Cancer treatment with MET kinase inhibitors

Abstract

Compositions and methods for the treatment of cancer are provided herein. The composition comprises a MET kinase inhibitor. Some embodiments include combination therapies comprising the MET kinase inhibitor and at least one tumor therapeutic agent.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits of U.S. Provisional Application No. 63 / 496,667 filed on 17 April 2023 and U.S. Provisional Application No. 63 / 595,233 filed on 1 November 2023. Both of these provisional applications are incorporated herein by reference in their entirety. [Background technology]

[0002] MET is a member of the class IV receptor tyrosine kinase family and is expressed on the surface of many different cell types, including epithelial cells of many organs, including the liver, pancreas, prostate, kidney, muscle, and bone marrow, during both embryonic development and adulthood. Binding to hepatocyte growth factor induces receptor dimerization and activation. MET modulates many essential cellular processes during development and wound healing, including cell proliferation, survival, motility, and morphogenesis. Abnormal MET activity is found in many different human cancers. Therefore, therapies targeting MET kinase activity are desirable for use in the treatment of cancer and other disorders characterized by abnormal MET pathway signaling. [Overview of the Initiative]

[0003] One embodiment provides a method for treating cancer in a patient requiring treatment for cancer, comprising the step of administering (S)-N-(3,5-difluoro-4-{[6-((1-hydroxypropan-2-yl)oxy)-7-methoxyquinoline-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide, or a pharmaceutically acceptable salt or solvate thereof, to the patient.

[0004] One embodiment provides a method for treating cancer in a patient requiring treatment for cancer, comprising the step of administering to the patient a pharmaceutical composition comprising (S)-N-(3,5-difluoro-4-{[6-((1-hydroxypropan-2-yl)oxy)-7-methoxyquinoline-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0005] One embodiment is a method for treating cancer in a patient who requires treatment for cancer, (a) A composition comprising (S)-N-(3,5-difluoro-4-{[6-((1-hydroxypropan-2-yl)oxy)-7-methoxyquinoline-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide, or a pharmaceutically acceptable salt or solvate thereof, (b) At least one oncological treatment selected from EGFR kinase inhibitors, EGFR antibodies, EGFR PROTAC therapies, immune checkpoint inhibitors, ALK inhibitors, ROS1 inhibitors, FGFR inhibitors, BRAF inhibitors, CDK2 / 4 / 6 inhibitors, RET inhibitors, TRK inhibitors, KRAS inhibitors, RAS inhibitors, glutaminase inhibitors, or VEGFR inhibitors The present invention provides a method that includes the step of administering a substance to a patient. [Brief explanation of the drawing]

[0006] Novel features of this disclosure are described in detail in the appended claims. A better understanding of the features and advantages of this disclosure will be obtained by referring to the following detailed description and appended drawings which describe exemplary embodiments in which the principles of this disclosure are utilized. [Figure 1] Figure 1 shows the antitumor activity of compound 1 across c-MET NSCLC mutation models. [Figure 2] Figures 2A and 2B show results from a xenograft tumor study derived from LU2503 (MET gene amplification and exon 14 deletion) patients. [Figure 3]Figures 3A and 3B show results from the MET D1228N xenograft tumor study. [Figure 4] Figure 4 shows the research schema for the Phase 1 dose escalation and dose increase study.

[0007] Reference All publications, patents, and patent applications referenced herein are incorporated herein by reference for the specific purposes specified herein. [Modes for carrying out the invention]

[0008] Specific terms Where used herein and in the appended claims, the singular forms “a,” “and,” and “the” include multiple references unless the context clearly indicates otherwise. Thus, for example, a reference to “an agent” includes multiple such agents, and a reference to “the cell” includes one or more cells (or more cells) and their equivalents known to those skilled in the art. Where a range is used herein with respect to physical properties such as molecular weight, or chemical properties such as chemical formula, it is intended to include all combinations and partial combinations of the range and any particular embodiment within it. Where a number or numerical range is referred to, the term “about” means that the number or numerical range referred to is an approximation within experimental variability (or statistical experimental error), and therefore the number or numerical range may, in some cases, vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude, in other specific embodiments, from “consisting of” or “consisting essentially of” the features described herein, for example, in embodiments of any composition, method, or process described herein.

[0009] As used herein and in the appended claims, unless otherwise specified, the following terms have the meanings set forth below.

[0010] "Pharmacopoetically acceptable salt" includes both acid-addition salts and base-addition salts. The pharmaceutically acceptable salts of heterocyclic MET kinase inhibitors described herein are intended to encompass any and all pharmaceutically acceptable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid-addition salts and pharmaceutically acceptable base-addition salts.

[0011] A "pharmaceutically acceptable acid addition salt" refers to a salt formed using an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, or phosphorous acid, which retains the biological efficacy and properties of the free base and is biologically or otherwise undesirable. Salts formed using organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanos, hydroxyalkanoics, alkanedionic acids, aromatic acids, and aliphatic and aromatic sulfonic acids are also included, such as acetic acid, trifluoroacetic 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, and salicylic acid. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, suberinate succinates, sebacinates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates. Salts of amino acids such as alginates, glucons, and galacturonates are also considered (see, for example, Berge SM et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared in some embodiments by contacting the free base form with a sufficient amount of the desired acid to produce the salt, according to methods and techniques familiar to those skilled in the art.

[0012] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological efficacy and properties of a free acid, and is not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to a free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed using metals or amines such as alkali metals and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Examples of 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, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydravamin, choline, betaine, ethylenediamine, ethylenedianiline, A-methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. See Berge et al. above.

[0013] A "pharmaceutically acceptable solvate" refers to a composition of a substance in a solvent-added form. In some embodiments, the solvate is formed during a process using a pharmaceutically acceptable solvent, such as water or ethanol, and contains either a stoichiometric or non-stoichiometric amount of solvent. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. The solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein may optionally exist in either a non-solvated or solvated form.

[0014] The terms "subject" or "patient" encompass mammals. Examples of mammals include, but are not limited to, any member of the following mammalian classes: humans, non-human primates such as chimpanzees, and other apes and monkey species; domesticated animals such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one aspect, a mammal is a human.

[0015] As used herein, “treat,” “treating,” “palliating,” and “ameliorating” are interchangeable. These terms refer to approaches to obtain beneficial or desired outcomes, including but not limited to therapeutic and / or preventive benefits. “Therapeutic benefit” means the eradication or improvement of the underlying disease being treated. The therapeutic benefit is also achieved by the eradication or improvement of one or more physiological symptoms associated with the underlying disease, such that improvement is observed in the patient, even though the patient still has the underlying disease. For a preventive benefit, the composition is administered, in some embodiments, to a patient at risk of developing a particular disease, or to a patient who reports one or more physiological symptoms of the disease, even if a diagnosis of the disease has not been made. As used herein, the term “treating” means, unless otherwise indicated, to reverse, alleviate, inhibit the progression of, or prevent the disorder or disease to which such term applies, or one or more symptoms of such disorder or disease. In some embodiments, the term “treating” includes slowing or delaying the progression of a disease or disorder to which the term applies. Furthermore, in some embodiments, the term “treating” applies to one or more complications arising from a disease or disorder to which the term applies. As used herein, the term “treatment” refers to the act of treating as defined above, unless otherwise indicated.

