Use of 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea and analogs thereof for the treatment of cancer associated with genetic abnormalities of platelet-derived growth factor receptor alpha

Abstract

To provide a method of treating or preventing a PDGFR kinase-mediated tumor growth or tumor progression.SOLUTION: The method comprises administering an effective amount of 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea, 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea, or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: Figure 1A

Description

Technical Field

[0001] Description of an electronically submitted text file: The content of the electronically submitted text file is hereby incorporated by reference in its entirety: a computer-readable format copy of the Sequence Listing (file name: DECP_073_00US_SeqList_ST25.txt, recording date: May 30, 2017, file size 24 kilobytes).

[0002] The present disclosure relates to the use of 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea or 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea in the treatment of cancer. Specifically, the present disclosure aims at a method of inhibiting PDGFR kinase and a method of treating cancers and disorders associated with the inhibition of PDGFR kinase, including adenocarcinoma of the lung, squamous cell lung cancer, glioblastoma, pediatric glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor (GIST), malignant peripheral nerve sheath sarcoma, endometrial sarcoma, hypereosinophilic syndrome, eosinophilia associated acute myeloid leukemia, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, or lymphoblastic T cell lymphoma.

Background Art

[0003] Carcinogenic genomic changes of PDGFRα kinase, or overexpression of PDGFRα kinase, have been shown to cause human cancers.

[0004] Missense mutations of the PDGFRα kinase have also been shown to cause a GIST subgroup. Mutations of PDGFRα are the inducing factors of carcinogenesis in approximately 8-10% of GISTs (Corless, Modern Pathology 2014;27:Sl-16). The dominant mutation of PDGFRα is exon 18 D842V, but other exon 18 mutations including D846Y, N848K, and Y849K, as well as exon 18 insertion-deletion mutations (INDELs) including RD841-842KI, DI842-843-IM, and HDSN845-848P have also been reported. Furthermore, rare mutations have also been reported in exons 12 and 14 of PDGFRα (Corless et al, J Clinical Oncology 2005;23:5357-64).

[0005] Deletion mutations of exons 18 of PDGFRα, ΔD842-H845 and ΔI843-D846, have been reported in GIST (Lasota et al, Laboratory Investigation 2004;84:874-83).

[0006] Amplification or mutation of PDGRFα has also been reported in human tissues of malignant peripheral nerve sheath tumors (MPNST) (Holtkamp et al, Carcinogenesis 2006;27:664-71).

[0007] Amplification of PDGFRα has been reported in multiple skin lesions of undifferentiated pleomorphic sarcoma (Osio et al, J.Cutan Pathol 2017;44:477-79) and intimal sarcoma (Zhao et a l, Genes Chromosomes and Cancer,2002;34:48-57; Dewaele et al, Cancer Res 2010;70:7304-14). Amplification of PDGFRα has been associated with a subset of lung cancer patients. 4q12 contains the gene locus of PDGFRα and is amplified in 3 - 7% of lung adenocarcinomas and 8 - 10% of lung squamous cell carcinomas (Ramos et al, Cancer Biol Ther. 2009;8:2042---50; Heist et al, J Thorac Oncol. 2012;7:924 - 33).

[0008] Mutations in IDH proteins produce a new oncometabolite, 2 - hydroxyglutarate, which interferes with iron - dependent hydroxylases, including the TET family of 5’-methylcytosine hydroxylases. TET enzymes catalyze an important step in the removal of DNA methylation. Flavahan et al. showed that human IDH - mutant gliomas exhibit hypermethylation at the binding sites of DNA cohesin and CCCTC - binding factor (CTCF), thereby impairing the binding of this methylation - sensitive insulator protein (Flavahan et al., Nature 2016;529:110). A decrease in CTCF binding has been associated with the loss of insulation between topological domains and abnormal gene activation. Specifically, the disappearance of CTCF at domain boundaries allows structural enhancers to interact abnormally with PDGFRA, a receptor tyrosine kinase gene that is an important glioma oncogene. Therefore, IDH - mutated cancers may be prone to mediate oncogenic events through the activation and overexpression of wild - type PDGFRα.

[0009] PDGFRα amplification is common in pediatric and adult high - grade astrocytomas and identifies a poor - prognosis group in IDH1 - mutant glioblastomas. PDGFRα amplification was frequent in pediatric (29.3%) and adult (20.9%) tumors. PDGFRα amplification has been reported to be associated with grade elevation and, in particular, a poor prognosis in IDH1 - mutant de novo GBM (Phillips et al, Brain Pathology, 2013;23:565 - 73).

[0010] The PDGFRα locus in this PDGFRα-amplified glioma has been shown to exhibit an intragenic deletion rearrangement of exons 8 and 9 of PDGFRα. This intragenic deletion is prevalent and present in 40% of glioblastoma multiforme (GBM) tumors that exhibit PDGFRα amplification. Tumors with this rearrangement exhibit histological features of oligodendroglioma, and the intragenic deletion of PDGFRα exons 8 and 9 has been shown to exhibit increased structural tyrosine kinase activity (Ozawa et al, Genes and Development 2010;24:2205-18).

[0011] The FIP1L1-PDGFRA fusion protein is oncogenic in a subset of patients with hypereosinophilic syndrome (Elling et al, Blood 2011;117;2935). The FIP1L1-PDGFRα fusion has also been identified in eosinophilic acute myeloid leukemia and lymphoblastic T-cell lymphoma (Metzgeroth et al, Leukemia 2007;21:1183-88).

[0012] In summary, mutations, deletions, rearrangements, and amplifications of the PDGFRα gene have been associated with many solid and hematological cancers. Given the complex function of the PDGFRα gene and the potential utility of PDGFRα inhibitors in the treatment of various solid and hematological cancers, there is a need for inhibitors with good therapeutic performance.

Summary of the Invention

[0013] One aspect of the present invention relates to a method of treating or preventing PDGFR kinase-mediated tumor growth or tumor progression, the method comprising administering to a patient in need thereof an effective amount of 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea or a pharmaceutically acceptable salt thereof.

[0014] Another aspect of the present invention is directed to a method of inhibiting PDGFR kinase, the method comprising administering to a patient in need thereof an effective amount of 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea or a pharmaceutically acceptable salt thereof.

[0015] Another aspect of the present invention relates to a method of inhibiting PDGFR kinase, or a method of treating PDGFR kinase-mediated tumor growth or tumor progression. The method comprises administering to a patient in need thereof an effective amount of 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea or a pharmaceutically acceptable salt thereof, either as a single agent or in combination with another cancer target therapeutic agent, cancer target biologic, immune checkpoint inhibitor, or chemotherapeutic agent.

[0016] Yet another aspect of the present invention provides a method of treating glioblastoma, the method comprising administering to a patient in need thereof an effective amount of 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea or a pharmaceutically acceptable salt thereof.

[0017] Another aspect of the present invention relates to a method of treating PDGFRα-mediated gastrointestinal stromal tumor, the method comprising administering to a patient in need thereof an effective amount of 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea or a pharmaceutically acceptable salt thereof.

[0018] Another aspect of the present invention relates to a method for treating or preventing PDGFR kinase-mediated tumor growth or tumor progression, the method comprising administering to a patient in need thereof an effective amount of 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea or a pharmaceutically acceptable salt thereof.

[0019] Another aspect of the present invention relates to a method for inhibiting PDGFR kinase, the method comprising administering to a patient in need thereof an effective amount of 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea or a pharmaceutically acceptable salt thereof.

[0020] Another aspect of the present invention relates to a method for inhibiting PDGFR kinase or a method for treating PDGFR kinase-mediated tumor growth or tumor progression. The method comprises administering to a patient in need thereof an effective amount of 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea or a pharmaceutically acceptable salt thereof as a single agent or in combination with other cancer target therapeutic agents, cancer target biologics, immune checkpoint inhibitors, or chemotherapeutic agents.

[0021] Yet another aspect of the present invention provides a method for treating glioblastoma, the method comprising administering to a patient in need thereof an effective amount of 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea or a pharmaceutically acceptable salt thereof.

[0022] Another aspect of the present invention relates to a method for treating PDGFRα-mediated gastrointestinal stromal tumors, the method comprising administering to a patient in need thereof an effective amount of 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea or a pharmaceutically acceptable salt thereof.

[0023] Another aspect of the present invention relates to the in vivo biosynthetic formation of 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea (Compound B) after oral administration of 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea (Compound A).

[0024] The present disclosure aims to provide a method for inhibiting PDGFR kinase and a method for treating cancers and disorders associated with the inhibition of PDGFR kinase, including adenocarcinoma of the lung, squamous cell lung cancer, glioblastoma, pediatric glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath sarcoma, endometrial sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic acute myeloid leukemia, or lymphoblastic T cell lymphoma.

[0025] The present invention also provides a method for inhibiting PDGFRα kinase, an oncogenic missense mutation of PDGFRα, an oncogenic deletion mutation of PDGFRα, an oncogenic rearrangement of the PDGFRα gene that gives rise to a PDGFRα fusion protein, or an oncogenic amplification of the PDGFRα gene.

[0026] The present invention also provides a method of using 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea or 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea.

Brief Description of the Drawings

[0027]

Figure 1A

Figure 1B

Figure 1C

Modes for Carrying Out the Invention

[0028] 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea (Compound A) and 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea (Compound B) unexpectedly exhibit wild-type and oncogenic protein-type P It has been found to inhibit DGFR kinase. The present invention provides a method for treating cancer by inhibiting oncogenic PDGFRα kinase-mediated tumor growth or tumor progression, which method comprises administering to a patient in need thereof an effective amount of 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea, 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea, or a pharmaceutically acceptable salt thereof. Definitions

[0029] As used herein, Compounds A and B refer to 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea, and 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl1)-3-phenylurea. Pharmaceutically acceptable salts, tautomers, hydrates, and solvates of Compounds A and B are also contemplated in the present disclosure. The structures of Compounds A and B are shown below: [Chemical formula] 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea (Compound A) [Chemical formula] 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea (Compound B)

[0030] The manufacturing methods of Compound A and Compound B are disclosed in US8461179B1, the content of which is incorporated herein by reference. The details of the present invention are described in the following attached description. Methods and materials similar to or equivalent to those described herein can be used in the practice or verification of the present invention, but methods and materials as examples are described herein. Other characteristics, objects, and advantages of the present invention will be apparent from the specification and claims. In the specification and the appended claims, unless the context clearly indicates otherwise, the singular form also includes the plural form. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention pertains.

[0031] Throughout this disclosure, various patents, patent applications, and published documents are referenced. The disclosures of these patents, patent applications, and published documents are hereby incorporated by reference in their entirety to further elaborate the state of the art as known to those skilled in the art as of the date of this disclosure. In the event of any inconsistency between those patents, patent applications, and published documents and this disclosure, this disclosure shall prevail.

[0032] For the sake of simplicity, the specific terms employed in this specification, examples, and claims are collected herein. Unless otherwise specified, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by those skilled in the art to which this application pertains. The initial definitions presented for a group or term presented in this disclosure apply to that group or term individually or as part of another group throughout this disclosure, unless otherwise suggested.

[0033] "Pharmaceutically acceptable carrier, diluent or excipient" refers to any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifying agent that has been approved by the United States Food and Drug Administration as being acceptable for use in humans or livestock, but is not limited thereto. "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts.

