Crystal form of quinazolinone derivative, preparation method therefor and use thereof

Abstract

The present invention provides a crystal form of a BRAF kinase inhibitor, a preparation method therefor and a use thereof, and specifically relates to crystal form A of a compound as shown in formula (I), a preparation method for the crystal form A and a use of the crystal form A in the preparation of drugs for treating / preventing BRAF-mediated diseases.

Description

A crystal form of a quinazolinone derivative, its preparation method and application Technical Field

[0001] The present invention relates to a crystal form of a BRAF kinase inhibitor, a preparation method and application thereof, and particularly to a crystal form A of a quinazolinone derivative, a preparation method and application thereof, belonging to the technical field of medicinal chemistry. Background Art

[0002] MAP kinases (MAPKs) are a family of serine / threonine kinases that respond to a variety of extracellular growth signals. For example, growth hormone, epidermal growth factor, platelet-derived growth factor, and insulin are all thought to participate in mitogenic stimulation of the MAPK pathway. Activation of this pathway at the receptor level triggers a signaling cascade whereby the Ras GTPase exchanges GDP for GTP. Next, Ras activates Raf kinase (also known as MAPKKK), which in turn activates MEK (MAPKK).

[0003] The BRAF protein is a member of the RAF family of serine / threonine kinases that participates in the Ras Raf MEK extracellular signal-regulated kinase (ERK) pathway or the mitogen-activated protein kinase (MAPK) / ERK signaling pathway cascade that affects cell division and differentiation. BRAF gene mutations can lead to uncontrolled growth and subsequent tumor formation. BRAF is mutated and / or overactivated in common human cancers such as melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, and ovarian cancer and its metastatic cancers, and primary brain tumors. Although some BRAF inhibitors produce excellent extracranial responses, cancer may still develop brain metastases during or subsequently with BRAF inhibitor therapy. An estimated 20% of subjects with cancer will develop brain metastases, with the majority of brain metastases occurring in those subjects with melanoma, colorectal cancer, lung cancer, and renal cell carcinoma. Brain metastases remain a substantial contributor to overall cancer mortality in subjects with advanced cancer, and despite multimodality treatment and advances in systemic therapy, which includes combinations of surgery, radiotherapy, chemotherapy, immunotherapy, and / or targeted therapies, the prognosis remains poor.

[0004] In addition, BRAF has been identified as a potential target for the treatment of primary brain tumors. The prevalence of the BRAF V600E mutation in primary brain tumors has been reported by Schindler et al. in their analysis of 1,320 central nervous system (CNS) tumors and Behling et al. in their analysis of 969 CNS tumors in pediatric and adult populations. These studies, combined with other studies, have reported the presence of the BRAF V600E mutation in various cancers, including papillary craniopharyngioma, pleomorphic xanthomatous astrocytoma (PXA), ganglioglioma, astroblastoma, and others.

[0005] The blood-brain barrier (BBB) ​​is a highly selective physical transport and metabolic barrier that separates the CNS from the blood. The BBB prevents certain drugs from entering brain tissue and is a limiting factor for many peripherally administered agents to be delivered to the CNS. Many drugs commonly used to treat cancer cannot cross the blood-brain barrier. This means that these drugs cannot penetrate the brain and therefore cannot effectively kill cancer cells in the brain. Current treatments for subjects with brain tumors include surgical resection, radiotherapy, and / or chemotherapy using agents such as temozolomide and / or bevacizumab. However, surgical treatment of brain cancer is not always possible, for example, the tumor may not be accessible, or the subject may not be able to withstand neurosurgical trauma. In addition, known radiotherapy and treatments using cytotoxic agents have undesirable side effects. For example, there is increasing evidence that the use of temozolomide itself can induce mutations and worsen prognosis in a large proportion of subjects, and the bevacizumab label has a black box warning for gastrointestinal perforation, surgical and wound healing complications, and bleeding. Kinase inhibitors are used to treat many peripheral cancers. However, due to their structural properties, many kinase inhibitors such as BRAF inhibitors (e.g., vemurafenib and dabrafenib) are substrates of active transporters such as P-glycoprotein (P gp) or breast cancer resistance protein (BCRP). For example, dabrafenib was reported to have an MDR1 efflux ratio of 11.4, a BCRP efflux ratio of 21.0, and a total brain to plasma ratio of 0.023; whereas vemurafenib was reported to have an MDR1 efflux ratio of 83, a BCRP efflux ratio of 495, and a total brain to plasma ratio of 0.004.

