Indole compounds, processes for their preparation and uses thereof

Abstract

The present application relates to a kind of indole compounds and its preparation method and application, belong to the technical field of pharmaceutical chemistry.The compound includes the compound with the structure of formula IThe compound has good atopic dermatitis treatment effect.

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to an indole compound, a preparation method and application thereof. Background Art

[0002] Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease. It has been reported that many factors influence the pathophysiology of AD, including genetics, environmental factors, changes in epidermal lipid composition, immune disorders, and microbial disorders. In addition to skin symptoms such as erythema, papules, exudation, scaling, dry skin, plaques, and lichenification, AD may also cause psychiatric disorders and increase the risk of cardiovascular disease. It is also believed to be associated with depression and suicidal tendencies. From an epidemiological perspective, AD is more common in children, and most symptoms persist into adulthood. Statistical analysis of clinical data from the United States has been relatively sufficient, and research results on children and adolescents indicate that only 1% of people who develop the disease before the age of 12 will not subsequently develop the disease.

[0003] Related studies have shown that the prevalence of AD in China is gradually increasing, especially among children, and the prevalence in urban areas is higher than in rural areas. In summary, AD has a significant impact on patients' quality of life and mental health. The continued rise in AD prevalence in recent years, especially among urban children, has created a clinical and societal need for the development of safer and more effective AD treatments and programs.

[0004] Currently, traditional medications for AD treatment fall into three main categories: 1) moisturizers that improve dry skin; 2) corticosteroids with broad anti-inflammatory and immunosuppressive effects; and 3) calcineurin inhibitors, which bind to immunophilins, inhibiting calcineurin and ultimately suppressing the secretion of multiple cytokines, thereby reducing inflammation. Furthermore, because AD patients often suffer from Staphylococcus aureus infections and are more susceptible to fungal infections than healthy individuals, systemic antibiotics to eliminate pathogens can alleviate AD symptoms. Each of these traditional treatments has its limitations: 1) Moisturizers primarily slow water loss from the skin and have limited therapeutic efficacy; 2) Long-term use of corticosteroids can cause systemic adverse reactions and suppress the hypothalamic-pituitary-adrenal axis, potentially adversely affecting development in children; 3) calcineurin inhibitors often cause local burning and itching; and 4) pathogens are prone to recolonization after discontinuation of antibiotics, and long-term antibiotic use may induce the development of drug-resistant strains.

[0005] Because AD pathophysiology is closely related to epidermal barrier dysfunction and immune disorders, AD patients often show abnormal expression of cytokines, and some scholars have proposed that AD should be classified into different endotypes according to the molecular mechanisms associated with different phenotypes. In recent years, small molecule inhibitors targeting cytokine receptors, and biological agents targeting specific cytokines or their receptors have become a hot spot for the development of AD treatment drugs. At present, small molecule inhibitors targeting phosphodiesterase (PDE)-4, Janus tyrosine kinase (JAK), histamine 4 receptor (H4R) antagonists, aryl hydrocarbon receptor (AhR) agonists, interleukin-4 (IL-4) receptor, interleukin-13 (IL-13) monoclonal antibodies are in the clinical trial or clinical approved drug stage. Among them, IL-4 receptor monoclonal antibody Dupixent (Dupilumab), topical PDE-4 antagonist Eucrisa (Crisaborole) and oral JAK1 inhibitor Cibinqo (Abrocitinib) have been approved by FDA. At present, Benvitimod, an AhR agonist and T cell tyrosine protein kinase inhibitor, is the main active ingredient of the drug approved for listing by the National Medical Products Administration, but it is currently limited to psoriasis treatment. In order to solve the safety and drug resistance problems of long-term drug use, and improve the absorption efficiency of skin drugs, more natural small molecule drugs need to be developed. SUMMARY

[0006] Therefore, it is necessary to provide an indole compound for the above problems, which has good atopic dermatitis treatment effect.

[0007] An indole compound, comprising a compound having the structure of Formula I

[0008]

[0009] wherein,

[0010] W is selected from COR2, CR3R4OR5;

[0011] X is selected from CO, CR3R4, or nothing;

[0012] Y is selected from O or nothing;

[0013] Z is selected from CR3R4 or nothing;

[0014] R1 is selected from C1-20 alkyl and substituted alkyl, C1-20 alkenyl and substituted alkyl, aryl and substituted aryl, heteroaryl, aryl, heteroaryl-substituted alkyl, and oxyalkyl;

[0015] R is selected from the group consisting of: H, D, C1-6 alkyl and substituted alkyl, C1-6 alkenyl and substituted alkyl, aryl and substituted aryl, heteroaryl, halogen, OR5, NR6R7, CO2R7, CONR6R7, OCOR8, NHCOR8, NHSO2R8, CN;

[0016] R2, R3, R4, R6, R7, R8 are independently selected from: H, D, C1-6 alkyl and substituted alkyl, C1-6 alkenyl and substituted alkyl, aryl and substituted aryl, heteroaryl;

[0017] R5 is selected from: H, D, COR1.

[0018] In one embodiment, the compound is configured as shown in Formula II:

[0019]

[0020] In one embodiment, W is selected from: COR2, CR3R4OR5;

[0021] X is selected from: CO or None;

[0022] Y is selected from: O or None;

[0023] Z is selected from: CR3R4 or none;

[0024] R1 is selected from: C1-20 alkyl and substituted alkyl, aryl and substituted aryl and oxyalkyl;

[0025] R is selected from: H;

[0026] R2, R3, R4, R5 are selected from: H.

[0027] In one embodiment, R1 is selected from the group consisting of C5-15 alkyl and substituted alkyl, acetoxy substituted aryl, (2,6-dichlorophenyl)amino substituted aryl and pentaoxopentadecyl.

[0028] In one embodiment, W is selected from: COH, CH2OH;

[0029] XYZ is selected from: COOCH2, CH2;

[0030] R1 is selected from the group consisting of: C7-C15 alkyl, acetoxy substituted aryl, (2,6-dichlorophenyl)amino substituted aryl and pentaoxopentadecyl;

[0031] R is selected from: H.

[0032] In one embodiment, W is selected from: COH;

[0033] XYZ is selected from: CH2;

[0034] R1 is selected from the group consisting of: C7-C15 alkyl, acetoxy substituted aryl, (2,6-dichlorophenyl)amino substituted aryl and pentaoxopentadecyl;

[0035] R is selected from: H.

[0036] In one embodiment, the compound is selected from the following:

[0037]

[0038]

[0039]

[0040] The X-ray powder diffraction pattern of compound 4 using Cu-Kα radiation expressed in 2θ angles has characteristic peaks at the following positions: 4.9±0.2°, 7.3±0.2°, 9.9±0.2°, 14.9±0.2°, 22.0±0.2°;

[0041] Preferably, the X-ray powder diffraction pattern expressed in 2θ angle has characteristic peaks at the following 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°;

[0042] More preferably, the X-ray powder diffraction pattern expressed in 2θ angle has characteristic peaks at the following 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°, 25.3±0.2°;

[0043] The X-ray powder diffraction pattern of compound 8 using Cu-Kα radiation expressed in 2θ angles has characteristic peaks at the following positions: 5.2±0.2°, 11.6±0.2°, 12.6±0.2°, 16.0±0.2°, 19.3±0.2°;

[0044] Preferably, the X-ray powder diffraction pattern expressed in 2θ angle has characteristic peaks at the following 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°;

[0045] More preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at the following 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°, 27.6±0.2°;

[0046] The X-ray powder diffraction pattern of compound 9 using Cu-Kα radiation expressed in 2θ angles has characteristic peaks at the following positions: 12.3±0.2°, 14.9±0.2°, 19.9±0.2°, 23.4±0.2°, 27.3±0.2°;

[0047] Preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at the following 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°;

[0048] More preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at the following 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°, 27.3±0.2°;

[0049] The X-ray powder diffraction pattern of compound 22 using Cu-Kα radiation expressed in 2θ angles has characteristic peaks at the following positions: 3.4±0.2°, 5.3±0.2°, 6.9±0.2°, 10.2±0.2°, 19.9±0.2°;

[0050] Preferably, the X-ray powder diffraction pattern expressed in 2θ angle has characteristic peaks at the following 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°;

[0051] More preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at the following 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°, 23.2±0.2°;

[0052] The X-ray powder diffraction pattern of compound 23 using Cu-Kα radiation expressed in 2θ angles has characteristic peaks at the following positions: 10.6±0.2°, 11.0±0.2°, 18.4±0.2°, 21.2±0.2°, 21.7±0.2°;

[0053] Preferably, the X-ray powder diffraction pattern of MC20-875-034A1 expressed in 2θ degrees has characteristic peaks at the following 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°, 24.2±0.2°;

[0054] More preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at the following 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°, 24.2±0.2°;

[0055] The X-ray powder diffraction pattern of compound 24 using Cu-Kα radiation expressed in 2θ angles has characteristic peaks at the following positions: 4.4±0.2°, 6.6±0.2°, 8.9±0.2°, 21.0±0.2°, 22.6±0.2°;

[0056] Preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at the following 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°;

[0057] More preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at the following 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°, 26.5±0.2°;

[0058] The X-ray powder diffraction pattern of compound 26 using Cu-Kα radiation expressed in 2θ angles has characteristic peaks at the following positions: 3.6±0.2°, 10.5±0.2°, 11.8±0.2°, 13.9±0.2°, 19.7±0.2°;

[0059] Preferably, the X-ray powder diffraction pattern expressed in 2θ angle has characteristic peaks at the following 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°;

[0060] More preferably, the X-ray powder diffraction pattern expressed in 2θ angle has characteristic peaks at the following 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°, 26.0±0.2°;

[0061] The X-ray powder diffraction pattern of compound 27 using Cu-Kα radiation expressed in 2θ angles has characteristic peaks at the following positions: 6.5±0.2°, 10.2±0.2°, 13.2±0.2°, 15.0±0.2°, 23.8±0.2°;

[0062] Preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at the following 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°;

[0063] More preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at the following 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°, 30.6±0.2°;

[0064] The X-ray powder diffraction pattern of compound 35 using Cu-Kα radiation expressed in 2θ angles has characteristic peaks at the following positions: 12.4±0.2°, 14.7±0.2°, 15.3±0.2°, 17.3±0.2°, 23.5±0.2°;

[0065] Preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at the following 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°;

[0066] More preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at the following 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°, 27.4±0.2°;

[0067] The X-ray powder diffraction pattern of compound 41 using Cu-Kα radiation expressed in 2θ angles has characteristic peaks at the following positions: 3.1±0.2°, 5.2±0.2°, 6.7±0.2°, 10.2±0.2°, 19.9±0.2°;

[0068] Preferably, the X-ray powder diffraction pattern expressed in 2θ angle has characteristic peaks at the following 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°;

[0069] More preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at the following 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°.

