New methylquinazolinone derivatives

Abstract

Compounds are provided for use in the treatment or prevention of thyroid cancer, colorectal cancer, brain cancer, melanoma or NSCLC. The present invention provides a compound represented by general formula (I): TIFF2022124458000031.tif44170 or a pharmaceutically acceptable salt thereof. The compound of formula (I) can be used as a medicine.

Description

[Technical Field]

[0001] The present invention provides novel compounds, their preparation, pharmaceutical compositions containing them, and their use as therapeutically active substances.The compounds of the present invention are BRAF inhibitors and have paradox-blocking properties.

[0002] The present invention particularly relates to compounds of formula (I) The present invention provides a novel compound of TIFF0007802514000001.tif63170, or a pharmaceutically acceptable salt thereof. [Background technology]

[0003] The rapidly progressing 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 the three RAF isoforms in signal propagation via phosphorylation of MEK1 and MEK2, frequent oncogenic activating mutations are commonly found only in BRAF. In particular, substitution of V600 with glutamic acid or lysine results in highly activated kinases, resulting in overstimulation of the MAPK pathway independent of external stimuli (Cell. 2015 Jun 18;161(7):1681-1696).

[0004] Mutant BRAF is a targetable oncogenic driver, and three BRAF inhibitors (vemurafenib, dabrafenib, and encorafenib) are currently on the market and have shown efficacy in BRAFV600E-positive melanoma. However, rapid acquisition of drug resistance is nearly universally observed, and the duration of therapeutic benefit associated with targeted therapy remains limited.

[0005] Furthermore, developed BRAF inhibitors revealed the unexpected "paradoxical" ability to suppress MAPK signaling in BRAFV600E-driven tumors, while the same inhibitors exhibited MAPK-stimulating activity in BRAF wild-type (WT) models (N Engl J Med 2012;366:271-273; and British Journal of Cancer volume 111, pages 640-645 (2014)).

[0006] Subsequently, mechanistic studies on the RAF paradox revealed that while oncogenic BRAFV600E phosphorylates MEK1 / 2 in its monomeric cytosolic form, activation of WT BRAF and RAF1 requires a complex series of events, including plasma membrane translocation and homo- and / or heterodimerization promoted by activated RAS (KRAS, NRAS, HRAS) (Nature Reviews Cancer volume 14, pages 455-467 (2014)).

[0007] Binding of inhibitors such as vemurafenib, dabrafenib, or encorafenib to WT BRAF or RAF1 protomers rapidly induces RAF homo- and / or heterodimerization and membrane association of the newly formed RAF dimers. In the dimeric conformation, one RAF protomer allosterically induces a conformational change in the second RAF protomer, resulting in a kinase-active state and, importantly, a conformation unfavorable for inhibitor binding. As a result, the dimers induced by drug treatment promote MEK phosphorylation, with catalytic activity driven by the unbound protomer resulting in pathway hyperactivation.

[0008] The RAF paradox has two clinically relevant consequences: 1) the promotion of secondary tumor growth (mainly keratinoma and squamous cell carcinoma) during BRAFi monotherapy (N Engl J Med 2012;366:271-273), and 2) the acquisition of drug resistance in the BRAFi+MEKi combination as well as in the BRAFi monotherapy setting, indicating activation of dimer-mediated RAF signaling by genetically driven events including RAS mutation, BRAF amplification, and expression of dimer-acting BRAF splice variants (Nature Reviews Cancer volume 14, pages 455-467 (2014)). Therefore, RAF inhibitors that can block this paradox are needed.

