Novel Solid Form of (3R)-N-[2-Cyano-4-Fluoro-3-(3-Methyl-4-Oxoquinazolin-6-yl)oxyphenyl]-3-Fluoro-Pyrrolidine-1-Sulfonamide

Abstract

The present invention provides a solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide and its solvate, as well as its therapeutic use and pharmaceutical compositions containing the same.

Description

[Technical Field]

[0001] The present invention provides a novel solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide, as well as its therapeutic use and pharmaceutical compositions comprising the said form. [Background technology]

[0002] The RAF (Rapidly Accelerated Fibrosarcoma; RAF) class of serine-threonine kinases includes three members (ARAF, BRAF, and RAF1) that constitute the first node of the MAP kinase signaling pathway. Despite the apparent redundancy of these three RAF isoforms in signaling through phosphorylation of MEK1 and MEK2, frequently occurring oncogene-activating mutations are usually found only in BRAF. In particular, substitutions of V600 at glutamate or lysine highly activate the kinase, resulting in hyperstimulation of the MAPK pathway independently of external stimuli (Cell. 2015 Jun 18;161(7):1681-1696).

[0003] Mutant BRAF is a targetable oncogenic driver, and three BRAF inhibitors (vemurafenib, dabrafenib, and encorafenib) have reached the market and shown efficacy against BRAFV600E-positive melanoma. However, rapid drug resistance is observed almost universally, and the duration of therapeutic benefit from targeted therapies remains limited.

[0004] Furthermore, the developed BRAF inhibitors revealed an unexpected "paradoxical" ability: the same inhibitors exhibited MAPK stimulating activity in BRAF wild-type (WT) models while suppressing MAPK signaling in tumors driven by BRAFV600E (N Engl J Med 2012;366:271-273; and British Journal of Cancer volume 111, pp. 640-645 (2014)).

[0005] Subsequent research into the mechanisms behind the RAF paradox revealed that the oncogene BRAFV600E phosphorylates MEK 1 / 2 in its monomeric cytosolic form, but activation of WT BRAF and RAF1 requires a complex series of events, including cell membrane translocation and homodimerization promoted by activated RAS (KRAS, NRAS, HRAS) (Nature Reviews Cancer volume 14, pp. 455-467 (2014)).

[0006] Binding of inhibitors such as vemurafenib, dabrafenib, or encorafenib to WT BRAF or RAF1 protomers rapidly induces RAF homodimerization and / or heterodimerization, as well as membrane association of the newly formed RAF dimers. In the dimer structure, one RAF protomer allosterically induces a structural change in the second protomer, resulting in a kinase-active state, and importantly, a structure unfavorable to inhibitor binding. Consequently, the drug-induced dimers promote MEK phosphorylation via catalytic action by the unbound protomer, accompanied by hyperactivation of the pathway.

[0007] The RAF paradox leads to two clinically relevant consequences: 1) accelerated growth of secondary tumors (primarily keratochantoma and squamous cell carcinoma) with BRAFi monotherapy (N Engl J Med 2012;366:271-273), and 2) acquisition of drug resistance in the BRAFi monotherapy environment. Furthermore, the BRAFi + MEKi combination suggests activation of dimer-mediated RAF signaling through genetically driven events including RAS mutations, BRAF proliferation, and expression of dimer-acting BRAF splice variants (Nature Reviews Cancer volume 14, pp. 455-467 (2014)). Therefore, an RAF inhibitor capable of overcoming this paradox is needed.

[0008] Furthermore, the currently approved classical BRAF inhibitors, vemurafenib (Mol.Pharmaceutics 2012,9,11,3236-3245), dabrafenib (J Pharmacol Ex Ther 2013,344(3)655-664), and encorafenib (Pharmacol Res. 2018;129:414-423), all have extremely low brain permeability. This is the biggest limitation of using these classical BRAF inhibitors to treat brain cancer or brain metastases. Therefore, there is a need for BRAF inhibitors with improved brain permeability.

[0009] In response, there is a need for compounds that are efficient BRAF inhibitors that exhibit a reduction in the paradoxical activation of the MAPK signaling pathway while maintaining a high titer. Such compounds can be referred to as paradox breakers or RAF paradox breakers, as opposed to compounds that induce the RAF paradox (which can be referred to as paradox inducers or RAF paradox inducers). (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide is a paradox-avoiding BRAF inhibitor that meets these needs and has favorable brain penetration properties.

[0010] Polymorphs are different crystalline forms of the same compound. Polymorphs generally have different crystal structures due to differences in the packing of molecules within the lattice. Polymorphic forms have attracted attention in the pharmaceutical industry and particularly among those involved in the development of appropriate dosage forms. If the polymorphic form is not maintained consistently during clinical studies, the exact dosage form or study used will not be comparable between lots. Also, when a compound is used in clinical studies or commercial products, it is desirable to obtain methods for producing the compound with the selected polymorphic form in high purity, as any impurities can have undesirable effects (such as toxicity). Some polymorphs may exhibit enhanced stability or can be easily manufactured in large quantities and in high purity and are more suitable for inclusion in pharmaceutical formulations. Some polymorphs may exhibit other advantageous physical properties such as not having a tendency to absorb moisture, having improved solubility, and an increased dissolution rate due to differences in lattice energy.