[0006] The compound represented by Formula (I) is a selective BRAF kinase inhibitor. However, the crystalline structure of the active pharmaceutical ingredient often affects the chemical stability of the drug. Different crystallization and storage conditions can lead to changes in the compound's crystalline structure, sometimes accompanied by the formation of other crystalline forms. Generally speaking, amorphous drug products lack a regular crystalline structure and often have other defects, such as poor product stability, fine crystallization, difficulty in filtration, easy agglomeration, and poor flowability. Therefore, in-depth research on the crystalline form of the compound represented by Formula (I) and related preparation methods is necessary to improve various properties of the compound represented by Formula (I). Summary of the Invention

[0007] The present invention provides a crystalline form A of a compound represented by formula (I) and a preparation method thereof, as well as pharmaceutical compositions and medical uses thereof.

[0008] The present invention provides a crystalline form A of a compound of formula (I):

[0009] The crystal A of the compound represented by formula (I) of the present invention has the advantages of being easy to process and crystallize, having good stability, good fluidity, being convenient for formulation process, and having good solubility and bioavailability.

[0010] The present invention provides a crystalline form A of the compound represented by formula (I), which has an X-ray powder diffraction pattern using Cu-Kα radiation and has characteristic diffraction peaks at the following 2θ positions: 14.54°±0.2°, 15.98°±0.2°, 16.17°±0.2°, 17.65°±0.2°, and 20.62°±0.2°.

[0011] The crystalline form A of the compound represented by formula (I) of the present invention, using Cu-Kα radiation, has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions: 7.43°±0.2°, 8.79°±0.2°, 19.87°±0.2°, 20.22°±0.2°, 23.18°±0.2°, 24.95°±0.2°, 26.63°±0.2°, and 30.27±0.2°.

[0012] The crystalline form A of the compound represented by formula (I) of the present invention, using Cu-Kα radiation, has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions: 11.71°±0.2°, 14.92°±0.2°, 18.12°±0.2°, 18.39°±0.2°, 18.55°±0.2°, 22.51°±0.2°, 24.74°±0.2°, 26.02°±0.2°, and 27.31°±0.2°.

[0013] The X-ray powder diffraction pattern of the crystalline form A of the compound represented by formula (I) of the present invention using Cu-Kα radiation is substantially as shown in FIG3 .

[0014] The differential scanning calorimetry (DSC) curve of the crystalline form A of the compound represented by formula (I) of the present invention shows a melting endothermic signal at around 191° C., as shown in FIG1 .

[0015] The thermogravimetric analysis (TGA) curve of Form A of the compound represented by formula (I) of the present invention shows no obvious weight loss during heating to 150° C., and decomposes above 230° C., as shown in FIG. 2 .

[0016] The dynamic moisture adsorption curve analysis chart of the crystal form A of the compound represented by formula (I) of the present invention is shown in FIG4 .

[0017] The X-ray powder diffraction patterns of Form A of the compound represented by formula (I) of the present invention before and after DVS testing are shown in FIG5 .

[0018] FIG6 shows the X-ray powder diffraction patterns of Form A of the compound represented by formula (I) of the present invention before and after testing with artificial simulated gastric fluid, artificial simulated fasting intestinal fluid, and artificial simulated full intestinal fluid.

[0019] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of Form A of the compound represented by formula (I) above, and a pharmaceutically acceptable carrier and / or excipient, preferably 1-1500 mg. The pharmaceutical composition may be in the form of a unit dosage form (also referred to as a "dosage strength").

