Metanilamidosuberamide compounds, methods of making, pharmaceutical compositions, and uses

Abstract

This invention discloses a m-sulfamylbenzamide compound, its preparation method, pharmaceutical composition, and applications. The compound has the structure of Formula I and includes its stereoisomers, pharmaceutically acceptable salts, or mixtures thereof. This class of compounds and its pharmaceutical compositions can specifically inhibit butyrylcholinesterase activity, optimally achieving nanomolar concentrations; they also possess excellent blood-brain barrier permeability, enabling effective delivery to the lesion, and are virtually non-toxic at effective inhibitory doses; furthermore, they exhibit good neuroprotective effects and significantly improve memory and cognitive function, achieving therapeutic efficacy for Alzheimer's disease through multiple mechanisms of action.

Description

Technical Field

[0001] This invention relates to a m-sulfamylbenzamide compound, its preparation method, pharmaceutical composition, and application, and more particularly to a m-sulfamylbenzamide compound that can be prepared as a highly selective butyrylcholinesterase inhibitor, its preparation method, pharmaceutical composition, and application. Background Technology

[0002] Neurodegenerative diseases are a group of medical conditions that affect the survival and function of neurons in the brain. Neuronal loss often leads to cognitive decline and the development of dementia. Dementia is a common feature of neurodegenerative diseases. Alzheimer's disease (AD) is a common cause of dementia in the elderly, leading to severe disability and dependence on others. Finding effective drugs and treatment strategies for AD has become a critical challenge that urgently needs to be addressed in the global medical field.

[0003] The pathogenesis of Alzheimer's disease (AD) is extremely complex, and the exact cause remains inconclusive. Previous studies have shown that AD is primarily induced by the combined effects of genetic factors, aging, and environmental factors, leading to several hypotheses, including cholinergic dysfunction, amyloid-β (Aβ) plaques, neurofibrillary tangles, and oxidative stress. Drugs related to the cholinergic hypothesis are among the main treatments used clinically to improve AD symptoms.

[0004] Acetylcholine (ACh) is a cholinergic neurotransmitter widely distributed in the peripheral and central nervous systems. At the neuronal level, cholinergic neurotransmission is primarily mediated by acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). In healthy adults, AChE plays a major regulatory role in cholinergic activity, while BChE plays a co-regulatory role. However, the co-regulatory function of BChE changes with the progression of Alzheimer's disease (AD), with a significant increase in the BChE / AChE ratio in late-stage AD patients. BChE replaces AChE in hydrolyzing choline. Currently, AChE inhibitors are widely used to restore ACh levels; however, patients taking AChE inhibitors may experience side effects such as nausea and vomiting, and even some rare fatal events, such as donepezil-induced rhabdomyolysis. These adverse reactions are related to the broad physiological functions of AChE, particularly peripheral AChE.

[0005] Currently, there are few highly selective butyrylcholinesterase structures, with only one currently in clinical trials. This compound is bisnorcymserine, a carbamate structure and a covalent inhibitor of BChE. No reversible BChE inhibitors have yet entered clinical trials. Summary of the Invention

[0006] Purpose of the invention: In view of the problems of poor efficacy and serious adverse reactions of existing AChE inhibitor drugs in patients with advanced Alzheimer's disease, and the problems of single structural type and low selectivity of existing BChE inhibitor compounds, the present invention aims to provide a m-sulfamylbenzamide compound with specific inhibitory activity against butyrylcholinesterase, as well as its preparation method, pharmaceutical composition and application.

[0007] Technical solution: As a first aspect of the present invention, the m-sulfamylbenzamide compounds of the present invention have the structure of Formula I, comprising their stereoisomers, pharmaceutically acceptable salts, or mixtures thereof:

[0008]

[0009] in:

[0010] n = 0 to 2;

[0011] Ring A is selected from a 6-membered aromatic ring, a 6-9-membered aromatic heterocycle, a 6-7-membered cyclic heterogroup, or a 7-membered cyclic heterogroup-substituted acyl group; the C group of the aromatic heterogroup or cyclic heterogroup is substituted with one or more N groups; the 6-membered aromatic ring is substituted with one or more hydrogen, halogen, or C1-C3 alkoxy groups.

[0012] X is selected from -C(O)- or -S(O)2-;

[0013] R1 is selected from C1-C4 alkyl, 6-membered aryl, or a 6-membered cyclic heterogroup formed by N and the attached group; the C1-C4 alkyl is one or more straight-chain or branched alkyl groups, substituted by one or more hydrogens, 6-10-membered aryl or 9-membered aromatic heterogroups; the C of the cyclic heterogroup or aromatic heterogroup is substituted by one or more Ns.

[0014] R2 is selected from one or more 6-membered cyclic heterogroups formed by hydrogen, halogen, C1-C3 alkoxy, C1-C3 alkyl, or cyclic ring fused with a benzene ring; wherein the C of the cyclic heterogroup is substituted by one or more O atoms;

[0015] R3 is selected from one or more hydrogen atoms or C1 to C3 alkyl groups; when R3 is attached to a chiral C, the configuration of the chiral C is R, S or racemic.

[0016] The above-mentioned compounds are selective BChE inhibitors, which can avoid the toxicity of existing cholinergic inhibitors. Compared with selective inhibition of acetylcholinesterase, they will have more significant therapeutic effects, especially suitable for patients with mid-to-late stage AD.

[0017] Preferably, in the above structure:

[0018] n = 1 to 2;

[0019] Ring A is selected from phenyl, pyridyl, indolyl, 6-7 membered nitrogen-containing heterocyclic rings or formyl groups substituted with one or more hydrogen, fluorine, chlorine, or methoxy groups;

[0020] R1 is selected from C1-C4 alkyl, phenyl, or a 6-membered ring heterogroup formed by N and the attached group; the C1-C4 alkyl is 1-2 straight-chain or branched alkyl groups, which are substituted by one or more hydrogen, phenyl, naphthyl, or indole groups.

[0021] R2 is selected from one or more of hydrogen, halogen, methoxy, methyl, or ethyl;

[0022] R3 is selected from one or more hydrogens, methyl groups, or ethyl groups; when R3 is attached to a chiral C, the configuration of the chiral C is R, S, or a racemic mixture.

[0023] Further optimization, in the above structure:

[0024] Ring A is selected from:

[0025]

[0026] R1 is selected from:

[0027]

[0028] Furthermore, in the above structure:

[0029] n = 1;

[0030] Ring A is selected from:

[0031]

[0032] R1 is selected from:

[0033]

[0034] The most preferred compound is any of the following:

[0035]

[0036]

[0037]

[0038] The pharmaceutically acceptable salts of the above-mentioned m-aminosulfonylbenzamide compounds are salts formed by the compounds with an acid, wherein the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, or mandelic acid.

[0039] As a second aspect of the present invention, the method for preparing the above-mentioned m-aminosulfonylbenzamide compounds is selected from any of the following methods:

[0040] (1) When n=1, ring A is pyridyl, X is -S(O)2-, R2 is methoxy, R3 is hydrogen, and R1 is defined as described above.

[0041]

[0042] Compound A1 undergoes a two-step acylation, hydrolysis, and acylation reaction to yield compound I;

[0043] (2) When n=1, X is -S(O)2-, R1 is propyl, R2 is methoxy, R3 is hydrogen, and the definition of ring A is as described above.

[0044]

[0045] Compound A1 undergoes a two-step acylation, hydrolysis, and acylation reaction to yield compound I;

[0046] (3) When n = 1, ring A is When X is -S(O)2-, R1 is ethyl, and R2 and R3 are hydrogen...

[0047]

[0048] Compound I is obtained by esterification, halogenation, acylation, hydrolysis, and acylation of compound A7;

[0049] (4) When n = 1, ring A is When X is -C(O)-, R1 is propyl, and R2 and R3 are hydrogen...

[0050]

[0051] Compound I is a product of compound A14 undergoing acylation, hydrolysis, and acylation reactions.

[0052] (5) When n = 1, ring A is X is -S(O)2-, R1 is propyl or When R2 is methyl and R3 is hydrogen,

[0053]

[0054] Compounds A17a to A17l were subjected to acylation, esterification, acylation, hydrolysis, and acylation reactions to yield compound I;

[0055] (6) When n = 0, ring A is When X is -S(O)2-, R1 is propyl, R2 is methyl, and R3 is hydrogen,

[0056]

[0057] Compound A22 was acylated and deprotected to give compound A24; compound A14a was acylated in two steps to give compound A26; and compounds A24 and A26 were acylated to give compound I.

[0058] (7) When n = 1 to 2, ring A is When X is -S(O)2-, R1 is propyl, R2 is methyl, and R3 is hydrogen, methyl, or ethyl,

[0059]

[0060] Compound C26 was acylated, halogenated, and substituted to give compound I;

[0061] The corresponding acid is used to form a salt with compound I prepared by the above method to obtain a pharmaceutically acceptable salt of the above-mentioned m-sulfamylbenzamide compounds.

[0062] As a third aspect of the present invention, the above-mentioned m-sulfamylbenzamides are combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition.

[0063] Specifically, pharmaceutically acceptable carriers can be added to produce common pharmaceutical preparations, such as tablets, capsules, syrups, suspensions, or injections. Common pharmaceutical excipients such as flavorings, sweeteners, liquid / solid fillers, and diluents can be added to the preparations.

[0064] As a fourth aspect of the present invention, the above-mentioned m-sulfamylbenzamide compounds or their pharmaceutical compositions are used in the preparation of butyrylcholinesterase inhibitor drugs, specifically in the preparation of drugs for treating neurodegenerative diseases, especially drugs for treating Alzheimer's disease.

[0065] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0066] (1) These compounds and their drug compositions can specifically inhibit butyrylcholinesterase activity, IC50 50 The concentration values ​​all reach the micromolar concentration level or even the nanomolar concentration level, with the best being less than 5 nM, and the butyrylcholinesterase inhibition selectivity coefficient is better than 20; at the same time, it has excellent blood-brain barrier permeability, which can effectively deliver it to the lesion; in addition, it is almost non-toxic at effective inhibitory doses.

[0067] (2) These compounds and their drug compositions have good neuroprotective effects and significantly improve memory and cognitive function, achieving therapeutic effects on Alzheimer's disease through multiple mechanisms of action;

[0068] (3) The preparation method is applicable to a variety of chemical structures and has strong versatility. Attached Figure Description

[0069] Figure 1 The compound was used to study the cytotoxicity of human neuroblastoma cells SH-SY5Y and mouse microglia BV-2.

[0070] Figure 2 The neuroprotective efficacy of compounds 30 and 44(R) against glutamate-induced cytotoxicity against human neuroblastoma cells SH-SY5Y is presented as mean ± SEM from three independent experiments.

[0071] Figure 3 The time (s) for mice to reach the platform in the water maze experiment is given. Data are expressed as mean ± SEM (n = 8; **P < 0.01, ***P < 0.001, ****P < 0.0001 vs. model group). Detailed Implementation

[0072] The technical solution of the present invention will be further described below with reference to the embodiments.

[0073] The structure of the compound was determined by nuclear magnetic resonance (NMR). The instrument used was a Bruker AVANCE-300 NMR spectrometer, the solvent was CDCl3, the internal standard was TMS, and the chemical shift was 10⁻¹⁰. -6 ppm.

[0074] Example 1: Preparation of Compound 1

[0075] Methyl 3-(chlorosulfonyl)-4-methoxybenzoate (A2)

[0076] Add chlorosulfonic acid (10 eq) to a dry reaction flask and place it in an ice bath. Add methyl anisinate (10 mmol) in portions. After the addition is complete, transfer the reaction solution to room temperature and react overnight. After the reaction is complete, pour the reaction solution into ice water and stir vigorously. A white solid precipitates. Filter the solid and wash the filter cake with ice water. Dry the filter cake and perform column chromatography (PE:EA = 15:1).

