Solid 3, 4-dihydroisoquinoline compound as well as preparation method and application thereof

Abstract

The invention provides a solid compound shown in a formula (A), a crystalline compound shown in the formula (A), a crystal form of the compound, a pharmaceutical composition containing the compound and application of the pharmaceutical composition. The solid compound shown in the formula (A) is convenient to transfer and weigh and has high purity, and the preferable crystal form has good crystallinity, low hygroscopicity and good physical and chemical stability and is suitable for being stored as a raw material medicine. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, 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 Art

[0002] Protein arginine methyltransferases (PRMTs) are a class of S-adenosylmethionine (SAM or AdoMet)-dependent methyltransferases that can catalyze protein arginine methylation reactions. Specifically, they are responsible for transferring the methyl group from AdoMet to the guanidinium 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. According to the different ways of catalyzing arginine methylation, members of the PRMTs family can be divided into three categories: PRMT1-4, PRMT6, and PRMT8 belong to type I, catalyzing monomethyl and asymmetric dimethyl; PRMT5 and PRMT9 belong to type II, catalyzing symmetric dimethyl; PRMT7 belongs to type III and can catalyze monomethyl.

[0003] PRMT5 was first isolated from a protein complex bound to Jak2 (Janus tyrosinekinase 2) by Pollack et al. in yeast two-hybrid studies, so it is also called JBP1 (jak-binding protein 1). PRMT5 can not only regulate the process of gene transcription and protein modification, but also has the function of regulating cell proliferation, differentiation, and apoptosis during the growth of tumor cells. Overexpression of PRMT5 is found in many tumors or cancers, and it is a very potential target for tumor treatment. For example, studies have shown that PRMT5 is upregulated 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 blood tumors (e.g., lymphoma, leukemia, chronic and acute leukemia, acute myeloid leukemia). So far, the research and development of PRMT5 inhibitors is in the early stages. GSK3326595 released by GSK is in Phase II clinical trials. JNJ-64619178 developed by Janssen, PF-06939999 developed by Pfizer, and PRT-543 developed by Prelude Therapeutics are all in Phase I clinical trials.

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

[0005] Summary of the invention

[0006] WO2021244542A1 does not record the physical form of the compound shown in the obtained formula (A). According to the preparation method described in WO2021244542A1, the compound shown in formula (A) obtained by the inventor is a colloid (or colloid, oil), and after trying various methods, no solid form of the compound shown in formula (A) was obtained. Unexpectedly, the inventor discovered a method that can convert the compound shown in formula (A) from a colloid to a solid, thereby obtaining a solid form of the compound shown in formula (A).

[0007] In a first aspect, the present invention provides a compound of formula (A) in solid form,

[0008]

[0009] According to some embodiments of the present invention, the compound of formula (A) in solid form, using the KBr tablet method, has an infrared spectrum including characteristic peaks at the following positions (±4 cm -1 ): 3360, 3260, 2919, 1664, 1620, 1533; preferably, the KBr tablet method is used, and its infrared spectrum includes characteristic peaks at the following positions (±4 cm -1 ): 3360, 3260, 2919, 1664, 1620, 1533, 1455, 1050; further preferably, using the KBr tablet method, its infrared spectrum includes characteristic peaks at the following positions (±4cm -1 ): 3360, 3260, 3151, 2919, 1664, 1620, 1533, 1455, 1362, 1117, 1050, 979, 878, 743; further preferably, the KBr tableting method is used, which has substantially Figure 1 Infrared spectrum shown.

[0010] According to some embodiments of the present invention, the compound of formula (A) in solid form is a compound of formula (A) in crystalline form.

[0011] According to some embodiments of the present invention, the crystalline form of the compound of formula (A) is a hydrate form of the compound of formula (A); preferably, it is a monohydrate form of the compound of formula (A).

[0012] According to some embodiments of the present invention, the monohydrate is in crystalline form I.

