NEW METHYLQUINAZOLINONE DERIVATIVES

Abstract

The invention provides a novel compound having the general Formula (I) (see Formula) (I), or a pharmaceutically acceptable salt thereof. The compound of Formula (I) can be used as a medicament.

Description

NEW METHYLQUINAZOLINONE DERIVATIVES The present invention provides a novel compound, its preparation, pharmaceutical compositions containing it, and its use as a therapeutically active substance. The compound of the invention is a BRAF inhibitor and has paradox-breaking properties. The present invention provides in particular a novel compound of Formula (I) pq t αηη / ζζητ: / β / υιλι (l) or a pharmaceutically acceptable salt thereof. The rapidly accelerating fibrosarcoma (RAF) class of serine-threonine kinases comprises three members (ARAF, BRAF, RAF1) that form the first node of the MAPK signal transduction pathway. Despite the apparent redundancy of the three RAF isoforms in signal propagation along MEK1 and 2 phosphorylation, frequent oncogenic activation mutations are typically found only for BRAF. In particular, substitution of V600 with glutamic acid or Usine results in highly activated kinase, with consequent hyperstimulation of the MAPK pathway, independent of external stimuli (Cell. June 18, 2015; 161(7): 1681-1696). The BRAF mutant is a targetable oncogenic driver, and three BRAF inhibitors (vemurafenib, dabrafenib, and encorafenib) have reached the market to date, demonstrating efficacy in BRAFV600E-positive melanoma. However, rapid acquisition of drug resistance is almost universally observed, and the duration of therapeutic benefits from targeted therapy remains limited. Furthermore, the BRAF inhibitors developed revealed the unexpected and paradoxical ability to repress MAPK signaling in BRAFV600E-driven tumors, while the same inhibitors exhibited MAPK-stimulatory activities in wild-type (WT) BRAF models (N Engl J Med 2012; 366:271-273; and British Journal of Cancer, Volume 111, Pages 640-645(2014)). Mechanistic studies on the RAF paradox then clarified that oncogenic BRAFV600E phosphorylates MEK 1 / 2 in its cytosolic monomeric form, whereas activation of WT BRAF and RAF1 requires a complex stage of events including cell membrane translocation and homo- and / or heterodimerization promoted by activated RAS (KRAS, NRAS, HRAS) (Nature Reviews Cancer, Volume 14, Pages 455-467(2014)). The binding of inhibitors such as vemurafenib, dabrafenib, or encorafenib to a wild-type BRAF or RAF1 promoter rapidly induces RAF homo- and / or heterodimerization and membrane association of the newly formed RAF dimer. In the dimeric conformation, one RAF promoter allosterically induces conformational changes in the second, resulting in an active kinase state and, importantly, a conformation unfavorable for inhibitor binding. The drug-induced dimer then promotes MEK phosphorylation via catalysis operated by the unbound promoter, leading to hyperactivation of the pathway. The RAF paradox results in two clinically relevant consequences: 1) accelerated growth of secondary tumors following BRAFi monotherapy (primarily keratoacanthoma and squamous cell carcinomas) (N Engl J Med 2012; 366:271-273) and 2) the acquisition of drug resistance in the context of BRAFi monotherapy, as well as in BRAFi+MEKi combinations, exhibits dimer-mediated RAF signaling activation by genetically driven events including RAS mutations, BRAF amplifications, and the expression of dimeric BRAF splicing variants (Nature Reviews Cancer, Volume 14, Pages 455-467 (2014)). Therefore, there is a need for RAF inhibitors capable of overcoming this paradox. 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), have very poor permeability in the brain. This is a major limitation for the use of these classic BRAF inhibitors in the treatment of brain cancer or brain metastases. Therefore, there is a need for BRAF inhibitors with improved permeability in the brain. The present invention relates to the surprising finding that the BRAF inhibitor of Formula (I) is a more potent and selective BRAF inhibitor that exhibits considerably less paradoxical activation of the MAPK signal transduction pathway while still maintaining high potency. Therefore, this compound may be termed a paradox breaker or RAF paradox breaker, as distinct from compounds that induce the RAF paradox (and which could be termed paradox inducers or RAF paradox inducers). In addition to being a paradox breaker, the compound of Formula (I) also has very potent brain penetration properties, providing an urgently needed alternative treatment for certain types of brain cancer. BRIEF DESCRIPTION OF THE FIGURES: Figure 1 discloses the P-ERK inhibition curve induced by example 1 in the BRAFA375 mutant cell line. Figure 2 discloses the P-ERK inhibition curve induced by example 2 in the BRAFA375 mutant cell line. Figure 3 discloses the P-ERK inhibition curve induced by the reference compound AR-25 in the BRAF A375 mutant cell line. Figure 4 discloses the P-ERK activation curve induced by example 1 in the BRAF WT HCT-116 cell line. For comparative purposes, data generated by treatment with the control compounds dabrafenib (paradox inducer) and PLX-8394 (paradox breaker) are also shown. Figure 5 discloses the P-ERK activation curve induced by example 2 in the BRAF WT HCT-116 cell line. For comparative purposes, data generated by treatment with the control compounds dabrafenib (paradox inducer) and PLX-8394 (paradox breaker) are also shown. Figure 6 discloses the P-ERK activation curve induced by the reference compound AR-25 in the BRAF WT HCT-116 cell line. For comparative purposes, data generated by treatment with the control compounds dabrafenib (paradox inducer) and PLX-8394 (paradox breaker) are also shown. Figure 7 illustrates the paradoxical activation of the MAP kinase pathway induced by first-generation BRAF inhibitors. BRAF