Crystalline form or amorphous form of oxoisoindole-5-carboxamide compound or salt and solvate thereof

Abstract

Relates to a crystal form or an amorphous form of an oxoisoindole-5-carboxamide compound or a salt and a solvate of the oxoisoindole-5-carboxamide compound. The invention also discloses a composition containing the crystal form or the amorphous form, and a preparation method and application thereof. The obtained crystal form or amorphous form has good solid stability, and has very important value for drug development, preparation development and production.

Description

Oxyisoindole-5-carboxamide compound or its salt, crystalline form or amorphous form of solvate Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to an oxoindole-5-carboxamide compound or its salt, a crystalline form or an amorphous form of a solvate thereof used as a CK1α selective molecular glue degrader, as well as a preparation method and application thereof. Background Art

[0002] Casein kinase 1α (CK1α), encoded by the gene CSNK1A1, is a ubiquitously expressed serine / threonine protein kinase in the CK1 kinase family. CK1α is involved in regulating various physiological and pathological processes in cells and coordinates the orderly progress of life through different signal transduction pathways (Jiang et al., Cell Commun Signal (2018) 16:23). For example, CK1α, as a key regulator of the Wnt / β-catenin pathway, directly phosphorylates β-catenin at Ser45, making it a target for proteomic degradation (Liu et al., Cell (2002) 108:837-847). CK1α is also thought 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 is reported to be overexpressed in many types of human cancers, however, the exact role of CK1α in the development of various tumor types has not been clearly elucidated (Richter et al., BMC Cancer (2018) 18: 140). The Cancer Dependency Map (DepMap) database shows that inactivation of CK1α by CRISPR / cas9-mediated gene knockout or shRNA-mediated gene inhibition significantly reduces the proliferation and / or survival of many cancer cell lines of various cancer types (Tsherniak et al., Cell (2017) 170: 564-576; Behan et al., Nature (2019) 568: 511-516). In addition, by using shRNA interference or D4476 (a CK1α inhibitor) to inhibit CK1α activity, this method can effectively inhibit the progression of MLL-AF9 leukemia and has little effect on normal hematopoietic stem and progenitor cells (HSPCs) (Jaras et al, J Exp Med (2014) 211 (4): 605-612). In summary, these data indicate that CK1α is a potential target for the treatment of hematological malignancies and solid tumor indications.

[0003] The compound of formula A is a new generation of CK1α selective molecular glue degrader and is currently in the early clinical research stage.

[0004] However, there has been no research or report on the crystalline or amorphous form of the compound of formula A or its salts or solvates, as well as its preparation method, application, and formulation.

[0005] Solid substances, due to various factors such as molecular structure configuration, conformation, molecular arrangement, molecular forces, and eutectic substances, can have different spatial arrangements of the molecular lattice, forming two or more different crystal structures. This phenomenon is known as polymorphism or isomorphism. Polymorphism is widespread in solid pharmaceuticals. 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, dissolution rate, and bioavailability. This phenomenon is particularly evident in oral solid dosage forms. Furthermore, the form and quantity of polymorphic compounds are unpredictable. Different crystalline forms of the same drug can exhibit significant differences in solubility, melting point, density, and stability, thus affecting drug homogeneity, bioavailability, efficacy, and safety to varying degrees.

[0006] In addition to polymorphic forms, some solid compounds may also exist in amorphous forms. Amorphism refers to the structure of some non-completely crystalline amorphous regions (non-crystalline regions) or the composition of some amorphous solids (non-crystalline solids). For a specific solid drug, the existence and amount of its amorphous form is also unpredictable and may also have a significant impact on the drug's solubility, melting point, density, stability, etc.

[0007] Therefore, comprehensive screening of pharmaceutical compounds is necessary during the new drug development process, taking multiple factors into consideration. In particular, for the compound of Formula A described above for treating proliferative disorders, developing potentially pharmaceutically useful dosage forms of the compound, or its derivatives, crystalline forms, amorphous forms, or pharmaceutically acceptable salts, hydrates, or solvates has potential medicinal and clinical value in improving the compound's stability, solubility, bioavailability, and other properties.

[0008] Summary of the Invention

[0009] The present invention provides a crystalline or amorphous form of an oxoisoindole-5-carboxamide compound, or its salt or solvate, as a selective molecular glue degrader for CK1α, as well as a preparation method and application thereof. The crystalline or amorphous form of the present invention is of great value in drug development, formulation development, and production.

[0010] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments of the present invention. However, 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 carried out with the understanding that this disclosure is considered as an example of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments shown. The titles used throughout the present invention are provided only for convenience and should not be interpreted as limiting the claims in any way. The embodiments shown under any title can be combined with the embodiments shown under any other title.

[0011] Furthermore, the term "substantially as shown" when referring to, for example, an XRPD pattern, a TGA pattern, a DSC pattern, etc., refers to a pattern that is not necessarily the same as those described herein, but that falls within the limits of experimental error or deviation when considered by one of ordinary skill in the art.

[0012] 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.

[0013] 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.

[0014] 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 as follows:

[0015] Solvate crystalline form A1 of the compound of formula A

[0016] In one embodiment, it is a solvate crystalline form A1 of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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°.

[0017] In some preferred embodiments, it has XRPD characteristic peaks substantially at the positions shown in Table 1 below:

[0018] Table 1

[0019] In some preferred embodiments, the XRPD pattern is substantially as shown in Figure 1c, and optionally has one or more of the following characteristics:

[0020] 1) In the DSC graph, there is one endothermic peak at 147.77℃±2℃ and one endothermic peak at 159.25℃±2℃;

[0021] 2) In the TGA graph, there was a weight loss of 10.64±0.2 wt% before 240°C;

[0022] 3) a DSC pattern substantially as shown in Figure 1d; and / or

[0023] 4) A TGA pattern substantially as shown in Figure 1e.

[0024] Solvate crystalline form A2 of the compound of formula A

[0025] In one embodiment, it is a solvate crystalline form A2 of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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°.

[0026] In some preferred embodiments, it has XRPD characteristic peaks substantially at the positions shown in Table 2 below:

[0027] Table 2

[0028] In some preferred embodiments, the XRPD pattern is substantially as shown in Figure 2a, and optionally has one or more of the following characteristics:

[0029] 1) In the DSC graph, there is one endothermic peak at 153.88℃±2℃ and one endothermic peak at 178.46℃±2℃;

[0030] 2) in the TGA graph, there was 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.;

[0031] 3) a DSC pattern substantially as shown in Figure 2b; and / or

[0032] 4) A TGA pattern substantially as shown in Figure 2c.

[0033] Solvate crystalline form A3 of the compound of formula A

[0034] In one embodiment, it is a solvate crystalline form A3 of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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°.

[0035] In some preferred embodiments, it has XRPD characteristic peaks substantially at the positions shown in Table 3 below:

[0036] Table 3

[0037] In some preferred embodiments, the XRPD pattern is substantially as shown in Figure 3a, and optionally has one or more of the following characteristics:

[0038] 1) In the DSC graph, there is an exothermic peak at 90.56℃±2℃, and an endothermic peak at 152.55℃±2℃ and 177.33℃±2℃ respectively;

[0039] 2) in the TGA graph, there was 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.;

[0040] 3) a DSC pattern substantially as shown in Figure 3b; and / or

[0041] 4) A TGA pattern substantially as shown in Figure 3c.

[0042] Solvate crystalline form A4 of the compound of formula A

[0043] In one embodiment, it is a solvate crystalline form A4 of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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°.

[0044] In some preferred embodiments, it has XRPD characteristic peaks substantially at the positions shown in Table 4 below:

[0045] Table 4

[0046] In some preferred embodiments, the XRPD pattern is substantially as shown in Figure 4a, and optionally has one or more of the following characteristics:

[0047] 1) In the DSC graph, there is an endothermic peak at 149.48℃±2℃;

[0048] 2) In the TGA graph, there was a weight loss of 3.01±0.2 wt% before 160°C;

[0049] 3) a DSC pattern substantially as shown in Figure 4b; and / or

[0050] 4) A TGA graph substantially as shown in Figure 4c.

[0051] Solvate crystalline form A5 of the compound of formula A

[0052] In one embodiment, it is a solvate crystalline form A5 of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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°.

[0053] In some preferred embodiments, it has XRPD characteristic peaks substantially at the positions shown in Table 5 below:

[0054] Table 5

[0055] In some preferred embodiments, the XRPD pattern is substantially as shown in Figure 5a, and optionally has one or more of the following characteristics:

[0056] 1) In the DSC graph, there is an endothermic peak at 154.86℃±2℃;

[0057] 2) In the TGA graph, there was a weight loss of 6.75±0.2 wt% before 220°C;

[0058] 3) a DSC pattern substantially as shown in Figure 5b; and / or

[0059] 4) A TGA graph substantially as shown in Figure 5c.

[0060] Crystalline Form B of the compound of formula A

[0061] In one embodiment, it is a crystalline form B of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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°.

