CN103450149B - Tolylthiophene sulfamide compound and its production and use - Google Patents

Abstract

The invention discloses tolylthiophene sulfamide compound, preparation method and purposes, its structural formula is such as formula shown in (I) and (II).Result shows, this compounds can suppress the propagation of human liver cancer cell and human lung carcinoma cell, active good, for the preparation of the antitumor drug of Hepatoma therapy or lung cancer.

Description

Phenylthiophene sulfonamide compounds and their preparation methods and uses

technical field

The invention relates to medicinal chemistry and pharmacology research results, in particular to phenylthiophene sulfonamide compounds and their preparation methods and applications.

Background technique

In the research of medicinal chemistry, thiophene is often regarded as the bioisostere of benzene based on the similarity of aroma and shape to benzene, while maintaining sufficient structural differences, which may bring different physical and biological properties. Both biotin and vitamin H contain a tetrahydrothiophene structure, which suggests that the thiophene structure plays an important role in living organisms. Compounds containing thiophene have a broad spectrum of biological activities. For example, some thiophene derivatives have powerful analgesic, anticonvulsant, anti-inflammatory, antibacterial, antipyretic, antitumor, antiparasitic, bactericidal, antihistamine, anxiolytic, Antiarrhythmic and serotonin antagonist action. Arylthiophenes linked to polyacetylenes are used in animal husbandry as anthelmintics.

Sulfonamide compounds also play an important role in living organisms. Primary sulfonamide and its bioelectronic isosteres such as sulfamate and sulfonamide compounds are typical carbonic anhydrase inhibitors. Many sulfonamides are clinically used as diuretics and agents for the treatment of glaucoma. Recent studies have found that these compounds also have potential anticonvulsant, anti-obesity, anti-cancer, analgesic, anti-infection and other effects. Aromatic sulfonamides or heteroaromatic sulfonamides may act as a tumor suppressor by disrupting G1 phase, microtubule assembly, inhibiting angiogenesis, and inhibiting transcriptional activator NF-Y through various pathways, among which the most notable mechanism is the inhibition of carbonic anhydrase isozyme agent.

The compound described in the present invention connects the chemical structure with phenylthiophene sulfonamide and urea group (or thiourea group) in an appropriate manner. The preparation method and potential application of this type of compound have not been reported before. Our experimental results show that these compounds have obvious killing effects on human lung cancer and liver cancer cells, and have the potential to be prepared as new antitumor drugs.

Contents of the invention

One of the objects of the present invention is to provide a new class of phenylthiophene sulfonamide compounds, the general structural formula of which is shown in Figures (I) and (II).

The second object of the present invention is to provide a preparation method of the above-mentioned phenylthiophene sulfonamide compounds.

The third object of the present invention is to provide the use of the above-mentioned phenylthiophene sulfonamide compounds, which are recommended for the preparation of antitumor drugs for the treatment of lung cancer and liver cancer. The compound described in the present invention uses tumor cell lines and normal cell lines to test its anti-tumor effect, and it has been proved that it has strong anti-tumor cell activity on multiple tumor cell lines, and it is found that this type of compound has little toxicity to normal cells .

A class of phenylthiophene sulfonamide compounds described in the present invention specifically includes phenyl thiophene sulfonamide N-alkyl (thio) urea compounds (structural formula such as: I), a class of phenyl thiophene sulfonamide N-alkylamide Compounds (structural formula such as: II), the phenylthiophene sulfonamide N-alkyl (thio) urea compounds of the present invention represent phenyl thiophene sulfonamide N-alkyl urea compounds and phenylthiophene sulfonamide N- A general term for alkylthiourea compounds. Above-mentioned compound has following structural formula:

In the above structural formulas (I) and (II):

R ₁ is selected from Z substituted or unsubstituted aryl Ar, Z substituted or unsubstituted heteroaryl, or cyclohexyl; the aryl Ar or heteroaryl is selected from 5-7 membered aryl, 5-7 One-membered heteroaryl, 5-7-membered aryl combined with 5-7-membered heteroaryl; the heteroatoms in the heterocyclic aryl are N, O or S, and the number of heteroatoms contained is 1 or 2 or 3; the Z substituent is selected from: halogen, C ₁ -C ₄ alkoxy, nitro, C ₁ -C ₆ straight chain or branched hydrocarbon group, hydroxyl, hydroxyl substituted C ₁ -C ₆ straight chain or branched hydrocarbon group, C ₃ -C ₇ saturated or unsaturated cycloalkyl; the number of Z substituents is _1-4 ; position or para position; the phenyl and sulfone substituents on the thiophene ring are in the meta or ortho position;

X is O, S or NH;

R ₂ and R ₃ are selected from H, halogen, C ₁ -C ₆ straight chain or branched hydrocarbon group, hydroxyl group, C ₁ -C ₄ alkoxy group, carboxyl group, C ₁ -C ₄ ester group, cyano group, nitro group, Amino, hydroxymethyl, trifluoromethyl, trifluoromethoxy, methoxy, hydrogen atom, mercapto or C ₁ -C ₄ acyl; R ₂ and R ₃ are the same or different groups; R ₄ and R ₅ is H or is jointly selected from -(CH ₂ ) _m -, that is, a cyclic diamine structure, wherein m is an integer of 0-2; R ₆ is acetyl or trifluoroacetyl or 4-nitrophenylsulfonyl;

n is an integer of 0-4.

Phenylthiophene sulfonamide compounds of the present invention can be further specifically described as follows:

1. The phenylthiophene sulfonamide N-alkyl (thio) urea compound I refers to 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3- Phenylureido) ethyl) -2-thienylsulfonamides: 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3-(4-nitro phenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3-(3,5 -dichlorophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3-(4 -Chlorophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3-(4- Methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3-(3 , 5-dimethylphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3 -(3,5-ditrifluoromethylphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N- (2-(3-(3-nitrophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N- (2-(3-(3-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N -(2-(3-(4-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl) -N-(2-(3-(3-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl )-N-(2-(3-(3,5-ditrifluoromethylphenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichloro Phenyloxy)phenyl)-N-(2-(3-(3-chlorophenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichloro Phenyloxy)phenyl)-N-(2-(3-(3-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4- Dichlorophenoxy)phenyl)-N-(2-(3-(4-chlorophenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4- Dichlorophenoxy)phenyl)-N-(2-(3-(4-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4 -Dichlorophenoxy)phenyl)-N-(2-(3-(3-methylphenyl)thioureido)ethyl)-2-thienylsulfonamide;

2. The phenylthiophene sulfonamide N-alkyl (thio) urea compound refers to 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3-benzene Urido)propyl)-2-thienylsulfonamide: 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3-(4-nitrophenyl ) ureido) propyl) -2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3-(3,5-dichlorophenoxy) Phenyl)ureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3-(4-chlorobenzene base) ureido) propyl) -2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3-(4-methoxy Phenyl)ureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3-(3,5- Dimethylphenyl)ureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3-(4 -Methoxyphenyl)thioureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3- (3-nitrophenyl)thioureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3 -(3,5-ditrifluoromethylphenyl)thioureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N -(3-(3-(3-chlorophenyl)thioureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N -(3-(3-(3-methoxyphenyl)thioureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl) -N-(3-(3-(4-chlorophenyl)thioureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl) -N-(3-(3-(4-nitrophenyl)thioureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl )-N-(3-(3-(3-methylphenyl)thioureido)propyl)-2-thienylsulfonamide;

3. The phenylthiophenesulfonamide N-alkyl (thio) urea compound refers to 3-(2-(1-naphthyl)phenyl)-N-(2-(3-(3,5- Dichlorophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(1-naphthyl)phenyl)-N-(2-(3-(4-methoxybenzene base) ureido) ethyl) -2-thienylsulfonamide, 3-(2-(1-naphthyl)phenyl)-N-(2-(3-(3,5-ditrifluoromethyl Phenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(1-naphthyl)phenyl)-N-(2-(3-(4-nitrophenyl)urea Base) ethyl)-2-thienylsulfonamide, 3-(2-(1-naphthyl)phenyl)-N-(2-(3-(3-methoxyphenyl)ureido)ethyl Base)-2-thienylsulfonamide, 3-(2-(1-naphthyl)phenyl)-N-(2-(3-(3-nitrophenyl)ureido)ethyl)-2 -Thienylsulfonamide, 3-(2-(1-naphthyl)phenyl)-N-(2-(3-(4-methoxyphenyl)thioureido)ethyl)-2-thiophene Sulfonamide, 3-(2-(1-naphthyl)phenyl)-N-(2-(3-(3-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide , 3-(2-(1-naphthyl)phenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)thioureido)ethyl)-2-thienyl Sulfonamide, 3-(2-(1-naphthyl)phenyl)-N-(2-(3-(3-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonamide , 3-(2-(1-naphthyl)phenyl)-N-(2-(3-(4-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide, 3- (2-(1-naphthyl)phenyl)-N-(2-(3-(3-methylphenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2- (1-naphthyl)phenyl)-N-(2-(3-phenylthioureido)ethyl)-2-thienylsulfonamide;

4. The phenylthiophene sulfonamide N-alkyl (thio) urea compound refers to 3-(2-sesaminol phenyl)-N-(2-(3-(3,5-dichlorophenyl ) ureido) ethyl) -2-thienyl sulfonamide, 3-(2-sesaminol phenyl) -N-(2-(3-(4-methoxyphenyl) ureido) ethyl) -2-Thienylsulfonamide, 3-(2-Sesamolylphenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)ureido)ethyl)-2- Thienylsulfonamide, 3-(2-sesaminolphenyl)-N-(2-(3-(4-nitrophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-( 2-Sesamolylphenyl)-N-(2-(3-(3-Methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-Sesamolylphenyl )-N-(2-(3-(3-nitrophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-sesaminolphenyl)-N-(2-( 3-(4-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-sesaminolphenyl)-N-(2-(3-(3-nitro phenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-sesaminolphenyl)-N-(2-(3-(3,5-ditrifluoromethylbenzene Base) thioureido) ethyl) -2-thienyl sulfonamide, 3-(2-sesaminol phenyl) -N-(2-(3-(3-methoxyphenyl) thioureido) Ethyl)-2-thienylsulfonamide, 3-(2-sesaminolphenyl)-N-(2-(3-(4-nitrophenyl)thioureido)ethyl)-2-thiophene Sulfonamide, 3-(2-sesaminolphenyl)-N-(2-(3-(3-methylphenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-( 2-Sesamolylphenyl)-N-(2-(3-phenylthioureido)ethyl)-2-thienylsulfonamide;

5. The phenylthiophenesulfonamide N-alkyl (thio) urea compound refers to 3-(2-(2-naphthyl)phenyl)-N-(2-(3-(4-methoxy phenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2-naphthyl)phenyl)-N-(2-(3-(3,5-ditrifluoro Methylphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2-naphthyl)phenyl)-N-(2-(3-(3-methoxybenzene base) ureido) ethyl) -2-thienyl sulfonamide, 3-(2-(2-naphthyl) phenyl) -N-(2-(3-(3-nitrophenyl) ureido ) ethyl)-2-thienylsulfonamide, 3-(2-(2-naphthyl)phenyl)-N-(2-(3-(3,5-dichlorophenyl)ureido)ethyl Base)-2-thienylsulfonamide, 3-(2-(2-naphthyl)phenyl)-N-(2-(3-(4-methoxyphenyl)thioureido)ethyl) -2-thienylsulfonamide, 3-(2-(2-naphthyl)phenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)thioureido)ethyl Base)-2-thienylsulfonamide, 3-(2-(2-naphthyl)phenyl)-N-(2-(3-(4-nitrophenyl)thioureido)ethyl)- 2-Thienylsulfonamide, 3-(2-(2-naphthyl)phenyl)-N-(2-(3-(3-nitrophenyl)thioureido)ethyl)-2-thiophene Sulfonamide, 3-(2-(2-naphthyl)phenyl)-N-(2-(3-(4-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide , 3-(2-(2-naphthyl)phenyl)-N-(2-(3-(3-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonamide;

6. The phenylthiophenesulfonamide N-alkyl (thio) urea compound refers to 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(3 -(4-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2 -(3-(3,5-ditrifluoromethylphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4-dimethoxyphenoxy)benzene Base)-N-(2-(3-(3,5-dichlorophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4-dimethoxybenzene Oxy)phenyl)-N-(2-(3-(3-nitrophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4-dimethoxy ylphenoxy)phenyl)-N-(2-(3-(4-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4 -dimethoxyphenoxy)phenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)thioureido)ethyl)-2-thienylsulfonamide, 3 -(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(3-(4-nitrophenyl)thioureido)ethyl)-2-thienylsulfonyl Amide, 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(3-phenylthioureido)ethyl)-2-thienylsulfonamide, 3 -(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(3-(3-nitrophenyl)thioureido)ethyl)-2-thienylsulfonyl Amide, 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(3-(4-nitrophenyl)thioureido)ethyl)-2- Thienylsulfonamide;

7. The phenylthiophenesulfonamide N-alkyl (thio) urea compound refers to 3-(2-(3,4-dihydroxyphenoxy)phenyl)-N-(2-(3-( 4-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4-dihydroxyphenoxy)phenyl)-N-(2-(3- (3,5-ditrifluoromethylphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4-dihydroxyphenoxy)phenyl)-N-( 2-(3-(4-nitrophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4-dihydroxyphenoxy)phenyl)-N- (2-(3-(3,5-dichlorophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4-dihydroxyphenoxy)phenyl)- N-(2-(3-(3-nitrophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4-dihydroxyphenoxy)phenyl)- N-(2-(3-(3-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4-dihydroxyphenoxy)phenyl) -N-(2-(3-(4-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4-dihydroxyphenoxy)benzene Base)-N-(2-(3-(4-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4-dihydroxyphenoxy) Phenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4- Dihydroxyphenoxy)phenyl)-N-(2-(3-(3-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4 -Dihydroxyphenoxy)phenyl)-N-(2-(3-(3-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonamide;

8. The phenylthiophenesulfonamide N-alkyl (thio) urea compound can also refer to 4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone Base)-1-N-(3,5-dichloroanilino)formylpiperazine, 4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone )-1-N-(4-methoxyanilino)formylpiperazine, 4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)- 1-N-(3,5-ditrifluoromethylanilino)formylpiperazine, 4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone )-1-N-(4-methoxyanilino)thioformylpiperazine, 4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone )-1-N-(4-methoxyanilino)thioformylpiperazine, 4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone )-1-N-(3-nitroanilino)thioformylpiperazine, 4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone) -1-N-(3,5-ditrifluoromethylanilino)thioformylpiperazine, 4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl )sulfone group)-1-N-(3-methoxyanilino)thioformylpiperazine, 4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl )sulfone group)-1-N-(4-nitroanilino)thioformylpiperazine, 4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl) Sulfone)-1-N-(3-methylanilino)thioformylpiperazine, 4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone Base)-1-N-anilinothioformylpiperazine;

9. The phenylthiophene sulfonamide N-alkylamide compound (II) as claimed in claim 1 refers to 3-(2(2,4-dichlorophenoxy)phenyl)-N-amidoalkyl -2-thienylsulfonamide: 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-trifluoroacetamidoethyl)-2-thienylsulfonamide, 3 -(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(4-nitrobenzenesulfonamido)ethyl)-2-thienylsulfonamide;

10. The phenylthiophenesulfonamide N-alkylamide compound refers to 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-acetamidopropyl)- 2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-trifluoroacetamidopropyl)-2-thienylsulfonamide, 3- (2-(2,4-dichlorophenoxy)phenyl)-N-(3-(4-nitrobenzenesulfonamido)propyl)-2-thienylsulfonamide;

11. The phenylthiophenesulfonamide N-alkylamide compound refers to 3-(2-(1-naphthyl)phenyl)-N-(2-acetamidoethyl)-2-thienyl Sulfonamide, 3-(2-(1-naphthyl)phenyl)-N-(2-(4-nitrobenzenesulfonamido)ethyl)-2-thienylsulfonamide;

12. The phenylthiophenesulfonamide N-alkylamide compound refers to 3-(2-sesaminolphenyl)-N-(2-acetamidoethyl)-2-thienylsulfonamide, 3 -(2-Sesamolylphenyl)-N-(2-(4-nitrobenzenesulfonamido)ethyl)-2-thienylsulfonamide;

13. The phenylthiophenesulfonamide N-alkylamide compound refers to 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(acetamidoethyl) Base)-2-thienylsulfonamide, 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(4-nitrobenzenesulfonamido)ethyl) -2-thienylsulfonamide;

14. The phenylthiophenesulfonamide N-alkylamide compound refers to 4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-1- N-acetylpiperazine, 4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-1-N-trifluoroacetylpiperazine, 4- N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-1-N-4-nitrobenzenesulfonylpiperazine;

15. The phenylthiophenesulfonamide N-alkylamide compound can also refer to 3-(2-(3,4-dihydroxyphenoxy)phenyl)-N-(2-acetylaminoethyl) -2-Thienylsulfonamide

The preparation method of phenylthiophene sulfonamide compound of the present invention is as follows:

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are as defined above:

R ₁ is selected from Z substituted or unsubstituted aryl Ar, Z substituted or unsubstituted heteroaryl, or cyclohexyl; the aryl Ar or heteroaryl is selected from 5-7 membered aryl, 5-7 One-membered heteroaryl, 5-7-membered aryl combined with 5-7-membered heteroaryl; the heteroatoms in the heterocyclic aryl are N, O or S, and the number of heteroatoms contained is 1 or 2 or 3; the Z substituent is selected from: halogen, C ₁ -C ₄ alkoxy, nitro, C ₁ -C ₆ straight chain or branched hydrocarbon group, hydroxyl, hydroxyl substituted C ₁ -C ₆ straight chain or branched hydrocarbon group, C ₃ -C ₇ saturated or unsaturated cycloalkyl; the number of Z substituents is _1-4 ; position or para position; the phenyl and sulfone substituents on the thiophene ring are in the meta or ortho position; X is O, S or NH;

R ₂ and R ₃ are selected from H, halogen, C ₁ -C ₆ straight chain or branched hydrocarbon group, hydroxyl group, C ₁ -C ₄ alkoxy group, carboxyl group, C ₁ -C ₄ ester group, cyano group, nitro group, Amino, hydroxymethyl, trifluoromethyl, trifluoromethoxy, methoxy, hydrogen atom, mercapto or C ₁ -C ₄ acyl; R ₂ and R ₃ are the same or different groups; R ₄ and R ₅ is H or is jointly selected from -(CH ₂ ) _m -, that is, a cyclic diamine structure, wherein m is an integer of 0-2; R ₆ is acetyl or trifluoroacetyl or 4-nitrophenylsulfonyl;

n is an integer of 0-4.

Specifically, the following steps (8), or (7) and (8), or (6), (7) and (8), or (5), (6), (7) and (8), or (4), (6), (7) and (8), or (4), (5), (6), (7) and (8), or (3), (4), (5), (6), (7) and (8), or (2), (3), (4), (5), (6), (7) and (8), or (1), (2), (3), (4), (5), (6), (7) and (8), or (15), or (14) and (15), or (13), (14) and (15) , or (12), (13), (14) and (15), or (5), (13), (14) and (15), or (11), (12), (5), (13 ), (14) and (15), or (10), (11), (12), (5), (13), (14) and (15), or (3), (10), (11 ), (12), (5), (13), (14) and (15), or (2), (3), (10), (11), (12), (5), (13) , (14) and (15), or (1), (2), (3), (10), (11), (12), (5), (13), (14) and (15), Obtain phenylthiophene sulfonamide N-alkyl (thio) urea compound;

By following steps (9), or (7) and (9), or (6), (7) and (9), or (5), (6), (7) and (9), or (4) , (6), (7) and (9), or (4), (5), (6), (7) and (9), or (3), (4), (5), (6) , (7) and (9), or (2), (3), (4), (5), (6), (7) and (9), or (1), (2), (3) , (4), (5), (6), (7) and (9), or (16), or (14) and (16), or (13), (14) and (16), or ( 12), (13), (14) and (16), or (5), (13), (14) and (16), or (11), (12), (5), (13), ( 14) and (16), or (10), (11), (12), (5), (13), (14) and (16), or (3), (10), (11), ( 12), (5), (13), (14) and (16), or (2), (3), (10), (11), (12), (5), (13), (14 ) and (16), or (1), (2), (3), (10), (11), (12), (5), (13), (14) and (16), to obtain phenyl Thiophenesulfonamide N-alkyl amides.

(1) In the organic solvent, the molar ratio of hydroxyl compound, K ₂ CO ₃ , NaH and fluoronitrobenzene is 1:(0~5):(0~2):(0.8~2), in the order of 10~ React at 200°C for 2 to 10 hours to get

Compound A;

Described hydroxy compound can be example following typical compound:

The structural formula of the compound A is as follows:

(2) In an organic solvent, the molar ratio of compound A, Pd/C, NH ₂ NH ₂ ·H ₂ O is 1:(0.01～0.1):(1～5) in turn, react at 10～200°C for 2～ Compound B was obtained in 10 hours; or the molar ratio of compound A, zinc powder and hydrochloric acid was 1: (1-5): (2-10) in turn, and compound B was obtained by reacting at 10-200° C. for 2-10 hours;

The structural formula of the compound B is as follows:

(3) In the solvent, the molar ratios of compound B, H ₂ SO ₄ , NaNO ₂ , and Kl are 1:(1~3):(1~2):(1~2), at -5~10°C React for 2 to 10 hours to obtain compound C;

The structural formula of the compound C is as follows:

(4) In the solvent, the molar ratio of compound C, n-butyllithium and trimethyl borate is 1:(1~2):(1~2) successively, react at -78~0°C for 1~5 hours to obtain Compound D;

The structural formula of the compound D is as follows:

(5) in organic solvent, the mol ratio of 3-bromo-2-thienyl yellow acid chloride, 1-N-Boc diamine, triethylamine is 1: (1～2): (1～2) successively, in Compound E was obtained by reacting at 0-200°C for 2-5 hours;

The structural formula of the compound E is as follows:

(6) In the solvent, the molar ratio of compound E, compound D, triphenylphosphine or Sphos, K ₃ PO ₄ and palladium acetate is 1: (1～1.5): (0.05～0.2): (1～3 ): (0.02～0.1), react at 10～200°C for 2～15 hours to obtain compound F;

The structural formula of the compound F is as follows:

(7) In the solvent, the molar ratio of compound F and trifluoroacetic acid is 1: (1-3) in sequence, and react at 10-200° C. for 2-15 hours to obtain compound G;

The structural formula of the compound G is as follows:

(8) In an organic solvent, the molar ratio of compound G, isocyanate or isothiocyanate is 1: (1-1.5), reacting at 10-200°C for 2-12 hours to obtain compound H;

The structural formula of the compound H is as follows:

The solvents are: THF, DMF, toluene, CH ₂ Cl ₂ , CHCl ₃ , 1,4-dioxane, ethanol, water, methanol, acetonitrile;

(9) In the solvent, the molar ratio of compound G, acid chloride and triethylamine is 1: (1-1.5): (1-3) successively, react at 10-200° C. for 2-15 hours to obtain compound I;

The structural formula of the compound I is as follows:

(10) In the solvent, the molar ratio of compound C6 and boron tribromide is 1: (1 ~ 3), react at -78 ° C ~ room temperature for 2 ~ 5 hours to obtain compound J,

The structural formula of the compound J is as follows:

(11) In the solvent, the molar ratio of compound J, TBSCl, imidazole or triethylamine is 1: (1-3): (1-3), react at 0-room temperature for 2-15 hours to obtain compound C7; The TBSCl represents tert-butyldimethylsilyl chloride; The structural formula of the compound C7 is as follows:

(12) In the solvent, the molar ratio of compound C7, n-butyllithium and trimethyl borate is 1:(1~2):(1~2) in turn, react at -78~0°C for 1~5 hours to obtain Compound D7;

The structural formula of the compound D7 is as follows:

(13) In the solvent, the molar ratio of compound E, compound D7, triphenylphosphine or Sphos, K ₃ PO ₄ and palladium acetate is 1:(1～1.5):(0.05～0.2):(1～3 ): (0.02～0.1), reacted at 10～200°C for 2～15 hours to obtain compound F7;

The structural formula of the compound F7 is as follows:

(14) In the solvent, the molar ratio of compound F7 and trifluoroacetic acid is 1: (1～3) successively, react at 10～200° C. for 2～15 hours to obtain compound G7; the structural formula of said compound G7 is as follows:

(15) In an organic solvent, the molar ratio of compound G7, isocyanate or isothiocyanate and hydrofluoric acid is 1: (1-1.5): (2-20), react at room temperature for 2-12 hours to obtain compound H7 ;

The structural formula of the compound H7 is as follows:

(16) In the solvent, the molar ratio of compound G7, acid chloride and triethylamine is 1: (1-1.5): (1-3) in sequence, reacting at 10-200° C. for 2-15 hours to obtain compound I7;

The structural formula of the compound I7 is as follows:

The concrete preparation method of compound described above can comprise the following steps:

(1) 10g of substituted phenol is placed in a 250ml pear-shaped bottle, and an inert solvent DMF 60ml or THF 60ml is added, then K ₂ CO ₃ or 60% NaH 2 molar equivalents, and then 1.0 molar equivalents of o-fluoronitrobenzene, Stir and heat to reflux, stop stirring and heating after 2 to 4 hours, after cooling, add 200ml of water, extract three times with ethyl acetate, 200ml each time, combine the ethyl acetate extracts, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a liquid or Compound A as a solid.

(2) Put 7g of Compound A in a 1L three-neck flask, add 5 molar equivalents of zinc powder and 80ml of ethanol, slowly add 500ml of 2mol/L hydrochloric acid solution under mechanical stirring, stir for 12 to 24 hours, and extract the aqueous solution with ethyl acetate for 3 Once, 300ml each time, combined ethyl acetate solution, washed with saturated brine, dried ethyl acetate solution with anhydrous sodium sulfate, filtered, and concentrated to obtain liquid product B; or add 100ml ethanol, then add 0.7g Pd/C, Finally, 5.0 molar equivalents of hydrazine hydrate was slowly added. After the reaction was exothermic, heat and reflux for 2 to 5 hours, stop stirring, filter through a Buchner funnel, remove the solvent by distillation under reduced pressure, add 200 ml of water, extract three times with ethyl acetate, 200 ml each time, Combine ethyl acetate, add anhydrous sodium sulfate to dry, filter and concentrate to obtain liquid aniline compound B.

(3) Add 6g of compound B into a 500ml three-necked flask, add 3 molar equivalents of 3mol/L sulfuric acid solution, put the three-necked flask into an ice-water bath at -5～ ₅ °C, and slowly add 1.5 moles of 0.4mol/L NaNO2 solution under stirring Equivalent, after stirring for one hour, slowly add 0.8 mol/L Kl solution with 1.5 molar equivalents under stirring, and stir in an ice-water bath at -5 to 5°C for one hour, then stop stirring at room temperature for 3 hours, and extract with ethyl acetate Three times, 100ml each time, combined the ethyl acetate solution and washed with saturated sodium thiosulfate and saturated brine, dried the ethyl acetate solution with anhydrous sodium sulfate, filtered, and concentrated to obtain compound C as a liquid or solid product.

(4) Put 2.8g of compound C in a 250ml eggplant-shaped bottle. After fully removing water and oxygen, add 40ml of anhydrous tetrahydrofuran under the protection of argon, place it in a dry ice acetone bath at -78°C, and then add 2.5mol/L 1.2 molar equivalents of n-butyllithium solution, 1.2 molar equivalents of trimethyl borate was added after one hour, and after another hour, the eggplant-shaped bottle was placed at room temperature, and after stirring at room temperature for 3 hours, 1mol/L hydrochloric acid solution was added to quench extinguished, the solvent was distilled off under reduced pressure, and ethyl acetate was added for extraction three times, 50ml each time, the ethyl acetate solution was combined, washed with a saturated sodium chloride solution, the ethyl acetate solution was dried with anhydrous sodium sulfate, filtered, concentrated, and column chromatography Compound D.

