Novel compound

Abstract

Various embodiments of the present invention relate to a novel compound capable of increasing NAD+.

Description

novel compounds

[0001] Various embodiments of the present invention relate to novel compounds capable of increasing NAD+.

[0002] As cells age, the amount of nicotinamide adenine dinucleotide (NAD+) naturally decreases. This reduced NAD+ contributes to various age-related problems. Numerous studies have demonstrated the effectiveness of increasing NAD+ in alleviating symptoms.

[0003] NAD+ is produced through the reactions of NAM (nicotinamide), NMN (nicotinamide mononucleotide), and NR (nicotinamide riboside) involving various enzymes, or through tryptophan metabolism (De novo biosynthesis, Preiss-Handler pathway, Salvage pathway). NAD+ produced in this way helps the actions of various biological enzymes (SIRTs, PARPs, etc.) related to antioxidants, gene repair, and immunity, and is used as an energy source, thereby increasing the effects of anti-aging, apoptosis inhibition, anti-obesity, muscle strength increase, and whitening, playing an important role in maintaining normal biological activity.

[0004] The present invention aims to provide a novel compound capable of increasing NAD+.

[0005] The novel compound of the present invention can be represented by any one of the following chemical formulas 1 to 4.

[0006] [Chemical Formula 1]

[0007]

[0008] The above R1 and R2 are each independently -OH or -OCH3, A is a 5- to 6-membered substituted or unsubstituted heterocycloalkyl having one oxygen atom, and the substituted heterocycloalkyl is substituted with C2 to C4 alkyl.

[0009]

[0010] [Chemical Formula 2]

[0011]

[0012] The above R3 and R4 are each independently -OH or -OCH3, B is a 5-membered heterocycloalkenyl having 1 to 2 heteroatoms selected from oxygen and nitrogen, and the heterocycloalkenyl is substituted with C1 to C4 alkyl.

[0013] [Chemical Formula 3]

[0014]

[0015] Among the above R5 and R6, one is H,

[0016] The remaining one is -O(CH2)nOH (n is an integer from 1 to 3), (Rx is a butenyl group including an ester substituent represented by a C1 to C5 alkyl group substituted or unsubstituted with alkylene, a C1 to C5 alkyl group not including alkylene, or a C2 to C10 alkenyl group), or a butenyl group including an acetoxy group (OAc),

[0017] The above R7 and R8 are each independently -OH, -OCH3 or an acetoxy group (OAc).

[0018] [Chemical Formula 4]

[0019]

[0020] The above R9 and R 10 are each independently a hydroxyl group (-OH) or an alkyl group having C1 to C5, and the R 11 and R 12 are each independently a hydroxyl group (-OH) or -OCH3, and X is oxygen.

[0021] Novel compounds according to various embodiments of the present invention can increase NAD+. Novel compounds according to various embodiments of the present invention can have the activity of substituting NADH for NAD as a substrate. Novel compounds according to various embodiments of the present invention can have anti-aging, anti-apoptotic, anti-obesity, muscle strengthening, and whitening effects.

[0022] Figure 1 shows H NMR data of W001 compound (compound 3A), and Figure 2 shows HPLC (EC9180-53-P1H) data.

[0023] Figure 3 is H NMR data of W003 compound (compound 14), and Figure 4 is HPLC (EC9180-167-P1AH3) data.

[0024] Figure 5 shows H NMR data of the W004 compound (compound 27 precursor), and Figure 6 shows HPLC data.

[0025] Figure 7 is H NMR data of the W005 compound (compound 1a precursor), and Figure 8 is H PLC data.

[0026] Figure 9 is H NMR data of the W006 compound (compound 8 int.2a), and Figure 10 is HPLC data.

[0027] Figure 11 is H NMR data of the W010 compound (compound 8 int.10), and Figure 12 is HPLC data.

[0028] Figure 13 shows H NMR data of the W011 compound (compound 8), and Figure 14 shows HPLC data.

[0029] Figure 15 is H NMR data of W013 (compound 23), and Figure 16 is HPLC (EC9180-53-P1H) data.

[0030] Figure 17 is H NMR data of the W014 compound (compound 18_int.6A), and Figure 18 is HPLC data.

[0031] Figure 19 is H NMR data of compound W017 (compound 19 int.9), and Figure 20 is HPLC data.

[0032] Figure 21 is H NMR data of compound 9 (M004).

[0033] Figure 22 is H NMR data of compound 11 (M003).

[0034] Figure 23 is H NMR data of compound 12 (M002).

[0035] Figure 24 is H NMR data of compound 13 (M001).

[0036] Figure 25 is H NMR data of compound 14 (M007).

[0037] Figure 26 confirms the NAD substitution activity of W series compounds.

[0038] Figure 27 confirms the NAD substitution activity of M series compounds.

[0039] Hereinafter, various embodiments of this document are described with reference to the attached drawings. The embodiments and terminology used herein are not intended to limit the technology described in this document to specific embodiments, but should be understood to encompass various modifications, equivalents, and / or alternatives of the embodiments.

[0040]

[0041] Novel compounds according to various embodiments of the present invention can increase NAD+. Novel compounds according to various embodiments of the present invention can have the activity of substituting NADH for NAD as a substrate. Novel compounds according to various embodiments of the present invention can have anti-aging, anti-apoptotic, anti-obesity, muscle strengthening, and whitening effects.

[0042] The novel compound of the present invention can be represented by any one of the following chemical formulas 1 to 4.

[0043] [Chemical Formula 1]

[0044]

[0045] The above R1 and R2 are each independently a hydroxy group (-OH) or an alkoxy group having C1 to C10,

[0046] A is a substituted or unsubstituted heterocycloalkyl,

[0047] The above heterocycloalkyl is a group consisting of 5 to 14 members having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,

[0048] The above substituted heterocycloalkyl may be substituted with a straight or branched chain alkyl having C1 to C10.

[0049] More specifically, R1 and R2 are each independently -OH or -OCH3, A is a 5- to 6-membered substituted or unsubstituted heterocycloalkyl having one oxygen atom, and the substituted heterocycloalkyl may be substituted with C1 to C4 alkyl.

[0050]

[0051] [Chemical Formula 2]

[0052]

[0053] The above R3 and R4 are each independently a hydroxy group (-OH) or an alkoxy group having C1 to C10,

[0054] B is a substituted or unsubstituted heterocycloalkyl,

[0055] The above heterocycloalkyl is a group consisting of 5 to 14 members having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,

[0056] The above substituted heterocycloalkyl may be substituted with a straight or branched chain alkyl having C1 to C10.

[0057] More specifically, R3 and R4 are each independently -OH or -OCH3, B is a 5- to 6-membered heterocycloalkenyl having 1 to 2 heteroatoms selected from oxygen and nitrogen, and the heterocycloalkenyl may be substituted with C1 to C4 alkyl.

[0058]

[0059] [Chemical Formula 3]

[0060]

[0061]

[0062] The above R5 and R6 are each independently H, a substituted or unsubstituted C1 to C10 alkyl group, or a substituted or unsubstituted C1 to C10 alkoxy group,

[0063] The above substituted alkyl group is substituted with -OH or oxygen,

[0064] The above substituted alkoxy group is substituted with -OH or oxygen,

[0065] The above alkyl group includes an alkylene, an ester substituent or a combination thereof,

[0066] The above ester substituent is can be expressed as,

[0067] The above Rx is a C1 to C10 alkyl group or a C2 to C10 alkenyl group with or without alkylene,

[0068] The above R7 and R8 are each independently a hydroxy group (-OH), a C1 to C10 alkoxy group, a C2 to C10 alkenyl group, or a substituted or unsubstituted C1 to C10 alkyl group,

[0069] The above alkyl group includes an alkylene, an ester substituent or a combination thereof,

[0070] The above ester substituent is can be expressed as,

[0071] The above Rx may be a C1 to C10 alkyl group or a C2 to C10 alkenyl group with or without alkylene.

[0072] More specifically, R5 and R6 are each independently H, -O(CH2)nOH (n is an integer from 1 to 3), (Rx is a butenyl group including an ester substituent represented by a C1 to C5 alkyl group substituted or unsubstituted with alkylene, a C1 to C5 alkyl group not including alkylene, or a C2 to C10 alkenyl group), or a butenyl group including an acetoxy group (OAc),

[0073] The above R7 and R8 are each independently -OH, -OCH3 or an acetoxy group (OAc).

[0074]

[0075] [Chemical Formula 4]

[0076]

[0077]

[0078] The above R9 and R 10 are each independently a hydroxy group (-OH) or an alkyl group having C1 to C10,

[0079] The above R 11 and R 12 are each independently a hydroxy group (-OH) or an alkoxy group having C1 to C10,

[0080] X is at least one of oxygen (O), sulfur (S), and nitrogen (N).

[0081] More specifically, the above R9 and R 10 are each independently a hydroxyl group (-OH) or an alkyl group having C1 to C5, and the R 11 and R 12 are each independently -OH or -OCH3, and X is oxygen.

[0082]

[0083] The compound represented by the chemical formula 1 according to an example of the present invention may be any one of the compounds shown in Table 1 below.

[0084] [Table 1]

[0085] [Correction pursuant to Rule 91, November 19, 2025]

[0086] The compound represented by the chemical formula 2 according to an example of the present invention may be any one of the compounds shown in Table 2 below.

[0087] [Table 2]

[0088] [Correction pursuant to Rule 91, November 19, 2025]

[0089] The compound represented by the chemical formula 3 according to an example of the present invention may be any one of the compounds shown in Table 3 below.

[0090] [Table 3]

[0091] [Correction pursuant to Rule 91, November 19, 2025]

[0092] The compound represented by the chemical formula 4 according to an example of the present invention may be any one of the compounds shown in Table 4 below.

[0093] [Table 4]

[0094] [Correction pursuant to Rule 91, November 19, 2025]

[0095] Hereinafter, the present invention will be described in detail through specific examples. However, the following examples are only for illustrating the present invention, and the present invention is not limited by the following examples.

[0096]

[0097] <Example 1> Synthesis of compound W001

[0098] The overall reaction schematic for the synthesis of compound W001 (compound 3A) is as follows.

[0099] [Correction pursuant to Rule 91, November 19, 2025]

[0100]

[0101] Below, each step is explained.

[0102] Step 1. Synthesis of Intermediate 2

[0103] Intermediate 2 was synthesized according to the following reaction schematic diagram.

[0104]

[0105]

[0106] A solution of NBS (22.9 g, 129 mmol, 2.20 eq) dissolved in ACN (150 mL) was added dropwise to a suspension of compound 1 (11.0 g, 58.5 mmol, 1.00 eq) dissolved in ACN (100 mL) and cooled in a salt-ice bath (0°C). The resulting mixture was stirred at 20°C under N2 for 6 h. TLC (petroleum ether / ethyl acetate = 5 / 1) indicated that compound 1 had reacted completely. The crude solid was collected by filtration. The crude material was washed with methanol and then with petroleum ether. Compound 2 (15.0 g, 43.4 mmol, 74.2% yield) was obtained as a green powder, which was confirmed by H NMR (EC9180-26-P1A).

