 20.798. In some embodiments, the P-crystal form of the compound shown in formula (I) exhibits characteristic peaks at 5.359, 7.491, 9.905, 10.786, 13.192, 14.249, 16.527, 17.729, 18.862, and 20.798. In some embodiments, the P-crystal form of the compound shown in formula (I) exhibits characteristic peaks at 5.359, 7.491, 9.905, 10.786, 13.192, 14.249, 16.527, 17.729, 18.862, 20.798, 23.799, and 26.555. In some embodiments, the X-ray powder diffraction pattern of the P-crystal form of the compound shown in formula (I), expressed as a diffraction angle 2θ, is shown below. Figure 17 As shown.

[0077] This disclosure further provides a method for preparing the crystal form P of the compound shown in formula (I), comprising: a) mixing the crystal form C of the compound shown in formula (I) with 1,4-dioxane, b) slurrying and crystallizing.

[0078] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing the P-crystal form of the compound of formula (I) described in this disclosure further includes steps such as filtration, washing, or drying.

[0079] This disclosure provides the Q crystal form of the compound shown in formula (I), with X-ray powder diffraction patterns expressed as diffraction angles 2θ, exhibiting characteristic peaks at 5.038, 10.152, 15.850, 16.574, 18.892, 20.760, and 21.835. In some embodiments, the Q crystal form of the compound shown in formula (I) exhibits characteristic peaks at 5.038, 10.152, 11.175, 15.850, 16.574, 18.892, 20.760, 21.835, 23.905, and 25.784. In some embodiments, the Q crystal form of the compound shown in formula (I) has characteristic peaks at 5.038, 7.682, 10.152, 11.175, 14.218, 15.850, 16.574, 18.892, 20.760, 21.835, 23.905, 25.784, and 26.418. In some embodiments, the X-ray powder diffraction pattern of the Q crystal form of the compound shown in formula (I), expressed as a diffraction angle 2θ, is as follows: Figure 18 As shown.

[0080] This disclosure further provides a method for preparing the Q crystal form of the compound shown in formula (I), comprising: method 1: a) mixing the compound shown in formula (I) with ethyl acetate, b) slurrying and crystallizing, and drying the solid at 70°C or 130°C;

[0081] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing the Q crystal form of the compound of formula (I) described in this disclosure further includes steps such as filtration, washing, or drying.

[0082] This disclosure provides the U-form of the compound shown in formula (I) with an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, exhibiting characteristic peaks at 14.155, 15.745, 17.314, 17.997, 18.838, 20.512, and 21.415. In some embodiments, the U-form of the compound shown in formula (I) exhibits characteristic peaks at 14.155, 15.745, 16.564, 17.314, 17.997, 18.838, 20.512, 21.415, 23.557, and 26.313. In some embodiments, the U-form of the compound shown in formula (I) exhibits characteristic peaks at 7.657, 14.155, 15.745, 16.564, 17.314, 17.997, 18.838, 20.512, 21.415, 23.557, 25.711, 26.313, and 28.029. In some embodiments, the X-ray powder diffraction pattern of the U-form of the compound shown in formula (I), expressed as a diffraction angle 2θ, is as follows: Figure 19 As shown.

[0083] This disclosure further provides a method for preparing the U-crystal form of the compound shown in formula (I), comprising: method 1: a) mixing the Q-crystal form of the compound shown in formula (I) with water, b) slurrying and crystallization;

[0084] Alternatively, method 2: a) mix the compound shown in formula I with DMSO, heat to dissolve, b) add water to crystallize.

[0085] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing the U-crystal form of the compound of formula (I) described in this disclosure further includes steps such as filtration, washing, or drying.

[0086] This disclosure provides the X-ray powder diffraction pattern of the compound shown in formula (I), expressed in diffraction angles of 2θ, with characteristic peaks at 6.864, 9.873, 10.963, 13.801, 16.089, 18.006, and 20.929. In some embodiments, the X-ray powder diffraction pattern of the compound shown in formula (I), expressed in diffraction angles of 2θ, is as follows: Figure 20 As shown.

[0087] This disclosure further provides a method for preparing the X crystal form of the compound shown in formula (I), comprising: method 1: a) mixing the D crystal form of the compound shown in formula (I) with isopropyl ether or n-heptane, b) slurrying and crystallizing.

[0088] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing the X crystal form of the compound shown in formula (I) according to this disclosure further includes steps such as filtration, washing, or drying.

[0089] This disclosure provides the Y-crystal form of the compound shown in formula (I), and its X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 5.676, 7.666, 14.260, 16.562, 18.020, 21.802, and 26.425. In some embodiments, the Y-crystal form of the compound shown in formula (I) has characteristic peaks at 5.676, 7.666, 9.985, 12.634, 14.260, 16.562, 18.020, 21.802, 26.425, and 26.974. In some embodiments, the Y-crystal form of the compound shown in formula (I) exhibits characteristic peaks at 5.676, 7.666, 9.985, 12.634, 14.260, 16.562, 18.020, 21.802, 24.051, 25.846, 26.425, and 26.974. In some embodiments, the X-ray powder diffraction pattern of the Y-crystal form of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is as follows: Figure 21 As shown.

[0090] This disclosure further provides a method for preparing the Y crystal form of the compound shown in formula (I), comprising: a) mixing the Q crystal form of the compound shown in formula (I) with isopropyl ether or n-heptane, b) slurrying and crystallizing.

[0091] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing the Y-crystal form of the compound of formula (I) described in this disclosure further includes steps such as filtration, washing, or drying.

[0092] This disclosure provides the V-form of the compound shown in formula (I), and its X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 5.649, 6.154, 6.720, 11.651, 18.757, 19.813, and 23.948. In some embodiments, the V-form of the compound shown in formula (I) has characteristic peaks at 5.649, 6.154, 6.720, 9.778, 11.651, 17.570, 18.757, 19.813, 23.948, and 26.995. In some embodiments, the V-form of the compound shown in formula (I) exhibits characteristic peaks at 5.649, 6.154, 6.720, 9.778, 11.651, 13.576, 17.570, 18.757, 19.813, 21.905, 23.948, 25.825, and 26.995. In some embodiments, the X-ray powder diffraction pattern of the V-form of the compound shown in formula (I), expressed as a diffraction angle 2θ, is shown below. Figure 22 As shown.

[0093] This disclosure further provides a method for preparing the V crystal form of the compound shown in formula (I), comprising: method 1: a) mixing the compound shown in formula (I) with N,N-dimethylformamide and dissolving it; b) adding acetone or acetonitrile to crystallize.

[0094] Alternatively, method 2) a) mix the compound shown in formula I with N,N-dimethylformamide, b) cool to crystallize or stir to crystallize.

[0095] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing the V-crystal form of the compound of formula (I) described in this disclosure further includes steps such as filtration, washing, or drying.

[0096] This disclosure provides the R-crystal form of the compound shown in formula (I), and its X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 5.534, 7.611, 10.033, 15.782, 17.101, 19.017, and 20.567. In some embodiments, the R-crystal form of the compound shown in formula (I) has characteristic peaks at 5.534, 7.611, 10.033, 11.857, 12.737, 15.782, 17.101, 19.017, 20.567, and 23.692. In some embodiments, the R-crystal form of the compound shown in formula (I) has characteristic peaks at 5.534, 7.611, 10.033, 11.148, 11.857, 12.737, 14.179, 15.782, 17.101, 19.017, 20.567, 21.871, and 23.692. In some embodiments, the X-ray powder diffraction pattern of the R-crystal form of the compound shown in formula (I), expressed as a diffraction angle 2θ, is as follows: Figure 23 As shown.

