Aryl sulfonamide compound, pharmaceutical composition and application

Abstract

The invention discloses an aryl sulfonamide compound, a pharmaceutical composition and application, the aryl sulfonamide compound or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition containing the aryl sulfonamide compound as Nav1.7 inhibitors can limit the conformation of sodion channels and block the flow of sodions between cells, so that the action potential is prevented, and the activity of the sodions is improved. The medicine effect is further exerted; the medicine is used for treating various pain diseases of human and animals, such as diabetic peripheral neuropathy, and has a great application prospect.

Description

Technical Field

[0001] The present invention relates to an aryl sulfonamide compound, and also relates to a pharmaceutical composition containing the aryl sulfonamide compound and application thereof. Background Art

[0002] Voltage-gated ion channels are key to the generation of electrical signals in mammalian cell membranes. Voltage-gated sodium channels (Navs) play a crucial role in both the generation and conduction of voltage-sensitive cellular electrical signals. Navs are a crucial class of transmembrane proteins in cells involved in electrical signal transmission. Their activity is regulated by the potential difference across the cell membrane surface, and the opening of these channels can lead to a strong inward current in the cell.

[0003] When the body senses harmful stimuli such as pain from the outside world, voltage-gated sodium ion channels (Nav channels) in the sensory nerves are activated one after another to generate and transmit pain signals. The Nav1.7 channel is the most advantageous target in pain research among the nine sodium channel subtypes (Nav1.1-Nav1.9) that have been discovered so far: (1) The Nav1.7 channel is an "amplifier" of pain and other stimuli. It is mainly distributed in the somatic sensory and sympathetic nerves. More than 85% of pain sensory nerves express this channel. The detailed tissue distribution shows that the Nav1.7 channel is expressed in both peripheral and central sensory nerve endings, providing a material basis for its important role in the occurrence and transmission of pain; (2) Enhanced function of the Nav1.7 channel leads to congenital pain and lacks effective treatment drugs, including three hereditary pain diseases caused by Nav1.7: inherited erythromelalgia, paroxysmal extreme pain disorder, and small fiber neuropathy. Commonly used analgesics, such as aspirin, nonsteroidal anti-inflammatory drugs, and lidocaine, have no effective relief effect. Discovered Nav1.7 inhibitors, such as Funap1de, are only effective in some patients. (3) Nav1.7 dysfunction results in a loss of pain perception without affecting other physiological functions. Complete loss of Nav1.7 function results in congenital insensitivity to pain (CIP), in which patients are insensitive to various pains, but their other senses (touch, temperature, proprioception, and taste) remain normal. This suggests that inhibiting the Nav1.7 channel can effectively avoid side effects while producing analgesic effects. Other analgesic targets, such as NGF, mediate painlessness while affecting physiological functions such as intelligence and sweat secretion. (4) Inhibition of Nav1.7 channel function is directly involved in the clinical analgesic effects of traditional analgesics, such as local anesthetics and antidepressants. In addition, Nav1.7 dysfunction is associated with respiratory diseases such as epilepsy, pruritus, weight regulation, and cough. Based on the above-mentioned important physiological characteristics of Nav1.7 channels, Nav1.7 channel inhibitors can not only be used to treat pain, including acute pain induced by trauma, inflammatory pain and neuropathic pain, but can also be used for the intervention and treatment of respiratory diseases such as epilepsy, itching, weight regulation, cough, etc.

[0004] To date, several companies have developed drugs targeting Nav1.7. Xenon's Funapide, a drug for the treatment of erythromelalgia, was discontinued after completing Phase II clinical trials. GDC-0276, a collaboration between Xenon and Genentech, was discontinued after completing Phase I clinical trials for the treatment of pain. AstraZeneca's AZD-3161, a drug for the treatment of neuropathic pain, was discontinued after completing Phase I clinical trials. Pfizer's series of compounds, PF-05150122, PF-05186462, and PF-05241328, were discontinued as novel non-opioid analgesics after completing Phase I clinical trials. PF-05089771, the compound furthest along in clinical development, was discontinued after completing Phase II clinical trials due to failure to achieve its primary clinical objective. This was primarily due to its high plasma binding rate, poor selectivity, and inhibitory activity against Nav1.1 and Nav1.5. Therefore, there is an urgent need to develop compounds with greater selectivity and inhibitory activity against Nav1.7. Summary of the Invention

[0005] Purpose of the invention: The purpose of the present invention is to provide an aryl sulfonamide compound, and also to provide a pharmaceutical composition containing the above-mentioned aryl sulfonamide compound and its use in the preparation of drugs that inhibit Nav1.7 protein or block intercellular sodium ion flow.

[0006] Technical solution: The present invention discloses an arylsulfonamide compound, which uses a benzenesulfonamide group as a parent nucleus, replaces the benzene ring with a substituent, and introduces a flexible fatty chain between the substituent A and the left benzene ring to obtain a stronger inhibitory activity in vivo and in vitro. The compound structure is shown in Formula I:

[0007]

[0008] in:

[0009] R 1 is independently a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0010] R 2 or R 3 are independently -H, halogen, (C3-C6)cycloalkyl, -CF3, -OCF3, -CN, -NO2, or (C l -C 12 ) alkoxy;

[0011] A is selected from -(CH2) p R a 、-CHR a Rb , (C1-C6) alkyl, (C3-C8) cycloalkyl, adamantyl, 1H-tetrazol-5-yl; wherein each R a and R b independently C1-C6 alkyl having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, (C3-C8) cycloalkyl, 4-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted indolyl, -COOH, CONH2 and any combination thereof.

[0012] X is independently -O-, -NH- or -S-.

[0013] m is independently an integer from 0 to 4.

[0014] More preferably, R 2 or R 3 Selected from -H, halogen, -CF3, -NO2.

[0015] More preferably, A is selected from -(CH2) n R a 、-CHR a R b , (C3-C8) cycloalkyl, adamantyl, 1H-tetrazolyl-5-yl; wherein each R a and R b are independently C1-C6 alkyl, (C3-C8) cycloalkyl, 5-6 membered heteroaromatic ring, substituted or unsubstituted C6-C8 alkyl, (C3-C8) cyclo ... 10 Aryl, substituted or unsubstituted indolyl, -COOH, CONH2 and any combination thereof.

[0016] More preferably, A is selected from any of the following structures:

[0017]

[0018] More preferably, the compound is selected from any one of the compounds shown in the following table:

[0019]

[0020]

[0021] The compound also includes pharmaceutically acceptable salts thereof.

[0022] Here, "alkyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, which contains no unsaturation and has one to ten carbon atoms (e.g., C1-C 10 Alkyl). Whenever it appears in this article, a numerical range such as "1 to 10" refers to each integer in the given range. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc. The alkyl group is connected to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (isopropyl), n-butyl, n-butyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, etc.

[0023] Here, "heteroaromatic ring" refers to a 5-, 6-, or 10-membered aromatic group (e.g., C5-C 13 The term "heteroaromatic" refers to an aromatic ring ("heteroaryl") that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur and can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system. Whenever it appears in this article, the numerical range refers to each integer within the given range. The "heteroaromatic" or "heteroaromatic ring" moiety containing N refers to an aromatic group in which at least one ring backbone atom is a nitrogen atom. Polycyclic heteroaromatic rings can be fused or non-fused. The heteroatoms in the heteroaromatic ring are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heteroaromatic ring is connected to the rest of the molecule through any atom of the ring.

[0024] Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acid groups, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, butanedioic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, enanthic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid and galacturonic acid. Examples of pharmaceutically unacceptable acid addition salts include, for example, perchlorate and tetrafluoroborate. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, methanesulfonate, gluconate, lactobionate, laurylsulfonate, and amino acid salts, among others.

[0025] The method for preparing the arylsulfonamide compound or a pharmaceutically acceptable salt thereof of the present invention comprises the following steps:

[0026] (1) Preparation of 2-((3-(5-chloro-2-hydroxyphenyl)propyl)amino)-2-cyclopropylacetamide

[0027]

[0028] A (5-chloro-2-hydroxybenzaldehyde) and 2-(triphenyl-5-phosphinylidene)acetaldehyde are dissolved in anhydrous tetrahydrofuran and heated under reflux to undergo a Witting reaction to obtain B (3-(5-chloro-2-hydroxyphenyl)propenal). B reacts with methyl 2-amino-2-cyclopropylacetate in the presence of triethylamine to form a Schiff base intermediate, which is then reduced under the presence of sodium borohydride to obtain C (methyl 2-((3-(5-chloro-2-hydroxyphenyl)allyl)amino)-2-cyclopropylacetate). C is reduced to a carbon-carbon double bond under palladium-carbon catalysis to obtain D (methyl 2-((3-(5-chloro-2-hydroxyphenyl)propyl)amino)-2-cyclopropylacetate). D is then subjected to aminolysis in ammonia methanol solution under reflux under heating to obtain E (2-((3-(5-chloro-2-hydroxyphenyl)propyl)amino)-2-cyclopropylacetamide).

[0029] (2) Preparation of tert-butyl (5-chloro-2,4-difluorophenyl)sulfonyl(thiazol-4-yl)carbamate

[0030]

[0031] In the presence of lithium bis(trimethylsilyl)amide (LIHMDS), G(tert-butyl thiazol-4-ylcarbamate) reacts with F(5-chloro-2,4-difluorobenzenesulfonyl chloride) to produce H(tert-butyl (5-chloro-2,4-difluorophenyl)sulfonyl(thiazol-4-yl)carbamate).

[0032] (3) Preparation of target compound aryl sulfonamide compound

[0033]

[0034] E(2-((3-(5-chloro-2-hydroxyphenyl)propyl)amino)-2-cyclopropylacetamide) and H(tert-butyl 5-chloro-2,4-difluorophenyl)sulfonyl(thiazol-4-yl)carbamate) under the action of cesium carbonate undergo nucleophilic substitution reaction to give I(tert-butyl(4-(2-(3-((2-amino-1-cyclopropyl-2-oxoethyl)amino)propyl)-4-chlorophenoxy)-5-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate). I is then deprotected by the Boc protecting group under the action of trifluoroacetic acid or HCl in EtOAc to give arylsulfonamide compound J(2-((3-(5-chloro-2-(4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)-2-cyclopropylacetamide).

[0035] The present invention also discloses a pharmaceutical composition comprising the above-mentioned arylsulfonamide compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0036] The present invention also discloses the use of the above-mentioned arylsulfonamide compound or pharmaceutical composition in preparing Nav1.7 inhibitors or preparing drugs for treating diseases related to Nav1.7 activity.

[0037] The present invention also discloses the use of the arylsulfonamide compound or pharmaceutical composition in preparing medicines for treating pain.

[0038] The pain includes acute pain, chronic pain, inflammatory pain or neuropathic pain.

[0039] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: the aromatic sulfonamide compounds of the present invention have stronger selectivity and inhibitory activity on the Nav1.7 channel, have extremely strong analgesic effect, have no toxic side effects, have strong oral absorption, and are suitable for clinical application; compared with the existing positive drug PF-05089771, the inhibitory activity of the compounds of the present invention can be increased by up to 1-3 times, and the in vivo drug effect takes effect faster, and the analgesic effect is significantly better than the positive reference, which has great application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 is the structural formula of the arylsulfonamide compound of the present invention;

[0041] Figure 2 .This is a table showing the changes in rat body weight under the action of different drugs;

[0042] Figure 3 These are the results of the effects of different drugs on MWT values in the spinal nerve ligation model analgesia test. DETAILED DESCRIPTION

[0043] The technical solution of the present invention is further described below with reference to the examples. The test materials used in the examples can all be purchased through conventional channels.

