NOVEL COMPOUND FOR INHIBITING HISTONE ACETYLTRANSFERASE P300 AND ANTI-FIBROSIS COMPOSITION COMPRISING SAME

Abstract

The present invention relates to a novel compound, which enables additional hydrogen bonding with amino acids at specific positions of histone acetyltransferase (HAT) p300, through structure analysis of HAT p300. The novel compound of the present invention has a remarkably excellent effect of inhibiting HAT p300 activity and thus can be very effectively used in the prevention, alleviation, or treatment of fibrosis, which is a disease associated with activation of HAT p300.

Claims

1. A compound selected from a compound represented by the following Formula 1, and a pharmaceutically acceptable salt, an optical isomer, a hydrate, and a solvate thereof: ##STR00011## wherein: p and q are each independently an integer ranging from 1 to 5; r is an integer ranging from 1 to 4; m and n are each independently an integer ranging from 1 to 3, provided that m+n is not greater than 4; R.sub.1 is a carbamoyl group (—C(=O)(NH.sub.2)) or a halogen, wherein when R.sub.1 is present in a plural number, they are the same or different from each other; R.sub.2 and R.sub.3 are each independently a C.sub.1-C.sub.6 alkoxy group or a halogen, wherein when each of R.sub.2 and R.sub.3 is present in a plural number, they are the same or different from each other; and R.sub.4 comprises any one selected from the group consisting of a C.sub.1-C.sub.6 alkoxy group, an amine group (-NH.sub.2), a carbamoyl group, and a hydroxyl group (—OH), wherein when R.sub.4 is present in a plural number, they are the same or different from each other.

2. The compound of claim 1, wherein p and q are each independently an integer ranging from 1 to 3; r is an integer of 1 or 2; m and n are an integer of 1 or 2.

3. The compound of claim 1, wherein R.sub.1 is a carbamoyl group (—C(=O)(NH.sub.2)).

4. The compound of claim 1, wherein R.sub.4 comprises any one selected from an amine group, a carbamoyl group, or a hydroxyl group.

5. The compound of claim 1, wherein the compound comprises any one selected from the group consisting of the following compounds: ##STR00012## ##STR00013## ##STR00014## ##STR00015##

6. A method for inhibiting histone acetyltransferase p300, comprising administering a compound selected from a compound represented by the following Formula 1, and a pharmaceutically acceptable salt, an optical isomer, a hydrate, and a solvate thereof to a subject in need thereof: ##STR00016## wherein: p and q are each independently an integer ranging from 1 to 5; r is an integer ranging from 1 to 4; m and n are each independently an integer ranging from 1 to 3, provided that m+n is not greater than 4; Ri is a carbamoyl group (—C(=O)(NH.sub.2)) or a halogen, wherein when R.sub.1 is present in a plural number, they are the same or different from each other; R.sub.2 and R.sub.3 are each independently a C.sub.1-C.sub.6 alkoxy group or a halogen, wherein when each of R.sub.2 and R.sub.3 is present in a plural number, they are the same or different from each other; and R.sub.4 comprises any one selected from the group consisting of a C.sub.1-C.sub.6 alkoxy group, an amine group, a carbamoyl group, and a hydroxyl group (—OH), wherein when R.sub.4 is present in a plural number, they are the same or different from each other.

7. A pharmaceutical composition for preventing or treating a histone acetyltransferase p300-associated disease, comprising, as an active ingredient, a compound selected from a compound represented by the following Formula 1, and a pharmaceutically acceptable salt, an optical isomer, a hydrate, and a solvate thereof: ##STR00017## wherein: p and q are each independently an integer ranging from 1 to 5; r is an integer ranging from 1 to 4; m and n are each independently an integer ranging from 1 to 3, provided that m+n is not greater than 4; Ri is a carbamoyl group (—C(=O)(NH.sub.2)) or a halogen, wherein when R.sub.1 is present in a plural number, they are the same or different from each other; R.sub.2 and R.sub.3 are each independently a C.sub.1-C.sub.6 alkoxy group or a halogen, wherein when each of R.sub.2 and R.sub.3 is present in a plural number, they are the same or different from each other; and R.sub.4 comprises any one selected from the group consisting of a C.sub.1-C.sub.6 alkoxy group, an amine group (—NH.sub.2), a carbamoyl group, and a hydroxyl group (—OH), wherein when R.sub.4 is present in a plural number, they are the same or different from each other.

8. The pharmaceutical composition of claim 7, wherein the histone acetyltransferase p300-associated disease is fibrosis.

9. The pharmaceutical composition of claim 8, wherein the fibrosis comprises one or more selected from the group consisting of pulmonary fibrosis, uterine myoma, myelofibrosis, liver fibrosis, heart fibrosis, multiple sclerosis, kidney fibrosis, cystic fibrosis, neutropenia, skeletal muscle fibrosis, scleroderma, dermatomyositis, mediastinal fibrosis, and splenic fibrosis caused by sickle-cell anemia.

10. The pharmaceutical composition of claim 9, wherein the pulmonary fibrosis comprises one or more selected from the group consisting of idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, acute interstitial pneumonia, cryptogenic organizing pneumonia, a respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, interstitial pulmonary fibrosis, and diffuse pulmonary fibrosis.

11. A method for preventing or ameliorating a histone acetyltransferase p300-associated disease, comprising: administering or taking a food composition comprising a compound according to claim 1 to a subject person in need thereof.

12. A method for preventing or ameliorating a histone acetyltransferase p300-associated disease, comprising: administering or applying a cosmetic composition comprising a compound according to claim 1 to a subject in need thereof.

13. A method for preventing or treating a histone acetyltransferase p300-associated disease, comprising: administering a compound according to claim 1 to a target subject.

14. The method of claim 13, wherein the histone acetyltransferase p300-associated disease is fibrosis.

15. The method of claim 6, wherein the histone acetyltransferase p300-associated disease is fibrosis.

16. The method of claim 11, wherein the histone acetyltransferase p300-associated disease is fibrosis.

17. The method of claim 12, wherein the histone acetyltransferase p300-associated disease is fibrosis.

Description

BEST MODE

[0082] According to one embodiment of the present invention, there is provided a compound selected from a compound represented by the following Formula 1, and a pharmaceutically acceptable salt, an optical isomer, a hydrate, and a solvate thereof:

##STR00008##

[0083] wherein p and q are each independently an integer ranging from 1 to 5; r is an integer ranging from 1 to 4; m and n are each independently an integer ranging from 1 to 3, provided that m+n is not greater than 4; R.sub.1 is a carbamoyl group (—C(=O)(NH.sub.2)) or a halogen, wherein when R.sub.1 is present in a plural number, they are the same or different from each other; R.sub.2 and R.sub.3 are each independently a C.sub.1-C.sub.6 alkoxy group or a halogen, wherein when each of R.sub.2 and R.sub.3 is present in a plural number, they are the same or different from each other; and R.sub.4 includes any one selected from the group consisting of a C.sub.1-C.sub.6 alkoxy group, an amine group (—NH.sub.2), a carbamoyl group, and a hydroxyl group (—OH) , wherein when R.sub.4 is present in a plural number, they are the same or different from each other.

[0084] According to another embodiment of the present invention, there is provided a composition for preventing, ameliorating or treating a HAT p300-associated disease, which includes, as an active ingredient, a compound selected from a compound represented by Formula 1, and a pharmaceutically acceptable salt, an optical isomer, a hydrate, and a solvate thereof.

[0085] According to still another embodiment of the present invention, there is provided a method of preventing, ameliorating or treating a HAT p300-associated disease, which includes, as an active ingredient, a compound selected from a compound represented by Formula 1, and a pharmaceutically acceptable salt, an optical isomer, a hydrate, and a solvate thereof.

Mode for Invention

[0086] Hereinafter, the present invention will be described in detail with reference to the following examples. It will be apparent to those skilled in the art that the following examples are merely provided to exemplify the present invention, and are not intended to limit the scope of the present invention without departing from the scope of the present invention.

EXAMPLES

[0087] [Example 1] Confirmation of Protein Expression Level in Tissue of Fibrosis Patient

[0088] Tissues obtained from a patient with idiopathic pulmonary fibrosis or a normal person were fixed in 10% formalin, and embedded in paraffin, and a 7 μm-thick section was attached to a slide. Thereafter, the section was deparaffinized using xylene, and treated with a high concentration to a low concentration of ethanol. Then, immunostaining was performed using antibodies specific to HAT p300 (histone acetyltransferase p300), GCN5 (histone acetyltransferase GCN5), and PCAF (P300/CBP-associated factor), and an expression level of each proteins was measured using an optical microscope. The results are shown in FIGS. 1 to 3.

[0089] As shown in FIGS. 1 to 3, it was confirmed that among the histone acetyltransferases (hereinafter referred to as “‘HAT’”) p300, GCN5, and PCAF, the expression of p300 increased in the tissue from the patient with idiopathic pulmonary fibrosis, compared to the tissue obtained from the normal person.

[0090] Based on the results, it can be seen that the fibrosis is able to be effectively treated when the expression or function of p300 is specifically inhibited because especially p300 among the histone acetyltransferases is present at a high level in the fibrosis such as idiopathic pulmonary fibrosis, compared to the normal tissue.

[0091] [Example 2] Screening of p300 Activity Inhibitors

[0092] [2-1] Primary Screening

[0093] Candidates 1 to 67, which are HAT inhibitors manufactured based on the PCAF structure, and HAT-24, HAT-26, and HAT-28 were diluted to 100 μM, and the degree of inhibition of HAT activity of p300 (inhibitory activity) was then determined using a kit for measuring HAT activity (Biovision, Cat No. K332, U.S.A) according to the method provided by the manufacturer. The results are shown in FIG. 4. Here, the tissue was treated with C646 (HAT inhibitor) as a positive control.

[0094] As shown in FIG. 4, 80% of the HAT activity was inhibited by Candidates 1 to 14, but Candidate 15 to 67, HAT-25, HAT-26, and HAT-28 had a HAT activity inhibitory effect of only 20% to 50%.

