Crystalline form VI of acrylamide and methods for preparing this crystalline form VI.

Abstract

The invention proposes a crystalline form VI of an acrylamide compound. The acrylamide compound is (S)-N-(5-((6-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentane[4,5]pyrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridine-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)5-phenyl)acrylamide, and the X-ray powder diffraction pattern of the crystalline form VI has diffraction peaks at the following 2θ angle values: 8.3±0.2°, 13.2±0.2° and 18.9±0.2°. Crystalline form VI has the advantages of good stability and low hygroscopicity, and is suitable for large-scale industrial drug production and formulation development of pharmaceutical preparations.

Description

A crystal form VI of an acrylamide compound and its preparation method and use Technical Field

[0001] The present invention belongs to the technical field of research and development of chemical small molecule drugs; more specifically, it relates to a crystal form VI of an acrylamide compound, a preparation method and uses thereof. Background Art

[0002] Bruton's tyrosine kinase (BTK) is a non-receptor protein kinase of the Tec family, which is expressed in most hematopoietic cells such as B cells, mast cells and macrophages, but not in T cells, natural killer cells and plasma cells [Smith, CI et al. Journal of Immunology (1994), 152(2), 557-65]. BTK is a key part of the BCR and FcR signaling pathways, and targeted inhibition of BTK is a new approach to treating many different human diseases, such as B cell malignancies, autoimmune diseases and inflammatory disorders [Uckun, Fatih M. et al, Anti-Cancer Agents in Medicinal Chemistry (2007), Shinohara et al, Cell 132 (2008) pp794-806; Pan, Zhengying, Drug News & Perspectives (2008), 21(7); 7(6), 624-632; Gilfillan et al, Immunological Reviews 288 (2009) pp 149-169; Davis et al, Nature, 463 (2010) pp 88-94].

[0003] Covalent Bruton's tyrosine kinase (BTK) inhibitors, including ibrutinib and acalabrutinib, have transformed the treatment of several BTK-dependent B-cell malignancies, including chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, mantle cell lymphoma, and marginal zone lymphoma. Despite impressive clinical responses to ibrutinib in B-cell malignancies, cases of primary and secondary resistance continue to emerge, with poor prognosis and limited treatment options. The majority of CLL patients who develop resistance to irreversible BTK inhibitors such as ibrutinib harbor the BTK-C481S mutation. It has been reported that 80% of patients with relapsed CLL will harbor the C481S mutation [Maddocks KJ, et al., JAMA Oncol. 2015;1:80–87]. Another research group at Ohio State University reported in the Journal of Clinical Oncology [Vol 35, No. 13, 2017, p. 1437] that by the fourth year, approximately 20% of patients taking ibrutinib had clinical progression. Of these patients who relapsed, 85% had acquired the C481S mutation. Furthermore, these mutations were detected an average of nine months before relapse.

[0004] Although BTK inhibitors such as ibrutinib and ACP-196 have made significant contributions to the field, there is a strong need to continue to search for highly potent and selective BTK inhibitors that can not only irreversibly inhibit WT BTK, but also reversibly inhibit C481S mutant BTK.

[0005] Patent publication number CN111741959A discloses small molecule BTK inhibitors for treating neoplastic diseases, tumors, autoimmune diseases, and inflammatory conditions, and specifically discloses representative compounds:

[0006] Chinese chemical name: (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide.

[0007] English chemical name: (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyr idin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide.

[0008] Due to various factors, such as the molecular structure's configuration, conformation, molecular arrangement, molecular forces, and eutectic properties, solid 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, thus affecting the drug's uniformity, bioavailability, efficacy, and safety to varying degrees. Furthermore, the form and quantity of polymorphic compounds are unpredictable, and the physical and chemical stability, processability, bioavailability, efficacy, and safety of different crystalline forms are not always obvious.

[0009] Therefore, during the new drug development process, comprehensive screening of both crystalline and amorphous forms of drug compounds is necessary, taking multiple factors into consideration. In particular, for the aforementioned small molecule BTK inhibitors, their hygroscopicity, stability, and morphology require further improvement. Therefore, developing potentially pharmaceutically valuable crystalline forms of the compounds or their salts, and improving their stability and other properties, has potential medicinal and clinical value.

[0010] Summary of the Invention

[0011] In view of the above-mentioned problems in the prior art, the primary object of the present invention is to provide a crystalline form VI of an acrylamide compound, wherein the crystalline form VI has the advantages of good stability and low hygroscopicity.

[0012] The above-mentioned purpose of the present invention is achieved through the following technical solutions:

[0013] The above-mentioned acrylamide compound, whose Chinese name is: (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide, is a known inhibitor of BTK and its mutants.

[0014] The first object of the present application is to provide a crystalline form VI of the above-mentioned compound, wherein the X-ray powder diffraction pattern of the crystalline form VI comprises diffraction peaks at the following 2θ angle values: 8.3±0.2°, 13.2±0.2°, 13.6±0.2° and 18.9±0.2°;

[0015] Patent CN111741959A discloses a (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide compound. The amorphous X-ray powder diffraction pattern of the above compound is shown in Figure 4. The amorphous form has some difficulties in drug formulation and development, such as low stability, high hygroscopicity and poor powder properties, which are not conducive to drug development.

[0016] The inventors have discovered a stable crystalline form of the above-mentioned compound, Form VI, through a large number of experimental studies. The Form VI provided by the present invention has the advantages of good stability, low hygroscopicity, and good crystal morphology. The suspension formed by Form VI in pure water and buffer solutions of different pH values ​​has extremely excellent stability. In addition, the crystal form of Form VI remains unchanged when placed at 60°C for 30 days, at 25°C / 60% RH for 24 months, and at 40°C / 75% RH for 6 months, and the related substances do not change significantly, and the physical and chemical stability is good. The DVS results of Form VI show that it gains weight by 0.79% at 80% relative humidity and by 1.34% at 95% relative humidity, and is slightly hygroscopic. The crystals of Form VI are long rods with good dispersibility and fluidity.

[0017] In some embodiments, the X-ray powder diffraction pattern of Form VI comprises diffraction peaks at the following 2θ angle values: 8.3±0.2°, 11.3±0.2°, 13.2±0.2°, 13.6±0.2°, 18.9±0.2°, and 21.5±0.2°;

[0018] In some embodiments, the X-ray powder diffraction pattern of the Form VI comprises diffraction peaks at the following 2θ angle values: 4.3±0.2°, 8.3±0.2°, 11.3±0.2°, 13.2±0.2°, 13.6±0.2°, 17.8±0.2°, 18.9±0.2°, and 21.5±0.2°.

[0019] In some embodiments, the X-ray powder diffraction pattern of Form VI comprises diffraction peaks at the following 2θ angle values: 4.3±0.2°, 6.9±0.2°, 8.3±0.2°, 9.7±0.2°, 11.3±0.2°, 13.2±0.2°, 13.6±0.2°, 14.5±0.2°, 17.8±0.2°, 18.9±0.2°, 20.1±0.2°, and 21.5±0.2°.

[0020] In some embodiments, characteristic peak information of a portion of the X-ray powder diffraction pattern of the Form VI is shown in Table 1 below.

[0021] Table 1

[0022] In some embodiments, the Form VI has an X-ray powder diffraction pattern substantially consistent with FIG. 1 .

