KR20190056814A - Quinolin-8-ylmethanamines, preparation method thereof and pharmaceutical compositions for the prevention and treatment of cancer containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel quinoline-8-ylmethanamine having an anticancer activity, a manufacturing method thereof, and a pharmaceutical composition containing the quinoline-8-ylmethanamine as active ingredients, and more specifically, to a quinoline-8-ylmethanamine generated by results of C-H amination reaction using rhodium (III) as a catalyst, to a manufacturing method thereof and a composition for preventing or treating cancer containing the quinoline-8-ylmethanamine as active ingredients. According to the present invention, the novel quinoline-8-ylmethanamine has an excellent anticancer activity for various human cancer cell lines such that it is expected to be used as a pharmaceutical composition for preventing and treating cancer. In addition, the manufacturing method of the quinoline-8-ylmethanamine using rhodium (III) as a catalyst may be applied and introduced in a wide range of functional groups and may be very useful in novel medicines and compound synthesis having biological activities, as a reaction having regioselectivity and chemoselectivity.

Description

Quinolin-8-ylmethanamine, a process for preparing the same, and a composition for preventing and treating cancer comprising the same as an active ingredient. ingredient}

The present invention relates to a novel quinolin-8-ylmethanamine having an anticancer activity, a process for producing the same, and a pharmaceutical composition containing the same as an active ingredient.

With the catalytic carbon-hydrogen functionalization, the carbon-nitrogen bond formation reaction has become the most attractive topic in organic and medical chemistry due to the presence of the heterocycle containing the bioactive nitrogen. In this regard, various amine surrogates such as N-carboxylate, N-tosylate, organic azides, dioxazolones and anthranil have been used in sp ² carbon-hydrogen amination reactions. Studies on palladium (II) -catalyzed carbon (sp3) -hydrogenamination of O-methyloxime and 8-methylquinoline have been carried out and have been carried out under suitable oxidative reductive or oxidative conditions When trapped, significant progress has been made on transition metal catalyzed sp3 carbon-hydrogen amination reactions of 8-methylquinoline. For example, benzyl carbon (sp3) -hydrogen bonding palladium (II) -catalyzed oxidative amination reaction using NFSI as an amine reagent is known. In addition, organic azides and sp ³ Iridium (III) -catalyst carbon-nitrogen bond formation of carbon-hydrogen bonds has been reported. In addition, rhodium (III) - and ruthenium (II) -catalyzed amination of 8-methylquinoline with N-sulfonyl azide has also been disclosed.

Azodicarboxylates have been recognized as important subunits of carbon-nitrogen forming reactions. Accordingly, the present inventors have attempted to induce a carbon-nitrogen formation reaction through the transition metal catalyzed arylation of azodicarboxylate using boric acid. In addition, the present inventors have attempted to induce a carbon-nitrogen formation reaction by using azodicarboxylate as a photocatalytic, radical- The cross-linking reaction was studied according to the corresponding hydrazide derivative. Conversely, ethoxyacryl radicals and sp ² and sp ³ carbon-hydrogen bonding palladium (II) -catalyzed ethoxycarbonylation resulting from pyrolysis of diethyl azodicarboxylate are known. Thereafter, the unique role of azodicarboxylate as a carbonyl source for the synthesis of phthalimides under Co (II) catalysts is also known (J. Ni, J. Li, Z. Fan and A. Zhang, Org. Lett., 2016, 18, 5960.). Recently, it has been demonstrated that a? -Amino acid derivative is synthesized by amide-induced palladium (II) -catalyst carbon-hydrogen amination reaction using azodicarboxylate as an amino source.

SUMMARY OF THE INVENTION The present invention has been made in order to solve the above-mentioned problems in the prior art, and the present inventors have found that by preparing novel quinolin-8-ylmethanamine having anticancer activity and treating it, The present invention has been completed on the basis thereof.

Accordingly, an object of the present invention is to provide novel quinolin-8-ylmethanamine having anticancer activity and a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for preparing novel quinolin-8-ylmethanamine having anticancer activity.

Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, which comprises novel quinolin-8-ylmethanamine having anticancer activity and a pharmaceutically acceptable salt thereof as an active ingredient.

However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.

In order to accomplish the object of the present invention, the present invention provides quinolin-8-ylmethanamine represented by Chemical Formula 1, Chemical Formula 4, Chemical Formula 5 or Chemical Formula 6, an isomer thereof or a pharmaceutically acceptable salt thereof .

[Chemical Formula 1]

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

In this case, in Formula 1,

Wherein R ₁ is hydrogen, or C ₁ -C ₆ alkyl;

R < ₂ > is hydrogen;

R < ₃ > is hydrogen or halogen;

The R ₄ And R ₅ are each independently hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or nitro;

이며;Wherein R < ₆ > is hydrogen, halogen, or

;

Wherein R ₇ is C ₁ -C ₆ alkyl, C ₇ -C ₂₀ arylalkyl or C ₂ -C ₆ alkoxyalkyl;

The R ₈ may be hydrogen, halogen, or C ₁ -C ₆ alkyl.

The present invention also relates to a process for the production of quinolin-8-ylmethanamine represented by the above formula (1), comprising reacting a compound represented by the following formula (2) with an azodicarboxylate represented by the following formula A method of manufacturing is provided:

(2)

In this case, in Formula 2,

Wherein R ₁ is hydrogen, or C ₁ -C ₆ alkyl;

R < ₂ > is hydrogen;

R < ₃ > is hydrogen or halogen;

The R ₄ And R ₅ are each independently hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or nitro;

이고;Wherein R < ₆ > is hydrogen, halogen, or

ego;

The R ₈ may be hydrogen, halogen, or C ₁ -C ₆ alkyl.

(3)

In this case, in Formula 3,

R ₇ can be C ₁ -C ₆ alkyl, C ₇ -C ₂₀ arylalkyl, or C ₂ -C ₆ alkoxyalkyl.

In another embodiment of the present invention, the rhodium catalyst may be cyclopentadienyl rhodium (III) complex catalyst substituted with C ₁ -C ₅ alkyl or more preferably pentamethyl (RhCp * Cl ₂ ) ₂ ) catalyst. The catalyst may be a catalyst such as tetramethylcyclopentadienylrhodium (III) chloride dimer.

In another embodiment of the present invention, the reaction may be carried out further comprising an additive.

In another embodiment of the present invention, the additive is selected from the group consisting of silver hexafluoroantimonate (AgSbF ₆ ), lithium acetate (LiOAc), and lithium carbonate (Li ₂ CO ₃ ) Lt; / RTI >

In another embodiment of the present invention, the preparation method may be carried out in a dichloroethane (DCE) solvent.

The present invention relates to a pharmaceutical composition for preventing or treating cancer comprising quinolin-8-ylmethanamine represented by the above Chemical Formulas 1, 4, 5 or 6, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient .

In one embodiment of the present invention, the cancer may be prostate cancer or breast cancer.

Further, the present invention provides a method for preventing or treating cancer, comprising the step of administering the pharmaceutical composition to a subject.

In addition, the present invention provides the use of the pharmaceutical composition for the prevention or treatment of cancer.

The novel quinolin-8-ylmethanamine according to the present invention shows excellent anticancer activity against various human cancer cells and is expected to be useful as a pharmaceutical composition for cancer prevention and treatment.

The production process according to the present invention is a process for synthesizing quinolin-8-ylmethanamine by sp ³ carbon-hydrogen amination reaction under a rhodium (III) catalyst, 8-ylmethanamine derivative, which is very useful for the synthesis of a new drug or a compound having biological activity.

1 shows a process for preparing quinolin-8-ylmethanamine using the rhodium (III) catalyst of the present invention (this work) and a conventional work (previous work).
2 is a graph showing the activity of quinolin-8-ylmethanamine synthesized as a result of carrying out C (sp ³ ) -H amination reaction under the rhodium catalyst of the present invention using various 8-methylquinoline compounds and azodicarboxylates, Yield.
Figure 3 shows the expected mechanism of the quinolin-8-ylmethane amine formation reaction via C (sp ³ ) -H amination reaction under the rhodium catalyst of the present invention.

The present invention provides a novel quinolin-8-ylmethanamine having an anticancer activity, an isomer thereof, a pharmaceutically acceptable salt thereof and a composition for preventing or treating cancer comprising the same as an active ingredient. In addition, the compound according to the present invention inhibits the proliferation of cancer cells and has a prophylactic or therapeutic effect on cancer, and thus can be usefully used for prevention or treatment of cancer.

Hereinafter, the present invention will be described in detail.

The present invention provides quinolin-8-ylmethanamine represented by the following Chemical Formulas 1, 4, 5 or 6, an isomer thereof or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

In this case, in Formula 1,

Wherein R ₁ is hydrogen, or C ₁ -C ₆ alkyl;

R < ₂ > is hydrogen;

R < ₃ > is hydrogen or halogen;

The R ₄ And R ₅ are each independently hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or nitro;

이며;Wherein R < ₆ > is hydrogen, halogen, or

;

R ₇ is C ₁ -C ₆ alkyl, C ₇ -C ₂₀ arylalkyl, or C ₂ -C ₆ alkoxyalkyl;

The R ₈ may be hydrogen, halogen, or C ₁ -C ₆ alkyl.

More preferably, in Formula 1, R ₁ is hydrogen or methyl, R ₂ is hydrogen, R ₃ may be hydrogen or chloro, R ₄ is hydrogen, fluoro, chloro, bromo Methyl, methoxy or nitro and R ₅ can be hydrogen, fluoro, chloro, bromo, methyl, methoxy or nitro, and R ₆ is hydrogen, fluoro, chloro, bromo, phenyl (Para-tolyl ethynyl), and R ₇ is isopropyl, ethyl, benzyl, (2-methoxyethyl), or tert- Butyl.

Most preferably, in Formula 1, R ₁ to R ₅ are each hydrogen, and R ₆ is chloro, bromo, or phenylethynyl, and R ₇ may be isopropyl.

The following describes the definitions of the various substituents for preparing the compounds according to the invention.

