Salts of 3,4-dihydroisoquinoline compounds, processes for their preparation and uses thereof

Abstract

The present invention provides a hippurate salt of a compound represented by formula (A), its solid form, crystalline form, and specific crystal form, a pharmaceutical composition comprising the same, and its uses. The hippurate salt of the compound represented by formula (A) has the characteristics of good solubility, low hygroscopicity, and good stability, and is suitable for use as a bulk drug.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and relates to a hippuric acid salt of a 3,4-dihydroisoquinoline compound, a solid form, a crystalline form and a specific crystal form thereof, a preparation method thereof, a pharmaceutical composition containing the same, and an 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, studies have 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), and 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 formula (A) below).

[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 gel (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). Further, the inventors tried to solidify it by salification, using various common acids, but failed to obtain a solid or the obtained solid was unstable in properties. Surprisingly, the inventors found a hippuric acid salt of the compound as shown in formula (A), which is not only in a solid form, but also has good properties, suitable for use as a drug substance.

[0007] In a first aspect, the present application provides a compound, which is a hippuric acid salt of a compound as shown in formula (A),

[0008]

[0009] According to some embodiments of the present application, the compound is a compound as shown in formula (A-1),

[0010]

[0011] wherein n is selected from 0.5-2; preferably 1-1.5; further preferably 1, 1.1, 1.2, 1.3, 1.4 or 1.5; further preferably 1, 1.3, 1.4 or 1.5; and more further preferably 1.

[0012] According to some embodiments of the present application, the compound is a compound as shown in formula (B):

[0013]

[0014] According to some embodiments of the present application, the compound, the compound as shown in formula (A-1) or the compound as shown in formula (B) is in a solid form.

[0015] According to some embodiments of the present application, the compound as shown in formula (B) in a solid form has an infrared spectrum comprising characteristic peaks (±4 cm -1) : 3281, 2939, 1653, 1524, 1373, 1305; preferably, using the KBr pellet method, its infrared spectrum comprises characteristic peaks (± 4 cm -1 ) : 3281, 2939, 1653, 1524, 1373, 1305, 1121, 1038, 750; further preferably, using the KBr pellet method, its infrared spectrum comprises characteristic peaks (± 4 cm -1 ) : 3281, 2939, 1653, 1612, 1524, 1457, 1373, 1305, 1147, 1121, 1038, 976, 750, 690; further preferably, using the KBr pellet method, its infrared spectrum comprises characteristic peaks (± 4 cm Figure 1 as shown.

[0016] According to some embodiments of the application, the compound, the compound of formula (A-1) or the compound of formula (B) is in crystalline form.

[0017] According to some embodiments of the application, the compound of formula (B) is the crystalline form I of the compound of formula (B), having an X-ray powder diffraction pattern, expressed in angles 2 theta, using Cu-Ka radiation, comprising the following characteristic diffraction peaks (± 0.3°, preferably ± 0.2°): 6.1, 16.0, 18.4, 20.1, 21.7.

[0018] According to some embodiments of the application, the crystalline form I of the compound of formula (B), has an X-ray powder diffraction pattern, expressed in angles 2 theta, using Cu-Ka radiation, comprising the following characteristic diffraction peaks (± 0.3°, preferably ± 0.2°): 6.1, 13.3, 16.0, 18.4, 20.1, 21.7.

[0019] According to some embodiments of the application, the crystalline form I of the compound of formula (B), has an X-ray powder diffraction pattern, expressed in angles 2 theta, using Cu-Ka radiation, comprising the following characteristic diffraction peaks (± 0.3°, preferably ± 0.2°): 6.1, 8.1, 13.3, 16.0, 18.4, 20.1, 21.7.

[0020] According to some embodiments of the application, the crystalline form I of the compound of formula (B), has an X-ray powder diffraction pattern, expressed in angles 2 theta, using Cu-Ka radiation, comprising the following characteristic diffraction peaks (± 0.3°, preferably ± 0.2°): 6.1, 8.1, 13.3, 15.0, 16.0, 18.4, 20.1, 21.7.

[0021] According to some embodiments of the present invention, the crystalline form I of the compound represented by formula (B) has an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation, comprising the following characteristic diffraction peaks (±0.3°, preferably ±0.2°): 6.1, 8.1, 13.3, 15.0, 16.0, 17.8, 18.4, 20.1, 21.7.

