Indole compounds, their preparation and use

Abstract

The present invention belongs to the technical field of medicinal chemistry and discloses an indole compound, its preparation method and use, including a compound having the structure of Formula I, and such a compound has good therapeutic effect on atopic dermatitis. [50] TIFF2024508093000065.tif48166

Description

[Technical Field]

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to indole compounds, their preparation and use. [Background technology]

[0002] Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease. Numerous factors, including genetics, environmental factors, alterations in epidermal lipid composition, immune disorders, and microbial dysbiosis, have been reported to influence the pathophysiology of AD. In addition to skin symptoms such as erythema, papules, exudation, scaling, dry skin, macules, and lichenification, AD may cause psychiatric disorders and increase the risk of cardiovascular disease. It is also thought to be associated with depression and suicide. Epidemiologically, AD is prevalent in children, and symptoms persist into adulthood. Statistical analyses and research on clinical data in the United States are relatively well documented, and studies of children and adolescents have shown that only 1% of patients under the age of 12 years do not develop persistent disease.

[0003] Related research has revealed that the prevalence of AD in China is gradually increasing, particularly among children, and that the prevalence rate in urban areas is higher than in rural areas. From the above, it is clear that AD has a clear impact on patients' quality of life and mental health. Given the current situation in which the prevalence of AD has been steadily increasing in recent years, especially among children in urban areas, there is a clinical and social need for the development of safer and more effective AD treatments and methods.

[0004] Currently, conventional treatments for AD mainly include three types: 1) moisturizers, which improve dry skin; 2) corticosteroids, which have broad-spectrum anti-inflammatory and immunosuppressive effects; and 3) calcineurin inhibitors, which bind to immunophilins, inhibit calcineurin, ultimately reducing inflammation by inhibiting the secretion of various cytokines. Furthermore, AD patients often suffer from Staphylococcus aureus infections and are more susceptible to fungal infections than healthy controls. Eliminating the pathogens with systemic antibiotics can alleviate the symptoms of AD. Each of these conventional treatments has limitations: 1) moisturizers have limited therapeutic efficacy because their primary role is to slow skin moisture loss. 2) Long-term use of corticosteroids can cause systemic adverse reactions, inhibiting the hypothalamic-pituitary-adrenal axis and potentially adversely affecting growth in children. 3) Calcineurin inhibitors consistently cause local burning and itching. 4) Since pathogens are likely to re-establish themselves when antibiotics are discontinued, long-term use of antibiotics is likely to lead to the emergence of resistant strains.

[0005] Because the pathophysiology of AD is closely related to epidermal barrier dysfunction and immune disorders, many AD patients exhibit abnormal cytokine expression. Some scholars have proposed dividing AD into different endotypes based on the molecular mechanisms associated with different pathological phenotypes. In recent years, small molecule inhibitors targeting cytokine receptors and biologics targeting specific cytokines or their receptors have become hotspots in the development of AD treatments. Currently, small molecule inhibitors of phosphodiesterase (PDE)-4, Janus tyrosine kinase (JAK), histamine 4 receptor (H4R) antagonists, and aryl hydrocarbon receptor (AhR) agonists are available. Monoclonal antibodies targeting interleukin-4 (IL-4) receptor and interleukin-13 (IL-13) are in clinical trials or are under clinical approval. Among these, the IL-4 receptor monoclonal antibody Dupixent (Dupilumab), the topical PDE-4 antagonist Eucrisa (Crisaborole), and the oral JAK1 inhibitor Cibinqo (Abrocitinib) have already been approved by the FDA. In China, a drug containing the AhR agonist and T-cell tyrosine protein kinase inhibitor benvitimod as its active ingredient has been approved for sale by the National Medical Products Administration, but its use is currently limited to the treatment of psoriasis. To address the issues of long-term drug safety and drug resistance and to improve the absorption efficiency of dermal drugs, the development of more naturally derived small molecule drugs is urgently needed. Summary of the Invention

[0006] In view of this, it is necessary to provide an indole compound that has a good therapeutic effect on atopic dermatitis in order to solve the above problems.

[0007] Indole compounds, including compounds having the structure of Formula I. [ka] (In the formula, W is selected from COR2, CR3R4OR5, X is selected from CO, CR3R4 or absent; Y is selected from O or absent; Z is selected from CR3R4 or is absent; R1 is C 1~20 Alkyl and substituted alkyl groups, C 1~20 selected from alkenyl groups and substituted alkenyl groups, aryl groups and substituted aryl groups, heteroaryl groups, aryl-substituted alkyl groups, heteroaryl-substituted alkyl groups, and oxyalkyl groups; R is H, D, C 1~6 Alkyl and substituted alkyl groups, C 1~6 selected from alkenyl and substituted alkenyl groups, aryl and substituted aryl groups, heteroaryl groups, halogen, OR, NR, R, CO, R, CONR, R, OCOR, NHCOR, NHSOR, and CN; R2, R3, R4, R6, R7, and R8 are independently H, D, and C 1~6 Alkyl and substituted alkyl groups, C 1~6 arbitrarily selected from an alkenyl group and a substituted alkenyl group, an aryl group and a substituted aryl group, and a heteroaryl group; R5 is selected from H, D, and COR1.

[0008] In one embodiment, the configuration of the compound is shown in Formula II. [ka]

[0009] In one embodiment, W is selected from COR2, CR3R4OR5; X is selected from CO or is absent; Y is selected from O or absent; Z is selected from CR3R4 or is absent; R1 is C 1~20 selected from alkyl groups and substituted alkyl groups, aryl groups and substituted aryl groups, and oxyalkyl groups; R is selected from H; R2, R3, R4, R5 are selected from H.

[0010] In one embodiment, R1 is C 5~15 It is selected from alkyl and substituted alkyl groups, acetoxy-substituted aryl groups, (2,6-dichlorophenyl)amino-substituted aryl groups, and pentaoxopentadecyl groups.

[0011] In one embodiment, W is selected from COH, CHOH; XYZ is selected from COOCH2 and CH2, R1 is C7~C 15 selected from alkyl groups, acetoxy-substituted aryl groups, (2,6-dichlorophenyl)amino-substituted aryl groups, and pentaoxopentadecyl groups; R is selected from H.

[0012] In one embodiment, W is selected from COH; XYZ is selected from CH2, R1 is C7~C 15 selected from alkyl groups, acetoxy-substituted aryl groups, (2,6-dichlorophenyl)amino-substituted aryl groups, and pentaoxopentadecyl groups; R is selected from H.

[0013] In one embodiment, the compound is selected from the following: [ka] TIFF0007763510000004.tif247168

[0014] Compound 4 was analyzed using Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ angles had characteristic peaks at positions 4.9±0.2°, 7.3±0.2°, 9.9±0.2°, 14.9±0.2°, and 22.0±0.2°. Preferably, the X-ray powder diffraction pattern, expressed in terms of 2θ angles, has characteristic peaks at the positions 4.9±0.2°, 7.3±0.2°, 9.9±0.2°, 11.3±0.2°, 11.8±0.2°, 14.9±0.2°, 19.0±0.2°, 19.9±0.2°, 21.6±0.2°, 22.0±0.2°, More preferably, the X-ray powder diffraction pattern, expressed in terms of 2θ angles, has characteristic peaks at positions 4.9±0.2°, 7.3±0.2°, 9.9±0.2°, 10.7±0.2°, 11.3±0.2°, 11.8±0.2°, 13.4±0.2°, 14.6±0.2°, 14.9±0.2°, 18.4±0.2°, 19.0±0.2°, 19.9±0.2°, 21.6±0.2°, 22.0±0.2°, and 25.3±0.2°; Compound 8 was analyzed using Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ angles had characteristic peaks at positions 5.2±0.2°, 11.6±0.2°, 12.6±0.2°, 16.0±0.2°, and 19.3±0.2°. Preferably, the X-ray powder diffraction pattern, expressed in terms of 2θ angles, has characteristic peaks at the positions 5.2±0.2°, 6.3±0.2°, 10.0±0.2°, 11.6±0.2°, 12.6±0.2°, 12.9±0.2°, 14.3±0.2°, 16.0±0.2°, 19.3±0.2°, 21.3±0.2°, More preferably, the X-ray powder diffraction pattern, expressed in terms of 2θ angles, has characteristic peaks at the positions 5.2±0.2°, 6.3±0.2°, 10.0±0.2°, 11.6±0.2°, 12.6±0.2°, 12.9±0.2°, 14.3±0.2°, 16.0±0.2°, 19.3±0.2°, 20.4±0.2°, 21.3±0.2°, 23.2±0.2°, 25.2±0.2°, 26.3±0.2°, and 27.6±0.2°; Compound 9 was analyzed using Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ angles had characteristic peaks at positions 12.3±0.2°, 14.9±0.2°, 19.9±0.2°, 23.4±0.2°, and 27.3±0.2°. Preferably, the X-ray powder diffraction pattern, expressed in terms of 2θ angles, has characteristic peaks at the positions 10.3±0.2°, 12.3±0.2°, 12.7±0.2°, 14.9±0.2°, 15.6±0.2°, 19.2±0.2°, 19.9±0.2°, 23.4±0.2°, 25.1±0.2°, 27.3±0.2°, More preferably, the X-ray powder diffraction pattern, expressed in terms of 2θ angles, has characteristic peaks at positions 4.9±0.2°, 10.3±0.2°, 12.3±0.2°, 12.7±0.2°, 14.9±0.2°, 15.6±0.2°, 17.3±0.2°, 19.2±0.2°, 19.9±0.2°, 20.3±0.2°, 20.7±0.2°, 23.4±0.2°, 24.8±0.2°, 25.1±0.2°, and 27.3±0.2°; Compound 22 was analyzed using Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ angles had characteristic peaks at positions 3.4±0.2°, 5.3±0.2°, 6.9±0.2°, 10.2±0.2°, and 19.9±0.2°. Preferably, the X-ray powder diffraction pattern, expressed in terms of 2θ angles, has characteristic peaks at the positions 3.4±0.2°, 5.3±0.2°, 6.9±0.2°, 9.7±0.2°, 10.2±0.2°, 11.7±0.2°, 14.9±0.2°, 17.7±0.2°, 19.9±0.2°, 20.6±0.2°, More preferably, the X-ray powder diffraction pattern, expressed in terms of 2θ angles, has characteristic peaks at the positions 3.4±0.2°, 5.3±0.2°, 6.9±0.2°, 9.7±0.2°, 10.2±0.2°, 11.7±0.2°, 12.5±0.2°, 14.0±0.2°, 14.9±0.2°, 15.4±0.2°, 17.7±0.2°, 19.9±0.2°, 20.6±0.2°, 21.9±0.2°, and 23.2±0.2°; Compound 23 was analyzed using Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ angles had characteristic peaks at positions 10.6±0.2°, 11.0±0.2°, 18.4±0.2°, 21.2±0.2°, and 21.7±0.2°. Preferably, MC20-875-034A1 has an X-ray powder diffraction pattern, expressed in 2θ angles, having characteristic peaks at positions 10.6±0.2°, 11.0±0.2°, 15.2±0.2°, 18.4±0.2°, 19.9±0.2°, 20.6±0.2°, 21.2±0.2°, 21.7±0.2°, 23.6±0.2°, and 24.2±0.2°; More preferably, the X-ray powder diffraction pattern, expressed in terms of 2θ angles, has characteristic peaks at the positions 5.2±0.2°, 10.2±0.2°, 10.6±0.2°, 11.0±0.2°, 13.0±0.2°, 14.0±0.2°, 15.2±0.2°, 18.4±0.2°, 19.9±0.2°, 20.6±0.2°, 21.2±0.2°, 21.7±0.2°, 22.4±0.2°, 23.6±0.2°, and 24.2±0.2°; The X-ray powder diffraction pattern of compound 24, measured using Cu-Kα radiation, shows characteristic peaks at 4.4±0.2°, 6.6±0.2°, 8.9±0.2°, 21.0±0.2°, and 22.6±0.2° angles. Preferably, the X-ray powder diffraction pattern, expressed in terms of 2θ angles, has characteristic peaks at the positions 4.4±0.2°, 6.6±0.2°, 8.9±0.2°, 11.1±0.2°, 12.2±0.2°, 13.4±0.2°, 19.5±0.2°, 20.6±0.2°, 21.0±0.2°, 22.6±0.2°, More preferably, the X-ray powder diffraction pattern, expressed in terms of 2θ angles, has characteristic peaks at positions 4.4±0.2°, 6.6±0.2°, 8.9±0.2°, 10.4±0.2°, 11.1±0.2°, 12.2±0.2°, 13.4±0.2°, 16.1±0.2°, 17.8±0.2°, 19.5±0.2°, 20.6±0.2°, 21.0±0.2°, 22.6±0.2°, 24.8±0.2°, and 26.5±0.2°; The X-ray powder diffraction pattern of compound 26, expressed as 2θ angles using Cu-Kα radiation, had characteristic peaks at positions 3.6±0.2°, 10.5±0.2°, 11.8±0.2°, 13.9±0.2°, and 19.7±0.2°. Preferably, the X-ray powder diffraction pattern, expressed in terms of 2θ angles, has characteristic peaks at the positions 3.6±0.2°, 7.4±0.2°, 10.5±0.2°, 11.8±0.2°, 13.9±0.2°, 14.9±0.2°, 16.8±0.2°, 19.7±0.2°, 21.2±0.2°, 23.5±0.2°, More preferably, the X-ray powder diffraction pattern, expressed in terms of 2θ angles, has characteristic peaks at the positions 3.6±0.2°, 7.4±0.2°, 10.5±0.2°, 11.8±0.2°, 13.9±0.2°, 14.9±0.2°, 16.8±0.2°, 19.7±0.2°, 21.2±0.2°, 21.5±0.2°, 22.0±0.2°, 23.5±0.2°, 25.0±0.2°, and 26.0±0.2°; Compound 27 was analyzed using Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ angles had characteristic peaks at positions 6.5±0.2°, 10.2±0.2°, 13.2±0.2°, 15.0±0.2°, and 23.8±0.2°. Preferably, the X-ray powder diffraction pattern, expressed in terms of 2θ angles, has characteristic peaks at the positions 6.5±0.2°, 10.2±0.2°, 13.2±0.2°, 15.0±0.2°, 16.3±0.2°, 20.2±0.2°, 20.6±0.2°, 21.4±0.2°, 23.8±0.2°, 27.0±0.2°, More preferably, the X-ray powder diffraction pattern, expressed in terms of 2θ angles, has characteristic peaks at positions 6.5±0.2°, 10.2±0.2°, 13.2±0.2°, 15.0±0.2°, 16.3±0.2°, 19.3±0.2°, 20.2±0.2°, 20.6±0.2°, 21.4±0.2°, 23.8±0.2°, 24.1±0.2°, 26.0±0.2°, 27.0±0.2°, 27.3±0.2°, and 30.6±0.2°; Compound 35 was analyzed using Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ angles had characteristic peaks at positions 12.4±0.2°, 14.7±0.2°, 15.3±0.2°, 17.3±0.2°, and 23.5±0.2°. Preferably, the X-ray powder diffraction pattern, expressed in terms of 2θ angles, has characteristic peaks at the positions 10.8±0.2°, 12.4±0.2°, 13.3±0.2°, 14.7±0.2°, 15.3±0.2°, 17.3±0.2°, 21.8±0.2°, 22.7±0.2°, 23.5±0.2°, 24.0±0.2°, More preferably, the X-ray powder diffraction pattern, expressed in terms of 2θ angles, has characteristic peaks at the positions 10.8±0.2°, 12.4±0.2°, 13.3±0.2°, 14.7±0.2°, 15.3±0.2°, 17.3±0.2°, 17.8±0.2°, 19.8±0.2°, 21.8±0.2°, 22.7±0.2°, 23.5±0.2°, 24.0±0.2°, 25.6±0.2°, 26.2±0.2°, and 27.4±0.2°; Compound 41 was analyzed using Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ angles had characteristic peaks at positions 3.1±0.2°, 5.2±0.2°, 6.7±0.2°, 10.2±0.2°, and 19.9±0.2°. Preferably, the X-ray powder diffraction pattern, expressed in terms of 2θ angles, has characteristic peaks at the positions 3.1±0.2°, 5.2±0.2°, 6.7±0.2°, 9.1±0.2°, 9.8±0.2°, 10.2±0.2°, 11.5±0.2°, 19.9±0.2°, 20.5±0.2°, 21.6±0.2°, More preferably, the X-ray powder diffraction pattern, expressed in terms of 2θ angles, has characteristic peaks at the positions 3.1±0.2°, 5.2±0.2°, 6.7±0.2°, 9.1±0.2°, 9.8±0.2°, 10.2±0.2°, 10.5±0.2°, 11.5±0.2°, 14.1±0.2°, 14.8±0.2°, 19.3±0.2°, 19.9±0.2°, 20.5±0.2°, 21.6±0.2°, and 23.1±0.2°.