[0011] (3R)-N-[2-Cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide is a paradox-avoiding BRAF inhibitor having favorable brain penetration properties and is useful in the treatment of cancer, particularly melanoma, lung cancer, and metastatic cancer of the brain. Therefore, for the development and commercialization of pharmaceuticals, it is necessary to identify solid forms of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide having desired properties, such as high crystallinity, high purity, and favorable physical stability, chemical stability, dissolution, and mechanical properties. WO 2022 / 258584 describes procedures for isolating polymorphic solid form A and amorphous (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide. The present invention provides (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide in a novel solid form, namely crystalline polymorphic form B.

Mode for Carrying Out the Invention

[0012] The present invention relates to a solid form of a compound of formula (I) TIFF2026521852000002.tif43170, wherein the solid form is crystalline polymorph B.

[0013] The compound of formula (I) is also referred to as (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide.

[0014] Crystalline polymorph B is a thermodynamically stable form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide. Crystalline polymorph B is characterized by desirable physicochemical properties, such as improved fluidity, and enhances the processability of this form, making it suitable for large-scale production of pharmaceutical active ingredients.

[0015] The terms "pharmaceutically acceptable carrier" and "pharmaceutically acceptable auxiliary substance" refer to carriers and auxiliary substances, such as diluents or excipients, that are compatible with the other components of the formulation.

[0016] The term "BRAF-associated cancer" refers to cancer associated with and / or caused by the activation of BRAF mutations. Non-exclusive examples of such mutations include, for example, BRAF V600E and V600K mutations.

[0017] The term "room temperature" refers to 18-30°C, particularly 20-25°C, and more specifically, 20°C.

[0018] The terms "approximately" and "roughly" are interchangeable and refer to a range of values ​​that fall within 5% above or below the stated reference value. More specifically, "approximately" or "roughly" refers to ±0.2 degrees 2θ or ±0.5°C.

[0019] As used herein, the term “equivalent amount” may mean at least 50%, particularly at least 60%, and more specifically at least 70% of the initial abundance of a particular substance within a given fraction. For example, a fraction containing an equivalent amount of a particular substance after a purification step will contain at least 50%, particularly at least 60%, and more specifically at least 70% of the initial abundance of the particular substance prior to the purification step.

[0020] "Crystallization" and "recrystallization" are interchangeable terms and refer to methods that lead to a stable polymorph or crystalline form of a particular chemical compound, which may be in an amorphous form or dissolved or suspended in a solvent system prior to this method. For example, the crystallization step can be carried out by forming crystals in a solvent and a poor solvent.

[0021] "XRPD" refers to the X-ray powder diffraction analysis method. The reproducibility of the angular values ​​is within the range of 2θ ± 0.2°. The term "approximately," used in combination with the angular value, indicates reproducibility within the range of 2θ. The relative XRPD peak intensity depends on numerous factors, including structure factor, temperature factor, crystallinity, polarization state factor, multiplicity, and Lorentz factor. The relative intensity can vary significantly from measurement to measurement due to the preferential orientation effect. According to USP 941 (United States Pharmacopeia, 37th Edition, General Chapter 941), the relative intensity between two samples of the same material can vary significantly due to the "preferred orientation" effect. Anisotropic materials employing preferred orientation exhibit anisotropic distributions of properties such as elastic modulus, strength, ductility, toughness, conductivity, and thermal expansion, as described in Kocks UFet al. (Texture and Anisotropy: Preferred Orientations in Polycrystals and Their Effect on Materials Properties, Cambridge University Press, 2000). In both XRPD and Raman spectroscopy, preferential orientation causes changes in the intensity distribution. The preferential orientation effect is particularly pronounced in crystalline APIs with relatively large grain sizes.

[0022] The "characteristic peak" refers to the presence of a powder X-ray diffraction peak that definitively identifies (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide as the reference crystal form (form B). Generally, powder X-ray diffraction analysis is performed under ambient conditions in a transmission geomitre using a STOE STADI P diffractometer (Cu Kα1 irradiation, primary monochromator, silicon strip detector, angular range 3 to 42 degrees 2θ, total measurement time approximately 30 minutes). Samples (approximately 10 to 50 mg) are prepared between thin polymer films and analyzed without further processing of the substrate (e.g., grinding or sieving).

[0023] A "polymorph" refers to a crystalline form that has the same chemical composition but differs in the spatial arrangement of molecules, atoms, and / or ions that form the crystal. Generally, as referred to herein, the polymorph refers to the polymorph of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide. As used herein, the term "polymorph" may or may not include other crystalline solid molecular forms of the same compound, including hydrates (e.g., bound water present in the crystal structure). Polymorphs generally have different crystalline structures due to different packing of molecules within the lattice. This results in different crystal symmetries and / or unit cell parameters, which directly affect the physical properties of the crystal or powder, such as the X-ray diffraction properties.