[0034] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness and properties of the free base, which are neither biological nor otherwise undesirable, and are formed, for example but not limited to, by inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and, for example but not limited to, by organic acids such as acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, borneolic acid, borneol-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0035] "Pharmaceutical composition" refers to a formulation of a medium generally accepted in the art for delivering the compounds of the present invention and biologically active compounds to mammals, such as humans. Thus, such media include all pharmaceutically acceptable carriers, diluents, or excipients.

[0036] "Subjects" or "patients" "in need of treatment" using the compounds of the present disclosure, or "patients in need of PDGFRα inhibition" include patients having diseases and / or conditions that can be treated with the compounds of the present disclosure and obtain beneficial treatment outcomes. Beneficial outcomes include objective responses, prolongation of progression-free survival, improvement in survival, prolongation of stable disease state, and / or reduction in symptom severity or delay in symptom onset. For example, patients in need of treatment are suffering from tumor growth or tumor progression. Such patients include, but are not limited to, those suffering from lung adenocarcinoma, squamous cell lung cancer, glioblastoma, pediatric glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath tumor, endometrial sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic acute myeloid leukemia, or lymphoblastic T cell lymphoma.

[0037] An "effective amount" (or "pharmaceutically effective amount") of a compound disclosed herein, as used herein, is an amount that results in a beneficial clinical outcome of the condition treated with the compound as compared to not being treated. The amount of the compound administered will depend on the degree, severity and type of the disease or condition, the amount of treatment desired, as well as the release characteristics of the pharmaceutical formulation. It will also depend on the health status, size, weight, age, gender and drug tolerance of the subject. Typically, the compound is administered for a sufficient period of time to achieve the desired therapeutic effect.

[0038] The terms "treatment", "treating", and "treatment of" mean, in a patient having "cancer", all interventions of any kind carried out with the intention of preventing the growth of a tumor with which the patient is afflicted and / or of preventing the tumor from progressing with respect to a given treatment, and include, for example, administration of an active compound which reduces, delays, or reverses one or more of the symptoms and delays the progression of the cancer, even if the cancer is not actually eradicated. Treating may also mean curing, ameliorating, or at least partially improving the disorder.

[0039] As defined herein, "cancer" refers to a neoplasm having the ability to invade surrounding tissue and the ability to metastasize (spread to other organs), and which ultimately, if untreated, causes death in the patient. "Cancer" can be a solid tumor or a liquid tumor.

[0040] As used herein, "tumor" refers to a mass. This is a term that can refer to a benign (generally harmless) or malignant (cancerous) growth. Malignant growths can originate from solid organs or bone marrow. The latter often refers to liquid tumors.

[0041] As defined herein, "tumor growth" refers to the growth of a mass caused by genomic modification of the PDGFRα kinase.

[0042] As defined herein, "tumor progression" refers to the tumor growth of an existing PDGFRα-dependent tumor, in which case the tumor growth of the existing mass is caused by further genomic modification of the treatment-resistant PDGFRα kinase.

[0043] One aspect of the present invention relates to a method for treating or preventing PDGFR kinase-mediated tumor growth or tumor progression, the method comprising administering to a patient in need thereof an effective amount of 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea (Compound A) or a pharmaceutically acceptable salt thereof.

[0044] In one embodiment, compound A or a pharmaceutically acceptable salt thereof is administered to a cancer patient, wherein tumor growth or tumor progression is caused by overexpression of PDGFRα kinase, oncogenic missense mutations of PDGFRα, oncogenic deletion mutations of PDGFRα, oncogenic rearrangements of the PDGFRα gene that give rise to PDGFRα fusion proteins, in-frame deletions within the gene of PDGFRα, and / or oncogenic gene amplifications of PDGFRα. In one embodiment, tumor growth or tumor progression is caused by overexpression of PDGFRα kinase. In another embodiment, tumor growth or tumor progression is caused by an oncogenic missense mutation of PDGFRα. In another embodiment, tumor growth or tumor progression is caused by an oncogenic deletion mutation of PDGFRα. In another embodiment, tumor growth or tumor progression is caused by an oncogenic gene rearrangement of PDGFRα that gives rise to a PDGFRα fusion protein. In another embodiment, tumor growth or tumor progression is caused by an in-frame deletion within the gene of PDGFRα. In another embodiment, tumor growth or tumor progression is caused by an oncogenic gene amplification of PDGFRα.

[0045] In another embodiment, compound A or a pharmaceutically acceptable salt thereof is administered to a cancer patient, wherein tumor growth or tumor progression is caused by D842V mutant PDGFRα, V561D mutant PDGFRα, exon 18 deletion mutant PDGFRα including 842-845 deletion mutant PDGFRα, in-frame deletion mutant PDGFRα of exons 8 and 9, PDGFRα fusion including FIP1L1-PDGFRα or PDGFRα amplification.

[0046] In another embodiment, compound A or a pharmaceutically acceptable salt thereof is administered to a cancer patient, wherein the cancer is adenocarcinoma of the lung, squamous cell lung cancer, glioblastoma, pediatric glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath sarcoma, endometrial sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic acute myeloid leukemia, or lymphoblastic T-cell lymphoma. In one embodiment, the cancer is glioblastoma. In another embodiment, the cancer is a gastrointestinal stromal tumor.

[0047] In another embodiment, compound A or a pharmaceutically acceptable salt thereof is administered to a cancer patient as a single agent or in combination with another cancer targeting therapeutic agent, cancer targeting biologic agent, immune checkpoint inhibitor, or chemotherapeutic agent.

[0048] Another aspect of the present invention relates to a method of treating or preventing PDGFR kinase-mediated tumor growth or tumor progression, the method comprising administering to a patient in need thereof an effective amount of 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea (compound B) or a pharmaceutically acceptable salt thereof.

[0049] In one embodiment, compound B or a pharmaceutically acceptable salt thereof is administered to a cancer patient, wherein tumor growth or tumor progression is caused by overexpression of PDGFRα kinase, oncogenic missense mutations of PDGFRα, oncogenic deletion mutations of PDGFRα, oncogenic rearrangement of the PDGFRα gene that gives rise to a PDGFRα fusion protein, in-frame deletion within the gene of PDGFRα, and / or oncogenic gene amplification of PDGFRα. In one embodiment, tumor growth or tumor progression is caused by overexpression of PDGFRα kinase. In another embodiment, tumor growth or tumor progression is caused by an oncogenic missense mutation of PDGFRα. In another embodiment, tumor growth or tumor progression is caused by an oncogenic deletion mutation of PDGFRα. In another embodiment, tumor growth or tumor progression is caused by an oncogenic gene rearrangement of PDGFRα that gives rise to a PDGFRα fusion protein. In another embodiment, tumor growth or tumor progression is caused by an in-frame deletion within the gene of PDGFRα. In another embodiment, tumor growth or tumor progression is caused by oncogenic gene amplification of PDGFRα.

[0050] In another embodiment, compound B or a pharmaceutically acceptable salt thereof is administered to a cancer patient, wherein tumor growth or tumor progression is caused by D842V mutant PDGFRα, V561D mutant PDGFRα, exon 18 deletion mutant PDGFRα including 842-845 deletion mutant PDGFRα, in-frame deletion mutant PDGFRα of exons 8 and 9, PDGFRα fusion including FIP1L1-PDGFRα or PDGFRα amplification.

[0051] In another embodiment, compound B or a pharmaceutically acceptable salt thereof is administered to a cancer patient, where the cancer is adenocarcinoma of the lung, squamous cell lung cancer, glioblastoma, pediatric glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath tumor, endometrial sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic acute myeloid leukemia, or lymphoblastic T cell lymphoma. In one embodiment, the cancer is glioblastoma. In another embodiment, the cancer is a gastrointestinal stromal tumor. In another embodiment, compound B or a pharmaceutically acceptable salt thereof is administered to a cancer patient as a single agent or in combination with other cancer target therapeutic agents, cancer target biologics, immune checkpoint inhibitors, or chemotherapeutic agents. Pharmaceutical composition and treatment method

[0052] It should be noted that the present disclosure is also directed to a method of treatment comprising administration of a compound of the present disclosure or a pharmaceutical composition comprising such a compound. The pharmaceutical compositions or pharmaceutical preparations described herein can be used in accordance with the present disclosure for the treatment of various cancers, including adenocarcinoma of the lung, squamous cell lung cancer, glioblastoma, pediatric glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath tumor, endometrial sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic acute myeloid leukemia, or lymphoblastic T cell lymphoma.

[0053] The compounds utilized in the methods of treatment of the present disclosure, as well as the pharmaceutical compositions comprising such compounds, may be appropriately administered alone or as part of a treatment protocol or treatment regimen that includes the administration or use of other beneficial compounds (further detailed elsewhere in this specification).

[0054] In some embodiments, the present invention relates to a method of using a pharmaceutical composition containing a pharmaceutically acceptable carrier comprising compound A or B, and one or more additional therapeutic agents. The additional therapeutic agents include, but are not limited to, the cytotoxic agents cisplatin, doxorubicin, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, lonafarnib, tipifarnib, 4-((5-((4-(3-chlorophenyl)-3-oxopiperazin-1-yl)methyl)-1H-imidazol-1-yl)methyl)benzonitrile hydrochloride, (R)-1-((1H-imidazol-5-yl)methyl)-3-benzyl-4-(thiophen-2-ylsulfonyl)-2,3,4,5-tetrahydro-1H-benzodiazepine-7-carbonitrile, cetuximab, imatinib, interferon alpha-2b, pegylated interferon alpha-2b, aromatase combination, gemcitabine, uracil mustard, chloromethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, leucovorin, oxaliplatin, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mitomycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17α-ethinyl estradiol, diethylstil Lubestrol, Testosterone, Prednisone, Fluoxymesterone, Drostanolone Propionate, Testolactone, Megestrol Acetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, 17α-Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesterone Acetate, Leuprolide Acetate, Flutamide, Toremifene Citrate, Goserelin Acetate, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Vinorelbine, Anastrozole, Letrozole, Capecitabine, Raloxifene, Droloxafine, Hexamethylmelamine, Bevacizumab, Trastuzumab, Tositumomab, Bortezomib, Ibritumomab Tiuxetan, Arsenic Trioxide, Porfimer Sodium, Cetuximab, Thiotepa, Altretamine, Fulvestrant, Exemestane, Rituximab, Alemtuzumab, Dexamethasone, Bicalutamide, Chlorambucil, and Valrubicin are mentioned.

[0055] In other embodiments, the invention relates to a method of using a pharmaceutical composition comprising a pharmaceutically acceptable carrier containing compound A or B, and one or more additional therapeutic agents. The additional therapeutic agents include, but are not limited to, AKT inhibitors, alkylating agents, all-trans retinoic acid, anti-androgens, azacitidine, BCL2 inhibitors, BCL-XL inhibitors, BCR-ABL inhibitors, BTK inhibitors, BTK / LCK / LYN inhibitors, CDK1 / 2 / 4 / 6 / 7 / 9 inhibitors, CDK4 / 6 inhibitors, CDK9 inhibitors, CBP / p300 inhibitors, EGFR inhibitors, endothelin receptor antagonists, ERK inhibitors, farnesyltransferase inhibitors, FLT3 inhibitors, glucocorticoid receptor agonists, HDM2 inhibitors, histone deacetylase inhibitors, IKKβ inhibitors, immunomodulatory agents (IMiDs), ingenol, ITK inhibitors, JAK1 / JAK2 / JAK3 / TYK2 inhibitors, MEK inhibitors, such as, but not limited to, trametinib, selumetinib and cobimetinib, midostaurin, mTOR inhibitors, PI3 kinase inhibitors, dual PI3 kinase / mTOR inhibitors, proteasome inhibitors, protein kinase C agonists, SUV39H1 inhibitors, TRAIL, VEGFR2 inhibitors, Wnt / β-catenin signaling inhibitors, decitabine, and anti-CD20 monoclonal antibodies.

