Novel Uses of Quinazolinone Compounds for the Treatment of Cancer - Patent application

Abstract

The present invention relates to (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer, wherein a patient suffering from said cancer has previously been treated with a different BRAF inhibitor.

Description

[Technical field]

[0001]

[0011] The present invention relates to the use of a novel, potent, brain-penetrant paradox breaker, BRAFi (compound Ia), developed to better address unmet needs in metastatic cancer patients, particularly those with brain metastases, who have a BRAF mutation, e.g., V600E / K.

[0002]

[0012] In vivo testing of compound Ia in primary tumors from brain metastatic lesions progressing on BRAFi monotherapy or in combination with MEKi revealed potent antitumor activity of compound Ia, providing preclinical support for the activity of this agent even after relapse on BRAFi / MEKi.

[0003]

[0013] By modeling brain metastatic and peripheral lesions in vivo, compound Ia promoted long-lasting responses in both compartments and induced dramatic responses at relapse to available BRAFi and BRAFi / MEKi co-treatments.

[0004]

[0014] Taken together, our results reveal that compound Ia may promote efficacy after relapse with approved BRAFi as monotherapy or even at the time of relapse with approved BRAFi / MEKi combination therapy. Moreover, compound Ia may also significantly extend the overall survival of affected individuals when switching to treatment with compound Ia. Surprisingly, switching to compound Ia after relapse with an approved BRAF inhibitor may result in partial remission, and even complete remission of the disease. In conclusion, compound Ia may provide a new beneficial treatment option for cancer patients with BRAF mutations who previously relapsed under BRAFi in monotherapy or MEKi combination therapy, especially those who develop brain metastases. [Background technology]

[0005]

[0008] The therapeutic benefits of approved BRAF inhibitors (BRAFi) as monotherapy or in combination with MEK inhibitors (MEKi) in patients with metastatic BRAF-mutated cancers are of rather limited duration, highlighting the need for better treatment options. For example, in patients with BRAF V600E / K-positive melanoma and brain metastases, the clinical benefit of available BRAFi / MEKi combination therapy is much shorter-lasting than in patients with non-brain metastatic sites, and recurrences often occur mainly at brain metastatic sites (Lancet Oncol.2017 Jul;18(7):863-873).

[0006]

[0009] The mechanism of resistance to the three approved BRAFi (vemurafenib, dabrafenib, and encorafenib) as well as their combination with MEKi (cobimetinib, trametinib, and binimetinib) occurs in most cases through restoration of MAPK signaling, mediated primarily by the acquisition of genetic events that allow RAF dimerization (Cancer Discov. 2019 Mar;9(3):329-341). Indeed, mechanistic studies revealed that BRAF V600E / K signals as a monomeric protein, a conformation that is effectively inhibited by available inhibitors, while in the RAF dimer, only one protomer can be efficiently bound by the BRAFi, while the second protomer manifests a conformation unfavorable for drug binding (Nature 2010;464(7287):427-30 doi 10.1038 / nature08902.).

[0007]

[0010] Preclinical and clinical reports have described multiple genetic events that enable signaling through RAF dimers, including RAS (HRAS, KRAS, NRAS) mutations, activation of receptor tyrosine kinase (RTK) signals, BRAF amplification, and expression of the dimer-forming BRAF splice variant p61 (Cancer Discov. 2014 Jan;4(1):94-109 Eur J Cancer 2015;51(18):2792-9 doi 10.1016 / j.ejca.2015.08.022). Summary of the Invention

[0008] The present invention relates to a compound of formula (I) for use in the treatment of cancer. TIFF2024539852000001.tif44170, or a pharma- ceutically acceptable salt thereof, wherein the patient suffering from the cancer has previously been treated with a different BRAF inhibitor.

[0009] The present invention further relates to novel methods and uses of the compounds of formula (I) as defined above.

[0010] The chemical name of the compound of formula (I) is (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide. In this specification, the compound of formula (I) is also referred to as compound Ia. [Brief description of the drawings]

[0011] [Figure 1A]

[0004] Figure 1 shows the effect of compound Ia on tumor volume in individual mice implanted subcutaneously with A375 tumors treated with either vehicle, dabrafenib, or compound Ia. In the fourth treatment cohort, dabrafenib was administered until tumor recurrence occurred, at which point dabrafenib treatment was discontinued and mice were treated with compound Ia instead. [Figure 1B]Figure 1 shows the effect of drug treatment on the survival rate of mice implanted with subcutaneous A375 tumors. Mice were treated with either vehicle, dabrafenib, or compound Ia. In the fourth treatment cohort, dabrafenib was administered until tumor recurrence occurred, at which point dabrafenib treatment was discontinued and mice were treated with compound Ia instead. [Figure 2A]

[0005] Figure 1 shows the effect of compound Ia on the survival probability of mice implanted intracranially with A375 tumors. Mice were treated with either vehicle, dabrafenib, or compound Ia. In the fourth treatment cohort, dabrafenib was administered until tumor recurrence occurred, at which point dabrafenib treatment was discontinued and mice were treated with compound Ia instead. [Figure 2B]

[0006] We show the effect of compound Ia on tumor volume in individual mice implanted intracranially with A375 tumors and demonstrate disease recurrence under dabrafenib treatment. [Diagram 3]

[0007] Figure 1 shows the effect of compound Ia on the survival probability of mice implanted intracranially with A375 tumors after relapse under dabrafenib / trametinib or encorafenib / binimetinib treatment. Mice were treated with either vehicle, dabrafenib / trametinib, encorafenib / binimetinib, or compound Ia. In two additional treatment cohorts, dabrafenib / trametinib and encorafenib / binimetinib were administered until tumor recurrence, at which point treatment was discontinued and mice were treated with compound Ia instead. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012]

[0015] The term "inhibitor" refers to a compound that competes with, reduces or prevents the binding of a particular ligand to a particular receptor, or reduces or prevents the function of a particular protein. In particular, inhibitor as used herein refers to a compound that targets, reduces or inhibits the activity of a respective target selected from BRAF and MEK, with particular inhibitors having IC50 values ​​of less than 1 μM, less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 25 nM, less than 10 nM, less than 5 nM, less than 2 nM or less than 1 nM. In some embodiments of the present invention, the term "BRAF inhibitor" refers to a compound that reduces BRAF kinase activity by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99%. In some embodiments of the invention, the term "MEK inhibitor" refers to a compound that reduces MEK kinase activity by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99%.

