Aza-fused ring compounds, and pharmaceutical composition and use thereof

Abstract

Disclosed in the present invention are aza-fused ring compounds, and a pharmaceutical composition and the use thereof. The structure of the compounds is shown as formula I. The compounds can effectively inhibit ASM activity, wherein under a micromolar concentration level, the enzyme inhibition rate reaches 100% optimally and the enzyme inhibition IC50 value thereof is lower than 5 nM optimally. The compounds can exert pharmaceutical effects at all of the molecular level, the cell level and the animal level, and exhibit excellent therapeutic effects, and have application prospects in treating ASM-related diseases, e.g. depression, senile dementia, cognitive disorders, stroke, myocardial ischemia, pulmonary fibrosis, chronic obstructive pulmonary diseases, pulmonary injury, pulmonary arterial hypertension, respiratory distress syndrome, cystic fibrosis, fatty liver, liver fibrosis, autoimmune diseases, tumors and diabetes.

Description

Azahexacyclic compounds, their pharmaceutical compositions and applications Technical Field

[0001] This invention relates to a nitrogen-containing heterocyclic compound, pharmaceutical compositions thereof, and applications, and more particularly to a nitrogen-containing heterocyclic compound with acid sphingomyelinase inhibitory activity, pharmaceutical compositions thereof, and applications. Background Technology

[0002] Acid sphingomyelinase (ASM), a member of the phosphodiesterase family, catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorycholine, and is a major source of ceramide (Cer) under pathological conditions. Ceramide, as a lipid second messenger, spontaneously aggregates on the cell membrane to form lipid rafts, thereby regulating physiological processes such as cell proliferation and apoptosis. Studies have found that this signaling pathway induces apoptosis through molecular mechanisms such as regulating autophagy, endoplasmic reticulum stress, and lysosomal membrane permeability, and participates in intracellular and extracellular signal transduction and substance transport, closely related to the occurrence and development of various diseases. Research indicates that diseases involving acid sphingomyelinase include depression, stroke, myocardial ischemia, fatty liver, liver fibrosis, autoimmune diseases, tumors, pulmonary fibrosis, and cystic fibrosis. Inhibiting ASM activity with drugs or knocking out ASM through gene therapy can effectively improve the phenotype of related diseases; ASM inhibitors are an effective strategy for developing treatments for various diseases. Currently, the number of direct ASM inhibitors is limited, and there is an urgent need to develop novel direct ASM inhibitors as candidate drugs for treating related diseases. Summary of the Invention

[0003] Objectives of the invention: The first objective of this invention is to provide a nitrogen-containing heterocyclic compound and its pharmaceutically acceptable salt; the second objective is to provide a pharmaceutical composition containing the compound and its pharmaceutically acceptable salt; and the third objective is to provide a pharmaceutical application of the compound, its pharmaceutically acceptable salt, and the pharmaceutical composition.

[0004] Technical solution: The azahexacyclic compound of the present invention has the structure of Formula I:

[0005] in:

[0006] X is selected from CR4 and N;

[0007] L is selected from 6-10 aryl-O-(CH2) n - Chemical bonds, benzo4-7 membered nitrogen-containing heterocyclic ketone groups, 3-7 membered saturated or unsaturated nitrogen-containing formyl groups;

[0008] R1 is selected from H, halogen, C1-C9 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, 3-7 membered cycloalkyl, 4-7 membered cycloalkyl containing 1-2 N, O, S ring heteroatoms, 4-7 membered cycloalkyl-substituted C1-C4 alkyl containing 1-2 N, O, S ring heteroatoms, phenyl, halophenyl, C1-C4 alkyl-substituted phenyl, C1-C4 alkoxy-substituted phenyl, C1-C4 haloalkyl-substituted phenyl, C1-C4 haloalkoxy-substituted phenyl, amino-substituted C1-C4 alkyl, C1-C4 alkylamino-substituted C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, 4-7 membered heteroaryl containing 1-3 N, O, S ring heteroatoms, wherein the phenyl group has at least one substituent;

[0009] R2 and R3 are selected from at least one H, halogen, C1-C9 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or 3-7 membered cycloalkyl-substituted C1-C4 alkoxy.

[0010] R4 is selected from H, C1-C4 alkyl, and 3-7 membered cycloalkyl;

[0011] n is selected from 1, 2, 3, and 4.

[0012] Preferably, in the structure:

[0013] X is selected from CH;

[0014] L is selected from 6-10 aryl-O-CH2-, chemical bonds, benzo5-6 aziridine ketones, and 5-6 saturated or unsaturated aziridine formyl groups.

[0015] Preferably, in the structure:

[0016] R1 is selected from H, halogen, C1-C9 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, 3-6 membered cycloalkyl, 5-6 membered cycloalkyl containing 1-2 N, O ring heteroatoms, 5-6 membered cycloalkyl-substituted C1-C4 alkyl containing 1-2 N, O ring heteroatoms, 5-6 membered cycloalkyl-substituted C1-C4 alkyl, C1-C4 alkoxy-substituted phenyl, C1-C4 haloalkyl-substituted phenyl, C1-C4 haloalkoxy-substituted phenyl, amino-substituted C1-C4 alkyl, C1-C4 alkylamino-substituted C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, 5-6 membered heteroaryl containing 1-2 N, S ring heteroatoms, wherein the phenyl group has at least 1-2 substituents;

[0017] R2 and R3 are selected from at least one H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or 3-5 membered cycloalkyl-substituted C1-C4 alkoxy.

[0018] Preferably, in the structure:

[0019] L is selected from chemical bonds,

[0020] R1 is selected from CF3-, CHF2-, CH2F-, H,

[0021] Selected from

[0022] The heterocyclic compounds described in this invention are selected from any of the following compounds:

[0023] The compounds designed in this invention retain the characteristic of small ligand molecules binding to ASM, while introducing a larger fragment at the nitrogen atom, improving the compound's membrane permeability and enhancing its drug-like properties. Furthermore, the group on the nitrogen atom can occupy a side chain of the substrate sphingomyelin, which binds to ASM, significantly enhancing enzyme inhibitory activity. Moreover, this invention, for the first time, expands the binding regions of co-crystal small molecule ligands to ASM, laying a theoretical foundation for the development of direct ASM inhibitors.

[0024] The pharmaceutically acceptable salts of the azahexacyclic compounds of the present invention are formed by the compound with a pharmaceutically acceptable acid or base.

[0025] Further preferably, the pharmaceutically acceptable acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, and ferulic acid; the pharmaceutically acceptable base is selected from alkali metal cation bases, alkaline earth metal cation bases, ammonium cation bases, and choline.

[0026] "Pharmaceutically acceptable salt" refers to the salt of the compounds of this invention, prepared by reacting a compound with a specific substituent discovered in this invention and a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogen phosphates, dihydrogen phosphates, sulfuric acid (forming sulfates or bisulfates), hydroiodic acid, phosphorous acid, etc.); and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Acids such as citric acid, tartaric acid, and methanesulfonic acid; organic acid salts also include salts of organic acids such as amino acids (e.g., arginine), glucuronic acid, etc. Certain specific compounds of the present invention contain basic and acidic functional groups, thus allowing them to be converted into any base or acid addition salt. Preferably, the salt is contacted with a base or acid in a conventional manner, and then the parent compound is separated, thereby regenerating the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as different solubilities in polar solvents.

[0027] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both. Non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred.

[0028] The pharmaceutical compositions of the present invention comprise the azahexacyclic compounds of the present invention or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers.

[0029] The pharmaceutically acceptable carrier can be an excipient widely used in the pharmaceutical manufacturing industry. Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition, and may also provide methods to allow the active ingredient to dissolve at a desired rate after administration to a subject, or to promote the effective absorption of the active ingredient after administration to a subject. The pharmaceutical excipient can be an inert filler, or it may provide a function such as stabilizing the overall pH of the composition or preventing the degradation of the active ingredient. The pharmaceutical excipient may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulators, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0030] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0031] The pharmaceutical compositions of this invention can be administered in any form, including by injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical, or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical compositions of this invention can also be controlled-release or sustained-release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, tablets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of parenteral formulations include, but are not limited to, solutions for injection, dry powder formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories; and tablets.

[0032] The azahexacyclic compounds or their pharmaceutically acceptable salts and pharmaceutical compositions described in this invention are used in the preparation of acid sphingomyelinase inhibitor drugs.

[0033] Preferably, the drug is a drug for treating depression, Alzheimer's disease, cognitive impairment, stroke, myocardial ischemia, pulmonary fibrosis, COPD, lung injury, pulmonary hypertension, respiratory distress syndrome, cystic fibrosis, fatty liver, liver fibrosis, autoimmune diseases, tumors, and diabetes.

[0034] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0035] The compound designed in this invention can effectively inhibit ASM activity, with an optimal enzyme inhibition rate of 100% at micromolar concentration levels and an enzyme inhibition IC50 value. 50 The optimal value is below 5 nM; it can exert its efficacy at the molecular, cellular, and animal levels, and has excellent therapeutic effects. It has the potential to treat diseases related to ASM, such as depression, Alzheimer's disease, cognitive impairment, stroke, myocardial ischemia, pulmonary fibrosis, COPD, lung injury, pulmonary hypertension, acute respiratory distress syndrome, cystic fibrosis, fatty liver, liver fibrosis, autoimmune diseases, tumors, and diabetes. Attached Figure Description

[0036] Figure 1 shows the results of the protective effect of the compound on pulmonary edema induced by LPS in early COPD mice;

[0037] Figure 2 shows the results of the inhibitory effect of the compound on the LPS-induced inflammatory response in early lung injury;

[0038] Figure 3 shows the effects of the compound on cardiac hemodynamics in rats with myocardial ischemia. AB: Comparison of the maximum rate of increase (+dp / dtmax) and the maximum rate of decrease (-dp / dtmax) of left ventricular pressure 7 days after modeling and drug administration in the sham-operated group, model group, and I06 treatment group; CE: Comparison of the values ​​of left ventricular diastolic pressure (LVDP), left ventricular mean pressure (LVAP), and left ventricular end-diastolic pressure (LVEDP).

[0039] Figure 4 shows the results of serum lactate dehydrogenase (LDH) activity in rats;

[0040] Figure 5 shows the survival rate of primary rat cardiomyocytes. Detailed Implementation

[0041] The technical solution of the present invention will be further described below with reference to the embodiments.

[0042] Example 1: Synthesis of compounds I01-I31

[0043] Preparation of ethyl 3-bromo-1H-indole-5-carboxylic acid (1a)

[0044] 5.01 g (26.44 mmol) of ethyl indole-5-carboxylate was weighed into a 100 mL round-bottom flask. An appropriate amount of DMF was added to dissolve the flask, and the mixture was stirred in an ice bath (0 °C). Then, 5.65 g (31.73 mmol) of NBS dissolved in DMF was slowly added dropwise using a constant-pressure dropping funnel under ice bath conditions. The system color deepened, and the reaction continued under ice bath conditions. After 1 h of reaction, TLC monitoring showed the reaction was complete. The reaction was stopped, quenched with water, extracted with ethyl acetate, washed with saturated brine, and then the two aqueous phases were combined and extracted with ethyl acetate. The organic phases were combined, concentrated, and dried in a vacuum drying oven to obtain 5.60 g of a pink powdery solid, with a yield of 79%. 1 H NMR (300MHz, DMSO-d6) δ11.88(s,1H),8.11–8.06(m,1H),7.81(dd,J=8.6,1.7Hz,1H),7.72(d,J=2.6Hz,1H ),7.53(dd,J=8.6,0.7Hz,1H),4.33(q,J=7.1Hz,2H),1.35(t,J=7.1Hz,3H)ppm; ESI-MS(m / z):268.0[M+H] + .

