KR101525019B1 - Novel compound capable of activating Nrf2, and pharmaceutical compositions comprising the same - Google Patents

Abstract

The present invention relates to a novel compound having an ability to activate Nrf2, which is effective for inhibiting neuronal cell death and preventing and treating neuronal diseases by activating Nrf2, a transcription factor involved in expression of a quinone reductase gene, .
(I)

Description

[0001] The present invention relates to a novel compound having an Nrf2 activating ability, a novel compound capable of activating Nrf2,

The present invention relates to a novel compound having Nrf2 activating ability which is effective for inhibiting neuronal cell death and preventing and treating neuronal diseases by activating Nrf2, a transcription factor involved in expression of a quinone reductase gene, and a pharmaceutical composition containing the same .

Recent improvements in living standards and advances in health and medical technology have led to an increase in the average life span and a surge in the elderly population. Therefore, among the public health problems inevitably caused by the aging of the population structure, senile dementia and Parkinsons disease, which are degenerative neurological diseases commonly observed in the elderly, are becoming serious problems.

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. Primary symptoms include slow motion, tremor at rest, instability in posture, Depression, insomnia, dementia, and other secondary symptoms are associated with disease progression. [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]. At present, more than 50,000 people are diagnosed with Parkinson's disease each year, but despite much research in the past, they have not been able to elucidate a clear cause for the pathogenesis (Arevalo et al., Mov. Disord., 1997, 12, 277- 284).

Currently, a therapeutic agent for Parkinson's disease is used as a therapeutic agent. Typically, a precursor of dopamine, L-3,4-dihydroxyphenylalanine (L-3,4- dihydroxyphenylalanine (L-DOPA), monoamine oxidase inhibitors and dopamine receptor antagonists (agonists). However, these treatments delay the progression of the disease, do not lead to the underlying treatment, and are associated with long-term side effects and complications. Recently, neuroprotection (neuroprotection) to move the direction of the disease is progressing actively.

Parkinson's disease 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 as it is converted to dopaquinone (Dopamine-o-quinone, DAquinone). Dopaquinone forms a covalent bond with cellular nucleophiles such as cysteine residues of proteins and forms a reactive aminochrome when dopaquinone is produced and is converted into a superoxide radical by redox- To produce superoxide, or to reduce 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 (NQ) by a reducing cofactor such as NADH or NADPH. 2000, 23, 554-558]. It is expressed on the substantia nigra of Parkinson's patients and results from 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). Therefore, 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 is associated with protein 1 (Kelch-like ECH-associated protein 1: Keap1), but it migrates to the nucleus when disassociated with Keap1 [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. One of its reaction products, biliverdin, is converted to an antioxidant, bilirubin, which consequently protects nerve cells from oxidative stress.

On the other hand, sulforaphane (1-isothiocyanato- (methylsulfinyl) butane) inhibits cell membrane damage, DNA fragmentation and accumulation of reductive oxygen species, and It is known that QR increases enzymatic activity and mRNA levels (Han et al., J. Pharmacol. Exp. Ther. 2007, 321 (1), 249-256). This suggests that sulforaphane can inhibit the toxicity of dopaminergic cells by inducing QR gene expression and eliminating dopaquinone in cells [1]. Iida et al. Cancer Res. 2004, 64, 6424-6431; 2) Xu et al. Cancer Res. 2006, 66, 8293-8296].

Accordingly, a problem to be solved by the present invention is to provide a novel compound capable of activating Nrf2 with low cytotoxicity and capable of activating Nrf2, which is effective for expression of QR gene, or a pharmaceutically acceptable salt thereof will be.

It is another object of the present invention to provide a pharmaceutically acceptable carrier or diluent, and a pharmaceutical composition containing the compound as an active ingredient and having an effect of inhibiting neuronal cell death and preventing or treating neuronal diseases.

In order to achieve the above object,

A compound represented by the following formula [I] and having an Nrf2 activating ability, or a pharmaceutically acceptable salt thereof.

(I)

In the above formula (I)

Wherein R ₁ , R ₃ and R ₄ are each independently H or OCH ₃ ,

Wherein the X-Y bond is C-O, C = O or S = O,

Wherein p is 1 or 2,

Wherein R ₂ is H, CH ₃ , OCH ₃ , F, Cl, OH or O (CH ₂ ) _n Z (n is 1 or 2) and Z is N (CH ₃ ) ₂ or Lt; / RTI > group,

[Structural formula 1]

Wherein R ₅ is _{NH 2, NCS, NHCH 3,} N (CH 3) 2, NHCOCH 3, NHCOCH 2 CH 3, NHCOCH (CH 3) 2, NHCONHCH 3, NHCONHCH 2 CH 3, NHCONHCH (CH 3) 2, NHCSCH _{3, NHCSCH 2 CH 3, NHCSCH} (CH 3) 2, NHCSNHCH 3, NHCSNHCH 2 CH 3, NHCSNHCH (CH 3) 2, NHCOC 6 H 5 And NHCONHC ₆ H ₅ ; Or [Formula 2] below.

[Structural formula 2]

The compound of the formula (I) having the ability to activate Nrf2 according to the present invention may be any one selected from the group consisting of the following formulas (II) to (VII).

[Formula II] [Formula (III)

[Formula IV] [Formula V]

(VI) < RTI ID = 0.0 > [VII]

In the above formulas (II) to (VII)

The R ₁ , R ₂ , R ₅ And p is the same as defined in the above formula (I)

Wherein R ₆ is any one selected from the group consisting of O (CH ₂ ) _n Z (n is 1 or 2) and Z is N (CH ₃ ) ₂ or the following formula 1:

[Structural formula 1]

According to an embodiment of the present invention, the pharmaceutically acceptable salts include salts with 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, It may be at least one member 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 solve the above problems,

There is provided a pharmaceutical composition for suppressing neuronal cell death comprising a compound having Nrf2 activating ability as an active ingredient together with a pharmaceutically acceptable carrier or diluent.

In addition, the present invention provides a composition for treating a neurological disease containing a compound having the above-mentioned ability to activate Nrf2 as an active ingredient together with a pharmaceutically acceptable carrier or diluent.

According to an embodiment of the present invention, the neurological disease may be selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, Lou Gehrig's disease, epilepsy, depression, pain anxiety, and degenerative brain disease.

The term " treatment " refers to stopping or delaying the progress of a disease when used in an object having an onset symptom.

The 'pharmaceutical composition' may include, if necessary, a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof together with the compound of the present invention.

The term "carrier" refers to a substance that facilitates the addition of a compound into a cell or tissue.

The term 'diluent' is defined as a substance that not only stabilizes the biologically active form of the compound of interest but also dilutes in water to dissolve the compound.

The term " pharmaceutically acceptable " means a property that does not impair the biological activity and physical properties of the compound.

Other terms and abbreviations used herein can be interpreted as commonly understood by a person skilled in the art to which the present invention belongs, unless otherwise defined.

The pharmaceutical composition containing the compound having Nrf2 activating activity according to the present invention as an active ingredient can prevent the death of brain cells by activating Nrf2 in vivo to express enzyme genes that prevent cytotoxicity. It can also be used to treat cranial nerve diseases caused by neuronal cell death, particularly Parkinson's disease, Alzheimer's disease, Huntington's disease, Lou Gehrig's disease, epilepsy, depression, insomnia, anxiety and degenerative brain disease.

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

The present invention provides a compound represented by the following formula [I] and having low cytotoxicity, but capable of activating Nrf2 and thus having an effect on QR gene expression, or a pharmaceutically acceptable salt thereof.

(I)

In the above formula (I)

Wherein R ₁ , R ₃ and R ₄ are each independently H or OCH ₃ ,

Wherein the X-Y bond is C-O, C = O or S = O,

Wherein p is 1 or 2,

Wherein R ₂ is H, CH ₃ , OCH ₃ , F, Cl, OH or O (CH ₂ ) _n Z (n is 1 or 2) and Z is N (CH ₃ ) ₂ or Lt; / RTI > group,

[Structural formula 1]

Wherein R ₅ is _{NH 2, NCS, NHCH 3,} N (CH 3) 2, NHCOCH 3, NHCOCH 2 CH 3, NHCOCH (CH 3) 2, NHCONHCH 3, NHCONHCH 2 CH 3, NHCONHCH (CH 3) 2, NHCSCH _{3, NHCSCH 2 CH 3, NHCSCH} (CH 3) 2, NHCSNHCH 3, NHCSNHCH 2 CH 3, NHCSNHCH (CH 3) 2, NHCOC 6 H 5 , and NHCONHC ₆ H ₅ which is selected from one of; Or [Formula 2] below.

[Structural formula 2]

It will be apparent to those skilled in the art that the scope of the present invention is not limited thereby. According to a preferred embodiment of the present invention, the compound of formula (I) according to the present invention is specifically May be any one of the compounds represented by Formulas (7a) to (190) described in the claims.

The pharmaceutically acceptable salts in the present invention include salts with inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid and the like, which are non-toxic acid addition salts containing pharmacologically acceptable anions, And organic acids such as formic acid, citric acid, acetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, lactic acid, malonic acid, malic acid, salicylic acid, succinic acid, oxalic acid, propionic acid, The acid moieties formed by sulfonic acids such as p-toluenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like can be salts.

The compound having Nrf2 activating activity according to the present invention can be converted into a salt thereof by a conventional method and the preparation of the salt can be easily carried out by those skilled in the art based on the structure of the above formula There will be.

The compounds having Nrf2 activating ability include pharmaceutically acceptable salts thereof, unless otherwise described below, all of which should be construed as being included in the scope of the present invention.

The compound having Nrf2 activating activity according to the present invention has low cytotoxicity and is able to activate Nrf2, which is effective for the expression of QR gene, thereby inhibiting neuronal apoptosis, and thereby inhibiting Parkinson's disease, Alzheimer's disease, Huntington's disease, Lou Gehrig's disease, epilepsy, depression, pain anxiety, and degenerative brain disease can be used as preventive or therapeutic agents.

According to a preferred embodiment of the present invention, the salt dissolved in the buffer solution is used as a diluent, and the buffer solution usually used may be phosphate buffer saline that mimics the salt form of the human solution. Since buffer salts can control the pH of the solution at low concentrations, the buffer diluent does not alter the biological activity of the compound.

The compounds of the present invention may be formulated for use as pharmaceutical or veterinary compositions also containing a pharmaceutically or veterinarily acceptable carrier or diluent. The composition according to the present invention can be generally prepared according to a conventional method, and can be administered in a pharmaceutically or veterinarily appropriate form.

According to a preferred embodiment of the present invention, it may be administered orally, such as in the form of tablets, capsules, sugar-coated tablets, film-coated tablets, liquid solutions or suspensions, or administered orally or intravenously May be administered parenterally.

The dosage can be determined according to various factors including the patient's age, body weight and condition and administration route. The daily dose can vary within wide limits and can be tailored to individual requirements in each individual case. In general, however, 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 in the range of 0.001 to 10 mg / kg body weight, for example, 0.01 to 1 mg / kg You can lose weight.

Such dosage can be provided, for example, 1 to 5 times per day. For intravenous injection, the appropriate daily dose is 0.0001 to 1 mg / kg body weight, preferably 0.0001 to 0.1 mg / kg body weight. The daily dose may be administered as a single dose or according to a divided dose schedule.

Hereinafter, the present invention will be described in more detail with reference to preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. It will be clear to those who have knowledge.

Those skilled in the art can also prepare compounds of the formula (I) by various methods based on the structure of the formula (I), all of which are in the scope of the present invention Should be interpreted to include.

That is, it is possible to prepare the compound of the formula (I) by any of the synthesis methods described in the following examples or various synthetic methods disclosed in the prior art, and it is understood that it belongs to the scope of the present invention, The method of preparing the compound is not limited to those described below.

<Examples>

1. Synthesis of compound 2 (4-hyroxybutyl4-methylbenzenesulfonate).

Butan-1,4-diol (Compound 1) (5.00 g, 55.48 mmol) was dissolved in CH ₂ Cl ₂ and triethylamine (Et ₃ N) (4.56 mL, 33.29 mmol), 4-dimethylaminopyridine (DMAP) , 2.77 mmol) and toluenesulfonyl chloride (TsCl) (5.29 g, 27.74 mmol) were successively added thereto, followed by stirring at room temperature for 0.5 hour. 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: 3) to obtain Compound 2 (2.20 g) in a yield of 45%.

Yellow oil; _Rf = 0.45 (hexanes / EtOAc 1/1);

^{1 H-NMR (400MHz, CDCl} 3): δ 7.79-7.73 (m, 2H), 7.35-7.26 (d, J = 8.0Hz, 2H), 6.19 (s, 1H), 4.04 (t, J = 4.0Hz 2H), 3.66 (t, J = 6.3 Hz, 2H), 2.45 (s, 3H), 1.74 - 1.69 (m, 2H), 1.61 - 1.58 (m, 2H).

2. General synthesis of compounds 4a to 4e (Method A)

Compounds 3a to 3e (1.0 eq) were dissolved in DMF, K ₂ CO ₃ (1.0 eq) and Compound 2 (1.0 eq) were added successively, and the mixture was stirred at room temperature for 4 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 distillation of the solvent under reduced pressure was purified by column chromatography (ethyl acetate / n-hexane 1: 2) to obtain the compounds 4a to 4e in a yield of 69-97%.

(1) 4- (p-Tolythio) butan-1-ol (4a)

Compound 4a was obtained by using Method A using 4-Methylbenzenethiol (Compound 3a) (0.76 g, 6.13 mmol), K ₂ CO ₃ (0.85 g, 6.13 mmol) and Compound 2 (1.5 g, 6.13 mmol).

Colorless oil (1.08 g, 90% yield); R _f = 0.6 (hexane / EtOAc 1/1);

^{1 H-NMR (400MHz, CDCl} 3): δ 7.28 (d, J = 8.0Hz, 2H), 7.08 (t, J = 8.0Hz, 2H), 3.64 (t, J = 6.0Hz, 2H), 2.90 ( t, J = 6.8 Hz, 2H), 2.30 (s, 3H), 1.72 - 1.67 (m, 4H).

(2) 4- (p-Methoxyphenylthio) butan-1-ol (4b)

Compound 4b was obtained by using Method A using 4-methoxybenzenethiol (compound 3b) (1.09 g, 7.78 mmol), K ₂ CO ₃ (1.08 g, 7.78 mmol) and compound 2 (1.90 g, 7.78 mmol).

Colorless oil (1.47 g, 89.1% yield); R _f = 0.6 (hexane / EtOAc 1/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.34 (d, J = 8.8Hz, 2H), 6.84 (d, J = 9.2Hz, 2H), 3.80 (s, 3H), 3.64 (t, J = 5.6Hz, 2H), 2.85 (t, J = 7.0 Hz, 2H), 1.65-1.61 (m, 4H).

(3) 4- (p-Fluorophenylthio) butan-1-ol (4c)

Compound 4c was obtained by using Method A using 4-Fluorobenzenethiol (Compound 3c) (0.47 g, 3.68 mmol), K ₂ CO ₃ (0.51 g, 3.68 mmol) and Compound 2 (0.90 g, 3.68 mmol).

Yellow oil (0.51 g, 69% yield); R _f = 0.6 (hexane / EtOAc 1/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.36-7.31 (m, 2H), 7.01-6.96 (m, 2H), 3.65 (d, J = 5.2Hz, 2H), 2.91-2.88 (m, 2H), 1.72 -1.67 (m, 4H).

(4) 4- (p-Chlorophenylthio) butan-1-ol (4d)

Compound 4d was obtained by using Method A using 4-chlorobenzenethiol (compound 3d) (2.25 g, 15.55 mmol), K ₂ CO ₃ (2.49 g, 15.55 mmol) and compound 2 (4.40 g, 15.55 mmol).

Yellow oil (3.20 g, 96.9% yield); R _f = 0.6 (hexane / EtOAc 1/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.25 (s, 4H), 3.67 (t, J = 5.5Hz, 2H), 2.94 (t, J = 6.7Hz, 2H), 1.74-1.71 (m, 4H).

(5) 4- (3,4-Dimethoxyphenylthio) butan-1-ol (4e)

3,4-Dimethoxybenzenethiol (Compound 3e) (0.69 g, 4.09 mmol), K ₂ CO ₃ (0.56 g, 4.09 mmol) and Compound 2 (1.00 g, 4.09 mmol) were subjected to Method A to obtain Compound 4e.

Colorless oil (0.80 g, 80.1% yield); _Rf = 0.65 (hexane / EtOAc 1/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 6.98 (d, J = 2.0Hz, 1H), 6.96 (d, J = 2.0Hz, 1H), 6.80 (d, J = 8.3Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.66-3.62 (m, 2H), 2.88-2.84 (m, 2H), 1.69-1.67 (m, 4H).

3. General suitability of compounds 5a to 5e (Method B)

Compounds 4a to 4e (1.0 eq) were dissolved in CH ₂ Cl ₂ and m-chloroperbenzoic acid (mCPBA) (1.0 eq) was added at -20 ° C and stirred at -20 ° C for 2h. After the reaction was terminated with sodium sulfite, the reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate / n-hexane 1: 3) to give compounds 5a to 5e in a yield of 76.7-96.3% .

(1) 4- (p-Tolylsulfinyl) butan-1-ol (5a)

Compound 4a (0.25 g, 1.27 mmol) was dissolved in CH ₂ Cl ₂ and mCPBA (0.28 g, 1.65 mmol) was used to obtain Compound 5a using Method B.

Colorless oil (0.25 g, 92.9% yield); R _f = 0.4 (EtOAc);

^{1 H-NMR (400MHz, CDCl} 3): δ 7.50 (d, J = 8.1Hz, 2H), 7.31 (d, J = 8.1Hz, 2H), 3.64-3.60 (m, 2H), 2.84-2.79 (m , 2H), 2.39 (s, 3H), 1.73 - 1.63 (m, 4H).

(2) 4- (p-Methoxyphenylsulfinyl) butan-1-ol (5b)

Compound 4b (0.72 g, 3.39 mmol) was dissolved in CH ₂ Cl ₂ and mCPBA (0.76 g, 4.40 mmol) was reacted with Compound B to obtain compound 5b.

Colorless oil (0.71 g, 92.2% yield); R _f = 0.4 (EtOAc);

^{1 H-NMR (400MHz, CDCl} 3): δ 7.55 (d, J = 8.8Hz, 2H), 7.02 (d, J = 9.2Hz, 2H), 3.86 (s, 3H), 3.65 (t, J = 6.0 Hz, 2H), 2.82-2.80 (m, 2H), 1.71-1.69 (m, 4H).

(3) 4- (p-Fluorophenylsulfinyl) butan-1-ol (5c)

Compound 4c (0.50 g, 2.50 mmol) was dissolved in CH ₂ Cl ₂ and mCPBA (0.56 g, 3.25 mmol) was reacted with Method B to give compound 5c.

Yellow oil (0.52 g, 96.3% yield); _Rf = 0.35 (EtOAc);

^{1 H-NMR (400MHz, CDCl} 3): δ 7.65-7.60 (m, 2H), 7.25-7.20 (m, 2H), 3.68-3.48 (m, 2H), 1.92-1.66 (m, 4H).

(4) 4- (p-Chlorophenylsulfinyl) butan-1-ol (5d)

Compound 4d (4.5 g, 20.00 mmol) was dissolved in CH ₂ Cl ₂ and mCPBA (4.64 g, 27.00 mmol) was reacted with Method B to give compound 5d.

Yellow oil (0.4 g, 76.7% yield); _Rf = 0.35 (EtOAc);

^{1 H-NMR (400MHz, CDCl} 3): δ 7.56 (dt, J = 8.6Hz, 4.2Hz, 2H), 7.49 (dt, J = 8.6Hz, 4.2Hz, 2H), 3.62 (t, J = 5.9Hz , 2H), 2.84 (td, J = 7.6, 3.4 Hz, 2H), 1.83-1.63 (m, 4H).

(5) 4- (3,4-Dimethoxyphenylsulfinyl) butan-1-ol (5e)

Compound 4e (0.6 g, 2.48 mmol) was dissolved in CH ₂ Cl ₂ , and mCPBA (0.55 g, 3.21 mmol) was used to obtain Compound 5e using Method B.

Yellow oil (0.55 g, 78.1% yield); R _f = 0.4 (EtOAc);

^{1 H-NMR (400MHz, CDCl} 3): δ 7.22 (d, J = 1.9Hz, 1H), 7.12 (dd, J = 8.3Hz, 1.9Hz, 1H), 6.96 (d, J = 8.3Hz, 1H) , 3.93 (s, 3H), 3.92 (s, 3H), 3.68 (t, J = 6.0 Hz, 2H), 2.90 - 2.78 (m, 2H), 1.85 - 1.66 (m, 4H).

4. General suitability of compounds 6a to 6e (Method C)

Compounds 5a to 5e (1.0 eq) were dissolved in CH ₂ Cl ₂ , Et ₃ N (1.5 eq) and MsCl (1.5 eq) were added successively, and the mixture was stirred at room temperature for 3 hours. When the reaction was completed, the reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and water, and the organic layer was dried with anhydrous Na ₂ SO ₄ and filtered. The solvent was distilled off under reduced pressure, the residue was dissolved in DMF, NaN ₃ (2.0 eq) was added, 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 (ethyl acetate / n-hexane 3: 1) to obtain compounds 6a to 6e in a yield of 77-92.3%.

(1) 1- (4-Azidobutylsulfinyl) -4-methylbenzene (6a)

Compound 5a (0.53 g, 2.50 mmol) , Et 3 N (0.52 mL, 3.75 mmol), MsCl (0.38 mL, 5.00 mmol), NaN 3 (0.26 g, 3.95 mmol) for using the Method C to give the compound 6a.

Colorless oil (0.41 g, 90.8% yield); _Rf = 0.5 (hexanes / EtOAc 1/5);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.50 (d, J = 8.4Hz, 2H), 7.31 (d, J = 8.4Hz, 2H), 3.30-3.26 (m, 2H), 2.80-2.76 (m, 2H ), 2.40 (s, 3H), 1.72-1.66 (m, 4H).

(2) 1- (4-Azidobutylsulfinyl) -4-methoxybenzene (6b)

Compound 6b was obtained by Method C using Compound 5b (0.45 g, 1.97 mmol), Et ₃ N (0.35 mL, 2.56 mmol), MsCl (0.38 mL, 4.93 mmol) and NaN ₃ (0.20 g, 3.13 mmol).

Colorless oil (0.36 g, 92.3% yield); _Rf = 0.5 (hexanes / EtOAc 1/5);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.56 (d, J = 8.4Hz, 2H), 7.03 (d, J = 8.4Hz, 2H), 3.86 (s, 3H), 3.31-3.28 (m, 2H), 2.81-2.78 (m, 2H), 1.74-1.69 (m, 4H).

(3) 1- (4-Azidobutylsulfinyl) -4-fluorobenzene (6c)

Compound 5c (0.27 g, 1.25 mmol) , Et 3 N (0.19 mL, 1.37 mmol), MsCl (0.09 mL, 1.25 mmol), NaN 3 (0.08 g, 1.36 mmol) for using the Method C to give the compound 6c.

Yellow oil (0.12 g, 75% yield); R _f = 0.6 (hexanes / EtOAc 1/5);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.64-7.61 (m, 2H), 7.26-7.21 (m, 2H), 3.33-3.27 (m, 2H), 2.81-2.78 (m, 2H), 1.85-1.62 ( m, 2H).

(4) 1- (4-Azidobutylsulfinyl) -4-chlorobenzene (6d)

Compound 5d (3.00 g, 0.01 mmol) , Et 3 N (2.10 mL, 0.015 mmol), MsCl (1.50 mL, 0.02 mmol), NaN 3 (1.30 g, 0.02 mmol) for using the Method C to give the compound 6d.

Yellow oil (2.2 g, 90.2% yield); _Rf = 0.7 (hexanes / EtOAc 1/5);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.56 (dt, J = 8.5, 3.2Hz, 2H), 7.52 (dt, J = 8.5Hz, 3.2Hz, 2H), 3.34-3.29 (m, 2H), 2.83- 2.77 (m, 2H), 1.74-1.69 (m, 4H).

(5) 4- (4-Azidobutylsulfinyl) -1,2-dimethoxybenzene (6e)

Compound 6e was obtained by Method C using Compound 5e (0.35 g, 1.35 mmol), Et ₃ N (0.28 mL, 2.03 mmol), MsCl (0.2 mL, 2.7 mmol) and NaN ₃ (0.18 g, 2.80 mmol).

Yellow oil (0.3 g, 76.9% yield); _Rf = 0.7 (hexanes / EtOAc 1/5);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.19 (d, J = 1.9Hz, 1H), 7.10 (dd, J = 8.3Hz, 1.9Hz, 1H), 6.95 (d, J = 8.3Hz, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.30-3.27 (m, 2H), 2.85-2.75 (m, 2H), 1.81-1.65 (m, 4H).

5. General synthesis of compounds 7a to 7e (Method D)

Compounds 6a to 6e (1.0 eq) were dissolved in EtOH, NH ₄ Cl (6.0 eq) and zinc dust (3.0 eq) dissolved in water were added successively, and 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 the zinc dust. The filtrate was distilled under reduced pressure, and the residue was purified by column chromatography (MeOH / CH ₂ Cl ₂ 1: 9) to give compounds 7a to 7e in a yield of 61-86.4%.

(1) 4- (p-Tolylsulfinyl) butan-1-amine (7a)

Compound 6a (0.53 g, 2.23 mmol) was dissolved in EtOH and NH ₄ Cl (0.72 g, 13.38 mmol) and zinc di (0.42 g, 6.69 mmol) dissolved in water (3 mL) .

Colorless oil (0.3 g, 63% yield); R _f = 0.2 (CH ₂ Cl ₂ / MeOH 9/1);

^{1 HNMR (400MHz, MeOD):} δ 7.48 (d, J = 8.0Hz, 2H), 7.26 (d, J = 8.0Hz, 2H), 3.13 (t, J = 6.64Hz, 2H), 2.80 (q, J = 6.04 Hz, 2H), 2.36 (s, 3H), 1.90 - 1.30 (m, 4H);

¹³ C-NMR (100 MHz, MeOD):? 143.6, 140.4, 131.2, 125.4, 56.4, 40.2, 27.4, 21.4, 20.4;

^{LPMS (M + H) + (} ESI +) 212 (calcd for C 11 H 18 NOS + 212.32);

_{Purity52% (t R = 46.82min)} .

(2) 4- (p-Methoxyphenylsulfinyl) butan-1-amine (7b)

Compound 6b (0.18 g, 0.71 mmol) was dissolved in EtOH and NH ₄ Cl (0.23 g, 1.26 mmol) and zincdust (0.13 g, 2.13 mmol) dissolved in water (1 mL) .

Colorless oil (0.12 g, 74.5% yield); R _f = 0.2 (CH ₂ Cl ₂ / MeOH 9/1);

^{1 HNMR (400MHz, DMSO-d} 6): δ 7.58 (d, J = 7.6Hz, 2H), 7.12 (d, J = 7.6Hz, 2H), 3.81 (s, 3H), 2.91-2.89 (m, 2H ), 2.79-2.74 (m, 2H), 1.64-1. 60 (m, 4H);

¹³ CNMR (100 MHz, MeOD):? 164.1, 134.4, 128.7, 127.6, 116.1, 114.4, 57.0, 56.2, 30.8, 29.3, 20.9.

(3) 4- (p-Fluorophenylsulfinyl) butan-1-amine (7c)

Compound 6c (0.37 g, 1.54 mmol) was dissolved in EtOH and NH ₄ Cl (0.49 g, 9.26 mmol) and zinc di (0.29 g, 4.63 mmol) dissolved in water (1 mL) .

Yellow oil (0.2 g, 61% yield); R _f = 0.2 (CH ₂ Cl ₂ / MeOH 9/1);

^{1 HNMR (400MHz, DMSO-d} 6): δ 7.75-7.71 (m, 2H), 7.46-7.42 (m, 2H), 2.98 (t, J = 7.5Hz, 2H), 2.74 (t, J = 7.1Hz , &Lt; / RTI &gt; 2H), 1.66-1.62 (m, 4H);

_{Purity100% (t R = 18.37min)} .

(4) 4- (p-Chlorophenylsulfinyl) butan-1-amine (7d)

Compound 6d (2.06 g, 7.99 mmol) was dissolved in EtOH and NH ₄ Cl (2.56 g, 48.00 mmol) and zincdust (1.53 g, 24.00 mmol) dissolved in water (6 mL) .

Yellow oil (1.6 g, 86.4% yield); R _f = 0.2 (CH ₂ Cl ₂ / MeOH 9/1);

^{1 HNMR (400MHz, DMSO-d} 6): δ 7.74-7.72 (m, 2H), 7.65-7.63 (m, 2H), 3.33-3.32 (m, 2H), 2.92 (t, J = 6.9Hz, 2H) , 1.85-1.84 (m, 4H);

_{Purity100% (t R = 6.65min)} .

(5) 4- (3,4-Dimethoxyphenylsulfinyl) butan-1-amine (7e)

Compound 6e (0.1 g, 0.35 mmol) was dissolved in EtOH and NH ₄ Cl (56 mg, 1.05 mmol) and zincdust (0.13 g, 2.11 mmol) dissolved in water (1 mL) .

Colorless oil (70 mg, 77% yield); R _f = 0.2 (CH ₂ Cl ₂ / MeOH 9/1);

^{1 HNMR (400MHz, MeOD):} δ 7.20-7.17 (m, 2H), 7.06 (d, J = 8.2Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 2.94-2.86 (m, 4H), 1.76-1.62 (m, 4H).

6. General synthesis of compounds 8a to 8e (Method E)

Compounds 7a to 7e (1.0 eq) were dissolved in CH ₂ Cl ₂ , Et ₃ N (1.1 eq) and DPT (1.1 eq) were added successively, and the mixture was stirred at room temperature for 2 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 over anhydrous MgSO ₄ and filtered. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography (ethyl acetate / n-hexane 6: 1) to give compounds 8a to 8e in a yield of 72-86.5%.

(1) 1- (p-Isothiocyanatobutylsulfinyl) -4-methylbenzene (8a)

Compound 7a (0.13 g, 0.61 mmol) was dissolved in CH ₂ Cl ₂ and Et ₃ N (0.09 mL, 0.68 mmol) and DPT (141 mg, 0.61 mmol)

Yellow oil (0.12 g, 77.9% yield); R _f = 0.4 (EtOAc);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.51 (d, J = 8.2Hz, 2H), 7.35 (d, J = 8.2Hz, 2H), 3.53 (td, J = 6.14, 2.9Hz, 2H), 2.82- 2.77 (m, 2 H), 2.41 (s, 3 H), 1.84 - 1.77 (m, 4 H);

¹³ C-NMR (100 MHz, CDCl ₃ ):? 140.7, 139.2, 129.8, 129.1, 122.9, 54.9, 43.6, 27.9, 20.4, 18.5;

FT-IR (neat), cm ^-1 : 1706.77 (NCS).

