Crystal forms of compound having fused five- and six-membered rings, preparation method therefor, and use thereof

Abstract

Provided are crystal forms of a compound having fused five- and six-membered rings, a preparation method therefor, and the use thereof. Particularly provided are a crystal form A, a crystal form B, a crystal form C, a crystal form D, a crystal form F, a crystal form G, a crystal form H, a crystal form I or a crystal form J of said compound represented by formula X. The X-ray powder diffraction pattern of the crystal form A using Cu-Kα radiation and represented by 2θ has diffraction peaks at 6.9±0.2°, 11.2±0.2°, 12.2±0.2°, 13.7±0.2°, 17.3±0.2°, 18.2±0.2° and 24.3±0.2°. The crystal forms of said compound have IRAK4 inhibition or / and degradation effects, have potential value in clinical application, and are expected to be capable of improving the prognosis of patients and reducing the possibility of drug resistance; in addition, said crystal forms have good solubility, physical and chemical stability and mechanical stability.

Description

A crystal form of a penta-hexa-membered compound, its preparation method and application

[0001] This application claims priority to Chinese Patent Application No. 2023117127653 filed on December 13, 2023, and Chinese Patent Application No. 202411656766.5 filed on November 18, 2024. This application incorporates the entire contents of the aforementioned Chinese patent applications. Technical Field

[0002] The present invention relates to a crystal form of a penta- and hexa-membered compound, a preparation method and application thereof. Background Art

[0003] Kinases have long been an important therapeutic target for the development of anti-inflammatory drugs (Current Opinion in Cell Biology 2009, 21, 1-8). Interleukin-1 receptor-associated kinases (IRAKs) are serine / threonine protein kinases that belong to the tyrosine-like kinase (TLK) family. IRAKs are located downstream of the toll-like receptor and IL-1R pathways, with IRAK1 and IRAK4 exhibiting kinase activity. IRAK4 acts upstream of the IRAKs family kinase activation pathway and plays a crucial role in innate immune signaling (Science 1996, 271(5252):1128-31). TLR stimulation recruits myeloid differentiation primary response 88 (MYD88) and activates the receptor to form the Myddosome complex, which then forms a complex with IRAK4 to activate IRAK1. Subsequently, TRAF6 is activated by IRAK1, leading to the activation of NF-κB and AMPK signaling pathways, and ultimately leading to the expression of inflammatory cytokines (Molecules 2016, 21, 1529, J Biol Chem. 2018 Sep 28; 293(39): 15195-15207, Eur J. Immunol. 2008. 38: 614-618).

[0004] A very important feature of IRAK4 is that it has two functions: scaffolding and kinase phosphorylation in the TLR and IL-1R signaling pathways. The kinase domain (KD) provides kinase function, and the death domain (DD) provides scaffolding function for the Myddosome (Molecules 2016, 21 (11), 1529). Myddosome is associated with a variety of diseases, not only autoimmune diseases and inflammatory diseases, but also cancer. For example, MYD88 mutations account for 39% of patients with active B-cell-like diffuse large B-cell lymphoma (ABC DLBCL) and 86%-100% in several other types of B-cell malignancies and primary central nervous system lymphomas (Cell Chemical Biology 27, 1-10, December 17, 2020).

[0005] Studies in IRAK4 knockout mice and clinical pathology have shown that IRAK4 deficiency itself is not lethal, and individuals with IRAK4 mutations have protective effects against chronic lung disease and inflammatory bowel disease (Eur. J. Immunol. 2008. 38: 614–618). IRAK4 inhibitors have long been considered targets for treating immune diseases such as autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis (Expert Opinion on Therapeutic Patents Volume 29, 2019-Issue 4). IRAK4 is also a popular target for treating tumors, and a few IRAK4 kinase inhibitors have entered the clinical stage. However, these clinical-stage investigational drugs are inhibitors of IRAK4 kinase function (KD) and do not directly inhibit the scaffold function of IRAK4. Protein degraders (PROTACs) targeting IRAK4 are expected to simultaneously eliminate its kinase activity and scaffold function, resulting in better and broader efficacy (Nature Biotechnology 2020, volume 38, pages 1221-1223, ACS Med Chem Lett. 2019 Jul 11; 10(7): 1081-1085). Summary of the Invention

[0006] The present invention discloses a crystalline form of a penta- and hexa-membered compound, its preparation method, and application. The crystalline form of the penta- and hexa-membered compound has an inhibitory and / or degradation effect on IRAK4, has potential clinical application value, is expected to improve patient prognosis, and reduce the likelihood of drug resistance. It also exhibits good solubility, physicochemical stability, and mechanical stability.

[0007] The present invention solves the above technical problems through the following technical methods.

[0008] The present invention provides a crystalline form A of a penta- and hexa-membered compound as shown in formula X, which has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles at 6.9±0.2°, 11.2±0.2°, 12.2±0.2°, 13.7±0.2°, 17.3±0.2°, 18.2±0.2° and 24.3±0.2°;

[0009] In a certain embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form A using Cu-Kα radiation and expressed in 2θ angles further has diffraction peaks at one or more of 9.7±0.2°, 10.2±0.2°, 15.1±0.2° and 20.6±0.2°.

[0010] In one embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form A using Cu-Kα radiation and expressed in 2θ angles has diffraction peak positions as shown in the following table:

[0011] In one embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form A using Cu-Kα radiation and expressed in 2θ angles has diffraction peak positions and relative intensities as shown in the following table:

[0012] In one embodiment, the crystalline form A has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles as shown in FIG2 .

[0013] In one embodiment, the differential scanning calorimetry (DSC) diagram of the crystalline form A has an endothermic peak at 262.80±5°C.

[0014] In one embodiment, the differential scanning calorimetry (DSC) diagram of Form A is substantially as shown in FIG3 .

[0015] In one embodiment, the thermogravimetric analysis (TGA) graph of Form A shows a weight loss of 0.548% before 200±5°C.

[0016] In one embodiment, the thermogravimetric analysis (TGA) diagram of Form A is substantially as shown in FIG4 .

[0017] The present invention also provides a crystalline form C of a penta- and hexa-membered compound as shown in Formula X, which has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles at 9.7±0.2°, 10.8±0.2°, 13.1±0.2°, 14.1±0.2°, 18.7±0.2°, and 21.7±0.2°;

[0018] In a certain embodiment, the crystalline form C has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles, and further has diffraction peaks at one or more of 12.5±0.2°, 15.5±0.2°, and 24.3±0.2°.

[0019] In one embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form C using Cu-Kα radiation and expressed in 2θ angles has diffraction peak positions as shown in the following table:

[0020] In one embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form C using Cu-Kα radiation and expressed in 2θ angles has diffraction peak positions and relative intensities as shown in the following table:

[0021] In one embodiment, the Form C has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles as shown in FIG6 .

[0022] In one embodiment, the differential scanning calorimetry (DSC) diagram of the crystalline form C has an endothermic peak at 261.8±5°C and an exothermic peak at 266.8±5°C.

[0023] In one embodiment, the differential scanning calorimetry (DSC) diagram of Form C is substantially as shown in FIG7 .

[0024] In one embodiment, the thermogravimetric analysis (TGA) graph of the crystalline form C shows substantially no weight loss before 300±5°C.

[0025] In one embodiment, the thermogravimetric analysis (TGA) diagram of Form C is substantially as shown in FIG8 .

[0026] The present invention also provides a crystalline form F of a penta- and hexa-membered compound as shown in formula X, which has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles at 5.8±0.2°, 6.6±0.2°, 7.2±0.2°, 12.2±0.2°, 14.5±0.2°, 15.7±0.2°, 18.9±0.2°, and 24.6±0.2°;

[0027] In a certain embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form F using Cu-Kα radiation and expressed in 2θ angles further has diffraction peaks at one or more of 9.8±0.2°, 13.3±0.2°, 17.5±0.2° and 20.8±0.2°.

[0028] In one embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form F using Cu-Kα radiation and expressed in 2θ angles has diffraction peak positions as shown in the following table:

[0029] In one embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form F using Cu-Kα radiation and expressed in 2θ angles has diffraction peak positions and relative intensities as shown in the following table:

[0030] In one embodiment, the crystalline form F has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles as shown in FIG. 10 .

[0031] In one embodiment, the differential scanning calorimetry (DSC) diagram of the crystalline form F has endothermic peaks at 249.1±5°C and 262.9±5°C, and an exothermic peak at 258.6±5°C.

[0032] In one embodiment, the differential scanning calorimetry (DSC) diagram of Form F is substantially as shown in FIG11 .

[0033] In one embodiment, the thermogravimetric analysis (TGA) graph of the Form F shows substantially no weight loss before 300±5°C.

[0034] In one embodiment, the thermogravimetric analysis (TGA) diagram of Form F is substantially as shown in FIG12 .

[0035] The present invention also provides a crystalline form H of a penta- and hexa-membered compound as shown in formula X, which has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles at 5.8±0.2°, 8.5±0.2°, 9.5±0.2°, 11.7±0.2°, 14.1±0.2°, 16.9±0.2°, and 20.8±0.2°;

[0036] In a certain embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form H using Cu-Kα radiation and expressed in 2θ angles further has diffraction peaks at one or more of 10.9±0.2°, 19.1±0.2°, 26.5±0.2° and 33.0±0.2°.

[0037] In one embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form H using Cu-Kα radiation and expressed in 2θ angles has diffraction peak positions as shown in the following table:

[0038] In one embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form H using Cu-Kα radiation and expressed in 2θ angles has diffraction peak positions and relative intensities as shown in the following table:

[0039] In one embodiment, the Form H has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles as shown in FIG. 14 .

[0040] In one embodiment, the differential scanning calorimetry (DSC) diagram of the crystalline form H has an endothermic peak at 288.5±5°C.

