N-(4-methylphenyl)-indole compound, and pharmaceutical composition and use thereof

Abstract

Disclosed in the present invention are an N-(4-methylphenyl)-indole compound as represented by general formula (I) or a pharmaceutically acceptable salt, an enantiomer, a diastereoisomer or a racemate thereof, and a pharmaceutical composition containing same, and the use of such compound, as a cGAS-STING-TBK1 signaling pathway inhibitor targeting TBK1 to inhibit cGAMP-activated cGAS-STING-TBK1 pathway signaling by means of blocking the interaction between a STING protein and a TBK1 protein, in the preparation of a drug for the treatment and / or prevention of inflammatory diseases and autoimmune diseases.

Description

N-(4-methylphenyl)-indole compound, pharmaceutical composition thereof and application TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to an N-(4-methylphenyl)-indole compound, a pharmaceutical composition thereof and application. The compound has strong cGAS-STING-TBK1 pathway signal inhibition activity in a stable THP1 cell. BACKGROUND

[0002] Innate immunity is the first line of defense against infectious microorganisms such as viruses and bacteria, and can activate the adaptive immunity of the body to collectively clear the invading pathogens and maintain the homeostasis of the body. The cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes)-TBK1 (TANK-binding kinase 1) innate immune signaling pathway mediated by intracellular dsDNA (double-stranded DNA) can induce interferon secretion and inflammatory response, and help the body resist microbial infection. However, excessive activation of the cGAS-STING-TBK1 pathway caused by abnormal accumulation of intracellular dsDNA can cause the host to have an immune response to self-antigens, and induce a series of self-inflammatory diseases, such as STING associated vasculopathy of infancy (SAVI), systemic lupus erythematosus (SLE) and COPA syndrome.

[0003] The secretion of interferon and pro-inflammatory factors induced by the cGAS-STING-TBK1 signaling pathway occurs in a cascade reaction. First, cGAS is activated after recognizing the abnormal dsDNA (such as from bacteria, viruses or tumor cells) in the cytoplasm as a DNA sensor, and rapidly synthesizes the important messenger molecule 2',3'-cGAMP. Then, 2',3'-cGAMP binds and induces the polymerization of STING protein. The polymerized STING protein is transferred from the endoplasmic reticulum to the Golgi and then to the perinuclear body, and then recruits TBK1 in the cytoplasm to form a STING-TBK1 complex, and phosphorylates interferon regulatory factor 3 (IRF3). Then, the phosphorylated IRF3 forms a homodimer and is translocated into the nucleus, binds to the promoter region of the target gene, and induces the transcription and expression of genes such as interferon, cytokine and T cell recruitment factor, and exerts biological effects.

[0004] In the above cascade reaction, the STING-TBK1 protein-protein interaction is an important prerequisite for multiple phosphorylation events downstream. After being activated by 2',3'-cGAMP, the STING protein exposes its hydrophobic C-terminal tail (CTT) domain; the TBK1 protein binds to the CTT and undergoes trans-autophosphorylation. The phosphorylated TBK1 further phosphorylates the STING protein Ser366, enabling it to bind to IRF3. Subsequently, IRF3 binds to the STING protein and is phosphorylated by TBK1. The phosphorylated IRF3 forms a dimer and undergoes nuclear translocation, inducing the secretion of interferons and proinflammatory cytokines.

[0005] Therefore, hindering the STING-TBK1 protein-protein interaction, reducing the secretion of interferons and alleviating the inflammatory response, can be a new idea for treating autoimmune diseases. SUMMARY

[0006] The present application aims to provide an N-(4-methylphenyl)-indole compound of the general formula I or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof:

[0007]

[0008] wherein,

[0009] R 1 selected from hydrogen, R a substituted 3-10 membered cycloheteroalkyl, 0-2 R b substituted 5-12 membered heteroaryl or -NR c R d ; wherein the number of heteroatoms is 1-3;

[0010] R 2 selected from C1-C6 alkoxycarbonyl, C1-C6 alkylacyl, carbamoyl substituted with 1-2 C1-C6 alkyl, carboxyl, halogen, 5-10 membered heteroaryl, 5-10 membered cycloheteroalkylcarbonyl, carbamoyl or cyano;

[0011] R 3 selected from hydrogen or C1-C6 alkyl;

[0012] R a selected from C1-C6 alkyl, aryl or 3-10 membered cycloalkyl; the aryl is unsubstituted or optionally substituted with 1-3 U 1 substitutions;

[0013] R b selected from hydrogen, C1-C6 alkoxy;

[0014] Rc R d are each independently selected from hydrogen, Ci-C6alkyl, C3-C6cycloalkyl, aryl, or benzyl; said alkyl is unsubstituted or optionally substituted with 1-3 U 2 substituents;

[0015] U 1 is selected from hydrogen or halogenated Ci-C6alkyl;

[0016] U 2 is selected from hydrogen, Ci-C6alkyl, or aryl; said alkyl is unsubstituted or optionally substituted with 1-3 U 3 substituents;

[0017] U 3 is selected from hydrogen or hydroxyl.

[0018] In certain preferred embodiments,

[0019] R 1 is selected from hydrogen, 1-methylpiperazin-4-yl, 1-phenylpiperazin-4-yl, 1-(4- trifluoromethylphenyl)-piperazin-4-yl, 1-cyclohexylpiperazin-4-yl, triazol-1-yl, triazol-2-yl, tetrahydroisoquinolin-2-yl, 7,8-dimethoxytetrahydroisoquinolin-2-yl, t-butylamino, isopropylamino, methylamino, cyclopropylamino, amino, anilino, benzylamino, N-methylbenzylamino, or tris(hydroxymethyl)methylamino.

[0020] In certain preferred embodiments,

[0021] R 2 is selected from acetyl, methoxyformyl, ethoxyformyl, n-propoxyformyl, isopropoxyformyl, isobutoxyformyl, carboxyl, methylaminoformyl, ethylaminoformyl, bromo, furan-2-yl, cyano, amido, hydrogen, N-methylethylaminoformyl, or tetrahydropyrrol-N-ylformyl.

[0022] In certain preferred embodiments,

[0023] R 3 is selected from hydrogen or methyl.

[0024] In some preferred embodiments, the pharmaceutically acceptable salt comprises an acid addition salt of a compound of Formula I with hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, pyruvic acid, citric acid, tartaric acid, lactic acid, maleic acid, benzenesulfonic acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, fumaric acid, salicylic acid, or phenylacetic acid; and also an acid salt of a compound of Formula I with an inorganic base or an organic salt made from a basic amine.

[0025] The compounds of Formula I of the present application are preferably the following compounds:

[0026]

[0027]

[0028]

[0029] The compounds of the above general formula I according to the present application can also exist in the form of their salts, which are converted in the body into the compounds of general formula I. For example, it is within the scope of the present application to convert the compounds according to the present application into the form of a pharmaceutically acceptable salt according to processes known in the art and to use them in the form of a salt.

[0030] All tautomeric forms of the compounds of general formula I according to the present application are included within the scope of the present application. The compounds according to the present application can exist in particular geometric or stereoisomeric forms. Further asymmetric carbon atoms can be present in the substituents alkyl and the like, all these isomers and mixtures thereof are included within the scope of the present application.

[0031] The present application also provides a synthesis route for the compounds of general formula I.

[0032] Synthesis route one:

[0033]

[0034] Reagents and conditions: (a) zinc oxide, 80 °C, 3 h; (b) p-benzoquinone, zinc chloride, toluene, 50 °C, 2 h; (c) epibromohydrin, cesium carbonate, acetonitrile, 80 °C, 6 h; (d) substituted amine, ethanol, 78 °C, 3 h.

[0035] Synthesis route two:

[0036]

[0037] Reagents and conditions: (e) zinc oxide, 80 °C, 3 h; (f) p-benzoquinone, zinc chloride, toluene, 50 °C, 2 h; (g) hydrogen, 10% palladium on carbon, methanol, 25 °C, 12 h; (h) R 2 -NH2, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine, N,N-dimethylformamide, 25 °C, 8 h; (i) epibromohydrin, cesium carbonate, acetonitrile, 80 °C, 6 h; (j) substituted amine, ethanol, 78 °C, 3 h.

[0038] Synthesis route three:

[0039]

[0040] Reagents and conditions: (k) epibromohydrin, cesium carbonate, acetonitrile, 80 °C, 6 h; (1) substituted amine, ethanol, 78 °C, 3 h; (m) hydrogen, 10% palladium on carbon, methanol, 25 °C, 12 h.

[0041] Synthetic Route Four:

[0042]

[0043] Reagents and conditions: (o) 4-bromotoluene, tris(dibenzylideneacetone)dipalladium, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, sodium t-butoxide, toluene, 100 °C, 18 h; (p) 1) trifluoroacetic anhydride, dichloromethane, 25 °C, 12 h; 2) sodium hydroxide, methanol-water, 50 °C, 8 h; 3) dichlorosulfoxide, substituted alcohol, 25 °C, 2 h; (q) hydrogen, 10% palladium on carbon, methanol, 25 °C, 12 h; (r) epibromohydrin, cesium carbonate, acetonitrile, 80 °C, 6 h; (s) substituted amine, ethanol, 78 °C, 3 h.

[0044]

[0045] Synthetic Route Five:

[0046]

[0047] Reagents and conditions: (a) 1) zinc oxide, 80 °C, 3 h; 2) p-benzoquinone, zinc chloride, toluene, 50 °C, 2 h; (b) acetic anhydride, triethylamine, dichloromethane, 25 °C, 8 h; (c) trifluoroacetic acid, dichloromethane, 25 °C, 18 h; (d) sodium methoxide, tetrahydrofuran-methanol, 25 °C, 8 h; (e) epibromohydrin, cesium carbonate, acetonitrile, 80 °C, 6 h; (f) substituted amine, ethanol, 78 °C, 3 h.

[0048] R1, R2, R3in the above synthetic routes are defined as in Formula I.

[0049] The compounds of Formula I can be prepared by the above or similar methods. The appropriate starting materials can be selected according to the different substituents and their positions. Those skilled in the art will recognize that the above routes are useful for understanding the present application, but are not limiting of the present application, and the variables are defined as mentioned in Formula I, unless otherwise specified.

[0050] Another object of the present application is to provide a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof and a pharmaceutically acceptable carrier.

[0051] ​The pharmaceutical compositions of the present application can be administered in a variety of known ways, e.g., orally, parenterally, by inhalation spray, or via an implanted reservoir. The pharmaceutical compositions of the present application can be administered alone or in combination with other drugs. Oral compositions can take a variety of forms, including but not limited to tablets, capsules, emulsions, and suspensions, dispersions and solutions. Commonly used pharmaceutically acceptable carriers or excipients include stabilizers, diluents, surfactants, lubricants, antioxidants, binders, colorants, fillers, emulsifiers, and the like.

[0052] Sterile injectable compositions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The pharmaceutically acceptable carriers that can be employed include water, mannitol, sodium chloride, and the like.

[0053] Topical compositions can be formulated into ointments, lotions, creams, etc. Carriers for topical compositions include vegetable or mineral oils, animal fats, and high molecular weight alcohols, etc. A pharmaceutically acceptable carrier is one in which the active ingredient is soluble.

[0054] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this application can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration, without being toxic to the patient. The selected dosage level will depend on a variety of factors including the activity of the particular compound of the present application or salt thereof employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds, and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0055] Another object of the present application is to provide the use of the compound of general formula I or its pharmaceutically acceptable salt, enantiomer, diastereomer, racemate thereof in the preparation of a drug for preventing and / or treating diseases related to the function of cGAS-STING-TBK1 pathway.

[0056] The disease related to the function of cGAS-STING-TBK1 pathway is a disease caused by over-activation of cGAS-STING-TBK1 pathway.

[0057] Another object of the present application is to provide the use of the compound of general formula I or its pharmaceutically acceptable salt, enantiomer, diastereomer, racemate thereof in the preparation of a drug for preventing and / or treating inflammatory diseases and autoimmune diseases.

[0058] The diseases related to the function of the cGAS-STING-TBK1 pathway, the inflammatory diseases and the autoimmune diseases include SAVI (STING-associated vasculopathy with onset in infancy), Aicardi-Goutières syndrome (AGS), COPA syndrome caused by coatomer protein complex subunit alpha gene variation, systemic lupus erythematosus (SLE), familial chilblain lupus (FCL), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease, non-alcoholic steatohepatitis (NASH), alcoholic liver disease, nerve injury, rheumatoid arthritis, renal fibrosis, systemic sclerosis, intervertebral disc degeneration, pulmonary fibrosis, aging, scleroderma, psoriasis, inflammatory bowel disease, autoimmune colitis, irritable bowel syndrome, ulcerative colitis, Crohn's disease, uveitis, mucositis, diabetes, cardiovascular disease or neurodegenerative disease. Beneficial effects:

[0059] The present application is based on the discovery and synthesis of a series of N-(4-methylphenyl)-indole compounds by cell phenotype screening, the compounds have good cGAS-STING-TBK1 pathway inhibitory activity, show strong IRF gene transcription inhibitory activity in stably transfected THP1 cells, can be prepared into drugs for treating diseases related to the function of the cGAS-STING-TBK1 pathway, have the prospect of preparing drugs for treating and / or preventing inflammatory diseases and autoimmune diseases, and provide a reliable way for clinical application. DETAILED DESCRIPTION

[0060] The preparation methods of the compounds of general formula I of the present application are described below in combination with specific examples, but these specific methods do not constitute any limitation to the present application. The compounds of the present application can also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combination can be easily performed by those skilled in the art to which the present application belongs.

[0061] The starting materials and reaction reagents used in the specific examples of the present application are all commercially available. The present application can be prepared into a salt form by using the salt formation method commonly used in the art, for example: at room temperature, the compound is dissolved in hydrochloric acid ethanol for reaction to generate hydrochloride; or benzene sulfonic acid is added thereto for reaction to generate benzene sulfonate.

