Crystals of sulfur-containing isoindoline derivatives

Abstract

The present disclosure relates to a crystal of a sulfur-containing isoindoline derivative. Specifically, the present disclosure relates to a crystal of a compound represented by formula (I) and a method for producing the same. [Case 1] TIFF2025503063000067.tif35168

Description

[Technical field]

[0001] This application claims priority to Chinese patent application No. 202210060175.6, filed on January 19, 2022. This application cites the above-mentioned Chinese patent application in full.

[0002] (Technical field) The present invention relates to a crystal of a sulfur-containing isoindoline derivative and a method for producing the same, specifically, to a crystal of a compound represented by formula (I) and a method for producing the same. [Background technology]

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

[0004] Currently, there are four main categories of drugs widely used in clinical practice: domide-based immunomodulators, proteasome inhibitors, hormones, and monoclonal antibodies. Drugs in clinical research include dual antibodies, ADCs, CAR-Ts, etc. These drugs have different mechanisms of action, and in clinical practice, better results may be obtained by using two, three, or even four drugs in combination. Usually, immunomodulators, proteasome inhibitors, and hormones are used in combination, and antibodies are sometimes added. Among them, lenalidomide is the most commonly used immunomodulator and is used in first-line treatment, maintenance treatment after stem cell transplantation, and second- and third-line treatment after relapse. The sales revenue of the above drugs reached $9.7 billion in 2018 / 2019. In addition, the overall MM market is also large and growing rapidly, which is due to the continuous improvement and refinement of MM diagnosis and treatment, and the associated extension of patient survival and treatment duration. The MM market is expected to reach US$33 billion in 2022, with immunomodulatory agents, led by lenalidomide, still accounting for the largest proportion of the market.

[0005] The main mechanism of action of immunomodulators (IMiDs) in the treatment of MM is that IMiD drugs bind to Cereblon (CRBN) protein, then activate the E3 ligase activity of CRBN, and then selectively bind to the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), which leads to the rapid ubiquitination and degradation of Ikaros and Aiolos. Downregulation of Ikaros / Aiolos leads to downregulation of c-Myc, followed by downregulation of IRF4, ultimately leading to the inhibition of myeloma cell proliferation and apoptosis. In addition, IKZF3 can also inhibit the transcription of IL2 and TNF cytokines in T / NK cells, and after IKZF3 is degraded, this inhibition is relieved to promote the release of these cytokines, which can play an immunomodulatory role. Clinical trials have also shown that the clinical benefits of IMiD drugs are also related to the amount of CRBN expression. After knockdown of CRBN in lenalidomide-sensitive cell lines (OPM2 and KMS18), the loss of lenalidomide's ability to inhibit cell proliferation and the emergence of resistance were confirmed, and it was found that the level of CRBN knockdown is related to the degree of drug resistance. In cell proliferation experiments, reducing the intracellular CRBN expression level (U266-CRBN60 and U266-CRBN75) reduced the activity of lenalidomide and pomalidomide to inhibit cell proliferation.

[0006] Currently approved IMiD drugs include thalidomide, lenalidomide, and pomalidomide, all of which are manufactured by Celgene (now part of BMS). The binding ability of the three compounds to CRBN is successively enhanced, leading to successively reduced clinical doses. The main indication for the three compounds is MM, but thalidomide and lenalidomide also have other indications, particularly lenalidomide, which can be used to treat myelodysplastic syndromes (MDS). In terms of side effects, lenalidomide and pomalidomide are similar, with significant bone marrow inhibition effects, and their side effects are target-related toxicity, while thalidomide has other side effects such as sedation, constipation, and neurological side effects.

[0007] The adipimide moiety of all IMiDs binds to a hydrophobic pocket defined by three tryptophan residues (termed the "thalidomide-binding pocket") in CRBN. In contrast, the phthalimide / isoindolone ring is exposed to the solvent, altering the molecular surface of CRBN and thereby modulating substrate recognition. Different IMiDs induce significant modifications on the surface of the CRBN molecule and have different substrate recognition preferences. Thus, modifications of IMiDs may trigger the degradation of other transcription factors and cause unwanted toxic side effects. This mechanism of action of IMiDs, also called molecular glue, vividly describes the binding effect of this small molecule on two protein substrates.

[0008] Since the current median survival time for multiple myeloma is more than 5 years, with the prolonged survival, most patients will experience a high rate of resistance to currently marketed drugs such as lenalidomide and pomalidomide, which will significantly reduce the therapeutic efficacy of these drugs. Therefore, we envision developing drug molecules with better activity to overcome the problem of drug resistance while minimizing the toxic side effects of such compounds.

[0009] Patent applications disclosed related to Cereblon regulators include WO2008115516A2, WO2011100380A1, WO2019226770A1, WO2019014100A1, and WO2020064002A1.

[0010] The applicant's patent application WO2022017365 provides a compound represented by formula (I), whose chemical name is (S)-4-(4-((5-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)pyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile, which has excellent cereblon regulating effect. [ka] [Prior art documents] [Patent documents]

[0011] [Patent Document 1] International Publication No. 2008115516 [Patent Document 2] International Publication No. 2011100380 [Patent Document 3] International Publication No. 2019226770 [Patent Document 4] International Publication No. 2019014100 [Patent Document 5] International Publication No. 2020064002 [Patent Document 6] International Publication No. 202201736 Summary of the Invention [Problem to be solved by the invention]

[0012] In general, the crystal structure of the active ingredient of a drug and its salt not only affects the physical and chemical stability of the drug itself, but also affects the ease and production cost of the subsequent pharmaceutical production, and the crystal structure of the compound and its salt may change depending on the crystallization conditions and storage conditions, and other crystals may be formed in some cases. Therefore, it is necessary to thoroughly consider the crystal of the compound represented by formula (I) from the viewpoints of stability, ease of pharmaceutical production, production cost, etc. [Means for solving the problem]

[0013] (Summary of the invention) The present disclosure provides crystals of a compound represented by formula (I), whose chemical name is (S)-4-(4-((5-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)pyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile, and a method for producing the same. [ka]

[0014] The present disclosure provides an amorphous form of the compound represented by formula (I) that has no significant characteristic peak in the range of diffraction angle 2θ of 2 to 48° in a powder X-ray diffraction pattern.

[0015] The present disclosure further provides a method for preparing an amorphous form of compound of formula (I), comprising: Process 1: a) combining compound of formula (I) with propylene glycol methyl ether, n-heptane or petroleum ether; and b) slurrying to crystallize.

[0016] In some embodiments, the volume (μl) of the solvent described herein 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 of preparing an amorphous form of the compound of Formula (I) described herein further comprises a filtering, washing, or drying step.

[0017] The present disclosure provides a type A crystal of the compound represented by formula (I), in which the powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 5.765, 8.061, 9.925, 16.632, 17.900, 19.469, and 21.115. In some embodiments, the type A crystal of the compound represented by formula (I) has 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-type crystal of the compound of formula (I) has 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 powder X-ray diffraction pattern of the A-type crystal of the compound of formula (I), expressed in terms of diffraction angle 2θ, is as shown in FIG.

[0018] The present disclosure further provides a method 1: a) mixing the compound represented by formula (I) with tetrahydrofuran to dissolve it transparently, and b) adding n-heptane to crystallize it; Alternatively, method 2: mixing the compound represented by formula (I) with dichloromethane to dissolve it transparently, and b) adding ethyl acetate to crystallize it; or method 3: mixing the compound represented by formula (I) with water, isopropyl acetate, acetone, ethyl acetate / ethanol or ethyl acetate / n-heptane, and b) slurrying and crystallizing; The present invention provides a method for producing type A crystals of the compound represented by formula (I), which includes the steps of:

[0019] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing type A crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0020] The present disclosure provides a B-type crystal of the compound represented by formula (I), in which the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 4.977, 6.788, 10.047, 14.143, 15.684, 18.547, and 20.840. In some embodiments, the B-type crystal of the compound represented by 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 powder X-ray diffraction pattern of the B-type crystal of the compound represented by formula (I), expressed in terms of the 2θ angle of the diffraction angle, is as shown in FIG.

[0021] The present disclosure further provides a process for the preparation of the compound of formula (I) comprising: a) mixing the compound of formula (I) with ethyl acetate or acetonitrile / methanol; and b) slurrying and crystallizing the compound and drying at 30° C. The present invention provides a method for producing type B crystals of the compound represented by formula (I), comprising:

[0022] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing type B crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0023] The present disclosure provides a C-type crystal of the compound represented by formula (I), in which the powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 5.653, 7.974, 9.989, 16.143, 17.860, 18.992, and 20.972. In some embodiments, the C-type crystal of the compound represented by 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-type crystals of the compound of formula (I) have 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 powder X-ray diffraction pattern of the C-type crystals of the compound of formula (I), expressed in terms of the 2θ angle of the diffraction angle, is as shown in FIG.

[0024] The disclosure further provides Method 1: a) mixing the compound of formula I with ethanol, isopropanol, methyl tert-butyl ether, methyl isobutyl ketone, water / ethanol, water / isopropanol, water / methanol (1:1), cyclohexane, isopropyl ether, and b) slurrying to effect crystallization; Alternatively, method 2: A method of mixing the compound represented by formula (I) with dichloromethane, water / acetone, or tetrahydrofuran / ethanol, stirring to dissolve it transparently, and b) evaporating it to crystallize it. The present invention provides a method for producing a C-type crystal of the compound represented by formula (I), which includes the steps of:

[0025] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing C-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0026] The present disclosure provides a D-type crystal of the compound represented by formula (I), in which the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 6.831, 9.845, 13.453, 18.225, 20.117, 20.891, and 23.006. In some embodiments, the D-type crystal of the compound represented by 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 powder X-ray diffraction pattern of the D-type crystal of the compound represented by formula (I), expressed in terms of the 2θ angle of the diffraction angle, is as shown in FIG.

[0027] The present disclosure further provides a method of producing a compound of formula (I) comprising the steps of: a) mixing the compound of formula (I) with acetonitrile; and b) slurrying and crystallizing the compound of formula (I). The present invention provides a method for producing a D-type crystal of the compound represented by formula (I), comprising:

[0028] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing type D crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0029] The present disclosure provides a type E crystal of the compound represented by formula (I), in which the powder X-ray diffraction pattern expressed in terms of 2θ angles has characteristic peaks at 5.864, 7.573, 8.087, 10.003, 16.444, 19.349, and 20.553. In some embodiments, the type E crystal of the compound represented by 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-type crystals of the compound of formula (I) have 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 powder X-ray diffraction pattern of the E-type crystals of the compound of formula (I), expressed in terms of the 2θ angle of the diffraction angle, is as shown in FIG.