[0107] H NMR: EC9180-26-P1A, (400 MHz, CDCl3)

[0108] δ7.71 (d,J= 8.4 Hz, 2H), 6.75 (d,J= 8.4 Hz, 2H), 3.93 (s, 6H)

[0109] Step 2. Synthesis of Intermediate 3

[0110] Intermediate 3 was synthesized according to the following reaction schematic diagram.

[0111]

[0112]

[0113] A mixture of compound 2 (15.0 g, 43.4 mmol, 1.00 eq), CuI (24.8 g, 130 mmol, 3.00 eq), NaOMe (23.4 g, 130 mmol, 30% purity, 3.00 eq), DMF (100 mL), and MeOH (100 mL) was stirred at 70 °C for 24 h. TLC (petroleum ether / ethyl acetate = 5 / 1, I2) indicated that compound 2 had reacted completely. The mixture was filtered while hot, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). Compound 3 (3.50 g, 14.1 mmol, 30.5% yield) was obtained as a yellow solid, which was confirmed by H NMR (EC9180-30-P1A).

[0114] H NMR: EC9180-30-P1A, (400 MHz, CDCl3)

[0115] δ6.86 (s, 4H), 3.92 (s, 12H).

[0116] Step 3. Synthesis of Intermediate 4

[0117] Intermediate 4 was synthesized according to the following reaction schematic diagram.

[0118]

[0119]

[0120] To a solution of compound 3 (3.50 g, 14.1 mmol, 1.00 eq) dissolved in ACN (150 mL) was added CAN (23.2 g, 42.3 mmol, 21.08 mL, 3.00 eq). The mixture was stirred at 0°C for 2 h. TLC (petroleum ether / ethyl acetate = 1 / 1) indicated that compound 3 had reacted completely. Next, EtOAc (500 mL) was added to the mixture. The mixture was washed with 500 mL of water and 250 mL of brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a brown residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10:1 to 1:1). Compound 4 (2.00 g, 9.17 mmol, 65.0% yield) was obtained as a red solid.

[0121] Step 4. Synthesis of Intermediate 5

[0122] Intermediate 5 was synthesized according to the following reaction schematic diagram.

[0123]

[0124]

[0125] To a solution of compound 4 (2.00 g, 9.17 mmol, 1.00 eq) in DCM (200 mL) were added UHP (3.10 g, 33.0 mmol, 3.6 eq) and DBU (1.67 g, 11.0 mmol, 1.66 mL, 1.20 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h. LC-MS (EC9180-43-P1C) indicated that compound 4 was completely reacted. The reaction mixture was quenched by the addition of saturated 1 M Na2SO3 (50.0 mL) at 25 °C, diluted with H2O (150 mL), and extracted with DCM (160 mL * 3). The combined organic layers were washed with brine (50.0 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1). Compound 5 (1.60 g, 6.83 mmol, 74.5% yield) was obtained as a red solid.

[0126] LC-MS: EC9180-43-P1C, (M+H) + : 235.1.

[0127] Step 5. Synthesis of Intermediate 6

[0128] Intermediate 6 was synthesized according to the following reaction schematic.

[0129]

[0130]

[0131] To a solution of compound 5 (2.00 g, 8.54 mmol, 1.00 eq) in DCM (200 mL) was added H2SO4 (837 mg, 8.54 mmol, 455 μL, 1.00 eq). The mixture was stirred at 40 °C for 0.5 h. LC-MS (EC9180-47-P1A) indicated that compound 5 was completely reacted. For workup, the crude reaction mixture of EC9180-46 (0.100 g scale) and EC9180-47 (2.00 g scale) was combined with EC9180-47. The combined reaction mixture was poured into water (200 mL) and extracted with DCM (100 mL * 2). The combined organic phases were concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1). Compound 6 (1.50 g, 6.40 mmol, 75.0% yield) was obtained as a red solid, which was confirmed by LC-MS (EC9180-47-P1M1).

[0132] LC-MS: EC9180-47-P1A. (M+H) + : 235.0.

[0133] Step 6. Synthesis of Intermediate 8

[0134] Intermediate 8 was synthesized according to the following reaction schematic diagram.

[0135]

[0136]

[0137] Compound 7 (718 mg, 8.54 mmol, 2.00 eq) was added to a solution of compound 6 (1.00 g, 4.27 mmol, 1.00 eq) dissolved in t-BuOH (10.0 mL) and pyridine (10.0 mL). The mixture was stirred at 80 °C for 15 h. LC-MS (EC9180-49-P1A) indicated that compound 6 was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1). Compound 8 (0.740 g, 2.32 mmol, 54.4% yield) was obtained as a red solid, which was confirmed by LC-MS (EC9180-49-P1B).

[0138] LC-MS: EC9180-49-P1A, EC9180-49-P1B, (M+H) + : 319.1.

[0139] LC-MS: EC9180-49-P1B, (M+H) + : 319.1.

[0140] Step 7. Synthesis of Intermediate 9

[0141] Intermediate 9 was synthesized according to the following reaction schematic.

[0142]

[0143]

[0144] To a solution of compound 8 (0.740 g, 2.32 mmol, 1.00 eq) in THF (200 mL) and MeOH (10.0 mL) was added NaBH4 (0.528 g, 14.0 mmol, 6.0 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. TLC (petroleum ether / ethyl acetate = 0 / 1) showed that compound 8 was completely reacted. The reaction mixture was quenched by the addition of 2 M HCl (3.00 mL) at 0 °C, diluted with H2O (200 mL), and extracted with ethyl acetate (200 mL * 3). The combined organic layers were washed with brine (150 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. Compound 9 (650 mg, crude) was obtained as a red solid.

[0145] Step 8. Synthesis of Intermediate 10

[0146] Intermediate 10 was synthesized according to the following reaction schematic.

[0147]

[0148]

[0149] To a solution of compound 9 (650 mg, 2.03 mmol, 1.00 eq) dissolved in EtOH (20.0 mL) was added HCl (12 M, 845 μL, 5.00 eq). The mixture was stirred at 80 °C for 16 h. LC-MS (EC9180-52-P1C) showed that compound 9 was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). Compound 10 (140 mg, 463 μmol, 22.8% yield) was obtained as a red solid, which was identified by LC-MS (EC9180-52-P1M1).

[0150] LC-MS: EC9180-52-P1C, EC9180-52-P1M1, (M+H) + : 303.1.

[0151] LC-MS: EC9180-52-P1M1, (M+H) + : 303.1.

[0152] Step 9. Synthesis of W001 compound (compound 3A)

[0153] Compound W001 (compound 3A) was synthesized according to the following reaction schematic.

[0154]

[0155]

[0156] To a solution of compound 10 (140 mg, 463 μmol, 1.00 eq) in DCM (30.0 mL) was added BBr3 (232 mg, 926 μmol, 89.2 μL, 2.00 eq) at 0 °C, and the mixture was stirred at 0 °C under N2 atmosphere for 0.5 h. LC-MS (EC9180-53-P1A) indicated that compound 10 was completely reacted. The reaction mixture was quenched by adding MeOH (2.00 mL) at 0 °C, diluted with H2O (10.0 mL), and extracted with DCM (10.0 mL* 3). The combined organic layers were washed with brine (10.0 mL* 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-HPLC (Column: Welch Xtimate C18 150 * 25 mm * 5 μm; Mobile phase: [water (HCl)-ACN]; B%: 41%-71%, 11 min). W001 compound (compound 3A) (23.43 mg, 89.0 μmol, 22.7% yield, 96.3% purity) was obtained as a red solid, which was confirmed by LC-MS (EC9180-53-P1M3), HPLC (EC9180-53-P1H), and H NMR (EC9180-53-P1A). Figure 1 shows H NMR data of W001 compound (compound 3A), and Figure 2 shows HPLC (EC9180-53-P1H) data.

[0157] H NMR: EC9180-53-P1A, (400 MHz, CDCl3)

[0158] δ12.74 (s, 1H), 12.26 (s, 1H), 7.24 (d,J= 9.6 Hz, 1H), 7.18 (d,J= 9.2 Hz, 1H), 4.15-4.09 (m, 1H), 2.78-2.71 (m, 1H), 2.56-2.48 (m, 1H), 2.15-2.09 (m, 1H), 1.97-1.88 (m, 1H), 1.82-1.68 (m, 2H), 1.10 (t,J= 7.6 Hz, 3H).

[0159] LC-MS: EC9180-53-P1A, (M+H) + : 275.1.

[0160] LC-MS: EC9180-53-P1M3, Purity: 96.39% (220 nm), (M+H) + : 275.1.

[0161] HPLC: EC9180-53-P1H, Purity: 99.99% (220 nm).

[0162]

[0163] <Example 2> Synthesis of W003 compound 1

[0164] The overall reaction schematic for the synthesis of W003 compound (compound 14) is as follows.

[0165] [Correction pursuant to Rule 91, November 19, 2025]

[0166]

[0167] Below, each step is explained.

[0168] Step 1. Synthesis of Intermediate 2

[0169] Intermediate 2 was synthesized according to the following reaction schematic diagram.

[0170]

[0171] To a solution of compound 1 (2.20 g, 11.6 mmol, 1.00 eq) in CHCl3 (220 mL) were added Ag2O (8.04 g, 34.7 mmol, 3.00 eq) and CH3I (6.57 g, 46.3 mmol, 2.88 mL, 4.00 eq). The mixture was stirred at 60 °C for 20 h. LC-MS (EC9180-162-P1A3) showed that compound 1 was completely reacted. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:0 to 1:1; SiO2, petroleum ether: ethyl acetate = 1:1; Rf = 0.18). Compound 2 (970 mg, 4.45 mmol, 38.4% yield) was obtained as a red solid and confirmed by H NMR (EC9180-162-P1A1).

[0172] LC-MS: EC9180-162-P1A3, (M+H) + : 219.1.

[0173] H NMR: EC9180-162-P1A1, (400 MHz, CDCl3)

[0174] δ7.34 (s, 2H), 6.79 (s, 2H), 3.97 (s, 6H)

[0175] Step 2. Synthesis of Intermediate 3

[0176] Intermediate 3 was synthesized according to the following reaction schematic diagram.

