WO2022065894A1 - Flt3 저해 활성을 갖는 신규한 퀴나졸린 유도체 및 이의 용도 - Google Patents
Flt3 저해 활성을 갖는 신규한 퀴나졸린 유도체 및 이의 용도 Download PDFInfo
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- WO2022065894A1 WO2022065894A1 PCT/KR2021/012997 KR2021012997W WO2022065894A1 WO 2022065894 A1 WO2022065894 A1 WO 2022065894A1 KR 2021012997 W KR2021012997 W KR 2021012997W WO 2022065894 A1 WO2022065894 A1 WO 2022065894A1
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- WO
- WIPO (PCT)
- Prior art keywords
- quinazolin
- carboxamide
- compound
- alkyl
- phenyl
- Prior art date
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- 101100335081 Mus musculus Flt3 gene Proteins 0.000 title claims description 5
- 230000002401 inhibitory effect Effects 0.000 title abstract description 15
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title abstract description 3
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- 230000002265 prevention Effects 0.000 claims abstract description 4
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 46
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 claims description 38
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
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- 150000003246 quinazolines Chemical class 0.000 claims description 14
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 12
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- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Images
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- the present invention relates to a novel quinazoline derivative having FLT3 (fms-like tyrosine kinase 3) inhibitory activity and uses thereof.
- the present invention was made by project number NRF-2019M3A9A8066500 under the support of the Ministry of Science and ICT (2017Y) of the Republic of Korea.
- Technology development project / new drug target discovery and verification project the research project title is “Verification of a treatment for Alzheimer’s dementia with a JNK inhibitor that has the effect of inhibiting nerve cell death and improving cognitive function”, research period “2019.06.01.-2020.02.29 "am.
- Fms-like tyrosine kinase (fms-like tyrosine kinase 3, FLT3) is a type of trans-membrane receptor tyrosine kinase expressed in lymph-hematopoietic cells. Hematopoietic mothers of acute myeloid leukemia (AML) patients / Because it is involved in the regulation of survival, proliferation, and differentiation of progenitor cells, it is a popular target for AML. When FLT3 ligand binds to FLT3 kinase, FLT3 is activated and autophosphorylated.
- AML acute myeloid leukemia
- FLT3 signal transducer and activator of transcription 5 (STAT5), Ras/mitogen-activated protein kinase (Ras/MAPK) and phosphatidylinositol 3-kinase It activates multiple downstream signaling pathways, including kinase)/Akt pathways, and consequently plays an important role in cell proliferation, survival, and immune response.
- Ras/MAPK Ras/mitogen-activated protein kinase
- phosphatidylinositol 3-kinase phosphatidylinositol 3-kinase It activates multiple downstream signaling pathways, including kinase)/Akt pathways, and consequently plays an important role in cell proliferation, survival, and immune response.
- the mutated FLT3 activates independently of the presence or absence of a ligand. FLT3 mutations can be classified according to the location and type of mutations, representing internal tandem duplications (ITD) and point mutation in tyrosine kinase domain (TKD).
- FLT3-ITD mutations account for 20-30% of AML patients and are importantly directly associated with abnormal increases in leukocytes and poor prognosis. Point mutations in TKD are found in 5% of AML cases. Despite the importance of finding a cure for AML, there are very few therapeutic agents approved to date, such as Midostaurine and Gilteritinib (ASP2215).
- Protein kinase inhibitors can be classified into type I, type II, and type III based on the binding mode (Non-Patent Document 0001). Among these inhibitors, type II kinase inhibitors acquire selectivity with further interaction with the DFG pocket adjacent to the ATP-binding pocket at the top of the hinge hydrogen bond at the ATP-site and may show promising efficacy (non-patented). literature 0002).
- the quinazoline structure is well known as a privileged structure in medicinal chemistry and exhibits a variety of biologically active properties, but it was first attempted in type II PKI modification. By introducing this structure into an in-house type II kinase inhibitor, novel FLT3 inhibitors could be discovered. In addition, the novel FLT3 inhibitors of the present invention achieved a selective profile, especially compared to cKIT and FMS kinases.
- Non-Patent Document 0001 Wu P, Nielsen TE, Clausen MH. 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.
- the present invention was devised to solve the above problems, and as a result of intensive research to find new substances with potential for development as a treatment for acute myeloid leukemia (AML), the present inventors developed a novel quinazoline derivative exhibiting FLT3 inhibitory activity. It was confirmed, and based on this, the present invention was completed.
- AML acute myeloid leukemia
- Another object of the present invention is to provide a method for preparing a novel quinazoline derivative having FLT3 inhibitory activity.
- Another object of the present invention is to provide a pharmaceutical composition for preventing or treating acute leukemia disease, comprising the quinazoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention provides a compound of Formula 7 or a pharmaceutically acceptable salt thereof.
- R 1 is ego
- R 2 is indazolyl, naphthalenyl, dihydrobenzofuranyl, pyridinyl, acetyl piperidine, phenyl unsubstituted or substituted with one or more non-hydrogen substituents, pyrazolyl unsubstituted or substituted with one or more non-hydrogen substituents , dihydroisoxazole unsubstituted or substituted with one or more non-hydrogen substituents,
- the non-hydrogen substituent in R 2 is,
- phenyl is selected from the group consisting of phenyl, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 halogenated alkyl or halogen atom,
- R 3 is a hydrogen atom, hydroxy, C 1 -C 6 alkyl or C 1 -C 6 halogenated alkyl
- R 4 is a hydrogen atom, hydroxy or C 1 -C 6 alkyl or absent;
- X is a nitrogen or oxygen atom
- 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 C 1 -C 6 alkyl
- Double line of solid and dotted lines ( ) represents a single carbon-carbon bond or a double carbon-carbon bond.
- the present invention provides a pharmaceutical composition for preventing or treating acute myeloid leukemia (AML) disease, comprising the derivative of Formula 7 or a pharmaceutically acceptable salt thereof as an active ingredient.
- AML acute myeloid leukemia
- the composition may inhibit the activity of FLT 3 (fms-like tyrosine kinase 3).
- the present invention provides a method for treating acute myeloid leukemia (AML), comprising administering to an individual the derivative of Formula 7 or a pharmaceutically acceptable salt thereof.
- AML acute myeloid leukemia
- the present invention provides a therapeutic use of the derivative of Formula 7 or a pharmaceutically acceptable salt thereof for acute myeloid leukemia (AML) disease.
- AML acute myeloid leukemia
- novel quinazoline derivative or a pharmaceutically acceptable salt thereof according to the present invention is an excellent target for FLT 3 (fms-like tyrosine kinase 3, fms-like tyrosine kinase 3) and exhibits inhibitory activity.
- the pharmaceutical composition may be usefully used for the prevention and treatment of cancer including acute myeloid leukemia (AML).
- 1 is a diagram showing the selective FLT3 inhibitory activity of compound 7d of the present invention.
- the present invention provides a compound of Formula 7 or a pharmaceutically acceptable salt thereof.
- R 1 is ego
- R 2 is indazolyl, naphthalenyl, dihydrobenzofuranyl, pyridinyl, acetyl piperidine, phenyl unsubstituted or substituted with one or more non-hydrogen substituents, pyrazolyl unsubstituted or substituted with one or more non-hydrogen substituents , dihydroisoxazole unsubstituted or substituted with one or more non-hydrogen substituents,
- the non-hydrogen substituent in R 2 is,
- phenyl hydroxy, C 1 -C 6 alkyl, C 1 -C 6 halogenated alkyl or halogen atom selected from,
- R 3 is a hydrogen atom, hydroxy, C 1 -C 6 alkyl or C 1 -C 6 halogenated alkyl
- R 4 is a hydrogen atom, hydroxy or C 1 -C 6 alkyl or absent;
- X is a nitrogen or oxygen atom
- 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 C 1 -C 6 alkyl
- Double line of solid and dotted lines ( ) represents a single carbon-carbon bond or a double carbon-carbon bond.
- alkyl generally refers to a straight or branched chain saturated hydrocarbon group having the specified number of carbon atoms (eg, from 1 to 12 carbon atoms).
- alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and n-heptyl and the like.
- Alkyl may be attached to a parent group or substrate at any ring atom provided that attachment does not violate valence requirements.
- an alkyl or alkenyl group may contain one or more non-hydrogen substituents provided that attachment does not violate valence requirements.
- Cycle refers to saturated monocyclic and polycyclic hydrocarbon rings generally having the specified number of carbon atoms, including the ring (ie, C 3-10 cycloalkyl is 3, 4, 5, 6, 7, 8, 9 as a ring member). or a cycle with 10 carbon atoms).
- Halogen is an element belonging to group 17 of the periodic table, and since there are 7 electrons in the outermost electron shell, it is easy to obtain electrons from other elements and become negative ions. It exists mainly in the form of other elements and compounds because of its high non-metallic properties and high reactivity in each cycle. These include fluorine, chlorine, bromine, and iodine.
- Halogenated alkyl refers to a compound in which one hydrogen atom of alkyl is substituted with a halogen element, and is named as primary, secondary, or tertiary alkyl halide depending on how many carbons are attached to the carbon to which the halogen is attached.
- alkyl halide include, without limitation, methyl halide, vinyl halide, aryl halide, allyl halide, benzyl halide, and the like.
- An alkyl halide may be attached to a parent group or substrate at any ring atom provided that attachment does not violate valence requirements.
- Hydrox is a functional group whose structural formula is represented by -OH.
- the compound of Formula 7 may have a structure of Formula 7' below.
- R 2 is indazolyl, naphthalenyl, dihydrobenzofuranyl, pyridinyl, acetyl piperidine, phenyl unsubstituted or substituted with one or more non-hydrogen substituents, pyrazolyl unsubstituted or substituted with one or more non-hydrogen substituents , dihydroisoxazole unsubstituted or substituted with one or more non-hydrogen substituents,
- the non-hydrogen substituent in R 2 is,
- phenyl is selected from the group consisting of phenyl, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 halogenated alkyl or halogen atom,
- R 3 is a hydrogen atom, hydroxy, C 1 -C 6 alkyl or C 1 -C 6 halogenated alkyl
- R 4 is a hydrogen atom, hydroxy or C 1 -C 6 alkyl or absent;
- X is a nitrogen or oxygen atom
- 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 C 1 -C 6 alkyl
- Double line of solid and dotted lines ( ) represents a single carbon-carbon bond or a double carbon-carbon bond.
- R 2 is indazolyl, pyridinyl, phenyl unsubstituted or substituted with one or more non-hydrogen substituents; It is selected from the group consisting of
- the non-hydrogen substituent in R 2 is,
- R 3 is C 1 -C 6 alkyl
- R 4 is C 1 -C 6 alkyl
- X is an oxygen atom
- Y is a halogen or an oxygen atom
- R 6 is hydrogen or C 1 -C 6 alkyl
- Double line of solid and dotted lines ( ) represents a single carbon-carbon bond or a double carbon-carbon bond .
- R 3 in the above formulas is
- R 3 may be C 1 -C 6 alkyl.
- R 2 in the above formulas is
- R 3 in the above formulas is
- R 3 is C 1 -C 6 alkyl
- the quinazoline compound of Formula 7 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-N-phenyl
- the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising the derivative of Formula 7 or a pharmaceutically acceptable salt thereof as an active ingredient.
- the cancer disease may be myeloid leukemia (AML).
- AML myeloid leukemia
- the composition may inhibit the activity of FLT 3 (fms-like tyrosine kinase 3).
- the compound in the present invention synthesizes the compound of Formula 2 by amide formation of the compound of Formula 1, and then reducing it to the compound of Formula 3 using borane in the amide group. (Steps 1-2);
- step 3 The compounds of formulas 4a-1 and 4n-u prepared in step 3 were cycled by irradiation with microwaves at 150° C. in acetic acid under an acid catalyst to obtain a dihydroquinazoline compound, and then, without further purification, p-chloranyl treatment with an oxidizing agent to prepare compounds of formulas 5a-1 and 5n-u, which are quinazoline derivatives as a core intermediate (step 4);
- the quinazoline derivative of claim 1 may be prepared by a method comprising a step (step 7) of preparing compound 7w through a reduction process of 7j by a hydrogenation reaction, but the present invention is not limited thereto.
- the compound in the present invention synthesizes the compound of Formula 2 by amide formation of the compound of Formula 1, and then reducing it to the compound of Formula 3 using borane in the amide group. (Steps 1-2);
- step 3-1 first synthesizing tetrahydroquinazoline using indazole-6-carbaldehyde from the compound of formula 3 prepared in steps 1 and 2 (step 3-1);
- the compound of the present invention may be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt.
- Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanoates. It is obtained from non-toxic organic acids such as acids, aromatic acids, aliphatic and aromatic sulfonic acids.
- Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, ioda.
- the acid addition salt according to the invention can be prepared in a conventional manner, for example by dissolving the compound in an aqueous solution of an excess of acid and precipitating the salt using a water-miscible organic solvent, for example methanol, ethanol, acetone or acetonitrile. It can be manufactured by It can also be prepared by evaporating the solvent or excess acid from the mixture and drying the mixture, or by suction filtration of the precipitated salt.
- a water-miscible organic solvent for example methanol, ethanol, acetone or acetonitrile.
- a pharmaceutically acceptable metal salt may be prepared using a base.
- the alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate.
- it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt.
- the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).
- the compound of the present invention includes all salts, isomers, hydrates and solvates that can be prepared by conventional methods as well as pharmaceutically acceptable salts.
- the compound of Formula 7 can be used as an FLT3 inhibitor, and as described in the background of the present invention, it is widely known to those skilled in the art that the FLT3 inhibitor can be used for cancer treatment.
- the present invention provides a pharmaceutical composition for preventing or treating cancer, more specifically, a pharmaceutical composition for preventing or treating acute myeloid leukemia (AML), comprising the quinazoline derivative of Formula 7 or a pharmaceutically acceptable salt thereof as an active ingredient.
- Composition, use of the quinazoline derivative of Formula 7 or a pharmaceutically acceptable salt thereof for the treatment of the above disease, and administering to a subject a therapeutically effective amount of the compound of Formula 7 or a pharmaceutically acceptable salt thereof It provides a method for treating the above disease.
- prevention refers to any action that suppresses or delays the onset of acute myeloid leukemia (AML) by administration of the pharmaceutical composition according to the present invention.
- AML acute myeloid leukemia
- treatment refers to any action in which symptoms for acute myeloid leukemia (AML) are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention.
- AML acute myeloid leukemia
- the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient.
- pharmaceutically acceptable carriers are those commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose. , polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil.
- a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. may be additionally included in addition to the above components.