[0056] In other embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of Compound A or Compound B and one or more additional therapeutic agents in a pharmaceutically acceptable carrier, wherein the additional therapeutic agent is an immune checkpoint inhibitor, and a CTLA4 inhibitor such as, but not limited to, ipilimumab and tremelimumab; a PD1 inhibitor such as, but not limited to, pembrolizumab and nivolumab; a PDL1 inhibitor such as, but not limited to, atezolizumab (previously MPDL3280A), MEDI4736, avelumab, PDR001; an inhibitor of 4-1BB or 4-1BB ligand such as, but not limited to, urelumab and PF-05082566; an rOX40 ligand agonist such as, but not limited to, MEDI6469; a GITR inhibitor such as, but not limited to, TRX518; a CD27 inhibitor such as, but not limited to, balstilimab; a TNFRSF25 or TL1A inhibitor; a CD40 agonist such as, but not limited to, CP-870893; an inhibitor of HVEM or LIGHT or LTA or BTLA or CD160; a LAG3 inhibitor such as, but not limited to, BMS-986016; a TIM3 inhibitor; a Siglecs inhibitor; an agonist of ICOS or ICOS ligand; a B7-H3 inhibitor such as, but not limited to, MGA271; a B7-H4 inhibitor; a VISTA inhibitor; an HHLA2 or TMIGD2 inhibitor; an inhibitor of butyrophilins including a BTNL2 inhibitor; an inhibitor of CD244 or CD48; an inhibitor of family members of TIGIT and PVR; a KIR inhibitor such as, but not limited to, lirilumab; an inhibitor of ILT and LIR; an inhibitor of NKG2D and NKG2A such as, but not limited to, IPH2201; an inhibitor of MICA and MICB; a CD244 inhibitor; CSF1R Inhibitors, such as, but not limited to, emactuzumab, cabiralizumab, pexidartinib, ARRY382, BLZ945; IDO inhibitors, such as, but not limited to, INCB024360; TGFβ inhibitors, such as, but not limited to, galunisertib; inhibitors of adenosine or CD39 or CD73; inhibitors of CXCR4 or CXCL12, such as, but not limited to, ulocuplumab and (3S,6S,9S,12R,17R,20S,23S,26S,29S,34aS)-N-((S)-1-amino-5-guanidino-1-oxopentan-2-yl)-26,29-bis(4-aminobutyl)-17-((S)-2-((S)-2-((S)-2-(4-fluorobenzamide)-5-guanidinopentanamide)-5-guanidinopentanamide)-3-(naphthalen-2-yl)propanamide)-6-(3-guanidinopropyl)-3,20-bis(4-hydroxybenzyl)-1,4,7,10,18,21,24,27,30-nonaoxo-9,23-bis(3-ureidopropyl)triacontahydro-1H,16H-pyrrolo[2,1-p][1,2]dithia[5,8,11,14,17,20,23,26,29]nonaazacyclodotriacontin-12-carboxamide BKT140; phosphatidylserine inhibitors, such as, but not limited to, bavituximab; SIRPA or CD47 inhibitors, such as, but not limited to, CC-90002; VEGF inhibitors, such as, but not limited to, bevacizumab; and neuropilin inhibitors, such as, but not limited to, MNRP1685A, are selected from the group consisting of.

[0057] In the use of the pharmaceutical compositions of the compounds described herein, the pharmaceutically acceptable carrier can be either solid or liquid. Solid forms include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Powders and tablets may consist of about 5 to about 95 percent active ingredient. Suitable solid carriers are well known in the art. Examples are magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and of methods for manufacturing various compositions can be found in A. Gennaro (ed.), Remington’s Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa, which is hereby incorporated by reference in its entirety.

[0058] Preparations in liquid form include solutions, suspensions and emulsions. For example, for parenteral injection, water or water-propylene glycol solutions, or for oral solutions, suspensions and emulsions, such as the addition of sweetening and opacifying agents. Preparations in liquid form also include solutions for nasal administration.

[0059] Liquids, particularly injection compositions, can be prepared, for example, by dissolution, dispersion, etc. For example, the disclosed compounds are dissolved or mixed in a pharmaceutically acceptable solvent such as water, physiological saline, aqueous dextrose, glycerol, ethanol, etc., thereby forming an isotonic solution or suspension for injection. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

[0060] Parenteral injection administration is generally used for subcutaneous injection, intramuscular injection, or intravenous injection and infusion. The injectable substance can be prepared in either solution or suspension, or in the conventional form of a solid suitable for dissolution in a liquid prior to injection.

[0061] Aerosol preparations suitable for inhalation can also be used. These preparations may include solutions and solids in powder form, which may be used in combination with a pharmaceutically acceptable carrier such as an inert compressed gas such as nitrogen.

[0062] Also, for use, solid preparations intended to be converted immediately before use into liquid preparations for either oral or parenteral administration are expected. Such liquid forms include solutions, suspensions and emulsions. As described above, the compounds described herein can be used alone or in combination with other agents. For example, the compounds can be administered together with a cancer target therapeutic agent, a cancer target biologic, an immune checkpoint inhibitor, or a chemotherapeutic agent. In another embodiment, Compound A or Compound B can be used alone or singly. The agents can be administered together with the compounds described herein or sequentially with those compounds in combination therapy. Combination therapy

[0063]

[0064] ​Combination therapy can be achieved by administering two or more agents, in which case each of those agents is formulated and administered separately, or can be achieved by administering two or more agents in a single formulation. Other combinations are also included in combination therapy. For example, two agents can be formulated together and administered in combination with a separate formulation containing a third agent. In combination therapy, two or more agents can be administered simultaneously, but this is not essential. For example, administration of the first agent (or combination of agents) can precede administration of the second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, two or more agents can be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9 weeks or more of each other. In some cases, even longer intervals are possible. In many cases, it is desirable but not essential for two or more agents used in combination therapy to be present in the patient's body simultaneously.

[0065] Combination therapy can also include administration of one or more of the agents used in combination two or more times using the component agents in different orders. For example, if agent X and agent Y are used in combination, they can be administered one or more times in any combination, consecutively. For example, they can be administered in the order of X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc.

[0066] In one embodiment, compound A or compound B is a cytotoxic agent such as cisplatin, doxorubicin, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, lonafarnib, tipifarnib, 4-((5-((4-(3-chlorophenyl)-3-oxopiperazin-1-yl)methyl)-1H-imidazol-1-yl)methyl)benzonitrile hydrochloride, (R)-1-((1H-imidazol-5-yl)methyl)-3-benzyl-4-(thiophen-2-ylsulfonyl)-2,3,4,5-tetrahydro-1H-benzodiazepine-7-carbonitrile, cetuximab, imatinib, interferon alpha-2b, pegylated interferon alpha-2b, aromatase combination, gemcitabine, uracil mustard, chloromethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, leucovorin, oxaliplatin, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mitomycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide, 17α-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone It is administered to a patient in need of treatment in combination with a therapeutic agent selected from nandrolone propionate, tetralone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, 17α-hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide acetate, flutamide, tamoxifen citrate, goserelin acetate, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, vinorelbine, anastrozole, letrozole, capecitabine, raloxifene, droloxafine, hexamethylmelamine, bevacizumab, trastuzumab, tositumomab, bortezomib, ibritumomab tiuxetan, arsenic trioxide, porfimer sodium, cetuximab, thiotepa, altretamine, fulvestrant, exemestane, rituximab, alemtuzumab, dexamethasone, bicalutamide, chlorambucil, and valrubicin.

[0067] In one embodiment, compound A or compound B is a CTLA4 inhibitor, such as but not limited to ipilimumab and tremelimumab; a PD1 inhibitor, such as but not limited to pembrolizumab and nivolumab; a PDL1 inhibitor, such as but not limited to atezolizumab (previously MPDL3280A), MEDI4736, avelumab, PDR001; an inhibitor of 4-1BB or 4-1BB ligand, such as but not limited to urelumab and PF-05082566; an OX40 ligand agonist, such as but not limited to MEDI6469; a GITR inhibitor, such as but not limited to TRX518; a CD27 inhibitor, such as but not limited to balstilimab; a TNFRSF25 or TL1A inhibitor; a CD40 ligand agonist, such as but not limited to CP-870893; an inhibitor of HVEM or LIGHT or LTA or BTLA or CD160; a LAG3 inhibitor, such as but not limited to BMS-986016; a TIM3 inhibitor; a Siglecs inhibitor; an inhibitor of ICOS or ICOS ligand; a B7H3 inhibitor, such as but not limited to MGA271; a B7H4 inhibitor; a VISTA inhibitor; an HHLA2 or TMIGD2 inhibitor; an inhibitor of butyrophilins including BTNL2 inhibitor; an inhibitor of CD244 or CD48; an inhibitor of family members of TIGIT and PVR; a KIR inhibitor, such as but not limited to lirilumab; an inhibitor of ILT and LIR; an inhibitor of NKG2D and NKG2A, such as but not limited to IPH2201; an inhibitor of MICA and MICB; a CD244 inhibitor; a CSF1R inhibitor, such as but not limited to emactuzumab, cabiralizumab, pexidartinib, ARRY382, and BLZ945; an IDO inhibitor, such as but not limited to INCB024360; a TGFβ inhibitor, such as but not limited to galunisertib; an inhibitor of adenosine or CD39 or CD73;An inhibitor of CXCR4 or CXCL12, such as, but not limited to, ulocuplumab and (3S,6S,9S,12R,17R,20S,23S,26S,29S,34aS)-N-((S)-1-amino-5-guanidino-1-oxopentan-2-yl)-26,29-bis(4-aminobutyl)-17-((S)-2-((S)-2-((S)-2-(4-fluorobenzamide)-5-guanidinopentanamide)-5-guanidinopentanamide)-3-(naphthalen-2-yl)propanamide)-6-(3-guanidinopropyl)-3,20-bis(4-hydroxybenzyl)-1,4,7,10,18,21,24,27,30-nonaoxo-9,23-bis(3-ureidopropyl)triacontahydro-1H,16H-pyrrolo[2,1-p][1,2]dithia[5,8,11,14,17,20,23,26,29]nonaazacyclodotriacontin-12-carboxamide BKT140; a phosphatidylserine inhibitor, such as, but not limited to, bavituximab; a SIRPA or CD47 inhibitor, such as, but not limited to, CC-90002; a VEGF inhibitor, such as, but not limited to, bevacizumab; or a neuropilin inhibitor, such as, but not limited to, MNRP1685A, is administered to a patient in need of treatment in combination with an immune checkpoint inhibitor selected from these.;

[0068] According to another embodiment of the present invention, an additional therapeutic agent can be used in combination with Compound A or Compound B. These agents include, but are not limited to, AKT inhibitors, alkylating agents, all-trans retinoic acid, anti-androgens, azacitidine, BCL2 inhibitors, BCL-XL inhibitors, BCR-ABL inhibitors, BTK inhibitors, BTK / LCK / LYN inhibitors, CDK1 / 2 / 4 / 6 / 7 / 9 inhibitors, CDK4 / 6 inhibitors, CDK9 inhibitors, CBP / p300 inhibitors, EGFR inhibitors, endothelin receptor antagonists, ERK inhibitors, farnesyltransferase inhibitors, FLT3 inhibitors, glucocorticoid receptor agonists, HDM2 inhibitors, histone deacetylase inhibitors, IKKβ inhibitors, immunomodulatory agents (IMiDs), ingenol, ionizing radiation, ITK inhibitors, JAK1 / JAK2 / JAK3 / TYK2 inhibitors, MEK inhibitors, such as, but not limited to, trametinib, selumetinib, and cobimetinib, midostaurin, MTOR inhibitors, PI3 kinase inhibitors, dual PI3 kinase / MTOR inhibitors, proteasome inhibitors, protein kinase C agonists, SUV39H1 inhibitors, TRAIL, VEGFR2 inhibitors, Wnt / β-catenin signaling inhibitors, decitabine, and anti-CD20 monoclonal antibodies. Dosage

[0069] In some embodiments where Compound A or Compound B is used in combination with other agents with respect to a treatment protocol, the compositions may be administered together or may be administered in a "dual regimen", in which case the two therapeutic agents are taken and administered separately. When Compound A or B and the additional agent are dosed separately, typical dosages administered to a subject in need of treatment are typically from about 5 mg / day to about 5000 mg / day, and in other embodiments, from about 50 mg / day to about 1000 mg / day. Other dosages may be from about 10 mmol to a maximum of about 250 mmol / day, from about 20 mmol to about 70 mmol / day, or from about 30 mmol to about 60 mmol / day.

