Solid form of metalloenzyme inhibitor compound

Abstract

The present invention provides a solid form of a metalloenzyme inhibitor compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazine-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, and in particular to a crystal form and an amorphous solid form, and a preparation method for the compound, a pharmaceutical composition comprising the compound, and a use of the compound.

Description

Solid forms of metalloenzyme inhibitor compounds Technical Field

[0001] The present disclosure relates to solid forms of the metalloenzyme inhibitor compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, in particular to crystalline and amorphous solid forms, as well as preparation methods, pharmaceutical compositions, and uses thereof. Background Art

[0002] The compound of formula (I) below, 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, is a metalloenzyme inhibitor, specifically a selective inhibitor of aldosterone synthase CYP11B2, and has promising application in the treatment of aldosterone-related diseases. Herein, it is also referred to as "Compound A."

[0003] The chemical formula of compound A is C 15 N4H 10 F4, molecular weight 322.3. Compound A is a metalloenzyme inhibitor, specifically a selective inhibitor of aldosterone synthase CYP11B2. The synthesis method and biological activity of Compound A can be found in, for example, WO2018 / 125800, the entire contents of which are incorporated herein by reference.

[0004] In order to promote the development of the above-mentioned compounds as solid pharmaceutical substances and ensure the quality and efficacy of the compounds during production, packaging, storage or use, at least one solid form of the compound is required, such as a crystalline form with superior physicochemical properties, or an amorphous solid form that can exist stably, so that it is conducive to use in drug processing and pharmaceutical compositions. Summary of the Invention

[0005] The present invention provides a variety of crystal forms and amorphous solids of a metalloenzyme inhibitor compound A, as well as preparation methods, pharmaceutical compositions and uses thereof.

[0006] One aspect of the present invention relates to Form I of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 8.9°, 12.4°, 17.6°, 25.0°, and 25.8° in an X-ray powder diffraction (XRPD) pattern.

[0007] The present invention also relates to a crystalline form I of compound A, which has characteristic peaks at diffraction angles 2θ of approximately 8.9°, 12.4°, 17.6°, 18.2°, 19.6°, 24.2°, 25.0°, 25.8°, 26.7°, 28.0°, and 28.8° in the X-ray powder diffraction (XRPD) pattern.

[0008] The present invention also relates to Form I of Compound A having an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG1 .

[0009] In some embodiments, Form I of Compound A is an anhydrous crystalline form.

[0010] In some specific embodiments, Form I of Compound A has an endothermic peak at approximately 211.6°C ± 2.0°C when thermally analyzed using differential scanning calorimetry (DSC).

[0011] In some embodiments, Form I of Compound A has a DSC pattern substantially as shown in FIG2 , when subjected to thermal analysis using differential scanning calorimetry (DSC).

[0012] In some embodiments, Form I of Compound A has a TGA pattern substantially as shown in FIG3 , when subjected to thermal analysis using thermogravimetric analysis (TGA).

[0013] In some embodiments, Form I of Compound A, when analyzed using dynamic water sorption (DVS), has a DVS pattern substantially as shown in FIG6 .

[0014] The present invention also relates to a method for preparing the crystalline form I of compound A, comprising the following steps:

[0015] (1) dissolving or suspending the solid of Compound A in an organic solvent, wherein the organic solvent is one or more selected from organic acids, amides, sulfones, alcohols, ethers, and nitriles, preferably selected from organic acids and amides;

[0016] (2) adding water to the above solution or suspension to precipitate crystals, wherein the amount of water is 0.1 to 100 times the volume of the organic solvent;

[0017] (3) The crystals were collected by filtration and dried to obtain Form I of Compound A.

[0018] In some specific embodiments, in the preparation method of Form I of Compound A, the organic solvent is selected from formic acid, acetic acid, propionic acid, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, C1-C6 alcohol or polyol, tetrahydrofuran, anisole or acetonitrile.

[0019] Another aspect of the present invention relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 8.4°, 10.2°, 12.4°, 16.7°, 18.1°, 22.1°, 24.8°, and 25.7° in the X-ray powder diffraction (XRPD) pattern.

[0020] The present invention also relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 8.4°, 10.2°, 12.4°, 14.0°, 15.8°, 16.7°, 17.5°, 18.1°, 20.2°, 22.1°, 22.6°, 23.4°, 24.8°, 25.2°, 25.7°, and 28.2° in the X-ray powder diffraction (XRPD) pattern.

[0021] The present invention also relates to Form III of Compound A, which has an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG7 .

[0022] In some specific embodiments, the crystalline form III of compound A is an acetic acid-containing crystalline form, preferably an acetic acid solvate (AcOH solvate) crystalline form.

[0023] In some specific embodiments, Form III of Compound A has endothermic peaks at approximately 78.3°C±2°C, 121.4°C±2°C, and / or 212.2°C±2°C when thermally analyzed using differential scanning calorimetry (DSC).

[0024] In some embodiments, Form III of Compound A has a DSC pattern substantially as shown in FIG8 , when subjected to thermal analysis using differential scanning calorimetry (DSC).

[0025] In some embodiments, Form III of Compound A has a TGA pattern substantially as shown in FIG9 , when subjected to thermal analysis using thermogravimetric analysis (TGA).

[0026] The present invention also relates to a method for preparing Form III of Compound A, comprising the following steps:

[0027] (1) Adding the solid of Compound A to anhydrous acetic acid and suspending it under heating conditions;

[0028] (2) filtering, and allowing the filtrate to settle under cooling conditions;

[0029] (3) The crystals were collected by filtration and dried to obtain Form III of Compound A.

[0030] In some specific embodiments, in the preparation method of Form III of Compound A, the temperature of the heating suspension is <60°C, preferably ≤55°C, more preferably ≤50°C; the temperature of the cooling and standing is ≤10°C, preferably ≤5°C.

[0031] Another aspect of the present invention relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 9.7°, 13.0°, 15.6°, 19.1°, 23.0°, 24.1°, and 24.5° in the X-ray powder diffraction (XRPD) pattern.

[0032] The present invention also relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 9.7°, 13.0°, 15.6°, 17.2°, 17.9°, 19.1°, 20.4°, 21.3°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, 32.7°, and 34.3° in the X-ray powder diffraction (XRPD) pattern.

[0033] The present invention also relates to Form IV of Compound A having an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG10 .

[0034] In some specific embodiments, the crystalline form IV of compound A is a hydrochloric acid-containing crystalline form, preferably a crystalline form of the hydrochloride salt of the compound, and more preferably an anhydrous crystalline form.

[0035] In some specific embodiments, Form IV of Compound A has endothermic peaks at approximately 180.5°C±2°C and 209.0°C±2°C when thermally analyzed using differential scanning calorimetry (DSC).

[0036] In some embodiments, Form IV of Compound A has a DSC pattern substantially as shown in FIG11 when subjected to thermal analysis using differential scanning calorimetry (DSC).

[0037] In some embodiments, Form IV of Compound A has a TGA pattern substantially as shown in FIG12 when subjected to thermal analysis using thermogravimetric analysis (TGA).

[0038] The present invention also relates to a method for preparing Form IV of Compound A, comprising the following steps:

[0039] (1) dissolving the solid of compound A in a heated organic solvent containing HCl, wherein the organic solvent preferably comprises isopropyl acetate and isopropyl alcohol;

[0040] (2) Under an inert atmosphere, the solution was cooled to room temperature and stirred to allow crystals to precipitate;

[0041] (3) Filter, wash the wet cake with isopropyl acetate and dry to obtain Form IV of Compound A.

[0042] In some specific embodiments, in the method for preparing Form IV of Compound A, the molar number of HCl is 2 to 5 times the molar number of Compound A, preferably 3 to 4 times.

[0043] Another aspect of the present invention relates to a composition comprising:

[0044] Form I of compound A, and

[0045] At least one of the crystalline form III of compound A and the crystalline form IV of compound A.

[0046] In some specific embodiments, the above composition is a mixture of two or more crystal forms of Compound A, which is a mixed crystal form directly prepared from a solution or suspension of Compound A.

[0047] In some specific embodiments, the composition comprises any ratio of Form I, Form III and / or Form IV of Compound A. In some preferred embodiments, the composition comprises any ratio of Form I and Form III of Compound A.

[0048] Another aspect of the present invention relates to a pharmaceutical composition comprising:

[0049] (i) Form I of Compound A, and / or

[0050] Form III of compound A, and / or

[0051] Form IV of compound A, and

[0052] (ii) a pharmaceutically acceptable carrier, diluent or excipient.

[0053] In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent.

[0054] In some embodiments, the pharmaceutical composition comprises an additional therapeutic agent selected from the group consisting of an anticancer agent, an antifungal agent, a cardiovascular therapeutic agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an antiproliferative agent, an agent for treating metabolic diseases, an agent for treating ophthalmic diseases, an agent for treating central nervous system (CNS) diseases, an agent for treating urological diseases, and an agent for treating gastrointestinal diseases.

[0055] Another aspect of the present invention relates to an amorphous solid of Compound A, which has no obvious crystal diffraction characteristic peaks in its X-ray powder diffraction (XRPD) pattern.

[0056] In some embodiments, the amorphous solid of Compound A has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 15.

[0057] In some embodiments, the amorphous solid of Compound A further comprises a pharmaceutically acceptable polymer.

[0058] In some embodiments, the amorphous solid of Compound A is a solid dispersion of the compound and a polymer.

[0059] In some specific embodiments, in the amorphous solid of compound A, the polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP) and acrylic acid resin copolymer (Eudragit).

[0060] In some embodiments, in the amorphous solid of Compound A, the hypromellose is selected from HPMC E3, HPMC E5 or HPMC E50LV;

[0061] The hydropropyl methylcellulose acetate succinate is selected from HPMCAS LG, HPMCAS MG, HPMCAS HG, HPMCAS MMP or HPMCAS MF;

[0062] The hydropropyl methylcellulose phthalate is selected from HPMCP HP50;

[0063] The acrylic resin copolymer is selected from methacrylic acid / methyl methacrylate copolymer (Eudragit L100) or butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate copolymer (Euragit EPO).

[0064] In some specific embodiments, in the amorphous solid of compound A, the polymer is selected from one or more of HPMC E3, HPMC E5, HPMC E50LV, HPMCAS LG, HPMCAS MG, HPMCAS HG, HPMCAS MMP, HPMCAS MF, HPMCP HP50, Eudragit L100, and Euragit EPO, preferably one or more of HPMCAS MG, HPMCAS MMP, and HPMCAS MF.

[0065] In some specific embodiments, in the amorphous solid of compound A, the compound accounts for about 5% to 25% by weight of the amorphous solid, preferably about 5% to 20%, more preferably about 10% to 20%, and particularly preferably about 10% to 15%.

[0066] In some specific embodiments, in the amorphous solid of compound A, the mass ratio of the compound to the polymer is about 1:3 to 1:20, preferably about 1:4 to 1:20, more preferably about 1:4 to 1:9, and particularly preferably about 1:5.6 to 1:9.

[0067] In some embodiments, the amorphous solid of Compound A is prepared by spray drying or hot melt extrusion.

[0068] Another aspect of the present invention relates to a method for preparing an amorphous solid of compound A, comprising the following steps:

[0069] dissolving the compound and a pharmaceutically acceptable polymer in a solvent to form a solution;

[0070] The solution is spray dried to form a solid dispersion, which is the amorphous solid.

[0071] In some specific embodiments, in the method for preparing the amorphous solid of Compound A, the polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP) and acrylic resin copolymer (Eudragit).

[0072] In some embodiments, in the method for preparing the amorphous solid of Compound A, the solvent is one or more selected from alcohols, alkyl halides, ketones, ethers, esters, amides, sulfones, and nitriles. In some embodiments, the solvent is one or more selected from C1-C6 alcohols or polyols, dichloromethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, anisole, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, and acetonitrile.

[0073] In some specific embodiments, in the method for preparing the amorphous solid of compound A, the solvent is a mixture of dichloromethane and methanol, preferably a mixture of dichloromethane and methanol in a volume ratio of 2:1.

[0074] In some specific embodiments, in the method for preparing an amorphous solid of Compound A, the concentration of the compound in the solution is about 3-15 mg / mL, preferably about 4-12 mg / mL, and more preferably about 5-10 mg / mL.

[0075] Therefore, the present invention also relates to the amorphous solid of compound A prepared according to the above-mentioned spray drying method.

[0076] Another aspect of the present invention relates to a method for preparing an amorphous solid of compound A, comprising the following steps:

[0077] The compound is mixed evenly with a pharmaceutically acceptable polymer, and the mixture is extruded through a hot melt extruder to obtain the amorphous solid.