[0024] "Amorphous" refers to solid materials that lack the long-range order characteristic of crystalline solids.

[0025] In this specification, the term “solvate” refers to a molecular complex comprising the compound of formula (I) and one or more solvent molecules (e.g., ethanol) in stoichiometric or non-stoichiometric amounts. In this specification, “hydrate” refers to a solvate comprising the compound of formula (I) and water in stoichiometric or non-stoichiometric amounts.

[0026] The terms “pharmaceutically acceptable excipient,” “pharmaceutically acceptable carrier,” and “therapeutically inactive excipient” are interchangeable and refer to any pharmaceutically acceptable component in a pharmaceutical composition that does not have therapeutic activity and is nontoxic to the target of administration, such as disintegrants, binders, fillers, solvents, buffers, isotonic agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants used in the formulation of pharmaceutical products.

[0027] The term “pharmaceutical composition” encompasses products containing specific components in predetermined amounts or proportions, as well as any products resulting directly or indirectly from combinations of specific components in predetermined amounts. In particular, the term encompasses products containing one or more active components and any carrier containing inactive components, as well as any products resulting directly or indirectly from combinations of any two or more of those components, from complex formation or aggregation, from the dissociation of one or more of those components, or from other types of reactions or interactions of one or more of those components.

[0028] The terms "pharmaceutically acceptable carrier" and "pharmaceutically acceptable auxiliary substance" refer to carriers and auxiliary substances, such as diluents or excipients, that are compatible with the other components of the formulation.

[0029] "Therapeutic effective dose" refers to the amount that is effective in preventing, alleviating, or improving the symptoms of a disease, or in prolonging the life of the person being treated.

[0030] The term “substantially pure” is used in reference to the solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide, meaning that the polymorph has a purity >90%. The solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide does not contain more than 10% of any other compound, and in particular does not contain more than 10% of any other solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide.

[0031] More specifically, the term “substantially pure” means that, when used in reference to the solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide, the said solid has a purity of >95%. The solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide does not contain more than 5% of any other compound, and in particular, no other solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide.

[0032] More specifically, the term “substantially pure” means that, when used in reference to the solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide, the said solid form has a purity of >97%. The solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide contains no more than 3% of any other compound, and in particular no more than 3% of any other solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide.

[0033] Most specifically, the term “substantially pure” means that, when used in reference to the solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide, the polymorph has a purity of >99%. The solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide contains no more than 1% of any other compound, and in particular no more than 1% of any other solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide.

[0034] Most specifically, the term “substantially pure” means that, when used in reference to the solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide, the said polymorph has a purity of >99.5%. The solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide contains no more than 1% of any other compound, and in particular no more than 1% of any other solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide.

[0035] While the present invention has been described in relation to specific embodiments, those skilled in the art will understand that various modifications can be made to the invention and that it can be replaced by equivalents without departing from the true spirit and scope of the invention. In addition, many modifications can be made to adapt specific situations, materials, composition of substances, methods, or one or more steps of a method to the objective spirit and scope of the invention. All such modifications are intended to be included within the claims. All individual embodiments can be combined.

[0036] The specific embodiments of the present invention, with designated numbers, are as follows:

[0037] Appearance 1. Equation (I) A solid form of the compound TIFF2026521852000003.tif41170, which is a crystalline polymorph B characterized by an X-ray powder diffraction pattern that includes a peak at a diffraction angle of about 12.88 degrees 2θ and includes at least one additional peak represented by values ​​of about 10.62, 15.96, 16.82, 17.20, 20.04, 21.24, 23.78, 25.62, 25.88 or 26.90 degrees 2θ.

[0038] Appearance 2. The solid form according to embodiment 1, characterized by an X-ray powder diffraction pattern including a peak at a diffraction angle of approximately 12.88 degrees 2θ and a peak at approximately 10.62 degrees 2θ.

[0039] Appearance 3. A solid form according to embodiment 1 or 2, characterized by an X-ray powder diffraction pattern including a peak at a diffraction angle of approximately 12.88 degrees 2θ and a peak at approximately 10.62 degrees 2θ; the pattern further includes at least one additional peak represented by a value of approximately 15.96, 16.82, 17.20, 20.04, 21.24, 23.78, 25.62, 25.88, or 26.90 degrees 2θ.

[0040] Appearance 4. A solid form according to any one of embodiments 1 to 3, characterized by an X-ray powder diffraction pattern including at least three peaks at diffraction angles of approximately 10.62, 12.88, 16.82, 20.04, or 26.90 degrees 2θ.

[0041] Appearance 5. A solid form according to any one of embodiments 1 to 4, characterized by an X-ray powder diffraction pattern including peaks at diffraction angles of approximately 10.62, 12.88, 15.96, 16.82, 17.20, 20.04, 21.24, 23.78, 25.62, 25.88 and 26.90 degrees 2θ.

[0042] Appearance 6. A solid form according to any one of embodiments 1 to 5, further comprising a peak represented by a value of approximately 8.38 degrees 2θ.