[0015] The present invention further discloses a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient.

[0016] In one embodiment, the pharmaceutical composition is in the form of a tablet, dispersion, tincture, gel, capsule, spray, suppository, granule, oral liquid dosage form, or granule.

[0017] In one embodiment, the pharmaceutical composition is in the form of an external preparation.

[0018] The present invention further discloses the use of said compounds in the manufacture of a medicament for treating dermatitis and / or immune system disorders.

[0019] In one embodiment, the drug is used to treat atopic dermatitis and / or asthma. [Effects of the Invention]

[0020] Compared with the prior art, the present invention has the following beneficial effects: The indole compounds of the present invention were obtained by structural optimization based on the lead compound, the natural small molecule IAId (indole-3-carbaldehyde), and another related small molecule I3C (indole-3-carbinol). When tested using a mouse model of AD-like symptoms in the ear induced by calcipotriol (MC903), they demonstrated a certain therapeutic effect on AD-like symptoms in the mouse ear, and the effects of some compounds were superior to those of IAId and I3C, making them highly promising for use as drugs. [Brief explanation of the drawings]

[0021] [Figure 1] FIG. 1 is an XRPD pattern of compound 4 of Example 7. [Figure 2] FIG. 2 is an XRPD pattern of compound 22 of Example 8. [Figure 3] FIG. 3 is an XRPD pattern of compound 23 of Example 10. [Figure 4] FIG. 4 is an XRPD pattern of compound 24 of Example 12. [Figure 5] FIG. 5 is an XRPD pattern of compound 8 of Example 14. [Figure 6] FIG. 6 is an XRPD pattern of compound 26 of Example 15. [Figure 7]FIG. 7 is an XRPD pattern of compound 9 of Example 16. [Figure 8] FIG. 8 is an XRPD pattern of compound 27 of Example 17. [Figure 9] FIG. 9 is an XRPD pattern of compound 41 of Example 27. [Figure 10] FIG. 10 is an XRPD pattern of compound 35 of Example 31. [Figure 11] FIG. 11 is a schematic diagram of serum total IgE levels in mice from the first batch of experiments in Example 32. [Figure 12] FIG. 12 is a schematic diagram of the thickness levels of the ears of mice in the first batch of experiments in Example 32. [Figure 13] FIG. 13 is a schematic diagram of the weight changes of mice in the first batch experiment of Example 32. [Figure 14] FIG. 14 shows photographs of representative mouse ears when administered different drugs in the first batch of experiments in Example 32. [Figure 15] FIG. 15 shows HE staining images of representative mouse ear tissues when different drugs were administered in the first batch of experiments in Example 32. [Figure 16] FIG. 16 is a schematic diagram of serum total IgE levels in mice from the second batch of experiments in Example 32. [Figure 17] FIG. 17 is a schematic diagram of the thickness levels of the ears of mice in the second batch of experiments in Example 32. [Figure 18] FIG. 18 is a schematic diagram of the weight changes of mice in the second batch of experiments in Example 32. [Figure 19] FIG. 19 shows photographs of representative mouse ears when administered different drugs in the second batch of experiments in Example 32. [Figure 20] FIG. 20 shows HE staining images of representative mouse ear tissues when different drugs were administered in the second batch of experiments in Example 32. [Figure 21] FIG. 21 is a schematic diagram of the serum total IgE levels of mice in each group in Example 33. [Figure 22]FIG. 22 is a schematic diagram of the serum total IgE levels of mice in each group in Example 33. [Figure 23] FIG. 23 is a schematic diagram of the serum total IgE levels of mice in each group in Example 33. [Figure 24] FIG. 24 is a schematic diagram of the thickness levels of the ears of mice in each group in Example 33. [Figure 25] FIG. 25 is a schematic diagram of the thickness levels of the ears of mice in each group in Example 33. [Figure 26] FIG. 26 is a schematic diagram of the thickness levels of the ears of mice in each group in Example 33. [Figure 27] FIG. 27 is a schematic diagram showing changes in body weight of mice in each group in Example 33. [Figure 28] FIG. 28 is a schematic diagram showing changes in body weight of mice in each group in Example 33. [Figure 29] FIG. 29 is a schematic diagram showing changes in body weight of mice in each group in Example 33. [Figure 30] FIG. 30 is a photograph of a representative mouse ear from Example 33. DETAILED DESCRIPTION OF THE INVENTION

[0022] To facilitate understanding of the present invention, the present invention will now be described more fully with reference to the accompanying drawings. While the drawings show preferred embodiments of the present invention, the present invention may be embodied in many different forms and is not limited to the embodiments set forth herein. Rather, the purpose of providing these embodiments is to provide a more complete and thorough understanding of the present disclosure.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the ordinary meanings understood by those skilled in the art. Terms used in the present specification are for the purpose of describing particular embodiments and are not intended to limit the present invention. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0024] The pharmaceutical compositions provided herein may be formulated in any dosage form suitable for topical administration to produce a local or systemic effect, such as an emulsion, solution, suspension, cream, gel, hydrogel, ointment, powder, dressing, elixir, wash, suspension, tincture, paste, foam, film, aerosol, irrigation, spray, suppository, bandage, skin patch, etc.

[0025] The oral pharmaceutical compositions provided herein may be provided as oral solid, semi-solid or liquid dosage forms.

[0026] As used herein, oral also includes oral, lingual, or sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fast dissolving tablets, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, granules, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral aerosols, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient, the pharmaceutical compositions may contain one or more pharmaceutically acceptable excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, color flow inhibitors, sweeteners, flavoring agents, emulsifiers, suspending or dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and carbon dioxide sources.

[0027] Unless otherwise specified, the raw materials used in the following examples may all be commercially available products, and the methods used in the following examples may all be realized by conventional methods unless otherwise specified.

[0028] The X-ray powder diffraction detection parameters for the compounds in the following examples are as follows: Scan range: 3~40°, scan step: 0.02°, scan speed: 0.1° / step, copper target, wavelength: 1.54Å.

[0029] Example 1 Preparation of methyl (hexyloxy)3-formyl-1H-indole-1-carboxylate (Compound 1)

[0030] (1) Synthesis of chloromethyl 3-formyl-1H-indole-1-carboxylate (Compound B) [ka]

[0031] Under argon protection, compound A, 3-indole-carbaldehyde (5.0 g, 34 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL). The temperature was lowered to -78°C, and a solution of bis(trimethylsilyl)aminolithium in tetrahydrofuran (1 M, 51.7 mL, 51.7 mmol) was added dropwise and reacted at -78°C for 1 hour. Next, a solution of chloromethyl chloroformate (6.62 g, 51.7 mmol) in tetrahydrofuran (20 mL) was added dropwise to the reaction mixture and reacted at -78°C for 2 hours. TLC (petroleum ether / ethyl acetate = 5:1) showed the completion of the reaction.

[0032] The reaction mixture was extracted with saturated aqueous ammonium chloride (50 mL) and ethyl acetate (3 × 40 mL). The combined organic phase was washed with water (80 mL) and saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to give the target compound, chloromethyl 3-formyl-1H-indole-1-carboxylate (2) (3.0 g, 37.5% yield), as a yellow solid.

[0033] Analysis data of compound B: 1 1H NMR (400MHz, DMSO) δ 10.10(s,1H),8.77(s,1H),8.17(dd,J=7.9,3.2Hz,2H),7.55~7.40(m,2H),6.25(s,2H).

[0034] (2) Synthesis of (hexyloxy) 3-formyl-1H-indole-1-carboxylate methyl ester (compound 1) [ka] Sodium iodide (252 mg, 1.69 mmol) and potassium carbonate (1.4 g, 10.11 mmol) were added to a solution of chloromethyl 3-formyl-1H-indole-1-carboxylate (Compound B) (800 mg, 3.37 mmol) and hexanoic acid (391 mg, 3.37 mmol) in anhydrous DMF (8.0 mL) at 0 °C. After 18 hours of reaction at room temperature, TLC (petroleum ether / ethyl acetate = 3:1) indicated completion of the reaction. The reaction mixture was extracted with water (50 mL) and ethyl acetate (3 × 40 mL). The combined organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain the target compound, (hexyloxy) methyl 3-formyl-1H-indole-1-carboxylate (compound 1) (570 mg, yield 53.6%), as a yellow oil.

[0035] Analytical data for compound 1: 1 H NMR(400MHz,DMSO):δ 9.98(s,1H),8.43(s,1H),8.12(d,J=7.7Hz,1H),7.70(d,J=8.1Hz,1H),7.34(dtd,J=14.9,7.6,1.1Hz ,2H),6.31(s,2H),2.32(t,J=7.3Hz,2H),1.54~1.40(m,2H),1.23~1.05(m,4H),0.75(t,J=7.0Hz,3H).

[0036] The purity of Compound 1 was measured by HPLC, and the purity at 254 nm was determined to be 98.71% and the purity at 214 nm was determined to be 98.70% by the peak area normalization method.