[0022] According to some embodiments of the present invention, the crystalline form I of the compound represented by formula (B) has an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation, comprising the following characteristic diffraction peaks (±0.3°, preferably ±0.2°): 4.9, 6.1, 8.1, 13.3, 15.0, 16.0, 17.8, 18.4, 20.1, 21.7.

[0023] According to some embodiments of the present invention, the crystalline form I of the compound represented by formula (B) has a substantially Figure 2 or Figure 4 The X-ray powder diffraction pattern is shown.

[0024] According to some embodiments of the present invention, the crystalline form I of the compound represented by formula (B) has an endothermic peak at 167°C±5°C in its differential scanning calorimetry curve.

[0025] In a second aspect, the present invention provides a crystalline composition comprising Form I of the compound represented by formula (B).

[0026] According to some embodiments of the present invention, the crystalline form I of the compound represented by formula (B) accounts for more than 50%, more than 60%, more than 70%, more than 80%, more than 90% or more than 95% by weight of the crystalline composition.

[0027] In a third aspect, the present invention provides a pharmaceutical composition comprising the hippurate salt of the compound represented by the aforementioned formula (A), the compound represented by formula (A-1), the compound represented by formula (B), the crystalline form I of the compound represented by formula (B), or the crystalline composition described in the second aspect above, optionally further comprising a pharmaceutically acceptable carrier.

[0028] In a fourth aspect, the present invention provides the use of the hippurate salt of the compound represented by formula (A) described in the first aspect, the compound represented by formula (A-1), the compound represented by formula (B), the crystalline form I of the compound represented by formula (B), the crystalline composition described in the second aspect, or the pharmaceutical composition described in the third aspect in the preparation of drugs.

[0029] According to some embodiments of the present application, the medicament is for preparing 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 the cancer is a hematological tumor or a solid tumor; further preferably, a malignant hematological tumor or an advanced solid tumor; further preferably, a relapsed / refractory hematological tumor or an advanced malignant solid tumor.

[0030] According to some embodiments of the present application, the medicament is for preparing a medicament for preventing and / or treating a disease mediated at least in part by PRMT5.

[0031] According to some embodiments of the present application, the disease mediated at least in part by PRMT5 is a cell proliferative disease; preferably, the cell proliferative disease is a tumor or a cancer; further preferably, the tumor or the cancer is a hematological tumor or a solid tumor; further preferably, a malignant hematological tumor or an advanced solid tumor; further preferably, a relapsed / refractory hematological tumor or an advanced malignant solid tumor.

[0032] According to some embodiments of the present application, the cell proliferative disease is a tumor or a cancer; preferably, the tumor or the cancer is a hematological tumor or a solid tumor; further preferably, a malignant hematological tumor or an advanced solid tumor; further preferably, a relapsed / refractory hematological tumor or an advanced malignant solid tumor.

[0033] According to some embodiments of the present application, the tumor or the 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, lymphoma, leukemia, and chronic and acute leukemia; preferably, the acute leukemia is acute myeloid leukemia (AML).

[0034] In a fifth aspect, the present application provides a preparation method of a hippurate salt of a compound represented by formula (A), comprising: reacting a compound represented by formula (A) with hippuric acid in a reaction solvent to obtain a hippurate salt of the compound represented by formula (A).

[0035] In some embodiments, the present application provides a preparation method of a compound represented by formula (A-1), comprising: reacting a compound represented by formula (A) with an acid in a solvent to obtain a compound represented by formula (A-1):

[0036]

[0037] wherein X is hippuric acid; n is selected from 0.5-2.

[0038] According to some embodiments of the present application, n is selected from 1-1.5; preferably 1, 1.1, 1.2, 1.3, 1.4 or 1.5; further preferably 1, 1.3, 1.4 or 1.5; more further preferably 1.

[0039] According to the preparation method of the present application, the molar ratio of the compound of formula (A) to the acid is 1-2:0.5-2, preferably 1:1-2, further preferably 1:1.1-2, for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:2.

[0040] According to the preparation method of the present application, the reaction temperature is 0°C to 90°C, preferably 5°C to 80°C, preferably 20°C to 60°C, more preferably room temperature to 50°C.