[0043] Appearance 7. A solid form characterized by an X-ray powder diffraction pattern according to any one of embodiments 1 to 6, further comprising at least one additional peak represented by a value of approximately 9.76, 10.44, 12.74, 16.68, 17.54, 18.76, 19.00, 19.40, 19.52, 20.98, 23.02, 23.30, 24.02, 26.10, 26.48, 27.24, 27.46, 28.56, 28.72, 28.94, 29.08, 29.28, 29.80, or 30.22 degrees 2θ.

[0044] Aspect 8. The solid form according to any one of Aspects 1 to 7, characterized by the X-ray powder diffraction pattern shown in FIG. 1.

[0045] Aspect 9. The solid form according to any one of Aspects 1 to 8, characterized by having a melting point including a peak signal at about 214.2°C to about 215.2°C, particularly a peak signal at about 214.7°C, when using differential scanning calorimetry with a heating rate of 10 K / min.

[0046] Aspect 10. The solid form according to any one of Aspects 1 to 9, characterized by the differential scanning calorimetry thermogram shown in FIG. 2.

[0047] Aspect 11. The solid form according to any one of Aspects 1 to 9, characterized by the thermogravimetric analysis thermogram shown in FIG. 3.

[0048] Aspect 12. Formula (I) A solid form of the compound of TIFF2026521852000004.tif39170, at position 1685 cm -1( (±2) cm -1 1617 cm -1( (±2) cm -1 1425 cm -1( (±2) cm -1 852 cm -1( (±2) cm -1 or 762 cm -1 (±2) cm -1 including at least one peak at one of them, particularly at position 1685 cm -1( (±2) cm -1 1617 cm -1( (±2) cm -1 1425 cm -1( (±2) cm -1 852 cm -1( (±2) cm -1 or 762 cm -1 (±2) cm-1 It includes at least two peaks at a position of 1685 cm. -1( ±2 cm -1 , 1617cm -1( ±2 cm -1 , 1425cm -1( ±2 cm -1 , 852cm -1( ±2 cm -1 and 762cm -1 (±2)cm -1 A solid form of crystalline polymorph B characterized by an IR spectrum containing a peak at [location].

[0049] Appearance 13. Furthermore, a solid form according to any one of embodiments 1 to 11, characterized by an IR spectrum according to embodiment 12.

[0050] Appearance 14. Furthermore, the position is 1685cm. -1( ±2 cm -1 A solid form according to any one of embodiments 1 to 11, characterized by the presence of an IR spectrum.

[0051] Appearance 15. A solid form according to any one of embodiments 1 to 14, characterized by the IR spectrum shown in Figure 5.

[0052] Appearance 16. Equation (I) The solid form of the compound TIFF2026521852000005.tif35170, at position 114 (±2) cm -1 , 132 (±2) cm -1 , 167(±2)cm -1 349 (±2) cm -1 Or 1620 (±2) cm -1 It includes at least one peak in one of the locations, particularly at position 114 (±2) cm. -1 , 132 (±2) cm -1 , 167(±2)cm -1 349 (±2) cm -1 Or 1620 (±2) cm -1It includes at least two peaks at a position of 114 (±2) cm, and more specifically at a position of 114 (±2) cm. -1 , 132 (±2) cm -1 , 167(±2)cm -1 349 (±2) cm -1 and 1620 (±2) cm -1 A solid form of crystalline polymorph B, characterized by a Raman spectrum containing peaks in the region.

[0053] Appearance 17. Furthermore, a solid form according to any one of embodiments 1 to 15, characterized by a Raman spectrum according to embodiment 16.

[0054] Appearance 18. Furthermore, the position is 1620cm. -1( ±2 cm -1 A solid form according to any one of embodiments 1 to 11, characterized by the Raman spectrum contained therein.

[0055] Appearance 19. A solid form according to any one of embodiments 1 to 18, characterized by the Raman spectrum shown in Figure 4.

[0056] Appearance 20. A substantially pure solid form as described in any one of embodiments 1 to 19.

[0057] Appearance 21. A solid form according to any one of embodiments 1 to 20 for use as a pharmaceutical.

[0058] Appearance 22. A solid form according to any one of embodiments 1 to 20 for the treatment or prevention of cancer, particularly BRAF-related cancer.

[0059] Appearance 23. A solid form according to any one of embodiments 1 to 20 for the treatment or prevention of melanoma or colorectal cancer, particularly colorectal cancer.

[0060] Appearance 24. A pharmaceutical composition comprising a solid form according to any one of embodiments 1 to 20 and one or more pharmaceutically acceptable auxiliary substances.

[0061] Appearance 25. Use of a solid form according to any one of embodiments 1 to 20 for the treatment of cancer, particularly BRAF-associated cancer.

[0062] Appearance 26. Use of the solid form according to any one of embodiments 1 to 20 for the treatment of melanoma or colorectal cancer, particularly colorectal cancer.

[0063] Appearance 27. Use of a solid form according to any one of embodiments 1 to 20 for the preparation of a pharmaceutical for the treatment of cancer, particularly BRAF-related cancer.