is part of the first node of the MAP kinase signal transduction pathway, and mutant BRAF is an oncogenic driver (left). In tumors with the BRAF V600E / K mutation, BRAF is signaled as a monomer, a condition in which first-generation BRAF inhibitors inhibit the protein (center). First-generation BRAF inhibitors promote homo- and / or heterodimerization of BRAF WT (top right). In this context, the promoter not occupied by the BRAF inhibitor adopts a conformation unfavorable for inhibitor binding (center right). The result of treatment with a first-generation BRAF inhibitor, in this context, is paradoxically increased MAPK activation and subsequent tumor growth in BRAF WT cells (bottom right). Figure 8 discloses that Example 1 of the compound produced dose-dependent antitumor activity starting at 1 mg / kg per day, which is evidence of potent permeability-mediated efficacy in the brain. WO2012 / 118492 discloses reference compounds AR-25 as example 25, AR-30 as example 30, and AR-31 as example 31. ρρ / αηη / ζζηζ / Ε / γίΛΐ ro t αηη / ζζητvb / υιλι Ν AR-25 AR-30 AR-31 The term "pharmaceutically acceptable salt" refers to those salts of the compound of Formula (I) that retain the biological efficacy and properties of the free bases or free acids, and are not undesirable either biologically or otherwise. These salts are formed from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, particularly hydrochloric acid, and organic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, and the like. Furthermore, these salts can be prepared by adding an inorganic or organic base to the free acid.Salts derived from an inorganic base include, among others, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, and the like. Salts derived from organic bases include, among others, salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion-exchange resins, such as resins of isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine, and the like. Pharmaceutically acceptable salts of the compound of Formula (I) include hydrochloride salts, methanesulfonic acid salts, and citric acid salts. The compound of Formula (I) contains an asymmetric center and may be present in the form of optically pure enantiomers or mixtures of enantiomers such as, for example, racemates. According to the Cahn-Ingold-Prelog convention, the asymmetric carbon atom can be of the R or S configuration. Another embodiment of the present invention is the compound according to Formula (I) as described herein or a pharmaceutically acceptable salt thereof, in particular the compound according to Formula (I) as described herein, more particularly the compound of Formula (Ia) or (Ib) as described herein. The invention also relates to a pharmaceutically acceptable salt of the compound of Formula (I), and wherein the pharmaceutically acceptable salt may be selected from hydrochloride salts, methanesulfonic acid salts, and citric acid salts. Another form of embodiment of the present invention is the compound according to Formula (a). ro t αηη / ζζητvb / υιλι (the) Another embodiment of the present invention is the compound according to Formula (Ib). (Ib) Also included in the invention are the processes for preparing the compounds of Formulas (1a) and (1b) as described herein. The preparation of the compound of Formula (I) of the present invention can be carried out by sequential or convergent synthetic routes. The following general scheme shows syntheses of the invention. Persons of intermediate skill are familiar with the abilities necessary to carry out the reactions and purifications of the resulting products. In more detail, the compound of Formula (I) can be prepared using the methods provided below, the methods provided in the examples, or analogous methods. Those of intermediate skill are familiar with suitable reaction conditions for the individual reaction steps. The reaction sequence is not limited to that shown in Scheme 1. However, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered. The starting materials are commercially available or can be prepared using methods analogous to those provided below, methods described in the references cited in the description or examples, or methods known in the art. Scheme 1 ρρ / αηη / ζζηζ / Ε / γίΛΐ It will be appreciated that the compound of Formula (I) in this invention can be derivatized into functional groups to provide derivatives that are capable of being converted back into the parent compound in vivo. Therefore, the invention also relates to a process for preparing a compound according to the invention, comprising the reaction of a compound of Formula (B1) ρρ / αηη / ζζηζ / E / γίΛΐ The reaction can be conveniently carried out in a solvent. The solvent can be, for example, DMF. The reaction can be conveniently carried out in the presence of a base. The base can be, for example, cesium carbonate. Suitable conditions for the reaction can be between approximately 30°C and approximately 150°C, particularly between approximately 50°C and approximately 130°C, and more specifically between approximately 70°C and approximately 120°C. Suitable conditions are around 100°C for between approximately 1 hour and approximately 48 hours, particularly between approximately 2 hours and approximately 20 hours. The invention also refers to a compound according to the invention when it is prepared according to a process of the invention. The invention also relates in particular to: A compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance; A pharmaceutical composition comprising a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier; A compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of cancer; A compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis against thyroid cancer, colorectal cancer, brain cancer, melanoma, or non-small cell lung cancer (NSCLC); The use of