[0041] According to the preparation method of the present application, the solvent is selected from one or a combination of two of methanol, ethanol, dichloromethane, methyl tert-butyl ether; preferably a single solvent of methanol, ethanol or dichloromethane or a mixed solvent of methanol and methyl tert-butyl ether; further preferably ethanol; preferably, when it is a mixed solvent of methanol and methyl tert-butyl ether, the volume ratio of the two is 1-20:20-1, preferably 1-19:19-1, preferably 1-10:10-1, preferably 1-5:5-1, preferably 3:5.

[0042] According to the preparation method of the present application, after the reaction is completed, further comprising a cooling step, cooling to -15°C to room temperature; preferably -10°C to room temperature; further preferably -5°C to room temperature; for example, -5°C to 5°C (0±5°C), 0°C to 10°C (5±5°C).

[0043] According to the preparation method of the present application, after the reaction is completed, further comprising a crystallization step, preferably stirring crystallization or standing crystallization.

[0044] According to the preparation method of the present application, after the reaction is completed, the standing crystallization is selected from solvent evaporation crystallization or solvent-in crystallization.

[0045] According to the preparation method of the present application, the reaction is carried out for 0.5 hours to 10 days, preferably 0.5 hours to 8 days, 0.5 hours to 6 days, 0.5 hours to 5 days, 0.5 hours to 4 days, 0.5 hours to 3 days, 0.5 hours to 2 days, 0.5 hours to 24 hours, 0.5 hours to 12 hours, for example, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours. According to the preparation method of the present application, the reaction is carried out to completion, further comprising a separation step, which is any suitable method for separation to obtain a solid. Preferably, the separation is selected from suction filtration, centrifugation, filtration, and filtration under suction.

[0046] According to the preparation method of the present application, further comprising a drying step to obtain the compound of formula (A-1).

[0047] According to the preparation method of the present application, the drying method can use 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. The specific drying conditions are, for example, the drying time is preferably 1 hour to 5 days, more preferably 3 hours to 3 days, more preferably 3 hours to 1 day, for example, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours. Regardless of the drying means, the solvent residue in the obtained product should meet the quality standards.

[0048] The compound of formula (A) mentioned herein is prepared by the method disclosed in WO2021244542A1, or any known method disclosed in other prior art or a combination thereof, or by substitution, combination or improvement of the method disclosed in WO2021244542A1 and / or other prior art.

[0049] Definitions and explanations

[0050] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be construed to be indefinite or unclear unless specifically defined, but should be understood according to the ordinary meaning.

[0051] The compounds of formula (A), formula (A-1) and / or formula (B) according to the present application can exist in specific stereoisomeric forms, including cis and trans isomers, (R)- and (S)- enantiomers, and mixtures thereof, such as racemates. The compounds of the present application can contain a carbon-nitrogen double bond in the E or Z configuration, wherein the term "E" denotes the higher order substitution of the carbon-nitrogen double bond on opposite sides, and the term "Z" denotes the higher order substitution of the carbon-nitrogen double bond on the same side (determined using the Cahn-Ingold Prelog priority rules), and the compounds of the present application can also exist in the form of mixtures of "E" and "Z" isomers. Preferably, the compounds of the present application exist in the E isomer. The substituents around the heterocycloalkyl group are in the cis or trans configuration.

[0052] The term "solid form" according to the present application means a compound in a solid state, including but not limited to crystalline forms and amorphous forms of the compound.

[0053] The term "crystalline form" according to the present application means a compound in a crystalline state, including but not limited to anhydrous and solvent-free forms, hydrate forms and solvate forms.

[0054] The term "solvate" also referred to as "solvation" means an association including a complex or a complex ion of a compound according to the present application with a stoichiometric or non-stoichiometric amount of solvent molecules, 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.

[0055] The term "hydrate" means an association including a complex or a complex ion of a compound according to the present application with a stoichiometric or non-stoichiometric amount of water molecules.

[0056] The term "anhydrous and solvent-free form" means that the compound according to the present application is free of water molecules or solvent molecules, or that water molecules or solvent molecules are present in a non-intermolecularly bound manner, for example in an adsorbed manner.

[0057] The term "crystalline composition" means a solid form comprising one or more of the specific crystalline forms of the compounds according to the present application, for example, in one embodiment according to the present application, it comprises the crystalline form I of the compound of formula (B) according to the present application. Furthermore, the crystalline composition can optionally comprise, in addition to the crystalline form according to the present application, other crystalline forms, other crystalline modifications or other amorphous forms of the compounds according to the present application, or impurities in addition to these. It is understood by the person skilled in the art that the sum of the contents of the individual components in the crystalline composition should be 100%.