[0062] The experimental methods not specified in the examples of the present application are usually carried out according to the conventional conditions, or according to the conditions suggested by the manufacturers of raw materials or commodities. The structure of the compound is determined by nuclear magnetic resonance hydrogen spectrum (HNMR) through a Bruker Avance 300MHz spectrometer, using TMS as an internal standard, and the recording temperature is 300K. 1 HNMR) through a Bruker Avance 300MHz spectrometer, using TMS as an internal standard, and the recording temperature is 300K.

[0063] Unless otherwise specified, the reactions in the examples are carried out under air atmosphere.

[0064] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0065] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20-30 °C.

[0066] Example 1 5-[2-Hydroxy-3-(tert-butylamino)-propoxy]-2-methyl-1-(methylphenyl)indole-3- carboxylic acid ethyl ester (1)

[0067]

[0068] Step 1: Preparation of compound 1-1

[0069] Compound 4-methylaniline (2 g, 18.70 mmol), zinc oxide (160 mg, 1.90 mmol) and ethyl acetoacetate (2.6 mL, 20.60 mmol) were placed in a round-bottom flask and reacted at 80 °C for 3 h. The reaction solution was diluted with ethyl acetate, filtered with diatomite, the filtrate was washed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, the solvent was evaporated, and the product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 200: 1, v / v) to obtain 3.67 g of a colorless oily liquid, with a yield of 89.56%. 1 H NMR (300 MHz, DMSO-d6) δ (ppm) 10.27 (s, 1H), 7.16 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 4.65 (s, 1H), 4.05 (q, J = 7.1 Hz, 2H), 2.29 (s, 3H), 1.96 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H).

[0070] Step 2: Preparation of compound 1-2

[0071] Compound p-benzoquinone (940 mg, 8.40 mmol) and zinc chloride (920 mg, 6.80 mmol) were dissolved in toluene (15 mL) and reacted at 50 °C for 1.5 h. Compound 1-1 (2 g, 9.12 mmol) was added in toluene (5 mL), and the reaction was continued at 50 °C for 2 h. The temperature was returned to room temperature, methanol was added to dilute the reaction solution, diatomite was used for filtration, the filtrate was evaporated, and the product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1, v / v) to obtain 1.81 g of a yellow solid, with a yield of 64.20%. 1H NMR (300 MHz, DMSO-d6) d (ppm) 9.03 (s, 1H), 7.47-7.38 (m, 3H), 7.31 (d, J = 8.3 Hz, 2H), 6.76 (d, J = 8.7 Hz, 1H), 6.61 (dd, J = 8.7, 2.4 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.47 (s, 3H), 2.43 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H).

[0072] Step 3: Preparation of compound 1-3

[0073] Compound 1-2 (2 g, 6.50 mmol) was dissolved in acetonitrile (80 mL), cesium carbonate (2.77 g, 8.50 mmol) was added, stirred at 25 °C for 30 min. Epibromohydrin (700 μL, 8.50 mmol) was added, reacted at 80 °C for 6 h. Evaporated to dryness, diluted with ethyl acetate, washed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1, v / v) to give 1.89 g of white solid, yield 79.63%. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 7.70 (d, J = 2.5 Hz, 1H), 7.35 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 6.90 (d, J = 8.8 Hz, 1H), 6.81 (dd, J = 8.9, 2.5 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 4.30 (dd, J = 11.0, 3.3 Hz, 1H), 4.06 (dd, J = 11.1, 5.6 Hz, 1H), 3.46-3.34 (m, 1H), 2.92 (t, J = 4.5 Hz, 1H), 2.79 (dd, J = 5.0, 2.6 Hz, 1H), 2.55 (s, 3H), 2.47 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H).

[0074] Step 4: Preparation of compound 1

[0075] Compound 1-3 (150 mg, 0.41 mmol) was dissolved in ethanol (3 mL), tert-butylamine (86 μL, 0.82 mmol) was added, reacted at 78 °C for 3 h. Evaporated to dryness, purified by silica gel column chromatography (dichloromethane:methanol = 200:1, v / v) to give 91 mg of white solid, yield 50.64%. 1H NMR (300 MHz, Methanol-d4) δ (ppm) 7.65 (d, J = 2.3 Hz, 1H), 7.42 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 6.86 (d, J = 8.8 Hz, 1H), 6.81 (dd, J = 8.9, 2.3 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.12 - 4.05 (m, 3H), 2.92 (dd, J = 11.6, 3.3 Hz, 1H), 2.80 (dd, J = 11.7, 8.2 Hz, 1H), 2.51 (s, 3H), 2.47 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H), 1.20 (s, 9H).

[0076] Example 2 5-[2-Hydroxy-3-(isopropylamino)-propoxy]-2-methyl-l-(methylphenyl)- indole-3-carboxylic acid ethyl ester (2)

[0077]

[0078] Preparation method is the same as Example 1, step 4, replace tert-butylamine with isopropylamine (72 μL, 0.82 mmol). Purification by silica gel column chromatography (dichloromethane:methanol = 200:1, v / v) to get 101 mg white solid, yield 58.06%. 1 H NMR (500 MHz, Methanol-d4) δ (ppm) 7.68 (d, J = 2.4 Hz, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 6.88 (d, J = 8.8 Hz, 1H), 6.83 (dd, J = 8.9, 2.4 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.28 - 4.21 (m, 1H), 4.12 (dd, J = 9.7, 5.0 Hz, 1H), 4.05 (dd, J = 9.7, 5.7 Hz, 1H), 3.49 - 3.40 (m, 1H), 3.16 (dd, J = 12.7, 9.5 Hz, 1H), 2.53 (s, 3H), 2.48 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H), 1.37 (dd, J = 6.6, 4.1 Hz, 6H).

[0079] Example 3 5-[2-Hydroxy-3-(methylamino)-propoxy]-2-methyl-l-(methylphenyl)- indole-3-carboxylic acid ethyl ester (3)

[0080]

[0081] Preparation method same as Example 1 Step 4, replace tert-butylamine with methylamine hydrochloride (56 mg, 0.82 mmol). Purification by silica gel column chromatography (dichloromethane:methanol = 200:1, v / v) to get 83 mg white solid, yield 51.09%. 1 HNMR (500 MHz, Methanol-d4) δ (ppm) 7.65 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.16 - 4.08 (m, 1H), 4.05-3.99 (m, 2H), 2.85 (dd, J = 12.3, 3.8 Hz, 1H), 2.75 (dd, J = 12.3, 8.3 Hz, 1H), 2.51 (s, 3H), 2.47 (s, 3H), 2.46 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H).

[0082] Example 4 5-[2-Hydroxy-3-(cyclopropylamino)-propoxy]-2-methyl-1- (methylphenyl)indole-3-carboxylic acid ethyl ester (4)

[0083]

[0084] Preparation method same as Example 1 Step 4, replace tert-butylamine with cyclopropylamine (58 μL, 0.82 mmol). Purification by silica gel column chromatography (dichloromethane:methanol = 200:1, v / v) to get 92 mg white solid, yield 53.14%. 1 HNMR (300 MHz, Methanol-d4) δ (ppm) 7.64 (d, J = 2.3 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 6.86 (d, J = 8.8 Hz, 1H), 6.80 (dd, J = 8.9, 2.3 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.17 - 4.06 (m, 1H), 4.00 (d, J = 5.3 Hz, 2H), 2.97 (dd, J = 12.4, 3.9 Hz, 1H), 2.83 (dd, J = 12.4, 8.4 Hz, 1H), 2.52 (s, 3H), 2.47 (s, 3H), 2.31 - 2.20 (m, 1H), 1.45 (t, J = 7.1 Hz, 3H), 0.56 - 0.48 (m, 2H), 0.46 - 0.38 (m, 2H).

[0085] Example 5 5-[2-Hydroxy-3-(phenylamino)-propoxy]-2-methyl-l-(methylphenyl)- indole-3-carboxylic acid ethyl ester (5)

[0086]

[0087] Preparation method was the same as Example 1, Step 4, replacing tert-butylamine with aniline (75 μL, 0.82 mmol). Purification by silica gel column chromatography (dichloromethane:methanol = 200: 1, v / v) to give 108 mg of white solid, yield 57.48%. 1 H NMR (300 MHz, Methanol-d4) δ (ppm) 7.66 (d, J = 2.1 Hz, 1H), 7.42 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.15 - 7.03 (m, 2H), 6.90 - 6.77 (m, 2H), 6.68 (d, J = 7.6 Hz, 2H), 6.61 (t, J = 7.3 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.21 - 4.12 (m, 1H), 4.12 - 4.01 (m, 2H), 3.43 (dd, J = 13.2, 5.0 Hz, 1H), 3.23 (dd, J = 13.1, 6.7 Hz, 1H), 2.51 (s, 3H), 2.46 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H).

[0088] Example 6 5-[2-Hydroxy-3-(benzylamino)-propoxy]-2-methyl-l-(methylphenyl)- indole-3-carboxylic acid ethyl ester (6)

[0089]

[0090] Preparation method was the same as Example 1, Step 4, replacing tert-butylamine with aniline (75 μL, 0.82 mmol). Purification by silica gel column chromatography (dichloromethane:methanol = 200: 1, v / v) to give 108 mg of white solid, yield 57.48%. 1H NMR (300 MHz, Methanol-d4) d (ppm) 7.63 (d, J = 2.3 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.39-7.25 (m, 5H), 7.25-7.18 (m, 2H), 6.85 (d, J = 8.8 Hz, 1H), 6.78 (dd, J = 8.9, 2.4 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.19-4.07 (m, 1H), 4.00 (d, J = 5.3 Hz, 2H), 3.92-3.75 (m, 2H), 2.89 (dd, J = 12.2, 3.9 Hz, 1H), 2.76 (dd, J = 12.2, 8.3 Hz, 1H), 2.51 (s, 3H), 2.47 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H).

[0091] Example 7 Ethyl 5-[2-hydroxy-3-(trishydroxymethylmethylamino)-propoxy]-2-methyl-1- (methylphenyl)indole-3-carboxylate (7)

[0092]

[0093] Preparation method same as Example 1, step 4, replace tert-butylamine with tris(hydroxymethyl)aminomethane (100 mg, 0.82 mmol). Purified by silica gel column chromatography (dichloromethane:methanol = 200:1, v / v) to get white solid 118 mg, yield 59.19%. 1 H NMR (500 MHz, Methanol-d4) d (ppm) 7.66 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 8.8 Hz, 1H), 6.83-6.79 (m, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.04 (s, 3H), 3.62-3.54 (m, 6H), 2.96 (dd, J = 11.8, 2.9 Hz, 1H), 2.84 (dd, J = 11.8, 3.9 Hz, 1H), 2.52 (s, 3H), 2.47 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H).

[0094] Example 8 Ethyl 5-[2-hydroxy-3-(trishydroxymethylmethylamino)-propoxy]-1- (methylphenyl)indole-3-carboxylate (8)

[0095]

[0096] Step 1: Preparation of compound 8-1

[0097] Into a Schlenk tube was placed 5-benzyloxyindole (1 g, 4.48 mmol), 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.17 g, 2.46 mmol), tris(dibenzylideneacetone)dipalladium (201 mg, 0.22 mmol) and sodium tert-butoxide (861 mg, 8.96 mmol). After purging with nitrogen, 4-bromotoluene (662 μL, 5.38 mmol) in toluene (20 mL) was injected and the reaction was carried out at 100 °C for 24 h. The solvent was evaporated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1, v / v) to give 1.39 g of white solid with a yield of 99.08%. 1 H NMR (300 MHz, DMSO-d6) d (ppm) 7.56 (d, J = 3.2 Hz, 1H), 7.51-7.33 (m, 10H), 7.23 (d, J = 2.5 Hz, 1H), 6.90 (dd, J = 9.0, 2.5 Hz, 1H), 6.58 (d, J = 3.2 Hz, 1H), 5.13 (s, 2H), 2.38 (s, 3H).

[0098] Step 2: Preparation of compound 8-2

[0099] Compound 8-1 (1.26 g, 4.02 mmol) was dissolved in dry dichloromethane (10 mL) and trifluoroacetic anhydride (1.68 mL, 12.06 mmol) was added. The reaction was carried out at 25 °C for 1 h. The solvent was evaporated and 15% aqueous sodium hydroxide solution (10 mL) was added. The reaction was continued at 80 °C for 8 h. The pH was adjusted to 5 with 1M hydrochloric acid and the solvent was evaporated. The residue was dissolved in ethanol (10 mL) and dichloro sulfoxide (1.36 mL, 18.80 mmol) was added dropwise at 0 °C. The reaction was carried out at 50 °C for 2 h after stirring for 30 min. The solvent was evaporated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to give 500 mg of white solid with a total yield of 32.29% over three steps. 1 H NMR (300 MHz, DMSO-d6) d (ppm) 8.18 (s, 1H), 7.67 (d, J = 2.5 Hz, 1H), 7.54-7.46 (m, 4H), 7.45-7.36 (m, 5H), 7.36-7.28 (m, 1H), 7.01 (dd, J = 9.0, 2.6 Hz, 1H), 5.18 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 2.40 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H).

[0100] Step 3: Preparation of compound 8-3

[0101] Compound 8-2 (150 mg, 0.39 mmol) was dissolved in methanol (4 mL), 10% palladium carbon (15 mg) was added, and the reaction was carried out under hydrogen at 25 °C for 12 h. The diatomite was filtered, and the solvent was evaporated. Purification was performed by silica gel column chromatography (petroleum ether: ethyl acetate = 60: 1, v / v) to obtain 83 mg of white solid with a yield of 72.11%. 1 H NMR (300 MHz, DMSO-d6) δ (ppm) 9.22 (s, 1H), 8.11 (s, 1H), 7.50 (d, J = 8.1 Hz, 3H), 7.39 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.9 Hz, 1H), 6.77 (dd, J = 8.9, 2.4 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.40 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H).