[0037] Example 2 Preparation of (hexyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 19) [ka] Methyl (hexyloxy) 3-formyl-1H-indole-1-carboxylate (compound 1) (240 mg, 0.76 mmol) was dissolved in anhydrous methanol (8 mL), the temperature was lowered to 0 °C, and sodium borohydride (28.8 mg, 0.76 mmol) was added. The reaction was allowed to proceed at 0 °C for 2 h, after which completion of the reaction was confirmed by TLC (petroleum ether / ethyl acetate = 3:1). The reaction mixture was extracted with saturated aqueous ammonium chloride (15 mL) and ethyl acetate (3 × 20 mL). The combined organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain the target compound (hexyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (compound 19) (200 mg, 82.9% yield) as a yellow oil.

[0038] Analytical data for compound 19: 1 H NMR(400MHz,DMSO):δ 7.61(d,J=7.8Hz,1H),7.54(d,J=8.2Hz,1H),7.34(s,1H),7.24~7.16(m,1H),7.13~7.04(m,1H),6.17(s,2H),4.91(t,J =5.4Hz,1H),4.62(d,J=5.2Hz,2H),2.26(t,J=7.3Hz,2H),1.52~1.41(m,2H),1.30~1.08(m,4H),0.78(t,J=7.0Hz,3H).

[0039] The purity of compound 19 was measured by HPLC, and the purity at 254 nm was determined to be 96.18% and the purity at 214 nm was determined to be 96.51% by the peak area normalization method.

[0040] Example 3 Preparation of methyl (octyloxy)3-formyl-1H-indole-1-carboxylate (Compound 2)

[0041] (1) Compound B was prepared by following the method of Example 1.

[0042] (2) Synthesis of (octyloxy) 3-formyl-1H-indole-1-carboxylate methyl ester (compound 2) [ka] Sodium iodide (504 mg, 3.37 mmol) and potassium carbonate (1.4 g, 10.11 mmol) were added to a solution of chloromethyl 3-formyl-1H-indole-1-carboxylate (Compound B) (800 mg, 3.37 mmol) and octanoic acid (583.2 mg, 4.05 mmol) in anhydrous DMF (8.0 mL) at 0 °C. After 18 hours at room temperature, TLC (petroleum ether / ethyl acetate = 3:1) indicated the completion of the reaction. The reaction mixture was extracted with water (50 mL) and ethyl acetate (3 × 40 mL). The combined organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain the target compound (octyloxy) methyl 3-formyl-1H-indole-1-carboxylate (compound 2) (480 mg, yield 41.3%) as a yellow oil.

[0043] Analytical data for compound 2: 1H NMR(400MHz,DMSO)δ 9.97(s,1H),8.42(s,1H),8.11(d,J=7.7Hz,1H),7.70(d,J=8.1Hz,1H),7.44~7.26(m,2H), 6.30(s,2H),2.32(t,J=7.2Hz,2H),1.50~1.41(m,2H),1.11(s,8H),0.80(t,J=7.0Hz,3H).

[0044] The purity of Compound 2 was measured by HPLC, and the purity at 254 nm was determined to be 99.42% and the purity at 214 nm was determined to be 98.47% by the peak area normalization method.

[0045] Example 4 Preparation of (octyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 20) [ka] Methyl (octyloxy) 3-formyl-1H-indole-1-carboxylate (compound 2) (240 mg, 0.76 mmol) was dissolved in anhydrous methanol (8 mL), the temperature was lowered to 0 °C, and sodium borohydride (28.8 mg, 0.76 mmol) was added. The reaction was allowed to proceed at 0 °C for 2 hours, after which completion of the reaction was confirmed by TLC (petroleum ether / ethyl acetate = 3:1). The reaction mixture was extracted with saturated aqueous ammonium chloride (15 mL) and ethyl acetate (3 × 20 mL). The combined organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain the target compound ((octyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (compound 20) (150 mg, 57% yield) as a yellow oil.

[0046] Analytical data for compound 20: 1H NMR(400MHz,DMSO)δ 7.61(d,J=7.8Hz,1H),7.53(d,J=8.2Hz,1H),7.34(s,1H),7.19(t,J=7.1Hz,1H),7.09(t,J=7.0Hz,1H),6.17(s,2H),4.90(t,J=5.4Hz ,1H),4.62(d,J=5.4Hz,2H),2.26(t,J=7.3Hz,2H),1.47(d,J=6.9Hz,2H),1.22(d,J=10.1Hz,2H),1.16(s,7H),0.82(t,J=7.0Hz,3H).

[0047] The purity of compound 20 was measured by HPLC, and the purity at 254 nm was determined to be 95.69% and the purity at 214 nm was determined to be 95.81% by the peak area normalization method.

[0048] Example 5 Preparation of methyl (decanoyloxy)3-formyl-1H-indole-1-carboxylate (Compound 3)

[0049] (1) Compound B was prepared by following the method of Example 1.

[0050] (2) Synthesis of (decanoyloxy)methyl 3-formyl-1H-indole-1-carboxylate (compound 3) [ka] Sodium iodide (442 mg, 2.95 mmol) and potassium carbonate (1.2 g, 8.85 mmol) were added to a solution of chloromethyl 3-formyl-1H-indole-1-carboxylate (Compound B) (700 mg, 2.95 mmol) and decanoic acid (560 mg, 3.24 mmol) in anhydrous DMF (8.0 mL) at 0 °C. After 18 hours at room temperature, TLC (petroleum ether / ethyl acetate = 3:1) indicated the completion of the reaction. The reaction mixture was extracted with water (50 mL) and ethyl acetate (3 × 40 mL). The combined organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by passing through a column (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain the target compound, methyl (decanoyloxy) 3-formyl-1H-indole-1-carboxylate (550 mg, yield 50%), as a yellow oil.

[0051] Analytical data for compound 3: 1 H NMR(400MHz,DMSO)δ 9.97(s,1H),8.42(s,1H),8.11(d,J=7.8Hz,1H),7.70(d,J=8.1Hz,1H),7.34(dt,J=25.0,7.2Hz,2H),6.30(s,2H), 2.31(t,J=7.2Hz,2H),1.47(d,J=6.6Hz,2H),1.23(d,J=6.0Hz,2H),1.13(d,J=12.2Hz,10H),0.84(t,J=7.0Hz,3H).

[0052] The purity of the compound 3 was measured by HPLC, and the purity at 254 nm was determined to be 98.70% and the purity at 214 nm was determined to be 98.85% by the peak area normalization method.

[0053] Example 6 Preparation of (decanoyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 21) [ka] Methyl (decanoyloxy) 3-formyl-1H-indole-1-carboxylate (compound 3) (300 mg, 0.803 mmol) was dissolved in anhydrous methanol (8 mL), the temperature was lowered to 0 °C, and sodium borohydride (31 mg, 0.803 mmol) was added. The reaction was allowed to proceed at 0 °C for 2 h, after which completion of the reaction was confirmed by TLC (petroleum ether / ethyl acetate = 3:1). The reaction mixture was extracted with saturated aqueous ammonium chloride (15 mL) and ethyl acetate (3 × 20 mL). The combined organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain the target compound (decanoyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (compound 21) (200 mg, 66.5% yield) as a white solid.

[0054] Analytical data for compound 21: MC20-875-030A Compound 21: 1 H NMR(400MHz,DMSO)δ 7.61(d,J=7.8Hz,1H),7.53(d,J=8.2Hz,1H),7.34(s,1H),7.19(t,J=7.2Hz,1H),7.09(t,J=7.4Hz,1H),6.17(s,2H),4.90(t, J=5.4Hz,1H), 4.61(d,J=5.2Hz,2H),2.26(t,J=7.3Hz,2H),1.52~1.38(m,2H),1.20(d,J=31.1Hz,12H),0.85(t,J=6.9Hz,3H).

[0055] The purity of compound 21 was measured by HPLC, and the purity at 254 nm was determined to be 97.36% and the purity at 214 nm was determined to be 97.56% by the peak area normalization method.

[0056] Example 7 Preparation of methyl (dodecyloxy)3-formyl-1H-indole-1-carboxylate (Compound 4)

[0057] (1) Compound B was prepared by following the method of Example 1.

[0058] (2) Synthesis of (dodecyloxy) 3-formyl-1H-indole-1-carboxylate methyl ester (compound 4) [ka] Sodium iodide (504 mg, 3.37 mmol) and potassium carbonate (1.4 g, 10.11 mmol) were added to a solution of chloromethyl 3-formyl-1H-indole-1-carboxylate (Compound B) (800 mg, 3.36 mmol) and dodecanoic acid (800 mg, 4.03 mmol) in anhydrous DMF (8.0 mL) at 0 °C. After 18 hours at room temperature, TLC (petroleum ether / ethyl acetate = 3:1) indicated the completion of the reaction. The reaction mixture was extracted with water (50 mL) and ethyl acetate (3 × 40 mL). The combined organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain the target compound, (dodecyloxy) methyl 3-formyl-1H-indole-1-carboxylate (compound 4) (500 mg, yield 37%), as a yellow solid.

[0059] Analytical data for compound 4: 1 H NMR(400MHz,DMSO)δ 9.97(s,1H),8.42(s,1H),8.11(d,J=7.7Hz,1H),7.70(d,J=8.3Hz,1H),7.34(dd,J=17.5,7.4Hz, 2H),6.30(s,2H),2.31(t,J=7.2Hz,2H),1.46(s,2H),1.27~1.05(m,17H),0.85(t,J=6.9Hz,3H).

[0060] The purity of the compound 4 was measured by HPLC, and the purity at 254 nm was determined to be 98.06% and the purity at 214 nm was determined to be 96.38% by the peak area normalization method.

[0061] The compound 4 was crystallized to obtain the pure compound 4 of crystalline form I. The pure compound was subjected to X-ray powder diffraction detection, and the results are shown in Table 1 and Figure 1. [Table 1]

[0062] Example 8 Preparation of (dodecyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 22) [ka] Methyl (dodecyloxy) 3-formyl-1H-indole-1-carboxylate (compound 4) (250 mg, 0.76 mmol) was dissolved in anhydrous methanol (8 mL), the temperature was lowered to 0 °C, and sodium borohydride (28.8 mg, 0.76 mmol) was added. The reaction was allowed to proceed at 0 °C for 2 h, after which completion of the reaction was confirmed by TLC (petroleum ether / ethyl acetate = 3:1). The reaction mixture was extracted with saturated aqueous ammonium chloride (15 mL) and ethyl acetate (3 × 20 mL). The combined organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain the target compound (dodecyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (compound 22) (150 mg, 57% yield) as a yellow solid.

[0063] Analytical data for compound 22: 1H NMR(400MHz,DMSO)δ 7.61(d,J=7.7Hz,1H),7.53(d,J=8.2Hz,1H),7.34(s,1H),7.18(dd,J=11.2,4.1Hz,1H),7.09(t,J=7.0Hz,1H),6.17(s,2H),4.89(t,J= 5.4Hz,1H), 4.61(d,J=5.1Hz,2H),2.26(t,J=7.3Hz,2H),1.48~1.40(m,2H),1.23(d,J=7.9Hz,8H),1.15(s,8H),0.85(t,J=6.9Hz,3H).

[0064] The purity of compound 22 was measured by HPLC, and the purity at 254 nm was determined to be 98.63% and the purity at 214 nm was determined to be 98.21% by the peak area normalization method.

[0065] The compound 22 was crystallized to obtain the pure compound 22 in crystalline form I. The pure compound was subjected to X-ray powder diffraction detection, and the results are shown in Table 2 and Figure 2 below. [Table 2]

[0066] Measurement conditions: Scan: 3.0001 / 39.9937 / 0.01948 / 16 (sec), Cu, I (max) = 3038.

[0067] PEAK: 19-pts / Parbolic Filter, Threshold=3.0, Cutoff=0.1%, BG=3 / 1.0, Peak-Top=Summit.

[0068] Note: Intensity = Counts, 2T(0) = 0.0 (deg), wavelength used to calculate d-spacing = 1.54056 Å (Cu / K-alpha).

[0069] Example 9 Preparation of methyl (tetradecyloxy)3-formyl-1H-indole-1-carboxylate (Compound 5)

[0070] (1) Compound B was prepared by following the method of Example 1.

[0071] (2) Synthesis of (tetradecyloxy) 3-formyl-1H-indole-1-carboxylate methyl ester (compound 5) [ka] Sodium iodide (442 mg, 2.95 mmol) and potassium carbonate (1.2 g, 8.85 mmol) were added to a solution of chloromethyl 3-formyl-1H-indole-1-carboxylate (2) (700 mg, 2.95 mmol) and myristic acid (738 mg, 3.24 mmol) in anhydrous DMF (8.0 mL) at 0 °C. After 18 h at room temperature, TLC (petroleum ether / ethyl acetate = 3:1) indicated completion of the reaction. The reaction mixture was extracted with water (50 mL) and ethyl acetate (3 × 40 mL). The combined organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain the target compound (tetradecyloxy) methyl 3-formyl-1H-indole-1-carboxylate (compound 5) (500 mg, yield 39.7%) as a yellow oil.

[0072] Analytical data for compound 5: 1 H NMR(400MHz,DMSO)δ 9.97(s,1H),8.42(s,1H),8.11(d,J=7.7Hz,1H),7.69(d,J=8.1Hz,1H),7.46~7.22(m,2H),6.30(s,2 H),2.31(t,J=7.2Hz,2H),1.53~1.37(m,2H),1.27~1.17(m,12H),1.11(s,8H),0.85(t,J=6.8Hz,3H).