[0030] The present disclosure further provides Method 1: a) mixing the compound of formula (I) with 2-butanone or 10% water / methanol, and b) slurrying and crystallizing; Alternatively, Method 2: A method of mixing the compound represented by formula (I) with DCM, dissolving it transparently, and b) adding n-heptane to crystallize it. The present invention provides a method for producing type E crystals of the compound represented by formula (I), which includes the steps of:

[0031] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing type E crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0032] The present disclosure provides a crystalline form of the compound represented by formula (I), in which the powder X-ray diffraction pattern, expressed in terms of diffraction angles of 2θ, has characteristic peaks at 5.062, 7.820, 10.077, 14.231, 16.672, 18.586, and 20.435. In some embodiments, the crystalline form of the compound represented by formula (I) has 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-type crystals of the compound of formula (I) have 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 powder X-ray diffraction pattern of the F-type crystals of the compound of formula (I), expressed in terms of the 2θ angle of the diffraction angle, is as shown in FIG.

[0033] The present disclosure further provides a process 1: a) mixing the compound represented by formula (I) with a solvent II, wherein the solvent II is selected from p-xylene, methanol, 2-methyltetrahydrofuran, o-xylene, or toluene; and b) slurrying and crystallizing the compound; Alternatively, method 2: mixing the compound represented by formula (I) with dichloromethane or tetrahydrofuran to dissolve it transparently, and b) adding isopropyl acetate, methyl tert-butyl ether or methyl isobutyl ketone to crystallize it; Alternatively, method 3: A method of mixing the compound represented by formula (I) with 1,4-dioxane, dissolving it transparently, and b) evaporating it to crystallize it. The present invention provides a method for producing an F-type crystal of the compound represented by formula (I), which includes the steps of:

[0034] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing the F-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0035] The present disclosure provides a G-type crystal of the compound represented by formula (I), in which the powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 5.999, 7.972, 9.951, 11.388, 17.812, 20.975, and 25.819. In some embodiments, the G-type crystal of the compound represented by formula (I) has 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-type crystal of the compound of 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 powder X-ray diffraction pattern of the G-type crystal of the compound of formula (I), expressed in terms of the 2θ angle of the diffraction angle, is as shown in FIG.

[0036] The present disclosure further provides a method of: a) mixing the compound represented by formula (I) with chloroform to dissolve it transparently; and b) evaporating and crystallizing it; Alternatively, method 2: mixing the compound represented by formula (I) with 1,2-dichloroethane, and b) slurrying and crystallizing the mixture; The present invention provides a method for producing a G-type crystal of the compound represented by formula (I), comprising:

[0037] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing the G-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0038] The present disclosure provides a crystalline form of the compound represented by formula (I), having a powder X-ray diffraction pattern, expressed in terms of diffraction angles 2θ, with characteristic peaks at 5.758, 7.533, 9.901, 14.267, 16.420, 18.103, and 26.356, and in some embodiments, the crystalline form of the compound represented by 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-form crystal of the compound of 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 powder X-ray diffraction pattern of the H-form crystal of the compound of formula (I), expressed in terms of diffraction angle 2θ, is as shown in FIG.

[0039] The present disclosure further provides a method for crystallization comprising: Method 1: mixing the compound represented by formula (I) with n-octane or n-hexane; and b) slurrying the compound; The present invention provides a method for producing an H-type crystal of the compound represented by formula (I), comprising:

[0040] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing H-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0041] The present disclosure provides a type I crystal of the compound represented by formula (I), which has a powder X-ray diffraction pattern expressed in terms of 2θ angles of diffraction angle, with characteristic peaks at 5.294, 6.826, 7.564, 10.739, 13.699, 16.812 and 20.709. In some embodiments, the powder X-ray diffraction pattern of the type I crystal of the compound represented by formula (I), expressed in terms of 2θ angles of diffraction angle, is as shown in FIG.

[0042] The present disclosure further provides a method of: a) mixing the compound represented by formula (I) with tetrahydrofuran to dissolve it transparently; and b) evaporating and crystallizing it; Alternatively, method 2: mixing the compound represented by formula (I) with tetrahydrofuran to dissolve it transparently, and b) adding water to crystallize it; The present invention provides a method for producing type I crystals of the compound represented by formula (I), comprising:

[0043] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing type I crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0044] The present disclosure provides a type J crystal of the compound represented by formula (I), in which the powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 5.041, 10.068, 16.424, 20.544, 21.190, 24.077, and 25.433. In some embodiments, the type J crystal of the compound represented by formula (I) has 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-type crystals of the compound of formula (I) have 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 powder X-ray diffraction pattern of the J-type crystals of the compound of formula (I), expressed in terms of 2θ angles of diffraction angles, is as shown in FIG.

[0045] The present disclosure further provides a method of: a) mixing the compound represented by formula (I) with dimethyl sulfoxide to dissolve it transparently; and b) adding water, isopropyl acetate or methyl tert-butyl ether to crystallize the compound; The present invention provides a method for producing a J-type crystal of the compound represented by formula (I), comprising:

[0046] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing type J crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0047] The present disclosure provides a K-type crystal of the compound represented by formula (I), in which the powder X-ray diffraction pattern expressed in terms of 2θ angles of the diffraction angle has characteristic peaks at 5.156, 7.699, 10.339, 14.334, 16.203, 18.327, and 23.418. In some embodiments, the K-type crystal of the compound represented by 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 powder X-ray diffraction pattern of the K-type crystal of the compound represented by formula (I), expressed in terms of 2θ angles of the diffraction angle, is as shown in FIG.

[0048] The present disclosure further provides a method of: a) mixing the compound represented by formula (I) with N-methylpyrrolidone to dissolve it transparently; and b) volatilizing and crystallizing the compound; The present invention provides a method for producing a K-type crystal of the compound represented by formula (I), comprising:

[0049] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing type K crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0050] The present disclosure provides a crystalline form of the compound of formula (I), in which the X-ray powder diffraction pattern, expressed in terms of the 2θ angle of the diffraction angle, has characteristic peaks at 4.932, 5.360, 9.831, 14.844, 18.244, 20.104, and 24.914. In some embodiments, the X-ray powder diffraction pattern, expressed in terms of the 2θ angle of the diffraction angle of the compound of 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, expressed in terms of the 2θ angle of the diffraction angle of the compound of formula (I), is as shown in FIG.

[0051] The present disclosure further provides a method of: a) mixing the compound represented by formula (I) with N,N-dimethylacetamide to dissolve it transparently; and b) volatilizing and crystallizing the compound; The present invention provides a method for producing an L-type crystal of the compound represented by formula (I), comprising:

[0052] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing the L-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0053] The present disclosure provides a type M crystal of the compound represented by formula (I), in which the powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 14.959, 16.322, 18.410, 20.748, 22.067, 23.670, and 26.863. In some embodiments, the type M crystal of the compound represented by formula (I) has 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-type crystal of the compound of formula (I) has 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 powder X-ray diffraction pattern of the M-type crystal of the compound of formula (I), expressed in terms of the 2θ angle of the diffraction angle, is as shown in FIG.

[0054] The present disclosure further provides a method of producing a compound represented by formula (I), comprising the steps of: a) heating a type A crystal, a type B crystal, a type C crystal, a type E crystal, a type H crystal, or a type I crystal to 225° C.; The present invention provides a method for producing an M-type crystal of a compound represented by formula (I), comprising:

[0055] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing M-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0056] The present disclosure provides a crystalline form of the compound of formula (I) having a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angles, which has characteristic peaks at 5.028, 9.942, 10.900, 15.428, 18.410, 20.274, and 25.252. In some embodiments, the crystalline form of the compound of formula (I) has 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-type crystal of the compound represented by formula (I) has 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 powder X-ray diffraction pattern of the N-type crystal of the compound represented by formula (I), expressed in terms of the 2θ angle of the diffraction angle, is as shown in FIG.

[0057] The present disclosure further provides a method of preparing the compound of formula (I) by: a) mixing the compound of formula (I) with ethyl acetate / tetrahydrofuran (1:1) and heating to obtain a clear solution; and b) cooling to obtain crystallization. The present invention provides a method for producing N-type crystals of the compound represented by formula (I), comprising:

[0058] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing N-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0059] The present disclosure provides a type O crystal of the compound represented by formula (I), in which the powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 11.796, 17.423, 18.081, 19.136, 21.707, 22.165, and 25.719. In some embodiments, the type O crystal of the compound represented by 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-type crystals of the compound of formula (I) have 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 powder X-ray diffraction pattern of the O-type crystals of the compound of formula (I), expressed in terms of the 2θ angle of the diffraction angle, is as shown in FIG.

[0060] The present disclosure further provides a method for crystallization comprising: a) mixing the compound represented by formula (I) with acetonitrile and benzenesulfonic acid, heating the mixture, and b) cooling the mixture to crystallize the compound; The present invention provides a method for producing an O-type crystal of a compound represented by formula (I), comprising:

[0061] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing O-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0062] The present disclosure provides a P-type crystal of the compound represented by formula (I), in which the powder X-ray diffraction pattern, expressed in terms of diffraction angles 2θ, has characteristic peaks at 5.359, 7.491, 10.786, 14.249, 16.527, 17.729, and 20.798. In some embodiments, the P-type crystal of the compound represented by formula (I) has 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-type crystal of the compound represented by Formula (I) has 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 powder X-ray diffraction pattern of the P-type crystal of the compound represented by Formula (I), expressed in terms of diffraction angle 2θ, is as shown in FIG.

[0063] The present disclosure further provides a method for crystallization comprising: a) mixing the C-type crystals of the compound represented by formula (I) with 1,4-dioxane; and b) slurrying the mixture to crystallize the compound. The present invention provides a method for producing P-type crystals of the compound represented by formula (I), comprising:

[0064] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing P-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0065] The present disclosure provides a Q-type crystal of the compound of formula (I), in which the powder X-ray diffraction pattern, expressed in terms of diffraction angles of 2θ, has characteristic peaks at 5.038, 10.152, 15.850, 16.574, 18.892, 20.760, and 21.835. In some embodiments, the Q-type crystal of the compound of formula (I) has 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-type crystal of the compound of 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 powder X-ray diffraction pattern of the Q-type crystal of the compound of formula (I), expressed in terms of the 2θ angle of the diffraction angle, is as shown in FIG.