a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis against thyroid cancer, colorectal cancer, brain cancer, melanoma, or NSCLC; The use of a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis against thyroid cancer, colorectal cancer, brain cancer, melanoma, or NSCLC; A method for the treatment of cancer, the method comprising administering an effective quantity of a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, to a patient in need; and A method for the treatment or prophylaxis against thyroid cancer, colorectal cancer, brain cancer, melanoma or NSCLC, the method comprising administering an effective amount of a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, to a patient in need. One particular embodiment of the invention relates to the compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of cancer, in particular a type of cancer driven by BRAF mutant, more particularly thyroid cancer, colorectal cancer, brain cancer, melanoma or NSCLC. One particular embodiment of the invention relates to the compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic and / or prophylactic treatment of cancer, in particular a type of cancer driven by BRAF mutant, more particularly thyroid cancer, colorectal cancer, brain cancer, melanoma or NSCLC. A specific embodiment of the invention relates to a pharmaceutical composition comprising the compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment of the invention relates to a method for the therapeutic and / or prophylactic treatment of cancer, in particular a type of cancer driven by BRAF mutants, more particularly thyroid cancer, colorectal cancer, brain cancer, melanoma, or non-small cell lung cancer (NSCLC), by administering an effective amount of the compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, to a patient in need. One particular embodiment of the invention relates to the compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as a medicament in the therapeutic and / or prophylactic treatment of a patient with BRAF mutant-driven cancer types, in particular thyroid cancer, colorectal cancer, brain cancer, melanoma, or NSCLC, comprising determining the BRAF mutation status in said patient and then administering the compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, to said patient. ro t αηη / ζζητve / υιλι One particular embodiment of the invention relates to the compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as a medicament in the therapeutic and / or prophylactic treatment of brain metastases. Furthermore, the invention includes all substituents in their corresponding deuterated form, where applicable, of the compound of Formula (I). Furthermore, the invention includes all substituents in their corresponding tritiated form, where applicable, of the compound of Formula (I). One embodiment of the invention relates to the compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein at least one substituent comprises at least one radioisotope. Particular examples of radioisotopes are 2H, 3H, 13C, 14C, and 18F. Furthermore, the invention includes all optical isomers, i.e., diastereomers, diastereomeric mixtures, racemic mixtures, all corresponding enantiomers and / or tautomers, as well as the solvates, where applicable, of the compound of Formula (I). If desired, racemic mixtures of the compound of the invention can be separated to isolate the individual enantiomers. The separation can be carried out using methods known in the art, such as coupling a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers using standard methods such as chromatography or fractional crystallization. In the embodiments, when an optically pure enantiomer is provided, optically pure enantiomer means that the compound contains >90% of the desired isomer by weight, particularly >95% of the desired isomer by weight, or more particularly >99% of the desired isomer by weight, where said weight percentage is a function of the total weight of the isomers in the compound. A chirally pure or chirally enriched compound can be produced by chirally selective synthesis or by enantiomer separation. Enantiomer separation can be carried out in the final product or alternatively in a suitable intermediate. Another embodiment of the invention provides a pharmaceutical composition or medicament containing a compound of the invention and a therapeutically inert carrier, diluent, or excipient, as well as a method for using the compounds of the invention to prepare such a composition and such medicament. In one example, the compound of Formula (I) can be formulated by mixing at room temperature, at a suitable pH, and to the desired degree of purity with physiologically acceptable carriers, i.e., carriers that are non-toxic to the recipients at the doses and concentrations employed in a galenic form of administration. The pH of the formulation depends primarily on the particular use and concentration of the compound but is preferably in the range of about 3 to about 8. In one example, a compound of Formula (I) is formulated in an acetate buffer at pH 5.In another embodiment, the compound of Formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution. The compositions are formulated, dosed, and administered in accordance with good medical practice. Factors to consider in this context include the specific disorder being treated, the specific mammal being treated, the individual patient's clinical condition, the cause of the disorder, the site of administration of the agent, the method of administration, the administration schedule, and other factors known to healthcare professionals. Another embodiment of the present invention is the compound of Formula (I) as described herein, when prepared according to any of the processes described. Test procedures Materials DMEM medium without phenol red supplemented with L-glutamine from Thermo Fisher