[0097] This disclosure further provides a method for preparing the R crystal form of the compound shown in formula (I), comprising: a) mixing the compound shown in formula (I) with tetrahydrofuran and dissolving it, b) concentrating and crystallizing it.

[0098] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing the R crystal form of the compound shown in formula (I) according to this disclosure further includes steps such as filtration, washing, or drying.

[0099] This disclosure provides the S-crystal form of the compound shown in formula (I), and its X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 6.576, 9.082, 10.921, 13.592, 19.965, 21.403, and 24.207. In some embodiments, the S-crystal form of the compound shown in formula (I) has characteristic peaks at 6.576, 9.082, 10.921, 13.592, 16.805, 19.965, 21.403, 24.207, 25.662, and 27.457. In some embodiments, the S-crystal form of the compound shown in formula (I) exhibits characteristic peaks at 6.576, 7.890, 9.082, 10.921, 13.592, 15.043, 16.805, 19.965, 21.403, 24.207, 25.662, 26.537, and 27.457. In some embodiments, the X-ray powder diffraction pattern of the S-crystal form of the compound shown in formula (I), expressed as a diffraction angle 2θ, is shown below. Figure 24 As shown.

[0100] This disclosure further provides a method for preparing the S-crystal form of the compound shown in formula (I), comprising: method 1: a) mixing the compound shown in formula (I) with DMF, heating to dissolve, cooling to precipitate, b) filtering, mixing the filter cake with acetonitrile, slurrying, c) filtering, mixing the filter cake with water, slurrying, d) filtering, drying, then slurrying with acetonitrile to precipitate crystals, and drying.

[0101] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the method for preparing the S-crystal form of the compound of formula (I) described in this disclosure further includes steps such as filtration, washing, or drying.

[0102] This disclosure provides the T-crystal form of the compound shown in formula (I), and its X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 6.915, 9.177, 9.984, 11.012, 13.595, 16.156, and 20.138. In some embodiments, the T-crystal form of the compound shown in formula (I) has characteristic peaks at 6.915, 9.177, 9.984, 11.012, 13.595, 15.174, 16.156, 20.138, 24.261, and 26.391. In some embodiments, the T-crystal form of the compound shown in formula (I) exhibits characteristic peaks at 6.915, 9.177, 9.984, 11.012, 13.595, 15.174, 16.156, 18.509, 20.138, 22.954, 24.261, 26.391, and 27.514. In some embodiments, the X-ray powder diffraction pattern of the T-crystal form of the compound shown in formula (I), expressed as a diffraction angle 2θ, is shown below. Figure 25 As shown.

[0103] This disclosure further provides a method for preparing the T-crystal form of the compound shown in formula (I), comprising: method 1: a) mixing the compound shown in formula (I) with DMF, heating to dissolve, cooling to crystallize, b) filtering, mixing the filter cake with water and stirring, c) filtering, mixing the filter cake with water again and stirring, d) filtering, drying, mixing with acetonitrile, stirring to crystallize, and drying.

[0104] In some embodiments, the volume (μl) of the solvent used in this disclosure may be 1-200 times the mass (mg) of the compound of formula (I), and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200. In some embodiments, the method for preparing the T-crystal form of the compound shown in formula (I) according to this disclosure further includes steps such as filtration, washing, or drying.

[0105] This disclosure also provides pharmaceutical compositions prepared from the crystal form of the compound shown in formula (I) above.

[0106] This disclosure also provides a pharmaceutical composition comprising the aforementioned crystal form and optionally a pharmaceutically acceptable carrier, diluent, or excipient.

[0107] This disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing the aforementioned crystal form with a pharmaceutically acceptable carrier, diluent, or excipient.

[0108] This disclosure also provides the use of the aforementioned crystal form, or the aforementioned composition, or the composition prepared by the aforementioned method in the preparation of a medicament for treating and / or preventing diseases related to CRBN protein.

[0109] This disclosure also provides the use of the aforementioned crystal form, or the aforementioned composition, or the composition prepared by the aforementioned method in the preparation of medicaments for treating and / or preventing cancer, angiogenesis-related conditions, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS diseases, CNS damage, atherosclerosis or related conditions, sleep disorders or related conditions, infectious diseases, hemoglobinopathies or related conditions, or TNFα-related conditions; preferably, in the preparation of medicaments for treating and / or preventing cancer or CNS damage.

[0110] In some embodiments, the cancer is selected from leukemia, myeloma, lymphoma, melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal carcinoma, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial carcinoma, ureteral tumors, prostate cancer, seminoma, testicular tumors, head and neck tumors, head and neck squamous cell carcinoma, endometrial cancer, thyroid cancer, sarcoma, osteoma, neuroblastoma, neuroendocrine carcinoma, brain tumor, CNS cancer, astrocytoma, and glioma; preferably, the liver cancer is hepatocellular carcinoma; the colorectal cancer is colon cancer or rectal cancer; the sarcoma is osteosarcoma or soft tissue sarcoma; and the glioma is glioblastoma.

[0111] In some embodiments, the myeloma is multiple myeloma (MM) and myelodysplastic syndrome (MDS); preferably, the multiple myeloma is relapsed, refractory, or resistant.

[0112] In some embodiments, the multiple myeloma is lenalidomide or pomalidomide refractory or resistant.

[0113] The "2θ or 2θ angle" mentioned in this disclosure refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degree; the error range of 2θ for each characteristic peak is ±0.20 (including the case where the number has more than one decimal place after rounding), and can be -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.

[0114] According to the description of hygroscopic characteristics and the definition of hygroscopic weight gain in the "Guiding Principles on Hygroscopicity of Drugs" in Part IV of the 2015 edition of the Chinese Pharmacopoeia,

[0115] Deliquescence: Absorbs sufficient moisture to form a liquid;

[0116] Extremely hygroscopic: the weight gain due to hygroscopic absorption is not less than 15%;

[0117] It has hygroscopic properties: the weight gain due to hygroscopic absorption is less than 15% but not less than 2%;

[0118] Slightly hygroscopic: the weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0119] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0120] The “differential scanning calorimetry or DSC” described in this disclosure refers to measuring the temperature difference and heat flow difference between the sample and the reference material during the sample heating or isothermal process, in order to characterize all physical and chemical changes related to thermal effects and obtain phase transition information of the sample.

[0121] The drying temperature described in this disclosure is generally 25℃~150℃, preferably 40℃~80℃, and can be dried under normal pressure or reduced pressure.

[0122] "Pharmaceutical composition" means a mixture containing one or more compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, along with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0123] The crystal forms described in this disclosure include, but are not limited to, solvates of compounds of formula (I), wherein the solvents include, but are not limited to, water, methanol, ethanol, isopropanol, acetone, ethyl acetate, acetonitrile, isopropyl acetate, methyl tert-butyl ether, 2-butanone, tetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidone, methyl isobutyl ketone, dichloromethane, n-heptane, 1,4-dioxane, nitromethane, propylene glycol methyl ether, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, p-xylene, cyclohexane, dichloroethane, n-hexane, petroleum ether, n-octane, o-xylene, toluene, and isopropyl ether.

[0124] The "solvents" described in this disclosure include, but are not limited to, complexes formed by combining compounds of formula (I) with solvents. Attached Figure Description

[0125] Figure 1 XRPD spectrum of the amorphous compound shown in formula (I).

[0126] Figure 2 XRPD pattern of compound A crystal form shown in formula (I).

[0127] Figure 3 XRPD pattern of compound B crystal form shown in formula (I).