[0013] According to some embodiments of the present invention, the crystalline form I of the compound represented by formula (A) has an X-ray powder diffraction pattern expressed at an angle of 2θ using Cu-Kα 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 present invention, the crystalline form I of the compound represented by formula (A) has an X-ray powder diffraction pattern expressed at an angle of 2θ using Cu-Kα 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 present invention, the crystalline form I of the compound represented by formula (A) has an X-ray powder diffraction pattern expressed at an angle of 2θ using Cu-Kα 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 present invention, the crystalline form I of the compound represented by formula (A) has an X-ray powder diffraction pattern expressed at an angle of 2θ using Cu-Kα 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 present invention, the crystalline form I of the compound represented by formula (A) has an X-ray powder diffraction pattern expressed at an angle of 2θ using Cu-Kα 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, and 23.5.

[0018] According to some embodiments of the present invention, the crystalline form I of the compound represented by formula (A) has an X-ray powder diffraction pattern expressed at an angle of 2θ using Cu-Kα 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, and 23.5.

[0019] According to some embodiments of the present invention, the crystalline form I of the compound represented by formula (A) has an X-ray powder diffraction pattern expressed at an angle of 2θ using Cu-Kα 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 present invention, the crystalline form I of the compound represented by formula (A) has an X-ray powder diffraction pattern expressed at an angle of 2θ using Cu-Kα 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 present invention, the crystalline form I of the compound represented by formula (A) has substantially the following properties when irradiated with Cu-Kα: Figure 2 or Figure 4 The X-ray powder diffraction pattern is shown.

[0022] According to some embodiments of the present invention, the crystalline form I of the compound represented by formula (A) has a weight loss of 3.4%±0.5% between room temperature and 135°C±5°C using TGA testing.

[0023] According to some embodiments of the present invention, the crystalline form I of the compound represented by 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 present invention, the compound represented by formula (A) in the crystalline form is crystal form II.

[0025] According to some embodiments of the present invention, the crystalline form II of the compound represented by formula (A) has an X-ray powder diffraction pattern expressed at an angle of 2θ using Cu-Kα 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 present invention, the crystalline form II of the compound represented by formula (A) has an X-ray powder diffraction pattern expressed at an angle of 2θ using Cu-Kα 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 present invention, the crystalline form II of the compound represented by formula (A) has an X-ray powder diffraction pattern expressed at an angle of 2θ using Cu-Kα 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 present invention, the crystalline form II of the compound represented by formula (A) has an X-ray powder diffraction pattern expressed at an angle of 2θ using Cu-Kα 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 present invention, the crystalline form II of the compound represented by formula (A) has substantially the following properties when irradiated with Cu-Kα: Figure 5 The X-ray powder diffraction pattern is shown.

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

[0031] According to some embodiments of the invention, 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 of impurities.

[0032] According to some embodiments of the present invention, the solid form of the compound represented by formula (A) is as described in the first aspect.

[0033] In a third aspect, the present invention provides a crystalline composition comprising one or both of the crystalline form I of the compound represented by formula (A) or the crystalline form II of the compound represented by formula (A).

[0034] According to some embodiments of the present invention, the crystalline form I of the compound represented by formula (A) accounts for 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% of the weight of the crystalline composition.

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

[0036] In a fifth aspect, the present invention provides the use of a compound of formula (A) in solid form as described in the first aspect, a compound of formula (A) in crystalline form, Form I of the compound of formula (A), Form II of the compound of formula (A), or a composition as described in the second aspect, or a crystalline composition as described in the third aspect, or a pharmaceutical composition as described in the fourth aspect in the preparation of a drug.

[0037] According to some embodiments of the present invention, the drug is used to prepare a drug for preventing and / or treating a cell proliferative disease; preferably, the cell proliferative disease is a tumor or cancer; further preferably, the tumor or cancer is a blood tumor or a solid tumor; further preferably, it is a malignant blood tumor or an advanced solid tumor; further preferably, it is a relapsed refractory blood tumor or an advanced malignant solid tumor.

[0038] According to some embodiments of the present invention, the drug is for preparing a drug for preventing and / or treating a disease at least partially mediated by PRMT5.

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

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

[0041] According to some embodiments of the present invention, the tumor or cancer is selected from 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; preferably, the acute leukemia is acute myeloid leukemia (AML).

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

[0043] According to the preparation method of the present invention, the time for the non-solid compound represented by formula (A) in the aqueous solvent is 5 hours to 5 days; preferably 10 hours to 4 days; preferably 12 hours to 3 days; preferably 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 invention, 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 invention, the balance of the aqueous solvent is an organic solvent or an inorganic solvent miscible with water; preferably, the balance is an organic solvent miscible with water.

