Alpha5-gaba a receptor inverse agonists and methods of making and using the same

Abstract

The application discloses an alpha5-GABAA receptor reverse agonist, a preparation method and application thereof, and belongs to the field of medicine. The alpha5-GABAA receptor reverse agonist is a compound with a general formula I, a pharmaceutically acceptable salt thereof and a pharmaceutical composition thereof. Experimental results show that the compound has high affinity to alpha5-GABAA receptor protein. Meanwhile, animal test results show that the compound has good analgesic activity in a mouse acetic acid writhing and a paclitaxel-induced pain model, and the effect is better than that of an existing positive control. The application provides a new choice for preparing a medicine for preventing and treating pain-related diseases.

Description

Technical Field

[0001] This invention pertains to the synthesis of organic drugs, specifically relating to an α5-GABAA receptor inverse agonist, its preparation method, and its application. Background Technology

[0002] Neuropathic pain is a severe chronic pain syndrome directly caused by primary lesions or dysfunctions of the somatosensory nervous system. Currently, first-line clinical treatments have low response rates (approximately 50%-60% of patients do not achieve substantial relief) and severe side effects such as drowsiness and sedation.

[0003] Recent studies have shown that GABAA receptors containing the α5 subunit (α5-GABAA) mediate abnormal pro-pain currents under pathological conditions, making them highly promising analgesic targets. These novel small molecules can specifically bind to allosteric sites on the receptor, potently weakening or blocking the abnormal depolarization pro-pain currents mediated by the α5 receptor under pathological conditions, thus correcting the pain amplification effect at its source. Simultaneously, due to its highly selective action on the α5 subtype, this strategy avoids the α1 subtype associated with sedation and drowsiness, and the α2 / α3 subtypes associated with anxiolytics and muscle relaxation, thus completely eliminating the severe neurological side effects of traditional GABAergic drugs while exerting a potent analgesic effect.

[0004] Therefore, based on the central role of α5-GABAA receptor in the mechanism of chronic neuropathic pain and the dual advantages of its inverse agonists in "de-analgesia and safety," developing novel selective α5-GABAA receptor inverse agonists with both high target affinity and excellent in vivo analgesic efficacy can not only overcome the clinical bottlenecks of poor efficacy and difficult-to-overcome side effects of existing analgesics, but also provide a new and safe targeted therapy option for patients suffering from neuropathic pain. This has significant scientific research value and broad clinical translation prospects. Summary of the Invention

[0005] Purpose of the invention: The purpose of this invention is to provide a novel α5-GABAA receptor inverse agonist that has a high affinity for the α5-GABAA receptor and exhibits excellent analgesic activity in various pain models, in order to solve the technical problems of insufficient efficacy or significant side effects of existing analgesic drugs.

[0006] Technical solution: This invention provides compounds represented by general formula I or pharmaceutically acceptable salts thereof: ;

[0007] I Wherein, R is selected from C3-C8 cycloalkyl, four- to six-membered oxygen-containing heterocyclic groups, methyl, C3-C5 branched alkyl, methoxy, ethoxy, phenyl, substituted phenyl or 3-pyridyl; n is an integer of 0, 1, 2, 3 or 4; The substituted phenyl group may optionally be replaced by one substituent selected from halogens or methyl groups.

[0008] In some embodiments, when R is selected from C3-C8 cycloalkyl groups, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and n = 0.

[0009] In some embodiments, when R is selected from quaternary to hexaternary oxygen-containing heterocyclic groups, the heterocyclic group is selected from oxetane-3-yl, tetrahydrofuran-3-yl, or tetrahydropyran-4-yl, and n = 0.

[0010] In some embodiments, when R is selected from the substituted phenyl group, the substituted phenyl group is selected from 4-chlorophenyl, 4-methylphenyl, 3-chlorophenyl, 3-methylphenyl or 3-fluorophenyl, and n = 1.

[0011] In some embodiments, R is selected from methyl and n is an integer from 1 to 4; or R is selected from isopropyl, sec-butyl, isobutyl or isopentyl and n is 0.

[0012] This invention provides the compound or a pharmaceutically acceptable salt thereof: N-Cyclopropyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-Cyclobutyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-Cyclopentyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-Cyclohexyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-Cycloheptyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-Cyclooctyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(oxetanebut-3-yl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(tetrahydrofuran-3-yl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(tetrahydropyran-4-yl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-Ethyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-propyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-Butyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-pentyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-Isopropyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(butan-2-yl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(3-methylbutyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(2-methylpropyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(3-methoxypropyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(2-methoxyethyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(2-ethoxyethyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-Benzyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(3-phenylpropyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(pyridin-3-ylmethyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(4-chlorobenzyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(4-methylbenzyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(3-chlorobenzyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(3-methylbenzyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(3-Fluorobenzyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide.

[0013] In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt.

[0014] The present invention also provides a method for preparing a compound of general formula I or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0015] (S1): 3-chloro-4-(pyridin-4-yl)-1,2,5-thiadiazole reacts with methyl 4-(hydroxymethyl)benzoate in the presence of a basic reagent (such as cesium carbonate) and an organic solvent (such as DMF) to give compound B-1; (S2): Compound B-1 obtained in step (S1) undergoes hydrolysis in the presence of lithium hydroxide aqueous solution to give the key carboxylic acid compound B-2; (S3): The compound B-2 obtained in step (S2) undergoes an amidation reaction with various amine substrates (R-(CH2)n-NH2) under the action of a condensing agent (such as HBTU) and a basic reagent (such as DIPEA) to finally obtain the compound of general formula I. R and n are as defined above.

[0016] In step (S1), the molar ratio of 3-chloro-4-(pyridin-4-yl)-1,2,5-thiadiazole to methyl 4-(hydroxymethyl)benzoate is 1: (1~1.5), the basic reagent is selected from cesium carbonate, and the reaction solvent is selected from N,N-dimethylformamide (DMF). The reagent for the hydrolysis reaction in step (S2) is selected from lithium hydroxide, and the reaction solvent is selected from a mixture of methanol and water; In step (S3), the molar ratio of compound B-2 to the amine substrate is 1:(1~2), the coupling agent is selected from O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), the basic reagent is selected from N,N-diisopropylethylamine (DIPEA), and the reaction solvent is selected from dichloromethane (DCM).