[0095] [2-2] Secondary Screening

[0096] Candidates 1 to 14 having a good HAT activity inhibitory effect in Section [2-1] were diluted to concentrations of 0.5 μM, 1 μM, 10 μM, and 100 μM. Thereafter, the degree of inhibition of HAT activity was determined in the same manner as in Section [2-1]. The results are shown in FIG. 5 and Table 1.

TABLE-US-00001 TABLE 1 Candidate 1 2 3 4 5 6 7 8 9 10 11 12 13 14 IC.sub.50 50.84 44.09 28.9 12.12 32.4 10.14 27.65 35.52 9.01 13.12 41.67 0.953 32.84 35.82 (μM)

[0097] As shown in FIG. 5 and Table 1, it was confirmed that among Candidates 1 to 14, Candidate 12 (HAT-12) had an IC.sub.50 of 0.953.

[0098] [Example 3] Structural Analysis of Candidate 12

[0099] To obtain information on the structure-activity correlation of a candidate through a molecular docking simulation, a molecule model was established using a co-crystal structure (pdb: 3biy) of a HAT p300 domain and its substrate inhibitor Lys-CoA. The Lys-CoA was finally re-docked into the molecule model thus established, and the co-crystal structures were compared. As a result, it was confirmed that the candidates had a similar binding pattern. From the results, the accuracy of the docking results was evaluated (FIG. 6), the main residues participating in the binding between the HAT p300 domain and the Lys-CoA were analyzed (FIG. 7), and a molecular docking simulation was performed with Candidate 12 (HAT-12) (FIG. 8).

[0100] As shown in FIG. 6, it was confirmed that there was a high similarity between a predicted binding pattern of the HAT p300 domain-ligand (Lys-CoA) and the co-crystal structure.

[0101] As shown in FIG. 7, it was confirmed that when the main residues participating in the binding between the Lys-CoA and the HAT p300 domain were analyzed, hydrogen bonds were observed at R1410, T1411, W1466, Y1467, L1398, S1400, I1457, W1436, and Y1397. Among these, the interactions with R1410, T1411, W1466, and Y1467 were important for drug inhibitory activity. Especially, it can be seen that W1466 played a key role in drug inhibitory activity (see, for example, Erin M.Bowers et al., Virtual Ligand Screening of the p300/CBP Histone Acetyltransferase: Identification of a Selective Small Molecule Inhibitor, Chem Biol. 2010 May 28; 17(5): 471-82).

[0102] As shown in FIG. 8, it was confirmed that when the main residues participating in the binding between Candidate 12 and the HAT p300 domain were analyzed, the interactions with R1410, T1411, W1466, and Y1467 were not observed, but e hydrogen bonds were formed with L1398 and S1400.

[0103] From the results, it can be expected that L1398 and S1400 also play an important role in drug inhibitory activity. Also, it can be seen that when the additional hydrogen bonding with R1410, T1411, W1466, and Y1467 was hindered, HAT p300 inhibitory activity was further enhanced.

[0104] Based on these results, Synthesis Examples 1 to 24 (A20 to A43) having the above-described characteristics were prepared to further enhance HAT p300 inhibitory activity, as follows.

[0105] [Synthesis Examples 1 to 24] Preparation of Novel Compounds for Inhibiting Histone Acetyltransferase p300

##STR00009##

[0106] [Synthesis Method 1] Compounds 1 to 17

[0107] Substituted 4-hydroxybenzaldehyde (1 equivalent) and its corresponding substituted benzyl chloride (1 equivalent), and K.sub.2CO.sub.3 (1 equivalent) were cultured in a DMF solvent at 80° C. for an hour. The reaction mixture was cooled to room temperature, and extracted using ethyl acetate. The extract was washed with water, NaHCO.sub.3, and brine, and then dried over MgSO.sub.4. Thereafter, the solvent was completely removed under reduced pressure, and silica gel chromatography was then performed to obtain Compounds 1 to 17 as O-benzylated compounds (see Table 2).

TABLE-US-00002 TABLE 2 Compound R R.sub.1 R.sub.2 1 3-chlorophenyl OCH.sub.3 Cl 2 3-chlorophenyl OCH.sub.3 Br 3 3-chlorophenyl OCH.sub.3 I 4 3-ethoxy carbonylphenyl OCH.sub.3 Cl 5 3-ethoxy carbonylphenyl OCH.sub.3 Br 6 3-ethoxy carbonylphenyl OCH.sub.3 I 7 3-cyanophenyl OCH.sub.3 Cl 8 3-cyanophenyl OCH.sub.3 Br 9 3-cyanophenyl OCH.sub.3 I 10 3-fluorophenyl OCH.sub.3 Cl 11 3-chlorophenyl OCH.sub.3 H 12 4-carbamoylphenyl OCH.sub.3 Cl 13 4-carbamoylphenyl OCH.sub.3 Br 14 4-carbamoylphenyl OCH.sub.3 I 15 3-carbamoylphenyl OCH.sub.3 Cl 16 3-carbamoylphenyl OCH.sub.3 Br 17 3-carbamoylphenyl OCH.sub.3 I

[0108] [Compound 1] 3-chloro-4-(3-chlorobenzyloxy)-5-methoxybenzaldehyde

[0109] 5-chlorovanillin (1.00 g, 5.36 mmol) and 3-chlorobenzyl chloride (0.70 g, 5.36 mmol) were used to obtain Compound 1 as an ivory solid (1.50 g, 96.5%).

[0110] R.sub.f 0.54 (ethyl acetate:n-hexane=1:3); .sup.1H-NMR (CDCl.sub.3, 400 MHz) δ 3.95 (s, 3H), 5.13 (s, 2H), 7.30-7.32 (m, 2H), 7.36 (d, J=2.0 Hz, 1H), 7.37-7.39 (m, 1H), 7.51 (d, J=2.0 Hz, 1H), 7.53-7.54 (m, 1H), 9.86 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 100 MHz) 56.5, 74.3, 109.6, 125.9, 126.4, 128.5, 128.6, 129.4, 129.9, 132.9, 134.5, 138.7, 149.4, 154.5, 190.1 ppm.

[0111] [Compound 2] 3-bromo-4-(3-chlorobenzyloxy)-5-methoxybenzaldehyde

[0112] 5-bromovanillin (1.00 g, 4.33 mmol) and 3-chlorobenzyl chloride (0.58 g, 5.36 mmol) were used to obtain Compound 2 as an ivory solid (1.50 g, 96.5%).

[0113] R.sub.f0.65 (ethyl acetate:n-hexane=1:3); .sup.1H-NMR (CDCl.sub.3, 400 MHz) δ 3.94 (s, 3H), 5.12 (s, 2H), 7.30-7.32 (m, 2H), 7.38 (dd, J=8.4, 1.2 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.54-7.56 (m, 1H), 7.66 (d, J=2.0 Hz, 1H), 9.85 (s, 1H); .sup.13C-NMIt (CDCl.sub.3, 100 MHz) 56.5, 74.2, 110.3, 118.5, 126.5, 128.6, 129.0, 129.9, 133.5, 134.5, 138.7, 150.4, 154.4, 190.0 ppm.

[0114] [Compound 3] 4-((3-chlorobenzyl)oxy)-3-iodo-5-methoxybenzaldehyde

[0115] 5-iodovanillin (1.00 g, 3.60 mmol) and 3-chlorobenzyl chloride (0.58 g, 5.36mmo1) were used to obtain Compound 3 as an ivory solid (1.423 g, 98.1%).

[0116] R.sub.f0.67 (ethyl acetate:n-hexane=1:3); .sup.1hd-NMR (CDCl.sub.3, 400 MHz) δ 3.94 (s, 3H), 5.10 (s, 2H), 7.31-7.33 (m, 2H), 7.41 (dd, J=8.4, 1.2 Hz, 1H), 7.43 (d, J=1.6 Hz, 1H), 7.57-7.58 (m, 1H), 7.87 (d, J=1.6 Hz, 1H), 9.84 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 100 MHz) 56.4, 74.0, 92.8, 111.2, 126.6, 128.7, 128.8, 129.9, 134.4, 134.5, 135.1, 138.7, 152.9, 153.2, 189.9 ppm.

[0117] [Compound 4] Ethyl 3-((2-chloro-4-formyl-6-methoxyphenoxy)methyl)benzoate

[0118] 5-chlorovanillin (1.00 g, 5.36 mmol) and ethyl 3-(chloromethyl)benzoate (1.06 g, 5.36 mmol) were used to obtain Compound 4 as a yellow solid (1.18 g, 63.1%).

[0119] R.sub.f0.39 (ethyl acetate:n-hexane =1:3); .sup.1H-NMR (CDCl.sub.3, 400 MHz) δ 1.41 (t, J=7.2 Hz, 3H), 3.95 (s, 3H), 4.39 (q, J=7.2 Hz, 2H), 5.21 (s, 2H), 7.30 (ddd, J=7.6, 1.2, 1.2 Hz, 1H), 7.36 (d, J=1.6 Hz, 1H), 7.46 (dd, J=7.6, 7.6 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 8.02 (ddd, J=7.6, 1.2, 1.2 Hz, 1H), 8.18 (dd, J=1.2, 1.2 Hz, 1H), 9.85 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 100 MHz) 14.6, 56.5, 61.3, 74.7, 109.6, 126.0, 128.7, 129.4, 129.6, 129.7, 130.9, 132.8, 132.9, 137.1, 149.5, 154.6, 166.6, 190.2 ppm.

[0120] [Compound 5] Ethyl 3-((2-bromo-4-formyl-6-methoxyphenoxy)methyl)benzoate

[0121] 5-bromovanillin (1.00 g, 4.33 mmol) and ethyl 3-(chloromethyl)benzoate (0.86 g, 4.33 mmol) were used to obtain Compound 5 as a pale yellow solid (1.53 g, 90.1%).