[0016] As used herein, the terms "tumor" or "cancer" refer to neoplastic cell growth, including pre-cancerous and cancerous cells and tissues, unless otherwise specified. Tumors typically exist as lesions or masses. As used herein, "treating" a tumor means that the tumor itself, tumor angiogenesis, or other parameters by which the disease is characterized are reduced, improved, inhibited, placed in a remission state, or maintained in a remission state, meaning one or more symptoms of the disease. "Treating" a tumor also means that one or more characteristics of the tumor can be removed, reduced, or prevented by treatment. Non-limiting examples of such characteristics include uncontrolled degradation of the basement membrane and proximal extracellular matrix, migration, division, and organization of endothelial cells into new functional capillaries, and persistence of such functional capillaries.

[0017] The term "refractory" or "refractory to therapy" indicates that a patient has never responded to therapy.

[0018] The terms "relapsed" or "relapsed after therapy" indicate that a patient has progressive disease due to acquired resistance and / or intolerance after initially responding to previous therapy.

[0019] The terms "resistance to therapy" or "acquired resistance to therapy" indicate that a patient has progressive disease due to clinical or molecular resistance to therapy after initially responding to previous therapy. Acquired resistance can result from the emergence of resistance mutations in the molecular target of the therapy or in the development of physiological functions such as efflux pumps.

[0020] As used herein, the phrase "therapeutically effective amount" refers to the amount of a drug or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal or human that is sought by a researcher, veterinarian, physician or other.

[0021] Other aspects, advantages, and features of the present invention will become apparent from the following detailed description.

[0022] MET tyrosine kinase The MET protein is a member of the class IV receptor tyrosine kinase family and is expressed on the surface of many different cell types, including epithelial cells of many organs such as the liver, pancreas, prostate, kidney, muscle and bone marrow, both during embryonic development and in adulthood. MET regulates many essential cellular processes during development and wound healing, including cell proliferation, survival, motility, and morphogenesis. Aberrant MET activity is found in many different human cancers, such as non-small cell lung cancer, medulloblastoma, lymphoma, melanoma, glioma, breast cancer, pancreatic cancer, colorectal cancer, ovarian cancer and prostate cancer, as well as osteosarcoma and some soft tissue sarcomas.

[0023] The c-MET proto-oncogene is located on chromosome 7q21-31 and its transcription is regulated by Ets (E-twenty six), Pax3 (paired box 3), AP2 (activator protein-2) and Tcf-4 (transcription factor 4). It is represented as multiple mRNA transcripts of 8, 7, 4.5, 3 and 1.5 kilobases. The protein product of this gene is the MET receptor tyrosine kinase.

[0024] Structurally, MET is a single-pass transmembrane protein with an extracellular domain, a transmembrane hydrophobic sequence, and an intracellular portion containing a tyrosine kinase domain. The extracellular domain of MET consists of three domain types: a semaphorin (Serna) domain, a PSI domain, and four immunoglobulin-plexin-transcription (IPT) domains. The N-terminal 500 residues fold to form a large Serna domain, which shares sequence homology with domains found in the semaphorin and plexin families. The PSI domain (found in plexins, semaphorins, and integrins) follows the Serna domain, connecting the Serna domain to the IPT domain over approximately 50 residues. The four IPT domains are associated with immunoglobulin-like domains and are found in integrins, plexins, and transcription factors. The c-terminal IPT domains are then connected to a single transmembrane helix that connects the extracellular domain to the intracellular domain. The intracellular domain of the MET receptor includes a perimembrane domain containing the Y1003 residue, which is involved in receptor downregulation; the tyrosine kinase catalytic domain contains the Y1234 and Y1235 residues, which are involved in signal transduction; and the docking site of the adapter protein contains the Y1349 and Y1356 residues.

[0025] The extracellular portion of MET binds to its homologous ligand, hepatocyte growth factor (HGF), and its native isoform, NK1, resulting in dimerization of the two MET proteins. This dimerization leads to trans-autophosphorylation of two tyrosine residues (Y1234 and Y1235) located within the catalytic loop of the intracellular tyrosine kinase domain. Subsequently, tyrosine residues 1349 and 1356 in the carboxy-terminal tail are phosphorylated, thereby forming a unique tandem SH2 recognition motif and leading to the recruitment of signal effector proteins involved in downstream signal transduction (e.g., GABI, GRB2, SHC, CRK, PI3K, PLCγ1, SHP2, and STAT3).

[0026] HGF, the primary ligand for MET, is a secreted single-chain 83kDa precursor protein. Full-length HGF contains an N-terminal (N) domain, four consecutive kringle (K1-K4) domains, and a serine protease homology (SPH) domain. Proteolytic cleavage between Arg494 and Val495 of HGF produces a 57kDa α-subunit and a 26kDa β-subunit, which are covalently linked by a disulfide bond between Cys487 of the α-subunit and Cys604 of the β-subunit. Both pro-HGF and cleaved HGF can bind to MET with high affinity, but only cleaved mature HGF can activate MET signaling. NK1, a native isoform of HGF, can also bind to and activate MET.

[0027] In malignant solid tumors, HGF is primarily expressed and released by surrounding stromal cells, enabling tumor and stromal cells to communicate with each other via HGF and creating a microenvironment that contributes to cancer progression. For example, HGF derived from the tumor stroma acts on tumor cells, stimulating not only proliferation and metastasis but also the production of HGF inducers. These HGF inducers, including bFGF, IL-1β, TGF-α, PDGF, and prostaglandin E2 (PGE2), act on stromal fibroblasts, inducing further HGF expression. This creates a feedback loop that drives increased MET activation in the tumor. Thus, the interaction between tumor and stromal cells continuously drives tumor growth, invasion, and metastasis. Furthermore, HGF can also be produced by the tumor itself, a phenomenon that has been detected in renal cell carcinoma, colorectal cancer, breast cancer, glioma, multiple myeloma, as well as synovial sarcoma, osteosarcoma, and fibrosarcoma.

[0028] Dysregulation of the MET pathway in cancer occurs through various mechanisms, including gene mutations, amplification, rearrangement, and protein overexpression. Several MET fusions have been identified, including the fusion between c-MET and TPR (translocated promoter region nuclear basket protein gene) found in mutagenic osteosarcoma cell lines, and the fusion between C-MET and KIF5B (kinesin family member 5B gene) detected in patients with lung adenocarcinoma. Furthermore, mutations at the splice site of MET resulting in exon 14 skipping are a key molecular driver in non-small cell lung cancer (NSCLC). Such exon-skipping mutations have recently been shown to occur in 3%–4% of NSCLC adenocarcinomas, 2% of squamous cell carcinomas, and 1%–8% of other subtypes of lung cancer. These exon-skipping mutations often result in persistent MET activation, driving tumorigenesis via downstream signaling pathways.

[0029] MET activation and intracellular signaling pathways MET activation initiates a series of intracellular signaling pathways, including PI3K / AKT, Ras / MAPK, JAK / STAT, SRC, Wnt / β-catenin, and other signaling pathways, thereby regulating proliferation, motility, migration, and invasion. Under normal physiological conditions, MET is crucial in regulating tissue homeostasis and wound healing, but in cancer, abnormal MET activation drives tumor growth, enhanced metastasis, and drug resistance via these pathways.