- the pharmaceutical composition of the present invention may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically) according to a desired method, and the dosage may vary depending on the condition and weight of the patient, and the disease. Although it varies depending on the degree, drug form, administration route and time, it may be appropriately selected by those skilled in the art.
- the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
- pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type, severity, drug activity, and type of the patient's disease; Sensitivity to the drug, administration time, administration route and excretion rate, treatment period, factors including concurrent drugs and other factors well known in the medical field may be determined.
- the pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.
- the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, weight, absorption of the active ingredient into the body, inactivation rate and excretion rate, disease type, and drugs used in combination, in general 0.0001 to 1000 mg, preferably 0.001 to 500 mg per 1 kg of body weight may be administered daily or every other day, or divided into 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, the severity of obesity, sex, weight, age, etc., the dosage is not intended to limit the scope of the present invention in any way.
- “individual” refers to a subject in need of treatment for a disease, and more specifically, refers to mammals such as humans or non-human primates, mice, dogs, cats, horses and cattle. .
- Table 1 shows the results of evaluating the FLT3 and FLT-ITD kinase activities of all quinazoline compounds 7a-7w.
- compounds containing a piperazine structure showed selective activity against FLT3.
- Tyrosine kinase inhibitors were bound to the ATP-binding site.
- FLT3 mutations such as ITD and point mutations (TKDs) were found on the opposite side of tyrosine kinases except for the ATP binding site. Therefore, it showed only inhibitory activity similar to FLT3 on FLT3-ITD and TKD.
- Compound 7d showed an inhibitory activity of 96.6% in FLT3 and 95.2% in FLT-ITD, and 7d also maintained selectivity for FMS.
- the quinazoline compound 7d showed a selectivity profile compared to cKIT because it did not show inhibitory activity on cKIT.
- High selectivity for cKIT may be an opportunity to circumvent the myelosuppressive toxicity reported from dual FLT3/cKIT kinase inhibitors.
Abstract
본 발명은 FLT3 (fms-유사 티로신 키나아제 3, fms-like tyrosine kinase 3) 저해 활성을 갖는 신규한 퀴나졸린 유도체 및 이의 용도에 관한 것이다. 본 발명에 따른 신규 퀴나졸린 유도체 또는 이의 약학적으로 허용가능한 염은 FLT3에 대한 우수한 저해 활성을 나타내는 바, 급성 골수성 백혈병(AML)의 예방 또는 치료에 있어서, 보다 근본적으로 접근하여 타겟 치료할 수 있을 것으로 기대된다.
Description
본 발명은 FLT3 (fms-like tyrosine kinase 3) 저해 활성을 갖는 신규한 퀴나졸린 유도체 및 이의 용도에 관한 것이다.
본 발명은 대한민국 과학기술정보통신부(2017Y)의 지원 하에서 과제번호 NRF-2019M3A9A8066500에 의해 이루어진 것으로서, 상기 과제의 연구관리전문기관은 "한국연구재단", 연구사업명은 "원천기술개발사업 / 바이오·의료기술개발사업 / 신 약타겟 발굴·검증사업", 연구과제명은 "신경세포 사멸 억제 및 인지기능 개선 효력을 가진 JNK 저해제의 알츠하이머성 치매 치료제 검증", 연구기간은 "2019.06.01.-2020.02.29"이다.
본 특허출원은 2020년 09월 25일에 대한민국 특허청에 제출된 대한민국 특허출원 제10-2020-0124692호에 대하여 우선권을 주장하며, 상기 특허출원의 개시 사항은 본 명세서에 참조로서 삽입된다.
Fms-유사 티로신 키나아제(fms-like tyrosine kinase 3, FLT3)는 림프-조혈 세포에서 발현되는 트랜스-멤브레인 리셉터 티로신 키나아제(trans-membrane receptor tyrosine kinase)의 일종으로 급성 골수성 백혈병(AML) 환자의 조혈 모/전구세포의 생존, 증식, 분화 조절에 관여하기 때문에 AML의 각광받는 표적이다. FLT3 리간드가 FLT3 키나아제에 결합할 때, FLT3는 활성화되고 자가인산화 된다. 그 다음 신호 변환기 및 전사 활성제 5(signal transducer and activator of transcription 5 (STAT5)), Ras/미토겐 활성 단백질 키나아제(mitogen-activated protein kinase) (Ras/MAPK) 와 포스파티딜 이노시톨 3-키나아제(phosphatidylinositol 3-kinase)/Akt 경로(Akt Pathways)를 포함한 다중 하류 신호 전달 경로를 활성화시켜 결과적으로 세포의 증식과 생존 그리고 면역 반응에 중요한 역할을 하게 된다. 그러나 변이된 FLT3는 리간드 유무와는 독립적으로 활성화를 일으킨다. FLT3돌연변이는 내부 진열 중복(Internal tandem duplications, ITD)과 티로신 키나아제 도메인의 점 돌연변이(point mutation in tyrosine kinase domain, TKD)를 대표로 돌연변이의 위치와 유형에 따라 분류할 수 있다. FLT3-ITD 돌연변이는 AML 환자의 20-30 %를 차지하며 중요하게 백혈구의 이상 증가 및 좋지 못한 예후와 직결되며 TKD의 점 돌연변이는 AML의 5 %에서 발견된다. AML 치료법을 찾는 것의 중요성에도 불구하고 미도스타우린(Midostaurine)과 길터리티닙(Gilteritinib) (ASP2215)과 같이 지금까지 승인된 치료 물질은 그 수가 매우 적다.
단백질 키나아제 억제제는 결합 방식에 기초하여 유형 I, 유형 II 및 유형 III으로 분류될 수 있다(비특허문헌 0001). 이들 억제제 중에서, 유형 II 키나아제 억제제는 ATP-사이트(site)에서 힌지 수소 결합의 상부에서 ATP-결합 포켓에 인접한 DFG 포켓과의 추가 상호 작용을 갖는 선택성을 획득하고 유망한 효능을 나타낼 수 있다(비특허문헌 0002).
퀴나졸린 구조는 의약 화학에서 특권 구조로 잘 알려져 있으며, 다양한 생물학적 활성특성을 보이지만, II 형 PKI 변형에서 먼저 시도되었다. 이러한 구조를 인-하우스(in-house) 타입 II 키나제 억제제에 도입함으로써, 신규한 FLT3 억제제를 발견 할 수 있었다. 또한, 본 발명의 신규한 FLT3 억제제는 특히 cKIT 및 FMS 키나제에 비해 선택적 프로파일을 달성 하였다.
(비특허문헌 0001) Wu P, Nielsen TE, Clausen MH. FDA-approved small-molecule kinase inhibitors. Trends Pharmacol Sci. 2015;36(7):422-439.
(비특허문헌 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.
본 발명은 상기와 같은 문제점을 해결하기 위해 안출된 것으로서, 본 발명자들은 급성 골수성 백혈병(AML) 치료제로 개발 가능성이 있는 신규 물질을 찾고자 예의 연구한 결과, FLT3 저해 활성을 나타내는 신규한 퀴나졸린 유도체를 확인하고, 이에 기초하여 본 발명을 완성하게 되었다.
이에, 본 발명의 목적은, FLT3 저해 활성을 갖는 신규한 퀴나졸린 유도체 또는 이의 약학적으로 허용가능한 염을 제공하는 것이다.
본 발명의 다른 목적은, FLT3 저해 활성을 갖는 신규한 퀴나졸린 유도체의 제조방법을 제공하는 것이다.
본 발명의 또 다른 목적은, 상기 퀴나졸린 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 급성 백혈병 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.
상기와 같은 본 발명의 목적을 달성하기 위하여, 본 발명은, 하기 화학식 7의 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다.
[화학식 7]
상기 화학식 7에서,
R2는 인다졸일, 나프탈레닐, 다이하이드로벤조퓨란일, 피리딘일, 아세틸 피페리딘, 하나 이상의 비수소치환기로 치환되거나 비치환된 페닐, 하나 이상의 비수소치환기로 치환되거나 비치환된 피라졸일, 하나 이상의 비수소치환기로 치환되거나 비치환된 다이하이드로이속사졸,
상기 R2에서 비수소치환기는,
R3는 수소 원자, 하이드록시, C1-C6 알킬 또는 C1-C6 할로겐화 알킬이며,
R4는 수소 원자, 하이드록시 또는 C1-C6 알킬이거나 존재하지 않고,
여기에서, X는 질소 또는 산소 원자이며, Y는 할로겐 또는 산소 원자이고,
R5는 수소 원자, 하이드록시, 할로겐 원자 또는 C1-C6 할로겐화 알킬이며,
R6는 수소 원자, 하이드록시 또는 C1-C6 알킬이고,
또한, 본 발명은 상기 화학식 7의 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 급성 골수성 백혈병(AML) 질환의 예방 또는 치료용 약학적 조성물을 제공한다.
본 발명의 일 구현예로서, 상기 조성물은 FLT 3 (fms-like tyrosine kinase 3)의 활성을 저해할 수 있다.
또한, 본 발명은, 상기 화학식 7의 유도체 또는 이의 약학적으로 허용가능한 염을 개체에 투여하는 단계를 포함하는, 급성 골수성 백혈병(AML) 질환의 치료 방법을 제공한다.
또한, 본 발명은, 상기 화학식 7의 유도체 또는 이의 약학적으로 허용가능한 염의 급성 골수성 백혈병(AML) 질환에 대한 치료 용도를 제공한다.
본 발명에 따른 신규 퀴나졸린 유도체 또는 이의 약학적으로 허용 가능한 염은 FLT 3 (fms-유사 티로신 키나아제 3, fms-like tyrosine kinase 3)에 대한 우수한 표적으로 저해 활성을 나타내는바, 상기 유도체를 포함하는 약학적 조성물은 급성 골수성 백혈병(AML)을 비롯한 암의 예방 및 치료에 유용하게 이용될 수 있다.
도 1은, 본 발명의 화합물 7d의 선택적 FLT3 저해활성을 나타낸 도이다.
이하, 본 발명을 상세히 설명하기로 한다.
본 발명은, 하기 화학식 7의 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다.
[화학식 7]
상기 화학식 7에서,
R2는 인다졸일, 나프탈레닐, 다이하이드로벤조퓨란일, 피리딘일, 아세틸 피페리딘, 하나 이상의 비수소치환기로 치환되거나 비치환된 페닐, 하나 이상의 비수소치환기로 치환되거나 비치환된 피라졸일, 하나 이상의 비수소치환기로 치환되거나 비치환된 다이하이드로이속사졸,
상기 R2에서 비수소치환기는,
R3는 수소 원자, 하이드록시, C1-C6 알킬 또는 C1-C6 할로겐화 알킬이며,
R4는 수소 원자, 하이드록시 또는 C1-C6 알킬이거나 존재하지 않고,
여기에서, X는 질소 또는 산소 원자이며, Y는 할로겐 또는 산소 원자이고,
R5는 수소 원자, 하이드록시, 할로겐 원자 또는 C1-C6 할로겐화 알킬이며,
R6는 수소 원자, 하이드록시 또는 C1-C6 알킬이고,
여기에서, "알킬"은 일반적으로 명시된 수의 탄소원자 (예컨대, 1 내지 12개의 탄소원자)를 갖는 직쇄 또는 분지쇄 포화 탄화수소 기를 의미한다. 알킬기의 예는 제한 없이 메틸, 에틸, n-프로필, 이소프로필, n-부틸, sec-부틸, 이소부틸, tert-부틸, n-펜틸, n-헥실 및 n-헵틸 등을 포함한다. 알킬은 부착이 원자가 필요조건을 위반하지 않는다면 임의의 고리 원자에서 부모 기(parent group) 또는 기재(substrate)에 부착될 수 있다. 마찬가지로, 알킬기 또는 알케닐기는, 부착이 원자가 요구조건을 위반하지 않는다면 하나 이상의 비수소 치환기를 포함할 수 있다.
"사이클"은 고리를 포함하는 명시된 수의 탄소원자를 일반적으로 갖는 포화 일환 및 다환 탄화수소 고리를 말한다 (즉, C3-10사이클로알킬은 고리원으로서 3, 4, 5, 6, 7, 8, 9 또는 10개의 탄소원자를 갖는 사이클 말한다).
"할로겐"은 주기율표 17족에 속하는 원소들로, 최외각 전자 껍질에 전자가 7개 존재하기 때문에 다른 원소로부터 전자를 얻어 음이온이 되기 쉽다. 각 주기에서 비금속성이 가장 크고, 반응성이 크기 때문에 주로 다른 원소와 화합물의 형태로 존재한다. 불소, 염소, 브롬, 아이오딘 등이 있다.
"할로겐화 알킬"은 알킬의 수소원자 1개를 할로겐원소로 치환한 화합물을 말하며 할로겐이 붙은 탄소에 몇 개의 탄소가 붙었는지에 따라 1, 2, 3차 할로겐화 알킬 등으로 명명한다. 할로겐화 알킬의 예는 제한 없이 할로겐화 메틸, 할로겐화 비닐, 할로겐화 아릴, 할로겐화 알릴, 할로겐화 벤질 등을 포함한다. 할로겐화 알킬은 부착이 원자가 필요조건을 위반하지 않는다면 임의의 고리 원자에서 부모 기(parent group) 또는 기재(substrate)에 부착될 수 있다.
"하이드록시"는 구조식이 -OH 으로 표시되는 작용기이다.
본 발명의 한 구체 예에서, 상기 화학식 7의 화합물은 하기 화학식 7'의 구조를 갖는 것일 수 있다.
[화학식 7']
상기 화학식 7'에서,
R2는 인다졸일, 나프탈레닐, 다이하이드로벤조퓨란일, 피리딘일, 아세틸 피페리딘, 하나 이상의 비수소치환기로 치환되거나 비치환된 페닐, 하나 이상의 비수소치환기로 치환되거나 비치환된 피라졸일, 하나 이상의 비수소치환기로 치환되거나 비치환된 다이하이드로이속사졸,
상기 R2에서 비수소치환기는,
R3는 수소 원자, 하이드록시, C1-C6 알킬 또는 C1-C6 할로겐화 알킬이며,
R4는 수소 원자, 하이드록시 또는 C1-C6 알킬이거나 존재하지 않고,
여기에서, X는 질소 또는 산소 원자이며, Y는 할로겐 또는 산소 원자이고,
R5는 수소 원자, 하이드록시, 할로겐 원자 또는 C1-C6 할로겐화 알킬이며,
R6는 수소 원자, 하이드록시 또는 C1-C6 알킬이고,
본 발명의 또 다른 구현 예로서, 상기 화학식들에서,
상기 R2에서 비수소치환기는,
R3는 C1-C6 알킬이며,
R4는 C1-C6 알킬이고,
여기에서, X는 산소 원자이며, Y는 할로겐 또는 산소 원자이고, R6는 수소 또는 C1-C6 알킬이며,
본 발명의 또 다른 구현 예로서, 상기 화학식들에서 R3는
R3는 C1-C6알킬일 수 있다.