[0044] Example 1: Synthesis of 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)-2-cyclopropylacetamide

[0045] The synthetic route is as follows:

[0046]

[0047]

[0048] Compound 1

[0049]

[0050] 5-Chloro-2-hydroxybenzaldehyde (10 g, 63.5 mmol) was dissolved in 100 mL of tetrahydrofuran (THF) at room temperature, and (formylmethylene)triphenylphosphine (23 g, 70 mmol) was added to the solution. The mixture was stirred at reflux for 20 h at 100°C. The reaction mixture was then cooled to room temperature and extracted with water (100 mL) and ethyl acetate (3 x 125 mL). The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (PE:EA = 8:1) afforded the product 1 as a yellow solid (10 g, 86% yield, 98% purity). MS (ESI) m / z: 183.4 [M+H] + ;

[0051] Compound 2

[0052]

[0053] At room temperature, 1 (500 mg, 2.7 mmol) and methyl 2-amino-2-cyclopropylacetate hydrochloride (413 mg, 3.2 mmol) were dissolved in dichloromethane (15 mL), and MgSO4 (659 mg, 5.5 mmol) and TEA (1.2 mL, 8.2 mmol) were added to the solution. Stir at room temperature for 18 h. Then concentrate under reduced pressure. The concentrate was dissolved in methanol (10 mL) and cooled to 5-10 ° C. Then a small amount of NaBH4 (303 mg, 8.2 mmol) was added, and the addition process was kept at a low temperature. After the addition was complete, the mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. Water (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (3x25 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography purification (DCM: MeOH = 25: 1) gave a yellow solid product 2 (463 mg, yield 58%, purity 96%), MS (ESI) m / z: 296.8 [M+H] + ;

[0054] Compound 3

[0055]

[0056] 2 (230 mg, 0.78 mmol) was dissolved in methanol (15 mL), and then 10% palladium on carbon (10 mg, 0.04 mmol) was added. After replacing the hydrogen atmosphere three times, the mixture was reacted at room temperature for 30 min and filtered through celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to give the product 3 as a yellow oily liquid (200 mg, yield 86%, purity 95%). MS (ESI) m / z: 298.7 [M+H] + ;.

[0057] Compound 4

[0058]

[0059] 3 (185 mg, 0.62 mmol) was dissolved in ammonia methanol solution (5 mL) and transferred to a 15 mL pressure tube. The mixture was reacted in a 90°C oil bath for 12 h, then concentrated under reduced pressure and purified by column chromatography (DCM:MeOH=50:1) to give a white solid product 4 (86 mg, yield 49%, purity 96%). MS (ESI) m / z: 283.6 [M+H] + ;.

[0060] Compound 5

[0061]

[0062] Under N₂ protection, N-Boc-4-aminothiazole (8.0 g, 0.04 mol) was dissolved in anhydrous THF (80 mL), cooled to -78°C, and a THF solution of LiHMDS (1 M, 48 mL, 0.048 mol) was added dropwise. After the addition was complete, the mixture was stirred at -78°C for 0.5 h. The reaction solution was slowly warmed to room temperature and stirred for 1 h. The temperature was then lowered to -78°C, and a THF solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (11.11 g, 0.048 mol) was added dropwise to the reaction solution. The mixture was stirred at -78°C for 1 h, then warmed to room temperature and stirred at room temperature for 16 h. Saturated aqueous ammonium chloride (250 mL) was added, and the mixture was extracted with ethyl acetate (3 x 100 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography purification (PE:EA=10:1) gave a white solid 5 (8.3 g, yield 51%, purity 98%), MS (ESI) m / z: 411.3 [M+H] + ;

[0063] Compound 6

[0064]

[0065] To a solution of 4 (135 mg, 0.48 mmol) in DMF (2 mL) under N₂ conditions was added K₂CO₃ (133 mg, 0.96 mmol). After stirring at room temperature for 15 min, 5 (197 mg, 0.48 mmol) was added and stirred at room temperature for 3 h. Water (20 mL) was added and the mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic phases were washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (PE:EA = 8:1) afforded the product 6 (184 mg, 57% yield, 95% purity) as a white solid. MS (ESI) m / z: 599.5 [M+H] + ;

[0066] Compound 7

[0067]

[0068] 6 (170 mg, 0.25 mmol) was dissolved in 5 mL of dichloromethane, and then a 4 M HCl solution in EtOAc (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=10:1) to give the white powder product 7 (100 mg, yield 69%, purity 97%). MS (ESI) m / z: 573.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ8.74 (d, J=2.2Hz, 1H), 7.90 (d, J=7.0Hz, 1H), 7.55 (s, 1H), 7.48 ( d, J=2.7Hz, 1H), 7.39 (s, 1H), 7.31 (dd, J=8.7, 2.7Hz, 1H), 7.00 (d, J=8.7Hz, 1H), 6.81 (d , J=10.3Hz, 1H), 6.60-6.49(m, 1H), 2.74(d, J=8.9Hz, 1H), 2.66(t, J=7.3Hz, 2H), 2.58(d d, J=13.4, 6.7Hz, 2H), 1.87-1.70 (m, 2H), 0.93 (m, J=8.9, 4.1Hz, 1H), 0.61-0.26 (m, 4H). 13 C NMR (100MHz, DMSO-d6) δ171.95, 158.95, 156.42, 155.15, 155.07, 151.38, 150.94, 134.73, 131.11, 130 .70, 129.23, 128.00, 121.02, 117.59, 107.18, 106.91, 64.26, 45.69, 27.52, 26.54, 12.84, 4.55, 2.32.

[0069] Example 2: Synthesis of 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)aminosulfonyl)phenoxy)phenyl)propyl)amino)-3-(methylthio)propionamide

[0070] The synthetic route is as follows:

[0071]

[0072] Compound 8

[0073]

[0074] At room temperature, 1 (663 mg, 3.6 mmol) and S-methylcysteine methyl ester (650 mg, 4.36 mmol) were dissolved in DCM (10 mL), and MgSO4 (873 mg, 7.26 mmol) and TEA (1.52 mL, 10.9 mmol) were added to the solution. It was then concentrated under reduced pressure. The concentrate was dissolved in methanol (10 mL) and cooled to 5-10 ° C. A small amount of NaBH4 (412 mg, 10.9 mmol) was then added, and the addition process was kept low temperature. After the addition was complete, the mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. Water (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (3x25 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH=50:1) gave a yellow solid product 8 (581 mg, yield 54%, purity 97%), MS (ESI) m / z: 315.8 [M+H] + ;

[0075] Compound 9

[0076]

[0077] 8 (250 mg, 0.79 mmol) was dissolved in methanol (15 mL), and then 10% palladium on carbon (10 mg, 0.04 mmol) was added. After replacing the hydrogen atmosphere three times, the mixture was reacted at room temperature for 30 min and filtered through celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 25:1) to give the product 9 (213 mg, 85% yield, 95% purity) as a yellow oily liquid. MS (ESI) m / z: 317.7 [M+H] + ;

[0078] Compound 10

[0079]

[0080] 9 (100 mg, 0.31 mmol) was dissolved in ammonia methanol solution (5 mL) and transferred to a 15 mL pressure tube. The mixture was reacted in an oil bath at 90°C for 12 h, then concentrated under reduced pressure and purified by column chromatography (DCM:MeOH=70:1) to give a white solid product 10 (52 mg, yield 55%, purity 96%). MS (ESI) m / z: 303.1 [M+H] + ;;

[0081] Compound 11

[0082]

[0083] To a solution of 10 (100 mg, 0.33 mmol) in DMF (2 mL) under N₂ conditions was added K₂CO₃ (91 mg, 0.66 mmol). After stirring at room temperature for 15 min, 5 (203 mg, 0.49 mmol) was added and stirred at room temperature for 3 h. Water (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 100:1) afforded the product 11 as a white solid (103 mg, 45% yield, 95% purity). MS (ESI) m / z: 693.7 [M+H] + ;

[0084] Compound 12

[0085]

[0086] 11 (100 mg, 0.14 mmol) was dissolved in 5 mL of dichloromethane, and then a 4 M HCl solution in EtOAc (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=25:1) to give the yellow powder product 12 (45 mg, 54% yield, 97% purity). MS (ESI) m / z: 592.9 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.87 (d, J=2.2Hz, 1H), 7.95 (d, J=7.1Hz, 1H), 7.57-7.38 (m, 2H), 7.33 (dd, J=8.7, 2.7Hz, 1H), 7.17 (s, 1H), 7.08 (d, J=8.7Hz, 1H), 6.98 (s, 1H), 6.87 (d, J=10.6Hz, 1H), 3.17 (t, J=6.5Hz, 2H), 2.62 (tt, J=13.3, 5.9Hz, 4H), 2.03 (s, 3H), 1.68 (p, J=7.5Hz, 2H). 13 C NMR (100MHz, DMSO-d6) δ173.92, 158.97, 156.42, 152.82, 150.87, 135.53, 131.18, 130.77, 1 29.65, 127.85, 121.57, 117.86, 106.72, 106.46, 60.67, 46.55, 36.27, 28.97, 26.81, 15.33.

[0087] Example 3: Synthesis of 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)aminosulfonyl)phenoxy)phenyl)propyl)amino)-3-phenylpropanamide

[0088] The synthetic route is as follows:

[0089]

[0090] Compound 13

[0091]

[0092] At room temperature, 1 (500 mg, 2.74 mmol) and phenylalanine methyl ester (709 mg, 3.29 mmol) were dissolved in DCM (10 mL), and MgSO4 (659 mg, 5.48 mmol) and TEA (1.14 mL, 8.21 mmol) were added to the solution. It was then concentrated under reduced pressure. The concentrate was dissolved in methanol (15 mL) and cooled to 5-10 ° C. A small amount of NaBH4 (311 mg, 8.21 mmol) was then added, and the temperature was kept low during the addition. After the addition was complete, the mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. Water (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (3x25 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH=100:1) gave a yellow solid product 13 (510 mg, yield 54%, purity 98%), MS (ESI) m / z: 345.8 [M+H] + ;

[0093] Compound 14

[0094]

[0095] 13 (330 mg, 0.95 mmol) was dissolved in methanol (15 mL), and then 10% palladium on carbon (15 mg, 0.06 mmol) was added. After replacing the hydrogen atmosphere three times, the mixture was reacted at room temperature for 30 min and filtered through celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 30:1) to give the yellow solid product 14 (260 mg, yield 79%, purity 95%). MS (ESI) m / z: 347.7 [M+H] + ;.

[0096] Compound 15

[0097]

[0098] 14 (150 mg, 0.43 mmol) was dissolved in methanolic ammonia (5 mL) and transferred to a 15 mL pressure tube. The mixture was reacted in a 90°C oil bath for 12 h and then concentrated under reduced pressure. Column chromatography (DCM:MeOH = 50:1) afforded the product 15 as a white solid (41 mg, 29% yield, 96% purity). MS (ESI) m / z: 332.8 [M+H] + ;.