[0077] White solid, yield 38%. Mp 114~116℃. 1 H NMR (300MHz, DMSO) δ8.33(dd,J=5.6,2.3Hz,1H),7.96(dd,J1=8.6,J2=2.3Hz,1H),7.13(d,J=8.6Hz,1H),3.87(s,3H),3.85(s,3H).

[0078] Methyl 4-methoxy-3-(N-(2-(pyridin-2-yl)ethyl)aminosulfonyl)benzoate (A3)

[0079] 2-Pyridylethylamine was placed in dry dichloromethane, and triethylamine (1.2 eq) was added. C2 (1.1 eq) dissolved in dichloromethane was gradually added to the reaction flask under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 2 h. The mixture was then subjected to column chromatography (DCM).

[0080] White solid, yield 62%. Mp 142~144℃ 1 H NMR (300MHz, DMSO) δ8.44(d,J=4.8Hz,1H),8.30(d,J=2.2Hz,1H),8.18(dd,J1=8.7,J2=2.3Hz,1H),7.68(td,J1=7.7,J2=1.8Hz,1H),7.58( t,J=5.8Hz,1H),7.34(d,J=8.8Hz,1H),7.23–7.16(m,2H),3.96(s,3H),3.88(s,3H),3.20(dd,J1=13.2,J2=7.1,2H),2.84(t,J=7.2Hz,2H).

[0081] 4-Methoxy-3-(N-(2-(pyridin-2-yl)ethyl)aminosulfonyl)benzoic acid (A4)

[0082] Dissolve the raw material in 10 mL of methanol, add lithium hydroxide (5 eq), and heat at 50 °C for 6 h. After the reaction is complete, adjust the pH to below 5 with 2N hydrochloric acid. A solid precipitates. Filter to obtain the final product.

[0083] White solid, yield 80%. Mp 165~167℃ 1 H NMR (300MHz, DMSO) δ8.76(d,J=4.8Hz,1H),8.43(t,J=7.8Hz,1H),8.23(d,J=2.1Hz,1H),8.14(dd,J1=8.7,J2=2.1Hz,1H),7.85(d, J=7.8Hz,2H),7.72(t,J=5.8Hz,1H),7.30(d,J=8.8Hz,1H),3.96(s,3H),3.31(dd,J1=11.9,J2=5.8Hz,2H),3.18(t,J=6.1Hz,2H).

[0084] Example 2: 4-Methoxy-N-phenylethyl-3-(N-(2-(pyridin-2-yl)ethyl)aminosulfonyl)benzamide (2)

[0085] A4 was dissolved in 5 mL of dichloromethane, and EDCI-HCl, HOBT, and DIEA were added under ice bath conditions. After stirring for 0.5 h, dipropylamine was added. The mixture was then allowed to react overnight at room temperature. The reaction solution was washed with water, extracted with dichloromethane, and the organic phases were combined. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under vacuum, and the mixture was subjected to column chromatography (DCM:MEOH = 100:1).

[0086] White solid, yield 70%. Mp 121~123℃. 1 H NMR (300MHz, CDCl3) δ8.48 (d, J=4.1Hz, 1H), 8.18 (s, 1H), 8.07 (dd, J1=8.7, J2=2.3Hz, 1H), 7.58 (td, J1=7. 7, J2=1.8Hz, 1H), 7.33 (dd, J1=10.7, J2=3.8Hz, 2H), 7.24 (dd, J1=5.1, J2=2.4Hz, 3H), 7.15 (dd, J1=7.0, J2 =5.4Hz,1H),7.04(d,J=7.8Hz,1H),6.99(d,J=8.7Hz,1H),6.43(t,J=5.6Hz,1H),6.29(t,J=6.1Hz,1H),3. 85(s,3H),3.70(dd,J1=13.3,J2=7.0Hz,2H),3.35(q,J=6.1Hz,2H),3.21–3.16(m,2H),3.16–3.12(m,2H). 13 C NMR (75MHz, CDCl3) δ165.63,158.73,158.36,148.94,138.95,136.69,134.41,128.82,128.63,128.3 3,127.14,126.96,126.49,123.61,121.74,112.00,56.41,42.30,41.48,36.16,35.75.ESI:m / z[M+H] + ,calcd.for C 23 H 26 N3O4S + :440.1639; found:440.1642.

[0087] Example 3: Preparation of Compound 3

[0088] Steps 1 to 3 are described in Example 1.

[0089] 4-Methoxy-N-propyl-3-(N-(2-(pyridin-2-yl)ethyl)aminosulfonyl)benzamide (3)

[0090] Referring to the synthesis of compound 1, tryptophan was replaced with n-propylamine.

[0091] A colorless oily substance with a yield of 73%. 1 H NMR (300MHz, CDCl3) δ8.54(d,J=4.1Hz,1H),8.25(d,J=2.3Hz,1H),8.17(dd,J1=8.7,J 2=2.3Hz,1H),7.63(d,J=1.8Hz,1H),7.23–7.17(m,1H),7.09(d,J=7.8Hz,1H),7.03(s ,1H),6.36(dd,J1=11.7,J2=5.6Hz,2H),3.89(s,3H),3.50–3.44(m,2H),3.43–3.37(m ,2H),2.95(t,J=6.1Hz,2H),1.69(dd,J1=14.6,J2=7.3Hz,2H),1.03(t,J=7.4Hz,3H). 13 C NMR (75MHz, CDCl3) δ165.58,158.78,148.95,136.67,134.56,128.06,127.09,1 23.60,121.72,111.98,56.39,41.92,36.12,30.32,22.86,11.51.ESI:m / z[M+H] + ,calcd.for C 18 H 24 N3O4S + :378.1482; found:378.1486.

[0092] Example 4: Preparation of Compound 4

[0093] Steps 1 to 3 are described in Example 1.

[0094] N-(2-(dimethylamino)ethyl)-4-methoxy-3-(2-(pyridin-2-yl)ethyl)aminosulfonyl)benzamide (4)

[0095] Referring to the synthesis of compound 1, tryptamine was replaced with N,N-dimethylethylamine.

[0096] A pale yellow oily substance, yield 51%. 1H NMR (300MHz, CD3OD) δ8.41(d,J=4.3Hz,1H),8.37(d,J=2.2Hz,1H),8.09(dd,J1=8.7,J2=2.2Hz,1H),7.72(td,J1=7.7,J2=1.7Hz,1H),7.25 (s,2H),7.22(s,1H),3.96(s,3H),3.66(t,J=6.2Hz,2H),3.29(t,J=6.9Hz,2H),2.99(t,J=6.2Hz,2H),2.92(t,J=6.9Hz,2H),2.66(s,6H). 13 C NMR(75MHz,MeOD)δ167.33,158.99,158.39,148.38,137.21,133.54,129.09,127.73,12 5.77,123.82,121.87,112.04,57.66,55.69,43.44,42.37,36.97,36.26.ESI:m / z[M+H] + ,calcd.for C 19 H 27 N4O4S + 407.1748; found: 407.1754.

[0097] Example 5: Preparation of Compound 5

[0098] Steps 1 to 3 are described in Example 1.

[0099] 4-Methoxy-N-(3-Methoxypropyl)-3-(2-(pyridin-2-yl)ethyl)aminosulfonyl)benzamide (5)

[0100] Referring to the synthesis of compound 1, tryptamine was replaced with 3-methoxypropylamine.

[0101] A pale yellow oily substance, with a yield of 68%. 1H NMR (300MHz, CDCl3) δ8.50(d,J=4.8Hz,1H),8.20(d,J=2.2Hz,1H),8.11(dd,J1=8.6,J 2=2.2Hz,1H),7.59(td,J1=7.7,J2=1.7Hz,1H),7.19–7.12(m,2H),7.02(dd,J1=16.4,J 2=8.2Hz,2H),6.23(t,J=6.0Hz,1H),3.85(s,3H),3.58(dd,J1=11.6,J2=5.9Hz,4H),3. 43(s,3H),3.37(dd,J1=12.2,J2=6.1Hz,2H),2.91(t,J=6.0Hz,2H),1.97–1.84(m,2H). 13 C NMR (75MHz, CDCl3) δ165.21,158.82,158.28,148.99,136.65,134.32,128.09,127.26,127. 02,123.61,121.70,111.94,72.31,58.97,56.38,42.23,39.29,36.16,28.73.ESI:m / z[M+H] + ,calcd.for C 19 H 25 N3O5S + :408.1588; found:408.1592.

[0102] Example 6: Preparation of Compound 6

[0103] Steps 1 to 3 are described in Example 1.

[0104] 4-Methoxy-N,N-dipropyl-3-(N-(2-(pyridin-2-yl)ethyl)aminosulfonyl)benzamide (6)

[0105] Referring to the synthesis of compound 1, tryptamine was replaced with dipropylamine.

[0106] A colorless oily substance with a yield of 65%. 1H NMR (300MHz, CDCl3) δ8.54(d,J=4.2Hz,1H),7.98(d,J=2.1Hz,1H),7.66–7.56(m ,2H),7.19(dd,J1=7.1,J2=5.3Hz,1H),7.10(d,J=7.8Hz,1H),7.02(s,1H),6.32( t,J=6.0Hz,1H),3.88(s,3H),3.44(d,J=15.8Hz,2H),3.40–3.34(m,2H),3.22(s ,2H),2.95(t,J=6.0Hz,2H),1.74(s,2H),1.60(s,2H),1.01(s,3H),0.80(s,3H). 13 C NMR (75MHz, CDCl3) δ169.91,158.86,156.68,148.95,136.64,133.32,129.56,128.60,1 27.17,123.59,121.67,111.96,56.26,51.01,42.26,36.12,20.68,11.04.ESI:m / z[M+H] + ,calcd.for C 21 H 30 N3O4S + 420.1952; found: 420.1955.

[0107] Example 7: Preparation of Compound 7

[0108] Step 1 is described in Example 1.

[0109] Step 2: Methyl 4-methoxy-3-(N-phenylethylaminosulfonyl)benzoate (C5a)

[0110]

[0111] See the synthesis of C3, where 2-pyridylethylamine is replaced with β-phenylethylamine.

[0112] A colorless oily substance, yield 70%.

[0113] Step 3: 4-Methoxy-3-(N-phenylethylaminosulfonyl)benzoic acid (C6a)

[0114]

[0115] See the synthesis of C4, where C3 is replaced with C5a.

[0116] White solid, yield 70%. Mp 145~147℃. 1H NMR (300MHz, DMSO) δ13.08(s,1H),8.28(d,J=2.2Hz,1H),8.14(dd,J1=8.7,J2=2.2Hz,1H),7.49(t,J=5.8Hz,1H),7 .30(d,J=8.8Hz,1H),7.28–7.14(m,3H),7.13–7.09(m,2H),3.93(s,3H),3.07–2.96(m,2H),2.67(t,J=7.4Hz,2H).

[0117] Step 4: 4-Methoxy-3-(N-phenylethylaminosulfonyl)-N,N-dipropylbenzamide (7)

[0118]

[0119] C6a was dissolved in 5 mL of dichloromethane, and EDCI-HCl (1.5 eq), HOBT (1.5 eq), and DIEA (3 eq) were added under ice bath conditions. After stirring for 0.5 h, dipropylamine (1.1 eq) was added. The mixture was then transferred to room temperature and allowed to react overnight. The reaction solution was washed with water, extracted with dichloromethane, and the organic phases were combined. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under vacuum, and the mixture was subjected to column chromatography (DCM:MEOH = 100:1).

[0120] A pale yellow oily substance, yield 75%. 1 H NMR (300MHz, CDCl3) δ8.48 (s, 1H), 7.80 (d, J=2.0Hz, 1H), 7.43 (dd, J1=8.5, J2= 2.1Hz,1H),7.28–7.18(m,2H),7.08(t,J=7.6Hz,1H),6.96–6.88(m,2H),6.58(d ,J=8.6Hz,1H),4.75(t,J=5.9Hz,1H),3.37(s,2H),3.18–3.07(m,3H),3.06(s, 4H), 2.86 (t, J = 6.0Hz, 2H), 1.60 (s, 2H), 1.48 (s, 2H), 0.90 (s, 3H), 0.68 (s, 3H). 13 C NMR (75MHz, CDCl3) δ170.07,156.22,136.66,135.77,133.29,128.60,126.79,125.9 0,123.25,119.46,111.68,55.38,51.05,43.17,30.33,24.93,11.13.ESI:m / z[M+H] + ,calcd.for C 22 H30 N2O4S + :419.1999; found:419.2000.