(2) 1- (p-Isothiocyanatobutylsulfinyl) -4-methoxybenzene (8b)

Compound 7b (0.36 g, 1.58 mmol) was dissolved in CH ₂ Cl ₂ and Et ₃ N (0.24 mL, 1.73 mmol) and DPT (0.40 g, 1.73 mmol)

Yellow oil (0.42 g, 80% yield); R _f = 0.4 (EtOAc);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.56 (d, J = 8.8Hz, 2H), 7.04 (d, J = 8.4Hz, 2H), 3.86 (s, 3H), 3.55-3.52 (m, 2H), 2.81-2.77 (m, 2H), 1.88-1.74 (m, 4H);

^{13 C} NMR (100 MHz, CDCl ₃ ):? 162.1, 134.1, 130.6, 125.9, 114.9, 56.0, 55.6, 44.6, 28.9, 19.6.

(3) 1- (p-Isothiocyanatobutylsulfinyl) -4-fluorobenzene (8c)

Compound 7c (0.10 g, 0.46 mmol) was dissolved in CH ₂ Cl ₂ , Et ₃ N (0.07 mL, 5.10 mmol) and DPT (0.35 g, 5.10 mmol)

Yellow oil (91 mg, 77% yield); R _f = 0.4 (EtOAc);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.63-7.61 (m, 2H), 7.25-7.20 (m, 2H), 3.55-3.52 (m, 2H), 2.82-2.77 (m, 2H), 1.84-1.77 ( m, 4H);

_{^{13 CNMR (100MHz, CDCl 3)}} : δ 165.7, 163.2, 138.8, 130.9, 126.4, 116.9, 56.1, 44.6, 28.9, 19.5.

(4) 1- (p-Isothiocyanatobutylsulfinyl) -4-chlorobenzene (8d)

Compound 7d (0.20 g, 0.86 mmol) was dissolved in CH ₂ Cl ₂ and Et ₃ N (0.13 mL, 0.95 mmol) and DPT (61 mg, 0.86 mmol) were used to obtain compound 8d.

Yellow oil (0.20 g, 86.5% yield); R _f = 0.4 (EtOAc);

¹ HNMR (400MHz, CDCl ₃ ):? 7.5-7.51 (m, 4H), 3.57-3.53 (m, 2H), 2.84-2.77 (m, 2H), 1.88-1.56 (m, 4H);

¹³ C-NMR (100 MHz, CDCl ₃ ):? 141.9, 137.4, 129.6, 125.4, 55.9, 44.6, 28.9, 19.4;

FT-IR (neat), cm ^-1 : 2003.77 (NCS).

(5) 1- (p-Isothiocyanatobutylsulfinyl) -3,4-dimethoxybenzene (8e)

Compound 7e (0.22 g, 0.85 mmol) was dissolved in CH ₂ Cl ₂ and Et ₃ N (0.13 mL, 0.94 mmol) and DPT (0.65 g, 0.94 mmol)

Yellow oil (0.18 g, 72% yield); R _f = 0.45 (EtOAc);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.20 (s, 1H), 7.11 (m, 1H), 6.96 (d, J = 8.4Hz, 1H), 3.93 (d, J = 8.8Hz, 6H), 3.54 ( m, 2 H), 2.80 (m, 2 H), 1.80 (m, 2 H)

¹³ C-NMR (100 MHz, CDCl ₃ ):? 151.5, 150.2, 134.5, 117.5, 111.2, 106.2, 56.3, 44.7, 30.9, 28.9, 19.8.

7. General synthesis of compounds 9a-9d (Method F)

Compound 5a-d (1.0 eq) was dissolved in CH ₂ Cl ₂ , added with Dess-martin periodinane (DMP) (1.1 eq) and stirred at room temperature for 2 hours. After the reaction was terminated with a saturated aqueous solution of sodium thiosulfate, the reaction solution was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over 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 9: 1) to give compound 9a-d in a yield of 76.5-89.7% .

(1) 4- (p-Tolylsulfinyl) butanal (9a)

Compound 5a (0.4 g, 1.88 mmol) was dissolved in CH ₂ Cl ₂ and DMP (0.88 g, 2.07 mmol) was used to obtain Compound 9a by Method F.

Colorless oil (0.35 g, 89.7% yield); _Rf = 0.4 (hexane / EtOAc 1/9);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 9.74 (s, 1H), 7.50 (d, J = 8.0Hz, 2H), 7.33 (d, J = 8.0Hz, 2H), 2.84-2.78 (m, 2H), 2.65 - 2.61 (m, 2H), 2.41 (s, 3H), 2.07 - 1.94 (m, 2H).

(2) 4- (p-Methoxyphenylsulfinyl) butanal (9b)

Compound 5b (0.20 g, 0.87 mmol) was dissolved in CH ₂ Cl ₂ , and DMP (0.48 g, 1.13 mmol) was used to obtain Compound 9b using Method F.

Colorless oil (0.15 g, 76.5% yield); _Rf = 0.65 (hexane / EtOAc 1/9);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 9.74 (s, 1H), 7.51 (d, J = 8.8Hz, 2H), 6.98 (d, J = 8.8Hz, 2H), 3.81 (s, 3H), 2.82- 2.78 (m, 2H), 2.62 (t, J = 7.2 Hz, 2H), 2.04 - 1.94 (m, 2H).

(3) 4- (p-Fluorophenylsulfinyl) butanal (9c)

Compound 5c (0.30 g, 1.38 mmol) was dissolved in CH ₂ Cl ₂ , and DMP (0.64 g, 1.52 mmol) was used to obtain Compound 9c using Method F.

Yellow oil (0.24 g, 80% yield); _Rf = 0.65 (hexane / EtOAc 1/9);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 9.76 (s, 1H), 7.64-7.60 (m, 2H), 7.28-7.21 (m, 2H), 2.90-2.78 (m, 2H), 2.68-2.64 (m, 2H), 2.07-2.05 (m, 2H).

(4) 4- (p-Chlorophenylsulfinyl) butanal (9d)

Compound 5d (0.30 g, 1.31 mmol) was dissolved in CH ₂ Cl ₂ and DMP (0.61 g, 1.43 mmol) was used to obtain compound 9d using Method F.

Yellow oil (0.28 g, 93.3% yield); _Rf = 0.65 (hexane / EtOAc 1/9);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 9.75 (s, 1H), 7.59-7.30 (m, 4H), 2.88-2.77 (m, 2H), 2.65 (td, J = 6.3, 0.8Hz, 2H), 2.08 -1.94 (m, 2H).

8. General synthesis of compound 10a-10d (Method G)

Compound 9a to 9d (1.0 eq) and MeNH ^_2. HCl (1.2 eq) and NaBH (OAc) ₃ (2.8 eq) were dissolved in DCE, Et ₃ N (1.5 eq) was added and the mixture was stirred at room temperature for 24 hours. After the reaction was completed with a saturated aqueous sodium bicarbonate solution, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over 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 1: 9) to obtain the compounds 10a to 10d in a yield of 26-53%.

(1) 4- (p-Tolylsulfinyl) -N-methylbutan-1-amine (10a)

Compound 9a (130 mg, 0.60 mmol) and MeNH ^_2. HCl (49 mg, 0.72 mmol), NaBH (OAc) ₃ (0.36 g, 1.68 mmol) was dissolved in DCE and Et ₃ N (0.13 mL, 0.9 mmol) was treated with Method G to give compound 10a.

Colorless oil (35 mg, 26% yield); R _f = 0.35 (CH ₂ Cl ₂ / MeOH 9/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.49 (d, J = 8.0Hz, 2H), 7.31 (d, J = 8.0Hz, 2H), 2.77-2.74 (m, 2H), 2.39 (s, 3H), 2.32 (t, J = 6.84 Hz, 2H), 2.16 (s, 3H), 1.61 - 1.52 (m, 4H);

¹³ CNMR (100 MHz, CDCl ₃ ):? 141.4, 140.6, 129.9, 124.0, 57.2, 57.0, 41.8, 26.2, 21.4, 20.2;

Purity100% (t _R = 15.10min)

(2) 4- (p-Methoxyphenylsulfinyl) -N-methylbutan-1-amine (10b)

Compound 9b (150 mg, 0.66 mmol) and MeNH ^_2. HCl (49 mg, 0.73 mmol), NaBH (OAc) ₃ (0.19 g, 0.93 mmol) was dissolved in DCE and Et ₃ N (0.13 mL, 0.99 mmol) was treated with Method G to give compound 10b.

Colorless oil (45 mg, 28.3% yield); R _f = 0.35 (CH ₂ Cl ₂ / MeOH 9/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.57 (dt, J = 8.8, 2.3Hz, 2H), 7.12 (dt, J = 8.8, 2.3Hz, 2H), 3.81 (s, 3H), 2.51-2.49 (m , 2H), 2.19-2.10 (m, 2H), 1.43-1. 41 (m, 4H);

_{^{13 CNMR (100MHz, CDCl 3)}} : δ 161.9, 134.7, 125.9, 114.8, 57.2, 56.9, 55.6, 41.9, 26.1, 20.3;

_{Purity100% (t R = 18.60min)} .

(3) 4- (p-Fluorophenylsulfinyl) -N-methylbutan-1-amine (10c)

Compound 9c (70 mg, 0.33 mmol) and MeNH ^_2. Compound 10c was obtained using Method G by dissolving HCl (10.7 mg, 0.34 mmol), NaBH (OAc) ₃ (98 mg, 0.46 mmol) in DCE and Et ₃ N (0.07 mL, 0.49 mmol) , 31% yield)

R _f = 0.35 (CH ₂ Cl ₂ / MeOH 9/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.64-7.60 (m, 2H), 7.26-7.20 (m, 2H), 2.78 (t, J = 7.7Hz, 2H), 2.33 (t, J = 7.3Hz, 2H ), 2.17 (s, 3H), 1.64 - 1.54 (m, 4H);

_{^{13 CNMR (100MHz, CDCl 3)}} : δ 165.5, 139.5, 126.4, 116.8, 57.3, 42.0, 29.5, 26.2, 20.2;

_{Purity88.04% (t R = 8.38min)} .

(4) 4- (p-Chlorophenylsulfinyl) -N-methylbutan-1-amine (10d)

Compound 9d (0.12 g, 0.54 mmol) and MeNH ^_2. HCl (43.75 mg, 0.65 mmol), NaBH (OAc) ₃ (0.32 g, 1.51 mmol) was dissolved in DCE and Et ₃ N (0.10 mL, 0.81 mmol) was treated with Method G to give compound 10a.

Colorless oil (70 mg, 53% yield); R _f = 0.2 (CH ₂ Cl ₂ / MeOH 9/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.59 (dd, J = 8.6, 1.9Hz, 2H), 7.53 (dd, J = 8.6, 1.9Hz, 2H), 2.83-2.79 (m, 2H), 2.29 (t , J = 6.5 Hz, 2H), 2.16 (s, 3H), 1.65 - 1.53 (m, 4H);

_{^{13 CNMR (100MHz, CDCl 3)}} : δ 141.5, 136.1, 128.5, 123.4, 56.2, 56.1, 40.9, 25.3, 19.1;

_{Purity100% (t R = 20.36min)} .

9. General synthesis of compounds 11a-11d (Method H)

Compound 9a to 9d (1 eq) and Me ₂ ^NH. HCl (1.2 eq), NaBH (OAc) ₃ (2.8 eq) were dissolved in DCE, Et ₃ N (1.5 eq) was added and the mixture was stirred at room temperature for 24 hours. After the reaction was completed with a saturated aqueous sodium bicarbonate solution, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over 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 1: 9) to obtain the compounds 11a to 11d in a yield of 14.3-36.8%.

(1) 4- (p-Tolylsulfinyl) -N, N-dimethylbutan-1-amine (11a)

Compound 9a (0.1 g, 0.47 mmol) and Me ₂ ^NH. HCl (25 mg, 0.56 mmol) and NaBH (OAc) ₃ (0.28 g, 1.32 mmol) were dissolved in DCE and Et ₃ N (0.1 ml, 0.71 mmol) was reacted with Method H to give compound 11a.

Colorless oil (16 mg, 14.3% yield); R _f = 0.35 (CH ₂ Cl ₂ / MeOH 9/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.51 (d, J = 8.0Hz, 2H), 7.33 (d, J = 8.0Hz, 2H), 2.79 (t, J = 7.76Hz, 2H), 2.41 (s, 3H), 2.33 (t, J = 7.32 Hz, 2H), 2.24 (s, 6H), 1.65 - 1.60 (m, 4H);

_{^{13 CNMR (100MHz, CDCl 3)}} : δ 140.4, 139.5, 128.9, 123.0, 57.7, 55.9, 43.9, 25.1, 20.3, 19.1;

LPMS (M + H) ⁺ (ESI ⁺ ) 240 (calcdforC ₁₃ H ₂₂ NOS ⁺ 240.38);

_{Purity88% (t R = 5.27min)} .

(2) 4- (p-Methoxyphenylsulfinyl) -N, N-dimethylbutan-1-amine (11b)

Compound 9b (34 mg, 0.15 mmol) and Me ₂ ^NH. HCl (15 mg, 0.33 mmol) and NaBH (OAc) ₃ (95 mg, 0.45 mmol) were dissolved in DCE and Et ₃ N (0.06 mL, 0.45 mmol) was reacted with Method H to obtain compound 11b.

Colorless oil (14 mg, 36.8% yield); R _f = 0.45 (CH ₂ Cl ₂ / MeOH 9/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.57 (d, J = 8.8Hz, 2H), 7.03 (d, J = 8.8Hz, 2H), 3.86 (s, 3H), 2.80-2.70 (m, 2H), 2.31-2.27 (m, 2H), 2.22 (s, 6H), 1.63 - 1.58 (m, 4H);

LPMS (M + H) ⁺ (ESI ⁺ ) 256 (calcdforC ₁₃ H ₂₂ NO ₂ S ⁺ 256.38).

(3) 4- (p-Fluorophenylsulfinyl) -N, N-dimethylbutan-1-amine (11c)

Compound 9c (70 mg, 0.33 mmol) and Me ₂ ^NH. HCl (27 mg, 0.34 mmol), NaBH (OAc) ₃ (98 mg, 0.46 mmol) was dissolved in DCE and Et ₃ N (0.07 ml, 0.49 mmol) was reacted with Method H to give compound 11c.

Yellow oil (20 mg, 25% yield); R _f = 0.35 (CH ₂ Cl ₂ / MeOH 9/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.57-7.54 (m, 2H), 7.17-7.13 (m, 2H), 2.75-2.71 (m, 2H), 2.24 (t, J = 7.4Hz, 2H), 2.16 (s, 6H), 1.59 - 1.51 (m, 4H);

^{13 C} NMR (100 MHz, CDCl ₃ ): δ 165.6, 139.1, 126.3, 116.7, 58.3, 58.2, 44.4, 29.7, 19.9.

(4) 4- (p-Chlorophenylsulfinyl) -N, N-dimethylbutan-1-amine (11d)

Compound 9d (0.14 g, 0.63 mmol) and Me ₂ ^NH. HCl (56 mg, 1.26 mmol) and NaBH (OAc) ₃ (0.53 g, 2.52 mmol) were dissolved in DCE and Et ₃ N (0.13 mL, 0.95 mmol) was reacted with Method H to give compound 11d.

Colorless oil (41 mg, 16% yield); R _f = 0.2 (CH ₂ Cl ₂ / MeOH 9/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.56 (d, J = 8.3Hz, 2H), 7.50 (d, J = 8.3Hz, 2H), 2.79 (t, J = 7.0Hz, 2H), 2.26 (t, J = 7.0 Hz, 2H), 2.19 (s, 6H), 1.59 - 1.43 (m, 4H);

_{^{13 CNMR (100MHz, CDCl 3)}} : δ 141.4, 136.2, 128.5, 124.5, 57.9, 56.2, 44.3, 25.6, 19.1;

LPMS (M + H) &lt; ⁺ & gt ^; (ESI ⁺ ) 260 (calcdforC ₁₂ H ₁₉ ClNOS ⁺ 260.80);

_{Purity70% (t R = 7.60min)} .

10. General synthesis of compounds 12a-12h (Method I)

R ₃ CO ₂ H (1.1 eq), 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) (1.0 eq) and DMAP (0.1 eq) were dissolved in CH ₂ Cl ₂ and Et ₃ N ) And the compounds 7a, 7b and 7d (1.0 eq) were added thereto, followed by stirring at room temperature for 4 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) to give compounds 12a to 12h in a yield of 34.4-87.6%.

(1) N- (4- (p-Tolylsulfinyl) butylacetamide (12a)

Was dissolved in CH ₂ Cl ₂ , Et ₃ N (0.13 ml, 0.94 mmol), and compound 7a (0.94 mmol) were dissolved in MeC ₂ H (28 mg, 0.47 mmol) and EDC 90 mg, 0.43 mmol), Compound 12a was obtained by Method I.

Colorless oil (0.92 g, 85.1% yield);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.50 (d, J = 8.0Hz, 2H), 7.33 (d, J = 8.0Hz, 2H), 5.71 (s, 1H), 3.27-3.23 (m, 2H), 2.81-2.77 (m, 2H), 2.42 (s, 3H), 1.96 (s, 3H), 1.81 - 1.61 (m, 4H);

^{13 C} NMR (100 MHz, CDCl ₃ ): δ 170.1, 141.5, 140.3, 129.9, 123.9, 56.3, 38.8, 28.4, 23.3, 21.4, 19.5

LPMS (M + H) ⁺ (ESI ⁺ ) 254 (calcdforC ₁₃ H ₁₉ NO ₂ S ⁺ 254.36);

_{Purity100% (t R = 5.70min)} .

(2) N- (4- (p-Tolylsulfinyl) butyl) propionamide (12b)

A solution of Et ₃ N (0.03 mL, 0.27 mmol), compound 7a (0.27 mmol), and diisopropylethylamine (0.06 mL, 0.13 mmol) were dissolved in CH ₂ Cl ₂ with EtCO ₂ H (9.6 mg, 0.13 mmol) 26 mg, 0.12 mmol), Compound 12b was obtained by Method I.

white solid (10 mg, 34.4% yield); R _f = 0.3 (CH ₂ Cl ₂ / MeOH 9/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.50 (d, J = 8.1Hz, 2H), 7.33 (d, J = 8.1Hz, 2H), 3.25 (qd, J = 6.4, 2.6Hz), 2.80-2.78 ( m, 2H), 2.41 (s, 3H), 2.17 (q, J = 7.6 Hz, 2H), 1.66-1.62 (m, 4H), 1.13 (t, J = 7.6 Hz, 3H);

¹³ CNMR (100 MHz, CDCl ₃ ):? 173.9, 141.5, 140.3, 130.9, 129.9, 123.9, 56.3, 39.7, 29.7, 28.5, 21.4, 16.5, 9.9;

LPMS (M + H) ⁺ (ESI ⁺ ) 268 (calcdforC ₁₄ H ₂₂ NO ₂ S ⁺ 268.39);

_{Purity95.8% (t R = 5.19min)} .

(3) N- (4- (p-Tolylsulfinyl) butyl) isobutyramide (12c)

_{iPrCO 2 H (12.3 mg, 0.14} mmol) and EDC (25 mg, 0.13 mmol) , DMAP (1.50 mg, 0.013 mmol) was dissolved in _{CH 2 Cl 2, Et 3 N} (0.04 mL, 0.29 mmol), compound 7d ( 28.2 g, 0.13 mmol), Compound 12c was obtained by Method I.

white solid (21.2 mg, 59% yield); R _f = 0.45 (CH ₂ Cl ₂ / MeOH 9/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.49 (d, J = 8.1Hz, 2H), 7.33 (d, J = 8.1Hz, 2H), 5.68 (s, 1H), 3.22 (q, J = 6.3Hz, 2H), 2.79-2.76 (m, 2H), 2.41 (s, 3H), 2.32-2.29 (m, 1H), 1.64-1.62 (m, 4H), 1.11 (dd, J = 6.8, 2.8Hz, ;

^{13 C} NMR (100 MHz, CDCl ₃ ): δ 176.0, 140.5, 139.3, 128.9, 129.9, 55.3, 37.5, 34.6, 27.5, 20.4, 18.6, 18.4;

LPMS (M + H) &lt; ⁺ & gt ^; (ESI ⁺ ) 282 (calcdforC ₁₅ H ₂₃ NO ₂ S ⁺ 282.41);

_{Purity100% (t R = 5.99min)} .

(4) N- (4- (p-Methoxyphenylsulfinyl) butyl) acetamide (12d)

Et ₂ N (72 μl, 0.52 mmol), Compound 7b (55 mg, 0.24 mmol) and MeOH ₂ H (16 mg, 0.26 mmol) were dissolved in CH ₂ Cl ₂ and EDC mg, 0.24 mmol) using Method I to give compound 12d.

Colorless oil (45 mg, 69.2% yield); R _f = 0.4 (CH ₂ Cl ₂ / MeOH 9/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.54 (d, J = 8.8Hz, 2H), 7.02 (d, J = 8.8Hz, 2H), 5.76 (br, 1H), 3.85 (s, 3H), 3.24- 2.80 (m, 2H), 2.78-2.00 (m, 2H), 1.95 (s, 3H), 1.76 - 1.59 (m, 4H);

¹³ CNMR (100 MHz, CDCl ₃ ):? 170.5, 162.0, 134.2, 125.9, 114.8, 56.5, 55.5, 39.4, 38.7, 28.4, 23.1, 19.7.

(5) N- (4- (p-Methoxyphenylsulfinyl) butyl) isobutyramide (12e)

_{iPrCO 2 H (33 mg, 0.38} mmol) and EDC (74 mg, 0.38 mmol) , DMAP (4.3 mg, 0.03 mmol) was dissolved in _{CH 2 Cl 2, Et 3 N} (0.11 mL, 0.77 mmol), compound 7b ( 80 mg, 0.35 mmol), Compound 12e was obtained by Method I.

Colorless oil (70 mg, 66.7% yield); R _f = 0.2 (CH ₂ Cl ₂ / MeOH 9/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.54 (d, J = 8.8Hz, 2H), 7.02 (d, J = 8.8Hz, 2H), 5.66 (br, 1H), 3.85 (s, 3H), 3.24 ( J = 6.0 Hz, 2H), 2.78 (t, J = 7.0 Hz, 2H), 2.32-2.74 (m, 2H), 1.78-1.63 );

^{13 C} NMR (100 MHz, CDCl ₃ ): δ 177.2, 161.9, 134.4, 125.8, 114.8, 56.5, 55.5, 38.5, 35.6, 28.5, 19.6.

(6) N- (4- (p-Chlorophenylsulfinyl) butyl) acetamide (12f)

_{MeCO 2 H (51 mg, 0.86} mmol) and EDC (0.14 g, 0.78 mmol) , DMAP (9.5 mg, 0.078 mmol) was dissolved in _{CH 2 Cl 2, Et 3 N} (0.24 mL, 1.72 mmol), compound 7d ( 0.18 g, 0.78 mmol) using Method I to give compound 12f.

white solid (0.18 g, 84.5% yield); R _f = 0.4 (CH ₂ Cl ₂ / MeOH 9/1);

mp: 89.2-92.0;

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.55-7.49 (m, 4H), 5.67 (s, 1H), 3.25-3.24 (m, 2H), 2.83-2.76 (m, 2H), 1.95 (s, 3H) , 1.66-1.61 (m, 4H);

_{^{13 CNMR (100MHz, CDCl 3)}} : δ 170.4, 142.0, 137.2, 127.9, 125.4, 56.4, 38.6, 28.4, 23.1, 19.4;

LPMS (M + Na) ⁺ (ESI ⁺ ) 296 (calcdforC ₁₂ H ₁₆ ClNO ₂ SNa ⁺ 274.78);

_{Purity100% (t R = 4.58min)} .

(7) N- (4- (p-Chlorophenylsulfinyl) butyl) propionamide (12 g)

_{EtCO 2 H (38 mg, 0.52} mmol) and EDC (90 mg, 0.47 mmol) , DMAP (5.7 mg, 0.047 mmol) was dissolved in _{CH 2 Cl 2, Et 3 N} (0.15 mL, 1.04 mmol), compound 7d ( 0.11 g, 0.47 mmol), Method 12 was used to obtain 12 g of a compound.

white solid (0.11 g, 76.9% yield); R _f = 0.45 (CH ₂ Cl ₂ / MeOH 9/1);

mp: 81-84;

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.55-7.48 (m, 4H), 5.67 (s, 1H), 3.24 (qb, J = 6.4, 1.3Hz, 2H), 2.83-2.76 (m, 2H), 2.15 (q, J = 7.6, 3.6 Hz, 2H), 1.65-1.63 (m, 4H), 1.12 (t, J = 7.6, 3.6 Hz, 3H);

¹³ CNMR (100 MHz, CDCl ₃ ):? 170.4, 142.1, 137.2, 129.5, 125.4, 56.4, 29.6, 28.5, 19.3, 9.9;

LPMS (M + Na) ⁺ (ESI ⁺ ) 310 (C ₁₃ H ₁₈ ClNO ₂ SNa ⁺ 310.81);

_{Purity100% (t R = 13.58min)} .

(8) N- (4- (p-Chlorophenylsulfinyl) butyl) isobutyramide (12h)

_{iPrCO 2 H (0.24 g, 0.81} mmol) and EDC (139 mg, 0.73 mmol) , DMAP (8.9 mg, 0.073 mmol) was dissolved in _{CH 2 Cl 2, Et 3 N} (0.22 ml, 1.61 mmol), compound 7d ( 0.17 g, 0.73 mmol) using Method I to give compound 12h.

white solid (0.19 g, 87.6% yield); R _f = 0.45 (CH ₂ Cl ₂ / MeOH 9/1);

mp: 118.9-122;

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.55-7.48 (m, 4H), 5.64 (s, 1H), 3.23 (q, J = 6.4Hz, 2H), 2.84-2.78 (m, 2H), 2.32-2.28 (m, 1H), 1.65-1.62 (m, 4H), 1.16-1.09 (m, 6H);

^{13 C} NMR (100 MHz, CDCl ₃ ): δ 177.7, 141.5, 137.3, 129.6, 125.5, 56.1, 38.4, 35.5, 33.8, 28.3, 18.9;

^{LPMS (M + Na) + (} ESI +) 324 (calcdfor; C 14 H 20 ClNO 2 SNa + 324.83);

_{Purity100% (t R = 6.24min)} .

10. General synthesis of compounds 13a, 13d, 13f (Method J)

Compound 7a, 7b, 7d (1.0 eq) was dissolved in CH ₂ Cl ₂ , Et ₃ N (1.0 eq) and triphosgene (1.1 eq) were added in this order and stirred at room temperature for 2 hours. When the reaction is terminated, MeNH ₂ ^. HCl (2.0 eq) and Et ₃ N (2.0 eq) were added thereto, followed by stirring at room temperature for 12 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 1: 9) to obtain the compounds 13a, 13d and 13f in a yield of 19.4-47.9%.

(1) 1- (4-p-Tolylsulfinyl) butyl) -3-methylurea (13a)

Compound 7a (130 mg, 0.61 mmol) was dissolved in a CH _{2 Cl 2, Et 3 N (0.08} mL, 0.61 mmol), triphosgene (62 mg, 0.21 mmol) After completion of the reaction MeNH ₂ in the reaction ^solution. HCl (82.3 mg, 1.22 mmol) and Et ₃ N (0.34 ml, 2.44 mmol), Compound 13a was obtained by Method J.

white solid (30.5 mg, 19.4% yield); R _f = 0.2 (CH ₂ Cl ₂ / MeOH 9/1);

mp: 97.1-97.8;

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.23 (d, J = 8.0Hz, 2H), 7.09 (d, J = 8.0Hz, 2H), 4.76 (s, 1H), 4.74 (s, 1H), 3.15 ( (q, J = 6.0 Hz, 2H), 2.87 (t, J = 6.67 Hz, 2H), 2.73 (d, J = 4.1 Hz, 3H), 2.30 (s, 3H), 1.68-1.62

¹³ CNMR (100 MHz, CDCl ₃ ):? 158.2, 135.1, 131.6, 128.9, 128.7, 38.9, 33.0, 28.3, 26.1, 25.4, 19.9;

LPMS (M + Na) ⁺ (ESI ⁺ ) 291 (calcdforC ₁₃ H ₂₀ N ₂ O ₂ SNa ⁺ 291.38);

_{Purity100% (t R = 7.34min)} .

(2) 1- (4- (p-Methoxyphenylsulfinyl) butyl) -3-methylurea (13d)

Compound 7b (40 mg, 0.17 mmol) was dissolved in a CH _{2 Cl 2, Et 3 N (25} ㎕, 0.17 mmol), triphosgene (18 mg, 0.06 mmol) After completion of the reaction MeNH ₂ in the reaction ^solution. HCl (24 mg, 0.35 mmol) and Et ₃ N (98 μL, 0.70 mmol) were used to obtain compound 13d.

Colorless oil (20 mg, 40% yield); R _f = 0.2 (CH ₂ Cl ₂ / MeOH 9/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.53 (d, J = 8.4Hz, 2H), 7.04 (d, J = 8.8Hz, 2H), 5.08 (t, J = 5.2Hz, 1H), 4.91 (d, (M, 2H), 2.71 (d, J = 4.8 Hz, 3H), 1.76-1.57 (m, , 4H);

^{13 C} NMR (100 MHz, CDCl ₃ ): δ 162.6, 159.8, 134.4, 125.9, 114.8, 57.0, 39.6, 29.6, 27.1, 19.7.

(3) 1- (4- (p-Chlorophenylsulfinyl) butyl) -3-methylurea (13f)

Compound 7d (80 mg, 0.34 mmol) was dissolved in a CH _{2 Cl 2, Et 3 N (0.05} mL, 0.34 mmol), triphosgene (51 mg, 0.17 mmol) After completion of the reaction MeNH ₂ in the reaction ^solution. HCl (45 mg, 0.68 mmol) and Et ₃ N (0.18 mL, 1.36 mmol), Compound 13f was obtained by Method J.

white solid (47.5 mg, 47.9% yield); R _f = 0.2 (CH ₂ Cl ₂ / MeOH 9/1);

mp: 93.0-95.0;

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.33-7.21 (m, 4H), 4.81 (br, 2H), 3.17 (q, J = 6.4Hz, 2H), 2.89 (t, J = 6.8Hz, 2H), 2.47 (d, J = 4.8 Hz, 3H), 1.66-1.12 (m, 4H);

_{^{13 CNMR (100MHz, CDCl 3)}} : δ 159.2, 135.1, 131.8, 130.4, 129.0, 39.9, 33.6, 29.4, 27.1, 26.3;

LPMS (M + Na) ⁺ (ESI ⁺ ) 311 (calcdforC ₁₂ H ₁₇ ClN ₂ O ₂ SNa ⁺ 311.79);

_{Purity92.08% (t R = 71.95min)} .

