KR20130122420A - Novel substituted benzyl derivatives including actvated vinyl group and pharmaceutical compositions for prevention and treatment of neurological diseases through both activating of nrf2 and inhibiting of producing nitric oxide - Google Patents

Abstract

The present invention relates to a benzyl derivative compound containing an activated vinyl group, pharmaceutically acceptable salt of the same, and a pharmaceutical composition which contains the benzyl derivative compound as an active component. The benzyl derivative compound has nitric oxide production inhibiting and NF-E2-related factor-2 (Nrf2) activating effects for preventing and treating brain neurological diseases, especially Parkinson`s disease, dementia of the Alzheimers type, Huntington disease, Lou Gehrig`s disease, epilepsy, depression, insomnia, uneasiness, and degenerative cerebral nerve diseases caused by the functional disorder and death of nerve cells.

Description

TECHNICAL FIELD [0001] The present invention relates to a benzyl derivative compound containing an activated vinyl group that can be used for the prevention and treatment of cranial nervous diseases through inhibition of nitric oxide formation and Nrf2 activity, and a pharmaceutical composition thereof. neurological diseases through both activating of Nrf2 and inhibiting of producing nitric oxide}

The present invention relates to a benzyl derivative containing an activated vinyl group which inhibits nitric oxide production and acts on NF-E2-related factor-2 (Nrf2) Possible salts, and pharmaceutical compositions containing these compounds as active ingredients.

As the development of rapid medical technology prolongs the life span of human beings, degenerative brain disease becomes a social problem as it enters into an aging society. Degenerative brain disease refers to a disease that occurs in the brain of a degenerative disease caused by age, such as the death of brain cells that are most important to the transmission of brain nervous system, the formation of synapses that transmit information between brain cells and brain cells Or functional problems, and an ideal increase or decrease in the electrical activity of the brain. These diseases are manifested in various forms. Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common diseases.

The incidence of Parkinson's disease is 1% in patients over 60 years old, 3.4% in patients over 70 years old, and 4% in patients over 80 years old. The primary symptoms are slow motion, tremor at rest, instability of posture, It is associated with secondary symptoms such as depression, insomnia, and dementia as the disease progresses. [1] de Lau et al., Lancet Neurol. 2006, 5, 525-535; 2) Chaudhuri et al., Lancet Neurol. 2009, 8, 464-474; 3) Fahn, In Handbook Exp. Pharmacol, 1989, 8, Calne, D. B., (Ed.) Pp. 386-409]. More than 50,000 people are diagnosed every year, but despite many studies, they have not been able to identify a clear cause for the etiology [Arevalo et al., Mov. Disord. 1997, 12,277-284].

Currently, treatment methods are based on the use of a proactive therapeutic agent. Typical examples of the therapeutic method include treatment with L-3,4-dihydroxyphenylalanine (L-DOPA), a precursor of dopamine, a monoamine oxidase inhibitor (inhibitor) Antagonists (agonists). However, these methods delay the progression of the disease but do not lead to the underlying treatment, and are associated with long-term side effects and complications. Recently, efforts have been made to change the direction of the disease through neuroprotection.

Oxidative stress is caused by an imbalance between reactive oxygen species (ROS) and intracellular antioxidant activity, which is thought to be a fundamental reason for dysfunction or death of nerve cells in Parkinson's disease. The metabolism of dopamine is known to cause the modification of macromolecules, which play an important role in cell growth in association with oxidative stress. In addition, the active oxygen produced by activated microglia in the neuroinflammation process was further accelerated by dopaminergic neuron-secreted substances, resulting in neuronal death [1] Andersen et al. al., Nat. Med. 2004, 10 Suppl, S18-25; 2) Jenner et al., Annal. Neurol. 2003, 53 Suppl3, S26-36].

Among these active oxygen species, nitric oxide (NO) is a gaseous substance that exists in vivo and is a nitrate (NO ₃ ^- ), nitrite (NO ₂ ^- ), peroxynitrite (ONOO ^- ), It is easily converted to highly reactive intermediates such as tyrosine. When NO is produced excessively, NO and its intermediates induce nitrooxidative stress that causes DNA, protein and lipid changes that make up the cells. In particular, the dysfunction of various proteins required for cell survival results in cell dysfunction and apoptosis. In addition, nerve cells are particularly vulnerable to NO. This is because NO induces excitatory toxicity in neurons and increases its cytotoxicity when present in association with superoxide generated by microglia. Therefore, overexpression of NO may result in the death of neurons and contribute to the development of various degenerative brain diseases. In fact, in the case of Parkinson's disease, the nitrite concentration is increased in the spinal fluid [Qureshi et al., Neuroreport 1995, 6 (12), 1642-1644], the alpha-synuclein present in the brain lesion and the Lewy body α-synuclein), and 3-nitrotyrosine increases [Good et al., J Neuropathol. Exp. Neurol. 1998, 57 (4), 338-342]. Parkin and XIAP, which are important for cell survival, have been found to be S-nitrosylated [1] Yao et al., Proc. Natl. Acad. Sci. USA. 2004, 101 (29), 10810-10814; 2) Tsang et al., Proc. Natl. Acad. Sci. USA. 2009, 106 (12), 4900-4905; 3) Pathak et al., Biochim. Biophys. Acta 2008, 1777 (7-8), 777-782). In addition, NO and production are known to be associated with Parkinson's disease as well as neurodegeneration following Alzheimer's disease, Huntington's disease, Lou Gehrig's disease, and stroke.

Parkinson's disease, on the other hand, is known to be caused by the loss of dopaminergic neurons, which contain dopamine, a neurotransmitter, in the midbrain region, called the substantia nigra pars compacta. Dopamine is oxidized by enzymes or spontaneously, and is lost to dopaquinone. Dopaquinone readily covalently binds to cellular necleophiles such as cysteinyl residues of proteins and forms reactive aminochromes when dopaquinone is over a defined amount and generates superoxide by redox-cycling , Which reduces intracellular NADPH. Therefore, dopamine quinone mediates dopaminergic neuronal loss by oxidative stress, and dopaminergic neuron death by inhibiting oxidative stress through dopamine quinone removal.

Quinone oxidoreductase 1 (NQO-1) is an enzyme capable of reducing quinone to redox-stable hydroquinone, which is converted to quinone (NQP) through a reducing cofactor such as NADH or NADPH Two electrons are reduced to protect the cells [Ryu et al. Arch. Pharm. Res. 2000, 23, 554-558]. It is known that it is expressed on the dark part of Parkinson's patients and can protect dopaminergic neurons from toxic substances produced by dopamine quinone [Choi et al. J. Neurochem. 2005, 95, 1755-1765].

The gene expression of NQO1 is induced by the binding of the transcription factor Nrf2 to the antioxidant response element (ARE). Nrf2 is a transcriptional factor that can induce the ability to protect cells in response to oxidative stress [Goldring et al. Toxicology 2008, 246, 24-33] In the cytoplasm, it binds to Kelch-like ECH-associated protein 1 (Keap1) but moves to the nucleus when the binding to Keap1 is weak [1] Itoh et al. Genes Dev. 1999, 13, 76-86; 2) Eggler et al. Proc. Natl. Acad. Sci. USA 2005, 102, 10070-10075; 3) Kobayashi et al. Mol. Cell. Biol. 2006, 26, 221-229; 4) Tong et al. Biol. Chem. 2006, 387, 1311-1320]. It binds to ARE in the nucleus and induces expression of NQO1 and at the same time induces expression of heme oxygenase (HO-1) [Venugopal et al. Proc. Natl. Acad. Sci. USA. 1996, 93, 14960-14965). HO-1 is an enzyme that acts on heme degradation, and one of its reaction products, biliverdin, is converted to an antioxidant, bilirubin, which consequently protects nerve cells from oxidative stress.

1-isothiocyanato- (methylsulfinyl) butane induces NQO1 expression and protects dopaminergic neurons from oxidative stress [Han et al. J. Pharmacol. Exp. Ther. 2007, 321 (1), 249-256). However, sulforaphane has a disadvantage in that it can non-selectively denature various proteins in a cell having a thiol group to induce cytotoxicity, and has a very low blood-brain barrier permeability. In addition, the administration of sulfo-p-phenylenediamine in the body disappeared within 1 hour, so that the induction effect of Nrf2 activity is not sustained.

Therefore, there is a desperate need for a compound for the prevention and treatment of neuronal diseases capable of inducing Nrf2 activity and nitric oxide production inhibition without the problems of the sulfuroide described above.

The first technical problem to be solved by the present invention is to inhibit the generation of nitric oxide in vivo and at the same time to induce Nrf2 activity and thereby to prevent the death of cranial nerve cells by expressing an enzyme gene which prevents cytotoxicity, The present invention provides a benzyl derivative compound containing an activated vinyl group that can be utilized for treating a cranial nerve disease or a pharmaceutically acceptable salt thereof.

A second object of the present invention is to provide a pharmaceutical composition comprising the benzyl derivative compound containing the activated vinyl group, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier or diluent as an active ingredient .

In order to solve the above-mentioned first problem, the present invention provides a benzyl derivative compound having an activated vinyl group represented by the following formula (1): or a pharmaceutically acceptable salt thereof:

≪ Formula 1 >

R ₁ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, including a linear, branched, or cyclic carbon chain, a substituted or unsubstituted linear, branched or cyclic carbon chain having 7 to 12 carbon atoms An alkyl group having 1 to 10 carbon atoms, which is substituted or unsubstituted, and the alkyl group containing a straight, branched or cyclic carbon chain is an oxygen-bonded alkoxy group, a substituted or unsubstituted allyl group having 2 to 12 carbon atoms , A substituted or unsubstituted C 1 -C 10 alcohol group, a substituted or unsubstituted C 6 -C 18 aryl group, a substituted or unsubstituted C 3 -C 18 heteroaryl group, a substituted or unsubstituted C 1 -C 12 A substituted or unsubstituted arylamine group having 6 to 18 carbon atoms, a substituted or unsubstituted heteroarylamine group having 6 to 18 carbon atoms, a substituted or unsubstituted C1- A substituted or unsubstituted C6 to C18 arylthio group, a substituted or unsubstituted C6 to C18 aryloxy group, a substituted or unsubstituted C1 to C6 amide group,

R ₂ and R ₃ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl groups containing from 1 to 6 carbon atoms, straight, branched or cyclic carbon chain, substituted or unsubstituted carbon A substituted or unsubstituted allyl group having 2 to 12 carbon atoms, a substituted or unsubstituted alcohl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, An alkyl group having from 1 to 10 carbon atoms in which a straight chain, branched or cyclic carbon chain is substituted by an oxygen atom, an aryl group having 6 to 18 carbon atoms, an aryloxy group having 6 to 18 carbon atoms connected to oxygen , An alkylcarbamate group having 1 to 5 carbon atoms, a heteroaryl group having 3 to 18 carbon atoms, a heteroaryloxy group having 3 to 18 carbon atoms and a heteroaryl group connected to oxygen, An alkylammonooxy group whose alkylammono group is bonded to oxygen, an alkylammonoxy group whose alkylammono group has 1 to 8 carbon atoms connected to oxygen, an alkylthioxy group whose alkylthiol group has 1 to 10 carbon atoms connected to oxygen, To 18 arylthiol groups may be aryl thioloxy groups linked to oxygen,

,

또는

이다.Y is

,

or

to be.

According to one embodiment of the present invention, the pharmaceutically acceptable salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, But is not limited to, any one or more selected from the group consisting of oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, ethanesulfonic acid, aspartic acid and glutamic acid.

In order to achieve the second technical object, the present invention relates to a benzyl derivative compound having an activated vinyl group represented by the general formula (1), a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier or diluent as an active ingredient ≪ / RTI >

The benzyl derivative compound having an activated vinyl group according to the present invention and its pharmaceutically acceptable salt and a pharmaceutical composition containing these compounds as an active ingredient can inhibit the production of nitric oxide in vivo and activate Nrf2 Neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, Lou Gehrig's disease, epilepsy, depression, insomnia, anxiety and degenerative brain disease caused by dysfunction and death of nerve cells due to oxidative stress.

Hereinafter, the present invention will be described in more detail.

Nitric oxide (NO) is produced by the nitric oxide synthase (NOS) enzyme in the cell. In particular, inducible NOS (iNOS) is an enzyme that acts on microglia and astrocytes in the brain. It is usually present at very low concentrations and is expressed when cells are activated, resulting in a significant increase in brain NO concentration (about 100 times). In the brains of patients with degenerative brain disease, this increased expression of iNOS fails to return to resting state and produces NO over a long period of time. Therefore, controlling iNOS may be used to prevent and treat degenerative brain diseases including Parkinson's disease. In particular, the method of inhibiting the expression of iNOS to a resting level without affecting the activity of other NOS (neuronal, endothelial type) does not affect the normal function of NO, so the related side effects can be minimized. In addition, Nrf2 is a transcriptional factor that can induce the ability to protect cells against oxidative stress. After transferring to the nucleus, the enzyme heme oxygenase (HO-1), which binds to ARE to prevent cytotoxicity, , NAD (P) H / quinine oxidoreductase 1 (NQO-1)).

Therefore, the present invention can inhibit the overproduction of nitric oxide in the brain by inhibiting the expression of iNOS to rest state level, and can induce the expression of enzyme genes that prevent cytotoxicity by activating Nrf2, And a benzyl derivative compound containing an activated vinyl group represented by the following formula (1), which can act as a therapeutic agent, or a pharmaceutically acceptable salt thereof:

≪ Formula 1 >

R ₁ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, including a linear, branched, or cyclic carbon chain, a substituted or unsubstituted linear, branched or cyclic carbon chain having 7 to 12 carbon atoms An alkyl group having 1 to 10 carbon atoms, which is substituted or unsubstituted, and the alkyl group containing a straight, branched or cyclic carbon chain is an oxygen-bonded alkoxy group, a substituted or unsubstituted allyl group having 2 to 12 carbon atoms , A substituted or unsubstituted C 1 -C 10 alcohol group, a substituted or unsubstituted C 6 -C 18 aryl group, a substituted or unsubstituted C 3 -C 18 heteroaryl group, a substituted or unsubstituted C 1 -C 12 A substituted or unsubstituted arylamine group having 6 to 18 carbon atoms, a substituted or unsubstituted heteroarylamine group having 6 to 18 carbon atoms, a substituted or unsubstituted C1- A substituted or unsubstituted C6 to C18 arylthio group, a substituted or unsubstituted C6 to C18 aryloxy group, a substituted or unsubstituted C1 to C6 amide group,

R ₂ and R ₃ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl groups containing from 1 to 6 carbon atoms, straight, branched or cyclic carbon chain, substituted or unsubstituted carbon A substituted or unsubstituted allyl group having 2 to 12 carbon atoms, a substituted or unsubstituted alcohl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, An alkyl group having from 1 to 10 carbon atoms in which a straight chain, branched or cyclic carbon chain is substituted by an oxygen atom, an aryl group having 6 to 18 carbon atoms, an aryloxy group having 6 to 18 carbon atoms connected to oxygen , An alkylcarbamate group having 1 to 5 carbon atoms, a heteroaryl group having 3 to 18 carbon atoms, a heteroaryloxy group having 3 to 18 carbon atoms and a heteroaryl group connected to oxygen, An alkylammonooxy group whose alkylammono group is bonded to oxygen, an alkylammonoxy group whose alkylammono group has 1 to 8 carbon atoms connected to oxygen, an alkylthioxy group whose alkylthiol group has 1 to 10 carbon atoms connected to oxygen, To 18 arylthiol groups may be aryl thioloxy groups linked to oxygen,

,

또는

이다.Y is

,

or

to be.

