Isoindole thioimine compound, preparation thereof and application of isoindole thioimine compound as sigma-2 receptor inhibitor

Abstract

The invention relates to an isoindole thioimine compound, preparation thereof and application of the isoindole thioimine compound as a sigma-2 receptor inhibitor. Catechol and isobutene are subjected to a series of reactions under certain conditions to obtain a solid product; carrying out a series of reactions on o-xylene and chlorosulfonic acid under certain conditions to obtain an oily product; and reacting the solid product with the oily product under a certain condition to obtain the isoindole thioimine compound. Compared with the prior art, when the isoindole thioimine compound prepared by the invention is combined with a sigma-2 receptor and allosteric regulates a sigma-2 receptor compound, the combination of adjacent A beta oligomers and a receptor on synapse is unstable, so that the A beta oligomers are removed from the synapse, the activity of the sigma-2 receptor can be effectively inhibited, and the activity of the sigma-2 receptor can be inhibited. The compound can be further used for preparing new medicines for treating tumors and neurodegenerative diseases.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and more particularly to an isoindole thioimide compound and its preparation and application as a sigma-2 receptor inhibitor. Background Art

[0002] Alzheimer's disease (AD) is a type of neurodegenerative disorder, and its main clinical manifestations are the gradual loss of language, memory, and cognitive function. In the past few decades, the treatment of AD has been full of challenges. On the one hand, the treatment and care costs for AD worldwide are huge. On the other hand, except for aducanumab and Lecanemab (Brain. 2023, 146(10), 3969 - 3990), the Food and Drug Administration (FDA) has not approved any drug for the treatment of AD since 2003. Currently, the drugs clinically used for the treatment of AD are mainly donepezil, rivastigmine, galantamine, and memantine. Among them, donepezil, rivastigmine, and galantamine belong to acetylcholinesterase inhibitors (AChEI). Memantine belongs to an N-methyl-D-aspartic acid (NMDA) receptor antagonist. However, these drugs only temporarily delay the progression of the disease and cannot completely treat AD. According to the estimation of the International Alzheimer's Association, about 50 million people suffered from dementia in 2018, and it is expected to triple by 2050 (Alzheimers Dement. 2023, 19(4), 1598 - 1695). Therefore, developing drugs for the treatment of AD is a difficult task, and due to the high medical costs and the increasing number of patients, it is urgent to research and develop drugs for the treatment of AD.

[0003] Sigma-2 receptors are a class of receptors widely distributed in the central nervous system, pancreas, liver, gastrointestinal tract and other peripheral tissues, and they may be potential targets for the treatment of tumors, neurodegenerative diseases and neuralgia. In recent years, sigma-2 receptors have been isolated from calf liver (Proc. Natl. Acad. Sci. U.S.A. 2017, 114(27), 7160–7165), and through biochemical analysis, sigma-2 receptors are considered to be transmembrane protein 97 (TMEM97). TMEM97 is associated with the low-density lipoprotein receptor (LDLR), and knocking out TMEM97 using siRNA will reduce the endocytosis of low-density lipoprotein (LDL) by the low-density lipoprotein receptor. Some other studies have found that the sigma-2 / TMEM97 receptor and PGRMC1 are jointly involved in the formation of the LDL-LDLR complex, which plays an important role in the uptake of LDL. In addition, the activation of the sigma-2 / TMEM97 receptor has a neuroprotective effect (ACS Chem Neurosci, 2019, 10(3), 1595-1602). In 2021, the crystal structure of the sigma-2 receptor was also resolved, which provides great convenience for the design of sigma-2 receptor ligands (Nature 2021, 600(23), 759).

[0004] A synapse refers to the structure of the mutual contact where the impulse of one neuron is transmitted to another neuron or to another cell, and it is the site where neurons functionally connect with each other. Some studies have shown that even in some populations with pathological features related to AD in the brain (such as amyloid plaques and neurofibrillary tangles), they do not develop AD. This may be because the unique synaptic protein composition in these populations resists amyloid-beta protein and tau protein, thus avoiding damage to synaptic function. However, for most AD patients, Aβ oligomers bind to multiple receptors on synapses, leading to synaptic dysfunction and synaptic loss, and further affecting the transmission of information between brain neurons. Cognition Therapeutic, a company in the United States, found through research that by inhibiting the sigma-2 receptor, the binding of Aβ oligomers to receptors on synapses can be made unstable, resulting in the removal of Aβ oligomers from synapses and thus restoring synaptic function. Cognition Therapeutic used supercritical fluid extraction (SFE) technology to discover that N-aryl-N-arylmethylamine or arylpropylisoindole compounds in ginger oil have good sigma-2 receptor binding activity. After docking and design modification with the crystal structure of the sigma-2 receptor protein, the candidate compound CT1812 has good in vitro and in vivo activities and the ability to cross the blood-brain barrier (BBB). In vivo probe test experiments have proven that the concentration of cerebrospinal fluid amyloid-beta protein (aβ) can be increased 1 hour after administration of CT1812, showing potential for AD treatment. Currently, it is in the clinical phase II study stage (Alzheimers Dement. 2021, 17(8), 1365-1382). However, CT1812 has the disadvantages of poor selectivity between sigma-1 and sigma-2 receptors and poor oral bioavailability of the compound.

[0005] Therefore, there is an urgent need to study a compound that can effectively inhibit the activity of the sigma-2 receptor and its preparation method. Summary of the Invention

[0006] The purpose of the present invention is to overcome the defects of the above-mentioned existing technologies and provide an isoindole thioimine compound, its preparation, and its application as a sigma-2 receptor inhibitor. By binding to the sigma-2 receptor and allosterically regulating the sigma-2 receptor complex, it can effectively inhibit the activity of the sigma-2 receptor and can be further used to prepare new drugs for the treatment of tumors and neurodegenerative diseases.

[0007] The purpose of the present invention can be achieved through the following technical solutions:

[0008] The present invention provides an isoindole thioimine compound, and the chemical structural formula of the isoindole thioimine compound is shown as formula (I):

[0009]

[0010] Among them, R1 is an alkyl group with 1 - 4 carbon atoms or a haloalkyl group with 1 - 4 carbon atoms; R2 is one of hydrogen, an alkyl group with 1 - 4 carbon atoms, a haloalkyl group with 1 - 4 carbon atoms, and an acyl group with 1 - 4 carbon atoms.

[0011] Furthermore, the isoindole thioimide compound is one of the following compounds 1 - 22:

[0012]

[0013] The present invention provides a method for preparing an isoindole thioimide compound, comprising the following steps:

[0014] Step A: React catechol with isobutene to obtain intermediate A, react intermediate A with potassium iodide to obtain intermediate B, then react intermediate B with 2 - methylbut - 3 - yne - 2 - amine to obtain intermediate C, and react intermediate C with hydrazine hydrate to obtain solid D;

[0015] Step B: React o - xylene with chlorosulfonic acid to obtain intermediate E; react intermediate E with triphenylphosphine to obtain intermediate F; react intermediate F successively with sodium borohydride, a halogenated hydrocarbon with different alkyl or fluoroalkyl substitutions, and m - chloroperoxybenzoic acid to obtain intermediate G; react intermediate G with ammonium carbamate and diacetoxyiodobenzene to obtain intermediate H; react intermediate H with an acyl chloride with different alkyl or fluoroalkyl substitutions to obtain intermediate I; react intermediate I with N - bromosuccinimide to obtain oily substance J;

[0016] React the solid D obtained in Step A with the oily substance J obtained in Step B to obtain the isoindole thioimide compound.

[0017] Furthermore, in Step A, the specific preparation process of the intermediate B includes:

[0018] Dissolve catechol in dichloromethane, add concentrated sulfuric acid at - 30°C, then slowly dropwise add isobutene, slowly warm up to room temperature and stir overnight to obtain a reaction solution;

[0019] Add triethylamine to the reaction solution at - 30°C to quench, evaporate to dryness and separate by column chromatography to obtain intermediate A;

[0020] Dissolve intermediate A in methanol, add potassium iodide and sodium hydroxide, slowly dropwise add sodium hypochlorite at 0°C, after reacting for 3 h, add saturated ammonium chloride to the reaction solution, and extract with ethyl acetate, then evaporate to dryness to obtain intermediate B.

[0021] Further, in step A, the specific preparation process of the solid D includes:

[0022] Dissolve the intermediate B in triethylamine, add 2-methylbut-3-yn-2-amine, bis(triphenylphosphine)palladium chloride, and copper(I) iodide, react for 3 h under nitrogen protection, then directly filter and evaporate the reaction solution to dryness, and obtain the intermediate C by column chromatography separation;

[0023] Dissolve the intermediate C in ethanol, add hydrazine hydrate, copper(II) sulfate pentahydrate, and neocuproine, reflux overnight, extract with ethyl acetate, evaporate to dryness, and obtain the solid D by column chromatography separation.

[0024] Further, in step B, the specific preparation process of the intermediate F includes:

[0025] Dissolve o-xylene in chloroform, slowly add chlorosulfonic acid dropwise at 0 °C, stir at room temperature for two days after addition to obtain a reaction solution, add the reaction solution to ice water, extract with dichloromethane, and evaporate to dryness to obtain the intermediate E;

[0026] Dissolve the intermediate E in xylene, add triphenylphosphine in batches, react overnight at room temperature, then evaporate to dryness, add petroleum ether and stir at -10 °C to remove the excess triphenylphosphine, obtain a filtrate, evaporate the filtrate to dryness and obtain the intermediate F by column chromatography separation.

