Isoindole sulfirimine compounds and their use as sigma 2 receptor inhibitors

Abstract

This invention relates to isoindole sulfirimine compounds, methods for preparing them, and their use as sigma 2 receptor inhibitors. Compared to the prior art, the isoindole sulfirimine compounds prepared according to this invention can destabilize the binding of adjacent Aβ oligomers to synaptic receptors and remove Aβ oligomers from synapses by binding to sigma 2 receptors and deformatively regulating the sigma 2 receptor complex. This allows for further use in the preparation of novel therapeutic agents for tumors and neurodegenerative diseases.

Description

[Technical Field]

[0001] The present invention relates to the art of medicinal chemistry, and more particularly to isoindole sulfirimine compounds, methods for preparing the same, and their use as sigma 2 receptor inhibitors. [Background technology]

[0002] Alzheimer's disease (AD) is a group of neurodegenerative diseases characterized by the progressive loss of language, memory, and cognitive function. Treating AD has been extremely challenging over the past few decades. On the one hand, the global cost of treating and caring for AD is enormous. On the other hand, with the exception of aducanumab and lecanemab, the Food and Drug Administration (FDA) has not approved any AD treatments since 2003 (Brain. 2023, 146(10), 3969-3990). The main AD treatments currently used clinically are donepezil, carboplatin, galantamine, and memantine. Donepezil, carboplatin, and galantamine are acetylcholinesterase inhibitors (AChEIs). Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist. However, these drugs only temporarily slow the progression of the disease and cannot completely cure AD. According to the International Alzheimer's Disease Association, approximately 50 million people suffered from dementia in 2018, and this number is projected to triple by 2050 (Alzheimers Dement. 2023, 19 (4), 1598-1695). Therefore, developing treatments for Alzheimer's Disease is a challenging task, and with rising healthcare costs and an increasing number of people suffering from the disease, research and development of Alzheimer's Disease treatments has become an urgent priority.

[0003] Sigma-2 receptors are a type of receptor widely distributed in peripheral tissues such as the central nervous system, pancreas, liver, and gastrointestinal tract, and may be a potential target for the treatment of tumors, neurodegenerative diseases, and neuralgia. Recently, sigma-2 receptors were isolated from calf liver (Proc. Natl. Acad. Sci. USA 2017, 114 (27), 7160-7165), and biochemical analysis suggests that the sigma-2 receptor is transmembrane protein 97 (TMEM97). TMEM97 is associated with low-density lipoprotein receptor (LDLR), and siRNA knockdown of TMEM97 reduces LDLR-mediated endocytosis of low-density lipoprotein (LDL). Other studies have shown that the sigma-2 / TMEM97 receptor and PGRMC1 are jointly involved in the formation of the LDL-LDLR complex and are important for LDL uptake. Furthermore, activation of the sigma-2 / TMEM97 receptor has neuroprotective effects (ACS Chem Neurosci, 2019, 10(3), 1595-1602). In 2021, the crystal structure of the sigma-2 receptor was also elucidated, providing significant convenience for the design of sigma-2 receptor ligands (Nature 2021, 600(23), 759).

[0004] A synapse is a structure through which an impulse from one neuron is transmitted to another neuron or other intercellular contact, and is the site where functional connections between neurons take place. Some populations have been shown to have AD-related pathological features in their brains (e.g., amyloid plaques and neurofibrillary tangles) but do not develop AD, possibly because the unique synaptic protein composition of such populations is resistant to β-amyloid and tau proteins, thus avoiding impairment of synaptic function. However, in most AD patients, Aβ oligomers cause synaptic dysfunction and synaptic loss by binding to various receptors on the synapse, affecting information transmission between neurons in the brain. Cognition Therapeutic has discovered that inhibition of sigma-2 receptors destabilizes the binding of Aβ oligomers to synaptic receptors, removing Aβ oligomers from the synapse and restoring synaptic function. Cognition Therapeutic discovered that N-allylpropyl-N-allylmethylamine or allylpropylisoindole compounds from ginger oil possess good sigma-2 receptor binding activity using supercritical fluid extraction (SFE). After docking and designing the crystal structure of the sigma-2 receptor protein, candidate compound CT1812 was obtained. CT1812 exhibits good in vitro and in vivo activity and BBB permeability, and in vivo probe testing has shown that CT1812 increases cerebrospinal fluid β-amyloid (aβ) concentration 1 hour after administration, suggesting potential for the treatment of AD, and is currently in Phase II clinical trials (Alzheimers Dement. 2021, 17(8), 1365-1382). However, CT1812 has low selectivity for sigma-1 and sigma-2 receptors and low oral bioavailability.

[0005] Therefore, it is urgent to research compounds that effectively inhibit sigma 2 receptor activity and methods for preparing them. [Overview of the project] [Problems that the invention aims to solve]

[0006] The object of the present invention is to provide isoindole sulfirimine compounds, methods for preparing them, and their use as sigma 2 receptor inhibitors, in order to overcome the aforementioned drawbacks of the prior art. The present invention effectively inhibits sigma 2 receptor activity by binding to the sigma 2 receptor and deformatively modulating the sigma 2 receptor complex, and can be further used in the preparation of novel therapeutic agents for tumors and neurodegenerative diseases. [Means for solving the problem]

[0007] The object of the present invention can be achieved by the following technical solutions:

[0008] A first aspect of the present invention provides an isoindole sulfirimine compound or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, characterized in that the isoindole sulfirimine compound has the chemical structural formula shown in chemical formula (I). JPEG2026515577000001.jpg2789 Equation (I)

[0009] Here, R1 is an alkyl group having 1 to 4 carbon atoms or a halogenated alkyl group having 1 to 4 carbon atoms, and R2 is hydrogen, an alkyl group having 1 to 4 carbon atoms, a halogenated alkyl group having 1 to 4 carbon atoms, or an acyl group having 1 to 4 carbon atoms.

[0010] In some embodiments, R1 is one selected from methyl, ethyl, propyl, and butyl.

[0011] In some embodiments, R1 is selected from fluorine-substituted methyl, fluorine-substituted ethyl, fluorine-substituted propyl, and fluorine-substituted butyl.

[0012] In some embodiments, the number of fluorine atoms is 1, 2, or 3.

[0013] In some embodiments, R1 is -CH2F.

[0014] In some embodiments, R2 is H.

[0015] In some embodiments, R2 is one selected from formyl, acetyl, propionyl, and butyryl.

[0016] In some embodiments, the isoindole sulfirimine compound is one of the following compounds 1-22. JPEG2026515577000002.jpg129166

[0017] A second aspect of the present invention provides a pharmaceutical composition comprising an isoindole sulfirimine compound described in any one of the above descriptions, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0018] A third aspect of the present invention provides the use of any of the isoindole sulfirimine compounds described in the first aspect of the present invention, their stereoisomers, solvates, or pharmaceutically acceptable salts, or the pharmaceutical composition described in the second aspect of the present invention, as a sigma-2 receptor inhibitor.