[0122] R.sub.f0.35 (ethyl acetate:n-hexane=1:3); .sup.1H-NMR (CDCl.sub.3, 400 MHz) δ1.41 (t, J=7.2 Hz, 3H), 3.95 (s, 3H), 4.39 (q, J=7.2 Hz, 2H), 5.21 (s, 2H), 7.40 (d, J=2.0 Hz, 1H), 7.46(dd, J=7.6, 7.6 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.75 (ddd, J=7.6, 1.2, 1.2 Hz, 1H), 8.02 (ddd, J=7.6, 1.2, 1.2 Hz, 1H), 8.19 (dd, J=1.2, 1.2 Hz, 1H), 9.85 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 100 MHz) 14.6, 56.5, 61.3, 74.6, 110.3, 118.6, 128.7, 129.0, 129.7, 130.9, 133.0, 133.4, 137.1, 150.6, 154.4, 166.6, 190.0 ppm.

[0123] [Compound 6] Ethyl 3-((4-formyl-2-iodo-6-methoxyphenoxy)methyl)benzoate

[0124] 5-iodovanillin (1.00 g, 3.60 mmol) and ethyl 3-(chloromethyl)benzoate (0.71 g, 3.60 mmol) were used to obtain Compound 6 as a pale yellow solid (1.41 g, 88.8%).

[0125] R.sub.f0.39 (ethyl acetate:n-hexane=1:3); .sup.1H-NMR (CDCl.sub.3, 400 MHz) δ 1.41 (t, J=7.2 Hz, 3H), 3.95 (s, 3H), 4.39 (q, J=7.2 Hz, 2H), 5.21 (s, 2H), 7.43 (d, J=1.6 Hz, 1H), 7.47 (dd, J=7.6, 7.6 Hz, 1H), 7.78 (ddd, J=7.6, 1.2, 1.2 Hz, 1H), 7.86 (d, J=1.6 Hz, 1H), 8.02 (ddd, J=7.6, 1.2, 1.2 Hz, 1H), 8.22 (dd, J=1.6, 1.6 Hz, 1H), 9.83 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 100 MHz) 14.6, 56.3, 61.3, 74.4, 92.8, 111.2, 128.7, 129.7, 129.8, 130.9, 133.1, 134.3, 135.1, 137.1, 152.9, 153.2, 166.6, 189.9 ppm.

[0126] [Compound 7] 3-((2-chloro-4-formyl-6-methoxyphenoxy)methyl)benzonitrile

[0127] 5-chlorovanillin (1.00 g, 5.36 mmol) and ethyl 3-(bromomethyl)benzonitrile (1.05 g, 5.36 mmol) were used to obtain Compound 7 as a white solid (1.30 g, 80.5%).

[0128] R.sub.f0.25 (ethyl acetate:n-hexane=1:3); .sup.1H-NMR (CDCl.sub.3, 400 MHz) δ 3.96 (s, 3H), 5.17 (s, 2H), 7.38 (d, J=2.0 Hz, 1H), 7.50 (dd, J=7.6, 7.6 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.64 (ddd, J=7.6, 1.6, 1.6 Hz, 1H), 7.75 (ddd, J=7.6, 1.6, 1.6 Hz, 1H), 7.84 (dd, J=1.6, 1.2 Hz, 1H), 9.87 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 100 MHz) 56.6, 73.8, 109.6, 112.8, 118.9, 126.0, 129.4, 129.5, 131.8, 132.1, 132.5, 133.1, 138.4, 149.1, 154.5, 190.1 ppm.

[0129] [Compound 8] 3-((2-bromo-4-formyl-6-methoxyphenoxy)methyl)benzonitrile

[0130] 5-bromovanillin (1.00 g, 4.33 mmol) and ethyl 3-(bromomethyl)benzonitrile (0.85 g, 4.33 mmol) were used to obtain Compound 8 as a white solid (1.53 g, 83.8%).

[0131] R.sub.f0.24 (ethyl acetate:n-hexane=1:3); .sup.1H-NMR (CDCl.sub.3, 400 MHz) δ 3.95 (s, 3H), 5.16 (s, 2H), 7.42 (d, J=2.0 Hz, 1H), 7.50 (dd, J=8.0, 7.6 Hz, 1H), 7.64 (ddd, J=7.6, 2.0, 1.6 Hz, 1H), 7.67 (d, J=1.6 Hz, 1H), 7.70 (ddd, J=8.0, 1.6, 1.2 Hz, 1H), 7.86 (dd, J=1.6, 1.6 Hz, 1H), 9.86 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 100 MHz) 56.5, 73.6, 110.3, 112.8, 118.5, 118.9, 129.0, 129.5, 131.9, 132.1, 132.6, 133.7, 138.4, 150.1, 154.3, 189.9 ppm.

[0132] [Compound 9] 3-((4-formyl-2-iodo-6-methoxyphenoxy)methyl)benzonitrile

[0133] 5-iodovanillin (1.00 g, 3.60 mmol) and ethyl 3-(bromomethyl)benzonitrile (0.71 g, 3.60 mmol) were used to obtain Compound 9 as a white solid (1.20 g, 84.4%).

[0134] R.sub.f0.27 (ethyl acetate:n-hexane=1:3); .sup.1H-NMR (CDCl.sub.3, 400 MHz) δ 3.95 (s, 3H), 5.15 (s, 2H), 7.44 (d, J=2.0 Hz, 1H), 7.51 (dd, J=8.0, 7.6 Hz, 1H), 7.65 (ddd, J=7.6, 1.6, 1.2 Hz, 1H), 7.78 (ddd, J=7.6, 1.6, 1.2 Hz, 1H), 7.88 (d, J=2.0 Hz, 1H), 7.89 (dd, J=1.6, 1.2 Hz, 1H), 9.85 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 100 MHz) 56.4, 73.4, 92.7, 111.3, 112.8, 118.9, 129.5, 132.0, 132.1, 132.7, 134.6, 135.0, 138.3, 152.5, 153.2, 189.8 ppm.

[0135] [Compound 10] 3-chloro-4-((3-fluorobenzyl)oxy)-5-methoxybenzaldehyde

[0136] 5-chlorovanillin (1.00 g, 5.36 mmol) and ethyl 3-fluorobenzyl chloride (0.78 g, 5.36 mmol) were used to obtain Compound 10 as a white solid (1.15 g, 72.8%).

[0137] R.sub.f0.58 (ethyl acetate:n-hexane=1:3); .sup.1H-NMR (CDCl.sub.3, 400 MHz) δ 3.95 (s, 3H), 5.15 (s, 2H), 7.00-7.05 (m, 1H), 7.24-7.28 (m, 2H), 7.34 (dd, J=8.0, 2.0 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.51 (d, J=2.0 Hz, 1H), 9.85 (s, 1H); .sup.13C-NMR (CDCl.sub.13, 100 MHz) 56.5, 74.4, 109.7, 115.3, 115.5, 123.8, 126.0, 130.1, 132.9, 139.3, 149.5, 154.6, 161.8, 164.3, 190.2 ppm.

[0138] [Compound 11] 4-((3-chlorobenzyl)oxy)-3-methoxybenzaldehyde

[0139] Vanillin (1.00 g, 6.57 mmol) and 3-methoxybenzyl chloride (1.03 g, 6.57 mmol) were used to obtain Compound 11 as a yellow semisolid (1.48 g, 99.6%).

[0140] R.sub.f0.45 (ethyl acetate:n-hexane=1:3); .sup.1H-NMR (CDCl.sub.3, 400 MHz) δ 3.95 (s, 3H), 5.19 (s, 2H), 6.95 (d, J=8.4 Hz, 1H), 7.29-7.32 (m, 3H), 7.39 (dd, J=8.0, 1.6 Hz, 1H), 7.43-7.44 (m, 2H), 9.84 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 100 MHz) 56.2, 70.2, 109.7, 112.6, 125.4, 126.6, 127.4, 128.6, 130.2, 130.7, 134.8, 138.3, 150.3, 153.4, 191.0 ppm.

[0141] [Compound 12] 4-((2-chloro-4-formyl-6-methoxyphenoxy)methyl)benzamide

[0142] 5-chlorovanillin (0.18 g, 0.96 mmol) and 4-(chloromethyl)benzamide (0.16 g, 0.96 mmol) were used to obtain Compound 12 as a white solid (0.22 g, 73.2%).

[0143] R.sub.f0.25 (ethyl acetate:n-hexane=1:1); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 3.88 (s, 3H), 5.12 (s, 2H), 7.29 (d, J=1.6 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.83 (d, J=8.0 Hz, 2H), 9.78 (s, 1H); .sup.13C-NMR (400 MHz, DMSO-d.sub.6) 55.2, 73.7, 109.5, 124.5, 127.2, 127.4, 128.3, 132.0, 133.2, 139.4, 148.4, 153.7, 168.4, 189.4 ppm.

[0144] [Compound 13] 4-((2-bromo-4-formyl-6-methoxyphenoxy)methyl)benzamide 5-bromovanillin (0.18 g, 0.79 mmol) and 4-(chloromethyl)benzamide (0.13 g, 0.79 mmol) were used to obtain Compound 13 as a white solid (0.20 g, 73.2%).

[0145] R.sub.f0.16 (ethyl acetate:n-hexane=1:1); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 3.88 (s, 3H), 5.11 (s, 2H), 7.34 (d, J=2.0 Hz, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.60 (d, J=1.6 Hz, 1H), 7.83 (d, J=8.4 Hz, 2H), 9.78 (s, 1H); .sup.13C-NMR (400 MHz, DMSO-d.sub.6) 55.7, 73.6, 100.1, 117.6, 127.2, 127.4, 127.5, 132.6, 133.2, 139.4, 149.5, 153.5, 168.4, 189.3 ppm.

[0146] [Compound 14] 4-((4-formyl-2-iodo-6-methoxyphenoxy)methyl)benzamide

[0147] 5-iodovanillin (0.26 g, 0.94 mmol) and 4-(chloromethyl)benzamide (0.16 g, 0.94 mmol) were used to obtain Compound 14 as a white solid (0.28 g, 72.4%).