[0121] Example 8: Synthesis of Compound 8

[0122] 3-(N-(2-fluorophenylethyl)aminosulfonyl)-4-methoxy-N,N-dipropylbenzamide (8)

[0123] See the synthesis in 7, where C6a is replaced with C6b.

[0124] A pale yellow oily substance, yield 72%. 1 H NMR (300MHz, CDCl3) δ7.92 (d, J=1.9Hz, 1H), 7.61 (dd, J=8.5, 1.9Hz, 1H), 7.2 5–7.18(m,1H),7.15(t,J=6.7Hz,1H),7.07(t,J=7.4Hz,1H),7.01(t,J=8.2H z,2H),4.86(t,J=6.2Hz,1H),3.80(s,3H),3.43(s,2H),3.16(dd,J1=13.5,J 2=6.5Hz,4H),2.85(t,J=6.7Hz,2H),1.43(s,2H),0.97(s,3H),0.75(s,3H). 13 CNMR (75MHz, CDCl3) δ169.75,156.48,133.57,131.22,129.72,128.69,126.57,124.82,1 24.62,124.32,115.54,112.10,56.32,51.00,43.15,29.25,20.70,11.03.ESI:m / z[M+H] + ,calcd.for C 22 H 30 FN2O4S + 437.1905; found: 437.1906.

[0125] Example 9: Synthesis of Compound 9

[0126] 3-(N-(3-fluorophenylethyl)aminosulfonyl)-4-methoxy-N,N-dipropylbenzamide (9)

[0127] See the synthesis in 7, where C6a is replaced with C6c.

[0128] A pale yellow oily substance, yield 75%. 1H NMR (300MHz, CDCl3) δ7.97(t,J=2.3Hz,1H),7.73–7.64(m,1H),7.32(d,J=2.6Hz,2H),7.09–6.98(m,2H),6.96(d,J=7.3Hz,1H),6.84(d,J=9.7Hz, 1H),4.89(s,1H),3.82(t,J=7.2Hz,3H),3.49(s,2H),3.26–3.16(m,4H), 2.86(dd,J1=8.3,J2=4.4Hz,2H),1.70(s,2H),1.03(s,3H),0.82(s,3H). 13 C NMR (75MHz, CDCl3) δ169.74,164.54,156.42,140.48,133.59,130.32,129.83,128.69,126.51,1 24.53,124.50,115.59,113.89,56.25,51.00,44.13,35.09,35.07,21.96,11.44.ESI:m / z[M+H] + ,calcd.for C 22 H 30 FN2O4S + :437.1905; found:437.1905.

[0129] Example 10: Synthesis of Compound 10

[0130] 3-(N-(4-fluorophenylethyl)aminosulfonyl)-4-methoxy-N,N-dipropylbenzamide (10)

[0131] See the synthesis in 7, where C6a is replaced with C6d.

[0132] A pale yellow oily substance, yield 66%. 1 H NMR (300MHz, CDCl3) δ7.92(d,J=2.0Hz,1H),7.60(dd,J=8.5,2.1Hz,1H),7.06(dd,J1=8.4,J2=5.5Hz,2H),7.02–6.96(m,2H),6.94(d,J=8.6Hz,1 H),5.03(t,J=6.0Hz,1H),3.76(s,3H),3.43(s,2H),3.26–3.04(m,4H), 2.76(t,J=6.7Hz,2H),1.62(d,J=26.4Hz,4H),0.97(s,3H),0.76(s,3H). 13C NMR (75MHz, CDCl3) δ169.77,163.31,156.45,133.59,133.49,130.16,129.72,128.6 8,126.54,115.58,112.07,56.27,51.00,44.49,34.59,21.94,11.43.ESI:m / z[M+H] + ,calcd.for C 22 H 30 FN2O4S + 437.1905; found: 437.1906.

[0133] Example 11: Synthesis of Compound 11

[0134] 4-Methoxy-3-(N-(3-methoxyphenylethyl)aminosulfonyl)-N,N-dipropylbenzamide (11)

[0135] See the synthesis in 7, where C6a is replaced with C6e.

[0136] A pale yellow oily substance, yield 63%. 1 H NMR (300MHz, CDCl3) δ7.91 (s, 1H), 7.60 (d, J = 8.5Hz, 1H), 7.20 (t, J = 7.8Hz, 1H) ,6.97(d,J=8.5Hz,1H),6.77(d,J=8.2Hz,1H),6.67(d,J=7.5Hz,1H),6.60(s,1 H),4.93(t,J=6.0Hz,1H),3.76(s,3H),3.69(s,3H),3.43(s,2H),3.27–3.11(m ,4H),2.76(t,J=6.5Hz,2H),1.62(d,J=26.0Hz,4H),0.97(s,3H),0.77(s,3H). 13 C NMR (75MHz, CDCl3) δ169.81,159.87,156.45,139.36,133.53,129.77,129.65,128.68,126.37,1 20.96,114.23,112.20,111.98,56.19,55.19,51.04,44.32,35.18,21.97,11.49.ESI:m / z[M+H] + ,calcd.for C 23 H 33 N2O5S + :449.2105; found:449.2106.

[0137] Example 12: Synthesis of Compound 12

[0138] 3-(N-(3-chlorophenylethyl)aminosulfonyl)-4-methoxy-N,N-dipropylbenzamide (12)

[0139] See the synthesis in 7, where C6a is replaced with C6f.

[0140] A pale yellow oily substance, yield 61%. 1 H NMR (300MHz, CDCl3) δ7.90 (d, J=2.0Hz, 1H), 7.59 (dd, J1=8.5, J2=2.0Hz, 1H), 7.25–7.15 (m, 2H), 7.00 (dd, J1=9.1, J2=6.9Hz, 3H), 5.02 (t, J=6. 1Hz,1H),3.75(s,3H),3.41(s,2H),3.13(dd,J1=12.9,J2=6.5Hz,4H),2.74(t,J=6.6Hz,2H),1.59(d,J=23.5Hz,4H),0.94(s,3H),0.74(s,3H). 13 C NMR (75MHz, CDCl3) δ169.77,156.45,139.98,134.39,133.57,130.02,129.72,128.65,127.1 4,127.05,126.99,126.54,112.12,56.30,51.03,44.13,35.02,21.97,11.44.ESI:m / z[M+H] + ,calcd.forC 22 H 30 ClN2O4S + 453.1609; found: 453.1610.

[0141] Example 13: Synthesis of Compound 13

[0142] 3-(N-(2-bromophenyl)aminosulfonyl)-4-methoxy-N,N-dipropylbenzamide (13)

[0143] See the synthesis in 7, where C6a is replaced with C6g.

[0144] A pale yellow oily substance, yield 64%. 1H NMR (300MHz, CDCl3) δ7.71 (d, J=2.0Hz, 1H), 7.39 (dd, J=8.5, 2.0Hz, 1H), 7.29 ( d,J=7.9Hz,1H),7.09–6.95(m,2H),6.93–6.84(m,1H),6.79(d,J=8.6Hz,1H),4. 76(t,J=6.1Hz,1H),3.60(s,3H),3.21(s,2H),2.94(dd,J=13.2,6.7Hz,4H),2.7 2(t,J=6.9Hz,2H),1.39(d,J=25.2Hz,4H),0.75(s,3H),0.58(d,J=22.0Hz,4H). 13 C NMR (75MHz, CDCl3) δ169.77,156.49,137.09,133.58,132.99,131.19,129.77,128.86,128.6 0,127.72,126.51,124.40,112.10,56.38,51.01,42.72,35.87,21.98,11.14.ESI:m / z[M+H] + ,calcd.for C 22 H 30 BrN2O4S + 497.1104; found: 497.1108.

[0145] Example 14: Synthesis of Compound 14

[0146] 3-(N-(3-bromophenyl)aminosulfonyl)-4-methoxy-N,N-dipropylbenzamide (14)

[0147] See the synthesis in 7, where C6a is replaced with C6h.

[0148] A pale yellow oily substance, yield 64%. 1H NMR (300MHz, CDCl3) δ7.71 (d, J=2.0Hz, 1H), 7.39 (dd, J=8.5, 2.0Hz, 1H), 7.29 ( d,J=7.9Hz,1H),7.09–6.95(m,2H),6.93–6.84(m,1H),6.79(d,J=8.6Hz,1H),4. 76(t,J=6.1Hz,1H),3.60(s,3H),3.21(s,2H),2.94(dd,J=13.2,6.7Hz,4H),2.7 2(t,J=6.9Hz,2H),1.39(d,J=25.2Hz,4H),0.75(s,3H),0.58(d,J=22.0Hz,4H). 13 C NMR (75MHz, CDCl3) δ169.77,156.44,140.29,133.58,131.57,130.32,129.95,129.74,128.6 4,127.53,126.53,122.70,112.14,56.35,51.02,44.15,35.00,21.98,11.50.ESI:m / z[M+H] + ,calcd.for C 22 H 30 BrN2O4S + :497.1104; found:497.1103.

[0149] Example 15: Synthesis of Compound 15

[0150] 3-(N-(2-(1H-indol-3-yl)ethyl)aminosulfonyl)-4-methoxy-N,N-dipropylbenzamide (15)

[0151] See the synthesis in 7, where C6a is replaced with C6i.

[0152] A pale yellow oily substance, yield 69%. 1 H NMR (300MHz, CDCl3) δ7.92(s,1H),7.60(d,J=8.5Hz,1H),7.35–7.21(m,3H),7.09(d,J=7.3Hz,2H),6.96(d,J=8.5Hz,1H),4. 91(t,J=5.9Hz,1H),3.66(s,3H),3.50–3.03(m,6H),2.79(t,J=6.5Hz,2H),1.60(d,J=23.3Hz,4H),0.96(s,3H),0.76(s,3H). 13C NMR (75MHz, CDCl3) δ169.77,156.49,137.09,133.58,132.99,131.19,129.77,128.86,128.6 0,127.72,126.51,124.40,112.10,56.38,51.01,42.72,35.87,21.98,11.14.ESI:m / z[M+H] + ,calcd.for C 24 H 31 N3O4S + :458.2108; found:458.2109.

[0153] Example 16: Synthesis of Compound 16

[0154] 4-Methoxy-3-(N-(2-(piperidin-1-yl)ethyl)aminosulfonyl)-N,N-dipropylbenzamide (16)

[0155] See the synthesis in 7, where C6a is replaced with C6j.

[0156] A pale yellow oily substance, yield 60%. 1 H NMR (300MHz, CDCl3) δ7.98(s,1H),7.67(d,J=8.3Hz,1H),7.10(d,J=8.5Hz,1H),4.07(s,3H),3.48(s,2H),3.22(s,2H) ,2.97(t,J=5.6Hz,2H),2.37(dd,J1=13.1,J2=7.6Hz,2H),2.28(s,4H),1.78–1.42(m,10H),1.02(s,3H),0.82(s,3H). 13 C NMR (75MHz, CDCl3) δ169.89,156.79,133.50,129.63,128.90,126.66,112.05, 56.53,56.49,54.02,51.06,39.90,26.01,24.26,21.94,11.48.ESI:m / z[M+H] + ,calcd.forC 21 H 36 N3O4S + :426.2421; found:426.2425.

[0157] Example 17: Synthesis of Compound 17

[0158] 3-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-4-methoxy-N,N-dipropylbenzamide (17)

[0159] See the synthesis in 7, where C6a is replaced with C6k.