11. General synthesis of compound 13c, 13e, 13g, 13h (Method K)

Compounds 7a, 7b and 7d (1.0 eq) were dissolved in CH ₂ Cl ₂ , Et ₃ N (1.0 eq) and R ₃ NCO (1.1 eq) were added in this order 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 1: 9) to obtain the compounds 13b, 13c, 13e, 13g and 13h in a yield of 55.4-90.3%.

(1) 1-Ethyl-3- (4- (p-Tolylsulfinyl) butyl) urea (13b)

Compound 13a (15 mg, 0.07 mmol) was dissolved in CH ₂ Cl ₂ , Et ₃ N (9.8 μL, 0.07 mmol) and EtNCO (5.4 μL, 0.07 mmol)

Colorless oil (10.5 mg, 65.6% yield); R _f = 0.2 (CH ₂ Cl ₂ / MeOH 9/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.56 (m, 4H), 5.26 (d, J = 4.3Hz, 1H), 5.09 (d, J = 4.0Hz, 1H), 3.20-3.18 (m, 4H), 2.81-2.77 (m, 2H), 1.79-1.60 (m, 4H), 1.12 (t, J = 7.2 Hz, 3H);

¹³ CNMR (100 MHz, CDCl ₃ ): d 158.3, 142.1, 137.3, 129.6, 125.4, 56.6, 39.5, 35.3, 29.2, 19.4, 15.5;

LPMS (M + H) ⁺ (ESI ⁺ ) 283 (calcdforC ₁₄ H ₂₃ N ₂ O ₂ S ⁺ 283.40);

_{Purity98.6% (t R = 13.11min)} .

(2) 1-Isopropyl-3- (4- (p-Tolylsulfinyl) butyl) urea (13c)

Compound 7a (60 mg, 0.28 mmol) was dissolved in CH ₂ Cl ₂ and Et ₃ N (0.04 ml, 0.28 mmol) and iPrNCO (0.03 ml, 0.28 mmol)

white solid (46.1 mg, 55.4% yield); R _f = 0.2 (EtOAc); mp: 88.9-91.2;

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.48 (d, J = 8.0Hz, 2H), 7.31 (d, J = 8.0Hz, 2H), 3.83-3.78 (m, 1H), 3.16-3.13 (m, 2H ), 2.78-2.75 (m, 2H), 2.39 (s, 3H), 1.77-1.56 (m, 4H), 1.08 (d, J = 4.0 Hz, 6H);

^{13 C} NMR (100 MHz, CDCl ₃ ):? 157.5, 142.2, 137.3, 129.6, 125.4, 56.5, 42.2, 39.5, 29.2, 23.5, 19.4;

LPMS (M + H) ⁺ (ESI ⁺ ) 297 (calcdforC ₁₅ H ₂₅ N ₂ O ₂ S ⁺ 297.43);

_{Purity100% (t R = 9.46min)} .

(3) 1-Isopropyl-3- (4- (p-Methoxyphenylsulfinyl) butyl) urea (13e)

Compound 7b (50 mg, 0.22 mmol) was dissolved in CH ₂ Cl ₂ , Et ₃ N (30 μl, 0.22 mmol) and iPrNCO (21 μl, 0.22 mmol)

Colorless oil (50 mg, 73.5% yield); R _f = 0.2 (EtOAc);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.53 (d, J = 8.8Hz, 2H), 7.02 (d, J = 8.8Hz, 2H), 4.85 (t, J = 5.4Hz, 1H), 4.55 (d, J = 8.0 Hz, 1H), 3.85 (s, 3H), 3.80 (q, J = 6.5 Hz, 1H), 3.60-3.09 (m, 2H), 2.80-2.75 (m, 2H), 1.68-1.57 , 4H), 1.10 (d, J = 6.4 Hz, 6H);

^{13 C} NMR (100 MHz, CDCl ₃ ): δ 162.1, 158.0, 134.3, 125.9, 114.9, 56.9, 55.6, 41.9, 39.4, 29.3, 23.5, 19.9.

(4) 1- (4- (p-Chlorophenylsulfinyl) butyl) -3-ethylurea (13 g)

Compound 7d (85 mg, 0.36 mmol) was dissolved in CH ₂ Cl ₂ , Et ₃ N (0.05 mL, 0.40 mmol) and EtNCO (0.03 mL, 0.36 mmol)

white solid (98.5 mg, 90.3% yield); _Rf = 0.3 (EtOAc); mp: 115.8-117.3;

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.56-7.49 (m, 4H), 5.26 (d, J = 4.3Hz, 1H), 5.09 (d, J = 4.0Hz, 1H), 3.22-3.17 (m, 4H ), 2.83-2.77 (m, 2H), 1.67-1.61 (m, 4H), 1.12 (t, J = 7.2 Hz, 3H);

_{^{13 CNMR (100MHz, CDCl 3)}} : δ 158.3, 142.1, 137.3, 129.6, 125.4, 56.6, 39.5, 35.3, 29.2, 19.4, 15.5;

LPMS (M + Na) ⁺ (ESI ⁺ ) 325 (calcdforC ₁₃ H ₁₉ ClN ₂ O ₂ SNa ⁺ 325.82);

_{Purity100% (t R = 27.78min)} .

(5) 1- (4- (p-Chlorophenylsulfinyl) butyl) -3-isopropylurea (13h)

Compound 7d (100 mg, 0.43 mmol) was dissolved in CH ₂ Cl ₂ , Et ₃ N (0.065 mL, 0.47 mmol) and iPrNCO (0.04 mL, 0.43 mmol)

white solid (113.6 mg, 83.4% yield); _Rf = 0.3 (EtOAc); mp: 127.2 ~ 128.4;

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.56-7.49 (m, 4H), 4.54 (t, J = 5.2Hz, 1H), 4.31 (d, J = 7.5Hz, 1H), 3.84-3.81 (m, 1H ), 3.21-3.18 (m, 2H), 2.84-2.78 (m, 2H), 1.73-1.60 (m, 4H), 1.13 (d, J = 6.5 Hz, 6H);

^{13 C} NMR (100 MHz, CDCl ₃ ):? 157.5, 142.2, 137.3, 129.6, 125.4, 56.5, 42.2, 39.5, 29.2, 23.5, 19.4;

LPMS (M + Na) ⁺ (ESI ⁺ ) 339 (calcdforC ₁₄ H ₂₁ ClN ₂ O ₂ SNa ⁺ 339.85);

_{Purity100% (t R = 11.96min)} .

12. General synthesis of compounds 14a-14e (Method L)

Compounds 8a, 8b and 8d (1.0 eq) were dissolved in THF, R ₃ MgBr (4.0 eq) was added and the mixture was stirred at room temperature for 24 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 distillation of the solvent under reduced pressure was purified by column chromatography (ethyl acetate / n-hexane 1: 1) to obtain compounds 14a to 14e in a yield of 22-96.3%.

(1) N- (4- (p-Tolylsulfinyl) butyl) ethanethioamide (14a)

Compound 8a (62.8 mg, 0.24 mmol) was dissolved in THF and Compound 14a was obtained using 3M MeMgBr (0.35 mL, 0.99 mmol) Method L.

Colorless oil (64.1 mg, 96.3% yield); R _f = 0.2 (EtOAc);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.49 (d, J = 8.1Hz, 2H), 7.34 (d, J = 8.1Hz, 2H), 3.69-3.65 (m, 2H), 2.85-2.81 (m, 2H ), 2.54 (d, J = 8.6 Hz, 3H), 2.52 (d, J = 8.6 Hz, 3H), 1.87 - 1.74 (m, 4H);

_{^{13 CNMR (400MHz, CDCl 3)}} : δ 200.9, 141.9, 139.8, 130.1, 123.9, 56.1, 45.5, 33.9, 26.5, 21.4, 20.1;

LPMS (M + H) ⁺ (ESI ⁺ ) 270 (calcdforC ₁₃ H ₂₁ NOS ₂ ⁺ 270.43);

_{Purity100% (t R = 10.23min)} .

(2) N- (4- (p-Tolylsulfinyl) butyl) propanethioamide (14b)

Compound 8a (31.6 mg, 0.12 mmol) was dissolved in THF and 1M MeBr (0.4 mL, 0.49 mmol) was added to compound 14b using Method L.

Colorless oil (8 mg, 22% yield); R _f = 0.2 (CH ₂ Cl ₂ / MeOH 9/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.49 (d, J = 8.1Hz, 2H), 7.34 (d, J = 7.9Hz, 2H), 3.71-3.68 (m, 2H), 2.85-2.82 (m, 2H ), 2.69-2.67 (m, 2H), 2.42 (s, 3H), 1.88-1.83 (m, 4H), 1.30 (t, J = 7.5 Hz, 3H);

^{13 C} NMR (100 MHz, CDCl ₃ ):? 205.9, 140.7, 138.9, 129.1, 122.9, 54.8, 44.1, 38.9, 25.5, 20.4, 18.9, 12.7;

LPMS (M + H) ⁺ (ESI ⁺ ) 284 (calcdforC ₁₄ H ₂₂ NOS ₂ ⁺ 284.45);

_{Purity100% (t R = 6.39min)} .

(3) N- (4- (p-Tolylsulfinyl) butyl) -2-methylpropanethioamide (14c)

Compound 8a (17 mg, 0.07 mmol) was dissolved in THF and 2M MeMgBr (0.14 mL, 0.27 mmol) was coupled with Method L to obtain compound 14c.

Colorless oil (11 mg, 61.1% yield); R _f = 0.2 (EtOAc);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.49 (d, J = 8.1Hz, 2H), 7.34 (d, J = 8.1Hz, 2H), 3.70-3.69 (m, 2H), 2.85-2.82 (m, 2H ), 2.42 (s, 3H), 1.87-1.83 (m, 5H), 1.28-1.24 (m, 6H);

LPMS (M + Na) ⁺ (ESI ⁺ ) 320 (calcdforC ₁₅ H ₂₃ NOS ₂ Na ⁺ 320.48);

_{Purity97.3% (t R = 5.18min)} .

(4) N- (4- (p-Methoxyphenylsulfinyl) butyl) ethanethioamide (14d)

Compound 8b (100 mg, 0.37 mmol) was dissolved in THF and 3M MeMgBr (0.49 mL, 1.48 mmol) was reacted with Method L to obtain compound 14d.

Colorless oil (45 mg, 43% yield); _Rf = 0.2 (hexanes / EtOAc 1/2);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 8.32 (br, 1H), 7.53 (d, J = 8.4Hz, 2H), 7.03 (d, J = 8.8Hz, 2H), 3.86 (s, 3H), 3.68- 3.62 (m, 2H), 2.82 (t, J = 6.8 Hz, 2H), 2.54 (s, 3H), 1.85 - 1.74 (m, 4H);

^{13 C} NMR (100 MHz, CDCl ₃ ):? 200.9, 162.2, 133.7, 125.9, 114.9, 56.2, 55.6, 45.5, 33.8, 26.5, 20.1.

(5) N- (4- (p-Methoxyphenylsulfinyl) butyl) -2-methylpropanethioamide (14e)

Compound 8b (100 mg, 0.37 mmol) was dissolved in THF, and Compound 14e was obtained by using 2M iPrMgBr (0.74 mL, 1.48 mmol) using Method L.

Colorless oil (37 mg, 32% yield); R _f = 0.2 (hexanes / EtOAc 2/3);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.91 (br, 1H), 7.54 (d, J = 9.2Hz, 2H), 7.03 (d, J = 8.8Hz, 2H), 3.86 (s, 3H), 3.70- 3.66 (m, 2H), 2.84-2.78 (m, 2H), 1.87-1.73 (m, 4H), 1.24 (d, J = 6.8Hz, 6H);

_{^{13 CNMR (100MHz, CDCl 3)}} : δ 200.9, 162.2, 133.9, 125.9, 114.9, 56.2, 55.6, 44.8, 44.0, 26.6, 22.6, 19.9.

13. General synthesis of compound 15a, 15d, 15f (Method M)

Compound 8a, 8b, 8d (1.0 eq) was dissolved in CH ₂ Cl ₂ and Et ₃ N (1.1 eq) and MeNH ₂ ^. HCl (1.1 eq), and the mixture was stirred at room temperature for 12 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 1: 9) to give compounds 15a, 15d and 15f in a yield of 91.2-93.6%.

(1) 1- (4- (p-Tolylsulfinyl) butyl) -3-methylthiourea (15a)

Compound 8a (32 mg, 0.12 mmol) was dissolved in CH ₂ Cl ₂ , Et ₃ N (0.02 mL, 0.13 mmol), MeNH ₂ ^. HCl (8.1 mg, 0.12 mmol), Compound 15a was obtained by Method M.

white solid (31.1 mg, 91.2% yield); R _f = 0.2 (CH ₂ Cl ₂ / MeOH 9/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.48 (d, J = 8.1Hz, 2H), 7.33 (d, J = 8.1Hz, 2H), 2.97 (s, 3H), 2.84-2.80 (m, 2H), 2.42 - 2.38 (m, 3 H), 1.80 - 1.69 (m, 4 H);

_{^{13 CNMR (100MHz, CDCl 3)}} : δ 182.7, 141.9, 139.7, 130.1, 123.9, 56.3, 43.8, 30.9, 27.9, 21.4, 19.8;

LPMS (M + H) ⁺ (ESI ⁺ ) 285 (calcdforC ₁₃ H ₂₁ N ₂ OS ₂ ⁺ 285.44);

_{Purity100% (t R = 8.31min)} .

(2) 1- (4- (p-Methoxyphenylsulfinyl) butyl) -3-methylthiourea (15d)

Compound 8b (60 mg, 0.22 mmol) was dissolved in CH ₂ Cl ₂ , treated with Et ₃ N (0.12 mL, 0.89 mmol), MeNH ₂ ^. HCl (30 mg, 0.44 mmol), Compound 15d was obtained by Method M.

Colorless oil (58 mg, 86.6% yield); R _f = 0.2 (CH ₂ Cl ₂ / MeOH 9/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.54 (d, J = 8.8Hz, 2H), 7.02 (d, J = 8.8Hz, 2H), 6.38 (br, 1H), 6.31 (br, 1H), 3.86 ( 2H), 1.85-1.77 (m, 4H); 2.85 (br, 2H), 2.99 (d, J = 4.4 Hz, 3H), 2.82 (t, J = 7.0 Hz, 2H).

^{13 C} NMR (100 MHz, CDCl ₃ ): δ 183.0, 162.2, 133.7, 125.9, 114.9, 56.5, 55.6, 43.7, 31.0, 28.1, 19.9.

(3) 1- (4- (p-Chlorophenylsulfinyl) butyl) -3-methylthiourea (15f)

Compound 8d (94.5 mg, 0.34 mmol) was dissolved in CH ₂ Cl ₂ , Et ₃ N (0.05 mL, 0.37 mmol), MeNH ₂ ^. HCl (22.95 mg, 0.34 mmol), Compound 15f was obtained by Method M.

White solid (98.5 mg, 93.6% yield); R _f = 0.45 (CH ₂ Cl ₂ / MeOH 9/1);

mp: 127.2 ~ 128.4;

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.61-7.50 (m, 4H), 6.19 (br, 2H), 3.57 (br, 2H), 3.00 (d, J = 4.5Hz, 3H), 2.89-2.81 (m , &Lt; / RTI &gt; 2H), 1.90-1.68 (m, 4H);

_{^{13 CNMR (100MHz, CDCl 3)}} : δ 182.7, 141.8, 137.4, 129.7, 125.4, 56.1, 53.4, 43.7, 27.8, 19.6;

LPMS (M + H) ⁺ (ESI ⁺ ) 305 (calcdforC ₁₂ H ₁₇ ClN ₂ OS ₂ Na ⁺ 305.86);

_{Purity100% (t R = 4.82min)} .

14. General synthesis of compound 15b, 15c, 15e, 15g, 15h (Method N)

Compounds 7a, 7b and 7d (1.0 eq) were dissolved in CH ₂ Cl ₂ , Et ₃ N (1.0 eq) and R ₃ NCS (1.1 eq) were added in this order 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 residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography (MeOH: CH ₂ Cl ₂ = 1: 9) to obtain compound 15b, c, e, g, h in a yield of 64-94.3%.

(1) 1- (4- (p-Tolylsulfinyl) butyl) -3-ethylthiourea (15b)

Compound 7a (87.3 mg, 0.41 mmol) was dissolved in CH ₂ Cl ₂ , Et ₃ N (0.07 mL, 0.53 mmol) and EtNCS (0.04 mL, 0.53 mmol)

White solid (77.5 mg, 64% yield); R _f = 0.45 (CH ₂ Cl ₂ / MeOH 9/1);

mp: 124.2-125.0;

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.47 (d, J = 8.1Hz, 2H), 7.32 (d, J = 8.0Hz, 2H), 6.63 (s, 1H), 3.54-3.42 (m, 2H), 2.83-2.79 (m, 2H), 2.40 (d, J = 6.7 Hz, 3H), 1.83-1.68 (m, 4H), 1.14 (t, J = 7.2 Hz, 3H);

¹³ CNMR (100 MHz, CDCl ₃ ):? 181.9, 141.9, 139.7, 130.1, 123.9, 56.5, 43.7, 39.1, 28.1, 21.4, 19.9, 14.4;

LPMS (M + Na) ⁺ (ESI ⁺ ) 321 (calcdforC ₁₄ H ₂₂ N ₂ OS ₂ Na ⁺ 321.47);

_{Purity100% (t R = 11.91min)} .

(2) 1- (4- (p-Tolylsulfinyl) butyl) -3-isopropylthiourea (15c)

Compound 7a (68 mg, 0.41 mmol) was dissolved in CH ₂ Cl ₂ and Et ₃ N (0.06 mL, 0.45 mmol) and iPrNCS (0.04 mL, 0.45 mmol) were reacted with Method N to obtain compound 15c.

White solid (94.4 mg, 73.8% yield); R _f = 0.6 (CH ₂ Cl ₂ / MeOH 9/1);

mp: 116.4-117.5;

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.46 (d, J = 8.1Hz, 2H), 7.31 (d, J = 8.1Hz, 2H), 6.65 (s, 1H), 6.32 (s, 1H), 4.30 ( (m, 4H), 1.14 (d, J = 6.4 Hz, 6H), 2.40 ;

^{13 C} NMR (100 MHz, CDCl ₃ ):? 181.1, 141.9, 139.7, 130.1, 123.9, 56.5, 45.8, 43.6, 28.1, 22.6, 21.4, 19.9;

LPMS (M + Na) ⁺ (ESI ⁺ ) 335 (calcdforC ₁₅ H ₂₄ N ₂ OS ₂ Na ⁺ 335.49);

_{Purity100% (t R = 18.74min)} .

(3) 1- (4- (p-Methoxyphenylsulfinyl) butyl) -3-isopropylthiourea (15e)

Compound 7b (55 mg, 0.20 mmol) was dissolved in CH ₂ Cl ₂ , Et ₃ N (0.03 mL, 0.22 mmol) and iPrNCS (0.03 mL, 0.22 mmol)

White solid (60 mg, 89.6% yield); R _f = 0.3 (CH ₂ Cl ₂ / MeOH 9/1);

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.54 (d, J = 8.8Hz, 2H), 7.02 (d, J = 8.8Hz, 2H), 6.25 (br, 1H), 5.97 (br, 1H), 4.19- 2H), 1.82-1.69 (m, 4H), 1.15 (d, J = 6.4Hz, 6H), 3.91 (m, 1H) ;

^{13 C} NMR (100 MHz, CDCl ₃ ): δ 181.1, 162.2, 133.8, 125.9, 114.9, 56.6, 55.6, 45.3, 28.1, 22.6, 20.1.

(4) 1- (4- (p-Chlorophenylsulfinyl) butyl) -3-ethylthiourea (15 g)

Compound 7d (0.11 g, 0.47 mmol) was dissolved in CH ₂ Cl ₂ , Et ₃ N (0.07 mL, 0.52 mmol) and EtNCS (0.04 mL, 0.52 mmol)

White solid (0.14 g, 94.3% yield); R _f = 0.2 (CH ₂ Cl ₂ / MeOH 9/1);

mp: 93.4-95.4;

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.55-7.49 (m, 4H), 6.34 (br, 2H), 3.55 (br, 2H), 3.42 (br, 2H), 2.88-280 (m, 2H), 1.87 -1.74 (m, 4H), 1.81 (t, J = 7.1 Hz, 3H);

_{^{13 CNMR (100MHz, CDCl 3)}} : δ 181.8, 141.5, 137.4, 129.7, 125.4, 56.4, 43.6, 39.1, 28.0, 19.7, 14.4;

LPMS (M + Na) ⁺ (ESI ⁺ ) 341 (calcdforC ₁₃ H ₁₉ ClN ₂ OS ₂ Na ⁺ 341.89);

_{Purity100% (t R = 29.64min)} .

(5) 1- (4- (p-Chlorophenylsulfinyl) butyl) -3-isopropylthiourea (15h)

Compound 7d (70 mg, 0.30 mmol) was dissolved in CH ₂ Cl ₂ , Et ₃ N (0.05 mL, 0.45 mmol) and iPrNCS (0.04 mL, 0.45 mmol) were reacted with Method N to obtain compound 15h.

White solid (68.4 mg, 71.5% yield) R _f = 0.2 (CH ₂ Cl ₂ / MeOH 9/1);

mp: 104.4, 106.4;

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.54 (q, J = 8.5Hz, 4H), 6.51 (s, 1H), 6.27 (br, 1H), 4.08 (br, 1H), 3.51 (br, 2H), 2.84-2.78 (m, 2H), 1.79-1.66 (m, 4H), 1.61 (d, J = 6.5 Hz, 6H);

^{13 C} NMR (100 MHz, CDCl ₃ ): δ 180.9, 141.5, 137.5, 129.7, 125.4, 56.4, 43.5, 28.0, 26.6, 19.7;

LPMS (M + Na) ⁺ (ESI ⁺ ) 355 (calcdforC ₁₄ H ₂₁ ClN ₂ OS ₂ Na ⁺ 355.91);

_{Purity88.38% (t R = 25.90min)} .

15. Synthesis of compounds 16 to 61

(1) 5-Chloro-1- (4-methoxyphenyl) pentan-1-one (16)

Dissolve AlCl ₃ (3.69 g, 27.7 mmol) in dichloromethane (40 mL) and slowly add 5-Chlorovalerylchloride (3.58 mL, 27.7 mmol) at 0 ° C. After 10 minutes, anisole (2.50 g, 23.1 mmol) was slowly added dropwise to the reaction solution at the same temperature, followed by stirring at room temperature for one hour. After confirming the termination of the reaction, the reaction solution is diluted with dichloromethane and poured into ice water. After the mixture was extracted with saturated Na ₂ CO ₃ solution, the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. Compound 16 (5.23 g, 98%, white solid) was synthesized without further purification.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.91 - 7.97 (m, 2H), 6.92 - 6.96 (m, 2H), 3.87 (s, 3H), 3.56 - 3.61 (m, 2H), 2.94 - 2.99 (m, 2H), 1.84-1.91 (m, 4H).

(2) 5-Chloro-1- (4-fluorophenyl) pentan-1-one (17)

After dissolving AlCl ₃ (10.4 g, 27.7 mmol) in dichloromethane (60 mL), add 5-Chlorovalerylchloride (8.06 mL, 62.4 mmol) slowly at 0 ° C. After 10 minutes, florobenzene (5.00 g, 52.0 mmol) was slowly added dropwise to the reaction solution at the same temperature, followed by stirring at room temperature for 1 hour. After confirming the termination of the reaction, the reaction solution is diluted with dichloromethane and poured into ice water. After the mixture was extracted with saturated Na ₂ CO ₃ solution, the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. Compound 17 (2.18 g, 20%, light yellow oil) was synthesized using column chromatography (Hex: EtOAc = 10: 1)

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.95 - 8.01 (m, 2H), 7.10 - 7.17 (m, 2H), 3.54 - 3.62 (m, 2H), 2.96 - 3.01 (m, 2H), 1.83 - 1.94 ( m, 4H).

(3) 5- (Dimethylamino) -1- (4-methoxyphenyl) pentan-1-one (18)

The compound 16 (100 mg, 0.441 mmol) was added dropwise to acetonitrile (2 mL), and the mixture was refluxed with stirring for 18 hours. After confirming the completion of the reaction by TLC, the reaction solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified through column chromatography (DCM: MeOH = 10: 1 to only MeOH) to synthesize Compound 18 (49.1 mg, 47%, yellow oil).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.93 (dd, J = 1.94, 6.92Hz, 2H), 6.92 (dd, J = 1.94, 6.92Hz, 2H), 3.87 (s, 3H), 2.95 (t, J = 7.10 Hz, 2H), 2.37 (t, J = 7.50 Hz, 2H), 2.27 (s, 6H), 1.12-180 (m, 4H).

¹³ C-NMR (300 MHz, CDCl ₃ ) 隆 198.7, 163.4, 130.3, 130.1, 113.7, 59.4, 55.4, 45.2, 37.9, 27.1, 22.3.

(4) 2- (4-Chlorobutyl) -2- (4-methoxyphenyl) -1,3-dioxane (19)

After dissolving Et2ylene glycol (1.48 mL, 26.5 mmol), p-toluenesulfonic acid (126 mg, 0.66 mmol) and compound 16 (3.00 g, 13.2 mmol) in benzene (120 mL), dean- Lt; / RTI &gt; After confirming that the reaction is completed, the reaction solution is concentrated under reduced pressure, diluted with DCM, and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 10: 1) to obtain Compound 19 (2.95 g, 83%, colorless oil).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.32 - 7.38 (m, 2H), 6.83 - 6.88 (m, 2H), 3.95 - 4.05 (m, 2H), 3.82 (s, 3H), 3.72 - 3.81 (m, 2H), 3.48 (t, J = 6.7 Hz, 2H), 1.85-1.93 (m, 2H), 1.70-1.84 (m, 2H), 1.43-1.52 (m, 2H).

(5) 2- (4-Chlorobutyl) -2- (4-fluorophenyl) 1,3-dioxolane (20)

Compound 17 (442 mg, 2.06 mmol) was dissolved in benzene (20 mL), and the mixture was refluxed for 2 days with dean-stark. . After confirming that the reaction is completed, the reaction solution is concentrated under reduced pressure, diluted with DCM, and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 20 (533 mg, as a crude compound, white solid) was synthesized without further purification.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.36-7.45 (m, 2H), 6.96-7.04 (m, 2H), 3.99-4.03 (m, 2H), 3.73-3.78 (m, 2H), 3.48 (t, J = 6.6 Hz, 2H), 1.86-1.92 (m, 2H), 1.70-1.78 (m, 2H), 1.44-1.56 (m, 2H).

(6) 2- (4-Azidobutyl) -2- (4-methoxyphenyl) -1,3-dioxolane (21)

Sodium azide (1.27 g, 19.5 mmol) was slowly added dropwise at room temperature to a solution of compound 19 (2.64 g, 9.76 mmol) in DMF (53 mL) and the mixture was stirred at 80 ° C for 4 hours. After confirming the termination of the reaction, the reaction solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 10: 1) to obtain Compound 21 (2.17 g, 80%, yellow oil).

_{^{1 H NMR (300MHz, CDCl 3}} ) d 7.34 (d, J = 8.7Hz, 2H), 6.86 (d, J = 8.7Hz, 2H), 3.90-4.02 (m, 2H), 3.80 (s, 3H), 3.72-3.80 (m, 2H), 3.21 (t, J = 6.8 Hz, 2H), 1.87-1.93 (m, 2H), 1.30-1.62 (m, 4H).

(7) 2- (4-Azidobutyl) -2- (4-fluorophenyl) 1,3-dioxolane (22)

Sodium azide (268 mg, 4.12 mmol) was slowly added dropwise at room temperature to a solution of Compound 20 (533 mg, 2.06 mmol) in DMF (10 mL) and the mixture was stirred at 80 ° C for 6 hours. After confirming the termination of the reaction, the reaction solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 10: 1) to obtain Compound 22 (448 mg, 82% for 2 steps, yellow oil).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.38-7.43 (m, 2H), 6.98-7.04 (m, 2H), 3.98-4.04 (m, 2H), 3.73-3.78 (m, 2H), 3.22 (t, J = 6.7 Hz, 2H), 1.86-1.91 (m, 2H), 1.54-1.60 (m, 2H), 1.40-1.44 (m, 2H).

(8) 4- [2- (4-Methoxyphenyl) -1,3-dioxolan-2-yl] butane-

Lithium aluminium hydride solution (1.59 mL, 1.59 mmol, 1M in diethyl ether) was slowly added dropwise at 0 over 21 (200 mg, 0.721 mmol) which was dissolved in diethyl ether (5 mL) and stirred at room temperature for 3 hours. After confirming the termination of the reaction, the reaction solution is diluted with DCM, and Na ₂ SO ₄ .10H ₂ O is slowly added dropwise at 0 ° C. The mixed solution is filtered under reduced pressure using celite, and the filtrate is concentrated. Compound 23 (172 mg, 92%, colorless oil) was synthesized without further purification.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.33-7.37 (m, 2H), 6.82-6.89 (m, 2H), 3.97-4.02 (m, 2H), 3.80 (s, 3H), 3.73-3.79 (m, 2H), 2.64 (t, J = 6.6 Hz, 2H), 1.86-1.92 (m, 2H), 1.62 (br, 2H), 1.31-1.

(9) 4- [2- (4-Fluorophenyl) -1,3-dioxolan-2-yl] butan-

Lithium aluminum hydride solution (3.72 mL, 3.72 mmol, 1M in diethyl ether) was slowly added dropwise to compound 22 (448 mg, 1.69 mmol) dissolved in diethyl ether (10 mL) at 0 ° C and stirred at room temperature for 3 hours . After confirming the termination of the reaction, the reaction solution is diluted with DCM, and Na ₂ SO ₄ .10H ₂ O is slowly added dropwise at 0 ° C. The mixed solution is filtered under reduced pressure using celite, and the filtrate is concentrated. Compound 24 (356 mg, 88%, yellow oil) was synthesized without further purification.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.39-7.42 (m, 2H), 7.01 (t, J = 6.5Hz, 2H), 3.99-4.02 (m, 2H), 3.73-3.76 (m, 2H), 2.64 (t, J = 5.0 Hz, 2H), 1.85-1.89 (m, 2H), 1.25-1.40 (m, 6H).