[0148] R.sub.f0.10 (ethyl acetate:n-hexane =1:1); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 3.87 (s, 3H), 5.10 (s, 2H), 7.36 (d, J=2.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 2H), 7.79 (d, J=1.6 Hz, 1H), 7.83 (d, J=8.4 Hz, 2H), 9.76 (s, 1H); .sup.13C-NMR (400 MHz, DMSO-d.sub.6) 55.6, 73.4, 92.1, 111.0, 127.2, 127.6, 133.1, 133.5, 133.6, 139.4, 151.9, 152.3, 168.4, 189.1 ppm.

[0149] [Compound 15] 3-((2-chloro-4-formyl-6-methoxyphenoxy)methyl)benzamide

[0150] 5-chlorovanillin (0.40 g, 2.14 mmol) and 3-(chloromethyl)benzamide (0.36 g, 2.14 mmol) were used to obtain Compound 15 as a white solid (0.32 g, 45.0%).

[0151] R.sub.f0.10 (ethyl acetate:n-hexane=1:1); .sup.1H-NMR (CDCl.sub.3, 400 MHz) δ 3.88 (s, 3H), 5.11 (s, 2H), 7.30 (d, J=2.0 Hz, 1H), 7.37 (dd, J=7.6, 7.6 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.77 (ddd, J=7.6, 1.6, 1.2 Hz, 1H), 794 (dd, J=1.6, 1.6 Hz, 1H), 9.78 (s, 1H);); .sup.13C-NMR (400 MHz, DMSO-d.sub.6) 56.4, 74.1, 110.9, 124.1, 127.2, 127.6, 127.9, 128.2, 131.1, 132.6, 134.4, 136.6, 148.2, 154.0, 167.6, 191.1 ppm.

[0152] [Compound 16] 3-((2-bromo-4-formyl-6-methoxyphenoxy)methyl)benzamide

[0153] 5-bromovanillin (0.18 g, 0.79 mmol) and 3-(chloromethyl)benzamide (0.13 g, 0.79 mmol) were used to obtain Compound 16 as a white solid (0.20 g, 73.2%).

[0154] R.sub.f0.16 (ethyl acetate:n-hexane=1:1); .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ 3.88 (s, 3H), 5.10 (s, 2H), 7.34 (d, J=2.0 Hz, 1H), 7.38 (dd, J=8.0, 8.0 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.62 (ddd, J=7.6, 1.2, 1.2 Hz 1H), 7.78 (ddd, J=7.6, 1.2, 1.2 Hz 1H), 7.96 (dd, J=1.2, 1.2 Hz, 1H), 9.78 (s, 1H); .sup.13C-NMR (400 MHz, DMSO-d.sub.6) 55.7, 73.8, 110.0, 117.7, 126.9, 127.2, 127.6, 127.9, 131.0, 132.6, 133.5, 136.3, 149.5, 153.6, 168.5, 189.3 ppm.

[0155] [Compound 17] 3-((4-formyl-2-iodo-6-methoxyphenoxy)methyl)benzamide

[0156] 5-iodovanillin (0.26 g, 0.94 mmol) and 3-(chloromethyl)benzamide (0.16 g, 0.94 mmol) were used to obtain Compound 17 as a white solid (0.28 g, 72.4%).

[0157] R.sub.f0.10 (ethyl acetate:n-hexane=1:1); .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ 3.88 (s, 3H), 5.09 (s, 2H), 7.36 (d, J=2.0 Hz, 1H), 7.38 (dd, J=8.0, 8.0 Hz, 1H), 7.65 (ddd, J=7.6, 1.6, 1.6 Hz 1H), 7.78 (ddd, J=7.6, 1.2, 1.2, Hz 1H), 7.79 (d, J=2.0 Hz, 1H), 7.98 (dd, J=1.6, 1.6 Hz, 1H), 9.76 (s, 1H); .sup.13C-NMR (400 MHz, DMSO-d.sub.6) 55.6, 73.6, 92.2, 111.0, 126.9, 127.3, 127.8, 131.1, 133.5, 113.6, 133.7, 136.2, 151.9, 152.4, 168.5, 189.1 ppm.

[0158] [Synthesis Method 2] Synthesis Examples 1 to 24(A20 to A43)

##STR00010##

[0159] The substituted O-benzylated benzaldehyde derivative was mixed with an acetophenone derivative using 10 mL of ethanol as a solvent, and 50% NaOH (2.0 to 5.0 equivalents) was added thereto. Thereafter, the mixture was stirred at room temperature for 24 hours, and water was further added thereto. Then, the mixture was extracted using ethyl acetate, and the extract was washed with water, NaHCO.sub.3, and brine, and then dried over MgSO.sub.4. Then, the solvent was completely removed under reduced pressure, and silica gel chromatography was then performed to obtain Synthesis Examples 1 to 24 (see Table 3).

TABLE-US-00003 TABLE 3 Synthesis Example R.sub.1 R.sub.2 R.sub.3 R.sub.4 1 (A20) 3-aminophenyl OCH.sub.3 Cl 3-carbamoylphenyl 2 (A21) 3-aminophenyl OCH.sub.3 Br 3-carbamoylphenyl 3 (A22) 3-aminophenyl OCH.sub.3 I 3-carbamoylphenyl 4 (A23) 3-carbamoylphenyl OCH.sub.3 Cl 3-carbamoylphenyl 5 (A24) 3-carbamoylphenyl OCH.sub.3 Br 3-carbamoylphenyl 6 (A25) 3-carbamoylphenyl OCH.sub.3 I 3-carbamoylphenyl 7 (A26) 3-hydroxyphenyl OCH.sub.3 Cl 3-carbamoylphenyl 8 (A27) 3-hydroxyphenyl OCH.sub.3 Br 3-carbamoylphenyl 9 (A28) 3-hydroxyphenyl OCH.sub.3 I 3-carbamoylphenyl 10 (A29) 3,4,5-trimethoxyphenyl OCH.sub.3 Cl 3-chlorophenyl 11 (A30) 3,4,5-trimethoxyphenyl OCH.sub.3 Br 3-chlorophenyl 12 (A31) 3,4,5-trimethoxyphenyl OCH.sub.3 1 3-chlorophenyl 13 (A32) 3,4,5-trimethoxyphenyl OCH.sub.3 Cl 3-carbamoylphenyl 14 (A33) 3,4,5-trimethoxyphenyl OCH.sub.3 Br 3-carbamoylphenyl 15 (A34) 3,4,5-trimethoxyphenyl OCH.sub.3 1 3-carbamoylphenyl 16 (A35) 3-hydroxyphenyl OCH.sub.3 Cl 3-chlorophenyl 17 (A36) 3-hydroxyphenyl OCH.sub.3 Br 3-chlorophenyl 18 (A37) 3-hydroxyphenyl OCH.sub.3 I 3-chlorophenyl 19 (A38) 3-aminophenyl OCH.sub.3 Cl 3-chlorophenyl (3-aminophenyl) 20 (A39) 3-aminophenyl OCH.sub.3 Br 3-chlorophenyl 21 (A40) 3-aminophenyl OCH.sub.3 I 3-chlorophenyl 22 (A41) 3-carbamoylphenyl OCH.sub.3 Cl 3-chlorophenyl 23 (A42) 3-carbamoylphenyl OCH.sub.3 Br 3-chlorophenyl 24 (A43) 3-carbamoylphenyl OCH.sub.3 I 3-chlorophenyl

[0160] [Synthesis Example 1] (E)-3-((4-(3-(3-aminophenyl)-3-oxoprop-1-en-1-yl)-2-chloro -6-methoxyphenoxy)methyl) benzamide (A20)

[0161] This synthesis was performed using Compound 15 (200 mg, 0.63 mmol) and 3-aminoacetophenone (85 mg, 0.63 mmol), and the resulting product was extracted by silica gel column chromatography (elution: ethyl acetate:dichloromethane=4:1) to obtain Synthesis Example 1 (A20) as a yellow solid (78 mg, 28.6%).

[0162] R.sub.f0.42 (ethyl acetate:dichloromethane=4:1); .sup.1H-NMR (400MHz, DMSO-d.sub.6) δ 3.95 (s, 3H), 5.11 (s, 2H), 5.36 (s, 2H), 6.86 (ddd, J=7.6, 2.0, 0.8 Hz, 1H), 7.21 (dd, J=8.0, 7.6 Hz, 1H), 7.27 (dd, J=2.0, 2.0 Hz, 1H), 7.37-7.39 (m, 2H), 7.47 (dd, J=8.0, 7.6 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.62 (d, J=1.6 Hz, 1H), 7.63 (d, J=15.6 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.83 (d, J=15.6 Hz, 1H), 7.86 (ddd, J=7.6, 1.6, 1.2 Hz, 1H), 8.00 (br s, 2H).

[0163] [Synthesis Example 2] (E)-3-((4-(3-(3-aminophenyl)-3-oxoprop-1-en-l-yl)-2-bromo-6-methoxyphenoxy)methyl) benzamide (A21)

[0164] This synthesis was performed using Compound 16 (150 mg, 0.41 mmol) and 3-aminoacetophenone (49 mg, 0.36 mmol), and the resulting product was extracted by silica gel column chromatography (elution: ethyl acetate:dichloromethane=4:1) to obtain Synthesis Example 2 (A21) as a yellow solid (35 mg, 20.1%).