The term " C ₁ -C ₆ alkyl " as used herein means a monovalent alkyl group of 1 to 6 carbon atoms. The term includes functional groups such as methyl, ethyl, n - propyl, i - propyl, n - butyl, i - butyl, tert - butyl, n - hexyl and the like.

The alkyls described in the present invention, as well as the substituents comprising other alkyl moieties, include both straight chain and branched forms.

The term "C ₁ -C ₄ alkoxy" as used herein refers to the group -OR, where R means "C ₁ -C ₄ alkyl". Preferred alkoxy groups include, for example, methoxy, ethoxy, phenoxy, and the like.

Substituents comprising alkyl, alkoxy and other alkyl moieties described in this invention include both straight chain and branched forms.

The term " C ₂ -C ₆ alkoxyalkyl " as used herein means an alkyl group having an alkoxy substituent including 2-methoxyethyl and the like.

The terms used in the present invention, "C ₇ -C ₂₀ arylalkyl" is a benzyl, to mean alkyl groups having an aryl substituent, or the like phenethyl, "C ₆ -C ₂₀ aryl group" is a single ring (e.g. phenyl Or an unsaturated aromatic ring compound having 6 to 20 carbon atoms and having a plurality of condensed rings (for example, naphthyl). The aryl includes phenyl, naphthyl, and the like.

Preferred embodiments of the quinolin-8-ylmethanamine represented by the formula (1) according to the present invention are as follows:

Diisopropyl 1- (quinolin-8-ylmethyl) hydrazine-1,2-dicarboxylate (3a); diisopropyl 1- (quinolin-8-ylmethyl) hydrazine-1,2-dicarboxylate;

Diisopropyl 1 - ((4-fluoroazetin-3-yl) methyl) hydrazine-1,2-dicarboxylate -dicarboxylate, 3b);

Diisopropyl 1 - ((7-chloroquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate dicarboxylate, 3c)

Diisopropyl 1 - ((7-bromoquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate -dicarboxylate, 3d);

Diisopropyl 1 - ((6-methoxyquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate -dicarboxylate, 3e);

Diisopropyl 1 - ((6-methoxyquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate -dicarboxylate, 3f);

Diisopropyl 1 - ((6-fluoroquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate -dicarboxylate, 3g);

Diisopropyl 1 - ((6-chloroquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate dicarboxylate, 3h);

Diisopropyl 1 - ((6-bromoquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate -dicarboxylate, 3i);

Diisopropyl 1 - ((6-nitroquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate dicarboxylate, 3j);

Diisopropyl 1 - ((5-methoxyquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate -dicarboxylate, 3k);

Diisopropyl 1 - ((5-methylquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate dicarboxylate, 31);

Diisopropyl 1 - ((5-fluoroquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate -dicarboxylate, 3m);

Diisopropyl 1 - ((5-chloroquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate dicarboxylate, 3n);

Diisopropyl 1 - ((5-bromoquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate -dicarboxylate, 3o);

Diisopropyl 1 - ((5-nitroquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate dicarboxylate, 3p);

Diisopropyl 1 - ((7-phenylethynyl) quinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate hydrazine-1,2-dicarboxylate, 3q);

Diisopropylethylamine, 1 - ((7- (p-tolyl ethynyl) quinoline-8-yl) methyl) hydrazine-1,2-di carboxylate (Diisopropyl 1 - ((7- (p -tolylethynyl) quinolin-8 -yl) methyl) hydrazine-1,2-dicarboxylate, 3R);

Diisopropyl 1 - ((7 - ((4-fluorophenyl) ethynyl) quinolin-8-yl) methyl) hydrazine- fluorophenyl) ethynyl) quinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate, 3s);

Diisopropyl 1 - ((4-chloroquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate dicarboxylate, 3t);

Diisopropyl 1 - ((4-chloro-2-methylquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate methyl) hydrazine-1,2-dicarboxylate, 3u);

Diethyl 1- (quinolin-8-ylmethyl) hydrazine-1,2-dicarboxylate (Diethyl 1- (quinolin-8-ylmethyl) hydrazine-1,2-dicarboxylate, 4b);

Dibenzyl 1- (quinolin-8-ylmethyl) hydrazine-1,2-dicarboxylate (Dibenzyl 1- (quinolin-8-ylmethyl) hydrazine-1,2-dicarboxylate, 4c);

Bis (2-methoxyethyl) l- (quinolin-8-ylmethyl) hydrazine-l, 2-dicarboxylate, dicarboxylate, 4d);

Di- tert- butyl 1- (quinolin-8-ylmethyl) hydrazine-1,2-dicarboxylate, 4e) ;

Diisopropyl 1- (4-methoxyphenyl) -2- (quinolin-8-ylmethyl) hydrazine- ylmethyl) hydrazine-1,2-dicarboxylate, 6a);

Isopropyl quinolin-8-ylmethylcarbamate (6b); And

Diisopropyl 1 - ((1,2,3,4-tetrahydroquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate (diisopropyl 1 - ((1,2,3,4-tetrahydroquinolin- 8-yl) methyl) hydrazine-1,2-dicarboxylate, 7a).

The quinolin-8-ylmethanamine represented by Formula 1 according to the present invention is more preferably a diisopropyl 1 - ((7-chloroquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate (3c), diisopropyl 1 - ((7-bromoquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate (3d) and diisopropyl 1 - Quinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate (3q).

The compound of the present invention can be used in the form of a pharmaceutically acceptable salt. As the salt, acid addition salt formed by a pharmaceutically acceptable free acid is useful.

As used herein, the term " salt " is useful as an acid addition salt formed by a pharmaceutically acceptable free acid. Acid addition salts include those derived from 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, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the above compound in an excess amount of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile . It may also be prepared by evaporating a solvent or excess acid in this mixture and then drying or by suction filtration of the precipitated salt.

In addition, the base may be used to make a pharmaceutically acceptable metal salt. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

In addition, the compounds of the present invention include not only pharmaceutically acceptable salts, but also all salts, isomers, hydrates and solvates which can be prepared by conventional methods.

According to another aspect of the present invention, there is provided a process for producing a quinoline-1,3-dicarboxylic acid represented by Formula 1, comprising reacting a compound represented by Formula 2 below with an azodicarboxylate represented by Formula 3, 8-ylmethanamine. ≪ / RTI >

(2)

(3)

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ in the general formulas (2) and (3)

Quinolin-8-yl methanamine production method of the present invention under the rhodium catalyst as azo die through carboxylate bonding reaction synthesize quinolin-8-yl methanamine, carbon (sp ³⁾ - hydrogen Oh Formula 1 by reaction folk 8-ylmethanamine < / RTI >

The rhodium catalyst of the present invention may be a C ₁ -C ₅ alkyl substituted or unsubstituted cyclopentadienyl rhodium (III) complex catalyst, more preferably pentamethylcyclopentadienylhodium (RhCp * Cl ₂ ) ₂ ) catalyst, and may be used in an amount of 1 to 4 mol%, preferably 2 to 3 mol%, based on 1 mol of the compound of the formula (2) Can be used.

In the production process of the present invention, it is preferable that the reaction is carried out by further comprising an additive. The additive may be at least one selected from the group consisting of silver hexafluoroantimonate (AgSbF ₆ ), lithium acetate (LiOAc), and lithium carbonate (Li ₂ CO ₃ ) Is preferable in terms of yield, but is not limited thereto.

The reaction according to an embodiment of the present invention can be carried out in an organic solvent, and it is not necessary to limit the organic solvent as long as it can dissolve the reactant. Examples of the organic solvent include dichloroethane (DCE), toluene, tetrahydrofuran (THF), tert-amyl alcohol (t-AmOH), ethanol ), And mixtures thereof. Dichloroethane (DCE) or THF is preferably used in view of the solubility and ease of removal of the reactants and the reaction efficiency. More preferably, DCE can be used.

In one embodiment of the present invention, the quinolin-8-ylmethanamine represented by Formula 1 was prepared and its structure was analyzed and confirmed by NMR or Mass spectroscopy (see Examples 1 to 4).

In another aspect of the present invention, the present invention includes quinolin-8-ylmethanamine represented by the above Chemical Formulas 1, 4, 5 or 6, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient Or a pharmaceutically acceptable salt thereof.

As used herein, the term " prophylactic " means any act that inhibits cancer or delays the onset of cancer by administration of the pharmaceutical composition according to the present invention.

As used herein, the term " treatment " refers to any action that improves or alters the symptoms of cancer by the administration of the pharmaceutical composition according to the present invention.

&Quot; Cancer " which is a preventive and therapeutic disease caused by the composition of the present invention is classified into diseases in which normal tissue cells proliferate unlimitedly for some reason and continue rapid development regardless of the life phenomenon of the living body or the surrounding tissue state. The cancer in the invention may preferably be prostate cancer, or breast cancer, but is not limited to this kind.

In one embodiment of the present invention, quinolin-8-ylmethanamine synthesized according to the production method of the present invention was used to evaluate anticancer activity against various human cancer cells (see Example 6) 3d and 3q showed stronger anticancer activities than doxorubicin, a known anticancer drug.

Accordingly, the quinolin-8-ylmethanamine represented by the above-mentioned formulas (1), (4), (5) or (6) according to the present invention, an isomer thereof or a pharmaceutically acceptable salt thereof, Or a pharmaceutical composition for therapeutic use.

The pharmaceutical composition according to the present invention may contain, in addition to the active ingredient, a pharmaceutically acceptable carrier. Herein, pharmaceutically acceptable carriers are those conventionally used at the time of formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose But are not limited to, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Further, in addition to the above components, a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like may be further included.