[0177]

[0178] To a solution of compound 2 (900 mg, 4.12 mmol, 1.00 eq) dissolved in CH2Cl2 (100 mL) were added UHP (1.44 g, 15.25 mmol, 3.70 eq) and DBU (753 mg, 4.95 mmol, 746 μL, 1.20 eq). The mixture was stirred at 25 °C for 2 h. LC-MS (EC9180-164-P1A1) showed that the desired mass was detected. The reaction mixture was quenched by adding 2 M Na2SO3 (8.00 mL) at 0 °C, diluted with H2O (100 mL), and extracted with CH2Cl2 (100 mL * 4). The combined organic layers were washed with brine (100 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO2, ethyl acetate:petroleum ether = 1:1; SiO2, ethyl acetate:petroleum ether = 1:1, Rf = 0.15). Compound 3A (320 mg, 1.37 mmol, 33.1% yield) was obtained as a yellow solid. Compound 3 (200 mg, 854 μmol, 20.7% yield) was also obtained as a red solid.

[0179] LC-MS: EC9180-164-P1A1, (M+H) + : 235.1.

[0180] Step 3. Synthesis of Intermediate 5

[0181] Intermediate 5 was synthesized according to the following reaction schematic diagram.

[0182]

[0183] To a solution of compound 3 (200 mg, 854 μmol, 1.00 eq) in DMF (5.00 mL) were added K2CO3 (236 mg, 1.71 mmol, 2.00 eq) and compound 4 (207 mg, 1.71 mmol, 2 eq). The mixture was stirred at 55 °C for 2 h. LC-MS (EC9183-165-P1A3) showed that compound 3 was completely reacted and the desired mass was detected. The reaction mixture was partitioned between H2O (40.0 mL) and ethyl acetate (40.0 mL * 4). The organic phase was separated, washed with brine (40.0 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO2, petroleum ether:ethyl acetate = 1:1, SiO2, petroleum ether:ethyl acetate = 1:1, Rf = 0.23). Compound 5 (136 mg, 496 μmol, 58.1% yield) was obtained as a yellow solid.

[0184] LC-MS: EC9180-165-P1A3, (M+H) + : 275.1.

[0185] Step 4. Synthesis of intermediate 6

[0186] Intermediate 6 was synthesized according to the following reaction schematic.

[0187]

[0188] A mixture of compound 5 (136 mg, 495.87 μmol, 1.00 eq) dissolved in toluene (10.0 mL) was stirred in a microwave at 180 °C for 2 h. TLC (SiO2, petroleum ether: ethyl acetate = 0:1, Rf = 0.50) showed that compound 5 was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a residue. Compound 6 (130 mg, crude) was obtained as a yellow solid.

[0189] Step 5. Synthesis of W003 compound (compound 14)

[0190] Compound W003 (compound 14) was synthesized according to the following reaction schematic.

[0191]

[0192] To a solution of compound 6 (130 mg, 474 μmol, 1.00 eq) in DCM (3.00 mL) was added H2SO4 (94.9 mg, 948 μmol, 186 μL, 98% purity, 2.00 eq). The mixture was stirred at 0 °C for 2 h. TLC (SiO2, petroleum ether: ethyl acetate = 0:1) indicated that compound 6 was completely reacted. The reaction mixture was quenched by the addition of 2 M NaHCO3 (2.00 mL) at 0 °C, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified twice by Prep-TLC (SiO2, petroleum ether: ethyl acetate = 0:1, Rf = 0.20) to obtain a red solid. Next, the product was triturated with MTBE (2.00 mL) and pounded to obtain the pure product. Compound 14 (41.46 mg, 0.151 μmol, 31.78% yield, 99.64% purity) was obtained as a red solid, which was confirmed by H NMR (EC9180-167-P1A1), LC-MS (EC9180-167-P1A1), and HPLC (EC9180-167-P1AH3). Figure 3 shows H NMR data of W003 compound (compound 14), and Figure 4 shows HPLC (EC9180-167-P1AH3) data.

[0193] H NMR: EC9180-167-P1A1, (400 MHz, CDCl3).

[0194] δ7.25 (d,J= 9.6 Hz, 1H), 7.18 (d,J= 9.6 Hz, 1H), 5.29 - 5.15 (m, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.20 (dd,J=15.2, 9.9, Hz, 1H), 2.66 (dd,J=15.3, 7.3, Hz, 1H), 1.56 (d,J= 6.4 Hz, 1H).

[0195] LC-MS: EC9180-140-P1A1, (M+H) + : 275.1

[0196] HPLC: EC9180-140-P1H3, Purity: 99.64% (220 nm)

[0197] <Example 3> Synthesis of W003 compound 2

[0198] The overall reaction schematic for the synthesis of the JH-W003 compound is as follows.

[0199] [Correction pursuant to Rule 91, November 19, 2025]

[0200] Step 1. Synthesis of compound A

[0201] Compound A was synthesized according to the reaction schematic below.

[0202]

[0203] Add 259 g (1.91 mole) of AlCl3 and 61 g (1.04 mole) of NaCl. Heat to an internal temperature of 140°C. Add a mixture of 30 g (0.22 mole) of 1,4-dimethoxybenz and 72.5 g (0.43 mole) of 3,4-dichlorofuran-2,5-dione. Heat to an internal temperature of 170°C and stir for 30 minutes. Once stirring is complete, cool to room temperature. Dissolve in 2730 mL of distilled water. Add 213 g (2.04 mole) of 35% c-HCl and stir for 12 hours. Filter to obtain 50 g of compound A as a dark red solid. (Yield: 90%)

[0204] Step 2. Synthesis of compound B

[0205] Compound B was synthesized according to the reaction schematic below.

[0206]

[0207] Add 50 g (0.19 mole) of Compound A. Add 2865 mL of 4M HCl solution and begin stirring. Add 304.8 g (1.35 mole) of SnCl2.2H2O. Heat to an internal temperature of 100°C. Reflux for 5 hours. After 5 hours, filter at 90°C or higher. After filtration is complete, cool and filter the precipitated solid. After vacuum drying at 55°C for 12 hours, 18.5 g of dark green Compound B is obtained. (Yield: 50%)

[0208] Step 3. Synthesis of compound C

[0209] Compound C was synthesized according to the following reaction schematic.

[0210]

[0211] Add 20 g (0.10 mole) of Compound B. Add 800 mL of DMF (N,N-dimethylformamide) and stir. Add 105 g (0.83 mole) of Me2SO4 and cool the internal temperature to 0°C. Once cooled, slowly add 30 g (0.62 mole) of NaH in portions. Once added, raise the internal temperature to 40°C and stir for 1 hour. Once stirred, cool to room temperature. At room temperature, add 43 g (0.34 mole) of Me2SO4 and stir for 30 minutes. Dissolve 99 g (1.77 mole) of KOH in 7000 mL of distilled water and slowly add the reactant dropwise. Once the addition is complete, stir for 12 hours and filter. After vacuum drying at 55°C for 12 hours, 20 g of compound C, a dark yellow solid, is obtained. (Yield: 80%)

[0212] Step 4. Synthesis of compound D

[0213] Compound D was synthesized according to the following reaction schematic.

[0214]

[0215] Add 20 g (0.08 mole) of Compound C. Add 400 mL of Acetonitrile and stir. Add 176.6 g (0.32 mole) of Ceric Ammonium Nitrate dissolved in 706 g of distilled water. Stir at room temperature for 1 hour, then add 1000 mL of dichloromethane and 600 mL of distilled water to separate the layers. Wash twice with 600 mL of distilled water, and remove moisture from the dichloromethane layer using MgSO4. Concentrate under reduced pressure at 40°C to obtain 14 g of Compound D as a red solid (yield 80%).

[0216] Step 5. Synthesis of compound F

[0217] Compound F was synthesized according to the following reaction schematic.

[0218]

[0219] Add 10 g (0.04 mole) of Compound D. Add 200 mL of 1,4-dioxane and 150 mL of H2O and stir. Add 55 g (0.53 mole) of 95% H2SO4 and 337 g (0.09 mole) of Fe2(SO4). Raise the internal temperature to 100°C and reflux for 3 hours. When the reaction is complete, add 1500 mL of dichloromethane and 1000 mL of distilled water and separate the layers. Extract the separated aqueous layer with 1500 mL of dichloromethane and combine it with the previously separated dichloromethane layer. Remove moisture from the combined organic layers with MgSO4 and filter. Concentrate under reduced pressure at 55°C to obtain 5 g of compound F as a dark red solid (yield: 50%).

[0220] Step 6. Synthesis of compound G

[0221] Compound G was synthesized according to the following reaction schematic.

[0222]

[0223] Add 5 g (0.02 mole) of Compound F. Add 100 mL of DMF and stir. Add 35 g (0.028 mole) of K2CO and slowly add 21 g (0.05 mole) of Allyl bromide. Raise the internal temperature to 40°C and stir for 3 hours. When the reaction is complete, add 750 mL of dichloromethane and 500 mL of distilled water and separate the layers. Wash the separated dichloromethane layer with 500 mL of distilled water. Remove moisture from the combined organic layers with MgSO4 and filter. Concentrate under reduced pressure at 55°C to obtain 3.5 g of compound G as a dark red solid (yield 60%).

[0224] Step 7. Synthesis of compound H

[0225] Compound H was synthesized according to the following reaction schematic.

[0226]

[0227] Add 5 g (0.02 mole) of compound F. Add 50 mL of dichlorobenzene and stir. Raise the internal temperature to 140°C and stir for 1 hour. When the reaction is complete, remove all dichlorobenzene by concentrating under reduced pressure at 70°C. Dry under vacuum at 55°C to obtain 4 g of compound H as a dark red solid. (Yield: 80%)

[0228] Step 8. Synthesis of compound H

[0229] JH-W003 was synthesized according to the following reaction schematic.

[0230]

[0231] Add 4 g (0.02 mole) of Compound H. Add 50 mL of dichloromethane and cool to -10°C. Slowly add 95% H2SO4 and stir for 10 minutes. Add 50 mL of dichloromethane and 50 mL of distilled water and separate the layers. Wash the separated organic layer with 50 mL of distilled water. Concentrate under reduced pressure at 55°C to obtain 1.5 g of a dark red solid, JH-W003 (yield: 30%).

[0232]

[0233] <Example 4> Synthesis of W004 compound

[0234] The overall reaction schematic for the synthesis of compound W004 (compound 27 precursor) is as follows.

[0235] [Correction pursuant to Rule 91, November 19, 2025]

[0236] Below, each step is explained.

[0237] Step 1. Synthesis of intermediate 3

[0238] Intermediate 3 was synthesized according to the following reaction schematic diagram.

[0239]

[0240] To a solution of compound 1 (200 mg, 853 μmol, 1.00 eq), 4A MOLECULAR sieve (1.60 g), and compound 2 (124 mg, 1.71 mmol, 169 μL, 2.00 eq) in toluene (6.00 mL) was added TsOH·H2O (16.2 mg, 85.4 μmol, 0.100 eq). The mixture was stirred at 110°C for 10 h under N2. LC-MS (EC9173-85-P1A2) indicated that compound 1 was completely reacted. The mixture was quenched with ice-water (20.0 mL), filtered, and extracted with EtOAc (10.0 mL * 2). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue. The residue was purified twice by Prep-TLC (SiO2, petroleum ether:ethyl acetate = 1:1). Compound 3 (50.0 mg, 174 μmol, 20.3% yield) was obtained as a yellow solid, which was confirmed by H NMR (EC9173-85-P1C1).