[0019] A fourth aspect of the present invention provides a method for treating or preventing a disease associated with hyperactivation of the sigma-2 receptor, comprising administering a therapeutically or prophylactically effective amount of any isoindole sulfirimine compound described in the first aspect of the present invention, its stereoisomer, solvate, or pharmaceutically acceptable salt, or a pharmaceutical composition described in the second aspect of the present invention.

[0020] In some embodiments, the disease is selected from tumorigenesis, non-malignant hyperplasia, neurodegenerative diseases, and nerve conduction disorders.

[0021] In some embodiments, the disease is selected from ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, hepatocellular carcinoma, cervical cancer, bone metastasis, papillary thyroid carcinoma, colorectal cancer, gastrointestinal stromal tumors, melanoma, mesothelioma, glioblastoma, osteosarcoma, multiple myeloma, hyperproliferative disorders, metastasis of primary tumor sites, myeloproliferative disorders, leukemia, metabolic disorders, neurodegenerative diseases, schizophrenia, dementia, tachycardia, Parkinson's disease, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease (COPD), osteoporosis, eosinophilic syndrome, mast cell hyperplasia, mast cell leukemia, Alzheimer's disease, schizophrenia, and Lewy body dementia.

[0022] In some embodiments, the disease is Alzheimer's disease.

[0023] A fifth aspect of the present invention provides a method for producing an isoindole sulfirimine compound, comprising the following steps:

[0024] Step A: Catechol is reacted with isobutene to obtain intermediate A, intermediate A is reacted with potassium iodide to obtain intermediate B, intermediate B is reacted with 2-methylbuto-3-in-2-amine to obtain intermediate C, and intermediate C is reacted with hydrazine hydrate to obtain solid D.

[0025] Step B: React o-xylene with chlorosulfonic acid to obtain intermediate E, react intermediate E with triphenylphosphine to obtain intermediate F, and sequentially react intermediate F with a sodium boron reducing agent, a halogenated hydrocarbon having a different alkyl or fluoroalkyl substituent, and m-chloroperbenzoic acid to obtain intermediate G. React intermediate G with ammonium carbamate and diacetyliodobenzene to obtain intermediate H, react intermediate H with acyl loride having a different alkyl or fluoroalkyl substituent to obtain intermediate I, and react intermediate I with N-bromosubstituted butanezimide to obtain oily substance J.

[0026] The solid D obtained in step A and the oily substance J obtained in step B are reacted to obtain an isoindole sulfirimine compound.

[0027] Furthermore, in step A, the specific manufacturing process for intermediate B is as follows:

[0028] Catechol is dissolved in dichloromethane, concentrated sulfuric acid is added at -30°C, isobutene is slowly added dropwise, and the mixture is stirred overnight while gradually returning to room temperature to obtain the reaction solution.

[0029] The reaction mixture is quenched by adding triethylamine at -30°C, then dried under reduced pressure and separated by column chromatography.

[0030] Intermediate A is dissolved in methanol, potassium iodide and sodium hydroxide are added, then sodium hypochlorite is slowly added dropwise at 0°C, saturated ammonium chloride is added to the reaction mixture after 3 hours, and after extraction with ethyl acetate, intermediate B is obtained by drying under reduced pressure.

[0031] Furthermore, in step A, the specific manufacturing process for the solid D described above is as follows:

[0032] Intermediate B is dissolved in triethylamine, and 2-methylbuto-3-in-2-amine, bis(triphenylphosphine)palladium(II) chloride, and copper(I) iodide are added. The mixture is reacted under a nitrogen atmosphere for 3 hours, then removed by direct suction filtration and dried under reduced pressure. Intermediate C is separated and obtained by column chromatography.

[0033] Intermediate C is dissolved in ethanol, hydrazine hydrate, copper sulfate pentahydrate, and neocuproin are added, and after refluxing overnight, the mixture is extracted with ethyl acetate, and after drying under reduced pressure, solid D is obtained by column chromatography.

[0034] Furthermore, in step B, the specific manufacturing process for the above intermediate F is as follows:

[0035] Dissolve o-xylene in chloroform, slowly add chlorosulfonic acid dropwise at 0°C, and stir at room temperature for 2 days to obtain the reaction mixture. Add the reaction mixture to ice water, extract with dichloromethane, and then reduce to dryness to obtain intermediate E.

[0036] Intermediate E is dissolved in xylene, triphenylphosphine is added in batches, and the mixture is reacted overnight at room temperature. After drying under reduced pressure, petroleum ether is added and the mixture is stirred at -10°C. After removing excess triphenylphosphine, the filtrate is obtained, dried under reduced pressure, and intermediate F is separated and obtained by column chromatography.

[0037] Furthermore, in step B, the specific manufacturing process for the above intermediate H is as follows:

[0038] Intermediate F is dissolved in anhydrous ethanol, sodium borohydride is added in batches, then halogenated hydrocarbons having different alkyl substituents and different fluoroalkyl substituents are added, and the mixture is reacted overnight to obtain the reaction solution;

[0039] After extracting the reaction mixture with dichloromethane, m-chloroperbenzoic acid is added at -30°C and the mixture is reacted for 3 hours. After returning the reaction mixture to room temperature, saturated sodium carbonate solution is added to adjust the pH to neutral, followed by dichloromethane extraction, removal of the solvent under reduced pressure, and separation of intermediate G by column chromatography.

[0040] Intermediate G is dissolved in methanol, ammonium carbamate and diacetyliodobenzene are added, and the mixture is stirred at room temperature for 30 minutes. Then, it is extracted with dichloromethane, dried under reduced pressure, and intermediate H is obtained by column chromatography.

[0041] Furthermore, in step B, the specific manufacturing process for the oily substance J is as follows:

[0042] Intermediate H is dissolved in dichloromethane, triethylamine is added, and then different alkyl-substituted or fluoroalkyl-substituted acilclorides are slowly added dropwise at 0°C. The reaction is allowed to proceed at room temperature for 1 hour, and then directly reduced to dryness under reduced pressure. Intermediate I is obtained and purified by column chromatography;

[0043] Intermediate I is dissolved in 1,2-dichloroethane, N-bromosuccinimide and azobisisobutyronitrile are added, the mixture is purged with nitrogen and refluxed overnight, extracted with dichloromethane, and purified by column chromatography to obtain oily substance J.

[0044] Furthermore, in step B, the specific manufacturing process for the above heteroindole-thioimidazoline compound is as follows:

[0045] The oil J obtained in step B and the solid D obtained in step A were dissolved in tetrahydrofuran (THF), triethylamine was added, and the mixture was reacted at 50°C for 18 hours under nitrogen protection. The reaction mixture was vacuum filtered, and the filtrate was directly evaporated and dried to obtain a light brown oily substance by column chromatography. Subsequently, potassium carbonate was added, and the mixture was reacted in a reflux state at 70°C. The mixture was extracted with ethyl acetate, and the target compound was obtained by purification using column chromatography and pre-HPLC.

