Derivatives of a class of ether amides or sulfonamides, and methods of making and using the same

Abstract

The application discloses a derivative of ether amide or sulfonamide, a preparation method and application thereof, and belongs to the field of medicine. 1‑5 The derivative of ether amide or sulfonamide is shown in the general formula (I), wherein R1 and R2 are independently selected from H, CH3, CF3, Et, n-Pr, i-Pr, cyclopropyl, butyl, cyclobutyl, cyclopentyl and the like C straight-chain or branched alkyl; m=0~4; n=1~5; X=‑CO‑NH‑,‑NH‑CO‑ or‑NH‑SO2‑; Ar=phenyl, pyridyl, pyrimidyl, furanyl, thienyl, pyrrolyl, and the aromatic ring can carry one or two substituents or a combination thereof, such as methyl, trifluoromethyl, ethyl, isopropyl, propyl, nitro, fluorine, chlorine, bromine, iodine, cyano, methoxy, hydroxyl, methylsulfonyl and acetyl. The ether amide or sulfonamide derivative provided by the application can effectively inhibit the coupling of nNOS-SERT, plays a role in treating depression, and has a good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry, and relates to a class of ether amide or sulfonamide derivatives, their preparation methods, and applications. Specifically, it relates to a class of ether amide or sulfonamide compounds that can inhibit nNOS-SERT coupling and have rapid antidepressant effects. Background Technology

[0002] Depression is a common mental disorder affecting approximately 300 million people worldwide. It is reported that about one million people die by suicide due to depression each year, placing a heavy burden on individuals, families, and society. Currently used first-line antidepressants, such as fluoxetine, sertraline, citalopram, and venlafaxine, generally suffer from drawbacks including long onset of action (requiring 3-4 weeks), low efficacy (approximately half of patients experience no effect or a weak response), and numerous side effects (nausea, vomiting, drowsiness, decreased libido, etc.). While ketamine (trade name: Sukailang) has a rapid antidepressant effect, its use is strictly controlled because ketamine, its raw material, is classified as a narcotic. It is limited to patients who are unresponsive to first-line drugs and have suicidal tendencies, and must be used under the supervision of a hospital doctor, severely restricting its clinical usability. Therefore, developing novel antidepressants that are rapid-acting, effective, have fewer side effects, and are convenient to use is a critical need urgently needing to be addressed in the field of mental health.

[0003] The coupling of neuronal nitric oxide synthase (nNOS) and serotonin transporter (SERT) is a novel antidepressant target discovered by the inventors of this patent (Science, 2022, 378, 390-398). Inhibiting nNOS-SERT coupling promotes SERT expression at the cell membrane, reduces the concentration of serotonin (5-HT) outside the cells of neurons in the DRN brain region, avoids the negative feedback regulation of the 5-HT2AR receptor, promotes neuronal firing, and thus exerts a rapid antidepressant effect. Because nNOS-SERT coupling has a DRN-specific distribution and does not affect the function of nNOS and SERT in the uncoupled state, it avoids many of the side effects of currently used monoamine neurotransmitter-based antidepressants, and does not induce addiction or dissociative consciousness like ketamine.

[0004] For this target, we have disclosed "A class of indole derivatives and their preparation methods and applications (ZL202111142560.7)," "A dipeptide compound with rapid antidepressant effect and its application (ZL202111121666.9)," and "A class of carboxylic acids and their derivatives and their preparation methods and applications (Application No. 202410932778.X)." In-depth research on the compound in patent application No. 202410932778.X revealed a series of compounds with better nNOS-SERT inhibitory activity.

[0005] Therefore, this patent provides a class of ether amide or sulfonamide derivatives that can inhibit the coupling of nNOS-SERT and exert a therapeutic effect on depression. Summary of the Invention

[0006] The purpose of this invention is to provide a class of ether amides or sulfonamide derivatives or their pharmaceutically acceptable salts, and their application in inhibiting nNOS-SERT coupling to exert rapid antidepressant effects, which has broad application prospects.

[0007] The technical solution of the present invention is as follows:

[0008] This invention provides a class of ether amides or sulfonamide derivatives or pharmaceutically acceptable salts thereof, characterized in that their chemical structures are shown in the following general structural formula:

[0009]

[0010] Wherein: R1 and R2 are each independently selected from H, CH3, CF3, Et, n-Pr, i-Pr, cyclopropyl, butyl, cyclobutyl, cyclopentyl, etc. 1-5 Straight-chain or branched alkyl groups;

[0011] m = 0~4; n = 1~5;

[0012] X = -CO-NH-, -NH-CO-, -NH-SO2-, -CO-NH-SO2-;

[0013] Ar = phenyl, pyridyl, pyrimidinyl, furanyl, thiophene, pyrroleyl, and the aromatic ring may carry one or two of the following substituents or combinations thereof: methyl, trifluoromethyl, ethyl, isopropyl, propyl, nitro, fluorine, chlorine, bromine, iodine, cyano, methoxy, hydroxy, methanesulfonyl, acetyl.

[0014] In a preferred embodiment, R1 and R2 are independently H, CH3, and CF3, respectively, X is -CO-NH- or -NH-SO2-, and Ar is substituted or unsubstituted phenyl or pyridyl; the substituents on the aromatic ring are selected from one or two of methyl, cyano, hydroxy, nitro, methoxy, acetyl, methanesulfonyl or fluorine, n=1~3, m=0~2.

[0015] As a preferred embodiment, R1 and R2 are CF 3， X is -CO-NH- or -NH-SO2-, n=1, 2 or 3, m=0 or 1.

[0016] In a preferred embodiment, Ar is a substituted or unsubstituted phenyl or pyridyl group; the substituents on the aromatic ring are selected from cyano or fluorine groups.

[0017] Furthermore, the derivatives described in this invention are selected from any one or more of the following compounds:

[0018]

[0019]

[0020] Furthermore, the ether amide or sulfonamide derivative is selected from any one of the following compounds:

[0021] .

[0022] The present invention also provides a pharmaceutical composition comprising the ether amide or sulfonamide derivative described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0023] Furthermore, the pharmaceutically acceptable salt is selected from hydrochloride, acetate, citrate, tartrate, p-toluenesulfonate, benzenesulfonate, or fumarate.

[0024] The present invention also provides the use of the ether amide or sulfonamide derivatives or pharmaceutically acceptable salts thereof, as well as pharmaceutically acceptable carriers or the pharmaceutical compositions thereof, in the preparation of medicaments for treating depression.

[0025] Furthermore, the ether amide or sulfonamide derivative or its pharmaceutically acceptable salt or the composition thereof exerts a rapid antidepressant effect by inhibiting the coupling of nNOS-SERT.