[0013]

[0016] The term "IC50" refers to the concentration of a particular compound required to inhibit 50% of a measured specific activity.

[0014]

[0017] The term "pharmaceutical acceptable salt" refers to a salt of a compound of formula (I) or MEK inhibitor that retains the biological effectiveness and properties of the free base or free acid, which is not biologically or otherwise undesirable. These salts can be formed, for example, with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, 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, N-acetylcysteine, and the like. These salts can 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 salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, and the like. 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 the compound of formula (I) are hydrochloride, methanesulfonate, and citrate. Particular pharmaceutically acceptable salts of [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl]methanone or cobimetinib are fumarate and succinate, particularly hemifumarate and hemisuccinate.

[0015]

[0018] The term "solvate" refers to a non-covalent stoichiometric or non-stoichiometric combination of a solvent and a solute. The term "hydrate" refers to a non-covalent stoichiometric or non-stoichiometric combination of water and a solute. For example, the compound of formula (I) and its pharmaceutically acceptable salts may exist in unsolvated form and in solvated form with pharmaceutically acceptable solvents such as anisole, dichloromethane, toluene, 1,4-dioxane, water, etc.

[0016]

[0019] A particular embodiment of the invention relates to a compound of formula (I) for use in the treatment of cancer. TIFF2024539852000002.tif44170, or a pharma- ceutically acceptable salt thereof, wherein the patient suffering from the cancer has previously been treated with a different BRAF inhibitor.

[0017]

[0020] Non-limiting examples of MEK inhibitors for use according to the present invention include cobimetinib, binimetinib, trametinib, selumetinib, pimasertib, refametinib, N-[2(R),3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide (PD-325901), 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (Cl-1040), and 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733).

[0018]

[0021] In some embodiments of the invention, the MEK inhibitor is cobimetinib. Cobimetinib is an orally available, potent and highly selective inhibitor of MEK1 and MEK2, central components of the RAS / RAF pathway. Cobimetinib has the chemical name [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl]methanone and the following structure: TIFF2024539852000003.tif37170.

[0019]

[0022] Cobimetinib can be prepared according to the methods described in WO 2007 / 044515. Cobimetinib is commercially available and has the following CAS Registry Number: 934660-93-2.

[0020]

[0023] In some embodiments of the invention, the MEK inhibitor is binimetinib. Binimetinib is an orally available, potent and highly selective inhibitor of MEK1 and MEK2, central components of the RAS / RAF pathway. Binimetinib has the chemical name 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide and the following structure: TIFF2024539852000004.tif41170.

[0021]

[0024] Binimetinib can be prepared according to the methods described in WO 2003 / 077914. Binimetinib is commercially available and has the following CAS Registry Number: 606143-89-9.

[0022] Materials and Methods

[0025] Abbreviation: DNA = deoxyribonucleic acid, PCR = polymerase chain reaction, PO = per os (Latin), QD = once a day (quaque die) (Latin).

[0023]

[0026] Cell line: A375 was obtained from the American Type Culture Collection (ATCC) and maintained at 37°C in a humidified atmosphere of 5% CO2. Culture conditions are shown in the table below: TIFF2024539852000005.tif40170

[0024]

[0027] Cell line manipulation: A375 parental cells were transduced with EF1a-Luciferase(Firefly)-2A-GFP(Puromycin) viral particles (GenTarget Inc. Cat. No. LVP437-PBS). Luciferase activity was confirmed through Luciferase Assay Reagent (Promega Cat. No. E1483) according to the manufacturer's instructions. Viral transduction was performed for 24 hours in the presence of 0.8ug / ml Polybrene Infection Reagent (Millipore Cat. No. TR-1003-G) and cells were selected by adding 1ug / ml Puromycin (Thermo Fisher Cat. No. A1113803).

[0025]

[0028] Test Agents: Encorafenib (HY-15605), dabrafenib (HY-14660A), binimetinib (HY-15202) and trametinib (cHY-10999) were purchased from MedChemExpress. Compound Ia was synthesized in-house. Compound Ia can be synthesized according to the procedure described in WO2021116055A1.

[0026]

[0029] In vivo experiments: All animal experiments were approved by and performed in accordance with the guidelines of the Institutional Animal Care Committee of the Vall d'Hebron Institute, in accordance with European Union and national directives. Male and female NOD scid gamma (NSG) mice, 4- to 5-weeks old, were purchased from Charles River.

[0027]

[0030] For the intracranial model, 5 × 10 5 A375 luc cells were stereotactically inoculated into the striatum of the right hemisphere of mice (1 mm anterior and 1.8 mm lateral to lambda, 2.5 mm intraparenchyma). Brain-implanted tumors were monitored through routine bioluminescence (BLI) signal detection, and recurrence was determined when a progressive increase in BLI signal was observed.

[0028]

[0031] For the subcutaneous model, 5 × 10 6A375 melanoma cells were injected subcutaneously into one flank of mice, and tumor growth was monitored with Caliper. EXAMPLES

[0029]

[0032] The following examples and figures are provided to illustrate the invention and do not have a limiting character.

