3,4-dihydroisoquinoline compounds in solid form, processes for their preparation and uses thereof

Abstract

The present application provides a solid form of a compound represented by formula (A), a crystalline form of a compound represented by formula (A) and a crystal form thereof, a pharmaceutical composition comprising the same and uses thereof. The solid form of the compound represented by formula (A) is convenient for transfer and weighing, and has high purity, preferably the crystal form has good crystallinity, low hygroscopicity and good physical and chemical stability, and is suitable for storage as a bulk drug.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and relates to a solid form, a crystalline form and a specific crystal form of a 3,4-dihydroisoquinoline compound, a preparation method thereof, a pharmaceutical composition containing the same and application thereof in the medical field. BACKGROUND

[0002] Protein arginine methyltransferases (PRMTs) are a class of S-adenosyl methionine (SAM or AdoMet) dependent methyltransferases, which are enzymes capable of catalyzing protein arginine methylation reactions, and specifically, are responsible for transferring a methyl group from AdoMet to the guanidino nitrogen atom at the end of the arginine residue of histones or other proteins. PRMTs play an important role in protein methylation, such as participating in alternative splicing, post-transcriptional regulation, RNA processing, cell proliferation, cell differentiation, apoptosis and tumor formation, etc. According to the different ways of catalyzing arginine methylation, the members of the PRMTs family can be divided into three categories: PRMT1-4, PRMT6 and PRMT8 belong to type I, which catalyze monomethylation and asymmetric dimethylation; PRMT5 and PRMT9 belong to type II, which catalyze symmetric dimethylation; and PRMT7 belongs to type III, which can catalyze monomethylation.

[0003] PRMT5 was first isolated from a protein complex associated with Jak2 (Janus tyrosine kinase 2) in a yeast two-hybrid study by Pollack et al., and is also known as JBP1 (jak-binding protein 1). PRMT5 not only regulates the processes of gene transcription and protein modification, but also has the effects of regulating cell proliferation, differentiation and apoptosis in the growth process of tumor cells. The overexpression of PRMT5 is found in various tumors or cancers, and is a very potential tumor treatment target. For example, it has been shown that PRMT5 is up-regulated in solid tumors (e.g., lung cancer, bone cancer, gastric cancer, pancreatic cancer, adenoid cystic carcinoma, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, brain cancer, pituitary adenoma, melanoma, epidermoid carcinoma) and hematological tumors (e.g., lymphoma, leukemia, chronic and acute leukemia, acute myeloid leukemia). So far, the development of PRMT5 inhibitors is still in the early stage. GSK3326595 developed by GSK is in the highest research and development state of phase II clinical. JNJ-64619178 developed by Janssen, PF-06939999 developed by Pfizer and PRT-543 developed by Prelude Therapeutics are all in phase I clinical.

[0004] WO2021244542A1 discloses a series of structurally novel PRMT5 inhibitors, including compound PR-4 (a compound as shown in the following Formula (A)).

[0005] SUMMARY

[0006] WO2021244542A1 does not disclose the physical form of the compound as shown in Formula (A). The inventors obtained the compound as shown in Formula (A) as a gum (or colloidal, oily substance) according to the preparation method disclosed in WO2021244542A1, and tried various methods but failed to obtain a solid form of the compound as shown in Formula (A). Surprisingly, the inventors found a method that can convert the compound as shown in Formula (A) from a gum to a solid, thereby obtaining a solid form of the compound as shown in Formula (A).

[0007] In a first aspect, the present application provides a compound as shown in Formula (A) in a solid form,

[0008]

[0009] According to some embodiments of the present application, the compound as shown in Formula (A) in a solid form has an infrared spectrum comprising characteristic peaks (±4 cm -1 ) at 3360, 3260, 2919, 1664, 1620, 1533; preferably, an infrared spectrum comprising characteristic peaks (±4 cm -1 ) at 3360, 3260, 2919, 1664, 1620, 1533, 1455, 1050; further preferably, an infrared spectrum comprising characteristic peaks (±4 cm -1 ) at 3360, 3260, 3151, 2919, 1664, 1620, 1533, 1455, 1362, 1117, 1050, 979, 878, 743; further preferably, an infrared spectrum substantially as shown in Figure 1 .

[0010] According to some embodiments of the present application, the compound as shown in Formula (A) in a solid form is a compound as shown in Formula (A) in a crystalline form.

[0011] According to some embodiments of the present application, the compound as shown in Formula (A) in a crystalline form is a compound as shown in Formula (A) in a hydrate form; preferably, a compound as shown in Formula (A) in a monohydrate form.

[0012] According to some embodiments of the application, the monohydrate is crystalline Form I.

[0013] According to some embodiments of the application, the crystalline Form I of the compound of Formula (A) has an X-ray powder diffraction pattern, expressed in angles 2Q, using Cu-Ka radiation, comprising the following characteristic diffraction peaks (±0.2°): 4.5, 16.2, 16.8, 18.9, 23.5.

[0014] According to some embodiments of the application, the crystalline Form I of the compound of Formula (A) has an X-ray powder diffraction pattern, expressed in angles 2Q, using Cu-Ka radiation, comprising the following characteristic diffraction peaks (±0.2°): 4.5, 16.2, 16.8, 18.9, 19.4, 23.5.