[0045] Preparation of ethyl 3-bromo-1-cyclopropyl-1H-indole-5-carboxylic acid (1b)

[0046] 1.2 g (4.5 mmol) of intermediate 1a and 4.4 g (13.5 mmol) of cesium carbonate were weighed into a 50 mL double-necked flask, dissolved in an appropriate amount of DMF, and then 0.91 g (8.4 mmol) of bromomethylcyclopropane was added. The mixture was then heated to 65 °C overnight under N2 protection. The reaction was monitored by TLC the next day until complete, and the reaction was stopped. The mixture was neutralized with 10% HCl solution until no more bubbles were produced. The product was extracted with ethyl acetate, washed with saturated brine, and then the two aqueous phases were combined and extracted with ethyl acetate. The organic phases were combined, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 16:1). The product was dried in a vacuum drying oven to give 1.43 g of white lumpy solid, with a yield of 98%. 1 H NMR (300MHz, DMSO-d6) δ8.08(dd,J=1.6,0.6Hz,1H),7.85–7.80(m,2H),7.68(dd,J=8.8,0.7Hz,1H),4.33(q,J=7 .1Hz,2H),4.08(d,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H),1.29–1.15(m,1H),0.63–0.45(m,2H),0.44–0.33(m,2H).

[0047] Preparation of ethyl 3-(4-hydroxyphenyl)-1-cyclopropylmethyl-1H-indole-5-carboxylic acid (1c)

[0048] Weigh 1.3 g (4.05 mmol) of intermediate 1b, 1.11 g (8.1 mmol) of potassium carbonate, 1.11 g (8.1 mmol) of 4-hydroxyphenylboronic acid, and 360 mg (0.32 mmol) of Pd(pph3)4 into a 25 mL double-necked flask. Dissolve the powder in a suitable amount of dioxane, protect with N2, and react at 90 °C. After 8 h of reaction, monitor the reaction by TLC until complete. Stop the reaction, concentrate the product, redissolve it in ethyl acetate, filter with diatomaceous earth, wash the filtrate with saturated brine, dry it with anhydrous sodium sulfate, concentrate it, and purify it by column chromatography (petroleum ether:ethyl acetate = 8:1). Dry the product in a vacuum oven to obtain 950 mg of white powdery solid, with a yield of 70%. 1 H NMR (300MHz, DMSO-d6) δ9.45 (s, 1H), 8.43 (d, J = 1.4Hz, 1H), 7.80 (dd, J = 8.7 ,1.6Hz,1H),7.71(s,1H),7.68–7.60(m,1H),7.45(d,J=8.5Hz,2H),6.90(d ,J=8.5Hz,2H),4.32(q,J=7.1Hz,2H),4.09(d,J=7.0Hz,2H),1.33(t,J=7.1 Hz,3H),1.28–1.06(m,1H),0.59–0.46(m,2H),0.42(qd,J=4.9,2.0Hz,2H).

[0049] Preparation of ethyl 3-(4-((4-chlorophenyl)oxy)phenyl)-1-(cyclopropylmethyl)-1H-indole-5-carboxylate (1d)

[0050] 350 mg (1.045 mmol) of intermediate 1c and 1.1 g (3.135 mmol) of cesium carbonate were weighed into a 25 mL double-necked flask, dissolved in an appropriate amount of DMF, and then 322 mg (1.57 mmol) of 4-chlorobenzyl bromide was added. The mixture was then heated to 65 °C overnight under N2 protection. The reaction was monitored by TLC the next day until complete, and the reaction was stopped. The mixture was neutralized with 10% HCl solution until no more bubbles were produced. The product was extracted with ethyl acetate, washed with saturated brine, and then the two aqueous phases were combined and extracted with ethyl acetate. The organic phases were combined, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 20:1). The product was dried in a vacuum drying oven to give 352 mg of a white flocculent solid, with a yield of 75%. 1H NMR (300MHz, DMSO-d6) δ8.54–8.37(m,1H),7.81(d,J=7.0Hz,2H),7.67(d,J =8.8Hz,1H),7.62–7.42(m,6H),7.36(dd,J=8.5,6.3Hz,3H),7.22–7.08(m,2 H),5.35–5.24(m,1H),5.16(s,2H),4.48(d,J=5.8Hz,2H),4.32(q,J=7.1Hz, 2H), 4.11 (d, J=7.1Hz, 2H), 1.32 (dq, J=10.7, 5.3Hz, 4H), 0.59–0.36 (m, 4H).

[0051] Preparation of 3-(4-((4-chlorophenyl)oxy)phenyl)-1-(cyclopropylmethyl)-N-hydroxy-1H-indole-5-carboxamide (I01)

[0052] Weigh 2.36 g (34.0 mmol) of hydroxylamine hydrochloride into a 100 mL double-necked flask, add 12 mL of methanol, and reflux under N2 protection at 75 °C. Weigh 2.86 g (51.0 mmol) of potassium hydroxide into a 100 mL conical flask, add 7 mL of methanol, stir to dissolve, and add this solution to the double-necked flask containing hydroxylamine hydrochloride. Stir for 2 h, stop the reaction, and filter to obtain a 1.76 mol / L pale yellow clear potassium hydroxylamine solution.

[0053] 352 mg (0.78 mmol) of intermediate 1d was weighed into a round-bottom flask, 10 mL of methanol was added, and the mixture was stirred. 4 mL (7.8 mmol) of potassium hydroxylamine solution was added, and the mixture was reacted under N2 protection at room temperature for 12 h. The reaction was monitored by TLC until complete. The reaction was stopped, and 10% HCl solution was added. A large amount of solid precipitated in the flask. The solid was filtered, and the filter cake was recrystallized in tetrahydrofuran and dried in a vacuum oven to obtain 181 mg of white powder, with a yield of 52%. 1 H NMR (300MHz, DMSO-d6) δ11.18(s,1H),8.89(d,J=1.7Hz,1H),8.26(s,1H),7.76(s,1H),7.67–7.58(m,4H),7.55–7.44(m, 4H),7.11(d,J=8.7Hz,2H),5.17(s,2H),4.09(d,J=7.0Hz,2H),1.31–1.23(m,1H),0.56–0.47(m,2H),0.46–0.39(m,2H).

[0054] Preparation of ethyl 3-(4-((4-difluoromethoxyphenyl)oxy)phenyl)-1-(cyclopropylmethyl)-1H-indole-5-carboxylate (2a)

[0055] The synthesis method of 2a is the same as that of 2d, except that the starting material is changed from 4-chlorobenzyl bromide to 4-difluoromethoxybenzyl bromide, and intermediate 2a is obtained as a white powder with a yield of 78%. 1 H NMR (300MHz, DMSO-d6) δ8.48–8.39(m,1H),7.86–7.77(m,2H),7.67(d,J=8.6Hz,1H),7.62–7.48(m,4H),7.28–7.18(m,3H),7.18–7.11(m ,2H),5.15(s,2H),4.32(q,J=7.1Hz,2H),4.11(d,J=7.0Hz,2H),1.41–1.14(m,4H),0.52(dtd,J=9.3,6.4,3.2Hz,2H),0.47–0.38(m,2H).

[0056] Preparation of 3-(4-((4-difluoromethoxyphenyl)oxy)phenyl)-1-(cyclopropylmethyl)-N-hydroxy-1H-indole-5-carboxamide (I02)

[0057] The synthesis method of I02 is the same as that of I01, and I02 is obtained as a white powder with a yield of 48%. 1 H NMR (300MHz, DMSO-d6) δ11.18(s,1H),8.89(d,J=1.7Hz,1H),8.26(s,1H),7.76(s,1H),7.67–7.58(m,4H),7.55–7.44(m, 4H),7.11(d,J=8.7Hz,2H),5.17(s,2H),4.09(d,J=7.0Hz,2H),1.31–1.23(m,1H),0.56–0.47(m,2H),0.46–0.39(m,2H).

[0058] Preparation of ethyl 3-bromo-1-cyclohexyl-1H-indole-5-carboxylic acid (3a)

[0059] The synthesis method of 3a is the same as that of 1b, except that the starting material is replaced by bromomethylcyclopropane. The intermediate 3a is obtained as a white powder with a yield of 81%. 1H NMR (300MHz, DMSO-d6) δ8.08–8.05(m,1H),7.81(dd,J=8.7,1.7Hz,1H),7.73(s,1H),7.66(dd,J=8.8,1.7Hz,1H),4.32(d,J=7.1Hz,2H),4.05( d,J=7.3Hz,2H),1.77(ddd,J=10.9,7.4,3.5Hz,1H),1.59(d,J=14.5Hz,3H),1.45(d,J=12.5Hz,2H),1.34(t,J=7.1Hz,3H),1.16–0.87(m,5H).

[0060] Preparation of ethyl 3-(4-hydroxyphenyl)-1-cyclohexylmethyl-1H-indole-5-carboxylic acid (3b)

[0061] The synthesis method of 3b is the same as that of 1c, and the intermediate 3b is obtained as a white powder with a yield of 68%. 1 H NMR(300MHz, DMSO-d6)δ9.46(s,1H),8.41(d,J=1.6Hz,1H),7.78(dd,J=8.7,1.6Hz,1H),7.61(d,J=9.2Hz,2H),7.48–7.40(m,2H),6.94–6.84(m, 2H),4.31(q,J=7.1Hz,2H),4.06(d,J=7.1Hz,2H),1.81(d,J=7.1Hz,1H), 1.70–1.44(m,5H),1.32(t,J=7.1Hz,3H),1.05(dd,J=35.2,10.1Hz,5H).

[0062] Preparation of ethyl 3-(4-((4-chlorophenyl)oxy)phenyl)-1-(cyclohexylmethyl)-1H-indole-5-carboxylate (3c)

[0063] The synthesis method of 3c is the same as that of 1d, and the intermediate 3c is obtained as a white powder with a yield of 76%. 1H NMR(300MHz,DMSO-d6)δ8.44(d,J=1.5Hz,1H),7.80(dd,J=8.7,1.6Hz,1H),7.70 (s,1H),7.63(d,J=8.7Hz,1H),7.61–7.52(m,3H),7.56–7.42(m,5H),7.42–7.28 (m,6H),7.18–7.09(m,2H),5.16(s,2H),4.32(q,J=7.1Hz,2H),4.07(d,J=7.1Hz ,2H),1.83(m,1H),1.71–1.44(m,5H),1.32(t,J=7.1Hz,3H),1.21–0.91(m,5H).

[0064] Preparation of 3-(4-((4-chlorophenyl)oxy)phenyl)-1-(cyclohexylmethyl)-N-hydroxy-1H-indole-5-carboxamide (I03)

[0065] The synthesis method of I03 is the same as that of I01, and I03 is obtained as a white powder with a yield of 53%. 1 H NMR (300MHz, DMSO-d6) δ11.17(s,1H),8.90(d,J=1.6Hz,1H),8.26(d,J=1.5Hz,1H),7.69–7.55(m,5H),7.54–7.44 (m,4H),7.15–7.07(m,2H),5.16(s,2H),4.05(d,J=7.1Hz,2H),1.82(m,1H),1.69–1.43(m,5H),1.21–0.89(m,5H).