[0066] The present disclosure further provides Method 1: a) mixing the compound of formula (I) with ethyl acetate; b) slurrying to crystallize and drying the solid at 70° C. or 130° C.; The present invention provides a method for producing a Q-type crystal of a compound represented by formula (I), comprising:

[0067] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing type Q crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0068] The present disclosure provides a U-type crystal of the compound represented by formula (I), in which the powder X-ray diffraction pattern expressed in terms of 2θ angles has characteristic peaks at 14.155, 15.745, 17.314, 17.997, 18.838, 20.512, and 21.415. In some embodiments, the U-type crystal of the compound represented by formula (I) has 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-shaped crystal of the compound of formula (I) has 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 powder X-ray diffraction pattern of the U-shaped crystal of the compound of formula (I), expressed in terms of the 2θ angle of the diffraction angle, is as shown in FIG.

[0069] The present disclosure further provides a method for producing a compound represented by formula (I) by crystallization using the following method: Method 1: a) mixing the Q-type crystal of the compound represented by formula (I) with water; and b) slurrying the resulting crystallized product; Alternatively, method 2: a) mixing the compound represented by formula (I) with DMSO, dissolving by heating, and b) adding water to crystallize; The present invention provides a method for producing a U-type crystal of a compound represented by formula (I), comprising:

[0070] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing U-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0071] The present disclosure provides a crystalline form X of the compound represented by formula (I), which has characteristic peaks at 6.864, 9.873, 10.963, 13.801, 16.089, 18.006, and 20.929 in the powder X-ray diffraction pattern expressed in 2θ angles of the diffraction angle. In some embodiments, the crystalline form X of the compound represented by formula (I) has characteristic peaks at 6.864, 9.873, 10.963, 13.801, 16.089, 18.006, 20.929, and 26.203. In some embodiments, the crystalline form X of the compound represented by formula (I), which has characteristic peaks at 6.864, 9.873, 10.963, 13.801, 16.089, 18.006, 20.929, and 26.203 in the powder X-ray diffraction pattern expressed in 2θ angles of the diffraction angle, is as shown in FIG. 20.

[0072] The present disclosure further provides a method for crystallization comprising: Method 1: a) mixing the D-type crystals of the compound represented by formula (I) with isopropyl ether or n-heptane; and b) slurrying the mixture to crystallize the resulting product; The present invention provides a method for producing type X crystals of the compound represented by formula (I), comprising:

[0073] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing type X crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0074] The present disclosure provides a type Y crystal of the compound represented by formula (I), in which the powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 5.676, 7.666, 14.260, 16.562, 18.020, 21.802, and 26.425. In some embodiments, the type Y crystal of the compound represented by 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-type crystal of the compound of formula (I) has 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 powder X-ray diffraction pattern of the Y-type crystal of the compound of formula (I), expressed in terms of the 2θ angle of the diffraction angle, is as shown in FIG.

[0075] The present disclosure further provides a method for crystallization comprising: a) mixing the Q-type crystals of the compound of formula (I) with isopropyl ether or n-heptane; and b) slurrying the mixture to crystallize the compound of formula (I). The present invention provides a method for producing type Y crystals of the compound represented by formula (I), comprising:

[0076] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing type Y crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0077] The present disclosure provides a type V crystal of the compound represented by formula (I), in which the powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 5.649, 6.154, 6.720, 11.651, 18.757, 19.813, and 23.948. In some embodiments, the type V crystal of the compound represented by 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-type crystal of the compound of formula (I) has 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 powder X-ray diffraction pattern of the V-type crystal of the compound of formula (I), expressed in terms of the 2θ angle of the diffraction angle, is as shown in FIG.

[0078] The present disclosure further provides a method 1: a) mixing the compound represented by formula (I) with N,N-dimethylformamide to dissolve it transparently, and b) adding acetone or acetonitrile to crystallize it; Alternatively, method 2: mixing the compound of formula I with N,N-dimethylformamide, and b) cooling or stirring to crystallize; The present invention provides a method for producing type V crystals of the compound represented by formula (I), comprising:

[0079] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing type V crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0080] The present disclosure provides a R-type crystal of the compound represented by formula (I), in which the powder X-ray diffraction pattern expressed in terms of 2θ angles has characteristic peaks at 5.534, 7.611, 10.033, 15.782, 17.101, 19.017, and 20.567. In some embodiments, the R-type crystal of the compound represented by 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-type crystals of the compound of formula (I) have 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 powder X-ray diffraction pattern of the R-type crystals of the compound of formula (I), expressed in terms of the 2θ angle of the diffraction angle, is as shown in FIG.

[0081] The present disclosure further provides a method of producing a compound of formula (I) by: a) mixing and dissolving the compound of formula (I) in tetrahydrofuran; and b) concentrating and crystallizing the compound of formula (I). The present invention provides a method for producing an R-type crystal of the compound represented by formula (I), comprising:

[0082] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing R-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0083] The present disclosure provides a crystalline form S of the compound represented by formula (I), in which the powder X-ray diffraction pattern, expressed in terms of diffraction angles of 2θ, has characteristic peaks at 6.576, 9.082, 10.921, 13.592, 19.965, 21.403, and 24.207. In some embodiments, the crystalline form S of the compound represented by 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-form crystal of the compound of formula (I) has 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 powder X-ray diffraction pattern of the S-form crystal of the compound of formula (I), expressed in terms of diffraction angle 2θ, is as shown in FIG.

[0084] The disclosure further provides Method 1: a) mixing compound of formula (I) with DMF, heating to dissolve, cooling to precipitate, b) filtering, mixing the cake with acetonitrile and slurrying, c) filtering, mixing the cake with water and slurrying, d) filtering, drying, then slurrying with acetonitrile to crystallize and drying; The present invention provides a method for producing an S-type crystal of the compound represented by formula (I), comprising:

[0085] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing the S-type crystal of the compound represented by formula (I) described herein further includes a step such as filtration, washing, or drying.

[0086] The present disclosure provides a T-type crystal of the compound represented by formula (I), in which the powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 6.915, 9.177, 9.984, 11.012, 13.595, 16.156, and 20.138. In some embodiments, the T-type crystal of the compound represented by 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-type crystals of the compound of formula (I) have 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 powder X-ray diffraction pattern of the T-type crystals of the compound of formula (I), expressed in terms of the 2θ angle of the diffraction angle, is as shown in FIG.

[0087] The disclosure further provides Method 1: a) mixing the compound of formula (I) with DMF, heating to dissolve, cooling to crystallize, b) filtering, mixing the cake with water and stirring, c) filtering, mixing the cake with more water and stirring, d) filtering, drying, then mixing with acetonitrile, stirring to crystallize, and drying; The present invention provides a method for producing a T-type crystal of the compound represented by formula (I), comprising:

[0088] In some embodiments, the volume (μl) of the solvent described herein may be 1 to 200 times the mass (mg) of the compound represented by 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 producing T-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0089] The present disclosure further provides a pharmaceutical composition prepared from the crystals of the compound represented by formula (I).

[0090] The present disclosure further provides a pharmaceutical composition comprising said crystal and optionally a pharma- ceutically acceptable carrier, diluent or excipient.

[0091] The present disclosure further provides a method for preparing a pharmaceutical composition comprising the step of mixing said crystals with a pharma- ceutically acceptable carrier, diluent or excipient.

[0092] The present disclosure further provides the use of said crystal, or said composition, or a composition produced by said method, in the manufacture of a medicament for treating and / or preventing a disease associated with a CRBN protein.

[0093] The disclosure further provides the use of said crystals, or said composition, or a composition produced by said method, in the manufacture of a medicament for treating and / or preventing cancer, angiogenesis-related disorders, 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 diseases, preferably in the manufacture of a medicament for treating and / or preventing cancer or CNS damage.

[0094] In some embodiments, the cancer is selected from leukemia, myeloma, lymphoma, melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, 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 cancer, ureteral cancer, prostate cancer, seminoma, testicular tumor, head and neck tumor, head and neck squamous cell carcinoma, endometrial cancer, thyroid cancer, sarcoma, osteoma, neuroblastoma, neuroendocrine cancer, 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.

[0095] In some embodiments, the myeloma is multiple myeloma (MM) and myelodysplastic syndromes (MDS), preferably, the multiple myeloma is relapsed, refractory or resistant.

[0096] In some embodiments, the multiple myeloma is refractory or resistant to lenalidomide and pomalidomide.

[0097] The term "2θ or 2θ angle" as used herein refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degrees. The error range of each characteristic peak 2θ is ±0.20 (including cases where numbers beyond the first decimal place are rounded up or down), and specifically includes -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.1 It may be 0, -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, or 0.20.

[0098] According to the "9103 Guideline for Hygroscopicity of Medicines" in the 2015 edition of Part IV of the "Chinese Pharmacopoeia", the description of hygroscopic properties and hygroscopic weight gain are defined as follows: Deliquescence: Absorbing enough water to form a liquid; Very hygroscopic: Weight gain on moisture is 15% or more; Hygroscopic: Weight increase due to moisture absorption is less than 15% and more than 2%; Slightly hygroscopic: The weight gain due to moisture absorption is less than 2% and more than 0.2%; Not or barely hygroscopic: Weight increase due to moisture absorption is less than 0.2%.

[0099] "Differential scanning calorimetry or DSC" in the present disclosure refers to measuring the temperature difference, heat flow difference between a sample and a reference material during the heating or isothermal process of the sample to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.

[0100] The drying temperature described in the present disclosure is generally 25° C. to 150° C., and preferably 40° C. to 80° C., and drying may be performed at normal pressure or under reduced pressure.

[0101] A "pharmaceutical composition" refers to a mixture containing one or more compounds of formula (I) as described herein or pharma- ceutically acceptable salts thereof and other chemical components, as well as other components such as pharma- ceutically acceptable carriers and excipients. The purpose of a "pharmaceutical composition" is to facilitate administration to an organism and facilitate absorption of the active ingredient, thereby exerting a biological activity.

[0102] The crystals described herein include, but are not limited to, solvates of the compound represented by formula (I), and 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, dimethylsulfoxide, 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.