(10) N- [5- (4-Methoxyphenyl) -5-oxopentyl] aceamide (25)

To a solution of Compound 23 (100 mg, 0.398 mmol) in DCM (2 mL) was slowly added dropwise acetyl chloride (34 L, 0.477 mmol) at 0 ° C and stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC, the reaction solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 3) to obtain Compound 25 (43.1 mg, 43%, yellow solid).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.90-7.96 (m, 2H), 6.90-6.96 (m, 2H), 5.83 (br, 1H), 3.87 (s, 3H), 3.27 (q, J = 6.6 2H), 2.96 (t, J = 7.0 Hz, 2H), 1.98 (s, 3H), 1.72-1.80 (m, 2H), 1.25-1.63 (m, 2H).

(11) N- [5- (4-Methoxyphenyl) -5-oxopentyl] isobutyramide (26)

To a solution of compound 23 (54.0 mg, 0.214 mmol) in DCM (1.5 mL), isobutyryl chloride (27.0 μL, 0.257 mmol) was slowly added dropwise at 0 ° C. and the mixture was stirred at room temperature for 5 hours. After confirming the completion of the reaction by TLC, the reaction solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 1) to synthesize Compound 26 (26.8 mg, 45%, white solid).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.59 (dd, J = 1.93, 8.37Hz, 1H), 7.51-7.53 (m, 1H), 6.88 (d, J = 9.37Hz, 1H), 5.70 (br, 1H ), 3.95 (s, 3H), 3.94 (s, 3H), 3.29 (q, J = 6.78 Hz, 2H), 2.98 (t, J = 6.98 Hz, 2H), 2.31-2.39 -1.83 (m, 2H), 1.56-1.65 (m, 2H), 1.60 (d, J = 6.88Hz, 6H).

¹³ C-NMR (300 MHz, CDCl ₃ ) d 198.8, 177.0, 153.3, 149.1, 130.2, 122.7, 110.1, 110.0, 56.1, 55.9, 38.9, 37.3, 35.7, 29.1, 31.3, 19.7.

(12) N- {5- (4-Methoxyphenyl) -5-oxopentyl} benzamide (27)

^{1 H-NMR (300MHz, CDCl} 3) δ 7.96 - 7.99 (m, 2H), 7.81 - 7.84 (m, 2H), 7.45 - 7.51 (m, 3H), 6.94 - 6.97 (m, 2H), 6.50 (br 2H), 1.83-1.90 (m, 2H), 1.70-1.77 (m, 2H), 3.03 (t, J = 6.9Hz, 2H) 2H).

(13) 1- {4- [2- (4-Methoxyphenyl) -1,3-dioxolan-2- yl] butyl} -3-phenylurea (28)

To a solution of compound 23 (108 mg, 0.430 mmol) in DCM (2 mL), phenyl isocyanate (61.0 μL, 0.516 mmol) was slowly added dropwise at 0 ° C. and the mixture was stirred at room temperature for 3 hours. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 1) to obtain Compound 28 (122 mg, 77%, white solid).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.29-7.41 (m, 2H), 7.10-7.27 (m, 5H), 6.95-7.01 (m, 1H), 6.80-6.86 (m, 2H), 5.34-5.40 (m, 2H), 1.24-1. 45 (m, 4H), 3.80-3. .

(14) 1- [5- (4-Methoxyphenyl) -5-oxopentyl) -3-phenylurea (29)

Pyridinium p-toluenesulfonate (33.0 mg, 0.132 mmol) was added dropwise to a solution of Compound 28 (122 mg, 0.329 mmol) in acetone / water (2.50 / 0.50 mL) and the mixture was refluxed for 4 hours. After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 1) to obtain Compound 29 (100 mg, 94%, white solid).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.88 (d, J = 8.9Hz, 2H), 7.19-7.37 (m, 5H), 6.98 (t, J = 7.2Hz, 1H), 6.87 (d, J = J = 6.6 Hz, 2H), 2.88 (t, J = 7.1 Hz, 2H), 1.66 (s, -1.80 (m, 2H), 1.48-1.60 (m, 2H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 199.2, 163.5, 156.3, 139.1, 130.3, 129.8, 129.0, 123.1, 120.2, 113.7, 55.4, 39.8, 37.6, 29.6, 21.4.

(15) 1- {4- [2- (4-Methoxyphenyl) -1,3-dioxolan-2- yl] butyl} -3-methylthiourea (30)

To a solution of Compound 23 (171 mg, 0.680 mmol) in DCM (3 mL), methyl isothiocyanate (56.0 μL, 0.816 mmol) was slowly added dropwise at 0 ° C. and the mixture was stirred at room temperature for 3 hours. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified through column chromatography (Hex: EtOAc = 1: 1) to obtain Compound 30 (191 mg, 86%, colorless oil).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.34 (d, J = 8.2Hz, 2H), 6.86 (d, J = 8.2Hz, 2H), 5.70 (br, 2H), 3.80-4.03 (m, 2H) 2H), 3.37 (m, 2H), 3.81 (s, 3H) .

(16) 1- [5- (4-Methoxyphenyl) -5-oxopentyl] -3-methylthiourea (31)

Pyridinium p-toluenesulfonate (58.9 mg, 0.234 mmol) was added dropwise to a solution of Compound 30 (190 mg, 0.586 mmol) in acetone / water (3.50 / 0.70 mL) and refluxed for 4 hours. After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 1) to obtain Compound 31 (133 mg, 81%, white solid).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.93 (d, J = 8.9Hz, 2H), 6.92 (d, J = 8.9Hz, 2H), 6.35 (br, 1H), 6.22 (br, 1H), 3.87 (s, 3H), 3.52 (br, 2H), 2.97-3.05 (m, 5H), 1.74-1.86 (m, 2H), 1.64-1.73 (m, 2H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 199.0, 182.3, 163.6, 130.3, 129.8, 113.8, 55.5, 44.2, 37.3, 33.2, 28.4, 20.9.

(17) 1-Isopropyl-3- {4- [2- (4-methoxyphenyl) -1,3-dioxolan-2-yl] butyl} thiourea (32)

Isopropyl isothiocyanate (60.0,, 0.540 mmol) was slowly added dropwise at 0 째 C to a solution of Compound 23 (113 mg, 0.450 mmol) in DCM (2 mL), and the mixture was stirred at room temperature for 3 hours. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 1) to obtain Compound 32 (150 mg, 95%, colorless oil).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.28-7.41 (m, 2H), 5.62 (br, 1H), 5.42 (br, 1H), 3.95-4.04 (m, 2H), 3.81 (s, 3H), 2H), 1.22 (d, J = 6.4 (m, 2H), 3.70-3.80 (m, 2H) Hz, 6H).

(18) 1-Isopropyl-3- [5- (4-methoxyphenyl) -5-oxopentyl] thiourea (33)

Pyridinium p-toluenesulfonate (41.9 mg, 0.167 mmol) was added dropwise to a solution of Compound 32 (147 mg, 0.417 mmol) in acetone / water (2.50 / 0.50 mL) and refluxed for 4 hours. After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 2) to obtain Compound 33 (104 mg, 81%, white solid).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.93 (dd, J = 2.01, 6.93Hz, 2H), 6.93 (dd, J = 2.01, 6.93Hz, 2H), 6.32 (br, 1H), 5.89 (br, 2H), 1.65-1.83 (m, 4H), 1.24 (d, 1H), 4.32 (br, , J = 6.45 Hz, 6H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 199.0, 180.5, 163.6, 130.4, 129.8, 113.8, 55.5, 45.9, 44.1, 37.3, 28.4, 22.6, 21.0.

(19) Dimethyl 1- {4- [2- (4-methoxyphenyl) -1,3-dioxolan-2- yl] butyl} -1H- 1,2,3-triazole-4,5- dicarboxylate (34)

To a solution of Compound 21 (200 mg, 0.721 mmol) in anhydrous xylene (4 mL) was added dropwise dimethyl acetylene dicarboxylate (102 mg, 0.721 mmol) at room temperature and refluxed for 2 hours. After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 2: 1) to obtain Compound 34 (259 mg, 86%, colorless oil).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.29-7.36 (m, 2H), 6.82-6.92 (m, 2H), 4.54 (t, J = 7.4Hz, 2H), 3.93-3.99 (m, 8H), 3.80 (s, 3H), 3.71 - 3.78 (m, 2H), 1.87 - 1.93 (m, 4H), 1.32 - 1.43 (m, 2H).

(20) Dimethyl 1- [5- (4-methoxyphenyl) -5-oxopentyl] -1H-1,2,3-triazole-4,5- dicarboxylate (35)

Pyridinium p-toluenesulfonate (62.1 mg, 0.247 mmol) was added dropwise to a solution of compound 34 (259 mg, 0.618 mmol) in acetone / water (4.50 / 0.90 mL) and the mixture was refluxed for 4 hours. After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 2: 1) to obtain Compound 35 (229 mg, 98%, yellow oil).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.87-7.95 (m, 2H), 6.90-6.97 (m, 2H), 4.65 (t, J = 7.2 Hz, 2H), 4.00 (s, 3H), 3.97 ( s, 3H), 3.87 (s, 3H), 2.97 (t, J = 7.0 Hz, 2H), 1.97-2.10 (m, 2H), 1.71-1.84 (m, 2H).

¹³ C-NMR (300 MHz, CDCl ₃ ) 隆 197.6, 163.5, 160.5, 158.9, 139.9, 130.2, 129.8, 113.7, 55.4, 53.4, 52.6, 50.3, 37.0, 26.9, 20.9.

(21) 1- {4- [2- (4-Methoxyphenyl) -1,3-dioxolan-2-yl] butyl} -1H- 1,2,3-triazole- 4,5- dicarboxylic acid (36)

To a solution of compound 35 (412 mg, 0.982 mmol) in methanol (8 mL) was added aq. 2N sodium hydroxide (1.08 mL, 2.16 mmol) was slowly added dropwise at 0 ° C, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction is confirmed by TLC, the solution is concentrated under reduced pressure. Dilute the filtrate in EtOAc and extract with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 36 (168 mg, 49%, yellow solid) was synthesized without further purification.

^{1 H-NMR (300MHz, DMSO} -d 6) δ 7.92 (d, J = 8.8Hz, 2H), 7.02 (d, J = 8.8Hz, 2H), 4.75 (t, J = 6.9Hz, 2H), 3.83 (s, 3H), 2.99 (t, J = 7.2 Hz, 2H), 1.82-1.92 (m, 2H), 1.52-1.60 (m, 2H).

¹³ C-NMR (300 MHz, DMSO-d ₆ )? 198.4, 163.4, 161.9, 159.7, 158.6, 140.0, 130.6, 128.7, 114.3, 55.9, 49.8, 49.0, 37.2, 29.7, 21.2.

(22) 2- (4-Fluorophenyl) -2- (4-isothiocyanoatobutyl) -1,3-dioxolane (37)

Di- (2-pyridyl) thionocarbonate (97.1 mg, 0.418 mmol) was slowly added dropwise to the solution of Compound 29 (100 mg, 0.418 mmol) in DCM (2 mL) at 0 ° C and the mixture was stirred at room temperature for 3 hours . After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 1) to obtain Compound 37 (92.7 mg, 79%, yellow oil).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.38-7.43 (m, 2H), 6.99-7.05 (m, 2H), 3.99-4.04 (m, 2H), 3.73-3.77 (m, 2H), 3.48 (t , J = 6.6 Hz, 2H), 1.86-1.91 (m, 2H), 1.63-1.73 (m, 2H), 1.43-1.51 (m, 2H).

(23) 5-Isothiocyanato-1- (4-fluorophenyl) pentan-1-one (38)

Pyridinium p-toluenesulfonate (33.1 mg, 0.132 mmol) was added dropwise to a solution of Compound 37 (92.7 mg, 0.329 mmol) in acetone / water (2.50 / 0.50 mL) and the mixture was refluxed for 4 hours. After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified through column chromatography (Hex: EtOAc = 7: 1) to synthesize Compound 38 (39.5 mg, 51%, yellow oil).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.95-8.03 (m, 2H), 7.10-7.19 (m, 2H), 3.58 (t, J = 6.3Hz, 2H), 3.02 (t, J = 6.8Hz, 2H), 1.78-1.91 (m, 4H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 197.5, 167.4, 164.0, 133.18, 133.14, 130.7, 130.5, 127.4, 115.9, 115.6, 44.9, 37.3, 29.4, 21.1.

(24) N- [5- (4-Fluorophenyl) -5-oxopentyl] isobutyramide (39)

To a solution of compound 24 (100 mg, 0.430 mmol) in DCM (1.5 mL), isobutyryl chloride (52.0 μL, 0.516 mmol) was slowly added dropwise at 0 ° C. and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC, the reaction solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 2: 1) to obtain Compound 39 (42.5 mg, 38%, white solid).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.95-8.01 (m, 2H), 7.08-7.16 (m, 2H), 5.75 (br, 1H), 3.15 (dd, J = 6.7, 12.7Hz, 2H), 2H), 1.15 (d, J = 6.9 Hz, 6H), 2.99 (t, J = 7.0 Hz, 2H), 2.30-2.38 (m, .

¹³ C-NMR (300 MHz, CDCl ₃ )? 198.4, 177.0, 167.4, 163.2, 133.2, 130.7, 130.5, 115.8, 115.5, 38.8, 37.7, 35.6, 29.1, 21.0, 19.6.

(25) 1- {4- [2- (4-Fluorophenyl) -1,3-dioxolan-2-yl] butyl} -3-isopropylurea (40)

Isopropyl isocyanate (52.0 μL, 0.251 mmol) was slowly added dropwise at 0 ° C. to a solution of Compound 24 (119 mg, 0.418 mmol) in DCM (1.5 mL), and the mixture was stirred at room temperature for 2 hours. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 1) to obtain Compound 40 (137 mg, 85%, white solid).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.37-7.42 (m, 2H), 6.97-7.03 (m, 2H), 4.07 (br, 1H), 3.97-4.02 (m, 3H), 3.72-3.97 (m , 3H), 3.06-3.11 (m, 2H), 1.85-1.90 (m, 2H), 1.11-1.37 (m, 4H), 1.12 (d, J = 6.4Hz, 6H).

(26) 1- [5- (4-Fluorophenyl) -5-oxopentyl] -3-isopropylurea (41)

Pyridinium p-toluenesulfonate (42.5 mg, 0.169 mmol) was added dropwise to a solution of compound 40 (137 mg, 0.422 mmol) in acetone / water (2.50 / 0.50 mL) and refluxed for 4 hours. After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 2: 1) to obtain Compound 41 (97.0 mg, 82%, white solid).

¹ H-NMR (300 MHz, CDCl ₃ )? 7.95-8.00 (m, 2H), 7.10-7.16 (m, 2H), 4.33 2H), 1.72-1.81 (m, 2H), 1.55-1.63 (m, 2H), 1.14 (d, J = d, J = 6.4 Hz, 6H).

¹³ C-NMR (300 MHz, CDCl ₃ ) 隆 198.5, 167.4, 164.0, 157.6, 133.3, 130.7, 130.5, 115.8, 115.5, 42.2, 39.9, 37.8, 29.7, 23.4, 21.1.

(27) 1- {4- [2- (4-fluorophenyl) -1,3-dioxolan-2-yl] butyl} -3-phenylurea (42)

To a solution of Compound 24 (100 mg, 0.418 mmol) in DCM (2 mL) was slowly added dropwise phenyl isocynate (60.9 mg, 0.501 mmol) at 0 ° C and the mixture was stirred at room temperature for 2 hours. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 3: 1) to obtain Compound 42 (45.3 mg, 30%, white solid).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.22-7.41 (m, 6H), 7.10-7.13 (m, 1H), 7.00 (t, J = 8.7Hz, 2H), 6.06 (br, 1H), 4.58 ( (m, 2H), 1.50-1.55 (m, 2H), 3.21 (q, J = 6.6Hz, 2H), 3.97-4.01 2H), 1.35-1.37 (m, 2H).

(28) 1- [5- (4-Fluorophenyl) -5-oxopentyl] -3-phenylurea (43)

Pyridinium p-toluenesulfonate (12.6 mg, 0.050 mmol) was added dropwise to a solution of compound 42 (45.0 mg, 0.126 mmol) in acetone / water (2.50 / 0.50 mL) and refluxed for 4 hours. After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 2: 1) to obtain Compound 43 (32.2 mg, 81%, white solid).

¹ H-NMR (300 MHz, CDCl ₃ )? 7.92-7.98 (m, 2H), 7.24-7.32 (m, 4H), 7.01-7.14 (M, 2H), 3.26 (q, J = 6.4 Hz, 2H), 2.94 (t, J = 7.0 Hz, 2H), 1.70-1.78 (m, 2H), 1.53-1.62

¹³ C-NMR (300 MHz, CDCl ₃ ) 隆 198.6, 156.0, 138.7, 130.7, 130.6, 129.2, 123.6, 120.6, 115.8, 115.5, 39.8, 37.8, 29.5, 21.1.

(29) 1- {4- [2- (4-Fluorophenyl) -1,3-dioxolan-2-yl] butyl} -3-methylthiourea (44)

To a solution of compound 24 (100 mg, 0.418 mmol) in DCM (2 mL), methyl isothiocyanate (34.0 μL, 0.501 mmol) was slowly added dropwise at 0 ° C. and the mixture was stirred at room temperature for 2 hours. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 2) to obtain Compound 44 (94.9 mg, 72%, colorless oil).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.37-7.42 (m, 2H), 6.98-7.04 (m, 2H), 5.57-5.98 (m, 2H), 3.95-4.03 (m, 2H), 3.72-3.77 (m, 2H), 3.36 (br, 2H), 3.00-3.02 (m, 3H), 1.87-1.93 (m, 2H), 1.55-1.68 (m, 2H), 1.36-1.

(30) 1- [5- (4-Fluorophenyl) -5-oxopentyl] -3-methylthiourea (45)

Pyridinium p-toluenesulfonate (38.6 mg, 0.152 mmol) was added dropwise to a solution of Compound 44 (94.9 mg, 0.304 mmol) in acetone / water (2.50 / 0.50 mL) and refluxed for 4 hours. After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 2) to obtain Compound 45 (61.9 mg, 76%, white solid).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.96-8.02 (m, 2H), 7.10-7.18 (m, 2H), 6.38 (br, 2H), 3.54 (br, 2H), 2.98-3.06 (m, 5H ), 1.67-1.84 (m, 4H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 198.8, 182.1, 167.5, 164.1, 133.1, 130.7, 130.6, 115.9, 115.6, 44.2, 37.7, 28.4, 20.8.

(31) 1- {4- [2- (4-fluorophenyl) -1,3-dioxolan-2-yl] butyl} -3-isopropylthiourea (46)

Isopropyl isothiocyanate (66.0 ㎕, 0.620 mmol) was slowly added dropwise at 0 째 C to a solution of Compound 24 (124 mg, 0.517 mmol) in DCM (2 mL), and the mixture was stirred at room temperature for 2 hours. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 3: 1) to obtain Compound 46 (127 mg, 72%, white solid).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.37-7.42 (m, 2H), 6.98-7.04 (m, 2H), 5.88 (br, 1H), 5.66 (br, 1H), 4.13 (br, 1H), (M, 2H), 1.36-1. 44 (m, 2H), 3.94 (m, ), 1.21 (d, J = 6.4 Hz, 6H).

(32) 1- [5- (4-Fluorophenyl) -5-oxopentyl] -3-isopropylthiourea (47)

Pyridinium p-toluenesulfonate (37.5 mg, 0.149 mmol) was added dropwise to a solution of Compound 46 (127 mg, 0.373 mmol) in acetone / water (2.50 / 0.50 mL) and refluxed for 4 hours. After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 2: 1) to obtain Compound 47 (104 mg, 94%, white solid).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.96-8.02 (m, 2H), 7.13 (t, J = 8.5Hz, 2H), 6.38 (br, 1H), 6.04 (br, 1H), 4.25 (br, 1H), 3.48-4.07 (m, 2H), 3.03 (t, J = 6.6Hz, 2H), 1.65-1.86 (m, 4H), 1.24 (d, J = 6.4Hz, 6H).

¹³ C-NMR (300 MHz, CDCl ₃ ) δ 198.7, 180.4, 167.4, 164.1, 133.1, 130.7, 130.6, 115.8, 115.6, 45.9, 44.0, 37.7, 28.4, 22.6, 20.8.

(33) Dimethyl 1- {4- [2- (4-fluorophenyl) -1,3-dioxolan-2-yl] butyl} -1H- 1,2,3-triazole-4,5- dicarboxylate (48)

To a solution of compound 22 (100 mg, 0.377 mmol) in anhydrous xylene (2 mL) was added dropwise dimethyl acetylene dicarboxylate (46.0 μL, 0.377 mmol) at room temperature and refluxed for 3 hours. After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 2: 1) to obtain Compound 48 (143 mg, 93%, yellow oil).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.35-7.40 (m, 2H), 6.98-7.03 (m, 2H), 4.55 (t, J = 7.3Hz, 2H), 3.96-4.00 (m, 8H), 3.71-3.75 (m, 2H), 1.86-1.91 (m, 4H), 1.38-1.40 (m, 2H).

(34) Dimethyl 1- [5- (4-fluorophenyl) -5-oxopentyl] -1H-1,2,3-triazole-4,5- dicarboxylate (49)

Pyridinium p-toluenesulfonate (35.0 mg, 0.139 mmol) was added dropwise to a solution of Compound 48 (142 mg, 0.349 mmol) in acetone / water (2.50 / 0.50 mL) and the mixture was refluxed for 4 hours. After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified through column chromatography (Hex: EtOAc = 1: 1) to synthesize Compound 49 (110 mg, 87%, light yellow oil).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.94-8.00 (m, 2H), 7.10-7.17 (m, 2H), 4.65 (t, J = 7.1Hz, 2H), 4.00 (s, 3H), 3.97 ( s, 3H), 3.00 (t, J = 7.0 Hz, 2H), 2.00-2.05 (m, 2H), 1.74-1.81 (m, 2H).

¹³ C-NMR (300 MHz, CDCl ₃ ) δ 197.4, 167.4, 164.0, 160.5, 158.9, 139.9, 133.1, 130.6, 130.5, 129.7, 115.8, 115.5, 53.4, 52.6, 50.3, 37.2, 29.5, 21.0, 20.6.

(35) N- [5- (3,4-Dimethoxyphenyl) -5-oxopentyl] acetamide (51)

To a solution of Compound 50 (41.2 mg, 0.146 mmol) in DCM (1.5 mL), acetyl chloride (13.0 μL, 0.176 mmol) was slowly added dropwise at 0 ° C. and the mixture was stirred at room temperature for 5 hours. After confirming the completion of the reaction by TLC, the reaction solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 3) to obtain Compound 51 (19.1 mg, 47%, yellow solid).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.59 (dd, J = 1.96, 8.37Hz, 1H), 7.51-7.53 (m, 1H), 6.89 (d, J = 8.37Hz, 1H), 5.82 (br, 2H), 1.99 (s, 3H), 1.73 (s, 3H), 2.94 (s, 1.94 (m, 2 H), 1.57 - 1.65 (m, 2 H).

¹³ C-NMR (300 MHz, CDCl ₃ ) 隆 198.8, 170.1, 153.3, 149.1, 130.1, 122.8, 110.1, 110.0, 56.1, 55.9, 39.2, 37.3, 29.1, 23.3, 21.4.

(36) N- [5- (3,4-Dimethoxyphenyl) -5-oxopentyl] isobutyramide (52)

To a solution of compound 50 (41.2 mg, 0.146 mmol) in DCM (1.5 mL), isobutyryl chloride (18.0 μL, 0.176 mmol) was slowly added dropwise at 0 ° C. and the mixture was stirred at room temperature for 5 hours. After confirming the completion of the reaction by TLC, the reaction solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 3) to obtain Compound 52 (20.7 mg, 46%, white solid).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.59 (dd, J = 1.93, 8.37Hz, 1H), 7.51-7.53 (m, 1H), 6.88 (d, J = 9.37Hz, 1H), 5.70 (br, 1H ), 3.95 (s, 3H), 3.94 (s, 3H), 3.29 (q, J = 6.78 Hz, 2H), 2.98 (t, J = 6.98 Hz, 2H), 2.31-2.39 -1.83 (m, 2H), 1.56-1.65 (m, 2H), 1.60 (d, J = 6.88Hz, 6H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 198.8, 177.0, 153.3, 149.1, 130.2, 122.7, 110.1, 110.0, 56.1, 55.9, 38.9, 37.3, 35.7, 29.1, 31.3, 19.7.

(37) N- {5- (3,4-Dimethoxyphenyl) -5-oxopentyl} benzamide (53)

Benzoyl chloride (30 μl, 0.26 mmol) was slowly added dropwise at 0 ° C to a solution of compound 50 (51.0 mg, 0.22 mmol) in DCM (2 mL), and the mixture was stirred at room temperature for 6 hours. After confirming the completion of the reaction by TLC, the reaction solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified through column chromatography (Hex: EtOAc = 1: 1 to only EtOAc) to synthesize Compound 53 (52.0 mg, 69%).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.82 (dd, J = 2.0, 8.4Hz, 2H), 7.62 (dd, J = 2.0, 8.4Hz, 1H), 7.45-7.55 (m, 4H), 6.90 ( 3H), 3.95 (s, 3H), 3.52 (q, J = 6.0 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H), 1.86-1.91 (m, 2H), 1.71-1.76 (m, 2H).

(38) 5-Isothiocyanato-1- (4-methoxyphenyl) pentan-1-one (55)

Pyridinium p-toluenesulfonate (24.0 mg, 0.100 mmol) was added dropwise to a solution of Compound 54 (71.0 mg, 0.240 mmol) in acetone / water (2.00 / 1.00 mL) and the mixture was refluxed for 5 hours. After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous MgSO ₄ , filtered and concentrated. Compound 55 (57.0 mg, 95%) was synthesized using column chromatography (Hex: EtOAc = 3: 1)

^{1 H-NMR (300MHz, CDCl} 3) δ 7.92-7.98 (m, 2H), 6.93-6.98 (m, 2H), 3.89 (s, 3H), 3.58 (t, J = 6.3Hz, 2H), 3.00 ( t, J = 6.7 Hz, 2H), 1.78-1.89 (m, 4H).

16. Synthesis of compounds 62 to 101

(1) 5-Chloro-1- (4-methoxyphenyl) pentan-1-ol (62)

To a solution of Compound 16 (500 mg, 2.21 mmol) in methanol (11 mL) was added dropwise sodium borohydride (125 mg, 3.31 mmol) at 0 ° C and the mixture was stirred at room temperature for 1 hour. After completion of the reaction was confirmed by TLC, 1M aqueous HCl solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 62 (502 mg, quant., Colorless oil) was synthesized without further purification.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.24-7.29 (m, 2H), 6.86-6.91 (m, 2H), 4.61-4.65 (n, 1H), 3.81 (s, 3H), 3.51 (t, J = 6.7 Hz, 2H), 1.55-1.85 (m, 7H).

(2) 5-Azido-1- (4-methoxyphenyl) pentan-1-ol (63)

Sodium azide (285 mg, 4.38 mmol) was slowly added dropwise at room temperature to a solution of Compound 62 (501 mg, 2.19 mmol) in DMF (10 mL), and the mixture was stirred at 80 ° C for 6 hours. After confirming the termination of the reaction, the reaction solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 5: 1) to obtain Compound 63 (421 mg, 82%, yellow oil).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.22-7.28 (m, 2H), 6.85-6.92 (m, 2H), 4.57-4.67 (m, 1H), 3.81 (s, 3H), 3.24 (t, J = 6.8 Hz, 2H), 1.56-1.86 (m, 7H).

(3) 5-Amino-1- (4-methoxyphenyl) pentan-1-ol (64)

Lithium aluminum hydride solution (3.93 mL, 3.93 mmol, 1M in diethyl ether) was slowly added dropwise to compound 63 (420 mg, 1.79 mmol) dissolved in diethyl ether (9 mL) at 0 ° C. and stirred at room temperature for 3 hours . After confirming the termination of the reaction, the reaction solution is diluted with DCM, and Na ₂ SO ₄ .10H ₂ O is slowly added dropwise at 0 ° C. The mixed solution is filtered under reduced pressure using celite, and the filtrate is concentrated. Compound 64 (340 mg, 91%, light yellow oil) was synthesized without further purification.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.24-7.29 (m, 2H), 6.85-6.91 (m, 2H), 4.58-4.67 (m, 1H), 3.80 (s, 3H), 2.66 (t, J = 6.7 Hz, 2H), 1.40-1.82 (m, 9H).

(4) 5-Isothiocyanato-1- (4-methoxyphenyl) pentan-1-ol (65)

Di- (2-pyridyl) thionocarbonate (222 mg, 0.956 mmol) was slowly added dropwise to the solution of Compound 64 (200 mg, 0.956 mmol) in DCM (3 mL) at 0 ° C and the mixture was stirred at room temperature for 3 hours . After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified through column chromatography (Hex: EtOAc = 5: 1) to synthesize Compound 65 (216 mg, 90%, yellow oil).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.23 (d, J = 8.5Hz, 2H), 6.86 (d, J = 8.5Hz, 2H), 4.59 (t, J = 6.4Hz, 1H), 3.79 (s , 3H), 3.47 (t, J = 6.6 Hz, 2H), 2.16 (br, IH), 1.21-1.80 (m, 6H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 159.1, 136.6, 129.7, 127.0, 113.9, 73.8, 55.3, 44.9, 37.9, 29.8, 22.9.

(5) Dimethyl 1- [5-hydroxy-5- (4-methoxyphenyl) -pentyl] -1H-1,2,3-triazole-4,5-dicarboylate (67)

To a solution of Compound 63 (56.0 mg, 0.238 mmol) in anhydrous xylene (2 mL) was added dropwise dimethyl acetylene dicarboxylate (29.0 μL, 0.238 mmol) at room temperature and refluxed for 3 hours. After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 1) to synthesize Compound 67 (77.6 mg, 86%, yellow oil).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.19-7.25 (m, 2H), 6.82-6.89 (m, 2H), 4.52-4.64 (m, 3H), 3.98 (s, 3H), 3.96 (s, 3H ), 3.79 (s, 3H), 2.11 (br, IH), 1.22-2.03 (m, 6H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 160.5, 159.0, 158.9, 139.8, 136.6, 129.7, 127.0, 113.8, 73.6, 55.2, 53.4, 52.6, 50.4, 38.0, 30.0, 22.7.

(6) N- [5-Hydroxy-5- (40methoxyphenyl) pentyl] acetamide (68)

To a solution of Compound 25 (43.0 mg, 0.172 mmol) in methanol (1 mL), sodium borohydride (9.78 mg, 0.259 mmol) was added dropwise at 0 ° C and the mixture was stirred at room temperature for 1 hour. After completion of the reaction was confirmed by TLC, 1M aqueous HCl solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 68 (33.8 mg, 78%, yellow oil) was synthesized without further purification.