[0070] The present invention also discloses a pharmaceutical composition comprising the above compound and pharmaceutically acceptable excipients.

[0071] In one embodiment, the pharmaceutical composition is in the form of tablets, dispersions, tinctures, gels, capsules, sprays, suppositories, granules, oral liquid dosage forms, and granules.

[0072] In one embodiment, the pharmaceutical composition is in the form of an external preparation.

[0073] The present invention also provides the use of the above compounds in preparing medicines for treating dermatitis and / or immune system diseases.

[0074] In one embodiment, the medicament is used to treat atopic dermatitis and / or asthma.

[0075] Compared with the prior art, the present invention has the following beneficial effects:

[0076] An indole compound of the present invention is structurally optimized based on the lead compound, the natural small molecule compound IAId (indole-3-carboxaldehyde), and another related small molecule I3C (indole-3-methanol). The resulting indole compound was validated using a mouse model of calcipotriol (MC903)-induced AD-like symptoms in the ear. The compound showed a certain therapeutic effect on AD-like symptoms in the mouse ear, and some compounds were more effective than IAId and I3C, indicating good pharmaceutical prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0077] Figure 1-10XRPD patterns of compounds 4, 22, 23, 24, 8, 26, 9, 27, 41, 35 of Examples 7, 8, 10, 12, 14, 15, 16, 17, 27, 31, respectively;

[0078] Figure 11 Graph of serum total IgE levels of mice in the first batch of Example 32;

[0079] Figure 12 Graph of ear thickness of mice in the first batch of Example 32;

[0080] Figure 13 Graph of body weight change of mice in the first batch of Example 32;

[0081] Figure 14 Representative mouse ear photos after administration of different drugs in the first batch of Example 32;

[0082] Figure 15 Representative mouse ear HE staining photos after administration of different drugs in the first batch of Example 32;

[0083] Figure 16 Graph of serum total IgE levels of mice in the second batch of Example 32;

[0084] Figure 17 Graph of ear thickness of mice in the second batch of Example 32;

[0085] Figure 18 Graph of body weight change of mice in the second batch of Example 32;

[0086] Figure 19 Representative mouse ear photos after administration of different drugs in the second batch of Example 32;

[0087] Figure 20 Representative mouse ear HE staining photos after administration of different drugs in the second batch of Example 32;

[0088] Figure 21-23 Graph of serum total IgE levels of mice in each group of Example 33;

[0089] Figures 24-26 Graph of ear thickness of mice in each group of Example 33;

[0090] Figures 27-29 Graph of body weight change of mice in each group of Example 33;

[0091] Figure 30 Representative mouse ear photos of Example 33. DETAILED DESCRIPTION

[0092] To facilitate understanding of the present invention, the present invention will be described more fully below with reference to the accompanying drawings. Preferred embodiments of the present invention are shown in the accompanying drawings. However, the present invention may be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and comprehensive understanding of the present disclosure.

[0093] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains. The terms used herein in the specification of the present invention are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0094] The pharmaceutical compositions provided herein can be formulated into any dosage form suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, douches, sprays, suppositories, bandages, and skin patches.

[0095] The pharmaceutical compositions provided herein for oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration.

[0096] As used herein, oral administration also includes buccal, 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, medical chewing gums, bulk powders, effervescent or non-effervescent powders or granules, oral aerosols, solutions, emulsions, suspensions, wafers, powders, sprinkles, elixirs and syrups. In addition to the active ingredient, the pharmaceutical composition may contain one or more pharmaceutically acceptable excipients, including but not limited to adhesives, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye migration inhibitors, sweeteners, flavorings, emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids and carbon dioxide sources.

[0097] Unless otherwise specified, the raw materials used in the following examples are all commercially available; the methods used in the following examples are all achievable by conventional methods unless otherwise specified.

[0098] The X-ray powder diffraction detection parameters of the compounds in the following examples are as follows:

[0099] Scanning range: 3-40°, scanning step: 0.02°, scanning rate: 0.1° / step, copper target, wavelength:

[0100] Example 1

[0101] Preparation of methyl (hexyloxy) 3-formyl-1H-indole-1-carboxylate (Compound 1).

[0102] (1) Synthesis of chloromethyl 3-formyl-1H-indole-1-carboxylate (Compound B).

[0103]

[0104] Under argon, compound A3-indolecarboxaldehyde (5.0 g, 34 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL). The mixture was cooled to -78°C and a solution of lithium bistrimethylsilylamide in tetrahydrofuran (1 M, 51.7 mL, 51.7 mmol) was added dropwise. The mixture was allowed to react at -78°C for 1 hour. A solution of chloromethyl chloroformate (6.62 g, 51.7 mmol) in tetrahydrofuran (20 mL) was then added dropwise to the reaction mixture. The reaction was continued at -78°C for 2 hours. TLC (petroleum ether / ethyl acetate = 5:1) indicated the reaction was complete.

[0105] Saturated aqueous ammonium chloride (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, washed with water (80 mL) and saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) afforded the target compound, chloromethyl 3-formyl-1H-indole-1-carboxylate (2) (3.0 g, yield: 37.5%), as a yellow solid.

[0106] The characterization data of compound B are: 1H NMR (400 MHz, DMSO) δ10.10 (s, 1H), 8.77 (s, 1H), 8.17 (dd, J=7.9, 3.2 Hz, 2H), 7.55–7.40 (m, 2H), 6.25 (s, 2H).

[0107] (2) Synthesis of methyl (hexyloxy) 3-formyl-1H-indole-1-carboxylate (Compound 1).

[0108]

[0109] 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) was added sodium iodide (252 mg, 1.69 mmol) and potassium carbonate (1.4 g, 10.11 mmol) at 0°C. The reaction was allowed to react at room temperature for 18 hours. TLC (petroleum ether / ethyl acetate = 3:1) indicated the reaction was complete. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain the target compound (hexyloxy) 3-formyl-1H-indole-1-carboxylic acid methyl ester (Compound 1) (570 mg, yield: 53.6%) as a yellow oil.

[0110] The characterization data of compound 1 are: 1H NMR (400 MHz, DMSO): δ9.98 (s, 1H), 8.43 (s, 1H), 8.12 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.34 (dtd, J = 14.9, 7.6, 1.1 Hz, 2H), 6.31 (s, 2H), 2.32 (t, J = 7.3 Hz, 2H), 1.54–1.40 (m, 2H), 1.23–1.05 (m, 4H), 0.75 (t, J = 7.0 Hz, 3H).

[0111] The purity of compound 1 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 98.71%, and the purity at 214 nm was 98.70%.

[0112] Example 2

[0113] Preparation of (hexyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 19).

[0114]

[0115] Methyl (hexyloxy) 3-formyl-1H-indole-1-carboxylate (Compound 1) (240 mg, 0.76 mmol) was dissolved in anhydrous methanol (8 mL), cooled to 0°C, and sodium borohydride (28.8 mg, 0.76 mmol) was added. The mixture was reacted at 0°C for 2 hours, and the reaction was complete as determined by TLC (petroleum ether / ethyl acetate = 3:1). Saturated aqueous ammonium chloride (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) afforded the target compound, (hexyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 19) (200 mg, yield: 82.9%), as a yellow oil.

[0116] The characterization data of compound 19 are: 1H NMR (400 MHz, DMSO): δ7.61 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 8.2 Hz, 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 = 5.4 Hz, 1H), 4.62 (d, J = 5.2 Hz, 2H), 2.26 (t, J = 7.3 Hz, 2H), 1.52–1.41 (m, 2H), 1.30–1.08 (m, 4H), 0.78 (t, J = 7.0 Hz, 3H).

[0117] The purity of compound 19 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 96.18%, and the purity at 214 nm was 96.51%.

[0118] Example 3

[0119] Preparation of methyl (octyloxy) 3-formyl-1H-indole-1-carboxylate (Compound 2).

[0120] (1) Compound B was prepared according to the method of Example 1.

[0121] (2) Synthesis of methyl (octyloxy) 3-formyl-1H-indole-1-carboxylate (Compound 2).

[0122]

[0123] 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) was added sodium iodide (504 mg, 3.37 mmol) and potassium carbonate (1.4 g, 10.11 mmol) at 0°C. The reaction was allowed to react at room temperature for 18 hours. TLC (petroleum ether / ethyl acetate = 3:1) indicated the reaction was complete. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The target compound (octyloxy) 3-formyl-1H-indole-1-carboxylic acid methyl ester (Compound 2) (480 mg, yield: 41.3%) was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain a yellow oil.

[0124] The characterization data of compound 2 are as follows: 1H NMR (400 MHz, DMSO) δ9.97 (s, 1H), 8.42 (s, 1H), 8.11 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.44–7.26 (m, 2H), 6.30 (s, 2H), 2.32 (t, J = 7.2 Hz, 2H), 1.50–1.41 (m, 2H), 1.11 (s, 8H), 0.80 (t, J = 7.0 Hz, 3H).

[0125] The purity of compound 2 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 99.42%, and the purity at 214 nm was 98.47%.

[0126] Example 4

[0127] Preparation of (octyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 20).

[0128]

[0129] Methyl (octyloxy) 3-formyl-1H-indole-1-carboxylate (Compound 2) (240 mg, 0.76 mmol) was dissolved in anhydrous methanol (8 mL), cooled to 0°C, and sodium borohydride (28.8 mg, 0.76 mmol) was added. The mixture was reacted at 0°C for 2 hours, and the reaction was complete as determined by TLC (petroleum ether / ethyl acetate = 3:1). Saturated aqueous ammonium chloride (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) afforded the target compound ((octyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 20)) (150 mg, yield: 57%) as a yellow oil.

[0130] The characterization data of compound 20 are: 1H NMR (400 MHz, DMSO) δ7.61 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H), 7.19 (t, J = 7.1 Hz, 1H), 7.09 (t, J = 7.0 Hz, 1H), 6.17 (s, 2H), 4.90 (t, J = 5.4 Hz, 1H), 4.62 (d, J = 5.4 Hz, 2H), 2.26 (t, J = 7.3 Hz, 2H), 1.47 (d, J = 6.9 Hz, 2H), 1.22 (d, J = 10.1 Hz, 2H), 1.16 (s, 7H), 0.82 (t, J = 7.0 Hz, 3H).