[0160] A colorless oily substance with a yield of 68%. 1 H NMR (300MHz, CDCl3) δ7.93(d,J=2.1Hz,1H),7.62(dd,J1=8.5,J2=2.1Hz,1H),7.05(d,J=8.5Hz,1H),4.00(s,3H),3.43(s,2H) ,3.19(s,2H),2.95–2.86(m,2H),2.56(s,2H),2.53(d,J=5.1Hz,4H),1.64(s,2H),1.57(s,10H),0.96(s,3H),0.77(s,3H).13C NMR (75MHz, CDCl3) δ169.92,156.80,133.50,128.89,126.68,125.52,112.07, 56.46,55.50,55.06,51.07,40.88,30.31,28.00,21.97,11.40.ESI:m / z[M+H] + ,calcd.for C 22 H 38 N3O4S + :440.2578; found:440.2579.HPLC:0~16min(A:B=80:20),t R =5.34min, Purity: 97.54%.

[0161] Example 18: Synthesis of Compound 18

[0162] Synthesis of sodium 3-(methoxycarbonyl)benzenesulfonate (C8)

[0163]

[0164] Sodium 3-carboxybenzenesulfonate was dissolved in methanol, and concentrated hydrochloric acid was added. The mixture was heated under reflux for 12 hours. After the reaction was completed, most of the solvent was removed under vacuum, and a white solid precipitated. The solid was filtered, the filter cake was washed with a small amount of ice-cold methanol, and then dried to obtain the final product.

[0165] White solid, yield 94%. Mp 198~200℃. 1H NMR (300MHz, DMSO) δ8.24(t,J=1.5Hz,1H),7.97–7.92(m,1H),7.92–7.87(m,1H),7.53(t,J=7.7Hz,1H),3.90(s,3H).

[0166] Synthesis of methyl 3-(chlorosulfonyl)benzoate (C9)

[0167]

[0168] Sodium 3-(methoxycarbonyl)benzenesulfonate (10 mmol) was placed in a reaction flask, and 10 mL of thionyl chloride was added. The mixture was heated to reflux. After the reaction was complete, the reaction solution was evaporated to dryness. The residue was methyl 3-(chlorosulfonyl)benzoate, which was directly proceeded to the next step without purification.

[0169] 3-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)methyl benzoate (C11)

[0170]

[0171] C10 was placed in a dry reaction flask, and 40 mL of DCM and 1.5 eq of triethylamine were added. C9 (1.2 eq) was dissolved in 10 mL of DCM and added dropwise to the reaction flask under ice bath conditions. After the addition was complete, the mixture was brought to room temperature and stirred for 2 h. The reaction solution was then subjected to direct column chromatography (DCM:MeOH = 100:1).

[0172] A pale yellow oily substance, yield 64.5%. 1 H NMR (300MHz, CDCl3) δ8.54(t,J=1.6Hz,1H),8.26(dd,J1=4.5,J2=3.3Hz,1H),8.09(ddd,J1=7.8,J2=1.8,J3=1.2H z,1H),7.64(dt,J1=7.8,J2=3.9Hz,1H),2.95(d,J=5.9Hz,2H),2.56–2.50(m,2H),2.48–2.42(m,4H),1.54(s,8H).

[0173] 3-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)benzoic acid (C12)

[0174]

[0175] C11 was dissolved in 30 mL of methanol (10 mmol), and LiOH (50 mmol) was added. The mixture was heated at 50 °C for 6 h. After the reaction was completed, most of the solvent was removed under vacuum, and the pH was adjusted to 5 with 2N hydrochloric acid. A white solid precipitated, which was filtered, the filter cake was washed with water, and then dried to obtain the final product.

[0176] White solid, yield 78%. Mp 170~172℃.

[0177] 3-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-N,N-dipropylbenzamide (18)

[0178]

[0179] C12 (0.5 mmol) was dissolved in 10 mL of dichloromethane. EDCI-HCl (1.5 eq), HOBT (1.5 eq), and DIPEA (3 eq) were added under ice bath conditions. After stirring for 30 min, C13a (1.1 eq) was added, and the mixture was transferred to room temperature and reacted overnight. The reaction solution was washed with water, and the aqueous phase was extracted 1–2 times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed under vacuum, and the mixture was subjected to column chromatography (DCM:MeOH = 100:1).

[0180] A pale yellow oily substance, yield 74.1%. 1 H NMR (300MHz, CDCl3) δ7.97–7.92(m,1H),7.90(s,1H),7.65–7.57(m,2H),3.55–3.46(m,2H),3.21–3.13(m,2H),3.02–2.94 (m,2H),2.59–2.53(m,2H),2.50(s,4H),1.74(d,J=6.7Hz,2H),1.58(s,10H),1.03(t,J=7.1Hz,3H),0.79(t,J=7.1Hz,3H). 13 C NMR (75MHz, CDCl3) δ169.82,140.05,138.27,130.65,129.44,127.48,125. 14,55.30,54.91,50.79,40.26,28.06,26.85,21.92,11.46.ESI:m / z[M+H] + ,calcd.for C 21 H 36 N3O3S + :410.2472; found:410.2474.

[0181] Example 19: Synthesis of Compound 19

[0182] 3-(2-(azacyclopropane-1-yl)ethyl)carbamoyl)methyl benzoate (C15)

[0183]

[0184] C14 (0.5 mmol) was dissolved in 10 mL of dichloromethane. EDCI-HCl (1.5 eq), HOBT (1.5 eq), and DIPEA (3 eq) were added under ice bath conditions. After stirring for 30 min, C10 (1.1 eq) was added, and the mixture was transferred to room temperature and reacted overnight. The reaction solution was washed with water, and the aqueous phase was extracted 1–2 times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed under vacuum, and the mixture was subjected to column chromatography (DCM:MeOH = 100:1).

[0185] A colorless oily substance, yield 80%. 1 H NMR (300MHz, CDCl3) δ8.47(t,J=1.5Hz,1H),8.24–8.18(m,1H),8.12–8.08(m,1H),7.58(t,J=7.7Hz,1 H),3.98(s,4H),3.55(dd,J1=10.9,J2=5.7Hz,2H),2.82–2.77(m,2H),2.77–2.72(m,4H),1.69(s,8H).

[0186] 3-(2-(azacyclopropane-1-yl)ethyl)carbamoyl)benzoic acid (C16)

[0187]

[0188] See the synthesis of C12, where C11 is replaced with C15.

[0189] A colorless oily substance with a yield of 72%.

[0190] N 1 -(2-(azacyclopropane-1-yl)ethyl)-N 3 N 3 -Dipropylbenzamide (19)

[0191] See the synthesis in 18, where C12 is replaced with C16.

[0192] A pale yellow oily substance, yield 65%. 1 H NMR (300MHz, CDCl3) δ7.84 (ddd, J1=5.1, J2=3.1, J3=1.7Hz, 1H), 7.78 (s, 1H), 7.47 (dd, J1=3.6, J2=2.0Hz, 2H), 7.29 (s, 1H), 3.51 ( dt,J1=11.7,J2=5.8Hz,4H),3.16(s,2H),2.82–2.66(m,6H),1.76–1.59(m,10H),1.52(d,J=6.3Hz,2H),0.99(s,3H),0.74(s,3H).13 C NMR (75MHz, CDCl3) δ170.93,166.62,137.62,134.88,129.28,128.77,127.59, 125.08,55.92,55.12,50.70,37.20,27.88,26.99,21.87,11.44.ESI:m / z[M+H] + ,calcd.for C 22 H 36 N3O2S + :374.2802; found:374.2804.

[0193] Example 20: Synthesis of Compound 20

[0194] 3-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-N,N-diethylbenzamide (20)

[0195] See the synthesis in 18, where C13a is replaced with C13b.

[0196] A colorless oily substance with a yield of 68%. 1 H NMR (300MHz, CDCl3) δ7.97–7.91(m,2H),7.66–7.57(m,2H),3.59(d,J=6.8Hz,2H),3.26(d,J=6.7Hz,2H),3. 04–2.95(m,2H),2.63–2.55(m,2H),2.52(s,4H),1.58(s,8H),1.30(t,J=6.9Hz,3H),1.16(t,J=6.4Hz,3H). 13 C NMR (75MHz, CDCl3) δ169.35,140.10,138.17,130.44,129.48,127.55,125.02,55.33,54.93,43.46,40.19,27.92,26.85,14.19.ESI:m / z[M+H] + ,calcd.for C 19 H 32 N3O3S + :382.2159; found:382.2159.

[0197] Example 21: Synthesis of Compound 21

[0198] 3-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-N,N-dibutylbenzamide (21)

[0199] See the synthesis in 18, where C13a is replaced with C13c.

[0200] A colorless oily substance with a yield of 75%. 1 H NMR (300MHz, CDCl3) δ7.97–7.91(m,1H),7.90(s,1H),7.62(dd,J1=4.2,J2=1.1Hz,1H),7. 59(dd,J1=6.0,J2=4.6Hz,1H),3.53(t,J=7.2Hz,2H),3.25–3.11(m,2H),3.03–2.94(m,2H) ,2.60–2.53(m,2H),2.50(s,4H),1.76–1.63(m,2H),1.58(s,10H),1.44(dd,J1=14.2,J2=7 .0Hz,2H),1.17(dd,J1=14.2,J2=7.2Hz,2H),1.02(t,J=7.0Hz,3H),0.83(t,J=7.0Hz,3H). 13 C NMR (75MHz, CDCl3) δ169.64,140.03,138.23,130.59,129.39,127.45,125.10, 55.34,54.89,48.87,40.21,30.74,27.95,26.82,20.26,13.90.ESI:m / z[M+H] + ,calcd.for C 23 H 32 N3O3S + :438.2785; found:438.2785.

[0201] Example 22: Synthesis of Compound 22

[0202] 3-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-N,N-diisobutylbenzamide (22)

[0203] See the synthesis in 18, where C13a is replaced with C13d.

[0204] A colorless oily substance with a yield of 68%. 1H NMR (300MHz, CDCl3) δ8.11–8.00(m,1H),7.95(s,1H),7.68(s,1H),7.67(s,1H),3.48(d,J=7.4Hz,2H),3.20–3.12(m,4H) ,2.79(t,J=9.5Hz,6H),2.32–2.14(m,1H),2.03–1.90(m,1H),1.71(s,8H),1.11(d,J=6.3Hz,6H),0.86(d,J=6.4Hz,6H). 13 C NMR (151MHz, CDCl3) δ170.59,140.17,138.47,131.17,129.51,127.56,125 .45,56.58,55.84,55.07,51.35,39.65,26.82,26.60,20.22.ESI:m / z[M+H] + ,calcd.for C 23 H 32 N3O3S + :438.2785; found:438.2786.

[0205] Example 23: Synthesis of Compound 23

[0206] N-(2-(azacyclopropane-1-yl)ethyl)-3-(piperidine-1-carbonyl)benzenesulfonamide (23)

[0207] See the synthesis in 18, where C13a is replaced with C13e.

[0208] A colorless oily substance with a yield of 66%. 1 H NMR (300MHz, CDCl3) δ7.97–7.91(m,2H),7.68–7.57(m,2H),3.75(s,2H),3.35(s,2 H),3.04–2.92(m,2H),2.60–2.54(m,2H),2.50(s,4H),1.73(s,4H),1.57(s,10H). 13 C NMR (75MHz, CDCl3) δ168.31,140.14,137.47,130.91,129.45,125.44,55.34,54.91,48.80,40.25,27.96,26.84,26.44,24.40.ESI:m / z[M+H] + ,calcd.for C 20 H 32 N3O3S +:394.2159; found:394.2160.

[0209] Example 24: Synthesis of Compound 24

[0210] N-(2-(aza-1-yl)ethyl)-3-(4-methylpiperazine-1-carbonyl)benzenesulfonamide (24)

[0211] See the synthesis in 18, where C13a is replaced with C13f.

