Solid of compound and preparation method therefor and use thereof

Abstract

The present disclosure provides a solid of (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (hereinafter referred to as "compound I") and a preparation method therefor, a pharmaceutical composition containing compound I, and a use of compound I in the preparation of a PRMT5 inhibitor drug.

Description

Solid compound and its preparation method and use Priority Declaration

[0001] This disclosure claims priority to Chinese patent application No. 202410211808.8, filed on February 26, 2024. This disclosure incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present disclosure relates to the field of crystal chemistry, and in particular to a solid of (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide. Background Art

[0003] (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide has the structure of formula (I), which is referred to herein as Compound I:

[0004] In the development of small molecule drugs, polymorphism refers to the phenomenon of a compound existing in multiple forms and is a significant factor affecting drug quality. A crystal is a solid in which the compound molecules are arranged in a three-dimensional, ordered microstructure, forming a crystalline lattice. An amorphous form is a solid lacking a long-range, ordered structure, formed by the disordered arrangement of the compound molecules within the microstructure. A compound may exist in one or more crystalline forms, but their existence and properties cannot be specifically predicted. The changes in properties caused by different crystalline forms can also improve the final dosage form. For example, such changes can increase solubility and thereby improve bioavailability, or improve the stability of the active ingredient. Or, more surprisingly, increase solubility while maintaining good stability and lower hygroscopicity. For Compound I, a comprehensive study of polymorphism is necessary to obtain a form that meets the pharmaceutical requirements of Compound I. Summary of the Invention

[0005] The technical problem to be solved by the present disclosure is to overcome the defect of Compound I lacking a pharmaceutical solid and improve its physical and chemical properties, thereby providing a solid of Compound I, which can be a crystal and / or amorphous form of an anhydrate or solvate.

[0006] Applicants have discovered solid forms of Compound 1 that are physically and chemically stable over a range of storage conditions and that can be subjected to additional processing.

[0007] In some embodiments, the solid of Compound 1 provided herein is crystalline.

[0008] In some embodiments, the solid form of Compound 1 provided herein is amorphous.

[0009] In some embodiments, the solid of Compound 1 provided herein is an anhydrate.

[0010] In some embodiments, the solid form of Compound 1 provided herein is a solvate, which may also be a hydrate; further, the solvent molecules and Compound 1 may be in a stoichiometric ratio or a non-stoichiometric ratio.

[0011] The present disclosure provides a crystal A of Compound 1 (hereinafter referred to as "Form A")

[0012] In some embodiments, Form A has an X-ray powder diffraction pattern substantially as shown in FIG1 using Cu-ka radiation.

[0013] In some embodiments, the thermogravimetric analysis / differential scanning calorimetry analysis diagram of Form A is substantially as shown in Figure 2. The results show that Form A loses 0.36% of its mass when heated from 31°C to 120°C, and an endothermic peak begins to appear near 224.0°C.

[0014] Without limitation, Form A is an anhydrate.

[0015] In some embodiments, the X-ray powder diffraction pattern of the crystalline form A has a diffraction angle 2θ value of 7.10°±0.2°, 8.63°±0.2°, 11.55°±0.2°, 12.40°±0.2°, 14.07°±0.2°, 16.01°±0.2°, 17.20°±0.2°, 17.78°±0.2°, 18.20°±0.2°, 19.16°±0.2°, There are characteristic peaks at any one, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16 of 19.77°±0.2°, 20.21°±0.2°, 21.43°±0.2°, 23.24°±0.2°, 24.25°±0.2°, and 29.02°±0.2°.

[0016] In some embodiments, the X-ray powder diffraction pattern of the crystalline form A has a characteristic peak at a 2θ value of 16.01°±0.2°, and arbitrarily has two characteristic peaks at 2θ values ​​of 8.63°±0.2°, 11.55°±0.2°, 17.78°±0.2°, 21.43°±0.2°, and 23.24°±0.2°.

[0017] In some embodiments, the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2θ values ​​of 8.63°±0.2° and 16.01°±0.2°, and arbitrarily has one characteristic peak at 2θ values ​​of 11.55°±0.2°, 17.78°±0.2°, 21.43°±0.2°, and 23.24°±0.2°.

[0018] In some embodiments, the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2θ values ​​of 8.63°±0.2°, 16.01°±0.2°, and 21.43°±0.2°.

[0019] In some embodiments, the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2θ values ​​of 8.63°±0.2°, 16.01°±0.2° and 21.43°±0.2°, and arbitrarily has one characteristic peak at 2θ values ​​of 11.55°±0.2°, 17.78°±0.2° and 23.24°±0.2°.

[0020] In some embodiments, the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2θ values ​​of 8.63°±0.2°, 11.55°±0.2°, 16.01°±0.2°, and 21.43°±0.2°.

[0021] In some embodiments, the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at diffraction angles 2θ of 8.63°±0.2°, 11.55°±0.2°, 16.01°±0.2°, 17.78°±0.2°, 21.43°±0.2°, and 23.24°±0.2°.

[0022] In some embodiments, the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at diffraction angles 2θ of 7.10°±0.2°, 8.63°±0.2°, 11.55°±0.2°, 12.40°±0.2°, 16.01°±0.2°, 17.20°±0.2°, 17.78°±0.2°, 18.20°±0.2°, 20.21°±0.2°, 21.43°±0.2°, and 23.24°±0.2°.

[0023] The present disclosure provides Crystal B of the compound (hereinafter referred to as "Form B").

[0024] In some embodiments, Form B has an X-ray powder diffraction pattern substantially as shown in FIG. 3 using Cu-ka radiation.

[0025] In some embodiments, the thermogravimetric analysis / differential scanning calorimetry analysis diagram of Form B is substantially as shown in Figure 4. The results show that Form B has a mass loss of approximately 2.24% when heated from 31°C to 120°C; the first endothermic peak appears at 43°C-90°C, which is a dehydration signal, and the second endothermic peak begins to appear around 209.6°C, which is a melting signal.