[0103] A "solvate" as used herein includes, but is not limited to, a complex formed by combining a compound represented by Formula (I) with a solvent. [Brief description of the drawings]

[0104] [Figure 1] 1 is an amorphous XRPD pattern of the compound represented by formula (I). [Diagram 2] 1 is an XRPD pattern of crystal form A of the compound represented by formula (I). [Diagram 3] 1 is an XRPD pattern of the B-type crystals of the compound represented by formula (I). [Figure 4] 1 is an XRPD pattern of the C-type crystal of the compound represented by formula (I). [Diagram 5] 1 is an XRPD pattern of the D-type crystal of the compound represented by formula (I). [Figure 6] 1 is an XRPD pattern of E-type crystals of the compound represented by formula (I). [Figure 7] 1 is an XRPD pattern of the F-type crystal of the compound represented by formula (I). [Figure 8] 1 is an XRPD pattern of the G-type crystal of the compound represented by formula (I). [Figure 9] 1 is an XRPD pattern of H-type crystals of the compound represented by formula (I). [Figure 10] 1 is an XRPD pattern of type I crystals of the compound represented by formula (I). [Figure 11] 1 is an XRPD pattern of type J crystal of the compound represented by formula (I). [Figure 12] 1 is an XRPD pattern of the K-type crystal of the compound represented by formula (I). [Figure 13] 1 is an XRPD pattern of the L-type crystal of the compound represented by formula (I). [Figure 14] 1 is an XRPD pattern of M-type crystals of the compound represented by formula (I). [Figure 15] 1 is an XRPD pattern of N-type crystals of the compound represented by formula (I). [Figure 16] 1 is an XRPD pattern of O-type crystals of the compound represented by formula (I). [Figure 17] 1 is an XRPD pattern of P-type crystals of the compound represented by formula (I). [Figure 18] 1 is an XRPD pattern of the Q-type crystal of the compound represented by formula (I). [Figure 19] 1 is an XRPD pattern of U-type crystals of the compound represented by formula (I). [Figure 20] 1 is an XRPD pattern of the X-type crystal of the compound represented by formula (I). [Figure 21] 1 is an XRPD pattern of the Y-type crystal of the compound represented by formula (I). [Figure 22] 1 is an XRPD pattern of type V crystals of the compound represented by formula (I). [Figure 23] 1 is an XRPD pattern of the R-type crystal of the compound represented by formula (I). [Figure 24] 1 is an XRPD pattern of the S-form crystal of the compound represented by formula (I). [Diagram 25] 1 is an XRPD pattern of the T-type crystal of the compound represented by formula (I). [Figure 26] 1 shows efficacy data for the compound of Example 1 and control CC-92480 against NCI-H929 xenograft tumors in CB-17 SCID mice. [Figure 27] Effect of the compound of Example 1 and control CC-92480 on body weight in CB-17 SCID mice. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0105] Hereinafter, the present invention will be described in more detail with reference to examples or experimental examples. However, the examples or experimental examples of the present disclosure are only used to illustrate the technical solutions of the present disclosure, and are not intended to limit the essence and scope of the present disclosure.

[0106] In the examples of this disclosure, the experimental methods for which no specific conditions are described follow the usual conditions or those recommended by the manufacturers of the raw materials or products. Reagents for which no specific source is indicated are ordinary reagents purchased on the market.

[0107] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) are 10 -6 The units are expressed in ppm. NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic resonance spectrometer, with the measurement solvents being deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0108] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0109] High performance liquid chromatography (HPLC) analyses are performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatographs.

[0110] Chiral HPLC analytical measurements are performed using an Agilent 1260 DAD high performance liquid chromatograph.

[0111] Preparative high performance liquid chromatography is performed using Waters 2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs.

[0112] Preparative chiral chromatography uses a Shimadzu LC-20AP preparative chromatograph.

[0113] The CombiFlash flash chromatograph used is Combiflash Rf200 (TELEDYNE ISCO).

[0114] Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate, thin layer chromatography (TLC) uses silica gel plate with specifications of 0.15mm~0.2mm, thin layer chromatography separation and purification of products uses silica gel plate with specifications of 0.4mm~0.5mm.

[0115] In silica gel column chromatography, Yantai Yellow Sea silica gel 200-300 mesh silica gel is generally used as the carrier.

[0116] Mean kinase inhibition rate and IC 50 Values ​​are measured using a NovoStar microplate reader (BMG, Germany).

[0117] Known starting materials of the present disclosure can be synthesized by methods known in the art or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Shanghai Darui Fine Chemicals Co., Ltd. Unless otherwise specified in the examples, all reactions can be carried out under an argon gas atmosphere or a nitrogen gas atmosphere.

[0118] An argon gas atmosphere or nitrogen gas atmosphere refers to connecting the reaction bottle to a balloon of argon gas or nitrogen gas with a volume of about 1 L.

[0119] A hydrogen gas atmosphere refers to connecting the reaction bottle to a balloon of hydrogen gas with a volume of approximately 1 L.

[0120] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0121] The hydrogenation reaction is usually performed by evacuating and filling with hydrogen gas three times.

[0122] Microwave reactions use a CEM Discover-S 908860 microwave reactor.

[0123] Unless otherwise specified in the examples, solutions refer to aqueous solutions.

[0124] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0125] In the examples, the reaction process is monitored by thin layer chromatography (TLC). The developer used in the reaction, the eluent system of column chromatography used for purifying the compound, and the developer system of thin layer chromatography include A: n-hexane / ethyl acetate system, B: dichloromethane / methanol system, and the volume ratio of the solvents is adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of a basic or acidic reagent such as triethylamine or acetic acid.

[0126] Measurement conditions of the equipment used in the experiments of this disclosure:

[0127] 1. Differential Scanning Calorimeter (DSC) Instrument model: Mettler Toledo DSC 3+STARe System Purge gas: Nitrogen gas; Nitrogen gas purge rate: 50mL / min Heating rate: 10.0℃ / min Temperature range: 25~350℃

[0128] 2. X-ray Powder Diffraction (XRPD) Instrument model: BRUKER D8 Discover X-ray powder diffractometer Radiation: Monochromatic Cu-Kα ray (λ=1.5418Å) Scanning mode: θ / 2θ, Scanning range (2θ range): 3~50° Voltage: 40kV, Current: 40mA

[0129] 3. Thermogravimetric Analysis (TGA) Instrument model: Mettler Toledo TGA2 Purge gas: Nitrogen gas; Nitrogen gas purge rate: 50mL / min Heating rate: 10.0℃ / min Temperature range: 25~350℃

[0130] Example 1: Preparation of a compound represented by formula (I) (S)-4-(4-((5-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)pyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile (Compound 1) [ka]

[0131] [ka]

[0132] Step 1 tert-Butyl 4-((5-formylpyridin-2-yl)thio)piperidine-1-carboxylate 1b 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 solution was heated to 80° C. and reacted for 1 hour. The reaction solution was diluted with water (30 mL), 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, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using elution system B to obtain the title compound 1b (1.0 g, yield: 96%). MS m / z (ESI): 267.1 [M-55].

[0133] Step 2 6-(Piperidin-4-ylthio)nicotinaldehyde trifluoroacetate 1c Compound 1b (950 mg, 2.95 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was slowly added under ice bath, and the mixture was reacted for 1 hour. The reaction solution was concentrated and dried to obtain the title compound 1c, and the crude product was used directly in the next step without purification. MS m / z (ESI): 223.1 [M+1].

[0134] Step 3 3-Fluoro-4-(4-((5-formylpyridin-2-yl)thio)piperidin-1-yl)benzonitrile 1d 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), the reaction solution was heated to 80 ° C. and reacted overnight. Water (50 mL) was added to the reaction solution, 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, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography using elution system B to obtain the title compound 1d (850 mg, yield: 84%). MS m / z (ESI): 342.1 [M+1].

[0135] Step 4 3-Fluoro-4-(4-((5-(hydroxymethyl)pyridin-2-yl)thio)piperidin-1-yl)benzonitrile 1e Compound 1d (600mg, 1.76mmol) was added to methanol (10mL) under ice bath, sodium borohydride (133mg, 3.51mmol) was slowly added, and the mixture was reacted for 1 hour. The reaction solution was quenched with water (10mL), then extracted with ethyl acetate (30mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using elution system B to obtain the title compound 1e (580mg, yield: 96%). MS m / z (ESI): 344.1 [M+1].

[0136] Step 5 4-(4-((5-(bromomethyl)pyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile 1f Compound 1e (200 mg, 0.582 mmol) was added to dichloromethane (6 mL), and triphenylphosphine (199 mg, 0.757 mmol) and carbon tetrabromide (251 mg, 0.757 mmol) were added in sequence, and the mixture was allowed to react for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography using eluent system B to obtain the title compound 1f (190 mg, yield: 80%). MS m / z (ESI):406.0 [M+1];408.0 [M+3].

[0137] Step 6 tert-Butyl (S)-5-amino-4-(4-((6-((1-(4-cyano-2-fluorophenyl)piperidin-4-yl)thio)pyridin-3-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoic acid 1g tert-Butyl (S)-5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoic acid 1-3a (82 mg, 0.246 mmol, prepared using the usual method "Journal of Medicinal Chemistry, 2020, 63 (13), 6648-6676"), anhydrous potassium carbonate (65 mg, 0.468 mmol) was added to N,N-dimethylformamide (3 mL), compound 1f (95 mg, 0.244 mmol) was added, and the reaction was carried out for 2 hours. The reaction solution was poured into ice water (10 mL), then 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, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using elution system B to obtain the title compound 1g (145 mg, yield: 94%). MS m / z (ESI): 660.2 [M+1].

[0138] Step 7 (S)-4-(4-((5-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)pyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile 1 Compound 1g (60 mg, 0.091 mmol) was added to acetonitrile (5 mL), and benzenesulfonic acid (16 mg, 0.091 mmol) was added at room temperature, followed by reaction at 80° C. for 8 hours. The reaction solution was decompressed to remove the solvent, and the resulting residue was subjected to preparative high performance liquid chromatography (Gilson GX-281, elution system: 10 mmol / L aqueous solution of ammonium hydrogen carbonate and acetonitrile, acetonitrile gradient: 60% to 80%, flow rate: 30 mL / min) to obtain the title compound 1 (42 mg, yield: 78%). When detected using a powder X-ray diffractometer, the title compound 1 was found to be amorphous. MS m / z (ESI): 586.4 [M+1]. 1H NMR (500 MHz, DMSO-d6): δ 10.98 (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).

[0139] Biological evaluation

[0140] Test Example 1 Biological evaluation of NCI-H929 proliferation experiment The following method was used to measure the inhibitory activity of the compounds of the present disclosure against the proliferation of NCI-H929 cells. The experimental method is briefly described below.