[0212] A colorless oily substance with a yield of 66%. 1 H NMR (300MHz, CDCl3) δ8.01–7.97(m,1H),7.95(s,1H),7.67–7.59(m,2H),3.85(s,2H),3.45(s,2H),3.13(dd,J1=9.5 ,J2=4.1Hz,2H),2.79(dd,J1=11.4,J2=6.8Hz,6H),2.54(s,2H),2.41(s,2H),2.37(s,3H),1.71(s,4H),1.65(s,4H). 13 C NMR (75MHz, CDCl3) δ168.35,140.29,136.73,131.09,129.64,128.17,125. 63,56.13,55.08,53.71,53.52,45.88,39.18,26.71,25.49.ESI:m / z[M+H] + ,calcd.for C 20 H 33 N4O3S + :409.2268; found:409.2268.

[0213] Example 25: Synthesis of Compound 25

[0214] 3-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-N-benzamide (25)

[0215] See the synthesis in 18, where C13a is replaced with C13g.

[0216] Yellow oily substance, yield 71%. 1H NMR (300MHz, CDCl3) δ8.71(s,1H),8.40(s,1H),8.15(d,J=7.5Hz,1H),7.98(d,J=7.4Hz,1H),7.70(d,J=7.8Hz,2H),7.60(td,J1=7.7,J2= 3.3Hz,1H),7.35(dd,J1=10.0,J2=5.3Hz,2H),7.15(t,J=7.3Hz,1H),5.32–5.18(m,1H),2.97(s,2H),2.51(d,J=13.6Hz,6H),1.52(s,8H). 13 C NMR (75MHz, CDCl3) δ164.35,140.17,137.91,136.21,132.24,129.77,129.64,12 9.00,125.35,124.82,120.72,55.29,54.85,39.99,27.03,26.91.ESI:m / z[M+H] + ,calcd.for C 21 H 28 N3O3S + :402.1846; found:402.1846.

[0217] Example 26: Synthesis of Compound 26

[0218] N-((1H-indol-3-yl)methyl)-3-(N-(2-(azacyclo-1-yl)ethyl)aminosulfonyl)-N-propylbenzamide (26)

[0219] See the synthesis in 18, where C13a is replaced with C13h.

[0220] A pale yellow oily substance, yield 75%. 1 H NMR (300MHz, CDCl3) δ8.31(d,J=23.1Hz,1H),8.03–7.85(m,2H),7.72(d,J=16.3Hz,1H),7.50(dd,J1=30.7,J2=22.6Hz,3H),7.25–7.05(m,2H),4. 78(d,J=104.6Hz,2H),3.49(s,2H),2.99(d,J=38.1Hz,2H),2.44(t,J=19 .3Hz,6H),1.61(d,J=54.8Hz,10H),0.84(d,J=68.9Hz,3H).ESI:m / z[M+H] + ,calcd.forC 27 H 37N4O3S + :497.2581; found:497.2581.

[0221] Example 27: Synthesis of Compound 27

[0222] 3-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-N-(naphth-2-ylmethyl)-N-propylbenzamide (27)

[0223] See the synthesis in 18, where C13a is replaced with C13i.

[0224] A pale yellow oily substance, with a yield of 78%. 1 H NMR (300MHz, CDCl3) δ8.04–7.75(m,6H),7.65(d,J=11.7Hz,2H),7.56–7.48(m,3H),7.28(s,1H),4.80(d,J=95.3Hz,2H ),3.33(d,J=123.2Hz,2H),2.90(d,J=45.2Hz,2H),2.62–2.35(m,6H),1.64(d,J=59.4Hz,10H),0.86(d,J=71.1Hz,3H). 13 C NMR (75MHz, CDCl3) δ170.30,140.28,137.81,134.47,133.81,133.32,132.85,130.71,130.44,129.51,128.79,127.80, 127.75,127.07,126.06,125.33,124.41,55.24,54.88,52.75,47.70,40.25,28.09,26.86,21.52,11.45.ESI:m / z[M+H] + ,calcd.forC 29 H 38 N3O3S + :508.2628; found:508.2630.

[0225] Example 28: Synthesis of Compound 28

[0226] 3-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-N-(naphth-1-ylmethyl)-N-propylbenzamide (28)

[0227] See the synthesis in 18, where C13a is replaced with C13j.

[0228] A pale yellow oily substance, yield 71%. 1H NMR(300MHz, CDCl3)δ8.15(s,1H),7.99–7.81(m,4H),7.58(dd,J1=32.6,J2=16.2Hz,6H),5.11(d,J=105.4Hz,2H) ,2.98(s,2H),2.52(d,J=19.0Hz,4H),2.31(s,2H),1.66(d,J=62.8Hz,10H),0.84(d,J=88.8Hz,3H).ESI:m / z[M+H] + ,calcd.for C 29 H 38 N3O3S + :508.2628; found:508.2627.

[0229] Example 29: Synthesis of Compound 29

[0230] 3-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-N-benzyl-N-propylbenzamide (29)

[0231] See the synthesis in 18, where C13a is replaced with C13k.

[0232] A pale yellow oily substance, yield 70%. 1 H NMR (300MHz, CDCl3) δ7.92 (s, 2H), 7.57 (d, J = 24.0Hz, 2H), 7.35 (s, 4H), 7.14 (s, 1H), 3.08 (s, 2H), 2.90(d,J=25.4Hz,2H),2.45(s,6H),1.60(d,J=42.8Hz,10H),1.26(s,2H),0.84(d,J=70.3Hz,3H). 13 CNMR(75MHz, CDCl3)δ170.21,140.21,137.78,136.91,136.32,130.69,129.49,128.93,128.09,127.75,12 7.63,126.61,125.29,55.26,54.90,52.56,49.92,47.49,40.26,28.08,26.85,21.46,11.41.ESI:m / z[M+H] + ,calcd.for C 25 H 36 N3O3S + :458.2472; found:458.2471.

[0233] Example 30: Synthesis of Compound 30

[0234] 3-(chlorosulfonyl)-4-methylbenzoic acid (C18a)

[0235]

[0236] In a dry reaction flask, chlorosulfonic acid (5 eq) was added, followed by the addition of C17a under ice bath conditions. The mixture was then heated to 80°C for 8 hours. After the reaction was complete, the reaction solution was poured into ice water, and a solid precipitated. The solid was filtered, the filter cake was washed with water, and then dried to obtain the final product.

[0237] White solid, yield 78%. Mp 173~175℃. 1 H NMR (300MHz, DMSO) δ12.42(s,1H),8.34(d,J=1.8Hz,1H),7.79(dd,J=7.8,1.9Hz,1H),7.28(d,J=7.9Hz,1H),2.60(s,3H).

[0238] methyl 3-(chlorosulfonyl)-4-methylbenzoate (C19a)

[0239]

[0240] C18a (8 mmol) was placed in a dry reaction flask, and 8 mL of thionyl chloride was added. The mixture was heated under reflux for 6 h. The reaction solution was removed under vacuum, and the residue was dissolved in dry dichloromethane and slowly added to cold methanol in an ice bath. The mixture was stirred for another 0.5 h under these conditions, and then stirred at room temperature for about 1 h. After the reaction was complete, the solvent was removed under vacuum at a temperature not exceeding 40 °C, and the mixture was subjected to column chromatography (PE:EA = 10:1).

[0241] White solid, yield 68%. Mp 113~115℃. 1 H NMR (300MHz, CDCl3) δ8.73(d,J=1.7Hz,1H),8.28(dd,J1=7.9,J2=1.7Hz,1H),7.55(d,J=8.0Hz,1H),3.99(s,3H),2.87(s,3H).

[0242] 3-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-4-methylbenzoate (C20a)

[0243]

[0244] C10 was placed in a dry reaction flask, and 40 mL of DCM and 1.5 eq of triethylamine were added. C19a (1.2 eq) was dissolved in 10 mL of DCM and added dropwise to the reaction flask under ice bath conditions. After the addition was complete, the mixture was moved to room temperature and stirred for 2 h. The reaction solution was then subjected to direct column chromatography (DCM:MeOH = 100:1).

[0245] A pale yellow oily substance, yield 80%. 1 H NMR (300MHz, CDCl3) δ8.63(d,J=1.6Hz,1H),8.14–8.02(m,1H),7.43(d,J=7.9Hz,1H ),3.95(s,3H),3.02–2.92(m,2H),2.75(s,3H),2.51(t,J=5.4Hz,6H),1.58(s,8H).

[0246] 3-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-4-methylbenzoic acid (C21a)

[0247]

[0248] See the synthesis of C12, where C20a is replaced with C11.

[0249] Pale yellow solid, yield 90%. Mp 167~170℃.

[0250] 3-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-4-methyl-N,N-dipropylbenzamide (30)

[0251]

[0252] See the synthesis in 18, where C12 is changed to C21a.

[0253] A pale yellow oily substance, with a yield of 74%. 1 H NMR (300MHz, CDCl3) δ7.98(s,1H),7.48(d,J=6.2Hz,1H),7.36(d,J=6.9Hz,1H),3.44(s,2H),3.14( s,2H),2.90(s,2H),2.69(s,3H),2.49(s,6H),1.68(s,2H),1.56(s,12H),0.97(s,3H),0.75(s,3H). 13C NMR (75MHz, CDCl3) δ169.96,137.92,137.71,135.26,132.71,130.85,127.55, 55.52,55.10,50.83,40.21,27.97,26.80,21.91,20.16,11.44.ESI:m / z[M+H] + ,calcd.for C 22 H 38 N3O3S + :424.2628; found:424.2628.HPLC:0~16min(A:B=80:20),t R =4.253 min, Purity: 98.92%.

[0254] Example 31: Synthesis of Compound 31

[0255] 3-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-4-fluoro-N,N-dipropylbenzamide (31)

[0256] See the synthesis in 18, where C12 is changed to C21b.

[0257] A pale yellow oily substance, with a yield of 78%. 1 H NMR (300MHz, CDCl3) δ7.92 (dd, J1=6.7, J2=2.1Hz, 1H), 7.63 (ddd, J1=8.3, J2=4.7, J3=2.2Hz, 1H), 7.27 (dd, J1=9.5, J2=8.6Hz, 1H) ,3.46(s,2H),3.16(s,2H),3.03–2.96(m,2H),2.60–2.54(m,2H),2.52(s,4H),1.64(d,J=30.3Hz,12H),1.00(s,3H),0.79(s,3H). 13 C NMR (75MHz, CDCl3) δ169.02,157.22,133.90,133.55,128.74,127.87,117. 41,55.49,55.10,50.92,40.51,28.16,26.78,21.94,11.45.ESI:m / z[M+H] + ,calcd.for C 21 H 35 FN3O3S + :428.2378; found:428.2382.

[0258] Example 32: Synthesis of Compound 32

[0259] 3-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-4-chloro-N,N-dipropylbenzamide (32)

[0260] See the synthesis in 18, where C12 is changed to C21c.

[0261] A pale yellow oily substance, yield 71%. 1 H NMR(300MHz, CDCl3)δ8.08(s,1H),7.65–7.47(m,2H),3.44(s,2H),3.13(s,2H),2. 96–2.86(m,2H),2.51(s,6H),1.68(s,2H),1.57(s,10H),0.98(s,3H),0.77(s,3H). 13 C NMR (75MHz, CDCl3) δ168.95,137.11,136.39,132.17,131.90,131.87,129. 24,55.60,55.19,50.86,40.63,28.10,26.81,21.93,11.44.ESI:m / z[M+H] + ,calcd.for C 21 H 35 ClN3O3S + :444.2082; found:444.2082.

[0262] Example 33: Synthesis of Compound 33

[0263] 3-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-4-bromo-N,N-dipropylbenzamide (33)

[0264] See the synthesis in 18, where C12 is changed to C21d.