[0070] The amount and frequency of administration of the compounds of the present invention and / or their pharmaceutically acceptable salts will be controlled according to the judgment of the attending physician, taking into account factors such as the age, condition and size of the patient, and the severity of the condition being treated. An effective dosage of the disclosed compounds, when used for the specified effect, will range from about 0.5 mg to about 5000 mg of the disclosed compounds, depending on the need for treatment of the condition. Compositions for use in vivo or in vitro can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compounds, or can contain a range of the disclosed compounds from one amount in the list of dosages to another amount. With respect to oral administration, a typical recommended daily dosage regimen can be in the range of about 1 mg / day to about 500 mg / day or 1 mg / day to 200 mg / day, in one dose or in two to four divided doses. In one embodiment, a typical daily dosage regimen is 150 mg.

[0071] The disclosed compounds can be administered by any suitable route, with or without the additional agents described herein. The compounds can be administered orally (e.g., with food) in capsules, suspensions, tablets, pills, dragees, liquids, gels, syrups, slurries, etc. Methods for encapsulating the compositions (such as coatings of hard gelatin or cyclodextrin) are known in the art (Baker, et al, “Controlled Release of Biological Active Agents”, John Wiley and Sons, 1986, which is incorporated herein by reference in its entirety). The compounds can be administered to a subject in conjunction with a pharmaceutically acceptable carrier that is acceptable as part of a pharmaceutical composition. The formulation of the pharmaceutical composition will vary according to the selected route of administration. Suitable pharmaceutical carriers can include inert ingredients that do not interact with the compounds. The carrier is biocompatible i.e., non-toxic, non-inflammatory, non-immunogenic, and does not produce other undesirable reactions at the site of administration.

[0072] Exemplary pharmaceutical compositions include the compounds of the present invention and pharmaceutically acceptable carriers, such as a) diluents, such as purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oils or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, such as EPA or DHA, or their esters, triglycerides or mixtures, omega-3 fatty acids or their derivatives, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; also for tablets; c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural gums and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, if desired; d) disintegrants, such as starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or foaming mixtures; e) absorbents, colorants, flavorants and sweeteners; f) emulsifiers or dispersants, such as Tween80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifiers; and / or; g) agents that enhance the absorption of compounds such as cyclodextrin, hydroxypropyl cyclodextrin, PEG400, PEG200, etc., and are tablets and gelatin capsules containing them.

[0073] When formulated as a fixed dosage, such combination products use the compounds of the invention within the dosage ranges described herein or known to those of skill in the art.

[0074] Since the compounds of the invention (Compound A and Compound B) are intended for use in pharmaceutical compositions, those skilled in the art will understand that they can be provided in a substantially pure form, for example, in a form that is at least 60% pure, at least 75% pure, at least 85% pure, and at least 98% pure (w / w). The pharmaceutical preparation may be in unit dosage form. In such form, the preparation is divided into unit dosages of appropriate size containing an appropriate amount of Compound A or Compound B, such as an effective amount to achieve the desired objectives described herein. Section 1 - Comparison of important structures for biological activity using WO / 2008 / 034008 and WO / 2013 / 184119.

[0075] WO / 2008 / 034008 describes various kinases that cause or are involved in the pathogenesis of various proliferative diseases, and these kinases include BRaf, CRaf, Abl, KDR (VEGFR2), EGFR / HER1, HER2, HER3, c-MET, FLT-3, PDGFR-α, PDGFR-β, p38, c-KIT, JAK2 family. The disclosure of this PCT application clearly shows selective inhibition against Braf and CRaf kinases using analogs of Compound A and Compound B described herein. At the same time, WO / 2013 / 184119 describes the inhibition of mutant c-KIT using Compounds A and B. However, WO / 2013 / 184119 states that mutations in c-KIT and PDGFRα are mutually exclusive in GIST It also describes that this is because most GISTs have primary activating mutations in genes encoding closely related RTKs c-KIT (75 - 80% of GISTs) or PDGFRα (8% of non-c-KIT mutant GISTs) in a mutually exclusive manner.

[0076] In the present application, it has been found that the inevitable mutual exclusivity between c-KIT and PDGFRα mutations in GIST patients is reconciled, and compounds A and B can treat both patient groups. Indeed, it was unexpected that compounds A and B, which are known to inhibit c-KIT mutants, also inhibit wild-type and oncogenic mutant PDGFR kinases, oncogenic fusion protein-type PDGFRα kinases, and cancers of the PDGFRα amplification type, which was the exact opposite of the past disclosure contents of WO / 2008 / 034008 and WO / 2013 / 184119. The experimental data described below further reinforce this discovery. The direct application of this discovery is the treatment of resistant-type cancers described herein and cancer patient subgroups of the PDGFR-induced type.

Examples

[0077] Biological data It was an unexpected discovery that compounds A and B inhibit wild-type and oncogenic mutant PDGFR kinases, oncogenic fusion protein-type PDGFRα kinases, and cancers of the PDGFRα mutant or amplification type. The analysis of this unexpected discovery was conducted in biochemical assays, cell assays, and in vivo clinical evaluations in cancer patients.

[0078] The present disclosure is further illustrated by the following examples, which are not to be construed as limiting the disclosure in scope or spirit with respect to the specific procedures described herein. The examples are presented to illustrate specific embodiments, and it should be understood that there is no intention to limit the scope of the present disclosure by the examples. Furthermore, it should be understood that various other embodiments, modifications, and equivalents that may be suggested to those skilled in the art without departing from the spirit of the present disclosure and / or the scope of the appended claims are reclassified. Example 1. Inhibition of the Enzyme Activity of Wild-Type PDGFRα Biochemical Assay against PDGFRα (GenBank Accession Number NP_006197)

[0079] The activity of the PDGFRα kinase was determined spectroscopically using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al. Science (2000) 289:1938-1942, which is incorporated herein by reference in its entirety). The assay was performed in a 384-well plate using an assay buffer (90 mM Tris, pH 7.5, 18 mM MgCl2, 1 mM DTT, and 0.2% octyl-glucoside) solution of 4.8 nM PDGFRA (Decode Biostructure, Bainbridge Island, WA), 5 units of pyruvate kinase, 7 units of lactate dehydrogenase, 1 mM phosphoenolpyruvate, 0.28 mM NADH, 2.5 mg / mL PolyEY, and 0.5 mM ATP (final volume was 100 μL). Inhibition of PDGFRA was measured after addition of serially diluted test compounds (final assay concentration of 1% DMSO). The decrease in absorption at 340 nm on a multimode microplate reader (BioTek, Winooski, VT) was continuously monitored at 30 °C for 6 hours. The reaction rate was calculated using a time frame of 1-2 hours. The reaction rate at each concentration of the compound was converted to an inhibition percentage using a control (i.e., reaction without the test compound and reaction with a known inhibitor). IC50 The value was calculated by fitting a four-parameter S-shaped curve to the data using Prism (GraphPad, San Diego, California). Protein sequence of PDGFRα (residues 550 - 1089. GST tag attached to the N-terminus; Genbank accession number 1). [Chemical Structure]

[0080] Compound A inhibited the enzymatic activity of recombinant wild-type PDGFRα at an IC 50 value of 12 nM. Compound B inhibited the enzymatic activity of recombinant wild-type PDGFRα at an IC 50 value of 6 nM. Example 2. Inhibition of the enzymatic activity of D842V mutant PDGFRα Biochemical assay against PDGFRα D842V (GenBank accession number NP_006197)

[0081] The activity of the PDGFRα D842V kinase was determined spectroscopically using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al. Science (2000) 289:1938-1942, which is incorporated herein by reference in its entirety). The assay was performed in 384-well plates (final volume 100 μL) using an assay buffer (90 mM Tris, pH 7.5, 18 mM MgCl2, 1 mM DTT and 0.2% octyl-glucoside) solution of 3 nM PDGFRA D842V (Invitrogen, Carlsbad, CA), 5 units of pyruvate kinase, 7 units of lactate dehydrogenase, 1 mM phosphoenolpyruvate, 0.28 mM NADH, 2.5 mg / mL PolyEY and 0.5 mM ATP. Inhibition of PDGFRA D842V was measured after addition of serially diluted test compounds (final assay concentration of 1% DMSO). Decreases in absorption at 340 nm were continuously monitored at 30 °C for 6 hours on a multimode microplate reader (BioTek, Winooski, VT). Reaction rates were calculated using a time frame of 2-3 hours. The reaction rate at each concentration of the compound was converted to a percentage of inhibition using controls (i.e., reactions without test compound and reactions with known inhibitors). IC 50 values were calculated by fitting a 4-parameter sigmoidal curve to the data using Prism (GraphPad, San Diego, CA). The protein sequence of PDGFRα D842V (residues 550-1089. HIS-GST tag attached to the N-terminus; Genbank accession number 2).