[0078] In some specific embodiments, in the method for preparing the amorphous solid of Compound A, the polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP) and acrylic resin copolymer (Eudragit).

[0079] In some specific embodiments, in the method for preparing the amorphous solid of compound A, the heating temperature of the hot melt extruder is 150-200°C, preferably 160-180°C.

[0080] In some specific embodiments, the method for preparing the amorphous solid of Compound A further comprises the steps of crushing and screening the hot-melt extrudate.

[0081] The present invention also relates to the amorphous solid of compound A prepared according to the hot melt extrusion method.

[0082] Another aspect of the present invention relates to a pharmaceutical composition comprising:

[0083] (i) an amorphous solid of Compound A, and

[0084] (ii) a pharmaceutically acceptable carrier, diluent or excipient.

[0085] In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent.

[0086] In some embodiments, the pharmaceutical composition comprises an additional therapeutic agent selected from the group consisting of an anticancer agent, an antifungal agent, a cardiovascular therapeutic agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an antiproliferative agent, an agent for treating metabolic diseases, an agent for treating ophthalmic diseases, an agent for treating central nervous system (CNS) diseases, an agent for treating urological diseases, and an agent for treating gastrointestinal diseases.

[0087] Another aspect of the present invention relates to the use of the crystalline form I, crystalline form III, crystalline form IV or amorphous solid of Compound A in the preparation of medicines.

[0088] In some embodiments, the drug is used to modulate metalloenzyme activity.

[0089] In some embodiments, the drug is used to regulate the activity of aldosterone synthase CYP11B2.

[0090] In some embodiments, the medicament is used to treat a metalloenzyme-related disorder or disease, wherein the disorder or disease is cancer, cardiovascular disease, endocrine disease, fibrosis, kidney disease, inflammatory disease, infectious disease, gynecological disease, metabolic disease, ophthalmic disease, central nervous system (CNS) disease, urological disease, or gastrointestinal disease.

[0091] In some embodiments, the condition or disease is adrenal cancer, adrenal adenoma, leukemia, breast cancer, hypertension, resistant hypertension, pulmonary hypertension, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, post-myocardial infarction syndrome, coronary heart disease, myocardial necrotic lesions, atrial fibrillation, atherosclerosis, restenosis, endothelial dysfunction, vascular injury, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial thickening, arterial fibrinoid necrosis, vascular disease, diseases associated with primary or secondary aldosteronism and adrenal hyperplasia. Hypertension, diabetes mellitus, metabolic syndrome, insulin resistance, neuropathy, insulinopathy, diabetic nephropathy, diseases characterized by increased collagen formation, fibrosis, and matrix remodeling following hypertension, diseases characterized by fibrosis and matrix remodeling following endothelial cell dysfunction, myocardial fibrosis, vascular fibrosis, renal failure, chronic renal failure, nephropathy, renal dysfunction, kidney disease, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, hypokalemia, retinopathy, sleep apnea, obstructive sleep apnea, muscular dystrophy, stroke, liver disease, nonalcoholic steatohepatitis, cirrhosis, or nonalcoholic fatty liver disease.

[0092] In a preferred embodiment, the condition or disease is hypertension, resistant hypertension, pulmonary hypertension, atherosclerosis or hypokalemia.

[0093] Another aspect of the present invention relates to a method for treating a condition or disease, comprising administering to a subject in need thereof an effective amount of Form I, Form III, or Form IV of Compound A, or a mixture of at least two of the above forms in any proportion. The condition or disease is as described above. BRIEF DESCRIPTION OF THE DRAWINGS

[0094] FIG1 shows the X-ray powder diffraction (XRPD) pattern of Form I of Compound A.

[0095] FIG2 shows the differential scanning calorimetry (DSC) spectrum of Form I of Compound A.

[0096] FIG3 shows a thermogravimetric analysis (TGA) spectrum of Form I of Compound A.

[0097] Figure 4 shows the crystal form I of compound A 1 H NMR spectrum.

[0098] Figure 5 shows the crystal form I of compound A 13 C NMR spectrum.

[0099] FIG6 shows a dynamic water sorption (DVS) spectrum of Form I of Compound A.

[0100] FIG7 shows the X-ray powder diffraction (XRPD) pattern of Form III of Compound A.

[0101] FIG8 shows the differential scanning calorimetry (DSC) spectrum of Form III of Compound A.

[0102] FIG9 shows a thermogravimetric analysis (TGA) spectrum of Form III of Compound A.

[0103] FIG10 shows the X-ray powder diffraction (XRPD) pattern of Form IV of Compound A.

[0104] FIG11 shows the differential scanning calorimetry (DSC) spectrum of Form IV of Compound A.

[0105] FIG12 shows a thermogravimetric analysis (TGA) spectrum of Form IV of Compound A.

[0106] FIG13 shows the crystal form IV of compound A. 1 H NMR spectrum.

[0107] FIG14 shows the XRPD pattern of a portion of the solid dispersion prepared in Example 22.

[0108] FIG15 shows the X-ray powder diffraction (XRPD) pattern of the amorphous solid of Compound A prepared in Example 24.

[0109] Figure 16 shows the modulated differential scanning calorimetry (mDSC) spectrum of the amorphous solid of Compound A prepared in Example 24. The three curves from top to bottom in the figure are the reversible sample heat flow, the irreversible sample heat flow and the total heat flow, respectively.

[0110] FIG17 shows a thermogravimetric analysis (TGA) spectrum of the amorphous solid of Compound A prepared in Example 24.

[0111] FIG18 shows the X-ray powder diffraction (XRPD) pattern of the amorphous solid of Compound A prepared in Example 27.

[0112] Figure 19 shows the modulated differential scanning calorimetry (mDSC) spectrum of the amorphous solid of Compound A prepared in Example 27. The three curves from top to bottom in the figure are the irreversible sample heat flow, the total heat flow, and the reversible sample heat flow.

[0113] FIG20 shows a thermogravimetric analysis (TGA) spectrum of the amorphous solid of Compound A prepared in Example 27. DETAILED DESCRIPTION

[0114] definition

[0115] In order to make the present invention more easily understood, certain terms are first defined herein for convenience.

[0116] As used herein, the term "treating" a disease includes preventing, ameliorating, alleviating, and / or managing the disease and / or conditions that may cause the disease. The terms "treat" and "treating" refer to methods of alleviating or alleviating a disease and / or its associated symptoms. According to the present disclosure, "treating" includes preventing, blocking, inhibiting, attenuating, protecting, regulating, reversing, and reducing the effects of a disease, such as the harmful effects of a disease.

[0117] As used herein, "inhibit" includes preventing, reducing, and halting progression. The term "modulate" refers to an increase or decrease in the activity of an enzyme in response to exposure to a compound of the present disclosure.

[0118] In some embodiments, the metalloenzyme activity of the present invention is the metalloenzyme activity that is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.

[0119] The term "administration" or "application" includes a route of introducing a compound into a subject to achieve its intended function. Examples of routes of administration that can be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal administration.

[0120] The term "effective amount" includes an amount effective to achieve the desired result at the dosage and time period necessary. The effective amount of a compound may vary depending on factors such as the subject's disease state, age, and weight, as well as the compound's ability to elicit the desired response in the subject. The dosage regimen may be adjusted to provide the optimal therapeutic response. An effective amount is also an amount in which the therapeutic benefits outweigh any toxic or deleterious effects (e.g., side effects) of the inhibitor compound.

[0121] As used herein, the phrases "systemic administration," "systemic administration," "peripheral administration," and "peripheral administration" refer to the administration of a compound, drug, or other substance so that it enters the patient's system and thereby undergoes metabolism and other similar processes.

[0122] The term "therapeutically effective amount" refers to that amount of the compound being administered which is sufficient to prevent or alleviate to some extent the development of one or more symptoms of the disease or condition being treated.

[0123] The therapeutically effective amount (i.e., effective dose) of the compound can be from about 0.005 μg / kg body weight to about 200 mg / kg body weight, preferably from about 0.01 mg / kg body weight to about 200 mg / kg body weight, more preferably from about 0.015 mg / kg body weight to about 30 mg / kg body weight. In other embodiments, the therapeutically effective amount can be from about 1.0 pM to about 10 μM. It will be understood by those skilled in the art that certain factors can affect the dosage required for the effective treatment of the subject, including but not limited to the severity of the disease or condition, previous treatment, the subject's overall health status and / or age, and other diseases present. In addition, treating a subject with a therapeutically effective amount of the compound can include a single treatment or preferably can include a series of treatments. In one example, a subject is treated with a compound of about 0.005 μg / kg body weight to about 200 mg / kg body weight, once a day, for about 1 to 10 weeks, preferably 2 to 8 weeks, more preferably about 3 to 7 weeks, and even more preferably about 4, 5, or 6 weeks. In another example, in the case of a chronic condition or disease, the subject can be treated every day for several years. It is also understood that the effective dosage of the compound used in therapy may be increased or decreased during the course of a particular treatment.

[0124] The term "subject" refers to an animal, such as a mammal, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some embodiments, the subject is a human.

[0125] As used herein, the term "pharmaceutically acceptable" means the carrier, vehicle, diluent, excipient and / or salt must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0126] As used herein, the term "pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or animals, and any carrier in various forms that has no side effects on the composition of the pharmaceutical composition.

[0127] In this article, the X-ray powder diffraction (XRPD) pattern, differential scanning calorimetry (DSC) pattern, thermogravimetric analysis (TGA) pattern, 1 H and 13 C nuclear magnetic resonance (NMR) spectra, the term "substantially as shown in..." means spectra that are not necessarily identical to those depicted in the present disclosure, but are within the limits of experimental error or deviation as considered by one of ordinary skill in the art.

[0128] As used herein, the term "substantially the same" when referring to X-ray powder diffraction (XRPD) peak positions is intended to take into account typical peak position and intensity variability. For example, those skilled in the art understand that peak positions (2θ) can exhibit some variability, typically as much as 0.1° to 0.2°, depending on the solvent used and the apparatus used to measure diffraction. Furthermore, those skilled in the art understand that relative peak intensities can exhibit inter-instrument variability as well as variability due to crystallinity, preferred orientation, the surface of the sample being prepared, and other factors known to those skilled in the art, and should be considered only as qualitative measurements.

[0129] As used herein, the term "2θ value" or "2θ" refers to the peak position in degrees based on the experimental setup of an X-ray powder diffraction (XRPD) experiment and is a common unit of the abscissa of a diffraction pattern. The experimental setup requires that if the incident light beam forms an angle θ (theta) with a certain crystal plane, the reflection is recorded at an angle of 2θ (2theta). It should be understood that references herein to a specific 2θ value for a specific crystalline form are intended to refer to the 2θ value (in degrees) measured using the X-ray powder diffraction (XRPD) experimental conditions described in this disclosure. For example, as described herein, using CuKα As a radiation source.

[0130] As used herein, the term "amorphous" refers to a solid substance having an irregular microstructure, which may be referred to as a non-crystalline substance. The amorphous solid herein may comprise only one substance or more than one substance. For example, when the amorphous solid comprises substance A and substance B, the amorphous solid may be referred to as an amorphous solid of substance A, or as an amorphous solid of substance B. In some embodiments, the amorphous solid may be a solid dispersion formed of two or more substances. For example, when substance A and substance B form a solid dispersion, it may be referred to as a solid dispersion or an amorphous solid of substance A, or as a solid dispersion or an amorphous solid of substance B.

[0131] As used in this application, including the claims, a term not preceded by a quantifier means "one or more than one." Thus, for example, reference to "a sample" includes a plurality of samples unless the context clearly indicates otherwise (e.g., a plurality of samples), and so forth.

[0132] Throughout the specification and claims, the words "comprises," "comprising," and "including" are used in a non-exclusive sense, unless the context requires otherwise.

[0133] As used herein, the term "about" when referring to a value is intended to include variations based on the specified amount, in some embodiments within ±20%, in some embodiments within ±10%, in some embodiments within ±5%, in some embodiments within ±1%, in some embodiments within ±0.5%, and in some embodiments within ±0.1%, as such variations are suitable for performing the disclosed methods or using the disclosed compositions. When referring to a value for the diffraction angle 2θ, "about" can mean that the error in the value for the diffraction angle 2θ is within ±0.2°.

[0134] It should be understood that the singular articles "a," "an," and "the" as used in the specification and appended claims of this disclosure include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a pharmaceutical composition comprising "a pharmaceutically acceptable carrier, diluent, or excipient" includes one pharmaceutically acceptable carrier, diluent, or excipient, or two or more pharmaceutically acceptable carriers, diluents, or excipients.