[0165] R.sub.f0.29 (ethyl acetate:dichloromethane=4:1); .sup.1H-NMR (400MHz, DMSO-d.sub.6) δ 3.95 (s, 3H), 5.09 (s, 2H), 5.36 (s, 2H), 6.85 (ddd, J=8.0, 2.4, 1.2 Hz, 1H), 7.21 (dd, J=8.0, 7.6 Hz, 1H), 7.26 (dd, J=2.0, 2.0 Hz, 1H), 7.37-7.39 (m, 2H), 7.48 (dd, J=7.6, 7.6 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.62 (d, J=16.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.82 (d, J=15.6 Hz, 1H), 7.85 (ddd, J=8.0, 1.2, 1.2 Hz, 1H), 8.00 (br s, 2H); .sup.13C-NMR (100 MHz, DMSO-d.sub.6) 51.7, 69.1, 107.8, 108.2, 111.8, 112.7, 114.0, 118.3, 120.2, 122.4, 122.8, 123.4, 124.4, 126.3, 127.7, 129.6, 132.1, 133.6, 137.0, 141.1, 144.4, 148.8, 162.9, 184.7 ppm.

[0166] [Synthesis Example 3] (E)-3-((4-(3-(3-aminophenyl)-3-oxoprop-1-en-l-yl)-2-iodo -6-methoxyphenoxy)methyl) benzamide (A22)

[0167] This synthesis was performed using Compound 17 (150 mg, 0.36 mmol) and 3-aminoacetophenone (49 mg, 0.36 mmol), and the resulting product was extracted by silica gel column chromatography (elution: ethyl acetate:dichloromethane=4:1) to obtain Synthesis Example 3 (A22) as a yellow solid (13 mg, 6.8%).

[0168] R.sub.f0.38 (ethyl acetate:dichloromethane=4:1); .sup.1H-NMR (400MHz, DMSO-d.sub.6) δ 3.94 (s, 3H), 5.06 (s, 2H), 5.35 (s, 2H), 6.85 (ddd, J=7.6, 2.0, 0.8 Hz, 1H), 7.21 (dd, J=7.6, 7.6 Hz, 1H), 7.26 (dd, J=2.0, 2.0 Hz, 1H), 7.36-7.39 (m, 2H), 7.49 (dd, J=7.6, 7.6 Hz, 1H), 7.60 (d, J=16.0 Hz, 1H), 7.61 (d, J=1.6 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.80 (d, J=15.6 Hz, 1H), 7.85 (ddd, J=8.0, 1.6, 1.2 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H), 8.06 (br s, 2H).

[0169] [Synthesis Example 4] (E)-3-(3-(4-((3-carbamoylbenzyl)oxy)-3-chloro-5-methoxyphenyl)acryloyl) benzamide (A23)

[0170] This synthesis was performed using Compound 15 (100 mg, 0.31 mmol) and 3-carbamoylacetophenone (51 mg, 0.31 mmol), and the resulting product was extracted by silica gel column chromatography (elution: methanol:dichloromethane=1:10) to obtain Synthesis Example 4 (A23) as a pale yellow solid (60 mg, 41.3%).

[0171] R.sub.f0.50 (methanol:dichloromethane=1:9); .sup.1H-NMR (400MHz, DMSO-d.sub.6) δ 3.89 (s, 3H), 5.06 (s, 2H), 7.12 (d, J=2.0 Hz, 1H), 7.32 (d, J=1.6 Hz, 1H), 7.37 (dd, J=8.0, 7.6 Hz, 1H), 7.52 (dd, J=8.0, 7.6 Hz, 1H), 7.57 (d, J=16.0 Hz, 1H), 7.61 (d, J=8.0, 1.6 Hz, 1H), 7.63 (d, J=16.0 Hz, 1H), 7.78 (d, J=8.0, 1.6, 1.2 Hz, 1H), 7.95 (dd, J=2.0, 1.2 Hz, 1H), 8.09-8.13 (m, 2H), 8.55 (dd, J=1.6, 1.6 Hz, 1H); .sup.13C-NMIR (100 MHz, DMSO-d6) 56.5, 74.0, 112.5, 122.1, 122.6, 127.1, 127.3, 127.6, 127.7, 128.2, 128.9, 131.1, 131.2, 131.6, 132.0, 134.3, 134.9, 136.9, 137.5, 143.0, 145.0, 153.8, 167.2, 167.7, 188.8 ppm.

[0172] [Synthesis Example 5] (E)-3-(3-(3-bromo-4-((3-carbamoylbenzyl)oxy)-5-methoxyphenyl)acryloyl) benzamide (A24)

[0173] This synthesis was performed using Compound 16 (100 mg, 0.27 mmol) and 3-carbamoylacetophenone (45 mg, 0.31 mmol), and the resulting product was extracted by silica gel column chromatography (elution: methanol:dichloromethane=1:10) to obtain Synthesis Example 5 (A24) as a pale yellow solid (40 mg, 28.5%).

[0174] R.sub.f0.50 (methanol:dichloromethane=1:9); .sup.1H-NMR (400MHz, DMSO-d.sub.6) δ 3.89 (s, 3H), 5.05 (s, 2H), 7.15 (d, J=2.0 Hz, 1H), 7.38 (dd, J=8.0, 7.6 Hz, 1H), 7.47 (d, J=1.6 Hz, 1H), 7.52 (dd, J=8.0, 7.6 Hz, 1H), 7.58 (d, J=15.6 Hz, 1H), 7.61 (d, J=8.0, 1.6 Hz, 1H), 7.63 (d, J=15.6 Hz, 1H), 7.64 (d, J=7.6, 2.0, 1.2 Hz, 1H), 7.78 (ddd, J=8.0, 1.6, 1.2 Hz, 1H), 7.97 (dd, J=2.0, 2.0 Hz, 1H), 8.09-8.13 (m, 2H), 8.55 (dd, J=1.6, 1.6 Hz, 1H); .sup.13C-NMR (100 MHz, DMSO-d.sub.6) 56.5, 73.9, 113.1, 117.5, 122.6, 125.0, 127.1, 127.4, 127.6, 128.2, 128.9, 131.1, 131.2, 132.0, 132.3, 134.3, 134.9, 136.9, 137.6, 142.9, 146.1, 153.6, 167.2, 167.7, 188.8 ppm.

[0175] [Synthesis Example 6] (E)-3-(3-(4-((3-carbamoylbenzyl)oxy)-3-iodo-5-methoxyphenyl)acryloyl) benzamide (A25)

[0176] This synthesis was performed using Compound 17 (100 mg, 0.24 mmol) and 3-carbamoylacetophenone (40 mg, 0.24 mmol), and the resulting product was extracted by silica gel column chromatography (elution: methanol:dichloromethane=1:10) to obtain Synthesis Example 6 (A25) as a pale yellow solid (35 mg, 25.9%).

[0177] R.sub.f0.50 (methanol:dichloromethane=1:9); .sup.1H-NMR (400MHz, DMSO-d.sub.6) δ 3.94 (s, 3H), 5.05 (s, 2H), 7.42 (dd, J=7.6, 7.6 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.58 (dd, J=7.6, 7.6 Hz, 1H), 7.65 (d, J=15.6 Hz, 1H), 7.67 (dd, J=8.0, 2.0 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.83 (ddd, J=7.6, 1.6, 1.2 Hz, 1H), 7.84 (d, J=15.6 Hz, 1H), 8.01 (dd, J=2.0, 1.6 Hz, 1H), 8.12-8.15 (m, 1H), 8.21 (ddd, J=8.0, 1.6, 1.2 Hz, 1H), 8.58 (ddd, J=1.6, 1.6 Hz, 1H); .sup.13C-NMR (100 MHz, DMSO-d.sub.6) 56.3, 73.6, 93.7, 113.8, 122.3, 127.1, 127.3, 127.6, 128.2, 128.9, 130.8, 131.1, 131.2, 132.0, 133.1, 134.3, 134.8, 136.9, 137.6, 142.8, 148.7, 152.4, 167.2, 167.7, 188.8 ppm.

[0178] [Synthesis Example 7] (E)-34(2-chloro-4-(3-(3-hydroxyphenyl)-3-oxoprop-1-en-1-yl) -6-methoxyphenoxy) methyl) benzamide (A26)

[0179] This synthesis was performed using Compound 15 (200 mg, 0.63 mmol) and 1-(2-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethan-1-one (138 mg, 0.63 mmol), and the resulting product was extracted by silica gel column chromatography (elution: ethyl acetate:dichloromethane=4:1) to obtain Synthesis Example 7 (A26) as a yellow solid (35 mg, 12.8%).

[0180] R.sub.f0.45 (ethyl acetate:dichloromethane=4:1); .sup.1H-NMR (400MHz, DMSO-d.sub.6) δ 3.96 (s, 3H), 5.11 (s, 2H), 7.07 (ddd, J=8.0, 2.4, 0.8 Hz, 1H), 7.36-7.40 (m, 2H),7.47 (dd, J=8.0, 7.6 Hz, 1H), 7.49 (dd, J=1.6, 1.6 Hz, 1H), 7.59 (d, J=16.0 Hz, 1H), 7.63-7.67 (m, 4H), 7.85 (ddd, J=8.0, 1.6, 1.2 Hz, 1H), 7.90 (d, J=15.6 Hz, 1H), 7.98-8.01 (m, 2H); .sup.13C-NMIt (100 MHz, DMSO-d.sub.6) 56.5, 74.0, 112.0, 114.7, 119.7, 120.4, 122.3, 122.8, 127.1, 127.5, 127.6, 128.2, 129.8, 131.1, 131.7, 134.3, 136.9, 138.9, 142.4, 144.9, 153.8, 157.7, 167.7, 189.0 ppm.

[0181] [Synthesis Example 8] (E)-34(2-bromo-4-(3-(3-hydroxyphenyl)-3-oxoprop-1-en-1-yl)-6-methoxyphenoxy) methyl) benzamide (A27)

[0182] This synthesis was performed using Compound 16 (100 mg, 0.27 mmol) and 1-(2-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethan-1-one (60 mg, 0.27 mmol), and the resulting product was extracted by silica gel column chromatography (elution: methanol:dichloromethane=1:10) to obtain Synthesis Example 8 (A27) as a pale yellow solid (38 mg, 28.9%).