[0046] The present invention further provides applications for isoindole sulfirimine compounds, which are used as sigma-2 receptor inhibitors. [Effects of the Invention]

[0047] Compared to conventional technology, the present invention offers the following advantages and beneficial effects:

[0048] The isoindole sulfirimine compounds prepared according to the present invention effectively inhibit sigma 2 receptor activity by binding to the sigma 2 receptor and deformatively regulating the sigma 2 receptor complex, thereby destabilizing the binding of adjacent Aβ oligomers to the receptor on the synapse and removing Aβ oligomers from the synapse. This allows for further use in the preparation of novel therapeutic agents for tumors and neurodegenerative diseases.

[0049] As used herein, “pharmaceutically acceptable salt” refers to a derivative of a disclosed compound, which is modified by converting an existing acidic or base portion of the parent compound into its salt form (for example, by reacting a free base with a suitable organic acid). Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic salts of basic residues such as amines, and base or organic salts of acidic residues such as carboxylic acids. Typical acid addition salts include acetates, adipices, alginates, ascorbicates, aspartates, benzenesulfons, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfons, citrates, cyclopentanepropions, diglucons, dodecyl sulfates, ethanesulfons, fumarates, glucoheptons, hydrobroms, hydrochlorides, hydroiodides, 2-hydroxyethanesulfons, lactates, and laurates. This includes lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, hexadecanate, pectinate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecylate, trifluoroacetate, valerate, etc. [Modes for carrying out the invention]

[0050] Specific embodiments of the present invention will be described in detail below with reference to examples. These embodiments are carried out based on the programs described herein and provide detailed embodiments and specific operating procedures, but the scope of protection of the present invention is not limited to the following embodiments.

[0051] The present invention will be described in more detail using the following specific examples. Unless explicitly stated in this invention, features such as component models, material names, connection structures, preparation methods, materials, structures, or composition ratios are considered general technical features disclosed in the prior art. The present invention provides an isoindole-sulfirumimine compound having the chemical structure shown in formula (I). JPEG2026515577000003.jpg2789 Equation (I)

[0052] Here, R1 is an alkyl group having 1 to 4 carbon atoms or a halogenated alkyl group having 1 to 4 carbon atoms, and R2 is hydrogen, an alkyl group having 1 to 4 carbon atoms, a halogenated alkyl group having 1 to 4 carbon atoms, or an acyl group having 1 to 4 carbon atoms.

[0053] The present invention also provides a method for preparing isoindole-sulfylimine compounds, comprising the following steps:

[0054] Step A: Dissolve catechol in dichloromethane, add a catalytic amount of concentrated sulfuric acid at -30°C, then slowly add isobutene dropwise, slowly return to room temperature and stir overnight, quench the reaction mixture with triethylamine at -30°C, dry the reaction mixture and separate by column chromatography to obtain brown oil A; dissolve oil A in methanol, add potassium iodide and sodium hydroxide, then slowly add sodium hypochlorite dropwise at 0°C. After reacting at 0°C for 3 hours, add saturated ammonium chloride to the reaction mixture and extract with ethyl acetate to obtain brown oil B; dissolve oil B in triethylamine, then add 2-methylbuto-3-in-2-amine, bis(triphenylphosphine)palladium copper chloride and copper iodide, react under nitrogen protection for 3 hours, then filter the reaction mixture directly, dry and separate by column chromatography to obtain yellow solid C. The yellow solid C is dissolved in ethanol, then hydrazine hydrate, copper sulfate pentahydrate, and neocuproine are added, and after refluxing overnight, the mixture is extracted with ethyl acetate and separated by column chromatography to obtain the yellow solid D. The reaction equation is shown in equation (II). JPEG2026515577000004.jpg17157 Formula (II)

[0055] Step B: Dissolve oxylene in chloroform, slowly add chlorosulfonic acid dropwise at 0°C, stir at room temperature for 2 days after addition, add the reaction mixture to ice water, extract with dichloromethane, and dry to obtain pale yellow oil E; dissolve oil E in xylene, add triphenylphosphine in batches, react overnight at room temperature, dry, add petroleum ether at -10°C to remove excess triphenylphosphine, evaporate the filtrate to obtain yellow-green oil F; dissolve yellow-green oil F in anhydrous ethanol, add sodium boride in batches, then add different alkyl-substituted or different fluoroalkyl-substituted halogenated hydrocarbons, react overnight, extract the reaction mixture with dichloromethane, and proceed directly to the next step; add m-chlorophosphate to the above dichloromethane solution at -30°C Add fuzzy acid, then react at this temperature for 3 hours, then return the reaction mixture to room temperature, add saturated sodium carbonate solution to adjust the pH to neutral, extract with dichloromethane, evaporate the solvent and separate by column chromatography to obtain pale yellow oil G; dissolve pale yellow oil G in methanol, then add ammonium carbamate and diacetyliodobenzene, stir at room temperature for 30 minutes, extract the reaction mixture with dichloromethane and separate by column chromatography to obtain brown oil H; dissolve brown oil H in dichloromethane, then add triethylamine, slowly add different alkyl-substituted and different fluoroalkyl-substituted acyl lorides dropwise at 0°C, react at room temperature for 1 hour, then evaporate directly and purify by column chromatography to obtain oil I. Dissolve oil I in 1,2-dichloroethane, then add N-bromo-substituted succinimide and azobisisobutyronitrile, reflux overnight under nitrogen protection, extract with dichloromethane and purify by column chromatography to obtain brown oil J. Finally, the brown oil J obtained is separated by column chromatography, and the reaction mixture is extracted with dichloromethane. The final brown oil J and the yellow solid D obtained in step A are dissolved in tetrahydrofuran, then triethylamine is added, and the mixture is reacted at 50°C for 18 hours under nitrogen protection. The mixture is then filtered by suction, the filtrate is evaporated, and the mixture is separated by column chromatography to obtain a light brown oil. Potassium carbonate is then added, and the mixture is refluxed at 70°C for 1.5 hours.The target compound is extracted with ethyl acetate and purified by column chromatography and pre-HPLC. The reaction equation is shown in equation (III): JPEG2026515577000005.jpg35157 Formula (III) [Examples]

[0056] Example 1 This example provides a method for preparing compound 1, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(methyl)(oxo)-λ6-thioimide)acetamide.

[0057] Step A Step 1: Catechol (30.00 g, 272.45 mmol) and dichloromethane (150 ml) were added to a 500 ml three-necked flask. A catalytic amount of concentrated sulfuric acid (1.4 ml) was added at -35°C, and then freshly prepared isobutene (152.62 g, 2720 mmol) was slowly added dropwise. After addition, the reaction mixture was gradually returned to room temperature and stirred overnight. Triethylamine (3 ml) was added to the reaction mixture to quench it, and after drying, it was separated by column chromatography (EA / PE = 1:10) to obtain 30 g of brown oil A. Yield: 65.60%. LC-MS (ESI): m / z [M+H] + Calculated value C 10 H 14 N a O2189.1; Measured value 189.1.