[0131] The purity of compound 20 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 95.69%, and the purity at 214 nm was 95.81%.

[0132] Example 5

[0133] Preparation of methyl (decanoyloxy) 3-formyl-1H-indole-1-carboxylate (Compound 3).

[0134] (1) Compound B was prepared according to the method of Example 1.

[0135] (2) Synthesis of methyl (decanoyloxy) 3-formyl-1H-indole-1-carboxylate (Compound 3).

[0136]

[0137] To a solution of chloromethyl 3-formyl-lH-indole-l-carboxylate (compound B) (700 mg, 2.95 mmol) and decanoic acid (560 mg, 3.24 mmol) in dry DMF (8.0 mL) was added sodium iodide (442 mg, 2.95 mmol) and potassium carbonate (1.2 g, 8.85 mmol) at 0 °C. The reaction was stirred at room temperature for 18 h. TLC (petroleum ether / ethyl acetate = 3: 1) showed the reaction was completed. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 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. Purification by column chromatography (eluent: petroleum ether / ethyl acetate = 100: 1 to 1: 1) gave the target compound, (decanoyloxy)methyl 3-formyl-lH-indole-l-carboxylate (550 mg, yield: 50%) as a yellow oil.

[0138] The characterization data of compound 3 were as follows: 1H NMR (400 MHz, DMSO) δ 9.97 (s, 1H), 8.42 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.34 (dt, J = 25.0, 7.2 Hz, 2H), 6.30 (s, 2H), 2.31 (t, J = 7.2 Hz, 2H), 1.47 (d, J = 6.6 Hz, 2H), 1.23 (d, J = 6.0 Hz, 2H), 1.13 (d, J = 12.2 Hz, 10H), 0.84 (t, J = 7.0 Hz, 3H).

[0139] The purity of compound 3 was determined by HPLC, and the purity was 98.70% at 254 nm and 98.85% at 214 nm according to the peak area normalization method.

[0140] Example 6

[0141] Preparation of (decanoyloxy)methyl 3-(hydroxymethyl)-lH-indole-l-carboxylate (compound 21).

[0142]

[0143] Methyl (decanoyloxy) 3-formyl-1H-indole-1-carboxylate (Compound 3) (300 mg, 0.803 mmol) was dissolved in anhydrous methanol (8 mL), cooled to 0°C, and sodium borohydride (31 mg, 0.803 mmol) was added. The reaction was allowed to react at 0°C for 2 hours, and the reaction was determined to be complete by TLC (petroleum ether / ethyl acetate = 3:1). Saturated aqueous ammonium chloride (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) afforded the target compound, (decanoyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 21) (200 mg, yield: 66.5%), as a white solid.

[0144] The characterization data of compound 21 are: MC20-875-030A Compd21: 1H NMR (400 MHz, DMSO) δ7.61 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H), 7.19 (t, J = 7.2 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.17 (s, 2H), 4.90 (t, J = 5.4 Hz, 1H), 4.61 (d, J = 5.2 Hz, 2H), 2.26 (t, J = 7.3 Hz, 2H), 1.52–1.38 (m, 2H), 1.20 (d, J = 31.1 Hz, 12H), 0.85 (t, J = 6.9 Hz, 3H).

[0145] The purity of compound 21 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 97.36%, and the purity at 214 nm was 97.56%.

[0146] Example 7

[0147] Preparation of methyl (dodecyloxy) 3-formyl-1H-indole-1-carboxylate (Compound 4).

[0148] (1) Compound B was prepared according to the method of Example 1.

[0149] (2) Synthesis of methyl (dodecyloxy) 3-formyl-1H-indole-1-carboxylate (Compound 4).

[0150]

[0151] To a solution of chloromethyl 3-formyl-lH-indole-l-carboxylate (compound B) (800 mg, 3.36 mmol) and dodecanoic acid (800 mg, 4.03 mmol) in anhydrous DMF (8.0 mL) was added sodium iodide (504 mg, 3.37 mmol) and potassium carbonate (1.4 g, 10.11 mmol) at 0 °C. The reaction was stirred at room temperature for 18 h. TLC (petroleum ether / ethyl acetate = 3: 1) showed that the reaction was completed. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 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 residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100: 1 to 1: 1) to give the target compound, (dodecyloxy)methyl 3-formyl-lH-indole-l-carboxylate (compound 4) (500 mg, yield: 37%) as a yellow solid.

[0152] The characterization data of compound 4 were as follows: 1H NMR (400 MHz, DMSO) δ 9.97 (s, 1H), 8.42 (s, 1H), 8.11 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.34 (dd, J = 17.5, 7.4 Hz, 2H), 6.30 (s, 2H), 2.31 (t, J = 7.2 Hz, 2H), 1.46 (s, 2H), 1.27 - 1.05 (m, 17H), 0.85 (t, J = 6.9 Hz, 3H).

[0153] The purity of compound 4 was determined by HPLC, and the purity was 98.06% at 254 nm and 96.38% at 214 nm according to the peak area normalization method.

[0154] The above compound 4 was subjected to crystallization treatment to obtain a pure compound 4 of crystal form I, and the pure compound was subjected to x-ray powder diffraction (X-ray powder diffraction) detection, and the results are shown in Table 1 and Figure 1

[0155] Table 1. XRPD data of compound 4 crystal form I

[0156]

[0157]

[0158] Example 8

[0159] Preparation of (dodecyloxy)methyl 3-(hydroxymethyl)-lH-indole-l-carboxylate (compound 22).

[0160] ​

[0161] Methyl (dodecyloxy) 3-formyl-1H-indole-1-carboxylate (Compound 4) (250 mg, 0.76 mmol) was dissolved in anhydrous methanol (8 mL), cooled to 0°C, and sodium borohydride (28.8 mg, 0.76 mmol) was added. The mixture was reacted at 0°C for 2 hours, and the reaction was complete as determined by TLC (petroleum ether / ethyl acetate = 3:1). Saturated aqueous ammonium chloride (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) afforded the target compound ((dodecyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 22)) (150 mg, yield: 57%) as a yellow solid.

[0162] The characterization data of compound 22 are: 1H NMR (400 MHz, DMSO) δ7.61 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H), 7.18 (dd, J = 11.2, 4.1 Hz, 1H), 7.09 (t, J = 7.0 Hz, 1H), 6.17 (s, 2H), 4.89 (t, J = 5.4 Hz, 1H), 4.61 (d, J = 5.1 Hz, 2H), 2.26 (t, J = 7.3 Hz, 2H), 1.48–1.40 (m, 2H), 1.23 (d, J = 7.9 Hz, 8H), 1.15 (s, 8H), 0.85 (t, J = 6.9 Hz, 3H).

[0163] The purity of compound 22 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 98.63%, and the purity at 214 nm was 98.21%.

[0164] The above compound 22 was crystallized to obtain a pure compound 22 of form I. The pure compound was subjected to X-ray powder diffraction analysis. The results are shown in Tables 2 and 3. Figure 2 shown.

[0165] Table 2. XRPD of Compound 22 Form I

[0166]

[0167]

[0168] Measurement conditions: SCAN: 3.0001 / 39.9937 / 0.01948 / 16 (sec), Cu, I(max)=3038.

[0169] PEAK: 19-pts / Parabolic Filter, Threshold=3.0, Cutoff=0.1%, BG=3 / 1.0, Peak-Top=Summit.

[0170] NOTE:Intensity=Counts,2T(0)=0.0(deg),Wavelength to Compute (Cu / K-alpha1).

[0171] Example 9

[0172] Preparation of methyl (tetradecyloxy) 3-formyl-1H-indole-1-carboxylate (Compound 5).

[0173] (1) Compound B was prepared according to the method of Example 1.

[0174] (2) Synthesis of methyl (tetradecyloxy) 3-formyl-1H-indole-1-carboxylate (Compound 5).

[0175]

[0176] 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) was added sodium iodide (442 mg, 2.95 mmol) and potassium carbonate (1.2 g, 8.85 mmol) at 0°C. The mixture was allowed to react at room temperature for 18 hours. TLC (petroleum ether / ethyl acetate = 3:1) indicated the reaction was complete. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×40 mL). The organic phases were combined, washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain the target compound (tetradecyloxy) 3-formyl-1H-indole-1-carboxylic acid methyl ester (Compound 5) (500 mg, yield: 39.7%) as a yellow oil.

[0177] The characterization data of compound 5 are: 1H NMR (400 MHz, DMSO) δ9.97 (s, 1H), 8.42 (s, 1H), 8.11 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.46–7.22 (m, 2H), 6.30 (s, 2H), 2.31 (t, J = 7.2 Hz, 2H), 1.53–1.37 (m, 2H), 1.27–1.17 (m, 12H), 1.11 (s, 8H), 0.85 (t, J = 6.8 Hz, 3H).

[0178] The purity of compound 5 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 99.76%, and the purity at 214 nm was 99.69%.

[0179] Example 10

[0180] Preparation of (tetradecyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 23).

[0181]

[0182] 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), cooled to 0°C, and sodium borohydride (22 mg, 0.58 mmol) was added. The mixture was reacted at 0°C for 1 hour, and the reaction was complete as determined by TLC (petroleum ether / ethyl acetate = 3:1). Saturated aqueous ammonium chloride (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) afforded the target compound, (tetradecyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 23) (200 mg, yield: 80%), as a white solid.

[0183] The characterization data of compound 23 are: 1H NMR (400 MHz, DMSO) δ7.60 (dd, J = 7.6, 3.7 Hz, 1H), 7.53 (dd, J = 8.2, 3.8 Hz, 1H), 7.33 (d, J = 3.8 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.09 (td, J = 7.3, 3.5 Hz, 1H), 6.16 (d, J = 3.9 Hz, 2H), 4.89 (dd, J = 10.0, 5.2 Hz, 1H), 4.68–4.55 (m, 2H), 2.25 (td, J = 7.2, 3.8 Hz, 2H), 1.45 (s, 2H), 1.23 (s, 12H), 1.15 (s, 8H), 0.93–0.78 (m, 3H).

[0184] The purity of compound 23 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 98.71%, and the purity at 214 nm was 98.03%.

[0185] The above compound 23 was crystallized to obtain a pure compound 23 of form I. The pure compound was subjected to X-ray powder diffraction analysis. The results are shown in Tables 3 and 4. Figure 3 shown.

[0186] Table 3. XRPD of Compound 23 Form I

[0187]

[0188] Example 11

[0189] Preparation of methyl (palmitoyloxy) 3-formyl-1H-indole-1-carboxylate (Compound 6).