[0023] In some embodiments, the Form VI is an anhydrate.

[0024] In some embodiments, the purity of Form VI is >85%.

[0025] In some embodiments, the purity of Form VI is >95%.

[0026] In some embodiments, the purity of Form VI is >99%.

[0027] In some embodiments, the melting point onset peak of the crystalline form VI is at 218.5±3°C, and the endothermic melting peak is at 227.0±3°C.

[0028] In some embodiments, the Form VI has a DSC pattern substantially consistent with FIG. 2 .

[0029] In some embodiments, the weight loss of the crystal form VI in a thermogravimetric analysis curve at 30-150° C. is 0.21%±0.1%. The crystal form VI has no significant step-wise weight loss at 30-150° C.

[0030] In some embodiments, the Form VI has a TGA pattern substantially consistent with FIG. 3 .

[0031] Furthermore, the present invention also provides a new crystalline form V of the above compound.

[0032] The X-ray powder diffraction pattern of the crystalline form V of the above-mentioned compound provided by the present invention comprises diffraction peaks with the following 2θ angle values: 9.2±0.2°, 15.4±0.2° and 21.5±0.2°.

[0033] In some embodiments, the X-ray powder diffraction pattern of the Form V comprises diffraction peaks at the following 2θ angle values: 9.2±0.2°, 15.4±0.2°, 19.9±0.2°, 20.5±0.2°, 21.5±0.2°, 22.2±0.2°, and 25.0±0.2°.

[0034] In some embodiments, the X-ray powder diffraction pattern of the crystalline Form V comprises diffraction peaks at the following 2θ angle values: 4.1±0.2°, 9.2±0.2°, 11.7±0.2°, 14.8±0.2°, 15.4±0.2°, 18.2±0.2°, 19.9±0.2°, 20.5±0.2°, 21.5±0.2°, 22.2±0.2°, 25.0±0.2°, and 27.7±0.2°.

[0035] In some embodiments, the Form V has an X-ray powder diffraction pattern substantially consistent with FIG. 7 .

[0036] In some embodiments, the crystalline Form V is a hydrate.

[0037] Furthermore, the present invention also provides a new crystalline form XIII of the above compound.

[0038] The X-ray powder diffraction pattern of the crystalline form XIII of the above-mentioned compound provided by the present invention comprises diffraction peaks with the following 2θ angle values: 14.8±0.2°, 16.9±0.2°, 17.6±0.2° and 21.5±0.2°.

[0039] In some embodiments, the X-ray powder diffraction pattern of Form XIII comprises diffraction peaks at the following 2θ angle values: 11.5±0.2°, 14.8±0.2°, 16.9±0.2°, 17.6±0.2°, 20.0±0.2°, 20.8±0.2°, 21.5±0.2°, and 24.3±0.2°.

[0040] In some embodiments, the X-ray powder diffraction pattern of Form XIII comprises diffraction peaks at the following 2θ angle values: 11.5±0.2°, 14.5±0.2°, 14.8±0.2°, 15.1±0.2°, 16.9±0.2°, 17.6±0.2°, 18.8±0.2°, 19.3±0.2°, 20.0±0.2°, 20.8±0.2°, 21.5±0.2°, and 24.3±0.2°.

[0041] In some embodiments, the Form XIII has an X-ray powder diffraction pattern substantially consistent with FIG. 8 .

[0042] In some embodiments, the crystalline Form XIII is a hydrate.

[0043] In some embodiments, the differential scanning calorimetry curve of the crystalline Form XIII has an endothermic melting peak at 129.0±3°C and 261.5±3°C, respectively.

[0044] In some embodiments, the Form XIII has a DSC pattern substantially consistent with FIG. 9 .

[0045] In some embodiments, the thermogravimetric analysis curve of the Form XIII shows a weight loss of approximately 14.71% between 30°C and 170°C.

[0046] In some embodiments, the Form XIII has a TGA pattern substantially consistent with FIG. 10 .

[0047] Furthermore, a second object of the present invention is to provide a method for preparing the crystalline form VI of the compound, comprising adding the compound to a first solvent, dissolving it to form a clear solution, and then treating the clear solution by a crystallization method to obtain the crystalline form VI; the first solvent is selected from one or more polar solvents of alcohols, carboxylates, nitriles, ketones, amides, sulfones, sulfoxides, carboxylic acids, nitro compounds, pyridines, furans, alkylbenzenes, and halogenated hydrocarbons; or

[0048] The compound is added to a second solvent, slurried, cooled, and separated to precipitate the crystalline form VI; the second solvent is selected from one or more of alcohols, ethers, alkanes, carboxylates, nitriles, ketones, or alkylbenzenes.

[0049] The preparation method provided by the invention has simple process, green and environmentally friendly solvent, high yield and is suitable for industrial scale-up production.

[0050] In some embodiments, the crystallization method is to volatilize and crystallize the supernatant, and slowly evaporate the first solvent to obtain the crystal form VI.

[0051] When the crystallization is performed by volatile crystallization, in some embodiments, the first solvent is selected from ketones and / or carboxylic acid ester polar solvents; more specifically, the first solvent is selected from ketones polar solvents containing 3 to 6 carbon atoms and / or carboxylic acid ester polar solvents containing 3 to 10 carbon atoms; more specifically, the first solvent is a mixed solvent of acetone and isopropyl acetate.

[0052] In some embodiments, when the first solvent is a mixed solvent of acetone and isopropyl acetate, the volume mass ratio of acetone to the compound is 40-60 mL / g, and the volume mass ratio of isopropyl acetate to the compound is 5-25 mL / g.

[0053] In some embodiments, the crystallization method is to evaporate and crystallize the supernatant to obtain the crystal form VI.

[0054] When the crystallization is performed by evaporation crystallization, in some embodiments, the first solvent is selected from halogenated hydrocarbons and / or ketone polar solvents; more specifically, the first solvent is selected from halogenated hydrocarbon polar solvents containing 1 to 6 carbon atoms and / or ketone polar solvents containing 3 to 6 carbon atoms; more specifically, the first solvent is dichloromethane and acetone.

[0055] In some embodiments, when the first solvent is dichloromethane and acetone, the volume mass ratio of the dichloromethane to the compound is 1 to 50 mL / g, and the volume mass ratio of the acetone to the compound is 1 to 100 mL / g; more specifically, the volume mass ratio of the dichloromethane to the compound is 1 to 30 mL / g, and the volume mass ratio of the acetone to the compound is 1 to 50 mL / g.

[0056] In some embodiments, the compound is added to dichloromethane, dissolved at room temperature to form a clear solution, concentrated under reduced pressure to 1 / 6 to 1 / 4 volume, acetone is slowly added dropwise at 35 to 45°C to precipitate Form VI, concentrated under reduced pressure to 2 / 5 to 2 / 3 volume, cooled to 10 to 25°C, stirred, and filtered to obtain Form VI.

[0057] In some embodiments, the crystallization method is to add a poor solvent to the supernatant to precipitate Form VI.

[0058] When a poor solvent is used for crystallization, the first solvent is selected from one or more polar solvents selected from amides, halogenated hydrocarbons, sulfoxides, and furans; and the poor solvent is selected from one or more polar solvents selected from alcohols, carboxylates, nitriles, ketones, alkanes, ethers, nitro compounds, and alkylbenzenes. Form VI has good solubility in the first solvent; therefore, the first solvent can serve as a good solvent for Form VI. In contrast, Form VI has poor solubility in the poor solvent.