본 발명의 또 다른 구현 예로서, 상기 화학식들에서 R2는
본 발명의 또 다른 구현예로서, 상기 화학식들에서 R3는
R3는 C1-C6알킬이고,
R2는
본 발명의 또 다른 구현예로서, 화학식 7의 퀴나졸린 화합물은,
5-메틸-N-(2-(3-모폴리노-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)이속사졸-4-카복사미드 (7a);
5-메틸-N-(2-(3-모폴리노-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)이속사졸-4-카복사미드 (7b);
5-메틸-N-(2-(3-(4-메틸-1H-이미다졸-1-일)-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)이속사졸-4-카복사미드 (7c);
5-메틸-N-(2-(3-(4-메틸피페라진-1-일)-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)이속사졸-4-카복사미드 (7d);
N-(2-(3-((4-에틸피페라진-1-일)메틸)-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7e);
N-(2-(3-플루오로-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7f);
N-(2-(4-클로로-3-(트리플루오로메틸)페닐)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7g);
5-메틸-N-(2-(1-페닐-5-(트리플루오로메틸)-1H-피라졸-4-일)퀴나졸린-7-일)이속사졸-4-카복사미드 (7h);
N-(2-(3-클로로페닐)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7i);
(E)-N-(2-(4-메톡시스타이릴)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7j);
(E)-N-(2-(4-클로로스타이릴)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7k);
N-(2-(5-(터트-부틸)이속사졸-3-일)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7l);
N-(2-(1H-인다졸-5-일)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7m);
5-메틸-N-(2-(3-((1-메틸피페리딘-4-일)옥시)-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)이속사졸-4-카복사미드 (7n);
N-(2-(1-아세틸피페리딘-4-일)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7o);
5-메틸-N-(2-(피리딘-4-일)퀴나졸린-7-일)이속사졸-4-카복사미드 (7p);
5-메틸-N-(2-(피리딘-2-일)퀴나졸린-7-일)이속사졸-4-카복사미드 (7q);
N-(2-(3,4-다이클로로페닐)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7r);
N-(2-(4-플루오로벤질)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7s);
5-메틸-N-(2-(2-(트리플루오로메틸)벤질)퀴나졸린-7-일)이속사졸-4-카복사미드 (7t);
5-메틸-N-(2-(나프탈렌-2-일)퀴나졸린-7-일)이속사졸-4-카복사미드 (7u);
N-(2-(2,3-다이하이드로벤조퓨란-5-일)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7v); 또는
N-(2-(4-메톡시페네틸)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7w);일 수 있다.
본 발명은 상기 화학식 7의 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 암의 예방 또는 치료용 약학적 조성물을 제공한다.
본 발명의 또 다른 구현예로서, 상기 암 질환은 골수성 백혈병(AML)일 수 있다.
본 발명의 또 다른 구현예로서, 상기 조성물은 FLT 3(fms-like tyrosine kinase 3)의 활성을 저해하는 것일 수 있다.
또한, 본 발명에서의 화합물은 하기 반응식 1에 표시된 바와 같이, 화학식 1 화합물을 아마이드 형성(amide formation)하여 화학식 2 화합물를 합성하고, 그런 다음, 아마이드 그룹에서 보란을 사용하여 화학식 3 화합물로 환원시키는 단계 (단계 1~2);
상기 단계 1~2에서 제조된 화학식 3 화합물을 다양한 벤조일클로라이드와 아마이드 형성하여 화학식 4a-l, 4n-u의 화합물을 제조하는 단계 (단계 3);
상기 단계 3에서 제조된 화학식 4a-l, 4n-u 화합물은, 산 촉매 하에 아세트산, 150℃조건 에서 마이크로파 조사하여 사이클화시켜 다이하이드로 퀴나졸린 화합물을 수득한 후, 추가 정제 없이, p-클로라닐 산화제로 처리하여 코어 중간체인 퀴나졸린 유도체인 화학식 5a-l, 5n-u 화합물을 제조하는 단계 (단계4);
화학식 5a-l, 5n-u화합물의 나이트로 그룹을 Fe 촉매를 사용하여 아닐린으로 환원시켜 화학식 6a-v 화합물을 제조하는 단계(단계5); 및
화학식 6a-v 화합물을 이속사졸 클로라이드와 아마이드 형성하여 최종 화합물인 [화학식 1]로 표현되는 화합물 7a-v 를 제조하는 단계(단계 6); 및
7j를 수소화 반응으로 변형(reduction)과정을 거쳐 화합물 7w를 제조하는 단계(단계 7)을 포함하는 방법으로 제 1항의 퀴나졸린 유도체를 제조할 수 있으며, 이 예에 한정되는 것은 아니다.
[반응식 1]
또한, 본 발명에서의 화합물은 하기 반응식 2에 표시된 바와 같이, 화학식 1 화합물을 아마이드 형성(amide formation)하여 화학식 2 화합물를 합성하고, 그런 다음, 아마이드 그룹에서 보란을 사용하여 화학식 3 화합물로 환원시키는 단계 (단계 1~2);
상기 단계 1~2에서 제조된 화학식 3 화합물을 인다졸-6-카바알데하이드를 활용해 테트라하이드로퀴나졸린을 먼저 합성하는 단계 (단계3-1);
그 후 상기 반응식 1과 동일한 단계 (단계 5~6)를 거쳐 최종 화합물인 [화학식 1]로 표현되는 화합물 7m, 7v를 제조하는 단계를 포함하는 방법으로, 제 1항의 퀴나졸린 유도체를 제조할 수 있으며, 이 예에 한정되는 것은 아니다.
[반응식 2]
한편, 본 발명의 상기 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다.
본 발명에서 사용되는 용어 "염"은 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 다이카복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸다이오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 나이트레이트, 포스페이트, 모노하이드로겐 포스페이트, 다이하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-다이오에이트, 헥산-1,6-다이오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 다이나이트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함한다.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 화합물을 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토나이트릴을 사용하여 침전시켜서 제조할 수 있다. 또한 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시키거나 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수도 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면, 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염 (예, 질산은)과 반응시켜 얻는다.
또한, 본 발명의 화합물은 약학적으로 허용되는 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 이성질체, 수화물 및 용매화물을 모두 포함한다.
하기 실시예에서 확인할 수 있는 바와 같이 화학식 7의 화합물은 FLT3 저해제로서 사용할 수 있으며, 발명의 배경 기술에 서술 하였듯이, FLT3 저해제를 암 치료 용도로 사용할 수 있음은 해당 분야 당업자들에게는 널리 알려진 사실이다.
본 발명은 상기 화학식 7의 퀴나졸린 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 암 예방 또는 치료용 약학적 조성물, 더 자세하게는 급성 골수성 백혈병(AML)의 예방 또는 치료용 약학적 조성물, 상기 질환의 치료를 위한 상기 화학식 7의 퀴나졸린 유도체 또는 이의 약학적으로 허용가능한 염의 용도, 및 치료상 유효량의 상기 화학식 7의 화합물 또는 그의 약학적으로 허용가능한 염을 대상체에게 투여하는 것을 포함하는 상기 질환의 치료 방법을 제공한다.
본 발명에서 사용되는 용어, "예방"이란 본 발명에 따른 약학적 조성물의 투여에 의해 급성 골수성 백혈병(AML)을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.
본 발명에서 사용되는 용어, "치료"란 본 발명에 따른 약학적 조성물의 투여에 의해 급성 골수성 백혈병(AML)에 대한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.
본 발명의 약학적 조성물은 유효성분 이외에 약제학적으로 허용되는 담체를 포함할 수 있다. 이때, 약제학적으로 허용되는 담체는 제제 시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세 결정성셀룰로스, 폴리비닐피로리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필 히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일등을 포함하나, 이에 한정되는 것은 아니다. 또한, 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다.
본 발명의 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다.
본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 얄려진 요소에 따라 결정될 수 있다. 본 발명에 다른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래 의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.
구체적으로 본 발명의 약학적 조성물의 유효량은 환자의 연령, 성별, 상태, 체중, 체내에 활성 성분의 흡수도, 불활성율 및 배설속도, 질병종류, 병용되는 약물에 따라 달라질 수 있으며, 일반적으로는 체중 1kg 당 0.0001 내지 1000mg, 바람직하게는 0.001 내지 500mg을 매일 또는 격일 투여하거나, 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나 투여 경로, 비만의 중증도, 성별, 체중, 연령 등에 따라서 증감 될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.
본 발명에서 "개체"란 질병의 치료를 필요로 하는 대상을 의미하고, 보다 구체적으로는, 인간 또는 비-인간인 영장류, 생쥐(mouse), 개, 고양이, 말 및 소 등의 포유류를 의미한다.
이하, 본 발명의 이해를 돕기 위하여 바람직한 제조예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 제조예에 의해 본 발명의 내용이 한정되는 것은 아니다.
<제조예 1> 2-아미노-4-나이트로벤즈아마이드 (2)의 합성
2-아미노-4-나이트로-벤조익산 (546.39 mg, 3 mmol)과 CH2Cl2 (30 ml) 혼합물에 EDC (690.12 mg, 3.6 mmol), HOBt (450.42 mg, 3 mmol), TEA (0.72 ml) 및 NH3 in MeOH (2 M, 40 ml)를 첨가하여 실온에서 밤새 교반하였다. 반응 확인 후 생성된 침전물을 진공 여과하여 2-아미노-4-나이트로-벤즈아마이드 (2) (487.8 mg. 89.76%)를 얻었다.
<제조예 2> 2-(아미노메틸)-5-나이트로아닐린 (3)의 합성
보란-테트라하이드로퓨란 복합체 (1.0 M 테트라하이드로퓨란 용액(solution of tetrahydrofuran)) (2.2 ml)을 2-아미노-4-나이트로벤즈아마이드 (100.0 mg)의 테트라하이드로퓨란(6.0 ml) 용액에 첨가하고 2시간 동안 교반시켰다. 반응 종결 후 혼합물을 냉각시켰다. 이어서, 메탄올을 혼합물에 첨가하고 10% 염화수소가 포함된 메탄올로 중화시킨 후 용매를 감압 농축하였다. 이후 잔류물에 1 N 수산화나트륨용액을 첨가하여 메틸렌 클로라이드로 추출하였다. 유기층을 포화 식염수로 세정하고, 무수 황산나트륨으로 건조시켰다. 용매를 감압 농축한 후 화합물 3 (87.47 mg, 95.13%)를 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 7.28-7.22 (m, 1H), 6.48 (s, 2H), 5.73 (dd, J = 7.6, 1.9 Hz, 2H), 5.27 (s, 2H).
<제조예 3> 일반 절차 (General procedure) A: 화합물4a-l, 4n-u의 합성
2-아미노-4-나이트로벤질아민 (1 eq)과 트리에틸아민 (TEA) (3.5 eq)을 다이클로로메테인 (DCM) (0.1 M)에서 0 ℃를 유지해 교반하고 벤조일 클로라이드 (0.9 eq)가 포함된 DCM (0.1 M)을 천천히 적가하며 0 ℃를 계속 유지한다. 이후 약 3시간동안 실온에서 교반하고, 상기 혼합 용매에 물을 첨가하여 층을 나누어 유기층을 얻는다. 무수 Na2SO4를 이용해 잔여 수분을 제거하고 여과한 후, 실리카겔 칼럼 크로마토그래피를 수행하여 화합물 4을 얻는다.
상기 제조예 3의 방법으로 하기의 화합물들을 수득하였다.
N
-(2-아미노-4-나이트로벤질)-4-모폴리노-3-(트리플루오로메틸)벤즈아마이드 (4a)
화합물 3로부터 일반 절차 A를 이용하여 합성하였다. 칼럼 크로마토그래피 (EA:Hex = 1 : 1)로 정제하여 목적 화합물 4a (91%)를 고체로 얻었다; HRMS (ESI+) calculated for C19H19F3N4O4 [M+H]+: 425.1358, found 425.0768.
N
-(2-아미노-4-나이트로벤질)-3-모폴리노-5-(트리플루오로메틸)벤즈아마이드 (4b)
화합물 3로부터 일반 절차 A를 이용하여 합성하였다. 목적 화합물 4b (70%)를 고체로 얻었다; HRMS (ESI+) calculated for C19H19F3N4O4 [M+H]+: 425.1358, found 425.3289.
N
-(2-아미노-3-나이트로페닐)-3-(4-메틸-1
H-
이미다졸-1-일)-5 (트리플루오로메틸) 벤즈아마이드 (4c)
화합물 3로부터 일반 절차 A를 이용하여 합성하였다. 목적 화합물 4c (57.2%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.34 (t, J = 5.8 Hz, 1H), 8.38 (s, 1H), 8.36 (d, J = 1.3 Hz, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 7.67 (s, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.37 (dd, J = 8.3, 2.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 5.82 (s, 2H), 4.44 (d, J = 5.8 Hz, 2H), 2.18 (d, J = 0.8 Hz, 3H); HRMS (ESI+) calculated for C19H16F3N5O3 [M+H]+: 420.1205, found 420.3815.
N
-(2-아미노-4-나이트로벤질)-3-(4-메틸피페라진-1-일)-5-(트리플루오로메틸)벤즈아마이드 (4d)
화합물 3로부터 일반 절차 A를 이용하여 합성하였다. 목적 화합물 4d (79%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.19 (t, J = 5.9 Hz, 1H), 7.68 (s, 1H), 7.57 (s, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.36 (dd, J = 8.3, 2.5 Hz, 2H), 7.23 (d, J = 8.3 Hz, 1H), 5.82 (s, 2H), 4.39 (d, J = 5.8 Hz, 2H), 3.31-3.27 (m, 4H), 2.48-2.44 (m, 4H), 2.23 (s, 3H); HRMS (ESI+) calculated for C20H22F3N5O3 [M+H]+: 438.1675, found 438.3749.
