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 for treatment of cancers associated with genetic abnormalities in platelet derived growth factor receptor alpha

Abstract

To provide a novel method for treating PDGFR kinase-mediated tumors such as gastrointestinal stromal tumors and glioblastoma.SOLUTION: A method for treating or preventing tumor growth or tumor progression mediated by PDGFR kinases, 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.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] Instructions for electronically submitted text files: The contents of the electronically submitted text file are incorporated herein by reference in their entirety: Computer-readable copy of the Sequence Listing (Filename: DECP_073_00US_SeqList_ST25.txt, Recording Date: May 30, 2017, File Size: 24 KB).

[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 disclosure is directed to methods of inhibiting PDGFR kinase and treating cancers and disorders associated with inhibition of PDGFR kinase, including lung adenoma, squamous cell lung carcinoma, glioblastoma, pediatric glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor (GIST), malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, eosinophilia associated acute myeloid leukemia, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, or lymphoblastic T-cell lymphoma. [Background technology]

[0003] Oncogenic genomic alterations in PDGFRα kinase or overexpression of PDGFRα kinase have been shown to cause human cancers.

[0004] Missense mutations in the PDGFRα kinase have also been shown to be causative in a subgroup of GISTs. PDGFRα mutations are the primary oncogenic factor in approximately 8%–10% of GISTs (Corless, Modern Pathology 2014;27:S1-16). The dominant mutation in 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 in exons 12 and 14 of PDGFRα have also been reported (Corless et al, J Clinical Oncology 2005;23:5357-64).

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

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

[0007] PDGFRα amplification is associated with undifferentiated pleomorphic sarcoma (Osio et al., J. Cutan Pathol 2017;44:477-79) and intimal sarcoma (Zhao et al. l, Genes Chromosomes and Cancer, 2002;34:48-57; Dewaele et al, Cancer Res 2010;70:7304-14) have been reported in multiple skin lesions. PDGFRα amplification has been associated with a subgroup of lung cancer patients. 4q12 contains the PDGFRα locus and is amplified in 3-7% of lung adenomas 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 novel oncogenic metabolite, 2-hydroxyglutarate, which interferes with iron-dependent hydroxylases, including the TET family of 5'-methylcytosine hydroxylase. TET enzymes catalyze a critical step in the removal of DNA methylation. Flavahan et al. showed that human IDH-mutant gliomas exhibit hypermethylation at DNA cohesin and CCCTC-binding factor (CTCF) binding sites, thereby impairing the binding of this methylation-sensitive insulating protein (Flavahan et al., Nature 2016;529:110). Reduced CTCF binding has been associated with loss of topological interdomain insulation and aberrant gene activation. Specifically, loss of CTCF at domain boundaries allows structural enhancers to aberrantly interact with the receptor tyrosine kinase gene PDGFRA, a key glioma oncogene. Therefore, IDH-mutated cancers may be more susceptible to mediating oncogenic events through activation and overexpression of wild-type PDGFRα.

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

[0010] The PDGFRα locus in these PDGFRα-amplified gliomas has been shown to exhibit an intragenic deletion rearrangement of PDGFRα exons 8 and 9. This intragenic deletion is common, present in 40% of glioblastoma multiforme (GBM) cases with PDGFRα amplification. Tumors with this rearrangement exhibit histological characteristics of oligodendroglioma, and the intragenic deletion of PDGFRα exons 8 and 9 resulted in elevated constitutive tyrosine kinase activity (Ozawa et al., Genes and Development 2010;24:2205-18).

[0011] The FIP1L1-PDGFRA fusion protein is oncogenic in a subgroup 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 functions 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 favorable therapeutic potential. Summary of the Invention

[0013] One embodiment 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 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 for inhibiting PDGFR kinase or treating PDGFR kinase-mediated tumor growth or 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, as a single agent or in combination with other targeted cancer therapeutics, targeted cancer biologics, immune checkpoint inhibitors, or chemotherapeutic agents.

[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 tumors, 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 of 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 treating PDGFR kinase-mediated tumor growth or progression, 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, as a single agent or in combination with other targeted cancer therapeutics, targeted cancer biologics, immune checkpoint inhibitors, or chemotherapeutic agents.

[0021] 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-(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 of 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) following 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 is directed to methods of inhibiting PDGFR kinase and methods of treating cancers and disorders associated with inhibition of PDGFR kinase, including lung adenoma, squamous cell lung carcinoma, glioblastoma, pediatric glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic acute myeloid leukemia, or lymphoblastic T-cell lymphoma.

[0025] The present invention also provides methods for inhibiting PDGFRα kinase, oncogenic missense mutations of PDGFRα, oncogenic deletion mutations of PDGFRα, oncogenic rearrangements of the PDGFRα gene resulting in PDGFRα fusion proteins, or oncogenic amplifications of the PDGFRα gene.

[0026] The present invention also provides methods 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 explanation of the drawings]

[0027] [Figure 1A] Figures 1A-1C show MRI scans of the brain of a patient with glioblastoma exhibiting PDGFRα amplification. Figure 1A shows an MRI scan of the patient's brain at baseline. Figure 1B shows evidence of tumor reduction after cycle 9. Figure 1C shows an MRI scan of the same brain after cycle 12. [Figure 1B] Same as above. [Figure 1C] Same as above. DETAILED DESCRIPTION OF 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 inhibited wild-type and oncogenic forms of the protein P The present invention provides a method for treating cancer by inhibiting oncogenic PDGFRα kinase-mediated tumor growth or 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, 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. definition

[0029] As used herein, Compound A and Compound 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 this disclosure. The structures of Compound A and Compound B are shown below: [ka] 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea (Compound A) [ka] 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 preparation method of Compound A and Compound B is disclosed in US8461179B1, the contents of which are incorporated herein by reference. Details of the present invention are described in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used to practice or test the present invention, the methods and materials are described here as illustrative. Other features, objects, and advantages of the present invention will become apparent from the description and claims. In the specification and the appended claims, the singular forms include the plural forms unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0031] Throughout this disclosure, various patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications in their entireties are incorporated by reference into this disclosure to more fully describe 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 these patents, patent applications, and publications and this disclosure, the present disclosure will control.

[0032] For convenience, certain terms employed in the specification, examples, and claims are collected here. Unless otherwise specified, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The original definition provided for a group or term provided in this disclosure applies to that group or term individually or as part of another group throughout this disclosure, unless otherwise indicated.

[0033] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the United States Food and Drug Administration as acceptable for use in humans or veterinary medicine. A "pharmaceutically acceptable salt" includes both acid and base addition salts.

[0034] "Pharmaceutically acceptable acid addition salts" refers to salts that retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and with acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-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, galacic acid, guar ... It is formed from organic acids such as octaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric 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, etc.

[0035] A "pharmaceutical composition" refers to a formulation of a compound of the invention and a vehicle generally accepted in the art for the delivery of biologically active compounds to mammals, e.g., humans. Such vehicles therefore include any pharmaceutically acceptable carrier, diluent, or excipient.

[0036] A subject or patient "in need of treatment" with a compound of the present disclosure, or a ... subject "in need of treatment" with a compound of the present disclosure, or a patient "in need of Patients "in need of inhibition" include those having a disease and / or condition that can be treated with the disclosed compounds to achieve a beneficial therapeutic result. Beneficial outcomes include objective response, prolonged progression-free survival, increased survival, prolonged stable disease, and / or reduced symptom severity or delayed symptom onset. For example, the patient in need of treatment is suffering from tumor growth or tumor progression. The patient may be suffering from, but is not limited to, lung adenoma, squamous cell lung carcinoma, glioblastoma, pediatric glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath sarcoma, intimal 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 being treated with the compound compared to no treatment. The amount of compound administered will depend on the extent, severity, and type of disease or condition, the amount of treatment desired, and the release characteristics of the pharmaceutical formulation. It will also depend on the subject's health, size, weight, age, sex, and tolerance to drugs. Typically, the compound is administered for a period of time sufficient to achieve the desired therapeutic effect.