[0041] In one embodiment, the differential scanning calorimetry (DSC) diagram of Form H is substantially as shown in FIG15 .

[0042] In one embodiment, the thermogravimetric analysis (TGA) graph of the crystalline form H shows substantially no weight loss before 300±5°C.

[0043] In one embodiment, the thermogravimetric analysis (TGA) diagram of Form H is substantially as shown in FIG16 .

[0044] The present invention also provides a crystalline form I of a penta- and hexa-membered compound as shown in Formula X, which has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles at 8.0±0.2°, 11.3±0.2°, 15.5±0.2°, 17.6±0.2°, 20.2±0.2°, and 25.6±0.2°;

[0045] In a certain embodiment, the crystalline form I uses Cu-Kα radiation and the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles also has diffraction peaks at one or more of 7.6±0.2°, 18.6±0.2°, 22.0±0.2° and 31.7±0.2°.

[0046] In one embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form I using Cu-Kα radiation and expressed in 2θ angles has diffraction peak positions as shown in the following table:

[0047] In one embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form I using Cu-Kα radiation and expressed in 2θ angles has diffraction peak positions and relative intensities as shown in the following table:

[0048] In one embodiment, the Form I has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles as shown in FIG. 17 .

[0049] In one embodiment, the differential scanning calorimetry (DSC) diagram of the crystalline form I has an endothermic peak at 279.6±5°C.

[0050] In one embodiment, the differential scanning calorimetry (DSC) diagram of Form I is substantially as shown in FIG18 .

[0051] In one embodiment, the thermogravimetric analysis (TGA) graph of the Form I shows a weight loss of 0.865% before 150±5°C.

[0052] In one embodiment, the thermogravimetric analysis (TGA) diagram of Form I is substantially as shown in FIG19 .

[0053] The present invention also provides a crystalline form B of a penta-hexa-membered compound as shown in formula X, which has diffraction peaks at 8.6±0.2°, 11.8±0.2°, 15.8±0.2° and 18.9±0.2° in an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles using Cu-Kα radiation;

[0054] In a certain embodiment, the crystalline form B further has diffraction peaks at 17.3±0.2° and / or 25.9±0.2° in an X-ray powder diffraction (XRPD) pattern expressed in 2θ angles using Cu-Kα radiation.

[0055] In one embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form B using Cu-Kα radiation and expressed in 2θ angles has diffraction peak positions and relative intensities as shown in the following table:

[0056] In one embodiment, the Form B has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles as shown in FIG5 .

[0057] The present invention also provides a crystalline form D of a penta- and hexa-membered compound as shown in Formula X, which has diffraction peaks at 6.5±0.2°, 7.0±0.2°, 11.4±0.2°, 13.0±0.2°, 17.9±0.2°, and 22.0±0.2° in an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles;

[0058] In a certain embodiment, the crystalline form D has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles, and further has diffraction peaks at one or more of 10.4±0.2°, 16.8±0.2°, and 26.4±0.2°.

[0059] In one embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form D using Cu-Kα radiation and expressed in 2θ angles has diffraction peak positions and relative intensities as shown in the following table:

[0060] In one embodiment, the crystalline form D has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles as shown in FIG. 9 .

[0061] The present invention also provides a crystalline form G of a penta- and hexa-membered compound as shown in Formula X, which has diffraction peaks at 9.0±0.2°, 13.4±0.2°, 14.5±0.2°, 19.3±0.2°, and 24.8±0.2° in an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles;

[0062] In a certain embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form G using Cu-Kα radiation and expressed in 2θ angles further has diffraction peaks at one or more of 16.9±0.2°, 20.6±0.2° and 27.3±0.2°.

[0063] In one embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form G using Cu-Kα radiation and expressed in 2θ angles has diffraction peak positions and relative intensities as shown in the following table:

[0064] In one embodiment, the Form G has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles as shown in FIG. 13 .

[0065] The present invention also provides a crystalline form J of a penta- and hexa-membered compound as shown in formula X, which has diffraction peaks at 6.4±0.2°, 9.6±0.2°, 12.9±0.2°, 16.5±0.2°, 17.7±0.2°, and 22.8±0.2° in an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles;

[0066] In a certain embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form J using Cu-Kα radiation and expressed in 2θ angles further has diffraction peaks at one or more of 16.9±0.2°, 20.9±0.2°, 25.9±0.2° and 28.8±0.2°.

[0067] In one embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form J using Cu-Kα radiation and expressed in 2θ angles has diffraction peak positions and relative intensities as shown in the following table:

[0068] In one embodiment, the Form J has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles as shown in FIG. 20 .

[0069] The present invention also provides a hydrochloride or sulfate of a five-membered and six-membered compound as shown in Formula X,

[0070] The hydrochloride of the five-membered and six-membered compound as shown in Formula X can be as shown in Formula X-1,

[0071] The sulfate of the penta- and hexa-membered compound as shown in Formula X can be as shown in Formula X-2,

[0072] The present invention also provides a method for preparing the crystalline Form A of the penta- and hexa-membered compound represented by Formula X, comprising the steps of slurrying the penta- and hexa-membered compound represented by Formula X in a ketone solvent to obtain the crystalline Form A. The ketone solvent is, for example, acetone. The penta- and hexa-membered compound represented by Formula X may be amorphous.

[0073] The present invention also provides a method for preparing the crystalline form C of the penta- and hexa-membered compound represented by Formula X, comprising the steps of slurrying the penta- and hexa-membered compound represented by Formula X in a nitrile solvent to obtain the crystalline form C. The nitrile solvent is, for example, acetonitrile. The penta- and hexa-membered compound represented by Formula X may be amorphous.

[0074] The present invention also provides a method for preparing the crystalline Form F of the penta- and hexa-membered compound represented by Formula X, comprising the steps of: subjecting the penta- and hexa-membered compound represented by Formula X to gas-solid diffusion with a chloroalkane to obtain the crystalline Form F. The chloroalkane is, for example, dichloromethane. The penta- and hexa-membered compound represented by Formula X may be amorphous.

[0075] The present invention also provides a method for preparing the crystalline form H of the penta- and hexa-membered compound represented by Formula X, comprising the steps of adding a benzene hydrocarbon solvent to a solution of the penta- and hexa-membered compound represented by Formula X in an amide solvent, and crystallizing to obtain the crystalline form H. The amide solvent is, for example, DMF. The benzene hydrocarbon solvent is, for example, toluene.

[0076] The mass volume ratio of the five-membered and six-membered compound represented by Formula X to the amide solvent may be 80-150 mg / mL, preferably 100-125 mg / mL, for example 100 mg / mL or 125 mg / mL.

[0077] The volume ratio of the benzene hydrocarbon solvent to the amide solution can be (5-15):1, preferably (8-12):1, for example 10:1.

[0078] The crystallization temperature may be room temperature.

[0079] The present invention also provides a method for preparing the crystalline Form I of the penta- and hexa-membered compound represented by Formula X, comprising the steps of adding an ether solvent to a solution of the penta- and hexa-membered compound represented by Formula X in a sulfoxide solvent, and crystallizing to obtain the crystalline Form I. The sulfoxide solvent may be, for example, DMSO. The ether solvent may be, for example, MTBE.

[0080] The mass volume ratio of the penta- and hexa-membered compound represented by Formula X to the sulfoxide solvent may be 80-150 mg / mL, preferably 100-125 mg / mL, for example 100 mg / mL or 125 mg / mL.

[0081] The volume ratio of the ether solvent to the sulfoxide solvent may be (5-15):1, preferably (8-12):1, for example 10:1.

[0082] The crystallization temperature may be room temperature.

[0083] The present invention also provides a pharmaceutical composition comprising: (1) the crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form F, crystalline form G, crystalline form H, crystalline form I or crystalline form J of the pentad and hexaad compound as represented by formula X, or the hydrochloride or sulfate salt of the pentad and hexaad compound as represented by formula X; and

[0084] (2) Pharmaceutically acceptable carrier.

[0085] The present invention also provides a use of a substance Z in the preparation of an IRAK4 degrader, wherein the substance Z is the crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form F, crystalline form G, crystalline form H, crystalline form I or crystalline form J of the penta- and hexa-membered compound represented by formula X, or the hydrochloride or sulfate of the penta- and hexa-membered compound represented by formula X, or the pharmaceutical composition described above.

[0086] The present invention also provides a use of a substance Z in the preparation of a drug, wherein the drug is used to treat and / or prevent Myd88 and / or IRAK4-related diseases; the substance Z is the crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form F, crystalline form G, crystalline form H, crystalline form I or crystalline form J of the penta- and hexa-membered compound as shown in Formula X, or the hydrochloride or sulfate of the above-mentioned penta- and hexa-membered compound as shown in Formula X, or the above-mentioned pharmaceutical composition.

[0087] In one embodiment, the IRAK4-related diseases include one or more of chronic lung diseases, autoimmune diseases, inflammatory diseases, tumors, cardiovascular and cerebrovascular diseases, and central nervous system diseases.

[0088] In one embodiment, the autoimmune disease includes psoriasis and rheumatoid arthritis.

[0089] In one embodiment, the autoimmune disease includes psoriasis, systemic lupus erythematosus, and rheumatoid arthritis.

[0090] In one embodiment, the inflammatory disease comprises ulcerative colitis.

[0091] In one embodiment, the inflammatory disease comprises inflammatory bowel disease, such as ulcerative colitis.

[0092] In one embodiment, the tumor can be a hematological tumor or a solid tumor.

[0093] In one embodiment, the hematological malignancy includes large B-cell lymphoma, acute or chronic lymphocytic leukemia.

[0094] In one embodiment, the solid tumor includes colorectal cancer and skin cancer caused by MYD88 mutation.