The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may vary depending on the condition and weight of the patient, The mode of administration, the route of administration, and the time, but may be appropriately selected by those skilled in the art.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, " pharmaceutically effective amount " means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dosage level is determined depending on the type of disease, severity, , Sensitivity to the drug, time of administration, route of administration and rate of excretion, duration of treatment, factors including co-administered drugs, and other factors well known in the medical arts. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, sequentially or concurrently with conventional therapeutic agents, and may be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, body weight, absorbency, inactivation rate and excretion rate of the active ingredient in the body, type of disease, 0.001 to 150 mg, preferably 0.01 to 100 mg, per kg of body weight may be administered daily or every other day, or one to three divided doses per day. However, the dosage may be varied depending on the route of administration, the severity of obesity, sex, weight, age, etc. Therefore, the dosage is not limited to the scope of the present invention by any means.

In another aspect of the present invention, the present invention provides a method of treating cancer comprising administering the pharmaceutical composition to a subject. In the present invention, the term " individual " refers to a subject in need of treatment for a disease, and more specifically refers to a human or non-human primate, a mouse, a mammal such as a dog, a cat, a horse and a cow.

As confirmed in Example 6 of the present invention, the novel quinolin-8-ylmethanamine produced as a result of the reaction using the rhodium (III) catalyst of the present invention showed excellent anticancer activity against various human cancer cells, And a pharmaceutical composition for treatment. Further, the process for preparing quinolin-8-ylmethanamine using the rhodium (III) catalyst of the present invention can be applied to various substrates, and it has been confirmed that the reaction proceeds even at excellent functional groups. It is believed to be very useful in the application of the synthesis of compounds.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.

[ Example ]

In the examples of the present invention, commercially available reagents were used without further purification unless otherwise stated. Closed tubes (13 x 100 mm ² ) were purchased from Fischer Scientific, dried overnight in the oven and then cooled to room temperature prior to use and thin layer chromatography was performed using plates coated with Kieselgel 60F ₂₅₄ (Merck) . For flash column chromatography, E. Merck Kieselgel 60 (230-400 mesh) was used.

Nuclear magnetic resonance spectra ( ¹ H and ¹³ C NMR) were recorded using a CDCl ₃ solution in a Bruker Unity 400 and 500 spectrometer with chemical shifts reported in parts per million (ppm). The resonance pattern is represented by s (singlet), d (doublet), t (triplet), q (quartet), quint Is used. The coupling constant (J) is expressed in hertz (Hz).

IR spectra were recorded on a Varian 2000 infrared spectrophotometer and reported in cm ^-1 . High resolution mass spectra (HRMS) were analyzed using a JEOL JMS-600 spectrometer.

Example  1. Quinolin-8- Monomethanamine  Optimal reaction conditions for synthesis

As shown in FIG. 1, the reaction of conventional 8-methylquinoline and azodicarboxylate has been carried out via CH 2 alkoxycarbonylation under palladium (II) catalyst, but in Example 1, 8-methylquinoline and azodicarboxylate Quinolin-8-ylmethanamine was prepared by CH amination under rhodium (III) catalyst, as shown in Scheme 1 below.

[Reaction Scheme 1]

More specifically, in Example 1, quinolin-8-ylmethanamines were obtained through a coupling reaction of 8-methylquinoline (1a) and diisopropyl azodicarboxylate (DIAD, 2a) Coupling reaction of 8-methylquinoline (1a) and diisopropyl azodicarboxylate (2a) under a rhodium catalyst was investigated as shown in Reaction Scheme 2 below to set the optimum reaction conditions for the synthesis of derivatives, Respectively. As a result, it was confirmed that a carbon-hydrogen aminated product 3a was produced in a yield of 22% in the combination of [RhCp * Cl ₂ ] ₂ and AgSbF _{6 in} the presence of lithium acetate at DCE at 120 ° C as shown in Table 1 (Table 1, items 1 and 2). As confirmed in item 3, confirming that product formation was not observed when the rhodium catalyst was not used, confirming that the cationic rhodium catalyst plays a crucial role in this coupling reaction and [Ru (p-cymene) Cl ₂ ] ₂ and [CoCp * (CO) I ₂ ] were found to be ineffective in this reaction.

Interestingly, it has been found that, if further treatment of Ag ₂ CO ₃ under different conditions, the product 3a to be produced can be obtained in a sufficiently increased yield of 74% (Table 1, item 4). It was also confirmed that when Li ₂ CO ₃ was used, 3a could be obtained in the above reaction in 86% yield (Table 1, item 5-8). Screening of the acetate additive showed that LiOAc was more efficient than Cu (OAc) ₂ or ZnOAc (Table 1, items 9 and 10). Various studies on the solvent effect have been made and it has been confirmed that DCE is most effective in this coupling reaction (Table 1, items 11-14).

In addition, it was confirmed that the yield was somewhat lowered when the amount of Li ₂ CO ₃ or LiOAc was reduced (Table 1, items 15 and 16). It can be seen that the reaction of the present invention is preferably carried out at 120 ° C since 3a was obtained at 68% (Table 1, item 17) when proceeding at low temperature (60 ° C). Finally, reducing the amount of 2a used reduced the formation of 3a (Table 1, item 18).

[Reaction Scheme 2]

Entry Additive (mol%) Solvent Yield (%) ^b One AgSbF ₆ (10) DCE N.R. 2 AgSbF ₆ (10), LiOAc (30) DCE 22 3 LiOAc (30) DCE N.R. 4 AgSbF ₆ (10), LiOAc (30), Ag ₂ CO ₃ (100) DCE 74 5 AgSbF ₆ (10), LiOAc (30), Na ₂ CO ₃ (100) DCE 72 6 AgSbF ₆ (10), LiOAc (30), K ₂ CO ₃ (100) DCE 76 7 AgSbF ₆  (10), LiOAc  (30), Li ₂ CO ₃  (100) DCE 86 8 AgSbF ₆ (10), LiOAc (30), K ₂ S ₂ O ₈ (100) DCE 80 9 AgSbF ₆ (10), Cu (OAc) ₂ (30), Li ₂ CO ₃ (100) DCE 65 10 AgSbF ₆ (10), ZnOAc (30), Li ₂ CO ₃ (100) DCE 60 11 AgSbF ₆ (10), LiOAc (30), Li ₂ CO ₃ (100) toluene 26 12 AgSbF ₆ (10), LiOAc (30), Li ₂ CO ₃ (100) THF 28 13 AgSbF ₆ (10), LiOAc (30), Li ₂ CO ₃ (100) t- AmOH 19 14 AgSbF ₆ (10), LiOAc (30), Li ₂ CO ₃ (100) EtOH N.R. 15 AgSbF ₆ (10), LiOAc (30), Li ₂ CO ₃ (50) DCE 70 16 AgSbF ₆ (10), LiOAc (10), Li ₂ CO ₃ (100) DCE 78 17 ^c AgSbF ₆ (10), LiOAc (30), Li ₂ CO ₃ (100) DCE 68 18 ^d AgSbF ₆ (10), LiOAc (30), Li ₂ CO ₃ (100) DCE 45

Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [RhCp * Cl ₂ ] ₂ (2.5 mol%), additives (mol% Lt; RTI ID = 0.0 >

Yield is derived by flash column chromatography

- in item 17 the reaction was carried out at 60 ° C and item 18 was used in 0.24 mmol of 2a

Example  2. Various 8- Methylquinoline  And Azodicarboxylate  Lt; RTI ID = 0.0 > quinolin-8- Monomethanamine  synthesis

At the optimum conditions of the coupling reaction determined in Example 1 above, coupling reactions of various compounds were carried out. More specifically, various 8-methylquinolines (1a to 1v) were reacted with azodicarboxylates (2a to 2e), as shown in Scheme 3 below. The resulting products 3a to 3u and 4b to 4e are shown in FIG.

[Reaction Scheme 3]

- Reaction conditions: 1a-1v (0.2 mmol) , 2a-2e (0.4 mmol), [RhCp * Cl 2] 2 (2.5 mol%), AgSbF 6 (10 mol%), LiOAc (30 mol%), Li 2 CO ₃ (100 mol%), DCE (1 mL), reaction at 120 ° C for 20 hours in a pressure tube

Yield is derived by flash column chromatography

- 2e was obtained by reacting 1.0 mmol, 5 equiv. At room temperature

As a result, regardless of the electronic properties of the substituent, the C7-substituted 8-methylquinoline 1b-1d showed good reactivity with the corresponding quinolin-8-ylmethanamine 3b-3d at a yield of 70% -91%. In addition, the 8-methylquinoline 1e-1i having an electron-donor and a halogen group at the C6-position has a high yield of 3e-3i, which is a good substrate for amination reaction for carbon (sp3) Respectively. The structure of the synthesized product 3f was confirmed by X-ray crystal data of the compound.

It should be noted that the NO ₂ group, which is very poor in electrons, which is often a problem in carbon-hydrogen activation processes, produces the corresponding product 3j with a slightly reduced yield (56%). In addition, the C5-substituted compound 1k-1p was position-selective carbon-hydrogen amination and was coupled with 2a to yield the corresponding quinolin-8-ylmethanamine derivative 3k-3p in high yield. The C7-acyl-substituted 8-methylquinoline 1q-1s also produced 3q-3s, which is the product to be produced, at a fairly high yield.

From the results obtained by the reaction of 1t and 1u of C2- and C4-substituted 8-methylquinoline, it was confirmed that the conversion was considerably sensitive considering the steric effect in the pyridine ring. In addition, in the case of the sterically complex 8-ethylquinoline 1v, formation of 3v did not occur under optimum reaction conditions.

From these results, the substrate range of the above process was also confirmed in the range of azodicarboxylate. (DEAD, 2b) and dibenzyl azodicarboxylate (2c) are not amenable to the desired product 4b (84%) due to the smooth amination reaction. And 4c (75%), respectively. In addition, the? -Methoxyethyl-substituted azodicarboxylate 2d showed somewhat decent yields under current reaction conditions. In particular, it was confirmed that Cbz and MEM groups in 4c and 4d were easily removed by hydrogenation and acidic hydrolysis. In addition, the di-tert-butyl azodicarboxylate (2e) did not form 4e under optimal reaction conditions, presumably due to the instability of the Boc group at high temperatures. After further screening of the reaction conditions, it was confirmed that 4e could be obtained in 22% yield using 5 eq of 2e at ambient temperature.