[0017] The present invention also provides a pharmaceutical composition comprising the above-described compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0018] The present invention also provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of α5-GABAA receptor-mediated diseases.

[0019] In some embodiments, the α5-GABAA receptor-mediated diseases are selected from pain-related diseases.

[0020] In some embodiments, the pain-related disease is selected from neuropathic pain, including but not limited to peripheral nerve damage or inflammatory pain induced by chemotherapy drugs (such as paclitaxel).

[0021] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) The compound of general formula I provided by the present invention has a high in vitro binding affinity for α5-GABAA receptor; (2) The compound described in this invention exhibits excellent analgesic activity in a mouse acetic acid-induced writhing model, and the activity is significantly dose-dependent. (3) The compound described in this invention can significantly improve paclitaxel-induced neuropathic pain and significantly increase the mechanical withdrawal threshold of mice. Its efficacy is superior to that of the existing positive control drug SR-419, which is currently in the clinical research stage. Attached Figure Description

[0022] Figure 1 The hydrogen spectrum of compound 1; Figure 2 The carbon spectrum of compound 1; Figure 3 The hydrogen spectrum of compound 7; Figure 4 The carbon spectrum of compound 7; Figure 5 The hydrogen spectrum of compound 20; Figure 6 The carbon spectrum of compound 20; Figure 7 A schematic diagram showing the results of the acetic acid writhing test in mice of compounds 1, 7, and 20; Figure 8This is a schematic diagram showing the change in the inhibition rate of compound 7 over time in a paclitaxel-induced mouse model of neuropathic pain. Detailed Implementation

[0023] The technical solution of the present invention will be further described below with reference to the accompanying drawings and embodiments.

[0024] Test method: The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR measurements were performed using a Bruker AV-500 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO) as the solvent. d 6 (or deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard. Chemical shift (δ) is expressed in ppm.

[0025] HR-MS measurements were performed using an Agilent LC-MS / MS QTOF 6530 (manufacturer: Agilent, MS model: QTOF6530).

[0026] The following examples are for illustrative purposes only and are not intended to limit the invention.

[0027] All temperatures are in Celsius (°C).

[0028] A. Compound Synthesis Examples Example 1 Synthesis of N-cyclopropyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (1)

[0029] Synthesis of S1) 4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzoate (compound B-1) 3-Chloro-4-(pyridin-4-yl)-1,2,5-thiadiazole (10.0 g, 50.6 mmol, 1.0 eq), methyl 4-(hydroxymethyl)benzoate (8.4 g, 50.6 mmol, 1.0 eq), and cesium carbonate (24.7 g, 75.9 mmol, 1.5 eq) were placed in a round-bottom flask, and DMF (100 mL) was added to form a homogeneous solution. The reaction was stirred at 80 °C for 6 hours. After confirmation of the reaction by thin-layer chromatography (TLC), the reaction was quenched with an appropriate amount of water. The organic product was extracted with dichloromethane (three times, 100 mL each time), and the organic phases were combined and washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed by rotary evaporation. The crude product was purified by silica gel column chromatography (200–300 mesh, PE / EA = 6:1) to give intermediate compound B-1.

[0030] 1 H NMR (500 MHz, Chloroform- d ) δ 8.82 (d, J = 5.8 Hz, 2H), 8.03 (d, J =8.2 Hz, 2H), 7.88 (d, J = 5.8 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 5.42 (s, 2H), 3.93 (s, 3H). (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 16 H 14 N3O3S + [M + H] + 328.0750. Found 328.0750. Synthesis of S2) 4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzoic acid (compound B-2) The reaction product from step S1 (9.6 g, 29.3 mmol, 1.0 eq) was weighed into a round-bottom flask, and a methanol / water mixture was added. Then, lithium hydroxide (146.5 mmol, 5.0 eq) was added. The mixture was stirred magnetically at room temperature for 3 h. TLC monitoring showed the reaction was not yet complete, so stirring was continued for another 3 h, after which TLC monitoring indicated the reaction was complete. The organic solvent was then removed by rotary evaporation under reduced pressure. A suitable amount of water was added to the reaction system, and the pH was adjusted to 3–4 with dilute hydrochloric acid, causing a solid to precipitate. The precipitate was collected by filtration and dried to obtain the crude product. The crude product was purified by rapid column chromatography (silica gel 200–300 mesh, DCM / MeOH = 8:1) to obtain intermediate compound B-2.

[0031] 1 H NMR (500 MHz, DMSO- d 6 ) δ 13.12 (br s, 1H), 8.84 (d, J = 5.8 Hz, 2H), 8.01 (d, J = 8.1 Hz, 2H), 7.96 (d, J = 5.8 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 5.39 (s, 2H). (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 15 H 12 N3O3S + [M + H] + 314.0594. Found 314.0594. Synthesis of S3) N-cyclopropyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide Intermediate B-2 (200 mg, 0.64 mmol, 1.0 eq) and HBTU (364 mg, 0.96 mmol, 1.5 eq) were weighed into a 25 mL round-bottom flask. DCM (8 mL) was added to dissolve the product, followed by DIPEA (0.33 mL, 1.92 mmol, 3.0 eq). The mixture was stirred at room temperature for 10 min to activate the product. Cyclopropylamine (0.96 mmol, 1.5 eq) was then added, and the reaction mixture was heated to 40 °C and stirred for 6–10 h. The reaction progress was monitored by TLC. After the reaction was complete, the organic product was extracted with dichloromethane (three times, 100 mL each time). The organic phases were combined and washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed by rotary evaporation. The crude product was then eluted by silica gel column chromatography with a DCM / MeOH gradient from 85:1 to 60:1. The fractions containing the target product were combined and concentrated under reduced pressure to remove the solvent, yielding product 1.

