O-sulfonyl benzimide compound as well as preparation method and application thereof

Abstract

The invention provides a compound containing o-sulfonyl benzimide as well as a preparation method and application of the compound. Specifically, the invention provides a compound as shown in a formula I. The o-sulfonyl benzimide-containing compound disclosed by the invention has good 20S proteasome agonistic activity and is expected to be used for treating proteotoxic diseases such as neurodegenerative diseases, cardiovascular diseases and metabolic diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceuticals. Specifically, the present invention relates to a new class of o-sulfonylbenzoyl imide compounds, their preparation methods and applications, and the use of the compounds in the preparation of therapeutic drugs for protein-toxic diseases. Background Art

[0002] The proteasome is a large multi-subunit complex located within eukaryotic cells and is mainly responsible for degrading misfolded, damaged, or unwanted proteins. Its normal function is crucial for maintaining key cellular processes such as cell cycle progression, signal transduction, and protein quality control. However, with aging, the function of the proteasome inevitably declines gradually, leading to the accumulation of damaged and misfolded proteins within cells, thereby triggering various protein-toxicity-related diseases, including neurodegenerative diseases and cardiovascular diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), cardiomyopathy, and thromboembolic diseases, etc. By enhancing the activity of the proteasome, the degradation of toxic proteins can be promoted, thus providing a new approach for the treatment of these diseases.

[0003] Currently, the research on proteasome agonists is still in its infancy, but the related research is advancing steadily and is expected to bring new breakthroughs to future treatment strategies. Summary of the Invention

[0004] Aiming at the deficiencies of the prior art, the technical problem to be solved by the present invention is: designing and synthesizing a new class of o-sulfonylbenzoyl imide compounds and evaluating the 20S proteasome agonist activity of the compounds. The results show that the compounds have good 20S proteasome agonist activity and can be used as a class of proteasome agonists with a completely new skeleton, and are expected to become an effective option for ischemic cardiomyopathy and other protein-toxic diseases.

[0005] Term Definitions:

[0006] As used herein, the term "aryl" refers to a fully carbon monocyclic or fused polycyclic group of 5 - 12 carbon atoms with a completely conjugated π-electron system. Non-limiting examples of aromatic rings include benzene rings, quinoline, benzofuran, naphthalene rings, and phenothiazine. The aromatic ring can be substituted or unsubstituted. The substituents of the aromatic ring are selected from halogens, trifluoromethyl, nitro, methoxy, C 1-2 alkyl.

[0007] As used herein, the term "heteroaryl" refers to an unsaturated carbocyclic ring of 5 - 6 ring atoms, in which one or more carbons are replaced by heteroatoms such as oxygen, nitrogen, sulfur, etc. Specific heteroaryls can be: pyridyl, furyl, thienyl, thiazolyl, etc.

[0008] As used herein, the term "heterocyclic group" refers to a monocyclic group having 4 to 6 ring atoms, at least one or two of which are heteroatoms selected from nitrogen, oxygen, and sulfur, and the remaining ring atoms are all carbon atoms. Specific heterocyclic groups may be piperidine, azetidinyl, etc.

[0009] As used herein, the term "alkoxy" refers to an -O-alkyl group. Specific alkoxy groups may be methoxy, etc.

[0010] As used herein, the term "alkaryl" refers to an aryl group substituted by an alkyl group. The aryl group is preferably phenyl, and the alkyl group preferably has 1 to 6 carbon atoms. Specific alkaryl groups may be methylphenyl, ethylphenyl, etc.

[0011] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine, preferably fluorine, chlorine, or bromine.

[0012] An object of the present invention is to provide a novel saccharin compound, and the compound has the following general formula (I) structure:

[0013]

[0014] Wherein:

[0015] X is selected from or absent;

[0016] Y is selected from NH, O, or absent;

[0017] Linker is selected from C 1-4 alkyl, alkamino, aryl, substituted aryl, C 4-7 cycloalkyl, heterocycloalkyl;

[0018] A is selected from C 1-4 alkyl, aralkyl, ethoxycarbonyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted alkaryl; the substitution is arbitrarily substituted by halogen, nitro, trifluoromethyl, methoxy, C 1-2 alkyl;

[0019] R is selected from C 1-3 alkyl, C 3-7 cycloalkyl, heterocyclic group, benzheterocyclic group, substituted or unsubstituted aryl; the substituted aryl is arbitrarily substituted by halogen, ethyl, nitro, methoxy.

[0020] Preferably, Linker is selected from ethyl, ethylamino, anilino, piperidinyl, azetidinyl, cyclobutyl, cyclohexyl;

[0021] A is selected from methyl, ethyl, isopropyl, isobutyl, ethoxycarbonyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, alkaryl, wherein the unsubstituted or substituted aryl is selected from phenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, benzoyl, and the unsubstituted or substituted heteroaryl is selected from furyl, 2-nitrofuran, thiazolyl, pyridyl, thienyl, and the alkaryl is selected from benzyl, phenethyl;

[0022] R is selected from methyl, isopropyl, C 3-7 cycloalkyl, heterocyclic group, benzheterocyclic group, substituted or unsubstituted aryl; wherein, the C 3-7 cycloalkyl is selected from cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, the heterocyclic group is selected from piperidyl, isoxazolyl, the benzheterocyclic group is selected from quinolinyl, benzofuranyl, phenothiazinyl, benzothiazolyl, and the substituted or unsubstituted aryl is selected from phenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-fluorophenethyl, 4-fluorostyryl, tetrahydronaphthyl, naphthyl, diphenylmethyl, bis(4-fluorophenyl)methyl, fluorenyl. More specifically, the preferred compounds of the present invention having the general formula (Ⅰ) structure are:

[0023]

[0024]

[0025]

[0026]

[0027]

[0028]

[0029]

[0030] Another object of the present invention is to provide a preparation method of the above target compound, which is achieved through the following steps:

[0031] (1) Compound a and compound b react under the action of triethylamine to obtain compound c, the reaction temperature is 0°C to room temperature, the reaction time is 5 - 10 min, and the crude product can be directly used for the next step of reaction.

[0032] (2) Compound c and compound d react to obtain compound e, and the obtained crude product is separated by column chromatography to obtain the pure product, the reaction temperature is 120°C, and the reaction time is 3 - 4 d.

[0033] (3) Compound f reacts under the action of thionyl chloride to obtain compound g. The reaction temperature is 100 °C and the reaction time is 12 h. The crude product can be directly used for the next reaction.

[0034] (4) Compound e and compound g react under the action of triethylamine to obtain compound k. The obtained crude product is separated by column chromatography to obtain the pure product. The reaction temperature is rt and the reaction time is 5 - 10 min.

[0035] (5) Compound h and compound i react under the action of potassium carbonate to obtain compound j. The obtained crude product is separated by column chromatography to obtain the pure product. The reaction temperature is 60 °C and the reaction time is 12 h.

[0036] (6) Compound j and compound g react under the action of triethylamine to obtain compound l. The obtained crude product is separated by column chromatography to obtain the pure product. The reaction temperature is rt and the reaction time is 15 min.

[0037] (7) After removing the protecting groups from compound k and compound l respectively, they react with compound m to obtain compound I. The obtained crude product is separated by column chromatography to obtain the pure product.

[0038]

[0039] Among them, the Protecting Group in compound h is any one of Boc or methyl ester;

[0040] After deprotecting compound k, it reacts with compound m, where compound m is any one of After deprotecting compound l, it reacts with compound m, where compound m is any one of R - NH2, ;

[0041] Another object of the present invention is to provide a pharmaceutical composition, wherein the pharmaceutical composition comprises at least one compound in any of the forms described above, the stereoisomers or pharmaceutically acceptable salts of the compound as active ingredients, or further comprises one or more pharmaceutically acceptable carriers or excipients.

[0042] The pharmaceutical composition of the present invention can be made into various pharmaceutical dosage forms, such as oral, injection, inhalation, implantation and other administration methods. The preferred administration methods are injection or oral administration, such as injection, freeze-dried powder injection, tablets, capsules or granules, etc.

[0043] The pharmaceutical composition of the present invention and various preparations of this composition can be prepared using conventional pharmaceutical carriers.

[0044] Another object of the present invention is to provide the medicinal use of the compound of general formula (I) and the pharmaceutical composition containing said compound, which can be used as a proteasome agonist. That is, the present invention provides the use of the compound of general formula (I) and the pharmaceutical composition containing said compound in the preparation of a medicament for treating protein-toxic diseases.

[0045] Furthermore, the diseases are selected from neurodegenerative diseases, cardiovascular diseases, and metabolic diseases. The neurodegenerative diseases are Alzheimer's disease, amyotrophic lateral sclerosis, ataxia-telangiectasia, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellar atrophy, multiple sclerosis, Parkinson's disease, primary lateral sclerosis, spinal muscular atrophy, cerebral ischemia, spastic paraplegia, and myasthenia gravis; the cardiovascular diseases are coronary heart disease, stroke, heart failure, cardiomyopathy, rheumatic heart disease, abnormal heart rhythm, congenital heart disease, myocarditis, thromboembolic diseases, and venous thrombosis; the metabolic diseases are diabetes and non-alcoholic fatty liver.

[0046] Experiments have proved that the o-sulfonylbenzoyl imide compounds of the present invention have good proteasome agonist activity. The raw materials required for the synthesis of the compounds of the present invention are easily available, the route design is reasonable, the reaction conditions are mild, the yields of each step are high, the operation is simple, and it is suitable for industrial production. Detailed implementation manners

[0047] The present invention will be further described in conjunction with the embodiments. The following embodiments are only illustrative of the present invention and do not limit the present invention in any way.

[0048] Example 1 Preparation of tert-butyl 2-[3-(cyclohexylamino)-3-oxopropyl]hydrazine-1-carboxylate

[0049]

[0050] Step 1: Synthesis of compound 3: Dissolve cyclohexylamine (2 g, 20.2 mmol) and triethylamine (4.09 g, 40.4 mmol) in 10 ml of dichloromethane, cool in an ice bath, and slowly add dropwise a solution of acryloyl chloride (1.83 g, 20.2 mmol) in dichloromethane (5 mL). After the addition is complete, remove the ice bath and continue the reaction for 5 min. After TLC plate monitoring shows complete reaction, add 50 ml of saturated ammonium chloride aqueous solution to quench the reaction, extract, take the organic layer, and extract the aqueous layer twice with dichloromethane (10 ml). Combine the organic layers and evaporate to dryness to obtain the white solid product 3 (2.94 g, 95.1%). 11H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 6.36 (dd, J = 16.8, 10.6 Hz, 1H), 6.13 (dd, J = 16.8, 1.4 Hz, 1H), 5.43 (dd, J = 10.6, 1.4 Hz, 1H), 3.62 (td, J = 14.6, 7.3 Hz, 1H), 1.90 - 1.85 (m, 2H), 1.69 - 1.62 (m, 2H), 1.58 (dd, J = 9.1, 3.8 Hz, 1H), 1.29 (td, J = 12.2, 3.4 Hz, 2H), 1.19 - 1.11 (m, 3H). ESI-MS: m / z = 154.1221 [M+H] + .

[0051] Step 2. Synthesis of Compound 5: Dissolve Compound 3 (2.94 g, 19.2 mmol) and Compound 4 (5.07 g, 38.4 mmol) in 30 ml of isopropanol and react at 120 °C for 3 days. Monitor by TLC plate. After the reaction is completed, rotary evaporate the isopropanol, add 50 ml of dichloromethane for dilution, then add 100 ml of water for extraction. Take the organic layer, and extract the organic layer with water (100 ml) twice. Combine the organic layers and rotary evaporate to obtain a yellow oily crude product. The crude product is purified by column chromatography to obtain white solid 5 (2.7 g, 49.3%). 1 1H NMR (400 MHz, CDCl3) δ 6.69 (s, 1H), 6.15 (s, 1H), 3.81–3.71 (m, 1H), 3.10 (t, J = 6.1 Hz, 2H), 2.33 (t, J = 6.1 Hz, 2H), 1.89 (dd, J = 12.4, 3.2 Hz, 2H), 1.73–1.64 (m, 2H), 1.62–1.56 (m, 1H), 1.45 (s, 9H), 1.41–1.30 (m, 2H), 1.30–1.09 (m, 4H). ESI-MS: m / z = 286.2124 [M+H] + .

[0052] Example 2 Preparation of tert-Butyl 2-[3-(phenylamino)-3-oxopropyl]hydrazine-1-carboxylate

[0053]

[0054] Synthesis of Compound 7: Using Compound 6 as the raw material, the synthesis and post-treatment are the same as in Step 1 of Example 1 to obtain white solid 7 with a yield of 93.4%; 11H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 7.64 (dd, J = 29.0, 7.9 Hz, 2H), 7.32 (dd, J = 14.2, 6.7 Hz, 2H), 7.15 (t, J = 7.2 Hz, 1H), 6.45 (d, J = 6.0 Hz, 2H), 5.72 (t, J = 5.8 Hz, 1H). ESI-MS: m / z = 148.0753 [M+H] + .

[0055] Synthesis of Compound 8: Using Compound 7 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 1, and white solid 8 was obtained with a yield of 50.2%; 1 1H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 7.66 (d, J = 7.9 Hz, 2H), 7.34 (t, J = 7.8 Hz, 2H), 7.11 (t, J = 7.3 Hz, 1H), 6.27 (s, 1H), 3.47 (s, 1H), 3.26–3.20 (m, 2H), 2.58–2.51 (m, 2H), 1.52 (s, 9H). ESI-MS: m / z = 280.1653 [M+H] + .

[0056] Example 3 Preparation of tert-Butyl 2-[3-(Cyclopropylamino)-3-oxopropyl]hydrazine-1-carboxylate

[0057]

[0058] Synthesis of Compound 10: Using Compound 9 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 1, and white solid 10 was obtained with a yield of 96.1%; 1 1H NMR (400 MHz, CDCl3) δ 6.27 (d, J = 17.0 Hz, 1H), 6.03 (dd, J = 17.0, 10.4 Hz, 1H), 5.72 (d, J = 7.4 Hz, 1H), 5.61 (d, J = 10.3 Hz, 1H), 3.17–3.05 (m, 1H), 2.80 (ddd, J = 10.3, 6.8, 3.4 Hz, 1H), 1.41 (t, J = 7.3 Hz, 1H), 0.81 (q, J = 6.2 Hz, 2H), 0.58–0.50 (m, 2H). ESI-MS: m / z = 112.0758 [M+H] + .