[0095] In one embodiment, the cardiovascular and cerebrovascular diseases include stroke and atherosclerosis.

[0096] In one embodiment, the central nervous system disease comprises primary central nervous system lymphoma.

[0097] The present invention also provides a use of a substance Z in preparing a drug, wherein the drug is used to treat one or more of chronic lung disease, autoimmune disease, inflammatory disease, tumor, cardiovascular and cerebrovascular disease, and central nervous system disease; the substance Z is the crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form F, crystalline form G, crystalline form H, crystalline form I, or crystalline form J of the penta- and hexa-membered compound represented by formula X, or the hydrochloride or sulfate of the penta- and hexa-membered compound represented by formula X, or the above-mentioned pharmaceutical composition.

[0098] The present invention also provides a method for treating and / or preventing Myd88 and / or IRAK4-related diseases, comprising administering to a patient an effective amount of substance Z, wherein substance Z is crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form F, crystalline form G, crystalline form H, crystalline form I or crystalline form J of the penta- and hexa-membered compound as shown in formula X, or the hydrochloride or sulfate of the penta- and hexa-membered compound as shown in formula X, or the above-mentioned pharmaceutical composition.

[0099] The present invention also provides a substance Z for treating and / or preventing Myd88 and / or IRAK4-related diseases, wherein the substance Z is the crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form F, crystalline form G, crystalline form H, crystalline form I or crystalline form J of the penta- and hexa-membered compound as shown in Formula X, or the hydrochloride or sulfate of the above-mentioned penta- and hexa-membered compound as shown in Formula X, or the above-mentioned pharmaceutical composition.

[0100] The crystal forms of the present invention can be identified and characterized using one or more solid-state analytical methods, such as X-ray powder diffraction, single crystal X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. Those skilled in the art will appreciate that the peak intensities and / or peak configurations of X-ray powder diffraction may vary depending on experimental conditions. Furthermore, due to varying instrumental precision, the measured 2θ values ​​may have an error of approximately ±0.20°. The relative peak intensity depends more on certain properties of the sample being measured, such as crystal size and purity, than the peak position. Therefore, the measured peak intensity may vary by approximately ±0.2°. Despite experimental error, instrumental error, and orientation bias, those skilled in the art can still obtain sufficient information to identify individual crystal forms from the X-ray powder diffraction data provided in this patent. In DSC measurements, the measured initial temperature, maximum temperature, and heat of fusion of the endothermic peak all exhibit a certain degree of variability, depending on the heating rate, crystal shape, purity, and other measurement parameters.

[0101] In the present invention, "room temperature" refers to 15 to 35°C.

[0102] In the present invention, "gas-solid diffusion" means placing the compound solid in one container and the solvent in another container, and then placing the former open in the latter, sealing and allowing to stand.

[0103] Explanation of terms:

[0104] The term “substantially” means that the positions of the peaks in the graph may vary slightly with slight variations in the measuring equipment, measuring conditions, and batches of the product to be measured, and are not to be regarded as absolute values.

[0105] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0106] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0107] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0108] The reagents and raw materials used in the present invention are commercially available.

[0109] The positive advances of the present invention include: Disclosed are a crystalline form of a penta- and hexa-membered compound, its preparation method, and its application. The crystalline form of the penta- and hexa-membered compound has an inhibitory and / or degradative effect on IRAK4, possessing potential clinical applications, and is expected to improve patient prognosis and reduce the likelihood of drug resistance. Furthermore, the compound exhibits excellent solubility, physicochemical stability, and mechanical stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0110] FIG1 is an XRPD pattern of the amorphous form of compound X.

[0111] Figure 2 is the XRPD pattern of Form A.

[0112] FIG3 is a DSC diagram of Form A.

[0113] FIG4 is a TGA diagram of Form A.

[0114] FIG5 is an XRPD pattern of Form B.

[0115] FIG6 is an XRPD pattern of Form C.

[0116] FIG7 is a DSC diagram of Form C.

[0117] FIG8 is a TGA diagram of Form C.

[0118] FIG9 is an XRPD pattern of Form D.

[0119] FIG10 is an XRPD pattern of Form F.

[0120] FIG11 is a DSC graph of Form F.

[0121] FIG12 is a TGA diagram of Form F.

[0122] FIG13 is an XRPD pattern of Form G.

[0123] FIG14 is an XRPD pattern of Form H.

[0124] FIG15 is a DSC graph of Form H.

[0125] FIG16 is a TGA chart of Form H.

[0126] FIG17 is an XRPD pattern of Form I.

[0127] FIG18 is a DSC graph of Form I.

[0128] FIG19 is a TGA chart of Form I.

[0129] FIG20 is an XRPD pattern of Form J.

[0130] FIG21 is a DVS adsorption isotherm diagram of Form I.

[0131] FIG22 is a DVS dynamic adsorption curve diagram of Form I.

[0132] FIG23 is a DVS adsorption isotherm diagram of Form A.

[0133] FIG24 is a DVS dynamic adsorption curve diagram of Form A. DETAILED DESCRIPTION

[0134] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0135] abbreviation:

[0136] Instruments and methods:

[0137] 1. X-ray powder diffraction (XRPD)

[0138] The diffraction data of the solid samples were collected using a Bruker D8 ADVANCE (Bruker, Germany) X-ray powder diffractometer at room temperature, with the X-ray source being Cu Kα ( Light tube voltage and current: 40 kV, 40 mA. For sample preparation, place an appropriate amount of sample on a zero-background sample pan and gently press the surface flat. Scan the sample from 3° to 42° (2θ) with a step size of 0.02° (2θ) and a scan time of 0.05 s per step.

[0139] 2. Differential Scanning Calorimetry (DSC)

[0140] DSC analysis of the samples was performed using a Discovery DSC25 (TA Instruments, USA) equipped with an RCS90 refrigerator. Samples (0.5-5 mg) were placed in a perforated aluminum pan and heated at a rate of 10°C / min from 25°C to the endpoint temperature under a nitrogen atmosphere at 50 mL / min. Measurements were performed under a constant nitrogen flow rate of 50 mL / min.

[0141] 3. Thermogravimetric analysis (TGA)

[0142] Thermogravimetric analysis of the samples was performed using a Discovery TGA550 (TA Instruments, USA). 1–5 mg of the sample was placed in a tared alumina pan and heated from room temperature to the endpoint temperature at a rate of 10°C / min under a 60 mL / min nitrogen atmosphere.

[0143] 4. H NMR spectroscopy ( 1 H-NMR)

[0144] Crystalline characterization The samples were analyzed by nuclear magnetic resonance (NMR) using a Varian Mercury plus 400 MHz NMR spectrometer (Varian, USA) in deuterated dimethyl sulfoxide (DMSO).

[0145] 5. Dynamic moisture sorption (DVS)

[0146] Hygroscopicity analysis of the samples was performed using an Intrinsic DVS (System Measurement System, UK). The sample size was approximately 10-30 mg. The test chamber temperature was controlled at 25 ± 1°C. The specific test parameters are as follows:

[0147] 6. Ion Chromatography (IC)

[0148] The samples were analyzed using a Dionex ICS-1500 ion chromatograph with the following parameters:

[0149] Example 1: Synthesis of Compound X

[0150] Step 1: Synthesis of Int-A1

[0151] 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (5.0 g, 18.0 mmol) was dissolved in anhydrous dimethyl sulfoxide (20.0 mL). DIPEA (N,N-diisopropylethylamine, 4.7 g, 36.2 mmol) and tert-butyl piperidine-4-carboxylate (4.0 g, 21.6 mmol) were then added. The reaction mixture was stirred in an oil bath at 90°C for 2 hours until the reaction was complete. After cooling to room temperature, the reaction system was diluted with water and extracted with ethyl acetate (50 mL). The aqueous phase was further extracted with EA (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to yield the crude product. The crude product was purified by column chromatography (PE / EA=5 / 1) to give a yellow solid product Int-A1 (7.5 g, yield 94.2%), MS (ESI) m / z: 442.2 [M+H] + .

[0152] Step 2: Synthesis of Int-A

[0153] TFA (trifluoroacetic acid, 20 mL) was added dropwise to a solution of Int-A1 (5 g, 11.3 mmol) and DCM (dichloromethane, 50 mL) at 0°C. The reaction mixture was stirred at 25°C for 16 hours until the reaction was complete. The reaction mixture was washed three times with ether to remove residual TFA, yielding the yellow solid product Int-A (3.7 g, 84.9% yield). MS (ESI) m / z: 386.1 [M+H] + .

[0154] Step 3: Synthesis of I-1-A

[0155] A mixture of 7-tert-butoxycarbonyl-7-azaspiro[3.5]-2-nonanol (600 mg, 2.49 mmol), 4-dimethylaminopyridine (60.75 mg, 497.25 μmol, 83.68 μL), triethylamine (503.17 mg, 4.97 mmol, 693.07 μL), and dichloromethane (1.35 mL) was stirred to dissolve. p-Toluenesulfonyl chloride (521.40 mg, 2.73 mmol) was added and the mixture was heated to 40°C and stirred for 18 hours until the reaction was complete. The reaction system was diluted with water (30 mL) and extracted with dichloromethane (20 mL x 3) with stirring. The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford I-1-A (1 g, crude product). MS (ESI) m / z: 396.2 [M+H] + .

[0156] Step 4: Synthesis of I-1-1

[0157] A mixture of 6-methoxy-5-nitro-2H-indazole (2 g, 10.35 mmol), Pd / C (0.3 g, 10% purity), and methanol (30 mL) was stirred and replaced with hydrogen three times. The mixture was stirred and reacted under a hydrogen atmosphere at 25°C for 18 hours until the reaction was complete. The mixture was filtered through celite to remove the catalyst, and the filter cake was washed with methanol (10 mL x 2). The filtrate was concentrated under reduced pressure to obtain the brown solid product I-1-1 (1.59 g, crude product). MS (ESI) m / z: 164.1 [M+H] + , used directly in the next step.