[0032] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.23 (d, J = 2.2 Hz, 1H), 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 8.44 (d, J = 4.3 Hz, 1H), 8.39 (dt, J = 8.0, 2.0 Hz, 1H), 7.85 (d, J =8.3 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.56 (ddd, J = 8.0, 4.9, 1.0 Hz, 1H), 5.62(s, 2H), 2.91–2.80 (m, 1H), 0.74–0.65 (m, 2H), 0.61–0.53 (m, 2H). 13 C NMR (101MHz, DMSO- d 6 ) δ 167.60, 162.53, 150.93, 148.43, 145.57, 139.07, 135.12,134.97, 128.29, 127.91, 127.43, 124.38, 72.45, 23.51, 6.21. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C18 H 17 N4O2S + [M+H] + 353.1067. Found 353.1064. Example 2 Synthesis of N-cyclobutyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (2) The only difference from Example 1 is that cyclopropylamine is replaced with cyclobutylamine in step S3. The other steps are basically the same and will not be described in detail here.

[0033] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.23 (d, J = 2.0 Hz, 1H), 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 8.61 (d, J = 7.6 Hz, 1H), 8.39 (dt, J = 8.0, 2.0 Hz, 1H), 7.88 (d, J =8.3 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.56 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 5.63(s, 2H), 4.47–4.33 (m, 1H), 2.28–2.17 (m, 2H), 2.13–1.99 (m, 2H), 1.75–1.60(m, 2H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 165.37, 162.53, 150.92, 148.43, 145.57,139.05, 135.11, 135.04, 128.29, 128.01, 127.43, 124.37, 72.46, 45.04, 30.54,15.20. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 19 H 19 N4O2S + [M+H] + 367.1223. Found 367.1221. Example 3 Synthesis of N-cyclopentyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (3) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with cyclopentylamine. The other steps are basically the same and will not be described in detail here.

[0034] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.23 (d, J = 1.5 Hz, 1H), 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 8.39 (dt, J = 8.0, 2.0 Hz, 1H), 8.28 (d, J = 7.2 Hz, 1H), 7.88 (d, J =8.3 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.56 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 5.63(s, 2H), 4.29–4.16 (m, 1H), 1.95–1.81 (m, 2H), 1.77–1.63 (m, 2H), 1.63–1.47(m, 4H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 166.06, 162.54, 150.93, 148.43, 145.57,138.89, 135.38, 135.11, 128.26, 128.05, 127.43, 124.38, 72.48, 51.42, 32.60,24.11. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 20 H 21 N4O2S + [M+H] + 381.1380. Found 381.1377. Example 4 Synthesis of N-cyclohexyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (4) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with cyclohexylamine. The other steps are basically the same and will not be described in detail here.

[0035] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.23 (s, 1H), 8.67 (d, J = 4.8 Hz, 1H), 8.39(d, J = 8.0 Hz, 1H), 8.20 (d, J = 7.9 Hz, 1H), 7.87 (d, J = 7.8 Hz, 2H), 7.61 (d, J =7.7 Hz, 2H), 7.56 (t, J = 6.4 Hz, 1H), 5.62 (s, 2H), 3.76 (s, 1H), 1.82 (s,2H), 1.73 (s, 2H), 1.65–1.49 (m, 2H), 1.30 (t, J = 10.0 Hz, 4H). 13 C NMR (101MHz, DMSO- d 6 ) δ 165.49, 162.54, 150.93, 148.43, 145.57, 138.90, 135.45,135.11, 128.28, 128.03, 127.43, 124.38, 72.48, 48.83, 32.87, 25.74, 25.39. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 21 H 23 N4O2S + [M+H] + 395.1530. Found 395.1531. Example 5 Synthesis of N-cycloheptyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (5) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with cycloheptylamine. The other steps are basically the same and will not be described in detail here.

[0036] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.23 (d, J = 1.4 Hz, 1H), 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 8.39 (dt, J = 8.1, 1.9 Hz, 1H), 8.23 ​​(d, J = 7.9 Hz, 1H), 7.87 (d, J =8.3 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 7.56 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 5.62(s, 2H), 4.05–3.98 (m, 1H), 1.76–1.65 (m, 6H), 1.56–1.49 (m, 6H). 13C NMR (101 MHz, DMSO- d 6 ) δ 165.26, 162.54, 150.93, 148.43, 145.57, 138.85, 135.53,135.12, 128.27, 128.04, 127.43, 124.38, 72.48, 50.92, 34.78, 28.29, 24.43. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 24 H 25 N4O2S + [M+H] + 409.1693. Found 409.1687. Example 6 Synthesis of N-cyclooctyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (6) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with cyclooctylamine. The other steps are basically the same and will not be described in detail here.

[0037] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.23 (d, J = 2.3 Hz, 1H), 8.67 (dd, J= 4.8, 1.7 Hz, 1H), 8.39 (dt, J = 8.1, 2.0 Hz, 1H), 8.24 (d, J = 7.9 Hz, 1H), 7.87 (d, J =7.9 Hz, 2H), 7.61 (d, J = 7.9 Hz, 2H), 7.56 (dd, J = 8.0, 4.8 Hz, 1H), 5.62 (s,2H), 4.00–3.91 (m, 1H), 1.89–1.80 (m, 2H), 1.72–1.36 (m, 12H). 13 C NMR (101MHz, DMSO- d 6 ) δ 165.26, 162.53, 150.92, 148.42, 145.55, 138.83, 135.56,135.10, 128.25, 128.04, 127.42, 124.37, 72.48, 49.74, 32.15, 27.28, 25.65,24.04. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 23 H 27 N4O2S + [M+H] + 423.1849. Found 423.1845. Example 7 Synthesis of N-(oxetanebut-3-yl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (7) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with oxadiazine-3-amine. The other steps are basically the same and will not be described in detail here.