[0059] In some embodiments, the first solvent is selected from halogenated hydrocarbon polar solvents, and the poor solvent is selected from ether solvents; more specifically, the first solvent is selected from halogenated hydrocarbon polar solvents containing 1 to 6 carbon atoms, and the poor solvent is selected from ether solvents containing 2 to 6 carbon atoms; more specifically, the first solvent is dichloromethane, and the poor solvent is methyl tert-butyl ether.

[0060] In some embodiments, the volume mass ratio of the first solvent to the compound is 1 to 50 mL / g; the volume mass ratio of the poor solvent to the compound is 1 to 80 mL / g; more specifically, the volume mass ratio of the first solvent to the compound is 3 to 40 mL / g; the volume mass ratio of the poor solvent to the compound is 3 to 50 mL / g.

[0061] When the slurry method is used for crystallization, in some embodiments, the second solvent is selected from ketones and / or nitrile solvents; more specifically, the second solvent is selected from ketone solvents containing 3 to 6 carbon atoms and / or nitrile solvents containing 2 to 6 carbon atoms; more specifically, the second solvent is acetonitrile or acetone.

[0062] In some embodiments, the volume mass ratio of the second solvent to the compound is 1 to 30 mL / g; more specifically, the volume mass ratio is 5 to 20 mL / g.

[0063] In some embodiments, the slurrying temperature is 0-80°C; more specifically, the slurrying temperature is 10-50°C.

[0064] In some embodiments, the slurrying time is 1 to 120 hours, more specifically, the slurrying time is 4 to 20 hours.

[0065] In some embodiments, the slurrying process further includes stirring, for example, stirring for 1 to 24 hours, or longer; more specifically, stirring for at least 4 hours, for example, 5 hours.

[0066] Furthermore, the third object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form VI of the above-mentioned compound and optionally a pharmaceutically acceptable carrier or excipient.

[0067] In some embodiments, the excipients include, but are not limited to, fillers, excipients, binders, disintegrants, surfactants, pH adjusters, glidants, lubricants or other suitable additives and the like.

[0068] In some embodiments, the method for preparing the pharmaceutical composition is to fill the pharmaceutical composition containing Form VI in the form of powder, granules, pellets, etc. into capsules or tablets; more specifically, the granules can be prepared by wet granulation or dry granulation and other suitable granulation methods.

[0069] In some embodiments, the crystalline form VI may account for 1 to 99% (weight) of the pharmaceutical composition; more specifically, 1 to 60% (weight); more specifically, 1 to 50% (weight); more specifically, 1 to 30% (weight).

[0070] Furthermore, a fourth object of the present invention is to provide use of the crystalline form VI of the compound or the above-mentioned pharmaceutical composition in the preparation of drugs for preventing and / or treating neoplastic diseases, tumors, autoimmune diseases and inflammatory disorders.

[0071] In some embodiments, the autoimmune disease and inflammatory disorder is pemphigus vulgaris, rheumatoid arthritis, asthma, multiple sclerosis, systemic lupus erythematosus, or allergy.

[0072] In some embodiments, the neoplastic disease tumor is a B-cell malignancy or a solid tumor.

[0073] In some embodiments, the neoplastic disease tumor is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), or multiple myeloma (MM).

[0074] Furthermore, a fifth object of the present invention is to provide a method for preventing and / or treating neoplastic diseases, tumors, autoimmune diseases and inflammatory disorders, comprising administering to a subject a therapeutically effective amount of the crystalline form VI of the compound.

[0075] In some embodiments, the dosage of Form VI is 0.5 to 200 mg / day; in some embodiments, the dosage of Form VI is 1 to 100 mg / day; in some embodiments, the dosage of Form VI is 5 to 50 mg / day. The above dosage frequency is one to three times per day.

[0076] In some embodiments, the crystalline form VI or pharmaceutical composition of the present invention can be preferably administered orally. More specifically, the oral administration can be preferably carried out in the form of capsules or tablets.

[0077] Compared with the prior art, the present invention has the following beneficial effects:

[0078] The crystal form VI provided by the present invention has the advantages of good stability, low hygroscopicity, and good crystal morphology. Crystal form VI has extremely excellent stability when formed into suspensions in pure water and buffer solutions of different pH values. In addition, the crystal form VI remains unchanged after being placed at 60°C for 30 days, at 25°C / 60% RH for 24 months, and at 40°C / 75% RH for 6 months, and the related substances do not change significantly, indicating good physical and chemical stability. The DVS results of crystal form VI show that it gains weight by 0.79% at 80% relative humidity and by 1.34% at 95% relative humidity, indicating slight hygroscopicity. The crystals of crystal form VI are long rods with good dispersibility and fluidity. In addition, the preparation of the crystal form VI shows good exposure in animal PK, meeting the in vivo exposure requirements of the drug. The crystal form VI of the compound provided by the present invention is beneficial for the storage of raw materials and the preparation of preparations, is beneficial for improving the quality and stability of drugs, and is suitable for industrial production of raw materials and formulation formulation development. BRIEF DESCRIPTION OF THE DRAWINGS

[0079] FIG1 is an X-ray powder diffraction (XRPD) pattern of Form VI.

[0080] FIG2 is a differential scanning calorimetry (DSC) diagram of Form VI.

[0081] FIG3 is a thermogravimetric analysis (TGA) diagram of Form VI.

[0082] FIG4 is an X-ray powder diffraction (XRPD) pattern of an amorphous form.

[0083] Figure 5 is the H NMR spectrum of the compound.

[0084] FIG6 is an infrared spectrum of the compound.

[0085] FIG7 is an X-ray powder diffraction (XRPD) pattern of Form V.

[0086] FIG8 is an X-ray powder diffraction (XRPD) pattern of Form XIII.

[0087] FIG9 is a differential scanning calorimetry (DSC) diagram of Form XIII.

[0088] FIG10 is a thermogravimetric analysis (TGA) diagram of Form XIII.

[0089] FIG11 is a dynamic moisture sorption (DVS) test graph of Form VI.

[0090] FIG12 is a dynamic moisture sorption (DVS) test diagram of amorphous.

[0091] FIG13 is a dynamic moisture sorption (DVS) test graph of Form XIII.

[0092] FIG14 is a graph showing the stability test of factors affecting Form VI.

[0093] FIG15 is a polarizing microscope image (400X) of Form VI.

[0094] FIG16 is a polarizing microscope image (100X) of amorphous structure.

[0095] FIG17 is a polarizing microscope image (400X) of Form XIII. DETAILED DESCRIPTION

[0096] In the following description, certain specific details are set forth to provide a thorough understanding of the various embodiments of the present invention. However, those skilled in the art will appreciate that the present invention can be implemented without using these details. The description of multiple embodiments hereinafter is made with the understanding that this disclosure is to be regarded as an example of the subject matter claimed for protection and is not intended to limit the appended claims to the specific embodiments described. The headings used throughout this disclosure are merely for convenience and are not to be interpreted as limiting the claims in any way. The embodiments described under any heading may be combined with the embodiments described under any other heading.