[0066] Preparation of 3-(4-((4-chlorophenyl)oxy)phenyl)-1-(cyclopentylmethyl)-N-hydroxy-1H-indole-5-carboxamide (I04)

[0067] The synthesis method of I04 is the same as that of I01, except that the raw material is replaced by bromomethylcyclopropane. The final product I4 is a white powder with a yield of 56%. 1H NMR (300MHz, DMSO-d6) δ11.17(s,1H),8.90(d,J=1.7Hz,1H),8.27(d,J=1.4Hz,1H),7.72(s,1H),7.66–7.58(m,4H ),7.53–7.45(m,4H),7.13–7.07(m,2H),5.16(s,2H),4.13(d,J=7.4Hz,2H),1.69–1.42(m,7H),1.30–1.22(m,2H).

[0068] Preparation of 3-(4-((4-chlorophenyl)oxy)phenyl)-1-(2,2,2-trifluoroethyl)-N-hydroxy-1H-indole-5-carboxamide (I05): The synthesis method of I05 is the same as that of I01, except that the starting material is replaced by 1-bromo-2,2,2-trifluoroethane instead of bromomethylcyclopropane. I05 is finally obtained as a white powder with a yield of 61%. 1 H NMR (300MHz, DMSO-d6) δ11.22(s,1H),8.95(s,1H),8.26(s,1H),7.71(d,J=5.8Hz, 3H),7.62(d,J=8.7Hz,2H),7.55–7.44(m,4H),7.14(d,J=8.7Hz,2H),5.18(s,2H).

[0069] Preparation of 3-(4-((4-chlorophenyl)oxy)phenyl)-1-(tetrahydropyranmethyl)-N-hydroxy-1H-indole-5-carboxamide (I06)

[0070] The synthesis method of I06 is the same as that of I01, except that the raw material is replaced by 1-bromomethyltetrahydropyran instead of bromomethylcyclopropane. I06 is finally obtained as a white powder with a yield of 59%. 1 H NMR (300MHz, DMSO-d6) δ11.17(s,1H),8.90(d,J=1.7Hz,1H),8.26(s,1H),7.70(s,1H),7.66–7.59(m,4H),7.55–7.43(m,4H),7.15–7. 07(m,2H),5.16(s,2H),4.12(d,J=7.1Hz,2H),3.81(dd,J=11.0,3.7Hz,2H),3.27–3.12(m,2H),2.16–1.99(m,1H),1.47–1.22(m,4H).

[0071] Preparation of 3-(4-((4-chlorophenyl)oxy)phenyl)-1-(2,2-difluoroethyl)-N-hydroxy-1H-indole-5-carboxamide (I07)

[0072] The synthesis method of I07 is the same as that of I01, except that the raw material is replaced by 1-bromo-2,2-difluoroethane instead of bromomethylcyclopropane. I07 is finally obtained as a white powder with a yield of 48%. 1 H NMR(300 MHz, DMSO-d6)δ11.21(s,1H),8.92(s,1H),8.26(s,1H),7.71–7.59(m,5H),7.56–7 .45(m,4H),7.17–7.09(m,2H),6.64–6.22(m,1H),5.17(s,2H),4.90–4.64(m,2H).

[0073] Preparation of 3-(4-((4-chlorophenyl)oxy)phenyl)-1-(4-chlorophenyl)-N-hydroxy-1H-indole-5-carboxamide (I08)

[0074] The synthesis method of I08 is the same as that of I01, except that the raw material is replaced by bromomethylcyclopropane with 4-chlorobenzyl bromide. I08 is a white powder with a yield of 58%. 1 H NMR (300 MHz, DMSO-d6) δ11.17(s,1H),8.91(s,1H),8.27(s,1H),7.87(s,1H),7.68–7.55(m,4H),7.55–7.44(m,4H),7.38(d,J=8.5 Hz,2H),7.29(d,J=8.5Hz,2H),7.12(d,J=8.7Hz,2H),5.48(s,2H),5.17(s,2H).

[0075] Preparation of 3-(4-((4-chlorophenyl)oxy)phenyl)-1-(4-fluorophenyl)-N-hydroxy-1H-indole-5-carboxamide (I09)

[0076] The synthesis method of I09 is the same as that of I01, except that the raw material is replaced by bromomethylcyclopropane with 4-fluorobenzyl bromide. I09 is a white powder with a yield of 60%. 1 H NMR (300 MHz, DMSO-d6) δ11.18(s,1H),8.93(s,1H),8.27(t,J=1.1 Hz,1H),7.87(s,1H),7.68–7.58(m,4H),7.54–7.44(m,4H),7.34(dd,J=8.6,5.6 Hz,2H),7.20–7.07(m,4H),5.46(s,2H),5.16(s,2H).

[0077] Preparation of ethyl 3-bromo-1-tert-butyl ester-1H-indole-5-carboxylic acid (I10a)

[0078] 1.2 g (4.5 mmol) of intermediate 1a and 1.28 g (5.87 mmol) of di-tert-butyl dicarbonate were weighed into a 50 mL double-necked flask, dissolved in an appropriate amount of dichloromethane, and then 55 mg (0.45 mmol) of 4-dimethylaminopyridine and 596 mg (5.9 mmol) of triethylamine were added sequentially. The reaction was carried out at room temperature for 8 h. The reaction was monitored by TLC until complete. An appropriate amount of water and dichloromethane were added, and the mixture was extracted. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 20:1). 1.38 g of white powder was obtained, with a yield of 84%. 1 H NMR (300 MHz, DMSO-d6) δ8.19 (d, J=8.7 Hz, 1H), 8.08–7.98 (m, 3H), 4.35 (q, J=7.1 Hz, 2H), 1.63 (s, 9H), 1.35 (t, J=7.0 Hz, 3H).

[0079] Preparation of ethyl 3-(4-hydroxyphenyl)-1-tert-butyl ester-1H-indole-5-carboxylic acid (I10b)

[0080] 1.4 g (3.8 mmol) of intermediate I10a, 1.05 g (7.6 mmol) of potassium carbonate, 1.05 g (7.6 mmol) of 4-hydroxyphenylboronic acid, and 450 mg (0.38 mmol) of Pd(pph3)4 were weighed into a 25 mL double-necked flask, dissolved in an appropriate amount of dioxane, and reacted under N2 protection at 90 °C for 8 h. The reaction was monitored by TLC until complete. The reaction solution was filtered with diatomaceous earth, the filtrate was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1). The product was dried in a vacuum drying oven to give 941 mg of white powdery solid, with a yield of 65%. 1 H NMR(300 MHz, DMSO-d6)δ9.66(s,1H),8.32(dd,J=1.7,0.7 Hz,1H),8.26–8.17(m,1H),7.98(dd,J=8.8,1.7 Hz,1H),7.82(s,1H),7.54–7.41(m,2H),6.97–6.86(m,2H),4.33(q,J=7.1 Hz,2H),1.65(s,9H),1.33(t,J=7.1Hz,3H).

[0081] Preparation of 3-(4-((4-chlorophenyl)oxy)phenyl)-1-tert-butyl ester-1H-indole-5-carboxylic acid ethyl ester (I10c)

[0082] 150 mg (0.394 mmol) of intermediate I10b and 257 mg (0.787 mmol) of cesium carbonate were weighed into a 25 mL double-necked flask, dissolved in an appropriate amount of DMF, and then 162 mg (0.787 mmol) of 4-chlorobenzyl bromide was added. The mixture was reacted under N2 protection at 65 °C for 8 h. The reaction was monitored by TLC until complete, at which point the reaction was stopped. An appropriate amount of 10% HCl solution was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated before purification by column chromatography (petroleum ether:ethyl acetate = 10:1). The product was dried in a vacuum drying oven to give 169 mg of a white flocculent solid, with a yield of 85%. 1 H NMR (300MHz, DMSO-d6) δ8.31(d,J=1.7Hz,1H),8.20(d,J=8.8Hz,1H),7.97(dd,J=8.7,1.7Hz,1H),7.86(s,1H),7.65–7. 54(m,2H),7.52–7.40(m,4H),7.19–7.10(m,2H),5.16(s,2H),4.32(q,J=7.1Hz,2H),1.64(s,9H),1.32(t,J=7.1Hz,3H).

[0083] Preparation of ethyl 3-(4-((4-chlorophenyl)oxy)phenyl)-1H-indole-5-carboxylate (I10d)

[0084] Weigh 300 mg (0.59 mmol) of intermediate I10c into a 25 mL double-necked flask, add 10 mL of dichloromethane to dissolve it, stir at 0 °C for 10 minutes, then add 600 mg of trifluoroacetic acid, react at room temperature for 6 h, a white solid precipitates, add saturated sodium bicarbonate solution to adjust the pH to 8-9, filter, and obtain 187 mg of white powder, with a yield of 78%. 1 H NMR (300MHz, DMSO-d6) δ11.67(d,J=2.5Hz,1H),8.45(d,J=1.6Hz,1H),7.78(dd,J=8.6,1.6Hz,1H),7.70(d,J=2.4Hz,1 H),7.62–7.55(m,2H),7.54–7.43(m,5H),7.18–7.08(m,2H),5.16(s,2H),4.31(q,J=7.1Hz,2H),1.33(t,J=7.1Hz,3H).

[0085] Preparation of 3-(4-((4-chlorophenyl)oxy)phenyl)-N-hydroxy-1H-indole-5-carboxamide (I10)

[0086] The synthesis method of I10 is the same as that of I01, and I10 is finally obtained as a white powder with a yield of 57%. 1 H NMR(300MHz,DMSO-d6)δ11.50(d,J=2.6Hz,1H),11.15(s,1H),8.87(s,1H),8. 27(d,J=1.6Hz,1H),7.71–7.56(m,4H),7.54–7.42(m,5H),7.15–7.05(m,2H).

[0087] Preparation of ethyl 3-(4-((4-chlorophenyl)oxy)phenyl)-1-(2-dimethylaminoethyl)-1H-indole-5-carboxylate (I11a)

[0088] The synthesis method of I11a is the same as that of 1b. The starting material is 2-bromo-N,N-dimethylethylamine hydrobromide. The intermediate I11a is obtained as a white powder with a yield of 73%. 1 H NMR (300MHz, DMSO-d6) δ8.44(d,J=1.6Hz,1H),7.81(dd,J=8.7,1.6Hz,1H),7.75(s,1H),7.63(d,J=8.8Hz,1H),7.59– 7.43(m,7H),7.17–7.10(m,2H),5.15(s,2H),4.31(m,4H),2.65(t,J=6.4Hz,2H),2.18(s,6H),1.32(t,J=7.1Hz,3H).

[0089] Preparation of 3-(4-((4-chlorophenyl)oxy)phenyl)-1-(2-dimethylaminoethyl)-N-hydroxy-1H-indole-5-carboxamide (I11)

[0090] The synthesis method of I11 is the same as that of I01, and I11 is finally obtained as a white powder with a yield of 41%. 1H NMR(300MHz,DMSO-d6)δ11.17(s,1H),8.90(s,1H),8.26(d,J=1.5Hz,1H),7.72(s,1H),7.67–7.55(m,4H),7 .55–7.43(m,4H),7.16–7.06(m,2H),5.16(s,2H),4.30(t,J=6.4Hz,2H),2.64(t,J=6.4Hz,2H),2.19(s,6H).

[0091] Preparation of ethyl 3-(4-((4-chlorophenyl)oxy)phenyl)-1-(2-morpholinylethyl)-1H-indole-5-carboxylate (I12a)

[0092] The synthesis method of I12a is the same as that of 1b. The starting material is 4-(2-bromoethyl)morpholine hydrobromide. The intermediate I12a is obtained as a white powder with a yield of 73%. 1 H NMR(300MHz, DMSO-d6)δ8.43(d,J=1.6Hz,1H),7.81(dd,J=8.7,1.6Hz,1H),7.76(s,1H),7.67–7.62(m,1H),7.59–7.51(m,3H),7.51–7 .44(m,3H),7.17–7.10(m,2H),5.15(s,2H),4.33(p,J=6.7Hz,4H),3.53(t,J=4.6Hz,4H),2.70(t,J=6.4Hz,2H),2.44(t,J=4.7Hz,4H).