[0073] The purity of Compound 5 was measured by HPLC, and the purity at 254 nm was determined to be 99.76% and the purity at 214 nm was determined to be 99.69% by the peak area normalization method.

[0074] Example 10 Preparation of (tetradecyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 23) [ka] Methyl (tetradecyloxy) 3-formyl-1H-indole-1-carboxylate (compound 5) (250 mg, 0.58 mmol) was dissolved in anhydrous methanol / tetrahydrofuran (5 mL / 5 mL). The temperature was lowered to 0 °C, and sodium borohydride (22 mg, 0.58 mmol) was added. After 1 h of reaction at 0 °C, the reaction was confirmed to be complete by TLC (petroleum ether / ethyl acetate = 3:1). The reaction mixture was extracted with saturated aqueous ammonium chloride (15 mL) and ethyl acetate (3 × 20 mL). The combined organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain the target compound (tetradecyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (compound 23) (200 mg, 80% yield) as a white solid.

[0075] Analytical data for compound 23: 1 H NMR(400MHz,DMSO)δ 7.60(dd,J=7.6,3.7Hz,1H),7.53(dd,J=8.2,3.8Hz,1H),7.33(d,J=3.8Hz,1H),7.19(t,J=7.5Hz,1H),7.09(td,J=7.3,3.5Hz,1H),6.16(d,J=3.9 Hz,2H),4.89(dd,J=10.0,5.2Hz,1H),4.68~4.55(m,2H),2.25(td,J=7.2 ,3.8Hz,2H),1.45(s,2H),1.23(s,12H),1.15(s,8H),0.93~0.78(m,3H).

[0076] The purity of compound 23 was measured by HPLC, and the purity at 254 nm was determined to be 98.71% and the purity at 214 nm was determined to be 98.03% by the peak area normalization method.

[0077] Compound 23 was crystallized to obtain pure compound 23 in crystalline form I. X-ray powder diffraction was performed on the pure compound 23, and the results are shown in Table 3 and Figure 3 below. [Table 3]

[0078] Example 11 Preparation of methyl (palmitoyloxy)3-formyl-1H-indole-1-carboxylate (Compound 6)

[0079] (1) Compound B was prepared by following the method of Example 1.

[0080] (2) Synthesis of iodomethyl 3-formyl-1H-indole-1-carboxylate (Compound C) [ka] Chloromethyl 3-formyl-1H-indole-1-carboxylate (Compound B) (2.3 g, 9.66 mmol) and sodium iodide (4.3 g, 29.2 mmol) were dissolved in acetonitrile (20 mL), the temperature was raised to 70 °C, and the reaction was allowed to proceed for 4 hours. TLC (petroleum ether / ethyl acetate = 5:1) showed the completion of the reaction. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate and concentrated to give iodomethyl 3-formyl-1H-indole-1-carboxylate (Compound C) (2.4 g, 77% yield).

[0081] (3) Synthesis of silver palmitate (compound C-2) [ka] Palmitic acid (C-1) (2 g, 7.8 mmol) was dissolved in aqueous sodium hydroxide (312 mg / 40 mL), the temperature was raised to 80 °C, and silver nitrate (1.32 g, 7.8 mmol) was added to precipitate a white solid. The solid was cooled to room temperature, filtered, and the filter cake was washed with water and baked to obtain silver palmitate (compound C-2) (2.5 g, 89% yield).

[0082] (4) Synthesis of (palmitoyloxy) 3-formyl-1H-indole-1-carboxylate methyl ester (compound 6) [ka] Silver palmitate (2.1 g, 5.1 mmol) was added to a solution of iodomethyl 3-formyl-1H-indole-1-carboxylate (1.5 g, 4.6 mmol) in anhydrous toluene (20 mL) at 0 °C. The temperature was raised to 55 °C and the reaction was allowed to proceed for 4 h. TLC (petroleum ether / ethyl acetate = 3:1) indicated the completion of the reaction. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (3 × 50 mL). The combined organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain the desired compound (palmitoyloxy)methyl 3-formyl-1H-indole-1-carboxylate (compound 6) (800 mg, 38% yield) as a white solid.

[0083] Analytical data for compound 6: 1 H NMR(400MHz,DMSO)δ 7.60(dd,J=7.6,3.7Hz,1H),7.53(dd,J=8.2,3.8Hz,1H),7.33(d,J=3.8Hz,1H),7.19(t,J=7.5Hz,1H),7.09(td,J=7.3,3.5Hz,1H),6.16(d,J=3.9 Hz,2H),4.89(dd,J=10.0,5.2Hz,1H),4.68~4.55(m,2H),2.25(td,J=7.2 ,3.8Hz,2H),1.45(s,2H),1.23(s,12H),1.15(s,8H),0.93~0.78(m,3H).

[0084] The purity of the compound 6 was measured by HPLC, and the purity at 254 nm was determined to be 99.03% and the purity at 214 nm was determined to be 97.54% by the peak area normalization method.

[0085] Example 12 Preparation of (palmitoyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 24) [ka] Methyl (palmitoyloxy) 3-formyl-1H-indole-1-carboxylate (compound 6) (300 mg, 0.65 mmol) was dissolved in anhydrous tetrahydrofuran (8 mL), the temperature was lowered to 0 °C, and sodium borohydride (25.8 mg, 0.65 mmol) was added. After 2 h of reaction at 0 °C, the reaction was confirmed to be complete by TLC (petroleum ether / ethyl acetate = 3:1). The reaction mixture was extracted with saturated aqueous ammonium chloride (15 mL) and ethyl acetate (3 × 20 mL). The combined organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain the target compound (palmitoyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (compound 24) (150 mg, 50% yield) as a white solid.

[0086] Analytical data for compound 24: 1 H NMR(400MHz,DMSO)δ 8.05(d,J=7.8Hz,1H),7.67(d,J=7.7Hz,1H),7.54(s,1H),7.36(dd,J=11.3,4.2Hz,1H),7.29(t,J=7.5Hz,1H),6.00(s,2H),5.16(t,J=5.5 Hz,1H), 4.64(dd,J=5.5,1.0Hz,2H),2.41(t,J=7.2Hz,2H),1.59~1.47(m,2H),1.25(d,J=16.2Hz,16H),1.14(s,8H),0.85(t,J=6.8Hz,3H).

[0087] The purity of compound 24 was measured by HPLC, and the purity at 254 nm was determined to be 97.66% and the purity at 214 nm was determined to be 98.28% by the peak area normalization method.

[0088] Compound 24 was crystallized to obtain pure compound 24 in crystalline form I. X-ray powder diffraction was performed on the pure compound, and the results are shown in Table 4 and Figure 4 below. [Table 4]

[0089] Example 13 Preparation of esterified 3-oxo-2,5,8,11,14,17-hexaoxyoctyl-3-formyl-1H-indole-1-carboxylate (compound 7)

[0090] (1) Compound B was prepared by following the method of Example 1.

[0091] (2) Synthesis of esterified 3-oxo-2,5,8,11,14,17-hexaoxyoctyl-3-formyl-1H-indole-1-carboxylate (compound 7) [ka] Sodium iodide (1.1 g, 7.5 mmol) and potassium carbonate (3.1 g, 22.5 mmol) were added to a solution of chloromethyl 3-formyl-1H-indole-1-carboxylate (Compound B) (1.78 g, 7.5 mmol) and 2,5,8,11,14-pentaoxohexadecane-16-oleic acid (2.0 g, 7.5 mmol) in anhydrous DMF (8.0 mL) at 0 °C. After 2 hours of reaction at room temperature, TLC (petroleum ether / ethyl acetate = 3:1) indicated completion of the reaction. The reaction mixture was extracted with water (50 mL) and ethyl acetate (3 × 40 mL). The combined organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain the target compound, esterified 3-oxo-2,5,8,11,14,17-hexaoxyoctyl-3-formyl-1H-indole-1-carboxylate (compound 7) (600 mg, yield 17.1%), as a yellow oil.

[0092] Analytical data for compound 7: 1 H NMR(400MHz,CDCl3)δ 10.04(s,1H),8.36~8.25(m,1H),7.95(s,1H),7.54(d,J=7.4Hz,1H),7.38(dq,J=7.2,6.0Hz,2H),6.20( s,2H),4.18(s,2H),3.68(d,J=5.2Hz,2H),3.66~3.56(m,12H),3.53(dd,J=5.7,3.5Hz,2H),3.36(s,3H).

[0093] The purity of Compound 7 was measured by HPLC, and the purity at 254 nm was determined to be 96.07% and the purity at 214 nm was determined to be 95.59% by the peak area normalization method.

[0094] Example 14 Preparation of ((2-acetoxybenzoyl)oxy)methyl 3-formyl-1H-indole-1-carboxylate (Compound 8)

[0095] (1) Synthesis of silver acetoxybenzoate (R8_Ag+) [ka] 2-Acetoxybenzoic acid (compound R8) (2.0 g, 11.1 mmol) was dissolved in 1 M aqueous ammonia (30 mL), the temperature was lowered to 0 °C, and an aqueous silver nitrate solution (1.89 g, 11.1 mmol, 10 mL) was added. The mixture was allowed to react at 0 °C for 30 minutes, causing a large amount of white solid to precipitate. The white solid was collected by filtration, washed with water, and dried to give silver 2-acetoxybenzoate (R8_Ag+) (2.5 g, 78.6% yield).

[0096] (2) Synthesis of ((2-acetoxybenzoyl)oxy)methyl 3-formyl-1H-indole-1-carboxylate (Compound 8) [ka] Silver 2-acetoxybenzoate (1.25 g, 4.35 mmol) and iodomethyl 3-formyl-1H-indole-1-carboxylate (Compound C) (1.0 g, 3.0 mmol) were added to toluene (10 mL) and reacted at 40 °C for 4 hours. LCMS analysis indicated complete reaction of iodomethyl 3-formyl-1H-indole-1-carboxylate. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (3 × 20 mL) and water (40 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain the target compound ((2-acetoxybenzoyl)oxy)methyl 3-formyl-1H-indole-1-carboxylate (Compound 8) (500 mg, 43.7% yield) as a pale yellow solid.

[0097] Analytical data for compound 8: 1H NMR(400MHz,DMSO)δ 10.11(s,1H),8.75(s,1H),8.17(d,J=9.1Hz,2H),8.05(dd,J=7.9,1.6Hz,1H),7.80-7.70(m ,1H),7.47(ddd,J=24.6,16.8,8.2Hz,3H),7.29(d,J=7.2Hz,1H),6.28(s,2H),2.27(s,3H).

[0098] The purity of the compound 8 was measured by HPLC, and the purity at 254 nm was determined to be 95.96% and the purity at 214 nm was determined to be 95.28% by the peak area normalization method.

[0099] The compound 8 was crystallized to obtain the pure compound 8 of crystalline form I. The pure compound was subjected to X-ray powder diffraction detection, and the results are shown in Table 5 and Figure 5 below. [Table 5]

[0100] Example 15 Preparation of ((2-acetoxybenzoyl)oxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 26) [ka] ((2-Acetoxybenzoyl)oxy)methyl 3-formyl-1H-indole-1-carboxylate (Compound 8) (170 mg, 0.446 mmol) was dissolved in anhydrous methanol / tetrahydrofuran (3 mL / 3 mL), the temperature was lowered to 0°C, and sodium borohydride (17 mg, 0.446 mmol) was added. The reaction was allowed to proceed at 0°C for 3 hours, after which completion of the reaction was confirmed by TLC (petroleum ether / ethyl acetate = 3:1). The reaction mixture was extracted with saturated aqueous ammonium chloride (15 mL) and ethyl acetate (3 × 20 mL). The combined organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain the target compound ((2-acetoxybenzoyl)oxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (compound 26) (110 mg, yield 64.7%) as a pale yellow solid.

[0101] Analytical data for compound 26: 1 H NMR(400MHz,DMSO)δ 8.09(d,J=8.4Hz,1H),8.01(dd,J=7.9,1.6Hz,1H),7.74(td,J=7.8,1.7Hz,1H),7.68(d,J=7.6Hz,1H),7.58(s,1H),7.44(dd,J= 11.0,4.3Hz,1H),7.39(t,J=7.3Hz,1H),7.33~7.23(m,2H),6.22(s,2H),5.16(t,J=5.5Hz,1H),4.69~4.59(m,2H),2.26(s,3H).

[0102] The purity of the compound 26 was measured by HPLC, and the purity at 254 nm was determined to be 96.35% and the purity at 214 nm was determined to be 95.62% by the peak area normalization method.