[0027] Further, in step B, the specific preparation process of the intermediate H includes:

[0028] Dissolve the intermediate F in absolute ethanol, add sodium borohydride in batches, and then add halogenated hydrocarbons with different alkyl substitutions and different fluoroalkyl substitutions to react overnight to obtain a reaction solution;

[0029] Extract the reaction solution with dichloromethane, add meta-chloroperoxybenzoic acid at -30 °C and react for 3 h. After the reaction solution returns to room temperature, add saturated sodium carbonate solution to adjust the pH to neutral, then extract with dichloromethane, evaporate the solvent, and obtain the intermediate G by column chromatography separation;

[0030] Dissolve the intermediate G in methanol, add ammonium carbamate and diacetoxyiodobenzene, stir at room temperature for 30 min, extract with dichloromethane, evaporate to dryness and obtain the intermediate H by column chromatography separation.

[0031] Further, in step B, the specific preparation process of the oily substance J includes:

[0032] Dissolve the intermediate H in dichloromethane, add triethylamine, slowly add acyl chlorides with different alkyl substitutions and different fluoroalkyl substitutions dropwise at 0 °C, transfer to room temperature and react for 1 h, then directly evaporate to dryness, and obtain the intermediate I by column chromatography purification;

[0033] Dissolve the intermediate I in 1,2-dichloroethane, add N-bromosuccinimide and azobisisobutyronitrile, replace the air with nitrogen, reflux the reaction overnight, extract with dichloromethane, and purify by column chromatography to obtain an oily substance J.

[0034] Further, in step B, the specific preparation process of the isoindole thioimide compound includes:

[0035] Dissolve the oily substance J obtained in step B and the solid D obtained in step A in tetrahydrofuran, add triethylamine, react at 50 °C for 18 h under nitrogen protection, filter by suction, directly evaporate the filtrate to dryness, separate by column chromatography, obtain a light brown oily substance, then add potassium carbonate, reflux at 70 °C for 1.5 h, extract with ethyl acetate, and further separate by column chromatography and purify by pre-HPLC to obtain the target compound.

[0036] The present invention also provides an application of an isoindole thioimide compound, and the isoindole thioimide compound is used as a sigma-2 receptor inhibitor.

[0037] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0038] When the isoindole thioimide compound prepared by the present invention binds to the sigma-2 receptor and allosterically regulates the sigma-2 receptor complex, it will cause the instability of the binding of adjacent Aβ oligomers to the receptors on the synapse, thereby causing the Aβ oligomers to be removed from the synapse. Therefore, the isoindole thioimide compound prepared by the present invention can effectively inhibit the activity of the sigma-2 receptor and can be further used for the preparation of new drugs for the treatment of tumors and neurodegenerative diseases. Detailed implementation manners

[0039] The following further elaborates on the specific implementation manners of the present invention through examples. These examples are implemented on the premise of the solution described in the present invention, and the detailed implementation manners and specific operation processes are given. However, the protection scope of the present invention is not limited to the following examples.

[0040] The following further elaborates on the present invention in combination with specific examples. Features such as component models, material names, connection structures, preparation means, materials, structures or composition ratios that are not clearly described in the present technical solution are regarded as common technical features disclosed in the prior art.

[0041] The present invention provides an isoindole thioimide compound, and the chemical structural formula of the isoindole thioimide compound is shown as formula (I):

[0042]

[0043] Among them, R1 is an alkyl group with 1 to 4 carbon atoms or a haloalkyl group with 1 to 4 carbon atoms; R2 is one of hydrogen, an alkyl group with 1 to 4 carbon atoms, a haloalkyl group with 1 to 4 carbon atoms, and an acyl group with 1 to 4 carbon atoms.

[0044] The present invention also provides a method for preparing an isoindole thioimine compound, comprising the following steps:

[0045] Step A: Dissolve catechol in dichloromethane, add a catalytic amount of concentrated sulfuric acid at -30°C, then slowly dropwise add isobutene. After slowly returning to room temperature, stir overnight. Quench the reaction solution by adding triethylamine at -30°C. After evaporating the reaction solution to dryness, separate it by column chromatography to obtain a yellowish-brown oily substance A; dissolve the oily substance A in methanol, add potassium iodide and sodium hydroxide, then slowly dropwise add sodium hypochlorite at 0°C. After reacting at 0°C for 3 h, add saturated ammonium chloride to the reaction solution, extract with ethyl acetate, and evaporate to dryness to obtain a brown oily substance B; dissolve the oily substance B in triethylamine, then add 2-methylbut-3-yn-2-amine, bis(triphenylphosphine)palladium chloride, and copper(I) iodide. After reacting under nitrogen protection for 3 h, directly filter and evaporate the reaction solution to dryness, and separate it by column chromatography to obtain a yellow solid C; dissolve the yellow solid C in ethanol, then add hydrazine hydrate, copper(II) sulfate pentahydrate, and neocuproine. After refluxing overnight, extract with ethyl acetate, evaporate to dryness, and separate by column chromatography to obtain a yellow solid D. The reaction formula is shown in Formula (Ⅱ):

[0046]

[0047] Step B: Dissolve o-xylene in chloroform, slowly add chlorosulfonic acid dropwise at 0 °C. After addition, stir for two days at room temperature. Add the reaction solution to ice water, extract with dichloromethane, and evaporate to dryness to obtain a light yellow oily substance E. Dissolve the oily substance E in xylene, add triphenylphosphine in batches, react overnight at room temperature. After evaporation to dryness, add petroleum ether and stir at -10 °C to remove the excess triphenylphosphine. Evaporate the filtrate to dryness and separate by column chromatography to obtain a yellowish-green oily substance F. Dissolve the yellowish-green oily substance F in absolute ethanol, add sodium borohydride in batches, and then add halogenated hydrocarbons with different alkyl substitutions and different fluoroalkyl substitutions and react overnight. The reaction solution is directly extracted with dichloromethane and used in the next step. Add m-chloroperbenzoic acid to the above dichloromethane solution at -30 °C, and then react at this temperature for 3 h. Restore the reaction solution to room temperature, add saturated sodium carbonate solution to adjust the pH to neutral, extract with dichloromethane, evaporate the solvent to dryness and separate by column chromatography to obtain a light yellow oily substance G. Dissolve the light yellow oily substance G in methanol, then add ammonium carbamate, stir with diacetoxyiodobenzene at room temperature for 30 min. Extract the reaction solution with dichloromethane, evaporate to dryness and separate by column chromatography to obtain a brown oily substance H. Dissolve the brown oily substance H in dichloromethane, add triethylamine, and then slowly add acyl chlorides with different alkyl substitutions and different fluoroalkyl substitutions dropwise at 0 °C. Transfer to room temperature and react for 1 h, then evaporate to dryness directly. Purify by column chromatography to obtain an oily substance I. Dissolve the oily substance I in 1,2-dichloroethane, then add N-bromosuccinimide and azobisisobutyronitrile, displace with nitrogen and reflux overnight. Extract with dichloromethane and purify by column chromatography to obtain a brown oily substance J. Dissolve the finally obtained brown oily substance J and the yellow solid D obtained in the last step of Step A in tetrahydrofuran, then add triethylamine, react at 50 °C for 18 h under nitrogen protection, filter by suction, evaporate the filtrate directly to dryness and separate by column chromatography to obtain a light brown oily substance. Then add potassium carbonate, reflux at 70 °C for 1.5 h, extract with ethyl acetate, and further separate by column chromatography and purify by pre-HPLC to obtain the target compound. The reaction formula is shown in Formula (Ⅲ):

[0048]

[0049] Example 1

[0050] This example provides a preparation method of a compound 1, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(methyl)(oxo)-λ6-thioimidoyl)acetamide.

[0051] Step A:

[0052] Step 1: Add catechol (30.00 g, 272.45 mmol) and dichloromethane (150 ml) into a 500-ml three-necked flask. Then add a catalytic amount of concentrated sulfuric acid (1.4 ml) at -35 °C, and subsequently slowly dropwise add freshly prepared isobutene (152.62 g, 2720 mmol). After the addition is complete, gradually warm the reaction mixture to room temperature overnight. Add 3 ml of triethylamine to quench the reaction. After evaporating the reaction mixture to dryness, separate it by column chromatography (EA / PE = 1:10) to obtain 30 g of a yellowish-brown oily substance A, yield: 65.60%. LC-MS (ESI): m / z [M+H]+ calcd for C 10 H 14 NaO2 189.1; found 189.1.

[0053] Step 2: Add the yellowish-brown oily substance A (14.00 g, 84.23 mmol), potassium iodide (13.98 g), sodium hydroxide (3.37 g, 84.23 mmol) and methanol (80 ml) into a 500-ml three-necked flask. Slowly dropwise add sodium hypochlorite (83.86 ml, 84.23 mmol) at 0 °C, complete the addition within 1 h, and then react at 0 °C for 3 h. Add 250 ml of saturated ammonium chloride solution to the reaction mixture, extract with ethyl acetate (250 ml × 2), wash once with saturated brine (400 ml), dry over anhydrous sodium sulfate, and evaporate to dryness to obtain 23.8 g of a brown oily substance B, yield 96.71%. LC-MS (ESI): m / z [M-H]- calcd for C 10 H 12 IO2 291.0; found 291.0.