Chemical formula

[0082] Compound A inhibited the enzymatic activity of recombinant D842V mutant PDGFRα with an IC50 value of 42 nM. Compound B inhibited the enzymatic activity of recombinant D842V mutant PDGFRα with an IC50 inhibited by the value. Example 3. Inhibition of the Enzyme Activity of Wild-Type PDGFRβ Biochemical assay against PDGFRB (GenBank accession number NP_002600)

[0083] The activity of PDGFRβ kinase was determined spectroscopically using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al. Science (2000) 289:1938 - 1942, which is incorporated herein by reference in its entirety). The assay was performed in a 384-well plate using an assay buffer (90 mM Tris, pH 7.5, 18 mM MgCl2, 1 mM DTT, and 0.2% octyl-glucoside) solution of 9 nM PDGFRB (Decode Biostructure, Bainbridge Island, WA), 5 units of pyruvate kinase, 7 units of lactate dehydrogenase, 1 mM phosphoenolpyruvate, 0.28 mM NADH, 2.5 mg / mL PolyEY and 0.5 mM ATP (final volume 100 μL). Inhibition of PDGFRB was measured after addition of serially diluted test compounds (final assay concentration of 1% DMSO). The decrease in absorption at 340 nm was continuously monitored at 30 °C for 6 hours on a multimode microplate reader (BioTek, Winooski, VT). The reaction rate was calculated using a time frame of 2 - 3 hours. The reaction rate at each concentration of the compound was converted to an inhibition percentage using a control (i.e., reaction without the test compound and reaction with a known inhibitor). IC 50 values were calculated by fitting a four-parameter sigmoidal curve to the data using Prism (GraphPad, San Diego, CA). The protein sequence of PDGFRβ (residues 557 - 1106. HIS-GST-tag attached to the N-terminus; Genbank accession number 3)

Chemical formula

[0084] Compound A inhibited the enzymatic activity of recombinant wild-type PDGFRβ at an IC 50 value of 9 nM. Compound B inhibited the enzymatic activity of recombinant wild-type PDGFRβ at an IC 50 value of 5 nM. Example 4. Growth Inhibition of D842V Mutant PDGFRα Expressed in Ba / F3 Cells Cell Culture of BaF3 PDGFRα D842V

[0085] BaF3 cells were transfected with a construct encoding D842V PDGFRα and selected for IL-3 independence. Briefly, cells were grown in RPMI 1640 medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 1 unit / mL penicillin G, 1 μg / mL streptomycin, and 0.29 mg / mL L-glutamine at 37 °C, 5% CO2, and 95% humidity. Cell Proliferation Assay of BaF3 PDGFRα D842V

[0086] Serial dilutions of the test compound were dispensed into 96-well black clear-bottom plates (Corning, Corning, NY). 10,000 cells per well were added in 200 μL of complete growth medium. The plates were incubated at 37 °C, 5% CO2, and 95% humidity for 67 hours. At the end of the incubation period, 40 μL of a PBS solution of 440 μM resazurin (Sigma, St. Louis, MO) was added to each well and the plates were incubated for an additional 5 hours at 37 °C, 5% CO2, and 95% humidity. The plates were read on a Synergy2 reader (Biotek, Winooski, VT) using excitation at 540 nm and emission at 600 nm. Data were analyzed using Prism software (GraphPad, San Diego, CA) to calculate the IC 50 values.

[0087] Compound A inhibited the growth of D842V mutant PDGFRα BaF3 cells at an IC 50 value of 36 nM. Compound B inhibited the growth of D842V mutant PDGFRα BaF3 cells at an IC 50 value of 42 nM. Example 5. Inhibition of phosphorylation of D842V mutant PDGFRα expressed in BaF3 cells Cell culture of BaF3 PDGFRα D842V

[0088] BaF3 cells were transfected with a construct encoding D842V PDGFRα and selected for IL-3 independence. Briefly, cells were grown in RPMI 1640 medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 1 unit / mL penicillin G, 1 μg / mL streptomycin, and 0.29 mg / mL L-glutamine at 37 °C, 5% CO2, and 95% humidity. BaF3 PDGFRα D842V Western blot

[0089] Cells suspended in serum-free RPMI 1640 medium were added to 24-well tissue culture treatment plates at 2 million cells per well. Serial dilutions of the test compound were added to the plates containing the cells. The plates were incubated for 4 hours at 5% CO2, 95% humidity, and 37 °C. The cells were washed with PBS and then lysed. The cell lysates were separated by SDS-PAGE and transferred to PVDF. Phospho-PDGFRα (Tyr754) was detected using an antibody from Cell Signaling Technology (Beverly, MA), ECL Plus detection reagent (GE Healthcare, Piscataway, NJ), and a Molecular Devices Storm 840 phosphorimager in fluorescence mode. The blot was stripped and probed for total PDGFRα using an antibody from Cell Signaling Technology (Beverly, MA). The IC50 values were calculated using Prism software (GraphPad, San Diego, CA).

[0090] Compound A inhibited the phosphorylation of the D842V mutant PDGFRα expressed in BaF3 cells at an IC 50 value of 24 nM. Compound B inhibited the phosphorylation of the D842V mutant PDGFRα expressed in BaF3 cells at an IC 50 value of 26 nM. Example 6. Inhibition of phosphorylation of V561D mutant PDGFRα expressed in CHO cells Chinese hamster ovary (CHO) cells were transiently transfected with a V561D mutant PDGFRA cDNA construct cloned into the pcDNA3.1 plasmid (Invitrogen, Carlsbad, CA). Twenty-four hours after transfection, the cells were treated with various concentrations of the compound for 90 minutes. Cell-derived protein lysates were prepared, immunoprecipitation was performed using an anti-PDGFRA antibody (SC-20, Santa Cruz Biotechnology, Santa Cruz, CA), and then sequential immunoblotting for phosphotyrosine was performed using a monoclonal antibody (PY-20, BD Transduction Labs, Sparks, MD) or total PDGFRα (SC-20, Santa Cruz Biotechnology, Santa Cruz, CA). Concentration measurements were performed using Photoshop 5.1 software, the drug effect was quantified, and the level of phospho-PDGFRα was normalized to total protein. The results of the concentration measurement experiments were analyzed using Calcusyn 2.1 software (Biosoft, Cambridge, UK), and the IC 50 value was determined mathematically.

[0091] Compound A inhibited the phosphorylation of V561D mutant PDGFR□ expressed in CHO cells at an IC 50 value of 25 nM. Example 7. Inhibition of phosphorylation of exon 18 842-845 deletion mutant PDGFRα expressed in CHO cells

[0092] Chinese hamster ovary (CHO) cells were transfected with the pcDNA3.1 plasmid (Inv The mutant ΔD842-H845 PDGFRA cDNA construct cloned into Nitrogen (Carlsbad, California) was transiently transfected. Twenty-four hours after transfection, cells were treated for 90 minutes with various concentrations of the compounds. Cell-derived protein lysates were prepared and immunoprecipitation was performed using an anti-PDGFRA antibody (SC-20, Santa Cruz Biotechnology, Santa Cruz, California), followed by sequential immunoblotting for phosphotyrosine using a monoclonal antibody (PY-20, BD Transduction Labs, Sparks, Maryland) or total PDGFRα (SC-20, Santa Cruz Biotechnology, Santa Cruz, California). Densitometry was performed using Photoshop5.1 software, and the drug effect was quantified by normalizing the level of phospho-PDGFRA to total protein. The results of the densitometry experiments were analyzed using Calcusyn2.1 software (Biosoft, Cambridge, UK) to mathematically determine the IC 50 value.

[0093] Compound A inhibited the phosphorylation of exon 18 842-845 deletion mutant PDGFRα expressed in CHO cells with an IC 50 value of 77 nM. Example 8. Growth Inhibition of FIP1L1-PDGFRα Fusion in EOL-1 Cells EOL-1 (FIP1L1 / PDGFRα Fusion) Cell Culture

[0094] EOL-1 cells were grown at 37 °C, 5% CO2, 95% humidity in RPMI1640 medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, California), 1 unit / mL penicillin G, 1 μg / mL streptomycin, and 0.29 mg / mL L-glutamine. EOL-1 Cell Growth Assay

[0095] Serial dilutions of the test compound were dispensed into 96-well black clear-bottom plates (Corning, Corning, NY). 10,000 cells per well were added in 200 μL of complete growth medium. The plates were incubated at 37 °C, 5% CO2, 95% humidity for 67 hours. At the end of the incubation period, 40 μL of a PBS solution of 440 μM resazurin (Sigma, St. Louis, MO) was added to each well and the plates were incubated for an additional 5 hours at 37 °C, 5% CO2, 95% humidity. The plates were read on a Synergy2 reader (Biotek, Winooski, VT) using 540 nm excitation and 600 nm emission. Data were analyzed using Prism software (GraphPad, San Diego, CA) to calculate the IC50 value.

[0096] Compound A inhibited the growth of the FIP1L1-PDGFRα fusion in EOL-1 cells with an IC 50 value of 0.029 nM. Compound B inhibited the growth of the FIP1L1-PDGFRα fusion in EOL-1 cells with an IC 50 value of 0.018 nM. Example 9. Inhibition of phosphorylation of FIP1L1-PDGFRα fusion in EOL-1 cells EOL-1 (FIP1L1 / PDGFRα fusion) cell culture

[0097] EOL-1 cells were grown in RPMI 1640 medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 1 unit / mL penicillin G, 1 μg / mL streptomycin, and 0.29 mg / mL L-glutamine at 37 °C, 5% CO2, 95% humidity. EOL-1 Western blot

[0098] Cells suspended in serum-free RPMI 1640 medium were added to 24-well tissue culture treatment plates at 2 million cells per well. Serial dilutions of the test compound were added to the plates containing the cells. The plates were incubated for 4 hours at 5% CO2, 95% humidity, and 37 °C. The cells were washed with PBS and then lysed. The cell lysates were separated by SDS-PAGE and transferred to PVDF. Phospho-PDGFRα (Tyr754) was detected using an antibody from Cell Signaling Technology (Beverly, MA), ECL Plus detection reagent (GE Healthcare, Piscataway, NJ), and a Molecular Devices Storm 840 phosphorimager in fluorescence mode. The blot was stripped and probed for total PDGFRα using an antibody from Cell Signaling Technology (Beverly, MA). The IC50 values were calculated using Prism software (GraphPad, San Diego, CA).

[0099] Compound A inhibited the phosphorylation of the FIP1L1-PDGFRα fusion in EOL-1 cells at an IC 50 value of 0.12 nM. Compound B inhibited the phosphorylation of the FIP1L1-PDGFRα fusion in EOL-1 cells at an IC 50 value of less than 0.1 nM. Example 10. Treatment of Human Cancer Patients with the PDGFRα D842V Mutation

[0100] Clinical trial protocol DCC-2618-01-001 “A Multi-center Phase I Open-label Study to Evaluate Compound A with Respect to Safety, Tolerability, and Pharmacokinetics in Patients with Advanced Malignancies” is the first human trial for Compound A (ClinicalTrials.gov Identifier: NCT02571036). The purpose of this dose-escalation study is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of Compound A. The investigational drug is dosed escalated within the range of 20 mg BID to 200 mg BID and administered orally either once or twice a day. Preliminary anti-tumor activity was measured by CT scan every cycle (every 56 days) according to RECIST 1.1. Pharmacodynamic effects were measured as a decrease in the mutant allele frequency (MAF) in cell-free plasma (cf) DNA and analyzed using the Guardant 360 v2.9 or v2.10 (Guardant Health, Redwood City, CA), a next-generation sequencing panel of 73 genes.

[0101] All patients were assumed to have progressive disease against standard treatment and would progress immediately without treatment. Three patients with PDGFRα-mutated gastrointestinal stromal tumors (GISTs) were enrolled in this study. The PDGFRα D842V mutation was identified in each patient by tumor biopsy. Based on non-clinical data and pharmacokinetic data available from the DCC-2618-01-001 study, a dose level of ≥50 mg BID (total daily dose equal to 100 mg) was sufficient to result in tumor control, i.e., growth arrest in these progressive sarcomas of PDGFRα D842V-mutated tumors in patients with GIST. Of the three evaluable patients, two were enrolled at the target effective dose levels (150 mg QD and 100 mg BID) or above. The other patient was enrolled at 30 mg BID and progressed after two treatment cycles of 28 days. The patient at 100 mg BID is currently on cycle 11 (>40 weeks) and continues to benefit from treatment. The most recent tumor evaluation confirmed "stable disease" according to RECIST 1.1. Tumor evaluations throughout the study included the most recent evaluation after cycle 9 (36 weeks) and revealed some tumor shrinkage (5 - 10%). The patient treated at the 150 mg QD dose level was on cycle 6 (>20 weeks) and ongoing, stable disease by RECIST, with some tumor shrinkage observed. These two patients had each received tyrosine kinase inhibitor therapy 1 and 3 times in the past.