[0026] In some embodiments, the X-ray powder diffraction pattern of the crystalline form B has a diffraction angle 2θ value of 5.77°±0.2°, 8.25°±0.2°, 11.82°±0.2°, 13.07°±0.2°, 14.38°±0.2°, 15.62°±0.2°, 16.40°±0.2°, 17.41°±0.2°, 17.65°±0.2°, 18.49°±0.2°, There are characteristic peaks at any one, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16 of 20.02°±0.2°, 20.89°±0.2°, 21.16°±0.2°, 25.59°±0.2°, 26.01°±0.2°, and 28.83°±0.2°.

[0027] In some embodiments, the X-ray powder diffraction pattern of the crystalline form B has characteristic peaks at diffraction angles 2θ of 5.77°±0.2°, 13.07°±0.2°, 16.40°±0.2°, and 20.89°±0.2°.

[0028] In some embodiments, the X-ray powder diffraction pattern of the crystalline form B has characteristic peaks at diffraction angles 2θ of 5.77°±0.2°, 11.82°±0.2°, 13.07°±0.2°, 16.40°±0.2°, 20.89°±0.2° and 21.16°±0.2°.

[0029] In some embodiments, the X-ray powder diffraction pattern of the crystalline form B has characteristic peaks at diffraction angles 2θ of 5.77°±0.2°, 11.82°±0.2°, 13.07°±0.2°, 15.62°±0.2°, 16.40°±0.2°, 20.02°±0.2°, 20.89°±0.2°, 21.16°±0.2°, 25.59°±0.2°, and 26.01°±0.2°.

[0030] In some embodiments, Form B is a hydrate, and further, the ratio of water molecules to Compound I is non-stoichiometric.

[0031] The present disclosure provides Crystal D of the compound (hereinafter referred to as "Crystal Form D").

[0032] In some embodiments, Form D has an X-ray powder diffraction pattern substantially as shown in FIG. 9 using Cu-ka radiation.

[0033] In some embodiments, when heated from 31° C. to 240° C., Form D has two endothermic peaks and one exothermic peak. The first endothermic peak begins to appear at 167.58° C., and there is a melting point near 176.8° C.

[0034] In some embodiments, the X-ray powder diffraction pattern of the crystalline form D has diffraction angles 2θ of 4.12°±0.2°, 5.05°±0.2°, 8.04°±0.2°, 9.81°±0.2°, 11.72°±0.2°, 13.14°±0.2°, 14.61°±0.2°, 15.32°±0.2°, 15.70°±0.2°, 16.4 There are characteristic peaks at any one, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15 of 2°±0.2°, 18.52°±0.2°, 19.79°±0.2°, 21.29°±0.2°, 22.20°±0.2° and 25.28°±0.2°.

[0035] In some embodiments, the X-ray powder diffraction pattern of the crystalline form D has characteristic peaks at diffraction angles 2θ of 5.05°±0.2°, 11.72°±0.2°, 14.61°±0.2°, and 16.42°±0.2°.

[0036] In some embodiments, the X-ray powder diffraction pattern of the crystalline form D has characteristic peaks at diffraction angles 2θ of 4.12°±0.2°, 5.05°±0.2°, 8.04°±0.2°, 9.81°±0.2°, 11.72°±0.2°, 14.61°±0.2°, 15.32°±0.2°, 15.70°±0.2°, 16.42°±0.2°, 18.52°±0.2°, and 21.29°±0.2°.

[0037] The present disclosure provides Crystal E of the compound (hereinafter referred to as "Form E").

[0038] In some embodiments, the X-ray powder diffraction pattern of the crystalline form E has characteristic peaks at any one of the diffraction angles 2θ of 5.83°±0.2°, 10.95°±0.2°, 11.93°±0.2°, 14.05°±0.2°, 14.61°±0.2°, 14.98°±0.2°, 17.95°±0.2°, 18.70°±0.2°, 21.53°±0.2°, 24.01°±0.2°, and 25.22°±0.2°, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11.

[0039] In some embodiments, the X-ray powder diffraction pattern of the crystalline form E has characteristic peaks at diffraction angles 2θ of 5.83°±0.2°, 14.61°±0.2°, 14.98°±0.2°, 17.95°±0.2° and 21.53°±0.2°.

[0040] In some embodiments, when heated from 31° C. to 240° C., Form E has two endothermic peaks and one exothermic peak. The first endothermic peak begins to appear at 187.9° C., and there is a melting point near 192.9° C.

[0041] The present disclosure provides Crystal Form F of the compound (hereinafter referred to as "Form F").

[0042] In some embodiments, the X-ray powder diffraction pattern of the crystalline form F has characteristic peaks at any one of the diffraction angles 2θ of 5.83°±0.2°, 10.95°±0.2°, 11.93°±0.2°, 14.05°±0.2°, 14.61°±0.2°, 14.98°±0.2°, 17.95°±0.2°, 18.70°±0.2°, 21.53°±0.2°, 24.01°±0.2°, and 25.22°±0.2°, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11.

[0043] In some embodiments, the X-ray powder diffraction pattern of the crystalline form F has characteristic peaks at diffraction angles 2θ of 7.88°±0.2°, 10.37°±0.2°, 11.97°±0.2°, and 18.54°±0.2°.

[0044] In some embodiments, the X-ray powder diffraction pattern of the crystalline form F has characteristic peaks at diffraction angles 2θ of 7.88°±0.2°, 10.37°±0.2°, 11.97°±0.2°, 13.06°±0.2°, 16.74°±0.2°, 17.53°±0.2°, and 18.54°±0.2°.

[0045] The present disclosure provides a crystal O of a compound (hereinafter referred to as "form O").

[0046] In some embodiments, Form O has an X-ray powder diffraction pattern substantially as shown in Figure 31 using Cu-ka radiation.

[0047] In some embodiments, the DSC curve of Form O shows that Form O begins to have a melting endothermic peak at around 226.0°C and has a melting point at around 230.4°C.