[0190] (1) Compound B was prepared according to the method of Example 1.

[0191] (2) Synthesis of iodomethyl 3-formyl-1H-indole-1-carboxylate (Compound C).

[0192]

[0193] 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), heated to 70°C, and reacted for 4 h. TLC (petroleum ether / ethyl acetate = 5:1) indicated the reaction was complete. The reaction solution was filtered, and the filtrate was extracted with ethyl acetate and concentrated to afford iodomethyl 3-formyl-1H-indole-1-carboxylate (Compound C) (2.4 g, yield: 77%).

[0194] (3) Synthesis of Silver Palmitate (Compound C-2)

[0195]

[0196] Palmitic acid (C-1) (2 g, 7.8 mmol) was dissolved in a sodium hydroxide aqueous solution (312 mg / 40 mL), and the temperature was raised to 80°C. Silver nitrate (1.32 g, 7.8 mmol) was added to precipitate a white solid. The mixture was cooled to room temperature, filtered, and the filter cake was washed with water and dried to obtain silver palmitic acid (compound C-2) (2.5 g, yield: 89%).

[0197] (4) Synthesis of methyl (palmitoyloxy) 3-formyl-1H-indole-1-carboxylate (Compound 6).

[0198]

[0199] At 0°C, a solution of iodomethyl 3-formyl-1H-indole-1-carboxylate (2) (1.5 g, 4.6 mmol) and silver palmitate (2.1 g, 5.1 mmol) in anhydrous toluene (20 mL) was heated to 55°C for 4 hours. TLC (petroleum ether / ethyl acetate = 3:1) indicated the reaction was complete. The reaction solution was filtered, and the filtrate was extracted with ethyl acetate (3×50 mL). The organic phases were combined, washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The target compound (palmitoyloxy) 3-formyl-1H-indole-1-carboxylic acid methyl ester (Compound 6) (800 mg, yield: 38%) was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain the target compound (palmitoyloxy) 3-formyl-1H-indole-1-carboxylic acid methyl ester (Compound 6) (800 mg, yield: 38%) as a white solid.

[0200] The characterization data of compound 6 are: 1H NMR (400 MHz, DMSO) δ7.60 (dd, J = 7.6, 3.7 Hz, 1H), 7.53 (dd, J = 8.2, 3.8 Hz, 1H), 7.33 (d, J = 3.8 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.09 (td, J = 7.3, 3.5 Hz, 1H), 6.16 (d, J = 3.9 Hz, 2H), 4.89 (dd, J = 10.0, 5.2 Hz, 1H), 4.68–4.55 (m, 2H), 2.25 (td, J = 7.2, 3.8 Hz, 2H), 1.45 (s, 2H), 1.23 (s, 12H), 1.15 (s, 8H), 0.93–0.78 (m, 3H).

[0201] The purity of compound 6 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 99.03%, and the purity at 214 nm was 97.54%.

[0202] Example 12

[0203] Preparation of (palmitoyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 24).

[0204]

[0205] Methyl (palmitoyloxy) 3-formyl-1H-indole-1-carboxylate (Compound 6) (300 mg, 0.65 mmol) was dissolved in anhydrous tetrahydrofuran (8 mL), cooled to 0°C, and sodium borohydride (25.8 mg, 0.65 mmol) was added. The reaction was allowed to react at 0°C for 2 hours, and the reaction was determined to be complete by TLC (petroleum ether / ethyl acetate = 3:1). Saturated aqueous ammonium chloride (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) afforded the target compound, (palmitoyloxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 24) (150 mg, yield: 50%), as a white solid.

[0206] The characterization data of compound 24 are: 1H NMR (400 MHz, DMSO) δ8.05 (d, J=7.8 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.54 (s, 1H), 7.36 (dd, J=11.3, 4.2 Hz, 1H), 7.29 (t, J=7.5 Hz, 1H), 6.00 (s, 2H), 5.16 (t, J=5.5 Hz, 1H), 4.64 (dd, J=5.5, 1.0 Hz, 2H), 2.41 (t, J=7.2 Hz, 2H), 1.59–1.47 (m, 2H), 1.25 (d, J=16.2 Hz, 16H), 1.14 (s, 8H), 0.85 (t, J=6.8 Hz, 3H).

[0207] The purity of compound 24 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 97.66%, and the purity at 214 nm was 98.28%.

[0208] The above compound 24 was crystallized to obtain a pure compound 24 in form I. The pure compound was subjected to X-ray powder diffraction analysis. The results are shown in Tables 4 and 5. Figure 4 as shown.

[0209] Table 4. XRPD of compound 24 form I

[0210]

[0211]

[0212] Example 13

[0213] Preparation of esterification of 3-oxo-2,5,8,11,14,17-hexaoxyoctadecyl-3- formyl-1H-indole-1-carboxylate (compound 7).

[0214] (1) Compound B was prepared according to the method of Reference Example 1.

[0215] (2) Synthesis of synthesis of esterification of 3-oxo-2,5,8,11,14,17- hexaoxyoctadecyl-3-formyl-1H-indole-1-carboxylate (compound 7).

[0216]

[0217] 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-pentaoxyhexadecanoic-16-oleic acid (2.0 g, 7.5 mmol) in anhydrous DMF (8.0 mL) was added sodium iodide (1.1 g, 7.5 mmol) and potassium carbonate (3.1 g, 22.5 mmol) at 0 °C. The reaction was stirred at room temperature for 2 hours, TLC (petroleum ether / ethyl acetate = 3:1) showed the reaction was completed. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 40 mL), the organic phase was combined, washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The target compound esterification of 3-oxo-2,5,8,11,14,17-hexaoxyoctadecyl-3-formyl-1H-indole-1-carboxylate (compound 7) (600 mg, yield: 17.1%) was obtained as a yellow oil after purification by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 ~ 1:1).

[0218] The characterization data of compound 7 are: 1H NMR (400 MHz, CDCl3) δ10.04 (s, 1H), 8.36–8.25 (m, 1H), 7.95 (s, 1H), 7.54 (d, J = 7.4 Hz, 1H), 7.38 (dq, J = 7.2, 6.0 Hz, 2H), 6.20 (s, 2H), 4.18 (s, 2H), 3.68 (d, J = 5.2 Hz, 2H), 3.66–3.56 (m, 12H), 3.53 (dd, J = 5.7, 3.5 Hz, 2H), 3.36 (s, 3H).

[0219] The purity of compound 7 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 96.07%, and the purity at 214 nm was 95.59%.

[0220] Example 14

[0221] Preparation of ((2-acetoxybenzoyl)oxy)methyl 3-formyl-1H-indole-1-carboxylate (Compound 8).

[0222] (1) Synthesis of silver acetoxybenzoate (R8_Ag+):

[0223]

[0224] 2-Acetoxybenzoic acid (Compound R8) (2.0 g, 11.1 mmol) was dissolved in 1 M aqueous ammonia (30 mL), cooled to 0°C, and an aqueous silver nitrate solution (1.89 g, 11.1 mmol, 10 mL) was added. The reaction was allowed to proceed at 0°C for half an hour, during which time a large amount of white solid precipitated. The white solid was collected by filtration, the filter cake was washed with water, and the solid was dried to obtain silver 2-acetoxybenzoate (R8_Ag+) (2.5 g, yield: 78.6%).

[0225] (2) Synthesis of ((2-acetoxybenzoyl)oxy)methyl 3-formyl-1H-indole-1-carboxylate (Compound 8):

[0226]

[0227]

[0228] 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 h. LCMS indicated that the reaction of iodomethyl 3-formyl-1H-indole-1-carboxylate was complete. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (3 × 20 mL) and water (40 mL). The combined organic phases were 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 afford the target compound ((2-acetoxybenzoyl)oxy)methyl 3-formyl-1H-indole-1-carboxylate) (Compound 8) (500 mg, yield: 43.7%) as a pale yellow solid.

[0229] The characterization data of compound 8 are: 1H NMR (400 MHz, DMSO) δ10.11 (s, 1H), 8.75 (s, 1H), 8.17 (d, J = 9.1 Hz, 2H), 8.05 (dd, J = 7.9, 1.6 Hz, 1H), 7.80–7.70 (m, 1H), 7.47 (ddd, J = 24.6, 16.8, 8.2 Hz, 3H), 7.29 (d, J = 7.2 Hz, 1H), 6.28 (s, 2H), 2.27 (s, 3H).

[0230] The purity of compound 8 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 95.96%, and the purity at 214 nm was 95.28%.

[0231] The above compound 8 was crystallized to obtain a pure compound 8 of form I. The pure compound was subjected to X-ray powder diffraction analysis. The results are shown in Tables 5 and 6. Figure 5 shown.

[0232] Table 5. XRPD of Compound 8 Form I

[0233]

[0234] Example 15

[0235] Preparation of ((2-acetoxybenzoyl)oxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 26).

[0236]

[0237] Dissolve ((2-acetoxybenzoyl)oxy)methyl 3-formyl-1H-indole-1-carboxylate (Compound 8) (170 mg, 0.446 mmol) in anhydrous methanol / tetrahydrofuran (3 mL / 3 mL), cool to 0°C, and add sodium borohydride (17 mg, 0.446 mmol). Incubate at 0°C for 3 hours. TLC (petroleum ether / ethyl acetate = 3:1) indicates completion of the reaction. Add saturated aqueous ammonium chloride (15 mL) to the reaction solution, extract with ethyl acetate (3 × 20 mL), combine the organic phases, wash with water (20 mL) and saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue 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 light yellow solid.

[0238] The characterization data of compound 26 are: 1H NMR (400 MHz, DMSO) δ8.09 (d, J = 8.4 Hz, 1H), 8.01 (dd, J = 7.9, 1.6 Hz, 1H), 7.74 (td, J = 7.8, 1.7 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.44 (dd, J = 11.0, 4.3 Hz, 1H), 7.39 (t, J = 7.3 Hz, 1H), 7.33–7.23 (m, 2H), 6.22 (s, 2H), 5.16 (t, J = 5.5 Hz, 1H), 4.69–4.59 (m, 2H), 2.26 (s, 3H).

[0239] The purity of compound 26 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 96.35%, and the purity at 214 nm was 95.62%.

[0240] The above compound 26 was crystallized to obtain a pure compound 26 of Form I. The pure compound was subjected to X-ray powder diffraction analysis. The results are shown in Tables 6 and 7. Figure 6 shown.