[0128] Figure 4 XRPD pattern of the C crystal form of the compound shown in formula (I).

[0129] Figure 5 XRPD pattern of compound D crystal form shown in formula (I).

[0130] Figure 6 XRPD pattern of compound E crystal form shown in formula (I).

[0131] Figure 7 XRPD pattern of compound F crystal form shown in formula (I).

[0132] Figure 8 XRPD pattern of compound G crystal form shown in formula (I).

[0133] Figure 9 XRPD pattern of compound H crystal form shown in formula (I).

[0134] Figure 10 XRPD pattern of compound I crystal form shown in formula (I).

[0135] Figure 11 XRPD pattern of compound J crystal form shown in formula (I).

[0136] Figure 12 XRPD pattern of compound K crystal form shown in formula (I).

[0137] Figure 13 XRPD pattern of the L crystal form of the compound shown in formula (I).

[0138] Figure 14 XRPD pattern of compound M crystal form shown in formula (I).

[0139] Figure 15 XRPD pattern of the N crystal form of the compound shown in formula (I).

[0140] Figure 16 XRPD pattern of compound O crystal form shown in formula (I).

[0141] Figure 17 XRPD pattern of the P crystal form of compound shown in formula (I).

[0142] Figure 18 XRPD pattern of the Q crystal form of the compound shown in formula (I).

[0143] Figure 19 XRPD pattern of the U-crystal form of the compound shown in formula (I).

[0144] Figure 20 XRPD pattern of compound X crystal form shown in formula (I).

[0145] Figure 21 XRPD pattern of the Y crystal form of the compound shown in formula (I).

[0146] Figure 22 XRPD pattern of the V crystal form of the compound shown in formula (I).

[0147] Figure 23 XRPD pattern of compound R crystal form shown in formula (I).

[0148] Figure 24 XRPD pattern of the S crystal form of the compound shown in formula (I).

[0149] Figure 25 XRPD pattern of compound T crystal form shown in formula (I).

[0150] Figure 26 Example 1: Efficacy data of compound CC-92480 and control CC-92480 against NCI-H929 xenografts in CB-17SCID mice.

[0151] Figure 27 Example 1: Effects of compound CC-92480 and control CC-92480 on body weight of CB-17SCID mice. Detailed Implementation Plan

[0152] The present disclosure will be explained in more detail below with reference to embodiments or experimental examples. The embodiments or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure and are not intended to limit the substance and scope of the present disclosure.

[0153] Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.

[0154] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (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), with tetramethylsilane (TMS) as the internal standard.

[0155] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a waters ACQuity UPLC-QD / SQD system (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), or a THERMO Ultimate3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0156] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 high-performance liquid chromatograph.

[0157] Chiral HPLC analysis was performed using an Agilent 1260 DAD high-performance liquid chromatograph.

[0158] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0159] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0160] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0161] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0162] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0163] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0164] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, and Darui Chemicals.

[0165] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0166] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0167] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0168] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0169] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0170] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0171] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0172] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0173] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, and the developing solvent system for TLC included: A: n-hexane / ethyl acetate system, B: dichloromethane / methanol system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0174] The testing conditions of the instruments used in the experiments in this disclosure are as follows:

[0175] 1. Differential Scanning Calorimeter (DSC)

[0176] Instrument Model: Mettler Toledo DSC 3+STARe System

[0177] Purging gas: nitrogen; Nitrogen purging rate: 50 mL / min

[0178] Heating rate: 10.0℃ / min

[0179] Temperature range: 25-350℃

[0180] 2. X-ray Powder Diffraction (XRPD)

[0181] Instrument Model: BRUKER D8 Discover X-ray Powder Diffractometer

[0182] Rays: Monochromatic Cu-Kα rays

[0183] Scanning mode: θ / 2θ, scanning range (2θ range): 3~50°

[0184] Voltage: 40kV, Current: 40mA

[0185] 3. Thermogravimetric Analysis (TGA)

[0186] Instrument model: Mettler Toledo TGA2

[0187] Purging gas: nitrogen; Nitrogen purging rate: 50 mL / min

[0188] Heating rate: 10.0℃ / min

[0189] Temperature range: 25-350℃

[0190] Example 1: Preparation of the compound shown in formula (I)

[0191] (S)-4-(4-((5-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)pyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile (Compound 1)

[0192]

[0193]

[0194] first step

[0195] 4-((5-formylpyridin-2-yl)thio)piperidine-1-carboxylic acid tert-butyl ester 1b

[0196] Compound 1-1a (700 mg, 3.22 mmol), 6-fluoropyridine-3-carboxaldehyde 1a (443 mg, 3.54 mmol), and potassium carbonate (1.11 g, 8.05 mmol) were added to N,N-dimethylformamide (10 mL). The reaction mixture was heated to 80 °C and reacted for 1 hour. The reaction mixture was diluted with water (30 mL) and then extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give title compound 1b (1.0 g, yield: 96%).

[0197] MS m / z (ESI): 267.1 [M-55].

[0198] Step 2

[0199] 6-(piperidin-4-ylthio)nicotinaldehyde trifluoroacetate 1c

[0200] Compound 1b (950 mg, 2.95 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was slowly added under ice bath conditions. The reaction mixture was reacted for 1 hour. The reaction solution was concentrated and dried to give the title compound 1c. The crude product was used directly in the next reaction without purification.

[0201] MS m / z (ESI): 223.1 [M+1].

[0202] Step 3

[0203] 3-Fluoro-4-(4-(((5-formylpyridin-2-yl)thio)piperidin-1-yl)benzonitrile 1d

[0204] Compound 1c (760 mg, 2.94 mmol), 3,4-difluorobenzonitrile (817 mg, 5.87 mmol), and potassium carbonate (1.22 g, 8.81 mmol) were added to N,N-dimethylformamide (15 mL), and the reaction mixture was heated to 80 °C and reacted overnight. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give title compound 1d (850 mg, yield: 84%).

[0205] MS m / z (ESI): 342.1 [M+1].

[0206] Step 4

[0207] 3-Fluoro-4-(4-((5-(hydroxymethyl)pyridin-2-yl)thio)piperidin-1-yl)benzonitrile 1e

[0208] Compound 1d (600 mg, 1.76 mmol) was added to methanol (10 mL) under ice bath conditions, followed by slow addition of sodium borohydride (133 mg, 3.51 mmol), and the reaction was allowed to proceed for 1 hour. The reaction mixture was quenched with water (10 mL) and then extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 1e (580 mg, yield: 96%).

[0209] MS m / z (ESI): 344.1 [M+1].

[0210] Step 5

[0211] 4-(4-((5-(bromomethyl)pyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile 1f

[0212] Compound 1e (200 mg, 0.582 mmol) was added to dichloromethane (6 mL), followed by the addition of triphenylphosphine (199 mg, 0.757 mmol) and carbon tetrabromide (251 mg, 0.757 mmol). The reaction mixture was reacted for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography using eluent system B to give the title compound 1f (190 mg, yield: 80%).

[0213] MS m / z(ESI): 406.0[M+1]; 408.0[M+3].

[0214] Step 6

[0215] (S)-5-amino-4-(4-((6-((1-(4-cyano-2-fluorophenyl)piperidin-4-yl)thio)pyridin-3-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxovalerate tert-butyl ester 1g

[0216] (S)-5-amino-4-(4-hydroxy-1-oxoisoindoline-2-yl)-5-oxovalerate tert-butyl ester 1-3a (82 mg, 0.246 mmol, prepared by a known method, "Journal of Medicinal Chemistry, 2020, 63(13), 6648-6676") and anhydrous potassium carbonate (65 mg, 0.468 mmol) were added to N,N-dimethylformamide (3 mL), and compound 1f (95 mg, 0.244 mmol) was added. The reaction mixture was reacted for 2 hours. The reaction mixture was poured into ice water (10 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give 1 g (145 mg, yield: 94%) of the title compound.