[0099] Compound 16

[0100]

[0101] To a solution of 15 (70 mg, 0.21 mmol) in DMF (2 mL) was added KCO (58 mg, 0.42 mmol) under N2 conditions. After stirring at room temperature for 15 min, 5 (129 mg, 0.32 mmol) was added and stirred at room temperature for 3 h. Water (20 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 100:1) afforded the product 16 as a white solid (83 mg, 55% yield, 95% purity). MS (ESI) m / z: 723.5 [M+H] + ;

[0102] Compound 17

[0103]

[0104] 16 (80 mg, 0.14 mmol) was dissolved in 5 mL of dichloromethane, and then a 4 M HCl solution in EtOAc (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 50:1) gave the product 17 as a white powder (45 mg, 54% yield, 97% purity). MS (ESI) m / z: 622.9 [M+H] + ; 1H NMR (400MHz, Methanol-d4) δ8.72 (q, J=2.5Hz, 1H), 7.97 (dq, J=6.0, 3.7, 3.1Hz, 1H ), 7.40 (q, J=2.7Hz, 2H), 7.37-7.14 (m, 6H), 7.14-7.03 (m, 1H), 7.02-6.86 (m, 2H), 6.70 (dtd, J=20.7, 6.8, 5.5, 3.7Hz, 1H), 4.05-3.93 (m, 1H), 3.12 (tdt, J=13.5, 9.1 , 5.3Hz, 2H), 2.92 (td, J=8.4, 4.3Hz, 2H), 2.60 (q, J=7.2Hz, 2H), 2.04-1.90 (m, 2H). 13 C NMR (100MHz, Methanol-d4) δ170.70, 160.95, 159.08, 158.98, 158.72, 154.01, 152.37, 148.36, 135.37, 135.28, 133.17, 132 .42, 132.15, 130.48, 130.00, 129.80, 128.83, 122.66, 120.21, 107.45, 107.18, 105.65, 62.90, 47.44, 37.88, 30.89, 27.63.

[0105] Example 4: Synthesis of 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)aminosulfonyl)phenoxy)phenyl)propyl)amino)-2-cyclopropylacetic acid

[0106] The synthetic route is as follows:

[0107]

[0108] Compound 18

[0109]

[0110] 3 (200 mg, 0.67 mmol) was dissolved in methanol (5 mL) and transferred to a 25 mL eggplant-shaped flask. Lithium hydroxide monohydrate (84 mg, 2 mmol), H2O (2 mL), and THF (2 mL) were then added. The mixture was reacted at room temperature for 1 h, then concentrated under reduced pressure and purified by column chromatography (DCM:MeOH=20:1) to give a white solid product 18 (131 mg, yield 69%, purity 95%). MS (ESI) m / z: 283.1 [M+H] + ;.

[0111] Compound 19

[0112]

[0113] To a solution of 18 (100 mg, 0.35 mmol) in DMF (2 mL) was added KCO (98 mg, 0.7 mmol) under N2 conditions. After stirring at room temperature for 15 min, 5 (172 mg, 0.42 mmol) was added and stirred at room temperature for 3 h. Water (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 30:1) afforded the product 19 as a white solid (87 mg, 37% yield, 97% purity). MS (ESI) m / z: 673.2 [M+H] + ;

[0114] Compound 20

[0115]

[0116] 19 (120 mg, 0.18 mmol) was dissolved in 5 mL of dichloromethane, and then a 4 M HCl solution in EtOAc (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=15:1) to give the white powder product 20 (63 mg, yield 61%, purity 97%). MS (ESI) m / z: 573, .3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.82 (d, J=2.2Hz, 1H), 7.94 (d, J=7.1Hz, 1H), 7.52-7.46 (m, 1H), 7.42 (dd, J=8.4, 2.7Hz, 1H), 7.34 (d, J=8.5Hz, 1H), 7.03 (d , J=10.2Hz, 1H), 6.79 (d, J=18.5Hz, 1H), 2.85-2.72 (m, 3H), 2.62 (t, J=7. 6Hz, 2H), 1.83 (q, J=8.1Hz, 2H), 0.93 (d, J=8.2Hz, 1H), 0.50-0.36 (m, 4H). 13 CNMR (100MHz, DMSO-d6) δ172.95, 158.95, 156.42, 155.15, 155.07, 151.38, 150.94, 134.73, 131.11, 13 0.70, 129.23, 128.00, 121.02, 117.59, 107.18, 106.91, 64.26, 45.69, 27.52, 26.54, 12.84, 7.55, 7.32.

[0117] Example 5: Synthesis of (3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)aminosulfonyl)phenoxy)phenyl)propyl)lysine

[0118] The synthetic route is as follows:

[0119]

[0120] Compound 21

[0121]

[0122] At room temperature, 1 (600 mg, 3.23 mmol) and lysine methyl ester (631 mg, 3.95 mmol) were dissolved in DCM (25 mL), and MgSO4 (777 mg, 6.46 mmol) and TEA (1.35 mL, 9.69 mmol) were added to the solution. It was then concentrated under reduced pressure. The concentrate was dissolved in methanol (10 mL) and cooled to 5-10 ° C. A small amount of NaBH4 (366 mg, 9.69 mmol) was then added, and the addition process was kept low temperature. After the addition was complete, the mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. Water (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (3x25 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH=70:1) gave a yellow solid product 21 (709 mg, yield 67%, purity 97%), MS (ESI) m / z: 327.6 [M+H] + ;

[0123] Compound 22

[0124]

[0125] 21 (500 mg, 1.53 mmol) was dissolved in methanol (15 mL), and then 10% palladium on carbon (20 mg, 0.08 mmol) was added. After replacing the hydrogen atmosphere three times, the mixture was reacted at room temperature for 30 min and filtered through celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 10:1) to give the yellow oily liquid product 22 (310 mg, yield 62%, purity 96%). MS (ESI) m / z: 329.4 [M+H] + ;.

[0126] Compound 23

[0127]

[0128] 22 (300 mg, 0.91 mmol) was dissolved in methanol (5 mL) and transferred to a 25 mL eggplant-shaped flask. Lithium hydroxide monohydrate (113 mg, 2.7 mmol), H2O (2 mL), and THF (2 mL) were then added. The mixture was reacted at room temperature for 1 h, then concentrated under reduced pressure and purified by column chromatography (DCM:MeOH=20:1) to give a white solid product 23 (232 mg, yield 81%, purity 96%). MS (ESI) m / z: 315.3 [M+H] + ;.

[0129] Compound 24

[0130]

[0131] To a solution of 23 (150 mg, 0.48 mmol) in DMF (2 mL) under N₂ conditions was added K₂CO₃ (133 mg, 0.96 mmol). After stirring at room temperature for 15 min, 5 (236 mg, 0.58 mmol) was added and stirred at room temperature for 3 h. Water (20 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 30:1) afforded the product 24 (135 mg, 40% yield, 96% purity) as a white solid. MS (ESI) m / z: 706.2 [M+H] + ;

[0132] Compound 25

[0133]

[0134] 24 (100 mg, 0.14 mmol) was dissolved in 5 mL of dichloromethane, and then a 4 M HCl solution in EtOAc (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=10:1) to give the product 25 as a white powder (47 mg, 55% yield, 95% purity). MS (ESI) m / z: 606.4 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ8.70 (d, J=2.2Hz, 1H), 7.88 (d, J=7.1Hz, 1H), 7.46 (d, J=2.5Hz, 1H), 7.30 (dd, J=8.7, 2.6Hz, 1H), 6.98 (d, J=8.7Hz, 1H), 6.79 (d, J=1 0.2Hz, 1H), 6.41 (d, J=2.1Hz, 1H), 3.17 (s, 2H), 2.86-2.63 (m, 4H), 2.56 (q, J= 10.1, 8.8Hz, 2H), 1.87 (q, J=7.5Hz, 2H), 1.65-1.45 (m, 4H), 1.44-1.12 (m, 4H). 13 C NMR (100MHz, DMSO-d6) δ175.05, 158.93, 152.56, 151.81, 148.36, 133.49, 131.23, 131.15, 129.65, 127.98, 126.00, 120.12, 117.48, 117.45, 105.84, 105.57, 66.58, 46.43, 41.62, 31.37, 30.24, 27.13, 26.96, 23.52.

[0135] Example 6: Synthesis of (3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)aminosulfonyl)phenoxy)phenyl)propyl)tryptophan

[0136] The synthetic route is as follows:

[0137]

[0138] Compound 26

[0139]

[0140] At room temperature, 1 (500 mg, 2.74 mmol) and tryptophan methyl ester hydrochloride (719 mg, 3.3 mmol) were dissolved in DCM (20 mL), and MgSO4 (659 mg, 5.48 mmol) and TEA (1.14 mL, 8.21 mmol) were added to the solution. It was then concentrated under reduced pressure. The concentrate was dissolved in methanol (10 mL) and cooled to 5-10 ° C. A small amount of NaBH4 (311 mg, 8.21 mmol) was then added, and the addition process was kept low temperature. After the addition was complete, the mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. Water (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (3x25 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH=50:1) gave a yellow solid product 26 (623 mg, yield 59%, purity 97%), MS (ESI) m / z: 385.5 [M+H] + ;

[0141] Compound 27

[0142]

[0143] 26 (400 mg, 1.04 mmol) was dissolved in methanol (15 mL), and then 10% palladium on carbon (20 mg, 0.08 mmol) was added. After replacing the hydrogen atmosphere three times, the mixture was reacted at room temperature for 30 min and filtered through celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 15:1) to give the product 27 (235 mg, 58% yield, 96% purity) as a yellow oily liquid. MS (ESI) m / z: 387.7 [M+H] + ;.

[0144] Compound 28

[0145]

[0146] 27 (200 mg, 0.52 mmol) was dissolved in methanol (5 mL) and transferred to a 25 mL eggplant-shaped flask. Lithium hydroxide monohydrate (65 mg, 1.55 mmol), H2O (2 mL), and THF (2 mL) were then added. The mixture was reacted at room temperature for 1 h, then concentrated under reduced pressure and purified by column chromatography (DCM:MeOH=15:1) to give a white solid product 28 (173 mg, yield 89%, purity 96%). MS (ESI) m / z: 373.3 [M+H] + ;.

[0147] Compound 29

[0148]

[0149] To a solution of 28 (100 mg, 0.27 mmol) in DMF (2 mL) was added K2CO3 (74 mg, 0.54 mmol) under N2 conditions. After stirring at room temperature for 15 min, 5 (133 mg, 0.32 mmol) was added and stirred at room temperature for 3 h. Water (20 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 10:1) afforded the product 29 as a white solid (91 mg, 44% yield, 95% purity). MS (ESI) m / z: 764.5 [M+H] + ;

[0150] Compound 30

[0151]

[0152] 29 (100 mg, 0.14 mmol) was dissolved in 5 mL of dichloromethane, and then a 4 M HCl solution in EtOAc (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=8:1) to give the product 30 as a white powder (39 mg, 42% yield, 96% purity). MS (ESI) m / z: 664.1 [M+H] + ; 1 H NMR (400MHz, Methanol-d4) δ8.70 (d, J=2.1Hz, 1H), 7.98 (d, J=7.1Hz, 1H), 7.62 (d, J=7.9H z, 1H), 7.44-7.24 (m, 3H), 7.18 (s, 1H), 7.15-7.05 (m, 2H), 7.00 (t, J=7.3Hz, 1H), 6.92 (d, J=8.3Hz, 1H), 6.63 (d, J=10.6Hz, 1H), 3.93-3.79 (m, 1H), 3.46 (dd, J=15.3, 4.4Hz, 1H), 3. 25 (dd, J=15.4, 7.9Hz, 1H), 3.02-2.74 (m, 2H), 2.46 (t, J=7.5Hz, 2H, 1.82 (p, J=7.5Hz, 2H). 13C NMR (100MHz, Methanol-d4) δ159.07, 158.98, 154.00, 152.30, 148.38, 138.19, 135.36, 133.15, 132.28, 132.07, 129.63, 128.40 , 125.19, 124.35, 122.82, 122.52, 120.21, 119.24, 112.53, 108.97, 107.48, 107.21, 105.51, 63.72, 47.54, 27.75, 27.59, 27.37.