[0048] In some embodiments, the X-ray powder diffraction pattern of the crystalline form O has characteristic peaks at any one of the diffraction angles 2θ values ​​of 9.24°±0.2°, 12.00°±0.2°, 12.31°±0.2°, 13.44°±0.2°, 13.95°±0.2°, 14.22°±0.2°, 17.23°±0.2°, 18.90°±0.2°, 21.15°±0.2°, 21.55°±0.2°, 26.26°±0.2°, and 28.22°±0.2°, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12.

[0049] In some embodiments, the X-ray powder diffraction pattern of the crystalline form O has a characteristic peak at a 2θ value of 9.24°±0.2°, and arbitrarily has two characteristic peaks at 2θ values ​​of 12.00°±0.2°, 12.31°±0.2°, 13.95°±0.2°, 14.22°±0.2°, 17.23°±0.2° and 18.90°±0.2°.

[0050] In some embodiments, the X-ray powder diffraction pattern of the crystalline form O has characteristic peaks at 2θ values ​​of 9.24°±0.2° and 17.23°±0.2°, and arbitrarily has one characteristic peak at 2θ values ​​of 12.00°±0.2°, 12.31°±0.2°, 13.95°±0.2°, 14.22°±0.2° and 18.90°±0.2°.

[0051] In some embodiments, the X-ray powder diffraction pattern of the crystalline form O has characteristic peaks at 2θ values ​​of 9.24°±0.2°, 12.00°±0.2°, and 17.23°±0.2°.

[0052] 37. In some embodiments, the X-ray powder diffraction pattern of the crystalline form O has characteristic peaks at 2θ values ​​of 9.24°±0.2°, 12.00°±0.2°, 12.31°±0.2° and 17.23°±0.2°.

[0053] In some embodiments, the X-ray powder diffraction pattern of the crystalline form O has characteristic peaks at diffraction angles 2θ of 9.24°±0.2°, 12.00°±0.2°, 12.31°±0.2°, 13.95°±0.2°, 14.22°±0.2°, 17.23°±0.2° and 18.90°±0.2°.

[0054] The present disclosure provides an amorphous form of Compound 1.

[0055] In some embodiments, the PLM image of the amorphous Compound 1 is shown in FIG33 , in which the PLM image lacks birefringence and exhibits a polygonal granular crystal habit.

[0056] In some embodiments, the XRPD pattern of the amorphous form of Compound 1 is shown in Figure 32, and the X-ray powder diffraction pattern has no obvious diffraction peaks.

[0057] In some embodiments, Compound 1 Amorphous Form exhibits no change in its XRPD pattern after DVS testing.

[0058] The present disclosure provides a pharmaceutical composition comprising a solid form of a compound of formula (I).

[0059] The present disclosure provides the use of a solid compound I in the preparation of a pharmaceutical preparation for treating diseases associated with PRMT5 inhibitors.

[0060] In order to improve the properties of Compound I and obtain a crystalline form with low hygroscopicity and high stability, the inventors of the present application studied Compound I through solid-liquid separation technology, suspension equilibrium method, volatilization method, antisolvent method, and cooling crystallization method, hoping to obtain a solid form suitable for pharmaceutical use.

[0061] Through creative work, the inventors of the present application unexpectedly obtained multiple solid forms of Compound I, such as hydrates, anhydrates, solvates and amorphous forms. Table 1

[0062] As shown in Table 1, Form A, Form B, Form D, Form E, Form F, Form O and amorphous form have low hygroscopicity and high crystallinity while maintaining high stability, and are more suitable for pharmaceutical development. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an XRPD pattern of Form A; Figure 2 is the TGA&DSC curve of Form A; FIG3 is an XRPD pattern of Form B; Figure 4 is the TGA&DSC curve of Form B; Figure 5 is a comparison of XRPD images of Form B before and after stability (top: heated to 120°C, bottom: before heating); FIG6 is a DVS diagram of Form B; FIG7 is a comparison of XRPD images of Form B before and after DVS testing (top: after testing, bottom: before testing); Figure 8 is a comparison of XRPD images of Form B after being placed at 25°C / 92.5% RH (from top to bottom: 3 days, 2 days, and 1 day, Form B reference); FIG9 is an XRPD pattern of Form D; Figure 10 is a comparison of XRPD images before and after the stability test of Form D (from top to bottom: heating to 218°C, heating to 120°C, Form D reference); FIG11 is a comparison of XRPD images of Form E before and after stability testing (top: Form O after heating, bottom: Form E for reference); FIG12 is an XRPD pattern of Form I; Figure 13 is the TGA & DSC curve of Form I; FIG14 is an XRPD pattern of Form J; Figure 15 is the TGA&DSC curve of Form J; Figure 16 shows the crystal form J 1 H-NMR spectrum; Figure 17 is a comparison of XRPD images before and after the stability test of Form J (from top to bottom: Form B reference, Form J heated to 180°C for crystal transformation The crystal form B is obtained, and the crystal form J is heated to 100 ° C to obtain a mixed crystal of the crystal form B and the crystal form J, and the crystal form J is used as a reference); Figure 18 is an XRPD pattern of Form L; Figure 19 is the TGA & DSC curve of Form L; Figure 20 is an XRPD pattern of Form M; Figure 21 shows the crystal form M 1 H NMR spectra; Figure 22 is the TGA & DSC curve of Form M; Figure 23 is an XRPD pattern of Form N; Figure 24 is the TGA & DSC curve of Form N; Figure 25 is an XRPD pattern of Form P; Figure 26 is the TGA & DSC curve of Form P; Figure 27 is a comparison of XRPD images before and after the stability test of Form P (from top to bottom: Form P is heated to 80°C and then transformed into Form A, Form P is Ratio, Form A reference); Figure 28 is an XRPD pattern of Form Q; Figure 29 is the TGA & DSC curve of Form Q; FIG30 is a comparison of XRPD images of Form Q before and after the stability test (from top to bottom; Form O, Form Q is heated to 100 degrees and transformed into Form O, Form Q (control); Figure 31 is an XRPD pattern of Form O; FIG32 is an XRPD pattern of amorphous form of Compound 1; Figure 33 is a PLM image of the amorphous form of Compound 1; FIG34 is a comparison of XRPD images of the amorphous form of Compound 1 before and after stability testing (top: after heating, bottom: before heating); Figure 35 is a comparison of XRPD images of the amorphous form of Compound 1 before and after the DVS test (top: after the test, bottom: before the test). DETAILED DESCRIPTION

[0063] Terms and Definitions

[0064] The present disclosure is further described in conjunction with the following examples, which describe in detail the preparation and use of the disclosed crystalline forms. It will be apparent to those skilled in the art that many changes in both materials and methods may be made without departing from the scope of the present disclosure.