[0093] Preparation of 3-(4-((4-chlorophenyl)oxy)phenyl)-1-(2-morpholinylethyl)-N-hydroxy-1H-indole-5-carboxamide (I12)

[0094] The synthesis method of I12 is the same as that of I01, and I12 is finally obtained as a white powder with a yield of 37%. 1 H NMR (300MHz, DMSO-d6) δ11.18(s,1H),8.90(s,1H),8.26(d,J=1.5Hz,1H),7.72(s,1H),7.66–7.56(m,4H),7.54–7.44(m ,4H),7.16–7.07(m,2H),5.16(s,2H),4.33(t,J=6.5Hz,2H),3.53(t,J=4.6Hz,5H),2.69(t,J=6.5Hz,2H),2.45(m,4H).

[0095] Preparation of 3-(4-((4-chlorophenyl)oxy)phenyl)-1-(2-propynyl)-N-hydroxy-1H-indole-5-carboxamide (I13)

[0096] The synthesis method of I13 is the same as that of I11, with 3-bromopropyne as the starting material, and I13 is finally obtained as a white powder with a yield of 35%. 1 H NMR (300MHz, DMSO-d6) δ11.20(s,1H),8.92(d,J=1.8Hz,1H),8.27(dd,J=1.5,0.7Hz,1H),7.71(s,1H),7.68(dd, J=8.7,1.6Hz,1H),7.65–7.58(m,3H),7.55–7.45(m,4H),7.16–7.09(m,2H),5.17(s,4H),3.46(t,J=2.4Hz,1H).

[0097] Preparation of 3-(4-((4-chlorophenyl)oxy)phenyl)-1-(pyridin-4-methylene)-N-hydroxy-1H-indole-5-carboxamide (I14)

[0098] The synthesis method of I14 is the same as that of I11, with 4-bromomethylpyridine as the starting material. The final product I14 is a white powder with a yield of 65%. 1 H NMR (300MHz, DMSO-d6) δ11.18(s,1H),8.92(s,1H),8.49(d,J=5.0Hz,2H),8.29(s,1H),7.87( s,1H),7.56(ddd,J=39.5,15.0,8.3Hz,8H),7.14(t,J=6.7Hz,4H),5.55(s,2H),5.17(s,2H).

[0099] Preparation of 3-(4-((4-chlorophenyl)oxy)phenyl)-1-(pyridin-4-methylene)-N-hydroxy-1H-indole-5-carboxamide (I15)

[0100] The synthesis method of I15 is the same as that of I11, with 2-bromomethylthiazole as the starting material, and I14 is finally obtained as a white powder with a yield of 65%. 1H NMR(300MHz,DMSO-d6)δ11.17(s,1H),9.05(d,J=1.9Hz,1H),8.91(s,1H),8.26(s,1H),7.80(s,1H), 7.63(dd,J=7.7,3.6Hz,5H),7.51(t,J=6.8Hz,4H),7.11(d,J=8.2Hz,2H),5.59(s,2H),5.16(s,2H).

[0101] Preparation of 3-(4-((4-trifluoromethyl)oxy)phenyl)-1-methyl-N-hydroxy-1H-indole-5-carboxamide (I16)

[0102] The synthesis method of I16 is the same as that of I01. The raw materials are iodomethane and 4-trifluoromethylbenzyl bromide. I16 is finally obtained as a white powder with a yield of 45%. 1 H NMR (300MHz, DMSO-d6) δ11.19(s,1H),8.90(s,1H),8.27(s,1H),7.80(d,J=8.1Hz,2H),7.72(d,J=8.1Hz,2H) ,7.69–7.64(m,3H),7.62(s,1H),7.54(d,J=8.6Hz,1H),7.14(d,J=8.2Hz,2H),5.30(s,2H),3.85(s,3H)ppm.

[0103] Preparation of 3-(4-((4-fluoro)oxy)phenyl)-1-methyl-N-hydroxy-1H-indole-5-carboxamide (I17)

[0104] The synthesis method of I17 is the same as that of I01. The raw materials are iodomethane and 4-fluorobenzyl bromide. I17 is finally obtained as a white powder with a yield of 48%. 1 H NMR (300MHz, DMSO-d6) δ11.20(s,1H),8.90(s,1H),8.27(d,J=1.4Hz,1H),7.64(t,J=8.4Hz,4H),7.55(t ,J=4.2Hz,2H),7.52(s,1H),7.25(t,J=8.7Hz,2H),7.12(d,J=8.2Hz,2H),5.15(s,2H),3.85(s,3H)ppm.

[0105] Preparation of 3-(4-((3,5-bis(trifluoromethyl)oxy)phenyl)-1-methyl-N-hydroxy-1H-indole-5-carboxamide (I18)

[0106] The synthesis method of I18 is the same as that of I01. The raw materials are iodomethane and 3,5-bis(trifluoromethyl)benzyl bromide. I18 is finally obtained as a white powder with a yield of 48%. 1 H NMR (300MHz, DMSO-d6) δ11.20(s,1H),8.90(s,1H),8.27(d,J=1.4Hz,1H),7.64(t,J=8.4Hz,4H),7.55(t ,J=4.2Hz,2H),7.52(s,1H),7.25(t,J=8.7Hz,2H),7.12(d,J=8.2Hz,2H),5.15(s,2H),3.85(s,3H)ppm.

[0107] Preparation of 3-(4-((2-trifluoromethyl)oxy)phenyl)-1-methyl-N-hydroxy-1H-indole-5-carboxamide (I19)

[0108] The synthesis method of I19 is the same as that of I01. The raw materials are iodomethane and 2-trifluoromethylbenzyl bromide. I19 is finally obtained as a white powder with a yield of 44%. 1 H NMR (300MHz, DMSO-d6) δ11.20(s,1H),8.91(s,1H),8.28(d,J=1.5Hz,1H),7.88–7.79(m,2H),7.75(t,J=7.4Hz,1H),7.67(d,J=5. 4Hz,2H),7.64(d,J=5.4Hz,2H),7.60(d,J=7.4Hz,1H),7.54(d,J=8.6Hz,1H),7.12(d,J=8.3Hz,2H),5.30(s,2H),3.85(s,3H)ppm.

[0109] Preparation of 3-(4-((4-trifluoromethoxy)oxy)phenyl)-1-methyl-N-hydroxy-1H-indole-5-carboxamide (I20)

[0110] The synthesis method of I20 is the same as that of I01. The raw materials are iodomethane and 4-trifluoromethoxybenzyl bromide. I20 is finally obtained as a white powder with a yield of 51%. 1 H NMR (300MHz, DMSO-d6) δ11.19(s,1H),8.89(s,1H),8.27(d,J=1.5Hz,1H),7.66(dt,J=8.6,1.8Hz,4H),7.62(d, J=1.4Hz,2H),7.54(d,J=8.6Hz,1H),7.43(d,J=8.2Hz,2H),7.13(d,J=8.6Hz,2H),5.21(s,2H),3.85(s,3H)ppm.

[0111] Preparation of 3-(4-((4-trifluoromethyl)oxy)phenyl)-1-isobutyl-N-hydroxy-1H-indole-5-carboxamide (I21)

[0112] The synthesis method of I21 is the same as that of I01, with the raw materials being bromoisobutane and 4-trifluoromethylbenzyl bromide, respectively. I21 is finally obtained as a white powder with a yield of 55%. 1 H NMR (300MHz, DMSO-d6) δ11.17(s,1H),8.90(s,1H),8.27(s,1H),7.80(d,J=8.1Hz,2H),7.72(d,J=7.1Hz,3H),7.65(d,J=8.1Hz, 2H),7.62–7.54(m,2H),7.14(d,J=8.3Hz,2H),5.30(s,2H),4.04(d,J=7.2Hz,2H),2.23–2.10(m,1H),0.88(d,J=6.6Hz,6H)ppm.

[0113] Preparation of 3-(4-((4-trifluoromethyl)oxy)phenyl)-1-pentyl-N-hydroxy-1H-indole-5-carboxamide (I22)

[0114] The synthesis method of I22 is the same as that of I01, with bromopentane and 4-trifluoromethylbenzyl bromide as the raw materials. I22 is finally obtained as a white powder with a yield of 77%. 1 H NMR (300MHz, DMSO-d6) δ11.17(s,1H),8.89(d,J=1.7Hz,1H),8.26(s,1H),7.80(d,J=8 .2Hz,2H),7.73(s,2H),7.70(s,1H),7.65(d,J=8.6Hz,2H),7.61(d,J=1.5Hz,1H),7.5 8(d,J=8.7Hz,1H),7.13(d,J=8.6Hz,2H),5.30(s,2H),4.22(t,J=6.9Hz,2H),1.80(p, J=8.3,7.7Hz,2H),1.40–1.27(m,2H),1.25(d,J=6.1Hz,2H),0.84(t,J=6.9Hz,3H)ppm.

[0115] Preparation of 3-(4-((4-trifluoromethyl)oxy)phenyl)-1-decyl-N-hydroxy-1H-indole-5-carboxamide (I23)

[0116] The synthesis method of I23 is the same as that of I01, with bromodecane and 4-trifluoromethylbenzyl bromide as the raw materials. I23 is finally obtained as a white powder with a yield of 90%. 1 H NMR (300MHz, DMSO-d6) δ11.21–11.14(m,1H),8.90(d,J=1.8Hz,1H),8.27(d ,J=1.5Hz,1H),7.80(d,J=8.2Hz,2H),7.73(s,2H),7.71–7.64(m,2H),7.62 (q,J=1.8Hz,2H),7.57(d,J=8.7Hz,1H),7.17–7.09(m,2H),5.30(s,2H),4. 21(t,J=7.0Hz,2H),1.78(s,2H),1.34–1.10(m,14H),0.88–0.78(m,3H)ppm.

[0117] Preparation of 3-(4-((4-trifluoromethyl)oxy)phenyl)-1-benzyl-N-hydroxy-1H-indole-5-carboxamide (I24)

[0118] The synthesis method of I24 is the same as that of I01, with benzyl bromide and 4-trifluoromethylbenzyl bromide as the raw materials. I24 is finally obtained as a white powder with a yield of 56%. 1 H NMR (300MHz, DMSO-d6) δ11.17(s,1H),8.90(s,1H),8.27(s,1H),7.88(s,1H),7.80(d,J=8.1Hz,2H),7.72(d,J=8.1Hz,2 H),7.66(d,J=8.6Hz,2H),7.59(d,J=1.8Hz,2H),7.38–7.22(m,5H),7.14(d,J=8.7Hz,2H),5.49(s,2H),5.30(s,2H)ppm.

[0119] Preparation of 3-(4-((4-trifluoromethyl)oxy)phenyl)-1-(4-methoxy)phenyl-N-hydroxy-1H-indole-5-carboxamide (I25)

[0120] The synthesis method of I25 is the same as that of I01, with 4-methoxybenzyl bromide and 4-trifluoromethylbenzyl bromide as the raw materials. I25 is finally obtained as a white powder with a yield of 47%. 1H NMR (300MHz, DMSO-d6) δ11.14(s,1H),8.87(s,1H),8.26(s,1H),7.84(s,1H),7.79(d,J=8.2Hz,2H),7.72(d,J=8.1Hz,2H),7.65(d,J=8.6Hz ,2H),7.59(d,J=1.1Hz,2H),7.27(d,J=8.5Hz,2H),7.14(d,J=8.7Hz,2H),6.88(d,J=8.6Hz,2H),5.39(s,2H),5.30(s,2H),3.70(s,3H)ppm.