(5) Add 2.5g of compound 3-bromo-2-thienyl yellow acid chloride into a 50ml eggplant-shaped bottle, add 15ml of dichloromethane, add 1.2 molar equivalents of triethylamine and 1-N-Boc diamine again, and stir at room temperature After 5 hours, stop stirring, add 50ml of water, extract three times with dichloromethane, 50ml each time, combine the dichloromethane solution, wash with saturated sodium chloride solution, dry the dichloromethane solution with anhydrous sodium sulfate, filter, and concentrate to obtain the compound e.

(6) Add 1.4g of compound D, 1.9g of compound E, 0.1 molar equivalent of Sphos, 2 molar equivalent of K ₃ PO ₄ , and 0.05 molar equivalent of palladium acetate into a 100ml Shrek tube at one time. After replacing the argon, add 25ml of THF and 5ml of water , start heating and stirring under argon protection, stop stirring for 5 hours, add 50ml of water, extract three times with ethyl acetate, 50ml each time, combine ethyl acetate solution and wash with saturated sodium chloride solution, ethyl acetate solution is washed with anhydrous sodium sulfate After drying, filtering, concentrating, and column chromatography, Compound F was obtained.

(7) Put 1.3g of compound F in a 25ml eggplant-shaped bottle, add 10ml of dichloromethane, then add 3ml of trifluoroacetic acid, stir at room temperature for 12 hours, add saturated sodium bicarbonate solution to neutralize the trifluoroacetic acid until no bubbles are generated, add water 50ml, dichloromethane extracted three times, 50ml each time, the dichloromethane solution was combined and washed with saturated brine, the dichloromethane solution was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound G.

(8) 60 mg of compound G is placed in a 25 ml pear-shaped bottle, and 3 ml of methylene chloride is added to the pear-shaped bottle, and 1.1 molar equivalents of isocyanate or isothiocyanate are added, stirred at room temperature for 5 hours, concentrated, and obtained by column chromatography Compound H.

(9) 60mg of compound G is placed in a 25ml pear-shaped bottle, and 3ml of dichloromethane is added to the pear-shaped bottle, and each 1.1 molar equivalent of acetyl chloride or trifluoroacetic anhydride or 4-nitroflavinyl chloride and triethylamine is added. , stirred at room temperature for 5 hours, added 20 ml of water, extracted three times with dichloromethane, 25 ml each time, combined the dichloromethane solution and washed with saturated brine, dried the dichloromethane solution with anhydrous sodium sulfate, filtered, concentrated, and obtained the compound by column chromatography I.

(10) Put 3.0 g of compound C6 in a 100 ml pear-shaped bottle, add 25 ml of dichloromethane, place the pear-shaped bottle in an ice bath, add 2 molar equivalents of 1 mol/L boron tribromide solution, slowly rise to room temperature and stir After 5 hours, slowly add 50ml of water to quench. Dichloromethane was extracted three times, 50ml each time, the dichloromethane solution was combined and washed with saturated brine, the dichloromethane solution was dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography gave Compound J.

(11) Put 2.0 g of compound J in a 100 ml pear-shaped bottle, add 40 ml of dichloromethane, put the pear-shaped bottle in an ice bath, add 2 molar equivalents of imidazole and TBSCl, slowly rise to room temperature and stir for 5 hours, add 50 ml of water Quenched. Dichloromethane was extracted three times, 50ml each time, the dichloromethane solution was combined and washed with saturated brine, the dichloromethane solution was dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography gave compound C7.

(12) Put 2.8g of compound C7 in a 250ml eggplant-shaped bottle. After fully removing water and oxygen, add 40ml of anhydrous tetrahydrofuran under the protection of argon, place it in a dry ice acetone bath at -78°C, and then add 2.5mol/L 1.2 molar equivalents of n-butyllithium solution, 1.2 molar equivalents of trimethyl borate was added after one hour, and after another hour, the eggplant-shaped bottle was placed at room temperature, and after stirring at room temperature for 3 hours, 1mol/L hydrochloric acid solution was added to quench extinguished, the solvent was distilled off under reduced pressure, and ethyl acetate was added for extraction three times, 50ml each time, the ethyl acetate solution was combined, washed with a saturated sodium chloride solution, the ethyl acetate solution was dried with anhydrous sodium sulfate, filtered, concentrated, and column chromatography Compound D7.

(13) Add 1.4g of compound D7, 1.0 molar equivalent of compound E, 0.1 molar equivalent of Sphos, 2 molar equivalent of K ₃ PO ₄ , and 0.05 molar equivalent of palladium acetate into a 100ml Shrek tube at one time. After replacing the argon, add 25ml of THF, 5ml of water, started heating and stirring under argon protection, 5 hours, stopped stirring, added 50ml of water, extracted three times with ethyl acetate, 50ml each time, combined ethyl acetate solution and washed with saturated sodium chloride solution, ethyl acetate solution was washed with anhydrous Dry over sodium sulfate, filter, concentrate, and perform column chromatography to obtain compound F7.

(14) Put 1.3g of compound F7 in a 25ml eggplant-shaped bottle, add 10ml of dichloromethane, then add 3ml of trifluoroacetic acid, stir at room temperature for 12 hours, add saturated sodium bicarbonate solution to neutralize the trifluoroacetic acid until no bubbles are generated, add water 50ml, extracted three times with 50ml of dichloromethane, combined the dichloromethane solution and washed with saturated brine, dried the dichloromethane solution with anhydrous sodium sulfate, filtered and concentrated to obtain compound G7.

(15) 60 mg of compound G7 was placed in a 25 ml pear-shaped bottle, and 3 ml of dichloromethane was added to the pear-shaped bottle, and 1.1 molar equivalents of isocyanate or isothiocyanate were added, stirred at room temperature for 5 hours, concentrated, and obtained by column chromatography Compound H7.

(16) 60mg of compound G7 is placed in a 25ml pear-shaped bottle, and 3ml of dichloromethane is added to the pear-shaped bottle, and each 1.1 molar equivalent of acetyl chloride or trifluoroacetic anhydride or 4-nitroflavinyl chloride and triethylamine is added. , stirred at room temperature for 5 hours, added 20 ml of water, extracted three times with dichloromethane, 25 ml each time, combined the dichloromethane solution and washed with saturated brine, dried the dichloromethane solution with anhydrous sodium sulfate, filtered, concentrated, and obtained the compound by column chromatography I7.

The Sphos means 2-bicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl;

The organic solvent is: THF, N, N-dimethylformamide (DMF), toluene, CH ₂ Cl ₂ , CHCl ₃ , 1,4-dioxane, ethanol, methanol, acetonitrile, toluene or a mixed solution thereof.

The solvents are: tetrahydrofuran THF, N,N-dimethylformamide (DMF), toluene, CH ₂ Cl ₂ , CHCl ₃ , 1,4-dioxane, ethanol, water, methanol, acetonitrile, Toluene or its mixed solution.

The inert solvent described in the above (1)-(15) description includes tetrahydrofuran, dichloromethane, chloroform, dioxane and toluene, wherein preferred tetrahydrofuran

Detailed ways

The invention is further illustrated in the following examples. These examples serve only to illustrate the invention, but do not limit the invention in any way. Unless otherwise specified, all descriptions in the following examples are in units of mass (gram), and the mentioned room temperature refers to 20°C-30°C.

Example 1

2-(2,4-Dichlorophenoxy)nitrobenzene (A1)

Add 28g (171.8mmol) of 2,4-dichlorophenol, 19.572g (138.8mmol) of o-fluoronitrobenzene, 23.848g of K ₂ CO ₃ , and 60ml of DMF into a 250ml egg-shaped flask, and reflux for 5h. Heating was stopped, 500ml of ethyl acetate was added, washed with 200ml of water × 3, dried, filtered, concentrated, PE:ethyl acetate=10:1 column chromatography, 36.789g of orange-red liquid was obtained, yield 93.3%. ¹ H NMR (400MHz, CDCl ₃ ) δ8.00(dd, J=1.2, 8.0Hz, 1H), 7.50-7.52(m, 2H), 7.24-7.27(m, 2H), 6.99(d, 1H, J =8.8Hz), 6.87 (dd, 1H, J=1.2, 8.4Hz); ¹³ C NMR (100MHz, CDCl ₃ ) δ145.7, 145.4, 136.4, 130.2, 126.5, 126.4, 124.1, 122.5, 121.7, 119.6, 117.4, 115.1; EI-MSm/z, 283(M) ⁺ ; EI-HRMS calcd for C ₁₂ H ₇ NO ₃ Cl ₂ ⁺ (M) ⁺ 282.9803, observed 282.9801.

Example 2

2-(2,4-Dichlorophenoxy)aminobenzene (B1)

Add 36.563g (128.7mmol) of 2-(2,4-dichlorophenoxy)nitrobenzene, 300ml of ethanol to a 2L four-neck flask, add a little ethyl acetate to help dissolve, add 30g (461.5mmol) of zinc powder Slowly add 20ml of 1N hydrochloric acid dropwise under stirring with a mechanical stirrer at room temperature until the gray color of the zinc powder disappears. Stop stirring. Add 500ml of ethyl acetate, wash with 200ml×3 water, dry, filter, concentrate, PE:ethyl acetate=10:1 column chromatography, and obtain 36.789g of orange-red liquid with a yield of 94.6%. ¹ H NMR (400M Hz, CDCl ₃ ) δ7.45(d, J=2.4Hz, 1H), 7.14(dd, J=8.8, 2.4Hz, 1H), 7.01(td, J=7.6, 1.2Hz, 1H ), 6.83(dd, J=8.0, 1.6Hz, 1H), 6.78-6.81(m, 2H), 6.73td, J=7.4, 1.4Hz, 1H), 3.82(s, 2H); ¹³ C NMR (100MHz , CDCl ₃ ) δ151.8, 142.6, 138.3, 130.3, 128.2, 127.9, 125.5, 125.0, 119.5, 118.9, 118.8, 116.7; EI-MS m/z, 253(M) ⁺ ; EI-HRMS calcd for C ₁₂ H ₉ NOCl ₂ ⁺ (M) ⁺ 253.0062, observed 253.0061.

Example 3

2-(2,4-Dichlorophenoxy)iodobenzene (C1)

Place a 500ml three-necked flask in an ice bath, add 10.7g (42.1mmol) of 2-(2,4-dichlorophenoxy)aminobenzene, 7ml of concentrated sulfuric acid diluted with 45ml of water and add it after cooling, and slowly add it under mechanical stirring Add NaNO ₂ 3.9533g (57.3mmol) water (16ml) solution in 10 minutes, then add Kl11.5542g (69.6mmol) water (10ml) solution, move to room temperature and stir after half an hour. The reaction at room temperature was stopped after 4 hours, and 200ml of water was added, extracted with CH ₂ Cl ₂ 300ml×3, combined, and washed once with saturated Na ₂ S ₂ O ₃ . After drying, filtering, concentrating, and column chromatography, 13.0956 g of nearly colorless liquid was obtained with a yield of 85.2%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.87(dd, J=8.0, 1.6Hz, 1H), 7.85(d, J=2.8Hz, 1H), 7.30(td, J=7.7, 1.1Hz, 1H, ), 7.18(dd, J=8.8, 2.4Hz, 1H), 6.90(td, J=7.6, 1.2Hz, 1H), 6.80-6.77(m, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ156. 489, 152.253, 141.176, 131.229, 131.193, 129.274, 129.473, 127.232, 126.398, 121.511, _119.854 , 88.634; EI-MS m/z, 363(MH) ^- ; EI-HRMS calcd for O Cl ₁₂ H ⁺ ₇ (M) ⁺ 363.8919, observed 363.8922.

Example 4

2-(2,4-Dichlorophenoxy)phenylboronic acid (D1)

Add 2.4743g (6.8mmol) of 2-(2,4-dichlorophenoxy) iodobenzene into a 100ml reaction tube for ventilation, add 32ml of anhydrous THF under the protection of argon, and drop slowly in a cold bath at -78°C Add 3.2ml of n-butyllithium, react for 1 hour, add 14ml of trimethyl borate at -78°C, and move the reaction tube to room temperature after 2 hours to stir. After 1 h, 1 ml of concentrated hydrochloric acid was added, extracted with ethyl acetate, dried, filtered, and concentrated to obtain 1.4978 g of white solid, with a yield of 78.3%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.95(dd, J=7.6, 2.0Hz, 1H), 7.51(d, J=2.8Hz, 1H), 7.37(td, J=7.8, 1.6Hz, 1H) , 7.25-7.28(m, 1H), 7.17(td, J=7.2, 0.8Hz, 1H), 7.05(d, J=8.8Hz, 1H), 6.62(d, J=8.0Hz, 1H), 5.54( s, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ162.1, 157.0, 149.6, 137.4, 132.9, 130.8, 130.7, 128.4, 127.5, 123.7, 122.8, 114.8; EI-MS m/z, 282 (M ) ⁺ ; EI-HRMS calcd for C ₁₂ H ₉ O ₃ Cl ₂ B ⁺ (M) ⁺ 282.0022, observed 282.0020.

Example 5

3-Bromo-N-(2-(N-Bocamino)ethyl)-2-thienylsulfonamide (E1)

Add 138.6 mg (0.86 mmol) of N-Boc protected 2-aminoethylamine, 3 ml of CH ₂ Cl ₂ , and 0.16 ml (1.12 mmol) of triethylamine into a 20 ml egg-shaped flask, and slowly add 3-bromo under stirring in an ice bath, 200.8 mg (0.77 mmol) of 2-thienylsulfone chloride. After 5 minutes, move to room temperature and stir for one hour. Stop stirring. Add 50ml of water, extract with CH ₂ Cl ₂ 100ml×3, dry, filter, and concentrate to obtain 290.1mg of light yellow solid with a yield of 98.1%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.51(d, J=5.2Hz, 1H), 7.11(d, J=5.2Hz, 1H), 5.66(s, 1H), 4.83(s, 1H), 3.28 (dd, J=11.2, 5.6Hz, 2H), 3.17 (dd, J=11.4, 5.8Hz, 2H), 1.48(s, 9H); ESI-MS m/z, 407.1(M+Na) ⁺ .

Example 6

3-(2-(2,4-Dichlorophenoxy)phenyl)-N-(2-(N-Bocamino)ethyl)-2-thienylsulfonamide (F1-1)

Add 1.8521g (4.8mmol) of 3-bromo-N-(2-(N-Bocamino)ethyl)-2-thienylsulfonamide to a 250ml reaction tube, 2-(2,4-dichlorophenoxy ) Phenylboronic acid 1.3600g (4.8mmol), Sphos 109mg (0.27mmol), palladium acetate 57.4mg (0.26mmol), K ₃ PO ₄ 3.1012g (14.6mmol), add THF 25ml after ventilation, reflux for 8 hours, stop Heat and stir. Add 100ml of water, extract with 250ml of ethyl acetate × 2, dry, filter, concentrate, PE: ethyl acetate = 2.5: 1 column chromatography, and obtain 1.3117g of yellow floc with a yield of 50.2%, and recovery, 2-( 3-bromothienyl)sulfonamido N-Boc ethylamine 670.8 mg. ¹ H NMR (400MHz, CDCl ₃ ) δ7.56(d, J=5.6Hz, 1H), 7.50(d, J=4.8Hz, 1H), 7.36-7.42(m, 2H), 7.22-7.26(m, 1H), 7.18(d, J=8.8Hz, 1H), 7.12(d, J=5.2Hz, 1H,), 6.91(d, J=8.8Hz, 1H), 6.81(d, 8.4Hz, 1H), 4.85(s, 1H), 4.77(s, 1H), 3.17(t, J=5.4Hz, 3H), 3.06(t, J=5.2Hz, 3H), 1.42(s, 9H); ¹³ CNMR(100MHz, CDCl ₃ ) δ156.2, 153.5, 151.0, 139.8, 137.1, 132.4, 131.7, 130.5, 130.4, 129.4, 129.0, 128.3, 126.0, 125.1, 123.9, 121.2, 117.6, 79.7, 43.5, 40.4, 28 MS-MS m/z, 565.2(M+Na) ⁺ ; ESI-H RMS acalcd for C ₂₃ H ₂₅ N ₂ O ₅ Cl ₂ S ₂ Na(M+Na) ⁺ 565.0396, observed 565.0399.

Example 7

3-(2-(2,4-Dichlorophenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide (G1-1)

Add 3-(2-(2,4-dichlorophenoxy) phenyl)-N-(2-(N-Boc amino) ethyl)-2-thienylsulfonamide 1.3117g ( 2.35mmol), CH ₂ Cl ₂ 15ml, CF ₃ CO ₂ H 5ml, stirred at room temperature for 1 hour. Add potassium carbonate to neutralize CF ₃ CO ₂ H to make it alkaline, add water, extract with CH ₂ Cl ₂ 200ml×3, dry, filter, and concentrate to obtain 992.1 mg of a pale yellow solid with a yield of 95.1%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.60(d, 1H, J=6.8Hz), 7.49(d, J=4.8Hz, 1H), 7.41(d, J=2.4Hz, 1H), 7.37(t , J=7.6Hz, 1H), 7.21-7.26(m, 1H), 7.18(dd, J=8.6, 2.2Hz, 1H), 7.10(d, J=5.2Hz, 1H), 6.92(d, J= 8.8Hz, 1H), 6.82(d, J=8.0Hz, 1H), 2.97(t, J=5.6Hz, 2H), 2.75(t, J=5.4Hz, 2H); ESI-MS m/z, 443.2 (M+H) ⁺ , 465.2(M+Na) ⁺ ; ESI-HRMS acalcd for C ₁₈ H ₁₇ N ₂ O ₃ Cl ₂ S ₂ (M+H) ⁺ 443.0052, observed 443.0052.

Example 8 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3-(4-nitrophenyl)ureido)ethyl)-2-thienylsulfonyl Amide (H1-1)

Add 63.8mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 4-nitrobenzene 1.1 molar equivalents of isocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE:ethyl acetate=1:2 column chromatography, the product was collected to obtain 85.9mg, yield 98.2%. Y37: ¹ H NMR (400MHz, Acetone-d ₆ ) δ2.96(q, J=5.8Hz, 2H), 3.20(q, J=6.0Hz, 2H), 6.03(s, 2H), 6.48(t, J=5.6Hz, 1H), 6.75(d, J=8.0Hz, 1H), 7.02(d, J=8.8Hz, 1H), 7.07-7.11(m, 2H), 7.19(dd, J=8.8, 2.4 Hz, 1H), 7.27(t, J=8.0Hz, 1H), 7.40(d, J=2.4Hz, 1H), 7.46(d, J=7.6Hz, 1H), 7.57(d, J=9.2Hz, 2H), 7.64(d, J=5.2Hz, 1H), 8.02(d, J=9.2Hz, 2H), 8.59(s, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ155.7, 154.5 , 152.2, 147.8, 142.4, 140.6, 138.9, 133.4, 132.8, 131.1, 130.9, 130.0, 129.6, 129.4, 126.6, 126.3, 125.7, 124.6, 122.5, 118.4, 118.1, 44.2, 40.4 (94.6 IR); , 1614.1, 1557.0, 1505.1, 1472.9, 1329.2, 1153.4, 1109.5, 850.1, 751.4, 587.9; ESI-MSm/z 607.2(M+H) ⁺ ; ESI-HRMS calcd for C ₂₅ H ₂₀ N ₄ O ₆ Cl ₂ S ₂ Na(M+Na) ⁺ 629.0104, observed 629.0094.

Example 9

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3-(3,5-dichlorophenyl)ureido)ethyl)-2-thienylsulfonyl Amide (H1-2)

Add 57.0 mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 3,5-di 1.1 molar equivalents of chlorophenyl isocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 76.7 mg, yield 93.7%. Y38: ¹ H NMR (400MHz, Acetone-d ₆ ) δ3.17(q, J=6.1Hz, 2H), 2.93(q, J=5.9Hz, 2H), 5.93(s, 2H), 6.46(t, J=5.4Hz, 1H), 6.74(d, J=8.4Hz, 1H), 6.87(t, J=1.6Hz, 1H), 7.04(d, J=8.8Hz, 1H), 7.09(t, J= 4.4Hz, 2H), 7.19(dd, J=9.0, 2.6Hz, 1H), 7.25(td, J=8.0, 1.6Hz, 1H), 7.40(d, J=1.6Hz, 1H), 7.46(dd, J=7.6, 1.6Hz, 1H), 7.64(d, J=5.2Hz, 1H), 8.24(s, 1H); ¹³ CNMR (100MHz, Acetone-d ₆ ) δ155.9, 154.5, 152.2, 143.9, 140.6 , 138.9, 135.5, 133.4, 132.8, 131.1, 130.9, 129.9, 129.7, 129.4, 126.7, 126.3, 124.5, 122.6, 121.6, 118.3, 117.0, 44.3, 40.6; , 1473.2, 1447.8, 1256.6, 1153.9, 1100.9, 836.3, 742.8, 587.8; ESI-MSm/z 628.4(MH) ^- ; ESI-HRMS calcd for C ₂₅ H ₁₈ N ₃ O ₄ Cl ₄ S ₂ (MH) ^- 627.94929 , observed 627.9498.

Example 10

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3-(4-chlorophenyl)ureido)ethyl)-2-thienylsulfonamide (H1 -3)

Add 60.3mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 4-chlorophenyl 1.1 molar equivalent of isocyanate, 3 ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 74.0 mg, the yield was 87.2%. Y39: ¹ H NMR (400MHz, Acetone-d ₆ ) δ2.93(q, J=5.9Hz, 2H), 3.17(q, J=5.9Hz, 2H), 5.82(s, 1H), 6.50(t, J=5.0Hz, 1H), 6.74(d, J=8.4Hz, 1H), 7.02(d, J=8.8Hz, 1H), 7.06-7.11(m, 4H), 7.18(dd, J=8.8, 2.4 Hz, 1H), 7.26(td, J=7.8, 1.6Hz, 1H), 7.35(d, J=8.8Hz, 2H), 7.40(d, J=2.4Hz, 1H), 7.46(dd, J=7.6 , 1.6Hz, 1H), 7.63(d, J=5.2Hz, 1H), 8.01(s, 1H), ¹³ C NMR (100MHz, Acetone-d ₆ ) δ156.4, 154.5, 152.2, 140.6, 140.4, 139.0 , 133.4, 132.7, 131.1, 130.9, 129.9, 129.6, 129.5, 129.4, 126.7, 126.6, 126.4, 124.6, 122.6, 120.5, 118.4, 44.6, 40.5; , 1446.8, 1398.9, 1307.1, 1256.9, 1233.9, 1154.1, 1099.8, 828.3, 588.7; ESI-MS m/z 594.4(MH) ^- ; ESI-HRMS calcd for C ₂₅ H ₁₉ N ₃ O ₄ Cl ₃ S ₂ -( MH) ^- 693.9888, observed 693.9888.

Example 11

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3-(4-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide (H1-4)

60.3 mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 4-methoxy 1.1 molar equivalent of phenyl isocyanate, 3 ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 74.0 mg, and the yield was 90.4%. Y40: ¹ H NMR (400MHz, Acetone-d ₆ ) δ2.92(q, J=5.6Hz, 2H), 3.16(q, J=6.1Hz, 2H), 3.16(s, 3H), 5.70(t, J=5.0Hz, 1H), 6.55(t, J=5.2Hz, 1H), 6.68(dd, J=9.4, 2.6Hz, 2H), 6.73(d, J=7.6Hz, 1H), 7.03(d, J=9.2Hz, 1H), 7.07-7.10(m, 2H), 7.17(dd, J=8.8, 2.8Hz, 1H), 7.20-7.27(m, 3H), 7.39(d, J=2.4Hz, 1H ), 7.46(dd, J=7.8, 1.4Hz, 1H), 7.63(d, J=5.2Hz, 1H), 7.66(s, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ157.0, 156.0, 154.5, 152.2, 140.5, 139.0, 134.3, 133.4, 132.7, 131.1, 130.8, 129.8, 129.6, 129.4, 126.6, 126.4, 124.6, 122.7, 121.2, 118.3, 114.7, 55.7, 3360.6, 2926.0, 1651.7, 1557.3, 1510.5, 1473.1, 1235.3, _1154.5 , 1100.7, _1056.3 , _1035.0 , _829.3 , 588.3; ESI-MS m/z 590.4(MH) ^- ; Cl ₂ S ₂ -(MH) ^- 590.0395, observed 590.0383.

Example 12

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3-(3,5-dimethylphenyl)ureido)ethyl)-2-thienyl Sulfonamide (H1-5)

Add 64.0mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 3,5-di 1.1 molar equivalents of methylphenyl isocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 54.2 mg, the yield was 63.6%. Y41: ¹ H NMR (400MHz, Acetone-d ₆ ) δ2.08(s, 6H), 2.92(q, J=5.7Hz, 2H), 3.16(q, J=6.0Hz, 2H), 5.75(s, 1H), 6.45(s, 1H), 6.52(t, J=5.4Hz, 1H), 6.72(d, J=8.0Hz, 1H), 6.95(s, 2H), 7.04(d, J=9.2Hz, 1H), 7.09(t, J=5.4Hz, 2H), 7.17(dd, J=8.6Hz, 2.6H), 7.24(td, J=8.0, 1.8Hz, 1H), 7.40(d, J=2.4Hz , 1H), 7.46(dd, J=7.8, 1.8Hz, 1H), 7.63(d, J=4.8Hz, 1H), 7.69(s, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ156. 7, 154.5, 152.2, 141.2, 140.5, 139.0, 138.8, 133.4, 132.7, 131.1, 130.8, 129.8, 129.6, 129.4, 126.7, 126.3, 124.5, 124.2, 122.7, 118.3, 117.14, 44.9 (IR film) 3396.0, 2922.5, 1651.9, 1564.2, 1473.2, 1257.1, 1155.1, 1100.3, 837.9, 589.0; ESI-MS m/z 588.5 (MH) ^- ; ESI-H RMS calcd for C ₂₇ H ₂₇ N ₃ O ₄ Cl ₂ S ₂ -(MH) ^- 588.0596, observed 588.0591.

Example 13

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)ureido)ethyl)-2- Thienylsulfonamide (H1-6)

Add 40mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 3,5-Ditri 1.1 molar equivalents of fluoromethylphenyl isocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 52.9 mg, the yield was 84%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.78(s, 2H), 7.55(d, J=5.1Hz, 1H), 7.47(dd, J=7.6, 1.5Hz, 1H), 7.42(s, 1H) , 7.39(d, J=2.5Hz, 1H), 7.34-7.27(m, 2H), 7.19-7.12(m, 3H), 6.87(d, J=8.8Hz, 1H), 6.78(d, J=8.2 Hz, 1H), 5.56(s, 1H), 5.22(s, 1H), 3.33(q, J=5.3Hz, 2H), 3.11(q, J=5.6Hz, 2H); ESI-MS m/z698. 1(M+H) ⁺ , 720.1(M+Na) ⁺ ; MALDI-HRMS calcd. for C ₂₇ H ₁₉ N ₃ O ₄ F ₆ S ₂ Cl ₂ Na(M+Na) ⁺ 719.9990, observed 719.9981.

Example 14

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3-(3-nitrophenyl)ureido)ethyl)-2-thienylsulfonamide ( H1-7)

Add 40mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 3-nitrophenyl 1.1 molar equivalent of isocyanate, 3 ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 44 mg, the yield was 81%. ¹ H NMR (400MHz, CDCl ₃ ) δ8.04(s, 1H), 7.62(d, J=7.6Hz, 1H), 7.48-7.40(m, 4H), 7.28(s, 1H), 7.23-7.16( m, 2H), 7.09-7.05(m, 3H), 6.81(d, J=8.8Hz, 1H), 6.68(d, J=8.4Hz, 1H), 5.62(s, 1H), 5.48(s, 1H ), 3.24(s, 2H), 3.03(s, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ155.5, 153.6, 150.8, 148.4, 140.6, 140.4, 135.9, 132.1, 132.0, 130.6, 130.5, 130.5 , 129.7, 129.5, 128.4, 126.0, 124.8, 124.5, 123.9, 121.3, 117.5, 117.0, 113.3, 43.7, 39.8; ESI-MS m/z 607.1(M+H) ⁺ , 629.3(M+Na) ⁺ ; MALDI -HRMS calcd. for C ₂₅ H ₃₀ N ₄ O ₆ S ₂ Cl ₂ Na (M+Na) ⁺ 629.0094, observed 629.0077.