[0065] The abbreviations used in this disclosure are explained as follows:

[0066] XRPD: X-ray powder diffraction

[0067] DSC: Differential Scanning Calorimetry

[0068] TGA: Thermogravimetric analysis

[0069] 1 HNMR: Liquid-state hydrogen nuclear magnetic spectroscopy

[0070] RH: relative humidity

[0071] DVS: Dynamic Water Sorption

[0072] PLM: Polarized Light Microscopy

[0073] XRPD patterns were obtained using a Bruker D8Advance diffractometer. Before the experiment, the voltage was set to 40 kV and the current was set to 40 mA. The sample was loaded onto a zero-background sample holder and scanned over an angle range of 2° to 40°. The scan step was set to 0.01°, and the wavelength of the X-ray used in the measurement was

[0074] Differential scanning calorimetry experiments were performed using a Mettler-Toledo DSC3 differential scanning calorimeter (DSC). Prior to the experiment, the heating rate and melting enthalpy were calibrated using indium as a reference material. The sample was placed in a standard 40 μL aluminum crucible and then covered with a perforated lid. The weight of the sample was accurately recorded. The sample pan containing the sample was placed in the sample cavity. At the reference position, a standard 40 μL aluminum crucible was placed, which was configured identically to the sample pan except that it did not contain the sample. DSC measurements were performed by heating the sample from 30°C to 300°C at a heating rate of 10°C / min. Nitrogen was purged during the experiment at a flow rate of 50 mL / min.

[0075] TGA data were acquired using a Mettler-Toledo TGA2. Prior to sample analysis, the TGA2 was calibrated with nickel. Samples were placed in an open aluminum pan, automatically weighed, and then placed in the TGA furnace. The furnace was heated from 31°C to 300°C at a heating rate of 10°C / min, with a nitrogen flow rate of 20 mL / min.

[0076] Moisture sorption and desorption data were acquired using a dynamic vapor sorption instrument (Model TA Discovery SA). At the beginning of the experiment, the sample was equilibrated at 25°C / 0% RH for 300 minutes. Subsequently, the humidity level was controlled and maintained over a range of 0% to 95% RH in 5% steps using nitrogen. A mass change rate of less than 0.02% / min over 10 minutes was considered equilibrium during testing, with a maximum equilibration time of 120 minutes.

[0077] The data of the samples were collected using a Bruker 400 MHz nuclear magnetic resonance spectrometer with DMSO-d6 as the solvent.

[0078] The "room temperature" is not a specific temperature value, but refers to the temperature range of 10-30°C.

[0079] The term "solvate" refers to a solid substance containing stoichiometric and non-stoichiometric solvent molecules (including water and organic solvents).

[0080] The "anhydrous substance" refers to a solid substance that does not contain crystal water or crystallization solvent.

[0081] The “characteristic peak” refers to a representative diffraction peak used to identify crystals. When tested using Cu-Ka radiation, the peak position can usually have an error of ±0.2°.

[0082] In the present disclosure, "crystal", "crystal form" or "amorphous" can be characterized by X-ray powder diffraction. The XRPD diffraction data of the crystal has fingerprint properties. Different crystal forms are identified in the art based on the diffraction data of XRPD. Those skilled in the art will select several representative peaks in the XRPD spectrum as characteristic peaks to characterize the crystal, and will comprehensively consider the peak position, peak intensity and peak shape when selecting characteristic peaks. However, those skilled in the art will understand that the X-ray powder diffraction pattern is affected by the conditions of the instrument, the preparation of the sample and the purity of the sample. The peak intensity of the diffraction peak in the X-ray powder diffraction pattern may also change with changes in the experimental conditions. In fact, the peak intensity of the diffraction peak in the X-ray powder diffraction pattern is related to the preferred orientation of the crystal. The diffraction peak intensity shown in the present disclosure is illustrative and not for absolute comparison. Therefore, when identifying whether the crystal forms are the same, the matching of the peak positions within the above-mentioned error range is the first priority.

[0083] It will be understood by those skilled in the art that the X-ray powder diffraction pattern of the crystalline form or amorphous form protected by the present disclosure does not have to be completely consistent with the X-ray powder diffraction patterns in the embodiments referred to herein, and any crystalline form or amorphous form having an X-ray powder diffraction pattern that is identical or similar to the characteristic peaks in these patterns falls within the scope of the present disclosure. For example, when peaks are marked in an X-ray powder diffraction pattern, it refers to any X-ray powder diffraction pattern that has an error within the range of ±0.2° from the peaks in these patterns. Those skilled in the art can compare the X-ray powder diffraction patterns listed in the present disclosure with the X-ray powder diffraction patterns of an unknown crystalline form to confirm whether the two sets of patterns reflect the same or different crystalline forms.

[0084] In some embodiments, the disclosed Form A, Form B, Form D, Form E, Form F, Form I, Form J, Form L, Form M, Form N, Form O, Form P, Form Q, and amorphous forms of Compound 1 are pure and substantially free of any other forms. As used herein, "substantially free" when referring to a new crystalline form or amorphous form means that the crystalline form or amorphous form contains less than 20% (by weight) of other forms, particularly less than 10% (by weight) of other forms, more particularly less than 5% (by weight) of other forms, and even more particularly less than 1% (by weight) of other forms.