[0009] Furthermore, the currently approved classical BRAF inhibitors vemurafenib (Mol. Pharmaceuticals 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 very poor brain penetration. This is a major limitation for the use of these classical BRAF inhibitors in the treatment of brain cancer or brain metastases. Therefore, there is a need for BRAF inhibitors with improved brain penetration. Summary of the Invention

[0010] The present invention relates to the surprising discovery that the BRAF inhibitor of formula (I) is a more potent and selective BRAF inhibitor that retains high efficacy while exhibiting significantly less paradoxical activation of the MAPK signaling pathway. Thus, this compound can be referred to as a paradox blocker or RAF paradox blocker, in contrast to compounds that induce the RAF paradox (which can be referred to as a paradox inducer or RAF paradox inducer). In addition to being a paradox blocker, the compound of formula (I) also has very strong brain-penetrating properties, thus providing an urgently needed alternative therapy for the treatment of cancer in the brain. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 discloses the P-ERK inhibition curve induced by Example 1 in the BRAF mutant cell line A375. [Figure 2] FIG. 2 discloses the P-ERK inhibition curve induced by Example 2 in the BRAF mutant cell line A375. [Figure 3] FIG. 3 discloses the P-ERK inhibition curve induced by the reference compound AR-25 in the BRAF mutant cell line A375. [Figure 4] Figure 4 discloses the P-ERK activation curve induced by Example 1 in the WT BRAF cell line HCT-116. For comparison, data generated by treatment with the control compounds dabrafenib (paradox inducer) and PLX-8394 (paradox blocker) are also shown. [Figure 5] Figure 5 discloses the P-ERK activation curves induced by Example 2 in the WT BRAF cell line HCT-116. For comparison, data generated by treatment with the control compounds dabrafenib (paradox inducer) and PLX-8394 (paradox blocker) are also shown. [Figure 6] Figure 6 shows the P-ERK activation curve induced by the reference compound AR-25 in the WT BRAF cell line HCT-116. For comparison, data generated by treatment with the control compounds dabrafenib (paradox inducer) and PLX-8394 (paradox blocker) are also shown. [Figure 7]Figure 7 shows 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 signaling pathway, and mutant BRAF is an oncogenic driver (left). In BRAF V600E / K mutant tumors, BRAF signals as a monomer, a state in which the protein is inhibited by first-generation BRAF inhibitors (center). First-generation BRAF inhibitors promote BRAF WT homo- and / or heterodimerization (top, right). In this context, protomers not occupied by the BRAF inhibitor acquire a conformation unfavorable for inhibitor binding (center, right). The consequence of treatment with first-generation BRAF inhibitors is, in this context, paradoxically increased MAPK activation and consequent tumor proliferation of BRAF WT cells (bottom, right). [Figure 8] FIG. 8 discloses that compound Example 1 elicits dose-dependent antitumor activity starting at 1 mg / kg daily, demonstrating potent brain penetration-mediated efficacy. DETAILED DESCRIPTION OF THE INVENTION

[0012] WO 2012 / 118492 discloses compounds AR-25 as Example 25, AR-30 as Example 30, and AR-31 as Example 31. TIFF0007802514000002.tif94170

[0013] The term "pharmaceutically acceptable salt" refers to a salt of a compound of Formula (I) that retains the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid (especially 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, and N-acetylcysteine. These salts may also be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, etc. Particular pharmaceutically acceptable salts of compounds of formula (I) include hydrochloride, methanesulfonate, citrate, etc.

[0014] The compounds of formula (I) contain one asymmetric center and can exist in the form of optically pure enantiomers or mixtures of enantiomers, eg racemates.

[0015] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0016] Also, one embodiment of the present invention is a compound according to formula (I) as described herein or a pharmaceutically acceptable salt thereof, particularly a compound according to formula (I) as described herein, more particularly a compound of formula (Ia) or (Ib) as described herein.

[0017] The present invention also relates to pharmaceutically acceptable salts of the compounds of formula (I), which may be selected from hydrochloride, methanesulfonate and citrate salts.

[0018] Also, one embodiment of the present invention is a compound represented by formula (Ia) This compound is from TIFF0007802514000003.tif74170.

[0019] Also, one embodiment of the present invention is a compound represented by formula (Ib) This compound is from TIFF0007802514000004.tif74170.

[0020] Processes for preparing the compounds of formula (Ia) and (Ib) described herein are also an object of the present invention.

[0021] The preparation of compounds of formula (I) of the present invention can be carried out by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art.