[0158] Step 5: Synthesis of I-1-2

[0159] To a mixed solution of I-1-1 (1.59 g, 9.74 mmol), 6-(trifluoromethyl)pyridine-2-carboxylic acid (2.05 g, 10.72 mmol), diisopropylethylamine (3.78 g, 29.23 mmol, 5.09 mL) and tetrahydrofuran (25 mL) was added dropwise with stirring at 0°C. After the addition, the reaction system was stirred at 15°C under nitrogen for 2 hours until the reaction was complete. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL x 5). The combined organic phases were washed with water (30 mL) and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the brown solid product I-1-2 (3.08 g, crude product). MS (ESI) m / z: 337.1 [M+H] + , used directly in the next step.

[0160] Step 6: Synthesis of I-1-3

[0161] A mixed solution of I-1-A (500 mg, 1.49 mmol), I-1-2 (705.71 mg, 1.78 mmol), cesium carbonate (968.93 mg, 2.97 mmol), and N,N-dimethylformamide (4 mL) was stirred at 90°C for 5 hours until the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (eluent PE / EA: 1 / 1) to afford I-1-3 (250 mg, 446.76 μmol, yield 30.05%). MS (ESI) m / z: 560.2 [M+H] + .

[0162] Step 7: Synthesis of I-1-4

[0163] A mixture of I-1-3 (250 mg, 446.76 μmol), dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was stirred at room temperature for 2 hours until the reaction was complete. The reaction solution was dried and the crude product was purified by C18 column chromatography to give a yellow solid I-1-4 (200 mg, 435.29 μmol, yield 97.43%). MS (ESI) m / z: 460.2 [M+H] + .

[0164] Step 8: Synthesize X

[0165] To a solution of Int-A (709 mg, 1.84 mmol), HATU (840 mg, 2.21 mmol) and DMF (10 mL) was added DIPEA (475 mg, 3.68 mmol) and I-1-4 (850 mg, 1.84 mmol) at 0°C. The resulting reaction mixture was then stirred at 25°C for 1 hour until the reaction was complete. Water (10 mL) and ethyl acetate (30 mL x 3) were added to the reaction mixture for extraction. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a crude product. The crude product was purified by preparative HPLC to give a white solid product X (904 mg, 59.4% yield). MS (ESI) m / z: 827.3 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ11.08(s,1H),10.51(s,1H),8.69(s,1H),8.46(d,J=8.0Hz,1H),8.41(t,J=8.0Hz,1H),8.37(s,1H) ,8.22(d,J=8.0Hz,1H),7.67(d,J=8.5Hz,1H),7.33(s,1H),7.25(d,J=8.5Hz,1H),7.21(s,1H),5.24–5.12(m,1H),5.07(dd, The XRPD of compound X was shown in Figure 1.

[0166] Example 2: Application of Compound X

[0167] 2.1 Evaluation of the inhibition of compound X on kinase activity

[0168] A fluorescent microfluidics mobility shift assay-based assay to determine the IC of compounds against the competitive binding of ATP to the kinase IRAK4. 50 The initial concentration of the compound tested was 10 μM, and the assay was performed in duplicate using a 4-fold gradient dilution down to 0.38 nM. Commercially available staurosporine was used as the standard control in this experiment.

[0169] 2.1.1 Reagent and consumables information is as follows:

[0170] 2.1.2 Experimental operation method

[0171] 1) IRAK4 kinase was dissolved in kinase buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01% Brij-35) to a final concentration of 6 nM.

[0172] 2) Dissolve the substrate peptide FAM-P8 and ATP in the above kinase buffer. The final concentrations of the IRAK4 substrate peptide FAM-P8 and ATP are 3 μM and 10 μM, respectively.

[0173] 3) Compound Dilution: Initially dilute the compound to 50 μM, then serially dilute with DMSO in a 4-fold gradient. A solution without compound and kinase serves as the blank control, corresponding to the "Minimum Value" shown below. A solution without compound but containing kinase, adenosine 5'-triphosphate disodium salt hydrate, DMSO, and buffer serves as the positive control, corresponding to the "Maximum Value" shown below.

[0174] 4) Kinase Reaction and Termination: 10 μL of kinase buffer was added to a 384-well plate containing 5 μL of the test compound and incubated at room temperature for 10 minutes. Separately, 10 μL of a buffer containing the substrate peptide and adenosine 5'-triphosphate disodium salt hydrate was added to the 384-well plate. After incubation at 28°C for one hour, 25 μL of stop solution (100 mM HEPES pH 7.5, 50 mM EDTA, 0.2% Coating Reagent #3, and 0.015% Brij-35) was added to each well to terminate the reaction.

[0175] 5) Data reading: The conversion rate data was read using a Caliper EZ Reader II instrument. The setting conditions were: downstream voltage -500 V, upstream voltage -2250 V, base pressure -0.5 PSI, and screening pressure -1.2 PSI.

[0176] 6) Data calculation: Copy the conversion rate data from CaliperEZ ReaderⅡ and convert the conversion rate into inhibition rate data. The calculation formula is as follows:

[0177] Inhibition percentage (%) = (maximum value - conversion rate) / (maximum value - minimum value) * 100%

[0178] IC fitting using XLFit Excel add-in version 5.4.0.8 50 value,

[0179] Fitting formula: Y=Bottom+(Top-Bottom) / (1+(IC 50 / X)^HillSlope)

[0180] 2.1.3 Experimental Results

[0181] The kinase activity data of compound X are shown in Table 1.

[0182] Table 1 Kinase activity data of compound X

[0183] 2.2 LPS stimulates THP-1 to release cytokines

[0184] 2.2.1 Experimental Materials

[0185] 2.2.2 PROTAC-induced IRAK4 protein degradation in THP-1

[0186] 2.2.2.1 Using a Western blot assay, THP-1 cell samples treated with gel electrophoresis were stained with specific antibodies. The degradation activity of the compounds against IRAK4 protein in THP-1 cells was determined by analyzing the location and depth of staining. Compounds were tested at concentrations of 0 μM, 0.3 μM, 1 μM, and 3 μM, and cells were treated for 8, 16, 24, and 48 hours. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an internal control protein in this experiment.

[0187] 2.2.2.2 Information on cells, reagents, and consumables is as follows:

[0188] 2.2.2.3 Equipment

[0189] 2.2.2.4 Reagent preparation method

[0190] Running buffer: Dilute 50 mL of MOPSSDS Running Buffer (20x) and 50 mL of 20× TBS Tween-20 buffer to 1 L with deionized water as running buffer;

[0191] 5% skim milk (w / v): Prepare 5% skim milk by diluting 2.5 g skim milk with 50 mL 1× TBS Tween-20 buffer.

[0192] 5% BSA (w / v): Dilute 2.5 g BSA with 50 mL 1× TBS Tween-20 buffer to prepare 5% BSA.

[0193] Dilute the Anti-IRAK4 antibody at 1:1000 with 5% BSA to prepare the primary antibody working solution;

[0194] Dilute Goat Anti-Rabbit IgG H&L (HRP) at 1:2000 with 5% BSA to prepare the secondary antibody working solution;

[0195] Dilute Goat Anti-Mouse IgG H&L (HRP) at 1:2000 with 5% BSA to prepare the secondary antibody working solution.

[0196] THP-1 cells were plated at a density of 1.5 x 106 cells / mL in a 6-well plate and incubated for 2 hours in a cell culture incubator set at 37°C and 5% CO2. Compounds were diluted in DMSO to 0.6 mM, 0.2 mM, and 0.06 mM, and 10 μL of compound solution was added to the corresponding wells. The cells were then incubated in the incubator for 16, 24, and 48 hours, respectively. The drug-treated THP-1 cells were harvested from the wells and lysed with 120 μL of RIPA lysis buffer containing protease inhibitors, phosphatase inhibitor solution II, and phosphatase inhibitor solution III. The cells were lysed on wet ice for 30 minutes. The cell lysate was centrifuged at high speed for 5 minutes, and the supernatant was collected. Protein concentration of the cell samples was determined according to the instructions in the Pierce™ BCA Protein Assay Kit.

[0197] Use lysis buffer and 1M DTT Adjust the sample concentration to a consistent level using LDS sample buffer. Heat the sample at 95°C for 5 minutes and centrifuge at low temperature at high speed. Add 20 μL of the prepared protein sample and 4 μL of PageRuler Prestained Protein Ladder to the gel wells. Run the gel at 80V for 0.5 hours, then adjust the voltage to 120V and continue running the gel for 1.5 hours. Remove the gel and transfer the proteins from the gel to the IBlotTM 2 transfer membrane set at 20V. After successful transfer, cut out the bands at 65kDa-40kDa and 40kDa-30kDa respectively. Block the membrane with 5% skim milk at room temperature for 1 hour. Wash the membrane three times with 1x TBST and incubate with IRAK4 antibody working solution overnight at 4°C. Discard the IRAK4 antibody working solution, wash the membrane three times with 1x TBST, and incubate the corresponding membranes with Goat Anti-Rabbit IgG H&L (HRP) working solution and Goat Anti-Mouse IgG H&L (HRP) working solution at room temperature for 1 hour. Discard the antibody working solution and wash the membrane three times with 1x TBST. According to the SuperSignal™ West Femto Maximum Sensitivity Substrate kit instructions, mix the reagents in the kit in equal volumes to prepare a luminescent solution mixture. Incubate the membranes for 1 minute, then remove the membranes and expose them to light.

