KR20210057300A - Novel compound for preventing or treating neuroinflammatory disease and pharmaceutical composition including the same - Google Patents

Abstract

The present invention relates to a novel 2-halogen or haloalkyl 4,5-dihydroxy piperine analog and a composition for preventing or treating neuroinflammatory diseases containing the same as an active ingredient and, more particularly, to a composition for preventing and treating neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis and the like, which provides an effect of inhibiting NO release, inhibiting iNOS and COX-2 expression, and inhibiting the production of proinflammatory cytokines in LPS-stimulated BV-2 microglia, and also provides an effect of protecting nerve cells and thus an anti-neuroinflammatory protective activity by increasing Nurr1 mRNA expression in undifferentiated or differentiated cells to increase the expression of tyrosine hydroxylase (TH), which is involved in the production of dopamine.

Description

A novel compound for the prevention or treatment of neuroinflammatory diseases and a pharmaceutical composition containing the same {NOVEL COMPOUND FOR PREVENTING OR TREATING NEUROINFLAMMATORY DISEASE AND PHARMACEUTICAL COMPOSITION INCLUDING THE SAME}

The present invention relates to a novel 2-halogen or haloalkyl 4,5-dihydroxy piperine analogue and a composition for the prevention or treatment of neuroinflammatory diseases containing the same as an active ingredient, and more specifically, LPS-stimulated BV -2 Inhibits NO release in microglia, inhibits iNOS and COX-2 expression, inhibits proinflammatory cytokine production, and increases the expression of Nurr1 mRNA in undifferentiated or differentiated cells. By increasing the expression of TH (tyrosine hydroxylase), it has a protective effect on nerve cells, and has anti-neuro-inflammatory protective activity, so it is resistant to neurodegenerative diseases, and prevents degenerative neurological diseases such as Alzheimer's, Parkinson's disease, stroke and multiple sclerosis. It relates to a composition for treatment.

The number of patients with degenerative degenerative diseases is rapidly increasing due to the rapid increase of the aging population around the world. Neurological damage and cognitive impairment due to the onset of degenerative brain diseases are acting as a tolerance that increases the economic and social burden. However, due to the characteristics of degenerative brain diseases caused by various factors, targeting the control and treatment of one type of cell variable cannot be a complete treatment strategy. (Social burden of dementia and prevention and management measures for responding to an ultra-aged society)

In the central nervous system, many studies have been reported that neuroinflammatory reactions are the cause of Parkinson's disease, Alzheimer's disease, traumatic injury, stroke, and brain injury caused by seizures. (J Neuroinflammation, 3, 5, 2006) The development of neuroinflammation control and nerve damage suppression technology related to oxidative stress can be an important target for the prevention and treatment of degenerative brain diseases.

Inflammatory response is a characteristic of acute brain injury, and neutrophils, monocytes, and phagocytic cells are introduced into the brain tissue due to the activation of stellate cells in the resting period, and proinflammatory cytokines, conjugate molecules and other inflammatory mediators are active. Neuroinflammation occurs mainly due to the activation of glial cells that make up about 20% of the brain. (Dheen, S.T. et al., Curr Med Chem. 14 1189-97, 2007)

The activation of microglial cells usually results from three pathways of signal transduction. First, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), which are inflammatory enzymes. Second, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin, which are well known as inflammatory cytokines. -6 (IL-6), and finally, it has been reported to be induced by nuclear factor-κB (NF-κB), a transcription factor (Mc Geer et al., Neurology, 38, 1285-91, 1988; Minghetti, L. Et al., Prog Neurobiol, 54, 99-125, 1998; Le, W. et al., J Neurosci, 21, 8447-55, 2001)

Induction of inflammation in glial cells is accompanied by the production of nitrite (NO) by LPS (lipopolysaccharide), and the increase of nitrite (NO) is a pathological mechanism that plays a very important role in cytotoxicity during brain injury. Is known. (Chen et al., J Biol Chem, 273, 19424-30, 1998)

Among degenerative brain diseases, Parkinson's disease is mainly caused by the disappearance of dopamine neurons in the substantia nigra of the midbrain.Nurr1, one of the Orphan nuclear receptors, is expressed in the substantia nigra and ventral tegmental regions of the midbrain during development, and the dopamine neuron precursor is complete It is known to play an important role in differentiating into dopamine neurons. (Kinoshita, K. et al., Life Sci. 137, 28-36, 2015) Therefore, Nurr1 is thought to be an important transcription factor in inducing the expression of the TH (tyrosine hydroxylase) gene during development. (Kaoru, S. Cell 137, 47-59, 2009) In addition, studies showing that it is also involved in the onset of Alzheimer's disease are being conducted, so an important role is expected in the treatment of degenerative brain diseases through Nurr1. (Moon, M et al., Aging Cell. 18 e12866, 2019)

Piperine is an alkaloid aromatic compound that is responsible for the spicy taste of pepper we eat. The spicy taste of pepper is not the same as other spicy tastes, but the reaction of our nociceptive nerves to chemical reactions. The process of this reaction has not been fully elucidated. It is believed that this is because the shape fits well. (Derosa, G Adv Exp Med Biol. 928, 173-184, 2016) Piperine is a compound found in jang pepper, pepper, cubeb or dill, and the structural formula is C ₁₇ H ₁₉ NO ₃ . As the physiological activity of piperine known to date, antioxidant, antimutagenic, and anticancer activity have been reported, and it plays a role in enhancing the bioavailability of drugs such as resveratrol. As a result of treatment with piperine on endothelial cells, it has an effective function in immune response, such as enhancing the adhesion of neutrophils and leukocytes, and inhibiting the migration of the NK-kB subunit p65 molecule from the cytoplasm to the nucleus. Indicated. (Meghwal, M. et al., Phytother Res. 27, 1121-30, 2013) Administered benzo[α]pyrene, a carcinogen that causes lung cancer in Swiss albino mice, at 50 mg/kg of body weight twice a week for 16 weeks As a result of comparing one group with the group administered piperine at 100 mg/kg body weight once a day for 4 weeks prior to administration of benzo[α]pyrene, tissue superoxide dismutase (SOD) in the group pretreated with piperine , CAT (catalase), GPX (Glutathione peroxidase), GSH (Reduced glutathione), vitamin E, vitamin C, and other antioxidant indicators were significantly higher, demonstrating that piperine has antioxidant effects. Accordingly, piperine is commercially used in various dietary supplements products in the form of complexes with other plant extracts and phytochemicals, and is sold for the purpose of improving general health functions, including antioxidant functions. (Shityakov, S.1. et al., Eur J Med Chem. 176, 149-161, 2019)

In the case of piperine, various patents have been disclosed for new use. Among the domestic patents, compounds containing a pharmaceutically acceptable salt of piperine as an active ingredient are used for the prevention and treatment of obesity (Korea It is also used for preventing and treating inflammatory diseases by effectively inhibiting the inflammatory reaction caused by LP3. (Republic of Korea Patent Laid-Open Patent 10-2010-0091495) In addition, piperine derivatives inhibit the differentiation of adipocytes and reduce the accumulation of triglycerides in the cells, ultimately consisting of obesity, diabetes, dyslipidemia, fatty liver and insulin resistance syndrome It is also used as a pharmaceutical or functional food composition exhibiting a prophylactic or therapeutic activity of metabolic diseases selected from. (10-2010-11865000) In addition, as a novel pipelin analog, a patent has been registered as a structure for the treatment of neurological conditions or acting as a modulator of GABA receptors. (WO2011/080313, WO2009/004071)

The metabolites of piperine vary depending on the species. Known metabolites in rats include piperic acid, piperonalic acid, piperonal, piperonyl alcohol and vanillic acid. -(3,4-dihydroxyphenyl)-2,4-pentadienoic acid piperidine (AJ-2137) and 5-(3,4-dihydroxyphenyl) bareric acid 4-hydroxypiperidine , 5-(3,4-dihydroxyphenyl)bareric acid 4-piperidine is known. (McCalley, D.V. J. Sep. Sci. 26, 943-946, 2003)

Metabolites appearing in humans are the most recently published material patents that have a structure similar to 5-(3,4-dihydroxyphenyl)-2,4-pentadienoic acid piperidine (AJ-2137). There are patents WO2017/129061 and WO2015/043522. This patent has been applied as a material patent for the treatment of anti-anxiety, limited to amide alkaloids containing trifluoromethyl and containing an analogue having a substituted cinnamic amide structure. In the case of AJ-2137, since it has a structure in which double bonds are increased in cinnamic acid, it was included in the scope of a material patent for a catechol analog or a cinamic acid analog. (WO2008/028314)

The experiment was conducted on AJ-2137, which is known as a metabolite of piperine in humans, and as a result, a result of suppressing neuroinflammation through various pathways was obtained. Based on this, various substituents were introduced into the structure of AJ-2137, and AJ- While maintaining the structure of 2137, a new structure was introduced to increase the inhibitory effect of neuroinflammation and increase the expression of Nurr1.

As described above, the possibility of preventing and treating degenerative brain diseases through the control of neuroinflammation has become rich, so it is recognized as an important field in recent years.Thus, the development of a compound that can maximize the neuroinflammation inhibitory effect through additional research on ingredients derived from natural products is Is being demanded.

An object of the present invention is to provide a novel 2-halogen or haloalkyl 4,5-dihydroxy piperine analogue, and the novel 2-halogen or haloalkyl 4,5-dihydroxy piperine analogue or a medicament thereof It relates to a composition for the prevention and treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's disease, stroke and multiple sclerosis, including a scientifically acceptable salt as an active ingredient.

The present invention relates to a 2-halogen or haloalkyl 4,5-dihydroxy piperine analogue and a pharmaceutically acceptable salt thereof as a novel substance excellent in the inhibitory effect of neuroinflammation represented by Chemical Chamber 1 below.

In addition, the present invention contains a 2-halogen or haloalkyl 4,5-dihydroxy piperine analog of the following Structural Formula 1 to Structural Formula 6 as an active ingredient to inhibit the production of inflammatory mediators including NO, iNOS and COX-2, and Neuroinflammation can be regulated through inhibition of production of inflammatory cytokines including IL-1β, IL-6 and TNF-α, translocation of NF-κB subunit p65 into the nucleus, inhibition of IκB-α phosphorylation and degradation.

In addition, through the expression of Nurr1 mRNA in undifferentiated or differentiated dopamine neuron cells, TH expression can be increased and neurite expression can be regulated.

[Formula 1]

(Wherein, A is the following formula 2, formula 3 or formula 4, and each of X and Y is independently selected from N, O, and S (C3-C7) heterocycloalkyl, or aromatic A ring may be formed or a ring may be formed by linking with (C3-C7)alkylene, and at least one of the carbon atoms of the (C3-C7)alkylene is NR, O or S, and R is (C1- C5) alkyl);

[Formula 2]

(Wherein, R ₁ or R ₂ are each independently OH, F, Cl, Br, I, CF ₃ , NO ₂ , CH ₃ , OMe, COOH, NMe ₂ , or NH ₂ ,

R ₃ is F, Cl, Br, OMe, or t-Bu,

R ₄ is F, Br, or CF ₃ );

[Formula 3]

(Wherein, Z is CH or N);

[Formula 4]

.

.

The compound represented by Formula 1 may be a compound of the following Structural Formulas 1 to 4.

[Structural Formula 1]

(In the above Structural Formula 1, X and Y are each independently linked by (C3-C7) heterocycloalkyl or (C3-C7) alkylene containing at least one hetero atom selected from N, O, and S to form a ring. And at least one of the carbon atoms of the (C3-C7)alkylene is NR, O or S, and R is (C1-C5)alkyl)

[Structural Formula 2]

(In the above Structural Formula 2, R ₁ , R ₂ are each independently OH, F, Cl, Br, I, CF ₃ , NO ₂ , CH ₃ , OMe, COOH, NMe ₂ , or NH ₂ ,

Each of X and Y may be independently linked with (C3-C7)heterocycloalkyl or (C3-C7)alkylene containing at least one hetero atom selected from N, O, and S to form a ring, and the ( At least one of the carbon atoms of C3-C7)alkylene is NR, O or S, and R is (C1-C5)alkyl)

[Structural Formula 3]

(Wherein, R ₁ is F, Br, or CF ₃ ,

Each of X and Y may be independently linked with (C3-C7)heterocycloalkyl or (C3-C7)alkylene containing at least one hetero atom selected from N, O, and S to form a ring, and the ( At least one of the carbon atoms of C3-C7)alkylene is NR, O or S, and R is (C1-C5)alkyl)

[Structural Formula 4]

(Wherein, R ₁ is F, Cl, Br, CF ₃ , OMe, or t-Bu,

Each of X and Y may be independently linked with (C3-C7)heterocycloalkyl or (C3-C7)alkylene containing at least one hetero atom selected from N, O, and S to form a ring, and the ( At least one of the carbon atoms of C3-C7)alkylene is NR, O or S, and R is (C1-C5)alkyl)

[Structural Formula 5]

(In formula 5, X is CH or N, and Z and Y are each independently (C3-C7) heterocycloalkyl or (C3-C7) alkylene containing at least one hetero atom selected from N, O, and S. It may be connected to form a ring, wherein at least one of the carbon atoms of the (C3-C7)alkylene is NR, O or S, and R is (C1-C5)alkyl).

The compound represented by Formula 1 may be, for example, the following compounds, but is not limited thereto.

The numbers listed together with the above compounds are compounds corresponding to the number of Examples to be described later.

The 2-halogen or haloalkyl 4,5-dihydroxy piperine analog according to the present invention uses 2-halogen or haloalkyl 4,5-dimethoxybenzaldehyde as a starting material as shown in Schemes 1 to 5 below. After reacting with various crotonyl amides, a 2-halogen or haloalkyl 4,5-dihydroxy piperine analog of Formula 1 can be prepared through dimethylation. The method of preparing the halogen or haloalkyl 4,5-dihydroxy piperine analogue is not limited, and variations of the following preparation method will be apparent to those skilled in the art.

[Scheme 1]

[X, Y in Reaction Scheme 1 are the same as defined in Structural Formula 1]

[Scheme 2]

[In Reaction Scheme 2, R ₁ , X, Y are the same as defined in Structural Formula 2]

[Scheme 3]

[In Reaction Scheme 3, R ₁ , X, Y are the same as defined in Structural Formula 3]

[Scheme 4]

[In Reaction Scheme 4, R ₁ , X, Y are the same as defined in Structural Formula 4]

[Scheme 5]

[In Reaction Scheme 5, R, X, Y, Z are the same as defined in Structural Formula 5].

2-halogen or haloalkyl 4,5-dihydroxy piperine analogs according to the present invention are iNOS and COX-2 mRNA and protein expression levels, pro-inflammatory cytokine production and NF in LPS-stimulated BV-2 microglia. The effect of HMA on -κB (p65) activity and IκBα phosphorylation/degradation was confirmed, and it was confirmed that it exhibited a strong inhibitory effect on neuroinflammation control at the Parkinson's disease experimental animal model and cellular level.

In the present invention, the neuroinflammatory disease is composed of multiple sclerosis, neuroblastoma, ischemic stroke, Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, Huntington's disease, Creutzfeldt-Jakob disease, post-traumatic stress disorder, depression, schizophrenia or amyotrophic lateral sclerosis. It can be selected from the group.