[0038] The terms "treatment," "treat," and "treating" are meant to include the full range of interventions made in patients with "cancer" with the intention of preventing the growth of tumors afflicting the patient and / or preventing the progression of tumors to a given treatment, such as the administration of active compounds that alleviate, delay, or reverse one or more of the symptoms and slow the progression of cancer, even if the cancer is not actually eliminated. Treating may also mean curing, ameliorating, or at least partially ameliorating the disorder.

[0039] "Cancer," as defined herein, refers to a neoplasm that has the ability to invade surrounding tissues, metastasize (spread to other organs), and ultimately, if untreated, cause death to the patient. A "cancer" may be a solid tumor or a liquid tumor.

[0040] As used herein, "tumor" refers to a mass. It 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] "Tumor growth," as defined herein, refers to the growth of a mass resulting from genomic alterations in the PDGFRα kinase.

[0042] "Tumor progression," as defined herein, refers to tumor growth of a pre-existing PDGFRα-dependent tumor, where tumor growth of the pre-existing mass occurs due to further genomic alterations of the PDGFRα kinase that are resistant to therapy.

[0043] One embodiment 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 due to overexpression of PDGFRα kinase, an oncogenic missense mutation of PDGFRα, an oncogenic deletion mutation of PDGFRα, In one embodiment, tumor growth or progression is caused by an oncogenic rearrangement of the PDGFRα gene resulting in a PDGFRα fusion protein, an intragenic in-frame deletion of PDGFRα, and / or an oncogenic gene amplification of PDGFRα. In one embodiment, tumor growth or progression is caused by overexpression of PDGFRα kinase. In another embodiment, tumor growth or progression is caused by an oncogenic missense mutation of PDGFRα. In another embodiment, tumor growth or progression is caused by an oncogenic deletion mutation of PDGFRα. In another embodiment, tumor growth or progression is caused by an oncogenic gene rearrangement of PDGFRα resulting in a PDGFRα fusion protein. In another embodiment, tumor growth or progression is caused by an intragenic in-frame deletion of PDGFRα. In another embodiment, tumor growth or 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 the tumor growth or progression is caused by a D842V mutant PDGFRα, a V561D mutant PDGFRα, an exon 18 deletion mutant PDGFRα including a 842-845 deletion mutant PDGFRα, an in-frame deletion mutant PDGFRα of exons 8 and 9, a PDGFRα fusion including FIP1L1-PDGFRα, or a PDGFRα amplification.

[0046] In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered to a patient with cancer, wherein the cancer is lung adenoma, squamous cell lung carcinoma, glioblastoma, pediatric glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath sarcoma, intimal 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 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 other targeted cancer therapeutics, targeted cancer biologics, immune checkpoint inhibitors, or chemotherapeutic agents.

[0048] 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 (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 progression is caused by overexpression of PDGFRα kinase, oncogenic missense mutations of PDGFRα, oncogenic deletion mutations of PDGFRα, oncogenic rearrangements of the PDGFRα gene resulting in PDGFRα fusion proteins, intragenic in-frame deletions of PDGFRα, and / or oncogenic gene amplifications of PDGFRα. In one embodiment, tumor growth or progression is caused by overexpression of PDGFRα kinase. In another embodiment, tumor growth or progression is caused by oncogenic missense mutations of PDGFRα. In another embodiment, tumor growth or progression is caused by oncogenic deletion mutations of PDGFRα. In another embodiment, tumor growth or progression is caused by oncogenic gene rearrangements of PDGFRα resulting in PDGFRα fusion proteins. In another embodiment, tumor growth or progression is caused by intragenic in-frame deletions of PDGFRα. In another embodiment, the tumor growth or 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 progression is caused by D842V mutant PDGFRα, V561D mutant PDGFRα, exon 18 deletion mutant PDGFRα including a 842-845 deletion mutant PDGFRα, an 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 patient with cancer, wherein the cancer is lung adenoma, squamous cell lung carcinoma, glioblastoma, pediatric glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath sarcoma, intimal 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 gastrointestinal stromal tumor. In another embodiment, Compound B or a pharmaceutically acceptable salt thereof is administered to a patient with cancer as a single agent or in combination with other targeted cancer therapeutics, targeted cancer biologics, immune checkpoint inhibitors, or chemotherapeutic agents. Pharmaceutical compositions and methods of treatment

[0052] It should be further noted that the present disclosure is directed to a method of treatment comprising administering the compounds of the present disclosure or pharmaceutical compositions comprising such compounds.The pharmaceutical compositions or pharmaceutical preparations described herein can be used in accordance with the present disclosure to treat various cancers, including lung adenoma, squamous cell lung carcinoma, glioblastoma, childhood glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic acute myeloid leukemia or lymphoblastic T-cell lymphoma.

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

[0054] In some embodiments, the present invention relates to methods of using pharmaceutical compositions containing Compound A or B and a pharmaceutically acceptable carrier containing one or more additional therapeutic agents. 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, lonafarib, 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 alfa-2b, pegylated ... Lon alfa-2b, aromatase combination, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, leucovorin, oxaliplatin, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17α-ethynylestradiol, diethylsulfite Rubestrol, testosterone, prednisone, fluoxymesterone, dromostanolone 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, mitotsine These include fluoxantrone, mitoxantrone, levamisole, vinorelbine, anastrazole, 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.

[0055] In another embodiment, the present invention relates to methods of using a pharmaceutical composition comprising Compound A or B and a pharmaceutically acceptable carrier comprising one or more additional therapeutic agents, including, but not limited to, AKT inhibitors, alkylating agents, all-trans retinoic acid, antiandrogens, azacytidine, 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, and the like. enzyme inhibitors, IKKβ inhibitors, immunomodulatory agents (IMiDs), ingenols, 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 another embodiment, the present invention relates to a pharmaceutical composition comprising Compound A or Compound B and a pharmaceutically acceptable carrier comprising a therapeutically effective amount of one or more additional therapeutic agents, wherein the additional therapeutic agents are immune checkpoint inhibitors and are selected from the group consisting of CTLA4 inhibitors, such as, but not limited to, ipilimumab and tremelimumab; PD1 inhibitors, such as, but not limited to, pembrolizumab and nivolumab; PDL1 inhibitors, such as, but not limited to, atezolizumab (formerly MPDL3280A), MEDI4736, avelumab, PDR001; 4 1BB or 4 inhibitors of 1BB ligands, such as, but not limited to, urelumab and PF-05082566; rOX40 ligand agonists, such as, but not limited to, MEDI6469; GITR inhibitors, such as, but not limited to, TRX518; CD27 inhibitors, such as, but not limited to, varlilumab; TNFRSF25 or TL1A inhibitors; CD40 agonists, such as, but not limited to, CP-870893; HVEM or LIGHT or LTA or BTLA or inhibitors of CD160; LAG3 inhibitors, such as, but not limited to, BMS-986016; TIM3 inhibitors; Siglecs inhibitors; ICOS or ICOS ligand agonists; B7 H3 inhibitors, such as, but not limited to, MGA271; B7 H4 inhibitors; VISTA inhibitors; HHLA2 or TMIGD2 inhibitors; inhibitors of Butyrophilins, including BTNL2 inhibitors; inhibitors of CD244 or CD48; inhibitors of TIGIT and PVR family members; KIR inhibitors, such as but not limited to lirilumab; inhibitors of ILT and LIR; inhibitors of NKG2D and NKG2A, such as but not limited to IPH2201; inhibitors of MICA and MICB; CD244 inhibitors; CSF1R inhibitors, such as but not limited to emactuzumab, cabilalizumab, pexidartinib, ARRY382, BLZ945; IDO inhibitors, such as but not limited to INCB024360; TGFβ inhibitors, such as but not limited to galunisertib; adenosine or inhibitors of CD39 or CD73; CXCR4 or CXCL12 inhibitors, such as but not limited to urocuprumab 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-fluorobenzamido)-5-guanidinopentanamido)-5-guanidinopentanamido)-3-(naphthalen-2-yl)propanamido)-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.