[0153] Example 7: Synthesis of 1-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)aminosulfonyl)phenoxy)phenyl)propyl)amino)cyclopropane-1-carboxylic acid

[0154] The synthetic route is as follows:

[0155]

[0156] Compound 31

[0157]

[0158] At room temperature, 1 (500 mg, 2.74 mmol) and 1-aminocyclopropane-1-methyl carboxylate (380 mg, 3.3 mmol) were dissolved in DCM (20 mL), and MgSO4 (659 mg, 5.48 mmol) and TEA (1.14 mL, 8.21 mmol) were added to the solution. It was then concentrated under reduced pressure. The concentrate was dissolved in methanol (10 mL) and cooled to 5-10 ° C. A small amount of NaBH4 (311 mg, 8.21 mmol) was then added, and the addition process was kept low temperature. After the addition was complete, the mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. Water (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (3x25 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH=50:1) gave a yellow solid product 31 (592 mg, yield 76%, purity 96%), MS (ESI) m / z: 283.1 [M+H] + ;

[0159] Compound 32

[0160]

[0161] 31 (500 mg, 1.77 mmol) was dissolved in methanol (15 mL), and then 10% palladium on carbon (20 mg, 0.08 mmol) was added. After replacing the hydrogen atmosphere three times, the mixture was reacted at room temperature for 30 min and filtered through celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 2:1) to give the product 32 as a yellow oily liquid (243 mg, 48% yield, 96% purity). MS (ESI) m / z: 285.3 [M+H] + ;.

[0162] Compound 33

[0163]

[0164] 32 (200 mg, 0.70 mmol) was dissolved in methanol (5 mL) and transferred to a 25 mL eggplant-shaped flask. Lithium hydroxide monohydrate (88 mg, 2.1 mol), H2O (2 mL), and THF (2 mL) were then added. The mixture was reacted at room temperature for 1 h, then concentrated under reduced pressure and purified by column chromatography (DCM:MeOH=25:1) to give a white solid product 33 (163 mg, yield 86%, purity 96%). MS (ESI) m / z: 271.2 [M+H] + ;.

[0165] Compound 34

[0166]

[0167] To a solution of 33 (100 mg, 0.37 mmol) in DMF (2 mL) under N₂ conditions was added K₂CO₃ (102 mg, 0.74 mmol). After stirring at room temperature for 15 min, 5 (180 mg, 0.44 mmol) was added and stirred at room temperature for 3 h. Water (20 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 15:1) afforded the product 34 as a white solid (97 mg, 40% yield, 95% purity). MS (ESI) m / z: 661.5 [M+H] + ;

[0168] Compound 35

[0169]

[0170] 34 (100 mg, 0.15 mmol) was dissolved in 5 mL of dichloromethane, and then a 4 M HCl solution in EtOAc (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=10:1) to give the product 35 as a white powder (43 mg, 51% yield, 96% purity). MS (ESI) m / z: 561.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.92 (d, J=2.2Hz, 1H), 7.97 (d, J=7.1Hz, 1H), 7.51 (d, J=2.7Hz, 1H), 7.35 (dd, J=8.7, 2.7Hz, 1H), 7.14-7.04 (m, 2 H), 6.95 (d, J=10.8Hz, 1H), 2.92 (t, J=7.6Hz, 2H), 2.57 (t, J=7.5Hz, 2H), 1.83 (p, J=7.7Hz, 2H), 1.33 (d, J=3.9Hz, 2H), 1.19-1.13 (m, 2H). 13 C NMR (100MHz, DMSO-d6) δ171.88, 157.13, 156.47, 153.49, 150.91, 146.71, 134.75, 131.23, 130.81, 1 29.74, 128.16, 123.33, 123.17, 121.56, 118.21, 107.02, 46.14, 31.61, 29.02, 26.47, 14.11, 13.61.

[0171] Example 8: Synthesis of 4-(2-(3-(adamantan-1-ylamino)propyl)-4-chlorophenoxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[0172] The synthetic route is as follows:

[0173]

[0174] Compound 36

[0175]

[0176] At room temperature, 1 (500 mg, 2.74 mmol) and adamantane-1-amine (498 mg, 3.3 mmol) were dissolved in DCM (20 mL), and MgSO4 (659 mg, 5.48 mmol) and TEA (1.14 mL, 8.21 mmol) were added to the solution. The mixture was then concentrated under reduced pressure. The concentrate was dissolved in methanol (10 mL) and cooled to 5-10°C. A small amount of NaBH4 (311 mg, 8.21 mmol) was then added, and the temperature was kept low during the addition. After the addition was complete, the mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. Water (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH=50:1) gave a yellow solid product 36 (603 mg, yield 69%, purity 96%), MS (ESI) m / z: 318.7 [M+H] + ;

[0177] Compound 37

[0178]

[0179] 36 (400 mg, 1.26 mmol) was dissolved in methanol (15 mL), and 10% palladium on carbon (20 mg, 0.08 mmol) was added. The hydrogen atmosphere was replaced three times, and the mixture was reacted at room temperature for 30 min before filtration through celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 3:1) to afford the product 37 (231 mg, 58% yield, 96% purity) as a yellow oily liquid. MS (ESI) m / z: 320.4 [M+H] + ;.

[0180] Compound 38

[0181]

[0182] To a solution of 37 (200 mg, 0.63 mmol) in DMF (2 mL) under N₂ conditions was added K₂CO₃ (174 mg, 1.26 mmol). After stirring at room temperature for 15 min, 5 (215 mg, 0.53 mmol) was added and stirred at room temperature for 3 h. Water (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic phases were washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 25:1) afforded the product 38 (176 mg, 39% yield, 95% purity) as a white solid. MS (ESI) m / z: 712.1 [M+H] + ;

[0183] Compound 39

[0184]

[0185] 38 (100 mg, 0.16 mmol) was dissolved in 5 mL of dichloromethane, and then a 4 M HCl solution in EtOAc (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=15:1) to give the product 39 as a white powder (51 mg, 52% yield, 96% purity). MS (ESI) m / z: 611.9 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ11.47 (s, 1H), 8.92 (d, J = 2.1Hz, 1H), 7.98 (d, J = 7.1Hz, 1H), 7.54 (d, J = 2.7Hz, 1H), 7.36 (dd, J = 8.7, 2.7Hz, 1H), 7.15-7.04 (m, 2 H), 6.99 (d, J=10.7Hz, 1H), 2.82 (t, J=7.9Hz, 2H), 2.62 (t, J=7.5Hz, 2H), 2. 09 (s, 3H), 1.93 (p, J=7.9Hz, 2H), 1.82 (d, J=2.8Hz, 6H), 1.71-1.49 (m, 6H). 13 CNMR (100MHz, DMSO-d6) δ153.25, 150.89, 147.26, 134.43, 131.18, 130.59, 129.77, 128.24, 121.55, 118.14, 107.01, 56.11, 54.89, 37.53, 35.18, 28.36, 26.29, 26.21.

[0186] Example 9: Synthesis of 4-(2-(3-((1H-tetrazol-5-yl)amino)propyl)-4-chlorophenoxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[0187] The synthetic route is as follows:

[0188]

[0189] Compound 40

[0190]

[0191] At room temperature, 1 (500 mg, 2.74 mmol) and 1H-tetrazol-5-amine (280 mg, 3.3 mmol) were dissolved in DCM (20 mL), and MgSO4 (659 mg, 5.48 mmol) and TEA (1.14 mL, 8.21 mmol) were added to the solution. It was then concentrated under reduced pressure. The concentrate was dissolved in methanol (10 mL) and cooled to 5-10 ° C. A small amount of NaBH4 (311 mg, 8.21 mmol) was then added, and the addition process was kept low temperature. After the addition was complete, the mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. Water (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (3x25 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH=100:1) gave a yellow solid product 40 (447 mg, yield 64%, purity 96%), MS (ESI) m / z: 252.6 [M+H] + ;

[0192] Compound 41

[0193]

[0194] 40 (400 mg, 1.58 mmol) was dissolved in methanol (15 mL), and then 10% palladium on carbon (20 mg, 0.08 mmol) was added. After replacing the hydrogen atmosphere three times, the mixture was reacted at room temperature for 30 min and filtered through celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 50:1) to give the product 41 (192 mg, 48% yield, 96% purity) as a yellow oily liquid. MS (ESI) m / z: 254.2 [M+H] + ;.

[0195] Compound 42

[0196]

[0197] To a solution of 41 (200 mg, 0.79 mmol) in DMF (3 mL) was added KCO (218 mg, 1.58 mmol) under N2 conditions. After stirring at room temperature for 15 min, 5 (387 mg, 0.94 mmol) was added and stirred at room temperature for 3 h. Water (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 20:1) afforded the product 42 as a white solid (261 mg, 30% yield, 95% purity). MS (ESI) m / z: 645.1 [M+H] + ;

[0198] Compound 43

[0199]

[0200] 42 (100 mg, 0.15 mmol) was dissolved in 5 mL of dichloromethane, and then a 4 M HCl solution in EtOAc (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=10:1) to give the product 43 as a white powder (40 mg, 49% yield, 96% purity). MS (ESI) m / z: 544.9 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ14.51 (s, 1H), 11.47 (s, 1H), 8.91 (dd, J=3.9, 2.2Hz, 1H), 7.95 (d, J=7.2Hz, 1H), 7.45 (dd, J=30.7, 2.6Hz, 1H), 7.32 ( ddd, J=10.9, 8.6, 2.7Hz, 1H), 7.20-7.01 (m, 3H), 6.91 (t, J=10.4Hz, 1H), 3.19-3.12 (m, 2H), 2.60-2.52 (m, 2H), 1.77 (dp, J=20.3, 7.1Hz, 2H). 13 C NMR (100MHz, DMSO-d6) δ153.89, 151.53, 151.28, 148.10, 136.43, 135.75, 131.66, 131.22 , 130.65, 130.25, 128.42, 127.58, 124.69, 122.11, 118.57, 104.88, 43.43, 29.55, 27.01.

[0201] Example 10: Synthesis of 5-chloro-4-(4-chloro-2-(3-(((5-methylfuran-2-yl)methyl)amino)propyl)phenoxy)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[0202] The synthetic route is as follows:

[0203]

[0204] Compound 44

[0205]

[0206] At room temperature, 1 (500 mg, 2.74 mmol) and (5-methylfuran-2-yl)methylamine (367 mg, 3.3 mmol) were dissolved in DCM (20 mL), and MgSO4 (659 mg, 5.48 mmol) and TEA (1.14 mL, 8.21 mmol) were added to the solution. It was then concentrated under reduced pressure. The concentrate was dissolved in methanol (10 mL) and cooled to 5-10 ° C. A small amount of NaBH4 (311 mg, 8.21 mmol) was then added, and the addition process was kept low temperature. After the addition was complete, the mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. Water (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (3x25 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH=50:1) gave a yellow solid product 44 (497 mg, yield 65%, purity 96%), MS (ESI) m / z: 278.5 [M+H] + ;

[0207] Compound 45

[0208]

[0209] 44 (500 mg, 1.79 mmol) was dissolved in methanol (15 mL), and then 10% palladium on carbon (20 mg, 0.08 mmol) was added. After replacing the hydrogen atmosphere three times, the mixture was reacted at room temperature for 30 min and filtered through celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 5:1) to give the product 45 (221 mg, 44% yield, 96% purity) as a yellow oily liquid. MS (ESI) m / z: 280.1 [M+H] + ;.