The present invention confirmed that 2-halogen or haloalkyl 4,5-dihydroxy piperine analogs effectively inhibit neuroinflammation at a lower concentration than AJ-2137, which is a metabolite of piperine. In addition, inhibition of production of inflammatory factors including NO, iNOS and COX-2, inhibition of production of inflammatory cytokines including IL-1β, IL-6 and TNF-α, regulation of translocation of NF-κB subunit p65 into the nucleus, It was confirmed that neuroinflammation can be effectively controlled through inhibition of IκB-α phosphorylation and decomposition. In addition, it was confirmed that TH expression was increased and neurite was expressed through the expression of Nurr1 mRNA in undifferentiated or differentiated dopamine neuron cells. Furthermore, in an animal model of Parkinson's disease, a representative disease of degenerative brain disease, behavioral and molecular mechanism changes were confirmed. Although MPTP treatment induced dopamine cell death and decreased motility, 2-halogen or haloalkyl 4,5 -It was confirmed that the dihydroxy piperine analog inhibited the death of dopamine cells, resulting in behavioral changes and improved behavior. Through this, it can be usefully used in a pharmaceutical composition or health functional food for the prevention or treatment of neuroinflammatory diseases.

1 shows the results of measuring the inhibitory activity of AJ-2137, a piperine metabolite, on the reduction of dopamine-positive cells (tyrosine hydroxylase positive cells) in MPTP poisoned mice according to an embodiment of the present application. In normal mice that did not cause MPTP poisoning, it was confirmed that only administration of AJ-2137 resulted in an increase in dopamine-positive cells.
2 is data confirming the effect of AJ-2137 on behavioral deficits in MPTP-addicted mice according to an embodiment of the present application by a Paul test.
3 is data confirming that the expression of Nurr1 increases in a concentration-dependent manner when AJ-2137 is treated by concentration according to an embodiment of the present application.
4 is data confirming that some of the analogs synthesized according to an embodiment of the present application have a similar or better Nurr1 expression effect as AJ-2137.

In the following, for a detailed understanding of the present invention, a method for preparing a 2-halogen or haloalkyl 4,5-dihydroxy piperine analogue thereof according to the present invention, and a pharmaceutically acceptable salt thereof, will be described with reference to the representative compound of the present invention. However, this is only for exemplifying the embodiment, and does not limit the scope of the present invention.

[Example 1] (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienoic acid

Pipeline (8 g, 28.0 mmol) and potassium hydroxide (18.9 g, 336 mmol) were added, dissolved in ethanol (95 mL) and water (5 mL), and heated to reflux for 18 hours. After completion of the reaction, distillation under reduced pressure to remove the solvent, the pH was adjusted to 1 with 1N aqueous hydrogen chloride solution, and the resulting solid was filtered under reduced pressure and dried under vacuum. (5.9 g, 96.4%) ¹ H NMR (DMSO-d ₆ ) δ 5.86-5.96 (d, 1H), 6.03 (s, 2H), 6.86-7.02 (m, 4H), 7.21 (s, 1H), 7.25 -7.35 (m, 1H)

[Example 2] (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(piperidin-1-yl)penta-2,4-diene- 1-on (1, AJ-2137)

Pipeline (1 g, 3.50 mmol) was dissolved in dichloromethane, and boron tribromide aqueous solution was slowly added dropwise at 0 degrees. The temperature was raised to room temperature and stirred for 24 hours. After completion of the reaction, ethyl acetate and water were added, and the organic layer was dried with anhydrous sodium sulfate and then distilled under reduced pressure to remove the solvent. The compound was obtained by column chromatography. (300 mg, 31.3%) ¹ H NMR (CDCl ₃ ) δ 1.46-1.62 (m, 6H), 3.40-3.60 (m, 4H), 6.36-6.42 (d, 1H), 6.70-6.78 (m, 3H) , 6.90-6.96 (m, 2H), 7.30-7.42 (m, 1H)

[Example 3] (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(4-hydroxypiperidin-1-yl)penta-2,4 -Dien-1-one

(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienoic acid (400 mg, 1.83 mmol) was added to dichloromethane/dimethylformamide ( 2:1, 12 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrogen chloride (387 mg, 2.02 mmol) and hydroxybenzotriazole (272 mg, 2.02 mmol) were added. It was stirred at room temperature for 30 minutes. 4-hydroxypiperine (185 mg, 1.83 mmo) and diisopropylethylamine (671 μL, 3.85 mmol) were added and the reaction was terminated after 1 hour. Ethyl acetate and water were added, and the organic layer was washed with 1N aqueous hydrogen chloride solution, washed with brine, and then dried with anhydrous sodium sulfate. After distillation under reduced pressure to remove the solvent, a compound was obtained. (150 mg, 28.7%) ¹ H NMR (CDCl ₃ ) δ 1.50-1.60 (m, 2H), 1.85-1.95 (m, 2H), 3.87 (s, 2H), 3.92-4.00 (m, 1H), 4.24 (s, 2H), 5.97 (s, 2H), 6.41-6.46 (d, 1H), 6.68-6.90 (m, 3H), 6.86-6.92 (m, 1H), 6.96-6.95 (m, 1H), 7.37 -7.43 (m, 1H)

[Example 4] (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-morpholinopenta-2,4-dien-1-one

(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienoic acid (250 mg, 1.15 mmol) and morpholine (99.8 mg, 1.15) mmol) was used to obtain a compound in the same manner and conditions as in Example 3. (163 mg, 49.5%) ¹ H NMR (CDCl ₃ ) δ 3.60-3.80 (m, 8H), 5.98 (s, 2H), 6.38-6.38 (d, 1H), 6.70-6.84 (m, 3H), 6.86 -6.94 (m, 1H), 6.94-7.00 (m, 1H), 7.44-7.50 (m, 1H)

[Example 5] (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(4-methylpiperazin-1-yl)penta-2,4- Dien-1-one

(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienoic acid (200 mg, 0.917 mmol) and methylpiperazine (91.8 mg, 0.917 mmol) was used to obtain a compound in the same manner and conditions as in Example 3. (170 mg, 61.8%) ¹ H NMR (CDCl ₃ ) δ 1.60-1.75 (m, 4H), 2.60-2.70 (m, 1H), 3.00-3.10 (m, 1H), 3.90-4.05 (m, 1H) , 4.60-4.70 (m, 1H), 5.96 (s, 2H), 6.40-6.48 (m, 1H), 6.68-6.80 (m, 3H), 6.85-7.00 (m, 2H), 7.32-7.44 (m, 1H)

[Example 6] (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(pyrrolidin-1-yl)penta-2,4-diene -1-one

A compound was obtained in the same manner and conditions as in Example 3, except that pyrrolidine (130 mg, 1.83 mmol) was used. (360 mg, 72.4%) ¹ H NMR (CDCl ₃ ) δ 1.65-1.86 (m, 4H), 3.52-3.60 (m, 4H), 5.98 (s, 2H), 6.24-6.30 (d, 1H), 6.70 -6.85 (m, 3H), 6.86-7.04 (m, 2H), 7.40-7.50 (m, 1H)

[Example 7] 1-((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienoyl)pyrrolidine-2-car Foxy acid

A compound was obtained in the same manner and conditions as in Example 3, except that proline carboxylic acid methyl ester (130 mg, 1.83 mmol) was used. (360 mg, 72.4%) ¹ H NMR (CDCl ₃ ) δ 1.91-2.14 (m,2H), 2.13-2.34 (2H), 3.55-3.63 (m, 1H), 3.64-3.69 (m, 1H), 3.69 -3.75 (m, 2H), 3.74 (s, 3H), 4.61-4.74 (1H), 5.96 (s, 2H), 6.20-6.30 (d, 2H), 6.70-7.05 (m, 5H), 7.40-7.50 (m, 1H)

[Example 8] (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(1H-imidazol-1-yl)penta-2,4-di En-1-one

A compound was obtained in the same manner and conditions as in Example 3, except that imidazole (125 mg, 1.83 mmol) was used. (200 mg, 40.7%) ¹ H NMR (CDCl ₃ ) δ 6.01 (s, 2H), 6.58 (d, 1H), 6.80-6.88 (m, 2H), 6.96-7.14 (m, 4H), 7.57 (t , 1H), 7.78-7.84 (m, 1H), 8.25 (s, 1H)

[Example 9] (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(3,4-dihydroxyisoquinolin-2(1H)-yl ) Penta-2,4-dien-1-one

A compound was obtained in the same manner and conditions as in Example 3, except that tetrahydroisoquinoline (244 mg, 1.83 mmol) was used. (230 mg, 30.6%) ¹ H NMR (CDCl ₃ ) δ 2.82-3.00 (m, 2H), 3.70-3.94 (m, 2H), 4.70-4.86 (m, 2H), 5.96 (s, 2H), 6.44 -6.58 (m, 1H), 6.72-6.86 (m, 3H), 6.88-6.94 (dd, 1H), 6.98-7.04 (d, 1H), 7.10-7.24 (m, 4H), 7.40-7.54 (m, 1H)

[Example 10] (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N,N-diethylpenta-2,4-dienamide

A compound was obtained in the same manner and conditions as in Example 3, except that dimethylamine (134 mg, 1.83 mmol) was used. (230 mg, 30.6%) ¹ H NMR (CDCl ₃ ) δ 1.12-1.28 (m, 6H), 3.32-3.52 (m, 4H), 5.95 (s, 2H), 6.34-6.44 (d, 1H), 6.76 -6.82 (m, 3H), 6.85-6.96 (m, 1H), 6.90-7.04 (m, 1H), 7.40-7.50 (m, 1H)

[Example 11] (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N,N-diisopropylpenta-2,4-dienamide

(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienoic acid (500 mg, 2.29 mmol) and methylpiperazine (278 mg, 2.75 mmol) was used to obtain a compound in the same manner and conditions as in Example 3. (400 mg, 57.9%) ¹ H NMR (CDCl ₃ ) δ 1.10-1.55 (d, 12H), 3.40-4.35 (m, 2H), 5.95 (s, 2H), 6.30-6.45 (m, 1H), 6.70-6.80 (m, 2H), 6.84-6.90 (m, 1H), 6.94-7.05 (m, 1H), 7.27-7.45 (m, 1H)

[Example 12] (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N,N-dihexylpenta-2,4-dienamide

A compound was obtained in the same manner and conditions as in Example 3, except that dihexylamine (340 mg, 1.83 mmol) was used. (450 mg, 63.6%) ¹ H NMR (CDCl ₃ ) δ 0.84-0.97 (m, 9H), 1.25-1.43 (m, 12H), 1.56-1.71 (m, 4H), 3.35 (m, 4H), 5.97 (s, 2H), 6.30-6.40 (d, 1H), 6.72-6.84 (m, 3H), 6.85-6.95 (m, 1H), 6.95-7.00 (d, 1H), 7.36-7.50 (m, 1H)

[Example 13] (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N-(cyclohexylmethyl)penta-2,4-dienamide

A compound was obtained in the same manner and conditions as in Example 3, except that cyclohexanemethylamine (208 mg, 1.83 mmol) was used. (430 mg, 74.9%) ¹ H NMR (CDCl ₃ ) δ 0.90-1.01 (m, 2H), 1.13-1.28 (m, 3H), 1.38-1.56 (m, 1H), 1.60-1.80 (m, 5H) , 3.16-3.25 (t, 2H), 5.57-5.81 (1H), 5.88-5.95 (d, 1H), 5.97 (s, 2H), 6.60-6.82 (m, 3H), 6.83-7.01 (m, 2H) , 7.29-7.41 (m, 1H)

[Example 14] (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N-(piperidin-1-yl)penta-2,4-dienamide

A compound was obtained in the same manner and conditions as in Example 3, except that aminopiperidine (184 mg, 1.83 mmol) was used. (250 mg, 45.4%) ¹ H NMR (DMSO-d ₆ ) δ 1.47 (s, 4H), 1.56-1.64 (t, 2H), 3.51 (s, 4H), 6.04 (s, 2H), 6.62-6.74 (d, 1H), 6.85-6.98 (m, 4H), 7.16-7.23 (m, 2H)

[Example 15] (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N-(4-methylpiperazin-1-yl)penta-2,4- Dienamide

A compound was obtained in the same manner and conditions as in Example 3, except that aminomethylpiperazine (211 mg, 1.83 mmol) was used. (150 mg, 26.0%) ¹ H NMR (CDCl ₃ ) δ 2.14-3.40 (m, 9H), 5.99 (s, 2H), 6.70-7.05 (m, 6H), 7.41-7.54 (m, 1H)

[Example 16] (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N-((1R,5R)-3-methylbicyclo[3.3.1] Nonan-1-yl)penta-2,4-dienamide

A compound was obtained in the same manner and conditions as in Example 3, except that adamantylamine (278 mg, 1.83 mmol) was used. (150 mg, 46.6%) ¹ H NMR (CDCl ₃ ) δ 1.72-1.80 (m, 6H), 2.12-2.20 (m, 9H), 6.01 (s, 2H), 6.66-6.80 (m, 3H), 6.86 -6.92 (d, 1H), 6.99 (s, 1H), 7.28-7.42 (m, 1H)

[Example 17] (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(4H-1,2,4-triazol-4-yl)penta -2,4-dien-1-one

A compound was obtained in the same manner and conditions as in Example 3, except that triazole (127 mg, 1.83 mmol) was used. (400 mg, 81.0%) ¹ H NMR (DMSO-d ₆ ) δ 6.09 (s, 2H), 6.98 (d, 1H), 7.09-7.19 (m, 2H), 7.27-7.34 (m, 3H), 7.76 -7.89 (m, 1H), 8.34 (s, 1H), 9.35 (s, 1H)

[Example 18] (2E,4E)-1-(1H-benzo[d][1,2,3]triazol-1-yl)-5-(benzo[d][1,3]dioxole- 5-day) penta-2,4-dien-1-one

A compound was obtained in the same manner and conditions as in Example 3, except that benzotriazole (218 mg, 1.83 mmol) was used. (360 mg, 61.5%) ¹ H NMR (CDCl ₃ ) δ 6.02 (s, 2H), 6.78-6.88 (d, 1H), 6.90-7.11 (m, 4H), 7.46-7.72 (m, 3H), 7.82 -7.95 (s, 1H), 8.08-8.18 (d, 1H), 8.35-8.45 (d, 1H)

[Example 19] (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(6,7-dihydroxy-3,4-dihyidoiso Quinoline-2(1H)-yl)penta-2,4-dien-1-one

A compound was obtained in the same manner and conditions as in Example 3, except that 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrogen chloride (354 mg, 1.83 mmol) was used. (340 mg, 47.2%) ¹ H NMR (CDCl ₃ ) δ 2.75-2.86 (m, 2H), 3.74-3.92 (m, 8H), 4.60-4.78 (m, 2H), 5.98 (s, 2H), 6.42 -6.54 (d, 1H), 6.60-6.70 (m, 2H), 6.72-6.80 (m, 3H), 6.84-7.05 (m, 2H), 7.20-7.30 (m, 2H), 7.50-7.60 (m, 1H), 7.70-7.84 (m, 1H)

[Example 20] (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N-benzylpenta-2,4-dienamide

A compound was obtained in the same manner and conditions as in Example 3, except that benzylamine (196 mg, 1.83 mmol) was used. (230 mg, 40.9%) ¹ H NMR (CDCl ₃ ) δ 5.96 (s, 2H), 6.03-6.10 (d, 1H), 6.70-6.97 (m, 5H), 7.10 (s, 1H), 7.20-7.40 (m, 3H), 7.45-7.57 (m, 3H)

[Example 21] (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N-phenethylpenta-2,4-dienamide

A compound was obtained in the same manner and conditions as in Example 3, except that phenylethylamine (222 mg, 1.83 mmol) was used. (320 mg, 54.3%) ¹ H NMR (CDCl ₃ ) δ 2.80-2.92 (t, 2H), 3.54-3.66 (q, 2H), 5.93-5.87 (m, 4H), 6.60-6.78 (m, 3H) , 6.80-6.96 (m, 2H), 7.19-7.36 (m, 6H)