[0038] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.24 (d, J = 1.6 Hz, 1H), 9.11 (d, J = 6.4 Hz, 1H), 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 8.40 (dt, J= 8.1, 2.0 Hz, 1H), 7.93 (d, J =8.2 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.56 (dd, J = 8.1, 4.8 Hz, 1H), 5.64 (s,2H), 5.08–4.95 (m, 1H), 4.78 (t, J = 6.9 Hz, 2H), 4.60 (t, J = 6.4 Hz, 2H). 13 C NMR (101 MHz, DMSO-) d 6 ) δ 166.10, 162.52, 150.92, 148.43, 145.56, 139.47, 135.12,134.37, 128.35, 128.12, 127.42, 124.37, 77.40, 72.41, 45.10. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 18 H 17 N4O3S + [M+H] + 369.1016. Found 369.1013. Example 8 Synthesis of N-(tetrahydrofuran-3-yl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (8) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with tetrahydrofuran-3-amine. The other steps are basically the same and will not be described in detail here.

[0039] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.23 (d, J = 1.6 Hz, 1H), 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 8.54 (d, J = 6.5 Hz, 1H), 8.39 (dt, J = 8.1, 2.0 Hz, 1H), 7.90 (d, J =8.3 Hz, 2H), 7.63 (d, J= 8.2 Hz, 2H), 7.56 (ddd, J = 8.1, 4.8, 1.0 Hz, 1H), 5.63(s, 2H), 4.52–4.40 (m, 1H), 3.91–3.81 (m, 2H), 3.77–3.67 (m, 1H), 3.59 (dd, J =8.9, 4.4 Hz, 1H), 2.22–2.09 (m, 1H), 1.99–1.86 (m, 1H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 166.59, 162.53, 150.92, 148.43, 145.56, 139.18, 135.12, 134.85, 128.28,128.13, 127.43, 124.37, 72.76, 72.45, 66.98, 50.77, 32.32. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 19 H 19 N4O3S + [M+H] + 383.1172. Found 383.1166. Example 9 Synthesis of N-(tetrahydropyran-4-yl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (9) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with tetrahydropyran-4-amine. The other steps are basically the same and will not be described in detail here.

[0040] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.23 (d, J = 1.4 Hz, 1H), 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 8.39 (dt, J = 8.1, 1.9 Hz, 1H), 8.32 (d, J = 7.7 Hz, 1H), 7.89 (d, J =8.3 Hz, 2H), 7.63 (d, J= 8.2 Hz, 2H), 7.56 (ddd, J = 8.1, 4.8, 0.9 Hz, 1H), 5.63(s, 2H), 4.06–3.96 (m, 1H), 3.92–3.84 (m, 2H), 3.39 (td, J = 11.8, 2.2 Hz, 2H), 1.81–1.72 (m, 2H), 1.64–1.51 (m, 2H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 165.73,162.52, 150.92, 148.43, 145.56, 139.07, 135.21, 135.10, 128.30, 128.05,127.42, 124.37, 72.45, 66.62, 46.24, 32.88. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 20 H 21 N4O3S + [M+H] + 397.1329. Found 397.1324. Example 10 Synthesis of N-ethyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (10) The only difference from Example 1 is that cyclopropylamine is replaced with ethylamine in step S3. The other steps are basically the same and will not be described in detail here.

[0041] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.24 (d, J = 1.4 Hz, 1H), 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 8.47 (t, J = 5.6 Hz, 1H), 8.39 (dt, J = 8.0, 2.0 Hz, 1H), 7.89 (d, J =8.3 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.56 (ddd, J= 8.0, 4.8, 1.0 Hz, 1H), 5.63(s, 2H), 3.33–3.26 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6 )δ 166.05, 162.54, 150.91, 148.44, 145.56, 138.98, 135.22, 135.11, 128.33,127.87, 127.43, 124.37, 72.46, 34.52, 15.23. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 17 H 17 N4O2S + [M+H] + 341.1067. Found 341.1067. Example 11 Synthesis of N-propyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (11) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with n-propylamine. The other steps are basically the same and will not be described in detail here.

[0042] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.23 (d, J = 1.8 Hz, 1H), 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 8.46 (t, J = 5.7 Hz, 1H), 8.39 (dt, J = 8.1, 1.9 Hz, 1H), 7.89 (d, J =8.3 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.56 (ddd, J = 8.1, 4.8, 0.9 Hz, 1H), 5.63(s, 2H), 3.23 (q, J = 6.7 Hz, 2H), 1.57–1.50 (m, 2H), 0.90 (t, J= 7.4 Hz, 3H). 13 CNMR (101 MHz, DMSO- d 6 ) δ 166.26, 162.53, 150.91, 148.42, 145.54, 138.96,135.26, 135.09, 128.32, 127.89, 127.41, 124.36, 72.45, 41.47, 22.84, 11.91. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 18 H 19 N4O2S + [M+H] + 355.1223. Found 355.1220. Example 12 Synthesis of N-butyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (12) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with n-butylamine. The other steps are basically the same and will not be described in detail here.

[0043] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.23 (d, J = 2.2 Hz, 1H), 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 8.44 (t, J = 5.7 Hz, 1H), 8.39 (dt, J = 8.0, 2.0 Hz, 1H), 7.92–7.85(m, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.56 (dd, J = 8.0, 4.8 Hz, 1H), 5.63 (s, 2H), 3.31–3.22 (m, 2H), 1.54–1.48 (m, 2H), 1.38–1.29 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 166.21, 162.53, 150.90, 148.42, 145.54,138.95, 135.26, 135.09, 128.32, 127.88, 127.41, 124.36, 72.45, 39.35, 31.70,20.12,14.17. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 19 H 21 N4O2S + [M+H] + 369.1380. Found 369.1379. Example 13 Synthesis of N-pentyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (13) The only difference from Example 1 is that in step S3, cyclopropylamine is replaced with n-pentylamine. The other steps are basically the same and will not be described in detail here.

[0044] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.24 (d, J = 1.4 Hz, 1H), 8.67 (dd, J = 4.8,1.7 Hz, 1H), 8.48–8.36 (m, 2H), 7.88 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.56 (ddd, J = 8.1, 4.8, 0.9 Hz, 1H), 5.63 (s, 2H), 3.30–3.21 (m, 2H), 1.59–1.47 (m, 2H), 1.36–1.24 (m, 4H), 0.92–0.84 (m, 3H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 166.19, 162.54, 150.92, 148.44, 145.57, 138.96, 135.26, 135.11,128.33, 127.89, 127.43, 124.37, 72.46, 29.25, 29.17, 22.34, 14.38. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 20 H 23 N4O2S + [M+H] + 383.1536. Found 383.1532. Example 14 Synthesis of N-isopropyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (14) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with isopropylamine. The other steps are basically the same and will not be described in detail here.

