Novel solid forms of (3r)-n-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl) oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

Abstract

The present invention provides solid forms of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl) oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide of formula (I) and solvates thereof, as well as their therapeutic use and pharmaceutical compositions comprising them.

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)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide, as well as its therapeutic use and pharmaceutical compositions comprising said form. Background Technology

[0002] Rapidly accelerating fibrosarcoma (RAF) serine-threonine kinases comprise three members (ARAF, BRAF, and RAF1) that form the first node in the MAP kinase signaling pathway. Although the three RAF isoforms exhibit significant redundancy in signal transduction via phosphorylation of MEK1 and 2, oncogenic activating mutations are typically found only for BRAF. In particular, substitution of V600 with glutamate or lysine leads to hyperactivation of the kinase, resulting in overstimulation of the MAPK pathway regardless of external stimuli (Cell. 2015, 18 June; 161(7): 1681–1696).

[0003] Mutant BRAF is a targetable oncogenic driver, and three BRAF inhibitors (vemurafenib, dabrafenib, and cannefenib) are currently marketed and have shown efficacy in BRAFV600E-positive melanoma. However, rapid acquisition of resistance has been almost universally observed, and the duration of the therapeutic benefit of targeted therapy remains limited.

[0004] Furthermore, developed BRAF inhibitors have demonstrated an unexpected and “abnormal” ability to inhibit MAPK signaling in BRAFV600E-driven tumors, while the same inhibitors have shown MAPK stimulatory activity in BRAF wild-type (WT) models (N Engl J Med 2012; 366:271-273; and British Journal of Cancer Vol. 111, pp. 640-645 (2014)).

[0005] Then, the mechanism of the RAF paradox was elucidated, showing that oncogenic BRAFV600E phosphorylates MEK 1 / 2 in its monomeric cytoplasmic form, while the activation of WT BRAF and RAF1 requires complex event steps, including cell membrane translocation and homodimerization and / or heterodimerization promoted by activated RAS (KRAS, NRAS, HRAS) (Nature Reviews Cancer, Vol. 14, pp. 455-467 (2014)).

[0006] Inhibitors (such as vemurafenib, dabrafenib, or cannefenib) rapidly induce RAF homodimerization and / or heterodimerization, as well as membrane association of newly formed RAF dimers, upon binding to WT BRAF or RAF1 protomers. In the dimer conformation, one RAF protomer conformationally induces a conformational change in the second protomer, resulting in a kinase active state, and importantly, a conformation unfavorable to inhibitor binding. Consequently, the drug-induced dimer promotes MEK phosphorylation through catalytic action manipulated by the unbound protomer, and overactivates this pathway.

[0007] The RAF paradox leads to two clinically relevant consequences: 1) accelerated secondary tumor growth following BRAFi monotherapy (primarily keratochantoma and squamous cell carcinoma) (N Engl J Med 2012; 366:271-273) and 2) the acquisition of resistance in both BRAFi monotherapy and the BRAFi+MEKi combination is driven by genetic events (including RAS mutations, BRAF amplification, and expression of BRAF splice variants with dimer effects) that activate dimer-mediated RAF signaling (Nature Reviews Cancer Vol. 14, pp. 455-467 (2014)). Therefore, a RAF inhibitor capable of breaking this paradox is needed.

[0008] Furthermore, the currently approved classic 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 exhibit poor brain permeability. This is a major limitation in using these classic BRAF inhibitors to treat brain cancer or brain metastases. Therefore, there is a need for BRAF inhibitors with improved brain permeability.

[0009] Therefore, compounds are needed as effective BRAF inhibitors that exhibit relatively little paradoxical activation of the MAPK signaling pathway while maintaining high potency. Such compounds can also be called paradox breaker or RAF paradox disruptors, in contrast to compounds that induce the RAF paradox (and which may be called 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 meets these requirements, and it is a paradox-breaking BRAF inhibitor with good brain penetration properties.