[0026] The beneficial effects of this invention are:

[0027] Currently, commonly used antidepressants in clinical practice generally have shortcomings such as slow onset of action and numerous side effects. The ether amide or sulfonamide derivative provided by this invention is a novel antidepressant that can effectively inhibit the coupling of nNOS-SERT and exert a rapid antidepressant effect. Attached Figure Description

[0028] Figure 1 (a) Reproducibility test of compound 12 in HEK293T cells, n=3, showed statistically significant differences; (b) Comparison of uncoupling activity between compound 12 and XJ-2, n=3, showed statistically significant differences.

[0029] Figure 2(a) Changes in the level of nNOS-SERT complex in the brain DRN region of physiological mice after intraperitoneal administration of 12 (10 mg / kg) for 2 h, n=3, showed statistically significant differences. (b) Behavioral tests of TST and FST 2 h after intraperitoneal administration of 12 (10 mg / kg and 20 mg / kg) to physiological mice, n=15, showed statistically significant differences in TST and a trend in FST, but no statistically significant differences.

[0030] Figure 3 (a) After 21 days of corticosterone administration to water-induced depressed mice, the level of nNOS-SERT complex in the brain DRN region changed 2 hours after administration of 12 mg / kg corticosterone (n=3), showing a statistically significant difference. (b) After 21 days of intraperitoneal administration of 12 mg / kg corticosterone to water-induced depressed mice, behavioral tests of TST and FST were performed 2 hours after administration of 12 mg / kg corticosterone (n=15), showing a statistically significant difference. Detailed Implementation

[0031] The following examples are provided to better understand the present invention, but are not intended to limit the invention. Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the experimental materials used in the following examples were purchased from conventional biochemical reagent stores.

[0032] Example 1: Synthesis of 2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)acetic acid (XJ-2) Synthesis of 2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)acetic acid (XJ-2)

[0033] Synthesis of 2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)ethyl acetate (1): In a 100 mL dry flask, hexafluoroisopropanol (5 g, 29.8 mmol), 50 mL of acetone, and potassium carbonate (11.8 g, 85.5 mmol) were added sequentially. The mixture was stirred at room temperature for 10 min, followed by the slow addition of ethyl bromoacetate (3.15 mL, 28.5 mmol) while stirring continuously at room temperature for 6 h. After the reaction was complete, the mixture was filtered, and the residue was washed three times with EtOAc. The filtrate was collected. The organic solvent was removed by rotary evaporation, and the residue was dissolved in 50 mL of EtOAc. The residue was washed three times with ice water and three times with saturated brine. The organic layer was collected and dried over anhydrous sodium sulfate. The residue was filtered, concentrated, and analyzed by silica gel column chromatography using petroleum ether and ethyl acetate (15:1) as eluent to obtain 17 g of a colorless, transparent liquid product, with a yield of 98%. 1¹H NMR (400 MHz, CDCl₃) d 4.48 (hept, J = 5.8 Hz, 1H), 4.41 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). Synthesis of 2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)acetic acid (XJ-2) Compound 1 (4 g, 17.7 mmol), 35 mL of methanol, and 35 mL of 1 M NaOH solution (35 mL, 35 mmol) were added to a dry 100 mL flask and stirred overnight at room temperature. After the reaction was complete, the organic solvent was removed by rotary evaporation, and the product was dissolved in an appropriate amount of water. The pH was adjusted to 1 with 2 M hydrochloric acid solution, and the mixture was extracted three times with EtOAc. The organic layer was collected and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness to give 3.5 g of white solid product XJ-2, with a yield of 98%. 1 H NMR (400 MHz, CDCl3) d 10.38 (s, 1H), 4.49 (s, 2H), 4.47-4.36 (m, 1H). MS (ESI) calculated for C5H4F6O3: 226.006; foundm / z: 225.0224 [MH] - .

[0034] Example 2 Synthesis of 2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)ethylamine (6)

[0035] Synthesis of tert-butyl (2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)ethyl)carbamate (5) Take a dry 50 mL flask, dissolve hexafluoroisopropanol (2 g, 12 mmol) in 10 mL ethanol, add KOH (0.8 g, 14.4 mmol), stir at room temperature until KOH is completely dissolved, slowly add N-Boc-bromoethylamine (1.2 g, 5.4 mmol), heat and stir under reflux overnight. After the reaction is complete, remove most of the ethanol by rotary evaporation, dissolve in water, extract with diethyl ether, collect the organic layer, wash 3 times with 1 M NaOH solution, wash 3 times with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and perform chromatographic chromatography on a silica gel column using petroleum ether-ethyl acetate (5:1) as eluent to obtain 5 1.2 g of yellow transparent oily product, yield 60%. 1H NMR (400 MHz, DMSO-d6) d 6.85 (s, 1H), 5.40 (s, 1H), 3.79 (s, 2H), 3.08 (s, 2H), 1.33 (s, 9H).

[0036] Synthesis of 2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)ethylamine (6) Take a dry 50 mL flask, add 10 mL of 5 (2 g, 12 mmol) 2 M ethyl hydrochloride solution, stir at room temperature for 2 h. After the reaction is complete, remove the solvent by rotary evaporation to give 61.94 g of pale yellow oily product. Yield: 75.1%. 1 HNMR (400 MHz, DMSO-d6) δ 5.62 (p, J = 6.7 Hz, 1H), 4.07 (t, J = 5.5 Hz, 2H), 3.06 (q, J = 5.7 Hz, 2H), 1.90 (s, 2H). MS (ESI) calculated for C5H7F6NO: 211.0432; found m / z: 212.0514 [M+H] ＋ .

[0037] Example 3 Synthesis of N-(4-cyanobenzyl)-2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)acetamide (8)

[0038] Take a dry 50 mL flask, dissolve XJ-2 in 10 mL of CHCl3, slowly add SOCl2 (342 mg, 2.87 mmol), and heat under reflux for 2 h. After the reaction is complete, evaporate to dryness, and dissolve in a small amount of DMF. Dissolve 4-cyanoanisole (292 mg, 2.21 mmol) in DMF, add triethylamine (342 mg, 2.87 mmol), and then slowly add a DMF solution of acyl chloride. Stir at room temperature for 6 h. After the reaction is complete, add 50 mL of water, adjust the pH to neutral with 1 M dilute hydrochloric acid, extract with EtOAc, wash three times with saturated brine, dry with anhydrous sodium sulfate, filter, remove organic solvent by rotary evaporation, prepare an eluent with petroleum ether and ethyl acetate at a volume ratio of 2:1, and perform chromatographic chromatography on a silica gel column. 80.6 g of colorless, transparent, oily liquid product was obtained, with a yield of 80%. 1H NMR (400 MHz, CDCl3) d 7.56 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2Hz, 2H), 6.97 (t, J = 6.4 Hz, 1H), 4.51 (d, J = 6.4 Hz, 2H), 4.37 (s, 2H),4.34–4.27 (m, 1H). 13 C NMR (101 MHz, CDCl3) d 167.02, 143.22, 132.55, 128.15,121.16 (q, J = 284.82 Hz), 118.66, 111.43, 76.14 (m, J = 32.32), 42.54. MS(ESI)calculated for C 13 H 10 F6N2O2: 340.0646; found m / z: 375.0329 [M+Cl] - .