Example  3. Quinolin-8- Monomethanamine  variety Availability for synthesis  Confirm

(I) -mediated N-arylation reaction of 3a with 4-iodoanisole (5a) in order to confirm that it can be applied to the synthesis of various compounds using quinolin-8-ylmethane amine derivatives , Resulting in the N-aryla ted hydrazine derivative 6a in 98% yield (Scheme 4).

[Reaction Scheme 4]

Further, the reduction decomposition reaction of N-N bond of 3a was obtained by N-alkylation using methyl bromoacetate (5b) in a yield of 60% through base-mediated removal (Scheme 5).

[Reaction Scheme 5]

Then, the selective reduction of the quinoline ring is _{NiCl 2 · 6H 2 O (10} mol%) and NaBH ₄ was carried out using (8 eq.), The resulting tetrahydro-quinoline derivatives 7a was obtained in 53% yield (Scheme 6) .

[Reaction Scheme 6]

Example  4. Quinolin-8- Yl methane amine  Identify the mechanism of production reaction

In order to confirm the mechanism of the formation of the novel compound quinolin-8-ylmethanamine produced in the present invention, this example was carried out as shown in the following Reaction Schemes 7 to 10. To confirm the reversibility of the carbon (sp ³ ) - hydrogen bonding activity, the CD ₃ OD was added under basic reaction conditions without 2a (Scheme 7). Carbon-hydrogen bonds were expected to be irreversible when H / D exchange was not observed.

[Reaction Scheme 7]

This irreversibility is observed along the reported processes (S. Kim, S. Han, J. Park, S. Sharma, NK Mishra, H. Oh, JH Kwak and IS Kim, Chem. Commun., 2017, 53, It was also observed in the reaction between the prepared deuterio-1a and 2a (Scheme 8).

[Reaction Scheme 8]

Next, the dynamic isotope effect (KIE) experiment showed a value of 1.05, confirming that the carbon-hydrogen cleavage may not be involved in the rate determining step (Scheme 9).

[Reaction Scheme 9]

In addition, Rhodocycle A was found to be active in this modification (Scheme 10).

[Reaction Scheme 10]

The proposed reaction procedure is shown in FIG. 3 based on the above-described mechanism confirmation result. The cationic [Cp * Rh (Ⅲ) OAc] [SbF ₆ ] catalyst can be combined with the nitrogen atom of 8-methylquinoline (1a) and then cleaved to form a rhodium (Ⅲ) intermediate A . The combination of 2a and the oxidative addition reaction can carry the high valence electrons B of rhodium (V). Reduction removal by protonolysis can occur to provide the product 3a to be produced, and activated rhodium (III) can be recycled in the catalytic pathway.

Example  5. Structural analysis of new compounds by NMR analysis

5-1. Diisopropyl  One-( quinolin -8- ylmethyl ) hydrazine-1,2- dicarboxylate  (3a) and analysis of structure

8-methyl-quinoline (1a, 28.6 mg, 0.2 mmol , 100 mol%) at room _{temperature, [RhCp * Cl 2] 2} (3.1 mg, 0.005 mmol, 2.5 mol%), LiOAc (4.0 mg, 0.06 mmol, 30 mol% ), Li ₂ CO ₃ (14.8 mg, 0.2 mmol, 100 mol%) and AgSbF ₆ (6.8 mg, 0.02 mmol, 10 mol%) were added to a sealed tube which was dried in an oven filled with diisopropyl azodicarboxylate (2a, 80.9 mg, 0.4 mmol, 200 mol%) and DCE (1 mL). The reaction mixture was stirred at 120 < 0 > C for 20 hours and cooled at room temperature. The reaction mixture was diluted with EtOAc (3 mL) and concentrated in vacuo. The concentrated residue was purified by flash column chromatography (n-hexanes / EtOAc = 3: 1) to obtain 59.3 mg of 3a in 86% yield, which was analyzed by NMR. Hereinafter, the production of 3a-u and 4b-4e was also produced in accordance with the above conditions.

[Chemical Formula 3]

59.3 mg (86%); white solid; mp = 105.0-107.4 [ ^deg .] ^C ; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.92 (dd, J = 4.1, 1.6 Hz, 1H), 8.16 (dd, J = 8.2, 1.6 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H) , 7.66 (br s, 1 H), 7.50 (t, J = 7.6 Hz, 1 H), 7.42 (dd, J = 8.2, 4.2 Hz, , 5.00-4.88 (m, 2H), 1.24 (d, J = 6.2 Hz, 6H), 1.20 (br s, 6H); ^{13 C NMR (100 MHz, CDCl} 3) δ 156.2, 149.9, 146.9, 136.7, 135.5, 130.4, 129.8, 128.6, 128.0, 126.4, 121.3, 70.0, 69.7, 52.8, 22.3, 22.2; IR (KBr) υ 3298, 3044, 2979, 2936, 1699, 1498, 1406, 1374, 1263, 1214, 1179, 1105, 1033, 937, 822, 788, 761 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 18 H 23 N 3 O 4 [M] + 345.1689, found 345.1687.

5-2. Diisopropyl  1 - ((4- fluoroazecin -3- yl ) methyl) hydrazine-1,2-dicarboxylate (3b)

(3b)

66.0 mg (91%); white solid; mp = 86.9-88.4 [deg.] C; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.93 (dd, J = 4.2, 1.6 Hz, 1H), 8.14 (dd, J = 8.2, 1.3 Hz, 1H), 7.76 (dd, J = 9.0, 5.9 Hz, (D, J = 8.2, 4.2 Hz, 1H), 7.33 (t, J = 9.1 Hz, 1H), 5.23-4.88 (m, 4H), 1.23 J = 5.9 Hz, 6H), 1.18 (br s, 6H); ^{13 C NMR (100 MHz, CDCl} 3) δ 161.5 (d, J C -F = 268.1 Hz), 155.8, 150.9, 148.0, 143.3, 136.7, 129.6 (d, J C -F = 10.6 Hz), 129.0, 125.5 , 120.5, 117.2 (d, J _CF = 14.4 Hz), 70.0, 69.5, 45.1, 22.2, 22.0; IR (KBr) υ 3303, 3057, 2980, 2937, 1701, 1622, 1582, 1504, 1467, 1406, 1374, 1312, 1257, 1223, 1179, 1105, 1053, 1033, 1010, 922, 834, 805, 761 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 18 H 22 FN 3 O 4 [M] + 363.1594, found 363.1593.

5-3. Diisopropyl  1 - ((7- chloroquinoline -8- yl ) methyl) hydrazine-1,2-dicarboxylate (3c)

 [Chemical Formula 3c]

61.4 mg (81%); pale yellow sticky oil; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.92 (d, J = 2.7 Hz, 1H), 8.13 (dd, J = 8.2, 1.5 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.41 (dd, J = 8.2, 4.2 Hz, 1H), 6.55 (br s, 1.21 (br s, 12H); ¹³ C NMR (100 MHz, CDCl ₃ )? 156.0, 150.8, 147.9, 137.8, 136.6, 132.4, 128.8, 128.7, 128.5, 127.1, 121.3, 70.0, 69.5, 48.9, 22.2, 22.1; IR (KBr) ν 3296, 3064, 2979, 2936, 1702, 1607, 1489, 1404, 1373, 1253, 1177, 1105, 1037, 970, 834, 804, 759 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C ₁₈ H ₂₃ ClN ₃ O ₄ [M + H] ⁺ 380.1377, found 380.1374.

5-4. Diisopropyl  1 - ((7- bromoquinoline -8- yl ) methyl) hydrazine-1,2-dicarboxylate (3d)

(3d)

59.4 mg (70%); pale yellow sticky oil; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.91 (d, J = 2.4 Hz, 1H), 8.12 (dd, J = 8.2, 1.5 Hz, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.42 (dd, J = 8.2, 4.2 Hz, 1H), 6.48 (br s, 1H), 5.63-5.43 1.21 (br s, 12H); ¹³ C NMR (100 MHz, CDCl ₃ )? 156.0, 150.6, 148.0, 136.6, 134.7, 134.0, 131.4, 129.0, 128.9 127.5, 121.5, 70.0, 69.5, 51.7, 22.2, 22.1; IR (KBr) υ 3302, 3055, 2979, 2935, 1702, 1605, 1590, 1487, 1404, 1373, 1308, 1256, 1224, 1177, 1105, 1034, 964, 833, 802, 761 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C 18 H 23 BrN 3 O 4 [M + H] + 424.0872, found 424.08624.

5-5. Diisopropyl  1 - ((6- methoxyquinoline -8- yl ) methyl) hydrazine-1,2-dicarboxylate (3e)

[Formula 3e]

60.9 mg (81%); pale yellow sticky oil; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.74 (dd, J = 4.2, 1.7 Hz, 1H), 8.03 (dd, J = 8.2, 1.4 Hz, 1H), 7.36-7.33 (m, 3H), 6.98 ( d, J = 2.6 Hz, 1H ), 5.20 (br s, 2H), 5.00-4.88 (m, 2H), 3.90 (s, 3H), 1.24 (d, J = 6.2 Hz, 6H), 1.21 (d, J = 1.4 Hz, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) 隆 157.5, 156.2, 147.3, 143.0, 137.2, 135.4, 129.8, 122.6, 122.5, 121.6, 104.9, 70.1, 70.0, 55.6, 51.9, 22.2, 22.1; IR (KBr) v 3301, 2979, 2936, 1698, 1623, 1596, 1375, 1262, 1207, 1105, 1053, 1026, 946, 841, 781, 761 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C 19 H 26 N 3 O 5 [M + H] + 376.1872, found 376.18654.