^{1 H-NMR (300MHz, CDCl} 3) δ 7.24 (d, J = 8.5Hz, 2H), 6.86 (d, J = 8.5Hz, 2H), 5.71 (br, 1H), 4.60 (t, J = 6.8Hz 2H), 2.41 (br, IH), 1.92 (s, 3H), 1.25-1.79 (m, 6H).

¹³ C-NMR (300 MHz, CDCl ₃ ) d 170.2, 158.9, 136.9, 127.0, 113.8, 73.8, 55.2, 39.4, 38.4, 29.3, 23.2, 23.0.

(7) N- [5-Hydroxy-5- (4-methoxyphenyl) pentyl] isobutyramide (69)

To a solution of Compound 26 (82.0 mg, 0.296 mmol) in methanol (2 mL), sodium borohydride (16.6 mg, 0.443 mmol) was added dropwise at 0 ° C and the mixture was stirred at room temperature for 1 hour. After completion of the reaction was confirmed by TLC, 1M aqueous HCl solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 69 (42.9 mg, 52%, yellow oil) was synthesized without further purification.

^{1 H-NMR (300MHz, CDCl} 3) δ 7.23 (d, J = 8.5Hz, 2H), 6.85 (d, J = 8.5Hz, 2H), 5.64 (br, 1H), 4.53-4.63 (m, 1H) (M, 2H), 1.23-1.58 (m, 2H), 3.79 (s, 3H) (m, 4H), 1.10 (d, J = 6.8 Hz, 6H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 177.0, 158.9, 137.0, 127.0, 113.7, 73.8, 55.2, 39.0, 38.4, 35.6, 29.6, 22.9, 19.6.

(8) N- [5-Hydroxy-5- (4-methoxyphenyl) pentyl] benzamide (70)

To a solution of compound 27 (16.5 mg, 0.053 mmol) in methanol (2 mL) was added dropwise sodium borohydride (3.00 mg, 0.080 mmol) at 0 ° C and the mixture was stirred at room temperature for 1 hour. After completion of the reaction was confirmed by TLC, 1M aqueous HCl solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 70 (16.6 mg, quant., Yellow oil) was synthesized without further purification.

^{1 H-NMR (300MHz, CDCl} 3) δ 7.70-7.76 (m, 2H), 7.36-7.52 (m, 3H), 7.21-7.29 (m, 2H), 6.82-6.90 (m, 2H), 6.18 (br J = 6.6 Hz, 2H), 1.20-2. 08 (m, 7H), 4.63 (t, J = 6.3 Hz, 1H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 167.5, 159.0, 136.8, 134.7, 131.3, 128.5, 127.0, 126.8, 113.8, 73.9, 55.2, 39.8, 38.3, 29.4, 23.1.

(9) 1- [5-Hydroxy-5- (4-methoxyphenyl) pentyl] -3-isopropylurea (72)

To a solution of compound 71 (21.6 mg, 0.074 mmol) in methanol (2 mL), sodium borohydride (4.19 mg, 0.111 mmol) was added dropwise at 0 ° C and the mixture was stirred at room temperature for 1 hour. After completion of the reaction was confirmed by TLC, 1M aqueous HCl solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 72 (21.8 mg, quant., Yellow oil) was synthesized without further purification.

^{1 H-NMR (300MHz, CDCl} 3) δ 7.22-7.28 (m, 2H), 6.82-6.89 (m, 2H), 4.54-4.65 (m, 2H), 4.39 (d, J = 7.8Hz, 1H), (M, 7H), 1.10 (d, J = 6.5 Hz, 6H), 3.79 (s, 3H), 3.11 (q, J = 6.1 Hz, 2H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 158.9, 157.8, 137.0, 127.0, 113.8, 73.8, 55.2, 42.1, 40.1, 38.5, 30.0, 23.4, 23.0.

(10) 1- [5-Hydroxy-5- (4-methoxyphenyl) -pentyl] -3-phenylurea (73)

To a solution of Compound 29 (35.0 mg, 0.107 mmol) in methanol (2 mL) was added dropwise sodium borohydride (6.08 mg, 0.161 mmol) at 0 ° C and the mixture was stirred at room temperature for 1 hour. After completion of the reaction was confirmed by TLC, 1M aqueous HCl solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 73 (31.8 mg, 91%, white oil) was synthesized without further purification.

^{1 H-NMR (300MHz, CDCl} 3) δ 7.14-7.28 (m, 7H), 6.95-7.04 (m, 1H), 6.79-6.86 (m, 2H), 5.36 (t, J = 5.5Hz, 1H), 2H), 2.70 (br, IH), 1.21-1.87 (m, 6H), 4.50-4.57 (m, IH), 3.76 (s, 3H), 3.13 (q, J =

¹³ C-NMR (300 MHz, CDCl ₃ )? 158.9, 156.4, 138.9, 136.8, 129.1, 127.0, 123.2, 120.3, 113.8, 73.8, 55.2, 39.9, 38.4, 29.8, 23.0.

(11) 1- [5-Hydroxy-5- (4-methoxyphenyl) pentyl] -3-methylthiourea (74)

To a solution of compound 31 (22.1 mg, 0.079 mmol) in methanol (2 mL), sodium borohydride (4.50 mg, 0.118 mmol) was added dropwise at 0 ° C and the mixture was stirred at room temperature for 1 hour. After completion of the reaction was confirmed by TLC, 1M aqueous HCl solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 74 (22.2 mg, quant., Yellow oil) was synthesized without further purification.

^{1 H-NMR (300MHz, CDCl} 3) δ 7.24 (d, J = 8.5Hz, 2H), 6.87 (d, J = 8.5Hz, 2H), 5.90-6.11 (m, 2H), 4.59-5.66 (m, 1H), 3.79 (s, 3H), 3.40 (br, IH), 2.97 (d, J = 4.3 Hz, 3H), 1.25-1.86 (m, 7H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 182.3, 159.0, 136.7, 127.0, 113.9, 73.9, 55.3, 44.2, 38.2, 30.8, 28.7, 23.1.

(12) 1- [5- (Hydroxy-5- (4-methoxyphenyl) pentyl) -3-isopropylthiourea (75)

To a solution of Compound 33 (14.5 mg, 0.047 mmol) in methanol (1 mL), sodium borohydride (2.66 mg, 0.071 mmol) was added dropwise at 0 ° C and the mixture was stirred at room temperature for 1 hour. After completion of the reaction was confirmed by TLC, 1M aqueous HCl solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 75 (14.6 mg, quant., Yellow oil) was synthesized without further purification.

^{1 H-NMR (300MHz, CDCl} 3) δ 7.23-7.27 (m, 2H), 6.87-6.92 (m, 2H), 5.78 (br, 1H), 5.56 (br, 1H), 4.60-4.68 (m, 1H ), 3.80 (s, 3H), 3.37 (br, 2H), 1.30-1.97 (m, 8H), 1.21 (d, J = 6.5 Hz, 6H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 180.4, 159.1, 136.7, 127.0, 113.9, 73.9, 55.3, 45.0, 44.0, 38.25, 28.7, 23.1, 22.6.

(13) 5-Chloro-1- (4-fluorophenyl) pentan-1-ol (76)

To a solution of Compound 17 (885 mg, 4.12 mmol) in methanol (18 mL) was added dropwise sodium borohydride (234 mg, 6.19 mmol) at 0 ° C and the mixture was stirred at room temperature for 1 hour. After completion of the reaction was confirmed by TLC, 1M aqueous HCl solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 76 (820 mg, 92%, yellow oil) was synthesized without further purification.

^{1 H-NMR (300MHz, CDCl} 3) δ 7.29-7.33 (m, 2H), 7.00-7.06 (m, 2H), 4.67 (br, 1H), 3.52 (t, J = 6.6Hz, 2H), 1.51- 1.84 (m, 7 H).

(14) 5-Azido-1- (4-fluorophenyl) pentan-1-ol (77)

Sodium azide (491 mg, 7.56 mmol) was slowly added dropwise at room temperature to a solution of compound 76 (819 mg, 3.78 mmol) in DMF (18 mL) and the mixture was stirred at 80 ° C for 6 hours. After confirming the termination of the reaction, the reaction solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 5: 1) to obtain Compound 77 (637 mg, 76%, yellow oil).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.27-7.33 (m, 2H), 7.00-7.06 (m, 2H), 4.64-4.70 (m, 2H), 3.26 (t, J = 6.7Hz, 2H), 1.55 -1.84 (m, 7H).

(15) 5-Amino-1- (4-fluorophenyl) pentan-1-ol (78)

Lithium aluminum hydride solution (0.985 mL, 0.985 mmol, 1M in diethyl ether) was slowly added dropwise to compound 77 (100 mg, 0.448 mmol) dissolved in diethyl ether (2 mL) at 0 ° C and stirred at room temperature for 3 hours . After confirming the termination of the reaction, the reaction solution is diluted with DCM, and Na ₂ SO ₄ .10H ₂ O is slowly added dropwise at 0 ° C. The mixed solution is filtered under reduced pressure using celite, and the filtrate is concentrated. Compound 78 (74.8 mg, 85%, colorless oil) was synthesized without further purification.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.26-7.31 (m, 2H), 6.97-7.03 (m, 2H), 4.57-4.62 (m, 1H), 2.60 (t, J = 6.6Hz, 2H), 2.08 (br, 2H), 1.25-1.72 (m, 7H).

(16) 1- (4-Fluorophenyl) -5-isothiocyanatopentan-1-ol (79)

Di- (2-pyridyl) thionocarbonate (80.1 mg, 0.345 mmol) was slowly added dropwise to a solution of Compound 78 (68.0 mg, 0.345 mmol) in DCM (2 mL) at 0 ° C and the mixture was stirred at room temperature for 3 hours . After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 5: 1) to obtain Compound 79 (50.2 mg, 61%, colorless oil).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.26-7.33 (m, 2H), 7.00-7.08 (m, 2H), 4.66 (t, J = 6.2Hz, 1H), 3.49 (t, J = 6.6Hz, 2H), 2.00 (br, IH), 1.42 - 1.82 (m, 6H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 163.8, 160.6, 140.2, 140.1, 127.5, 127.4, 115.5, 115.2, 73.6, 44.9, 38.1, 29.8, 22.8.

(17) Dimethyl 1- [5- (4-fluorophenyl) -5-hydroxypentyl] -1H-1,2,3-triazole-4,5-dicarboxylate (80)

To a solution of Compound 77 (50.0 mg, 0.224 mmol) in anhydrous xylene (2 mL) was added dropwise dimethyl acetylene dicarboxylate (27.0 μL, 0.224 mmol) at room temperature and refluxed for 3 hours. After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified through column chromatography (Hex: EtOAc = 2: 1) to synthesize Compound 80 (47.1 mg, 58%, yellow oil).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.25-7.31 (m, 2H), 6.97-7.04 (m, 2H), 4.60-4.66 (m, 1H), 4.57 (t, J = 7.1Hz, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 2.12-2.14 (m, 1H), 1.67-1.96 (m, 4H), 1.24-1.50 (m, 2H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 163.7, 160.5, 158.9, 140.2, 140.2, 139.9, 129.7, 127.4, 127.3, 115.4, 115.1, 73.4, 53.4, 52.7, 50.4, 38.2, 29.9, 22.5.

(18) N - [- (4-Fluorophenyl) -5-hydroxypentyl] isobutyramide (81)

To a solution of Compound 39 (19.0 mg, 0.072 mmol) in methanol (1 mL), sodium borohydride (4.06 mg, 0.107 mmol) was added dropwise at 0 ° C and the mixture was stirred at room temperature for 1 hour. After completion of the reaction was confirmed by TLC, 1M aqueous HCl solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 81 (17.5 mg, 91%, yellow oil) was synthesized without further purification.

^{1 H-NMR (300MHz, CDCl} 3) δ 7.26-7.33 (m, 2H), 6.97-7.04 (m, 2H), 5.22 (br, 1H), 4.62-4.66 (m, 1H), 3.18-3.22 (m , 2H), 2.27-2.42 (m, 2H), 1.25-1.69 (m, 6H), 1.12 (d, J = 6.8Hz, 6H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 177.0, 163.7, 160.4, 140.6, 127.4, 127.3, 115.3, 115.0, 73.5, 38.9, 38.5, 35.7, 30.9, 29.5, 22.7, 19.6.

(19) 1- [5- (4-Fluorophenyl) -5-hydroxypentyl] -3-isopropylurea (82)

To a solution of Compound 41 (26.9 mg, 0.143 mmol) in methanol (1 mL) was added dropwise sodium borohydride (5.44 mg, 0.214 mmol) at 0 ° C and the mixture was stirred at room temperature for 1 hour. After completion of the reaction was confirmed by TLC, 1M aqueous HCl solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 82 (26.1 mg, 96%, light yellow oil) was synthesized without further purification.

^{1 H-NMR (300MHz, CDCl} 3) δ 7.26-7.30 (m, 2H), 6.96-7.03 (m, 2H), 4.48-4.70 (m, 2H), 4.45-4.48 (m, 1H), 3.78-3.81 (m, 2H), 1.30-1.48 (m, 4H), 1.08-1.22 (m, 6H) .

¹³ C-NMR (300 MHz, CDCl ₃ )? 167.4, 164.2, 157.9, 140.7, 127.4, 127.3, 115.2, 114.9, 73.4, 42.1, 39.9, 38.6, 30.0, 23.4, 22.8.

(20) 1- [5- (4-Fluorophenyl) -5-hydroxypentyl] -3-phenylurea (83)

To a solution of Compound 43 (16.0 mg, 0.051 mmol) in methanol (1 mL), sodium borohydride (2.89 mg, 0.076 mmol) was added dropwise at 0 ° C and the mixture was stirred at room temperature for 1 hour. After completion of the reaction was confirmed by TLC, 1M aqueous HCl solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 83 (15.7 mg, 97%, light yellow oil) was synthesized without further purification.

^{1 H-NMR (300MHz, CDCl} 3) δ 7.01-7.27 (m, 7H), 6.92-7.03 (m, 3H), 5.37 5.41 (m, 1H), 4.53-4.58 (m, 1H), 3.10-3.17 ( m, 2H), 1.60-1.69 (m, 2H), 1.25-1. 43 (m, 4H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 156.5, 140.4, 138.7, 129.2, 127.4, 127.3, 123.5, 120.6, 115.3, 115.0, 73.5, 39.8, 38.6, 29.8, 22.8.

(21) 1- [5- (4-Fluorophenyl) -5-hydroxypentyl] -3-methylthiourea (84)

To a solution of compound 45 (21.1 mg, 0.079 mmol) in methanol (1 mL), sodium borohydride (4.46 mg, 0.118 mmol) was added dropwise at 0 ° C and the mixture was stirred at room temperature for 1 hour. After completion of the reaction was confirmed by TLC, 1M aqueous HCl solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 84 (15.9 mg, 75%, white solid) was synthesized without further purification.

^{1 H-NMR (300MHz, CDCl} 3) δ 7.25-7.33 (m, 2H), 6.98-7.06 (m, 2H), 5.92-6.04 (m, 2H), 4.64-4.70 (m, 1H), 3.42 (br , 2H), 2.97-3.00 (m, 3H), 2.42 (br, IH), 1.38-1.80 (m, 6H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 182.2, 163.7, 160.5, 140.4, 140.3, 127.4, 127.3, 115.4, 115.1, 73.6, 44.2, 38.4, 32.6, 28.7, 22.9.

(22) 1- [5- (4-Fluorophenyl) -5-hydroxypentyl] -3-isopropylthiourea (85)

To a solution of Compound 47 (52.0 mg, 0.175 mmol) in methanol (1 mL), sodium borohydride (9.96 mg, 0.263 mmol) was added dropwise at 0 ° C and the mixture was stirred at room temperature for 1 hour. After completion of the reaction was confirmed by TLC, 1M aqueous HCl solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 85 (50.7 mg, 97%, light yellow oil) was synthesized without further purification.

^{1 H-NMR (300MHz, CDCl} 3) δ 7.26-7.32 (m, 2H), 6.98-7.04 (m, 2H), 6.04 (br, 1H), 5.82 (br, 1H), 4.62-4.68 (m, 1H ), 4.18 (br, IH), 3.38 (br, 2H), 2.70 (br, IH), 1.55-1.80 (m, 6H), 1.20 (d, J = 6.4Hz, 6H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 180.2, 163.7, 160.4, 140.4, 140.3, 127.5, 127.3, 115.3, 115.0, 73.4, 46.1, 43.9, 38.5, 28.7, 23.0, 22.6.

(23) 1- [5- (3,4-Dimethoxyphenyl) -5-hydroxypentyl] -3-isopropylurea (87)

To a solution of compound 86 (18.1 mg, 0.056 mmol) in methanol (2 mL) was added dropwise sodium borohydride (3.19 mg, 0.084 mmol) at 0 ° C and the mixture was stirred at room temperature for 1 hour. After completion of the reaction was confirmed by TLC, 1M aqueous HCl solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 87 (18.0 mg, quant., Yellow oil) was synthesized without further purification.

^{1 H-NMR (300MHz, CDCl} 3) δ 6.88-6.93 (m, 1H), 6.78-6.86 (m, 2H), 4.52-4.63 (m, 2H), 4.37 (d, J = 7.8Hz, 1H), J = 6.2 Hz, 2H), 2.59-2.62 (m, 1H), 1.24-1.94 (m, 7H), 1.11 (d, J = 6.5 Hz, 6H).

¹³ C-NMR (300 MHz, CDCl ₃ ) 隆 157.8, 149.0, 148.3, 137.6, 118.0, 111.0, 109.0, 74.0, 55.9, 55.8, 42.1, 40.1, 38.5, 30.0, 23.4, 23.0.

(24) 5- (2-Methoxyphenyl) -5-oxopentanoic acid (88)

Ethyl acrylate (354 μl, 3.25 mmol) was slowly added dropwise at 125 ° to a mixture of ethyl ether (2-methoxybenzoyl) acetate (721 mg, 3.25 mmol) and sodium ethoxide powder (3.75 mg, 0.055 mmol) Lt; / RTI &gt; After 30 minutes, the reaction solution is cooled to room temperature, diluted with diethyl ether, and extracted with 1N HCl aqueous solution and brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. To the concentrated filtrate, 20% aqueous H ₂ SO ₄ (15 mL) is added dropwise and the mixture is boiled for 48 hours. The reaction solution is cooled to room temperature and extracted with DCM. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was diluted with MeOH (5 mL), and 10% NaOH (3.00 mL) was added dropwise thereto, followed by stirring at 50 DEG C for 30 minutes. After the reaction is completed, the reaction solution is concentrated under reduced pressure, the filtrate is diluted with distilled water, and 10% aqueous HCl solution is added. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 2) to obtain Compound 88 (473 mg, 66%, yellow solid).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.68 (dd, J = 1.8, 7.7Hz, 1H), 7.43-7.47 (m, 1H), 6.94-7.02 (m, 2H), 3.89 (s, 3H), 3.06 (t, J = 7.1 Hz, 2H), 2.46 (t, J = 7.3 Hz, 2H), 2.01-2.07 (m, 2H).

(25) 5- (2-Methoxyphenyl) -5-oxopentanamide (89)

3- (3-dimethylaminopropyl) carbodiimide (490 mg, 2.55 mmol), hydroxybenzotriazole (345 mg, 2.55 mmol), and ammonia (4 mL) were added to a solution of compound 88 (473 mg, 2.13 mmol) in DCM 1.28 mL, 2.55 mmol, 2N solution in MeOH) and diisopropylethylamine (0.927 mL, 5.32 mmol) were slowly added dropwise at 0 ° C, and the mixture was stirred at room temperature for 1 hour. After confirming the reaction is complete by TLC, the reaction solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified through column chromatography (Hex: EtOAc = 1: 3) to synthesize Compound 89 (286 mg, 61%, light yellow solid).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.68 (dd, J = 1.8, 7.6Hz, 1H), 7.43-7.48 (m, 1H), 6.95-7.03 (m, 2H), 5.58 (br, 1H), (T, J = 6.8 Hz, 2H), 2.32 (t, J = 7.4 Hz, 2H), 2.01-2.08 (m, 2H).

(26) 5-Hydroxy-5- (2-methoxyphenyl) pentanamide (90)

To a solution of compound 89 (286 mg, 1.29 mmol) in methanol (6.5 mL) was added dropwise sodium borohydride (73.4 mg, 1.94 mmol) at 0 ° C and the mixture was stirred at room temperature for 1 hour. After completion of the reaction was confirmed by TLC, 1M aqueous HCl solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with EtOAc and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 90 (241 mg, 83%, yellow oil) was synthesized without further purification.

^{1 H-NMR (400MHz, CDCl} 3) δ 7.32 (dd, J = 1.5, 7.5Hz, 1H), 7.21-7.24 (m, 1H), 6.92-6.96 (m, 1H), 5.71 (br, 1H), 2H), 1.70-1.83 (m, 4H). &Lt; RTI ID = 0.0 &gt;

(27) 5-Amino-1- (2-methoxyphenyl) pentan-1-ol (91)

Lithium aluminum hydride solution (7.52 mL, 7.52 mmol, 1M in diethyl ether) was slowly added dropwise to compound 90 (240 mg, 1.08 mmol) dissolved in anhydrous THF (20 mL) at 0 ° C and refluxed for 3 hours. After confirming the termination of the reaction, the reaction solution is cooled to room temperature, diluted with DCM, and then Na ₂ SO ₄ .10H ₂ O is slowly added dropwise at 0 ° C. The mixed solution is filtered under reduced pressure using celite, and the filtrate is concentrated. Compound 91 (225 mg, quant., Colorless oil) was synthesized without further purification.

^{1 H-NMR (400MHz, CDCl} 3) δ 7.31 (dd, J = 1.6, 7.5Hz, 1H), 7.21-7.23 (m, 1H), 6.94-6.96 (m, 1H), 6.87 (d, J = 8.2 1H), 4.86-4.89 (m, 1H), 3.84 (s, 3H), 2.67 (t, J = 6.6Hz, 2H), 1.43-2.10 (m, 9H).

(28) 1- {5-Hydroxy-5- (2-methoxyphenyl) pentyl} -3-methylthiourea (92)

To a solution of Compound 90 (27.7 mg, 0.132 mmol) in DCM (1 mL) was slowly added dropwise methyl isothiocyanate (10.9 L, 0.159 mmol) at 0 ° C and stirred at room temperature for 18 hours. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 2) to synthesize Compound 92 (23.9 mg, 64%, light white oil).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.22-7.30 (m, 2H), 6.95-6.97 (m, 1H), 6.88 (d, J = 8.2Hz, 1H), 5.79-6.11 (m, 2H), 2H), 2.98-3.01 (m, 3H), 2.73-2.74 (m, 1H), 1.53-1.82 (m, 6H).

¹³ C-NMR (400 MHz, CDCl ₃ )? 182.3, 156.4, 132.2, 128.4, 126.7, 120.8, 110.5, 70.5, 55.3, 44.2, 36.5, 30.8, 28.7, 23.3.

(29) 1- {5-Hydroxy-5- (2-methoxyphenyl) pentyl} -3-isopropylthiourea (93)

Isopropyl isothiocyanate (27.5 μL, 0.258 mmol) was slowly added dropwise at 0 ° C. to a solution of Compound 91 (45.0 mg, 0.215 mmol) in DCM (1 mL), and the mixture was stirred at room temperature for 2 hours. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 1) to obtain Compound 93 (45.4 mg, 68%, light yellow oil).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.22-7.30 (m, 2H), 6.93-6.97 (m, 1H), 6.88 (d, J = 8.1Hz, 1H), 5.84 (br, 1H), 5.64 ( (br, 2H), 2.71 (d, J = 5.9 Hz, 1H), 1.74-1.84 (m, 2H), 1.62-1.65 (m, 4H), 1.22 (d, J = 6.4 Hz, 6H).

¹³ C-NMR (400MHz, CDCl ₃ ) 隆 180.4, 156.4, 132.2, 128.3, 126.7, 120.7, 110.5, 70.4, 55.3, 46.0, 44.1, 36.5, 28.7, 23.3, 22.6.

(31) 1- {5-Hydroxy-5- (2-methoxyphenyl) pentyl} -3-isopropylurea (94)

Isopropyl isocyanate (25.3 μl, 0.258 mmol) was slowly added dropwise at 0 ° C. to a solution of compound 91 (45.0 mg, 0.215 mmol) in DCM (1 mL), and the mixture was stirred at room temperature for 2 hours. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 2) to obtain Compound 94 (45.5 mg, 72%, light yellow oil).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.20-7.31 (m, 2H), 6.91-6.95 (m, 1H), 6.85 (d, J = 8.1Hz, 1H), 4.82-4.89 (m, 2H), 2H), 1.45-1.52 (m, 4H), 1.61-1.30 (m, 2H) 1.10 (d, J = 6.4 Hz, 6 H).

¹³ C-NMR (400 MHz, CDCl ₃ )? 158.0, 156.3, 132.6, 128.1, 126.7, 120.7, 110.4, 70.2, 55.2, 42.0, 40.1, 36.8, 30.0, 23.4, 23.2.

(32) 5-Isothiocyanato-1- (2-methoxyphenyl) pentan-1-ol (95)

Di- (2-pyridyl) thionocarbonate (74.9 mg, 0.323 mmol) was slowly added dropwise to the solution of Compound 91 (67.5 mg, 0.323 mmol) in DCM (1.5 mL) at 0 ° C and stirred at room temperature for 18 hours . After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified through column chromatography (Hex: EtOAc = 5: 1) to synthesize Compound 95 (57.0 mg, 70%, light yellow oil).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.23-7.31 (m, 2H), 6.95-6.98 (m, 1H), 6.89 (d, J = 8.1Hz, 1H), 4.87 (dd, J = 1.9, 5.8 J = 6.6 Hz, 2H), 2.49 (d, J = 6.1 Hz, 1H), 1.71-1.85 (m, 4H), 1.58-1.67 (m, , &Lt; / RTI &gt; 2H), 1.49-1.55 (m, 2H).

¹³ C-NMR (400 MHz, CDCl ₃ )? 156.4, 132.2, 129.6, 128.4, 126.7, 120.8, 110.5, 70.4, 55.3, 45.0, 36.3, 29.8, 23.1.

m / z (M-17) 234, (M + 23) 274.

(33) 5-Oxo-5- (3,4,5-trimethoxyphenyl) pentanoic acid (96)

Ethyl acrylate (1.64 mL, 15.0 mmol) was slowly added dropwise at 125 ° C to a mixed solution of ethyl 3,4,5-trimethoxybenzoylacetate (4.24 g, 15.0 mmol) and sodium ethoxide powder (17.4 mg, 0.255 mmol) Lt; / RTI &gt; for 30 minutes. After 30 minutes, the reaction solution is cooled to room temperature, diluted with diethyl ether, and extracted with 1N HCl aqueous solution and brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. To the concentrated filtrate, 20% aqueous H ₂ SO ₄ (60 mL) was added dropwise and the mixture was boiled for 48 hours. The reaction solution is cooled to room temperature and extracted with DCM. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was diluted with MeOH (13 mL), and an aqueous solution of 10% NaOH (8.65 mL) was added dropwise, followed by stirring at 50 DEG C for 30 minutes. After the reaction is completed, the reaction solution is concentrated under reduced pressure, the filtrate is diluted with distilled water, and 10% aqueous HCl solution is added. The crude solid was filtered off under reduced pressure and washed with diethyl ether to obtain Compound 96 (3.30 g, 78%, light beige solid).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.23 (s, 2H), 3.91 (s, 9H), 3.04 (t, J = 7.1Hz, 2H), 2.52 (t, J = 6.9Hz, 2H), 2.06 -2.11 (m, 2H).

(34) 5-Oxo-5- (3,4,5-trimethoxyphenyl) pentanamide (97)

3-dimethylaminopropyl carbodiimide (407 mg, 2.13 mmol), hydroxybenzotriazole (288 mg, 2.13 mmol) and ammonia (100 mg) were added to a solution of Compound 96 (500 mg, 1.77 mmol) 1.07 mL, 2.13 mmol, 2N solution in MeOH) and diisopropylethylamine (0.771 mL, 4.43 mmol) at 0 ° C, and the mixture was stirred at room temperature for 4 hours. After confirming the reaction is complete by TLC, the reaction solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Diethyl ether was added to the concentrated filtrate, and the resulting solid was filtered to synthesize Compound 97 (385 mg, 77%, white solid).

^{1 H-NMR (300MHz, CDCl} 3) δ 7.24 (s, 2H), 5.43 (br, 1H), 5.29 (br, 1H), 3.90-3.92 (m, 9H), 3.05 (t, J = 6.9Hz, 2H), 2.36 (t, J = 7.1 Hz, 2H), 2.07-2.12 (m, 2H).

(35) 5-Hydroxy-5- (3,4,5-trimethoxyphenyl) pentanamide (98)

To a solution of Compound 97 (385 mg, 1.37 mmol) in methanol (8 mL) was added dropwise sodium borohydride (77.7 mg, 2.05 mmol) at 0 ° C and the mixture was stirred at room temperature for 1 hour. After completion of the reaction was confirmed by TLC, 1M aqueous HCl solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (DCM: MeOH = 15: 1) to obtain Compound 98 (366 mg, 94%, colorless oil).

^{1 H-NMR (400MHz, CDCl} 3) δ 6.56 (s, 2H), 5.91-5.96 (m, 2H), 4.56-4.59 (m, 1H), 3.83 (s, 6H), 3.81 (s, 3H), 2.25 (br, IH), 2.16-2.25 (m, 2H), 1.67-1.78 (m, 4H).

(36) 5-Amino-1- (3,4,5-trimethoxyphenyl) pentan-1-ol (99)

Lithium aluminum hydride solution (10.3 mL, 10.3 mmol, 1M in diethyl ether) was slowly added dropwise to compound 98 (366 mg, 1.29 mmol) dissolved in anhydrous tetrahydrofuran (20 mL) at 0 ° C and refluxed for 3 hours. After confirming the termination of the reaction, the reaction solution is cooled to room temperature, diluted with DCM, and then Na ₂ SO ₄ .10H ₂ O is slowly added dropwise at 0 ° C. The mixed solution is filtered under reduced pressure using celite, and the filtrate is concentrated. Compound 99 (250 mg, 72%, yellow oil) was synthesized without further purification.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 6.57 (s, 2H), 4.65-4.68 (m, 1H), 3.87 (s, 6H), 3.83 (s, 3H), 3.69 (br, 1H), 2.69-2.72 (m, 2 H), 1.49 - 1.71 (m, 6 H).

(36) 5-Isothiocyanato-1- (3,4,5-trimethoxyphenyl) pentan-1-ol (100)

Di- (2-pyridyl) thionocarbonate (86.2 mg, 0.371 mmol) was slowly added dropwise to the solution of Compound 99 (100 mg, 0.371 mmol) in DCM (2 mL) at 0 ° C and the mixture was stirred at room temperature for 2 hours . After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 2: 1) to obtain Compound 100 (73.4 mg, 64%, yellow oil).