[0102] To date, cfDNA follow-up data on the plasma PDGFRα D842V mutant allele frequency are available only for patients on 100 mg BID. The PDGFRα D842V mutation was not detected by cfDNA at baseline. However, on Day 1 (8 weeks) after Cycle 3 of treatment, a frequency of 0.59% was detected. The non-detection of the D842V mutation at baseline may be due to the limitations of the data interpretation performance. However, the fact that the mutation present in the tumor tissue is "undetectable", i.e., below the detection limit at two consecutive analysis points (Day 1 of Cycle 5 (16 weeks) and Day 1 of Cycle 7 (24 weeks)), strongly supports the suppression of this PDGFRα D842V mutation by treating human cancer patients with Compound A. Example 11. Treatment of human glioblastoma patients with PDGFRα amplification

[0103] The clinical trial protocol DCC-2618-01-001 "A Multicenter Phase I Open-Label Study to Evaluate Compound A with Respect to Safety, Tolerability, and Pharmacokinetics in Patients with Progressive Malignancies" is the first human trial of Compound A (ClinicalTrials.gov Identifier: NCT02571036). The purpose of this dose escalation study is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of Compound A. The investigational drug is dosed escalated within the range of 20 mg BID to 200 mg BID and administered orally either once or twice a day. The preliminary antitumor activity was measured by CT scan every cycle according to the RANO (Revised Assessment in Neuro-Oncology) criteria and then every 3 cycles (every 56 or 84 days). The pharmacodynamic effect was measured as a decrease in circulating tumor cells (CTC). Whole blood was enriched for CTCs in OncoQuick tubes. The CTC layer was incubated with an adenovirus that replicates and expresses GFP in cells with high levels of telomerase (Oncolys BioPharma Inc.). The cells were then incubated with a fluorescently labeled antibody, fixed, and DAPI stained. Cells positive for DAPI, GFP, PDGFRα, and GFAP fluorescence were counted as circulating glioblastoma tumor cells using a BioTek Cytation 5 imaging device. Glial fibrillary acidic protein (GFAP) clearly originates from glial cells.

[0104] All patients were considered to have progressive disease against standard treatment and would progress immediately without treatment. One patient with PDGFRα-amplified glioblastoma (GBM; 6x amplification, 12 copies) was enrolled in this study at a dose level of 20 mg BID. The patient was first treated with a combination of radiotherapy and chemotherapy and then treated with temozolomide alone and progressed after 3 months. The GBM patient is currently ongoing in Cycle 19 (>17 months, during the study) and continues to benefit from the treatment. After tumor evaluation at Cycle 12 (48 weeks), the patient has a "partial response" according to the RANO criteria. Figure 1 shows the MRI scans at baseline (Figure 1A) and after Cycle 12 (Figure 1C). Figure 1B provides additional evidence of tumor reduction after Cycle 9.

[0105] The relevance of PDGFRα amplification was evaluated in high-grade astrocytomas (HGAs), including pediatric and adult glioblastomas. In an initial large-scale study on human tissues, a significant association of HGA with PDGFRα amplification has been proposed, and it has been suggested that PDGFRα amplification is associated with increased grade and poor prognosis in IDH1-mutant de novo GBM (Philips et al., Brain Pathol. (2013) 23(5):565-73, which is incorporated herein by reference in its entirety). Dunn et al. provided additional illumination that PDGFRα amplification is an inducing factor for genomic modification of GBM (Dunn et al., Genes Dev. (2012) 26(8):756-84). Based on these findings, the pharmacodynamic effect measured as a decrease in CTCs observed in GBM patients after treatment with Compound A strongly supports that the partial response observed in GBM patients is the result of treating PDGFRα-amplified tumors with Compound A. Double-positive CTCs (PDGFRα+ / GFAP+) were first measured at Cycle 7 (28 weeks), and the frequency was 2.22 CTC / mL. The frequency decreased to 1.11 and 0.58 CTC / mL at Cycle 13 (52 weeks) and Cycle 17 (68 weeks), respectively. Example 12 Compound B is biosynthetically formed after oral administration of Compound A.

[0106] Clinical trial protocol DCC-2618-01-001 "A multi-center, Phase I, open-label study to evaluate the safety, tolerability, and pharmacokinetics of Compound A in patients with progressive malignancies" is the first human study on Compound A (ClinicalTrials.gov Identifier: NCT02571036). The purpose of this dose-escalation study is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity of Compound A. The investigational drug is dosed escalated within the range of 20 mg BID to 200 mg BID and administered orally either once or twice a day. By orally administering Compound A to patients, systemic exposure of Compound A and in vivo transformation of Compound A to Compound B by in vivo N-demethylation occur. For pharmacokinetic (PK) analysis, blood samples were collected on Day 15 of Cycle 1, immediately before dosing Compound A in the morning, and at 0.5, 1, 2, 4, 6, 8, and 10 - 12 hours after dosing. Compound A and its active metabolite, Compound B, were evaluated using a validated bioanalytical method. Phoenix The plasma concentrations for the time data were analyzed using Phoenix WinNonlin version 6.3, and standard non-compartmental PK parameters were calculated. All PK calculations were completed using the scheduled sample collection times.

[0107] For example, when Compound A is administered to a patient cohort at a dose of 150 mg twice a day or 150 mg once a day, a stable exposure state occurs for both Compound A and Compound B on Day 15 of Cycle 1, as shown in the following table.

[0108] For a cohort of 5 patients, oral administration of compound A at a dose of 150 mg BID (twice daily) for 15 days resulted in exposure to compound A with an average Cmax = 1,500 ng / mL and an average area under the curve (AUC) = 11,400 ng*h / mL. This 15-day administration resulted in in vivo changes to compound B with an average Cmax = 1,520 ng / mL and an average AUC = 15,100 ng*h / mL. For a cohort of 4 patients, oral administration of compound A at a dose of 150 mg QD (once daily) for 15 days resulted in exposure to compound A with an average Cmax = 861 ng / mL and an average area under the curve (AUC) = 8,070 ng*h / mL. This 15-day administration resulted in in vivo changes to compound B with an average Cmax = 794 ng / mL and an average AUC = 8,600 ng*h / mL. Table 1