[0135] Numerical limits or ranges stated herein are inclusive of the endpoints and specifically include all values ​​and subranges within the numerical limits or ranges.

[0136] The present invention will be further described below through specific embodiments. Unless otherwise defined, the terms used herein have the same meanings as those generally understood by those skilled in the art.

[0137] The present invention relates to crystalline and solid forms of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole ("Compound A") of formula (I). The chemical formula of Compound A is C 15 N4H 10 F4, molecular weight 322.3. Compound A is a metalloenzyme inhibitor, specifically a selective inhibitor of aldosterone synthase CYP11B2. The synthesis method and biological activity of Compound A can be found in, for example, WO2018 / 125800, the entire contents of which are incorporated herein by reference.

[0138] Crystalline Form I of Compound A

[0139] One aspect of the present invention relates to Form I of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 8.9°, 12.4°, 17.6°, 25.0°, and 25.8° in an X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.9°±0.2°, 12.4°±0.2°, 17.6°±0.2°, 25.0°±0.2°, and 25.8°±0.2°.

[0140] The present invention also relates to a crystalline form I of compound A, which has characteristic peaks at diffraction angles 2θ of approximately 8.9°, 12.4°, 17.6°, 24.2°, 25.0°, and 25.8° in an X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.9°±0.2°, 12.4°±0.2°, 17.6°±0.2°, 24.2°±0.2°, 25.0°±0.2°, and 25.8°±0.2°.

[0141] The present invention also relates to a crystalline form I of compound A, which has characteristic peaks at diffraction angles 2θ of approximately 8.9°, 12.4°, 17.6°, 18.2°, 24.2°, 25.0°, and 25.8° in an X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.9°±0.2°, 12.4°±0.2°, 17.6°±0.2°, 18.2°±0.2°, 24.2°±0.2°, 25.0°±0.2°, and 25.8°±0.2°.

[0142] The present invention also relates to a crystalline form I of compound A, which has characteristic peaks at diffraction angles 2θ of approximately 8.9°, 12.4°, 17.6°, 18.2°, 24.2°, 25.0°, 25.8°, and 26.7° in an X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.9°±0.2°, 12.4°±0.2°, 17.6°±0.2°, 18.2°±0.2°, 24.2°±0.2°, 25.0°±0.2°, 25.8°±0.2°, and 26.7°±0.2°.

[0143] The present invention also relates to a crystalline form I of compound A, which has characteristic peaks at diffraction angles 2θ of approximately 8.9°, 12.4°, 17.6°, 18.2°, 24.2°, 25.0°, 25.8°, 26.7°, and 28.0° in an X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.9°±0.2°, 12.4°±0.2°, 17.6°±0.2°, 18.2°±0.2°, 24.2°±0.2°, 25.0°±0.2°, 25.8°±0.2°, 26.7°±0.2°, and 28.0°±0.2°.

[0144] The present invention also relates to a crystalline form I of compound A, which has characteristic peaks at diffraction angles 2θ of about 8.9°, 12.4°, 17.6°, 18.2°, 19.6°, 24.2°, 25.0°, 25.8°, 26.7°, and 28.0° in an X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.9°±0.2°, 12.4°±0.2°, 17.6°±0.2°, 18.2°±0.2°, 19.6°±0.2°, 24.2°±0.2°, 25.0°±0.2°, 25.8°±0.2°, 26.7°±0.2°, and 28.0°±0.2°.

[0145] The present invention also relates to a crystalline form I of compound A, which has characteristic peaks at diffraction angles 2θ of about 8.9°, 12.4°, 17.6°, 18.2°, 19.6°, 24.2°, 25.0°, 25.8°, 26.7°, 28.0°, and 28.8° in an X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.9°±0.2°, 12.4°±0.2°, 17.6°±0.2°, 18.2°±0.2°, 19.6°±0.2°, 24.2°±0.2°, 25.0°±0.2°, 25.8°±0.2°, 26.7°±0.2°, 28.0°±0.2°, and 28.8°±0.2°.

[0146] The present invention also relates to Form I of Compound A having an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG1 .

[0147] In some embodiments, Form I of Compound A is an anhydrous crystalline form.

[0148] In some specific embodiments, Form I of Compound A has an endothermic peak at approximately 211.6°C ± 2.0°C when thermally analyzed using differential scanning calorimetry (DSC).

[0149] In some embodiments, when thermally analyzed using differential scanning calorimetry (DSC), Form I of Compound A has a DSC pattern substantially as shown in Figure 2. As shown in Figure 2, Form I of Compound A has only one endothermic peak, which corresponds to the melting point of Form I.

[0150] In some embodiments, when thermally analyzed using thermogravimetric analysis (TGA), Form I of Compound A has a TGA pattern substantially as shown in Figure 3. As shown in Figure 3, Form I of Compound A loses only about 0.5% of its weight within the heating range of 110-180°C, indicating that Form I is an anhydrous crystalline form.

[0151] In some embodiments, when analyzed using dynamic moisture sorption (DVS), Form I of Compound A has a DVS pattern substantially as shown in Figure 6. As shown in Figure 6, Form I of Compound A has a weight change of <0.2% during a cycle of relative humidity of 0-90%, indicating that Form I is not hygroscopic.

[0152] The present invention also relates to a method for preparing the crystalline form I of compound A, comprising the following steps:

[0153] (1) dissolving or suspending the solid of Compound A in an organic solvent, wherein the organic solvent is one or more selected from organic acids, amides, sulfones, alcohols, ethers, and nitriles, preferably selected from organic acids and amides;

[0154] (2) adding water to the above solution or suspension to precipitate crystals, wherein the amount of water is 0.1 to 100 times the volume of the organic solvent;

[0155] (3) The crystals were collected by filtration and dried to obtain Form I of Compound A.

[0156] In some specific embodiments, in the preparation method of Form I of Compound A, the organic solvent is selected from formic acid, acetic acid, propionic acid, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, C1-C6 alcohol or polyol, tetrahydrofuran, anisole or acetonitrile.

[0157] In the present invention, the crystalline form I of compound A is a dominant crystalline form, which can remain stable under high temperature, high humidity, light conditions and when suspended in water.

[0158] Crystalline Form III of Compound A

[0159] Another aspect of the present invention relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 8.4°, 10.2°, 12.4°, 16.7°, 18.1°, 22.1°, 24.8°, and 25.7° in an X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 10.2°±0.2°, 12.4°±0.2°, 16.7°±0.2°, 18.1°±0.2°, 22.1°±0.2°, 24.8°±0.2°, and 25.7°±0.2°.

[0160] The present invention also relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 8.4°, 10.2°, 12.4°, 16.7°, 18.1°, 22.1°, 24.8°, 25.2°, and 25.7° in an X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 10.2°±0.2°, 12.4°±0.2°, 16.7°±0.2°, 18.1°±0.2°, 22.1°±0.2°, 24.8°±0.2°, 25.2°±0.2°, and 25.7°±0.2°.

[0161] The present invention also relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 8.4°, 10.2°, 12.4°, 16.7°, 18.1°, 22.1°, 23.4°, 24.8°, 25.2°, and 25.7° in an X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 10.2°±0.2°, 12.4°±0.2°, 16.7°±0.2°, 18.1°±0.2°, 22.1°±0.2°, 23.4°±0.2°, 24.8°±0.2°, 25.2°±0.2°, and 25.7°±0.2°.

[0162] The present invention also relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2θ of about 8.4°, 10.2°, 12.4°, 16.7°, 17.5°, 18.1°, 22.1°, 23.4°, 24.8°, 25.2°, and 25.7° in an X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 10.2°±0.2°, 12.4°±0.2°, 16.7°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 22.1°±0.2°, 23.4°±0.2°, 24.8°±0.2°, 25.2°±0.2°, and 25.7°±0.2°.

[0163] The present invention also relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 8.4°, 10.2°, 12.4°, 16.7°, 17.5°, 18.1°, 22.1°, 23.4°, 24.8°, 25.2°, 25.7°, and 28.2° in the X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 10.2°±0.2°, 12.4°±0.2°, 16.7°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 22.1°±0.2°, 23.4°±0.2°, 24.8°±0.2°, 25.2°±0.2°, 25.7°±0.2°, and 28.2°±0.2°.

[0164] The present invention also relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 8.4°, 10.2°, 12.4°, 16.7°, 17.5°, 18.1°, 22.1°, 22.6°, 23.4°, 24.8°, 25.2°, 25.7°, and 28.2° in the X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 10.2°±0.2°, 12.4°±0.2°, 16.7°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 22.1°±0.2°, 22.6°±0.2°, 23.4°±0.2°, 24.8°±0.2°, 25.2°±0.2°, 25.7°±0.2°, and 28.2°±0.2°.

[0165] The present invention also relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 8.4°, 10.2°, 12.4°, 16.7°, 17.5°, 18.1°, 20.2°, 22.1°, 22.6°, 23.4°, 24.8°, 25.2°, 25.7°, and 28.2° in the X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 10.2°±0.2°, 12.4°±0.2°, 16.7°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 20.2°±0.2°, 22.1°±0.2°, 22.6°±0.2°, 23.4°±0.2°, 24.8°±0.2°, 25.2°±0.2°, 25.7°±0.2°, and 28.2°±0.2°.

[0166] The present invention also relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 8.4°, 10.2°, 12.4°, 15.8°, 16.7°, 17.5°, 18.1°, 20.2°, 22.1°, 22.6°, 23.4°, 24.8°, 25.2°, 25.7°, and 28.2° in the X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 10.2°±0.2°, 12.4°±0.2°, 15.8°±0.2°, 16.7°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 20.2°±0.2°, 22.1°±0.2°, 22.6°±0.2°, 23.4°±0.2°, 24.8°±0.2°, 25.2°±0.2°, 25.7°±0.2°, and 28.2°±0.2°.

[0167] The present invention also relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 8.4°, 10.2°, 12.4°, 14.0°, 15.8°, 16.7°, 17.5°, 18.1°, 20.2°, 22.1°, 22.6°, 23.4°, 24.8°, 25.2°, 25.7°, and 28.2° in the X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 10.2°±0.2°, 12.4°±0.2°, 14.0°±0.2°, 15.8°±0.2°, 16.7°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 20.2°±0.2°, 22.1°±0.2°, 22.6°±0.2°, 23.4°±0.2°, 24.8°±0.2°, 25.2°±0.2°, 25.7°±0.2°, and 28.2°±0.2°.

[0168] The present invention also relates to Form III of Compound A, which has an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG7 .

[0169] In some specific embodiments, the crystalline form III of compound A is an acetic acid-containing crystalline form, preferably an acetic acid solvate crystalline form.

[0170] In some embodiments, Form III of Compound A has endothermic peaks at approximately 78.3, 121.4, and / or 212.2°C ± 2°C when thermally analyzed using differential scanning calorimetry (DSC).

[0171] In some specific embodiments, when thermally analyzed using differential scanning calorimetry (DSC), Form III of Compound A exhibits a DSC pattern substantially as shown in Figure 8. As shown in Figure 8, the endothermic peak of Form III of Compound A at approximately 63-90°C corresponds to the decomposition of the acetic acid solvate; the endothermic peak at approximately 121°C corresponds to the boiling point of acetic acid; and the endothermic peak at approximately 212°C corresponds to the melting point of Compound A.

[0172] In some embodiments, when thermally analyzed using thermogravimetric analysis (TGA), Form III of Compound A has a TGA pattern substantially as shown in Figure 9. As shown in Figure 9, Form III of Compound A loses approximately 15.2% weight in the heating range of 50-150°C, indicating that the stoichiometric ratio of Compound A to acetic acid in Form III of acetic acid solvate is 1:1, and Form III of Compound A is an anhydrous crystalline form.

[0173] The present invention also relates to a method for preparing Form III of Compound A, comprising the following steps:

[0174] (1) Adding the solid of Compound A to anhydrous acetic acid and suspending it under heating conditions;

[0175] (2) filtering, and allowing the filtrate to settle under cooling conditions;

[0176] (3) The crystals were collected by filtration and dried to obtain Form III of Compound A.

[0177] In some specific embodiments, in the preparation method of Form III of Compound A, the temperature of the heating suspension is <60°C, preferably ≤55°C, more preferably ≤50°C; the temperature of the cooling and standing is ≤10°C, preferably ≤5°C.