N
-(2-아미노-4-나이트로벤질)-3-((4-에틸피페라진-1-일)메틸)-5-(트리플루오로메틸)벤즈아마이드 (4e)
화합물 3로부터 일반 절차 A를 이용하여 합성하였다. 목적 화합물 4e (67%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.31 (t, J = 5.8 Hz, 1H), 8.15 (d, J = 5.3 Hz, 2H), 7.85 (s, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.38 (dd, J = 8.3, 2.4 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 5.84 (s, 2H), 4.42 (d, J = 5.8 Hz, 2H), 3.64 (s, 2H), 3.40-3.33 (s, 2H), 3.33-3.29 (m, 4H), 2.45 (s, 4H), 1.02 (t, J = 6.9 Hz, 3H); HRMS (ESI+) calculated for C22H26F3N5O3 [M+H]+: 466.1988, found 466.5619.
N
-(2-아미노-4-나이트로벤질)-3-플루오로-5-(트리플루오로메틸)벤즈아마이드 (4f)
화합물 3로부터 일반 절차 A를 이용하여 합성하였다. 목적 화합물 4f (65%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.35 (t, J = 5.8 Hz, 1H), 8.12 (d, J = 0.6 Hz, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.36 (dd, J = 8.3, 2.4 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 5.80 (s, 2H), 4.41 (d, J = 5.8 Hz, 2H); HRMS (ESI+) calculated for C15H11F4N3O3 [M+H]+: 358.0737, found 358.0891.
N
-(2-아미노-4-나이트로벤질)-3-클로로-4-(트리플루오로메틸)벤즈아마이드 (4g)
화합물 3로부터 일반 절차 A를 이용하여 합성하였다. 목적 화합물 4g (73%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.35 (t, J = 5.8 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.20 (dd, J = 8.4, 2.0 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.35 (dd, J = 8.3, 2.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 5.80 (s, 2H), 4.40 (d, J = 5.8 Hz, 2H); HRMS (ESI+) calculated for C15H11ClF3N3O3 [M+H]+: 374.0441, found 374.4039.
N
-(2-아미노-4-나이트로벤질)-1-페닐-5-(트리플루오로메틸)-1
H-
피라졸-4-카복사미드 (4h)
화합물 3로부터 일반 절차 A를 이용하여 합성하였다. 목적 화합물 4h (73%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.12 (t, J = 6.0 Hz, 1H), 8.26-8.20 (m, 1H), 7.62-7.56 (m, 3H), 7.52 (dd, J = 6.2, 2.4 Hz, 3H), 7.37 (dd, J = 8.3, 2.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 5.80 (s, 2H), 4.36 (d, J = 6.0 Hz, 2H); HRMS (ESI+) calculated for C18H14F3N5O3 [M+H]+: 406.1049, found 406.1158.
N
-(2-아미노-4-나이트로벤질)-3-클로로벤즈아마이드 (4i)
화합물 3로부터 일반 절차 A를 이용하여 합성하였다. 목적 화합물 4i (78%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.16 (t, J = 5.9 Hz, 1H), 7.94 (t, J = 1.8 Hz, 1H), 7.89-7.84 (m, 1H), 7.64 (ddd, J = 8.0, 2.1, 1.1 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.36 (dd, J = 8.3, 2.4 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 5.81 (s, 2H), 4.37 (d, J = 5.9 Hz, 2H); HRMS (ESI+) calculated for C14H12ClN3O3 [M+H]+: 306.0567, found 306.2976.
(E)-
N
-(2-아미노-4-나이트로벤질)-3-(4-메톡시페닐)아크릴아마이드 (4j)
화합물 3로부터 일반 절차 A를 이용하여 합성하였다. 목적 화합물 4j (79%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.58 - 7.53 (m, 2H), 7.50 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 15.8 Hz, 1H), 7.37 (dd, J = 8.3, 2.4 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.02 - 6.98 (m, 2H), 6.56 (d, J = 15.8 Hz, 1H), 5.85 (s, 2H), 4.32 (d, J = 6.1 Hz, 2H), 3.81 (s, 3H); HRMS (ESI+) calculated for C17H17N3O4 [M+H]+: 328.1219, found 328.3400.
(E)-
N
-(2-아미노-4-나이트로벤질)-3-(4-클로로페닐)아크릴아마이드 (4k)
화합물 3로부터 일반 절차 A를 이용하여 합성하였다. 목적 화합물 4k (44%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 8.67 (t, J = 6.2 Hz, 1H), 7.65-7.58 (m, 2H), 7.53-7.43 (m, 4H), 7.35 (dd, J = 8.3, 2.4 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 6.70 (d, J = 15.8 Hz, 1H), 5.82 (s, 2H), 4.31 (d, J = 6.1 Hz, 2H); HRMS (ESI+) calculated for C16H14ClN3O3 [M+H]+: 332.0724, found 332.2657.
N
-(2-아미노-4-나이트로벤질)-5-(터트-부틸)이속사졸-3-카복사미드 (4l)
화합물 3로부터 일반 절차 A를 이용하여 합성하였다. 목적 화합물 4l (37%)를 고체로 얻었다; 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.70 (dd, J = 8.2, 1.7 Hz, 1H), 7.47 (s, 1H), 7.38 (d, J = 8.3 Hz, 1H), 6.44 (s, 1H), 4.69 (d, J = 6.5 Hz, 2H), 1.38 (s, 9H); HRMS (ESI+) calculated for C15H18N4O4 [M+H]+: 319.1328, found 319.4438.
N
-(2-아미노-4-나이트로벤질)-3-((1-메틸피페리딘-4-일)옥시)-5-(트리플루오로메틸)벤즈아마이드 (4n)
화합물 3로부터 일반 절차 A를 이용하여 합성하였다. 목적 화합물 4n (33%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.30 (t, J = 5.9 Hz, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.52 (t, J = 2.5 Hz, 2H), 7.38 (dd, J = 8.3, 2.4 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 5.83 (d, J = 7.1 Hz, 2H), 4.72 (s, 1H), 4.41 (d, J = 5.8 Hz, 2H), 3.32 (s, 3H), 2.85 (s, 2H), 2.40 (s, 2H), 2.05 (s, 2H), 1.79 (s, 2H); HRMS (ESI+) calculated for C16H14ClN3O3 [M+H]+: 453.1671, found 453.2374.
1-아세틸-
N
-(2-아미노-4-나이트로벤질)피페리딘-4-카복사미드 (4o)
화합물 3로부터 일반 절차 A를 이용하여 합성하였다. 목적 화합물 4o (67%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 8.39 (t, J = 6.0 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.35 (dd, J = 8.3, 2.4 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 5.78 - 5.71 (m, 2H), 4.39 - 4.34 (m, 1H), 4.17 (d, J = 6.1 Hz, 2H), 3.83 (d, J = 13.7 Hz, 1H), 3.04 (dd, J = 18.4, 7.6 Hz, 1H), 2.62 - 2.54 (m, 1H), 2.49 - 2.42 (m, 1H), 2.00 (s, 3H), 1.75 (t, J = 13.4 Hz, 2H), 1.60 - 1.49 (m, 1H), 1.45 - 1.34 (m, 1H); HRMS (ESI+) calculated for C16H14ClN3O3 [M+H]+: 321.1485, found 321.7849.
N
-(2-아미노-4-나이트로벤질)아이소니코틴아마이드 (4p)
화합물 3로부터 일반 절차 A를 이용하여 합성하였다. 목적 화합물 4p (60%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.34 (t, J = 5.9 Hz, 1H), 8.77 (dd, J = 4.4, 1.7 Hz, 2H), 7.82 (dd, J = 4.4, 1.7 Hz, 2H), 7.52 (d, J = 2.4 Hz, 1H), 7.38 (dd, J = 8.3, 2.4 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 5.82 (d, J = 7.1 Hz, 2H), 4.41 (d, J = 6.0 Hz, 2H); HRMS (ESI+) calculated for C16H14ClN3O3 [M+H]+: 273.0909, found 273.3772.
N
-(2-아미노-4-나이트로벤질)피콜린아마이드 (4q)
화합물 3로부터 일반 절차 A를 이용하여 합성하였다. 목적 화합물 4q (70%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.46 (t, J = 6.3 Hz, 1H), 8.69 (ddd, J = 4.8, 1.6, 1.0 Hz, 1H), 8.10-8.05 (m, 1H), 8.05-8.00 (m, 1H), 7.64 (ddd, J = 7.3, 4.8, 1.5 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.35 (dd, J = 8.3, 2.4 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 5.90 (s, 2H), 4.40 (d, J = 6.4 Hz, 2H); HRMS (ESI+) calculated for C16H14ClN3O3 [M+Na]+: 295.0802, found 295.3123.
N
-(2-아미노-4-나이트로벤질)-3,4-다이클로로벤즈아마이드 (4r)
화합물 3로부터 일반 절차 A를 이용하여 합성하였다. 목적 화합물 4r (84.5%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO) δ 8.23 (t, J = 5.9 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 6.89 (dd, J = 8.4, 2.1 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.37 (dd, J = 8.3, 2.4 Hz, 1H), 6.24 (d, J = 8.3 Hz, 1H), 4.82 (s, 2H), 3.39 (d, J = 5.9 Hz, 2H).
N
-(2-아미노-4-나이트로벤질)-2-(4-플루오로페닐)아세트아마이드 (4s)
화합물 3로부터 일반 절차 A를 이용하여 합성하였다. 목적 화합물 4s (33.0%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO) δ 8.58 (t, J = 6.0 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.32 (tt, J = 5.3, 2.6 Hz, 3H), 7.15 (ddd, J = 9.7, 6.5, 2.7 Hz, 3H), 5.75 (s, 2H), 4.18 (d, J = 6.1 Hz, 2H), 3.52 (s, 2H).
N
-(2-아미노-4-나이트로벤질)-2-(2-(트리플루오로메틸)페닐)아세트아마이드 (4t)
화합물 3로부터 일반 절차 A를 이용하여 합성하였다. 목적 화합물 4t (32.0%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO) δ 8.65 (t, J = 6.0 Hz, 1H), 7.69 (s, 1H), 7.67 (s, 1H), 7.52 (s, 1H), 7.50 (s, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.32 (dd, J = 8.3, 2.4 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 5.74 (s, 2H), 4.18 (d, J = 6.0 Hz, 2H), 3.64 (s, 2H).
N
-(2-아미노-4-나이트로벤질)-2-나프타마이드 (4u)
화합물 3로부터 일반 절차 A를 이용하여 합성하였다. 목적 화합물 4u (41.5%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO) δ 9.22 (t, J = 5.9 Hz, 1H), 8.52 (s, 1H), 8.06 - 7.96 (m, 4H), 7.66 - 7.58 (m, 2H), 7.51 (d, J = 2.4 Hz, 1H), 7.37 (dd, J = 8.3, 2.4 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 5.87 (s, 2H), 4.44 (d, J = 6.0 Hz, 2H).
<제조예 4> 일반 절차 (General procedure) B: 화합물5a-l, 5n-u의 합성
화합물 4 (0.2515 mmol)과 concd aq HCl (1.2 eq)를 바이알에 취해 아세트산 (0.838 mL)에 천천히 적가한 후 마이크로파 환경 150 ℃에서 10분간 반응시켰다. 반응 후 혼합물을 냉각시킨 0 ℃에서 1 N NaOH로 중화시킨다. 중화 시 생성물이 석출된다면 진공 여과한 후 드라이하여 별도의 정제없이 다이하이드로퀴나졸린 중간체를 얻는다. 생성물이 석출되지 않으면 EA로 층을 분리하여 유기층을 얻은 뒤, 무수 Na2SO4를 이용해 잔여 수분을 제거한 뒤 여과하고 별도의 정제없이 다이하이드로퀴나졸린 중간체를 얻는다. 이후 다이하이드로퀴나졸린 (1 eq)와 p-클로라닐 (1.2 eq)을 톨루엔 (0.1 M)에서 환류하여 밤새 교반한다. 반응 확인 후 냉각시킨 이후에 감압 농축하고 0.5 N NaOH와 다이클로로메테인 혹은 EA로 층분리하여 유기층을 얻은 뒤, 무수 Na2SO4를 이용해 잔여 수분을 제거한 뒤 여과하고 실리카겔 칼럼 크로마토그래피를 통해 정제하여 화합물 5을 얻는다.
상기 제조예 4의 방법으로 하기의 화합물을 수득하였다.
4-(4-(7-나이트로퀴나졸린-2-일)-2-(트리플루오로메틸)페닐)모폴린 (5a)
화합물 4a로부터 일반 절차 B를 이용하여 합성하였다. 목적 화합물 5a (62%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.98 (d, J = 0.8 Hz, 1H), 8.87 (d, J = 1.9 Hz, 2H), 8.83 (dd, J = 8.5, 2.0 Hz, 1H), 8.50 (dd, J = 8.9, 0.5 Hz, 1H), 8.46 (dd, J = 8.9, 2.1 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 3.81-3.74 (m, 4H), 3.07-2.99 (m, 4H); HRMS (ESI+) calculated for C19H15F3N4O3 [M+H]+: 405.1096, found 405.0978.
4-(3-(7-나이트로퀴나졸린-2-일)-5-(트리플루오로메틸)페닐)모폴린 (5b)
화합물 4b로부터 일반 절차 B를 이용하여 합성하였다. 목적 화합물 5b (57%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.97 (d, J = 0.7 Hz, 1H), 8.89 (d, J = 2.1 Hz, 1H), 8.50 (d, J = 8.6 Hz, 1H), 8.46 (dd, J = 8.9, 2.1 Hz, 1H), 8.40 (s, 1H), 8.27 (s, 1H), 7.45 (s, 1H), 3.85-3.78 (m, 4H), 3.36-3.29 (m, 4H); HRMS (ESI+) calculated for C19H15F3N4O3 [M+H]+: 405.1096, found 405.1609.
2-(3-(4-메틸-1
H-
이미다졸-1-일)-5-(트리플루오로메틸)페닐)-7-나이트로퀴나졸린 (5c)
화합물 4c로부터 일반 절차 B를 이용하여 합성하였다. 목적 화합물 5c (48%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.97 (s, 2H), 8.78 (s, 1H), 8.58-8.48 (m, 3H), 8.29 (s, 1H), 7.77 (s, 1H), 2.24 (s, 3H); HRMS (ESI+) calculated for C19H12F3N5O2 [M+H]+: 400.0943, found 400.1503.
2-(3-(4-메틸피페라진-1-일)-5-(트리플루오로메틸)페닐)-7-나이트로퀴나졸린 (5d)
화합물 4d로부터 일반 절차 B를 이용하여 합성하였다. 목적 화합물 5d (41%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.96 (d, J = 0.8 Hz, 1H), 8.91-8.87 (m, 1H), 8.49 (dd, J = 8.9, 0.5 Hz, 1H), 8.45 (dd, J = 8.9, 2.1 Hz, 1H), 8.38 (s, 1H), 8.23 (s, 1H), 7.42 (s, 1H), 3.40-3.35 (m, 4H), 2.53 (d, J = 5.0 Hz, 4H), 2.26 (s, 3H); HRMS (ESI+) calculated for C20H18F3N5O2 [M+H]+: 418.1413, found 418.1756.