[0030] The Ras / MAPK / ERK signaling pathway transmits signals from cell surface receptors, including MET, to DNA in the cell nucleus, where regulation of gene expression occurs. While the signaling cascade involves many different proteins that propagate signals through protein phosphorylation, the pathway can generally be divided into three steps: (i) Ras activation, (ii) kinase signaling cascade, and (iii) translation and transcription regulation. Briefly, MET activation leads to Ras activation, which in turn phosphorylates and activates the protein kinase activity of RAF kinase. In cancer, abnormal Ras activation can lead to tumor growth, evasion of apoptosis, local tissue invasion, and metastasis. RAF kinase then phosphorylates and activates MEK (MEK1 and MEK2), which in turn phosphorylates and activates the MAPK (also known as ERK) protein. MAPK activation modulates the activity of several transcription factors, thereby regulating protein expression. By altering the levels and activity of transcription factors, MAPK alters the transcription of genes crucial to the cell cycle. Depending on the stimulus and cell type, this pathway can transmit signals that result in the prevention or induction of apoptosis or cell cycle progression. For example, the major regulators of angiogenesis involved in the Ras / MAPK / ERK signaling pathway are vascular endothelial growth factor (VEGF) and its homologous receptor VGFR. Activation of the VEGF pathway has been identified in numerous disease processes, including cancer, and within the tumor environment, the VEGFR and MET signaling pathways have been shown to have synergistic effects on tumor growth.

[0031] The phosphatidylinositol 3-kinase (PI3K) / protein kinase B (PKB / AKT) signaling pathway is involved in regulating multiple cellular physiological processes, including metabolism, proliferation, cell survival, growth, and angiogenesis. PI3K is a member of the lipid kinase family and is activated by phosphorylation of the 3-hydroxyl group of phosphatidylinositol lipids in the cell membrane, forming phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 binds to PKB / Akt in the plasma membrane, allowing pirubate dehydrogenase kinase 1 (PDK1) to access and phosphorylate T308 in the Akt "activation loop," resulting in partial PKB / Akt activation. Subsequent phosphorylation of Akt at S473 in the carboxyl-terminal hydrophobic motif, either by mTOR or DNA-PK, stimulates full Akt activity. Akt activation leads to further substrate-specific phosphorylation events in both the cytoplasm and nucleus, including CREB activation, p27 inhibition, FOXO localization in the cytoplasm, Ptdlns-3ps activation, and mTOR activation. Through these downstream effectors, the PI3K / Akt pathway mediates numerous cellular functions that drive cancer progression, including angiogenesis, metabolism, growth, proliferation, survival, protein synthesis, transcription, and apoptosis.

[0032] The JAK-STAT pathway is essential for a wide range of cytokines and growth factors, leading to critical cellular events such as cell differentiation, hematopoiesis, and immune system development. The JAK / STAT signaling pathway also plays a major role in the growth and survival of different cancer types. Activation of Janus kinase (JAK) by MET results in phosphorylation of signaling molecules and activator of transcription (STAT) proteins, which then dimerize and translocate to the nucleus, where they regulate gene expression and drive tumor growth. For example, STAT3 is a key driver of tumorigenesis, regulating the expression of many oncogenes, including BCL-XL, c-MYC, Mell, Survivin, BEGF, HIF-1α, HGF, IL-12, and MMPs. In this way, the JAK / STAT pathway drives tumor progression by enhancing cell proliferation, angiogenesis, metastasis, and immune escape.

[0033] The Wnt / p-catenin signaling pathway is a conserved signaling axis involved in diverse physiological processes such as proliferation, differentiation, apoptosis, migration, invasion, and tissue homeostasis. Activation of the Wnt / p-catenin signaling pathway leads to an increase in cytosolic P-catenin concentration, which translocates to the nucleus and interacts with T cell-specific factor (TCF) / lymphoid enhancer binding factor (LEF) and its co-activators, such as Pygopus and Bcl-9. This then enhances the expression of target genes, including c-Myc, cyclin DI, and CDKN1A, which drive cancer stem cell regeneration, cell proliferation, and differentiation, and therefore plays a crucial role in tumorigenesis and therapeutic response. Thus, by modulating various oncogenetic signaling pathways, MET is a major driver of tumor growth, survival, invasion, and metastasis.

[0034] MET kinase inhibitors Several drugs targeting MET or HGF, including small molecule inhibitors and monoclonal antibodies, are under development. Monoclonal antibodies currently FDA-approved or undergoing clinical evaluation include anti-MET antibodies (e.g., onartuzumab and emibetuzumab), anti-HGF antibodies (e.g., ficratuzumab and rilotumumab), and anti-MET / EGFR bispecific antibodies (e.g., amivantamab). These therapies prevent HGF from binding to MET, thereby halting MET activation. Furthermore, many small molecule MET inhibitors, including capatinib, tepotinib, crizotinib, cabozantinib, MGCD265, AMG208, artiratinib, and golvatinib, are FDA-approved for the treatment of cancer. Of these, two selective MET inhibitors, capmatinib (Tabrecta®) and tepotinib (Tepmetko®), are FDA approved for the treatment of patients with advanced NSCLC with MET exon 14 skipping mutations. Cabozantinib (Cabometyx®) is FDA approved for the treatment of locally advanced or metastatic differentiated thyroid cancer.

[0035] Small molecule MET-specific inhibitors can be divided into two functionally distinct classes: type I inhibitors (e.g., crizotinib, capatinib, tepotinib, and savolitinib) that preferentially bind to the active conformation of MET, and type II inhibitors (e.g., cabozantinib and gresatinib) that preferentially bind to the inactive conformation of MET. Furthermore, selective MET inhibitors include adenosine triphosphate competitors and adenosine triphosphate non-competitives (e.g., tivantinib). Type I MET inhibitors are further subdivided into type Ia inhibitors (e.g., crizotinib) that interact with the solvent front G1163 residue, and type Ib inhibitors (e.g., capmatinib, tepotinib, and savolitinib) that bind to the kinase domain.

[0036] Resistance to type I and type II MET inhibitors is often associated with MET kinase domain mutations. For example, mutations at kinase domain residues D1228 and Y1230 confer resistance to type I MET inhibitors in vitro by weakening the interaction between the drug and the MET kinase domain. Resistance to all type I MET inhibitors has been clinically identified, and patients have secondary mutations at these locations. Furthermore, mutations at the solvent front G1163R confer resistance to the type Ia MET inhibitor crizotinib, but not to type Ib MET inhibitors such as tepotinib, savolitinib, or capatinib in vitro. Type II MET inhibitors retain varying degrees of efficacy against many cancers with these mutations that render type I inhibitors ineffective. However, the MET L1195V mutation confers resistance to type II MET inhibitors, and it has been suggested that resistance to type II MET inhibitors may be driven by high levels of local amplification of the MET exon 14 mutant allele. Growing evidence suggests that MET mutations are a consistent mechanism of acquired resistance and post-tyrosine kinase inhibition in several oncogene-driven molecular subsets of cancer. Therefore, resistance to MET inhibitors has become a major challenge to the clinical efficacy of targeted therapies. Given the considerable resistance that mutations confer to MET inhibitors, there is a significant unmet clinical need for MET inhibitors that can not only maintain efficacy against tumors but also against tumors with acquired MET-resistant mutations and other mutations.

[0037] Heterocyclic MET kinase inhibitors The heterocyclic MET kinase inhibitor described herein refers to compound 1 having the following structure and chemical name (S)-N-(3,5-difluoro-4-{[6-((1-hydroxypropan-2-yl)oxy)-7-methoxyquinoline-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide. This compound is also known as KIN-8741.