[0183] R.sub.f0.56 (methanol:dichloromethane=1:9); .sup.1H-NMR (400MHz, DMSO-d.sub.6) δ 3.96 (s, 3H), 5.09 (s, 2H), 7.07 (ddd, J=7.6, 2.0, 1.2 Hz, 1H), 7.38 (dd, J=8.0, 8.0 Hz, 1H), 7.39 (br s, 1H), 7.48 (dd, J=8.0, 7.6 Hz, 1H), 7.49 (d, J=2.4 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.65 (d, J=15.6 Hz, 1H), 7.67 (dd, J=7.6, 1.6 Hz, 1H), 7.79 (d, J=1.6 Hz, 1H), 7.85 (ddd, J=7.6, 1.6, 1.2 Hz, 1H), 7.89 (d, J=15.6 Hz, 1H), 8.00 (br s, 1H); .sup.13C-NMIR (100 MHz, DMSO-d.sub.6) 56.5, 73.9, 112.6, 114.7, 117.4, 119.7, 120.3, 122.8, 125.1, 127.1, 127.6, 128.2, 129.8, 131.1, 132.4, 134.3, 136.9, 138.9, 142.3, 145.9, 153.6, 157.7, 167.7, 188.9 ppm.

[0184] [Synthesis Example 9] (E)-34(4-(3-(3-hydroxyphenyl)-3-oxoprop-1-en-1-yl)-2-iodo-6-methoxyphenoxy) methyl) benzamide (A28)

[0185] This synthesis was performed using Compound 17 (200 mg, 0.49 mmol) and 1-(2-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethan-1-one (107 mg, 0.49 mmol), and the resulting product was extracted by silica gel column chromatography (elution: methanol:dichloromethane=1:20) to obtain Synthesis Example 9 (A28) as a yellow solid (136 mg, 52.9%).

[0186] R.sub.f0.53 (methanol:dichloromethane=1:9); .sup.1H-NMR (400MHz, DMSO-d.sub.6) δ 3.87 (s, 3H), 5.02 (s, 2H), 7.00 (ddd, J=7.6, 2.0, 1.2 Hz, 1H), 7.13 (d, J=1.6 Hz, 1H), 7.22 (dd, J=8.0, 8.0 Hz, 1H), 7.35-7.41 (m, 4H), 7.53 (d, J=15.6 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.78 (dd, J=8.0, 1.6 Hz, 1H), 7.99 (dd, J=1.6, 1.6 Hz, 1H)).

[0187] [Synthesis Example 10] (E)-3-(3-chloro-4-((3-chlorobenzyl)oxy)-5-methoxyphenyl)-1-(3, 4,5-trimethoxyphenyl) prop-2-en-1-one (A29)

[0188] This synthesis was performed using Compound 1 (100 mg, 0.32 mmol) and 3,4,5-trimethoxyacetophenone (67.4 mg, 0.32 mmol), and the resulting product was extracted by silica gel column chromatography (elution: ethyl acetate:n-hexane=1:3) to obtain Synthesis Example 10 (A29) as an off-white solid (30 mg, 18.6%).

[0189] R.sub.f0.19 (ethyl acetate:n-hexane=1:3); .sup.1-H-NMR (400MHz, CDCl.sub.3) δ 3.93 (s, 3H), 3.95 (s, 3H), 3.96 (s, 6H), 5.07 (s, 2H), 7.04 (d, J=2.0 Hz, 1H), 7.26 (d, J=2.4 Hz, 2H), 7.30-7.32 (m, 2H), 7.34 (d, J=2.0 Hz, 1H), 7.37 (d, J=15.6 Hz, 1H), 7.37-7.39 (m, 1H), 7.55 (dd, J=0.8, 0.8 Hz, 1H), 7.68 (d, J=15.6 Hz, 1H); .sup.13C-NMR (100 MHz, CDCl.sub.3) 56.5, 56.7, 61.2, 74.4, 106.1, 106.5, 111.5, 121.9, 122.4, 126.5, 128.5, 128.6, 129.4, 129.9, 131.9, 133.5, 134.5, 139.0, 143.3, 146.0, 153.4, 154.2, 189.1 ppm.

[0190] [Synthesis Example 11] (E)-3-(3-bromo-4((3-chlorobenzyl)oxy)-5-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl) prop-2-en-1-one (A30)

[0191] This synthesis was performed using Compound 2 (100 mg, 0.28 mmol) and 3,4,5-trimethoxyacetophenone (59 mg, 0.28 mmol), and the resulting product was extracted by silica gel column chromatography (elution: ethyl acetate: n-hexane=1:3) to obtain Synthesis Example 11 (A30) as a yellow solid (55 mg, 35.8%).

[0192] R.sub.f0.26 (ethyl acetate: n-hexane=1:3); .sup.1H-NMR (400MHz, CDCl.sub.3) δ 3.94 (s, 3H), 3.95 (s, 3H), 3.96 (s, 6H), 5.06 (s, 2H), 7.08 (d, J=2.0 Hz, 1H), 7.26 (d, J=2.4 Hz, 2H), 7.31-7.34 (m, 2H), 7.36 (d, J=15.6 Hz, 1H), 7.41 (ddd, J=8.4, 1.2, 1.2 Hz, 1H), 7.51 (d, J=1.6 Hz, 1H), 7.57 (br s, 1H), 7.68 (d, J=15.6 Hz, 1H); .sup.13C-NMR (100 MHz, DMSO-d.sub.6) 56.3, 56.5, 60.2, 73.2, 106.4, 113.4, 117.4, 122.6, 124.6, 126.7, 127.9, 128.0, 130.2, 132.4, 132.9, 139.3, 142.1, 142.3, 145.7, 152.9, 153.4, 187.9 ppm.

[0193] [Synthesis Example 12] (E)-3-(4-((3-chlorobenzyl)oxy)-3-iodo-5-methoxyphenyl)-1-(3, 4,5-trimethoxyphenyl) prop-2-en-1-one (A31)

[0194] This synthesis was performed using Compound 3 (100 mg, 0.25 mmol) and 3,4,5-trimethoxyacetophenone (52 mg, 0.25 mmol), and the resulting product was extracted by silica gel column chromatography (elution: ethyl acetate:n-hexane=1:3) to obtain Synthesis Example 12 (A31) as a pale yellow solid (57 mg, 38.7%).

[0195] R.sub.f0.23 (ethyl acetate:n-hexane=1:3); .sup.1-H-NMR (400MHz, CDCl.sub.3) δ 3.93 (s, 3H), 3.95 (s, 3H), 3.96 (s, 6H), 5.05 (s, 2H), 7.12 (d, J=2.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 2H), 7.32-7.34 (m, 2H), 7.35 (d, J=15.6 Hz, 1H), 7.44 (ddd, J=7.2, 1.6, 1.2 Hz, 1H), 7.59 (dd, J=1.2, 1.2 Hz, 1H), 7.67 (d, J=15.6 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H); .sup.13C-NMR (100 MHz, DMSO-d.sub.6) 56.3, 56.4, 60.2, 72.9, 93.6, 106.4, 114.0, 122.4, 126.7, 127.9, 130.2, 130.6, 132.8, 132.9, 133.2, 139.3, 142.1, 142.2, 148.4, 152.3, 152.9, 187.9 ppm.

[0196] [Synthesis Example 13] (E)-3-((2-chloro-6-methoxy-4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenoxy) methyl)benzamide (A32)

[0197] This synthesis was performed using Compound 15 (170 mg, 0.53 mmol) and 3,4,5-trimethoxyacetophenone (112 mg, 0.53 mmol), and the resulting product was extracted by silica gel column chromatography (elution: ethyl acetate:n-hexane=2:1) to obtain Synthesis Example 13 (A32) as a pale yellow solid (140 mg, 51.3%).

[0198] R.sub.f0.13 (ethyl acetate:n-hexane=2:1); .sup.1H-NMR (400MHz, DMSO-d.sub.6) δ 3.84 (s, 3H), 3.87 (s, 3H), 3.88 (s, 6H), 5.05 (s, 2H), 7.06 (d, J=1.6 Hz, 1H), 7.22 (s, 2H), 7.29 (d, J=2.0 Hz, 1H), 7.38 (dd, J=7.6, 7.6 Hz, 1H), 7.39 (d, J=15.6 Hz, 1H), 7.58 (d, J=15.6 Hz, 1H), 7.60 (dd, J=7.6, 7.6 Hz, 1H), 7.77 (ddd, J=7.6, 1.6, 1.2 Hz, 1H), 7.95 (dd, J=1.6, 1.2 Hz, 1H); .sup.13C-NMR (100 MHz, DMSO-d.sub.6) 56.0, 56.1, 60.5, 74.1, 105.9, 110.9, 121.5, 122.0, 127.1, 127.4, 128.1, 128.5, 131.2, 131.3, 133.0, 133.6, 136.8, 142.2, 142.6, 145.3, 152.8, 153.7, 168.8, 188.4 ppm.

[0199] [Synthesis Example 14] (E)-3-((2-bromo-6-methoxy-4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenoxy) methyl)benzamide (A33)

[0200] This synthesis was performed using Compound 16 (100 mg, 0.27 mmol) and 3,4,5-trimethoxyacetophenone (58 mg, 0.27 mmol), and the resulting product was extracted to obtain Synthesis Example 14 (A33) as a pale yellow solid (100 mg, 65.4%).

[0201] R.sub.f0.13 (ethyl acetate:n-hexane=2:1); .sup.1-H-NMR (400MHz, CDCl.sub.3) δ 3.84 (s, 3H), 3.88 (s, 9H), 5.04 (s, 2H), 7.11 (d, J=1.6 Hz, 1H), 7.22 (s, 2H), 7.29 (d, J=2.0 Hz, 1H), 7.38 (dd, J=8.0, 8.0 Hz, 1H), 7.40 (d, J=15.6 Hz, 1H), 7.44 (d, J=1.6 Hz, 1H), 7.58 (d, J =15.6 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.78 (ddd, J=7.6, 1.6, 1.2 Hz, 1H), 7.97 (dd, J=1.6, 1.2 Hz, 1H); .sup.13C-NMR (100 MHz, DMSO-d.sub.6) 55.7, 55.9, 60.3, 73.8, 105.7, 111.3, 117.7, 121.8, 124.2, 126.8, 127.2, 127.8, 131.0, 131.7, 132.7, 133.4, 136.6, 141.9, 142.2, 146.1, 152.5, 153.3, 168.6, 188.1 ppm.