[0020] As used herein, an "effective amount" or "therapeutically effective amount" refers to administering a sufficient amount of a crystalline form disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a crystalline form disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5 -150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg;

[0021] In some embodiments, the pharmaceutical composition or formulation of the present invention contains the above-mentioned therapeutically effective amount of the crystalline form of the present invention;

[0022] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, comprising a therapeutically effective amount of the crystalline form of the present invention and a carrier and / or excipient. The pharmaceutical composition can be in the form of a unit dosage form (the amount of the main drug in the unit dosage form is also referred to as a "preparation specification"). In some embodiments, the pharmaceutical composition includes but is not limited to 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, , 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg and 1500mg of the crystalline form of the present invention.

[0023] The present invention also provides use of the above-mentioned crystal form A or composition in drugs for treating / preventing BRAF-mediated diseases.

[0024] The present invention also provides a method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of the above-described crystalline Form A, preferably 1-1500 mg, wherein the disease is preferably a tumor, more preferably a brain tumor. In some embodiments, the mammal of the present invention includes a human.

[0025] A method for treating a disease in a mammal, comprising administering a crystalline form of the present invention and a pharmaceutically acceptable carrier and / or excipient to a subject at a daily dose of 1-1500 mg / day, wherein the daily dose can be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, 100-1000 mg / day, In some embodiments, the daily dose includes but is not limited to 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, 1500 mg / day.

[0026] The present invention also relates to a kit, which may include a crystalline form in a single-dose or multi-dose form. The kit contains the crystalline form of the present invention, and the amount of the crystalline form of the present invention is the same as that in the above-mentioned pharmaceutical composition.

[0027] The amounts of the crystalline forms according to the invention in the present invention are in each case calculated as the free base.

[0028] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0029] The crystalline form of the present invention is present in an amount of about 5% to about 100% by weight of the drug substance; in certain embodiments, it is present in an amount of about 10% to about 100% by weight of the drug substance; in certain embodiments, it is present in an amount of about 15% to about 100% by weight of the drug substance; in certain embodiments, it is present in an amount of about 20% to about 100% by weight of the drug substance; in certain embodiments, it is present in an amount of about 25% to about 100% by weight of the drug substance; in certain embodiments, it is present in an amount of about 30% to about 100% by weight of the drug substance; in certain embodiments, it is present in an amount of about 35% to about 100% by weight of the drug substance; in certain embodiments, it is present in an amount of about 40% to about 100% by weight of the drug substance; in certain embodiments, it is present in an amount of about 45% to about 100% by weight of the drug substance; in certain embodiments, it is present in an amount of about 50% to about 100% by weight of the drug substance; in certain embodiments, it is present in an amount of about 55% to about 100% by weight of the drug substance. In certain embodiments, the drug substance is present at about 60% to about 100% by weight of the drug substance; in certain embodiments, the drug substance is present at about 65% to about 100% by weight of the drug substance; in certain embodiments, the drug substance is present at about 70% to about 100% by weight of the drug substance; in certain embodiments, the drug substance is present at about 75% to about 100% by weight of the drug substance; in certain embodiments, the drug substance is present at about 80% to about 100% by weight of the drug substance; in certain embodiments, the drug substance is present at about 85% to about 100% by weight of the drug substance; in certain embodiments, the drug substance is present at about 90% to about 100% by weight of the drug substance; in certain embodiments, the drug substance is present at about 95% to about 100% by weight of the drug substance; in certain embodiments, the drug substance is present at about 98% to about 100% by weight of the drug substance; in certain embodiments, the drug substance is present at about 99% to about 100% by weight of the drug substance; in certain embodiments, substantially all of the drug substance is substantially pure crystals.

[0030] The present invention also provides a method for preparing the crystalline form A of the compound represented by formula (I), which is a dissolution crystallization method, comprising: dissolving the compound of formula I in a good solvent, taking a certain amount of the solution and dropping it into a poor solvent or adding the poor solvent into the solution, stirring to precipitate a solid, separating and drying to obtain the solid.