[0015] According to some embodiments of the application, the crystalline Form I of the compound of Formula (A) has an X-ray powder diffraction pattern, expressed in angles 2Q, using Cu-Ka radiation, comprising the following characteristic diffraction peaks (±0.2°): 4.5, 16.2, 16.8, 18.9, 19.4, 20.0, 20.6, 23.5.

[0016] According to some embodiments of the application, the crystalline Form I of the compound of Formula (A) has an X-ray powder diffraction pattern, expressed in angles 2Q, using Cu-Ka radiation, comprising the following characteristic diffraction peaks (±0.2°): 4.5, 7.5, 13.4, 16.2, 16.8, 18.9, 19.4, 20.0, 20.6, 23.5.

[0017] According to some embodiments of the application, the crystalline Form I of the compound of Formula (A) has an X-ray powder diffraction pattern, expressed in angles 2Q, using Cu-Ka radiation, comprising the following characteristic diffraction peaks (±0.2°): 4.5, 7.5, 13.4, 16.2, 16.8, 18.9, 19.4, 20.0, 20.6, 22.2, 23.5.

[0018] According to some embodiments of the application, the crystalline Form I of the compound of Formula (A) has an X-ray powder diffraction pattern, expressed in angles 2Q, using Cu-Ka radiation, comprising the following characteristic diffraction peaks (±0.2°): 4.5, 7.5, 13.4, 14.5, 15.0, 16.2, 16.8, 18.9, 19.4, 20.0, 20.6, 22.2, 23.5.

[0019] According to some embodiments of the application, the crystalline Form I of the compound of Formula (A) has an X-ray powder diffraction pattern, expressed in angles 2 theta, using Cu-Ka radiation, comprising the following characteristic diffraction peaks (±0.2°): 4.5, 7.5, 13.4, 14.5, 15.0, 16.2, 16.8, 17.6, 18.9, 19.4, 20.0, 20.6, 22.2, 23.5, 26.7.

[0020] According to some embodiments of the application, the crystalline Form I of the compound of Formula (A) has an X-ray powder diffraction pattern, expressed in angles 2 theta, using Cu-Ka radiation, comprising the following characteristic diffraction peaks (±0.2°): 4.5, 7.5, 13.4, 14.5, 15.0, 16.2, 16.8, 17.6, 18.3, 18.9, 19.4, 20.0, 20.6, 22.2, 23.5, 26.7.

[0021] According to some embodiments of the application, the crystalline Form I of the compound of Formula (A) has an X-ray powder diffraction pattern, expressed in angles 2 theta, using Cu-Ka radiation, comprising the following characteristic diffraction peaks (±0.2°): 4.5, 7.5, 13.4, 14.5, 15.0, 16.2, 16.8, 17.6, 18.9, 19.4, 20.0, 20.6, 22.2, 23.5, 26.7. Figure 2 or Figure 4 According to some embodiments of the application, the crystalline Form I of the compound of Formula (A) has an X-ray powder diffraction pattern, expressed in angles 2 theta, using Cu-Ka radiation, comprising the following characteristic diffraction peaks (±0.2°): 4.5, 7.5, 13.4, 14.5, 15.0, 16.2, 16.8, 17.6, 18.9, 19.4, 20.0, 20.6, 22.2, 23.5, 26.7.

[0022] According to some embodiments of the application, the crystalline Form I of the compound of Formula (A) has a TGA test with a weight loss of 3.4% ± 0.5% between room temperature and 135 °C ± 5 °C.

[0023] According to some embodiments of the application, the crystalline Form I of the compound of Formula (A) has a purity value of at least 95%; preferably, at least 95.5%; preferably, at least 96%; preferably, at least 96.5%; preferably, at least 97%; preferably, at least 97.5%; preferably, at least 98%; preferably, at least 98.5%; preferably, at least 99%.

[0024] According to some embodiments of the application, the crystalline Form II of the compound of Formula (A).

[0025] According to some embodiments of the application, the crystalline Form II of the compound of Formula (A) has an X-ray powder diffraction pattern, expressed in angles 2 theta, using Cu-Ka radiation, comprising the following characteristic diffraction peaks (±0.2°): 4.6, 9.3, 13.7, 16.4, 18.5.

[0026] According to some embodiments of the application, the crystalline Form II of the compound of Formula (A) has an X-ray powder diffraction pattern, expressed in terms of 2 theta (θ) angles using Cu-Ka radiation, comprising the following characteristic diffraction peaks (±0.2°): 4.6, 9.3, 13.7, 14.1, 16.4, 18.5.

[0027] According to some embodiments of the application, the crystalline Form II of the compound of Formula (A) has an X-ray powder diffraction pattern, expressed in terms of 2 theta (θ) angles using Cu-Ka radiation, comprising the following characteristic diffraction peaks (±0.2°): 4.6, 9.3, 13.7, 14.1, 16.4, 18.5, 19.5.