2-(3-((4-에틸피페라진-1-일)메틸)-5-(트리플루오로메틸)페닐)-7-나이트로퀴나졸린 (5e)
화합물 4e로부터 일반 절차 B를 이용하여 합성하였다. 목적 화합물 5e (33%)를 고체로 얻었다; 1H NMR (400 MHz, CDCl3) δ 9.68 (d, J = 0.8 Hz, 1H), 9.05 (d, J = 2.2 Hz, 1H), 8.87 (s, 1H), 8.81 (s, 1H), 8.45 (dd, J = 8.8, 2.2 Hz, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.85 (s, 1H), 3.75 (s, 2H), 2.63 (s, 4H), 2.54-2.47 (m, 2H), 1.64-1.58 (m, 4H), 1.14 (t, J = 7.2 Hz, 3H); HRMS (ESI+) calculated for C22H22F3N5O2 [M+H]+: 446.1726, found 446.8992.
2-(3-플루오로-5-(트리플루오로메틸)페닐)-7-나이트로퀴나졸린 (5f)
화합물 4f로부터 일반 절차 B를 이용하여 합성하였다. 목적 화합물 5f (88%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 10.02 (d, J = 0.8 Hz, 1H), 8.94-8.89 (m, 1H), 8.71 (d, J = 0.4 Hz, 1H), 8.60 (d, J = 9.6 Hz, 1H), 8.53 (dd, J = 8.9, 0.6 Hz, 1H), 8.49 (dd, J = 8.9, 2.1 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H); HRMS (ESI+) calculated for C15H7F4N3O2 [M+H]+: 338.0474, found 338.0284.
2-(4-클로로-3-(트리플루오로메틸)페닐)-7-나이트로퀴나졸린 (5g)
화합물 4g로부터 일반 절차 B를 이용하여 합성하였다. 목적 화합물 5g (89%)를 고체로 얻었다; 1H NMR (400 MHz, CDCl3) δ 9.67 (d, J = 0.8 Hz, 1H), 9.07 (d, J = 2.1 Hz, 1H), 9.03 (dd, J = 1.5, 0.7 Hz, 1H), 8.82 (dd, J = 8.4, 2.1 Hz, 1H), 8.46 (dd, J = 8.9, 2.2 Hz, 1H), 8.22-8.17 (m, 1H), 7.74 (d, J = 8.4 Hz, 1H); HRMS (ESI+) calculated for C15H7ClF3N3O2 [M+H]+: 354.0179, found 354.3435.
7-나이트로-2-(1-페닐-5-(트리플루오로메틸)-1
H-
피라졸-4-일)퀴나졸린 (5h)
화합물 4h로부터 일반 절차 B를 이용하여 합성하였다. 목적 화합물 5h (65%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.97 (d, J = 0.8 Hz, 1H), 8.73 (dt, J = 1.8, 0.8 Hz, 1H), 8.58-8.55 (m, 1H), 8.52-8.47 (m, 2H), 7.63 (s, 5H); HRMS (ESI+) calculated for C18H10F3N5O2 [M+H]+: 386.0787, found 386.0962.
2-(3-클로로페닐)-7-나이트로퀴나졸린 (5i)
화합물 4i로부터 일반 절차 B를 이용하여 합성하였다. 목적 화합물 5i (78.6%)를 고체로 얻었다; 1H NMR (400 MHz, CDCl3) δ 9.66 (d, J = 0.8 Hz, 1H), 9.01 (d, J = 2.2 Hz, 1H), 8.70 (dd, J = 2.5, 1.2 Hz, 1H), 8.59 (dt, J = 7.2, 1.6 Hz, 1H), 8.43 (dd, J = 8.9, 2.2 Hz, 1H), 8.19-8.15 (m, 1H), 7.57 (dt, J = 8.0, 1.7 Hz, 1H), 7.54 (dd, J = 11.3, 4.0 Hz, 1H); HRMS (ESI+) calculated for C14H8ClN3O2 [M+H]+: 286.0305, found 286.2357.
(E)-2-(4-메톡시스타이릴)-7-나이트로퀴나졸린 (5j)
화합물 4j로부터 일반 절차 B를 이용하여 합성하였다. 목적 화합물 5j (34%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.69 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 8.8 Hz, 1H), 8.38 (dd, J = 8.9, 2.1 Hz, 1H), 8.19 (d, J = 15.9 Hz, 1H), 7.80 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 15.9 Hz, 1H), 7.04 (d, J = 8.7 Hz, 2H), 3.84 (s, 3H); HRMS (ESI+) calculated for C17H13N3O3 [M+H]+: 308.0957, found 308.3506.
(E)-2-(4-클로로스타이릴)-7-나이트로퀴나졸린 (5k)
화합물 4k로부터 일반 절차 B를 이용하여 합성하였다. 목적 화합물 5k (60%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.72 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 8.9 Hz, 1H), 8.42 (dd, J = 8.8, 2.1 Hz, 1H), 8.21 (d, J = 16.0 Hz, 1H), 7.90 (m, 2H), 7.54 (m, 3H); HRMS (ESI+) calculated for C16H10ClN3O2 [M+H]+: 312.0462, found 312.2404.
5-(터트-부틸)-3-(7-나이트로퀴나졸린-2-일)이속사졸 (5l)
화합물 4l로부터 일반 절차 B를 이용하여 합성하였다. 목적 화합물 5l (82%)를 고체로 얻었다; 1H NMR (400 MHz, CDCl3) δ 9.73 (d, J = 0.6 Hz, 1H), 9.08 (dd, J = 1.5, 0.7 Hz, 1H), 8.51 (dd, J = 8.9, 2.2 Hz, 1H), 8.25-8.21 (m, 1H), 6.87 (d, J = 4.5 Hz, 1H), 1.49 (s, 9H); HRMS (ESI+) calculated for C15H14N4O3 [M+H]+: 299.1066, found 299.0941.
<제조예 5> 일반 절차 (General procedure) C: 화합물5m, 5v의 합성
화합물 3 (1.326 mmol)과 카발데하이드(carbaldehyde, 1.194 mmol)를 THF (13.26 ml, 0.1 M)에 녹여 상온에서 16시간 교반시켰다. 화합물 3가 모두 소진된 것을 TLC를 통해 확인 후, 반응 용액에 p-클로라닐 (1.618 mmol)을 첨가하여 65 ℃에서 12시간 교반시켰다. 반응 확인 후 냉각 시킨 이후에 감압 농축하고 0.5 N NaOH와 다이클로로메테인 혹은 EA로 층분리하여 유기층을 얻은 뒤, 무수 Na2SO4를 이용해 잔여 수분을 제거한 뒤 여과하고 실리카겔 칼럼 크로마토그래피를 통해 정제하여 화합물 5m과 5v를 고체로 얻는다.
상기 제조예 5의 방법으로 하기의 화합물을 수득하였다.
2-(1
H-
인다졸-5-일)-7-나이트로퀴나졸린 (5m)
화합물 3으로부터 일반 절차 C를 이용하여 합성하였다. 목적 화합물 5m (42%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 13.43 (s, 1H), 9.97 (s, 1H), 8.85 (s, 1H), 8.82 (s, 1H), 8.49 (d, J = 8.8 Hz, 1H), 8.44 (dd, J = 8.9, 1.9 Hz, 1H), 8.40 (d, J = 8.5 Hz, 1H), 8.20 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H); HRMS (ESI+) calculated for C15H9N5O2 [M+H]+: 292.0756, found 292.3588.
2-(3-((1-메틸피페리딘-4-일)옥시)-5-(트리플루오로메틸)페닐)-7-나이트로퀴나졸린 (5n)
화합물 4n로부터 일반 절차 B를 이용하여 합성하였다. 목적 화합물 5n (53%)를 고체로 얻었다; 1H NMR (400 MHz, CDCl3) δ 9.67 (d, J = 0.8 Hz, 1H), 9.04 (d, J = 2.2 Hz, 1H), 8.57 (s, 1H), 8.45 (dd, J = 8.9, 2.2 Hz, 1H), 8.43 (s, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.36 (s, 1H), 4.63 (s, 1H), 2.78 (s, 2H), 2.47 (s, 2H), 2.40 (s, 3H), 2.21 (s, 1H), 2.16 (dd, J = 13.1, 3.7 Hz, 2H), 2.04-1.95 (m, 2H); HRMS (ESI+) calculated for C21H19F3N4O3 [M+H]+: 433.1409, found 433.7546.
1-(4-(7-나이트로퀴나졸린-2-일)피페리딘-1-일)에탄-1-온 (5o)
화합물 4o로부터 일반 절차 B를 이용하여 합성하였다. 목적 화합물 5o (30%)를 고체로 얻었다; 1H NMR (400 MHz, CDCl3) δ 9.55 (d, J = 0.8 Hz, 1H), 8.91 (d, J = 2.2 Hz, 1H), 8.42 (dd, J = 8.9, 2.2 Hz, 1H), 8.16 - 8.12 (m, 1H), 4.82 - 4.74 (m, 1H), 4.03 (d, J = 13.5 Hz, 1H), 3.39 (ddd, J = 15.1, 7.6, 3.6 Hz, 1H), 3.32 (dt, J = 13.6, 4.0 Hz, 1H), 2.87 (td, J = 12.8, 2.9 Hz, 1H), 2.26 - 2.20 (m, 2H), 2.20 (s, 3H), 2.14 - 2.05 (m, 1H), 1.96 (ddd, J = 25.6, 12.1, 4.3 Hz, 1H); HRMS (ESI+) calculated for C15H16N4O3 [M+H]+: 301.1222, found 301.4713.
7-나이트로-2-(피리딘-4-일)퀴나졸린 (5p)
화합물 4p로부터 일반 절차 B를 이용하여 합성하였다. 목적 화합물 5p (11%)를 고체로 얻었다; 1H NMR (400 MHz, CDCl3) δ 9.72 (d, J = 0.8 Hz, 1H), 9.05 (dd, J = 1.5, 0.7 Hz, 1H), 8.89 (dd, J = 4.6, 1.5 Hz, 2H), 8.55 (dd, J = 4.5, 1.6 Hz, 2H), 8.49 (dd, J = 8.9, 2.2 Hz, 1H), 8.26-8.20 (m, 1H); HRMS (ESI+) calculated for C13H8N4O2 [M+H]+: 253.0647, found 253.2785.
7-나이트로-2-(피리딘-2-일)퀴나졸린 (5q)
화합물 4q로부터 일반 절차 B를 이용하여 합성하였다. 목적 화합물 5q (35%)를 고체로 얻었다; 1H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 9.18 (d, J = 2.1 Hz, 1H), 9.01 (d, J = 4.0 Hz, 1H), 8.80 (d, J = 7.9 Hz, 1H), 8.49 (dd, J = 8.9, 2.2 Hz, 1H), 8.26 - 8.21 (m, 1H), 8.03 (td, J = 7.8, 1.7 Hz, 1H), 7.59 - 7.54 (m, 1H); HRMS (ESI+) calculated for C13H8N4O2 [M+H]+: 253.0647, found 253.2424.
2-(3,4-다이클로로페닐)-7-나이트로퀴나졸린 (5r)
화합물 4r로부터 일반 절차 B를 이용하여 합성하였다. 목적 화합물 5r (61%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO) δ 9.99 (d, J = 0.8 Hz, 1H), 8.91 - 8.86 (m, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.55 (dd, J = 8.5, 2.0 Hz, 1H), 8.51 (d, J = 8.3 Hz, 1H), 8.48 (dd, J = 8.9, 2.0 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H).
2-(4-플루오로벤질)-7-나이트로퀴나졸린 (5s)
화합물 4s로부터 일반 절차 B를 이용하여 합성하였다. 목적 화합물 5s (59%)를 고체로 얻었다; 1H NMR (400 MHz, CDCl3) δ 9.53 (d, J = 0.7 Hz, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.41 (dd, J = 8.9, 2.2 Hz, 1H), 8.12 (d, J = 8.9 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.08 - 7.01 (m, 2H), 4.50 (s, 2H).
7-나이트로-2-(2-(트리플루오로메틸)벤질)퀴나졸린 (5t)
화합물 4t로부터 일반 절차 B를 이용하여 합성하였다. 목적 화합물 5t (31.4%)를 고체로 얻었다; 1H NMR (400 MHz, CDCl3) δ 9.48 (s, 1H), 8.87 (d, J = 1.8 Hz, 1H), 8.36 (dd, J = 8.9, 2.1 Hz, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.58 - 7.51 (m, 4H), 4.53 (s, 2H).
2-(나프탈렌-2-일)-7-나이트로퀴나졸린 (5u)
화합물 4u로부터 일반 절차 B를 이용하여 합성하였다. 목적 화합물 5u (49%)를 고체로 얻었다; 1H NMR (400 MHz, CDCl3) δ 9.66 (s, 1H), 9.22 (s, 1H), 9.02 (d, J = 1.8 Hz, 1H), 8.74 (dd, J = 8.6, 1.6 Hz, 1H), 8.38 (dd, J = 8.8, 2.1 Hz, 1H), 8.13 (d, J = 8.9 Hz, 1H), 8.08 - 8.04 (m, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.92 (d, J = 7.0 Hz, 1H), 7.61 - 7.54 (m, 2H).
2-(2,3-다이하이드로벤조퓨란-5-일)-7-나이트로퀴나졸린 (5v)
화합물 3로부터 일반 절차 C를 이용하여 합성하였다. 목적 화합물 5v (43%)를 고체로 얻었다; 1H NMR (400 MHz, CDCl3) δ 9.57 (d, J = 0.8 Hz, 1H), 8.93 (d, J = 2.2 Hz, 1H), 8.59 - 8.51 (m, 2H), 8.34 (dd, J = 8.8, 2.2 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.74 (dd, J = 10.3, 7.2 Hz, 2H), 3.38 (t, J = 8.7 Hz, 2H).
<제조예 6> 일반 절차(General procedure) D: 화합물6a-q의 합성
화합물5 (1 eq)을 EtOH/AcOH/H2O (2:2:1, 0.1 M)에 용해시켜 Fe (5 eq)을 추가하여 60 ℃에서 1시간 동안 교반시켰다. 상온에서 냉각시킨 후 용매를 감압 증류한 후 셀라이트를 통과시켜 여과한 후 EtOAc와 1 M NaOH를 이용해 염기 조건에서 층분리를 진행하였다. 유기층을 얻어 다시 포화 NaCl(brine)과 층분리를 시켰고 유기층을 얻어 무수 Na2SO4로 잔여 수분을 제거 후 화합물 6을 얻었다.