[0045] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.24 (d, J = 1.3 Hz, 1H), 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 8.39 (dt, J = 8.1, 1.9 Hz, 1H), 8.23 ​​(d, J = 7.7 Hz, 1H), 7.89 (d, J =8.3 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.56 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 5.63(s, 2H), 4.19–4.03 (m, 1H), 1.18 (d, J = 6.6 Hz, 6H). 13 C NMR (101 MHz, DMSO- d 6 )δ 165.50, 162.52, 150.91, 148.42, 145.54, 138.90, 135.40, 135.08, 128.27,127.99, 127.42, 124.35, 72.47, 41.48, 22.78. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 18 H 19 N4O2S + [M+H] +355.1223. Found 355.1222. Example 15 Synthesis of N-(butan-2-yl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (15) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with sec-butylamine. The other steps are basically the same and will not be described in detail here.

[0046] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.24 (d, J = 1.4 Hz, 1H), 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 8.46 (t, J = 5.8 Hz, 1H), 8.40 (dt, J = 8.1, 2.0 Hz, 1H), 7.89 (d, J =8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.56 (ddd, J = 8.0, 4.8, 1.0 Hz, 1H), 5.63(s, 2H), 3.09 (t, 2H), 1.93–1.78 (m, 1H), 0.89 (d, J = 6.7 Hz, 6H). 13 C NMR (101MHz, DMSO- d 6 ) δ 166.41, 162.54, 150.91, 148.44, 145.56, 138.96, 135.34,135.11, 128.33, 127.93, 127.43, 124.37, 72.46, 47.20, 28.57, 20.68. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 19 H 21 N4O2S + [M+H] + 369.1380. Found 369.1377. Example 16 Synthesis of N-(3-methylbutyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (16) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with isoamylamine. The other steps are basically the same and will not be described in detail here.

[0047] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.24 (dd, J = 2.4, 1.0 Hz, 1H), 8.67 (dt, J =5.0, 1.4 Hz, 1H), 8.46–8.35 (m, 2H), 7.88 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0Hz, 2H), 7.56 (ddd, J = 8.1, 4.9, 1.1 Hz, 1H), 5.63 (s, 2H), 3.31–3.24 (m, 2H), 1.66–1.55 (m, 1H), 1.43 (q, J = 7.1 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H). 13 C NMR (101MHz, DMSO- d 6 ) δ 166.15, 162.54, 150.91, 148.43, 145.56, 138.96, 135.27,135.11, 128.33, 127.88, 127.43, 124.37, 72.46, 40.72, 38.58, 37.94, 25.79,22.90. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 20 H 23 N4O2S + [M+H] + 383.1536. Found 383.1532. Example 17 Synthesis of N-(2-methylpropyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (17) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with isobutylamine. The other steps are basically the same and will not be described in detail here.

[0048] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.24 (d, J = 2.2 Hz, 1H), 8.67 (dd, J = 4.9, 1.7 Hz, 1H), 8.40 (dt, J = 8.1, 2.0 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.89 (d, J =7.9 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.56 (dd, J = 8.0, 4.8 Hz, 1H), 5.63 (s,2H), 4.00–3.85 (m, 1H), 1.62–1.43 (m, 2H), 1.14 (d, J = 6.6 Hz, 3H), 0.87 (t, J =7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 165.80, 162.53, 150.91, 148.43,145.56, 138.88, 135.50, 135.10, 128.30, 127.99, 127.43, 124.37, 72.48, 46.92,29.30, 20.70, 11.18. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 19 H 21 N4O2S + [M+H] + 383.1536. Found 383.1532. Example 18 Synthesis of N-(3-methoxypropyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (18) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with 2-methoxypropylamine. The other steps are basically the same and will not be described in detail here.

[0049] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.24 (d, J = 2.2 Hz, 1H), 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 8.47 (t, J = 5.6 Hz, 1H), 8.40 (dt, J = 8.0, 1.9 Hz, 1H), 7.88 (d, J =8.3 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.56 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 5.63(s, 2H), 3.38 (t, J = 6.3 Hz, 2H), 3.34–3.32 (m, 1H), 3.31–3.28 (m, 1H), 3.24 (s, 3H), 1.82–1.71 (m, 2H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 166.30, 162.54,150.92, 148.44, 145.57, 139.03, 135.17, 135.12, 128.34, 127.90, 127.43,124.38, 72.45, 70.22, 58.37, 37.05, 29.69. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 19 H 21 N4O3S + [M+H] + 385.1329. Found 385.1325. Example 19 Synthesis of N-(2-methoxyethyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (19) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with 3-methoxyethylamine. The other steps are basically the same and will not be described in detail here.

[0050] 1H NMR (400 MHz, DMSO- d 6 ) δ 9.23 (d, J = 2.3 Hz, 1H), 8.67 (dd, J = 4.8,1.7 Hz, 1H), 8.57–8.50 (m, 1H), 8.39 (dt, J = 8.1, 2.0 Hz, 1H), 7.90 (d, J = 8.3Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.56 (ddd, J = 8.1, 4.9, 0.9 Hz, 1H), 5.63 (s,2H), 3.49–3.46 (m, 1H), 3.45–3.40 (m, 2H), 3.31 (s, 1H), 3.27 (s, 3H). 13 C NMR (101 MHz, DMSO-) d 6 ) δ 166.39, 162.54, 150.92, 148.45, 145.57, 139.14, 135.11,134.91, 128.33, 127.95, 127.43, 124.37, 72.44, 70.92, 58.40, 40.71. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 18 H 19 N4O3S + [M+H] + 371.1172. Found 371.1170. Example 20 Synthesis of N-(2-ethoxyethyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (20) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with 2-ethoxyethylamine. The other steps are basically the same and will not be described in detail here.