[0202] [Synthesis Example 15] (E)-3-((2-iodo-6-methoxy-4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenoxy) methyl)benzamide (A34)

[0203] This synthesis was performed using Compound 17 (100 mg, 0.24 mmol) and 3,4,5-trimethoxyacetophenone (51 mg, 0.24 mmol), and the resulting product was extracted to obtain Synthesis Example 15 (A34) as a pale yellow solid (75 mg, 51.2%).

[0204] R.sub.f0.13 (ethyl acetate:n-hexane =2:1); .sup.1-H-NMR (400MHz, CDCl.sub.3) δ 3.84 (s, 3H), 3.87 (s, 3H), 3.88 (s, 6H), 5.03 (s, 2H), 7.14 (d, J=1.6 Hz, 1H), 7.21 (s, 2H), 7.38 (d, J=15.2 Hz, 1H), 7.39 (dd, J=7.6, 7.6 Hz, 1H), 7.57 (d, J=15.6 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.78 (ddd, J=8.0, 1.6, 1.2 Hz, 1H), 7.99 (dd, J=1.6, 1.2 Hz, 1H); .sup.13C-NMR (100 MHz, DMSO-d.sub.6) 55.6, 55.9, 60.3, 73.6, 92.6, 105.7, 112.3, 121.7, 126.8, 127.3, 127.8, 130.2, 131.1, 132.6, 132.7, 133.5, 136.5, 141.9, 142.1, 148.6, 152.1, 152.5, 168.5, 188.1 ppm.

[0205] [Synthesis Example 16] (E)-3-(3-chloro-4-((3-chlorobenzyl)oxy)-5-methoxyphenyl)-1-(3-hydroxyphenyl)prop-2-en-1-one (A35)

[0206] This synthesis was performed using Compound 1 (100 mg, 0.32 mmol) and 1-(3-((tetrahydro-2H-pyran -2-yl)oxy)phenyl)ethan-1-one (70.1 mg, 0.32 mmol), and the resulting product was extracted by silica gel column chromatography (elution: ethyl acetate:n-hexane=1:3) to obtain Synthesis Example 16 (A35) as an ivory solid (26 mg, 18.9%).

[0207] R.sub.f0.13 (ethyl acetate:n-hexane=1;3); .sup.1H-NMR (400MHz, DMSO-d.sub.6) δ 3.88 (s, 3H), 4.98 (s, 2H), 7.00 (ddd, J=8.0, 1.6, 0.8 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 7.22-7.26 (m, 4H),7.30 (ddd, J=8.0, 2.0, 1.6 Hz, 1H), 7.37-7.41 (m, 2H), 7.39 (d, J=15.6 Hz, 1H), 7.46 (d, J=2.4 Hz, 1H), 7.54 (d, J=15.6 Hz, 1H).

[0208] [Synthesis Example 17] (E)-3-(3-bromo-44(3-chlorobenzyl)oxy)-5-methoxyphenyl)-1-(3-hydroxyphenyl)prop-2-en-1-one (A36)

[0209] This synthesis was performed using Compound 2 (100 mg, 0.28 mmol) and 1-(3-((tetrahydro-2H-pyran -2-yl)oxy)phenyl)ethan-1-one (62 mg, 0.28 mmol), and the resulting product was extracted by silica gel column chromatography (elution: ethyl acetate:n-hexane=1:3) to obtain Synthesis Example 17 (A36) as an ivory solid (62 mg, 46.5%).

[0210] R.sub.f0.14 (ethyl acetate:n-hexane=1;3); .sup.1H-NMR (400MHz, DMSO-d.sub.6) δ 3.95 (s, 3H), 5.07 (s, 2H), 7.07 (dd, J=8.0, 2.4 Hz, 1H), 7.38 (dd, J=8.0, 7.6 Hz, 1H), 7.41-7.49 (m, 4H), 7.57 (br s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.65 (d, J=16.0 Hz, 1H), 7.79 (dd, J=2.0, 1.6 Hz, 1H), 7.90 (d, J=15.6 Hz, 1H), 9.81 (s, 1H); .sup.13C-NMR (100 MHz, DMSO-d.sub.6) 56.5, 73.2, 112.6, 114.7, 117.3, 119.7, 120.3, 122.8, 125.1, 126.7, 127.9, 128.0, 129.8, 130.2, 132.4, 132.9, 138.9, 139.3, 142.2, 145.8, 153.5, 157.7, 188.9 ppm.

[0211] [Synthesis Example 18] (E)-3-(4-((3-chlorobenzyl)oxy)-3-iodo-5-methoxyphenyl)-1-(3-hydroxyphenyl)prop-2-en-1-one (A37)

[0212] This synthesis was performed using Compound 3 (100 mg, 0.25 mmol) and 1-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethan-1-one (55 mg, 0.25 mmol), and the resulting product was extracted by silica gel column chromatography (elution: ethyl acetate:n-hexane=1:3) to obtain Synthesis Example 18 (A37) as a yellow solid (57 mg, 43.8%).

[0213] R.sub.f0.15 (ethyl acetate:n-hexane=1;3); .sup.1H-NMR (400MHz, CDCl.sub.3) δ 3.84 (s, 3H), 4.94 (s, 2H), 7.00 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 7.05 (d, J=1.6 Hz, 1H), 7.22-7.26 (m, 3H), 7.31 (d, J=15.6 Hz, 1H), 7.33-7.36 (m, 1H), 7.38-7.41 (m, 2H), 7.50 (br s, 1H), 7.53 (d, J=16.0 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 9.02 (s, 1H); .sup.13C-NMIR (100 MHz, DMSO-d.sub.6) 56.3, 72.9, 93.6, 113.3, 114.7, 119.7, 120.3, 122.6, 126.7, 127.9, 128.0, 129.8, 130.2, 131.0, 132.9, 133.2, 138.9, 139.3, 142.2, 148.4, 152.3, 157.7, 188.9 ppm.

[0214] [Synthesis Example 19] (E)-1-(3-aminophenyl)-3-(3-chloro-4-((3-chlorobenzyl)oxy)-5-methoxyphenyl)prop-2-en-l-one (A38)

[0215] This synthesis was performed using Compound 1 (230 mg, 0.74 mmol) and 3-aminoacetophenone (100 mg, 0.74 mmol), and the resulting product was extracted by silica gel column chromatography (elution: ethyl acetate:n-hexane=1:3) to obtain Synthesis Example 19 (A38) as an orange solid (60 mg, 18.9%).

[0216] R.sub.f0.06 (ethyl acetate:n-hexane=1:3); .sup.1H-NMR (400MHz, CDCl.sub.3) δ 3.72 (s, 3H), 4.82 (s, 2H), 5.36 (s, 2H), 6.91 (d, J=2.0 Hz, 1H), 6.91-6.93 (m, 1H), 7.07-7.14 (m, 5H), 7.22 (d, J=15.6 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.30 (br s, 1H), 7.33 (dd, J=1.6, 1.6 Hz, 1H), 7.39 (d, J=15.6 Hz, 1H).

[0217] [Synthesis Example 20] (E)-1-(3-aminophenyl)-3-(3-bromo-4-((3-chlorobenzyl)oxy)-5-methoxyphenyl)prop-2-en-1-one (A39)

[0218] This synthesis was performed using Compound 2 (100 mg, 0.28 mmol) and 3-aminoacetophenone (38 mg, 0.28 mmol)), and the resulting product was extracted by silica gel column chromatography (elution: ethyl acetate:n-hexane=1:3) to obtain Synthesis Example 20 (A39) as an orange solid (57 mg, 42.9%).

[0219] R.sub.f0.07 (ethyl acetate:n-hexane=1:3); .sup.1H-NMR (400MHz, CDCl.sub.3) δ 3.93 (s, 3H), 5.05 (s, 2H), 6.91 (ddd, J=8.0, 1.6, 0.8 Hz, 1H), 7.08 (d, J=1,6 Hz, 1H), 7.29 (dd, J=7.6, 7.6 Hz, 1H), 7.31-7.33 (m, 3H), 7.38 (d, J=15.6 Hz, 1H), 7.37 (dd, J=1.6, 1.2 Hz, 1H), 7.40-7.42 (m, 1H), 7.47 (d, J=1,6 Hz, 1H), 7.57 (br s, 1H), 7.65 (d, J=16.0 Hz, 1H); .sup.13C-NMR (100 MHz, DMSO-d.sub.6) 56.5, 73.2, 112.5, 112.9, 116.6, 117.3, 118.7, 123.1, 124.9, 126.7, 127.9, 128.0, 129.1, 130.2, 132.5, 132.9, 138.3, 139.3, 141.7, 145.7, 149.1, 153.5, 189.5 ppm.

[0220] [Synthesis Example 21] (E)-1-(3-aminophenyl)-3-(4-((3-chlorobenzyl)oxy)-3-iodo-5-methoxyphenyl)prop -2-en-1-one (A40)

[0221] This synthesis was performed using Compound 3 (200 mg, 0.50 mmol) and 3-aminoacetophenone (67 mg, 0.50 mmol), and the resulting product was extracted by silica gel column chromatography (elution: ethyl acetate:n-hexane=1:3) to obtain Synthesis Example 21 (A40) as a yellow solid (64 mg, 42.9%).