[0241] Table 6. XRPD of Compound 26 Form I

[0242]

[0243] Example 16

[0244] Preparation of (2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)methyl 3-formyl-1H-indole-1-carboxylate (Compound 9).

[0245] (1) Synthesis of 2-(2-((2,6-dichlorophenyl)amino)phenyl)silver acetate (R9_Ag+).

[0246]

[0247] 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), cooled 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 half an hour, during which time a large amount of white solid precipitated. The white solid was collected by filtration, the filter cake was washed with water, and the solid was dried to obtain 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetic acid silver (R9_Ag+) (2.9 g, yield: 71%).

[0248] (2) Synthesis of (2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)methyl 3-formyl-1H-indole-1-carboxylate (Compound 9).

[0249]

[0250] 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 h. LCMS showed that iodomethyl 3-formyl-1H-indole-1-carboxylate (Compound C) disappeared. The reaction solution was filtered and the filtrate was extracted with ethyl acetate (3×20 mL) and water (40 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue 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.

[0251] The characterization data of compound 9 are: 1H NMR (400MHz, DMSO) δ10.08(s,1H),8.68(s,1H),8.14(dd,J=19.1,7.6Hz,2H),7.45(t,J=12.0Hz,4H),7.24–7.1 3(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).

[0252] The purity of compound 9 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 98.7%, and the purity at 214 nm was 98.8%.

[0253] The above compound 9 was crystallized to obtain a pure compound 9 of Form I. The pure compound was subjected to X-ray powder diffraction analysis. The results are shown in Tables 7 and 8. Figure 7 shown.

[0254] Table 7. XRPD of Compound 9 Form I

[0255]

[0256]

[0257] Example 17

[0258] Preparation of (2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 27).

[0259]

[0260] (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), cooled to 0°C, and sodium borohydride (6 mg, 0.16 mmol) was added. The mixture was reacted at 0°C for 2 hours. TLC (petroleum ether / ethyl acetate = 3:1) confirmed the reaction was complete. Saturated aqueous ammonium chloride (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was combined with MC20-875-048 and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 1:1) to give the target compound (2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)methyl 3-(hydroxymethyl)-1H-indole-1-carboxylate (Compound 27) (110 mg, yield: 52%) as a light yellow solid.

[0261] The characterization data of compound 27 are: 1 H NMR (400MHz, DMSO) δ8.04(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).

[0262] The purity of compound 27 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 95.96%, and the purity at 214 nm was 95.28%.

[0263] The above compound 27 was crystallized to obtain a pure compound 27 in form I. The pure compound was subjected to X-ray powder diffraction analysis. The results are shown in Tables 8 and 9. Figure 8 shown.

[0264] Table 8. XRPD of Compound 27 Form I

[0265]

[0266]

[0267] Example 18

[0268] Preparation of methyl (3-formyl-1H-indol-1-yl)hexanoate (Compound 28).

[0269] (1) Synthesis of chloromethyl hexanoate.

[0270]

[0271] Dissolve hexanoic acid (1.0 g, 8.62 mmol), sodium bicarbonate (2.89 g, 34.48 mmol), and BuNHSO4 (0.29 g, 0.862 mmol) in a mixture of dichloromethane and water (10 mL / 10 mL). Stir for 10 minutes, then cool to 0°C and add (chloromethoxy)methanesulfonyl chloride (1.71 g, 10.34 mmol) dropwise. Allow to warm to room temperature and react for 2 hours. TLC (petroleum ether / ethyl acetate = 5:1) indicates completion of the reaction. Separate the reaction mixture, extract the aqueous phase with dichloromethane (30 mL x 3), and wash the organic phase with water (30 mL x 2). Combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 5:1) to obtain the target compound chloromethylhexanoate (400 mg, yield: 28.3%) as a yellow oil.

[0272] (2) Synthesis of methyl (3-formyl-1H-indol-1-yl)hexanoate (Compound 28).

[0273]

[0274] 1H-Indole-3-carboxaldehyde (176 mg, 1.22 mmol) was dissolved in tetrahydrofuran and sodium iodide (18 mg, 0.122 mmol) was added. Under anhydrous and oxygen-free conditions at -78°C, lithium bis(trimethylsilyl)amide (1.83 mL, 1.83 mmol) was added dropwise. The mixture was allowed to react at -78°C for half an hour, followed by the addition of a solution of chloromethylhexanoate (400 mg, 2.44 mmol) in tetrahydrofuran. The reaction was continued at -78°C for three hours. LCMS (MC20-874-3-P1B) indicated the reaction was complete. Aqueous ammonium chloride (10 mL) was added to the reaction mixture, which was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by PRE-TLC (PE:EA=4:1, Rf=0.4) gave the target compound (3-formyl-1H-indol-1-yl)hexanoic acid methyl ester (200 mg, yield: 30.0%) as a yellow oil.

[0275] The characterization data of compound 28 are: 1H NMR (400 MHz, DMSO): δ1H NMR (400 MHz, CDCl3) δ10.02 (s, 1H), 8.30 (dd, J = 6.9, 1.5 Hz, 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 = 7.5 Hz, 2H), 1.64–1.51 (m, 2H), 1.31–1.11 (m, 4H), 0.81 (t, J = 7.0 Hz, 3H).

[0276] Example 19

[0277] Preparation of methyl (3-(hydroxymethyl)-1H-indol-1-yl)methylhexanoate (Compound 37).

[0278]

[0279] Methyl (3-formyl-1H-indol-1-yl)hexanoate (400 mg, 1.47 mmol) was dissolved in anhydrous methanol (6 mL), cooled to 0°C, and sodium borohydride (56 mg, 1.47 mmol) was added. The mixture was reacted at 0°C for 0.5 h, and the reaction was complete as determined by TLC (petroleum ether / ethyl acetate = 3:1). Saturated aqueous ammonium chloride (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, 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 target compound, methyl (3-(hydroxymethyl)-1H-indol-1-yl)methylhexanoate (Compound 37) (115 mg, yield: 28.5%), as a yellow oil.

[0280] The characterization data of compound 28 are: 1H NMR (400 MHz, DMSO) δ7.61 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H), 7.19 (dd, J = 11.2, 4.0 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 6.17 (s, 2H), 4.90 (s, 1H), 4.62 (s, 2H), 2.26 (t, J = 7.3 Hz, 2H), 1.46 (dd, J = 14.6, 7.3 Hz, 2H), 1.23–1.09 (m, 4H), 0.78 (t, J = 6.9 Hz, 3H).

[0281] The purity of the compound 28 was determined by HPLC and was found to be 97.07% at 254 nm and 96.37% at 214 nm by peak area normalization method.

[0282] Example 20

[0283] Preparation of (3-formyl-lH-indol-l-yl) octanoic acid methyl ester (Compound 29).

[0284] (1) Synthesis of chloromethyl octanoate.

[0285]

[0286] 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 minutes. Then chloromethyl sulfonyl chloride (2.746 g, 16.642 mmol) was added slowly at 0 °C and the reaction was carried out at room temperature for 2 hours. TLC (petroleum ether / ethyl acetate = 5:1) showed that the reaction was complete. The organic phase was extracted with dichloromethane (2 x 30 mL), combined and washed with water (60 mL) and saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 80:1) gave the target compound chloromethyl octanoate (1.827 g, yield: 68.4%) as a colorless oil.

[0287] The characterization data of chloromethyl octanoate were: 1H NMR (400 MHz, CDC13) δ 5.71 (s, 2H), 2.38 (t, J = 7.5 Hz, 2H), 1.73 - 1.58 (m, 2H), 1.36 - 1.22 (m, 8H), 0.88 (t, J = 6.9 Hz, 3H).

[0288] (2) Synthesis of (3-formyl-lH-indol-l-yl) octanoic acid methyl ester (Compound 29).

[0289]

[0290] 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 lithium bistrimethylsilylamine in tetrahydrofuran (1 M, 4.1 mL, 4.132 mmol) was added dropwise. The mixture was reacted at -78 ° C for 0.5 hours. Then, a solution of chloromethyl octanoate (2) (1.061 g, 5.510 mmol) in tetrahydrofuran (6 mL) was added dropwise to the reaction solution. The mixture was reacted at -78 ° C for 2 hours. TLC (petroleum ether / ethyl acetate = 3:1) showed that the reaction was complete. Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2×50 mL). The organic phases were combined, 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 column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 70:1) to obtain the target compound (3-formyl-1H-indol-1-yl)octanoic acid methyl ester (Compound 29) (580 mg, yield: 69.9%) as a yellow oil.

[0291] The characterization data of compound 29 are: 1H NMR (400 MHz, CDCl3) δ10.03 (s, 1H), 8.31 (dd, J = 6.8, 1.5 Hz, 1H), 7.92 (s, 1H), 7.53 (dd, J = 7.1, 1.2 Hz, 1H), 7.44–7.31 (m, 2H), 6.12 (s, 2H), 2.32 (t, J = 7.5 Hz, 2H), 1.71–1.47 (m, 2H), 1.31–1.08 (m, 8H), 0.84 (t, J = 7.0 Hz, 3H).

[0292] The purity of compound 29 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 99.06%, and the purity at 214 nm was 99.06%.

[0293] Example 21

[0294] Preparation of methyl (3-(hydroxymethyl)-1H-indol-1-yl)octanoate (Compound 38).

[0295]

[0296] Methyl (3-formyl-1H-indol-1-yl)octanoate (Compound 29) (250 mg, 0.829 mmol) was dissolved in anhydrous methanol (3 mL), cooled to 0°C, and sodium borohydride (31 mg, 0.829 mmol) was added. The mixture was reacted at 0°C for 0.5 hours, and the reaction was complete as determined by TLC (petroleum ether / ethyl acetate = 3:1). Saturated aqueous ammonium chloride (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, 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 give the target compound (3-(hydroxymethyl)-1H-indol-1-yl)octanoic acid methyl ester (Compound 38) (60 mg, yield: 24.0%) as a yellow oil, which was combined with MC20-877-017P and MC20-877-018P to give the target compound (3-(hydroxymethyl)-1H-indol-1-yl)octanoic acid methyl ester (Compound 38) (103 mg).

[0297] The characterization data of compound 38 are: 1H NMR (400 MHz, DMSO) δ7.61 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H), 7.19 (t, J = 7.1 Hz, 1H), 7.09 (t, J = 7.1 Hz, 1H), 6.17 (s, 2H), 4.90 (t, J = 5.4 Hz, 1H), 4.61 (d, J = 5.3 Hz, 2H), 2.26 (t, J = 7.3 Hz, 2H), 1.51–1.39 (m, 2H), 1.17 (d, J = 13.5 Hz, 8H), 0.82 (t, J = 7.0 Hz, 3H).