[0178] In the present invention, Form III of Compound A is stable at room temperature. Form III converts to Form I when heated to temperatures above 110°C in air. Furthermore, Form III is stable in an anhydrous acetic acid solvent system at temperatures below 60°C, preferably ≤55°C; at temperatures above 60°C, Form III spontaneously converts to Form I.

[0179] Form IV of Compound A

[0180] Another aspect of the present invention relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 9.7°, 13.0°, 15.6°, 19.1°, 23.0°, 24.1°, and 24.5° in an X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 9.7°±0.2°, 13.0°±0.2°, 15.6°±0.2°, 19.1°±0.2°, 23.0°±0.2°, 24.1°±0.2°, and 24.5°±0.2°.

[0181] The present invention also relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 9.7°, 13.0°, 15.6°, 19.1°, 23.0°, 24.1°, 24.5°, and 28.1° in an X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 9.7°±0.2°, 13.0°±0.2°, 15.6°±0.2°, 19.1°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 24.5°±0.2°, and 28.1°±0.2°.

[0182] The present invention also relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 9.7°, 13.0°, 15.6°, 19.1°, 23.0°, 24.1°, 24.5°, 25.2°, and 28.1° in an X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 9.7°±0.2°, 13.0°±0.2°, 15.6°±0.2°, 19.1°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 24.5°±0.2°, 25.2°±0.2°, and 28.1°±0.2°.

[0183] The present invention also relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 9.7°, 13.0°, 15.6°, 19.1°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, and 29.0° in an X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 9.7°±0.2°, 13.0°±0.2°, 15.6°±0.2°, 19.1°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 24.5°±0.2°, 25.2°±0.2°, 28.1°±0.2°, and 29.0°±0.2°.

[0184] The present invention also relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 9.7°, 13.0°, 15.6°, 19.1°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, and 32.7° in an X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 9.7°±0.2°, 13.0°±0.2°, 15.6°±0.2°, 19.1°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 24.5°±0.2°, 25.2°±0.2°, 28.1°±0.2°, 29.0°±0.2°, and 32.7°±0.2°.

[0185] The present invention also relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 9.7°, 13.0°, 15.6°, 17.2°, 19.1°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, and 32.7° in the X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 9.7°±0.2°, 13.0°±0.2°, 15.6°±0.2°, 17.2°±0.2°, 19.1°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 24.5°±0.2°, 25.2°±0.2°, 28.1°±0.2°, 29.0°±0.2°, and 32.7°±0.2°.

[0186] The present invention also relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 9.7°, 13.0°, 15.6°, 17.2°, 19.1°, 21.3°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, and 32.7° in the X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 9.7°±0.2°, 13.0°±0.2°, 15.6°±0.2°, 17.2°±0.2°, 19.1°±0.2°, 21.3°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 24.5°±0.2°, 25.2°±0.2°, 28.1°±0.2°, 29.0°±0.2°, and 32.7°±0.2°.

[0187] The present invention also relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 9.7°, 13.0°, 15.6°, 17.2°, 19.1°, 21.3°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, 32.7°, and 34.3° in the X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 9.7°±0.2°, 13.0°±0.2°, 15.6°±0.2°, 17.2°±0.2°, 19.1°±0.2°, 21.3°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 24.5°±0.2°, 25.2°±0.2°, 28.1°±0.2°, 29.0°±0.2°, 32.7°±0.2°, and 34.3°±0.2°.

[0188] The present invention also relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 9.7°, 13.0°, 15.6°, 17.2°, 19.1°, 20.4°, 21.3°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, 32.7°, and 34.3° in the X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of 9.7°±0.2°, 13.0°±0.2°, 15.6°±0.2°, 17.2°±0.2°, 19.1°±0.2°, 20.4°±0.2°, 21.3°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 24.5°±0.2°, 25.2°±0.2°, 28.1°±0.2°, 29.0°±0.2°, 32.7°±0.2°, and 34.3°±0.2°.

[0189] The present invention also relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2θ of approximately 9.7°, 13.0°, 15.6°, 17.2°, 17.9°, 19.1°, 20.4°, 21.3°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, 32.7°, and 34.3° in the X-ray powder diffraction (XRPD) pattern. Preferably, it has characteristic peaks at diffraction angles 2θ of approximately 9.7°±0.2°, 13.0°±0.2°, 15.6°±0.2°, 17.2°±0.2°, 17.9°±0.2°, 19.1°±0.2°, 20.4°±0.2°, 21.3°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 24.5°±0.2°, 25.2°±0.2°, 28.1°±0.2°, 29.0°±0.2°, 32.7°±0.2°, and 34.3°±0.2°.

[0190] The present invention also relates to Form IV of Compound A having an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG10 .

[0191] In some specific embodiments, the crystalline form IV of compound A is a hydrochloric acid-containing crystalline form, preferably a crystalline form of the hydrochloride salt of the compound, and more preferably an anhydrous crystalline form.

[0192] In some specific embodiments, Form IV of Compound A has endothermic peaks at approximately 180.5°C and 209.0°C±2°C when thermally analyzed using differential scanning calorimetry (DSC).

[0193] In some specific embodiments, when thermally analyzed using differential scanning calorimetry (DSC), Form IV of Compound A has a DSC spectrum substantially as shown in Figure 11. As shown in Figure 11, the endothermic peak of Form IV of Compound A at about 160-180°C corresponds to the decomposition of the hydrochloride salt, and the endothermic peak at about 209°C corresponds to the melting point of Compound A.

[0194] In some embodiments, when thermally analyzed using thermogravimetric analysis (TGA), Form IV of Compound A exhibits a TGA pattern substantially as shown in Figure 12. As shown in Figure 12, Form IV of Compound A exhibits a weight loss of approximately 10% within the heating range of 145-205°C, indicating that the stoichiometric ratio of Compound A to hydrochloric acid in the hydrochloride salt is 1:1, and Form IV of Compound A is an anhydrous crystalline form.

[0195] The present invention also relates to a method for preparing Form IV of Compound A, comprising the following steps:

[0196] (1) dissolving the solid of compound A in a heated organic solvent containing HCl, wherein the organic solvent preferably comprises isopropyl acetate and isopropyl alcohol;

[0197] (2) Under an inert atmosphere, the solution was cooled to room temperature and stirred to allow crystals to precipitate;

[0198] (3) Filter, wash the wet cake with isopropyl acetate and dry to obtain Form IV of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole.

[0199] In some specific embodiments, in the method for preparing Form IV of Compound A, the molar number of HCl is 2 to 5 times the molar number of Compound A, preferably 3 to 4 times.

[0200] In some embodiments, in the method for preparing Form IV of Compound A, the heating temperature in step (1) is about 65±5°C.

[0201] In the present invention, the crystalline form IV of compound A can remain stable at room temperature. Under high temperature conditions (for example, greater than 100° C.), the crystalline form IV will convert into the crystalline form I.

[0202] Composition

[0203] Another aspect of the present invention relates to a composition comprising:

[0204] Form I of compound A, and

[0205] At least one of the crystalline form III of compound A and the crystalline form IV of compound A.

[0206] In some specific embodiments, the above composition is a mixture of two or more crystal forms of Compound A, which is a mixed crystal form directly prepared from a solution or suspension of Compound A.

[0207] In some specific embodiments, the composition comprises any ratio of Form I, Form III and / or Form IV of Compound A. In some preferred embodiments, the composition comprises any ratio of Form I and Form III of Compound A.

[0208] Pharmaceutical composition (crystal form)

[0209] The present invention also provides a pharmaceutical composition comprising one or more of the above-mentioned crystalline forms of Compound A.

[0210] In particular, another aspect of the present invention relates to a pharmaceutical composition comprising:

[0211] (i) Form I of Compound A, and / or

[0212] Form III of compound A, and / or

[0213] Form IV of compound A, and

[0214] (ii) a pharmaceutically acceptable carrier, diluent or excipient.

[0215] In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent.

[0216] In some embodiments, the pharmaceutical composition comprises an additional therapeutic agent selected from the group consisting of an anticancer agent, an antifungal agent, a cardiovascular therapeutic agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an antiproliferative agent, an agent for treating metabolic diseases, an agent for treating ophthalmic diseases, an agent for treating central nervous system (CNS) diseases, an agent for treating urological diseases, and an agent for treating gastrointestinal diseases.

[0217] Amorphous solid of compound A

[0218] Another aspect of the present invention relates to an amorphous solid of Compound A, which has no obvious crystal diffraction characteristic peaks in its X-ray powder diffraction (XRPD) pattern.

[0219] In some embodiments, the amorphous solid of Compound A has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 15.

[0220] In some embodiments, the amorphous solid of Compound A further comprises a pharmaceutically acceptable polymer.

[0221] In some embodiments, the amorphous solid of Compound A is a solid dispersion of the compound and a polymer.

[0222] In some specific embodiments, in the amorphous solid of compound A, the polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP) and acrylic acid resin copolymer (Eudragit).

[0223] In some embodiments, in the amorphous solid of Compound A, the hypromellose is selected from HPMC E3, HPMC E5 or HPMC E50LV;

[0224] The hydropropyl methylcellulose acetate succinate is selected from HPMCAS LG, HPMCAS MG, HPMCAS HG, HPMCAS MMP or HPMCAS MF;

[0225] The hydropropyl methylcellulose phthalate is selected from HPMCP HP50;

[0226] The acrylic resin copolymer is selected from methacrylic acid / methyl methacrylate copolymer (Eudragit L100) or butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate copolymer (Euragit EPO).

[0227] Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is a pharmaceutically acceptable polymer based on hypromellose, in which the hydroxyl groups on the cellulose backbone are partially substituted with acetyl and succinyl groups. Commercially available HPMCAS products can have varying dissolution pHs, such as 5.5, 6.0, and 6.5, by adjusting the chemical substitution levels of acetyl and succinyl groups. These grades are designated as -L, -M, and -H, respectively. HPMCAS can also be formulated into solid particles of varying particle sizes, such as 5μm, 200μm, and 1000μm, resulting in grades designated as -F, -MP, and -G, respectively. Thus, HPMCAS with a particle size of 1000μm and a dissolution pH of 6.5 can be designated HPMCAS HG; HPMCAS with a particle size of 200μm and a dissolution pH of 6.0 can be designated HPMCAS MMP, and so on.

[0228] In some specific embodiments, in the amorphous solid of compound A, the polymer is selected from one or more of HPMC E3, HPMC E5, HPMC E50LV, HPMCAS LG, HPMCAS MG, HPMCAS HG, HPMCAS MMP, HPMCAS MF, HPMCP HP50, Eudragit L100, and Euragit EPO, preferably one or more of HPMCAS MG, HPMCAS MMP, and HPMCAS MF.

[0229] In some specific embodiments, in the amorphous solid of Compound A, Compound A accounts for about 5% to 25% by weight of the amorphous solid, preferably about 5% to 20%, more preferably about 10% to 20%, and particularly preferably about 10% to 15%.

[0230] In some specific embodiments, in the amorphous solid of Compound A, the mass ratio of Compound A to polymer is about 1:3 to 1:20, preferably about 1:4 to 1:20, more preferably about 1:4 to 1:9, and particularly preferably about 1:5.6 to 1:9.

[0231] In some embodiments, the amorphous solid of Compound A is prepared by spray drying or hot melt extrusion.

[0232] The amorphous solid of Compound A of the present invention, particularly the amorphous solid dispersion of Compound A, can significantly improve the aqueous solubility and bioavailability of Compound A, such as the solubility of Compound A in fasted simulated intestinal fluid (FaSSIF), fed simulated intestinal fluid (FeSSIF), and simulated gastric fluid (SGF). The solubility of the amorphous solid of Compound A is more than three times, and preferably more than five times, that of Compound A crystals.

[0233] The amorphous solid of compound A of the present invention, especially the amorphous solid dispersion of compound A, can remain stable under high temperature, high humidity and light conditions without undergoing crystal transformation, which is conducive to its application in pharmaceutical compositions, pharmaceutical dosage forms and drug preparation.

[0234] The present invention also provides a method for preparing the amorphous solid of compound A, comprising a spray drying method or a hot melt extrusion method.

[0235] Another aspect of the present invention relates to a method for preparing an amorphous solid of compound A, comprising the following steps:

[0236] dissolving compound A and a pharmaceutically acceptable polymer in a solvent to form a solution;

[0237] The solution is spray dried to form a solid dispersion, which is an amorphous solid of Compound A.

[0238] In some specific embodiments, in the method for preparing the amorphous solid of Compound A, the polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP) and acrylic resin copolymer (Eudragit).