[0058] The term "room temperature" means the room temperature in the usual sense of the term in the art, generally between 10 and 30°C, preferably 25°C ± 5°C.

[0059] In the context of the present application, the diffraction angles in the X-ray powder diffractograms are expressed in degrees (°) in terms of 2 theta angles.

[0060] In the context of the present application, the term "substantially" or "substantially as shown in the figure" in the context of X-ray powder diffractograms means that a certain crystal form is substantially pure, wherein 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 diffractogram of the form occur in the given pattern. Further, as the amount of a certain crystal form in a product is gradually reduced, some of the diffraction peaks attributed to that form in the X-ray powder diffractogram can be lost due to instrumental sensitivity factors. In addition, for any given crystal form, there can be slight errors in the position of the peaks, which are well known in the art of crystallography. For example, due to changes in temperature, sample movement or calibration of the instrument during analysis of the sample, the position of the peaks can shift, and there can be some error in the measurement of the 2 theta values. Therefore, when determining the structure of each crystal form, this error should be taken into account, 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 ± 0.3°, preferably ± 0.2°.

[0061] In the context of the present application, the term "substantially" or "substantially as shown in the figure" in the context of DSC patterns means that for a certain crystal form of a certain compound, the error in the onset temperature of the thermal transition, the peak temperature of the endotherm, the peak temperature of the exotherm, the melting point, the onset temperature of the weight loss or the end temperature of the weight loss, etc. is typically within about 5°C, usually within about 3°C, in successive analyses. When a certain compound is described as having a certain onset temperature of the thermal transition, a certain peak temperature of the endotherm, a certain peak temperature of the exotherm, a certain melting point, a certain onset temperature of the weight loss or a certain end temperature of the weight loss, etc., this means the temperature ± 5°C.

[0062] 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 lower or higher than expected under given physiological conditions and circumstances.

[0063] The term "tumor" includes benign, malignant, and borderline tumors, with malignant tumors collectively referred to as cancer.

[0064] The term "prevention" as used herein means, when used in the context of a disease or disorder (e.g. cancer), that the compound or drug (e.g. the combination product as claimed in the present application) reduces the frequency or delays the onset of symptoms of the medical disorder in a subject as compared to a subject to which the compound or drug is not administered.

[0065] The term "treatment" as used herein refers to reducing, alleviating or ameliorating the symptoms of a disease or condition, ameliorating the underlying metabolic cause of symptoms, inhibiting the disease or condition, 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.

[0066] The term "pharmaceutically acceptable carrier" can also be referred to as "pharmaceutically acceptable vehicle" or "pharmaceutically acceptable adjuvant" and refers to those carriers or adjuvants that do not produce an allergic or similar untoward reaction in organisms when administered in a sufficient dose.

[0067] "Colloids" as referred to herein, also called "gels" or "oils", are in a state similar to an oil, in a non-solid form.

[0068] The above embodiments represent exemplary embodiments of the present application, but the present application is not limited to the above embodiments. In addition, each technical feature in the above embodiments of the present application can be combined with each other to constitute one or more new technical solutions, which also fall within the scope of the present application, as long as such new technical solutions are technically feasible.

[0069] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance does not occur.

[0070] 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 listed below, embodiments formed using a combination of the other chemical synthetic methods well known to those skilled in the art, and equivalents thereof as appreciated by those skilled in the art, preferred embodiments including but not limited to the examples of the present application.

[0071] 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 changes being effected. In some instances, the solvent can be changed after a given reaction to facilitate the further reactions or to facilitate purification. In some instances, it is desirable to remove the protecting groups used in the synthesis of the compounds of the present application.

[0072] The present application will now be described in greater detail by way of reference only to the following Examples, which are not meant to limit the present application in any way.

[0073] All solvents used in the present application are commercially available and used without further purification.