[0097] In the present invention, the crystal form can be determined by various technical means, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

[0098] In the present invention, X-ray powder diffraction (XRPD) can detect information such as changes in crystal form, crystallinity, and crystalline state, and is a common means of identifying crystal forms. The peak position of the XRPD pattern depends mainly on the structure of the crystal form and is relatively insensitive to experimental details, while its relative peak height depends on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by an XRPD pattern with certain peak positions, which is substantially as shown in the XRPD pattern provided in the accompanying drawings of the present invention. At the same time, the measurement of 2θ of the XRPD pattern may have experimental errors, and the measurement of 2θ of the XRPD pattern may be slightly different between different instruments and different samples, so the value of 2θ cannot be regarded as absolute. According to the instrument conditions used in the test of the present invention, the diffraction peak has an error tolerance of ±0.2°. In the present invention, the XRPD test was tested using a Bruker D8 Advance model instrument with a copper target and a wavelength of Kα radiation (voltage: 40 kV, current: 40 mA).

[0099] In the present invention, differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference material (usually α-Al2O3) as a function of temperature by continuously heating or cooling the sample under program control. The height of the melting peak of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystal form described in the present invention is characterized by a DSC graph with a characteristic peak position, which is substantially as shown in the DSC graph provided in the accompanying drawings of the present invention. At the same time, DSC spectra may have experimental errors, and the peak positions and peak values ​​of the DSC spectra may vary slightly between different instruments and different samples. Therefore, the peak position or peak value of the DSC endothermic peak cannot be considered absolute. According to the instrument conditions used in the test of the present invention, the melting peak has an error tolerance of ±3°C.

[0100] In the present invention, differential scanning calorimetry (DSC) can also be used to detect and analyze whether a crystal form has a crystal transformation or mixed crystal phenomenon. Solids with the same chemical composition often form isomers with different crystal structures under different thermodynamic conditions, or are called variants. This phenomenon is called polymorphism or homogeneous phase phenomenon. When the temperature and pressure conditions change, the variants will transform into each other, and this phenomenon is called crystal form transformation. Due to the crystal form transformation, the mechanical, electrical, magnetic and other properties of the crystal will undergo huge changes. When the temperature of the crystal form transformation is within the measurable range, this transformation process can be observed on the differential scanning calorimetry (DSC) graph, which is characterized by having an exothermic peak reflecting this transformation process and two or more endothermic peaks, which are the characteristic endothermic peaks of the different crystal forms before and after the transformation.

[0101] In the present invention, thermogravimetric analysis (TGA) is a program-controlled technique that measures the mass change of a substance as it changes with temperature. It is suitable for examining the loss of solvent from crystals or the sublimation and decomposition of samples, and can be used to infer the presence of water of crystallization or solvent in the crystals. The mass change shown by the TGA curve depends on many factors, including sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and samples. Depending on the instrumentation used in the present invention, the mass change has an error tolerance of ±0.1%.

[0102] Furthermore, the term "substantially consistent with a pattern..." when referring to, for example, an XRPD pattern, a TGA pattern, a DSC pattern, a DVS pattern, etc., refers to a pattern that is not necessarily identical to those described herein, but that falls within the limits of experimental error or deviation when considered by one of ordinary skill in the art.

[0103] In the present invention, the "first solvent" refers to one or more polar solvents selected from alcohols, carboxylates, nitriles, ketones, amides, sulfones, sulfoxides, carboxylic acids, nitro compounds, pyridines, furans, alkylbenzenes, and halogenated hydrocarbons. More specifically, the first solvent includes, but is not limited to, methanol, ethanol, trifluoroethanol, propanol, isopropanol, butanol, tert-butanol, polyethylene glycol, ethyl acetate, isopropyl acetate, acetonitrile, acetone, butanone, methyl ethyl ketone, l-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, dimethyl sulfoxide, chloroform, dichloromethane, formic acid, acetic acid, nitromethane, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof. The alkylbenzene is a benzene in which hydrogen atoms are substituted by one or more alkanes containing 1 to 6 carbon atoms. More specifically, the alkylbenzene is a benzene in which hydrogen atoms are substituted by one or more methyl groups.

[0104] In the present invention, the "second solvent" refers to one or more solvents selected from alcohols, ethers, alkanes, carboxylates, nitriles, ketones, or alkylbenzenes. More specifically, the second solvent includes, but is not limited to, 1,4-dioxane, ethyl acetate, acetone, methyl ethyl ketone, l-methyl-2-pyrrolidone, 2-propanone, and mixtures thereof. Alkylbenzenes are benzenes in which hydrogen atoms are substituted with one or more alkanes containing 1 to 6 carbon atoms; more specifically, benzenes in which hydrogen atoms are substituted with one or more methyl groups.

[0105] In the present invention, the good solvent is selected from one or more polar solvents selected from amides, halogenated hydrocarbons, sulfoxides, and furans; more specifically, the good solvent includes but is not limited to N,N-dimethylacetamide, N,N-dimethylformamide, chloroform, dichloromethane, dimethyl sulfoxide, tetrahydrofuran, and mixtures thereof.

[0106] In the present invention, the poor solvent is selected from one or more of alcohols, carboxylates, nitriles, ketones, alkanes, ethers, nitro compounds, and alkylbenzenes. More specifically, the poor solvent includes, but is not limited to, isopropyl alcohol, isopropyl acetate, acetonitrile, acetone, butanone, methyl ethyl ketone, heptane, hexane, 1,4-dioxane, methyl tert-butyl ether, isopropyl ether, nitromethane, toluene, and mixtures thereof. The alkylbenzene is a benzene in which hydrogen atoms are substituted with one or more alkanes containing 1 to 6 carbon atoms. More specifically, the alkylbenzene is a benzene in which hydrogen atoms are substituted with one or more methyl groups.

[0107] As used herein, a "good solvent" refers to a solvent in which the solubility of Form VI of the compound is greater than 1 g / L, greater than 2 g / L, greater than 3 g / L, greater than 4 g / L, greater than 5 g / L, greater than 6 g / L, greater than 7 g / L, greater than 8 g / L, greater than 9 g / L, greater than 10 g / L, greater than 15 g / L, greater than 20 g / L, greater than 30 g / L, greater than 40 g / L, greater than 50 g / L, greater than 60 g / L, greater than 70 g / L, greater than 80 g / L, greater than 90 g / L, or greater than 100 g / L. In certain embodiments, the solubility of Form VI of the compound in a good solvent differs from that in a poor solvent by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, based on the solubility in the dissolving solvent. In some embodiments, the solubility of Form VI of the compound in a good solvent is greater than its solubility in a poor solvent, and the solubility of Form VI of the compound in a good solvent is approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% higher than its solubility in a poor solvent.

[0108] In the present invention, "poor solvent" refers to a solvent that can promote supersaturation and / or crystallization of a solution. In some embodiments, the solubility of Form VI of the compound in the poor solvent is less than 0.001 g / L, less than 0.1 g / L, less than 0.2 g / L, less than 0.3 g / L, less than 0.4 g / L, less than 0.5 g / L, less than 0.6 g / L, less than 0.7 g / L, less than 0.8 g / L, or less than 1 g / L.