[0102] Step 4: Preparation of compound 8-4

[0103] Compound 8-3 (70 mg, 0.24 mmol) was dissolved in acetonitrile (4 mL), and cesium carbonate (118 mg, 0.36 mmol) was added. After stirring at 25 °C for 30 min, epibromohydrin (30 μL) was added, and the reaction was carried out at 80 °C for 4 h. The reaction solution was diluted with dichloromethane, diatomite was used for filtration, and the solvent was evaporated. Purification was performed by silica gel column chromatography (petroleum ether: ethyl acetate = 80: 1, v / v) to obtain 79 mg of white solid with a yield of 93.74%. 1 H NMR (300 MHz, DMSO-d6) δ (ppm) 9.22 (s, 1H), 8.11 (s, 1H), 7.50 (d, J = 8.1 Hz, 3H), 7.39 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.9 Hz, 1H), 6.77 (dd, J = 8.9, 2.4 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.40 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H).

[0104] Step 5: Preparation of compound 8

[0105] Compound 8-4 (70 mg, 0.20 mmol) was dissolved in ethanol (3 mL), and tris(hydroxymethyl)aminomethane (50 mg, 0.40 mmol) was added. The reaction was carried out at 78 °C for 3 h. The solvent was evaporated, and purification was performed by silica gel column chromatography (dichloromethane:methanol = 30: 1, v / v) to obtain 52 mg of white solid with a yield of 55.05%.1 H NMR (300 MHz, Methanol-d4) δ (ppm) 8.03 - 7.97 (m, 1H), 7.71 - 7.65 (m, 1H), 7.41 - 7.29 (m, 5H), 6.95 (d, J = 6.5 Hz, 1H), 4.37 (q, J = 7.0 Hz, 2H), 4.13 - 4.00 (m, 3H), 3.60 (s, 6H), 3.05 - 2.95 (m, 1H), 2.94 - 2.82 (m, 1H), 2.43 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). Example 9 5-[2-Hydroxy-3-(trishydroxymethylmethylamino)-propoxy]-2-methyl-1- (methylphenyl)indole-3-carboxylic acid ethyl ester (9)

[0106]

[0107] Compound 6 (100 mg, 0.21 mmol) was dissolved in methanol (5 mL), 10% palladium carbon (10 mg) was added, and the reaction was stirred under hydrogen at 25 °C for 12 h. Methanol was added to dilute the reaction, and celite was added to filter. The reaction was evaporated to dryness and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v) to give 47 mg of a white solid, with a yield of 58.56%. 1 H NMR (300 MHz, Methanol-d4) δ (ppm) 7.65 (d, J = 2.3 Hz, 1H), 7.42 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.8 Hz, 1H), 6.80 (dd, J = 8.9, 2.3 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.05 - 3.91 (m, 3H), 2.93 (dd, J = 13.0, 3.4 Hz, 1H), 2.78 (dd, J = 13.1, 6.9 Hz, 1H), 2.51 (s, 3H), 2.47 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H).

[0108] Example 10 5-[2-Hydroxypropoxy]-2-methyl-1-(methylphenyl)indole-3-carboxylic acid ethyl ester (10)

[0109]

[0110] Compound 1-2 (200 mg, 0.65 mmol) was dissolved in water (4 mL), sodium hydroxide (52 mg, 1.30 mmol) and propylene oxide (70 μL, 0.98 mmol) were added, and the reaction was stirred at 45 °C for 8 h. The reaction was evaporated to dryness and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:1, v / v) to give 182 mg of a white solid, with a yield of 73.45%.1 H NMR (300 MHz, Methanol-d4) d (ppm) 7.63 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 6.87 - 6.74 (m, 2H), 4.36 (q, J = 7.1 Hz, 2H), 4.20 - 4.05 (m, 1H), 3.89 (d, J = 5.5 Hz, 2H), 2.49 (s, 3H), 2.46 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H), 1.28 (d, J = 6.4 Hz, 3H).

[0111] Example 11 5-[2-Hydroxy-3-(N-methylbenzylamino)-propoxy]-2-methyl-l- (methylphenyl)indole-3-carboxylic acid ethyl ester (11)

[0112]

[0113] Preparation method same as Example 1, step 4, replace tert-butylamine with N- methylbenzylamine (107 μL, 0.82 mmol). Purification by silica gel column chromatography (dichloromethane:methanol = 200:1, v / v) to get 108 mg white solid, yield 54.17%. 1 H NMR (300 MHz, DMSO-d6) d (ppm) 7.64 (d, J = 2.4 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.35 - 7.17 (m, 7H), 6.84 (d, J = 8.8 Hz, 1H), 6.77 (dd, J = 8.9, 2.4 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.19 - 4.09 (m, 1H), 4.05 (dd, J = 9.7, 4.0 Hz, 1H), 3.95 (dd, J = 9.7, 5.9 Hz, 1H), 3.61 (d, J = 2.6 Hz, 2H), 2.68 (dd, J = 12.9, 5.3 Hz, 1H), 2.57 (dd, J = 12.8, 7.3 Hz, 1H), 2.51 (s, 3H), 2.46 (s, 3H), 2.30 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H).

[0114] Example 12 5-[2-Hydroxy-3-(l,2,3-triazol-2-yl)-propoxy]-2-methyl-l- (methylphenyl)indole-3-carboxylic acid ethyl ester (12)

[0115]

[0116] Preparation method same as Example 1, Step 4, replace tert-butylamine with 1,2,3- triazole (47 μL, 0.82 mmol). Purification by silica gel column chromatography (dichloromethane:methanol = 100:1, v / v) to give 49 mg of white solid, yield 27.52%. 1 H NMR (300 MHz, Methanol-d4) δ (ppm) 7.70 (d, J = 1.8 Hz, 2H), 7.63 (s, 1H), 7.41 (d, J = 7.8 Hz, 2H), 7.21 (d, J = 6.5 Hz, 2H), 6.89 - 6.76 (m, 2H), 4.78 - 4.57 (m, 2H), 4.54 - 4.47 (m, 1H), 4.37 (q, J = 7.1, 6.3 Hz, 2H), 4.06 - 4.00 (m, 2H), 2.50 (s, 3H), 2.46 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H).

[0117] Example 13 Ethyl 5-[2-hydroxy-3-(1,2,3-triazol-1-yl)-propoxy]-2-methyl-1- (methylphenyl)indole-3-carboxylate (13)

[0118]

[0119] Preparation method same as Example 1, Step 4, replace tert-butylamine with 1,2,3- triazole (47 μL, 0.82 mmol). Purification by silica gel column chromatography (dichloromethane:methanol = 100:1, v / v) to give 49 mg of white solid, yield 27.52%. 1 H NMR (300 MHz, Methanol-d4) δ (ppm) 7.70 (d, J = 1.8 Hz, 2H), 7.63 (s, 1H), 7.41 (d, J = 7.8 Hz, 2H), 7.21 (d, J = 6.5 Hz, 2H), 6.89 - 6.76 (m, 2H), 4.78 - 4.57 (m, 2H), 4.54 - 4.47 (m, 1H), 4.37 (q, J = 7.1, 6.3 Hz, 2H), 4.06 - 4.00 (m, 2H), 2.50 (s, 3H), 2.46 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H).

[0120] Example 14 Ethyl 5-[2-hydroxy-3-(4-methylpiperazin-1-yl)-propoxy]-2-methyl-1- (methylphenyl)indole-3-carboxylate (14)

[0121]

[0122] Preparation method same as example 1 step 4, replace tert-butylamine with 4- methylpiperazine (92 mg, 0.82 mmol). Purification by silica gel column chromatography (dichloromethane:methanol = 150:1, v / v) to get white solid 141 mg, yield 73.91%. 1 H NMR (300 MHz, Methanol-d4) δ 7.64 (d, J = 2.3 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 8.8 Hz, 1H), 6.80 (dd, J = 8.8, 2.3 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.19 - 4.09 (m, 1H), 4.07 - 3.90 (m, 2H), 2.77 - 2.37 (m, 16H), 2.28 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H).

[0123] Example 15 5-[2-Hydroxy-3-(4-phenylpiperazin-1-yl)-propoxy]-2-methyl-1- (methylphenyl)indole-3-carboxylic acid ethyl ester (15)

[0124]

[0125] Preparation method same as example 1 step 4, replace tert-butylamine with 4- phenylpiperazine (126 μL, 0.82 mmol). Purification by silica gel column chromatography (dichloromethane:methanol = 200:1, v / v) to get white solid 134 mg, yield 61.98%. 1 H NMR (300 MHz, Methanol-d4) δ (ppm) 7.67 (d, J = 2.1 Hz, 1H), 7.42 (d, J = 7.9 Hz, 2H), 7.26 - 7.16 (m, 4H), 6.96 (d, J = 7.8 Hz, 2H), 6.90 - 6.77 (m, 3H), 4.37 (q, J = 7.1 Hz, 2H), 4.25 - 4.14 (m, 1H), 4.13 - 3.95 (m, 2H), 3.23 - 3.14 (m, 4H), 2.78 - 2.72 (m, 4H), 2.70 - 2.56 (m, 2H), 2.51 (s, 3H), 2.47 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H).

[0126] Example 16 5-{2-Hydroxy-3-[4-(4-trifluoromethoxyphenyl)piperazin-1-yl]- propoxy}-2-methyl-1-(methylphenyl)indole-3-carboxylic acid ethyl ester (16)

[0127]

[0128] The preparation method is the same as step 4 in example 1, replacing tert-butylamine with 4-(4-trifluoromethoxyphenyl)piperazine (202 mg, 0.82 mmol). Purification by silica gel column chromatography (dichloromethane:methanol = 200:1, v / v) to obtain 153 mg of white solid, with a yield of 61.04%. 1 H NMR (300 MHz, Methanol-d4) d (ppm) 7.67 (d, J = 2.2 Hz, 1H), 7.42 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 9.2 Hz, 2H), 6.86 (d, J = 9.1 Hz, 1H), 6.81 (dd, J = 8.9, 2.2 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.22 - 4.14 (m, 1H), 4.11 - 3.96 (m, 2H), 3.23 - 3.17 (m, 4H), 2.77 - 2.70 (m, 4H), 2.69 - 2.56 (m, 2H), 2.51 (s, 3H), 2.46 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H).

[0129] Example 17 5-{2-Hydroxy-3-[4-cyclohexylpiperazin-1-yl]-propoxy}-2-methyl-1- (methylphenyl)indole-3-carboxylic acid ethyl ester (17)

[0130]

[0131] The preparation method is the same as step 4 in example 1, replacing tert-butylamine with 4-(4-trifluoromethoxyphenyl)piperazine (202 mg, 0.82 mmol). Purification by silica gel column chromatography (dichloromethane:methanol = 200:1, v / v) to obtain 153 mg of white solid, with a yield of 61.04%. 1 H NMR (300 MHz, Methanol-d4) d (ppm) 7.67 (d, J = 2.2 Hz, 1H), 7.42 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 9.2 Hz, 2H), 6.86 (d, J = 9.1 Hz, 1H), 6.81 (dd, J = 8.9, 2.2 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.22 - 4.14 (m, 1H), 4.11 - 3.96 (m, 2H), 3.23 - 3.17 (m, 4H), 2.77 - 2.70 (m, 4H), 2.69 - 2.56 (m, 2H), 2.51 (s, 3H), 2.46 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H).

[0132] Example 18 5-[2-Hydroxy-3-(1,2,3,4-tetrahydroisoquinolin-2-yl)-propoxy]-2-methyl-1 - (methylphenyl)indole-3-carboxylic acid ethyl ester (18)

[0133]

[0134] Preparation method was the same as Example 1 Step 4, replacing tert-butylamine with tetrahydroisoquinoline (106 μL, 0.82 mmol). Purification by silica gel column chromatography (dichloromethane:methanol = 200:1, v / v) to give 117 mg of white solid, yield 57.27%. 1 H NMR (300 MHz, Methanol-d4) d (ppm) 7.66 (d, J = 1.2 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 7.13 - 6.98 (m, 4H), 6.89 - 6.76 (m, 2H), 4.36 (d, J = 7.1 Hz, 2H), 4.31 - 4.21 (m, 1H), 4.13 - 3.96 (m, 2H), 3.76 (s, 2H), 2.95 - 2.87 (m, 4H), 2.82 (dd, J = 13.1, 4.4 Hz, 1H), 2.73 (dd, J = 13.0, 7.6 Hz, 1H), 2.50 (s, 3H), 2.46 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H).

[0135] Example 19 5-[2-Hydroxy-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)- propoxy]-2-methyl-1 -(methylphenyl)indole-3-carboxylic acid ethyl ester (19)

[0136]

[0137] Preparation method was the same as Example 1 Step 4, replacing tert-butylamine with tetrahydroisoquinoline (106 μL, 0.82 mmol). Purification by silica gel column chromatography (dichloromethane:methanol = 200:1, v / v) to give 117 mg of white solid, yield 57.27%. 1H NMR (300 MHz, Methanol-d4) δ (ppm) 7.66 (d, J = 1.8 Hz, 1H), 7.41 (d, J = 7.9 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 6.89 - 6.76 (m, 2H), 6.67 (s, 1H), 6.61 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 4.29 - 4.21 (m, 1H), 4.12 - 3.96 (m, 2H), 3.78 (s, 3H), 3.76 (s, 3H), 3.69 (s, 2H), 2.88 - 2.78 (m, 5H), 2.73 (dd, J = 13.0, 7.7 Hz, 1H), 2.51 (s, 3H), 2.46 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H).