[0039] Example 4 Synthesis of 2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)-N-(2-hydroxy-4-methylphenyl)acetamide (9)

[0040] Take a dry 50 mL flask, dissolve XJ-2 (500 mg, 2.21 mmol), DIPEA (571 mg, 4.42 mmol), and HATU (841 mg, 2.21 mmol) in 5 mL DMF, stir at room temperature for 10 min, then add 2-amino-5-methylphenol (272 mg, 2.21 mmol), and continue stirring at room temperature for 6 h. After the reaction is complete, add 50 mL of water, and a pale yellow solid precipitates. Filter to obtain 90.62 g of white solid product, yield 84.9%. 1 H NMR (400 MHz, DMSO-d6) d9.88 (s, 1H), 8.91 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 6.66 (s, 1H), 6.56 (d,J = 7.8 Hz, 1H), 5.65 (hept, J = 6.6 Hz, 1H), 4.52 (s, 2H), 2.16 (s, 3H). 13CNMR (101 MHz, DMSO-d6) d 165.38, 147.29, 134.33, 126.38, 123.52, 120.84,120.06, 116.04, 72.78, 72.78, 21.21.MS (ESI) calculated for C 12 H 11 F6NO3: 331.0643; found m / z: 330.0570 [MH] - .

[0041] Example 5 Synthesis of 2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)-N-((4-methoxyphenyl)sulfonyl)acetamide (10)

[0042] The synthesis method was the same as for compound 8, starting with 500 mg of compound XJ-2. After the reaction was complete, dichloromethane and methanol were prepared as eluents at a volume ratio of 50:1. The remaining product was analyzed by silica gel column chromatography. 0.75 g of a white solid was obtained. The yield was 86.2%. 1 H NMR (400 MHz, DMSO-d6) d 7.82 (d, J = 8.7 Hz, 2H), 7.08 (d, J =9.1 Hz, 2H), 5.47 (p, J = 6.2 Hz, 1H), 4.33 (s, 2H), 3.81 (s, 3H). 13 C NMR(101 MHz, CDCl3) d 164.29, 130.83, 129.65, 128.69, 121.44 (q, J = 284.82 Hz), 114.30, 76.14 (m, J =32.32), 72.59, 55.81. MS (ESI) calculated forC 12 H 11 F6NO5S: 395.0262; found m / z: 394.0189[MH] - .

[0043] Example 6 Synthesis of 2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)-N-(4-hydroxyphenyl)acetamide (11)

[0044] The synthesis method was the same as that for compound 8, starting from 500 mg of compound XJ-2. After the reaction was completed, petroleum ether and ethyl acetate were prepared as eluent at a volume ratio of 2:1, and the mixture was subjected to chromatographic chromatography on a silica gel column. 11 0.52 g of a white solid product was obtained, with a yield of 74.3%. 1 H NMR (400 MHz, CDCl3) d 9.75 (s, 1H), 9.25 (s, 1H), 7.35 (d, J =8.8 Hz, 2H), 6.81 (d, J = 8.9 Hz, 2H), 4.45 (s, 2H). 13 MS (ESI) calculated for C 11 H9F6NO3: 317.0487: found m / z: 318.0559[M+H] ＋ .

[0045] Example 7 Synthesis of N-(2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)ethyl)benzenesulfonamide (12)

[0046]

[0047] Take a dry 50 mL flask, dissolve 6 (1 g, 4.74 mmol) in 10 mL of acetonitrile, then dissolve Na₂CO₃ (1.26 g, 11.8 mmol) in 10 mL of water. Mix and stir for 10 min, then slowly add benzenesulfonyl chloride (0.84 g, 4.74 mmol). Stir the mixture at room temperature for 6 h. After the reaction is complete, evaporate the organic solvent, extract the product with EtOAc, wash three times with saturated brine, dry under anhydrous sodium sulfate, and remove the solvent under reduced pressure. Perform chromatographic chromatography on silica gel using petroleum ether and ethyl acetate (5:1) as eluent. 12 1.05 g of white solid product was obtained, yield 63.3%. 1H NMR (400MHz, CDCl3) d 7.86 (d, J = 7.2 Hz, 2H), 7.63-7.48 (m, 3H), 4.86 (s, 1H), 3.99(p, J = 5.8 Hz, 1H), 3.87 (t, J = 5.1 Hz, 2H), 3.24 (q, J = 5.0 Hz, 2H). 13 CNMR (101 MHz, CDCl3) d 139.77, 133.09, 129.39, 127.05, 122.72, 76.55, 73.87,42.80. MS (ESI) calculated for C 11 H 11 F6NO3S: 351.0364; found m / z: 350.0812[MH] - .

[0048] Example 8 Synthesis of N-(4-cyanophenyl)-2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)acetamide (13)

[0049] Take a dry 50 mL flask, dissolve XJ-2 (500 mg, 2.21 mmol) in 10 mL DCM, then add SOCl2 (316 mg, 2.65 mmol), stir at room temperature for 10 min, then add trimethylamine (183 mg, 3.09 mmol) and p-aminobenzonitrile (261 mg, 2.21 mmol), stir overnight at room temperature. After the reaction is complete, extract with EtOAc, wash the extract three times with 1 M dilute hydrochloric acid, then three times with 1 M NaOH solution, and then three times with saturated brine. Dry the extract with anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Perform chromatographic chromatography on silica gel using petroleum ether and ethyl acetate (2:1) as eluent. 13 0.2 g of pale yellow solid product was obtained, yield 28%. 1 H NMR (400 MHz, CDCl3) d 8.17 (s, 1H), 7.71-7.60 (m,4H), 4.48 (d, J = 9.7 Hz, 2H), 4.27 (dt, J = 11.3, 5.6 Hz, 1H). 13C NMR (101MHz, CDCl3) d 164.75, 140.41, 133.51, 122.44, 120.04, 118.59, 108.43, 76.54,73.05. MS (ESI) calculated for C 12 H8F6N2O2: 326.0490; found m / z: 325.0211[MH] - .

[0050] Example 9 Synthesis of 2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)-N-(4-nitrophenyl)acetamide (14)

[0051] Take a dry 50 mL flask, dissolve XJ-2 (500 mg, 2.21 mmol) in 5 mL DCM, add 1,3-dicyclohexylcarbodiimide (DCC) (479 mg, 2.32 mmol), stir at room temperature for 10 min, add p-nitroaniline (305 mg, 2.21 mmol), and stir at room temperature for 12 h. After the reaction is complete, filter. Wash the residue three times with DCM, collect the filtrate, and concentrate under reduced pressure to remove the solvent. Prepare an eluent with petroleum ether and ethyl acetate at a volume ratio of 3:1, and perform chromatographic chromatography on a silica gel column. 14 0.7 g of pale yellow solid product was obtained, with a yield of 92.1%. 1 H NMR (400 MHz, CDCl3) δ 8.30(s, 1H), 8.22 (d, J = 9.1 Hz, 2H), 7.74 (d, J = 9.3 Hz, 2H), 4.51 (s, 2H), 4.31 (p, J = 5.6 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 164.86, 144.37, 142.15,125.24, 122.46, 119.69, 76.54, 73.04. MS (ESI) calculated for C 11 H8F6N2O4:346.0388; found m / z: 345.0132[MH] - .