[0109] Suitable pharmaceutical carriers include water, various organic solvents, various inert diluents, etc.; suitable excipients include fillers, excipients, binders, disintegrants, surfactants, pH regulators, glidants, lubricants or other suitable additives, etc. If necessary, the pharmaceutical composition may contain various additives such as flavorings, binders and excipients. For oral administration, tablets and capsules may contain various excipients. Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup and methylcellulose; various fillers such as lactose monohydrate and microcrystalline cellulose; various glidants such as silicon dioxide; various disintegrants such as cross-linked sodium carboxymethyl cellulose, starch, alginic acid and some silicates; and various binders such as povidone K30, sucrose, gelatin and gum arabic; and pH regulators such as fumaric acid. In addition, lubricants or anti-adherents including magnesium stearate and talc fillers are commonly used in the production of tablets. The same type of solid components can also be used to formulate soft and hard gelatin capsules. When an aqueous suspension is required for oral administration, the active compound can be mixed with various sweeteners or flavorings, pigments, or dyes. If desired, various emulsifiers can be used or suspensions can be produced; diluents such as water, ethanol, propylene glycol, glycerol, or combinations thereof can be used.

[0110] In the present invention, the pharmaceutical composition can be administered in the following forms: oral administration in the form of capsules, tablets, pills, powders, sustained release injections (such as sterile solutions, suspensions or emulsions); by topical treatment forms such as pastes, creams or ointments; or by suppositories such as suppositories; or by inhalation or insufflation. The pharmaceutical composition can be in a unit dosage form suitable for precise dosage application.

[0111] The pharmaceutical compositions can be formulated in unit dosage form, each dosage containing from about 5 mg to about 100 mg, more usually from about 10 mg to about 30 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.

[0112] Pharmaceutical compositions for inhalation or insufflation include solutions, suspensions, or powders in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered via the oral or nasal respiratory route for local or systemic effect. The compositions may be nebulized using an inert gas. Nebulized solutions may be breathed directly from a nebulizer device, or the nebulizer device may be connected to a mask tent or intermittent positive pressure breathing apparatus. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0113] The amount of the crystalline form or composition administered to a patient will depend on the intended recipient, the purpose of administration, such as prophylaxis or treatment, the patient's condition, the route of administration, and other factors. In therapeutic applications, the composition can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the disease condition being treated and on the judgment of the attending clinician based on factors such as the severity of the disease, the patient's age, weight, and general condition.

[0114] The term "treating" refers to, for example, preventing, inhibiting, and ameliorating a disease, condition, or disorder in a subject.

[0115] The phrase "therapeutically effective amount" refers to that amount of an active compound or pharmaceutical agent that will elicit the biological or medical response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0116] Example 1

[0117] 1. Preparation of Form VI by dissolution and crystallization in a dichloromethane / methyl tert-butyl ether system

[0118] (1) Referring to the preparation method in Patent Publication No. CN111741959A, the compound (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide (not limited to solid form) was obtained;

[0119] (2) 5.0 g of the compound raw material was added to dichloromethane (20 mL), heated to 40 ° C to dissolve, methyl tert-butyl ether (80 mL) was added dropwise, crystallized, and then slowly cooled to 0 ° C., stirred for 5 h, filtered, and dried to obtain 4.51 g of off-white solid powder with a yield of 90.2%. XRPD was measured and it was Form VI.

[0120] 2. Identification of Form VI

[0121] (1) The off-white solid powder prepared in the above step (2) was analyzed and identified by Bruker D8 Advance X-ray powder diffraction (XRPD): using Cu-Kα radiation, it has the following characteristic peaks expressed in angles 2θ: 4.3±0.2°, 6.9±0.2°, 8.3±0.2°, 9.7±0.2°, 11.3±0.2°, 13.2±0.2°, 13.6±0.2°, 14.5±0.2°, 17.8±0.2°, 18.9±0.2°, 20.1±0.2° and 21.5±0.2°, and its spectrum is shown in FIG1 , which is Form VI of the compound.

[0122] (2) The off-white solid powder prepared in the above step (2) was analyzed and identified by TA Q200 differential scanning calorimetry (DSC): the scanning speed was 10°C / min, and it contained an endothermic peak at 227.0°C (the melting point onset peak was 218.5°C), with an error tolerance of ±3°C, and its spectrum is shown in Figure 2.

[0123] (3) The off-white solid powder prepared in step (2) was analyzed and identified by TA Q500 thermogravimetric (TGA): the scanning speed was 10°C / min, and the weight loss was 0.21% between 30°C and 150°C. The spectrum is shown in FIG3 .

[0124] Example 2

[0125] 1. Preparation of Form VI by Evaporative Crystallization in a Dichloromethane / Acetone System

[0126] (1) Referring to the preparation method in Patent Publication No. CN111741959A, the compound (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide (not limited to solid form) was obtained;

[0127] (2) 30.0 g of the compound raw material was added to dichloromethane (150 mL), stirred at room temperature to dissolve, and then 4 / 5 of the dichloromethane solution was concentrated under reduced pressure. Acetone (300 mL) was slowly added dropwise at 40°C to crystallize, and then 1 / 2 of the solution was further concentrated under reduced pressure. The temperature was then lowered to 20°C, stirred for 1 h, filtered, and dried to obtain 27.9 g of an off-white solid powder with a yield of 93.0%. XRPD analysis showed that the product was Form VI.

[0128] 2. Identification of Form VI

[0129] (1) The off-white solid powder prepared in the above step (2) was identified by Bruker D8 Advance X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, it has the following characteristic peaks expressed in angles 2θ: 4.3±0.2°, 6.9±0.2°, 8.3±0.2°, 9.7±0.2°, 11.3±0.2°, 13.2±0.2°, 13.6±0.2°, 14.5±0.2°, 17.8±0.2°, 18.9±0.2°, 20.1±0.2° and 21.5±0.2°, and its spectrum is basically consistent with Figure 1.

[0130] (2) The off-white solid powder prepared in the above step (2) was analyzed and identified by TA Q200 differential scanning calorimetry (DSC): the scanning speed was 10°C / min, and it contained an endothermic peak at 227.0°C (the melting point onset peak was 218.5°C), with an error tolerance of ±3°C, and its spectrum was basically consistent with Figure 2.

[0131] (3) The off-white solid powder prepared in step (2) above was analyzed and identified by TA Q500 thermogravimetric (TGA): the scanning speed was 10°C / min, and the weight loss was 0.21% between 30°C and 150°C. The spectrum was basically consistent with Figure 3.

[0132] Example 3

[0133] 1. Preparation of Form VI by volatile crystallization in the acetone / isopropyl acetate system

[0134] (1) Referring to the preparation method in Patent Publication No. CN111741959A, the compound (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide (not limited to solid form) was obtained;

[0135] (2) 100 mg of the compound raw material was added to acetone (5 mL) and isopropyl acetate (1.5 mL), heated to 50°C to dissolve, then opened and slowly evaporated to precipitate the solvent. The solid was dried to obtain 83 mg of off-white solid powder with a yield of 83%. XRPD analysis showed that it was Form VI.

[0136] 2. Identification of Form VI

[0137] (1) The off-white solid powder prepared in the above step (2) was identified by Bruker D8 Advance X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, it has the following characteristic peaks expressed in angles 2θ: 4.3±0.2°, 6.9±0.2°, 8.3±0.2°, 9.7±0.2°, 11.3±0.2°, 13.2±0.2°, 13.6±0.2°, 14.5±0.2°, 17.8±0.2°, 18.9±0.2°, 20.1±0.2° and 21.5±0.2°, and its spectrum is basically consistent with Figure 1.

