Crystalline or amorphous forms of oxoisoindole-5-carboxamide compounds or their salts and solvates

Abstract

This document relates to crystalline or amorphous forms of oxoisoindole-5-carboxamide compounds, or salts or solvates thereof. It also discloses compositions containing the crystalline or amorphous forms, as well as methods for preparing and using the crystalline or amorphous forms. The resulting crystalline or amorphous forms have excellent solid-state stability and are of great value in drug development, formulation development, and production.

Description

[Technical Field]

[0001] The present invention relates to the field of medicine, and in particular to an oxoisoindole-5-carboxamide compound or its salt or solvate in crystalline or amorphous form, which is used as a CK1α selective molecular adhesive decomposition agent, as well as a preparation method and use thereof. [Background technology]

[0002] Casein kinase 1α (CK1α), encoded by the gene CSNK1A1, is a widely expressed serine / threonine kinase in the CK1 kinase family. CK1α is involved in the regulation of many physiological and pathological processes in cells and regulates the regular progression of life through various signaling pathways (Jiang et al., Cell Commun Signal (2018) 16: 23). For example, as a key regulator of the Wnt / β-catenin pathway, CK1α directly phosphorylates β-catenin at Ser45, targeting it for proteasomal degradation (Liu et al., Cell (2002) 108: 837-847). CK1α has also been reported to regulate the protein stability of the tumor suppressor p53 by regulating the activity of the MDM2 / MDMX E3 ligase complex (Huart et al., J Biol Chem (2009) 284: 32384-94; Wu et al., Mol Cell Biol (2012) 32:4821-4832). CK1α has been reported to be overexpressed in many types of human cancer, but the precise role of CK1α in the progression of many types of tumors remains unclear (Richter et al., BMC Cancer (2018) 18: 140). The Cancer Dependency Map (DepMap) database showed that inactivation of CK1α by CRISPR / cas9-mediated gene knockout or shRNA-mediated gene knockdown significantly reduced the proliferation and / or survival of many cancer cell lines across multiple cancer types (Tsherniak et al., Cell (2017) 170:564-576; Behan et al., Nature (2019) 568: 511-516). Furthermore, suppression of CK1α activity with shRNA interference or D4476 (a CK1α inhibitor) effectively suppressed the progression of MLL-AF9 leukemia while minimizing the impact on normal hematopoietic stem and progenitor cells (HSPCs) (Jaras et al., J Exp Med (2014) 211(4): 605-612). These data suggest that CK1α is a potential therapeutic target for hematological malignancies and solid tumor indications. The compound of formula A is currently in early clinical research as a new generation of CK1α selective molecular adhesive degrader. [ka]

[0003] However, no research or report has been found on the crystalline or amorphous forms of the compound of formula A or its salts or solvates, nor on their production methods, uses, formulations, etc. In solid substances, the molecular arrangement in the crystal lattice space varies due to various factors such as molecular structure, conformation, molecular arrangement, molecular interaction, and co-crystallization. This phenomenon is called "polymorphism" or "polymorphism." Polymorphism is widespread in solid drugs, and different crystalline forms of the same drug may exhibit significant differences in physical and chemical properties, such as appearance, density, hardness, melting point, solubility, stability, dissolution rate, dissolution rate, and bioavailability. This phenomenon is particularly evident in oral solid dosage forms. Furthermore, the presence of polymorphic compounds is unpredictable, and different crystalline forms of the same drug may exhibit significant differences in solubility, melting point, density, stability, and other aspects, which may affect the drug's uniformity, bioavailability, therapeutic efficacy, and stability to different degrees.

[0004] In addition to polymorphism, some solid compounds may exist in amorphous form, which is the structure of amorphous regions (amorphous regions) in some imperfect crystals or the constitutional form of some amorphous solids (amorphous bodies). For a particular solid drug, the number and form of amorphous forms present are similarly unpredictable and may have significant effects on the drug's solubility, melting point, density, stability, etc. Therefore, in the process of drug discovery, it is necessary to comprehensively screen drug compounds and consider multiple factors.In particular, for the compound of formula A used to treat the above-mentioned proliferative diseases, the development of a dosage form that may have medicinal value of the compound or its derivative, crystalline form, amorphous form, or its pharmaceutically acceptable salt, hydrate or solvate, and the improvement of the properties of the compound such as stability, solubility, bioavailability, etc., has potential medicinal and clinical value. Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention provides crystalline or amorphous forms of oxoisoindole-5-carboxamide compounds or their salts or solvates, which can be used as CK1α selective molecular adhesive decomposition agents, as well as methods for preparing and using the same. The crystalline or amorphous forms of the present invention are of great value in the development and production of drugs and formulations. [Means for solving the problem]

[0006] In the following description, some specific details are set forth to provide a thorough understanding of each embodiment of the present invention, but it will be understood by those skilled in the art that the present invention can be practiced without these details. The following description of several embodiments is made with the understanding that the disclosure is to be considered as an example of the subject matter sought to be protected, and is not intended to limit the appended claims to the specific embodiments set forth. The headings used throughout the present description are for convenience and should not be construed as any limitation on the claims. An embodiment set forth under any heading can be combined with an embodiment set forth under any other heading. Also, for example, when referring to an XRPD pattern, TGA graph, DSC chart, or the like, the term "essentially as shown in ..." does not necessarily mean a drawing that is identical to that described herein, but that would be considered by one of ordinary skill in the art to fall within the bounds of experimental error or deviation.

[0007] In one aspect, the present invention provides an amorphous or crystalline form of a compound of formula A, or a pharmaceutically acceptable salt or solvate thereof. [ka] The chemical name of the compound is N-((S)-(5-chloropyridin-2-yl)(cyclobutyl)methyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide.

[0008] The present invention includes, but is not limited to, crystalline form A1, crystalline form A2, crystalline form A3, crystalline form A4, crystalline form A5, crystalline form B, crystalline form C, crystalline form D1, crystalline form D2, crystalline form E, crystalline form F, crystalline form G, crystalline form H and amorphous form. Specifically, they are as follows: Crystalline form A1 of the solvate of the compound of formula A In one embodiment, the solvate of compound of formula A in crystalline form A1 has an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles of at least three, at least four, at least five, at least six, or seven characteristic peaks at 6.54±0.2°, 19.64±0.2°, 9.21±0.2°, 16.35±0.2°, 18.48±0.2°, 9.79±0.2°, and 17.23±0.2°. In some preferred embodiments, the XRPD characteristic peaks are essentially those shown in Table 1 below. [Table 1]

[0009] In some preferred embodiments, the XRPD pattern has essentially the pattern shown in FIG. 1c, and optionally has one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 147.77°C ± 2°C and one endothermic peak at 159.25°C ± 2°C; 2) In the TGA graph, there is a weight loss of 10.64±0.2 wt% before 240°C; 3) essentially in accordance with the DSC chart shown in Figure 1d; and / or 4) Essentially as per the TGA graph shown in Figure 1e.

[0010] Crystalline form A2 of the solvate of the compound of formula A In one embodiment, the crystalline form A2 of the solvate of compound of formula A has an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles of at least three, at least four, at least five, at least six, or seven characteristic peaks at 18.57±0.2°, 19.67±0.2°, 16.38±0.2°, 9.28±0.2°, 17.38±0.2°, 25.18±0.2°, and 13.11±0.2°. In some preferred embodiments, the XRPD characteristic peaks are essentially those shown in Table 2 below. [Table 2]

[0011] In some preferred embodiments, the XRPD pattern has essentially the pattern shown in FIG. 2a, and optionally has one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 153.88°C ± 2°C and one endothermic peak at 178.46°C ± 2°C; 2) In the TGA graph, there is a weight loss of 11.32±0.2 wt% before 165.00°C, and a weight loss of 2.83±0.2 wt% between 165.00°C and 230.00°C; 3) essentially according to the DSC chart shown in Figure 2b; and / or 4) Essentially as per the TGA graph shown in Figure 2c.

[0012] Crystalline form A3 of the solvate of the compound of formula A In one embodiment, the solvate of compound of formula A in crystalline form A3 has an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles of at least three, at least four, at least five, at least six, or seven characteristic peaks at 19.61±0.2°, 18.45±0.2°, 9.22±0.2°, 16.33±0.2°, 6.54±0.2°, 17.24±0.2°, and 9.80±0.2°. In some preferred embodiments, the XRPD characteristic peaks are essentially those shown in Table 3 below. [Table 3]

[0013] In some preferred embodiments, the XRPD pattern has essentially the pattern shown in FIG. 3a, and optionally has one or more of the following characteristics: 1) In the DSC chart, there is one exothermic peak at 90.56°C ± 2°C, and one endothermic peak at 152.55°C ± 2°C and 177.33°C ± 2°C respectively; 2) In the TGA graph, there is a weight loss of 12.08±0.2 wt% before 165.00℃, and a weight loss of 2.12±0.2 wt% between 165.00℃ and 230.00℃; 3) essentially according to the DSC chart shown in Figure 3b; and / or 4) Essentially as per the TGA graph shown in Figure 3c.

[0014] Crystalline form A4 of the solvate of the compound of formula A In one embodiment, the solvate of compound of formula A in crystalline form A4 has an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles of at least three, at least four, at least five, at least six, or seven characteristic peaks at 9.22±0.2°, 17.51±0.2°, 6.54±0.2°, 19.59±0.2°, 25.03±0.2°, 16.37±0.2°, and 18.51±0.2°. In some preferred embodiments, the XRPD characteristic peaks are essentially those shown in Table 4 below.

[0015] [Table 4]

[0016] In some preferred embodiments, the XRPD pattern has essentially the pattern shown in FIG. 4a, and optionally has one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 149.48℃±2℃; 2) In the TGA graph, there is a weight loss of 3.01±0.2 wt% before 160°C; 3) essentially according to the DSC chart shown in Figure 4b; and / or 4) Essentially as per the TGA graph shown in Figure 4c.

[0017] Crystalline form A5 of the solvate of the compound of formula A In one embodiment, the solvate of compound of formula A in crystalline form A5 has an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles of at least three, at least four, at least five, at least six, or seven characteristic peaks at 16.43±0.2°, 19.74±0.2°, 6.58±0.2°, 9.27±0.2°, 18.53±0.2°, 17.37±0.2°, and 9.88±0.2°. In some preferred embodiments, the XRPD characteristic peaks are essentially those shown in Table 5 below. [Table 5]

[0018] In some preferred embodiments, the XRPD pattern has essentially the pattern shown in FIG. 5a, and optionally has one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 154.86°C ± 2°C; 2) In the TGA graph, there is a weight loss of 6.75±0.2 wt% before 220°C; 3) essentially according to the DSC chart shown in Figure 5b; and / or 4) Essentially as per the TGA graph shown in Figure 5c.