The compound of Formula 1 may be a compound of Formula 2 to 4:

&Lt; Formula 2 > < EMI ID =

&Lt; Formula 4 >

In the above Chemical Formulas 2 to 4,

R ₁ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, including a linear, branched, or cyclic carbon chain, a substituted or unsubstituted linear, branched or cyclic carbon chain having 7 to 12 carbon atoms An alkyl group having 1 to 10 carbon atoms, which is substituted or unsubstituted, and the alkyl group containing a straight, branched or cyclic carbon chain is an oxygen-bonded alkoxy group, a substituted or unsubstituted allyl group having 2 to 12 carbon atoms , A substituted or unsubstituted C 1 -C 10 alcohol group, a substituted or unsubstituted C 6 -C 18 aryl group, a substituted or unsubstituted C 3 -C 18 heteroaryl group, a substituted or unsubstituted C 1 -C 12 A substituted or unsubstituted arylamine group having 6 to 18 carbon atoms, a substituted or unsubstituted heteroarylamine group having 6 to 18 carbon atoms, a substituted or unsubstituted C1- A substituted or unsubstituted C6 to C18 arylthio group, a substituted or unsubstituted C6 to C18 aryloxy group, a substituted or unsubstituted C1 to C6 amide group,

R ₂ and R ₃ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl groups containing from 1 to 6 carbon atoms, straight, branched or cyclic carbon chain, substituted or unsubstituted carbon An alkyl group having from 7 to 15 straight-chain, branched or cyclic carbon chains, a substituted or unsubstituted allyl group having 3 to 15 carbon atoms, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, A substituted or unsubstituted aryl group having 6 to 18 carbon atoms, a substituted or unsubstituted monovalent group having 6 to 18 carbon atoms, a substituted or unsubstituted aryl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkyl group having 1 to 10 linear, A substituted or unsubstituted C 1 -C 5 alkylcarbamate group, a substituted or unsubstituted C 3 -C 18 heteroaryl group, a substituted or unsubstituted aryloxy group, Or an unsubstituted heteroaryloxy group having 3 to 18 carbon atoms, a substituted or unsubstituted heteroaryl group having 3 to 18 carbon atoms connected to oxygen, a substituted or unsubstituted alkylmorpholin group having 5 to 15 carbon atoms, A substituted or unsubstituted alkylaminooxy group in which a substituted or unsubstituted alkylamine group having 1 to 11 carbon atoms is connected to oxygen, an alkylthioxy group in which a substituted or unsubstituted alkylthiol group having 1 to 13 carbon atoms is connected to oxygen, a substituted Or an unsubstituted aryl thiol group having 6 to 18 carbon atoms may be an aryl thioloxy group connected to oxygen,

R ₄ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, including a linear, branched, or cyclic carbon chain, a substituted or unsubstituted linear, branched or cyclic carbon chain having 7 to 12 carbon atoms A substituted or unsubstituted aryl group having 3 to 12 carbon atoms, a substituted or unsubstituted heteroaryl group having 3 to 15 carbon atoms, a substituted or unsubstituted heterocyclic group having 3 to 15 carbon atoms, A substituted or unsubstituted alkylamine group having 1 to 8 carbon atoms, a substituted or unsubstituted alkylthiol group having 1 to 10 carbon atoms, a substituted or unsubstituted alkylene group having 6 to 15 carbon atoms Arylthiol group,

,

또는

이다.Y is

,

or

to be.

The alkyl group may be selected from the group consisting of a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group And the aryl group may be a phenyl group, a halophenyl group, a benzyl group, a halobenzyl group, a tolyl group, a naphthyl group, a biaryl group, a trihalophenyl group, a trihalomethylphenyl group, a halonitrobenzyl group, an anthryl group, And the heteroaryl group may be selected from the group consisting of a thiazolyl group, an oxazolyl group, a thiophenyl group, a furanyl group, a pyrrolyl group, an imidazolyl group, an isoxazolyl group, an isothiazolyl group, a pyrazolyl group, A thiadiazolyl group, a tetrazolyl group, an oxadiazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidyl group, a pyrazinyl group, an indolyl group, a benzothiophenyl group, a benzofuranyl group, a benzimidazole group Zolyl group, benzoxazole And the alkylamine group may be selected from the group consisting of a methylamine group, an ethylamine group, an isothiazolyl group, an isothiazolyl group, a quinolyl group, an isoquinoline group, a furylpyridyl group, , An ethylamine group, a propylamine group, a butylamine group, an isobutylamine group and a pentylamine group, and the arylamine group may be selected from the group consisting of an aniline group, a haloaniline group, a methylaniline group, And an aniline group, but the present invention is not limited thereto.

More specifically, R ₁ is preferably a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a methoxy group, an ethoxy group, A benzyl group, an acetamido group, a nitrobenzyl group, an anesyl group, an ethyloxybenzyl group, an ethoxynitrobenzyl group, a halonitrobenzyl group, a methylthio group, a methylthio group, a methylthio group, An amine group, an ethylamine group, a methylacetamide group, an ethylacetamide group, and a propylacetamide group, but the present invention is not limited thereto,

R ₂ and R ₃ are each independently selected from the group consisting of a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a normal butyl group, an isobutyl group, a tert-butyl group, a methoxy group, an ethoxy group, a dimethoxy group, , A morpholine group, a methoxyethylmorpholine group, a methoxypropylmorpholine group, a methoxybutylmorpholine group, and a methoxypropylpiperazyl group, but is not limited thereto.

Particularly preferred examples of the benzyl derivative represented by the above formula (1) are as follows:

Compound 1: (Z) -4- (para-methylphenylsulfinyl) -3-en-1-amine;

Compound 2: (Z) -4- (para-methoxyphenylsulfinyl) -3-en-1-amine;

Compound 3: (E) -4- (para-methoxyphenylsulfinyl) -3-en-1 -amine;

Compound 4: (Z) -4- (3,4-dimethoxyphenylsulfinyl) -3-tent-l-amine;

Compound 5: (E) -1-chloro-2- (2- (4-methoxyphenylsulfinyl) vinyl) benzene;

Compound 6: (Z) -1-chloro-2- (2- (4-methoxyphenylsulfinyl) vinyl) benzene;

Compound 7: (E) -2- (2- (4-methoxyphenylsulfinyl) vinyl) aniline hydrochloride;

Compound 8: (E) -1- (2- (4-methoxyphenylsulfinyl) vinyl) -2- (trifluoromethyl) benzene;

Compound 9: (Z) -1- (2- (4-methoxyphenylsulfinyl) vinyl) -2- (trifluoromethyl) benzene;

Compound 10: (E) -4- (4-Methoxyphenylsulfonyl) but-3-en-1-amine hydrochloride;

Compound 11: (E) -1-Fluoro-2- (2- (4-methoxyphenylsulfonyl) vinyl) benzene;

Compound 12: (E) -1-Fluoro-3- (2- (4-methoxyphenylsulfonyl) vinyl) benzene;

Compound 13: (E) -1-Fluoro-4- (2- (4-methoxyphenylsulfonyl) vinyl) benzene;

Compound 14: (E) -1-chloro-2- (2- (4-methoxyphenylsulfonyl) vinyl) benzene;

Compound 15: (E) -1-chloro-4- (2- (4-methoxyphenylsulfonyl) vinyl) benzene;

Compound 16: (E) -1- (2- (4-methoxyphenylsulfonyl) vinyl) -2- (trifluoromethyl) benzene;

Compound 17: (E) -1- (2- (4-methoxyphenylsulfonyl) vinyl) -3- (trifluoromethyl) benzene;

Compound 18: (E) -1-Methoxy-4- (4- (trifluoromethyl) styrylsulfonylbenzene;

Compound 19: (E) -1- (2- (3-methoxyphenylsulfonyl) vinyl) -2- (trifluoromethyl) benzene;

Compound 20: (E) -1- (2- (3-methoxyphenylsulfonyl) vinyl) -3- (trifluoromethyl) benzene;

Compound 21: (E) -1- (2- (2-methoxyphenylsulfonyl) vinyl) -2- (trifluoromethyl) benzene;

Compound 22: (E) -1- (2- (2-methoxyphenylsulfonyl) vinyl) -3- (trifluoromethyl) benzene;

Compound 23: (E) -1- (2- (2-methoxyphenylsulfonyl) vinyl) -4- (trifluoromethyl) benzene;

Compound 24: (E) -1-Fluoro-2- (2- (2-methoxyphenylsulfonyl) vinyl) benzene;

Compound 25: (E) -1-Fluoro-3- (2- (2-methoxyphenylsulfonyl) vinyl) benzene;

Compound 26: (E) -4- (3- (4- (2-Fluorostyrylsulfinyl) phenoxy) propyl) morpholine hydrochloride;

Compound 27: (E) -4- (3- (4- (2-chlorostyrylsulfinyl) phenoxy) propyl) morpholine hydrochloride;

Compound 28: (E) -4- (3- (4- (2-Trifluoromethylstyrylsulfinyl) phenoxy) propyl) morpholine hydrochloride;

Compound 29: (E) -4- (3- (4- (2-Aminostyrylsulfanyl) phenoxy) propyl) morpholine hydrochloride;

Compound 30: (E) -4- (4- (3-morpholinopropoxy) phenylsulfonyl) but-3-en-1-amine hydrochloride;

Compound 31: (E) -N- (4- (4- (3-morpholinopropoxy) phenylsulfonyl) -3-thienylacetamide;

Compound 32: (E) -4- (3- (4- (2-Fluorostyrylsulfonyl) phenoxy) propyl) morpholine hydrochloride;

Compound 33: (E) -4- (3- (4- (3-Fluorostyrylsulfonyl) phenoxy) propyl) morpholine hydrochloride;

Compound 34: (E) -4- (3- (4- (4-Fluorostyrylsulfonyl) phenoxy) propyl) morpholine hydrochloride;

Compound 35: (E) -4- (3- (4- (2- (chlorostyrylsulfonyl) phenoxy) propyl) morpholine hydrochloride;

Compound 36: (E) -2- (2- (4- (3-morpholinopropoxy) phenylsulfonyl) vinyl) aniline hydrochloride;

Compound 37: (E) -4- (3- (4- (2- (trifluoromethyl) styrylsulfonyl) phenoxy) propyl) morpholine hydrochloride;

Compound 38: (E) -3- (2-fluorophenyl) -1- (4- (3-morpholinoproxy) phenyl) prop-2-en-1-one hydrochloride;

Compound 39: (E) -3- (2-Chlorophenyl) -l- (4- (3-morpholinoproxy) phenyl) prop-2-en-1-one hydrochloride;

Compound 40: (E) -3- (2-Bromophenyl) -1- (4- (3-morpholinoproxy) phenyl) prop-2-en-1-one hydrochloride;

Compound 41: (E) -1- (4- (3-morpholinoproxyphenyl) phenyl) -3- (2-nitrophenyl) prop-2-en-1-one hydrochloride;

Compound 42: (E) -3- (2-aminophenyl) -1- (4- (3-morpholinoproxy) phenyl) prop-2-en-1-one hydrochloride;

Compound 43: (E) -3- (2-methoxyphenyl) -1- (4- (3 -morpholinoproxy) phenyl) prop-2-en-1-one hydrochloride;

Compound 44: (E) -1- (4- (3 -morpholinopropoxy) phenyl) -3- (2- (trifluoromethyl) phenyl) prop-2-pen-1-one hydrochloride;

Compound 45: (E) -1- (4- (3-morpholinopropoxy) phenyl) -3- (3- (trifluoromethyl) phenyl) prop-2-en-1-one hydrochloride;

Compound 46: (E) -1- (4- (3-morpholinoproxy) phenyl) -3- (4- (trifluoromethyl) phenyl) prop-2-en-1-one hydrochloride;

Compound 47: (E) -3- (2-Chloro-5-nitrophenyl) -1- (4- (3-morpholinoproxy) phenyl) prop-2-en-1-one hydrochloride;

Compound 48: (E) -3- (2-ethoxy-5-nitrophenyl) -1- (4- (3 -morpholinoproxy) phenyl) prop-2-en-1-one hydrochloride;

But is not limited thereto.

The pharmaceutically acceptable salts of the present invention include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, But are not limited to, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, ethanesulfonic acid, aspartic acid and glutamic acid.

The benzyl derivative compound containing an activated vinyl group according to the present invention can be converted into a salt thereof by a conventional method and the preparation of the salt is easily carried out by a person skilled in the art based on the structure of the formula It will be possible.

Unless otherwise stated, the benzyl derivative compounds containing an activated vinyl group include pharmaceutically acceptable salts thereof, all of which should be construed as being included in the scope of the present invention.

The present invention provides a pharmaceutical composition comprising an active vinyl group-containing benzyl derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier or diluent as an active ingredient.

The pharmaceutical composition of the present invention may be formulated into a benzyl derivative compound having an activated vinyl group represented by the above formula (1), a pharmaceutically acceptable salt thereof, a carrier, an adjuvant or a diluent by a formulation method and administered orally or parenterally And the like. Oral administration may be prepared in the form of tablets, capsules, solutions, syrups, suspensions and the like, parenteral administration may be prepared in the form of injections for the abdominal cavity, subcutaneous, muscle, transdermal.

The pharmaceutical composition of the present invention is a regulator that acts to inhibit nitric oxide production and inhibit neuronal cell death, which shows the effect of Nrf2 activity. The dosage can be determined according to various factors including age, body weight and condition of the patient and administration route. In general, when the present compound is administered alone to an adult, the dosage administered by route of administration is 0.0001 to 50 mg / kg body weight, for example, 0.01 to 1 mg / kg body weight in the range of 0.001 to 10 mg / kg body weight .

The pharmaceutical composition of the present invention can be used for the prevention and treatment of cranial nerve diseases. The cranial nerve diseases are selected from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease, Lou Gehrig's disease, epilepsy, depression, insomnia, anxiety and degenerative brain disease It can be more than one.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to preferred embodiments for better 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 thereto.

Example . Synthesis of Benzyl Derivatives

Example  1.1. ( Diethoxyphosphoryl ) methyl  4- Methylbenzenesulfonate  synthesis

(Diethoxyphosphoryl) methyl 4-methylbenzenesulfonate was synthesized according to Reaction Scheme 1 below.

<Reaction Scheme 1>

Diethyl hydroxymethylphosphonate (10 g, 0.06 mol) was dissolved in methylene chloride (MC) and triethylamine (9.80 mL, 0.07 mmol) and 4-toluenesulfonyl chloride (13.3 g, 0.07 mol) And the mixture was stirred at room temperature for 3.5 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (EtOAc), washed with water and brine, and then the organic layer was dried with anhydrous Na ₂ SO ₄ and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / n-hexane 1: 3) to obtain methyl 4-methylbenzenesulfonate (diethoxyphosphoric acid) in a yield of 52% .

Yellow oil; _Rf = 0.3 (hexanes / EtOAc 1/2); ^{1 H NMR (400 MHz, CDCl} 3): δ7.80 (d, J = 7.6 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.19-4.12 (m, 6H), 2.46 (s, 3H), 1.31 (t, J = 7.4 Hz, 6H)

Example  1.2. 3- ( Triisopropylsilyloxy ) Propane-1-ol

3- (triisopropylsilyloxy) propan-1-ol was synthesized according to Reaction Scheme 2 below.

<Reaction Scheme 2>

(1.00 g, 0.013 mol) was dissolved in dimethylformamide (DMF) and imidazole (0.88 g, 0.013 mol) and triisopropylsilyl chloride (TIPSCl) (2.5 g, 0.013 mol ) In that order, followed by stirring at room temperature for 3 hours. When the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water and brine, and then the organic layer was dried with anhydrous Na ₂ SO ₄ and filtered. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography (ethyl acetate / n-hexane 1:10) to give 3- (triisopropylsilyloxy) propan-1-ol (1.3 g) in a yield of 45% .

Yellow oil; _Rf = 0.3 (hexanes / EtOAc 5/1); ^{1 H NMR (400 MHz, CDCl} 3): δ 3.93 (t, J = 5.5 Hz, 2H), 3.84 (q, J = 5.1 Hz, 2H), 2.83 (t, J = 5.1 Hz, 2H), 1.83- 1.77 (m, 2H), 1.09-1.04 (m, 21H)

Example  1.3. 3- ( Triisopropylsilyloxy ) Propanal  synthesis

3- (triisopropylsilyloxy) propane was synthesized according to Reaction Scheme 3 below.