[0054] Step 3: Add the brown oily substance B (3.30 g, 11.30 mmol), 2-methylbut-3-yn-2-amine (1.32 g, 15.82 mmol), bis(triphenylphosphine)palladium(II) chloride (0.16 g, 0.226 mmol), copper(I) iodide (0.11 g, 0.57 mmol) and triethylamine (40 ml) into a 100-ml single-necked flask. React under nitrogen protection for 3 h. Evaporate the reaction mixture directly to dryness and filter by suction. Separate it by column chromatography (EA / PE = 1:4) to obtain 2.38 g of a yellow solid C, yield: 85.00%. LC-MS (ESI): m / z [M+H]+ calcd for C 15 H 22 NO2 248.1; found 248.1.

[0055] Step 4: Add yellow solid C (0.3 g, 1.2 mmol), hydrazine hydrate (0.3 g, 4.9 mmol), copper sulfate pentahydrate (30 mg, 0.12 mmol), neocuproine (25 mg, 0.12 mmol) and absolute ethanol (10 ml) into a 50 ml single-necked flask, and then reflux the reaction in air for 18 h. After the reaction solution is cooled to room temperature, add 20 ml of water, extract with ethyl acetate (15 ml × 3), wash once with saturated brine (50 ml), and dry over anhydrous sodium sulfate. After column chromatography separation (EA / PE = 1:1), 0.20 g of yellow solid D is obtained, yield: 66.67%. LC-MS (ESI): m / z [M+H]+ calcd for C 15 H 26 NO2 252.1; found 252.1.

[0056] Step B:

[0057] Step 1: Add o-xylene (7.30 g, 282.59 mmol) and chloroform (90 ml) into a 500 ml single-necked flask, and then slowly add chlorosulfonic acid (72.55 g, 721.70 mmol) dropwise at 0 °C. After the addition is complete, gradually restore the reaction solution to room temperature and stir for two days. Slowly add the reaction solution to ice water, extract with dichloromethane (200 ml × 3), wash once with saturated brine (500 ml), and dry over anhydrous sodium sulfate. After evaporating the solvent, 54.30 g of light yellow oily substance E is obtained, yield: 94.00%. LC-MS (ESI): m / z [M+H]+ calcd for C8H 11 O3S187.0; found 187.1.

[0058] Step 2: Add light yellow oily substance E (10.00 g, 48.90 mmol) and xylene (80 ml) into a 250 ml single-necked flask, and then add triphenylphosphine (38.00 g, 146.60 mmol) in batches at 0 °C. After the addition is complete, restore the reaction solution to room temperature and react overnight. After evaporating the reaction solution, add 80 ml of petroleum ether, stir at -10 °C for 30 min, and then filter to remove the excess triphenylphosphine. After evaporating the filtrate, perform column chromatography separation (100% PE) to obtain 5.80 g of yellow-green oily substance F, yield: 86.60%. LC-MS (ESI): m / z [M+H]+ calcd for C 16 H 18 S2275.1; found 275.1.

[0059] Step 3: Add F (0.5 g, 1.82 mmol) and anhydrous ethanol (20 ml) into a 100-ml two-necked flask. Then, add sodium borohydride (0.21 g, 5.47 mmol) portionwise to the reaction solution at 0 °C. After stirring for 30 min, add methyl iodide (0.57 g, 4.00 mmol). Transfer the reaction solution to room temperature and react for 3 h. Pour the reaction solution into 20 ml of saturated ammonium chloride, extract with dichloromethane (20 ml × 3), wash once with saturated brine (50 ml), dry over anhydrous sodium sulfate, and filter the filtrate into a two-necked flask for direct use in the next step reaction.

[0060] Step 4: Cool the above filtrate to -30 °C, then add m-chloroperoxybenzoic acid (0.63 g, 3.61 mmol) portionwise, and then react at this temperature for 3 h. Gradually restore the reaction solution to room temperature, adjust the pH to neutral with saturated sodium carbonate solution, transfer the reaction solution to a separatory funnel, extract with dichloromethane (50 ml × 3), wash once with saturated brine (150 ml), and dry over anhydrous sodium sulfate. Evaporate the solvent and separate by column chromatography (EA / PE = 2:3) to obtain 0.45 g of a light yellow oil G, yield: 73.77%. LC-MS (ESI): m / z [M+H]+ calcd for C9H 13 OS 169.1; found 169.1.

[0061] Step 5: Add light yellow oil G (2.30 g, 13.67 mmol), ammonium carbamate (4.27 g, 54.68 mmol), diacetoxyiodobenzene (13.20 g, 41.01 mmol) and methanol (45 ml) into a 100-ml single-necked flask, and then stir at room temperature for 30 min. Pour the reaction solution into saturated sodium bicarbonate solution, extract with dichloromethane (50 ml × 3), wash once with saturated brine (100 ml), and dry over anhydrous sodium sulfate. Separate by column chromatography (EA / PE = 1:1) to obtain 2.00 g of a brown oil H, yield: 79.83%. LC-MS (ESI): m / z [M+H]+ calcd for C9H 14 NOS 184.1; found 184.1.

[0062] Step 6: Add brown oil H (0.50 g, 2.73 mmol), triethylamine (0.36 g, 3.55 mmol) and anhydrous dichloromethane (15 ml) into a 100 ml single-necked flask. Replace the air with nitrogen. When the temperature of the reaction solution drops to 0 °C, slowly add acetyl chloride (0.26 g, 3.28 mmol). After the addition, transfer the reaction solution to room temperature and react for 1 h. Directly evaporate the reaction solution to dryness and purify it by column chromatography (EA / PE = 1:4) to obtain 0.59 g of white oil I, yield: 95.92%. LC-MS (ESI): m / z [M+H]+ calcd for C 11 H 16 NO2S226.1; found 226.1.

[0063] Step 7: Add I (0.30 g, 1.33 mmol), N-bromosuccinimide (0.57 g, 3.19 mmol), 2,2'-azobis(2-methylpropionitrile) (21.84 mg, 0.13 mmol) and 1,2-dichloroethane (20 ml) into a 50 ml single-necked flask. Replace the air with nitrogen and reflux the reaction overnight. After the reaction solution cools to room temperature, pour it into water, extract with dichloromethane (20 ml × 3), wash once with saturated brine (50 ml), and dry over anhydrous sodium sulfate. Separate by column chromatography (EA / PE = 1:4) to obtain 0.26 g of brown oil J, yield: 51.82%.

[0064] Step 8:

[0065] Add brown oil J (0.13 g, 0.52 mmol), the yellow solid D (0.23 g, 0.59 mmol) obtained in Step A, triethylamine (0.16 g, 1.57 mmol) and tetrahydrofuran (15 ml) into a 50 ml single-necked flask. React at 50 °C for 18 h under nitrogen protection. After the reaction solution cools to room temperature, filter by suction. Directly evaporate the filtrate to dryness and separate by column chromatography (EA / DCM = 1:4) to obtain 0.15 g of light brown oil, yield: 60.00%. Further purify by pre-HPLC (C18 column, ACN: 0.1% TFA gradient elution from 10% to 60%) to obtain 120 mg of the trifluoroacetate salt of target compound 1, yield: 39.12%.

[0066] The structural formula of compound 1 is shown as follows:

[0067]

[0068] The NMR and MS data of compound 1 are shown as follows:

[0069] 11H NMR (400 MHz, Chloroform-d) δ 7.91 (s, 1H), 7.82 (s, 1H), 7.48 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H), 6.78 (dd, J = 8.2, 2.1 Hz, 1H), 4.99 (s, 2H), 4.53 (s, 2H), 3.27 (s, 3H), 2.71–2.58 (m, 2H), 2.13 (s, 3H), 2.08–1.96 (m, 2H), 1.51 (s, 6H), 1.40 (s, 9H).

[0070] 13 13C NMR (101 MHz, Chloroform-d) δ 180.82, 148.56, 142.24, 139.77, 139.52, 135.39, 131.11, 124.26, 123.68, 122.31, 115.06, 80.85, 64.86, 52.47, 52.38, 44.14, 39.68, 29.79, 28.85, 26.57, 22.05.

[0071] LC-MS (ESI): m / z [M+H]+ calcd for C 26 H 37 N2O4S 473.2; found 473.2.

[0072] Example 2

[0073] This example provides a preparation method of compound 2, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(methyl)(oxo)-λ6-thioimidoyl)propanamide. Referring to the preparation method of the compound in Example 1, the difference from Example 1 is that propionyl chloride is used as the raw material in the sixth step of step B, and the remaining steps are the same as those in Example 1. 112 mg of the trifluoroacetate salt of compound 2, a white solid, was prepared.

[0074] The structural formula of compound 2 is as follows:

[0075]

[0076] The NMR and mass spectrometry data of compound 2 are as follows:

[0077] 11H NMR (400 MHz, Chloroform-d) δ 7.91 (s, 1H), 7.82 (s, 1H), 7.48 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H), 6.78 (dd, J = 8.1, 2.1 Hz, 1H), 4.99 (s, 2H), 4.54 (s, 2H), 3.26 (s, 3H), 2.71–2.58 (m, 2H), 2.41 (q, J = 7.5 Hz, 2H), 2.08–1.93 (m, 2H), 1.51 (s, 6H), 1.40 (s, 9H), 1.09 (t, J = 7.5 Hz, 3H).