[0028] According to some embodiments of the application, the crystalline Form II of the compound of Formula (A) has an X-ray powder diffraction pattern, expressed in terms of 2 theta (θ) angles using Cu-Ka radiation, comprising the following characteristic diffraction peaks (±0.2°): 4.6, 9.3, 13.7, 14.1, 16.4, 18.5, 19.5, 23.1.

[0029] According to some embodiments of the application, the crystalline Form II of the compound of Formula (A) has an X-ray powder diffraction pattern, expressed in terms of 2 theta (θ) angles using Cu-Ka radiation, comprising the following characteristic diffraction peaks (±0.2°): 4.6, 9.3, 13.7, 14.1, 16.4, 18.5, 19.5, 23.1. Figure 5

[0030] In a second aspect, the present application provides a composition comprising at least 95% of the compound of Formula (A) in solid form and the remainder impurities.

[0031] According to some embodiments of the application, the composition comprises at least 95.5%, at least 96%, at least 96.5%, at least 97%, at least 97.5%, at least 98%, at least 98.5%, or at least 99% of the compound of Formula (A) in solid form and the remainder impurities.

[0032] According to some embodiments of the application, the compound of Formula (A) in solid form is as described in the first aspect.

[0033] In a third aspect, the present application provides a crystalline composition comprising one or both of the crystalline Form I of the compound of Formula (A) or the crystalline Form II of the compound of Formula (A).

[0034] According to some embodiments of the application, the crystalline Form I of the compound of Formula (A) comprises more than 50%, more than 60%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, or more than 95% by weight of the crystalline composition.

[0035] ​In a fourth aspect, the present application provides a pharmaceutical composition comprising the solid form of the compound of formula (A), the crystalline form of the compound of formula (A), the crystalline form I of the compound of formula (A), the crystalline form II of the compound of formula (A), or the composition of the second aspect, or the crystalline composition of the third aspect, optionally, further comprising a pharmaceutically acceptable carrier.

[0036] In a fifth aspect, the present application provides use of the solid form of the compound of formula (A), the crystalline form of the compound of formula (A), the crystalline form I of the compound of formula (A), the crystalline form II of the compound of formula (A), or the composition of the second aspect, or the crystalline composition of the third aspect, or the pharmaceutical composition of the fourth aspect in the manufacture of a medicament.

[0037] According to some embodiments of the present application, the medicament is for the manufacture of a medicament for preventing and / or treating a cell proliferative disease; preferably, the cell proliferative disease is a tumor or a cancer; further preferably, the tumor or cancer is a hematological tumor or a solid tumor; more preferably, a malignant hematological tumor or an advanced solid tumor; more preferably, a relapsed / refractory hematological tumor or an advanced malignant solid tumor.

[0038] According to some embodiments of the present application, the medicament is for the manufacture of a medicament for preventing and / or treating a disease mediated at least in part by PRMT5.

[0039] According to some embodiments of the present application, the disease mediated at least in part by PRMT5 is a cell proliferative disease.

[0040] According to some embodiments of the present application, the cell proliferative disease is a tumor or a cancer; preferably, the tumor or cancer is a hematological tumor or a solid tumor; further preferably, a malignant hematological tumor or an advanced solid tumor; more preferably, a relapsed / refractory hematological tumor or an advanced malignant solid tumor.

[0041] According to some embodiments of the present application, the tumor or cancer is selected from lung cancer, bone cancer, stomach cancer, pancreatic cancer, adenoid cystic carcinoma, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, brain cancer, pituitary adenoma, melanoma, epidermoid carcinoma, and chronic and acute leukemia; preferably, the acute leukemia is acute myeloid leukemia (AML).

[0042] In a sixth aspect, the present application provides a method for preparing a solid form of the compound of formula (A), comprising crystallizing the compound of formula (A) in a non-solid state in an aqueous solvent to obtain the solid form of the compound of formula (A).

[0043] According to the preparation method of the present application, the non-solid compound of formula (A) is in the aqueous solvent for 5 hours to 5 days; preferably for 10 hours to 4 days; preferably for 12 hours to 3 days; preferably for 24 hours to 2 days; for example, 5 hours, or 6 hours, or 7 hours, or 8 hours, or 9 hours, or 10 hours, or 11 hours, or 12 hours, or 13 hours, or 14 hours, or 15 hours, or 16 hours, or 17 hours, or 18 hours, or 19 hours, or 20 hours, or 21 hours, or 22 hours, or 23 hours, or 24 hours, or 25 hours, or 26 hours, or 27 hours, or 28 hours, or 29 hours, or 30 hours, or 31 hours, or 32 hours, or 33 hours, or 34 hours, or 35 hours, or 36 hours, or 37 hours, or 38 hours, or 39 hours, or 40 hours, or 41 hours, or 42 hours, or 43 hours, or 44 hours, or 45 hours, or 46 hours, or 47 hours, or 48 hours.

[0044] According to some embodiments of the present application, the aqueous solvent, wherein the volume fraction of water is at least 10%; preferably at least 20%, preferably at least 25%, preferably at least 30%, preferably at least 35%, preferably at least 40%, preferably at least 45%, preferably at least 50%, preferably at least 55%, preferably at least 60%, preferably at least 65%, preferably at least 70%, preferably at least 75%, preferably at least 80%, preferably at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 96%, preferably at least 97%, preferably at least 98%, preferably at least 99%, preferably 100%.