[0030]

[0033] Example 1 As a melanoma model, we used the A375 cell line expressing BRAF V600E. To facilitate tumor size monitoring, this cell line was stably transduced with a luciferase-expressing vector. A375 luc were implanted subcutaneously to mimic peripheral disease, and tumors were subsequently allowed to grow to between 100 and 300 mm. 3 The mice were randomized when tumor size reached 300 mm (10 mice / group). Mice were administered either vehicle, Compound Ia 10 mg / kg (QD Po), or dabrafenib 100 mg / kg (QD PO). In the fourth treatment cohort, dabrafenib 100 mg / kg (QD PO) was administered until tumor recurrence, at which point dabrafenib treatment was discontinued and mice were treated instead with Compound Ia 10 mg / kg (QD PO). Tumor size at recurrence was 300 mm 3 and 700mm 3 The average value is 558 mm. 3 FIG. 1(A) shows the effect of compound Ia on tumor volume in individual mice implanted with subcutaneous A375 tumors after relapse under dabrafenib treatment. FIG. 1(B) shows the effect of compound Ia on survival probability in mice implanted with subcutaneous A375 tumors after relapse under dabrafenib treatment.

[0031]

[0034] Example 2 As a melanoma model, the A375 cell line expressing BRAF V600E was used. To facilitate tumor size monitoring, this cell line was stably transduced with a luciferase expression vector. To mimic brain metastasis, A375 luc was implanted into the forebrain and mice were randomized (10 mice / group). Brain-implanted tumors were monitored through routine bioluminescence (BLI) signal detection and recurrence was determined when a progressive increase in BLI signal was observed. Mice were administered either vehicle, compound Ia 10 mg / kg (QD Po) or dabrafenib 100 mg / kg (QD PO). In the fourth treatment cohort, dabrafenib 100 mg / kg (QD PO) was administered until tumor recurrence occurred, at which point dabrafenib treatment was discontinued and mice were treated with compound Ia 10 mg / kg (QD PO) instead. Figure 2(A) shows the effect of Compound Ia on the survival probability of mice implanted with intracranial A375 tumors after relapse under dabrafenib treatment, and Figure 2(B) shows the effect of Compound Ia on tumor volume in individual mice implanted with intracranial A375 tumors after relapse under dabrafenib treatment.

[0032]

[0035] Example 3 As a melanoma model, we used the A375 cell line expressing BRAF V600E. To facilitate tumor size monitoring, this cell line was stably transduced with a luciferase expression vector. To mimic brain metastasis, A375 luc was implanted into the forebrain and mice were randomized before treatment. Brain-implanted tumors were monitored through routine bioluminescence (BLI) signal detection and recurrence was determined when a progressive increase in BLI signal was observed (total luminous flux (p / s) was used to estimate tumor size). Tumor size at recurrence was 2 × 10 8 p / s and 5.9×10 9 p / s, and the mean recurrence rate in the D+T treatment group was approximately 2 × 10 9 The tumor size at the time of recurrence was 2×10 8 p / s and 2.5×10 9p / s, and the mean recurrence rate in the D+T treatment group was approximately 1.3 × 10 9 p / s. Figure 3 shows the effect of Compound Ia on the survival probability of mice implanted intracranially with A375 tumors after relapse under treatment with approved BRAFi / MEKi combinations dabrafenib / trametinib or encorafenib / binimetinib. Mice were administered either vehicle (n = 19), Compound Ia 75 mg / kg (n = 10), dabrafenib 100 mg / kg and trametinib 0.25 mg / kg (D+T; n = 19), or encorafenib 36 mg / kg and binimetinib 10 mg / kg (E+B; n = 19). In the fifth cohort, the dabrafenib / trametinib combination (D+T) was administered until relapse (10 mice from the D+T cohort), at which point treatment was discontinued and mice were instead administered compound Ia 75 mg / kg QD PO. In the sixth cohort, the encorafenib / binimetinib combination (E+B) was administered until relapse (10 mice from the E+B cohort), at which point treatment was discontinued and mice were instead administered compound Ia 75 mg / kg QD PO. All groups were orally administered once daily.

[0033]

[0036] In the following, specific embodiments of the present invention are described. All the separate embodiments described below can be combined.