5-6. Diisopropyl  1 - ((6- methylquinoline -8- yl ) methyl) hydrazine-1,2-dicarboxylate (3f)

(3f)

57.3 mg (80%); white solid; mp = 120.1-122.0 DEG C; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.84 (dd, J = 4.1, 1.8 Hz, 1H), 8.06 (dd, J = 8.3, 1.7 Hz, 1H), 7.51 (s, 2H), 7.37 (dd, J = 8.3, 4.2 Hz, 1H ), 5.18 (br s, 2H), 5.01-4.87 (m, 2H), 2.51 (s, 3H), 1.25 (d, J = 6.2 Hz, 6H), 1.20 (d, J = 4.9 Hz, 6H); ^{13 C NMR (100 MHz, CDCl} 3) δ 156.2, 149.0, 145.5, 136.3, 136.0, 135.1, 132.7, 132.2, 128.8, 126.7, 121.3, 70.0, 69.6, 52.8, 22.3, 22.2, 21.8; IR (KBr) v 3286, 2980, 2936, 1729, 1698, 1494, 1385, 1355, 1264, 1107, 1036, 979, 863, 784 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 19 H 25 N 3 O 4 [M] + 359.1845, found 359.1844.

5-7. Diisopropyl  1 - ((6- fluoroquinoline -8- yl ) methyl) hydrazine-1,2-dicarboxylate (3g)

[Formula 3g]

46.6 mg (64%); white solid; ¹ H NMR (400 MHz, CDCl ₃ )? 8.86 (dd, J = 4.2, 1.6 Hz, 1H), 8.10 (dd, J = 8.3, 1.6 Hz, 1H), 7.52 (br s, 1H), 7.42 2H, J = 8.3, 4.2 Hz, 1 H), 7.35 (dd, J = 8.5, 2.7 Hz, 1 H), 7.20 (br s, 1.24 (d, J = 6.2 Hz, 6H), 1.21 (br s, 6H); ^{13 C NMR (100 MHz, CDCl} 3) δ 160.2 (d, J C -F = 246.8 Hz), 156.2, 149.0, 143.9, 138.9, 136.1 (d, J C -F = 5.5 Hz), 130.9, 129.4 (d _{, J C -F = 10.0 Hz)} , 122.1, 119.9 (d, J C -F = 8.8 Hz), 110.4 (d, J C -F = 21.1 Hz), 70.5, 69.8, 51.6, 22.2, 22.1; IR (KBr) ν 3289, 2981, 2938, 1697, 1626, 1583, 1497, 1374, 1263, 1214, 1104, 1034, 980, 860, 782, 762 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C 18 H 23 FN 3 O 4 [M + H] + 364.1673, found 364.1668.

5-8. Diisopropyl  1 - ((6- chloroquinoline -8- yl ) methyl) hydrazine-1,2-dicarboxylate (3h)

[Chemical Formula 3h]

55.9 mg (74%); white solid; mp = 118.2-121.0 [deg.] C; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.88 (dd, J = 4.2, 1.7 Hz, 1H), 8.06 (dd, J = 8.2, 1.0 Hz, 1H), 7.72-7.66 (m, 2H), 7.42 ( dd, J = 8.2, 4.2 Hz, 1H), 7.20 (br s, 1H), 5.22 (br s, 2H), 5.00-4.89 (m, 2H), 1.25-1.21 (m, 12H); ^{13 C NMR (100 MHz, CDCl} 3) δ 156.2, 150.0, 145.2, 137.7, 135.7, 132.2, 130.7, 130.5, 129.2, 126.3, 122.2, 70.4, 69.9, 51.5, 22.2, 22.1; IR (KBr) ν 3293, 3060, 2980, 2925, 1698, 1590, 1490, 1384, 1263, 1213, 1105, 1032, 864, 782, 760 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 18 H 22 ClN 3 O 4 [M] + 379.1299, found 379.1298.

5-9. Diisopropyl  1 - ((6- bromoquinoline -8- yl ) methyl) hydrazine-1,2-dicarboxylate (3i)

[Formula 3i]

64.2 mg (76%); white solid; mp = 127.5-128.9 [deg.] C; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.90 (dd, J = 4.2, 1.8 Hz, 1H), 8.06 (dd, J = 8.3, 1.4 Hz, 1H), 7.91 (d, J = 1.8 Hz, 1H) 2H), 5.00-4.89 (m, 2H), 1.25 (br s, 1H), 7.78 (br s, 1H), 7.43 (dd, J = 8.3, 4.2 Hz, 1H) 1.22 (m, 12 H); ^{13 C NMR (100 MHz, CDCl} 3) δ 156.1, 150.2, 145.5, 137.8, 137.7, 135.7, 133.1, 133.0, 129.7, 122.2, 120.3, 70.5, 69.9, 51.4, 22.2, 22.1; IR (KBr) ν 3296, 3058, 2980, 2932, 1735, 1698, 1590, 1490, 1385, 1355, 1266, 1106, 1034, 866, 844, 783 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 18 H 22 BrN 3 O 4 [M] + 423.0794, found 423.0794.

5-10. Diisopropyl  1 - ((6- nitroquinoline -8- yl ) methyl) hydrazine-1,2-dicarboxylate (3j)

[Chemical formula 3j]

43.9 mg (56%); light yellow solid; mp = 148.6-149.4 [deg.] C; ^{1 H NMR (400 MHz, CDCl} 3) δ 9.09 (dd, J = 4.2, 1.7 Hz, 1H), 8.73 (br s, 1H), 8.48 (br s, 1H), 8.36 (d, J = 8.1 Hz, 2H), 1.24 (d, J = 6.2 Hz, 1H), 7.59 (dd, J = 8.1, 4.0 Hz, , 12H); ^{13 C NMR (100 MHz, CDCl} 3) δ 156.2, 153.2, 148.7, 145.4, 138.6, 138.5, 127.4, 124.2, 124.1, 123.1, 122.7, 70.7, 70.0, 52.2, 22.2, 22.1; IR (KBr) ν 3353, 3078, 2981, 2938, 1732, 1698, 1618, 1530, 1493, 1385, 1344, 1315, 1265, 1105, 1036, 906, 798 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 18 H 22 N 4 O 6 [M] + 390.1539, found 390.1541.

5-11. Diisopropyl  1 - ((5- methoxyquinoline -8- yl ) methyl) hydrazine-1,2-dicarboxylate (3k)

[Chemical Formula 3k]

61.4 mg (82%); white solid; mp = 92.8-95.6 [deg.] C; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.89 (dd, J = 4.2, 1.8 Hz, 1H), 8.56 (dd, J = 8.4, 1.7 Hz, 1H), 7.62 (br s, 1H), 7.47 (br (s, 1H), 7.37 (dd, J = 8.4, 4.2 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 5.11 s, 3H), 1.23 (d, J = 6.2 Hz, 6H), 1.20 (d, J = 6.2 Hz, 6H); ^{13 C NMR (100 MHz, CDCl} 3) δ 156.1, 155.1, 150.2, 147.5, 131.4, 131.0, 130.2, 127.1, 121.1, 120.3, 103.8, 69.9, 69.5, 55.9, 51.9, 22.2, 22.1; IR (KBr) ν 3296, 2979, 2935, 1730, 1698, 1590, 1466, 1384, 1268, 1206, 1105, 1088, 1034, 812, 783, 764 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 19 H 25 N 3 O 5 [M] + 375.1794, found 375.1795.

5-12. Diisopropyl  1 - ((5- methylquinoline -8- yl ) methyl) hydrazine-1,2-dicarboxylate (3l)

≪ EMI ID =

54.6 mg (76%); white solid; mp = 107.7-109.2 [deg.] C; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.91 (dd, J = 4.2, 1.7 Hz, 1H), 8.32 (dd, J = 8.5, 1.7 Hz, 1H), 7.60 (br s, 1H), 7.45-7.42 (m, 2H), 7.32 ( d, J = 7.2 Hz, 1H), 5.19 (br s, 2H), 5.01-4.87 (m, 2H), 2.66 (s, 3H), 1.24 (d, J = 6.3 Hz , 6H), 1.20 (d, J = 6.2 Hz, 6H); ^{13 C NMR (100 MHz, CDCl} 3) δ 156.1, 149.4, 147.1, 134.7, 133.4, 133.1, 130.3, 129.5, 128.0, 126.8, 120.8, 70.0, 69.6, 52.7, 22.3, 22.2, 18.8; IR (KBr) ν 3289, 3053, 2980, 2933, 1700, 1598, 1503, 1385, 1364, 1267, 1107, 1041, 826, 736 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 19 H 25 N 3 O 4 [M] + 359.1845, found 359.1843.

5-13. Diisopropyl  1 - ((5- fluoroquinoline -8- yl ) methyl) hydrazine-1,2-dicarboxylate (3m)

[Formula 3m]

62.6 mg (86%); white solid; mp = 130.8-131.9 [deg.] C; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.95 (dd, J = 4.2, 1.8 Hz, 1H), 8.42 (dd, J = 8.4, 1.8 Hz, 1H), 7.67 (br s, 1H), 7.46 (dd 2H, J = 8.4, 4.2 Hz, 1H), 7.24 (br s, 1H), 7.16 (dd, J = 1.21 (dd, J = 8.2, 6.4 Hz, 12H); ^{13 C NMR (100 MHz, CDCl} 3) δ 157.6 (d, J C -F = 253.8 Hz), 156.1, 156.0, 150.7, 147.3, 131.4, 130.1, 129.9 (d, J C -F = 4.8 Hz), 121.3 _{, 119.3 (d, J C -F} = 16.3 Hz), 109.8 (d, J C -F = 14.6 Hz), 70.2, 69.7, 51.5, 22.2, 22.1; IR (KBr) υ 3301, 3073, 2981, 2938, 1735, 1690, 1631, 1597, 1474, 1385, 1255, 1204, 1104, 1056, 1007, 933, 839, 781, 765 cm ^-1 ; HRMS (quadrupole, EI) calcd for C ₂₆ H ₁₈ ClN ₃ O [M] ⁺ 363.1594, found 363.1592.