[0038] [ka]

[0039] Throughout this disclosure, when referring to a heterocyclic MET kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof, we are referring to Compound 1 or a pharmaceutically acceptable salt or solvate thereof.

[0040] Cancer and Treatment Methods In one embodiment, a method for inhibiting a MET kinase enzyme is provided, comprising the step of contacting the enzyme with compound 1 disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In a particular embodiment, a method for treating cancer in an individual requiring treatment of cancer is disclosed herein, comprising the step of administering an effective amount of a heterocyclic MET kinase inhibitor disclosed herein to the individual. In a particular embodiment, a heterocyclic MET kinase inhibitor for use in the treatment of cancer is disclosed herein. In a particular embodiment, a heterocyclic MET kinase inhibitor described herein for use in the preparation of a pharmacopoeia for the treatment of cancer is disclosed herein.

[0041] One embodiment provides a method for treating cancer in a patient requiring treatment for cancer, comprising the step of administering (S)-N-(3,5-difluoro-4-{[6-((1-hydroxypropan-2-yl)oxy)-7-methoxyquinoline-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide, or a pharmaceutically acceptable salt or solvate thereof, to the patient.

[0042] One embodiment provides a method for treating cancer in a patient requiring treatment for cancer, comprising the step of administering to the patient a pharmaceutical composition comprising (S)-N-(3,5-difluoro-4-{[6-((1-hydroxypropan-2-yl)oxy)-7-methoxyquinoline-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0043] Another embodiment provides a method characterized in that cancer has oncogenic MET dysregulation. Another embodiment provides a method in which oncogenic MET dysregulation arises from MET chromosome rearrangement, somatic or germline mutation, MET gene amplification, or transcriptional upregulation.

[0044] Another embodiment provides a method characterized in that the cancer has an oncogenic MET change. Another embodiment provides a method in which the oncogenic MET change is an exon 14 skipping change. Another embodiment provides a method in which the oncogenic MET change is a D1228 or Y1230 mutation. Another embodiment provides a method in which the oncogenic MET change is at least one of D1228N, D1228H, Y1230H, Y1230C, Y1230S, H1094Y, L1195V, or F1200I. Another embodiment provides a method in which the oncogenic MET variant is at least one of D1228A, D1228G, D1228V, D1228Y, H1094L, K1244R, L1195F, M1250I, M1250T, P991S, T1173I, T992I, V1092I, Y1230A, Y1230D, Y1235D, D1228E, F1200L, or Y1230N. Another embodiment provides a method in which the oncogenic MET variant is at least one of G1163R, G1090A, or D1228E. Another embodiment provides a method in which the oncogenic MET variant is a double variant in codons D1228 and M1229.

[0045] Another embodiment provides a method for treating cancer in a patient who requires treatment for cancer, wherein the cancer is a solid tumor.

[0046] Another embodiment provides a method in which cancer is selected from lung cancer, colon cancer, colorectal cancer, gastric cancer, adenocarcinoma of the gastroesophageal junction (GEJ), breast cancer, medullary thyroid carcinoma, kidney cancer, renal cell carcinoma, papillary renal cell carcinoma, liver cancer, hepatocellular carcinoma, thyroid cancer, glioblastoma, gastroesophageal cancer (GEC), melanoma, sarcoma, ovarian cancer, glioma, biliary tract adenocarcinoma, gallbladder cancer, head and neck squamous cell carcinoma (HNSCC), and prostate cancer.

[0047] Another embodiment provides a method in which the cancer is selected from lung cancer, colon cancer, colorectal cancer, gastric cancer, adenocarcinoma of the gastroesophageal junction (GEJ), breast cancer, medullary thyroid cancer, kidney cancer, renal cell carcinoma, papillary renal cell carcinoma, liver cancer, hepatocellular carcinoma, thyroid cancer, and glioblastoma.

[0048] Another embodiment provides a method in which the cancer is lung cancer. Another embodiment provides a method in which the lung cancer is non-small cell lung cancer. Another embodiment provides a method in which the non-small cell lung cancer is anaplastic lymphoma kinase (ALK) positive. Another embodiment provides a method in which the non-small cell lung cancer includes a pulmonary sarcomatoid carcinoma subtype.

[0049] Another embodiment provides a method in which non-small cell lung cancer is lung adenocarcinoma. Another embodiment provides a method characterized in that non-small cell lung cancer has an oncogenic MET alteration. Another embodiment provides a method in which the oncogenic MET alteration includes an exon 14 skipping mutation.

[0050] Another embodiment provides a method characterized in that non-small cell lung cancer has an oncogenic EGFR mutation. Another embodiment provides a method in which the oncogenic EGFR mutation includes an EGFR exon 18 mutation, an EGFR exon 19 mutation, an EGFR in-frame exon 19 deletion, an EGFR exon 20 mutation, an EGFR exon 21 mutation, an EGFR L858R mutation, an EGFR L861Q mutation, an EGFR S768I mutation, or an EGFR T790M mutation. Another embodiment provides a method characterized in that non-small cell lung cancer has wild-type EGFR.

[0051] Another embodiment provides a method in which the cancer is colon cancer or colorectal cancer.

[0052] Another embodiment provides a method in which the cancer is gastroesophageal cancer (GEC). Another embodiment provides a method in which the gastroesophageal cancer (GEC) includes esophagogastric junction cancer, esophageal squamous cell carcinoma, or gastric cancer.

[0053] Another embodiment provides a method in which the cancer is gastric cancer or adenocarcinoma of the gastroesophageal junction (GEJ).

[0054] Another embodiment provides a method in which the cancer is breast cancer.

[0055] Another embodiment provides a method in which the cancer is renal cancer, renal cell carcinoma, or papillary renal cell carcinoma.

[0056] Another embodiment provides a method for determining whether the cancer is liver cancer or hepatocellular carcinoma.

[0057] Another embodiment provides a method in which the cancer is thyroid cancer. Another embodiment provides a method in which the thyroid cancer is differentiated thyroid cancer.

[0058] Another embodiment provides a method in which the cancer is medullary thyroid carcinoma.

[0059] Another embodiment provides a method in which the cancer is glioblastoma.

[0060] Another embodiment provides a method in which the cancer is a glioma.

[0061] Another embodiment provides a method in which the cancer is melanoma.

[0062] Another embodiment provides a method in which the cancer is a sarcoma. Another embodiment provides a method in which the sarcoma includes osteosarcoma, clear cell sarcoma, or soft tissue sarcoma.

[0063] Another embodiment provides a method in which the cancer is ovarian cancer.

[0064] Another embodiment provides a method in which the cancer is biliary tract adenocarcinoma.

[0065] Another embodiment provides a method in which the cancer is biliary tract and gallbladder cancer.

[0066] Another embodiment provides a method in which the cancer is head and neck squamous cell carcinoma (HNSCC).