[0138] (2) The off-white solid powder prepared in the above step (2) was analyzed and identified by TA Q200 differential scanning calorimetry (DSC): the scanning speed was 10°C / min, and it contained an endothermic peak at 227.0°C (the melting point onset peak was 218.5°C), with an error tolerance of ±3°C, and its spectrum was basically consistent with Figure 2.

[0139] (3) The off-white solid powder prepared in step (2) above was analyzed and identified by TA Q500 thermogravimetric (TGA): the scanning speed was 10°C / min, and the weight loss was 0.21% between 30°C and 150°C. The spectrum was basically consistent with Figure 3.

[0140] Example 4

[0141] 1. Preparation of Form VI by acetone slurry conversion method

[0142] (1) Referring to the preparation method in Patent Publication No. CN111741959A, the compound (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide (not limited to solid form) was obtained;

[0143] (2) 2.0 g of the compound-raw material was added to acetone (30 mL), suspended and stirred at 50°C for 12 h, then slowly cooled to 0°C, stirred for 5 h, filtered, and dried to obtain 1.88 g of an off-white solid powder with a yield of 94.0%. XRPD analysis showed that it was Form VI.

[0144] 2. Identification of Form VI

[0145] (1) The off-white solid powder prepared in the above step (2) was identified by Bruker D8 Advance X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, it has the following characteristic peaks expressed in angles 2θ: 4.3±0.2°, 6.9±0.2°, 8.3±0.2°, 9.7±0.2°, 11.3±0.2°, 13.2±0.2°, 13.6±0.2°, 14.5±0.2°, 17.8±0.2°, 18.9±0.2°, 20.1±0.2° and 21.5±0.2°, and its spectrum is basically consistent with Figure 1.

[0146] (2) The off-white solid powder prepared in the above step (2) was analyzed and identified by TA Q200 differential scanning calorimetry (DSC): the scanning speed was 10°C / min, and it contained an endothermic peak at 227.0°C (the melting point onset peak was 218.5°C), with an error tolerance of ±3°C, and its spectrum was basically consistent with Figure 2.

[0147] (3) The off-white solid powder prepared in step (2) above was analyzed and identified by TA Q500 thermogravimetric (TGA): the scanning speed was 10°C / min, and the weight loss was 0.21% between 30°C and 150°C. The spectrum was basically consistent with Figure 3.

[0148] Example 5

[0149] 1. Preparation of Form VI by Acetonitrile System Slurry Conversion Method

[0150] (1) Referring to the preparation method in Patent Publication No. CN111741959A, the compound (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide (not limited to solid form) was obtained;

[0151] (2) 1.0 g of the compound raw material was added to acetonitrile (10 mL), suspended and stirred at 25° C. for 24 h, filtered, and dried to obtain 0.89 g of an off-white solid powder with a yield of 89.0%. XRPD analysis showed that it was Form VI.

[0152] 2. Identification of Form VI

[0153] (1) The off-white solid powder prepared in the above step (2) was identified by Bruker D8 Advance X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, it has the following characteristic peaks expressed in angles 2θ: 4.3±0.2°, 6.9±0.2°, 8.3±0.2°, 9.7±0.2°, 11.3±0.2°, 13.2±0.2°, 13.6±0.2°, 14.5±0.2°, 17.8±0.2°, 18.9±0.2°, 20.1±0.2° and 21.5±0.2°, and its spectrum is basically consistent with Figure 1.

[0154] (2) The off-white solid powder prepared in the above step (2) was analyzed and identified by TA Q200 differential scanning calorimetry (DSC): the scanning speed was 10°C / min, and it contained an endothermic peak at 227.0°C (the melting point onset peak was 218.5°C), with an error tolerance of ±3°C, and its spectrum was basically consistent with Figure 2.

[0155] (3) The off-white solid powder prepared in step (2) above was analyzed and identified by TA Q500 thermogravimetric (TGA): the scanning speed was 10°C / min, and the weight loss was 0.21% between 30°C and 150°C. The spectrum was basically consistent with Figure 3.

[0156] Comparative Example 1

[0157] 1. Preparation of Compounds

[0158] With reference to the preparation method in patent publication number CN111741959A, the compound (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide was obtained.

[0159] 2. Identification of Compounds

[0160] An appropriate amount of the solid compound from step 1 was tested for XRPD. The XRPD spectrum, as shown in Figure 4, indicated an amorphous form. The H NMR spectrum and IR spectrum of the compound from step 1 were measured. The results showed that both H NMR and IR spectra were consistent with the structure of the target compound. The H NMR spectrum is shown in Figure 5, and the specific H NMR spectrum data is shown in Table 2 below. The IR spectrum is shown in Figure 6, and the specific IR spectrum data is shown in Table 3 below.

[0161] Table 2

[0162] Note: m is a multiplet; s is a singlet; d is a doublet; t is a triplet; dd is a doublet of doublets.

[0163] Table 3

[0164] Note: m stands for medium, s stands for strong, and w stands for weak.

[0165] Comparative Example 2

[0166] 1. Preparation of Form V by Crystallization in Trifluoroethanol / Water System

[0167] (1) Referring to the preparation method in Patent Publication No. CN111741959A, the compound (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide (not limited to solid form) was obtained;

[0168] (2) 1.0 g of the compound raw material was added to trifluoroethanol (3 mL), stirred at 50° C. to dissolve, and then pure water (8 mL) was slowly added dropwise to crystallize. The mixture was stirred at 50° C. for 18 h, filtered, and allowed to stand at room temperature for 4 h to obtain 0.95 g of an off-white solid powder with a yield of 95.0%. XRPD analysis showed that the product was Form V.

[0169] 2. Identification of Form V

[0170] The off-white solid powder prepared in the above step (2) was identified by Bruker D8 Advance X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, it has the following characteristic peaks expressed in angles 2θ: 4.1±0.2°, 9.2±0.2°, 11.7±0.2°, 14.8±0.2°, 15.4±0.2°, 18.2±0.2°, 19.9±0.2°, 20.5±0.2°, 21.5±0.2°, 22.2±0.2°, 25.0±0.2° and 27.7±0.2°, and its spectrum is shown in Figure 7, which is Form V.

[0171] Comparative Example 3

[0172] 1. Preparation of Form XIII by dimethyl sulfoxide system slurry conversion method

[0173] (1) Referring to the preparation method in Patent Publication No. CN111741959A, the compound (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide (not limited to solid form) was obtained;

[0174] (2) 1.5 g of the compound starting material was added to dimethyl sulfoxide (18 mL), suspended and stirred at 25° C. for 24 h, filtered, and dried to obtain 1.34 g of an off-white solid powder with a yield of 89.3%. XRPD analysis showed that it was Form XIII.

[0175] 2. Identification of Form XIII

[0176] (1) The off-white solid powder prepared in step (2) above was identified by Bruker D8 Advance X-ray powder diffraction (XRPD) analysis using Cu-Kα radiation, and had the following characteristic peaks expressed in angles 2θ: 11.5±0.2°, 14.5±0.2°, 14.8±0.2°, 15.1±0.2°, 16.9±0.2°, 17.6±0.2°, 18.8±0.2°, 19.3±0.2°, 20.0±0.2°, 20.8±0.2°, 21.5±0.2°, and 24.3±0.2°. Its spectrum is shown in FIG8 , indicating Form XIII.