[0010] Polymorphs are different crystalline forms of the same compound. Due to the different ways in which molecules are packed in the crystal lattice, polymorphs typically have different crystal structures. Polymorphism is of interest to the pharmaceutical industry, especially those involved in the development of suitable dosage forms. If the polymorphism does not remain constant during clinical studies, it may be impossible to compare batches of the exact dosage form used or studied. When a compound is used in clinical studies or as a commercial product, it is also desirable to have a process for producing compounds with the selected polymorphism in high purity, as any impurities can have undesirable effects (e.g., toxicity). Some polymorphs may exhibit enhanced stability or can be more easily manufactured in large quantities with high purity, and are more suitable for inclusion in pharmaceutical formulations. Some polymorphs may exhibit other advantageous physical properties, such as lack of hygroscopicity, improved solubility, and increased dissolution rate due to different lattice energies.

[0011] (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide is a paradoxically disruptive BRAF inhibitor with good brain penetration properties and potential applications in cancer therapy, particularly melanoma, lung cancer, and brain metastases. Accordingly, for drug development and commercialization, it is necessary to identify a solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide with desired properties such as high crystallinity, high purity, and favorable physical, chemical, solubility, and mechanical properties. WO2022 / 258584 describes a procedure for separating polycrystalline solid type A and amorphous (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide. This invention provides (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide in a novel solid form, namely crystalline polycrystalline type B. Detailed Implementation

[0012] This invention relates to the solid form of compounds of formula (I). The solid form is a crystalline polymorph, type B.

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

[0014] The crystalline polymorph B is the thermodynamically stable form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide. Crystalline polymorph B is characterized by favorable physicochemical properties, such as improved flowability, and provides enhanced processability, making this form suitable for the large-scale manufacture of active pharmaceutical ingredients.

[0015] The terms “pharmaceutically acceptable carrier” and “pharmaceuticalally acceptable excipient” refer to carriers and excipients, such as diluents or excipients that are compatible with other components of the formulation.

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

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

[0018] The terms “about” and “approximately” are used interchangeably and refer to a range of values ​​that fall within 5% of the reference value. More specifically, “about” or “approximately” means ±0.2° 2θ or ±0.5°C.

[0019] As used herein, the term "large amount" can mean at least 50%, particularly at least 60%, and more particularly at least 70% of the initial amount of a particular substance in a defined fraction. For example, after a purification step, a fraction containing a large amount of a particular substance will contain at least 50%, particularly at least 60%, and more particularly at least 70% of the initial amount of that particular substance before the purification step.

[0020] "Crystallization" and "recrystallization" are used interchangeably; they refer to the process of producing a stable polymorph or crystalline form of a particular compound, which may have been in an amorphous form or dissolved or suspended in a solvent system prior to the process. For example, the crystallization step can be accomplished by forming crystals using a solvent and an antisolvent.

[0021] "XRPD" refers to the X-ray powder diffraction analysis method. The repeatability of angular values ​​is within the range of 2θ ± 0.2°. The term "approximately" given in combination with angular values ​​indicates repeatability within the 2θ range. Relative XRPD peak intensities depend on many factors, such as structure factor, temperature factor, crystallinity, polarization factor, multiplicity, and Lorentz factor. Due to the preferred orientation effect, relative intensities can vary considerably from one measurement to another. According to USP 941 (United States Pharmacopoeia, 37th edition, General 941), the relative intensities between two samples of the same material can vary considerably due to the "preferred orientation" effect. Preferred orientation in anisotropic materials leads to anisotropic distributions of properties such as modulus, strength, ductility, toughness, electrical conductivity, and thermal expansion, as described, for example, in Kocks UF et al. (Texture and Anisotropy: Preferred Orientations in Polycrystals and Their Effect on Materials Properties, Cambridge University Press, 2000). In XRPD and Raman spectroscopy, preferred orientation results in variations in intensity distribution. The preferred orientation effect is particularly pronounced in crystalline APIs with relatively large grain sizes.

[0022] “Characteristic peaks” refer to powder X-ray diffraction peaks that can be definitively identified as the crystalline form (Type B) of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide. Typically, powder X-ray diffraction analysis is performed under ambient conditions using a STOE STADI P diffractometer (Cu Kα1 radiation, master monochromator, silicon strip detector, angular range of 3°2θ to 42°2θ, total measurement time approximately 30 minutes) in transmission geometry mode. Samples (approximately 10 mg to 50 mg) are prepared between thin polymer films and can be analyzed without further processing (e.g., grinding or sieving).