Example 15

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3-(3-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide (H1-8)

40mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 3-methoxybenzene 1.1 molar equivalents of isocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE:ethyl acetate=1:2 column chromatography, the product was collected to obtain 42 mg, the yield was 79%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.53(d, J=7.6Hz, 1H), 7.49(d, J=5.1Hz, 1H), 7.39(d, J=2.5Hz, 1H), 7.32(t , J=7.8Hz, 1H), 7.21-7.10(m, 4H), 6.97(t, J=2.2Hz, 1H), 6.90(d, J=8.8Hz, 1H), 6.75(dd, J=10.7, 4.9Hz, 2H), 6.59(d, J=8.2Hz, 2H), 5.24(s, 2H), 3.75(s, 3H), 3.28(t, J=5.0Hz, 2H), 3.07(q, J= 5.6Hz, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ160.2, 156.2, 153.6, 150.8, 140.2, 140.0, 136.6, 132.2, 131.8, 130.5, 130.4, 129.7, 129.5, 129.3, 128.3, 1246.1, 12 , 123.8, 121.5, 117.3, 112.3, 108.9, 105.8, 55.2, 43.8, 39.9; ESI-MS m/z 591.9(M+H) ⁺ , 614.2(M+Na) ⁺ ; MALDI-HRMS calcd.for C ₂₆ H ₂₄ N ₃ O ₅ S ₂ Cl ₂ (M+H) ⁺ 592.0529, observed 592.0514.

Example 16

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3-(4-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonyl Amide (H1-9)

Add 60.5mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 4-methoxy 1.1 molar equivalent of phenyl isothiocyanate, 3 ml of dichloromethane, stirred at room temperature for 5 hours. PE:ethyl acetate=1:2 column chromatography, the product was collected to obtain 79.8mg, yield 96.1%. Y42: ¹ H NMR (400MHz, Acetone-d ₆ ) δ3.04(q, J=6.0Hz, 2H), 3.61(q, J=6.0Hz, 2H), 3.66(s, 3H), 6.53(t, J=5.4Hz, 1H), 6.77(t, J=8.0Hz, 3H), 6.89(s, 1H), 7.03(d, J=8.8Hz, 1H), 7.06-7.12(m, 4H), 7.21( dd, J=7.8, 1.6Hz, 1H), 7.29(td, J=7.8, 1.6Hz, 1H), 7.41(d, J=2.4Hz, 1H), 7.46(dd, J=7.6, 2.4Hz, 1H ), 7.64 (d, J=5.2Hz, 1H), 8.58 (s, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ183.1, 159.0, 154.5, 152.2, 140.6, 139.0, 133.5, 132.7, 131.4, 131.1, 130.9, 130.0, 129.6, 129.4, 127.9, 126.6, 126.4, 124.6, 122.6, 118.4, 115.4, 55.8, 44.8, 43.7; 1154.7, 1099.9, 832.2, 587.7; ESI-MS m/z 606.5(MH) ^- ; ESI-HRMS calcd for C ₂₆ H ₂₂ N ₃ O ₄ Cl ₂ S ₃ -(MH) ^- 606.0159, observed 606.0155.

Example 17

3-(2-(2,4-Dichlorophenoxy)phenyl)-N-(2-(3-(3-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide (H1-10)

Add 58.3mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 3-nitrobenzene 1.1 molar equivalents of isothiocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 78.0 mg, yield 95.1%.

Y43: ¹ H NMR (400MHz, Acetone-d ₆ ) δ3.09(q, J=6.1Hz, 2H), 3.63(q, J=5.9Hz, 2H), 6.54(t, J=5.8Hz, 1H) , 6.77(d, J=8.0Hz, 1H), 7.03(d, J=2.8Hz, 1H), 7.09(t, J=6.0Hz, 2H), 7.20(dd, J=8.4, 2.4Hz, 1H) , 7.29(td, J=7.7, 1.4Hz, 1H), 7.40-7.48(m, 4H), 7.65(d, J=5.2Hz, 1H), 7.60(d, J=8.0Hz, 1H), 7.84( dd, J=7.6, 1.4Hz, 1H), 8.48(t, J=2.0Hz, 1H), 9.20(s, 1H); ¹³ CNMR (100MHz, Acetone-d ₆ ) δ182.9, 154.5, 152.2, 149.2 , 141.7, 140.8, 138.7, 133.5, 132.8, 131.1, 130.9, 130.1, 130.5, 130.0, 129.7, 129.4, 126.7, 126.3, 124.6, 122.6, 119.6, 118.6, 118.4, 44.8, 43.1 (43.1); , 1527.4, 1472.9, 1346.5, 1257.0, 1153.4, 1099.2, 740.2, 586.9; ESI-MS m/z621.4(MH) ^- ; ESI-HRMS calcd for C ₂₅ H ₁₉ N ₂ O ₅ Cl ₃ S ₃ -(MH ) ^- 620.9914, observed 620.9900.

Example 18

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)thioureido)ethyl)-2 -Thienylsulfonamide (H1-11)

Add 57.5mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 3,5-di 1.1 molar equivalents of trifluoromethylphenyl isothiocyanate, 3 ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 90.1 mg, the yield was 97.2%.

Y44: ¹ H NMR (400MHz, Acetone-d ₆ ) δ3.09(q, J=6.0Hz, 2H), 3.63(q, J=5.9Hz, 2H), 6.54(s, 1H), 6.77(d, J=8.0Hz, 1H), 7.03(d, J=8.8Hz, 1H), 7.10(t, J=6.6Hz, 2H), 7.19(dd, J=8.8, 2.4Hz, 1H), 7.29(td, J=7.9, 1.7Hz, 1H), 7.40(d, J=2.8Hz, 1H), 7.46(dd, J=7.6, 1.6Hz, 1H), 7.57(brd, 1H), 7.59(s, 1H), 7.66 (d, J=5.6Hz, 1H), 8.17 (s, 1H), 9.34 (brd, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ182.8, 154.5, 152.2, 142.7, 140.8, 138.7 , 133.5, 132.8, 132.2, 131.9, 131.1, 130.9, 130.1, 129.6, 129.4, 126.7, 126.4, 124.6, 123.8, 122.5, 118.4, 117.8, 44.7, 42.9; , 1330.8, 1277.7, 1130.9, 887.7, 588.4; ESI-MS m/z 712.5(MH) ^- ; ESI-H RMS calcd for C ₂₇ H ₁₈ N ₃ O ₃ Cl ₂ S ₃ F ₆ -(MH) ^- 711.9789, observed 711.9797.

Example 19

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3-(3-chlorophenyl)thioureido)ethyl)-2-thienylsulfonamide ( H1-12)

Add 58.5mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 3-chlorophenyl 1.1 molar equivalent of isothiocyanate, 3 ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 79.2 mg, the yield was 97.9%. Y45: ¹ H NMR (400 MHz, Acetone-d ₆ ) δ 3.07 (q, J=6.0 Hz, 2H), 3.62 (q, J=6.0 Hz, 2H), 6.53 (t, J=5.6, 1H), 6.76(d, J=8.0Hz, 1H), 7.02-7.04(m, 2H), 7.08-7.10(m, 2H), 7.18-7.21(m, 3H), 7.29(td, J=7.9, 1.4Hz, 2H), 7.41(d, J=2.0Hz, 1H), 7.46(dd, J=7.6, 1.6Hz, 1H), 7.51(s, 1H), 7.65(d, J=5.2Hz, 1H), 8.92( s, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ182.7, 154.5, 152.2, 141.3, 140.7, 138.8, 134.6, 133.5, 132.8, 131.1, 130.9, 130.0, 129.6, 129.4, 126.7, 126.4, 125.6, 124.6, 124.4, 122.9, 122.6, 118.4, 44.8, 43.3; IR (film) 3334.0, 2924.6, 1593.9, 1538.1, 1473.0, 1332.4, 1256.4, 1153.7, 1099.1, 870.1, 586.9 (ES-MS0.9; MH) ^- ; ESI-HRMS calcd for C ₂₅ H ₁₉ N ₃ O ₃ Cl ₃ S ₃ -(MH) ^- 609.9657, observed 609.9660.

Example 20

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3-(3-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonyl Amides (H1-13)

Add 57.7mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 3-methoxy 1.1 molar equivalent of phenyl isothiocyanate, 3 ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 79.2 mg, the yield was 100%.

Y46: ¹ H NMR (400MHz, Acetone-d ₆ ) δ3.07(q, J=6.0Hz, 2H), 3.61-3.65(m, 5H), 6.53(t, J=5.6, 1H), 6.61(dd , J=8.4, 2.2Hz, 1H), 6.76(d, J=8.4Hz, 2H), 6.89(s, 1H), 7.03(d, J=8.8Hz, 1H), 7.08-7.13(m, 3H) , 7.17(brd, 1H), 7.21(dd, J=9.0, 2.0Hz, 1H), 7.28((td, J=7.8, 1.6Hz, 1H), 7.40(d, J=2.4Hz, 1H), 7.46 (dd, J=7.8, 1.4Hz, 1H), 7.64 (d, J=9.2Hz, 1H), 8.76(s, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ182.5, 161.4, 154.5 ( ) 3363.7, 2924.9, 1603.7, 1538.1, 1473.0, 1331.0, 1257.5, 1154.3, 1099.6, 745.1, 587.1; ESI-MS m/z 606.4 (MH) ^- ; ESI-H RMS calcd for C ₂₆ H ₂₂ N ₃ O ₄ Cl ₂ S ₃ -(MH) ^- 606.0149, observed 606.0155.

Example 21

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3-(4-chlorophenyl)thioureido)ethyl)-2-thienylsulfonamide ( H1-14)

Add 60.9mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 4-chlorophenyl 1.1 molar equivalent of isothiocyanate, 3 ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 84.2 mg, and the yield was 100%.

Y47: ¹ H NMR (400 MHz, Acetone-d ₆ ) δ 3.06 (q, J=6.0 Hz, 2H), 3.62 (q, J=5.9 Hz, 2H), 6.53 (t, J=6.2, 1H), 6.76(d, J=8.4Hz, 1H), 7.02(d, J=8.8Hz, 2H), 7.08-7.12(m, 2H), 7.19-7.22(m, 4H), 7.27-7.34(m, 3H) , 7.41(d, J=2.4Hz, 1H), 7.46(dd, J=7.6, 1.6Hz, 1H), 7.65(d, J=4.0Hz, 1H), 8.86(s, 1H); ¹³ C NMR ( 100MHz, Acetone-d ₆ ) δ181.4, 153.1, 150.8, 139.2, 137.4, 137.1, 132.0, 131.3, 129.7, 129.5, 129.2, 128.6, 128.3, 128.2, 128.0, 125.3, 125.1, 123.14, 121 , 41.9; IR (film) 3333.9, 2924.7, 1537.7, 1489.6, 1472.7, 1332.3, 1256.5, 1154.0, 1098.8, 830.3, 744.0, 587.1; ESI-MSm/z 610.4 (MH) ^- ; ESI-HRMS H calcd for C _{2 19} N ₃ O ₃ Cl ₃ S ₃ -(MH) ^- 609.9655, observed 609.9660.

Example 22

3-(2-(2,4-Dichlorophenoxy)phenyl)-N-(2-(3-(4-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide (H1-15)

Add 59.8mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 4-nitrobenzene 1.1 molar equivalents of isothiocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 84.1 mg, the yield was 100%. Y48: ¹ H NMR (400 MHz, Acetone-d ₆ ) δ 3.10 (q, J=6.0 Hz, 2H), 3.64 (q, J=5.9 Hz, 2H), 6.65 (t, J=5.8, 1H), 6.77(d, J=8.0Hz, 1H), 7.03(d, J=8.8Hz, 2H), 7.09(t, J=6.2Hz, 1H), 7.20(dd, J=7.6, 2.6Hz, 1H), 7.29(td, J=8.0, 1.6Hz, 1H), 7.41(d, J=2.4Hz, 1H), 7.46(dd, J=7.6, 1.6Hz, 1H), 7.56(brd, 1H), 7.60( d, J=4.8Hz, 1H), 7.76(d, J=9.2Hz, 1H), 8.05(d, J=9.2Hz, 1H), 9.38(s, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ 182.2, 154.5, 152.2, 146.7, 144.0, 140.8, 138.7, 133.5, 132.8, 131.2, 130.9, 130.1, 129.7, 129.4, 126.6, 126.3, 125.2, 124.6, 122.5, 122.3, 14.1 IR (film) 3334.2, 2924.8, 1597.3, 1509.1, 1472.8, 1329.1, 1256.2, 1153.4, 1100.2, 744.6, 587.2; ESI-MSm/z 621.5(MH) ^- ; ESI-H RMS calcd for C ₂₅ H ₁₉ N ₄ O ₅ Cl ₂ S ₃ -(MH)-620.9913, observed 620.9900.

Example 23

3-(2-(2,4-Dichlorophenoxy)phenyl)-N-(2-(3-(3-methylphenyl)thioureido)ethyl)-2-thienylsulfonamide (H1-16)

Add 63.6mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 3-methylbenzene 1.1 molar equivalents of isothiocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 85.0 mg, and the yield was 100%.

Y49: ¹ H NMR (400MHz, Acetone-d ₆ ) δ2.17(s, 3H), 3.06(q, J=5.7Hz, 2H), 3.62(q, J=6.0Hz, 2H), 6.54(brd, 1H), 6.75(d, J=8.4Hz, 1H), 6.87(d, J=7.6Hz, 1H), 7.00(m, 7H), 7.20(dd, J=8.8, 2.4Hz, 1H), 7.28( td, J=7.8, 1.6Hz, 1H), 7.40(d, J=2.8Hz, 1H), 7.46(dd, J=7.6, 1.6Hz, 1H), 7.64(d, J=4.8Hz, 1H), 8.72(s, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ182.6, 154.5, 152.2, 140.6, 140.0, 139.0, 138.9, 133.5, 132.7, 131.1, 130.9, 130.0, 129.6, 129.4, 127.1, 126.6, 126.4, 125.8, 124.6, 122.6, 122.3, 118.4, 44.8, 43.6, 21.4; 590.4(MH) ^- ; ESI-HRMS calcd for C ₂₆ H ₂₂ N ₃ O ₃ Cl ₂ S ₃ -(MH) ^- 590.0205, observed 590.0206.

Example 24

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-trifluoroacetamidoethyl)-2-thienylsulfonamide (I1-1)

Add 60.5 mg of 3-(2-(2,4-dichlorophenoxy) phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide and 1.1 g of trifluoroacetic anhydride to a 25 ml egg-shaped bottle Molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 48.8 mg, the yield was 63.5%. Y50: ¹ H NMR (400MHz, Acetone-d ₆ ) δ3.02(q, J=6.3Hz, 2H), 3.30(q, J=6.1Hz, 2H), 6.61(t, J=6.2Hz, 1H) , 6.77(d, J=8.0Hz, 1H), 7.00(d, J=8.8Hz, 1H), 7.08-7.12(m, 2H), 7.20(dd, J=8.6, 2.6Hz, 1H), 7.30( td, J=7.9, 1.9Hz, 1H), 7.41(d, J=2.4Hz, 1H), 7.44(dd, J=7.6, 2.4Hz, 1H), 7.65(d, J=4.2Hz, 1H), 8.35(s, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ154.2, 152.3, 140.7, 138.9, 133.4, 132.8, 131.2, 130.9, 130.1, 129.6, 129.3, 126.6, 126.4, 124.6, 122.4, 118.5, 42.5, 40.7; IR (film) 3364.5, 3272.9, 1707.1, 1567.3, 1474.4, 1448.5, 1331.8, 1258.4, 1155.7, 1101.7, 827.5, 586.3; ESI-MS m/z539.4(M+1.H) ⁺ 3, 56 (M+Na) ⁺ ; ESI-HRMS calcd for C ₂₀ H ₁₅ N ₂ O ₄ F ₃ Cl ₂ S ₂ Na ⁺ (M+Na) ⁺ 560.9689, observed 560.9695.

Example 25

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(4-nitrobenzenesulfonamido)ethyl)-2-thienylsulfonamide (I1-2)

Add 63.2mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 4-nitrobasic yellow to a 25ml egg-shaped bottle Acyl chloride 1.1 molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE:ethyl acetate=1:2 column chromatography, the product was collected to obtain 49.6mg, yield 55.4%.

Y51: ¹ H NMR (400MHz, Acetone-d ₆ ) δ2.95(t, J=7.0Hz, 4H), 6.43(d, J=5.2Hz, 1H), 6.71(d, J=8.4Hz, 1H) , 6.83(d, J=4.8Hz, 1H), 6.98(d, J=8.8Hz, 1H), 7.06-7.09(m, 2H), 7.19(dd, J=8.6, 2.6Hz, 1H), 7.27( td, J=6.8, 2.4Hz, 1H), 7.41(dd, J=6.0, 2.0Hz, 2H), 7.66(d, J=4.8Hz, 1H), 7.93(d, J=8.8Hz, 2H), 8.26 (d, J=8.8Hz, 2H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ154.5, 152.1, 151.0, 147.3, 140.8, 138.8, 133.4, 132.9, 131.1, 130.9, 130.2, 129.8, 129.4 ,129.2,126.8,126.1,125.3,124.5,122.7,118.2,43.8,43.7; z 626.4(MH) ^- ; ESI-HRMS calcd for C ₂₄ H ₁₉ N ₃ O ₇ Cl ₂ S ₃ Na ⁺ (M+Na) ⁺ 649.9656, observed 649.9654.

Example 26

3-Bromo-N-(3-(N-Bocamino)propyl)-2-thienylsulfonamide (E2)

Add 1.3g (7.46mmol) of N-Boc-protected 3-aminopropylamine, 10ml of CH ₂ Cl ₂ , 1ml of triethylamine to a 20ml egg-shaped flask under ice-bath stirring, slowly add 3-bromo, 2-thienyl chloride dropwise Sulfone 1.8467g (7.06mmol). After the addition was complete, move to room temperature and stir for one hour. Add 200ml of water, extract with CH ₂ Cl ₂ 200ml×3, dry, filter, and concentrate to obtain 2.6831g of light yellow solid with a yield of 95.2%. ¹ H NMR (400MHz, CDCl ₃ ) δ1.63(quint, J=7.2Hz, 2H), 1.42(s, 9H), 3.09(q, J=6.4Hz, 2H), 3.23(q, J=6.1Hz , 2H), 4.66 (brd, 1H), 6.01 (brd, 1H), 7.09 (d, J=5.2Hz, 1H), 7.48 (d, J=5.2Hz, 2H); ESI-MS m/z 422.9 ( M+Na) ⁺ ; ESI-HRMScalcd for C ₁₂ H ₁₉ BrN ₂ O ₄ S ₂ Na ⁺ 420.9862(M+Na) ⁺ , observed 420.9881.

Example 27

3-(2-(2,4-Dichlorophenoxy)phenyl)-N-(3-(N-Bocamino)propyl)-2-thienylsulfonamide (F1-2)

Add 1.5781g (4.8mmol) of 3-bromo-N-(3-(N-Bocamino)propyl)-2-thienylsulfonamide to a 250ml reaction tube, 2-(2,4-dichlorophenoxy 1.5183g (5.4mmol) of phenylboronic acid, 140.1mg (0.47mmol) of Sphos, 105.5mg (0.34mmol) of palladium acetate, 3.0693g (14.5mmol) of K ₃ PO ₄ , add THF 25ml after ventilation, and reflux for 8 hours , stop heating and stirring. Add 100ml of water, extract with 250ml of ethyl acetate x 2, dry, filter, concentrate, PE:ethyl acetate=2.5:1 column chromatography, and obtain 1.3117g of yellow floc with a yield of 55.5%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.26(t, J=7.2Hz, 2H), 2.98(q, J=6.4Hz, 2H), 3.14(q, J=5.6Hz, 2H), 4.65(brd , 1H), 5.12(brd, 1H), 6.84(d, J=8.0Hz, 1H), 6.89(d, J=8.8Hz, 1H), 7.12(d, J=5.2Hz, 1H), 7.16(dd , J=8.8, 2.4Hz, 1H), 7.24(td, J=7.4, 1.0Hz, 1H), 7.37(dd, J=8.2, 1.5Hz, 1H), 7.40(d, J=2.4Hz, 1H) , 7.48 (d, J=9.2Hz, 1H), 7.59 (d, J=8.4Hz, 1H); ¹³ CNMR (100MHz, CDCl ₃ ) δ156.5, 153.4, 151.2, 139.6, 137.5, 132.4, 131.6, 130.4 , 130.3, 129.2, 128.7, 128.2, 125.8, 125.5, 124.0, 121.0, 117.8, 79.5, 40.4, 37.1, 30.4, 28.4; ESI-MS m/z 579.4(M+Na) ⁺ ; ESI-HRMS calcd for C ₂₄ H ₂₆ N ₂ O ₅ Cl ₂ S ₂ Na ⁺ (M+Na) ⁺ 579.0544, observed 579.0552.

Example 28

3-(2-(2,4-Dichlorophenoxy)phenyl)-N-(3-aminopropyl)-2-thienylsulfonamide (G1-2)

Add 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(1-N-Boc amino)propyl)-2-thienylsulfonamide 1.4015 to a 50ml egg-shaped bottle g (2.51 mmol), CH ₂ Cl ₂ 15 ml, CF ₃ CO ₂ H 5 ml, stirred at room temperature for 1 hour. Add potassium carbonate to neutralize CF ₃ CO ₂ H to make it alkaline, add water, extract with CH ₂ Cl ₂ 200ml×3, dry, filter, and concentrate to obtain 1.1183g of light yellow solid, with a yield of 97.3%. ¹ H NMR (400MHz, CDCl ₃ ) δ1.54(quint, J=6.1Hz, 2H), 2.74(t, J=6.0Hz, 2H), 3.06(t, J=6.0Hz, 2H), 6.84(d , J=8.0Hz, 1H), 6.92(d, J=8.8Hz, 1H), 7.10(d, J=5.2Hz, 1H), 7.18(dd, J=6.4, 2.4Hz, 1H), 7.22(t , J=7.4Hz, 1H), 7.36(td, J=6.9, 1.4Hz, 1H), 7.42(d, J=2.4Hz, 1H), 7.47(d, J=4.8Hz, 1H), 7.65(dd , J=7.4, 1.4Hz, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ153.5, 151.2, 139.3, 137.5, 132.8, 131.6, 130.4, 130.2, 129.2, 128.6, 128.3, 126.0, 125.4, 123.9, 120.9, 117.6, 42.6, 40.3, 31.1; ESI-MS m/z 457.0(M+H) ⁺ ; ESI-HRMS calcd. for C ₁₉ H ₁₉ ClN ₂ O ₃ S ₂ 457.0209(M+H) ⁺ , observed 457.0218 .

Example 29

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3-(4-nitrophenyl)ureido)propyl)-2-thienylsulfonamide ( H1-17)

Add 62.5mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-aminopropyl)-2-thienylsulfonamide, 4-nitrobenzene 1.1 molar equivalents of isocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 67.6 mg, yield 79.6%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ1.57(quint, J=6.6Hz, 2H), 2.73(q, J=6.5Hz, 2H), 3.13(q, J=6.4Hz, 2H), 5.95 (t, J=5.2Hz, 1H), 6.37(t, J=6.2Hz, 1H), 6.76(d, J=8.0Hz, 1H), 6.99(d, J=58.8Hz, 1H), 7.07-7.13 (m, 2H), 7.18(dd, J=8.8, 2.4Hz, 1H), 7.28(td, J=7.7, 1.8Hz, 1H), 7.38(d, J=2.4Hz, 1H), 7.47(dd, J=7.8, 1.4Hz, 1H), 7.56(d, J=9.2Hz, 2H), 7.62(d, J=4.2Hz, 1H), 8.01(d, J=8.8Hz, 2H), 8.54(s, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ155.7, 154.4, 152.3, 147.9, 142.4, 140.5, 139.3, 133.5, 132.8, 131.1, 130.8, 129.8, 129.5, 129.3, 126.6, 126.5, 125. 124.6, 122.4, 118.5, 118.1, 41.4, 37.6, 31.1; IR (film) 3364.8, 2925.6, 1682.5, 1552.6, 1473.1, 1329.1, 1232.8, 1153.4, 1111.0, 751.3, 568.0; ESI-MS 19 m/z ^- ; MALDI/DHB-HRMS calcd for C ₂₆ H ₂₂ N ₄ O ₅ C1 ₂ S ₂ Na ⁺ (M+Na) ⁺ 643.0245, observed 643.0250.

Example 30

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3-(3,5-dichlorophenyl)ureido)propyl)-2-thienylsulfonyl Amide (H1-18)

Add 61.1 mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-aminopropyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 3,5-di 1.1 molar equivalents of chlorophenyl isocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 76.9 mg, the yield was 89.2%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ1.53(quint, J=6.5Hz, 2H), 2.86(q, J=6.5Hz, 2H), 3.11(q, J=6.4Hz, 2H), 5.85 (t, J=5.2Hz, 1H), 6.35(t, J=7.2Hz, 1H), 6.65(d, J=8.4Hz, 1H), 6.84(t, J=1.8Hz, 1H), 6.99(d , J=8.8Hz, 1H), 7.07-7.13(m, 2H), 7.18(dd, J=8.6, 2.6Hz, 1H), 7.28(td, J=7.9, 1.4Hz, 1H), 7.39(t, J=2.6Hz, 3H), 7.47(dd, J=7.8, 1.4Hz, 1H), 7.62(d, J=5.2Hz, 1H), 8.19(s, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ156.0, 154.4, 152.3, 144.0, 140.4, 139.3, 135.4, 133.5, 132.7, 131.1, 130.9, 129.7, 129.5, 129.3, 126.6, 126.5, 124.6, 122.4, 121.5, 113.0, 118.5, 1 31.2; IR (film) 3382.0, 2920.4, 1667.2, 1587.5, 1539.0, 1473.2, 1447.6, 1256.5, 1153.7, 1100.5, 588.0; ESI-MS m/z 642.4 (MH) ^- ; MALDI/DHB-H RMS ₆ calcd for C 2 H ₂₁ N ₃ O ₄ Cl ₄ S ₂ Na ⁺ (M+Na) ⁺ 665.9608, observed 665.9620.

Example 31

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3-(4-chlorophenyl)ureido)propyl)-2-thienylsulfonamide (H1 -19)

Add 67.3mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-aminopropyl)-2-thienylsulfonamide, 4-chlorophenyl 1.1 molar equivalent of isocyanate, 3 ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 81.2 mg, the yield was 90.0%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ1.52(quint, J=6.4Hz, 2H), 2.85(q, J=6.5Hz, 2H), 3.10(q, J=6.3Hz, 2H), 5.73 (t, J=5.4Hz, 1H), 6.43(t, J=6.2Hz, 1H), 6.75(d, J=8.4Hz, 1H), 6.98(d, J=8.8Hz, 1H), 7.09(q , J=6.9Hz, 4H), 7.17(dd, J=8.8, 2.8Hz, 1H), 7.28(td, J=7.9, 1.6Hz, 1H), 7.34(d J=8.8Hz, 2H), 7.38( d, J=2.8Hz, 1H), 7.48(dd, J=7.6, 1.6Hz, 1H), 7.61(d, J=4.8Hz, 1H), 7.97(s, 1H); ¹³ C NMR (100MHz, Acetone -d ₆ )δ156.5, 154.4, 152.3, 140.5, 139.4, 133.5, 132.7, 131.1, 130.9, 129.7, 129.5, 129.3, 126.6, 126.5, 124.6, 122.3, 120.5, 118.5, 41.3, 31.4, 3 film)3361.4, 2926.9, 1659.3, 1594.9, 1547.8, 1491.7, 1473.2, 1256.9, 1233.8, 1153.9, 1099.8, 827.8, 587.9; ESI-MS m/ _z608.5 (MH) ^- ; MALDI/DHB-HRMS 2 calcd for H ₂₂ N ₃ O ₄ Cl ₃ S ₂ Na ⁺ (M+Na) ⁺ 632.0010, observed 632.0003.