[0067] One embodiment is a method for treating cancer in a patient who requires treatment for cancer, (a) A composition comprising (S)-N-(3,5-difluoro-4-{[6-((1-hydroxypropan-2-yl)oxy)-7-methoxyquinoline-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide, or a pharmaceutically acceptable salt or solvate thereof, (b) At least one oncological treatment selected from EGFR kinase inhibitors, EGFR antibodies, EGFR PROTAC therapies, immune checkpoint inhibitors, ALK inhibitors, ROS1 inhibitors, FGFR inhibitors, BRAF inhibitors, CDK2 / 4 / 6 inhibitors, RET inhibitors, TRK inhibitors, KRAS inhibitors, RAS inhibitors, glutaminase inhibitors, or VEGFR inhibitors The present invention provides a method that includes the step of administering a substance to a patient.

[0068] Another embodiment provides a method in which at least one oncology therapeutic agent is selected from EGFR kinase inhibitors, EGFR antibodies, EGFR PROTAC therapeutic agents, immune checkpoint inhibitors, ALK inhibitors, ROS1 inhibitors, FGFR inhibitors, BRAF inhibitors, CDK2 / 4 / 6 inhibitors, RET inhibitors, TRK inhibitors, or KRAS inhibitors.

[0069] Another embodiment provides a method in which at least one tumor therapeutic agent is an EGFR kinase inhibitor or antibody. Another embodiment provides a method in which the EGFR kinase inhibitor is selected from nazartinib, gefitinib, erlotinib, afatinib, brigatinib, icotinib, sorafenib, neratinib, osimertinib, razertinib, dacomitinib, lapatinib, BLU-701, BLU-945, BLU-451, BDTX-189, BDTX-1535, ERAS-80, STX-721, STX-241, EAI045, and TQB3804. Another embodiment provides a method in which the EGFR antibody is cetuximab, panitumumab, zaltumumab, nimotuzumab, nivolumab, or matuzumab. Another embodiment provides a method in which the EGFR antibody is amivantamab, EMB-01, MCLA-129, or GB263T.

[0070] Another embodiment provides a method in which at least one tumor therapeutic agent is an immune checkpoint inhibitor. Another embodiment provides a method in which the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, or a LAG-3 inhibitor. Another embodiment provides a method in which the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor.

[0071] Another embodiment provides a method in which the immune checkpoint inhibitor is a CTLA-4 inhibitor. Another embodiment provides a method in which the CTLA-4 inhibitor is ipilimumab. Another embodiment provides a method in which the CTLA-4 inhibitor is tremelimumab.

[0072] Another embodiment provides a method in which the immune checkpoint inhibitor is a PD-1 inhibitor. Another embodiment provides a method in which the PD-1 inhibitor is spartalizumab, nivolumab, pembrolizumab, or semilimab.

[0073] Another embodiment provides a method in which the immune checkpoint inhibitor is a PD-L1 inhibitor. Another embodiment provides a method in which the PD-L1 inhibitor is atezolizumab, avelumab, or durvalumab.

[0074] Another embodiment provides a method in which the immune checkpoint inhibitor is a LAG-3 inhibitor. Another embodiment provides a method in which the LAG-3 inhibitor is relatrimab.

[0075] Another embodiment provides a method in which at least one tumor therapeutic agent is an ALK inhibitor. Another embodiment provides a method in which the ALK inhibitor is selected from ensartinib, alectinib, brigatinib, ceritinib, lorlatinib, and crizotinib.

[0076] Another embodiment provides a method in which at least one tumor therapeutic agent is a ROS1 inhibitor. Another embodiment provides a method in which the ROS1 inhibitor is selected from taretrectinib, crizotinib, and entrectinib.

[0077] Another embodiment provides a method in which at least one tumor therapeutic agent is an FGFR inhibitor. Another embodiment provides a method in which the FGFR inhibitor is selected from erdafitinib, pemigatinib, infiglatinib, futivatinib, RLY-4008, TYRA-300, TYRA-200, and KIN-3248.

[0078] Another embodiment provides a method in which the FGFR inhibitor is KIN-3248.

[0079] Another embodiment provides a method in which at least one tumor therapeutic agent is a BRAF inhibitor. Another embodiment provides a method in which the BRAF inhibitor is selected from encorafenib, vemurafenib, rifirafenib, dabrafenib, exalafenib, BGB-3245, rifirafenib, tovorafenib, verbarafenib, napolafenib, PF-07284890, PF-07799933, and JZP815. Another embodiment provides a method in which the BRAF inhibitor is exalafenib.

[0080] Another embodiment provides a method in which at least one tumor therapeutic agent is a CDK2 / 4 / 6 inhibitor. Another embodiment provides a method in which the CDK2 / 4 / 6 inhibitor is selected from palbociclib, abemaciclib, ribociclib, lerocyclib, PF-07104091, PF-06873600, and PF-07220060. Another embodiment provides a method in which the CDK2 / 4 / 6 inhibitor is selected from dinacyclib, cericlib, and SNS-032.

[0081] Another embodiment provides a method in which at least one tumor therapeutic agent is a RET inhibitor. Another embodiment provides a method in which the RET inhibitor is selected from serpercatinib or praresetinib.

[0082] Another embodiment provides a method in which at least one tumor therapeutic agent is a TRK inhibitor. Another embodiment provides a method in which the TRK inhibitor is selected from larotrectinib or entrectinib.

[0083] Another embodiment provides a method in which at least one tumor therapeutic agent is a KRAS inhibitor. Another embodiment provides a method in which the KRAS inhibitor is selected from sotarasib, adagrasib, and BI-1701963.

[0084] Another embodiment provides a method in which at least one tumor therapeutic agent is a RAS inhibitor. Another embodiment provides a method in which the RAS inhibitor is selected from RMC-6291, RMC-9805, RMC-8839, and RMC-6236.

[0085] Another embodiment provides a method in which at least one tumor therapeutic agent is a glutaminase inhibitor. Another embodiment provides a method in which the glutaminase inhibitor comprises CB-839.

[0086] Another embodiment provides a method in which at least one tumor therapeutic agent is a VEGFR inhibitor. Another embodiment provides a method in which the VEGFR inhibitor is selected from axitinib and sunitinib.

[0087] Another embodiment provides a method for when the cancer is metastatic.

[0088] Another embodiment provides a method for when the cancer is locally progressive.

[0089] Another embodiment provides a method which is adjuvant therapy after surgical resection.

[0090] Another embodiment provides a method for when a patient has experienced a relapse after previous treatment.

[0091] Another embodiment provides a method in which the patient has acquired resistance to previous treatments.

[0092] Another embodiment provides a method for patients who are refractory to previous treatments.

[0093] Another embodiment provides a method in which (S)-N-(3,5-difluoro-4-{[6-((1-hydroxypropane-2-yl)oxy)-7-methoxyquinoline-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide, or a pharmaceutically acceptable salt or solvate thereof, is administered orally. Another embodiment provides a method in which the oral administration is carried out every other day, once daily, twice daily, or three times daily.

[0094] Pharmaceutical composition In certain embodiments, the heterocyclic MET kinase inhibitors described herein are administered as pure chemical substances. In other embodiments, the heterocyclic MET kinase inhibitors described herein are combined with a pharmaceutically appropriate or acceptable carrier (also referred to herein as a pharmaceutically appropriate or acceptable excipient, a physiologically appropriate or acceptable excipient, or a physiologically appropriate or acceptable carrier) selected based on a selected route of administration and standard pharmacopoeia.

[0095] Pharmaceutical compositions comprising a heterocyclic MET kinase inhibitor, or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier (or excipient) is acceptable or appropriate if the carrier is compatible with the other components of the composition and is not harmful to the recipient of the composition (i.e., the subject or patient).