[0074] Technical Effects

[0075] The hippurate salt of the compound represented by formula (A), the solid form thereof, the crystalline form thereof and the crystal form thereof provided by the present application have one or more of the following beneficial effects:

[0076] The hippurate salt of the compound represented by formula (A) is obtained for the first time, can be prepared and separated at a high purity (more than 95%), and has the following beneficial effects:

[0077] The hippurate salt of the compound represented by formula (A) is obtained in a solid form for the first time, preferably, in a crystalline form, which is convenient for separation, transfer, weighing and formulation process operation;

[0078] The crystalline form of the compound represented by formula (B) is obtained for the first time, has good crystallinity, and is convenient for separation, transfer, weighing and formulation process operation;

[0079] The crystal form I of the compound represented by formula (B) is obtained for the first time, has good properties and good crystallinity;

[0080] The crystal form I of the compound represented by formula (B) has good solubility in water and biological solvents;

[0081] Compared with other controls, the crystal form I of the compound represented by formula (B) has no obvious hygroscopicity;

[0082] The crystal form I of the compound represented by formula (B) has good physical stability;

[0083] The compound represented by formula (B) and the crystal form I thereof have good chemical stability;

[0084] The tablet (tablet core) prepared using the crystal form I of the compound represented by formula (B) has good dissolution effect, preferably, can be quickly dissolved. BRIEF DESCRIPTION OF DRAWINGS

[0085] Figure 1 : Infrared spectrum of the compound of formula (B) in Example 1.

[0086] Figure 2 : X-ray powder diffraction spectrum of the crystal form I of the compound of formula (B) in Example 1.

[0087] Figure 3 : Differential scanning calorimetric spectrum of the crystal form I of the compound of formula (B) in Example 1.

[0088] Figure 4 : X-ray powder diffraction spectrum of the sample in Example 1 after stability detection. DETAILED DESCRIPTION

[0089] 1. X-ray powder diffractometer (XRPD)

[0090]

[0091]

[0092] 2. Differential Scanning Calorimeter (DSC)

[0093]

[0094] 3. Nuclear Magnetic Resonance Spectroscopy (NMR) Instrument Model: Bruker 400M NMR spectrometer (Bruker, GER)

[0095] Content and test solvent: 1 H-NMR, test solvent is DMSO-d6.

[0096] 4. High Performance Liquid Chromatography (HPLC)

[0097] 4.1 Detection instrument: Waters H-Class UPLC (Ultra Performance Liquid Chromatography)

[0098]

[0099] 4.2 Detection instrument: Waters e2695 (High Performance Liquid Chromatograph)

[0100]

[0101] 5. Hygroscopicity test

[0102] Hygroscopicity characteristic description and definition of hygroscopicity weight gain:

[0103] Hygroscopicity Weight gain ratio Highly hygroscopic Hygroscopic weight gain not less than 15% Hygroscopic Hygroscopic weight gain less than 15% but not less than 2% Slightly hygroscopic Hygroscopic weight gain less than 2% but not less than 0.2% Non- or almost non-hygroscopic Hygroscopic weight gain less than 0.2%

[0104] 5.1 Dynamic vapor sorption (DVS)

[0105] Instrument model SMS (Surface Measurement Systems) Sample Example 1 Sample amount 20 to 40 mg Protective gas and flow rate Nitrogen, 200 mL / min dm / dt 0.002% / min

[0106] 5.2 Hygroscopic weight gain test

[0107] Sample: Preparation Example 1

[0108] Determined by the method in Chinese Pharmacopoeia, the specific test method is as follows:

[0109] 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);

[0110] 2) Take an appropriate amount of test sample and lay it flat in the above weighing bottle. The thickness of the test sample is generally about 1 mm, and accurately weigh the weight (m2);

[0111] 3) Open the weighing bottle and place the cap in the above constant temperature and humidity conditions for 24 hours;

[0112] 4) Close the weighing bottle cap and accurately weigh the weight (m3);

[0113] Weight gain percentage = (m3-m2) / (m2-m1) x 100%.

[0114] 6, moisture determination

[0115] Instrument model 915KF Ti-Touch Test sample Preparation Example 1 Sample amount 100 mg Solvent Anhydrous methanol Karl Fischer reagent KFR-08 type

[0116] 7, infrared spectroscopy (Infrared Spectroscopy, IR)

[0117] Detection instrument: PerkinElmer Spectrum 100 infrared spectrum analyzer

[0118] Test method: take 3 mg of sample, dilute with KBr and press into a tablet, and detect at room temperature. The specific parameters are: detection range: 4000-400 cm -1 Wave number, resolution: 4 cm -1 .