Example 32

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3-(4-methoxyphenyl)ureido)propyl)-2-thienylsulfonamide (H1-20)

66.8 mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-aminopropyl)-2-thienylsulfonamide, 4-methoxy 1.1 molar equivalent of phenyl isocyanate, 3 ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 80.0 mg, and the yield was 90.3%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ1.50(quint, J=6.4Hz, 2H), 2.85(q, J=6.3Hz, 2H), 3.10(q, J=6.1Hz, 2H), 3.61 (s, 3H), 5.58(t, J=5.4Hz, 1H), 6.49(t, J=6.2Hz, 1H), 6.67(dd, J=9.8, 3.0Hz, 2H), 6.75(d, J= 8.4Hz, 1H), 6.98(d, J=9.2Hz, 1H), 7.07-7.12(m, 2H), 7.16(dd, J=9.0, 2.6Hz, 1H), 7.20(dd, J=9.8, 3.0 Hz, 2H), 7.27(td, J=7.8, 1.6Hz, 1H), 7.38(d, J=2.4Hz, 1H), 7.49(dd, J=7.4, 1.4Hz, 1H), 7.60(d, J =8.2Hz, 2H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ157.1, 156.0, 154.4, 152.3, 140.4, 139.5, 134.4, 133.5, 132.7, 131.0, 130.8, 129.6, 129.4, 129.3, 126.6, 126.5，124.7，122.3，121.3，118.6，114.7，55.7，41.2，37.3，31.6；IR(film)3354.0，2930.0，1651.5，1662.6，1556.7，1510.6，1473.2，1234.7，1154.0，1100.5，1035.7，828.8，587.4； ESI-MS m/z 604.4(MH) ^- ; MALDI/DHB-HRMS calcd for C ₂₇ H ₂₅ N ₃ O ₅ Cl ₂ S ₂ Na ⁺ (M+Na) ⁺ 628.0518, observed 628.0505.

Example 33

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3-(4-methoxyphenyl)thioureido)propyl)-2-thienylsulfonyl Amide (H1-21)

Add 64.0mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-aminopropyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 4-methoxy 1.1 molar equivalent of phenyl isothiocyanate, 3 ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 73.2 mg, the yield was 84.0%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ1.61(quint, J=6.5Hz, 2H), 2.85(q, J=6.5Hz, 2H), 3.52(q, J=6.3Hz, 2H), 3.67 (s, 3H), 6.47(t, J=6.4Hz, 1H), 6.77(t, J=8.0Hz, 1H), 7.02(d, J=8.8Hz, 1H), 7.05-7.13(m, 4H) , 7.20 (dd, J=8.8, 2.4Hz, 1H), 7.29 (td, J=8.8, 1.4Hz, 1H), 7.40 (d, J=2.4Hz, 1H), 7.48 (dd, J=7.8, 1.4 Hz, 1H), 7.63(d, J=4.8Hz, 1H), 8.47(s, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ182.8, 159.0, 154.4, 152.3, 140.4, 139.4, 133.5 , 132.7, 131.4, 131.1, 130.9, 129.7, 129.5, 129.4, 128.0, 126.6, 126.5, 124.6, 122.5, 118.5, 115.4, 55.8, 42.4, 41.2, 30.6; , 1331.7, 1247.5, 1153.7, 1100.2, 743.6, 586.9; ESI-MS m/z 620.5(MH) ^- ; MALDI/DHB-HRMS calcd for C ₂₇ H ₂₅ N ₃ O ₄ Cl ₂ S ₃ Na ⁺ (M+Na) ^+644.0267 , observed 644.0277.

Example 34

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3-(3-nitrophenyl)thioureido)propyl)-2-

Thienylsulfonamide (H1-22)

Add 65.9mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-aminopropyl)-2-thienylsulfonamide, 3-nitrobenzene 1.1 molar equivalents of isothiocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 89.3 mg, the yield was 97.2%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ1.69 (quint, J=6.6Hz, 2H), 2.90 (q, J=6.4Hz, 2H), 3.55 (q, J=6.1Hz, 2H), 6.40 (t, J=6.2Hz, 1H), 6.76(t, J=8.4Hz, 1H), 7.01(d, J=8.8Hz, 1H), 7.08-7.12(m, 2H), 7.19(dd, J= 9.0, 2.2Hz, 1H), 7.28(td, J=7.8, 1.2Hz, 1H), 7.39(d, J=2.0Hz, 2H), 7.44-7.48(m, 2H), 7.63(d, J=5.2 Hz, 1H), 7.75(d, J=7.6Hz, 1H), 7.84(d, J=8.0Hz, 1H), 8.46(s, 1H), 9.09(s, 1H); ¹³ CNMR (100MHz, Acetone- d6) _δ182.6 , 154.4, 152.3, 149.2, 141.8, 140.5, 139.2, 133.5, 132.8, 131.1, 130.9, 130.5, 129.9, 129.6, 129.4, 126.6, 126.5, 124.6, 122.4, 118.4, 119.5, , 42.3, 41.4, 30.6; IR (film) 3334.0, 2957.7, 1704.0, 1529.0, 1473.0, 1350.7, 1257.0, 1152.8, 1099.4, 739.6, 587.2; ESI-MS m/z 635.00623 (MH) ^- ; ESI-forMS _{C26H21N4O5Cl2S3- ( MH ) -635.0062} ^, observed _623.0057 .

Example 35

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3-(3,5-ditrifluoromethylphenyl)thioureido)propyl)-2 -Thienylsulfonamide (H1-23)

Add 66.2 mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-aminopropyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 3,5-di 1.1 molar equivalents of trifluoromethylphenyl isothiocyanate, 3 ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 100.9 mg, the yield was 95.7%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ1.71(quint, J=6.8Hz, 2H), 2.90(q, J=6.5Hz, 2H), 3.55(q, J=6.1Hz, 2H), 6.38 (t, J=6.2Hz, 1H), 6.76(d, J=8.4Hz, 1H), 7.01(d, J=8.8Hz, 1H), 7.10(t, J=7.2Hz, 2H), 7.19(dd , J=8.8, 2.4Hz, 1H), 7.28(td, J=8.0, 1.6Hz, 1H), 7.40(d, J=2.4Hz, 1H), 7.46(dd, J=7.6, 1.2Hz, 1H) , 7.53(brd, 1H), 7.58(s, 1H), 7.64(d, J=4.8Hz, 1H), 8.16(s, 2H), 9.23(s, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ 182.5, 154.5, 152.3, 142.9, 140.5, 139.1, 133.5, 132.8, 132.1, 131.8, 131.1, 130.9, 129.9, 129.6, 129.3, 126.6, 126.5, 125.8, 125, 6, 123.4, 12 41.4, 30.4; IR (film) 3334.9, 2926.2, 1537.8, 1473.8, 1384.4, 1278.0, 1135.1, 681.8, 587.8; ESI-MS m/z 726.5 (MH) ^- ; ESI-HRMS calcd for C ₂₈ H ₂₀ N ₃ O ₃ Cl ₂ F ₃ S ₃ ^- (MH)-725.9951, observed725.9954.

Example 36

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3-(3-chlorophenyl)thioureido)propyl)-2-thienylsulfonamide ( H1-24)

Add 64.9mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-aminopropyl)-2-thienylsulfonamide, 3-chlorophenyl 1.1 molar equivalent of isothiocyanate, 3 ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 72.1 mg, the yield was 81.0%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ1.66(quint, J=6.3Hz, 2H), 2.88(q, J=6.5Hz, 2H), 3.54(q, J=6.4Hz, 2H), 6.42 (t, J=6.2Hz, 1H), 6.70(d, J=8.0Hz, 1H), 7.00-7.04(m, 2H), 7.09(d, J=4.8Hz, 1H), 7.11(d, J= 8.0Hz, 1H), 7.18(d, J=2.4Hz, 1H), 7.20-7.21(m, 2H), 7.24(d, J=6.0Hz, 1H), 7.29(td, J=7.9, 1.80Hz, 1H), 7.40(d, J=2.4Hz, 1H), 7.47(dd, J=7.6, 1.6Hz, 2H), 7.63(d, J=5.2Hz, 1H), 8.81(s, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ )δ182.4, 154.4, 152.3, 141.4, 140.4, 139.3, 134.6, 133.5, 132.7, 131.2, 131.1, 130.9, 129.8, 129.5, 129.4, 126.6, 126.5, 1245.6, 1245.5, , 122.9, 122.4, 118.5, 42.3, 41.3, 30.6; IR (film) 3333.9, 2925.3, 1537.7, 1473.2, 1330.7, 1256.5, 1152.8, 1099.0, 743.4, 586.3; ESI-MS m/z 624.4; (MALDI) ^- /DHB-HRMS calcd for C ₂₆ H ₂₂ N ₃ O ₃ Cl ₃ S ₃ Na ⁺ (M+Na) ⁺ 647.9770, observed 647.9781.

Example 37

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3-(3-methoxyphenyl)thioureido)propyl)-2-thienylsulfonyl Amide (H1-25)

Add 66.2mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-aminopropyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 3-methoxy 1.1 molar equivalent of phenyl isothiocyanate, 3 ml of dichloromethane, stirred at room temperature for 5 hours. PE:ethyl acetate=1:2 column chromatography, the product was collected to obtain 57.7mg, yield 64.0%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ1.65(quint, J=6.5Hz, 2H), 2.87(q, J=6.4Hz, 2H), 3.55(q, J=6.1Hz, 2H), 6.46 (t, J=6.2Hz, 1H), 6.62(dd, J=8.4, 2.4Hz, 1H), 6.76(t, J=7.4Hz, 2H), 6.86(s, 1H), 7.01(d, J= 8.8Hz, 1H), 7.08-7.14(m, 4H), 7.19(dd, J=9.0, 2.2Hz, 1H), 7.28(t, J=7.8Hz, 1H), 7.40(d, J=2.4Hz, 1H), 7.47(d, J=7.6Hz, 1H), 7.62(d, J=5.2Hz, 1H), 8.67(s, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ180.8, 160.0 , 153.0, 150.9, 139.0, 138.9, 138.0, 132.1, 131.3, 129.7, 129.5, 128.3, 128.1, 128.0, 125.2, 125.1, 123.2, 121.0, 117.1, 115.6, 110.6, 109.4, 94.2, IR (film)3341.8, 2930.0, 1603.7, 1538.0, 1472.8, 1329.1, 1257.5, 1099.5, 1039.9, 744.6, 586.6; ESI-MS m/z 620.5(MH) ^- ; ESI-H RMS calcd for C ₂₇ H ₂₄ N ₃ O ₄ Cl ₂ S ₃ -(MH) ^- 620.0303, observed 620.0312.

Example 38

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3-(4-chlorophenyl)thioureido)propyl)-2-thienylsulfonamide ( H1-26)

Add 62.5mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-aminopropyl)-2-thienylsulfonamide, 4-chlorophenyl 1.1 molar equivalent of isothiocyanate, 3 ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 64.1 mg, and the yield was 74.8%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ1.52(quint, J=6.6Hz, 2H), 2.86(q, J=6.4Hz, 2H), 3.10(q, J=6.3Hz, 2H), 5.74 (t, J=5.4Hz, 1H), 6.42(t, J=6.0Hz, 1H), 6.75(d, J=8.4Hz, 1H), 6.98(d, J=8.8Hz, 1H), 7.09(dd , J=14.8, 6.0Hz, 4H), 7.17(dd, J=8.8, 2.0Hz, 1H), 7.28(td, J=7.7, 1.4Hz, 1H), 7.34(d, J=8.8Hz, 2H) , 7.38(d, J=2.8Hz, 1H), 7.48(d, J=2.8Hz, 1H), 7.61(d, J=5.2Hz, 1H), 7.96(s, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ 181.1, 153.0, 150.9, 139.0, 137.8, 137.2, 132.1, 131.3, 129.7, 129.5, 129.1, 128.4, 128.3, 128.1, 128.0, 127.9, 125.2, 123.2, 1791.0, 1 , 39.9, 28.9; IR (film) 333.8, 2926.4, 1537.5, 1473.0, 1360.5, 1256.9, 1153.5, 820.2, 744.3, 587.0; ESI-MS m/z624.4 (MH) ^- ; ESI-HRMS calcd for C ₂₆ H ₂₁ N ₃ O ₃ Cl ₃ S ₃ -(MH) ^- 623.9806, observed 623.9816.

Example 39

3-(2-(2,4-Dichlorophenoxy)phenyl)-N-(3-(3-(4-nitrophenyl)thioureido)propyl)-2-thienylsulfonamide (H1-27)

Add 62.9mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-aminopropyl)-2-thienylsulfonamide, 4-nitrobenzene 1.1 molar equivalents of isothiocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 62.8 mg, the yield was 71.6%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ1.71(quint, J=6.7Hz, 2H), 2.90(q, J=6.5Hz, 2H), 3.56(q, J=6.1Hz, 2H), 6.40 (t, J=6.0Hz, 1H), 6.77(d, J=8.4Hz, 1H), 7.01(d, J=8.8Hz, 1H), 7.10(t, J=7.0Hz, 2H), 7.19(dd , J=8.8, 2.8Hz, 1H), 7.28(td, J=7.8, 1.6Hz, 1H), 7.39(d, J=2.4Hz, 1H), 7.46(d, J=7.6Hz, 1H), 7.53 (brd, 1H), 7.64(d, J=5.2Hz, 1H), 7.73(d, J=9.2Hz, 2H), 8.05(d, J=9.6Hz, 2H), 9.27(s, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ182.0, 154.5, 152.3, 146.9, 143.9, 140.5, 139.1, 133.5, 132.8, 131.1, 130.9, 129.9, 129.6, 129.4, 126.4, 126.5, 125.3, 122.4, 124.6, ⁽ MH) HRMS calcd for C ₂₆ H ₂₁ N ₄ O ₅ Cl ₂ S ₃ -(MH) ^- 635.0064, observed 637.0057.

Example 40

3-(2-(2,4-Dichlorophenoxy)phenyl)-N-(3-(3-(3-methylphenyl)thioureido)propyl)-2-thienylsulfonamide (H1-28)

Add 62.7mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-aminopropyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 3-methylbenzene 1.1 molar equivalents of isothiocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 58.5 mg, yield 70.3%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ1.63(quint, J=6.6Hz, 2H), 2.17(s, 3H), 2.86(q, J=6.3Hz, 2H), 3.54(q, J= 6.3Hz, 2H), 6.46(t, J=6.0Hz, 1H), 6.76(d, J=8.4Hz, 1H), 6.88(d, J=7.6Hz, 1H), 6.99-7.02(m, 4H) , 7.08-7.12(m, 3H), 7.19(dd, J=8.8, 2.4Hz, 1H), 7.28(td, J=7.9, 1.4Hz, 1H), 7.40(d, J=2.4Hz, 1H), 7.47(dd, J=7.6, 2.6Hz, 1H), 7.26(d, J=5.6Hz, 1H), 8.61(s, 1H); ¹³ C NMR(100MHz, Acetone-d ₆ ) δ182.3, 154.4, IR film) 3334.1, 2924.5, 1537.8, 1473.1, 1257.0, 1099.7, 744.3, 587.0; ESI-MS m/z 604.4 ([MH] ^- ); ESI-HRMS calcd for C ₂₇ H ₂₄ N ₃ O ₃ Cl ₂ S ₃ -( MH) ^- 604.0382, observed 604.0362.

Example 41

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-trifluoroacetamidopropyl)-2-thienylsulfonamide (I1-3)

Add 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-aminopropyl)-2-thienylsulfonamide 65.2mg, trifluoroacetic anhydride 1.1 Molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE:ethyl acetate=1:2 column chromatography, the product was collected to obtain 48.9 mg, the yield was 62.0%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ1.78(quint, J=7.0Hz, 2H), 3.01(q, J=6.5Hz, 2H), 3.36(q, J=6.7Hz, 2H), 6.48 (t, J=6.0Hz, 1H), 6.91(d, J=8.4Hz, 1H), 7.13(d, J=8.8Hz, 1H), 7.21-7.25(m, 2H), 7.35(dd, J= 8.8, 2.4Hz, 1H), 7.43(td, J=7.8, 1.2Hz, 1H), 7.54(d, J=2.8Hz, 1H), 7.57(d, J=7.6Hz, 1H), 7.77(d, J=5.2Hz, 1H), 8.39(s, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ154.5, 152.4, 140.6, 133.5, 132.8, 132.4, 131.9, 131.1, 130.9, 129.9, 129.6, 129.3, 126.6, 126.5, 124.6, 122.7, 122.3, 118.6, 41.4, 41.3, 37.8; 551.1(MH) ^- ; ESI-HRMS calcd for C ₂₁ H ₁₆ N ₂ O ₄ Cl ₂ F ₃ S ₂ -(MH) ^- 550.9873, observed 550.9886.

Example 42

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(4-nitrobenzenesulfonamido)propyl)-2-thienylsulfonamide (I1-4)

Add 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-aminopropyl)-2-thienylsulfonamide 68mg, 4-nitrobenzene yellow to a 25ml egg-shaped bottle Acyl chloride 1.1 molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE:ethyl acetate=1:2 column chromatography, the product was collected to obtain 45.7 mg, the yield was 47.9%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ1.70(quint, J=6.9Hz, 2H), 2.95-3.03(m, 4H), 6.40(t, J=5.2Hz, 1H), 6.80(t, J=6.4Hz, 1H), 6.89(d, J=8.0Hz, 1H), 7.12(d, J=8.8Hz, 1H), 7.18-7.24(m, 2H), 7.33(dd, J=8.8, 2.4 Hz, 1H), 7.42(t, J=8.0Hz, 1H), 7.55(dd, J=9.4, 1.8Hz, 2H), 7.77(d, J=5.2Hz, 1H), 8.10(d, J=8.8 Hz, 2H), 8.43 (d, J=8.8Hz, 2H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ154.4, 152.3, 151.0, 147.5, 140.5, 139.0, 139.0, 133.4, 132.7, 131.1, 130.9，129.9，129.5，129.3，129.2，126.5，126.4，125.3，124.6，122.3，118.5，41.4，41.3，30.7；IR(film)3300.6，3104.7，2926.5，1530.3，1473.5，1348.6，1158.9，1097.6，744.9， 588.5; ESI-MS m/z 640.2(MH) ^- ; ESI-HRMS calcd for C ₂₅ H ₂₀ N ₃ O ₇ Cl ₂ S ₃ -(MH) ^- 639.9852, observed 639.9846.

Example 43

3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-acetamidopropyl)-2-thienylsulfonamide (I1-5)

Add 63.2mg of 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-aminopropyl)-2-thienylsulfonamide and 1.1 molar equivalent of acetic anhydride to a 25ml egg-shaped bottle , dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 66.4 mg, the yield was 96%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ1.61(quint, J=6.6Hz, 2H), 1.84(s, 3H), 2.94(q, J=6.4Hz, 2H), 3.18(q, J= 6.3Hz, 2H), 6.56(t, J=5.4Hz, 1H), 6.92(d, J=8.0Hz, 1H), 7.08(brd, 1H), 7.13(d, J=8.8Hz, 1H), 7.21 (d, J=5.2Hz, 1H), 7.25(t, J=7.4Hz, 1H), 7.34(dd, J=8.8, 2.4Hz, 1H), 7.43(td, J=7.7, 1.4Hz, 1H) , 7.54(d, J=2.4Hz, 1H), 7.61(d, J=7.6Hz, 1H), 7.76(d, J=5.2Hz, 1H); ¹³ CNMR(100MHz, Acetone-d ₆ )δ170.7 , 154.4, 152.4, 140.4, 139.5, 133.5, 132.6, 131.0, 130.8, 129.7, 129.4, 129.3, 126.6, 126.5, 124.7, 122.3, 118.6, 41.2, 36.8, 30.8, 22.9; IR(41.72) 328 , 1574.0, 1473.4, 1259.3, 1146.7, 802.0, 589.2; ESI-MS m/z 497.2(MH) ^- ; ESI-HRMS calcd for C ₂₁ H ₁₉ N ₂ O ₄ Cl ₂ S ₂ -(MH) ^- 497.0172, observed 497.0169 .

Example 44

2-(1-Naphthyl)nitrobenzene (A4)

Add 10.104g of 1-naphthol, 10.137g of o-fluoronitrobenzene, 11.744g of K ₂ CO ₃ , and 46ml of DMF into a 250ml egg-shaped bottle, and reflux for 5h. Heating was stopped, 500ml of ethyl acetate was added, washed with 200ml of water × 3, dried, filtered and concentrated to obtain 18.590g of orange-red liquid with a yield of 100%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.14 (d, J=8.4Hz, 1H), 8.01 (dd, J=8.2, 1.4Hz, 1H), 7.90 (d, J=7.2Hz, 1H), 7.72 (d, J=8.4Hz, 1H), 7.57-7.50(m, 2H), 7.46-7.40(m, 2H), 7.19(t, J=7.7Hz, 1H), 7.04(d, J=7.5Hz, 1H), 6.91 (d, J=8.3Hz, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ151.3, 151.3, 140.9, 135.1, 134.3, 128.0, 127.0, 126.6, 126.6, 125.8, 125.7, 125.0, 123.0, 121.8, 119.7, 114.5; ESI-MSm/z 266.0(M+H) ⁺ ; HRMS calcd. for C ₁₆ H ₁₁ NO ₃ Na(M+Na) ⁺ 288.0632, observed 288.0632.

Example 45

2-(1-Naphthyl)aminobenzene (B4)

Add 18.590g of 2-(1-naphthyl)nitrobenzene and 20ml of ethanol to a 1L eggplant-shaped bottle, add a little ethyl acetate to aid dissolution, add 20g of zinc powder, and slowly add 1mol/L dropwise at room temperature with a mechanical stirrer 360ml of hydrochloric acid until the gray color of the zinc powder disappears. Stop stirring. Add 500ml of ethyl acetate, wash with 200ml×3 water, dry, filter and concentrate to obtain 16.48g of orange-red liquid with a yield of 100%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.35-8.33(m, 1H), 7.89-7.86(m, 1H), 7.58-7.51(m, 3H), 7.33(t, J=7.9Hz, 1H), 7.01(m, 1H), 6.91-6.87(m, 2H), 6.82(d, J=7.6Hz, 1H), 6.76-6.72(m, 1H), 3.30(s, 2H);

Example 46

2-(1-Naphthyl)iodobenzene (C4)

Place a 500ml three-necked flask in an ice bath, add 10.318g of 2-(1-naphthyl)aminobenzene, 7ml of concentrated sulfuric acid, dilute and cool with 170ml of water, then add, slowly add NaNO ₂ 4.069g of water (60ml) under mechanical stirring After adding the solution in ten minutes, add Kl 9.929g water (40ml) solution after 1 hour, then move to room temperature and stir after half an hour. The reaction at room temperature was stopped after 4 hours, and 200ml of water was added, extracted with CH ₂ Cl ₂ 300ml×3, combined, and washed once with saturated Na ₂ S ₂ O ₃ . After drying, filtering, concentrating, and column chromatography, 13.093 g of nearly colorless liquid was obtained with a yield of 75.3%.

EI-MS m/z 346(M+H) ⁺ ; EI-HRMS calcd. for C ₁₆ H11OI(M) ⁺ 345.9855, observed 345.9859;

Example 47

2-(1-Naphthyl)phenylboronic acid (D4)

Add 3.073g of 2-(1-naphthyl)iodobenzene into a 100ml reaction tube, fully remove oxygen and water, add anhydrous THF 32ml under the protection of argon, slowly add 2.5mol/ L n-butyllithium solution 4.2ml, reacted for 1 hour, added 1.4ml of trimethyl borate at -78°C, moved the reaction tube to room temperature and stirred after 2 hours. After stirring at room temperature for 2 h, 1 ml of concentrated hydrochloric acid was added, extracted with ethyl acetate, dried, filtered, and concentrated to obtain 1.498 g of white solid, with a yield of 64%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.05 (d, J=8.4Hz, 1H), 7.99 (dd, J=6.6, 1.4Hz, 1H), 7.92 (d, J=8.0Hz, 1H), 7.74 (d, J=8.0Hz, 1H), 7.57-7.53(m, 1H), 7.51(d, J=7.1Hz, 1H), 7.46(d, J=8.0Hz, 1H), 7.31-7.27(m, 1H), 7.13(t, J=7.6Hz, 2H), 6.59(d, J=8.4Hz, 1H), 5.73(s, 2H); EI-MS m/z 264.0(M) ⁺ ; EI-HRMScalcd. for C ₁₆ H ₁₃ BO ₃ (M) ⁺ 263.0994, observed 263.0989.

Example 48

3-(2-(1-Naphthyl)phenyl)-N-(2-(N-Bocamino)ethyl)-2-thienylsulfonamide (F4)

Add 0.810g of 3-bromo-N-(2-(N-Bocamino)ethyl)-2-thienylsulfonamide and 1.92g of 2-(1-naphthyl)phenylboronic acid to a 250ml Shrek tube, Sphos 126mg, palladium acetate 48mg, K ₃ PO ₄ 0.889g, add THF 50ml after fully deoxygenating, reflux for 8 hours, stop heating and stirring. Add 100ml of water, extract with 100ml of ethyl acetate x 2, dry, filter, concentrate, and perform column chromatography to obtain 700mg of yellow floc with a yield of 43.5%. ESI-MS m/z 525.0(M+H) ⁺ ;

Example 49

3-(2-(1-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide (G4)

Add 700mg of 3-(2-(1-naphthyl)phenyl)-N-(2-(N-Bocamino)ethyl)-2-thienylsulfonamide, CH ₂ Cl ₂ to a 25ml egg-shaped bottle 6ml, CF ₃ CO ₂ H 1.5ml, stirred at room temperature for 12 hours. Add potassium carbonate to neutralize CF ₃ CO ₂ H until basic, add water, extract with CH ₂ Cl ₂ 60ml×3, dry, filter, and concentrate to obtain 539 mg of yellow solid, yield 95.2%.

ESI-MS m/z 425.0(M+H) ⁺ ; ESI-HRMS calcd. for C ₁₆ H ₁₁ NO ₃ Na 425.0988(M+H) ⁺ , observed 425.0092;

Example 50

3-(2-(1-naphthyl)phenyl)-N-(2-(3-(3,5-dichlorophenyl)ureido)ethyl)-2-thienylsulfonamide (H4- 1)

Add 3-(2-(1-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide 39.5mg, 3,5-dichlorophenyl 1.1 molar equivalent of isocyanate, 3 ml of dichloromethane, stirred at room temperature for 5 hours. PE:ethyl acetate=1:2 column chromatography, the product was collected to obtain 49.6mg, the yield was 87%.