[0141] NCI-H929 cells (ATCC, CRL-9068) were cultured in complete medium, i.e., RPMI1640 medium (Hyclone, SH30809.01) containing 10% fetal bovine serum (Corning, 35-076-CV) and 0.05 mM 2-mercaptoethanol (Sigma, M3148). On the first day of the experiment, NCI-H929 cells were seeded in a 96-well plate at a density of 6000 cells / well using complete medium, and 100 μL of cell suspension was added per well, and at the same time, 10 μL of gradient-diluted test compound prepared in complete medium was added to each well, in which the compound was first dissolved in DMSO at a starting concentration of 10 mM, and then gradient-diluted at 5-fold concentrations, for a total of 9 concentrations, and the blank control was 100% DMSO. In addition, 5 μL of the compound dissolved in DMSO was added to 95 μL of complete medium, i.e., the compound was diluted 20-fold in complete medium. Finally, 10 μL / well of the compound diluted in complete medium was added to the cell suspension, i.e., the final concentration of the compound was 9 concentration points obtained by 5-fold gradient dilution starting from 50 μM, and a blank control containing 0.5% DMSO was set up, and the cells were cultured at 37°C and 5% CO2 in a cell incubator for 5 days. On the 6th day, the 96-well cell culture plate was taken out, and 50 μL of CellTiter-Glo® Luminescent Cell Activity Detection Reagent (Promega, G7573) was added to each well, and the plate was left at room temperature for 10 minutes, after which the luminescence signal value was read using a multi-mode microplate reader (PerkinElmer, EnVision2015), and the IC of the inhibitory activity of the compound was calculated using Graphpad Prism software. 50 The values ​​were calculated and the results are shown in Table I.

[0142] [Table I]

[0143] Conclusion: Compound 1 of the present disclosure has good inhibitory activity against the proliferation of NCI-H929 cells.

[0144] Test Example 2: Efficacy test

[0145] 1. Purpose of the experiment The objective of the present invention is to evaluate the effect of the compound of Example 1 and the control compound CC-92480 on inhibiting the growth of human multiple myeloma cell NCI-H929 transplanted tumors in CB-17 SCID mice.

[0146] 2. Experimental medicines

[0147] The compound of Example 1; Control Example CC-92480 (see compound 2 in WO2019014100A1 and synthesized according to the method disclosed therein) [ka]

[0148] The compound of Example 1 and control CC-92480 were prepared in 5% DMSO + 20% PEG400 + 70% (10% TPGS) + 5% (1% HPMC K100LV).

[0149] 3. Experimental methods and materials

[0150] 3.1. Experimental animals and breeding conditions Thirty CB-17 SCID female mice were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (certification number: 20170011006049, SCXK(Shanghai)2017-0011). They weighed approximately 19 g at the time of purchase. They were housed in cages of 5 mice, regulated with a 12 / 12 hour light / dark cycle, kept at a constant temperature of 23±1°C, and had a humidity of 50-60%. They were allowed to eat and drink freely.

[0151] 3.2. Animal Grouping: CB-17 SCID mice were adaptively bred and then divided into groups as shown below.

[0152] TIFF2025503063000008.tif46168

[0153] 3.3. Experimental Method: 5 × 10 NCI-H929 cells in logarithmic growth phase 6 100 μL of cells / mouse (containing 50 μL of Matrigel) were inoculated subcutaneously into the right rib of 30 female CB-17 SCID mice, and 10 days later, the tumor volume of the tumor-bearing mice was approximately 200 mm 3 When the tumor volume reached 2000 mm, the mice were randomly divided into three groups according to tumor volume and body weight, with 7 mice in each group: a solvent control group, CC-92480-1mpk, and the compound of Example 1-1mpk. The day of grouping was designated Day 0 (D0), and intragastric administration was started once a day for a total of 11 days (Table 2). The tumor volume of the tumor-bearing mice was measured twice a week with a vernier caliper, and the body weight was measured with a balance, and the data was recorded. ... 3 When the tumor-bearing animals reached 0.1 mg / kg / day, or when most of the tumors ruptured, or when they lost 20% of their body weight, they were euthanized, which was the end point of the experiment.

[0154] 3.4. Data Statistics All data were plotted and statistical analysis was performed using Excel and GraphPad Prism 5 software.

[0155] The formula for calculating tumor volume (V) is V = 1 / 2 × a × b 2 and Here, a and b represent the long axis and width of the tumor, respectively.

[0156] Relative tumor growth rate T / C(%)=(T-T0) / (C-C0)■100(%), where: T, C are the tumor volumes in the treatment and control groups at the end of the experiment, and T0, C0 are the tumor volumes at the start of the experiment.

[0157] Tumor inhibition rate TGI(%)=1-T / C(%). After TGI(%) exceeds 100%, no specific value is displayed, only when it is >100%.

[0158] Tumor regression (%)=[(T0-T) / T0]×100(%).

[0159] 4, results Efficacy data for the compound of Example 1 and control CC-92480 against NCI-H929 xenograft tumors in CB-17 SCID mice are shown in Table II below and in FIG.

[0160] The effects of the compound of Example 1 and the control CC-92480 on body weight in CB-17 SCID mice are shown in FIG.

[0161] [Table II]

[0162] 5. Conclusion The compound of Example 1 was administered once a day 10 days after tumor cell implantation, and the tumor volume was significantly reduced 11 days after administration. The calculated tumor inhibition rate was >100%, and the tumor regression rate was 88%, which was statistically different (p<0.05) compared with the same dose of CC-92480 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 control CC-92480 was 34%.

[0163] Test Example 3 Pharmacokinetic evaluation

[0164] 1. Overview Mice are used as test animals, and LC / MS / MS method is used to measure the drug concentration in the plasma of mice at different time points after intragastric administration of the compound of Example 1 and control CC-92480.The pharmacokinetic behavior of the compound of the present disclosure in mice is studied, and its pharmacokinetic properties are evaluated.

[0165] 2. Test protocol

[0166] 2.1 Test Medications The compound of Example 1 and control CC-92480.

[0167] 2.2 Test animals Eighteen mice (female) were purchased from Weitong Lihua Laboratory Animal Technology Co., Ltd., Animal Production Permit Number: SCXK (Shanghai) 2017-0005.

[0168] 2.3 Pharmaceutical manufacturing The compound of Example 1 was weighed out, dissolved by adding 5% volume of DMSO and 5% Tween 80 (SHANGHAI TITANCHEM CO.LTD), and then 90% saline was added to prepare a 0.1 mg / mL clear solution.

[0169] Control example CC-92480 was weighed out and dissolved by adding 5% volume of DMSO and 5% Tween 80 (SHANGHAI TITANCHEM CO.LTD), and then 90% saline was added to prepare a 0.1 mg / mL clear solution.

[0170] 2.4 Administration Nine mice were intragastrically administered the compound of Example 1 at a dose of 2 mg / kg and a dose volume of 0.2 mL / 10 g.

[0171] Nine mice were intragastrically administered the compound control CC-92480 at a dose of 2 mg / kg and a dose volume of 0.2 mL / 10 g.

[0172] 3, operation The compound of Example 1 and control CC-92480 were intragastrically administered to mice, and 0.2mL of blood was collected before administration and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration (three animals at each time point), placed in EDTA-K2 anticoagulant tubes, centrifuged at 10000 rpm for 1 minute (4°C), and plasma was separated within 1 hour and stored at -20°C for testing. The process from blood collection to centrifugation was carried out under ice bath conditions.

[0173] The content of test compound in mouse plasma after drug administration at different concentrations was measured: 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 Institute of Biological Product Control) and 175 μL of acetonitrile were added, vortexed for 5 minutes, centrifuged (3700 rpm / min) for 10 minutes, and 1 μL of the supernatant was taken as the plasma sample and analyzed by LC / MS / MS (API4000 triple quadrupole tandem mass spectrometer, Applied Biosystems, USA; Shimadzu LC-30AD ultra-high performance liquid chromatography system, Shimadzu, Japan).

[0174] 4. Pharmacokinetic parameters The pharmacokinetic parameters of the compounds of the present disclosure are shown below in Table III.

[0175] [Table III]

[0176] Conclusion: The compounds of the present disclosure have good pharmacokinetic absorption and have pharmacokinetic advantages.

[0177] Test Example 4 Evaluation of plasma stability of the compounds of the present disclosure

[0178] 1. Overview Using LC-MS / MS, the stability of the compound of Example 1 and control CC-92480 was quantitatively measured after incubation in frozen preserved monkey plasma at 37°C for 0, 15, 30, 60, 120, 180, and 240 minutes, respectively.

[0179] 2. Testing Protocol

[0180] 2.1 Test Medications The compound of Example 1 and control CC-92480.

[0181] 2.2 Test plasma Monkey plasma was purchased from Shanghai Medicilon Inc.

[0182] 2.3 Preparation of compound solutions A certain amount of the compound of Example 1 was weighed out and DMSO was added to prepare a 30 mM stock solution, a certain volume of the stock solution was taken and diluted with DMSO to a concentration of 1600 μM solution I, and a certain volume of the 1600 μM solution I was further diluted with 50% methanol to a concentration of 16 μM working solution II. Using the above method, a 30 mM stock solution, a 1600 μM solution I', and a 16 μM working solution II' of CC-92480 were prepared.

[0183] 2.4 Sample cultivation Take 16μM working solution of compound of Example 1 and 5μL of control CC-92480, and add them to 75μL plasma respectively until the final concentration of compound is 1μM. Samples are incubated in 37℃ water bath for 0, 15, 30, 60, 90, 120, 180 minutes. After incubation is completed, add 240μL acetonitrile containing internal standard, then shake on shaker at 800rpm for 10 minutes, centrifuge at 3700rpm, 4℃ for 20 minutes, and analyze the supernatant by LC-MS, injection volume is 2μL.

[0184] 3, results The conversion of compounds of the present disclosure in monkey plasma is shown in Table IV below. [Table IV]

[0185] Conclusion: The compounds of the present disclosure have the advantage of stability in monkey plasma.

[0186] Example 2: Preparation of amorphous compound of formula (I) The compound represented by formula (I) (10 mg) was added to propylene glycol methyl ether (1.0 ml), slurried at room temperature, centrifuged, and the solid was dried to obtain a product, which was found to be amorphous by powder X-ray diffraction, and the XRPD pattern was shown in Figure 1.