[0031] Further, the good solvent and poor solvent are relative, and in a pair of solvents, the one with higher solubility is a good solvent, and the one with lower solubility is a poor solvent. In some embodiments, the good solvent is selected from ethylene glycol methyl ether, ethylene glycol dimethyl ether, dioxane, DMF, DMSO, ethanol, n-propyl alcohol, 4-methyl-2-pentanone, tetrahydrofuran, isopropyl alcohol, ethyl acetate, n-heptane, dichloromethane, isopropyl ether, water, acetonitrile, toluene, chloroform, acetone, ethyl formate, MTBE, and cyclohexane with higher solubility, and the poor solvent is selected from the one with lower solubility in the above-mentioned solvents. In some embodiments, the good solvent is selected from one or more mixed solvents in acetone, ethylene glycol dimethyl ether, dioxane, DMF, DMSO, dichloromethane, tetrahydrofuran, ethyl acetate, ethyl formate, acetonitrile, and chloroform. In some embodiments, the poor solvent is selected from one or a mixture of two or more of n-propanol, isopropyl ether, n-heptane, ethanol, water, toluene, MTBE, cyclohexane, and isopropanol.

[0032] The present invention also provides another method for preparing the crystalline form A of the compound represented by formula (I), which is a volatilization experiment method: comprising adding the compound of formula (I) to a selected single solvent or binary solvent to form a clear sample solution, and then evaporating it open at different temperatures until the solvent is dry.

[0033] Furthermore, the solvent of the evaporation method is one or a mixed solvent of two or more of methanol, acetone, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate, ethyl formate, butyl formate, dioxane, ethylene glycol methyl ether, ethylene glycol dimethyl ether, acetonitrile, DMF, DMSO, dichloromethane, chloroform, and tetrahydrofuran.

[0034] The present invention also provides another method for preparing the crystalline form A of the compound represented by formula (I), which is a suspension method: comprising adding the compound of formula (I) to a selected single solvent or binary solvent until a suspension is formed, suspending and stirring at room temperature to 50°C for a certain period of time (for example, 1 hour to 10 days, or 2 hours to 24 hours, or 2 hours to 12 hours, or 3 to 5 hours), and then centrifuging the suspension and drying to obtain the crystalline form A.

[0035] Furthermore, the solvent used in the suspension method is one or a mixed solvent of two or more of ethylene glycol methyl ether, ethylene glycol dimethyl ether, dioxane, DMF, DMSO, ethanol, n-propanol, 4-methyl-2-pentanone, tetrahydrofuran, isopropanol, ethyl acetate, n-heptane, dichloromethane, isopropyl ether, water, methanol, isopropyl acetate, butyl formate, acetonitrile, toluene, chloroform, acetone, ethyl formate, MTBE, and cyclohexane.

[0036] The present invention also provides another method for preparing the crystalline form A of the compound represented by formula (I), which is a cooling method: comprising dissolving a certain amount of sample in a corresponding solvent at high temperature, transferring the solution to room temperature for cooling, standing or stirring for crystallization, separating, and drying to obtain the crystalline form A.

[0037] Furthermore, the solvent used in the cooling method is one or a mixed solvent of two or more of methanol, ethyl acetate, isopropyl acetate, butyl formate, acetonitrile, ethylene glycol methyl ether, 4-methyl-2-pentanone, dioxane, ethanol, acetonitrile, DMF, tetrahydrofuran, methanol, ethylene glycol dimethyl ether, and DMSO;

[0038] The present invention also provides another method for preparing the crystalline form A of the compound represented by formula (I), which is a thermal crystallization method: the method comprises taking a certain amount of sample, placing a glass slide on a hot table, heating to a target temperature at a certain rate (such as 5-20°C / min, or 10-15°C / min), and maintaining the temperature for a period of time (such as 0.5-5min, or 1-3min, or 1-2min), and then naturally cooling to room temperature to obtain a solid.

[0039] The present invention also provides another method for preparing Form A of the compound represented by Formula (I), which is a vapor diffusion experiment: the method comprises dropwise adding an appropriate amount of a good solvent to a certain amount of the compound represented by Formula (I) at room temperature to completely dissolve the sample or to prepare a saturated solution of the good solvent; taking a certain amount of each solution, placing the clear solution in a poor solvent atmosphere and standing at room temperature until solid precipitates, and separating to obtain the Form A. Alternatively, the Form A can be obtained by directly placing the solid compound represented by Formula I in a solvent atmosphere and standing at room temperature for 1 to 7 days.