[0059] Synthesis of Compound 11: Using Compound 10 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 1, and white solid 11 was obtained with a yield of 39.8%; 11H NMR (400 MHz, CDCl3) δ 7.10 (s, 1H), 6.10 (s, 1H), 4.02 (s, 1H), 3.08 (t, J = 5.9 Hz, 2H), 2.78–2.69 (m, 1H), 2.34–2.28 (m, 2H), 1.45 (s, 9H), 0.74 (q, J = 6.8 Hz, 2H), 0.55–0.48 (m, 2H). ESI-MS: m / z = 244.2658 [M+H] + .

[0060] Example 4 Preparation of tert-butyl 2-[3-(dibenzylamino)-3-oxopropyl]hydrazine-1-carboxylate

[0061]

[0062] Synthesis of Compound 13: Using Compound 12 as the starting material, the synthesis and post-treatment were the same as in Step 1 of Example 1 to obtain white solid 13 in a yield of 94.5%; 1 1H NMR (400 MHz, DMSO) δ 9.03 (d, J = 8.7 Hz, 1H), 7.37–7.24 (m, 10H), 6.44 (dd, J = 17.1, 10.2 Hz, 1H), 6.22 (d, J = 8.7 Hz, 1H), 6.15 (dd, J = 17.1, 2.1 Hz, 1H), 5.65 (dd, J = 10.2, 2.1 Hz, 1H). ESI-MS: m / z = 238.1229 [M+H] + .

[0063] Synthesis of Compound 14: Using Compound 13 as the starting material, the synthesis and post-treatment were the same as in Step 2 of Example 1 to obtain white solid 14 in a yield of 47.3%; 1 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.53 (s, 1H), 7.28 (dd, J = 12.6, 7.3 Hz, 10H), 6.32 (d, J = 8.2 Hz, 1H), 6.09 (s, 1H), 3.17 (d, J = 5.1 Hz, 2H), 2.47 (t, J = 5.6 Hz, 2H), 2.37 (dt, J = 12.1, 5.7 Hz, 3H), 1.50 (s, 10H). ESI-MS: m / z = 370.2119 [M+H] + .

[0064] Example 5 Preparation of tert-butyl 2-[3-(cycloheptylamino)-3-oxopropyl]hydrazine-1-carboxylate

[0065]

[0066] Synthesis of Compound 16: Using Compound 15 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 1 to obtain white solid 16 with a yield of 94.5%; 1 H NMR (400 MHz, DMSO) 1 H NMR (400 MHz, CDCl3) δ 6.24 (d, J = 16.9 Hz, 1H), 6.05 (ddd, J = 16.9, 10.2, 1.7 Hz, 1H), 5.59 (d, J = 10.2 Hz, 1H), 4.03 (dt, J = 7.8, 6.2 Hz, 1H), 1.99–1.91 (m, 2H), 1.61 (d, J = 5.2 Hz, 4H), 1.53–1.38 (m, 6H)..ESI-MS: m / z = 168.1387 [M + H] + .

[0067] Synthesis of Compound 17: Using Compound 16 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 1 to obtain white solid 17 with a yield of 50.9%; 1 H NMR (400 MHz, CDCl3) δ 4.08 (s, 1H), 4.00–3.92 (m, 1H), 3.09 (t, J = 6.0 Hz, 2H), 2.31 (t, J = 6.0 Hz, 2H), 1.90 (dd, J = 8.1, 2.9 Hz, 2H), 1.68 (s, 2H), 1.60 (d, J = 1.7 Hz, 4H), 1.51 (d, J = 8.9 Hz, 4H), 1.46 (s, 9H).ESI-MS: m / z = 300.2288 [M + H] + .

[0068] Preparation of tert-Butyl 2-[3-oxo-3-(1,2,3,4-tetrahydronaphthalen-1-ylamino)propyl]hydrazine-1-carboxylate in Example 6

[0069]

[0070] Synthesis of Compound 19: Using Compound 18 as the starting material, the synthesis and post-treatment were the same as in Step 1 of Example 1, to obtain white solid 19 with a yield of 92.5%; 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 7.8 Hz, 1H), 7.25–7.19 (m, 2H), 7.15 (d, J = 7.5 Hz, 1H), 6.36 (d, J = 16.9 Hz, 1H), 6.13 (dd, J = 16.9, 10.3 Hz, 1H), 5.70 (d, J = 10.3 Hz, 1H), 5.31 (dd, J = 14.1, 6.8 Hz, 1H), 2.91–2.76 (m, 2H), 2.16–2.07 (m, 1H), 1.95–1.87 (m, 3H). ESI-MS: m / z = 202.1227 [M+H] + .

[0071] Synthesis of Compound 20: Using Compound 19 as the starting material, the synthesis and post-treatment were the same as in Step 2 of Example 1, to obtain white solid 20 with a yield of 53.5%; 1 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 3.0 Hz, 1H), 7.18 (d, J = 3.3 Hz, 2H), 7.12 (s, 1H), 5.26–5.19 (m, 1H), 3.18 (t, J = 4.4 Hz, 2H), 2.81 (d, J = 7.4 Hz, 2H), 2.46–2.40 (m, 2H), 1.85 (d, J = 2.3 Hz, 4H), 1.46 (s, 9H). ESI-MS: m / z = 334.2126 [M+H] + .

[0072] Preparation of tert-Butyl 2-[3-oxo-3-(piperidin-1-yl)propyl]hydrazine-1-carboxylate in Example 7

[0073]

[0074] Synthesis of Compound 22: Using Compound 21 as the starting material, the synthesis and post-treatment were the same as in Step 1 of Example 1, to obtain white solid 22 with a yield of 92.8%; 1 1H NMR (400 MHz, CDCl3) δ 6.56 (dd, J = 16.8, 10.6 Hz, 1H), 6.23 (dd, J = 16.8, 1.4 Hz, 1H), 5.63 (dd, J = 10.6, 1.4 Hz, 1H), 3.62–3.46 (m, 4H), 1.65 (d, J = 4.8 Hz, 2H), 1.56 (dd, J = 10.6, 5.3 Hz, 4H). ESI-MS: m / z = 140.1078 [M+H] + .

[0075] Synthesis of Compound 23: Using Compound 22 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 1, to obtain white solid 23 with a yield of 45.6%; 1 H NMR (400 MHz, CDCl3) δ 6.19 (s, 1H), 3.60–3.55 (m, 2H), 3.43–3.38 (m, 2H), 3.16 (t, J = 6.5 Hz, 2H), 2.54 (t, J = 6.5 Hz, 2H), 1.70–1.63 (m, 2H), 1.56 (dd, J = 12.1, 7.1 Hz, 4H), 1.48 (s, 9H). ESI-MS: m / z = 272.1960 [M+H] + .

[0076] Preparation of tert-Butyl 2-[3-(isoxazol-3-ylamino)-3-oxopropyl]hydrazine-1-carboxylate in Example 8

[0077]

[0078] Synthesis of Compound 25: Using Compound 24 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 1, to obtain white solid 25 with a yield of 90.7%; 1 H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 8.31 (d, J = 1.3 Hz, 1H), 7.20 (d, J = 1.0 Hz, 1H), 6.55–6.46 (m, 2H), 6.41 (dd, J = 17.0, 10.1 Hz, 1H), 5.88 (dd, J = 10.1, 0.8 Hz, 1H). ESI-MS: m / z = 139.0510 [M+H] + .

[0079] Synthesis of Compound 26: Using Compound 25 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 1, to obtain white solid 26 with a yield of 42.9%; 1 H NMR (400 MHz, CDCl3) δ 10.26 (s, 1H), 8.26 (d, J = 1.2 Hz, 1H), 7.04 (s, 1H), 6.26 (s, 1H), 4.30 (s, 1H), 3.25–3.18 (m, 2H), 2.59–2.55 (m, 2H), 1.46 (s, 9H). ESI-MS: m / z = 271.1411 [M+H] + .

[0080] Preparation of tert-Butyl 2-[3-(naphthalen-2-ylamino)-3-oxopropyl]hydrazine-1-carboxylate in Example 9

[0081]

[0082] Synthesis of Compound 28: Using Compound 27 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 1 to obtain white solid 28 with a yield of 93.6%; 1 H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.06 (s, 1H), 7.75 (d, J = 8.5 Hz, 3H), 7.55 (d, J = 8.3 Hz, 1H), 7.46–7.37 (m, 2H), 6.42 (qd, J = 16.8, 5.6 Hz, 2H), 5.75 (dd, J = 9.9, 1.5 Hz, 1H). ESI-MS: m / z = 198.0910 [M+H] + .

[0083] Synthesis of Compound 29: Using Compound 28 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 1 to obtain white solid 29 with a yield of 20.3%; ESI-MS: m / z = 330.1811 [M+H] + .

[0084] Preparation of tert-Butyl 2-(3-Methoxy-3-oxopropyl)hydrazine-1-carboxylate in Example 10

[0085]

[0086] Synthesis of Compound 31: Using Compound 30 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 1 to obtain white solid 31 with a yield of 95.5%; ESI-MS: m / z = 87.0446 [M+H] + .

[0087] Synthesis of Compound 32: Using Compound 31 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 1 to obtain white solid 32 with a yield of 40.5%; ESI-MS: m / z = 219.1341 [M+H] + .

[0088] Preparation of tert-Butyl 2-[3-(4-Nitrophenylamino)-3-oxopropyl]hydrazine-1-carboxylate in Example 11

[0089]

[0090] Synthesis of Compound 34: Using Compound 33 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 1 to obtain white solid 34 with a yield of 89.2%; ESI-MS: m / z = 193.0615 [M+H] + .

[0091] Synthesis of Compound 35: Using Compound 34 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 1 to obtain white solid 35 with a yield of 40.9%; ESI-MS: m / z = 325.1501 [M+H] + .

[0092] Preparation of tert-Butyl 2-[3-(4-Methoxyphenylamino)-3-oxopropyl]hydrazine-1-carboxylate in Example 12

[0093]

[0094] Synthesis of Compound 37: Using Compound 36 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 1 to obtain white solid 37 with a yield of 97.1%; ESI-MS: m / z = 178.0859 [M+H] + .

[0095] Synthesis of Compound 38: Using Compound 37 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 1 to obtain white solid 38 with a yield of 48.3%; ESI-MS: m / z = 310.1770 [M+H] + .

[0096] Preparation of 3-Chlorobenzo[d]isothiazole-1,1-dioxide in Example 13

[0097]

[0098] Dissolve 39 (10 g, 54.6 mmol) in 1,4-dioxane (60 ml), add SOCl2 (32.47 g, 273.0 mmol) and DMF (0.5 ml), and react at 100 °C for 12 h. After the reaction is completed, evaporate 1,4-dioxane under reduced pressure, add 50 ml of ether for washing, filter by suction, and wash the filter cake with ether (30 ml × 2) to obtain white solid 40 (10.3 g, 93.6%). 1 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 6.9 Hz, 1H), 7.92 (dd, J = 7.8, 3.6 Hz, 1H), 7.88 (s, 2H).

[0099] Preparation of N-Cyclohexyl-3-[1-(1,1-Dioxidobenzo[d]isothiazol-3-yl)hydrazino]propanamide in Example 14

[0100]

[0101] Step 1. Synthesis of Compound 41: Dissolve Compound 5 (2.7 g, 9.46 mmol) in dichloromethane (20 ml), add triethylamine (1.91 g, 18.92 mmol), cool in an ice bath, and dropwise add a solution of Compound 40 (1.91 g, 9.46 mmol) in dichloromethane (10 ml). After the addition is complete, continue the reaction at room temperature for 5 - 10 min. Monitor the completion of the reaction by TLC plate. Quench the reaction by adding saturated ammonium chloride solution (30 ml), extract, collect the organic layer, evaporate the organic layer to dryness, and purify the crude product by column chromatography to obtain white solid 41 (3.96 g, 92.9%). 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.13 (d, J = 7.9 Hz, 1H), 7.89 (d, J = 7.4 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.61 (t, J = 7.7 Hz, 1H), 5.89 (d, J = 7.4 Hz, 1H), 4.56 (dt, J = 14.0, 3.8 Hz, 1H), 3.75–3.64 (m, 1H), 3.56–3.47 (m, 1H), 3.16–3.05 (m, 1H), 2.56 (dd, J = 13.9, 3.2 Hz, 1H), 1.86 (dd, J = 30.6, 11.6 Hz, 2H), 1.68 (d, J = 15.2 Hz, 2H), 1.47 (s, 9H), 1.29 (dt, J = 14.5, 10.0 Hz, 3H), 1.14 (dtd, J = 23.8, 12.1, 3.1 Hz, 3H). ESI-MS: m / z = 451.2005 [M + H] + .

[0102] Step 2. Synthesis of Compound 42: Dissolve Compound 41 (3.96 g, 8.8 mmol) in dichloromethane (20 ml), add trifluoroacetic acid (5 ml), and react at room temperature for 1 - 2 h. Monitor the completion of the reaction by TLC plate and evaporate to dryness to obtain Compound 42.

[0103] Preparation of N-Phenyl-3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)hydrazino]propanamide in Example 15

[0104]

[0105] Synthesis of Compound 43: Using Compound 8 as the raw material, the synthesis and post-treatment are the same as in Step 1 of Example 14 to obtain white solid 43 with a yield of 93.1%; 11H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.25 (s, 1H), 8.17 (d, J = 7.9 Hz, 1H), 7.92 (d, J = 7.5 Hz, 1H), 7.71 (t, J = 7.5 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.32 (t, J = 7.8 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H), 4.63 (d, J = 14.2 Hz, 1H), 3.70 (t, J = 11.8 Hz, 1H), 3.41–3.27 (m, 1H), 2.88 (d, J = 17.2 Hz, 1H), 1.50 (s, 9H). ESI-MS: m / z = 445.1531 [M+H] + .