[0023] "Polymorphic" refers to a crystalline form having the same chemical composition but with different spatial arrangements of molecules, atoms, and / or ions forming the crystal. Generally, this specification will refer throughout to the polymorphic form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide. The term "polymorphic form" as used herein may or may not include other crystalline solid molecular forms of the same compound, including hydrates (e.g., bound water present in a crystalline structure). Polymorphs typically have different crystal structures due to the different ways in which molecules are packed in the crystal lattice. This results in different crystal symmetries and / or unit cell parameters, directly affecting their physical properties, such as the X-ray diffraction characteristics of the crystal or powder.

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

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

[0026] The terms “pharmaceuticalally acceptable excipient,” “pharmaceuticalally acceptable carrier,” and “therapeutic inert excipient” are used interchangeably and refer to any pharmaceutically acceptable component in a pharmaceutical composition that is not therapeutically active and is non-toxic to the subject to which it is administered, such as disintegrants, binders, fillers, solvents, buffers, tensioning agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants used in the formulation of pharmaceutical products.

[0027] The term "pharmaceutical composition" encompasses products containing specific ingredients in predetermined amounts or proportions, and any product resulting directly or indirectly from the combination of specific amounts of specific ingredients. In particular, it encompasses products containing one or more active ingredients and optionally a carrier containing an inert ingredient; and any product resulting directly or indirectly from the combination, compounding, or aggregation of two or more of the ingredients, or the dissociation of one or more of the ingredients, or other types of reactions or interactions of one or more of the ingredients.

[0028] The terms “pharmaceutically acceptable carrier” and “pharmaceuticalally acceptable excipient” refer to carriers and excipients, such as diluents or excipients that are compatible with other components of the formulation.

[0029] "Therapeutic effective dose" refers to the amount that effectively prevents, alleviates, or reduces disease symptoms or prolongs the survival of the treated subject.

[0030] When used to refer to the solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide, the term "substantially pure" means that the polymorph is >90% pure. The solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-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-quinazoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide.

[0031] More specifically, when used to refer to the solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide, the term "substantially pure" means that the solid is >95% pure. The solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide does not contain more than 5% of any other compound, and in particular, does not contain more than 5% of any other solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide.

[0032] Even more specifically, when used to refer to the solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quino-azoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide, the term "substantially pure" means that the solid form is >97% pure. The solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quino-azoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide does not contain more than 3% of any other compound, and in particular, does not contain more than 3% of any other solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quino-azoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide.

[0033] Most notably, when used to refer to the solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide, the term "substantially pure" means that the polymorph is >99% pure. The solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide does not contain more than 1% of any other compound, and in particular, does not contain more than 1% of any other solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide.

[0034] Most notably, when used to refer to the solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide, the term "substantially pure" means that the polymorph is >99.5% pure. The solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide does not contain more than 1% of any other compound, and in particular, does not contain more than 1% of any other solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide.

[0035] While the invention has been described with reference to specific embodiments thereof, those skilled in the art will understand that various changes and equivalent substitutions can be made without departing from the true nature and scope of the invention. Furthermore, many modifications can be made to adapt particular circumstances, materials, composition, methods, or one or more method steps to the objective nature and scope of the invention. All such modifications are intended to be within the scope of the appended claims. All independent embodiments can be combined.

[0036] The specific designation of this invention is as follows: 1. A solid form of a compound of formula (I) The solid form is a crystalline polymorphic type B, characterized in that the X-ray powder diffraction pattern contains a peak at a diffraction angle of about 12.88 degrees 2θ and at least one additional peak, expressed in 2θ degrees, at about 10.62, 15.96, 16.82, 17.20, 20.04, 21.24, 23.78, 25.62, 25.88 or 26.90.