[0119] 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 a limitation on the content of the present application. The test method in the following preparation example, example, comparative example or test example without specific conditions is selected according to conventional method and condition, or according to the instruction manual.

[0120] Preparation example 1: preparation of compound of formula (A)

[0121] 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.

[0122]

[0123] Example 1: preparation of compound of formula (B)

[0124] To a reaction flask was added the sample of Preparation 1 (18.38 g), absolute ethanol (550 mL) and hippuric acid (6.47 g) in sequence and stirred to dissolve. The stirring was continued overnight and a large amount of solid precipitated. The reaction flask was cooled to 0±5°C and the stirring was continued for 2 hours to crystallize. The solid was collected by filtration and dried under vacuum at 50±5°C for 5 hours to give a solid (20.2 g). The sample was tested by1H NMR and confirmed to be a salt with a base / acid ratio of 1:1.

[0125] The sample was tested by infrared spectroscopy, IR (KBr, cm -1 ): 3281.34, 2939.10, 1652.92, 1612.15, 1524.15, 1456.64, 1373.01, 1305.15, 1147.29, 1121.18, 1037.56, 975.67, 750.23, 689.66. The spectrum is shown in Figure 1 .

[0126] The sample was tested by X-ray powder diffraction and showed a crystalline solid (Form I) with good crystallinity. The spectrum is shown in Figure 2 and the main XRPD diffraction peak data is shown in the following table. The sample was tested by DSC and the DSC graph showed an endothermic peak at 168.77°C. The spectrum is shown in Figure 3 .

[0127] Table 1. XRPD diffraction peak data of the sample obtained in Example 1

[0128]

[0129] Examples 2-4: Crystal Form Screening

[0130] The sample of Example 1 (about 100 mg) was weighed into a sample bottle, solvent was added and the operation was carried out according to the following table. The sample obtained was tested by X-ray powder diffraction and DSC, and the results are shown in the following table:

[0131] Table 2. Crystal form screening method and results

[0132]

[0133] Note: The drying conditions were all 50±5°C, vacuum drying for 5 hours.

[0134] Comparative Example

[0135] During the research and development, the inventors found that (1) the compound of formula (A) could not be obtained in solid form under various solid state research methods and different experimental conditions; (2) the compound of formula (A) could not be obtained in solid form after reacting with various common acids under different experimental conditions, or the obtained solid sample was unstable in property. Exemplary schemes include, but are not limited to, the following comparative examples:

[0136] Comparative Example 1: Preparation attempt of the compound of formula (A) in solid form

[0137] The sample obtained in Preparation Example 1 was subjected to various physical operations such as rotary evaporation under reduced pressure (circulating water pump, water bath 50℃, 2-5 hours), vacuum pumping under reduced pressure (oil pump, 3-8 hours), or purification by column chromatography for multiple times, but the sample property did not change.

[0138] Comparative Example 2: Preparation attempt of the compound of formula (A) in solid form

[0139] 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.

[0140] Table 3. Preparation attempt conditions and results of the compound of formula (A) in solid form

[0141] Comparative example Solvent Result 1-1 Ethanol Gel [1] 1-2 Ethyl acetate Gel [1] 1-3 2-Methyltetrahydrofuran Gel [1] 1-4 Acetone / water (19:1, v / v) Gel [1] 1-5 Acetone Gel [1] 1-6 Acetonitrile Gel [1] 1-7 Tetrahydrofuran Gel [1] 1-8 Methyl tert-butyl ether Gel [2] 1-9 Dichloromethane Gel [1]

[0142] [1]: After stirring at room temperature for 3 days, it was still clear, and after stirring at 5℃ for 3 days, it was still clear. No solid or oil / gel was obtained after adding anti-solvent n-hexane or methyl tert-butyl ether, and it was transferred to room temperature for evaporation.

[0143] [2]: After stirring at room temperature for 3 days, no solid or oil / gel was obtained, and it was transferred to room temperature for evaporation.

[0144] Comparative Example 3: Preparation of other salts of the compound of formula (A)

[0145] The sample of Preparation Example 1 was dissolved in the solvents shown in the following table respectively to prepare a solution with a concentration of 40 mg / mL. The sample solution (0.5 mL) of Preparation Example 1 and the corresponding acid ligand in equimolar ratio were added to a vial. The specific test methods and results are shown in the following table.