^{1 H-NMR (400MHz, CDCl} 3) δ 6.55 (s, 2H), 4.60 (br, 1H), 3.85 (s, 6H), 3.82 (s, 3H), 3.51 (t, J = 6.1Hz, 2H) , 2.28 (br, IH), 1.70-1.76 (m, 6H).

¹³ C-NMR (400 MHz, CDCl ₃ )? 153.2, 140.5, 137.1, 130.2, 77.4, 77.1, 76.7, 74.4, 60.8, 56.0, 44.9, 38.1, 29.8, 23.0.

(37) 1- [5-Hydroxy-5- (3,4,5-trimethoxyphenyl) pentyl] -3-methylthiourea (101)

To a solution of compound 99 (100 mg, 0.371 mmol) in DCM (2 mL), methyl isothiocyanate (30.0 μL, 0.446 mmol) was slowly added dropwise at 0 ° C. and the mixture was stirred at room temperature for 2 hours. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 2) to obtain Compound 101 (69.3 mg, 55%, colorless oil).

^{1 H-NMR (400MHz, CDCl} 3) δ 6.56 (s, 2H), 6.01-6.24 (m, 2H), 4.60 (br, 1H), 3.85 (s, 6H), 3.82 (s, 3H), 3.43 ( br, 2H), 2.98 (br, 3H), 2.62 (br, IH), 1.24-1.64 (m, 6H).

¹³ C-NMR (400 MHz, CDCl ₃ )? 182.2, 153.1, 140.7, 136.9, 102.6, 74.3, 60.8, 56.1, 44.2, 38.5, 28.7, 23.1, 14.1.

17. Synthesis of compounds 102 to 123

(1) 1- {4- (2-Bromoethoxy) phenyl} -5-chloropentan-1-one (102)

AlCl ₃ (796 g, 5.97 mmol) is dissolved in dichloromethane (10 mL) and then 5-Chlorovalerylchloride (771 μL, 5.97 mmol) is slowly added dropwise at 0 ° C. After 10 minutes, a solution of β-bromophenetole (1.00 g, 4.97 mmol) in DCM (10 mL) was slowly added dropwise to the reaction solution at the same temperature, followed by stirring at room temperature for 1 hour. After confirming the termination of the reaction, the reaction solution is diluted with DCM and poured into ice water. After the mixture was extracted with saturated Na ₂ CO ₃ solution, the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. Compound 102 (1.58 g, quant., White solid) was synthesized without further purification.

^{1 H-NMR (400MHz, CDCl} 3) δ 7.93 (d, J = 1.9Hz, 2H), 6.96 (d, J = 1.9Hz, 2H), 4.35 (t, J = 6.2Hz, 2H), 3.66 (t , J = 6.2 Hz, 2H), 3.57-3.61 (m, 2H), 2.94-2.99 (m, 2H), 1.87-1.92 (m, 4H).

(2) 1- {4- (2-Bromoethoxy) phenyl} -5-chloropentan-1-ol (103)

Sodium borohydride (282 mg, 7.46 mmol) was added dropwise to a solution of Compound 102 (1.58 g, 4.97 mmol) in methanol (15 mL) and DCM (15 mL) at 0 ° C and the mixture was stirred at room temperature for 1 hour. After completion of the reaction was confirmed by TLC, 1M aqueous HCl solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 7: 1) to obtain Compound 103 (1.40 g, 87%, white solid).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.26-7.28 (m, 2H), 6.88-6.91 (m, 2H), 4.63-4.64 (m, 1H), 4.29 (t, J = 6.3Hz, 2H), 3.63 (t, J = 6.3 Hz, 2H), 3.51 (t, J = 6.7 Hz, 2H), 1.27-1.83 (m, 7H).

(3) 5-Chloro-1- [4- {2- (piperidin-1-yl) ethoxy} phenyl] pentan-

Compound 103 (1.39 g, 4.32 mmol) was dissolved in acetonitrile (30 mL), piperidine (538,, 5.45 mmol) and diisopropylethylamine (948,, 5.45 mmol) were slowly dropped at room temperature, . After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 104 (1.17 g, 83%, yellow oil) was synthesized using column chromatography (DCM: MeOH = 10: 1).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.23-7.26 (m, 2H), 6.87-6.89 (m, 2H), 4.60-4.63 (m, 1H), 4.10 (t, J = 6.0Hz, 2H), (T, J = 6.7 Hz, 2H), 2.78 (t, J = 6.0 Hz, 2H), 2.52 (br, 4H), 1.42-1.83 (m, 13H).

(4) 5-Azido-1- [4- {2- (piperidin-1-yl) ethoxy} phenyl] pentan-

Sodium azide (630 mg, 9.70 mmol) was slowly added dropwise at room temperature to a solution of compound 104 (1.58 g, 4.85 mmol) in DMF (30 mL) and the mixture was stirred at 80 ° C for 18 hours. After confirming the termination of the reaction, the reaction solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (DCM: MeOH = 10: 1) to obtain Compound 105 (1.53 g, 95%, yellow oil).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.23-7.26 (m, 2H), 6.86-6.89 (m, 2H), 4.59-4.63 (m, 1H), 4.08 (t, J = 6.1Hz, 2H), 3.24 (t, J = 6.8 Hz, 2H), 2.76 (t, J = 6.1 Hz, 2H), 2.50 (br, 4H), 1.44-1.84 (m, 13H).

(6) 5-Amino-1- [4- {2- (piperidin-1-yl) ethoxy} phenyl] pentan-

Lithium aluminum hydride solution (993 쨉 L, 0.993 mmol, 1.0 M in ether solution) was slowly added dropwise at 0 째 C to compound 105 (150 mg, 0.451 mmol) dissolved in anhydrous DCM (3 mL) and stirred at room temperature for 3 hours . After confirming the termination of the reaction, the reaction solution is diluted with DCM, and Na ₂ SO ₄ .10H ₂ O is slowly added dropwise at 0 ° C. The mixed solution is filtered under reduced pressure using celite, and the filtrate is concentrated. Compound 106 (122 mg, 88%, colorless oil) was synthesized without further purification.

^{1 H-NMR (400MHz, CDCl} 3) δ 7.23-7.26 (m, 2H), 6.86-6.88 (m, 2H), 4.60-4.63 (m, 1H), 4.09 (t, J = 6.1Hz, 2H), 2.76 (t, J = 6.1 Hz, 2H), 2.67 (t, J = 6.7 Hz, 2H), 2.50 (br, 4H), 1.44-1.63 (m, 15H).

(7) 5-Isothiocyanato-1- [4- {2- (piperidin-1-yl) ethoxy} phenyl] pentan-

Di- (2-pyridyl) thionocarbonate (73.8 mg, 0.318 mmol) was slowly added dropwise to the solution of Compound 106 (97.4 mg, 0.318 mmol) in DCM (2 mL) at 0 ° C and the mixture was stirred at room temperature for 3 hours . After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (only EtOAc) to synthesize Compound 107 (72.1 mg, 50%, light yellow oil).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.23 (d, J = 8.5Hz, 2H), 6.83 (d, J = 8.5Hz, 2H), 4.56-4.61 (m, 1H), 4.02 (t, J = 2H), 2.47 (br, 4H), 1.25-1.71 (m, 2H), 3.48 (t, J = 6.6 Hz, 2H) 12H).

¹³ C-NMR (400 MHz, CDCl ₃ )? 158.2, 136.9, 130.3, 127.0, 114.5, 73.6, 65.8, 57.8, 55.0, 44.9, 38.1, 29.8, 25.8, 24.1, 23.0.

m / z (M + 1) 349.

(8) 1- [5-Hydroxy-5- {4 - [(2- (piperidin-1-yl) ethoxy)) phenyl} pentyl] -3-methyl thiourea (108)

To a solution of Compound 106 (121 mg, 0.395 mmol) in DCM (2 mL) was slowly added dropwise methyl isothiocyanate (32.4 L, 0.474 mmol) at 0 ° C and stirred at room temperature for 18 hours. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (DCM: MeOH = 10: 1) to synthesize Compound 108 (99.0 mg, 66%, white solid like the foam).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.23 (d, J = 8.6Hz, 2H), 6.87 (d, J = 8.6Hz, 2H), 5.86 (br, 1H), 5.79 (br, 1H), 4.61 2H), 3.41 (br, 2H), 2.98-3.01 (m, 3H), 2.78 (t, J = 6.0 Hz, 2H), 2.52 (br, 4H), 1.44-1.71 (m, 13H).

¹³ C-NMR (400 MHz, CDCl ₃ )? 182.2, 158.0, 137.2, 127.0, 114.4, 73.5, 65.6, 57.8, 54.9, 44.2, 38.4, 30.9, 28.7, 25.6, 24.0, 23.1.

m / z (M + 1) 380.

(9) Dimethyl 1- [5-hydroxy-5- {4 - ((2- (piperidin-1-yl) ethoxy) phenyl} pentyl] -1H-1,2,3-triazole-4,5-dicarboxylate (109)

To a solution of Compound 105 (78.4 mg, 0.236 mmol) in anhydrous xylene (2 mL) was added dropwise dimethyl acetylene dicarboxylate (31.0 μL, 0.236 mmol) at room temperature and refluxed for 2 hours. After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (DCM: MeOH = 15: 1) to synthesize Compound 109 (62.5 mg, 56%, brown oil).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.21 (d, J = 8.6Hz, 2H), 6.83 (d, J = 8.6Hz, 2H), 4.54-4.57 (m, 3H), 4.06 (t, J = 3H), 2.76 (t, J = 6.0 Hz, 2H), 2.52 (br, 4H), 1.45-1.92 (m, 13H).

¹³ C-NMR (400 MHz, CDCl ₃ )? 160.5, 158.9, 158.1, 139.8, 136.9, 129.7, 126.9, 114.5, 73.5, 65.6, 57.7, 54.9, 53.4, 52.6, 50.5, 38.1, 30.0, 25.6, 23.9, .

m / z (M + 1) 475.

(10) 5-Chloro-1- {4- (2-morpholinoethoxy) phenyl} pentan-1-ol (110)

The compound 103 (300 mg, 0.933 mmol) was dissolved in acetonitrile (6 mL), morpholine (102 μL, 1.18 mmol) and diisopropylethylamine (205 μL, 1.18 mmol) were slowly dropped at room temperature and stirred at 50 ° C. for 18 hours . After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 110 (259 mg, 85%, colorless oil) was synthesized using column chromatography (DCM: MeOH = 20: 1).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.24-7.26 (m, 2H), 6.87-6.89 (m, 2H), 4.58-4.64 (m, 1H), 4.10 (t, J = 5.7Hz, 2H), 2H), 2.79 (t, J = 5.7 Hz, 2H), 2.55-2.58 (m, 4H), 1.57-1.81 (m, 7H) .

(11) 5-Azido-1- {4- (2-morpholinoethoxy) phenyl} pentan-1-ol (111)

Sodium azide (103 mg, 1.58 mmol) was slowly added dropwise at room temperature to a solution of compound 110 (259 mg, 0.789 mmol) in DMF (6 mL) and the mixture was stirred at 80 ° C for 18 hours. After confirming the termination of the reaction, the reaction solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (DCM: MeOH = 15: 1) to obtain Compound 111 (226 mg, 85%, yellow oil).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.25 (d, J = 8.6Hz, 2H), 6.88 (d, J = 8.6Hz, 2H), 4.62 (t, J = 6.6Hz, 1H), 4.10 (t J = 5.7 Hz, 2H), 3.73 (t, J = 4.6 Hz, 4H), 3.25 (t, J = 6.8 Hz, 2H), 2.80 = 4.4 Hz, 4H), 1.38-1.88 (m, 7H).

(12) Dimethyl 1- [5-hydroxy-5- {4- (2-morpholinoethoxy) phenyl} pentyl] -1H-1,2,3-triazole-4,5- dicarboxylate (112)

To a solution of compound 111 (73.2 mg, 0.219 mmol) in anhydrous xylene (2 mL) was added dropwise dimethyl acetylene dicarboxylate (26.9 μL, 0.219 mmol) at room temperature and refluxed for 3 hours. After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified through column chromatography (DCM: MeOH = 20: 1) to synthesize Compound 112 (86.2 mg, 83%, yellow oil).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.22 (d, J = 8.6Hz, 2H), 6.85 (d, J = 8.6Hz, 2H), 4.54-4.60 (m, 3H), 4.07 (t, J = J = 5.7 Hz, 2H), 2.55 (t, J = 5.7 Hz, 2H), 3.98 (s, 3H) 4.5 Hz, 4H), 1.62-1.94 (m, 4H), 1.38-1.49 (m, 2H).

¹³ C-NMR (400 MHz, CDCl ₃ )? 160.5, 158.9, 158.1, 139.8, 136.9, 129.7, 127.0, 114.5, 73.5, 66.8, 65.7, 57.5, 54.0, 53.4, 52.7, 50.4, 38.1, 30.0, 22.7.

m / z (M + 1) &lt; / RTI &gt;

(13) 5-Amino-1- {4- (2-morpholinoethoxy) phenyl} pentan-1-ol (113)

Lithium aluminum hydride solution (964 쨉 L, 0.964 mmol, 1.0 M in ether solution) was slowly added dropwise to compound 111 (146 mg, 0.438 mmol) dissolved in DCM (3 mL) at 0 째 C and then stirred at room temperature for 3 hours . After confirming the termination of the reaction, the reaction solution is diluted with DCM, and Na ₂ SO ₄ .10H ₂ O is slowly added dropwise at 0 ° C. The mixed solution is filtered under reduced pressure using celite, and the filtrate is concentrated. Compound 113 (118 mg, 87%, colorless oil) was synthesized without further purification.

^{1 H-NMR (400MHz, CDCl} 3) δ 7.24-7.27 (m, 2H), 6.87-6.89 (m, 2H), 4.61-4.63 (m, 1H), 4.10 (t, J = 5.7Hz, 2H), 2H), 2.68 (t, J = 6.7 Hz, 2H), 2.55-2.60 (m, 4H), 1.44-1.48 (m, 9H) .

(14) 1- [5-Hydroxy-5- {4- (2-morpholinoethoxy) phenyl} pentyl] -3-methyl thiourea (114)

To a solution of Compound 113 (117 mg, 0.379 mmol) in DCM (2 mL) was slowly added dropwise methyl isothiocyanate (31.1 L, 0.455 mmol) at 0 ° C and the mixture was stirred at room temperature for 2 hours. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified through column chromatography (DCM: MeOH = 15: 1) to synthesize Compound 114 (102 mg, 71%, white oil).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.22 (d, J = 8.6Hz, 2H), 6.85 (d, J = 8.6Hz, 2H), 6.38 (br, 1H), 6.23 (br, 1H), 4.57 2H), 3.67-3.70 (m, 4H), 3.21-3.53 (m, 3H), 2.94 (br, 3H), 2.76 (t, J = 5.6 Hz, 2H), 2.51-2.56 (m, 4H), 1.53-1.60 (m, 6H).

¹³ C-NMR (400 MHz, CDCl ₃ )? 182.0, 158.0, 137.2, 127.0, 114.4, 73.6, 66.7, 65.7, 57.5, 54.0, 44.2, 38.4, 30.8, 28.7, 23.1.

m / z (M + 1) 382.

(15) tert-Butyl 4- [2 - {- 4- (5-chloro-1-hydroxypentyl) phenoxy} ethyl] piperazine-

Boc-piperazine (347 mg, 1.87 mmol) and diisopropylethylamine (325 쨉 L, 1.87 mmol) were slowly added dropwise at room temperature to the compound 103 (500 mg, 1.56 mmol) dissolved in acetonitrile And stirred at 50 ° C. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 115 (318 mg, 48%, colorless oil) was synthesized using column chromatography (DCM: MeOH = 15: 1).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.24-7.26 (m, 2H), 6.87-6.89 (m, 2H), 4.62-4.63 (m, 1H), 4.09-4.13 (m, 2H), 3.51 (t (M, 4H), 2.81 (t, J = 5.7 Hz, 2H), 2.51-2.54 (m, 4H), 1.67-2.04 1.46 (m, 10 H).

(16) tert-Butyl 4- [2- (4- (5-azido-1-hydroxypentyl) phenoxy} ethyl] piperazine zin-

Sodium azide (96.8 mg, 1.49 mmol) was slowly added dropwise at room temperature to a solution of compound 115 (318 mg, 0.745 mmol) in DMF (4 mL) and the mixture was stirred at 80 ° C for 18 hours. After confirming the termination of the reaction, the reaction solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (DCM: MeOH = 15: 1) to obtain Compound 116 (266 mg, 82%, colorless oil).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.24-7.27 (m, 2H), 6.87-6.89 (m, 2H), 4.60-4.72 (m, 1H), 4.10 (t, J = 5.7Hz, 2H), 2H), 2.81 (t, J = 5.7 Hz, 2H), 2.50-2.54 (m, 4H), 1.51-1.65 (m, 7H) , 1.46 (s, 9 H).

(17) Dimethyl 1- [5 - {{4- {2 - ((4- (tert-butoxycarbonyl) piperazin-1-yl)) ethoxy} phenyl} -5-hydroxypentyl] 3-triazole-4,5 &lt; / RTI &gt; didcarboxylate (117)

To a solution of compound 116 (100 mg, 0.231 mmol) in anhydrous xylene (2 mL) was added dropwise dimethyl acetylene dicarboxylate (28.4 μL, 0.231 mmol) at room temperature and refluxed for 3 hours. After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (only EtOAc) to synthesize Compound 117 (86.0 mg, 62%, yellow oil).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.21-7.24 (m, 2H), 6.84-6.87 (m, 2H), 4.54-4.58 (m, 3H), 4.08 (br, 2H), 3.95-3.98 (m 2H), 3.31 (br, 4H), 3.43 (br, 4H), 2.78-2.79 (m, 2H), 2.51 (br, 1.24 - 1.27 (m, 2H).

¹³ C-NMR (400 MHz, CDCl ₃ )? 160.5, 158.9, 158.1, 154.6, 139.8, 136.9, 129.7, 127.0, 114.5, 79.6, 73.6, 65.8, 60.3, 57.2, 53.4, 53.3, 52.6, 50.4, , 28.4, 22.7.

m / z (M + 1) &lt; / RTI &gt;

(18) tert-Butyl 4- [2- {4- (5-amino-1-hydroxypentyl) phenoxy} ethyl] piperazine-

To the compound 116 (166 mg, 0.388 mmol) dissolved in anhydrous DCM (3 mL) was slowly added dropwise lithium aluminum hydride solution (842,, 0.842 mmol, 1.0 M in ether solution) at 0 째 C, followed by stirring at room temperature for 3 hours . After confirming the termination of the reaction, the reaction solution is diluted with DCM, and Na ₂ SO ₄ .10H ₂ O is slowly added dropwise at 0 ° C. The mixed solution is filtered under reduced pressure using celite, and the filtrate is concentrated. Compound 118 (134 mg, 86%, colorless oil) was synthesized without further purification.

^{1 H-NMR (400MHz, CDCl} 3) δ 7.24-7.27 (m, 2H), 6.85-6.89 (m, 2H), 4.56-4.67 (m, 1H), 4.10 (t, J = 5.7Hz, 2H), 2H), 2.67 (t, J = 6.7 Hz, 2H), 2.50-2.54 (m, 4H), 1.50-1.91 (m, 9H) , 1.46 (s, 9 H).

(19) tert-Butyl 4- [2- (4 - ((1-hydroxy-5- (3- methylthioureido) pentyl)) phenoxy} ethyl] piperazine-

To a solution of compound 118 (133 mg, 0.326 mmol) in DCM (3 mL), methyl isothiocyanate (26.8 L, 0.392 mmol) was slowly added dropwise at 0 占 폚 and stirred at room temperature for 2 hours. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (DCM: MeOH = 15: 1) to obtain 119 (127 mg, 81%, white solid like foam).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.22 (d, J = 8.4Hz, 2H), 6.84 (d, J = 8.4Hz, 2H), 6.44 (br, 1H), 6.30 (br, 1H), 4.52 J = 5.4 Hz, 2H), 2.48 (m, 2H), 2.63 (s, 3H) t, J = 4.7 Hz, 4H), 1.52-1.84 (m, 4H), 1.44 (s, 9H), 1.23-1.26 (m, 2H).

¹³ C-NMR (400 MHz, CDCl ₃ )? 182.2, 157.9, 154.7, 137.2, 127.0, 114.4, 79.7, 73.5, 65.8, 60.4, 57.1, 53.3, 44.2, 38.4, 30.9, 28.8, 28.4, 23.1.

m / z (M + 1) 481.

(20) 5-Chloro-1- [4- {2- (dimethylamino) ethoxy} phenyl] pentan-

The compound 103 (227 mg, 0.705 mmol) was dissolved in acetonitrile (5 mL), dimethylamine hydrochloride (86.1 mg, 1.06 mmol) and potassium carbonate (292 mg, 2.11 mmol) were slowly dropped at room temperature, Lt; / RTI &gt; After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 120 (85.5 mg, 43%, colorless oil) was synthesized using column chromatography (DCM: MeOH = 10: 1).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.23 (d, J = 8.4Hz, 2H), 6.85 (d, J = 8.4Hz, 2H), 4.57-5.59 (m, 1H), 4.00 (t, J = (T, J = 5.7 Hz, 2H), 2.30 (s, 3H), 1.66-1.82 (m, 7H).

(21) 5-Azido-1- [4- {2- (dimethylamino) ethoxy} phenyl] pentan-

Sodium azide (58.8 mg, 0.905 mmol) was slowly added dropwise at room temperature to a solution of compound 120 (129 mg, 0.452 mmol) in DMF (3 mL) and the mixture was stirred at 80 ° C for 18 hours. After confirming the termination of the reaction, the reaction solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (DCM: MeOH = 10: 1) to obtain Compound 121 (105 mg, 79%, light yellow oil).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.23-7.26 (m, 2H), 6.87-6.91 (m, 2H), 4.60-4.64 (m, 1H), 4.05 (t, J = 5.7Hz, 2H), 3.24 (t, J = 6.8 Hz, 2H), 2.72 (t, J = 5.7 Hz, 2H), 2.33 (s, 6H), 1.59-1.82 (m, 7H).

(22) 1- [5- {4 - ((2- (Dimethylamino) ethoxy)) phenyl} -5-hydroxypentyl] -3-methyl thiourea (122)

Lithium aluminum hydride solution (527,, 0.527 mmol, 1.0 M in ether solution) was slowly added dropwise at 0 째 C to compound 121 (70.0 mg, 0.239 mmol) which was dissolved in anhydrous DCM (2 mL) and stirred at room temperature for 3 hours . After confirming the termination of the reaction, the reaction solution is diluted with DCM, and Na ₂ SO ₄ .10H ₂ O is slowly added dropwise at 0 ° C. The mixed solution is filtered under reduced pressure using celite, and the filtrate is concentrated. The concentrated filtrate was dissolved in DCM (3 mL), methyl isothiocyanate (16.3 μL, 0.239 mmol) was slowly added dropwise at 0 ° C., and the mixture was stirred at room temperature for 18 hours. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified through column chromatography (DCM: MeOH = 10: 1) to synthesize Compound 122 (42.1 mg, 52% for steps, light yellow oil).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.22 (d, J = 8.3Hz, 2H), 6.85 (d, J = 8.3Hz, 2H), 6.32 (br, 1H), 6.18 (br, 1H), 4.57 (T, J = 5.5 Hz, 2H), 2.29 (m, 2H), 2.39 s, 6H), 1.25-1.78 (m, 6H).

¹³ C-NMR (400 MHz, CDCl ₃ )? 182.3, 158.1, 137.2, 127.0, 114.4, 73.6, 65.8, 58.2, 45.7, 44.3, 38.4, 30.9, 28.7, 23.1.

m / z (M + 1) &lt; / RTI &gt; 340.

(23) Dimethyl 1- [5- {4 - ((2- (dimethylamino) ethoxy) phenyl} -5-hydroxypentyl] -1H-1,2,3-triazole-4,5- dicarboxylate (123)

To a solution of Compound 121 (35.0 mg, 0.120 mmol) in anhydrous xylene (2 mL) was added dropwise dimethyl acetylene dicarboxylate (14.7 L, 0.120 mmol) at room temperature and refluxed for 2 hours. After confirming the reaction is complete by TLC, the solution is cooled to room temperature, diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (DCM: MeOH = 10: 1) to obtain Compound 123 (15.9 mg, 31%, yellow oil).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.22 (d, J = 8.5Hz, 2H), 6.87 (d, J = 8.5Hz, 2H), 4.53-4.61 (m, 3H), 4.04 (t, J = 2H), 2.33 (s, 3H), 3.96 (s, 3H), 2.73 (t, J = 5.7 Hz, 2H) m, 6H).

m / z (M + 1) &lt; / RTI &gt; 435.

18. Synthesis of compounds 124 to 141

(1) 5-bromo-1- (4-methoxyphenyl) pentan-1-one (124)

AlCl ₃ (4.62 g, 34.7 mmol) is dissolved in DCM (55 mL) and then 5-bromovalerylchloride (3.71 mL, 27.7 mmol) is slowly added dropwise at 0 ° C. After 10 minutes, anisole (2.50 g, 23.1 mmol) was slowly added dropwise to the reaction solution at the same temperature, followed by stirring at room temperature for two hours. After confirming the reaction is complete by TLC, the reaction solution is diluted with DCM and poured into ice water. After the mixture was extracted with saturated Na ₂ CO ₃ solution, the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The concentrated filtrate was subjected to column chromatography (Hex: EtOAc = 15: 1) to synthesize Compound 124 in the form of white solid (6.27 g, quant).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.98 (d, J = 8.8Hz, 2H), 6.97 (d, J = 8.8Hz, 2H), 3.91 (s, 3H), 3.49 (t, J = 6.4Hz, 2H), 3.00 (t, J = 6.5 Hz, 2H), 1.93-2.02 (m, 4H).

(2) 2- (4-bromobutyl) -2- (4-methoxyphenyl) -1,3-dioxolane (125)

The compound 124 (6.27 g, 23.1 mmol) was dissolved in benzene (120 mL), and dean-stark was added thereto to reflux for two days. Lt; / RTI &gt; After completion of the reaction is confirmed by TLC, the solution is cooled to room temperature. The reaction solution is concentrated under reduced pressure, diluted with DCM, and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 10: 1) to give compound 125 (5.54 g, 76%) in the form of a clear oil.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.39 (d, J = 8.8Hz, 2H), 6.90 (d, J = 8.8Hz, 2H), 4.01-4.06 (m, 2H), 3.82 (s, 3H), 3.78-3.81 (m, 2H), 3.40 (t, J = 6.9 Hz, 2H), 1.85-1.96 (m, 4H), 1.49-1.55 (m, 2H).

(3) Compound 126

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.39 (d, J = 8.8Hz, 2H), 6.90 (d, J = 8.8Hz, 2H), 4.66 (q, J = 7.1Hz, 2H), 4.01-4.06 ( J = 8.0 Hz, 2H), 1.68-1.73 (m, 2H), 3.82 (s, 3H), 3.78-3.81 , &Lt; / RTI &gt; 2H), 1.48-1.52 (m, 4H).

(4) 4- (2- (4-methoxyphenyl) -1,3-dioxolan-2-yl) butane- 1 -thiol (127)

Compound 125 (2.00 g, 6.35 mmol) dissolved in acetone (6 mL) was slowly added dropwise at 0 ° C to a solution of potassium ethylxanthate (1.12 g, 6.99 mmol) dissolved in acetone (15 mL) do. After confirming the reaction is complete by TLC, the solution is filtered and concentrated at 60 [deg.] C for 30 minutes. Lithium aluminum hydride (14.7 mL, 14.7 mmol, 1M in diethyl ether solution) was added dropwise to a solution of the synthesized Compound 126 in anhydrous diethyl ether (35 mL), followed by reflux stirring for one day. After the completion of the reaction is confirmed by TLC, the solution is allowed to reach room temperature. The reaction solution is diluted with DCM and Na ₂ SO ₄ .10H ₂ O is slowly added dropwise at 0 ° C. The mixed solution is filtered under reduced pressure using celite, and the filtrate is concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 10: 1) to obtain compound 127 (376 mg, 22% for 2 steps) in the form of a clear oil.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.39 (d, J = 8.7Hz, 2H), 6.90 (d, J = 8.7Hz, 2H), 4.01-4.06 (m, 2H), 3.82 (s, 3H), 2H), 1.43-1.51 (m, 2H), 1.93 (t, J = 8.0 Hz, 2H) , 1.34 (t, J = 7.8 Hz, 1 H).

(5) 2- (4- (2-bromoethylthio) butyl) -2- (4-methoxyphenyl) -1,3-dioxolane (128)

To a suspension of sodium hydride (67.2 mg, 1.54 mmol) in anhydrous THF (6 mL) was slowly added dropwise the compound 127 (375 mg, 1.40 mmol) dissolved in anhydrous THF (7 mL) at 0 ° C., do. After 30 minutes, 1,2-dibromoethane (150 μL, 1.68 mmol) was slowly added dropwise under the same conditions, followed by stirring at room temperature for four hours. The reaction is terminated by TLC, diluted with EtOAc and extracted with distilled water. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 10: 1) to give compound 128 (152 mg, 29%) in the form of a bright yellow oil.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.39 (d, J = 8.9Hz, 2H), 6.90 (d, J = 8.9Hz, 2H), 4.01-4.06 (m, 2H), 3.82 (s, 3H), J = 8.4 Hz, 2H), 2.54 (t, J = 7.4 Hz, 2H), 1.93 (t, J = = 8.0 Hz, 2H), 1.55-1.65 (m, 2H), 1.49-1.50 (m, 2H).

(6) 2- (4-methoxyphenyl) -2- (4- (vinylthio) butyl) -1,3-dioxolane (129)

To a suspension of sodium hydride (21.0 mg, 0.480 mmol) in anhydrous THF (2.3 mL) was slowly added dropwise the compound 128 (150 mg, 0.400 mmol) dissolved in anhydrous THF (3.2 mL) at 0 ° C, do. After confirming the completion of the reaction by TLC, the solution is cooled to room temperature, diluted with EtOAc, and extracted with distilled water. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 10: 1) to obtain Compound 129 (80.0 mg, 68%) in the form of a clear oil.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.39 (d, J = 8.8Hz, 2H), 6.90 (d, J = 8.8Hz, 2H), 6.63 (dd, J = 10.1, 16.7Hz, 1H), 5.20 ( (d, J = 10.1 Hz, 1H), 5.10 (d, J = 16.7 Hz, 2H), 4.01-4.06 (m, 2H), 3.82 (s, 3H), 3.78-3.81 2H), 1.93 (t, J = 8.0 Hz, 2H), 1.53-1.68 (m, 2H), 1.45-1.52

(7) 1- (4-methoxyphenyl) -5- (vinylthio) pentan-1-one (130)

Pyridinium p-toluenesulfonate (27.6 mg, 0.110 mmol) was added dropwise to a solution of compound 129 (80.0 mg, 0.270 mmol) in acetone / water (5/1 mL) and refluxed for one day. After confirming the termination of the reaction by TLC, the solution is cooled to room temperature and then concentrated. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 10: 1) to synthesize Compound 130 (19.6 mg, 29%) in the form of a white solid.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.97 (d, J = 8.6Hz, 2H), 6.97 (d, J = 8.6Hz, 2H), 6.39 (dd, J = 10.1, 16.7Hz, 1H), 5.22 ( (d, J = 10.1 Hz, 1H), 5.14 (d, J = 16.7 Hz, 1H), 3.82 2H), 1.82-1.94 (m, 2H), 1.65-1.80 (m, 2H).