[0210] Compound 46

[0211]

[0212] To a solution of 45 (300 mg, 1.07 mmol) in DMF (4 mL) under N₂ conditions was added K₂CO₃ (295 mg, 2.14 mmol). After stirring at room temperature for 15 min, 5 (527 mg, 1.29 mmol) was added and stirred at room temperature for 3 h. Water (20 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 15:1) afforded the product 46 (285 mg, 40% yield, 95% purity) as a white solid. MS (ESI) m / z: 671.4 [M+H] + ;

[0213] Compound 47

[0214]

[0215] 46 (100 mg, 0.15 mmol) was dissolved in 5 mL of dichloromethane, and then a 4 M HCl solution in EtOAc (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=5:1) to give the product 47 as a white powder (44 mg, 51% yield, 96% purity). MS (ESI) m / z: 571.7 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.74 (s, 1H), 7.90 (d, J = 7.0Hz, 1H), 7.45 (d, J = 2.4Hz , 1H), 7.31 (dd, J=8.7, 2.5Hz, 1H), 7.00 (d, J=8.7Hz, 1H), 6.81 (d, J=10.3Hz, 1H), 6.59 (s, 1H), 6.29 (d, J=2.8Hz, 1H), 6.06-6.01 (m, 1H), 3.93 (s, 3H), 2.7 3(t, J=7.7Hz, 2H), 2.56 (t, J=7.6Hz, 2H), 2.22 (s, 3H), 1.81 (p, J=7.6Hz, 2H). 13 C NMR (100MHz, DMSO-d6) δ159.38, 156.85, 152.40, 151.79, 151.51, 147.62, 147.60, 135.05, 131.56, 131.07, 1 29.70, 128.44, 121.44, 118.13, 118.09, 111.41, 107.61, 107.34, 107.19, 46.79, 43.87, 27.37, 26.90, 13.74.

[0216] Example 11: Synthesis of 4-(2-(3-((2-(1H-indol-3-yl)ethyl)amino)propyl)-4-chlorophenoxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[0217] The synthetic route is as follows:

[0218]

[0219] Compound 48

[0220]

[0221] At room temperature, 1 (500 mg, 2.74 mmol) and 2-(1H-indol-3-yl)ethyl-1-amine (529 mg, 3.3 mmol) were dissolved in DCM (20 mL), and MgSO4 (659 mg, 5.48 mmol) and TEA (1.14 mL, 8.21 mmol) were added to the solution. It was then concentrated under reduced pressure. The concentrate was dissolved in methanol (10 mL) and cooled to 5-10 ° C. A small amount of NaBH4 (311 mg, 8.21 mmol) was then added, and the addition process was kept low temperature. After the addition was complete, the mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. Water (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (3x25 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH=70:1) gave a yellow solid product 48 (506 mg, yield 56%, purity 96%), MS (ESI) m / z: 327.6 [M+H] + ;

[0222] Compound 49

[0223]

[0224] 48 (500 mg, 1.52 mmol) was dissolved in methanol (15 mL), and 10% palladium on carbon (20 mg, 0.08 mmol) was added. The hydrogen atmosphere was replaced three times, and the mixture was reacted at room temperature for 30 min before filtration through celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 10:1) to afford the product 49 (214 mg, 43% yield, 96% purity) as a yellow oily liquid. MS (ESI) m / z: 329.3 [M+H] + ;.

[0225] Compound 50

[0226]

[0227] To a solution of 49 (200 mg, 0.61 mmol) in DMF (3 mL) under N₂ conditions was added K₂CO₃ (168 mg, 1.22 mmol). After stirring at room temperature for 15 min, 5 (299 mg, 0.73 mmol) was added and stirred at room temperature for 3 h. Water (20 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 50:1) afforded the product 50 (107 mg, 24% yield, 95% purity) as a white solid. MS (ESI) m / z: 720.5 [M+H] + ;

[0228] Compound 51

[0229]

[0230] 50 (100 mg, 0.14 mmol) was dissolved in 5 mL of dichloromethane, and then a 4 M HCl solution in EtOAc (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=15:1) to give the product 51 as a white powder (51 mg, 59% yield, 96% purity). MS (ESI) m / z: 620.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.94 (s, 1H), 8.72 (d, J = 2.2Hz, 1H), 7.91 (d, J = 7.1Hz, 1H), 7 .50 (dd, J=24.4, 5.3Hz, 2H), 7.39-7.25 (m, 2H), 7.20 (d, J=2.4Hz, 1H), 7.08 (t, J=7.5H z, 1H), 7.04-6.92 (m, 2H), 6.81 (d, J=10.3Hz, 1H), 6.49 (s, 1H), 3.20-3.12 (m, 2H), 2. 99 (dt, J=23.0, 8.0Hz, 4H), 2.61 (t, J=7.6Hz, 2H), 1.93 (p, J=7.9Hz, 2H), 1.48 (s, 1H). 13 C NMR (100MHz, DMSO-d6) δ158.90, 151.49, 150.61, 136.26, 134.02, 130.51, 129.11, 128.08, 126.7 4, 123.26, 121.17, 120.73, 118.45, 118.12, 111.53, 109.34, 107.37, 47.22, 46.30, 26.25, 21.86.

[0231] Example 12: Synthesis of 2-((3-(5-chloro-2-(4-(N-(thiazol-4-yl)aminosulfonyl)phenoxy)phenyl)propyl)amino)-2-cyclopropylacetic acid

[0232] The synthetic route is as follows:

[0233]

[0234] Compound 52

[0235]

[0236] 3 (200 mg, 0.671 mmol) was dissolved in methanol (5 mL) and transferred to a 25 mL eggplant-shaped flask. Lithium hydroxide monohydrate (84 mg, 2.0 mol), H2O (2 mL), and THF (2 mL) were then added. The mixture was reacted at room temperature for 1 h, then concentrated under reduced pressure and purified by column chromatography (DCM:MeOH=25:1) to give a white solid product 52 (163 mg, yield 86%, purity 96%). MS (ESI) m / z: 284.2 [M+H] + ;

[0237] Compound 53

[0238]

[0239] Under N₂ protection, N-Boc-4-aminothiazole (8.0 g, 0.04 mol) was dissolved in anhydrous THF (80 mL), cooled to -78°C, and a THF solution of LiHMDS (1 M, 48 mL, 0.048 mol) was added dropwise. After the addition was complete, the mixture was stirred at -78°C for 0.5 h. The reaction solution was slowly warmed to room temperature and stirred for 1 h. The temperature was then lowered to -78°C, and a THF solution of 4-fluorobenzenesulfonyl chloride (9.36 g, 0.048 mol) in 50 mL was added dropwise to the reaction solution. The mixture was stirred at -78°C for 1 h, then warmed to room temperature and stirred at room temperature for 16 h. Saturated aqueous ammonium chloride (250 mL) was added, and the mixture was extracted with ethyl acetate (3 x 100 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (PE:EA=15:1) gave 53 as a white solid (8.1 g, yield 56%, purity 98%). MS (ESI) m / z: 359.2 [M+H] + ;

[0240] Compound 54

[0241]

[0242] To a solution of 52 (200 mg, 0.71 mmol) in DMF (3 mL) was added KCO (340 mg, 1.42 mmol) under N2 conditions. After stirring at room temperature for 15 min, 53 (304 mg, 0.85 mmol) was added and stirred at room temperature for 3 h. Water (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 20:1) afforded the product 54 as a white solid (101 mg, 23% yield, 95% purity). MS (ESI) m / z: 623.3 [M+H] + ;

[0243] Compound 70

[0244]

[0245] 54 (100 mg, 0.16 mmol) was dissolved in 5 mL of dichloromethane, and then a 4 M HCl solution in EtOAc (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=10:1) to give the product 55 as a white powder (38 mg, 45% yield, 96% purity). MS (ESI) m / z: 523.1 [M+H] + ; 1 H NMR (400MHz, Methanol-d4) δ8.72 (d, J=3.1Hz, 1H), 8.47 (s, 2H), 7.63 (m, 2H), 7.39 ( dd, J=20.2, 2.6Hz, 1H), 7.28 (dt, J=8.7, 3.2Hz, 2H), 7.17-7.06(m, 2H), 7.06-6.94( m, 1H), 3.14 (dd, J=11.8, 9.8Hz, 1H), 3.07-2.84 (m, 2H), 2.65 (ddt, J=14.1, 11.5, 6. 7Hz, 2H), 2.07-1.90 (m, 2H), 1.15 (dtt, J=11.4, 3.4, 1.8Hz, 1H), 0.87-0.50 (m, 4H). 13 C NMR (100MHz, Methanol-d4) δ171.57, 169.43, 155.36, 153.05, 149.35, 135.83, 132.52, 131.00, 130.83, 129. 96, 128.79, 128.30, 125.08, 124.99, 118.03, 117.17, 65.80, 49.21, 46.97, 27.85, 27.69, 12.92, 5.78, 3.70.

[0246] Example 13: Synthesis of 2-((3-(5-chloro-2-(4-(N-(thiazol-4-yl)aminosulfonyl)-2-(trifluoromethyl)phenoxy)phenyl)propyl)amino)acetamide

[0247] The synthetic route is as follows:

[0248]

[0249] Compound 56

[0250]

[0251] Under N2 protection, 3-aminoisoxazole (2.0 g, 0.024 mol) was dissolved in anhydrous THF (80 mL), cooled to -78°C, and a THF solution of LiHMDS (1 M, 29 mL, 0.029 mol) was added dropwise. After the addition was complete, the mixture was stirred at -78°C for 0.5 h. The reaction solution was slowly warmed to room temperature and stirred for 1 h. The temperature was then lowered to -78°C, and a THF solution of 5-bromo-2,4-difluorobenzenesulfonyl chloride (8.47 g, 0.029 mol) in 30 mL was added dropwise to the reaction solution. The mixture was stirred at -78°C for 1 h, then warmed to room temperature and stirred at room temperature for 16 h. Saturated aqueous ammonium chloride (250 mL) was added, and the mixture was extracted with ethyl acetate (3 x 100 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (PE:EA=5:1) gave 56 as a white solid (2.3 g, yield 28%, purity 98%). MS (ESI) m / z: 340.3 [M+H] + ;.

[0252] Compound 57

[0253]

[0254] To a solution of 4 (300 mg, 1.06 mmol) in DMF (4 mL) under N₂ conditions was added Cs₂CO₃ (695 mg, 2.12 mmol). After stirring at room temperature for 15 min, 56 (429 mg, 1.27 mmol) was added and the mixture was stirred overnight in a 90°C oil pan. Water (20 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 10:1) afforded the product 57 (112 mg, 18% yield, 96% purity) as a yellow solid. MS (ESI) m / z: 602.7 [M+H] + ; 1H NMR (400MHz, Methanol-d4) δ8.50 (d, J=50.5Hz, 1H), 8.16 (d, J=7.3Hz, 1H), 7.43 (d, J=2. 4Hz, 1H), 7.30 (dd, J=8.6, 2.5Hz, 1H), 7.13 (d, J=1.7Hz, 1H), 6.96 (d, J=8.7Hz, 1H), 6.72- 6.48 (m, 1H), 3.18 (d, J=9.7Hz, 1H), 2.66 (q, J=11.3, 7.6Hz, 2H), 2.58 (t, J=8.1Hz, 1H), 2 .22 (p, J=7.7Hz, 1H), 2.00 (dt, J=14.8, 7.4Hz, 2H), 1.24-1.07 (m, 1H), 0.88-0.53 (m, 4H). 13 C NMR (100MHz, Methanol-d4) δ171.16, 161.07, 159.77, 159.03, 158.75, 152.73, 135.75, 135.40, 132.12, 132.03, 129.62, 122.55, 107.31, 107.04, 100.79, 98.77, 65.75, 47.09, 32.34, 27.93, 12.86, 5.80, 3.76.

[0255] Example 14: Synthesis of 1-((3-(2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)aminosulfonyl)phenoxy)phenyl)propyl)amino)cyclopropane-1-carboxylic acid

[0256] The synthetic route is as follows:

[0257]

[0258] Compound 58

[0259]

[0260] 32 (500 mg, 1.77 mmol) was dissolved in methanol (15 mL), and 10% palladium on carbon (20 mg, 0.08 mmol) was added. The mixture was replaced with hydrogen three times, heated to 50°C, reacted for 2 h, and filtered through celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 100:1) to afford the product 58 (201 mg, 45% yield, 96% purity) as a yellow oily liquid. MS (ESI) m / z: 250.2 [M+H] + ;.