[0138] Example 20 (R)-5-[2-hydroxy-3-(trishydroxymethylmethylamino)-propoxy]-2-methyl-1- (methylphenyl)indole-3-carboxylic acid ethyl ester (20)

[0139]

[0140] Step 1: Preparation of compound 20-1

[0141] Compound 1-2 (500 mg, 1.62 mmol) was dissolved in acetonitrile (15 mL), cesium carbonate (792 mg, 2.43 mmol) was added, stirred at 25 °C for 30 min, (S)-2- (chloromethyl)oxirane (200 μL, 2.43 mmol) was added, and reacted at 80 °C for 4 h. The solvent was evaporated, diluted with ethyl acetate, washed with saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1, v / v) to obtain 581 mg of a white solid at a yield of 98.21%. 1 H NMR (300 MHz, Chloroform-d) δ (ppm) 7.70 (d, J = 2.5 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.3 Hz, 2H), 6.90 (d, J = 8.8 Hz, 1H), 6.81 (dd, J = 8.8, 2.5 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 4.30 (dd, J = 11.0, 3.3 Hz, 1H), 4.06 (dd, J = 11.0, 5.6 Hz, 1H), 3.46 - 3.35 (m, 1H), 2.92 (dd, J = 5.0, 4.1 Hz, 1H), 2.79 (dd, J = 5.0, 2.7 Hz, 1H), 2.55 (s, 3H), 2.47 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H).

[0142] Step 2: Preparation of compound 20

[0143] Preparation Method same as Example 7, replace compound 1-3 with compound 20-1 (150 mg, 0.41 mmol). Purified by silica gel column chromatography (dichloromethane:methanol = 200:1, v / v) to give 113 mg of white solid, yield 56.68%. 1 H NMR (300 MHz, Methanol-d4) d (ppm) 7.65 (d, J = 2.2 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 6.89 - 6.76 (m, 2H), 4.38 (q, J = 7.1 Hz, 2H), 4.12 - 3.99 (m, 3H), 3.65 - 3.54 (m, 6H), 2.99 (dd, J = 11.5, 2.4 Hz, 1H), 2.86 (dd, J = 11.9, 7.0 Hz, 1H), 2.51 (s, 3H), 2.47 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H).

[0144] Example 21 (S)-5-[2-Hydroxy-3-(trihydroxymethylmethylamino)-propoxy]-2-methyl-1- (methylphenyl)indole-3-carboxylic acid ethyl ester (21)

[0145]

[0146] Step 1: Preparation of compound 21-1

[0147] Preparation Method same as Example 20, Step 1, replace (S)-2-(chloromethyl)oxirane with (R)-2-(chloromethyl)oxirane (200 pL, 2.43 mmol). Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1, v / v) to give 537 mg of white solid, yield 90.77%. 1H NMR (300 MHz, Chloroform-d) d (ppm) 7.70 (d, J = 2.5 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 6.90 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 2.5 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 4.30 (dd, J = 11.0, 3.3 Hz, 1H), 4.06 (dd, J = 11.0, 5.6 Hz, 1H), 3.46 - 3.35 (m, 1H), 2.92 (dd, J = 5.0, 4.1 Hz, 1H), 2.79 (dd, J = 5.0, 2.6 Hz, 1H), 2.55 (s, 3H), 2.47 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H).

[0148] Step 2: Preparation of compound 21

[0149] Preparation Method as Example 7, replace compound 1-3 with compound 21-1 (150 mg, 0.41 mmol). Purified by silica gel column chromatography (dichloromethane:methanol = 200:1, v / v) to get 102 mg white solid, yield 51.16%. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 7.70 (d, J = 2.5 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 6.90 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 2.5 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 4.30 (dd, J = 11.0, 3.3 Hz, 1H), 4.06 (dd, J = 11.0, 5.6 Hz, 1H), 3.46 - 3.35 (m, 1H), 2.92 (dd, J = 5.0, 4.1 Hz, 1H), 2.79 (dd, J = 5.0, 2.6 Hz, 1H), 2.55 (s, 3H), 2.47 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H).

[0150] Example 22 (R)-5-[2-hydroxy-3-(anilino)-propoxy]-2-methyl-l-(methylphenyl)- indole-3-carboxylic acid ethyl ester (22)

[0151]

[0152] Preparation Method as Example 20 Step 2, replace tris(hydroxymethyl)aminomethane with aniline (75 μL, 0.82 mmol). Purified by silica gel column chromatography (dichloromethane:methanol = 200:1, v / v) to get 138 mg white solid, yield 73.45%. 1H NMR (300 MHz, Methanol-d4) δ (ppm) 7.66 (d, J = 1.7 Hz, 1 H), 7.42 (d, J = 7.9 Hz, 2 H), 7.22 (d, J = 8.2 Hz, 2 H), 7.15 - 7.03 (m, 2 H), 6.90 - 6.77 (m, 2 H), 6.69 (d, J = 7.4 Hz, 2 H), 6.61 (t, J = 7.3 Hz, 1 H), 4.37 (q, J = 7.1 Hz, 2 H), 4.21 - 4.12 (m, 1 H), 4.12 - 4.02 (m, 2 H), 3.43 (dd, J = 13.2, 5.0 Hz, 1 H), 3.23 (dd, J = 13.2, 6.7 Hz, 1 H), 2.51 (s, 3 H), 2.47 (s, 3 H), 1.43 (t, J = 7.1 Hz, 3 H).

[0153] Example 23 (S)-5-[2-Hydroxy-3-(anilino)-propoxy]-2-methyl-1-(methylphenyl)- indole-3-carboxylic acid ethyl ester (23)

[0154]

[0155] Preparation method same as example 21 step 2, replace tris(hydroxymethyl)aminomethane with aniline (75 μL, 0.82 mmol). Purification by silica gel column chromatography (dichloromethane:methanol = 200:1, v / v) to get white solid 121 mg, yield 64.40%. 1 H NMR (300 MHz, Methanol-d4) δ (ppm) 7.66 (s, 1 H), 7.41 (d, J = 7.8 Hz, 2 H), 7.20 (d, J = 7.9 Hz, 2 H), 7.09 (t, J = 7.8 Hz, 2 H), 6.87 - 6.77 (m, 2 H), 6.68 (d, J = 7.9 Hz, 2 H), 6.61 (t, J = 7.2 Hz, 1 H), 4.36 (q, J = 7.1 Hz, 2 H), 4.21 - 4.11 (m, 1 H), 4.11 - 4.01 (m, 2 H), 3.42 (dd, J = 13.0, 4.8 Hz, 1 H), 3.27 - 3.20 (m, 1 H), 2.50 (s, 3 H), 2.46 (s, 3 H), 1.42 (t, J = 7.1 Hz, 3 H).

[0156] Example 24 (R)-5-[2-Hydroxy-3-(anilino)-propoxy]-2-methyl-1-(methylphenyl)- indole-3-carboxylic acid methyl ester (24)

[0157]

[0158] Step 1: Preparation of compound 24-1

[0159] The preparation method was same as step 1 in example 1, ethyl acetoacetate was replaced by methyl acetoacetate (2.23 mL, 20.60 mmol). Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to get white solid 3.58 g, yield 84.72%.

[0160] Step 2: Preparation of compound 24-2

[0161] The preparation method was same as step 2 in example 1, compound 1-1 was replaced by compound 24-1 (1.87 g, 9.12 mmol). Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to get white solid 1.97 g, yield 73.19%. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 7.66 (d, J = 2.5 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 8.7 Hz, 1H), 6.72 (dd, J = 8.7, 2.5 Hz, 1H), 3.95 (s, 3H), 2.55 (s, 3H), 2.47 (s, 3H).

[0162] Step 3: Preparation of compound 24-3

[0163] The preparation method was same as step 3 in example 1, compound 1-2 was replaced by compound 24-2 (1.92 g, 6.50 mmol), and epibromohydrin was replaced by (S)-2-(chloromethyl)oxirane (697 μL, 8.50 mmol). Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to get white solid 2.05 g, yield 89.81%. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 7.68 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 7.9 Hz, 2H), 6.90 (d, J = 8.9 Hz, 1H), 6.87-6.77 (m, 1H), 4.31 (dd, J = 11.0, 3.3 Hz, 1H), 4.07 (dd, J = 11.0, 5.6 Hz, 1H), 3.95 (s, 3H), 3.44-3.36 (m, 1H), 2.92 (t, J = 4.5 Hz, 1H), 2.82-2.76 (m, 1H), 2.55 (s, 3H), 2.47 (s, 3H).

[0164] Step 4: Preparation of compound 24

[0165] Preparation Method same as example 5, replace compound 1-3 with compound 24-3 (144 mg, 0.41 mmol). Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to give white solid 95 mg, yield 52.16%. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 7.68 (d, J = 2.5 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 7.9 Hz, 2H), 6.90 (d, J = 8.9 Hz, 1H), 6.82 (dd, J = 8.8, 2.4 Hz, 1H), 4.31 (dd, J = 10.9, 3.2 Hz, 1H), 4.07 (dd, J = 11.0, 5.6 Hz, 1H), 3.95 (s, 3H), 3.45 - 3.36 (m, 1H), 2.97 - 2.86 (m, 1H), 2.80 (dd, J = 5.0, 2.6 Hz, 1H), 2.55 (s, 3H), 2.47 (s, 3H).

[0166] Example 25 (S)-5-[2-Hydroxy-3-(phenylamino)-propoxy]-2-methyl-1- (methylphenyl)indole-3-carboxylic acid methyl ester (25)

[0167]

[0168] Step 1: Preparation of compound 25-3

[0169] Preparation Method same as example 24, step 3, replace (S)-2-(chloromethyl)oxirane with (R)-2-(chloromethyl)oxirane (697 μL, 8.50 mmol). Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to give white solid 1.87 g, yield 81.92%. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 7.68 (d, J = 2.5 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 7.9 Hz, 2H), 6.90 (d, J = 8.9 Hz, 1H), 6.82 (dd, J = 8.8, 2.4 Hz, 1H), 4.31 (dd, J = 10.9, 3.2 Hz, 1H), 4.07 (dd, J = 11.0, 5.6 Hz, 1H), 3.95 (s, 3H), 3.45 - 3.36 (m, 1H), 2.97 - 2.86 (m, 1H), 2.80 (dd, J = 5.0, 2.6 Hz, 1H), 2.55 (s, 3H), 2.47 (s, 3H).

[0170] Step 2: Preparation of compound 25

[0171] Preparation Method same as Example 24, replace compound 24-3 with compound 25-3 (144 mg, 0.41 mmol). Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to get white solid 125 mg, yield 68.63%. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 7.68 (d, J = 2.5 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.24 - 7.13 (m, 4H), 6.91 (d, J = 8.8 Hz, 1H), 6.83 - 6.67 (m, 4H), 4.37 - 4.24 (m, 1H), 4.22 - 4.09 (m, 2H), 3.95 (s, 3H), 3.47 (dd, J = 12.9, 4.3 Hz, 1H), 3.33 (dd, J = 12.9, 7.2 Hz, 1H), 2.55 (s, 3H), 2.47 (s, 3H).

[0172] Example 26 (R)-5-[2-Hydroxy-3-(anilino)-propoxy]-2-methyl-l-(methylphenyl)- indole-3-carboxylic acid (26)

[0173]

[0174] Step 1: Preparation of compound 26-1

[0175] Preparation Method same as Example 1 Step 1, replace ethyl acetoacetate with benzyl acetoacetate (3.57 mL, 20.60 mmol). Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to get white solid 4.80 g, yield 91.35%. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 10.26 (brs, 1H), 7.43 - 7.28 (m, 5H), 7.12 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.2 Hz, 2H), 5.15 (s, 2H), 4.74 (s, 1H), 2.33 (s, 3H), 1.95 (s, 3H).

[0176] Step 2: Preparation of compound 26-2

[0177] Preparation Method same as Example 1 Step 2, replace compound 1-1 with compound 26-1 (2.56 g, 9.12 mmol). Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to get white solid 2.12 g, yield 68.12%. 1HNMR (300 MHz, Chloroform-d) d (ppm) 7.62 (d, J = 2.5 Hz, 1H), 7.49 (d, J = 6.5 Hz, 2H), 7.43 - 7.31 (m, 5H), 7.17 (d, J = 8.2 Hz, 2H), 6.87 (d, J = 8.7 Hz, 1H), 6.71 (dd, J = 8.7, 2.5 Hz, 1H), 5.42 (s, 2H), 2.55 (s, 3H), 2.46 (s, 3H).

[0178] Step 3: Preparation of compound 26-3

[0179] Preparation method same as step 3 in example 24, replace compound 24-2 with compound 26-2 (2.41 g, 6.50 mmol). Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to get 2.00 g white solid, yield 72.21%. 1 HNMR (300 MHz, Chloroform-d) d (ppm) 7.62 (d, J = 2.5 Hz, 1H), 7.49 (d, J = 6.5 Hz, 2H), 7.43 - 7.31 (m, 5H), 7.17 (d, J = 8.2 Hz, 2H), 6.87 (d, J = 8.7 Hz, 1H), 6.71 (dd, J = 8.7, 2.5 Hz, 1H), 5.42 (s, 2H), 2.55 (s, 3H), 2.46 (s, 3H).

[0180] Step 4: Preparation of compound 26-4

[0181] Preparation method same as step 4 in example 24, replace compound 24-3 with compound 26-3 (175 mg, 0.41 mmol). Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to get 152 mg white solid, yield 82.04%. 1H NMR (300 MHz, Chloroform-d) d (ppm) 7.62 (dd, J = 5.5, 2.4 Hz, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.44 - 7.27 (m, 5H), 7.24 - 7.14 (m, 4H), 6.90 (d, J = 8.8 Hz, 1H), 6.83 - 6.67 (m, 4H), 5.41 (s, 2H), 4.31 - 4.22 (m, 1H), 4.05 - 3.95 (m, 2H), 3.45 - 3.35 (m, 1H), 3.30 - 3.20 (m, 1H), 2.57 (s, 3H), 2.47 (s, 3H).

[0182] Step 5: Preparation of compound 26

[0183] Compound 26-4 (2 g, 3.84 mmol) was dissolved in methanol (20 mL), 10% palladium carbon (200 mg) was added, and the reaction was carried out under hydrogen at 25 °C for 12 h. Methanol was added to dilute the reaction solution, and diatomite was used for filtration. The filtrate was evaporated to dryness, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1, v / v) to obtain 1.42 g of white solid, with a yield of 86.31%. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 7.62 (dd, J = 5.5, 2.4 Hz, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.44 - 7.27 (m, 5H), 7.24 - 7.14 (m, 4H), 6.90 (d, J = 8.8 Hz, 1H), 6.83 - 6.67 (m, 4H), 5.41 (s, 2H), 4.31 - 4.22 (m, 1H), 4.05 - 3.95 (m, 2H), 3.45 - 3.35 (m, 1H), 3.30 - 3.20 (m, 1H), 2.57 (s, 3H), 2.47 (s, 3H).