[0045] According to some embodiments of the present application, the aqueous solvent, the balance is an organic solvent or an inorganic solvent that is miscible with water; preferably, the balance is an organic solvent that is miscible with water.

[0046] According to the preparation method of the present application, the aqueous solvent is a mixed solvent of an organic solvent and water; preferably, the organic solvent is added first to dissolve the non-solid compound of formula (A), and then water is added.

[0047] According to the preparation method of the present application, the organic solvent is an organic solvent that is miscible with water, for example, an alcohol solvent, a nitrile solvent, a heterocyclic organic solvent, DMF, DMSO, etc.; specifically, for example, methanol, ethanol, isopropanol, n-butanol, acetonitrile, 2-methylfuran, 2-methyltetrahydrofuran, acetone, glycerol, ethylene glycol, tetrahydrofuran, pyridine, DMF, DMSO, etc. Preferably, the organic solvent is acetonitrile.

[0048] According to the preparation method of the present application, the compound of formula (A) is crystallized from water to obtain the compound of formula (A) in solid form. Preferably, according to the preparation method of the present application, the compound of formula (A) in solid form is crystalline form I of the compound of formula (A).

[0049] In a seventh aspect, the present application provides a preparation method of crystalline form I of the compound of formula (A), which comprises dissolving the crude compound of formula (A) in an organic solvent, adding water, optionally adding seed crystals, optionally including a step of adding water again, and crystallizing to obtain the crystalline form I of the compound of formula (A).

[0050] According to the preparation method of the present application, the seed crystals, also known as seed particles, are crystalline form I of the compound of formula (A).

[0051] According to the preparation method of the present application, the organic solvent is a water-miscible organic solvent, for example, an alcohol solvent, a nitrile solvent, a heterocyclic organic solvent, DMF, DMSO, etc.; specifically, for example, methanol, ethanol, isopropanol, n-butanol, acetonitrile, 2-methylfuran, 2-methyltetrahydrofuran, acetone, glycerol, ethylene glycol, tetrahydrofuran, pyridine, DMF, DMSO, etc. Preferably, the organic solvent is acetonitrile.

[0052] According to the preparation method of the present application, the amount of water added is such that the volume fraction of water in the system is at least 10%, preferably at least 20%, preferably at least 25%, preferably at least 30%, preferably at least 35%, preferably at least 40%, preferably at least 45%, preferably at least 50%, preferably at least 55%, preferably at least 60%, preferably at least 65%, preferably at least 70%, preferably at least 75%, preferably at least 80%, preferably at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 96%, preferably at least 97%, preferably at least 98%, preferably at least 99%.

[0053] According to the preparation method of the sixth and seventh aspects of the present application, the amount of organic solvent used is appropriate to dissolve or dissolve the compound of formula (A).

[0054] According to the preparation method of the present application, the crude product is prepared according to the method disclosed in WO2021244542A1, or any known method disclosed in other prior art or a combination thereof, or a replacement, combination or improvement of the method disclosed in WO2021244542A1 and / or other prior art. Preferably, the form of the crude product can be non-solid or semi-solid (e.g., oil, gel, colloid), poor solid or poor purity solid, etc.

[0055] According to the preparation method of the sixth and seventh aspects of the present application, the temperature of the crystallization process can be controlled, and the temperature of the crystallization process is -20°C to room temperature, preferably -5°C to room temperature, preferably -5°C to 10°C, more preferably 0°C to 10°C, and more preferably 0°C to 5°C.

[0056] According to the preparation method of the sixth and seventh aspects of the present application, the separation step is any suitable method, and the separation is preferably selected from suction filtration, centrifugation, filtration, and suction filtration.

[0057] According to the preparation method of the sixth and seventh aspects of the present application, the drying step is further included.

[0058] According to the preparation method of the sixth and seventh aspects of the present application, the drying method can use any suitable known method, and the drying method is preferably room temperature drying, room temperature vacuum drying, drying at 50°C±5°C, drying at 60°C±5°C, or drying at 65°C±5°C. Regardless of the drying method, the solvent residue in the obtained product should meet the quality standards.

[0059] Definitions and explanations

[0060] The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular phrase or term should not be construed as indefinite or unclear unless specifically defined, but should be understood according to the ordinary meaning.

[0061] The compound of formula (A) mentioned in the present application can exist in specific stereoisomeric forms, including cis and trans isomers, (R)- and (S)-enantiomers, and racemic mixtures thereof, etc. The compound of the present application can contain a carbon-nitrogen double bond in the E or Z configuration, wherein the term "E" represents the higher order substituents on the opposite side of the carbon-nitrogen double bond, and the term "Z" represents the higher order substituents on the same side of the carbon-nitrogen double bond (determined by the Cahn-Ingold Prelog priority rules), and the compound of the present application can also exist in the form of a mixture of "E" and "Z" isomers, preferably, the compound of the present application exists in the form of an E isomer. The substituents around the heterocycloalkyl group are in the cis or trans configuration.