[0052] Example 10 Synthesis of 2-(1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)-N-(4-(methanesulfonyl)phenyl)acetamide (15)

[0053] Take a dry 50 mL flask, dissolve XJ-2 (500 mg, 2.21 mmol) in 5 mL of DCM, then add DCC (479 mg, 2.32 mmol), stir at room temperature for 10 min, add 4-methanesulfonylaniline (379 mg, 2.21 mmol), and stir at room temperature for 12 h. After the reaction is complete, filter, wash the residue three times with DCM, collect the filtrate, remove the organic solvent by rotary evaporation, and perform chromatographic chromatography on a silica gel column using petroleum ether and ethyl acetate (1:1) as the eluent to obtain 15 0.56 g of white solid product, yield 67.5%. 1 H NMR (400 MHz, CDCl3) d 8.24 (s, 1H), 7.91 (d, J = 8.7Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H), 4.51 (s, 2H), 4.31 (p, J = 5.7 Hz, 1H), 3.04 (s, 3H). 13 C NMR (101 MHz, CDCl3) d 164.90, 141.30, 136.50, 128.99,122.47, 120.10, 76.53, 73.05, 44.73. MS (ESI) calculated for C 12 H 11 F6NO4S:379.0313; found m / z: 377.9259 [MH] - .

[0054] Example 11 Synthesis of N-(4-acetylphenyl)-2-(1,1,1,3,3-hexafluoroprop-2-yl)oxy)acetamide (16)

[0055] Take a dry 50 mL flask, dissolve compound XJ-2 (500 mg, 2.21 mmol) in 5 mL DCM, add DCC (479 mg, 2.32 mmol), stir at room temperature for 10 min, add 4-aminoacetophenone (299 mg, 2.21 mmol), and stir at room temperature for 12 h. After the reaction is complete, filter, wash the residue three times with DCM, and then collect the filtrate. Concentrate under reduced pressure to remove the solvent. Prepare an eluent with petroleum ether and ethyl acetate at a volume ratio of 3:1, and perform chromatographic chromatography on a silica gel column to give 16 0.7 g of white solid product, yield 93.3%. 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H),7.96 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H), 4.49 (s, 2H), 4.28 (hept,J = 5.6 Hz, 1H), 2.58 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 196.98, 164.70,140.69, 133.81, 129.89, 122.50, 119.41, 73.10, 60.51, 26.59. MS (ESI) calculated for C 13 H 11 F6NO3: 343.0643; found m / z: 342.0312[MH] - .

[0056] Example 12 Synthesis of 2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)-N-(pyridin-3-ylmethyl)acetamide (17)

[0057] XJ-2 (500 mg, 2.21 mmol) was dissolved in 5 mL of DCM, and DCC (479 mg, 2.32 mmol) was added. The mixture was stirred at room temperature for 10 min, and then 3-aminomethylpyridine (239 mg, 2.21 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was filtered. The resulting residue was washed three times with DCM, and the filtrate was collected. The solvent was removed by concentration under reduced pressure, and the eluent was prepared by preparing a solution of petroleum ether and ethyl acetate at a volume ratio of 1:2. Chromatographic chromatography was performed on a silica gel column to give 170.6 g of a white solid product, with a yield of 87%. 1 H NMR (400 MHz, CDCl3) d 8.56 (s, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.30 (d, J= 8 Hz, 1H), 6.75 (s, 1H), 4.53 (d, J = 6.2 Hz, 2H), 4.40 (s, 2H), 4.18(p, J = 5.6 Hz, 1H). 13C NMR (101 MHz, CDCl3) d 166.71, 149.31, 149.23,135.60, 133.20, 123.79, 122.10, 76.42, 73.22, 40.66. MS (ESI) calculated forC 11 H 10 F6N2O2: 316.0646; found m / z: 316.9699 [M+H] + .

[0058] Example 13 Synthesis of 2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)-N-(pyrimidin-5-yl)acetamide (18)

[0059] XJ-2 (500 mg, 2.21 mmol) was dissolved in 5 mL of tetrahydrofuran, and DCC (479 mg, 2.32 mmol) was added. The mixture was stirred at room temperature for 10 min, and then 5-aminopyrimidine (210 mg, 2.21 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was filtered. The resulting residue was washed three times with DCM, and the filtrate was collected and the solvent was removed under reduced pressure. The eluent was prepared by preparing a solution of petroleum ether and ethyl acetate at a volume ratio of 1:2. Chromatographic chromatography was performed on a silica gel column to give 180.51 g of a pale yellow solid product, with a yield of 76.1%. 1 H NMR (400 MHz, CDCl3) d 9.04-9.01 (m, 3H), 8.03 (s, 1H), 4.54 (s,2H), 4.28 (dt, J = 10.3, 5.3 Hz, 1H). 13 C NMR (101 MHz, CDCl3) d 165.11,155.24, 148.32, 132.09, 121.44, 76.51, 72.96. MS (ESI) calculated for C9H7F6N3O2:303.0442; found m / z: 304.0222[M+H] + .

[0060] Example 14 Synthesis of 2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)-N-(pyridin-3-yl)acetamide (19)

[0061] XJ-2 (500 mg, 2.21 mmol) was dissolved in 5 mL of DCM, and DCC (479 mg, 2.32 mmol) was added. The mixture was stirred at room temperature for 10 min, and then 3-aminopyridine (208 mg, 2.21 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was filtered. The resulting residue was washed three times with DCM, and the filtrate was collected. The solvent was removed under reduced pressure. The eluent was prepared by preparing a solution of petroleum ether and ethyl acetate at a volume ratio of 1:2. Chromatographic chromatography was performed on a silica gel column to give 190.65 g of a white solid product, with a yield of 97%. 1 H NMR (400 MHz, CDCl3) d 8.63 (s, 1H), 8.40 (s, 1H), 8.20-8.08 (m, 2H), 7.29 (dd, J = 8.3, 4.8 Hz, 1H), 4.49 (s, 2H), 4.31 (p, J = 5.7 Hz, 1H). 13 CNMR (101 MHz, CDCl3) d 171.35, 165.12, 146.30, 141.62, 133.42, 127.60,123.86, 73.02, 60.51. MS (ESI) calculated for C 10 H8F6N2O2: 302.0490; found m / z:302.9679[M+H] + .