[0034] The present invention relates in particular to: A compound of formula (I) for use in the treatment of cancer. TIFF2024539852000006.tif44170 or a pharma- ceutically acceptable salt thereof, wherein the patient suffering from said cancer has previously been treated with a different BRAF inhibitor; A method for the treatment or prevention of cancer comprising administering to a patient in need thereof a compound of formula (I) administering an effective amount of TIFF2024539852000007.tif44170 or a pharma- ceutically acceptable salt thereof, wherein the patient suffering from cancer has previously been treated with a different BRAF inhibitor; Compounds of formula (I) for the preparation of a medicament for the treatment or prevention of cancer Use of TIFF2024539852000008.tif44170 or a pharma- ceutically acceptable salt thereof, wherein the patient suffering from cancer has previously been treated with a different BRAF inhibitor; The compound for use, method or use as described herein, wherein the prior treatment BRAF inhibitor is selected from vemurafenib, dabrafenib and encorafenib; The compound for use, method or use as described herein, wherein the prior treatment BRAF inhibitor is selected from dabrafenib and encorafenib; A compound for use, method or use as described herein, wherein the prior treatment BRAF inhibitor is vemurafenib; A compound for use, method or use as described herein, wherein the patient has also been previously treated with a MEK inhibitor; The compound for use, method or use as described herein, wherein the previously used MEK inhibitor is selected from binimetinib, trametinib and cobimetinib; The compound for use, method or use as described herein, wherein the previously used MEK inhibitor is selected from binimetinib and trametinib; A compound for use, method or use as described herein, wherein the previously used MEK inhibitor is cobimetinib; A compound for use, method or use as described herein in which tumor recurrence has occurred under previous treatment; The compound for use, method or use as described herein, wherein the cancer is thyroid cancer, colorectal cancer, melanoma, brain cancer or non-small cell lung cancer. The compound for use, method or use as described herein, wherein the cancer is melanoma or non-small cell lung cancer; a compound for use, method or use as described herein, wherein the patient is suffering from brain metastases; Cancer is BRAF V600 a compound for use, a method or a use as described herein relating to a mutation; A compound of formula (I) in combination with one or more further anti-cancer agents selected from MEK inhibitors, MEK degraders, EGFR inhibitors, EGFR degraders, HER2 and / or HER3 inhibitors, HER2 and / or HER3 degraders, SHP2 inhibitors, SHP2 degraders, Axl inhibitors, Axl degraders, ALK inhibitors, ALK degraders, PI3K inhibitors, PI3K degraders, SOS1 inhibitors, SOS1 degraders, signal transduction pathway inhibitors, checkpoint inhibitors, modulators of apoptosis pathways, cytotoxic chemotherapeutic agents, angiogenesis targeted therapeutics, immune targeted agents, and antibody-drug conjugates, for use as described herein; A compound of formula (I) in combination with a MEK inhibitor for use as described herein; A combination as described herein, wherein the MEK inhibitor is cobimetinib or a pharma- ceutically acceptable salt thereof; The methods described herein, wherein the patient is treated with one or more additional anti-cancer agents selected from MEK inhibitors, MEK degraders, EGFR inhibitors, EGFR degraders, HER2 and / or HER3 inhibitors, HER2 and / or HER3 degraders, SHP2 inhibitors, SHP2 degraders, Axl inhibitors, Axl degraders, ALK inhibitors, ALK degraders, PI3K inhibitors, PI3K degraders, SOS1 inhibitors, SOS1 degraders, signal transduction pathway inhibitors, checkpoint inhibitors, modulators of apoptosis pathways, cytotoxic chemotherapeutic agents, angiogenesis targeted therapeutics, immune targeted agents, and antibody-drug conjugates; The methods described herein, wherein the patient is treated with a MEK inhibitor; The method described herein, wherein the MEK inhibitor is cobimetinib or a pharma- ceutically acceptable salt thereof; Use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof as described herein in combination with one or more further anti-cancer agents selected from MEK inhibitors, MEK degraders, EGFR inhibitors, EGFR degraders, HER2 and / or HER3 inhibitors, HER2 and / or HER3 degraders, SHP2 inhibitors, SHP2 degraders, Axl inhibitors, Axl degraders, ALK inhibitors, ALK degraders, PI3K inhibitors, PI3K degraders, SOS1 inhibitors, SOS1 degraders, signal transduction pathway inhibitors, checkpoint inhibitors, modulators of apoptosis pathways, cytotoxic chemotherapeutic agents, angiogenesis targeted therapeutics, immune targeted agents, and antibody-drug conjugates; Use of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, in combination with a MEK inhibitor; and The use of a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof, wherein the MEK inhibitor is cobimetinib.

[0035]

[0037] Structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. 2 H, 3 H, 13 C. 14 C and 18 F. For example, a structure in which one or more hydrogen atoms are replaced by deuterium or tritium, or one or more carbon atoms are 13 C or 14 Structures replaced with C-enriched carbons are within the scope of the present invention.

[0036]

[0038] Furthermore, the present invention includes, where applicable, all optical isomers of the compounds of formula (I), i.e., diastereomers, diastereomeric mixtures, racemic mixtures, all corresponding enantiomers and / or tautomers thereof, as well as solvates thereof. If necessary, 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.

[0037]

[0039] In embodiments, when optically pure enantiomers are 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, said 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 on a suitable intermediate.

[0038]

[0040] In some embodiments, one of the additional anti-cancer agents is an EGFR inhibitor. Non-limiting examples of EGFR inhibitors include cetuximab (Erbitux®), panitumumab (Vectibix®), osimertinib (merelectinib, Tagrisso®), erlotinib (Tarceva®), gefitinib (lressa®), necitumumab (Portrazza™), neratinib (Nerlynx®), lapatinib (Tykerb®), vandetanib (Caprelsa®), and brigatinib (Alunbrig®). Further examples of EGFR inhibitors are known in the art. In some embodiments, the EGFR inhibitor is an allosteric EGFR inhibitor.

[0039]

[0041] In some embodiments, one of the additional anticancer agents is an inhibitor of HER2 and / or HER3. Non-limiting examples of HER2 and / or HER3 inhibitors include lapatinib, canertinib, (E)-2-methoxy-N-(3-(4-(3-methyl-4-(6-methylpyridin-3-yloxy)phenylamino)quinazolin-6-yl)allyl)acetamide (GP-724714), sapitinib, 7-[[4-[(3-ethynylphenyl)amino]-7-methoxy-6-quinazolinyl]oxy]-N-hydroxy-heptanamide (CUDC-101), mubritinib, 6-[4-[(4-ethylpiperazin-1-yl)methyl]phenyl]-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d] pyrimidin-4-amine (AEE788), irbinitinib (tucatinib), poziotinib, N-[4-[1-[4-acetyl-1-piperazinyl)cyclohexyl]-4-amino-3-pyrazolo[3,4-d]pyrimidinyl-2-methoxyphenyl]-1-methyl-2-indolecarboxamide (KIN001-111), 7-cyclopentyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (KIN001-051), 6,7-dimethoxy-N-(4-phenoxyphenyl)quinazolin-4-amine (KIN001-30), dasatinib and bosutinib.

[0040]

[0042] In some embodiments, one of the additional anticancer agents is an inhibitor of SHP2. Non-limiting examples of SHP2 inhibitors include 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099), [3-[(3S,4S)-4amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methanol (RMC-4550), RM C-4630, TNO155, and compounds disclosed in WO 2015 / 107493, WO 2015 / 107494, WO 2015 / 107495, WO 2019 / 075265, PCT / U82019 / 056786, and PCT / 182020 / 053019.