(8) 1- (4-methoxyphenyl) -5- (vinylsulfinyl) pentan-1-one (131)

To a solution of sodium metaperiodate (16.7 mg, 0.078 mmol) in water (300 μl) was slowly added dropwise the compound 130 (19.6 mg, 0.078 mmol) dissolved in a 70% ethanol aqueous solution (220 μl) at 0 ° C., After stirring for four hours, it is stirred at room temperature for one day. After completion of the reaction is confirmed by TLC, ethanol is added dropwise, and the solution is filtered and concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (only EtOAc) to synthesize Compound 131 (13.0 mg, 63%) in the form of a white solid.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.96 (d, J = 8.9Hz, 2H), 6.97 (d, J = 8.9Hz, 2H), 6.65 (dd, J = 9.8, 16.5Hz, 1H), 6.13 ( 2H), 2.78-2.90 (m, 1H), 2.70-2.77 (m, 1H), 1.78 (m, 1.94 (m, 4 H).

¹³ C NMR (300 MHz, CDCl ₃ )? 198.0, 163.5, 140.5, 130.3, 122.1, 113.8, 55.5, 53.2, 37.6, 23.4, 21.6.

(9) 5-chloro-1- (4-fluorophenyl) pentan-1-one (132)

AlCl ₃ (832 mg, 6.24 mmol) is dissolved in DCM (28 mL) and then 5-bromovalerylchloride (0.830 mL, 6.24 mmol) is slowly added dropwise at 0 ° C. After 10 minutes, fluorobenzene (500 mg, 5.20 mmol) was slowly added dropwise to the reaction solution at the same temperature, followed by stirring at room temperature for 2 hours. After confirming the reaction is complete by TLC, the reaction solution is diluted with DCM and poured into ice water. After the mixture was extracted with saturated Na ₂ CO ₃ solution, the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 10: 1) to obtain a bright yellow oil-like compound 132 (876 mg, 65%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.97-8.01 (m, 2H), 7.12-7.15 (m, 2H), 3.46 (t, J = 6.4Hz, 2H), 2.99 (t, J = 6.9Hz, 2H ), 1.90-1.97 (m, 4H).

(10) 2- (4-bromobutyl) -2- (4-fluorophenyl) -1,3-dioxolane (133)

After dissolving ethyleneglycol (1.30 mL, 23.2 mmol), p-toluenesulfonic acid (110 mg, 0.581 mmol) and compound 132 (3.01 g, 11.6 mmol) in benzene (100 mL), dean- Lt; / RTI &gt; After completion of the reaction is confirmed by TLC, the solution is cooled to room temperature. The reaction solution is concentrated under reduced pressure, diluted with DCM, and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 15: 1) to give a bright yellow oil compound 133 (2.13 g, 61%).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.40-7.47 (m, 2H), 7.06 (t, J = 8.8 Hz, 2H), 4.03-4.08 (m, 2H), 3.77-3.85 (m, 2H), 3.40 (t, J = 6.8 Hz, 2H), 1.83-1.95 (m, 4H), 1.46-1.55 (m, 2H).

(11) 4- (2- (4-fluorophenyl) -1,3-dioxolan-2-yl) butane-1-thiol (135)

Compound 133 (1.21 g, 4.00 mmol) dissolved in acetone (8 mL) was slowly added dropwise at 0 ° C to a solution of potassium ethyloxanthate (705 mg, 4.40 mmol) in acetone (5 mL) and stirred at room temperature for 6 hours do. After confirming the reaction is complete by TLC, the solution is filtered and concentrated at 60 [deg.] C for 30 minutes. Lithium aluminum hydride (8.40 mL, 8.40 mmol, 1M in diethyl ether solution) was added dropwise to a solution of synthesized compound 134 in anhydrous diethyl ether (22 mL), followed by reflux stirring for one day. After the completion of the reaction is confirmed by TLC, the solution is allowed to reach room temperature. The reaction solution is diluted with DCM and Na ₂ SO ₄ .10H ₂ O is slowly added dropwise at 0 ° C. The mixed solution is filtered under reduced pressure using celite, and the filtrate is concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 10: 1) to obtain compound 135 (596 mg, 58% for 2 steps) in the form of a clear oil.

(12) Compound 134

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.36-7.47 (m, 2H), 6.97-7.08 (m, 2H), 4.58-4.70 (m, 2H), 3.99-4.07 (m, 2H), 3.74-3.81 ( m, 2H), 3.02-3.13 (m, 2H), 1.85-1.96 (m, 2H), 1.66-1.73 (m, 2H), 1.48-1.52 (m, 5H).

(13) Compound 135

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.42-7.47 (m, 2H), 7.05 (t, J = 8.7Hz, 2H), 4.03-4.07 (m, 2H), 3.77-3.81 (m, 2H), 2.48 2H), 1.91 (t, J = 8.0 Hz, 2H), 1.58-1.68 (m, 2H), 1.40-1.51 Hz, 1H).

(14) 2- (4- (2-bromoethylthio) butyl) -2- (4-fluorophenyl) -1,3-dioxolane 136

To a suspension of sodium hydride (151 mg, 3.47 mmol) in anhydrous THF (13 mL) was slowly added dropwise a compound 135 (806 mg, 3.15 mmol) dissolved in anhydrous THF (16 mL) at 0 ° C., Lt; / RTI &gt; After 30 minutes, 1,2-dibromoethane (0.330 mL, 3.78 mmol) was slowly added dropwise under the same conditions, followed by stirring at room temperature for four hours. The reaction is terminated by TLC, diluted with EtOAc and extracted with distilled water. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 10: 1) to obtain a yellowish oil-like compound 136 (448 mg, 39%).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.42-7.47 (m, 2H), 7.05 (t, J = 8.7Hz, 2H), 4.03-4.07 (m, 2H), 3.77-3.81 (m, 2H), 3.48 (t, J = 8.0 Hz, 2H), 2.93 (dd, J = 8.3, 8.5 Hz, 2H) , 1.50-1.66 (m, 2H), 1.42-1. 49 (m, 2H).

(15) 2- (4-fluorophenyl) -2- (4- (vinylthio) butyl) -1,3-dioxolane (137)

To a suspension of sodium hydride (64.6 mg, 1.48 mmol) in anhydrous THF (7 mL) was slowly added dropwise the compound 136 (448 mg, 1.23 mmol) dissolved in anhydrous THF (10 mL) at 0 ° C, do. After confirming the completion of the reaction by TLC, the solution is cooled to room temperature, diluted with EtOAc, and extracted with distilled water. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was subjected to column chromatography (Hex: EtOAc = 16: 1) to synthesize a yellowish oil-like compound 137 (214 mg, 62%).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.42-7.47 (m, 2H), 7.05 (t, J = 8.8Hz, 2H), 6.36 (dd, J = 10.1, 16.7Hz, 1H), 5.20 (d, J 2H), 2.69 (t, J = 7.3 Hz, 2H), 1.93 (m, (t, J = 8.0 Hz, 2H), 1.61-1.69 (m, 2H), 1.45-1.53 (m, 2H).

(16) 1- (4-fluorophenyl) -5- (vinylthio) pentan-1-one (138)

Pyridinium p-toluenesulfonate (40.2 mg, 0.160 mmol) was added dropwise to a solution of compound 137 (100 mg, 0.350 mmol) in acetone / water (7.5 / 1.5 mL) and refluxed for one day. After confirming the termination of the reaction by TLC, the solution is cooled to room temperature and then concentrated. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 16: 1) to synthesize Compound 138 (38.5 mg, 39%) in the form of a white solid.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 8.00-8.05 (m, 2H), 7.17 (t, J = 8.8Hz, 2H), 6.40 (dd, J = 10.1, 16.7Hz, 1H), 5.24 (d, J = 10.1 Hz, 1H), 5.15 (d, J = 16.7 Hz, 1H), 3.02 (t, J = 7.1 Hz, 2H), 2.79 (t, J = 7.1 Hz, 2H), 1.86-1.94 ), 1.75-1.83 (m, 2H).

(17) 1- (4-fluorophenyl) -5- (vinylthio) pentan-1-ol (139)

Sodium borohydride (6.43 mg, 0.170 mmol) was slowly added dropwise at 0 ° C to a solution of compound 138 (25.7 mg, 0.110 mmol) in MeOH (4.5 mL) and stirred at room temperature for 1 hour. After the completion of the reaction was confirmed by TLC, 1N HCl solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with EtOAc and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 139 (26.1 mg, 99%) was synthesized in the form of a clear oil without further purification.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.33-7.37 (m, 2H), 7.07 (t, J = 8.8Hz, 2H), 6.37 (dd, J = 10.1, 16.7Hz, 1H), 5.22 (d, J 2H), 1.83-1.84 (m, 2H), 1.69-1.74 (d, J = (m, 4H).

(18) 1- (4-fluorophenyl) -5- (vinylsulfinyl) pentan-1-ol (140)

To a solution of sodium metaperiodate (23.5 mg, 0.110 mmol) in water (400 μl), compound 139 (25.8 mg, 0.110 mmol) dissolved in a 70% ethanol aqueous solution (300 μl) was slowly dropped at 0 ° C, Stir for 4 hours and then stir at room temperature for one day. After completion of the reaction is confirmed by TLC, ethanol is added dropwise, and the solution is filtered and concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (only EtOAc) to synthesize Compound 140 (15.2 mg, 54%) in the form of white oil.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.30-7.35 (m, 2H), 7.05 (t, J = 8.6Hz, 2H), 6.59 (dd, J = 9.8Hz, 1H), 6.09 (d, J = 16.5 1H), 5.97 (d, J = 9.8 Hz, 1H), 4.69 (t, J = 6.4 Hz, 1H), 2.60-2.77 (m, 3H), 1.67-1.89 (m, 4H), 1.44-1.63 (m, 2H).

_{^{13 C NMR (300MHz, CDCl 3}} ) δ 162.3, 140.3, 127.5, 122.2, 115.4, 115.2, 73.4, 53.1, 38.6, 24.9, 21.7.

(19) 1- (4-fluorophenyl) -5- (vinylsulfinyl) pentan-1-one (141)

To a solution of sodium metaperiodate (34.2 mg, 0.160 mmol) in water (580 μl) was slowly dropwise added dropwise at 0 ° C the compound 138 (37.8 mg, 0.160 mmol) dissolved in a 70% ethanol aqueous solution (400 μl) After stirring for four hours, it is stirred at room temperature for one day. After completion of the reaction is confirmed by TLC, ethanol is added dropwise, and the solution is filtered and concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (only EtOAc) to synthesize compound 141 (24.5 mg, 60%) in the form of a white solid.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.98-8.03 (m, 2H), 7.16 (t, J = 8.6Hz, 2H), 6.64 (dd, J = 9.8, 16.5Hz, 1H), 6.13 (d, J 2H), 2.78-2.90 (m, 1H), 2.70-2.76 (m, 1H), 1.81-1.97 (m, m, 4H).

_{^{13 C NMR (300MHz, CDCl 3}} ) δ 197.8, 162.3, 140.4, 130.7, 122.2, 115.9, 115.6, 53.0, 37.9, 23.1, 21.5.

19. Synthesis of compounds 142 to 157

(1) 3-bromo-1- (4-methoxyphenyl) propan-1-one (142)

After dissolving AlCl ₃ (3.70 g, 27.7 mmol) in DCM (55 mL), 3-bromopropionyl chloride (2.76 mL, 27.7 mmol) was slowly added dropwise at 0 ° C. After 10 minutes, anisole (2.51 mL, 23.1 mmol) was slowly added dropwise to the reaction solution at the same temperature, followed by stirring at room temperature for two hours. After confirming the reaction is complete by TLC, the reaction solution is diluted with DCM and poured into ice water. After the mixture was extracted with saturated Na ₂ CO ₃ solution, the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 10: 1) to obtain Compound 142 (3.89 g, 69%) in the form of a light brown solid.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.98 (d, J = 8.9Hz, 2H), 6.99 (d, J = 8.9Hz, 2H), 3.92 (s, 3H), 3.78 (t, J = 6.8Hz, 2H), 3.56 (t, J = 6.9 Hz, 2H).

(2) 3-bromo-1- (4-methoxyphenyl) propan-1-ol (143)

Sodium borohydride (117 mg, 3.09 mmol) was slowly added dropwise at 0 ° C to a solution of compound 142 (500 mg, 2.06 mmol) in MeOH (10 mL) and the mixture was stirred at room temperature for 1 hour. After the completion of the reaction was confirmed by TLC, 1N HCl aqueous solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with EtOAc and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 143 (478 mg, 95%) was synthesized in the form of a clear oil without further purification.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.34 (d, J = 8.6Hz, 2H), 6.94 (d, J = 8.6Hz, 2H), 4.89-4.94 (m, 1H), 3.85 (s, 3H), (M, 1H), 3.40-3.47 (m, 1H), 2.33-2.41 (m, 1H), 2.18-2.23 (m, 1H), 1.89 (d, J = 3.1 Hz, 1H).

(3) 3-azido-1- (4-methoxyphenyl) propan-1-ol (144)

Sodium azide (57.2 mg, 0.880 mmol) was slowly added dropwise at room temperature to a solution of Compound 143 (109 mg, 0.440 mmol) in DMF (2.2 mL) and the mixture was stirred at 80 ° C for 3 hours. After confirming the termination of the reaction, the reaction solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 5: 1) to obtain compound 144 (88.5 g, 97%) in the form of a clear oil.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.31-7.34 (m, 2H), 6.92-6.95 (m, 2H), 4.80-4.86 (m, 1H), 3.85 (s, 3H), 3.48-3.56 (m, 1H), 3.36-3.44 (m, 1H), 2.01-2.15 (m, 1H), 1.92-1.98 (m, 2H).

(4) 3-amino-1- (4-methoxyphenyl) propan-1-ol (145)

Lithium aluminum hydride solution (800 쨉 l, 0.800 mmol, 1M in diethyl ether solution) was slowly added dropwise to compound 144 (82.8 mg, 0.400 mmol) dissolved in diethyl ether (2 mL) at 0 째 C and then stirred at room temperature for 1 hour . After confirming the termination of the reaction, the reaction solution is diluted with DCM, and Na ₂ SO ₄ .10H ₂ O is slowly added dropwise at 0 ° C. The mixed solution is filtered under reduced pressure using celite, and the filtrate is concentrated. Compound 145 (67.6 mg, 93%) in the form of a white solid was synthesized without further purification.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.35 (d, J = 8.5Hz, 2H), 6.91-6.94 (m, 2H), 4.94-4.98 (m, 1H), 3.85 (s, 3H), 3.11-3.19 (m, 1 H), 2.94-3.03 (m, 1 H), 1.73-1.91 (m, 3H).

(5) 3-isothiocyanato-1- (4-methoxyphenyl) propan-1-ol (146)

Di-2-pyridyl thiono-carbonate (52.1 mg, 0.220 mmol) was slowly added dropwise at 0 ° C to a solution of Compound 145 (33.5 mg, 0.180 mmol) in DCM (1 mL), and the mixture was stirred at room temperature for one day . After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 3: 1) to give 146 (40.2 mg, quant) in the form of a clear oil.

^{1 H-NMR (300MHz, CDCl} 3) δ 7.29-7.33 (m, 2H), 6.92-6.96 (m, 2H), 4.80-4.85 (m, 1H), 3.84 (s, 3H), 3.71-3.80 (m , 1H), 3.52-3.61 (m, 1H), 1.99-2.18 (m, 3H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 159.4, 135.3, 130.1, 127.1, 114.2, 70.8, 55.4, 42.0, 38.6.

(6) 1- (3-hydroxy-3- (4-methoxyphenyl) propyl) -3-methylthiourea (147)

To a solution of Compound 145 (33.0 mg, 0.180 mmol) in DCM (500 μL) was slowly added dropwise methylene diisocyanate (16.6 mg, 0.220 mmol) dissolved in DCM (500 μL) at 0 ° C., . After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc: DCM = 1: 3: 1) to synthesize Compound 147 (45.6 mg, quant) in the form of a white solid.

^{1 H-NMR (300MHz, DMSO} ) δ 7.41 (br, 2H), 7.24 (d, J = 8.7Hz, 2H), 6.88 (d, J = 8.7Hz, 2H), 5.20 (d, J = 4.4Hz, 2H), 2.80 (br, 3H), 1.77 (br, 2H), 4.50-4.55 (m, 1H), 3.73 (s, 3H).

¹³ C-NMR (300 MHz, MeOD)? 159.1, 136.6, 126.8, 113.3, 71.2, 54.3, 37.9

(7) 1- (3-hydroxy-3- (4-methoxyphenyl) propyl) -3-isopropylthiourea (148)

Isopropyl isothiocyanate (24.2 쨉 L, 0.220 mmol) was slowly added dropwise at 0 째 C to a solution of Compound 145 (32.0 mg, 0.180 mmol) in DCM (1 mL), and the mixture was stirred at room temperature for one day. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 3) to synthesize Compound 148 (49.0 mg, 96%) in the form of white oil.

^{1 H-NMR (300MHz, CDCl} 3) δ 7.28 (d, J = 8.7Hz, 2H), 6.89 (d, J = 8.7Hz, 2H), 6.62 (br, 1H), 6.12 (d, J = 7.6Hz (Br, 1H), 4.78 (br, IH), 4.05-4.14 (br, IH), 3.81-3.95 ), 1.91-1.97 (m, 2H), 1.23 (dd, J = 1.5, 6.4 Hz, 6H)

¹³ C-NMR (300 MHz, CDCl ₃ )? 180.2, 159.2, 135.9, 126.9, 113.9, 72.2, 55.3, 38.1, 29.7, 22.6, 22.5.

(8) 1- (3-Hydroxy-3- (4-methoxyphenyl) propyl) -3-phenylthiourea (149)

To a solution of Compound 145 (36.1 mg, 0.200 mmol) in DCM (1 mL), phenyl isothiocyanate (29.3 μL, 0.240 mmol) was slowly added dropwise at 0 ° C. and stirred at room temperature for one day. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 2: 1) to obtain Compound 149 (53.4 mg, 84%) in the form of white oil.

^{1 H-NMR (300MHz, CDCl} 3) δ 8.14 (br, 1H), 7.40-7.45 (m, 2H), 7.21-7.30 (m, 5H), 6.94 (br, 1H), 6.83-6.86 (m, 2H ), 4.72-4.76 (m, IH), 4.0-4.09 (m, IH), 3.78 (s, 3H), 3.55-3.65 ).

¹³ C-NMR (300 MHz, CDCl ₃ )? 180.2, 159.1, 136.0, 129.9, 127.0, 126.9, 125.2, 113.9, 72.5, 55.3, 43.4, 37.7.

(9) 3-Bromo-1- (4-fluorophenyl) propan-1-one (150)

AlCl ₃ (833 mg, 6.24 mmol) is dissolved in DCM (9 mL) and 3-bromopropionyl chloride (622 μL, 6.24 mmol) is slowly added dropwise at 0 ° C. After 10 minutes, fluorobenzene (488,, 5.20 mmol) was slowly added dropwise to the reaction solution at the same temperature, followed by stirring at room temperature for one and a half hours. After confirming the reaction is complete by TLC, the reaction solution is diluted with DCM and poured into ice water. The mixture was extracted with saturated aqueous Na ₂ CO ₃ solution, and the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 10: 1) to give Compound 150 (1.03 g, 85%) in the form of a light yellow solid.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 8.01-8.06 (m, 2H), 7.17-7.23 (m, 2H), 3.78 (t, J = 6.8Hz, 2H), 3.60 (t, J = 6.9Hz, 2H ).

(10) 3-Bromo-1- (4-fluorophenyl) propan-1-ol (151)

Sodium borohydride (246 mg, 6.50 mmol) was slowly added dropwise at 0 ° C to a solution of compound 150 (1.00 g, 4.33 mmol) in MeOH (22 mL) and stirred at room temperature for 1 hour. After the completion of the reaction was confirmed by TLC, 1N HCl solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 91 (965 mg, 96%) was synthesized as a light yellow solid without further purification.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.37-7.41 (m, 2H), 7.06-7.12 (m, 2H), 4.95-5.00 (m, 1H), 3.59-3.67 (m, 1H), 3.41-3.48 ( m, 1H), 2.29-2.40 (m, 1H), 2.13-2.24 (m, 1H), 1.97 (d, J = 3.4 Hz, 1H).

(11) 3-azido-1- (4-fluorophenyl) propan-1-ol (152)

Sodium azide (547 mg, 8.41 mmol) was slowly added dropwise at room temperature to a solution of compound 151 (980 mg, 4.21 mmol) in DMF (19 mL) and the mixture was stirred at 80 ° C for 3 hours. After confirming the termination of the reaction, the reaction solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was subjected to column chromatography (Hex: EtOAc = 4: 1) to synthesize a yellowish oil-like compound 152 (784 mg, 90%).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.35-7.40 (m, 2H), 7.06-7.12 (m, 2H), 4.85-4.91 (m, 1H), 3.51-3.59 (m, 1H), 3.38-3.46 ( m, 1 H), 1.91 - 2.12 (m, 3 H).

(12) 3-amino-1- (4-fluorophenyl) propan-1-ol (153)

Lithium aluminum hydride solution (8.71 mL, 8.71 mmol, 1M in diethyl ether solution) was slowly added dropwise to compound 152 (773 mg, 3.96 mmol) dissolved in diethyl ether (20.0 mL) at 0 ° C., . After confirming the termination of the reaction, the reaction solution is diluted with DCM, and Na ₂ SO ₄ .10H ₂ O is slowly added dropwise at 0 ° C. The mixed solution is filtered under reduced pressure using celite, and the filtrate is concentrated. Compound 153 (659 mg, 98%) was synthesized in the form of light yellow oil without further purification.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.36-7.41 (m, 2H), 7.03-7.10 (m, 2H), 5.00 (dd, J = 2.9Hz, 8.8Hz, 1H), 3.14-3.21 (m, 1H ), 2.96-3.05 (m, 1H), 1.69-1.92 (m, 2H).

(13) 1- (4-fluorophenyl) -3-isothiocyanatopropan-1-ol (154)

Di-2-pyridyl thiono-carbonate (83.6 mg, 0.360 mmol) was slowly added dropwise at 0 ° C to a solution of compound 153 (50.0 mg, 0.300 mmol) in DCM (1.5 mL) . After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 5: 1) to obtain Compound 154 (52.9 mg, 83%) in the form of a transparent solid.

^{1 H-NMR (300MHz, CDCl} 3) δ 7.34-7.38 (m, 2H), 7.09 (t, J = 8.6Hz, 2H), 4.88 (br, 1H), 3.74-3.83 (m, 1H), 3.47- 3.63 (m, 1 H), 2.29 (br, 1 H), 2.02 - 2.12 (m, 2 H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 164.1, 160.8, 139.1, 127.5, 115.7, 710.5, 41.9, 38.8.

(15) 1- (3- (4-fluorophenyl) -3-hydroxypropyl) -3-methylthiourea (155)

Methyl thiocyanate (27.1 mg, 0.360 mmol) dissolved in DCM (1 mL) was slowly added dropwise at 0 ° C to a solution of compound 153 (50.0 mg, 0.300 mmol) in DCM (500 μL) . After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 2) to obtain Compound 155 (66 mg, 91%) in the form of white solid.

^{1 H-NMR (300MHz, MeOD} ) δ 7.37-7.42 (m, 2H), 7.04-7.10 (m, 2H), 4.88 (s, 3H), 4.73 (td, J = 5.4Hz, 7.7Hz, 1H), 3.53 (br, 2H), 2.93 (br, 3H), 1.89-2.00 (m, 2H).

¹³ C-NMR (300 MHz, MeOD)? 163.7, 160.5, 140.7, 127.4, 127.3, 114.7, 114.4, 70.8, 38.1.

(16) 1- (3- (4-fluorophenyl) -3-hydroxypropyl) -3-isopropylthiourea (156)

Isopropyl isothiocyanate (41.6 쨉 L, 0.390 mmol) was slowly added dropwise at 0 째 C to a solution of Compound 153 (50.0 mg, 0.300 mmol) in DCM (1.5 mL), and the mixture was stirred at room temperature for one day. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 1) to give compound 156 (81 mg, quant) in the form of a clear oil.

^{1 H-NMR (300MHz, CDCl} 3) δ 7.27-7.32 (m, 2H), 7.01 (t, J = 8.6Hz, 2H), 6.72 (t, J = 4.9Hz, 1H), 6.21 (d, J = 2H), 3.87 (br, IH), 1.84-1.89 (m, 2H), 4.87 (br, 1.21 (td, J = 1.5 Hz, 6.4 Hz, 6H).

¹³ C-NMR (300 MHz, CDCl ₃ )? 180.1, 163.8, 160.5, 139.7, 127.4, 115.5, 71.5, 38.4, 22.5.

(17) 1- (3- (4-fluorophenyl) -3-hydroxypropyl) -3-phenylthiourea (157)

Phenyl isothiocyanate (66.9 μL, 0.560 mmol) was slowly added dropwise at 0 ° C. to a solution of Compound 153 (80.0 mg, 0.470 mmol) in DCM (2.4 mL), and the mixture was stirred at room temperature for four hours. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 2: 1) to give compound 157 (129 mg, 90%) in the form of a clear oil.

^{1 H-NMR (300MHz, DMSO} ) δ 9.55 (br, 1H), 7.81 (br, 1H), 7.29-7.40 (m, 6H), 7.07-7.18 (m, 3H), 5.42 (d, J = 4.2Hz 1H), 4.60-4.66 (m, 1H), 3.52 (d, J = 5.4 Hz, 2H), 1.77-1.92 (m, 2H).

¹³ C-NMR (300 MHz, DMSO)? 180.6, 163.2, 162.3, 142.4, 129.1, 128.1, 124.5, 115.3, 115.0, 70.5, 42.0, 38.5.

20. Synthesis of compounds 165-190

(1) Ethyl S-3-hydroxy-3- (4-methoxyphenyl) propyl carbonodithioate

The compound (100 mg, 0.410 mmol) dissolved in acetone (1.4 mL) was slowly added dropwise at 0 ° C to a solution of potassium ethylxanthate (81.1 mg, 0.510 mmol) in acetone (700 μL) and stirred at room temperature for 12 hours . After confirming the reaction is complete by TLC, the solution is filtered and concentrated at 60 [deg.] C for 30 minutes. The filtrate was diluted with EtOAc and then concentrated and extracted with brine, then the organic layer was dried over anhydrous Na ₂ SO _4, and filtered. Compound 165 (117 mg, 99%, light yellow oil) was synthesized without further purification of the concentrated filtrate

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.29-7.34 (m, 2H), 6.91-6.95 (m, 2H), 4.78-4.81 (m, 1H), 4.68 (q, J = 7.1Hz, 2H), 3.85 J = 7.0 Hz, 2H), 2.09-2.22 (m, 2H), 1.96 (d, J = 3.3 Hz, 1H), 1.46 (t, J = .

(2) 3-Mercapto-1- (4-methoxyphenyl) propan-1-ol

Lithium aluminum hydride (0.780 mL, 0.780 mmol, 1M in diethyl ether solution) was added dropwise to a solution of Compound 165 (111 mg, 0.390 mmol) in anhydrous THF (4 mL) and the mixture was stirred at room temperature for one day. After confirming the completion of the reaction by TLC, the reaction solution is diluted with DCM, and Na ₂ SO ₄ .10H ₂ O is slowly added dropwise at 0 ° C. The mixed solution is filtered under reduced pressure using celite, and the filtrate is concentrated. Compound 166 (60.2 mg, 39%, colorless oil) was synthesized using column chromatography (Hex: EtOAc = 5: 1)

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.32 (d, J = 8.6Hz, 2H), 6.94 (d, J = 8.7Hz, 2H), 4.84-4.89 (m, 1H), 3.85 (s, 3H), (M, 2H), 2.08-2.21 (m, 1H), 1.97-2.04 (m, 2H), 1.44 (t, J = 8.0 Hz, 1H).

(3) 1- (4-Methoxyphenyl) -3- (vinylthio) propan-1-ol

To a suspension of sodium hydride (24.4 mg, 0.560 mmol) in anhydrous THF (700 μl) was slowly added dropwise Compound 166 (56.1 mg, 0.280 mmol) dissolved in anhydrous THF (700 μl) at 0 ° C., 1,2-dibromoethane (24.7 쨉 L, 0.280 mmol) was slowly added dropwise, followed by stirring at room temperature for one hour. The reaction is terminated by TLC, diluted with DCM, and extracted with distilled water. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 167 (34.2 mg, 54%, white oil) was synthesized using column chromatography (Hex: EtOAc = 5: 1)

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.32 (d, J = 8.7Hz, 2H), 6.93 (d, J = 8.6Hz, 2H), 6.38 (dd, J = 10.1, 16.7Hz, 1H), 5.24 ( (d, J = 10.1 Hz, 1H), 5.15 (d, J = 16.7 Hz, 1H), 4.81-4.86 (m, 1.99-2.21 (m, 2H), 1.91 (d, J = 3.3 Hz, 1 H)

(4) 1- (4-Methoxyphenyl) -3- (vinylsulfinyl) propan-1-ol

To a solution of sodium metaperiodate (32.1 mg, 0.150 mmol) in water (580 μl), Compound 167 (34.2 mg, 0.150 mmol) dissolved in a 70% ethanol aqueous solution (440 μl) was slowly dropped at 0 ° C, After stirring for four hours, it is stirred at room temperature for one day. After completion of the reaction is confirmed by TLC, ethanol is added dropwise, and the solution is filtered and concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 168 (16.8 mg, 47%, colorless oil) was synthesized using column chromatography (Hex: EtOAc = 2: 1 only EtOAc only MeOH).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.30 (d, J = 8.5Hz, 2H), 6.90 (d, J = 8.6Hz, 2H), 6.58 (dd, J = 9.8, 16.4Hz, 1H), 6.12 ( (d, J = 1.6, 16.4 Hz, 1H), 6.02 (d, J = 9.8 Hz, 1H), 4.76-4.85 , 2.91-3.03 (m, 1H), 2.70-2.80 (m, 1H), 2.07-2.26 (m, 2H).