[0261] Compound 59

[0262]

[0263] 58 (200 mg, 0.80 mmol) was dissolved in methanol (5 mL) and transferred to a 25 mL eggplant-shaped flask. Lithium hydroxide monohydrate (101 mg, 2.40 mmol) and H2O (2 mL) were then added. The mixture was reacted at room temperature for 1 h, then concentrated under reduced pressure and purified by column chromatography (DCM:MeOH=20:1) to give a white solid product 59 (171 mg, yield 91%, purity 96%). MS (ESI) m / z: 236.1 [M+H] + ;.

[0264] Compound 60

[0265]

[0266] To a solution of 59 (100 mg, 0.42 mmol) in DMF (2 mL) was added KCO (116 mg, 0.84 mmol) under N2 conditions. After stirring at room temperature for 15 min, 5 (208 mg, 0.51 mmol) was added and stirred at room temperature for 3 h. Water (20 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 25:1) afforded the product 60 (98 mg, 37% yield, 95% purity) as a white solid. MS (ESI) m / z: 626.9 [M+H] + ;

[0267] Compound 61

[0268]

[0269] 60 (100 mg, 0.16 mmol) was dissolved in 5 mL of dichloromethane, and then a 4 M HCl solution in EtOAc (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=10:1) to give the white powder product 61 (50 mg, yield 59%, purity 96%). MS (ESI) m / z: 527.1 [M+H] + ; 1H NMR (400MHz, Methanol-d4) δ8.73-8.49 (m, 1H), 7.97 (t, J=7.2Hz, 1H), 7.42 (t, J=19.1Hz, 2H), 7.34-7.16 (m, 2H), 6.94 (d, J=8.3H z, 1H, Ph), 6.67-6.48 (m, 1H), 3.05 (s, 2H), 2.94 (t, J=7.8Hz, 2H), 2.70-2.56 (m, 2H), 1.97 (s, 2H), 1.60 (s, 2H), 1.45-1.39 (m, 2H). 13 C NMR (100MHz, DMSO-d6) δ174.30, 158.82, 156.30, 152.57, 149.60, 143.06, 133.75, 132.54, 130.96, 1 29.64, 129.03, 128.01, 125.30, 119.10, 117.12, 106.60, 47.51, 46.33, 28.67, 26.93, 13.93, 13.58.

[0270] Example 15: Synthesis of methyl 1-((3-(2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)aminosulfonyl)phenoxy)phenyl)propyl)amino)cyclopropane-1-carboxylate

[0271] The synthetic route is as follows:

[0272]

[0273] Compound 62

[0274]

[0275] To a solution of 58 (200 mg, 0.80 mmol) in DMF (3 mL) under N₂ conditions was added K₂CO₃ (221 mg, 1.6 mmol). After stirring at room temperature for 15 min, 5 (394 mg, 0.96 mmol) was added and stirred at room temperature for 3 h. Water (20 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 25:1) afforded the product 62 (115 mg, 22% yield, 95% purity) as a white solid. MS (ESI) m / z: 641.2 [M+H] + ;

[0276] Compound 63

[0277]

[0278] 62 (100 mg, 0.16 mmol) was dissolved in 5 mL of dichloromethane, and then a 4 M HCl solution in EtOAc (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=10:1) to give the product 63 as a white powder (41 mg, 47% yield, 96% purity). MS (ESI) m / z: 540.8 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.85 (d, J=2.2Hz, 1H), 7.94 (d, J=7.2Hz, 1H), 7.38 (dd, J=7.3, 2.0Hz, 1H), 7.33-7.21 (m, 2H), 7.05 (dd, J=7.8, 1.5Hz, 1H), 6.91 (d, J=10.2Hz, 1H), 6.64 (d, J=10.8Hz, 1H), 3.55 (s, 3H, CH3), 2.55 (t, J=7.0 Hz, 2H), 1.58 (p, J=7.2Hz, 2H), 1.06 (q, J=3.8Hz, 2H), 0.85 (t, J=6.7Hz, 2H). 13 C NMR (100MHz, DMSO-d6) δ175.05, 158.93, 152.56, 151.81, 133.49, 131.23, 131.15, 129.65, 127. 98, 126.00, 120.12, 117.48, 117.45, 105.84, 105.57, 51.62, 46.43, 40.37, 30.24, 27.13, 16.96.

[0279] Example 16: Synthesis of 4-(2-(3-(adamantan-1-ylamino)propyl)phenoxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[0280] The synthetic route is as follows:

[0281]

[0282] Compound 64

[0283]

[0284] 36 (500 mg, 1.57 mmol) was dissolved in methanol (15 mL), and then 10% palladium on carbon (20 mg, 0.08 mmol) was added. The mixture was replaced with hydrogen three times, heated to 50°C, reacted for 2 h, and filtered through celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 100:1) to give the product 64 (277 mg, 62% yield, 96% purity) as a yellow oily liquid. MS (ESI) m / z: 286.1 [M+H] + ;.

[0285] Compound 65

[0286]

[0287] To a solution of 64 (300 mg, 1.05 mmol) in DMF (3 mL) under N₂ conditions was added K₂CO₃ (290 mg, 2.1 mmol). After stirring at room temperature for 15 min, 5 (516 mg, 1.26 mmol) was added and stirred at room temperature for 3 h. Water (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 25:1) afforded the product 65 as a white solid (203 mg, 29% yield, 95% purity). MS (ESI) m / z: 677.3 [M+H] + ;

[0288] Compound 66

[0289]

[0290] 65 (100 mg, 0.15 mmol) was dissolved in 5 mL of dichloromethane, and then a 4 M HCl solution in EtOAc (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=10:1) to give the product 66 as a white powder (44 mg, 51% yield, 96% purity). MS (ESI) m / z: 576.9 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ11.46 (s, 1H), 8.93 (s, 1H), 7.99 (d, J = 6.7Hz, 1H), 7.45 (d, J = 7.2Hz, 1H), 7.31 (p, J = 7.7Hz, 2H), 7.15-7.0 4(m, 2H), 6.81(d, J=10.3Hz, 1H), 2.83(s, 2H), 2.64-2.57(m, 2H), 2.09(s, 3H), 1.95-1.89(m, 2H), 1.81(s, 6H), 1.67-1.54(m, 6H). 13 C NMR (100MHz, DMSO-d6) δ157.24, 156.31, 153.07, 151.83, 146.86, 131.91, 131.03, 130.83, 128.30, 125 .93, 119.66, 117.96, 106.36, 106.10, 104.40, 56.06, 54.68, 37.48, 35.07, 28.81, 28.28, 26.38, 26.23.

[0291] Example 17: Synthesis of 2-((1H-indol-3-yl)methyl)-6-(2-(2-bromo-5-fluoro-4-(N-(isoxazol-3-yl)aminosulfonyl)phenoxy)-5-chlorophenyl)hexanoic acid

[0292]

[0293] Compound 67

[0294]

[0295] To a solution of 28 (400 mg, 1.07 mmol) in DMF (4 mL) under N₂ conditions was added Cs₂CO₃ (702 mg, 2.12 mmol). After stirring at room temperature for 15 min, 56 (435 mg, 1.28 mmol) was added and the mixture was stirred overnight in a 90°C oil pan. Water (20 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 8:1) afforded the product 67 (110 mg, 15% yield, 95% purity) as a gray solid. MS (ESI) m / z: 692.05 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ12.52(s,1H),10.81(d,J=42.8Hz,1H),9.60(s,1H),8.64-7.79(m,2H),7.61-6.61(m,9H),6. 53-6.14(m,1H),4.65(d,J=154.1Hz,1H),3.98-3.61(m,1H),2.93-2.66(m,2H),2.33-1.52(m,4H),1.42-1.00(m,2H). 13 C NMR(100MHz,DMSO-d6)δ170.50,158.77,158.35,158.04,146.60,133.75,131.35,130.61,129.11,1 28.15,127.21,121.13,120.77,118.65,110.79,100.43,99.97,99.66,59.88,54.99,20.85,14.17.

[0296] Example 18: Synthesis of 2-((1H-indol-3-yl)methyl)-6-(2-(2-bromo-5-fluoro-4-(N-(isoxazol-3-yl)aminosulfonyl)phenoxy)-5-chlorophenyl)hexanamide

[0297]

[0298] Compound 68

[0299]

[0300] 27 (200 mg, 0.52 mmol) was dissolved in methanolic ammonia (5 mL) and transferred to a 15 mL pressure tube. The mixture was reacted in a 90°C oil bath for 12 h and then concentrated under reduced pressure. Column chromatography (DCM:MeOH = 40:1) afforded the product 68 (56 mg, 29% yield, 97% purity) as a yellow solid. MS (ESI) m / z: 372.9 [M+H] + ;

[0301] Compound 69

[0302]

[0303] Under N2 conditions, Cs2CO3 (702 mg, 2.12 mmol) was added to a solution of 68 (200 mg, 1.07 mmol) in DMF (4 mL). After stirring at room temperature for 15 min, 56 (435 mg, 1.28 mmol) was added and the mixture was stirred in a 90°C oil pan overnight. Water (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 8:1) gave the product 69 (110 mg, 15% yield, 95% purity) as a gray solid. MS (ESI) m / z: 690.9 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ11.07-10.93(m,1H),8.28(d,J=1.8Hz,1H),8.16-7.76(m,2H),7.69-7.21(m,5H),7.17-6.93(m, 3H),6.74(d,J=10.2Hz,1H),6.14(d,J=1.8Hz,1H),4.31-4.01(m,1H),2.98-2.64(m,3H),1.91(s,4H),1.55-1.02(m,2H). 13 C NMR(100Hz,Methanol-d4)δ160.09,152.53,138.10,135.75,135.44,132.03,129.48,128.31,125.42, 122.81,122.44,120.23,119.16,112.54,108.29,107.20,100.51,62.36,47.67,28.46,28.06,27.87.

[0304] Example 19: Synthesis of 2-((3-(5-chloro-2-(2-cyclopropyl-5-fluoro-4-(N-(isoxazol-3-yl)aminosulfonyl)phenoxy)phenyl)propyl)amino)-2-cyclopropylacetamide

[0305]

[0306] Compound 56-A

[0307]

[0308] 56 (169 mg, 0.5 mmol) was dissolved in a mixture of 10 mL of toluene and 1 mL of water. Cyclopropaneboronic acid (65 mg, 0.75 mmol), tricyclohexylphosphine fluoroborate (36.8 mg, 0.1 mmol), and potassium phosphate (477 mg, 2.25 mmol) were then added. A reflux line was set up and the atmosphere was purged three times. Palladium acetate (11 mg, 0.05 mmol) was then quickly weighed and added. The atmosphere was purged three more times, and the mixture was stirred in a 110°C oil pan for 18 h. Water (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 25:1) afforded the product 56-A (96 mg, 63% yield, 95% purity) as a pale yellow solid. MS (ESI) m / z: 300.9 [M+H] + ;

[0309] Compound 56-B

[0310]

[0311] 56-A (100 mg, 0.33 mmol) was dissolved in 3 mL of dichloromethane, followed by the addition of (Boc)2O (115 μL, 0.50 mmol), TEA (92 μL, 0.66 mmol), and DMAP (8 mg, 0.07 mmol). After stirring at room temperature for 2 h, water (20 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic phases were washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (PE:EA = 15:1) afforded the product 56-B (43 mg, 33% yield, 95% purity) as a white solid. MS (ESI) m / z: 399.9 [M+H] + ;

[0312] Compound 70

[0313]

[0314] To a solution of 4 (100 mg, 0.35 mmol) in DMF (2 mL) under N₂ conditions was added Cs₂CO₃ (233 mg, 0.70 mmol). After stirring at room temperature for 15 min, 56-B (156 mg, 0.39 mmol) was added and the mixture was stirred overnight in a 120°C oil pan. Water (20 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 15:1) afforded the product 70 (14 mg, 7% yield, 95% purity) as a yellow solid. MS (ESI) m / z: 563.1 [M+H] + ; 1 H NMR (400MHz, Methanol-d4) δ8.13(d,J=1.7Hz,1H),7.51-7.09(m,3H),6.81(d,J=8.7Hz,1H),6.35(d,J=10.8Hz,1H),6.11(d,J=1 .8Hz,1H),3.57(dt,J=47.5,4.6Hz,1H),2.87(s,1H),2.81-2.45(m,4H),2.19-1.79(m,3H),1.13-0.99(m,1H),0.94-0.32(m,8H). 13 C NMR(100MHz,Methanol-d4)δ172.41,160.54,160.12,159.54,157.61,153.64,135.40,131.83,131.02,130 .61,129.25,128.64,122.08,106.02,100.69,66.01,47.34,28.34,27.98,13.30,10.29,8.25,5.69,3.65.