[0041]

[0043] In some embodiments, one of the additional anticancer agents is a PI3K inhibitor. Non-limiting examples include buparlisib (BKM120), alpelisib (BYL719), samotricisib (LY3023414), 8-[(1R)-1-[(3,5-difluorophenyl)amino]ethyl]-N,N-dimethyl-2-(morpholin-4-yl)-4-oxo-4H-chromene-6-carboxamide (AZD8186), tenalisib (RP6530), voxtalisib hydrochloride (voxtalisib hydrochloride) (SAR-245409), gedatricisib (PF-05212384), panulisib (P-7170), taselisib (GDC-0032), trans-2-amino-8-[4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PF-04691502), duvelisib (ABBV -954), N2-[4-oxo-4-[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholin-4-ium-4-ylmethoxy]butyryl]-L-arginyl-glycyl-L-aspartyl-L-serine acetate (SF-1126), pictilisib (GDC-0941), 2-methyl-1-[2-methyl-3-(trifluoromethyl)benzyl]-6-(morpholin-4-yl)-1H -benzimidazole-4-carboxylic acid (GSK2636771), idelalisib (GS-1101), umbralisib tosylate (TGR-1202), pictilisib (GDC-0941), copanlisib hydrochloride (BAY84-1236), dactolisib (BEZ-235), 1-(4-[5-[5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-1-ethyl [6,6-dimethyl-4-(morpholin-4-yl)-8,9-dihydro-6H-[1,4]oxazino[4,3-e]purin-2-yl]pyrimidin-2-amine (GDC-0084), everolimus, rapamycin, perifosine, sirolimus, and temsirolimus.

[0042]

[0044] In some embodiments, one of the additional anticancer agents is an ALK inhibitor. Non-limiting examples include crizotinib (PF-02341066), ceritinib (LDK378), alectinib (Alecensa), brigatinib (AP26113), lorlatinib (PF-6463922), ensartinib (X-396), entrectinib (RXDX-101), reprotectinib (TPX-0005), berizatinib (TSR-011), arcotinib (ZG-0418), foritinib (SAF-189), CEP-37440, TQ-B3139, PLB1003, and TPX-0131.

[0043]

[0045] In some embodiments, one of the additional anti-cancer agents is a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab (Yervoy®) or tremelimumab (GP-675,206). In some embodiments, the PD-1 inhibitor is selected from pembrolizumab (Keytruda®), nivolumab (Opdivo®), and RN888. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (Tecentriq®), avelumab (Bavencio®), and durvalumab (Imfinzi®). TM In some embodiments, the PD-L1 inhibitor is atezolizumab (Tecentriq®).

[0044]

[0046] In some embodiments, one of the additional anticancer drugs is an antibody-drug conjugate. Non-limiting examples of antibody-drug conjugates include gemtuzumab ozogamicin (Mylotarg™), inotuzumab ozogamicin (Besponsa®), brentuximab vedotin (Adcetris®), ado-trastuzumab emtansine (TDM-f; Kadcyla®), mirvetuximab soravtansine (IMGN853), and anetumab ravtansine.

[0045]

[0047] In some embodiments, one of the additional anticancer agents is bevacizumab (Mvasti TM ), Avastin®), trastuzumab (Herceptin®), avelumab (Bavencio®), rituximab (MabThera TM , Rituxan®), edrecolomab (Panorex), daratumumab (Darzalex®), olaratumumab (Lartruvo TM), ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®), oregovomab, pembrolizumab (Keytruda®), dinutuximab (Unituxin®), obinutuzumab (Gazyva®), tremelimumab (GP-675,206), ramucirumab (Cyramza®), ublituximab (TG-1101), panitumumab (Vectibix®), elotuzumab (EmplicitiT'V'), necit Antibodies such as cimutuzumab (PortrazzaT'V'), cimutuzumab (UC-961), ibritumomab (Zevalin®), isatuximab (SAR650984), nimotuzumab, fresolimumab (GC1008), lirilumab (INN), mogamulizumab (Poteligeo®), ficlatuzumab (AV-299), denosumab (Xgeva®), ganitumab, urelumab, pidilizumab, amatuximab, blinatumomab (AMG103; Blincyto®) or midostaurin (Rydapt).

[0046]

[0048] Another embodiment of the present invention provides pharmaceutical compositions containing one or more compositions, each of which contains one or more compounds for use according to the present invention and one or more therapeutically inert carriers, diluents or additives, and methods for preparing such pharmaceutical compositions. In one example, the compound of formula (I) can be formulated by mixing with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to recipients at doses and concentrations employed in galenical dosage forms, at ambient temperature, appropriate pH, and desired purity. The pH of the formulation depends primarily on the particular application and the concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula (I) is formulated in 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.

[0047]

[0049] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard include 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 delivery of the agent, the method of administration, the administration schedule, and other factors known to medical practitioners.

[0048]

[0050] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" is intended to include any and all substances compatible with pharmaceutical administration, including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials and compounds compatible with pharmaceutical administration. Except insofar as any conventional media or agent is incompatible with the active compound, its use in the compositions of the present invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0049]

[0051] Pharmaceutical compositions can be obtained by processing the compounds of formula (I) described herein with pharma-ceutically acceptable inorganic or organic carriers or additives. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as carriers for tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules, for example. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. However, depending on the nature of the active substance, carriers are usually not required for soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils, etc. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc.

[0050]

[0052] In addition, pharmaceutical compositions may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

[0051]

[0053] Pharmaceutical compositions of the compounds of formula (I) may be prepared in the form of a lyophilized formulation or an aqueous solution by mixing the active ingredient having the desired degree of purity, alone or in combination with a second anticancer drug, with optional pharma- ceutically acceptable carriers, additives, or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. (ed.) (1980)) for storage. Acceptable carriers, additives, or stabilizers include those that are non-toxic to recipients at the dosages and concentrations used, such as buffers, such as phosphoric acid, citric acid, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives, such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol; low molecular weight (less than about 10 residues) 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 dextrins; 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 TWEEN. TM , PLURONICS TM or non-ionic surfactants such as polyethylene glycol (PEG).