[0064] Appearance 28. A method for the treatment or prophylactic treatment of cancer, particularly BRAF-associated cancer, comprising administering an effective amount of a solid form according to any one of embodiments 1 to 20 to a patient in need thereof.

[0065] In one embodiment, crystalline polymorph B of the compound of formula (I) is anhydrous, meaning it does not contain water bound to the crystal lattice and is non-hygroscopic (water absorption <0.2% according to the European Pharmacopoeia).

[0066] The present invention also relates to compounds according to the present invention when produced by the method of the present invention.

[0067] Pharmaceutical composition The compounds of formula (I) in various solid forms can be used as therapeutically active substances, for example, in the form of pharmaceutical compositions. Pharmaceutical compositions can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions, or suspensions. However, administration can also be carried out parenterally, for example, in the form of suppositories or in the form of injections.

[0068] The compound of formula (I) can be treated with a pharmaceutically inert inorganic or organic carrier for the production of pharmaceutical compositions. Lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof, etc., can be used as such carriers for tablets, coated tablets, dragées and hard gelatin capsules, for example. Suitable carriers for soft gelatin capsules include, for example, vegetable oils, waxes, fats and oils, semi-solid and liquid polyols. However, depending on the properties of the active substance, a carrier is usually not required for soft gelatin capsules. Suitable carriers for the production of solutions and syrups include, for example, water, polyols, glycerol and vegetable oils. Suitable carriers for suppositories include, for example, natural oils or hydrogenated oils, waxes, fats and oils and semi-liquid or liquid polyols.

[0069] Furthermore, the pharmaceutical composition may contain pharmaceutically acceptable auxiliary substances, such as preservatives, solubilizers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts for altering osmotic pressure, buffers, masking agents, or antioxidants. The pharmaceutical composition may also contain other therapeutically effective substances.

[0070] Pharmaceutical compositions containing compounds of formula (I), either alone or in combination, can be prepared for storage in the form of lyophilized formulations or aqueous solutions by mixing the active ingredient of desired purity with an optional pharmaceutically acceptable carrier, excipient, or stabilizer (Remington's Pharmaceutical Sciences 16th edition, Osol, A. (ed.) (1980)). Acceptable carriers, excipients, or stabilizers are nontoxic to the recipient at the dosage and concentration used and include buffers such as phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyl dimethiolbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkylparabens, e.g., methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-crezo Low molecular weight (less than approximately 10 residues) polypeptides; proteins, e.g., serum albumin, gelatin, or immunoglobulin; hydrophilic polymers, e.g., polyvinylpyrrolidone; amino acids, e.g., glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, e.g., EDTA; sugars, e.g., sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, e.g., sodium, metal complexes (e.g., Zn-protein complexes); and / or TWEEN TM PLURONICS TM Alternatively, it may contain a nonionic surfactant such as polyethylene glycol (PEG).

[0071] Pharmaceuticals comprising a solid form of a compound of formula (I) described herein and a therapeutically inert carrier are also provided by the present invention, as are methods for their manufacture, which include forming a galenic dosage form with one or more compounds of formula (I) and / or pharmaceutically acceptable solvates thereof, and optionally one or more other therapeutically valuable substances, together with one or more therapeutically inert carriers.

[0072] The pharmaceutical compositions of BRAF inhibitors include those suitable for oral administration, intranasal administration, topical administration (including buccal and sublingual administration), rectal administration, vaginal administration, and / or parenteral administration.

[0073] Dosages can vary within a broad range and, needless to say, must be adjusted to the individual requirements in each specific case. For oral administration, adult doses may range from approximately 200 mg to approximately 4000 mg per day of the corresponding amount of the compound of general formula (I) or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate. Daily doses may be administered as a single dose or in divided doses, and may exceed the upper limit if indicated.

[0074] The following examples illustrate the present invention without limitation, but are merely representative examples. Pharmaceutical preparations typically contain about 5 to 500 mg, particularly 100 to 500 mg, of the compound of formula (I). Examples of compositions according to the present invention are as follows.

[0075] Example A Manufacture tablets with the following composition using the standard method: TIFF2026521852000006.tif61170

[0076] Manufacturing procedure 1. Mix ingredients 1, 2, 3, and 4, and granulate with purified water. 2. Dry the granules at 50°C. 3. Pass the granules through an appropriate grinding machine. 4. Add ingredient 5 and mix for 3 minutes; compress with an appropriate press.

[0077] Example B-1 Manufacture capsules with the following composition: TIFF2026521852000007.tif61170

[0078] Manufacturing procedure 1. Mix ingredients 1, 2, and 3 in a suitable blender for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 minutes. 3. Fill into appropriate capsules.

[0079] The compound of formula (I), lactose, and corn starch are first mixed in a mixer, and then mixed in a grinder. The mixture is returned to the mixer; talc is added and mixed thoroughly. The mixture is then filled into suitable capsules, such as hard gelatin capsules, using a machine.