[0106] Synthesis of Compound 44: Using compound 43 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 14 to obtain compound 44.

[0107] Example 16 Preparation of N-Cyclopropyl-3-[1-(1,1-Dioxidobenzo[d]isothiazol-3-yl)hydrazino]propanamide

[0108]

[0109] Synthesis of Compound 45: Using compound 11 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 14 to obtain white solid 45 with a yield of 95.0%; 1 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.13 (d, J = 7.9 Hz, 1H), 7.88 (d, J = 7.3 Hz, 1H), 7.68 (t, J = 7.1 Hz, 1H), 7.62 (dd, J = 11.1, 4.2 Hz, 1H), 6.19 (s, 1H), 4.54 (dt, J = 14.2, 3.9 Hz, 1H), 3.58–3.48 (m, 1H), 3.17–3.04 (m, 1H), 2.67 (tq, J = 7.0, 3.6 Hz, 1H), 2.55 (dt, J = 17.0, 3.3 Hz, 1H), 1.47 (s, 9H), 0.81–0.70 (m, 2H), 0.58–0.47 (m, 2H). ESI-MS: m / z = 409.1538 [M+H] + .

[0110] Synthesis of Compound 46: Using compound 45 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 14 to obtain compound 46.

[0111] Preparation of Example 17: N-Dibenzyl-3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)hydrazino]propanamide

[0112]

[0113] Synthesis of Compound 47: Using Compound 14 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 14 to obtain white solid 47 with a yield of 91.9%; 1 H NMR(400MHz,CDCl3)δ8.22(s,1H),8.02(d,J=7.6Hz,1H),7.87(d,J=7.4Hz,1H),7.67(t,J=7.4Hz,1H),7.57(t,J=7.7Hz,1H),7.32(t,J=7.1Hz,2H),7.27(d,J=6.6Hz,1H),7.20(d,J=7.4Hz,2H),7.14(d,J=9.3Hz,5H),6.38(d,J=6.3Hz,1H),6.13(d,J=7.5Hz,1H),4.57(d,J=13.9Hz,1H),3.53(t,J=11.9Hz,1H),3.28(t,J=12.3Hz,1H),2.63(d,J=16.9Hz,1H),1.43(s,9H).ESI-MS:m / z=535.2009[M+H] + .

[0114] Synthesis of Compound 48: Using Compound 47 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 14 to obtain Compound 48.

[0115] Preparation of Example 18: N-Cycloheptyl-3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)hydrazino]propanamide

[0116]

[0117] Synthesis of Compound 49: Using Compound 17 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 14 to obtain white solid 49 with a yield of 93.8%; 1 H NMR(400MHz,CDCl3) δ8.60 (singlet, 1H), 8.12 (doublet, J = 7.9 Hz, 1H), 7.89 (doublet, J = 7.4 Hz, 1H), 7.68 (triplet, J = 7.5 Hz, 1H), 7.60 (triplet, J = 7.7 Hz, 1H), 5.85 (doublet, J = 7.8 Hz, 1H), 4.56 (doublet of triplets, J = 13.9, 3.9 Hz, 1H), 3.94–3.83 (multiplet, 1H), 3.57–3.47 (multiplet, 1H), 3.18–3.04 (multiplet, 1H), 2.53 (doublet, J = 16.8 Hz, 1H), 1.93–1.80 (multiplet, 2H), 1.58 (doublet of doublets, J = 14.5, 10.0 Hz, 6H), 1.47 (singlet, 9H), 1.44–1.23 (multiplet, 4H). ESI-MS: m / z = 465.2174 [M+H] + .

[0118] Synthesis of Compound 50: Using Compound 49 as the starting material, the synthesis and post-treatment were carried out in the same manner as in Step 2 of Example 14 to obtain Compound 50.

[0119] Example 19 Preparation of 3-[1-(1,1-Dioxidobenzo[d]isothiazol-3-yl)hydrazino]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)propanamide

[0120]

[0121] Synthesis of Compound 51: Using Compound 20 as the starting material, the synthesis and post-treatment were carried out in the same manner as in Step 1 of Example 14 to obtain white solid 51 with a yield of 95.4%; 1 H NMR (400 MHz, CDCl3) δ 8.56 (singlet, 1H), 8.15 (doublet, J = 7.6 Hz, 1H), 7.89 (doublet, J = 7.4 Hz, 1H), 7.69 (triplet, J = 6.4 Hz, 1H), 7.62 (triplet, J = 6.6 Hz, 1H), 7.19–7.02 (multiplet, 4H), 5.99 (doublet, J = 7.5 Hz, 1H), 5.18–5.08 (multiplet, 1H), 4.66–4.56 (multiplet, 1H), 3.57 (doublet of triplets, J = 15.1, 9.3, 3.4 Hz, 1H), 3.19 (doublet of triplets, J = 16.1, 10.5, 4.4 Hz, 1H), 2.82–2.70 (multiplet, 2H), 2.57 (doublet of triplets, J = 12.8, 8.0, 3.8 Hz, 1H), 1.87–1.73 (multiplet, 4H), 1.49 (singlet, 9H). ESI-MS: m / z = 499.2013 [M+H] + .

[0122] Synthesis of Compound 52: Using Compound 51 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 14 to obtain Compound 51.

[0123] Example 20 Preparation of 3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)hydrazinyl]-1-(piperidin-1-yl)propan-1-one

[0124]

[0125] Synthesis of Compound 53: Using Compound 23 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 14 to obtain white solid 53 with a yield of 89.7%; 1 H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 4.62 (d, J = 14.0 Hz, 1H), 3.65–3.57 (m, 1H), 3.53–3.34 (m, 4H), 3.28 (ddd, J = 14.8, 10.9, 4.9 Hz, 1H), 2.62 (d, J = 17.6 Hz, 1H), 1.67–1.61 (m, 3H), 1.57–1.51 (m, 3H), 1.47 (s, 9H). ESI-MS: m / z = 437.1852 [M+H] + .

[0126] Synthesis of Compound 54: Using Compound 53 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 14 to obtain Compound 54.

[0127] Example 21 Preparation of 3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)hydrazinyl]-N-(isoxazol-3-yl)propanamide

[0128]

[0129] Synthesis of Compound 55: Using Compound 26 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 14 to obtain white solid 55 with a yield of 88.7%; ESI-MS: m / z = 436.1281 [M+H] + .

[0130] Synthesis of Compound 56: Using Compound 55 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 14 to obtain Compound 56.

[0131] Example 22 Preparation of 3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)hydrazinyl]-N-(naphthalen-2-yl)propanamide

[0132]

[0133] Synthesis of Compound 57: Using Compound 29 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 14 to obtain white solid 57 with a yield of 94.1%; ESI-MS: m / z = 495.1702 [M+H] + .

[0134] Synthesis of Compound 58: Using Compound 57 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 14 to obtain Compound 58.

[0135] Preparation of Example 23 Methyl 3 - [1 - (1,1 - dioxobenzo[d]isothiazol - 3 - yl)hydrazino]propionate

[0136]

[0137] Synthesis of Compound 59: Using Compound 32 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 14 to obtain white solid 59 with a yield of 94.5%; ESI-MS: m / z = 384.1220 [M+H] + .

[0138] Synthesis of Compound 60: Using Compound 59 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 14 to obtain Compound 60.

[0139] Preparation of Example 24 3 - [1 - (1,1 - dioxobenzo[d]isothiazol - 3 - yl)hydrazino]-N-(4 - nitrophenyl)propanamide

[0140]

[0141] Synthesis of Compound 61: Using Compound 35 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 14 to obtain white solid 61 with a yield of 90.7%; ESI-MS: m / z = 490.1391 [M+H] + .

[0142] Synthesis of Compound 62: Using Compound 61 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 14 to obtain Compound 62.

[0143] Preparation of Example 25 3 - [1 - (1,1 - dioxobenzo[d]isothiazol - 3 - yl)hydrazino]-N-(4 - nitrophenyl)propanamide

[0144]

[0145] Synthesis of Compound 63: Using compound 38 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 14 to obtain white solid 63 with a yield of 93.9%; ESI-MS: m / z = 475.1644 [M+H] + .

[0146] Synthesis of Compound 64: Using compound 63 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 14 to obtain compound 64.

[0147] Example 26 Preparation of N-Cyclohexyl-3-[1-(1,1-Dioxidobenzo[d]isothiazol-3-yl)-2-(furan-2-ylmethylene)hydrazino]propanamide

[0148]

[0149] Dissolve compound 42 (70 mg, 0.16 mmol) and compound 65 (18.0 mg, 0.19 mmol) in isopropanol (2 ml), add acetic acid (100 μl), and react at 80 °C for 12 h. Monitor the reaction by TLC plate until completion, evaporate the solvent, and purify the crude product by column chromatography to obtain white solid D-1 (45.2 mg, 67.6%). 1 H NMR (400 MHz, DMSO- D6 ) δ 9.03–8.92 (m, 1H), 8.36 (s, 1H), 8.10–8.04 (m, 1H), 8.01–7.94 (m, 2H), 7.91–7.85 (m, 2H), 7.09 (d, J = 2.8 Hz, 1H), 6.74 (s, 1H), 4.48 (t, J = 6.7 Hz, 2H), 3.54–3.47 (m, 1H), 2.55 (t, J = 6.9 Hz, 2H), 1.69 (d, J = 10.9 Hz, 2H), 1.62 (d, J = 12.8 Hz, 2H), 1.51 (d, J = 11.9 Hz, 1H), 1.21 (dd, J = 23.4, 11.4 Hz, 2H), 1.07 (dd, J = 21.5, 10.8 Hz, 3H). ESI-MS: m / z = 429.1577 [M+H] + .

[0150] Example 27 Preparation of 3-[2-Benzylidene-1-(1,1-dioxidobenzo[d]isothiazol-3-yl)hydrazino]-N-cyclohexylpropanamide

[0151]

[0152] Except for different raw materials, the synthesis and post-treatment of compound D-2 were the same as in Example 26 to obtain white solid D-2 with a yield of 65.7%; 11H NMR (400 MHz, DMSO- D6 ) δ 8.80 (d, J = 7.8 Hz, 1H), 8.54 (s, 1H), 8.09 (d, J = 7.1 Hz, 1H), 7.99–7.88 (m, 3H), 7.86 (d, J = 8.0 Hz, 2H), 7.60–7.51 (m, 3H), 4.56 (t, J = 7.1 Hz, 2H), 3.55–3.44 (m, 1H), 2.58 (t, J = 7.2 Hz, 2H), 1.72–1.65 (m, 2H), 1.60 (dd, J = 9.6, 3.3 Hz, 2H), 1.50 (d, J = 12.1 Hz, 1H), 1.19 (dd, J = 24.2, 12.1 Hz, 2H), 1.05 (dt, J = 8.9, 7.1 Hz, 3H). ESI-MS: m / z = 439.1784 [M+H] + .

[0153] Example 28 Preparation of N-cyclohexyl-3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)-2-(thiazol-2-ylmethylene)hydrazino]propanamide

[0154]

[0155] Except for different raw materials, the synthesis and post-treatment of compound D-3 were the same as those in Example 26 to obtain white solid D-3 with a yield of 61.0%; 1 1H NMR (400 MHz, DMSO- D6 ) δ 8.78 (d, J = 7.1 Hz, 1H), 8.67 (s, 1H), 8.12 (dd, J = 10.3, 4.9 Hz, 2H), 8.00 (d, J = 7.0 Hz, 2H), 7.95–7.88 (m, 2H), 4.56 (t, J = 6.4 Hz, 2H), 3.48 (d, J = 6.7 Hz, 1H), 2.58 (t, J = 6.5 Hz, 2H), 1.67 (d, J = 10.8 Hz, 2H), 1.60 (d, J = 12.5 Hz, 2H), 1.50 (d, J = 11.6 Hz, 1H), 1.19 (dd, J = 24.0, 11.8 Hz, 2H), 1.06 (dd, J = 20.5, 8.5 Hz, 3H). ESI-MS: m / z = 446.1312 [M+H] + .

[0156] Example 29 Preparation of N-cyclohexyl-3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)-2-(4-(trifluoromethyl)benzylidene)hydrazino]propanamide

[0157]

[0158] Except for different raw materials, the synthesis and post-treatment of compound D-4 were the same as those in Example 26 to obtain white solid D-4 with a yield of 66.3%; 1 H NMR(400MHz,DMSO- D6 ) δ 8.77–8.73(m,1H),8.63(s,1H),8.13–8.09(m,1H),8.06(d,J=8.1Hz,2H),7.98–7.89(m,5H),4.57(t,J=7.1Hz,2H),3.54–3.44(m,1H),2.59(t,J=7.1Hz,2H),1.67(d,J=11.6Hz,2H),1.60(d,J=12.8Hz,2H),1.50(d,J=12.1Hz,1H),1.19(dd,J=24.2,12.0Hz,2H),1.11–1.02(m,3H).ESI-MS:m / z=507.1667[M+H] + .

[0159] Example 30 Preparation of N-cyclohexyl-3-[1-(1,1-dioxobenzo[d]isothiazol-3-yl)-2-(4-methoxybenzylidene)hydrazino]propanamide

[0160]

[0161] Except for different raw materials, the synthesis and post-treatment of compound D-5 were the same as those in Example 26 to obtain white solid D-5 with a yield of 60.1%; 1 H NMR(400MHz,DMSO- D6 )δ8.77(d,J=7.6Hz,1H),8.46(s,1H),8.05(d,J=6.9Hz,1H),7.95–7.83(m,3H),7.78(d,J=8.7Hz,2H),7.10(d,J=8.7Hz,2H),4.50(t,J=7.2Hz,2H),3.82(s,3H),3.52–3.42(m,1H),2.54(t,J=7.2Hz,2H),1.66(d,J=11.5Hz,2H),1.59(dd,J=9.9,3.1Hz,2H),1.48(d,J=12.4Hz,1H),1.23–1.12(m,2H),1.09–1.00(m,3H).ESI-MS:m / z=469.1901[M+H] + .