Table 1

[0109] Equal One of ordinary skill in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific embodiments specifically described herein. Such equivalents are intended to be encompassed in the following claims. Claims at the time of filing 〔Item 1〕 A method of treating or preventing PDGFR kinase-mediated tumor growth or tumor progression, comprising administering to a patient in need thereof an effective amount of 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea or a pharmaceutically acceptable salt thereof. 〔Item 2〕 The method according to claim 1, wherein the tumor growth or tumor progression is caused by one or more of overexpression of PDGFRα kinase, oncogenic missense mutation of PDGFRα, oncogenic deletion mutation of PDGFRα, oncogenic rearrangement of the PDGFRα gene resulting in a PDGFRα fusion protein, in-frame deletion within the PDGFRα gene, or oncogenic gene amplification of PDGFRα. 〔Item 3〕 The method according to claim 1 or 2, wherein the tumor growth or tumor progression is caused by overexpression of PDGFRα kinase. 〔Item 4〕 The method according to claim 1 or 2, wherein the tumor growth or tumor progression is caused by an oncogenic missense mutation of PDGFRα or an oncogenic deletion mutation of PDGFRα. 〔Item 5〕 The method according to claim 1 or 2, wherein the tumor growth or tumor progression is caused by an oncogenic rearrangement of the PDGFRα gene resulting in a PDGFRα fusion protein or an in-frame deletion within the PDGFRα gene. 〔Item 6〕 The method according to claim 1 or 2, wherein the tumor growth or tumor progression is caused by oncogenic gene amplification of PDGFRα. 〔Item 7〕 The method according to any one of claims 1 to 6, wherein the tumor is adenocarcinoma of the lung, squamous cell lung cancer, glioblastoma, pediatric glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath tumor, endometrial sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic acute myeloid leukemia, or lymphoblastic T cell lymphoma. 〔Item 8〕 The method according to any one of claims 1 to 7, wherein the tumor is glioblastoma. 〔Item 9〕 The method according to any one of claims 1 to 7, wherein the tumor is a gastrointestinal stromal tumor. 〔Item 10〕The method according to any one of claims 1 to 9, wherein 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea or a pharmaceutically acceptable salt thereof is administered as a single agent or in combination with another cancer target therapeutic agent, cancer target biologic agent, immune checkpoint inhibitor, or chemotherapeutic agent. [Item 11] The therapeutic agent is a cytotoxic agent such as cisplatin, doxorubicin, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, lonafarnib, tipifarnib, 4-((5-((4-(3-chlorophenyl)-3-oxopiperazin-1-yl)methyl)-1H-imidazol-1-yl)methyl)benzonitrile hydrochloride, (R)-1-((1H-imidazol-5-yl)methyl)-3-benzyl-4-(thiophen-2-ylsulfonyl)-2,3,4,The method according to claim 10, selected from 5-tetrahydro-1H-benzodiazepine-7-carbonitrile, cetuximab, imatinib, interferon alpha-2b, pegylated interferon alpha-2b, combination of aromatase, gemcitabine, uracil mustard, chlorambucil, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, leucovorin, oxaliplatin, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mitomycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17α-ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, drostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, 17α-hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide acetate, flutamide, tamoxifen citrate, goserelin acetate, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, vinorelbine, anastrozole, letrozole, capecitabine, raloxifene, droloxafine, hexamethylmelamine, bevacizumab, trastuzumab, tositumomab, bortezomib, ibritumomab tiuxetan, arsenic trioxide, porfimer sodium, cetuximab, thiotepa, altretamine, fulvestrant, exemestane, rituximab, alemtuzumab, dexamethasone, bicalutamide, chlorambucil, or valrubicin., 〔Item 12〕 The immune checkpoint inhibitor is ipilimumab and tremelimumab which are CTLA4 inhibitors; pembrolizumab and nivolumab which are PD1 inhibitors; atezolizumab (previously MPDL3280A), durvalumab (MEDI4736), avelumab, and PDR001 which is a monoclonal antibody; urelumab and utomilumab (PF05082566) which are 4-1BB ligand inhibitors; monoclonal antibody MEDI6469 which is an OX40 agonist; monoclonal antibody TRX518 which is a glucocorticoid-induced tumor necrosis factor receptor (GITR) inhibitor; balstilimab which is a CD27 inhibitor; TNFRSF25-TL1A inhibitor; monoclonal antibody CP870893 which is a CD40 agonist; inhibitors of HVEM-LIGHT-LTA and HVEM-BTLA-CD160; monoclonal antibody BMS986016 which is a LAG3 inhibitor; TIM3 inhibitor; Siglecs inhibitor; agonist of ICOS ligand; enoblituzumab MGA271 which is a B7-H3 inhibitor; B7-H4 inhibitor; VISTA inhibitor; HHLA2-TMIGD2 inhibitor; Butyrophilins inhibitor; BTNL2 inhibitor; inhibitor of CD244-CD48; inhibitor of TIGIT and family members of PVR; lirilumab which is a KIR inhibitor; inhibitor of ILT and LIR; monoclonal antibody IPH2201 which is an inhibitor of NKG2D and NKG2A; inhibitor of MICA and MICB; CD244 inhibitor; emactuzumab, cabiralizumab, pexidartinib, ARRY382, and BLZ945 which are CSF1R inhibitors; (3E)-3-[(3-bromo-4-fluoroanilino)-nitrosomethylidene]-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole, INCB024360 which are IDO inhibitors; galunisertib which is a TGFβ inhibitor; inhibitor of adenosine-CD39-CD73;The method according to claim 10, selected from ulocuplumab, an inhibitor of CXCR4-CXCL12, and (3S,6S,9S,12R,17R,20S,23S,26S,29S,34aS)-N-((S)-1-amino-5-guanidino-1-oxopentan-2-yl)-26,29-bis(4-aminobutyl)-17-((S)-2-((S)-2-((S)-2-(4-fluorobenzamide)-5-guanidinopentanamide)-5-guanidinopentanamide)-3-(naphthalen-2-yl)propanamide)-6-(3-guanidinopropyl)-3,20-bis(4-hydroxybenzyl)-1,4,7,10,18,21,24,27,30-nonaoxo-9,23-bis(3-ureidopropyl)triacontahydro-1H,16H-pyrrolo[2,1-p][1,2]dithia[5,8,11,14,17,20,23,26,29]nonaazacyclodotriacontin-12-carboxamide BKT140; babiximab, a phosphatidylserine inhibitor; monoclonal antibody CC90002, an SIRPA-CD47 inhibitor; bevacizumab, a VEGF inhibitor; and / or monoclonal antibody MNRP1685A, a neuropilin inhibitor. [Article 13] The method according to claim 11, wherein the therapeutic agent is temozolomide. [Article 14] The method according to claim 1, further comprising administering ionizing radiation. [Article 15] The method according to claim 1, further comprising administering temozolomide and ionizing radiation. 〔Item 16〕 The method according to claim 10, wherein the additional therapeutic agent is selected from an AKT inhibitor, an alkylating agent, all-trans retinoic acid, an anti-androgen, azacitidine, a BCL2 inhibitor, a BCL-XL inhibitor, a BCR-ABL inhibitor, a BTK inhibitor, a BTK / LCK / LYN inhibitor, a CDK1 / 2 / 4 / 6 / 7 / 9 inhibitor, a CDK4 / 6 inhibitor, a CDK9 inhibitor, a CBP / p300 inhibitor, an EGFR inhibitor, an endothelin receptor antagonist, an ERK inhibitor, a farnesyl transferase inhibitor, an FLT3 inhibitor, a glucocorticoid receptor agonist, an HDM2 inhibitor, a histone deacetylase inhibitor, an IKKβ inhibitor, an immunomodulatory agent (IMiD), ingenol, ionizing radiation, an ITK inhibitor, a JAK1 / JAK2 / JAK3 / TYK2 inhibitor, an MEK inhibitor, midostaurin, an MTOR inhibitor, a PI3 kinase inhibitor, a dual PI3 kinase / MTOR inhibitor, a proteasome inhibitor, a protein kinase C agonist, an SUV39H1 inhibitor, TRAIL, a VEGFR2 inhibitor, a Wnt / β-catenin signaling inhibitor, decitabine, and an anti-CD20 monoclonal antibody. 〔Item 17〕 A method for inhibiting PDGFR kinase, comprising administering to a patient in need thereof an effective amount of 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea or a pharmaceutically acceptable salt thereof. 〔Item 18〕 The method according to claim 17, wherein the PDGFR kinase is PDGFRα or PDGFRβ. 〔Item 19〕 The method according to claim 17, further comprising administering a cancer target therapeutic agent, a cancer target biologic agent, an immune checkpoint inhibitor, or a chemotherapeutic agent. [Item 20] The therapeutic agent is a cytotoxic agent such as cisplatin, doxorubicin, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, lonafarnib, tipifarnib, 4-((5-((4-(3-chlorophenyl)-3-oxopiperazin-1-yl)methyl)-1H-imidazol-1-yl)methyl)benzonitrile hydrochloride, (R)-1-((1H-imidazol-5-yl)methyl)-3-benzyl-4-(thiophen-2-ylsulfonyl)-2,3,4,The method according to claim 19, selected from 5-tetrahydro-1H-benzodiazepine-7-carbonitrile, cetuximab, imatinib, interferon alpha-2b, pegylated interferon alpha-2b, combination of aromatase, gemcitabine, uracil mustard, chloromethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, leucovorin, oxaliplatin, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mitomycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide, 17α-ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, drostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, 17α-hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide acetate, flutamide, tamoxifen citrate, goserelin acetate, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, vinorelbine, anastrozole, letrozole, capecitabine, raloxifene, droloxafine, hexamethylmelamine, bevacizumab, trastuzumab, tositumomab, bortezomib, ibritumomab tiuxetan, arsenic trioxide, porfimer sodium, cetuximab, thiotepa, altretamine, fulvestrant, exemestane, rituximab, alemtuzumab, dexamethasone, bicalutamide, chlorambucil, or valrubicin., 〔Item 21〕The immune checkpoint inhibitor is ipilimumab and tremelimumab which are CTLA4 inhibitors; pembrolizumab and nivolumab which are PD1 inhibitors; atezolizumab (previously MPDL3280A), durvalumab (previously MEDI4736), avelumab, and PDR001 which is a monoclonal antibody; urelumab and utomilumab (PF05082566) which are 4-1BB ligand inhibitors; monoclonal antibody MEDI6469 which is an OX40 ligand agonist; monoclonal antibody TRX518 which is a glucocorticoid-induced tumor necrosis factor receptor (GITR) inhibitor; balstilimab which is a CD27 inhibitor; TNFRSF25-TL1A inhibitor; monoclonal antibody CP870893 which is a CD40 ligand agonist, inhibitors of HVEM-LIGHT-LTA and HVEM-BTLA-CD160; monoclonal antibody BMS986016 which is a LAG3 inhibitor; TIM3 inhibitor; Siglecs inhibitor; agonist of ICOS ligand; enoblituzumab MGA271 which is a B7-H3 inhibitor; B7-H4 inhibitor; VISTA inhibitor; HHLA2-TMIGD2 inhibitor; Butyrophilins inhibitor; BTNL2 inhibitor; inhibitor of CD244-CD48; inhibitor of family members of TIGIT and PVR; lirilumab which is a KIR inhibitor; inhibitor of ILT and LIR; monoclonal antibody IPH2201 which is an inhibitor of NKG2D and NKG2A; inhibitor of MICA and MICB; CD244 inhibitor; emactuzumab, cabiralizumab, pexidartinib, ARRY382, and BLZ945 which are CSF1R inhibitors; (3E)-3-[(3-bromo-4-fluoroanilino)-nitrosomethylidene]-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole, INCB024360 which are IDO inhibitors; galunisertib which is a TGFβ inhibitor; inhibitor of adenosine-CD39-CD73;Ulocuplumab, an inhibitor of CXCR4-CXCL12, and (3S,6S,9S,12R,17R,20S,23S,26S,29S,34aS)-N-((S)-1-amino-5-guanidino-1-oxopentan-2-yl)-26,29-bis(4-aminobutyl)-17-((S)-2-((S)-2-((S)-2-(4-fluorobenzamide)-5-guanidinopentanamide)-5-guanidinopentanamide)-3-(naphthalen-2-yl)propanamide)-6-(3-guanidinopropyl)-3,20-bis(4-hydroxybenzyl)-1,4,7,10,18,21,24,27,30-nonaoxo-9,23-bis(3-ureidopropyl)triacontahydro-1H,16H-pyrrolo[2,1-p][1,2]dithia[5,8,11,14,17,20,23,26,29]nonaazacyclodotrriacontine-12-carboxamide BKT140; babiximab, a phosphatidylserine inhibitor; monoclonal antibody CC90002, a SIRPA-CD47 inhibitor; bevacizumab, a VEGF inhibitor; and / or monoclonal antibody MNRP1685A, a neuropilin inhibitor, the method according to claim 19.; 〔Item 22〕 The method according to claim 19, wherein the therapeutic agent is temozolomide. 〔Item 23〕 The method according to claim 16, further comprising administering ionizing radiation. 〔Item 24〕 The method according to claim 16, further comprising administering temozolomide and ionizing radiation. 