Search

US-12617758-B2 - Quinazoline derivative having FLT3 inhibitory activity, and use thereof

US12617758B2US 12617758 B2US12617758 B2US 12617758B2US-12617758-B2

Abstract

The present invention relates to a novel quinazoline derivative having fms-like tyrosine kinase 3 (FLT3) inhibitory activity, and a use thereof. A novel quinazoline derivative or a pharmaceutically acceptable salt thereof, according to the present invention, exhibits excellent inhibitory activity against FLT3, and thus targeted treatment through more fundamental approaches is expected in the prevention or treatment of acute myeloid leukemia (AML).

Inventors

  • Jung-Mi Hah
  • Da Seul Im

Assignees

  • INDUSTRY-UNIVERSITY COOPERATION FOUNDATION HANYANG UNIVERSITY ERICA CAMPUS

Dates

Publication Date
20260505
Application Date
20210924
Priority Date
20200925

Claims (13)

  1. 1 . A compound of the following Chemical Formula 7 or a pharmaceutically acceptable salt thereof: wherein, in Chemical Formula 7, R 1 is R 2 is selected from the group consisting of indazolyl, naphthalenyl, dihydrobenzofuranyl, pyridinyl, acetyl piperidine, phenyl which is unsubstituted or substituted with one or more non-hydrogen substituents, pyrazolyl which is unsubstituted or substituted with one or more non-hydrogen substituents, dihydroisoxazole which is unsubstituted or substituted with one or more non-hydrogen substituents, or a C 3 -C 7 cycloalkyl, the non-hydrogen substituent in R 2 is selected from the group consisting of phenyl, hydroxy, a C 1 -C 6 alkyl, a C 1 -C 6 halogenated alkyl, or a halogen atom, R 3 is a hydrogen atom, hydroxy, a C 1 -C 6 alkyl or a C 1 -C 6 halogenated alkyl, R 4 is a hydrogen atom, hydroxy or a C 1 -C 6 alkyl, or is absent, here, X is a nitrogen or oxygen atom, and Y is a halogen or oxygen atom, R 5 is a hydrogen atom, hydroxy, a halogen atom or a C 1 -C 6 halogenated alkyl, R 6 is a hydrogen atom, hydroxy or a C 1 -C 6 alkyl, and a connecting line expressed as a double line ( ) of a solid line and a dotted line represents a single carbon-carbon bond or a double carbon-carbon bond.
  2. 2 . The compound of claim 1 , wherein the compound of Chemical Formula 7 has a structure of the following Chemical Formula 7′, in Chemical Formula 7′, R 2 is selected from the group consisting of indazolyl, naphthalenyl, dihydrobenzofuranyl, pyridinyl, acetyl piperidine, phenyl which is unsubstituted or substituted with one or more non-hydrogen substituents, pyrazolyl which is unsubstituted or substituted with one or more non-hydrogen substituents, dihydroisoxazole which is unsubstituted or substituted with one or more non-hydrogen substituents, or a C 3 -C 7 cycloalkyl, the non-hydrogen substituent in R 2 is selected from the group consisting of phenyl, hydroxy, a C 1 -C 6 alkyl, a C 1 -C 6 halogenated alkyl, or a halogen atom, R 3 is a hydrogen atom, hydroxy, a C 1 -C 6 alkyl or a C 1 -C 6 halogenated alkyl, R 4 is a hydrogen atom, hydroxy or a C 1 -C 6 alkyl, or is absent, here, X is a nitrogen or oxygen atom, and Y is a halogen or oxygen atom, R 5 is a hydrogen atom, hydroxy, a halogen atom or a C 1 -C 6 halogenated alkyl, R 6 is a hydrogen atom, hydroxy or a C 1 -C 6 alkyl, and a connecting line expressed as a double line (z, 25 ) of a solid line and a dotted line represents a single carbon-carbon bond or a double carbon-carbon bond.