상기 제조예 6의 방법으로 하기의 화합물을 수득하였다.
2-(4-모폴리노-3-(트리플루오로메틸)페닐)퀴나졸린-7-아민 (6a)
화합물 5a로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6a (47%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J = 0.6 Hz, 1H), 8.77 (d, J = 2.0 Hz, 1H), 8.72 (dd, J = 8.4, 1.9 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.07 (dd, J = 8.8, 2.1 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 6.52 (s, 2H), 3.80 - 3.73 (m, 4H), 3.00 - 2.95 (m, 4H); HRMS (ESI+) calculated for C19H17F3N4O [M+H]+: 375.1354, found 375.0339.
2-(3-모폴리노-5-(트리플루오로메틸)페닐)퀴나졸린-7-아민 (6b)
화합물 5b로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6b (83%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.14 (d, J = 0.5 Hz, 1H), 8.30 (s, 1H), 8.18 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.35 (s, 1H), 7.06 (dd, J = 8.8, 2.1 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 6.51 (s, 2H), 3.82-3.78 (m, 4H), 3.32-3.28 (m, 4H); HRMS (ESI+) calculated for C19H17F3N4O [M+H]+: 375.1354, found 375.3806.
2-(3-(4-메틸-1
H-
이미다졸-1-일)-5-(트리플루오로메틸)페닐)퀴나졸린-7-아민 (6c)
화합물 5c로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6c (100%)를 고체로 얻었다; 1H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 8.38 (s, 1H), 8.15 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.69 (s, 1H), 7.10 (d, J = 8.6 Hz, 1H), 6.90 (s, 1H), 6.59 (s, 2H), 2.20 (s, 3H); HRMS (ESI+) calculated for C19H14F3N5 [M+H]+: 370.1201, found 370.2122.
2-(3-(4-메틸피페라진-1-일)-5-(트리플루오로메틸)페닐)퀴나졸린-7-아민 (6d)
화합물 5d로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6d (80%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.32 (s, 1H), 8.17 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.34 (s, 1H), 7.08 (dd, J = 8.8, 2.1 Hz, 1H), 6.88 (d, J = 1.9 Hz, 1H), 6.52 (s, 2H), 3.30 (m, 4H), 2.54 (m, 4H), 2.27 (s, 3H); HRMS (ESI+) calculated for C20H20F3N5 [M+H]+: 388.1671, found 388.3958.
2-(3-((4-에틸피페라진-1-일)메틸)-5-(트리플루오로메틸)페닐)퀴나졸린-7-아민 (6e)
화합물 5e로부터 일반 절차 D를 이용하여 합성하였다. 칼럼 크로마토그래피 (MC:Methanol = 15 : 1)로 정제하여 목적 화합물 6e (33%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.71 (s, 1H), 8.66 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.77 (s, 1H), 7.09 (dd, J = 8.8, 2.1 Hz, 1H), 6.89 (d, J = 2.1 Hz, 1H), 6.54 (d, J = 3.7 Hz, 2H), 3.69 (s, 2H), 3.31 (s, 4H), 2.46 (s, 4H), 2.36-2.30 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H); HRMS (ESI+) calculated for C18H14F3N5 [M+H]+: 416.1984, found 416.8992.
2-(3-플루오로-5-(트리플루오로메틸)페닐)퀴나졸린-7-아민 (6f)
화합물 5f로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6f (89%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J = 0.6 Hz, 1H), 8.61 (s, 1H), 8.47 (d, J = 10.0 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.10 (dd, J = 8.8, 2.1 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 6.58 (s, 2H); HRMS (ESI+) calculated for C15H9F4N3 [M+H]+: 308.0733, found 308.3506.
2-(4-클로로-3-(트리플루오로메틸)페닐)퀴나졸린-7-아민 (6g)
화합물 5g로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6g (97%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.16 (d, J = 0.6 Hz, 1H), 8.87 (d, J = 2.0 Hz, 1H), 8.73 (dd, J = 8.5, 2.0 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.08 (dd, J = 8.8, 2.1 Hz, 1H), 6.87 (d, J = 2.1 Hz, 1H), 6.56 (s, 2H); HRMS (ESI+) calculated for C15H9ClF3N3 [M+H]+: 324.0437, found 324.1620.
2-(1-페닐-5-(트리플루오로메틸)-1
H-
피라졸-4-일)퀴나졸린-7-아민 (6h)
화합물 5h로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6h (86%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J = 0.6 Hz, 1H), 8.36 (s, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 1.7 Hz, 5H), 7.07 (dd, J = 8.8, 2.1 Hz, 1H), 6.81 (d, J = 2.1 Hz, 1H), 6.50 (s, 2H); HRMS (ESI+) calculated for C18H12F3N5 [M+H]+: 356.1045, found 356.2275.
2-(3-클로로페닐)퀴나졸린-7-아민 (6i)
화합물 5i로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6i (98%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J = 0.6 Hz, 1H), 8.49-8.42 (m, 2H), 7.79 (d, J = 8.8 Hz, 1H), 7.62-7.54 (m, 2H), 7.08 (dd, J = 8.8, 2.1 Hz, 1H), 6.86 (d, J = 2.1 Hz, 1H), 6.52 (s, 2H); HRMS (ESI+) calculated for C14H10ClN3 [M+H]+: 256.0563, found 256.0520.
(E)-2-(4-메톡시스타이릴)퀴나졸린-7-아민 (6j)
화합물 5j로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6j (80%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 7.92 (d, J = 16.0 Hz, 1H), 7.68 (dd, J = 8.8, 2.2 Hz, 3H), 7.12 (d, J = 16.0 Hz, 1H), 6.98 (dd, J = 8.6, 6.2 Hz, 3H), 6.74 (d, J = 2.0 Hz, 1H), 6.35 (s, 2H), 3.80 (s, 3H); HRMS (ESI+) calculated for C17H15N3O [M+H]+: 278.1215, found 278.3117.
(E)-2-(4-클로로스타이릴)퀴나졸린-7-아민 (6k)
화합물 5k로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6k (83%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 7.96 (d, J = 16.0 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 16.0 Hz, 1H), 7.07-6.98 (m, 1H), 6.78 (s, 1H), 6.41 (s, 2H); HRMS (ESI+) calculated for C16H12ClN3 [M+H]+: 282.0720, found 282.2737.
2-(5-(터트-부틸)이속사졸-3-일)퀴나졸린-7-아민 (6l)
화합물 5l로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6l (88%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.11 (dd, J = 8.8, 2.1 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.77 (s, 1H), 6.58 (s, 2H), 1.38 (s, 9H); HRMS (ESI+) calculated for C15H16N4O [M+H]+: 269.1324, found 269.1630.
2-(1
H-
인다졸-5-일)퀴나졸린-7-아민 (6m)
화합물 5m로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6m (74%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 9.16 (s, 1H), 8.69 (d, J = 0.9 Hz, 1H), 8.31 (dd, J = 8.5, 1.3 Hz, 1H), 8.14 (d, J = 1.1 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.05 (dd, J = 8.7, 2.1 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 6.45 (d, J = 4.1 Hz, 2H); HRMS (ESI+) calculated for C15H11N5 [M+H]+: 262.1014, found 262.3553.
2-(3-((1-메틸피페리딘-4-일)옥시)-5-(트리플루오로메틸)페닐)퀴나졸린-7-아민 (6n)
화합물 5n로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6n (100%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.34 (s, 1H), 8.28 (s, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.41 (s, 1H), 7.09 (dd, J = 8.8, 2.1 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 6.54 (s, 2H), 4.69-4.61 (m, 1H), 2.63 (d, J = 5.6 Hz, 2H), 2.27 (t, J = 8.7 Hz, 2H), 2.22 (s, 3H), 1.99 (s, 2H), 1.79-1.68 (m, 2H); HRMS (ESI+) calculated for C21H21F3N4O [M+H]+: 403.1667, found 403.5034.
1-(4-(7-아미노퀴나졸린-2-일)피페리딘-1-일)에탄-1-온 (6o)
화합물 5o로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6o (83%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 7.70 (t, J = 6.4 Hz, 1H), 7.00 (dd, J = 8.8, 2.1 Hz, 1H), 6.72 (d, J = 2.1 Hz, 1H), 6.36 (s, 2H), 4.46 (d, J = 13.1 Hz, 1H), 3.92 (d, J = 13.6 Hz, 1H), 3.24 - 3.16 (m, 1H), 3.05 (tt, J = 11.4, 3.8 Hz, 1H), 2.75 - 2.67 (m, 1H), 2.06 - 2.03 (m, 3H), 1.96 (dd, J = 24.1, 7.7 Hz, 2H), 1.80 (ddd, J = 25.0, 12.5, 4.3 Hz, 1H), 1.64 (ddd, J = 16.5, 12.6, 4.4 Hz, 1H); HRMS (ESI+) calculated for C15H18N4O [M+H]+: 271.1481, found 271.4682.
2-(피리딘-4-일)퀴나졸린-7-아민 (6p)
화합물 5p로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6p (96%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 9.20 (d, J = 0.6 Hz, 1H), 8.76 (dd, J = 4.5, 1.6 Hz, 2H), 8.35 (dd, J = 4.5, 1.6 Hz, 2H), 7.82 (d, J = 8.8 Hz, 1H), 7.12 (dd, J = 8.8, 2.1 Hz, 1H), 6.90 (d, J = 2.1 Hz, 1H), 6.58 (s, 2H); HRMS (ESI+) calculated for C13H10N4 [M+H]+: 223.0905, found 223.3095.
2-(피리딘-2-일)퀴나졸린-7-아민 (6q)
화합물 5q로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6q (84%)를 고체로 얻었다; 1H NMR (400 MHz, CDCl3) δ 9.26 (d, J = 0.6 Hz, 1H), 8.90 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.65 (dt, J = 8.0, 1.0 Hz, 1H), 7.90 (td, J = 7.8, 1.8 Hz, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.42 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 7.25 (d, J = 2.2 Hz, 1H), 7.04 (dd, J = 8.7, 2.2 Hz, 1H), 4.46 (d, J = 14.2 Hz, 2H); HRMS (ESI+) calculated for C13H10N4 [M+H]+: 223.0905, found 223.1655.
2-(3,4-다이클로로페닐)퀴나졸린-7-아민 (6r)
화합물 5r로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6r (88.9%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO) δ 9.14 (s, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.43 (dd, J = 8.5, 2.0 Hz, 1H), 7.78 (dd, J = 8.6, 3.4 Hz, 2H), 7.07 (dd, J = 8.8, 2.1 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.54 (s, 2H).
2-(4-플루오로벤질)퀴나졸린-7-아민 (6s)
화합물 5s로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6s (100%)를 고체로 얻었다. 해당 화합물은 별도의 정제 과정 없이 다음 단계 반응에 이용하였다.
2-(2-(트리플루오로메틸)벤질)퀴나졸린-7-아민 (6t)
화합물 5t로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6t (100%)를 고체로 얻었다. 해당 화합물은 별도의 정제 과정 없이 다음 단계 반응에 이용하였다; 1H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 6.99 (dd, J = 8.8, 2.1 Hz, 1H), 6.72 (d, J = 1.8 Hz, 1H), 6.39 (s, 2H), 4.27 (s, 2H).
2-(나프탈렌-2-일)퀴나졸린-7-아민 (6u)
화합물 5u로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6u (78%)를 고체로 얻었다. 해당 화합물은 별도의 정제 과정 없이 다음 단계 반응에 이용하였다; 1H NMR (400 MHz, DMSO) δ 9.18 (d, J = 0.6 Hz, 1H), 9.07 (s, 1H), 8.62 (dd, J = 8.6, 1.7 Hz, 1H), 8.14 - 8.11 (m, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.99 - 7.96 (m, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.05 (dd, J = 8.7, 2.1 Hz, 1H), 6.90 (d, J = 2.1 Hz, 1H), 6.47 (s, 2H).
2-(2,3-다이하이드로벤조퓨란-5-일)퀴나졸린-7-아민 (6v)
화합물 5v로부터 일반 절차 D를 이용하여 합성하였다. 목적 화합물 6v (77.1%)를 고체로 얻었다. 해당 화합물은 별도의 정제 과정 없이 다음 단계 반응에 이용하였다; 1H NMR (400 MHz, DMSO) δ 9.05 (d, J = 0.6 Hz, 1H), 8.36 (d, J = 1.3 Hz, 1H), 8.28 (dd, J = 8.4, 1.9 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 6.97 (dd, J = 8.7, 2.1 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 2.1 Hz, 1H), 6.37 (s, 2H), 4.62 (dd, J = 14.4, 5.7 Hz, 2H), 3.27 (t, J = 8.7 Hz, 2H).
<실시예> 일반 절차 (General procedure) E: 화합물7a-v의 합성 및 화합물 7w의 합성
5-메틸이속사졸-4-카보닐 클로라이드 (1.2 eq ~ 2 eq)와 화합물 6 (1 eq)를 MC 또는 THF (0.1 M)에 용해시켜 65 ℃에서 교반시켰다. 화합물 6을 최대한 소진시켜 반응을 종결시킨 후 상온에서 냉각하고 감압 증류하였다. EtOAc와 포화 중탄산나트륨 수용액을 이용해 약한 염기성 조건에서 층분리를 하여 여분의 메틸 이속사졸을 제거한 후 무수 Na2SO4를 이용해 여분의 수분을 제거하였다. 실리카겔 칼럼 크로마토그래피를 통해 정제하여 최종 화합물 7을 얻었다.
상기 실시예의 방법으로 하기의 화합물을 수득하였다.
<실시예 1> 5-메틸-
N
-(2-(4-모폴리노-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)이속사졸-4-카복사미드 (7a)
화합물 6a로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7a (33%)를 고체로 얻었다; 1H NMR (400 MHz, , DMSO-d
6) δ 10.54 (s, 1H), 9.56 (d, J = 0.7 Hz, 1H), 9.16 (d, J = 0.6 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.77 (dd, J = 8.5, 1.9 Hz, 1H), 8.59 (d, J = 1.9 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.90 (dd, J = 8.8, 2.0 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 3.79 - 3.75 (m, 4H), 3.02 - 2.97 (m, 4H), 2.75 (d, J = 0.4 Hz, 3H); 13C NMR (101 MHz, , DMSO-d
6) δ 173.6, 160.2, 159.9, 158.6, 153.7, 150.9, 149.0, 144.1, 133.6, 132.8, 128.5, 125.5, 125.0, 124.2, 122.8, 121.7, 120.1, 115.0, 111.8, 66.5, 53.2, 12.2; HRMS (ESI+) calculated for C24H20F3N5O3 [M+H]+: 484.1518, found 484.4126.