[0057] For use in pharmaceutical compositions of the compounds described herein, pharmaceutically acceptable carriers can be either solid or liquid. Solid forms include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Powders and tablets may be comprised of about 5 to about 95 percent active ingredient. Suitable solid carriers are well known in the art. Examples include 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 methods for manufacturing various compositions can be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa., incorporated herein by reference in its entirety.

[0058] Liquid form preparations include solutions, suspensions, and emulsions, such as water or water-propylene glycol solutions for parenteral injection, or the addition of sweeteners and opacifiers for oral solutions, suspensions, and emulsions. Liquid form preparations also include solutions for intranasal administration.

[0059] Liquids, particularly injectable compositions, can be prepared, for example, by dissolving, dispersing, etc. For example, the disclosed compounds are dissolved or mixed with a pharmaceutically acceptable solvent, such as water, saline, aqueous dextrose, glycerol, ethanol, etc., to form 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, intramuscular, or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, or in solid forms suitable for dissolving in liquid prior to injection.

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

[0062] In addition, regarding use, it is for liquid preparations intended for either oral or parenteral administration. Solid form preparations, intended to be converted shortly before use, are also contemplated.Such liquid forms include solutions, suspensions, and emulsions. Combination therapy

[0063] As mentioned above, the compounds described herein can be used alone or in combination with other agents. For example, the compounds can be administered together with cancer targeting therapeutic agents, cancer targeting biologics, immune checkpoint inhibitors, or chemotherapeutic agents. In another embodiment, compound A or compound B can be used alone or singly. The agent can be administered together with the compounds described herein in combination therapy or sequentially with the compounds.

[0064] Combination therapy can be achieved by administering two or more agents, each of which can be formulated and administered separately, or by administering two or more agents in a single formulation. Other combinations are also encompassed by combination therapy. For example, two agents can be formulated together and administered in conjunction with a separate formulation containing a third agent. In combination therapy, two or more agents can be administered simultaneously, but this is not required. For example, administration of a first agent (or combination of agents) can precede administration of a 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, or 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9 weeks or more of each other. Longer intervals are also possible in some cases. In many cases, it is desirable, but not necessary, for the two or more agents used in combination therapy to be present in the patient's body at the same time.

[0065] Combination therapy can also include more than one administration of one or more of the agents used in the combination, with the component agents being administered in a different order. For example, when agent X and agent Y are used in combination, they can be administered one or more times sequentially in any combination. For example, they can be administered in the order XYX, XXY, YXY, YYX, XXYY, etc.

[0066] In one embodiment, Compound A or Compound B is selected from the group consisting of cytotoxic agents cisplatin, doxorubicin, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, lonafarib, tipifarnib, 4-((5-((4-(3-chlorophenyl)-3-oxopiperazine-1- (R)-1-((1H-imidazol-5-yl)methyl)-3-benzyl-4-(thiophen-2-ylsulfonyl)-2,3,4,5-tetrahydro-1H-benzodiazepine-7-carbonitrile, (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 alfa-2b, pegylated interferon alfa-2b, aromatase inhibitors combinations, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, leucovorin, oxaliplatin, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide, 17α-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone dromostanolone 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, anastasiabine and in combination with a therapeutic agent selected from the group consisting of bromocriptine, 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 to a patient in need of treatment.

[0067] In one embodiment, Compound A or Compound B is selected from the group consisting of CTLA4 inhibitors, such as but not limited to ipilimumab and tremelimumab; PD1 inhibitors, such as but not limited to pembrolizumab and nivolumab; PDL1 inhibitors, such as but not limited to atezolizumab (formerly MPDL3280A), MEDI4736, avelumab, PDR001; 4 1BB or 4 Inhibitors of 1BB ligands, for example, but not limited to, urelumab and PF-05082566; OX40 ligand agonists, for example, but not limited to, MEDI6469; GITR inhibitors, for example, but not limited to, TRX518; CD27 inhibitors, for example, but not limited to, varlilumab; TNFRSF25 or TL1A inhibitors; CD40 ligand agonists, for example, but not limited to, CP-870893; inhibitors of HVEM or LIGHT or LTA or BTLA or CD160; LAG3 inhibitors, for example, but not limited to, BMS-986016; TIM3 inhibitors; Siglecs inhibitors; inhibitors of ICOS or ICOS ligands; B7H3 inhibitors, for example, but not limited to, MGA271; B7H4 inhibitors; VISTA inhibitors; HH LA2 or TMIGD2 inhibitors; inhibitors of Butyrophilins, including BTNL2 inhibitors; inhibitors of CD244 or CD48; inhibitors of TIGIT and PVR family members; KIR inhibitors, such as but not limited to lirilumab; inhibitors of ILT and LIR; inhibitors of NKG2D and NKG2A, such as but not limited to IPH2201; inhibitors of MICA and MICB; CD244 inhibitors; CSF1R inhibitors, such as but not limited to emactuzumab, cabilalizumab, pexidartinib, ARRY382, and 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, urocupulumab 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-fluorobenzamido)-5-guanidinopentanamido)-5-guanidinopentan Amido)-3-(naphthalen-2-yl)propanamido)-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, administered to a patient in need of treatment.

[0068] According to another embodiment of the present invention, additional therapeutic agents may 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, antiandrogens, azacytidine, 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, and the like. 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 in which Compound A or Compound B is used in combination with other agents in a treatment protocol, the compositions may be administered together or in a "dual regimen," in which the two therapeutic agents are taken and administered separately. When Compound A or B and the additional agent are administered 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 up to 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 determined according to the judgment of the attending physician, taking into account factors such as the age, condition, and size of the patient, as well as the severity of the symptoms being treated. Effective dosages of the disclosed compounds, when used for a designated effect, range from about 0.5 mg to about 5,000 mg of the disclosed compounds, depending on the need for treatment of the condition. Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1,000, 1,250, 2,500, 3,500, or 5,000 mg of the disclosed compounds, or can contain a range of amounts from one amount to another listed in the dosage list. For oral administration, a typical recommended daily dosage regimen can range from about 1 mg / day to about 500 mg / day, or from 1 mg / day to 200 mg / day, in a single dose or in two to four divided doses. In one embodiment, a typical daily dosage regimen is 150 mg.

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

[0072] Exemplary pharmaceutical compositions comprise a compound of the invention in a pharmaceutically acceptable carrier, such as a) a diluent, such as purified water, triglyceride oil, such as hydrogenated or partially hydrogenated vegetable oil or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, such as EPA or DHA, or esters, triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, such as silica, talc, stearic acid, magnesium or calcium salts thereof, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and / or polyethylene glycol; also for tablets; c) binders, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, if desired; d) disintegrants, for example starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbents, colorants, flavors and sweeteners; f) emulsifiers or dispersants, for example Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and / or; g) an agent that enhances absorption of the compound, such as cyclodextrin, hydroxypropyl cyclodextrin, PEG 400, PEG 200, etc.