[0184] Example 27 (S)-N-ethyl-5-[2-hydroxy-3-(anilino)-propoxy]-2-methyl-l- (methylphenyl)indole-3-carboxamide (27)

[0185]

[0186] Step 1: Preparation of compound 27-3

[0187] The preparation method was the same as that in Example 26, Step 3, except that (S)-2-(chloromethyl)oxirane was replaced by (R)-2-(chloromethyl)oxirane (697 μL, 8.50 mmol). Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) obtained 2.31 g of white solid, with a yield of 83.40%.1 H NMR (300 MHz, DMSO-d6) d (ppm) 7.56 - 7.49 (m, 3H), 7.47 - 7.39 (m, 4H), 7.39 - 7.30 (m, 3H), 6.88 (d, J = 8.8 Hz, 1H), 6.80 (dd, J = 8.9, 2.5 Hz, 1H), 5.37 (s, 2H), 4.22 (dd, J = 11.2, 2.6 Hz, 1H), 3.72 (dd, J = 11.2, 6.5 Hz, 1H), 3.33 - 3.27 (m, 1H), 2.84 (t, J = 4.7 Hz, 1H), 2.69 (dd, J = 5.1, 2.6 Hz, 1H), 2.51 (s, 3H), 2.43 (s, 3H).

[0188] Step 2: Preparation of compound 27-4

[0189] Preparation method same as Example 26 step 4, replace compound 26-3 with compound 27-3 (175 mg, 0.41 mmol). Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to get white solid 145 mg, yield 78.26%. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 7.63 (d, J = 2.5 Hz, 1H), 7.52 (d, J = 6.8 Hz, 2H), 7.42 - 7.30 (m, 5H), 7.25 - 7.14 (m, 4H), 6.90 (d, J = 8.8 Hz, 1H), 6.83 - 6.69 (m, 4H), 5.41 (s, 2H), 4.32 - 4.20 (m, 1H), 4.07 - 3.91 (m, 2H), 3.40 (dd, J = 12.8, 4.1 Hz, 1H), 3.27 (dd, J = 12.8, 7.4 Hz, 1H), 2.57 (s, 3H), 2.47 (s, 3H).

[0190] Step 3: Preparation of compound 27

[0191] Preparation method same as Example 26 step 5, replace compound 26-4 with compound 27-4 (2 g, 3.84 mmol). Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to get white solid 1.54 g, yield 93.60%. 1H NMR (300 MHz, Chloroform-d) d (ppm) 7.83-7.74 (m, 1H), 7.42-7.32 (m, 2H), 7.27-7.16 (m, 5H), 6.96-6.75 (m, 5H), 4.43-4.27 (m, 1H), 4.26-4.06 (m, 2H), 3.59-3.28 (m, 2H), 2.62 (s, 3H), 2.49 (s, 3H).

[0192] Example 28 (R)-N-ethyl-5-[2-hydroxy-3-(phenylamino)-propoxy]-2-methyl-1- (methylphenyl)indole-3-carboxamide (28)

[0193]

[0194] Compound 26 (150 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (5 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (175 mg, 0.46 mmol) and N,N-diisopropylethylamine (185 μL, 1.06 mmol) were added at 0 °C, and the reaction was carried out at 0 °C for 30 min. Ethylamine hydrochloride (38 mg, 0.46 mmol) was added, and the reaction was carried out at 25 °C for 8 h. The reaction solution was poured into water, extracted with ethyl acetate (3 x 50 mL), washed with water and saturated sodium chloride solution in turn, and the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1, v / v) to obtain 132 mg of a white solid, with a yield of 82.48%. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 7.34 (dd, J = 5.4, 2.7 Hz, 3H), 7.23-7.12 (m, 4H), 6.93 (d, J = 8.8 Hz, 1H), 6.82-6.66 (m, 4H), 5.86 (s, 1H), 4.34-4.24 (m, 1H), 4.19-4.05 (m, 2H), 3.62-3.50 (m, 2H), 3.46 (dd, J = 12.9, 4.2 Hz, 1H), 3.38-2.89 (m, 2H), 2.50 (s, 3H), 2.46 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H).

[0195] Example 29 (S)-N-ethyl-5-[2-hydroxy-3-(phenylamino)-propoxy]-2-methyl-1- (methylphenyl)indole-3-carboxamide (29)

[0196]

[0197] Preparation method as Example 28, replace compound 26 with compound 27 (150 mg, 0.35 mmol). Purify by column chromatography on silica gel (petroleum ether: ethyl acetate = 50: 1, v / v) to give 125 mg of white solid, yield 78.10%. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 7.39 - 7.30 (m, 3H), 7.24 - 7.13 (m, 4H), 6.94 (d, J = 8.8 Hz, 1H), 6.82 - 6.69 (m, 4H), 5.86 (s, 1H), 4.36 - 4.25 (m, 1H), 4.19 - 4.05 (m, 2H), 3.63 - 3.51 (m, 2H), 3.47 (dd, J = 12.9, 4.2 Hz, 1H), 3.33 (dd, J = 12.9, 7.3 Hz, 1H), 2.50 (s, 3H), 2.47 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H).

[0198] Example 30 (R)-N-methyl-5-[2-hydroxy-3-(phenylamino)-propoxy]-2-methyl-1- (methylphenyl)indole-3-carboxamide (30)

[0199]

[0200] Preparation method as Example 28, replace ethylamine hydrochloride with methylamine hydrochloride (31 mg, 0.46 mmol). Purify by column chromatography on silica gel (petroleum ether: ethyl acetate = 50: 1, v / v) to give 116 mg of white solid, yield 72.48%. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 7.39 - 7.30 (m, 3H), 7.24 - 7.13 (m, 4H), 6.94 (d, J = 8.8 Hz, 1H), 6.82 - 6.69 (m, 4H), 5.86 (s, 1H), 4.36 - 4.25 (m, 1H), 4.19 - 4.05 (m, 2H), 3.63 - 3.51 (m, 2H), 3.47 (dd, J = 12.9, 4.2 Hz, 1H), 3.33 (dd, J = 12.9, 7.3 Hz, 1H), 2.50 (s, 3H), 2.47 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H).

[0201] Example 31 (S)-N-methyl-5-[2-hydroxy-3-(phenylamino)-propoxy]-2-methyl-1- (methylphenyl)indole-3-carboxamide (31)

[0202]

[0203] The preparation method is the same as Example 29, and ethylamine hydrochloride is replaced by methylamine hydrochloride (31 mg, 0.46 mmol). Purification is performed by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1, v / v) to obtain 129 mg of white solid, with a yield of 80.60%. 1 H NMR (300 MHz, Chloroform-d) δ (ppm) 7.34 (d, J = 8.0 Hz, 3H), 7.24-7.12 (m, 4H), 6.94 (d, J = 8.8 Hz, 1H), 6.81-6.77 (m, 1H), 6.77-6.67 (m, 3H), 5.90 (d, J = 5.0 Hz, 1H), 4.32-4.22 (m, 1H), 4.20-4.07 (m, 2H), 3.45 (dd, J = 12.9, 4.2 Hz, 1H), 3.32 (dd, J = 12.9, 7.1 Hz, 1H), 3.07 (d, J = 4.8 Hz, 3H), 2.86 (s, 3H), 2.50 (s, 3H), 2.47 (s, 3H).

[0204] Example 32 (R)-5-[2-Hydroxy-3-(phenylamino)-propoxy]-2-methyl-1- (methylphenyl)indan-3-one (32)

[0205]

[0206] Step 1: Preparation of compound 32-1

[0207] 4-methylaniline (1 g, 9.33 mmol), acetylacetone (1.25 mL, 12.13 mmol) and zinc oxide (77 mg, 0.94 mmol) were placed in a bottle and reacted at 90 °C for 8 h. Ethyl acetate was added to dilute the reaction solution, diatomite was used for filtration, the filtrate was washed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and purification was performed by silica gel column chromatography (petroleum ether: ethyl acetate = 200:1, v / v) to obtain 1.73 g of white liquid, with a yield of 98.04%. 1 H NMR (300 MHz, Chloroform-d) δ (ppm) 12.40 (s, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.2 Hz, 2H), 5.17 (s, 1H), 2.34 (s, 3H), 2.09 (s, 3H), 1.96 (s, 3H).

[0208] Step 2: Preparation of compound 32-2

[0209] Compound 32-2 (1.65 g, 8.72 mmol) was added, and the mixture was stirred at 50 °C for 2 h. The reaction mixture was diluted with methanol, filtered through celite, and the filtrate was evaporated to dryness. Purification by column chromatography on silica gel (petroleum ether: ethyl acetate = 30: 1, v / v) gave 1.25 g of a yellow solid, in 51.31% yield. 1 H NMR (300 MHz, DMSO-d6) d (ppm) 9.09 (s, 1H), 7.50 (d, J = 2.3 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 6.75 (d, J = 8.7 Hz, 1H), 6.63 (dd, J = 8.7, 2.3 Hz, 1H), 2.54 (s, 3H), 2.47 (s, 3H), 2.43 (s, 3H).

[0210] Step 3: Preparation of compound 32-3

[0211] Compound 32-2 (300 mg, 1.07 mmol) was dissolved in acetonitrile (10 mL), and cesium carbonate (521 mg, 1.60 mmol) was added. The mixture was stirred at 25 °C for 30 min, and (S)-2-(chloromethyl)oxirane (131 μL, 1.60 mmol) was added. The mixture was stirred at 80 °C for 8 h. The reaction mixture was diluted with ethyl acetate, filtered through celite, and the filtrate was evaporated to dryness. Purification by column chromatography on silica gel (petroleum ether: ethyl acetate = 100: 1, v / v) gave 285 mg of a white solid, in 74.99% yield. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 7.67 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 8.3 Hz, 2H), 6.91 (d, J = 8.9 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 4.34 (dd, J = 11.0, 3.1 Hz, 1H), 4.04 (dd, J = 11.0, 5.8 Hz, 1H), 3.47-3.36 (m, 1H), 2.93 (t, J = 4.5 Hz, 1H), 2.80 (dd, J = 4.9, 2.7 Hz, 1H), 2.68 (s, 3H), 2.55 (s, 3H), 2.48 (s, 3H).

[0212] Step 4: Preparation of compound 32

[0213] Compound 32-3 (150 mg, 0.42 mmol) was dissolved in ethanol (4 mL), and tris(hydroxymethyl)aminomethane (101 μL, 0.84 mmol) was added. The reaction was stirred at 78 °C for 6 h. The reaction was evaporated to dryness and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1, v / v) to give 146 mg of white solid, 81.37% yield. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 7.66 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 7.9 Hz, 2H), 7.23 - 7.14 (m, 4H), 6.91 (d, J = 8.8 Hz, 1H), 6.81 (dd, J = 8.9, 2.3 Hz, 1H), 6.78 - 6.67 (m, 3H), 4.37 - 4.25 (m, 1H), 4.23 - 4.07 (m, 2H), 3.47 (dd, J = 12.9, 4.3 Hz, 1H), 3.33 (dd, J = 12.9, 7.2 Hz, 1H), 2.66 (s, 3H), 2.54 (s, 3H), 2.48 (s, 3H).

[0214] Example 33 (R)-5-[2-Hydroxy-3-(phenylamino)-propoxy]-2-methyl-l- (methylphenyl)indole-3-carboxylic acid propyl ester (33)

[0215]

[0216] Step 1: Preparation of compound 33-1

[0217] The preparation method was the same as Example 32, Steps 1 and 2, with the replacement of acetylacetone by propyl acetoacetate (1.73 mL, 12.13 mmol). Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1, v / v) gave 1.21 g of white solid, 40.17% yield over two steps. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 7.68 (d, J = 2.5 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 6.86 (d, J = 8.7 Hz, 1H), 6.72 (dd, J = 8.7, 2.5 Hz, 1H), 4.33 (t, J = 6.6 Hz, 2H), 2.55 (s, 3H), 2.47 (s, 3H), 1.94 - 1.79 (m, 2H), 1.08 (t, J = 7.4 Hz, 3H).

[0218] Step 2: Preparation of compound 33-2

[0219] The preparation method is the same as that of Example 32 step 3, and compound 32-2 is replaced by compound 33-1 (345 mg, 1.07 mmol). Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1, v / v) to obtain 312 mg of white solid, with a yield of 76.90%. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 7.70 (d, J = 2.5 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 6.91 (d, J = 8.8 Hz, 1H), 6.82 (dd, J = 8.8, 2.5 Hz, 1H), 4.39-4.25 (m, 3H), 4.06 (dd, J = 11.0, 5.6 Hz, 1H), 3.45-3.35 (m, 1H), 2.92 (t, J = 4.5 Hz, 1H), 2.79 (dd, J = 5.0, 2.7 Hz, 1H), 2.56 (s, 3H), 2.47 (s, 3H), 1.95-1.77 (m, 2H), 1.10 (t, J = 7.4 Hz, 3H).

[0220] Step 3: Preparation of compound 33

[0221] The preparation method is the same as that of Example 32 step 4, and compound 32-3 is replaced by compound 33-2 (159 mg, 0.42 mmol). Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1, v / v) to obtain 162 mg of white solid, with a yield of 80.67%. 1 H NMR (300 MHz, Chloroform-d) d (ppm)) 7.72 (s, 1H), 7.35 (d, J = 7.8 Hz, 2H), 7.23-7.12 (m, 4H), 6.91 (d, J = 8.8 Hz, 1H), 6.84-6.66 (m, 4H), 4.38-4.25 (m, 3H), 4.22-4.05 (m, 2H), 3.46 (dd, J = 12.8, 4.2 Hz, 1H), 3.38-3.26 (m, 1H), 2.56 (s, 3H), 2.47 (s, 3H), 1.89-1.79 (m, 2H), 1.09 (t, J = 7.2 Hz, 3H).