[0187] Example 3: Preparation of A-type crystals of the compound represented by formula (I) The compound represented by formula (I) (7.3 g) was added to dichloromethane (300 mL), dissolved by adding methanol (30 mL), added water (300 mL), and spun to remove most of the dichloromethane. A large amount of solid was precipitated, filtered, and the solid was obtained and then dried overnight. Dichloromethane (500 mL) was added to the solid, dissolved, suction filtered, filtrate (500 mL) was obtained, anhydrous sodium sulfate was added to dry, filtered, ethyl acetate (200 mL) was added, and spun to dry to obtain the product. When detected using a powder X-ray diffraction apparatus, the product was defined as A-type crystals, and the XRPD pattern is as shown in FIG. 2, and its characteristic peak positions are as shown in Table 1. The DSC pattern shows that the peak values ​​of the endothermic peaks are 155.26 ° C, 183.19 ° C, and 244.74 ° C. The TGA pattern shows that the weight loss is 9.48% at 25 ° C to 220 ° C.

[0188] [Table 1]

[0189] Example 4: Preparation of A-type crystals of the compound represented by formula (I) The compound represented by formula (I) (10 mg) was added to water (1 ml), slurried at room temperature, centrifuged, and the solid was dried in vacuum to obtain a product, which was found to be A-type crystals by powder X-ray diffraction.

[0190] Example 5: Preparation of A-type crystals of the compound represented by formula (I) The compound represented by formula (I) (10 mg) was added to acetone (1 ml), slurried, centrifuged, and the solid was dried in vacuum to obtain a product, which was found to be A-type crystals by powder X-ray diffraction.

[0191] Example 6: Preparation of A-type crystals of the compound represented by formula (I) The compound represented by formula (I) (10 mg) was added to THF (300 ul) and dissolved transparently, and then n-heptane (450 ul) was added to precipitate a solid, which was then slurried at room temperature, centrifuged, and vacuum dried to obtain a product. When detected using a powder X-ray diffractometer, the product was A-type crystals.

[0192] Example 7: Preparation of B-type crystals of the compound represented by formula (I) The compound represented by formula (I) (150 mg) was added to 1.0 ml of acetonitrile / methanol (V / V=1:1), slurried, centrifuged, and the solid was dried under vacuum to obtain the product. When detected using powder X-ray diffraction, the product was defined as B-type crystals, with an XRPD pattern as shown in FIG. 3 and characteristic peak positions as shown in Table 2. The DSC pattern shows that the peak values ​​of the endothermic peaks are 182.74°C and 245.37°C. The TGA pattern shows that the weight loss is 4.57% from 25°C to 225°C.

[0193] [Table 2]

[0194] Example 8: Preparation of C-type crystals of the compound represented by formula (I) The compound represented by formula (I) (10 mg) was added to ethanol (1.0 ml), slurried at room temperature, centrifuged, and the solid was dried under vacuum to obtain the product. When detected using powder X-ray diffraction, the product was defined as a C-type crystal, with an XRPD pattern as shown in FIG. 4 and characteristic peak positions as shown in Table 3. The DSC pattern shows that the peak values ​​of the endothermic peaks are 153.48°C, 182.76°C, and 244.05°C. The TGA pattern shows that the weight loss is 3.00% from 25°C to 215°C.

[0195] [Table 3]

[0196] Example 9: Preparation of C-type crystals of the compound represented by formula (I) The compound of formula (I) (10 mg) was added to 10% water / acetone (0.9 ml) and evaporated to crystallize the product, which was found to be crystalline form C by powder X-ray diffraction.

[0197] Example 10: Preparation of D-type crystals of the compound represented by formula (I) The compound of formula (I) (10 mg) was added to acetonitrile (1.0 ml), slurried, centrifuged, and the solid was dried under vacuum at 30° C. to obtain the product. When detected using powder X-ray diffraction, the product was defined as D-type crystals, with an XRPD pattern as shown in FIG. 5 and characteristic peak positions as shown in Table 4. The DSC pattern shows endothermic peaks at 156.12° C. and 245.38° C. The TGA pattern shows a weight loss of 1.17% from 25° C. to 205° C.

[0198] [Table 4]

[0199] Example 11: Preparation of E-type crystals of the compound represented by formula (I) The compound represented by formula (I) (10 mg) was added to 10% water / methanol (1.0 ml), slurried, centrifuged, and the solid was dried under vacuum to obtain the product. When detected using powder X-ray diffraction, the product was defined as E-type crystals, with an XRPD pattern as shown in FIG. 6 and characteristic peak positions as shown in Table 5. The DSC pattern shows endothermic peak values ​​of 182.71°C and 245.00°C. The TGA pattern shows a weight loss of 0.68% from 25°C to 235°C.

[0200] [Table 5]

[0201] Example 12: Preparation of E-type crystals of the compound represented by formula (I) The compound represented by formula (I) (10 mg) was added to DCM (300 ul) and dissolved transparently, and n-heptane (300 ul) was added to precipitate a solid, which was then slurried at room temperature, centrifuged, and vacuum dried to obtain a product. When detected by powder X-ray diffraction, the product was E-form crystals.

[0202] Example 13: Preparation of F-type crystals of the compound represented by formula (I) The compound represented by formula (I) (10 mg) was added to methanol (1.0 ml), slurried at room temperature, centrifuged, and the solid was dried under vacuum to obtain the product. When detected using powder X-ray diffraction, the product was defined as F-type crystals, with an XRPD pattern as shown in FIG. 7 and characteristic peak positions as shown in Table 6. The DSC pattern shows that the peak values ​​of the endothermic peaks are 181.22°C and 245.03°C. The TGA pattern shows that the weight loss is 8.63% from 25°C to 210°C.

[0203] [Table 6]

[0204] Example 14: Preparation of F-type crystals of the compound represented by formula (I) The compound represented by formula (I) (10 mg) was added to dichloromethane (0.3 ml) and dissolved transparently, and then isopropyl acetate (0.9 ml) was added to precipitate a solid, which was then slurried at room temperature, centrifuged, and vacuum dried to obtain a product. When detected by powder X-ray diffraction, the product was F-type crystals.

[0205] Example 15: Preparation of F-type crystals of the compound represented by formula (I) The compound represented by formula (I) (10 mg) was added to 1,4-dioxane (900 μl), dissolved transparently, and evaporated to obtain a product, which was found to be F-type crystals by powder X-ray diffraction.

[0206] Example 16: Preparation of G-type crystals of the compound represented by formula (I) The compound represented by formula (I) (10 mg) was added to 1,2-dichloroethane (1.0 ml), slurried at room temperature, centrifuged, and the solid was dried under vacuum to obtain the product. When detected using powder X-ray diffraction, the product was defined as G-type crystals, with an XRPD pattern as shown in FIG. 8 and characteristic peak positions as shown in Table 7. The DSC pattern shows that the peak values ​​of the endothermic peaks are 160.43°C, 182.11°C, and 244.42°C. The TGA pattern shows that the weight loss is 9.97% from 25°C to 235°C.

[0207] [Table 7]

[0208] Example 17: Preparation of G-type crystals of the compound represented by formula (I) The compound represented by formula (I) (10 mg) was added to chloroform (500 μl), dissolved transparently, and evaporated to obtain a product, which was found to be G-type crystals by powder X-ray diffraction.

[0209] Example 18: Preparation of H-type crystals of the compound represented by formula (I) The compound represented by formula (I) (about 10 mg) was added to n-hexane (1.0 ml), slurried at room temperature, centrifuged, and dried under vacuum to obtain the product. When detected using powder X-ray diffraction, the product was defined as H-type crystals, with an XRPD pattern as shown in FIG. 9 and characteristic peak positions as shown in Table 8. The DSC pattern shows endothermic peak values ​​of 184.53°C and 247.90°C. The TGA pattern shows a weight loss of 4.13% from 25°C to 215°C.

[0210] [Table 8]

[0211] Example 19: Preparation of Form I Crystals of the Compound Represented by Formula (I) The compound represented by formula (I) (10 mg) was added to tetrahydrofuran (0.4 ml) and slowly evaporated at room temperature to obtain the product. When detected by powder X-ray diffraction, the product was defined as type I crystals, with an XRPD pattern as shown in FIG. 10 and its characteristic peak positions as shown in Table 9. The DSC pattern shows that the peak values ​​of the endothermic peaks are 182.58°C and 245.04°C. The TGA pattern shows that the weight loss is 5.44% from 25°C to 225°C.

[0212] [Table 9]

[0213] Example 20: Preparation of Form I crystals of the compound represented by formula (I) The compound represented by formula (I) (10 mg) was added to tetrahydrofuran (0.3 ml) to dissolve transparently, and water (0.6 ml) was added to precipitate a solid. The solid was centrifuged and dried in vacuum to obtain a product. When detected by powder X-ray diffraction, the product was a type I crystal.

[0214] Example 21: Preparation of J-type crystals of the compound represented by formula (I) The compound represented by formula (I) (10 mg) was added to DMSO (0.2 ml) to dissolve transparently, and water (0.2 ml) was added to precipitate a solid. The product was obtained by centrifugation and vacuum drying. When detected using powder X-ray diffraction, the product was defined as a J-type crystal, and the XRPD pattern was as shown in FIG. 11, and its characteristic peak positions are as shown in Table 10. The DSC pattern shows that the peak values ​​of the endothermic peaks are 154.09 ° C, 165.41 ° C, and 247.39 ° C. The TGA pattern shows that the weight loss is 10.48% from 30 ° C to 220 ° C.

[0215] [Table 10]

[0216] Example 22: Preparation of J-type crystals of the compound represented by formula (I) The compound represented by formula (I) (10 mg) was added to DMSO (0.2 ml) to dissolve it transparently, and methyl tert-butyl ether (0.4 ml) was added to precipitate a solid. The solid was centrifuged and dried in vacuum to obtain a product. When detected by powder X-ray diffraction, the product was a J-type crystal.

[0217] Example 23: Preparation of K-type crystals of the compound represented by formula (I) The compound represented by formula (I) (10 mg) was added to N-methylpyrrolidone (50 μl) and slowly evaporated at room temperature to obtain a product, which was defined as a K-type crystal by powder X-ray diffraction detection, and the XRPD pattern is shown in Figure 12, and its characteristic peak positions are shown in Table 11.

[0218] [Table 11]

[0219] Example 24: Preparation of L-type crystals of the compound represented by formula (I) The compound represented by formula (I) (10 mg) was added to N,N-dimethylacetamide (200 μl) to dissolve transparently, and slowly evaporated at room temperature to obtain a product. When detected by powder X-ray diffraction, the product was defined as L-type crystal, and the XRPD pattern is shown in Figure 13, and its characteristic peak positions are shown in Table 12.