[0019] Crystalline Form B of the Compound of Formula A In one embodiment, crystalline form B of the compound of formula A has an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles of at least three, at least four, at least five, at least six, or seven characteristic peaks at 3.98±0.2°, 12.35±0.2°, 12.05±0.2°, 19.09±0.2°, 7.92±0.2°, 15.78±0.2°, and 14.32±0.2°. In some preferred embodiments, the XRPD characteristic peaks are essentially as shown in Table 6 below.

[0020] [Table 6] In some preferred embodiments, the XRPD pattern has essentially the pattern shown in Figure 6c, and optionally has one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 25.54°C ± 2°C and one endothermic peak at 183.52°C ± 2°C; 2) In the TGA graph, there is a weight loss of 1.03±0.2 wt% before 100°C; 3) essentially according to the DSC chart shown in Figure 6d; and / or 4) Essentially as per the TGA graph shown in Figure 6e.

[0021] Crystalline Form C of the solvate of the compound of formula A In one embodiment, crystalline form C of the solvate of compound of formula A has an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles of at least three, at least four, at least five, at least six, or seven characteristic peaks at 20.60±0.2°, 17.94±0.2°, 13.110±0.2°, 19.42±0.2°, 23.97±0.2°, 26.31±0.2°, and 11.95±0.2°. In some preferred embodiments, the XRPD characteristic peaks are essentially those shown in Table 7 below. [Table 7]

[0022] In some preferred embodiments, the XRPD pattern has essentially the pattern shown in Figure 7a, and optionally has one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 127.33°C ± 2°C; 2) In the TGA graph, there is a weight loss of 16.21±0.2 wt% before 160.00°C, and a weight loss of 9.29±0.2 wt% between 160.00°C and 260.00°C; 3) essentially according to the DSC chart shown in Figure 7b; and / or 4) Essentially as per the TGA graph shown in Figure 7c. Crystalline form D1 of the solvate of the compound of formula A In one embodiment, the solvate of compound of formula A in crystalline form D1 has an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles of at least three, at least four, at least five, at least six, or seven characteristic peaks at 17.99±0.2°, 8.82±0.2°, 17.32±0.2°, 9.26±0.2°, 19.14±0.2°, 9.95±0.2°, and 31.53±0.2°. In some preferred embodiments, the XRPD characteristic peaks are essentially as shown in Table 8 below.

[0023] [Table 8] In some preferred embodiments, the XRPD pattern has essentially the pattern shown in Figure 8a, and optionally has one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 161.17℃±2℃; 2) In the TGA graph, there is a weight loss of 11.30±0.2 wt% before 210°C; 3) essentially according to the DSC chart shown in Figure 8b; and / or 4) Essentially as per the TGA graph shown in Figure 8c.

[0024] Crystalline form D2 of the solvate of the compound of formula A In one embodiment, the solvate of compound of formula A in crystalline form D2 has an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles of at least three, at least four, at least five, at least six, or seven characteristic peaks at 17.38±0.2°, 17.99±0.2°, 19.57±0.2°, 9.80±0.2°, 31.55±0.2°, 25.05±0.2°, and 6.55±0.2°. In some preferred embodiments, the XRPD characteristic peaks are essentially those shown in Table 9 below.

[0025] [Table 9]

[0026] In some preferred embodiments, the XRPD pattern has essentially the pattern shown in Figure 9a, and optionally has one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 83.30°C ± 2°C and one endothermic peak at 126.89°C ± 2°C; 2) In the TGA graph, there is a weight loss of 12.51±0.2 wt% before 110.00°C, and a weight loss of 12.26±0.2 wt% between 110.00°C and 250.00°C; 3) essentially according to the DSC chart shown in Figure 9b; and / or 4) Essentially as per the TGA graph shown in Figure 9c.

[0027] Crystalline Form E of the Compound of Formula A In one embodiment, crystalline form E of the compound of formula A has at least three, at least four, at least five, at least six, or seven characteristic peaks in an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles at 11.14±0.2°, 15.76±0.2°, 12.59±0.2°, 19.71±0.2°, 9.56±0.2°, 17.83±0.2°, and 13.58±0.2°. In some preferred embodiments, the XRPD characteristic peaks are essentially those shown in Table 10 below.

[0028] [Table 10] In some preferred embodiments, the XRPD pattern has essentially the pattern shown in Figure 10c, and optionally has one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 37.94°C ± 2°C and one endothermic peak at 190.71°C ± 2°C; 2) In the TGA graph, there is a weight loss of 1.17±0.2 wt% before 130°C; 3) essentially according to the DSC chart shown in Figure 10d; and / or 4) Essentially as per the TGA graph shown in Figure 10e.

[0029] Crystalline Form F of the compound of formula A In one embodiment, crystalline form F of the compound of formula A has at least three, at least four, at least five, at least six, or seven characteristic peaks in an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles at 17.70±0.2°, 21.46±0.2°, 27.66±0.2°, 19.20±0.2°, 17.17±0.2°, 19.44±0.2°, and 22.01±0.2°. In some preferred embodiments, the XRPD characteristic peaks are essentially those shown in Table 11 below. [Table 11]

[0030] In some preferred embodiments, the XRPD pattern has essentially the pattern shown in FIG. 11a, and optionally has one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 216.58°C ± 2°C; 2) In the TGA graph, there is a weight loss of 0.598±0.2 wt% before 100°C; 3) essentially according to the DSC chart shown in Figure 11b; and / or 4) Essentially as per the TGA graph shown in Figure 11c.

[0031] Crystalline Form G of the Compound of Formula A In one embodiment, crystalline form G of the compound of formula A has at least three, at least four, at least five, at least six, or seven characteristic peaks in an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles at 18.83±0.2°, 13.88±0.2°, 21.45±0.2°, 26.75±0.2°, 15.92±0.2°, 17.95±0.2°, and 13.14±0.2°. In some preferred embodiments, the XRPD characteristic peaks are essentially those shown in Table 12 below. [Table 12]

[0032] In some preferred embodiments, the XRPD pattern has essentially the pattern shown in Figure 12c, and optionally has one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 236.59°C ± 2°C; 2) In the TGA graph, there is a weight loss of 0.52±0.2 wt% before 150°C; 3) essentially according to the DSC chart shown in Figure 12d; and / or 4) Essentially as per the TGA graph shown in Figure 12e.

[0033] Crystalline form H of the compound of formula A In one embodiment, the compound of formula A has crystalline form H, which has at least three, at least four, at least five, at least six, or seven characteristic peaks in an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles at 18.30±0.2°, 3.80±0.2°, 19.05±0.2°, 18.53±0.2°, 11.81±0.2°, 11.33±0.2°, and 16.04±0.2°. In some preferred embodiments, the XRPD characteristic peaks are essentially those shown in Table 13 below. [Table 13] In some preferred embodiments, the XRPD pattern has essentially the pattern shown in Figure 13a, and optionally has one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 77.45°C ± 2°C and one endothermic peak at 154.75°C ± 2°C; 2) In the TGA graph, there is a weight loss of 0.19±0.2 wt% before 120°C; 3) essentially according to the DSC chart shown in Figure 13b; and / or 4) Essentially as per the TGA graph shown in Figure 13c.

[0034] The amorphous form of the compound of formula A shown in PLM Figure 14d In one embodiment, the amorphous form of the compound of formula A shown in PLM Figure 14d preferably has an XRPD pattern shown in Figure a14a, and optionally has one or more of the following characteristics: 1) In the mDSC chart, there is one glass transition temperature at 129.30°C ± 2.0°C; 2) In the TGA graph, there is a weight loss of 2.7 wt% before 210°C ± 2.0°C; 3) essentially as shown in Figure 14b; and / or 4) Essentially as per the TGA graph shown in Figure 14c.

[0035] In a second aspect, the present invention provides a method for preparing a crystalline or amorphous form of a compound of formula A, or a pharmaceutically acceptable salt thereof, or a solvate thereof, comprising obtaining said crystalline or amorphous form from a compound of formula A, or a pharmaceutically acceptable salt thereof, by turbidity, slow cooling, fast cooling, slow evaporation, fast evaporation, anti-solvent dropping, anti-solvent back dropping, vapor diffusion, or heat-cool DSC crystallization methods, or by spray drying, hot melt extrusion, or solvent evaporation. In the preparation method, the compound of formula A is synthesized in a laboratory by the method described in the specific examples. The solvent may be one or more of solvents commonly used in laboratories, such as water, alkane solvents, alcohol solvents, ketone solvents, ester solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, nitrile solvents, ether solvents, aliphatic hydrocarbon solvents, and polar aprotic solvents such as DMF and DMSO. Here, the mass / volume ratio of the compound of formula A to the solvent may be 100 mg:(0.1-1 mL). In one embodiment, the present invention provides a method for preparing a crystalline form of a solvate of a compound of formula A, comprising the steps of mixing a compound of formula A with a solvent corresponding to the type of solvate and isolating and drying the resulting solid to obtain a crystalline form of a solvate of a compound of formula A.

[0036] In some preferred embodiments, the solvent corresponding to the type of solvate is, for example, but not limited to, 1,4-dioxane, ethyl acetate, toluene, chloroform, 2-methyltetrahydrofuran, methyl-t-butyl ether, acetone, N,N-dimethylformamide, acetonitrile, and the like. In one embodiment, the present invention provides a method for preparing an amorphous form of a compound of formula A, comprising the steps of combining a compound of formula A with a solvent and spray drying the resulting solution to obtain the amorphous form of the compound of formula A. In some preferred embodiments, the solvent may be one or more of solvents commonly used in laboratories, such as water, alkane solvents, alcohol solvents, ketone solvents, ester solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, nitrile solvents, ether solvents, aliphatic hydrocarbon solvents, polar aprotic solvents such as DMF and DMSO, and preferably dichloromethane (DCM).

[0037] In a third aspect, the present invention provides a pharmaceutical composition comprising: (a) the form described in the first aspect; and (b) a pharmaceutically acceptable carrier or excipient. The compound of formula A or its salt, solvate, crystalline or amorphous form may be in a therapeutically effective amount. The pharmaceutically acceptable excipient may be any excipient well known in the art, and in the case of solid formulations, includes, but is not limited to, bases, binders, disintegrants, lubricants, flow agents, release rate controlling agents, plasticizers, preservatives, antioxidants, etc. In a fourth aspect, the present invention provides a pharmaceutical formulation comprising the above-described pharmaceutical composition, which may be a solid formulation, or may be a powder, granules, tablet, capsule, drop pill or film.