[0222] Example 34 (R)-5-[2-hydroxy-3-(anilino)-propoxy]-2-methyl-1-(methylphenyl)indole-3- carboxylic acid isopropyl ester (34)

[0223]

[0224] Step 1: Preparation of compound 34-1

[0225] Preparation method as Example 32, step 1 and 2, replace acetylacetone with isopropyl acetoacetate (1 g, 9.34 mmol). Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1, v / v) to get white solid 1.34 g, two-step yield 44.39%. 1 HNMR (300 MHz, Chloroform-d) d (ppm) 7.66 (d, J = 2.6 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.7 Hz, 1H), 6.71 (dd, J = 8.8, 2.5 Hz, 1H), 5.37-5.27 (m, 1H), 2.55 (s, 3H), 2.47 (s, 3H), 1.44 (s, 3H), 1.42 (s, 3H).

[0226] Step 2: Preparation of compound 34-2

[0227] Preparation method as Example 32, step 3, replace compound 32-2 with compound 34-1 (280 mg, 0.87 mmol). Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to get white solid 271 mg, yield 96.36%. 1 HNMR (300 MHz, Chloroform-d) d (ppm) 7.66 (d, J = 2.6 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.7 Hz, 1H), 6.71 (dd, J = 8.8, 2.5 Hz, 1H), 5.37-5.27 (m, 1H), 2.55 (s, 3H), 2.47 (s, 3H), 1.44 (s, 3H), 1.42 (s, 3H).

[0228] Step 3: Preparation of compound 34

[0229] Preparation method as Example 32, step 4, replace compound 33-3 with compound 34-2 (220 mg, 0.58 mmol). Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1, v / v) to get white solid 176 mg, yield 80.02%. 1H NMR (300 MHz, Chloroform-d) d (ppm) 7.73 (d, J = 2.5 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.23 - 7.13 (m, 3H), 6.90 (d, J = 8.8 Hz, 1H), 6.83 - 6.68 (m, 2H), 5.39 - 5.24 (m, 1H), 4.37 - 4.25 (m, 1H), 4.23 - 4.08 (m, 1H), 3.47 (dd, J = 12.9, 4.2 Hz, 1H), 3.33 (dd, J = 12.9, 7.3 Hz, 1H), 2.55 (s, 3H), 2.47 (s, 3H), 1.44 (s, 3H), 1.42 (s, 3H).

[0230] Example 35 5-[2-Hydroxy-3-(trishydroxymethylmethylamino)-propoxy]-2-methyl-1- (methylphenyl)indolin-3-one (35)

[0231]

[0232] Step 1: Preparation of compound 35-3

[0233] Preparation method same as Example 32 Step 3, replace (S)-2-(chloromethyl)oxetane with epibromohydrin (132 μL, 1.60 mmol). Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to give 273 mg of white solid, yield 76.12%. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 7.67 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 7.7 Hz, 2H), 7.18 (d, J = 7.4 Hz, 2H), 6.90 (d, J = 8.9 Hz, 1H), 6.86 - 6.78 (m, 1H), 4.33 (dd, J = 11.0, 3.3 Hz, 1H), 4.05 (dd, J = 11.0, 5.5 Hz, 1H), 3.46 - 3.32 (m, 1H), 2.95 - 2.88 (m, 1H), 2.80 (dd, J = 5.2, 2.7 Hz, 1H), 2.67 (s, 3H), 2.55 (s, 3H), 2.48 (s, 3H).

[0234] Step 2: Preparation of compound 35

[0235] Preparation method same as Example 32 Step 4, replace compound 32-3 with compound 35-3 (250 mg, 0.75 mmol). Purification by silica gel column chromatography (dichloromethane:methanol = 30: 1, v / v) to give 132 mg of white solid, yield 38.57%. 1H NMR (300 MHz, Methanol-d4) d (ppm) 7.67 (s, 1 H), 7.44 (d, J = 7.9 Hz, 2 H), 7.22 (d, J = 8.3 Hz, 2 H), 6.85 (d, J = 1.5 Hz, 2 H), 4.09 - 4.03 (m, 3 H), 3.59 (s, 6 H), 3.04 - 2.94 (m, 1 H), 2.92 - 2.80 (m, 1 H), 2.65 (s, 3 H), 2.52 (s, 3 H), 2.48 (s, 3 H).

[0236] Example 36 N-ethyl-5-[2-hydroxy-3-(trishydroxymethylmethylamino)- propoxy]-2-methyl-1 -(methylphenyl)indole-3-carboxamide (36)

[0237]

[0238] Step 1 : Preparation of compound 36-3

[0239] Compound 26-2 (1 g, 2.69 mmol) was dissolved in methanol (15 mL), 10% palladium carbon (100 mg) was added, and the reaction was stirred under hydrogen at 25 °C for 12 h. The reaction was diluted with methanol, filtered through celite, and the filtrate was evaporated to dryness. Purification was performed by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1, v / v) to give 554 mg of a white solid, in 73.25% yield. 1 H NMR (300 MHz, DMSO-d6) d (ppm) 12.02 (s, 1 H), 8.95 (s, 1 H), 7.47 (d, J = 2.4 Hz, 1 H), 7.42 (d, J = 8.0 Hz, 2 H), 7.31 (d, J = 8.1 Hz, 2 H), 6.75 (d, J = 8.7 Hz, 1 H), 6.59 (dd, J = 8.7, 2.4 Hz, 1 H), 2.47 (s, 3 H), 2.43 (s, 3 H).

[0240] Step 2: Preparation of compound 36-4

[0241] Compound 36-3 (300 mg, 1.07 mmol) was dissolved in N,N-dimethylformamide (5 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (608 mg, 1.60 mmol) and N,N-diisopropylethylamine (280 μL, 1.60 mmol) were added at 0 °C, and the reaction was allowed to proceed at 0 °C for 30 min. Ethylamine hydrochloride (104 mg, 1.28 mmol) was added, and the reaction was allowed to proceed at 25 °C for 8 h. The reaction solution was poured into water, extracted with ethyl acetate (3 x 50 mL), washed with water and saturated sodium chloride solution in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off. Purification by column chromatography on silica gel (petroleum ether: ethyl acetate = 30: 1, v / v) gave 321 mg of a white solid, and the yield was 97.35%. 1 H NMR (300 MHz, DMSO-d6) δ (ppm) 8.90 (s, 1H), 7.60-7.51 (m, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 6.4 Hz, 2H), 7.17 (d, J = 2.3 Hz, 1H), 6.77 (d, J = 8.7 Hz, 1H), 6.59 (dd, J = 8.7, 2.3 Hz, 1H), 3.33-3.23 (m, 2H), 2.42 (s, 3H), 2.36 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H).

[0242] Step 3: Preparation of compound 36-5

[0243] Compound 36-4 (300 mg, 0.98 mmol) was dissolved in acetonitrile (10 mL), and cesium carbonate (479 mg) was added. After stirring at 25 °C for 30 min, epibromohydrin (120 μL, 1.47 mmol) was added, and the reaction was allowed to proceed at 80 °C for 8 h. The reaction solution was diluted with dichloromethane, filtered through celite, and the filtrate was distilled off. Purification by column chromatography on silica gel (petroleum ether: ethyl acetate = 50: 1, v / v) gave 321 mg of a white solid, and the yield was 97.35%. 1H NMR (300 MHz, Chloroform-d) d (ppm) 7.38 - 7.29 (m, 3H), 7.17 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 8.9 Hz, 1H), 6.80 (dd, J = 8.8, 2.4 Hz, 1H), 5.90 (s, 1H), 4.33 (dd, J = 11.2, 3.0 Hz, 1H), 4.01 (dd, J = 11.3, 5.8 Hz, 1H), 3.65 - 3.52 (m, 2H), 3.44 - 3.33 (m, 1H), 2.97 - 2.89 (m, 1H), 2.78 (dd, J = 4.9, 2.7 Hz, 1H), 2.51 (s, 3H), 2.46 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H).

[0244] Step 4: Preparation of compound 36

[0245] Compound 36-5 (200 mg, 0.62 mmol) was dissolved in ethanol (4 mL), and tris(hydroxymethyl)aminomethane (150 mg, 1.24 mmol) was added, and reacted at 78 °C for 8 h. The reaction solution was evaporated to dryness, and purified by silica gel column chromatography (dichloromethane:methanol = 30:1, v / v) to obtain 121 mg of a white solid, with a yield of 40.21%. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 7.38 - 7.29 (m, 3H), 7.17 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 8.9 Hz, 1H), 6.80 (dd, J = 8.8, 2.4 Hz, 1H), 5.90 (s, 1H), 4.33 (dd, J = 11.2, 3.0 Hz, 1H), 4.01 (dd, J = 11.3, 5.8 Hz, 1H), 3.65 - 3.52 (m, 2H), 3.44 - 3.33 (m, 1H), 2.97 - 2.89 (m, 1H), 2.78 (dd, J = 4.9, 2.7 Hz, 1H), 2.51 (s, 3H), 2.46 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H).

[0246] Example 3 75-[2-Hydroxy-3-(trishydroxymethylmethylamino)-propoxy]-N-ethyl-2,N- dimethyl-1-(methylphenyl)indole-3-carboxamide (37)

[0247]

[0248] Step 1: Preparation of compound 37-4

[0249] The preparation method is the same as that of Example 36 step 2, and ethylamine hydrochloride is replaced by N-methylethylamine hydrochloride (123 mg, 1.28 mmol). Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1, v / v) to obtain 150 mg of white solid, with a yield of 43.51%. 1 H NMR (300 MHz, DMSO-d6) δ (ppm) 8.89 (s, 1H), 7.39 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 6.82 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 2.3 Hz, 1H), 6.58 (dd, J = 8.7, 2.3 Hz, 1H), 3.46 (q, J = 7.1 Hz, 2H), 2.98 (s, 3H), 2.41 (s, 3H), 2.19 (s, 3H), 1.12 (s, 3H).

[0250] Step 2: Preparation of compound 37-5

[0251] The preparation method is the same as that of Example 36 step 3, and compound 36-4 is replaced by compound 37-4 (140 mg, 0.44 mmol). Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to obtain 132 mg of white solid, with a yield of 79.32%.

[0252] Step 3: Preparation of compound 37

[0253] The preparation method is the same as that of Example 36 step 4, and compound 36-5 is replaced by compound 37-5 (104 mg, 0.28 mmol). Purification by silica gel column chromatography (dichloromethane:methanol = 50: 1, v / v) to obtain 67 mg of white solid, with a yield of 47.92%. 1 H NMR (300 MHz, Methanol-d4) δ (ppm) 7.40 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 6.95 (d, J = 2.4 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.80 (dd, J = 8.8, 2.3 Hz, 1H), 4.01 (s, 3H), 3.63-3.50 (m, 8H), 3.13 (s, 3H), 2.97-2.88 (m, 1H), 2.86-2.76 (m, 1H), 2.46 (s, 3H), 2.26 (s, 3H).

[0254] Example 38 {5-[2-hydroxy-3-(trihydroxymethylmethylamino)-propoxy]-2-methyl-1- (methylphenyl)indol-3-yl} (tetrahydropyrrol-1-yl)methanone (38)

[0255]

[0256] Step 1: Preparation of compound 38-4

[0257] Preparation method same as example 36 step 2, replace ethylamine hydrochloride with tetrahydropyrrole (105 μL, 1.28 mmol). Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1, v / v) to get white solid 325 mg, yield 75.98%. 1 H NMR (300 MHz, DMSO-d6) δ (ppm) 8.88 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 6.86-6.76 (m, 2H), 6.58 (dd, J = 8.7, 2.4 Hz, 1H), 3.54-3.38 (m, 4H), 2.41 (s, 3H), 2.22 (s, 3H), 1.92-1.75 (m, 4H).

[0258] Step 2: Preparation of compound 37-5

[0259] Preparation method same as example 36 step 3, replace compound 36-4 with compound 38-4 (300 mg, 0.90 mmol). Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to get white solid 231 mg, yield 65.77%. 1 H NMR (300 MHz, DMSO-d6) δ (ppm) 7.41 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 2.4 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.76 (dd, J = 8.9, 2.4 Hz, 1H), 4.32 (dd, J = 11.3, 2.5 Hz, 1H), 3.82 (dd, J = 11.3, 6.5 Hz, 1H), 3.61-3.39 (m, 5H), 2.84 (t, J = 4.7 Hz, 1H), 2.77-2.70 (m, 1H), 2.42 (s, 3H), 2.24 (s, 3H), 1.94-1.75 (m, 4H).

[0260] Step 3: Preparation of compound 37

[0261] Preparation method same as example 36 step 4, replace compound 36-5 with compound 37-5 (180 mg, 0.46 mmol). Purification by silica gel column chromatography (dichloromethane: methanol = 50: 1, v / v) to get white solid 131 mg, yield 55.70%. 1H NMR (300 MHz, Methanol-d4) d (ppm) 7.41 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 7.00 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 8.9 Hz, 1H), 6.82 (dd, J = 8.9, 2.3 Hz, 1H), 4.11 - 3.96 (m, 3H), 3.74 - 3.63 (m, 2H), 3.60 (s, 6H), 3.57 - 3.44 (m, 2H), 3.05 - 2.95 (m, 1H), 2.89 (dd, J = 11.9, 7.1 Hz, 1H), 2.46 (s, 3H), 2.28 (s, 3H), 2.12 - 1.97 (m, 2H), 1.97 - 1.84 (m, 2H).