[0239] In some embodiments, in the method for preparing the amorphous solid of Compound A, the solvent is one or more selected from alcohols, alkyl halides, ketones, ethers, esters, amides, sulfones, and nitriles. In some embodiments, the solvent is one or more selected from C1-C6 alcohols or polyols, dichloromethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, anisole, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, and acetonitrile.

[0240] In some specific embodiments, in the method for preparing the amorphous solid of compound A, the solvent is a mixture of dichloromethane and methanol, preferably a mixture of dichloromethane and methanol in a volume ratio of 2:1.

[0241] In some specific embodiments, in the method for preparing Compound A, the concentration of Compound A in the solution is about 3-15 mg / mL, preferably about 4-12 mg / mL, and more preferably about 5-10 mg / mL.

[0242] Therefore, the present invention also relates to the amorphous solid of compound A prepared according to the above-mentioned spray drying method.

[0243] Another aspect of the present invention relates to a method for preparing an amorphous solid of compound A, comprising the following steps:

[0244] Compound A is mixed evenly with a pharmaceutically acceptable polymer, and the mixture is extruded through a hot melt extruder to obtain an amorphous solid of Compound A.

[0245] In some specific embodiments, in the method for preparing the amorphous solid of Compound A, the polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP) and acrylic resin copolymer (Eudragit).

[0246] In some specific embodiments, in the method for preparing the amorphous solid of compound A, the heating temperature of the hot melt extruder is 150-200°C, preferably 160-180°C.

[0247] In some specific embodiments, the method for preparing the amorphous solid of Compound A further comprises the steps of crushing and screening the hot-melt extrudate.

[0248] Therefore, the present invention also relates to the amorphous solid of compound A prepared according to the above hot melt extrusion method.

[0249] Pharmaceutical composition (amorphous)

[0250] The present invention also provides a pharmaceutical composition comprising the amorphous solid of Compound A.

[0251] In particular, another aspect of the present invention relates to a pharmaceutical composition comprising:

[0252] (i) an amorphous solid of Compound A, and

[0253] (ii) a pharmaceutically acceptable carrier, diluent or excipient.

[0254] In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent.

[0255] In some embodiments, the pharmaceutical composition comprises an additional therapeutic agent selected from the group consisting of an anticancer agent, an antifungal agent, a cardiovascular therapeutic agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an antiproliferative agent, an agent for treating metabolic diseases, an agent for treating ophthalmic diseases, an agent for treating central nervous system (CNS) diseases, an agent for treating urological diseases, and an agent for treating gastrointestinal diseases.

[0256] Pharmaceutical uses of the crystalline form and amorphous solid of Compound A

[0257] Another aspect of the present invention relates to the use of Form I, Form III, or Form IV of Compound A (1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole), or a mixture of any two or more of these forms in any proportion, or an amorphous solid of Compound A in the preparation of a drug.

[0258] In some embodiments, the drug is used to modulate metalloenzyme activity.

[0259] In some embodiments, the drug is used to regulate the activity of aldosterone synthase CYP11B2.

[0260] In some embodiments, the medicament is used to treat a metalloenzyme-related disorder or disease, wherein the disorder or disease is cancer, cardiovascular disease, endocrine disease, fibrosis, kidney disease, inflammatory disease, infectious disease, gynecological disease, metabolic disease, ophthalmic disease, central nervous system (CNS) disease, urological disease, or gastrointestinal disease.

[0261] In some embodiments, the condition or disease is adrenal cancer, adrenal adenoma, leukemia, breast cancer, hypertension, resistant hypertension, pulmonary hypertension, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, post-myocardial infarction syndrome, coronary heart disease, myocardial necrotic lesions, atrial fibrillation, atherosclerosis, restenosis, endothelial dysfunction, vascular injury, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial thickening, arterial fibrinoid necrosis, vascular disease, diseases associated with primary or secondary aldosteronism and adrenal hyperplasia. Hypertension, diabetes mellitus, metabolic syndrome, insulin resistance, neuropathy, insulinopathy, diabetic nephropathy, diseases characterized by increased collagen formation, fibrosis, and matrix remodeling following hypertension, diseases characterized by fibrosis and matrix remodeling following endothelial cell dysfunction, myocardial fibrosis, vascular fibrosis, renal failure, chronic renal failure, nephropathy, renal dysfunction, kidney disease, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, hypokalemia, retinopathy, sleep apnea, obstructive sleep apnea, muscular dystrophy, stroke, liver disease, nonalcoholic steatohepatitis, cirrhosis, or nonalcoholic fatty liver disease.

[0262] In a preferred embodiment, the condition or disease is hypertension, resistant hypertension, pulmonary hypertension, atherosclerosis or hypokalemia.

[0263] The various crystal forms and amorphous solids of Compound A of the present invention can act as regulators and inhibitors of aldosterone synthase CYP11B2 and can effectively and specifically target CYP11B2, and thus can be used to prevent or treat various conditions or diseases associated with CYP11B2.

[0264] Treatment

[0265] The present invention also provides a method for treating a condition or disease, comprising administering to a subject in need thereof an effective amount of Form I, Form III, or Form IV of Compound A (1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole), or a mixture of any two or more of these forms in any ratio, or an amorphous solid of Compound A. The condition or disease is as described above.

[0266] Example

[0267] The present invention is described in detail below by way of examples, which are not intended to limit the present invention. The experimental methods in the following examples are conventional methods unless otherwise specified. The various reagents and equipment used in the following examples are all commercially available products and there are no special requirements.

[0268] Example 1 Preparation of Form I of Compound A

[0269] The solid of compound A was prepared according to the method described in WO2018 / 125800.

[0270] The solid of compound A is dissolved in an organic solvent selected from formic acid, acetic acid, propionic acid, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, C1-C6 alcohol or polyol, tetrahydrofuran, anisole or acetonitrile, or suspended in the organic solvent, and heated appropriately if necessary to obtain a solution or suspension.

[0271] Add water to the above solution or suspension to precipitate crystals, and stir at room temperature for about 2 hours. The amount of water used is 0.1 to 100 times the volume of the organic solvent used, depending on the mutual solubility of water and the organic solvent used.

[0272] The mixture was filtered, the wet cake was washed with water, and dried at 50±5°C for 16 hours to obtain a crystalline form I sample of compound A.

[0273] Example 2 X-ray powder diffraction (XRPD) test of Form I of Compound A

[0274] The X-ray powder diffraction (XRPD) pattern was measured using a Bruker XRD-D2Phaser X-ray diffractometer at room temperature. The specific information collected is as follows: The radiation source is Cu-Kα radiation. The scanning range (2θ range) was from 3° to 40°, the rotation speed was 20 rpm, the scanning speed was 0.2 s / step, the scanning step size was 0.02°, and the slit width was 0.01. The sample was processed by pressing a glass slide directly onto the test plate. Subsequent XRPD patterns were measured using a similar method.

[0275] The XRPD pattern of Form I of Compound A prepared according to Example 1 was measured, and characteristic diffraction peaks were found at 2θ = 8.87°, 12.41°, 12.97°, 13.92°, 15.39°, 17.61°, 18.20°, 19.64°, 20.37°, 24.17°, 25.06°, 25.84°, 26.65°, 28.00°, 28.79°, 31.96°, and 36.05°, as shown in Figure 1. The error range of the 2θ value was ±0.2°.

[0276] A detailed list of characteristic X-ray diffraction peaks derived from this spectrum is listed in Table 1.

[0277] Table 1 List of XRPD diffraction peaks in Figure 1

[0278] Those skilled in the art will appreciate that these diffraction peaks do not represent an exhaustive representation of the diffraction peaks exhibited by Form I of Compound A. The 2θ values ​​of X-ray powder diffraction patterns can vary slightly between machines, variations in sample preparation, and batches, and the values ​​cited are not to be considered absolute. It should also be understood that the relative intensities of peaks may vary due to orientational effects, and therefore the intensities shown in the XRPD traces included herein are exemplary and are not intended for absolute comparison.

[0279] Example 3 Differential Scanning Calorimetry (DSC) Test of Form I of Compound A

[0280] A DSC spectrum of Form I of Compound A prepared according to Example 1 was measured using a TA Instrument (Discovery DSC 250) thermal analyzer. The DSC test conditions were a heating rate of 10°C / min and a temperature range of room temperature (25°C) to 300°C. The resulting DSC spectrum is shown in Figure 2.

[0281] As shown in Figure 2, the crystal form I of compound A has only one endothermic peak in the DSC test, with an onset temperature of 210.87°C and a peak temperature of 211.60°C. That is, the melting point of the crystal form I of compound A is 211.60°C.

[0282] Example 4 Thermogravimetric analysis (TGA) test of Form I of Compound A

[0283] The TGA spectrum of Form I of Compound A prepared according to Example 1 was measured using a TA Instrument (Discovery TA 55) thermal analyzer. The TGA test conditions were a heating rate of 10°C / min and a temperature range of room temperature (25°C) to 300°C. The resulting TGA spectrum is shown in Figure 3.

[0284] As shown in FIG3 , the weight loss of Form I of Compound A in the heating range of 110-180° C. is only about 0.5%, which means that Form I is an anhydrous crystalline form.

[0285] Example 5 Form I of Compound A 1 H NMR testing

[0286] The crystal form I of compound A prepared in Example 1 was analyzed using an instrument model: AVANCE NEO 400 MHz. 1 H NMR test, the test frequency is: 400 MHz, the solvent is DMSO-d6.

[0287] Tested 1 The H NMR spectrum is shown in FIG4 .

[0288] 1 H NMR(400MHz, DMSO-d6)δ10.00(d,J=2.0Hz,1H),8.56(d,J=2.0Hz,1H),7.93–7.85(m, 2H),7.43(t,J=54.0Hz,1H),4.03–3.97(m,1H),1.22–1.17(m,2H),0.83–0.79(m,2H).

[0289] Example 6 Form I of Compound A 13 C NMR testing

[0290] The crystal form I of compound A prepared in Example 1 was analyzed using an instrument model: AVANCE NEO 400 MHz. 13 C NMR test, the test frequency is: 400 MHz, the solvent is DMSO-d6.

[0291] Tested 13The C NMR spectrum is shown in FIG5 .

[0292] 13 C NMR(100MHz,DMSO-d6)δ155.68,155.43,155.17,151.95,149.86,149.82,149.73,149.57,149.24,149.09,147.32,147.16,146.86,146.71 ,137.92,137.81,133.56,133.45,129.95,123.13,123.10,123.07,1 16.06,113.68,111.30,107.98,107.78,100.74,100.51,26.90,8.99.

[0293] According to the NMR test results of Example 5 and Example 6, the crystalline form I of Compound A contains only molecules of Compound A and does not contain water or other solvents.

[0294] Example 7 Dynamic Water Sorption (DVS) Test of Form I of Compound A

[0295] The dynamic moisture sorption profile of Form I of Compound A prepared according to Example 1 was measured using a ProUmid (instrument model: Vsorp-Enhanced) dynamic moisture sorption instrument. The sample was first dried at 40°C / 0% RH for 3 hours. The experiment was then conducted at 25°C with equilibrium conditions of 0.01% / 45 min. The relative humidity (RH) was increased by 10% in each step (maximum 2 hours, minimum 50 minutes, the same below), ranging from RH 0% to 90%. After equilibration at RH 90% for a maximum of 2 hours, the relative humidity was decreased by 10% in each step (maximum 2 hours, minimum 50 minutes) until RH 0%. The weight change of the sample was recorded during the process and reported as the percentage deviation relative to the minimum sample weight. The resulting dynamic moisture sorption profile is shown in Figure 6.

[0296] As shown in FIG6 , the weight change of Form I of Compound A during the cycle of relative humidity of 0-90% was <0.2%, indicating that Form I was not hygroscopic and was stable under various humidity conditions.

[0297] Example 8 Stability Test of Form I of Compound A

[0298] High-temperature stability: Form I of Compound A prepared according to Example 1 was placed in a 60°C oven. Samples were removed after 5 and 10 days for XRPD analysis to investigate the temperature stability of the crystal form. The results showed that Form I was stable under high-temperature conditions.

[0299] High Humidity Stability: Form I of Compound A prepared according to Example 1 was placed in 92.5% humidity. Samples were removed after 5 and 10 days for XRPD analysis to investigate the humidity stability of the crystal form. The results showed that Form I was stable under high humidity conditions.

[0300] Accelerated stability: Form I of Compound A prepared according to Example 1 was placed in a laboratory chamber at 40°C and 75% relative humidity. After one month, the sample was removed and analyzed by XRPD to assess its stability under high temperature and humidity conditions. The results demonstrated that Form I is stable under these conditions, facilitating the preparation and storage of both the API and the pharmaceutical formulation.