[0038] In a fifth aspect, the present invention provides the use of the above crystalline form, amorphous form or drug composition in the manufacture of a medicament for treating a proliferative disorder, wherein the proliferative disorder is selected from the group consisting of breast cancer, colon cancer, brain cancer, prostate cancer, kidney cancer, pancreatic adenocarcinoma, ovarian cancer, head and neck cancer, melanoma, colorectal cancer, gastric cancer, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, testicular cancer, Merkel cell carcinoma, glioblastoma, neuroblastoma, leukemia (acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML ... (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMOL), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, adult T-cell leukemia), lymphomas (small lymphocytic lymphoma (SLL), Hodgkin's lymphoma (nodular sclerosing, mixed cell, lymphocyte-rich, lymphopenic or non-reduced and nodular lymphocyte-driven) Hodgkin's lymphoma (all subtypes), non-Hodgkin's lymphoma (all subtypes), chronic lymphocytic leukemia / small lymphocytic lymphoma, precursor B-lymphoblastic leukemia, lymphoma (e.g., Waldenstrom's macroglobulinemia), splenic marginal zone lymphoma, plasma cell neoplasms (plasma cell myeloma, plasmacytoma, monoclonal gammopathy, heavy chain disease), extranodal marginal zone B-cell lymphoma (MALT lymphoma), lymphoma (NMZL) , follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, aggressive NK-cell leukemia, adult T-cell leukemia / lymphoma, extranodal NK / T-cell lymphoma (nasal type), enteropathy-type T-cell lymphoma, hepatosplenic Uses include cancers of the lymphoid organs and hematological malignancies, including T-cell lymphoma, blastic NK-cell lymphoma, mycosis fungoides / Sezary syndrome, primary cutaneous CD30-positive T-cell lymphoma disease, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma (non-specific), anaplastic large cell lymphoma), multiple myeloma (plasma cell myeloma or Kahler's disease). In a sixth aspect, the present invention provides a method of treating a proliferative disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a form of the first aspect of the invention or a pharmaceutical composition of the third aspect of the invention or a pharmaceutical formulation of the fourth aspect of the invention.

[0039] In some preferred embodiments, the subject is a mammal, for example, a human. The crystalline or amorphous forms of the compound of formula A or its salts or solvates of the present invention have the following advantages: In the present invention, for the first time, several unreported crystalline or amorphous forms of the compound of formula A or its salts or solvates have been discovered, and said forms serve as an important basis for subsequent drug development, formulation development and production. Of course, it is understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be described here one by one due to space limitations. [Brief explanation of the drawings]

[0040] [Figure 1a] FIG. 1a shows the chemical purity spectrum of crystalline form A1 of the compound of formula A. [Figure 1b] FIG. 1b shows the chiral purity spectrum of crystalline form A1 of the compound of formula A. [Figure 1c] FIG. 1c shows the powder X-ray diffraction pattern of crystalline form A1 of the compound of formula A. [Figure 1d] FIG. 1d shows the differential scanning calorimetry chart of crystalline form A1 of the compound of formula A. [Figure 1e] FIG. 1e shows the thermogravimetric analysis graph of crystalline form A1 of the compound of formula A. [Figure 1f] FIG. 1f shows the 1H NMR spectrum of crystalline form A1 of the compound of formula A. [Figure 2a] FIG. 2a shows the powder X-ray diffraction pattern of crystalline form A2 of the compound of formula A. [Figure 2b] FIG. 2b shows the differential scanning calorimetry chart of crystalline form A2 of the compound of formula A. [Figure 2c] FIG. 2c shows the thermogravimetric analysis graph of crystalline form A2 of the compound of formula A. [Figure 2d] FIG. 2d shows the 1H NMR spectrum of crystalline form A2 of the compound of formula A. [Figure 3a] FIG. 3a shows the powder X-ray diffraction pattern of crystalline form A3 of the compound of formula A. [Figure 3b] FIG. 3b shows the differential scanning calorimetry chart of crystalline form A3 of the compound of formula A. [Figure 3c] FIG. 3c shows the thermogravimetric analysis graph of crystalline form A3 of the compound of formula A. [Figure 3d] FIG. 3d shows the 1H NMR spectrum of crystalline form A3 of the compound of formula A. [Figure 4a] FIG. 4a shows the powder X-ray diffraction pattern of crystalline form A4 of the compound of formula A. [Figure 4b] FIG. 4b shows the differential scanning calorimetry chart of crystalline form A4 of the compound of formula A. [Figure 4c] FIG. 4c shows the thermogravimetric analysis graph of crystalline form A4 of the compound of formula A. [Figure 4d] FIG. 4d shows the 1H NMR spectrum of crystalline form A4 of the compound of formula A. [Figure 5a] FIG. 5a shows the powder X-ray diffraction pattern of crystalline form A5 of the compound of formula A. [Figure 5b] FIG. 5b shows the differential scanning calorimetry chart of crystalline form A5 of the compound of formula A. [Figure 5c] FIG. 5c shows the thermogravimetric analysis graph of crystalline form A5 of the compound of formula A. [Figure 5d] FIG. 5d shows the 1H NMR spectrum of crystalline form A5 of the compound of formula A. [Figure 6a] FIG. 6a shows the chemical purity spectrum of crystalline form B of compound of formula A. [Figure 6b] FIG. 6b shows the chiral purity spectrum of crystalline form B of compound of formula A. [Figure 6c] FIG. 6c shows the powder X-ray diffraction pattern of crystalline form B of the compound of formula A. [Figure 6d] FIG. 6d shows the differential scanning calorimetry chart of crystalline form B of the compound of formula A. [Figure 6e] FIG. 6e shows the thermogravimetric analysis graph of crystalline form B of compound of formula A. [Figure 6f] FIG. 6f shows the 1H NMR spectrum of crystalline form B of compound of formula A. [Figure 7a] FIG. 7a shows the powder X-ray diffraction pattern of crystalline form C of the compound of formula A. [Figure 7b] FIG. 7b shows the differential scanning calorimetry chart of crystalline form C of the compound of formula A. [Figure 7c] FIG. 7c shows the thermogravimetric analysis graph of crystalline form C of the compound of formula A. [Figure 7d] FIG. 7d shows the 1H NMR spectrum of crystalline form C of compound of formula A. [Figure 8a] FIG. 8a shows the powder X-ray diffraction pattern of crystalline form D1 of the compound of formula A. [Figure 8b] FIG. 8b shows the differential scanning calorimetry chart of crystalline form D1 of the compound of formula A. [Figure 8c] FIG. 8c shows the thermogravimetric analysis graph of crystalline form D1 of the compound of formula A. [Figure 8d] FIG. 8d shows the 1H NMR spectrum of crystalline form D1 of the compound of formula A. [Figure 9a] FIG. 9a shows the powder X-ray diffraction pattern of crystalline form D2 of the compound of formula A. [Figure 9b] FIG. 9b shows the differential scanning calorimetry chart of crystalline form D2 of the compound of formula A. [Figure 9c] FIG. 9c shows the thermogravimetric analysis graph of crystalline form D2 of the compound of formula A. [Figure 9d] FIG. 9d shows the 1H NMR spectrum of crystalline form D2 of the compound of formula A. [Figure 10a] FIG. 10a shows the chemical purity spectrum of crystalline form E of compound of formula A. [Figure 10b] FIG. 10b shows the chiral purity spectrum of crystalline form E of compound of formula A. [Figure 10c]FIG. 10c shows the powder X-ray diffraction pattern of crystalline form E of the compound of formula A. [Figure 10d] FIG. 10d shows the differential scanning calorimetry chart of crystalline form E of the compound of formula A. [Figure 10e] FIG. 10e shows the thermogravimetric analysis graph of crystalline form E of the compound of formula A. [Figure 10f] FIG. 10f shows the 1H NMR spectrum of crystalline form E of compound of formula A. [Figure 11a] FIG. 11a shows the powder X-ray diffraction pattern of crystalline form F of the compound of formula A. [Figure 11b] FIG. 11b shows the differential scanning calorimetry chart of crystalline form F of the compound of formula A. [Figure 11c] FIG. 11c shows the thermogravimetric analysis graph of crystalline form F of the compound of formula A. [Figure 11d] FIG. 11d shows the 1H NMR spectrum of crystalline form F of the compound of formula A. [Figure 12a] FIG. 12a shows the chemical purity spectrum of crystalline form G of compound of formula A. [Figure 12b] FIG. 12b shows the chiral purity spectrum of crystalline form G of compound of formula A. [Figure 12c] FIG. 12c shows the powder X-ray diffraction pattern of crystalline form G of the compound of formula A. [Figure 12d] FIG. 12d shows the differential scanning calorimetry chart of crystalline form G of the compound of formula A. [Figure 12e] FIG. 12e shows the thermogravimetric analysis graph of crystalline form G of the compound of formula A. [Figure 12f] FIG. 12f shows the 1H NMR spectrum of crystalline form G of the compound of formula A. [Figure 13a] FIG. 13a shows the powder X-ray diffraction pattern of crystalline form H of the compound of formula A. [Figure 13b] FIG. 13b shows the differential scanning calorimetry chart of crystalline form H of the compound of formula A. [Figure 13c] FIG. 13c shows the thermogravimetric analysis graph of crystalline form H of the compound of formula A. [Figure 13d]FIG. 13d shows the 1H NMR spectrum of crystalline form H of compound of formula A. [Figure 14a] FIG. 14a shows the powder X-ray diffraction pattern of the amorphous compound of formula A. [Figure 14b] FIG. 14b shows a modulated differential scanning calorimetry (mDSC) chart of the amorphous form of the compound of formula A. [Figure 14c] FIG. 14c shows the amorphous thermogravimetric analysis graph of the compound of formula A. [Figure 14d] FIG. 14d shows a polarized light microscope (PLM) view of the amorphous form of the compound of formula A. [Figure 15a] FIG. 15a shows the chemical purity of crystalline form B of the compound of formula A. [Figure 15b] FIG. 15b shows the chiral purity of crystalline form B of the compound of formula A. [Figure 15c] FIG. 15c shows the chemical purity of crystalline form B of the compound of formula A. [Figure 15d] FIG. 15d shows the chiral purity of crystalline form B of the compound of formula A. [Figure 15e] FIG. 15e shows the powder X-ray diffraction pattern overlay of the stability experiment of crystalline form B of compound of formula A. [Figure 15f] FIG. 15f shows the chemical purity of crystalline form B of the compound of formula A. [Figure 15g] FIG. 15g shows the chiral purity of crystalline form B of the compound of formula A. [Figure 15h] FIG. 15h shows the chemical purity of crystalline form B of the compound of formula A. [Figure 15i] FIG. 15i shows the chiral purity of crystalline form B of the compound of formula A. [Figure 16a] FIG. 16a shows the chemical purity of crystalline form E of the compound of formula A. [Figure 16b] FIG. 16b shows the chiral purity of crystalline form E of the compound of formula A. [Figure 16c] FIG. 16c shows the chemical purity of crystalline form E of the compound of formula A. [Figure 16d] FIG. 16d shows the chiral purity of crystalline form E of the compound of formula A. [Figure 16e]FIG. 16e shows the powder X-ray diffraction pattern overlay of the stability experiment of crystalline form E of the compound of formula A. [Figure 16f] FIG. 16f shows the chemical purity of crystalline form E of the compound of formula A. [Figure 16g] FIG. 16g shows the chiral purity of crystalline form E of the compound of formula A. [Figure 16h] FIG. 16h shows the chemical purity of crystalline form E of the compound of formula A. [Figure 16i] FIG. 16i shows the chiral purity of crystalline form E of the compound of formula A. [Figure 17a] FIG. 17a shows the chemical purity of crystalline form G of the compound of formula A. [Figure 17b] FIG. 17b shows the chiral purity of crystalline form G of the compound of formula A. [Figure 17c] FIG. 17c shows the powder X-ray diffraction pattern overlay of the stability experiment of crystalline form G of the compound of formula A. [Figure 17d] FIG. 17d shows the chemical purity of crystalline form G of the compound of formula A. [Figure 17e] FIG. 17e shows the chiral purity of crystalline form G of the compound of formula A. [Figure 17f] FIG. 17f shows the chemical purity of crystalline form G of the compound of formula A. [Figure 17g] FIG. 17g shows the chiral purity of crystalline form G of the compound of formula A. [Figure 18a] FIG. 18a shows the DVS spectrum of crystalline form B of the compound of formula A. [Figure 18b] FIG. 18b shows the powder X-ray diffraction patterns of crystalline form B of compound of formula A before and after the hygroscopicity experiment. [Figure 19a] FIG. 19a shows the DVS spectrum of crystalline form E of the compound of formula A. [Figure 19b] FIG. 19b shows the powder X-ray diffraction patterns of crystalline form E of compound of formula A before and after the hygroscopicity experiment. [Figure 20a] FIG. 20a shows the DVS spectrum of crystalline form G of the compound of formula A. [Figure 20b]FIG. 20b shows the powder X-ray diffraction patterns of crystalline form G of compound of formula A before and after the hygroscopicity experiment. [Figure 21a] FIG. 21a shows the overlay of the XRPD pattern of the sample obtained in crystalline form G after a tableting simulation experiment of the compound of formula A.