[0078] 13 13C NMR (101 MHz, Chloroform-d) δ 183.93, 148.64, 142.31, 140.13, 139.61, 135.52, 131.27, 124.34, 123.78, 122.43, 115.14, 80.92, 64.78, 52.49, 52.40, 44.30, 39.70, 32.71, 29.90, 28.95, 22.12, 9.64.

[0079] LC-MS (ESI): m / z [M+H]+ calcd for C 27 H 38 N2O4S 487.2; found 487.2.

[0080] Example 3

[0081] This example provides a preparation method of Compound 3, N-((2-(4-(3-(tert-Butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(methyl)(oxo)-λ6-thioimidoyl)butanamide. Referring to the preparation method of the compound in Example 1, different from Example 1, in the sixth step of Step B, butyryl chloride was used as the raw material, and the remaining steps were the same as those in Example 1. 84 mg of the trifluoroacetate salt of Compound 3, a white solid, was prepared.

[0082] The structural formula of Compound 3 is as follows:

[0083]

[0084] The NMR and mass spectrometry data of Compound 3 are as follows:

[0085] 11H NMR (400 MHz, Chloroform-d) δ 7.87 (s, 1H), 7.80 (s, 1H), 7.45 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.82 (d, J = 2.2 Hz, 1H), 6.75 (dd, J = 8.2, 2.1 Hz, 1H), 4.97 (s, 2H), 4.54 (s, 2H), 3.24 (s, 3H), 2.69–2.54 (m, 2H), 2.32 (t, J = 7.4 Hz, 2H), 2.06–1.93 (m, 2H), 1.59 (p, J = 7.4 Hz, 2H), 1.49 (s, 6H), 1.38 (s, 9H), 0.90 (t, J = 7.4 Hz, 3H).

[0086] 13 13C NMR (101 MHz, Chloroform-d) δ 183.28, 148.63, 142.31, 140.17, 139.61, 135.52, 131.27, 124.33, 123.78, 122.41, 115.13, 80.92, 64.75, 52.48, 52.38, 44.30, 41.50, 39.70, 29.91, 28.95, 22.13, 19.03, 13.89.

[0087] LC-MS (ESI): m / z [M+H]+ calcd for C 28 H 40 N2O4S 501.2; found 501.2.

[0088] Example 4

[0089] This example provides a preparation method of compound 4, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(ethyl)(oxo)-λ6-thioimidoyl)acetamide. Referring to the preparation method of the compound in Example 1, different from Example 1, iodoethane was used as the raw material in the third step of step B, and acetyl chloride was used as the raw material in the sixth step of step B. The remaining steps were the same as those in Example 1, and 243 mg of the trifluoroacetate salt of compound 4, a white solid, was prepared.

[0090] The structural formula of compound 4 is as follows:

[0091]

[0092] The NMR and mass spectrometry data of compound 4 are as follows:

[0093] 11H NMR (400 MHz, Chloroform-d) δ 8.02–7.60 (m, 2H), 7.48 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 2.1 Hz, 1H), 6.78 (dd, J = 8.3, 2.0 Hz, 1H), 4.99 (s, 2H), 4.54 (s, 2H), 3.51–3.18 (m, 2H), 2.72–2.52 (m, 2H), 2.13 (s, 3H), 2.09–1.97 (m, 2H), 1.52 (s, 7H), 1.41 (d, J = 1.0 Hz, 10H), 1.24 (t, J = 7.3 Hz, 4H).

[0094] 13 13C NMR (101 MHz, Chloroform-d) δ 180.88, 148.63, 142.31, 139.60, 137.70, 135.48, 131.24, 124.27, 123.77, 122.39, 115.13, 80.93, 64.78, 52.49, 52.39, 50.60, 39.81, 29.87, 28.95, 26.68, 22.18, 6.71.

[0095] LC-MS (ESI): m / z [M+H]+ calcd for C 27 H 39 N2O4S 487.2; found 487.2.

[0096] Example 5

[0097] This example provides a preparation method of compound 5, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(ethyl)(oxo)-λ6-sulfinimine)propanamide. Referring to the preparation method of the compound in Example 1, different from Example 1, iodoethane was used as the raw material in the third step of Step B, and propionyl chloride was used as the raw material in the sixth step of Step B. The remaining steps were the same as those in Example 1, and 100 mg of the trifluoroacetate salt of compound 5, a white solid, was prepared.

[0098] The structural formula of compound 5 is as follows:

[0099]

[0100] The NMR and mass spectrometry data of compound 5 are as follows:

[0101] 11H NMR (400 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.76 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H), 6.78 (dd, J = 8.2, 2.0 Hz, 1H), 4.98 (s, 2H), 4.53 (s, 2H), 3.53–3.19 (m, 2H), 2.71–2.57 (m, 2H), 2.41 (q, J = 7.5 Hz, 2H), 2.11–1.95 (m, 2H), 1.51 (s, 6H), 1.41 (s, 9H), 1.23 (t, J = 7.3 Hz, 3H), 1.10 (t, J = 7.5 Hz, 3H).

[0102] 13 13C NMR (101 MHz, Chloroform-d) δ 183.97, 148.62, 142.31, 139.59, 137.95, 135.50, 131.30, 124.26, 123.78, 122.41, 115.12, 80.91, 64.64, 52.43, 52.34, 50.60, 39.75, 32.75, 29.89, 28.95, 22.17, 9.75, 6.80.

[0103] LC-MS (ESI): m / z [M+H]+ calcd for C 28 H 41 N2O4S 501.2; found 501.2.

[0104] Example VI

[0105] This example provides a method for preparing compound 6, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(ethyl)(oxo)-λ6-thioimidoyl)butanamide. Referring to the preparation method of the compound in Example 1, different from Example 1, in the third step of step B, iodoethane was used as the raw material, and in the sixth step of step B, butyryl chloride was used as the raw material. The remaining steps were the same as those in Example 1, and 112 mg of the trifluoroacetate salt of compound 6, a white solid, was prepared.

[0106] The structural formula of compound 6 is as follows:

[0107]

[0108] The NMR and mass spectrometry data of compound 6 are as follows:

[0109] 11H NMR (400 MHz, Chloroform-d) δ 7.87 (s, 1H), 7.76 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 2.6 Hz, 1H), 6.78 (dd, J = 8.2, 2.0 Hz, 1H), 4.99 (s, 2H), 4.53 (s, 2H), 3.37 (p, J = 7.3 Hz, 2H), 2.73–2.57 (m, 2H), 2.35 (t, J = 7.4 Hz, 2H), 2.08–1.97 (m, 2H), 1.64 (q, J = 7.4 Hz, 2H), 1.51 (s, 6H), 1.41 (d, J = 0.9 Hz, 9H), 1.23 (t, J = 7.3 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H).

[0110] 13 13C NMR (101 MHz, Chloroform-d) δ 183.20, 148.62, 142.32, 139.61, 138.02, 135.52, 131.31, 124.22, 123.76, 122.38, 115.11, 80.89, 64.58, 52.41, 52.31, 50.61, 41.56, 39.73, 29.90, 28.96, 22.17, 19.12, 13.92, 6.82.

[0111] LC-MS (ESI): m / z [M+H]+ calcd for C 29 H 43 N2O4S 515.2; found 515.2.

[0112] Example VII

[0113] This example provides a preparation method of compound 7, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(propyl)(oxo)-λ6-thioimidoyl)acetamide. Referring to the preparation method of the compound in Example 1, different from Example 1, in the third step of step B, 1-bromopropane was used as the raw material, and in the sixth step of step B, acetyl chloride was used as the raw material. The remaining steps were the same as those in Example 1, and 233 mg of the trifluoroacetate salt of compound 7, a white solid, was prepared.

[0114] The structural formula of compound 7 is as follows:

[0115]

[0116] The NMR and mass spectrometry data of compound 7 are as follows:

[0117] 1 1H NMR (400 MHz, Chloroform-d) δ 7.87 (s, 1H), 7.79 (s, 1H), 7.48 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 6.78 (dd, J = 8.2, 2.1 Hz, 1H), 4.99 (s, 2H), 4.54 (s, 2H), 3.35 (ddd, J = 14.0, 11.0, 5.2 Hz, 1H), 3.25 (ddd, J = 14.1, 10.9, 5.2 Hz, 1H), 2.75–2.57 (m, 2H), 2.12 (s, 3H), 2.07–1.98 (m, 2H), 1.74 (dt, J = 12.3, 6.3 Hz, 1H), 1.68–1.57 (m, 1H), 1.52 (s, 6H), 1.41 (s, 9H), 0.98 (t, J = 7.4 Hz, 3H).

[0118] 13 13C NMR (101 MHz, Chloroform-d) δ 180.91, 148.63, 142.31, 139.54, 138.30, 135.46, 131.24, 124.27, 123.78, 122.40, 115.14, 80.93, 64.78, 57.50, 52.49, 52.39, 39.81, 29.86, 28.95, 26.70, 22.18, 15.89, 12.59.

[0119] LC-MS (ESI): m / z [M+H]+ calcd for C 28 H 41 N2O4S 501.2; found 501.2.