[0096] One embodiment provides a method for preparing a pharmaceutical composition, comprising the step of mixing a heterocyclic MET kinase inhibitor, or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, or solvate thereof, with a pharmaceutically acceptable carrier.

[0097] Methods for orally administering pharmaceutical compositions are provided herein. Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules made of hard or soft gelatin, methylcellulose, or other suitable materials readily soluble in the gastrointestinal tract. In some embodiments, suitable non-toxic solid carriers are used, for example, those comprising pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. (e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21)). st See Ed. Mack Pub. Co., Easton, PA (2005).

[0098] Methods for administering pharmaceutical compositions by injection are provided herein. In some embodiments, heterocyclic MET kinase inhibitors described herein, or pharmaceutically acceptable salts or solvates thereof, are formulated for administration by injection. In some examples, the injectable formulation is an aqueous formulation. In some examples, the injectable formulation is a non-aqueous formulation. In some examples, the injectable formulation is an oil-based formulation, such as sesame oil.

[0099] The dose of compositions comprising heterocyclic MET kinase inhibitors, or their stereoisomers, pharmaceutically acceptable salts, hydrates, or solvates, as described herein, varies depending on the subject or patient's (e.g., human) condition. In some embodiments, such factors include overall health, age, and other factors. The pharmaceutical composition is administered in a manner appropriate to the disease being treated (or prevented). The appropriate dose, as well as the appropriate duration and frequency of administration, is determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Generally, the appropriate dose and treatment regimen provides the composition in an amount sufficient to provide therapeutic and / or preventive benefits (e.g., more frequent complete or partial remission, or longer disease-free survival and / or overall survival, or improved clinical outcomes such as reduced symptom severity). The optimal dose is generally determined using experimental models and / or clinical trials. The optimal dose depends on the patient's body weight, weight, or blood volume. [Examples]

[0100] The following exemplary embodiments are representative of the systems and methods described herein and are not intended to limit the scope of the claims provided herein.

[0101] Example 1: In vitro MET kinase inhibitory activity of compound 1 Compound 1 was tested in biochemical assays (Table 1) and cellular assays (Table 2) to evaluate its activity against both wild-type and mutant MET kinase family members in multiple independent experiments.

[0102] Methods: The biochemical activity of compound 1 was determined by a reaction biology kinase hotspot assay. All kinase targets were reacted with 10 μM ATP. Appropriate substrates were diluted in reaction buffer containing 20 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01% Brij35, 0.02 mg / mL BSA, 0.1 mM sodium orthovanadate, 2 mM DTT, and 1% DMSO, as well as the appropriate substrate. After incorporating the kinase into the solution, compound 1 was added using a 10-point 3x dose curve, starting at 10 μM, 3 μM, or 1 μM as the maximum concentration during a 20-minute pre-incubation at room temperature. 33 P-ATP was added to the reaction mixture to initiate the reaction, which was incubated at room temperature for 2 hours. Kinase activity was detected by the P81 filter-bound method: after incubation, the reaction mixture was spotted onto P81 ion-exchange filter paper (Whatman). Unbound phosphate was removed by extensive washing of the filter in 0.75% phosphoric acid. After subtracting background from a control reaction containing inactive enzyme, kinase activity data was expressed as the percentage of residual kinase activity in the test sample compared to the vehicle reaction. Maximum half-volume inhibitory concentration (IC50) values ​​were calculated using the conversion ratio inhibition with Dotmatics Knowledge Solutions Studies curve fitting.

[0103] Cell viability profiling was performed on manipulated TPR-MET Ba / F3 cells. Ba / F3 manipulated cells were placed in 3 × 10⁶ wells of culture medium in a 96-well plate. 3 Cells were seeded in wells. The following day, the compound was diluted in PBS and added to plates to a final concentration ranging from 0.46 nM to 10 μM in 0.1% DMSO, with 0.1% DMSO in 10% FBS culture medium as a negative control. Cells were incubated at 37°C in 5% CO2 for 3 days. Then, the CTG reagent was added, and the plates were incubated at room temperature for 15–20 minutes according to the manufacturer's instructions. The plates were read in luminescence mode, and the EC50 values ​​were calculated by dose-response regression curve fitting using a four-parameter analysis method.

[0104] Results: Biochemical assays tested the potency of compound 1 against both wild-type and mutant c-Met family members. Table 1 lists the mean potency of compound 1 inhibition against the enzymes. c-Met enzymes with kinase domain mutations showed IC50 values ​​ranging from the most potent 0.6 nM for the M1250I mutation to the least potent 10.6 nM for the G1163R mutant enzyme. The mean IC50 concentration across all tested c-Met and c-Met mutant enzymes was 3.2 nM. The inhibition of cell proliferation by compound 1 was evaluated across a panel of IL-3-independent mouse manipulated Ba / F3 cell lines by overexpression of translocated promoter region (TPR)-MET fusion genes with specific MET mutations. Cell viability was measured using a CTG assay 3 days after compound 1 treatment in multiple independent experiments. As shown in Table 2, the EC50 values ​​of compound 1 ranged from 1.0 nM (TPR-METL1195F) to 613 nM (TPR-METG1163R) in mutant cells, and the EC50 values ​​were <60 nM in 18 of the 19 strains tested. Furthermore, compound 1 performed better than capmatinib, tepotinib, cabozantinib, and merestinib.

[0105] [Table 1]

[0106] [Table 2]

[0107] Example 2: Determination of antitumor activity in a MET mutant mouse xenograft model Compound 1, a MET inhibitor, inhibits clinically observed secondary mutations known to drive resistance to approved MET kinase inhibitors. Preclinical studies have shown that compound 1 is potent against activating mutations in non-small cell lung cancer. The mutations studied include, among others, MET exon 14 skipping mutations and MET amplification with low nanomolar biochemical and cellular target binding half-opinion inhibitory concentrations (IC50) values. As shown in Table 3 and Figures 1-3, the antitumor activity of compound 1 was evaluated in xenograft models exhibiting MET activating mutations, including MET exon 14 skipping mutations, MET amplification, and BAF3 TPR-MET D1228N acquired resistance mutations. Oral administration of compound 1 was generally well-tolerated and effective in mouse xenograft models of MET-driven cancer. Furthermore, compound 1 performed better than capmatinib in mouse xenograft models with resistant MET mutations.

[0108] Method: In the right flank of thymus-deficient BALB / c nude mice, 5x10 6 EBC-1 cells, 1x10 6 BaF3 TPR-MET D1228N cells or LU2503 tumors with MET mutations, 2-3 mm in size. 3 Fragments were subcutaneously inoculated. Mice were grouped based on their initial tumor volume and body weight, so that the mean values ​​were the same for each treatment group. Oral administration of compound 1 and / or capatinib was used when the tumor volume was approximately 200-300 mm. 3 The study began when the target was reached and continued for 10–21 days. Animals were monitored for tumor growth, weight changes, and overall health / behavior.