[0058] Step 2: Brown oil A (14.00 g, 84.23 mmol), potassium iodide (13.98 g), sodium hydroxide (3.37 g, 84.23 mmol), and methanol (80 ml) were added to a 500 ml three-necked flask. Sodium hypochlorite (83.86 ml, 84.23 mmol) was slowly added dropwise at 0 °C over 1 hour, and then the reaction was carried out at 0 °C for 3 hours. A saturated ammonium chloride solution (250 ml) was added to the reaction solution, and it was extracted with ethyl acetate (250 ml × 2), washed once with saturated brine (400 ml), dried over anhydrous sodium sulfate, and 23.8 g of brown oil B was obtained. Yield: 96.71%. LC-MS (ESI): m / z [M-H]- calculated value C 10 H 12 IO2291.0; measured value 291.0.

[0059] Step 3: Brown oil 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), iodine (0.11 g, 0.57 mmol), and triethylamine (40 ml) were added to a 100 ml vial and reacted for 3 hours under nitrogen protection. The reaction solution was directly evaporated, filtered, and separated by column chromatography (EA / PE = 1:4) to obtain 2.38 g of yellow solid C. Yield: 85.00%. LC-MS (ESI): m / z [M+H] + Calculated value C 15 H 26 NO2248.1; measured value 248.1.

[0060] Step 4: 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 anhydrous ethanol (10 ml) were added to a 50 ml vial and refluxed under reduced pressure for 18 hours. The reaction mixture was cooled to room temperature, water (20 ml) was added, and the mixture was extracted with ethyl acetate (15 ml × 3). The mixture was washed once with saturated brine (50 ml) and dried over anhydrous sodium sulfate. Separation by column chromatography (EA / PE = 1:1) yielded 0.20 g of yellow solid D. Yield: 66.67%. LC-MS (ESI): m / z [M+H] + Calculated value C 15 H 26 NO2252.1; Measured value: 252.1.

[0061] Step B: Step 1: Oxylene (7,30 g, 282.59 mmol) and chloroform (90 ml) were added to a 500 ml vial, and chlorosulfonic acid (72.55 g, 721.70 mmol) was slowly added dropwise at 0°C. After addition, the reaction mixture was gradually returned to room temperature and stirred for 2 days. The reaction mixture was slowly added to ice water, extracted with dichloromethane (200 ml x 3), washed once with saturated brine (500 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 54.30 g of pale yellow oil E. Yield: 94.00%. LC-MS (ESI): m / z [M+H] + Calculated value C8H 11 O3S 187.0; Measured value 187.1.

[0062] Step 2: Pale yellow oil E (10.00 g, 48.90 mmol) and xylene (80 ml) were added to a 250 ml single-necked flask. Triphenylphosphine (38.00 g, 146.60 mmol) was added in batches at 0°C, and the mixture was allowed to react overnight at room temperature. The reaction mixture was dried, petroleum ether (80 ml) was added, and the mixture was stirred at -10°C for 30 minutes. Excess triphenylene was filtered off. The filtrate was dried and separated by column chromatography (100% PE) to obtain 5.80 g of yellowish-green oil F. Yield: 86.60%. LC-MS (ESI): m / z [M+H] + Calculated value C 16 H 18 S2275.1; Measured value 275.1.

[0063] Step 3: Add F (0.5 g, 1.82 mmol) and anhydrous ethanol (20 ml) to a 100 ml two-necked flask. Add sodium boride (0.21 g, 5.47 mmol) in batches at 0°C, stir for 30 minutes, then add iodomethane (0.57 g, 4.00 mmol) and react at room temperature for 3 hours. Pour the reaction mixture into saturated ammonium chloride (20 ml), extract with dichloromethane (20 ml x 3), wash once with saturated saline solution (50 ml), dry with anhydrous sodium sulfate, and draw the filtrate into a two-necked flask to proceed directly to the next reaction.

[0064] Step 4: The above filtrate was cooled to -30°C, m-chloroperbenzoic acid (0.63 g, 3.61 mmol) was added in batches, and the mixture was reacted at this temperature for 3 hours. The reaction mixture was gradually returned to room temperature, the pH was adjusted to neutral by adding saturated sodium carbonate solution, and the mixture was transferred to a separatory funnel. It was extracted with dichloromethane (50 ml × 3), washed once with saturated saline solution (150 ml), and dried over anhydrous sodium sulfate. The solvent was dried, and the mixture was separated by column chromatography (EA / PE = 2:3) to obtain 0.45 g of pale yellow oil G. Yield: 73.77%. LC-MS (ESI): m / z [M+H] + Calculated value C9H 13 OS 169.1; Measured value 169.1.

[0065] Step 5: Pale yellow oil G (2.30 g, 13.67 mmol), ammonium carbamate (4.27 g, 54.68 mmol), diacetyliodobenzene (13.20 g, 41.01 mmol), and methanol (45 ml) were added to a 100 ml single-necked flask and stirred at room temperature for 30 minutes. The reaction mixture was poured into saturated sodium bicarbonate solution, extracted with dichloromethane (50 ml x 3), washed once with saturated brine (100 ml), and dried over anhydrous sodium sulfate. Separation by column chromatography (EA / PE = 1:1) yielded 2.00 g of brown oil H. Yield: 79.83%. LC-MS (ESI): m / z [M+H] + Calculated value C9H 14 NOS 184.1; Measured value 184.1.

[0066] Step 6: Brown oil H (0.50 g, 2.73 mmol), triethylamine (0.36 g, 3.55 mmol), and anhydrous dichloromethane (15 ml) were added to a 100 ml vial. After purging with nitrogen, the reaction mixture temperature was lowered to 0°C, and acetyl chloride (0.26 g, 3.28 mmol) was slowly added dropwise. The mixture was reacted for 1 hour after addition. The reaction mixture was dried directly and purified 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] + Calculated value C 11 H 16 NO2S 226.1; Measured value 226.1.

[0067] Step 7: I (0.30 g, 1.33 mmol), N-bromosuccinimide (0.57 g, 3.19 mmol), azobisisobutyronitrile (21.84 mg, 0.13 mmol), and 1,2-dichloroethane (20 ml) were added to a 50 ml single-necked flask and refluxed overnight under nitrogen purging. The reaction mixture was cooled to room temperature, poured into water, extracted with dichloromethane (20 ml × 3), washed once with saturated saline (50 ml), and dried over anhydrous sodium sulfate. Separation by column chromatography (EA / PE = 1:4) yielded 0.26 g of brown oil J. Yield: 51.82%.

[0068] Step 8: To a 50 ml vial, brown oil J (0.13 g, 0.52 mmol), yellow solid D obtained in Step A (0.23 g, 0.59 mmol), triethylamine (0.16 g, 1.57 mmol), and tetrahydrofuran (15 ml) were added and the mixture was reacted at 50°C for 18 hours under nitrogen protection. The reaction mixture was cooled to room temperature, the filtrate was dried directly, and the mixture was separated by column chromatography (EA / DCM = 1:4) to obtain 0.15 g of light brown oil. Yield: 60.00%. Further purification by pre-HPLC (C18 column, ACN: 0.1%, TFA 10%~60% gradient elution) was performed to obtain 120 mg of trifluoroacetate of target compound 1. Yield: 39.12%.