[0198] 2.2.2.5 Experimental results

[0199] The drug concentration was 1 μM, and the results of protein immunoblotting 24 hours after administration are shown in Table 2:

[0200] Table 2 IRAK4 degradation rate of compound X 24 hours after administration

[0201] The concentration of IRAK4 that degraded 50% by Western blotting 24 hours after administration is shown in Table 3:

[0202] Table 3 IRAK4 DC of compound X 24 hours after administration 50 (nM)

[0203] Example 3: Preparation and characterization of Form A

[0204] 300 mg of Compound X obtained in Example 1 was weighed into a 30-mL glass vial, 5 mL of acetone was added, and the mixture was stirred at room temperature for 20 hours. The mixture was filtered to obtain a yellow solid, which was then dried under vacuum at 50°C for 4 hours. A total of 240 mg of Form A was obtained (yield: 80%). The obtained solid was characterized by XRPD, DSC, and TGA. The results showed that the obtained solid was Form A.

[0205] Table 4 XRPD peak list of Form A

[0206] The XRPD of Form A is shown in Table 4 and Figure 2. DSC results showed an endothermic peak at 262.80°C, which was determined to be the melting point of Form A, as shown in Figure 3. TGA results showed that Form A experienced a 0.548% weight loss before 200°C, as shown in Figure 4. NMR results showed no significant residual solvent.

[0207] Example 4: Preparation and Characterization of Form B

[0208] To a 4 mL vial, 30 mg of sample (Compound X obtained in Example 1) was added, along with 0.5 mL of DCM:MeOH (volume ratio = 3:1) and 1.1 N hydrochloric acid. The mixture was stirred at room temperature for 24 hours. 1 mL of MTBE was added to precipitate a yellow solid, which was filtered and dried under vacuum at 50°C for 24 hours. The resulting solid was characterized by XRPD, DSC, and TGA. The results showed that the solid was Form B.

[0209] Table 5 XRPD peak list of Form B

[0210] The XRPD pattern of Form B is shown in Table 5 and Figure 5. DSC results revealed endothermic peaks at 177.2°C and 243.4°C, and an exothermic peak at 214.0°C. TGA analysis revealed two weight loss periods for Form B, the first of which was 3.465% and the second of which was 3.021%. NMR analysis revealed the absence of residual solvent and acid.

[0211] Example 5: Preparation and characterization of Form C

[0212] Approximately 100 mg of sample (Compound X obtained in Example 1) was added to an 8 mL vial, followed by 2 mL of acetonitrile. The mixture was stirred continuously at 50°C for 3 days, and the solid was filtered. The resulting solid was characterized by XRPD, DSC, and TGA. The results showed that the resulting solid was Form C.

[0213] Table 6 XRPD peak list of Form C

[0214] The XRPD of Form C is shown in Table 6 and Figure 6. DSC results show that Form C has an endothermic peak at 261.8°C and an exothermic peak at 266.8°C, as shown in Figure 7. TGA results show that Form C has essentially no weight loss before 300°C, as shown in Figure 8.

[0215] Example 6: Preparation and characterization of Form D

[0216] Experimental Procedure: Approximately 100 mg of sample (Compound X obtained in Example 1) was added to an 8-mL vial, followed by 2 mL of 1,4-Dioxane. The mixture was stirred continuously at 50°C for 3 days, and the solid was filtered. The resulting solid was characterized by XRPD, DSC, and TGA. The results showed that the solid was Form D.

[0217] Table 7 XRPD peak list of Form D

[0218] The XRPD of Form D is shown in Table 7 and Figure 9. DSC results show that Form D has absorption peaks at 262.5°C and 284.2°C, and an exothermic peak at 262.7°C. TGA results show that Form D has essentially no weight loss before 300°C.

[0219] Example 7: Preparation and characterization of Form F

[0220] Approximately 100 mg of sample (Compound X obtained in Example 1) was weighed into a 4 mL vial. Approximately 5 mL of DCM was added to another 30 mL vial. The 4 mL vial containing the sample was placed open in the 30 mL vial. The 30 mL vial was then sealed and allowed to stand at room temperature for 3 days to precipitate a solid. The resulting solid was characterized by XRPD, DSC, and TGA. The results showed that the solid was Form F.

[0221] Table 8 XRPD peak list of Form F

[0222] The XRPD of Form F is shown in Table 8 and Figure 10. DSC results show that Form F has absorption peaks at 249.1°C and 262.9°C, and an exothermic peak at 258.6°C, as shown in Figure 11. TGA results show that Form F has essentially no weight loss before 300°C, as shown in Figure 12.

[0223] Example 8: Preparation and characterization of Form G

[0224] Approximately 100 mg of sample (Compound X obtained in Example 1) was dissolved in 0.8 mL of DMF to obtain a saturated solution. n-Heptane was then added dropwise to the saturated solution until solid precipitated. The resulting solid was characterized by XRPD, DSC, and TGA. The results showed that the resulting solid was Form G.

[0225] Table 9 XRPD peak list of Form G

[0226] The XRPD of Form G is shown in Table 9 and Figure 13. DSC results showed that Form G had endothermic peaks at 124.9°C, 259.5°C, and 289.3°C, and an exothermic peak at 264.4°C. TGA results showed that Form G had a weight loss of 7.95%.

[0227] Example 9: Preparation and Characterization of Form H

[0228] At room temperature, approximately 100 mg of sample (Compound X obtained in Example 1) was dissolved in 0.8 mL of DMF to obtain a saturated solution. Toluene was then added dropwise to the saturated solution until solid precipitated. The volume ratio of toluene to DMF was approximately 10:1. The resulting solid was characterized by XRPD, DSC, and TGA. The results showed that the solid was Form H.

[0229] Table 10 XRPD peak list of Form H

[0230] The XRPD of Form H is shown in Table 10 and Figure 14. DSC results show that Form H has an absorption peak at 288.5°C, as shown in Figure 15. TGA results show that Form H has almost no weight loss before 300°C, as shown in Figure 16.

[0231] Example 10: Preparation and Characterization of Form I

[0232] At room temperature, approximately 100 mg of sample (Compound X obtained in Example 1) was dissolved in 0.8 mL of DMSO to obtain a saturated solution. MTBE was then added dropwise to the saturated solution until solid precipitated. The resulting solid was characterized by XRPD, DSC, and TGA. The results showed that the resulting solid was Form I.

[0233] Table 11 XRPD peak list of Form I

[0234] The XRPD of Form I is shown in Table 11 and Figure 17. DSC results show that Form I has an endothermic peak at 279.6°C, which is the melting point peak, as shown in Figure 18. TGA results show that Form I has a weight loss of 0.865% before 150°C, as shown in Figure 19.

[0235] Example 11: Preparation and characterization of Form J

[0236] At 50°C, approximately 100 mg of sample (Compound X obtained in Example 1) was dissolved in 1 mL of DMSO. 0.3 mL of a 4:1 (volume ratio) EtOH-water mixture was added dropwise. The mixture was allowed to stabilize for 2 hours, and the precipitated solid was filtered. The resulting solid was characterized by XRPD, DSC, and TGA. The results showed that the solid was Form J.

[0237] Table 12 XRPD peak list of Form J

[0238] The XRPD of Form J is shown in Table 12 and Figure 20. DSC results showed that Form J had endothermic peaks at 181.1°C, 216.1°C, 264.5°C, and 290.4°C, and exothermic peaks at 223.8°C and 267.4°C. TGA results showed that Form J had a weight loss of 1.726% before 220°C.

[0239] Example 12: Effects of Form A and Form I

[0240] 12.1 Liquid Phase Method

[0241] The solubility tests of Form A and Form I, as well as the stability test of Form I, were performed on the samples using an Agilent 1200 HPLC (Agilent, USA) equipped with a DAD detector. The detailed chromatographic conditions are as follows:

[0242] 12.2 Solubility of Form A and Form I

[0243] The solubility of Form A and Form I was evaluated by preparing 5 mg / mL suspensions of the two forms in pH 1.2 buffer, pH 3.0 buffer, pH 4.5 buffer, pH 6.8 buffer, pH 7.4 buffer, simulated gastric fluid (SGF), fasted simulated intestinal fluid (FaSSIF), fed simulated intestinal fluid (FeSSIF), and water, respectively. The suspensions were stirred at 37° C. for 24 hours, and their solubility at 2 hours and 24 hours, as well as the solution pH at 24 hours, were tested. The solids were filtered, and the resulting solids were analyzed by XRPD. The results are shown in Table 13.

[0244] Table 13 Solubility evaluation of Form A and Form I Note: LOQ refers to limit of quantitation.

[0245] The results show that Form A can reach a concentration of approximately 0.004 mg / mL in FaSSIF and FeSSIF, while Form I can reach approximately 0.01 mg / mL in FeSSIF after stirring at 37°C for 24 hours. The crystalline forms of Form A and Form I remained unchanged in each medium.

[0246] 12.3 Physicochemical Stability Evaluation of Form A

[0247] 12.3.1 Liquid Phase Method

[0248] The solubility of the samples was determined using an Agilent 1200 HPLC (Agilent, USA) equipped with a DAD detector. The detailed chromatographic conditions are as follows:

[0249] 12.3.2 Stability Test

[0250] Form A (obtained in Example 3) was weighed into a liquid phase vial to prepare five portions. These portions were placed in a light stability chamber (closed), 25°C / 60% RH (open), 40°C / 75% RH (open), and a closed light stability chamber. The physical and chemical stability of the vials were measured after 10 days of light exposure and one week at 60°C, 25°C / 60% RH, and 40°C / 75% RH. The results are shown in Table 14.

[0251] Table 14 Stability evaluation of Form A Note: N / A means not applicable.

[0252] The results show that Form A has basically no degradation under all stability conditions, and the crystal form has not changed, and has good physical and chemical stability.