[0301] Light stability: Form I of Compound A prepared according to Example 1 was exposed to 4500 lux light intensity. Samples were removed after 5 and 10 days for XRPD analysis to investigate the stability of the sample under light exposure. The results showed that Form I was stable under light exposure.

[0302] Example 9 Preparation of Form III of Compound A

[0303] 300 mg of Form I of Compound A prepared in Example 1 was weighed and placed in 3 mL of anhydrous acetic acid. The mixture was mixed and heated to 50°C to obtain a suspension. The suspension was then filtered, and the filtrate was cooled to 4°C and allowed to stand. After one day, large crystals were observed to precipitate. The precipitated crystals were collected and dried with filter paper to obtain a Form III sample of Compound A. Observation of the Form III crystals using a polarizing microscope revealed a particle size of approximately 100 μm.

[0304] Example 10 X-ray powder diffraction (XRPD) test of Form III of Compound A

[0305] The XRPD pattern of Form III of Compound A prepared in Example 9 was measured in the same manner as in Example 2, and characteristic diffraction peaks were found at 2θ = 8.39°, 10.21°, 12.40°, 14.05°, 15.75°, 16.66°, 17.53°, 18.10°, 20.22°, 22.07°, 22.55°, 23.37°, 25.84°, 25.23°, 25.70°, 28.18°, 29.34°, 31.37°, 31.92°, and 34.45°, as shown in Figure 7. The error range of the 2θ value was ±0.2°.

[0306] A detailed list of characteristic X-ray diffraction peaks derived from this spectrum is listed in Table 2.

[0307] Table 2 XRPD diffraction peaks in Figure 7

[0308] Those skilled in the art will appreciate that these diffraction peaks do not represent an exhaustive representation of the diffraction peaks exhibited by Form III of Compound A. The 2θ values ​​of X-ray powder diffraction patterns can vary slightly between machines, variations in sample preparation, and batches, and the values ​​cited are not to be considered absolute. It should also be understood that the relative intensities of peaks may vary due to orientational effects, and therefore the intensities shown in the XRPD traces included herein are exemplary and are not intended for absolute comparison.

[0309] Example 11 Differential Scanning Calorimetry (DSC) Test of Form III of Compound A

[0310] The DSC spectrum of the crystalline form III of compound A prepared according to Example 9 was measured in the same manner as in Example 3. The DSC spectrum obtained by the measurement is shown in FIG8 .

[0311] As shown in Figure 8, Form III of Compound A exhibits three endothermic peaks at approximately 63°C, 121°C, and 212°C (onset temperatures) in DSC testing. The endothermic peak with an onset temperature of 62.7°C and a peak temperature of 78.3°C corresponds to the decomposition of acetic acid solvate; the endothermic peak with an onset temperature of 121°C and a peak temperature of 121.4°C corresponds to the boiling point of acetic acid; and the endothermic peak at 212°C corresponds to the melting point of Compound A.

[0312] Example 12 Thermogravimetric analysis (TGA) test of Form III of Compound A

[0313] The TGA spectrum of the crystalline form III of compound A prepared according to Example 9 was measured in the same manner as in Example 4. The TGA spectrum obtained by the measurement is shown in FIG9 .

[0314] As shown in Figure 9, the weight loss of Form III of Compound A in the heating range of 50-150°C is about 15.2%, corresponding to the decomposition of the acetic acid solvate and the volatilization of acetic acid, which means that the stoichiometric ratio of Compound A to acetic acid in the Form III of the acetic acid solvate is 1:1, and the Form III of Compound A is an anhydrous crystalline form.

[0315] Example 13 Thermal Conversion Test of Form III of Compound A

[0316] Several samples of Form III of Compound A prepared according to Example 9 were heated to 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, and 150°C for 30 minutes, then naturally cooled to room temperature. XRPD spectra were then measured for each sample. The results showed that Form III of Compound A spontaneously converted to Form I upon heating to 110°C or higher.

[0317] Example 14 Slurry competition experiment between Form III and Form I of Compound A

[0318] Identical samples of Form I of Compound A prepared according to Example 1 and Form III of Compound A prepared according to Example 9 (10-15 mg each) were weighed and added to 0.5 mL of a solution pre-saturated with Form I. The suspensions were then suspended at room temperature (RT), 50°C, 55°C, 60°C, or 65°C. After a specified period of time, the solids were filtered and immediately analyzed for their crystalline forms by XRPD. The solvents used, suspension temperatures, testing times, XRPD results, and stable crystalline forms are listed in Table 3.

[0319] Table 3 Slurry competition test results of Form III and Form I of Compound A

[0320] As shown in Table 3, Form III of Compound A is a stable crystalline form in an acetic acid solvent system at temperatures <60°C, preferably ≤55°C. Under these conditions, Form I can spontaneously convert to Form III. When the temperature of the acetic acid solvent system is ≥60°C, Form I is a stable crystalline form, and under these conditions, Form III can spontaneously convert to Form I. This phenomenon generally corresponds to the decomposition temperature of the acetic acid solvate observed in DSC testing.

[0321] Furthermore, when the solvent was changed from anhydrous acetic acid to an aqueous system, Form III spontaneously converted to Form I, which remained a stable crystalline form, regardless of temperature. This suggests that the acetic acid molecules in Form III have a lower free energy of binding with water and spontaneously migrate into water in an aqueous solvent system, disrupting the structure of the acetic acid solvate. Furthermore, Form I of Compound A remained a thermodynamically stable crystalline form throughout the crystallization process.

[0322] Example 15 Preparation of Form IV of Compound A

[0323] Under N2 atmosphere, the solid of compound A was dissolved in isopropyl acetate at 65±5°C, and a 4M HCl isopropanol solution was added so that the molar number of HCl was 3 times that of compound A, and stirred for 2 hours.

[0324] Under N2 atmosphere, the solution was cooled to 25±5°C and stirred for 2 hours to allow crystals to precipitate.

[0325] The mixture was filtered, the wet cake was washed with isopropyl acetate, and dried at 50±5° C. for 16 hours to obtain a Form IV sample of Compound A.

[0326] Example 16 X-ray powder diffraction (XRPD) test of Form IV of Compound A

[0327] The XRPD pattern of Form IV of Compound A prepared in Example 15 was measured in the same manner as in Example 2, showing characteristic diffraction peaks at 2θ = 9.70°, 10.34°, 12.97°, 15.55°, 17.18°, 17.85°, 19.13°, 20.37°, 21.31°, 23.00°, 24.06°, 24.49°, 25.15°, 28.08°, 28.54°, 29.05°, 32.71°, and 34.27°, as shown in Figure 10. The error range of the 2θ value is ±0.2°.

[0328] A detailed list of characteristic X-ray diffraction peaks derived from this spectrum is listed in Table 4.

[0329] Table 4 XRPD diffraction peak list in Figure 10

[0330] Those skilled in the art will appreciate that these diffraction peaks do not represent an exhaustive representation of the diffraction peaks exhibited by Form IV of Compound A. The 2θ values ​​of X-ray powder diffraction patterns can vary slightly between instruments, variations in sample preparation, and batches, and the values ​​cited are not to be considered absolute. It should also be understood that the relative intensities of peaks may vary due to orientational effects, and therefore the intensities shown in the XRPD traces included herein are exemplary and not intended for absolute comparison.

[0331] Example 17 Differential Scanning Calorimetry (DSC) Test of Form IV of Compound A

[0332] The DSC spectrum of the crystalline form IV of compound A prepared according to Example 15 was measured in the same manner as in Example 3. The DSC spectrum obtained by the measurement is shown in FIG11 .

[0333] As shown in Figure 11, the crystal form IV of compound A has a broad endothermic peak in the range of about 160-180°C in the DSC test, which corresponds to the decomposition of the hydrochloride salt; in addition, the endothermic peak with an onset temperature of 205.81°C and a peak temperature of 208.92°C corresponds to the melting point of compound A.

[0334] Example 18 Thermogravimetric analysis (TGA) test of Form IV of Compound A

[0335] The TGA spectrum of the crystalline form IV of compound A prepared according to Example 15 was measured in the same manner as in Example 4. The TGA spectrum obtained by the measurement is shown in FIG12 .

[0336] As shown in Figure 12, the weight loss of Form IV of Compound A in the heating range of 145-205°C is about 9.9%, corresponding to the decomposition of the hydrochloride and the volatilization of hydrochloric acid (HCl), which means that the stoichiometric ratio of Compound A to HCl in the hydrochloride is 1:1, and Form IV of Compound A is an anhydrous crystalline form.

[0337] Example 19 Form IV of Compound A 1 H NMR testing

[0338] The same method as in Example 5 was used to prepare Form IV of Compound A in Example 15. 1 H NMR test. 1 The H NMR spectrum is shown in FIG13 .

[0339] 1 H NMR (400MHz, DMSO-d6) δ10.00(d,J=2.0Hz,1H),9.00(s,1H),8.58(d,J=2.0Hz,1H),7.89 (m,2H),7.46(t,J=54.0Hz,1H),4.03–3.97(m,1H),1.22–1.17(m,2H),0.83–0.79(m,2H).

[0340] According to the above 1 The H NMR test results show that Form IV of Compound A contains molecules of Compound A and HCl in a stoichiometric ratio of 1:1, and does not contain water or other solvents.

[0341] Example 20 Slurry competition experiment of Form IV of Compound A

[0342] Approximately 200 mg of Form IV of Compound A prepared according to Example 15 was weighed and placed in 1 mL of anhydrous acetic acid. The suspension was allowed to suspend at room temperature for 3 days. A sample was collected and filtered to obtain a solid, which was immediately analyzed by XRPD. The XRPD pattern showed that the crystalline form was still Form IV.

[0343] The suspension was heated to 65°C and stirred until the solid was completely dissolved.

[0344] 1 mL of water was added, and solid precipitation was observed. The mixture was then stirred at 65° C. for 3 hours, and a sample was taken and filtered to obtain a solid, which was immediately tested for its crystal form by XRPD. The XRPD pattern showed that the crystal form was Form I + Form III (a small amount).

[0345] The suspension was stirred at 65° C. for 2 days, and a sample was taken and filtered to obtain a solid, which was immediately tested for its crystal form by XRPD. The XRPD pattern showed that the crystal form was Form I.

[0346] The above experiments show that the crystalline form IV of compound A is a stable crystalline form in an acetic acid solvent system or an anhydrous system at room temperature.

[0347] In addition, after Form IV is completely dissolved by heating, its crystallization behavior is the same as that of Form I and Form III described in Example 14, that is, Form I is a thermodynamically stable form in an aqueous system, and other forms of Compound A will eventually spontaneously convert into Form I.

[0348] Example 21 Solubility test of compound A

[0349] To test the equilibrium solubility of Form I of Compound A in FaSSIF, approximately 2 mg of a sample of Compound A was added to an 8 mL glass vial, 1 mL of FaSSIF was added, and the mixture was stirred at 25°C for 24 hours. The suspension was then centrifuged and the concentration of Compound A in the supernatant was tested by HPLC to be 5.6 μg / mL. This concentration was taken as the equilibrium solubility of Compound A in FaSSIF.

[0350] The solubility of Compound A in organic solvents was further tested. Approximately 2 mg of Compound A sample was added to a 2 mL glass vial. Organic solvent was added in 10 μL increments until the solid was completely dissolved or 1 mL of organic solvent had been added. The concentration of Compound A in the solution was then measured by HPLC. The organic solvents used and the solubility of Compound A are listed in Table 5.

[0351] Table 5 Solubility test of compound A in organic solvents

[0352] Based on the results of the above solubility tests, a mixture of methanol / DCM with a volume ratio of 1:2 was used as the solvent in the experiment of preparing amorphous solids by the solvent method.

[0353] Example 22 Testing of the Inhibitory Ability of Pharmaceutically Acceptable Polymers on the Crystallization of Compound A

[0354] In this example, the ability of the polymer to inhibit the crystallization of Compound A was first preliminarily screened by the rapid evaporation method, and then the spray drying method was used to determine whether the obtained solid dispersion was amorphous and the degree of crystallization of Compound A.