[0022] More specifically, the compound of formula (I) can be prepared by the methods shown below, the methods shown in the Examples, or similar methods. Suitable reaction conditions for each reaction step are known to those skilled in the art. The reaction order is not limited to that shown in Scheme 1, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities. The starting materials are commercially available or can be prepared by methods similar to those shown below, methods described in the references or examples cited herein, or methods known in the art. Scheme 1 TIFF0007802514000005.tif88170TIFF0007802514000006.tif88170

[0023] It will be appreciated that the compounds of formula (I) in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.

[0024] The present invention therefore also relates to a process for the preparation of a compound according to the invention, comprising the steps of: TIFF0007802514000007.tif41170 and the compound of formula (B2) TIFF0007802514000008.tif33170 in the presence of a base.

[0025] The reaction can conveniently be carried out in a solvent, which can be, for example, DMF.

[0026] The reaction is conveniently carried out in the presence of a base, which may be, for example, cesium carbonate.

[0027] Convenient conditions for the reaction can be about 30° C. to about 150° C., particularly about 50° C. to about 130° C., and more particularly about 70° C. to about 120° C. Convenient conditions are about 100° C. for about 1 hour to about 48 hours, particularly about 2 hours to about 20 hours.

[0028] The present invention also relates to a compound according to the invention when prepared according to a process of the invention.

[0029] The present invention also relates, inter alia, 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 prevention of cancer; a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of thyroid cancer, colorectal cancer, brain cancer, melanoma or non-small cell lung cancer (NSCLC); Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for treating or preventing thyroid cancer, colorectal cancer, brain cancer, melanoma or NSCLC; Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for the preparation of a medicament for treating or preventing thyroid cancer, colorectal cancer, brain cancer, melanoma or NSCLC; A method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof; and A method for treating or preventing thyroid cancer, colorectal cancer, brain cancer, melanoma or NSCLC, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0030] A particular embodiment of the present invention relates to a 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 BRAF mutation-driven cancer, more particularly thyroid cancer, colorectal cancer, brain cancer, melanoma or NSCLC.

[0031] A particular embodiment of the present invention relates to a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of cancer, in particular a BRAF mutation-driven cancer, more particularly thyroid cancer, colorectal cancer, brain cancer, melanoma or NSCLC.

[0032] Certain embodiments of the present invention relate to pharmaceutical compositions comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0033] Certain embodiments of the present invention relate to a method for the therapeutic and / or prophylactic treatment of cancer, in particular BRAF mutation-driven cancer, more particularly thyroid cancer, colorectal cancer, brain cancer, melanoma or non-small cell lung cancer (NSCLC), by administering to a patient in need thereof an effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0034] A particular embodiment of the present invention relates to a 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 patients with a BRAF mutation-driven cancer, in particular thyroid cancer, colorectal cancer, brain cancer, melanoma or NSCLC, wherein the therapeutic and / or prophylactic treatment comprises determining the BRAF mutation status in said patient and then administering to said patient a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0035] A particular embodiment of the present invention relates to a 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.

[0036] Furthermore, the present invention includes all substituents of the compounds of formula (I) in their corresponding deuterated forms, where applicable.

[0037] Furthermore, the present invention includes all applicable substituents of compounds of formula (I) in their corresponding tritiated form.

[0038] Certain embodiments of the present invention relate to compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein at least one substituent comprises at least one radioisotope. Particular examples of radioisotopes include: 2 H, 3 H, 13 C. 14 C, and 18 It's F.

[0039] Furthermore, the present invention includes, where applicable, all optical isomers of the compounds of formula (I), i.e., diastereoisomers, diastereomeric mixtures, racemic mixtures, all corresponding enantiomers and / or tautomers thereof, and solvates thereof.

[0040] If desired, racemic mixtures of the compounds of the present invention can be separated to isolate the individual enantiomers. Separation can be carried out by methods known in the art, such as coupling a racemic mixture of a compound to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods such as fractional recrystallization or chromatography.