[0103] Compound 26 was crystallized to obtain pure compound 26 in crystalline form I, which was subjected to X-ray powder diffraction detection, and the results are shown in Table 6 and Figure 6 below. [Table 6]

[0104] Example 16 Preparation of (2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)methyl 3-formyl-1H-indole-1-carboxylate (Compound 9)

[0105] (1) Synthesis of 2-(2-((2,6-dichlorophenyl)amino)phenyl)silver acetate (R9_Ag+) [ka] 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetic acid (compound R9) (3.0 g, 10.1 mmol) was dissolved in 1 M aqueous ammonia (30 mL), the temperature was lowered to 0 °C, and an aqueous silver nitrate solution (1.7 g, 10.1 mmol, 10 mL) was added. The reaction was allowed to proceed at 0 °C for 30 minutes, resulting in the precipitation of a large amount of white solid. The white solid was collected by filtration, washed with water, and dried to obtain 2-(2-((2,6-dichlorophenyl)amino)phenyl)silver acetate (R9_Ag+) (2.9 g, 71% yield).

[0106] (2) Synthesis of (2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)methyl 3-formyl-1H-indole-1-carboxylate (Compound 9) [ka] 2-(2-((2,6-dichlorophenyl)amino)phenyl)silver acetate (R9_Ag+) (2.2 g, 5.5 mmol) and iodomethyl 3-formyl-1H-indole-1-carboxylate (Compound C) (1.5 g, 4.6 mmol) were dissolved in toluene and reacted at 40 °C for 4 hours. LCMS showed the disappearance of iodomethyl 3-formyl-1H-indole-1-carboxylate (Compound C). The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (3 × 20 mL) and water (40 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain the target compound (2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)methyl 3-formyl-1H-indole-1-carboxylate (compound 9) (500 mg, yield 43.7%) as a white solid.

[0107] Analytical data for compound 9: 1 H NMR(400MHz,DMSO)δ 10.08(s,1H),8.68(s,1H),8.14(dd,J=19.1,7.6Hz,2H),7.45(t,J=12.0Hz,4H),7.24~7.13(m,2H),7 .03(dd,J=17.5,10.2Hz,2H),6.82(d,J=7.4Hz,1H),6.20(d,J=8.4Hz,1H),6.11(s,2H),3.98(s,3H).

[0108] The purity of the compound 9 was measured by HPLC, and the purity at 254 nm was determined to be 98.7% and the purity at 214 nm was determined to be 98.8% by the peak area normalization method.

[0109] The compound 9 was crystallized to obtain the pure compound 9 of crystalline form I. The pure compound was subjected to X-ray powder diffraction detection, and the results are shown in Table 7 and Figure 7 below. [Table 7]

[0110] Example 17 Preparation of (2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 27) [ka] (2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)methyl 3-formyl-1H-indole-1-carboxylate (Compound 9) (80 mg, 0.16 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), the temperature was lowered to 0 °C, and sodium borohydride (6 mg, 0.16 mmol) was added. The reaction was allowed to proceed at 0 °C for 2 hours, after which completion of the reaction was detected by TLC (petroleum ether / ethyl acetate = 3:1). The reaction mixture was extracted with saturated aqueous ammonium chloride solution (15 mL) and ethyl acetate (3 × 20 mL). The combined organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was combined with MC20-875-048 and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain the target compound (2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 27) (110 mg, 52% yield) as a pale yellow solid.

[0111] Analytical data for compound 27: 1 H NMR(400MHz,DMSO)δ 8.04(d,J=7.7Hz,1H),7.67(d,J=7.7Hz,1H),7.57~7.44(m,3H),7.31(dt,J=25.2,6.8Hz,2H),7.19(t,J=8.1Hz,2H),7.10~ 6.95(m,2H),6.80(t,J=7.4Hz,1H),6.25~6.15(m,1H),6.05(s,2H),5.15(t,J=5.5Hz,1H),4.67~4.56(m,2H),3.95(s,2H).

[0112] The purity of compound 27 was measured by HPLC, and the purity at 254 nm was determined to be 95.96% and the purity at 214 nm was determined to be 95.28% by the peak area normalization method.

[0113] The compound 27 was crystallized to obtain the pure compound 27 of crystalline form I, which was subjected to X-ray powder diffraction detection, and the results are shown in Table 8 and Figure 8 below. [Table 8]

[0114] Example 18 Preparation of methyl (3-formyl-1H-indol-1-yl)hexanoate (Compound 28)

[0115] (1) Synthesis of chloromethyl hexanoate [ka] Hexanoic acid (1.0 g, 8.62 mmol), sodium bicarbonate (2.89 g, 34.48 mmol), and BuNHSO4 (0.29 g, 0.862 mmol) were dissolved in a mixture of dichloromethane and water (10 mL / 10 mL). After stirring for 10 minutes, the temperature was lowered to 0 °C, and (chloromethoxy)methanesulfonyl chloride (1.71 g, 10.34 mmol) was added dropwise. The mixture was allowed to warm to room temperature and react for 2 hours. TLC (petroleum ether / ethyl acetate = 5:1) indicated the completion of the reaction. The reaction mixture was separated, and the aqueous phase was extracted with dichloromethane (3 × 30 mL). The organic phase was washed with water (2 × 30 mL). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing through a column (eluent: petroleum ether / ethyl acetate = 100:1 to 5:1) to obtain the target compound chloromethyl hexanoate (400 mg, yield 28.3%) as a yellow oil.

[0116] (2) Synthesis of methyl (3-formyl-1H-indol-1-yl)hexanoate (compound 28) [ka] 1H-Indole-3-carbaldehyde (176 mg, 1.22 mmol) was dissolved in tetrahydrofuran, sodium iodide (18 mg, 0.122 mmol) was added, and bis(trimethylsilyl)aminolithium (1.83 mL, 1.83 mmol) was added dropwise under anhydrous and oxygen-free conditions at -78 °C. After 30 minutes at -78 °C, a solution of chloromethyl hexanoate (400 mg, 2.44 mmol) in tetrahydrofuran was added dropwise. After 3 hours at -78 °C, LCMS (MC20-874-3-P1B) indicated the completion of the reaction. The reaction mixture was diluted with aqueous ammonium chloride (10 mL), diluted with water (50 mL), and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by PRE-TLC (PE:EA=4:1, Rf=0.4) to obtain the target compound, methyl (3-formyl-1H-indol-1-yl)hexanoate (200 mg, yield 30.0%), as a yellow oil.

[0117] Analytical data for compound 28: 1 H NMR (400 MHz, DMSO): δ 1 H NMR(400MHz,CDCl3)δ 10.02(s,1H),8.30(dd,J=6.9,1.5Hz,1H),7.91(s,1H),7.58~7.46(m,1H),7.44~7.28(m,2H),6 .11(s,2H),2.31(t,J=7.5Hz,2H),1.64-1.51(m,2H),1.31~1.11(m,4H),0.81(t,J=7.0Hz,3H).

[0118] Example 19 Preparation of methyl (3-(hydroxymethyl)-1H-indol-1-yl)methylhexanoate (Compound 37) [ka] Methyl (3-formyl-1H-indol-1-yl)hexanoate (400 mg, 1.47 mmol) was dissolved in anhydrous methanol (6 mL), the temperature was lowered to 0 °C, and sodium borohydride (56 mg, 1.47 mmol) was added. After 30 min at 0 °C, the reaction was confirmed to be complete by TLC (petroleum ether / ethyl acetate = 3:1). The reaction mixture was extracted with saturated aqueous ammonium chloride (15 mL) and ethyl acetate (3 × 20 mL). The combined organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by pre-TLC (PE:EA = 3:1, Rf = 0.25) afforded the desired compound, methyl (3-(hydroxymethyl)-1H-indol-1-yl)methylhexanoate (compound 37) (115 mg, 28.5% yield), as a yellow oil.

[0119] Analytical data for compound 28: 1 H NMR(400MHz,DMSO)δ 7.61(d,J=7.8Hz,1H),7.54(d,J=8.2Hz,1H),7.34(s,1H),7.19(dd,J=11.2,4.0Hz,1H),7.10(t,J=7.4Hz,1H),6.17(s,2H) ),4.90(s,1H),4.62(s,2H),2.26(t,J=7.3Hz,2H),1.46(dd,J=14.6,7.3Hz,2H),1.23~1.09(m,4H),0.78(t,J=6.9Hz,3H).

[0120] The purity of compound 28 was measured by HPLC, and the purity at 254 nm was determined to be 97.07% and the purity at 214 nm was determined to be 96.37% by the peak area normalization method.

[0121] Example 20 Preparation of methyl (3-formyl-1H-indol-1-yl)octanoate (Compound 29)

[0122] (1) Synthesis of chloromethyl octanoate [ka] Octanoic acid (2.0 g, 13.868 mmol), sodium bicarbonate (4.660 g, 55.473 mmol), and tetrabutylammonium hydrogen sulfate (471 mg, 1.387 mmol) were dissolved in dichloromethane and water (32 mL, 1:1) and stirred at room temperature for 5 min. Chloromethylsulfonyl chloride (2.746 g, 16.642 mmol) was then added slowly at 0 °C. The mixture was then allowed to react at room temperature for 2 h, and TLC (petroleum ether / ethyl acetate = 5:1) showed the reaction was complete. The mixture was extracted with dichloromethane (2 × 30 mL), and the combined organic phase was washed with water (60 mL) and saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing through a column (eluent: petroleum ether / ethyl acetate=100:1 to 80:1) to obtain the target compound, chloromethyl octanoate (1.827 g, yield 68.4%), as a colorless oil.

[0123] Analytical data for chloromethyl octanoate: 1 H NMR(400MHz, CDCl3)δ 5.71(s,2H),2.38(t,J=7.5Hz,2H),1.73~1.58(m,2H),1.36~1.22(m,8H),0.88(t,J=6.9Hz,3H).

[0124] (2) Synthesis of methyl (3-formyl-1H-indol-1-yl)octanoate (compound 29) [ka] Under argon protection, 1H-indole-3-acetaldehyde (400 mg, 2.755 mmol) and sodium iodide (83 mg, 0.551 mmol) were dissolved in anhydrous tetrahydrofuran (6 mL). The temperature was lowered to -78 °C, and a solution of bis(trimethylsilyl)aminolithium in tetrahydrofuran (1 M, 4.1 mL, 4.132 mmol) was added dropwise and reacted at -78 °C for 30 minutes. Next, a solution of chloromethyl octanoate (2) (1.061 g, 5.510 mmol) in tetrahydrofuran (6 mL) was added dropwise to the reaction mixture and reacted at -78 °C for 2 hours. TLC (petroleum ether / ethyl acetate = 3:1) showed the completion of the reaction. The reaction mixture was added with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic phase was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 70:1) to give the target compound, methyl (3-formyl-1H-indol-1-yl)octanoate (Compound 29) (580 mg, 69.9% yield), as a yellow oil.

[0125] Analytical data for compound 29: 1 H NMR(400MHz,CDCl3)δ 10.03(s,1H),8.31(dd,J=6.8,1.5Hz,1H),7.92(s,1H),7.53(dd,J=7.1,1.2Hz,1H),7.44~7.31(m,2 H),6.12(s,2H),2.32(t,J=7.5Hz,2H),1.71~1.47(m,2H),1.31~1.08(m,8H),0.84(t,J=7.0Hz,3H).

[0126] The purity of the compound 29 was measured by HPLC, and the purity at 254 nm was determined to be 99.06% and the purity at 214 nm was determined to be 99.06% by the peak area normalization method.

[0127] Example 21 Preparation of methyl (3-(hydroxymethyl)-1H-indol-1-yl)octanoate (compound 38) [ka] Methyl (3-formyl-1H-indol-1-yl)octanoate (Compound 29) (250 mg, 0.829 mmol) was dissolved in anhydrous methanol (3 mL), the temperature was lowered to 0 °C, and sodium borohydride (31 mg, 0.829 mmol) was added. The reaction was allowed to proceed at 0 °C for 30 minutes, after which completion of the reaction was confirmed by TLC (petroleum ether / ethyl acetate = 3:1). Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (2 × 30 mL). The combined organic phase was washed with water (60 mL) and saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by prep-TLC (eluent: petroleum ether / ethyl acetate = 3:1) to obtain the target compound (3-(hydroxymethyl)-1H-indol-1-yl) methyl octanoate (compound 38) (60 mg, yield 24.0%) (yellow oil). This was combined with MC20-877-017P and MC20-877-018P to obtain the target compound (3-(hydroxymethyl)-1H-indol-1-yl) methyl octanoate (compound 38) (103 mg).

[0128] Analytical data for compound 38: 1 H NMR(400MHz,DMSO)δ 7.61(d,J=7.8Hz,1H),7.53(d,J=8.2Hz,1H),7.34(s,1H),7.19(t,J=7.1Hz,1H),7.09(t,J=7.1Hz,1H),6.17(s,2H),4.90(t, J=5.4Hz,1H), 4.61(d,J=5.3Hz,2H),2.26(t,J=7.3Hz,2H),1.51~1.39(m,2H),1.17(d,J=13.5Hz,8H),0.82(t,J=7.0Hz,3H).

[0129] The purity of the compound 38 was measured by HPLC, and the purity at 254 nm was determined to be 93.04% and the purity at 214 nm was determined to be 93.86% by the peak area normalization method.