[0062] The "solid form" mentioned in the present application refers to a compound in a solid form, including but not limited to a crystalline form and an amorphous form of the compound, etc.

[0063] The "crystalline form" mentioned in the present application refers to a compound in a crystalline form, including but not limited to an anhydrous and solvent-free form, a hydrate form, and a solvate form.

[0064] The term "solvate" is intended to mean an association or complex of one or more solvent molecules and a compound of the application, whether chemical or physical in nature. It is understood by those skilled in the art that a solvate of a compound of the application can be a hydrate.

[0065] The term "hydrate" is intended to mean an association or complex of water molecules and a compound of the application, whether chemical or physical in nature.

[0066] The "anhydrous and solvent-free form" means that the compound of the application is free of water molecules or solvent molecules, or that water molecules or solvent molecules are present in an intermolecularly bound manner, for example, in an adsorbed manner.

[0067] The term "crystalline composition" means a solid form comprising one or more of the specific crystalline forms of the compounds of the application, for example, in an embodiment according to the application, it comprises the crystalline form I of the compound of formula (A) mentioned in the application. Furthermore, the crystalline composition can optionally comprise, in addition to the crystalline form of the application, other crystalline forms, other crystalline forms or other amorphous forms of the compounds of the application, or impurities in addition to these substances. It will be understood by those skilled in the art that the sum of the contents of the components in the crystalline composition should be 100%.

[0068] The "room temperature" is the room temperature in the conventional sense of the art, generally 10 to 30°C, preferably 25°C ± 5°C.

[0069] In the context of the present application, in the X-ray powder diffractogram, 2Θ is the diffraction angle, and the 2Θ values are all in degrees (°).

[0070] The term "substantially" or "substantially as shown in the figure" in the context of X-ray powder diffraction patterns means that a substantially pure form of a crystalline form has at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the peaks in its powder X-ray diffraction pattern appearing in the given pattern. Further, as the amount of a form in a product is gradually reduced, some of the diffraction peaks attributed to that form in the X-ray powder diffraction pattern can be lost due to the sensitivity of the instrument. In addition, there can be slight errors in the position of the peaks for any given form, as is known in the art of crystallography. For example, the position of the peaks can shift due to changes in the instrument, temperature of the sample during analysis, sample movement, or calibration of the instrument, and the error in the measurement of the 2-theta values is typically about ± 0.2°. Thus, this error should be taken into account in determining the structure of each form, and the term "substantially" or "substantially as shown in the figure" is intended to encompass such differences in the position of the diffraction peaks, to ± 0.2°.

[0071] The term "cell proliferative disorder" as used herein refers to a condition in which a population of cells is growing at a rate that is less than or greater than the expected rate under given physiological conditions.

[0072] The term "tumor" includes benign, malignant, and borderline tumors, with malignant tumors collectively referred to as cancer.

[0073] The term "prevent" as used herein refers to the reduction in the frequency or delay in the onset of symptoms of a medical condition in a subject when a compound or drug (e.g., a combination product as claimed in the present application) is administered to a subject as compared to a subject not administered the compound or drug.

[0074] The term "treat" as used herein refers to alleviating, relieving, or improving the symptoms of a disease or condition, ameliorating the underlying metabolic cause of symptoms, inhibiting the disease or symptoms, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.

[0075] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" means a carrier or excipient that does not cause an appreciable level of stimulation to an organism and does not interfere with the biological activity and properties of the active compound.

[0076] "Jelly" as referred to herein, also known as "gel" or "oil", is a state similar to an oil, a non-solid form.

[0077] The intermediate compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the specific embodiments set forth below with other chemical synthetic methods well known in the art, and equivalents thereof as appreciated by those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present application.

[0078] The chemical reactions of the specific embodiments of the present application are performed in solvents appropriate to the reagents and materials employed and suitable for the chemical transformations being effected. In the event that solvents are not specifically mentioned, the reaction can be performed in any solvent or mixture of solvents of choice. In order to obtain the compounds of the present application, it can be necessary to modify or select the synthetic sequence or reaction route based on the reagents and materials available.

[0079] The present application will now be described in detail by examples, which are not intended to limit the present application in any manner.

[0080] All the solvents used in the present application are commercially available and can be used without further purification.

[0081] Technical effects

[0082] The solid form of the compound represented by formula (A), the crystalline form of the compound represented by formula (A), and the crystal form I of the compound represented by formula (A) provided by the present application have one or more of the following beneficial effects:

[0083] (1) The solid form of the compound represented by formula (A) is obtained accidentally for the first time, and is easy to separate, purify, transfer and weigh;

[0084] (2) The crystalline form of the compound represented by formula (A) is obtained accidentally for the first time, and has good crystallinity, and is easy to separate, purify, transfer and weigh;

[0085] (3) The solid form of the compound represented by formula (A), the crystalline form of the compound represented by formula (A), and / or the crystal form I of the compound represented by formula (A) has high purity;

[0086] (4) The crystal form I of the compound represented by formula (A) has good physical and chemical stability;

[0087] (5) The crystal form I of the compound represented by formula (A) has low hygroscopicity, and is suitable for storage as a raw drug;

[0088] (6) The preparation method of the solid form of the compound represented by formula (A), the crystalline form of the compound represented by formula (A), and / or the crystal form I of the compound represented by formula (A) is simple, feasible, economical and environmentally friendly, and is conducive to industrial application. BRIEF DESCRIPTION OF DRAWINGS

[0089] Figure 1 : The infrared spectrum of the compound of formula (A) of Example 1.