[0265] A pale yellow oily substance, with a yield of 78%. 1 H NMR (300MHz, CDCl3) δ8.28(s,1H),7.95(d,J=8.0Hz,1H),7.60(d,J=8.1Hz,1H),3.62(s,2H),3.30 (s,2H),3.08(d,J=4.5Hz,2H),2.69(s,6H),1.85(s,2H),1.75(s,10H),1.15(s,3H),0.94(s,3H). 13C NMR (75MHz, CDCl3) δ168.99,138.82,137.00,135.39,131.79,129.40,120.5 0,55.60,55.22,50.85,40.64,28.11,26.86,21.94,11.46.ESI:m / z[M+2+H] + ,calcd.for C 21 H 35 BrN3O3S + :490.1575; found:490.1575.

[0266] Example 34: Synthesis of Compound 34

[0267] 3-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-4-ethyl-N,N-dipropylbenzamide (34)

[0268] See the synthesis in 18, where C12 is changed to C21e.

[0269] A pale yellow oily substance, yield 70%. 1 H NMR (300MHz, CDCl3) δ8.00(d,J=1.6Hz,1H),7.57(dd,J1=7.9,J2=1.7Hz,1H),7.46(d,J=7.9Hz,1H),3.47(s,2H),3.18(s,2H),3. 10(q,J=7.5Hz,2H),2.97–2.90(m,2H),2.53(t,6H),1.71(s,2H),1.59(s,10H),1.38(d,J=7.4Hz,3H),1.01(s,3H),0.79(s,3H). 13 C NMR (75MHz, CDCl3) δ170.04,144.00,137.33,135.03,131.07,130.67,127.62,55.5 4,55.08,50.85,40.27,29.67,28.07,25.74,21.93,14.78,11.47.ESI:m / z[M+2+H] + ,calcd.for C 23 H 40 N3O3S + :438.2786; found:438.2786.

[0270] Example 35: Synthesis of Compound 35

[0271] 7-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-N,N-dipropyl-2,3-dihydrobenzo[b][1,4]dioxin-5-carboxamide (35)

[0272] See the synthesis in 18, where C12 is changed to C21f.

[0273] A pale yellow oily substance, yield 79%. 1 H NMR (300MHz, CDCl3) δ7.38(d,J=2.2Hz,1H),7.29(d,J=2.2Hz,1H),4.31(s,4H),3.53–3.41(m,2H),3.07(s,2H),2.92(t,J=5.7Hz,2H), 2.54(d,J=5.9Hz,2H),2.49(s,4H),1.68(dd,J1=15.0,J2=7.5Hz,2H),1.58–1.46(m,10H),0.97(t,J=7.4Hz,3H),0.76(t,J=7.4Hz,3H). 13 C NMR (75MHz, CDCl3) δ166.52,143.80,143.17,132.30,127.25,118.89,116.56,64. 67,64.08,55.34,54.94,50.28,40.24,28.15,26.85,21.66,11.36.ESI:m / z[M+H] + ,calcd.for C 23 H 38 N3O4S + :468.2527; found:468.2531.

[0274] Example 36: Synthesis of Compound 36

[0275] 3-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-4,5-dimethyl-N,N-dipropylbenzamide (36)

[0276] See the synthesis in section 18, where C12 is replaced with C21g.

[0277] A pale yellow oily substance, yield 70%. 1H NMR (300MHz, CDCl3) δ7.87(s,1H),7.40(s,1H),3.44(s,2H),3.15(s,2H),2.94–2.85(m,2H),2.59(s,3 H),2.49(t,J=5.3Hz,6H),2.37(s,3H),1.69(d,J=6.5Hz,2H),1.57(s,10H),0.98(s,3H),0.76(s,3H). 13 C NMR (75MHz, CDCl3) δ168.48,141.26,136.08,134.36,133.20,131.16,128.83,55. 64,55.20,50.29,40.57,28.14,26.81,21.72,20.65,18.93,11.50.ESI:m / z[M+H] + ,calcd.for C 23 H 40 N3O3S + :438.2785; found:438.2789.

[0278] Example 37: Synthesis of Compound 37

[0279] 5-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-4-chloro-2-methyl-N,N-dipropylbenzamide (37)

[0280] See the synthesis in 18, where C12 is changed to C21h.

[0281] A pale yellow oily substance, yield 66%. 1 H NMR (300MHz, CDCl3) δ7.89(s,1H),7.39(s,1H),3.47(s,2H),3.06–2.95(m,2H),2.91(s,1H),2.53(s,6H),2.35(s,3 H),1.79–1.65(m,2H),1.58(s,8H),1.48(dt,J1=15.0,J2=7.5Hz,2H),0.99(t,J=7.4Hz,3H),0.75(t,J=7.4Hz,3H). 13 C NMR (75MHz, CDCl3) δ168.54,141.14,136.71,136.64,136.09,128.99,119.55, 55.67,55.25,50.30,40.57,28.11,26.86,21.74,18.82,11.52.ESI:m / z[M+H] +,calcd.forC 22 H 37 ClN3O3S + :458.2239; found:458.2239.

[0282] Example 38: Synthesis of Compound 38

[0283] 5-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-4-bromo-2-methyl-N,N-dipropylbenzamide (38)

[0284] See the synthesis in 18, where C12 is changed to C21i.

[0285] A pale yellow oily substance, yield 67%. 1 H NMR(300MHz, CDCl3)δ7.98(s,1H),7.66(s,1H),3.52(s,2H),3.11–3.01(m,2H),2.94(s,2H),2.58(s,6H),2.40(s,3H),1.7 7(dt,J1=15.0,J2=7.6Hz,2H),1.64(s,8H),1.53(dt,J1=14.7,J2=7.4Hz,2H),1.05(t,J=7.3Hz,3H),0.80(t,J=7.4Hz,3H). 13 C NMR (75MHz, CDCl3) δ168.54,141.14,136.71,136.64,136.09,128.99,119.55,5 5.67,55.25,50.30,40.57,28.11,26.86,21.74,18.82,11.52.ESI:m / z[M+2+H] + ,calcd.for C 22 H 37 BrN3O3S + :504.1734; found:504.1733.

[0286] Example 39: Synthesis of Compound 39

[0287] 5-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-2-methyl-N,N-dipropylbenzamide (39)

[0288] See the synthesis in 18, where C12 is changed to C21j.

[0289] A pale yellow oily substance, yield 60%. 1H NMR (300MHz, CDCl3) δ7.81(d,J=7.9Hz,1H),7.72(s,1H),7.42(d,J=8.1Hz,1H),3.53(s,2H),3.10–2.98(m,4H),2.67–2.55(m,6 H),2.42(s,3H),1.84–1.69(m,2H),1.62(s,8H),1.52(dt,J1=13.4,J2=6.8Hz,2H),1.05(t,J=7.4Hz,3H),0.79(t,J=7.4Hz,3H). 13 C NMR (75MHz, CDCl3) δ169.33,139.49,137.79,137.30,131.22,126.98,124.69, 55.59,54.96,50.18,39.95,27.44,26.82,21.67,19.13,11.53.ESI:m / z[M+H] + ,calcd.for C 22 H 38 N3O3S + :424.2628; found:424.2625.

[0290] Example 40: Synthesis of Compound 40

[0291] 5-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-2-methoxy-N,N-dipropylbenzamide (40)

[0292] See the synthesis in 18, where C12 is replaced with C21k.

[0293] A pale yellow oily substance, yield 60%. 1 H NMR (300MHz, CDCl3) δ7.86 (dd, J1=8.7, J2=1.9Hz, 1H), 7.70 (d, J=1.9Hz, 1H), 7.00(d,J=8.8Hz,1H),3.89(s,3H),3.47(d,J=25.6Hz,2H),3.01(d,J=5.2Hz, 2H),2.92(t,J=5.6Hz,2H),2.56–2.51(m,2H),2.48(s,4H),1.76–1.62(m,2H) ,1.55(s,8H),1.52–1.40(m,2H),0.98(t,J=7.4Hz,3H),0.73(t,J=7.4Hz,3H). 13CNMR (75MHz, CDCl3) δ167.24,158.30,131.64,129.50,127.47,127.01,111.04 ,56.00,55.35,54.88,50.13,40.21,28.04,26.84,21.59,11.29.ESI:m / z[M+H] + ,calcd.forC 22 H 38 N3O4S + :440.2578; found:440.2580.

[0294] Example 41: Synthesis of Compound 41

[0295] 5-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-2-chloro-N,N-dipropylbenzamide (41)

[0296] See the synthesis in 18, where C12 is changed to C21l.

[0297] A pale yellow oily substance, yield 57%. 1 H NMR (300MHz, CDCl3) δ7.84(dd,J1=8.4,J2=2.2Hz,1H),7.80(d,J=2.0Hz,1H),7.57(d,J=8.4Hz,1H),3.76–3.61(m,1H),3.38–3.22(m,1H),3.12 –2.93(m,4H),2.64(dd,J1=10.4,J2=4.8Hz,6H),1.74(dq,J1=15.5,J2=7.6Hz,2H),1.60(s,10H),1.02(t,J=7.4Hz,3H),0.77(t,J=7.4Hz,3H). 13 C NMR (75MHz, CDCl3) δ166.48,139.00,137.51,134.92,130.55,128.22,126. 67,55.56,54.99,50.16,39.95,27.34,26.85,20.47,11.16.ESI:m / z[M+H] + ,calcd.for C 21 H 35 ClN3O3S + :444.2082; found:444.2083.

[0298] Example 42: Synthesis of Compound 42

[0299] 3-(N-(2-(azacyclopropane-1-yl)ethyl)aminosulfonyl)-4-methyl-N-(naphth-2-ylmethyl)-N-propylbenzamide (42)

[0300] See the synthesis in 18, where C12 is changed to C13i.

[0301] A pale yellow oily substance, yield 57%. 1 H NMR (300MHz, CDCl3) δ8.19 (s, 0.5H), 8.10 (s, 1H), 7.92 (dd, J1=20.4, J2=7.6 6.4Hz,2H),7.73–7.47(m,6H),7.41(s,0.5H),5.14(d,J=103.6Hz,2H),3.70–2.91(m,4H),2.74(s,3H ),2.55(s,3H),2.36(t,J=37.0Hz,4H),1.71(d,J=58.0Hz,10H),0.87(d,J=85.7Hz,3H).ESI:m / z[M+H] + ,calcd.for C 30 H 40 N3O3S + :522.2785; found:522.2787.

[0302] Example 43: Synthesis of Compound 43

[0303] tert-Butyl (2-(aza-1-yl)-2-oxoethyl)carbamate (C23)

[0304]

[0305] N-Boc-glycine (5 mmol) was dissolved in 20 mL of DCM. EDCI-HCl (1.5 eq), HOBT (1.5 eq), and DIEA (3 eq) were added under ice bath conditions. After stirring for 0.5 h, C22 was added, and the reaction was allowed to proceed to room temperature for 4 h. Column chromatography (PE:EA = 5:1) yielded a colorless oily substance, 65% yield.

[0306] 2-Amino-1-(aza-1-yl)ethane-1-one (C24)

[0307]

[0308] C23 was dissolved in 5 mL of TFA and stirred at room temperature for 8 hours. After the reaction was complete, the TFA was removed directly under vacuum for use in the next step.

[0309] 4-Methyl-N,N-dipropylbenzamide (C25)

[0310]

[0311] C14a (5 mmol) was dissolved in 20 mL of DCM, and EDCI-HCl (1.5 eq), HOBT (1.5 eq), and DIEA (3 eq) were added under ice bath conditions. After dissolution, dipropylamine was added, and the mixture was allowed to react at room temperature for 2 h. Column chromatography (PE:EA = 20:1) was performed. A colorless oily substance was obtained, with a yield of 85%.

[0312] 5-(dipropylcarbamoyl)-2-toluenesulfonyl chloride (C26)

[0313]

[0314] Chlorosulfonic acid (5 eq) was placed in a dry reaction flask, and C25 was added under ice bath conditions, followed by heating at 100°C for 8 hours. After the reaction was complete, the reaction solution was immersed in ice water and stirred vigorously. Extraction was performed three times with DCM, and the solution was dried over anhydrous sodium sulfate. Column chromatography (PE:EA = 5:1) yielded a brown oily substance with a yield of 76%.