[0062] In some preferred embodiments, it has XRPD characteristic peaks substantially at the positions shown in Table 6 below:

[0063] Table 6

[0064] In some preferred embodiments, the XRPD pattern is substantially as shown in Figure 6c, and optionally has one or more of the following characteristics:

[0065] 1) In the DSC graph, there is one endothermic peak at 25.54℃±2℃ and one endothermic peak at 183.52℃±2℃;

[0066] 2) In the TGA graph, there was a weight loss of 1.03±0.2 wt% before 100°C;

[0067] 3) a DSC pattern substantially as shown in Figure 6d; and / or

[0068] 4) A TGA pattern substantially as shown in Figure 6e.

[0069] Solvate crystalline form C of the compound of formula A

[0070] In one embodiment, it is a solvate crystalline form C of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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°.

[0071] In some preferred embodiments, it has XRPD characteristic peaks substantially at the positions shown in Table 7 below:

[0072] Table 7

[0073] In some preferred embodiments, the XRPD pattern is substantially as shown in Figure 7a, and optionally has one or more of the following characteristics:

[0074] 1) In the DSC graph, there is an endothermic peak at 127.33℃±2℃;

[0075] 2) in the TGA graph, there was 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.;

[0076] 3) a DSC pattern substantially as shown in Figure 7b; and / or

[0077] 4) A TGA graph substantially as shown in Figure 7c.

[0078] Solvate crystalline form D1 of the compound of formula A

[0079] In one embodiment, it is a solvate crystalline form D1 of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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°.

[0080] In some preferred embodiments, it has XRPD characteristic peaks substantially at the positions shown in Table 8 below:

[0081] Table 8

[0082] In some preferred embodiments, the XRPD pattern is substantially as shown in Figure 8a, and optionally has one or more of the following characteristics:

[0083] 1) In the DSC graph, there is an endothermic peak at 161.17℃±2℃;

[0084] 2) In the TGA graph, there was a weight loss of 11.30 ± 0.2 wt% before 210 °C;

[0085] 3) a DSC pattern substantially as shown in Figure 8b; and / or

[0086] 4) A TGA pattern substantially as shown in FIG8c.

[0087] Solvate crystalline form D2 of the compound of formula A

[0088] In one embodiment, it is a solvate crystalline form D2 of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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°.

[0089] In some preferred embodiments, it has XRPD characteristic peaks substantially at the positions shown in Table 9 below:

[0090] Table 9

[0091] In some preferred embodiments, the XRPD pattern is substantially as shown in Figure 9a, and optionally has one or more of the following characteristics:

[0092] 1) In the DSC graph, there is one endothermic peak at 83.30℃±2℃ and one endothermic peak at 126.89℃±2℃;

[0093] 2) in the TGA graph, there was 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.;

[0094] 3) a DSC pattern substantially as shown in Figure 9b; and / or

[0095] 4) A TGA graph substantially as shown in FIG9c.

[0096] Crystalline Form E of the compound of formula A

[0097] In one embodiment, it is a crystalline form E of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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°.

[0098] In some preferred embodiments, it has XRPD characteristic peaks substantially at the positions shown in Table 10 below:

[0099] Table 10

[0100] In some preferred embodiments, the XRPD pattern is substantially as shown in Figure 10c, and optionally has one or more of the following characteristics:

[0101] 1) In the DSC graph, there is one endothermic peak at 37.94℃±2℃ and one endothermic peak at 190.71℃±2℃;

[0102] 2) In the TGA graph, there was a weight loss of 1.17 ± 0.2 wt% before 130 °C;

[0103] 3) a DSC pattern substantially as shown in Figure 10d; and / or

[0104] 4) A TGA pattern substantially as shown in FIG10e.

[0105] Crystalline Form F of the compound of formula A

[0106] In one embodiment, it is crystalline Form F of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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°.

[0107] In some preferred embodiments, it has XRPD characteristic peaks substantially at the positions shown in Table 11 below:

[0108] Table 11

[0109] In some preferred embodiments, the XRPD pattern is substantially as shown in Figure 11a, and optionally has one or more of the following characteristics:

[0110] 1) In the DSC graph, there is an endothermic peak at 216.58℃±2℃;

[0111] 2) In the TGA graph, there was a weight loss of 0.598±0.2 wt% before 100°C;

[0112] 3) a DSC pattern substantially as shown in Figure 11b; and / or

[0113] 4) A TGA pattern substantially as shown in FIG. 11c .

[0114] Crystalline Form G of the compound of formula A

[0115] In one embodiment, it is a crystalline form G of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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°.

[0116] In some preferred embodiments, it has XRPD characteristic peaks substantially at the positions shown in Table 12 below:

[0117] Table 12

[0118] In some preferred embodiments, the XRPD pattern is substantially as shown in Figure 12c, and optionally has one or more of the following characteristics:

[0119] 1) In the DSC graph, there is an endothermic peak at 236.59℃±2℃;

[0120] 2) In the TGA graph, there was a weight loss of 0.52±0.2 wt% before 150°C;

[0121] 3) a DSC pattern substantially as shown in Figure 12d; and / or

[0122] 4) A TGA pattern substantially as shown in Figure 12e.

[0123] Crystalline Form H of the compound of formula A

[0124] In one embodiment, it is a crystalline form H of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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°;

[0125] In some preferred embodiments, it has XRPD characteristic peaks substantially at the positions shown in Table 13 below:

[0126] Table 13

[0127] In some preferred embodiments, the XRPD pattern is substantially as shown in Figure 13a, and optionally has one or more of the following characteristics:

[0128] 1) In the DSC graph, there is one endothermic peak at 77.45℃±2℃ and one endothermic peak at 154.75℃±2℃;

[0129] 2) In the TGA graph, there was a weight loss of 0.19±0.2 wt% before 120°C;

[0130] 3) a DSC pattern substantially as shown in Figure 13b; and / or

[0131] 4) A TGA pattern substantially as shown in Figure 13c.

[0132] The amorphous form of compound PLM of formula A is shown in FIG14d.

[0133] In one embodiment, it is the amorphous form of the compound of formula A PLM shown in Figure 14d, preferably, it has an XRPD pattern as shown in Figure 14a, and optionally has one or more of the following characteristics:

[0134] 1) In the mDSC graph, there is a glass transition temperature at 129.30℃±2.0℃;

[0135] 2) In the TGA graph, there is a 2.7 wt% weight loss before 210°C ± 2.0°C;

[0136] 3) an mDSC plot substantially as shown in Figure 14b; and / or

[0137] 4) A TGA pattern substantially as shown in Figure 14c.

[0138] In a second aspect, the present invention provides a method for preparing a crystalline form or an amorphous form of a compound of formula A or a pharmaceutically acceptable salt or solvate thereof, comprising the steps of: subjecting the compound of formula A or a pharmaceutically acceptable salt thereof to suspension, slow cooling, rapid cooling, slow volatilization, rapid volatilization, anti-solvent addition, anti-solvent reverse addition, vapor diffusion or heating-cooling DSC crystallization method, or spray drying, hot melt extrusion or solvent evaporation, thereby obtaining the crystalline form or amorphous form.

[0139] In the preparation method, the compound of Formula A is synthesized in the laboratory as described in the specific examples. The solvent can be a commonly used laboratory solvent, such as one or more of 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. The mass-to-volume ratio of the compound of Formula A to the solvent can be 100 mg:(0.1-1 mL).

[0140] 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 solvate type, separating the resulting solid and drying it, thereby obtaining a crystalline form of a solvate of a compound of formula A.

[0141] In some preferred embodiments, the solvent corresponding to the solvate type is, for example but not limited to, 1,4-dioxane, ethyl acetate, toluene, chloroform, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetone, N,N-dimethylformamide, acetonitrile, and the like.

[0142] In one embodiment, the present invention provides a method for preparing an amorphous form of a compound of formula A, comprising the steps of mixing the compound of formula A with a solvent and spray drying the resulting solution, thereby obtaining the amorphous form of the compound of formula A.

[0143] In some preferred embodiments, the solvent can be a commonly used laboratory solvent, for example, one or more of 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. Dichloromethane (DCM) is preferred.

[0144] In a third aspect, the present invention provides a pharmaceutical composition comprising:

[0145] (a) in the form described in the first aspect; and

[0146] (b) a pharmaceutically acceptable carrier or excipient.

[0147] The crystalline or amorphous form of the compound of formula A or its salt or solvate can be a therapeutically effective amount. The pharmaceutically acceptable excipients can be excipients well known in the art, and in the case of solid preparations, include but are not limited to: diluents, binders, disintegrants, lubricants, glidants, release rate control agents, plasticizers, preservatives, antioxidants, etc.

[0148] In a fourth aspect, the present invention provides a pharmaceutical preparation comprising the above-mentioned pharmaceutical composition; wherein the pharmaceutical preparation may be a solid preparation, or may be a powder, granule, tablet, capsule, pill or film preparation.