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

[0074] Because the compounds of the present invention (Compound A and Compound B) are intended for use in pharmaceutical compositions, those skilled in the art will understand that they may be provided in substantially pure form, for example, 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 suitably sized unit doses containing an appropriate amount of Compound A or Compound B, such as, for example, an effective amount to achieve the desired purpose described herein. Section 1 - Comparison of key structures for biological activity using WO / 2008 / 034008 and WO / 2013 / 184119.

[0075] WO / 2008 / 034008 describes various kinases that cause or contribute to the pathology of various proliferative diseases, including BRaf, CRaf, Abl, KDR (VEGFR2), EGFR / HER1, HER2, HER3, c-MET, FLT-3, PDGFR-α, PDGFR-β, p38, c-KIT, and JAK2 families. The disclosure of this PCT application clearly demonstrates selective inhibition of 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 c-KIT and PDGFRα mutations are not mutually exclusive in GISTs. This is because most GISTs harbor, in a mutually exclusive manner, primary activating mutations in the genes encoding the closely related RTKs c-KIT (75–80% of GISTs) or PDGFRα (8% of non-c-KIT-mutated GISTs).

[0076] In the present application, the inevitable mutual exclusivity between c-KIT and PDGFRα mutations in GIST patients has been reconciled, and Compound A and Compound B have been found to be able to treat both patient groups. Indeed, it was unexpected that Compound A and Compound B, known to inhibit c-KIT mutants, also inhibit wild-type and oncogenic mutant PDGFR kinase, oncogenic fusion protein-type PDGFRα kinase, and PDGFRα-amplified cancers, contrary to previous disclosures in WO / 2008 / 034008 and WO / 2013 / 184119. The experimental data described below further support this finding. The direct application of this discovery is the treatment of the subgroup of patients with resistant and PDGFR-induced cancers described herein. [Example]

[0077] Biological data The unexpected discovery that Compound A and Compound B inhibit wild-type and oncogenic mutant forms of PDGFR kinase, oncogenic fusion protein forms of PDGFRα kinase, and mutated or amplified forms of PDGFRα in cancers was analyzed in biochemical assays, cellular assays, and in vivo clinical evaluations in cancer patients.

[0078] The present disclosure is further illustrated by the following examples, which should not be construed as limiting the disclosure in scope or spirit to the specific procedures described herein. It should be understood that the examples are presented to illustrate particular embodiments and are not intended to limit the scope of the disclosure. It should also be understood that various other embodiments, modifications, and equivalents that may be suggested to those skilled in the art may be reclassified without departing from the spirit of the present disclosure and / or the scope of the appended claims. Example 1. Inhibition of wild-type PDGFRα enzymatic activity Biochemical assay for PDGFRα (GenBank accession number NP_006197)

[0079] The activity of PDGFRα kinase was determined spectrophotometrically using a coupled pyruvate kinase / lactate dehydrogenase assay, which continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al., Science (2000) 289:1938-1942, incorporated herein by reference in its entirety). The assay was performed in a 384-well plate (final volume 100 μL) using 4.8 nM PDGFRA (Decode Biostructure, Bainbridge Island, WA), 5 units of pyruvate kinase, 7 units of lactate dehydrogenase, 1 mM pyruvate phosphoenol, 0.28 mM NADH, 2.5 mg / mL PolyEY, and 0.5 mM ATP in assay buffer (90 mM Tris, pH 7.5, 18 mM MgCl, 1 mM DTT, and 0.2% octyl-glucoside). Inhibition of PDGFRA was measured after the addition of serially diluted test compounds (final assay concentration of 1% DMSO). The decrease in absorbance at 340 nm was monitored continuously for 6 hours at 30°C on a multimode microplate reader (BioTek, Winooski, VT). Reaction rates were calculated using a 1-2 hour time frame. The reaction rate at each compound concentration was converted to percent inhibition using controls (i.e., reactions without test compound and reactions with a known inhibitor). IC50 The values ​​were calculated using four parameters for the data using Prism (GraphPad, San Diego, CA). The data were calculated by fitting a sigmoidal curve. Protein sequence of PDGFRα (residues 550 to 1089, with an N-terminal GST tag; Genbank SEQ ID NO: 1). [ka]

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

[0081] The activity of PDGFRA D842V kinase was determined spectrophotometrically using a coupled pyruvate kinase / lactate dehydrogenase assay, which continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al., Science (2000) 289:1938-1942, incorporated herein by reference in its entirety). Assays were performed in 384-well plates (final volume 100 μL) using 3 nM PDGFRA D842V (Invitrogen, Carlsbad, CA), 5 units of pyruvate kinase, 7 units of lactate dehydrogenase, 1 mM phosphoenol pyruvate, 0.28 mM NADH, 2.5 mg / mL PolyEY, and 0.5 mM ATP in assay buffer (90 mM Tris, pH 7.5, 18 mM MgCl, 1 mM DTT, and 0.2% octyl-glucoside). Inhibition of PDGFRA D842V was measured after the addition of serially diluted test compounds (final assay concentration of 1% DMSO). The decrease in absorbance at 340 nm was monitored continuously for 6 hours at 30°C on a multimode microplate reader (BioTek, Winooski, VT). Reaction rates were calculated using a 2-3 hour time frame. The reaction rate at each compound concentration was converted to percent inhibition using controls (i.e., reactions without test compound and reactions with known inhibitors). IC 50 Values ​​were calculated by fitting a four-parameter sigmoidal curve to the data using Prism (GraphPad, San Diego, CA). Protein sequence of PDGFRα D842V (residues 550 to 1089, with an N-terminal HIS-GST tag; Genbank SEQ ID NO: 2). [ka]

[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 value of 20 nM.50 was inhibited by the value. Example 3. Inhibition of wild-type PDGFRβ enzymatic activity Biochemical assay for PDGFRB (GenBank accession number NP_002600)

[0083] PDGFRβ kinase activity was determined spectrophotometrically using a coupled pyruvate kinase / lactate dehydrogenase assay, which continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al. Science (2000) 289:1938-1942, incorporated herein by reference in its entirety). The assay contained 9 nM PDGFRB (Decode Biostructure, Bainbridge Island, WA), 5 units of pyruvate kinase, 7 units of lactate dehydrogenase, 1 mM phosphoenol pyruvate, 0.28 mM NADH, 2.5 mg / mL ATP. Assays were performed in 384-well plates (final volume 100 μL) using PolyEY and 0.5 mM ATP in assay buffer (90 mM Tris, pH 7.5, 18 mM MgCl2, 1 mM DTT, and 0.2% octyl-glucoside). PDGFRB inhibition was measured after the addition of serially diluted test compounds (final assay concentration of 1% DMSO). The decrease in absorbance at 340 nm was monitored continuously for 6 hours at 30°C on a multimode microplate reader (BioTek, Winooski, VT). Reaction rates were calculated using a 2-3 hour time frame. Reaction rates at each compound concentration were converted to percent inhibition using controls (i.e., reactions without test compound and reactions with known inhibitors). IC 50 Values ​​were calculated by fitting a four-parameter sigmoidal curve to the data using Prism (GraphPad, San Diego, CA). Protein sequence of PDGFRβ (residues 557 to 1106, N-terminally HIS-GST-tagged; Genbank SEQ ID NO: 3) [ka]

[0084] Compound A inhibited the enzymatic activity of recombinant wild-type PDGFRβ with an IC of 9 nM. 50 Compound B inhibited the enzymatic activity of recombinant wild-type PDGFRβ with an IC value of 5 nM. 50 was inhibited by the value. Example 4. Growth inhibition of D842V mutant PDGFRα expressed in Ba / F3 cells BaF3 PDGFRα D842V cell culture

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

[0086] Serial dilutions of test compounds were dispensed into 96-well black, clear-bottom plates (Corning, Corning, NY). Ten thousand cells per well were added in 200 μL of complete growth medium. Plates were incubated for 67 hours at 37°C, 5% CO2, and 95% humidity. At the end of the incubation period, 40 μL of 440 μM resazurin (Sigma, St. Louis, MO) in PBS was added to each well, and the plates were incubated for an additional 5 hours at 37°C, 5% CO2, and 95% humidity. 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 determine IC 50 The value was calculated.