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

[0047] According to the preparation method of the present invention, the organic solvent is an organic solvent 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] The preparation method according to the present invention comprises crystallizing the non-solid compound represented by formula (A) in water to obtain the compound represented by formula (A) in solid form. Preferably, according to the preparation method of the present invention, the compound represented by formula (A) in solid form is the crystalline form I of the compound represented by formula (A).

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

[0050] According to the preparation method of the present invention, the seed crystal is also called a crystal grain, which is the crystal form I of the compound represented by formula (A).

[0051] According to the preparation method of the present invention, the organic solvent is an organic solvent 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.

[0052] According to the preparation method of the present invention, 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%, and preferably at least 99%.

[0053] According to the preparation methods of the sixth and seventh aspects of the present invention, the amount of the organic solvent used is preferably such that it can dissolve or clear the compound represented by formula (A).

[0054] According to the preparation method of the present invention, the crude product is prepared according to the method disclosed in WO2021244542A1, or any known method disclosed in other prior arts or a combination thereof, or a replacement, combination or improvement of the method disclosed in WO2021244542A1 and / or other prior arts. Preferably, the crude product may be in the form of a non-solid or semi-solid (e.g., an oily substance, a jelly, a colloid), a solid with poor properties, or a solid with poor purity, etc.

[0055] According to the preparation method described in the sixth and seventh aspects of the present invention, the crystallization temperature can be controlled during the crystallization process, and the crystallization temperature 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, more preferably 0°C to 5°C.

[0056] The preparation method according to the sixth and seventh aspects of the present invention further comprises a separation step, wherein the separation step is any suitable method to separate to obtain a solid. Preferably, the separation is selected from suction filtration, centrifugation, filtration, and suction filtration.

[0057] The preparation method according to the sixth and seventh aspects of the present invention further comprises a drying step.

[0058] According to the preparation method described in the sixth and seventh aspects of the present invention, the drying method can be any suitable known method, 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 used, it is preferred that the residual solvent content in the obtained product meets the quality standards.

[0059] Definition and Description

[0060] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered ambiguous or unclear without special definition, but should be understood according to the ordinary meaning.

[0061] The compounds of formula (A) mentioned in the present invention may exist in specific stereoisomer forms, including cis and trans isomers, (R)- and (S)-enantiomers, and racemic mixtures thereof. The compounds of the present invention may contain carbon-nitrogen double bonds in E or Z configuration, wherein the term "E" represents a higher order substituent on the opposite side of the carbon-nitrogen double bond, and the term "Z" represents a higher order substituent on the same side of the carbon-nitrogen double bond (determined using the Cahn-Ingold Prelog priority rule). The compounds of the present invention may also exist in the form of a mixture of "E" and "Z" isomers, preferably, the compounds of the present invention exist in the form of E isomers. The substituents around the heterocycloalkyl group are made into cis or trans configurations.

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

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

[0064] The term "solvate" also known as "solvate" refers to an association formed by a stoichiometric or non-stoichiometric ratio of solvent molecules and the compounds of the present invention, including an association containing both water molecules and one or more other solvent molecules, and an association containing only one or more other solvent molecules.

[0065] The term "hydrate" refers to an association formed between a stoichiometric or non-stoichiometric ratio of water molecules and a compound of the present invention.

[0066] The "anhydrous and solvent-free form" refers to the absence of water molecules or solvent molecules, or the coexistence of water molecules or solvent molecules with the compound of the present invention in a manner that is not bound by intermolecular forces, such as by adsorption.

[0067] The term "crystalline composition" refers to a solid form that contains one or more of the specific crystal forms of the compound of the present invention. For example, in one embodiment according to the present invention, it contains the crystal form I of the compound of formula (A) mentioned in the present invention. Moreover, in addition to the crystal form of the present invention, the crystalline composition may optionally contain other crystalline forms, other crystal forms or other amorphous forms of the compound of the present invention, or impurities other than these substances. It should be understood by those skilled in the art that the sum of the contents of each component in the crystalline composition should be 100%.