[0040] Furthermore, the gas phase used in the gas diffusion method is one or a mixed solvent of two or more of cyclohexane, MTBE, ethanol, n-heptane, isopropyl ether, isopropanol, and toluene.

[0041] The present invention also provides another method for preparing the crystalline form A of the compound represented by formula (I), which is a polymer-induced volatilization method: the method comprises adding a certain amount of the compound of formula (I) to a clear solution of a small amount of polymer and allowing it to stand in the open air at room temperature until the solvent is completely volatilized to obtain a solid.

[0042] Furthermore, the polymer used in the polymer induced volatilization method is one or a mixed solvent of two or more of polyvinyl alcohol, polyacrylamide, polyisobutyl methacrylate, polyethylene glycol, cellulose acetate, polyvinyl pyrrolidone PVP10, polyvinyl pyrrolidone K88-96, high viscosity hydroxyethyl cellulose HEC-100000, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose.

[0043] The solvent used in the above preparation method, unless otherwise specified, may be a single solvent or a combination of two or more solvents.

[0044] The X-ray powder diffraction, DSC pattern, and TGA pattern disclosed in the present invention, and those substantially the same also fall within the scope of the present invention.

[0045] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0046] As used herein, "the crystal of the present invention", "the crystal form of the present invention", "the crystal form of the present invention" and the like can be used interchangeably.

[0047] The "room temperature" mentioned in the present invention generally refers to 4-30°C, preferably 20±5°C.

[0048] The crystal structure of the present invention can be analyzed using various analytical techniques known to those skilled in the art, including but not limited to, X-ray powder diffraction (XRD), differential scanning calorimetry (DSC) and / or thermogravimetric analysis (TGA), also known as thermogravimetry (TG).

[0049] As used herein, "2θ or 2θ angle" refers to the peak position expressed in degrees (°) based on the setup of an X-ray diffraction experiment, and is typically the unit of the abscissa in a diffraction pattern. If the incident beam forms an angle θ with a certain lattice plane and the reflection is diffracted, the experimental setup requires recording the reflected beam in 2θ angles. It should be understood that the specific 2θ value of a specific crystal form mentioned herein is intended to represent the 2θ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein, and the error range of the 2θ may be ±0.3, ±0.2, or ±0.1.

[0050] It is understood that the numerical values ​​described and protected by the present invention are approximate values. Variations in the numerical values ​​may be due to equipment calibration, equipment errors, crystal purity, crystal size, sample size and other factors.

[0051] It is understood that the crystal form of the present invention is not limited to the characteristic spectra that are exactly the same as the characteristic spectra described in the drawings disclosed in the present invention, such as XRD, DSC, TGA, and DVS. Any crystal form having characteristic spectra that are substantially the same or essentially the same as those described in the drawings falls within the scope of the present invention.

[0052] It is understood that, as is well known in the art of differential scanning calorimetry (DSC), the melting peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline compound of the present invention has a DSC pattern with characteristic peak positions, has substantially the same properties as the DSC pattern provided in the accompanying drawings of the present invention, and has a measurement error tolerance of within ±5°C, generally required to be within ±3°C.

[0053] "Carrier" refers to a system that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0054] "Excipient" refers to a substance that is not itself a therapeutic agent and is used as a diluent, adjuvant, binder, and / or vehicle that is added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a compound or pharmaceutical composition into a unit dosage form for administration. As known to those skilled in the art, pharmaceutical excipients can provide various functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, and cross-linked carboxymethylcellulose (e.g., sodium cross-linked carboxymethylcellulose); (4) tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solutions; (21) polyesters, polycarbonates, and / or polyanhydrides; and (22) other nontoxic compatible substances used in pharmaceutical preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] FIG1 is a differential scanning calorimetry analysis curve of Form A of the compound represented by formula (I).

[0056] FIG2 is a thermogravimetric analysis spectrum of Form A of the compound represented by formula (I).