[0069] The structural formula of compound 1 is as follows. JPEG2026515577000006.jpg3173

[0070] The NMR and MS data for compound 1 are as follows: 1H 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). 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. LC-MS (ESI): m / z [M+H] + Calculated value C 26 H 37 N2O4S 473.2; Measured value 473.2. [Examples]

[0071] Example 2 This example provides a method for preparing compound 2, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(methyl)(oxo)-λ6-thioimide)propionamide. The preparation method of the compound is the same as in Example 1, except that propionyl chloride is used as a starting material in step 6 of step B, and the other steps are the same as in Example 1. 112 mg of the trifluoroacetate of compound 2 was prepared as a white solid and obtained.

[0072] The structural formula of compound 2 is as follows. JPEG2026515577000007.jpg3177

[0073] The NMR and MS data for compound 2 are as follows: 1 H 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). 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. LC-MS (ESI): m / z [M+H] + Calculated value C 27 H 38 N2O4S 487.2; Measured value 487.2. [Examples]

[0074] Example 3 This example provides a method for preparing compound 3, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(methyl)(oxo)-λ6-thioimide)butanamide. The preparation method of the compound is the same as in Example 1, except that butyryl chloride is used as a starting material in step 6 of step B, and the other steps are the same as in Example 1. 84 mg of the trifluoroacetate of compound 3 was prepared as a white solid and obtained.

[0075] The structural formula of compound 3 is as follows. JPEG2026515577000008.jpg2883

[0076] The NMR and MS data for compound 3 are as follows: 1 H 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). 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. LC-MS (ESI): m / z [M+H] + Calculated value C 28 H 40 N2O4S 501.2; Measured value 501.2. [Examples]

[0077] Example 4 This example provides a method for preparing compound 4, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(ethyl)(oxo)-λ6-thioimide)acetamide. The preparation method of the compound in Example 1 is the same as in Example 1, except that ethyl iodide is used as a starting material in the third step of step B, and acetyl chloride is used as a starting material in the sixth step of step B, while the other steps are the same as in Example 1. 243 mg of the trifluoroacetate of compound 4 was prepared as a white solid and obtained.

[0078] The structural formula of compound 4 is as follows. JPEG2026515577000009.jpg2879

[0079] The NMR and MS data for compound 4 are as follows: 1 H 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). 13¹³C 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. LC-MS (ESI): m / z [M+H] + Calculated value C 27 H 39 N2O4S 487.2; Measured value 487.2. [Examples]

[0080] Example 5 This example provides a method for preparing compound 5, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(ethyl)(oxo)-λ6-thioimide)propionamide. Referring to the compound preparation method of Example 1, the difference from Example 1 is that ethyl iodide is used as a starting material in step 3 of step B, and propionyl chloride is used as a starting material in step 6 of step B; the other steps are the same as in Example 1. 100 mg of the trifluoroacetate of compound 5 was prepared as a white solid.

[0081] The structural formula of compound 5 is as follows. JPEG2026515577000010.jpg2774

[0082] The NMR and MS data for compound 5 are as follows: 1H NMR (400 MHz, クロロホルム-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). 13 C NMR (101 MHz, クロロホルム-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. LC-MS (ESI): m / z [M+H] + Calculate value C 28 H 41 N2O4S 501.2; measured value 501.2.

Example

[0083] Example 6 This example provides a method for preparing compound 6, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(ethyl)(oxo)-λ6-thioimide)butylamide. The preparation method of the compound in Example 1 was followed, with the only difference being that ethyl iodide was used as a starting material in step 3 of step B, and butyryl chloride was used as a starting material in step 6. The other steps were the same as in Example 1. 112 mg of the trifluoroacetate of compound 6 was prepared to obtain a white solid.

[0084] The structural formula of compound 6 is shown below. JPEG2026515577000011.jpg2775

[0085] The NMR and MS data for compound 6 are shown below. 1 H 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). 13¹³C NMR (10¹ MHz, chloroform-d) δ values: 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. LC-MS (ESI): m / z [M+H] + Calculated value C 29 H 43 N2O4S 515.2; found 515.2. [Examples]

[0086] Example 7 This example provides a method for preparing compound 7, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(propyl)(oxo)-λ6-thioimino)acetamide. The preparation method of the compound in Example 1 was followed, with the only difference being that bromopropane was used as a starting material in step 3 of step B, and acetyl chloride was used as a starting material in step 6; the other steps were the same as in Example 1. 233 mg of the trifluoroacetate of compound 7 was prepared to obtain a white solid.

[0087] The structural formula of compound 7 is shown below. JPEG2026515577000012.jpg2966

[0088] The NMR and MS data for compound 7 are shown below. 1H NMR (400 MHz, クロロホルム-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). 13 C NMR (101 MHz, クロロホルム-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. LC-MS (ESI): m / z [M+H] + Calculate value C 28 H 41 N2O4S 501.2; found 501.2.

Example

[0089] Example 8 This example provides a method for preparing compound 8, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(propyl)(oxo)-λ6-thioimide)propionamide. The preparation method of the compound in Example 1 was followed, with the only difference being that bromopropane was used as a starting material in step 3 of step B, and propionyl chloride was used as a starting material in step 6; the other steps were the same as in Example 1. 112 mg of the trifluoroacetate of compound 8 was prepared to obtain a white solid.

[0090] The structural formula of compound 8 is shown below. JPEG2026515577000013.jpg2871

[0091] The NMR and MS data for compound 8 are shown below. 1 H NMR (400 MHz, chloroform-d) δ 7.88 (s, 1H), 7.70 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.82 (d, J = 2.1 Hz, 1H), 6.75 (dd, J = 8.2, 2.1 Hz, 1H), 4.96 (s, 2H), 4.45 (s, 2H), 3.32 (ddd, J = 14.1, 10.9, 5.2 Hz, 1H), 3.23 (ddd, J = 14.1, 10.9, 5.2 Hz, 1H), 2.69 - 2.54 (m, 2H), 2.38 (q, J = 7.5 Hz, 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 = 0.9 Hz, 9H), 1.07 (t, J = 7.5 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). 13¹³C NMR (10¹ MHz, chloroform-d) δ values: 183.97, 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. LC-MS (ESI): m / z [M+H] + Calculated value C 29 H 43 N2O4S 515.2; found 515.2. [Examples]

[0092] Example 9 This example provides a method for preparing compound 9, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(propyl)(oxo)-λ6-thioimide)butanamide. The preparation method of the compound was the same as in Example 1, except that bromopropane was used as a starting material in step 3 of step B, and butyryl chloride was used as a starting material in step 6. The other steps were the same as in Example 1. 55 mg of the trifluoroacetate of compound 9 was prepared to obtain a white solid.