[0109] Results: Compound 1 had good tolerance, no weight loss was observed, and it was effective in a xenograft model of athymic nude mice with MET mutant cancer at doses up to 60 mg / kg BID daily. Dose-dependent tumor growth inhibition was observed in the LU2503 PDX model of lung cancer with MET gene amplification and exon 14 deletion, the EBC-1 CDX model with MET amplification, and the Ba / F3 TPR-MET fusion model with the MET D1228N resistant mutation. The lowest doses of 2 and 6 mg / kg of Compound 1 resulted in moderate TGIs in all three models (the average TGI for LU2503 was 43 - 77% for 2 - 6 mg / kg of Compound 1 respectively; the average TGI for EBC-1 was 25 - 52% for 2 - 6 mg / kg of Compound 1 respectively; the average TGI for Ba / F3 TPR-MET D1228N was 26 - 44% for 2 - 6 mg / kg of Compound 1 respectively). Compound 1 resulted in tumor regression at high doses in all three models (the average TGI for LU2503 was 110 - 113% for 20 - 60 mg / kg of Compound 1 respectively; the average TGI for EBC-1 was 110% for 60 mg / kg of Compound 1; the average TGI for Ba / F3 TPR-MET D1228N was 128% for 60 mg / kg of Compound 1, and p < 0.0001 for all). These data identify that Compound 1 has potent antitumor activity in exon 14 deletion-mediated cancer, gene amplification cancer, and D1228N mutant MET-driven cancer.

[0110]

Table 3

[0111] Example 3: Use of Compound 1 in Human Clinical Trials Figure 4 shows a representative Phase 1 / 1b, first-in-human, non-blind, multi-center, dose-escalation and expansion study to investigate the safety, tolerance, pharmacokinetics and antitumor activity of Compound 1 in adult patients with a MET solid tumor schema.

[0112] While preferred embodiments of the Disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided only as examples. Those skilled in the art will be able to conceive of numerous variations, alterations, and substitutions without departing from the Disclosure. It should be understood that various alternatives to the embodiments of the Disclosure described herein may be adopted when carrying out the Disclosure.

Claims

1. A method for treating cancer in a patient requiring treatment for cancer, comprising the step of administering (S)-N-(3,5-difluoro-4-{[6-((1-hydroxypropan-2-yl)oxy)-7-methoxyquinoline-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide, or a pharmaceutically acceptable salt or solvate thereof, to the patient.

2. A method for treating cancer in a patient requiring treatment for cancer, comprising the step of administering to the patient a pharmaceutical composition comprising (S)-N-(3,5-difluoro-4-{[6-((1-hydroxypropan-2-yl)oxy)-7-methoxyquinoline-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

3. The method according to claim 1 or 2, characterized in that the cancer has oncogenic MET dysregulation.

4. The method according to claim 3, wherein the oncogenic MET dysregulation is caused by MET chromosome rearrangement, somatic or germline mutation, MET gene amplification, or transcriptional upregulation.

5. The method according to claim 3, characterized in that the cancer has a carcinogenic MET change.

6. The method according to claim 5, wherein the carcinogenic MET change is an exon 14 skipping change.

7. The method according to claim 5, wherein the carcinogenic MET mutation is a D1228 or Y1230 mutation.

8. The method according to claim 5, wherein the carcinogenic MET change is at least one of D1228N, D1228H, Y1230H, Y1230C, Y1230S, H1094Y, L1195V, or F1200I.

9. The method according to claim 5, wherein the carcinogenic MET change is at least one of D1228A, D1228G, D1228V, D1228Y, H1094L, K1244R, L1195F, M1250I, M1250T, P991S, T1173I, T992I, V1092I, Y1230A, Y1230D, Y1235D, D1228E, F1200L, or Y1230N.

10. The method according to claim 5, wherein the carcinogenic MET change is at least one of G1163R, G1090A, or D1228E.

11. The method according to claim 5, wherein the carcinogenic MET change is a double mutant in codons D1228 and M1229.

12. The method according to any one of claims 1 to 11, wherein the cancer is a solid tumor.

13. The method according to any one of claims 1 to 12, wherein the cancer is selected from lung cancer, colon cancer, colorectal cancer, gastric cancer, adenocarcinoma of the gastroesophageal junction (GEJ), breast cancer, medullary thyroid carcinoma, kidney cancer, renal cell carcinoma, papillary renal cell carcinoma, liver cancer, hepatocellular carcinoma, thyroid cancer, glioblastoma, gastroesophageal cancer (GEC), melanoma, sarcoma, ovarian cancer, glioma, biliary tract adenocarcinoma, gallbladder cancer, head and neck squamous cell carcinoma (HNSCC), and prostate cancer.

14. The method according to any one of claims 1 to 12, wherein the cancer is selected from lung cancer, colon cancer, colorectal cancer, gastric cancer, adenocarcinoma of the gastroesophageal junction (GEJ), breast cancer, medullary thyroid carcinoma, kidney cancer, renal cell carcinoma, papillary renal cell carcinoma, liver cancer, hepatocellular carcinoma, thyroid cancer, and glioblastoma.

15. The method according to any one of claims 1 to 14, wherein the cancer is lung cancer.

16. The method according to claim 15, wherein the lung cancer is non-small cell lung cancer.

17. The method according to claim 16, wherein the non-small cell lung cancer is positive for anaplastic lymphoma kinase (ALK).

18. The method according to claim 16, wherein the non-small cell lung cancer includes a pulmonary sarcomatoid carcinoma subtype.

19. The method according to claim 16, wherein the non-small cell lung cancer is lung adenocarcinoma.

20. The method according to claim 16, characterized in that the non-small cell lung cancer has carcinogenic MET changes.

21. The method according to claim 20, wherein the carcinogenic MET change includes an exon 14 skipping mutation.

22. The method according to claim 16, characterized in that the non-small cell lung cancer has oncogenic EGFR changes.

23. The method according to claim 22, wherein the oncogenic EGFR mutation includes an EGFR exon 18 mutation, an EGFR exon 19 mutation, an EGFR in-frame exon 19 deletion, an EGFR exon 20 mutation, an EGFR exon 21 mutation, an EGFR L858R mutation, an EGFR L861Q mutation, an EGFR S768I mutation, or an EGFR T790M mutation.

24. The method according to claim 16, characterized in that the non-small cell lung cancer has wild-type EGFR.

25. The method according to any one of claims 1 to 14, wherein the cancer is colon cancer or colorectal cancer.

26. The method according to any one of claims 1 to 13, wherein the cancer is gastroesophageal cancer (GEC).

27. The method according to claim 26, wherein the gastroesophageal cancer (GEC) includes esophagogastric junction cancer, esophageal squamous cell carcinoma, or gastric cancer.

28. The method according to any one of claims 1 to 14, wherein the cancer is gastric cancer or adenocarcinoma of the gastroesophageal junction (GEJ).

29. The method according to any one of claims 1 to 14, wherein the cancer is breast cancer.

30. The method according to any one of claims 1 to 14, wherein the cancer is renal cancer, renal cell carcinoma, or papillary renal cell carcinoma.

31. The method according to any one of claims 1 to 14, wherein the cancer is liver cancer or hepatocellular carcinoma.

32. The method according to any one of claims 1 to 14, wherein the cancer is thyroid cancer.

33. The method according to claim 32, wherein the thyroid cancer is differentiated thyroid cancer.

34. The method according to any one of claims 1 to 14, wherein the cancer is medullary thyroid carcinoma.

35. The method according to any one of claims 1 to 14, wherein the cancer is glioblastoma.

36. The method according to any one of claims 1 to 13, wherein the cancer is a glioma.

37. The method according to any one of claims 1 to 13, wherein the cancer is melanoma.

38. The method according to any one of claims 1 to 13, wherein the cancer is a sarcoma.

39. The method according to claim 38, wherein the sarcoma includes osteosarcoma, clear cell sarcoma, or soft tissue sarcoma.