[0162] Example 31 Preparation of N-cyclohexyl-3-[1-(1,1-dioxobenzo[d]isothiazol-3-yl)-2-((5-nitrofuran-2-yl)methylene)hydrazino]propanamide

[0163]

[0164] Except for different raw materials, the synthesis and post-treatment of compound D-6 were the same as those in Example 26, and yellow solid D-6 was obtained with a yield of 68.1%; 1 H NMR(400MHz,DMSO- D6 )δ8.98(d,J=7.6Hz,1H),8.45(s,1H),8.11(d,J=6.9Hz,1H),7.96(d,J=7.6Hz,1H),7.93–7.83(m,3H),7.37(d,J=3.9Hz,1H),4.49(t,J=7.2Hz,2H),3.53–3.45(m,1H),2.57(t,J=7.2Hz,2H),1.74–1.67(m,2H),1.62(dd,J=9.5,3.3Hz,2H),1.51(dd,J=8.6,3.5Hz,1H),1.21(dd,J=24.2,12.2Hz,2H),1.14–1.04(m,3H).ESI-MS:m / z=474.1425[M+H] + .

[0165] Example 32 Preparation of N-cyclohexyl-3-[1-(1,1-dioxobenzo[d]isothiazol-3-yl)-2-(2-phenylethylidene)hydrazino]propanamide

[0166]

[0167] Except for different raw materials, the synthesis and post-treatment of compound D-7 were the same as those in Example 26, and white solid D-7 was obtained with a yield of 61.7%; 1 H NMR(400MHz,DMSO- D6)δ 8.03–7.89 (m, 4H), 7.77 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.40 (dd, J = 11.2, 4.6 Hz, 2H), 7.34 (t, J = 8.0 Hz, 2H), 7.22 (ddd, J = 20.7, 14.0, 7.6 Hz, 1H), 4.35 (t, J = 7.2 Hz, 2H), 3.86 (d, J = 4.2 Hz, 2H), 3.54–3.44 (m, 1H), 2.46 (d, J = 7.4 Hz, 2H), 1.73–1.61 (m, 4H), 1.56–1.49 (m, 1H), 1.23 (dd, J = 24.2, 12.1 Hz, 2H), 1.09 (dt, J = 16.8, 6.3 Hz, 3H). ESI-MS: m / z = 453.1944 [M + H] + .

[0168] Example 33 Preparation of N-Cyclohexyl-3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)-2-(pyridin-2-ylmethylene)hydrazino]propanamide

[0169]

[0170] Except for different raw materials, the synthesis and post-treatment of compound D-8 were the same as those in Example 26 to obtain white solid D-8 with a yield of 67.9%; 1 H NMR (400 MHz, DMSO- D6 )δ 9.01 (d, J = 7.2 Hz, 1H), 8.74 (d, J = 4.6 Hz, 1H), 8.44 (s, 1H), 8.10–8.07 (m, 1H), 8.01–7.93 (m, 3H), 7.92–7.85 (m, 2H), 7.53–7.48 (m, 1H), 4.55 (t, J = 7.1 Hz, 2H), 3.53–3.42 (m, 1H), 2.57 (t, J = 7.1 Hz, 2H), 1.67 (d, J = 11.8 Hz, 2H), 1.59 (dd, J = 9.9, 2.9 Hz, 2H), 1.49 (d, J = 12.1 Hz, 1H), 1.18 (dd, J = 24.2, 12.1 Hz, 2H), 1.11–0.99 (m, 3H). ESI-MS: m / z = 440.1741 [M + H] + .

[0171] Example 34 Preparation of N-Cyclohexyl-3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)-2-(3-phenylpropylidene)hydrazino]propanamide

[0172]

[0173] Except for different raw materials, the synthesis and post-treatment of compound D-9 were the same as those in Example 26 to obtain white solid D-9 with a yield of 62.1%; 1 H NMR(400MHz,DMSO- D6 )δ8.53(d,J=7.9Hz,1H),8.02(d,J=7.4Hz,1H),7.92(d,J=7.6Hz,1H),7.85(dt,J=15.3,6.2Hz,2H),7.76(t,J=7.6Hz,1H),7.31(d,J=4.4Hz,4H),7.19(dd,J=9.8,6.6Hz,1H),4.36(t,J=7.2Hz,2H),3.61–3.49(m,1H),2.97(t,J=7.5Hz,2H),2.86–2.79(m,2H),2.47(d,J=7.2Hz,2H),1.76(d,J=11.6Hz,2H),1.68(d,J=12.8Hz,2H),1.56(d,J=12.5Hz,1H),1.27(dd,J=24.3,12.1Hz,2H),1.14(dd,J=20.4,9.7Hz,3H).ESI-MS:m / z=467.2110[M+H] + .

[0174] Example 35 Preparation of 3-[2-(3-chlorobenzylidene)-1-(1,1-dioxidobenzo[d]isothiazol-3-yl)hydrazino]-N-cyclohexylpropanamide

[0175]

[0176] Except for different raw materials, the synthesis and post-treatment of compound D-10 were the same as those in Example 26 to obtain white solid D-10 with a yield of 64.3%; 1 H NMR(400MHz,DMSO- D6)δ8.71(d, J = 7.6 Hz, 1H), 8.51(s, 1H), 8.09(d, J = 7.1 Hz, 1H), 7.90(dd, J = 16.3, 7.7 Hz, 3H), 7.84(dd, J = 9.6, 5.5 Hz, 2H), 7.59(d, J = 4.7 Hz, 2H), 4.53(t, J = 7.1 Hz, 2H), 3.53–3.43(m, 1H), 2.56(t, J = 7.1 Hz, 2H), 1.67(d, J = 11.0 Hz, 2H), 1.60(d, J = 12.9 Hz, 2H), 1.50(d, J = 11.8 Hz, 1H), 1.19(dd, J = 24.2, 12.1 Hz, 2H), 1.11–1.01(m, 3H). ESI-MS: m / z = 473.1403 [M+H] + .

[0177] Example 36 Preparation of Ethyl 2-[2-(3-(Cyclohexylamino)-3-oxopropyl)-2-(1,1-dioxidobenzo[d]isothiazol-3-yl)hydrazonomethyl]acetate

[0178]

[0179] Except for different raw materials, the synthesis and post-treatment of compound D-11 were the same as those in Example 26, and white solid D-11 was obtained with a yield of 53.7%; 1 H NMR(400 MHz, DMSO- D6 )δ8.96(d, J = 6.9 Hz, 1H), 8.12–8.08(m, 1H), 7.95(d, J = 7.6 Hz, 1H), 7.90–7.82(m, 2H), 7.71(s, 1H), 4.41(t, J = 6.8 Hz, 2H), 4.31(q, J = 7.1 Hz, 2H), 3.51–3.41(m, 1H), 1.71–1.65(m, 2H), 1.62(dd, J = 13.0, 2.9 Hz, 2H), 1.50(d, J = 12.2 Hz, 1H), 1.34(t, J = 7.1 Hz, 3H), 1.21(s, 4H), 1.10–1.00(m, 3H). ESI-MS: m / z = 435.1677 [M+H] + .

[0180] Example 37 Preparation of 3-[2-(2-(4-Fluorophenyl)ethylidene)-1-(1,1-dioxidobenzo[d]isothiazol-3-yl)hydrazino]-N-cyclohexylpropanamide

[0181]

[0182] Except for different raw materials, the synthesis and post-treatment of compound D-12 were the same as those in Example 26 to obtain white solid D-12 with a yield of 64.0%; 1 H NMR(400MHz,DMSO- D6 )δ8.07(d,J=8.0Hz,1H),8.00(d,J=7.6Hz,1H),7.96(t,J=4.2Hz,1H),7.90(d,J=7.6Hz,1H),7.81(t,J=7.5Hz,1H),7.51(t,J=7.7Hz,1H),7.42–7.34(m,2H),7.23(t,J=8.8Hz,2H),4.36(t,J=7.1Hz,2H),3.87(d,J=4.1Hz,2H),3.55–3.44(m,1H),2.48(d,J=7.2Hz,2H),1.68(t,J=15.5Hz,4H),1.54(d,J=11.7Hz,1H),1.24(dd,J=23.9,11.9Hz,2H),1.15–1.04(m,3H).ESI-MS:m / z=471.1854[M+H] + .

[0183] Example 38 Preparation of 3-[2-(2-(4-chlorophenyl)ethylidene)-1-(1,1-dioxidobenzo[d]isothiazol-3-yl)hydrazino]-N-cyclohexylpropanamide

[0184]

[0185] Except for different raw materials, the synthesis and post-treatment of compound D-13 were the same as those in Example 26 to obtain white solid D-13 with a yield of 63.2%; 1 H NMR(400MHz,DMSO- D6 )δ8.02–7.94(m,3H),7.90(d,J=7.5Hz,1H),7.81(t,J=7.5Hz,1H),7.48(dd,J=14.7,7.9Hz,3H),7.37(d,J=8.2Hz,2H),4.36(t,J=7.0Hz,2H),3.88(d,J=3.8Hz,2H),3.54–3.44(m,1H),2.48(d,J=7.3Hz,2H),1.68(t,J=15.2Hz,4H),1.54(d,J=11.7Hz,1H),1.24(dd,J=23.6,11.6Hz,2H),1.09(dt,J=16.6,8.4Hz,3H).ESI-MS:m / z=487.1596[M+H] + .

[0186] Example 39 Preparation of 3-[2-(2-(4-bromophenyl)ethylidene)-1-(1,1-dioxidobenzo[d]isothiazol-3-yl)hydrazino]-N-cyclohexylpropanamide

[0187]

[0188] Except for different raw materials, the synthesis and post-treatment of compound D-14 were the same as those in Example 26, and white solid D-14 was obtained with a yield of 61.9%; 1 H NMR(400MHz,DMSO- D6 )δ7.98(dd,J=11.3,8.1Hz,3H),7.89(d,J=7.6Hz,1H),7.80(t,J=7.5Hz,1H),7.59(d,J=8.1Hz,2H),7.49(t,J=7.7Hz,1H),7.30(d,J=8.1Hz,2H),4.35(t,J=7.1Hz,2H),3.85(d,J=3.9Hz,2H),3.53–3.43(m,1H),2.47(d,J=7.1Hz,2H),1.67(t,J=15.2Hz,4H),1.53(d,J=12.1Hz,1H),1.23(dd,J=24.0,12.1Hz,2H),1.13–1.05(m,3H).ESI-MS:m / z=531.1093[M+H] + .

[0189] Example 40 Preparation of N-cyclohexyl-3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)-2-(thiophen-2-ylmethylene)hydrazino]propanamide

[0190]

[0191] Except for different raw materials, the synthesis and post-treatment of compound D-15 were the same as those in Example 26, and white solid D-15 was obtained with a yield of 60.6%; 1 H NMR(400MHz,DMSO- D6)δ 8.81 (d, J = 7.4 Hz, 1H), 8.74 (s, 1H), 8.09 (d, J = 6.4 Hz, 1H), 7.91 (dd, J = 13.0, 6.5 Hz, 3H), 7.82 (d, J = 4.7 Hz, 1H), 7.63 (d, J = 3.1 Hz, 1H), 7.28–7.22 (m, 1H), 4.52 (t, J = 7.0 Hz, 2H), 3.52 (ddd, J = 14.4, 11.1, 5.9 Hz, 1H), 2.58 (t, J = 7.1 Hz, 2H), 1.71 (d, J = 11.7 Hz, 2H), 1.63 (d, J = 12.8 Hz, 2H), 1.52 (d, J = 11.5 Hz, 1H), 1.22 (d, J = 12.3 Hz, 2H), 1.11 (dd, J = 13.9, 7.8 Hz, 3H). ESI-MS: m / z = 445.1363 [M+H] + .

[0192] Example 41 Preparation of N-Cyclohexyl-3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)-2-(2-oxo-2-phenylethylidene)hydrazino]propanamide

[0193]

[0194] Except for different raw materials, the synthesis and post-treatment of compound D-16 were the same as those in Example 26 to obtain white solid D-16 with a yield of 64.1%; 1 H NMR (400 MHz, DMSO- D6 )δ 8.53 (s, 1H), 8.48 (d, J = 7.9 Hz, 1H), 8.08 (d, J = 7.3 Hz, 3H), 7.99 (d, J = 7.3 Hz, 1H), 7.82 (t, J = 7.4 Hz, 1H), 7.74 (t, J = 7.1 Hz, 1H), 7.64–7.56 (m, 3H), 4.57 (t, J = 5.8 Hz, 2H), 3.49 (dd, J = 4.0, 2.9 Hz, 1H), 2.58 (t, J = 6.2 Hz, 2H), 1.65 (d, J = 10.4 Hz, 2H), 1.58 (d, J = 11.8 Hz, 2H), 1.48 (d, J = 11.6 Hz, 1H), 1.22–1.13 (m, 2H), 1.04 (dd, J = 21.5, 10.3 Hz, 3H). ESI-MS: m / z = 467.1732 [M+H] + .

[0195] Example 42 Preparation of 3-[2-Benzoyl-1-(1,1-dioxidobenzo[d]isothiazol-3-yl)hydrazino]-N-cyclohexylpropanamide

[0196]

[0197] Compound 81 (21.0 mg, 0.17 mmol), HATU (89.03 mg, 0.23 mmol), and DIPEA (60.4 mg, 0.47 mmol) were dissolved in dichloromethane (2 ml), stirred at room temperature for 15 min, compound 42 (70 mg, 0.16 mmol) was added, and the reaction was continued at room temperature for 2 h. The reaction was monitored by TLC plate. After completion, saturated ammonium chloride solution (5 ml) was added to quench the reaction, and extraction was carried out. The organic layer was taken, and the aqueous layer was extracted twice with dichloromethane (2 ml). The organic layer was evaporated to dryness, and the crude product was purified by column chromatography to obtain compound D-17 (46.7 mg, 65.8%). 1 H NMR (400 MHz, DMSO- D6 ) δ 11.89 (s, 1H), 8.07 (d, J = 7.5 Hz, 1H), 8.00 (d, J = 7.6 Hz, 2H), 7.91 (t, J = 7.4 Hz, 2H), 7.81 (t, J = 7.5 Hz, 1H), 7.71 (dd, J = 11.2, 7.4 Hz, 2H), 7.61 (t, J = 7.5 Hz, 2H), 4.25–4.17 (m, 1H), 3.95 (dt, J = 13.8, 6.9 Hz, 1H), 3.51–3.42 (m, 1H), 2.61 (t, J = 7.1 Hz, 2H), 1.72–1.59 (m, 4H), 1.51 (d, J = 11.8 Hz, 1H), 1.24–1.15 (m, 2H), 1.13–1.04 (m, 3H). ESI-MS: m / z = 455.1748 [M+H] + .