[0315] Biological solutions

[0316] Test Example 1: In vitro Nav1.7 current inhibition experiment

[0317] The Nav1.7 current assay is an initial screening assay used to determine the inhibitory activity of the arylsulfonamide compounds of the present invention against Nav1.7 currents. As mentioned above, inhibition of Nav1.7 currents can inhibit the conduction of electrical signals, reduce the occurrence of action potentials, and thus reduce pain. In this experiment, PF-05089771 was synthesized according to the preparation method of compound Z-0 in patent CN106243003, using PF-05089771 as the activity reference.

[0318] 1. Cell Culture

[0319] 1.1 Cell Information

[0320] HEK293T cells were purchased from the ATCC Cell Bank of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. HEK293T cells were cultured in high-glucose DMEM supplemented with 10% fetal bovine serum (FBS) and 1% anti-antibody (antibody) added to complete medium. The cells were stored at 4°C in the dark. DMEM and anti-antibody were purchased from Gibco. Fetal bovine serum was purchased from Biological Industries (Israel).

[0321] 1.2 Cell recovery

[0322] (1) Remove the cryovial from liquid nitrogen and quickly place it in a 37°C water bath while gently shaking the cryovial to accelerate the thawing process.

[0323] (2) Transfer the dissolved cell suspension into a 15 mL centrifuge tube with 5 mL of complete culture medium, dilute the DMSO in the cryopreservation solution, and centrifuge at 1000 rpm for 3 minutes.

[0324] (3) Gently remove the supernatant, gently suspend the cell pellet with 1 mL of complete culture medium, and evenly add it dropwise to a 6.0 cm culture dish containing 5 mL of complete culture medium. Place it in an incubator at 37°C and 5% CO2, and observe the cell status after culturing for 24 hours.

[0325] (4) Cell passage

[0326] The cells were grown under standard culture conditions (37°C, 5% CO2) and passaged when the cell density reached about 80%-90%, usually every 2 days.

[0327] 1.3 Cell passaging

[0328] (1) First, add the culture medium to a new culture dish. For a 3.5 cm dish, add 2 mL of culture medium, and for a 6.0 cm dish, add 5 mL of culture medium. Place the dish in a 37°C incubator to preheat.

[0329] (2) Then remove the cells from the incubator, remove the culture medium in the clean bench, add 1 mL of sterile PBS, gently tilt the culture dish left and right to allow the PBS to fully wash the cells and remove the PBS.

[0330] (3) Add 300 μl of 0.25% trypsin preheated at 37°C, gently rotate the culture dish to evenly distribute the trypsin, aspirate the trypsin, and place the culture dish in a 37°C incubator for about 1 min. Add 1 mL of fresh culture medium containing fetal bovine serum to terminate the digestion.

[0331] (4) Gently pipette to resuspend the cells, and then add dropwise to the prepared culture dish as needed. Cryopreserve the cells when they are in good condition (cells are plump, growing rapidly, and the cell surface is smooth and free of particles under high magnification).

[0332] 1.4 Cell cryopreservation

[0333] (1) When the cell density of the 6.0 cm cell culture dish reaches 90%, remove the culture medium.

[0334] (2) Add 1 mL of PBS to wash away the residual culture medium, add 300 μL of 0.25% trypsin, gently rotate the culture dish to evenly distribute the trypsin, aspirate the trypsin, and place the culture dish in a 37°C incubator for 1 min.

[0335] (3) Add 1 mL of cell freezing solution to terminate digestion. The freezing solution formula is 90% fetal bovine serum + 10% DMSO.

[0336] (4) Gently pipette to resuspend the cells and add the resuspended cells to the cell cryopreservation tube.

[0337] (5) Place the cryovials in a programmed cooling box (1°C drop per minute) and store them in a -80°C refrigerator overnight. The next day, quickly place the cryovials in liquid nitrogen for storage.

[0338] 1.5 Cell transfection

[0339] After thawed cells have been subcultured 3-4 times, they can be used for transfection experiments. The cell density should reach 80%-90% before transfection; a higher cell density improves transfection efficiency. The sodium channel plasmids used in this experiment were transfected using lipofectamine. The procedure was performed according to the instructions for X-treme GENE HP DNA Transfection Reagent (Roche).

[0340] (1) Cell preparation: The day before transfection, transfer the cells to a 35 mm culture dish and control the density to reach more than 80% at the time of transfection.

[0341] (2) Remove the old culture medium, wash once with 1 mL of PBS, and add 2 mL of serum-free culture medium (Opti-MEM) for starvation treatment.

[0342] (3) Take a 600 μL EP tube and add 250 μL Opti-MEM. Then add 2 μg Nav1.7 plasmid, 0.5 μg green fluorescent protein gene eGFP, and 5 μL liposomes (the ratio of liposomes to plasmid is 2:1). Mix gently with a 200 μL pipette and let it stand for 5 minutes.

[0343] (4) The liquid in the EP tube was evenly added dropwise to the starved cells and cultured in a constant temperature incubator at 37°C and 5% CO2.

[0344] (5) After culturing for 4-6 hours, the cells were divided into dishes and cultured in DMEM medium containing 10% FBS for 12 hours before use in subsequent electrophysiological experiments.

[0345] 2. Experimental Method for Testing Nav1.7 Inhibitory Activity

[0346] Solution preparation

[0347] Extracellular solution (mM): 140 NaCl, 5 KCl, 2 CaCl2, 1 MgCl2, 10 D-Glucose, and 10 HEPES. Adjust pH to 7.4 with NaOH.

[0348] Intracellular solution (mM): 10 NaCl, 140 CsF, 1 EGTA, and 10 HEPES, pH adjusted to 7.4 with CsOH. Sucrose was used to adjust the osmotic pressure of the intracellular and extracellular solution to 300-320 mOsm.

[0349] Drug preparation

[0350] The concentrations of all test compounds were set according to conventional concentrations, and they were dissolved in physiological saline as the solvent to prepare seven drug concentrations of 0.05mM, 0.1mM, 1mM, 5mM, 10mM, 50mM, and 100mM for experimental use.

[0351] Experimental steps:

[0352] Whole-cell patch-clamp recordings were performed at room temperature (20-25°C) using an EPC10USB Amplifier for recording and data acquisition, and PatchMaster software for data recording and control. Glass electrodes were drawn from microelectrode glass capillaries using a two-step process using a PC-10 electrode drawing instrument. The drawing temperature was adjusted to maintain a water resistance of 2-3 MΩ.

[0353] (1) Cell preparation: ND7 / 23 and HEK293T cells transfected with various sodium channels were removed from the incubator, the culture medium was aspirated, and the cells were washed with extracellular fluid. 1.5 mL of extracellular fluid was then added to a 3.5 cm culture dish.

[0354] (2) Preparation of glass electrodes: After filtering the electrode liquid through a 0.22 μm filter, inject it into the end of the electrode using a syringe. The injected volume should just touch the silver wire of the probe connected to the amplifier. Excessive liquid in the electrode may introduce large fast capacitance. Gently flick the electrode to expel air bubbles from the tip. Place the electrode into the patch clamp probe, apply positive pressure, and place the reference electrode in the culture dish so that it contacts the extracellular fluid. The experiment can then be carried out.

[0355] (3) Glass electrode immersed in water: Select single cells with green fluorescence and good morphology for the experiment under a fluorescence microscope. First, use the micromanipulator under a low-power microscope to immerse the glass electrode in water. The water resistance should be between 2-3 MΩ. Too much resistance means that the electrode opening is too small. On the contrary, too little water resistance means that the electrode opening is too large or the electrode tip is broken, which will make it difficult to seal the cell and break the membrane. In this case, the electrode should be replaced immediately and the experiment should be restarted. Therefore, appropriate electrode resistance is a prerequisite for whole-cell patch clamp recording.

[0356] (4) Cell seal formation: After the electrode is immersed in water, the liquid junction potential is compensated, the objective lens is switched to a high-power field of view, and the glass electrode is carefully manipulated to approach the selected target cell. Furthermore, after moving the electrode to the top of the target cell, the micromanipulator uses the electrode to lightly press the middle of the cell. Observe the deformation of the cell surface under a high-power microscope. When the tip of the electrode contacts the cell, a depression will be created on the cell surface. After the electrode contacts the cell, the cell seal can be started. Apply a small negative pressure by gently sucking with your mouth at one end of the hose connected to the electrode. The cell membrane will be tightly attached to the tip of the electrode under the action of the negative pressure. The R-memb column will show the resistance change of the entire closed loop. After complete sealing, the resistance is generally >GΩ.

[0357] (5) Cell membrane rupture: After sealing, perform fast capacitance compensation and set the recording mode to WHOLE-CELL mode. Apply a short negative pressure at one end of the hose to rupture the cell membrane. At this time, two sharp slow capacitance peaks (upward and downward) can be observed on the oscilloscope interface. To compensate for the slow capacitance, the amplifier window series resistance R-series should be less than 10MΩ.

[0358] (6) Whole-cell current recording: Clamp the cell at -90 mV, compensate the series resistance by 80% to eliminate voltage clamping errors, compensate for leakage current, and allow 5 minutes of stabilization to allow the exchange of electrode and intracellular fluid to reach equilibrium. The various parameters of the detection channel can be edited in the Pulse Generator File window for different stimulation modes. In this study, unless otherwise specified, cells were clamped at -90 mV during whole-cell patch clamp recording.

[0359] Data Analysis

[0360] The data statistics involved in this experiment are Mean ± SD. Statistical analysis was performed using paired t-test or ANOVA analysis of variance. The results were considered statistically significant at P < 0.05. In this experiment, the concentration of the compound was used as the horizontal axis, and the current inhibition rate of the cells transfected with the sodium channel plasmid was used as the vertical axis. Linear fitting and data visualization were performed using Igor Pro 6.10A software and GraphPad Prism 7 to obtain the IC value of the compound's inhibitory effect on Nav1.7 current. 50 value.

[0361] 3. Experimental Results

[0362] Table 1: IC values of compounds 50 Value data

[0363]

[0364]

[0365] As can be seen from Table 1, several compounds showed strong Nav1.7 inhibitory activity, among which compounds 7, 30 and 57 inhibited Nav1.7 with IC 50 The values were 0.74μM, 0.22μM and 0.49μM, respectively, which were significantly better than the positive reference PF-05089771 in its inhibitory activity against Nav1.7. The excellent activity of these compounds may be due to the fact that the flexible fatty chain connected to the benzene ring can better bind to the pocket, thereby enhancing the inhibitory activity.