[0217] MS m / z (ESI): 660.2 [M+1].

[0218] Step 7

[0219] (S)-4-(4-((5-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)pyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile1

[0220] 1 g (60 mg, 0.091 mmol) of compound was added to acetonitrile (5 mL), and benzenesulfonic acid (16 mg, 0.091 mmol) was added at room temperature. The reaction mixture was reacted at 80 °C for 8 hours. The solvent was removed from the reaction solution under reduced pressure, and the residue was prepared by high performance liquid chromatography (Gilson GX-281, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 60%-80%, flow rate: 30 mL / min) to give title compound 1 (42 mg, yield: 78%).

[0221] X-ray powder diffraction analysis revealed that compound 1 is amorphous.

[0222] MS m / z (ESI): 586.4 [M+1].

[0223] 1H NMR (500MHz, DMSO-d6): δ10.98(s,1H),8.60(s,1H),7.78(dd,1H),7.69(dd,1H),7.59-7. 48(m,2H),7.38-7.33(m,3H),7.16(t,1H),5.24(s,2H),5.12(dd,1H),4.42(d,1H),4.26( d,1H),4.07-3.99(m,1H),3.56-3.48(m,2H),3.13-3.03(m,2H),2.96-2.87(m,1H),2.63- 2.55(m,1H),2.46-2.38(m,1H),2.21-2.12(m,2H),2.02-1.94(m,1H),1.82-1.70(m,2H).

[0224] Biological evaluation

[0225] Test Example 1: Biological Evaluation of NCI-H929 Proliferation Experiment

[0226] The following method was used to determine the inhibitory activity of the disclosed compound on the proliferation of NCI-H929 cells. The experimental method is briefly described below.

[0227] NCI-H929 cells (ATCC, CRL-9068) were cultured in complete medium containing 10% fetal bovine serum (Corning, 35-076-CV) and 0.05 mM 2-mercaptoethanol (Sigma, M3148) in RPMI 1640 medium (Hyclone, SH30809.01). On day 1, NCI-H929 cells were seeded at a density of 6000 cells / well in 96-well plates using complete medium, with 100 μL of cell suspension per well. Simultaneously, 10 μL of serially diluted test compounds prepared in complete medium were added to each well. The compounds were first dissolved in DMSO at an initial concentration of 10 mM, and then serially diluted 5-fold to a total of 9 concentration points. The blank control was 100% DMSO. Then, 5 μL of the DMSO-dissolved compound was added to 95 μL of complete medium, resulting in a 20-fold dilution of the compound in complete medium. Finally, 10 μL of the compound diluted in complete culture medium was added to each well of the cell suspension, resulting in nine concentration points representing a 5-fold serial dilution starting from 50 μM. A blank control containing 0.5% DMSO was included. The plates were incubated at 37°C in a 5% CO2 cell culture incubator for 5 days. On the sixth day, the 96-well cell culture plates were removed, and 50 μL of CellTiter- was added to each well. Luminescent cell viability assay reagent (Promega, G7573), after being left at room temperature for 10 minutes, the luminescence signal value was read using a multi-mode microplate reader (PerkinElmer, EnVision2015), and the IC for the compound's inhibitory activity was calculated using Graphpad Prism software 50 values are shown in Table I.

[0228] Table I IC of the compounds of the present disclosure for inhibiting NCI-H929 cell proliferation 50 values

[0229]

[0230] Conclusion: Compound 1 of the present disclosure has excellent activity in inhibiting the proliferation of NCI-H929 cells.

[0231] Test Example 2 Pharmacodynamic Test

[0232] 1. Test Purpose

[0233] To evaluate the effect of the compound of Example 1 and the control example CC-92480 on inhibiting the growth of human multiple myeloma cell NCI-H929 xenograft tumors in CB-17SCID mice.

[0234] 2. Test Drugs

[0235] The compound of Example 1;

[0236] Control example CC-92480 (see Compound 2 in WO2019014100A1, synthesized according to the method disclosed therein)

[0237]

[0238] The compound of Example 1 and the control example CC-92480 were formulated with 5% DMSO + 20% PEG400 + 70% (10% TPGS) + 5% (1% HPMC K100LV).

[0239] 3. Test Methods and Test Materials

[0240] 3.1. Test Animals and Feeding Conditions

[0241] 30 female CB-17SCID mice, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Certificate No.: 20170011006049, SCXK (Shanghai) 2017-0011), with a body weight of about 19g at the time of purchase, 5 mice per cage, housed under a 12 / 12 hour light / dark cycle, at a constant temperature of 23±1°C, with a humidity of 50-60%, and free access to food and water.

[0242] 3.2. Animal Grouping:

[0243] After acclimatization, CB-17SCID rats were grouped as follows:

[0244]

[0245] Note: qd means once a day; ig means by gavage.

[0246] 3.3 Experimental Methods:

[0247] 5 × 10⁵ NCI-H929 cells in logarithmic growth phase 6 Cells / mouse / 100μL (containing 50μL Matrigel) were subcutaneously injected into the right rib area of ​​30 female CB-17SCID mice. After 10 days, the tumor volume of the tumor-bearing mice reached 200mm². 3 Around 11:00 AM, mice were randomly divided into three groups based on tumor volume and body weight: a solvent control group, a CC-92480-1mpk group, and a compound from Example 1-1mpk group, with seven mice in each group. The day of grouping was designated Day 0 (D0), and administration began once daily via gavage for 11 days (Table 2). Tumor volume was measured twice weekly using calipers, and body weight was measured using a balance; data were recorded. When the tumor volume reached 2000 mm², the mice were considered tumor-bearing mice. 3 The experimental endpoint was to euthanize the tumor-bearing animals when most tumors ulcerated or the animals lost 20% of their body weight.

[0248] 3.4 Data Statistics

[0249] All data were plotted and statistically analyzed using Excel and GraphPad Prism 5 software.

[0250] The formula for calculating tumor volume (V) is: V = 1 / 2 × a × b 2 , where a and b represent length and width, respectively.

[0251] The 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.

[0252] Tumor inhibition rate TGI (%) = 1 - T / C (%). When TGI (%) exceeds 100%, the specific value will not be displayed, but only >100% will be used.

[0253] Tumor regression (%) = [(T0-T) / T0] × 100 (%).

[0254] 4. Results

[0255] The efficacy data of the Example 1 compound and the comparative example CC-92480 on NCI-H929 xenografts in CB-17 SCID mice are shown in Table II below and Figure 26 .

[0256] The effects of the Example 1 compound and the comparative example CC-92480 on the body weight of CB-17 SCID mice are shown in Figure 27 .

[0257] Table II Efficacy of the compounds of the present disclosure on NCI-H929 xenografts in CB-17 SCID mice

[0258]

[0259] Note: qd means administration once a day; po means oral administration.

[0260] 5. Conclusion

[0261] Administration of the Example 1 compound was started 10 days after tumor cell transplantation, once a day. Significant regression of tumor volume was observed 11 days after administration. The calculated tumor inhibition rate was >100%, the tumor regression rate was 88%, and there was a statistically significant difference (p<0.05) compared with CC-92480 at the same dose at the end of the experiment, and the administration had no effect on the body weight of the mice. Under the same conditions, the tumor regression rate of the comparative example CC-92480 was 34%.