[0298] The purity of compound 38 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 93.04%, and the purity at 214 nm was 93.86%.

[0299] Example 22

[0300] Preparation of methyl (3-formyl-1H-indol-1-yl)decanoate (Compound 30).

[0301] (1) Synthesis of chloromethyl decanoate.

[0302]

[0303] Under argon, decanoic acid (1.0 g, 5.80 mmol), sodium bicarbonate (1.95 g, 23.20 mmol), and tetrabutylammonium hydrogensulfate (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 mixture 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 was complete, the mixture was allowed to return to room temperature and the reaction was continued 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 to separate the organic phase. 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 purified by column chromatography and separated on a flash 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.

[0304] The characterization data of chloromethyl decanoate are: 1H NMR (400 MHz, CDCl3) δ5.71 (s, 2H), 2.38 (t, J = 7.5 Hz, 2H), 1.69–1.59 (m, 2H), 1.31 (s, 2H), 1.28 (d, J = 13.6 Hz, 10H), 0.88 (t, J = 6.8 Hz, 3H).

[0305] (2) Synthesis of methyl (3-formyl-1H-indol-1-yl)decanoate (Compound 30).

[0306]

[0307] To a stirred solution of 3-formyl-1H-indole (438 mg, 3.02 mmol) and sodium iodide (46 mg, 0.30 mmol) in anhydrous tetrahydrofuran (15 mL) under an Ar atmosphere at -78°C was added lithium trimethylsilylamide (4.6 mL, 4.60 mmol, 1 M) and allowed to react for half an hour. Chloromethyl decanoate (1.00 g, 4.56 mmol) was then slowly added. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for two hours. LCMS and TLC (petroleum ether / ethyl acetate = 15:2) indicated that the reaction was nearly complete. Saturated aqueous ammonium chloride (50 mL) was added to the reaction solution, which was then extracted with ethyl acetate (2 x 40 mL). The combined organic phases were 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 using a column precipitator / flash silica gel column (eluent: petroleum ether / ethyl acetate = 100:1 to 100:15) and preparative separation and purification by prep-TLC (petroleum ether / ethyl acetate = 5:1) to obtain the target compound (3-formyl-1H-indol-1-yl) methyl decanoate (Compound 30) (660 mg, yield: 66.3%) as a colorless oily liquid.

[0308] The characterization data of compound 30 are: 1 H NMR (400MHz, CDCl3) δ10.04(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).

[0309] The purity of compound 30 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 96.43%, and the purity at 214 nm was 97.83%.

[0310] Example 23

[0311] Preparation of methyl (3-(hydroxymethyl)-1H-indol-1-yl)decanoate (Compound 39).

[0312]

[0313] Methyl (3-formyl-1H-indol-1-yl)decanoate (Compound 30) (450 mg, 1.37 mmol) was dissolved in anhydrous methanol (8 mL), cooled to 0°C, and sodium borohydride (52 mg, 1.37 mmol) was added. The mixture was allowed to react at 0°C for half an hour, and the reaction was complete as determined by TLC (petroleum ether / ethyl acetate = 5:1). Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 × 25 mL). The organic phases were combined, 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 target compound, methyl (3-(hydroxymethyl)-1H-indol-1-yl)decanoate (Compound 39) (187 mg, yield: 41.3%), as a light yellow oil.

[0314] The characterization data of compound 39 are: 1 H NMR (400MHz, DMSO): δ7.61(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).

[0315] The purity of compound 39 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 94.60%, and the purity at 214 nm was 93.91%.

[0316] Example 24

[0317] Preparation of methyl (3-formyl-1H-indol-1-yl)dodecanoate (Compound 31).

[0318] (1) Synthesis of chloromethyl dodecanoate

[0319]

[0320] 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 ratio) and stirred at room temperature for 5 minutes. Chloromethylsulfonyl chloride (2.965 g, 17.971 mmol) was then slowly added at 0°C and allowed to react at room temperature for 2 hours. TLC (petroleum ether / ethyl acetate = 5:1) indicated the reaction was complete. The mixture was extracted with dichloromethane (2 x 40 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. Purification by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 80:1) afforded the target compound, chloromethyl dodecanoate (3.490 g, yield: 93.7%), as a colorless oil.

[0321] The characterization data of chloromethyl dodecanoate are: 1H NMR (400 MHz, H2O+D2O) δ5.72 (s, 2H), 2.40 (t, J=7.5 Hz, 2H), 1.72–1.62 (m, 2H), 1.35–1.20 (m, 16H), 0.90 (t, J=6.8 Hz, 3H).

[0322] (2) Synthesis of methyl (3-formyl-1H-indol-1-yl) dodecanoate (Compound 31)

[0323]

[0324] 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 lithium bistrimethylsilylamide in tetrahydrofuran (1 M, 6.2 mL, 6.200 mmol) was added dropwise. The mixture was reacted at -78°C for 0.5 hours. Then, a solution of chloromethyl dodecanoate (2) (2.0 g, 8.267 mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction solution. The mixture was reacted at -78°C for 2 hours. TLC (petroleum ether / ethyl acetate = 3:1) showed that the reaction was complete. Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2×30 mL). The organic phases were combined, 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 column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 70:1) to obtain the target compound (3-formyl-1H-indol-1-yl) dodecanoic acid methyl ester (Compound 31) (665 mg, yield: 45.0%) as a light yellow solid.

[0325] The characterization data of compound 31 are: 1H NMR (400 MHz, CDCl3) δ10.05 (s, 1H), 8.44–8.24 (m, 1H), 7.92 (s, 1H), 7.53 (d, J = 7.4 Hz, 1H), 7.45–7.29 (m, 2H), 6.12 (s, 2H), 2.32 (t, J = 7.5 Hz, 2H), 1.57 (s, 2H), 1.21 (d, J = 16.2 Hz, 16H), 0.88 (t, J = 6.9 Hz, 3H).

[0326] The purity of compound 31 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 99.17%, and the purity at 214 nm was 97.86%.

[0327] Example 25

[0328] Preparation of methyl (3-(hydroxymethyl)-1H-indol-1-yl)dodecanoate (Compound 40).

[0329]

[0330] Methyl (3-formyl-1H-indol-1-yl) dodecanoate (Compound 31) (250 mg, 0.695 mmol) was dissolved in anhydrous methanol (5 mL), cooled to 0°C, and sodium borohydride (26 mg, 0.695 mmol) was added. The mixture was reacted at 0°C for 0.5 hours, and the reaction was complete as determined by TLC (petroleum ether / ethyl acetate = 3:1). Saturated aqueous ammonium chloride (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phases were combined, 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, yield: 56.0%), as a light yellow solid.

[0331] The characterization data of compound 40 are: 1H NMR (400 MHz, DMSO) δ7.61 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H), 7.19 (t, J = 7.2 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.17 (s, 2H), 4.90 (t, J = 5.4 Hz, 1H), 4.61 (d, J = 5.3 Hz, 2H), 2.26 (t, J = 7.3 Hz, 2H), 1.45 (s, 2H), 1.19 (d, J = 26.6 Hz, 16H), 0.85 (t, J = 6.8 Hz, 3H).

[0332] The purity of compound 40 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 98.23%, and the purity at 214 nm was 97.03%.

[0333] Example 26

[0334] Preparation of methyl (3-formyl-1H-indol-1-yl)tetradecanoate (Compound 32).

[0335] (1) Synthesis of chloromethyl tetradecanoate.

[0336] Myristic 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 ratio) and stirred at room temperature for 5 minutes. Chloromethylsulfonyl chloride (2.6 g, 15.764 mmol) was then slowly added at 0°C and allowed to react at room temperature for 2 hours. TLC (petroleum ether / ethyl acetate = 3:1) indicated the reaction was complete. The mixture was extracted with dichloromethane (2 x 40 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. Purification by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 80:1) afforded the target compound, chloromethyl myristic ester (3.316 g, yield: 91.2%), as a translucent solid.

[0337] The characterization data of chloromethyl tetradecanoate are: 1H NMR (400 MHz, CDCl3) δ 5.70 (s, 2H), 2.38 (t, J = 7.5 Hz, 2H), 1.78–1.51 (m, 2H), 1.37–1.23 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H).

[0338] (2) Synthesis of methyl (3-formyl-1H-indol-1-yl)tetradecanoate (Compound 32).

[0339]

[0340] Under argon, 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 mixture was cooled to -78°C and a solution of lithium bistrimethylsilylamide in tetrahydrofuran (1 M, 4.1 mL, 4.132 mmol) was added dropwise. The mixture was allowed to react at -78°C for 1 hour. A solution of chloromethyl myristate (1.525 g, 5.510 mmol) in tetrahydrofuran (8 mL) was then added dropwise to the reaction mixture. The mixture was allowed to react at -78°C for 2 hours. TLC (petroleum ether / ethyl acetate = 3:1) indicated the reaction was complete. Saturated aqueous ammonium chloride (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phases were combined, 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 column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 70:1) to obtain the target compound (3-formyl-1H-indol-1-yl)tetradecanoic acid methyl ester (Compound 32) (827 mg, yield: 77.8%) as a light yellow solid.

[0341] The characterization data of compound 32 are: 1H NMR (400 MHz, CDCl3) δ10.04 (s, 1H), 8.32 (d, J = 7.0 Hz, 1H), 7.92 (s, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.44–7.32 (m, 2H), 6.12 (s, 2H), 2.32 (t, J = 7.5 Hz, 2H), 1.59 (s, 2H), 1.22 (d, J = 22.3 Hz, 20H), 0.88 (t, J = 6.8 Hz, 3H).

[0342] The purity of compound 32 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 98.67%, and the purity at 214 nm was 99.35%.

[0343] Example 27

[0344] Preparation of methyl (3-(hydroxymethyl)-1H-indol-1-yl)tetradecanoate (Compound 41).

[0345]

[0346] Methyl (3-formyl-1H-indol-1-yl)tetradecanoate (Compound 32) (300 mg, 0.778 mmol) was dissolved in anhydrous methanol (6 mL), cooled to 0°C, and sodium borohydride (29.4 mg, 0.778 mmol) was added. The reaction was allowed to react at 0°C for 0.5 hours, and the reaction was complete as determined by TLC (petroleum ether / ethyl acetate = 3:1). Saturated aqueous ammonium chloride (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, 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 afford the target compound, methyl (3-(hydroxymethyl)-1H-indol-1-yl)tetradecanoate (Compound 41) (130 mg, yield: 43.1%), as a light yellow solid.