[0037] 2. The solid form according to aspect 1 is characterized in that the X-ray powder diffraction pattern contains a peak at a diffraction angle of about 12.88 degrees 2θ and a peak at about 10.62 degrees 2θ.

[0038] 3. The solid form according to aspect 1 or 2, characterized in that the X-ray powder diffraction pattern includes a peak at a diffraction angle of about 12.88 degrees 2θ and a peak at about 10.62 degrees 2θ; wherein the pattern further includes at least one additional peak, expressed in 2θ degrees, at about 15.96, 16.82, 17.20, 20.04, 21.24, 23.78, 25.62, 25.88 or 26.90.

[0039] 4. The solid form according to any one of aspects 1 to 3, characterized in that the X-ray powder diffraction pattern includes at least three of the peaks at diffraction angles of about 10.62, 12.88, 16.82, 20.04 or 26.90 degrees 2θ.

[0040] 5. The solid form according to any one of aspects 1 to 4, characterized in that the X-ray powder diffraction pattern contains peaks at diffraction angles of about 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.

[0041] 6. The solid form according to any one of aspects 1 to 5 further comprises a peak at about 8.38, expressed in 2θ degree values.

[0042] 7. A solid form characterized by an X-ray powder diffraction pattern according to any one of aspects 1 to 6, further comprising at least one additional peak, expressed in 2θ degrees, at about 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.

[0043] 8. The solid form according to any one of aspects 1 to 7, characterized by the X-ray powder diffraction pattern shown in FIG1.

[0044] 9. The solid form according to any one of aspects 1 to 8, characterized in that, using differential scanning calorimetry with a heating rate of 10 K / min, it has a melting point with a peak signal at about 214.2°C to about 215.2°C, particularly with a peak signal at about 214.7°C.

[0045] 10. The solid form according to any one of aspects 1 to 9, characterized by the differential scanning calorimetry thermogram shown in FIG2.

[0046] 11. The solid form according to any one of aspects 1 to 9, characterized by the thermogravimetric analysis pyrometry spectrum shown in FIG3.

[0047] 12. A solid form of a compound of formula (I) The solid form is a crystalline polymorphic type B, characterized in that the IR spectrum is contained at position 1685 cm⁻¹. -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 At least one peak is located at one of the peaks, 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 At least two peaks are present, more specifically 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 and 762 cm -1(±2) cm -1 The peak at that location.

[0048] 13. The solid form according to any one of aspects 1 to 11, further characterized by the IR spectrum according to aspect 12.

[0049] 14. The solid form according to any one of aspects 1 to 11, further characterized in that the IR spectrum is contained at position 1685 cm⁻¹ -1 (±2) cm -1 The peak at that location.

[0050] 15. The solid form according to any one of aspects 1 to 14, characterized by the IR spectrum shown in FIG5.

[0051] 16. A solid form of a compound of formula (I) The solid form is a crystalline polymorph B, characterized in that the Raman spectrum is contained at position 114 (±2) cm. -1 132 (±2) cm -1 167 (±2) cm -1 349 (±2) cm -1 Or 1620 (±2) cm -1 At least one peak at one of them, particularly contained at position 114 (±2) cm. -1 132 (±2) cm -1 167 (±2) cm -1 349 (±2) cm -1 Or 1620 (±2) cm -1 At least two peaks are present at position 114 (±2) cm, more specifically contained at position 114 (±2) cm. -1 132 (±2) cm -1 167 (±2) cm -1 349 (±2) cm -1 and 1620 (±2) cm -1 The peak at that location.

[0052] 17. The solid form according to any one of aspects 1 to 15, further characterized by the Raman spectrum according to aspect 16.

[0053] 18. The solid form according to any one of aspects 1 to 11, further characterized in that the Raman spectrum is contained at position 1620 cm⁻¹. -1(±2) cm -1 The peak at that location.

[0054] 19. The solid form according to any one of aspects 1 to 18, characterized by the Raman spectrum shown in FIG4.

[0055] 20. Essentially pure solid form according to any one of aspects 1 to 19.

[0056] 21. In solid form according to any one of aspects 1 to 20, it is used as a medicine.

[0057] 22. In solid form according to any one of aspects 1 to 20, for the treatment or prevention of cancer, particularly BRAF-related cancers.