[Example 22] (2E,4E)-5-(3,4-dihydroxyphenyl)-1-(4-hydroxypiperidin-1-yl) penta-2,4-dien-1-one (2)

(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(4-hydroxypiperidin-1-yl)penta-2,4-diene-1 Using -one (100 mg, 0.332 mmol) as a starting material, a compound was obtained in the same manner and conditions as in Example 2. (30 mg, 31.2%) ¹ H NMR (CD ₃ OD) δ 1.45-1.55 (m, 2H), 1.80-1.98 (m, 2H), 3.88 (s, 2H), 3.92-4.00 (m, 1H), 4.24 (s, 2H), 6.50-6.55 (d, 1H), 6.58-6.80 (m, 3H), 6.83-6.97 (m, 1H), 6.93-6.97 (m, 1H), 7.33-7.45 (m, 1H) )

[Example 23] (2E,4E)-5-(3,4-dihydroxyphenyl)-1-morpholinopenta-2,4-dien-1-one (3)

(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-morpholinopenta-2,4-dien-1-one (100 mg, 0.348 mmol) As a starting material, a compound was obtained in the same manner and conditions as in Example 2. (40 mg, 41.7%) ¹ H NMR (CD ₃ OD) δ 3.65-3.78 (m, 8H), 6.33-6.35 (d, 1H), 6.75-6.88 (m, 3H), 6.80-6.90 (m, 1H) ), 6.95-7.05 (m, 1H), 7.00-7.55 (m, 1H)

[Example 24] (2E,4E)-5-(3,4-dihydroxyphenyl)-1-(4-methylpiperazin-1-yl)penta-2,4-dien-1-one ( 4)

(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(4-methylpiperazin-1-yl)penta-2,4-diene-1- On (100 mg, 0.333 mmol) was used as a starting material to obtain a compound in the same manner and conditions as in Example 2. (35 mg, 36.5%) ¹ H NMR (CD ₃ OD) δ 3.16 (d, 3H), 3.40-3.80 (m, 6H), 4.06-4.57 (m, 2H), 6.60-6.70 (d, 1H), 6.70-6.75 (d, 1H), 6.76-6.89 (m, 3H), 6.91-6.97 (d, 1H), 7.25-7.35 (m, 1H)

[Example 25] (2E,4E)-5-(3,4-dihydroxyphenyl)-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one (5)

(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one ( 100 mg, 0.369 mmol) as a starting material to obtain a compound in the same manner and conditions as in Example 2. (25 mg, 26.2%) ¹ H NMR (DMSO-d ₆ ) δ 1.72-1.84 (q, 3H), 1.86-1.93 (q, 2H), 3.33-3.39 (t, 2H), 3.49-3.54 (t, 2H), 6.34-6.45 (d, 1H), 6.67-6.87 (m, 4H), 6.92 (s, 1H), 7.14-7.26 (m, 1H)

[Example 26] 1-((2E,4E)-5-(3,4-dihydroxyphenyl) penta-2,4-dienoyl)pyrrolidine-2-carboxylic acid (6)

1-((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienoyl)pyrrolidine-2-carboxylic acid (100 mg , 0.304 mmol) as a starting material to obtain a compound in the same manner and conditions as in Example 2. (45 mg, 48.9%) ¹ H NMR (DMSO-D ₆ ) δ 1.89-2.10 (m,2H), 2.10-2.24 (2H), 3.45-3.53 (m, 1H), 3.60-3.65 (m, 1H) , 3.69-3.70 (m, 2H), 4.65-4.75 (1H), 6.15-6.25 (d, 2H), 6.75-7.00 (m, 5H), 7.30-7.40 (m, 1H)

[Example 27] (2E,4E)-5-(3,4-dihydroxyphenyl)-1-(1H-imidazol-1-yl)penta-2,4-dien-1-one (7 )

(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(1H-imidazol-1-yl)penta-2,4-dien-1-one (100 mg, 0.373 mmol) as a starting material to obtain a compound in the same manner and conditions as in Example 2. (36 mg, 37.7%) ¹ H NMR (CD ₃ OD) δ 5.86-5.97 (d, 1H), 6.67-6.90 (m, 5H), 6.91-7.07 (m, 4H), 7.34-7.47 (m, 1H) ), 7.65 (s, 1H)

[Example 28] (2E,4E)-1-(3,4-dihydroisoquinoline-2(1H)-yl)-5-(3,4-dihydroxyphenyl)penta-2,4-di En-1-one (8)

(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(3,4-dihydroxyisoquinolin-2(1H)-yl)penta-2, Using 4-dien-1-one (100 mg, 0.300 mmol) as a starting material, a compound was obtained in the same manner and conditions as in Example 2. (46 mg, 47.7%) ¹ H NMR (CD ₃ OD) δ 2.91-2.86 (m, 2H), 3.84 (s, 2H), 4.60-4.87 (m, 2H), 6.58-6.68 (t, 1H), 6.74-6.87 (m, 4H), 6.98 (d, 1H), 7.10-7.22 (m, 4H), 7.30-7.46 (m, 1H)

[Example 29] (2E,4E)-5-(3,4-dihydroxyphenyl)-N,N-diethylpenta-2,4-dienamide (9)

Starting (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N,N-diethylpenta-2,4-dienamide (100 mg, 0.366 mmol) As a substance, a compound was obtained in the same manner and conditions as in Example 2. (52 mg, 54.4%) ¹ H NMR (CD ₃ OD) δ 0.79-0.95 (m, 6H), 3.24-3.44 (m, 4H), 6.20-6.32 (d, 1H), 6.61-6.70 (m, 1H) ), 6.78-6.88 (m, 2H), 7.00-7.10 (m, 1H), 7.40-7.51 (m, 1H)

[Example 30] (2E,4E)-5-(3,4-dihydroxyphenyl)-N,N-diisopropylpenta-2,4-dienamide (10)

(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N,N-diisopropylpenta-2,4-dienamide (100 mg, 0.332 mmol) As a starting material, a compound was obtained in the same manner and conditions as in Example 2. (43 mg, 44.8%) ¹ H NMR (CD ₃ OD) δ 1.15-1.50 (d, 12H), 3.30-3.40 (m, 2H), 6.25-6.40 (m, 1H), 6.60-6.70 (m, 2H), 6.80-6.95 (m, 1H), 6.98-7.15 (m, 1H), 7.17-7.35 (m, 1H)

[Example 31] (2E,4E)-5-(3,4-dihydroxyphenyl)-N,N-dihexylpenta-2,4-dienamide (11)

Starting (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N,N-dihexylpenta-2,4-dienamide (100 mg, 0.259 mmol) As a substance, a compound was obtained in the same manner and conditions as in Example 2. (24 mg, 24.8%) ¹ H NMR (CD ₃ OD) δ 0.79-0.95 (t, 6H), 1.18-1.38 (m, 12H), 1.49-1.65 (m, 4H), 3.24-3.44 (m, 4H) ), 6.21-6.33 (d, 1H), 6.61-6.77 (m, 1H), 6.80-6.98 (m, 2H), 7.02-7.12 (s, 1H), 7.38-7.51 (1H)

[Example 32] (2E,4E)-N-(cyclohexylmethyl)-5-(3,4-dihydroxyphenyl)penta-2,4-dienamide (12)

(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N-(cyclohexylmethyl)penta-2,4-dienamide (100 mg, 0.319 mmol) As a starting material, a compound was obtained in the same manner and conditions as in Example 2. (45 mg, 46.8%) ¹ H NMR (CD ₃ OD) δ 0.99-0.92 (m, 2H), 1.26-1.14 (m, 3H), 1.53-1.49 (m, 1H), 1.75-1.65 (m, 5H) ), 3.15-3.25 (t, 2H), 5.77 (s, 1H), 5.96-5.93 (d, 1H), 6.77-6.64 (m, 3H), 6.96-6.86 (m, 2H), 7.37-7.27 (m , 1H)

[Example 33] (2E,4E)-5-(3,4-dihydroxyphenyl)-N-(piperidin-1-yl)penta-2,4-dienamide (13)

(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N-(piperidin-1-yl)penta-2,4-dienamide (100 mg, 0.333 mmol) as a starting material to obtain a compound in the same manner and conditions as in Example 2. (55 mg, 57.3%) ¹ H NMR (DMSO-d ₆ ) δ 1.40-1.65 (m, 6H), 3.40-3.50 (m, 4H), 6.60-6.70 (d, 1H), 6.80-6.95 (m, 4H), 7.10-7.20 (m, 2H)

[Example 34] (2E,4E)-5-(3,4-dihydroxyphenyl)-N-(4-methylpiperazin-1-yl)penta-2,4-dienamide (14)

(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N-(4-methylpiperazin-1-yl)penta-2,4-dienamide (100 mg, 0.317 mmol) as a starting material to obtain a compound in the same manner and conditions as in Example 2. (12 mg, 12.5%) ¹ H NMR (CDCl ₃ ) δ 2.14-2.96 (m, 6H), 3.00-3.40 (m, 5H), 6.65-7.00 (m, 6H), 7.35-7.50 (m, 1H)

[Example 35] (2E,4E)-N-((3s,5s,7s)-adamantan-1-yl)-5-(3,4-dihydroxyphenyl)penta-2,4-di Enamide (15)

(2E,4E)-5-(Benzo[d][1,3]dioxol-5-yl)-N-((1R,5R)-3-methylbicyclo[3.3.1]nonan-1-yl ) Using penta-2,4-dienamide (100 mg, 0.285 mmol) as a starting material, a compound was obtained in the same manner and conditions as in Example 2. (23 mg, 23.8%) ¹ H NMR (CD ₃ OD) δ 1.65-1.75 (m, 6H), 2.00-2.15 (m, 9H), 6.60-6.80 (m, 3H), 6.85-6.95 (d, 1H) ), 7.00 (s, 1H), 7.20-7.35 (m, 1H)

[Example 36] (2E,4E)-5-(3,4-dihydroxyphenyl)-1-(4H-1,2,4-triazol-4-yl)penta-2,4-diene -1-one (16)

(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(4H-1,2,4-triazol-4-yl)penta-2,4- Dien-1-one (100 mg, 0.371 mmol) was used as a starting material to obtain a compound in the same manner and conditions as in Example 2. (26 mg, 27.2%) ¹ H NMR (DMSO-d ₆ ) δ 6.79 (d, 1H), 7.10-7.20 (m, 2H), 7.20-7.30 (m, 3H), 7.75-7.90 (m, 1H) , 8.25 (s, 1H), 9.25 (s, 1H)

[Example 37] (2E,4E)-1-(1H-benzo[d][1,2,3]triazol-1-yl)-5-(3,4-dihydroxyphenyl)penta-2 ,4-dien-1-one (17)

(2E,4E)-1-(1H-Benzo[d][1,2,3]triazol-1-yl)-5-(benzo[d][1,3]dioxol-5-yl)penta Using -2,4-dien-1-one (100 mg, 0.313 mmol) as a starting material, a compound was obtained in the same manner and conditions as in Example 2. (27 mg, 28.1%) ¹ H NMR (DMSO-d ₆ ) δ 6.70-6.90 (d, 1H), 6.95-7.15 (m, 4H), 7.35-7.75 (m, 3H), 7.75-7.90 (s, 1H), 8.05-8.20 (d, 1H), 8.30-8.40 (d, 1H)

[Example 38] (2E,4E)-1-(6,7-dihydroxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3,4-dihydroxyphenyl ) Penta-2,4-dien-1-one (18)

(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(6,7-dihydroxy-3,4-dihydoisoquinoline-2(1H) )-Yl)penta-2,4-dien-1-one (100 mg, 0.254 mmol) was used as a starting material to obtain a compound in the same manner and conditions as in Example 2. (35 mg, 39.0%) ¹ H NMR (CD ₃ OD) δ 2.60-2.85 (m, 2H), 3.72-3.85 (m, 8H), 4.50-4.70 (m, 2H), 6.35-6.55 (d, 1H) ), 6.68-6.78 (m, 2H), 6.80-6.90 (m, 3H), 6.90-7.15 (m, 2H), 7.20-7.35 (m, 2H), 7.57-7.70 (m, 1H), 7.80-7.90 (m, 1H)

[Example 39] (2E,4E)-N-benzyl-5-(3,4-dihydroxyphenyl) penta-2,4-dienamide (19)

Using (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N-benzylpenta-2,4-dienamide (100 mg, 0.325 mmol) as a starting material A compound was obtained in the same manner and conditions as in Example 2. (55 mg, 57.2%) ¹ H NMR (CD ₃ OD) δ 4.46 (s, 2H), 6.03-6.13 (d, 1H), 6.70-6.81 (m, 3H), 6.82-6.88 (d, 1H), 6.96 (s, 1H), 7.23-7.27 (m, 1H), 7.27-7.36 (m, 5H)

[Example 40] (2E,4E)-5-(3,4-dihydroxyphenyl)-N-phenethylpenta-2,4-dienamide (20)

(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N-phenethylpenta-2,4-dienamide (100 mg, 0.311 mmol) as a starting material Then, a compound was obtained in the same manner and conditions as in Example 2. (44 mg, 45.7%) ¹ H NMR (CD ₃ OD) δ 2.91-2.98 (t, 2H), 3.57-3.63 (t, 2H), 6.07-6.13 (d, 1H), 6.79-6.90 (m, 3H) ), 6.93-6.98 (d, 1H), 7.04-7.08 (s, 1H), 7.28-7.42 (m, 6H)

[Example 41] (2E,4E)-5-(3-fluoro-4-hydroxyphenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one (21 )

Crotonyl piperidine (447 mg, 2.92 mmol) was dissolved in anhydrous dimethyl sulfoxide (10 mL), potassium tertiarybutoxide (546 mg, 4.87 mmol) was added, followed by stirring at room temperature for 10 minutes. To this, 3-fluoro-4-methoxybenzaldehyde (500 mg, 3.24 mmol) was dissolved in anhydrous dimethyl sulfoxide (2 mL) and added. It was terminated after 1 hour at room temperature, ethyl acetate and water were added, and the 1 N aqueous hydrogen chloride solution was acidified, the organic layer was washed with brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and concentrated, followed by column chromatography to obtain a compound. (2E,4E)-5-(3-fluoro-4-methoxyphenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one (100 mg, 0.346 mmol) Was dissolved in dichloromethane solution, the temperature was lowered to 0 degrees, and boron tribromide aqueous solution was added. The temperature was raised to room temperature and stirred for 24 hours. After completion of the reaction, ethyl acetate and water were added, and the organic layer was dried with anhydrous sodium sulfate and then distilled under reduced pressure to remove the solvent. The compound was obtained by column chromatography. (30 mg, 31.5%) ¹ H NMR (CD ₃ OD) δ 1.55-1.75 (m, 6H), 3.55-3.70 (t, 4H), 6.56-6.68 (d, 1H), 6.75-6.94 (m, 3H) ), 7.10-7.18 (m, 1H), 7.25-7.38 (m, 2H) MS (ESI) m/z 276.23 [M+H] ⁺

[Example 42] (2E, 4E)-5-(3-fluoro-4-hydroxyphenyl)-1-morpholinopenta-2,4-dien-1-one (22)

A compound was obtained in the same manner and conditions as in Example 41, except that crotonyl morpholine (453 mg, 2.92 mmol) was used. (40 mg, 42.0%) MS (ESI) m/z 278.31 [M+H] ⁺

[Example 43] (2E,4E)-5-(3-fluoro-4-hydroxyphenyl)-1-(1H-imidazol-1-yl)penta-2,4-dien-1-one (23)