[0149] In a fifth aspect, the present invention provides the use of the above-mentioned crystalline form, amorphous form or pharmaceutical composition in the preparation of a medicament for treating a proliferative disease, wherein the proliferative disease includes breast cancer, colon cancer, brain cancer, prostate cancer, kidney cancer, pancreatic cancer, 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, lymphoid organ cancer and hematological malignancies including leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (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 lymphomas (nodular sclerosis, mixed cellularity, lymphocyte-rich, lymphocyte-depleted or non-depleted, and nodular lymphocyte-predominant Hodgkin lymphoma), non-Hodgkin lymphomas (all subtypes), chronic lymphocytic leukemia / small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphomas (such as macroglobulinemia), splenic marginal zone lymphoma, plasma cell neoplasms (plasma cell myeloma, plasmacytoma, monoclonal immunoglobulin deposition disease, 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 lymphoma / leukemia, T-cell prolymphocytes Leukemia, T-cell large granular lymphocytic leukemia, aggressive NK-cell leukemia, adult T-cell leukemia / lymphoma, extranodal NK / T-cell lymphoma (nasal type), enteropathy T-cell lymphoma, hepatosplenic T-cell lymphoma, blastic NK-cell lymphoma, mycosis fungoides / Sézary syndrome, primary cutaneous CD30-positive T-cell lymphoma, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma (unspecified), anaplastic large cell lymphoma, multiple myeloma (plasma cell myeloma or Kahler disease).

[0150] In a sixth aspect, the present invention provides a method for treating a proliferative disease, comprising the step of administering to a subject in need thereof a therapeutically effective amount of the form of the first aspect of the invention, the pharmaceutical composition of the third aspect of the invention, or the pharmaceutical formulation of the fourth aspect of the invention.

[0151] In some preferred embodiments, the subject is a mammal, such as a human.

[0152] The crystalline or amorphous form of the compound of formula A or its salt or solvate of the present invention has the following advantages. The present invention is the first to discover multiple previously unreported crystalline or amorphous forms of the compound of formula A or its salt or solvate, which can serve as an important basis for subsequent drug development, formulation development and production.

[0153] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0154] Figure 1a shows the chemical purity spectrum of the crystalline form A1 of the compound of formula A.

[0155] Figure 1b shows the chiral purity spectrum of crystalline form A1 of the compound of formula A.

[0156] FIG1c shows the X-ray powder diffraction pattern of the crystalline form A1 of the compound of formula A.

[0157] Figure 1d shows a differential scanning calorimetry graph of the crystalline form A1 of the compound of formula A.

[0158] Figure 1e shows the thermogravimetric analysis of the crystalline form A1 of the compound of formula A.

[0159] Figure 1f shows the crystalline form A1 of the compound of formula A 1 HNMR spectrum.

[0160] Figure 2a shows the X-ray powder diffraction pattern of the crystalline form A2 of the compound of formula A.

[0161] Figure 2b shows a differential scanning calorimetry graph of the crystalline form A2 of the compound of formula A.

[0162] FIG2c shows a thermogravimetric analysis of the crystalline form A2 of the compound of formula A.

[0163] Figure 2d shows the crystalline form A2 of the compound of formula A. 1 HNMR spectrum.

[0164] Figure 3a shows the X-ray powder diffraction pattern of the crystalline form A3 of the compound of formula A.

[0165] Figure 3b shows a differential scanning calorimetry graph of the crystalline form A3 of the compound of formula A.

[0166] FIG3 c shows a thermogravimetric analysis of the crystalline form A3 of the compound of formula A.

[0167] Figure 3d shows the crystalline form A3 of the compound of formula A 1 HNMR spectrum.

[0168] Figure 4a shows the X-ray powder diffraction pattern of the crystalline form A4 of the compound of formula A.

[0169] Figure 4b shows a differential scanning calorimetry graph of crystalline form A4 of the compound of formula A.

[0170] FIG4c shows a thermogravimetric analysis of the crystalline form A4 of the compound of formula A.

[0171] Figure 4d shows the crystalline form A4 of the compound of formula A. 1 HNMR spectrum.

[0172] Figure 5a shows the X-ray powder diffraction pattern of the crystalline form A5 of the compound of formula A.

[0173] Figure 5b shows a differential scanning calorimetry graph of the crystalline form A5 of the compound of formula A.

[0174] Figure 5c shows the thermogravimetric analysis of the crystalline form A5 of the compound of formula A.

[0175] Figure 5d shows the crystalline form A5 of the compound of formula A 1 HNMR spectrum.

[0176] FIG6a shows a chemical purity spectrum of crystalline form B of the compound of formula A.

[0177] FIG6 b shows the chiral purity spectrum of crystalline form B of the compound of formula A.

[0178] FIG6 c shows the X-ray powder diffraction pattern of crystalline form B of the compound of formula A.

[0179] FIG6d shows a differential scanning calorimetry graph of crystalline form B of the compound of formula A.

[0180] FIG6e shows a thermogravimetric analysis of crystalline form B of the compound of formula A.

[0181] Figure 6f shows the crystalline form B of the compound of formula A. 1 HNMR spectrum.

[0182] FIG7a shows an X-ray powder diffraction pattern of crystalline form C of the compound of formula A.

[0183] FIG7 b shows a differential scanning calorimetry graph of crystalline form C of the compound of formula A.

[0184] FIG7c shows a thermogravimetric analysis of crystalline form C of the compound of formula A.

[0185] Figure 7d shows the crystalline form C of the compound of formula A. 1 HNMR spectrum.

[0186] Figure 8a shows the X-ray powder diffraction pattern of the crystalline form D1 of the compound of formula A.

[0187] Figure 8b shows a differential scanning calorimetry graph of the crystalline form D1 of the compound of formula A.

[0188] FIG8c shows a thermogravimetric analysis of the crystalline form D1 of the compound of Formula A.

[0189] Figure 8d shows the crystalline form D1 of the compound of formula A. 1 HNMR spectrum.

[0190] Figure 9a shows the X-ray powder diffraction pattern of the crystalline form D2 of the compound of formula A.

[0191] Figure 9b shows a differential scanning calorimetry graph of the crystalline form D2 of the compound of formula A.

[0192] Figure 9c shows the thermogravimetric analysis of the crystalline form D2 of the compound of formula A.

[0193] Figure 9d shows the crystalline form D2 of the compound of formula A. 1 HNMR spectrum.

[0194] Figure 10a shows the chemical purity profile of crystalline form E of the compound of formula A.

[0195] Figure 10b shows the chiral purity spectrum of crystalline form E of the compound of formula A.

[0196] FIG10c shows the X-ray powder diffraction pattern of crystalline form E of the compound of formula A.

[0197] Figure 10d shows a differential scanning calorimetry graph of crystalline Form E of the compound of Formula A.

[0198] Figure 10e shows the thermogravimetric analysis of crystalline form E of the compound of formula A.

[0199] Figure 10f shows the crystalline form E of the compound of formula A 1 HNMR spectrum.

[0200] Figure 11a shows the X-ray powder diffraction pattern of crystalline form F of the compound of formula A.

[0201] FIG. 11 b shows a differential scanning calorimetry graph of crystalline form F of the compound of formula A.

[0202] FIG. 11c shows a thermogravimetric analysis of crystalline form F of the compound of formula A.

[0203] Figure 11d shows the crystalline form F of the compound of formula A. 1 HNMR spectrum.

[0204] Figure 12a shows the chemical purity profile of crystalline form G of the compound of formula A.

[0205] Figure 12b shows the chiral purity spectrum of crystalline form G of the compound of formula A.

[0206] Figure 12c shows the X-ray powder diffraction pattern of crystalline form G of the compound of formula A.

[0207] Figure 12d shows a differential scanning calorimetry graph of crystalline Form G of the compound of Formula A.

[0208] Figure 12e shows a thermogravimetric analysis of crystalline form G of the compound of formula A.

[0209] Figure 12f shows the crystalline form G of the compound of formula A. 1 HNMR spectrum.

[0210] Figure 13a shows the X-ray powder diffraction pattern of crystalline form H of the compound of formula A.

[0211] Figure 13b shows a differential scanning calorimetry graph of crystalline Form H of the compound of Formula A.

[0212] Figure 13c shows a thermogravimetric analysis of crystalline form H of the compound of formula A.

[0213] Figure 13d shows the crystalline form H of the compound of formula A. 1 HNMR spectrum.

[0214] FIG14a shows the X-ray powder diffraction pattern of the amorphous form of the compound of Formula A.

[0215] FIG14b shows a modulated differential scanning calorimetry (mDSC) graph of the amorphous form of the compound of Formula A.

[0216] FIG14c shows a thermogravimetric analysis of the amorphous form of the compound of Formula A.

[0217] Figure 14d shows a polarized light microscopy (PLM) image of the amorphous form of the compound of Formula A.

[0218] Figure 15a shows the chemical purity of crystalline Form B of the compound of formula A.

[0219] Figure 15b shows the chiral purity of crystalline Form B of the compound of Formula A.

[0220] Figure 15c shows the chemical purity of crystalline Form B of the compound of formula A.

[0221] Figure 15d shows the chiral purity of crystalline Form B of the compound of Formula A.

[0222] Figure 15e shows an X-ray powder diffraction stack of the stability test of the crystalline form B of the compound of formula A.

[0223] Figure 15f shows the chemical purity of crystalline Form B of the compound of Formula A.

[0224] Figure 15g shows the chiral purity of crystalline Form B of the compound of Formula A.