<Reaction Scheme 3>

(COCl) ₂ (1.03 g, 7.27 mmol) was dissolved in methylene chloride (MC), and dimethylsulfoxide (DMSO; 0.63 mL, 14.53 mmol) dissolved in methylene chloride was added thereto. Isopropylsilyloxy) propan-1-ol (1.3 g, 5.59 mmol) and triethylamine (0.8 mL, 55.9 mmol) were successively added thereto, followed by stirring at -78 ° C for 3 hours. When the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water and brine, and then the organic layer was dried with anhydrous Na ₂ SO ₄ and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / n-hexane 1:10) to give 3- (triisopropylsilyloxy) propane (1.02 g) was obtained in 78% yield.

Yellow oil; _Rf = 0.45 (hexanes / EtOAc 9/1); ^{1 H NMR (400 MHz, CDCl} 3): δ 9.84 (s, 1H), 4.08 (t, J = 6.0 Hz, 2H), 2.63-2.59 (m, 2H), 1.12-1.03 (m, 21H)

Example  1.4. Synthesis of [1.4a] to [1.4f]

The following compounds [1.4a] to [1.4f] were synthesized according to Reaction Scheme 4 below.

<Reaction Scheme 4>

Substituted benzenethiol (1.0 eq) was dissolved in DMF, and cesium carbonate (Cs ₂ CO ₃ ; 1.2 eq) and the compound synthesized in Example 1.1 (1.2 eq) were added in this order, followed by stirring at room temperature for 3 hours Respectively. When the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water and brine, and then the organic layer was dried with anhydrous Na ₂ SO ₄ and filtered. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography (ethyl acetate / n-hexane 3: 1) to obtain the compounds [1.4a] to [1.4f].

In the above Reaction Scheme 4, R is as shown in Table 1 below.

division R division R 1.4a 4'-CH ₃ 1.4d 2'-OCH ₃ 1.4b 4'-OCH ₃ 1.4e 3'-OCH ₃ 1.4c _{3'-OCH 3, 4'-OCH} 3 1.4f 4'-OH

Example  1.4.1. Diethyl  (4- Methylphenylthio ) Methylphosphonate  [1.4a]

Colorless oil; Yield: 90%; Rf = 0.4 (hexane / EtOAc 1/1); ^{1 H NMR (400 MHz, CDCl} 3): δ 7.36 (d, J = 8Hz, 2H), 7.12 (d, J = 8Hz, 2H), 4.17-4.09 (m, 4H), 3.17 (d, J = 14 Hz, 2H), 2.31 (s, 3H), 1.30 (t, J = 7.2 Hz, 6H)

Example  1.4.2. Diethyl  (4- Methoxyphenylthio ) Methylphosphonate  [1.4b]

Colorless oil; Yield: 84%; Rf = 0.3 (hexane / EtOAc 1/2); ^{1 H NMR (400 MHz, CDCl} 3): δ 7.46 (d, J = 6.8 Hz, 2H), 6.84 (d, J = 6.4 Hz, 2H), 4.14-4.08 (m, 4H), 3.79 (s, 3H ), 3.09 (d, J = 12.8 Hz, 2H), 1.30 (t, J = 7.0 Hz,

Example  1.4.3. Diethyl  (3,4- Dimethoxyphenylthio ) Methylphosphonate  [1.4c]

Colorless oil; Yield: 78.9%; Rf = 0.2 (hexane / EtOAc 1/1); ^{1 H NMR (400 MHz, CDCl} 3): δ 7.81 (d, J = 8.3 Hz, 1H), 7.38 (d, J = 8.3 Hz, 1H), 6.82 (dd, J = 8.9 Hz, 2.4 Hz, 1H) J = 7.8 Hz, 6H), 3.14 (d, J = 13.6 Hz, 2H), 1.31 (t, J = 7.1 Hz, 6H)

Example  1.4.4. Diethyl  (2- Methoxyphenylthio ) Methylphosphonate  [1.4d]

Colorless oil; Yield: 87%; ^{1 H NMR (400 MHz, CDCl} 3): δ 7.42 (dd, J = 1.64, 7.68 Hz, 1H), 7.24 (m, 1H), 6.91 (td, J = 1.12, 7.56Hz, 1H), 6.85 (d J = 8.2 Hz, 1H), 4.07-4.13 (m, 4H), 3.88 (s, 3H), 3.20 (s,

Example  1.4.5. Diethyl  (3- Methoxyphenylthio ) Methylphosphonate  [1.4e]

Colorless oil; Yield: 86%; ^{1 H NMR (400 MHz, CDCl} 3): Yield: 86%; (D, J = 7.88, 7.84 Hz, 1H), 6.98-7.00 (m, 2H), 6.74-6.76 (m, 1H), 4.10-4.17 (m, 4H), 3.79 (s, 3H), 3.22 (s, IH), 3.18 (s, IH) 1.30 (t, J = 7.08 Hz, 6H)

Example  1.4.6. Diethyl  (4- Hydroxyphenylthio ) Methylphosphonate  [1.4f]

Yield: 78%; ^{1 H NMR (400 MHz, CDCl} 3): δ 7.37 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 4.19-4.10 (m, 4H), 3.06 (d, J = 12.8 Hz, 2H), 1.31 (t, J = 7.00 Hz, 6H)

Example  1.5. Synthesis of [1.5a] to [1.5d]

The following compounds [1.5a] to [1.5d] were synthesized according to Reaction Scheme 5 below.

<Reaction Scheme 5>

(1.0 eq) of the compound [1.4a] to [1.4f] synthesized in Example 1.4 was dissolved in methylene chloride and meta-chloroperoxybenzoic acid (mCPBA; 1 eq) was added at -20 ° C , And stirred at -20 [deg.] C for 2 hours. After the reaction was terminated with sodium sulfite, the reaction mixture was diluted with ethyl acetate and washed with a saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous Na ₂ SO ₄ and filtered. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate / n-hexane 1: 3) to give compounds [1.5a] to [1.5d] &Lt; / RTI &gt;

In the above Reaction Scheme 5, R is as shown in Table 2 below.

division R division R 1.5a 4'-CH ₃ 1.5c _{3'-OCH 3, 4'-OCH} 3 1.5b 4'-OCH ₃ 1.5d 4'-OH

Example  1.5.1. Diethyl (4- Methylphenylsulfinyl ) Methylphosphonate  [1.5a]

Colorless oil; Yield: 82.6%; Rf = 0.2 (hexane / EtOAc 1/1); ^{1 H NMR (400 MHz, CDCl} 3): δ 7.65 (d, J = 8Hz, 2H), 7.35 (d, J = 8Hz, 2H), 4.22-4.08 (m, 4H), 3.46 (t, J = 14.4 1H), 3.32 (t, J = 14.4Hz, 1H), 2.42 (s, 3H), 1.35-1.32

Example  1.5.2. Diethyl (4- Methoxyphenylsulfinyl ) Methylphosphonate  [1.5b]

Colorless oil; Yield: 98.2%; Rf = 0.3 (EtOAc); ^{1 H NMR (400 MHz, CDCl} 3): δ 7.68 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 4.17-4.10 (m, 4H), 3.86 (s, 3H ), 3.42-3.23 (m, 2H), 1.33-1.27 (m, 6H)

Example  1.5.3. Diethyl (3,4- Dimethoxyphenylsulfinyl ) Methylphosphonate  [1.5c]

Colorless oil; Yield: 92.3%; Rf = 0.2 (hexane / EtOAc 1/1); ¹ H NMR (400 MHz, CDCl ₃ ):? 7.32 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 8.3 Hz, 2.0 Hz, , 4.21-4.07 (m, 4H), 3.95 (d, J = 8.4 Hz, 6H), 3.43 (t, J = 14.6 Hz, 1H) m, 6H)

Example  1.5.4. Diethyl (4- Hydroxyphenylsulfinyl ) Methylphosphonate  [1.5d]

Colorless oil; Yield: 74%; ^{1 H NMR (400 MHz, CDCl} 3): δ 7.52 (d, J = 8.72 Hz, 2H), 6.92 (d, J = 8.68 Hz, 2H), 4.14-4.00 (m, 4H), 3.46 (t, J = 22.06 Hz, 1H), 3.29 (t, J = 14.94 Hz, 1H), 1.27-1.19 (m, 6H); ^{13 C NMR (400 MHz, CDCl} 3): δ 161.0, 132.4, 126.4, 116.4, 63.0, 54.5

Example  1.6. Synthesis of [1.6a] to [1.6d]

The following compounds [1.6a] to [1.6d] were synthesized according to the following Reaction Scheme 6.

<Reaction Scheme 6>

Compound [1.5a] to [1.5d] (1.0 eq) synthesized in Example 1.5 above was dissolved in tetrahydrofuran (THF) under nitrogen gas and 2.0 M BuLi (1.0 eq) was added dropwise at -78 ° C , And stirred for 1 hour. While maintaining the temperature at -78 ° C, the compound (1.0 eq) synthesized in Example 1.3 dissolved in THF was added dropwise to the reaction solution, followed by stirring for 1 hour. When the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and filtered, and the filtrate was distilled under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate / n-hexane 1: 4) to give compounds [1.6a] to [1.6d] .

In Scheme 6, isomers and R are shown in Table 3 below.

division R Isomer division R Isomer 1.6a 4'-CH ₃ Z 1.6c 4'-OCH ₃ E 1.6b 4'-OCH ₃ Z 1.6d _{3'-OCH 3, 4'-OCH} 3 Z

Example  1.6.1. (Z) -triisopropyl (4- (para- Methylphenylsulfinyl ) -3- Tennyloxy ) Silane [1.6a]

Yield: 61.3%; Rf = 0.6 (hexane / EtOAc 3/1); ^{1 H NMR (400 MHz, CDCl} 3): δ 7.51 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 6.35-6.26 (m, 2H), 3.86-3.80 (m 2H), 2.86-2.79 (m, 2H), 2.40 (s, 3H), 1.13-1.03 (m,

Example  1.6.2. (Z) -triisopropyl (4- (para- Methoxyphenylsulfinyl ) -3- Tennyloxy Silane [1.6b]

Yield: 44.9%; Rf = 0.3 (hexane / EtOAc 2/1); ^{1 H NMR (400 MHz, CDCl} 3): δ 7.56 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.31-6.28 (m, 2H), 3.85-3.79 (m , 5H), 2.82-2.78 (m, 2H), 1.11-1.00 (m, 21H)

Example  1.6.3. (E) -triisopropyl (4- (para- Methoxyphenylsulfinyl ) -3- Tennyloxy ) Silane [1.6c]

Yield: 21.5%; Rf = 0.3 (hexane / EtOAc 2/1); ^{1 H NMR (400 MHz, CDCl} 3): δ 7.56 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 6.61 (dt, J = 15.2, 7.0 Hz, 1H), (D, J = 15.0,1.0 Hz, 1H), 3.83 (s, 3H), 3.80 (t, J = 3.2 Hz, 5H), 2.46 (q, J = 6.6 Hz, 2H), 1.08-1.04 , 21H)

Example  1.6.4. (Z) -triisopropyl (4- (3,4- Dimethoxyphenylsulfinyl ) -3- Tennyloxy ) Silane [1.6d]

Yield: 69%; Rf = 0.35 (hexane / EtOAc 1/1); ^{1 H NMR (400 MHz, CDCl} 3): δ 7.24 (. M 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.35-6.31 (m, 2H ), 3.94 (d, J = 8.6 Hz, 6H), 3.84 (t, J = 6.2 Hz, 2H), 3.88-2.76 (m, 2H), 1.12-1.05

Example  1.7. Synthesis of [1.7a] to [1.7d]

The following compounds [1.7a] to [1.7d] were synthesized according to the following Reaction Scheme 7.

<Reaction Scheme 7>

Compound [1.6a] to [1.6d] (1.0 eq) synthesized in Example 1.6 was dissolved in tetrahydrofuran, and 1 M tetra-n-butylammonium fluoride (TBAF) (1.0 eq) , And the mixture was stirred at room temperature for 3 hours. When the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water and brine, and then the organic layer was dried with anhydrous Na ₂ SO ₄ and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (MeOH / CH ₂ Cl ₂ 9: 1) to give compounds [1.7a] to [1.7d].

In Scheme 7, isomers and R are shown in Table 4 below.

division R Isomer division R Isomer 1.7a 4'-CH ₃ Z 1.7c 4'-OCH ₃ E 1.7b 4'-OCH ₃ Z 1.7d _{3'-OCH 3, 4'-OCH} 3 Z

Example  1.7.1. (Z) -4- (para- Methylphenylsulfinyl ) -3-buten-l-ol [1.7a]

Yield: 76.9%; Rf = 0.23 (hexane / EtOAc 1/3); ^{1 H NMR (400 MHz, CDCl} 3): δ 7.54 (d, J = 8.4 Hz, 2H), 6.35-6.25 (m, 2H), 3.81-3.74 (m, 2H), 2.80-7.74 (m, 1H) , 2.94-2.87 (m, 1 H), 2.41 (s, 3 H)

Example  1.7.2. (Z) -4- (para- Methoxyphenylsulfinyl ) -3-buten-l-ol [1.7b] &lt;

Yield: 80.9%; Rf = 0.3 (EtOAc); ^{1 H NMR (400 MHz, CDCl} 3): δ 7.58 (d, J = 9.6 Hz, 2H), 6.99 (d, J = 9.6 Hz, 2H), 6.33-6.24 (m, 2H), 3.88-3.75 (m , 5H), 2.89-2.60 (m, 2H), 2.61 (br, IH)

Example  1.7.3. (E) -4- (para- Methoxyphenylsulfinyl ) -3-buten-l-ol [1.7c] &lt;

Yield: 77%; Rf = 0.3 (EtOAc); ^{1 H NMR (400 MHz, CDCl} 3): δ 7.54 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.58 (dt, J = 15.2, 7.0 Hz, 1H), 2H), 2.96 (br, IH), 2.46 (q, J = 6.4 Hz, 2H), 3.79 (d, J = )

Example  1.7.4. (Z) -4- (3,4- Dimethoxyphenylsulfinyl ) -3-buten-l-ol [1.7d] &lt;

Yield: 86.1%); Rf = 0.2 (hexane / EtOAc 1/5); ^{1 H NMR (400 MHz, CDCl} 3): δ 7.27-7.19 (m, 1H), 7.19-7.16 (m, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.36 (d, J = 9.8 Hz 2H), 2.79-2.29 (m, 2H), 3.93 (d, J = 6.2 Hz, 6H), 3.83-3.78

Example  1.8. [1.8a] to [1.8d] Synthesis

The following compounds [1.8a] to [1.8d] were synthesized according to the following Reaction Scheme 8.

<Reaction Scheme 8>

(1.2 eq), tetramethylpropylenediamine (TMPDA; 0.2 eq), TsCl (1.2 eq) were dissolved in acetonitrile and the compounds [1.7a] to [1.7d] eq) in that order, followed by stirring at room temperature for 3 hours. When the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with a saturated sodium bicarbonate aqueous solution and water, and then the organic layer was dried with anhydrous Na ₂ SO ₄ and filtered. The solvent was distilled off under reduced pressure, and the residue was dissolved in DMF. Sodium azide (2.0 eq) was added thereto, followed by stirring at room temperature for 3 hours. When the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water and brine, and then the organic layer was dried with anhydrous Na ₂ SO ₄ and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / n-hexane 2: 1) to give compounds [1.8a] to [1.8d].