A compound was obtained in the same manner and conditions as in Example 41, except that crotonyl imidazole (397 mg, 2.92 mmol) was used. (53 mg, 55.9%) MS (ESI) m/z 279.21 [M+H] ⁺

[Example 44] (2E,4E)-1-(3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-fluoro-4-hydroxyphenyl)penta-2,4 -Dien-1-one (24)

A compound was obtained in the same manner and conditions as in Example 41, except that crotonyl dihydroisoquinoline (588 mg, 2.92 mmol) was used. (43 mg, 44.9%) MS (ESI) m/z 324.34 [M+H] ⁺

[Example 45] (2E,4E)-5-(3-fluoro-4-hydroxyphenyl)-N-(piperidin-1-yl)penta-2,4-dienamide (25)

A compound was obtained in the same manner and conditions as in Example 41, except that crotonyl aminopiperidine (491 mg, 2.92 mmol) was used. (37 mg, 38.8%) MS (ESI) m/z 291.44 [M+H] ⁺

[Example 46] (2E, 4E)-N-benzyl-5-(3-fluoro-4-hydroxyphenyl)penta-2,4-dienamide (26)

A compound was obtained in the same manner and conditions as in Example 41, except that crotonyl benzylamine (512 mg, 2.92 mmol) was used. (25 mg, 26.2%) MS (ESI) m/z 298.38 [M+H] ⁺

[Example 47] (2E,4E)-5-(3-chloro-4-hydroxyphenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one (27)

A compound was obtained in the same manner and conditions as in Example 41, except that 3-chloro-4-methoxybenzaldehyde (500 mg 2.93 mmol) and crotonyl piperidine (449 mg, 2.64 mmol) were used. (35 mg, 36.7%) ¹ H NMR (CD ₃ OD) δ 1.55-1.70 (m, 6H), 3.50-3.70 (m, 4H), 6.40-6.58 (d, 1H), 6.70-6.95 (m, 3H) ), 7.24-7.52 (m, 3H) MS (ESI) m/z 292.31 [M+H] ⁺

[Example 48] (2E, 4E)-5-(3-chloro-4-hydroxyphenyl)-1-morpholinopenta-2,4-dien-1-one (28)

A compound was obtained in the same manner and conditions as in Example 41, except that 3-chloro-4-methoxybenzaldehyde (500 mg 2.93 mmol) and crotonyl morindin (455 mg, 2.64 mmol) were used. (38 mg, 39.8%) MS (ESI) m/z 294.11 [M+H] ⁺

[Example 49] (2E,4E)-5-(3-chloro-4-hydroxyphenyl)-1-(1H-imidazol-1-yl)penta-2,4-dien-1-one ( 29)

A compound was obtained in the same manner and conditions as in Example 41, except that 3-chloro-4-methoxybenzaldehyde (500 mg 2.93 mmol) and crotonyl imidazole (399 mg, 2.64 mmol) were used. (24 mg, 25.2%) MS (ESI) m/z 275.46 [M+H] ⁺

[Example 50] (2E,4E)-1-(3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-chloro-4-hydroxyphenyl)penta-2,4- Dien-1-one (30)

A compound was obtained in the same manner and conditions as in Example 41, except that 3-chloro-4-methoxybenzaldehyde (500 mg 2.93 mmol) and crotonyl dihydroisoquinoline (590 mg, 2.64 mmol) were used. (44 mg, 45.8%) MS (ESI) m/z 340.22 [M+H] ⁺

[Example 51] (2E,4E)-5-(3-chloro-4-hydroxyphenyl)-N-(piperidin-1-yl)penta-2,4-dienamide (31)

A compound was obtained in the same manner as in Example 41, except that 3-chloro-4-methoxybenzaldehyde (500 mg 2.93 mmol) and crotonyl aminopiperidine (493 mg, 2.64 mmol) were used. (16 mg, 16.7 %) MS (ESI) m/z 307.37 [M+H] ⁺

[Example 52] (2E,4E)-N-benzyl-5-(3-chloro-4-hydroxyphenyl)penta-2,4-dienamide (32)

A compound was obtained in the same manner and conditions as in Example 41, except that 3-chloro-4-methoxybenzaldehyde (500 mg 2.93 mmol) and crotonyl benzylamine (514 mg, 2.64 mmol) were used. (33 mg, 34.5%) MS (ESI) m/z 314.51 [M+H] ⁺

[Example 53] (2E,4E)-5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1-(piperidin-1-yl)penta-2,4-diene-1 -On (33)

Except using 4-((2-methoxyethoxy)methoxy)-3-(trifluoromethyl)benzaldehyde (700 mg 1.80 mmol) and crotonyl piperidine (275 mg, 1.62 mmol) A compound was obtained in the same manner and conditions as in Example 41. (22 mg, 28.0%) ¹ H NMR (CD ₃ OD) δ 1.55-1.70 (m, 6H), 3.50-3.70 (m, 4H), 6.40-6.58 (d, 1H), 6.70-6.95 (m, 3H) ), 7.24-7.52 (m, 3H) MS (ESI) m/z 326.23 [M+H] ⁺

[Example 54] (2E, 4E)-5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1-morpholinopenta-2,4-dien-1-one (34)

Except using 4-((2-methoxyethoxy)methoxy)-3-(trifluoromethyl)benzaldehyde (700 mg 1.80 mmol) and crotonyl morphorindine (279 mg, 1.62 mmol) To obtain a compound in the same manner and conditions as in Example 41. (15 mg, 19.0%) MS (ESI) m/z 328.48 [M+H] ⁺

[Example 55] (2E,4E)-5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1-(1H-imidazol-1-yl)penta-2,4-diene -1-one (35)

Except using 4-((2-methoxyethoxy)methoxy)-3-(trifluoromethyl)benzaldehyde (700 mg 1.80 mmol) and crotonyl imidazole (245 mg, 1.62 mmol) A compound was obtained in the same manner and conditions as in Example 41. (35 mg, 45.0%) MS (ESI) m/z 309.23 [M+H] ⁺

[Example 56] (2E,4E)-1-(3,4-dihydroisoquinolin-2(1H)-yl)-5-(4-hydroxy-3-(trifluoromethyl)phenyl)penta -2,4-dien-1-one (36)

Except using 4-((2-methoxyethoxy)methoxy)-3-(trifluoromethyl)benzaldehyde (700 mg 1.80 mmol) and crotonyl dihydroisoquinoline (362 mg, 1.62 mmol) Then, a compound was obtained in the same manner and conditions as in Example 41. (42 mg, 52.0%) MS (ESI) m/z 374.25 [M+H] ⁺

[Example 57] (2E,4E)-5-(4-hydroxy-3-(trifluoromethyl)phenyl)-N-(piperidin-1-yl)penta-2,4-dienamide ( 37)

Except using 4-((2-methoxyethoxy)methoxy)-3-(trifluoromethyl)benzaldehyde (700 mg 1.80 mmol) and crotonyl aminopiperidine (302 mg, 1.62 mmol) To obtain a compound in the same manner and conditions as in Example 41. (38 mg, 47.8 %) MS (ESI) m/z 341.41 [M+H] ⁺

[Example 58] (2E, 4E)-N-benzyl-5-(4-hydroxy-3-(trifluoromethyl)phenyl)penta-2,4-dienamide (38)

Except using 4-((2-methoxyethoxy)methoxy)-3-(trifluoromethyl)benzaldehyde (700 mg 1.80 mmol) and crotonyl benzylamine (315 mg, 1.62 mmol) A compound was obtained in the same manner and conditions as in Example 41. (56 mg, 70.2%) MS (ESI) m/z 348.51 [M+H] ⁺

[Example 59] (2E,4E)-5-(4-hydroxy-3-nitrophenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one (39 )

A compound was obtained in the same manner and conditions as in Example 41, except that 4-methoxy-3-nitrobenzaldehyde (500 mg 2.76 mmol) and crotonyl piperidine (423 mg, 2.48 mmol) were used. (30 mg, 31.4%) ¹ H NMR (CD ₃ OD) δ 1.55-1.70 (m, 6H), 3.50-3.70 (m, 4H), 6.45-6.60 (d, 1H), 6.70-6.90 (m, 2H) ), 7.10-7.20 (m, 1H), 7.30-7.50 (m, 1H), 7.60-7.70 (m, 1H), 8.05-8.10 (m, 1H); MS (ESI) m/z 303.14 [M+H] ⁺

[Example 60] (2E,4E)-5-(4-hydroxy-3-nitrophenyl)-1-morpholinopenta-2,4-dien-1-one (40)

A compound was obtained in the same manner and conditions as in Example 41, except that 4-methoxy-3-nitrobenzaldehyde (500 mg 2.76 mmol) and crotonyl morphoindin (428 mg, 2.48 mmol) were used. (50 mg, 52.3%) MS (ESI) m/z 305.22 [M+H] ⁺

[Example 61] (2E,4E)-5-(4-hydroxy-3-nitrophenyl)-1-(1H-imidazol-1-yl)penta-2,4-dien-1-one (41)

A compound was obtained in the same manner and conditions as in Example 41, except that 4-methoxy-3-nitrobenzaldehyde (500 mg 2.76 mmol) and crotonyl imidazole (376 mg, 2.48 mmol) were used. (45 mg, 47.2%) MS (ESI) m/z 286.08 [M+H] ⁺

[Example 62] (2E,4E)-1-(3,4-dihydroisoquinolin-2(1H)-yl)-5-(4-hydroxy-3-nitrophenyl)penta-2,4 -Dien-1-one (42)

A compound was obtained in the same manner and conditions as in Example 41, except that 4-methoxy-3-nitrobenzaldehyde (500 mg 2.76 mmol) and crotonyl dihydroisoquinoline (565 mg, 2.48 mmol) were used. . (75 mg, 78.0%) MS (ESI) m/z 351.14 [M+H] ⁺

[Example 63] (2E,4E)-5-(4-hydroxy-3-nitrophenyl)-N-(piperidin-1-yl)penta-2,4-dienamide (43)

A compound was obtained in the same manner as in Example 41, except that 4-methoxy-3-nitrobenzaldehyde (500 mg 2.76 mmol) and crotonyl aminopiperidine (473 mg, 2.48 mmol) were used. (25 mg, 26.1 %) MS (ESI) m/z 318.18 [M+H] ⁺

[Example 64] (2E,4E)-N-benzyl-5-(4-hydroxy-3-nitrophenyl)penta-2,4-dienamide (44)

A compound was obtained in the same manner and conditions as in Example 41, except that 4-methoxy-3-nitrobenzaldehyde (500 mg 2.76 mmol) and crotonyl benzylamine (492 mg, 2.48 mmol) were used. (65 mg, 67.8%) MS (ESI) m/z 325.12 [M+H] ⁺

[Example 65] (2E,4E)-5-(4-hydroxy-3-methylphenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one (45)

Same as in Example 41, except that 4-((2-methoxyethoxy)methoxy)-3-methylbenzaldehyde (700 mg 3.12 mmol) and crotonyl piperidine (430 mg, 2.81 mmol) were used. Compounds were obtained by methods and conditions. (40 mg, 53.0%) ¹ H NMR (CD ₃ OD) δ 1.55-1.75 (m, 6H), 2.19 (s, 3H), 3.60-3.70 (t, 4H), 6.55-6.60 (d, 1H), 6.70-6.90 (m, 3H), 7.15-7.40 (m, 3H); MS (ESI) m/z 272.18 [M+H] ⁺

[Example 66] (2E,4E)-5-(4-hydroxy-3-methylphenyl)-1-morpholinopenta-2,4-dien-1-one (46)

Example 41 and Example 41 except that 4-((2-methoxyethoxy)methoxy)-3-methylbenzaldehyde (700 mg 3.12 mmol) and crotonyl morforindine (436 mg, 2.81 mmol) were used. Compounds were obtained by the same method and conditions. (65 mg, 86.0%) MS (ESI) m/z 274.15 [M+H] ⁺

[Example 67] (2E,4E)-5-(4-hydroxy-3-methylphenyl)-1-(1H-imidazol-1-yl)penta-2,4-dien-1-one (47 )

Same as in Example 41, except that 4-((2-methoxyethoxy)methoxy)-3-methylbenzaldehyde (700 mg 3.12 mmol) and crotonyl imidazole (382 mg, 2.81 mmol) were used. Compounds were obtained by methods and conditions. (52 mg, 70.0%) MS (ESI) m/z 255.12 [M+H] ⁺

[Example 68] (2E,4E)-1-(3,4-dihydroisoquinoline-2(1H)-yl)-5-(4-hydroxy-3-methylphenyl)penta-2,4-di En-1-one (48)

Example 41 except that 4-((2-methoxyethoxy)methoxy)-3-methylventaldehyde (700 mg 3.12 mmol) and crotonyl dihydroisoquinoline (565 mg, 2.81 mmol) were used. A compound was obtained in the same manner and conditions as described above. (66 mg, 84.2%) MS (ESI) m/z 320.17 [M+H] ⁺

[Example 69] (2E,4E)-5-(4-hydroxy-3-methylphenyl)-N-(piperidin-1-yl)penta-2,4-dienamide (49)

Example 41 and Example 41 except that 4-((2-methoxyethoxy)methoxy)-3-methylventaldehyde (700 mg 3.12 mmol) and crotonyl aminopiperidine (473 mg, 2.81 mmol) were used. Compounds were obtained by the same method and conditions. (28 mg, 36.6 %) MS (ESI) m/z 287.19 [M+H] ⁺

[Example 70] (2E, 4E)-N-benzyl-5-(4-hydroxy-3-methylphenyl)penta-2,4-dienamide (50)

Same as in Example 41, except that 4-((2-methoxyethoxy)methoxy)-3-methylventaldehyde (700 mg 3.12 mmol) and crotonyl benzylamine (492 mg, 2.81 mmol) were used. Compounds were obtained by methods and conditions. (51 mg, 66.3%) MS (ESI) m/z 294.15 [M+H] ⁺

[Example 71] (2E,4E)-5-(4-hydroxy-3-methoxyphenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one (51 )

Example 41 and Example 41 except that 4-((2-methoxyethoxy)methoxy)-3-methoxyventaldehyde (700 mg 2.91 mmol) and crotonyl piperidine (402 mg, 2.62 mmol) were used. Compounds were obtained by the same method and conditions. (40 mg, 52.3%) ¹ H NMR (CD ₃ OD) δ 1.50-1.70 (m, 6H), 3.37 (s, 3H), 3.50-3.80 (m, 4H), 6.40-6.50 (d, 1H), 6.72-6.86 (m, 2H), 6.96-7.04 (m, 2H), 7.12-7.20 (d, 1H), 7.38-7.48 (m, 1H); MS (ESI) m/z 288.16 [M+H] ⁺

[Example 72] (2E,4E)-5-(4-hydroxy-3-methoxyphenyl)-1-morpholinopenta-2,4-dien-1-one (52)

Example 41, except that 4-((2-methoxyethoxy)methoxy)-3-methoxybenthaldehyde (700 mg 2.91 mmol) and crotonyl morpholindine (407 mg, 2.62 mmol) were used. A compound was obtained in the same manner and conditions as described above. (20 mg, 26.1%) MS (ESI) m/z 290.14 [M+H] ⁺

[Example 73] (2E,4E)-5-(4-hydroxy-3-methoxyphenyl)-1-(1H-imidazol-1-yl)penta-2,4-dien-1-one (53)

Example 41 and Example 41 except that 4-((2-methoxyethoxy)methoxy)-3-methoxybenthaldehyde (700 mg 2.91 mmol) and crotonyl imidazole (357 mg, 2.62 mmol) were used. Compounds were obtained by the same method and conditions. (30 mg, 39.8%) MS (ESI) m/z 294.15 [M+H] ⁺