[0220] [Table 12]

[0221] Example 25: Preparation of M-type crystals of the compound represented by formula (I) A type A crystal (10 mg) of the compound of formula (I) was heated to 225° C. to obtain a product, which was defined as a type M crystal as detected by powder X-ray diffraction, and the XRPD pattern is shown in FIG. 14, and its characteristic peak positions are shown in Table 13.

[0222] [Table 13]

[0223] Example 26: Preparation of N-type crystals of the compound represented by formula (I) The compound represented by formula (I) (80 mg) was added to 4.0 mL of a mixed solvent of ethyl acetate and tetrahydrofuran (V / V=1:1), heated to dissolve transparently, recrystallized, filtered, and the obtained solid was dried to obtain a product. When detected using powder X-ray diffraction, the product was defined as N-type crystals, and the XRPD pattern was as shown in FIG. 15, and its characteristic peak positions are as shown in Table 14. The DSC pattern shows that the peak values ​​of the endothermic peaks are 185.49 ° C and 188.82 ° C. The TGA pattern shows that the weight loss is 4.86% from 30 ° C to 225 ° C.

[0224] [Table 14]

[0225] Example 27: Preparation of O-type crystals of the compound represented by formula (I) The compound represented by formula (I) (60 mg) was added to acetonitrile (5 mL), and benzenesulfonic acid (16 mg) was added at room temperature, followed by reaction at 80° C. for 8 hours. After a solid precipitated from the reaction solution, the solution was filtered, and the solid was vacuum dried at 45° C. to obtain a product. When detected using powder X-ray diffraction, the product was defined as O-type crystals, and the XRPD pattern was as shown in FIG. 16, and its characteristic peak positions were as shown in Table 15.

[0226] [Table 15]

[0227] Example 28: Preparation of P-type crystals of the compound represented by formula (I) The C-type crystals (40 mg) of the compound represented by formula (I) were added to dioxane (2.0 mL), slurried at room temperature, filtered, and the solid was dried under vacuum to obtain the product. The product was defined as P-type crystals as detected by powder X-ray diffraction, and the XRPD pattern is shown in FIG. 17. The DSC pattern shows that the peak values ​​of the endothermic peaks are 127.49°C, 180.10°C, and 249.23°C; the TGA pattern shows that the weight loss is 8.79% from 40°C to 230°C.

[0228] [Table 16]

[0229] Example 27: Preparation of Q-type crystals of the compound represented by formula (I) The compound represented by formula (I) (150 mg) was added to ethyl acetate (3 mL), slurried at room temperature, filtered, and the solid was dried under vacuum at 130°C to obtain the product. When detected using powder X-ray diffraction, the product was defined as Q-type crystals, with an XRPD pattern as shown in Figure 18 and characteristic peak positions as shown in Table 17. The DSC pattern shows endothermic peak values ​​of 188.58°C and 249.61°C. The TGA pattern shows a weight loss of 0.54% from 25°C to 225°C.

[0230] [Table 17]

[0231] Example 29: Preparation of U-type crystals of the compound represented by formula (I) The compound represented by formula (I) (50 mg) was added to DMSO (0.6 ml), heated to 50°C to dissolve transparently, added with water (1.2 ml), crystallized, centrifuged, added with water (2 ml) to the solid, stirred to wash, centrifuged, and dried in vacuum to obtain the product. When detected using powder X-ray diffraction, the product was defined as U-type crystals, and the XRPD pattern is as shown in Figure 19, and its characteristic peak positions are as shown in Table 18. The DSC pattern shows that the peak values ​​of the endothermic peak are 183.28°C and 248.22°C. The TGA pattern shows that the weight loss is 0.62% from 40°C to 215°C.

[0232] [Table 18]

[0233] Example 30: Preparation of U-type crystals of the compound represented by formula (I) The Q-type crystals of the compound of formula (I) (10 mg) were added to water (1.0 ml) and slurried at room temperature for 1 day to obtain a product, which was determined to be a U-type crystal by powder X-ray diffraction.

[0234] Example 31: Preparation of X-type crystals of the compound represented by formula (I) The D-type crystals of the compound of formula (I) (10 mg) were added to n-heptane (1.0 ml), slurried at room temperature, centrifuged, and the solid was dried under vacuum to obtain a product. When detected by powder X-ray diffraction, the product was defined as the X-type crystals, and the XRPD pattern is shown in Figure 20, and its characteristic peak positions are shown in Table 19. The DSC pattern shows endothermic peaks at 158.81°C, 184.14°C, and 249.04°C.

[0235] [Table 19]

[0236] Example 32: Preparation of Y-type crystals of the compound represented by formula (I) The Q-type crystals of the compound of formula (I) (10 mg) were added to n-heptane (1.0 ml), slurried at room temperature, centrifuged, and the solid was dried under vacuum to obtain a product. The product was defined as a Y-type crystal when detected by powder X-ray diffraction, and the XRPD pattern was shown in Figure 21, and its characteristic peak positions are shown in Table 20. The DSC pattern showed that the peak values ​​of the endothermic peaks were 184.97 ° C and 248.72 ° C.

[0237] [Table 20]

[0238] Example 33: Preparation of Type V Crystals of the Compound of Formula (I) The compound represented by formula (I) (200 mg) was added to N,N-dimethylformamide (0.4 mL), and then acetonitrile (2 mL) was added to the reaction system, which was stirred at 20-30°C, suction filtered, and the cake was dried to obtain the product. When detected using powder X-ray diffraction, the product was defined as V-type crystals, and the XRPD pattern was as shown in Figure 22, and its characteristic peak positions were as shown in Table 21. The DSC pattern showed that the peak value of the endothermic peak was 147.78°C. The TGA pattern showed that the weight loss was 10.73% at 30°C to 210°C.

[0239] [Table 21]

[0240] Example 34: Preparation of Type V Crystals of the Compound of Formula (I) The compound represented by formula (I) (200 mg) was added to N,N-dimethylformamide (1 mL), heated to 60°C to dissolve, naturally cooled to 20-30°C, stirred at 20-30°C, suction filtered, the cake was rinsed with N,N-dimethylformamide (0.2 mL), and dried under reduced pressure at 45°C for 26 hours to obtain a product. When detected using powder X-ray diffraction, the product was a V-type crystal.

[0241] Example 35: Preparation of R-type crystals of the compound represented by formula (I) The compound represented by formula (I) (8 g) was added to tetrahydrofuran (150 mL), stirred to dissolve, and concentrated under reduced pressure until no distillate remained to obtain the product. The product was defined as R-type crystals as detected by powder X-ray diffraction, and the XRPD pattern was shown in Figure 23, and its characteristic peak positions are shown in Table 22.

[0242] [Table 22]

[0243] Example 36: Preparation of S-type crystals of the compound represented by formula (I) The compound of formula (I) was dissolved in N,N-dimethylformamide at elevated temperature, then cooled to precipitate, slurried with acetonitrile, filtered, the cake was slurried once with water, filtered, dried the sample at 60°C, added 1 L of acetonitrile, stirred at 20-30°C, filtered, and dried to obtain the product. When detected by powder X-ray diffraction, the product was defined as S-type crystals, with an XRPD pattern as shown in Figure 24 and characteristic peak positions as shown in Table 23.

[0244] [Table 23]

[0245] Example 37: Preparation of T-type crystals of the compound represented by formula (I) The compound represented by formula (I) (70.9 g) was added to N,N-dimethylformamide (200 mL), heated to 70-80°C to dissolve, then cooled to 20-30°C, precipitated, stirred, filtered, the cake was added to water (1200 mL), stirred, filtered, the cake was further added to water (1200 mL), stirred, filtered, and the cake was dried at 40-45°C. The dried sample (45.0 g) was added to acetonitrile (450 mL), magnetically stirred at 20-30°C for 29 hours, suction filtered, and dried under reduced pressure for 17 hours to obtain the product. When detected using powder X-ray diffraction, the product was defined as a T-type crystal, and the XRPD pattern was as shown in Figure 25, and its characteristic peak positions are as shown in Table 24. The DSC pattern shows that the peak values ​​of the endothermic peaks are 164.78°C and 247.66°C.

[0246] [Table 24]

[0247] Example 38: Hygroscopicity Study of D, E, Q and U Forms of Compound (I) (October 15, 2021, Nanjing) Surface Measurement Systems advantage 2 was used at 25°C, starting with 50% humidity, the humidity range considered was 0% to 95%, with a step of 10%, and the criteria were that the mass change dM / dT for each gradient was less than 0.002%, TMAX 360 min, and 2 cycles.

[0248] [Table 25] Example 39: Influence factors of stability of D, E, Q and U crystal forms of compound of formula (I) Each crystal was spread open and the stability of the sample was examined under the conditions of light irradiation (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH75%, RH92.5%). The sampling period was 30 days.

[0249] [Table 26] TIFF2025503063000038.tif237168

[0250] Conclusion: Experiments on influencing factors show that D, E, Q and U types of crystals of compound of formula (I) have good physical and chemical stability under high humidity conditions of 75% and 92.5%, and the purity slightly decreased under light conditions at 60°C, and the crystals did not transform.

[0251] Example 40: Long-term / accelerated stability of crystal forms D, E, Q and U of compound of formula (I) The crystals of types D, E, Q and U of the compound represented by formula (I) were placed at 25°C, 60% RH and 40°C, 75% RH, respectively, and their stability was examined.

[0252] [Table 27]

[0253] [Table 28]

[0254] [Table 29]

[0255] [Table 30]

[0256] Conclusion: Free forms D, E, Q and U crystals showed good physical and chemical stability when placed under long-term accelerated stability conditions for 6 months.

Claims

1. A type crystal of the compound represented by formula (I). 【Chemistry 1】 (However, the powder X-ray diffraction pattern expressed by the 2θ angle of the diffraction angle has characteristic peaks at 5.765, 8.061, 9.925, 16.632, 17.900, 19.469 and 21.115, and preferably has characteristic peaks at 5.765, 7.465, 8.061, 9.925, 12.890, 15.085, 16.632, 17.900, 19.469 and 21.

115. It has characteristic peaks, more preferably 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, and most preferably has a powder X-ray diffraction pattern expressed in terms of 2θ angles as shown in FIG.

2.

2. A B-type crystal of the compound represented by formula (I). 【Chemistry 2】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 4.977, 6.788, 10.047, 14.143, 15.684, 18.547, and 20.840, preferably has characteristic peaks at 4.977, 6.788, 10.047, 14.143, 15.684, 18.547, 20.840, 24.096, and 25.505, and more preferably has a powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle as shown in FIG. 3.)