In Scheme 8, isomers and R are as shown in Table 5 below.

division R Isomer division R Isomer 1.8a 4'-CH ₃ Z 1.8c 4'-OCH ₃ E 1.8b 4'-OCH ₃ Z 1.8d _{3'-OCH 3, 4'-CH} 3 Z

Example  1.8.1 &lt; RTI ID = 0.0 &gt; (Z) -1- (para- A leadership -One- Decenylsulphinyl ) -4-methylbenzene [1.8a]

Yield: 94.1%; Rf = 0.2 (hexane / EtOAc 5/1); ^{1 H NMR (400 MHz, CDCl} 3): δ 7.54 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8 Hz, 2H), 6.37-6.33 (m, 1H), 6.21-6.14 (m (M, 2H), 2.41 (s, 3H), &lt; RTI ID =

Example  1.8.2. (Z) -1- (para- A leadership -One- Decenylsulphinyl )-4- Methoxybenzene  [1.8b]

Yield: 89.1%; Rf = 0.2 (hexane / EtOAc 1/1); ^{1 H NMR (400 MHz, CDCl} 3): δ 7.59 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.35 (dd, J = 9.6, 0.8 Hz, 1H), 2H), 2.87-2.82 (m, 2H), 3.85 (d, J = 10.0, 7.6 Hz,

Example  1.8.3. (E) -1- (para- A leadership -One- Decenylsulphinyl )-4- Methoxybenzene  [1.8c]

Yield: 94%; Rf = 0.2 (hexane / EtOAc 1/1); ^{1 H NMR (400 MHz, CDCl} 3): δ 7.56 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.54 (dt, J = 14.8, 6.9 Hz, 1H), (Dt, J = 15.2,1.4 Hz, 1H), 3.85 (s, 3H), 3.43 (t, J = 6.8 Hz, 2H), 2.52

Example  1.8.4. (Z) -1- (para- A leadership -One- Decenylsulphinyl ) -3,4- Dimethoxybenzene  [1.8d]

Yield: 83.3%; Rf = 0.4 (hexane / EtOAc 3/1); ^{1 H NMR (400 MHz, CDCl} 3): δ 7.25 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 8.3 Hz, 2.0 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H) , 6.39 (dt, J = 9.7 Hz, 1.3 Hz, IH), 6.19-6.13 (m, IH), 3.95 (d, J = 7.3 Hz, 6H), 3.58-3.52 m, 1 H), 2.90 - 2.84 (m, 2 H)

Example  1.9 Synthesis of [Compound 1] to [Compound 4]

[Compound 1] to [Compound 4] were synthesized according to the following Reaction Scheme 9.

<Reaction Scheme 9>

The compound [1.8a] to [1.8d] (1.0 eq) synthesized in Example 1.8 was dissolved in ethanol, ammonium chloride (6.0 eq) dissolved in water and zinc dust (3.0 eq) The mixture was stirred at room temperature for 5 hours. The reaction was terminated with a saturated aqueous ammonia solution and then filtered through celite to remove zinc dust. The filtrate was distilled under reduced pressure, and the resulting residue was purified by column chromatography (MeOH / CH ₂ Cl ₂ 1: 9) to obtain the compounds [Compound 1] to [Compound 4].

In Scheme 9, isomers and R are as shown in Table 6 below.

division R Isomer division R Isomer Compound 1E 4'-CH ₃ Z Compound 3 4'-OCH ₃ E Compound 2 4'-OCH ₃ Z Compound 4 _{3'-OCH 3, 4'-OCH} 3 Z

Example  1.9.1 &lt; RTI ID = 0.0 &gt; (Z) -4- (para- Methylphenylsulfinyl ) -3-butene-1-amine [Compound 1]

Yield: 85%; _{Rf = 0.25 (CH 2 Cl 2} / MeOH 9/1); ^{1 H NMR (400 MHz, MeOD} ): δ 7.51 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 6.39 (d, J = 10.0 Hz, 1H), 6.29-6.23 (m, 1H), 2.85-2.76 (m, 2H), 2.75-2.56 (m, 2H), 2.72 (s, 3H); ¹³ C NMR (100 MHz, MeOD):? 143.8, 140.9, 139.7, 138.4, 131.5, 125.7, 39.8, 30.9, 28.5, 21.4

Example  1.9.2. (Z) -4- (para- Methoxyphenylsulfinyl ) -3-butene-1-amine [Compound 2]

Yield: 86.1; _{Rf = 0.25 (CH 2 Cl 2} // MeOH 9/1); ^{1 H NMR (400 MHz, DMSO} -d 6): δ 8.27 (br, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 9.2 Hz, 2H), 6.38 (d, J = 10.0 Hz, 1 H), 6.39-6.19 (m, 1 H), 3.81 (s, 3 H), 2.88 - 2.80 (m, 4 H); ¹³ C-NMR (100 MHz, MeOD):? 164.2, 139.8, 137.9, 134.9, 127.9, 116.5, 56.3, 39.7, 28.4

Example  1.9.3. (E) -4- (para- Methoxyphenylsulfinyl ) -3-butene-1-amine [Compound 3]

Yield: 90.6%; _{Rf = 0.25 (CH 2 Cl 2} // MeOH 9/1); ^{1 H NMR (400 MHz, DMSO} -d 6): δ 7.57 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 15.2 Hz, 1H), J = 7.0 Hz, 2H), 2.51 (q, J = 7.2 Hz, 2H); ¹³ C-NMR (100 MHz, MeOD):? 164.3, 138.2, 135.6, 134.6, 128.6, 116.3, 56.3, 39.5, 30.9

Example  1.9.4. (Z) -4- (3,4- Dimethoxyphenylsulfinyl ) -3-butene-1-amine [Compound 4]

Yield: 76%; _{Rf = 0.25 (CH 2 Cl 2} // MeOH 9/1); ^{1 H NMR (400 MHz, MeOD} ): δ 7.23 (d, J = 2.0Hz, 1H), 7.22 (d, J = 2.9Hz, 1H), 7.05 (d, J = 8.0Hz, 1H), 6.46 (m , 6.22 (m, 1H), 3.81 (d, J = 6.2 Hz, 6H), 3.04 (t, J = 7.6 Hz, 2H), 2.90-2.80 (m, 2H); ¹³ C NMR (100 MHz, MeOD):? 153.6, 151.7, 139.9, 137.8, 135.3, 119.7, 113.2, 108.4, 56.7

Example  2. Synthesis of [Compound 5] to [Compound 9]

[Compound 5] to [Compound 9] were synthesized according to the following Reaction Scheme 10.

<Reaction formula 10>

Compound [1.5b] (1.0 eq) synthesized in Example 1.5 was dissolved in THF under nitrogen gas, 2.0 M BuLi (1.0 eq) was added dropwise at -78 째 C, and the mixture was stirred for 1 hour. Various benzaldehyde (1.0 eq) was added dropwise to the reaction solution while keeping the temperature at -78 ° C, and the mixture was stirred for 1 hour. When the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and filtered, and the filtrate was distilled under reduced pressure. The residue was purified by column chromatography (ethyl acetate / n-hexane 1: 4) to give the compound [Compound 5] to [Compound 9] .

In Scheme 10, isomers and R are as shown in Table 7 below.

division R Isomer division R Isomer Compound 5 2'-Cl E Compound 8 2'-CF ₃ E Compound 6 2'-Cl Z Compound 9 2'-CF ₃ Z Compound 7 2'-NH ₃ Cl E

Example  2.1. (E) -1- Chloro -2- (2- (4- Methoxyphenylsulfinyl ) Vinyl) benzene [Compound 5]

Yield: 52%; ^{1 H NMR (400 MHz, CDCl} 3): δ 7.75 (d, J = 15.5 Hz, 1H) 7.62-7.66 (m, 2H), 7.40-7.50 (m, 2H), 7.21-7.30 (m, 2H), 2H), 6.86 (d, J = 15.5 Hz, 1H), 3.85 (s, 3H)

Example  2.2. (Z) -1- Chloro -2- (2- (4- Methoxyphenylsulfinyl ) Vinyl) benzene [Compound 6]

Yield: 24%; ^{1 H NMR (400 MHz, CDCl} 3): δ 7.65-7.68 (m, 1H), 7.55-7.58 (m, 2H), 7.26-7.46 (m, 4H), 7.03 (d, J = 8.7 Hz, 2H) , 6.59 (d, J = 10.4 Hz, IH), 3.86 (s, 3H)

Example  2.3. (E) -2- (2- (4- Methoxyphenylsulfinyl ) Vinyl) aniline Hydrochloride  [Compound 7]

(E) -2- (2- (4-methoxyphenylsulfinyl) vinyl) aniline was synthesized by the method of Scheme 9 and dissolved in EtOAc. 4 M HCl (2 eq) was added dropwise, To give [Compound 7].

Yield: 48%; ^{1 H NMR (400 MHz, CDCl} 3): δ 7.64-7.69 (m, 3H), 7.51 (d, J = 15.2 Hz, 1H) 7.22-7.35 (m, 3H), 7.14 (d, J = 8.6 Hz, 2H), 7.03-7.10 (m, 1 H), 3.82 (s, 3 H)

Example  2.4. (E) -1- (2- (4- Methoxyphenylsulfinyl ) Vinyl) -2- ( Trifluoromethyl ) Benzene [Compound 8]

Yield: 22%; ^{1 H NMR (400 MHz, CDCl} 3): 1H NMR (400 MHz, CDCl3): δ 7.73 (dd, J = 1.80, 15.36Hz, 1H), 7.69 (d, J = 8.16Hz, 1H), 7.62 (d J = 8.72 Hz, 2H), 6.79 (d, J = 15.24 Hz, 2H), 7.50-7.57 (m, 2H), 7.44 , &Lt; / RTI &gt; 1H), 3.85 (s, 3H)

Example  2.5. (Z) -1- (2- (4- Methoxyphenylsulfinyl ) Vinyl) -2- ( Trifluoromethyl ) Benzene [Compound 9]

Yield: 28%; ^{1 H NMR (400 MHz, CDCl} 3): δ 7.73 (t, J = 8.08Hz, 2H), 7.65 (t, J = 7.41Hz, 1H), 7.49-7.55 (m, 3H), 7.38 (dd, J = 2.32, 10.36 Hz, 1H), 7.01 (d, J = 8.84 Hz, 2H), 6.61 (d, J = 10.32 Hz,

Example  3.1. Synthesis of [3.1a] to [3.1d]

[3.1a] to [3.1d] were synthesized according to Reaction Scheme 11 below.

<Reaction Scheme 11>

The compounds [1.4a] to [1.4f] (1.0 eq) synthesized in Example 1.4 were dissolved in methylene chloride, mCPBA (2.2 eq) was added at 0 占 폚, and the mixture was stirred at room temperature for 2 hours. After the reaction was terminated with sodium sulfite, the reaction mixture was diluted with ethyl acetate and washed with a saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous Na ₂ SO ₄ and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate / n-hexane 1: 1 to 1: 3) [3.1d].

In Scheme 11, isomers and R are as shown in Table 8 below.

division R division R 3.1a 2'-OCH ₃ 3.1c 4'-OCH ₃ 3.1b 3'-OCH ₃ 3.1d 4'-OH

Example  3.1.1 Diethyl  (2- Methoxyphenylsulfonyl ) Methylphosphonate  [3.1a]

Yield: 95%; ¹ H NMR (400 MHz, CDCl ₃ )? 7.96 (dd, J = 1.68,7.84 Hz, 1H), 7.60 (ddd, J = 1.72, (d, J = 8.32 Hz, 1H), 4.07-4.15 (m, 4H), 4.06 (s, IH), 4.02 (s, )

Example  3.1.2. Diethyl  (2- Methoxyphenylsulfonyl ) Methylphosphonate  [3.1b]

Yield: 95%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.51 (d, J = 7.72Hz, 1H), 7.40-7.44 (m, 2H), 7.13 (dd, J = 2.60, 8.28Hz, 1H), 4.08-4.26 (m (S, 3H), 3.82 (s, 3H), 3.75 (s,

Example  3.1.1. Diethyl  (2- Methoxyphenylsulfonyl ) Methylphosphonate  [3.1c]

Yield: 96%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.92 (d, J = 8.92Hz, dH), 7.02 (d, J = 8.92Hz, 2H), 4.13-4.21 (m, 4H), 3.88 (s, 3H), 1H), 3.74 (s, 1H), 1.31 (t, J = 7.04 Hz, 6H)

Example  3.1.1. Diethyl  (2- Hydroxyphenylsulfonyl ) Methylphosphonate  [3.1d]

Yield: 80%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.80 (d, J = 8.76Hz, 2H), 6.76 (d, J = 8.76Hz, 2H), 4.25-4.19 (m, 4H), 3.82 (d, J = 16.68 Hz, 2H), 1.37 (t, J = 7.04 Hz, 6H); ¹³ C NMR (400 MHz, CDCl 3)? 162.6, 130.8, 130.7, 129.0, 116.0, 64.0, 16.2

Example 3.2. tert - butyl synthesis of 3-oxo-propyl carbamate

Tert-butyl 3-oxopropylcarbamate was synthesized according to the following Reaction Scheme 12.

<Reaction Scheme 12>

(2.0 M in CH ₂ Cl ₂ , 1.2 eq, 3.43 ml, 6.85 mmol) was added to the reactor, which was then dissolved in methylene chloride (0.425 M, 13.43 ml) . After sufficiently lowering the reaction temperature at -78 ° C, anhydrous dimethyl sulfoxide (3.6 eq, 1.46 ml, 20.55 mmool) was added and stirred for 30 minutes. Thereafter, a commercially available reagent, tert-butyl 3-hydroxypropyl carbazole Mate (1 g, 5.71 mmol) was added thereto, followed by stirring for 30 minutes. Triethylamine (7.2 eq, 5.73 ml, 41.112 mmol) was added to the reaction mixture, and the mixture was slowly added dropwise over 10 minutes, followed by stirring for another 15 minutes. The reaction mixture was cooled to room temperature and extracted with methylene chloride and water. The organic layer was dried over anhydrous MgSO ₄ to remove a small amount of water. The solvent was removed by distillation under reduced pressure, and the residue was vacuum dried without separation and purification by column chromatography. To obtain an oily compound (916 mg).

Crude yield: 93%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 9.76 (s, 1H), 4.88 (brs, 1H), 3.37 (q, J = 5.96Hz, 5.98Hz, 2H), 2.66 (t, J = 5.8Hz, 2H) , 1.38 (s, 9H)

Example  3.3. (E) - tert -Butyl 2- (4- (4- Methoxyphenylsulfonyl ) Butte -3- Enil Mamino ) Acetate

Example 3.3 was synthesized according to Scheme 13 below.

<Reaction Scheme 13>

[3.1c] (1 eq, 0.62 g, 1.43 mmol) synthesized in Example 3.1 was dissolved in anhydrous THF (0.1 M, 14.3 ml) and then cooled to -78 ° C using dry ice and acetone . (1.2 eq, 2.0 M in cyclohexane, 0.86 ml, 1.7162 mmol) was slowly added dropwise to the solution, and the mixture was stirred for 1 hour to obtain tert-butyl 3-oxopropyl carbamate [ 12] (1.2 eq, 0.30 g, 1.72 mmol) was added thereto, followed by further reaction for 1 hour. After completion of the reaction with a small amount of water, the reaction mixture was extracted with water and 10% MeOH / CH ₂ Cl _{2. The} organic layer was washed with anhydrous MgSO 4 to remove a small amount of water, distilled under reduced pressure, and the solvent was removed. Thereafter, the product was separated and purified by column chromatography using 50% EtOAc / Hexane and 100% EtOAc and 10% MeOH / CH ₂ Cl ₂ to obtain a transparent oily compound.

Yield: 71%; ^{1 H NMR (400MHz, MeOD)} δ 7.78 (d, J = 8.9 Hz, 2H), 6.98 (d, J = 8.9 Hz, 2H), 6.85 (dt, J = 7.3 Hz, 15.1 Hz, 1H), 6.36 ( 2H), 1.41 (s, 9H) (including 10% of Z isomers), 3.40 (s, 3H)

Example  3.4 (E) -4- (4- Methoxyphenylsulfonyl ) Butte -3-en-1-amine Hydroclaw De [ Compound 10 ] Synthesis of

[Compound 10] was synthesized according to the following Reaction Scheme 14.

<Reaction Scheme 14>

The compound synthesized in Example 3.3 was dissolved in EtOAc, excess HCl (4.0 M in 1,4-dioxane) was added, and the reaction was allowed to proceed at room temperature for 2 hours. The formed precipitate was washed several times with hexane and EtOAc Filtration was conducted to obtain a white solid compound [Compound 10].