[0052]

[0054] Pharmaceutical compositions of the compounds of formula (I) include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will usually be that amount of the compound of formula (I) which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about 90 percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent. Methods of preparing these compositions include the step of bringing the compound of formula (I) into association with the carrier and, optionally, one or more accessory ingredients. Typically, the pharmaceutical compositions can be prepared by uniformly and intimately bringing the compound of formula (I) into association with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product. Pharmaceutical compositions suitable for oral administration may be in the form of capsules, cachets, sachets, pills, tablets, lozenges (with flavored bases, usually sucrose and acacia or tragacanth), powder, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (with inert bases such as gelatin and glycerin, or sucrose and acacia), and / or as mouthwashes and the like, each containing a predetermined amount of a compound of formula (I) as an active ingredient.

[0053]

[0055] In a further embodiment of the invention, the compound of formula (I) and the MEK inhibitor are formulated in one or two separate pharmaceutical compositions.

[0054]

[0056] The active ingredient may also be incorporated into microcapsules prepared, for example, by coacervation techniques or interfacial polymerization, such as hydroxymethylcellulose or gelatin-microcapsules and poly-(methyl methacrylate) microcapsules, respectively, into colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules), or into macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed.) (1980).

[0055]

[0057] The formulations to be used for in vivo administration must be sterile, which is readily accomplished by filtration through sterile filtration membranes.

[0056]

[0058] The dosage can vary in 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 8000 mg per day of the compound of general formula (I) or the corresponding amount of its pharmacologic acceptable solvate.The daily dosage can be administered in single or divided doses, and can also exceed the upper limit if it proves to be indicated.When administered orally, it can be administered after a high-fat meal or after 10 hours of fasting.

[0057]

[0059] The following examples are illustrative of the present invention without limiting it, but merely representative thereof. The pharmaceutical composition advantageously contains about 1-500 mg, particularly 5-250 mg, of a compound of formula (I). In a particular embodiment, the pharmaceutical composition containing a compound of formula (I) further contains about 1-500 mg, particularly 5-80 mg, of a MEK inhibitor in a fixed dose combination.

[0058]

[0060] Non-limiting examples of compositions according to the present invention are as follows: Example A-1 Tablets of the following composition are prepared in the usual manner: TIFF2024539852000009.tif52170 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, mix for 3 minutes and compress in a suitable press.

[0059] Example B-1 A capsule of the following composition is prepared: TIFF2024539852000010.tif52170 Manufacturing procedure 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. Fill into suitable capsules.

[0060] The compound of formula (I), lactose and cornstarch are mixed first in a mixer and then in a grinder. The mixture is returned to the mixer, talc is added thereto and mixed well. The mixture is filled by machine into a suitable capsule, for example a hard gelatin capsule.

[0061] Example B-2 Soft gelatin capsules are prepared having the following composition: TIFF2024539852000011.tif51170TIFF2024539852000012.tif50170Manufacturing procedure The compound of formula (I) is dissolved in a warm melt of the other ingredients and the mixture is filled into a suitable sized soft gelatin capsule The filled soft gelatin capsule is treated according to the usual procedures.

[0062] Example C Prepare a suppository of the following composition: TIFF2024539852000013.tif27170 Manufacturing procedure The suppository mass is melted in a glass or steel container, mixed thoroughly and cooled to 45° C. The finely powdered compound of formula (I) is immediately added thereto and stirred until completely dispersed. The mixture is poured into suitable sized suppository molds and allowed to cool, then the suppositories are removed from the molds and individually wrapped in wax paper or metal foil.

[0063] Example D An injection solution having the following composition is prepared: TIFF2024539852000014.tif32170 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 and the volume is adjusted to 1.0 ml. The solution is filtered, filled into vials with appropriate overages, and sterilized.

[0064] Example E A sachet of the following composition is prepared: TIFF2024539852000015.tif63170 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 flavour additives and filled into sachets.

[0065] Specific numbered embodiments: All the separate embodiments described below can be combined. 1. A compound of formula (I) for use in the treatment of cancer TIFF2024539852000016.tif44170 or a pharma- ceutically acceptable salt thereof, wherein a patient suffering from said cancer has previously been treated with a BRAF inhibitor other than a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0066] 2. A compound of formula (I) for use in the treatment of patients with recurrent cancer. TIFF2024539852000017.tif44170 or a pharma- ceutically acceptable salt thereof, which has previously been treated with a BRAF inhibitor other than a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0067] 3. Compounds of formula (I) for preventing the formation of therapeutic resistance TIFF2024539852000018.tif44170 or a pharma- ceutically acceptable salt thereof, in particular, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein the formation has been observed in patients who have been treated with a BRAF inhibitor other than a compound of formula (I).

[0068] 4. A compound of formula (I) for use in reducing resistance to cancer therapy. TIFF2024539852000019.tif44170 or a pharma- ceutically acceptable salt thereof.

[0069] 5. A compound of formula (I) for use in treating the recurrence of cancer with a BRAF mutation. TIFF2024539852000020.tif44170 or a pharma- ceutically acceptable salt thereof.

[0070] 6. A method for the treatment or prevention of cancer comprising administering to a subject a compound of formula (I) A method comprising administering an effective amount of TIFF2024539852000021.tif44170 or a pharma- ceutically acceptable salt thereof to a patient in need thereof, wherein the patient suffering from cancer has previously been treated with a different BRAF inhibitor.