[0262] Test Example 3 Pharmacokinetic Evaluation

[0263] 1. Overview

[0264] Using mice as test animals, the LC / MS / MS method was applied to determine the drug concentration in plasma at different time points after intragastric administration of the Example 1 compound and the comparative example CC-92480 to mice. The pharmacokinetic behavior of the compounds of the present disclosure in mice was studied to evaluate their pharmacokinetic characteristics.

[0265] 2. Test Protocol

[0266] 2.1 Test Drugs

[0267] The Example 1 compound and the comparative example CC-92480.

[0268] 2.2 Test Animals

[0269] 18 female mice, purchased from Vital River Laboratory Animal Co., Ltd., Animal Production License No.: SCXK(Shanghai) 2017-0005.

[0270] 2.3 Drug Formulation

[0271] Weigh the compound from Example 1, add 5% by volume of DMSO and 5% Tween 80 (Shanghai Titan Technology Co., Ltd.) to dissolve it, and then add 90% physiological saline to prepare a clear solution of 0.1 mg / mL.

[0272] Weigh out the control example CC-92480, add 5% volume of DMSO and 5% Tween 80 (Shanghai Titan Technology Co., Ltd.) to dissolve it, and then add 90% physiological saline to prepare a clear solution of 0.1 mg / mL.

[0273] 2.4 Administration

[0274] Nine mice were administered the compound of Example 1 by gavage at a dose of 2 mg / kg and an administration volume of 0.2 mL / 10 g.

[0275] Nine mice were administered the control compound CC-92480 by gavage at a dose of 2 mg / kg and an administration volume of 0.2 mL / 10 g.

[0276] 3. Operation

[0277] Mice were administered compound 1 (Example 1) and control CC-92480 via gavage. Blood samples of 0.2 mL (3 animals per time point) were collected before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The samples were placed in EDTA-K2 anticoagulant tubes and centrifuged at 10,000 rpm for 1 minute (4°C). Plasma was separated within 1 hour and stored at -20°C for analysis. The blood collection and centrifugation processes were performed under ice bath conditions.

[0278] Determination of the content of the analyte compound in mouse plasma after administration of different drug concentrations: 25 μL of mouse plasma was collected at each time point after drug administration, and 50 μL (100 ng / mL) of internal standard solution camptothecin (China National Institutes for Biological Products Control) and 175 μL of acetonitrile were added. The mixture was vortexed for 5 minutes and centrifuged for 10 minutes (3700 rpm). 1 μL of the supernatant from the plasma sample was analyzed by LC / MS / MS (API4000 triple quadrupole tandem mass spectrometer, Applied Biosystems, USA; Shimadzu LC-30AD ultra-high performance liquid chromatography system, Shimadzu Corporation, Japan).

[0279] 4. Pharmacokinetic Parameter Results

[0280] The pharmacokinetic parameters of the compounds disclosed herein are shown in Table III below.

[0281] Table III. Pharmacokinetic parameters of the compounds disclosed herein

[0282]

[0283]

[0284] Conclusion: The compound disclosed in this study exhibits good pharmacokinetic absorption and has advantages in pharmacokinetic properties.

[0285] Test Example 4: Evaluation of the plasma stability of the disclosed compounds

[0286] 1. Abstract

[0287] The stability of the compound of Example 1 and CC-92480 and the control example CC-92480 in monkey frozen plasma at 37°C for 0, 15, 30, 60, 120, 180 and 240 minutes was determined by LC-MS / MS.

[0288] 2. Test Plan

[0289] 2.1 Test Drugs

[0290] Compound of Example 1 and Control Example CC-92480.

[0291] 2.2 Test plasma

[0292] Monkey plasma was purchased from Shanghai Medicilon Biopharmaceutical Co., Ltd.

[0293] 2.3 Preparation of Compound Solutions

[0294] Weigh a certain amount of the compound from Example 1 and add DMSO to prepare a 30 mM stock solution. Take a certain volume of the stock solution and dilute it with DMSO to prepare a 1600 μM solution I. Then take a certain volume of the 1600 μM solution I and dilute it with 50% methanol to prepare a 16 μM working solution II. Prepare the 30 mM stock solution, 1600 μM solution I', and 16 μM working solution II' of CC-92480 using the above method.

[0295] 2.4 Sample incubation

[0296] Take 5 μL of the working solution of 16 μM of the compound from Example 1 and the control example CC-92480, and add them to 75 μL of plasma respectively to bring the final concentration of the compound to 1 μM. Incubate the samples in a 37°C water bath for 0, 15, 30, 60, 90, 120, and 180 minutes. After incubation, add 240 μL of acetonitrile containing the internal standard, then shake at 800 rpm for 10 minutes, centrifuge at 3700 rpm at 4°C for 20 minutes, and analyze the supernatant using LC-MS with an injection volume of 2 μL.

[0297] 3. Results

[0298] The conversion of the disclosed compounds in monkey plasma is shown in Table IV below.

[0299] Table IV. Stability data of the disclosed compounds in monkey plasma.

[0300]

[0301]

[0302] Conclusion: The disclosed compound has a stability advantage in monkey plasma.

[0303] Example 2: Preparation of the amorphous form of the compound shown in formula (I)

[0304] 10 mg of compound (I) was added to 1.0 ml of propylene glycol methyl ether, stirred at room temperature, centrifuged, and dried to obtain the product. X-ray powder diffraction (XRPD) analysis showed that the product was amorphous, as shown in the XRPD pattern below. Figure 1 As shown.

[0305] Example 3: Preparation of the crystal form of compound A shown in formula (I)

[0306] 7.3 g of the compound shown in formula (I) was added to 300 mL of dichloromethane, dissolved in 30 mL of methanol, and then 300 mL of water was added. Most of the dichloromethane was removed by rotary evaporation, resulting in a large amount of solid precipitation. The solid was filtered and dried overnight. Dichloromethane (500 mL) was added to the solid, dissolved, and filtered to obtain 500 mL of filtrate. Anhydrous sodium sulfate was added for drying, and the solution was filtered. Ethyl acetate (200 mL) was added, and the solution was evaporated to dryness to obtain the product. X-ray powder diffraction (XRPD) analysis identified the product as crystal form A. The XRPD spectrum is shown below. Figure 2 As shown in Table 1, the positions of its characteristic peaks are as follows. The DSC spectrum shows endothermic peaks at 155.26℃, 183.19℃, and 244.74℃. The TGA spectrum shows a weight loss of 9.48% between 25℃ and 220℃.

[0307] Table 1

[0308]

[0309] Example 4: Preparation of the crystal form of compound A shown in formula (I)

[0310] 10 mg of compound (I) was added to 1 ml of water, slurried at room temperature, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was crystal form A.

[0311] Example 5: Preparation of the crystal form of compound A shown in formula (I)

[0312] 10 mg of compound (I) was added to 1 ml of acetone, slurry was prepared, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was crystal form A.

[0313] Example 6: Preparation of the crystal form of compound A shown in formula (I)

[0314] 10 mg of compound (I) was dissolved in 300 μL of THF, and then 450 μL of n-heptane was added. The precipitated solid was slurried at room temperature, centrifuged, and the solid was dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was crystal form A.

[0315] Example 7: Preparation of the crystal form of compound B shown in formula (I)

[0316] 150 mg of compound (I) was added to 1.0 ml of acetonitrile / methanol (V / V = 1:1), slurry was prepared, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as crystal form B. The XRPD spectrum is shown below. Figure 3 As shown in Table 2, the positions of its characteristic peaks are as follows. The DSC spectrum shows endothermic peaks at 182.74℃ and 245.37℃. The TGA spectrum shows a weight loss of 4.57% between 25℃ and 225℃.