[0085] The term "about" in this disclosure, when used to refer to a measurable value, such as mass, time, temperature, etc., means that there is a certain floating range around the specific value, which can be ±10%, ±5%, ±1%, ±0.5%, or ±0.1%.

[0086] Example 1 Preparation method of crystalline form and amorphous form

[0087] (1) Suspension equilibrium method

[0088] The suspension equilibrium method involves adding an appropriate amount of solid to a specified solvent under specified conditions, ensuring the presence of undissolved solid. The resulting suspension is magnetically stirred at 500 rpm in a sealed vial for 5 or 10 days at room temperature or 50°C. The supernatant is then centrifuged to separate the solid, which is then vacuum-dried at 40°C for approximately 20 hours.

[0089] (2) Antisolvent method

[0090] The samples were dissolved in different good solvents and filtered through a 0.22 μm nylon filter into a new sample vial. Different antisolvents were slowly added dropwise to each vial under magnetic stirring, stirring until a precipitate formed. The supernatant was then removed by centrifugation to isolate the solid, which was then vacuum-dried at 40°C for approximately 20 hours.

[0091] (3) Volatilization method

[0092] Different solvents were used to prepare evaporation method solutions, which were filtered into a new sample bottle using a 0.22 μm nylon filter membrane. The sample bottle was left open (covered with a perforated membrane) and placed in a fume hood. The solvent was naturally evaporated at room temperature. After a large amount of solid was precipitated, it was characterized by XRPD.

[0093] The preparation methods of the crystalline form and amorphous form provided in this application are shown in Table 2. Table 2

[0094] Example 2 Characterization and properties of Form A

[0095] The XRPD pattern of Form A is shown in Figure 1, and the XRPD data are shown in Table 3.

[0096] The TGA & DSC curves of Form A are shown in Figure 2. The results show that when Form A is heated from 31°C to 120°C, the mass loss is 0.36%, and an endothermic peak begins to appear around 223.96°C. Table 3

[0097] Example 3 Characterization and properties of Form B

[0098] The XRPD pattern of Form B is shown in Figure 3, and the XRPD data are shown in Table 4.

[0099] The TGA&DSC curves of Form B are shown in Figure 4. The results show that there is a mass loss of about 2.24% when heated from 31°C to 120°C; the first endothermic peak appears at 43°C-90°C, which is a dehydration signal, and the second endothermic peak begins to appear around 209.6°C, which is a melting signal.

[0100] Form B was heated to 120°C. The XRPD comparison diagrams before and after heating are shown in Figure 5. The results show that the crystal form did not change before and after heating, and Form B has good thermodynamic stability.

[0101] The DVS of Form B is shown in FIG6 . The moisture absorption weight gain of Form B under 40-80% RH conditions is approximately 0.6%. The XRPD comparison diagrams before and after the DVS test are shown in FIG7 .

[0102] Form B was stored at 25°C / 92.5% RH for 3 days. XRPD tests were performed after 1, 2, and 3 days, respectively. The results are shown in FIG8 . Form B showed no significant changes. Table 4

[0103] Example 4 Characterization and properties of Form D

[0104] The XRPD pattern of Form D is shown in Figure 9, and the XRPD data are shown in Table 5.

[0105] When heated from 31°C to 240°C, Form D has two endothermic peaks and one exothermic peak. The first endothermic peak begins to appear at 167.6°C, and the melting point is around 176.8°C.

[0106] Form D was heated to 120°C and 218°C at a heating rate of 10°C / min, and then cooled back to room temperature. The sample was subjected to XRPD analysis, and the results are shown in Figure 10. Results: Form D did not undergo transformation after being heated to 120°C. Table 5

[0107] Example 5 Characterization and properties of Form E

[0108] Form E has characteristic peaks at 5.83°±0.2°, 10.95°±0.2°, 11.93°±0.2°, 14.05°±0.2°, 14.61°±0.2°, 14.98°±0.2°, 17.95°±0.2°, 18.70°±0.2°, 21.53°±0.2°, 24.01°±0.2°, and 25.22°±0.2°.

[0109] When heated from 31°C to 240°C, Form E has two endothermic peaks and one exothermic peak. The first endothermic peak begins to appear around 187.9°C, and the melting point is around 192.9°C.

[0110] Form E was heated to 226°C at a heating rate of 10°C / min, then cooled back to room temperature and tested by XRPD. The test results are shown in Figure 11. The results show that when heated to 226°C, Form E transforms into Form O.

[0111] Example 6 Characterization and Properties of Form F

[0112] Form F has characteristic peaks at 6.50°±0.2°, 7.88°±0.2°, 10.37°±0.2°, 11.13°±0.2°, 11.97°±0.2°, 13.06°±0.2°, 15.78°±0.2°, 15.96°±0.2°, 16.74°±0.2°, 17.53°±0.2°, 18.54°±0.2°, and 25.45°±0.2°.

[0113] When heated from 31°C to 240°C, Form F has two endothermic peaks and one exothermic peak. The first endothermic peak begins to appear at 179.2°C, and the melting point is around 188.1°C.

[0114] Example 7 Characterization and Properties of Form I

[0115] The XRPD pattern of Form I is shown in Figure 12.

[0116] The TGA&DSC curve of Form I is shown in Figure 13, which shows six complex endothermic signals with onset temperatures of 40.0°C, 96.3°C, 165.3°C, 186.9°C, 212.1°C and 229.9°C, respectively; there is one exothermic peak with an onset temperature of 197.9°C.

[0117] Example 8 Characterization and Properties of Form J

[0118] The XRPD pattern of Form J is shown in FIG14 .