[0068] The "room temperature" is the room temperature conventionally known in the art, generally 10-30°C, preferably 25°C±5°C.

[0069] In the context of the present invention, in an X-ray powder diffraction pattern, 2θ is the diffraction angle, and the 2θ value is in degrees (°).

[0070] In the X-ray powder diffraction pattern, the term "substantially" or "substantially as shown" refers to a substantially pure crystalline form, in which 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 the powder X-ray diffraction pattern appear in the given pattern. Further, when the content of a certain crystalline form in the product gradually decreases, some of the diffraction peaks in its X-ray powder diffraction pattern attributable to the crystalline form may become less due to the detection sensitivity of the instrument. In addition, for any given crystalline form, there may be slight errors in the position of the peak, which is also well known in the field of crystallography. For example, due to the replacement of the instrument, the change of temperature when analyzing the sample, the movement of the sample or the calibration of the instrument, the position of the peak can move, and the measurement error of the 2θ value is usually about ± 0.2°. Therefore, when determining each crystalline structure, this error should be taken into account, and the term "substantially" or "substantially as shown in the accompanying drawings" is also intended to cover such differences in the diffraction peak positions, which refers to ±0.2°.

[0071] As used herein, the term "cell proliferative disorder" refers to a condition in which a population of cells grows at a rate that is slower or faster than expected under given physiological conditions and circumstances.

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

[0073] As used herein, the term "prevent" or "prevent" means that when used for a disease or condition (e.g., cancer), the compound or drug (e.g., the combination product claimed herein) can reduce the frequency of symptoms of the medical condition or delay its onset in a subject compared to a subject to which the compound or drug (e.g., the combination product claimed herein) is not administered.

[0074] As used herein, the term "treat," "treat," "treat," "treat," or "treat" refers to alleviating, relieving, or ameliorating symptoms of a disease or condition, ameliorating underlying metabolically caused symptoms, inhibiting a disease or symptom, such as arresting the development of a disease or condition, alleviating a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or arresting symptoms of a disease or condition.

[0075] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to those carriers or excipients that have no significant irritation to organisms and will not impair the biological activity and properties of the active compound.

[0076] The "jelly" mentioned herein is also called "colloid" or "oil", which is in a state similar to oil and is not in a solid form.

[0077] The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.

[0078] The chemical reactions of the specific embodiments of the present invention are carried out in a suitable solvent, which must be suitable for the chemical changes of the present invention and the reagents and materials required. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

[0079] The present invention will be described in detail below by way of examples, which are not intended to limit the present invention in any way.

[0080] All solvents used in the present invention were commercially available and used without further purification.

[0081] Technical Effects

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

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

[0084] (2) unexpectedly obtaining for the first time a compound of formula (A) in crystalline form, which has good crystallinity and is easy to separate, purify, transfer and weigh;

[0085] (3) the obtained solid form of the compound of formula (A), the crystalline form of the compound of formula (A) and / or the crystalline form I of the compound of formula (A) have a high purity;

[0086] (4) Form I of the compound represented by formula (A), which has good physical and chemical stability;

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

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

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

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

[0091] Figure 3 : Thermogravimetric analysis spectrum of Form I of the compound of formula (A) of Example 2.

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

[0093] Figure 5 : X-ray powder diffraction pattern of 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 samples Example 2 Sample quantity 2-10 mg Sample tray Alumina crucible, covered Temperature range 50～300℃ Heating rate 20℃ / min Protective gas Nitrogen

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

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

[0100] Content and test solvent: 1 H-NMR, the test solvent was 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 determination. The specific test method is as follows:

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

[0107] 2) Take an appropriate amount of the test sample and spread it flat in the above-mentioned weighing bottle. The thickness of the test sample is generally about 1mm. Accurately weigh the weight (m2);

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

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

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

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

[0112] Moisture-absorbing properties Weight gain ratio Highly hygroscopic The weight gain due to moisture absorption is not less than 15% Hygroscopic The weight gain due to moisture absorption is less than 15% but not less than 2% Slightly hygroscopic The weight gain due to moisture absorption is less than 2% but not less than 0.2% No or almost no hygroscopicity The weight gain due to moisture absorption is less than 0.2%

[0113] 5. Moisture determination

[0114] Instrument Model 915KF Ti-Touch Test samples Example 2, Preparation Example 1 Sample quantity 100mg Solvents Anhydrous methanol Karl Fischer reagent KFR-08

[0115] 6. Infrared Spectroscopy (IR)

[0116] Detection instrument: PerkinElmer Spectrum 100 infrared spectrometer

[0117] Test method: Weigh 3 mg of sample, dilute with KBr and press into tablets, and test at room temperature. Specific parameters are: Detection range: 4000-400cm -1 Wave number, resolution: 4cm -1 .