40. The method according to any one of claims 1 to 13, wherein the cancer is ovarian cancer.

41. The method according to any one of claims 1 to 13, wherein the cancer is biliary tract adenocarcinoma.

42. The method according to any one of claims 1 to 13, wherein the cancer is biliary tract and gallbladder cancer.

43. The method according to any one of claims 1 to 13, wherein the cancer is head and neck squamous cell carcinoma (HNSCC).

44. A method for treating cancer in patients who require treatment for cancer, (a) A composition comprising (S)-N-(3,5-difluoro-4-{[6-((1-hydroxypropane-2-yl)oxy)-7-methoxyquinoline-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide, or a pharmaceutically acceptable salt or solvate thereof, (b) At least one oncological treatment selected from EGFR kinase inhibitors, EGFR antibodies, EGFR PROTAC therapies, immune checkpoint inhibitors, ALK inhibitors, ROS1 inhibitors, FFFR inhibitors, BRAF inhibitors, CDK2 / 4 / 6 inhibitors, RET inhibitors, TRK inhibitors, KRAS inhibitors, RAS inhibitors, glutaminase inhibitors, or VEGFR inhibitors A method comprising the step of administering to the patient.

45. The method according to claim 44, wherein the at least one tumor therapeutic agent is selected from an EGFR kinase inhibitor, an EGFR antibody, an EGFR PROTAC therapeutic agent, an immune checkpoint inhibitor, an ALK inhibitor, a ROS1 inhibitor, an FFFR inhibitor, a BRAF inhibitor, a CDK2 / 4 / 6 inhibitor, a RET inhibitor, a TRK inhibitor, or a KRAS inhibitor.

46. The method according to claim 44, wherein the at least one tumor treatment agent is an EGFR kinase inhibitor or an antibody.

47. The method according to claim 44, wherein the EGFR kinase inhibitor is selected from nazartinib, gefitinib, erlotinib, afatinib, brigatinib, icotinib, sorafenib, neratinib, osimertinib, razertinib, dacomitinib, lapatinib, BLU-701, BLU-945, BLU-451, BDTX-189, BDTX-1535, ERAS-80, STX-721, STX-241, EAI045, and TQB3804.

48. The method according to claim 44, wherein the EGFR antibody is cetuximab, panitumumab, zaltumumab, nimotuzumab, nivolumab, or matuzumab.

49. The method according to claim 44, wherein the EGFR antibody is amivantamab, EMB-01, MCLA-129, or GB263T.

50. The method according to claim 44, wherein the at least one tumor treatment agent is an immune checkpoint inhibitor.

51. The method according to claim 50, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, or a LAG-3 inhibitor.

52. The method according to claim 50, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor.

53. The method according to claim 51, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.

54. The method according to claim 53, wherein the CTLA-4 inhibitor is ipilimumab or tremelimumab.

55. The method according to claim 51, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.

56. The method according to claim 55, wherein the PD-1 inhibitor is spartalizumab, nivolumab, pembrolizumab, or semilimab.

57. The method according to claim 51, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.

58. The method according to claim 57, wherein the PD-L1 inhibitor is atezolizumab, avelumab, or durvalumab.

59. The method according to claim 51, wherein the immune checkpoint inhibitor is a LAG-3 inhibitor.

60. The method according to claim 59, wherein the LAG-3 inhibitor is relatrimab.

61. The method according to claim 44, wherein the at least one tumor treatment agent is an ALK inhibitor.

62. The method according to claim 61, wherein the ALK inhibitor is selected from ensartinib, alectinib, brigatinib, ceritinib, lorlatinib, and crizotinib.

63. The method according to claim 44, wherein the at least one tumor treatment agent is a ROS1 inhibitor.

64. The method according to claim 63, wherein the ROS1 inhibitor is selected from taretrectinib, crizotinib, and entrectinib.

65. The method according to claim 44, wherein the at least one tumor treatment agent is an FGFR inhibitor.

66. The method according to claim 65, wherein the FGFR inhibitor is selected from erdafitinib, pemigatinib, infiglatinib, futivatinib, RLY-4008, TYRA-300, TYRA-200, and KIN-3248.

67. The method according to claim 65, wherein the FGFR inhibitor is KIN-3248.

68. The method according to claim 44, wherein the at least one tumor treatment agent is a BRAF inhibitor.

69. The method according to claim 68, wherein the BRAF inhibitor is selected from encorafenib, vemurafenib, rifirafenib, dabrafenib, exalafenib, BGB-3245, rifirafenib, tovorafenib, berbarafenib, napolafenib, PF-07284890, PF-07799933, and JZP815.

70. The method according to claim 44, wherein the at least one tumor treatment agent is a CDK2 / 4 / 6 inhibitor.

71. The method according to claim 44, wherein the CDK2 / 4 / 6 inhibitor is selected from palbociclib, abemaciclib, ribociclib, rerocyclib, PF-07104091, PF-06873600, and PF-07220060.

72. The method according to claim 44, wherein the CDK2 / 4 / 6 inhibitor is selected from dinaciclib, cericlib, and SNS-032.

73. The method according to claim 44, wherein the at least one tumor treatment agent is a RET inhibitor.

74. The method according to claim 73, wherein the RET inhibitor is selected from serpercatinib or praresetinib.

75. The method according to claim 44, wherein the at least one tumor treatment agent is a TRK inhibitor.

76. The method according to claim 75, wherein the TRK inhibitor is selected from larotrectinib or entrectinib.

77. The method according to claim 44, wherein the at least one tumor treatment agent is a KRAS inhibitor.

78. The method according to claim 77, wherein the KRAS inhibitor is selected from sotarasib, adaglab, and BI-1701963.

79. The method according to claim 44, wherein the at least one tumor treatment agent is a RAS inhibitor.

80. The method according to claim 79, wherein the RAS inhibitor is selected from RMC-6291, RMC-9805, RMC-8839, and RMC-6236.

81. The method according to claim 44, wherein the at least one tumor treatment agent is a glutaminase inhibitor.

82. The method according to claim 81, wherein the glutaminase inhibitor comprises CB-839.

83. The method according to claim 44, wherein the at least one tumor treatment agent is a VEGFR inhibitor.

84. The method according to claim 83, wherein the VEGFR inhibitor is selected from axitinib and sunitinib.

85. The method according to any one of claims 1 to 84, wherein the cancer is metastatic.

86. The method according to any one of claims 1 to 84, wherein the cancer is locally progressive.

87. The method according to any one of claims 1 to 84, which is adjuvant therapy after surgical resection.

88. The method according to any one of claims 1 to 84, wherein the patient has relapsed after previous treatment.

89. The method according to any one of claims 1 to 84, wherein the patient has acquired resistance to previous treatment.

90. The method according to any one of claims 1 to 84, wherein the patient is refractory to previous treatments.

91. The method according to any one of claims 1 to 90, wherein (S)-N-(3,5-difluoro-4-{[6-((1-hydroxypropan-2-yl)oxy)-7-methoxyquinoline-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide, or a pharmaceutically acceptable salt or solvate thereof, is administered orally.

92. The method according to claim 91, wherein the oral administration is performed every other day, once a day, twice a day, or three times a day.

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