[0241] LC-MS: EC9173-85-P1A2, (M+H) + : 288.1

[0242] H NMR: EC9173-85-P1C1, (400 MHz, CDCl3)

[0243] δ9.96 (s, 1H), 7.12 (s, 1H), 6.90 - 6.76 (m, 2H), 4.07 (d,J= 6.4 Hz, 6H), 3.42 - 3.32 (m, 1H), 1.49 (d,J= 7.2 Hz, 6H)

[0244] Step 2. Synthesis of W004 compound (compound 27 precursor)

[0245] Compound W004 (compound 27 precursor) was synthesized according to the following reaction schematic diagram.

[0246]

[0247] To a solution of compound 3 (10.0 mg, 34.8 μmol, 1.00 eq) dissolved in DMF (1.00 mL) was added IBX (11.7 mg, 41.7 μmol, 1.20 eq), and the mixture was stirred at 25 °C for 3 h. LC-MS (EC9173-86-P1A1) indicated that compound 3 was completely reacted. The mixture was quenched with ice-water (10.0 mL) and extracted with EtOAc (10.0 mL * 2). Next, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO2, petroleum ether: ethyl acetate = 0:1). The residue was purified by Prep-HPLC (Column: Phenomenex luna C18 150*25mm*10um; Mobile phase: [Water (FA) - ACN]; B%: 20% - 50%, 8 min). The residue was purified again by Prep-HPLC (Column: Waters xbridge 150 * 25 mm 10um; Mobile phase: [Water (NH4HCO3) - ACN]; B%: 17% - 47%, 8 min). Compound W004 (compound 27 precursor) (1.84 mg, 6.03 μmol, 17.3% yield, 98.7% purity) was obtained as a red solid and confirmed by H NMR (EC9173-86-P1C0), LC-MS (EC9173-86-P1L0), and HPLC (EC9173-86-P1H0). Figure 5 shows H NMR data of compound W004 (compound 27 precursor), and Figure 6 shows HPLC data.

[0248] LC-MS: EC9173-86-P1A1, (M+H) + : 302.0

[0249]

[0250] H NMR: EC9173-86-P1C0, (400 MHz, CDCl3)

[0251] δ7.31 (d,J= 9.6 Hz, 1H), 7.13 (d,J= 9.6 Hz, 1H), 3.99 (d,J= 12.4 Hz, 6H), 3.39 - 3.26 (m, 1H), 1.47 (d,J= 7.2 Hz, 6H)

[0252] LC-MS: EC9173-86-P1C0, (M+H) + : 301.9

[0253] HPLC: EC9173-86-P1C0, Purity: 98.7% (220 nm)

[0254]

[0255] <Example 5> Synthesis of compound W005

[0256] The overall reaction schematic for the synthesis of compound W005 (compound 1a precursor) is as follows.

[0257] [Correction pursuant to Rule 91, November 19, 2025]

[0258] Below, each step is explained.

[0259] Step 1. Synthesis of intermediate 3

[0260] Intermediate 3 was synthesized according to the following reaction schematic diagram.

[0261]

[0262] A mixture of compound 1 (100 mg, 427 μmol, 1.00 eq), compound 2 (70.0 mg, 467 μmol, 54.3 μL, 1.10 eq), TEA (47.5 mg, 467 μmol, 65.4 μL, 1.10 eq), and NaI (64.0 mg, 427 μmol, 1.00 eq) dissolved in DMF (2.00 mL) was degassed and purged three times with N2. Next, the mixture was stirred at 25°C for 16 h under N2 atmosphere. LC-MS (EC9180-80-P1A) indicated that compound 1 was completely reacted. The reaction mixture was diluted with H2O (10.0 mL) and extracted with DCM (10.0 mL * 3). The combined organic layers were washed with brine (10.0 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate = 0 / 1). Compound 3 (12.0 mg, 40.0 μmol, 9.30% yield) was obtained as a red solid, which was confirmed by LC-MS (EC9180-80-P1C).

[0263] LC-MS: EC9180-80-P1C, (M+H) + : 302.8.

[0264] Step 2. Synthesis of W005 compound (compound 1a precursor)

[0265] Compound W005 (compound 1a precursor) was synthesized according to the following reaction schematic diagram.

[0266]

[0267] To a solution of compound 3 (12.0 mg, 40.0 μmol, 1.00 eq) dissolved in DCM (2.00 mL) was added H2SO4 (7.94 mg, 80.0 μmol, 4.32 μL, 98.0% purity, 2.00 eq). The mixture was stirred at 0°C for 1 h. LC-MS (EC9180-81-P1A) indicated that compound 3 was completely reacted. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (10 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150 * 25 mm * 5 μm; mobile phase: [water (HCl) - ACN]; B%: 14% - 44%, 11 min). Compound W005 (compound 1a precursor) (6.07 mg, 32.50 μmol, 81.87% yield, 98.24% purity) was obtained as a yellow solid, which was confirmed by LC-MS (EC9180-81-P1D), H NMR (EC9180-81-P1), and H PLC (EC9180-81-P1H1). Figure 7 is H NMR data of compound W005 (compound 1a precursor), and Figure 8 is H PLC data.

[0268] H NMR: EC9180-81-P1,

[0269] 1 H NMR (400 MHz, CDCl3)

[0270] δ7.8 (d,J= 9.2 Hz, 1H), 7.22 (d,J= 9.2 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 2.56 (t,J= 6.4 Hz, 2H), 1.77 (t,J= 6.6 Hz, 2H), 1.39 (s, 6H).

[0271] LC-MS: EC9180-81-P1A, (M+H) + : 303.1.

[0272] LC-MS: EC9180-81-P1D, Purity: 99.17% (220 nm), (M+H) + : 303.1.

[0273] H PLC: EC9180-81-P1H1, Purity: 98.24% (220 nm)

[0274]

[0275] <Example 6> Synthesis of W006 compound

[0276] Compound W006 (compound 8 int.2a) was synthesized according to the following reaction schematic.

[0277]

[0278] A mixture of Int.6 (100 mg, 427 μmol, 1.00 eq), compound 1 (65.3 mg, 470 μmol, 42.4 μL, 1.10 eq), NaI (70.4 mg, 470 μmol, 1.10 eq), and TEA (86.4 mg, 854 μmol, 119 μL, 2.00 eq) dissolved in DMF (20.0 mL) was degassed and purged with N2 three times. Next, the mixture was stirred at 25 °C under N2 atmosphere. oC for 4 h. LC-MS (EC9180-89-P1A) showed that the desired mass was detected. The reaction mixture was diluted with H2O (20.0 mL) and extracted with DCM (10.0 mL * 3). The combined organic layers were washed with brine (10.0 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-HPLC (Column: Welch Xtimate C18 150* 25 mm* 5 um; Mobile phase: [water (HCl) - ACN]; B%: 0% - 27%, 11 min). Compound W006 (compound 8 int. 2a) (5.12 mg, 17.1 μmol, 4.01% yield, 100% purity) was obtained as a red solid, which was confirmed by H NMR (EC9180-89-P1A), LC-MS (EC9180-89-P1L3), and HPLC (EC9180-89-P1H1). Figure 9 shows H NMR data of compound W006 (compound 8 int. 2a), and Figure 10 shows HPLC data.

[0279] LC-MS: EC9180-89-P1A, (M+H) + : 293.0.

[0280] H NMR: EC9180-89-P1A, (400 MHz, CD3OD)

[0281] δ7.54 (d,J= 9.6 Hz, 1H), 7..49 (d,J= 9.6 Hz, 1H), 6.08 (s, 1H), 4.09 (t,J= 6.2 Hz, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.75 (t,J= 6.0 Hz, 2H).

[0282] LC-MS: EC9180-89-P1L3, (M+H) + : 293.1.

[0283] HPLC: EC9180-89-P1H1, Purity: 100.0% (220 nm).

[0284]

[0285] <Example 7> Synthesis of W010 compound

[0286] Compound W010 (compound 8 int.10) was synthesized according to the following reaction schematic diagram.

[0287]

[0288] To a solution of compound 1 (30.0 mg, 108 μmol, 1.00 eq) dissolved in MeOH (2.00 mL) was added HCl (12 M, 18.1 μL, 2.00 eq). The mixture was stirred at 68 °C for 1 h. LC-MS (EC9180-127-P1A3) showed that compound 1 was completely reacted and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-HPLC (Column: Welch Xtimate C18 150*25 mm*5 μm; Mobile phase: [water (HCl)-ACN]; B%: 5%-35%, 10 min). Compound W010 (compound 8 int.10) (4.37 mg, 15.93 μmol, 14.67% yield, 100% purity) was obtained as a yellow solid, which was confirmed by H NMR (EC9180-127-P2A2), LC-MS (EC9180-127-P2A1), and HPLC (EC9180-127-P2A2). Figure 11 shows H NMR data of compound W010 (compound 8 int.10), and Figure 12 shows HPLC data.

[0289] LC-MS: EC9180-127-P1A3 (M+H) + : 275.1

[0290] H NMR: EC9180-127-P2A2, (400 MHz, CDCl3).

[0291] δ= 7.30 (d,J= 9.6 Hz, 1H), 7.24 (d,J= 9.6 Hz, 1H), 4.27 (t,J= 5.2 Hz, 2H), 3.95 (d,J= 0.6 Hz, 6H), 2.55 (t,J= 6.4 Hz, 2H), 2.03 - 1.86 (m, 2H).

[0292] HPLC: EC9180-127-P2A2, Purity: 100% (220 nm)

[0293]

[0294] <Example 8> Synthesis of W011 compound

[0295] The overall reaction schematic for the synthesis of compound W011 (compound 8) is as follows.

[0296] [Correction pursuant to Rule 91, November 19, 2025]

[0297] Below, each step is explained.

[0298] Step 1. Synthesis of intermediate 3

[0299] Intermediate 3 was synthesized according to the following reaction schematic diagram.

[0300]

[0301] To a solution of compound 1 (2.16 g, 9.95 mmol, 1.00 eq) and compound 2 (14.0 g, 206 mmol, 20.7 eq) dissolved in THF (15.0 mL) was added LDA (2 M, 5.47 mL, 1.10 eq) at -78 °C. The mixture was stirred at -78 °C for 1 h. TLC (SiO2:petroleum ether:ethyl acetate = 5:1) confirmed that the reaction proceeded cleanly. The reaction mixture was quenched by adding 2 N NH4Cl solution (15.0 mL) at -78 °C, diluted with H2O (30.0 mL), and extracted with ethyl acetate (50.0 mL * 3). The combined organic layers were washed with brine (50.0 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain intermediate 3 (2.10 g, crude) as a yellow solid.