[0090] Figure 2 X-ray powder diffraction pattern of crystalline Form I of the compound of Formula (A) of Example 1.

[0091] Figure 3 Thermogravimetric analysis pattern of crystalline Form I of the compound of Formula (A) of Example 2.

[0092] Figure 4 X-ray powder diffraction pattern of crystalline Form I of the compound of Formula (A) of Example 2.

[0093] Figure 5 X-ray powder diffraction pattern of crystalline Form II of the compound of Formula (A) of Example 3. DETAILED DESCRIPTION

[0094] 1. X-ray powder diffractometer (XRPD)

[0095]

[0096] 2. Thermogravimetry Analysis (TGA)

[0097] Instrument model TGA 2 Test sample Example 2 Sample amount 2-10 mg Sample pan Alumina crucible, covered Temperature range 50～300℃ Heating rate 20°C / min Protective gas Nitrogen

[0098] 3. Nuclear Magnetic Resonance Spectroscopy (NMR)

[0099] Instrument model: Bruker 400M NMR spectrometer (Bruker, GER)

[0100] Content and test solvent: 1 H-NMR, test solvent is DMSO-d6.

[0101] 4. High Performance Liquid Chromatography (HPLC)

[0102] Detection instrument: Waters e2695 (high performance liquid chromatograph)

[0103]

[0104] 5. Hygroscopicity

[0105] The method in the Chinese Pharmacopoeia was used for the determination, and the specific test method was as follows:

[0106] 1) Take a dry stoppered glass weighing bottle (outer diameter 50 mm, height 15 mm) and place it in a suitable 25℃±1℃ constant temperature and dryness box (place ammonium chloride saturated solution in the lower part) one day before the test, and accurately weigh the weight (m1);

[0107] 2) Take an appropriate amount of test sample and lay it in the above weighing bottle, the thickness of the test sample is generally about 1 mm, and accurately weigh the weight (m2);

[0108] 3) Open the weighing bottle and place the cap in the above constant temperature and humidity conditions for 24 hours;

[0109] 4) Cover the weighing bottle cap and accurately weigh the weight (m3);

[0110] Weight gain percentage=(m3-m2) / (m2-m1)×100%;

[0111] 5) Description of hygroscopicity characteristics and definition of hygroscopicity weight gain:

[0112] Hygroscopicity characteristics Weight gain ratio Very hygroscopic Weight gain by hygroscopicity not less than 15% Hygroscopic Weight gain by hygroscopicity less than 15% but not less than 2% Slightly hygroscopic Weight gain by hygroscopicity less than 2% but not less than 0.2% Non- or almost non-hygroscopic Weight gain by hygroscopicity less than 0.2%

[0113] 5, moisture determination

[0114] Instrument model 915KF Ti-Touch Test sample Example 2, Preparation Example 1 Sample amount 100 mg Solvent Anhydrous methanol Karl Fischer reagent Type KFR-08

[0115] 6, infrared spectroscopy (Infrared Spectroscopy, IR)

[0116] Detection instrument: PerkinElmer Spectrum 100 infrared spectrum analyzer

[0117] Test method: take 3 mg of sample, dilute and press tablet with KBr, detect at room temperature, specific parameters are: detection range: 4000-400 cm -1 Wave number, resolution: 4 cm -1 .

[0118] In order to better understand the content of the present application, the following specific examples will be further described, but the specific implementation is not limited to the content of the present application. The test method without specific conditions in the following preparation example, example, comparative example or test example is selected according to conventional method and condition, or according to the commodity instruction.

[0119] Preparation example 1: preparation of compound of formula (A)

[0120] The preparation of the compound represented by formula (A) is carried out according to the method disclosed in WO2021244542A1, and the compound represented by formula (A) is obtained as a gel.

[0121]

[0122] Example 1: Preparation of a solid form of the compound of formula (A)

[0123] The gelatinous material (5 g) from Preparation 1 was weighed into a glass bottle, purified water (30 mL) was added, and the mixture was stirred at 30 ± 10 °C for about 12 hours. A small amount of white solid began to appear in the water, but a large amount of oil remained stuck to the walls of the bottle. The oil was scraped off and allowed to suspend in the water. Stirring was continued, and every so often, the material stuck to the walls of the bottle was scraped off and suspended in the water. This was repeated until a white solid suspension was obtained (about 48 hours of stirring). The solid was collected by suction filtration and dried under vacuum at room temperature to give a solid (4.2 g) having a purity of 98.37%.