[0058] 23. In any of the solid forms according to any one of aspects 1 to 20, for the treatment or prevention of melanoma or colorectal cancer, particularly colorectal cancer.

[0059] 24. A pharmaceutical composition comprising, in solid form according to any one of aspects 1 to 20, and one or more pharmaceutically acceptable adjuvant substances.

[0060] 25 Use in solid form according to any one of aspects 1 to 20 for the treatment of cancer, particularly BRAF-related cancers.

[0061] 26 Use in solid form according to any one of aspects 1 to 20 for the treatment of melanoma or colorectal cancer, particularly colorectal cancer.

[0062] 27 Use in solid form according to any one of aspects 1 to 20 for the preparation of a medicament for the treatment of cancer, particularly BRAF-related cancers.

[0063] 28. A method for therapeutic or preventative treatment of cancer, particularly BRAF-related cancer, the method comprising administering to a patient in need an effective amount of the solid form according to any one of aspects 1 to 20.

[0064] In one embodiment, the crystalline polymorph B of the compound of formula (I) is anhydrous (i.e., contains no bound water in the crystal lattice) and non-hygroscopic (water absorption <0.2% according to the European Pharmacopeia).

[0065] This invention also relates to compounds according to the invention manufactured according to the method of the invention.

[0066] Pharmaceutical Composition 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, sugar-coated pills, hard and soft gelatin capsules, solutions, emulsions, or suspensions. However, administration can also be made, for example, rectally in the form of suppositories, or parenterally, for example, in the form of injectable solutions.

[0067] Compounds of formula (I) can be processed with pharmaceutically inert inorganic or organic carriers for the production of pharmaceutical compositions. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as such carriers in tablets, coated tablets, sugar-coated pills, and hard gelatin capsules. Suitable carriers for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols. However, depending on the characteristics of the active substance, a carrier is often not required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups include, for example, water, polyols, glycerol, vegetable oils, etc. Suitable carriers for suppositories include, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc.

[0068] In addition, pharmaceutical compositions may contain pharmaceutically acceptable adjuvants, such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for altering osmotic pressure, buffers, masking agents, or antioxidants. They may also contain other substances with therapeutic value.

[0069] Pharmaceutical compositions comprising (I) compounds (alone or in combination) may be prepared for storage by mixing an active ingredient of desired purity with an optional pharmaceutically acceptable carrier, excipient, or stabilizer (Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed.) (1980)) in the form of a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients, or stabilizers are non-toxic to the recipient at the doses and concentrations used and include buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethyl ammonium chloride; benzalkonium chloride, benzyl chloride; phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoate, such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10). (1 residue) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants, such as TWEENTM, PLURONICS™, or polyethylene glycol (PEG).

[0070] The present invention also provides a medicament comprising a compound of formula (I) as described herein in solid form and a therapeutically inert carrier, and a method thereof for manufacturing the same, the method comprising forming a galen formulation for administration with one or more compounds of formula (I) and / or pharmaceutically acceptable solvates thereof, and (if desired) one or more other substances of therapeutic value, together with one or more therapeutically inert carriers.

[0071] Pharmaceutical compositions of BRAF inhibitors include those suitable for oral, nasal, topical (including oral and sublingual), rectal, vaginal, and / or parenteral administration.

[0072] Dosage is variable over a wide range, but will of course have to be adjusted according to individual needs for each specific situation. In the case of oral administration, the dosage for adults can be varied from about 200 mg to about 4000 mg daily of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof. The daily dose may be administered as a single dose or in multiple fractions, and may also be exceeded if there are indications that the upper limit may be exceeded.

[0073] The following examples are illustrative but not limiting of the invention, and are merely representative of it. Pharmaceutical formulations conveniently contain about 5 mg to 500 mg, particularly 100 mg to 500 mg, of the compound of formula (I). Examples of compositions according to the invention are: Example A The following compositions are manufactured in tablet form using conventional methods: Table 1: Possible tablet compositions Preparation procedure 1. Mix components 1, 2, 3 and 4 and granulate them together with purified water.