[0041] In one embodiment, when an optically pure enantiomer is provided, optically pure enantiomer means that the compound contains more than 90% by weight of the desired isomer, particularly more than 95% by weight of the desired isomer, or more particularly more than 99% by weight of the desired isomer, the weight percentage being based on the total weight of the isomers of the compound. Chirally pure or chirally enriched compounds can be prepared by chirally selective synthesis or by separation of enantiomers. Separation of enantiomers can be carried out on the final product or, alternatively, on a suitable intermediate.

[0042] Another embodiment of the present invention provides pharmaceutical compositions or medicaments containing a compound of the present invention and a therapeutically inert carrier, diluent, or excipient, as well as methods of using the compounds of the present invention to prepare such compositions and medicaments. In one example, a compound of Formula (I) may be formulated by mixing it with a physiologically acceptable carrier, i.e., a carrier that is not toxic to recipients at the dosages and concentrations used in herbal dosage forms, at an appropriate pH and desired purity, at ambient temperature. The pH of the formulation will depend primarily on the particular application and compound concentration, but is preferably in the range of about 3 to about 8. In one example, a compound of Formula (I) is formulated in acetate buffer at pH 5. In another embodiment, the compound of Formula (I) is sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0043] The compositions are formulated, dosed, and administered in a manner consistent with the principles of good medicine, including factors to consider in this regard, such as the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to medical practitioners.

[0044] Also, one embodiment of the present invention is a compound of formula (I) as described herein when prepared according to any one of the processes described.

[0045] Assay procedure material: DMEM phenol red-free medium supplemented with L-glutamine was purchased from (Thermo Fisher Scientific). Fetal bovine serum (FBS) was purchased from VWR. The Advanced ERK phospho-T202 / Y204 kit - 10,000 tests was purchased from Cisbio catalog number 64AERPEH. A375 and HCT116 cells were originally obtained from ATCC and stored by the Roche repository. 384-well microplates (with lid, HiBase, small volume catalog 784-080) were purchased from Greiner Bio-One.

[0046] HTRF assay for P-ERK determination in A375 or HCT116 cells A375 is a cell cancer model expressing V600E mutant BRAF, and HCT116 is a cell cancer model expressing wild-type BRAF. First-generation BRAF inhibitors, such as dabrafenib, induce paradoxical effects on tumor cells in that they inhibit the growth of V600E mutant BRAF cells (e.g., A375) while activating the growth of wild-type BRAF cells (e.g., HCT116). ERK1 and 2 phosphorylation (terminal members of the phosphorylation cascade of the MAPK pathway) has since been reported as a primary readout of the activation status of the MAPK pathway. Prior to the assay, A375 and HCT116 cell lines were maintained in DMEM phenol red-free medium supplemented with 10% fetal bovine serum (FBS). After compound treatment, P-ERK levels are determined by measuring the FRET fluorescence signal induced by the selective binding of the two antibodies provided in the mentioned kit (Cisbio catalog number 64AERPEH) to ERK protein when it is phosphorylated at Thr202 / Tyr204. Briefly, 8000 cells / well in 12 μl medium / well are seeded into a 384-well plate and placed in an incubator overnight (5% CO2 humidified atmosphere, 37 °C). 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, and 0.001 μM. All wells are subjected to DMSO normalization, and drug incubation is performed for 1 hour. 4 μl of the 4× lysis buffer supplied with the kit is then added to the wells, and the plate is then centrifuged for 30 seconds (300 rcf) and incubated for 1 hour at room temperature on a plate shaker.

[0047] At the end of the incubation, add 4 µL / well of proceeded P-ERK antibody solution (prepared according to manufacturer's instructions) followed by 4 µL / well of cryptate P-ERK antibody solution (prepared according to manufacturer's instructions) (Cisbio catalog number 64AERPEH) to the test wells.

[0048] To allow for adequate data, normalization control wells, non-drug treated wells reported in the table below, were always included on each plate (according to manufacturer's instructions). TIFF0007802514000009.tif91170

[0049] The plate is then centrifuged at 300 rcf for 30 seconds, sealed to prevent evaporation, and incubated overnight in the dark at room temperature.