[0121] Preparation of 3-(4-((3,4-dichlorophenyl)oxy)phenyl)-1-(tetrahydropyranmethyl)-N-hydroxy-1H-indole-5-carboxamide (I26)

[0122] The synthesis method of I26 is the same as that of I01, with 1-bromomethyltetrahydropyran and 3,4-dichlorobenzyl bromide as the raw materials. I26 is finally obtained as a white powder with a yield of 52%. 1 H NMR (300MHz, DMSO-d6) δ11.15(s,1H),8.87(s,1H),8.26(s,1H),7.76(d,J=2.0Hz,1H),7.72–7.57(m,6H),7.48(dd,J=8.3,2.0Hz,1H),7. 12(d,J=8.3Hz,2H),5.19(s,2H),4.13(d,J=7.1Hz,2H),3.81(dd,J=10.8,3.9Hz,2H),3.28–3.09(m,2H),2.08(s,1H),1.43–1.24(m,4H).

[0123] Preparation of compound I27

[0124] Preparation of 1-(tert-butyl)-5-ethyl-3-(4-(cyclopropylmethoxy)phenyl)-1H-indole-1,5-carboxylic acid ethyl ester (I27c)

[0125] The synthesis method was the same as that used on day 1, yielding 1.76 g of an orange oily substance. Yield: 77%.

[0126] 1H NMR (400MHz, DMSO) δ8.34(s,1H),8.24(d,J=8.7Hz,1H),8.00(dd,J=8.8,1.7Hz,1H),7.89(s,1H),7.59(d,J=8.7Hz,2H),7 .09(d,J=8.7Hz,2H),4.34(q,J=7.1Hz,2H),3.88(d,J=7.1Hz,2H),1.66(s,9H),1.33(t,J=7.1Hz,3H),0.69–0.20(m,6H).

[0127] Preparation of ethyl 3-(4-(cyclopropylmethoxy)phenyl)-1H-indole-5-carboxylic acid ethyl ester (I27d)

[0128] The synthesis method was the same as for I10d, yielding a white solid. Yield: 89%.

[0129] 1 H NMR (300MHz, DMSO) δ11.66(s,1H),8.44(s,1H),7.77(dd,J=8.6,1.6Hz,1H),7.69(s,1H),7.55(dd,J=7.2,5.2Hz,3H),7.04(d,J=8.7 Hz,2H),4.31(q,J=7.1Hz,2H),3.86(d,J=7.0Hz,2H),1.33(t,J=7.1Hz,3H),1.27–1.20(m,1H),0.63–0.54(m,2H),0.38–0.30(m,2H).

[0130] Preparation of ethyl-3-(4-(cyclopropylmethoxy)phenyl)-1-(2,2-difluoroethyl)-1H-indole-5-carboxylic acid ethyl ester (I27e)

[0131] The synthesis method was the same as in 1b, yielding 160 mg of a white solid. Yield: 54%.

[0132] 1H NMR(300MHz,DMSO)δ8.43(d,J=1.4Hz,1H),7.85(dd,J=8.7,1.6Hz,1H),7.72(d, J=8.0Hz,2H),7.56–7.50(m,2H),7.10–7.03(m,2H),6.65–6.23(m,1H),4.79(td, J=15.7,3.3Hz,2H),4.32(q,J=7.1Hz,2H),3.86(d,J=7.0Hz,2H),1.33(t,J=7.1H z,3H),1.25(ddt,J=10.1,8.0,4.0Hz,1H),0.64–0.54(m,2H),0.40–0.30(m,2H).

[0133] Preparation of 3-(4-(cyclopropylmethoxy)phenyl)-1-(2,2-difluoroethyl)-N-hydroxy-1H-indole-5-carboxamide (I27)

[0134] The synthesis method was the same as for I01, yielding 147 mg of a white solid. Yield: 92%.

[0135] 1 H NMR (300MHz, DMSO) δ11.20(s,1H),8.91(s,1H),8.26(s,1H),7.66(d,J=3.8Hz,3H),7.60(d,J=8.4Hz,2H),7.04(d,J=8.2Hz,2H), 6.43(t,J=54.9Hz,1H),4.76(t,J=15.3Hz,2H),3.86(d,J=6.9Hz,2H),1.24(s,1H),0.59(d,J=7.7Hz,2H),0.35(d,J=4.3Hz,2H).

[0136] Preparation of compound I28

[0137] Preparation of ethyl 1-(tert-butyl)-5-ethyl-3-(4-chlorophenyl)-1H-indole-1,5-carboxylic acid (I28b)

[0138] The reaction was the same as in 10b, yielding 1.1346 g of a white solid. Yield: 87%.

[0139] 1H NMR (400MHz, DMSO) δ8.34(dd,J=1.7,0.7Hz,1H),8.25(d,J=8.8Hz,1H),8.04(s,1H),8.01(dd,J=8.8,1.7 Hz,1H),7.75–7.68(m,2H),7.63–7.55(m,2H),4.34(q,J=7.1Hz,2H),1.66(s,9H),1.33(t,J=7.1Hz,3H).

[0140] Preparation of ethyl 3-(4-chlorophenyl)-1H-indole-5-carboxylic acid ethyl ester (I28c)

[0141] The same synthesis as I10d yielded 562 mg of a white solid, with a yield of 66%.

[0142] 1 H NMR (400MHz, DMSO) δ11.85(s,1H),8.52–8.44(m,1H),7.87(s,1H),7.80(dd,J=8.6,1.6Hz,1H ),7.70(d,J=8.3Hz,2H),7.53(d,J=8.5Hz,3H),4.32(q,J=7.1Hz,2H),1.33(t,J=7.1Hz,3H).

[0143] Preparation of ethyl-3-(4-chlorophenyl)-1-(2-(dimethylamino)ethyl)-1H-indole-5-carboxylic acid ethyl ester (I28d)

[0144] The reaction was the same as in 1b, yielding 230 mg of a white solid, with a yield of 73%.

[0145] 1 H NMR (300MHz, DMSO) δ8.45(d,J=1.6Hz,1H),7.91(s,1H),7.82(dd,J=8.7,1.6Hz,1H),7.67(dd,J=8.8,2.4Hz,3 H),7.57–7.50(m,2H),4.32(dt,J=9.6,6.4Hz,4H),2.67(t,J=6.4Hz,2H),2.19(s,6H),1.33(t,J=7.1Hz,3H).

[0146] Preparation of 3-(4-chlorophenyl)-1-(2-(dimethylamino)ethyl)-N-hydroxy-1H-indole-5-carboxamide (I28)

[0147] The same synthesis method as I01 yielded a white solid. The yield was 48%.

[0148] 1 H NMR (400MHz, DMSO) δ11.23(s,1H),8.93(s,1H),8.30(d,J=1.5Hz,1H),7.89(s,1H),7.77–7.72(m,2 H),7.69–7.61(m,2H),7.54–7.49(m,2H),4.34(t,J=6.4Hz,2H),2.70(t,J=6.5Hz,2H),2.22(s,6H).

[0149] Preparation of compound I29

[0150] Preparation of ethyl-3-(4-chlorophenyl)-1-(2,2-difluoroethyl)-1H-indole-5-carboxylic acid ethyl ester (I29d)

[0151] The reaction was the same as in 1b, yielding 138 mg of a pale yellow solid, with a yield of 43%.

[0152] Preparation of 3-(4-chlorophenyl)-1-(2,2-difluoroethyl)-N-hydroxy-1H-indole-5-carboxamide (I29)

[0153] The synthesis method was the same as I01, yielding 106 mg of a white solid, with a yield of 47%.

[0154] 1 H NMR(300MHz,DMSO)δ11.22(s,1H),8.94(d,J=1.5Hz,1H),8.29(s,1H),7.84(s,1H),7.7 6–7.68(m,4H),7.54(d,J=8.6Hz,2H),6.64–6.23(m,1H),4.79(td,J=15.8,3.4Hz,2H).

[0155] Preparation of compound I30

[0156] Preparation of ethyl 3-(4-(cyclopropylmethoxy)phenyl)-1-(2-fluoroethyl)-1H-indole-5-carboxylic acid (I30e)

[0157] The synthesis procedure was the same as in 1b, yielding 580 mg of a white solid. Yield: 62%.

[0158] 1H NMR (300MHz, DMSO) δ8.44(d,J=1.7Hz,1H),7.82(dd,J=8.7,1.6Hz,1H),7.73(s,1H),7.67( d,J=8.7Hz,1H),7.57–7.51(m,2H),7.09–7.03(m,2H),4.85(t,J=4.6Hz,1H),4.74(t,J=4.6 Hz,1H),4.63(t,J=4.7Hz,1H),4.56(t,J=4.7Hz,1H),4.32(q,J=7.1Hz,2H),3.86(d,J=6.9 Hz,2H),1.33(t,J=7.1Hz,3H),1.17(t,J=7.1Hz,1H),0.62–0.56(m,2H),0.37–0.32(m,2H).

[0159] Preparation of 3-(4-(cyclopropylmethoxy)phenyl)-1-(2-fluoroethyl)-N-hydroxy-1H-indole-5-carboxamide (I30)

[0160] The synthesis procedure was the same as in I01, yielding a pale pink solid. Yield: 51%.

[0161] 1 H NMR (300MHz, DMSO) δ11.20(s,1H),8.91(s,1H),8.26(s,1H),7.66(d,J=3.8Hz,3H),7.60(d,J=8.4Hz,2H),7.04(d,J=8.2Hz,2H) ,4.36(t,J=6.8Hz,2H),4.05(t,J=7.5Hz,2H),3.86(d,J=6.9Hz,2H),1.24(s,1H),0.59(d,J=7.7Hz,2H),0.35(d,J=4.3Hz,2H).

[0162] Preparation of compound I31

[0163] Preparation of ethyl 3-(4-(cyclopropylmethoxy)phenyl)-1-(2-(dimethylamino)ethyl)-1H-indole-5-carboxylic acid (I31e)

[0164] The synthesis steps were the same as in 1b, yielding a yellow oily substance. Yield: 89%.

[0165] 1H NMR (400MHz, DMSO) δ8.43(d,J=1.6Hz,1H),7.80(dd,J=8.7,1.6Hz,1H),7.74( s,1H),7.64(d,J=8.7Hz,1H),7.56–7.51(m,2H),7.08–7.02(m,2H),4.33(dd,J =7.9,6.3Hz,4H),3.86(d,J=7.0Hz,2H),2.67(t,J=6.4Hz,2H),2.19(s,6H),1 .33(t,J=7.1Hz,3H),1.27–1.22(m,1H),0.61–0.56(m,2H),0.36–0.32(m,2H).

[0166] Preparation of 3-(4-(cyclopropylmethoxy)phenyl)-1-(2-(dimethylamino)ethyl)-N-hydroxy-1H-indole-5-carboxamide (I31)

[0167] The synthesis procedure was the same as in I01, yielding a pale reddish-brown solid. The yield was 42%.