[0057] FIG3 is an X-ray powder diffraction pattern of Form A of the compound represented by formula (I).

[0058] FIG4 is a dynamic moisture adsorption curve analysis graph of Form A of the compound represented by formula (I).

[0059] FIG5 is an X-ray powder diffraction pattern of Form A of the compound represented by formula (I) before and after DVS testing.

[0060] FIG6 is an X-ray powder diffraction pattern of Form A of the compound represented by formula (I) before and after testing in artificial simulated gastric fluid, artificial simulated fasting intestinal fluid, and artificial simulated full intestinal fluid.

[0061] FIG7 is a microscope picture of the amorphous form of the compound of formula (I).

[0062] FIG8 is a microscope image of Form A of the compound of formula (I). DETAILED DESCRIPTION

[0063] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of ppm is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0064] MS was measured using Agilent 6120B (ESI) and Agilent 6120B (APCI).

[0065] HPLC measurement was performed using a LC-20AT (Shimadzu) high pressure liquid chromatograph (Shim-pack GIST C18, 4.6×250 mm (HSS), 5 μm).

[0066] XRD analysis was performed using a Bruker D8 Advance Diffractometer. The 2θ scan angle ranged from 3° to 45°, with a scan step size of 0.013° and an exposure time of 0.08 seconds. The tube voltage and current were 45 kV and 40 mA, respectively, and the sample pan was a zero-background sample pan.

[0067] TGA test conditions: Thermogravimetric analyzer (TGA) was used, model TA Instruments Q500TGA. A 2-5 mg sample was placed in a pre-equilibrated sample pan and automatically weighed in the TGA oven. The sample was heated to the final temperature at a rate of 10°C / min. A nitrogen purge rate of 60 mL / min was maintained at the sample and 40 mL / min at the balance.

[0068] DSC test conditions: A TA Instruments Q200DSC differential scanning calorimeter was used. A 1-2 mg sample was accurately weighed and placed in a standard pan or a perforated DSC Tzero pan. The sample was heated at a rate of 10°C / min to the final temperature. A nitrogen purge rate of 50 mL / min was used.

[0069] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0070] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0071] The following describes in detail the implementation process of the present invention and the beneficial effects produced by specific embodiments, which is intended to help readers better understand the essence and characteristics of the present invention and is not intended to limit the scope of implementation of this case.

[0072] Example 1: Preparation of compound of formula (I)

[0073] Step 1: Preparation of 2B

[0074] Compound 2A (500.00 g, 6168.30 mmol) was dissolved in ethyl formate (1380.00 g, 18628.50 mmol) and reacted at 55°C for 12 h. After the reaction, the mixture was cooled to room temperature and the reaction solution was concentrated to obtain compound 2B (640 g, yield 95%).

[0075] 1 H NMR (400MHz, CDCl3) δ8.18(s,1H),6.88(s,1H),5.97-5.67(m,1H),3.66-3.56(m,2H).

[0076] Step 2: 2D preparation

[0077] Compound 2C (85.00 g, 555.08 mmol) was dissolved in N-(2,2-difluoroethyl)formamide (2) (380.00 g, 3485.93 mmol) and reacted at 155°C for 12 h. After the reaction was completed, the mixture was cooled to room temperature, the reaction solution was filtered, the filter cake was washed three times with 100 mL of water, and the obtained solid was dried to obtain compound 2D (110 g, 87.62%).

[0078] LCMS (ESI): =227.1 [M+H] + .

[0079] Step 3: Preparation of int-1

[0080] Compound 2D (168.00 g, 742.77 mmol) was dissolved in 2000 mL of N,N-dimethylformamide, and cesium carbonate (390.00 g, 1196.94 mmol) was added. After stirring at room temperature for 30 min, 2,3,6-trifluorobenzonitrile (160.00 g, 1018.55 mmol) was added and stirred at room temperature for 3 h. After the disappearance of the starting material by TLC monitoring (DCM:MeOH = 30:1), the reaction solution was poured into 6000 mL of ice water with vigorous stirring. A large amount of solid precipitated, which was filtered and the filter cake was washed three times with 200 mL of water. The resulting solid was slurried with 200 mL of ethyl acetate, filtered, and the resulting solid was washed three times with 100 mL of ethyl acetate. The resulting solid was dried to obtain compound int-1 (260 g, 96.36%).