[0050] Plates are then analyzed and fluorescence values ​​collected at 665 nM and 620 nM by a Pherastast FSX (BMG Labtech) instrument.

[0051] The obtained fluorescence values ​​are processed according to the formula: Ratio = Signal (620 nm) / Signal (625 nm) * 10000, and then the average of the ratios over the blanks is subtracted from all values.

[0052] For A375 cells (BRAF inhibition), the average ratio induced by cells treated with DMSO alone (minus the blank) was considered 100%, and the average ratio induced by cells treated with 10 µM dabrafenib (minus the blank) was considered 0% to normalize the data. The average of the normalized points was fitted with a sigmoidal curve to determine the IC50. The results are shown in Tables 1-2 and Figures 1-3.

[0053] For HCT116 cells (BRAF activation), data were normalized by considering the average ratio induced by cells treated with DMSO alone (minus the blank) as 0% and the average ratio induced by cells treated with dabrafenib at the concentration providing the highest signal (minus the blank) as 100%. A sigmoidal or bell-shaped curve was fitted to the individual points to determine the percentage of activation compared to the maximal activation mediated by dabrafenib. EC50 is the concentration at which activation equal to 50% of the maximum achieved by dabrafenib is obtained. The results are shown in Table 2 and Figures 4-6.

[0054] If activation does not reach 50% of the maximum achieved by dabrafenib, the EC50 calculation is not applicable.

[0055] The percentage of maximal paradox-inducing effect from dabrafenib is determined by assessing the percentage at which the test compound induces its maximal P-ERK signal as a percentage of the maximal signal generated by dabrafenib within the dose range tested. TIFF0007802514000010.tif81170TIFF0007802514000011.tif88170

[0056] CSF K for assessing brain osmotic potential p、uu Measurement CSF K p、uu is the ratio of the concentration in cerebrospinal fluid (CSF) to the unbound plasma exposure, and K p、uu A value of ≥ 1 indicates good brain penetration. For compound Example 1, in a single oral dose study in mice and rats, serial plasma and CSF concentrations (up to 24 hours post-dose) were measured by LC-MS / MS to determine the CSF K p、uu For multiple oral dose studies in rats and minipigs, plasma and CSF concentrations near Tmax (3 hours after the last dose) were measured by LC-MS / MS, and CSF K p、uu was used to calculate TIFF0007802514000012.tif143170

[0057] Intracranial implant A375-Luc A375 BRAF V600E cancer cells constitutively expressing luciferase were injected intracranially into immunocompromised mice. Treatment with compound Example 1 began on the seventh day after intracranial injection and continued for two weeks. Different groups were subjected to 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.

[0058] The compound of formula (I) or a pharmaceutically acceptable salt thereof can be used as a medicine (e.g., in the form of a pharmaceutical preparation). The pharmaceutical preparation of the present invention can be administered 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 a nasal spray), rectally (e.g., in the form of a suppository), or topically to the eye (e.g., in the form of a solution, ointment, gel, or water-soluble polymer insert). However, administration can also be carried out parenterally (e.g., in the form of a sterile injection solution), such as intramuscularly, intravenously, or intraocularly.

[0059] The compound of formula (I) or its pharmaceutically acceptable salt can be processed with pharmaceutically inert, inorganic or organic adjuvants for the preparation of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injections or external preparations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as such adjuvants for tablets, dolazates and hard gelatin capsules, for example.

[0060] Suitable adjuvants for soft gelatin capsules include, by way of example, vegetable oils, waxes, fats, semisolids, liquid polyols, and the like.

[0061] Suitable adjuvants for the production of solutions and syrups are, by way of example, water, polyols, saccharose, invert sugar, glucose etc.

[0062] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0063] Suitable adjuvants for suppositories are, by way of example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0064] Suitable adjuvants for topical ophthalmic formulations are, by way of example, cyclodextrin, mannitol, or many other carriers and excipients known in the art.

[0065] Furthermore, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying osmotic pressure, buffers, masking agents, or antioxidants. The pharmaceutical preparations of the present invention may further contain other therapeutically valuable substances.