[0317] Table 2

[0318]

[0319] Example 8: Preparation of the C crystal form of the compound shown in formula (I)

[0320] 10 mg of compound (I) was added to 1.0 ml of ethanol, stirred at room temperature, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as crystal form C. The XRPD spectrum is shown below. Figure 4 As shown in Table 3, the positions of its characteristic peaks are as follows. The DSC spectrum shows endothermic peaks at 153.48℃, 182.76℃, and 244.05℃. The TGA spectrum shows a weight loss of 3.00% between 25℃ and 215℃.

[0321] Table 3

[0322]

[0323]

[0324] Example 9: Preparation of the C crystal form of the compound shown in formula (I)

[0325] 10 mg of compound (I) was added to 0.9 ml of 10% water / acetone, and the mixture was allowed to evaporate and crystallize to obtain the product. X-ray powder diffraction analysis showed that the product was crystalline form C.

[0326] Example 10: Preparation of crystal form D of the compound shown in formula (I)

[0327] 10 mg of compound (I) was added to 1.0 ml of acetonitrile, slurry was prepared, centrifuged, and the solid was dried under vacuum at 30 °C to obtain the product. X-ray powder diffraction analysis identified the product as crystal form D. The XRPD spectrum is shown below. Figure 5 As shown in Table 4, the positions of its characteristic peaks are as follows. The DSC spectrum shows endothermic peaks at 156.12℃ and 245.38℃. The TGA spectrum shows a weight loss of 1.17% between 25℃ and 205℃.

[0328] Table 4

[0329]

[0330]

[0331] Example 11: Preparation of the E crystal form of the compound shown in formula (I)

[0332] 10 mg of compound (I) was added to 1.0 ml of 10% water / methanol, slurry was prepared, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as crystal form E. The XRPD spectrum is shown below. Figure 6 As shown in Table 5, the positions of its characteristic peaks are as follows. The DSC spectrum shows endothermic peaks at 182.71℃ and 245.00℃. The TGA spectrum shows a weight loss of 0.68% between 25℃ and 235℃.

[0333] Table 5

[0334]

[0335] Example 12: Preparation of the E crystal form of the compound shown in formula (I)

[0336] 10 mg of compound (I) was dissolved in 300 μL of DCM, followed by the addition of 300 μL of n-heptane, resulting in the precipitation of a solid. The solid was then slurried at room temperature, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis confirmed that the product was of crystal form E.

[0337] Example 13: Preparation of crystal form F of compound (I)

[0338] 10 mg of compound (I) was added to 1.0 ml of methanol, slurried at room temperature, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as crystal form F, and the XRPD spectrum is shown below. Figure 7 As shown in Table 6, the positions of its characteristic peaks are as follows. The DSC spectrum shows endothermic peaks at 181.22℃ and 245.03℃. The TGA spectrum shows a weight loss of 8.63% between 25℃ and 210℃.

[0339] Table 6

[0340]

[0341] Example 14: Preparation of crystal form F of compound (I)

[0342] 10 mg of compound (I) was dissolved in 0.3 ml of dichloromethane, and then 0.9 ml of isopropyl acetate was added. A solid precipitated, which was then slurried at room temperature, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was of crystal form F.

[0343] Example 15: Preparation of crystal form F of compound (I)

[0344] 10 mg of compound (I) was dissolved in 900 μL of 1,4-dioxane, and the solution was evaporated to obtain the product. X-ray powder diffraction analysis showed that the product was of crystal form F.

[0345] Example 16: Preparation of the G crystal form of the compound shown in formula (I)

[0346] 10 mg of compound (I) was added to 1.0 mL of 1,2-dichloroethane, stirred at room temperature, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as crystal form G. The XRPD spectrum is shown below. Figure 8 As shown in Table 7, the positions of its characteristic peaks are as follows. The DSC spectrum shows endothermic peaks at 160.43℃, 182.11℃, and 244.42℃. The TGA spectrum shows a weight loss of 9.97% between 25℃ and 235℃.

[0347] Table 7

[0348]

[0349] Example 17: Preparation of the G crystal form of the compound shown in formula (I)

[0350] 10 mg of compound (I) was dissolved in 500 μL of chloroform, and the solution was evaporated to obtain the product. X-ray powder diffraction analysis showed that the product was of crystal form G.

[0351] Example 18: Preparation of the H crystal form of the compound shown in formula (I)

[0352] Approximately 10 mg of compound (I) was added to 1.0 mL of n-hexane, slurried at room temperature, centrifuged, and vacuum dried to obtain the product. X-ray powder diffraction analysis identified the product as crystal form H. The XRPD spectrum is shown below. Figure 9 As shown in Table 8, the positions of its characteristic peaks are as follows. The DSC spectrum shows endothermic peaks at 184.53℃ and 247.90℃. The TGA spectrum shows a weight loss of 4.13% between 25℃ and 215℃.

[0353] Table 8

[0354]

[0355] Example 19: Preparation of crystal form I of compound (I)

[0356] 10 mg of compound (I) was dissolved in 0.4 ml of tetrahydrofuran and allowed to evaporate slowly at room temperature to obtain the product. X-ray powder diffraction analysis identified this product as crystal form I, and the XRPD spectrum is shown below. Figure 10 As shown in Table 9, the positions of its characteristic peaks are as follows. The DSC spectrum shows endothermic peaks at 182.58℃ and 245.04℃. The TGA spectrum shows a weight loss of 5.44% between 25℃ and 225℃.

[0357] Table 9

[0358]

[0359] Example 20: Preparation of crystal form I of compound (I)

[0360] 10 mg of compound (I) was dissolved in 0.3 ml of tetrahydrofuran, followed by the addition of 0.6 ml of water. The solid precipitated, was centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis confirmed that the product was crystal form I.

[0361] Example 21: Preparation of crystal form J of compound (I)

[0362] 10 mg of compound (I) was dissolved in 0.2 ml of DMSO, followed by the addition of 0.2 ml of water. The solid precipitated, was centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as crystal form J. The XRPD spectrum is shown below. Figure 11 As shown in Table 10, the positions of its characteristic peaks are as follows. The DSC spectrum shows endothermic peaks at 154.09℃, 165.41℃, and 247.39℃. The TGA spectrum shows a weight loss of 10.48% between 30℃ and 220℃.

[0363] Table 10

[0364]

[0365]

[0366] Example 22: Preparation of crystal form J of compound (I)

[0367] 10 mg of compound (I) was dissolved in 0.2 ml of DMSO, followed by the addition of 0.4 ml of methyl tert-butyl ether. The solid precipitated out, and the product was obtained by centrifugation and vacuum drying. X-ray powder diffraction analysis showed that the product was crystal form J.

[0368] Example 23: Preparation of the K crystal form of compound shown in formula (I)

[0369] 10 mg of compound (I) was dissolved in 50 μL of N-methylpyrrolidone and allowed to evaporate slowly at room temperature to obtain the product. X-ray powder diffraction analysis identified the product as crystal form K, and the XRPD spectrum is shown below. Figure 12 As shown in Table 11, the positions of its characteristic peaks are as follows.

[0370] Table 11

[0371]

[0372] Example 24: Preparation of the L-crystal form of the compound shown in formula (I)

[0373] 10 mg of compound (I) was dissolved in 200 μL of N,N-dimethylacetamide and allowed to slowly evaporate at room temperature to obtain the product. X-ray powder diffraction analysis identified the product as crystal form L. The XRPD spectrum is shown below. Figure 13 As shown in Table 12, the positions of its characteristic peaks are as follows.