[0146] Table 4. Preparation and results of other acid addition salts

[0147]

[0148] [1]: After stirring at room temperature for 3 days, it was still clear, and after stirring at 5℃ for 3 days, it was still clear. No solid or oil / gel was obtained after adding anti-solvent n-hexane or methyl tert-butyl ether, and it was transferred to room temperature for evaporation.

[0149] [2]: clear or gel after stirring at room temperature for 3 days, transfer to 5°C and stir for 3 days to form a gel, transfer to room temperature and evaporate.

[0150] Result: the sample of Preparation Example 1 failed to obtain solid after reacting with some common organic acids or inorganic acids.

[0151] Comparative Example 4: preparation of salts of other compounds of formula (A)

[0152] The sample of Preparation Example 1 was reacted with equal molar ratio of sulfuric acid, phosphoric acid and succinic acid respectively in some solvents to obtain solid samples, but the samples all turned into gels or oils after being left open at ambient conditions for a period of time, which may be due to the instability of the solid or the presence of strong hygroscopicity.

[0153] Test Example 1: solubility test

[0154] The samples of Example 1 and Preparation Example 1 were weighed into glass vials and added to different media (water and three biological solvents, 4 mL in volume) for solubility test, and the results are shown in the table below.

[0155] Table 5. Solubility of different samples in biological solvents

[0156]

[0157] Note: ① Solubility, calculated as free form. ② FaSSIF: fasted state simulated intestinal fluid; FeSSIF: fed state simulated intestinal fluid; SGF: fasted state simulated gastric fluid; the preparation method or process can refer to WO2022063229A1.

[0158] Result: on the one hand, the sample of free base was improved in form after being prepared into hippurate; on the other hand, the hippurate sample obtained in Example 1 had good solubility in four different media, and compared with the free base, it had significantly better solubility in water and FeSSIF (pH 5.0) medium.

[0159] Test Example 2: hygroscopicity test

[0160] (1) Hygroscopicity test of the sample of Example 1

[0161] The sample of Example 1 was taken for DVS test.

[0162] Table 6. Hygroscopicity test results of the sample of Example 1

[0163]

[0164] Results: The hippurate salt and its crystal form I obtained in Example 1 were only slightly hygroscopic under high humidity conditions, and the crystal form did not change after DVS testing, as determined by X-ray powder diffraction.

[0165] (2) Hygroscopicity test of the sample of Preparation Example 1

[0166] The sample of Preparation Example 1 was left open at room temperature / 92.5% RH for 24 hours, and then the sample was subjected to moisture titration. The results are shown in the table below.

[0167] Table 7. Hygroscopic weight gain test results of the sample of Preparation Example 1

[0168]

[0169] Results: The sample of Preparation Example 1 showed significant hygroscopic weight gain (3.1% weight gain) after 24 hours, indicating that it was hygroscopic, and the sample remained in the form of a gel after being left under high humidity conditions for 24 hours.

[0170] Test Example 3: Stability test

[0171] (1) Stability test of the sample of Example 1

[0172] The sample of Example 1 was weighed and left open at 25°C / 60% RH and 40°C / 75% RH for 1 week, respectively, and then the sample was subjected to X-ray powder diffraction and purity test, respectively, to investigate the stability of the sample under different conditions. The results are shown in the table below.

[0173] Table 8. Solid stability test results of the sample of Example 1

[0174]

[0175] Results: The hippurate salt and its crystal form I of Example 1 remained unchanged in crystal form and showed no significant change in purity after being left under different conditions for 1 week.

[0176] Table 8.1. XRPD diffraction peak data of the sample of Example 1 after stability test at 25°C / 60% RH

[0177]

[0178] (2) Stability test of the sample of Preparation Example

[0179] The sample of Preparation Example 1 was left open at 40°C / 75% RH, and then the sample was subjected to detection.

[0180] Results: The sample of Preparation Example 1 was detected to have a decrease in purity after 7 days of storage, and the sample was still in the form of a gel after 7 days of storage under the high humidity conditions.