Scientific was purchased. Fetal bovine serum (FBS) was purchased from VWR. Advanced ERK phospho-T202 / Y204 kit: 10,000 tests were purchased from Cisbio, cat. no. 64AERPEH. A375 and HCT116 cells were obtained originally from ATCC and stored by the Roche depot. Greiner Bio-One 384-well microplates (with lid, HÍBase, low volume, cat. 784-080) were purchased. HTRF assay for the determination of P-ERK in A375 or HCT116 cells A375 is a cell-linked cancer model expressing the V600E-mutant BRAF, and HCT116 is a cell-linked cancer model expressing wild-type BRAF. First-generation BRAF inhibitors, such as dabrafenib, induce a paradoxical effect on tumor cells, inhibiting the growth of V600E-mutant BRAF cells (such as A375) while simultaneously activating the growth of wild-type BRAF cells (such as HCT116). ERK1.2 phosphorylation (the terminal member of the MAPK pathway phosphorylation cascade) is reported hereafter as the primary readout of MAPK pathway activation status. Prior to the assay, the A375 and HCT116 cell lines are maintained in phenol red-free DMEM medium supplemented with 10% fetal bovine serum (FBS).Following treatment with the compound, P-ERK levels are determined by measuring the FRET fluorescence signal induced by the selective binding of 2 antibodies provided in the aforementioned kit (Cisbio, Cat. No. 64AERPEH) to ERK protein when phosphorylated at Thr202 / Tyr204. Briefly, 8000 cells / cavity in 12 pL of medium / cavity are placed in the 384-cavity plate and left overnight in the incubator (at 37°C with a humidified atmosphere containing 5% CO2). The next day, the plate is treated in duplicate with the test compounds, dabrafenib and PLX8394 (the latter two as controls) at the following final drug concentrations: 10 μM-3 μM-1 μM-0.3 μM-0.1 μM-0.03 μM-0.01 μM-0.003 μM-0.001 μM. All cavities are normalized with DMSO and the drug is incubated for 1 hour.Next, 4 μI of a 4X lysis buffer provided with the kit is added to the cavities, and then the plate is centrifuged for 30 seconds (300 rcf) and incubated on a plate shaker for 1 h RT (room temperature). ro t αηη / ζζητve / υιλι At the end of the incubation, 4 µl / cavity of advanced anti-P-ERK antibody solution (prepared according to the manufacturer's instructions) and then 4 pl / cavity of cryptoate anti-PERK antibody solution (prepared according to the manufacturer's instructions) (Cisbio, Cat. No. 64AERPEH) are added to the test cavities. To allow for proper data normalization, each plate always includes (according to the manufacturer's instructions) drug-free control cavities, as indicated in the following table: ρρ / αηη / ζζηζ / Ε / γίΛΐ p-ERK HTRF cavity compositions (μI): Ctrl neg Ctrl pos Ctrl neut cpd blank - - 12 12 12 Cells 12 - - - - Medium - - - <0.05 - Cpd - 16 - - - Control lysate (ready to use) 4 - 4 4 4 Lysis buffer 4x 4 4 4 4 - Advanced p-ERK antibody solution - - - - 4 Advanced p-ERK1 / 2 cryptate antibody solution 20 20 20 20 20 Total volume in cavity The plate is then centrifuged at 300 rcf for 30 seconds, sealed to prevent evaporation, and incubated overnight in darkness at room temperature. Next, the plate is analyzed and the fluorescence emission value is obtained using a Pherasstat FSX apparatus (BMG Labtech) at 665 and 620 nM. The fluorescence values ​​obtained are processed according to the formula Ratio=Signal(620nm) / Signal(625nm)*10000, and then the average ratio in the blank is subtracted from all the values. Data were normalized for A375 cells (BRAF inhibition) by considering the average ratio (with blank subtraction) from cells treated with DMSO alone as 100% and the average ratio (with blank subtraction) from cells treated with Dabrafenib 10 µM as 0%. The mean of the normalized points was fitted with a sigmoidal curve, and the IC50 was determined. The results are shown in Tables 1-2 and Figures 1-3. Data are normalized for HCT116 cells (BRAF activation) by considering the average ratio (with blank subtraction) from cells treated with DMSO alone as 0% and the average ratio (with blank subtraction) from cells treated with dabrafenib at the concentration that provides the highest signal as 100%. Individual points are fitted with sigmoidal or bell curves, and the percentage of activation is determined relative to the maximum activation mediated by dabrafenib. The EC50 is the concentration at which activation equals 50% of the maximum activation achieved with dabrafenib. The results are shown in Table 2 and Figures 4-6. If the activation does not reach 50% of the maximum activation achieved with dabrafenib, then the EC50 calculation is not applicable. The percentage of maximum paradox induction effect of dabrafenib is determined by evaluating the percentage at which the test compound induces its maximum P-ERK signal as a percentage of the highest signal produced by dabrafenib within the evaluated dose range. pq t αηη / ζζητvb / υιλι Ex- Kd (μΜ) BRAF BRAF V600E CRAF CSK LCK 1 0.0006 0.0012 0.0017 23.3 40 2 0.0013 0.0009 0.0012 9.16 20.12 AR-25 0.0001 0.0002 0.0003 >40 >40 AR-30 0.1740 0.5040 0.8220 8.007 10.352 AR-31 0.0459 0.1190 0.1903 1.208 11.975 Table 1: Example 1 and Example 2 have high affinity for RAF kinases and high selectivity on C-terminal Src kinase (CSK) and lymphocyte-specific tyrosine protein kinase (LCK), compared to AR-30 and AR-31. Example: pERK IC50 (nM) pERK EC50 (nM) Concentration (nM) at which the compound induces pERK activation equal to 50% of that induced by Dabrafenib (Positive control paradox inducer) Percentage of maximum paradox induction effect of dabrafenib A375 HCT-116 1 6.9 not applicable 43.65% 2 10.6 not applicable 46.2% AR-25 1.1 9.6 103% AR-30 406 >1000 59% AR-31 311 >1000 51.2% Table 2: Example 1 and Example 2 disrupt the paradoxical activation of RAF in HCT-116 cancer cells expressing WT BRAF. Compared with dabrafenib or AR-25, the maximum paradox induction effect is