[0262] Example 39 5-[2-Hydroxy-3-(trishydroxymethylmethylamino)-propoxy]-2-methyl-1- (methylphenyl)indole-3-carboxamide (39)

[0263]

[0264] Step 1: Preparation of compound 39-3

[0265] Compound 1-2 (1 g, 3.24 mmol) was dissolved in acetonitrile (10 mL), potassium carbonate (896 mg, 6.48 mmol) was added, and the reaction was carried out at 25 °C for 30 min. Benzyl bromide (578 μL, 4.86 mmol) was added, and the reaction was carried out at 80 °C for 10 h. The reaction was quenched by adding water, and the solvent was evaporated. Ethyl acetate was added for dilution, and the solution was washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to obtain 916 mg of a white solid, with a yield of 70.82%. 1 H NMR (300 MHz, DMSO-d6) d (ppm) 7.50 - 7.38 (m, 6H), 7.37 - 7.28 (m, 4H), 6.87 (d, J = 1.5 Hz, 2H), 5.15 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 2.49 (s, 3H), 2.43 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H).

[0266] Step 2: Preparation of compound 39-4

[0267] Compound 39-3 (300 mg, 0.75 mmol) was dissolved in dioxane (5 mL), sodium hydroxide (150 mg, 3.75 mmol) and water (3 mL) were added, and the mixture was reacted at 120 °C for 6 h. 1M HC1 was added at 0 °C to adjust the pH to 4, and the mixture was extracted with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 50: 1, v / v) to obtain 168 mg of a white solid with a yield of 60.35%. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 7.91 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 7.4 Hz, 2H), 7.44-7.27 (m, 5H), 7.22 (d, J = 8.0 Hz, 2H), 6.97-6.84 (m, 2H), 2.63 (s, 3H), 2.48 (s, 3H).

[0268] Step 3: Preparation of compound 39-5

[0269] Compound 39-4 (200 mg, 0.54 mmol) was dissolved in tetrahydrofuran (3 mL), and dichlorosulfoxide (80 μL, 1.08 mmol) was added. The mixture was reacted at 50 °C for 1 h. The above liquid was slowly added dropwise into 37% ammonia water (5 mL) at 0 °C, and the mixture was reacted at 25 °C for 30 min. The reaction solution was filtered and washed with water, and the residue was dried to obtain 163 mg of a brown solid with a yield of 81.54%. 1 H NMR (300 MHz, DMSO-d6) d (ppm) 7.47 (d, J = 6.8 Hz, 3H), 7.45-7.31 (m, 5H), 7.28 (d, J = 8.1 Hz, 2H), 7.10 (br s, 2H), 6.86 (d, J = 8.8 Hz, 1H), 6.81 (dd, J = 8.8, 2.2 Hz, 1H), 5.14 (s, 2H), 2.43 (s, 3H), 2.41 (s, 3H).

[0270] Step 4: Preparation of compound 39-6

[0271] Compound 39-5 (400 mg, 1.08 mmol) was dissolved in methanol (8 mL), and 10% palladium-carbon (40 mg) was added. The mixture was reacted at 25 °C for 8 h under hydrogen gas. The mixture was filtered with celite, and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 20: 1, v / v) to obtain 253 mg of a white solid with a yield of 90.31%. 1H NMR (300 MHz, DMSO-d6) d (ppm) 8.89 (s, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.30-7.21 (m, 3H), 7.00 (s, 2H), 6.76 (d, J = 8.7 Hz, 1H), 6.58 (dd, J = 8.7, 2.3 Hz, 1H), 2.42 (s, 3H), 2.38 (s, 3H).

[0272] Step 5: Preparation of compound 39-7

[0273] Compound 39-6 (160 mg, 0.57 mmol) was dissolved in acetonitrile (4 mL), cesium carbonate (280 mg, 0.86 mmol) was added, and the reaction was stirred at 25 °C for 30 min. Epibromohydrin (70 μL, 0.86 mmol) was added, and the reaction was stirred at 80 °C for 8 h. The reaction was diluted with ethyl acetate, filtered through celite, and the filtrate was evaporated to dryness. Purification was performed by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1, v / v) to give 141 mg of a white solid in 73.59% yield. 1 H NMR (300 MHz, DMSO-d6) d (ppm) 7.42 (d, J = 7.9 Hz, 2H), 7.38 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 8.2 Hz, 2H), 7.10 (br s, 2H), 6.86 (d, J = 8.9 Hz, 1H), 6.76 (dd, J = 8.9, 2.3 Hz, 1H), 4.35 (dd, J = 11.2, 2.7 Hz, 1H), 3.87 (dd, J = 11.3, 6.5 Hz, 1H), 3.39-3.34 (m, 1H), 2.85 (t, J = 4.6 Hz, 1H), 2.73 (dd, J = 5.1, 2.6 Hz, 1H), 2.43 (s, 3H), 2.41 (s, 3H).

[0274] Step 6: Preparation of compound 39

[0275] Compound 39-7 (120 mg, 0.36 mmol) was dissolved in ethanol (3 mL), and tris(hydroxymethyl)aminomethane (88 mg, 0.72 mmol) was added. The reaction was stirred at 78 °C for 8 h. The solvent was evaporated to dryness, and purification was performed by silica gel column chromatography (dichloromethane:methanol = 20: 1, v / v) to give 67 mg of a white solid in 40.70% yield. 1H NMR (300 MHz, Methanol-d4) d (ppm) 7.47-7.39 (m, 3H), 7.22 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.9 Hz, 1H), 6.86-6.80 (m, 1H), 4.13-4.05 (m, 3H), 3.60 (s, 6H), 2.95 (dd, J = 11.5, 2.7 Hz, 1H), 2.90-2.79 (m, 1H), 2.47 (s, 3H), 2.46 (s, 3H).

[0276] Example 40 5-[2-Hydroxy-3-(trishydroxymethylmethylamino)-propoxy]-3-cyano-2- methyl-1-(methylphenyl)indole (40)

[0277]

[0278] Step 1: Preparation of compound 40-6

[0279] Compound 39-5 (200 mg, 0.54 mmol) was dissolved in dry dichloromethane (5 mL), N-(triethylammoniumsulfonyl)carbamic acid methyl ester (386 mg, 1.62 mmol) was added, and the reaction was stirred at 25 °C for 5 h under nitrogen protection. The reaction solution was diluted with dichloromethane, quenched with saturated sodium bicarbonate solution, and separated. The organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1, v / v) to obtain 152 mg of a white solid with a yield of 79.92%. 1 H NMR (300 MHz, DMSO-d6) d (ppm) 7.51-7.32 (m, 9H), 7.20 (d, J = 2.3 Hz, 1H), 6.99 (d, J = 8.9 Hz, 1H), 6.93 (dd, J = 8.9, 2.3 Hz, 1H), 5.18 (s, 2H), 2.43 (s, 3H), 2.38 (s, 3H).

[0280] Step 2: Preparation of compound 40-7

[0281] Compound 40-6 (270 mg, 0.77 mmol) was dissolved in dry dichloromethane (6 mL), and 1M boron tribromide in dichloromethane solution (1.93 mL, 1.93 mmol) was added dropwise at 0 °C. The reaction was stirred at 0 °C for 30 min and at 25 °C for 8 h.

[0282] Methanol was added dropwise at 0 °C to quench the reaction, and the reaction was evaporated to dryness. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1, v / v) to obtain 150 mg of a white solid with a yield of 57.22%. 1H NMR (300 MHz, DMSO-d6) d (ppm) 9.31 (s, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 6.93 - 6.84 (m, 2H), 6.71 (dd, J = 8.8, 2.3 Hz, 1H), 2.43 (s, 3H), 2.36 (s, 3H).

[0283] Step 3: Preparation of compound 40-8

[0284] Preparation method as Example 39 step 5, replace compound 39-6 with compound 40-7 (130 mg, 0.50 mmol). Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1, v / v) to get white solid 124 mg, yield 77.95%. 1 H NMR (300 MHz, Chloroform-d) d (ppm) 7.36 (d, J = 7.9 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 2.3 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 6.86 (dd, J = 8.9, 2.3 Hz, 1H), 4.32 (dd, J = 11.0, 2.9 Hz, 1H), 4.00 (dd, J = 11.0, 5.8 Hz, 1H), 3.46 - 3.34 (m, 1H), 2.99 - 2.90 (m, 1H), 2.80 (dd, J = 5.0, 2.6 Hz, 1H), 2.47 (s, 3H), 2.42 (s, 3H).

[0285] Step 4: Preparation of compound 40

[0286] Preparation method as Example 39 step 6, replace compound 39-7 with compound 40-8 (110 mg, 0.35 mmol). Purification by silica gel column chromatography (dichloromethane:methanol = 20: 1, v / v) to get white solid 68 mg, yield 44.23%. 1 H NMR (300 MHz, Methanol-d4) d (ppm) 7.43 (d, J = 7.9 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 2.3 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 6.88 (dd, J = 8.9, 2.3 Hz, 1H), 4.05 (s, 3H), 3.58 (s, 6H), 2.94 (d, J = 10.1 Hz, 1H), 2.89 - 2.75 (m, 1H), 2.47 (s, 3H), 2.41 (s, 3H).

[0287] Example 41 5-[2-Hydroxy-3-(trihydroxymethylmethylamino)-propoxy]-2-methyl-1- (methylphenyl)indole (41)

[0288]

[0289] Step 1: Preparation of compound 41-1

[0290] A flask was charged with 4-methylaniline (5 g, 46.66 mmol), tert-butyl acetoacetate (10 mL, 60.66 mmol) and zinc oxide (379 mg, 4.66 mmol) and the reaction was stirred at 80 °C for 3 h to give reaction solution 1. Benzene-1,2-dione (4.7 g, 41.99 mmol) was dissolved in toluene (40 mL) and zinc chloride (4.45 g, 32.66 mmol) was added and the reaction was stirred at 50 °C for 1.5 h. Reaction solution 1 was diluted with toluene (10 mL) and then added slowly to the reaction mixture at 50 °C and the reaction was stirred for an additional 3 h. The reaction was diluted with methanol and filtered through celite. The filtrate was evaporated to dryness and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40: 1, v / v) to give 3.5 g of a yellow-brown solid in 22.24% yield. 1 HNMR (300 MHz, DMSO-d6) δ (ppm) 8.98 (br s, 1H), 7.41 (dd, J = 5.4, 2.8 Hz, 3H), 7.29 (d, J = 8.1 Hz, 2H), 6.73 (d, J = 8.7 Hz, 1H), 6.60 (dd, J = 8.7, 2.4 Hz, 1H), 2.44 (s, 3H), 2.43 (s, 3H), 1.59 (s, 9H).

[0291] Step 2: Preparation of compound 41-2

[0292] Compound 41-1 (3 g, 8.90 mmol) was dissolved in dry dichloromethane (30 mL) and triethylamine (1.86 mL, 13.40 mmol) was added at 0 °C. Acetic anhydride (1.69 mL, 17.80 mmol) was added dropwise and the reaction was stirred for 10 min under nitrogen and then the temperature was raised to 25 °C and the reaction was stirred for 8 h. The reaction was diluted with dichloromethane and quenched with saturated sodium bicarbonate solution at 0 °C. The reaction was partitioned between dichloromethane and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to give 2.93 g of a yellow-brown solid in 97.64% yield. 1H NMR (300 MHz, DMSO-d6) d (ppm) 7.71 (d, J = 2.2 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 6.94 (d, J = 8.7 Hz, 1H), 6.88 (dd, J = 8.7, 2.2 Hz, 1H), 2.49 (s, 3H), 2.44 (s, 3H), 2.28 (s, 3H), 1.59 (s, 9H).

[0293] Step 3: Preparation of compound 41-3

[0294] Compound 41-2 (3 g, 8.90 mmol) was dissolved in dry dichloromethane (40 mL), trifluoroacetic acid (10 mL) was added at 0 °C, and the reaction was allowed to proceed at 25 °C for 18 h. The reaction was diluted with dichloromethane, quenched with saturated sodium bicarbonate solution, and separated. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to give 2.31 g of yellow-brown solid, with a yield of 92.91%. 1 H NMR (300 MHz, DMSO-d6) d (ppm) 7.71 (d, J = 2.2 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 6.94 (d, J = 8.7 Hz, 1H), 6.88 (dd, J = 8.7, 2.2 Hz, 1H), 2.49 (s, 3H), 2.44 (s, 3H), 2.28 (s, 3H), 1.59 (s, 9H).

[0295] Step 4: Preparation of compound 41-4

[0296] Compound 41-3 (500 mg, 1.78 mmol) was dissolved in a tetrahydrofuran-methanol mixed solvent (15 mL, 1: 1, v / v), and sodium methoxide (481 mg, 8.90 mmol) was added. The reaction was allowed to proceed at 25 °C for 8 h. The pH of the reaction was adjusted to 6 by adding 1M HCl in ethyl acetate, the solvent was evaporated, and the reaction was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1, v / v) to give 412 mg of yellow-brown solid, with a yield of 97.61%. 1 H NMR (300 MHz, DMSO-d6) d (ppm) 7.71 (d, J = 2.2 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 6.94 (d, J = 8.7 Hz, 1H), 6.88 (dd, J = 8.7, 2.2 Hz, 1H), 2.49 (s, 3H), 2.44 (s, 3H), 2.28 (s, 3H), 1.59 (s, 9H).

[0297] Step 5: Preparation of compound 41-5

[0298] Preparation method was same as Example 39 Step 5, compound 39-6 was replaced by compound 41-4 (160 mg, 0.67 mmol). Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1, v / v) to give 153 mg of white solid, yield 77.90%. 1 H NMR (300 MHz, DMSO-d6) d (ppm) 7.38 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 2.4 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.69 (dd, J = 8.8, 2.5 Hz, 1H), 6.31 (s, 1H), 4.29 (dd, J = 11.3, 2.7 Hz, 1H), 3.81 (dd, J = 11.3, 6.5 Hz, 1H), 3.32-3.29 (m, 1H), 2.88-2.79 (m, 1H), 2.71 (dd, J = 5.1, 2.7 Hz, 1H), 2.41 (s, 3H), 2.23 (s, 3H).