[0222] R.sub.f0.08 (ethyl acetate:n-hexane=1:3); .sup.1H-NMR (400MHz, DMSO-d.sub.6) δ 3.93 (s, 3H), 5.03 (s, 2H), 5.34 (s, 2H), 6.85 (ddd, J=8.0, 2.8, 0.8, 1H), 7.21 (dd, J=8.0, 7.6 Hz, 1H), 7.26 (dd, J=2.0, 2.0 Hz, 1H), 7.37 (ddd, J=7.6, 1.6, 1.2 Hz, 1H), 7.42-7.46 (m, 2H), 7.48 (ddd, J=7.6, 1.6, 1.2 Hz, 1H), 7.58-7.62 (m, 3H), 7.80 (d, J=16.0 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H); .sup.13C-NMR (100 MHz, DMSO-d.sub.6) 56.3, 72.9, 93.6, 112.9, 113.3, 116.5, 118.7, 122.9, 126.7, 127.8, 127.9, 129.1, 130.2, 130.7, 132.9, 133.3, 138.3, 139.3, 141.6, 148.3, 149.1, 152.3, 189.4 ppm.

[0223] [Synthesis Example 22] (E)-3-(3-(3-chloro-4-((3-chlorobenzyl)oxy)-5-methoxyphenyl)acryloyl)benzamide (A41)

[0224] This synthesis was performed using Compound 1 (100 mg, 0.32 mmol) and 3-carbamoylacetophenone (52 mg, 0.32 mmol), and the resulting product was extracted by silica gel column chromatography (elution: methanol:dichloromethane=1:10) to obtain Synthesis Example 22 (A41) as a pale yellow solid (41 mg, 28.2%).

[0225] R.sub.f0.72 (methanol:dichloromethane=1:9); .sup.1H-NMR (400MHz, DMSO-d.sub.6) δ 3.89 (s, 3H), 4.99 (s, 2H), 7.10 (d, J=1.6 Hz, 1H), 7.23 (dd, J=2.4, 2.0 Hz, 1H), 7.25 (dd, J=7.2, 7.2 Hz, 1H), 7.31 (ddd, J=7.2, 2.0, 1.6 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.46 (br s, 1H), 7.52 (dd, J=8.0, 7.6 Hz, 1H), 7.57 (d, J=15.6 Hz, 1H), 7.63 (d, J=15.6 Hz, 1H), 8.11 (dd, J=7.6, 1.6 Hz, 2H), 8,54 (dd, J=1.6, 1.6 Hz, 1H).

[0226] [Synthesis Example 23] (E)-3-(3-(3-bromo-4-((3-chlorobenzyl)oxy)-5-methoxyphenyl)acryloyl)benzamide (A42)

[0227] This synthesis was performed using Compound 3 (100 mg, 0.25 mmol) and 3-carbamoylacetophenone (41 mg, 0.25 mmol), and the resulting product was extracted by silica gel column chromatography (elution: methanol:dichloromethane=1:10) to obtain Synthesis Example 23 (A42) as a pale yellow solid (51 mg, 37.1%).

[0228] R.sub.f0.53 (methanol:dichloromethane=1:9); .sup.1H-NMR (400MHz, DMSO-d.sub.6) δ 3.94 (s, 3H), 5.05 (s, 2H), 7.42-7.44 (m, 2H), 7.48 (ddd, J=7.6, 0.8 Hz, 1H), 7.56 (br s, 1H), 7.61 (br s, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.71 (d, J=15.2 Hz, 1H), 7.96 (d, J=15.2 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H), 8.15 (ddd, J=8.0, 1.2, 1.2 Hz, 1H), 8.20 (br s, 1H), 8.32 (ddd, J=7.6, 1.2, 1.2 Hz, 1H), 8.57 (dd, J=2.0, 1.6 Hz, 1H); .sup.13C-NMR (100 MHz, DMSO-d.sub.6) 56.3, 72.9, 93.6, 113.8, 122.4, 126.7, 127.3, 127.9, 128.0, 128.8, 130.2, 130.8, 131.2, 132.0, 132.9, 133.1, 134.8, 137.6, 139.3, 142.8, 148.5, 152.3, 167.2, 188.8 ppm.

[0229] [Synthesis Example 24] (E)-3-(3-(4-((3-chlorobenzyl)oxy)-3-iodo-5-methoxyphenyl)acryloyl)benzamide (A43)

[0230] This synthesis was performed using Compound 3 (100 mg, 0.25 mmol) and 3-carbamoylacetophenone (41 mg, 0.25 mmol), and the resulting product was extracted by silica gel column chromatography (elution: methanol:dichloromethane=1:10) to obtain Synthesis Example 24 (A43) as a pale yellow solid (51 mg, 37.1%).

[0231] R.sub.f0.53 (methanol:dichloromethane=1:9); .sup.1H-NMR (400MHz, DMSO-d.sub.6) δ 3.94 (s, 3H), 5.05 (s, 2H), 7.42-7.44 (m, 2H), 7.48 (ddd, J=7.6, 0.8 Hz, 1H), 7.56 (br s, 1H), 7.61 (br s, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.71 (d, J=15.2 Hz, 1H), 7.96 (d, J=15.2 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H), 8.15 (ddd, J=8.0, 1.2, 1.2 Hz, 1H), 8.20 (br s, 1H), 8.32 (ddd, J=7.6, 1.2, 1.2 Hz, 1H), 8.57 (dd, J=2.0, 1.6 Hz, 1H); .sup.13C-NMR (100 MHz, DMSO-d.sub.6) 56.3, 72.9, 93.6, 113.8, 122.4, 126.7, 127.3, 127.9, 128.0, 128.8, 130.2, 130.8, 131.2, 132.0, 132.9, 133.1, 134.8, 137.6, 139.3, 142.8, 148.5, 152.3, 167.2, 188.8 ppm.

[0232] [Example 4] Confirmation of degree of inhibition of HAT activity of Synthesis Examples 1 to 24

[0233] Each of Synthesis Examples 1 to 24 was diluted to 100 μM, and the degree of inhibition of HAT p300 activity was determined in the same manner as in Section [2-1]. The results are shown in FIG. 9. Here, the tissues were treated with C646 and Candidate 12 (HAT-12) as the control instead of Synthesis Examples 1 to 24.

[0234] As shown in FIG. 9, it was confirmed that the HAT activity inhibitory effects of Synthesis Examples 1 to 24 (A20 to A43) was 90% or more, which was significantly higher than those of C646 and Candidate 12 corresponding to the control, indicating that the Synthesis Examples 1 to 24 (A20 to A43) inhibited HAT p300 activity. In addition, almost 100% of the HAT p300 activity was inhibited by Synthesis Example 6 (A25) and Synthesis Example 8 (A27).

[0235] Based on the results, it can be seen that Synthesis Examples 1 to 24 corresponding to the novel synthetic compounds according to the present invention have a very excellent degree of inhibition of HAT p300 activity. From the results, it can be seen that Synthesis Examples 1 to 24 can be very effectively used to prevent, ameliorate or treat diseases associated with the HAT p300.

[0236] [Example 5] Confirmation of degree of inhibition of HAT p300 activity of Synthesis Example 6 and 8

[0237] Synthesis Example 6 and 8 having very excellent HAT p300 inhibitory effects as described in Example 4 were diluted to 0.5 μM, 1 μM, 10 μM, or 100 μM, and the degree of inhibition of HAT p300 activity was determined at each concentration in the same manner as in Section [2-1], and ICso values were deduced from these results. The results are shown in FIG. 10 and Table 4 below.

TABLE-US-00004 TABLE 4 Synthesis Example 6 (A25) Synthesis Example 8 (A27) IC.sub.50 (μM) 0.87 ± 0.15 1.06 ± 0.16

[0238] As shown in FIG. 10 and Table 4, Synthesis Example 6 and 8 had an ICso value of 0.87 μM and 1.06 μM, respectively, indicating that Synthesis Example 6 and 8 every effectively inhibited HAT p300 activity.

[0239] Based on the results, it can be seen that the novel synthetic compound according to the present invention very effectively inhibited HAT p300 activity because the novel synthetic compound was modified so that additional hydrogen bonds were formed with R1410, T1411, W1466, Y1467 of HAT p300.

[0240] [Example 6] Structural Analysis of Candidate 6 (A25) and 8 (A27)

[0241] For Candidate 6 (A25) and Candidate 8 (A27) having the best HAT inhibitory effect as described in in Example 5, a molecular docking simulation was performed in the same manner as in Example 3. The results are shown in FIGS. 11A to 11C.

[0242] As shown in FIGS. 11A to 11C, it can be seen that, in addition to the hydrogen bonds with S1400 of HAT p300 confirmed from Candidate 12 (HAT-12) in Example 3, the hydrogen bonds with R1410, T1411 and W1466 were further expected in the case of Synthesis Example 6 (A25), and the entire docking pattern was also similar to that of the Lys-CoA. It was expected that the HAT p300 inhibitory activity of Synthesis Example 6 remarkably increased due to such a structure (IC.sub.50=0.87±0.15 (μM)). In addition, the hydrogen bonds with R1410 and T1411 were further expected in the case of Synthesis Example 8 (A27), and it was expected that the HAT p300 inhibitory activity of Synthesis Example 8 would increase due to such a structure (IC.sub.50=1.06±0.16 (μM)).

[0243] Based on the results, it can be seen that Synthesis Examples 6 and 8 according to the present invention interacted with the HAT p300 domain at a very high level through the additional hydrogen bonding with R1410, T1411 and W1466; or R1410 and T1411 of HAT p300, and thus very effectively inhibited HAT p300 activity.

[0244] While the present invention has been described in detail with reference to exemplary embodiments of the present invention, it will be obvious to those of ordinary skill in the art that this specific description is just a preferred embodiment, and is not intended to limit the scope of the present invention. Therefore, it should be understood that the technical scope of the present invention should be defined by the appended claims and equivalents thereof.

INDUSTRIAL APPLICABILITY

[0245] The present invention relates to a novel compound which enables additional hydrogen bonding with a specific amino acid position of histone acetyltransferase (HAT) p300 through the structural analysis of the HAT p300. The novel compound of the present invention has an excellent inhibitory effect on HAT p300 activity, and thus can be very effectively used to prevent, ameliorate or treat fibrosis that is a disease associated with the activation of HAT p300.