[0041] Specific Embodiments Through long-term and in-depth research, the inventors have found several crystalline and amorphous forms of the compound of formula A or its pharmaceutically acceptable salts, or solvates thereof, which have better drug bioavailability, and are highly pure and highly stable, making them suitable for the preparation of pharmaceutical compositions for treating proliferative diseases, and therefore more advantageous for the treatment of diseases such as cancer, bone marrow proliferative diseases, and inflammation. In addition, the crystalline and amorphous forms of the present invention are less likely to scatter and are easier to collect during the pharmaceutical preparation process, such as distribution, resulting in less waste and being more beneficial for protecting the health of operators. Based on this, the inventors have completed the present invention.

[0042] active ingredient In the present invention, the active ingredient is the amorphous or crystalline form of the compound of formula A, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Preferably, the active ingredient is crystalline form A1, crystalline form A2, crystalline form A3, crystalline form A4, crystalline form A5, crystalline form B, crystalline form C, crystalline form D1, crystalline form D2, crystalline form E, crystalline form F, crystalline form G, crystalline form H, and amorphous form as described above.

[0043] [Table 14]

[0044] Polymorph Solids exist in either amorphous or crystalline form. In crystalline form, molecules are located at sites in a three-dimensional crystal lattice. When a compound crystallizes from a solution or solution, it may crystallize in different spatial lattices (a phenomenon called "polymorphism"), resulting in the formation of crystals with different crystalline forms, each of which is called a "polymorph." Different polymorphs of a substance may differ from each other in one or more physical properties (e.g., solubility and dissolution rate, true specific gravity, crystal shape, sediment morphology, flowability, and / or solid-state stability). Crystal form screening Crystalline form A1 may be used as the starting material, and its chemical purity is shown in Figure 1a, and its chiral purity is shown in Figure 1b. In screening, the polymorphism of compound of formula A was investigated by turbidity, slow cooling, fast cooling, slow evaporation, fast evaporation, antisolvent dropwise addition, antisolvent reverse dropwise addition, vapor diffusion, or heating-cooling DSC crystallization methods. The compound of formula A exhibits complex polymorphic behavior, and 13 polymorphs and pseudopolymorphs have been discovered and identified, including two anhydrous crystalline forms, designated Form F and Form G. Three hydrates have been designated Form B, Form E, and Form H. Eight solvates have been designated Form A1, Form A2, Form A3, Form A4, Form A5, Form C, Form D1, and Form D2. Amorphous samples were also obtained in this study using solvent systems such as acetone and tetrahydrofuran. Forms A1, A2, A3, A4 and A5 have similar XRPD patterns, have similar crystal structures and are presumed to be isomorphous solvates of each other. Forms D1 and D2 also have similar XRPD patterns, have similar crystal structures and are presumed to be another set of isomorphous solvates of each other. As used herein, the term "room temperature" generally refers to 4 to 30°C, preferably 20±5°C. In the present invention, polymorphs of the compound of formula A were prepared and then their properties were studied using several methods and apparatuses as follows.

[0045] Powder X-ray diffraction Methods for measuring powder X-ray diffraction of crystalline forms are known in the art, for example, a Bruker D8 Advance powder X-ray diffractometer is used to obtain patterns with a Cu / K-α1 (λ=1.5406 Å) radiation target at a scan rate of 0.02° per minute. As is well known in the art, due to experimental variability, when X-ray diffraction patterns are measured on different instruments, peak positions are assumed to be equivalent if the difference between the two θ (2θ) values ​​is within 0.2° (i.e., ±0.2°). For example, the United States Pharmacopoeia specifies that the angular settings of the 10 strongest diffraction peaks and those of a reference material are considered similar if the difference between the angular settings is within ±0.2° and the relative intensities of the peaks change by no more than 20%. Therefore, peak positions within 0.2° of the positions listed herein are assumed to be similar. Unless otherwise stated, all X-ray diffraction angles listed herein are based on a copper K-α source.

[0046] Differential scanning calorimetry Also known as "differential scanning calorimetry" (DSC), this technique measures the relationship between the energy difference between a test substance and a reference substance and the temperature during heating. The position, shape, and number of peaks in a DSC graph are related to the properties of the substance, allowing for qualitative identification of the substance. In this field, this method is often used to measure multiple parameters of substances, such as phase transition temperatures, glass transition temperatures, and heat of reaction. The DSC measurement method is known in the art. For example, a TA Discovery 2500 differential scanning calorimeter is used, and the temperature is raised from 0°C to 250°C at a rate of 10°C / min to obtain a DSC scan chart of the crystalline form.

[0047] nuclear magnetism The structure of the crystalline form can also be identified with the aid of nuclear magnetic resonance (NMR), and the measurement method is known in the art. In the present invention, a Bruker Avance-AV-400 MHz spectrometer is preferably used. Thermogravimetric analysis (TGA) measurement The sample (2-5 mg) is placed in an aluminum dish and analyzed by the following method: The test is terminated when the sample loses more than 20% weight by heating from room temperature to 300°C at a rate of 10°C / min under atmospheric conditions. Polarized Light Microscope (PLM) Measurement Nikon LV100POL with 5MP CCD -Physical Lens: 10x-50x

[0048] Dynamic Water Sorption (DVS) Measurement - DVS Intrinsic Dynamic Vapor Sorption Apparatus -Gas flow rate 200 sccm, chamber temperature 25℃. Crystalline Forms of the Present Invention As used herein, the term "crystalline forms of the present invention" includes amorphous or crystalline forms of the compound of formula A, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Preferably, the present invention includes, but is not limited to, crystalline form A1, crystalline form A2, crystalline form A3, crystalline form A4, crystalline form A5, crystalline form B, crystalline form C, crystalline form D1, crystalline form D2, crystalline form E, crystalline form F, crystalline form G, and crystalline form H.

[0049] Amorphous form "Amorphous" or "amorphous form" refers to a substance that forms when its particles (molecules, atoms, ions) are arranged non-periodically in three-dimensional space, and is characterized by a powder X-ray diffraction pattern that lacks sharp scattering peaks. Amorphous is a special physical form of solid matter, and its locally ordered structural characteristics suggest a close relationship to crystalline forms of matter. In the present invention, preferably the amorphous form has an XRPD pattern as shown in Figure 14a, and optionally has one or more of the following characteristics: 1) In the mDSC chart, there is one glass transition temperature at 129.30°C ± 2.0°C; 2) In the TGA graph, there is a weight loss of 2.7 wt% before 210°C ± 2.0°C; 3) essentially as shown in Figure 14b; and / or 4) Essentially as per the TGA graph shown in Figure 14c.

[0050] Methods for producing the crystalline or amorphous forms of the present invention The present invention provides a method for preparing a crystalline or amorphous form of a compound of formula A, or a pharmaceutically acceptable salt or solvate thereof, comprising obtaining said crystalline or amorphous form from a compound of formula A, or a pharmaceutically acceptable salt thereof, by turbidity, slow cooling, fast cooling, slow evaporation, fast evaporation, anti-solvent dropwise addition, anti-solvent back-dropwise addition, vapor diffusion, or heat-cool DSC crystallization methods, or by spray drying, hot melt extrusion, or solvent evaporation. In the preparation method, the compound of Formula A is synthesized in a laboratory by the method described in the specific examples. The solvent may be one or more of solvents commonly used in laboratories, such as water, alkane solvents, alcohol solvents, ketone solvents, ester solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, nitrile solvents, ether solvents, aliphatic hydrocarbon solvents, and polar aprotic solvents such as N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO). Here, the mass / volume ratio of the compound of Formula A to the solvent may be 100 mg:(0.1-1 mL).