reduced to less than 50%. Measurement of CSF KD.UU to assess brain penetration potential CSF Kp,uu is the ratio of cerebrospinal fluid (CSF) concentration to plasma free exposure, and Kp,uu values ​​≤1 indicate good brain penetration. For example 1 of the compound, in single oral dose studies in mice and rats, sequential plasma and CSF concentrations (up to 24 h post-dose) were measured by LC-MS / MS to calculate CSF Kp,uu. In multiple oral dose studies in rats and minipigs, plasma and CSF concentrations approaching Tmax (3 h post-last dose) were measured by LC-MS / MS and used to calculate CSF Kp,uu. ρρ / αηη / ζζηζ / Ε / γίΛΐ Value Class Molecular weight / polar surface area 461199 - BCS (Biopharmaceutical Classification System) - 2 'P-gp Apical Efluence Ratio 1.5 Low Plasma Protein Binding (%) (mouse, rat, minipig, monkey, human) >99 Very High Mouse CSF Kp,uu Single oral dose 10 mg / kg >1 High Rat CSF Kp,uu Single oral dose 20 mg / kg >1 High Rat CSF Kp,uu Multiple oral doses at 300 mg / kg / day (2-week DRF) >1 High Minipig CSF Kp,uu Multiple oral doses at 300 mg / kg / day (2-week DRF) >1 High *CLL-PK1 cell line transfected with MDR1, evaluated in the presence / absence of P-gp inhibitor Table 3: Physicochemical and ADME properties of Example 1 of the compound. The CSF Kpuu£1 values ​​indicate good cerebral penetration of Example 1. In addition, the temporal relationship of plasma and CSF was evaluated up to 24 h post-dose in the single-dose pharmacokinetic (PK) study in rats and indicated rapid and extensive distribution in CSF. A375-Luc implanted intracranially Intracranial injection of A375 BRAF V600E cancer cells constitutively expressing luciferase was performed on immunodeficient mice. Treatment with Example 1 of the compound was initiated on day 7 post-intracranial injection and continued for 2 weeks. The different groups received daily oral administration of 1 mg / kg, 5 mg / kg, and 20 mg / kg of Example 1, respectively. The results are shown in Figure 8. The compound of Formula (I) or a pharmaceutically acceptable salt thereof may be used as a medicament (e.g., in the form of a pharmaceutical preparation). The pharmaceutical preparation may be administered internally, such as orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions, or suspensions), nasally (e.g., in the form of nasal sprays), rectally (e.g., in the form of suppositories), or topically (e.g., in the form of solutions, ointments, gels, or water-soluble polymeric inserts). However, administration may also be parenteral, such as intramuscularly, intravenously, or intraocularly (e.g., in the form of sterile injectable solutions). The compound of Formula (I) or a pharmaceutically acceptable salt thereof may be processed with pharmaceutically inert inorganic or organic adjuvants for the production of tablets, coated tablets, dragees, hard gelatin capsules, injectable solutions or topical formulations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc., may be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules. Suitable adjuvants for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc. Suitable adjuvants for the production of solutions and syrups include, for example, water, polyols, sucrose, invert sugar, glucose, etc. Suitable adjuvants for injectable solutions include, for example, water, alcohols, polyols, glycerol, vegetable oils, etc. Suitable adjuvants for suppositories include, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc. Suitable adjuvants for topical ocular formulations include, for example, cyclodextrins, mannitol, or many other carriers and excipients known in the art. In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing agents, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, osmotic pressure regulators, buffers, masking agents, or antioxidants. They may also contain other therapeutically valuable substances. The dosage may vary widely and will, of course, be adjusted to individual requirements in each particular case. Generally, for oral administration, the daily dose is approximately 0.1 mg to 20 mg per kg of body weight, preferably approximately 0.5 mg to 4 mg per kg of body weight (e.g., approximately 300 mg per person), divided into preferably 1–3 individual doses, which may consist of, for example, the same amounts, if appropriate. For topical administration, the formulation may contain 0.001% to 15% by weight of the drug, and the required dose, which may be between 0.1 and 25 mg, may be administered as a single dose per day or per week, or in multiple doses (2 to 4) per day, or in multiple doses per week. However, it should be understood that the upper or lower limits given herein may be exceeded when it is demonstrated that this is indicated. Pharmaceutical compositions The compound of Formula (I) or a pharmaceutically acceptable salt thereof may be used as a therapeutically active substance, for example, in the form of a pharmaceutical preparation. The pharmaceutical preparation may be administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions, or suspensions. However, administration may also be rectal, for example, in the form of suppositories, or parenteral, for example, in the form of injectable solutions. The compound of Formula I and its pharmaceutically acceptable salts may be processed with pharmaceutically inert inorganic or organic carriers to produce a pharmaceutical preparation. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, and similar carriers may be used, for example, as carriers for tablets, coated tablets, dragees, and hard gelatin capsules. Suitable carriers for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, and similar carriers. However, depending on the nature of the active substance, carriers are not normally required for soft gelatin capsules. Suitable carriers for the production of solutions and syrups include, for example, water, polyols, glycerol, vegetable oil, and similar carriers.Suitable carriers for suppositories include, for example, natural or hardened oils, waxes, fats, liquid or semi-liquid polyols, and the like. The pharmaceutical preparation may also contain pharmaceutically acceptable excipients such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying osmotic pressure, buffers, masking agents, or antioxidants. It may also contain other therapeutically valuable substances. The present invention also provides medicaments containing the compound of Formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier, as well as a process for their production, comprising associating one or more compounds of Formula (I) and / or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances in a galenic form of administration together with one or more therapeutically inert carriers. The dosage may vary within broad limits and, of course, must be adjusted to individual requirements in each particular case. For oral administration, the adult dosage may range from approximately 0.01 mg to approximately 1000 mg per day of a compound of General Formula (I) or the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dose may be administered as a single dose or in divided doses, and the upper limit may also be exceeded when deemed appropriate. The following examples illustrate the present invention without limiting it, but serve merely as representative examples thereof. The pharmaceutical preparations conveniently contain approximately 1-500 mg, particularly 1-100 mg, of a compound of Formula (I). Examples of compositions according to the invention are: Example A ρρ / οηη / ζζηζ / Ε / γίΛΐ The tablets with the following composition are manufactured in the usual way: Ingredient mg / tablet 5 25 100 500 Formula Compound (I) 5 25 100 500 Lactose anhydrous DTG 125 105 30 150 Sta-Rx 1500 6 6 6 60 Microcrystalline cellulose 30 30 30 450 Magnesium stearate 1 1 1 1 Total 167 167 167 831 pp t αηη / ζζητ: / β / υιλι Table 4: Possible composition of the tablet Production process 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 a suitable grinding equipment. 4. Add ingredient 5 and mix for three minutes; compress in a suitable press. Example B-1 Capsules are manufactured with the following composition: Ingredient mg / capsule 5 25 100 500 Formula Compound (I) 5 25 100 500 Hydrated Lactose 159 123 148 - Corn Starch 25 35 40 70 Talc 10 15 10 25 Magnesium Stearate 1 2 2 5 Total 200 200 300 600 Table 5: Possible composition of the capsule ingredient Production process 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 minutes. 3. Place in a suitable capsule. The compound of Formula (I), lactose, and corn starch are first mixed in a mixer and then in a grinder. The mixture is returned to the mixer; talc is added and it is thoroughly mixed. The mixture is machine-filled into suitable capsules, for example, hard gelatin capsules. Example B-2 ρρ / αηη / ζζηζ / E / γίΛΐ Soft gelatin capsules are manufactured with the following composition: Ingredient mg / capsule Formula Compound (I) 5 Yellow wax 8 Hydrogenated soybean oil 8 Partially hydrogenated vegetable oils 34 Soybean oil 110 Total 165 Table 6: Possible ingredient composition of the soft gelatin capsule Ingredient mg / capsule Gelatin 75 85% Glycerol 32 Karion 83 8 (dry matter) Titanium dioxide 0.4 Yellow iron oxide 1.1 Total 116.5 Table 7: Possible composition of the soft gelatin capsule Production process The compound of Formula (I) is dissolved in a warm melt of the other ingredients, and the mixture is placed into appropriately sized soft gelatin capsules. The filled soft gelatin capsules are then processed according to standard procedures. Example C Suppositories are prepared with the following composition: Ingredient mg / sup. Formula Compound (I) 15 Suppository Mass 1285 Total 1300 Table 8: Possible composition of the suppository Production process The suppository mass is melted in a glass or steel container, thoroughly mixed, and cooled to 45°C. The finely powdered compound of Formula (I) is then added and stirred until completely dispersed. The mixture is poured into appropriately sized suppository molds and allowed to cool; the suppositories are then removed from the molds and individually wrapped in waxed paper or foil. Example D ρρ / αηη / ζζηζ / Ε / γίΛΐ Injectable solutions are prepared with the following composition: Ingredient mg / injectable solution Formula Compound (I) 3 Polyethylene glycol 400 150 acetic acid qs to pH 5.0 water for injection solutions up to 1.0 mL Table 9: Possible composition of the injectable solution Production process The compound of Formula (I) is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 with acetic acid. The volume is adjusted to 1.0 mL by adding the remaining amount of water. The solution is filtered, placed into vials using an appropriate excess, and sterilized. Example E Sachets are manufactured with the following composition: Ingredient mg / sachet Formula Compound (I) 50 Lactose, fine powder 1015 Microcrystalline cellulose (AVICEL PH 102) 1400 Sodium carboxymethylcellulose 14 Polyvinylpyrrolidone K 30 10 Magnesium stearate 10 Flavoring additives 1 Total 2500 Table 10: Possible composition of the sachet Production process The Formula (I) compound is mixed with lactose, microcrystalline cellulose, and sodium carboxymethylcellulose and granulated with a polyvinylpyrrolidone mixture in water. The granules are mixed with magnesium stearate and flavoring additives and placed in sachets. EXAMPLES Abbreviations DCM = dichloromethane; DMF = dimethylformamide; DMSO = dimethyl sulfoxide; DRF = dose range finding; ESI = electrospray ionization; EtOAc = ethyl acetate; LC-MS / MS = liquid chromatography-MS / MS; MeOH = methanol; MS = mass spectrometry; rt = room temperature; P-gp = P-glycoprotein; SFC = supercritical fluid chromatography. Reference compounds AR-25, AR-30 and AR-31 were prepared according to the synthesis disclosed in WO2012 / 118492 in example 25, example 30 and example 31 respectively. 