[0374] Table 12

[0375]

[0376] Example 25: Preparation of the crystal form M of the compound shown in formula (I)

[0377] 10 mg of compound A of formula (I) was heated to 225 °C to obtain the product. X-ray powder diffraction analysis identified this product as crystal form M, and the XRPD spectrum is shown below. Figure 14 As shown in Table 13, the positions of its characteristic peaks are as follows.

[0378] Table 13

[0379]

[0380] Example 26: Preparation of the N-crystal form of the compound shown in formula (I)

[0381] 80 mg of the compound shown in formula (I) was added to 4.0 mL of a mixed solvent of ethyl acetate and tetrahydrofuran (V / V = 1:1), heated until dissolved, recrystallized, filtered, and the resulting solid was dried to obtain the product. X-ray powder diffraction analysis identified the product as crystal form N, and the XRPD spectrum is shown below. Figure 15 As shown in Table 14, the positions of its characteristic peaks are as follows. The DSC spectrum shows that the endothermic peaks are at 185.49℃ and 188.82℃. The TGA spectrum shows a weight loss of 4.86% between 30℃ and 225℃.

[0382] Table 14

[0383]

[0384] Example 27: Preparation of the O crystal form of the compound shown in formula (I)

[0385] 60 mg of the compound shown in formula (I) was added to acetonitrile (5 mL), and 16 mg of benzenesulfonic acid was added at room temperature. The reaction was carried out at 80 °C for 8 h. A solid precipitated in the reaction solution. The solid was filtered and dried under vacuum at 45 °C to obtain the product. X-ray powder diffraction analysis identified the product as crystal form O. The XRPD spectrum is shown below. Figure 16 As shown in Table 15, the positions of its characteristic peaks are as follows.

[0386] Table 15

[0387]

[0388]

[0389] Example 28: Preparation of the P-type of the compound shown in formula (I)

[0390] 40 mg of the compound of crystal form C shown in formula (I) was added to 2.0 mL of dioxane, stirred at room temperature, filtered, and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as crystal form P. XRPD analysis showed that... Figure 17 As shown in the figure. The DSC spectrum shows that the endothermic peaks are 127.49℃, 180.10℃, and 249.23℃; the TGA spectrum shows that the weight loss is 8.79% between 40℃ and 230℃.

[0391] Table 16

[0392]

[0393] Example 27: Preparation of the Q crystal form of the compound shown in formula (I)

[0394] 150 mg of the compound shown in formula (I) was added to 3 mL of ethyl acetate, stirred at room temperature, filtered, and the solid was dried under vacuum at 130 °C to obtain the product. X-ray powder diffraction analysis identified the product as crystal form Q, and the XRPD pattern is shown below. Figure 18 As shown in Table 17, the positions of its characteristic peaks are as follows. The DSC spectrum shows endothermic peaks at 188.58℃ and 249.61℃. The TGA spectrum shows a weight loss of 0.54% between 25℃ and 225℃.

[0395] Table 17

[0396]

[0397]

[0398] Example 29: Preparation of the U-form of the compound shown in formula (I)

[0399] 50 mg of compound (I) was dissolved in 0.6 ml of DMSO by heating at 50 °C. 1.2 ml of water was added, and crystals were precipitated. After centrifugation, the solid was washed with 2 ml of water, centrifuged again, and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as crystal form U. The XRPD spectrum is shown below. Figure 19 As shown in Table 18, the positions of its characteristic peaks are as follows. The DSC spectrum shows endothermic peaks at 183.28℃ and 248.22℃. The TGA spectrum shows a weight loss of 0.62% between 40℃ and 215℃.

[0400] Table 18

[0401]

[0402] Example 30: Preparation of the U-form of the compound shown in formula (I)

[0403] 10 mg of the Q crystal form of compound (I) was added to 1.0 ml of water and stirred at room temperature for 1 day to obtain the product. X-ray powder diffraction analysis showed that the product was crystal form U.

[0404] Example 31: Preparation of the crystal form of compound X shown in formula (I)

[0405] 10 mg of compound D (formula I) was mixed with 1.0 ml of n-heptane, stirred at room temperature, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified this product as crystal form X. The XRPD spectrum is shown below. Figure 20 As shown in Table 19, the positions of its characteristic peaks are as follows. The DSC spectrum shows that the endothermic peaks are 158.81℃, 184.14℃, and 249.04℃.

[0406] Table 19

[0407]

[0408] Example 32: Preparation of the Y-type of the compound shown in formula (I)

[0409] 10 mg of compound Q (formula I) was mixed with 1.0 ml of n-heptane, stirred at room temperature, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as crystal form Y. The XRPD spectrum is shown below. Figure 21 As shown in Table 20, the positions of its characteristic peaks are as follows. The DSC spectrum shows that the endothermic peaks have peak values ​​of 184.97℃ and 248.72℃.

[0410] Table 20

[0411]

[0412]

[0413] Example 33: Preparation of the V crystal form of the compound shown in formula (I)

[0414] 200 mg of the compound shown in formula (I) was added to 0.4 mL of N,N-dimethylformamide, followed by 2 mL of acetonitrile. The mixture was stirred at 20–30 °C, filtered, and the filter cake was dried to obtain the product. X-ray powder diffraction analysis identified the product as crystal form V. The XRPD spectrum is shown below. Figure 22 As shown in Table 21, the positions of its characteristic peaks are as follows. The DSC spectrum shows that the endothermic peak has a peak value of 147.78℃. The TGA spectrum shows that the weight loss is 10.73% from 30℃ to 210℃.

[0415] Table 21

[0416]

[0417] Example 34: Preparation of the V crystal form of the compound shown in formula (I)

[0418] 200 mg of the compound shown in formula (I) was added to 1 mL of N,N-dimethylformamide, heated to 60 °C to dissolve, and allowed to cool naturally to 20–30 °C. The mixture was stirred at 20–30 °C, filtered, and the filter cake was washed with 0.2 mL of N,N-dimethylformamide. The filter cake was then dried under reduced pressure at 45 °C for 26 h to obtain the product. X-ray powder diffraction analysis showed that the product was crystal form V.

[0419] Example 35: Preparation of crystal form R of compound (I)

[0420] 8 g of the compound shown in formula (I) was added to 150 mL of tetrahydrofuran, stirred to dissolve, and concentrated under reduced pressure until no fractions appeared, yielding the product. X-ray powder diffraction analysis identified the product as crystal form R, and the XRPD spectrum is shown below. Figure 23 As shown in Table 22, the positions of its characteristic peaks are as follows.

[0421] Table 22

[0422]

[0423] Example 36: Preparation of the S-crystal form of the compound shown in formula (I)

[0424] The compound shown in formula (I) was dissolved in N,N-dimethylformamide by heating, then cooled to precipitate. The precipitate was slurried with acetonitrile and filtered. The filter cake was slurried once with water, filtered again, and dried at 60°C. 1 L of acetonitrile was added, and the mixture was stirred at 20–30°C, filtered, and dried to obtain the product. X-ray powder diffraction analysis identified the product as crystal form S. The XRPD spectrum is shown below. Figure 24 As shown in Table 23, the positions of its characteristic peaks are as follows.