[0177] (2) The off-white solid powder prepared in step (2) above was analyzed and identified by TA Q200 differential scanning calorimetry (DSC): the scanning speed was 10°C / min, and it contained two endothermic peaks at 129.0°C and 261.5°C, with an error tolerance of ±3°C. Its spectrum is shown in FIG9 .

[0178] (3) The off-white solid powder prepared in step (2) above was analyzed and identified by TA Q500 thermogravimetric (TGA): the scanning speed was 10°C / min, and the weight loss was about 14.71% between 30°C and 170°C. The spectrum is shown in FIG10 .

[0179] Test Example 1 Dynamic moisture adsorption experiment

[0180] Appropriate amounts of Form VI prepared in Example 1, the amorphous form prepared in Comparative Example 1, and Form XIII prepared in Comparative Example 3 were subjected to dynamic moisture sorption (DVS) testing. Table 4 shows the DVS test results for Form VI, the amorphous form, and Form XIII. As shown in Table 4, Form VI gained approximately 0.79% weight at 80% RH and approximately 1.34% weight at 95% RH (see Figure 11 , with a ±0.1% error margin for mass change), indicating slight hygroscopicity. The amorphous form gained approximately 4.55% weight at 80% RH and approximately 6.76% weight at 95% RH (see Figure 12 ), while Form XIII gained approximately 6.53% weight at 80% RH and approximately 14.45% weight at 95% RH (see Figure 13 ), indicating that all forms exhibited hygroscopicity. This indicates that Form VI exhibits lower hygroscopicity, facilitating long-term storage of pharmaceuticals.

[0181] Table 4

[0182] Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Guidelines for Hygroscopicity Test of Drugs in the Appendix of the 2010 edition of the Chinese Pharmacopoeia, experimental conditions: 25±0.2℃, 80% relative humidity):

[0183] Deliquescent: Absorbs sufficient water to form a liquid;

[0184] Highly hygroscopic: weight gain due to moisture absorption is not less than 15%;

[0185] Hygroscopic: weight gain due to moisture absorption is less than 15% but not less than 2%;

[0186] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0187] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%.

[0188] Test Example 2 Stability test in pure water and buffer solution

[0189] Form VI, amorphous form, Form V, and Form XIII of the compound were suspended in pure water and buffer solutions of varying pH values, respectively, and stirred at 25°C for 24 hours. The solids were filtered and sampled for XRPD analysis. The specific experimental results are shown in Table 5 below. Table 5 shows the stability of each form in pure water and buffer solutions. As shown in Table 5, Form VI remained unchanged after being suspended in pure water and buffer solutions at 25°C for 24 hours, while the amorphous form, Form V, and Form XIII transformed into other forms after being suspended in pure water and buffer solutions at 25°C for 24 hours, indicating that Form VI has superior stability.

[0190] Table 5

[0191] Test Example 3 Stability test of influencing factors

[0192] In accordance with the guidelines for stability testing of pharmaceutical preparations, influencing factor experiments were conducted on Form VI, amorphous form, and Form XIII of the compound, including high temperature testing, high humidity testing, and strong light exposure testing, to investigate factors influencing the stability of these forms. XRPD analysis was used to identify the forms under different conditions, and HPLC analysis was used to identify the purity under different conditions. The results for Form VI are shown in Figure 14 (in the figure, the intensity, from low to high, are 0 days, high temperature for 5 days, high temperature for 10 days, high temperature for 15 days, high temperature for 30 days, high humidity for 5 days, high humidity for 10 days, high humidity for 15 days, high humidity for 30 days, light exposure for 5 days, light exposure for 10 days, light exposure for 15 days, and light exposure for 30 days).

[0193] (1) High humidity test

[0194] Appropriate amounts of Form VI, amorphous form, and Form XIII samples were spread evenly into weighing bottles and placed in a constant temperature and humidity chamber at 25°C and 92.5±5%. Samples were then collected after 5, 10, 15, and 30 days, and their crystal forms were analyzed by X-ray powder diffraction (XRPD), and the sample purity was analyzed by HPLC. Table 6 shows the high humidity test results for Form VI, amorphous form, and Form XIII. As shown in Table 6, after 30 days of storage at 25°C and 92.5±5% RH, Form VI maintained its crystal form and its purity did not decrease significantly. However, after 30 days of storage at 25°C and 92.5±5% RH, the crystal forms of the amorphous form and Form XIII remained unchanged, but their purities decreased to varying degrees, indicating that Form VI has better stability.

[0195] Table 6

[0196] (2) High temperature test

[0197] Appropriate amounts of Form VI, amorphous form, and Form XIII samples were spread evenly into weighing bottles and placed in a 60°C drying oven. Samples were then collected after 5, 10, 15, and 30 days, and their crystal forms were analyzed by X-ray powder diffraction (XRPD). The purity of the samples was also analyzed by HPLC. Table 7 shows the high-temperature test results for Form VI, amorphous form, and Form XIII. As shown in Table 7, Form VI maintained its crystal form after 30 days at 60°C, but its purity decreased slightly. The amorphous form also maintained its crystal form after 30 days at 60°C, but its purity decreased significantly. Form XIII transformed after 5 days at 60°C, and its purity also decreased significantly after 30 days, indicating that Form VI has better stability.

[0198] Table 7

[0199] (3) Lighting test

[0200] Take appropriate amount of Form VI, amorphous form and Form XIII samples, spread them flatly into a weighing bottle, and place them under visible light 4500Lux±500Lux and ultraviolet light 1.7W*h / m 2 The samples were placed in a constant temperature and humidity chamber (25°C, RH 60% ± 5%), and then taken at 5, 10, 15, and 30 days. The crystal form was determined by X-ray powder diffraction (XRPD), and the purity of the samples was determined by HPLC. Table 8 shows the results of the illumination test of Form VI, amorphous form, and Form XIII. As shown in Table 8, Form VI exhibited a high irradiation rate under visible light of 4500 Lux ± 500 Lux and ultraviolet light of 1.7 W*h / m 2 The crystal form remained unchanged for 30 days under the conditions of visible light 4500Lux±500Lux and ultraviolet light 1.7W*h / m 2 After being placed under the conditions of 40 ° C for 30 days, the crystal form did not change, but the purity decreased significantly.

[0201] Table 8

[0202] Test Example 4 Accelerated stability test

[0203] Experimental Procedure: Form VI prepared in Example 1 was placed under accelerated stability conditions (40±2°C, RH=75±5%) for 1, 3, and 6 months before sampling and XRPD analysis. Table 9 shows the results of the accelerated stability test of Form VI. As shown in Table 9, Form VI maintained its crystalline form unchanged after 6 months under the accelerated stability conditions, demonstrating excellent physical and chemical stability.

[0204] Table 9

[0205] Test Example 5 Long-term stability test

[0206] Experimental Procedure: Form VI prepared in Example 1 was stored under long-term stability conditions (25±2°C, RH=60±5%) for 1, 6, 12, 18, and 24 months, and then samples were collected for XRPD analysis. Table 10 shows the long-term stability test results for Form VI. As shown in Table 10, Form VI maintained its crystalline form unchanged after 24 months under these conditions, with no significant decrease in purity, demonstrating excellent physical and chemical stability.