〔Item 25〕 The method according to claim 19, wherein the additional therapeutic agent is selected from an AKT inhibitor, an alkylating agent, all-trans retinoic acid, an anti-androgen, azacitidine, a BCL2 inhibitor, a BCL-XL inhibitor, a BCR-ABL inhibitor, a BTK inhibitor, a BTK / LCK / LYN inhibitor, a CDK1 / 2 / 4 / 6 / 7 / 9 inhibitor, a CDK4 / 6 inhibitor, a CDK9 inhibitor, a CBP / p300 inhibitor, an EGFR inhibitor, an endothelin receptor antagonist, an ERK inhibitor, a farnesyl transferase inhibitor, an FLT3 inhibitor, a glucocorticoid receptor agonist, an HDM2 inhibitor, a histone deacetylase inhibitor, an IKKβ inhibitor, an immunomodulatory agent (IMiD), ingenol, ionizing radiation, an ITK inhibitor, a JAK1 / JAK2 / JAK3 / TYK2 inhibitor, a MEK inhibitor, midostaurin, an MTOR inhibitor, a PI3 kinase inhibitor, a dual PI3 kinase / MTOR inhibitor, a proteasome inhibitor, a protein kinase C agonist, an SUV39H1 inhibitor, TRAIL, a VEGFR2 inhibitor, a Wnt / β-catenin signaling inhibitor, decitabine, and an anti-CD20 monoclonal antibody. 〔Item 26〕 A method for treating glioblastoma, comprising administering to a patient in need thereof an effective amount of 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea or a pharmaceutically acceptable salt thereof. 〔Item 27〕 The method according to claim 26, further comprising administering a cancer target therapeutic agent, a cancer target biologic agent, an immune checkpoint inhibitor, or a chemotherapeutic agent. [Item 28] The therapeutic agent is a cytotoxic agent such as cisplatin, doxorubicin, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, lonafarnib, tipifarnib, 4-((5-((4-(3-chlorophenyl)-3-oxopiperazin-1-yl)methyl)-1H-imidazol-1-yl)methyl)benzonitrile hydrochloride, (R)-1-((1H-imidazol-5-yl)methyl)-3-benzyl-4-(thiophen-2-ylsulfonyl)-2,3,4,The method according to claim 27, selected from 5-tetrahydro-1H-benzodiazepine-7-carbonitrile, cetuximab, imatinib, interferon alpha-2b, pegylated interferon alpha-2b, combination of aromatase, gemcitabine, uracil mustard, chlorambucil, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, leucovorin, oxaliplatin, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mitomycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide, 17α-ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, drostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, 17α-hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide acetate, flutamide, tamoxifen citrate, goserelin acetate, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, vinorelbine, anastrozole, letrozole, capecitabine, raloxifene, droloxafine, hexamethylmelamine, bevacizumab, trastuzumab, tositumomab, bortezomib, ibritumomab tiuxetan, arsenic trioxide, porfimer sodium, cetuximab, thiotepa, altretamine, fulvestrant, exemestane, rituximab, alemtuzumab, dexamethasone, bicalutamide, chlorambucil, or valrubicin., [Item 29] The immune checkpoint protein is ipilimumab and tremelimumab, which are CTLA4 inhibitors; pembrolizumab and nivolumab, which are PD1 inhibitors; atezolizumab (previously MPDL3280A), durvalumab (previously MEDI4736), avelumab, and PDR001, which is a monoclonal antibody, all of which are PDL1 inhibitors; urelumab and utomilumab (PF 05082566), which are 4-1BB ligand inhibitors; MEDI6469, which is a monoclonal antibody and an OX40 ligand agonist; TRX518, which is a monoclonal antibody and a glucocorticoid-induced tumor necrosis factor receptor (GITR) inhibitor; balilumab, which is a CD27 inhibitor; TNFRSF25-TL1A inhibitor; CP870893, which is a monoclonal antibody and a CD40 ligand agonist; inhibitors of HVEM-LIGHT-LTA and HVEM-BTLA-CD160; BMS986016, which is a monoclonal antibody and a LAG3 inhibitor; TIM3 inhibitor; Siglecs inhibitor; ICOS ligand agonist; enoblituzumab MGA271, which is a B7-H3 inhibitor; B7-H4 inhibitor; VISTA inhibitor; HHLA2-TMIGD2 inhibitor; butyrophilins inhibitor; BTNL2 inhibitor; CD244-CD48 inhibitor; inhibitors of TIGIT and family members of PVR; lirilumab, which is a KIR inhibitor; ILT and LIR inhibitors; monalizumab IPH2201, which is an inhibitor of NKG2D and NKG2A; MICA and MICB inhibitors; CD244 inhibitor; emactuzumab, cabiralizumab, pexidartinib, ARRY382, and BLZ945, which are CSF1R inhibitors; (3E)-3-[(3-bromo-4-fluoroanilino)-nitrosomethylidene]-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole and INCB024360, which are IDO inhibitors; galunisertib, which is a TGFβ inhibitor; inhibitors of adenosine-CD39-CD73;The method according to claim 27, selected from ulocuplumab, an inhibitor of CXCR4-CXCL12, and (3S,6S,9S,12R,17R,20S,23S,26S,29S,34aS)-N-((S)-1-amino-5-guanidino-1-oxopentan-2-yl)-26,29-bis(4-aminobutyl)-17-((S)-2-((S)-2-((S)-2-(4-fluorobenzamide)-5-guanidinopentanamide)-5-guanidinopentanamide)-3-(naphthalen-2-yl)propanamide)-6-(3-guanidinopropyl)-3,20-bis(4-hydroxybenzyl)-1,4,7,10,18,21,24,27,30-nonaoxo-9,23-bis(3-ureidopropyl)triacontahydro-1H,16H-pyrrolo[2,1-p][1,2]dithia[5,8,11,14,17,20,23,26,29]nonaazacyclodotriacontine-12-carboxamide BKT140; babiximab, a phosphatidylserine inhibitor; monoclonal antibody CC90002, a SIRPA-CD47 inhibitor; bevacizumab, a VEGF inhibitor; and / or monoclonal antibody MNRP1685A, a neuropilin inhibitor. 〔Item 30〕 The method according to claim 28, wherein the therapeutic agent is temozolomide. 〔Item 31〕 The method according to claim 26, further comprising administering ionizing radiation. 〔Item 32〕 The method according to claim 26, further comprising administering temozolomide and ionizing radiation. 〔Item 33〕 The method according to claim 27, wherein the additional therapeutic agent is selected from an AKT inhibitor, an alkylating agent, all-trans retinoic acid, an anti-androgen, azacitidine, a BCL2 inhibitor, a BCL-XL inhibitor, a BCR-ABL inhibitor, a BTK inhibitor, a BTK / LCK / LYN inhibitor, a CDK1 / 2 / 4 / 6 / 7 / 9 inhibitor, a CDK4 / 6 inhibitor, a CDK9 inhibitor, a CBP / p300 inhibitor, an EGFR inhibitor, an endothelin receptor antagonist, an ERK inhibitor, a farnesyl transferase inhibitor, an FLT3 inhibitor, a glucocorticoid receptor agonist, an HDM2 inhibitor, a histone deacetylase inhibitor, an IKKβ inhibitor, an immunomodulatory agent (IMiD), ingenol, ionizing radiation, an ITK inhibitor, a JAK1 / JAK2 / JAK3 / TYK2 inhibitor, a MEK inhibitor, midostaurin, an mTOR inhibitor, a PI3 kinase inhibitor, a dual PI3 kinase / mTOR inhibitor, a proteasome inhibitor, a protein kinase C agonist, an SUV39H1 inhibitor, TRAIL, a VEGFR2 inhibitor, a Wnt / β-catenin signaling inhibitor, decitabine, and an anti-CD20 monoclonal antibody. 〔Item 34〕 A method for treating a PDGFRα-mediated gastrointestinal stromal tumor, comprising administering to a patient in need thereof an effective amount of 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea or a pharmaceutically acceptable salt thereof. 〔Item 35〕 The method according to claim 34, further comprising administering a cancer target therapeutic agent, a cancer target biologic agent, an immune checkpoint inhibitor, or a chemotherapeutic agent. [Item 36] The therapeutic agent is a cytotoxic agent such as cisplatin, doxorubicin, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, lonafarnib, tipifarnib, 4-((5-((4-(3-chlorophenyl)-3-oxopiperazin-1-yl)methyl)-1H-imidazol-1-yl)methyl)benzonitrile hydrochloride, (R)-1-((1H-imidazol-5-yl)methyl)-3-benzyl-4-(thiophen-2-ylsulfonyl)-2,3,4,The method according to claim 35, selected from 5-tetrahydro-1H-benzodiazepine-7-carbonitrile, cetuximab, imatinib, interferon alpha-2b, pegylated interferon alpha-2b, a combination of aromatase, gemcitabine, uracil mustard, chloromethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, leucovorin, oxaliplatin, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mitomycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17α-ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, drostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, 17α-hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide acetate, flutamide, tamoxifen citrate, goserelin acetate, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, vinorelbine, anastrozole, letrozole, capecitabine, raloxifene, droloxafine, hexamethylmelamine, bevacizumab, trastuzumab, tositumomab, bortezomib, ibritumomab tiuxetan, arsenic trioxide, porfimer sodium, cetuximab, thiotepa, altretamine, fulvestrant, exemestane, rituximab, alemtuzumab, dexamethasone, bicalutamide, chlorambucil, or valrubicin., [Item 37] The immune checkpoint inhibitor is ipilimumab and tremelimumab as CTLA4 inhibitors; pembrolizumab and nivolumab as PD1 inhibitors; atezolizumab (previously MPDL3280A), MEDI4736 of durvalumab, avelumab, and PDR001 as a monoclonal antibody as PDL1 inhibitors; urelumab and PF05082566 of utomilumab as 4-1BB ligand inhibitors; monoclonal antibody MEDI6469 as an OX40 ligand agonist; monoclonal antibody TRX518 as a glucocorticoid-induced tumor necrosis factor receptor (GITR) inhibitor; balstilimab as a CD27 inhibitor; TNFRSF25-TL1A inhibitor; monoclonal antibody CP870893 as a CD40 ligand agonist; inhibitors of HVEM-LIGHT-LTA and HVEM-BTLA-CD160; monoclonal antibody BMS986016 as a LAG3 inhibitor; TIM3 inhibitor; Siglecs inhibitor; agonist of ICOS ligand; enoblituzumab MGA271 as a B7-H3 inhibitor; B7-H4 inhibitor; VISTA inhibitor; HHLA2-TMIGD2 inhibitor; butyrophilins inhibitor; BTNL2 inhibitor; inhibitor of CD244-CD48; inhibitor of family members of TIGIT and PVR; lirilumab as a KIR inhibitor; inhibitor of ILT and LIR; monoclonal antibody IPH2201 as an inhibitor of NKG2D and NKG2A; inhibitor of MICA and MICB; CD244 inhibitor; emactuzumab, cabiralizumab, pexidartinib, AMG382 and BLZ945 as CSF1R inhibitors; (3E)-3-[(3-bromo-4-fluoroanilino)-nitrosomethylidene]-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole, INCB024360 as an IDO inhibitor; galunisertib as a TGFβ inhibitor; inhibitor of adenosine-CD39-CD73;The method according to claim 35, selected from urolupumab, an inhibitor of CXCR4-CXCL12, and (3S,6S,9S,12R,17R,20S,23S,26S,29S,34aS)-N-((S)-1-amino-5-guanidino-1-oxopentan-2-yl)-26,29-bis(4-aminobutyl)-17-((S)-2-((S)-2-((S)-2-(4-fluorobenzamide)-5-guanidinopentanamide)-5-guanidinopentanamide)-3-(naphthalen-2-yl)propanamide)-6-(3-guanidinopropyl)-3,20-bis(4-hydroxybenzyl)-1,4,7,10,18,21,24,27,30-nonaoxo-9,23-bis(3-ureidopropyl)triacontahydro-1H,16H-pyrrolo[2,1-p][1,2]dithia[5,8,11,14,17,20,23,26,29]nonaazacyclodotriacontine-12-carboxamide BKT140; babiximab, a phosphatidylserine inhibitor; monoclonal antibody CC90002, a SIRPA-CD47 inhibitor; bevacizumab, a VEGF inhibitor; and / or monoclonal antibody MNRP1685A, a neuropilin inhibitor.; [Item 38] The method according to claim 36, wherein the therapeutic agent is temozolomide.; [Item 39] The method according to claim 34, further comprising administering ionizing radiation.; [Item 40] The method according to claim 34, further comprising administering temozolomide and ionizing radiation.; 〔Item 41〕 The method according to claim 35, wherein the additional therapeutic agent is selected from an AKT inhibitor, an alkylating agent, all-trans retinoic acid, an anti-androgen, azacitidine, a BCL2 inhibitor, a BCL-XL inhibitor, a BCR-ABL inhibitor, a BTK inhibitor, a BTK / LCK / LYN inhibitor, a CDK1 / 2 / 4 / 6 / 7 / 9 inhibitor, a CDK4 / 6 inhibitor, a CDK9 inhibitor, a CBP / p300 inhibitor, an EGFR inhibitor, an endothelin receptor antagonist, an ERK inhibitor, a farnesyl transferase inhibitor, an FLT3 inhibitor, a glucocorticoid receptor agonist, an HDM2 inhibitor, a histone deacetylase inhibitor, an IKKβ inhibitor, an immunomodulatory agent (IMiD), ingenol, ionizing radiation, an ITK inhibitor, a JAK1 / JAK2 / JAK3 / TYK2 inhibitor, a MEK inhibitor, midostaurin, an MTOR inhibitor, a PI3 kinase inhibitor, a dual PI3 kinase / MTOR inhibitor, a proteasome inhibitor, a protein kinase C agonist, an SUV39H1 inhibitor, TRAIL, a VEGFR2 inhibitor, a Wnt / β-catenin signaling inhibitor, decitabine, and an anti-CD20 monoclonal antibody.

Claims

1. A pharmaceutical composition comprising 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea, for use in a method of treating progressive gastrointestinal stromal tumors in patients who have received prior treatment with a tyrosine kinase inhibitor, the method comprising orally administering 150 mg of said compound once a day to a patient in need of such treatment, wherein the prior treatment with a tyrosine kinase inhibitor comprises prior imatinib administration, pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the progressive gastrointestinal stromal tumor has a PDGFRα mutation.

3. The pharmaceutical composition according to claim 1, wherein the progressive gastrointestinal stromal tumor has a c-KIT mutation.

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