[0253] 12.4 Physicochemical Stability Evaluation of Form I

[0254] Approximately 10 mg of Form I (obtained in Example 10) was weighed into a liquid phase vial to prepare five portions. These portions were placed in a light stability chamber (closed) at 60°C (closed), 25°C / 60% RH (open), 40°C / 75% RH (open), and a closed light stability chamber. The physical and chemical stability of the vials were measured after 10 days of light exposure and one week at 60°C, 25°C / 60% RH, and 40°C / 75% RH. The results are shown in Table 15.

[0255] Table 15 Stability evaluation of Form I Note: N / A means not applicable.

[0256] The results show that Form I degrades by 0.17% after being placed in a closed stability box at 60°C for one week. Under other stability conditions, there is basically no degradation and the crystal form does not change, indicating that it has good physical and chemical stability.

[0257] 12.5 Mechanical Stability Evaluation of Form A and Form I

[0258] The starting samples, Form A (obtained in Example 3) and Form I (obtained in Example 10), were subjected to grinding and tableting experiments, and the resulting solids were subjected to XRPD analysis. The results are shown in Table 16.

[0259] Dry grinding: About 10 mg of the starting sample was taken in a mortar and ground for 3 minutes before XRPD analysis.

[0260] Wet grinding: Take about 10 mg of the starting sample in a mortar, add 1 to 2 drops of solvent, grind for 3 minutes, and then perform XRPD analysis.

[0261] Tableting experiment: About 10 mg of the starting sample was compressed at 20 MPa for 3 minutes and then XRPD analysis was performed.

[0262] Table 16 Summary of mechanical stability experiments of Form A and Form I

[0263] The results show that the solid crystalline form of Form A and Form I remained unchanged after dry grinding, wet grinding, and tableting. However, the crystallinity decreased after dry grinding, while the crystallinity of the solid obtained after wet grinding and tableting remained almost unchanged. After grinding and tableting, the solid color of Form A was slightly darker than the yellow of the starting sample, while the solid color of Form I remained essentially unchanged.

[0264] 12.6 Hygroscopicity Evaluation of Form I

[0265] Form I (obtained in Example 10) was subjected to DVS testing. The results are shown in Figures 21 and 22.

[0266] The results show that Form I absorbs moisture at 80% RH and increases in weight by 0.3629%, which is considered to be slightly hygroscopic. The form remains unchanged after the DVS test.

[0267] 12.7 Hygroscopicity Evaluation of Form A

[0268] Form A (obtained in Example 3) was subjected to DVS testing. The results are shown in Figures 23 and 24.

[0269] The results show that Form A absorbs moisture at 80% RH and increases in weight by 2.213%, which indicates that it is hygroscopic. The form remains unchanged after the DVS test.

[0270] Example 13: Hydrochloride of Compound X

[0271] 13.1 Preparation

[0272] Weigh 300 mg of Compound X (obtained in Example 1) into a 30 mL glass vial, add 9 mL of ethyl acetate, dissolve 1.1 N hydrochloric acid in 1 mL of ethyl acetate, and slowly add dropwise to the suspension. Stir at room temperature for 48 hours, filter, and obtain a yellow solid, which is then dried under vacuum at 50°C for 24 hours. A total of 270 mg of the hydrochloride salt is obtained (yield: 86%).

[0273] 13.2 Identification

[0274] The hydrochloride obtained in 13.1 was tested by ion chromatography, and the results showed that it contained 3.3586% chloride ions and the ratio of hydrochloric acid to free base was about 0.8:1 (acid:free base).

[0275] Example 14: Sulfate Salt of Compound X

[0276] 14.1 Preparation

[0277] 300 mg of Compound X (obtained in Example 1) was weighed into a 30 mL glass vial and dissolved in 4 mL of a DCM:MeOH mixture (volume ratio = 3:1). 1.1 equivalents of sulfuric acid was weighed into 1 mL of the above mixture, mixed thoroughly, and slowly added dropwise to the solution. Stirring at room temperature for 40 hours resulted in a clear solution. 5 mL of MTBE was slowly added dropwise, causing the solution to become turbid. Stirring was continued at room temperature for 8 hours. Filtering afforded a yellow solid, which was then dried under vacuum at 50°C for 24 hours. A total of 250 mg of the sulfate salt was obtained (yield: 75%).

[0278] 14.2 Identification

[0279] The sulfate obtained in 14.1 was tested by ion chromatography, and the result showed that it contained 4.8766% sulfate ions and the salt ratio was about 0.5:1 (acid:free base).

Claims

1. A crystal form A, crystal form B, crystal form C, crystal form D, crystal form F, crystal form G, crystal form H, crystal form I, or crystal form J of a five-membered-fused six-membered compound of formula X, whereinthe crystal form A has an X-ray powder diffraction pattern using Cu-Ka radiation and represented by 29 angles comprising diffraction peaks at 6.9 ± 0.2°, 11.2 ± 0.2°, 12.2 ± 0.2°, 13.7 ± 0.2°, 17.3 ± 0.2°, 18.2 ± 0.2°, and 24.3 ± 0.2°;the crystal form C has an X-ray powder diffraction pattern using Cu-Ka radiation and represented by 29 angles comprising diffraction peaks at 9.7 ± 0.2°, 10.8 ± 0.2°, 13.1 ± 0.2°, 14.1 ± 0.2°, 18.7 ± 0.2°, and 21.7 ± 0.2°;the crystal form F has an X-ray powder diffraction pattern using Cu-Ka radiation and represented by 29 angles comprising diffraction peaks at 5.8 ± 0.2°, 6.6 ± 0.2°, 7.2 ± 0.2°, 12.2 ± 0.2°, 14.5 ± 0.2°, 15.7 ± 0.2°, 18.9 ± 0.2°, and 24.6 ± 0.2°;the crystal form H has an X-ray powder diffraction pattern using Cu-Ka radiation and represented by 29 angles comprising diffraction peaks at 5.8 ± 0.2°, 8.5 ± 0.2°, 9.5 ± 0.2°, 11.7 ± 0.2°, 14.1 ± 0.2°, 16.9 ± 0.2°, and 20.8 ± 0.2°;the crystal form I has an X-ray powder diffraction pattern using Cu-Ka radiation and represented by 29 angles comprising diffraction peaks at 8.0 ± 0.2°, 11.3 ± 0.2°, 15.5 ± 0.2°, 17.6 ± 0.2°, 20.2 ± 0.2°, and 25.6 ± 0.2°;the crystal form B has an X-ray powder diffraction pattern using Cu-Ka radiation and represented by 29 angles comprising diffraction peaks at 8.6 ± 0.2°, 11.8 ± 0.2°, 15.8 ± 0.2°, and 18.9 ± 0.2°;the crystal form D has an X-ray powder diffraction pattern using Cu-Ka radiation and represented by 29 angles comprising diffraction peaks at 6.5 ± 0.2°, 7.0 ± 0.2°, 11.4 ± 0.2°,13.0 ± 0.2°, 17.9 ± 0.2°, and 22.0 ± 0.2°;the crystal form G has an X-ray powder diffraction pattern using Cu-Ka radiation and represented by 29 angles comprising diffraction peaks at 9.0 ± 0.2°, 13.4 ± 0.2°, 14.5 ± 0.2°, 19.3 ± 0.2°, and 24.8 ± 0.2°;the crystal form J has an X-ray powder diffraction pattern using Cu-Ka radiation and represented by 29 angles comprising diffraction peaks at 6.4 ± 0.2°, 9.6 ± 0.2°, 12.9 ± 0.2°, 16.5 ± 0.2°, 17.7 ± 0.2°, and 22.8 ± 0.2°.

2. The crystal form A, crystal form B, crystal form C, crystal form D, crystal form F, crystal form G, crystal form H, crystal form I, or crystal form J according to claim 1, which satisfies one or more of the following conditions:(1) the X-ray powder diffraction pattern for the crystal form A, using Cu-Ka radiation and represented by 29 angles, further comprises diffraction peaks at one or more of 9.7 ± 0.2°, 10.2 ± 0.2°, 15.1 ± 0.2°, and 20.6 ± 0.2°;(2) the X-ray powder diffraction pattern for the crystal form C, using Cu-Ka radiation and represented by 29 angles, further comprises diffraction peaks at one or more of 12.5 ± 0.2°, 15.5 ± 0.2°, and 24.3 ± 0.2°;(3) the X-ray powder diffraction pattern for the crystal form F, using Cu-Ka radiation and represented by 29 angles, further comprises diffraction peaks at one or more of 9.8 ± 0.2°, 13.3 ± 0.2°, 17.5 ± 0.2°, and 20.8 ± 0.2°;(4) the X-ray powder diffraction pattern for the crystal form H, using Cu-Ka radiation and represented by 29 angles, further comprises diffraction peaks at one or more of 10.9 ± 0.2°, 19.1 ± 0.2°, 26.5 ± 0.2°, and 33.0 ± 0.2°;(5) the X-ray powder diffraction pattern for the crystal form I, using Cu-Ka radiation and represented by 29 angles, further comprises diffraction peaks at one or more of 7.6 ± 0.2°, 18.6 ± 0.2°, 22.0 ± 0.2°, and 31.7 ± 0.2°;(6) the X-ray powder diffraction pattern for the crystal form B, using Cu-Ka radiation and represented by 29 angles, further comprises diffraction peaks at 17.3 ± 0.2° and / or 25.9 ± 0.2°;(7) the X-ray powder diffraction pattern for the crystal form D, using Cu-Ka radiation and represented by 29 angles, further comprises diffraction peaks at one or more of 10.4 ± 0.2°,16.8 ± 0.2°, and 26.4 ± 0.2°;(8) the X-ray powder diffraction pattern for the crystal form G, using Cu-Ka radiation and represented by 29 angles, further comprises diffraction peaks at one or more of 16.9 ± 0.2°, 20.6 ± 0.2°, and 27.3 ± 0.2°;(9) the X-ray powder diffraction pattern for the crystal form J, using Cu-Ka radiation and represented by 29 angles, further comprises diffraction peaks at one or more of 16.9 ± 0.2°, 20.9 ± 0.2°, 25.9 ± 0.2°, and 28.8 ± 0.2°;(10) the crystal form A has a differential scanning calorimetry pattern comprising an endothermic peak at 262.80 ± 5°C;(11) the crystal form A has a thermogravimetric analysis pattern with a weight loss of 0.548% before 200 ± 5°C;(12) the crystal form C has a differential scanning calorimetry pattern comprising an endothermic peak at 261.8 ± 5°C and an exothermic peak at 266.8 ± 5°C;(13) the crystal form C has a thermogravimetric analysis pattern with essentially no weight loss before 300 ± 5°C;(14) the crystal form F has a differential scanning calorimetry pattern comprising endothermic peaks at 249.1 ± 5°C and 262.9 ± 5°C and an exothermic peak at 258.6 ± 5°C;(15) the crystal form F has a thermogravimetric analysis pattern with essentially no weight loss before 300 ± 5°C;(16) the crystal form H has a differential scanning calorimetry pattern comprising an endothermic peak at 288.5 ± 5°C;(17) the crystal form H has a thermogravimetric analysis pattern with essentially no weight loss before 300 ± 5°C;(18) the crystal form I has a differential scanning calorimetry pattern comprising an endothermic peak at 279.6 ± 5°C; and(19) the crystal form I has a thermogravimetric analysis pattern with a weight loss of 0.865% before 150 ± 5°C.