[0207] Table 10

[0208] Experimental Example 6 Comparative Study of the Morphologies of Form VI, Amorphous Form, and Form XIII

[0209] Experimental Procedure: Polarizing microscope images of Form VI prepared in Example 1, the amorphous solid prepared in Comparative Example 1, and Form XIII prepared in Comparative Example 3 were taken, as shown in Figures 15 to 17. As can be seen from Figures 15 to 17, the Form VI crystals are long, rod-shaped, and exhibit good dispersibility and flowability; the amorphous solid exhibits an irregular glassy state with significant agglomeration; and the Form XIII crystals are small, also exhibit agglomeration, and exhibit poor flowability.

[0210] Experimental Example 7: PK test of Form VI tablets in animals

[0211] Experimental Procedure: Tablets were prepared using the Form VI prepared in Example 1 as the API crystalline form, microcrystalline cellulose as the filler, croscarmellose sodium as the disintegrant, magnesium stearate as the anti-adherent, and fumaric acid as the pH adjuster as the basic formulation for in vivo animal PK testing. Table 11 shows the in vivo animal PK results of the Form VI formulation (beagle dogs, dosed at 10 mg / kg). As shown in Table 11, the Form VI tablets exhibited good in vivo drug exposure, meeting the required exposure levels.

[0212] Table 11

[0213] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A crystalline form VI of a (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide compound, characterized in that: The X-ray powder diffraction pattern of the crystalline form VI comprises diffraction peaks with the following 2θ angle values: 8.3±0.2°, 13.2±0.2° and 18.9±0.2°.

2. According to the crystal form VI of claim 1, it is characterized in that The X-ray powder diffraction pattern of the crystalline form VI comprises diffraction peaks with the following 2θ angle values: 8.3±0.2°, 13.2±0.2°, 13.6±0.2° and 18.9±0.2°.

3. According to the crystal form VI of claim 2, it is characterized in that The X-ray powder diffraction pattern of the crystalline form VI comprises diffraction peaks with the following 2θ angle values: 8.3±0.2°, 11.3±0.2°, 13.2±0.2°, 13.6±0.2°, 18.9±0.2° and 21.5±0.2°.

4. According to the crystal form VI of claim 3, it is characterized in that The X-ray powder diffraction pattern of the crystalline form VI contains diffraction peaks with the following 2θ angle values: 4.3±0.2°, 8.3±0.2°, 11.3±0.2°, 13.2±0.2°, 13.6±0.2°, 17.8±0.2°, 18.9±0.2° and 21.5±0.2°.

5. According to the crystal form VI of claim 4, it is characterized in that The X-ray powder diffraction pattern of the crystalline form VI contains diffraction peaks with the following 2θ angle values: 4.3±0.2°, 6.9±0.2°, 8.3±0.2°, 9.7±0.2°, 11.3±0.2°, 13.2±0.2°, 13.6±0.2°, 14.5±0.2°, 17.8±0.2°, 18.9±0.2°, 20.1±0.2° and 21.5±0.2°.

6. The crystal form VI according to claim 5, characterized in that: The crystalline form VI has an X-ray powder diffraction pattern substantially consistent with that in FIG1 .

7. The crystal form VI according to claim 1, characterized in that: The crystal form VI is an anhydrate.

8. The crystal form VI according to claim 1, characterized in that: The purity of the crystalline form VI is >85%; preferably, the purity of the crystalline form VI is >95%; preferably, the purity of the crystalline form VI is >99%.

9. The crystal form VI according to any one of claims 1 to 8, characterized in that: The melting point onset peak of the crystal form VI is at 218.5±3°C.

10. The crystal form VI according to claim 9, characterized in that: The crystal form VI has a DSC spectrum substantially consistent with that in FIG. 2 .

11. A method for preparing the crystalline form VI of the (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide compound according to any one of claims 1 to 10, characterized in that: The compound is added to a first solvent to dissolve it to form a clear solution, and then the clear solution is treated by a crystallization method to obtain the crystal form VI; the first solvent is selected from one or more of alcohols, carboxylates, nitriles, ketones, amides, sulfones, sulfoxides, carboxylic acids, nitro compounds, pyridines, furans, alkylbenzenes, and halogenated hydrocarbon polar solvents; or The compound is added to a second solvent, slurried, cooled, and separated to precipitate the crystal form VI; the second solvent is selected from one or more of alcohols, ethers, alkanes, carboxylates, nitriles, ketones or alkylbenzenes.

12. The preparation method according to claim 11, characterized in that: The crystallization method is to volatilize and crystallize the clear solution, volatilize the first solvent, and obtain the crystal form VI.

13. The preparation method according to claim 12, characterized in that: The first solvent is selected from ketone and / or carboxylic acid ester polar solvents; Preferably, the first solvent is selected from ketone polar solvents containing 3 to 6 carbon atoms and carboxylic acid ester polar solvents containing 3 to 10 carbon atoms.

14. The preparation method according to claim 11, characterized in that: The crystallization method is to evaporate and crystallize the clear solution to obtain the crystal form VI.

15. The preparation method according to claim 14, characterized in that: The first solvent is selected from halogenated hydrocarbons and / or ketone polar solvents; Preferably, the first solvent is selected from polar halogenated hydrocarbon solvents containing 1 to 6 carbon atoms and polar ketone solvents containing 3 to 6 carbon atoms.

16. The preparation method according to claim 11, characterized in that: The crystallization method is to add a poor solvent to the clear solution to precipitate the crystal form VI.

17. The preparation method according to claim 16, characterized in that: The first solvent is selected from one or more polar solvents of amides, halogenated hydrocarbons, sulfoxides, and furans; the poor solvent is selected from one or more polar solvents of alcohols, carboxylates, nitriles, ketones, alkanes, ethers, nitro compounds, and alkylbenzenes; Preferably, the first solvent is selected from halogenated hydrocarbon polar solvents, and the poor solvent is selected from ether solvents.

18. The preparation method according to claim 11, characterized in that: The second solvent is a ketone and / or nitrile solvent; Preferably, the second solvent is a ketone solvent containing 3 to 6 carbon atoms or a nitrile solvent containing 2 to 6 carbon atoms.

19. The preparation method according to claim 11 or 18, characterized in that: The volume mass ratio of the second solvent to the compound is 1 to 30 mL / g.

20. A pharmaceutical composition, characterized in that The invention comprises a therapeutically effective amount of the crystal form VI of any one of claims 1 to 10 and optionally a pharmaceutically acceptable carrier or auxiliary material.

21. Use of the crystalline form VI of the (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide compound according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 17 in the preparation of a medicament for preventing and / or treating neoplastic diseases, tumors, autoimmune diseases and inflammatory diseases.

22. The use according to claim 21, characterized in that The autoimmune diseases and inflammatory disorders are pemphigus vulgaris, rheumatoid arthritis, asthma, multiple sclerosis, systemic lupus erythematosus or allergies.

23. The use according to claim 22, characterized in that: The neoplastic disease tumor is a B-cell malignancy or a solid tumor.

24. The use according to claim 23, characterized in that The neoplastic disease tumor is chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma or multiple myeloma.

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