Yield: 89%; ^{1 H NMR (400MHz, DMSO-} d 6) δ 8.06 (brs, 3H), 7.79 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H), 6.80-6.89 (m, 2H ), 3.87 (s, 3H), 2.89-2.96 (m, 2H), 2.50-2.57

Example  4. Synthesis of [Compound 11] to [Compound 26]

[Compound 11] to [Compound 26] were synthesized according to the following Reaction Scheme 15.

<Reaction Scheme 15>

[3.1a] to [3.1c] (1eq) synthesized in Example 3.1 were dissolved in anhydrous THF (0.1 M) and then cooled to -78 ° C using dry ice and acetone. n-BuLi (1.05 eq, 2.0 M in cyclohexane) was slowly added dropwise to the solution, stirred for 1 hour, and each benzylaldehyde (1.1 eq) was added thereto and reacted for another 1 hour. After the reaction was completed with a small amount of water, the reaction mixture was extracted with water and EtOAc. The organic layer was washed with anhydrous Na ₂ SO ₄ to remove a small amount of water, distilled under reduced pressure, and the solvent was removed. Thereafter, the reaction mixture was separated and purified by column chromatography using EtOAc: Hex to obtain the compounds [11] to [26].

In Scheme 15, isomers and R are as shown in Table 9 below.

division R ₁ R division R ₁ R Compound 11 4'-OMe 2'-F Compound 19 3'-OMe 2'-CF ₃ Compound 12 4'-OMe 3'-F Compound 20 3'-OMe 3'-CF ₃ Compound 13 4'-OMe 4'-F Compound 21 2'-OMe 2'-CF ₃ Compound 14 4'-OMe 2'-Cl Compound 22 2'-OMe 3'-CF ₃ Compound 15 4'-OMe 4'-Cl Compound 23 2'-OMe 4'-CF ₃ Compound 16 4'-OMe 2'-CF ₃ Compound 24 2'-OMe 2'-F Compound 17 4'-OMe 3'-CF ₃ Compound 25 2'-OMe 3'-F Compound 18 4'-OMe 4'-CF ₃

Example  4.1. (E) -1- Fluoro -2- (2- (4- Methoxyphenylsulfonyl ) Vinyl) benzene [Compound 11]

Yield: 73.9%; ¹ H NMR (400 MHz, CDCl ₃ )? 7.88 (d, J = 8.96 Hz, 2H), 7.71 7.01 (d, J 8.96 Hz, 2H), 7.00 (d, 15.56 (d, J = Hz, &lt; / RTI &gt; 1H), 3.88 (s, 3H)

Example  4.2. (E) -1- Fluoro -3- (2- (4- Methoxyphenylsulfonyl ) Vinyl) benzene [Compound 12]

Yield: 85.3%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.87 (d, J = 8.92Hz, 2H), 7.58 (d, J = 15.40Hz, 1H), 7.36 (m, J = 1.6, 1H), 7.17-7.26 (m , 7.16 (dt, J = 2.08, 9.4 Hz, 1H), 7.10 (td, J = 2.48, 8.00 Hz, 1H), 7.01 ), 3.88 (s, 3H)

Example  4.3. (E) -1- Fluoro -4- (2- (4- Methoxyphenylsulfonyl ) Vinyl) benzene [Compound 13]

Yield: 83.4%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.86 (d, J = 8.84Hz, 2H), 7.59 (d, J = 15.4Hz, 1H), 7.46 (dd, J = 5.28, 8.8Hz, 2H), 7.07 ( J = 8.6 Hz, 2H), 7.01 (d, J = 8.88 Hz, 2H), 6.77 (d, J = 15.36 Hz,

Example  4.4. (E) -1- Chloro -2- (2- (4- Methoxyphenylsulfonyl ) Vinyl) benzene [Compound 14]

Yield: 75.7%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.03 (d, J = 15.44Hz, 1H), 7.89 (d, J = 9.00Hz, 2H), 7.50 (dd, J = 1.72, 7.76Hz, 1H), 7.43 ( (dd, J = 1.28,8 Hz, 1H), 7.33 (td, J = 1.68,7.40 Hz, 1H), 7.26 (td, J = 1.00, 7.44 Hz, 1H) (d, 15.64 Hz, 1 H), 3.88 (s, 3 H)

Example  4.5 (E) -1- Chloro -4- (2- (4- Methoxyphenylsulfonyl ) Vinyl) benzene [Compound 15]

Yield: 67.3%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.88 (d, J = 8.96Hz, 2H), 7.64 (d, J = 15.28Hz, 1H), 7.64 (d, J = 8.44Hz, 2H), 7.58 (d, J = 8.28 Hz, 2H), 7.02 (d, J = 8.92 Hz, 2H), 6.93 (d, J = 15.52 Hz,

Example  4.6. (E) -1- (2- (4- Methoxyphenylsulfonyl ) Vinyl) -2- ( Trifluoromethyl ) Benzene [Compound 16]

Yield: 73.5%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.98 (dd, J = 2, 15.2Hz, 1H), 7.88 (d, J = 8.88Hz, 2H), 7.71 (d, J = 7.56Hz, 1H), 7.48- 2H), 6.82 (d, J = 15.24 Hz, 1H), 3.88 (s, 3H)

Example  4.7. (E) -1- (2- (4- Methoxyphenylsulfonyl ) Vinyl) -3- ( Trifluoromethyl ) Benzene [compound 17]

Yield: 86.6%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.88 (d, J = 8.96Hz, 2H), 7.71 (s, 1H), 7.65 (d, J = 15.36Hz, 1H), 7.63-7.66 (m, 2H), J = 7.72 Hz, 1H), 7.02 (d, J = 9 Hz, 2H), 6.92 (d, J = 15.48 Hz, 1H), 3.88 3H)

Example  4.8. (E) -1- Methoxy -4- (4- ( Trifluoromethyl ) Styrylsulfonylbenzene  [Compound 18]

Yield: 87.6%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.88 (d, J = 8.92Hz, 2H), 7.64 (d, J = 15.32Hz, 1H), 7.64 (d, J = 8.41Hz, 2H), 7.58 (d, J = 8.24 Hz, 2H), 7.02 (d, J = 8.92 Hz, 2H), 6.93 (d, J = 15.44 Hz,

Example  4.9. (E) -1- (2- (3- Methoxyphenylsulfonyl ) Vinyl) -2- ( Trifluoromethyl ) Benzene [Compound 19]

Yield: 72%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.85-7.94 (m, 3H), 7.68-7.74 (m, 1H), 7.46-7.56 (m, 3H), 6.96-7.05 (m, 2H), 6.84 (d, J = 15.2 Hz, 1 H), 3.86 (s, 3 H)

Example  4.10. (E) -1- (2- (3- Methoxyphenylsulfonyl ) Vinyl) -3- ( Trifluoromethyl ) Benzene [Compound 20]

Yield: 74%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.83-7.95 (m, 3H), 7.67-7.74 (m, 1H), 7.46-7.56 (m, 3H), 6.96-7.04 (m, 2H), 6.84 (d, J = 15.2 Hz, 1 H), 3.87 (s, 3 H)

Example  4.11. (E) -1- (2- (2- Methoxyphenylsulfonyl ) Vinyl) -2- ( Trifluoromethyl ) Benzene [Compound 21]

Yield: 81%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.82-7.92 (m, 3H), 7.72 (d, J = 7.6 Hz, 1H), 7.48-7.59 (m, 3H), 6.95-7.03 (m, 2H), 6.83 (d, J = 15.2 Hz, 1 H), 3.87 (s, 3 H)

Example  4.12. (E) -1- (2- (2- Methoxyphenylsulfonyl ) Vinyl) -3- ( Trifluoromethyl ) Benzene [Compound 22]

Yield: 79%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.82-7.92 (m, 3H), 7.72 (d, J = 7.6 Hz, 1H), 7.48-7.59 (m, 3H), 6.95-7.03 (m, 2H), 6.83 (d, J = 15.2 Hz, 1 H), 3.87 (s, 3 H)

Example  4.13. (E) -1- (2- (2- Methoxyphenylsulfonyl ) Vinyl) -4- ( Trifluoromethyl ) Benzene [Compound 23]

Yield: 78%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.82-7.92 (m, 3H), 7.72 (d, J = 7.6 Hz, 1H), 7.48-7.59 (m, 3H), 6.95-7.03 (m, 2H), 6.83 (d, J = 15.2 Hz, 1 H), 3.87 (s, 3 H)

Example  4.14. (E) -1- Fluoro -2- (2- (2- Methoxyphenylsulfonyl ) Vinyl) benzene [Compound 24]

Yield: 73%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.87 (d, J = 8.96Hz, 2H), 7.71 (d, J = 15.56Hz, 1H), 7.45 (dd, J = 1.6, 7.56Hz, 1H), 7.08- 7.01 (d, 8.96 Hz, 2H), 7.00 (d, 15.56 (d, J = Hz, &lt; / RTI &gt; 1H), 3.88 (s, 3H)

Example  4.15. (E) -1- Fluoro -3- (2- (2- Methoxyphenylsulfonyl ) Vinyl) benzene [Compound 25]

Yield: 81%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.82-7.92 (m, 3H), 7.72 (d, J = 7.6 Hz, 1H), 7.48-7.59 (m, 3H), 6.95-7.03 (m, 2H), 6.83 (d, J = 15.2 Hz, 1 H), 3.87 (s, 3 H)

Example  5.1. 3- Morpholinopropyl Methanesulfonate  synthesis

Example 5.1 was synthesized according to Scheme 16 below.

<Reaction Scheme 16>

To the reactor was added 4- (3-hydroxypropyl) morpholine (1 eq, 4.76 ml, 34.43 mmol), a commercially available reagent, dissolved in methylene chloride (0.12 M, 280 ml), and triethylamine 1.2 eq, 5.76 ml, 41.32 mmol) and methanesulfonyl chloride (1.2 eq, 3.2 ml, 41.32 mmol) were added at 0 占 폚 and the reaction was allowed to proceed at room temperature for 1 hour. After extracting with 10% MeOH / CH ₂ Cl ₂ and water, the organic layer was dried over anhydrous MgSO ₄ to remove a small amount of water. The solvent was removed by distillation under reduced pressure, and the product was vacuum dried without separation and purification by column chromatography. To obtain a homogeneous compound (6.47 g).

Crude yield: 84%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 4.30 (t, J = 6.34Hz, 2H), 3.68 (t, J = 4.59Hz, 4H), 3.00 (s, 3H), 2.44 (t, J = 6.92Hz, 6H), 1.95-1.90 (m, 2H)

Example  5.2. Diethyl  (4- (3- Molypolynoproxis ) Phenylsulfinyl ) Methylphosphonate  synthesis

Example 5.2 was synthesized according to Scheme 17 below.

<Reaction Scheme 17>

The compound [1.5d] (1 eq, 0.52 g, 1.779 mmol) synthesized in Example 1.5 was dissolved in acetonitrile (0.05 M, 34 ml) and potassium carbonate (1.53 eq, 0.376 g, 2.718 mmol ) And the compound synthesized in Example 5.1 (1.53 eq, 0.607 g, 2.718 mmol) were added at room temperature and the mixture was refluxed at 82 ° C for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, extracted with water and 10% MeOH / CH ₂ Cl ₂ , and the organic layer was dried over anhydrous MgSO ₄ to remove a small amount of water. The solvent was removed by distillation under reduced pressure, followed by vacuum drying. Thereafter, the reaction mixture was separated and purified by column chromatography using 100% EtOAc and 10% MeOH / CH ₂ Cl ₂ to obtain a colorless transparent oily compound (0.73 g).

Colorless oil; Yield: 97%; ^{1 H NMR (400 MHz, MeOD} ): δ 7.63 (d, J = 8.86 Hz, 2H), 7.04 (d, J = 8.90 Hz, 2H), 4.04-3.96 (m, 6H), 3.62-3.49 (m, 2H), 2.42 (s, 4H), 2.13-2.06 (m, 2H), 1.22-1. 15 (m, 6H)

Example  5.3. Synthesis of [Compound 26] to [Compound 29]

[Compound 26] to [Compound 28] were synthesized according to the following Reaction Scheme 18.

<Reaction Scheme 18>

The compound (1 eq) synthesized in Example 5.2 was dissolved in anhydrous THF (0.1 M) and then cooled to -78 ° C using dry ice and acetone. n-BuLi (1.2 eq, 2.0 M in cyclohexane) was slowly added dropwise to the solution, stirred for 1 hour, and each benzylaldehyde (1.2 eq) was added thereto and reacted again for 1 hour. When the reaction was not completed while confirming TLC, the reaction was further continued at room temperature for 30 minutes. After completion of the reaction with a small amount of water, the reaction mixture was extracted with water and 10% MeOH / CH ₂ Cl _{2. The} organic layer was washed with anhydrous MgSO ₄ to remove a small amount of water, and the solvent was removed by vacuum distillation. Thereafter, the reaction mixture was separated and purified by column chromatography using EtOAc and 10% MeOH / CH ₂ Cl ₂ to obtain respective compounds. After dissolving each compound in ethyl acetate, excess HCl (4.0 M in 1,4-dioxane) was added and the reaction was allowed to proceed at room temperature for 2 hours. The formed precipitate was filtered while washing several times with hexane and ethyl acetate, Thereby obtaining the compounds [compounds 26] to [compound 28].

In Scheme 18, R is as shown in Table 10 below.

division R division R Compound 26 2'-F Compound 28 2'-CF ₃ Compound 27 2'-Cl Compound 29 2'-NH ₃ Cl

Example  5.3.1. (E) -4- (3- (4- (2- Fluorostyrylsulfinyl ) Phenoxy )profile) Morpholine  Hydrochloride [Compound 26]

Yield: 62%; ¹ H NMR (400 MHz, MeOD)? 7.69-7.72 (m, 2H), 7.55-7.66 (m, 1H), 7.49 (d, J = 15.48 Hz, 1H), 7.40-7.50 (M, 2H), 3.58 (d, J = 12.6 Hz, 2H), 7.31 (d, J = ), 3.39-3.44 (m, 2H), 3.18-3.24 (m, 2H), 2.28-2.33 (m, 2H); (Including 30% Z isomer)

Example  5.3.2. (E) -4- (3- (4- (2- Chlorostyrylsulfinyl ) Phenoxy )profile) Morpholine Ha Idrochloride [Compound 27]

Yield: 52%; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 13.36 (s, 1H), 7.75 (d, J = 15.5 Hz, 1H) 7.63-7.67 (m, 2H), 7.36-7.57 (m, 2H), 7.22-7.30 ( 2H), 3.99 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 4.02 (m, 2H), 3.50 (bd, J = 9.2 Hz, 2H), 3.22 (bs, 2H), 2.94 (bs, 2H), 2.52 (bs, 2H); (Including 20% Z isomer)

Example  5.3.3. (E) -4- (3- (4- (2- Trifluoromethylstyrylsulfinyl ) Phenoxy )profile) Morpholine Hydrochloride  [Compound 28]

Yield: 49%; ^{1 H NMR (400MHz, MeOD)} δ 7.69-7.84 (m, 3H), 7.54-7.67 (m, 4H), 7.18-7.23 (m, 3H), 4.23 (t, J = 5.8 Hz, 2H), 4.09- 2H), 3.79-3.85 (m, 2H), 3.57-3.60 (m, 2H), 3.39-3.44 (m, 2H) 3.22-3.25 (m, 2H) 2.30-2.36 (m, 2H); (Including 30% Z isomer)

Example  5.3.4. (E) -4- (3- (4- (2- Aminostyrylsulfinyl ) Phenoxy )profile) Morpholine Ha Idrochloride [Compound 29]

Yield: 43%; ^{1 H NMR (400MHz, MeOD)} δ 7.71-7.79 (m, 3H), 7.42-7.53 (m, 4H), 7.33 (d, J = 15.0 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H) , 4.20 (t, J = 5.7 Hz, 2H), 4.04-4.08 (m, 2H), 3.80 (t, J = 12.0 Hz, 2H) 3.40 (m, 2H), 3.15-3.21 (m, 2H), 2.27-2.32 (m, 2H)

Example  6.1. Diethyl  (4- (3- Molypolynoproxis ) Phenylsulfonyl ) Methylphosphonate  synthesis

Example 6.1 was synthesized according to Scheme 19 below.