[0118] In order to better understand the content of the present invention, the following is further described in conjunction with specific examples, but the specific implementation methods are not intended to limit the content of the present invention. The test methods without specific conditions in the following preparation examples, embodiments, comparative examples or test examples are selected according to conventional methods and conditions, or according to the product instructions.

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

[0120] The compound represented by formula (A) was prepared by referring to the method disclosed in WO2021244542A1 to obtain the compound represented by formula (A) as a colloid.

[0121]

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

[0123] Weigh the colloid (5 g) of Preparation Example 1 and place it in a glass bottle. Add purified water (30 mL) and stir at 30±10°C for about 12 hours. A small amount of white solid begins to appear in the water, and a large amount of oily substance still sticks to the bottle wall. Scrape off the oily substance so that it can be suspended in water. Continue stirring, and repeat the above operation at regular intervals, scrape off the sample attached to the wall, until a white solid suspension is obtained (stirring time is about 48 hours), filter to obtain a solid, and vacuum dry at room temperature to obtain a solid (4.2 g) with a purity of 98.37%.

[0124] Take samples for infrared spectrum test, 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. Spectrum as Figure 1 shown.

[0125] The obtained solid sample was subjected to X-ray powder diffraction, which showed a crystalline solid (form I) with good crystallinity. Figure 2 The main XRPD diffraction peak data are shown in Table 1.

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

[0127]

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

[0129] The colloid (10 g) of Preparation Example 1 was weighed and placed in a glass bottle. Acetonitrile (10 mL) was first added to completely dissolve it. After the solution was clear, purified water (10 mL) was added dropwise, and a small amount of the sample obtained in Example 1 was added as a seed crystal. Stirring was continued for 12 hours to precipitate solids. Purified water (200 mL) was added, the temperature was controlled at 5°C ± 5°C, stirring was continued for 2 days, a large amount of solids precipitated, and a solid (8 g) was obtained after suction filtration and vacuum drying at room temperature. The purity was 99.55%.

[0130] Take a sample for TGA test. The TGA graph shows that it has a weight loss of 3.4735% between room temperature and 132°C. Figure 3 . After testing and calculation, it is a monohydrate.

[0131] The obtained solid sample was subjected to X-ray powder diffraction, which showed a crystalline solid (form I) with good crystallinity. Figure 4 The main XRPD diffraction peak data 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 Crystalline Form II of Compound of Formula (A)

[0136] The sample of Example 1 was weighed and placed on the variable temperature sample stage of PANalytical Empyrean XRPD, heated to 70° C. under N 2 protection, and the sample was collected.

[0137] The sample was taken for X-ray powder diffraction, which showed a crystalline solid (form II) with good crystallinity. Figure 5 The main XRPD diffraction peak data 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 research and development process, the inventors found that the compound represented by formula (A) could not obtain a solid sample under various research methods and different experimental conditions. Exemplary solutions include but are not limited to the following comparative examples:

[0142] Comparative Example 1: Preparation attempt of the compound of formula (A) in solid form

[0143] The sample obtained in Preparation Example 1 was taken and various physical operations such as reduced pressure rotary evaporation (circulating water pump, water bath at 50°C, 2 to 5 hours) and reduced pressure vacuum extraction (oil pump, 3 to 8 hours) were attempted, or multiple column chromatography purification operations were attempted, but none of them could change the properties of the sample.

[0144] Comparative Example 2: Preparation attempt of the compound of formula (A) in solid form

[0145] The samples obtained in Preparation Example 1 were taken and the solvents shown in the following table were added to try crystallization. The specific test methods and results are shown in the following table. In the end, no solid was obtained and the samples were still in the form of colloid.