[0355] The polymers tested included: PVP (polyvinyl pyrrolidone) K30, PVP-VA64 (ethyl pyrrolidone / vinyl acetate (6:4) copolymer), SOLUPLUS (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer), HPMC E3 (molecular weight 20,000), HPMC E5, HPMC E50LV, HPMCAS MG (particle size 1,000 μm, dissolution pH 6.0), HPMCAS (hydroxypropyl methylcellulose acetate succinate) LG (particle size 1,000 μm, dissolution pH 5.5), HPMCPHP50 (dissolution pH 5.0), HPC SSL (molecular weight 40,000), Eudragit L100 (methacrylic acid / methacrylic acid ester (1:1) copolymer), Euragit EPO butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate (1:2:1) copolymer.

[0356] To prepare a solid dispersion using the rapid evaporation method, approximately 10 mg of Compound A was added to a 40 mL glass vial. The polymer was then added at a drug loading ratio of 10%-20%. 1 mL of a 1:2 methanol / DCM mixture was then added to dissolve the mixture to obtain a clear solution. The vial was covered with filter paper and heated in a vacuum oven at 60°C for 1 hour to rapidly evaporate the solvent to obtain a solid dispersion. Polarized light microscopy was used to determine whether the resulting solid was crystalline.

[0357] Testing revealed that PVP K30, PVP VA64, SOLUPLUS, HPC SSL, and Eudragit L100 exhibited a distinct crystalline structure when rapidly evaporated at a drug loading of 10%. HPMC E3, HPMC E5, HPMCP HP50, HPMCAS MG, HPMCAS HG, HPMCAS LG, Eudragit EPO, and HPMC E5 were able to achieve a substantially amorphous solid structure when rapidly evaporated at drug loadings of 10%-15% or higher. Furthermore, combining two or more polymers was tested, and it was found that the use of HPMC E50LV was beneficial in obtaining amorphous solids at higher drug loadings.

[0358] To prepare a spray-dried dispersion (SDD) via spray drying, approximately 200 mg of Compound A was added to a 100 mL flask. A polymer was then added at a drug loading of 10%-20%. 40 mL of a 1:2 methanol / DCM mixture was then added to dissolve the polymer into a clear solution. The solid dispersion obtained by spray drying was then analyzed by XRPD to determine if the resulting solid was crystalline.

[0359] Spray-dried dispersions of HPMC E3, HPMC E50LV, HPMCP HP50, HPMCAS MG, HPMCAS HG, HPMCAS LG, Eudragit L100, and Eudragit EPO with Compound A at a drug loading of 10% to 20% were tested to have amorphous or substantially amorphous structures. The XRPD pattern of a portion of the spray-dried dispersion is shown in Figure 14 .

[0360] The above experiments show that when the polymer used is selected from HPMC E3, HPMC E5, HPMC E50LV, HPMCAS, HPMCP HP50, Eudragit L100, Euragit EPO, etc., especially when the drug loading amount of the solid dispersion is 10% to 15%, an amorphous solid dispersion with substantially no characteristic X-ray diffraction peaks can be obtained by spray drying.

[0361] Example 23 Kinetic Solubility Test of Amorphous Solid Dispersion of Compound A

[0362] In a kinetic solubility test, the spray-dried dispersion (SDD) prepared in Example 22 was added to an 8 mL glass vial containing 5 mL of FaSSIF at a target concentration of 0.5 mg / mL of Compound A. The mixture was stirred magnetically at 150 rpm and 37°C. 0.5 mL samples were collected at 15, 30, 60, and 120 minutes, and the supernatant was centrifuged and appropriately diluted before analysis by HPLC to determine the solubility of Compound A. The endpoint pH of the solution at 120 minutes was also measured using a pH meter. The results are shown in Table 6.

[0363] Table 6 Kinetic solubility test of amorphous solid dispersion of compound A

[0364] These experiments demonstrate that when Compound A is mixed with a polymer to form an amorphous solid dispersion, the kinetic solubility of Compound A in FaSSIF is enhanced. For most amorphous solid dispersions of Compound A, the solubility is 3-5 times higher than that of Compound A crystals (Form I).

[0365] Example 24 Preparation of an amorphous solid of compound A by spray drying

[0366] 1.5 g of Compound A, 8.5 g of HPMCAS MG, and 200 mL of a 1:2 methanol / DCM mixture were added to a 200 mL flask and dissolved to obtain a clear solution. An amorphous solid of Compound A was prepared by spray drying. The spray-dried solid was collected and dried under vacuum at 50°C for 3 hours to obtain an 8.79 g amorphous solid sample. The XRPD pattern of the amorphous solid of Compound A was measured using the same method as in Example 2, and its TGA pattern was measured using the same method as in Example 4, and are shown in Figures 15 and 17, respectively.

[0367] In addition, a modulated differential scanning calorimetry (mDSC) spectrum of an amorphous solid of Compound A was measured using a TA Discovery Q2000 thermal analyzer. The test conditions were a temperature range of room temperature to 200°C, a modulation amplitude of ±0.32°C / minute, a modulation period of 60 seconds, and a heating rate of 2°C / minute. The resulting mDSC spectrum is shown in Figure 16. The three curves in Figure 16, from top to bottom, represent the reversible sample heat flow, the irreversible sample heat flow, and the total heat flow, respectively.

[0368] As shown in FIG15 , the amorphous solid of Compound A obtained in this example lacks characteristic X-ray diffraction peaks, demonstrating its amorphous nature. As shown in FIG16 , the mDSC spectrum shows a single glass transition temperature, Tg, of 95.59° C., demonstrating uniform distribution of Compound A and the polymer HPMCAS MG in the solid dispersion. As shown in FIG17 , the TGA spectrum reveals a weight loss of approximately 1.5% over the range of room temperature to 150° C.

[0369] In addition, the content of Compound A in the solid dispersion was determined to be approximately 14.93% by HPLC, which was highly consistent with the drug loading of 15%. GC also confirmed that the solid dispersion did not contain any residual solvent.

[0370] Example 25 Two-step dissolution test of amorphous solid of Compound A

[0371] A two-step dissolution test simulates the dissolution of Compound A in gastric and intestinal fluids after oral administration. 50 mg of the amorphous solid of Compound A prepared in Example 24 and 7.5 mg of Compound A crystals (Form I) were weighed and placed in a 40 mL glass vial. 5 mL of simulated gastric fluid (SGF, pH 1.3) was added. The mixture was magnetically stirred at 150 rpm for 30 minutes at 37°C. A 0.5 mL sample was taken and the supernatant was centrifuged. The supernatant was appropriately diluted and analyzed by HPLC to determine the solubility of Compound A.

[0372] Immediately after sampling, 10 mL of fasting simulated intestinal fluid (cFaSSIF, pH 12.1) was added to the glass bottle to a target concentration of 0.5 mg / mL of Compound A. Stirring was continued, and 0.5 mL of the sample was collected at 15, 30, 60, and 120 minutes, respectively. The supernatant was centrifuged and appropriately diluted before HPLC analysis to determine the solubility of Compound A. Furthermore, the endpoint pH of the solution at 120 minutes was measured using a pH meter. The results are shown in Table 7.

[0373] Table 7 Two-step dissolution test of amorphous solid of Compound A

[0374] These results demonstrate that a solid dispersion of Compound A with a 15% drug loading in HPMCAS MG significantly improves the solubility and dissolution performance of Compound A in gastric and intestinal fluids. Compared to Compound A crystals (Form I), the solubility in SGF increased approximately 7-fold, and the solubility in FaSSIF increased approximately 3-4-fold.

[0375] Example 26 Stability Test of Amorphous Solid of Compound A Prepared by Spray Drying

[0376] High-temperature stability: The amorphous solid of Compound A prepared according to Example 24 was placed in a 40°C oven. Samples were removed for XRPD analysis after one, two, and four weeks to assess the temperature stability of the sample. The results showed that the amorphous solid of Compound A remained amorphous after four weeks at 40°C, demonstrating that the amorphous solid of Compound A can remain stable at temperatures above room temperature.

[0377] Ambient Stability: The amorphous solid of Compound A prepared according to Example 24 was placed in a laboratory chamber at 25°C and 60% relative humidity. Samples were removed for XRPD analysis after one, two, and four weeks to assess the sample's stability under ambient conditions. The results demonstrated that the amorphous solid of Compound A remained amorphous after four weeks and was stable under ambient conditions.

[0378] Example 27 Preparation of an amorphous solid of compound A by hot melt extrusion

[0379] First, the thermal stability of compound A was tested by TGA. Compound A was placed in a TGA analyzer and heated to 150°C, 160°C, 170°C, 180°C, 190°C, 200°C, and 210°C for 30 minutes. The results showed that when the heating temperature was 170°C or lower, compound A had essentially no weight change within 30 minutes, and no thermal degradation was found by HPLC testing; when the heating temperature was 180°C, 190°C, 200°C, and 210°C, the sample weights after 30 minutes were 97.9%, 95.3%, 95.5%, and 53.6%, respectively, but no thermal degradation was found by HPLC testing, indicating that compound A had good thermal stability and only sublimated when approaching the melting point. In the following hot melt extrusion experiments, the temperature of the hot melt extruder was set to below 200°C, specifically 150°C, 160°C, 170°C, 180°C, or 190°C.

[0380] 3 g of Compound A and 17 g of HPMCAS MF were placed in a sealed bag and manually shaken for 10 minutes. The mixture was then loaded into a hot melt extruder (Three-Tec, Model: ZE 5HMI) and hot melt extruded at a set temperature of 150° C., 160° C., 170° C., 180° C., or 190° C. The extrudate (HME) was ground into a powder, and the crystal morphology was determined by XRPD, as shown in FIG18 , and the purity was determined by HPLC.

[0381] Visual inspection of the extrudates revealed that samples extruded at 160°C-190°C were all transparent, while samples extruded at 150°C were opaque, likely due to insufficient solid solution formation of Compound A. As shown in Figure 18, all five hot-melt extruded samples prepared above were amorphous. HPLC results indicated that the extrudates had a purity exceeding 99%.

[0382] The mDSC spectrum of the amorphous solid of Compound A extruded at 170°C was measured using the same method as in Example 24. The TGA spectrum of the amorphous solid of Compound A extruded at 170°C was measured using the same method as in Example 4, and are shown in Figures 19 and 20, respectively. In Figure 19, the three curves from top to bottom represent the irreversible sample heat flow, the total heat flow, and the reversible sample heat flow, respectively.

[0383] As shown in Figure 19 , the mDSC spectrum shows a single glass transition temperature, Tg, of 95.64°C, demonstrating uniform distribution of Compound A and polymer HPMCAS MF in the solid dispersion. As shown in Figure 20 , the TGA spectrum shows a weight loss of approximately 2.0% in the range from room temperature to 150°C.

[0384] Example 28 Two-step dissolution test of amorphous solid of Compound A

[0385] The two-step dissolution results of the amorphous solid of Compound A prepared in Example 27 were measured in the same manner as in Example 25, as shown in Table 8.

[0386] Table 8 Two-step dissolution test of amorphous solid of Compound A

[0387] The above results show that the hot melt extrudate of Compound A with a drug loading of 15% and HPMCAS MF can significantly improve the solubility and dissolution performance of Compound A in gastric juice and intestinal juice. Compared with Compound A crystals (crystalline form I), the solubility in SGF is increased by nearly 4 times, and the solubility in FaSSIF is increased by about 2 to 3 times. Under the same formula, the dissolution rate of the hot melt extrudate is lower than that of the spray-dried solid dispersion, mainly because the particle size of the solid particles obtained by the two preparation methods is different. The hot melt extrudate with a larger particle size has a smaller specific surface area, which limits the dissolution rate of the drug.

[0388] Example 29 Stability Test of Amorphous Solid of Compound A Prepared by Hot Melt Extrusion

[0389] High-temperature stability: The amorphous solid of Compound A prepared according to Example 27 was placed in an oven at 40°C or 60°C. Samples were removed after one, two, and four weeks for XRPD analysis to assess the temperature stability of the samples. The results showed that the amorphous solid of Compound A remained amorphous after four weeks at both 40°C and 60°C, demonstrating its stability under high-temperature conditions.

[0390] Ambient Stability: The amorphous solid of Compound A prepared according to Example 24 was placed in a laboratory chamber at 25°C and 60% relative humidity. Samples were removed for XRPD analysis after one, two, and four weeks to assess the sample's stability under ambient conditions. The results demonstrated that the amorphous solid of Compound A remained amorphous after four weeks and was stable under ambient conditions.

[0391] Accelerated stability: The amorphous solid of Compound A prepared according to Example 24 was placed in a test chamber at 40°C and 75% relative humidity. Samples were removed for XRPD analysis after one, two, and four weeks to assess the sample's stability under high temperature and humidity. The results showed that the amorphous solid of Compound A remained amorphous after four weeks, demonstrating stability under accelerated conditions.