[0062] Example 15 Synthesis of 2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)-N-(4-(methanesulfonyl)benzyl)acetamide (20)

[0063] XJ-2 (500 mg, 2.21 mmol) was dissolved in 5 mL of DCM, and DCC (479 mg, 2.32 mmol) was added. The mixture was stirred at room temperature for 10 min, and then 4-methylsulfonylbenzylamine (409 mg, 2.21 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was filtered. The resulting residue was washed three times with DCM, and the filtrate was collected. The solvent was removed by concentration under reduced pressure. An eluent was prepared by mixing petroleum ether and ethyl acetate in a 1:1 volume ratio. Chromatographic chromatography was performed on a silica gel column to give 20 0.8 g of a white solid product, with a yield of 92%. 1H NMR (400 MHz, CDCl3) d 7.90 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 6.86 (s, 1H), 4.60 (d, J = 6.3 Hz, 2H), 4.42 (s, 2H), 4.21 (hept, J = 5.7 Hz,1H), 3.03 (s, 3H). 13 C NMR (101 MHz, CDCl3) d 166.93, 144.03, 139.79, 128.39,127.96, 121.22, 76.35, 73.17, 44.59, 42.49. MS (ESI) calculated for C13H 13 F6NO4S:393.0469; found m / z: 392.0517[MH] - .

[0064] Example 16 Synthesis of 3-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)propylamine (22)

[0065] Synthesis of tert-butyl (3-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)propyl)carbamate (21) In a dry 50 mL flask, hexafluoroisopropanol (2 g, 12 mmol) was dissolved in 10 mL of ethanol, and KOH (0.8 g, 14.4 mmol) was added. The mixture was stirred at room temperature to dissolve, and N-Boc-3-bromopropylamine (2.27 g, 9.52 mmol) was slowly added. The mixture was heated and stirred under reflux overnight. After the reaction was complete, the ethanol was removed by rotary evaporation, the mixture was dissolved in water, and then extracted with diethyl ether. The organic layer was collected, washed three times with 1 M NaOH solution, and then washed three times with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Chromatographic chromatography was performed on a silica gel column using petroleum ether and ethyl acetate (10:1) as the eluent to obtain 212.94 g of a yellow oily liquid product, with a yield of 95.1%. 1 ¹H NMR (400 MHz, CDCl₃) d 4.69 (s, 1H), 4.08–4.00 (m, 1H), 3.87 (t, J = 6.0 Hz, 2H), 3.21 (d, J = 6.5 Hz, 2H), 1.86–1.79 (m, 2H), 1.41 (s, 9H). Synthesis of 3-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)propylamine (22) Take a dry 50 mL eggplant-shaped flask, add 21 (2 g, 6.15 mmol), 10 mL of 2 M ethyl hydrochloride solution, stir at room temperature for 2 h. After the reaction is complete, remove the EtOAc hydrochloride solution by rotary evaporation to obtain 22 1.2 g of pale yellow viscous product, with a yield of 96.9%. 1 H NMR (400 MHz, CDCl3) d 4.04 (s, 1H), 3.71-3.40 (m, 2H), 3.18(s, 2H), 2.05 (d, J = 8.0 Hz, 2H), 1.26-1.15 (m, 2H). MS (ESI)calculated forC6H9F6NO: 225.0588; found m / z: 226.0662 [M+H] + .

[0066] Example 17 Synthesis of N-(3-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)propyl)benzenesulfonamide (23)

[0067] 22 (0.77 g, 4.74 mmol) was dissolved in 10 mL of acetonitrile, and Na2CO3 (1.26 g, 11.8 mmol) was dissolved in 10 mL of water. The mixture was stirred for 10 min, and then benzenesulfonyl chloride (0.84 g, 4.74 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 6 h. After the reaction was complete, the product was extracted with EtOAc, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Chromatographic chromatography was performed on a silica gel column using petroleum ether and ethyl acetate (5:1) as eluent. A pale yellow liquid product 23 (1.2 g) was given, with a yield of 69.4%. 1 H NMR (400 MHz, CDCl3) d 7.88 -7.80 (m, 2H), 7.59 (t, J = 7.3 Hz,1H), 7.52 (t, J = 7.4 Hz, 2H), 4.64 (s, 1H), 4.02 (hept, J = 5.9 Hz, 1H),3.90 (t, J = 5.7 Hz, 2H), 3.08 (q, J = 6.4 Hz, 2H), 1.84 (p, J = 6.1 Hz, 2H). 13C NMR (101 MHz, CDCl3) d 139.68, 132.91, 129.30, 127.07, 121.00, 76.37,72.54, 39.95, 29.73. MS (ESI) calculated for C 12 H 13 F6NO3S: 365.0520, found m / z:388.04125 [M+Na] + .

[0068] Example 18 Synthesis of 4-cyano-N-(3-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)propyl)benzenesulfonamide (24)

[0069] The same synthesis method was used for 23, 22 (500 mg, 2.22 mmol), 4-cyanobenzenesulfonyl chloride (448 mg, 2.22 mmol), and sodium carbonate (589 mg, 5.55 mmol). Chromatographic chromatography was performed on a silica gel column using petroleum ether ethyl acetate (2:1) as the eluent to obtain 24 0.7 g of a pale yellow, oily, transparent liquid product, with a yield of 81.4%. 1 H NMR (400 MHz, CDCl3)d 7.95 (d, J = 8.5 Hz, 2H), 7.81 (d, J = 8.7 Hz, 2H), 5.05 (t, J = 6.2 Hz,1H), 4.05 (hept, J = 5.9 Hz, 1H), 3.89 (t, J = 5.6 Hz, 2H), 3.10 (q, J = 6.4Hz, 2H), 1.85 (p, J = 6.2 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 144.11, 133.14,127.74, 121.47, 117.37, 116.58, 76.1, 72.60, 40.29, 29.72. MS (ESI)calculated for C 13 H 12 F6N2O3S: 390.0433, found m / z: 413.0365 [M+Na] + .

[0070] Example 19 Synthesis of 4-fluoro-N-(3-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)propyl)benzenesulfonamide (25)

[0071] The synthesis method was the same as 24, starting from 22 (500 mg, 2.22 mmol). After reaction and treatment, the product was subjected to chromatographic chromatography on a silica gel column using petroleum ether and ethyl acetate (5:1) as eluent to obtain a pale yellow oily transparent liquid product 25 0.75 g, with a yield of 88.2%. 1 H NMR (400 MHz, CDCl3) d 7.86 (dd, J = 8.9, 5.0 Hz, 2H), 7.18 (t,J = 8.6 Hz, 2H), 4.90 (t, J = 6.3 Hz, 1H), 4.04 (hept, J = 5.9 Hz, 1H), 3.89(t, J = 5.8 Hz, 2H), 3.07 (q, J = 6.4 Hz, 2H), 1.83 (p, J = 6.1 Hz, 2H). 13 CNMR (101 MHz, CDCl3) d 166.52, 163.98, 135.80, 135.77, 121.50, 116.63, 72.59,40.05, 29.69. MS (ESI) calculated for C 12 H 12 F7NO3S: 383.0426; found m / z: 406.0318 [M+Na] + .