[0302] Step 2. Synthesis of Intermediate 4

[0303] Intermediate 4 was synthesized according to the following reaction schematic diagram.

[0304]

[0305] To a solution of intermediate 3 (2.10 g, 10.3 mmol, 1.00 eq) dissolved in MeOH (10.0 mL) was added HCl (12 M, 857 μL, 1.00 eq). The mixture was stirred at 70 °C for 2 h. TLC (SiO2, petroleum ether: ethyl acetate = 5:1) indicated that intermediate 3 had reacted completely. The reaction mixture was concentrated under reduced pressure to give intermediate 4 (2.10 g, crude) as a yellow solid.

[0306] Step 3. Synthesis of intermediate 6

[0307] Intermediate 6 was synthesized according to the following reaction schematic.

[0308]

[0309] Intermediate 5 (3.73 g, 30.9 mmol, 3.00 eq) was added to a solution of intermediate 4 (2.10 g, 10.3 mmol, 1.00 eq) and K2CO3 (2.84 g, 20.6 mmol, 2.00 eq) dissolved in ACN (20.0 mL). The mixture was stirred at 70°C for 5 h. The reaction mixture was concentrated under reduced pressure to obtain intermediate 6 (2.40 g, crude) as a brown solid.

[0310] Step 4. Synthesis of Intermediate 7

[0311] Intermediate 7 was synthesized according to the following reaction schematic diagram.

[0312]

[0313] Intermediate 6 (1.50 g, 6.15 mmol, 1.00 eq) was added to DMF (10.0 mL). The mixture was stirred at 180°C for 1 h. TLC (SiO2, petroleum ether: ethyl acetate = 10:1) indicated that 6 was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a residue. Intermediate 7 (1.40 g, crude) was obtained as a dark brown oil, which was confirmed by H NMR (EC9180-110-P1A) and LC-MS (EC9180-110-P1A1).

[0314] H NMR: EC9180-110-P1A, (400 MHz, CDCl3).

[0315] δ9.73 (s, 1H), 7.68 (d,J= 8.5 Hz, 1H), 7.29 (d,J= 8.5 Hz, 1H), 6.67 (d,J= 8.4 Hz, 1H), 6.61 (d,J= 8.4 Hz, 1H), 6.15 - 6.03 (m, 1H), 5.14 - 5.03 (m, 2H), 4.02 (s, 3H), 3.95 (s, 3H), 3.58 - 3.52 (d,J= 6.4 Hz,, 2H)

[0316] LC-MS: EC9180-110-P1A1, (M+H) +: 244.9.

[0317] Step 5. Synthesis of Intermediate 8

[0318] Intermediate 8 was synthesized according to the following reaction schematic diagram.

[0319]

[0320] To a solution of intermediate 7 (1.40 g, 5.73 mmol, 1.00 eq) dissolved in THF (20.0 mL) was added BH3·THF (1 M, 17.2 mL, 3 eq) dropwise at 0°C. After the addition, the mixture was stirred at this temperature for 2 h, and then H2O2 (2.80 g, 24.7 mmol, 1.65 mL, 30% purity, 4.31 eq) and NaOH (3 M, 5.73 mL, 3.00 eq) were added dropwise at 0°C. The resulting mixture was stirred at 25°C for 2 h. LC-MS (EC9180-116-P1A) indicated that intermediate 7 was completely reacted. The reaction mixture was quenched by adding 1 M Na2SO3 (20.0 mL) at 0 ℃, diluted with H2O (50.0 mL), and extracted with ethyl acetate (50.0 mL * 3). The combined organic layers were washed with brine (50.0 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:0 to 5:1). Intermediate 8 (850 mg, 3.24 mmol, 56.5% yield) was obtained as a green solid.

[0321] LC-MS: EC9180-116-P1A, (M+H) + : 263.1.

[0322] Step 6. Synthesis of Intermediate 9

[0323] Intermediate 9 was synthesized according to the following reaction schematic.

[0324]

[0325] To a solution of intermediate 8 (400 mg, 1.52 mmol, 1.00 eq) dissolved in ACN (16.0 mL) were added Na2B4O7 (0.25 M, 3.05 mL, 0.500 eq), Fremy's salt (822 mg, 3.05 mmol, 2.00 eq), and NaOH (0.1 M, 15.3 mL, 1.00 eq). The mixture was stirred at 25 °C for 10 h. TLC (SiO2, petroleum ether: ethyl acetate = 0:1) indicated that intermediate 8 was completely reacted. The reaction mixture was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO2, petroleum ether: ethyl acetate = 0:1, Rf = 0.25). Intermediate 9 (300 mg, 1.09 mmol, 71.2% yield) was obtained as a red solid and confirmed by LC-MS (EC9180-134-P1A1).

[0326] LC-MS: EC9180-134-P1A1, (M+H) + : 277.1

[0327] Step 7. Synthesis of compound 8 int.10

[0328] Compound 8_int.10 was synthesized according to the following reaction schematic.

[0329]

[0330] To a solution of intermediate 9 (400 mg, 1.45 mmol, 1.00 eq) dissolved in MeOH (20.0 mL) was added HCl (12 M, 241 μL, 2.00 eq). The mixture was stirred at 68 °C for 3 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-HPLC (Column: Phenomenex Luna C18 200*40mm*10 μm; Mobile phase: [Water (HCl) - ACN]; B%: 15% - 45%, 10 min) as a yellow solid. Compound 8_int.10 (130 mg, 474 μmol, 32.7% yield) was obtained as a yellow solid and confirmed by LC-MS (EC9180-136-P2A1) and HPLC (EC9180-136-P2A2).

[0331] LC-MS: EC9180-136-P2A1, (M+H) + : 275.1.

[0332] HPLC: EC9180-136-P2A2, Purity: 89.1% (254 nm)

[0333] Step 8. Synthesis of Compound 8

[0334] Compound W011 (compound 8) was synthesized according to the following reaction schematic.

[0335]

[0336] To a solution of compound 8_int.10 (80.0 mg, 292 μmol, 1.00 eq) in DCM (4.00 mL) was added BBr3 (146 mg, 583 μmol, 56.2 μL, 2.00 eq). The mixture was stirred at -40 °C for 1 h. TLC (SiO2, petroleum ether: ethyl acetate = 0:1) indicated that compound 8_int.10 was completely reacted. The reaction mixture was quenched by the addition of CH3OH (0.200 mL) at -20 °C to obtain a mixture. The mixture was purified by Prep-TLC (SiO2, petroleum ether: ethyl acetate = 0:1; Rf = 0.75) to obtain a residue. A red solid was obtained from the purified residue by Prep-HPLC (Column: Welch Ultimate C18 150 * 25 mm * 5 μm; Mobile phase: [Water (HCl) - ACN]; B%: 35% - 65%, 10 min). Compound 8 (35.0 mg, 141. μmol, 48.3% yield, 99.19% purity) was obtained as a red solid, which was confirmed by H NMR (EC9180-140-P1A2), LC-MS (EC9180-140-P1A3), and HPLC (EC9180-140-P1A4). Figure 13 shows H NMR data of W011 compound (compound 8), and Figure 14 shows HPLC data.

[0337] H NMR: EC9180-140-P1A2, (400 MHz, CDCl3).

[0338] δ12.73 (s, 1H), 12.22 (s, 1H), 7.27~7.18 (m, 2H), 4.38 (t,J= 5.2 Hz, 2H), 2.63 (t,J= 6.4 Hz, 2H), 2.09 - 1.55 (m, 2H).

[0339] LC-MS: EC9180-140-P1A3, (M+H) + : 247.2

[0340] HPLC: EC9180-140-P1A4, Purity: 99.19% (220 nm).

[0341]

[0342] <Example 9> Synthesis of W013 compound

[0343] The overall reaction schematic for the synthesis of compound W013 (compound 23) is as follows.

[0344] [Correction pursuant to Rule 91, November 19, 2025]

[0345] Below, each step is explained.

[0346] Step 1. Synthesis of Intermediate 2

[0347] Intermediate 2 was synthesized according to the following reaction schematic diagram.

[0348]

[0349] To a solution of compound 1 (10.0 g, 43.2 mmol, 1.00 eq) and CuI (4.12 g, 31.6 mmol, 0.500 eq) in DMF (100 mL) and MeOH (100 mL) was added NaOMe (15.5 g, 86.5 mmol, 30% purity, 2.00 eq) dropwise at 25 °C, and the mixture was stirred at 100 °C for 10 h. The mixture was diluted with water (200 mL), acidified to pH = 2 with HCl (1.00 M), filtered, and extracted with EtOAc (200 mL* 2). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:0 to 15:1). Compound 2 (4.00 g, 21.9 mmol, 50.7% yield) was obtained as a yellow solid and confirmed by H NMR (EC9173-155-P1C1).

[0350] H NMR: EC9173-52-P1C2, (400 MHz, CDCl3)

[0351] δ12.19 (s, 1H), 10.33 (s, 1H), 7.03 (d,J= 9.0 Hz, 1H), 6.28 (d,J= 9.0 Hz, 1H), 3.86 (s, 6H)

[0352] Step 2. Synthesis of Intermediate 3

[0353] Intermediate 3 was synthesized according to the following reaction schematic diagram.

[0354]

[0355] To a solution of intermediate 2 (500 mg, 2.74 mmol, 1.00 eq) and DBU (1.25 g, 8.23 ​​mmol, 1.24 mL, 3.00 eq) in MeCN (10.0 mL) was added TBSCl (620 mg, 4.12 mmol, 506 μL, 1.50 eq) in portions, and the mixture was stirred at 25 °C for 1 h. LC-MS (EC9173-160-P1B2) indicated that compound 2 was completely reacted. The reaction mixture was diluted with DCM (5.00 mL) and purified directly by prep-TLC (SiO2, petroleum ether:ethyl acetate = 5:1, Rf = 0.70). Intermediate 3 (660 mg, 2.23 mmol, 81.1% yield) was obtained as a yellow solid, which was confirmed by H NMR (EC9173-160-P1C2).

[0356] LC-MS: EC9173-160-P1B2, (M+H) + : 297.1

[0357] H NMR: EC9173-160-P1C2, (400 MHz, CDCl3)

[0358] δ10.52 (s, 1H), 6.99 (d,J= 9.0 Hz, 1H), 6.48 (d,J= 9.0 Hz, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 0.99 (s, 9H), 0.21 (s, 6H)

[0359] Step 3. Synthesis of Intermediate 5

[0360] Intermediate 5 was synthesized according to the following reaction schematic diagram.