<실시예 2> 5-메틸-
N
-(2-(3-모폴리노-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)이속사졸-4-카복사미드 (7b)
화합물 6b로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7b (53%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 9.59 (d, J = 0.7 Hz, 1H), 9.16 (d, J = 0.6 Hz, 1H), 8.67 (d, J = 1.9 Hz, 1H), 8.38 (s, 1H), 8.26 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.90 (dd, J = 8.8, 2.0 Hz, 1H), 7.41 (s, 1H), 3.87-3.74 (m, 4H), 3.34 (d, J = 4.9 Hz, 4H), 2.74 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 174.5, 160.2, 160.0, 159.4, 151.7 151.6, 148.1, 143.2, 139.6, 132.0, 131.7, 128.0, 125.7, 121.7, 120.9, 118.2, 116.7, 113.6, 111.9, 66.8, 48.9, 12.8; HRMS (ESI+) calculated for C24H20F3N5O3 [M+H]+: 484.1518, found 484.3579.
<실시예 3> 5-메틸-
N
-(2-(3-(4-메틸-1
H-
이미다졸-1-일)-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)이속사졸-4-카복사미드 (7c)
화합물 6c로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7c (11%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 9.65 (s, 1H), 9.17 (s, 1H), 8.89 (s, 1H), 8.74 (s, 1H), 8.72 (s, 1H), 8.42 (s, 1H), 8.23 (d, 1H), 8.21 (s, 1H), 7.93 (dd, J = 8.8, 1.8 Hz, 1H), 7.73 (s, 1H), 2.75 (s, 3H), 2.21 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 174.2, 161.5, 160.9, 160.5, 160.5, 151.4, 149.6, 149.5, 144.8, 141.0, 139.6, 138.8, 137.3, 137.0, 136.1, 136.1, 123.1, 122.9, 122.8, 122.2, 121.0, 112.3, 67.3, 12.7; HRMS (ESI+) calculated for C24H17F3N6O2 [M+H]+: 479.1365, found 479.3079.
<실시예 4> 5-메틸-
N
-(2-(3-(4-메틸피페라진-1-일)-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)이속사졸-4-카복사미드 (7d)
화합물 6d로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7d (3%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d
6) δ 10.60 (s, 1H), 9.60 (s, 1H), 9.19 (s, 1H), 8.69 (s, 1H), 8.39 (s, 1H), 8.25 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.93 (dd, J = 8.9, 1.9 Hz, 1H), 7.42 (s, 1H), 3.42 (s, 4H), 2.76 (s, 3H), 2.67 (s, 4H), 2.37 (s, 3H); 13C NMR (101 MHz, DMSO-d
6) δ 174.2, 160.6, 160.5, 159.5, 152.0, 151.4, 149.6, 149.6, 144.6, 139.8, 130.8, 129.1, 122.4, 122.4, 120.9, 120.9, 117.8, 115.6, 112.3, 54.6, 47.7, 47.7, 12.8; HRMS (ESI+) calculated for C25H23F3N6O2 [M+H]+: 497.1835, found 497.3947.
<실시예 5>
N
-(2-(3-((4-에틸피페라진-1-일)메틸)-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7e)
화합물 6e로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7e (12%)를 고체로 얻었다; 1H NMR (400 MHz, CDCl3) δ 9.38 (s, 1H), 8.80 (s, 1H), 8.73 (s, 2H), 8.32 (s, 2H), 8.02 (d, J = 7.6 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.77 (s, 1H), 3.75 (s, 2H), 2.86 (s, 3H), 2.72 (s, 4H), 2.64 (d, J = 7.2 Hz, 2H), 1.97 (s, 4H), 1.19 (d, J = 7.2 Hz, 3H); HRMS (ESI+) calculated for C27H27F3N6O2 [M+H]+: 525.2148, found 525.6202.
<실시예 6>
N
-(2-(3-플루오로-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7f)
화합물 6f로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7f (95%)를 고체로 얻었다; 1H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 9.15 (s, 1H), 8.93 (s, 1H), 8.72 (s, 1H), 8.50 (d, J = 9.9 Hz, 1H), 8.43 (s, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 2.83 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 174.6, 164.0, 161.6, 160.0, 159.6, 158.6, 151.3, 148.2, 143.6, 141.3, 141.2, 128.1, 122.3, 121.2, 120.9, 118.8, 118.6, 116.5, 111.9, 12.8; HRMS (ESI+) calculated for C20H12F4N4O2 [M+H]+: 417.0896, found 417.3687.
<실시예 7>
N
-(2-(4-클로로-3-(트리플루오로메틸)페닐)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7g)
화합물 6g로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7g (80%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.60 (s, 1H), 9.16 (s, 1H), 8.92 (d, J = 1.8 Hz, 1H), 8.79 (dd, J = 8.4, 1.8 Hz, 1H), 8.62 (d, J = 1.6 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.99-7.88 (m, 2H), 2.74 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 174.2, 170.8, 160.9, 160.5, 151.3, 149.5, 144.8, 137.5, 135.1, 133.6, 133.6, 132.9, 132.9, 132.9, 129.2, 122.7, 120.9, 115.5, 112.3, 12.8; HRMS (ESI+) calculated for C20H12ClF3N3O2 [M+H]+: 433.0601, found 433.1064.
<실시예 8> 5-메틸-
N
-(2-(1-페닐-5-(트리플루오로메틸)-1
H-
피라졸-4-일)퀴나졸린-7-일)이속사졸-4-카복사미드 (7h)
화합물 6h로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7h (80%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 9.58 (d, J = 0.7 Hz, 1H), 9.16 (d, J = 0.6 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.49 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.01 (dd, J = 8.9, 2.0 Hz, 1H), 7.61 (d, J = 7.5 Hz, 5H), 2.78-2.71 (m, 3H); 13C NMR (101 MHz, DMSO-d6) δ 174.3, 174.2, 163.1, 160.4, 151.3, 151.2, 149.6, 144.7, 142.3, 140.1, 130.2, 129.8, 129.0, 126.4, 125.6, 122.5, 121.7, 120.2, 115.3, 112.2, 12.8; HRMS (ESI+) calculated for C23H15F3N6O2 [M+H]+: 465.1209, found 465.3015.
<실시예 9>
N
-(2-(3-클로로페닐)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7i)
화합물 6i로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7i (95%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 9.56 (d, J = 0.7 Hz, 1H), 9.16 (d, J = 0.6 Hz, 1H), 8.59 (d, J = 2.0 Hz, 1H), 8.50 (dtd, J = 8.3, 2.4, 1.6 Hz, 2H), 8.15 (d, J = 8.8 Hz, 1H), 7.92 (dd, J = 8.8, 2.0 Hz, 1H), 7.63-7.57 (m, 2H), 2.74 (d, J = 0.5 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 174.1, 170.8, 160.7, 160.4, 159.3, 151.4, 149.6, 144.6, 140.2, 134.1, 131.2, 131.0, 129.0, 128.0, 122.4, 120.8, 115.6, 112.3, 12.7; HRMS (ESI+) calculated for C19H13ClN4O2 [M+H]+: 365.0727, found 365.6163
<실시예 10> (E)-
N
-(2-(4-메톡시스타이릴)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7j)
화합물 6j로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7j (95%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 9.44 (s, 1H), 9.16 (d, J = 0.6 Hz, 1H), 8.46 (d, J = 1.9 Hz, 1H), 8.09 (dd, J = 12.4, 8.8 Hz, 2H), 7.88 (dd, J = 8.8, 2.0 Hz, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 16.0 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H), 2.78 - 2.73 (m, 3H); 13C NMR (101 MHz, DMSO-d6) δ 174.0, 169.0, 161.8, 160.7, 160.4, 160.0, 151.5, 149.6, 144.2, 138.0, 129.8, 128.9, 126.1, 121.5, 120.2, 115.3, 114.9, 112.4, 55.8, 12.7; HRMS (ESI+) calculated for C22H18N4O3 [M+H]+: 387.1379, found 387.2971.
<실시예 11> (E)-
N
-(2-(4-클로로스타이릴)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7k)
화합물 6k로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7k (73%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 9.46 (s, 1H), 9.14 (d, J = 0.6 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.10 (dd, J = 12.4, 9.7 Hz, 2H), 7.89 (dd, J = 8.8, 2.0 Hz, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.53 - 7.47 (m, 2H), 7.43 (d, J = 16.0 Hz, 1H), 2.73 (d, J = 0.4 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 174.0, 161.2, 160.4, 160.0, 151.4, 149.5, 144.3, 136.7, 135.2, 134.0, 129.8, 129.4, 129.3, 128.9, 121.8, 120.3, 115.4, 112.3, 12.7; HRMS (ESI+) calculated for C21H15ClN4O2 [M+H]+: 391.0884, found 397.2947.
<실시예 12>
N
-(2-(5-(터트-부틸)이속사졸-3-일)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7l)
화합물 6l로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7l (59%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 9.58 (s, 1H), 9.14 (s, 1H), 8.62 (s, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 6.89 (s, 1H), 2.73 (s, 3H), 1.39 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 182.7, 174.4, 162.7, 160.3, 159.7, 154.6, 151.3, 148.5, 144.5, 128.0, 123.1, 121.2, 116.3, 112.0, 99.0, 33.0, 28.8, 12.8; HRMS (ESI+) calculated for C20H19N5O3 [M+H]+: 378.1488, found 378.4376.
<실시예 13>
N
-(2-(1
H-
인다졸-5-일)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7m)
화합물 6m로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7m (8%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 10.59 (s, 1H), 9.61 (s, 1H), 9.18 (s, 1H), 8.78 (d, J = 0.6 Hz, 1H), 8.62 (d, J = 1.5 Hz, 1H), 8.39 (dd, J = 8.6, 1.1 Hz, 1H), 8.20-8.15 (m, 2H), 7.97-7.91 (m, 2H), 2.77 (s, 3H); HRMS (ESI+) calculated for C20H14N6O2 [M+H]+: 371.1178, found 371.4147.
<실시예 14> 5-메틸-
N
-(2-(3-((1-메틸피페리딘-4-일)옥시)-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)이속사졸-4-카복사미드 (7n)
화합물 6n로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7n (4%)를 고체로 얻었다; 1H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 8.93 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 8.44 (d, J = 1.0 Hz, 1H), 8.32 (s, 1H), 8.14 (dd, J = 8.6, 1.1 Hz, 1H), 7.98 (d, J = 8.9 Hz, 1H), 7.25 (s, 1H), 4.83 (m, 1H), 3.11 (m, 2H), 2.86 (s, 3H), 2.46 (d, J = 20.9 Hz, 2H), 2.20 (d, J = 8.2 Hz, 2H), 2.06 (d, J = 6.9 Hz, 2H), 1.26 (s, 3H); HRMS (ESI+) calculated for C26H24F3N5O3 [M+H]+: 512.1831, found 512.6204.
<실시예 15>
N
-(2-(1-아세틸피페리딘-4-일)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7o)
화합물 6o로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7o (30%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.44 (s, 1H), 9.16 (s, 1H), 8.47 (d, J = 1.6 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.90 (dd, J = 8.8, 1.9 Hz, 1H), 4.48 (d, J = 13.0 Hz, 1H), 3.95 (d, J = 13.5 Hz, 1H), 3.28 - 3.20 (m, 2H), 2.81 - 2.72 (m, 4H), 2.12 - 2.01 (m, 5H), 1.86 (ddd, J = 16.0, 12.4, 4.2 Hz, 1H), 1.69 (ddd, J = 16.1, 12.5, 4.1 Hz, 1H); HRMS (ESI+) calculated for C20H21N5O3 [M+H]+: 380.1644, found 380.5264.
<실시예 16> 5-메틸-
N
-(2-(피리딘-4-일)퀴나졸린-7-일)이속사졸-4-카복사미드 (7p)
화합물 6p로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7p (50%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.67 (s, 1H), 9.19 (s, 1H), 8.83 (d, J = 6.0 Hz, 2H), 8.68 (s, 1H), 8.44 (dd, J = 4.5, 1.6 Hz, 2H), 8.24 (d, J = 8.8 Hz, 1H), 8.01 (dd, J = 8.8, 1.9 Hz, 1H), 2.76 (s, 3H); HRMS (ESI+) calculated for C18H13N5O2 [M+H]+: 332.1069, found 332.3738.
<실시예 17> 5-메틸-
N
-(2-(피리딘-2-일)퀴나졸린-7-일)이속사졸-4-카복사미드 (7q)
화합물 6q로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7q (33%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 9.61 (s, 1H), 9.15 (s, 1H), 8.79 (d, J = 4.1 Hz, 1H), 8.61 (d, J = 1.6 Hz, 1H), 8.54 (d, J = 7.9 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.01 (td, J = 7.8, 1.7 Hz, 1H), 7.97 (dd, J = 8.8, 1.9 Hz, 1H), 7.55 (dd, J = 6.6, 4.8 Hz, 1H), 2.74 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 174.0, 160.6, 160.5, 155.4. 151.5, 150.3, 150.1, 149.6, 144.5, 137.7, 128.9, 125.5, 124.4, 122.7, 121.0, 115.8, 112.3; HRMS (ESI+) calculated for C18H13N5O2 [M+H]+: 332.1069, found 332.5899.
<실시예 18>
N
-(2-(3,4-다이클로로페닐)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7r)
화합물 6r로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7r (77.3%)를 고체로 얻었다; 1H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 8.93 (s, 1H), 8.84 (s, 1H), 8.74 (s, 1H), 8.47 (d, J = 8.5 Hz, 1H), 8.41 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 2.84 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 170.63, 167.28, 166.91, 160.23, 160.18, 159.84, 148.06, 148.01, 130.57, 130.47, 128.12, 128.11, 127.67, 125.26, 123.33, 123.22, 111.87, 102.31, 22.51.
<실시예 19>
N
-(2-(4-플루오로벤질)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7s)
화합물 6s로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7s (17.8%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO) δ 10.51 (s, 1H), 9.39 (d, J = 0.6 Hz, 1H), 9.13 (d, J = 0.6 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.88 (dd, J = 8.8, 2.0 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.12 (ddd, J = 8.9, 5.9, 2.6 Hz, 2H), 4.32 (s, 2H), 2.72 (d, J = 0.4 Hz, 3H).