[0093] The structural formula of compound 9 is shown below. JPEG2026515577000014.jpg3177

[0094] The NMR and MS data for compound 9 are shown below. 1H NMR (400 MHz, クロロホルム-d) δ 7.89 (s, 1H), 7.74 (s, 1H), 7.46 (d, J = 8.1 Hz, 1H), 6.87 (dd, J = 8.2, 0.9 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 6.78 (dd, J = 8.1, 2.0 Hz, 1H), 4.99 (s, 2H), 4.51 (s, 2H), 3.35 (ddd, J = 15.9, 10.9, 5.2 Hz, 1H), 3.26 (td, J = 14.4, 12.7, 5.3 Hz, 1H), 2.72 - 2.58 (m, 2H), 2.35 (t, J = 7.4 Hz, 2H), 2.09 - 1.99 (m, 2H), 1.73 (q, J = 6.7, 6.2 Hz, 1H), 1.62 (p, J = 7.3 Hz, 3H), 1.51 (s, 6H), 1.41 (s, 9H), 0.98 (d, J = 7.4 Hz, 3H), 0.92 (d, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, クロロホルム-d) δ 183.17, 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. LC-MS (ESI): m / z [M+H] + Calculate value C 30 H 45 N2O4S 529.2; found 529.2.

Example

[0095] Example 10 This example provides a method for preparing compound 10, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(butyl)(oxo)-λ6-thioimino)acetamide. The preparation method of the compound in Example 1 was followed, with the only difference being that bromobutane was used as a starting material in step 3 of step B, and acetyl chloride was used as a starting material in step 6; the other steps were the same as in Example 1. 139 mg of the trifluoroacetate of compound 10 was prepared to obtain a white solid.

[0096] The structural formula of compound 10 is shown below. JPEG2026515577000015.jpg3173

[0097] The NMR and MS data for compound 10 are shown below. 1 H NMR (400 MHz, chloroform-d) δ 8.06 - 7.61 (m, 2H), 7.48 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 2.1 Hz, 1H), 6.78 (dd, J = 8.2, 2.1 Hz, 1H), 5.01 (s, 2H), 4.53 (s, 2H), 3.37 (ddd, J = 13.9, 11.3, 4.9 Hz, 1H), 3.26 (ddd, J = 14.0, 11.4, 5.0 Hz, 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, 5.0 Hz, 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 = 7.3 Hz, 3H). 13¹³C NMR (10¹ MHz, chloroform-d) δ values: 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. LC-MS (ESI): m / z [M+H] + Calculated value C 29 H 43 N2O4S 515.2; found 515.2. [Examples]

[0098] Example 11 This example provides a method for preparing compound 11, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(butyl)(oxo)-λ6-thioimide)propionamide. The preparation method of the compound is the same as in Example 1, except that bromobutane is used as a starting material in step 3 of step B, and propionyl chloride is used as a starting material in step 6 of step B, while the other steps are the same as in Example 1. 90 mg of trifluoride acetate of compound 11 was prepared to obtain a white solid.

[0099] The structural formula of compound 11 is shown below. JPEG2026515577000016.jpg3071

[0100] The NMR and MS data for compound 11 are shown below. 1H NMR (400 MHz, クロロホルム-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). 13 C NMR (101 MHz, クロロホルム-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. LC-MS (ESI): m / z [M+H] + Calculate value C 30 H 45 N2O4S 529.2; found 529.2.

Example

[0101] Example 12 This example provides a method for preparing compound 12, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(butyl)(oxo)-λ6-thioimido)butylamide. The preparation method of the compound is the same as in Example 1, except that bromobutane is used as a starting material in step 3 of step B, and butyryl chloride is used as a starting material in step 6 of step B, while the other steps are the same as in Example 1. 82 mg of trifluoride acetate of compound 12 was prepared to obtain a white solid.

[0102] The structural formula of compound 12 is shown below. JPEG2026515577000017.jpg2971

[0103] The NMR and MS data for compound 12 are shown below. 1 H NMR (400 MHz, chloroform-d) δ 7.88 (s, 1H), 7.69 (s, 1H), 7.45 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.83 (d, J = 2.0 Hz, 1H), 6.76 (dd, J = 8.1, 2.1 Hz, 1H), 4.97 (s, 2H), 4.49 (s, 2H), 3.35 (ddd, J = 16.0, 11.2, 4.9 Hz, 1H), 3.25 (ddd, J = 14.0, 11.3, 4.9 Hz, 1H), 2.68 - 2.55 (m, 2H), 2.32 (t, J = 7.4 Hz, 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 = 7.4 Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H). 13¹³C NMR (10¹ MHz, chloroform-d) δ values: 183.30, 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. LC-MS (ESI): m / z [M+H] + Calculated value C 31 H 47 N2O4S 543.2; found 543.2. [Examples]

[0104] Example 13 This example provides a method for preparing compound 13, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(fluoromethyl)(oxo)-λ6-thioimide)acetamide. The preparation method of the compound in Example 1 is the same as in Example 1, except that bromoiodomethane is used as a starting material in the third step of step B, and acetyl chloride is used as a starting material in the sixth step of step B. The other steps are the same as in Example 1. 145 mg of trifluoride acetate of compound 13 was prepared to obtain a white solid.

[0105] The structural formula of compound 13 is shown below. JPEG2026515577000018.jpg2871

[0106] The NMR and MS data for compound 13 are shown below. 1H NMR (400 MHz, クロロホルム-d) δ 8.05 - 7.79 (m, 2H), 7.52 (d, J = 8.1 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 2.8 Hz, 1H), 6.77 (dd, J = 8.1, 2.1 Hz, 1H), 5.71 (dd, J = 46.3, 9.3 Hz, 1H), 5.37 (dd, J = 46.8, 9.2 Hz, 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 = 1.0 Hz, 9H). 13 C NMR (101 MHz, クロロホルム-d) δ 180.87, 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 (376 MHz, クロロホルム-d) δ -75.48 (s), -203.48 (t, J = 47.4 Hz). LC-MS (ESI): m / z [M+H] + Calculate value C 26 H 36 FN2O4S 491.2; found 491.2.

Example

[0107] Example 14 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-thioimide)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 a raw material in the third step of Step B, and acetyl chloride is used as a raw material in the sixth step of Step B, and the other steps are the same as those in Example 1. 197 mg of the trifluoroacetate of compound 14 was prepared to obtain a white solid.

[0108] The structural formula of compound 14 is shown below. JPEG2026515577000019.jpg3277

[0109] The NMR and MS data of compound 14 are shown below. 1 H NMR (400 MHz, chloroform-d) δ 7.90 (s, 1H), 7.77 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 6.78 (dd, J = 8.1, 2.1 Hz, 1H), 5.84 (s, 2H), 4.98 (s, 2H), 4.53 (dd, J = 6.6, 4.5 Hz, 1H), 4.41 (dd, J = 6.6, 4.6 Hz, 1H), 3.53 (ddd, J = 15.2, 10.4, 5.2 Hz, 1H), 3.39 (ddd, J = 14.6, 10.3, 5.1 Hz, 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). 13¹³C NMR (10¹ MHz, chloroform-d) δ values: 180.98, 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 (376 MHz, chloroform-d): δ -75.61 (s), -220.65 (tt, J = 46.9, 25.0 Hz). LC-MS (ESI): m / z [M+H] + Calculated value C 28 H 40 FN2O4S 519.2; found 519.2. [Examples]

[0110] Example 15 This example provides a method for preparing compound 15, N-((2-(4-(3-(tert-butoxy)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(fluorobutyl)(oxo)-λ6-thioimide)acetamide. The preparation method of the compound is the same as in Example 1, except that 1-fluoro-4-bromobutane is used as a starting material in the third step of step B, and acetyl chloride is used as a starting material in the sixth step of step B, while the other steps are the same as in Example 1. 171 mg of trifluoride acetate of compound 15 was prepared to obtain a white solid.