[0315] 3-(N-(2-(azacyclopropane-1-yl)-2-oxoethyl)aminosulfonyl)-4-methyl-N,N-dipropylbenzamide (43)

[0316]

[0317] C26 was placed in a dry reaction flask, and 5 mL of DCM and 2.5 eq of triethylamine were added. C21a (1.2 eq) was dissolved in 5 mL of DCM and added dropwise to the reaction flask under ice bath conditions. After the addition was complete, the mixture was moved to room temperature and stirred for 2 h. The reaction solution was then subjected to direct column chromatography (DCM:MeOH = 100:1).

[0318] A colorless oily substance with a yield of 68%. 1 H NMR (300MHz, CDCl3) δ7.97(s,1H),7.49–7.43(m,1H),7.36(d,J=7.8Hz,1H),5.95(t,J=3.7Hz,1H),3.70(d,J=4.0Hz,2H),3.49–3.40(m,4H) ,3.25–3.19(m,2H),3.18–3.08(m,2H),2.73(s,3H),1.68(t,J=10.7Hz,6H),1.56–1.45(m,6H),0.98(t,J=6.9Hz,3H),0.76(t,J=6.8Hz,3H). 13C NMR (75MHz, CDCl3) δ169.99,166.05,138.61,137.08,135.24,132.97,130.97, 127.60,50.81,46.61,43.49,28.55,27.22,21.92,20.09,11.48.ESI:m / z[M+H] + ,calcd.for C 21 H 35 ClN3O3S + :438.2421; found:438.2424.

[0319] Example 44: Synthesis of Compound 44

[0320] 3-(N-(1-hydroxypropane-2-yl)aminosulfonyl)-4-methyl-N,N-dipropylbenzamide (C28a)

[0321]

[0322] C23 was placed in a dry reaction flask, and 5 mL of DCM, triethylamine (3 eq), and p-dimethylaminopyridine (0.2 eq) were added. C24a (1.1 eq) was dissolved in 5 mL of DCM and added dropwise to the reaction flask under ice bath conditions. After the addition was complete, the mixture was moved to room temperature and stirred for 2 h. The reaction solution was then subjected to direct column chromatography (PE:EA = 5:1, then EA). Chiral C25a was prepared using the corresponding chiral starting material C24a.

[0323] A pale yellow oily substance, with a yield of 85%. 1 H NMR (300MHz, CDCl3) δ8.00 (d, J=1.4Hz, 1H), 7.46 (dd, J1=7.7Hz, J2=1.5Hz, 1H), 7.3 6(d,J=7.8Hz,1H),5.32(d,J=6.9Hz,1H),3.52–3.39(m,3H),3.36–3.27(m,2H),3.21 –3.06(m,2H),2.77(s,1H),2.68(s,3H),1.69(dd,J=14.6,7.2Hz,2H),1.54(dd,J=1 4.1,7.1Hz,2H),1.07(d,J=6.3Hz,2H),0.97(d,J=7.0Hz,3H),0.75(t,J=7.0Hz,3H).

[0324] 3-(N-(1-bromopropan-2-yl)aminosulfonyl)-4-methyl-N,N-dipropylbenzamide (C29a)

[0325]

[0326] C25a was placed in a reaction flask, anhydrous DCM was added, and carbon tetrabromide (1.25 eq) and triphenylphosphine (1.5 eq) were added under ice bath conditions. The mixture was stirred at room temperature for 4 hours. After washing with water and drying with anhydrous sodium sulfate, column chromatography was performed (PE:EA = 5:1, then PE:EA = 2:1). A yellow oily substance was obtained, with a yield of 80%–85%.

[0327] 3-(N-(1-(azacyclopropan-1-yl)propan-2-yl)aminosulfonyl)-4-methyl-N,N-dipropylbenzamide (44)

[0328]

[0329] C19 was dissolved in 10 mL of acetonitrile, and sodium carbonate (1.5 eq) and C26a (1 eq) were added. The mixture was heated to 50 °C and reacted for 4 h. The insoluble matter was removed by filtration, and the solvent was removed from the filtrate under vacuum. The filtrate was then subjected to column chromatography (DCM:MeOH = 100:1).

[0330] A pale yellow oily substance, yield 82%. 1 H NMR (300MHz, CDCl3) δ8.02 (d, J=1.5Hz, 1H), 7.50 (dd, J1=7.7Hz, J2=1.6Hz, 1H), 7.3 7(d,J=7.8Hz,1H),3.47(d,J=6.5Hz,2H),3.22–3.13(m,2H),3.13–3.05(m,1H),2.7 3(s,3H),2.58–2.41(m,5H),2.29–2.19(m,1H),1.71(dd,J1=14.5Hz,J2=7.1Hz,2H) ,1.56(s,10H),1.07(d,J=6.2Hz,3H),1.00(t,J=6.9Hz,3H),0.77(t,J=6.8Hz,3H). 13 C NMR (75MHz, CDCl3) δ170.02,138.22,138.19,135.26,132.70,130.93,127.53,62. 50,55.45,50.87,46.99,27.52,26.99,21.96,20.50,19.13,11.49.ESI:m / z[M+H] + ,calcd.for C 23 H 40 N3O3S + :438.2785; found:438.2790.

[0331] (R)-3-(N-(1-(azacyclopropan-1-yl)propan-2-yl)aminosulfonyl)-4-methyl-N,N-dipropylbenzamide (44R)

[0332] See the synthesis in section 44, where C28a is changed to C28aR.

[0333] A pale yellow oily substance, with a yield of 78%. 1 H NMR (300MHz, CDCl3) δ8.02(s,1H),7.50(d,J=7.7Hz,1H),7.37(d,J=7.8Hz,1H),3.46(s,2H),3.21–3.13(m,2H),3.12–3.04(m,1H),2.73(s,3H) ),2.73(s,3H),2.56(s,1H),2.55–2.42(m,4H),2.29–2.16(m,1H),1.70 (s,2H),1.56(s,10H),1.07(d,J=6.1Hz,3H),1.00(s,3H),0.77(s,3H). 13 C NMR (75MHz, CDCl3) δ170.01,138.22,138.18,135.25,132.70,130.92,127.53,62. 50,55.45,50.87,47.00,27.52,26.99,21.95,20.49,19.13,11.48.ESI:m / z[M+H] + ,calcd.for C 23 H 40 N3O3S + :438.2785; found:438.2786.HPLC:0~16min(A:B=80:20),t R =6.000min, Purity: 98.57%.

[0334] (S)-3-(N-(1-(azacyclopropan-1-yl)propan-2-yl)aminosulfonyl)-4-methyl-N,N-dipropylbenzamide (44S)

[0335] See the synthesis in section 44, where C28a is replaced with C28aS.

[0336] A pale yellow oily substance, yield 75%. 1H NMR (300MHz, CDCl3) δ8.02(d,J=1.5Hz,1H),7.50(dd,J1=7.7Hz,J2=1.6Hz,1H),7.37(d,J=7.8Hz,1H), 3.47(d,J=6.5Hz,2H),3.15(d,J=7.2Hz,2H),3.09(dd,J1=11.5Hz,J2=5.3Hz,1H),2.73(s,3H),2.55(d, J=12.0Hz, 1H), 2.47 (dd, J1=15.2Hz, J2=11.1Hz, 4H), 2.28–2.16 (m, 1H), 1.71 (dd, J1=14.5Hz, J2=7.1H z,2H),1.56(s,10H),1.07(d,J=6.2Hz,3H),1.00(t,J=6.9Hz,3H),0.77(t,J=6.8Hz,3H).ESI:m / z[M+H] + ,calcd.for C 23 H 40 N3O3S + :438.2785; found:438.2782.

[0337] Example 45: Synthesis of Compound 45

[0338] 3-(N-(1-(azacyclopropan-1-yl)butan-2-yl)aminosulfonyl)-4-methyl-N,N-dipropylbenzamide (45)

[0339] See the synthesis in section 44, where C28a is changed to C28b.

[0340] A pale yellow oily substance, yield 75%. 1 H NMR (300MHz, CDCl3) δ8.02 (d, J=1.4Hz, 1H), 7.50 (dd, J1=7.7Hz, J2=1.5Hz, 1H), 7.37 (d,J=7.8Hz,1H),3.47(s,2H),3.17(s,2H),3.13–3.03(m,1H),2.74(s,3H),2.55(d,J =4.5Hz,1H),2.49(dd,J1=15.7Hz,J2=8.9Hz,4H),2.31(dd,J1=12.7Hz,J2=10.1Hz,1 H),1.70(s,2H),1.57(s,10H),1.55–1.42(m,2H),1.00(s,3H),0.77(t,J=7.4Hz,6H). 13C NMR (75MHz, CDCl3) δ170.03,138.41,138.25,135.21,132.66,130.88,127.41,59.45 ,55.62,52.29,50.86,27.63,27.01,25.53,21.95,20.51,11.47,8.66.ESI:m / z[M+H] + ,calcd.for C 24 H 42 N3O3S + :452.2941; found:452.2938.

[0341] Example 46: Synthesis of Compound 46

[0342] 3-(N-(3-(azacyclopropane-1-yl)propyl)aminosulfonyl)-4-methyl-N,N-dipropylbenzamide (46)

[0343] See the synthesis in section 44, where C28a is changed to C28c.

[0344] A pale yellow oily substance, yield 70%. 1 H NMR(300MHz, CDCl3)δ7.95(s,1H),7.46(d,J=7.7Hz,1H),7.34(d,J=7.8Hz,1H),3.44(s,2H),3.15(s,2H),3.08–2 .98(m,2H),2.69(s,3H),2.68–2.63(m,4H),2.61(d,J=5.5Hz,2H),1.78–1.51(m,14H),0.98(s,3H),0.76(s,3H). 13 CNMR (75MHz, CDCl3) δ170.18,138.13,138.12,135.20,132.65,130.51,127.45,58 .62,56.03,50.84,44.12,27.50,26.61,24.63,21.94,20.16,11.48.ESI:m / z[M+H] + ,calcd.forC 23 H 40 N3O3S + :438.2785; found:438.2786.

[0345] Example 47: Determination of cholinesterase inhibitory activity

[0346] Drugs and reagents: The compounds obtained in Examples 6-18, AChE (EC3.1.1.7, Type VI-S, selected from electric eel), BuChE (EC3.1.1.8, selected from horse serum), 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), acetylthiocholine (ATC) iodide and butyrylthiocholine (BTC) iodide were purchased from Sigma-Aldrich; tacrine was synthesized in our laboratory (purity > 95%).

[0347] Instrument: THERMO Varioskan Flash full-wavelength multi-functional microplate reader.

[0348] Experimental methods:

[0349] (1) Preparation of buffer solution: Dissolve 13.6g of potassium dihydrogen phosphate in 1L of water, and adjust the pH to 8±0.1 with potassium hydroxide. Store the solution at 4℃ for later use.

[0350] (2) Preparation of 0.01M DTNB solution: Dissolve 0.396g DTNB and 0.15g sodium bicarbonate in 100mL of water to prepare 0.01M DTNB solution, store at -20℃ for later use.

[0351] (3) Preparation of 0.075M ATC and BTC solution: Dissolve 0.217g ATC in 10mL of water to prepare 0.075M ATC and BTC solution, store at -20℃ for later use; Dissolve 0.237g BTC in 10mL of water to prepare 0.075M BTC solution, store at -20℃ for later use.

[0352] (4) Preparation of AChE and BChE solutions: Dissolve 5000 units of AChE in 1 mL of 1% gel solution, then dilute with water to 100 mL to obtain an AChE solution with a concentration of 5 units / mL. Store at -20℃ for later use. Dissolve 5000 units of BChE in 1 mL of 1% gel solution, then dilute with water to 100 mL to obtain a BChE solution with a concentration of 5 units / mL. Store at -30℃ for later use.