[0120] Example VIII

[0121] This example provides a preparation method of compound 8, N-((2-(4-(3-(tert-Butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(propyl)(oxo)-λ6-sulfinimine)propanamide. Referring to the preparation method of the compound in Example 1, different from Example 1, in the third step of step B, 1-bromopropane was used as the raw material, and in the sixth step of step B, propanoyl chloride was used as the raw material. The remaining steps were the same as those in Example 1, and 112 mg of the trifluoroacetate salt of compound 8, a white solid, was prepared.

[0122] The structural formula of compound 8 is shown as follows:

[0123]

[0124] The NMR and MS data of Compound 8 are as follows:

[0125] 1 H NMR(400MHz,Chloroform-d)δ7.88(s,1H),7.70(s,1H),7.44(d,J=8.0Hz,1H),6.85(d,J=8.1Hz,1H),6.82(d,J=2.1Hz,1H),6.75(dd,J=8.2,2.1Hz,1H),4.96(s,2H),4.45(s,2H),3.32(ddd,J=14.1,10.9,5.2Hz,1H),3.23(ddd,J=14.1,10.9,5.2Hz,1H),2.69–2.54(m,2H),2.38(q,J=7.5Hz,2H),2.05–1.94(m,2H),1.81–1.64(m,1H),1.64–1.52(m,1H),1.49(s,6H),1.38(d,J=0.9Hz,9H),1.07(t,J=7.5Hz,3H),0.95(t,J=7.4Hz,3H).

[0126] 13 C NMR(101MHz,Chloroform-d)δ183.97,148.62,142.31,139.50,138.61,135.46,131.28,124.25,123.77,122.38,115.12,80.91,64.64,57.53,52.43,52.34,39.77,32.77,29.89,28.96,22.18,15.96,12.63,9.74.

[0127] LC-MS(ESI):m / z[M+H]+calcd for C 29 H 43 N2O4S 515.2;found 515.2.

[0128] Example 9

[0129] This example provides a method for preparing compound 9, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(propyl)(oxo)-λ6-thiimine)butanamide. Referring to the preparation method of the compound in Example 1, the difference from Example 1 is that in the third step of step B, 1-bromopropane is used as the raw material, and in the sixth step of step B, butanoyl chloride is used as the raw material. The remaining steps are the same as those in Example 1, and 55 mg of the trifluoroacetate salt of compound 9, a white solid, was prepared.

[0130] The structural formula of compound 9 is shown below:

[0131]

[0132] The NMR and mass spectrometry data of compound 9 are shown below:

[0133] 1 H NMR(400MHz,Chloroform-d)δ7.89(s,1H),7.74(s,1H),7.46(d,J=8.1Hz,1H),6.87(dd,J=8.2,0.9Hz,1H),6.85(d,J=2.0Hz,1H),6.78(dd,J=8.1,2.0Hz,1H),4.99(s,2H),4.51(s,2H),3.35(ddd,J=15.9,10.9,5.2Hz,1H),3.26(td,J=14.4,12.7,5.3Hz,1H),2.72–2.58(m,2H),2.35(t,J=7.4Hz,2H),2.09–1.99(m,2H),1.73(q,J=6.7,6.2Hz,1H),1.62(p,J=7.3Hz,3H),1.51(s,6H),1.41(s,9H),0.98(d,J=7.4Hz,3H),0.92(d,J=7.4Hz,3H).

[0134] 13 C NMR(101MHz,Chloroform-d)δ183.17,148.61,142.32,139.54,138.67,135.50,131.30,124.21,123.75,122.35,115.10,80.89,64.55,57.55,52.39,52.30,41.59,39.74,29.91,28.97,22.18,19.11,15.99,13.92,12.64.

[0135] LC-MS(ESI):m / z[M+H]+calcd for C30 H 45 N2O4S 529.2; found 529.2.

[0136] Example Ten

[0137] This example provides a preparation method of Compound 10, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(butyl)(oxo)-λ6-sulfimide)acetamide. Referring to the preparation method of the compound in Example 1, the difference from Example 1 is that bromobutane is used as the raw material in the third step of Step B, and acetyl chloride is used as the raw material in the sixth step of Step B. The remaining steps are the same as those in Example 1. 139 mg of the trifluoroacetate of Compound 10, a white solid, was prepared.

[0138] The structural formula of Compound 10 is shown as follows:

[0139]

[0140] The NMR and mass spectrometry data of Compound 10 are shown as follows:

[0141] 1 H NMR(400MHz,Chloroform-d)δ8.06–7.61(m,2H),7.48(d,J = 8.0Hz,1H),6.87(d,J = 8.2Hz,1H),6.85(d,J = 2.1Hz,1H),6.78(dd,J = 8.2,2.1Hz,1H),5.01(s,2H),4.53(s,2H),3.37(ddd,J = 13.9,11.3,4.9Hz,1H),3.26(ddd,J = 14.0,11.4,5.0Hz,1H),2.73–2.59(m,2H),2.12(s,3H),2.07–2.00(m,2H),1.68(tdd,J = 12.5,8.9,5.0Hz,1H),1.62–1.54(m,1H),1.53(s,6H),1.41(s,9H),1.39–1.32(m,2H),0.89(t,J = 7.3Hz,3H).

[0142] 1313C NMR (101 MHz, Chloroform-d) δ 180.80, 148.63, 142.31, 139.55, 138.37, 135.47, 131.26, 124.27, 123.77, 122.38, 115.13, 80.92, 64.73, 55.74, 52.46, 52.36, 39.80, 29.88, 28.95, 26.72, 23.82, 22.18, 21.37, 13.43.

[0143] LC-MS (ESI): m / z [M+H]+ calcd for C 29 H 43 N2O4S 515.2; found 515.2.

[0144] Example XI

[0145] This example provides a preparation method of Compound 11, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(butyl)(oxo)-λ6-thioimidoyl)propanamide. Referring to the preparation method of the compound in Example 1, the difference from Example 1 is that bromobutane is used as the raw material in the third step of Step B, and propionyl chloride is used as the raw material in the sixth step of Step B. The remaining steps are the same as those in Example 1. 90 mg of the trifluoroacetate salt of Compound 11, a white solid, was prepared.

[0146] The structural formula of Compound 11 is shown as follows:

[0147]

[0148] The NMR and mass spectrometry data of Compound 11 are shown as follows:

[0149] 11H NMR (400 MHz, Chloroform-d) δ 7.89 (s, 1H), 7.75 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 2.1 Hz, 1H), 6.78 (dd, J = 8.1, 2.1 Hz, 1H), 5.00 (s, 2H), 4.51 (s, 2H), 3.38 (ddd, J = 15.9, 11.3, 4.9 Hz, 1H), 3.27 (ddd, J = 14.1, 11.3, 4.9 Hz, 1H), 2.69–2.58 (m, 2H), 2.40 (q, J = 7.5 Hz, 2H), 2.08–1.98 (m, 2H), 1.69 (dq, J = 13.4, 6.8, 6.0 Hz, 1H), 1.55 (d, J = 9.2 Hz, 1H), 1.51 (s, 7H), 1.41 (s, 10H), 1.39–1.30 (m, 2H).

[0150] 13 13C NMR (101 MHz, Chloroform-d) δ 183.85, 148.61, 142.31, 139.56, 138.65, 135.50, 131.32, 124.25, 123.77, 122.37, 115.11, 80.91, 64.52, 55.75, 52.38, 52.29, 39.74, 32.76, 29.91, 28.96, 23.91, 22.18, 21.39, 13.45, 9.74.

[0151] LC-MS (ESI): m / z [M+H]+ calcd for C 30 H 45 N2O4S 529.2; found 529.2.

[0152] Example XII

[0153] This example provides a preparation method of compound 12, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(butyl)(oxo)-λ6-sulfimido)butanamide. Referring to the preparation method of the compound in Example 1, 1-bromobutane was used as the raw material in the third step of Step B, and butanoyl chloride was used as the raw material in the sixth step of Step B. The remaining steps were the same as those in Example 1. 82 mg of the trifluoroacetate salt of compound 12 was prepared, which was a white solid.

[0154] The structural formula of compound 12 is as follows:

[0155]

[0156] The NMR and mass spectrometry data of Compound 12 are shown below:

[0157] 1 H NMR(400MHz,Chloroform-d)δ7.88(s,1H),7.69(s,1H),7.45(d,J=8.1Hz,1H),6.85(d,J=8.1Hz,1H),6.83(d,J=2.0Hz,1H),6.76(dd,J=8.1,2.1Hz,1H),4.97(s,2H),4.49(s,2H),3.35(ddd,J=16.0,11.2,4.9Hz,1H),3.25(ddd,J=14.0,11.3,4.9Hz,1H),2.68–2.55(m,2H),2.32(t,J=7.4Hz,2H),2.06–1.95(m,2H),1.75–1.52(m,4H),1.49(s,7H),1.38(s,10H),1.37–1.28(m,2H),0.90(t,J=7.4Hz,3H),0.86(t,J=7.3Hz,3H).

[0158] 13 C NMR(101MHz,Chloroform-d)δ183.30,148.62,142.31,139.47,138.67,135.43,131.27,124.24,123.76,122.36,115.11,80.92,64.64,55.74,52.43,52.33,41.56,39.79,29.90,28.96,23.89,22.19,21.38,19.12,13.92,13.44.