[0119] The TGA and DSC curves of Form J are shown in Figure 15. The TGA results show a 2.36% weight loss from 31°C to 120°C and a 4.26% weight loss from 120°C to 160°C. The DSC results show two endothermic peaks in Form J, at 99.2°C and 210.3°C, respectively.

[0120] Form J 1 The H-NMR results are shown in FIG16 , which indicate that there is 0.24 mol of residual toluene in Form J.

[0121] An attempt was made to remove the toluene solvent by heating. The XRPD comparison diagrams before and after heating are shown in Figure 17. The results show that Form J begins to transform when heated to 100°C and completely transforms to Form B when heated to 180°C.

[0122] Example 9 Characterization and Properties of Form L

[0123] The XRPD pattern of Form L is shown in FIG18 .

[0124] 1 H-NMR results showed that there was no obvious residual solvent in Form L, so Form L was a hydrate.

[0125] The TGA and DSC curves of Form L are shown in Figure 19. TGA results indicate a 9.75% mass loss upon heating from 31°C to 120°C, indicating that Form L begins to lose bound water at room temperature. DSC results indicate that Form L undergoes crystal transformation and recrystallization during the dehydration process.

[0126] Example 10 Characterization and properties of Form M

[0127] The XRPD pattern of Form M is shown in FIG20 .

[0128] Crystal form M 1 The HNMR results are shown in FIG21 , which indicate that there is no obvious organic solvent residue in Form M, and therefore Form M should be a hydrate.

[0129] The TGA and DSC curves of Form M are shown in Figure 22. The TGA results show that the mass loss of Form M is 10.9% when heated from 31°C to 120°C. Combining the TGA and DSC results, it can be seen that Form M begins to dehydrate at a lower temperature.

[0130] Example 11 Characterization and properties of Form N

[0131] The XRPD pattern of Form N is shown in FIG23 .

[0132] The TGA&DSC curves of Form N are shown in Figure 24. The results show that Form N recrystallizes into Form O after melting at 207.5°C.

[0133] Example 12 Characterization and Properties of Form P

[0134] The XRPD pattern of Form P is shown in FIG25 .

[0135] The TGA & DSC curves of Form P are shown in Figure 26. The TGA results show that the weight loss upon heating from 31°C to 120°C is 4.05%, which is consistent with the theoretical water content of Compound I monohydrate (4.04414% w / w).

[0136] It can be seen from the TGA and DSC curves that form P begins to dehydrate at around 40°C.

[0137] Further study of the stability of Form P shows that, as shown in Figure 27, Form P transforms into Form A when heated to 80°C. On the other hand, Form P transforms into Form A below 25°C / 45% RH.

[0138] Example 13 Characterization and Properties of Form Q

[0139] The XRPD pattern of Form Q is shown in Figure 28, and the XRPD data are shown in Table 6.

[0140] The TGA & DSC curves of Form Q are shown in Figure 29. The mass loss when heated from 31°C to 120°C is 3.97%, which is consistent with the theoretical water content of Compound I monohydrate.

[0141] It can be seen from the TGA and DSC curves that Form Q begins to dehydrate at around 40°C.

[0142] Further study of the stability of Form Q shows that Form Q dehydrates and crystallizes to Form O when heated to 100°C. On the other hand, Form Q begins to lose its crystalline water at 25°C / 40% RH. Table 6

[0143] Example 14 Characterization and Properties of Form O

[0144] The XRPD pattern of Form O is shown in Figure 31, and the XRPD data are shown in Table 7.

[0145] The DSC curve of Form O shows that Form O begins to have a melting endothermic peak at around 226.0°C and has a melting point at around 230.4°C.

[0146] The DVS results of Form O show that within the RH range of 0-80%, the moisture absorption weight gain of Form O is only 0.45%. Table 7

[0147] Example 15 Characterization and properties of amorphous

[0148] The XRPD pattern of the amorphous form of Compound I is shown in FIG32 , and the X-ray powder diffraction pattern has no obvious diffraction peaks.

[0149] The PLM image of the amorphous compound I is shown in Figure 33. The PLM image lacks birefringence and exhibits polygonal granular crystal habit.

[0150] As shown in FIG34 , when the amorphous compound I is heated to 100° C., its morphology does not change, indicating that the amorphous compound I has good thermal stability.

[0151] As shown in FIG35 , the XRPD pattern of the amorphous form of Compound 1 did not change after the DVS test, and thus the amorphous form of Compound 1 remained unchanged after the DVS test.

[0152] Example 16 Suspension competition between Form A and Form O

[0153] In suspension interconversion / competition studies, an excess of Compound I was added to ethanol, dichloromethane, isopropyl acetate, and n-heptane to form a suspension. The suspension was stirred at room temperature for approximately 20 hours and then filtered through a 0.22 μm nylon filter membrane. The resulting solution was labeled as the saturated Compound I solution. An aliquot of the saturated solution was taken and placed in a vial.

[0154] Form A and Form O were mixed in equal amounts in a glass bottle and added to ethanol, dichloromethane, isopropyl acetate, and n-heptane that had been pre-saturated with Compound I and centrifuged. The mixture was stirred at 500 rpm at room temperature. After one day, the solid was separated by centrifugation and characterized by XRPD. The results are shown in Table 8. The results show that Form A is the most thermodynamically stable form under the solvent system and room temperature conditions. Table 8

[0155] Example 17 Suspension competition of Form A, Form B and Form O

[0156] 206.4 mg of amorphous sample was weighed, 0.5 mL of ethylene glycol was added, and the mixture was stirred at 100 ° C for 1 h to obtain an ethylene glycol solution. 20.3 mg of Form B, 19.7 mg of Form O, and 20.0 mg of Form A solid samples were added after equal mixing, and magnetic stirring was continued at 100 ° C. After stirring overnight (18 h), the solution was dissolved; then 20.1 mg of Form B, 19.8 mg of Form O, and 19.7 mg of Form A were added after mixing, and magnetic stirring was continued at 100 ° C for 4 h after dissolving; then 20.5 mg of Form B, 20.3 mg of Form O, and 20.3 mg of Form A were added after mixing, and the suspension was still obtained after stirring at 100 ° C for 24 h. The solid wet sample was centrifuged and tested by XRPD, and the result was Form A.