[0168] 1 H NMR (400MHz, DMSO) δ11.23(s,1H),8.93(s,1H),8.30(d,J=1.5Hz,1H),7.89(s,1H),7.77–7.72(m,2H),7.69–7.61(m,2H),7.54–7.49(m,2H) ,4.34(t,J=6.4Hz,2H),3.86(d,J=6.9Hz,2H),2.70(t,J=6.5Hz,2H),2.22(s,6H).1.24(s,1H),0.59(d,J=7.7Hz,2H),0.35(d,J=4.3Hz,2H).

[0169] Example 2: Synthesis of compounds II01-II03

[0170] Preparation of 5-bromo-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (II1a)

[0171] Isoindoline-1-one (758 mg, 3.61 mmol) was dissolved in 10 mL of dichloromethane, and (Boc)₂O anhydride (1.57 g, 7.22 mmol), Et₃N (730 mg, 7.22 mmol), and DMAP (87.8 mg, 0.72 mmol) were added sequentially. The reaction was carried out at room temperature for 6 h. The reaction was monitored by TLC until complete. The reaction was quenched with 20 mL of water and extracted with ethyl acetate (2 × 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography was performed to obtain 1.01 g of pale yellow powder, with a yield of 90%. 1 H NMR (300MHz, DMSO-d6) δ7.92 (dd, J=1.7, 0.8Hz, 1H), 7.76–7.66 (m, 2H), 4.77 (s, 2H), 1.51 (s, 9H).

[0172] Preparation of N-Boc-isoindoline-5-boronic acid pinacol ester (II1b)

[0173] 5-Bromo-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (2.0 g, 6.42 mmol) was placed in a 50 mL double-necked flask, and then pinacol diboronate (3.2 g, 12.84 mmol) and potassium acetate (1.8 g, 19.28 mmol) were added sequentially. The mixture was then evacuated under N2 protection, and 20 mL of dioxane was injected. The reaction was carried out at 95 °C for 8 h. The reaction was monitored by TLC until complete. The reaction was quenched with 20 mL of water and extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography was performed to obtain N-Boc-isoindoline-5-boronate pinacol ester in 65% yield. 1 H NMR (300MHz, DMSO-d6) δ7.91 (s, 1H), 7.77 (q, J = 7.7Hz, 2H), 4.79 (s, 2H), 1.52 (s, 9H), 1.32 (s, 12H).

[0174] Preparation of ethyl 3-(2-(tert-butyl ester)-1-oxoisoindoline)-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-6-carboxylic acid (II1c)

[0175] N-Boc-isoindoline-5-boronic acid pinacol ester (1.5 g, 4.12 mmol) was placed in a 50 mL double-necked flask, and ethyl 3-bromo-1-(tetrahydro-2H-pyran-4-yl)methyl-1H-indole-5-carboxylic acid (1.0 g, 2.74 mmol), potassium carbonate (0.75 g, 5.48 mmol), and Pd(pph3)4 (0.32 g, 0.274 mmol) were added sequentially. Under nitrogen protection and vacuum, 20 mL of dioxane was injected, and the reaction was carried out at 95 °C for 8 h. The reaction was monitored by TLC until complete. 20 mL of water was added to the reaction mixture, and the mixture was filtered through diatomaceous earth. The filtrate was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 8:1). The product was dried in a vacuum drying oven to obtain a white powder with a yield of 71%. 1 H NMR (300MHz, DMSO-d6) δ8.61–8.48(m,2H),7.97(s,1H),7.85–7.80(m,2H),7.75–7.70(m,3H),4.46(s,2H),4.33(q,J=7.1Hz,2H),4. 19(d,J=7.1Hz,2H),3.82(dd,J=11.7,3.8Hz,2H),3.21(td,J=11.4,2.6Hz,2H),2.20–2.01(m,1H),1.52–1.10(m,7H),1.32(s,12H).

[0176] Preparation of ethyl 3-(1-oxoisoindoline)-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-6-carboxylic acid (II1d)

[0177] Ethyl 3-(2-(tert-butyl ester)-1-oxoisoindoline)-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-6-carboxylic acid (2.0 g, 3.86 mmol) was dissolved in 15 mL of dichloromethane. At 0 °C, 4.0 g of trifluoroacetic acid was added dropwise, and the mixture was stirred at room temperature for 6 h. A white powder precipitated out. The pH was adjusted to 8-9 by adding saturated sodium bicarbonate solution. The mixture was filtered and dried to obtain 1.32 g of white solid, with a yield of 82%. 1HNMR(300MHz,DMSO-d6)δ8.60–8.50(m,2H),7.99(s,1H),7.89–7.81(m,2H),7.79–7.71(m,3H),4.46(s,2H),4.33(q,J=7.1Hz ,2H),4.19(d,J=7.1Hz,2H),3.82(dd,J=11.7,3.8Hz,2H),3.21(td,J=11.4,2.6Hz,2H),2.22–2.01(m,1H),1.54–1.12(m,7H).

[0178] Preparation of ethyl 3-(2-(4-chlorophenyl)-1-oxoisoindoline)-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-6-carboxylic acid (II1e)

[0179] Ethyl 3-(1-oxoisoindoline)-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-6-carboxylic acid (600 mg, 1.48 mmol) was placed in a 25 mL double-necked flask, and cesium carbonate (1.40 g, 4.5 mmol), N,N′-dimethylethane-1,2-diamine (65 mg, 0.74 mmol), cuprous iodide (140 mg, 0.74 mmol), and 4-chlorobromobenzene (576 mg, 3.0 mmol) were added sequentially. The mixture was placed under nitrogen protection, evacuated, and 15 mL of dioxane was injected. The reaction was carried out at 120 °C for 16 h. The reaction was monitored by TLC until complete. The reaction was quenched with 20 mL of water, extracted with ethyl acetate (2 × 30 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 531 mg of white powder (68% yield). 1 H NMR(300MHz,DMSO-d6)δ8.58(d,J=1.6Hz,1H),8.09(d,J=19.4Hz,1H),8.02 –7.94(m,2H),7.94–7.81(m,4H),7.76(d,J=8.7Hz,1H),7.51(dd,J=9.1,2. 3Hz,2H),5.09(s,2H),4.34(q,J=7.1Hz,2H),4.20(d,J=7.1Hz,2H),3.82(d ,J=11.6Hz,2H),3.28–3.15(m,2H),2.12(s,1H),1.36(q,J=7.5,7.1Hz,7H).

[0180] Preparation of 3-(2-(4-chlorophenyl)-1-oxoisoindoline)-N-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-6-carboxamide (II01)

[0181] The synthesis method of II01 is the same as that of I01, and II01 is finally obtained as a white powder with a yield of 63%. 1 H NMR (300MHz, DMSO-d6) δ11.26(s,1H),8.98(s,1H),8.40(s,1H),8.06–7.84(m,6H),7.77–7.64(m,2H),7.52(d,J=8.6Hz,2H),5. 76(s,1H),5.11(s,2H),4.19(d,J=7.0Hz,2H),3.83(dd,J=10.7,3.8Hz,2H),3.29–3.13(m,2H),2.12(s,1H),1.46–1.30(m,4H).

[0182] Preparation of 3-(2-(4-methoxyphenyl)-1-oxoisoindoline)-N-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-6-carboxamide (IIO2)

[0183] The synthesis method of II02 is the same as that of I01, except that the raw material is replaced with 4-methoxybromobenzene. The final product II02 is a white powder with a yield of 68%. 1 H NMR (400MHz, DMSO-d6) δ11.25(s,1H),8.97(s,1H),8.40(s,1H),8.17–7.61(m,8H),7.03(d,J=8.3Hz,2H),5.06 (s,2H),4.18(d,J=6.9Hz,2H),3.80(d,J=13.4Hz,5H),3.22(t,J=11.5Hz,2H),2.12(s,1H),1.54–1.19(m,4H).

[0184] Preparation of 3-(2-(4-difluoromethylphenyl)-1-oxoisoindoline)-N-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-6-carboxamide (IIO3)

[0185] The synthesis method of II03 is the same as that of I01, except that the raw material is replaced with 4-difluoromethylbromobenzene. The final product II03 is a white powder with a yield of 55%. 1H NMR(300MHz, DMSO-d6)δ11.25(s,1H),8.98(s,1H),8.41(s,1H),8.07(dd,J=21.0,9.0Hz,4H),7.96–7.84(m,2H),7.74–7.64(m,4H),7 .05(t,J=56.1Hz,1H),5.15(s,2H),4.19(d,J=7.1Hz,2H),3.83(d,J=11.5Hz,2H),3.29–3.15(m,2H),2.12(s,1H),1.43–1.23(m,4H).

[0186] Example 3: Synthesis of compounds III01-III03

[0187] Preparation of ethyl 3-(1-(tert-butyl ester)-1,2,3,6-tetrahydropyridine)-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-6-carboxylic acid (III1a)

[0188] N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (340 mg, 1.10 mmol) was placed in a 25 mL double-necked flask, and ethyl 3-bromo-1-(tetrahydro-2H-pyran-4-yl)methyl-1H-indole-5-carboxylic acid (200 mg, 0.55 mmol), sodium carbonate (58 mg, 0.55 mmol), and Pd(dppf)Cl2 (73.2 mg, 0.11 mmol) were added sequentially. Under N2 protection and vacuum, 10 mL of DMF was injected, and the reaction was carried out at 95 °C for 8 h. The reaction was monitored by TLC until complete. 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain 150 mg of a pale yellow powder, with a yield of 58%. 1 H NMR(300MHz,DMSO-d6)δ8.46(d,J=1.6Hz,1H),7.83–7.74(m,1H),7.65(m 2H),6.11(d,J=16.3Hz,1H),4.32(q,J=7.1Hz,2H),4.09(d,J=8.6Hz,3H),3.80 (d,J=11.4Hz,2H),3.56(m,1H),3.19(m,2H),2.04(s,1H),1.49–1.24(m,16H).

[0189] Preparation of ethyl 3-(1,2,3,6-tetrahydropyridine)-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-6-carboxylic acid (III1b)

[0190] Ethyl 3-(1-(tert-butyl ester)-1,2,3,6-tetrahydropyridine)-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-6-carboxylic acid (500 mg, 1.07 mmol) was dissolved in 15 mL of dichloromethane. 1.0 g of trifluoroacetic acid was added dropwise at 0 °C, and the reaction was carried out at room temperature for 6 h. The reaction was monitored by TLC until complete. 10 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane:methanol = 100:1) to obtain 196 mg of a pale yellow powder, with a yield of 50%. 1 H NMR(300MHz,DMSO-d6)δ8.46(d,J=1.5Hz,1H),7.78(dd,J=8.7,1.6Hz,1H),7.63( d,J=8.7Hz,1H),7.56(s,1H),6.17(d,J=3.5Hz,1H),4.31(q,J=7.1Hz,2H),4.08( d,J=7.2Hz,2H),3.80(dd,J=11.0,3.6Hz,2H),3.52–3.47(m,2H),3.18(td,J=11. 2,3.0Hz,2H),3.02(t,J=5.7Hz,2H),2.42(m,2H),2.13–1.94(m,1H),1.31(m,7H).

[0191] Preparation of ethyl 3-(1-(4-chlorobenzoyl)-1,2,3,6-tetrahydropyridine)-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-6-carboxylic acid (III1c)

[0192] Ethyl 3-(1,2,3,6-tetrahydropyridine)-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-6-carboxylic acid (500 mg, 1.36 mmol) was placed in a 25 mL double-necked flask. 4-Chlorobenzoic acid (425 mg, 2.70 mmol), HOBT (365 mg, 2.70 mmol), EDCI (515 mg, 2.70 mmol), and DIPEA (870 mg, 2.70 mmol) were added sequentially. The mixture was dissolved in 10 mL of dichloromethane and reacted at room temperature for 6 h. The reaction was monitored by TLC until complete. 10 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain 495 mg of a pale yellow-white powder, with a yield of 72%. 1H NMR(300MHz,DMSO-d6)δ7.84–7.47(m,8H),6.16(m,1H),4.35–4.29(m,3H),4.10(m,3H),3 .80(m,3H),3.55(m,1H),3.19(m,2H),2.59(m,1H),2.11–1.99(m,1H),1.37–1.29(m,7H).