[0051] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.24 (d, J = 2.2 Hz, 1H), 8.67 (dd, J= 4.8, 1.7 Hz, 1H), 8.53 (t, J = 5.6 Hz, 1H), 8.40 (dt, J = 8.1, 2.0 Hz, 1H), 7.90 (d, J =8.2 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.56 (dd, J = 8.0, 4.8 Hz, 1H), 5.63 (s,2H), 3.53–3.39 (m, 6H), 1.11 (t, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6 ) δ166.40, 162.54, 150.91, 148.44, 145.56, 139.13, 135.10, 134.94, 128.33,127.94, 127.42, 124.37, 72.44, 68.77, 65.87, 15.58. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 19 H 21 N4O3S + [M+H] + 385.1329. Found 385.1324. Example 21 Synthesis of N-benzyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (21) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with benzylamine. The other steps are basically the same and will not be described in detail here.

[0052] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.24 (d, J = 2.0 Hz, 1H), 9.07 (t, J = 6.0 Hz, 1H), 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 8.40 (dt, J = 8.1, 2.0 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.56 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 7.33(d, J = 4.4 Hz, 4H), 7.28–7.19 (m, 1H), 5.64 (s, 2H), 4.50 (d, J = 6.0 Hz, 2H). 13 CNMR (101 MHz, DMSO- d 6 ) δ 166.35, 162.54, 150.92, 148.45, 145.57, 140.09,139.27, 135.11, 134.86, 128.74, 128.41, 128.03, 127.67, 127.43, 127.20,124.37, 72.44, 43.11. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 22 H 19 N4O2S + [M+H] + 403.1223. Found 403.1219. Example 22 Synthesis of N-(3-phenylpropyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (22) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with 3-phenylpropylamine. The other steps are basically the same and will not be described in detail here.

[0053] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.24 (d, J = 2.2 Hz, 1H), 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 8.50 (t, J = 5.6 Hz, 1H), 8.40 (dt, J = 8.1, 2.0 Hz, 1H), 7.89 (d, J =8.2 Hz, 2H), 7.63 (d, J= 8.1 Hz, 2H), 7.56 (dd, J = 8.0, 4.8 Hz, 1H), 7.31–7.21(m, 4H), 7.20–7.14 (m, 1H), 5.63 (s, 2H), 3.32 (s, 1H), 3.28 (d, J = 6.8 Hz, 1H), 2.64 (t, J = 7.7 Hz, 2H), 1.89–1.79 (m, 2H). 13 C NMR (101 MHz, DMSO- d 6 ) δ166.35, 162.54, 150.92, 148.44, 145.56, 142.23, 139.01, 135.23, 135.11,128.78, 128.74, 128.34, 127.93, 127.43, 126.18, 124.37, 72.46, 33.13, 31.32. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 22 H 18 N4O2S + [M+H] + 431.1536. Found 431.1533. Example 23 Synthesis of N-(pyridin-3-ylmethyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (23) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with 3-aminomethylpyridine. The other steps are basically the same and will not be described in detail here.

[0054] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.24 (d, J = 1.8 Hz, 1H), 9.12 (t, J = 5.9 Hz, 1H), 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.47 (dd, J = 4.8, 1.7 Hz, 1H), 8.40 (dt,J = 8.1, 1.9 Hz, 1H), 7.97–7.91 (m, 2H), 7.73 (dt, J =7.8, 2.0 Hz, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.56 (ddd, J = 8.1, 4.8, 0.9 Hz, 1H),7.36 (dd, J = 7.8, 4.8 Hz, 1H), 5.64 (s, 2H), 4.51 (d, J = 5.9 Hz, 2H). 13 C NMR (101 MHz, DMSO-) d 6 δ 166.51, 162.53, 150.91, 149.30, 148.55, 148.45, 145.56,139.40, 135.59, 135.51, 135.11, 134.62, 128.42, 128.04, 127.42, 124.37,123.94, 72.41, 40.92. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 21 H 18 N5O2S + [M+H] + 404.1176. Found 404.1170. Example 24 Synthesis of N-(4-chlorobenzyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (24) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with 4-chlorobenzylamine. The other steps are basically the same and will not be described in detail here.

[0055] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.24 (d, J = 2.2 Hz, 1H), 9.09 (t, J = 6.0 Hz, 1H), 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 8.40 (dt, J= 8.1, 1.9 Hz, 1H), 7.94 (d, J =8.3 Hz, 2H), 7.68–7.62 (m, 2H), 7.56 (dd, J = 8.1, 4.8 Hz, 1H), 7.42–7.31 (m,4H), 5.64 (s, 2H), 4.47 (d, J = 5.9 Hz, 2H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 166.40,162.53, 150.92, 148.44, 145.57, 139.36, 139.15, 135.12, 134.70, 131.77,129.56, 128.69, 128.42, 128.03, 127.43, 124.38, 72.42, 42.50. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 22 H 18 ClN4O2S + [M+H] + 437.0834. Found 437.0830. Example 25 Synthesis of N-(4-methylbenzyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (25) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with 4-methylbenzylamine. The other steps are basically the same and will not be described in detail here.

[0056] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.24 (d, J = 1.4 Hz, 1H), 9.01 (t, J = 6.0 Hz, 1H), 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 8.40 (dt, J = 8.1, 2.0 Hz, 1H), 7.93 (d, J =8.3 Hz, 2H), 7.64 (d, J = 8.2 Hz, 2H), 7.56 (ddd,J = 8.0, 4.7, 0.9 Hz, 1H), 7.21(d, J = 8.0 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 5.64 (s, 2H), 4.44 (d, J = 5.9 Hz, 2H), 2.27 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 166.27, 162.54, 150.91, 148.45,145.56, 139.22, 137.06, 136.22, 135.11, 134.91, 129.27, 128.39, 128.01,127.68, 127.43, 124.37, 72.44, 42.86, 21.12. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 23 H 21 N4O2S + [M+H] + 417.1380. Found 417.1373. Example 26 Synthesis of N-(3-chlorobenzyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (26) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with 3-chlorobenzylamine. The other steps are basically the same and will not be described in detail here.