[0124] The sample was tested by infrared spectroscopy, IR (KBr, cm -1 ): 3360.26, 3260.09, 3150.93, 2918.80, 1663.63, 1619.99, 1533.16, 1455.26, 1361.97, 1116.71, 1049.94, 978.79, 878.02, 743.00. The spectrum is shown in Figure 1 .

[0125] The sample was tested by X-ray powder diffraction and was shown to be a crystalline solid (Form I) with good crystallinity. The spectrum is shown in Figure 2 , and the main XRPD diffraction peak data are shown in Table 1.

[0126] Table 1. XRPD diffraction peak data for Form I of Example 1

[0127]

[0128] Example 2: Preparation of a solid form (Form I) of the compound of formula (A)

[0129] The gelatinous material (10 g) from Preparation 1 was weighed into a glass bottle, acetonitrile (10 mL) was added to dissolve the material, and purified water (10 mL) was added dropwise. A small amount of the sample from Example 1 was added as a seed crystal, and the mixture was stirred for 12 hours. Solid began to precipitate. Purified water (200 mL) was added, and the mixture was stirred at a temperature of 5 °C ± 5 °C for 2 days. A large amount of solid precipitated, and the solid was collected by suction filtration and dried under vacuum at room temperature to give a solid (8 g) having a purity of 99.55%.

[0130] The sample was tested by TGA, and the TGA plot showed a weight loss of 3.4735% between room temperature and 132 °C. The plot is shown in Figure 3 . This was determined and calculated to be a monohydrate.

[0131] The obtained solid sample was subjected to X-ray powder diffraction, which showed that it was a crystalline solid (Form I) with good crystallinity, and the spectrum is shown in Figure 4 The main XRPD diffraction peak data thereof are shown in Table 2.

[0132] Table 2. XRPD diffraction peak data table of Form I of Example 2

[0133]

[0134]

[0135] Example 3: Preparation of Form II of the compound of formula (A)

[0136] The sample of Example 1 was weighed on the temperature-variable sample stage of the Panalytical Empyrean XRPD, and heated to 70°C under N2protection, and the sample was collected.

[0137] The sample was subjected to X-ray powder diffraction, which showed that it was a crystalline solid (Form II) with good crystallinity, and the spectrum is shown in Figure 5 The main XRPD diffraction peak data thereof are shown in Table 3.

[0138] Table 3. XRPD diffraction peak data table of Form II of Example 3

[0139]

[0140] Comparative Example

[0141] During the development process, the inventors found that the compound of formula (A) could not be obtained in a solid form under various research methods and different experimental conditions. Exemplary schemes include, but are not limited to, the following comparative examples:

[0142] Comparative Example 1: Attempt to prepare the compound of formula (A) in a solid form

[0143] The sample obtained in Preparation Example 1 was subjected to various physical operations such as reduced pressure rotary evaporation (circulating water pump, water bath 50°C, 2-5 hours), reduced pressure vacuum (oil pump, 3-8 hours), or multiple column chromatography purification, and no changes in the sample properties were observed.

[0144] Comparative Example 2: Attempt to prepare the compound of formula (A) in a solid form

[0145] The sample obtained in Preparation Example 1 was added with the solvents shown in the following table, respectively, and crystallization was attempted. The specific test methods and results are shown in the following table. Finally, no solid was obtained, and the sample still showed a gel-like morphology.

[0146] Table 4. Attempted conditions and results for preparing the compound of formula (A) in a solid form

[0147]

[0148]

[0149] [1] : clear after stirring at room temperature for 3 days, still clear after stirring at 5°C for 3 days, no solid or oil / gel after adding anti-solvent n-hexane or methyl tert-butyl ether, transferred to room temperature and evaporated.

[0150] [2] : still no solid or oil / gel after stirring at room temperature for 3 days, transferred to room temperature and evaporated.

[0151] Test Example 1 : Hygroscopicity Test

[0152] Take the sample of Example 2 and the sample of Preparation Example 1, place them at room temperature / 92.5% RH for 24 hours, then take the samples for moisture titration, the results are shown in the following table.

[0153] Table 5. Hygroscopicity Test Results

[0154]

[0155] Results: The crystal form I obtained in Example 2 was detected to have no or little hygroscopicity under high humidity conditions; while the sample of Preparation Example 1 showed obvious hygroscopicity (weight gain 3.1%) after being placed for 24 hours, and the sample was still in the form of a gel after being placed at high humidity for 24 hours, without solid being produced.

[0156] Test Example 2: Stability Test

[0157] Take the sample of Example 2, place it at 40°C / 75% RH in an open container. Then take the sample for detection, the results are shown in the following table.

[0158] Table 6. Stability Test Results

[0159]

[0160] Results: The crystal form I obtained in Example 2 was detected to have no or little hygroscopicity under high humidity conditions; while the sample of Preparation Example 1 showed obvious hygroscopicity (weight gain 3.1%) after being placed for 24 hours, and the sample was still in the form of a gel after being placed at high humidity for 24 hours, without solid being produced.

[0161] Although the foregoing application has been described in some detail for purposes of clarity and understanding, it will be apparent that certain changes and modifications can be practiced within the scope of the appended claims, in view of the teachings of the present application.