<Reaction Scheme 19>

The compound [3.1d] (1 eq, 1.03 g, 3.34 mmol) synthesized in Example 3.1 was dissolved in acetonitrile (0.1 M, 34 ml) and potassium carbonate (0.6 eq, 0.692 g, 5.01 mmol ) And the compound (1.48 eq, 1.10 g, 4.95 mmol) synthesized in Example 5.1 were added at room temperature and refluxed at 82 ° C for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, extracted with water and 10% MeOH / CH ₂ Cl ₂ , and the organic layer was dried over anhydrous MgSO ₄ to remove a small amount of water. The solvent was removed by distillation under reduced pressure, followed by vacuum drying. Thereafter, the product was separated and purified by column chromatography using 100% EtOAc and 10% MeOH / CH ₂ Cl ₂ to obtain a white solid compound (1.41 g).

Yield: 97%; ^{1 H NMR (400MHz, MeOD)} δ 7.89 (d, J = 8.92Hz, 2H), 7.11 (d, J = 8.96Hz, 2H), 4.15-4.07 (m, 6H), 3.69 (t, J = 4.68Hz 2H), 2.48 (s, 4H), 2.02-1.99 (m, 2H), 1.26 (m, t, J = 7.0 Hz, 6H)

Example  6.2 (E) - tert -Butyl 4- (4- (3- Molypolynoproxis ) Phenylsulfonyl ) Butte -3- Nylcarbamate  synthesis

Example 6.2 was synthesized according to Scheme 20 below.

<Reaction Scheme 20>

(1 eq, 0.62 g, 1.43 mmol) synthesized in Example 6.1 and then anhydrous THF (0.1 M, 14.3 ml, ), And then cooled to -78 deg. C using dry ice and acetone. butyl-3-oxopropyl carbamate (1.2 eq, 2.0 M in cyclohexane, 0.86 ml, 1.7162 mmol) synthesized in Example 3.2 was slowly added dropwise to the solution and stirred for 1 hour. eq, 0.30 g, 1.72 mmol) was added thereto and reacted for another 1 hour. After completion of the reaction with a small amount of water, the reaction mixture was extracted with water and 10% MeOH / CH ₂ Cl _{2. The} organic layer was washed with anhydrous MgSO ₄ to remove a small amount of water, and the solvent was removed by vacuum distillation. Thereafter, the reaction mixture was separated and purified by column chromatography using 50% EtOAc / Hexane and 100% EtOAc and 10% MeOH / CH ₂ Cl ₂ to obtain a transparent oily compound (0.27 g).

Yield: 42%; ^{1 H NMR (400MHz, MeOD)} δ 7.81 (d, J = 8.92Hz, 2H), 7.12 (d, J = 8.96Hz, 2H), 6.88 (dt, J = 14.42Hz, 15.08Hz, 1H), 6.58 ( (t, J = 6.8 Hz, 2H), 2.57 (t, J = 2H), 2.50 (s, 4H), 2.46-2.41 (m, 2H), 2.07-2.00

Example  6.3 (E) -4- (4- (3- Molypolynoproxis ) Phenylsulfonyl ) Butte -3-en-1-amine Hydrochloride  Synthesis of [Compound 30]

[Compound 30] was synthesized according to the following Reaction Scheme 21.

<Reaction Scheme 21>

The compound synthesized in Example 6.2 was dissolved in EtOAc, excess HCl (4.0 M in 1,4-dioxane) was dropped, and the reaction was allowed to proceed at room temperature for 2 hours. The formed precipitate was washed several times with hexane and EtOAc Filtration gave the white solid compound [Compound 30] (0.2 g).

Yield: 77%; ^{1 H NMR (400MHz, DMSO-} d 6) δ 11.24 (brs, 1H), 8.04 (brs, 3H), 7.80 (d, J = 8.84Hz, 2H), 7.17 (d, J = 8.84Hz, 2H), (T, J = 5.90 Hz, 2H), 3.89 (brd, J = 10.80 Hz, 2H), 3.83 (brt, J = 11.92 Hz, 2H), 3.45 2H), 3.31-3.22 (m, 2H), 3.16-3.02 (m, 2H), 2.99-2.88 (m, 2H), 2.57-2.54 (m, 2H), 2.31-2.17 m, 2H)

Example  6.4. (E) -N- (4- (4- (3- Molypolynoproxis ) Phenylsulfonyl ) -3- Tenil Acetamide  Synthesis of [Compound 31]

[Compound 31] was synthesized according to the following Reaction Scheme 22.

<Reaction Formula 22>

(E) -4- (4- (3-morpholinopropoxy) phenylsulfonyl) but-3-en-1- amine hydrochloride [Compound 30] (1 eq, 20 mg , 0.05 mmol) was added and the mixture was dissolved in MC (0.1 M, 0.47 mL). To the solution was slowly added dropwise triethylamine (2 eq, 0.01 mL, 0.09 mmol) and acetyl chloride (1.5 eq, And stirred for 15 minutes. After removing the solvent by distillation under reduced pressure, the product was separated by column chromatography using 6-10% MeOH / CH ₂ Cl _{2. The} compound was further dissolved in EtOAc, and excess HCl (4.0 M in 1,4-dioxane) It was dropped and reacted for about 30 minutes. The precipitate formed was washed several times with EtOAc and diethyl ether and filtered to obtain a white solid compound [Compound 31] (16 mg).

Yield: ~ 60%; ^{1 H NMR (400MHz, MeOD)} δ 8.07 (brs, 1H), 7.84 (d, J = 14.68Hz, 2H), 7.14 (d, J = 4.92Hz, 2H), 6.86 (dt, J = 14.50Hz, 15.08 (M, 2H), 4.09 (brd, J = 14.00 Hz, 2H), 4.28 (d, J = (M, 2H), 1.85 (s, 3H), &lt; RTI ID = 0.0 &

Example  6.5. Synthesis of [Compound 32] to [Compound 37]

[Compound 32] to [Compound 37] were synthesized according to the following Reaction Scheme 23.

<Reaction Scheme 23>

(1 eq) of diethyl (4- (3-morpholinoproxy) phenylsulfonyl) methylphosphonate synthesized in Example 6.1 was dissolved in anhydrous THF (0.1 M) Lt; RTI ID = 0.0 &gt; -78 C &lt; / RTI &gt; n-BuLi (1.2 eq, 2.0 M in cyclohexane) was slowly added dropwise to the solution, stirred for 1 hour, and each benzylaldehyde (1.2 eq) was added thereto and reacted again for 1 hour. When the reaction was not completed while confirming TLC, the reaction was further continued at room temperature for 30 minutes. After completion of the reaction with a small amount of water, the reaction mixture was extracted with water and 10% MeOH / CH ₂ Cl _{2. The} organic layer was washed with anhydrous MgSO ₄ to remove a small amount of water, and the solvent was removed by vacuum distillation. Thereafter, the reaction mixture was separated and purified by column chromatography using EtOAc and 10% MeOH / CH ₂ Cl ₂ to obtain respective compounds. After dissolving each compound in EtOAc, the excess HCl (4.0 M in 1,4-dioxane) was dropped and the reaction was carried out at room temperature for 2 hours. The formed precipitate was filtered while washing with hexane and EtOAc several times, 32] to [Compound 37] were obtained.

In the above reaction formula 22, R is as shown in Table 11 below.

division R division R Compound 32 2'-F Compound 35 2'-Cl Compound 33 3'-F Compound 36 2'-NH ₃ Cl Compound 34 4'-F Compound 37 2'-CF ₃

Example  6.5.1 (E) -4- (3- (4- (2- Fluorostyrylsulfonyl ) Phenoxy )profile) Morpholine  Hydrochloride [Compound 32]

Yield: 72%; ^{1 H NMR (400MHz, DMSO-} d 6) δ 10.99 (brs, 1H), 7.90-7.86 (m, 3H), 7.63 (d, J = 4.08Hz, 2H), 7.54-7.51 (m, 1H), 7.36 J = 5.9 Hz, 2H), 3.97 (d, J = 12.28 Hz, 2H), 3.80 (t, J = 12.00 Hz, 2H), 3.58 (s, 1H), 3.34-3.21 (m, 3H), 3.17-3.00 (m, 2H), 2.28-2.16 (m, 2H);

Example  6.5.2. (E) -4- (3- (4- (3- Fluorostyrylsulfonyl ) Phenoxy )profile) Morpholine  Hydrochloride [Compound 33]

Yield: 99%; ^{1 H NMR (400MHz, MeOD)} δ 7.90 (d, J = 8.92Hz, 2H), 7.60 (d, J = 15.44Hz, 1H), 7.44-7.39 (m, 3H), 7.30 (d, J = 15.40Hz 2H), 3.90-3.75 (brm, 2H), 3.61-3.47 (m, 2H), 7.16 (d, J = 8.96 Hz, 2H), 2.32-2.27 (m, 2H), 3.39 (t, J = 8.02,2H), 3.27-3.12 (brm, 2H)

Example  6.5.3. (E) -4- (3- (4- (4- Fluorostyrylsulfonyl ) Phenoxy )profile) Morpholine  Hydrochloride [Compound 34]

Yield: 90%; ¹ H NMR (400 MHz, MeOD)? 7.89 (d, J = 8.92 Hz, 2H), 7.68-7.64 (m, 2H), 7.60 (d, J = 15.44 Hz, 2H), 3.56 (br d, J = 10.88 Hz, 2H), 7.07 (br, 2H), 3.39 (t, J = 8.04 Hz, 2H), 3.25-3.11 (brm, 2H), 2.33-2.26 (m, 2H);

Example  6.5.4. (E) -4- (3- (4- (2- ( Chlorostyrylsulfonyl ) Phenoxy )profile) Morpholine  Hydrochloride [Compound 35]

Yield: 79%; ^{1 H NMR (400MHz, DMSO-} d 6) δ 11.08 (brs, 1H), 7.91 (dd, J = 1.42Hz, 7.90Hz, 1H), 7.88 (d, J = 8.84Hz, 2H), 7.82 (s, J = 7.36 Hz, 1H), 7.72 (d, J = 15.36 Hz, 1H), 7.58 (d, J = 7.88 Hz, 1H), 7.48 (td, J = 1.36 Hz, J = 8.84 Hz, 2H), 4.20 (t, J = 5.94 Hz, 2H), 3.96 (brd, J = 11.68 Hz, 2H), 3.81 ), 3.45 (brd, J = 11.12 Hz, 2H), 3.31-3.20 (brm, 2H), 3.16-3.02 (brm, 2H), 2.32-2.19 (brm, 2H);

Example  6.5.5. (E) -2- (2- (4- (3- Molypolynoproxis ) Phenylsulfonyl ) Vinyl) aniline Ha Idrochloride [Compound 36]

Yield: 89%; ^{1 H NMR (400MHz, MeOD)} δ 7.93 (d, J = 8.96Hz, 2H), 7.85 (d, J = 15.16Hz, 1H), 7.71 (d, J = 7.92Hz, 1H), 7.52-7.44 (m J = 8.8 Hz, 2H), 7.31 (d, J = 15.16 Hz, 1H), 7.28-7.24 (m, 2H), 7.17 (d, J = 13.68 Hz, 2H), 3.83 (t, J = 12.46 Hz, 2H), 3.57 , J = 3.41 Hz, 12.12 Hz, 2H), 2.34-2.28 (m, 2H);

Example  6.5.6. (E) -4- (3- (4- (2- ( Trifluoromethyl ) Styrylsulfonyl ) Phenoxy )profile) Morpholine Hydrochloride  [Compound 37]

Yield: 86%; ^{1 H NMR (400MHz, MeOD)} δ 7.93-7.87 (m, 3H), 7.84-7.76 (m, 2H), 7.68-7.59 (m, 2H), 7.32 (dd, J = 15.16Hz, 15.20Hz, 1H) (M, 2H), 4.23 (q, J = 5.44 Hz, 5.68 Hz, 2H), 4.17-4.02 (brm, 2H), 3.90-3.77 (brm, 2H), 3.63-3.49 ), 3.42-3.36 (m, 2H), 3.27-3.13 (brm, 2H), 2.34-2.28 (m, 2H)

Example  7.1. 1-4- (3- Molopolyon proxy ) Phenyl Ethanon  synthesis

1-4- (3-morpholinoproxy) phenylethanone was synthesized according to the following reaction scheme.

<Reaction Scheme 24>

Commercially available 4-hydroxyacetophenone (8.3 g, 60.99 mmol) was dissolved in acetone (81 mL), K ₂ CO ₃ (25.3 g, 182.93 mmol) and 1-bromo-3- chloropropane (12.0 ml, 121.95 mmol) The resulting reaction mixture was heated and stirred at 60 占 폚 for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered. The filtrate was washed several times with acetone and dried under reduced pressure. The dried filtrate was dissolved in MC, and the organic layer was washed with saturated sodium bicarbonate aqueous solution and brine, dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was distilled under reduced pressure to obtain the substituted acetophenone intermediate, and the following reaction was carried out without further purification. The intermediate obtained above was dissolved in acetonitrile (122 ml) and morpholine (10.3 ml, 118.211 mmol), sodium iodide (11.8 g, 60.962 mmol) and potassium carbonate (25.3 g, 236.421 mmol) . The reaction mixture was heated at 82 DEG C for 24 hours, cooled to room temperature, and diluted by adding MC. After filtration, the filtrate was distilled under reduced pressure, and purified compound (15.1 g) was obtained by column chromatography (silica gel, CH ₂ Cl ₂ / MeOH, 95/5).

Yield: 89%; ^{1 H NMR (400 MHz, CDCl} 3) δ 7.88-7.92 (m, 2H), 6.88-6.92 (m, 2H), 4.07 (t, J = 6.3 Hz, 2H), 3.69 (t, J = 4.6 Hz, 2H), 2.48-2.45 (br m, 4H), 1.93-2.00 (m, 2H), 2.52 (s, 3H)

Example  7.2. Synthesis of [Compound 38] to [Compound 48]

[Compound 38] to [Compound 48] were synthesized according to the following Reaction Scheme 25.

<Reaction Scheme 25>

The compound (1 eq) synthesized in Example 7.1 was dissolved in ethanol (0.13-0.25 M), and each benzylaldehyde (1.02 eq) and lithium hydroxide hydrate (1 eq) Lt; / RTI &gt; After sufficiently adding cold water to the reaction solution, the precipitate was obtained by filtration. Each of the precipitates was confirmed to be a pure compound before the salts of the compounds [compounds 38] to [compound 48] were obtained. Each precipitated compound was dissolved in EtOAc, excess HCl (4.0 M in 1,4-dioxane) was added, and the reaction was allowed to proceed at room temperature for 2 hours. The precipitate formed was washed several times with hexane and EtOAc, [Compound 38] to [Compound 48] were obtained.

R in the above Reaction Scheme 25 are as shown in Table 12 below.

division R division R Compound 38 2'-F Compound 44 2'-CF ₃ Compound 39 2'-Cl Compound 45 3'-CF ₃ Compound 40 2'-Br Compound 46 4'-CF ₃ Compound 41 2'-NO ₂ Compound 47 2'-Cl, 5'-NO ₂ Compound 42 2'-NH ₃ Cl Compound 48 2'-OEt, 5'-NO ₂ Compound 43 2'-OMe

Example  7.2.1. (E) -3- (2- Fluorophenyl ) -1- (4- (3- Molopolyon proxy ) Phenyl ) PROPE 2-en-1-one hydrochloride [Compound 38]

Yield: 91%; ^{1 H NMR (400 MHz, DMSO} -d 6) δ 10.99 (s, 1H), 8.15 (d, J = 8.8Hz, 2H), 8.11 (t, J = 7.9 Hz, 1H), 7.97 (d, J = (M, 2H), 7.09 (d, J = 8.8 Hz, 2H), 4.19 (d, J = J = 6.0 Hz, 2H), 3.93-3.96 (m, 2H), 3.78 (t, J = 11.7 Hz, 2H), 3.43-3.46 ), 3.01-3.11 (m, 2H), 2.21 (qn, J = 6.0 Hz, 2H).