[0157] 201.2 mg of amorphous sample was weighed, 0.5 mL of isoamyl alcohol was added, and the mixture was stirred at 100°C for 1 hour to obtain an isoamyl alcohol saturated solution. Then, 20.3 mg of Form B, 19.8 mg of Form O, and 19.8 mg of Form A solid samples were added and mixed. After magnetic stirring at 100°C for 24 hours, a suspension remained. The suspension was centrifuged and the solid wet sample was subjected to XRPD analysis, which showed Form A. Table 9

[0158] The results show that under the solvent system and temperature conditions, Form A is the most thermodynamically stable form.

[0159] The above embodiments are intended only to illustrate the technical concepts and features of the present disclosure. Their purpose is to enable those familiar with the art to understand the contents of the present disclosure and implement them accordingly. They are not intended to limit the scope of protection of the present disclosure. Any equivalent changes or modifications made in accordance with the spirit of the present disclosure are intended to be covered by the scope of protection of the present disclosure.

Claims

1. A solid form of a compound of formula (I), 2. The solid form of the compound of formula (I) according to claim 1, characterized in that The solid form is crystalline.

3. The solid form of the compound of formula (I) according to claim 1, characterized in that The solid form is anhydrous.

4. The solid form of the compound of formula (I) according to claim 1, characterized in that The solid form is a solvate.

5. The solid form of the compound of formula (I) according to claim 2, characterized by at least one of the following: (i) using Cu-ka radiation, an X-ray powder diffraction pattern comprising three or more peaks at 2θ values ​​selected from the group consisting of 7.10°±0.2°, 8.63°±0.2°, 11.55°±0.2°, 12.40°±0.2°, 16.01°±0.2°, 17.20°±0.2°, 17.78°±0.2°, 18.20°±0.2°, 20.21°±0.2°, 21.43°±0.2°, and 23.24°±0.2°; (ii) using Cu-kα radiation, the X-ray powder diffraction pattern thereof is substantially as shown in FIG1 ; (iii) An endothermic peak begins to appear at 224.0℃±3℃.

6. The solid form of the compound of formula (I) according to claim 5, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has a characteristic peak at a 2θ value of 16.01°±0.2°, and arbitrarily has two characteristic peaks at 2θ values ​​of 8.63°±0.2°, 11.55°±0.2°, 17.78°±0.2°, 21.43°±0.2°, and 23.24°±0.2°.

7. The solid form of the compound of formula (I) according to claim 5, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.63°±0.2° and 16.01°±0.2°, and arbitrarily has one characteristic peak at 2θ values ​​of 11.55°±0.2°, 17.78°±0.2°, 21.43°±0.2°, and 23.24°±0.2°.

8. The solid form of the compound of formula (I) according to claim 5, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.63°±0.2°, 16.01°±0.2° and 21.43°±0.2°.

9. The solid form of the compound of formula (I) according to claim 5, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.63°±0.2°, 16.01°±0.2° and 21.43°±0.2°, and arbitrarily has one characteristic peak at 2θ values ​​of 11.55°±0.2°, 17.78°±0.2° and 23.24°±0.2°.

10. The solid form of the compound of formula (I) according to claim 5, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.63°±0.2°, 11.55°±0.2°, 16.01°±0.2° and 21.43°±0.2°.

11. The solid form of the compound of formula (I) according to claim 5, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 16.01°±0.2°, 17.78°±0.2°, 21.43°±0.2°, and 23.24°±0.2°.

12. The solid form of the compound of formula (I) according to claim 5, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.63°±0.2°, 11.55°±0.2°, 16.01°±0.2°, 17.78°±0.2°, 21.43°±0.2°, and 23.24°±0.2°.

13. The solid form of the compound of formula (I) according to claim 2, characterized by at least one of the following: (i) using Cu-ka radiation, an X-ray powder diffraction pattern comprising three or more 2θ values ​​selected from the group consisting of 9.24°±0.2°, 12.00°±0.2°, 12.31°±0.2°, 13.44°±0.2°, 13.95°±0.2°, 14.22°±0.2°, 17.23°±0.2°, 18.90°±0.2°, 21.15°±0.2°, 21.55°±0.2°, 26.26°±0.2°, and 28.22°±0.2°; (ii) an X-ray powder diffraction pattern substantially as shown in FIG31 ; (iii) a melting endothermic peak begins to appear at 226.0°C ± 3°C; (iv) a melting point at 230.4°C ± 3°C; (v) The weight gain from moisture absorption at 0-80% RH is less than 0.5%.

14. The solid form of the compound of formula (I) according to claim 13, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has a characteristic peak at a 2θ value of 9.24°±0.2°, and arbitrarily has two characteristic peaks at 2θ values ​​of 12.00°±0.2°, 12.31°±0.2°, 13.95°±0.2°, 14.22°±0.2°, 17.23°±0.2° and 18.90°±0.2°.

15. The solid form of the compound of formula (I) according to claim 13, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 9.24°±0.2° and 17.23°±0.2°, and arbitrarily has one characteristic peak at 2θ values ​​of 12.00°±0.2°, 12.31°±0.2°, 13.95°±0.2°, 14.22°±0.2° and 18.90°±0.2°.

16. The solid form of the compound of formula (I) according to claim 13, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 9.24°±0.2° and 12.00°±0.2°, and arbitrarily has one characteristic peak at 2θ values ​​of 12.31°±0.2°, 13.95°±0.2°, 14.22°±0.2°, 17.23°±0.2° and 18.90°±0.2°.

17. The solid form of the compound of formula (I) according to claim 13, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 9.24°±0.2°, 12.00°±0.2° and 17.23°±0.2°.

18. The solid form of the compound of formula (I) according to claim 13, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 9.24°±0.2°, 12.00°±0.2°, 12.31°±0.2° and 17.23°±0.2°.