[0130] Example 22 Preparation of methyl (3-formyl-1H-indol-1-yl)decanoate (Compound 30)

[0131] (1) Synthesis of chloromethyl decanoate [ka] Under argon protection, decanoic acid (1.0 g, 5.80 mmol), sodium bicarbonate (1.95 g, 23.20 mmol), and tetrabutylammonium hydrogen sulfate (197 mg, 0.58 mmol) were dissolved in dichloromethane (10 mL) and water (10 mL) and stirred at room temperature for 5 minutes. The reaction was placed in an ice-water bath at 0 °C, and chloromethyl chlorosulfonate (1.15 g, 6.96 mmol) was added dropwise. After the addition of the starting materials was complete, the mixture was allowed to warm to room temperature and react for 2 hours. TLC (petroleum ether / ethyl acetate = 20:1) indicated the reaction was complete. Water (50 mL) was added to the reaction mixture, which was then poured into a separatory funnel and the organic phase was separated. The aqueous phase was extracted with dichloromethane (3 × 50 mL). The combined organic phases were washed with water (80 mL) and saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was passed through a column and separated and purified using a high-performance silica gel column (eluent: petroleum ether / ethyl acetate = 100:1 to 100:5) to obtain the target compound, chloromethyl decanoate (1.04 g, yield 81.2%), as a colorless liquid.

[0132] Analytical data for chloromethyl decanoate: 1 H NMR(400MHz, CDCl3)δ 5.71(s,2H),2.38(t,J=7.5Hz,2H),1.69~1.59(m,2H),1.31(s,2H),1.28(d,J=13.6Hz,10H),0.88(t,J=6.8Hz,3H).

[0133] (2) Synthesis of methyl (3-formyl-1H-indol-1-yl)decanoate (compound 30) [ka] At −78 °C under an argon atmosphere, a solution of 3-formyl-1H-indole (438 mg, 3.02 mmol) and sodium iodide (46 mg, 0.30 mmol) in anhydrous tetrahydrofuran (15 mL) was stirred while adding (trimethylsilyl)aminolithium (4.6 mL, 4.60 mmol, 1 M) solution. The reaction mixture was then allowed to react for 30 minutes. Chloromethyl decanoate (1.00 g, 4.56 mmol) was then slowly added. After the addition of the starting materials was complete, the mixture was warmed to room temperature and stirred for 2 hours. LCMS and TLC (petroleum ether / ethyl acetate = 15:2) indicated that the reaction was essentially complete. Saturated aqueous ammonium chloride (50 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (2 × 40 mL). The combined organic phase was washed with saturated sodium thiosulfate (100 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated on a column / high-performance silica gel column (eluent: petroleum ether / ethyl acetate = 100:1 to 100:15) and purified by prep-TLC (petroleum ether / ethyl acetate = 5:1) to obtain the target compound, methyl (3-formyl-1H-indol-1-yl)decanoate (compound 30) (660 mg, 66.3% yield) as a colorless oily liquid.

[0134] Analytical data for compound 30: 1 H NMR(400MHz,CDCl3)δ 10.04(s,1H),8.31(dd,J=6.8,1.5Hz,1H),7.93(s,1H),7.57~7.48(m,1H),7.37(dtd,J=14.6,7.2,1.3Hz,2H),6.12( s, 2H), 2.32 (t, J = 7.5Hz, 2H), 1.62~1.51 (m, 2H), 1.26 (d, J = 6.5Hz, 2H), 1.19 (d, J = 2.6Hz, 11H), 0.87 (t, J = 7.0Hz, 3H).

[0135] The purity of the compound 30 was measured by HPLC, and the purity at 254 nm was determined to be 96.43% and the purity at 214 nm was determined to be 97.83% by the peak area normalization method.

[0136] Example 23 Preparation of methyl (3-(hydroxymethyl)-1H-indol-1-yl)decanoate (Compound 39) [ka] Methyl (3-formyl-1H-indol-1-yl)decanoate (compound 30) (450 mg, 1.37 mmol) was dissolved in anhydrous methanol (8 mL), the temperature was lowered to 0 °C, and sodium borohydride (52 mg, 1.37 mmol) was added. After 30 minutes at 0 °C, the reaction was confirmed to be complete by TLC (petroleum ether / ethyl acetate = 5:1). Water (50 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (2 × 25 mL). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified twice by prep-TLC (petroleum ether / ethyl acetate = 5:1) to afford the desired compound, methyl (3-(hydroxymethyl)-1H-indol-1-yl)decanoate (compound 39) (187 mg, 41.3% yield), as a pale yellow oil.

[0137] Analytical data for compound 39: 1 H NMR(400MHz,DMSO):δ 7.61(d,J=7.8Hz,1H),7.53(d,J=8.2Hz,1H),7.34(s,1H),7.23~7.14(m,1H),7.09(t,J=7.3Hz,1H),6.17(s,2H),4.90(s,1H) ,4.62(d,J=2.8Hz,2H),2.26(t,J=7.3Hz,2H),1.51~1.38(m,2H),1.23(d,J=7.3Hz,2H),1.16(s,10H),0.85(t,J=6.9Hz,3H).

[0138] The purity of the compound 39 was measured by HPLC, and the purity at 254 nm was determined to be 94.60% and the purity at 214 nm was determined to be 93.91% by the peak area normalization method.

[0139] Example 24 Preparation of methyl (3-formyl-1H-indol-1-yl)dodecanoate (Compound 31)

[0140] (1) Synthesis of chloromethyl dodecanoate [ka] Dodecanoic acid (3.0 g, 14.976 mmol), sodium bicarbonate (5.032 g, 59.904 mmol), and tetrabutylammonium hydrogen sulfate (508 mg, 1.498 mmol) were dissolved in dichloromethane and water (40 mL, 1:1) and stirred at room temperature for 5 min. Chloromethylsulfonyl chloride (2.965 g, 17.971 mmol) was then slowly added at 0 °C. The mixture was then allowed to react at room temperature for 2 h, and TLC (petroleum ether / ethyl acetate = 5:1) showed the reaction was complete. The mixture was extracted with dichloromethane (2 × 40 mL), and the combined organic phase was washed with water (80 mL) and saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing through a column (eluent: petroleum ether / ethyl acetate=100:1 to 80:1) to obtain the target compound, chloromethyl dodecanoate (3.490 g, yield 93.7%), as a colorless oil.

[0141] Analytical data for chloromethyl dodecanoate: 1 H NMR(400MHz,H2O+D2O)δ 5.72(s,2H),2.40(t,J=7.5Hz,2H),1.72~1.62(m,2H),1.35~1.20(m,16H),0.90(t,J=6.8Hz,3H).

[0142] (2) Synthesis of methyl (3-formyl-1H-indol-1-yl)dodecanoate (compound 31) [ka] Under argon protection, 1H-indole-3-acetaldehyde (600 mg, 4.133 mmol) and sodium iodide (62 mg, 0.413 mmol) were dissolved in anhydrous tetrahydrofuran (9 mL). The temperature was lowered to -78 °C, and a solution of bis(trimethylsilyl)aminolithium in tetrahydrofuran (1 M, 6.2 mL, 6.200 mmol) was added dropwise and reacted at -78 °C for 30 minutes. Next, a solution of chloromethyl dodecanoate (2) (2.0 g, 8.267 mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction mixture and reacted at -78 °C for 2 hours. TLC (petroleum ether / ethyl acetate = 3:1) showed the completion of the reaction. The reaction mixture was added with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic phase was washed with water (60 mL) and saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 70:1) to give the target compound, methyl (3-formyl-1H-indol-1-yl)dodecanoate (Compound 31) (665 mg, 45.0% yield) as a pale yellow solid.

[0143] Analytical data for compound 31: 1 H NMR(400MHz,CDCl3)δ 10.05(s,1H),8.44~8.24(m,1H),7.92(s,1H),7.53(d,J=7.4Hz,1H),7.45~7.29(m,2H),6.1 2(s,2H),2.32(t,J=7.5Hz,2H),1.57(s,2H),1.21(d,J=16.2Hz,16H),0.88(t,J=6.9Hz,3H).

[0144] The purity of the compound 31 was measured by HPLC, and the purity at 254 nm was determined to be 99.17% and the purity at 214 nm was determined to be 97.86% by the peak area normalization method.

[0145] Example 25 Preparation of methyl (3-(hydroxymethyl)-1H-indol-1-yl)dodecanoate (Compound 40) [ka] Methyl (3-formyl-1H-indol-1-yl)dodecanoate (Compound 31) (250 mg, 0.695 mmol) was dissolved in anhydrous methanol (5 mL), the temperature was lowered to 0 °C, and sodium borohydride (26 mg, 0.695 mmol) was added. After 30 minutes of reaction at 0 °C, the reaction was confirmed to be complete by TLC (petroleum ether / ethyl acetate = 3:1). Saturated aqueous ammonium chloride (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (2 × 20 mL). The combined organic phases were washed with water (40 mL) and saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by prep-TLC (eluent: petroleum ether / ethyl acetate = 3:1) to afford the target compound, methyl (3-(hydroxymethyl)-1H-indol-1-yl)dodecanoate (Compound 40) (140 mg, 56.0% yield), as a pale yellow solid.

[0146] Analytical data for compound 40: 1 H NMR(400MHz,DMSO)δ 7.61(d,J=7.8Hz,1H),7.53(d,J=8.2Hz,1H),7.34(s,1H),7.19(t,J=7.2Hz,1H),7.09(t,J=7.2Hz,1H),6.17(s,2H),4.90( t,J=5.4Hz,1H),4.61(d,J=5.3Hz,2H),2.26(t,J=7.3Hz,2H),1.45(s,2H),1.19(d,J=26.6Hz,16H),0.85(t,J=6.8Hz,3H).

[0147] The purity of the compound 40 was measured by HPLC, and the purity at 254 nm was determined to be 98.23% and the purity at 214 nm was determined to be 97.03% by the peak area normalization method.

[0148] Example 26 Preparation of methyl (3-formyl-1H-indol-1-yl)tetradecanoate (Compound 32)

[0149] (1) Synthesis of chloromethyl tetradecanoate Tetradecanoic acid (3.0 g, 13.136 mmol), sodium bicarbonate (4.414 g, 52.544 mmol), and tetrabutylammonium hydrogen sulfate (446 mg, 1.313 mmol) were dissolved in dichloromethane and water (40 mL, 1:1) and stirred at room temperature for 5 min. Chloromethylsulfonyl chloride (2.6 g, 15.764 mmol) was then slowly added at 0 °C. The mixture was then allowed to react at room temperature for 2 h, and TLC (petroleum ether / ethyl acetate = 3:1) showed the reaction was complete. The mixture was extracted with dichloromethane (2 × 40 mL), and the combined organic phases were washed with water (80 mL) and saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by passing through a column (eluent: petroleum ether / ethyl acetate = 100:1 to 80:1) to obtain the target compound, chloromethyl tetradecanoate (3.316 g, yield 91.2%), as a translucent solid.

[0150] Analytical data for chloromethyl tetradecanoate: 1 H NMR(400MHz, CDCl3)δ 5.70(s,2H),2.38(t,J=7.5Hz,2H),1.78~1.51(m,2H),1.37~1.23(m,20H),0.88(t,J=6.8Hz,3H).

[0151] (2) Synthesis of methyl (3-formyl-1H-indol-1-yl)tetradecanoate (compound 32) [ka] Under argon protection, 1H-indole-3-acetaldehyde (400 mg, 2.755 mmol) and sodium iodide (41 mg, 0.275 mmol) were dissolved in anhydrous tetrahydrofuran (8 mL). The temperature was lowered to -78 °C, and a solution of bis(trimethylsilyl)aminolithium in tetrahydrofuran (1 M, 4.1 mL, 4.132 mmol) was added dropwise and reacted at -78 °C for 1 hour. Next, a solution of chloromethyl tetradecanoate (1.525 g, 5.510 mmol) in tetrahydrofuran (8 mL) was added dropwise to the reaction mixture and reacted at -78 °C for 2 hours, at which point TLC (petroleum ether / ethyl acetate = 3:1) showed the completion of the reaction. The reaction mixture was added with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic phase was washed with water (60 mL) and saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 70:1) to give the target compound, methyl (3-formyl-1H-indol-1-yl)tetradecanoate (Compound 32) (827 mg, yield 77.8%), as a pale yellow solid.

[0152] Analytical data for compound 32: 1 H NMR(400MHz,CDCl3)δ 10.04(s,1H),8.32(d,J=7.0Hz,1H),7.92(s,1H),7.53(d,J=7.6Hz,1H),7.44-7.32(m,2H),6. 12(s,2H),2.32(t,J=7.5Hz,2H),1.59(s,2H),1.22(d,J=22.3Hz,20H),0.88(t,J=6.8Hz,3H).

[0153] The purity of compound 32 was measured by HPLC, and the purity at 254 nm was determined to be 98.67% and the purity at 214 nm was determined to be 99.35% by the peak area normalization method.