¹ H NMR (400MHz, Acetone-d ₆ ) 63.08(q, J=5.3Hz, 2H), 3.33(q, J=5.9Hz, 2H), 6.08(s, 1H), 6.67(s, 1H), 6.88 (d, J=8.0Hz, 1H), 6.99(s, 1H), 7.05(d, J=7.6Hz, 1H), 7.19(t, J=7.4Hz, 1H), 7.30(d, J=5.2Hz , 1H), 7.35(t, J=8.0Hz, 1H), 7.42(t, J=8.0Hz, 1H), 7.47-7.45(m, 2H), 7.54(d, J=1.6Hz, 2H), 7.63 (t, J=8.4Hz, 2H), 7.68(d, J=5.2Hz, 1H), 7.90(d, J=7.6Hz, 1H), 8.15(d, J=7.6Hz, 1H), 8.40(s , 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ155.9, 155.7, 153.8, 143.9, 141.2, 138.7, 135.9, 135.5, 133.2, 132.9, 131.0, 129.8, 128.7, 127.6, 127.4, 126.8, 12 , 126.7, 124.2, 124.0, 122.7, 121.6, 119.2, 117.0, 114.0, 44.3, 40.6;

Example 51

3-(2-(1-naphthyl)phenyl)-N-(2-(3-(4-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide (H4-2 )

Add 40.1mg of 3-(2-(1-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 4-methoxyphenylisocyanate to a 25ml egg-shaped bottle 1.1 molar equivalent, 3ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 50.6 mg, the yield was 93.4%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ3.06(t, J=6.0Hz, 2H), 3.31(q, J=5.9Hz, 2H), 3.34(s, 1H), 5.83(s, 1H) , 6.81(d, J=8.8Hz, 2H), 6.88(d, J=8.0Hz, 1H), 7.05(d, J=7.6Hz, 1H), 7.19(t, J=7.6Hz, 1H), 7.30 (d, J=4.8Hz, 1H), 7.36(q, J=8.9Hz, 4H), 7.42(d, J=7.6Hz, 1H), 7.47-7.54(m, 2H), 7.63(t, J= 8.0Hz, 2H), 7.68(d, J=5.2Hz, 1H), 7.80(s, 1H), 7.90(d, J=7.2Hz, 1H), 8.16(d, J=7.2Hz, 1H); ¹³ CNMR (100MHz, Acetone-d ₆ ) δ157.0, 155.9, 155.7, 153.8, 141.1, 138.8, 135.9, 134.4, 133.2, 132.8, 131.0, 129.7, 128.6, 127.5, 127.4, 126.9, 126.8, 1246.2, 1246.7 , 122.8, 121.2, 119.3, 114.7, 114.0, 55.7, 45.0, 40.5;

Example 52

3-(2-(1-naphthyl)phenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)ureido)ethyl)-2-thienylsulfonamide (H4-3)

Add 40.4 mg of 3-(2-(1-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 3,5-bistrifluoromethane into a 25ml egg-shaped bottle 1.1 molar equivalents of phenyl isocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE:ethyl acetate=1:2 column chromatography, the product was collected to obtain 58.4 mg, the yield was 90.3%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ3.09(t, J=6.0Hz, 2H), 3.35(q, J=6.0Hz, 2H), 6.19(s, 1H), 6.88(d, J= 8.0Hz, 1H), 7.05(d, J=7.6Hz, 1H), 7.19(t, J=7.4Hz, 1H), 7.31(d, J=5.2Hz, 1H), 7.36(td, J=7.8, 1.4Hz, 1H), 7.41(t, J=7.8Hz, 1H), 7.47-7.54(m, 4H), 7.61-7.67(m, 3H), 7.69(d, J=5.2Hz, 1H), 7.90( d, J=7.6Hz, 1H), 8.14(s, 2H), 8.16(s, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ155.9, 155.7, 153.8, 143.5, 141.2, 138.7, 135.9 , 133.2, 132.9, 132.6, 132.2, 131.0, 129.8, 128.6, 127.5, 126.9, 126.8, 126.7, 124.2, 124.0, 122.7, 119.2, 118.5, 114.9, 114.0, 44.1, 40.5;

Example 53

3-(2-(1-naphthyl)phenyl)-N-(2-(3-(4-nitrophenyl)ureido)ethyl)-2-thienylsulfonamide (H4-4)

Add 40 mg of 3-(2-(1-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide and 1.1 moles of 4-nitrophenyl isocyanate to a 25ml egg-shaped bottle Equivalent, 3ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 48.3 mg, the yield was 87%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.03-7.96(m, 3H), 7.83(d, J=8.2Hz, 1H), 7.59(d, J=8.2Hz, 1H), 7.54-7.46(m, 3H), 7.43(t, J=7.6Hz, 1H), 7.32(dd, J=17.3, 9.1Hz, 5H), 7.22(d, J=5.1Hz, 1H), 7.16(t, J=7.4Hz, 1H), 6.93(d, J=7.6Hz, 1H), 6.90(d, J=8.3Hz, 1H), 5.53(s, 1H), 5.23(s, 1H), 3.26(q, J=5.3Hz, 2H), 3.03 (q, J=5.5Hz, 2H); ESI-MS m/z 589.1 (M+H) ⁺ , 611.1 (M+Na) ⁺ ; MALDI-HRMS calcd.for C ₂₉ H ₂₄ N ₄ O ₆ S ₂ Na(M+Na) ⁺ 611.1030, observed611.1038.

Example 54

3-(2-(1-Naphthyl)phenyl)-N-(2-(3-(3-nitrophenyl)ureido)ethyl)-2-thienylsulfonyl

Amide (H4-5)

Add 40 mg of 3-(2-(1-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide and 1.1 moles of 4-nitrophenyl isocyanate to a 25ml egg-shaped bottle Equivalent, 3ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 48.3 mg, the yield was 87%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.11(t, J=2.1Hz, 1H), 8.00(d, J=8.2Hz, 1H), 7.82(d, J=8.1Hz, 1H), 7.70(d , J=8.2Hz, 1H), 7.58(d, J=8.2Hz, 1H), 7.53(dd, J=7.6, 1.5Hz, 2H), 7.50-7.45(m, 2H), 7.43(t, J= 7.6Hz, 1H), 7.32(dd, J=16.8, 8.7Hz, 2H), 7.25-7.19(m, 2H), 7.16(t, J=7.5Hz, 2H), 6.94(d, J=7.5Hz, 1H), 6.89(d, J=8.2Hz, 1H), 5.43(s, 1H), 5.31(s, 1H), 3.26(q, J=5.3Hz, 2H), 3.04(q, J=5.6Hz, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ155.6, 154.7, 152.6, 148.3, 141.2, 140.4, 135.8, 134.9, 132.1, 131.9, 130.5, 129.6, 129.4, 127.9, 126.8, 126.4, 1256.2, 125.1, 124.5, 123.8, 123.4, 121.6, 118.6, 116.9, 113.3, 113.1, 43.7, 39.7; ESI-MS m/z 589.3(M+H) ⁺ , 611.2(M+Na) ⁺ ; MALDI-HRMS calcd.for C ₂₉ H ₂₄ N ₄ O ₆ S ₂ Na(M+Na) ⁺ 611.1030, observed611.1044.

Example 55

3-(2-(1-naphthyl)phenyl)-N-(2-(3-(3-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide (H4-6 )

Add 3-(2-(1-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide 40mg, 3-methoxyphenylisocyanate 1.1 to a 25ml egg-shaped bottle Molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 50 mg, and the yield was 93%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.03(d, J=8.1Hz, 1H), 7.82(d, J=7.6Hz, 1H), 7.58-7.53(m, 2H), 7.46(dtd, J= 16.5, 6.9, 1.3Hz, 2H), 7.40(d, J=5.1Hz, 1H), 7.32(t, J=8.0Hz, 1H), 7.30-7.27(m, 1H), 7.19-7.14(m, 2H ), 7.10(t, J=8.1Hz, 1H), 6.96(t, J=2.2Hz, 1H), 6.93(d, J=7.1Hz, 1H), 6.89(dd, J=8.2, 0.8Hz, 1H ), 6.72(dd, J=8.0, 1.3Hz, 1H), 6.69(s, 1H), 6.55(dd, J=8.1, 2.1Hz, 1H), 5.33-5.14(m, 2H), 3.71(s, 3H), 3.20(q, J=5.6Hz, 2H), 2.98(q, J=5.6Hz, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ160.2, 156.2, 154.6, 152.8, 140.8, 140.1, 136.4, 134.9, 132.0, 131.9, 130.4, 129.7, 129.2, 127.8, 126.8, 126.4, 126.2, 125.8, 125.3, 123.6, 123.4, 121.7, 118.7, 113.0, 112.2, 108.9, 1305.6 /z 574.3(M+H) ⁺ , _596.1 (M+Na) ⁺ ; MALDI-HRMS calcd. for _{C30H27N3O5S2Na} ( _{M +} Na) ⁺ _596.1284 , observed 596.1288.

Example 56

3-(2-(1-naphthyl)phenyl)-N-(2-(3-(4-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonamide (H4- 7)

Add 40.8mg of 3-(2-(1-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 4-methoxyphenyliso Thiocyanate 1.1 molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 51.3 mg, and the yield was 90.5%. ¹ H NMR (400MHz, Acetone-d ₆ ) δ3.18(t, J=6.0Hz, 2H), 3.76(q, J=6.0Hz, 2H), 3.79(s, 3H), 6.88-6.91(m, 3H), 7.05(d, J=8.0Hz, 1H), 7.20-7.23(m, 3H), 7.31(d, J=4.8Hz, 1H), 7.38(td, J=7.9, 1.8Hz, 1H), 7.43(t, J=7.8Hz, 1H), 7.51-7.54(m, 2H), 7.61-7.66(m, 2H), 7.69(d, J=5.2Hz, 1H), 7.92(d, J=8.2Hz , 1H), 8.16 (d, J=8.0Hz, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ183.1, 158.9, 155.7, 153.8, 135.9, 133.3, 132.9, 141.2, 131.0, 129.8, 128.6 , 127.9, 127.6, 127.4, 127.0, 126.9, 126.8, 124.2, 124.1, 122.8, 119.3, 115.3, 114.0, 55.8, 44.8, 43.7;

Example 57

3-(2-(1-naphthyl)phenyl)-N-(2-(3-(3-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide (H4-7 )

Add 40.0 mg of 3-(2-(1-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 3-nitrophenyl isosulfur to a 25ml egg-shaped bottle 1.1 molar equivalent of cyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 54.0 mg, the yield was 94.7%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ3.22(t, J=6.0Hz, 2H), 3.76(t, J=5.6Hz, 2H), 6.90(d, J=8.0Hz, 1H), 7.06 (d, J=7.6Hz, 1H), 7.21(t, J=7.2Hz, 1H), 7.32(d, J=5.2Hz, 1H), 7.38(td, J=7.9, 1.4Hz, 1H), 7.43 (t, J=8.0Hz, 1H), 7.48-7.55(m, 2H), 7.58(d, J=8.0Hz, 1H), 7.63(d, J=8.6Hz, 1H), 7.65(d, J= 8.4Hz, 1H), 7.71(d, J=5.2Hz, 1H), 7.89-7.92(m, 2H), 6.97(d, J=6.4Hz, 1H), 7.16(d, J=8.8Hz, 1H) , 8.64 (d, J=7.6Hz, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ182.9, 155.7, 153.8, 149.2, 141.8, 141.3, 138.5, 135.9, 133.2, 133.0, 131.0, 130.5, 130.0, 128.7, 127.6, 127.4, 127.0, 126.9, 126.7, 124.2, 124.1, 124.1, 122.7, 119.6, 119.3, 118.6, 114.0, 44.8, 43.0;

Example 58

3-(2-(1-naphthyl)phenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)thioureido)ethyl)-2-thienylsulfonyl Amide (H4-8)

Add 40.2 mg of 3-(2-(1-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 3,5-bistrifluoromethyl to a 25ml egg-shaped bottle 1.1 molar equivalents of phenyl isothiocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 59.3 mg, yield 90.0%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ3.23(t, J=6.0Hz, 2H), 3.77(t, J=5.6Hz, 2H), 6.71(s, 1H), 6.90(d, J= 8.4Hz, 1H), 7.06(d, J=7.6Hz, 1H), 7.21(t, J=7.4Hz, 1H), 7.33(d, J=5.2Hz, 1H), 7.36-7.44(m, 2H) , 7.48-7.54(m, 2H), 7.62(dd, J=7.6, 1.2Hz, 1H), 7.65(d, J=8.0Hz, 1H), 7.68-7.72(m, 3H), 7.91(d, J =7.2Hz, 1H), 8.16(d, J=7.2Hz, 1H), 8.31(d, J=4.8Hz, 2H), 9.49(s, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ182 .8, 155.8, 153.8, 142.8, 141.4, 138.5, 135.9, 133.2, 133.0, 132.2, 131.9, 131.0, 130.0, 128.7, 127.6, 127.4, 127.0, 126.8, 126.7, 125.7, 12.7, 124.02, 2.3 , 114.0, 44.8, 42.9;

Example 59

3-(2-(1-naphthyl)phenyl)-N-(2-(3-(3-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonamide (H4- 9)

Add 3-(2-(1-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide 39.9mg, 3-methoxyphenyliso Thiocyanate 1.1 molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE:ethyl acetate=1:2 column chromatography, the product was collected to obtain 49.7 mg, the yield was 89.7%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ3.20(t, J=6.0Hz, 2H), 3.77-3.79(m, 5H), 6.74(dd, J=8.0, 2.0Hz, 1H), 6.88- 6.91(m, 2H), 7.05(d, J=7.6Hz, 2H), 7.19-7.25(m, 2H), 7.31(d, J=4.8Hz, 1H), 7.37(td, J=7.8, 1.4Hz , 1H), 7.43(t, J=7.8Hz, 1H), 7.50-7.54(m, 2H), 7.61-7.66(m, 2H), 7.69(d, J=5.2Hz, 1H), 7.91(d, J=7.6Hz, 1H), 8.16 (d, J=7.6Hz, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ182.4, 155.7, 153.8, 161.4, 141.2, 140.2, 138.7, 135.9, 133.2 ,132.9,131.0,130.9,129.9,128.6,127.6,127.4,127.0,126.9,126.9,126.8,124.2,124.1,122.8,119.3,116.9,114.0,112.1,110.5,55.43.7,45.9;

Example 60

3-(2-(1-naphthyl)phenyl)-N-(2-(3-(4-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide (H4-10 )

Add 39.5mg of 3-(2-(1-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 4-nitrophenylisosulfuramide to a 25ml egg-shaped bottle 1.1 molar equivalent of cyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 52.5 mg, the yield was 93.3%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ3.23(t, J=5.8Hz, 2H), 3.78(t, J=5.4Hz, 2H), 6.90(d, J=8.4Hz, 1H), 7.06 (d, J=7.6Hz, 1H), 7.21(t, J=7.6Hz, 1H), 7.32(d, J=5.2Hz, 1H), 7.36-7.45(m, 2H), 7.48-7.55(m, 2H), 7.62(d, J=7.6Hz, 1H), 7.66(d, J=8.0Hz, 1H), 7.71(d, J=5.2Hz, 1H), 7.87-7.92(m, 3H), 8.17( t, J=5.2Hz, 3H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ182.2, 155.7, 153.8, 146.8, 144.0, 141.4, 138.5, 135.9, 133.2, 133.0, 131.0, 130.0, 128.7, 127.6 , 127.4, 127.0, 126.9, 126.7, 125.3, 124.2, 124.1, 122.7, 122.3, 119.3, 114.0, 44.9, 42.9;

Example 61

3-(2-(1-naphthyl)phenyl)-N-(2-(3-(3-methylphenyl)thioureido)ethyl)-2-thienylsulfonamide (H4-11 )

Add 39.7mg of 3-(2-(1-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 3-methylphenylisosulfuramide to a 25ml egg-shaped bottle 1.1 molar equivalent of cyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 49.2 mg, the yield was 91.6%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ2.29(s, 3H), 3.19(t, J=6.2Hz, 2H), 3.77(t, J=5.6Hz, 2H), 6.89(d, J= 8.0Hz, 2H), 7.00(d, J=7.6Hz, 1H), 7.05(d, J=7.6Hz, 1H), 7.14(d, J=6.8Hz, 1H), 7.20-7.24(m, 3H) , 7.31(d, J=4.8Hz, 1H), 7.37(td, J=7.8, 1.6Hz, 1H), 7.43(t, J=8.0Hz, 1H), 7.49-7.55(m, 2H), 7.61- 7.66 (m, 2H), 7.69 (d, J=5.2Hz, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ182.5, 155.7, 153.8, 141.2, 140.0, 138.9, 135.9, 133.3, 132.9, 131.0, 130.0, 129.9, 128.6, 127.6, 127.4, 127.1, 127.0, 126.9, 126.8, 125.8, 125.7, 124.2, 124.1, 122.8, 122.3, 119.3, 114.0, 44.9, 43.5, 21.4;

Example 62

3-(2-(1-naphthyl)phenyl)-N-(2-(3-phenylthioureido)ethyl)-2-thienylsulfonamide (H4-12)

Add 3-(2-(1-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide 39.6mg, phenylisothiocyanate 1.1 to a 25ml egg-shaped bottle Molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 19.7 mg, yield 38%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ3.20(t, J=6.0Hz, 2H), 3.78(t, J=5.8Hz, 2H), 6.89(d, J=8.0Hz, 1H), 7.05 (d, J=7.6Hz, 1H), 7.15-7.23(m, 2H), 7.26(s, 1H), 7.31(d, J=5.2Hz, 1H), 7.35(d, J=7.6Hz, 1H) , 7.38(s, 2H), 7.40(d, J=4.0Hz, 1H), 7.44(d, J=8.0Hz, 1H), 7.49-7.55(m, 2H), 7.64(t, J=8.6Hz, 2H), 7.69(d, J=5.2Hz, 1H), 7.91(d, J=7.2Hz, 1H), 7.17(d, J=7.6Hz, 1H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ182.6, 155.7, 153.8, 141.3, 138.7, 135.9, 133.2, 132.9, 131.0, 130.0, 129.9, 128.6, 127.6, 127.4, 127.0, 126.9, 126.8, 126.2, 125.1, 125.0, 124.2 114.0, 44.9, 43.5;

Example 63

3-(2-(1-naphthyl)phenyl)-N-(2-(4-nitrobenzenesulfonyl)ethyl)-2-thienylsulfonamide (I4-1)

Add 3-(2-(1-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide 39.2mg, 4-nitrobenzenesulfonyl chloride 1.1 Molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 45.2 mg, the yield was 80.3%.

¹ H NMR (400MHz, Acetone-d ₆ ) δ3.06-3.12(m, 4H), 6.85(d, J=8.4Hz, 1H), 7.03(d, J=7.6Hz, 1H), 7.19(t, J=7.6Hz, 1H), 7.31(d, J=5.2Hz, 1H), 7.36(td, J=7.9, 1.8Hz, 1H), 7.41(t, J=8.0Hz, 1H), 7.47(d, J=6.8Hz, 1H), 7.51(d, J=6.8Hz, 1H), 7.55(t, J=6.2Hz, 2H), 7.66(d, J=8.0Hz, 1H), 7.71(d, J= 5.2Hz, 1H), 7.92(d, J=7.6Hz, 1H), 8.04(d, J=8.8Hz, 2H), 8.10(d, J=8.8Hz, 1H), 8.33(d, J=8.8Hz , 2H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ155.8, 153.7, 150.9, 147.3, 141.4, 138.6, 135.9, 133.2, 133.0, 131.0, 130.0, 129.2, 128.7, 127.6, 127.4, 1267.8, 12 , 126.5, 125.3, 124.3, 123.9, 122.7, 119.1, 114.3, 43.7;

Example 64

3-(2-(1-naphthyl)phenyl)-N-(2-acetamidoethyl)-2-thienylsulfonamide (I4-2)

Add 39.9mg of 3-(2-(1-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 1.1 molar equivalent of acetic anhydride, dichloro Methane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 45.8 mg, the yield was 95.8%. ESI-MS m/z 509.0(M+H) ⁺ ; synthetic route:

Example 65

2-Cyclohexanylnitrobenzene (A2)

Add 10.054 g of cyclohexanol, 14.180 g of o-fluoronitrobenzene, 13.962 g of K ₂ CO ₃ , and 46 ml of DMF into a 250 ml egg-shaped flask, and reflux for 5 hours. Heating was stopped, 500ml of ethyl acetate was added, washed with 200ml of water × 3, dried, filtered and concentrated to obtain 9.730g of orange-red liquid with a yield of 44%. ESI-MS m/z 222.0(M+H) ⁺ ;

Example 66

2-Cyclohexanylaminobenzene (B2)

Add 4.587g of 2-cyclohexylnitrobenzene, 100ml of ethanol, 0.450g of Pd/C into a 1L eggplant-shaped flask, and finally add 6.9ml of hydrazine hydrate, and stir at room temperature for 5 hours. After filtering and distilling the solvent under reduced pressure, 200ml of ethyl acetate was added, washed with 100ml×2 water, dried, filtered, and concentrated to obtain 3.569g of orange-red liquid with a yield of 90%. ESI-MS m/z 192.0(M+H) ⁺ ;

Example 67

2-cyclohexyl iodobenzene (C2)

Place a 500ml three-necked flask in an ice bath, add 3.9g of 2-cyclohexylaminobenzene, 3.25ml of concentrated sulfuric acid after dilution and cooling with 80ml of water, add NaNO ₂ 1.7g water (25ml) solution slowly under mechanical stirring, The addition was completed in ten minutes, and 4.29 g of K1 in water (40 ml) was added after 1 hour, and stirred at room temperature after half an hour. The reaction at room temperature was stopped after 4 hours, and 200ml of water was added, extracted with CH ₂ Cl ₂ 100ml×3, combined, and washed once with saturated Na ₂ S ₂ O ₃ . After drying, filtering, concentrating, and column chromatography, 4.84 g of nearly colorless liquid was obtained with a yield of 78.6%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.76(dd, J=7.8, 1.4Hz, 1H), 7.26-7.22(m, 1H), 6.83(d, J=8.2Hz, 1H), 6.68(t, J=7.5Hz, 1H), 4.42-4.26(m, 1H), 1.94-1.81(m, 4H), 1.74-1.65(m, 2H), 1.53-1.49(m, 1H), 1.46-1.34(m, 3H); EI-MS m/z 302 (M); EI-HRMS calcd. for C ₁₂ H ₁₅ IO (M) 302.1068, observed 302.1070.

Example 68

2-Cyclohexanylphenylboronic acid (D2)

Add 3.241g of 2-cyclohexanol iodobenzene to a 100ml reaction tube, fully remove oxygen and water, add anhydrous THF 50ml under the protection of argon, and slowly add 2.5mol/L n-butyl in a cold bath at -78°C Lithium solution 5.3ml, reacted for 1 hour, added 2.1ml trimethyl borate at -78°C, moved the reaction tube to room temperature after 2h and stirred. After stirring at room temperature for 2 h, 1 ml of concentrated hydrochloric acid was added, extracted with ethyl acetate, dried, filtered, and concentrated to obtain 2.2167 g of white solid, with a yield of 94%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.83(d, J=6.0Hz, 1H), 7.43-7.36(m, 1H), 6.99(t, J=7.3Hz, 1H), 6.92(d, J= 8.4Hz, 1H), 5.88(s, 2H), 4.41(td, J=8.7, 4.3Hz, 1H), 2.05(s, 2H), 1.85-1.76(m, 2H), 1.67-1.57(m, 3H ), 1.44-1.35 (m, 3H); EI-MS m/z 220 (M); EI-HRMS calcd. for C ₁₂ H ₁₇ BO ₃ (M) 219.1307, observed 219.1311.

Example 69

1-N-((3-bromo-2-thienyl)sulfone)-4-N-Boc piperazine (E3)

Under stirring in an ice bath, 0.985 g of 1-N-Boc piperazine, 30 ml of CH ₂ Cl ₂ , 1 ml of triethylamine were added to a 20 ml egg-shaped flask, and 1.309 g of 3-bromo, 2-thienyl sulfone chloride was slowly added dropwise. After the addition was complete, move to room temperature and stir for one hour. Add 100ml of water, extract with CH ₂ Cl ₂ 100ml×3, dry, filter, and concentrate to obtain 1.645g of light yellow solid with a yield of 80%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.53(d, J=5.3Hz, 1H), 7.12(d, J=5.3Hz, 1H), 3.57-3.49(m, 4H), 3.29-3.21(m, 4H), 1.45 (d, J=9.2Hz, 9H); ESI-MS m/z 433.1 (M+Na) ⁺ ; ESI-HRMS calcd. for C ₁₃ H ₁₉ BrN ₂ O ₄ S ₂ Na (M+ Na) ⁺ 432.9862, observed 432.9848.

Example 70

1-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-4-N-Boc piperazine (F2)

Add 0.555g of 1-N-((3-bromo-2-thienyl)sulfone)-4-N-Boc piperazine, 0.900g of 2-cyclohexylphenylboronic acid, and 94mg of Sphos into a 250ml Shrek tube. Palladium acetate 28mg, K ₃ PO ₄ 0.939g, after fully deoxygenated, THF 50ml was added, refluxed for 8 hours, and heating and stirring were stopped. Add 100ml of water, extract with 100ml of ethyl acetate x 2, dry, filter, concentrate, and perform column chromatography to obtain 875mg of yellow floc with a yield of 78.9%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.50 (d, J=5.1Hz, 1H), 7.45 (dd, J=7.5, 1.5Hz, 1H), 7.33 (dd, J=11.2, 4.5Hz, 1H) , 7.11(d, J=5.1Hz, 1H), 6.95(t, J=7.5Hz, 1H), 6.90(d, J=8.3Hz, 1H), 4.34-4.24(m, 1H), 3.33-3.24( m, 4H), 2.86-2.73(m, 4H), 1.87(d, J=6.3Hz, 2H), 1.66(d, J=6.2Hz, 2H), 1.49-1.37(m, 12H), 1.35-1.24 (m, 3H); ESI-MS m/z 529.4(M+Na) ⁺ ; ESI-HRMS _calcd . for _{C25H34N2O5S2Na} (M ₊ Na) ⁺ _529.1801 , observed _529.1814 .

Example 71

1-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-piperazine (G2)

Add 1-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-4-N-Boc piperazine 835mg, CH ₂ Cl ₂ 10ml into a 25ml egg-shaped bottle , CF ₃ CO ₂ H 1.5ml, stirred at room temperature for 12 hours. Add potassium carbonate to neutralize CF ₃ CO ₂ H to make it alkaline, add water, extract with CH ₂ Cl ₂ 60ml×3, dry, filter, and concentrate to obtain 670mg of yellow solid with a yield of 100%.

ESI-MS m/z 407.3(M+H) ⁺ ; MALDI-HRMS _calcd . for _C20H27N2O3S2 ( _{M +} H) ⁺ _407.1458 , observed 407.1472.