[0071] 7. A method for reducing recurrent proliferation of cancer cells comprising administering a therapeutically effective amount of a compound of formula (I), particularly where said administration reduces recurrent proliferation of cancer cells, more particularly where recurrence has been observed following prior administration of at least one BRAF inhibitor other than a compound of formula (I).

[0072] 8. A compound of formula (I) for the preparation of a medicament for the treatment or prevention of cancer. Use of TIFF2024539852000022.tif44170 or a pharma- ceutically acceptable salt thereof, wherein the patient suffering from cancer has previously been treated with a different BRAF inhibitor.

[0073] 9. The compound for use, method or use according to any one of embodiments 1 to 8, wherein the BRAF inhibitor of the prior treatment is selected from vemurafenib, dabrafenib and encorafenib.

[0074] 10. The compound for use, method or use according to any one of embodiments 1 to 9, wherein the BRAF inhibitor of the previous treatment is dabrafenib.

[0075] 11. The compound for use, method or use according to any one of embodiments 1 to 9, wherein the BRAF inhibitor of the previous treatment is vemurafenib.

[0076] 12.11. The compound for use, method or use according to any one of embodiments 1 to 9, wherein the prior treatment BRAF inhibitor is encorafenib.

[0077] 13. A compound for use, method or use according to any one of embodiments 1 to 12, wherein the patient has also previously been treated with a MEK inhibitor.

[0078] 14. The compound for use, method or use according to any one of embodiments 1 to 13, wherein the previously used MEK inhibitor is selected from binimetinib, trametinib and cobimetinib.

[0079] 15. The compound for use, method or use according to any one of embodiments 1 to 14, wherein the previously used BRAF inhibitor is binimetinib.

[0080] 16. The compound for use, method or use according to any one of embodiments 1 to 14, wherein the previously used BRAF inhibitor is trametinib.

[0081] 17. The compound for use, method or use according to any one of embodiments 1 to 14, wherein the previously used BRAF inhibitor is cobimetinib.

[0082] 18. The compound for use, method or use according to any one of embodiments 1 to 17, wherein the tumor recurrence occurred under a previous treatment.

[0083] 19. The compound for use, method or use according to any one of embodiments 1 to 18, wherein the cancer is thyroid cancer, colorectal cancer, melanoma, brain cancer or non-small cell lung cancer.

[0084] 20. The compound for use, method or use according to any one of the preceding embodiments, wherein the cancer is melanoma or non-small cell lung cancer.

[0085] 21. The compound for use, method or use according to any one of embodiments 1 to 19, wherein the cancer is melanoma or non-small cell lung cancer.

[0086] 22. The compound for use, method or use according to any one of embodiments 1 to 19, wherein the cancer is non-small cell lung cancer.

[0087] 23. The compound for use, method or use according to any one of embodiments 1 to 22, wherein the patient is suffering from brain metastases.

[0088] 24. Cancer is BRAF V600 24. A compound for use, a method or a use according to any one of embodiments 1 to 23, which is related to a mutation.

[0089] 25. Cancer is BRAF V600E 25. A compound for use, a method or a use according to any one of embodiments 1 to 24, which is related to a mutation.

[0090] 26. Cancer is BRAF V600K 25. A compound for use, a method or a use according to any one of embodiments 1 to 24, which is related to a mutation.

[0091] 27. A compound of formula (I) in combination with one or more further anti-cancer agents selected from MEK inhibitors, MEK degraders, EGFR inhibitors, EGFR degraders, HER2 and / or HER3 inhibitors, HER2 and / or HER3 degraders, SHP2 inhibitors, SHP2 degraders, Axl inhibitors, Axl degraders, ALK inhibitors, ALK degraders, PI3K inhibitors, PI3K degraders, SOS1 inhibitors, SOS1 degraders, signal transduction pathway inhibitors, checkpoint inhibitors, modulators of apoptosis pathways, cytotoxic chemotherapeutic agents, angiogenesis targeted therapeutics, immune targeted agents, and antibody-drug conjugates, for use according to any one of embodiments 1 to 5, or 9 to 26.

[0092] 28. A compound of formula (I) in combination with a MEK inhibitor, for use according to any one of embodiments 1 to 5, or 9 to 26.

[0093] 29. The combination according to embodiment 27 or 28, wherein the MEK inhibitor is selected from binimetinib, trametinib and cobimetinib, or a pharma- ceutically acceptable salt thereof.

[0094] 30. The combination according to embodiment 27 or 28, wherein the MEK inhibitor is cobimetinib or a pharma- ceutically acceptable salt thereof.

[0095] 31. The method of any one of embodiments 6, 7, or 9 to 26, wherein the patient is treated with one or more additional anti-cancer agents selected from MEK inhibitors, MEK degraders, EGFR inhibitors, EGFR degraders, HER2 and / or HER3 inhibitors, HER2 and / or HER3 degraders, SHP2 inhibitors, SHP2 degraders, Axl inhibitors, Axl degraders, ALK inhibitors, ALK degraders, PI3K inhibitors, PI3K degraders, SOS1 inhibitors, SOS1 degraders, signal transduction pathway inhibitors, checkpoint inhibitors, modulators of apoptosis pathways, cytotoxic chemotherapeutic agents, angiogenesis targeted therapeutics, immune targeted agents, and antibody-drug conjugates.

[0096] 32. The method of any one of embodiments 6, 7, or 9 to 26, wherein the patient is treated with a MEK inhibitor.

[0097] 33. The method according to embodiment 31 or 32, wherein the MEK inhibitor is selected from binimetinib, trametinib and cobimetinib, or a pharma- ceutically acceptable salt thereof.

[0098] 34. The method according to any one of embodiments 31 to 33, wherein the MEK inhibitor is cobimetinib or a pharma- ceutically acceptable salt thereof.

[0099] 35. The method of any one of embodiments 6, 7, or 9 to 26, wherein the patient is treated with a checkpoint inhibitor.