[0074] 2. Dry the granules at 50℃.

[0075] 3. Pass the particles through suitable grinding equipment.

[0076] 4. Add ingredient 5 and mix for three minutes; press on a suitable press.

[0077] Example B-1 Capsules for producing the following compositions: Table 2: Possible Capsule Ingredients Preparation procedure 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.

[0078] 2. Add ingredients 4 and 5 and mix for 3 minutes.

[0079] 3. Fill into the appropriate capsules.

[0080] First, the compound of formula (I), lactose, and corn starch are mixed in a mixer, and then mixed in a grinder. The mixture is then returned to the mixer; talc is added and thoroughly mixed. The mixture is then filled into suitable capsules, such as hard gelatin capsules, using a machine.

[0081] Example B-2 Manufacture soft gelatin capsules having the following composition: Table 3: Possible composition of soft gelatin capsules Table 4: Possible Compositions of Soft Gelatin Capsules Preparation procedure The compound of formula (I) is dissolved in a warm melt of the other components, and the mixture is filled into soft gelatin capsules of suitable size. The filled soft gelatin capsules are then processed according to standard procedures.

[0082] Example C Manufacturing suppositories having the following composition: Table 5: Possible Suppository Compositions Preparation procedure Melt the suppository matrix in a glass or steel container, mix thoroughly, and cool to 45°C. Then, add a fine powder of compound (I) and stir until the compound is completely dispersed. Pour the mixture into a suppository mold of suitable size and allow it to cool; then remove the suppository from the mold and individually package it in waxed paper or metal foil.

[0083] Example D To produce an injection solution of the following composition: Table 6: Possible Compositions of Injection Solutions Preparation procedure The compound of formula (I) was dissolved in a mixture of polyethylene glycol 400 and water for injection (partial). The pH was adjusted to 5.0 with acetic acid. The volume was adjusted to 1.0 ml by adding the remaining water. The solution was filtered, filled into vials using appropriate overfilling, and sterilized.

[0084] Example E Manufacturing a bagging agent having the following composition: Table 7: Possible Bag Composition Preparation procedure The compound of formula (I) was mixed with lactose, microcrystalline cellulose, and sodium carboxymethyl cellulose, and then granulated with a mixture of polyvinylpyrrolidone in water. The granules were then mixed with magnesium stearate and flavoring additives and filled into bags. Attached Figure Description

[0085] Figure 1 shows the X-ray powder diffraction pattern of polymorph B of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide.

[0086] Figure 2 shows the thermogram of polymorph B of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide obtained by differential scanning calorimetry (DSC). A sharp melting signal was observed (initial temperature 212.3 °C, peak temperature 214.7 °C, enthalpy 109 J / g), and decomposition occurred after melting.

[0087] Figure 3 shows the thermogravimetric spectrum of polymorph B of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide obtained by thermogravimetric analysis (TGA). No significant mass loss was observed (0.087%).

[0088] Figure 4 shows the Raman spectrum of polymorph B of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide.

[0089] Figure 5 shows the IR spectrum of polymorph B of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide.

[0090] Experimental Section The following experiments are provided to illustrate the invention. They should not be considered as limiting the scope of the invention, but merely as representative examples.

[0091] abbreviation: ATR = Attenuated Total Reflection; DCM = Dichloromethane; DIPEA = N,N-Diisopropylethylamine; DMF = Dimethylformamide; DMSO = Dimethyl sulfoxide; DSC = Differential Scanning Calorimetry; DVS = Dynamic Vapor Adsorption; ESI = Electrospray Ionization; EtOAc = Ethyl Acetate; FT = Fourier Transform; FTIR = Fourier Transform Infrared; IR = Infrared; 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 in transmission geometry mode. The X-ray diffraction patterns were recorded on a STOE STADI P diffractometer using CuKa1 radiation (1.5406 Å) and a Mythen position-sensitive detector. Samples (approximately 10 mg to 50 mg) were prepared between thin polymer films and typically require no further processing (e.g., grinding or sieving) for analysis.

[0093] For polymorphic type B, the following peaks (expressed as 2θ degrees) have been found by XRPD at approximately the following locations: 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, 30.22.