[0366] Test Case 2: Pharmacokinetic Study

[0367] Pharmacokinetics is a discipline that primarily studies the quantitative processes of drugs in the body (absorption, distribution, metabolism, and excretion), and uses mathematical principles and methods to explain the dynamic laws of drugs in the body. After oral administration, the drug must reach the target site and maintain a certain concentration, and then bind to the site of action to produce a drug-receptor interaction in order to produce the desired pharmacodynamic effect. The strength of the pharmacological effect is closely related to the drug concentration at the site of action. Therefore, it is necessary to study the pharmacokinetic parameters of the drug in vivo during the drug development process. Combined with the results of the compound's inhibitory activity on Nav1.7, we chose to test the pharmacokinetic properties of compounds 7 and 57 in male SD rats.

[0368] Experimental methods

[0369] Male SD rats (270 ± 20 g) were purchased from Hunan Slake Jingda Experimental Animal Co., Ltd. All experimental rats were housed in the SPF-grade animal room of the School of Life Sciences of Nanjing Normal University. All animal experiments were carried out in strict accordance with relevant management regulations and animal ethical standards.

[0370] The drug solution was prepared by precisely weighing a certain amount of compound into a glass vial and dissolving it in a certain volume of DMSO and polyoxyethylene castor oil. After clearing, physiological saline (DMSO:castor oil:physiological saline = 5:5:90, v:v) was added and the pH was adjusted to 4. The solution was dissolved by sonication to a final concentration of 0.2 mg / mL (for injection) and 1.0 mg / mL (for oral administration). Six male SD rats were divided into two groups, with three rats weighing 290±2 g (for injection) and three rats weighing 265±2 g (for oral administration). Compound N32 was administered via tail vein injection at a dose of 1.00 mg / kg and oral gavage at a dose of 10 mg / kg, respectively. Blood samples were collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. Approximately 0.20 mL of blood was collected from the eye sockets and placed in heparinized centrifuge tubes. The samples were then centrifuged at 4°C (6800 g, 6 min). After centrifugation, 20 μL of plasma sample was removed and protein precipitation was performed by adding 200 μL of a 10 ng / mL propranolol / glyburide-acetonitrile solution. After vortexing for 5 minutes, the sample was centrifuged at 5500 g for 10 minutes. 150 μL of the supernatant was removed and diluted with 150 μL of water. After vortexing, 20 μL was injected. The sample was analyzed by LC / MS / MS, and pharmacokinetic parameters were calculated using Winonlin software. The remaining plasma sample was stored at −80°C.

[0371] Analytical methods

[0372] SD rat plasma containing the compound was analyzed by LC-MS using the following method: mobile phases: phase A (0.1% formic acid + water) and phase B (acetonitrile); column: Ultimate AQ C18, 5 μm, 2.1 × 50 mm; flow rate: 0.6000 mL / min; scanning mode: MRM; injection volume: 8.00 μL; mobile phase gradient: 0.01 min - 10% B, 0.70 min - 95% B, 1.70 min - 95% B, 1.71 min - 10% B, 2.50 min - stop. Plasma concentrations of the test compound were measured.

[0373] Experimental results

[0374] Table 2: Pharmacokinetic studies of compounds 7 and 57

[0375]

[0376]

[0377] The experimental results are shown in Table 2. The elimination half-lives of compounds 7 and 57 after oral administration were 0.5h and 1.53h, respectively. max 451 ng / mL and 65.8 ng / mL, respectively; their AUC 0-t The oral bioavailabilities of the two drugs were 583 ng·h / mL and 268 ng·h / mL, respectively, and were 8.98% and 8.43%, respectively.

[0378] Test Example 3: Rat Toxicity Test

[0379] Experimental plan:

[0380] Experimental Animals: Healthy adult male Sprague-Dawley rats (8 rats weighing 170-180g at the start of the experiment, divided into three groups) were provided by Slack. Food and water were provided ad libitum and housed in separate cages, 2 rats per cage, with tail marking used for marking. Administration and Dosage: Sprague-Dawley rats were administered 200 mg / kg via gavage for 10 consecutive days.

[0381] Prescription plan

[0382] Drug 7: Dose 200 mg / kg, gavage volume 10 mL / kg, i.e., a concentration of 200 mg / 10 mL = 20 mg / mL, with a vehicle of 20% PEG + 5% DMA + 75% PBS. Prepare 20 mL of the solution with a vehicle of 4 mL PEG and 1 mL DMA. After sonication for half an hour, add 15 mL PBS, and sonicate again for approximately 1 minute before gavage administration.

[0383] Drug 57: The dose is 200 mg / kg, and the gavage volume is 10 mL / kg, i.e., the prepared concentration is 200 mg / 10 mL = 20 mg / mL, with the vehicle being 20% PEG + 5% DMA + 75% PBS. A 20 mL volume is prepared with 4 mL PEG and 1 mL DMA as the vehicle. After sonication for half an hour, 15 mL PBS is added, and sonication is continued for approximately 1 minute before gavage administration.

[0384] PF-05089771: The dose is 200 mg / kg, with a gavage volume of 10 mL / kg, resulting in a concentration of 200 mg / 10 mL = 20 mg / mL. The vehicle is 20% PEG + 5% DMA + 75% PBS. A 20 mL volume is prepared using 4 mL PEG and 1 mL DMA as the vehicle. After ultrasonication for half an hour, 15 mL PBS is added, and ultrasonication is continued for approximately 1 minute before administration by gavage.

[0385] The experimental results are as follows Figure 2 As shown in the figure, it can be seen that compounds 7 and 57, like the positive compound PF-05089771, did not show toxic side effects on rats.

[0386] Test Example 4: Spinal Nerve Ligation Model Analgesia Test

[0387] 1. Model Preparation

[0388] After SD rats were anesthetized with isoflurane, a 4-cm longitudinal incision was made centered at the L5 / 6 spinous process interval. The nerve was then separated layer by layer down to the lamina and articular process, exposing and isolating the left L5 spinal nerve. A 5-0 ligature was then placed. Hemostasis was achieved by thorough irrigation and layer-by-layer suture, and penicillin was injected intramuscularly to prevent infection. Following model establishment, the animals exhibited significant mechanical hyperalgesia. This model has the advantage of completely separating the injured and uninjured spinal cord segments, facilitating comparative studies of whether and how primary afferent fibers contribute to the pathogenesis of pain.

[0389] 2. Grouping and Dosage Regimen

[0390] One day after surgery, the mechanical withdrawal threshold (MWT) of the normal and affected sides of the rats was measured. Animals with a MWT value of more than 30% on the affected side were selected and grouped according to the MWT value on the affected side. The groups are detailed in Table 3 below:

[0391] Table 3: Animal groups and dosing regimens

[0392]

[0393]

[0394] 3. Drug preparation:

[0395] Drug 7: Dose 150 mg / kg, gavage volume 10 mL / kg, i.e., a concentration of 150 mg / 10 mL = 15 mg / mL, with a vehicle of 20% PEG + 5% DMA + 75% saline. Prepare 20 mL of the solution with a vehicle of 4 mL PEG and 1 mL DMA. After ultrasonication for half an hour, add 15 mL of saline, and ultrasonicate again for approximately 1 minute before gavage administration.

[0396] Drug 57: Dose 150 mg / kg, gavage volume 10 mL / kg, i.e., a concentration of 150 mg / 10 mL = 15 mg / mL, with a vehicle of 20% PEG + 5% DMA + 75% PBS. Prepare 20 mL of the solution with a vehicle of 4 mL PEG and 1 mL DMA. After sonication for half an hour, add 15 mL PBS, and sonicate again for approximately 1 minute before gavage administration.

[0397] PF-05089771: The dose is 150 mg / kg, with a gavage volume of 10 mL / kg, resulting in a concentration of 150 mg / 10 mL = 15 mg / mL. The vehicle is 20% PEG + 5% DMA + 75% saline. A 20 mL volume is prepared with 4 mL PEG and 1 mL DMA as the vehicle. After ultrasonication for half an hour, 15 mL of saline is added, and ultrasonication is continued for approximately 1 minute before gavage administration.

[0398] Prepare it every day, prepare it as needed, and discard the rest.

[0399] Detection index Mechanical withdrawal reflex threshold (MWT): Measure once before, 1, 3, and 5 hours after drug administration, and measure the MWT value of rats on 3d, 5d, and 7d (3d-7d, measure 2 hours after each administration).

[0400] The experimental results are as follows Figure 3 As shown, it can be seen that the positive control PF-05089771 has a certain analgesic effect only after 5 hours of single administration and its efficacy is weaker than that of compound 57. In contrast, the MWT value of compound 57 begins to increase 1 hour after a single administration, and reaches the highest MWT value after 3 hours (P<0.05), indicating that compound 57 takes effect quickly and has a better analgesic effect. In addition, the MWT values of drugs 7 and 57 increased significantly after multiple administrations of 3d to 7d (P<0.05), while the control drug PF-05089771 only increased significantly after 7d of administration, indicating that compounds 7 and 57 both showed better in vivo analgesic effects. This may be because the flexible fatty chain structure contained in these two compounds can bind to the pocket more quickly and more tightly, resulting in faster onset and better efficacy. Compared with 7 and 57, the other compounds claimed for protection in this application also have similar structures, and thus can also achieve better results.

[0401] Therefore, the aromatic sulfonamide compounds of the present invention, as Nav1.7 inhibitors, can effectively limit the conformation of sodium ion channels, block the flow of sodium ions between cells, thereby preventing the occurrence of action potentials and exerting their efficacy; they have stronger selectivity and inhibitory activity for Nav1.7 channels, have extremely strong analgesic effects, are non-toxic and have strong oral absorption, and act on a variety of pain diseases in humans and animals, such as diabetic peripheral neuropathy, and have great application prospects.

Claims

1. An arylsulfonamide compound, characterized in that: The compound structure is shown in Formula I: in: R 1 is independently a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 2 or R 3 are independently -H, halogen, (C3-C6)cycloalkyl, -CF3, -OCF3, -CN, -NO2, or (C l -C 12 ) alkoxy; A is selected from -(CH2) p R a 、-CHR a R b , (C1-C6) alkyl, (C3-C8) cycloalkyl, adamantyl, 1H-tetrazol-5-yl; wherein each R a and R b independently C1-C6 alkyl having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, (C3-C8) cycloalkyl, 4-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted indolyl, -COOH, CONH2 and any combination thereof; X is independently -O-, -NH- or -S-; m is independently an integer from 0 to 4.

2. The arylsulfonamide compound according to claim 1, characterized in that R 2 or R 3 Selected from -H, halogen, -CF3, -NO2.

3. The arylsulfonamide compound according to claim 1, characterized in that A is selected from -(CH2) n R a 、-CHR a R b , (C3-C8) cycloalkyl, adamantyl, 1H-tetrazolyl-5-yl; wherein each R a and R b are independently C1-C6 alkyl, (C3-C8) cycloalkyl, 5-6 membered heteroaromatic ring, substituted or unsubstituted C6-C8 alkyl, (C3-C8) cyclo ... 10 Aryl, substituted or unsubstituted indolyl, -COOH, CONH2 and any combination thereof.

4. The arylsulfonamide compound according to claim 1, characterized in that A is selected from any of the following structures:

5. The arylsulfonamide compound according to claim 1, characterized in that The compound is selected from any one of the compounds shown in the following table:

6. The compound according to claim 1, characterized in that The compound also includes pharmaceutically acceptable salts thereof.

7. A pharmaceutical composition, characterized in that Comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

8. Use of the compound according to claim 1 or the pharmaceutical composition according to claim 7 in the preparation of a Nav1.7 inhibitor or a medicament for treating a disease associated with Nav1.7 activity.

9. Use of the compound according to claim 1 or the pharmaceutical composition according to claim 7 in the preparation of a drug for treating pain.

10. The use according to claim 9, characterized in that The pain includes acute pain, chronic pain, inflammatory pain or neuropathic pain.

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