[0066] Dosages can vary widely and will, of course, be tailored to the individual requirements of each particular case. Generally, for oral administration, the daily dose is about 0.1 mg to about 20 mg per kg of body weight, preferably about 0.5 mg to about 4 mg per kg of body weight (e.g., about 300 mg per person), preferably administered individually in 1 to 3 doses, which, if appropriate, can be composed of equal amounts. For topical administration, the formulation can contain 0.001% to 15% by weight of the drug, and the required amount, which can be between 0.1 and 25 mg, can be administered as a single dose per day, a single dose per week, multiple doses (2 to 4 times per day), or multiple doses per week. However, it is clear that, where indicated, the upper or lower limits set forth herein may be exceeded.

[0067] Pharmaceutical Compositions The compound of formula (I) or its pharmaceutically acceptable salt can be used as a therapeutically active substance, for example, in the form of a pharmaceutical preparation.The pharmaceutical preparation 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 rectally, for example, in the form of suppositories, or parenterally, for example, in the form of injection solutions.

[0068] The compound of formula (I) and its pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or organic carriers to prepare pharmaceutical preparations. Lactose, corn starch or its derivatives, talc, and stearic acid or its salts can be used as carriers for tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules. Suitable carriers for soft gelatin capsules include vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. However, depending on the nature of the active substance, soft gelatin capsules usually do not require a carrier. Suitable carrier materials for the preparation of solutions and syrups include water, polyols, glycerol, vegetable oils, etc. Suitable carriers for suppositories include natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc.

[0069] Furthermore, the pharmaceutical preparations may contain pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying osmotic pressure, buffers, masking agents, or antioxidants. The pharmaceutical preparations of the present invention may further contain other therapeutically valuable substances.

[0070] Also provided by the present invention is a medicament containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier, the process for the preparation of which comprises bringing one or more compounds of formula (I) and / or a pharmaceutically acceptable salt thereof, and optionally one or more other therapeutically useful substances, together with one or more therapeutically inert carriers, into a galenical dosage form.

[0071] The dosage can vary within a wide range and, of course, must be adjusted to the individual requirements in each specific case.When administered orally, the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of the compound of general formula (I) or the corresponding amount of its pharmaceutically acceptable salt.The daily dosage can be administered in a single dose or in divided doses, and can also exceed the upper limit if it proves necessary.

[0072] The following examples illustrate the invention without limiting it, but are merely representative of the invention. Pharmaceutical preparations conveniently contain about 1 to 500 mg, in particular 1 to 100 mg, of a compound of formula (I). Examples of compositions according to the invention are as follows:

[0073] Example A Tablets of the following composition are prepared in the usual manner: TIFF0007802514000013.tif71170

[0074] 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 a suitable grinding device. 4. Add ingredient 5 and mix for 3 minutes, then compress using a suitable press.

[0075] Example B-1 Capsules of the following composition are prepared: TIFF0007802514000014.tif72170

[0076] Manufacturing Procedure 1. Mix ingredients 1, 2, and 3 in a suitable mixer for about 30 minutes. 2. Add ingredients 4 and 5 and mix for about 3 minutes. 3. Fill into suitable capsules.

[0077] The compound of formula (I), lactose, and cornstarch are first mixed in a mixer, then mixed in a pulverizer.The mixture is returned to the mixer, and talc is added thereto and mixed well.This mixture is then filled into a suitable capsule, such as a hard gelatin capsule, by machine. Example B-2

[0078] Soft gelatin capsules of the following composition are prepared: TIFF0007802514000015.tif63170TIFF0007802514000016.tif64170

[0079] Manufacturing Procedure The compound of formula (I) is dissolved in a warm melt of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to conventional procedures.

[0080] Example C Suppositories of the following composition are prepared: TIFF0007802514000017.tif39170

[0081] Manufacturing Procedure The suppository mix 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 thereto and stirred until completely dispersed. The mixture is poured into a suitable suppository mold and allowed to cool, after which the suppositories are removed from the molds and individually wrapped in wax paper or metal foil.