¹³ C NMR (300 MHz, CDCl ₃ )? 159.2, 139.8, 135.8, 126.9, 122.7, 113.9, 72.6, 55.3, 49.2, 31.4.

(5) O-Ethyl S-3- (4-fluorophenyl) -3-hydroxypropyl carbonodithioate

The compound (100 mg, 0.430 mmol) dissolved in acetone (1.5 mL) was slowly added dropwise at 0 ° C to a solution of potassium ethyloxanthate (75.3 mg, 0.470 mmol) dissolved in acetone (700 μL) and stirred at room temperature for one day. After confirming the reaction is complete by TLC, the solution is filtered and concentrated at 60 [deg.] C for 30 minutes. The filtrate was diluted with EtOAc and then concentrated and extracted with brine, then the organic layer was dried over anhydrous Na ₂ SO _4, and filtered. Compound 169 (116 mg, 98%, yellow oil) was synthesized without further purification of the concentrated filtrate.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.35-7.40 (m, 2H), 7.05-7.11 (m, 2H), 4.82-4.88 (m, 1H), 4.69 (q, J = 7.1Hz, 2H), 3.25 -3.30 (m, 2H), 2.07-2.20 (m, 3H), 1.46 (t, J = 7.1 Hz, 3H).

(6) 1- (4-Fluorophenyl) -3-mercaptopropan-1-ol

Lithium aluminum hydride (0.820 mL, 0.820 mmol, 1M in diethyl ether solution) was added dropwise to a solution of Compound 169 (113 mg, 0.410 mmol) in anhydrous THF (4 mL) and stirred at room temperature for one day. After confirming the completion of the reaction by TLC, the reaction solution is diluted with DCM, and Na ₂ SO ₄ .10H ₂ O is slowly added dropwise at 0 ° C. The mixed solution is filtered under reduced pressure using celite, and the filtrate is concentrated. Compound 170 (39.6 mg, 52%, colorless oil) was synthesized using column chromatography (Hex: EtOAc = 5: 1)

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.33-7.39 (m, 2H), 7.04-7.11 (m, 2H), 4.89-4.95 (m, 1H), 2.63-2.72 (m, 2H), 2.07-2.17 ( m, 1 H), 1.94 - 2.03 (m, 2 H), 1.45 (t, J = 7.95 Hz, 1 H).

(7) 1- (4-Fluorophenyl) -3- (vinylthio) propan-1-ol

To a suspension of sodium hydride (18.3 mg, 0.420 mmol) in anhydrous THF (500 μl) was slowly added dropwise compound 170 (39.6 mg, 0.210 mmol) dissolved in anhydrous THF (500 μl) at 0 ° C., 1,2-dibromoethane (18.6 쨉 L, 0.210 mmol) was slowly added dropwise, followed by stirring at room temperature for one hour. The reaction is terminated by TLC, diluted with DCM, and extracted with distilled water. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 171 (24.9 mg, 56%, light yellow oil) was synthesized using column chromatography (Hex: EtOAc = 5: 1).

¹ H NMR (300 MHz, CDCl ₃ )? 7.33-7.40 (m, 2H), 7.04-7.11 (m, 2H), 6.38 (dd, J = 10.1, 16.7 Hz, , 5.16 (d, J = 16.7 Hz, 1H), 4.87-4.92 (m, 1H), 2.81-2.86 (m, 2H), 1.99-2.21 (m, 3H).

(8) 1- (4-Fluorophenyl) -3- (vinylsulfinyl) propan-1-ol

To a solution of sodium metaperiodate (25.7 mg, 0.120 mmol) in water (460 μl) was slowly dropwise added dropwise at 0 ° C the compound 171 (24.9 mg, 0.120 mmol) dissolved in a 70% ethanol aqueous solution (360 μl) After stirring for four hours, it is stirred at room temperature for one day. After completion of the reaction is confirmed by TLC, ethanol is added dropwise, and the solution is filtered and concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 172 (8.10 mg, 30%, white oil) was synthesized using column chromatography (Hex: EtOAc = 2: 1 only EtOAc only MeOH).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.34-7.38 (m, 2H), 7.07 (t, J = 8.3Hz, 2H), 6.58 (dd, J = 9.8, 16.4Hz, 1H), 6.15 (dd, J = 1.6, 16.4 Hz, 1H), 6.05 (d, J = 9.8 Hz, 1H), 4.81-4.93 (m, 1H), 3.47 (dd, J = 3.8,28.6 Hz, 1H) 1H), 2.72-2.83 (m, 1H), 2.13-2.30 (m, 2H).

¹³ C NMR (300 MHz, CDCl ₃ )? 139.4, 127.3, 123.0, 115.5, 115.2, 71.8, 48.9, 31.8.

(9) 3-Bromo-1- {4- (3-bromopropoxy) phenyl} propan-1-

AlCl ₃ (1.86 g, 13.9 mmol) is dissolved in DCM (58 mL) and then 3-chloropropionyl chloride (1.33 mL, 13.9 mmol) is slowly added dropwise at 0 ° C. After 10 minutes, 3-phenoxypropyl bromide (1.84 mL, 11.6 mmol) was slowly added dropwise to the reaction solution at the same temperature, followed by stirring at room temperature for one and a half hours. After confirming the reaction is complete by TLC, the reaction solution is diluted with DCM and poured into ice water at 0 ° C. The mixture was extracted with saturated aqueous Na ₂ CO ₃ solution, and the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. Compound 173 (3.30 g, 93%, white solid) was synthesized using column chromatography (Hex: EtOAc = 10: 1).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.97 (d, J = 8.9Hz, 2H), 6.99 (d, J = 8.9Hz, 2H), 4.22 (t, J = 5.8Hz, 2H), 3.96 (t, J = 6.3 Hz, 2H), 3.45 (t, J = 6.9 Hz, 2H), 2.34 - 2.43 (m, 2H).

(10) 1- {4- (3-Bromopropoxy) phenyl} -3-chloropropan-1-ol

To a solution of Compound 173 (1.00 g, 3.27 mmol) in MeOH / DCM (8/8 mL) was slowly dropwise added sodium borohydride (186 mg, 4.91 mmol) at 0 ° C and stirred at room temperature for 1 hour. After the completion of the reaction was confirmed by TLC, 1N HCl aqueous solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 174 (1.01 g, quant., Colorless oil) was synthesized without further purification.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.32 (d, J = 8.6Hz, 2H), 6.93 (d, J = 8.6Hz, 2H), 4.90-4.97 (m, 1H), 4.14 (t, J = 5.8 Hz, 2H), 3.53-3.83 (m, 4H), 2.21-2.43 (m, 4H), 1.97-1.99 (m, 1H).

(11) 3-Chloro {4- (3-morpholinopropoxy) phenyl} propan-1-ol

Morpholine (368 쨉 L, 4.26 mmol) and diisopropylethylamine (742 쨉 L, 4.26 mmol) were slowly added dropwise at room temperature and then stirred at 50 째 C for 18 hours. Compound 174 (1.04 g, 3.38 mmol) was dissolved in acetonitrile . After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 175 (877 mg, 83%, white solid) was synthesized using column chromatography (DCM: MeOH = 15: 1).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.31 (d, J = 8.6Hz, 2H), 6.92 (d, J = 8.6Hz, 2H), 4.89-4.95 (m, 1H), 4.05 (t, J = 6.3 2H), 3.70-3.81 (m, 5H), 3.52-3.62 (m, 1H), 2.23-2.33 (m, 6H), 2.22-2.32 (m, 1H), 2.05-2.16 (m, 4H).

(12) 1- (4- (3-Morpholinopropoxy) phenyl) -3-azidopropan-1-ol

Sodium azide (148 mg, 2.28 mmol) was slowly added dropwise at room temperature to a solution of compound 175 (358 mg, 1.14 mmol) in DMF (5.7 mL) and the mixture was stirred at 80 ° C for one day. After confirming the termination of the reaction, the reaction solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 176 (276 mg, 76%, yellow oil) was synthesized using column chromatography (DCM: MeOH = 20: 1).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.31 (d, J = 8.6Hz, 2H), 6.93 (d, J = 8.7Hz, 2H), 4.82 (dd, J = 5.2, 7.9Hz, 1H), 4.06 ( 2H), 3.76 (t, J = 4.7 Hz, 4H), 3.47-3.56 (m, 1H), 3.36-3.44 (m, 1H), 2.49-2.58 -2.12 (m, 5 H).

(13) 1- (4- (3-Morpholinopropoxy) phenyl) -3-aminopropan-1-ol

Lithium aluminum hydride solution (1.72 mL, 1.72 mmol, 1M in diethyl ether solution) was slowly added dropwise to compound 176 (276 mg, 0.860 mmol) dissolved in diethyl ether (5 mL) at 0 ° C and stirred at room temperature for 2 hours . After confirming the termination of the reaction, the reaction solution is diluted with DCM, and Na ₂ SO ₄ .10H ₂ O is slowly added dropwise at 0 ° C. The mixed solution is filtered under reduced pressure using celite, and the filtrate is concentrated. Compound 177 (171 mg, 68%, white solid) was synthesized without further purification.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.33 (d, J = 8.6Hz, 2H), 6.91 (d, J = 8.6Hz, 2H), 4.95 (dd, J = 3.4, 8.4Hz, 1H), 4.06 ( 2H), 3.76 (t, J = 4.6 Hz, 4H), 3.10-3.18 (m, 1H), 2.94-3.02 (m, 1H), 2.50-2.58 (m, 6H), 1.95 -2.04 (m, 3H), 1.85-1.90 (m, 2H).

(14) 1- (3- (4- (3-Morpholinopropoxy) phenyl) -3-hydroxypropyl) -3-methylthiourea

To a solution of Compound 177 (42.0 mg, 0.140 mmol) in DCM (300 μl), methyl thiocyanate (12.4 mg, 0.170 mmol) dissolved in DCM (400 μl) was slowly added dropwise at 0 ° C., . After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 178 (41.0 mg, 80%, white solid) in the form of a white solid was synthesized using column chromatography (DCM: MeOH = 10: 1).

^{1 H NMR (300MHz, DMSO)} δ 7.41 (br, 2H), 7.21 (d, J = 8.5Hz, 2H), 6.85 (d, J = 8.5Hz, 2H), 5.19 (d, J = 4.3Hz, 1H 2H), 3.57 (t, J = 4.4 Hz, 4H), 3.34 (s, 2H), 2.79 (s, 3H), 2.35 -2.43 (m, 6H), 1.88 (t, J = 6.7 Hz, 2H), 1.73-1.83 (m, 2H).

¹³ C NMR (300 MHz, DMSO)? 157.9, 138.3, 127.3, 114.4, 70.4, 66.7, 66.2, 55.4, 53.9, 26.4.

(15) 1- (3- (4- (3-Morpholinopropoxy) phenyl) -3-hydroxypropyl) -3-isopropylthiourea

Isopropyl isothiocyanate (18.7 쨉 l, 0.170 mmol) was slowly added dropwise at 0 째 C to a solution of Compound 177 (42.0 mg, 0.140 mmol) in DCM (700 쨉 l), and the mixture was stirred at room temperature for one day. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 179 (51.3 mg, 93%, light yellow oil) was synthesized using column chromatography (DCM: MeOH = 20: 1).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.26 (d, J = 8.6Hz, 2H), 6.87 (d, J = 8.6Hz, 2H), 6.68 (s, 1H), 6.12 (d, J = 7.7Hz, J = 6.6 Hz, 1H), 4.76 (t, J = 6.2 Hz, 1H), 4.06 4H), 3.47 (br, 2H), 2.42-2.52 (m, 6H), 1.89-2.00 (m, 4H), 1.21-1.24 (m, 6H).

¹³ C NMR (300 MHz, CDCl ₃ )? 180.1, 158.5, 136.2, 126.9, 114.5, 66.9, 66.1, 55.5, 53.7, 53.5, 38.0, 26.3, 22.6, 22.5.

(16) 1- (3- (4- (3-Morpholinopropoxy) phenyl) -3-hydroxypropyl) -3-phenylthiourea

To a solution of Compound 177 (42.0 mg, 0.140 mmol) in DCM (700 μl), phenyl isothiocyanate (20.7 μl, 0.170 mmol) was slowly added dropwise at 0 ° C. and stirred at room temperature for one day. After confirming the reaction is complete by TLC, the solution is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 180 (58.0 mg, 97%, white solid) was synthesized using column chromatography (DCM: MeOH = 20: 1).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.76 (s, 1H), 7.45 (t, J = 7.7Hz, 2H), 7.23-7.34 (m, 5H), 7.24 (d, J = 8.5Hz, 3H), J = 6.4 Hz, 1H), 4.86-4.93 (m, 3H), 4.77 (t, , 2H), 3.61-3.75 (m, 1H), 2.73 (s, 1H), 2.46-2.55 (m, 6H), 1.94-2.02 (m, 4H).

¹³ C NMR (300 MHz, CDCl ₃ )? 180.6, 158.6, 140.0, 130.1, 127.2, 126.8, 125.3, 114.6, 72.8, 70.0, 66.2, 55.5, 53.8, 43.6, 37.7, 26.4.

(17) 4-Bromo-1- (4-methoxyphenyl) butan-1-one

AlCl ₃ (740 mg, 5.55 mmol) is dissolved in DCM (23 mL) and 4-bromobutyryl chloride (643 μL, 5.55 mmol) is slowly added dropwise at 0 ° C. After 10 minutes, anisole (503 [mu] L, 4.63 mmol) was slowly added dropwise to the reaction solution at the same temperature, followed by stirring at room temperature for one hour. After confirming the reaction is complete by TLC, the reaction solution is diluted with DCM and poured into ice water at 0 ° C. The mixture was extracted with saturated aqueous Na ₂ CO ₃ solution, and the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. Compound 181 (1.03 g, 86%, light yellow oil) was synthesized using column chromatography (Hex: EtOAc = 7: 1)

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.99 (d, J = 8.9Hz, 2H), 6.97 (d, J = 8.9Hz, 2H), 3.91 (s, 3H), 3.58 (t, J = 6.3Hz, 2H), 3.17 (t, J = 6.9 Hz, 2H), 2.30-2.37 (m, 2H).

(18) O-Ethyl S-4- (4-methoxyphenyl) -4-oxobutylcarbonodithioate

Sodium borohydride (227 mg, 6.01 mmol) was slowly added dropwise at 0 ° C to a solution of Compound 181 (1.03 g, 4.01 mmol) in MeOH (20 mL) and the mixture was stirred at room temperature for 1 hour. After the completion of the reaction was confirmed by TLC, 1N HCl aqueous solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The filtrate is dissolved in acetone (20 mL) and potassium ethylxanthane (649 mg, 4.05 mmol) is slowly added dropwise at 0 ° C. The reaction solution is stirred at room temperature for 18 hours. After completion of the reaction is confirmed by TLC, the reaction solution is filtered under reduced pressure. The filtrate is concentrated under reduced pressure, then diluted with EtOAc and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified using column chromatography (Hex: EtOAc = 5: 1) to synthesize Compound 182 (1.02 g, 85%, for 2 steps, light yellow oil).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.30 (d, J = 8.6Hz, 2H), 6.92 (d, J = 8.6Hz, 2H), 4.62-4.71 (m, 3H), 3.84 (s, 3H), 3.18 (t, J = 6.9 Hz, 2H), 1.64-2.01 (m, 5H), 1.44 (t, J = 7.1 Hz, 3H).

(19) 4-Mercapto-1- (4-methoxyphenyl) butan-1-ol

Lithium aluminum hydride (1.22 mL, 1.22 mmol, 1M in diethyl ether solution) was added dropwise to a solution of compound 182 (184 mg, 0.610 mmol) in anhydrous THF (3 mL) and the mixture was stirred at room temperature for one day. After confirming the completion of the reaction by TLC, the reaction solution is diluted with DCM, and Na ₂ SO ₄ .10H ₂ O is slowly added dropwise at 0 ° C. The mixed solution is filtered under reduced pressure using celite, and the filtrate is concentrated. Compound 183 (72.8 mg, 56%, colorless oil) was synthesized using column chromatography (Hex: EtOAc = 3: 1)

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.31 (d, J = 6.5Hz, 2H), 6.93 (d, J = 6.6Hz, 2H), 4.67 (br, 1H), 3.85 (s, 3H), 2.57 ( q, J = 7.3 Hz, 2H), 1.62-1.96 (m, 5H), 1.37 (t, J = 7.8 Hz, 1H).

(20) 1- (4-Methoxyphenyl) -4- (vinylthio) butan-1-ol

To a suspension of sodium hydride (29.7 mg, 0.680 mmol) in anhydrous THF (700 μl) was slowly dropwise added dropwise at 0 ° C the compound 183 (72.8 mg, 0.340 mmol) dissolved in anhydrous THF 1,2-dibromoethane (30.0 μL, 0.340 mmol) was slowly added dropwise, followed by stirring at room temperature for three hours. The reaction is terminated by TLC, diluted with DCM, and extracted with distilled water. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 184 (41.2 mg, 51%, white oil) was synthesized using column chromatography (Hex: EtOAc = 3: 1)

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.31 (d, J = 7.5Hz, 2H), 6.92 (d, J = 8.6Hz, 2H), 6.37 (dd, J = 10.1, 16.7Hz, 1H), 5.22 ( (d, J = 10.1 Hz, 1H), 5.13 (d, J = 16.7 Hz, 1H), 4.69 (br, 1.97 (m, 5 H)

(21) 1- (4-Methoxyphenyl) -4- (vinylsulfinyl) butan-1-ol

To a solution of sodium metaperiodate (36.4 mg, 0.170 mmol) in water (660 μl) was slowly dropwise added dropwise at 0 ° C the compound 184 (41.0 mg, 0.170 mmol) dissolved in a 70% ethanol aqueous solution (500 μl) After stirring for four hours, it is stirred at room temperature for one day. After completion of the reaction is confirmed by TLC, ethanol is added dropwise, and the solution is filtered and concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 187 (26.0 mg, 60%, light yellow solid) was synthesized using column chromatography (only EtOAc).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.29 (d, J = 9.0Hz, 2H), 6.90 (d, J = 8.6Hz, 2H), 6.59 (dd, J = 9.8, 16.4Hz, 1H), 6.09 ( (d, J = 2.3, 16.4 Hz, 1H), 5.97 (dd, J = 3.9, 9.8 Hz, 1H), 4.68 (br, 1 H), 1.77-1.97 (m, 4 H).

¹³ C NMR (300 MHz, CDCl ₃ )? 159.1, 140.4, 136.6, 127.1, 122.2, 113.9, 73.5, 55.3, 53.2, 37.8, 18.7.

(22) 4-Bromo-1- (4-fluorophenyl) butan-1-one

AlCl ₃ (167 mg, 1.25 mmol) is dissolved in DCM (5.20 mL) and then 4-bromobutyryl chloride (145 μL, 1.25 mmol) is slowly added dropwise at 0 ° C. After 10 minutes, fluorobenzene (98.0 μL, 1.04 mmol) was slowly added dropwise to the reaction solution at the same temperature, followed by stirring at room temperature for one hour. After confirming the reaction is complete by TLC, the reaction solution is diluted with DCM and poured into ice water at 0 ° C. The mixture was extracted with saturated aqueous Na ₂ CO ₃ solution, and the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. Compound 186 (83.8 mg, 33%, light yellow oil) was synthesized using column chromatography (Hex: EtOAc = 10: 1)

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 8.02-8.08 (m, 2H), 7.18 (t, J = 8.6Hz, 2H), 3.59 (t, J = 6.3Hz, 2H), 3.20 (t, J = 6.9 Hz, 2H), 2.30-2.40 (m, 2H).

(23) O-Ethyl S-4- (4-fluorophenyl) -4-oxobutylcarbonodithioate

Sodium borohydride (19.4 mg, 0.513 mmol) was slowly added dropwise at 0 ° C to a solution of compound 186 (83.8 mg, 0.342 mmol) in MeOH (2 mL) and stirred at room temperature for 1 hour. After the completion of the reaction was confirmed by TLC, 1N HCl aqueous solution was added dropwise at 0 ° C, and the mixture was concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The filtrate was dissolved in acetone (2 mL) and potassium ethylxanthane (55.4 mg, 0.345 mmol) was slowly added dropwise at 0 ° C. The reaction solution is stirred at room temperature for 18 hours. After completion of the reaction is confirmed by TLC, the reaction solution is filtered under reduced pressure. The filtrate is concentrated under reduced pressure, then diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 5: 1) to synthesize Compound 187 (70.1 mg, 71%, for 2 steps, light yellow oil).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.34-7.39 (m, 2H), 7.02-7.13 (m, 2H), 4.71-4.76 (m, 1H), 4.67 (q, J = 7.1Hz, 2H), 3.18 (t, J = 6.9 Hz, 2H), 1.82-1.93 (m, 5H), 1.44 (t, J = 7.1 Hz, 3H).

(24) 1- (4-Fluorophenyl) -4-mercaptobutan-1-ol

Lithium aluminum hydride (1.38 mL, 1.38 mmol, 1M in diethyl ether solution) was added dropwise to a solution of Compound 187 (200 mg, 0.690 mmol) in anhydrous THF (7 mL) and stirred at room temperature for one day. After confirming the completion of the reaction by TLC, the reaction solution is diluted with DCM, and Na ₂ SO ₄ .10H ₂ O is slowly added dropwise at 0 ° C. The mixed solution is filtered under reduced pressure using celite, and the filtrate is concentrated. Compound 188 (75.6 mg, 55%, colorless oil) was synthesized using column chromatography (Hex: EtOAc = 5: 1)

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.34 (m, 2H), 7.07 (m, 2H), 4.72 (t, J = 6.2Hz, 1H), 2.59 (q, J = 7.4Hz, 2H), 1.73- 1.93 (m, 4H), 1.65-1.66 (m, 1H), 1.65 (t, J = 7.8 Hz,

(25) 1- (4-Fluorophenyl) -4- (vinylthio) butan-1-ol

To a suspension of sodium hydride (33.2 mg, 0.760 mmol) in anhydrous THF (400 μl) was slowly added dropwise a compound 188 (75.6 mg, 0.380 mmol) dissolved in anhydrous THF (600 μl) at 0 ° C., 1,2-dibromoethane (33.6 쨉 L, 0.380 mmol) was slowly added dropwise, followed by stirring at room temperature for one day. The reaction is terminated by TLC, diluted with DCM, and extracted with distilled water. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 189 (34.3 mg, 40%, light yellow solid) was synthesized using column chromatography (Hex: EtOAc = 5: 1)

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.28-7.38 (m, 2H), 7.05-7.11 (m, 2H), 6.37 (dd, J = 10.1, 16.7Hz, 1H), 5.23 (d, J = 10.1Hz 1H), 5.13 (d, J = 16.7 Hz, 1H), 4.74 (br, IH), 2.76 (t, J = 6.7 Hz, 2H), 1.66-1.96 (m,

(26) 1- (4-Fluorophenyl) -4- (vinylsulfinyl) butan-1-ol

Compound 189 (31.7 mg, 0.140 mmol) dissolved in a 70% ethanol aqueous solution (410 μl) was slowly added dropwise at 0 ° C. to a solution of sodium metaperiodate (29.9 mg, 0.140 mmol) in water (540 μl) After stirring for four hours, it is stirred at room temperature for one day. After completion of the reaction is confirmed by TLC, ethanol is added dropwise, and the solution is filtered and concentrated under reduced pressure. The concentrated filtrate is diluted with DCM and extracted with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 190 (22.5 mg, 66%, white oil) was synthesized using column chromatography (only EtOAc).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.32-7.37 (m, 2H), 7.06 (t, J = 8.7Hz, 2H), 6.60 (dd, J = 9.8, 16.5Hz, 1H), 6.10 (dd, J 2H), 2.64 (dd, J = 3.5, 8.4 Hz, 1H), 5.98 (dd, J = 3.9, 9.8 Hz, 1H), 1.80-1.98 (m, 4H)

¹³ C NMR (300 MHz, CDCl ₃ )? 140.2, 127.4, 127.3, 122.2, 115.5, 115.2, 73.1, 52.8, 37.9, 18.5.

EXPERIMENTAL EXAMPLE 1 A compound according to the present invention has physiological activity

The effect of inducing HO-1 expression on the Nfr2-activating compound according to the present invention was first verified.

The expression of the gene for quinone reductase (NQO-1) is induced by binding of the transcription factor Nrf2 to the antioxidant response element (ARE), thus the activity of Nrf2 is required. In addition to NQO-1, the induction of Nrf2 induces enzyme genes (heme oxygenase (HO-1), glutamate-cysteine ligase nodifier subunit (GCLM)) that prevent cytotoxicity. Therefore, to investigate the activity inducing effect of Nrf2, a transcription factor, the expression of heme oxygenase-1 (HO-1) gene was evaluated by a sandwich ELISA method in a compound having Nfr2 activating ability according to the present invention. The results are shown in the following table.

ELISA assay, Cell: BV2 microglial cell, 2 x 10 ⁴ cell

Drug treatment time: 24 hr

Treat concentration: SFN (5 [mu] M), the compound having Nfr2 activating ability (20 [mu] M)

SFN: Sulforaphane

Cell death: Cell morphology

Compound (20 [mu] M) % SFN Cell death SFN (5 [mu] M) 100 7a 33.4 7b 57.6 7c 40.1 8a 73.2 O 8b 41.4 O 8c 10.3 O 8d 94.2 8e 0.6 O 10a 44.2 10b 41.7 10c 49.2 10d 62.4 11a 39.6 11b 34.5 11c 46.1 11d 37.8 12a 50.3 12b 40.0 12c 63.1 12d 75.8 12e 75.9 12f 47.0 12g 37.8 12h 39.7 13a 54.4 O 13b 51.9 13c 47.7 O 13d 68.9 13e 62.8 13f 35.4 13 38.3 13h 26.4 O 14a 63.4 14b 53.4 14c 83.9 14d 47.3 14e 55.5 15a 46.6 15b 60.9 15c 42.5 O 15d 65.7 15e 76.0 15f 41.1 15g 36.1 15h 37.9

Compounds (20 [mu] M) % SFN SFN (5 [mu] M) 100 18 33.5 25 29.2 26 35.5 27 35.5 29 35.9 31 38.8 33 34 35 51.4 36 31.9 38 72.4 39 38 41 39.2 43 58.8 45 59.7 47 51.6 49 62.4 51 40.0 52 41.3 53 52.8 55 45.6 57 79.0 59 2.7 61 58.1

Compounds (20 [mu] M) % SFN SFN (5 [mu] M) 100 63 59.3 64 53.4 65 76.7 67 44.4 68 44.1 69 43.7 70 37.4 72 43.5 73 36.6 74 59.0 75 37.6 79 121.1 80 63.2 81 52.0 82 60.0 83 70.9 84 56.4 85 57.7 87 40.4 92 55.2 93 66.0 94 96.8 95 150.5 100 122.6

Compounds (20 [mu] M) % SFN SFN (5 [mu] M) 100 107 114.2 108 41.6 109 52.1 112 48.2 114 48.0 117 53.3 119 51.5 122 47.8 123 50.1

Compounds (20 [mu] M) % SFN SFN (5 [mu] M) 100 131 51.3 140 54.5 141 54.8

Claims (7)

A compound represented by the following formula (I) and having an Nrf2 activating ability or a pharmaceutically acceptable salt thereof:
(I)

In the above formula (I)
Wherein R ₁ , R ₃ and R ₄ are each independently H or OCH ₃ ,
The XY bond may be CH-OH,

, Or C = O,
Wherein p is 1 or 2,
Wherein R ₂ is H, CH ₃ , OCH ₃ , F, Cl, OH or O (CH ₂ ) _n Z (n is 1 or 2) and Z is N (CH ₃ ) ₂ or Lt; / RTI &gt; group,
[Structural formula 1]

Wherein R ₅ is N _{3, NH 2, NCS, NHCH 3,} N (CH 3) 2, NHCOCH 3, NHCOCH 2 CH 3, NHCOCH (CH 3) 2, NHCONHCH 3, NHCONHCH 2 CH 3, NHCONHCH (CH 3) 2, NHCSCH 3, NHCSCH 2 CH ₃ , NHCSCH (CH ₃ ) ₂ , NHCSNHCH ₃ , NHCSNHCH ₂ CH ₃ , NHCSNHCH (CH ₃ ) ₂ , NHCOC ₆ H ₅ and NHCONHC ₆ H ₅ ; Or [Formula 2] below.
[Structural formula 2]

The method according to claim 1,
The compound of the above formula (I) is any one selected from the group consisting of the following formulas (III) to (VII): or a pharmaceutically acceptable salt thereof:
[Formula (III)

[Formula IV] [Formula V]

(VI) &lt; RTI ID = 0.0 &gt; [VII]

In the above formulas (III) to (VII)
Wherein R ₁ , R ₂ , R ₅ and p are as defined in the above formula (I)
Wherein R ₆ is any one selected from the group consisting of O (CH ₂ ) _n Z (n is 1 or 2) and Z is N (CH ₃ ) ₂ or the following formula 1:
[Structural formula 1]

The method according to claim 1,
The compound of the above formula (I) is any one selected from the group consisting of the following formulas (18) to (190): or a pharmaceutically acceptable salt thereof:
[Chemical Formula 18]

[Chemical Formula 25]

[Chemical Formula 27]

[Chemical Formula 31]

[Chemical Formula 35]

[Chemical Formula 38]

[Chemical Formula 41]

[Chemical Formula 45]

[Chemical Formula 49]

[Chemical Formula 52]

(55)

(63)

[Chemical Formula 65]

[Chemical Formula 68]

[Chemical Formula 70]

[Chemical Formula 73]

[Formula 75]

[Formula 80]

(83)

[Chemical Formula 84]

[Chemical Formula 87]

[Chemical Formula 93]

(100)

(108)

(112)

[Chemical Formula 114]

[Chemical Formula 119]

[Formula 123]

[Formula 140]

[Chemical Formula 146]

[Chemical Formula 148]

[Chemical Formula 154]

(157)

[Chemical Formula 168]

[179]

[Chemical Formula 185]

The method according to 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, Wherein the compound is at least one member selected from the group consisting of maleic acid, lactic acid, malic acid, tartaric acid, citric acid, ethanesulfonic acid, aspartic acid and glutamic acid or a pharmaceutically acceptable salt thereof. delete A composition for treating cerebral diseases, comprising a compound having an Nrf2 activating ability according to any one of claims 1 to 4 as an active ingredient together with a pharmaceutically acceptable carrier or diluent,
Wherein the cranial nerve disease is any one selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, Lou Gehrig's disease, epilepsy, depression, pain anxiety, and degenerative brain disease. delete