Example  7.2.2. (E) -3- (2- Chlorophenyl ) -1- (4- (3- Molopolyon proxy ) Phenyl ) PROPE 2-en-1-one Hydrochloride  [Compound 39]

Yield: 58%; ^{1 H NMR (400 MHz, DMSO} -d 6) δ 10.96 (s, 1H), 8.23 (d, J = 7.1 Hz, 1H), 8.20 (d, J = 8.8 Hz, 2H), 8.02 (s, 2H) (D, J = 8.8 Hz, 2H), 7.57 (d, J = 7.1 Hz, 1H), 7.44-7.50 (m, 2H), 7.11 2H), 3.80 (br, 2H), 3.44 (br, 2H).

Example  7.2.3. (E) -3- (2- Bromophenyl ) -1- (4- (3- Molopolyon proxy ) Phenyl ) PROPE 2-en-1-one Hydrochloride  [Compound 40]

Yield: 85%; ^{1 H NMR (400 MHz, DMSO} -d 6) δ 10.76 (s, 1H), 8.20 (d, J = 8.8 Hz, 3H), 7.97 (s, 2H), 7.74 (d, J = 8.0 Hz, 1H) , 7.50 (t, J = 7.6 Hz, 1 H), 7.39 (t, J = 7.9 Hz, 1 H), 7.11 2H), 3.94 (m, 2H), 3.78 (t, J = 11.9 Hz, 2H), 3.46-3.49 (m, 2H), 3.27-3.30 2.18-2.29 (m, 2H).

Example  7.2.4. (E) -1- (4- (3- Molopolyoxyphenyl phenyl ) Phenyl ) -3- (2- Nitrophenyl ) PROPE 2-en-1-one Hydrochloride  [Compound 41]

Yield: 64%; ^{1 H NMR (400 MHz, DMSO} -d 6) δ 10.87 (s, 1H), 8.21 (d, J = 6.4 Hz, 1H), 8.20 (d, J = 8.8Hz, 2H), 8.09 (d, J = 8.1 Hz, 1H), 7.94 (s, 2H), 7.84 (t, J = 7.6 Hz, 1H) 2H), 3.96-4.00 (m, 2H), 3.79 (t, J = 11.6 Hz, 2H), 3.42-3.50 (m, 2H), 3.21-3.30 3.02-3.14 (m, 2H), 2.15-2.28 (m, 2H).

Example  7.2.5. (E) -3- (2- Aminophenyl ) -1- (4- (3- Molopolyon proxy ) Phenyl ) PROPE 2-en-1-one Hydrochloride  [Compound 42]

A mixture of [25d] (68 mg, 0.173 mmol) synthesized in Example 9, tin chloride (467 mg, 2.070 mmol) and ethanol (4 mL) was heated and stirred for 3 hours and then cooled to 0 ° C . After neutralizing with 1N aqueous NaOH solution, the organic layer was extracted from the aqueous layer with a mixed solvent of CH ₂ Cl ₂ / MeOH (9/1). The combined organic layer was filtered over anhydrous in anhydrous Na ₂ SO _4. The filtrate was distilled under reduced pressure and purified by column chromatography (silica gel, CH ₂ Cl ₂ / MeOH, 95/5) to give compound [25e] (38 mg) in the form of a pale solid.

Yield: 60%; ^{1 H NMR (400 MHz, DMSO} -d 6) δ 11.32 (s, 1H), 8.77 (d, J = 8.2 Hz, 1H), 8.28-8.37 (m, 4H), 8.15 (t, J = 7.9 Hz, J = 7.9 Hz, 2H), 7.94 (t, J = 7.2 Hz, 1H), 7.74 J = 12.4 Hz, 2H), 3.85 (q, J = 11.8 Hz, 2H), 3.97 (d, J = 5.3 Hz, 2H), 3.05-3.14 (m, 2H), 2.23-2.30 (m, 2H).

Example  7.2.6. (E) -3- (2- Methoxyphenyl ) -1- (4- (3- Molopolyon proxy ) Phenyl ) PROPE 2-en-1-one Hydrochloride  [Compound 43]

Yield: 99%; ^{1 H NMR (400 MHz, DMSO} -d 6) δ 11.60 (s, 1H), 8.20 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 15.7 Hz, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 15.7 Hz, 1H), 7.42 (t, J = 8.2 Hz, 1H), 7.09 3H), 3.43 (d, J = 6.9 Hz, 2H), 7.00 (t, J = 7.4 Hz, 12.2 Hz, 2H), 3.23 (qr, J = 5.4 Hz, 2H), 3.02-3.10 (m, 2H), 2.21-2.28 (m, 2H); ^{13 C-NMR (100 MHz,} DMSO-d 6) δ 187.5, 162.1, 158.1, 137.7, 132.1, 130.8, 130,7, 128.4, 123.0, 121.7, 120.6, 114.5, 111.7, 65.4, 63.1, 55.7, 53.3, 50.9, 22.8.

Example  7.2.7. (E) -1- (4- (3- Molypolynoproxis ) Phenyl ) -3- (2- ( Trifluoromethyl ) Phenyl) Prop Phen-1-one Hydrochloride  [Compound 44]

Yield: 85%; ^{1 H NMR (400MHz, DMSO-} d 6) δ 11.54 (brs, 1H), 8.39 (d, J = 7.76Hz, 1H), 8.25 (d, J = 8.84Hz, 2H), 8.09 (d, J = 15.28 J = 7.42 Hz, 1H), 7.83 (t, J = 7.82 Hz, 1H), 7.70 (t, J = 7.42 Hz, J = 5.9 Hz, 2H), 4.00 (d, J = 12.20 Hz, 2H), 3.91 (t, J = 12.08 Hz, 2H) , 3.50 (d, J = 12.08 Hz, 2H), 3.33-3.28 (m, 2H), 3.16-3.09 (m, 2H), 2.30-2.29

Example  7.2.8. (E) -1- (4- (3- Molypolynoproxis ) Phenyl ) -3- (3- ( Trifluoromethane Yl) Phenyl ) Prop Phen-1-one Hydrochloride  [Compound 45]

Yield: 43%; ^{1 H NMR (400MHz, MeOD)} δ 8.16 (d, J = 8.88Hz, 2H), 8.03 (t, J = 7.84Hz, 2H), 7.86 (q, J = 15.68Hz, 23.20Hz, 2H), 7.73 ( (d, J = 7.56 Hz, 1H), 7.65 (t, J = 7.60 Hz, 1H), 7.11 2H), 3.91-3.71 (brm, 2H), 3.65-3.45 (brm, 2H), 3.29 (t, J = 8.00Hz, 2H), 3.28-3.14 2H)

Example  7.2.9. (E) -1- (4- (3- Molypolynoproxis ) Phenyl ) -3- (4- ( Trifluoromethyl ) Phenyl) Prop Phen-1-one Hydrochloride  [Compound 46]

Yield: 44%; ^{1 H NMR (400MHz, MeOD)} δ 8.14 (d, J = 8.92Hz, 2H), 7.93 (d, J = 7.92Hz, 2H), 7.89 (s, 1H), 7.81 (s, 1H), 7.74 (t J = 9.96 Hz, 2H), 7.10 (d, J = 8.92 Hz, 2H), 4.24 (t, J = 5.74 Hz, 2H), 4.09 2H), 3.58 (d, J = 12.24 Hz, 2H), 3.41 (t, J = 8.02 Hz, 2H), 3.21 (t, J = 12.16 Hz, 2H), 2.35-2.28 )

Example  7.2.10. (E) -3- (2- Chloro -5- Nitrophenyl ) -1- (4- (3- Molopolyon proxy ) Pe Neil) PROPE -2-en-1-one hydrochloride [Compound 47]

Yield: 63%; ^{1 H NMR (400 MHz, DMSO} -d 6) δ 10.64 (s, 1H), 9.01 (d, J = 2.6 Hz, 1H), 8.19-8.28 (m, 4H), 7.96 (d, J = 15.5 Hz, J = 8.8 Hz, 2H), 3.94-3.98 (m, 2H), 3.75 (d, J = t, J = 12.2 Hz, 2H), 3.40-3.47 (m, 2H), 3.22-3.28 (m, 2H), 3.02-3.13 (m, 2H), 2.19-2.22 (m, 2H).

Example  7.2.11. (E) -3- (2- Ethoxy -5- Nitrophenyl ) -1- (4- (3- Molopolyon proxy ) Phenyl ) PROPE 2-en-1-one hydrochloride [Compound 48]

Yield: 51%; ^{1 H NMR (400 MHz, DMSO} -d 6) δ 10.63 (s, 1H), 8.84 (d, J = 2.8 Hz, 1H), 8.28 (dd, J = 9.2 Hz, 2.8, 1H), 8.19 (d, J = 8.8 Hz, 2H), 8.13 (d, J = 15.7 Hz, 1H), 7.95 (d, J = J = 6.0 Hz, 2H), 3.94 (m, 2H), 3.75 (t, J = 11.0 Hz, 2H) 2H), 3.41-3.47 (m, 2H), 3.24-3.26 (m, 2H), 3.06-3.08 (m, 2H), 2.12-2.26

Comparative Example .

(E) -1- (4-methoxyphenyl) -3- (2- (trifluoromethyl) phenyl) prop-2-en-1-one [Kumar et al. Journal of Medicinal Chemistry 2011, 54, 4147-4159] was compared with the benzene derivative compound synthesized according to the present invention as a comparative compound.

<Compound 49>

Experimental example .

Experimental Example  One. Nitric oxide  ( NO Quantification

BV-2 cells were cultured in 96-well plates at 2 × 10 ⁴ cells / well and treated with lipopolysaccharide (0.2 μg / ml) to induce activity. At this time, the compound to be tested is co-treated at an appropriate concentration. After 24 hours, the nitrite present in the culture solution, that is, the NO oxidizing substance, is quantified by the following Griess reaction method. 200 μl of the culture was transferred to a new 96-well plate, and 100 μl of Griess reagent (1% sulphanilamide, 0.1% naphthylethylenediamine dihydrochloride, 2.5% H ₃ PO ₄ ) was added and reacted at room temperature for 10 minutes. Absorbance is measured at a wavelength of 540 nm using a SpectraMax Plus microplate spectrophotometer (Molecular Devices). NaNO ₂ And a standard curve for Quantify nitrite.

The percent inhibition results for the NO production of the novel compounds according to the invention are shown in Table 13 below.

Experimental Example  2. Nrf2  Active induction effect

NQO-1 expression is induced by the binding of Nrf2, a transcription factor, to ARE, and thus Nrf2 activity is required. In addition to NQO-1, induction of Nrf2 activity induces the expression of enzymes (heme oxygenase (HO-1), glutamate-cysteine ligase modulator subunit (GCLM)) to prevent cytotoxicity. In addition, since the expression pattern of NQO1 and HO-1 according to Nrf2 activity is similar to that of the present experimental system, the induction effect of Nrf2 activity of the derivatives synthesized by HO-1 sandwich ELISA method in which a relatively simple assay method has been developed was evaluated.

BV-2 cells are cultured in 96-well plates at 2 × 10 ⁴ cells / well and treated with test compound or 5 μM sulforaphane for 24 h. The cells are washed twice with phosphate buffered saline (PBS), and then 50 μl of lysis solution (150 mM NaCl, 50 mM Tris-HCl, pH 8.0, 1% Nonidet-p40) is added and left on ice for 20 minutes. Centrifuge at 4000 rpm for 15 minutes using a centrifuge and take 10 μl of supernatant. After mixing with 90 μl of 50 mM Tris pH 8.0 solution, take 10 μl again.

Dilute 250 times of HO-1 coating antibody (Assay Designs) with coating buffer (10 mM sodium phosphate, 15 mM NaCl, pH 7.4) and dispense 100 μl per well into U-shaped 96-well plate and incubate at room temperature. The next day, remove the coating buffer, add 100 μl of blocking buffer (10 mM sodium phosphate, 15 mM NaCl, 1% BSA, pH 7.4) per well and incubate at room temperature for 1 hour. Remove the blocking buffer and add 90 μl of assay buffer (100 mM sodium phosphate, 150 mM NaCl, 1% BSA, 1% Tween-20, pH 7.4) to each well. After incubation at room temperature for 1 hour, the plate is washed four times with washing buffer (10 mM sodium phosphate, 15 mM NaCl, 0.1% Tween-20, pH 7.4).

Dilute HO-1 detection antibody 250 times in assay buffer and add 100 μl per well. After reacting at room temperature for 1 hour, wash it 4 times with washing buffer. Dilute Horseradish peroxidase-labeled streptavidin 600-fold with assay buffer and add 100 μl per well. After reacting at room temperature for 1 hour, wash it 4 times with washing buffer. Add 100 μl Amplex-Red solution (0.05 mM Amplex-Red (Invitrogen), 0.0068% H ₂ O ₂ in PBS) and incubate at room temperature for 30 minutes. Measure the value at Ex / Em = 530/590 nm using a fluorescence spectrophotometer (Molecular Devices). The effect of each compound is expressed as a percentage of the sulforaphane treated group.

The HO-1 expression inducing effect of the novel compounds according to the present invention is shown in Table 13 below as a percentage of the induction effect of sulfurose (5 μM).

compound NO (% of LPS) HO-1 (% SFN) compound NO (% of LPS) HO-1 (% SFN) 5 [mu] M 20 μM 5 [mu] M 20 μM 5 [mu] M 20 μM 5 [mu] M 20 μM One 87.3 85.3 30 52.3 62.8 2 66.0 95.4 31 102.8 52.2 3 97.0 70.7 32 62.5 59.5 4 110.0 51.3 33 96.9 40.4 5 96.5 61.1 34 103.7 36.7 6 111.9 65.0 35 27.6 113.0 7 114.6 66.9 36 57.4 31.0 8 67.2 43.7 37 73.3 48.8 9 114.3 17.4 38 18.2 132.2 10 19.1 106.8 39 26.4 78.2 11 23.7 61.2 40 30.1 46.5 12 35.0 89.6 41 31.2 9.8 13 46.9 79.2 42 111.9 16.5 14 70.7 71.6 43 7.9 210.1 15 80.7 76.1 44 11.4 136.8 16 30.3 104.9 45 27.2 ND 17 39.3 93.7 46 32.6 35.8 26 93.1 43.2 47 32.8 34.5 27 88.3 36.9 48 30.1 21.5 28 56.3 35.0 49 85.3 36.8 29 74.7 44.4

The NO production inhibitory activity and the Nrf2 activity effect of the derivative compounds synthesized through Experimental Example 1 or 2 were tested and the results are shown in Table 13 above. The synthesized derivative compounds inhibited the production of active oxygen caused by lipopolysaccharide (LPS), and compounds 10, 11, 12, 13, 16, 17, 35, 38, 39, 40, 41, 43, 44, 45, 46, 47 and 48 showed an excellent effect of inhibiting NO production by 50% or more at a concentration of 20 μM.

1, 2, 10, 12, 13, 15, 16, 17, 25, 38, 39, 43, and 44 were found to inhibit the expression of HO-1 through the activation of Nrf2 75% or higher activity. Sulfolabas contain an isothiocyanate (NCS) group and are known to exhibit high toxicity due to their non-selective strong reactivity despite their high activity. Therefore, no toxicity was observed even at 20 μM, and it was regarded as exhibiting excellent activity when inducing 75% HO-1 expression inducing effect compared to sulfo group.

In the present invention, a compound 49 having excellent activity in a chalcone derivative known to induce the expression of HO-1 through activation of Nrf2 was synthesized together and used as a comparative compound (Kumar et al. Journal of Medicinal Chemistry 2011,54,4147-4159). As a result, many compounds including chalcone derivatives of the present invention exhibited superior activity to the comparative compounds. Among them, compounds 10, 16, 17, 43 and 44 showed excellent NO production inhibitory effect and at the same time higher HO-1 expression than 90% of sulforaphane.