[0057] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.24 (d, J = 2.2 Hz, 1H), 9.11 (t, J = 6.0 Hz, 1H), 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 8.40 (dt, J = 8.0, 2.0 Hz, 1H), 7.95 (d, J =8.2 Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.56 (dd, J= 8.1, 4.8 Hz, 1H), 7.41–7.26(m, 4H), 5.64 (s, 2H), 4.50 (d, J = 5.9 Hz, 2H). 13 C NMR (101 MHz, DMSO- d 6 ) δ166.45, 162.53, 150.91, 148.45, 145.56, 142.70, 139.41, 135.11, 134.62,133.44, 130.66, 128.43, 128.04, 127.53, 127.43, 127.19, 126.39, 124.37,72.42, 42.66, 40.66, 40.45, 40.25, 40.04, 39.83, 39.62, 39.41. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 22 H 18 ClN4O2S + [M+H] + 437.0834. Found 437.0832. Example 27 Synthesis of N-(3-methylbenzyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (27) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with 3-methylbenzylamine. The other steps are basically the same and will not be described in detail here.

[0058] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.24 (d, J = 2.2 Hz, 1H), 9.03 (t, J = 6.0 Hz, 1H), 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 8.40 (dt, J = 8.0, 2.0 Hz, 1H), 7.95 (d, J =8.3 Hz, 2H), 7.64 (d, J = 8.3 Hz, 2H), 7.56 (dd, J = 8.0, 4.8 Hz, 1H), 7.21 (t,J =7.5 Hz, 1H), 7.16–7.09 (m, 2H), 7.05 (d, J = 7.4 Hz, 1H), 5.64 (s, 2H), 4.46(d, J = 5.9 Hz, 2H), 2.28 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 166.27, 162.54,150.91, 148.45, 145.56, 140.00, 139.25, 137.79, 135.11, 134.87, 128.66,128.40, 128.30, 128.03, 127.83, 127.43, 124.80, 124.37, 72.44, 43.08, 40.72,21.50. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 23 H 21 N4O2S + [M+H] + 417.1380. Found 417.1375. Example 28 Synthesis of N-(3-fluorobenzyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide (28) The only difference from Example 1 is that cyclopropylamine in step S3 is replaced with 3-fluorobenzylamine. The other steps are basically the same and will not be described in detail here.

[0059] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.24 (d, J = 2.2 Hz, 1H), 9.10 (t, J = 6.0 Hz, 1H), 8.67 (dd, J = 4.8, 1.6 Hz, 1H), 8.40 (dt, J = 8.0, 2.0 Hz, 1H), 7.95 (d, J =8.1 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 7.56 (dd, J= 8.0, 4.8 Hz, 1H), 7.37 (td, J = 7.9, 6.0 Hz, 1H), 7.21–7.02 (m, 3H), 5.64 (s, 2H), 4.51 (d, J = 6.0 Hz, 2H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 166.47, 162.54, 150.92, 148.45, 145.57, 143.16,143.09, 139.39, 135.12, 134.68, 130.74, 130.65, 128.43, 128.04, 127.43,124.38, 123.66, 123.64, 114.43, 114.22, 114.07, 113.87, 72.42, 42.69. (+)-HR-ESI-MS(ESI, m / z): Calcd. for C 22 H 19 FN4O2S + [M+H] + 421.1129. Found 421.1128. Table 1. Compound numbers and structural formulas prepared in Examples 1-28

[0060]

[0061]

[0062]

[0063] B. Pharmacological Examples Example 29 α5-GABAA receptor surface plasmon resonance (SPR) experiment Experimental methods The in vitro affinity of the compounds synthesized in this invention was evaluated using surface plasmon resonance (SPR) technology. After purification of the commercially available GABRA5 protein, five concentration gradients (1×10⁻⁶) were prepared by dilution with PBST buffer (pH 7.4, containing 0.1% Tween-20). -8 M, 4×10 -8 M, 16×10 -8 M, 64×10 -8 M and 256×10 -8M). Using Biodot TM The AD1520 spotting instrument spotted the analyte and positive control SR-419 onto the surface of a 3D photocrosslinked chip. During the molecular interaction detection phase, the sample was injected at a flow rate of 0.5 μL / s, and the binding reaction was carried out at 4 °C. The binding and dissociation times were set to 600 s and 360 s, respectively. The equilibrium dissociation constant (K0) was calculated by fitting the binding / dissociation curves. D K D The smaller the value, the stronger the binding ability of the compound to the target.

[0064] Experimental results show that the various thiadiazole-benzamide derivatives synthesized in this invention exhibit high affinity for the α5-GABAA receptor. The test results for the compounds are shown in Table 2.

[0065] Table 2. SPR affinity of compounds for α5-GABAA

[0066] The thiadiazole-benzamide compounds of this invention exhibit different binding abilities to the α5-GABAA receptor during in vitro affinity evaluation, which are significantly affected by the spatial volume, flexibility, and heteroatom distribution of the terminal substituents. Among them, compounds 1, 2, 3, 7, 8, 11, 13, 14, 20, and 23 show excellent affinity at the nanomolar level, all reaching or exceeding the level of the positive control drug SR-419.

[0067] Example 30 Mouse Acetic Acid Writhing Test (In vivo analgesic activity screening and ED) 50 (Measurement) Healthy female ICR mice weighing 22-32g were randomly divided into a model group, a positive drug group, and a test compound group. The test compound group was administered the drug via gavage (ig), while the model group received an equal volume of physiological saline. Thirty minutes after administration, each group of mice was intraperitoneally injected with 1% acetic acid solution (10 mL / kg), and the number of writhing responses was recorded within 45 minutes. The writhing inhibition rate (maximum probable effect percentage, MPE%) was used as the evaluation index for analgesic activity. The calculation formula was: MPE% = (average number of writhing responses in the model group - average number of writhing responses in the drug group) / average number of writhing responses in the model group × 100%.