5-14. Diisopropyl  1 - ((5- chloroquinoline -8- yl ) methyl) hydrazine-1,2-dicarboxylate (3n)

(3n)

68.4 mg (90%); white solid; mp = 130.8-131.9 [deg.] C; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.93 (dd, J = 4.2, 1.7 Hz, 1H), 8.56 (dd, J = 8.5, 1.6 Hz, 1H), 7.66-7.56 (m, 2H), 7.50 ( dd, J = 8.5, 4.2 Hz, 1H), 7.21 (br s, 1H), 5.22 (br s, 2H), 4.96-4.88 (m, 2H), 1.23-1.20 (m, 12H); ^{13 C NMR (100 MHz, CDCl} 3) δ 156.1, 150.4, 147.3, 134.8, 133.4, 131.1, 130.0, 129.4, 126.5, 126.4, 122.0, 70.2, 69.7, 51.6, 22.2, 22.1; IR (KBr) ν 2997, 2955, 2900, 1765, 1695, 1613, 1576, 1499, 1466, 1394, 1358, 1321, 1194, 1067, 944, 928, 860, 804 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C ₁₈ H ₂₃ ClN ₃ O ₄ [M + H] ⁺ 380.1377, found 380.1371.

5-15. Diisopropyl  1 - ((5- bromoquinoline -8- yl ) methyl) hydrazine-1,2-dicarboxylate (3o)

≪ EMI ID =

71.9 mg (85%); white solid; mp = 150.8-152.3 [deg.] C; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.91 (dd, J = 4.2, 1.6 Hz, 1H), 8.53 (dd, J = 8.6, 1.6 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H) , 7.58 (br s, 1 H), 7.50 (dd, J = 8.5, 4.2 Hz, 1 H), 7.16 1.20 (m, 12 H); ^{13 C NMR (100 MHz, CDCl} 3) δ 156.2, 150.4, 147.4, 136.1, 135.6, 130.6, 130.2, 129.9, 127.8, 122.4, 121.7, 70.2, 69.8, 51.7, 22.2, 22.1; IR (KBr) υ 3297, 2980 , 2938, 1787, 1703, 1631, 1567, 1492, 1408, 1384, 1260, 1213, 1106, 1037, 916, 827, 779 cm -1 HRMS (orbitrap, ESI) calcd for C ₁₈ H ₂₃ BrN ₃ O ₄ [M + H] ⁺ 424.0872, found 424.0864.

5-16. Diisopropyl  1 - ((5- nitroquinoline -8- yl ) methyl) hydrazine-1,2-dicarboxylate (3p)

[Chemical Formula 3p]

28.2 mg (36%); pale yellow sticky oil; ¹ H NMR (500 MHz, CDCl ₃ )? 9.03-9.02 (m, 2H), 8.35 (d, J = 8.0 Hz, 1 H), 7.88 (br s, 1 H), 5.38 (br s, 2H), 4.96 (quint, J = 6.0 Hz, 2H), 1.24 (d, J = 6.3 Hz, 12H); ^{13 C NMR (125 MHz, CDCl} 3) δ 156.2, 150.8, 146.4, 145.2, 143.5, 132.6, 127.7, 124.6, 124.5, 124.0, 121.4, 70.7, 70.1, 52.2, 22.2, 22.1; IR (KBr) ν 3297, 3046, 2981, 2933, 1722, 1700, 1590, 1521, 1500, 1411, 1385, 1331, 1264, 1214, 1105, 1085, 1042, 985, 834, 805, 781 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C 18 H 23 N 4 O 6 [M + H] + 391.1618, found 391.1611.

5-17. Diisopropyl  1 - ((7- ( phenylethynyl ) quinolin -8- yl ) methyl) hydrazine-1,2-dicarboxylate (3q)

[Formula 3q]

51.3 mg (58%); yellow oil; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.94 (br s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.81 (br s, 1H), 7.72 (d, J = 8.5 Hz, 1H) , 7.66-7.64 (m, 3H), 7.38-7.37 (m, 4H), 5.50 (br s, 2H), 4.94-4.87 (m, 2H), 1.25-1.07 (m, 12H); ^{13 C NMR (100 MHz, CDCl} 3) δ 156.1, 150.6, 147.0, 136.6, 132.1, 132.0, 129.9, 128.9, 128.7, 128.6, 128.2, 127.8, 125.5, 123.1, 121.5, 96.2, 88.0, 69.9, 69.5, 51.5 , 22.3, 22.2; IR (KBr) v 3308, 2979, 2928, 1703, 1607, 1496, 1466, 1444, 1404, 1373, 1258, 1221, 1105, 1033, 997 cm ^-1 ; HRMS (quadrupole, EI) calcd for C ₂₆ H ₂₇ N ₃ O ₄ [M] ⁺ 445.2002, found 445.2005.

5-18. Diisopropyl  1 - ((7- ( p - tolylethynyl ) quinolin -8- yl ) methyl) hydrazine-1,2-dicarboxylate (3r)

[Chemical Formula 3]

43.9 mg (48%); white sticky solid; ^{1 H NMR (700 MHz, CDCl3} ) δ 8.94 (br s, 1H), 8.12 (d, J = 7.7 Hz, 1H), 7.86 (br s, 1H), 7.72 (d, J = 8.4 Hz, 1H), (M, 2H), 4.96-4.85 (m, 2H), 7.69-7.64 (m, , 2.38 (s, 3H), 1.23 - 1.05 (m, 12H); ^{13 C NMR (175 MHz, CDCl} 3) δ 156.0, 155.4, 150.4, 146.8, 139.1, 137.5, 136.6, 131.8, 129.9, 129.3, 128.1, 127.6, 125.6, 121.3, 119.9, 96.4, 87.4, 69.8, 69.4, 51.6 , 22.1, 21.7; IR (KBr) υ 3201, 2980, 2923, 1703, 1605, 1511, 1405, 1383, 1374, 1264, 1222, 1179, 1107, 1047, 949, 817 cm ^-1 ; HRMS (quadrupole, ESI) calcd for C ₂₇ H ₂₉ N ₃ NaO ₄ [M + Na] ⁺ 482.2050, found 482.2052.

5-19. Diisopropyl  1 - ((7 - ((4- fluorophenyl ) ethynyl ) quinolin -8-yl) methyl) hydrazine-1,2-dicarboxylate (3s)

[Chemical Formula 3s]

52.7 mg (57%); white sticky solid; ¹ H NMR (700 MHz, CDCl ₃ )? 8.94 (br s, 1 H), 8.11 (d, J = 8.4 Hz, 1 H), 7.71 (d, J = 8.4 Hz, 1 H), 7.64-7.62 ), 7.40 (br s, 1 H), 7.07 (br s, 2H), 5.69-5.48 (m, 2H), 4.94-4.86 (m, 2H), 1.21-1.07 (m, 12H); ^{13 C NMR (175 MHz, CDCl} 3) δ 162.9 (d, J C -F = 248.6 Hz), 155.9, 155.4, 105.5, 146.7, 137.6, 136.5, 133.9 (d, J C -F = 30.3 Hz), 129.7 , 128.2, 127.7, 125.2, 121.5 , 119.1, 115.8 (d, J C -F = 22.0 Hz), 94.8, 87.7, 69.9, 69.4, 51.3, 22.1; IR (KBr) ν 3211, 2979, 2923, 1701, 1597, 1508, 1468, 1453, 1404, 1383, 1374, 1262, 1222, 1201, 1178, 1106, 1046, 1029, 950 cm ^-1 ; HRMS (quadrupole, ESI) calcd for C ₂₆ H ₂₆ FN ₃ NaO ₄ [M + Na] ⁺ 486.1800, found 486.1803.

5-20. Diisopropyl  1 - ((4- chloroquinoline -8- yl ) methyl) hydrazine-1,2-dicarboxylate (3t)

[Formula 3t]

48.2 mg (63%); white sticky solid; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.76 (d, J = 4.8 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.76 (br s, 1H), 7.59 (t, J = 7.6 (M, 2H), 7.29 (m, 2H), 7.49 (d, J = 4.8 Hz, 1H), 7.18 (br s, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ) 隆 155.9, 155.7, 149.1, 147.7, 143.1, 135.7, 131.1, 127.2, 126.6, 123.9, 121.2, 69.9, 69.5, 51.6, 22.0, 21.9; IR (KBr) ν 3297, 2980, 2932, 1702, 1584, 1490, 1467, 1414, 1384, 1374, 1293, 1263, 1215, 1179, 1143, 1105, 1035, 983 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 18 H 22 ClN 3 O 4 [M] + 379.1299, found 379.1297.

5-21. Diisopropyl  1 - ((4- chloro -2- methylquinoline -8- yl ) methyl) hydrazine-1,2-dicarboxylate (3u)

[Chemical Formula 3u]

8.9 mg (11%); white solid; mp = 126.8-128.9 [deg.] C; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.14 (d, J = 8.4 Hz, 1H), 7.83-7.65 (m, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.41 (s, 1H) , 5.15 (s, 2H), 5.03-4.96 (m, 1H), 4.94-4.88 (m, 1H), 2.73 (s, 3H), 1.26 (d, J = 6.4 Hz, 6H), 1.20 (d, J = 5.6 Hz, 6H); ¹³ C NMR (100 MHz, CDCl ₃ )? 158.3, 156.0, 155.9, 147.1, 143.1, 135.2, 131.5, 126.1, 124.9, 123.9, 121.9, 69.9, 69.5, 52.0, 25.2, 22.1, 22.0; IR (KBr) ν 3300, 2980, 2924, 2853, 1706, 1591, 1508, 1492, 1466, 1404, 1385, 1264, 1221, 1179, 1107, 1039, 997 cm ^-1 ; HRMS (quadrupole, ESI) calcd for C ₁₉ H ₂₄ ClN ₃ NaO ₄ [M + Na] ⁺ 416.1348, found 416.1351.

5-22. Diethyl 1- ( quinolin -8- ylmethyl ) hydrazine-1,2- dicarboxylate  (4b) and analysis of structure

(4b)

53.3 mg (84%); white solid; mp = 103.9-105.7 [deg.] C; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.92 (dd, J = 4.2, 1.8 Hz, 1H), 8.17 (dd, J = 8.3, 1.7 Hz, 1H), 7.77-7.68 (m, 3H), 7.50 ( dd, J = 7.9, 7.4 Hz , 1H), 7.42 (dd, J = 8.2, 4.2 Hz, 1H), 5.22 (br s, 2H), 4.22-4.12 (m, 4H), 1.26 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ )? 156.4, 149.9, 146.8, 136.8, 135.3, 130.9, 129.9, 128.7, 128.1, 126.4, 121.3, 62.5, 62.0, 52.9, 14.7 (two carbons overlap); IR (KBr) ν 3292, 3041, 2981, 2933, 1702, 1498, 1380, 1263, 1212, 1131, 1059, 918, 824, 788, 761 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 16 H 19 N 3 O 4 [M] + 317.1376, found 317.1373.