[0087] Compound A has an IC of 36 nM 50 Compound B inhibited the proliferation of D842V mutant PDGFRα BaF3 cells with an IC value of 42 nM. 50 At this level, it inhibited the proliferation of D842V mutant PDGFRαBaF3 cells. Example 5. Inhibition of phosphorylation of D842V mutant PDGFRα expressed in BaF3 cells BaF3 PDGFRα D842V cell culture

[0088] BaF3 cells were transfected with a construct encoding D842V PDGFRα and selected for IL-3 independence. Briefly, cells were cultured in 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 1 unit / mL penicillin G, 1 μg / mL streptomycin, and 0.29 mg / mL IL-3. They were grown in RPMI 1640 medium supplemented with 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-treated plates at 2 million cells per well. Serial dilutions of test compounds were added to the cells. The plates were incubated for 4 hours at 37°C with 5% CO2 and 95% humidity. Cells were washed with PBS and then lysed. Cell lysates were separated by SDS-PAGE and transferred to PVDF. Phospho-PDGFRα (Tyr754) was detected using antibodies from Cell Signaling Technology (Beverly, MA), ECL Plus detection reagents (GE Healthcare, Piscataway, NJ), and a Molecular Devices Storm 840 phosphorimager in fluorescence mode. Blots were stripped and probed for total PDGFRα using antibodies from Cell Signaling Technology (Beverly, MA). IC50 values ​​were calculated using Prism software (GraphPad, San Diego, CA).

[0090] Compound A inhibited the phosphorylation of D842V mutant PDGFRα expressed in BaF3 cells with an IC of 24 nM. 50 Compound B inhibited the phosphorylation of D842V mutant PDGFRα expressed in BaF3 cells with an IC value of 26 nM. 50 was inhibited by the value. 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). 24 hours after transfection, they were treated with various concentrations of compounds for 90 minutes. Protein lysates from the cells were prepared and immunoprecipitated using an anti-PDGFRA antibody (SC-20, Santa Cruz Biotechnology, Santa Cruz, CA). Subsequently, 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). Densitometry was performed using Photoshop 5.1 software to quantify drug effects, and phospho-PDGFRα levels were normalized to total protein. The results of the densitometry experiments were analyzed using Calcusyn2.1 software (Biosoft, Cambridge, UK) and mathematically calculated as IC 50 value was determined.

[0091] Compound A inhibited the phosphorylation of V561D mutant PDGFR□ expressed in CHO cells with an IC of 25 nM. 50 was inhibited by the value. 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 Cells were transiently transfected with a mutant ΔD842-H845 PDGFRA cDNA construct cloned into the PDGFRA gene (Serotogen, Carlsbad, CA). 24 hours after transfection, cells were treated with various concentrations of compounds for 90 minutes. Protein lysates from the cells were prepared and analyzed by immunoblotting with an anti-PDGFRA antibody (SC-20, Santa Cruz Biosciences, Santa Cruz, CA). Immunoprecipitation was performed using a monoclonal antibody (PY-20, BD Transduction Labs, Sparks, MD) or total PDGFRα (SC-20, Santa Cruz Biotechnology, Santa Cruz, CA) followed by sequential immunoblotting for phosphotyrosine using a monoclonal antibody (PY-20, BD Transduction Labs, Sparks, MD) or total PDGFRα (SC-20, Santa Cruz Biotechnology, Santa Cruz, CA). Densitometry was performed using Photoshop 5.1 software to quantify drug effects and normalize levels of phospho-PDGFRA to total protein. Results of densitometry experiments were analyzed using Calcusyn 2.1 software (Biosoft, Cambridge, UK) and mathematically calculated as IC 50 value was determined.

[0093] Compound A inhibited the phosphorylation of exon 18 842-845 deletion mutant PDGFRα expressed in CHO cells with an IC of 77 nM. 50 was inhibited by the value. 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 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% CO , and 95% humidity. EOL-1 cell proliferation assay

[0095] Serial dilutions of test compounds were dispensed into 96-well black, clear-bottom plates (Corning, Corning, NY). Ten thousand cells were added per well in 200 μL of complete growth medium. Plates were incubated for 67 hours at 37°C, 5% CO2, and 95% humidity. At the end of the incubation period, 40 μL of 440 μM resazurin (Sigma, St. Louis, MO) in PBS was added to each well, and the plates were incubated for an additional 5 hours at 37°C, 5% CO2, and 95% humidity. 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 IC50 values.

[0096] Compound A had an IC of 0.029 nM 50 Compound B inhibited the proliferation of FIP1L1-PDGFRα fusion in EOL-1 cells with an IC value of 0.018 nM. 50 At this value, it inhibited the growth of FIP1L1-PDGFRα fusion in EOL-1 cells. 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% CO , and 95% humidity. EOL-1 Western blot

[0098] Cells suspended in serum-free RPMI 1640 medium were added to 24-well tissue culture-treated plates at 2 million cells per well. Serial dilutions of test compounds were added to the cell-containing plates. The plates were incubated for 4 hours at 37°C with 5% CO2 and 95% humidity. Cells were washed with PBS and then lysed. 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 reagents (GE Healthcare, Piscataway, NJ) and Molecular Devices Storm 840. Detection was performed using a phosphorimager in fluorescence mode. Blots were stripped and probed for total PDGFRα using antibodies from Cell Signaling Technology (Beverly, MA). IC50 values ​​were calculated using Prism software (GraphPad, San Diego, CA).

[0099] Compound A had an IC of 0.12 nM 50 Compound B inhibited phosphorylation of FIP1L1-PDGFRα fusion in EOL-1 cells with an IC value of less than 0.1 nM. 50 At this value, it inhibited phosphorylation of FIP1L1-PDGFRα fusion in EOL-1 cells. Example 10. Treatment of human cancer patients with the PDGFRα D842V mutation

[0100] Clinical trial protocol DCC-2618-01-001, "A Multicenter, Phase I, Open-Label Study Evaluating Compound A for Safety, Tolerability, and Pharmacokinetics in Patients with Advanced Malignancies," is the first-in-human study of Compound A (ClinicalTrials.gov The objective of this dose-escalation study was to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of Compound A. The investigational drug was administered orally either once or twice daily at dose escalation ranging from 20 mg BID to 200 mg BID. Preliminary antitumor activity was measured by CT scan every other cycle (every 56 days) according to RECIST 1.1. Pharmacodynamic efficacy was measured as a reduction in mutation allele frequency (MAF) in cell-free plasma (cf) DNA and analyzed using Guardant 360 v2.9 or v2.10 (Guardant Health, Redwood City, CA) with a 73-gene next-generation sequencing panel.