<실시예 20> 5-메틸-
N
-(2-(2-(트리플루오로메틸)벤질)퀴나졸린-7-일)이속사졸-4-카복사미드 (7t)
화합물 6s로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7t (17.8%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO) δ 10.52 (s, 1H), 9.41 (s, 1H), 9.13 (s, 1H), 8.45 (s, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.91 - 7.87 (m, 1H), 7.68 (s, 1H), 7.66 (s, 1H), 7.60 (s, 1H), 7.58 (s, 1H), 4.45 (s, 2H), 2.72 (s, 3H).
<실시예 21> 5-메틸-
N
-(2-(나프탈렌-2-일)퀴나졸린-7-일)이속사졸-4-카복사미드 (7u)
화합물 6u로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7u (61%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO) δ 10.58 (s, 1H), 9.62 (d, J = 0.7 Hz, 1H), 9.18 (s, 1H), 9.17 (d, J = 0.6 Hz, 1H), 8.69 (dd, J = 8.7, 1.7 Hz, 1H), 8.67 (d, J = 1.9 Hz, 1H), 8.18 (d, J = 8.7 Hz, 2H), 8.09 (d, J = 8.8 Hz, 1H), 8.01 (dd, J = 6.1, 3.2 Hz, 1H), 7.91 (dd, J = 8.8, 2.0 Hz, 1H), 7.64 - 7.57 (m, 2H), 2.76 (s, 3H); 13C NMR (101 MHz, DMSO) δ 173.56, 160.16, 160.01, 159.92, 151.04, 149.05, 143.92, 134.95, 134.16, 132.87, 129.10, 128.46, 128.32, 128.17, 127.60, 127.34, 126.51, 124.96, 121.51, 120.16, 115.12, 111.82, 12.24.
<실시예 22>
N
-(2-(2,3-다이하이드로벤조퓨란-5-일)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드 (7v)
화합물 6v로부터 일반 절차 E를 이용하여 합성하였다. 목적 화합물 7v (99.2%)를 고체로 얻었다; 1H NMR (400 MHz, DMSO) δ 10.52 (s, 1H), 9.48 (d, J = 0.7 Hz, 1H), 9.15 (d, J = 0.6 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 8.37 (dd, J = 8.4, 1.9 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.85 (dd, J = 8.8, 2.0 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 4.64 (t, J = 8.8 Hz, 2H), 3.31 - 3.27 (m, 2H), 2.74 (d, J = 0.5 Hz, 3H).
<실시예 23>
N
-(2-(4-메톡시페네틸)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드
(7w)
화합물 7j (1eq)와 Pd/C (10 wt. %)을 에틸아세테이트 (5 ml)에 용해시킨 후, 수소 기체 존재 하에서 40분 동안 실온에서 교반하였다. 반응이 종결된 후 셀라이트로 여과한 후 감압 증류하였다. 잔사 (residue)로부터 별다른 정제없이 화합물7w (57.3%)를 얻었다; 1H NMR (400 MHz, DMSO) δ 10.52 (s, 1H), 9.42 (s, 1H), 9.15 (s, 1H), 8.44 (d, J = 1.7 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.89 (dd, J = 8.8, 2.0 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 3.71 (s, 3H), 3.28 (dd, J = 9.1, 6.7 Hz, 2H), 3.14 (t, J = 7.7 Hz, 2H), 2.74 (s, 3H).
실험예 1. FLT3 및 FLT 효소활성 측정
본 발명에 따른 하기 표 1의 퀴나졸린 유도체 처리에 의한 FLT3 및 FLT 효소활성 변화를 IC50을 통해 확인하였다.
모든 퀴나졸린 화합물 7a-7w 의 FLT3, FLT-ITD 키나아제 활성을 평가한 결과를 표1 에 나타내었다. 합성된 유도체 중 특히 피페라진 구조가 포함된 화합물에서 FLT3에 대한 선택적 활성을 보였다. 그 중 화합물 7d는 FLT3에 대해 IC50 = 106 nM, FLT-ITD에 대해 IC50 = 301 nM 의 활성을 보였다.
실험예 2. 다양한 단백질 인산화 효소에 대한 저해 활성 측정
이어서, 다른 상이한 FLT3 돌연변이 체에 대한 화합물 7d의 억제 활성에 대해 추가로 조사하여 표 2에 나타내었다. 삽입 된 1 개의 아미노산 서열 (IC50 값 0.524 μM), 2 개의 아미노산 서열 (IC50 값 0.495 μM) 및 9 개의 아미노산 서열 (IC50 값 0.728 μM)의 결과로 보아, 서열 및 위치에 관계없이 강력하게 억제하였다. 또한 화합물 7d는 TKD에 위치한 FLT3 돌연변이에 강력했다. 7d는 FLT3 (D835Y)를 IC50 = 228nM로 억제하였다.
티로신 키나아제 억제제를 ATP-결합 부위에 결합시켰다. 그러나 ITD 및 점 돌연변이 (TKD)와 같은 잘 알려진 FLT3 돌연변이는 ATP 결합 부위를 제외하고 티로신 키나아제의 반대쪽에서 발견되었다. 그렇기 때문에 FLT3-ITD 및 TKD에 대해 FLT3와 유사한 억제활성만 나타냈다.
다음으로, 10 μM의 단일 복용량에서 36 개의 서로 다른 키나아제에 대해, 7d에 대한 키나아제 패널 스크리닝을 조사했다 (도 1, 표 3).
화합물 7d는 FLT3에서 96.6 %, FLT-ITD에서 95.2%의 억제 활성을 보였고, 7d는 또한 FMS에 대한 선택성을 유지하였다. 특히 퀴나졸린 화합물 7d는 cKIT에 대한 억제 활성을 나타내지 않기 때문에 cKIT에 비해 선택성 프로파일을 나타냈다. cKIT에 대한 높은 선택성은 이중 FLT3 / cKIT 키나아제 억제제로부터 보고된 골수 억제 독성을 피할 기회일 수 있다.
FLT3을 갖는 동일한 유형 III 수용체 티로신 키나아제 패밀리에 속하기 때문에 cKIT 및 FMS 키나아제에 비해 선택성을 달성하는 것이 어렵다는 점을 고려하여 이러한 키나아제 선택성 프로파일을 확보하는 것은 매우 귀중한 결과이다.
Kinase | IC50 (μM) |
FLT3 (F594_R595 ins R) | 0.524 |
FLT3 (F594_R595 ins EY) | 0.495 |
FLT3 (Y591_V592 ins VDFREYEYD) | 0.728 |
FLT3 (D835Y) | 0.228 |
키나아제 | % 저해율 | 스타우로스포린 IC50 (nM) |
ABL1 | 6.46 | 31.0 |
AKT1 | 5.48 | 1.98 |
ALK | 17.0 | 2.35 |
Aurora A | 20.1 | 0.502 |
AXL | 21.2 | 3.88 |
AXL (R499C) | 10.1 | 3.21 |
BRAF (V599E) | 5.19 | 6.79a |
BTK | 17.5 | 11.7 |
c-Kit | 0 | 1.40 |
c-MET | 13.2 | 57.8 |
c-Src | 14.6 | 1.20 |
CAMKK1 | 0 | 59.6 |
CDK4/cyclin D1 | 3.01 | 30.4 |
EGFR | 0 | 65.5 |
ERK1 | 15.0 | 4.47b |
FGFR3 | 1.00 | 8.87 |
FLT1/VEGFR1 | 5.23 | 5.65 |
FLT3 | 96.6 | 1.13 |
FLT3-ITD | 95.2 | 1.58 |
FMS | 5.49 | 1.34 |
FYN | 19.0 | 1.07 |
GSK3b | 8.06 | 4.4 |
IGF1R | 00 | 31.7 |
JAK3 | 0.80 | 0.0784 |
JNK3 | 19.5 | 65.8c |
KDR/VEGFR2 | 16.8 | 11.4 |
LCK | 19.7 | 1.39 |
LYN | 20.5 | 0.675 |
MEK1 | 0 | 14.7 |
P38a/MAPK14 | 0 | 16.0d |
PKA | 2.5 | 1.37 |
PLK1 | 0 | 111 |
RIPK3 | 12.8 | 1650a |
RON/MST1R | 13.5 | 140 |
ROS/ROS1 | 14.4 | 0.174 |
SYK | 22.4 | 0.436 |
a Data of GW507418 b Data of SCH77298419,20 c Data of JNKI VIII21, 22 d Data of SB20219023 |
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.
Claims (10)
- 하기 화학식 7의 화합물 또는 이의 약학적으로 허용 가능한 염:[화학식 7]상기 화학식 7에서,R2는 인다졸일, 나프탈레닐, 다이하이드로벤조퓨란일, 피리딘일, 아세틸 피페리딘, 하나 이상의 비수소치환기로 치환되거나 비치환된 페닐, 하나 이상의 비수소치환기로 치환되거나 비치환된 피라졸일, 하나 이상의 비수소치환기로 치환되거나 비치환된 다이하이드로이속사졸,상기 R2에서 비수소치환기는,R3는 수소 원자, 하이드록시, C1-C6 알킬 또는 C1-C6 할로겐화 알킬이며,R4는 수소 원자, 하이드록시 또는 C1-C6 알킬이거나 존재하지 않고,여기에서, X는 질소 또는 산소 원자이며, Y는 할로겐 또는 산소 원자이고,R5는 수소 원자, 하이드록시, 할로겐 원자 또는 C1-C6 할로겐화 알킬이며,R6는 수소 원자, 하이드록시 또는 C1-C6 알킬이고,
- 제 1항에 있어서,상기 화학식 7의 화합물은 하기 화학식 7'의 구조를 갖는 것인 화합물.[화학식 7']상기 화학식 7'에서,R2는 인다졸일, 나프탈레닐, 다이하이드로벤조퓨란일, 피리딘일, 아세틸 피페리딘, 하나 이상의 비수소치환기로 치환되거나 비치환된 페닐, 하나 이상의 비수소치환기로 치환되거나 비치환된 피라졸일, 하나 이상의 비수소치환기로 치환되거나 비치환된 다이하이드로이속사졸,상기 R2에서 비수소치환기는,R3는 수소 원자, 하이드록시, C1-C6 알킬 또는 C1-C6 할로겐화 알킬이며,R4는 수소 원자, 하이드록시 또는 C1-C6 알킬이거나 존재하지 않고,여기에서, X는 질소 또는 산소 원자이며, Y는 할로겐 또는 산소 원자이고,R5는 수소 원자, 하이드록시, 할로겐 원자 또는 C1-C6 할로겐화 알킬이며,R6는 수소 원자, 하이드록시 또는 C1-C6 알킬이고,
- 제 1항에 있어서,R3는 C1-C6 알킬인 화합물.
- 제 1항에 있어서,상기 화학식 7의 화합물은,5-메틸-N-(2-(4-모폴리노-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)이속사졸-4-카복사미드;5-메틸-N-(2-(3-모폴리노-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)이속사졸-4-카복사미드;5-메틸-N-(2-(3-(4-메틸-1H-이미다졸-1-일)-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)이속사졸-4-카복사미드;5-메틸-N-(2-(3-(4-메틸피페라진-1-일)-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)이속사졸-4-카복사미드;N-(2-(3-((4-에틸피페라진-1-일)메틸)-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드;N-(2-(3-플루오로-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드;N-(2-(4-클로로-3-(트리플루오로메틸)페닐)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드;5-메틸-N-(2-(1-페닐-5-(트리플루오로메틸)-1H-피라졸-4-일)퀴나졸린-7-일)이속사졸-4-카복사미드;N-(2-(3-클로로페닐)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드;(E)-N-(2-(4-메톡시스타이릴)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드;(E)-N-(2-(4-클로로스타이릴)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드;N-(2-(5-(터트-부틸)이속사졸-3-일)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드;N-(2-(1H-인다졸-5-일)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드;5-메틸-N-(2-(3-((1-메틸피페리딘-4-일)옥시)-5-(트리플루오로메틸)페닐)퀴나졸린-7-일)이속사졸-4-카복사미드;N-(2-(1-아세틸피페리딘-4-일)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드;5-메틸-N-(2-(피리딘-4-일)퀴나졸린-7-일)이속사졸-4-카복사미드;5-메틸-N-(2-(피리딘-2-일)퀴나졸린-7-일)이속사졸-4-카복사미드;N-(2-(3,4-다이클로로페닐)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드;N-(2-(4-플루오로벤질)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드;5-메틸-N-(2-(2-(트리플루오로메틸)벤질)퀴나졸린-7-일)이속사졸-4-카복사미드;5-메틸-N-(2-(나프탈렌-2-일)퀴나졸린-7-일)이속사졸-4-카복사미드;N-(2-(2,3-다이하이드로벤조퓨란-5-일)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드; 또는N-(2-(4-메톡시페네틸)퀴나졸린-7-일)-5-메틸이속사졸-4-카복사미드;인 화합물.
- 제 1항 내지 제 7항 중 어느 한 항의 퀴나졸린 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 암의 예방 또는 치료용 약학적 조성물.
- 제 8항에 있어서상기 암 질환은 급성 골수성 백혈병(AML)인 것을 특징으로 하는, 약학적 조성물.
- 제 9항에 있어서상기 조성물은 FLT 3(fms-like tyrosine kinase 3)의 활성을 저해하는 것을 특징으로 하는, 약학적 조성물.
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WO2004030671A2 (en) * | 2002-10-02 | 2004-04-15 | Merck Patent Gmbh | Use of 4-amino-quinazolines as anti cancer agents |
US20080207617A1 (en) * | 2002-10-29 | 2008-08-28 | Kirin Beer Kabushiki Kaisha | Quinoline Derivatives and Quinazoline Derivatives Inhibiting Autophosphrylation of Flt3 and Medicinal Compositions Containing the Same |
US20160194291A1 (en) * | 2013-08-09 | 2016-07-07 | Vichem Chemie Kutató Kft. | Styryl quinazoline derivatives as pharmaceutically active agents |
KR102085692B1 (ko) * | 2019-08-13 | 2020-03-06 | 한양대학교 에리카산학협력단 | Flt3 저해 활성을 갖는 신규한 이미다졸 유도체 및 이의 용도 |
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US20160194291A1 (en) * | 2013-08-09 | 2016-07-07 | Vichem Chemie Kutató Kft. | Styryl quinazoline derivatives as pharmaceutically active agents |
KR102085692B1 (ko) * | 2019-08-13 | 2020-03-06 | 한양대학교 에리카산학협력단 | Flt3 저해 활성을 갖는 신규한 이미다졸 유도체 및 이의 용도 |
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