[0072] Example 20 Synthesis of 3-cyano-4-fluoro-N-(3-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)propyl)benzenesulfonamide (26)

[0073] The synthesis method was the same as that for 24. Starting from 22 (500 mg, 2.22 mmol), after reaction and treatment, the product was subjected to chromatographic chromatography on a silica gel column using petroleum ether ethyl acetate (2:1) as the eluent to obtain a pale yellow oily transparent liquid product 26 0.85 g, with a yield of 93.4%. 1H NMR (400 MHz, CDCl3) d 8.18-8.05 (m, 2H), 7.39 (t, J = 8.5 Hz,1H), 5.23 (t, J = 6.1 Hz, 1H), 4.07 (hept, J = 5.9 Hz, 1H), 3.90 (t, J = 5.7Hz, 2H), 3.08 (q, J = 6.4 Hz, 2H), 1.86 (p, J = 6.2 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 166.50, 163.84, 137.48, 134.17, 133.10, 121.45, 117.84, 112.47,102.83, 72.50, 40.22, 29.60. MS (ESI) calculated for C 13 H 11 F7N2O3S: 408.0379;found m / z: 431.02708 [M+Na] + .

[0074] Example 21 Synthesis of N-(3-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)propyl)-4-methoxybenzenesulfonamide (27)

[0075] The synthesis method was the same as 24, starting from 22 (500 mg, 2.22 mmol). After reaction and treatment, the product was analyzed by chromatography on a silica gel column using petroleum ether and ethyl acetate (5:1) as eluent, yielding a colorless, oily, transparent liquid product 27 0.7 g, with a yield of 79.5%. 1 H NMR (400 MHz, CDCl3) d 7.80-7.74 (m, 2H), 7.00-6.94 (m, 2H), 4.87(t, J = 6.4 Hz, 1H), 4.03 (hept, J = 6.2 Hz, 1H), 3.88 (t, J = 5.9 Hz, 2H), 3.85 (s, 3H), 3.03 (q, J = 6.4 Hz, 2H), 1.81 (p, J = 6.2 Hz, 2H). 13C NMR (101MHz, CDCl3) d 163.09, 131.22, 129.27, 121.49, 114.40, 76.17, 72.56, 55.70,39.85, 29.70. MS (ESI) calculated for C 13 H 15 F6NO4S: 395.0626; found m / z:418.05182 [M+Na] + .

[0076] Example 22 Synthesis of N-(2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)ethyl)-4-methoxybenzenesulfonamide (28)

[0077] The synthesis method was the same as that for 12,6 (500 mg, 2.37 mmol), 4-methoxypyridinesulfonyl chloride (421 mg, 2.37 mmol), and sodium carbonate (628 mg, 5.93 mmol). After reaction and treatment, the product was subjected to chromatographic chromatography on a silica gel column with petroleum ether and ethyl acetate (5:1) as eluent to obtain 28 0.85 g of colorless transparent oily liquid product, with a yield of 94.1%. 1 H NMR(400 MHz, CDCl3) δ 7.77 (d, J = 9.1 Hz, 2H), 6.97 (d, J = 9.1 Hz, 2H), 4.91(t, J = 6.4 Hz, 1H), 4.03 (hept, J = 5.9 Hz, 1H), 3.86-3.80 (m, 5H), 3.19 (q,J = 5.5 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 163.21, 131.21, 129.25, 121.31,114.48, 76.2, 73.81, 55.72, 42.70. MS (ESI) calculated for C 12 H 13 F6NO4S:381.0469; found m / z: 404.03617[M+Na] + .

[0078] Example 23 Synthesis of N-(2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)ethyl)pyridine-3-sulfonamide (29)

[0079] The synthesis method was the same as 12, starting from 6 (500 mg, 2.37 mmol). After reaction and treatment, the product was chromatographically precipitated on silica gel with petroleum ether ethyl acetate (2:1) as the eluent to obtain 29 0.75 g of pale yellow transparent oily liquid product, with a yield of 90.4%. 1 H NMR (400 MHz, CDCl3) d 9.07 (d, J = 2.3 Hz, 1H), 8.82 (dd, J =4.8, 2.1 Hz, 1H), 8.14 (dt, J = 7.8, 2.3 Hz, 1H), 7.48 (dd, J = 8.0, 4.8 Hz,1H), 5.12 (t, J = 6.4 Hz, 1H), 4.03 (hept, J = 5.9 Hz, 1H), 3.93 (t, J = 4.8Hz, 2H), 3.34-3.27 (m, 2H). 13 C NMR (101 MHz, CDCl3) d 153.55, 147.96, 136.73,134.80, 123.99, 121.31, 76.77, 73.91, 42.81. MS (ESI) calculated forC 10 H 10 F6N2O3S: 352.0316; found m / z: 353.03891[M+H] + .

[0080] Example 24 Synthesis of N-(2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)ethyl)-4-methylbenzenesulfonamide (30)

[0081] The synthesis method was the same as 12, starting from 6 (500 mg, 2.37 mmol). After reaction and treatment, the product was chromatographically analyzed on a silica gel column using petroleum ether and ethyl acetate (2:1) as the eluent to obtain 30 0.7 g of colorless transparent oily liquid product, with a yield of 80.5%. 1H NMR (400 MHz, CDCl3) d 7.72 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.2Hz, 2H), 4.98 (t, J = 6.4 Hz, 1H), 4.04 (h, J = 5.9 Hz, 1H), 3.86 (t, J = 5.0Hz, 2H), 3.19 (q, J = 5.3 Hz, 2H), 2.41 (s, 3H). 13 C NMR (101 MHz, CDCl3) d143.97, 136.68, 129.90, 127.18, 122.73, 76.77, 73.78, 42.72, 21.53. MS (ESI)calculated for C 12 H 13 F6NO3S: 365.0520; found m / z: 388.04125[M+Na] + .

[0082] Example 25 Synthesis of 4-fluoro-N-(2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)ethyl)benzenesulfonamide (32)

[0083] The synthesis method was the same as 12, starting from 6 (500 mg, 2.37 mmol). After reaction and treatment, the product was subjected to chromatographic chromatography on a silica gel column using petroleum ether and ethyl acetate (2:1) as eluent to obtain 32 0.65 g of colorless transparent oily liquid product, with a yield of 74.7%. 1 H NMR (400 MHz, CDCl3) d 7.87 (dd, J = 9.1, 5.0 Hz, 2H), 7.19 (t, J =8.5 Hz, 2H), 4.94 (t, J = 6.4 Hz, 1H), 4.03 (hept, J = 5.7 Hz, 1H), 3.89 (t,J = 5.0 Hz, 2H), 3.23 (q, J = 5.0 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 166.60,164.06, 135.85, 125.50, 121.28, 116.59, 76.58, 73.81, 42.77. MS (ESI) calculated for C 11 H 10F7NO3S: 369.0270; found m / z: 392.01618[M+Na] + .