[0101] All patients had progressive disease on standard therapy 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 preclinical data and available pharmacokinetic data from the DCC-2618-01-001 study, dose levels of ≥50 mg BID (equivalent to a daily dose of 100 mg) were sufficient to achieve tumor control, i.e., growth arrest, in these aggressive sarcomas of PDGFRα D842V mutation-dependent tumors in patients with GISTs. Of the three evaluable patients, two were enrolled at or above the target effective dose level (150 mg QD and 100 mg BID). The other patient was enrolled at 30 mg BID and progressed after two 28-day treatment cycles. Patients on 100 mg BID are currently on cycle 11 (>40 weeks) and continue to receive benefit from treatment. The most recent tumor assessment confirmed "stable disease" according to RECIST 1.1. Tumor assessments throughout the study, including the most recent assessment after cycle 9 (36 weeks), revealed some tumor reduction (5-10%). Patients treated at the 150 mg QD dose level were on cycle 6. The two patients are currently undergoing treatment (>20 weeks), with stable disease per RECIST and some tumor regression observed. These two patients had previously received one and three prior tyrosine kinase inhibitor treatments, respectively.

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

[0103] Clinical trial protocol DCC-2618-01-001, "A Multicenter, Phase I, Open-Label Study Evaluating Compound A for Safety, Tolerability, and Pharmacokinetics in Patients with Advanced Malignancies," is the first-in-human study 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 will be administered orally either once or twice daily at escalating doses ranging from 20 mg BID to 200 mg BID. Preliminary antitumor activity was measured by CT scan every other cycle and then every three cycles (every 56 or 84 days) according to the Revised Assessment in Neuro-Oncology (RANO) criteria. Pharmacodynamic effects were measured as the reduction in circulating tumor cells (CTCs). 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). Cells were then incubated with fluorescently labeled antibodies, fixed, and stained with DAPI. Cells positive for DAPI, GFP, PDGFRα, and GFAP fluorescence were counted as circulating glioblastoma tumor cells using a BioTek Cytation 5 imager. Glial fibrillary acidic protein (GFAP) is specifically attributable to glial cells.

[0104] All patients had progressive disease on standard therapy 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 initially treated with combined radio-chemotherapy and then with temozolomide alone, progressing after 3 months. The GBM patient is currently progressing at cycle 19 (>17 months, on study) and continues to benefit from treatment. Since tumor evaluation after cycle 12 (48 weeks), the patient has achieved a "partial response" according to RANO criteria. Figure 1 shows 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 glioblastomas in children and adults. Initial large-scale studies on human tissues proposed a significant association of PDGFRα-amplified HGAs, suggesting that PDGFRα amplification was associated with higher grade and less favorable prognosis in IDH1-mutated de novo GBM (Philips et al., 2014, incorporated herein by reference in its entirety). l., Brain Pathol. (2013) 23(5):565-73). Dunn et al. provide further evidence that PDGFRα amplification is a driving factor in genomic alterations in GBM (Dunn et al., Genes Dev. (2012) 26(8):756-84). Based on these findings, the pharmacodynamic effect, measured as a reduction in CTCs, observed in GBM patients after treatment with Compound A strongly supports that the partial responses observed in GBM patients are the result of treating PDGFRα-amplified tumors with Compound A. Double-positive CTCs (PDGFRα+ / GFAP+) were first measured at cycle 7 (week 28) with a frequency of 2.22 CTCs / mL. At cycle 13 (week 52) and cycle 17 (week 68), the frequency decreased to 1.11 and 0.58 CTCs / mL, respectively. Example 12 Compound B is formed biosynthetically after oral administration of Compound A.

[0106] Clinical trial protocol DCC-2618-01-001, "A Multicenter, Phase I, Open-Label Study Evaluating Compound A for Safety, Tolerability, and Pharmacokinetics in Patients with Advanced Malignancies," is the first-in-human study of Compound A (ClinicalTrials.gov Identifier: NCT02571036). The purpose of this dose-escalation study was to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of Compound A. The investigational drug was administered orally either once or twice daily at escalating doses ranging from 20 mg BID to 200 mg BID. Oral administration of Compound A to patients resulted in systemic exposure of Compound A and biotransformation of Compound A to Compound B via in vivo N-demethylation. For pharmacokinetic (PK) analysis, blood samples were collected immediately prior to the morning administration of Compound A on Day 15 of Cycle 1 and at 0.5, 1, 2, 4, 6, 8, and 10–12 hours post-dose. Compound A and its active metabolite, Compound B, were evaluated using validated bioanalytical methods. Phoenix Plasma concentration versus time data were analyzed and standard non-compartmental PK parameters were calculated using WinNonlin version 6.3. All PK calculations were completed using scheduled sample collection times.

[0107] As an example, administering Compound A to a patient cohort at a dose of 150 mg twice daily or 150 mg once daily results in stable exposure to Compound A and also to Compound B on Cycle 1, Day 15 as shown in the table below.

[0108] In a cohort of five patients, oral administration of a 150 mg dose of Compound A BID (twice daily) for 15 days resulted in exposure to Compound A with a mean Cmax of 1,500 ng / mL and a mean area under the curve (AUC) of 11,400 ng*h / mL. This 15-day administration resulted in biotransformation to Compound B with a mean Cmax of 1,520 ng / mL and a mean AUC of 15,100 ng*h / mL. In a cohort of four patients, oral administration of a 150 mg dose of Compound A QD (once daily) for 15 days resulted in exposure to Compound A with a mean Cmax of 861 ng / mL and a mean area under the curve (AUC) of 8,070 ng*h / mL. This 15-day administration resulted in biotransformation to Compound B with a mean Cmax of 794 ng / mL and a mean AUC of 8,600 ng*h / mL. Table 1 [Table 1]

[0109] Equal Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments specifically described in this disclosure which equivalents are intended to be encompassed by the following claims.

Claims

1. A method for 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.

2. 2. The method of claim 1, wherein the tumor growth or progression is caused by one or more of overexpression of PDGFRα kinase, oncogenic missense mutations of PDGFRα, oncogenic deletion mutations of PDGFRα, oncogenic rearrangements of the PDGFRα gene resulting in PDGFRα fusion proteins, intragenic in-frame deletions of PDGFRα, or oncogenic gene amplification of PDGFRα.

3. 3. The method of claim 1 or 2, wherein the tumor growth or tumor progression is caused by overexpression of PDGFRα kinase.

4. 3. The method of claim 1 or 2, wherein the tumor growth or tumor progression is caused by an oncogenic missense mutation in PDGFRα or an oncogenic deletion mutation in PDGFRα.

5. 3. The method of claim 1 or 2, wherein the tumor growth or tumor progression is caused by an oncogenic rearrangement of the PDGFRα gene that results in a PDGFRα fusion protein or an intragenic in-frame deletion of PDGFRα.

6. 3. The method of claim 1 or 2, wherein the tumor growth or tumor progression is caused by oncogenic gene amplification of PDGFRα.

7. The method of any one of claims 1 to 6, wherein the tumor is lung adenoma, squamous cell lung carcinoma, glioblastoma, childhood glioma, astrocytoma, sarcoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilic acute myeloid leukemia, or lymphoblastic T-cell lymphoma.

8. The method of any one of claims 1 to 7, wherein the tumor is a glioblastoma.

9. The method according to any one of claims 1 to 7, wherein the tumor is a gastrointestinal stromal tumor.

10. The method of 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 other cancer targeted therapeutic agents, cancer targeted biologics, immune checkpoint inhibitors, or chemotherapeutic agents.

11. The therapeutic agent is selected from the group consisting of cytotoxic agents such as cisplatin, doxorubicin, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, lonafarib, 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, and interferon alpha-2. b, pegylated interferon alfa-2b, aromatase combination, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, leucovorin, oxaliplatin pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17α-ethynylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, methyl Prednisolone, 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, anastrazole, letrozole, 11. The method of claim 10, wherein the medicament is selected from pecitabine, 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.