[0392] The exemplary embodiments of the present invention have been described above by way of examples, but the present invention is not limited thereto. Those skilled in the art will appreciate that the above examples are for illustrative purposes only, and the specific embodiments and examples of the present invention should not be construed as limiting the scope of the present invention. The examples contain important additional information, illustrations, and guidance that can be practiced by the present disclosure in its various embodiments and equivalents. The embodiments can be changed and modified within the scope of the subject matter of the present invention, and the manner of such changes and modifications should fall within the scope of protection of the present invention.

Claims

1. Polymorph I of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, In the X-ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2θ of approximately 8.9°, 12.4°, 17.6°, 25.0°, and 25.8°.

2. Polymorph I of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, In the X-ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2θ of approximately 8.9°, 12.4°, 17.6°, 18.2°, 19.6°, 24.2°, 25.0°, 25.8°, 26.7°, 28.0°, and 28.8°.

3. Polymorph I of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, It has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1.

4. The crystalline form I of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 1 to 3, characterized in that, The crystalline form I is an anhydrous crystalline form.

5. The crystalline form I of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 1 to 3, characterized in that, The crystalline form I satisfies any one or more of the following: When performing thermal analysis using differential scanning calorimetry (DSC), it has an endothermic peak at approximately 211.6°C ± 2.0°C. Preferably, it has a DSC pattern substantially as shown in Figure 2. When performing thermal analysis using thermogravimetric analysis (TGA), it has a TGA pattern substantially as shown in Figure 3. And When performing analysis using dynamic vapor sorption (DVS), it has a DVS pattern substantially as shown in Figure 6.

6. A method for preparing crystalline form I of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 1 to 5, characterized in that, It includes the following steps: (1) Dissolve or suspend the solid of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole in an organic solvent, where the organic solvent is one or more selected from organic acids, amides, sulfones, alcohols, ethers, and nitriles, preferably selected from organic acids and amides. (2) Add water to the above solution or suspension to precipitate crystals, where the amount of water used is 0.1 to 100 times the volume of the organic solvent. (3) Filter and collect the crystals and dry them to obtain the crystalline form I of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole.

7. The preparation method according to claim 6, characterized in that, The organic solvent is selected from formic acid, acetic acid, propionic acid, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, C1-C6 alcohols or polyols, tetrahydrofuran, anisole, or acetonitrile.

8. Polymorph III of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, In the X-ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2θ of approximately 8.4°, 10.2°, 12.4°, 16.7°, 18.1°, 22.1°, 24.8°, and 25.7°.

9. Polymorph III of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, In the X-ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2θ of approximately 8.4°, 10.2°, 12.4°, 14.0°, 15.8°, 16.7°, 17.5°, 18.1°, 20.2°, 22.1°, 22.6°, 23.4°, 24.8°, 25.2°, 25.7°, and 28.2°.

10. Crystal form III of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, It has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 7.

11. Polymorph III of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 8 to 10, characterized in that, The crystalline form III is an acetic acid-containing crystalline form, preferably an acetic acid solvate crystalline form.

12. Polymorph III of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 8 to 10, characterized in that, The crystalline form III satisfies any one or more of the following: When performing thermal analysis using differential scanning calorimetry (DSC), it has endothermic peaks at approximately 78.3 °C ± 2 °C, 121.4 °C ± 2 °C, and / or 212.2 °C ± 2 °C. Preferably, it has a DSC pattern substantially as shown in Figure 8; and When performing thermal analysis using thermogravimetric analysis (TGA), it has a TGA pattern substantially as shown in Figure 9.

13. A compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo as claimed in any one of claims 8 to 12 [d]A method for preparing crystalline form III of imidazole, characterized in that it comprises the following steps: (1) Adding a solid of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole to anhydrous acetic acid and suspending it under heating conditions; (2) Filtering, and allowing the filtrate to stand for precipitation under cooling conditions; (3) Filtering to collect the crystals and drying them to obtain crystalline form III of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole.

14. The preparation method according to claim 13, characterized in that the temperature of the heating suspension is < 60 °C, preferably ≤ 55 °C, more preferably ≤ 50 °C; and / or 15. Polymorph IV of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, the temperature of the cooling and standing is ≤ 10 °C, preferably ≤ 5 °C.

16. Polymorph IV of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, In the X-ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2θ of approximately 9.7°, 13.0°, 15.6°, 19.1°, 23.0°, 24.1°, 24.5°.

17. Polymorph IV of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, In the X-ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2θ of approximately 9.7°, 13.0°, 15.6°, 17.2°, 17.9°, 19.1°, 20.4°, 21.3°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, 32.7°, 34.3°.

18. Polymorph IV of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 15 to 17, characterized in that, It has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 10. Crystal Form IV of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 15 to 17, characterized in that, The crystalline form is a hydrochloride-containing crystalline form, preferably the crystalline form of the hydrochloride of the compound, more preferably the anhydrous crystalline form. The crystalline form IV satisfies any one or more of the following: When performing thermal analysis using differential scanning calorimetry (DSC), it has endothermic peaks at approximately 180.5 °C ± 2 °C and / or 209 °C ± 2 °C. Preferably, it has a DSC pattern substantially as shown in Figure 11; and Process for preparing crystalline form IV of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 15 to 19, characterized in that, When performing thermal analysis using thermogravimetric analysis (TGA), it has a TGA pattern substantially as shown in Figure 12. It comprises the following steps: (1) Dissolving a solid of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole in a heated organic solvent containing HCl. The organic solvent preferably comprises isopropyl acetate and isopropanol; (2) Under an inert atmosphere, cooling the solution to room temperature and stirring to precipitate crystals; (3) Filtering, washing the wet filter cake with isopropyl acetate and drying to obtain crystalline form IV of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole.

21. The preparation method according to claim 20, characterized in that, The number of moles of the HCl is 2 to 5 times, preferably 3 to 4 times, the number of moles of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole.

22. A composition comprising: Polymorph I of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 1 to 5, and At least one of polymorph III of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 8 to 12 and polymorph IV of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 15 to 19.

23. A pharmaceutical composition comprising: (i) Polymorph I of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 1 to 5, and / or Polymorph III of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 8 to 12, and / or Polymorph IV of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 15 to 19, and (ii) A pharmaceutically acceptable carrier, diluent or excipient.

24. The amorphous solid of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, There are no obvious crystal diffraction characteristic peaks in the X-ray powder diffraction (XRPD) pattern.

25. The amorphous solid of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to claim 24, characterized in that, It has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 15.

26. The amorphous solid of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to claim 24 or 25, characterized in that, The amorphous solid further comprises a pharmaceutically acceptable polymer; preferably, the amorphous solid is a solid dispersion of the compound and the polymer.

27. The amorphous solid of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to claim 26, characterized in that, The polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), and acrylic resin copolymer (Eudragit).

28. The amorphous solid of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to claim 26, characterized in that, The polymer is selected from one or more of HPMC E3, HPMC E5, HPMC E50LV, HPMCAS LG, HPMCAS MG, HPMCAS HG, HPMCAS MMP, HPMCAS MF, HPMCP HP50, Eudragit L100, Euragit EPO, preferably one or more of HPMCAS MG, HPMCAS MMP, HPMCAS MF. The amorphous solid of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 26 to 28, characterized in that, The compound accounts for about 5% to 25% by weight of the amorphous solid, preferably about 5% to 20%, more preferably about 10% to 20%, and particularly preferably about 10% to 15%. The amorphous solid of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 26 to 28, characterized in that, The mass ratio of the compound to the polymer is about 1:3 to 1:19, preferably about 1:4 to 1:19, more preferably about 1:4 to 1:9, and particularly preferably about 1:5.6 to 1:

9.

31. An amorphous solid of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 24 to 30, characterized in that, The amorphous solid is prepared by a spray drying method or a hot melt extrusion method.

32. A method for preparing an amorphous solid of a compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, Comprising the following steps: Dissolve the compound and a pharmaceutically acceptable polymer in a solvent to form a solution; Spray dry the solution to form a solid dispersion, which is the amorphous solid.

33. The preparation method according to claim 32, wherein The polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), and acrylic resin copolymer (Eudragit).

34. The preparation method according to claim 32 or 33, characterized in that, The solvent is selected from one or more of alcohols, halogenated alkanes, ketones, ethers, esters, amides, sulfones, and nitriles; preferably, the solvent is selected from one or more of C1-C6 alcohols or polyols, dichloromethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, anisole, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, and acetonitrile.

35. The preparation method according to any one of claims 32 to 34, characterized in that, The solvent is a mixture of dichloromethane and methanol, preferably a mixture of dichloromethane and methanol with a volume ratio of 2:

1.

36. The preparation method according to any one of claims 32 to 35, characterized in that, The concentration of the compound in the solution is about 3-15 mg / mL, preferably about 4-12 mg / mL, and more preferably about 5-10 mg / mL.

37. An amorphous solid of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole prepared by the preparation method according to any one of claims 32 to 36.

38. A method for preparing an amorphous solid of a compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, Comprising the following steps: Mix the compound and a pharmaceutically acceptable polymer evenly and extrude through a hot melt extruder to obtain the amorphous solid.

39. The preparation method according to claim 38, wherein, The polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), and acrylic resin copolymer (Eudragit).

40. The preparation method according to claim 38 or 39, characterized in that, The heating temperature of the hot melt extruder is 150-200 °C, preferably 160-180 °C.

41. The preparation method according to any one of claims 38 to 40, characterized in that, It further includes the steps of crushing and sieving the hot melt extrudate.

42. An amorphous solid of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole prepared by the preparation method according to any one of claims 38 to 41.

43. A pharmaceutical composition, which comprises: (i) The amorphous solid of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 24 to 31, 37, and 42, and (ii) A pharmaceutically acceptable carrier, diluent, or excipient.

44. The pharmaceutical composition according to claim 23 or 43, which further comprises an additional therapeutic agent.

45. The pharmaceutical composition according to claim 44, wherein the additional therapeutic agent is selected from anti-cancer agents, anti-fungal agents, cardiovascular therapeutic agents, anti-inflammatory agents, chemotherapeutic agents, anti-angiogenic agents, cytotoxic agents, anti-proliferative agents, therapeutic agents for metabolic diseases, therapeutic agents for ophthalmic diseases, therapeutic agents for central nervous system (CNS) diseases, therapeutic agents for urinary diseases, and therapeutic agents for gastrointestinal diseases.

46. Use of crystalline form I of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 1 to 5, crystalline form III of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 8 to 12, crystalline form IV of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 15 to 19, or a mixture of any two or more crystalline forms in any proportion, or the amorphous solid of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 24 to 31, 37 and 42 in the preparation of a medicament.

47. The use according to claim 46, wherein the medicament is used to modulate metalloenzyme activity.

48. The use according to claim 46, wherein the medicament is used to modulate the activity of aldosterone synthase CYP11B2.

49. The use according to claim 46, wherein the medicament is used to treat a metalloenzyme-related disorder or disease, wherein the disorder or disease is cancer, cardiovascular disease, endocrine disease, fibrosis, kidney disease, inflammatory disease, infectious disease, gynecological disease, metabolic disease, ophthalmic disease, central nervous system (CNS) disease, urinary disease, or gastrointestinal disease.

50. Use according to claim 49, wherein the disorder or disease is adrenocortical carcinoma, adrenal adenoma, leukemia, breast cancer, hypertension, refractory hypertension, pulmonary arterial hypertension, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, post-myocardial infarction syndrome, coronary heart disease, myocardial necrosis lesions, atrial fibrillation, atherosclerosis, restenosis, endothelial dysfunction, vascular injury, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial thickening, arterial fibrinoid necrosis, vascular diseases, conditions associated with primary or secondary hyperaldosteronism and adrenal hyperplasia, diabetes, metabolic syndrome, insulin resistance, neuropathy, insulinopathy, diabetic nephropathy, diseases characterized by increased collagen formation, fibrosis and matrix remodeling after hypertension, diseases characterized by fibrosis and matrix remodeling after endothelial cell dysfunction, myocardial fibrosis, vascular fibrosis, renal failure, chronic renal failure, kidney diseases, renal dysfunction, kidney diseases, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, hypokalemia, retinopathy, sleep apnea, obstructive sleep apnea, muscular dystrophy, stroke, liver diseases, non-alcoholic steatohepatitis, cirrhosis or non-alcoholic fatty liver disease.

51. Use according to claim 50, wherein the disorder or disease is hypertension, refractory hypertension, pulmonary arterial hypertension, atherosclerosis or hypokalemia.

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