[0347] The characterization data of compound 41 are: 1H NMR (400 MHz, DMSO) δ7.61 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.34 (s, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.17 (s, 2H), 4.90 (t, J = 5.4 Hz, 1H), 4.61 (d, J = 5.1 Hz, 2H), 2.26 (t, J = 7.3 Hz, 2H), 1.45 (s, 2H), 1.19 (d, J = 32.7 Hz, 20H), 0.85 (t, J = 6.8 Hz, 3H).

[0348] The purity of compound 41 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 97.17%, and the purity at 214 nm was 96.91%.

[0349] The above compound 41 was crystallized to obtain a pure compound 41 of Form I. The pure compound was subjected to X-ray powder diffraction analysis. The results are shown in Tables 9 and 9. Figure 9 shown.

[0350] Table 9. XRPD of Compound 41 Form I

[0351]

[0352] Example 28

[0353] Preparation of methyl (3-formyl-1H-indol-1-yl)palmitate (Compound 33).

[0354] (1) Synthesis of chloromethyl palmitate.

[0355]

[0356] 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 ratio) and stirred at room temperature for 5 minutes. Chloromethylsulfonyl chloride (3.080 g, 18.719 mmol) was then slowly added at 0°C and allowed to react at room temperature for 2 hours. TLC (petroleum ether / ethyl acetate = 5:1) indicated the reaction was complete. Extraction was performed with dichloromethane (2 x 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. Purification by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 80:1) afforded the target compound, chloromethyl palmitate (3.727 g, yield: 78.4%), as a translucent solid.

[0357] The characterization data of chloromethyl palmitate are: 1H NMR (400 MHz, CDCl3) δ5.70 (s, 2H), 2.38 (t, J = 7.5 Hz, 2H), 1.72–1.54 (m, 2H), 1.33–1.23 (m, 24H), 0.88 (t, J = 6.8 Hz, 3H).

[0358] (2) Synthesis of methyl (3-formyl-1H-indol-1-yl) palmitate (Compound 33).

[0359]

[0360] 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 lithium bistrimethylsilylamide in tetrahydrofuran (1 M, 4.1 mL, 4.132 mmol) was added dropwise. The mixture was reacted at -78°C for 1 hour. Then, a solution of chloromethyl palmitate (2) (1.680 g, 5.511 mmol) in tetrahydrofuran (8 mL) was added dropwise to the reaction mixture. The mixture was reacted at -78°C for 2 hours. TLC (petroleum ether / ethyl acetate = 5:1) showed that the reaction was complete. Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2×40 mL). The organic phases were combined, 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 column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 80:1) to obtain the target compound (3-formyl-1H-indol-1-yl) palmitic acid methyl ester (Compound 33) (697 mg, yield: 61.2%) as a white solid.

[0361] The characterization data of compound 33 are: 1H NMR (400 MHz, CDCl3) δ10.04 (s, 1H), 8.32 (d, J = 6.8 Hz, 1H), 7.92 (s, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.37 (td, J = 13.8, 6.0 Hz, 2H), 6.12 (s, 2H), 2.32 (t, J = 7.5 Hz, 2H), 1.58 (s, 8H), 1.22 (d, J = 24.3 Hz, 24H), 0.88 (t, J = 6.8 Hz, 3H).

[0362] The purity of compound 31 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 97.69%, and the purity at 214 nm was 98.46%.

[0363] Example 29

[0364] Preparation of (3-(hydroxymethyl)-1H-indol-1-yl)methyl palmitate (Compound 42).

[0365]

[0366] 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), cooled to 0°C, and sodium borohydride (27 mg, 0.725 mmol) was added. The mixture was reacted at 0°C for 0.5 hours, and the reaction was complete as determined by TLC (petroleum ether / ethyl acetate = 3:1). Saturated aqueous ammonium chloride (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 x 30 mL). The organic phases were combined, 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 afford the target compound (3-(hydroxymethyl)-1H-indol-1-yl) methyl palmitate (Compound 42) (250 mg, yield: 83.0%) as a white solid.

[0367] The characterization data of compound 42 are: 1H NMR (400 MHz, DMSO) δ7.61 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.34 (s, 1H), 7.19 (t, J = 7.1 Hz, 1H), 7.09 (t, J = 7.0 Hz, 1H), 6.17 (s, 2H), 4.90 (t, J = 5.4 Hz, 1H), 4.61 (d, J = 5.1 Hz, 2H), 2.26 (t, J = 7.3 Hz, 2H), 1.45 (s, 2H), 1.19 (d, J = 33.6 Hz, 24H), 0.85 (t, J = 6.8 Hz, 3H).

[0368] The purity of compound 42 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 97.87%, and the purity at 214 nm was 98.43%.

[0369] Example 30

[0370] Preparation of (3-formyl-1H-indol-1-yl)methyl 2,5,8,11,14-pentaoxohexadecan-16-oate (Compound 34).

[0371] (1) Synthesis of chloromethyl 2,5,8,11,14-pentaoxahexadecan-16-olate.

[0372]

[0373] 2,5,8,11,14-pentaoxyhexadecane-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 ratio) and stirred at room temperature for 5 minutes. Chloromethylsulfonyl chloride (1.189 g, 7.210 mmol) was then slowly added at 0°C and allowed to react at room temperature for 2 hours. The mixture was extracted with dichloromethane (2 x 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 to obtain the target compound, chloromethyl 2,5,8,11,14-pentaoxyhexadecane-16-oleate (1.2 g, crude), as a yellow oil.

[0374] The characterization data of chloromethyl 2,5,8,11,14-pentaoxahexadecan-16-oate are: 1H NMR (400 MHz, 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, 3.6 Hz, 2H), 3.39 (d, J = 2.8 Hz, 3H).

[0375] (2) Synthesis of (3-formyl-1H-indol-1-yl)methyl 2,5,8,11,14-pentaoxohexadecan-16-olate (Compound 34).

[0376]

[0377] 1H-Indole-3-acetaldehyde (503 mg, 3.812 mmol), sodium iodide (52 mg, 0.347 mmol), chloromethyl 2,5,8,11,14-pentahydrohexadecane-16-olate (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 hours. 4-Dimethylaminopyridine (42 mg, 0.347 mmol) was then added and the reaction continued at 30°C for 12 hours. LCMS indicated the reaction was complete. Saturated aqueous ammonium chloride (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 × 60 mL). The organic phases were combined, washed with water (120 mL) and saturated brine (120 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The target compound (3-formyl-1H-indol-1-yl)methyl 2,5,8,11,14-pentaoxohexadecan-16-oate (Compound 34) (320 mg, yield: 21.8%) was purified by preparative HPLC as a yellow solid.

[0378] The characterization data of compound 34 are: 1H NMR (400 MHz, CDCl3) δ10.04 (s, 1H), 8.31 (d, J = 6.9 Hz, 1H), 7.95 (s, 1H), 7.54 (d, J = 7.4 Hz, 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).

[0379] The purity of compound 34 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 99.32%, and the purity at 214 nm was 99.38%.

[0380] Example 31

[0381] Preparation of (3-formyl-lH-indol-l-yl) 2-acetoxybenzoate (Compound 35).

[0382] (1) Synthesis of 2-acetoxybenzoic acid chloromethyl ester (2).

[0383]

[0384] To a solution of 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) in dichloromethane and water (40 ml, 1:1) was stirred at room temperature for 5 minutes, then chloromethyl sulfonyl chloride (3.297 g, 19.982 mmol) was added slowly at 0 °C and then the reaction was allowed to proceed at room temperature for 2 hours. TLC (petroleum ether / ethyl acetate = 5:1) showed that the reaction was complete. The organic phase was extracted with dichloromethane (2 x 40 mL), combined and washed with water (80 mL) and saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (eluent: petroleum ether / ethyl acetate = 100:1 to 80:1) gave the target compound 2-acetoxybenzoic acid chloromethyl ester (3.0 g, yield: 78.8%) as a colorless oil.

[0385] The characterization data of 2-acetoxybenzoic acid chloromethyl ester were as follows: 1H NMR (400 MHz, CDC13) δ 8.06 (dd, J = 7.9, 1.6 Hz, 1H), 7.62 (td, J = 7.9, 1.6 Hz, 1H), 7.41 - 7.29 (m, 1H), 7.22 - 7.07 (m, 1H), 5.90 (s, 2H), 2.38 (s, 3H).

[0386] (2) Synthesis of (3-formyl-lH-indol-l-yl) 2-acetoxybenzoate (Compound 35).

[0387]

[0388] 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 hours. TLC (petroleum ether / ethyl acetate = 1.5:1) showed that the reaction was complete. Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2×50 mL). The organic phases were combined, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The target compound was purified by preparative HPLC to give methyl (3-formyl-1H-indol-1-yl) 2-acetoxybenzoate (Compound 35) (233 mg, yield: 12.4%) as a white solid.

[0389] The characterization data of compound 35 are: 1H NMR (400 MHz, CDCl3) δ10.07 (s, 1H), 8.33 (d, J = 7.3 Hz, 1H), 8.13–7.86 (m, 2H), 7.58 (ddd, J = 7.8, 4.6, 1.7 Hz, 2H), 7.40 (ddd, J = 15.1, 13.9, 6.9 Hz, 2H), 7.29 (t, J = 8.1 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 6.33 (s, 2H), 2.14 (s, 3H).

[0390] The purity of compound 35 was determined by HPLC. According to the peak area normalization method, the purity at 254 nm was 99.7%, and the purity at 214 nm was 99.63%.

[0391] The above compound 35 was crystallized to obtain a pure compound 35 in form I. The pure compound was subjected to X-ray powder diffraction analysis. The results are shown in Tables 10 and 10. Figure 10 shown.

[0392] Table 10. XRPD of Compound 35 Form I

[0393]

[0394] Example 32

[0395] The compounds prepared in the above examples were tested for their activity.

[0396] 1. Method.

[0397] The therapeutic activity of these compounds against AD was investigated using a mouse model of AD-like symptoms in the ear induced by calcipotriol (MC903).

[0398] Referring to patent publication number CN110368385A, an MC903 (calcipotriol) mouse model was prepared. BALB / c mice were treated with MC903 or MC903 plus IAId or a compound prepared in the examples, applied to both ears for 11 consecutive days. At the end of the experiment, serum total IgE levels, auricle thickness, and body weight change compared to the baseline were measured. Due to the large number of test drugs, the efficacy of the drugs was evaluated in two batches.