[0159] LC-MS(ESI):m / z[M+H]+calcd for C31H47N2O4S 543.2;found 543.2.

[0160] Example XIII

[0161] This example provides a method for preparing Compound 13, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(fluoromethyl)(oxo)-λ6-sulfimido)acetamide. Referring to the preparation method of the compound in Example 1, different from Example 1, in the third step of Step B, bromoiodomethane was used as the raw material, and in the sixth step of Step B, acetyl chloride was used as the raw material. The remaining steps were the same as those in Example 1, and 145 mg of the trifluoroacetate salt of Compound 13, a white solid, was prepared.

[0162] The structural formula of target compound 13 is shown as follows:

[0163]

[0164] The NMR and MS data of target compound 13 are shown as follows:

[0165] 1 H NMR(400MHz,Chloroform-d)δ8.05–7.79(m,2H),7.52(d,J=8.1Hz,1H),6.86(d,J=8.4Hz,1H),6.85(d,J=2.8Hz,1H),6.77(dd,J=8.1,2.1Hz,1H),5.71(dd,J=46.3,9.3Hz,1H),5.37(dd,J=46.8,9.2Hz,1H),5.04(s,2H),4.57(s,2H),2.70–2.57(m,2H),2.20(s,3H),2.08–1.96(m,2H),1.51(s,6H),1.40(d,J=1.0Hz,9H).

[0166] 13 C NMR(101MHz,Chloroform-d)δ180.87,148.65,142.34,140.91,135.66,134.97,131.22,129.83,124.36,123.74,122.37,115.14,92.53,90.28,80.93,64.93,52.54,52.35,39.60,29.89,28.94,26.81,22.15.19F NMR(376MHz,Chloroform-d)δ-75.48(s),-203.48(t,J=47.4Hz).

[0167] LC-MS(ESI):m / z[M+H]+calcd for C 26 H 36 FN2O4S 491.2;found 491.2.

[0168] Example XIV

[0169] This example provides a method for preparing Compound 14, N-((2-(4-(3-(tert-Butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(fluoropropyl)(oxo)-λ6-thioimidoyl)acetamide. Referring to the preparation method of the compound in Example 1, the difference from Example 1 is that 1-Fluoro-3-bromopropane is used as the raw material in the third step of Step B, and acetyl chloride is used as the raw material in the sixth step of Step B. The remaining steps are the same as those in Example 1. 197 mg of the trifluoroacetate salt of Compound 14, a white solid, was prepared.

[0170] The structural formula of Compound 14 is as follows:

[0171]

[0172] The NMR and mass spectrometry data of Compound 14 are as follows:

[0173] 1 H NMR(400MHz,Chloroform-d)δ7.90(s,1H),7.77(s,1H),7.49(d,J=8.0Hz,1H),6.87(d,J=8.1Hz,1H),6.85(d,J=2.0Hz,1H),6.78(dd,J=8.1,2.1Hz,1H),5.84(s,2H),4.98(s,2H),4.53(dd,J=6.6,4.5Hz,1H),4.41(dd,J=6.6,4.6Hz,1H),3.53(ddd,J=15.2,10.4,5.2Hz,1H),3.39(ddd,J=14.6,10.3,5.1Hz,1H),2.69–2.60(m,2H),2.13(s,4H),2.07–1.91(m,3H),1.52(s,6H),1.41(s,9H).

[0174] 13 C NMR(101MHz,Chloroform-d)δ180.98,148.65,142.32,139.71,138.09,135.59,131.19,124.44,123.77,122.39,115.15,82.02,80.95,80.34,64.90,52.53,52.43,39.88,29.84,28.94,26.66,23.63,23.42,22.19.19F NMR(376MHz,Chloroform-d)δ-75.61(s),-220.65(tt,J=46.9,25.0Hz).

[0175] LC-MS (ESI): m / z [M+H]+ calcd for C 28 H 40 FN2O4S 519.2; found 519.2.

[0176] Example 15

[0177] This example provides a preparation method of Compound 15, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(fluorobutyl)(oxo)-λ6-sulfimide)acetamide. Referring to the preparation method of the compound in Example 1, different from Example 1, 1-fluoro-4-bromobutane was used as the raw material in the third step of Step B, and acetyl chloride was used as the raw material in the sixth step of Step B. The remaining steps were the same as those in Example 1. 171 mg of the trifluoroacetate of Compound 15, a white solid, was prepared.

[0178] The structural formula of Compound 15 is as follows:

[0179]

[0180] The NMR and MS data of Compound 15 are as follows:

[0181] 1 H NMR (400 MHz, Chloroform-d) δ 7.85 (s, 2H), 7.48 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 2.1 Hz, 1H), 6.78 (dd, J = 8.3, 2.1 Hz, 1H), 4.98 (s, 2H), 4.53 (s, 2H), 4.47 (t, J = 5.2 Hz, 1H), 4.35 (t, J = 5.3 Hz, 1H), 3.44 (ddd, J = 15.0, 10.2, 5.3 Hz, 1H), 3.33 (ddd, J = 14.3, 10.5, 4.4 Hz, 1H), 2.72–2.58 (m, 2H), 2.12 (s, 3H), 2.07–1.99 (m, 2H), 1.88 (dq, J = 12.7, 5.8 Hz, 1H), 1.82–1.67 (m, 3H), 1.51 (s, 6H), 1.41 (d, J = 1.0 Hz, 9H).

[0182] 1313C NMR (101 MHz, Chloroform-d) δ 180.64, 148.64, 142.33, 139.74, 138.21, 135.64, 131.28, 124.32, 123.76, 122.39, 115.13, 83.97, 82.32, 80.90, 64.64, 55.54, 52.42, 52.32, 39.77, 29.88, 28.95, 28.81, 28.61, 26.75, 22.17, 18.84, 18.80. 19F NMR (376 MHz, Chloroform-d) δ -75.47 (s), -219.09 (tt, J=48.9, 26.0 Hz).

[0183] LC-MS (ESI): m / z [M+H]+ calcd for C 29 H 42 FN2O4S 533.2; found 533.2.

[0184] Example XVI

[0185] This example provides a preparation method of compound 16, (2-(4-(3-(tert-butyl)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(imino)(methyl)-λ6-thiourea. Add compound 1 (87 mg, 0.18 mmol), anhydrous potassium carbonate (0.1 g, 0.74 mmol) and methanol (5 ml) into a 50 ml single-necked flask, and react at 75 °C for 1.5 h under nitrogen protection. After the reaction solution is cooled to room temperature, pour it into water, extract with ethyl acetate (15 ml × 3), wash once with saturated brine (40 ml), dry over anhydrous sodium sulfate, and purify by pre-HPLC (C18 column, ACN: 0.1% TFA gradient elution from 10% to 60%) to obtain 31 mg of the trifluoroacetate of compound 16 as a white solid, with a yield of 31.62%.

[0186] The structural formula of compound 16 is shown as follows:

[0187]

[0188] The NMR and mass spectrometry data of compound 16 are shown as follows:

[0189] 11H NMR (400 MHz, Chloroform-d) δ 8.00 (d, J = 8.2 Hz, 1H), 7.96 (s, 1H), 7.49 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 6.78 (dd, J = 8.1, 2.0 Hz, 1H), 5.07 (s, 2H), 4.52 (s, 2H), 3.23 (s, 3H), 2.70–2.60 (m, 2H), 2.21–1.89 (m, 2H), 1.54 (s, 6H), 1.41 (d, J = 0.9 Hz, 9H).

[0190] 13 13C NMR (101 MHz, Chloroform-d) δ 148.56, 142.22, 139.53, 135.28, 131.13, 128.98, 123.66, 122.89, 122.24, 115.04, 80.89, 64.74, 52.31, 39.59, 29.83, 28.86, 22.13.

[0191] LC-MS (ESI): m / z [M+H]+ calcd for C 24 H 35 N2O3S 431.2; found 431.2.

[0192] Example XVII

[0193] This example provides a preparation method of compound 17, (2-(4-(3-(tert-Butyl)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(ethyl)(imino)-λ6-thiourea. Referring to the preparation method of the compound in Example XVI, the difference from Example XVI is that 145 mg of the trifluoroacetate salt of compound 17 was synthesized from compound 4 as the raw material, a white solid, and the yield was 63.15%.

[0194] The structural formula of compound 17 is as follows:

[0195]

[0196] The nuclear magnetic resonance and mass spectrometry data of compound 17 are as follows:

[0197] 11H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 4.3 Hz, 1H), 6.84 (d, J = 2.9 Hz, 1H), 6.78 (dd, J = 8.2, 2.0 Hz, 1H), 4.92 (s, 2H), 4.66 (s, 2H), 3.69 (dd, J = 14.6, 7.4 Hz, 1H), 3.57 (dt, J = 14.6, 7.2 Hz, 1H), 2.71–2.53 (m, 2H), 2.10–1.98 (m, 2H), 1.51 (s, 6H), 1.39 (s, 9H), 1.25 (t, J = 7.3 Hz, 3H).

[0198] 13 13C NMR (101 MHz, Chloroform-d) δ 148.60, 142.17, 141.31, 136.03, 131.16, 130.04, 124.39, 124.06, 123.75, 122.51, 115.11, 80.90, 65.02, 52.45, 52.31, 50.57, 39.71, 29.76, 28.79, 21.93, 6.76.