[0051] In one embodiment, the present invention provides a method for preparing a crystalline form of a solvate of a compound of formula A, comprising the steps of mixing a compound of formula A with a solvent corresponding to the type of solvate and isolating and drying the resulting solid to obtain a crystalline form of a solvate of a compound of formula A. Preferably, the process for preparing crystalline form A1 comprises reslurrying the compound of formula A with MTBE, isolating and drying to obtain crystalline form A1. Preferably, the method for preparing crystalline form A2 comprises suspending crystalline form A1 with 1,4-dioxane and separating to obtain crystalline form A2. Preferably, the method for preparing crystalline form A3 comprises suspending crystalline form A1 with toluene and separating to obtain crystalline form A3. Preferably, the method for preparing crystalline form A4 includes mixing crystalline form A1 with dichloromethane and rapidly volatilizing it to obtain crystalline form A4. Preferably, the method for preparing crystalline form A5 comprises suspending crystalline form A1 with ethyl acetate and separating to obtain crystalline form A5.

[0052] Preferably, the method for preparing crystalline form B comprises suspending crystalline form A1 with ethanol, separating and drying to obtain crystalline form B. Preferably, the method for preparing crystalline form C comprises suspending crystalline form A1 with dimethyl sulfoxide and separating to obtain crystalline form C. Preferably, the method for preparing crystalline form D1 comprises suspending crystalline form A1 with isopropanol and separating to obtain crystalline form D1. Preferably, the method for preparing crystalline form D2 includes suspending crystalline form A1 in a mixed solution (DMSO:water=24:76, v / v) and separating to obtain crystalline form D2. Preferably, the method for preparing crystalline form E includes mixing crystalline form A1 with a mixed solution of acetonitrile / water (v:v=80:20), heating-cooling, separating, and drying to obtain crystalline form E.

[0053] Preferably, the method for preparing crystalline form F comprises suspending crystalline form A1 in water and separating to obtain crystalline form F. Preferably, the method for preparing crystalline form H comprises mixing crystalline form E with methanol, heating-cooling, and separating to obtain crystalline form H. In some preferred embodiments, the solvent corresponding to the type of solvate is, for example, but not limited to, 1,4-dioxane, ethyl acetate, toluene, chloroform, 2-methyltetrahydrofuran, methyl-t-butyl ether, acetone, N,N-dimethylformamide, acetonitrile, and the like. The solvent used in the amorphous preparation method described in the present invention is not particularly limited, and any solvent that can dissolve the starting materials to a certain extent and does not affect their properties is included in the present invention. In addition, many similar modifications, equivalent substitutions, or solvents, solvent combinations, and different ratios of solvent combinations equivalent to those described in the present invention are all included in the scope of the present invention. In the present invention, suitable solvents for use in each reaction step are shown.

[0054] In one embodiment, the present invention provides a method for preparing an amorphous form of a compound of formula A, comprising the steps of combining a compound of formula A with a solvent and spray drying the resulting solution to obtain the amorphous form of the compound of formula A. In some preferred embodiments, the solvent may be a solvent commonly used in laboratories, for example, the solvent is one or more of water, alcohol-based solvents, ester-based solvents, ketone-based solvents, halogenated hydrocarbon solvents, nitrile-based solvents, and ether-based solvents, wherein the alcohol-based solvent is preferably ethanol and / or methanol, the ester-based solvent is preferably ethyl acetate, the ketone-based solvent is preferably acetone, the halogenated hydrocarbon solvent is preferably dichloromethane, the nitrile-based solvent is preferably acetonitrile, and the ether-based solvent is preferably tetrahydrofuran, and preferably the solvent is one or more of ethyl acetate, acetone, tetrahydrofuran, methyl t-butyl ether, and acetonitrile.

[0055] Preferably, the separation is performed by centrifugation through a 0.45 μm nylon membrane centrifuge tube at a constant rotation speed (eg, 14,000 rpm). Drug Composition The crystalline and amorphous forms of the present invention have excellent effects in treating proliferative diseases, and therefore the crystalline and amorphous forms of the present invention and pharmaceutical compositions containing the crystalline and amorphous forms of the present invention as the main active ingredient are useful for treating, preventing, and alleviating proliferative diseases. According to existing technology, the forms described in the present invention are useful for treating diseases such as cancer, bone marrow proliferative diseases, and inflammation. The pharmaceutical composition of the present invention comprises a crystalline or amorphous form of the present invention within a safe and effective amount and a pharmaceutically acceptable excipient and / or carrier. The crystalline and amorphous forms of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds. The pharmaceutical composition may be in a dosage form suitable for administration to the human body, such as tablets, capsules, granules, powders, or pills, preferably tablets, capsules, granules, disintegrating tablets, sustained-release or controlled-release tablets, etc.

[0056] The pharmaceutical compositions according to the present invention can be prepared by various methods well known in the art, and can be prepared into dosage forms suitable for administration to the human body, such as tablets, capsules, granules, etc., by mixing a therapeutically effective amount of one or more of the compounds of formula A or its salts, solvates in crystalline or amorphous form with one or more pharmaceutically acceptable adjuvants. A "therapeutically effective amount" is an amount of a compound form according to the present invention that, when administered to a patient in need thereof, is sufficient to effect treatment of the disease state, condition, or disorder for which the compound acts. Such amount is sufficient to produce the biological or medical response in a tissue or system or patient that is desired by a researcher or clinician.

[0057] "Safe and effective amount" refers to an amount of the compound (polymorph) sufficient to significantly improve the symptoms without causing severe side effects. Typically, the pharmaceutical composition contains the crystalline or amorphous form of the present invention in an amount of 0.1 to 2000 mg / formulation, preferably 0.1 to 200 mg / formulation. Preferably, the "formulation" is a capsule or tablet. "Pharmaceutically acceptable vehicle" refers to one or more compatible solid or liquid fillers or gel substances that are applicable to humans and must have sufficient purity and sufficiently low toxicity. "Compatible" means that each component in the composition can be blended with the active ingredient of the present invention and with each other without significantly reducing the effectiveness of the active ingredient. Some examples of pharmaceutically acceptable vehicles include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., tinctures, etc.), and the like. R ), humectants (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, and pyrogen-free distilled water.

[0058] The mode of administration of the crystalline and amorphous forms or drug compositions of the present invention is not particularly limited, but typical modes of administration include, but are not limited to, oral administration, intratumoral administration, rectal administration, parenteral gastrointestinal administration (intravenous, intramuscular, or subcutaneous administration), and topical administration. When using pharmaceutical compositions, a safe and effective amount of the crystalline and amorphous forms of the present invention is administered to a mammal (e.g., a human) in need of treatment, at a dosage that is pharmacologically effective, typically 0.1-2000 mg, preferably 0.1-200 mg, daily for a human weighing 60 kg. Of course, the specific dosage should be determined taking into account factors such as the mode of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0059] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) a filler or compatibilizer, such as microcrystalline cellulose, starch, lactose, sucrose, glucose, mannitol, or silicic acid; (b) a binder, such as hydromethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, or gum arabic; (c) a humectant, such as glycerin; or (d) a disintegrant, such as agar, calcium carbonate, or potato. They are mixed with ingredients such as potato starch, tapioca starch, alginic acid, certain complex silicates, sodium carbonate, crospovidone, croscarmellose sodium, (e) solution retardants such as paraffin, (f) absorption promoters such as ammonium compounds, (g) wetting agents such as cetanol and glycerin monostearate, (h) adsorbents such as kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain a buffer.

[0060] Solid dosage forms, such as tablets, pills, capsules, pills, and granules, can be prepared with coatings or shells, such as enteric coatings and other materials known in the art. Opacifying agents may be included, and in such compositions, the release of the active ingredient may be delayed in a certain part of the digestive tract. Examples of encapsulating materials that can be used include polymeric materials and wax-based materials. If necessary, the active ingredient may also be formed into a microencapsulated form with one or more of the above-mentioned excipients.

[0061] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, compatibilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn oil, olive oil, castor oil, and sesame oil, or mixtures of these substances. Besides these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and perfumes. In addition to the active ingredient, suspensions may contain a suspending agent such as, for example, ethoxylated isooctadecanol, polyoxyethylene sorbitol or sorbitan esters, microcrystalline cellulose, aluminum methoxy or agar, or mixtures of these substances.

[0062] Compositions for parenteral injection include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions and emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof. The crystalline and amorphous dosage forms of the present invention for topical administration include ointments, powders, poultices, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants, as required. The main advantages of the present invention are as follows: 1. A series of novel N-((S)-5-chloropyridin-2-yl)(cyclobutyl)methyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoindole-5-carboxamides or their salts or solvates in crystalline or amorphous form are provided. 2. The resulting amorphous or crystalline forms have excellent stability, solubility, and bioavailability. Example 1 Preparation of Crystalline Form A1 The compound of formula A was prepared according to the method of Example 15 of PCT / CN2022 / 097236, and then reslurried in MTBE to obtain crystalline form A1. [ka] Compound 1 (3.25 g, 12.3 mmol, hydrochloride salt), compound 2 (4.67 g, 12.9 mmol), NMM (6.2 g, 61.3 mmol), and T3P (5.6 g, 17.6 mmol) were placed in a round-bottom flask containing dimethylacetamide (DMAc) (50 mL). The mixture was degassed and flushed with N2 three times. The mixture was stirred under N2 at 25 °C for 12 h. The mixture was poured into saturated aqueous sodium chloride (100 mL), filtered, and washed with water (100 mL). The cake was then dissolved in DCM (200 mL), washed with saturated aqueous NaHCO3 (100 mL), and the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound 3 (6.5 g, 99.7% calculated yield based on compound 1) as a white solid.

[0063] Compound 3 (6.5 g) was dissolved in CHCN (13 mL) and benzenesulfonic acid (1.1 g, 6.95 mmol) was added. The mixture was stirred at 70 °C for 14 h under N atmosphere. The mixture was then diluted with DCM (60 mL) and washed with saturated aqueous NaHCO (30 mL × 2), followed by HO (30 mL × 2). The organic phase was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The crude product was then reslurried in EA (5 mL) and MTBE (5 mL) at 25 °C for 0.5 h to give compound A (4.9 g) as a white solid, in 87% yield calculated based on compound 1. The chemical name of the compound of formula A is N-((S)-(5-chloropyridin-2-yl)(cyclobutyl)methyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide.