[0361]

[0362] Compound 4 (1.00 M, 5.00 mL, 2.12 eq) was added dropwise to a solution of intermediate 3 (700 mg, 2.36 mmol, 1.00 eq) dissolved in THF (70.0 mL) at -70 °C, and the mixture was stirred for 1 h under N2 atmosphere at -70 °C. LC-MS (EC9173-161-P1A2) indicated that intermediate 3 was completely reacted. The mixture was quenched with saturated NH4Cl (150 mL) at 0 °C and extracted with EtOAc (100 mL * 2). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue. The mixture was purified by Prep-TLC (SiO2, petroleum ether: ethyl acetate = 5:1, Rf = 0.50). Intermediate 5 (500 mg, 1.48 mmol, 62.5% yield) was obtained as a yellow solid, which was confirmed by H NMR (EC9173-161-P1C2).

[0363]

[0364] LC-MS: EC9173-161-P1A2, (M-OH) + : 321.3

[0365] H NMR: EC9173-161-P1C2, (400 MHz, CDCl3)

[0366] δ6.68 (d,J= 9.0 Hz, 1H), 6.45 (d,J= 9.0 Hz, 1H), 5.89 (tdd,J1= 17.2 Hz,J2= 10.2 Hz,J3= 7.2 Hz, 1H), 5.22 (dd,J1= 8.8 Hz,J2= 5.2 Hz, 1H), 5.12 - 5.00 (m, 2H), 3.83 (s, 3H), 3.74 (s, 3H), 2.69 (ddd,J1= 14.4 Hz,J2= 8.4 Hz,J3= 7.6 Hz, 1H), 2.52 - 2.42 (m, 1H), 1.00 (s, 9H), 0.21 (d,J= 8.4 Hz, 6H)

[0367] Step 4. Synthesis of intermediate 6

[0368] Intermediate 6 was synthesized according to the following reaction schematic.

[0369]

[0370] To a solution of intermediate 5 (500 mg, 1.48 mmol, 1.00 eq) dissolved in DMF (10.0 mL) was added IBX (500 mg, 1.79 mmol, 1.21 eq) and stirred at 25 °C for 3 h. LC-MS (EC9173-165-P1A1) indicated that intermediate 5 was completely reacted. The mixture was quenched with ice-water (20.0 mL) and extracted with EtOAc (20.0 mL * 2). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO2, petroleum ether:ethyl acetate = 5:1, Rf = 0.55). Intermediate 6 (420 mg, 1.25 mmol, 84.5% yield) was obtained as a yellow solid, which was confirmed by H NMR (EC9173-165-P1C1).

[0371]

[0372] LC-MS: EC9173-165-P1A1, (M+H) + : 337.6

[0373] H NMR: EC9173-165-P1C1, (400 MHz, CDCl3)

[0374] δ6.77 (d,J= 9.0 Hz, 1H), 6.44 (d,J= 9.0 Hz, 1H), 6.03 (tdd,J1= 17.2 Hz,J2= 10.4 Hz,J3= 6.8 Hz, 1H), 5.23 - 5.07 (m, 2H), 3.76 (s, 3H), 3.74 (s, 3H), 3.56 (dt,J1= 6.8 Hz,J2= 1.2 Hz, 2H), 0.94 (s, 9H), 0.15 (s, 6H)

[0375] Step 5. Synthesis of Compound 23 Int.7

[0376] Compound 23_Int.7 was synthesized according to the following reaction schematic.

[0377]

[0378] To a solution of intermediate 6 (200 mg, 594 μmol, 1.00 eq) dissolved in DCM (10.0 mL) was added H2SO4 (5.83 mg, 59.4 μmol, 3.17 μL, 0.100 eq) and stirred at 20 °C for 5 h. TLC (SiO2, petroleum ether: ethyl acetate = 1:1, Rf = 0.50) indicated that intermediate 6 was completely reacted. The mixture was poured into ice-water (20.0 mL) and extracted with DCM (20.0 mL * 2). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-HPLC (Column: Welch Ultimate C18 150 * 25 mm * 5 μm; Mobile phase: [Water (HCl) - ACN]; Gradient: 12% - 42% B over 10 min). Compound 23_Int.7 (40.0 mg, 179 μmol, 30.2% yield, 99.88% purity) was obtained as a white solid, which was confirmed by H NMR (EC9173-168-P1D1), LC-MS (EC9173-168-P1L1), and HPLC (EC9173-168-P1H1).

[0379] H NMR: EC9173-168-P1D1, (400 MHz, CDCl3)

[0380] δ7.01 (d,J= 9.0 Hz, 1H), 6.43 (d,J= 9.0 Hz, 1H), 4.71 - 4.55 (m, 1H), 3.86 (d,J= 5.2 Hz, 6H), 2.69 (d,J= 7.6 Hz, 2H), 1.56 (d,J=6.4 Hz, 3H)

[0381] LC-MS: EC9173-168-P1L1, (M+H) + : 222.9

[0382] HPLC: EC9173-168-P1H1, Purity: 99.88% (220 nm)

[0383] Step 6. Synthesis of W013 (Compound 23)

[0384] W013 (compound 23) was synthesized according to the following reaction schematic.

[0385]

[0386] To a solution of compound 23_Int.7 (100 mg, 449 μmol, 1.00 eq) in EtOH (4.00 mL) were added HCl (12.0 M, 5.00 mL, 133 eq) and i-amyl-nitrite (158 mg, 1.35 mmol, 181 μL, 3.00 eq) dropwise and stirred at 25 °C for 1 h. LC-MS (EC9173-173-P1A1) indicated that compound 23_Int.7 was completely reacted. The mixture was quenched with ice-water (20.0 mL) and extracted with EtOAc (20.0 mL * 2). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-HPLC (Column: Welch Xtimate C18 150 * 25 mm * 5 μm; Mobile phase: [Water (HCl) - ACN]; Gradient: 10% - 40% B over 10 min). Compound 23 (17.31 mg, 88.0 μmol, 15.6% yield, 96.09% purity) was obtained as a pale yellow solid, which was confirmed by H NMR (EC9173-173-P1C4), LC-MS (EC9173-173-P1L4), and HPLC (EC9173-173-P1H4). Figure 15 shows H NMR data of W013 (compound 23), and Figure 16 shows HPLC (EC9180-53-P1H) data.

[0387] LC-MS: EC9173-173-P1A1, (M+H) + : 237.1

[0388] H NMR: EC9173-173-P1C4, (400 MHz, CDCl3)

[0389] δ7.07 (d,J= 9.0 Hz, 1H), 6.68 (d,J= 9.0 Hz, 1H), 6.57 - 6.34 (m, 1H), 3.95 (d,J= 4.0 Hz, 6H), 2.51 (s, 3H)

[0390] LC-MS: EC9173-173-P1L4, (MH) + : 237.2

[0391]

[0392] <Example 10> Synthesis of W014 compound

[0393] The overall reaction schematic for the synthesis of compound W014 (compound 18 int.6A) is as follows.

[0394] [Correction pursuant to Rule 91, November 19, 2025]

[0395] Below, each step is explained.

[0396] Step 1. Synthesis of Compound 3

[0397] Compound 3 was synthesized according to the following reaction schematic.

[0398]

[0399] Compound 2 (134 mg, 548 μmol, 0.100 eq) was added to a solution of compound 1 (1.00 g, 5.49 mmol, 1.00 eq), (HCHO)n (1.00 g), and TEA (55.5 mg, 548 μmol, 76.4 μL, 0.100 eq) dissolved in EtOH (5.00 mL). The mixture was stirred at 60 °C for 36 h. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 3:1). Compound 3 (360 mg, 1.70 mmol, 30.9% yield) was obtained as a yellow solid, which was confirmed by H NMR (EC9173-192-P1C1).

[0400] H NMR: EC9173-192-P1C1, (400 MHz, CDCl3)

[0401] δ12.97 (s, 1H), 7.05 (d,J= 9.0 Hz, 1H), 6.33 (d,J= 9.0 Hz, 1H), 4.80 (s, 2H), 3.88 (d,J= 2.4 Hz, 6H)

[0402] Step 2. Synthesis of Compound 5

[0403] Compound 5 was synthesized according to the following reaction schematic.

[0404]

[0405] A solution of compound 3 (200 mg, 942 μmol, 1.00 eq) and sodium propionate (200.00 mg, 2.08 mmol, 2.21 eq) dissolved in compound 4 (1.00 g, 7.68 mmol, 990 μL, 8.15 eq) was stirred at 140 °C under N2 for 4 h. The mixture was diluted with EtOAc (5.00 mL) and purified directly by Prep-TLC (SiO2, petroleum ether:ethyl acetate = 1:1). Compound 5 (110 mg, 359 μmol, 38.1% yield) was obtained as a brown solid, which was confirmed by H NMR (EC9173-194-P1C1).

[0406] H NMR: EC9173-194-P1C1, (400 MHz, CDCl3)

[0407]

[0408] δ7.10 (d,J= 9.0 Hz, 1H), 6.69 (d,J= 9.0 Hz, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 2.69 (dq,J1= 12.0 Hz,J2= 7.6 Hz, 4H), 1.31 (m, 6H)

[0409] Step 3. Synthesis of compound W014

[0410]

[0411] Compound W014 (compound 18_int.6A) was synthesized according to the following reaction schematic.

[0412]

[0413] To a solution of compound 5 (110 mg, 359 μmol, 1.00 eq) dissolved in MeOH (5.00 mL) was added HCl (4.0 M, 5.00 mL, 55.6 eq) and stirred at 25°C for 10 h. LC-MS (EC9173-196-P1A4) indicated that compound 5 was completely reacted. The mixture was concentrated under reduced pressure to obtain a residue. The residue was triturated with MTBE (2.00 mL) and filtered. The filter cake was concentrated under reduced pressure to obtain the product. Compound W014 (compound 18_int.6A) (60.0 mg, 239 μmol, 66.7% yield, 100% purity) was obtained as a yellow solid, which was confirmed by H NMR (EC9173-196-P1C2), LC-MS (EC9173-196-P1L1), and HPLC (EC9173-196-P1H1). Figure 17 shows H NMR data of compound W014 (compound 18_int.6A), and Figure 18 shows HPLC data.

[0414] LC-MS: EC9173-196-P1A4, (M+H) +: 251.1

[0415] H NMR: EC9173-196-P1C2, (400 MHz, CDCl3)

[0416] δ7.07 (d,J= 9.0 Hz, 1H), 6.67 (d,J= 9.0 Hz, 1H), 6.48 (s, 1H), 3.95 (d,J= 6.0 Hz, 6H), 2.88 (q,J= 7.6 Hz, 2H), 1.36 (t,J= 7.6 Hz, 3H)

[0417] LC-MS: EC9173-196-P1L1, (M+H) + : 251.2

[0418] HPLC: EC9173-196-P1H1, Purity: 100% (220 nm)

[0419]

[0420] <Example 11> Synthesis of W017 compound

[0421] The overall reaction schematic for the synthesis of compound W017 (compound 19 int.9) is as follows.

[0422] [Correction pursuant to Rule 91, November 19, 2025]

[0423] Below, each step is explained.