[0299] Step 6: Preparation of compound 41

[0300] Preparation method was same as Example 39 Step 6, compound 39-7 was replaced by compound 41-5 (144 mg, 0.49 mmol). Purification by silica gel column chromatography (dichloromethane:methanol = 20: 1, v / v) to give 79 mg of white solid, yield 38.92%. 1 H NMR (300 MHz, Methanol-d4) d (ppm) 7.31 (d, J = 7.9 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 2.4 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.70 (dd, J = 8.8, 2.4 Hz, 1H), 6.25 (s, 1H), 4.07-3.91 (m, 3H), 3.58 (s, 6H), 2.92 (dd, J = 11.7, 3.2 Hz, 1H), 2.80 (dd, J = 11.9, 7.0 Hz, 1H), 2.41 (s, 3H), 2.20 (s, 3H).

[0301] Example 42 5-[2-Hydroxy-3-(trihydroxymethylmethylamino)-propoxy]-3-bromo-2-methyl-1- (methylphenyl)indole (42)

[0302]

[0303] Step 1: Preparation of compound 42-4

[0304] Compound 41-3 (500 mg, 1.80 mmol) was dissolved in tetrahydrofuran (10 mL), N-bromosuccinimide (385 mg, 2.15 mmol) was added slowly at 0 °C, and the reaction was allowed to proceed for 5 min. Saturated ammonium chloride solution was added, and the mixture was concentrated, diluted with ethyl acetate, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The organic phase was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 100: 1, v / v) to give 523 mg of a white solid, with a yield of 81.38%. 1 H NMR (300 MHz, DMSO-d6) d (ppm) 7.42 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 2.2 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.88 (dd, J = 8.8, 2.3 Hz, 1H), 2.43 (s, 3H), 2.28 (s, 3H), 2.26 (s, 3H).

[0305] Step 2: Preparation of compound 42-5

[0306] The preparation method was the same as that in Example 41, Step 4, except that compound 41-3 was replaced by compound 42-4 (200 mg, 0.58 mmol). Purification by column chromatography on silica gel (petroleum ether: ethyl acetate = 600: 1, v / v) gave 173 mg of a white solid, with a yield of 98.39%. 1 H NMR (300 MHz, DMSO-d6) d (ppm) 7.42 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 2.2 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.88 (dd, J = 8.8, 2.3 Hz, 1H), 2.43 (s, 3H), 2.28 (s, 3H), 2.26 (s, 3H).

[0307] Step 3: Preparation of compound 42-6

[0308] The preparation method was the same as that in Example 39, Step 5, except that compound 39-6 was replaced by compound 42-5 (217 mg, 0.72 mmol). Purification by column chromatography on silica gel (petroleum ether: ethyl acetate = 50: 1, v / v) gave 211 mg of a white solid, with a yield of 83.69%. 1H NMR (300 MHz, DMSO-d6) d (ppm) 7.40 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 6.95 (d, J = 8.9 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 6.80 (dd, J = 8.8, 2.5 Hz, 1H), 4.38 (dd, J = 11.3, 2.5 Hz, 1H), 3.86 (dd, J = 11.3, 6.6 Hz, 1H), 3.39 - 3.33 (m, 1H), 2.85 (dd, J = 5.2, 4.2 Hz, 1H), 2.74 (dd, J = 5.1, 2.7 Hz, 1H), 2.42 (s, 3H), 2.24 (s, 3H).

[0309] Step 4: Preparation of compound 42

[0310] Preparation method was the same as example 39 step 6, compound 39-7 was replaced by compound 42-6 (200 mg, 0.56 mmol). Purified by silica gel column chromatography (dichloromethane:methanol = 50:1, v / v) to get 89 mg of white solid, yield 32.29%. 1 H NMR (300 MHz, Methanol-d4) d (ppm) 7.38 (d, J = 6.1 Hz, 2H), 7.20 (d, J = 7.6 Hz, 2H), 6.96 (s, 1H), 6.90 (d, J = 8.6 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 4.14 - 3.98 (m, 3H), 3.61 (s, 6H), 3.02 (d, J = 11.2 Hz, 1H), 2.95 - 2.84 (m, 1H), 2.45 (s, 3H), 2.23 (s, 3H).

[0311] Example 43 5-[2-Hydroxy-3-(trishydroxymethylmethylamino)-propoxy]-3-furanyl-2-methyl-1- (methylphenyl)indole (43)

[0312]

[0313] Step 1: Preparation of compound 43-5

[0314] Compound 42-4 (440 mg, 1.24 mmol) was dissolved in N,N-dimethylformamide (10 mL), 2-(tributylstannyl)-furan (486 mg, 1.36 mmol), lithium chloride (58 mg, 1.36 mmol) and tetrakis(triphenylphosphine)palladium (140 mg, 0.12 mmol) were added, and the reaction was carried out at 100 °C for 3 h. The reaction solution was added with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1, v / v) to obtain 234 mg of white solid, with a yield of 54.67%. 1 H NMR (300 MHz, DMSO-d6) d (ppm) 7.77 (d, J = 1.9 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.7 Hz, 1H), 6.87 (dd, J = 8.7, 2.3 Hz, 1H), 6.64 (dd, J = 3.3, 1.9 Hz, 1H), 6.59 (d, J = 3.3 Hz, 1H), 2.44 (s, 3H), 2.41 (s, 3H), 2.28 (s, 3H).

[0315] Step 2: Preparation of compound 43-6

[0316] The preparation method was the same as that of Example 41 step 4, and compound 43-5 (200 mg, 0.58 mmol) was used instead of compound 41-3. Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 60: 1, v / v) to obtain 153 mg of white solid, with a yield of 87.02%. 1 H NMR (300 MHz, DMSO-d6) d (ppm) 8.92 (s, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 2.3 Hz, 1H), 6.83 (d, J = 8.7 Hz, 1H), 6.66-6.57 (m, 2H), 6.47 (d, J = 3.3 Hz, 1H), 2.42 (s, 3H), 2.36 (s, 3H).

[0317] Step 3: Preparation of compound 43-7

[0318] The preparation method was the same as that of Example 39 step 5, and compound 43-6 (217 mg, 0.72 mmol) was used instead of compound 39-6. Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1, v / v) to obtain 211 mg of white solid, with a yield of 83.69%. 1H NMR (300 MHz, DMSO-d6) d (ppm) 7.75 (d, J = 1.8 Hz, 1H), 7.42 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 8.1 Hz, 2H), 6.93 (d, J = 8.9 Hz, 1H), 6.80 (dd, J = 8.9, 2.4 Hz, 1H), 6.67 - 6.56 (m, 2H), 4.36 (dd, J = 11.3, 2.6 Hz, 1H), 3.87 (dd, J = 11.2, 6.5 Hz, 1H), 3.39 - 3.33 (m, 1H), 2.85 (t, J = 4.7 Hz, 1H), 2.74 (dd, J = 5.2, 2.7 Hz, 1H), 2.43 (s, 3H), 2.39 (s, 3H).

[0319] Step 4: Preparation of compound 43

[0320] The preparation method is the same as that in Example 39, step 6, and compound 39-7 is replaced by compound 43-7 (200 mg, 0.56 mmol). Purification is performed by silica gel column chromatography (dichloromethane:methanol = 50:1, v / v) to obtain 89 mg of white solid, with a yield of 33.09%. 1 H NMR (300 MHz, Methanol-d4) d (ppm) 7.56 (d, J = 1.9 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.34 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H), 6.87 (d, J = 8.8 Hz, 1H), 6.77 (dd, J = 8.8, 2.4 Hz, 1H), 6.54 (dd, J = 3.3, 1.9 Hz, 1H), 6.44 (d, J = 3.3 Hz, 1H), 4.10 - 3.96 (m, 3H), 3.60 (s, 6H), 3.00 (dd, J = 11.8, 3.1 Hz, 1H), 2.87 (dd, J = 11.9, 7.1 Hz, 1H), 2.43 (s, 3H), 2.34 (s, 3H).

[0321] Biological activity of Example 34

[0322] The inhibitory effect of the compound on the cGAMP agonistic cGAS-STING-TBK1 pathway in THP1-Dual cells was detected by the luciferase method, and the method was as follows:

[0323] (1) 4 x 105THP1-Dual cells (purchased from InvivoGen) in logarithmic growth phase were inoculated into each well of a 96-well plate, and incubated at 37°C in a 5% CO2 incubator for 24 hours. 4Compound was seeded in 96-well plates at 0.1 μg / well, and then gradient dilution (20 μM, 10 μM, 5 μM, 2.5 μM, 1.25 μM, 0.625 μM, 0.3125 μM, 0.15625 μM) of compound was added, and DMSO group was used as blank control.

[0324] (2) Cells were transfected with 10 μg / mL cGAMP and lipofectamine 2000 (Invitrogen) complex

[0325] 24h, the cGAMP group only added cGAMP without compound, as negative control.

[0326] (3) QUANTI-Luc was used to detect luciferase activity. TM 10 μL of cell culture supernatant was taken and added to a 96-well plate, and then 50 μL of QUANTI-Luc reagent was added, and a multifunctional enzyme label was used to read the value (Thermo).

[0327] Relative luciferase activity calculation method: RLU blank control = RLU (DMSO group), RLU negative control = RLU (cGAMP group), RLU represents the original luciferase value.

[0328] Relative luciferase activity = [RLU-RLU (blank control)] / [RLU (negative control)-RLU (blank control)].

[0329] GSK8612 was used as a positive control drug.

[0330] The IC 50 As shown in Table 1:

[0331] Table 1 Compound IC 50

[0332]

[0333] From the above table, it can be seen that the above-mentioned compound of the present application has a good inhibitory effect on the cGAS-STING-TBK1 pathway, which can provide a basis for preparing a drug for treating diseases related to the function of the cGAS-STING-TBK1 pathway, has the prospect of preparing a drug for treating and / or preventing inflammatory diseases and autoimmune diseases, and provides a reliable way for clinical application.

[0334] As described above, although the present application has been shown and described with reference to specific preferred embodiments, it is to be understood that such is by way of illustration and not of limitation. Various changes and modifications can be made therein without departing from the spirit and scope of the present application as defined in the appended claims.

Claims

1. An N-(4-methylphenyl)-indole compound of general formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof: wherein, R 1 selected from hydrogen, R a substituted 3-10 membered cycloheteroalkyl, 0-2 R b substituted 5-12 membered heteroaryl, or -NR c R d ; wherein the number of heteroatoms is 1-3; R 2 selected from C1-C6alkoxycarbonyl, C1-C6alkylcarbonyl, carbamoyl containing 1-2 C1-C6alkyl substituents, carboxyl, halogen, 5-10 membered heteroaryl, hydrogen, 5-10 membered cycloheteroalkylcarbonyl, carbamoyl, or cyano; R 3 selected from hydrogen or Ci-C6alkyl; R a selected from C1-C6alkyl, aryl, or 3-10 membered cycloalkyl; said aryl is unsubstituted or optionally substituted with 1-3 U 1 substituents; R b selected from hydrogen, C1-C6alkoxy; R c , R d are each independently selected from hydrogen, Ci-C6alkyl, C3-C6cycloalkyl, aryl, or benzyl; said alkyl is unsubstituted or optionally substituted with 1-3 U 2 substituents; U 1 selected from hydrogen or haloCi-C6alkyl; U 2 selected from hydrogen, C1-C6alkyl or aryl; said alkyl is unsubstituted or optionally substituted with 1-3 U 3 substituents; U 3 selected from hydrogen or hydroxyl.

2. The compound of claim 1, wherein, R 1 selected from hydrogen, 1-methylpiperazin-4-yl, 1-phenylpiperazin-4-yl, 1-(4- trifluoromethylphenyl)-piperazin-4-yl, 1-cyclohexylpiperazin-4-yl, triazol-1-yl, triazol-2-yl, tetrahydroisoquinolin-2-yl, 7,8-dimethoxytetrahydroisoquinolin-2-yl, t-butylamino, isopropylamino, methylamino, cyclopropylamino, amino, anilino, benzylamino, N-methylbenzylamino, or tris(hydroxymethyl)methylamino.

3. The compound of claim 1, wherein, R 2 is selected from acetyl, methoxycarbonyl, ethoxycarbonyl, n- propyloxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, carboxyl, methylaminocarbonyl, ethylaminocarbonyl, bromo, furan-2-yl, cyano, amido, hydrogen, N-methylethylaminocarbonyl, or tetrahydropyrrol-N- ylcarbonyl.

4. The compound of claim 1, wherein, R 3 is selected from hydrogen or methyl.

5. The compound of claim 1, wherein The pharmaceutically acceptable salt includes acid addition salt of the compound of general formula I with hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, pyruvic acid, citric acid, tartaric acid, lactic acid, maleic acid, benzenesulfonic acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, fumaric acid, salicylic acid or phenylacetic acid; also includes acid salt of the compound of general formula I with inorganic base or organic salt made by basic amine.

6. The compound of claim 1, wherein selected from the group consisting of:

7. A pharmaceutical composition, characterized by, The use of a compound of any one of claims 1-6, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof, and a pharmaceutically acceptable carrier.

8. Use of a compound of any one of claims 1-6 in the preparation of a medicament for preventing and / or treating a disease associated with the function of cGAS-STING-TBK1 pathway.

9. Use of a compound of any one of claims 1-6 in the preparation of a medicament for preventing and / or treating inflammatory diseases and autoimmune diseases.

10. Use according to claim 8, characterized in that, The disease associated with the function of cGAS-STING-TBK1 pathway includes STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutieres syndrome (AGS), COPA syndrome caused by mutations in the alpha subunit of the coatomer protein complex, systemic lupus erythematosus (SLE), familial chilblain lupus (FCL), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease, non-alcoholic steatohepatitis (NASH), alcoholic liver disease, nerve injury, rheumatoid arthritis, renal fibrosis, systemic sclerosis, intervertebral disc degeneration, pulmonary fibrosis, aging, scleroderma, psoriasis, inflammatory bowel disease, autoimmune colitis, irritable bowel syndrome, ulcerative colitis, Crohn's disease, uveitis, mucositis, diabetes, cardiovascular disease or neurodegenerative disease.

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