[Example 74] (2E,4E)-1-(3,4-dihydroisoquinolin-2(1H)-yl)-5-(4-hydroxy-3-methoxyphenyl)penta-2,4 -Dien-1-one (54)

Examples except that 4-((2-methoxyethoxy)methoxy)-3-methoxyventaldehyde (700 mg 2.91 mmol) and crotonyl dihydroisoquinoline (528 mg, 2.62 mmol) were used. A compound was obtained in the same manner and conditions as in 41. (50 mg, 63.1%) MS (ESI) m/z 336.16 [M+H] ⁺

[Example 75] (2E,4E)-5-(4-hydroxy-3-methoxyphenyl)-N-(piperidin-1-yl)penta-2,4-dienamide (55)

Example 41 except that 4-((2-methoxyethoxy)methoxy)-3-methoxyventaldehyde (700 mg 2.91 mmol) and crotonyl aminopiperidine (441 mg, 2.62 mmol) were used. A compound was obtained in the same manner and conditions as described above. (22 mg, 28.4%) MS (ESI) m/z 303.17 [M+H] ⁺

[Example 76] (2E,4E)-N-benzyl-5-(4-hydroxy-3-methoxyphenyl)penta-2,4-dienamide (56)

Example 41 and Example 41 except that 4-((2-methoxyethoxy)methoxy)-3-methoxyventaldehyde (700 mg 2.91 mmol) and crotonyl benzylamine (460 mg, 2.62 mmol) were used. Compounds were obtained by the same method and conditions. (35 mg, 45.0%) MS (ESI) m/z 310.15 [M+H] ⁺

[Example 77] (2E,4E)-5-(3,4-difluorophenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one (57)

A compound was obtained in the same manner as in Example 41, except that 3,4-difluorobenzaldehyde (500 mg 3.52 mmol) and crotonyl piperidine (485 mg, 3.17 mmol) were used. (300 mg, 30.7%) ¹ H NMR (CD ₃ OD) δ 1.55-1.78 (m, 6H), 3.50-3.70 (m, 4H), 6.46-6.56 (d, 1H), 6.70-6.84 (m, 2H) ), 7.06-7.18 (m, 1H), 7.20-7.30 (m, 1H), 7.32-7.46 (m, 1H); MS (ESI) m/z 278.14 [M+H] ⁺

[Example 78] (2E,4E)-5-(3,4-difluorophenyl)-1-morpholinopenta-2,4-dien-1-one (58)

A compound was obtained in the same manner and conditions as in Example 41, except that 3,4-difluorobenzaldehyde (500 mg 3.52 mmol) and crotonyl morporindine (491 mg, 3.17 mmol) were used. (250 mg, 25.4%) MS (ESI) m/z 280.13 [M+H] ⁺

[Example 79] (2E,4E)-5-(3,4-difluorophenyl)-1-(1H-imidazol-1-yl)penta-2,4-dien-1-one (59 )

A compound was obtained in the same manner and conditions as in Example 41, except that 3,4-difluorobenzaldehyde (500 mg 3.52 mmol) and crotonyl imidazole (431 mg, 3.17 mmol) were used. (350 mg, 38.2%) MS (ESI) m/z 261.09 [M+H] ⁺

[Example 80] (2E,4E)-1-(3,4-dihydroisoquinoline-2(1H)-yl)-5-(3,4-difluorophenyl)penta-2,4-di En-1-one (60)

A compound was obtained in the same manner and conditions as in Example 41, except that 3,4-difluorobenzaldehyde (500 mg 3.52 mmol) and crotonyl dihydroisoquinoline (637 mg, 3.17 mmol) were used. (450 mg, 39.3%) MS (ESI) m/z 326.14 [M+H] ⁺

[Example 81] (2E,4E)-5-(3,4-difluorophenyl)-N-(piperidin-1-yl)penta-2,4-dienamide (61)

A compound was obtained in the same manner as in Example 41, except that 3,4-difluorobenzaldehyde (500 mg 3.52 mmol) and crotonyl aminopiperidine (533 mg, 3.17 mmol) were used. (150 mg, 14.6 %) MS (ESI) m/z 293.15 [M+H] ⁺

[Example 82] (2E,4E)-N-benzyl-5-(3,4-difluorophenyl)penta-2,4-dienamide (62)

A compound was obtained in the same manner and conditions as in Example 41, except that 3,4-difluorobenzaldehyde (500 mg 3.52 mmol) and crotonyl benzylamine (555 mg, 3.17 mmol) were used. (700 mg, 66.5%) MS (ESI) m/z 300.13 [M+H] ⁺

[Example 83] (2E,4E)-5-(3,4-dinitrophenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one (63)

A compound was obtained in the same manner as in Example 41, except that 3,4-dinitrobenzaldehyde (500 mg 2.55 mmol) and crotonyl piperidine (352 mg, 2.29 mmol) were used. (250 mg, 29.6%) ¹ H NMR (CD ₃ OD) δ 1.55-1.70 (m, 6H), 3.50-3.70 (m, 4H), 6.45-6.60 (d, 1H), 6.70-6.90 (m, 2H) ), 7.10-7.20 (m, 1H), 7.30-7.50 (m, 1H), 7.60-7.70 (m, 1H), 8.05-8.10 (m, 1H); MS (ESI) m/z 332.13 [M+H] ⁺

[Example 84] (2E,4E)-5-(3,4-dinitrophenyl)-1-morpholinopenta-2,4-dien-1-one (64)

A compound was obtained in the same manner and conditions as in Example 41, except that 3,4-dinitrobenzaldehyde (500 mg 2.55 mmol) and crotonyl morporindine (356 mg, 2.29 mmol) were used. (280 mg, 33.0%) MS (ESI) m/z 334.11 [M+H] ⁺

[Example 85] (2E,4E)-5-(3,4-dinitrophenyl)-1-(1H-imidazol-1-yl)penta-2,4-dien-1-one (65 )

A compound was obtained in the same manner as in Example 41, except that 3,4-dinitrobenzaldehyde (500 mg 2.55 mmol) and crotonyl imidazole (312 mg, 2.29 mmol) were used. (330 mg, 41.2%) MS (ESI) m/z 315.08 [M+H] ⁺

[Example 86] (2E,4E)-1-(3,4-dihydroisoquinoline-2(1H)-yl)-5-(3,4-dinitrophenyl)penta-2,4-di En-1-one (66)

A compound was obtained in the same manner and conditions as in Example 41, except that 3,4-dinitrobenzaldehyde (500 mg 2.55 mmol) and crotonyl dihydroisoquinoline (462 mg, 2.29 mmol) were used. (440 mg, 45.5%) MS (ESI) m/z 380.13 [M+H] ⁺

[Example 87] (2E,4E)-5-(3,4-dinitrophenyl)-N-(piperidin-1-yl)penta-2,4-dienamide (67)

A compound was obtained in the same manner as in Example 41, except that 3,4-dinitrobenzaldehyde (500 mg 2.55 mmol) and crotonyl aminopiperidine (386 mg, 2.29 mmol) were used. (350 mg, 39.6 %) MS (ESI) m/z 347.14 [M+H] ⁺

[Example 88] (2E,4E)-N-benzyl-5-(3,4-dinitrophenyl)penta-2,4-dienamide (68)

A compound was obtained in the same manner as in Example 41, except that 3,4-dinitrobenzaldehyde (500 mg 2.55 mmol) and crotonyl benzylamine (402 mg, 2.29 mmol) were used. (600 mg, 66.6%) MS (ESI) m/z 354.14 [M+H] ⁺

[Example 89] (2E,4E)-5-(3,4-diaminophenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one (69)

(2E,4E)-5-(3,4-dinitrophenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one (200 mg, mmol) in ethanol ( 20 mL), and Zn (118.4 mg, 1.81 mmol) and acetic acid (145 mg, 2.41 mmol) were stirred at 0°C for 30 minutes, and then the temperature was raised and stirred at room temperature. After completion of the reaction, ethyl acetate and water were added, followed by filtration under reduced pressure in celite. The organic layer is anhydrous sodium sulfate?瀏? After removing water, it was concentrated and subjected to column chromatography to obtain a compound. (48 mg, 29.3%) ¹ H NMR (DMSO-d ₆ ) δ 1.50-1.65 (m, 6H), 3.45-3.65 (m, 4H), 6.30-6.40 (d, 1H), 6.65-6.75 (m, 3H), 6.80-6.90 (m, 2H), 7.20-7.45 (m, 1H); MS (ESI) m/z 272.18 [M+H] ⁺

[Example 90] (2E,4E)-5-(3,4-diaminophenyl)-1-morpholinopenta-2,4-dien-1-one (70)

Except for using (2E,4E)-5-(3,4-dinitrophenyl)-1-morpholinopenta-2,4-dien-1-one (200 mg, 0.600 mmol) A compound was obtained in the same manner and conditions as in Example 89. (56 mg, 34.1%) MS (ESI) m/z 274.16 [M+H] ⁺

[Example 91] (2E,4E)-5-(3,4-diaminophenyl)-1-(1H-imidazol-1-yl)penta-2,4-dien-1-one (71)

(2E,4E)-5-(3,4-dinitrophenyl)-1-(1H-imidazol-1-yl)penta-2,4-dien-1-one (200 mg, 0.636 mmol) Except for using, a compound was obtained in the same manner and conditions as in Example 89. (43 mg, 26.6%) MS (ESI) m/z 255.33 [M+H] ⁺

[Example 92] (2E,4E)-1-(3,4-dihydroisoquinoline-2(1H)-yl)-5-(3,4-diaminophenyl)penta-2,4-diene -1-one (72)

(2E,4E)-1-(3,4-dihydroisoquinoline-2(1H)-yl)-5-(3,4-dinitrophenyl)penta-2,4-dien-1-one A compound was obtained in the same manner and conditions as in Example 89, except that (200 mg, 0.527 mmol) was used. (68 mg, 40.4%) MS (ESI) m/z 320.28 [M+H] ⁺

[Example 93] (2E,4E)-5-(3,4-diaminophenyl)-N-(piperidin-1-yl)penta-2,4-dienamide (73)

Except for the use of (2E,4E)-5-(3,4-dinitrophenyl)-N-(piperidin-1-yl)penta-2,4-dienamide (200 mg, 0.577 mmol) Then, a compound was obtained in the same manner and conditions as in Example 89. (25 mg, 15.1%) MS (ESI) m/z 287.29 [M+H] ⁺

[Example 94] (2E,4E)-N-benzyl-5-(3,4-diaminophenyl)penta-2,4-dienamide (74)

The same as in Example 89 except that (2E,4E)-N-benzyl-5-(3,4-dinitrophenyl)penta-2,4-dienamide (200 mg, 0.566 mmol) was used. Compounds were obtained by methods and conditions. (53 mg, 31.9%) MS (ESI) m/z 294.16 [M+H] ⁺

[Example 95] 2-hydroxy-5-((1E,3E)-5-oxo-5-(piperidin-1-yl)penta-1,3-dien-1-yl)benzoic acid (75)

A compound was obtained in the same manner and conditions as in Example 41, except that methyl 5-formyl-2-methoxybenzoate (300 mg 1.54 mmol) and crotonyl piperidine (213 mg, 1.39 mmol) were used. (50 mg, 10.7%) ¹ H NMR (CD ₃ OD) δ 1.40-1.65 (m, 6H), 3.45-3.60 (m, 4H), 6.70-6.80 (d, 1H), 6.90-7.05 (m, 3H) ), 7.15-7.30 (m, 1H), 7.65-7.75 (m, 1H), 7.86-7.96 (m, 1H); MS (ESI) m/z 302.14 [M+H] ⁺

[Example 96] 2-hydroxy-5-((1E,3E)-5-morpholino-5-oxopenta-1,3-dien-1-yl)benzoic acid (76)

A compound was obtained in the same manner and conditions as in Example 41, except that methyl 5-formyl-2-methoxybenzoate (300 mg 1.54 mmol) and crotonyl morporindine (216 mg, 1.39 mmol) were used. (35 mg, 7.5%) MS (ESI) m/z 304.12 [M+H] ⁺

[Example 97] 5-((1E,3E)-5-(1H-imidazol-1-yl)-5-oxopenta-1,3-dien-1-yl)-2-hydroxybenzoic acid ( 77)

A compound was obtained in the same manner and conditions as in Example 41, except that methyl 5-formyl-2-methoxybenzoate (300 mg 1.54 mmol) and crotonyl imidazole (189 mg, 1.39 mmol) were used. (20 mg, 4.6%) MS (ESI) m/z 285.19 [M+H] ⁺

[Example 98] 5-((1E,3E)-5-(3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopenta-1,3-dien-1-yl) -2-hydroxybenzoic acid (78)

A compound was obtained in the same manner and conditions as in Example 41, except that methyl 5-formyl-2-methoxybenzoate (300 mg 1.54 mmol) and crotonyl dihydroisoquinoline (280 mg, 1.39 mmol) were used. . (90 mg, 16.7%) MS (ESI) m/z 350.14 [M+H] ⁺

[Example 99] 2-hydroxy-5-((1E,3E)-5-oxo-5-(piperidin-1-ylamino)penta-1,3-dien-1-yl)benzoic acid (79 )

A compound was obtained in the same manner as in Example 41, except that methyl 5-formyl-2-methoxybenzoate (300 mg 1.54 mmol) and crotonyl aminopiperidine (234 mg, 1.39 mmol) were used. (10 mg, 2.0 %) MS (ESI) m/z 317.15 [M+H] ⁺

[Example 100] 5-((1E,3E)-5-(benzylamino)-5-oxopenta-1,3-dien-1-yl)-2-hydroxybenzoic acid (80)

A compound was obtained in the same manner and conditions as in Example 41, except that methyl 5-formyl-2-methoxybenzoate (300 mg 1.54 mmol) and crotonyl benzylamine (244 mg, 1.39 mmol) were used. (25 mg, 5.0%) MS (ESI) m/z 324.13 [M+H] ⁺

[Example 101] (2E,4E)-5-(3-amino-4-hydroxyphenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one (81)

(2E,4E)-5-(4-hydroxy-3-nitrophenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one (200 mg, 0.662 mmol) Except for using, a compound was obtained in the same manner and conditions as in Example 89. (40 mg, 22.2%) ¹ H NMR (CD ₃ OD) δ 1.50-1.70 (m, 6H), 3.40-3.70 (m, 4H), 6.35-6.45 (d, 1H), 6.70-6.90 (m, 5H) ), 7.35-7.50 (m, 1H); MS (ESI) m/z 273.16 [M+H] ⁺

[Example 102] (2E, 4E)-5-(3-amino-4-hydroxyphenyl)-1-(morpholinopenta-2,4-dien-1-one (82)

Except using (2E,4E)-5-(4-hydroxy-3-nitrophenyl)-1-morpholinopenta-2,4-dien-1-one (200 mg, 0.657 mmol) To obtain a compound in the same manner and conditions as in Example 89. (65 mg, 36.1%) MS (ESI) m/z 275.14 [M+H] ⁺

[Example 103] (2E,4E)-5-(3-amino-4-hydroxyphenyl)-1-(1H-imidazol-1-yl)penta-2,4-dien-1-one ( 83)

(2E,4E)-5-(4-hydroxy-3-nitrophenyl)-1-(1H-imidazol-1-yl)penta-2,4-dien-1-one (200 mg, 0.701 mmol) was used to obtain a compound in the same manner and conditions as in Example 89. (35 mg, 19.6%) MS (ESI) m/z 256.16 [M+H] ⁺