3. The crystal form A, crystal form B, crystal form C, crystal form D, crystal form F, crystal form G, crystal form H, crystal form I, or crystal form J according to claim 2, whichsatisfies one or more of the following conditions:(1) the X-ray powder diffraction pattern for the crystal form A, using Cu-Ka radiation and represented by 29 angles, has positions of diffraction peaks as shown in the following table:No. Angle (°) No. Angle (°) 1 6.9 9 17.3 2 9.7 10 18.2 3 10.2 11 18.3 4 11.2 12 20.6 5 12.2 13 21.6 6 13.7 14 24.3 7 15.1 15 24.8 8 16.4;(2) the X-ray powder diffraction pattern for the crystal form C, using Cu-Ka radiation and represented by 29 angles, has positions of diffraction peaks as shown in the following table:No. Angle (°) No. Angle (°) 1 9.7 9 16.8 2 10.8 10 18.7 3 12.5 11 19.6 4 13.1 12 19.8 5 14.1 13 20.7 6 14.7 14 21.7 7 15.2 15 22.4 8 15.5 16 24.3;(3) the X-ray powder diffraction pattern for the crystal form F, using Cu-Ka radiation and represented by 29 angles, has positions of diffraction peaks as shown in the following table:No. Angle (°) No. Angle (°) 1 5.8 14 17.5 2 6.6 15 18.3 3 7.2 16 18.9 4 9.8 17 20.0 5 10.1 18 20.8 6 11.2 19 21.7 7 12.2 20 22.5 8 13.3 21 24.1 9 13.6 22 24.6 10 14.5 23 26.5 11 15.7 24 27.012 16.2 25 28.9 13 16.6 26 35.5;(4) the X-ray powder diffraction pattern for the crystal form H, using Cu-Ka radiation and represented by 29 angles, has positions of diffraction peaks as shown in the following table:No. Angle (°) No. Angle (°) 1 5.8 17 20.8 2 8.5 18 21.8 3 9.5 19 22.5 4 10.9 20 23.0 5 11.7 21 23.3 6 14.1 22 23.9 7 14.4 23 24.5 8 14.9 24 25.4 9 15.5 25 25.8 10 15.9 26 26.5 11 16.6 27 27.4 12 16.9 28 28.0 13 17.2 29 28.2 14 17.6 30 32.4 15 18.5 31 33.0 16 19.1;(5) the X-ray powder diffraction pattern for the crystal form I, using Cu-Ka radiation and represented by 29 angles, has positions of diffraction peaks as shown in the following table:No. Angle (°) No. Angle (°) 1 7.6 12 21.1 2 8.0 13 21.5 3 11.3 14 22.0 4 12.1 15 22.8 5 15.5 16 23.2 6 16.0 17 24.2 7 16.5 18 25.3 8 17.0 19 25.6 9 17.6 20 26.8 10 18.6 21 28.5 11 20.2 22 31.7;(6) the X-ray powder diffraction pattern for the crystal form B, using Cu-Ka radiation andrepresented by 29 angles, has positions and relative intensities of diffraction peaks as shown in the following table:No. Angle (°) Relative intensity No. Angle (°) Relative intensity 1 8.6 83.1% 9 17.3 39.7% 2 9.5 17.3% 10 18.4 58.7% 3 11.6 15.4% 11 18.9 100.0% 4 11.8 15.7% 12 24.1 18.4% 5 13.4 22.3% 13 24.6 20.2% 6 13.6 14.1% 14 25.9 26.4% 7 15.5 16.0% 15 27.0 13.9% 8 15.8 14.7% 16 33.2 14.4%;(7) the X-ray powder diffraction pattern for the crystal form. D, using Cu-Ka radiation and represented by 29 angles, has positions and relative intensities of diffraction peaks as shown in the following table:No. Angle (°) Relative intensity No. Angle (°) Relative intensity 1 6.5 27.2% 9 16.8 61.9% 2 7.0 100.0% 10 17.9 75.9% 3 10.4 9.2% 11 18.8 10.5% 4 11.4 48.6% 12 19.7 25.4% 5 13.0 34.8% 13 22.0 47.2% 6 14.1 81.1% 14 23.4 66.2% 7 15.0 22.8% 15 24.1 32.1% 8 16.1 17.8% 16 26.4 13.9%;(8) the X-ray powder diffraction pattern for the crystal form G, using Cu-Ka radiation and represented by 29 angles, has positions and relative intensities of diffraction peaks as shown in the following table:No. Angle (°) Relative intensity No. Angle (°) Relative intensity 1 6.6 12.1% 11 19.3 100.0% 2 9.0 66.3% 12 20.2 6.4% 3 13.4 46.8% 13 20.6 17.7% 4 13.9 5.6% 14 21.2 8.0% 5 14.2 7.3% 15 24.8 16.2% 6 14.5 4.9% 16 26.2 4.6%7 15.7 9.8% 17 26.7 2.0% 8 16.9 4.9% 18 27.3 22.0% 9 17.2 5.9% 19 28.2 10.4% 10 18.1 27.2% 20 30.1 6.9%;(9) the X-ray powder diffraction pattern for the crystal form J, using Cu-Ka radiation and represented by 29 angles, has positions and relative intensities of diffraction peaks as shown in the following table:No. Angle (°) Relative intensity No. Angle (°) Relative intensity 1 6.4 50.3% 17 21.3 36.8% 2 9.6 18.9% 18 22.4 24.3% 3 12.9 30.5% 19 22.8 55.0% 4 14.5 9.1% 20 23.3 32.5% 5 14.8 13.7% 21 23.9 30.4% 6 15.5 7.8% 22 24.1 32.5% 7 16.5 11.6% 23 25.2 42.1% 8 16.9 12.0% 24 25.9 45.9% 9. 17.7 26.4% 25 27.5 8.8% 10 18.2 20.5% 26 28.8 28.2% 11 18.7 100.0% 27 29.6 12.1% 12 19.0 94.6% 28 30.2 10.4% 13 19.2 82.5% 29 31.9 7.3% 14 19.9 11.5% 30 35.1 6.2% 15 20.3 11.0% 31 36.8 6.3% 16 20.9 57.0%4. The crystal form A, crystal form B, crystal form C, crystal form D, crystal form F, crystal form G, crystal form H, crystal form I, or crystal form J according to claim 3, which satisfies one or more of the following conditions:(1) the X-ray powder diffraction pattern for the crystal form A, using Cu-Ka radiation and represented by 29 angles, has positions and relative intensities of diffraction peaks as shown in the following table:No. Angle (°) Relative intensity No. Angle (°) Relative intensity 1 6.9 63.6% 9 17.3 43.2% 2 9.7 18.3% 10 18.2 52.4% 3 10.2 16.2% 11 18.3 47.0% 4 11.2 60.1% 12 20.6 32.7% 5 12.2 29.2% 13 21.6 29.8% 6 13.7 100.0% 14 24.3 27.6% 7 15.1 23.2% 15 24.8 19.8% 8 16.4 20.8%;(2) the X-ray powder diffraction pattern for the crystal form. C, using Cu-Ka radiation and represented by 29 angles, has positions and relative intensities of diffraction peaks as shown in the following table:No. Angle (°) Relative intensity No. Angle (°) Relative intensity 1 9.7 34.5% 9 16.8 21.6% 2 10.8 25.5% 10 18.7 100.0% 3 12.5 29.3% 11 19.6 55.4% 4 13.1 35.7% 12 19.8 57.1% 5 14.1 48.6% 13 20.7 69.5% 6 14.7 12.3% 14 21.7 27.0% 7 15.2 22.6% 15 22.4 45.7% 8 15.5 33.4% 16 24.3 13.1%;(3) the X-ray powder diffraction pattern for the crystal form F, using Cu-Ka radiation and represented by 29 angles, has positions and relative intensities of diffraction peaks as shown in the following table:No. Angle (°) Relative intensity No. Angle (°) Relative intensity 1 5.8 20.4% 14 17.5 43.5% 2 6.6 29.1% 15 18.3 17.5% 3 7.2 60.6% 16 18.9 39.1% 4 9.8 8.9% 17 20.0 24.5% 5 10.1 6.2% 18 20.8 38.9% 6 11.2 15.6% 19 21.7 17.6% 7 12.2 56.5% 20 22.5 48.3% 8 13.3 100.0% 21 24.1 18.1% 9 13.6 37.6% 22 24.6 21.4%10 14.5 28.2% 23 26.5 9.4% 11 15.7 74.0% 24 27.0 10.4% 12 16.2 30.9% 25 28.9 3.4% 13 16.6 13.9% 26 35.5 3.3%;(4) the X-ray powder diffraction pattern for the crystal form. H, using Cu-Ka radiation and represented by 29 angles, has positions and relative intensities of diffraction peaks as shown in the following table:No. Angle (°) Relative intensity No. Angle (°) Relative intensity 1 5.8 5.7% 17 20.8 100.0% 2 8.5 18.7% 18 21.8 8.1% 3 9.5 9.6% 19 22.5 3.4% 4 10.9 37.0% 20 23.0 6.1% 5 11.7 3.7% 21 23.3 4.8% 6 14.1 12.0% 22 23.9 6.7% 7 14.4 3.7% 23 24.5 6.0% 8 14.9 2.6% 24 25.4 7.5% 9 15.5 8.2% 25 25.8 42.5% 10 15.9 9.7% 26 26.5 11.0% 11 16.6 7.9% 27 27.4 3.6% 12 16.9 85.1% 28 28.0 3.9% 13 17.2 32.5% 29 28.2 4.8% 14 17.6 15.6% 30 32.4 3.1% 15 18.5 17.0% 31 33.0 3.3% 16 19.1 28.2%;(5) the X-ray powder diffraction pattern for the crystal form I, using Cu-Ka radiation and represented by 29 angles, has positions and relative intensities of diffraction peaks as shown in the following table:No. Angle (°) Relative intensity No. Angle (°) Relative intensity 1 7.6 11.0% 12 21.1 11.3% 2 8.0 41.7% 13 21.5 10.9% 3 11.3 100.0% 14 22.0 49.1% 4 12.1 81.3% 15 22.8 17.7% 5 15.5 21.0% 16 23.2 11.2% 6 16.0 31.3% 17 24.2 15.3% 7 16.5 28.7% 18 25.3 49.8%8 17.0 13.0% 19 25.6 21.0% 9 17.6 47.4% 20 26.8 12.0% 10 18.6 18.4% 21 28.5 12.6% 11 20.2 51.3 22 31.7 4.9%;(6) the X-ray powder diffraction pattern for the crystal form B, using Cu-Ka radiation and represented by 29 angles, is substantially as shown in FIG. 5;(7) the X-ray powder diffraction pattern for the crystal form D, using Cu-Ka radiation and represented by 29 angles, is substantially as shown in FIG. 9;(8) the X-ray powder diffraction pattern for the crystal form G, using Cu-Ka radiation and represented by 29 angles, is substantially as shown in FIG. 13;(9) the X-ray powder diffraction pattern for the crystal form J, using Cu-Ka radiation and represented by 29 angles, is substantially as shown in FIG. 20.