[0146] Table 4. Preparation conditions and results of the compound of formula (A) in solid form

[0147]

[0148]

[0149] [1]: The solution becomes clear after stirring at room temperature for 3 days. It remains clear after stirring at 5°C for 3 days. After adding the anti-solvent n-hexane or methyl tert-butyl ether, no solid or oil / gel is formed. It evaporates after being transferred to room temperature.

[0150] [2]: After stirring at room temperature for 3 days, if there is still no solid or oil / gel, transfer to room temperature for evaporation.

[0151] Test Example 1: Moisture absorption and weight gain test

[0152] The samples of Example 2 and Preparation Example 1 were placed under the conditions of room temperature / 92.5% RH for 24 hours, and then the samples were taken for water titration. The results are shown in the table below.

[0153] Table 5. Moisture absorption and weight gain test results

[0154]

[0155] Results: After testing, the crystal form I obtained in Example 2 did not show any moisture absorption and weight gain under high humidity conditions, indicating that it has no or almost no hygroscopicity; while the sample of Preparation Example 1 showed obvious moisture absorption and weight gain (weight gain of 3.1%) after being placed for 24 hours, indicating that it has hygroscopicity, and after being placed under high humidity conditions for 24 hours, the sample is still in the form of a gel, and no solid is produced.

[0156] Test Example 2: Stability Test

[0157] The sample of Example 2 was placed in an open state under the condition of 40°C / 75% RH. The sample was then taken for testing, and the results are shown in the table below.

[0158] Table 6. Stability test results

[0159]

[0160] Results: After testing, the purity of the crystal form I obtained in Example 2 did not change significantly after being placed under accelerated conditions for 7 days. Therefore, the sample obtained in Example 2 is more suitable for storage as a raw material drug.

[0161] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent to one skilled in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

1. A compound of formula (A) in solid form, 2. The compound of formula (A) in solid form according to claim 1, using the KBr tablet method, has an infrared spectrum comprising characteristic peaks (±4 cm-1) at the following positions: 3360, 3260, 2919, 1664, 1620, 1533.

3. The compound of formula (A) in solid form according to claim 1, which is a crystalline compound of formula (A).

4. A compound of formula (A) in solid form according to any one of claims 1 to 3, wherein The solid form of the compound represented by formula (A) is a hydrate form of the compound represented by formula (A); preferably, it is a monohydrate form of the compound represented by formula (A).

5. The compound of formula (A) in solid form according to any one of claims 1 to 4, which is Form I, using Cu-Kα radiation, and an X-ray powder diffraction pattern expressed in 2θ angles, comprising the following characteristic diffraction peaks (°): 4.5±0.2°, 16.2±0.2°, 16.8±0.2°, 18.9±0.2°, 23.5±0.2°.

6. The compound of formula (A) in solid form according to claim 1 or 3, which is in form II, and has an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation, comprising the following characteristic diffraction peaks (°): 4.6±0.2°, 9.3±0.2°, 13.7±0.2°, 16.4±0.2°, 18.5±0.2°.

7. A composition comprising at least 95% of the compound represented by formula (A) in solid form as claimed in any one of claims 1 to 6 and the remainder being impurities.

8. A crystalline composition comprising one or two of the compounds of formula (A) in solid form as claimed in any one of claims 5 to 6.

9. A pharmaceutical composition comprising a solid form of the compound of formula (A) as described in any one of claims 1 to 6, the composition as described in claim 7, or the crystalline composition as described in claim 8; optionally, further comprising a pharmaceutically acceptable carrier.

10. Use of the solid form of the compound of formula (A) according to any one of claims 1 to 6, the composition according to claim 7, the crystalline composition according to claim 8 or the pharmaceutical composition according to claim 9 in the preparation of a drug; Preferably, the drug is used for preparing a drug for preventing and / or treating a cell proliferative disease; preferably, the cell proliferative disease is a tumor or cancer; further preferably, the tumor or cancer is a blood tumor or a solid tumor; further preferably, it is a malignant blood tumor or an advanced solid tumor; further preferably, it is a relapsed refractory blood tumor or an advanced malignant solid tumor; Alternatively, the drug is used for preparing a drug for preventing and / or treating a disease at least partially mediated by PRMT5.

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