[0080] Example B-2 To manufacture soft gelatin capsules with the following composition: TIFF2026521852000008.tif55170

[0081] TIFF2026521852000009.tif55170

[0082] Manufacturing procedure The compound of formula (I) is dissolved in the warm molten state of the other components, and the mixture is filled into soft gelatin capsules of the appropriate size. The filled soft gelatin capsules are processed according to the usual procedure.

[0083] Example C To manufacture suppositories with the following composition: TIFF2026521852000010.tif33170

[0084] Manufacturing procedure The suppository mass is melted in a glass or steel container, thoroughly mixed, and cooled to 45°C. Then, the finely powdered compound of formula (I) is added and stirred until the powder is completely dispersed. The mixture is poured into suppository molds of appropriate size and allowed to cool; then the suppositories are removed from the molds and individually packed into wax paper or metal foil.

[0085] Example D Prepare an injectable solution with the following composition: TIFF2026521852000011.tif39170

[0086] Manufacturing procedure The compound of formula (I) is dissolved in a mixture of polyethylene glycol 400 and a portion of water for injection. The pH is adjusted to 5.0 with acetic acid. The volume is adjusted to 1.0 ml by adding the remaining water. The solution is filtered, filled into vials with an appropriate excess, and sterilized.

[0087] Example E To manufacture a sachet with the following composition: TIFF2026521852000012.tif68170

[0088] Manufacturing procedure The compound of formula I is mixed with lactose, microcrystalline cellulose, and sodium carboxymethylcellulose, and granulated in water with a mixture of polyvinylpyrrolidone. The granules are mixed with magnesium stearate and flavoring additives and filled into sachets. [Brief explanation of the drawing]

[0089] [Figure 1] This shows the X-ray powder diffraction pattern of polymorph B of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxoquinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide. [Figure 2] This is a thermogram of polymorph B of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide obtained by differential scanning calorimetry (DSC). A steep curve dissolution signal was observed (start 212.3°C, peak 214.7°C, enthalpy 10⁹ J / g). Decomposition occurs after dissolution. [Figure 3]This is a thermogram of polymorph B of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide obtained by thermogravimetric analysis (TGA). No significant mass loss was observed (0.087%). [Figure 4] This is the Raman spectrum of polymorph B of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide. [Figure 5] This is the IR spectrum of polymorph B of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide. [Examples]

[0090] The following embodiments are provided for the purpose of illustrating the present invention. These embodiments should not be considered as limiting the scope of the present invention, but merely as representative examples.

[0091] Abbreviation: ATR = Attenuated Total Reflectance; DCM = Dichloromethane; DIPEA = N,N-Diisopropylethylamine; DMF = Dimethylformamide; DMSO = Dimethyl Sulfoxide; DSC = Differential Scanning Calorimetry; DVS = Dynamic Vapor Adsorption; ESI = Electrospray Ionization; Ã = Ethyl Acetate; FT = Fourier Transform; FTIR = Fourier Transform Infrared Spectroscopy; IR = Infrared Spectroscopy; LC-MS / MS = Liquid Chromatography-MS / MS; MeOH = Methanol; MS = Mass Spectrometry; RH = Relative Humidity; rt = Room Temperature; SFC = Supercritical Fluid Chromatography; TGA = Thermogravimetric Analysis.

[0092] High resolution X-ray powder diffraction High-resolution X-ray powder diffraction (XRPD) patterns were recorded by transmission geomitri. X-ray diffraction patterns were recorded using a STOE STADI P diffractometer with CuKa1 irradiation (1.5406 Å) and a Mythen positional high-sensitivity detector. Samples (approximately 10 to 50 mg) were prepared between thin polymer films and analyzed as usual without further processing of the substrate (e.g., grinding or sieving).

[0093] For polymorphism B, XRPD revealed the following peaks (expressed in degrees 2θ) at approximately: 8.38, 9.76, 10.44, 10.62, 12.74, 12.88, 15.96, 16.68, 16.82, 17.20, 17.54, 18.76, 19.00, 19.40, 19.52, 20.04, 20.98, 21.24, 23.02, 23.30, 23.78, 24.02, 25.62, 25.88, 26.10, 26.48, 26.90, 27.24, 27.46, 28.56, 28.72, 28.94, 29.08, 29.28, 29.80, and 30.22.

[0094] Differential Scanning Calorimetry (DSC) The DSC curve is Mettler-Toledo TM The data was recorded using a differential scanning calorimeter (DSC2). System conformity testing was performed using indium as the reference material, and calibration was performed using indium, benzoic acid, biphenyl, and zinc as reference materials.

[0095] For measurement, approximately 2 to 6 mg (about 2.796 mg of form B) of the sample was placed in an aluminum pan, accurately weighed, and sealed with a perforated lid. Prior to measurement, the lid was perforated to create a pinhole of approximately 0.5 mm. The sample was then heated under a nitrogen flow of approximately 100 mL / min to a maximum temperature typically ranging from 180°C to 350°C, depending on the decomposition temperature, using a heating rate typically from 1 to 20, usually 10 K / min.