[0084] Example 26 Synthesis of 4-cyano-N-(2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)ethyl)benzenesulfonamide (33)

[0085] The synthesis method was the same as 12, starting from 6 (500 mg, 2.37 mmol). After reaction and treatment, the product was chromatographically analyzed on a silica gel column using petroleum ether and ethyl acetate (2:1) as eluent to obtain 33 0.77 g of colorless transparent oily liquid product, with a yield of 86.5%. 1 H NMR (400 MHz, CDCl3) d 7.97 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.2Hz, 2H), 4.97 (t, J = 6.3 Hz, 1H), 4.03 (hept, J = 5.7 Hz, 1H), 3.91 (t, J =5.0 Hz, 2H), 3.34-3.25 (m, 2H). 13 C NMR (101 MHz, CDCl3) d 144.28, 133.17,127.70, 121.22, 117.27, 116.80, 76.78, 73.82, 42.90. MS (ESI) calculated forC 12 H 10 F6N2O3S: 376.0316; found m / z: 399.02263[M+Na] + .

[0086] Example 27 Synthesis of 3-fluoro-N-(2-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)ethyl)benzenesulfonamide (34)

[0087] The synthesis method was the same as 12, starting from 6 (500 mg, 2.37 mmol). After reaction and treatment, the product was subjected to chromatographic chromatography on a silica gel column using petroleum ether and ethyl acetate (2:1) as eluent to obtain 34 0.78 g of colorless and transparent oily liquid product, with a yield of 89.6%. 1H NMR (400 MHz, CDCl3) d 7.65 (dd, J = 7.8, 0.9 Hz, 1H), 7.57-7.48(m, 2H), 7.29 (tdd, J = 8.2, 2.6, 1.0 Hz, 1H), 5.01 (t, J = 6.5 Hz, 1H), 4.03(p, J = 5.9 Hz, 1H), 3.89 (t, J = 5.1 Hz, 2H), 3.28-3.23 (m, 2H). 13 C NMR (101MHz, CDCl3) d 163.86, 161.35, 141.97, 131.23, 122.79, 120.29, 114.51, 76.62,73.86, 42.87. MS (ESI) calculated for C 11 H 10 F7NO3S: 369.0161; found m / z:392.01618 [M+Na] + .

[0088] Example 28 Synthesis of 3-fluoro-N-(3-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)propyl)benzenesulfonamide (35)

[0089] The synthesis method was the same as 24, starting from 22 (500 mg, 2.22 mmol). After reaction and treatment, the product was subjected to chromatographic chromatography on a silica gel column using petroleum ether and ethyl acetate (5:1) as the eluent to obtain 35 0.77 g of colorless transparent oily liquid product, with a yield of 90.6%. 1 H NMR (400 MHz, CDCl3) d 7.64 (d, J =8.7 Hz, 1H), 7.57–7.47 (m, 2H), 7.30-7.24 (m, 1H), 5.10 (t, J = 6.2 Hz, 1H), 4.05 (p, J = 5.9 Hz, 1H), 3.89(t, J = 5.7 Hz, 2H), 3.08 (q, J = 6.4 Hz, 2H), 1.84 (p, J = 6.4 Hz, 2H). 13CNMR (101 MHz, CDCl3) δ 163.85, 161.34, 141.70, 131.15, 122.91, 122.85,122.81, 114.45, 72.49, 40.06, 29.66. MS (ESI) calculated for C 12 H 12 F7NO3S:383.0426; found m / z: 406.03183 [M+Na] + .

[0090] Example 29 Synthesis of N-(3-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)propyl)-4-methylbenzenesulfonamide (36)

[0091] The synthesis method was the same as 24, starting from 22 (500 mg, 2.22 mmol). After reaction and treatment, the product was subjected to chromatographic chromatography on a silica gel column using petroleum ether and ethyl acetate (5:1) as eluent to obtain 36 0.75 g of colorless transparent oily liquid product, with a yield of 89.1%. 1 H NMR (400 MHz, CDCl3) d 7.72 (d, J = 6.4 Hz, 2H), 7.29 (d, J = 6.9Hz, 2H), 5.13 (t, J = 6.4 Hz, 1H), 4.08-3.99 (m, 1H), 3.89-3.82 (m, 2H), 3.01(t, J = 7.5 Hz, 2H), 2.40 (s, 3H), 1.80 (p, J = 6.2 Hz, 2H). 13 C NMR (101 MHz, CDCl3) d 143.74, 136.70, 129.86, 127.12, 121.22, 76.11, 72.47, 39.80, 29.66,21.48. MS (ESI) calculated for C 13 H 15 F6NO3S: 379.0677; found m / z: 402.0569 [M+Na] + .

[0092] Example 30 Synthesis of N-(3-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)propyl)pyridine-3-sulfonamide (37)

[0093] The synthesis method was the same as 24, starting from 22 (500 mg, 2.22 mmol). After reaction and treatment, the product was chromatographically analyzed on a silica gel column using petroleum ether-ethyl acetate (2:1) as the eluent to obtain 37 0.74 g of colorless and transparent oily liquid product, with a yield of 90.2%. 1 H NMR (400 MHz, CDCl3) δ 9.06 (d, J = 2.3 Hz, 1H), 8.80 (dd, J =5.0, 1.8 Hz, 1H), 8.13 (dt, J = 8.2, 1.8 Hz, 1H), 7.47 (dd, J = 8.2, 5.0 Hz,1H), 5.10 (t, J = 6.4 Hz, 1H), 4.05 (p, J = 5.9 Hz, 1H), 3.91 (t, J = 5.7 Hz,2H), 3.14 (q, J = 6.4 Hz, 2H), 1.88 (p, J = 6.2 Hz, 2H). 13 C NMR (101 MHz, CDCl3) d 153.36, 147.98, 136.63, 134.86, 123.92, 121.22, 76.11, 72.59, 40.17,29.80. MS (ESI) calculated for C 11 H 12 F6N2O3S: 366.0473; found m / z: 367.05773 [M+H] + .

[0094] Example 31 Synthesis of N-(3-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)propyl)-1-(4-nitrophenyl)methanesulfonamide (38)

[0095] The synthesis method was the same as 24, starting from 22 (500 mg, 2.22 mmol). After reaction and treatment, the product was subjected to chromatographic chromatography on a silica gel column using petroleum ether ethyl acetate (1:1) as the eluent to obtain 38 0.8 g of colorless transparent oily liquid product, with a yield of 85.1%. 1H NMR (400 MHz, CDCl3) d 8.25 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.7Hz, 2H), 4.34 (s, 2H), 4.05 (p, J = 5.7 Hz, 1H), 3.92 (t, J = 5.7 Hz, 2H), 3.16 (q, J = 6.4 Hz, 2H), 1.87 (p, J = 6.2 Hz, 2H). MS (ESI) calculated forC 13 H 14 F6N2O5S: 424.0528; found m / z: 447.04198 [M+Na] + .