  3. 3 . The compound of claim 2 , wherein R 2 is selected from the group consisting of indazolyl, pyridinyl, phenyl which is unsubstituted or substituted with one or more non-hydrogen substituents, or the non-hydrogen substituent in R 2 is selected from the group consisting of or a C 1 -C 6 halogenated alkyl, R 3 is a C 1 -C 6 alkyl, R 4 is a C 1 -C 6 alkyl or absent, here, X is an oxygen atom, Y is a halogen or oxygen atom, and R 6 is hydrogen or a C 1 -C 6 alkyl, and a connecting line expressed as a double line ( ) of a solid line and a dotted line represents a single carbon-carbon bond or a double carbon-carbon bond.
  4. 4 . The compound of claim 1 , wherein R 3 is a C 1 -C 6 alkyl.
  5. 5 . The compound of claim 1 , wherein R 2 is
  6. 6 . The compound of claim 2 , wherein R 3 is a C 1 -C 6 alkyl, and R 2 is
  7. 7 . The compound of claim 1 , wherein the compound of Chemical Formula 7 is 5-methyl-N-(2-(4-morpholino-5-(trifluoromethyl)phenyl)quinazolin-7-yl)isoxazole-4-carboxamide; 5-methyl-N-(2-(3-morpholino-5-(trifluoromethyl)phenyl)quinazolin-7-yl)isoxazole-4-carboxamide; 5-methyl-N-(2-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)quinazolin -7-yl)isoxazole-4-carboxamide; 5-methyl-N-(2-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)quinazolin-7-yl)isoxazole-4-carboxamide; N-(2-(3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)quinazolin-7-yl) -5-methylisoxazole-4-carboxamide; N-(2-(3-fluoro-5-(trifluoromethyl)phenyl)quinazolin-7-yl)-5-methylisoxazole-4-carboxamide; N-(2-(4-chloro-3-(trifluoromethyl)phenyl)quinazolin-7-yl)-5-methylisoxazole-4-carboxamide; 5-methyl-N-(2-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)quinazolin-7-yl)isoxazole-4-carboxamide; N-(2-(3-chlorophenyl) quinazolin-7-yl)-5-methylisoxazole-4-carboxamide; (E)-N-(2-(4-methoxystyryl)quinazolin-7-yl)-5-methylisoxazole-4-carboxamide; (E)-N-(2-(4-chlorostyryl)quinazolin-7-yl)-5-memthylisoxazole-4-carboxamide; N-(2-(5-(tert-butyl)isoxazol-3-yl)quinazolin-7-yl)-5-methylisoxazole-4-carboxamide; N-(2-(1H-indazol-5-yl)quinazolin-7-yl)-5-methylisoxazole-4-carboxamide; 5-methyl-N-(2-(3-((1-methylpiperidin-4-yl)oxy)-5-(trifluoromethyl)phenyl)quinazolin-7-yl)isoxazole-4-carboxamide; N-(2-(1-acetylpiperidin-4-yl)quinazolin-7-yl)-5-methylisoxazole-4-carboxamide; 5-methyl-N-(2-(pyridin-4-yl)quinazolin-7-yl)isoxazole-4-carboxamide; 5-methyl-N-(2-(pyridin-2-yl)quinazolin-7-yl)isoxazole-4-carboxamide; N-(2-(3,4-dichlorophenyl)quinazolin-7-yl)-5-methylisoxazole-4-carboxamide; N-(2-(4-fluorobenzyl)quinazolin-7-yl)-5-methylisoxazole-4-carboxamide; 5-methyl-N-(2-(2-(trifluoromethyl)benzyl)quinazolin-7-yl)isoxazole-4-carboxamide; 5-methyl-N-(2-(naphthalen-2-yl)quinazolin-7-yl)isoxazole-4-carboxamide; N-(2-(2,3-dihydrobenzofuran-5-yl)quinazolin-7-yl)-5-methylisoxazole-4-carboxamide; or N-(2-(4-methoxyphenethyl)quinazolin-7-yl)-5-methylisoxazole-4-carboxamide.
  8. 8 . A pharmaceutical composition for preventing or treating cancer, comprising the quinazoline derivative, or the pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.
  9. 9 . The pharmaceutical composition of claim 8 , wherein the cancer disease is acute myeloid leukemia (AML).
  10. 10 . The pharmaceutical composition of claim 9 , wherein the composition inhibits fms-like tyrosine kinase 3 (FLT 3) activity.
  11. 11 . A method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the quinazoline derivative, or the pharmaceutically acceptable salt thereof according to claim 1 .
  12. 12 . The method of claim 11 , wherein the cancer disease is acute myeloid leukemia (AML).
  13. 13 . The method of claim 12 , wherein the quinazoline derivative inhibits fms-like tyrosine kinase 3 (FLT 3) activity.