[0198] Example 43 Preparation of N-Phenyl-3-[1-(1,1-dioxobenzo[d]isothiazol-3-yl)-2-(furan-2-ylmethylene)hydrazino]propanamide

[0199]

[0200] Except for different raw materials, the synthesis and post-treatment of compound D-18 were the same as those in Example 26, and white solid D-18 was obtained with a yield of 61.7%; 1 H NMR (400 MHz, DMSO- D6)δ10.11(s,1H),8.98(dd,J=5.0,3.7Hz,1H),8.47(s,1H),8.10–8.05(m,1H),7.99(s,1H),7.91–7.85(m,2H),7.56(d,J=7.8Hz,2H),7.28(t,J=7.8Hz,2H),7.08(d,J=3.3Hz,1H),7.03(t,J=7.3Hz,1H),6.73(dd,J=3.2,1.7Hz,1H),4.58(t,J=7.3Hz,2H),2.84(t,J=7.3Hz,2H).ESI-MS:m / z=445.0938[M+H] + .

[0201] Example 44 Preparation of N-phenyl-3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)-2-(2-phenylethylidene)hydrazino]propanamide

[0202]

[0203] Except for different raw materials, the synthesis and post-treatment of compound D-19 were the same as those in Example 26 to obtain white solid D-19 with a yield of 65.4%; 1 H NMR(400MHz,DMSO- D6 )δ10.10(s,1H),8.05(t,J=4.4Hz,1H),8.00(dd,J=13.2,7.8Hz,2H),7.76(t,J=7.5Hz,1H),7.55(d,J=7.7Hz,2H),7.48(t,J=7.7Hz,1H),7.38–7.27(m,7H),7.03(t,J=7.4Hz,1H),4.45(t,J=7.3Hz,2H),3.84(d,J=4.3Hz,2H),2.75(t,J=7.3Hz,2H).ESI-MS:m / z=469.1293[M+Na] + .

[0204] Example 45 Preparation of N-cyclopropyl-3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)-2-(furan-2-ylmethylene)hydrazino]propanamide

[0205]

[0206] Except for different raw materials, the synthesis and post-treatment of compound D-20 were the same as those in Example 26 to obtain white solid D-20 with a yield of 64.7%; 1 H NMR(400MHz,DMSO- D6)δ9.00–8.94(m,1H),8.38(s,1H),8.12(d,J=3.2Hz,1H),8.08–8.04(m,1H),7.99(s,1H),7.91–7.85(m,2H),7.09(d,J=3.3Hz,1H),6.74(d,J=1.4Hz,1H),4.48(t,J=7.3Hz,2H),2.60(td,J=7.2,3.7Hz,1H),2.54(d,J=7.3Hz,2H),0.58(q,J=6.7Hz,2H),0.40–0.32(m,2H).ESI-MS:m / z=409.0966[M+Na] + .

[0207] Example 46 Preparation of N-cyclopropyl-3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)-2-(2-phenylethylidene)hydrazino]propanamide

[0208]

[0209] Except for different raw materials, the synthesis and post-treatment of compound D-21 were the same as those in Example 26 to obtain white solid D-21 with a yield of 66.1%; 1 H NMR(400MHz,CDCl3)δ8.08(d,J=3.6Hz,1H),8.02(d,J=8.0Hz,1H),7.96(d,J=6.9Hz,2H),7.76(t,J=7.5Hz,1H),7.48(t,J=7.6Hz,1H),7.42–7.36(m,2H),7.35–7.31(m,2H),7.21(ddd,J=21.1,14.3,7.3Hz,1H),4.35(t,J=7.3Hz,2H),3.86(d,J=4.3Hz,2H),2.58(ddd,J=10.9,7.3,3.7Hz,1H),2.42(s,2H),0.58(td,J=6.8,5.0Hz,2H),0.39–0.33(m,2H).ESI-MS:m / z=411.1377[M+H] + .

[0210] Example 47 Preparation of N-dibenzyl-3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)-2-(furan-2-ylmethylene)hydrazino]propanamide

[0211]

[0212] Except for the different raw materials, the synthesis and post-treatment of compound D-22 were the same as those in Example 26, and white solid D-22 was obtained with a yield of 59.5%; 1 H NMR(400MHz,DMSO- D6 )δ8.98(dd,J=20.6,7.1Hz,2H),8.37(s,1H),8.07(d,J=4.9Hz,1H),7.97(s,1H),7.91–7.85(m,2H),7.29–7.19(m,10H),7.02(s,1H),6.71(s,1H),6.11(d,J=8.2Hz,1H),4.52(t,J=6.3Hz,2H),2.74(t,J=6.4Hz,2H).ESI-MS:m / z=535.1414[M+Na] + .

[0213] Example 48 Preparation of N-dibenzyl-3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)-2-(2-phenylethylidene)hydrazino]propanamide

[0214]

[0215] Except for the different raw materials, the synthesis and post-treatment of compound D-23 were the same as those in Example 26, and white solid D-23 was obtained with a yield of 60.4%; 1 H NMR(400MHz,DMSO- D6 )δ8.99(d,J=8.4Hz,1H),7.95(t,J=6.4Hz,3H),7.74(t,J=7.5Hz,1H),7.47(d,J=7.8Hz,1H),7.34(dd,J=14.8,7.6Hz,3H),7.29–7.19(m,12H),6.10(d,J=8.4Hz,1H),4.38(t,J=6.9Hz,2H),3.73(d,J=3.6Hz,2H),2.65(t,J=6.8Hz,2H).ESI-MS:m / z=537.1958[M+H] + .

[0216] Example 49 Preparation of N-dibenzyl-3-[2-benzylidene-1-(1,1-dioxidobenzo[d]isothiazol-3-yl)hydrazino]propanamide

[0217]

[0218] Except for the different raw materials, the synthesis and post-treatment of compound D-24 were the same as those in Example 26, and white solid D-24 was obtained with a yield of 61.8%; 11H NMR (400 MHz, DMSO- D6 ) δ 9.02 (d, J = 8.5 Hz, 1H), 8.79 (d, J = 7.7 Hz, 1H), 8.54 (s, 1H), 8.09 (d, J = 7.3 Hz, 1H), 7.91 (dt, J = 20.7, 7.2 Hz, 2H), 7.82–7.78 (m, 2H), 7.54 (d, J = 6.3 Hz, 3H), 7.29–7.20 (m, 10H), 6.12 (d, J = 8.4 Hz, 1H), 4.61 (t, J = 7.0 Hz, 2H), 2.78 (t, J = 7.0 Hz, 2H). ESI-MS: m / z = 523.1796 [M+H] + .

[0219] Example 50 Preparation of N-cycloheptyl-3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)-2-(2-phenylethylidene)hydrazino]propanamide

[0220]

[0221] Except for different raw materials, the synthesis and post-treatment of compound D-25 were the same as those in Example 26 to obtain white solid D-25 with a yield of 67.3%; 1 1H NMR (400 MHz, CDCl3) δ 7.95 (dd, J = 8.0, 3.2 Hz, 2H), 7.84 (d, J = 7.6 Hz, 1H), 7.61 (t, J = 7.4 Hz, 1H), 7.38 (dd, J = 16.0, 8.5 Hz, 4H), 7.27 (s, 1H), 7.25–7.23 (m, 1H), 5.78 (d, J = 6.4 Hz, 1H), 4.44 (t, J = 7.1 Hz, 2H), 3.93–3.85 (m, 1H), 3.83 (d, J = 4.3 Hz, 2H), 2.61 (t, J = 7.1 Hz, 2H), 1.90–1.80 (m, 2H), 1.59–1.32 (m, 10H). ESI-MS: m / z = 467.2119 [M+H] + .

[0222] Example 51 Preparation of 3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)-2-(2-phenylethylidene)hydrazino]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)propanamide

[0223]

[0224] Except for different raw materials, the synthesis and post-treatment of compound D-26 were the same as those in Example 26 to obtain white solid D-26 with a yield of 65.1%; 11H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 10.5, 5.9 Hz, 2H), 7.72–7.67 (m, 1H), 7.49 (td, J = 7.1, 2.1 Hz, 1H), 7.28 (d, J = 7.0 Hz, 4H), 7.19–7.15 (m, 2H), 7.06–7.00 (m, 2H), 6.98–6.91 (m, 2H), 5.99 (d, J = 6.1 Hz, 1H), 5.01 (s, 1H), 4.38 (d, J = 6.3 Hz, 2H), 3.75 (s, 2H), 2.73–2.61 (m, 2H), 2.61–2.54 (m, 2H), 1.67 (s, 2H), 1.19–1.13 (m, 2H). ESI-MS: m / z = 501.1953 [M+H] + .

[0225] Example 52 Preparation of 3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)-2-(2-phenylethylidene)hydrazino]-1-(piperidin-1-yl)propan-1-one

[0226]

[0227] Except for different raw materials, the synthesis and post-treatment of compound D-27 were the same as those in Example 26 to obtain white solid D-27 with a yield of 51.8%; ESI-MS: m / z = 439.1791 [M+H] + .

[0228] Example 53 Preparation of 3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)-2-(2-phenylethylidene)hydrazino]-N-(isoxazol-3-yl)propanamide

[0229]

[0230] Except for different raw materials, the synthesis and post-treatment of compound D-28 were the same as those in Example 26 to obtain white solid D-28 with a yield of 63.9%; ESI-MS: m / z = 438.1230 [M+H] + .

[0231] Example 54 Preparation of 3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)-2-(2-phenylethylidene)hydrazino]-N-(naphthalen-2-yl)propanamide

[0232]

[0233] Except for the different raw materials, the synthesis and post-treatment of compound D-29 were the same as those in Example 26, and white solid D-29 was obtained with a yield of 58.3%; ESI-MS: m / z = 497.1642 [M+H] + .

[0234] Example 55 Preparation of Methyl 3-[1-(1,1-Dioxidobenzo[d]isothiazol-3-yl)-2-(furan-2-ylmethylene)hydrazino]propionate

[0235]

[0236] Except for the different raw materials, the synthesis and post-treatment of compound D-30 were the same as those in Example 26, and white solid D-30 was obtained with a yield of 57.6%; 1 H NMR (400 MHz, CDCl3) δ 9.00 (d, J = 7.4 Hz, 1H), 8.08 (s, 1H), 7.92 (d, J = 6.9 Hz, 1H), 7.74 (p, J = 7.4 Hz, 2H), 7.68 (s, 1H), 6.90 (d, J = 2.9 Hz, 1H), 6.63–6.59 (m, 1H), 4.59 (t, J = 7.3 Hz, 2H), 3.74 (s, 3H), 2.90 (t, J = 7.3 Hz, 2H). ESI-MS: m / z = 384.0628 [M+Na] + .

[0237] Example 56 Preparation of Methyl 3-[1-(1,1-Dioxidobenzo[d]isothiazol-3-yl)-2-(2-phenylethylidene)hydrazino]propionate

[0238]

[0239] Except for the different raw materials, the synthesis and post-treatment of compound D-31 were the same as those in Example 26, and white solid D-31 was obtained with a yield of 58.1%; 1 H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.76 (t, J = 4.4 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.46–7.37 (m, 4H), 7.30 (d, J = 6.8 Hz, 2H), 4.49 (t, J = 7.4 Hz, 2H), 3.88 (d, J = 4.3 Hz, 2H), 3.70 (s, 3H), 2.80 (t, J = 7.4 Hz, 2H). ESI-MS: m / z = 408.0985 [M+Na] + .

[0240] Example 57 Preparation of 3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)-2-(2-phenylethylidene)hydrazino]-N-(4-nitrophenyl)propanamide

[0241]

[0242] Except for different raw materials, the synthesis and post-treatment of compound D-32 were the same as those in Example 26 to obtain white solid D-32 with a yield of 64.8%; ESI-MS: m / z = 492.1333 [M+H] + .

[0243] Example 58 Preparation of 3-[1-(1,1-dioxidobenzo[d]isothiazol-3-yl)-2-(2-phenylethylidene)hydrazino]-N-(4-methoxyphenyl)propanamide

[0244]

[0245] Except for different raw materials, the synthesis and post-treatment of compound D-33 were the same as those in Example 26 to obtain white solid D-33 with a yield of 62.1%; ESI-MS: m / z = 477.1590 [M+H] + .

[0246] Example 59 Preparation of 3-[(2-aminoethyl)(phenethyl)amino]benzo[d]isothiazole 1,1-dioxide

[0247]

[0248] Step 1: Synthesis of compound 84: Dissolve compound 83 (2 g, 12.48 mmol), potassium carbonate (2.16 g, 15.6 mmol) and sodium iodide (311.8 mg, 2.08 mmol) in acetonitrile (15 ml), and dropwise add a solution of compound 82 (1.93 g, 10.4 mmol) in acetonitrile (5 ml) at room temperature. After the addition is complete, raise the reaction temperature to 60 °C and react for 12 h. Monitor by TLC. After the reaction is completed, filter off potassium carbonate, rotary evaporate the filtrate and purify by column chromatography to obtain compound 84 (1.9 g, 68.9%); 1HNMR(400MHz,CDCl3)δ7.32(dd,J=14.2,7.0Hz,2H),7.25(dd,J=10.2,4.3Hz,3H),4.94(s,1H),3.23(dd,J=11.2,5.4Hz,2H),2.92(dd,J=10.7,3.8Hz,2H),2.82(t,J=6.8Hz,2H),2.77(t,J=5.9Hz,2H),1.48(s,9H).ESI-MS:m / z=265.1912[M+H] + .