[0094] Differential scanning calorimetry (DSC) DSC curves were recorded using a Mettler-Toledo™ Differential Scanning Calorimeter (DSC2). System suitability testing was performed using indium as a reference, and calibration was performed using indium, benzoic acid, biphenyl, and zinc as references.

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

[0096] Thermogravimetric Analysis (TGA) Thermogravimetric analysis (TGA) was performed on a Mettler-Toledo™ thermogravimetric analyzer (TGA / DSC1 or TGA / DSC3+). System suitability testing was conducted using Hydranal as a reference material, and calibration was performed using aluminum and indium as reference materials.

[0097] For thermogravimetric analysis, approximately 5 to 15 mg (about 7.197 mg of type B) of sample is placed in an aluminum pan, accurately weighed, and sealed with a perforated cap. Prior to measurement, the cap is automatically punctured, creating a pinhole of approximately 0.5 mm. The sample is then heated to a maximum temperature, typically 350 °C, using a heating rate of 5 K / min under a nitrogen flow of approximately 50 mL / min.

[0098] Moisture adsorption / desorption Moisture adsorption / desorption data are collected on a DVS Advantage, DVS Adventure, or DVS Intrinsic (SMS Surface Measurement System) moisture balance system. Adsorption / desorption isotherms are typically measured stepwise at 25°C from 0%-RH to 90%-RH. A weight change typically <0.001% / min is selected as the criterion for switching to the next relative humidity level (if the weight change criterion is not met, the maximum equilibration time is typically 24 hours). Data are corrected for the initial moisture content of the sample by taking the weight of the sample after drying at 0%-RH as zero.

[0099] The hygroscopicity of a given substance is characterized by the increase in mass as the relative humidity increases from 0%-RH to 90%-RH (refer to the European Pharmacopoeia). IR spectrum ATR FTIR spectra were recorded using a ThermoNicolet iS5 FTIR spectrometer with an ATR accessory, requiring no sample preparation. The spectral range was between 4000 cm⁻¹. -1 With 650 cm -1 Between, resolution 2 cm -1 At least 50 co-added scans were collected. The Happ-Genzel apodization method was applied. Using ATR FTIR will result in a difference in the relative intensity of the infrared bands compared to the relative intensity seen in transmission FTIR spectra prepared using KBr disks or nujol mull samples. Due to the nature of ATR FTIR, bands at lower wavenumbers are stronger than those at higher wavenumbers.

[0100] Use the automatic "Peak Finder" function in Thermo Scientific Omnic 8.3 software to find peaks. Manually adjust the "Threshold" and "Sensitivity" to obtain a representative number of peaks.

[0101] Table 8: List of peaks identified by infrared spectroscopy for polymorphic type B.

[0102] Raman spectroscopy A Bruker MultiRam FT-Raman spectrometer equipped with an NdYAG 1064 nm laser and a liquid nitrogen-cooled germanium detector was used at 4000 cm⁻¹. -1 Up to 50 cm -1 FT-Raman spectra were recorded within the specified spectral range without any sample preparation. The laser power at the sample was approximately 300 mW, using a 2 cm⁻¹ laser. -1 Resolution was set, and a total of 2048 scans were added. A Blackman-Harris 4-term apodization function was used. Approximately 5 mg of sample (powder in a glass vial) was required. Peak finding was performed using the automatic "Peak Finder" function in ThermoScientific Omnic 8.3 software. The "Threshold" and "Sensitivity" were manually adjusted to obtain a representative number of peaks.

[0103] Table 9: List of peaks identified by Raman spectroscopy for polymorphic type B.

[0104] Synthesis and Crystallization Scheme The synthesis of the active pharmaceutical ingredient (API) (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide was previously disclosed in WO2021 / 116055 and WO2022 / 258584. Importantly, WO2022 / 258584 also describes a procedure for isolating the polycrystalline solid type A and amorphous forms of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazoline-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide.