[0424] Step 1. Synthesis of Compound 3

[0425] Compound 3 was synthesized according to the following reaction schematic.

[0426]

[0427] A solution of compound 1 (130 mg, 613 μmol, 1.00 eq) and sodium butyrate (148 mg, 1.35 mmol, 2.20 eq) in compound 2 (775 mg, 4.90 mmol, 801 μL, 8.00 eq) was stirred at 140°C under N2 atmosphere for 4 h. The mixture was cooled to room temperature to obtain the crude product. The residue was purified by Prep-TLC (SiO2, petroleum ether: ethyl acetate = 1:1; Rf = 0.25). Compound 3 (150 mg, 448 μmol, 73.2% yield) was obtained as a brown solid.

[0428] Step 2. Synthesis of W017 compound

[0429] Compound W017 (compound 19 int.9) was synthesized according to the following reaction schematic diagram.

[0430]

[0431] To a solution of compound 3 (90.0 mg, 269 μmol, 1.00 eq) dissolved in MeOH (2.00 mL) was added HCl (12.0 M, 89.7 μL, 4.00 eq). The mixture was stirred at 40°C for 8 h. LC-MS (EC9180-170-P1A3) indicated that compound 3 was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO2, petroleum ether:ethyl acetate = 1:1, Rf = 0.40). Compound W017 (compound 19 int. 9) (60.0 mg, 226 μmol, 84.1% yield, 99.78% purity) was obtained as an off-white solid, which was confirmed by H NMR (EC9180-170-P1A2), LC-MS (EC9180-170- P1AL1), and HPLC (EC9180-170-P1AH1). Figure 19 shows H NMR data of compound W017 (compound 19 int. 9), and Figure 20 shows HPLC data.

[0432]

[0433] <Example 12> Synthesis of compound M004

[0434] Step 1. Synthesis of intermediate compound 6

[0435] Compound 6, an intermediate, was synthesized according to the following reaction schematic diagram.

[0436]

[0437] 1,5-Dimethoxynaphthalene (5 g, 26.56 mmol) was placed in a round flask and acetonitrile (50 mL) was added. After placing the mixture in an ice bath, N-bromosuccinimide (11.8 g, 66.4 mmol, 2.5 eq) was dissolved in acetonitrile (120 mL) and dropped. The bath was removed and the reaction was allowed to proceed at room temperature for about 2 hours. The reaction mixture was placed in an ice bath again and cooled. The resulting solid was filtered and washed with MeOH and PET. Ether. After drying under reduced pressure, the desired substance, compound 2, was obtained in an amount of 6.35 g (69% yield).

[0438] 1 H NMR (DMSO-d6): δ 7.77 (d, 2H), 6.99 (d, 2H), 3.89 (s, 6H).

[0439]

[0440] Compound 2 (6.3 g, 18.2 mmol) was placed in a round flask and DMF (80 mL) was added. CuI (11.5 g, 60.3 mmol, 3.3 eq) and MeOH (70 mL) were added. NaOMe (11.2 mL, 30% w / w in MeOH, 3.3 eq) was added and the mixture was refluxed for 48 h. The mixture was cooled to room temperature and water (~100 mL) was added to form a solid. The resulting solid was filtered and dried. The crude material was dissolved in CHCl3 (200 mL). Insoluble impurities were filtered out, and the solution was purified by silica gel column chromatography (DCM:EA=9:1) to obtain 1.5 g of compound 3 in a yield of 33%.

[0441] 1 H NMR (CDCl3): δ 6.87 (s, 4H), 3.93 (s, 12H).

[0442]

[0443] Add N,N-Dimethylformamide (1.56 mL, 20.13 mmol, 5.0 eq) to a round flask. Slowly add POCl3 (1.88 mL, 20.13 mmol, 3.3 eq) at 0°C. Add compound 3 (1 g, 4.027 mmol) dissolved in CHCl3 (20 mL) at room temperature. Reflux and react for 24 h. Cool to room temperature and remove the solvent from the reaction solution. Add water to form a solid. Filter the formed solid and wash with water. Dry under reduced pressure to obtain 980 mg of compound 4 in a yield of 88%.

[0444] 1 H NMR (CDCl3): δ 10.58 (s, 1H), 7.22 (s, 1H), 7.05 (d, 1H), 6.94 (d, 1H), 4.02 (d, 6H), 3.93 (d, 6H).

[0445]

[0446] Compound 4 (5 g, 18.096 mmol) was placed in a round flask and dissolved in anhydrous THF (100 mL). Slowly add allylmagnesium bromide (27.6 mL, 1 M in ether, 1.3 eq) solution. React at room temperature for 3 hours. After TLC confirmation that the starting material has disappeared, extract the reaction solution by adding saturated NH4Cl solution and EA. Extract once more with ethyl acetate as an organic solvent, collect the organic solvent, and wash once more with brine. After adding MgSO4, filtering, and concentrating under reduced pressure, compound 5 was obtained (5.7 g, 98% yield).

[0447] 1 H NMR (CDCl3): δ 7.03 (s, 1H), 6.86 (s, 2H), 5.93 (m, 1H), 5.32 (m, 1H), 5.20 (m, 2H), 3.98 (s, 3H), 3.97 (s, 3H), 3.92 (s, 3H), 3.80 (s, 3H), 2.65 (m, 1H), 2.56 (m, 1H).

[0448]

[0449] Compound 5 (5.7 g, 17.90 mmol) was placed in a round flask and dissolved in acetonitrile (200 mL). Ceric ammonium nitrate (29.4 g, 53.71 mmol, 3.0 eq) was dissolved in H2O (100 mL) and dropped. The mixture was allowed to react at room temperature for approximately 30 minutes. After confirming by TLC that the starting material had disappeared, the reaction mixture was extracted with water and CHCl3. After extracting once more with CHCl3, the organic solvent was collected, MgSO4 was added, the mixture was filtered, and the mixture was concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography (EA:Hx=3:1) to obtain 1.56 g of compound 6 in a yield of 30%.

[0450]

[0451] 1 H NMR (CDCl3): δ 7.56 (s, 1H), 6.79 (d, 2H), 5.87 (m, 1H), 5.24 (s, 1H), 5.20 (m, 2H), 4.02 (s, 3H), 3.86 (s, 3H), 2.70 (m, 1H), 2.42 (m, 2H).

[0452] Step 2. Synthesis of compound M004

[0453] Compound 9 (M004) was synthesized using the above compound 6 according to the following reaction schematic diagram.

[0454]

[0455] Compound 6 (288 mg, 1 mmol) is placed in a round flask and dissolved in dichloromethane (10 mL). Place the mixture in an ice bath and add pyridine (0.163 mL, 2 mmol, 2.0 eq) and DMAP (24 mg, 0.2 mmol, 0.2 eq). Slowly add Ac2O (0.189 mL, 2 mmol, 2.0 eq). Warm to room temperature and stir for 30 minutes. After confirming by TLC that the starting material has disappeared, add water to the reaction solution to terminate the reaction. Extract with DCM organic solvent and wash once more with brine. Add MgSO4 to remove moisture, filter through filter paper, and concentrate under reduced pressure. Compound 7 was obtained as an orange sticky oil (300 mg, 91% yield).

[0456] 1 H NMR (CDCl3): δ 7.29 (s, 1H), 6.81 (d, 2H), 6.23 (m, 1H), 5.78 (m, 1H), 5.09 (m, 2H), 4.00 (s, 3H), 3.94 (s, 3H), 2.60 (m, 2H), 2.16 (s, 3H).

[0457]

[0458] Compound 7 (300 mg, 0.908 mmol) is placed in a round flask and dissolved by adding acetic ahydride (20 mL). Place the mixture in an ice bath and add TEA (4 mL) and DMAP (12 mg, 0.0968 mmol, 0.1 eq). Add Zn (633 mg, 9.68 mmol, 10.0 eq), warm to room temperature, and stir for 3 hours. After confirming by TLC that the starting material has disappeared, add water to the reaction solution to terminate the reaction. Extract three times with ethyl acetate as an organic solvent, collect the organic solvent, and wash three times with saturated NaHCO3 solution and once more with brine. Add MgSO4 to remove moisture, filter through filter paper, and concentrate under reduced pressure. The concentrated product was purified by silica gel column chromatography (EA:Hx=1:1) to obtain compound 8 as a pale yellow sticky oil (340 mg, 89% yield).

[0459] 1 H NMR (CDCl3): δ 7.13 (d, 1H), 7.05 (d, 1H), 6.84 (s, 1H), 6.37 (m, 1H), 5.77 (m, 1H), 5.09 (m, 2H), 3.94 (s, 3H), 3.85 (s, 3H), 2.60 (m, 2H), 2.38 (s, 6H), 2.12(s, 3H).

[0460]

[0461] Compound 8 (340 mg, 0.816 mmol) was placed in a round flask and dissolved in acetonitrile (20 mL). Ceric ammonium nitrate (2.01 g, 3.67 mmol, 4.5 eq) was dissolved in H2O (10 mL) and added slowly. Stirred at room temperature for 30 minutes. After confirming that the starting material has disappeared by TLC, add water to the reaction solution to terminate the reaction. Extract twice with ethyl acetate as an organic solvent, collect the organic solvent, and wash once more with brine. Remove moisture by adding MgSO4, filter through filter paper, and concentrate under reduced pressure. Compound 9 (M004) was obtained as a yellow sticky oil (310 mg, 98% yield). This was confirmed by H NMR data. Figure 21 shows the H NMR data of compound 9 (M004).

[0462] 1 H NMR (CDCl3): δ 7.41 (s, 2H), 6.71 (s, 1H), 5.98 (m, 1H), 5.76 (m, 1H), 5.11 (m, 2H), 2.65 (m, 1H), 2.47 (m, 7H), 2.13 (s, 3H).

[0463]

[0464] <Example 13> Synthesis of compound M003

[0465] Compound 11 (M003) was synthesized using the above compound 9 according to the following reaction schematic diagram.

[0466]

[0467] Compound 9 (100 mg, 0.258 mmol) was placed in a round flask and dissolved in 1 N LiOH aqueous solution (20 mL). Stir at room temperature for 3 hours. When the starting material disappears, acidify the reaction solution by slowly adding acetic acid. Extract the reaction solution by adding DCM and H2O. Wash the aqueous layer once more with DCM, collect the organic solvent, and wash with saturated NaHCO3 and brine, respectively. Add MgSO4 to remove moisture, filter through filter paper, and concentrate under reduced pressure. The concentrated product was purified by silica gel column chromatography (EA:Hx=1:2) to obtain 42 mg of compound 10 as a red solid in a yield of 62%.

[0468] 1 H NMR (CDCl3): δ 12.61 (s, 1H), 12.50 (s, 1H), 7.22 (m, 3H), 5.89 (m, 1H), 5.24 (m, 2H), 5.01 (m, 1H), 2.76 (m, 1H), 2.41 (m, 2H).