[0082] Example D An injection solution having the following composition is prepared. TIFF0007802514000018.tif47170

[0083] Manufacturing Procedure A compound of formula (I) is dissolved in a mixture of polyethylene glycol 400 and water for injection (partially). The pH is adjusted to 5.0 with acetic acid. The remaining amount of water is added to adjust the volume to 1.0 mL. The solution is filtered, filled into vials using an appropriate overage, and sterilized.

[0084] Example E A sachet of the following composition is prepared: TIFF0007802514000019.tif80170

[0085] Manufacturing Procedure A compound of formula (I) is mixed with lactose, microcrystalline cellulose, and sodium carboxymethylcellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granules are mixed with magnesium stearate and flavoring additives and filled into sachets.

[0086] Example Abbreviation DCM = dichloromethane; DMF = dimethylformamide; DMSO = dimethyl sulfoxide; DRF = dose ranging; 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.

[0087] Reference compounds AR-25, AR-30 and AR-31 were prepared according to the syntheses of Examples 25, 30 and 31, respectively, disclosed in WO 2012 / 118492. 6-Hydroxy-3-methyl-quinazolin-4-one TIFF0007802514000020.tif29170

[0088] 2-Amino-5-hydroxybenzoic acid (10 g, 65.3 mmol, equivalents: 1.0) and N-methylformamide (30 g, 29.9 mL, 503 mmol, equivalents: 7.7) were heated at 145° C. for 21 hours and 45 minutes, then cooled to room temperature. The reaction mixture was diluted with 50 mL of HO and stirred at room temperature for 20 minutes. The resulting precipitate was collected by filtration. The light brown solid was washed three times with 20 mL of water. The solid was dissolved in toluene and evaporated (three times). The solid was dried under high vacuum at 40° C. overnight to give the title compound as a light brown solid (10.3 g, 89% yield). MS (ESI) m / z: 177.1 [M+H] + 3,6-Difluoro-2-(3-methyl-4-oxo-quinazolin-6-yl)oxy-benzonitrile TIFF0007802514000021.tif39170

[0089] Cesium carbonate (3.22 g, 9.79 mmol, equiv.: 1.15) was added to a solution of 6-hydroxy-3-methylquinazolin-4-one (1500 mg, 8.51 mmol, equiv.: 1.0) in N,N-dimethylformamide (35 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes, and then 2,3,6-trifluorobenzonitrile (1.47 g, 1.08 mL, 9.37 mmol, equiv.: 1.1) was added. After 1 hour, the reaction was cooled on ice and diluted with water (120 mL). The resulting solid was collected by filtration, washed with ice water (100 mL) and heptane (100 mL), and dried under vacuum. The solid was dissolved in toluene, evaporated (3 times), and then dried under vacuum overnight to give the title compound as a light brown solid (2.58 g, 97% yield). MS(ESI)m / z:314.1[M+H] + . (3R)-3-Fluoropyrrolidine-1-sulfonamide TIFF0007802514000022.tif35170

[0090] (R)-3-Fluoropyrrolidine hydrochloride (1.8 g, 14.3 mmol, equiv.: 1.2) was added to a solution of sulfuric acid diamide (1.148 g, 11.9 mmol, equiv.: 1.0) and triethylamine (2.42 g, 3.33 mL, 23.9 mmol, equiv.: 2) in dioxane (10 mL). The reaction was stirred at 115 °C for 15.5 h, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with DCM, coevaporated with silica gel, and transferred to a column. Purification by flash chromatography (40 g silica, 80% EtOAc) afforded the title compound as a white crystalline solid (1.82 g, 91% yield). MS (ESI) m / z: 169.1 [M+H] + . (3S)-3-Fluoropyrrolidine-1-sulfonamide TIFF0007802514000023.tif35170