Example 72

4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-1-N-(3,5-dichloroanilino)formylpiperazine (H2 -1)

Add 1-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-piperazine 41mg, 3,5-dichlorophenylisocyanate 1.1 to a 25ml egg-shaped bottle Molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 60 mg, and the yield was 100%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.29-1.49 (m, 6H), 1.61-1.63 (m, 2H), 1.86-1.88 (m, 2H), 2.89 (t, J=4.8Hz, 4H), 3.34(t, J=4.8Hz, 4H), 4.26-4.28(m, 1H), 6.29(s, 1H), 6.90(d, J=8.0Hz, 1H), 6.96(t, J=7.4Hz, 1H ), 7.02(s, 1H), 7.10(d, J=4.8Hz, 1H), 7.27(d, J=1.2Hz, 2H), 7.33(t, J=7.8Hz, 1H), 7.45(d, J =6.0Hz, 1H), 7.52 (d, J=5.2Hz, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ155.1, 153.7, 143.2, 140.9, 135.2, 133.3, 133.1, 133.0, 130.3, 129.1, 123.4, 123.2, 119.7, 118.0, 112.4, 75.3, 45.3, 43.9, 31.9, 25.6, 23.7; ESIMS m/z 616.4(M+H) ⁺ ; HRMS calcd.for C ₂₇ H ₂₉ N ₃ O ₄ S ₂ Cl ₂ Na(M+Na) ⁺ 616.0869, observed 616.0857;

Example 73

4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-1-N-(4-methoxyanilino)formylpiperazine (H2- 2)

41 mg of 1-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-piperazine and 1.1 moles of 4-methoxyphenylisocyanate were added to a 25ml egg-shaped bottle Equivalent, 3ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 50.8 mg, the yield was 90.7%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.29-1.50(m, 6H), 1.61(m, 2H), 1.86(m, 2H), 2.89(t, J=5.2Hz, 4H), 3.33(t, J=5.2Hz, 4H), 3.77(s, 3H), 4.26-4.28(m, 1H), 6.08(s, 1H), 6.82(d, J=8.8Hz, 2H), 6.90(d, J=8.0 Hz, 1H), 6.96(t, J=7.4Hz, 1H), 7.10(d, J=5.2Hz, 1H), 7.17(d, J=8.8Hz, 2H), 7.32(t, J=7.4Hz, 1H), 7.46 (d, J=7.6Hz, 1H), 7.52 (d, J=5.2Hz, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ156.1, 155.1, 155.0, 142.9, 133.2, 133.1, 132.9, 131.6, 130.1, 128.8, ^123.4 , 122.4, 119.5, _114.1 , 112.2, 75.1, 55.5, 45.2, 43.6, 31.7, 25.5, 23.5; H ₃₃ N ₃ O ₅ S ₂ Na(M+Na) ⁺ 578.1754, observed578.1762;

Example 74

4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-1-N-(3,5-ditrifluoromethylanilino)formylpiper Hazine (H2-3)

Add 1-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-piperazine 41mg, 3,5-bistrifluoromethylbenzene to a 25ml egg-shaped bottle 1.1 molar equivalents of isocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 66.7 mg, the yield was 100%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.27-1.49(m, 6H), 1.58(m, 2H), 1.84-1.87(m, 2H), 2.91(t, J=5.0Hz, 4H), 3.38( t, J=5.0Hz, 4H), 4.25-4.26(m, 1H), 6.57(s, 1H), 6.90(d, J=8.8Hz, 1H), 6.96(t, J=7.4Hz, 1H), 7.11(d, J=5.2Hz, 1H), 7.33(t, J=7.8Hz, 1H), 7.46(d, J=7.2Hz, 1H), 7.53(d, J=5.2Hz, 2H), 7.83( s, 2H); ¹³ CNMR (100MHz, CDCl ₃ ) δ155.0, 153.6, 143.2, 140.5, 133.2, 132.9, 132.9, 132.3, 132.0, 130.2, 129.1, 123.3, 119.6, 119.3, 116.3, 112.3, 75.2, , 43.7, 31.8, 25.4, 23.5; ESIMS m/z 684.5(M+Na) ⁺ ; HRMS calcd. for C ₂₉ H ₂₉ N ₃ O ₄ S ₂ F ₆ Na(M+Na) ⁺ 684.1396, observed 684.1401;

Example 75

4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-1-N-(4-methoxyanilino)thioformylpiperazine ( H2-4)

Add 42.3 mg of 1-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-piperazine, 4-methoxyphenylisothio 1.1 molar equivalent of cyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 59.5 mg, and the yield was 100%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.28-1.49 (m, 6H), 1.67-1.68 (m, 2H), 1.89-1.92 (m, 2H), 2.92 (t, J=4.8Hz, 4H), 3.67(t, J=5.0Hz, 4H), 4.30-4.32(m, 1H), 6.84(d, J=8.8Hz, 2H), 6.91-6.97(m, 2H), 7.00(d, J=8.8Hz , 2H), 7.04(s, 1H), 7.12(d, J=5.2Hz, 1H), 7.32(t, J=7.2Hz, 1H), 7.43(dd, J=7.4, 1.0Hz, 1H), 7.52 (d, J=5.2Hz, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ183.6, 157.6, 155.0, 143.1, 133.1, 133.0, 132.9, 132.6, 130.1, 128.9, 125.7, 123.3, 119.5, 114.3, 112.3, 75.2, 55.5, 48.3, 44.9, 31.8, 25.5, 23.6; ESIMS m/z _582.5 (M+H) ⁺ ; HRMS calcd ^. for _{C28H33N3O4S3Na} ( _M +Na) _{+ 594.1525} , observed 594.1507;

Example 76

4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-1-N-(3-nitroanilino)thioformylpiperazine (H2 -5)

Add 42.4 mg of 1-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-piperazine, 3-nitrophenylisothiocyanate to a 25ml egg-shaped bottle Ester 1.1 molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 61.2 mg, the yield was 100%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.30-1.47(m, 6H), 1.66-1.67(m, 2H), 1.89-1.92(m, 2H), 2.98(t, J=5.0Hz, 4H), 3.76(t, J=4.8Hz, 4H), 4.31-4.32(m, 1H), 6.95(t, J=8.0Hz, 2H), 7.13(d, J=5.2Hz, 1H), 7.15(s, 1H ), 7.33(t, J=7.4Hz, 1H), 7.44(d, J=7.2Hz, 1H), 7.49-7.52(m, 2H), 7.54(d, J=5.2Hz, 1H), 8.01(t , J=2.0Hz, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ182.6, 155.0, 148.4, 143.3, 140.9, 133.2, 132.8, 132.7, 130.2, 129.9, 129.4, 129.2, 123.3, 119.9, 119.6, 118.4, 112.4, 75.2, 48.2, 44.9, 31.8, 25.5, 23.6; ESIMS m/z _587.5 (M+H) ⁺ ; HRMS calcd. for _{C27H30N4O5S3Na} ( _{M +} Na) ⁺ _609.1271 , observed 609.1277;

Example 77

4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-1-N-(3,5-ditrifluoromethylanilino)thioform Acylpiperazine (H2-6)

Add 45.0 mg of 1-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-piperazine to a 25ml egg-shaped bottle, 3,4-bistrifluoromethyl 1.1 molar equivalent of phenyl isothiocyanate, 3 ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 68 mg, the yield was 90.7%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.29-1.47 (m, 6H), 1.64-1.66 (m, 2H), 1.88-1.92 (m, 2H), 2.98 (t, J=4.8Hz, 4H), 3.78(t, J=5.0Hz, 4H), 4.29-4.31(m, 1H), 6.92-6.98(m, 2H), 7.13(d, J=5.2Hz, 1H), 7.17(s, 1H), 7.33 (t, J=7.2Hz, 1H), 7.44(d, J=7.6Hz, 1H), 7.54(d, J=5.2Hz, 1H), 7.64(s, 1H), 7.65(s, 2H); ¹³ CNMR (100MHz, CDCl ₃ ) δ182.2, 155.0, 143.6, 141.2, 132.8, 132.2, 132.0, 131.7, 130.3, 129.4, 124.4, 123.7, 123.1, 121.7, 119.6, 112.3, 75.2, 48.3, 44.9, 2 , 23.6; ESIMS m/z 687.5 (M+H) ⁺ ; HRMS calcd. for C ₂₉ H ₂₉ N ₃ O ₃ S ₃ F ₆ Na (M+Na) ⁺ 700.1167, observed 700.1190;

Example 78

4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-1-N-(3-methoxyanilino)thioformylpiperazine ( H2-7)

Add 42.1 mg of 1-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-piperazine, 3-methoxyphenylisothio 1.1 molar equivalent of cyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 57.7 mg, yield 97.5%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.31-1.45(m, 6H), 1.67(m, 2H), 1.89-1.92(m, 2H), 2.92(t, J=4.8Hz, 4H), 3.63( t, J=4.8Hz, 4H), 4.30(m, 1H), 6.55-6.56(m, 2H), 6.68(d, J=8.0Hz, 1H), 6.94(t, J=6.8Hz, 2H), 7.11(d, J=4.8Hz, 2H), 7.20(t, J=8.4Hz, 1H), 7.32(d, J=8.4Hz, 1H), 7.42(d, J=8.0Hz, 1H), 7.52( d, J=4.8Hz, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ183.4, 160.3, 154.9, 143.2, 140.9, 133.1, 132.8, 130.2, 130.0, 129.0, 129.0, 123.2, 119.5, 114.8, 112.2 , 110.5, 108.7, 75.1, 55.4, 48.9, 44.9, 31.8, 25.5, 23.6; ESIMS m/z 582.5(M+H) ⁺ ; HRMS calcd.for C ₂₈ H ₃₃ N ₃ O ₄ S ₃ Na(M+Na ) ⁺ 594.1525, observed 594.1519;

Example 79

4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-1-N-(4-nitroanilino)thioformylpiperazine (H2 -8)

Add 42.4 mg of 1-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-piperazine, 4-nitrophenylisothiocyanate to a 25ml egg-shaped bottle Ester 1.1 molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 59.0 mg, the yield was 96.4%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.30-1.44(m, 6H), 1.62(m, 2H), 1.89-1.92(m, 2H), 2.97(t, J=5.0Hz, 4H), 3.74( t, J=4.8Hz, 4H), 4.30(m, 1H), 6.92-6.97(m, 2H), 7.12(d, J=5.6Hz, 1H), 7.23(d, J=9.2Hz, 2H), 7.33(t, J=7.0Hz, 2H), 7.44(dd, J=7.6, 1.2Hz, 1H), 7.54(d, J=5.6Hz, 1H), 8.18(d, J=8.8Hz, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ182.1, 154.9, 145.8, 143.5, 143.5, 133.3, 132.8, 132.4, 130.3, 129.3, 124.8, 123.1, 121.6, 119.6, 112.3, 75.2, 48.6, 44.9, 35.1 , 23.6; ESIMS m/z 587.5 (M+H) ⁺ ; HRMS calcd. for C ₂₇ H ₃₀ N ₄ O ₅ S ₃ Na (M+Na) ⁺ 609.1271, observed 609.1264;

Example 80

4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-1-N-(3-methylanilino)thioformylpiperazine (H2 -9)

Add 43.0 mg of 1-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-piperazine, 3-methylphenylisothiocyanate to a 25ml egg-shaped bottle Ester 1.1 molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 55.0 mg, the yield was 93.5%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.29-1.53(m, 6H), 1.67-1.69(m, 2H), 1.90-1.93(m, 2H), 2.31(s, 3H), 2.91(t, J =5.0Hz, 4H), 3.64(t, J=5.0Hz, 4H), 4.31(m, 1H), 6.79-6.81(m, 2H), 6.91-6.96(m, 3H), 7.12(d, J= 4.8Hz, 2H), 7.19(t, J=8.2Hz, 1H), 7.32(td, J=7.9, 1.8Hz, 1H), 7.42(dd, J=7.6, 1.6Hz, 1H), 7.52(d, J=5.2Hz, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ183.5, 154.9, 143.2, 139.7, 139.2, 133.2, 133.1, 132.9, 132.8, 130.2, 129.0, 126.2, 123.5, 123.2, 120.0, 119.5 , 112.2, 75.1, 48.8, 44.9, 31.8, 25.5, 23.7, 21.4; ESIMS m/z 556.5(M+H) ⁺ ; HRMS calcd. for C ₂₈ H ₃₃ N ₃ O ₃ S ₃ Na(M+Na) ⁺ 578.1576, observed 578.1571;

Example 81

4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-1-N-anilinothioformylpiperazine (H2-10)

Add 42.7 mg of 1-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-piperazine and 1.1 moles of phenylisothiocyanate to a 25ml egg-shaped bottle Equivalent, 3ml of dichloromethane, stirred at room temperature for 5 hours. PE:ethyl acetate=1:2 column chromatography, the product was collected to obtain 56.3mg, yield 98.9%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.29-1.49 (m, 6H), 1.67-1.68 (m, 2H), 1.90-1.92 (m, 2H), 2.92 (t, J=5.0Hz, 4H), 3.65(t, J=5.0Hz, 4H), 4.29-4.33(m, 1H), 6.92-6.96(m, 2H), 7.01(d, J=8.0Hz, 2H), 7.11-7.17(m, 3H) , 7.29-7.33 (m, 3H), 7.43 (d, J=7.6Hz, 1H), 7.52 (d, J=4.8Hz, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ183.4, 155.0, 143.2 , 139.7, 133.1, 132.9, 132.8, 130.2, 129.2, 129.0, 125.4, 123.2, 123.0, 119.5, 112.2, 75.1, 48.7, 44.9, 31.8, 25.5, 23.6; ESIMS m/z 542.5(M+H) ⁺ ; calcd.for C ₂₇ H ₃₁ N ₃ O ₃ S ₃ Na(M+Na) ⁺ 564.1420, observed 564.1437;

Example 82

4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-1-N-4-nitrobenzenesulfonylpiperazine (I2-1)

42.3 mg of 1-N-((3-(2-(cyclohexyl) phenyl)-2-thienyl) sulfone)-piperazine and 1.1 molar equivalents of 4-nitroflavonyl chloride were added to a 25ml egg-shaped bottle , dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 44.3 mg, the yield was 76%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.30-1.47(m, 6H), 1.69-1.70(m, 2H), 1.88-1.91(m, 2H), 2.94(s, 8H), 4.24-4.26(m , 1H), 6.84(d, J=8.4Hz, 1H), 6.94(t, J=7.4Hz, 1H), 7.11(d, J=4.8Hz, 1H), 7.30(td, J=8.0, 1.6Hz , 1H), 7.41(dd, J=7.6, 1.6Hz, 1H), 7.52(d, J=4.8Hz, 1H), 7.86(d, J=8.8Hz, 2H), 8.38(d, J=8.8Hz , 2H); ¹³ CNMR (100MHz, CDCl ₃ ) δ154.9, 150.4, 143.0, 141.6, 133.2, 133.1, 133.0, 130.1, 129.0, 128.8, 124.5, 123.2, 119.6, 112.1, 75.0, 45.6, 48.9, 31. 25.5, 23.6; ESIMS m/z 614.4( _M +Na) ⁺ ; HRMS calcd. for _{C26H29N3O7S3Na} ( _M +Na) ⁺ _614.1060 , observed _614.1059 ;

Example 83

4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-1-N-acetylpiperazine (I2-2)

Add 42.0 mg of 1-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-piperazine, 4-methoxyphenylisothio 1.1 molar equivalent of cyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 32.4 mg, yield 70%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.28-1.42(m, 6H), 1.64-1.67(m, 2H), 1.86-1.89(m, 2H), 2.00(s, 3H), 2.82(t, J =5.2Hz, 2H), 2.85(t, J=4.8Hz, 2H), 3.29(t, J=5.0Hz, 2H), 3.46(t, J=5.0Hz, 2H), 4.28-4.30(m, 1H ), 6.91(d, J=8.4Hz, 1H), 6.96(t, J=7.8Hz, 1H), 7.11(d, J=5.0Hz, 1H), 7.32(td, J=7.9, 1.8Hz, 1H ), 7.54 (dd, J=7.6, 1.6Hz, 1H); 7.51 (d, J=5.2Hz, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ168.7, 155.0, 142.9, 133.2, 133.1, 133.0 , 130.1, 128.8, 123.3, 119.6, 112.1, 75.0, 45.8, 40.8, 31.8, 25.5, 23.5, 21.2; ESIMS m/z 449.5(M+H) ⁺ ; HRMS calcd.for C ₂₂ H ₂₈ N ₂ O ₄ S ₂ Na(M+Na) ⁺ 471.1383, observed 471.1386;

Example 84

4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-1-N-trifluoroacetylpiperazine (I2-3)

Add 41 mg of 1-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-piperazine and 4-methoxyphenylisothiocyanate to a 25ml egg-shaped bottle Ester 1.1 molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 39.0 mg, the yield was 77%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.29-1.42(m, 6H), 1.65-1.67(m, 2H), 1.86-1.88(m, 2H), 2.87-2.92(m, 4H), 3.42(t , J=4.8Hz, 2H), 3.52(t, J=4.8Hz, 2H), 4.26-4.28(m, 1H), 6.91(d, J=8.0Hz, 1H), 6.97(t, J=7.6Hz , 1H), 7.12(d, J=4.8Hz, 1H), 7.34(td, J=7.8, 1.6Hz, 1H), 7.46(dd, J=7.6, 1.6Hz, 1H); 7.53(d, J= 5.2Hz, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ155.0, 142.9, 133.2, 133.1, 133.1, 130.3, 129.1, 129.1, 123.1, 119.7, 112.1, 75.1, 45.4, 42.8, 31.8, 25.4, 23.5 ; ESIMS m/z 525.4(M+H) ⁺ ; HRMS _calcd ^{. for C22H25N2O4F3S2Na(M+Na)+} _{525.1100 , observed 525.1120 ;}

Example 85

2-Sesamolylnitrobenzene (A5)

Add 7.749g of sesamol, 7.5g of o-fluoronitrobenzene, 3.0g of 85% NaH, and 50ml of anhydrous tetrahydrofuran into a 250ml egg-shaped bottle, and reflux for 5h. Add 500ml of ethyl acetate, wash with 200ml of water x 3, dry, filter and concentrate to obtain 11.103g of khaki solid with a yield of 80.5%.

¹ H NMR (400MHz, CDCl ₃ ) δ6.94 (t, J=7.6Hz, 1H), 6.80 (d, J=7.8Hz, 2H), 6.70 (dd, J=15.9, 7.9Hz, 2H), 6.55 (d, J=2.4Hz, 1H), 6.43(dd, J=8.4, 2.4Hz, 1H), 5.94(s, 2H);

Example 86

2-Sesamolylaminobenzene (B5)

Add 6.052g of 2-sesaminol nitrobenzene, 100ml of ethanol, 0.700g of Pd/C into a 1L eggplant-shaped bottle, and finally add 8ml of hydrazine hydrate, and stir at room temperature for 5 hours. After filtering and distilling the solvent under reduced pressure, add 200ml of ethyl acetate, wash with 100ml×2 water, dry, filter, and concentrate to obtain 5.056g of orange-red liquid with a yield of 94.5%.

¹ H NMR (400MHz, CDCl ₃ ) δ6.95 (t, J=7.6Hz, 1H), 6.81 (d, J=7.8Hz, 2H), 6.70 (dd, J=16.2, 8.0Hz, 2H), 6.56 (d, J=2.3Hz, 1H), 6.44(dd, J=8.4, 2.3Hz, 1H), 5.95(s, 2H), 3.81(s, 2H);

Example 87

2-Sesamol-iodobenzene (C5)

Place a 500ml three-necked flask in an ice bath, add 3.092g of 2-sesaminolaminobenzene, 2.2ml of concentrated sulfuric acid diluted with 52ml of water and add after cooling, slowly add NaNO ₂ 1.246g of water (18ml) solution under stirring for ten minutes After the addition was complete, 2.883 g of Kl in water (18 ml) was added after 1 hour, and stirred at room temperature after half an hour. The reaction at room temperature was stopped after 4 hours, 100ml of water was added, extracted with CH ₂ Cl ₂ 100ml×3, combined, and washed once with saturated Na ₂ S ₂ O ₃ . After drying, filtering, concentrating, and column chromatography, 3.032 g of nearly colorless liquid was obtained, and the yield was 66.1%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.83(d, J=7.0Hz, 1H), 7.24(s, 1H), 6.83(t, J=7.0Hz, 2H), 6.75(d, J=8.4Hz , 1H), 6.56(d, J=2.2Hz, 1H), 6.45(dd, J=8.4, 2.3Hz, 1H), 5.97(s, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ157.3, 151.3, 148.5, 144.0, 139.8, 129.6, 124.9, 118.3, 111.4, 108.3, 101.8, 101.6, 88.0; EI-MSm/z340(M); EI-HRMS calcd.for C ₁₃ H ₉ lO ₃ (M) 339.9596, observed 339.9593.

Example 88

2-Sesamolylphenylboronic acid (D5)

Add 2.980g of 2-sesaminol iodobenzene into a 100ml reaction tube, fully remove oxygen and water, add anhydrous THF50ml under the protection of argon, and slowly add 2.5mol/L n-butyl lithium dropwise in a cold bath at -78°C Solution 4.0ml, after reacting for 1 hour, add 1.4ml of trimethyl borate at -78°C, after 2 hours, move the reaction tube to room temperature and stir. After stirring at room temperature for 2 h, 1 ml of concentrated hydrochloric acid was added, extracted with ethyl acetate, dried, filtered, and concentrated to obtain 2.261 g of a white solid, with a yield of 100%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.90(dd, J=7.4, 1.4Hz, 1H), 7.38-7.32(m, 1H), 7.10(t, J=7.3Hz, 1H), 6.80(d, J=8.4Hz, 1H), 6.71(d, J=8.3Hz, 1H), 6.62(d, J=2.3Hz, 1H), 6.56(dd, J=8.4, 2.3Hz, 1H), 6.00(s, 2H), 5.79(s, 2H);

Example 89

3-(2-Sesamolylphenyl)-N-(2-(N-Bocamino)ethyl)-2-thienylsulfonamide (F5)

Add 1.038g of 3-bromo-N-(2-(N-Bocamino)ethyl)-2-thienylsulfonamide, 0.772g of 2-sesaminolphenylboronic acid, 120mg of Sphos, and acetic acid to a 250ml Shrek tube Palladium 49mg, K ₃ PO ₄ 0.855g, after fully deoxygenated, add THF 50ml, water 10ml, reflux for 8 hours, stop heating and stirring. Add 100ml of water, extract with 100ml of ethyl acetate x 2, dry, filter, concentrate, and perform column chromatography to obtain 1.139g of yellow floc with a yield of 73.4%.

Example 90

3-(2-Sesamolylphenyl)-N-(2-aminoethyl)-2-thienylsulfonamide (G5)

Add 3-(2-sesaminolphenyl)-N-(2-(N-Bocamino)ethyl)-2-thienylsulfonamide 877mg, CH ₂ Cl ₂ 10ml, CF ₃ CO into a 25ml egg-shaped bottle ₂ H 1.5ml, stirred at room temperature for 12 hours. Add potassium carbonate to neutralize CF ₃ CO ₂ H to make it alkaline, add water, extract with CH ₂ Cl ₂ 60ml×3, dry, filter, and concentrate to obtain 487.4mg of yellow solid with a yield of 68.9%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.59-7.46(m, 2H), 7.33(t, J=7.8Hz, 1H), 7.16(t, J=7.5Hz, 1H), 7.09(d, J= 5.1Hz, 1H), 6.90(d, J=8.2Hz, 1H), 6.72(d, J=8.4Hz, 1H), 6.53(d, J=2.1Hz, 1H), 6.43(dd, J=8.4, 2.2Hz, 1H), 5.96(s, 2H), 2.94(t, J=5.7Hz, 2H), 2.72(t, J=5.7Hz, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ155.2, 151.2, 148.5, 144.0, 140.2, 136.8, 132.0, 131.8, 130.2, 128.8, 125.0, 123.0, 117.7, 111.6, 108.3, 101.8, 101.6, 45.8, 41.0; ESI-MS m/z 419.7 (M+H) ⁺ MALDI-HRMS calcd. for C ₁₉ H ₁₉ N ₂ O ₅ S ₂ (M+H) ⁺ 419.0730, observed 419.0720.

Example 91

3-(2-Sesamolylphenyl)-N-(2-(3-(3,5-dichlorophenyl)ureido)ethyl)-2-thienylsulfonamide (H5-1)

40.2 mg of 3-(2-sesaminol-phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide and 1.1 molar equivalents of 3,5-dichlorophenyl isocyanate were added to a 25ml egg-shaped bottle. Dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 58.3 mg, and the yield was 100%.

¹ H NMR (400MHz, Acetone) δ8.37(s, 1H), 7.77(d, J=5.6Hz, 1H), 7.53(d, J=2.4Hz, 2H), 7.49(dd, J=7.6, 2.0 Hz, 1H), 7.33(td, J=7.9, 1.6Hz, 1H), 7.21(d, J=5.2Hz, 1H), 7.11(td, J=7.5, 0.9Hz, 1H), 6.99(t, J =1.8Hz, 1H), 6.84(dd, J=8.4, 0.8Hz, 1H), 6.78(d, J=8.4Hz, 1H), 6.66(d, J=2.4Hz, 1H), 6.54-6.50(m , 2H), 6.06(t, J=5.4Hz, 1H), 5.99(s, 2H), 3.30(q, J=6.0Hz, 2H), 3.05(q, J= ^6.1Hz , 2H); (100MHz, Acetone) δ156.5, 155.9, 152.2, 149.5, 144.9, 143.9, 141.4, 138.5, 135.5, 133.0, 132.9, 130.8, 129.9, 126.0, 123.3, 121.6, 118.1, 117.0, 102.9.8, 12 , 44.3, 40.5;

Example 92

3-(2-Sesamolylphenyl)-N-(2-(3-(4-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide (H5-2)

39.4 mg of 3-(2-sesaminol-phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 1.1 molar equivalents of 4-methoxyphenyl isocyanate, two Chloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 53.4 mg, and the yield was 100%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.54-7.49(m, 2H), 7.33-7.28(m, 1H), 7.15-7.11(m, 3H), 7.08(d, J=5.2Hz, 1H), 6.88(d, J=7.6Hz, 1H), 6.82(dd, J=9.0, 3.0Hz, 2H), 6.70(dd, J=8.4, 1.6Hz, 1H), 6.51(d, J=2.4Hz, 1H ), 6.41(dd, J=8.4, 2.4Hz, 1H), 6.30(d, J=28.8Hz, 1H), 5.93(s, 2H), 5.16(s, 1H), 5.07-5.01(m, 1H) , 3.77(d, J=2.0Hz, 3H), 3.25(q, J=5.9Hz, 2H), 3.03(s, 2H); ¹³ CNMR(100MHz, CDCl ₃ ) δ156.9, 156.1, 155.1, 151.1, 148.5, 143.9, 140.8, 136.3, 131.8, 131.8, 131.4, 130.3, 129.2, 124.8, 123.1, 117.7, 114.3, 111.7, 108.4, 101.9, 101.6, 55.5, 43.9, 39.8, 29.7;

Example 93

3-(2-Sesamolylphenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)ureido)ethyl)-2-thienylsulfonamide (H5-3 )

Add 3-(2-sesamolylphenyl)-N-(2-aminoethyl)-2-thienylsulfonamide 39.7mg, 3,5-ditrifluoromethylphenylisocyanate 1.1 to a 25ml egg-shaped bottle Molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 55.1 mg, the yield was 86.2%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.76(s, 2H), 7.54(d, J=5.2Hz, 1H), 7.44-7.41(m, 2H), 7.31(td, J=7.9, 2.2Hz, 1H), 7.14-7.10(m, 3H), 6.89(dd, J=8.4, 0.8Hz, 1H), 6.68(d, J=8.4Hz, 1H), 6.48(d, J=2.4Hz, 1H), 6.39(dd, J=8.4, 2.4Hz, 1H), 5.92(s, 2H), 5.47(t, J=5.8Hz, 1H), 5.09(brs, 1H), 3.32(q, J=5.3Hz, 2H ), 3.10 (t, J=5.2Hz, 1H); ¹³ C NMR (100MHz, Acetone) δ156.5, 155.9, 152.2, 149.5, 144.9, 143.5, 141.5; 133.0, 132.9, 132.5, 132.2, 130.8, 129.9, 126.1, 123.3, 118.5, 118.5, 118.1, 112.8, 109.0, 102.8, 102.6, 44.2, 40.5,

Example 94

3-(2-Sesamolylphenyl)-N-(2-(3-(4-nitrophenyl)ureido)ethyl)-2-thienylsulfonamide (H5-4)

39.4 mg of 3-(2-sesaminol-phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 1.1 molar equivalent of 4-nitrophenyl isocyanate, dichloro Methane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 51.8 mg, the yield was 94.5%.

¹ H NMR (400MHz, Acetone) δ8.71(s, 1H), 8.14(d, J=9.2Hz, 2H), 7.77(d, J=4.8Hz, 1H), 7.71(d, J=9.2Hz, 2H), 7.49(dd, J=7.4, 1.4Hz, 2H), 7.36-7.30(m, 1H), 7.20(d, J=5.2Hz, 1H), 7.11(t, J=7.0Hz, 1H), 6.84(d, J=8.4Hz, 1H), 6.78(d, J=8.4Hz, 1H), 6.67(d, J=2.4Hz, 1H), 6.54-6.48(m, 2H), 6.15(t, J =6.2Hz, 1H), 5.99(s, 2H), 3.33-3.29(q, J=5.6Hz, 2H), 3.07(q, J=5.9Hz, 2H); ESI-MS m/z 583.2(M+ H) ⁺ , 605.5(M+Na) ⁺ ; MALDI-HRMS calcd. for C ₂₆ H ₂₂ N ₄ O ₈ S ₂ Na(M+Na) ⁺ 605.0771, observed 605.0775.

Example 95

3-(2-Sesamolylphenyl)-N-(2-(3-(3-nitrophenyl)ureido)ethyl)-2-thienylsulfonamide (H5-5)

40.3 mg of 3-(2-sesaminol-phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 1.1 molar equivalent of 3-nitrophenyl isocyanate, dichloro Methane 3ml, stirred at room temperature for 5 hours. PE:ethyl acetate=1:2 column chromatography, the product was collected to obtain 49.3 mg, the yield was 87.9%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.13(s, 1H), 7.74(s, 1H), 7.57(d, J=7.2Hz, 1H), 7.53(d, J=5.1Hz, 1H), 7.43 (d, J=7.2Hz, 1H), 7.29(s, 2H), 7.10(d, J=5.0Hz, 2H), 6.88(d, J=8.0Hz, 1H), 6.67(d, J=8.3Hz , 1H), 6.48(s, 1H), 6.40(d, J=8.4Hz, 1H), 5.92(s, 2H), 5.52(s, 1H), 5.28(s, 1H), 3.31(d, J= 4.9Hz, 2H), 3.09 (d, J=4.6Hz, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ155.5, 155.1, 151.0, 148.5, 148.4, 144.1, 141.3, 140.5, 135.7, 132.1, 131.6 , 130.4, 129.6, 129.4, 124.8, 124.5, 123.0, 117.9, 116.9, 113.4, 111.5, 108.3, 101.7, 101.7, 43.7, 39.8; ESI-MS m/z 583.1(M+H) ⁺ , 605.1(M+Na ) ⁺ ; MALDI-H RMS calcd. for C ₂₆ H ₂₂ N ₄ O ₈ S ₂ Na(M+Na) ⁺ 605.0771, observed 605.0767.