[0081] LCMS (ESI): =364.1 [M+H]+.

[0082] Step 4: Preparation of 2G

[0083] Dissolve compound 2F (2.6 g, 22.46 mmol) in dichloromethane (100 mL) and add triethylamine (6.82 g, 67.38 mmol). Slowly add sulfamoyl chloride (3.0 g, 22.45 mmol) under ice-cooling. Stir at room temperature for 1-2 hours. After the disappearance of the starting material by TLC (DCM:MeOH = 10:1), concentrate to give crude compound 2G (3.96 g, 100%), which is used directly in the next step.

[0084] LC-MS (ESI): m / z = 175.1 [MH] + .

[0085] Step 5: Preparation of compound of formula (I)

[0086] Compound int-1 (165.00 g, 454.21 mmol) was dissolved in 3000 mL of N,N-dimethylformamide, and cesium carbonate (225.00 g, 690.53 mmol) was added. After stirring at 50°C for 30 min, compound 2G (96.00 g, 545.05 mmol) was added and stirred at 85°C for 18 h. After TLC monitoring of the disappearance of the starting material (DCM:MeOH=10:1), the reaction solution was poured into 9000 mL of ice water with vigorous stirring to precipitate a large amount of solid. The solid was filtered and the filter cake was washed three times with 200 mL of water. The resulting solid was slurried with 200 mL of ethyl acetate, filtered, and the resulting solid was washed three times with 100 mL of ethyl acetate. The residue was repeatedly slurried with ethyl acetate until the purity met the standard. The obtained product was dissolved in DCM:MeOH=20:1, washed twice with saturated ammonium chloride, dried over anhydrous sodium sulfate, filtered, concentrated and dried to obtain pure compound (I) (115 g, yield 48.74%).

[0087] LCMS m / z=520.1[M+H]+;

[0088] 1 H NMR (400MHz, DMSO) δ10.38(s,1H),8.34(s,1H),7.91-7.84(m,1H),7.82(d,1H),7.73(dd,1H),7.54(dd,1 H),7.41(d,1H),6.51-6.22(m,1H),4.52-4.43(m,2H),3.84(s,4H),2.12-2.08(m,4H),1.78-1.70(m,2H).

[0089] Preparation of crystal forms

[0090] Example 2: Preparation of Form A of the Compound of Formula (I)

[0091] 40.6 mg of the compound of formula (I) was weighed and dissolved in 3.6 mL of ethyl acetate. 3.6 mL of the solution was added dropwise to 12.0 mL of n-heptane solution, stirred for 1 h, and centrifuged to obtain Form A of the compound of formula (I).

[0092] Example 3: Preparation of Form A of the Compound of Formula (I)

[0093] A 40.6 mg sample of the compound represented by formula (I) was weighed and added to 1.0 mL of acetone for dissolution. The solution was left to stand at room temperature in an open state until the solvent was completely evaporated to obtain a solid, thereby obtaining Form A of the compound represented by formula (I).

[0094] Crystal form test example

[0095] 1. Instrument information and detection method parameter table

[0096] 2. Specific peak characterization results of XRD tests of each crystal form obtained in the above examples

[0097] The X-ray powder diffraction pattern (XRD) of Form A of the compound of formula (I) is shown in Figure 3. The specific peaks are shown in Table 1.

[0098] Table 1. XRPD peak list of Form A

[0099] 3. DSC (Differential Scanning Calorimetry) and TGA (Thermogravimetric Analysis) test results of Form A obtained in the above embodiment

[0100] As shown in FIG1 , the differential scanning calorimetry (DSC) curve of Form A of the compound of formula (I) shows a melting endothermic signal at around 191° C., as shown in FIG1 , and its thermogravimetric analysis (TGA) curve shows no obvious weight loss during heating to 150° C., and decomposes after 230° C., as shown in FIG2 .