[0064] The compound of formula A (4.9 g) was reslurried in MTBE (25 ml) at room temperature for 24 h, filtered, and dried to give 4.41 g of a white solid, a 90% yield, which was identified as crystalline form A1 by XRPD (FIG. 1c). The spectrum of its chemical purity is shown in Figure 1a, the spectrum of its chiral purity in Figure 1b, the powder X-ray diffraction pattern in Figure 1c, the parameters of each peak in Table 1, the differential scanning calorimetry chart (DSC) in Figure 1d, and the thermogravimetric analysis graph in Figure 1e. 1 The H NMR spectrum is shown in Figure 1f. [Table 15]

[0065] Example 2 Preparation of Crystalline Form A2 Manufacturing method: Approximately 40 mg of crystalline form A1 was weighed, added to 0.2-1 mL of 1,4-dioxane, and suspended for 2 weeks at 25°C with stirring at 300 rpm. The resulting suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon membrane centrifuge tube to obtain crystalline form A2. The powder X-ray diffraction pattern is shown in Figure 2a, the parameters of each peak are shown in Table 2, the differential scanning calorimetry chart (DSC) is shown in Figure 2b, and the thermogravimetric analysis graph is shown in Figure 2c. 1 The H NMR spectrum is shown in Figure 2d. [Table 16]

[0066] Example 3 Preparation of crystalline form A3 Preparation method: Approximately 40 mg of crystalline form A1 was weighed, added to 0.2-1 mL of toluene, and suspended for 2 weeks at 25°C with stirring at 300 rpm. The resulting suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon membrane centrifuge tube to obtain crystalline form A3. The powder X-ray diffraction pattern is shown in Figure 3a, the parameters of each peak are shown in Table 3, the differential scanning calorimetry chart (DSC) is shown in Figure 3b, and the thermogravimetric analysis graph is shown in Figure 3c. 1 The H NMR spectrum is shown in Figure 3d. [Table 17] Example 4 Preparation of Crystalline Form A4 Preparation method: Approximately 30 mg of crystalline form A1 was weighed and thoroughly dissolved in 5 mL of DCM. The solution was then filtered through a 0.45 μm nylon membrane syringe filter to obtain a clear solution. The resulting clear solution was then blown with nitrogen gas at room temperature to rapidly evaporate the solvent. The solid obtained after evaporation of the collected solvent was crystalline form A4. The powder X-ray diffraction pattern is shown in Figure 4a, the parameters of each peak are shown in Table 4, the differential scanning calorimetry chart (DSC) is shown in Figure 4b, and the thermogravimetric analysis graph is shown in Figure 4c. 1 The H NMR spectrum is shown in Figure 4d.

[0067] [Table 18]

[0068] Example 5 Preparation of Crystalline Form A5 Preparation method: Approximately 60 mg of crystalline form A1 was weighed, 0.2-1 mL of ethyl acetate was added, and the mixture was stirred at 300 rpm at 50°C for 1 week. The resulting suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon membrane centrifuge tube to obtain crystalline form A5. Its powder X-ray diffraction pattern is shown in Figure 5a, the parameters of each peak are shown in Table 5, the differential scanning calorimetry chart (DSC) is shown in Figure 5b, and the thermogravimetric analysis graph is shown in Figure 5c. 1 The H NMR spectrum is shown in Figure 5d. [Table 19] Example 6 Preparation of Crystalline Form B Preparation method: 410 mg of crystalline form A1 was weighed and placed in an 8 mL glass bottle. 5 mL of ethanol was added and stirred at 25°C to obtain a suspension. Approximately 5 mg of seed crystals of crystalline form B were added to the suspension, and the mixture was stirred at 25°C for approximately 5 days. The solid was collected by filtration and dried in vacuum at 50°C for approximately 8 hours and then at 25°C for approximately 3 hours. Approximately 350 mg of crystalline form B was produced as an off-white powder, with a yield of approximately 87%. Its chemical purity is shown in Figure 6a, its chiral purity in Figure 6b, its powder X-ray diffraction pattern in Figure 6c, the parameters of each peak in Table 6, its differential scanning calorimetry chart (DSC) in Figure 6d, and its thermogravimetric analysis graph in Figure 6e. 1 The H NMR spectrum is shown in Figure 6f. [Table 20]

[0069] Example 7 Preparation of Crystalline Form C Manufacturing method: Approximately 40 mg of crystalline form A1 was weighed, 0.2-1 mL of DMSO was added, and the suspension was stirred at 300 rpm at 25°C for 2 weeks. The resulting suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon membrane centrifuge tube to obtain crystalline form C. The powder X-ray diffraction pattern is shown in Figure 7a, the parameters of each peak are shown in Table 7, the differential scanning calorimetry chart (DSC) is shown in Figure 7b, the thermogravimetric analysis graph is shown in Figure 7c, 1 The H NMR spectrum is shown in Figure 7d. [Table 21]

[0070] Example 8 Preparation of Crystalline Form D1 Manufacturing method: Approximately 40 mg of crystalline form A1 was weighed, added to 0.2-1 mL of IPA, and suspended for 2 weeks while stirring at 300 rpm at 25°C. The resulting suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon membrane centrifuge tube to obtain crystalline form D1. The powder X-ray diffraction pattern is shown in Figure 8a, the parameters of each peak are shown in Table 8, the differential scanning calorimetry chart (DSC) is shown in Figure 8b, the thermogravimetric analysis graph is shown in Figure 8c, 1 The H NMR spectrum is shown in Figure 8d. [Table 22]

[0071] Example 9 Preparation of Crystalline Form D2 Preparation method: Approximately 40 mg of crystalline form A1 was weighed, added to 0.2-1 mL of a mixed solution (DMSO:water = 24:76, v / v), and suspended for 2 weeks at 25°C with stirring at 300 rpm. The resulting suspension was centrifuged at 14,000 rpm using a 0.45 μm nylon membrane centrifuge tube to obtain crystalline form D2. The powder X-ray diffraction pattern is shown in Figure 9a, the parameters of each peak are shown in Table 9, the differential scanning calorimetry chart (DSC) is shown in Figure 9b, the thermogravimetric analysis graph is shown in Figure 9c, 1The H NMR spectrum is shown in Figure 9d. [Table 23]

[0072] Example 10 Preparation of Crystalline Form E Preparation method. 860 mg of crystalline form A1 was weighed and dissolved in 10 mL of an ACN / water (v:v=80:20) mixture at 50°C. The resulting solution was passed through a syringe filter with a 0.45 μm nylon membrane to obtain a clear solution. The clear solution was cooled to 5°C at a rate of 0.1°C / min. When the temperature was reduced to approximately 30°C, approximately 5 mg of seed crystals of crystalline form E were added. The resulting suspension was then cooled to 5°C at a rate of 0.1°C / min and stirred for 1 day while maintaining the temperature at 5°C. The solid was collected by filtration at 5°C and vacuum dried at 50°C for approximately 4.5 hours. Approximately 350 mg of crystalline form E was produced as an off-white powder, with a yield of approximately 41%. The spectrum of its chemical purity is shown in Figure 10a, the spectrum of its chiral purity in Figure 10b, the powder X-ray diffraction pattern in Figure 10c, the parameters of each peak in Table 10, the differential scanning calorimetry chart (DSC) in Figure 10d, the thermogravimetric analysis graph in Figure 10e, 1 The H NMR spectrum is shown in Figure 10f. [Table 24]

[0073] Example 11 Preparation of Crystalline Form F Manufacturing method: Approximately 40 mg of crystalline form A1 was weighed, added to 0.2-1 mL of water, and suspended for 2 weeks while stirring at 300 rpm at 25°C. The resulting suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon membrane centrifuge tube to obtain crystalline form F. Its powder X-ray diffraction pattern is shown in Figure 11a, the parameters of each peak are shown in Table 11, the differential scanning calorimetry chart (DSC) is shown in Figure 11b, the thermogravimetric analysis graph is shown in Figure 11c, 1 The 1 H NMR spectrum is shown in Figure 11d. [Table 25]

[0074] Example 12 Preparation of Crystalline Form G Preparation method: The compound of formula A was prepared by referring to the method of Example 15 of PCT / CN2022 / 097236, and then the compound was ring-closed under acidic conditions and crystallized from acetonitrile-water to obtain crystalline form G. [ka] Compound 1 (32.5 g, 121 mmol) and compound 2 (56 g, 155 mmol) were placed in DMAc (500 mL) and T3P (46.7 g, 147 mmol) and NMM (62 g, 613 mmol) were added. The mixture was degassed and flushed with N2 three times. The mixture was stirred under N2 at 25 °C for 12 h. The mixture was poured into saturated aqueous sodium chloride (1000 mL), filtered, and washed with water (1000 mL). The cake was dissolved in DCM (2000 mL), washed with saturated aqueous NaHCO3 (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound 3 (66 g) as a white solid (>98% pure, >98% chiral purity). Compound 3 (66 g) was dissolved in CHCN (660 mL) and benzenesulfonic acid (57.4 g, 363 mmol) was added. The mixture was stirred at 50 °C for 16 h under N gas atmosphere, cooled to 0 °C, and the pH was adjusted to 7-8 with 7% NaHCO. The solution was slowly added dropwise to water (3300 mL), stirred for 3 h, suction filtered, and the cake was washed with water (300 mL). The cake was dried under vacuum to give compound A (50 g) as a white solid in an 89% yield for both steps. The compound of formula A above was identified as crystalline form G by XRPD (FIG. 12c). The spectrum of its chemical purity is shown in Figure 12a, the spectrum of its chiral purity in Figure 12b, the powder X-ray diffraction pattern in Figure 12c, the parameters of each peak in Table 12, the differential scanning calorimetry chart (DSC) in Figure 12d, the thermogravimetric analysis graph in Figure 12e, 1 The H NMR spectrum is shown in Figure 12f. [Table 26]

[0075] Example 13 Preparation of Crystalline Form H Preparation method: Approximately 60 mg of crystalline form E was weighed, 0.2-1 mL of methanol was added, and the mixture was stirred at 300 rpm at 50°C for 1 week. The resulting suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon membrane centrifuge tube to obtain crystalline form H. Its powder X-ray diffraction pattern is shown in Figure 13a, the parameters of each peak are shown in Table 13, the differential scanning calorimetry chart (DSC) is shown in Figure 13b, the thermogravimetric analysis graph is shown in Figure 13c, 1 The 1 H NMR spectrum is shown in Figure 13d. [Table 27]

[0076] Example 14 Preparation of amorphous form of compound of formula A Preparation Method 1. Approximately 40 mg of crystalline form A1 was weighed, 0.2-1 mL of EA was added, and the suspension was stirred at 300 rpm at 25°C for 2 weeks. The resulting suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon membrane centrifuge tube to obtain the amorphous form of the compound of formula A. Preparation Method 2: Approximately 40 mg of crystalline form A1 was weighed, added to 0.2-1 mL of acetone, and suspended for 2 weeks at 25°C with stirring at 300 rpm. The resulting suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon membrane centrifuge tube to obtain the amorphous form of the compound of formula A. Preparation Method 3: Approximately 40 mg of crystalline form A1 was weighed, added to 0.2-1 mL of THF, and suspended for 2 weeks at 25°C with stirring at 300 rpm. The resulting suspension was centrifuged at 14,000 rpm through a 0.45 μm nylon membrane centrifuge tube to obtain the amorphous form of the compound of formula A.