[0225] Figure 15h shows the chemical purity of crystalline Form B of the compound of formula A.

[0226] Figure 15i shows the chiral purity of crystalline Form B of the compound of Formula A.

[0227] Figure 16a shows the chemical purity of crystalline Form E of the compound of formula A.

[0228] Figure 16b shows the chiral purity of crystalline Form E of the compound of Formula A.

[0229] Figure 16c shows the chemical purity of crystalline Form E of the compound of formula A.

[0230] Figure 16d shows the chiral purity of crystalline Form E of the compound of Formula A.

[0231] Figure 16e shows an X-ray powder diffraction stack of the stability test of the crystalline form E of the compound of formula A.

[0232] Figure 16f shows the chemical purity of crystalline Form E of the compound of formula A.

[0233] Figure 16g shows the chiral purity of crystalline Form E of the compound of Formula A.

[0234] Figure 16h shows the chemical purity of crystalline Form E of the compound of formula A.

[0235] Figure 16i shows the chiral purity of crystalline Form E of the compound of Formula A.

[0236] Figure 17a shows the chemical purity of crystalline Form G of the compound of formula A.

[0237] Figure 17b shows the chiral purity of crystalline Form G of the compound of Formula A.

[0238] Figure 17c shows an X-ray powder diffraction stack of the stability test of the crystalline form G of the compound of formula A.

[0239] Figure 17d shows the chemical purity of crystalline Form G of the compound of formula A.

[0240] Figure 17e shows the chiral purity of crystalline Form G of the compound of Formula A.

[0241] Figure 17f shows the chemical purity of crystalline Form G of the compound of Formula A.

[0242] Figure 17g shows the chiral purity of crystalline Form G of the compound of Formula A.

[0243] FIG18a shows the DVS spectrum of crystalline form B of the compound of formula A.

[0244] Figure 18b shows the X-ray powder diffraction patterns of crystalline form B of the compound of formula A before and after the hygroscopicity test.

[0245] Figure 19a shows the DVS spectrum of crystalline form E of the compound of formula A.

[0246] Figure 19b shows the X-ray powder diffraction patterns of crystalline form E of the compound of formula A before and after the hygroscopicity test.

[0247] Figure 20a shows the DVS spectrum of crystalline form G of the compound of formula A.

[0248] Figure 20b shows the X-ray powder diffraction patterns of crystalline form G of the compound of formula A before and after the hygroscopicity test.

[0249] Figure 21a shows an XRPD overlay of a sample of crystalline Form G obtained after simulated tableting experiments of the compound of Formula A. DETAILED DESCRIPTION

[0250] Through long and in-depth research, the inventors have discovered multiple crystalline and amorphous forms of the compound of Formula A, or its pharmaceutically acceptable salt, or its solvate. These crystalline and amorphous forms have improved drug bioavailability, are high in purity, and are very stable, making them suitable for use in preparing pharmaceutical compositions for treating proliferative diseases, thereby further facilitating the treatment of diseases such as cancer, myeloproliferative disorders, and inflammation. Furthermore, the crystalline and amorphous forms of the present invention are less susceptible to flying and easier to collect during the pharmaceutical manufacturing process, such as packaging, thereby minimizing waste and helping to protect the health of operators. Based on this, the inventors have completed the present invention.

[0251] Active ingredient

[0252] In the present invention, the active ingredient refers to the amorphous form or crystalline form of the compound of formula A or its pharmaceutically acceptable salt or solvate. Preferably, the active ingredient is the 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.

[0253] abbreviation

[0254] polymorphs

[0255] Solids exist in either amorphous or crystalline forms. In the crystalline form, the molecules are positioned within a three-dimensional lattice. When a compound crystallizes from a solution or slurry, it can crystallize in different spatial arrangements (a property known as "polymorphism"), forming crystals with different crystalline forms, which are known as "polymorphs." Different polymorphs of a given substance can differ from one another in one or more physical properties, such as solubility and dissolution rate, true specific gravity, crystal shape, packing pattern, flowability, and / or solid-state stability.

[0256] Crystal form screening

[0257] Crystalline Form A1 can be used as the starting material. The chemical purity is shown in Figure 1a, and the chiral purity is shown in Figure 1b. The polymorphism of the compound of Formula A was investigated during screening by suspension, slow cooling, rapid cooling, slow evaporation, rapid evaporation, dropwise addition of antisolvent, reverse dropwise addition of antisolvent, vapor diffusion, or heating-cooling DSC crystallization.

[0258] Compound A exhibits complex polymorphic behavior, with 13 polymorphs and pseudo-polymorphs discovered and identified, including two anhydrous crystalline forms, designated Form F and Form G. Three hydrates, designated Form B, Form E, and Form H, and eight solvates, designated Form A1, Form A2, Form A3, Form A4, Form A5, Form C, Form D1, and Form D2. In addition, amorphous samples were obtained in solvent systems such as acetone and tetrahydrofuran in this study.

[0259] Crystalline Forms A1, A2, A3, A4, and A5 have similar XRPD patterns, suggesting that they have similar crystal structures and are isomorphous solvates of each other. Crystalline Forms D1 and D2 also have similar XRPD patterns, suggesting that they also have similar crystal structures and are another group of isomorphous solvates of each other.

[0260] As used herein, the term "room temperature" generally refers to 4-30°C, preferably 20±5°C.

[0261] After preparing the polymorphs of the compound of formula A, the present invention used the following methods and instruments to study its properties.

[0262] X-ray powder diffraction

[0263] Methods for determining the crystal form by X-ray powder diffraction are known in the art. For example, a Bruker D8 Advance X-ray powder diffractometer is used with a scanning speed of 0.02° per minute using a Cu / K-Alpha 1 Radiation target acquisition map.

[0264] As is well known in the art, due to experimental variability, when measuring X-ray diffraction patterns on different instruments, if two θ (2θ) values ​​differ within 0.2° (i.e., ±0.2°), the positions of the peaks are assumed to be equal. For example, the United States Pharmacopoeia stipulates that if the angle settings of the 10 strongest diffraction peaks differ from the angle settings of the reference material within ±0.2°, and the relative intensity of the peaks does not change by more than 20%, then they are confirmed to be identical. Therefore, the peak positions within 0.2° of the positions listed herein are assumed to be the same. Unless otherwise stated, all X-ray diffraction angles listed herein are based on a copper K-alpha source.

[0265] Differential scanning calorimetry

[0266] Differential Scanning Calorimetry (DSC), also known as differential scanning calorimetry (DSC), is a technique that measures the relationship between the energy difference between a test substance and a reference substance and temperature during heating. The position, shape, and number of peaks on a DSC spectrum correlate with the properties of the substance and can therefore be used to qualitatively identify it. This method is commonly used in the field to measure various parameters, including phase transition temperature, glass transition temperature, and heat of reaction.

[0267] The DSC measurement method is known in the art. For example, a TA Discovery 2500 differential scanning calorimeter can be used to increase the temperature from 0°C to 250°C at a heating rate of 10°C per minute to obtain a DSC scan pattern of the crystal form.

[0268] NMR

[0269] Nuclear magnetic resonance (NMR) can also be used to assist in determining the crystal structure, and its determination method is known in the art. The present invention preferably uses Bruker Avance-AV-400 MHz.

[0270] Thermogravimetric analysis (TGA) determination

[0271] Place the sample (2-5 mg) on ​​an aluminum pan and run as follows:

[0272] The test is completed if the sample loses more than 20% of its weight by heating from room temperature to 300°C at a rate of 10°C / min under atmospheric conditions.

[0273] Polarized light microscopy (PLM) determination

[0274] -Nikon LV100POL is equipped with a 5-megapixel CCD

[0275] -Physical lens: 10x~50x.

[0276] Dynamic water sorption (DVS) determination

[0277] -DVS Intrinsic Dynamic Water Vapor Sorption Analyzer

[0278] - Gas flow rate 200 sccm, furnace temperature 25°C.

[0279] The crystalline form of the present invention

[0280] As used herein, the term "crystalline form of the present invention" includes an amorphous form or a crystalline form of the compound of formula A or a pharmaceutically acceptable salt or a solvate thereof.

[0281] 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.

[0282] Amorphous form

[0283] "Amorphous" or "amorphous form" refers to a substance whose particles (molecules, atoms, ions) are arranged in a three-dimensional space without periodicity. It is characterized by a diffuse, non-peaked X-ray powder diffraction pattern. Amorphous is a specialized physical form of solid matter, and its locally ordered structure suggests a close relationship to crystalline forms.

[0284] The amorphous form of the present invention preferably has an XRPD pattern as shown in FIG14a, and optionally has one or more of the following characteristics:

[0285] 1) In the mDSC graph, there is a glass transition temperature at 129.30℃±2.0℃;

[0286] 2) In the TGA graph, there is a 2.7 wt% weight loss before 210°C ± 2.0°C;

[0287] 3) an mDSC plot substantially as shown in Figure 14b; and / or

[0288] 4) A TGA pattern substantially as shown in Figure 14c.