[Example 104] (2E,4E)-5-(3-amino-4-hydroxyphenyl)-1-(3,4-dihydroisoquinolin-2(1H)-yl)penta-2,4- Dien-1-one (84)

(2E,4E)-1-(3,4-dihydroisoquinoline-2(1H)-yl)-5-(4-hydroxy-3-nitrophenyl)penta-2,4-diene-1 A compound was obtained in the same manner and conditions as in Example 89, except for using -on (200 mg, 0.571 mmol). (55 mg, 30.1%) MS (ESI) m/z 321.16 [M+H] ⁺

[Example 105] (2E,4E)-5-(3-amino-4-hydroxyphenyl)-1N-(piperidin-1-yl)penta-2,4-dienamide (85)

Using (2E,4E)-5-(4-hydroxy-3-nitrophenyl)-N-(piperidin-1-yl)penta-2,4-dienamide (200 mg, 0.630 mmol) Except that, a compound was obtained in the same manner and conditions as in Example 89. (45 mg, 24.9%) MS (ESI) m/z 288.17 [M+H] ⁺

[Example 106] (2E, 4E)-5-(3-amino-4-hydroxyphenyl)-1N-benzylpenta-2,4-dienamide (86)

Example 89, except that (2E,4E)-N-benzyl-5-(4-hydroxy-3-nitrophenyl)penta-2,4-dienamide (200 mg, 0.617 mmol) was used. A compound was obtained in the same manner and conditions as described above. (21 mg, 11.6%) MS (ESI) m/z 295.16 [M+H] ⁺

[Example 107] (2E, 4E)-5-(3-(diethylamino)-4-hydroxyphenyl)-1-(piperidin-1-yl)penta-2,4-diene-1- ON (87)

(2E,4E)-5-(3-amino-4-hydroxyphenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one (200 mg, 0.734 mmol) It was dissolved in dimethylformamide (10 mL), potassium carbonate (254 mg, 1.84 mmol) was added and stirred for 30 minutes. Methyl iodide (209 mg, 1.47 mmol) was added. After completion of the reaction, ethyl acetate and water were added, followed by filtration under reduced pressure in celite. The organic layer is anhydrous sodium sulfate?瀏? After removing water, it was concentrated and subjected to column chromatography to obtain a compound. (90 mg, 40.8%) ¹ H NMR (CD ₃ OD) δ 1.40-1.60 (m, 6H), 2.79 (s, 6H), 3.45-3.75 (m, 4H), 6.40-6.50 (d, 1H), 6.75-6.85 (m, 3H), 7.15-7.30 (m, 2H); MS (ESI) m/z 301.19 [M+H] ⁺

[Example 108] (2E, 4E)-5-(3-(dimethylamino)-4-hydroxyphenyl)-1-(morpholinopenta-2,4-dien-1-one (88)

Except using (2E,4E)-5-(3-amino-4-hydroxyphenyl)-1-(morpholinopenta-2,4-dien-1-one (200 mg, 0.729 mmol)) Was obtained in the same manner and conditions as in Example 89. (100 mg, 45.4%) MS (ESI) m/z 303.18 [M+H] ⁺

[Example 109] (2E, 4E)-5-(3-(dimethylamino)-4-hydroxyphenyl)-1-(1H-imidazol-1-yl)penta-2,4-diene- 1-on (89)

(2E,4E)-5-(3-amino-4-hydroxyphenyl)-1-(1H-imidazol-1-yl)penta-2,4-dien-1-one (200 mg, 0.783 mmol Except for using ), a compound was obtained in the same manner and conditions as in Example 89. (80 mg, 36.0%) MS (ESI) m/z 284.14 [M+H] ⁺

[Example 110] (2E,4E)-5-(3-(dimethylamino)-4-hydroxyphenyl)-1-(3,4-dihydroisoquinolin-2(1H)-yl)penta- 2,4-dien-1-one (90)

(2E,4E)-5-(3-amino-4-hydroxyphenyl)-1-(3,4-dihydroisoquinolin-2(1H)-yl)penta-2,4-diene-1- A compound was obtained in the same manner and conditions as in Example 89, except that on (200 mg, 0.624 mmol) was used. (75 mg, 34.5%) MS (ESI) m/z 349.19 [M+H] ⁺

[Example 111] (2E,4E)-5-(3-(dimethylamino)no-4-hydroxyphenyl)-1N-(piperidin-1-yl)penta-2,4-dienamide ( 91)

Using (2E,4E)-5-(3-amino-4-hydroxyphenyl)-1N-(piperidin-1-yl)penta-2,4-dienamide (200 mg, 0.696 mmol) Except for the same method and conditions as in Example 89 to obtain a compound. (35 mg, 15.9%) MS (ESI) m/z 316.25 [M+H] ⁺

[Example 112] (2E, 4E)-5-(3-(dimethylamino)-4-hydroxyphenyl)-1N-benzylpenta-2,4-dienamide (92)

Example 89 and Example 89 except that (2E,4E)-5-(3-amino-4-hydroxyphenyl)-1N-benzylpenta-2,4-dienamide (200 mg, 0.680 mmol) was used. Compounds were obtained by the same method and conditions. (50 mg, 22.8%) MS (ESI) m/z 323.18 [M+H] ⁺

[Example 113] (2E,4E)-5-(2-fluoro-4,5-dihydroxyphenyl)-1-(piperidin-1-yl)penta-2,4-diene-1- ON (93)

A compound was prepared in the same manner and conditions as in Example 41, except that 2-fluoro-4,5-dimethoxybenzaldehyde (500 mg 2.72 mmol) and crotonyl piperidine (374 mg, 2.44 mmol) were used. Got it. (30 mg, 32.9%) ¹ H NMR (CD ₃ OD) δ 1.50-1.75 (m, 6H), 3.55-3.75 (m, 4H), 6.50-6.70 (d, 1H), 6.80-6.90 (m, 2H) ), 7.30-7.50 (m, 1H), 7.60-7.70 (m, 1H); MS (ESI) m/z 292.14 [M+H] ⁺

[Example 114] (2E,4E)-5-(2-fluoro-4,5-dihydroxyphenyl)-1-morpholinopenta-2,4-dien-1-one (94)

Compounds in the same manner and conditions as in Example 41 except for the use of 2-fluoro-4,5-dimethoxybenzaldehyde (500 mg 2.72 mmol) and crotonyl morporindine (379 mg, 2.44 mmol). Got it. (25 mg, 27.4%) MS (ESI) m/z 294.13 [M+H] ⁺

[Example 115] (2E,4E)-5-(2-fluoro-4,5-dihydroxyphenyl)-1-(1H-imidazol-1-yl)penta-2,4-diene- 1-on (95)

A compound was prepared in the same manner and conditions as in Example 41, except that 2-fluoro-4,5-dimethoxybenzaldehyde (500 mg 2.72 mmol) and crotonyl imidazole (333 mg, 2.44 mmol) were used. Got it. (48 mg, 52.9%) MS (ESI) m/z 275.09 [M+H] ⁺

[Example 116] (2E,4E)-1-(3,4-dihydroisoquinolin-2(1H)-yl)-5-(2-fluoro-4,5-dihydroxyphenyl)penta- 2,4-dien-1-one (96)

In the same method and conditions as in Example 41, except that 2-fluoro-4,5-dimethoxybenzaldehyde (500 mg 3.52 mmol) and crotonyl dihydroisoquinoline (492 mg, 2.44 mmol) were used. The compound was obtained. (75 mg, 81.2%) MS (ESI) m/z 340.14 [M+H] ⁺

[Example 117] (2E,4E)-5-(2-fluoro-4,5-dihydroxyphenyl)-N-(piperidin-1-yl)penta-2,4-dienamide (97 )

Compounds in the same manner and conditions as in Example 41, except that 2-fluoro-4,5-dimethoxybenzaldehyde (500 mg 2.72 mmol) and crotonyl aminopiperidine (411 mg, 2.44 mmol) were used. Got it. (15 mg, 16.4 %) MS (ESI) m/z 307.15 [M+H] ⁺

[Example 118] (2E,4E)-N-benzyl-5-(2-fluoro-4,5-dihydroxyphenyl)penta-2,4-dienamide (98)

A compound was prepared in the same manner and conditions as in Example 41, except that 2-fluoro-4,5-dimethoxybenzaldehyde (500 mg 2.72 mmol) and crotonyl benzylamine (428 mg, 2.44 mmol) were used. Got it. (25 mg, 27.2%) MS (ESI) m/z 314.12 [M+H] ⁺

[Example 119] (2E,4E)-5-(2-bromo-4,5-dihydroxyphenyl)-1-(piperidin-1-yl)penta-2,4-diene-1- On (99)

A compound was prepared in the same manner and conditions as in Example 41, except that 2-bromo-4,5-dimethoxybenzaldehyde (700 mg 2.86 mmol) and crotonyl piperidine (394 mg, 2.57 mmol) were used. Got it. (80 mg, 43.2%) ¹ H NMR (CD ₃ OD) δ 1.55-1.75 (m, 6H), 3.50-3.70 (m, 4H), 6.55-6.75 (d, 1H), 6.80-6.90 (m, 2H) ), 7.25-7.35 (m, 1H), 7.40-7.60 (m, 1H); MS (ESI) m/z 352.16 [M+H] ⁺

[Example 120] (2E,4E)-5-(2-bromo-4,5-dihydroxyphenyl)-1-morpholinopenta-2,4-dien-1-one (100)

Compounds in the same manner and conditions as in Example 41 except for the use of 2-bromo-4,5-dimethoxybenzaldehyde (700 mg 2.86 mmol) and crotonyl morporindine (398 mg, 2.57 mmol). Got it. (90 mg, 48.6%) MS (ESI) m/z 354.05 [M+H] ⁺

[Example 121] (2E,4E)-5-(2-bromo-4,5-dihydroxyphenyl)-1-(1H-imidazol-1-yl)penta-2,4-diene- 1-on (101)

A compound was prepared in the same manner and conditions as in Example 41, except that 2-bromo-4,5-dimethoxybenzaldehyde (700 mg 2.86 mmol) and crotonyl imidazole (350 mg, 2.57 mmol) were used. Got it. (60 mg, 32.5%) MS (ESI) m/z 335.01 [M+H] ⁺

[Example 122] (2E,4E)-1-(3,4-dihydroisoquinoline-2(1H)-yl)-5-(2-bromo-4,5-dihydroxyphenyl)penta- 2,4-dien-1-one (102)

In the same method and conditions as in Example 41, except for using 2-bromo-4,5-dimethoxybenzaldehyde (700 mg 2.86 mmol) and crotonyl dihydroisoquinoline (517 mg, 2.57 mmol). The compound was obtained. (120 mg, 64.2%) MS (ESI) m/z 400.16 [M+H] ⁺

[Example 123] (2E,4E)-5-(2-bromo-4,5-dihydroxyphenyl)-N-(piperidin-1-yl)penta-2,4-dienamide (103 )

Compounds in the same manner and conditions as in Example 41, except that 2-bromo-4,5-dimethoxybenzaldehyde (700 mg 2.86 mmol) and crotonyl aminopiperidine (432 mg, 2.57 mmol) were used. Got it. (50 mg, 26.9 %) MS (ESI) m/z 367.17 [M+H] ⁺

[Example 124] (2E,4E)-N-benzyl-5-(2-bromo-4,5-dihydroxyphenyl)penta-2,4-dienamide (104)

The compound was prepared in the same manner and conditions as in Example 41, except that 2-bromo-4,5-dimethoxybenzaldehyde (700 mg 2.86 mmol) and crotonyl benzylamine (450 mg, 2.57 mmol) were used. Got it. (75 mg, 40.3%) MS (ESI) m/z 374.04 [M+H] ⁺

[Example 125] (2E,4E)-5-(4,5-dihydroxy-2-nitrophenyl)-1-(piperidin-1-yl)penta-2,4-diene-1- ON (105)

A compound was prepared in the same manner and conditions as in Example 41, except that 4,5-dimethoxy-2-nitrobenzaldehyde (700 mg 3.31 mmol) and crotonyl piperidine (457 mg, 2.98 mmol) were used. Got it. (90 mg, 49.0%) ¹ H NMR (CD ₃ OD) δ 1.45-1.65 (m, 6H), 3.50-3.70 (m, 4H), 6.60-6.75 (d, 1H), 6.90-7.00 (m, 2H) ), 7.25-7.55 (m, 1H), 7.60-7.70 (m, 1H); MS (ESI) m/z 319.13 [M+H] ⁺

[Example 126] (2E,4E)-5-(4,5-dihydroxy-2-nitrophenyl)-1-morpholinopenta-2,4-dien-1-one (106)

Compounds in the same manner and conditions as in Example 41 except for the use of 4,5-dimethoxy-2-nitrobenzaldehyde (700 mg 3.31 mmol) and crotonyl morporindine (463 mg, 2.98 mmol). Got it. (80 mg, 43.5%) MS (ESI) m/z 321.14 [M+H] ⁺

[Example 127] (2E,4E)-5-(4,5-dihydroxy-2-nitrophenyl)-1-(1H-imidazol-1-yl)penta-2,4-diene- 1-on (107)

A compound was prepared in the same manner and conditions as in Example 41, except that 4,5-dimethoxy-2-nitrobenzaldehyde (700 mg 3.31 mmol) and crotonyl imidazole (406 mg, 2.98 mmol) were used. Got it. (100 mg, 54.7%) MS (ESI) m/z 302.18 [M+H] ⁺

[Example 128] (2E,4E)-1-(3,4-dihydroisoquinolin-2(1H)-yl)-5-(4,5-dihydroxy-2-nitrophenyl)penta- 2,4-dien-1-one (108)

In the same method and conditions as in Example 41, except that 4,5-dimethoxy-2-nitrobenzaldehyde (700 mg 3.31 mmol) and crotonyl dihydroisoquinoline (600 mg, 2.98 mmol) were used. The compound was obtained. (110 mg, 59.2%) MS (ESI) m/z 367.14 [M+H] ⁺

[Example 129] (2E,4E)-5-(4,5-dihydroxy-2-nitrophenyl)-N-(piperidin-1-yl)penta-2,4-dienamide (109 )

Compounds in the same manner and conditions as in Example 41, except that 4,5-dimethoxy-2-nitrobenzaldehyde (700 mg 3.31 mmol) and crotonyl aminopiperidine (502 mg, 2.98 mmol) were used. Got it. (60 mg, 32.5%) MS (ESI) m/z 334.15 [M+H] ⁺

[Example 130] (2E,4E)-N-benzyl-5-(4,5-dihydroxy-2-nitrophenyl)penta-2,4-dienamide (110)

A compound was prepared in the same manner and conditions as in Example 41, except that 4,5-dimethoxy-2-nitrobenzaldehyde (700 mg 3.31 mmol) and crotonyl benzylamine (523 mg, 2.98 mmol) were used. Got it. (70 mg, 37.9%) MS (ESI) m/z 341.13 [M+H] ⁺

[Example 131] (2E,4E)-5-(4,5-dihydroxy-2-(trifluoromethyl)phenyl)-1-(piperidin-1-yl)penta-2,4-di En-1-one (96)

In the same manner as in Example 41, except that 4,5-dimethoxy-2-(trifluoromethyl)benzaldehyde (500 mg 2.14 mmol) and crotonyl piperidine (294 mg, 1.92 mmol) were used. The compound was obtained under conditions. (40 mg, 43.3%) ¹ H NMR (CD ₃ OD) δ 1.55-1.75 (m, 6H), 3.50-3.75 (m, 4H), 6.55-6.70 (d, 1H), 6.85-6.905 (m, 2H) ), 7.20-7.30 (m, 1H), 7.50-7.70 (m, 1H); MS (ESI) m/z 342.14 [M+H] ⁺