[0096] Thermogravimetric analysis (TGA) Calorimetry (TGA) is used in Mettler-Toledo TMThe tests were performed using a calorimeter (TGA / DSC1 or TGA / DSC3+). System conformity testing was conducted using hydranal as the standard material, and calibration was performed using aluminum and indium as the standard materials. For calorimetric analysis, approximately 5 to 15 mg (approximately 7.197 mg of form B) of the sample was placed in an aluminum pan, accurately weighed, and sealed with a perforated lid. Prior to measurement, the lid was automatically perforated to create a pinhole of approximately 0.5 mm. The sample was then heated to a maximum temperature of approximately 350 °C, typically using a heating rate of 5 K / min, under a nitrogen flow of approximately 50 mL / min.

[0097] Moisture absorption / dehydration Moisture absorption / dehumidification data were collected using a DVS Advantage, DVS Adventure, or DVS Intrinsic (SMS Surface Measurements Systems) moisture balance system. Moisture absorption / dehumidification isotherms were measured stepwise, typically at 25°C, within the range of 0%-RH to 90%-RH. A weight change of <0.001% / min was typically selected as the criterion for switching to the next relative humidity level (if the weight change criterion was not met, a maximum equilibrium time of 24 hours was typically used). Data were corrected for the initial moisture content of the sample by zeroing the weight after drying the sample at 0%-RH.

[0098] The hygroscopicity of a given substance was characterized by the increase in mass when the relative humidity was increased from 0%-RH to 90%-RH (using a method similar to that of the European Pharmacopoeia): TIFF2026521852000013.tif40170

[0099] IR spectroscopy ATR FTIR spectra were recorded without sample preparation using a ThermoNicolet iS5 FTIR spectrometer equipped with an ATR accessory. The spectral range was 4000 cm⁻¹. -1 From 650cm -1 The resolution is 2 cm. -1At least 50 additive scans were collected. Happ-Genzel apodization was applied. Using ATR FTIR results in different relative intensities of infrared bands compared to transmission FTIR spectra using KBr disks or the Nujoermal sample preparation method. Due to the properties of ATR FTIR, lower wavenumbers in a band are more intense than higher wavenumbers.

[0100] Peak picking was performed using Thermo Scientific Omnic 8.3 software with the automatic "Find Peaks" function. A representative number of peaks was obtained by manually adjusting the "threshold" and "sensitivity" settings.

[0101] TIFF2026521852000014.tif58170

[0102] Raman spectroscopy FT-Raman spectroscopy was performed using a Bruker MultiRam FT-Raman spectrometer equipped with an NdYAG 1064 nm laser and a liquid nitrogen-cooled germanium detector, without sample preparation, covering a range of 4000-50 cm⁻¹. -1 The spectral range was recorded. The laser power in the sample was approximately 300 mW, and the wavelength was 2 cm. -1 The resolution used was 2048 scans, and the results were summed. The Blackman-Harris quad-term apodization function was employed. Approximately 5 mg of sample (powder in a glass vial) was required. Peak picking was performed using Thermo Scientific Omnic 8.3 software with the automatic "Find Peaks" function. The "Threshold" and "Sensitivity" were manually adjusted to obtain a representative number of peaks.

[0103] TIFF2026521852000015.tif58170

[0104] Synthesis and crystallization protocols The synthesis of the active pharmaceutical ingredient (API) (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide was previously disclosed in International Publications 2021 / 116055 and 2022 / 258584. Importantly, International Publication 2022 / 258584 also describes the procedure for isolating polymorphic solid form A and amorphous form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxyphenyl]-3-fluoropyrrolidine-1-sulfonamide.

[0105] Crystallization - Protocol I: 100 g of API was suspended in 1.23 kg of acetone and 0.39 kg of water at 370-400 rpm. The suspension was heated to 40°C until a clear solution was obtained. The pressure was reduced from 400 mbar to 350 mbar and the suspension was distilled until a condensate of 450 mL (349.1 g) was collected. The suspension was heated to 55°C, and a suspension of Form A (390.91 mg of water and 250 mg of acetone in 1.23 g) was added, and the suspension was cooled to 40°C within 10 minutes while remaining suspended. The suspension was distilled at 45°C and 340 mbar until a distillate of 780 mL was collected. The suspension was cooled to room temperature (20-25°C) within 2 hours and stirred for 0.5 hours. The following day, the suspension was filtered and washed twice with a 1+1 (w / w) mixture of water and acetone (total 250 g). The resulting product was dried at 45°C and 20–25 mbar. The material was analyzed by XRPD and, surprisingly, identified as a novel solid morphology, hereafter referred to as morphology B.

[0106] Crystallization - (Alternative) Protocol II: 20 mg of Form A was dissolved in 2 mL of acetone at 40°C. The slightly brownish solution was filtered while still hot through a 0.45 μm syringe filter (PTFE) into a clear 2 mL vial and immediately placed at -10°C. After 17 hours, the off-white solid was separated from the solution and analyzed by XRPD without further drying, and identified as Form B.