5. The crystal form A, crystal form B, crystal form C, crystal form D, crystal form F, crystal form G, crystal form H, crystal form I, or crystal form J according to claim 4, which satisfies one or more of the following conditions:(1) the X-ray powder diffraction pattern for the crystal form A, using Cu-Ka radiation and represented by 29 angles, is substantially as shown in FIG. 2;(2) the differential scanning calorimetry pattern for the crystal form A is substantially as shown in FIG. 3;(3) the thermogravimetric analysis pattern for the crystal form A is substantially as shown in FIG. 4;(4) the X-ray powder diffraction pattern for the crystal form C, using Cu-Ka radiation and represented by 29 angles, is substantially as shown in FIG. 6;(5) the differential scanning calorimetry pattern for the crystal form C is substantially as shown in FIG. 7;(6) the thermogravimetric analysis pattern for the crystal form C is substantially as shown in FIG. 8;(7) the X-ray powder diffraction pattern for the crystal form F, using Cu-Ka radiation and represented by 29 angles, is substantially as shown in FIG. 10;(8) the differential scanning calorimetry pattern for the crystal form F is substantially as shown in FIG. 11;(9) the thermogravimetric analysis pattern for the crystal form F is substantially as shown in FIG. 12;(10) the X-ray powder diffraction pattern for the crystal form H, using Cu-Ka radiation and represented by 29 angles, is substantially as shown in FIG. 14;(11) the differential scanning calorimetry pattern for the crystal form H is substantially as shown in FIG. 15;(12) the thermogravimetric analysis pattern for the crystal form H is substantially as shown in FIG. 16;(13) the X-ray powder diffraction pattern for the crystal form I, using Cu-Ka radiation and represented by 29 angles, is substantially as shown in FIG. 17;(14) the differential scanning calorimetry pattern for the crystal form I is substantially as shown in FIG. 18;(15) the thermogravimetric analysis pattern for the crystal form I is substantially as shown in FIG. 19.

6. A hydrochloride or sulfate of a five-membered-fused six-membered compound offormula X,the hydrochloride of the five-membered-fused six-membered compound of formula X canbe as shown in formula X-1;X-1the sulfate of the five-membered-fused six-membered compound of formula X can be asshown in formula X-2;7. A preparation method for the crystal form A, crystal form C, crystal form F, crystal form H, or crystal form I of the five-membered-fused six-membered compound of formula X according to any one of claims 1 to 5, whereinthe preparation method for the crystal form A comprises the step of: slurrying the five-membered-fused six-membered compound of formula X in a ketone solvent to obtain the crystal form A; the ketone solvent is, for example, acetone; the five-membered-fused six-membered compound of formula X can be in an amorphous form;the preparation method for the crystal form C comprises the step of: slurrying the five-membered-fused six-membered compound of formula X in a nitrile solvent to obtain the crystal form C; the nitrile solvent is, for example, acetonitrile; the five-membered-fused six-membered compound of formula X can be in an amorphous form;the preparation method for the crystal form F comprises the step of: subjecting the five-membered-fused six-membered compound of formula X and a chloroalkane to gas-solid diffusion to obtain the crystal form F; the chloroalkane is, for example, dichloromethane; the five-membered-fused six-membered compound of formula X can be in an amorphous form;the preparation method for the crystal form H comprises the step of: adding a benzene hydrocarbon solvent to a solution of the five-membered-fused six-membered compound of formula X in an amide solvent for crystallization to obtain the crystal form H; the amide solvent is, for example, DMF; the benzene hydrocarbon solvent is, for example, toluene; the five-membered-fused six-membered compound of formula X and the amide solvent can have a mass-to-volume ratio of 80 to 150 mg / mL, preferably 100 to 125 mg / mL, for example, 100 mg / mL or 125 mg / mL; the benzene hydrocarbon solvent and the amide solvent can have a volume ratio of (5 to 15):1, preferably (8 to 12):1, for example, 10:1; the crystallization can be performed at room temperature;the preparation method for the crystal form I comprises the step of: adding an ether solvent to a solution of the five-membered-fused six-membered compound of formula X in a sulfoxide solvent for crystallization to obtain the crystal form I; the sulfoxide solvent is, for example, DMSO; the ether solvent is, for example, MTBE; the five-membered-fused six-membered compound of formula X and the sulfoxide solvent can have a mass-to-volume ratio of 80 to 150 mg / mL, preferably 100 to 125 mg / mL, for example, 100 mg / mL or 125 mg / mL; the ether solvent and the sulfoxide solvent can have a volume ratio of (5 to 15):1, preferably (8 to 12):1, for example, 10:1; the crystallization can be performed at room temperature.

8. A pharmaceutical composition, comprising: (1) the crystal form A, crystal form B, crystal form C, crystal form D, crystal form F, crystal form G, crystal form H, crystal form I, or crystal form J of the five-membered-fused six-membered compound of formula X according to any one of claims 1 to 5, or the hydrochloride or sulfate of the five-membered-fused six-membered compound of formula X according to claim 6; and(2) a pharmaceutically acceptable carrier.

9. A use of substance Z in the manufacture of an IRAK4 degrading agent, wherein the substance Z is the crystal form A, crystal form B, crystal form C, crystal form D, crystal form F, crystal form G, crystal form H, crystal form I, or crystal form J of the five-membered-fused sixmembered compound of formula X according to any one of claims 1 to 5, or the hydrochloride or sulfate of the five-membered-fused six-membered compound of formula Xaccording to claim 6, or the pharmaceutical composition according to claim 8.

10. A use of substance Z in the manufacture of a medicament for the treatment and / or prevention of a Myd88- and / or IRAK4-related disease; the substance Z is the crystal form A, crystal form B, crystal form C, crystal form D, crystal form F, crystal form G, crystal form H, crystal form I, or crystal form J of the five-membered-fused six-membered compound of formula X according to any one of claims 1 to 5, or the hydrochloride or sulfate of the five-membered-fused six-membered compound of formula X according to claim 6, or the pharmaceutical composition according to claim 8;preferably, the IRAK4-related disease comprises one or more of a chronic lung disease, an autoimmune disease, an inflammatory disease, a tumor, a cardiovascular and cerebrovascular disease, and a central nervous system disease;the autoimmune disease can comprise psoriasis, systemic lupus erythematosus, and rheumatoid arthritis;the inflammatory disease can comprise an inflammatory bowel disease, such as ulcerative colitis;the tumor can be a hematological tumor or a solid tumor; the hematological tumor can comprise large B-cell lymphoma and acute and chronic lymphocytic leukemia; the solid tumor can comprise intestinal cancer and skin cancer caused by MYD88 mutations;the cardiovascular and cerebrovascular disease can comprise stroke and atherosclerosis; the central nervous system disease can comprise primary central nervous system lymphoma.

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