[0289] Preparation method of the crystalline form or amorphous form of the present invention

[0290] The present invention provides a method for preparing a crystalline form or an amorphous form of a compound of formula A or a pharmaceutically acceptable salt or solvate thereof, comprising the steps of: subjecting the compound of formula A or a pharmaceutically acceptable salt thereof to suspension, slow cooling, rapid cooling, slow volatilization, rapid volatilization, antisolvent addition, antisolvent reverse addition, vapor diffusion or heating-cooling DSC crystallization, or spray drying, hot melt extrusion or solvent evaporation, thereby obtaining the crystalline form or amorphous form.

[0291] In the preparation method, the compound of Formula A is synthesized in the laboratory as described in the specific examples. The solvent can be a commonly used laboratory solvent, such as one or more of 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). The mass-to-volume ratio of the compound of Formula A to the solvent can be 100 mg:(0.1-1 mL).

[0292] 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 solvate type, separating the resulting solid and drying it, thereby obtaining a crystalline form of a solvate of a compound of formula A.

[0293] Preferably, the preparation method of crystalline form A1 comprises: mixing and slurrying the compound of formula A with MTBE, separating, and drying to obtain crystalline form A1.

[0294] Preferably, the preparation method of crystalline form A2 comprises: suspending crystalline form A1 and 1,4-dioxane, and separating to obtain crystalline form A2.

[0295] Preferably, the preparation method of crystalline form A3 comprises: suspending crystalline form A1 with toluene, and separating to obtain crystalline form A3.

[0296] Preferably, the preparation method of crystalline form A4 comprises: mixing crystalline form A1 with dichloromethane and rapidly volatilizing to obtain crystalline form A4.

[0297] Preferably, the preparation method of crystalline form A5 comprises: suspending crystalline form A1 with ethyl acetate, and separating to obtain crystalline form A5.

[0298] Preferably, the preparation method of crystalline form B comprises: suspending crystalline form A1 with ethanol, separating, and drying to obtain crystalline form B.

[0299] Preferably, the preparation method of crystalline form C comprises: suspending crystalline form A1 and dimethyl sulfoxide, and separating to obtain crystalline form C.

[0300] Preferably, the preparation method of crystalline form D1 comprises: suspending crystalline form A1 with isopropanol, and separating to obtain crystalline form D1.

[0301] Preferably, the preparation method of crystalline form D2 comprises: suspending crystalline form A1 with a mixed solution (DMSO:water=24:76, v / v), and separating to obtain crystalline form D2.

[0302] Preferably, the preparation method of crystalline form E comprises: mixing crystalline form A1 with an acetonitrile / water (v:v=80:20) mixed solution, heating-cooling, separating, and drying to obtain crystalline form E.

[0303] Preferably, the preparation method of crystalline form F comprises: suspending crystalline form A1 with water, and isolating to obtain crystalline form F.

[0304] Preferably, the preparation method of crystalline form H comprises: mixing crystalline form E with methanol, heating-cooling, and separating to obtain crystalline form H.

[0305] In some preferred embodiments, the solvent corresponding to the solvate type is, for example but not limited to, 1,4-dioxane, ethyl acetate, toluene, chloroform, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetone, N,N-dimethylformamide, acetonitrile, and the like.

[0306] The solvent used in the amorphous preparation method described herein is not particularly limited; any solvent that can dissolve the starting materials to some extent and does not affect their properties is encompassed by the present invention. Furthermore, many similar modifications, equivalent substitutions, or equivalent solvents, solvent combinations, and varying ratios of solvent combinations described herein are also encompassed by the present invention. The present invention provides preferred solvents for each reaction step.

[0307] In one embodiment, the present invention provides a method for preparing an amorphous form of a compound of formula A, comprising the steps of mixing the compound of formula A with a solvent and spray drying the resulting solution, thereby obtaining the amorphous form of the compound of formula A.

[0308] In some preferred embodiments, the solvent can be a commonly used solvent in the laboratory, for example: the solvent is one or more of water, alcohol solvents, ester solvents, ketone solvents, halogenated hydrocarbon solvents, nitrile solvents and ether solvents, wherein the alcohol solvent is preferably ethanol and / or methanol; the ester solvent is preferably ethyl acetate; the ketone solvent is preferably acetone; the halogenated hydrocarbon solvent is preferably dichloromethane; the nitrile solvent is preferably acetonitrile; the ether solvent is preferably tetrahydrofuran; preferably, the solvent is one or more of ethyl acetate, acetone, tetrahydrofuran, methyl tert-butyl ether and acetonitrile.

[0309] Preferably, the separation is performed by centrifugal filtration using a 0.45 μm nylon filter membrane centrifuge tube at a certain speed (such as 14,000 rpm).

[0310] Pharmaceutical composition

[0311] Because the crystalline and amorphous forms of the present invention have excellent therapeutic effects on proliferative diseases, the crystalline and amorphous forms of the present invention, as well as pharmaceutical compositions containing the crystalline and amorphous forms of the present invention as primary active ingredients, can be used to treat, prevent, and alleviate proliferative diseases. According to prior art, the forms described herein can be used to treat the following diseases: cancer, myeloproliferative disorders, and inflammatory diseases, among others.

[0312] The pharmaceutical composition of the present invention comprises a safe and effective amount of the crystalline form or amorphous form of the present invention and a pharmaceutically acceptable excipient and / or carrier.

[0313] The crystalline and amorphous forms of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0314] The pharmaceutical composition can be in a dosage form suitable for human consumption, such as tablets, capsules, granules, powders, or pills, preferably tablets, capsules, granules, disintegrating tablets, sustained-release or controlled-release tablets.

[0315] The pharmaceutical composition of the present invention can be prepared by various methods well known in the art, which can be prepared by mixing a therapeutically effective amount of one or more of the crystalline or amorphous forms of the compound of formula A or its salts or solvates with one or more pharmaceutically acceptable excipients to form a dosage form suitable for human administration, such as tablets, capsules, granules, etc.

[0316] "Therapeutically effective amount" refers to 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 has utility. Such an amount will be sufficient to elicit the biological or medical response of a tissue system or patient that is being sought by the researcher or clinician.

[0317] A "safe and effective amount" refers to an amount of the compound (polymorph) sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 0.1 to 2000 mg of the crystalline or amorphous form of the present invention per dose, more preferably 0.1 to 200 mg of the crystalline or amorphous form of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0318] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0319] The administration mode of the crystalline form and amorphous form or pharmaceutical composition of the present invention is not particularly limited. Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0320] When using the pharmaceutical composition, a safe and effective amount of the crystalline form or amorphous form of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 0.1 to 2000 mg, preferably 0.1 to 200 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0321] 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 the following ingredients: (a) fillers or extenders, for example, microcrystalline cellulose, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose; (e) solubilizing agents, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0322] Solid dosage forms such as tablets, drupes, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions can be delayed in a certain portion of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If desired, the active ingredient can also be microencapsulated with one or more of the above-mentioned excipients.

[0323] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0324] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0325] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0326] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0327] Dosage forms of the crystalline and amorphous forms of the invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0328] The main advantages of the present invention include:

[0329] 1. Provided are a series of novel crystalline or amorphous forms of N-((S)-5-chloropyridin-2-yl)(cyclobutyl)methyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindole-5-carboxamides or their salts or solvates.

[0330] 2. The obtained amorphous form or crystalline form has excellent stability, solubility and bioavailability.

[0331] Example 1 Preparation of Crystalline Form A1

[0332] Preparation method: Prepare the compound of formula A by referring to the method of Example 15 of PCT / CN2022 / 097236, and then slurry it with MTBE to obtain crystalline form A1.

[0333] In a round-bottom flask containing dimethylacetamide (DMAc) (50 mL), compound 1 (3.25 g, 12.3 mmol, hydrochloride), compound 2 (4.67 g, 12.9 mmol), NMM (6.2 g, 61.3 mmol) and T3P (5.6 g, 17.6 mmol) were added. The mixture was degassed and purged with N2 three times. The mixture was stirred at 25°C under N2 for 12 hours. The mixture was poured into a saturated aqueous sodium chloride solution (100 mL), then filtered and washed with water (100 mL). The filter cake was then dissolved in DCM (200 mL), washed with a saturated aqueous NaHCO3 solution (100 mL), and the organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain compound 3 (6.5 g, 99.7% yield based on compound 1) as a white solid.

[0334] Compound 3 (6.5 g) was dissolved in CH CN (13 mL) and benzenesulfonic acid (1.1 g, 6.95 mmol) was added. Under N environment, the mixture was stirred at 70 ° C for 14 hours. The mixture was diluted with DCM (60 mL), washed with saturated NaHCO aqueous solution (30 mL x 2), then washed with H O (30 mL x 2), and dried over anhydrous Na SO The organic phase was filtered and concentrated under reduced pressure to give a crude product. The crude product was then pulped with EA (5 mL) and MTBE (5 mL) at 25 ° C for 0.5 h to give compound A (4.9 g), a white solid with a yield of 87% 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.

[0335] The compound of formula A (4.9 g) was slurried in MTBE (25 ml) at room temperature for 24 h, filtered and dried to obtain 4.41 g of a white solid with a yield of 90%. XRPD ( FIG. 1 c ) confirmed the solid to be crystalline form A1.