12. The immune checkpoint inhibitors are selected from the group consisting of the CTLA4 inhibitors ipilimumab and tremelimumab; the PD1 inhibitors pembrolizumab and nivolumab; the PDL1 inhibitors atezolizumab (formerly MPDL3280A), durvalumab (MEDI4736), avelumab, and the monoclonal antibody PDR001; the 4-1BB ligand inhibitors urelumab and utomilumab PF05082566; and the OX40 agonist monoclonal antibody MEDI6. 469; monoclonal antibody TRX518, a glucocorticoid-induced tumor necrosis factor receptor (GITR) inhibitor; CD27 inhibitor varlilumab; TNFRSF25-TL1A inhibitor; CD40 agonist monoclonal antibody CP870893; HVEM-LIGHT-LTA and HVEM-BTLA-CD160 inhibitor; LAG3 inhibitor monoclonal antibody BMS986016; TIM3 inhibitor; Siglecs inhibitor; ICOS linker Gand agonists; B7-H3 inhibitor enoblituzumab MGA271; B7-H4 inhibitors; VISTA inhibitors; HHLA2-TMIGD2 inhibitors; butyrophilins inhibitors; BTNL2 inhibitors; CD244-CD48 inhibitors; inhibitors of TIGIT and PVR family members; KIR inhibitor lirilumab; ILT and LIR inhibitors; NKG2D and NKG2A inhibitor monalizumab IPH2201; MI CA and MICB inhibitors; CD244 inhibitors; CSF1R inhibitors emactuzumab, cabilalizumab, pexidartinib, ARRY382, and BLZ945; IDO inhibitor (3E)-3-[(3-bromo-4-fluoroanilino)-nitrosomethylidene]-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole, INCB024360; TGFβ inhibitor galunisertib; adenosine-CD39-CD73 inhibitors;the CXCR4-CXCL12 inhibitors urocupulumab 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-fluorobenzamido)-5-guanidinopentanamido)-5-guanidinopentanamido)-3-(naphthalen-2-yl)propanamido)-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; the phosphatidylserine inhibitor bavituximab; the SIRPA-CD47 inhibitor monoclonal antibody CC90002; the VEGF inhibitor bevacizumab; and / or the neuropilin inhibitor monoclonal antibody MNRP1685A.

13. 12. The method of claim 11, wherein the therapeutic agent is temozolomide.

14. The method of claim 1 further comprising administering ionizing radiation.

15. 10. The method of claim 1, further comprising administering temozolomide and ionizing radiation.

16. The additional therapeutic agent is selected from the group consisting of an AKT inhibitor, an alkylating agent, all-trans retinoic acid, an antiandrogen, 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 farnesyltransferase inhibitor, a FLT3 inhibitor, a glucocorticoid receptor agonist, an HDM2 inhibitor, and a histone 11. The method of claim 10, wherein the therapeutic agent is selected from a 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, a SUV39H1 inhibitor, TRAIL, a VEGFR2 inhibitor, a Wnt / β-catenin signaling inhibitor, decitabine, and an anti-CD20 monoclonal antibody.

17. 1. A method of 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.

18. 18. The method of claim 17, wherein the PDGFR kinase is PDGFRα or PDGFRβ.

19. 18. The method of claim 17, further comprising administering a cancer targeted therapeutic agent, a cancer targeted biologic, an immune checkpoint inhibitor, or a chemotherapeutic agent.

20. The therapeutic agent is selected from the group consisting of cytotoxic agents such as cisplatin, doxorubicin, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, lonafarib, tipifarnib, 4-((5-((4-(3-chlorophenyl)-3-oxopiperazin-1-yl)methyl)-1H-imidazol-1-yl)methyl)benzonitrile hydrochloride, (R)-1-((1H-imidazole-5 -yl)methyl)-3-benzyl-4-(thiophen-2-ylsulfonyl)-2,3,4,5-tetrahydro-1H-benzodiazepine-7-carbonitrile, cetuximab, imatinib, interferon alfa-2b, pegylated interferon alfa-2b, aromatase combinations, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan Antihistamine, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, leucovorin, oxaliplatin, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide, 17α-ethynylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, 17α-hydroxyprogesterone ron, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide acetate, flutamide, toremifene citrate, goserelin acetate, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, vinorelbine, anastrazole, letrozole, capecitabine, raloxifene, droloxafine 20. The method of claim 19, wherein the medicament is selected from the group consisting of benzodiazepine, benzodiazepine, benzocaine, benzodiazepine, benzocaine, benzocaine, benzocaine, hexamethylmelamine, bevacizumab, trastuzumab, tositumomab, bortezomib, ibritumomab tiuxetan, arsenic trioxide, porfimer sodium, cetuximab, thioTEPA, altretamine, fulvestrant, exemestane, rituximab, alemtuzumab, dexamethasone, bicalutamide, chlorambucil, and valrubicin.

21. The immune checkpoint inhibitors are selected from the group consisting of the CTLA4 inhibitors ipilimumab and tremelimumab; the PD1 inhibitors pembrolizumab and nivolumab; the PDL1 inhibitors atezolizumab (formerly MPDL3280A), durvalumab (formerly MEDI4736), avelumab, and the monoclonal antibody PDR001; the 4-1BB ligand inhibitors urelumab and utomilumab (PF05082566); and the OX40 ligand agonist monoclonal antibody MEDI6469; monoclonal antibody TRX518, a glucocorticoid-induced tumor necrosis factor receptor (GITR) inhibitor; varlilumab, a CD27 inhibitor; TNFRSF25-TL1A inhibitor; CD40 ligand agonist monoclonal antibody CP870893, an inhibitor of HVEM-LIGHT-LTA and HVEM-BTLA-CD160; LAG3 inhibitor monoclonal antibody BMS986016; TIM3 inhibitor; Siglecs inhibitor agents; ICOS ligand agonists; B7-H3 inhibitor enoblituzumab MGA271; B7-H4 inhibitors; VISTA inhibitors; HHLA2-TMIGD2 inhibitors; butyrophilins inhibitors; BTNL2 inhibitors; CD244-CD48 inhibitors; inhibitors of TIGIT and PVR family members; KIR inhibitor lirilumab; ILT and LIR inhibitors; NKG2D and NKG2A inhibitor monalizumab IPH2201 ; inhibitors of MICA and MICB; CD244 inhibitors; CSF1R inhibitors emactuzumab, caviralizumab, pexidartinib, ARRY382, and BLZ945; IDO inhibitor (3E)-3-[(3-bromo-4-fluoroanilino)-nitrosomethylidene]-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole, INCB024360; TGFβ inhibitor galunisertib; adenosine-CD39-CD73 inhibitors;The CXCR4-CXCL12 inhibitors urocupulumab 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-fluorobenzamido)-5-guanidinopentanamido)-5-gua Nidinopentanamido)-3-(naphthalen-2-yl)propanamido)-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]; 20. The method of claim 19, wherein the therapeutic agent is selected from nonazacyclodotriacontin-12-carboxamide BKT140; the phosphatidylserine inhibitor bavituximab; the SIRPA-CD47 inhibitor monoclonal antibody CC90002; the VEGF inhibitor bevacizumab; and / or the neuropilin inhibitor monoclonal antibody MNRP1685A.

22. 20. The method of claim 19, wherein the therapeutic agent is temozolomide.

23. 17. The method of claim 16, further comprising administering ionizing radiation.

24. 17. The method of claim 16, further comprising administering temozolomide and ionizing radiation.

25. The additional therapeutic agent is selected from the group consisting of an AKT inhibitor, an alkylating agent, all-trans retinoic acid, an antiandrogen, 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 farnesyltransferase inhibitor, a FLT3 inhibitor, a glucocorticoid receptor agonist, an HDM2 inhibitor, and a histone 20. The method of claim 19, wherein the therapeutic agent is selected from a 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, a SUV39H1 inhibitor, TRAIL, a VEGFR2 inhibitor, a Wnt / β-catenin signaling inhibitor, decitabine, and an anti-CD20 monoclonal antibody.