Claims (14)

1. A benzyl derivative compound represented by the following formula (1): < EMI ID =
&Lt; Formula 1 &gt;

In Formula 1,
R ₁ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, including a linear, branched, or cyclic carbon chain, a substituted or unsubstituted linear, branched or cyclic carbon chain having 7 to 12 carbon atoms An alkyl group having 1 to 10 carbon atoms, which is substituted or unsubstituted, and the alkyl group containing a straight, branched or cyclic carbon chain is an oxygen-bonded alkoxy group, a substituted or unsubstituted allyl group having 2 to 12 carbon atoms , A substituted or unsubstituted C 1 -C 10 alcohol group, a substituted or unsubstituted C 6 -C 18 aryl group, a substituted or unsubstituted C 3 -C 18 heteroaryl group, a substituted or unsubstituted C 1 -C 12 A substituted or unsubstituted arylamine group having 6 to 18 carbon atoms, a substituted or unsubstituted heteroarylamine group having 6 to 18 carbon atoms, a substituted or unsubstituted C1- A substituted or unsubstituted C6 to C18 arylthio group, a substituted or unsubstituted C6 to C18 aryloxy group, a substituted or unsubstituted C1 to C6 amide group,
R ₂ and R ₃ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl groups containing from 1 to 6 carbon atoms, straight, branched or cyclic carbon chain, substituted or unsubstituted carbon A substituted or unsubstituted allyl group having 2 to 12 carbon atoms, a substituted or unsubstituted alcohl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, An alkyl group having from 1 to 10 carbon atoms in which a straight chain, branched or cyclic carbon chain is substituted by an oxygen atom, an aryl group having 6 to 18 carbon atoms, an aryloxy group having 6 to 18 carbon atoms connected to oxygen , An alkylcarbamate group having 1 to 5 carbon atoms, a heteroaryl group having 3 to 18 carbon atoms, a heteroaryloxy group having 3 to 18 carbon atoms and a heteroaryl group connected to oxygen, An alkylammonooxy group whose alkylammono group is bonded to oxygen, an alkylammonoxy group whose alkylammono group has 1 to 8 carbon atoms connected to oxygen, an alkylthioxy group whose alkylthiol group has 1 to 10 carbon atoms connected to oxygen, To 18 arylthiol groups may be aryl thioloxy groups linked to oxygen,
Y is

,

or

to be. The method of claim 1,
The compound of Formula 1 is a benzyl derivative compound or a pharmaceutically acceptable salt thereof characterized in that the compound of any one of the following formulas 2 to 4:
&Lt; Formula 2 >< EMI ID =

&Lt; Formula 4 &gt;

In the above Chemical Formulas 2 to 4,
R ₁ is an alkyl group comprising a substituted or unsubstituted straight, pulverized or cyclic carbon chain having 1 to 6 carbon atoms, a substituted or unsubstituted straight, pulverized or cyclic carbon chain having 7 to 12 carbon atoms. Alkyl group containing a substituted, unsubstituted or unsubstituted carbon group having 1 to 10 carbon atoms, alkoxy group having 2 to 12 carbon atoms substituted or unsubstituted, substituted or unsubstituted allyl group having 1 to 10 carbon atoms , Substituted or unsubstituted C1-C10 alcohol group, substituted or unsubstituted C6-C18 aryl group, substituted or unsubstituted C3-C18 heteroaryl group, substituted or unsubstituted C1-C12 Alkylamine groups, substituted or unsubstituted C6-C18 arylamine groups, substituted or unsubstituted C6-C18 heteroarylamine groups, substituted or unsubstituted C1-C10 Alkylthiol groups, substituted or unsubstituted C6-C18 arylthiol groups, substituted or unsubstituted C6-C18 aryloxy groups, substituted or unsubstituted C1-C6 amide groups,
R ₂ and R ₃ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl groups containing from 1 to 6 carbon atoms, straight, branched or cyclic carbon chain, substituted or unsubstituted carbon An alkyl group having from 7 to 15 straight-chain, branched or cyclic carbon chains, a substituted or unsubstituted allyl group having 3 to 15 carbon atoms, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, A substituted or unsubstituted aryl group having 6 to 18 carbon atoms, a substituted or unsubstituted monovalent group having 6 to 18 carbon atoms, a substituted or unsubstituted aryl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkyl group having 1 to 10 linear, A substituted or unsubstituted C 1 -C 5 alkylcarbamate group, a substituted or unsubstituted C 3 -C 18 heteroaryl group, a substituted or unsubstituted aryloxy group, Or an unsubstituted heteroaryloxy group having 3 to 18 carbon atoms, a substituted or unsubstituted heteroaryl group having 3 to 18 carbon atoms connected to oxygen, a substituted or unsubstituted alkylmorpholin group having 5 to 15 carbon atoms, A substituted or unsubstituted alkylaminooxy group in which a substituted or unsubstituted alkylamine group having 1 to 11 carbon atoms is connected to oxygen, an alkylthioxy group in which a substituted or unsubstituted alkylthiol group having 1 to 13 carbon atoms is connected to oxygen, a substituted Or an unsubstituted aryl thiol group having 6 to 18 carbon atoms may be an aryl thioloxy group connected to oxygen,
R ₄ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, including a linear, branched, or cyclic carbon chain, a substituted or unsubstituted linear, branched or cyclic carbon chain having 7 to 12 carbon atoms A substituted or unsubstituted aryl group having 3 to 12 carbon atoms, a substituted or unsubstituted heteroaryl group having 3 to 15 carbon atoms, a substituted or unsubstituted heterocyclic group having 3 to 15 carbon atoms, A substituted or unsubstituted alkylamine group having 1 to 8 carbon atoms, a substituted or unsubstituted alkylthiol group having 1 to 10 carbon atoms, a substituted or unsubstituted alkylene group having 6 to 15 carbon atoms Arylthiol group,
Y is

,

or

to be. 3. The method of claim 2,
The alkyl group is selected from the group consisting of methyl group, ethyl group, normal propyl group, isopropyl group, normal butyl group, isobutyl group, tert-butyl group, pentyl, hexyl, heptyl, cyclopentyl group, cyclohexyl group, cycloheptyl group Benzyl derivative compounds or pharmaceutically acceptable salts thereof, characterized in that any one. 3. The method of claim 2,
The aryl group is selected from the group consisting of phenyl group, halophenyl group, benzyl group, halobenzyl group, tolyl group, naphthyl group, biaryl group, trihalophenyl group, trihalomethylphenyl, halonitrobenzyl, anthryl group, phenanthryl group Benzyl derivative compounds or pharmaceutically acceptable salts thereof, characterized in that any one of. 3. The method of claim 2,
The heteroaryl group is thiazolyl group, oxazolyl group, thiophenyl group, furanyl group, pyrrolyl group, imidazolyl group, isooxazolyl group, isothiazolyl group, pyrazolyl group, triazolyl group, triazinyl group, thiadia Zolyl group, tetrazolyl group, oxadiazolyl group, pyridyl group, pyridazinyl group, pyrimidyl group, pyrazinyl group, indolyl group, benzothiophenyl group, benzofuranyl group, benzimidazolyl group, benzoxazolyl group, Benzyl isoxazolyl, benzthiazolyl, benztriazolyl, benztriazolyl, quinoline, isoquinoline, purinyl, and furypyridinyl groups Possible salts. 3. The method of claim 2,
Wherein the alkylamine group is any one selected from the group consisting of a methylamine group, an ethylamine group, a propylamine group, a butylamine group, an isobutylamine group, and a pentylamine group, or a pharmaceutically acceptable salt thereof salt. 3. The method of claim 2,
The arylamine group may be any one selected from the group consisting of aniline group, haloaniline group, methylaniline group, ethylaniline group, propylaniline group and ethylmethylaniline group, or a pharmaceutically acceptable salt thereof. 3. The method of claim 2,
R ₁ is methyl group, ethyl group, normal propyl group, isopropyl group, normal butyl group, isobutyl group, tert-butyl group, methoxy group, ethoxy group, hydroxy group, phenyl group, halophenyl group, dihalophenyl group, aniline group , Aniline hydrochloride group, trihalomethylphenyl group, tolyl group, benzyl group, acetamide group, nitrobenzyl group, anisol group, ethyloxybenzyl group, ethoxy nitrobenzyl group, halogenonitrobenzyl group, methylamine, ethylamine, A benzyl derivative compound or a pharmaceutically acceptable salt thereof, which is any one selected from the group consisting of a methyl acetamide group, an ethyl acetamide group, and a propyl acetamide group. 3. The method of claim 2,
R ₂ and R ₃ are the same as or different from each other, and each independently hydrogen, halogen, methyl group, ethyl group, normal propyl group, isopropyl group, normal butyl group, isobutyl group, tert-butyl group, methoxy group, ethoxy group, Dimethoxy group, diethoxy group, hydroxy group, morpholine group, methoxyethyl morpholine group, methoxypropyl morpholine group, methoxybutyl morpholine group, selected from the group consisting of methoxypropyl piperazyl group Benzyl derivative compounds or pharmaceutically acceptable salts thereof, characterized in that any one. 3. The compound according to claim 2,
(Z) -4- (para-methylphenylsulfinyl) but-3-en-1-amine;
(Z) -4- (para-methoxyphenylsulfinyl) but-3-en-1-amine;
(E) -4- (para-methoxyphenylsulfinyl) -3-en-1-amine;
(Z) -4- (3,4-dimethoxyphenylsulfinyl) -3-thien-l-amine;
(E) -1-chloro-2- (2- (4-methoxyphenylsulfinyl) vinyl) benzene;
(Z) -1-chloro-2- (2- (4-methoxyphenylsulfinyl) vinyl) benzene;
(E) -2- (2- (4-methoxyphenylsulfinyl) vinyl) aniline hydrochloride;
(E) -1- (2- (4-methoxyphenylsulfinyl) vinyl) -2- (trifluoromethyl) benzene;
(Z) -1- (2- (4-methoxyphenylsulfinyl) vinyl) -2- (trifluoromethyl) benzene;
(E) -4- (4-methoxyphenylsulfonyl) bute-3-en-1-amine hydrochloride;
(E) -1-fluoro-2- (2- (4-methoxyphenylsulfonyl) vinyl) benzene;
(E) -1-fluoro-3- (2- (4-methoxyphenylsulfonyl) vinyl) benzene;
(E) -1-fluoro-4- (2- (4-methoxyphenylsulfonyl) vinyl) benzene;
(E) -1-chloro-2- (2- (4-methoxyphenylsulfonyl) vinyl) benzene;
(E) -1-chloro-4- (2- (4-methoxyphenylsulfonyl) vinyl) benzene;
(E) -1- (2- (4-methoxyphenylsulfonyl) vinyl) -2- (trifluoromethyl) benzene;
(E) -1- (2- (4-methoxyphenylsulfonyl) vinyl) -3- (trifluoromethyl) benzene;
(E) -1-methoxy-4- (4- (trifluoromethyl) styrylsulfonylbenzene;
(E) -1- (2- (3-methoxyphenylsulfonyl) vinyl) -2- (trifluoromethyl) benzene;
(E) -1- (2- (3-methoxyphenylsulfonyl) vinyl) -3- (trifluoromethyl) benzene;
(E) -1- (2- (2-methoxyphenylsulfonyl) vinyl) -2- (trifluoromethyl) benzene;
(E) -1- (2- (2-methoxyphenylsulfonyl) vinyl) -3- (trifluoromethyl) benzene;
(E) -1- (2- (2-methoxyphenylsulfonyl) vinyl) -4- (trifluoromethyl) benzene;
(E) -1-fluoro-2- (2- (2-methoxyphenylsulfonyl) vinyl) benzene;
(E) -1-fluoro-3- (2- (2-methoxyphenylsulfonyl) vinyl) benzene;
(E) -4- (3- (4- (2-fluorostyrylsulfinyl) phenoxy) propyl) morpholine hydrochloride;
(E) -4- (3- (4- (2-chlorostyrylsulfinyl) phenoxy) propyl) morpholine hydrochloride;
(E) -4- (3- (4- (2-Trifluoromethylstyrylsulfinyl) phenoxy) propyl) morpholine hydrochloride;
(E) -4- (3- (4- (2-aminostyrylsulfinyl) phenoxy) propyl) morpholine hydrochloride;
(E) -4- (4- (3-morpholinopropoxy) phenylsulfonyl) but-3-en-1-amine hydrochloride;
(E) -N- (4- (4- (3-morpholinopropoxy) phenylsulfonyl) -3-tehenylacetamide;
(E) -4- (3- (4- (2-fluorostyrylsulfonyl) phenoxy) propyl) morpholine hydrochloride;
(E) -4- (3- (4- (3-fluorostyrylsulfonyl) phenoxy) propyl) morpholine hydrochloride;
(E) -4- (3- (4- (4-fluorostyrylsulfonyl) phenoxy) propyl) morpholine hydrochloride;
(E) -4- (3- (4- (2- (chlorostyrylsulfonyl) phenoxy) propyl) morpholine hydrochloride;
(E) -2- (2- (4- (3-morpholinopropoxy) phenylsulfonyl) vinyl) aniline hydrochloride;
(E) -4- (3- (4- (2- (trifluoromethyl) styrylsulfonyl) phenoxy) propyl) morpholine hydrochloride;
(E) -3- (2-fluorophenyl) -1- (4- (3 -morpholinoproxy) phenyl) prop-2-en-1-one hydrochloride;
(E) -3- (2-Chlorophenyl) -1- (4- (3-morpholinoproxy) phenyl) prop-2-en-1-one hydrochloride;
(E) -3- (2-bromophenyl) -1- (4- (3 -morpholinoproxy) phenyl) prop-2-en-1-one hydrochloride;
(E) -1- (4- (3-morpholinoproxyphenyl) phenyl) -3- (2-nitrophenyl) prop-2-en-1-one hydrochloride;
(E) -3- (2-aminophenyl) -1- (4- (3-morpholinoproxy) phenyl) prop-2-en-1-one hydrochloride;
(E) -3- (2-methoxyphenyl) -1- (4- (3-morpholinoproxy) phenyl) prop-2-en-1-one hydrochloride;
(E) -1- (4- (3 -morpholinopropoxy) phenyl) -3- (2- (trifluoromethyl) phenyl) prop-2-en-1-one hydrochloride;
(E) -1- (4- (3 -morpholinopropoxy) phenyl) -3- (3- (trifluoromethyl) phenyl) prop-2-pen-1-one hydrochloride;
(E) -1- (4- (3 -morpholinopropoxy) phenyl) -3- (4- (trifluoromethyl) phenyl) prop-2-en-1-one hydrochloride;
(E) -3- (2-chloro-5-nitrophenyl) -1- (4- (3 -morpholinoproxy) phenyl) prop-2-en-1-one hydrochloride;
(E) -3- (2-ethoxy-5-nitrophenyl) -1- (4- (3-morpholinoproxy) phenyl) propen-2-en-1-one hydrochloride; A benzyl derivative or a pharmaceutically acceptable salt thereof. The method of claim 1,
The pharmaceutically acceptable salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, Benzyl derivative compound or a pharmaceutically acceptable salt thereof, wherein the compound is at least one selected from the group consisting of maleic acid, lactic acid, malic acid, tartaric acid, citric acid, ethanesulfonic acid, aspartic acid and glutamic acid. A pharmaceutical composition for inhibiting neuronal cell death, which exhibits an effect of inhibiting nitric oxide production or Nrf2 activity, containing a compound according to any one of claims 1 to 11 as an active ingredient together with a pharmaceutically acceptable carrier or diluent. A pharmaceutical composition for preventing or treating cranial nerve disease, comprising the compound according to any one of claims 1 to 11 as an active ingredient together with a pharmaceutically acceptable carrier or diluent. The method of claim 13,
The cranial nerve disease is a pharmaceutical composition, characterized in that any one or more selected from the group consisting of Parkinson's disease, Alzheimer's dementia, Huntington's disease, Lou Gehrig's disease, epilepsy, depression, insomnia, anxiety and degenerative neurological disease.