[0101] 4. DVS (Dynamic Water Sorption) Test Results of Form A Prepared in the Above Example

[0102] As shown in Figure 4 , the DVS results for Form A of the compound of Formula (I) show that Form A exhibited an adsorption weight gain of approximately 0.17% at 95% RH, an adsorption weight gain of approximately 0.11% at 80% RH, and a desorption weight gain of approximately 0.11%. At 0% RH, the desorption weight loss was 0.02%, indicating that Form A exhibited virtually no hygroscopicity. The XRPD results in Figure 5 demonstrate that the sample exhibited no crystalline form change after DVS testing.

[0103] 5. Study on the stability of influencing factors

[0104] As shown in Table 2, the crystalline form A of the compound of formula (I) was placed under different conditions for 30 days, and the results showed that it had good stability.

[0105] Table 2. Stability study data of Form A (0-30 days)

[0106] As shown in Table 3, the crystalline form A of the compound of formula (I) was placed under different conditions for 9 months, and the results showed that it had good stability.

[0107] Table 3. Stability study data of Form A (0-9 months)

[0108] 6. Solid-state property research

[0109] An amorphous form of the compound of formula (I) was prepared by liquid phase purification with reference to Example 10 of WO2024017294A1. This amorphous form exhibits high static charge and poor fluidity, making it unsuitable for industrial production of the API and formulation preparation. As shown in Table 4, Form A of the compound of formula (I) exhibits superior bulk density and crystal morphology, significantly improving its fluidity compared to the amorphous form.

[0110] Microscope images of the amorphous form of the compound of formula (I) and the crystalline form A of the compound of formula (I) are shown in Figures 7 and 8, respectively.

[0111] Table 4. Solid-state property research data of Form A

Claims

1. Crystalline Form A of the compound of formula (I): Its characteristics are: Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 14.54°±0.2°, 15.98°±0.2°, 16.17°±0.2°, 17.65°±0.2°, and 20.62°±0.2°.

2. The crystalline form A according to claim 1, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions: 7.43°±0.2°, 8.79°±0.2°, 19.87°±0.2°, 20.22°±0.2°, 23.18°±0.2°, 24.95°±0.2°, 26.63°±0.2°, and 30.27±0.2°.

3. The crystalline form A according to claim 2, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions: 11.71°±0.2°, 14.92°±0.2°, 18.12°±0.2°, 18.39°±0.2°, 18.55°±0.2°, 22.51°±0.2°, 24.74°±0.2°, 26.02°±0.2°, and 27.31°±0.2°.

4. The crystalline form A according to claim 3, characterized in that: Its X-ray powder diffraction pattern (XRPD) is basically shown in Figure 3.

5. A method for preparing Form A of the compound represented by formula (I), wherein the method is a solution crystallization method, comprising: The compound of formula (I) is dissolved in a good solvent, and a certain amount of the solution is added dropwise to a poor solvent, or the poor solvent is added dropwise to the solution, stirred to precipitate a solid, separated and dried to obtain the product.

6. The method according to claim 5, wherein the good solvent is selected from one or a mixed solvent of acetone, ethylene glycol dimethyl ether, dioxane, DMF, DMSO, dichloromethane, tetrahydrofuran, ethyl acetate, ethyl formate, acetonitrile, and chloroform; and the poor solvent is selected from one or a mixed solvent of two or more of n-propanol, isopropyl ether, n-heptane, ethanol, water, toluene, MTBE, cyclohexane, and isopropanol.

7. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form A according to any one of claims 1 to 4, and a pharmaceutically acceptable carrier and / or excipient.

8. The composition according to claim 7, wherein the therapeutically effective amount is preferably 1-1500 mg.

9. Use of the crystalline form A according to any one of claims 1 to 4, or the pharmaceutical composition according to any one of claims 7 to 8, in the preparation of a medicament for treating / preventing BRAF-mediated diseases.

10. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the crystalline form A according to any one of claims 1 to 4 or the pharmaceutical composition according to any one of claims 7 to 8, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and the disease is preferably a tumor, more preferably a brain tumor.

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