[0199] LC-MS (ESI): m / z [M+H]+ calcd for C 25 H 37 N2O3S 445.2; found 445.2.

[0200] Example XVIII

[0201] This example provides a method for preparing compound 18, (2-(4-(3-(tert-butyl)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(imino)(propyl)-λ6-thiourea. Referring to the preparation method of the compound in Example XVI, the difference from Example XVI is that 100 mg of the trifluoroacetate of compound 18 was synthesized using compound 7 as the raw material, a white solid, yield: 51.36%.

[0202] The structural formula of compound 18 is as follows:

[0203]

[0204] The NMR and mass spectrometry data of compound 18 are as follows:

[0205] 11H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J = 8.3 Hz, 1H), 7.89 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 6.86 (dd, J = 8.1, 1.0 Hz, 2H), 6.78 (dd, J = 8.2, 2.0 Hz, 1H), 4.79 (s, 4H), 3.33 (ddd, J = 15.8, 10.8, 5.3 Hz, 1H), 3.29–3.16 (m, 1H), 2.72–2.56 (m, 2H), 2.08–1.96 (m, 2H), 1.85–1.69 (m, 1H), 1.68–1.57 (m, 1H), 1.52 (s, 6H), 1.40 (d, J = 1.0 Hz, 9H), 0.96 (t, J = 7.4 Hz, 3H).

[0206] 13 13C NMR (101 MHz, Chloroform-d) δ 148.66, 142.30, 139.89, 135.49, 131.32, 129.67, 123.99, 123.79, 123.58, 122.53, 115.17, 80.94, 64.68, 58.49, 52.45, 52.33, 39.64, 29.90, 28.93, 22.16, 16.69, 12.60.

[0207] LC-MS (ESI): m / z [M+H]+ calcd for C 26 H 39 N2O3S 459.2; found 459.2.

[0208] Example XIX

[0209] This example provides a method for preparing compound 19, (2-(4-(3-(tert-butyl)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(butyl)(imino)-λ6-thiimide. Referring to the preparation method of the compound in Example XVI, the difference from Example XVI is that 100 mg of the trifluoroacetate of compound 19 was synthesized from compound 10 as the raw material, a white solid, and the yield was 67.37%.

[0210] The structural formula of compound 19 is as follows:

[0211]

[0212] The NMR and mass spectrometry data of compound 19 are as follows:

[0213] 11H NMR (400 MHz, Chloroform-d) δ 7.94–7.84 (m, 2H), 7.50 (d, J = 8.0 Hz, 1H), 6.83 (dd, J = 5.2, 3.1 Hz, 2H), 6.76 (dd, J = 8.2, 2.0 Hz, 1H), 4.92 (s, 2H), 4.61 (s, 2H), 3.76–3.63 (m, 1H), 3.58–3.45 (m, 1H), 2.71–2.53 (m, 2H), 2.09–1.94 (m, 2H), 1.75–1.60 (m, 1H), 1.49 (s, 7H), 1.37 (s, 9H), 1.35–1.25 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H).

[0214] 13 13C NMR (101 MHz, Chloroform-d) δ 148.68, 142.27, 141.75, 136.27, 131.21, 124.61, 124.15, 123.83, 122.55, 115.20, 81.00, 65.20, 55.22, 52.56, 52.43, 39.85, 29.84, 28.88, 23.94, 22.01, 21.01, 13.17.

[0215] LC-MS (ESI): m / z [M+H]+ calcd for C 27 H 41 N2O3S 473.2; found 473.2.

[0216] Example 20

[0217] This example provides a method for preparing compound 20, (2-(4-(3-(tert-butyl)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(fluoromethyl)(imino)-λ6-sulfimide. Referring to the preparation method of the compound in Example 16, different from Example 16, 81 mg of the trifluoroacetate salt of compound 20 was synthesized from compound 13 as the raw material, a white solid, yield: 65.44%.

[0218] The structural formula of compound 20 is as follows:

[0219]

[0220] The NMR and mass spectrometry data of compound 20 are as follows:

[0221] 11H NMR (400 MHz, Chloroform-d) δ 7.98 (d, J = 8.1 Hz, 1H), 7.92 (s, 1H), 7.48 (d, J = 8.1 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 6.77 (dd, J = 8.4, 2.1 Hz, 1H), 5.24–4.96 (m, 5H), 4.55 (s, 1H), 2.68–2.58 (m, 2H), 2.08–1.97 (m, 2H), 1.52 (s, 6H), 1.40 (d, J = 1.0 Hz, 9H).

[0222] 13 13C NMR (101 MHz, Chloroform-d) δ 148.65, 142.33, 139.94, 139.12, 135.09, 131.19, 130.27, 124.11, 123.97, 123.74, 122.35, 115.14, 93.83, 91.61, 80.96, 65.05, 52.63, 52.46, 39.63, 29.88, 28.93, 22.21. 19F NMR (376 MHz, Chloroform-d) δ -75.57 (s), -203.62 (t, J = 47.3 Hz).

[0223] LC-MS (ESI): m / z [M+H]+ calcd for C 24 H 34 FN2O3S 449.2; found 449.2.

[0224] Example 21

[0225] This example provides a method for preparing compound 21, (2-(4-(3-(tert-Butyl)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(fluoropropyl)(imino)-λ6-sulfimide. Referring to the preparation method of the compound in Example 16, different from Example 16, 126 mg of the trifluoroacetate salt of compound 21 was synthesized using compound 14 as the raw material, which was a white solid with a yield of 64.64%.

[0226] The structural formula of compound 21 is shown as follows:

[0227]

[0228] The NMR and MS data of compound 21 are shown as follows:

[0229] 11H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J = 6.5 Hz, 2H), 7.51 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 5.5 Hz, 1H), 6.84 (d, J = 2.6 Hz, 1H), 6.78 (dd, J = 8.2, 1.9 Hz, 1H), 4.95 (s, 2H), 4.61 (s, 2H), 4.49 (t, J = 5.7 Hz, 1H), 4.37 (t, J = 5.7 Hz, 1H), 3.73 (q, J = 7.9, 5.0 Hz, 1H), 3.58 (td, J = 10.1, 9.6, 5.3 Hz, 1H), 2.63 (dd, J = 11.1, 6.0 Hz, 2H), 2.23–1.85 (m, 4H), 1.51 (s, 6H), 1.39 (s, 9H).

[0230] 13 13C NMR (101 MHz, Chloroform-d) δ 148.69, 142.27, 141.11, 136.00, 131.23, 129.90, 124.50, 123.95, 123.83, 122.61, 115.21, 81.77, 81.01, 80.10, 65.12, 52.73, 52.55, 52.41, 39.82, 29.83, 28.87, 24.05, 23.84, 22.04, 19.84, 22.04. 19F NMR (376 MHz, Chloroform-d) δ -75.59 (s), -220.66 (tt, J = 47.9, 25.8 Hz).

[0231] LC-MS (ESI): m / z [M+H]+ calcd for C 26 H 38 FN2O3S 477.2; found 477.2.

[0232] Example 22

[0233] This example provides a method for preparing compound 22, (2-(4-(3-(tert-butyl)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindol-5-yl)(fluorobutyl)(imino)-λ6-sulfimide. Referring to the preparation method of the compound in Example 16, different from Example 16, 100 mg of the trifluoroacetate salt of compound 22 was synthesized from compound 15 as the raw material, which is a white solid, and the yield was 47.42%.

[0234] The structural formula of compound 22 is as follows:

[0235]

[0236] The NMR and mass spectrometry data of Compound 22 are as follows:

[0237] 1 H NMR(400MHz,Chloroform-d)δ7.91(d,J=8.8Hz,2H),7.48(d,J=8.0Hz,1H),6.85(dd,J=5.1,3.2Hz,2H),6.78(dd,J=8.3,2.0Hz,1H),4.77(s,4H),4.45(t,J=5.2Hz,1H),4.33(t,J=5.2Hz,1H),3.49(d,J=8.3Hz,1H),3.40(td,J=10.2,5.0Hz,1H),2.69–2.57(m,2H),2.10–1.97(m,2H),1.91–1.80(m,1H),1.80–1.64(m,3H),1.51(s,6H),1.39(d,J=1.0Hz,9H).

[0238] 13 C NMR(101MHz,Chloroform-d)δ148.68,142.30,140.38,135.74,131.32,129.74,124.20,123.81,123.71,122.60,115.20,83.96,82.31,80.94,64.82,56.14,52.47,52.36,39.70,29.87,28.91,28.68,28.48,22.10,19.40,19.36.19F NMR(376MHz,Chloroform-d)δ-75.45(s),-219.17(tt,J=47.6,26.5Hz).

[0239] LC-MS(ESI):m / z[M+H]+calcd for C 27 H 40 FN2O3S 491.2;found 491.2.