[0336] The chemical purity diagram is shown in FIG1a, the chiral purity diagram is shown in FIG1b, the X-ray powder diffraction diagram is shown in FIG1c, the parameters of each peak are shown in Table 1, the differential scanning calorimetry diagram (DSC) diagram is shown in FIG1d, and the thermogravimetric analysis diagram is shown in FIG1e. 1 The H NMR spectrum is shown in Figure 1f.

[0337] Table 1

[0338] Example 2 Preparation of Crystalline Form A2

[0339] Preparation: Weigh approximately 40 mg of crystalline Form A1, add 0.2-1 mL of 1,4-dioxane, and suspend with stirring at 300 rpm at 25°C for 2 weeks. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain crystalline Form A2.

[0340] Its X-ray powder diffraction pattern is shown in Figure 2a, the parameters of each peak are shown in Table 2, the differential scanning calorimetry (DSC) pattern is shown in Figure 2b, and the thermogravimetric analysis pattern is shown in Figure 2c. 1 The H NMR spectrum is shown in Figure 2d.

[0341] Table 2

[0342] Example 3 Preparation of Crystalline Form A3

[0343] Preparation: Weigh approximately 40 mg of crystalline Form A1, add 0.2-1 mL of toluene, and suspend under stirring at 300 rpm at 25°C for 2 weeks. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain crystalline Form A3.

[0344] Its X-ray powder diffraction pattern is shown in Figure 3a, the parameters of each peak are shown in Table 3, the differential scanning calorimetry (DSC) pattern is shown in Figure 3b, and the thermogravimetric analysis pattern is shown in Figure 3c. 1 The H NMR spectrum is shown in Figure 3d.

[0345] Table 3

[0346] Example 4 Preparation of Crystalline Form A4

[0347] Preparation Method: Weigh approximately 30 mg of crystalline Form A1 and dissolve thoroughly in 5 mL of DCM. Filter through a 0.45 μm nylon syringe filter to obtain a clear solution. Purge the resulting clear solution with nitrogen at room temperature to rapidly evaporate the solvent. Collect the resulting solid after solvent evaporation to obtain crystalline Form A4.

[0348] Its X-ray powder diffraction pattern is shown in FIG4a, the parameters of each peak are shown in Table 4, the differential scanning calorimetry (DSC) pattern is shown in FIG4b, and the thermogravimetric analysis pattern is shown in FIG4c. 1 The H NMR spectrum is shown in Figure 4d.

[0349] Table 4

[0350] Example 5 Preparation of Crystalline Form A5

[0351] Preparation Method: Weigh approximately 60 mg of crystalline Form A1, add 0.2-1 mL of ethyl acetate, and stir at 50°C and 300 rpm for 1 week. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain crystalline Form A5.

[0352] Its X-ray powder diffraction pattern is shown in FIG5a, the parameters of each peak are shown in Table 5, the differential scanning calorimetry (DSC) pattern is shown in FIG5b, and the thermogravimetric analysis pattern is shown in FIG5c. 1 The H NMR spectrum is shown in Figure 5d.

[0353] Table 5

[0354] Example 6 Preparation of Crystalline Form B

[0355] Preparation method. Weigh 410 mg of Form A1 and place it in an 8 mL glass bottle. Add 5 mL of ethanol and stir at 25°C to obtain a suspension. Add approximately 5 mg of Form B seed crystals to the suspension, stir at 25°C for approximately 5 days, collect the solid by filtration, and vacuum dry the resulting solid at 50°C for approximately 8 hours and at 25°C for approximately 3 hours. Approximately 350 mg of Form B off-white powder is obtained with a yield of approximately 87%.

[0356] Its chemical purity is shown in Figure 6a, its chiral purity is shown in Figure 6b, its X-ray powder diffraction pattern is shown in Figure 6c, the parameters of each peak are shown in Table 6, its differential scanning calorimetry (DSC) pattern is shown in Figure 6d, and its thermogravimetric analysis pattern is shown in Figure 6e. 1 The H NMR spectrum is shown in Figure 6f.

[0357] Table 6

[0358] Example 7 Preparation of Crystalline Form C

[0359] Preparation: Weigh approximately 40 mg of crystalline Form A1, add 0.2-1 mL of DMSO, and suspend with stirring at 300 rpm at 25°C for 2 weeks. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain crystalline Form C.

[0360] Its X-ray powder diffraction pattern is shown in FIG7a, the parameters of each peak are shown in Table 7, the differential scanning calorimetry (DSC) pattern is shown in FIG7b, and the thermogravimetric analysis pattern is shown in FIG7c. 1 The H NMR spectrum is shown in Figure 7d.

[0361] Table 7

[0362] Example 8 Preparation of Crystalline Form D1

[0363] Preparation: Weigh approximately 40 mg of crystalline Form A1, add 0.2-1 mL of IPA, and suspend with stirring at 300 rpm at 25°C for 2 weeks. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain crystalline Form D1.

[0364] Its X-ray powder diffraction pattern is shown in FIG8a, the parameters of each peak are shown in Table 8, the differential scanning calorimetry (DSC) pattern is shown in FIG8b, and the thermogravimetric analysis pattern is shown in FIG8c. 1 The H NMR spectrum is shown in Figure 8d.

[0365] Table 8

[0366] Example 9 Preparation of Crystalline Form D2

[0367] Preparation Method: Weigh approximately 40 mg of crystalline Form A1 and add 0.2-1 mL of a mixed solution (DMSO:water = 24:76, v / v). Stir and suspend at 25°C and 300 rpm for 2 weeks. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain crystalline Form D2.

[0368] Its X-ray powder diffraction pattern is shown in FIG9a, the parameters of each peak are shown in Table 9, the differential scanning calorimetry (DSC) pattern is shown in FIG9b, and the thermogravimetric analysis pattern is shown in FIG9c. 1 The H NMR spectrum is shown in Figure 9d.

[0369] Table 9

[0370] Example 10 Preparation of Crystalline Form E

[0371] Preparation method. 860 mg of crystalline form A1 was weighed and dissolved in 10 mL of a mixed solution of ACN / water (v:v=80:20) at 50°C. The resulting solution was filtered through a 0.45 μm nylon membrane syringe filter to obtain a clear solution. The clear solution was cooled to 5°C at a rate of 0.1°C / min. When the temperature dropped to about 30°C, about 5 mg of crystalline form E seed crystals were added, and the resulting suspension was further cooled to 5°C at a rate of 0.1°C / min and maintained at 5°C with stirring for 1 day. The solid was collected by filtration at 5°C, and the resulting solid was vacuum dried at 50°C for about 4.5 hours. About 350 mg of crystalline form E off-white powder was prepared with a yield of about 41%.

[0372] Its chemical purity is shown in FIG10a, its chiral purity is shown in FIG10b, its X-ray powder diffraction pattern is shown in FIG10c, and the parameters of each peak are shown in Table 10. Its differential scanning calorimetry (DSC) pattern is shown in FIG10d, and its thermogravimetric analysis pattern is shown in FIG10e. 1 The H NMR spectrum is shown in Figure 10f.

[0373] Table 10

[0374] Example 11 Preparation of Crystalline Form F

[0375] Preparation: Weigh approximately 40 mg of crystalline Form A1, add 0.2-1 mL of water, and suspend with stirring at 300 rpm at 25°C for 2 weeks. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain crystalline Form F.

[0376] Its X-ray powder diffraction pattern is shown in FIG11a, the parameters of each peak are shown in Table 11, the differential scanning calorimetry (DSC) pattern is shown in FIG11b, and the thermogravimetric analysis pattern is shown in FIG11c. 1 The H NMR spectrum is shown in Figure 11d.

[0377] Table 11

[0378] Example 12 Preparation of Crystalline Form G

[0379] Preparation method: The compound of formula A was prepared according to the method of Example 15 of PCT / CN2022 / 097236, and then the ring was closed under acidic conditions and crystallized in acetonitrile-water to obtain crystalline form G.

[0380] Compound 1 (32.5 g, 121 mmol) and compound 2 (56 g, 155 mmol) were added to DMAc (500 mL), and T3P (46.7 g, 147 mmol) and NMM (62 g, 613 mmol) were added. The mixture was degassed and purged with N2 three times. The mixture was stirred at 25°C under N2 for 12 hours. The mixture was poured into a saturated aqueous sodium chloride solution (1000 mL), then filtered and washed with water (1000 mL). The filter cake was dissolved in DCM (2000 mL), washed with a saturated aqueous NaHCO3 solution (1000 mL), and the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound 3 (66 g) as a white solid (purity greater than 98%, chiral purity greater than 98%).

[0381] Compound 3 (66 g) was dissolved in CH3CN (660 mL), and benzenesulfonic acid (57.4 g, 363 mmol) was added. The mixture was stirred at 50°C for 16 hours under N2 atmosphere, cooled to 0°C, and the pH was adjusted to 7-8 with 7% NaHCO3. The above solution was slowly added dropwise to water (3300 mL), stirred for 3 hours, and filtered. The filter cake was washed with water (300 mL) and dried under vacuum to obtain compound A (50 g) as a white solid. The yield over two steps was 89%.