[0399] 2. Results

[0400] The data shown in the results are the mean ± SD of 5 independent repeated experiments. The differences in the corresponding indicators of mice in the treatment group (MC903+EtOH group) treated with MC903 alone were analyzed for significance using the Mann-Whitney test, where: * indicates P < 0.05; ** indicates P < 0.01; *** indicates P < 0.001.

[0401] 2.1 The first batch of experiments.

[0402] In this batch of experiments, the dosage of modeling drug MC903 was 6.9 nmol / (day·mouse). The experimental results of compounds numbered 1, 2, 3, 6, 7, 19, 20, 28, 29, 30, 34, 37, 38 and 39 in this batch are as follows: Figure 11-13 shown.

[0403] in, Figure 11 is the total IgE level in the serum of mice after administration of different drugs. Figure 12 is the thickness of the mouse ear after administration of different drugs, Figure 13 The weight changes of mice after administration of different drugs compared with the initial stage of the experiment, Figure 14 These are representative photos of mouse auricles after administration of different drugs. Figure 15 Representative HE staining images of mouse ear tissues after administration of different drugs. The EtOH group was a blank control group given only ethanol, the MC903+EtOH group was a model control group given calcipotriol and ethanol, and the remaining groups were treated with MC903 modeling and then given different active drugs. The IAId (indole-3-carboxaldehyde) group was the IAId-administered group, the I3C (indole-3-methanol) group was the I3C-administered group, and the remaining compound groups were given corresponding compounds.

[0404] As shown in the figure, the model control group (MC903+EtOH) showed significant differences in serum total IgE levels, auricle thickness, and weight change compared to the baseline (P<0.001) compared to the blank control group (EtOH), indicating successful model establishment. Both the IAId and I3C groups significantly reduced serum total IgE levels and auricle thickness (P<0.05 or P<0.01). All compounds exhibited positive effects on serum total IgE, auricle thickness, and weight change. Compounds 1, 2, 29, 30, 34, 37, 38, and 39 showed statistically significant differences in reducing serum total IgE compared to the model group, with compounds 30 and 38 showing particularly strong effects. Compounds 1, 19, 20, 29, 30, 34, and 39 also showed statistically significant differences in reducing auricle thickness compared to the model group, with compounds 29 and 30 showing particularly strong effects. Combined with the results of mouse auricle inflammation and tissue HE staining analysis, compounds 29, 30, and 38 have obvious therapeutic effects on AD-like symptoms in mouse ears.

[0405] 2.2 Second batch of experiments.

[0406] In the first batch of drug tests, it was found that the survival status of mice was greatly affected by the modeling drug MC903, which was manifested by a significant decrease in body weight ( Figure 13 ), so in the second batch of drug testing, the dosage of MC903 was reduced to 5nmol / (day·mouse), and the testing period was shortened to 9 days; finally, as expected, the survival status of mice was significantly improved ( Figure 18 ).

[0407] The experimental results of compounds in this batch numbered 30, 38, 4, 5, 9, 21, 22, 23, 24, 26, 27, 31, 32, 33, 35, 40, 41, 42, 8, and 29 are as follows: Figure 16-20 shown.

[0408] in, Figure 16 is the total IgE level in the serum of mice after administration of different drugs. Figure 17 is the thickness of the mouse ear after administration of different drugs, Figure 18 The weight changes of mice after administration of different drugs compared with the initial stage of the experiment, Figure 19 These are representative photos of mouse auricles after administration of different drugs. Figure 20Representative HE staining images of mouse ear tissues after administration of different drugs. The EtOH group served as a blank control group given only ethanol, the MC903+EtOH group served as a model control group given calcipotriol and ethanol, and the remaining groups were treated with MC903 modeling and then given different active drugs. The IAId (indole-3-carboxaldehyde) group received IAId, the I3C (indole-3-methanol) group received IAId, and the remaining compound groups received the corresponding compound groups.

[0409] As can be seen from the figure, the model control group (MC903 + EtOH) showed significant differences in total serum IgE levels, auricle thickness, and weight change compared to the initial stage of the experiment (P < 0.01 or P < 0.001) compared to the blank control group (EtOH), indicating successful modeling. In terms of reducing total serum IgE in mice, compounds 30, 38, 4, 9, 22, 23, 24, 26, 27, 33, 35, 41, and 8 showed statistically significant differences compared to the model group, with compounds 30, 4, 9, 22, and 35 showing excellent effects in reducing total serum IgE in mice. In terms of reducing auricle thickness in mice, compounds 30, 38, 4, 9, 27, 8, and 29 showed statistically significant differences compared to the model group, with compound 9 showing excellent effects in reducing auricle thickness in mice. Combining the inflammation of the mouse auricle with the results of tissue HE staining analysis, and integrating multiple experiments and test indicators, drugs with therapeutic effects on AD-like symptoms in the mouse ears were screened out, and their numbers are 4, 9, 29, 30, 38, 22, and 35.

[0410] Example 33

[0411] Experiment on optimal effect concentration for the treatment of AD-like symptoms.

[0412] 1. Method.

[0413] The drugs obtained from the above screening that have therapeutic effects on AD-like symptoms in the mouse ears are selected to further explore the optimal dosage.

[0414] Referring to the animal model experimental method in Example 32, the optimal concentration for treating AD-like symptoms was explored by comparing the differences in auricle thickness, serum total IgE levels, and weight loss between the treated group and the group receiving only MC903 and the group receiving MC903.

[0415] Table 11. Groups and Dosage

[0416] Group Treatment and dosage #1 EtOH (blank) #2 MC903+EtOH (modeling) #3 MC903+IAId (10 μg / ml) #4 MC903+IAId (100 μg / ml) #5 MC903+IAId (1000 μg / ml) #6 MC903+I3C (10 μg / ml) #7 MC903+I3C (100 μg / ml) #8 MC903+I3C (1000 μg / ml) #9 MC903 + compound 4 (10 μg / ml) #10 MC903 + compound 4 (1000 μg / ml) #11 MC903 + compound 9 (10 μg / ml) #12 MC903 + compound 9 (100 μg / ml) #13 MC903 + compound 9 (1000 μg / ml) #14 MC903 + compound 22 (10 μg / ml) #15 MC903 + compound 22 (1000 μg / ml) #16 MC903 + compound 35 (10 μg / ml) #17 MC903 + compound 35 (100 μg / ml) #18 MC903 + compound 35 (1000 μg / ml) #19 MC903 + compound 29 (10 μg / ml) #20 MC903 + compound 29 (100 μg / ml) #21 MC903 + compound 29 (1000 μg / ml) #22 MC903 + compound 30 (10 μg / ml) #23 MC903 + compound 30 (100 μg / ml) #24 MC903 + compound 30 (1000 μg / ml) #25 MC903 + compound 38 (10 μg / ml) #26 MC903 + compound 38 (100 μg / ml) #27 MC903 + compound 38 (1000 μg / ml)

[0417] Note: The above administration methods are all for external application.

[0418] 2. Results.

[0419] The results are as follows Figure 21-30 As shown. Figure 21-23 is the total IgE level in the serum of mice in each group, Figures 24-26 is the thickness of the auricle of each group of mice, Figures 27-29 is the weight loss rate of mice in each group, Figure 30 Representative photos of mouse auricles.

[0420] By comparing the significant differences in auricle thickness, serum total IgE levels, and weight loss between the mice in the treatment group administered only MC903, it was found that compound No. 9 showed significant therapeutic effects on mouse ear AD symptoms at all tested concentrations; compounds 4, 9, 29, 30, 38, 22, 35 and others had a better inhibitory effect on systemic inflammation, manifested as lower levels of serum total IgE and improvement of mouse ear AD symptoms, especially compounds 4, 30, and 38, which had excellent inhibitory effects on systemic inflammation.

[0421] Example 34

[0422] This embodiment provides an external-use cream preparation.

[0423] 1. Matrix prescription

[0424]

[0425] 2. Preparation method

[0426] 2.1 Matrix preparation

[0427] Take stearic acid, glyceryl monostearate, liquid paraffin, white petrolatum, and lanolin as the oil phase, place them in an evaporating dish, and heat them on a water bath to approximately 80°C until mixed and melted. Separately, place triethanolamine and distilled water in a beaker and heat them on a water bath to approximately 80°C. Slowly pour the aqueous phase into the oil phase under constant stirring on a water bath until a milky white semisolid forms. Then, stir at room temperature until nearly condensed to obtain the matrix.

[0428] 2.2 Cream preparation.

[0429] A predetermined amount of active ingredient (each compound) is added to the above matrix, or each compound is dissolved and then added to the matrix and stirred, stirring while adding to uniformly disperse it in the matrix, to obtain creams of different concentrations.

[0430] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0431] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be determined by the appended claims.

Claims

1. Compounds of formula I: in, W is selected from: COH, CH2OH; X is selected from: CO, CH2 or none; Y is selected from: O or None; Z is selected from: CH2 or none; R1 is selected from the group consisting of: C5-20 alkyl and pentaoxopentadecyl.

2. The compound according to claim 1, characterized in that The compound configuration is shown in Formula II:

3. The compound according to claim 1 or 2, characterized in that W is selected from: COH, CH2OH; X is selected from: CO or None; Y is selected from: O or None; Z is selected from: CH2 or none; R1 is selected from the group consisting of: C5-20 alkyl and pentaoxopentadecyl.

4. The compound according to claim 1 or 2, characterized in that W is selected from: COH, CH2OH; XYZ is selected from: COOCH2, CH2; R1 is selected from the group consisting of: C7-C15 alkyl and pentaoxopentadecyl.

5. The compound according to claim 4, characterized in that W is selected from: COH; XYZ is selected from: CH2; R1 is selected from the group consisting of: C7-C15 alkyl and pentaoxopentadecyl.

6. An indole compound, characterized in that Selected from the following compounds:

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

8. A pharmaceutical composition, characterized in that The invention comprises the compound according to any one of claims 1 to 7, and pharmaceutically acceptable excipients.

9. The pharmaceutical composition according to claim 8, characterized in that The dosage form of the pharmaceutical composition is tablet, dispersant, tincture, gel, capsule, spray, suppository, granule, oral liquid dosage form, and granule.

10. The pharmaceutical composition according to claim 8, characterized in that The dosage form of the pharmaceutical composition is an external preparation.

11. Use of the compound according to any one of claims 1 to 7 in the preparation of a medicament for treating dermatitis.

12. The use according to claim 11, characterized in that: The medicament is used to treat atopic dermatitis.

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