3. C-type crystals of the compound represented by formula (I). 【Chemistry 3】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 5.653, 7.974, 9.989, 16.143, 17.860, 18.992 and 20.972, and preferably 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. More preferably, it has 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, and most preferably, the powder X-ray diffraction pattern expressed in terms of 2θ angles is as shown in FIG.

4.

4. D-type crystals of the compound represented by formula (I). 【Chemistry 4】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 6.831, 9.845, 13.453, 18.225, 20.117, 20.891, and 23.006, preferably 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, and more preferably has a powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle as shown in FIG. 5.)

5. Form E crystal of the compound represented by formula (I). 【Chemistry 5】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 5.864, 7.573, 8.087, 10.003, 16.444, 19.349 and 20.553, and preferably 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. It has characteristic peaks, more preferably 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, and most preferably has a powder X-ray diffraction pattern expressed in terms of 2θ angles as shown in FIG.

6.

6. F-type crystals of the compound represented by formula (I). 【Chemistry 6】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 5.062, 7.820, 10.077, 14.231, 16.672, 18.586, and 20.435, and preferably has characteristic peaks at 5.062, 7.820, 10.077, 14.231, 15.192, 16.672, 18.586, 20.435, 21.868, and 25.

442. More preferably, it has 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, and most preferably, the powder X-ray diffraction pattern expressed in terms of 2θ angles is as shown in FIG.

7.

7. A G-type crystal of the compound represented by formula (I). 【Chemistry 7】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 5.999, 7.972, 9.951, 11.388, 17.812, 20.975 and 25.819, and preferably has characteristic peaks at 5.999, 7.396, 7.972, 8.637, 9.951, 11.388, 15.291, 17.812, 20.975 and 25.

819. It has characteristic peaks, more preferably 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, and most preferably has a powder X-ray diffraction pattern expressed in terms of 2θ angles as shown in FIG.

8.

8. H-type crystals of the compound represented by formula (I). 【Chemistry 8】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 5.758, 7.533, 9.901, 14.267, 16.420, 18.103 and 26.356, preferably 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, more preferably has characteristic peaks at 5.758, 7.533, 9.901, 14.267, 16.420, 18.103, 18.917, 20.489, 21.563, 24.049 and 26.356, and most preferably has characteristic peaks at 2θ angle of the diffraction angle as shown in FIG. 9.)

9. A type I crystal of the compound represented by formula (I). 【Chemistry 9】 (However, the powder X-ray diffraction pattern represented by the 2θ angle of the diffraction angle has characteristic peaks at 5.294, 6.826, 7.564, 10.739, 13.699, 16.812 and 20.709, and preferably, the powder X-ray diffraction pattern represented by the 2θ angle of the diffraction angle is as shown in FIG. 10.)

10. A J-type crystal of the compound represented by formula (I). 【Chemistry 10】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 5.041, 10.068, 16.424, 20.544, 21.190, 24.077 and 25.433, and preferably has characteristic peaks at 5.041, 8.212, 10.068, 14.101, 15.167, 16.424, 20.544, 21.190, 24.077 and 25.

433. More preferably, it has 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, and most preferably, the powder X-ray diffraction pattern expressed in terms of 2θ angles is as shown in FIG.

11.

11. A K-type crystal of the compound represented by formula (I). 【Chemistry 11】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 5.156, 7.699, 10.339, 14.334, 16.203, 18.327, and 23.418, preferably 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, and more preferably has a powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle as shown in FIG. 12.)

12. A crystal of the compound represented by formula (I). 【Chemistry 12】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 4.932, 5.360, 9.831, 14.844, 18.244, 20.104, and 24.914, preferably 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, and more preferably has a powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle as shown in FIG. 13.)

13. M-type crystal of the compound represented by formula (I). 【Chemistry 13】 (However, the powder X-ray diffraction pattern expressed by the 2θ angle of the diffraction angle has characteristic peaks at 14.959, 16.322, 18.410, 20.748, 22.067, 23.670 and 26.863, and preferably has characteristic peaks at 14.959, 16.322, 18.410, 20.748, 22.067, 23.670, 24.839, 25.873, 26.863 and 27. 1.811, more preferably 14.959, 16.322, 18.410, 20.748, 22.067, 23.670, 24.322, 24.839, 25.873, 26.863 and 27.811, and most preferably a powder X-ray diffraction pattern expressed in terms of 2θ angles of diffraction angles as shown in FIG.

14.

14. N-type crystals of the compound represented by formula (I). 【Chemistry 14】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 5.028, 9.942, 10.900, 15.428, 18.410, 20.274 and 25.252, and preferably at 5.028, 7.671, 9.942, 10.900, 15.428, 16.560, 18.410, 20.274, 24.036 and 25.

252. More preferably, it has 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, and most preferably, the powder X-ray diffraction pattern expressed in terms of 2θ angles is as shown in FIG.

15.

15. O-type crystals of the compound represented by formula (I). 【Chemistry 15】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 11.796, 17.423, 18.081, 19.136, 21.707, 22.165, and 25.719, and preferably 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. More preferably, it 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, and most preferably, the powder X-ray diffraction pattern expressed in terms of 2θ angles is as shown in FIG.

16.

16. A P-type crystal of the compound represented by formula (I). 【Chemistry 16】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 5.359, 7.491, 10.786, 14.249, 16.527, 17.729 and 20.798, and preferably at 5.359, 7.491, 9.905, 10.786, 13.192, 14.249, 16.527, 17.729, 18.862 and 20.798.) More preferably, it has 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, and most preferably, the powder X-ray diffraction pattern expressed in terms of 2θ angles is as shown in FIG.

17.

17. A Q-type crystal of the compound represented by formula (I). 【Chemistry 17】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 5.038, 10.152, 15.850, 16.574, 18.892, 20.760 and 21.835, and preferably has characteristic peaks at 5.038, 10.152, 11.175, 15.850, 16.574, 18.892, 20.760, 21.835, 23.905 and 25.

784. More preferably, it 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, and most preferably, the powder X-ray diffraction pattern expressed in terms of 2θ angles is as shown in FIG.

18.

18. A U-type crystal of the compound represented by formula (I). 【Chemistry 18】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 14.155, 15.745, 17.314, 17.997, 18.838, 20.512 and 21.415, and preferably has characteristic peaks at 14.155, 15.745, 16.564, 17.314, 17.997, 18.838, 20.512, 21.415, 23.557 and 26.313.) More preferably, it has 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, and most preferably, the powder X-ray diffraction pattern expressed in terms of 2θ angles is as shown in FIG.

19.

19. A crystal of type X of the compound represented by formula (I). 【Chemistry 19】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 6.864, 9.873, 10.963, 13.801, 16.089, 18.006, and 20.929, preferably has characteristic peaks at 6.864, 9.873, 10.963, 13.801, 16.089, 18.006, 20.929, and 26.203, and more preferably has a powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle as shown in FIG. 20.)

20. A Y-type crystal of the compound represented by formula (I). 【Chemistry 20】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 5.676, 7.666, 14.260, 16.562, 18.020, 21.802 and 26.425, and preferably 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. More preferably, it has 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, and most preferably, the powder X-ray diffraction pattern expressed in terms of 2θ angles is as shown in FIG.

21.

21. A V-type crystal of the compound represented by formula (I). 【Chemistry 21】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 5.649, 6.154, 6.720, 11.651, 18.757, 19.813 and 23.948, and preferably 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. It has characteristic peaks, more preferably has 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, and most preferably has a powder X-ray diffraction pattern expressed in terms of 2θ angles as shown in FIG.

22.

22. An R-type crystal of the compound represented by formula (I). 【Chemical 22】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 5.534, 7.611, 10.033, 15.782, 17.101, 19.017 and 20.567, and preferably 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. It has characteristic peaks, more preferably 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, and most preferably has a powder X-ray diffraction pattern expressed in terms of 2θ angles as shown in FIG.

23.

23. An S-type crystal of the compound represented by formula (I). 【Chemistry 23】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 6.576, 9.082, 10.921, 13.592, 19.965, 21.403 and 24.207, and preferably 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. More preferably, it has 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, and most preferably, the powder X-ray diffraction pattern expressed in terms of 2θ angles is as shown in FIG.

24.

24. A T-type crystal of the compound represented by formula (I). 【Chemistry 24】 (However, the powder X-ray diffraction pattern expressed in terms of the 2θ angle of the diffraction angle has characteristic peaks at 6.915, 9.177, 9.984, 11.012, 13.595, 16.156 and 20.138, and preferably 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. It has characteristic peaks, more preferably has 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, and most preferably has a powder X-ray diffraction pattern expressed in terms of 2θ angles as shown in FIG.

25.

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

20.

26. A pharmaceutical composition produced from the crystal according to any one of claims 1 to 25.

27. A pharmaceutical composition comprising the crystal of any one of claims 1 to 25 and an optional pharma- ceutically acceptable carrier, diluent or excipient.

28. A method for producing a pharmaceutical composition, comprising the step of mixing the crystal according to any one of claims 1 to 25 with a pharma- ceutically acceptable carrier, diluent or excipient.

29. Use of the crystal of any one of claims 1 to 25, or the composition of claim 26 or 27, or the composition produced by the method of claim 28, in the manufacture of a medicament for treating and / or preventing a disease associated with a CRBN protein.

30. 29. Use of a crystal according to any one of claims 1 to 25, or a composition according to claim 26 or 27, or a composition produced by the method according to claim 28, in the manufacture of a medicament for the treatment and / or prevention of cancer, angiogenesis-related disorders, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS diseases, CNS injuries, atherosclerosis or related conditions, sleep disorders or related conditions, infectious diseases, hemoglobinopathies or related conditions, or TNFα-related diseases, preferably in the manufacture of a medicament for the treatment and / or prevention of cancer or CNS injuries.

31. 31. The use according to claim 30, wherein the cancer is selected from leukemia, myeloma, lymphoma, melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, choriocarcinoma, pancreatic cancer, polycythemia vera, childhood tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral cancer, prostate cancer, seminoma, testicular tumor, head and neck tumor, head and neck squamous cell carcinoma, endometrial cancer, thyroid cancer, sarcoma, osteoma, neuroblastoma, neuroendocrine cancer, 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.

32. The use according to claim 30, wherein said myeloma is multiple myeloma (MM) and myelodysplastic syndrome (MDS), preferably said multiple myeloma is relapsed, refractory or resistant.

33. 33. The use of claim 32, wherein the multiple myeloma is refractory or resistant to lenalidomide and pomalidomide.

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