[0382] The compound of formula A was identified as crystalline Form G by XRPD ( FIG. 12 c ).

[0383] The chemical purity diagram is shown in FIG12a, the chiral purity diagram is shown in FIG12b, the X-ray powder diffraction diagram is shown in FIG12c, the parameters of each peak are shown in Table 12, the differential scanning calorimetry diagram (DSC) diagram is shown in FIG12d, and the thermogravimetric analysis diagram is shown in FIG12e. 1 The H NMR spectrum is shown in Figure 12f.

[0384] Table 12

[0385] Example 13 Preparation of Crystalline Form H

[0386] Preparation: Weigh approximately 60 mg of crystalline Form E, add 0.2-1 mL of methanol, and stir at 300 rpm at 50°C for 1 week. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain crystalline Form H.

[0387] Its X-ray powder diffraction pattern is shown in FIG13a, the parameters of each peak are shown in Table 13, the differential scanning calorimetry (DSC) pattern is shown in FIG13b, and the thermogravimetric analysis pattern is shown in FIG13c. 1 The H NMR spectrum is shown in Figure 13d.

[0388] Table 13

[0389] Example 14 Preparation of amorphous form of compound of formula A

[0390] Preparation Method 1. Weigh approximately 40 mg of crystalline Form A1, add 0.2-1 mL of EA, and suspend with stirring at 300 rpm at 25°C for 2 weeks. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain the amorphous form of the compound of Formula A.

[0391] Preparation Method 2: Weigh approximately 40 mg of crystalline Form A1, add 0.2-1 mL of acetone, and suspend with stirring at 300 rpm at 25°C for 2 weeks. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain the amorphous form of the compound of Formula A.

[0392] Preparation Method 3. Weigh approximately 40 mg of crystalline Form A1, add 0.2-1 mL of THF, and suspend with stirring at 300 rpm at 25°C for 2 weeks. Filter the resulting suspension through a 0.45 μm nylon membrane centrifuge tube at 14,000 rpm to obtain the amorphous form of the compound of Formula A.

[0393] Preparation Method 4. Approximately 50 mg of crystalline Form A1 was weighed and added with 0.2-1 mL of EA. The mixture was subjected to 10 temperature cycles between 5°C and 50°C at a rate of 0.2°C / min while magnetically stirring at 300 rpm. The resulting suspension was centrifuged through a 0.45 μm nylon membrane centrifuge tube at 5°C and 14,000 rpm to obtain the amorphous form of the compound of Formula A.

[0394] Preparation method 5. The crude product was obtained according to the method of Example 1, and then the crude product was treated with EA (5 mL) and MTBE (5 mL) to obtain a filter cake. The filter cake was added to 30 mL of acetonitrile and ultrasonicated for 5 minutes to uniformly disperse it into a slurry solution. 70 mL of water was then added to make the entire solution clear and transparent. After lyophilization, an amorphous form of the compound of formula A was obtained as an off-white solid.

[0395] Preparation method 6. A crude product is obtained according to the method of Example 1, and then the crude product is spray-dried with a solvent such as DCM and EtOH, with the inlet air temperature set at 80°C to 120°C to obtain an amorphous compound of formula A.

[0396] The X-ray powder diffraction pattern of the amorphous form of the compound of formula A is shown in Figure 14a.

[0397] Example 15 Stability test of crystalline form B

[0398] Crystalline Form B. Chemical purity is shown in Figure 15a, and chiral purity is shown in Figure 15b. The open container was placed at 25°C / 92% RH and 40°C / 75% RH for 13 days, respectively; the sealed container was placed at 60°C for 13 days. Stability samples were analyzed by XRPD and HPLC, and the samples were observed for color change. Data are shown in Table 14.

[0399] Table 14

[0400] Example 16 Stability test of crystalline form E

[0401] Crystalline Form E, chemical purity shown in Figure 16a, and chiral purity shown in Figure 16b. The open container was placed at 25°C / 92% RH and 40°C / 75% RH for 13 days, respectively, and the sealed container was placed at 60°C for 13 days. Stability samples were analyzed by XRPD and HPLC, and the samples were observed for color change. Data are shown in Table 15.

[0402] Table 15

[0403] Example 17 Stability test of crystalline form G

[0404] Crystalline Form G, chemical purity shown in Figure 12a, chiral purity shown in Figure 12b. The open container was placed at 25°C / 92% RH and 40°C / 75% RH for 13 days, respectively; the sealed container was placed at 60°C for 13 days. Stability samples were analyzed by XRPD and HPLC, and the samples were observed for color change. Data are shown in Table 16.

[0405] Table 16

[0406] Example 18 Hygroscopicity test of crystalline form B

[0407] The water absorption and dehydration behavior of Form B was studied using DVS. The humidity profile was: 25°C, 40-0-95-0-40% RH, dm / dt 0.002, with a minimum equilibration time of 60 min and a maximum equilibration time of 360 min. XRPD analysis was also performed on samples after DVS testing to determine whether a crystal transformation occurred. The results are shown in Table 17.

[0408] Table 17

[0409] Note "N / A": Not implemented.

[0410] Example 19 Hygroscopicity test of crystalline form E

[0411] The water absorption and dehydration behavior of Form E was studied using DVS. The humidity profile was: 25°C, 40-0-95-0-40% RH, dm / dt 0.002, with a minimum equilibration time of 60 min and a maximum equilibration time of 360 min. XRPD analysis was also performed on samples after DVS testing to determine whether a crystal transformation occurred. The results are shown in Table 18.

[0412] Table 18

[0413] Note "N / A": Not implemented.

[0414] Example 20 Hygroscopicity test of crystalline form G

[0415] The water absorption and dehydration behavior of Form G was studied using DVS. The humidity profile was: 25°C, 40-0-95-0-40% RH, dm / dt 0.002, with a minimum equilibration time of 60 min and a maximum equilibration time of 360 min. XRPD analysis was also performed on samples after DVS testing to determine whether a crystal transformation occurred. The results are shown in Table 19.

[0416] Table 19

[0417] Note "N / A": Not implemented.

[0418] Example 21 Simulated tableting experiment

[0419] Approximately 10 mg of crystalline Form G was weighed and pressed at 2 MPa, 5 MPa, and 10 MPa for 5 min. XRPD characterization was performed to investigate the changes in crystal form and crystallinity. See Table 20.

[0420] Table 20

[0421] Example 22 Pharmaceutical composition

[0422] Table 21

[0423] According to the conventional method, as shown in Table 21, the above substances are mixed evenly and filled into ordinary gelatin capsules to obtain 10,000-100,000 capsules.

[0424] Example 23 Pharmacokinetic Evaluation of Crystalline Form G and Amorphous Form of Compound A in Mice by Oral Gavage

[0425] CD1 male mice were selected and the test compound was administered orally by gavage. The plasma drug concentration at different time points was quantitatively determined by LC / MS / MS to evaluate the pharmacokinetic characteristics of the test drug in mice.

[0426] Experimental materials: CD1 mice (male, 20-30 g, 6-8 weeks old, Zhejiang Weitong Lihua).

[0427] Experimental Procedure: As shown in Table 22, test compounds were formulated in 25 mM citrate buffer (pH 3) containing 5% Tween 80 and administered orally to CD1 mice (with free access to food and water). Blood was collected from the dorsal plantar vein at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. Blood was placed in tubes containing EDTA-K2, mixed, and centrifuged at 4000 g for 5 minutes at 4°C. Plasma concentrations were determined by LC-MS / MS, and pharmacokinetic parameters were calculated using the non-compartmental linear / log trapezoidal method using Phoenix WinNonlin 6.3 pharmacokinetic software.

[0428] Table 22

[0429] As shown in Table 22, the compound of Formula A exhibits good in vivo pharmacokinetic parameters, with the area under the drug-time curve being 3 to 4 times that of crystalline Form G. As shown in Tables 14, 15, and 16, crystalline Forms B, E, and G exhibit good stability, with no observed crystalline form changes. As shown in the hygroscopicity tests in Tables 17, 18, and 19, crystalline Forms B, E, and G exhibit good stability, with no observed crystalline form changes. In particular, crystalline Form G exhibited no significant change in crystallinity when tableted at pressures of 2 MPa, 5 MPa, and 10 MPa, as shown in Table 20. Therefore, the forms described herein are highly suitable for use in pharmaceutical compositions. Furthermore, the crystalline and amorphous forms of the present invention are less susceptible to flying and easier to collect during pharmaceutical manufacturing processes, such as packaging, thereby minimizing waste and helping to protect the health of operators.

[0430] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. Amorphous or crystalline form of a compound of formula A or a pharmaceutically acceptable salt or solvate thereof 2. The form according to claim 1, characterized in that It is a crystalline form G of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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, it has XRPD characteristic peaks at the positions substantially as shown in Table 12; more preferably, it has an XRPD pattern substantially as shown in Figure 12c; and optionally has one or more of the following characteristics: 1) In the DSC graph, there is an endothermic peak at 236.59℃±2℃; 2) In the TGA graph, there was a weight loss of 0.52±0.2 wt% before 150°C; 3) a DSC pattern substantially as shown in Figure 12d; and / or 4) A TGA pattern substantially as shown in Figure 12e.