[0111] The structural formula of compound 15 is shown below. JPEG2026515577000020.jpg3476

[0112] The NMR and MS data for compound 15 are shown below. 1H NMR (400 MHz, クロロホルム-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). 13 C NMR (101 MHz, クロロホルム-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, クロロホルム-d) δ -75.47 (s), -219.09 (tt, J = 48.9, 26.0 Hz). LC-MS (ESI): m / z [M+H] + Calculate value C 29 H 42 FN2O4S 533.2; found 533.2.

Example

[0113] Example 16 This example provides a method for preparing compound 16, (2-(4-(3-(tert-butyl)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(iminyl)(methyl)-λ6-thiamine. Compound 1 (87 mg, 0.18 mmol), anhydrous potassium carbonate (0.1 g, 0.74 mmol), and methanol (5 ml) were added to a 50 ml single-necked flask and reacted at 75°C for 1.5 hours under nitrogen protection. After cooling the reaction mixture to room temperature, it was poured into water, extracted with ethyl acetate (15 ml × 3), washed once with saturated brine (40 ml), and dried over anhydrous sodium sulfate. After removing the solvent by distillation, the trifluoroacetate of compound 16 was purified by pre-HPLC (C18 column, ACN: 0.1% TFA 10%~60% gradient elution) to obtain 31 mg of a white solid. Yield: 31.62%.

[0114] The structural formula of compound 16 is shown below. JPEG2026515577000021.jpg2564

[0115] The NMR and MS data for compound 16 are shown below. 1 H 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). 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. LC-MS (ESI): m / z [M+H] + Calculated value C 24 H 35 N2O3S 431.2; found 431.2. [Examples]

[0116] Example 17 This example provides a method for preparing compound 17, (2-(4-(3-(tert-butyl)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(ethyl)(iminyl)-λ6-thioimide. Referring to the compound preparation method of Example 16, the difference from Example 16 is that compound 4 was used as a starting material to obtain the trifluoroacetate of compound 17, yielding 145 mg of a white solid. Yield: 63.15%.

[0117] The structural formula of compound 17 is shown below. JPEG2026515577000022.jpg2867

[0118] The NMR and MS data for compound 17 are shown below. 1H 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). 13 C 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. LC-MS (ESI): m / z [M+H] + Calculated value C 25 H 37 N2O3S 445.2; found 445.2. [Examples]

[0119] Example 18 This example provides a method for preparing compound 18, (2-(4-(3-(tert-butyl)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(iminyl)(propyl)-λ6-thioimide. Referring to the compound preparation method of Example 16, the difference from Example 16 is that compound 7 was used as a starting material to obtain the trifluoroacetate of compound 18, yielding 100 mg of a white solid. Yield: 51.36%.

[0120] The structural formula of compound 18 is shown below. JPEG2026515577000023.jpg3071

[0121] The NMR and MS data for compound 18 are shown below. 1 H 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). 13 C 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. LC-MS (ESI): m / z [M+H] + Calculated value C 26 H 39 N2O3S 459.2; found 459.2. [Examples]

[0122] Example 19 This example provides a method for preparing compound 19, (2-(4-(3-(tert-butyl)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(butyl)(iminyl)-λ6-thioimide. Referring to the compound preparation method of Example 16, the difference from Example 16 is that compound 19 trifluoroacetate was synthesized using compound 10 as a starting material, yielding 100 mg of a white solid. Yield: 67.37%. The structural formula of compound 19 is shown below: JPEG2026515577000024.jpg2967

[0123] The NMR and MS data for compound 19 are shown below. 1 H 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). 13 C 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. LC-MS (ESI): m / z [M+H] + Calculated value C 27 H 41N2O3S 473.2; found 473.2. [Examples]

[0124] Example 20 This example provides a method for preparing compound 20, (2-(4-(3-(tert-butyl)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(fluoromethyl)(iminyl)-λ6-thioimine. The preparation method is based on that of Example 16, with the difference being that compound 13 was used as a starting material to obtain 81 mg of trifluoroacetate of compound 20. The result was a white solid, yield: 65.44%.

[0125] The structural formula of compound 20 is shown below. JPEG2026515577000025.jpg2867

[0126] The NMR and MS data for compound 20 are shown below. 1 H 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). 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). LC-MS (ESI): m / z [M+H] + Calculated value C 24 H 34 FN2O3S 449.2; found 449.2. [Examples]

[0127] Example 21 This example provides a method for preparing compound 21, (2-(4-(3-(tert-butyl)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(fluoropropyl)(iminyl)-λ6-thioimine. Referring to the compound preparation method of Example 16, the difference from Example 16 is that compound 21 trifluoroacetate was synthesized using compound 14 as a starting material, yielding 126 mg of a white solid. Yield: 64.64%.

[0128] The structural formula of compound 21 is shown below. JPEG2026515577000026.jpg3271

[0129] The NMR and MS data for compound 21 are shown below. 1H 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). 13 C 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. 19F NMR (376 MHz, Chloroform-d) δ -75.59 (s), -220.66 (tt, J = 47.9, 25.8 Hz). LC-MS (ESI): m / z [M+H] + Calculate value C 26 H 38 FN2O3S 477.2; found 477.2.

Example

[0130] Example 22 This example provides a method for preparing compound 22, (2-(4-(3-(tert-butyl)-4-hydroxyphenyl)-2-methylbutan-2-yl)isoindole-5-yl)(fluorobutyl)(iminyl)-λ6-thioimine. The preparation method is based on that of Example 16, with the difference being that compound 15 was used as a starting material to obtain 100 mg of the trifluoroacetate of compound 22. The result is a white solid, yield: 47.42%.

[0131] The structural formula of compound 22 is shown below. JPEG2026515577000027.jpg3475

[0132] The NMR and MS data for compound 22 are shown below. 1 H NMR (400 MHz, chloroform-d) δ 7.91 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.0 Hz, 1H), 6.85 (dd, J = 5.1, 3.2 Hz, 2H), 6.78 (dd, J = 8.3, 2.0 Hz, 1H), 4.77 (s, 4H), 4.45 (t, J = 5.2 Hz, 1H), 4.33 (t, J = 5.2 Hz, 1H), 3.49 (d, J = 8.3 Hz, 1H), 3.40 (td, J = 10.2, 5.0 Hz, 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 = 1.0 Hz, 9H). 13¹³C NMR (10¹ MHz, chloroform-d) δ values: 148.68, 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 (376 MHz, chloroform-d): δ -75.45 (s), -219.17 (tt, J = 47.6, 26.5 Hz). LC-MS (ESI): m / z [M+H] + Calculated value C 27 H 40 FN2O3S 491.2; found 491.2.

[0133] Examples The pharmacodynamic testing method employed in this embodiment is known to those skilled in the art. The sigma-2 receptor inhibitory activity assay kit used in this embodiment is commercially available to those skilled in the art. Sigma-1 / sigma-2 receptor affinity activity test.