[0193] Preparation of 3-(1-(4-chlorobenzoyl)-1,2,3,6-tetrahydropyridine)-N-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-6-carboxamide (III01)

[0194] The synthesis method of III01 is the same as that of I01, and III01 is finally obtained as a white powder with a yield of 52%. 1 H NMR (300MHz, DMSO-d6) δ11.14(d,J=24.2Hz,1H),8.91(s,1H),8.26(m,1H),7.95–7.43(m,7H),6.24(m,1H),4.33(s,1H),4 .07(d,J=7.0Hz,2H),3.80(m,2H),3.63–3.50(m,2H),3.19(t,J=10.8Hz,2H),2.59(m,2H),2.02(m,1H),1.40–1.19(m,4H).

[0195] Preparation of 3-(1-(4-trifluoromethylbenzoyl)-1,2,3,6-tetrahydropyridine)-N-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-6-carboxamide (IIIO2)

[0196] The synthesis method of III02 is the same as that of III01, except that the raw material is replaced with 4-trifluoromethylbenzoic acid. The final product III02 is a white powder with a yield of 62%. 1 H NMR (300MHz, DMSO-d6) δ11.19(s,1H),8.92(s,1H),8.26(m,1H),7.85(d,J=8.2Hz,2H),7.78–7.47(m,5H),6.24(m,1H),4.37(s,1 H),4.07(d,J=7.3Hz,3H),3.91(s,1H),3.80(d,2H),3.52(s,1H),3.25–3.10(m,2H),2.58(m,2H),2.01(m,1H),1.40–1.17(m,4H).

[0197] Preparation of 3-(1-(4-methoxybenzoyl)-1,2,3,6-tetrahydropyridine)-N-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-6-carboxamide (IIIO3)

[0198] The synthesis method of III03 is the same as that of III01, except that the raw material is replaced with 4-methoxybenzoyl. The final product III03 is a white powder with a yield of 55%. 1 H NMR (400MHz, DMSO-d6) δ11.15(s,1H),8.89(s,1H),8.27(s,1H),7.98–7.35(m,6H),7.01(d,J=8.2Hz,2H),6.27(s ,1H),4.26(s,2H),4.07(d,J=7.2Hz,2H),3.81(s,4H),3.19(m,2H),2.59(m,2H),2.02(m,1H),1.37–1.24(m,4H).

[0199] Example 4: Synthesis of compounds IV01-IV03

[0200] Preparation of ethyl 3-(4-chlorophenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-6-carboxylic acid (IVa)

[0201] 4-Chlorophenylboronic acid (688 mg, 4.4 mmol), ethyl 3-bromo-1-(tetrahydro-2H-pyran-4-yl)methyl-1H-indole-5-carboxylic acid (800 mg, 2.2 mmol), potassium carbonate (607 mg, 4.4 mmol), and Pd(pph3)4 (254 mg, 0.22 mmol) were placed in a 25 mL double-necked flask, dissolved in a suitable amount of dioxane, and reacted under N2 protection at 95 °C for 8 h. The reaction was monitored by TLC until complete. 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain 567 mg of a pale yellow powder, with a yield of 65%. 1 H NMR(300MHz,DMSO-d6)δ8.47(d,J=1.5Hz,1H),7.87–7.65(m,5H),7.53(dd,J=8.7,3.0Hz,2H),4.33(qd ,J=7.1,3.2Hz,2H),4.16(m,2H),3.87–3.75(m,2H),3.20(m,2H),2.18–2.02(m,1H),1.40–1.28(m,7H).

[0202] Preparation of 3-(4-chlorophenyl)-N-hydroxy-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-6-carboxamide (IV01)

[0203] The synthesis method of IV01 is consistent with that of I01, and IV01 is finally obtained as a white powder with a yield of 63%. ¹H NMR (300MHz, DMSO-d6) δ 11.14 (d, J = 24.2 Hz, 1H), 8.91 (s, 1H), 8.26 (m, 1H), 7.95–7.43 (m, 7H), 6.24 (m, 1H), 4.33 (s, 1H), 4.07 (d, J = 7.0 Hz, 2H), 3.80 (m, 2H), 3.63–3.50 (m, 2H), 3.19 (t, J = 10.8 Hz, 2H), 2.59 (m, 2H), 2.02 (m, 1H), 1.40–1.19 (m, 4H).

[0204] Preparation of 3-(4-trifluoromethoxyphenyl)-N-hydroxy-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-6-carboxamide (IV02)

[0205] The synthesis method of IV02 is the same as that of I01, and IV02 is finally obtained as a white powder with a yield of 67%.

[0206] 1 H NMR (300MHz, DMSO-d6) δ8.95(s,1H),8.31(s,1H),7.92–7.80(m,3H),7.68(s,2H),7.45(d,J=8.2Hz,2H),4.15(d,J=7.1H z,2H),3.81(dt,J=11.4,2.8Hz,2H),3.20(td,J=11.4,2.6Hz,2H),2.09(ddd,J=11.7,7.6,4.5Hz,1H),1.41–1.23(m,4H).

[0207] Preparation of 3-(4-difluoromethylphenyl)-N-hydroxy-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-6-carboxamide (IV03)

[0208] The synthesis method of IV03 is the same as that of I01, and IV03 is finally obtained as a white powder with a yield of 64%.

[0209] 1H NMR (300MHz, DMSO-d6) δ11.22(s,1H),8.95(s,1H),8.34(s,1H),8.01–7.56(m,7H),7.08(t,J=56.0Hz,1H),4.16(d, J=7.1Hz,2H),3.82(dd,J=11.2,3.8Hz,2H),3.21(td,J=11.6,2.6Hz,2H),2.11(d,J=3.8Hz,1H),1.45–1.19(m,4H).

[0210] Example 5: Evaluation of the enzyme activity of the compound

[0211] 1. Experimental Methods

[0212] In a buffer solution, ASM catalyzes the binding of fluorescently labeled HMU-PC (6-hexadecanoylamino-4-methylumbelliferylphosphatidylcholine) as a substrate. When ASM binds to HMU-PC, the artificial substrate releases HMU. In the assay, different inhibitors were first added. Under low pH conditions, the inhibitors competed with HMU-PC for binding to ASM, releasing different concentrations of HMU. Then, a stop solution was added to halt the enzymatic reaction, and the fluorescence value of HMU was measured. Finally, quantitative analysis was performed, and the inhibition rate of different inhibitors was calculated by comparing with the blank HMU-PC group.

[0213] (1) Dissolve the compound in DMSO and prepare a compound solution of the appropriate concentration.

[0214] (2) Dilute the enzyme with Tris-HCl buffer at pH 7.4.

[0215] (3) Dilute the substrate with substrate dissolution buffer.

[0216] (4) Add 1 mL of compound solution, 5 mL of enzyme solution, 5 mL of substrate solution, 10 mL of metal ion buffer and 20 mL of substrate dissolution buffer to a 96-well plate in sequence, and mix well.

[0217] (5) Incubate at 37°C for 2 hours.

[0218] (6) After incubation, add 200 mL of reaction termination solution.

[0219] (7) Place the 96-well plate in an ELISA reader to detect the fluorescence value, and set the wavelength to 360 / 460nm.

[0220] (8) Calculate the inhibition rate (IC) in Graphpad 50The assay requires setting the compound at six concentrations, with two replicates for each concentration. After obtaining the inhibition rate at each concentration, the IC50 is calculated using a GraphPad fitting curve. 50 ).

[0221] 2. Experimental Results

[0222] Table 1 shows the results of the enzyme inhibitory activities of the compounds.

[0223] As shown in Table 1, the compounds designed in this invention can effectively inhibit ASM activity, with the optimal enzyme inhibition rate reaching 100% at micromolar concentration levels, and an enzyme inhibition IC50 value of [missing value]. 50 The optimal value is below 5 nM, which allows the drug to exert its effect at the molecular level.

[0224] Example 6: Evaluation of the activity of the compound in inhibiting acute lung injury

[0225] 1. Experimental Methods

[0226] (1) Modeling

[0227] Mice were anesthetized by intraperitoneal injection of 3.5% chloral hydrate (0.2 mL / kg). After exposing the trachea of ​​the mice, 60 μL of lipopolysaccharide (LPS) solution was instilled into the trachea. The mice were then quickly rotated upright and suspended vertically for 2 minutes before the neck was sutured. The mice were then placed on a heating pad to wait for awakening, thus establishing a mouse model of endotoxin-induced acute lung injury.

[0228] For the first 5 days of LPS modeling: administer a single dose daily; 1 hour after administration on the 5th day, administer LPS (10 mg / kg) via intratracheal infusion; the last administration was 24 hours after LPS infusion, after which the animal was sacrificed and lung tissue was collected for testing.

[0229] (2) Administration

[0230] Control group: 7 animals per group; Model group: 10 animals per group; Positive drug: dexamethasone (DX, intraperitoneal injection dose 6 mg / kg, 10 animals per group; Compound group: compound I06, doses of 6 mg / kg and 12 mg / kg, 10 animals per group.

[0231] (3) Lung wet / dry weight ratio test

[0232] After mouse death, the mice were fixed on the operating table, the trachea was exposed, and the thoracic cavity was opened to observe and photograph the morphological changes of the lungs. The trachea was cut, the upper right lung was removed, and the wet weight was measured. The lung was then placed in a 60°C incubator to dry. After 72 hours, it was removed and the dry weight was measured. Finally, the wet / dry weight ratio (W / D) of the lung was calculated.

[0233] (4) Inflammatory factor content test

[0234] Appropriate amounts of lung tissue were taken from each group of mice, and the changes in the levels of inflammatory factors TNF-α, IL-1β, and IL-6 were measured using the ELISA method.

[0235] 2. Experimental Results

[0236] The wet / dry weight ratio of lung tissue is an important indicator for evaluating the degree of pulmonary edema. As shown in Figure 1, compared with the control group, the wet / dry weight ratio of lung tissue in the model group was significantly increased; compared with the model, the wet / dry weight ratio of lung tissue in mice in different drug administration groups was decreased, indicating that I06 has a protective effect against pulmonary edema induced by LPS in early COPD mice. Among them, the low-dose group of I06 had a better effect on alleviating LPS-induced pulmonary edema than the DX group.

[0237] # p<0.05 indicates a difference compared to the control group; * p<0.05 indicates that the data are expressed as mean ± SD compared to the model group.

[0238] This invention uses ELISA to detect the level of IL-1β in lung tissue to evaluate the inhibitory effect of I06 on LPS-induced early lung injury inflammatory response. As shown in Figure 2, compared with the control group, the expression of IL-1β in the lung tissue of mice treated with LPS was significantly increased; compared with the model group, the inflammation level in the lung tissue of mice in the low-dose and high-dose I06 groups was significantly reduced, and the anti-inflammatory effect of the low-dose and high-dose I06 groups was better than that of the DX group.

[0239] ### p<0.001 indicates a difference compared to the control group; * p<0.05, ** p<0.01, *** p<0.001 indicates that the data are expressed as mean ± SD compared to the model group.