5-23. Dibenzyl  One-( quinolin -8- ylmethyl ) hydrazine-1,2- dicarboxylate  (4c) and analysis of structure

[Chemical Formula 4c]

65.9 mg (75%); pale yellow sticky oil; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.87 (br s, 1H), 8.16 (dd, J = 8.3, 1.7 Hz, 1H), 7.87-7.75 (m, 3H), 7.50 (br s, 1H), 7.41 (dd, J = 8.2, 4.2 Hz, 1H), 7.33-7.26 (m, 10H), 5.25-5.14 (m, 6H); ^{13 C NMR (100 MHz, CDCl} 3) δ 156.2, 150.0, 146.9, 136.8, 136.1, 135.0, 131.0, 130.4, 128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 127.9, 126.5, 121.3, 68.0 , 67.7, 52.8; IR (KBr) ν 3294, 3063, 3033, 2954, 1708, 1498, 1455, 1408, 1263, 1211, 1131, 1050, 986, 823, 790 cm ^-1 ; HRMS (quadrupole, EI) calcd for C ₂₆ H ₂₃ N ₃ O ₄ [M] ⁺ 441.1689, found 441.1687.

5-24. Bis (2- 메틸oxyethyl ) One-( quinolin -8- ylmethyl ) Production and structure analysis of hydrazine-1,2-dicarboxylate (4d)

[Chemical formula 4d]

49.3 mg (65%); pale yellow sticky oil; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.92 (dd, J = 4.2, 1.7 Hz, 1H), 8.18 (dd, J = 8.3, 1.7 Hz, 1H), 7.78-7.10 (m, 3H), 7.51 ( t, J = 7.4 Hz, 1H ), 7.43 (dd, J = 8.3, 4.2 Hz, 1H), 5.24 (br s, 2H), 4.32-4.24 (m, 4H), 3.62-3.59 (m, 2H), 3.54 (br s, 2H), 3.38 (s, 3H), 3.31 (s, 3H); ^{13 C NMR (100 MHz, CDCl} 3) δ 156.1, 150.0, 146.8, 142.8, 136.9, 135.1, 130.9, 128.7, 128.2, 126.5, 121.3, 70.8, 70.7, 65.5, 65.1, 59.2, 59.1, 52.6; IR (KBr) ν 2954, 2922, 2853, 1753, 1714, 1499, 1458, 1270, 1198, 1124, 1065, 923, 855, 824, 795 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 18 H 23 N 3 O 6 [M] + 377.1587, found 377.1585.

5-25. Di - tert -butyl 1- ( quinolin -8- ylmethyl ) hydrazine-1,2- dicarboxylate  (4e) and structural analysis

[Chemical Formula 4e]

18.3 mg (10%); pale yellow sticky oil; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.92 (dd, J = 4.2, 1.8 Hz, 1H), 8.16 (dd, J = 8.2, 1.4 Hz, 1H), 7.76-7.65 (m, 3H), 7.51 ( t, J = 7.7 Hz, 1H), 7.41 (dd, J = 8.2, 4.2 Hz, 1H), 7.08 (br s, 1H), 5.23 (br s, 2H), 1.44 ¹³ C NMR (100 MHz, CDCl ₃ )? 155.7, 149.8, 146.9, 136.7, 135.8, 130.1, 128.6, 127.8, 126.5, 126.3, 121.2, 81.1, 81.0, 53.0, 28.4, 28.3; IR (KBr) υ 3054, 2977, 2990, 1730, 1697, 1499, 1393, 1272, 1156, 1051, 737 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 20 H 27 N 3 O 4 [M] + 373.2002, found 373.2001.

5-26. diisopropyl  1- (4- 메틸oxyphenyl )-2-( quinolin -8- ylmethyl ) Preparation and structural analysis of hydrazine-1,2-dicarboxylate (6a)

Diisopropyl 1- (quinolin-8-ylmethyl) hydrazine-1,2-dicarboxylate (3a, 51.8 mg, 0.15 mmol, 100 mol%), copper (I) iodide (28.6 mg, 0.15 dried in a sealed oven filled with 97.7 mg (0.3 mmol, 200 mol%) of Cs ₂ CO ₃ (5.7 mg, 0.03 mmol, 20 mol%) and 1,10-phenanthroline Was added p-methoxy-phenyl iodide (5a, 55.1 mg, 0.221 mmol, 200 mol%) and DCE (0.75 mL). The reaction mixture was stirred at 120 < 0 > C for 20 h, cooled at room temperature, filtered through a plug of silica gel, and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified by silica gel chromatography (n-hexanes / EtOAc = 3: 1) to give 66.3 mg of 6a in 98% yield, which was analyzed by NMR.

[Chemical Formula 6a]

66.3 mg (98%); colorless oil; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.87 (br s, 1H), 8.11-8.06 (m, 1H), 7.81-7.68 (m, 2H), 7.45-7.40 (m, 1H), 7.38-7.33 ( m, 1H), 7.26-7.22 (m , 2H), 6.72 (br s, 2H), 5.59-5.44 (m, 1H), 5.26 (d, J = 14.8 Hz, 1H), 5.14-5.05 (m, 1H J = 6.2 Hz, 3H), 1.27 (d, J = 6.2 Hz, 3H), 1.11-0.70 (m, 6H) ; ¹³ C NMR (100 MHz, CDCl ₃ ) δ 158.1, 157.8, 156.3, 154.4, 149.7, 147.2, 136.1, 135.0, 133.9, 131.1, 128.2, 127.7, 126.3, 121.1, 113.7, 70.5, 70.3, 55.6, 48.0, , 22.3; IR (KBr) ν 3048, 2979, 2935, 1710, 1509, 1373, 1245, 1107, 1031, 828, 796 cm ^-1 HRMS (orbitrap, ESI) calcd for C ₂₅ H ₃₀ N ₃ O ₅ [M + H] ⁺ 452.2185, found 452.2177.

5-27. isopropyl quinolin -8- ylmethylcarbamate  (6b) and analysis of structure

Diazopropyl 1- (quinolin-8-ylmethyl) hydrazine-1,2-dicarboxylate (3a, 69.1 mg, 0.2 mmol, 100 mol%) and Cs ₂ CO ₃ (162.9 mg, 0.5 mmol was added methyl bromoacetate (5b, 61.2 mg, 0.4 mmol , 200 mol%) and CH ₃ CN (1.0 mL) in a sealed tube dried in an oven is 250 mol%) filled. The reaction mixture was stirred at 50 < 0 > C for 20 hours and allowed to cool at room temperature. The reaction mixture was cooled to sat. NH ₄ Cl (aq), extracted with EtOAc, the resulting extract was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The oil was purified by column chromatography to give a pale yellow oil. The oil solution was added to acetonitrile (1.0 mL), cesium carbonate (195.5 mg, 0.6 mmol, 300 mol%) was added and the mixture was heated for 20 hours. The heated mixture was again cooled with saturated NH ₄ Cl (aq), extracted with EtOAC, the resulting extract was washed with brine, dried over Na ₂ SO ₄ , the filtrate was concentrated in vacuo, Purification by chromatography (n-hexanes / EtOAc = 2: 1) afforded 29.5 mg of 6b in 60% yield, which was analyzed by NMR.

[Formula 6b]

29.5 mg (60%); pale yellow sticky oil; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.92 (dd, J = 4.1, 1.5 Hz, 1H), 8.17 (dd, J = 8.2, 1.1 Hz, 1H), 7.77-7.72 (m, 2H), 7.50 ( t, J = 7.8 Hz, 1H ), 7.43 (dd, J = 8.2, 4.2 Hz, 1H), 5.95 (br s, 1H), 4.95-4.86 (m, 3H), 1.20 (d, J = 6.2 Hz, 6H); ^{13 C NMR (100 MHz, CDCl} 3) δ 156.6, 149.8, 136.8, 129.3, 128.7, 127.8 (two carbons overlap), 126.7, 121.4 (two carbons overlap), 68.1, 42.8, 22.4; IR (KBr) ν 3335, 3044, 2977, 2932, 1695, 1497, 1373, 1244, 1109, 948, 827, 789 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 14 H 16 N 2 O 2 [M] + 244.1212, found 244.1212.

5-28. diisopropyl  1 - ((1,2,3,4- tetrahydroquinoline -8- yl ) methyl) hydrazine-1,2-dicarboxylate (7a)

(3a, 138.2 mg, 0.4 mmol, 100 mol%) and NiCl ₂揃 6H ₂ O (9.5 mg, 0.04 mmol, 10 mmol) were added to a solution of diisopropyl 1- (quinolin-8-ylmethyl) hydrazine-1,2-dicarboxylate mol%) was added MeOH (4 mL) and CH ₂ Cl ₂ (2 mL). NaBH ₄ a dividing for one hour was added (121.0 mg, 3.2 mmol) under cooling, and then, it was further stirred for 1 hour. After removing the solvent, the residue was absorbed in a small amount of silica. The purification was performed by classical chromatography (n-hexanes / EtOAc = 6: 1) to give 74.0 mg of 7a in 53% yield.

[Formula 7a]

74.0 mg (53%); red sticky oil; ^{1 H NMR (400 MHz, CDCl} 3) δ 6.92 (d, J = 7.3 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H), 6.54 (br s, 1H), 6.36 (br s, 1H) (T, J = 6.4 Hz, 2H), 3.39 (t, J = 5.5 Hz, 2H), 6.19 (br s, 1.91 (quint, J = 6.3 Hz, 2H), 1.24 (d, J = 6.2 Hz, 6H), 1.23 (br s, 6H); ^{13 C NMR (100 MHz, CDCl} 3) δ 156.5, 155.5, 143.1, 129.9, 129.8, 121.7, 119.1, 116.1, 70.8, 69.9, 50.7, 42.1, 27.6, 22.2, 22.1, 21.7; IR (KBr) ν 3360, 2978, 2929, 2849, 1733, 1683, 1601, 1512, 1465, 1419, 1384, 1307, 1278, 1206, 1179, 1105, 1043, 931, 760 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 18 H 27 N 3 O 4 [M] + 349.2002, found 349.2006.