[0353] (5) Preparation of test solution: Dissolve the test compound in ethanol to prepare a solution with a concentration of 10. -3 A solution of M (ethanol does not affect the test results) was then diluted with water to obtain solutions with concentrations of 10. -4 10 -5 10 -6 10 -7 10 -8 10 -9 A solution of M.

[0354] Before the experiment, all solutions were warmed to room temperature, and the AChE and BChE solutions were diluted with water by half to prepare enzyme solutions with a concentration of 2.5 units / mL. Background UV absorbance was measured using a blank buffer (3 mL). 100 μL of the test compound solution, 100 μL of DTNB solution, and 100 μL of enzyme solution were added to 3 mL of buffer. After adding 20 μL of ATC or BTC solution to trigger the reaction, timing was immediately started, and the test solution was rapidly mixed. UV absorbance was measured at 412 nM after 2 min. An equal volume of water was used instead of the test compound solution for the blank control group. All tests were performed in triplicate. Using the UV absorbance of the blank control group as 100%, the absorbance (OD value) of the test compound at each concentration was recorded. The results were analyzed using a GraphPad Prism. TM The software (GraphPad Software, San Diego, CA, USA) calculates the corresponding IC using a non-linear regression analysis model. 50 The values ​​are shown in Table 1.

[0355] Table 1. Cholinesterase inhibitory activity of the compounds

[0356]

[0357]

[0358] NA: no active.

[0359] Results Analysis: The compounds of this invention exhibit a wide range of activity distributions. Among them, the inhibitory activity against eqBChE ranges from 0.003±0.0008 μM to NA, and the inhibitory activity against eeAChE ranges from 0.032±0.008 μM to NA. The inhibitory activity against hBChE of some preferred compounds was tested, with compound 44R showing the best inhibitory activity at 0.005±0.001 μM. Meanwhile, its inhibitory activity against hAChE was only 0.11±0.06 μM, and the selectivity coefficient reached 22.

[0360] Example 48: In vitro blood-brain barrier penetration test

[0361] Medicines and reagents:

[0362] Results Analysis: Compounds 30, 32, 33, 34, 44R, 44S, and 44RS were selected for in vitro blood-brain barrier penetration experiments using the PAMPA-BBB model. Six positive control drugs were used for validation, and the permeability of the compounds is shown in Table 4. Pe(×10) 6The result (cm / s) > 5.0936 indicates that the compound has good BBB permeability, and it can be seen that all the tested compounds have good BBB permeability.

[0363] Table 2. Permeability (Pe×10⁻¹⁰) in PAMPA-BBB analysis 6 cm / s)

[0364] Compound <![CDATA[BibLvalue a ]]> Experimental value <![CDATA[CNSpenetration classification b ]]> Hydrocortisone 1.9 3.09 CNS+ / - Piroxicam 2.5 2.55 CNS+ / - Chlorpromazine 6.5 9.24 CNS+ progesterone 9.3 9.99 CNS+ β-Estradiol 12 13.83 CNS+ Verapamil 13.2 13.76 CNS+ 30 / 8.2 CNS+ 32 / 8.8 CNS+ 33 / 9.4 CNS+ 34 / 6.9 CNS+ 44RS / 7.5 CNS+ 44R / 9.9 CNS+ 45 / 7.1 CNS+

[0365] a Values ​​are expressed as the mean±SD of three independent experiments.

[0366] b Ranges of permeability of PAMPA-BBB assays(Pe×10 -6 (cm / s).

[0367] Compounds of high BBB permeation(CNS+)Pe(×10 6 cm / s)>5.0936

[0368] Compounds of uncertain BBB permeation(CNS+ / -)5.0936>Pe>3.0476,

[0369] Compounds of low BBB permeation(CNS-)<3.0476,

[0370] Example 49: MTT Experiment

[0371] Drugs and reagents: 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (purchased from Aladdin)

[0372] Instrument: THERMO Varioskan Flash full-wavelength multi-functional microplate reader.

[0373] Experimental method: SH-SY5Y or BV-2 cells (5×10⁻⁶) were used. 3Cells (0.1 mL each) were placed in 96-well flat-bottomed culture plates and cultured overnight at 37°C until they adhered. Then, 100 μL of the test compound (final concentrations: 10, 20, and 50 μM) was added to each well for 24 h. 20 μL of MTT reagent was added to each well, and the cells were incubated at 37°C for 4 h. 50 μL of DMSO was added to each well to dissolve the formazan, and its UV absorbance was measured at 490 nm using a microplate reader. All experiments were performed in triplicate. Results Figure 1 As shown.

[0374] Results analysis: All compounds showed safety against SH-SY5Y at concentrations of 10, 20, and 50 μM, with cell viability exceeding 75% even at high concentrations. There was no significant difference in cytotoxicity between 44(R) and 44(S). Compared to SH-SY5Y, the compounds exhibited slightly increased toxicity to BV-2, primarily at a concentration of 50 μM, with the preferred compound 44R showing a cell viability of approximately 50%. However, this dose is significantly higher than the inhibitory activity of the compounds.

[0375] Example 50: Neuroprotective effect against glutamate-induced SH-SY5Y cell damage

[0376] Drugs and reagents: 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (purchased from Aladdin)

[0377] Instrument: THERMO Varioskan Flash full-wavelength multi-functional microplate reader.

[0378] Experimental method: Target cells (5 × 10⁻⁶) 3 Cells (0.1 mL each) were placed in 96-well flat-bottomed culture plates and incubated overnight at 37°C to allow them to adhere to the bottom of the plate. Cells were treated with various concentrations of compounds for 24 hours. MTT reagent was added to the wells, and the plates were incubated at 37°C for 4 hours. Cells were then lysed by adding 0.1 mL of lysis buffer to the wells. After incubation, the cells were kept at 37°C for another 24 hours, and the colorimetric reaction was measured at 490 nm using a microplate reader.

[0379] Analysis of experimental results: Given that compounds 30 and 44(R) exhibited optimal BChE inhibitory activity and a certain degree of selectivity, the neuroprotective effect on glutamate-induced SH-SY5Y cell damage was further investigated using the MTT assay. Figure 2As shown, when SH-SY5Y cells were exposed to 31 mM glutamate, cell viability decreased sharply to 48.6 ± 1.4% compared to the untreated group. Treatment with compounds 30 and 44(R) increased cell viability; at a low concentration of 1 μM, no protective effect was observed, while at 10 μM doses of compounds 30 and 44(R), cell viability increased to 62.1 ± 8.8% and 57.9 ± 2.3%, respectively. Therefore, the results indicate that compounds 30 and 44(R) have a protective effect against Aβ. 1-42 Induced SH-SY5Y cell damage exhibits a certain neuroprotective effect.

[0380] Example 51: Water Maze Experiment

[0381] Drugs and reagents: Scopolamine (purchased from Aladdin, purity 99%), compounds 30 and 44R, and Livans's amine (purchased from Shanghai Bide, purity 98%).

[0382] Experimental instrument: Panlab SMART 3.0 behavioral video analyzer

[0383] Animals: Adult male ICR mice (8-10 weeks old, weighing 20-25 grams) were purchased from Jiangsu Huachuang Xinno Pharmaceutical Technology Co., Ltd.

[0384] Experimental Methods: Forty mice were randomly divided into five subgroups (n=8 per group): (i) blank control group, (ii) scopolamine as the model group, (iii) levansin plus scopolamine as the positive control, (iv) compound 30 (5 mg / kg) plus scopolamine as the experimental group, and (v) compound 44R (1 mg / kg) plus scopolamine as the experimental group. Mice in the model group, levansin group, compound 30 group (5 mg / kg), and compound 44R group (1 mg / kg) were intraperitoneally injected with scopolamine (2 mg / kg), while the blank control group was injected with saline. Thirty minutes later, the compounds were injected intraperitoneally into their respective compound groups, while the model group and blank control group were injected with saline.

[0385] An escape platform (10cm in diameter) was fixed in a circular pool (120cm in diameter, 60cm in height) and filled with 40cm of fresh water (maintained at 25°C) to form a water maze. The pool was placed in a well-lit room. After 5 days of learning and memory training, a probe test was conducted on day 6. To assess cognitive function, each mouse was individually trained for 2 days on a visible platform (marked with a small flag, 5cm high), and from day 3 to day 5, trained in a water maze with a hidden platform (placed 1cm below the water surface). All mice underwent two training tests daily, each lasting 90 seconds. The time it took for each mouse to find the platform (successful escape) was recorded. If a mouse failed to reach the platform within 90 seconds, the test was terminated, and the mouse was carefully placed on the platform by hand. Regardless of success or failure, each mouse remained on the platform for 30 seconds. On the final day (day 6), the platform was removed from the pool, and the mice were given 90 seconds each to search for the platform. The time and trajectory of each mouse reaching the missing platform were recorded.

[0386] Results Analysis: Figure 3 As shown in Figure A, the average time to reach the platform was significantly different in the model group compared to the control group, indicating that scopolamine can induce memory deficits in mice, thus demonstrating successful model establishment. Compared to the model group, the time and distance reached by mice in the levamisole group were significantly reduced, indicating that levamisole significantly improves memory and cognitive function in mice. Furthermore, the average time and distance to reach the platform were lower in the compound 30 and compound 44R treatment groups than in the model group, indicating that compounds 30 and 44R have a beneficial effect on memory and cognitive function in mice.

[0387] Example 52: Water Maze Experiment

[0388] Drugs and reagents: Aβ (purchased from Beyotime), compounds 30 and 44R, and Rivander (purchased from Shanghai Bid, purity 98%).

[0389] Experimental instrument: Panlab SMART 3.0 behavioral video analyzer

[0390] Animals: Adult male ICR mice (8-10 weeks old, weighing 20-25 grams) were purchased from Jiangsu Huachuang Xinno Pharmaceutical Technology Co., Ltd.

[0391] Experimental Methods: Forty-eight mice were randomly divided into six subgroups (n=8 per group): (i) blank control group, (ii) sham-operated group, (iii) model group, (iv) levamisole group, (v) compound 30 (5 mg / kg) group, and (vi) compound 44R (1 mg / kg) group. Except for the blank control group, all mice underwent surgery in the hippocampus. The sham-operated group received 5 μL of saline, while the other groups received the same volume of Aβ (4 mg / mL). Drug administration was performed 2–14 days post-surgery, with the blank control and sham-operated groups receiving saline. Training was conducted from days 9–13, and exploratory experiments were performed on day 14.

[0392] Results Analysis: Figure 3 As shown in Figure B, there was no significant difference between the sham-operated group and the control group, indicating that the surgery did not affect the mice's motor and cognitive levels. The average time for mice in the model group to reach the platform was significantly different, indicating that Aβ could induce memory deficits in mice, demonstrating successful modeling. Compared to the model group, the time and distance spent in the levamisole group were significantly reduced, indicating that levamisole significantly improved the memory and cognitive functions of mice. The average time and distance for mice in the compound 30 and compound 44R treatment groups to reach the platform were both lower than those in the model group, indicating that compounds 30 and 44R had an improving effect on the memory and cognitive functions of mice.

[0393] Compound 44R showed comparable efficacy to the positive control at the same dose, indicating its good in vivo efficacy.

Claims

1. A metanil sulfonamide benzamide compound, characterized by, a compound selected from any one of the following compounds, including stereoisomers, pharmaceutically acceptable salts thereof: 。 2. The m-aminosulfonylbenzamide compound according to claim 1, characterized by, The pharmaceutically acceptable salt is a salt of the compound with an acid, the acid being hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, or mandelic acid.

3. A pharmaceutical composition, characterized by, The m-aminosulfonylbenzamide compound according to any one of claims 1 to 2, and a pharmaceutically acceptable carrier.

4. Use of the m-aminosulfonylbenzamide compound according to any one of claims 1 to 2 or the pharmaceutical composition according to claim 3 in the manufacture of a drug for inhibiting butyrylcholinesterase.

5. Use according to claim 4, characterized in that, The drug is a drug for treating neurodegenerative diseases.

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