[0134] In a 96-well plate, the test compound and reference compound were diluted fourfold in eight steps, and 1 μL of the compound was added to each well, after which the wells were rearranged. The reference compound, haloperidol, was added at an initial concentration of 1 μM. 1 μL of DMSO was added to the high-signal control well, and 1 μL of 200 μM (final concentration 1 μM) of haloperidol was added to the low-signal control well. Next, 100 μL of the desired concentration of Sigma-1R or Sigma-2R cell membrane, diluted in 50 mM Tris-HCl (pH 7.4, Sigma, Cat: T1503-1KG), was added to each well, and 100 μL of the desired concentration of 3H-DTG, diluted in 50 mM Tris-HCl (pH 7.4), was added to each well. The 96-well plate was sealed and incubated at room temperature on a 300 rpm shaker for 2 hours. Simultaneously, GF / C filter plates (PerkinElmer, Cat: NET986250UC) were immersed in 0.3% PEI (polyethyleneimine, Sigma, Cat: P3143). After incubation, cells were collected on the GF / C filter plates using a cell collector (PerkinElmer, model: C961961), washed four times with 50 mM Tris-HCl (pH 7.4) wash buffer, and dried in a 50°C oven for 1 hour. The bottom of the dried GF / C filter plates was sealed with a membrane, 50 μL of scintillation solution was added to each well and sealed, and cells were read using a Microbeta (PerkinElmer, model: 2450 Microplate Counter). The activity rate was calculated using Microsoft Excel software with the following formula: % activity = 100 × (raw sample value - high control mean) / (low control mean - high control mean). Using GraphPad Prism 5 data analysis software, a fitting analysis was performed by selecting the Dose-response-Stimulation-log[antagonist] vs. response-Variable slope model, and the IC50 value was obtained for each test sample. The results are shown in Table 1.As can be seen from Table 1, the compounds of the present invention possess excellent sigma-2 inhibitory activity and selectivity, and can be further developed for the treatment of sigma-2 receptor abnormality-related diseases (such as tumors, Alzheimer's disease, schizophrenia, and Lewy body dementia).

[0135] Table 1 Results of sigma 1 / sigma 2 receptor inhibition and affinity activity of the compounds of the present invention JPEG2026515577000028.jpg123127

[0136] The isoindole sulfirimine compounds prepared according to the present invention can act as sigma-2 receptor inhibitors and can be used to treat diseases associated with hyperactivation of sigma-2 receptors (such as tumorigenesis, non-malignant hyperproliferation, and nerve conduction disorders in neurodegenerative diseases). These diseases include ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, hepatocellular carcinoma, cervical cancer, bone metastasis, papillary thyroid carcinoma, colon cancer, gastrointestinal stromal tumors, melanoma, mesothelioma, glioblastoma, osteosarcoma, multiple myeloma, hyperproliferative disorders, metastasis of primary tumor sites, myeloproliferative disorders, leukemia, metabolic disorders, neurodegenerative diseases, schizophrenia, dementia, tachycardia, Parkinson's disease, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease (COPD), osteoporosis, eosinophilic syndrome, mast cell hyperplasia, or mast cell leukemia.

[0137] The above description of the embodiments is intended to facilitate understanding and use of the present invention for those skilled in the art. Those skilled in the art can easily make various modifications to these embodiments and apply the general principles presented herein to other embodiments. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art in accordance with the disclosure of the present invention should remain within the scope of the invention, as long as they do not depart from the scope of the invention.

Claims

1. An isoindole sulfirimine compound or its stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein the isoindole sulfirimine compound has the chemical structure shown in chemical formula (I) Something that possesses. Chemical formula (I) Here, R 1 R is an alkyl group having 1 to 4 carbon atoms or a halogenated alkyl group having 1 to 4 carbon atoms, 2 This is one of the following: hydrogen, an alkyl group having 1 to 4 carbon atoms, a halogenated alkyl group having 1 to 4 carbon atoms, or an acyl group having 1 to 4 carbon atoms.

2. The isoindole sulfirimine compound according to claim 1, or its stereoisomer, solvate, or pharmaceutically acceptable salt, R 1 A compound in which is one selected from methyl, ethyl, propyl, and butyl.

3. The isoindole sulfirimine compound according to claim 1, or its stereoisomer, solvate, or pharmaceutically acceptable salt, R 1 A compound in which is one selected from fluorine-substituted methyl, fluorine-substituted ethyl, fluorine-substituted propyl, and fluorine-substituted butyl.

4. A compound comprising the isoindole sulfylimine compound according to claim 3, or a stereoisomer thereof, solvate, or pharmaceutically acceptable salt thereof, wherein the number of fluorine atoms is 1, 2, or 3.

5. The isoindole sulfirimine compound according to claim 3, or its stereoisomer, solvate, or pharmaceutically acceptable salt, wherein R 1 A compound in which -CH2F.

6. The isoindole sulfirimine compound according to claim 1, or its stereoisomer, solvate, or pharmaceutically acceptable salt, R 2 A compound in which H is present.

7. The isoindole sulfirimine compound according to claim 1, or its stereoisomer, solvate, or pharmaceutically acceptable salt, R 2 A compound in which is one selected from formyl, acetyl, propionyl, and butyryl.

8. An isoindole sulfirimine compound according to claim 1, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein the isoindole sulfirimine compound is any of the following compounds 1-22.

9. A pharmaceutical composition comprising an isoindole sulfirimine compound according to any one of claims 1 to 8, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. Uses of an isoindole sulfirimine compound according to any one of claims 1 to 8, or a stereoisomer thereof, solvate, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, as a sigma-2 receptor inhibitor.

11. A method for treating or preventing a disease associated with hyperactivation of the sigma-2 receptor, comprising administering a therapeutically effective or prophylactically effective amount of an isoindole sulfirimine compound according to any one of claims 1 to 8, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9.

12. A method for treating or preventing a disease associated with hyperactivation of sigma-2 receptors, according to claim 11, wherein the disease is selected from tumorigenesis, non-malignant hyperproliferative disease, neurodegenerative disease, and nerve conduction disorder.

13. A method for treating or preventing a disease associated with hyperactivation of the sigma-2 receptor, according to claim 11, wherein the disease is selected from ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, hepatocellular carcinoma, cervical cancer, bone metastasis, papillary thyroid cancer, colorectal cancer, gastrointestinal stromal tumor, melanoma, mesothelioma, glioblastoma, osteosarcoma, multiple myeloma, hyperproliferative disorders, metastasis of a primary tumor site, myeloproliferative disorders, leukemia, metabolic disorders, neurodegenerative diseases, schizophrenia, dementia, tachycardia, Parkinson's disease, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease (COPD), osteoporosis, eosinophilic syndrome, mast cell hyperplasia, mast cell leukemia, Alzheimer's disease, schizophrenia, and Lewy body dementia.

14. A method for treating or preventing a disease associated with hyperactivation of the sigma-2 receptor, according to claim 13, wherein the disease is Alzheimer's disease.

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