[0096] Example 32: Identification of the inhibition of nNOS-SERT coupling by cell model compounds

[0097] HEK293T cells were simultaneously transfected with nNOS and SERT plasmids. HEK293T cells were incubated with 10 μM of the compound in vitro. The control group (Vehicle group) had an equal amount of solvent added to HEK293T cells in vitro. After 3 h, the effect of the compound on nNOS-SERT coupling was examined by immunoprecipitation.

[0098] Table 1. Inhibitory activity of compound nNOS-SERT coupling

[0099] XJ-2 70% 23 149.28% 8 95.70% 24 194.96% 9 89.30% 25 18.69% 10 104% 26 140.12% 11 99.40% 27 122.96% 12 34.26% 28 93.13% 13 56.07% 29 94.72% 14 100.31% 30 100.54% 15 114.97% 32 118.54% 16 77.87% 33 106.17% 17 155.16% 34 129.78% 18 157.03% 35 134.79% 19 99.77% 36 93.02% 20 97.04% 37 119.89% 22 94.70% 38 93.17%

[0100] The results are shown in Table 1. After administration of 10 μM of the compound, the nNOS-SERT coupling of XJ-2 decreased to 70% of that of the control group, and compounds 12, 13, and 25 decreased to 34.26%, 56.07%, and 16.89% of that of the control group, respectively, showing stronger inhibitory activity than XJ-2; compound 16 was 77.87%, which was slightly lower than that of XJ-2.

[0101] Based on the initial screening, verification experiments were conducted on compounds 12 and XJ-2. For example... Figure 1 As shown, the activities of compounds 12 and XJ-2 are reproducible. Figure 1 a), Compound 12 exhibits stronger coupling inhibition activity than XJ-2 ( Figure 1 b).

[0102] Example 33: Study on the rapid-onset antidepressant effect of compound 12 administered via intraperitoneal injection at physiological levels

[0103] Two hours after mice were intraperitoneally injected with compound 12 (10 mg / kg) or saline (10 mL / kg), they underwent the tail suspension test (TST) and the forced swim test (FST) to test the effect of the compound on nNOS-SERT coupling in the DRN brain region.

[0104] Figure 2 The study showed that, 2 hours after intraperitoneal administration of compound 12 (10 mg / kg) to physiological mice, the coupling level of nNOS and SERT in the dorsal raphe nucleus (DRN) brain region was significantly reduced (n=3), indicating that the compound can rapidly dissociate the nNOS-SERT complex. Figure 2 b shows that, under the same administration conditions, compound 12 dose-dependently reduced immobility time in mice during the tail suspension test (TST) (both 10 mg / kg and 20 mg / kg were statistically significant, n=15); in the forced swimming test (FST), although the 20 mg / kg group showed a decreasing trend, it did not reach statistical significance (ns). All of these behavioral effects were observed within 2 hours of a single dose. Compared to current first-line antidepressants that require continuous administration for 3-4 weeks to take effect, compound 12 exhibits antidepressant-like activity within 2 hours of administration, consistent with the characteristics of rapid antidepressant action.

[0105] Example 34: Study on the antidepressant effect of compound 12 in a pathological model

[0106] Mice were induced to develop a depression model by administering 0.1 mg / mL corticosterone aqueous solution for 3 weeks. Compound 12 (10 mg / kg) was administered intraperitoneally, and the level of the nNOS-SERT complex in the DRN brain region and behavioral tests were performed.

[0107] The results are as follows Figure 3 As shown. In 21-day corticosterone-induced water-drinking depressive mice, the nNOS-SERT coupling level in the DRN brain region was significantly increased compared to the normal control; after a single intraperitoneal administration of compound 12 (10 mg / kg) for 2 hours, this coupling level significantly decreased, returning to near the normal control level. Figure 3 a). Behavioral tests showed that the immobility time in corticosterone-induced mice was significantly increased in both the tail suspension test (TST) and the forced swimming test (FST) compared to normal controls; while two hours after a single dose of compound 12, the immobility time in both the TST and FST was significantly reduced in the induced mice. Figure 3 (b) and all results were statistically significant. These results indicate that in a mouse model of depression, compound 12 produced a significant antidepressant-like effect within 2 hours of a single dose, demonstrating its potential for rapid onset of action in treating depression.

Claims

1. A class of ether amides or sulfonamide derivatives or pharmaceutically acceptable salts thereof, characterized in that, Its chemical structure is shown in the following general structural formula: Wherein: R1 and R2 are each independently selected from H, CH3, CF3, Et, n-Pr, i-Pr, cyclopropyl, butyl, cyclobutyl, cyclopentyl, etc. 1-5 Straight-chain or branched alkyl groups; m=0~4; n=1~5; X=-CO-NH-, -NH-CO-, -NH-SO2-, -CO-NH-SO2-; Ar = phenyl, pyridyl, pyrimidinyl, furanyl, thiophene, pyrroleyl, and the aromatic ring may carry one or two of the following substituents or combinations thereof: methyl, trifluoromethyl, ethyl, isopropyl, propyl, nitro, fluorine, chlorine, bromine, iodine, cyano, methoxy, hydroxy, methanesulfonyl, acetyl.

2. The ether amide or sulfonamide derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R1 and R2 are independently H, CH3, CF3, X is -CO-NH- or -NH-SO2-, Ar is substituted or unsubstituted phenyl or pyridyl; the substituents on the aromatic ring are selected from one or two of methyl, cyano, hydroxy, nitro, methoxy, acetyl, methanesulfonyl or fluorine, n=, 1~3 or 3, m=0~2.

3. The ether amide or sulfonamide derivative or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that, R1 and R2 are CF 3， X is -CO-NH- or -NH-SO2-, n=1, 2 or 3, m=0 or 1.

4. The ether amide or sulfonamide derivative or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that, Ar represents substituted or unsubstituted phenyl or pyridyl groups; the substituents on the aromatic ring are selected from cyano or fluorine groups.

5. The ether amide or sulfonamide derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The etheramide or sulfonamide derivative is selected from any one of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 。 6. The ether amide or sulfonamide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, characterized in that, The etheramide or sulfonamide derivative is selected from any one of the following compounds: 、 、 。 7. A pharmaceutical composition comprising an ether amide or sulfonamide derivative or a pharmaceutically acceptable salt thereof as described in any one of claims 1-6, and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7, characterized in that, The pharmaceutically acceptable salt is selected from hydrochloride, acetate, citrate, tartrate, p-toluenesulfonate, benzenesulfonate, or fumarate.

9. The use of the ether amide or sulfonamide derivative of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 7-8, in the preparation of a medicament for treating depression.

10. The application according to claim 9, characterized in that, The etheramide or sulfonamide derivative or its pharmaceutically acceptable salt or the composition thereof exerts a rapid antidepressant effect by inhibiting the coupling of nNOS-SERT.

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