[0100] 36. The method of embodiment 35, wherein the checkpoint inhibitor is atezolizumab (Tecentriq®).

[0101] 37. The use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 8 to 26 in combination with one or more further anticancer agents selected from MEK inhibitors, MEK degraders, EGFR inhibitors, EGFR degraders, HER2 and / or HER3 inhibitors, HER2 and / or HER3 degraders, SHP2 inhibitors, SHP2 degraders, Axl inhibitors, Axl degraders, ALK inhibitors, ALK degraders, PI3K inhibitors, PI3K degraders, SOS1 inhibitors, SOS1 degraders, signal transduction pathway inhibitors, checkpoint inhibitors, regulators of apoptosis pathways, cytotoxic chemotherapeutic agents, angiogenesis targeted therapeutics, immune targeted agents, and antibody-drug conjugates.

[0102] 38. Use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, as defined in any one of embodiments 8 to 26, in combination with a MEK inhibitor.

[0103] 39. The use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 37 or 38, wherein the MEK inhibitor is cobimetinib or a pharma- ceutically acceptable salt thereof.

Claims

1. A compound of formula (I) for use in the treatment of cancer or a pharmaceutically acceptable salt thereof, wherein a patient suffering from said cancer has previously been treated with a BRAF inhibitor other than a compound of formula (I).

2. A method for the treatment or prevention of cancer, comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient suffering from cancer has previously been treated with a different BRAF inhibitor.

3. A compound of formula (I) for the preparation of a medicament for the treatment or prevention of cancer. or a pharmaceutically acceptable salt thereof, wherein the patient suffering from cancer has previously been treated with a different BRAF inhibitor.

4. 4. The compound for use, method or use according to any one of claims 1 to 3, wherein the BRAF inhibitor of the prior treatment is selected from vemurafenib, dabrafenib and encorafenib.

5. 4. The compound for use, method or use according to any one of claims 1 to 3, wherein the patient has also previously been treated with a MEK inhibitor.

6. 4. The compound for use, method or use according to any one of claims 1 to 3, wherein the previously used MEK inhibitor is selected from binimetinib, trametinib and cobimetinib, or a pharmaceutically acceptable salt thereof.

7. 4. The compound for use, method or use according to any one of claims 1 to 3, wherein tumor recurrence has occurred under previous treatment.

8. 4. The compound for use, method or use according to any one of claims 1 to 3, wherein the cancer is thyroid cancer, colorectal cancer, melanoma, brain cancer or non-small cell lung cancer.

9. 4. The compound for use, method or use according to any one of claims 1 to 3, wherein the cancer is melanoma or non-small cell lung cancer.

10. 4. The compound for use, method or use according to any one of claims 1 to 3, wherein the patient is suffering from brain metastases.

11. Cancer is BRAF Ｖ６００ 4. A compound for use, method or use according to any one of claims 1 to 3, which is associated with a mutation.

12. 2. The compound of formula (I) in combination with one or more further anti-cancer agents selected from a MEK inhibitor, a MEK degrader, an EGFR inhibitor, an EGFR degrader, an inhibitor of HER2 and / or HER3, a degrader of HER2 and / or HER3, a SHP2 inhibitor, a SHP2 degrader, an AxI inhibitor, an AxI degrader, an ALK inhibitor, an ALK degrader, a PI3K inhibitor, a PI3K degrader, an SOS1 inhibitor, an SOS1 degrader, a signal transduction pathway inhibitor, a checkpoint inhibitor, a modulator of an apoptosis pathway, a cytotoxic chemotherapeutic agent, an angiogenesis targeted therapeutic, an immune targeted agent, and an antibody-drug conjugate for use according to claim 1.

13. 2. A compound of formula (I) in combination with a MEK inhibitor for use according to claim 1.

14. 14. The compound of formula (I) according to claim 13, wherein the MEK inhibitor is cobimetinib or a pharmaceutically acceptable salt thereof.

15. 3. The method of claim 2, wherein the patient is treated with one or more additional anti-cancer agents selected from a MEK inhibitor, a MEK degrader, an EGFR inhibitor, an EGFR degrader, an inhibitor of HER2 and / or HER3, a degrader of HER2 and / or HER3, a SHP2 inhibitor, a SHP2 degrader, an AxI inhibitor, an AxI degrader, an ALK inhibitor, an ALK degrader, a PI3K inhibitor, a PI3K degrader, an SOS1 inhibitor, an SOS1 degrader, a signal transduction pathway inhibitor, a checkpoint inhibitor, a modulator of an apoptosis pathway, a cytotoxic chemotherapeutic agent, an angiogenesis targeted therapy, an immune targeted agent, and an antibody-drug conjugate.

16. 3. The method of claim 2, wherein the patient is treated with a MEK inhibitor.

17. 17. The method of claim 16, wherein the MEK inhibitor is cobimetinib or a pharmaceutically acceptable salt thereof.

18. 4. The use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 3 in combination with one or more further anti-cancer agents selected from a MEK inhibitor, a MEK degrader, an EGFR inhibitor, an EGFR degrader, an inhibitor of HER2 and / or HER3, a degrader of HER2 and / or HER3, a SHP2 inhibitor, a SHP2 degrader, an Axl inhibitor, an Axl degrader, an ALK inhibitor, an ALK degrader, a PI3K inhibitor, a PI3K degrader, an SOS1 inhibitor, an SOS1 degrader, a signal transduction pathway inhibitor, a checkpoint inhibitor, a modulator of an apoptosis pathway, a cytotoxic chemotherapeutic agent, an angiogenesis targeted therapeutic, an immune targeted agent, and an antibody-drug conjugate.

19. 4. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 3 in combination with a MEK inhibitor.

20. 20. The use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 19, wherein the MEK inhibitor is cobimetinib or a pharmaceutically acceptable salt thereof.

21. The invention described above.

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