6-hydroxy¡-3-methyl-quinaz¡n-4-one ro t αηη / ζζητ: / β / υιλι 2-Amino-5-hydroxybenzoic acid (10 g, 65.3 mmol, eq: 1.0) and N-methylformamide (30 g, 29.9 mL, 503 mmol, eq: 7.7) were heated at 145°C for 21 h 45 min and then cooled to room temperature. The reaction mixture was diluted with 50 mL of H₂O and stirred at room temperature for 20 min. The resulting precipitate was collected by filtration. The light brown solid was washed three times with 20 mL of water. The solid was absorbed in toluene and evaporated to dryness (3x). The solid was then dried under vacuum at 40°C overnight in high vacuum to obtain the title compound as a light brown solid (10.3 g, 89% yield). MS (ESI) m / z: 177.1 [M+H]+. Cesium carbonate (3.22 g, 9.79 mmol, eq: 1.15) was added to a solution of 6-hydroxy-3-methylquinazolin-4-one (1500 mg, 8.51 mmol, eq: 1.0) in A / ,A / -dimethylformamide (35 mL). The mixture was stirred for 30 min at rt and then 2,3,6-trifluorobenzonitrile (1.47 g, 1.08 mL, 9.37 mmol, eq: 1.1) was added. After 1 h, the reaction was cooled on ice and diluted with water (120 mL). The resulting solid was collected by filtration, washed with ice-cold water (100 mL) and heptane (100 mL), and dried by suction. The solid was adsorbed onto toluene and evaporated to dryness (3x), then dried overnight under vacuum to obtain the title compound as a light brown solid (2.58 g, 97% yield). MS (ESI) m / z: 314.1 [M+H]+. (3R)-3-fluoropyrroli¡din-1-sulfonamida pp / αηη / ζζητve / υιλι (R)-3-Fluoropyrrolidine hydrochloride (1.8 g, 14.3 mmol, eq: 1.2) was added to a solution of sulfuric diamide (1.148 g, 11.9 mmol, eq: 1.0) and triethylamine (2.42 g, 3.33 mL, 23.9 mmol, eq: 2) in dioxane (10 mL). The reaction was stirred in a sealed tube at 115°C for 15.5 h, then cooled to room temperature and concentrated under vacuum. The residue was diluted with DCM, evaporated with silica gel to dryness, and transferred to a column. Purification by flash chromatography (40 g silica, 80% EtOAc) yielded the title compound as a white crystalline solid (1.82 g, 91% yield). MS (ESI) miz: 169.1 [M+H]+. (3S)-3-fluoropyrrolidine-1-sulfonamide Triethylamine (304 pL; 419 pL, 3.01 mmol, eq: 2.0) was added to a suspension of sulfuric diamide (146 g, 1.5 mmol, eq: 1.0) and (S)-3-fluoropyrrolidine hydrochloride (234 mg, 1.8 mmol, eq: 1.2) in dioxane (1.3 mL). The reaction was stirred in a sealed tube at 115°C for 16 h 35 min and then concentrated under vacuum. The residue was diluted with MeOH, evaporated with silica gel to dryness, and transferred to a column. Purification by flash chromatography (40 g silica, 0–8% MeOH / DCM) yielded the title compound as a light yellow solid (193 g, 75% yield). MS (ESI) miz: 169.1 [M+H]+. (3R)-A / -[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-l)oxy-phenyl1-3-fluoro-pyrrolidin-1-sulfonamide (Example 1) (R)-3-Fluoropyrrolidine-1-sulfonamide (1.26 g, 7.51 mmol, eq: 2.1) and cesium carbonate (2.56 g, 7.87 mmol, eq: 2.2) were suspended in dry DMF (10.2 mL) under an argon atmosphere. The reaction was stirred at 50°C for 30 min. The reaction mixture was cooled to 100°C and a solution of 3,6-difluoro-2-((3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)benzonitrile (1.12 g, 3.58 mmol, eq: 1.0) in DMF (25.5 mL) was added. The reaction mixture was stirred at 100°C for 15 h and then concentrated under vacuum. The residue was adsorbed onto saturated aqueous NH4Cl (100 mL) and EtOAc (100 mL). The layers were separated, and the aqueous layer was further extracted with 2 x 100 mL of EtOAc. The combined organic layers were washed with water (200 mL) and brine (200 mL), dried (Na2SO4), filtered, and concentrated under vacuum. The aqueous layer was re-extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (200 mL), dried (Na2SO4), filtered, and concentrated under vacuum.The residue was diluted with DCM and MeOH and concentrated on silica. Purification by flash chromatography (120 g, 0.5–2% MeOH / DCM) yielded a whitish solid, which was ground with 1:1 heptane / DCM (20 mL) using ultrasound, then vacuum dried to obtain the title compound as a colorless solid (1.087 g, 66% yield). MS (ESI) miz: 426.2 [M+H]+. Chiral SFC: RT = 4.594 min [Chiralpak IC column, 4.6 x 250 mm, 5 pm particle size (Daicel); 20–40% MeOH gradient containing 0.2% NHEt2 for 8 min; flow: 2.5 mL / min, 140 bar back pressure], (3S)-A / -[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-1l)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (Example 2). ro t αηη / ζζητve / υιλι (S)-3-fluoropyrrolidine-1-sulfonamide (181 mg, 1.08 mmol, eq: 2.1) was dissolved in DMF (1.6 mL). At 1°C, cesium carbonate (368 mg, 1.13 mmol, eq: 2.2) was added, and the reaction mixture was stirred at 50°C for 30 min. The reaction mixture was cooled to 1°C, and a solution of 3,6-difluoro-2-((3-methyl-4-oxo-3,4-dihydroquinazolin-6-1)oxy)benzenitryl (160.8 mg, 513 pmol, eq: 1.0) in DMF (4 mL) was added. The reaction mixture was stirred at 105°C for 2 h 50 min and then concentrated under vacuum. The residue was absorbed in DCM and washed with saturated aqueous NH4Cl. The aqueous layer was re-extracted twice with DCM. The combined organic layers were dried in Na2SO4, filtered, and evaporated. The residue (brown oil) was diluted with DCM and transferred to a column.Purification by flash chromatography (80 g silica, 0-100% EtOAc in DCM) yielded a solid that was further purified by SFC to obtain the title compound as a light yellow solid (119 mg, 50% yield). MS (ESI) miz: 426.2 [M+H]+. Chiral SFC: RT = 4.411 min [Chiralpak IC column, 4.6 x 250 mm, 5 pm particle size (Daicel); 20-40% MeOH gradient containing 0.2% NHEt2 for 8 min; flow rate: 2.5 mL / min, 140 bar backpressure].