[0105] Crystallization – Scheme I:Suspend 100 g of API in 1.23 kg of acetone and 0.39 kg of water at 370 rpm to 400 rpm. Heat the suspension to 40°C until a clear solution is obtained. Reduce the pressure from 400 mbar to 350 mbar for distillation until a condensate volume of 450 mL (349.1 g) is collected. Heat the suspension to 55°C and add a suspension of type A seed crystals (250 mg in 390.91 mg of water and 1.23 g of acetone) and cool to 40°C with stirring for 10 minutes. Distill the suspension at 45°C and 340 mbar until a distillate volume of 780 mL is collected. Cool the suspension to 20°C to 25°C at room temperature over 2 hours and stir at this temperature for 0.5 hours. The next day, the suspension was filtered and washed twice with a 1+1 (w / w) mixture of water and acetone (total 250 g). The obtained product was dried at 45 °C and 20 mbar to 25 mbar. The material was analyzed by XRPD, and unexpectedly, it was identified as a new solid form, which was subsequently designated as type B.

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

Claims

1. A solid form of a compound of formula (I) The solid form is a crystalline polycrystalline type B, characterized in that, The X-ray powder diffraction pattern contains a peak at a diffraction angle of approximately 12.88 degrees 2θ and at least one additional peak, expressed in 2θ degrees, at approximately 10.62, 15.96, 16.82, 17.20, 20.04, 21.24, 23.78, 25.62, 25.88, or 26.

90.

2. The solid form according to claim 1, characterized in that, The X-ray powder diffraction pattern contains 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, characterized in that, The X-ray powder diffraction pattern contains a peak at a diffraction angle of about 12.88 degrees 2θ and a peak at about 10.62 degrees 2θ; wherein the pattern further contains at least one additional peak, expressed in 2θ degrees, at about 15.96, 16.82, 17.20, 20.04, 21.24, 23.78, 25.62, 25.88 or 26.

90.

4. The solid form according to any one of claims 1 to 3, characterized in that, The X-ray powder diffraction pattern contains at least three of the 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 in that, The X-ray powder diffraction pattern contains 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 at approximately 8.38 degrees, expressed in 2θ degrees.

7. A solid form, characterized in that... The X-ray powder diffraction pattern according to any one of claims 1 to 6 further comprises at least one additional peak, expressed in 2θ degrees, at about 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.

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

9. The solid form according to any one of claims 1 to 8, characterized in that, Using differential scanning calorimetry with a heating rate of 10 K / min, the melting point has a peak signal at about 214.2 °C to about 215.2 °C, particularly at about 214.7 °C.

10. A solid form of a compound of formula (I) The solid form is a crystalline polycrystalline type B, characterized in that, The IR spectrum is contained at position 1685 cm⁻¹ -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 At least one peak is located at one of the peaks, particularly at position 1685 cm. -1 (±2) cm -1 1617cm -1 (±2) cm -1 1425 cm -1 (±2) cm -1 852 cm -1 (±2) cm -1 Or 762 cm -1 (±2) cm -1 At least two peaks are present, more specifically at position 1685 cm. -1 (±2) cm -1 1617 cm -1 (±2) cm -1 1425cm -1 (±2) cm -1 852 cm -1 (±2) cm -1 and 762 cm -1 (±2) cm -1 The peak at that location.

11. A solid form of a compound of formula (I) The solid form is a crystalline polycrystalline type B, characterized in that, Raman spectra are contained at position 114 (±2) cm -1 132 (±2) cm -1 167 (±2) cm -1 349 (±2) cm -1 Or 1620 (±2) cm -1 At least one peak at one of them, particularly contained at position 114 (±2) cm. -1 132 (±2) cm -1 167 (±2) cm -1 349(±2) cm -1 Or 1620 (±2) cm -1 At least two peaks are present at position 114 (±2) cm, more specifically contained at position 114 (±2) cm. -1 132 (±2) cm -1 167 (±2) cm -1 349 (±2) cm -1 and 1620 (±2) cm -1 The peak at that location.

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

13. The solid form according to any one of claims 1 to 12, used as a medicine.

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

15. The 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: a solid form according to any one of claims 1 to 12, and one or more pharmaceutically acceptable adjuvant substances.

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

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

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

20. The invention as described herein.

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