Claims

1. A compound of formula (A) in solid form, ， in, The solid form of the compound represented by formula (A) is a monohydrate form of the compound represented by formula (A), and the X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation comprises the following characteristic diffraction peaks: 4.5±0.2°, 16.2±0.2°, 16.8±0.2°, 18.9±0.2°, and 23.5±0.2°.

2. The solid form of the compound represented by formula (A) according to claim 1, having an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation, comprising the following characteristic diffraction peaks: 4.5±0.2°, 16.2±0.2°, 16.8±0.2°, 18.9±0.2°, 19.4±0.2°, and 23.5±0.2°.

3. The solid form of the compound of formula (A) according to claim 1, having an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation, comprising the following characteristic diffraction peaks: 4.5±0.2°, 16.2±0.2°, 16.8±0.2°, 18.9±0.2°, 19.4±0.2°, 20.0±0.2°, 20.6±0.2°, and 23.5±0.2°.

4. The solid form of the compound of formula (A) according to claim 1, having an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation, comprising the following characteristic diffraction peaks: 4.5±0.2°, 7.5±0.2°, 13.4±0.2°, 16.2±0.2°, 16.8±0.2°, 18.9±0.2°, 19.4±0.2°, 20.0±0.2°, 20.6±0.2°, and 23.5±0.2°.

5. The solid form of the compound of formula (A) according to claim 1, having an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation, comprising the following characteristic diffraction peaks: 4.5±0.2°, 7.5±0.2°, 13.4±0.2°, 16.2±0.2°, 16.8±0.2°, 18.9±0.2°, 19.4±0.2°, 20.0±0.2°, 20.6±0.2°, 22.2±0.2°, and 23.5±0.2°.

6. The solid form of the compound of formula (A) according to claim 1, having an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation, comprising the following characteristic diffraction peaks: 4.5±0.2°, 7.5±0.2°, 13.4±0.2°, 14.5±0.2°, 15.0±0.2°, 16.2±0.2°, 16.8±0.2°, 18.9±0.2°, 19.4±0.2°, 20.0±0.2°, 20.6±0.2°, 22.2±0.2°, and 23.5±0.2°.

7. The solid form of the compound of formula (A) according to claim 1, having an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation, comprising the following characteristic diffraction peaks: 4.5±0.2°, 7.5±0.2°, 13.4±0.2°, 14.5±0.2°, 15.0±0.2°, 16.2±0.2°, 16.8±0.2°, 17.6±0.2°, 18.9±0.2°, 19.4±0.2°, 20.0±0.2°, 20.6±0.2°, 22.2±0.2°, 23.5±0.2°, and 26.7±0.2°.

8. The solid form of the compound of formula (A) according to claim 1, having an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation, comprising the following characteristic diffraction peaks: 4.5±0.2°, 7.5±0.2°, 13.4±0.2°, 14.5±0.2°, 15.0±0.2°, 16.2±0.2°, 16.8±0.2°, 17.6±0.2°, 18.3±0.2°, 18.9±0.2°, 19.4±0.2°, 20.0±0.2°, 20.6±0.2°, 22.2±0.2°, 23.5±0.2°, and 26.7±0.2°.

9. The solid form of the compound of formula (A) according to claim 1, having an X-ray powder diffraction pattern substantially as shown in Figure 2 or Figure 4 using Cu-Kα radiation.

10. The solid form of the compound of formula (A) according to any one of claims 1 to 9, which has a weight loss of 3.4%±0.5% between room temperature and 135°C±5°C as determined by TGA.

11. A composition comprising at least 95% of the solid form compound represented by formula (A) according to any one of claims 1 to 10 and the remainder being impurities.

12. A pharmaceutical composition comprising the solid form of the compound represented by formula (A) according to any one of claims 1 to 10, or the composition according to claim 11; and optionally, further comprising a pharmaceutically acceptable carrier.

13. Use of the solid form compound of formula (A) according to any one of claims 1 to 10, the composition according to claim 11, or the pharmaceutical composition according to claim 12 in the preparation of a medicament for preventing and / or treating a disease mediated at least in part by PRMT5. The use according to claim 13 , wherein the disease at least partially mediated by PRMT5 is a cell proliferative disease.

15. Use of the solid form compound of formula (A) according to any one of claims 1 to 10, the composition according to claim 11, or the pharmaceutical composition according to claim 12 in the preparation of a medicament for preventing and / or treating a cell proliferative disease. The use according to claim 14 or 15, wherein the cell proliferative disease is a tumor. The use according to claim 16 , wherein the tumor is a blood tumor or a solid tumor. The use according to claim 16 , wherein the tumor is a malignant hematological tumor or an advanced solid tumor.

19. The use according to claim 16, wherein the tumor is a relapsed or refractory hematological tumor or an advanced malignant solid tumor.

20. The method of claim 16, wherein the tumor is selected from the group consisting of lung cancer, bone cancer, gastric cancer, pancreatic cancer, adenoid cystic carcinoma, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, brain cancer, pituitary adenoma, melanoma, epidermoid carcinoma, and chronic and acute leukemia. The use according to claim 20, wherein the acute leukemia is acute myeloid leukemia.

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