[0154] Example 27 Preparation of methyl (3-(hydroxymethyl)-1H-indol-1-yl)tetradecanoate (Compound 41) [ka] Methyl (3-formyl-1H-indol-1-yl)tetradecanoate (Compound 32) (300 mg, 0.778 mmol) was dissolved in anhydrous methanol (6 mL), the temperature was lowered to 0 °C, and sodium borohydride (29.4 mg, 0.778 mmol) was added. The reaction was allowed to proceed at 0 °C for 30 minutes, after which completion of the reaction was confirmed by TLC (petroleum ether / ethyl acetate = 3:1). Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (2 × 30 mL). The combined organic phase was washed with water (60 mL) and saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by prep-TLC (eluent: petroleum ether / ethyl acetate = 2:1) to give the target compound (3-(hydroxymethyl)-1H-indol-1-yl) methyl tetradecanoate (Compound 41) (130 mg, yield 43.1%) as a pale yellow solid.

[0155] Analytical data for compound 41: 1 H NMR(400MHz,DMSO)δ 7.61(d,J=7.9Hz,1H),7.53(d,J=8.1Hz,1H),7.34(s,1H),7.19(t,J=7.5Hz,1H),7.09(t,J=7.5Hz,1H),6.17(s,2H),4.90( t,J=5.4Hz,1H),4.61(d,J=5.1Hz,2H),2.26(t,J=7.3Hz,2H),1.45(s,2H),1.19(d,J=32.7Hz,20H),0.85(t,J=6.8Hz,3H).

[0156] The purity of compound 41 was measured by HPLC, and the purity at 254 nm was determined to be 97.17% and the purity at 214 nm was determined to be 96.91% by the peak area normalization method.

[0157] Compound 41 was crystallized to obtain pure compound 41 in crystalline form I, which was subjected to X-ray powder diffraction detection, the results of which are shown in Table 9 below and Figure 9. [Table 9]

[0158] Example 28 Preparation of methyl (3-formyl-1H-indol-1-yl)palmitate (compound 33)

[0159] (1) Synthesis of chloromethyl palmitate [ka] Palmitic acid (4.0 g, 15.599 mmol), sodium bicarbonate (5.241 g, 62.396 mmol), and tetrabutylammonium hydrogen sulfate (530 mg, 1.560 mmol) were dissolved in dichloromethane and water (60 mL, 1:1) and stirred at room temperature for 5 min. Chloromethylsulfonyl chloride (3.080 g, 18.719 mmol) was then slowly added at 0 °C. The mixture was then allowed to react at room temperature for 2 h, and TLC (petroleum ether / ethyl acetate = 5:1) showed the reaction was complete. The mixture was extracted with dichloromethane (2 × 50 mL), and the combined organic phase was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by passing through a column (eluent: petroleum ether / ethyl acetate = 100:1 to 80:1) to obtain the target compound, chloromethyl palmitate (3.727 g, yield 78.4%), as a translucent solid.

[0160] Analytical data for chloromethyl palmitate: 1 H NMR(400MHz, CDCl3)δ 5.70(s,2H),2.38(t,J=7.5Hz,2H),1.72~1.54(m,2H),1.33~1.23(m,24H),0.88(t,J=6.8Hz,3H).

[0161] (2) Synthesis of methyl (3-formyl-1H-indol-1-yl)palmitate (compound 33) [ka] Under argon protection, 1H-indole-3-acetaldehyde (400 mg, 2.755 mmol) and sodium iodide (41 mg, 0.275 mmol) were dissolved in anhydrous tetrahydrofuran (8 mL). The temperature was lowered to -78 °C, and a solution of bis(trimethylsilyl)aminolithium in tetrahydrofuran (1 M, 4.1 mL, 4.132 mmol) was added dropwise and reacted at -78 °C for 1 hour. Next, a solution of chloromethyl palmitate (2) (1.680 g, 5.511 mmol) in tetrahydrofuran (8 mL) was added dropwise to the reaction mixture and reacted at -78 °C for 2 hours. TLC (petroleum ether / ethyl acetate = 5:1) showed the completion of the reaction. The reaction mixture was added with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (2 × 40 mL). The combined organic phase was washed with water (80 mL) and saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 80:1) to give the target compound, methyl (3-formyl-1H-indol-1-yl)palmitate (Compound 33) (697 mg, 61.2% yield) as a white solid.

[0162] Analytical data for compound 33: 1 H NMR(400MHz,CDCl3)δ 10.04(s,1H),8.32(d,J=6.8Hz,1H),7.92(s,1H),7.53(d,J=7.5Hz,1H),7.37(td,J=13.8,6.0Hz,2 H),6.12(s,2H),2.32(t,J=7.5Hz,2H),1.58(s,8H),1.22(d,J=24.3Hz,24H),0.88(t,J=6.8Hz,3H).

[0163] The purity of the compound 31 was measured by HPLC, and the purity at 254 nm was determined to be 97.69% and the purity at 214 nm was determined to be 98.46% by the peak area normalization method.

[0164] Example 29 Preparation of methyl (3-(hydroxymethyl)-1H-indol-1-yl)palmitate (Compound 42) [ka] Methyl (3-formyl-1H-indol-1-yl)palmitate (Compound 33) (300 mg, 0.725 mmol) was dissolved in anhydrous methanol (10 mL) and tetrahydrofuran (5 mL). The temperature was lowered to 0 °C, and sodium borohydride (27 mg, 0.725 mmol) was added. The reaction was allowed to proceed at 0 °C for 30 minutes, after which completion of the reaction was confirmed by TLC (petroleum ether / ethyl acetate = 3:1). Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (2 × 30 mL). The combined organic phase was washed with water (60 mL) and saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by prep-TLC (eluent: petroleum ether / ethyl acetate = 2:1) to give the target compound (3-(hydroxymethyl)-1H-indol-1-yl)methyl palmitate (compound 42) (250 mg, yield 83.0%) as a white solid.

[0165] Analytical data for compound 42: 1 H NMR(400MHz,DMSO)δ 7.61(d,J=7.9Hz,1H),7.53(d,J=8.3Hz,1H),7.34(s,1H),7.19(t,J=7.1Hz,1H),7.09(t,J=7.0Hz,1H),6.17(s,2H),4.90( t,J=5.4Hz,1H),4.61(d,J=5.1Hz,2H),2.26(t,J=7.3Hz,2H),1.45(s,2H),1.19(d,J=33.6Hz,24H),0.85(t,J=6.8Hz,3H).

[0166] The purity of compound 42 was measured by HPLC, and the purity at 254 nm was determined to be 97.87% and the purity at 214 nm was determined to be 98.43% by the peak area normalization method.

[0167] Example 30 Preparation of (3-formyl-1H-indol-1-yl)methyl 2,5,8,11,14-pentaoxohexadecan-16-ate (Compound 34)

[0168] (1) Synthesis of chloromethyl 2,5,8,11,14-pentaoxohexadecan-16-ate [ka] 2,5,8,11,14-Pentaoxohexadecane-16-oleic acid (1.6 g, 6.008 mmol), sodium bicarbonate (2.019 g, 24.032 mmol), and tetrabutylammonium hydrogen sulfate (204 mg, 0.600 mmol) were dissolved in dichloromethane and water (50 mL, 1:1) and stirred at room temperature for 5 minutes. Chloromethylsulfonyl chloride (1.189 g, 7.210 mmol) was then slowly added at 0° C., followed by reaction at room temperature for 2 hours. Extraction with dichloromethane (2 × 50 mL) was performed. The combined organic phase was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The target compound, chloromethyl 2,5,8,11,14-pentaoxohexadecan-16-ate (1.2 g, crude product), was obtained as a yellow oil.

[0169] Analytical data for chloromethyl 2,5,8,11,14-pentaoxohexadecan-16-ate: 1 H NMR(400MHz, CDCl3)δ 5.76(s,2H),4.25(s,2H),3.78~3.74(m,2H),3.72~3.65(m,12H),3.55(dd,J=5.6,3.6Hz,2H),3.39(d,J=2.8Hz,3H).

[0170] (2) Synthesis of (3-formyl-1H-indol-1-yl)methyl 2,5,8,11,14-pentaoxohexadecan-16-ate (Compound 34) [ka] 1H-Indole-3-acetaldehyde (503 mg, 3.812 mmol), sodium iodide (52 mg, 0.347 mmol), chloromethyl 2,5,8,11,14-pentaoxohexadecan-16-ate (1.2 g, 3.812 mmol), and triethylamine (1.052 mg, 10.398 mmol) were dissolved in N,N-dimethylformamide (20 mL) and reacted at 30 °C for 12 h. 4-Dimethylaminopyridine (42 mg, 0.347 mmol) was added and reacted at 30 °C for 12 h. LCMS indicated the reaction was complete. Saturated aqueous ammonium chloride (20 mL) was added to the reaction mixture, which was extracted with ethyl acetate (2 × 60 mL). The combined organic phase was washed with water (120 mL) and saturated brine (120 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to obtain the target compound, (3-formyl-1H-indol-1-yl)methyl 2,5,8,11,14-pentaoxohexadecan-16-ate (Compound 34) (320 mg, yield 21.8%), as a yellow solid.

[0171] Analytical data for compound 34: 1 H NMR(400MHz,CDCl3)δ 10.04(s,1H),8.31(d,J=6.9Hz,1H),7.95(s,1H),7.54(d,J=7.4Hz,1H),7. 43~7.32(m,2H),6.20(s,2H),4.18(s,2H),3.70~3.51(m,16H),3.36(s,3H).

[0172] The purity of the compound 34 was measured by HPLC, and the purity at 254 nm was determined to be 99.32% and the purity at 214 nm was determined to be 99.38% by the peak area normalization method.

[0173] Example 31 Preparation of methyl (3-formyl-1H-indol-1-yl) 2-acetoxybenzoate (Compound 35)

[0174] (1)2.14 Synthesis of chloromethyl 2-acetoxybenzoate (2) [ka] 2-Acetoxybenzoic acid (3.0 g, 15.599 mmol), sodium bicarbonate (5.595 g, 66.604 mmol), and tetrabutylammonium hydrogen sulfate (565 mg, 1.665 mmol) were dissolved in dichloromethane and water (40 mL, 1:1) and stirred at room temperature for 5 min. Chloromethylsulfonyl chloride (3.297 g, 19.982 mmol) was then slowly added at 0 °C. The mixture was then allowed to react at room temperature for 2 h, and TLC (petroleum ether / ethyl acetate = 5:1) showed the reaction was complete. The mixture was extracted with dichloromethane (2 × 40 mL), and the combined organic phase was washed with water (80 mL) and saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing through a column (eluent: petroleum ether / ethyl acetate=100:1 to 80:1) to obtain the target compound, chloromethyl 2-acetoxybenzoate (3.0 g, yield 78.8%), as a colorless oil.

[0175] Analytical data for chloromethyl 2-acetoxybenzoate: 1 H NMR(400MHz, CDCl3)δ 8.06(dd,J=7.9,1.6Hz,1H),7.62(td,J=7.9,1.6Hz,1H),7.41~7.29(m,1H),7.22~7.07(m,1H),5.90(s,2H),2.38(s,3H).

[0176] (2) Synthesis of methyl (3-formyl-1H-indol-1-yl) 2-acetoxybenzoate (compound 35) [ka] 1H-Indole-3-acetaldehyde (800 mg, 5.511 mmol), sodium iodide (83 mg, 0.551 mmol), 4-dimethylaminopyridine (67 mg, 0.551 mmol), chloromethyl 2-acetoxybenzoate (2) (2.520 g, 11.022 mmol), and triethylamine (1.673 mg, 16.533 mmol) were dissolved in N,N-dimethylformamide (32 mL) and reacted at 30 °C for 24 h. TLC (petroleum ether / ethyl acetate = 1.5:1) indicated the reaction was complete. Saturated aqueous ammonium chloride (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (2 × 50 mL). The combined organic phases were washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to obtain the target compound, methyl (3-formyl-1H-indol-1-yl)-2-acetoxybenzoate (Compound 35) (233 mg, yield 12.4%), as a white solid.

[0177] Analytical data for compound 35: 1 H NMR(400MHz,CDCl3)δ 10.07(s,1H),8.33(d,J=7.3Hz,1H),8.13~7.86(m,2H),7.58(ddd,J=7.8,4.6,1.7Hz,2H),7.40(dd d,J=15.1,13.9,6.9Hz,2H),7.29(t,J=8.1Hz,1H),7.09(d,J=8.1Hz,1H),6.33(s,2H),2.14(s,3H).

[0178] The purity of the compound 35 was measured by HPLC, and the purity at 254 nm was determined to be 99.7% and the purity at 214 nm was determined to be 99.63% by the peak area normalization method.

[0179] The compound 35 was crystallized to obtain the pure compound 35 in crystalline form I. The pure compound was subjected to X-ray powder diffraction detection, and the results are shown in Table 10 and Figure 10 below. [Table 10] TIFF0007763510000058.tif24170

[0180] Example 32 The compounds prepared in the above examples were tested for activity.

[0181] 1. Method The therapeutic activity of these compounds against AD was examined using a mouse model of AD-like symptoms induced by calcipotriol (MC903) in the ear.