Description

TECHNICAL FIELD The present invention relates to a novel quinazoline derivative having fms-like tyrosine kinase 3 (FLT3) inhibitory activity, and a use thereof. The present invention was made under the support of the Ministry of Science and ICT (2017Y) of the Republic of Korea with the project number NRF-2019M3A9A8066500, the research management institution for the project is the “National Research Foundation of Korea,” the research business title is “Core Technology Development Project/Bio & Medical Technology Development Project/Research Program for New Drug Target Identification and Validation,” the research project title is “Validation of JNK inhibitor having effects of suppressing nerve cell apoptosis and improving cognitive functions as therapeutic agent for Alzheimer's disease,” and the research period is “Jun. 1, 2019 to Feb. 29, 2020.” The present patent application claims priority to and the benefit of Korean Patent Application No. 10-2020-0124692, filed on Sep. 25, 2020, the disclosure of which is incorporated herein by reference in its entirety. BACKGROUND ART As fms-like tyrosine kinase 3 (FLT3) is a type of trans-membrane receptor tyrosine kinase expressed in lymph-hematopoietic cells and is a target of acute myeloid leukemia (AML), it is drawing attention because FLT3 is involved in the regulation of survival, proliferation and differentiation of hematopoietic stem/progenitor cells in an AML patient. When the FLT3 ligand binds to FLT3 kinase, FLT3 is activated and autophosphorylated. Subsequently, FLT3 activates multiple downstream signaling pathways including signal transducer and activator of transcription 5 (STATS), Ras/mitogen-activated protein kinase (Ras/MAPK) and phosphatidylinositol 3-kinase/Akt pathways, consequently playing an important role in the proliferation and survival of cells and immune responses. However, mutated FLT3 causes activation regardless of the presence or absence of a ligand. FLT3 mutations can be categorized by mutation location and type, represented by internal tandem duplications (ITDs) and point mutations in the tyrosine kinase domain (TKD). FLT3-ITD mutations account for 20 to 30% of AML patients and are importantly directly linked to an abnormal increase in leukocytes and poor prognosis, and point mutations in the TKD are found in 5% of AML cases. Despite the importance of finding a cure for AML, the number of therapeutic materials approved to date, such as midostaurin and gilteritinib (ASP2215), is very small. Protein kinase inhibitors can be classified into type I, type II and type III based on their binding mode (Non-Patent Document 0001). Among these inhibitors, type II kinase inhibitors can acquire selectivity having additional interactions with the DFG pocket adjacent to the ATP-binding pocket on top of the hinge hydrogen bond at the ATP-site and exhibit promising efficacy (Non-Patent Document 0002). Quinazoline structures are well-known as privileged structures in medicinal chemistry and exhibit diverse biologically active properties, but were first attempted in type II PKI modification. By introducing such a structure into an in-house type II kinase inhibitor, a novel FLT3 inhibitor could be discovered. Further, the novel FLT3 inhibitor of the present invention achieved a selectivity profile, particularly compared to cKIT and FMS kinases. (Non-Patent Document 0001) Wu P, Nielsen T E, Clausen M H. FDA-approved small-molecule kinase inhibitors. Trends Pharmacol Sci. 2015; 36(7):422-439.(Non-Patent Document 0002) Versele, M, Haefner, B, Wroblowski, B, Stansfield, I, Mevellec, L, Gilissen, R, et al. Covalent Flt3-Cys828 inhibition represents a novel therapeutic approach for the treatment of Flt3-ITD and Flt3-D835 mutant acute myeloid leukemia. Cancer Res. 2016; 76(14):4800. DISCLOSURE Technical Problem The present invention has been made to solve the problem as described above, and as a result of intensive studies to find a novel material which is likely to be developed as a therapeutic agent for acute myeloid leukemia (AML), the present inventors identified a novel quinazoline derivative showing FLT3 inhibitory activity, thereby completing the present invention based on this. Thus, an object of the present invention is to provide a novel quinazoline derivative having FLT3 inhibitory activity, or a pharmaceutically acceptable salt thereof. Another object of the present invention is to provide a method for preparing a novel quinazoline derivative having FLT3 inhibitory activity. Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating an acute leukemia disease, including the imidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient. However, technical problems to be solved by the present invention are not limited to the aforementioned problems, and other problems that are not mentioned may be clearly understood by those skilled in the art from the following descrip