[0240] Application Example 1

[0241] The pharmacodynamic test method used in this application example is a method well-known to those skilled in the art; the sigma-2 receptor inhibition activity detection kit used in this application example can be obtained by those skilled in the art through commercial purchase. Sigma1 / sigma-2 receptor affinity activity test:

[0242] In a 96-well plate, the test compound and the reference compound were serially diluted 4-fold at 8 points, with 1 μL added to each well, and duplicate wells were arranged. The starting concentration of the reference compound Haloperidol was 1 μM. 1 μL of DMSO was added to the high signal control well (High control), and 1 μL of Haloperidol with a concentration of 200 μM (final concentration 1 μM) was added to the low signal control well (Low control). 100 μL of sigma-1R or sigma-2R cell membrane diluted to the experimental required concentration with 50 mM Tris-HCl (pH 7.4, Sigma, Cat: T1503-1KG) buffer was added to each well. 100 μL of 3H-DTG diluted to the experimental required concentration with 50 mM Tris-HCl (pH 7.4) buffer was added to each well. The 96-well plate was sealed and incubated on a shaker at 300 rpm at room temperature for 2 hours. At the same time, a GF / C filter plate (PerkinElmer, Cat: NET986250UC) was soaked with 0.3% PEI (Poly ethyleneimine, Sigma, Cat: P3143). After incubation, it was collected onto the GF / C filter plate using a cell harvester (PerkinElmer, model: C961961), washed 4 times with 50 mM Tris-HCl (pH 7.4) wash buffer, dried in an oven at 50 °C for 1 hour, the bottom of the dried GF / C filter plate was sealed with a film, 50 μL of scintillation fluid was added to each well and sealed, and readings were taken using a Microbeta (PerkinElmer, model: 2450 Microplate Counter). The percentage of activity was calculated using Microsoft Excel software, formula: %Activity = 100×(Sample RawValue - High Control Average) / (Low Control Average - High Control Average). Using GraphPad Prism 5 data analysis software, the Dose-response-Stimulation—log[antagonist]vs.response--Variable slope mode was selected for fitting analysis to obtain the IC50 values of each test sample. The results are shown in Table 1. As can be seen from Table 1, the compounds of the present invention have good sigma-2 inhibitory activity and selectivity, and can be further developed for the treatment of diseases related to abnormal sigma-2 receptors, including but not limited to drugs for the treatment of diseases such as tumors, Alzheimer's disease, schizophrenia, Lewy body dementia, etc.

[0243] Table 1 Results of sigma1 / sigma-2 receptor inhibition and affinity activities of the compounds of the present invention.

[0244]

[0245] The isoindole thioimide compounds prepared by the present invention can be used as sigma-2 receptor inhibitors, including but not limited to their applications in diseases related to overactivation of sigma-2 receptors such as tumor formation, non-malignant hyperproliferation, and nerve conduction disorders in neurodegenerative diseases. The diseases include ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, liver cancer, cervical cancer, bone metastatic cancer, papillary thyroid cancer, colon cancer, gastrointestinal stromal tumor, melanoma, mesothelioma, glioblastoma, osteosarcoma, multiple myeloma, hyperproliferative diseases, metastasis of primary tumor sites, myeloproliferative diseases, leukemia, metabolic diseases, neurodegenerative diseases, schizophrenia, dementia, amyotrophic lateral sclerosis, Parkinson's disease, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, hypereosinophilic syndrome, mastocytosis or mast cell leukemia.

[0246] The above description of the embodiments is to enable those of ordinary skill in the art to understand and use the invention. Obviously, those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative efforts. Therefore, the present invention is not limited to the above embodiments, and the improvements and modifications made by those skilled in the art without departing from the scope of the present invention should be within the protection scope of the present invention.

Claims

1. An isoindole thioimide compound, characterized in that, The chemical structural formula of the isoindole thioimide compound is shown in formula (I): Wherein, R1 is an alkyl group with 1 - 4 carbon atoms or a haloalkyl group with 1 - 4 carbon atoms; R2 is one of hydrogen, an alkyl group with 1 - 4 carbon atoms, a haloalkyl group with 1 - 4 carbon atoms, and an acyl group with 1 - 4 carbon atoms.

2. The isoindole thioimide compound according to claim 1, wherein The isoindole thioimide compound is one of the following compounds 1 - 22:

3. A method for preparing an isoindolethioimine compound as described in any one of claims 1 or 2, characterized in that, It includes the following steps: Step A: React catechol with isobutene to obtain intermediate A, react intermediate A with potassium iodide to obtain intermediate B, then react intermediate B with 2 - methylbut - 3 - yne - 2 - amine to obtain intermediate C, and react intermediate C with hydrazine hydrate to obtain solid D; Step B: React o - xylene with chlorosulfonic acid to obtain intermediate E; React intermediate E with triphenylphosphine to obtain intermediate F; React intermediate F successively with sodium borohydride, a haloalkane with different alkyl or fluoroalkyl substitutions, and m - chloroperbenzoic acid to obtain intermediate G; React intermediate G with ammonium carbamate and diacetoxyiodobenzene to obtain intermediate H; React intermediate H with an acyl chloride with different alkyl or fluoroalkyl substitutions to obtain intermediate I; React intermediate I with N - bromosuccinimide to obtain oily substance J; React the solid D obtained in Step A with the oily substance J obtained in Step B to obtain the isoindole thioimide compound.

4. The preparation method of an isoindole thioimide compound according to claim 3, characterized in that, In Step A, the specific preparation process of the intermediate B includes: Dissolve catechol in dichloromethane, add concentrated sulfuric acid at - 30 °C, then slowly dropwise add isobutene, slowly warm up to room temperature and stir overnight to obtain a reaction solution; Add triethylamine to the reaction solution at - 30 °C to quench, evaporate to dryness and separate by column chromatography to obtain intermediate A; Dissolve intermediate A in methanol, add potassium iodide and sodium hydroxide, slowly dropwise add sodium hypochlorite at 0 °C, after reacting for 3 h, add saturated ammonium chloride to the reaction solution, and extract with ethyl acetate, evaporate to dryness to obtain intermediate B.

5. The preparation method of an isoindole thioimide compound according to claim 3, characterized in that, In Step A, the specific preparation process of the solid D includes: Dissolve intermediate B in triethylamine, add 2 - methylbut - 3 - yne - 2 - amine, bis(triphenylphosphine)palladium chloride and copper(I) iodide, react under nitrogen protection for 3 h, then directly filter the reaction solution, evaporate to dryness, and separate by column chromatography to obtain intermediate C; Dissolve intermediate C in ethanol, add hydrazine hydrate, copper(II) sulfate pentahydrate and neocuproine, reflux overnight, extract with ethyl acetate, evaporate to dryness and separate by column chromatography to obtain solid D.

6. The preparation method of an isoindolylsulfimine compound according to claim 3, wherein, In Step B, the specific preparation process of the intermediate F includes: Dissolve o - xylene in chloroform, slowly dropwise add chlorosulfonic acid at 0 °C, after adding, stir at room temperature for two days to obtain a reaction solution, add the reaction solution to ice water, extract with dichloromethane, evaporate to dryness to obtain intermediate E; Dissolve intermediate E in xylene, add triphenylphosphine in batches, react at room temperature overnight, then evaporate to dryness, add petroleum ether and stir at - 10 °C to remove the excess triphenylphosphine, obtain a filtrate, evaporate the filtrate to dryness and separate by column chromatography to obtain intermediate F.

7. The preparation method of an isoindole thioimide compound according to claim 3, wherein, In Step B, the specific preparation process of the intermediate H includes: Dissolve the intermediate F in absolute ethanol, add sodium borohydride in batches, and then add halogenated hydrocarbons with different alkyl substitutions and different fluoroalkyl substitutions to react overnight to obtain a reaction solution; Extract the reaction solution with dichloromethane, add m-chloroperoxybenzoic acid at -30 °C, react for 3 h, wait for the reaction solution to return to room temperature, add saturated sodium carbonate solution to adjust the pH to neutral, then extract with dichloromethane, evaporate the solvent, and separate by column chromatography to obtain intermediate G; Dissolve the intermediate G in methanol, add ammonium carbamate and diacetoxyiodobenzene, stir at room temperature for 30 min, extract with dichloromethane, evaporate and separate by column chromatography to obtain intermediate H.

8. The preparation method of an isoindole thioimide compound according to claim 3, characterized in that, In step B, the specific preparation process of the oily substance J includes: Dissolve the intermediate H in dichloromethane, add triethylamine, slowly dropwise add acyl chlorides with different alkyl substitutions and different fluoroalkyl substitutions at 0 °C, transfer to room temperature and react for 1 h, then directly evaporate to dryness, and purify by column chromatography to obtain intermediate I; Dissolve the intermediate I in 1,2-dichloroethane, add N-bromosuccinimide and azobisisobutyronitrile, replace with nitrogen and react under reflux overnight, extract with dichloromethane, and purify by column chromatography to obtain the oily substance J.

9. The preparation method of an isoindole thioimide compound according to claim 3, characterized in that, In step B, the specific preparation process of the isoindoline thioimide compound includes: Dissolve the oily substance J obtained in step B and the solid D obtained in step A in tetrahydrofuran, add triethylamine, react at 50 °C for 18 h under nitrogen protection, filter by suction, directly evaporate the filtrate to dryness and separate by column chromatography to obtain a light brown oily substance, then add potassium carbonate, reflux at 70 °C for 1.5 h, extract with ethyl acetate, and then separate by column chromatography and purify by pre-HPLC to obtain the target compound.

10. Use of an isoindole thioimide compound as described in claim 1, characterized in that, The isoindoline thioimide compound is used as a sigma-2 receptor inhibitor.

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