Example 96

3-(2-Sesamolylphenyl)-N-(2-(3-(3-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide (H5-6)

Add 3-(2-sesaminol-phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide 39.4 mg, 1.1 molar equivalents of 3-methoxyphenyl isocyanate, two Chloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 46.1 mg, and the yield was 86.3%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.49(d, J=5.1Hz, 2H), 7.30(s, 1H), 7.14(s, 2H), 7.08(d, J=5.1Hz, 1H), 6.98 (s, 1H), 6.89 (d, J = 9.3Hz, 1H), 6.74 (d, J = 8.1Hz, 1H), 6.70 (d, J = 8.5Hz, 1H), 6.60 (s, 1H), 6.51 (s, 1H), 6.42 (d, J = 8.4Hz, 1H), 5.93 (d, J = 2.2Hz, 2H), 5.13 (s, 2H), 3.76 (d, J = 3.2Hz, 3H), 3.27 (s, 2H), 3.06 (s, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ160.2, 156.1, 155.1, 151.2, 148.5, 144.0, 140.9, 140.2, 136.2, 131.9, 131.7, 130.3, 129.7, 129.3, 124.9, ^123.0 , ^117.8 , 112.1, 111.6, 108.8, 108.4, 105.5, 101.8, 101.6, 55.2, 43.8, 39.8 ; -HRMS calcd. for C ₂₇ H ₂₅ N ₃ O ₇ S ₂ Na(M+Na) ⁺ 590.1026, observed 590.1013.

Example 97

3-(2-Sesamolylphenyl)-N-(2-(3-(4-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonamide (H5-7)

Add 3-(2-sesaminol-phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide 39.0mg, 4-methoxyphenyl isothiocyanate 1.1 to a 25ml egg-shaped bottle Molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 54.4 mg, and the yield was 100%.

¹ H NMR (400MHz, Acetone) δ8.70(s, 1H), 7.77(d, J=5.2Hz, 1H), 7.49(dd, J=7.6, 1.6Hz, 1H), 7.37-7.33(m, 1H ), 7.23-7.19(m, 3H), 7.13(td, J=7.5, 1.1Hz, 1H), 7.02(brs, 1H), 6.91(dd, J=6.8, 2.0Hz, 2H), 6.86(dd, J=8.2, 0.6Hz, 1H), 6.79(d, J=8.4Hz, 1H), 6.65(d, J=2.4Hz, 1H), 6.56(t, J=5.8Hz, 1H), 6.52(dd, ^13C NMR (100MHz, Acetone) δ183.0, 158.9, 156.4, 152.3, 149.5, 144.9, 141.4, 138.5, 133.0, 132.9, 130.8, 129.9, 127.9, 127.8, 126.2, 123.5, 118.2, 115.4, 112.8, 1 102.6, 55.8, 44.8, 43.7;

Example 98

3-(2-Sesamolylphenyl)-N-(2-(3-(3-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide (H5-8)

39.6 mg of 3-(2-sesaminol-phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide and 1.1 moles of 3-nitrophenyl isothiocyanate were added to a 25ml egg-shaped bottle Equivalent, 3ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 56.6 mg, the yield was 100%.

¹ H NMR (400MHz, Acetone) δ9.34(s, 1H), 8.63-8.61(m, 1H), 7.98-7.96(m, 1H), 7.89(dd, J=8.0, 2.0Hz, 1H), 7.79 (d, J=5.2Hz, 1H), 7.59(t, J=8.2Hz, 1H), 7.55(brs, 1H), 7.49(dd, J=7.6, 1.6Hz, 1H), 7.38-7.34(m, 1H), 7.21(d, J=5.2Hz, 1H), 7.13(td, J=7.5, 1.1Hz, 1H), 6.87(dd, J=8.4, 0.4Hz, 1H), 6.78(d, J=8.8 Hz, 1H), 6.65(d, J=2.4Hz, 1H), 6.58(t, J=5.4Hz, 1H), 6.52(dd, J=8.4, 2.4Hz, 1H), 5.99(s, 2H), 3.76 (q, J=5.9Hz, 2H), 3.20 (q, J=6.0Hz, 2H); ¹³ C NMR (100MHz, Acetone) δ182.6, 156.5, 152.2, 149.5, 149.2, 144.9, 141.7, 141.6, 138.2, 133.1, 132.9, 130.9, 130.5, 130.1, 129.8, 126.1, 123.4, 119.6, 118.4, 118.2, 112.8, 109.1, 102.8, 102.6, 44.6, 42.9;

Example 99

3-(2-Sesamolylphenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)thioureido)ethyl)-2-thienylsulfonamide (H5- 9)

Add 38.5 mg of 3-(2-sesamolylphenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 3,5-ditrifluoromethylphenylisosulfuramide into a 25ml egg-shaped bottle 1.1 molar equivalent of cyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 63.4 mg, the yield was 100%. ¹ H NMR (400MHz, Acetone) δ9.47(s, 1H), 8.31(d, J=4.4Hz, 2H), 7.79(d, J=4.8Hz, 1H), 7.72(s, 1H), 7.69( brs, 1H), 7.49(dd, J=7.8, 1.8Hz, 1H), 7.38-7.34(m, 1H), 7.22(d, J=5.2Hz, 1H), 7.12(td, J=7.6, 1.2Hz , 1H), 6.87(d, J=8.4Hz, 1H), 6.78(d, J=8.8Hz, 1H), 6.65(d, J=2.8Hz, 1H), 6.58(brs, 1H), 6.52(dd , J=8.4, 2.4Hz, 1H), 5.98(s, 2H), 3.76(q, J=5.9Hz, 2H), 3.21(q, J=6.0Hz, 2H); ¹³ C NMR (100MHz, Acetone) δ182.7, 156.5, 152.2, 149.5, 144.9, 142.8, 141.6, 138.2, 133.1, 132.9, 132.2, 131.8, 130.8, 130.1, 126.1, 125.7, 123.7, 123.4, 123.0, 118.2, 102.8 44.7, 42.9;

Example 100

3-(2-Sesamolylphenyl)-N-(2-(3-(3-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonamide (H5-10)

Add 3-(2-sesaminol-phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide 38.7mg, 3-methoxyphenyl isothiocyanate 1.1 to a 25ml egg-shaped bottle Molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 54.0 mg, and the yield was 100%.

¹ H NMR (400MHz, Acetone) δ8.89(s, 1H), 7.77(d, J=5.2Hz, 1H), 7.49(dd, J=7.6, 1.6Hz, 1H), 7.37-7.33(m, 1H ), 7.30(BRs, 1H), 7.24(t, J=8.2Hz, 1H), 7.20(d, J=5.2Hz, 1H), 7.12(td, J=7.5, 1.1Hz, 1H), 7.03(t , J=2.2Hz, 1H), 6.89 (dd, J=7.8, 1.4Hz, 1H), 6.86 (dd, J=8.4, 0.8Hz, 1H), 6.79 (d, J=8.4Hz, 1H), 6.74 (dd, J=8.4, 2.4Hz, 1H), 6.65(d, J=2.8Hz, 1H), 6.56(t, J=5.8Hz, 1H), 6.52(dd, J=8.4, 2.4Hz, 1H) , 5.99 (s, 2H), 3.80-3.74 (m, 5H), 3.18 (q, J=6.0Hz, 2H); ¹³ C NMR (100MHz, Acetone) δ182.4, 161.3, 156.4, 152.3, 149.5, 144.9 , 141.5, 140.2, 138.4, 133.0, 132.9, 130.9, 130.8, 129.9, 126.1, 123.5, 118.2, 116.9, 112.8, 112.1, 110.5, 109.1, 102.8, 102.6, 55.7, 44.8, 43.5;

Example 101

3-(2-Sesamolylphenyl)-N-(2-(3-(4-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide (H5-11)

39.7 mg of 3-(2-sesaminol-phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide and 1.1 moles of 4-nitrophenyl isothiocyanate were added to a 25ml egg-shaped bottle Equivalent, 3ml of dichloromethane, stirred at room temperature for 5 hours. PE:ethyl acetate=1:2 column chromatography, the product was collected to obtain 49.6 mg, the yield was 87.3%.

¹ H NMR (400MHz, Acetone) δ9.54(s, 1H), 8.18(dd, J=6.8, 2.0Hz, 1H), 7.92-7.89(m, 2H), 7.79(d, J=5.2Hz, 1H ), 7.70(brs, 1H), 7.49(dd, J=7.6, 1.6Hz, 1H), 7.38-7.34(m, 1H), 7.21(d, J=5.2Hz, 1H), 7.12(td, J= 7.5, 1.2Hz, 1H), 6.86(dd, J=8.4, 0.8Hz, 1H), 6.79(d, J=8.4Hz, 1H), 6.66(d, J=2.4Hz, 1H), 6.59(t, J=6.0Hz, 1H), 6.52(dd, J=8.4, 2.4Hz, 1H), 5.99(s, 2H), 3.77(q, J=5.9Hz, 2H), 3.21(q, J=6.0Hz, 2H); ¹³ C NMR (100MHz, Acetone) δ181.9, 156.5, 152.2, 149.5, 146.7, 144.9, 143.9, 141.6, 138.2, 133.0, 132.9, 130.9, 130.1, 126.0, 125.2, 123.4, 122.0, 118 , 109.1, 102.8, 102.6, 44.7, 42.8;

Example 102

3-(2-Sesamolylphenyl)-N-(2-(3-(3-methylphenyl)thioureido)ethyl)-2-thienylsulfonamide (H5-12)

38.6mg of 3-(2-sesaminolphenyl)-N-(2-aminoethyl)-2-thienylsulfonamide and 1.1mol of 3-methylphenylisothiocyanate were added to a 25ml egg-shaped bottle Equivalent, 3ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 52.4 mg, and the yield was 100%.

¹ H NMR (400MHz, Acetone) δ8.84(s, 1H), 7.77(d, J=4.8Hz, 1H), 7.49(dd, J=7.6, 1.6Hz, 1H), 7.37-7.33(m, 1H ), 7.25-7.19(m, 4H), 7.15-7.10(m, 2H), 7.00(d, J=7.2Hz, 1H), 6.86(dd, J=8.2, 0.6Hz, 1H), 6.79(d, J=8.4Hz, 1H), 6.65(d, J=2.4Hz, 1H), 6.56(t, J=5.8Hz, 1H), 6.52(dd, J=8.4, 2.4Hz, 1H), 5.99(s, 2H), 3.75(q, J=5.9Hz, 2H), 3.17(q, J=6.0Hz, 2H), 2.30(s, 3H); ¹³ C NMR (100MHz, Acetone) δ182.5, 156.4, 152.3, 149.5, 144.9, 141.5, 140.0, 138.9, 138.4, 133.0, 132.9, 130.8, 130.0, 129.9, 127.2, 126.1, 125.8, 123.5, 122.3, 118.2, 112.8, 109.1, 5; 102.8, 4402.6

Example 103

3-(2-Sesamolylphenyl)-N-(2-(3-phenylthioureido)ethyl)-2-thienylsulfonamide (H5-13)

36.8 mg of 3-(2-sesaminol-phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 1.1 molar equivalent of phenyl isothiocyanate, dichloro Methane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 48.7 mg, and the yield was 100%.

¹ H NMR (400MHz, Acetone) δ8.92(s, 1H), 7.77(d, J=5.6Hz, 1H), 7.49(dd, J=7.6, 1.6Hz, 1H), 7.40-7.32(m, 5H ), 7.25(brs, 1H), 7.21-7.16(m, 2H), 7.14(td, J=7.5, 1.1Hz, 1H), 6.86(dd, J=8.4, 0.8Hz, 1H), 6.79(d, J=8.4Hz, 1H), 6.66(d, J=2.4Hz, 1H), 6.57(t, J=5.8Hz, 1H), 6.52(dd, J=8.4, 2.4Hz, 1H), 5.99(s, 2H), 3.76(q, J=6.0Hz, 2H), 3.18(q, J=6.0Hz, 2H); ¹³ CNMR(100MHz, Acetone) δ182.6, 156.5, 152.3, 149.5, 144.9, 141.5, 139.2, 138.4, 133.0, 132.9, 130.8, 130.1, 129.9, 126.2, 126.1, 125.1, 123.4, 118.2, 112.8, 109.1, 102.8, 102.6, 44.8, 43.5;

Example 104

3-(2-Sesamolylphenyl)-N-(2-(4-nitrobenzenesulfonamido)ethyl)-2-thienylsulfonamide (I5-1)

Add 43.5mg of 3-(2-sesaminolphenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 1.1 each of 4-nitrobenzenesulfonyl chloride and triethylamine to a 25ml egg-shaped bottle Molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 54.0 mg, and the yield was 86.1%.

¹ H NMR (400MHz, Acetone) δ8.38 (dd, J=7.0, 1.8Hz, 2H), 8.05 (dd, J=6.8, 2.0Hz, 1H), 7.79 (d, J=4.8Hz, 1H), 7.45(dd, J=7.6, 1.6Hz, 1H), 7.37-7.32(m, 1H), 7.20(d, J=5.2Hz, 1H), 7.10(td, J=7.5, 0.9Hz, 1H), 6.95 (brs, 1H), 6.81(dd, J=8.2, 0.6Hz, 1H), 6.77(d, J=8.0Hz, 1H), 6.57(d, J=2.0Hz, 1H), 6.47-6.45(m, 2H), 6.00(s, 2H), 3.09-3.05(m, 4H); ¹³ C NMR (100MHz, Acetone) δ156.5, 152.0, 150.9, 149.5, 147.3, 145.0, 141.5, 138.4, 133.1, 133.0, 130.9 , 130.1, 129.2, 125.8, 125.3, 123.3, 118.0, 112.8, 109.1, 102.8, 102.7, 43.7, 43.6;

Example 105

3-(2-Sesamolylphenyl)-N-(2-acetamidoethyl)-2-thienyl-N-sulfonylacetamide (I5-2)

Add 40 mg of 3-(2-sesaminolphenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 1.1 molar equivalents of acetic anhydride and triethylamine to a 25ml egg-shaped bottle, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 44.3 mg, and the yield was 92.3%.

¹ H NMR (400MHz, Acetone) δ7.98(d, J=5.2Hz, 1H), 7.42-7.38(m, 1H), 7.33(dd, J=7.6, 2.0Hz, 1H), 7.26(d, J =5.2Hz, 1H), 7.17(td, J=7.6, 1.2Hz, 1H), 7.04(brs, 1H), 6.81(t, J=8.0Hz, 2H), 6.63(d, J=2.4Hz, 1H ), 6.50(dd, J=8.4, 2.4Hz, 1H), 6.02(s, 2H), 3.27-3.20(m, 4H), 2.09(s, 3H), 1.82(s, 3H); ¹³ C NMR( 100MHz, Acetone) δ170.3, 170.3, 157.0, 151.4, 149.6, 145.4, 143.6, 137.7, 133.1, 132.6, 132.5, 131.5, 124.4, 123.2, 117.1, 113.5, 109.1, 103.3, 102.7, 467

Example 106

2-(2-Naphthyl)nitrobenzene (A3)

Add 4.071g of 2-naphthol, 3.690g of o-fluoronitrobenzene, 2.558g of 60% NaH, and 50ml of anhydrous tetrahydrofuran into a 250ml egg-shaped bottle, and reflux for 5h. Remove tetrahydrofuran, add 200ml of ethyl acetate, wash with 200ml of water × 3, dry, filter, concentrate, the product is 5.0g, and the yield is 72.0%.

Example 107

2-(2-Naphthyl)aminobenzene (B3)

Add 5.0g of 2-(2-naphthyl)nitrobenzene, 60ml of ethanol, 0.450g of Pd/C into a 250ml eggplant-shaped bottle, and finally add 7ml of hydrazine hydrate, and stir at room temperature for 5 hours. After filtration and distillation of the solvent under reduced pressure, 200ml of ethyl acetate was added, washed with 100ml×2 water, dried, filtered, and concentrated to obtain 3.965g of a light yellow solid with a yield of 89.4%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.84-7.78(m, 2H), 7.67(d, J=8.1Hz, 1H), 7.46-7.41(m, 1H), 7.38(ddd, J=8.1, 6.9 , 1.3Hz, 1H), 7.28(dd, J=8.9, 2.5Hz, 1H), 7.21(d, J=2.4Hz, 1H), 7.04(td, J=7.8, 1.4Hz, 1H), 6.95(dd , J=8.0, 1.3Hz, 1H), 6.87(dd, J=7.9, 1.5Hz, 1H), 6.78-6.73(m, 1H), 3.83(s, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ155.3, 143.0, 138.8, 134.4, 129.9, 129.9, 127.7, 127.1, 126.6, 125.2, 124.5, 120.6, 118.9, 116.6, 111.7;

Example 108

2-(2-Naphthyl)iodobenzene (C3)

Place a 500ml three-necked flask in an ice bath, add 3.965g of 2-(2-naphthyl)aminobenzene, 2.8ml of concentrated sulfuric acid, dilute and cool with 70ml of water, then add NaNO ₂ 1.415g of water (20ml) slowly under stirring The solution was added in ten minutes, and then 3.943 g of Kl in water (20 ml) was added after 1 hour, and stirred at room temperature after half an hour. The reaction at room temperature was stopped after 4 hours, 100ml of water was added, extracted with CH ₂ Cl ₂ 100ml×3, combined, and washed once with saturated Na ₂ S ₂ O ₃ . After drying, filtering, concentrating, and column chromatography, 2.009 g of nearly colorless liquid was obtained with a yield of 34.4%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.90(dd, J=7.9, 1.5Hz, 1H), 7.84(t, J=8.9Hz, 2H), 7.69(d, J=8.1Hz, 1H), 7.48 -7.43(m, 1H), 7.43-7.38(m, 1H), 7.32(td, J=8.2, 1.5Hz, 1H), 7.27(d, J=2.5Hz, 1H), 7.22(d, J=2.3 Hz, 1H), 6.97 (dd, J=8.2, 1.3Hz, 1H), 6.92 (td, J=7.8, 1.4Hz, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ156.5, 154.8, 140.1, 134.3, 130.3, 130.1, 129.8, 127.9, 127.3, 126.7, 125.7, 124.9, 120.0, 119.6, 113.6, 89.2;

Example 109

2-(2-Naphthyl)phenylboronic acid (D3)

Add 1.819g of 2-(2-naphthyl)iodobenzene into a 100ml reaction tube, fully remove oxygen and water, add anhydrous THF 50ml under the protection of argon, slowly add 2.5mol/ L n-butyllithium solution 2.5ml, after reacting for 1 hour, add 1.2ml trimethyl borate at -78°C, move the reaction tube to room temperature and stir after 2 hours. After stirring at room temperature for 2 h, 1 ml of concentrated hydrochloric acid was added, extracted with ethyl acetate, dried, filtered, and concentrated to obtain 0.902 g of white solid, with a yield of 65%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.96(dd, J=7.4, 1.8Hz, 1H), 7.90-7.84(m, 2H), 7.76(d, J=7.9Hz, 1H), 7.52-7.44( m, 3H), 7.36(ddd, J=8.4, 7.4, 1.9Hz, 1H), 7.28(dd, J=5.7, 3.2Hz, 1H), 7.16(td, J=7.3, 0.9Hz, 1H), 6.78 (d, J=8.3Hz, 1H), 5.64(s, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ163.4, 153.1, 137.1, 134.3, 132.9, 130.9, 130.4, 129.9, 127.9, 127.4, 126.9 , 125.5, 123.3, 120.4, 116.6, 116.5; EI-MS m/z 264(M+H) ⁺ ; EI-HRMS calcd. for C ₁₆ H ₁₃ BO ₃ (M) ⁺ 263.0994, observed 263.0998.

Example 110

3-(2-(2-Naphthyl)phenyl)-N-(2-(N-Bocamino)ethyl)-2-thienylsulfonamide (F3)

Add 0.375g of 3-bromo-N-(2-(N-Bocamino)ethyl)-2-thienylsulfonamide and 0.375g of 2-(2-naphthyl)phenylboronic acid to a 250ml Shrek tube, Sphos 58mg, palladium acetate 17mg, K ₃ PO ₄ 0.458g, after fully deoxygenated, add THF 50ml, water 5ml, reflux for 8 hours, stop heating and stirring. Add 100ml of water, extract with 100ml of ethyl acetate x 2, dry, filter, concentrate, and perform column chromatography to obtain 0.312g of yellow floc with a yield of 61.2%.

¹ H NMR (400MHz, Acetone) δ7.88(t, J=7.5Hz, 2H), 7.78(d, J=8.1Hz, 1H), 7.71(d, J=5.2Hz, 1H), 7.59(dd, J=7.7, 1.6Hz, 1H), 7.50-7.38(m, 4H), 7.26(ddd, J=14.0, 8.2, 4.5Hz, 2H), 7.21(d, J=5.2Hz, 1H), 7.03(dd , J=8.2, 0.9Hz, 1H), 6.48(s, OH), 5.98(s, 1H), 3.15(q, J=6.1Hz, 2H), 3.01(t, J=6.2Hz, 2H), 1.38 (s, 9H); ¹³ C NMR (100MHz, CDCl ₃ ) δ156.9, 156.0, 155.2, 141.1, 139.0, 135.3, 133.2, 132.8, 131.2, 131.0, 130.8, 129.8, 128.6, 128.1, 127.5, 127.3, 125. , 124.3, 120.6, 120.0, 114.7, 79.0, 44.2, 41.1; ESI-MS m/z 547.4 (M+Na) ⁺ ; MALDI-HRMS calcd.for C ₂₇ H ₂₈ N ₂ O ₅ S ₂ Na (M+Na ) ⁺ 547.1332, observed 547.1340.

Example 111

3-(2-(2-Naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide (G3)

Add 3-(2-(2-naphthyl)phenyl)-N-(2-(N-Bocamino)ethyl)-2-thienylsulfonamide 312mg, CH ₂ Cl ₂ 10ml into a 25ml egg-shaped bottle , CF ₃ CO ₂ H 1.0ml, stirred at room temperature for 12 hours. Add potassium carbonate to neutralize CF ₃ CO ₂ H until basic, add water, extract with CH ₂ Cl ₂ 60ml×3, dry, filter, and concentrate to obtain 238.4 mg of yellow solid, yield 94.4%.

¹ H NMR (400MHz, Acetone) δ7.87 (dd, J=8.2, 4.2Hz, 2H), 7.74 (t, J=7.5Hz, 2H), 7.65 (dd, J=7.6, 1.6Hz, 1H), 7.51-7.38(m, 4H), 7.30(dd, J=8.9, 2.4Hz, 1H), 7.28-7.22(m, 2H), 7.04(d, J=8.2Hz, 1H), 5.98(s, 0H) , 3.22(t, J=6.2Hz, 2H), 3.12(t, J=6.1Hz, 2H); ESI-MS m/z 425.1(M ₊ H) ⁺ ; ESI- _{HRMScalcd.for C22H21N2} O ₃ S ₂ (M+H) ⁺ 425.0988, observed 425.0988.

Example 112

3-(2-(2-naphthyl)phenyl)-N-(2-(3-(4-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide (H3-1 )

Add 3-(2-(2-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide 39.3mg, 4-methoxyphenylisocyanate 1.1 to a 25ml egg-shaped bottle Molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 46.2 mg, the yield was 87%.

¹ H NMR (400MHz, Acetone) δ7.88(dd, J=7.6, 1.6Hz, 1H), 7.78(t, J=7.8Hz, 2H), 7.70(d, J=5.2Hz, 1H), 7.60( dd, J=7.6, 1.6Hz, 1H), 7.45(td, J=7.5, 1.3Hz, 1H), 7.42-7.35(m, 5H), 7.27(dd, J=8.8, 2.4Hz, 1H), 7.23 -7.20(m, 2H), 7.00(dd, J=8.4, 0.8Hz, 1H), 6.81(dd, J=6.8, 2.4Hz, 1H), 6.66(brs, 1H), 5.82(brs, 1H), 3.74(s, 3H), 3.29(q, J=5.9Hz, 2H), 3.04(q, J=5.6Hz, 2H); ¹³ C NMR(100MHz, CDCl ₃ ) δ156.8, 156.2, 154.9, 153.9, 9

Example 113

3-(2-(2-naphthyl)phenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)ureido)ethyl)-2-thienylsulfonamide (H3-2)

Add 38.7 mg of 3-(2-(2-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 3,5-bistrifluoromethyl to a 25ml egg-shaped bottle 1.1 molar equivalent of phenyl isocyanate, 3 ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 52 mg, the yield was 89%.

¹ H NMR (400MHz, Acetone) δ8.69(s, 1H), 8.14(s, 2H), 7.85(t, J=8.6Hz, 2H), 7.76(d, J=8.0Hz, 1H), 7.71( d, J=5.2Hz, 1H), 7.60(dd, J=7.6, 1.6Hz, 1H), 7.53(s, 1H), 7.44-7.38(m, 4H), 7.27(dd, J=9.0, 2.6Hz , 1H), 7.24-7.20(m, 2H), 7.02(dd, J=8.2, 1.2Hz, 1H), 6.59(brs, 1H), 6.18(s, 1H), 3.33(q, J=6.1Hz, 2H), 3.06 (t, J=5.8Hz, 2H); ¹³ C NMR (100MHz, Acetone) δ156.0, 155.2, 143.5, 141.2, 138.6, 135.3, 133.2, 132.9, 132.6, 132.2, 131.9, 131.1, 131.0 , 130.8, 129.9, 128.6, 128.0, 127.4, 127.2, 125.9, 125.6, 124.3, 123.2, 120.5, 120.0, 118.5, 114.9, 114.7, 44.2, 40.6;

Example 114

3-(2-(2-Naphthyl)phenyl)-N-(2-(3-(3-nitrophenyl)ureido)ethyl)-2-thienylsulfonamide (H3-3)

Add 41.3 mg of 3-(2-(2-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide and 1.1 moles of 3-nitrophenylisocyanate to a 25ml egg-shaped bottle Equivalent, 3ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 57.3 mg, and the yield was 100%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.14(d, J=2.0Hz, 1H), 7.78-7.71(m, 3H), 7.65(d, J=7.6Hz, 1H), 7.58-7.51(m, 2H), 7.47(dd, J=5.4, 2.2Hz, 1H), 7.45-7.32(m, 3H), 7.28(d, J=8.0Hz, 1H), 7.25-7.18(m, 2H), 7.14-7.09 (m, 3H), 7.02(dd, J=8.4, 2.8Hz, 1H), 5.43(s, 1H), 5.27(s, 1H), 3.27(q, J=5.5Hz, 2H), 3.06(q, J=5.6Hz, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ155.6, 154.8, 154.1, 148.4, 141.2, 140.5, 135.7, 134.2, 132.0, 131.9, 130.5, 130.2, 129.6, 129.4, 127.8, 127.1 , 126.8, 125.8, 125.0, 124.5, 123.8, 119.5, 119.3, 116.9, 113.8, 113.3, 43.8, 39.7; ESI-MS m/z 589.0(M+H) ⁺ , 611.2(M+Na) ⁺ ; MALDI-HRMScalcd .for C ₂₉ H ₂₄ N ₄ O ₆ S ₂ Na(M+Na) ⁺ 611.1030, observed 611.1040.