[0240] Example 7: Evaluation of the activity of the compound in inhibiting myocardial infarction injury

[0241] 1. Experimental Methods

[0242] (1) Modeling

[0243] Male SD rats were acclimatized and then used to establish the model. Before the experiment, they were fasted and deprived of water for 2 hours and weighed. Anesthesia was administered via intraperitoneal injection of 50 mg / kg of 1% sodium pentobarbital. A BL-420s biological function experimental operating system was connected to record a lead II electrocardiogram. The neck and chest were disinfected using alternating iodine and alcohol. A longitudinal incision of approximately 1 cm was made in the midline of the neck with surgical scissors. The skin, superficial fascia, subfascial tissue, and anterior neck muscles were dissected layer by layer to expose the trachea. A small incision was made in the trachea, and a tube was inserted to the appropriate depth and connected to a ventilator. The ventilator was turned on and adjusted; the chest rise and fall should be consistent with the ventilator frequency. A longitudinal incision was made 1 cm from the left sternal border. The pectoralis major and serratus anterior muscles were bluntly dissected layer by layer to expose the 3rd and 4th intercostal spaces. The intercostal muscles were bluntly dissected along the intercostal space to the thoracic cavity using hemostatic forceps. The ribs were opened with a thoracotomy instrument to expose the beating heart. The pericardium was dissected with forceps, and the pericardium and lung tissue near the heart were separated using cotton wool moistened with physiological saline. Locate the left coronary artery and ligate the myocardial tissue containing the vessel using 6-0 surgical sutures. Stabilize for 2-5 minutes; darkening of the area around the ligated myocardium and ST-segment elevation on the electrocardiogram (ECG) will be observed. In the sham control group, only the left anterior descending artery is ligated using 6-0 surgical sutures, with the remaining steps the same as the coronary artery ligation group. Observe the ECG in lead II. Afterward, close the pleural cavity layer by layer, quickly suture the ribs with 4-0 surgical sutures, expel air from the pleural cavity using a syringe, suture the muscles and skin, and disinfect the incision. Clean the exudate around the trachea with absorbent cotton, retain the endotracheal tube, suture the anterior tracheal muscles and skin, and fix the tube. Disinfect the neck incision, wean the rat off the ventilator, observe whether the rat resumes spontaneous breathing, keep it warm, and wait for the rat to recover from anesthesia.

[0244] (2) Administration

[0245] In the myocardial infarction experiment, rats that survived the surgery were randomly divided into a model group and a drug treatment group. The drug treatment group was given intraperitoneal injection of I06 (18 mg / kg) for 7 days after modeling. The rat body weight, tibia length, and heart weight were recorded, and the ratio of heart weight to body weight (mg / g) and the ratio of heart weight to tibia length (mg / cm) were calculated.

[0246] (3) Hemodynamic measurement

[0247] Seven days after coronary artery ligation, rats were anesthetized by intraperitoneal injection of 50 mg / kg sodium pentobarbital to determine hemodynamic parameters. 50 μL of enzyme-labeled reagent was added to each well, except for the blank wells. The rats were incubated and washed as described above. 50 μL of chromogenic reagent A was added to each well, followed by 50 μL of chromogenic reagent B. The mixture was gently vortexed and incubated at 37°C in the dark for 10 minutes. 50 μL of stop solution was added to each well to terminate the reaction. The absorbance (OD value) of each well was measured sequentially at 450 nm using the blank well as the zeroing point. Measurements should be performed within 15 minutes of adding the stop solution.

[0248] (4) Serum lactate dehydrogenase (LDH) assay

[0249] Seven days after coronary artery ligation in rats, 1.5 mL of blood was collected from the rat's orbital cavity and centrifuged at 3000 rpm for 15 min. The supernatant serum was collected. Working reagents were prepared (reagent kit: Redu / Changchun Huili). The appropriate parameters were set on the fully automated biochemical analyzer and the sample was loaded. The fully automated biochemical analyzer performed automatic analysis.

[0250] 2. Experimental Results

[0251] Hemodynamic parameters were measured via cardiac catheterization, as shown in Figure 3. Compared with the sham-operated group, the absolute values ​​of left ventricular diastolic pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), left ventricular mean pressure (LVAP), maximum rate of increase of left ventricular pressure (+dp / dtmax), and maximum rate of decrease of left ventricular pressure (-dp / dtmax) in the model group were all significantly decreased. Compared with the model group, the absolute values ​​of the I06 treatment group were significantly increased, suggesting that it can improve the left ventricular systolic and diastolic function in rats with myocardial ischemia and restore the cardiac pumping function of rats with myocardial infarction to a certain extent.

[0252] # p<0.05, ### p<0.001 indicates a difference compared to the sham surgery group; * p<0.05, ** p<0.01, *** p<0.001 indicates that the data are expressed as mean ± SD compared to the model group.

[0253] LDH is a non-specific myocardial enzyme that begins to rise 9-20 hours after myocardial infarction, peaks at 36-60 hours, and returns to normal after 6-10 days. It can be used as an auxiliary diagnostic indicator in the later stages of acute myocardial infarction. As shown in Figure 4, compared with the sham-operated group, the serum LDH activity of rats in the model group was significantly increased, while the LDH activity in the I06 treatment group was significantly decreased compared with the model group, suggesting that I06 can effectively improve myocardial damage caused by coronary artery ligation-induced myocardial ischemia model.

[0254] # p<0.05 indicates a difference compared to the sham surgery group; * p<0.05 indicates that the data are expressed as mean ± SD compared to the model group.

[0255] Example 8: Evaluation of activity in inhibiting myocardial hypoxia injury

[0256] (1) Cell Culture

[0257] Cultured primary rat cardiomyocytes were randomly divided into a blank control group, a drug control group, a hypoxia model group, and a drug treatment group. The blank control group was cultured in a carbon dioxide incubator for 24 h; the drug control group was cultured in a carbon dioxide incubator for 24 h after adding IO6 to a final concentration of 2.5 μmol / L, 5 μmol / L, 10 μmol / L, and 20 μmol / L; the hypoxia model group was cultured in a hypoxia incubator (N2 93%, O2 2%, CO2 5%) for 24 h; and the drug treatment group was cultured in a hypoxia incubator (N2 93%, O2 2%, CO2 5%) for 24 h after adding IO6 to a final concentration of 2.5 μmol / L, 5 μmol / L, 10 μmol / L, and 20 μmol / L.

[0258] (2) Cell proliferation and toxicity analysis

[0259] After cell hypoxia-reoxygenation and drug treatment, 10 μL of CCK-8 reagent was added to each well of a 96-well plate. The plates were gently tapped to mix, and the plates were incubated in a CO2 incubator for 1.5 hours. The absorbance at 450 nm was then measured using a microplate reader. Cell viability = (OD value of experimental group - OD value of blank group) / (OD value of control group - OD value of blank group) × 100%.

[0260] 2. Experimental Results

[0261] Figure 5 shows the effect of different concentrations of I06 on the survival rate of primary rat cardiomyocytes after 24 hours of hypoxia in a rat model of hypoxic injury. Compared with the blank control group, the survival rate of primary rat cardiomyocytes was significantly reduced after 24 hours of hypoxia. Different concentrations of I06 did not affect the survival rate of normal cardiomyocytes. However, under hypoxic conditions, compared with the model group, 5 μmol / L I06 significantly increased the survival rate of primary rat cardiomyocytes after 24 hours of hypoxia, indicating that a final concentration of 5 μmol / L of I06 can effectively improve hypoxic injury in primary rat cardiomyocytes, thereby increasing cell survival.

[0262] *** p<0.001 indicates a difference compared to the blank control group (normal); ### p<0.001 indicates a comparison with the hypoxia model group. Data are expressed as mean ± SD.

Claims

1. An azapenam compound, characterized by, having the structure of Formula I: wherein: X is selected from CR4, N; L is selected from the group consisting of 6-10 membered aryl-O-(CH2) n -, a chemical bond, benzo 4-7 membered azepinonyl, 3-7 membered saturated or unsaturated azetidinoyl; R1is selected from H, halogen, C1-C9alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, 3-7 membered cycloalkyl, 4-7 membered cycloalkyl containing 1-2 N, O, S ring heteroatoms, C1-C4alkyl substituted with 4-7 membered cycloalkyl containing 1-2 N, O, S ring heteroatoms, phenyl, halophenyl, C1-C4alkyl substituted phenyl, C1-C4alkoxy substituted phenyl, C1-C4haloalkyl substituted phenyl, C1-C4haloalkoxy substituted phenyl, amino substituted C1-C4alkyl, C1-C4alkylamino substituted C1-C4alkyl, C1-C4alkenyl, C1-C4alkynyl, 4-7 membered heteroaryl containing 1-3 N, O, S ring heteroatoms, at least one substituent on the phenyl; R2, R3are selected from at least one H, halogen, C1-C9alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, 3-7 membered cycloalkyl substituted C1-C4alkoxy; R4is selected from H, C1-C4alkyl, 3-7 membered cycloalkyl; n is selected from 1, 2, 3, 4.

2. The azacyclic compound of claim 1, wherein, In the structure: X is selected from CH; L is selected from 6-10 membered aryl-O-CH2-, a bond, benzo 5-6 membered azepinyl, 5-6 membered saturated or unsaturated azetidinyl.

3. The azacyclic compound of claim 1, wherein In the structure: R1is selected from H, halogen, C1-C9alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, 3-6 membered cycloalkyl, 5-6 membered cycloalkyl containing 1-2 N, O ring heteroatoms, C1-C4alkyl substituted with 5-6 membered cycloalkyl containing 1-2 N, O ring heteroatoms, phenyl, halophenyl, C1-C4alkyl substituted phenyl, C1-C4alkoxy substituted phenyl, C1-C4haloalkyl substituted phenyl, C1-C4haloalkoxy substituted phenyl, amino substituted C1-C4alkyl, C1-C4alkylamino substituted C1-C4alkyl, C1-C4alkenyl, C1-C4alkynyl, 5-6 membered heteroaryl containing 1-2 N, S ring heteroatoms, at least one substituent on the phenyl; R2, R3are selected from at least one H, halogen, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, 3-5 membered cycloalkyl substituted C1-C4alkoxy.

4. The azacyclic compound of claim 1, wherein In the structure: L is selected from a chemical bond, R1is selected from CF3-, CHF2-, CH2F-, H, selected from the group consisting of 5. A nitrogen-containing heterocyclic compound, characterized in that, a compound selected from any one of:

6. A pharmaceutically acceptable salt of the azapericyclic compound of claim 1, characterized in that, formed by the compound with a pharmaceutically acceptable acid or base.

7. The pharmaceutically acceptable salt of claim 6, wherein, The pharmaceutically acceptable acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, ferulic acid; the pharmaceutically acceptable base is selected from alkali metal cation base, alkaline earth metal cation base, ammonium cation base, choline.

8. A pharmaceutical composition, characterized by, The azapenoid compound of claim 1 or the pharmaceutically acceptable salt of claim 6, and a pharmaceutically acceptable carrier.

9. Use of the azapericyclic compound of claim 1, the pharmaceutically acceptable salt of claim 6 or the pharmaceutical composition of claim 8 for the manufacture of a medicament for the inhibition of acid sphingomyelinase.

10. Use according to claim 9, characterized in that, The medicament is a medicament for the treatment of depression, senile dementia, cognitive impairment, cerebral stroke, myocardial ischemia, pulmonary fibrosis, chronic obstructive pulmonary disease, lung injury, pulmonary arterial hypertension, respiratory distress syndrome, respiratory cystic fibrosis, fatty liver, liver fibrosis, autoimmune diseases, tumors, diabetes.

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