Example  6. Quinolin-8- Monomethanamine  Evaluation of antitumor activity

To evaluate the anticancer activity of quinolin-8-ylmethanamine produced and analyzed in Examples 1 to 5, the cytotoxicity of human breast adenocarcinoma cell line (MCF-7) and human prostate adenocarcinoma cell line (LNCap) was confirmed.

More specifically, human breast cancer cell line (MCF-7) and human prostate cell line (LNCap) were cultured in DMEM medium supplemented with 1% penicillin / streptomycin and 10% fetal bovine serum (all from Life Technologies, Grand Island, NY) Lt; / RTI > Cells were seeded into 96-well plates (5 x 10 ³ cells / well) containing 50 μL growth medium for 24 hours. After the medium was removed, 100 μL of the medium containing different analog compounds was added to each well at each concentration, followed by incubation at 37 ° C. for 72 hours. After 24 hours of incubation, cells were supplemented with 10 [mu] L of test compound dissolved in DMSO (added less than 0.25% to each reagent). After 24 hours of culture, 15 占 퐇 of MTT reagent was added to each well. After incubation at 37 ° C for 4 hours, the supernatant was aspirated and the formazan crystals were dissolved in 100 μL of DMSO at 37 ° C for 10 minutes with gentle stirring. Absorbance per well was measured at 540 nm using a VERSA max microplate reader (Molecular Devices Corp.). IC ₅₀ values were defined as concentrations of compounds that inhibited cell proliferation by 50% compared to cells treated with the highest amount of DMSO (0.025%) and were considered to be 100% viability.

As shown in Table 2, the cancer cell line was treated for 24 hours while increasing the concentration of the synthetic derivative, and the cell survival rate was confirmed. As a result, compounds 3c, 3d, and 3q showed the best anticancer activity among the compounds treated with MCF-7 and LNCaP cell lines. The anticancer activity of the compound was observed as compared with the well known anticancer substance doxorubicin as a positive control.

Compounds MCF-7 LNCaP Compounds MCF-7 LNCaP 3a 21.3 > 50 3o > 50 > 50 3b 16.7 27.1 3p > 50 > 50 3c 4.9 9.1 3q 5.4 10.9 3d 4.6 8.2 3r 20.7 33.7 3e > 50 > 50 3s > 50 > 50 3f > 50 > 50 3t > 50 > 50 3g > 50 > 50 3u > 50 > 50 3h > 50 > 50 4b > 50 > 50 3i > 50 > 50 4c > 50 > 50 3j 14.7 29.1 4d > 50 > 50 3k > 50 > 50 4e > 50 > 50 3l > 50 > 50 6a > 50 > 50 3m > 50 > 50 6b > 50 > 50 3n > 50 > 50 7a > 50 > 50 doxorubicin 5.3 8.0

In conclusion, it was confirmed that quinolin-8-ylmethanamine was formed by rhodium (III) -catalyst sp3 carbon-hydrogen amination reaction of 8-methylquinoline and azodicarboxylate. The reaction was successful in various substrate ranges , And it has been confirmed that, in addition to excellent chemical reactions in general, the reaction proceeds even in an excellent functional group.

Further modification of the hydrazine and quinoline moieties in the synthesized quinolin-8-ylmethanamine shows the importance of the methodology presented in the present invention. The synthesized quinolin-8-ylmethanamine was tested for its in vitro anticancer activity against human breast adenocarcinoma cells (MCF-7) and human prostate adenocarcinoma cells (LNCaP) It was confirmed to be toxic.

It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.

Claims (12)

Quinolin-8-ylmethanamine represented by the formula (1), (4), (5) or (6), an isomer thereof or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

In this case, in Formula 1,
Wherein R ₁ is hydrogen, or C ₁ -C ₆ alkyl;
R < ₂ > is hydrogen;
R < ₃ > is hydrogen or halogen;
The R ₄ And R ₅ are each independently hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or nitro;
Wherein R < ₆ > is hydrogen, halogen, or

;
Wherein R ₇ is C ₁ -C ₆ alkyl, C ₇ -C ₂₀ arylalkyl or C ₂ -C ₆ alkoxyalkyl;
The R ₈ may be hydrogen, halogen, or C ₁ -C ₆ alkyl.
The method according to claim 1,
In Formula 1, R ₁ is hydrogen or methyl, R ₂ is hydrogen, and R ₃ Is hydrogen, or chloro, wherein R ₄ is hydrogen, fluoro, chloro, bromo, methyl, methoxy and ethoxy or nitro, R ₅ is hydrogen, fluoro, chloro, bromo, methyl, methoxy and ethoxy or nitro, R ₆ is hydrogen, fluoro, chloro, bromo, ethynyl, phenyl, or para-ethynyl (4-fluorophenyl) - phenyl ethynyl - a (p-ethynyl weekends), R ₇ is isopropyl, ethyl, 8-ylmethanamine, an isomer thereof or a pharmaceutically acceptable salt thereof, characterized in that it is benzyl, (2-methoxyethyl), or tert-butyl.
The method according to claim 1,
The quinolin-8-ylmethanamine is any one selected from the group consisting of the following compounds: isoquinolin-8-ylmethanamine, an isomer thereof or a pharmaceutically acceptable salt thereof,
Diisopropyl 1- (quinolin-8-ylmethyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1 - ((4-fluoroazen-3-yl) methyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1 - ((7-chloroquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1 - ((7-bromoquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1 - ((6-methoxyquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1 - ((6-methoxyquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1 - ((6-fluoroquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1 - ((6-chloroquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1 - ((6-bromoquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1 - ((6-nitroquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1 - ((5-methoxyquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1 - ((5-methylquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1 - ((5-fluoroquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1 - ((5-chloroquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1 - ((5-bromoquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1 - ((5-nitroquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1 - ((7-phenylethynyl) quinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1 - ((7- (para-tolylethynyl) quinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1 - ((7 - ((4-fluorophenyl) ethynyl) quinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1 - ((4-chloroquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1 - ((4-chloro-2-methylquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate;
Diethyl 1- (quinolin-8-ylmethyl) hydrazine-1,2-dicarboxylate;
Dibenzyl 1- (quinolin-8-ylmethyl) hydrazine-1,2-dicarboxylate;
Bis (2-methoxyethyl) 1- (quinolin-8-ylmethyl) hydrazine-1,2-dicarboxylate;
Di-tert-butyl 1- (quinolin-8-ylmethyl) hydrazine-1,2-dicarboxylate;
Diisopropyl 1- (4-methoxyphenyl) -2- (quinolin-8-ylmethyl) hydrazine-1,2-dicarboxylate;
Isopropylquinolin-8-ylmethylcarbamate; And
Diisopropyl 1 - ((1,2,3,4-tetrahydroquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate.
The method of claim 3,
The quinolin-8-ylmethanamine is any one selected from the group consisting of the following compounds: isoquinolin-8-ylmethanamine, an isomer thereof or a pharmaceutically acceptable salt thereof,
Diisopropyl 1 - ((7-chloroquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate; Diisopropyl 1 - ((7-bromoquinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate; And diisopropyl 1 - ((7-phenylethynyl) quinolin-8-yl) methyl) hydrazine-1,2-dicarboxylate.
A process for producing quinolin-8-ylmethanamine represented by the following formula (1), comprising reacting a compound represented by the following formula (2) with an azodicarboxylate represented by the formula (3) in the presence of a rhodium catalyst:
[Chemical Formula 1]

(2)

(3)

In the formulas of any one of formulas (1) to (3)
Wherein R ₁ is hydrogen, or C ₁ -C ₆ alkyl;
R < ₂ > is hydrogen;
R < ₃ > is hydrogen or halogen;
The R ₄ And R ₅ are each independently hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or nitro;
Wherein R < ₆ > is hydrogen, halogen, or

;
R ₇ is C ₁ -C ₆ alkyl, C ₇ -C ₂₀ arylalkyl, or C ₂ -C ₆ alkoxyalkyl;
The R ₈ may be hydrogen, halogen, or C ₁ -C ₆ alkyl.
6. The method of claim 5,
Wherein the rhodium catalyst is cyclopentadienyl rhodium (III) complex catalyst substituted with C ₁ -C ₅ alkyl, or unsubstituted cyclic pentadienyl rhodium (III) complex catalyst.
The method according to claim 6,
Wherein the rhodium catalyst is a catalyst of pentamethylcyclopentadienylrhodium (III) chloride dimer; [RhCp * Cl ₂ ] ₂ ) catalyst. Way.
6. The method of claim 5,
8. The process for preparing quinolin-8-ylmethanamine according to claim 1, wherein the reaction is carried out further comprising an additive.
9. The method of claim 8,
The additive is at least one selected from the group consisting of silver hexafluoroantimonate (AgSbF ₆ ), lithium acetate (LiOAc), and lithium carbonate (Li ₂ CO ₃ ) Lt; RTI ID = 0.0 > of quinolin-8-ylmethanamine. ≪ / RTI >
6. The method of claim 5,
8. The process for preparing quinolin-8-ylmethanamine according to claim 1, wherein the reaction is carried out in a solvent such as dichloroethane (DCE) or tetrahydrofuran (THF).
A pharmaceutical composition for preventing or treating cancer, which comprises as an active ingredient quinolin-8-ylmethanamine of any one of claims 1 to 4, an isomer thereof or a pharmaceutically acceptable salt thereof.
12. The pharmaceutical composition for preventing or treating cancer according to claim 11, wherein the cancer is prostate cancer or breast cancer.

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