[Example 132] (2E,4E)-5-(4,5-dihydroxy-2-(trifluoromethyl)phenyl)-1-morpholinopenta-2,4-dien-1-one ( 112)

The same method as in Example 41, except that 4,5-dimethoxy-2-(trifluoromethyl)benzaldehyde (500 mg 2.14 mmol) and crotonyl morphorindin (298 mg, 1.92 mmol) were used. The compound was obtained under the following conditions. (32 mg, 34.6%) MS (ESI) m/z 344.14 [M+H] ⁺

[Example 133] (2E,4E)-5-(4,5-dihydroxy-2-(trifluoromethyl)phenyl)-1-(1H-imidazol-1-yl)penta-2,4 -Dien-1-one (113)

In the same manner as in Example 41, except that 4,5-dimethoxy-2-(trifluoromethyl)benzaldehyde (500 mg 2.14 mmol) and crotonyl imidazole (262 mg, 1.92 mmol) were used. The compound was obtained under conditions. (44 mg, 47.8%) MS (ESI) m/z 325.09 [M+H] ⁺

[Example 134] (2E,4E)-1-(3,4-dihydroisoquinolin-2(1H)-yl)-5-(4,5-dihydroxy-2-(trifluoromethyl) Phenyl) penta-2,4-dien-1-one (114)

The same as in Example 41 except that 4,5-dimethoxy-2-(trifluoromethyl)benzaldehyde (500 mg 2.14 mmol) and crotonyl dihydroisoquinoline (387 mg, 1.92 mmol) were used. Compounds were obtained by methods and conditions. (62 mg, 66.5%) MS (ESI) m/z 390.13 [M+H] ⁺

[Example 135] (2E,4E)-5-(4,5-dihydroxy-2-(trifluoromethyl)phenyl)-N-(piperidin-1-yl)penta-2,4-di Enamide (115)

The same method as in Example 41 except that 4,5-dimethoxy-2-(trifluoromethyl)benzaldehyde (500 mg 2.14 mmol) and crotonyl aminopiperidine (323 mg, 1.92 mmol) were used. The compound was obtained under the following conditions. (20 mg, 21.6 %) MS (ESI) m/z 357.14 [M+H] ⁺

[Example 136] (2E,4E)-N-benzyl-5-(4,5-dihydroxy-2-(trifluoromethyl)phenyl)penta-2,4-dienamide (116)

In the same manner as in Example 41, except that 4,5-dimethoxy-2-(trifluoromethyl)benzaldehyde (500 mg 2.14 mmol) and crotonyl benzylamine (337 mg, 1.92 mmol) were used. The compound was obtained under conditions. (35 mg, 37.7%) MS (ESI) m/z 364.13 [M+H] ⁺

[Example 137] (2E,4E)-5-(2-amino-4,5-dihydroxyphenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one (117)

(2E,4E)-5-(4,5-dihydroxy-2-nitrophenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one (300 mg, 0.879 mmol) was used to obtain a compound in the same manner and conditions as in Example 89. (50 mg, 19.7%) MS (ESI) m/z 289.17 [M+H] ⁺

[Example 138] (2E,4E)-5-(2-amino-4,5-dihydroxyphenyl)-1-morpholinopenta-2,4-dien-1-one (118)

Using (2E,4E)-5-(4,5-dihydroxy-2-nitrophenyl)-1-morpholinopenta-2,4-dien-1-one (300 mg, 0.874 mmol) Except that, a compound was obtained in the same manner and conditions as in Example 89. (80 mg, 31.5%) MS (ESI) m/z 291.14 [M+H] ⁺

[Example 139] (2E,4E)-5-(2-amino-4,5-dihydroxyphenyl)-1-(1H-imidazol-1-yl)penta-2,4-diene-1 -On (119)

(2E,4E)-5-(4,5-dihydroxy-2-nitrophenyl)-1-(1H-imidazol-1-yl)penta-2,4-dien-1-one (300 mg, 0.925 mmol) was used to obtain a compound in the same manner and conditions as in Example 89. (45 mg, 17.9%) MS (ESI) m/z 293.15 [M+H] ⁺

[Example 140] (2E,4E)-1-(3,4-dihydroisoquinolin-2(1H)-yl)-5-(2-amino-4,5-dihydroxyphenyl)penta-2 ,4-dien-1-one (120)

(2E,4E)-1-(3,4-dihydroisoquinoline-2(1H)-yl)-5-(4,5-dihydroxy-2-nitrophenyl)penta-2,4-di A compound was obtained in the same manner and conditions as in Example 89, except that en-1-one (300 mg, 0.770 mmol) was used. (63mg, 24.3%) MS (ESI) m/z 337.16 [M+H] ⁺

[Example 141] (2E,4E)-5-(2-amino-4,5-dihydroxyphenyl)-N-(piperidin-1-yl)penta-2,4-dienamide (121)

(2E,4E)-5-(4,5-dihydroxy-2-nitrophenyl)-N-(piperidin-1-yl)penta-2,4-dienamide (300 mg, 0.842 mmol) Except for using, a compound was obtained in the same manner and conditions as in Example 89. (25 mg, 9.8%) MS (ESI) m/z 304.17 [M+H] ⁺

[Example 142] (2E,4E)-N-benzyl-5-(2-amino-4,5-dihydroxyphenyl)penta-2,4-dienamide (122)

Except for using (2E,4E)-N-benzyl-5-(4,5-dihydroxy-2-nitrophenyl)penta-2,4-dienamide (300 mg, 0.826 mmol) A compound was obtained in the same manner and conditions as in Example 89. (75 mg, 29.3%) MS (ESI) m/z 311.14 [M+H] ⁺

[Example 143] (2E,4E)-5-(3-chloro-5-fluoro-4-hydroxyphenyl)-1-(piperidin-1-yl)penta-2,4-diene-1 -On (123)

Compounds in the same manner and conditions as in Example 41, except that 3-chloro-5-fluoro-4-methoxybenzaldehyde (250 mg 1.33 mmol) and crotonyl piperidine (183 mg, 1.19 mmol) were used. Got it. (50 mg, 26.1%) ¹ H NMR (CD ₃ OD) δ 1.45-1.65 (m, 6H), 3.40-3.60 (m, 4H), 6.70-6.80 (d, 1H), 6.90-7.00 (m, 2H) ), 7.20-7.30 (m, 1H), 7.35-7.45 (m, 1H); MS (ESI) m/z 292.14 [M+H] ⁺

[Example 144] (2E, 4E)-5-(3-chloro-5-fluoro-4-hydroxyphenyl)-1-morpholinopenta-2,4-dien-1-one (124)

In the same method and conditions as in Example 41, except that 3-chloro-5-fluoro-4-methoxybenzaldehyde (250 mg 1.33 mmol) and crotonyl morporindine (185 mg, 1.19 mmol) were used. The compound was obtained. (275 mg, 39.2%) MS (ESI) m/z 312.08 [M+H] ⁺

[Example 145] (2E,4E)-5-(3-chloro-5-fluoro-4-hydroxyphenyl)-1-(1H-imidazol-1-yl)penta-2,4-diene -1-one (125)

Compounds in the same manner and conditions as in Example 41, except that 3-chloro-5-fluoro-4-methoxybenzaldehyde (250 mg 1.33 mmol) and crotonyl imidazole (162 mg, 1.19 mmol) were used. Got it. (90 mg, 47.2%) MS (ESI) m/z 293.06 [M+H] ⁺

[Example 146] (2E,4E)-1-(3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-chloro-5-fluoro-4-hydroxyphenyl)penta -2,4-dien-1-one (126)

The same method and conditions as in Example 41, except that 3-chloro-5-fluoro-4-methoxybenzaldehyde (250 mg 1.33 mmol) and crotonyl dihydroisoquinoline (240 mg, 1.19 mmol) were used. To obtain a compound. (100 mg, 52.0%) MS (ESI) m/z 358.10 [M+H] ⁺

[Example 147] (2E,4E)-5-(3-chloro-5-fluoro-4-hydroxyphenyl)-N-(piperidin-1-yl)penta-2,4-dienamide ( 127)

In the same method and conditions as in Example 41, except that 3-chloro-5-fluoro-4-methoxybenzaldehyde (250 mg 1.33 mmol) and crotonyl aminopiperidine (201 mg, 1.19 mmol) were used. The compound was obtained. (80 mg, 41.7%) MS (ESI) m/z 325.12 [M+H] ⁺

[Example 148] (2E,4E)-N-benzyl-5-(3-chloro-5-fluoro-4-hydroxyphenyl)penta-2,4-dienamide (128)

Compounds in the same manner and conditions as in Example 41, except that 3-chloro-5-fluoro-4-methoxybenzaldehyde (250 mg 1.33 mmol) and crotonyl benzylamine (209 mg, 1.19 mmol) were used. Got it. (110 mg, 57.3%) MS (ESI) m/z 332.10 [M+H] ⁺

[Example 149] (E)-3-(6-hydroxynaphthalen-2-yl)-1-(piperidin-1-yl)prop-2-en-1-one (129)

After suspending sodium hydride (644 mg, 16.1 mmol) in a solution of tetrahydrofuran (30 mL), triethyl phosphonoacetate (1.5 g, 8.06 mmol) was slowly added dropwise. 6-methoxy-2-naphthaldehyde (mg, mmol) was dissolved in tetrahydrofuran (10 mL) and slowly added dropwise. The reaction was terminated after 18 hours. After the reaction was completed, ethyl acetate and water were added, and the organic layer was dried with anhydrous sodium sulfate. The compound was separated by column chromatography to obtain (E)-ethyl 3-(6-methoxynaphthalen-2-yl)acrylate.

(E)-ethyl 3-(6-methoxynaphthalen-2-yl)acrylate (2 g, 7.80 mmol) was dissolved in tetrahydrofuran/water (1/1, 30 mL) and 2.5 N sodium hydroxide solution (9.36 mL, 23.4 mmol) was added and refluxed for 16 hours. After the reaction was completed, the temperature was lowered, ethyl acetate and 1 N aqueous hydrogen chloride solution were added to make acidification, and the organic layer was dried with anhydrous sodium sulfate. It was distilled under reduced pressure and concentrated to obtain (E)-3-(6-methoxynaphthalen-2-yl)acrylic acid.

(E)-3-(6-methoxynaphthalen-2-yl)acrylic acid (1 g, 4.38 mmol) was dissolved in dichloromethane (30 mL), and 1-(3-dimethylaminopropyl)-3-ethyl Carbodiimide hydrogen chloride (1.01 g, 5.26 mmol) and hydroxybenzotriazole (710 mg, 5.26 mmol) were added and stirred at room temperature for 30 minutes. Pipeline (448 mg, 5.26 mmo) and diisopropylethylamine (1.60 mL, 9.20 mmol) were added and the reaction was terminated after 3 hours. Ethyl acetate and water were added, and the organic layer was washed with 1N aqueous hydrogen chloride solution, washed with brine, and then dried with anhydrous sodium sulfate. Separating the compound by column chromatography and distilling under reduced pressure to remove the solvent (E)-3-(6-methoxynaphthalen-2-yl)-1-(piperidin-1-yl)prop-2-ene-1 -I got on.

(E)-3-(6-methoxynaphthalen-2-yl)-1-(piperidin-1-yl)prop-2-en-1-one (150 mg, 0.508 mmol) in dichloromethane ( 20 mL), and boron tribromide aqueous solution was slowly added dropwise at 0 degrees. The temperature was raised to room temperature and stirred for 24 hours. After completion of the reaction, ethyl acetate and water were added, and the organic layer was dried with anhydrous sodium sulfate and then distilled under reduced pressure to remove the solvent. The compound was obtained by column chromatography. (50 mg, 32.7%) ¹ H NMR (CD ₃ OD) δ 1.50-1.75 (m, 6H), 3.64-3.80 (m, 4H), 6.96-7.20 (m, 3H), 7.60-7.80 (m, 4H) ), 7.88 (s, 1H); MS (ESI) m/z 282.15 [M+H] ⁺

[Example 150] (E)-3-(6-hydroxynaphthalen-2-yl)-1-morpholinoprop-2-en-1-one (130)

A compound was obtained in the same manner and conditions as in Example 129, except that Morolin was used. (30 mg) MS (ESI) m/z 284.13 [M+H] ⁺

[Example 151] (E)-3-(6-hydroxynaphthalen-2-yl)-1-(1H-imidazol-1-yl)prop-2-en-1-one (131)

A compound was obtained in the same manner and conditions as in Example 129, except that imidazole was used. (45 mg) MS (ESI) m/z 265.11 [M+H] ⁺

[Example 152] (E)-1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(6-hydroxynaphthalen-2-yl)prop-2-ene-1 -On (132)

A compound was obtained in the same manner and conditions as in Example 129, except that dihydroisoquinoline was used. (50 mg) MS (ESI) m/z 330.15 [M+H] ⁺

[Example 153] (E)-3-(6-hydroxynaphthalen-2-yl)-N-(piperidin-1-yl)acrylamide (133)

A compound was obtained in the same manner and conditions as in Example 129, except that amino piperidine was used. (10 mg) MS (ESI) m/z 297.17 [M+H] ⁺

[Example 154] (E)-N-benzyl-3-(6-hydroxynaphthalen-2-yl)acrylamide (134)

A compound was obtained in the same manner and conditions as in Example 129, except that benzylamine was used. (40 mg) MS (ESI) m/z 304.14 [M+H] ⁺

[Example 155] (E)-6-hydroxy-2-(3-oxo-3-(piperidin-1-yl)prop-1-en-1-yl)quinoline-1-ium bromide (135 )

A compound was obtained in the same manner and conditions as in Example 129, except that 6-methoxyquinoline-2-carbaldehyde was used. (30 mg) ¹ H NMR (D ₂ O) δ 1.60-1.80 (m, 6H), 3.60-3.80 (m, 4H), 7.51 (s, 1H), 7.60-7.90 (m, 3H), 8.05-8.15 (d, 1H), 8.15-30 (d, 1H), 8.75-8.85 (d, 2H); MS (ESI) m/z 283.14 [M+H] ⁺

[Example 156] (E)-6-hydroxy-2-(3-morpholino-3-oxoprop-1-en-1-yl)quinoline-1-ium bromide (136)

A compound was obtained in the same manner and conditions as in Example 129, except that 6-methoxyquinoline-2-carbaldehyde and morpholine were used. (50 mg) MS (ESI) m/z 285.14 [M+H] ⁺

[Example 157] (E)-2-(3-(1H-imidazol-1-yl)-3-oxoprop-1-en-1-yl)-6-hydroxyquinoline-1-ium bromide (137)

A compound was obtained in the same manner and conditions as in Example 129, except that 6-methoxyquinoline-2-carbaldehyde and imidazole were used. (45 mg) MS (ESI) m/z 266.09 [M+H] ⁺

[Example 158] (E)-2-(3-(3,4-dihydroisoquinoline-2(1H)-yl)-oxoprop-1-en-1-yl)-6-hydroxyquinoline -1-ium bromide (138)

A compound was obtained in the same manner and conditions as in Example 129, except that 6-methoxyquinoline-2-carbaldehyde and dihydroisoquinoline were used. (50 mg) MS (ESI) m/z 331.15 [M+H] ⁺

[Example 159] (E)-6-hydroxy-2-(3-oxo-3-(piperidin-1-ylamino)prop-1-en-1-yl)quinoline-1-ium bromide ( 139)

A compound was obtained in the same manner and conditions as in Example 129, except that 6-methoxyquinoline-2-carbaldehyde and aminopiperidine were used. (10 mg) MS (ESI) m/z 298.18 [M+H] ⁺