[0249] Step 2. Synthesis of Compound 85: Using compound 84 as the raw material, the synthesis and post-treatment were the same as those in Step 1 of Example 14 to obtain white solid 85 with a yield of 94.6%; 1 H NMR(400MHz,CDCl3)δ7.90(d,J=96.2Hz,1H)7.89(d,J=7.5Hz,1H),7.63(dd,J=17.6,10.3Hz,2H),7.24(d,J=15.2Hz,2H),7.19(s,3H),4.75(d,J=94.2Hz,1H),3.92(d,J=82.7Hz,2H),3.73(t,J=7.6Hz,2H),3.35(d,J=79.0Hz,2H),3.05(t,J=7.6Hz,2H),1.32(s,9H).ESI-MS:m / z=430.1792[M+H] + .

[0250] Step 3. Synthesis of Compound 86: Using compound 85 as the raw material, the synthesis and post-treatment were the same as those in Step 2 of Example 14 to obtain compound 86.

[0251] Example 60 Preparation of 3-[(2-aminoethyl)(benzyl)amino]benzo[d]isothiazole 1,1-dioxide

[0252]

[0253] Synthesis of Compound 88: Using compound 83 as the raw material, the synthesis and post-treatment were the same as those in Step 1 of Example 59 to obtain white solid 88 with a yield of 70.1%; 1 H NMR(400MHz,CDCl3)δ7.24–7.15(m,5H),4.85(s,1H),3.68(s,2H),3.14(d,J=5.6Hz,2H),2.65(t,J=5.8Hz,2H),1.34(s,9H).ESI-MS:m / z=251.1756[M+H] + .

[0254] Synthesis of Compound 89: Using Compound 88 as the starting material, the synthesis and post-treatment were the same as in Step 1 of Example 14 to obtain white solid 89 with a yield of 94.8%; 1 H NMR(400MHz,CDCl3)δ7.95(d,J=7.1Hz,1H),7.66(dd,J=15.0,7.6Hz,1H),7.56–7.29(m,6H),7.24(d,J=6.1Hz,1H),5.14(s,2H),3.87(s,2H),3.67–3.50(m,2H),1.37(s,9H).ESI-MS:m / z=416.1631[M+H] + .

[0255] Synthesis of Compound 90: Using Compound 89 as the starting material, the synthesis and post-treatment were the same as in Step 2 of Example 14 to obtain Compound 90.

[0256] Example 61 Preparation of 3-[(phenethyl)(piperidin-4-yl)amino]benzo[d]isothiazole 1,1-dioxide

[0257]

[0258] Synthesis of Compound 92: Using Compound 91 as the starting material, the synthesis and post-treatment were the same as in Step 1 of Example 59 to obtain white solid 92 with a yield of 61.8%; 1 H NMR(400MHz,CDCl3)δ7.35(dd,J=14.4,7.3Hz,2H),7.27(t,J=6.5Hz,3H),2.98(t,J=7.0Hz,2H),2.87(t,J=7.1Hz,2H),2.72–2.64(m,1H),1.87(d,J=12.3Hz,2H),1.67(s,4H),1.50(s,9H),1.29(ddd,J=15.4,12.4,4.4Hz,2H).ESI-MS:m / z=305.2233[M+H] + .

[0259] Synthesis of Compound 93: Using Compound 92 as the starting material, the synthesis and post-treatment were the same as in Step 1 of Example 14 to obtain white solid 93 with a yield of 93.0%; 11H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7.4 Hz, 1H), 7.81 (s, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.67 (t, J = 7.3 Hz, 1H), 7.35 (dd, J = 24.7, 4.7 Hz, 4H), 7.24 (s, 1H), 4.92 (s, 1H), 4.30 (s, 2H), 3.92 (s, 2H), 3.13–3.07 (m, 2H), 2.86 (t, J = 12.1 Hz, 2H), 1.96 (d, J = 6.9 Hz, 2H), 1.79 (d, J = 11.3 Hz, 2H), 1.49 (s, 9H). ESI-MS: m / z = 470.1927 [M+Na] + .

[0260] Synthesis of Compound 94: Using Compound 93 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 14 to obtain Compound 94.

[0261] Example 62 Preparation of 3-[(Piperidin-4-yl)(ethyl)amino]benzo[d]isothiazole 1,1-dioxide

[0262]

[0263] Synthesis of Compound 96: Using Compound 95 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 14 to obtain white solid 96 with a yield of 95.9%; 1 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.3 Hz, 1H), 7.78 (d, J = 7.0 Hz, 1H), 7.69 (dt, J = 20.6, 7.4 Hz, 2H), 4.89 (s, 1H), 4.28 (s, 2H), 3.79 (d, J = 6.3 Hz, 2H), 2.84 (s, 2H), 1.94 (d, J = 11.5 Hz, 2H), 1.80–1.64 (m, 2H), 1.48 (s, 9H), 1.47–1.40 (m, 3H). ESI-MS: m / z = 349.1798 [M+H] + .

[0264] Synthesis of Compound 97: Using Compound 96 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 14 to obtain Compound 97.

[0265] Example 63 Preparation of 4-[(1,1-Dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino]cyclohexane-1-carboxylic acid

[0266]

[0267] Synthesis of Compound 99: Using compound 98 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 59 to obtain white solid 99 with a yield of 59.1%; 1 H NMR(400MHz,CDCl3)δ7.32(dd,J=13.5,6.2Hz,2H),7.24(t,J=6.0Hz,3H),3.69(s,3H),2.94(t,J=7.2Hz,2H),2.82(t,J=7.1Hz,2H),2.47(tt,J=10.9,3.2Hz,1H),2.28(tt,J=12.2,2.9Hz,1H),2.00(dd,J=10.5,7.7Hz,4H),1.51–1.42(m,2H),1.18–1.06(m,2H).ESI-MS:m / z=262.1805[M+H] + .

[0268] Synthesis of Compound 100: Using compound 99 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 14 to obtain white solid 100 with a yield of 94.3%; 1 H NMR(400MHz,CDCl3)δ7.99(d,J=7.4Hz,1H),7.69(dt,J=14.4,7.6Hz,3H),7.31(d,J=33.5Hz,4H),7.25(s,1H),4.54(d,J=116.5Hz,1H),4.04–3.74(m,2H),3.70(s,3H),3.15–3.08(m,2H),2.34(t,J=11.8Hz,1H),2.19(d,J=11.7Hz,2H),2.06(s,2H),1.72(dt,J=25.7,11.5Hz,4H).ESI-MS:m / z=427.1688[M+H] + .

[0269] Synthesis of Compound 101: Dissolve compound 100 (200 mg, 0.47 mmol) in methanol (3 ml), add LiOH (56.1 mg, 2.34 mmol) and water (1 ml), and react at room temperature for 2 h. Monitor the reaction by TLC plate. After evaporating the methanol, adjust the pH to weakly acidic (pH = 5 - 6) with 1 M dilute hydrochloric acid. A white solid precipitates. Filter by suction, wash the filtrate with water (1 ml × 2), and the filter cake can be directly used for the next step after drying.

[0270] Example 64 Preparation of 3-[(azetidin-3-yl)(phenethyl)amino]benzo[d]isothiazole 1,1-dioxide

[0271]

[0272] Synthesis of Compound 103: Using Compound 102 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 59 to obtain white solid 103 with a yield of 62.1%; 1 H NMR(400MHz,CDCl3)δ7.31(t,J = 7.3Hz,2H),7.21(dd,J = 14.0,7.1Hz,3H),4.11–4.01(m,2H),3.63–3.53(m,3H),2.85–2.76(m,4H),1.42(s,9H).ESI-MS:m / z = 277.1986[M+H] + .

[0273] Synthesis of Compound 104: Using Compound 103 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 14 to obtain white solid 103 with a yield of 92.7%; 1 H NMR(400MHz,CDCl3)δ7.86(d,J = 7.4Hz,1H),7.64(t,J = 7.4Hz,2H),7.57(t,J = 7.6Hz,1H),7.24(t,J = 7.3Hz,2H),7.18(d,J = 7.2Hz,1H),7.10(d,J = 7.1Hz,2H),4.89(s,1H),4.13(t,J = 7.9Hz,2H),4.03(s,2H),3.92(s,2H),2.98(t,J = 7.4Hz,2H),1.34(s,9H).ESI-MS:m / z = 442.1803[M+H] + .

[0274] Synthesis of Compound 105: Using Compound 104 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 14 to obtain Compound 105.

[0275] Example 65 Preparation of 3-[(4-Aminophenyl)(phenethyl)amino]benzo[d]isothiazole 1,1-dioxide

[0276]

[0277] Synthesis of Compound 107: Using Compound 106 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 59 to obtain white solid 107 with a yield of 58.3%; 11H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 7.3 Hz, 2H), 7.23 (dd, J = 13.3, 7.3 Hz, 3H), 7.16 (d, J = 6.9 Hz, 2H), 6.57 (d, J = 8.7 Hz, 2H), 3.55 (s, 1H), 3.37 (t, J = 6.7 Hz, 2H), 2.90 (t, J = 6.9 Hz, 2H), 1.50 (s, 9H). ESI-MS: m / z = 313.1978 [M+H] + .

[0278] Synthesis of Compound 108: Using Compound 107 as the starting material, the synthesis and post-treatment were the same as in Step 1 of Example 14 to obtain white solid 108 with a yield of 95.5%; 1 1H NMR (400 MHz, DMSO- D6 ) δ 8.02 (d, J = 6.4 Hz, 1H), 7.73 (t, J = 6.1 Hz, 1H), 7.50 (t, J = 6.7 Hz, 1H), 7.34 (d, J = 5.7 Hz, 2H), 7.27 (d, J = 5.4 Hz, 3H), 7.09 (d, J = 6.6 Hz, 2H), 6.75 (d, J = 6.8 Hz, 2H), 6.10 (d, J = 7.3 Hz, 1H), 4.15 - 4.07 (m, 2H), 3.10–3.02 (m, 2H), 1.49 (s, 9H). ESI-MS: m / z = 478.1794 [M+H] + .

[0279] Synthesis of Compound 109: Using Compound 108 as the starting material, the synthesis and post-treatment were the same as in Step 2 of Example 14 to obtain Compound 109.

[0280] Example 66 Preparation of 3-((4-aminophenyl)amino)benzo[d]isothiazole 1,1-dioxide

[0281]

[0282] Synthesis of Compound 110: Using Compound 106 as the starting material, the synthesis and post-treatment were the same as in Step 1 of Example 14 to obtain white solid 110 with a yield of 81.0%; ESI-MS: m / z = 374.1165 [M+H] + .

[0283] Synthesis of Compound 111: Using Compound 110 as the starting material, the synthesis and post-treatment were the same as in Step 2 of Example 14 to obtain Compound 111.

[0284] Example 67 Preparation of 3-((4-aminophenyl)(methyl)amino)benzo[d]isothiazole 1,1-dioxide

[0285]

[0286] Synthesis of Compound 112: Using compound 106 and CH3I as raw materials, the synthesis and post-treatment were the same as in Step 1 of Example 59 to obtain white solid 113 with a yield of 65.8%; ESI-MS: m / z = 223.1440 [M+H] + .

[0287] Synthesis of Compound 113: Using compound 112 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 14 to obtain white solid 113 with a yield of 94.2%; ESI-MS: m / z = 388.1321 [M+H] + .

[0288] Synthesis of Compound 114: Using compound 113 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 14 to obtain compound 114.

[0289] Example 68 Preparation of 3-((4-aminophenyl)(ethyl)amino)benzo[d]isothiazole 1,1-dioxide

[0290]

[0291] Synthesis of Compound 115: Using compound 106 and CH3CH2I as raw materials, the synthesis and post-treatment were the same as in Step 1 of Example 59 to obtain white solid 115 with a yield of 67.1%; ESI-MS: m / z = 237.1600 [M+H] + .

[0292] Synthesis of Compound 116: Using compound 115 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 14 to obtain white solid 116 with a yield of 95.6%; ESI-MS: m / z = 402.1481 [M+H] + .

[0293] Synthesis of Compound 117: Using compound 113 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 14 to obtain compound 117.

[0294] Example 69 Preparation of 3-[(4-aminophenyl)(benzyl)amino]benzo[d]isothiazole 1,1-dioxide

[0295]

[0296] Synthesis of Compound 118: Using compound 106 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 59 to obtain white solid 118 with a yield of 62.6%; ESI-MS: m / z = 299.1755 [M+H] + .

[0297] Synthesis of Compound 119: Using Compound 118 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 14, and white solid 119 was obtained with a yield of 96.3%; ESI-MS: m / z = 464.1638 [M+H] + .

[0298] Synthesis of Compound 120: Using Compound 119 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 14, and Compound 120 was obtained.

[0299] Example 70 Preparation of 3-[(4-Aminophenyl)(cyclohexylethyl)amino]benzo[d]isothiazole 1,1-dioxide

[0300]

[0301] Synthesis of Compound 122: Using Compound 106 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 59, and white solid 122 was obtained with a yield of 59.8%; ESI-MS: m / z = 319.2385 [M+H] + .

[0302] Synthesis of Compound 123: Using Compound 122 as the raw material, the synthesis and post-treatment were the same as in Step 1 of Example 14, and white solid 123 was obtained with a yield of 95.1%; ESI-MS: m / z = 484.2261 [M+H] + .

[0303] Synthesis of Compound 124: Using Compound 123 as the raw material, the synthesis and post-treatment were the same as in Step 2 of Example 14, and Compound 124 was obtained.

[0304] Example 71 Preparation of N-[2-[(1,1-Dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino]ethyl]cyclopentanecarboxamide

[0305]

[0306] Except for different raw materials, the synthesis and post-treatment of Compound D-34 were the same as in Example 42, and white solid D-34 was obtained with a yield of 71.8%; 11H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 5.6 Hz, 0.4H), 7.98 (d, J = 7.0 Hz, 1H), 7.81 (d, J = 7.7 Hz, 0.6H), 7.72 (dd, J = 17.8, 7.5 Hz, 2H), 7.46–7.21 (m, 5H), 6.35 (s, 0.6H), 5.90 (s, 0.4H), 4.13 (t, J = 7.2 Hz, 1.2H), 3.91 (s, 0.8H), 3.86 (t, J = 6.5 Hz, 2H), 3.66 (d, J = 5.3 Hz, 1.23H), 3.46 (s, 0.73H), 3.15 (d, J = 6.8 Hz, 2H), 2.65 - 2.45 (m, 3H), 1.9 - 1.79 (m, 2H), 1.72 - 1.60 (m, 4H), 1.60 - 1.47 (m, 2H). ESI-MS: m / z = 426.1850 [M+H] + .