[0068] First, compounds 1, 2, 3, 7, 8, 11, 13, 14, 20, and 23 (K) in Table 1 were tested at a dose of 5 mg / kg. DThe analgesic activity of compounds <50 nM was initially screened in vivo. The results showed that after gavage administration, all tested compounds showed significant pain inhibition compared with the model group. Among them, the inhibition rates of compounds 1, 7 and 20 were all over 90% (91.25%, 91.25% and 92.50%, respectively), which were far superior to the positive control SR-419 (50.0%).

[0069] Based on the initial screening results, compounds 1, 7 and 20 were further selected for dose-response evaluation (low, medium and high dose groups were set up), and the experimental results are shown in Table 3.

[0070] Table 3. Dose-response relationship of preferred compounds in acetic acid-induced writhing model

[0071] The preferred compounds of this invention exhibit extremely strong, dose-dependent analgesic efficacy in pain models. Compound 7, in particular, has an efficacy... 50 It is only 1.083 mg / kg, which is an extremely low effective dose.

[0072] Example 31: Paclitaxel-induced mouse model of neuropathic pain Experimental methods A paclitaxel-induced peripheral neuropathic pain model was used to evaluate the therapeutic effect of the compound on chronic neuropathic pain. Qualified female ICR mice were selected and administered paclitaxel (2 mg / kg / day) intraperitoneally for 5 consecutive days to establish the model. On day 6 of modeling, after confirming the formation of mechanopathic hyperalgesia, the mice were randomly divided into groups. The test compound group received different doses (0.3, 1, 3 mg / kg) of compound 7 orally by gavage, while the positive control group received 1 mg / kg of SR-419 by gavage. The mechanical withdrawal threshold (MWT) of the mice was measured using a mechanical needle acupuncture device, and dynamic monitoring was performed at multiple time points within 0-180 minutes after administration. The pain inhibition rate was calculated using the formula: MPE% = (Maximum MWT after administration - MWT after modeling) / (MWT before modeling - MWT after modeling) × 100%.

[0073] Experimental results The experimental results are shown in Table 4. After modeling, the MWT in mice decreased significantly (from approximately 7.0 g to approximately 2.6 g), indicating that the neuropathic pain model was successfully established. After administration, compound 7 significantly reversed paclitaxel-induced mechanodysia in a dose-dependent manner.

[0074] Table 4. Analgesic effect of compound 7 in a paclitaxel-induced neuropathic pain model.

[0075] In a paclitaxel-induced neuropathic pain model, compound 7 significantly and persistently increased the mechanical withdrawal threshold in model mice. Its pain inhibition rate at a dose of 3 mg / kg was as high as 80.47%, and the ED calculated using nonlinear fitting was [data missing]. 50 The value was 0.395 mg / kg. Under the same administration conditions or even at lower doses, the analgesic activity of the compound of this invention was significantly superior to that of the positive control drug SR-419, which is in the clinical stage, demonstrating great potential as a novel anti-neuropathic pain drug.

Claims

1. A compound represented by general formula I or a pharmaceutically acceptable salt thereof: ； I in, R is selected from C3-C8 cycloalkyl, four- to six-membered oxygen-containing heterocyclic groups, methyl, C3-C5 branched alkyl, methoxy, ethoxy, phenyl, substituted phenyl or 3-pyridyl; n is an integer of 0, 1, 2, 3 or 4; The substituted phenyl group may optionally be replaced by one substituent selected from halogens or methyl groups.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, When R is selected from C3-C8 cycloalkyl, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, and n = 0.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, When R is selected from a four- to six-membered oxygen-containing heterocyclic group, the heterocyclic group is selected from oxetane-3-yl, tetrahydrofuran-3-yl, or tetrahydropyran-4-yl, and n = 0.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, When R is selected from the substituted phenyl group, the substituted phenyl group is selected from 4-chlorophenyl, 4-methylphenyl, 3-chlorophenyl, 3-methylphenyl or 3-fluorophenyl, and n = 1.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein, R is selected from methyl and n is an integer from 1 to 4; or R is selected from isopropyl, sec-butyl, isobutyl or isopentyl and n is 0.

6. The following compounds or their pharmaceutically acceptable salts: N-Cyclopropyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-Cyclobutyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-Cyclopentyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-Cyclohexyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-Cycloheptyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-Cyclooctyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(oxetanebut-3-yl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(tetrahydrofuran-3-yl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(tetrahydropyran-4-yl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-Ethyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-propyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-Butyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-pentyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-Isopropyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(butan-2-yl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(3-methylbutyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(2-methylpropyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(3-methoxypropyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(2-methoxyethyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(2-ethoxyethyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-Benzyl-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(3-phenylpropyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(pyridin-3-ylmethyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(4-chlorobenzyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(4-methylbenzyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(3-chlorobenzyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(3-methylbenzyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide; N-(3-Fluorobenzyl)-4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzamide.

7. A pharmaceutical composition comprising the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

8. A method for preparing the compound of general formula I according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof, characterized in that, Includes the following steps: (S1) 3-chloro-4-(pyridin-4-yl)-1,2,5-thiadiazole is reacted with methyl 4-(hydroxymethyl)benzoate in the presence of a basic reagent and an organic solvent to give methyl 4-((((4-(pyridin-4-yl)-1,2,5-thiadiazole-3-yl)oxy)methyl)benzoate; (S2) The product obtained in step (S1) is hydrolyzed in an aqueous lithium hydroxide solution to give 4-((((4-(pyridin-4-yl)-1,2,5-thiadiazol-3-yl)oxy)methyl)benzoic acid; (S3) The product obtained in step (S2) is reacted with an amine compound of formula R-(CH2)n-NH2 under the action of a condensing agent and a basic reagent to undergo an amidation reaction to obtain the compound of general formula I; Wherein, R and n are as defined in claim 1.

9. The use of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 7, in the preparation of a medicament for the prevention and / or treatment of α5-GABAA receptor-mediated diseases.

10. The application according to claim 9, characterized in that, The α5-GABAA receptor-mediated diseases are selected from pain-related diseases.

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