[Example 160] (E)-2-(3-(Benzylamino)-3-oxoprop-1-en-1-yl)-6-hydroxyquinoline-1-ium bromide (140)

A compound was obtained in the same manner and conditions as in Example 129, except that 6-methoxyquinoline-2-carbaldehyde and benzylamine were used. (50 mg) MS (ESI) m/z 305.14 [M+H] ⁺

[Example 161] (E)-3-(6-hydroxy-1H-indol-2-yl)-1-(piperidin-1-yl)prop-2-en-1-one (141)

A compound was obtained in the same manner and conditions as in Example 129, except that 6-methoxy-1H-indole-2-carbaldehyde and piperidine were used. (30 mg) MS (ESI) m/z 271.15 [M+H] ⁺

[Example 162] (E)-3-(6-hydroxy-1H-indol-2-yl)-1-morpholinoprop-2-en-1-one (142)

A compound was obtained in the same manner and conditions as in Example 129, except that 6-methoxy-1H-indole-2-carbaldehyde and morpholine were used. (45 mg) MS (ESI) m/z 273.15 [M+H] ⁺

[Example 163] (E)-3-(6-hydroxy-1H-indol-2-yl)-1-(1H-imidazol-1-yl)prop-2-en-1-one (143 )

A compound was obtained in the same manner and conditions as in Example 129, except that 6-methoxy-1H-indole-2-carbaldehyde and imidazole were used. (20 mg) MS (ESI) m/z 254.10 [M+H] ⁺

[Example 164] (E)-1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(6-hydroxy-1H-indol-2-yl)prop-2- En-1-one (144)

A compound was obtained in the same manner and conditions as in Example 129, except that 6-methoxy-1H-indole-2-carbaldehyde and dihydroisoquinoline were used. (60 mg) MS (ESI) m/z 319.18 [M+H] ⁺

[Example 165] (E)-3-(6-hydroxy-1H-indol-2-yl)-N-(piperidin-1-yl)acrylamide (145)

A compound was obtained in the same manner and conditions as in Example 129, except that 6-methoxy-1H-indole-2-carbaldehyde and amino piperidine were used. (15 mg) MS (ESI) m/z 286.16 [M+H] ⁺

[Example 166] (E)-N-benzyl-3-(6-hydroxy-1H-indol-2-yl)acrylamide (146)

A compound was obtained in the same manner and conditions as in Example 129, except that 6-methoxy-1H-indole-2-carbaldehyde and benzylamine were used. (40 mg) MS (ESI) m/z 293.15 [M+H] ⁺

[Test Example 1] Confirmation of NO generation inhibitory effect

BV-2 microglia was obtained by a known method (Kim, BW et al. , PLoS One, 8:e55792. 2013). Briefly, cells were DMEM (Dulbecco's modified Eagle's medium; Gibco/Invitrogen; USA) medium supplemented with 5% Fetal bovine serum (PAA Laboratories Inc.; Canada) and 50 μg/ml penicillin-streptomycin. At 37° C., 5% CO ₂ was cultured under conditions.

BV-2 cells were dispensed into a 96-well plate at a concentration of 2.5 × 10 ⁴ cells/ml per well, and then the synthesized 2-halogen or haloalkyl 4,5-dihydroxy piperine analogues were treated at each concentration. It was pretreated for hours. Then, it was treated with LPS (200 ng/ml), which is a neuroinflammation inducing factor, and stimulated BV-2 cells for 24 hours, and the concentration of nitrite produced at this time was measured.

Nitrite (NO) was measured using a NO assay kit (Abcam) using a Grease reagent, and the measurement method was carried out according to the instruction manual of the kit. 100 µl of the cell culture solution and grease reagent were mixed, reacted for 10 minutes, and observed at an absorbance of 540 nm, and the concentration was finally confirmed using a standard curve.

The NO generation inhibitory effect of the compounds according to the present invention prepared in the above example was measured by the method described above, and the results are shown in Table 1 below.

compound Inhibitory effect (%) compound Inhibitory effect (%) compound Inhibitory effect (%) Example 2 90 Example 70 49 Example 119 11 Example 22 70 Example 71 12 Example 120 18 Example 23 12 Example 72 15 Example 121 15 Example 24 75 Example 73 23 Example 122 23 Example 25 23 Example 74 25 Example 123 25 Example 26 25 Example 75 16 Example 124 16 Example 27 16 Example 76 11 Example 125 11 Example 28 11 Example 77 25 Example 126 25 Example 29 25 Example 78 34 Example 127 34 Example 30 34 Example 79 23 Example 128 12 Example 31 23 Example 80 12 Example 129 33 Example 32 12 Example 81 22 Example 130 23 Example 33 28 Example 82 23 Example 131 56 Example 34 31 Example 83 24 Example 132 66 Example 35 24 Example 84 14 Example 133 78 Example 36 22 Example 85 26 Example 134 75 Example 37 26 Example 86 11 Example 135 59 Example 38 14 Example 87 13 Example 136 68 Example 39 8 Example 88 22 Example 137 11 Example 40 90 Example 89 60 Example 138 13 Example 41 80 Example 90 72 Example 139 14 Example 42 76 Example 91 55 Example 140 21 Example 43 67 Example 92 76 Example 141 12 Example 44 44 Example 93 55 Example 142 15 Example 45 50 Example 94 45 Example 143 23 Example 46 14 Example 95 12 Example 144 25 Example 47 26 Example 96 15 Example 145 16 Example 48 31 Example 97 23 Example 146 11 Example 49 26 Example 98 25 Example 147 25 Example 50 18 Example 99 16 Example 148 34 Example 51 22 Example 100 11 Example 149 12 Example 52 70 Example 101 25 Example 150 15 Example 53 65 Example 102 12 Example 151 23 Example 54 77 Example 103 15 Example 152 25 Example 55 47 Example 104 23 Example 153 16 Example 56 52 Example 105 25 Example 154 11 Example 57 50 Example 106 16 Example 155 25 Example 58 22 Example 107 11 Example 156 34 Example 59 23 Example 108 25 Example 157 16 Example 60 40 Example 109 34 Example 158 52 Example 61 18 Example 110 32 Example 159 21 Example 62 22 Example 111 22 Example 160 22 Example 63 15 Example 112 13 Example 161 70 Example 64 21 Example 113 67 Example 162 77 Example 65 13 Example 114 74 Example 163 67 Example 66 11 Example 115 59 Example 164 54 Example 67 23 Example 116 65 Example 165 57 Example 68 12 Example 117 55 Example 166 77 Example 69 22 Example 118 75

According to the results of Table 1, it can be seen that the analogue of the formula according to the present invention has an excellent NO inhibitory effect. Among them, Examples 2, 22, 24, 41, 42, and 54 , Example 90, Example 92 Example 114, Example 118, Example 133, Example 134 The effects of Example 162 and Example 166 were excellent.

Among them, the level of expression of Nurr1 in undifferentiated cells was measured, and as a result, Nurr1 was measured in Examples 2, 22, 24, 94, 111, 126, and 141.

[Test Example 2] Confirmation of cytotoxicity

In the present invention, in order to confirm whether the 2-halogen or haloalkyl 4,5-dihydroxy piperine analogue has cytotoxicity, BV-2 microglia at various concentrations (0.1, 1 and 10 μM) with or without LPS The effect of 2-halogen or haloalkyl 4,5-dihydroxy piperine analogues on the viability of cells was evaluated. A known method for measuring the degree of cytotoxicity according to the concentration of 2-halogen or haloalkyl 4,5-dihydroxy piperine analogue (Kim, JJ, et al. , Journal of Ethnopharmacology , 140:213-221, 2012) According to the BV-2 cell viability was measured.

First, BV-2 cells were dispensed into a 96-well plate so that each well was 2.5 × 10 ⁴ cells/ml, and then the synthesized 2-halogen or haloalkyl 4,5-dihydroxy piperine analog was treated at each concentration. Then, it was pretreated for 1 hour. Then, it was treated with LPS (200 ng/ml), which is a neuroinducing factor, and BV-2 cells were stimulated for 24 hours.

After 24 hours, the supernatant was removed, and then 100 µl DMEM medium containing MTT (500 µg/ml) was added to each well, followed by incubation at 37°C for 4 hours. After incubation, the supernatant was removed and DMSO (dimethyl sulfoxide); Compound Diluent/(1%) Vehicle control, Sigma, USA) was added to each well to dissolve formazan. Optical density was measured at 550 nm using a microplate reader (Tecan Trading AG, Switzerland), and the value was compared with the untreated group (control group) of 2-halogen or haloalkyl 4,5-dihydroxy piperine analogue.

As a result of treatment with various concentrations of 2-halogen or haloalkyl 4,5-dihydroxy piperine analog alone or LPS, it was confirmed that no cytotoxicity appeared.

[Test Example 3] Evaluation of the protective effect in C57BL/6 mice induced Parkinson's disease by administration of MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)

Seven-week-old C57BL/6 male mice (19-22 g) were sold in pre-sale and bred in the animal breeding room of Konkuk University for more than one week and adapted to be used. Water and feed were freely ingested, temperature (22±2 ℃), Humidity (53±3%) and contrast period (12 hours) were automatically adjusted.

(1) Protective effect in Parkinson's disease model by MPTP administration

Mice were divided into 5 groups, 4 for each group. Group 1 (control group) and group 2 (MPTP group) were orally administered 10% dimethyl sulfoxide at 5 mL per kg of mouse body weight once a day for 5 days, and group 3 was AJ-dissolved in 10% dimethyl sulfoxide. 2137 was orally administered once a day for 5 days in an amount of 10 and 30 mg/kg. Two hours after oral administration, the first group (control group) was intraperitoneally administered physiological saline at 5 mL per kg of mouse body weight for 5 days, and the second and third groups were dissolved in physiological saline at a concentration of 30 mg/kg of MPTP body weight for 5 days. It was administered intraperitoneally.

(1-1) Behavior test (pole test)

The day after the end of the 5-day administration, a pole test was performed on a rod having a height of 50 cm and a diameter of 1 cm. A C57bl/6 mouse was placed on a rod with its head facing up, and the time that the mouse turned 180° around the top and descended until the four legs touched the ground was measured. Each mouse was practiced 3 times, and then this experiment was performed 5 times.

(1-2) Evaluation of the protective activity of dopamine cells

After the mice of each group for which the pole test was completed were killed, brain tissues (striatum and substantia nigra) were isolated. After dehydration of the isolated brain tissue with hydrogen peroxide, Tyrosine hydroxylase (TH, millipore, rabbit origin 1:2000) was reacted overnight as a primary antibody, and biotinylated antirabbit (vector, goat origin) was used as a secondary antibody, followed by ABC reaction. Color was developed using diaminobenzidine through (ABC kit, vector). The protective effect of dopamine cells was confirmed by measuring the optical density in the striatum and counting the number of TH positive cells in the black matter.

[Test Example 4] Effect on Nurr1 mRNA expression in N27A cells

After dispensing N-27A cells ^{into a 6-well plate at 5 × 10 5} cells/well per well, the synthesized derivatives were cultured under various concentration conditions. After 6 hours, the cells were washed twice with ice cold PBS, and then 50 ml of RIPA buffer (PBS, 1% NP-40, 0.5% sodium deoxycholate, and 0.1% SDS, containing fresh protease inhibitor cocktail) or 100 ml was added to obtain total cell lysate. The Bio-Rad DC Protein Assay was used to determine the protein concentration.

40 µg of the total cell lysate was electrophoresed on a 10% SDS-PAGE gel, and then the separated protein was transferred to a PVDF membrane (Millipore, USA). In order to block non-specific binding, the PVDF membrane was reacted with PBS containing 5% skim milk for 1 hour. PVDF membrane was treated with anti-Nurr1 antibody (1:1000) and anti-β-actin antibody (1:2000) and reacted overnight at 4°C, followed by secondary antibody (horseradish peroxidase-conjugated secondary antibody; 1:1000). -2000) was treated and reacted for 1 hour.

Then, the optical density of the antibody-specific band was analyzed using an ECL detection kit and a luminescent image analyzer (LAS-3000, Fujifilm, Japan).

1 to 3 are results of Example 2 of the present application, and FIG. 4 is an experimental result of measuring Nurr1 expression after treatment with the compound of Example No.

Claims (8)

A compound represented by the following formula (1):
[Formula 1]

(Wherein, A is the following Formula 2, Formula 3, or Formula 4, and each of X and Y is independently selected from N, O, and S (C3-C7) heterocycloalkyl, or aromatic A ring may be formed or a ring may be formed by linking with (C3-C7)alkylene, and at least one of the carbon atoms of the (C3-C7)alkylene is NR, O or S, and R is (C1- C5) alkyl);
[Formula 2]

(Wherein, R ₁ or R ₂ are each independently OH, F, Cl, Br, I, CF ₃ , NO ₂ , CH ₃ , OMe, COOH, NMe ₂ , or NH ₂ ,
R ₃ is F, Cl, Br, OMe, or t-Bu,
R ₄ is F, Br, or CF ₃ );
[Formula 3]

(Wherein, Z is CH or N);
[Formula 4]

.
The method of claim 1,
The compound is represented by the following formula (5), a compound:
[Formula 5]

(Wherein, X and Y are each independently (C3-C7) heterocycloalkyl containing at least one hetero atom selected from N, O, and S, or to form an aromatic ring, or (C3-C7) alkylene At least one of the carbon atoms of the (C3-C7)alkylene is NR, O or S, and R is (C1-C5)alkyl,
R ₁ or R ₂ are each independently each independently OH, F, Cl, Br, I, CF ₃ , NO ₂ , CH ₃ , OMe, COOH, NMe ₂ , or NH ₂ ,
R ₃ is F, Cl, Br, OMe, or t-Bu,
R ₄ is F, Br, or CF ₃ ).
The method of claim 1,
The compound is represented by the following formula (6), a compound:
[Formula 6]

(Wherein, X and Y are each independently (C3-C7) heterocycloalkyl containing at least one hetero atom selected from N, O, and S, or to form an aromatic ring, or (C3-C7) alkylene At least one of the carbon atoms of the (C3-C7)alkylene is NR, O or S, and R is (C1-C5)alkyl,
Z is CH or N).
The compound of claim 1, wherein the compound is represented by the following formula (7):
[Formula 7]

(Wherein, X and Y are each independently (C3-C7) heterocycloalkyl containing at least one hetero atom selected from N, O, and S, or to form an aromatic ring, or (C3-C7) alkylene And at least one of the carbon atoms of the (C3-C7)alkylene is NR, O or S, and R is (C1-C5)alkyl).
A pharmaceutical composition for the prevention or treatment of neuroinflammatory diseases, comprising the compound according to any one of claims 1 to 4.
The method of claim 5,
The neuroinflammatory disease is selected from the group consisting of multiple sclerosis, neuroblastoma, ischemic stroke, Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, Huntington's disease, Creutzfeldt-Jakob disease, post-traumatic stress disorder, depression, schizophrenia and amyotrophic lateral sclerosis. That, a pharmaceutical composition for the prevention or treatment of neuroinflammatory diseases.
A pharmaceutical composition for preventing or treating neuroinflammatory diseases, comprising a compound represented by Chemical Formula 8 or Chemical Formula 9:
[Formula 8]

[Formula 9]

.
The method of claim 7,
The neuroinflammatory disease is selected from the group consisting of multiple sclerosis, neuroblastoma, ischemic stroke, Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, Huntington's disease, Creutzfeldt-Jakob disease, post-traumatic stress disorder, depression, schizophrenia, or amyotrophic lateral sclerosis. A pharmaceutical composition for preventing or treating neuroinflammatory diseases, characterized in that.

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