[0181] While the foregoing application has been described in some detail for purposes of clarity and understanding, it will be appreciated 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 in solid form, which is a hippurate salt of a compound represented by formula (A), 。 2. The solid form compound according to claim 1, wherein The compound is a compound represented by formula (B): 。 3. The solid form compound according to claim 1 or 2, wherein Using the KBr pellet method, its infrared spectrum includes characteristic peaks at the following positions: 3281 ± 4 cm -1 , 2939±4 cm -1 , 1652±4 cm -1 , 1524±4 cm -1 , 1373±4 cm -1 , 1305±4 cm -1 .

4. The solid form compound according to claim 1 or 2, wherein The compound is a crystalline compound, and its X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation comprises the following characteristic diffraction peaks: 6.1±0.3°, 16.0±0.3°, 18.4±0.3°, 20.1±0.3°, and 21.7±0.3°.

5. The solid form compound according to claim 4, wherein The X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation contains the following characteristic diffraction peaks: 6.1±0.3°, 13.3±0.3°, 16.0±0.3°, 18.4±0.3°, 20.1±0.3°, and 21.7±0.3°.

6. The solid form compound according to claim 4, wherein The X-ray powder diffraction pattern at 2θ angle using Cu-Kα radiation contains the following characteristic diffraction peaks: 6.1±0.3°, 8.1±0.3°, 13.3±0.3°, 16.0±0.3°, 18.4±0.3°, 20.1±0.3°, 21.7±0.3°.

7. The solid form compound according to claim 4, wherein The X-ray powder diffraction pattern at 2θ angle using Cu-Kα radiation contains the following characteristic diffraction peaks: 6.1±0.3°, 8.1±0.3°, 13.3±0.3°, 15.0±0.3°, 16.0±0.3°, 18.4±0.3°, 20.1±0.3°, 21.7±0.3°.

8. The solid form compound according to claim 4, wherein The X-ray powder diffraction pattern at 2θ angle using Cu-Kα radiation contains the following characteristic diffraction peaks: 6.1±0.3°, 8.1±0.3°, 13.3±0.3°, 15.0±0.3°, 16.0±0.3°, 17.8±0.3°, 18.4±0.3°, 20.1±0.3°, 21.7±0.3°.

9. The solid form compound according to claim 4, wherein The X-ray powder diffraction pattern at 2θ angle using Cu-Kα radiation contains the following characteristic diffraction peaks: 4.9±0.3°, 6.1±0.3°, 8.1±0.3°, 13.3±0.3°, 15.0±0.3°, 16.0±0.3°, 17.8±0.3°, 18.4±0.3°, 20.1±0.3°, 21.7±0.3°.

10. The solid form compound according to claim 4, wherein Using Cu-Kα radiation, it has an X-ray powder diffraction pattern substantially as shown in FIG. 2 or FIG. 4 .

11. The solid form compound according to claim 4, wherein Its differential scanning calorimetry curve has an endothermic peak at 167°C±5°C.

12. The solid form compound according to any one of claims 5 to 10, wherein Its differential scanning calorimetry curve has an endothermic peak at 167°C±5°C.

13. A crystalline composition comprising a compound according to any one of claims 1 to 12 in solid form.

14. A pharmaceutical composition comprising the solid form of the compound according to any one of claims 1 to 12 or the crystalline composition according to claim 13; optionally, further comprising a pharmaceutically acceptable carrier.

15. Use of the solid form compound according to any one of claims 1 to 12, the crystalline composition according to claim 13, or the pharmaceutical composition according to claim 14 in the preparation of a medicament for preventing and / or treating a disease mediated at least in part by PRMT5.

16. The use according to claim 15, wherein The disease mediated at least in part by PRMT5 is a cell proliferative disease.

17. Use of the solid form compound according to any one of claims 1 to 12, the crystalline composition according to claim 13, or the pharmaceutical composition according to claim 14 in the preparation of a medicament for preventing and / or treating a cell proliferative disease.

18. The use according to claim 16 or 17, wherein The cell proliferative disease is a tumor.

19. The use according to claim 18, wherein The tumor is a blood tumor or a solid tumor.

20. The use according to claim 18, wherein The tumor is a malignant hematological tumor or an advanced solid tumor.

21. The use according to claim 18, wherein The tumor is a relapsed and refractory blood tumor or an advanced malignant solid tumor.

22. The use according to claim 18, wherein The tumor is selected from the group consisting of 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, lymphoma, leukemia, chronic and acute leukemia.

23. The use according to claim 22, wherein The acute leukemia is acute myeloid leukemia.

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