Claims

CLAIMS 1. The compound of Formula (I) pp / αηη / ζζητvb / υιλι or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein the compound is the compound of Formula (I).

3. A compound according to claim 1 or 2, wherein the compound is the compound of Formula (a).

4. A compound according to claim 1 or 2, wherein the compound is the compound of Formula (b).

5. A process for the preparation of a compound according to any one of claims 1 to 4, comprising the reaction of a compound of Formula (B1) with a compound of Formula (B2) in the presence of a base.

6. A compound according to any of claims 1 to 4 when manufactured according to a process according to claim 5.

7. A compound according to any of claims 1 to 4 for use as a therapeutically active substance.

8. A pharmaceutical composition comprising a compound according to any of claims 1 to 4 and a therapeutically inert carrier.

9. A compound according to any of claims 1 to 4 for use in the treatment or prophylaxis of cancer.

10. A compound according to any of claims 1 to 4 for use in the treatment or prophylaxis of thyroid cancer, colorectal cancer, brain cancer, melanoma or NSCLC.

11. The use of a compound according to any of claims 1 to 4 for the treatment or prophylaxis against thyroid cancer, colorectal cancer, brain cancer, melanoma or NSCLC.

12. The use of a compound according to any of claims 1 to 4 for the preparation of a medicament for the treatment or prophylaxis against thyroid cancer, colorectal cancer, brain cancer, melanoma or NSCLC.