19. The solid form of the compound of formula (I) according to claim 13, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 9.24°±0.2°, 12.00°±0.2°, 12.31°±0.2°, 13.95°±0.2°, 14.22°±0.2°, 17.23°±0.2° and 18.90°±0.2°.

20. The solid of the compound of formula (I) according to claim 2, characterized in that At least one of the following: (i) using Cu-ka radiation, an X-ray powder diffraction pattern comprising three or more 2θ values ​​selected from the group consisting of 5.77°±0.2°, 8.25°±0.2°, 11.82°±0.2°, 13.07°±0.2°, 15.62°±0.2°, 16.40°±0.2°, 20.02°±0.2°, 20.89°±0.2°, 21.16°±0.2°, 25.59°±0.2°, and 26.01°±0.2°; (ii) an X-ray powder diffraction pattern substantially as shown in FIG3 ; (iii) a melting endothermic peak began to appear at 209.6°C ± 3°C; (iv) after storage at 25°C / 92.5% RH for 3 days, has an X-ray powder diffraction pattern substantially the same as (i) or (ii).

21. The solid form of the compound of formula (I) according to claim 20, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has a characteristic peak at a 2θ value of 5.77°±0.2°, and arbitrarily has two characteristic peaks at 2θ values ​​of 8.25°±0.2°, 11.82°±0.2°, 13.07°±0.2°, 16.40°±0.2°, 20.02°±0.2° and 20.89°±0.2°.

22. The solid form of the compound of formula (I) according to claim 20, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.77°±0.2° and 8.25°±0.2°, and arbitrarily has one characteristic peak at 2θ values ​​of 11.82°±0.2°, 13.07°±0.2°, 16.40°±0.2°, 20.02°±0.2°, 20.89°±0.2° and 21.16°±0.2°.

23. The solid form of the compound of formula (I) according to claim 2, characterized by at least one of the following: (i) using Cu-ka radiation, an X-ray powder diffraction pattern comprising three or more 2θ values ​​selected from the group consisting of 4.12°±0.2°, 5.05°±0.2°, 8.04°±0.2°, 9.81°±0.2°, 11.72°±0.2°, 14.61°±0.2°, 15.32°±0.2°, 15.70°±0.2°, 16.42°±0.2°, 18.52°±0.2°, and 21.29°±0.2°; (ii) an X-ray powder diffraction pattern substantially as shown in FIG9 ; (iii) an endothermic peak began to appear at 167.6°C ± 3°C; (iv) There is a melting point at 176.8°C ± 3°C.

24. The solid form of the compound of formula (I) according to claim 23, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has a characteristic peak at a 2θ value of 4.12°±0.2°, and arbitrarily has two characteristic peaks at 2θ values ​​of 5.05°±0.2°, 11.72°±0.2°, 14.61°±0.2°, 16.42°±0.2°, and 18.52°±0.2°.

25. The solid form of the compound of formula (I) according to claim 23, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 4.12°±0.2° and 14.61°±0.2°, and randomly has one characteristic peak at 2θ values ​​of 5.05°±0.2°, 11.72°±0.2°, 16.42°±0.2°, and 18.52°±0.2°.

26. The solid form of the compound of formula (I) according to claim 2, characterized by at least one of the following: (i) using Cu-ka radiation, an X-ray powder diffraction pattern comprising four or more 2θ values ​​selected from the group consisting of 5.83°±0.2°, 10.95°±0.2°, 11.93°±0.2°, 14.05°±0.2°, 14.61°±0.2°, 14.98°±0.2°, 17.95°±0.2°, 18.70°±0.2°, 21.53°±0.2°, 24.01°±0.2°, and 25.22°±0.2°; (ii) an endothermic peak began to appear at 187.9°C ± 3°C; (iii) There is a melting point at 192.9°C ± 3°C.

27. The solid form of the compound of formula (I) according to claim 26, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.83°±0.2°, 14.61°±0.2°, 14.98°±0.2°, 17.95°±0.2° and 21.53°±0.2°.

28. The solid form of a compound of formula (I) according to claim 2, characterized by at least one of the following: (i) using Cu-ka radiation, an X-ray powder diffraction pattern comprising four or more 2θ values ​​selected from the group consisting of 7.88°±0.2°, 10.37°±0.2°, 11.97°±0.2°, 13.06°±0.2°, 16.74°±0.2°, 17.53°±0.2°, and 18.54°±0.2°; (ii) an endothermic peak began to appear at 179.2°C ± 3°C; (iii) The melting point occurs at 188.1°C ± 3°C.

29. The solid form of the compound of formula (I) according to claim 28, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.88°±0.2°, 10.37°±0.2°, 11.97°±0.2° and 18.54°±0.2°.

30. The solid form of the compound of formula (I) according to claim 1, characterized in that The X-ray powder diffraction pattern has no obvious diffraction peaks and substantially contains no other forms of the compound of formula (I).

31. A solid form of a compound of formula (I) according to claim 30, characterized by at least one of the following: (i) The X-ray powder diffraction pattern is basically consistent with Figure 32; (ii) Polarized light microscopy (PLM) profiles lack birefringence.

32. The solid form of the compound of formula (I) according to claim 31, characterized in that The polarized light microscopy (PLM) profile is essentially as shown in FIG33 .

33. A solid form of a compound of formula (I) according to claim 31, characterized in that After dynamic moisture sorption (DVS) test, its X-ray powder diffraction pattern is basically the same as (i).

34. A solid form of a compound of formula (I) according to claim 31, characterized in that The morphology remains unchanged below 100°C.

35. A pharmaceutical composition comprising a solid form of a compound of formula (I) according to any one of claims 1 to 34.

36. Use of a solid form of a compound of formula (I) according to any one of claims 1 to 34 or a pharmaceutical composition according to claim 35 in the preparation of a medicament for treating diseases associated with PRMT5 inhibitors.

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