Claims

1. Equation (I) A solid form of the compound, characterized by a crystalline polymorph B having an X-ray powder diffraction pattern that includes a peak at a diffraction angle of about 12.88 degrees 2θ and at least one additional peak represented by values ​​of about 10.62, 15.96, 16.82, 17.20, 20.04, 21.24, 23.78, 25.62, 25.88 or 26.90 degrees 2θ.

2. The solid form according to claim 1, characterized by an X-ray powder diffraction pattern including a peak at a diffraction angle of approximately 12.88 degrees 2θ and a peak at approximately 10.62 degrees 2θ.

3. The solid form according to claim 1 or 2, characterized by an X-ray powder diffraction pattern including a peak at a diffraction angle of approximately 12.88 degrees 2θ and a peak at approximately 10.62 degrees 2θ; further comprising at least one additional peak represented by a value of approximately 15.96, 16.82, 17.20, 20.04, 21.24, 23.78, 25.62, 25.88 or 26.90 degrees 2θ.

4. The solid form according to any one of embodiments 1 to 3, characterized by an X-ray powder diffraction pattern that includes at least three peaks at diffraction angles of approximately 10.62, 12.88, 16.82, 20.04, or 26.90 degrees 2θ.

5. The solid form according to any one of claims 1 to 4, characterized by an X-ray powder diffraction pattern including peaks at diffraction angles of approximately 10.62, 12.88, 15.96, 16.82, 17.20, 20.04, 21.24, 23.78, 25.62, 25.88 and 26.90 degrees 2θ.

6. The solid form according to any one of claims 1 to 5, further comprising a peak represented by a value of approximately 8.38 degrees 2θ.

7. A solid form characterized by an X-ray powder diffraction pattern according to any one of claims 1 to 6, further comprising at least one additional peak represented by a value of approximately 9.76, 10.44, 12.74, 16.68, 17.54, 18.76, 19.00, 19.40, 19.52, 20.98, 23.02, 23.30, 24.02, 26.10, 26.48, 27.24, 27.46, 28.56, 28.72, 28.94, 29.08, 29.28, 29.80, or 30.22 degrees 2θ.

8. The solid form according to any one of claims 1 to 7, characterized by the X-ray powder diffraction pattern shown in Figure 1.

9. The solid form according to any one of claims 1 to 8, characterized in that, when differential scanning calorimetry is used with a heating rate of 10 K / min, it has a melting point that includes a peak signal between approximately 214.2°C and approximately 215.2°C, particularly a peak signal at approximately 214.7°C.

10. Equation (I) A solid form of the compound, with a position at 1685 cm －１ (±2) cm －１ , 1617 cm －１ (±2) cm －１ , 1425 cm －１ (±2) cm －１ , 852 cm －１ (±2) cm －１ or 762 cm －１ (±2) cm －１ containing at least one peak at one of them, particularly at a position of 1685 cm －１ (±2) cm －１ , 1617 cm －１ (±2) cm －１ , 1425 cm －１ (±2) cm －１ , 852 cm －１ (±2) cm －１ or 762 cm －１ (±2) cm －１ containing at least two peaks at it, more specifically at positions of 1685 cm －１（ (±2) cm －１ , 1617 cm －１ (±2) cm －１ , 1425 cm －１ (±2) cm －１ , 852 cm －１ (±2) cm －１ and 762 cm －１ (±2) cm －１ A solid form, which is crystalline polymorphic form B characterized by an IR spectrum containing peaks at them.

11. Equation (I) The compound in solid form, at position 114 (±2) cm －１ , 132 (±2) cm －１ 167 (±2) cm －１ 349 (±2) cm －１ Or 1620 (±2) cm －１ One of them includes at least one peak, particularly at position 114 (±2) cm. －１ , 132 (±2) cm －１ 167 (±2) cm －１ 349 (±2) cm －１ Or 1620 (±2) cm －１ It includes at least two peaks, and more specifically, at a position of 114 (±2) cm. －１ , 132 (±2) cm －１ 167 (±2) cm －１ 349 (±2) cm －１ and 1620 (±2) cm －１ Solid form, which is crystalline polymorph B, characterized by a Raman spectrum containing a peak.

12. A substantially pure solid form according to any one of claims 1 to 11.

13. A solid form according to any one of claims 1 to 12 for use as a pharmaceutical.

14. A solid form according to any one of claims 1 to 12 for the treatment or prevention of cancer, particularly BRAF-related cancer.

15. A solid form according to any one of claims 1 to 12 for the treatment or prevention of melanoma or colorectal cancer.

16. A pharmaceutical composition comprising the solid form according to any one of claims 1 to 12 and one or more pharmaceutically acceptable auxiliary substances.

17. Use of the solid form according to any one of claims 1 to 12 for the treatment of cancer, in particular BRAF-related cancer.

18. Use of a solid form according to any one of claims 1 to 12 for the preparation of a pharmaceutical for the treatment of cancer, particularly BRAF-related cancer.

19. A method for treating cancer, particularly BRAF-related cancer, comprising administering an effective amount of the solid form described in any one of claims 1 to 12 to a patient in need thereof.

20. The invention described here.

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