[0182] A MC903 (calcipotriol) mouse model was established based on patent publication number CN110368385A. BALB / c mice were smeared in both ears for 11 consecutive days. MC903, MC903 and IAId, or a compound prepared in the Examples were smeared in both ears, respectively. At the end of the experiment, serum total IgE levels, ear thickness, and weight change from the start of the experiment were measured. Due to the large number of test drugs, efficacy evaluation was performed in two batches.

[0183] 2.Results The data shown are the mean ± SD of five independent replicate experiments. The Mann-Whitney U test was used to analyze the significance of the differences between the MC903-only treatment group (MC903 + EtOH group) and the corresponding indexes. * indicates P<0.05, ** indicates P<0.01, and *** indicates P<0.001.

[0184] 2.1 First batch experiment In this batch of experiments, the dose of the model drug MC903 was 6.9 nmol / (day·animal), and the experimental results for compounds Nos. 1, 2, 3, 6, 7, 19, 20, 28, 29, 30, 34, 37, 38 and 39 in this batch are shown in Figures 11 to 13.

[0185] Figure 11 shows serum total IgE levels in mice administered with different drugs. Figure 12 shows ear thickness in mice administered with different drugs. Figure 13 shows changes in mouse weight relative to the start of the experiment in mice administered with different drugs. Figure 14 shows photographs of representative mouse ears administered with different drugs. Figure 15 shows HE staining of representative mouse ear tissue in mice administered with different drugs. The EtOH group was a blank control group administered with ethanol alone. The MC903 + EtOH group was a model control group administered with calcipotriol and ethanol. The remaining groups were all groups administered with different active drugs after administering MC903 to create a model. The IAId (indole-3-carbaldehyde) group was an IAId-administered group. The I3C (indole-3-carbinol) group was an I3C-administered group. The remaining compound groups were groups administered with the corresponding compounds.

[0186] As shown in the figure, compared with the blank control group (EtOH), the model control group (MC903+) showed significant differences (P<0.001) in serum total IgE levels, ear thickness, and weight change from the start of the experiment, indicating successful model creation. Both the IAId and I3C groups had a significant effect of reducing serum total IgE levels and ear thickness (P<0.05 or P<0.01), indicating that all compounds played a positive role in serum total IgE, ear thickness, and weight change in mice. Among them, in terms of reducing total serum IgE in mice, compounds 1, 2, 29, 30, 34, 37, 38, and 39 were statistically significantly different from the model group, with compounds 30 and 38 being particularly effective in reducing total serum IgE in mice. In terms of reducing ear thickness in mice, compounds 1, 19, 20, 29, 30, 34, and 39 were statistically significantly different from the model group, with compounds 29 and 30 being particularly effective in reducing ear thickness in mice. Combined with the inflammatory status of the mouse ear and the results of HE staining of the tissue, compounds 29, 30, and 38 had obvious therapeutic effects on AD-like symptoms in the mouse ear.

[0187] 2.2 Second batch experiment In the first batch of drug tests, we found that the survival status of mice was significantly affected by the model drug MC903, resulting in a significant decrease in body weight (Figure 13). Therefore, in the second batch of drug tests, the MC903 dose was reduced to 5 nmol / (day / mouse) and the test period was shortened to 9 days. As expected, the survival status of mice was significantly improved (Figure 18).

[0188] The experimental results for compounds of this batch number 30, 38, 4, 5, 9, 21, 22, 23, 24, 26, 27, 31, 32, 33, 35, 40, 41, 42, 8, and 29 are shown in Figures 16 to 20.

[0189] Figure 16 shows serum total IgE levels in mice administered with different drugs. Figure 17 shows ear thickness in mice administered with different drugs. Figure 18 shows changes in mouse weight relative to the start of the experiment in mice administered with different drugs. Figure 19 shows photographs of representative mouse ears administered with different drugs. Figure 20 shows HE staining of representative mouse ear tissue in mice administered with different drugs. The EtOH group was a blank control group administered with ethanol alone. The MC903 + EtOH group was a model control group administered with calcipotriol and ethanol. The remaining groups were all groups administered with different active drugs after administering MC903 to create a model. The IAId (indole-3-carbaldehyde) group was a group administered with IAId. The I3C (indole-3-carbinol) group was a group administered with IAId. The remaining compound groups were groups administered with the corresponding compounds.

[0190] As shown in the figure, the serum total IgE levels, ear thickness, and weight change from the start of the experiment were all significantly different (P<0.01 or P<0.001) between the model control group (MC903+) and the blank control group (EtOH), demonstrating successful model creation. Compounds 30, 38, 4, 9, 22, 23, 24, 26, 27, 33, 35, 41, and 8 showed statistically significant differences in serum total IgE levels compared to the model group, with compounds 30, 4, 9, 22, and 35 showing particularly strong effects. Compounds 30, 38, 4, 9, 27, 8, and 29 showed statistically significant differences in ear thickness compared to the model group, with compound 9 showing particularly strong effects. By combining the inflammatory status of the mouse ears and the results of HE staining of the tissues, and by combining multiple tests and test indicators, drugs with therapeutic effects on AD-like symptoms in the mouse ears were screened, and the results were 4, 9, 29, 30, 38, 22, and 35, respectively.

[0191] Example 33 Experiment to determine the optimal concentration for treating AD-like symptoms

[0192] 1. Method The best effective dose was determined using the drugs screened above that have a therapeutic effect on AD-like symptoms in the mouse ear.

[0193] Referring to the animal model experimental method in Example 32, the groups and doses shown in the table below were administered, and the optimal effective concentration for treating AD-like symptoms was determined by comparing the differences in ear thickness, serum total IgE level, weight loss, etc. between the group administered MC903 alone and the group administered MC903 alone. [Table 11] Note: All of the above administration methods are external application.

[0194] 2.Results The results are shown in Figures 21 to 30. Figures 21 to 23 show the serum total IgE levels of mice in each group, Figures 24 to 26 show the ear thickness levels of mice in each group, Figures 27 to 29 show the weight loss levels of mice in each group, and Figure 30 is a photograph of the ears of a representative mouse.

[0195] In the mice treated with MC903 alone, the significance of differences in ear thickness, serum total IgE levels, weight loss, etc. was compared. Compound No. 9 showed a significant therapeutic effect on AD symptoms in the mouse ears at each test concentration. Compounds 4, 9, 29, 30, 38, 22, 35, etc. had good inhibitory effects on systemic inflammation, which was manifested as a decrease in serum total IgE levels and an improvement in AD symptoms in the mouse ears. In particular, compounds 4, 30, and 38 had excellent inhibitory effects on systemic inflammation.

[0196] Example 34 This example provides a cream formulation for topical use.

[0197] 1. Base material composition Stearic acid 120g, glycerol monostearate 35g, liquid paraffin 60g, white petrolatum 10g, lanolin 50g, triethanolamine 4g, distilled water (supplement to 1000.0g).

[0198] 2. Manufacturing method 2.1 Substrate manufacturing Stearic acid, glycerol monostearate, liquid paraffin, white petrolatum, and lanolin were placed in an evaporating dish as an oil phase, heated to about 80°C in a water bath, and mixed to melt. Triethanolamine and distilled water were placed in a beaker and heated to about 80°C in a water bath. At the same temperature, the water phase was slowly poured into the oil phase, and stirred constantly in the water bath until it became a milky white semi-solid. The mixture was then stirred at room temperature to condense, yielding a base material.

[0199] 2.2 Cream production A predetermined amount of active ingredient (each compound) was added to the base material, or each compound was dissolved and then added to the base material and stirred, and by stirring while adding, the active ingredient was dispersed uniformly in the base material to obtain creams of different concentrations.

[0200] The technical features of the above embodiments can be freely combined, and for the sake of simplicity, not all possible combinations of the technical features of the above embodiments are described, but combinations of these technical features, if not inconsistent, are considered to be within the scope described in this specification.

[0201] The above examples are specifically and in detail described to merely illustrate some embodiments of the present invention, but are not intended to limit the scope of the claims of the present invention. Those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements fall within the scope of the claims of the present invention. Therefore, the scope of the claims of the present invention should be governed by the claims of the present invention.

Claims

1. A compound of formula I. 【Chemistry 47】 (In the formula, W is COR ２ , C.R. ３ R ４ OR ５ Selected from X is CO or absent; Y is selected from O or absent; Z is CR ３ R ４ selected from or absent, R １ is C ５～１５ selected from alkyl and substituted alkyl groups, acetoxy-substituted aryl groups, (2,6-dichlorophenyl)amino-substituted aryl groups, and pentaoxopentadecyl groups; R is selected from H or D; R ２ , R ３ , R ４ , and R ５ are each selected from H or D.

2. 2. The compound of claim 1, wherein the configuration of the compound is as shown in Formula II. 【Chemistry 48】

3. W is COH, CH ２ Selected from OH, Put X-Y-Z together to make COOCH ２ or CH ２ Forming R １ is C ７ ~C １５ selected from alkyl groups, acetoxy-substituted aryl groups, (2,6-dichlorophenyl)amino-substituted aryl groups, and pentaoxopentadecyl groups; 3. The compound according to claim 1, wherein R is selected from H.

4. W is selected from COH; Put X-Y-Z together to make CH ２ Forming R １ is C ７ ~C １５ selected from alkyl groups, acetoxy-substituted aryl groups, (2,6-dichlorophenyl)amino-substituted aryl groups, and pentaoxopentadecyl groups; 4. The compound of claim 3, wherein R is selected from H.

5. A compound selected from the following compounds: 【Chemistry 49】 【change】

6. A crystal selected from the following: The X-ray powder diffraction pattern of Compound 4, expressed as 2θ angles using Cu-Kα radiation, has characteristic peaks at positions 4.9±0.2°, 7.3±0.2°, 9.9±0.2°, 14.9±0.2°, and 22.0±0.2°. The X-ray powder diffraction pattern of Compound 8, expressed as 2θ angles using Cu-Kα radiation, has characteristic peaks at positions 5.2±0.2°, 11.6±0.2°, 12.6±0.2°, 16.0±0.2°, and 19.3±0.2°. The X-ray powder diffraction pattern of Compound 9, expressed as 2θ angles using Cu-Kα radiation, has characteristic peaks at positions 12.3±0.2°, 14.9±0.2°, 19.9±0.2°, 23.4±0.2°, and 27.3±0.2°. The X-ray powder diffraction pattern of Compound 22, expressed as 2θ angles using Cu-Kα radiation, has characteristic peaks at positions 3.4±0.2°, 5.3±0.2°, 6.9±0.2°, 10.2±0.2°, and 19.9±0.2°. The X-ray powder diffraction pattern of Compound 23, expressed as 2θ angles using Cu-Kα radiation, has characteristic peaks at positions 10.6±0.2°, 11.0±0.2°, 18.4±0.2°, 21.2±0.2°, and 21.7±0.2°. The X-ray powder diffraction pattern of compound 24, expressed as 2θ angles using Cu-Kα radiation, has characteristic peaks at positions 4.4±0.2°, 6.6±0.2°, 8.9±0.2°, 21.0±0.2°, and 22.6±0.2°. The X-ray powder diffraction pattern of compound 26, expressed as 2θ angles using Cu-Kα radiation, has characteristic peaks at positions 3.6±0.2°, 10.5±0.2°, 11.8±0.2°, 13.9±0.2°, and 19.7±0.2°. The X-ray powder diffraction pattern of Compound 27, expressed as 2θ angles using Cu-Kα radiation, has characteristic peaks at positions 6.5±0.2°, 10.2±0.2°, 13.2±0.2°, 15.0±0.2°, and 23.8±0.2°. The X-ray powder diffraction pattern of Compound 35, expressed as 2θ angles using Cu-Kα radiation, has characteristic peaks at positions 12.4±0.2°, 14.7±0.2°, 15.3±0.2°, 17.3±0.2°, and 23.5±0.2°. The X-ray powder diffraction pattern of compound 41, expressed as 2θ angles using Cu-Kα radiation, has characteristic peaks at positions 3.1±0.2°, 5.2±0.2°, 6.7±0.2°, 10.2±0.2°, and 19.9±0.2°. A crystal characterized in that Compound 4, Compound 8, Compound 9, Compound 22, Compound 23, Compound 24, Compound 26, Compound 27, Compound 35, and Compound 41 are defined in claim 5.

7. A pharmaceutical composition comprising the compound according to any one of claims 1, 2 and 5 or the crystal according to claim 6, and a pharmaceutically acceptable additive.

8. 8. The pharmaceutical composition according to claim 7, wherein the dosage form of the pharmaceutical composition is a tablet, dispersion, tincture, gel, capsule, spray, suppository, oral liquid dosage form, or granule.

9. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is in the form of an external preparation.

10. 10. A compound according to any one of claims 1, 2 and 5 for treating dermatitis and / or immune system disorders.

11. 11. The compound according to claim 10, wherein the dermatitis is atopic dermatitis and the immune system disease is asthma.

12. The crystal described in claim 6 for treating dermatitis and / or immune system diseases.

13. The crystal described in claim 12, characterized in that the dermatitis is atopic dermatitis and the immune system disease is asthma.

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