[0307] Example 72 Preparation of N-[2-[(1,1-Dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino]ethyl]cyclohexanecarboxamide

[0308]

[0309] Except for different raw materials, the synthesis and post-treatment of compound D-35 were the same as those in Example 42 to obtain white solid D-35 with a yield of 74.1%; 1 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 0.34H), 7.95 (d, J = 6.1 Hz, 1H), 7.78 (d, J = 7.4 Hz, 0.61H), 7.75 - 7.65 (m, 2H), 7.40 - 7.20 (m, 5H), 6.31 (s, 0.58H), 5.78 (s, 0.32H), 4.09 (s, 1.27H), 3.88 (s, 0.72H), 3.86 - 3.76 (s, 2H), 3.68 - 3.52 (m, 1.33H), 3.41 (s, 0.75H), 3.12 (d, J = 6.1 Hz, 2H), 2.12 - 2.06 (m, 1H), 1.80 - 1.50 (m, 7H), 1.42–1.17 (m, 3H). ESI-MS: m / z = 440.2002 [M+H] + .

[0310] Example 73 Preparation of N-[2-[(1,1-Dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino]ethyl]benzamide

[0311]

[0312] Except for different raw materials, the synthesis and post-treatment of compound D-36 were the same as those in Example 42 to obtain white solid D-36 with a yield of 77.6%; 1 H NMR(400MHz,CDCl3)δ8.39(s,0.24H),8.05-7.60(m,5H),7.50–7.15(m,9H),4.14(s,1.42H),4.14-3.65(m,4H),3.66(s,0.7H),3.15(t,J=7.3Hz,2H).ESI-MS:m / z=434.1538[M+H] + .

[0313] Example 74 Preparation of N-[2-[(1,1-dioxobenzo[d]isothiazol-3-yl)(phenethyl)amino]ethyl]-4-fluorobenzamide

[0314]

[0315] Except for different raw materials, the synthesis and post-treatment of compound D-37 were the same as those in Example 42 to obtain white solid D-37 with a yield of 75.4%; 1 H NMR(400MHz,CDCl3)δ8.85(s,0.55H),8.74(s,0.39H),8.40(d,J=7.3Hz,0.54H),8.07–7.98(m,1.43H),7.96-7.77(m,4H),7.37–7.18(m,7H),4.14(t,J=7.3Hz,0.83H),4.00(d,J=6.6Hz,1.15H),3.91–3.81(m,1.16H),3.76(d,J=5.2Hz,0.83H),3.65(d,J=5.4Hz,2H),3.14–2.98(m,2H).ESI-MS:m / z=452.1441[M+H] + .

[0316] Example 75 Preparation of N-[2-[(1,1-dioxobenzo[d]isothiazol-3-yl)(phenethyl)amino]ethyl]-10H-benzo[b]thiazine-10-carboxamide

[0317]

[0318] Except for different raw materials, the synthesis and post-treatment of compound D-38 were the same as those in Example 14 to obtain white solid D-38 with a yield of 86.2%; 11H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.53–7.43 (m, 4H), 7.24 (d, J = 7.6 Hz, 2H), 7.13 (d, J = 7.4 Hz, 2H), 7.07–6.96 (m, 5H), 6.82 (d, J = 7.2 Hz, 2H), 3.70–3.58 (m, 4H), 3.33–3.25 (m, 2H), 2.40–2.30 (m, 2H). ESI-MS: m / z = 555.1510 [M+H] + .

[0319] Preparation of Example 76 (E)-N-[2-[(1,1-Dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino]ethyl]-3-(4-fluorophenyl)acrylamide

[0320]

[0321] Except for different raw materials, the synthesis and post-treatment of Compound D-39 were the same as those in Example 42 to obtain white solid D-39 with a yield of 76.4%; 1 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 7.90 (d, J = 7.0 Hz, 1H), 7.76–7.67 (m, 3H), 7.60 (d, J = 15.3 Hz, 1H), 7.41 (dd, J = 8.3, 5.5 Hz, 2H), 7.35 (t, J = 7.4 Hz, 2H), 7.29 (d, J = 5.2 Hz, 1H), 7.23 (d, J = 7.7 Hz, 2H), 7.10 (t, J = 8.5 Hz, 2H), 6.45 (d, J = 15.3 Hz, 1H), 3.88–3.70 (m, 6H), 3.02 (t, J = 6.8 Hz, 2H). ESI-MS: m / z = 478.1602 [M+H] + .

[0322] Preparation of Example 77 N-[2-[(1,1-Dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino]ethyl]-2,2-diphenylacetamide

[0323]

[0324] Except for different raw materials, the synthesis and post-treatment of Compound D-40 were the same as those in Example 42 to obtain white solid D-40 with a yield of 73.2%; 11H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.1 Hz, 0.3H), 7.99 (d, J = 7.3 Hz, 1H), 7.84–7.56 (m, 2.7H), 7.46–7.11 (m, 15H), 6.52 (s, 0.6H), 6.08 (s, 0.26H), 4.88 (s, 1H), 4.00 (s, 1.25H), 3.83 (t, J = 6.5 Hz, 2.56H), 3.70 (d, J = 5.2 Hz, 1.32H), 3.49 (s, 0.64H), 3.20–2.99 (m, 2H). ESI-MS: m / z = 524.2002 [M+H] + .

[0325] Example 78 Preparation of N-[2-[(1,1-dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino]ethyl]-benzofuran-2-carboxamide

[0326]

[0327] Except for different raw materials, the synthesis and post-treatment of compound D-41 were the same as those in Example 42 to obtain white solid D-41 with a yield of 77.1%; 1 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 44.4 Hz, 0.22H), 8.00 (d, J = 7.0 Hz, 0.87H), 7.89–7.60 (m, 4.81H), 7.56–7.24 (m, 9.33H), 7.09 (s, 0.5H), 4.17 (s, 1.24H), 3.97 (d, J = 34.7 Hz, 4.09H), 3.70 (s, 0.72H), 3.19 (s, 2H). ESI-MS: m / z = 474.1488 [M+H] + .

[0328] Example 79 Preparation of N-[2-[(1,1-dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino]ethyl]-2,2-bis(4-fluorophenyl)acetamide

[0329]

[0330] Except for different raw materials, the synthesis and post-treatment of compound D-42 were the same as those in Example 42 to obtain white solid D-42 with a yield of 71.5%; 11H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.4 Hz, 1H), 7.75 (d, J = 5.1 Hz, 1H), 7.64 (s, 2H), 7.35 (t, J = 7.0 Hz, 2H), 7.30 (d, J = 6.9 Hz, 1H), 7.18 (d, J = 6.3 Hz, 5H), 6.98 (d, J = 7.4 Hz, 1H), 6.82 (t, J = 8.3 Hz, 3H), 6.68 (s, 1H), 4.74 (s, 1H), 3.95 (t, J = 7.5 Hz, 2H), 3.80 (d, J = 5.2 Hz, 2H), 3.68 (d, J = 5.4 Hz, 2H), 3.01 (t, J = 7.4 Hz, 2H). ESI-MS: m / z = 560.1825 [M+H] + .

[0331] Example 80 Preparation of N-[2-[(1,1-dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino]ethyl]-3-(4-fluorophenyl)propanamide

[0332]

[0333] Except for different raw materials, the synthesis and post-treatment of compound D-43 were the same as those in Example 42 to obtain white solid D-43 with a yield of 73.1%; 1 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 2H), 7.82–7.64 (m, 4H), 7.39–7.25 (m, 5H), 7.10 (s, 3H), 6.76 (s, 2H), 6.46 (s, 1H), 4.11 - 3.90 (m, 2H), 3.81 - 3.74 (m, 2H), 3.59 - 3.49 (m, 2H), 3.12 - 2.98 (m, 2H), 2.93 - 2.80 (m, 2H), 2.52 - 2.45 (m, 2H). ESI-MS: m / z = 480.1866 [M+H]+.

[0334] Example 81 Preparation of N-[2-(benzyl(1,1-dioxidobenzo[d]isothiazol-3-yl)amino)ethyl]cyclohexanecarboxamide

[0335]

[0336] Except for different raw materials, the synthesis and post-treatment of compound D-44 were the same as those in Example 42 to obtain white solid D-44 with a yield of 74.5%; 11H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.4 Hz, 1H), 7.69 (s, 1H), 7.58 - 7.33 (m, 5H), 7.33 - 7.17 (m, 2H), 6.51 (s, 0.74H), 6.09 (s, 0.15H), 3.93 (s, 2H), 3.71 (d, J = 4.4 Hz, 2H), 2.09 (d, J = 10.6 Hz, 1H), 1.76 - 1.61 (m, 4H), 1.45 - 1.14 (m, 6H). ESI-MS: m / z = 426.1847 [M+H] + .

[0337] Example 82 Preparation of 1-[4-[(1,1-dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino]piperidin-1-yl]-2,2-bis(4-fluorophenyl)ethan-1-one

[0338]

[0339] Except for different raw materials, the synthesis and post-treatment of compound D-45 were the same as those in Example 42 to obtain white solid D-45 with a yield of 77.3%; 1 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.4 Hz, 1H), 7.92 - 7.66 (m, 3H), 7.53 - 7.28 (m, 5H), 7.25 - 7.15 (m, 4H), 7.14 - 7.00 (m, 4H), 4.95 (d, J = 12.9 Hz, 1H), 4.10 (d, J = 13.4 Hz, 1H), 3.81 (s, 2H), 3.17 (t, J = 12.6 Hz, 1H), 3.11 - 2.91 (m, 2H), 2.75 (t, J = 12.4 Hz, 1H), 2.04 (s, 1H), 1.95 - 1.73 (m, 2H), 1.36 - 1.16 (m, 2H), 0.96 - 0.85 (m, 1H). ESI-MS: m / z = 600.2127 [M+H] + .

[0340] Example 83 Preparation of (4-[(1,1-dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino]piperidin-1-yl)(quinolin-2-yl)methanone

[0341]

[0342] Except for different raw materials, the synthesis and post-treatment of compound D-46 were the same as those in Example 42 to obtain white solid D-46 with a yield of 69.8%; 11H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 7.4 Hz, 1H), 7.97–7.64 (m, 7H), 7.50 - 7.20 (m, 5H), 5.25 - 5.05 (m, 2H), 4.39 (d, J = 11.1 Hz, 1H), 4.05 (s, 2H), 3.31 (t, J = 13.5 Hz, 1H), 3.17 (t, J = 8.3 Hz, 2H), 3.02 (t, J = 12.4 Hz, 1H), 2.31–1.98 (m, 4H). ESI-MS: m / z = 525.1957 [M+H] + .

[0343] Preparation of Example 84 (4-[(1,1-Dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino]piperidin-1-yl)(4-fluorophenyl)methanone

[0344]

[0345] Except for different raw materials, the synthesis and post-treatment of Compound D-47 were the same as those in Example 42 to obtain white solid D-47 with a yield of 76.8%; 1 1H NMR (400 MHz, CDCl3) δ 8.01 (t, J = 8.1 Hz, 1H), 7.90–7.63 (m, 3H), 7.55–7.26 (m, 7H), 7.15 (t, J = 8.5 Hz, 2H), 5.01 (s, 2H), 3.98 (s, 2H), 3.37–2.85 (m, 4H), 2.22–1.76 (m, 4H), 1.29 (dd, J = 12.4, 5.2 Hz, 1H). ESI-MS: m / z = 492.1748 [M+H] + .

[0346] Preparation of Example 85 N-Cyclohexyl-4-((1,1-dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino)piperidine-1-carboxamide

[0347]

[0348] Except for different raw materials, the synthesis and post-treatment of Compound D-48 were the same as those in Example 42 to obtain white solid D-48 with a yield of 76.4%; 11H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.0 Hz, 1H), 7.95–7.62 (m, 3H), 7.54–7.16 (m, 5H), 4.91 (d, J = 11.2 Hz, 1H), 4.19–3.61 (m, 2H), 3.33–3.00 (m, 2H), 2.60 (d, J = 52.2 Hz, 2H), 2.05 (s, 2H), 1.78 (dd, J = 30.6, 17.0 Hz, 8H), 1.59 (d, J = 32.7 Hz, 2H), 1.34 (t, J = 22.0 Hz, 5H). ESI-MS: m / z = 480.2317 [M+H] + .

[0349] Preparation of Example 86 (E)-1-[4-[(1,1-Dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino]piperidin-1-yl]-3-(4-fluorophenyl)prop-2-en-1-one

[0350]

[0351] Except for different raw materials, the synthesis and post-treatment of compound D-49 were the same as those in Example 42 to obtain white solid D-49 with a yield of 77.2%; 1 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 6.7 Hz, 1H), 7.68 (t, J = 6.5 Hz, 1H), 7.64–7.58 (m, 2H), 7.50–7.44 (m, 2H), 7.28 (d, J = 26.9 Hz, 3H), 7.18 (dd, J = 11.8, 4.5 Hz, 3H), 7.01 (t, J = 7.5 Hz, 2H), 6.78 (d, J = 14.9 Hz, 1H), 5.04–4.87 (m, 1H), 4.24–3.81 (m, 2H), 3.33–3.12 (m, 1H), 3.02 (t, J = 7.5 Hz, 2H), 2.73 (d, J = 1.9 Hz, 3H), 2.15–1.63 (m, 4H). ESI-MS: m / z = 518.1986 [M+H] + .