[0077] Preparation Method 4: Approximately 50 mg of crystalline Form A1 was weighed, 0.2-1 mL of EA was added, and the suspension was subjected to 10 cycles of heating and cooling at a rate of 0.2°C / min between 5°C and 50°C while simultaneously stirring magnetically at 300 rpm. The resulting suspension was centrifuged at 14,000 rpm at 5°C using a 0.45 μm nylon membrane centrifuge tube to obtain the amorphous form of the compound of formula A. Preparation Method 5: After obtaining the crude product according to the method of Example 1, the crude product was treated with EA (5 mL) and MTBE (5 mL) to obtain a cake. The cake was placed in 30 mL of acetonitrile and ultrasonicated for 5 minutes to uniformly disperse the cake into a slurry-like solution. 70 mL of water was added until the entire solution was clear and transparent, and the solution was lyophilized to obtain an amorphous compound of formula A as an off-white solid. Preparation Method 6: After obtaining the crude product according to the method of Example 1, the crude product was spray-dried with a solvent such as DCM or EtOH at a flow temperature of 80°C to 120°C to obtain the amorphous form of the compound of formula A. The powder X-ray diffraction pattern of the amorphous form of the compound of formula A is shown in Figure 14a. Example 15 Stability Study of Crystalline Form B The chemical purity of crystalline form B is shown in Figure 15a, and the chiral purity is shown in Figure 15b. Open containers were stored at 25°C / 92% RH and 40°C / 75% RH for 13 days, respectively, and closed containers were stored at 60°C for 13 days. Stability samples were detected by XRPD and HPLC to observe the presence or absence of discoloration of the samples. The data are shown in Table 14.

[0078] [Table 28]

[0079] Example 16 Stability Study of Crystalline Form E The chemical purity of crystalline form E is shown in Figure 16a, and the chiral purity is shown in Figure 16b. Open containers were stored at 25°C / 92% RH and 40°C / 75% RH for 13 days, respectively, and closed containers were stored at 60°C for 13 days. Stability samples were detected by XRPD and HPLC to observe the presence or absence of discoloration of the samples. The data are shown in Table 15. [Table 29]

[0080] Example 17 Stability study of crystalline form G The chemical purity of crystalline form G is shown in Figure 12a, and the chiral purity is shown in Figure 12b. Open containers were stored at 25°C / 92% RH and 40°C / 75% RH for 13 days, respectively, and closed containers were stored at 60°C for 13 days. Stability samples were detected by XRPD and HPLC to observe the presence or absence of discoloration of the samples. The data are shown in Table 16. [Table 30]

[0081] Example 18 Hygroscopicity Experiment of Crystalline Form B The water absorption and dehydration behavior of crystalline form B was studied by DVS under the following humidity program: 25°C, 40-0-95-0-40% RH, dm / dt 0.002, minimum equilibration time 60 min, maximum equilibration time 360 ​​min. After the DVS test, the samples were analyzed by XRPD to determine whether a crystal form transformation had occurred. The results are shown in Table 17. [Table 31]

[0082] Example 19 Hygroscopicity experiment of crystalline form E The water absorption and dehydration behavior of crystalline form E was studied by DVS under the following humidity program: 25°C, 40-0-95-0-40% RH, dm / dt 0.002, minimum equilibration time 60 min, maximum equilibration time 360 ​​min. After the DVS test, the samples were analyzed by XRPD to determine whether a crystal form transformation had occurred. The results are shown in Table 18. [Table 32]

[0083] Example 20 Hygroscopicity experiment of crystalline form G The water absorption and dehydration behavior of crystalline form G was studied by DVS under the following humidity program: 25°C, 40-0-95-0-40% RH, dm / dt 0.002, minimum equilibration time 60 min, maximum equilibration time 360 ​​min. After the DVS test, the samples were analyzed by XRPD to determine whether a crystal form transformation had occurred. The results are shown in Table 19. [Table 33]

[0084] Example 21 Tableting Simulation Experiment Approximately 10 mg of crystalline form G was weighed and pressed at pressures of 2 MPa, 5 MPa, and 10 MPa for 5 min, respectively. The state of crystalline form transformation and change in crystallinity was investigated by characterization by XRPD, as shown in Table 20. [Table 34]

[0085] Example 22 Drug Composition [Table 35] In a conventional manner, the above materials were homogeneously mixed as shown in Table 21 and then placed into ordinary gelatin capsules to obtain 10,000-100,000 capsules. Example 23 Pharmacokinetic evaluation of crystalline form G and amorphous form of compound of formula A after intragastric administration to mice Male CD1 mice were selected and the test compounds were administered orally via intragastric administration. Plasma drug concentrations were then quantitatively measured at different time points using LC / MS / MS to evaluate the pharmacokinetic characteristics of the test compounds in the mouse body. Experimental materials: CD1 mice (male, 20-30 g, 6-8 weeks old, Zhejiang Vital River). Experimental Procedure: As shown in Table 22, test compounds were prepared in 25 mM citrate buffer (pH 3) containing 5% Tween 80 and administered orally to CD1 mice (food and water intake ad libitum). Blood samples were collected from the dorsal metatarsal vein at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h post-dose, placed in an anticoagulant tube containing EDTA-K2, mixed, and centrifuged at 4000 xg for 5 minutes at 4°C. Blood drug concentrations were measured by LC-MS / MS, and relevant pharmacokinetic parameters were calculated using the non-compartmental linear / log trapezoidal method with Phoenix WinNonlin 6.3 pharmacokinetic software.

[0086] [Table 36] As shown in Table 22, compound of formula A had good pharmacokinetic parameters in the body, with an area under the blood concentration-time curve that was 3 to 4 times that of crystalline form G. As shown in Tables 14, 15, and 16, crystalline forms B, E, and G had good stability and no crystal form transformation was observed. As shown in the hygroscopicity tests in Tables 17, 18, and 19, crystalline forms B, E, and G had good stability and no crystal form transformation was observed. In particular, crystalline form G was compressed at pressures of 2 MPa, 5 MPa, and 10 MPa, respectively, and as shown in Table 20, there was no significant change in crystallinity. Therefore, the form described in the present invention is highly suitable for pharmaceutical compositions. Furthermore, the crystalline and amorphous forms of the present invention are less likely to scatter and are easier to collect, resulting in less waste during pharmaceutical manufacturing processes such as distribution, which is beneficial for protecting the health of operators. All documents related to the present invention are incorporated herein by reference as if each document were individually incorporated by reference. After reading the above content of the present invention, it should be understood that those skilled in the art can make various changes and modifications to the present invention, and that equivalents thereof are within the scope of the claims of the present invention.

Claims

1. An amorphous or crystalline form of a compound of formula A, or a pharmaceutically acceptable salt thereof, or a solvate thereof. 【Chemistry 1】

2. 10. The form of claim 1, wherein the crystalline form G of the compound of formula A has an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles of at least three, at least four, at least five, at least six, or seven characteristic peaks at 18.83±0.2°, 13.88±0.2°, 21.45±0.2°, 26.75±0.2°, 15.92±0.2°, 17.95±0.2°, and 13.14±0.2°, preferably having an XRPD characteristic peak at a position substantially as shown in Table 12, more preferably having an XRPD pattern substantially as shown in Figure 12c, and optionally having one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 236.59°C ± 2°C; 2) In the TGA graph, there is a weight loss of 0.52±0.2 wt % before 150°C; 3) essentially according to the DSC chart shown in Figure 12d; and / or 4) Essentially as per the TGA graph shown in Figure 12e.

3. 2. The form of claim 1, wherein the solvate of compound of formula A has a crystalline form A1, which has an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles of at least three, at least four, at least five, at least six, or seven characteristic peaks at 6.54±0.2°, 19.64±0.2°, 9.21±0.2°, 16.35±0.2°, 18.48±0.2°, 9.79±0.2°, and 17.23±0.2°, preferably having an XRPD characteristic peak at a position substantially as shown in Table 1, more preferably having an XRPD pattern substantially as shown in Figure 1c, and optionally having one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 147.77°C ± 2°C and one endothermic peak at 159.25°C ± 2°C; 2) In the TGA graph, there is a weight loss of 10.64±0.2 wt% before 240°C; 3) essentially according to the DSC chart shown in Figure 1d; and / or 4) Essentially as shown in the TGA graph in Figure 1e.

4. 2. The form of claim 1, wherein the solvate of compound of formula A2 has an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles of at least three, at least four, at least five, at least six, or seven characteristic peaks at 18.57±0.2°, 19.67±0.2°, 16.38±0.2°, 9.28±0.2°, 17.38±0.2°, 25.18±0.2°, and 13.11±0.2°, preferably having XRPD characteristic peaks at positions essentially as shown in Table 2, more preferably having an XRPD pattern essentially as shown in Figure 2a, and optionally having one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 153.88°C ± 2°C and one endothermic peak at 178.46°C ± 2°C; 2) In the TGA graph, there is a weight loss of 11.32±0.2 wt% before 165.00°C, and a weight loss of 2.83±0.2 wt% between 165.00°C and 230.00°C; 3) essentially according to the DSC chart shown in Figure 2b; and / or 4) Essentially as per the TGA graph shown in Figure 2c.

5. 2. The form of claim 1, wherein the solvate of compound of formula A is crystalline form A3, having an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles of at least three, at least four, at least five, at least six, or seven characteristic peaks at 19.61±0.2°, 18.45±0.2°, 9.22±0.2°, 16.33±0.2°, 6.54±0.2°, 17.24±0.2°, and 9.80±0.2°, preferably having an XRPD pattern essentially as shown in Table 3, more preferably having an XRPD pattern essentially as shown in Figure 3a, and optionally having one or more of the following characteristics: 1) In the DSC chart, there is one exothermic peak at 90.56°C ± 2°C, and one endothermic peak each at 152.55°C ± 2°C and 177.33°C ± 2°C; 2) In the TGA graph, there is a weight loss of 12.08±0.2 wt% before 165.00°C, and a weight loss of 2.12±0.2 wt% between 165.00°C and 230.00°C; 3) essentially according to the DSC chart shown in Figure 3b; and / or 4) Essentially as per the TGA graph shown in Figure 3c.