[0469]

[0470] Compound 10 (50 mg, 0.192 mmol) was placed in a round flask and dissolved by adding dichloromethane (5 mL). Place the flask in an ice bath and add pyridine (15.6 μL, 0.192 mmol, 1.0 eq) and DMAP (4.7 mg, 0.0384 mmol, 0.2 eq). Slowly add Ac2O (18 μL, 0.192 mmol, 1.0 eq). Warm to room temperature and stir for 30 minutes. After confirming by TLC that the starting material has disappeared, the solvent of the reaction solution was removed and purified by silica gel column chromatography (EA:Hx=1:2) to obtain 20 mg of compound 11 (M003) as a brown solid in a yield of 34%. This was confirmed by H NMR data. Figure 22 shows the H NMR data of compound 11 (M003).

[0471] 1 H NMR (CDCl3): δ 12.60 (s, 1H), 12.44 (s, 1H), 7.21 (s, 2H), 7.03 (s, 1H), 6.13 (m, 1H), 5.79 (m, 1H), 5.12 (m, 2H), 2.72 (m, 1H), 2.55 (m, 1H), 2.17 (s, 3H).

[0472]

[0473] <Example 14> Synthesis of compound M002

[0474] Compound 12 (M002) was synthesized using the above compound 9 according to the following reaction schematic diagram.

[0475]

[0476] Compound 9 (100 mg, 0.258 mmol) was placed in a round flask and dissolved in THF (8 mL). LiOH-H2O (10.8 mg, 0.258 mmol, 1.0 eq) was dissolved in water (1 mL) and added. Stirred at room temperature for approximately 20 minutes. After confirming by TLC, acidify the reaction solution by slowly adding acetic acid. Extract by adding EA and H2O to the reaction solution. Remove moisture from the organic layer by adding MgSO4, filter through filter paper, and concentrate under reduced pressure. The concentrated product was purified by silica gel column chromatography (EA:Hx=1:4) to obtain 30 mg of compound 12 (M002) as an orange solid in a yield of 33%. This was confirmed by H NMR data. Figure 23 shows H NMR data of compound 12 (M002).

[0477] 1H NMR (CDCl3): δ 12.35 (s, 1H), 7.30 (s, 2H), 6.81 (s, 1H), 5.98 (m, 1H), 5.75 (m, 1H), 5.11 (m, 2H), 2.67 (m, 1H), 2.42 (s, 3H), 2.41 (m, 1H), 2.14 (s, 3H).

[0478]

[0479] <Example 15> Synthesis of compound M001

[0480] Compound 13 (M001) was synthesized using the above compound 10 according to the following reaction schematic.

[0481]

[0482] Compound 10 (110 mg, 0.422 mmol) was placed in a round flask and dissolved in dichloromethane (10 mL). Place the mixture in an ice bath and add pyridine (69 μL, 0.845 mmol, 2.0 eq) and DMAP (10 mg, 0.084 mmol, 0.2 eq). Slowly add methacrylic anhydride (0.126 mL, 0.845 mmol, 2.0 eq). Warm to room temperature and stir for 1 hour. After TLC confirmation that the starting material has disappeared, the solvent of the reaction solution was removed and the product was purified by silica gel column chromatography (EA:Hx=1:3) to obtain compound 13 (M001) in a yield of 30 mg (24%). This was confirmed by H NMR data. Figure 24 shows H NMR data of compound 13 (M001).

[0483] 1H NMR (CDCl3): δ 12.61 (s, 1H), 12.44 (s, 1H), 7.21 (s, 2H), 7.01 (s, 1H), 6.25 (s, 1H), 6.17 (m, 1H), 5.81 (m, 1H), 5.69 (s, 1H), 5.13 (m, 2H), 2.75 (m, 1H), 2.57 (m, 1H), 2.01 (s, 3H).

[0484]

[0485] <Example 16> Synthesis of compound M007

[0486] Compound 14 (M007) was synthesized using the above compound 10 according to the following reaction schematic.

[0487]

[0488] 2-Hexenoic acid (26.3 mg, 0.23 mmol, 1.2 eq) and N,N′-dicyclohexylcarbodiimide (59 mg, 0.288 mmol, 1.5 eq) were placed in a round flask, dichloromethane (8 mL) was added, and stirred for about 10 minutes to dissolve. Compound 10 (50 mg, 0.192 mmol) and DMAP (2.3 mg, 0.019 mmol, 0.1 eq) were added, and stirred overnight at room temperature. After confirming by TLC, the solvent of the reaction solution was removed, and the mixture was purified by silica gel column chromatography (EA:Hx=1:4) to obtain compound 14 (M007) in a yield of 20 mg (29%). This was confirmed by H NMR data. Figure 25 is the H NMR data of compound 14 (M007).

[0489] 1H NMR (CDCl3): δ 12.58 (s, 1H), 12.42 (s, 1H), 7.19 (s, 2H), 7.05 (m, 1H), 7.00 (s, 1H), 6.15 (m, 1H), 5.91 (d, 1H), 5.78 (m, 1H), 5.10 (m, 2H), 2.75 (m, 1H), 2.58 (m, 1H), 2.22 (m, 2H), 1.52 (m, 2H), 0.96 (t, 3H).

[0490]

[0491] <Experimental Example 1> Confirmation of NAD substitution activity of compounds synthesized according to Examples 1 to 11

[0492] It was confirmed whether the compounds synthesized according to the above Examples 1 to 11 had the activity of substituting NADH as a substrate with NAD.

[0493] Activity was confirmed according to the following method.

[0494] NADH, the substrate to be used in the experiment, is prepared immediately before the experiment. The reaction buffer is prepared by mixing 25 mM Tris-HCl (pH 7.4) and 200 μg / ml BSA. NADH is prepared as a 10 mM stock, and the recombinant NQO1, the reaction enzyme, is prepared at a concentration of 0.05 mg / ml. The compounds synthesized according to Examples 1 to 11 are prepared as stocks according to the desired concentration. All preparations are carried out on ice to prevent enzymatic reaction. The spectrophotometer is pre-set to 37°C.

[0495] The experiment was conducted as follows.

[0496] 1) Add 500 ul of reaction buffer to each tube and drop 10 ul of NADH stock, 1 ul of recombinant NQO1 stock, and 1 ul of the compound synthesized according to Examples 1 to 11 onto the tube wall.

[0497] 2) Quickly vortex, then place directly into a spectrophotometer cuvette and measure the value. The wavelength used here is NADH 340 nm / ref 425 nm.

[0498] 3) Read the values ​​for 3-5 minutes and compare the slope of the graph, which changes with the difference in values ​​as NADH changes to NAD.

[0499] Meanwhile, for comparison, W002 represented by the following chemical formula 5 and W012 represented by the following chemical formula 6 were also prepared.

[0500] [Chemical Formula 5]

[0501]

[0502] [Chemical Formula 6]

[0503]

[0504] W001, W003, W004, W005, W006, W010, W011, W013, W014, and W017 synthesized according to Examples 1 to 11, and comparative examples W002 and W012 are referred to as the W series, and each compound number is described in Figure 26.

[0505] Figure 26 confirms the NAD substitution activity of W series compounds. Figure 26 compares the experimental values ​​for each drug by expressing them as fold changes, with the drug control value set to 1. Referring to Figure 26, it can be seen that the NAD substitution activity of the W series compounds synthesized according to the examples is superior to that of the comparative examples W002 and W012.

[0506] <Experimental Example 2> Confirmation of NAD substitution activity of compounds synthesized according to Examples 12 to 16

[0507] The compounds synthesized according to Examples 12 to 16 were tested for their activity in substituting NADH for NAD. That is, the activity of M004, M003, M002, M001, and M007 synthesized according to Examples 12 to 16 was tested. The experiment was conducted in the same manner as in Experimental Example 1. These were referred to as the M series, and each compound number is shown in Figure 27.

[0508] Figure 27 confirms the NAD substitution activity of the M series compounds. Figure 27 compares the experimental values ​​for each drug by expressing them as fold changes, with the drug control value set to 1. Referring to Figure 27, it can be seen that M004, M003, M002, M001, and M007 all have NAD substitution activity.

[0509]

[0510] The features, structures, effects, etc. described in the above-described embodiments are included in at least one embodiment of the present invention, and are not necessarily limited to just one embodiment. Furthermore, the features, structures, effects, etc. exemplified in each embodiment can be combined or modified in other embodiments by those skilled in the art to which the embodiments pertain. Therefore, the contents related to such combinations and modifications should be construed as falling within the scope of the present invention.

[0511] In addition, although the above description focuses on embodiments, these are merely examples and do not limit the present invention. Those skilled in the art to which the present invention pertains will appreciate that various modifications and applications not exemplified above are possible without departing from the essential characteristics of the present embodiments. For example, each component specifically shown in the embodiments can be modified and implemented. In addition, differences related to such modifications and applications should be interpreted as being included within the scope of the present invention defined in the appended claims.

Claims

1. A compound represented by any one chemical formula selected from the group consisting of the following chemical formulas 1 to 4. [Chemical Formula 1] The above R1 and R2 are each independently -OH or -OCH3, A is a 5- to 6-membered substituted or unsubstituted heterocycloalkyl having one oxygen atom, and the substituted heterocycloalkyl is substituted with C2 to C4 alkyl. [Chemical Formula 2] The above R3 and R4 are each independently -OH or -OCH3, B is a 5-membered heterocycloalkenyl having 1 to 2 heteroatoms selected from oxygen and nitrogen, and the heterocycloalkenyl is substituted with C1 to C4 alkyl. [Chemical Formula 3] Among the above R5 and R6, one is H, The remaining one is -O(CH2)nOH (n is an integer from 1 to 3), (Rx is a butenyl group including an ester substituent represented by a C1 to C5 alkyl group substituted or unsubstituted with alkylene, a C1 to C5 alkyl group not including alkylene, or a C2 to C10 alkenyl group), or a butenyl group including an acetoxy group (OAc), The above R7 and R8 are each independently -OH, -OCH3 or an acetoxy group (OAc). [Chemical Formula 4] The above R9 and R 10 are each independently a hydroxyl group (-OH) or an alkyl group having C1 to C5, and the R 11 and R 12 are each independently a hydroxyl group (-OH) or -OCH3, and X is oxygen.

2. In paragraph 1, The compound represented by the above chemical formula 1 is , , , and A compound characterized by being one selected from the group consisting of:

3. In paragraph 1, The compound represented by the above chemical formula 2 is or A compound characterized by:

4. In paragraph 1, The compound represented by the above chemical formula 3 is , , , , and A compound characterized by at least one selected from the group consisting of:

5. In paragraph 1, The compound represented by the above chemical formula 4 is , , and A compound characterized by at least one selected from the group consisting of:

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