[0091] Triethylamine (304 mg, 419 μL, 3.01 mmol, equiv.: 2.0) was added to a suspension of sulfuric acid diamide (146 mg, 1.5 mmol, equiv.: 1.0) and (S)-3-fluoropyrrolidine hydrochloride (234 mg, 1.8 mmol, equiv.: 1.2) in dioxane (1.3 mL). The reaction was stirred in a sealed tube at 115 °C for 16 hours and 35 minutes and then concentrated under reduced pressure. The residue was diluted with MeOH, coevaporated with silica gel, and transferred to a column. Purification by flash chromatography (40 g silica, 0-8% MeOH / DCM) afforded the title compound as a pale yellow solid (193 mg, 75% yield). MS (ESI) m / z: 169.1 [M+H] + . (3R)—N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (Example 1) TIFF0007802514000024.tif46170

[0092] (R)-3-Fluoropyrrolidine-1-sulfonamide (1.26 g, 7.51 mmol, equiv.: 2.1) and cesium carbonate (2.56 g, 7.87 mmol, equiv.: 2.2) were suspended in dry DMF (10.2 mL) under an argon atmosphere. The reaction mixture was stirred at 50° C. for 30 min. The reaction mixture was cooled to room temperature, 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, equiv.: 1.0) in DMF (25.5 mL) was added. The reaction mixture was stirred at 100° C. for 15 h and then concentrated under reduced pressure. The residue was taken up in a solution of saturated NH4Cl (100 mL) and EtOAc (100 mL). The phases were separated, and the aqueous layer was further extracted twice with 100 mL of EtOAc. The combined organic layers were washed with water (200 mL) and brine (200 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The aqueous layer was back-extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (200 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was diluted with DCM and MeOH and concentrated onto silica. Purification by flash chromatography (120 g, 0.5-2% MeOH / DCM) gave an off-white solid, which was triturated with 1:1 heptane / DCM (20 mL) with sonication and then dried under reduced pressure to give the title compound as a colorless solid (1.087 g, 66% yield). MS (ESI) m / z: 426.2 [M+H] + Chiral SFC: RT = 4.594 min [Chiralpak IC column, 4.6 × 250 mm, 5 μm particle size (Daicel); gradient of 20–40% MeOH containing 0.2% NHEt over 8 min; flow rate: 2.5 mL / min; back pressure: 140 bar]. (3S)—N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (Example 2) TIFF0007802514000025.tif44170

[0093] (S)-3-Fluoropyrrolidine-1-sulfonamide (181 mg, 1.08 mmol, equiv.: 2.1) was dissolved in DMF (1.6 mL). At room temperature, cesium carbonate (368 mg, 1.13 mmol, equiv.: 2.2) was added, and the reaction mixture was stirred at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature, and a solution of 3,6-difluoro-2-((3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)benzonitrile (160.8 mg, 513 μmol, equiv.: 1.0) in DMF (4 mL) was added. The reaction mixture was stirred at 105° C. for 2 hours and 50 minutes, then concentrated under reduced pressure. The residue was taken up in DCM and washed with saturated aqueous NH4Cl. The aqueous layer was back-extracted twice with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue (brown oil) was diluted with DCM and transferred to a column. Purification by flash chromatography (80 g, 0-100% EtOAc in DCM) gave a solid, which was further purified by SFC to give the title compound as a pale yellow solid (119 mg, 50% yield). MS (ESI) m / z: 426.2 [M+H] + Chiral SFC: RT = 4.411 min [Chiralpak IC column, 4.6 × 250 mm, 5 μm particle size (Daicel); gradient of 20–40% MeOH containing 0.2% NHEt over 8 min; flow rate: 2.5 mL / min; back pressure: 140 bar].

Claims

1. Formula (Ia) A pharmaceutically acceptable salt of the compound of formula (I).

2. A pharmaceutical composition comprising a compound of claim 1 and a therapeutically inert carrier.

3. 10. A medicament for use in the treatment of cancer, comprising a compound according to claim 1.

4. 10. A medicament for use in the treatment of thyroid cancer, colorectal cancer, brain cancer, melanoma or non-small cell lung cancer, comprising a compound of claim 1.

5. 10. Use of a compound according to claim 1 for the preparation of a medicament for the treatment of thyroid cancer, colorectal cancer, brain cancer, melanoma or non-small cell lung cancer.

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