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

4. The form according to claim 1, characterized in that It is a solvate crystalline form A2 of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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, it has XRPD characteristic peaks at the positions substantially as shown in Table 2; more preferably, it has an XRPD pattern substantially as shown in Figure 2a; and optionally has one or more of the following characteristics: 1) In the DSC graph, there is one endothermic peak at 153.88℃±2℃ and one endothermic peak at 178.46℃±2℃; 2) in the TGA graph, there was 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) a DSC pattern substantially as shown in Figure 2b; and / or 4) A TGA pattern substantially as shown in Figure 2c.

5. The form according to claim 1, characterized in that It is a solvate crystalline form A3 of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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, it has XRPD characteristic peaks at the positions substantially as shown in Table 3; more preferably, it has an XRPD pattern substantially as shown in Figure 3a; and optionally has one or more of the following characteristics: 1) In the DSC graph, there is an exothermic peak at 90.56℃±2℃, and an endothermic peak at 152.55℃±2℃ and 177.33℃±2℃ respectively; 2) in the TGA graph, there was 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) a DSC pattern substantially as shown in Figure 3b; and / or 4) A TGA pattern substantially as shown in Figure 3c.

6. The form according to claim 1, characterized in that It is a solvate crystalline form A4 of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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, it has XRPD characteristic peaks at the positions substantially as shown in Table 4; more preferably, it has an XRPD pattern substantially as shown in Figure 4a; and optionally has one or more of the following characteristics: 1) In the DSC graph, there is an endothermic peak at 149.48℃±2℃; 2) In the TGA graph, there was a weight loss of 3.01±0.2 wt% before 160°C; 3) a DSC pattern substantially as shown in Figure 4b; and / or 4) A TGA graph substantially as shown in Figure 4c.

7. The form according to claim 1, characterized in that It is a solvate crystalline form A5 of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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, it has XRPD characteristic peaks at the positions substantially as shown in Table 5; more preferably, it has an XRPD pattern substantially as shown in Figure 5a; and optionally has one or more of the following characteristics: 1) In the DSC graph, there is an endothermic peak at 154.86℃±2℃; 2) In the TGA graph, there was a weight loss of 6.75±0.2 wt% before 220°C; 3) a DSC pattern substantially as shown in Figure 5b; and / or 4) A TGA graph substantially as shown in Figure 5c.

8. The form according to claim 1, characterized in that It is a crystalline form B of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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, it has XRPD characteristic peaks at the positions substantially as shown in Table 6; more preferably, it has an XRPD pattern substantially as shown in Figure 6c; and optionally has one or more of the following characteristics: 1) In the DSC graph, there is one endothermic peak at 25.54℃±2℃ and one endothermic peak at 183.52℃±2℃; 2) In the TGA graph, there was a weight loss of 1.03±0.2 wt% before 100°C; 3) a DSC pattern substantially as shown in Figure 6d; and / or 4) A TGA pattern substantially as shown in Figure 6e.

9. The form according to claim 1, characterized in that It is a solvate crystalline form C of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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, it has XRPD characteristic peaks at the positions substantially as shown in Table 7; more preferably, it has an XRPD pattern substantially as shown in Figure 7a; and optionally has the following characteristics: 1) In the DSC graph, there is an endothermic peak at 127.33℃±2℃; 2) in the TGA graph, there was 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) a DSC pattern substantially as shown in Figure 7b; and / or 4) A TGA graph substantially as shown in Figure 7c.

10. The form according to claim 1, characterized in that It is a solvate crystalline form D1 of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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, it has XRPD characteristic peaks at the positions substantially as shown in Table 8; more preferably, it has an XRPD pattern substantially as shown in Figure 8a; and optionally has one or more of the following characteristics: 1) In the DSC graph, there is an endothermic peak at 161.17℃±2℃; 2) In the TGA graph, there was a weight loss of 11.30 ± 0.2 wt% before 210 °C; 3) a DSC pattern substantially as shown in Figure 8b; and / or 4) A TGA pattern substantially as shown in FIG8c.

11. The form according to claim 1, characterized in that It is a solvate crystalline form D2 of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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, it has XRPD characteristic peaks at the positions substantially as shown in Table 9; more preferably, it has an XRPD pattern substantially as shown in Figure 9a; and optionally has one or more of the following characteristics: 1) In the DSC graph, there is one endothermic peak at 83.30℃±2℃ and one endothermic peak at 126.89℃±2℃; 2) in the TGA graph, there was 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) a DSC pattern substantially as shown in Figure 9b; and / or 4) A TGA graph substantially as shown in FIG9c.

12. The form according to claim 1, characterized in that It is a crystalline form E of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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, it has XRPD characteristic peaks at the positions substantially as shown in Table 10; more preferably, it has an XRPD pattern substantially as shown in Figure 10c; and optionally has one or more of the following characteristics: 1) In the DSC graph, there is one endothermic peak at 37.94℃±2℃ and one endothermic peak at 190.71℃±2℃; 2) In the TGA graph, there was a weight loss of 1.17 ± 0.2 wt% before 130 °C; 3) a DSC pattern substantially as shown in Figure 10d; and / or 4) A TGA pattern substantially as shown in FIG10e.

13. The form according to claim 1, characterized in that It is a crystalline form F of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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, it has XRPD characteristic peaks at the positions substantially as shown in Table 11; more preferably, it has an XRPD pattern substantially as shown in Figure 11a; and optionally has one or more of the following characteristics: 1) In the DSC graph, there is an endothermic peak at 216.58℃±2℃; 2) In the TGA graph, there was a weight loss of 0.598±0.2 wt% before 100°C; 3) a DSC pattern substantially as shown in Figure 11b; and / or 4) A TGA pattern substantially as shown in FIG. 11c .

14. The form according to claim 1, characterized in that It is a crystalline form H of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles: 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, it has XRPD characteristic peaks at the positions substantially as shown in Table 13; more preferably, it has an XRPD pattern substantially as shown in Figure 13a; and optionally has one or more of the following characteristics: 1) In the DSC graph, there is one endothermic peak at 77.45℃±2℃ and one endothermic peak at 154.75℃±2℃; 2) In the TGA graph, there was a weight loss of 0.19±0.2 wt% before 120°C; 3) a DSC pattern substantially as shown in Figure 13b; and / or 4) A TGA pattern substantially as shown in Figure 13c.

15. The form according to claim 1, characterized in that It is an amorphous form of the compound of formula A, preferably, it has an XRPD pattern as shown in Figure 14a, more preferably, it optionally has one or more of the following characteristics: 1) In the mDSC graph, there is a glass transition temperature at 129.30℃±2.0℃; 2) In the TGA graph, there is a 2.7 wt% weight loss before 210°C ± 2.0°C; 3) an mDSC plot substantially as shown in Figure 14b; and / or 4) A TGA pattern substantially as shown in Figure 14c.

16. A method for preparing a form according to any one of claims 1 to 15, characterized in that The method comprises the steps of: suspending the compound represented by formula A or a pharmaceutically acceptable salt thereof, slowly cooling, rapidly cooling, slowly volatilizing, rapidly volatilizing, adding an antisolvent dropwise, adding an antisolvent reversely, vapor diffusion or heating-cooling DSC crystallization method, or spray drying, hot melt extrusion or solvent evaporation, thereby obtaining the form described in any one of claims 1 to 15.

17. A pharmaceutical composition, characterized in that Include: (a) the form of any one of claims 1 to 15; and (b) a pharmaceutically acceptable carrier or excipient.

18. A pharmaceutical preparation comprising the pharmaceutical composition according to claim 17; wherein The pharmaceutical preparation can be a solid preparation, and the dosage form of the solid preparation is selected from the following group: powder, granules, tablets, capsules, pills or films.

19. A use of a form according to any one of claims 1 to 15, or a pharmaceutical composition according to claim 17, or a pharmaceutical formulation according to claim 18, in the preparation of a medicament for treating a proliferative disease, preferably selected from the group consisting of breast cancer, colon cancer, brain cancer, prostate cancer, kidney cancer, pancreatic cancer, 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, cancers of lymphoid organs, and hematological malignancies including leukemias (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (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 lymphomas (nodular sclerosis, mixed cellularity, lymphocyte-rich, lymphocyte-depleted or non-depleted, and nodular lymphocyte-predominant Hodgkin lymphoma), non-Hodgkin lymphomas (all subtypes), chronic lymphocytic leukemia / small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphomas (such as macroglobulinemia), splenic marginal zone lymphoma, plasma cell neoplasms (plasma cell myeloma, plasmacytoma, monoclonal immunoglobulin deposition disease, 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 lymphoma / leukemia, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, aggressive N K-cell leukemia, adult T-cell leukemia / lymphoma, extranodal NK / T-cell lymphoma (nasal type), enteropathy T-cell lymphoma, hepatosplenic T-cell lymphoma, blastic NK-cell lymphoma, mycosis fungoides / Sézary syndrome, primary cutaneous CD30-positive T-cell lymphoma, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma (unspecified), anaplastic large cell lymphoma, multiple myeloma (plasma cell myeloma or Kahler disease).

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