[0352] Preparation of Example 87 1-[4-[(1,1-Dioxidobenzo[d]isothiazol-3-yl)(ethyl)amino]piperidin-1-yl]-2,2-bis(4-fluorophenyl)ethan-1-one

[0353]

[0354] Except for different raw materials, the synthesis and post-treatment of compound D-50 were the same as those in Example 42 to obtain white solid D-50 with a yield of 74.8%;1 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.2 Hz, 1H), 7.77–7.63 (m, 3H), 7.29 (d, J = 5.2 Hz, 2H), 7.18–7.11 (m, 2H), 7.07 (t, J = 8.3 Hz, 2H), 7.00 (t, J = 8.4 Hz, 2H), 5.23 (s, 1H), 4.87 (d, J = 11.4 Hz, 2H), 4.03 (d, J = 13.2 Hz, 1H), 3.64 (s, 2H), 3.11 (t, J = 12.6 Hz, 1H), 2.69 (t, J = 12.4 Hz, 1H), 1.97 (d, J = 11.3 Hz, 1H), 1.82 (d, J = 11.8 Hz, 1H), 1.69 (d, J = 11.0 Hz, 1H), 1.36 (t, J = 6.2 Hz, 3H), 1.06 (d, J = 8.2 Hz, 1H). ESI-MS: m / z = 524.1818 [M+H] + .

[0355] Preparation of cyclohexyl[4-[(1,1-dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino]cyclohexyl]methanone in Example 88

[0356]

[0357] Except for different raw materials, the synthesis and post-treatment of compound D-51 were the same as those in Example 42 to obtain white solid D-51 with a yield of 79.3%; 1 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.4 Hz, 1H), 7.73 (dt, J = 14.0, 7.3 Hz, 3H), 7.31 (t, J = 15.0 Hz, 6H), 5.47 (d, J = 6.5 Hz, 1H), 4.47 (s, 1H), 4.06–3.67 (m, 3H), 3.21–3.06 (m, 2H), 2.10 (d, J = 9.1 Hz, 6H), 1.94 (d, J = 9.9 Hz, 2H), 1.91–1.58 (m, 11H), 1.50–1.08 (m, 7H). ESI-MS: m / z = 496.2474 [M+H] + .

[0358] Preparation of 1-[3-[(1,1-dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino]azepan-1-yl]-2,2-bis(4-fluorophenyl)ethan-1-one in Example 89

[0359]

[0360] Except for the different raw materials, the synthesis and post-treatment of compound D-52 were the same as those in Example 42, and white solid D-52 was obtained with a yield of 70.5%; ESI-MS: m / z = 572.1821 [M+H] + .

[0361] Example 90 Preparation of N-(4-((1,1-dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino)phenyl)-2,2-bis(4-fluorophenyl)acetamide

[0362]

[0363] Except for the different raw materials, the synthesis and post-treatment of compound D-53 were the same as those in Example 42, and white solid D-53 was obtained with a yield of 71.1%; 1 H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.85 (d, J = 7.4 Hz, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.54 (t, J = 7.1 Hz, 1H), 7.40–7.32 (m, 4H), 7.27–7.15 (m, 7H), 7.07 (t, J = 8.4 Hz, 6H), 6.00 (d, J = 7.7 Hz, 1H), 4.19–4.08 (m, 2H), 3.15–3.05 (m, 2H). ESI-MS: m / z = 630.1620 [M+Na] + .

[0364] Example 91 Preparation of N-(4-((1,1-dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino)phenyl)cyclohexanecarboxamide

[0365]

[0366] Except for the different raw materials, the synthesis and post-treatment of compound D-54 were the same as those in Example 42, and white solid D-54 was obtained with a yield of 74.3%; ESI-MS: m / z = 488.2000 [M+H] + .

[0367] Example 92 Preparation of 2,2-bis(4-chlorophenyl)-N-(4-((1,1-dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino)phenyl)acetamide

[0368]

[0369] Except for the different raw materials, the synthesis and post-treatment of compound D-55 were the same as those in Example 42, and white solid D-55 was obtained with a yield of 68.2%; ESI-MS: m / z = 612.1278 [M+H] + .

[0370] Example 93 Preparation of N-(4-((1,1-dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino)phenyl)-9H-fluorene-9-carboxamide

[0371]

[0372] Except for the different raw materials, the synthesis and post-treatment of compound D-56 were the same as those in Example 42 to obtain white solid D-56 with a yield of 70.6%; ESI-MS: m / z = 470.1849 [M+H] + .

[0373] Example 94 Preparation of N-(4-((1,1-dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino)phenyl)-2,2-diphenylacetamide

[0374]

[0375] Except for the different raw materials, the synthesis and post-treatment of compound D-57 were the same as those in Example 42 to obtain white solid D-57 with a yield of 68.2%; ESI-MS: m / z = 544.2050 [M+H] + .

[0376] Example 95 Preparation of N-(4-((1,1-dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino)phenyl)benzamide

[0377]

[0378] Except for the different raw materials, the synthesis and post-treatment of compound D-58 were the same as those in Example 42 to obtain white solid D-58 with a yield of 79.6%; ESI-MS: m / z = 482.1528 [M+H] + .

[0379] Example 96 Preparation of N-(4-((1,1-dioxidobenzo[d]isothiazol-3-yl)(phenethyl)amino)phenyl)isobutyramide

[0380]

[0381] Except for the different raw materials, the synthesis and post-treatment of compound D-59 were the same as those in Example 42 to obtain white solid D-59 with a yield of 78.8%; ESI-MS: m / z = 448.1685 [M+H] + .

[0382] Example 97 Preparation of N-(4-((1,1-dioxidobenzo[d]isothiazol-3-yl)amino)phenyl)-2,2-bis(4-fluorophenyl)acetamide

[0383]

[0384] Except for different raw materials, the synthesis and post-treatment of compound D-60 were the same as those in Example 42 to obtain white solid D-60 with a yield of 64.5%; ESI-MS: m / z = 506.1651 [M+H] + .

[0385] Example 98 Preparation of N-(4-((1,1-dioxobenzo[d]isothiazol-3-yl)(methyl)amino)phenyl)-2,2-bis(4-fluorophenyl)acetamide

[0386]

[0387] Except for different raw materials, the synthesis and post-treatment of compound D-61 were the same as those in Example 42 to obtain white solid D-61 with a yield of 70.9%; ESI-MS: m / z = 518.1349 [M+H] + .

[0388] Example 99 Preparation of N-(4-((1,1-dioxobenzo[d]isothiazol-3-yl)(ethyl)amino)phenyl)-2,2-bis(4-fluorophenyl)acetamide

[0389]

[0390] Except for different raw materials, the synthesis and post-treatment of compound D-62 were the same as those in Example 42 to obtain white solid D-62 with a yield of 73.5%; ESI-MS: m / z = 532.1498 [M+H] + .

[0391] Example 100 Preparation of N-(4-((1,1-dioxobenzo[d]isothiazol-3-yl)(benzyl)amino)phenyl)-2,2-bis(4-fluorophenyl)acetamide

[0392]

[0393] Except for different raw materials, the synthesis and post-treatment of compound D-63 were the same as those in Example 42 to obtain white solid D-63 with a yield of 69.7%; ESI-MS: m / z = 594.1663 [M+H] + .

[0394] Example 101 Preparation of N-(4-((2-cyclohexylethyl)(1,1-dioxobenzo[d]isothiazol-3-yl)amino)phenyl)-2,2-bis(4-fluorophenyl)acetamide

[0395]

[0396] Except for different raw materials, the synthesis and post-treatment of compound D-64 were the same as those in Example 42, and white solid D-64 was obtained with a yield of 71.3%; ESI-MS: m / z = 614.2289 [M+H] + .

[0397] Testing of the 20S proteasome agonist activity of some saccharin compounds

[0398] Experimental method: The fluorescence substrate Suc-Leu-Leu-Val-Tyr-AMC was used to detect the activity, and the activation of the enzyme by different compounds was observed to preliminarily evaluate the activation effect of the compounds. The 20S proteasome hydrolyzes the Tyr-AMC sequence in the substrate to release AMC, and the fluorescence absorption value of the hydrolyzed product AMC can be detected under the conditions of excitation light at 355 nm and emission light at 460 nm to observe the activation of the enzyme activity by the compounds. The test results are shown in Table 1. Among them, if the 20S proteasome hydrolysis activity agonist multiple (Activity(%)@20μM) of the compound at a concentration of 20 μM is above 100%, it means that the compound has agonist activity, and if it is 200% and above, it means that the compound has good agonist activity. Other compounds prepared by the present invention that are not listed in the table also all have certain agonist activity.

[0399] The compounds of the present invention all have certain 20S proteasome agonist activity, and the results are shown in Table 1 and Table 2.

[0400] Table 1 Agonist activity of compounds on 20S proteasome at a concentration of 20 μM

[0401]

[0402]

[0403]

[0404] Activity(%)@20μM: 20S proteasome hydrolysis activity agonist multiple of the compound at a concentration of 20 μM

[0405] Table 2 Agonist activity of compounds on 20S proteasome

[0406]

[0407] Max Fold increase: Maximum agonist multiple of the compound on 20S proteasome

[0408] Most of the compounds of the present invention have good 20S proteasome agonist activity, and the half-maximal effective concentration of some compounds reaches the submicromolar level, indicating that this type of compound has excellent prospects for disease treatment applications and thus has good commercial value.

Claims

1. A compound having the general formula (I): in: X is selected from or lack thereof; Y is selected from NH, O, or lack thereof; Linker is selected from C 1-4 Alkyl, alkylamino, aryl, substituted aryl, C 4-7 Cycloalkyl, heterocycloalkyl; A is selected from C 1-4 Alkyl, aralkyl, ethyloxycarbonyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic aryl, unsubstituted or substituted alkaryl; the substitution is halogen, nitro, trifluoromethyl, methoxy, C 1-2 The alkyl group is arbitrarily substituted; R is selected from C 1-3 Alkyl, C 3-7 Cycloalkyl, heterocyclic group, benzoheterocyclic group, substituted or unsubstituted aryl; the substituted aryl is arbitrarily substituted by halogen, ethyl, nitro, methoxy.

2. The compound according to claim 1, characterized in that In the compound: Linker is selected from ethyl, ethylamino, anilino, piperidinyl, azetidinyl, cyclobutyl, cyclohexyl; A is selected from methyl, ethyl, isopropyl, isobutyl, ethyloxycarbonyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic aryl, and alkaryl, wherein the unsubstituted or substituted aryl is selected from phenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, and benzoyl, the unsubstituted or substituted heterocyclic aryl is selected from furanyl, 2-nitrofuranyl, thiazolyl, pyridyl, and thienyl, and the alkaryl is selected from benzyl and phenethyl; R is selected from methyl, isopropyl, C 3-7 Cycloalkyl, heterocyclic, benzoheterocyclic, substituted or unsubstituted aryl; wherein the C 3-7 The cycloalkyl group is selected from cyclopropyl, cyclopentyl, cyclohexyl, and cycloheptyl, the heterocyclic group is selected from piperidinyl and isoxazolyl, the benzoheterocyclic group is selected from quinolyl, benzofuranyl, phenothiazinyl, and phenylthiazolyl, and the substituted or unsubstituted aryl group is selected from phenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-fluorophenethyl, 4-fluorophenylvinyl, tetrahydronaphthyl, naphthyl, diphenylmethyl, bis(4-fluorophenyl)methyl, and fluorenyl.

3. The compound according to claim 1, characterized in that The compound is selected from:

4. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 3, a stereoisomer or a pharmaceutically acceptable salt of the compound as an active ingredient, or further comprising one or more pharmaceutically acceptable carriers or excipients.

5. The pharmaceutical composition according to claim 4, characterized in that: The administration method of the pharmaceutical composition is selected from oral administration, injection, inhalation and implantation.

6. The pharmaceutical composition according to claim 4, characterized in that: The dosage form of the pharmaceutical composition is injection, lyophilized powder injection, tablet, capsule or granule.

7. Use of the compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt, solvate, or the pharmaceutical composition according to claim 4 in the preparation of drugs for protein toxic diseases.

8. The use according to claim 7, characterized in that The diseases are neurodegenerative diseases, cardiovascular diseases, and metabolic diseases; wherein: the neurodegenerative diseases are Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellar atrophy, multiple sclerosis, Parkinson's disease, primary lateral sclerosis, spinal muscular atrophy, cerebral ischemia, spastic paraplegia, and myasthenia gravis; the cardiovascular diseases are coronary heart disease, stroke, heart failure, cardiomyopathy, rheumatic heart disease, abnormal heart rhythm, congenital heart disease, myocarditis, thromboembolic disease, and venous thrombosis; the metabolic diseases are diabetes and non-alcoholic fatty liver disease.

9. The method for preparing the compound according to any one of claims 1 to 3, characterized in that: The steps include: (1) Compound a and compound b react under the action of triethylamine to obtain compound c, the reaction temperature is from 0°C to room temperature, the reaction time is 5-10 min, and the crude product can be directly used for the next reaction; (2) Compound c and compound d react to obtain compound e, and the obtained crude product is separated by column chromatography to obtain a pure product. The reaction temperature is 120° C. and the reaction time is 3 to 4 days; (3) Compound f is reacted with thionyl chloride to obtain compound g at a reaction temperature of 100°C for 12 h. The crude product can be directly used in the next reaction; (4) Compound e and compound g react under the action of triethylamine to obtain compound k, and the obtained crude product is separated by column chromatography to obtain a pure product. The reaction temperature is rt and the reaction time is 5-10 min; (5) Compound h and compound i react under the action of potassium carbonate to obtain compound j. The obtained crude product is separated by column chromatography to obtain a pure product. The reaction temperature is 60° C. and the reaction time is 12 h. (6) Compound j and compound g react under the action of triethylamine to obtain compound l, and the obtained crude product is separated by column chromatography to obtain a pure product. The reaction temperature is rt and the reaction time is 15 min; (7) Compound k and compound l are respectively deprotected and reacted with compound m to obtain compound I, and the obtained crude product is separated by column chromatography to obtain a pure product; The reaction route is: Wherein, the Protecting Group in compound h is any one of Boc or methyl ester; Compound k is deprotected and reacted with compound m, wherein compound m is Any one of the above, compound 1 is deprotected and then reacted with compound m, wherein compound m is R-NH2, Any of .

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