26. 1. A method of 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.

27. 27. The method of claim 26, further comprising administering a cancer targeted therapeutic agent, a cancer targeted biologic, an immune checkpoint inhibitor, or a chemotherapeutic agent.

28. The therapeutic agent is selected from the group consisting of cytotoxic agents cisplatin, doxorubicin, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, lonafarib, 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, and pegylated interferon alpha-2b. , aromatase combinations, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, leucovorin, oxaliplatin, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17α-ethinylestradiol, diethylstilbestrol, Testosterone, prednisone, fluoxymesterone, dromostanolone 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, anastrazole, 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.

29. The immune checkpoint proteins are selected from the group consisting of the CTLA4 inhibitors ipilimumab and tremelimumab; the PD1 inhibitors pembrolizumab and nivolumab; the PDL1 inhibitors atezolizumab (formerly MPDL3280A), durvalumab (formerly MEDI4736), and avelumab, and the monoclonal antibody PDR001; the 4-1BB ligand inhibitors urelumab and utomilumab PF 05082566; the OX40 ligand agonist monoclonal antibody MEDI6469; the glucocorticoid-inducible tumor necrosis factor receptor (GITR) inhibitor monoclonal antibody TRX518; the CD27 inhibitor varlilumab; the TNFRSF25-TL1A inhibitor; the CD40 ligand agonist monoclonal antibody CP870893; and HVEM-LIGHT-L. TA and HVEM-BTLA-CD160 inhibitors; LAG3 inhibitor monoclonal antibody BMS986016; TIM3 inhibitors; Siglecs inhibitors; ICOS ligand agonists; B7-H3 inhibitor enoblituzumab MGA271; B7-H4 inhibitors; VISTA inhibitors; HHLA2-TMIGD2 inhibitors; butyrophilin (Butyro) philins inhibitors; BTNL2 inhibitors; CD244-CD48 inhibitors; TIGIT and PVR family member inhibitors; KIR inhibitor lirilumab; ILT and LIR inhibitors; NKG2D and NKG2A inhibitor monalizumab IPH2201; MICA and MICB inhibitors; CD244 inhibitors; CSF1R inhibitors emactuzumab, caviralizumab, pexidartinib, ARRY382, and BLZ945; IDO inhibitor (3E)-3-[(3-bromo-4-fluoroanilino)-nitrosomethylidene]-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole, INCB024360; TGFβ inhibitor galunisertib; adenosine-CD39-CD73 inhibitors;The CXCR4-CXCL12 inhibitors urocupulumab 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-fluorobenzamido)-5-guanidinopentanamido)-5-guanidinopentanamido)-3 -(naphthalen-2-yl)propanamido)-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 28. The method of claim 27, wherein the antibody is selected from BKT140, the phosphatidylserine inhibitor bavituximab, the SIRPA-CD47 inhibitor monoclonal antibody CC90002, the VEGF inhibitor bevacizumab, and / or the neuropilin inhibitor monoclonal antibody MNRP1685A.

30. 29. The method of claim 28, wherein the therapeutic agent is temozolomide.

31. 27. The method of claim 26, further comprising administering ionizing radiation.

32. 27. The method of claim 26, further comprising administering temozolomide and ionizing radiation.

33. The additional therapeutic agent is selected from the group consisting of an AKT inhibitor, an alkylating agent, all-trans retinoic acid, an antiandrogen, 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 farnesyltransferase inhibitor, a FLT3 inhibitor, a glucocorticoid receptor agonist, an HDM2 inhibitor, and a histone 28. The method of claim 27, wherein the therapeutic agent is selected from a 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, a SUV39H1 inhibitor, TRAIL, a VEGFR2 inhibitor, a Wnt / β-catenin signaling inhibitor, decitabine, and an anti-CD20 monoclonal antibody.

34. 1. A method for treating PDGFRα-mediated gastrointestinal stromal tumors, 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.

35. 35. The method of claim 34, further comprising administering a cancer targeted therapeutic agent, a cancer targeted biologic, an immune checkpoint inhibitor, or a chemotherapeutic agent.

36. The therapeutic agent is selected from the group consisting of cytotoxic agents such as cisplatin, doxorubicin, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, lonafarib, 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 alfa-2b, pegylated interferon alfa-2b, aromatase combinations, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptomethylidin, Putozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, leucovorin, oxaliplatin, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17α-ethinylestradiol, diethylstilbestrol, testosterone, protease inhibitors Rednisone, fluoxymesterone, dromostanolone 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, mitoxin 36. The method of claim 35, wherein the agent is selected from santrone, levamisole, vinorelbine, anastrazole, 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.

37. The immune checkpoint inhibitors include the CTLA4 inhibitors ipilimumab and tremelimumab; the PD1 inhibitors pembrolizumab and nivolumab; the PDL1 inhibitors atezolizumab (formerly MPDL3280A), durvalumab MEDI4736, avelumab, and the monoclonal antibody PDR001; the 4-1BB ligand inhibitors urelumab and utomilumab PF05082566; and the OX40 ligand agonist monoclonal antibody MEDI 6469; monoclonal antibody TRX518, a glucocorticoid-induced tumor necrosis factor receptor (GITR) inhibitor; CD27 inhibitor varlilumab; TNFRSF25-TL1A inhibitor; CD40 ligand agonist monoclonal antibody CP870893; HVEM-LIGHT-LTA and HVEM-BTLA-CD160 inhibitor; LAG3 inhibitor monoclonal antibody BMS986016; TIM3 inhibitor; Siglecs inhibitor; I COS ligand agonists; B7-H3 inhibitor enoblituzumab MGA271; B7-H4 inhibitors; VISTA inhibitors; HHLA2-TMIGD2 inhibitors; butyrophilins inhibitors; BTNL2 inhibitors; CD244-CD48 inhibitors; inhibitors of TIGIT and PVR family members; KIR inhibitor lirilumab; ILT and LIR inhibitors; NKG2D and NKG2A inhibitor monalizumab IPH2201; MICA and MICB inhibitors; CD244 inhibitors; CSF1R inhibitors emactuzumab, caviralizumab, pexidartinib, AMG382, and BLZ945; IDO inhibitor (3E)-3-[(3-bromo-4-fluoroanilino)-nitrosomethylidene]-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole, INCB024360; TGFβ inhibitor galunisertib; adenosine-CD39-CD73 inhibitors;The CXCR4-CXCL12 inhibitors urocupulumab 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-fluorobenzamido)-5-guanidinopentanamido)-5-guanidinopentanamido)-3 -(naphthalen-2-yl)propanamido)-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 The method of claim 35, wherein the antibody is selected from BKT140, the phosphatidylserine inhibitor bavituximab, the SIRPA-CD47 inhibitor monoclonal antibody CC90002, the VEGF inhibitor bevacizumab, and / or the neuropilin inhibitor monoclonal antibody MNRP1685A.

38. 37. The method of claim 36, wherein the therapeutic agent is temozolomide.

39. 35. The method of claim 34, further comprising administering ionizing radiation.

40. 35. The method of claim 34, further comprising administering temozolomide and ionizing radiation.

41. The additional therapeutic agent is an AKT inhibitor, an alkylating agent, all-trans retinoic acid, Antiandrogens, 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, immunosuppressants 36. The method of claim 35, wherein the therapeutic agent is selected from 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, a SUV39H1 inhibitor, TRAIL, a VEGFR2 inhibitor, a Wnt / β-catenin signaling inhibitor, decitabine, and an anti-CD20 monoclonal antibody.

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