[0425] Table 23

[0426]

[0427]

[0428] Example 37: Preparation of the T-type of the compound shown in formula (I)

[0429] 70.9 g of the compound shown in formula (I) was added to 200 mL of N,N-dimethylformamide, heated to 70-80 °C to dissolve, then cooled to 20-30 °C to precipitate and stirred. The mixture was filtered, and the filter cake was added to 1200 mL of water and stirred, then filtered again. The filter cake was then added to 1200 mL of water and stirred, filtered, and dried at 40-45 °C. 45.0 g of the dried material was added to 450 mL of acetonitrile and magnetically stirred at 20-30 °C for 29 h. The mixture was then filtered and dried under reduced pressure for 17 h to obtain the product. X-ray powder diffraction analysis identified the product as crystal form T. The XRPD spectrum is shown below. Figure 25 As shown in Table 24, the positions of its characteristic peaks are as follows. The DSC spectrum shows that the endothermic peaks have peak values ​​of 164.78℃ and 247.66℃.

[0430] Table 24

[0431]

[0432] Example 38: Hygroscopicity study of the crystal forms D, E, Q and U of the compound shown in formula (I) (October 15, 2021, Nanjing)

[0433] Using Surface Measurement Systems advantage 2, at 25°C and humidity starting from 50%, the humidity range was investigated from 0% to 95%, with a step size of 10%. The judgment criterion was that the mass change dM / dT for each gradient was less than 0.002%, TMAX 360 min, and two cycles were performed.

[0434] Table 25

[0435]

[0436] Example 39: Factors affecting the stability of crystal forms of compounds D, E, Q and U shown in formula (I)

[0437] Each crystal form was laid out flat in the open, and the stability of the samples was investigated under light (4500 Lux), high temperature (40℃, 60℃), and high humidity (RH75%, RH92.5%) conditions. The sampling period was 30 days.

[0438] Table 26

[0439]

[0440]

[0441]

[0442] Conclusion: The influencing factor experiment shows that the crystal forms D, E, Q and U of compound (I) have good physicochemical stability under high humidity conditions of 75% and 92.5%, and the purity decreases slightly under 60℃ and light conditions, but the crystal form does not change.

[0443] Example 40: Long-term / accelerated stability of crystal forms D, E, Q and U of formula (I)

[0444] The stability of compounds D, E, Q and U, as shown in formula (I), was investigated under conditions of 25°C, 60% RH and 40°C, 75% RH, respectively.

[0445] Table 27

[0446]

[0447] Table 28

[0448]

[0449] Table 29

[0450]

[0451] Table 30

[0452]

[0453] Conclusion: The free D, E, Q and U crystal forms exhibit good physical and chemical stability after being placed under long-term accelerated stability conditions for 6 months.

Claims

1. The D-crystal form of the compound shown in formula (I), Formula I, in, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 6.831, 9.845, 13.453, 18.225, 20.117, 20.891, and 23.

006.

2. The D-crystal form of the compound of formula (I) according to claim 1, wherein, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 6.831, 9.845, 10.927, 13.453, 16.096, 18.225, 20.117, 20.891, 23.006, and 26.

132.

3. The D-crystal form of the compound of formula (I) according to claim 1, wherein, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 5.

4. The E crystal form of the compound shown in formula (I), Formula I, in, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 5.864, 7.573, 8.087, 10.003, 16.444, 19.349, and 20.

553.

5. The E-crystal form of the compound of formula (I) according to claim 4, wherein, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 5.864, 7.573, 8.087, 10.003, 12.471, 15.165, 16.444, 17.432, 19.349, and 20.

553.

6. The E crystal form of the compound of formula (I) according to claim 4, wherein, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 5.864, 7.573, 8.087, 10.003, 11.701, 12.471, 15.165, 16.444, 17.432, 19.349, 20.553, 21.067, and 21.

709.

7. The E-crystal form of the compound of formula (I) according to claim 4, wherein, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 6.

8. The J-crystal form of the compound shown in formula (I), Formula I, in, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 5.041, 10.068, 16.424, 20.544, 21.190, 24.077, and 25.

433.

9. The J-crystal form of the compound of formula (I) according to claim 8, wherein, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 5.041, 8.212, 10.068, 14.101, 15.167, 16.424, 20.544, 21.190, 24.077, and 25.

433.

10. The J-crystal form of the compound of formula (I) according to claim 8, wherein, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 5.041, 8.212, 10.068, 14.101, 15.167, 16.424, 20.544, 21.190, 22.036, 22.679, 24.077, 25.433, and 26.

454.

11. The J-crystal form of the compound of formula (I) according to claim 8, wherein, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 11.

12. The Q crystal form of the compound shown in formula (I), Formula I, in, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 5.038, 10.152, 15.850, 16.574, 18.892, 20.760, and 21.

835.

13. The Q crystal form of the compound of formula (I) according to claim 12, wherein, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 5.038, 10.152, 11.175, 15.850, 16.574, 18.892, 20.760, 21.835, 23.905, and 25.

784.

14. The Q crystal form of the compound of formula (I) according to claim 12, wherein, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 5.038, 7.682, 10.152, 11.175, 14.218, 15.850, 16.574, 18.892, 20.760, 21.835, 23.905, 25.784, and 26.

418.

15. The Q crystal form of the compound of formula (I) according to claim 12, wherein, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 18.

16. The U-crystal form of the compound shown in formula (I), Formula I, in, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 14.155, 15.745, 17.314, 17.997, 18.838, 20.512, and 21.

415.

17. The U-crystal form of the compound of formula (I) according to claim 16, wherein, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 14.155, 15.745, 16.564, 17.314, 17.997, 18.838, 20.512, 21.415, 23.557, and 26.

313.

18. The U-crystal form of the compound of formula (I) according to claim 16, wherein, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 7.657, 14.155, 15.745, 16.564, 17.314, 17.997, 18.838, 20.512, 21.415, 23.557, 25.711, 26.313, and 28.

029.

19. The U-crystal form of the compound of formula (I) according to claim 16, wherein, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 19.

20. The V-crystal form of the compound shown in formula (I), Formula I, in, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 5.649, 6.154, 6.720, 11.651, 18.757, 19.813, and 23.

948.

21. The V-crystal form of the compound of formula (I) according to claim 20, wherein, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 5.649, 6.154, 6.720, 9.778, 11.651, 17.570, 18.757, 19.813, 23.948, and 26.

995.

22. The V-crystal form of the compound of formula (I) according to claim 20, wherein, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 5.649, 6.154, 6.720, 9.778, 11.651, 13.576, 17.570, 18.757, 19.813, 21.905, 23.948, 25.825, and 26.

995.

23. The V-crystal form of the compound of formula (I) according to claim 20, wherein, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 22.

24. The crystal form according to any one of claims 1-23, wherein, The error range of the 2θ angle is ±0.

20.

25. A pharmaceutical composition prepared from the crystal form according to any one of claims 1-24.

26. A pharmaceutical composition comprising the crystal form according to any one of claims 1-24 and optionally a pharmaceutically acceptable carrier, diluent, or excipient.

27. A method for preparing a pharmaceutical composition, comprising the step of mixing the crystal form described in any one of 1-24 with a pharmaceutically acceptable carrier, diluent or excipient.

28. Use of the crystal form according to any one of claims 1-24, or the composition according to any one of claims 25-26, or the composition prepared by the method of claim 27, in the preparation of a medicament for treating and / or preventing cancer, wherein the cancer is selected from myeloma.

29. The use according to claim 28, wherein the myeloma is multiple myeloma (MM) and myelodysplastic syndrome (MDS).

30. The use according to claim 29, wherein the multiple myeloma is relapsed, refractory, or resistant.

31. The use according to claim 29, wherein the multiple myeloma is lenalidomide- or pomalidomide-resistant.

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