6. 2. The form of claim 1, wherein the solvate of compound of formula A4 has an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles of at least three, at least four, at least five, at least six, or seven characteristic peaks at 9.22±0.2°, 17.51±0.2°, 6.54±0.2°, 19.59±0.2°, 25.03±0.2°, 16.37±0.2°, and 18.51±0.2°, preferably having an XRPD pattern essentially as shown in Table 4, more preferably having an XRPD pattern essentially as shown in Figure 4a, and optionally having one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 149.48°C ± 2°C; 2) In the TGA graph, there is a weight loss of 3.01±0.2 wt % before 160°C; 3) essentially according to the DSC chart shown in Figure 4b; and / or 4) Essentially as per the TGA graph shown in Figure 4c.

7. 2. The form of claim 1, wherein the solvate of compound of formula A5 has an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles of at least three, at least four, at least five, at least six, or seven characteristic peaks at 16.43±0.2°, 19.74±0.2°, 6.58±0.2°, 9.27±0.2°, 18.53±0.2°, 17.37±0.2°, and 9.88±0.2°, preferably having an XRPD pattern essentially as shown in Table 5, more preferably having an XRPD pattern essentially as shown in Figure 5a, and optionally having one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 154.86°C ± 2°C; 2) In the TGA graph, there is a weight loss of 6.75±0.2 wt % before 220°C; 3) essentially according to the DSC chart shown in Figure 5b; and / or 4) Essentially as per the TGA graph shown in Figure 5c.

8. 2. The form of claim 1, wherein the crystalline form B of the compound of formula A has an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles of at least three, at least four, at least five, at least six, or seven characteristic peaks at 3.98±0.2°, 12.35±0.2°, 12.05±0.2°, 19.09±0.2°, 7.92±0.2°, 15.78±0.2°, and 14.32±0.2°, preferably having an XRPD characteristic peak at a position substantially as shown in Table 6; more preferably having an XRPD pattern substantially as shown in Figure 6c, and optionally having one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 25.54°C ± 2°C and one endothermic peak at 183.52°C ± 2°C; 2) In the TGA graph, there is a weight loss of 1.03±0.2 wt % before 100°C; 3) essentially according to the DSC chart shown in Figure 6d; and / or 4) Essentially as per the TGA graph shown in Figure 6e.

9. 2. The form of claim 1, wherein the crystalline form C of the solvate of compound of formula A has an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles of at least three, at least four, at least five, at least six, or seven characteristic peaks at 20.60±0.2°, 17.94±0.2°, 13.11±0.2°, 19.42±0.2°, 23.97±0.2°, 26.31±0.2°, and 11.95±0.2°, preferably having an XRPD characteristic peak at a position substantially as shown in Table 7, more preferably having an XRPD pattern substantially as shown in Figure 7a, and optionally having the following characteristics: 1) In the DSC chart, there is one endothermic peak at 127.33°C ± 2°C; 2) In the TGA graph, there is a weight loss of 16.21±0.2 wt% before 160.00°C, and a weight loss of 9.29±0.2 wt% between 160.00°C and 260.00°C; 3) essentially according to the DSC chart shown in Figure 7b; and / or 4) Essentially as per the TGA graph shown in Figure 7c.

10. 2. The form of claim 1, wherein the solvate of compound of formula A has a crystalline form D1 in an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles of at least three, at least four, at least five, at least six, or seven characteristic peaks at 17.99±0.2°, 8.82±0.2°, 17.32±0.2°, 9.26±0.2°, 19.14±0.2°, 9.95±0.2°, and 31.53±0.2°, preferably having an XRPD characteristic peak at a position substantially as shown in Table 8, more preferably having an XRPD pattern substantially as shown in Figure 8a, and optionally having one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 161.17°C ± 2°C; 2) In the TGA graph, there is a weight loss of 11.30±0.2 wt% before 210°C; 3) essentially according to the DSC chart shown in Figure 8b; and / or 4) Essentially as per the TGA graph shown in Figure 8c.

11. 2. The form of claim 1, wherein the solvate of compound of formula A has a crystalline form D2 in an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles of at least three, at least four, at least five, at least six, or seven characteristic peaks at 17.38±0.2°, 17.99±0.2°, 19.57±0.2°, 9.80±0.2°, 31.55±0.2°, 25.05±0.2°, and 6.55±0.2°, preferably having an XRPD characteristic peak at a position essentially as shown in Table 9, more preferably having an XRPD characteristic peak at a position essentially as shown in Figure 9a, and optionally having one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 83.30°C ± 2°C and one endothermic peak at 126.89°C ± 2°C; 2) In the TGA graph, there is a weight loss of 12.51±0.2 wt% before 110.00°C, and a weight loss of 12.26±0.2 wt% between 110.00°C and 250.00°C; 3) essentially according to the DSC chart shown in Figure 9b; and / or 4) Essentially as per the TGA graph shown in Figure 9c.

12. 10. The form of claim 1, wherein the crystalline form E of the compound of formula A has an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles of at least three, at least four, at least five, at least six, or seven characteristic peaks at 11.14±0.2°, 15.76±0.2°, 12.59±0.2°, 19.71±0.2°, 9.56±0.2°, 17.83±0.2°, and 13.58±0.2°, preferably having an XRPD characteristic peak at a position substantially as shown in Table 10; more preferably having an XRPD pattern substantially as shown in Figure 10c, and optionally having one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 37.94°C ± 2°C and one endothermic peak at 190.71°C ± 2°C; 2) In the TGA graph, there is a weight loss of 1.17±0.2 wt% before 130°C; 3) essentially according to the DSC chart shown in Figure 10d; and / or 4) Essentially as per the TGA graph shown in Figure 10e.

13. 10. The form of claim 1, wherein the compound of formula A has crystalline form F, an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles, having at least three, at least four, at least five, at least six, or seven characteristic peaks at 17.70±0.2°, 21.46±0.2°, 27.66±0.2°, 19.20±0.2°, 17.17±0.2°, 19.44±0.2°, and 22.01±0.2°, preferably having an XRPD characteristic peak at a position substantially as shown in Table 11, more preferably having an XRPD pattern substantially as shown in Figure 11a, and optionally having one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 216.58°C ± 2°C; 2) In the TGA graph, there is a weight loss of 0.598±0.2 wt% before 100°C; 3) essentially according to the DSC chart shown in Figure 11b; and / or 4) Essentially as per the TGA graph shown in Figure 11c.

14. 10. The form of claim 1, wherein the compound of formula A has crystalline form H, an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles, with at least three, at least four, at least five, at least six, or seven characteristic peaks at 18.30±0.2°, 3.80±0.2°, 19.05±0.2°, 18.53±0.2°, 11.81±0.2°, 11.33±0.2°, and 16.04±0.2°, preferably having an XRPD characteristic peak at a position substantially as shown in Table 13; more preferably having an XRPD pattern substantially as shown in Figure 13a, and optionally having one or more of the following characteristics: 1) In the DSC chart, there is one endothermic peak at 77.45°C ± 2°C and one endothermic peak at 154.75°C ± 2°C; 2) In the TGA graph, there is a weight loss of 0.19±0.2 wt% before 120°C; 3) essentially according to the DSC chart shown in Figure 13b; and / or 4) Essentially as per the TGA graph shown in Figure 13c.

15. 10. The amorphous form of compound of formula A, preferably having an XRPD pattern as shown in FIG. 14a, more preferably further optionally having one or more of the following characteristics: 1) In the mDSC chart, there is one glass transition temperature at 129.30°C ± 2.0°C; 2) In the TGA graph, there is a weight loss of 2.7 wt % before 210°C ± 2.0°C; 3) essentially according to the mDSC chart shown in Figure 14b; and / or 4) Essentially as per the TGA graph shown in Figure 14c.

16. A process for preparing the form of any one of claims 1-15, comprising obtaining the form of any one of claims 1-15 from a compound of Formula A or a pharmaceutically acceptable salt thereof by turbidity, slow cooling, fast cooling, slow evaporation, fast evaporation, anti-solvent dropwise addition, anti-solvent back-dropwise addition, vapor diffusion, or heat-cool DSC crystallization methods, or by spray drying, hot melt extrusion, or solvent evaporation.

17. A pharmaceutical composition comprising: (a) any one of claims 1 to 15; and (b) a pharmaceutically acceptable carrier or excipient.

18. A pharmaceutical formulation comprising the pharmaceutical composition of claim 17, which may be a solid formulation, wherein the dosage form of the solid formulation is selected from the group consisting of powder, granules, tablets, capsules, drop pills, and films.

19. Use of the form according to any one of claims 1 to 15, or the pharmaceutical composition according to claim 17, or the pharmaceutical formulation according to claim 18 in the manufacture of a drug for treating a proliferative disease, preferably the proliferative disease being breast cancer, colon cancer, brain cancer, prostate cancer, kidney cancer, pancreatic adenocarcinoma, ovarian cancer, head and neck cancer, melanoma, colorectal cancer, gastric cancer, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, testicular cancer, Merkel cell carcinoma, glioblastoma, neuroblastoma, leukemia (acute phosphoinositide), Allergic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMOL), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, adult T-cell leukemia), lymphoma (small lymphocytic lymphoma (SLL), Hodgkin's lymphoma (nodular sclerosis, mixed cell, lymphocyte-rich, lymphopenic or non-reduced and lymphomas (e.g., Waldenstrom's macroglobulinemia), splenic marginal zone lymphoma, plasma cell neoplasms (plasma cell myeloma, plasmacytoma, monoclonal gammopathy, heavy chain disease), extranodal marginal zone B-cell lymphoma (MALT lymphoma), lymphomas (NMZL), follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, aggressive NK-cell leukemia, adult T-cell leukemia / lymphoma, extranodal NK / T-cell lymphoma (nasal type), enteropathy-type T-cell lymphoma, hepatosplenic 2. Use selected from cancers of the lymphoid organs and hematological malignancies, including T-cell lymphoma, blastic NK-cell lymphoma, mycosis fungoides / Sezary syndrome, primary cutaneous CD30-positive T-cell lymphoma disease, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma (non-specific), anaplastic large cell lymphoma), multiple myeloma (plasma cell myeloma or Kahler's disease).

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