Example 115

3-(2-(2-naphthyl)phenyl)-N-(2-(3-(3-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide (H3-4 )

Add 3-(2-(2-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide 42.0mg, 3-methoxyphenylisocyanate 1.1 to a 25ml egg-shaped bottle Molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 56.8 mg, and the yield was 100%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.77 (dd, J=8.4, 4.8Hz, 2H), 7.66 (d, J=8.0Hz, 1H), 7.56 (dd, J=7.6, 1.6Hz, 1H) , 7.45-7.33(m, 4H), 7.24-7.19(m, 2H), 7.15-7.10(m, 2H), 7.08(d, J=5.2Hz, 1H), 7.02(d, J=8.4Hz, 1H ), 6.97(t, J=2.2Hz, 1H), 6.72(dd, J=8.0, 1.2Hz, 1H), 6.58(dd, J=8.2, 2.2Hz, 1H), 6.52(s, 1H), 5.16 -5.10(m, 2H), 3.73(s, 3H), 3.21(q, J=5.5Hz, 2H), 3.00(q, J=5.7Hz, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ160. 2, 156.1, 154.9, 154.0, 140.8, 140.2, 136.4, 134.2, 132.1, 131.8, 130.5, 130.1, 129.7, 129.2, 127.8, 127.2, 126.7, 125.9, 124.9, 123.8, 119.5, 113.9 105.6, 55.2, 43.8, 39.8; ESI-MS m/z 574.3 (M+H) ⁺ , 596.3 (M+Na) ⁺ ; MALDI-HRMS calcd. for C ₃₀ H ₂₇ N ₃ O ₅ S ₂ Na (M+Na ) ⁺ 596.1284, observed 596.1275.

Example 116

3-(2-(2-naphthyl)phenyl)-N-(2-(3-(3,5-dichlorophenyl)ureido)ethyl)-2-thienylsulfonamide (H3- 5)

Add 41.3mg of 3-(2-(2-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 3,5-dichlorophenylisocyanate to a 25ml egg-shaped bottle 1.1 molar equivalent, 3ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 58.5 mg, the yield was 98.2%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.77 (dd, J=8.6, 4.6Hz, 2H), 7.65 (d, J=8.0Hz, 1H), 7.50 (dd, J=7.8, 1.8Hz, 1H) , 7.47(d, J=5.2Hz, 1H), 7.45-7.38(m, 2H), 7.35(td, J=8.0, 1.3Hz, 1H), 7.23-7.19(m, 2H), 7.18(d, J =1.6Hz, 2H), 7.13-7.09(m, 2H), 7.02(d, J=8.0Hz, 1H), 6.91(t, J=1.6Hz, 2H), 5.39(t, J=5.8Hz, 1H ), 5.24(t, J=6.0Hz, 1H), 3.23(q, J=5.5Hz, 2H), 3.02(q, J=5.6Hz, 2H); ESI-MS m/z612.2(M+H ) ⁺ , 633.8(M+Na) ⁺ ; MALDI-HRMS calcd. for C ₂₉ H ₂₃ N ₃ O ₄ S ₂ Cl ₂ Na(M+Na) ⁺ 634.0399, observed 634.0388.

Example 117

3-(2-(2-Naphthyl)phenyl)-N-(2-(3-(4-nitrophenyl)ureido)ethyl)-2-thienylsulfonamide (H3-6)

Add 40.7 mg of 3-(2-(2-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide and 1.1 moles of 3-nitrophenyl isocyanate to a 25ml egg-shaped bottle Equivalent, 3ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 56.4 mg, the yield was 100%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.01 (d, J=9.2Hz, 2H), 7.76 (dd, J=8.2, 5.3Hz, 2H), 7.64 (d, J=7.7Hz, 1H), 7.52 -7.47(m, 2H), 7.46-7.29(m, 6H), 7.23(d, J=2.4Hz, 1H), 7.19(t, J=7.5Hz, 1H), 7.11(dd, J=6.6, 3.8 Hz, 2H), 7.02(d, J=8.2Hz, 1H), 5.53(t, J=5.4Hz, 1H), 5.24(t, J=6.0Hz, 1H), 3.27(q, J=5.3Hz, 2H), 3.05 (q, J=5.6Hz, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ154.9, 154.7, 154.1, 145.8, 141.8, 141.3, 135.5, 134.2, 132.1, 131.9, 130.6, 130.2, 129.8, 127.8, 127.1, 126.9, 125.8, 125.1, 125.1, 123.8, 119.5, 119.2, 117.5, 113.8, 43.7, 39.6; ESI-MS m/z 589.2(M+H) ⁺ , 611.2(M+Na) ⁺ ; MALDI-HRMS calcd. for C ₂₉ H ₂₄ N ₄ O ₆ S ₂ Na(M+Na) ⁺ 611.1030, observed 611.1048.

Example 118

3-(2-(2-naphthyl)phenyl)-N-(2-(3-(3-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide (H3-7 )

Add 41.5 mg of 3-(2-(2-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 3-nitrophenyl isothiocyanate to a 25ml egg-shaped bottle Ester 1.1 molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 57.5 mg, the yield was 97.3%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.17(s, 1H), 8.03(d, J=8.4Hz, 1H), 7.86(s, 1H), 7.80-7.77(m, 2H), 7.67(d, J=8.0Hz, 2H), 7.52-7.47(m, 3H), 7.46-7.37(m, 3H), 7.25-7.20(m, 2H), 7.12-7.09(m, 2H), 7.05(d, J= 8.0Hz, 1H), 6.67(t, J=4.8Hz, 1H), 5.04(t, J=5.4Hz, 1H), 3.66(q, J=5.3Hz, 2H), 3.09(q, J=5.7Hz , 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ181.3, 154.7, 154.0, 148.4, 141.2, 138.9, 135.4, 134.2, 132.0, 132.0, 130.6, 130.3, 130.2, 130.1, 129.9, 129.8, 127.8, , 126.9, 125.7, 125.1, 123.9, 120.3, 119.6, 119.2, 119.0, 113.7, 44.3, 42.6; ESI-MS m/z 605.3(M+H)+, 627.3(M+Na) ⁺ ; MALDI-HRMScalcd.for C ₂₉ H ₂₄ N ₄ O ₅ S ₃ Na(M+Na) ⁺ 627.0801, observed 627.0816.

Example 119

3-(2-(2-naphthyl)phenyl)-N-(2-(3-(3-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonamide (H3- 8)

Add 40.7 mg of 3-(2-(2-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 3-methoxyphenyl isothio 1.1 molar equivalent of cyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 56.5 mg, and the yield was 100%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.78(d, J=8.9Hz, 2H), 7.68(d, J=8.1Hz, 1H), 7.62(s, 1H), 7.55(dd, J=7.6, 1.7Hz, 1H), 7.47-7.36(m, 4H), 7.31(t, J=8.1Hz, 1H), 7.25(td, J=7.5, 0.9Hz, 1H), 7.22(d, J=2.4Hz, 1H), 7.13(dd, J=8.9, 2.5Hz, 1H), 7.09(d, J=5.1Hz, 1H), 7.05(d, J=8.2Hz, 1H), 6.83(dd, J=8.3, 2.3 Hz, 1H), 6.77(d, J=7.8Hz, 1H), 6.71(t, J=2.1Hz, 1H), 6.41(t, J=5.5Hz, 1H), 4.88(t, J=5.9Hz, 1H), 3.78(s, 3H), 3.65(q, J=5.9Hz, 2H), 3.08(q, J=5.7Hz, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ180.9, 160.9, 154.9 ，153.9，140.7，137.1，136.3，134.2，132.3，131.9，130.9，130.5，130.2，129.2，127.8，127.2，126.8，126.0，125.0，123.9，119.7，119.3，117.1，113.5，113.3，110.5，55.5，44.5 , 42.7; ESI-MS m/z _590.2 ( _{M +} H) ⁺ , _612.2 ( _M ⁺ Na) ⁺ ; .

Example 120

3-(2-(2-naphthyl)phenyl)-N-(2-(3-(4-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonamide (H3- 9)

Add 39.4 mg of 3-(2-(2-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 4-methoxyphenylisosulfur to a 25ml egg-shaped bottle 1.1 molar equivalent of cyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 49 mg, the yield was 90%.

¹ H NMR (400MHz, Acetone) δ8.72(brs, 1H), 7.87(t, J=8.4Hz, 2H), 7.79(d, J=8.0Hz, 1H), 7.71(d, J=5.2Hz, 1H), 7.60(dd, J=7.6, 1.6Hz, 1H), 7.47-7.41(m, 4H), 7.27(dd, J=9.0, 2.6Hz, 1H), 7.25-7.20(m, 4H), 7.02 (dd, J=8.4, 0.8Hz, 1H), 6.90(dd, J=6.8, 2.4Hz, 1H), 6.64(brs, 1H), 3.78(s, 3H), 3.73(q, J=5.4Hz, 2H), 3.15 (t, J=6.0Hz, 2H); ¹³ C NMR (100MHz, Acetone) δ182.9, 158.9, 156.0, 155.2, 141.2, 138.6, 135.3, 133.3, 132.9, 131.2, 131.0, 130.9, 129.9 , 128.6, 128.1, 127.9, 127.8, 127.5, 127.3, 125.7, 124.4, 120.6, 120.0, 115.3, 114.8, 55.8, 44.7, 43.5.

Example 121

3-(2-(2-naphthyl)phenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)thioureido)ethyl)-2-thienylsulfonyl Amide (H3-10)

Add 40.2mg of 3-(2-(2-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 3,5-ditrifluoromethyl to a 25ml egg-shaped bottle 1.1 molar equivalent of phenyl isothiocyanate, 3 ml of dichloromethane, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 58.9 mg, the yield was 89%.

¹ H NMR (400MHz, Acetone) δ9.49(brs, 1H), 8.30(s, 2H), 7.87(t, J=8.6Hz, 2H), 7.77(d, J=8.4Hz, 1H), 7.74( d, J=5.2Hz, 1H), 7.72(s, 1H), 7.69(brs, 1H), 7.60(dd, J=7.6, 1.6Hz, 1H), 7.47-7.38(m, 4H), 7.28(dd , J=8.8, 2.4Hz, 1H), 7.25-7.21(m, 2H), 7.03(dd, J=8.4, 0.8Hz, 1H), 6.67(brs, 1H), 3.75(q, J=6.0Hz, 2H), 3.20 (q, J=6.1Hz, 2H); ¹³ C NMR (100MHz, Acetone) δ18.7, 155.9, 155.2, 142.8, 141.4, 138.4, 135.3, 133.2, 133.0, 132.2, 131.8, 131.2, 131.1 , 130.9, 130.1, 128.6, 128.0, 127.5, 127.2, 125.7, 124.3, 123.7, 123.0, 120.6, 120.0, 114.8, 44.8, 42.9.

Example 122

3-(2-(2-naphthyl)phenyl)-N-(2-(3-(4-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide (H3-11 )

Add 38.9 mg of 3-(2-(2-naphthyl)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, 4-nitrophenyl isosulfur to a 25ml egg-shaped bottle 1.1 molar equivalent of cyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 50 mg, and the yield was 91%.

¹ H NMR (400MHz, Acetone) δ9.53(brs, 1H), 8.18(dd, J=7.2, 2.0Hz, 2H), 7.92-7.85(m, 4H), 7.77(d, J=7.6Hz, 1H ), 7.74(d, J=5.2Hz, 1H), 7.69(brs, 1H), 7.60(dd, J=7.4, 1.4Hz, 1H), 7.47-7.39(m, 4H), 7.28(dd, J= 9.2, 2.4Hz, 1H), 7.25-7.21(m, 2H), 7.03(dd, J=8.0, 0.8Hz, 1H), 6.68(d, J=6.0Hz, 1H), 3.76(q, J=5.9 Hz, 2H), 3.20 (q, J=6.1Hz, 2H); ¹³ C NMR (100MHz, Acetone) δ182.1, 155.9, 155.2, 146.8, 144.0, 141.4, 138.4, 135.3, 133.2, 133.0, 131.2, 131.1 , 130.9, 130.1, 128.6, 128.1, 127.5, 127.1, 125.7, 125.3, 124.4, 122.2, 120.6, 120.0, 114.8, 44.9, 42.9.

Example 123

2-(3,4-Dimethoxyphenoxy)nitrobenzene (A6)

Add 4.920g of 3,4-dimethoxyphenol, 4.130g of o-fluoronitrobenzene, 2.022g of 60% NaH, and 50ml of anhydrous tetrahydrofuran into a 250ml egg-shaped bottle, and reflux for 5h. Remove tetrahydrofuran, add 200ml of ethyl acetate, wash with 200ml of water × 3, dry, filter and concentrate, the product is 8.063g of yellow liquid, and the yield is 100%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.93 (dd, J=8.1, 1.6Hz, 1H), 7.46 (ddd, J=8.9, 7.4, 1.7Hz, 1H), 7.17-7.10 (m, 1H), 6.95(dd, J=8.4, 1.1Hz, 1H), 6.85(d, J=8.7Hz, 1H), 6.69(d, J=2.7Hz, 1H), 6.60(dd, J=8.7, 2.7Hz, 1H ), 3.89(s, 3H), 3.85(s, 3H); EI-MS m/z 275(M); EI-HRMS calcd. for C ₁₄ H ₁₃ NO ₅ (M) 275.0794, observed 275.0797.

Example 124

2-(3,4-Dimethoxyphenoxy)aminobenzene (B6)

Add 4.508g of 2-(3,4-dimethoxyphenoxy)nitrobenzene, 60ml of ethanol, 0.450g of Pd/C into a 250ml eggplant-shaped bottle, and finally add 7ml of hydrazine hydrate, and stir at room temperature for 5 hours. After filtering and distilling the solvent under reduced pressure, 200ml of ethyl acetate was added, washed with 100ml×2 water, dried, filtered, and concentrated to obtain 4.017g of a light yellow solid with a yield of 100%.

¹ H NMR (400MHz, CDCl ₃ ) δ6.94 (td, J=7.7, 1.4Hz, 1H), 6.80 (ddd, J=10.0, 6.3, 2.4Hz, 3H), 6.72-6.66 (m, 1H), 6.65 (d, J=2.7Hz, 1H), 6.48 (dd, J=8.7, 2.8Hz, 1H), 3.84 (d, J=9.3Hz, 8H); ¹³ C NMR (100MHz, CDCl ₃ ) δ151.1 , 150.0, 145.02(s, 1H), 145.1, 144.3, 138.2, 124.2, 118.8, 118.7, 116.3, 111.9, 108.8, 103.1, 56.4, 56.0.

Example 125

2-(3,4-Dimethoxyphenoxy)iodobenzene (C6)

Place a 500ml three-neck flask in an ice bath, add 4.095g of _2- (3,4-dimethoxyphenoxy)aminobenzene, 2.8ml of concentrated sulfuric acid, dilute and cool with 70ml of water, then add NaNO2 slowly under stirring Add 1.415g of water (20ml) solution in 10 minutes, then add Kl 3.943g of water (20ml) solution in 1 hour, move to room temperature and stir after half an hour. The reaction at room temperature was stopped after 4 hours, 100ml of water was added, extracted with CH ₂ Cl ₂ 100ml×3, combined, and washed once with saturated Na ₂ S ₂ O ₃ . After drying, filtering, concentrating, and column chromatography, 3.654 g of nearly colorless liquid was obtained with a yield of 61.5%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.84(dd, J=7.8, 1.5Hz, 1H), 7.26-7.22(m, 1H), 6.85-6.77(m, 3H), 6.66(d, J=2.7 Hz, 1H), 6.50(dd, J=8.7, 2.7Hz, 1H), 3.87(s, 3H), 3.85(s, 3H); ¹³ C NMR (100MHz, CDCl ₃ ) δ157.4, 150.3, 150.1, 145.7, 139.8, 129.5, 124.7, 117.8, 111.7, 110.4, 104.3, 87.7, 56.3, 56.0; EI-MSm/z 356(M); EI-HRMS _{calcd.for C14H13lO3} ( _M )355.9909, observed355 .9906.

Example 126

2-(3,4-Dimethoxyphenoxy)phenylboronic acid (D6)

Add 1.958g of 2-(3,4-dimethoxyphenoxy)iodobenzene to a 100ml reaction tube, add 50ml of anhydrous THF under the protection of argon after fully removing oxygen and water, and place in a -78°C cooling bath Slowly add 2.8ml of 2.5mol/L n-butyllithium solution dropwise, react for 1 hour, add 1.2ml of trimethyl borate at -78°C, and move the reaction tube to room temperature to stir after 2 hours. After stirring at room temperature for 2 h, 1 ml of concentrated hydrochloric acid was added, extracted with ethyl acetate, dried, filtered, and concentrated to obtain 0.827 g of white solid, with a yield of 54.9%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.91 (dd, J=7.4, 1.8Hz, 1H), 7.34 (ddd, J=8.4, 7.3, 1.9Hz, 1H), 7.10 (td, J=7.4, 0.8 Hz, 1H), 6.87(d, J=8.5Hz, 1H), 6.71-6.62(m, 3H), 5.74(s, 2H), 3.90(s, 3H), 3.85(s, 3H);

Example 127

3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(N-Bocamino)ethyl)-2-thienylsulfonamide (F6)

Add 0.789g of 3-bromo-N-(2-(N-Bocamino)ethyl)-2-thienylsulfonamide, 2-(3,4-dimethoxyphenoxy) to a 250ml Shrek tube Phenylboronic acid 0.613g, triphenylphosphine 112mg, palladium acetate 37mg, K ₃ PO ₄ 0.886g, after fully deoxygenated, add THF 50ml, water 5ml, reflux for 8 hours, stop heating and stirring. Add 100ml of water, extract with 100ml of ethyl acetate x 2, dry, filter, concentrate, and perform column chromatography to obtain 0.769g of yellow floc with a yield of 70.2%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.51(d, J=5.1Hz, 1H), 7.48(dd, J=7.6, 1.7Hz, 1H), 7.37-7.31(m, 1H), 7.16(td, J=7.5, 1.1Hz, 1H), 7.10(d, J=5.1Hz, 1H), 6.90(d, J=8.3Hz, 1H), 6.79(d, J=8.7Hz, 1H), 6.60(d, J=2.7Hz, 1H), 6.51(dd, J=8.7, 2.7Hz, 1H), 4.78(d, J=5.8Hz, 2H), 3.86(s, 3H), 3.81(s, 3H), 3.17- 3.11(m, 2H), 3.04(dd, J=11.5, 5.6Hz, 2H), 1.40(s, 9H); ESI-MS m/z557.2(M+Na) ⁺ ; MALDI-HRMS calcd.for C ₂₅ H ₃₀ N ₂ O ₇ S ₂ Na(M+Na) ⁺ 557.1387, observed 557.1391.

Example 128

3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide (G6)

Add 745mg of 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(N-Bocamino)ethyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle , CH ₂ Cl ₂ 10ml, CF ₃ CO ₂ H 1.0ml, stirred at room temperature for 12 hours. Add potassium carbonate to neutralize CF ₃ CO ₂ H to make it alkaline, add water, extract with CH ₂ Cl ₂ 60ml×3, dry, filter, and concentrate to obtain 545mg of yellow solid with a yield of 90%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.51(q, J=2.1Hz, 2H), 7.36-7.29(m, 1H), 7.15(td, J=7.5, 1.1Hz, 1H), 7.11(d, J=5.1Hz, 1H), 6.89(dd, J=8.3, 0.9Hz, 1H), 6.79(d, J=8.7Hz, 1H), 6.61(d, J=2.7Hz, 1H), 6.52(dd, J=8.7, 2.7Hz, 1H), 3.86(s, 3H), 3.81(s, 3H), 2.98-2.93(m, 2H), 2.74-2.68(m, 2H); ESI-MS m/z 435.4 (M+H) ⁺ ; MALDI-H RMS calcd. for C ₂₀ H ₂₃ N ₂ O ₅ S ₂ (M+H) ⁺ 435.1043, observed 435.1038.

Example 129

3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(3-(4-methoxyphenyl)ureido)ethyl)-2-thienyl Sulfonamide (H6-1)

Add 43.0mg of 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 4-methyl 1.1 molar equivalent of oxyphenyl isocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 52.9 mg, yield 91.5%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.48(t, J=5.6Hz, 2H), 7.31(td, J=7.9, 1.4Hz, 1H), 7.15-7.12(m, 3H), 7.10(d, J=5.2Hz, 1H), 6.88(d, J=7.6Hz, 1H), 6.81(d, J=8.8Hz, 2H), 6.76(d, J=8.4Hz, 1H), 6.58(d, J= 1.6Hz, 1H), 6.49(dd, J=8.8, 2.8Hz, 1H), 6.32(brs, 1H), 5.13(d, J=5.6Hz, 1H), 5.02(d, J=4.4Hz, 1H) , 3.83(s, 3H), 3.78(s, 3H), 3.77(s, 3H), 3.25(q, J=5.6Hz, 2H), 3.04(q, J=5.7Hz, 2H); ¹³ C NMR ( 100MHz, CDCl ₃ ) δ156.8, 156.2, 155.3, 150.4, 150.0, 145.6, 140.9, 136.4, 131.9, 131.7, 131.4, 130.2, 129.1, 124.9, 123.0, 122.9, 117.5, 114.3, 110.3, 111.9 , 56.1, 55.5, 43.9, 39.9; ESI-MS m/z584.4(M+H) ⁺ , 606.4(M+Na) ⁺ ; MALDI-HRMS calcd.for C ₂₈ H ₂₉ N ₃ O ₇ S ₂ Na( M+Na) ⁺ 606.1339, observed 606.1335.

Example 130

3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)ureido)ethyl)- 2-Thienylsulfonamide (H6-2)

Add 42.7mg of 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 3,5 - Ditrifluoromethylphenyl isocyanate 1.1 molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 59.1 mg, the yield was 87.2%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.77(s, 2H), 7.54(d, J=4.8Hz, 1H), 7.43(d, J=8.4Hz, 2H), 7.31(td, J=7.9, 1.6Hz, 1H), 7.17-7.11(m, 3H), 6.90(d, J=8.0Hz, 1H), 6.77(d, J=8.4Hz, 1H), 6.55(d, J=2.8Hz, 1H) , 6.49(dd, J=9.0, 2.6Hz, 1H), 5.43(brs, 1H), 5.10(brs, 1H), 3.82(s, 3H), 3.77(s, 3H), 3.31(q, J=5.3 Hz, 2H), 3.09 (q, J=5.5Hz, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ155.2, 155.0, 150.1, 145.8, 141.6, 140.9, 135.2, 132.2, 132.1, 131.8, 131.5, 130.5, 129.8, 124.6, 123.0, 121.9, 118.0, 117.9, 115.3, 112.0, 110.5, 104.2, 56.3, 56.0, 43.6, 39.6; ESI-MS m/z 690.4(M+H) ⁺ , 712.4(M+Na) ⁺ ; MALDI-HRMS calcd. for C ₂₉ H ₂₅ N ₃ O ₆ F ₆ S ₂ Na(M+Na) ⁺ 712.0981, observed 712.0989.

Example 131

3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(3-(3-nitrophenyl)ureido)ethyl)-2-thienylsulfonyl Amide (H6-3)

Add 41.0mg of 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 3-nitro 1.1 molar equivalents of phenyl isocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 54.5 mg, the yield was 96.5%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.13 (t, J=2.2Hz, 1H), 7.74 (dd, J=8.2, 1.8Hz, 1H), 7.59 (dd, J=8.2, 1.0Hz, 1H) , 7.53(d, J=5.2Hz, 1H), 7.44(dd, J=7.6, 1.6Hz, 1H), 7.30(t, J=8.4Hz, 2H), 7.20(s, 1H), 7.14-7.09( m, 2H), 6.89(d, J=8.0Hz, 1H), 6.77(d, J=8.8Hz, 1H), 6.56(d, J=2.4Hz, 1H), 5.47(t, J=5.6Hz, 1H), 5.25(t, J=6.0Hz, 1H), 3.82(s, 3H), 3.77(s, 3H), 3.31(q, J=5.5Hz, 2H), 3.09(q, J=5.6Hz, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ155.4, 155.2, 150.3, 150.0, 148.4, 145.7, 141.4, 140.5, 135.6, 132.1, 131.6, 130.4, 129.6, 129.4, 124.7, 124.4, 127.8, 127.9, 116.8, 113.2, 112.0, 110.5, 104.3, 56.3, 56.1, 43.8, 39.7; ESI-MS m/z 599.3(M+H) ⁺ , 621.4(M+Na) ⁺ ; MALDI-HRMS calcd.for C ₂₇ H ₂₆ N ₄ O ₈ S ₂ Na(M+Na) ⁺ 621.1084, observed 621.1074.

Example 132

3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(3-(3,5-dichlorophenyl)ureido)ethyl)-2-thiophene Sulfonamide (H6-4)

Add 40.1mg of 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 3,5 - 1.1 molar equivalents of dichlorophenyl isocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 52.2 mg, the yield was 91.3%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.54(d, J=5.2Hz, 1H), 7.42(dd, J=7.6, 1.6Hz, 1H), 7.33-7.28(m, 1H), 7.19(d, J=1.6Hz, 2H), 7.14-7.10(m, 2H), 6.92-6.87(m, 3H), 6.76(d, J=8.8Hz, 1H), 6.55(d, J=2.4Hz, 1H), 6.48(dd, J=8.8, 2.8Hz, 1H), 5.41(s, 1H), 5.21(s, 1H), 3.82(s, 3H), 3.77(s, 3H), 3.27(t, J=5.0Hz , 2H), 3.07 (t, J=4.8Hz, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ155.2, 155.2, 150.2, 150.1, 145.8, 141.4, 141.2, 135.5, 134.9, 132.1, 131.5, 130.4 , 129.7, 124.7, 123.0, 122.2, 117.8, 116.9, 112.0, 110.5, 104.3, 56.3, 56.1, 43.7, 39.7; ESI-MS m/z 622.3(M+H) ⁺ , 644.1(M+Na) ⁺ ; MALDI -HRMS calcd. for C ₂₇ H ₂₅ N ₃ O ₆ S ₂ Cl ₂ Na(M+Na) ⁺ 644.0454, observed 644.0460.

Example 133

3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(3-(4-nitrophenyl)ureido)ethyl)-2-thienylsulfonyl Amide (H6-5)

Add 41.7mg of 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 4-nitro 1.1 molar equivalents of phenyl isocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 53.9 mg, the yield was 93.7%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.05 (d, J=9.2Hz, 2H), 7.55 (d, J=5.2Hz, 1H), 7.42 (dd, J=7.6, 1.6Hz, 1H), 7.38 (dd, J=9.2, 3.0Hz, 2H), 7.35-7.29(m, 2H), 7.15-7.10(m, 2H), 6.90(d, J=7.6Hz, 1H), 6.76(d, J=8.8 Hz, 1H), 6.54(d, J=2.8Hz, 1H), 6.48(dd, J=8.8, 2.8Hz, 1H), 5.50(t, J=5.8Hz, 1H), 5.17(t, J=6.2 Hz, 1H), 3.83(s, 3H), 3.77(s, 3H), 3.30(q, J=5.3Hz, 2H), 3.09(q, J=5.5Hz, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ155.2, 154.9, 150.2, 150.1, 145.8, 141.8, 141.5, 135.4, 132.2, 131.6, 130.4, 129.7, 125.1, 124.7, 123.0, 117.9, 117.4, 112.0, 110.5, 104.3, 66 39.7; ESI-MS m/z _599.2 (M+H) ⁺ , 621.2(M ₊ Na) ⁺ ; MALDI-HRMS calcd. for _{C27H26N4O8S2Na} (M ₊ Na) ⁺ _621.1084 , observed 621.1094.

Example 134

3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(3-(4-methoxyphenyl)thioureido)ethyl)-2-thiophene Sulfonamide (H6-6)

Add 41.8mg of 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 4-methyl 1.1 molar equivalents of oxyphenyl isothiocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 45.6 mg, the yield was 79.0%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.51(d, J=5.2Hz, 1H), 7.49(brs, 1H), 7.46(dd, J=7.6, 1.6Hz, 1H), 7.33(td, J= 7.9, 1.4Hz, 1H), 7.17-7.10(m, 4H), 6.94-6.89(m, 3H), 6.79(d, J=8.4Hz, 1H), 6.57(d, J=2.4Hz, 1H), 6.49(dd, J=8.8, 2.8Hz, 1H), 6.17(t, J=5.4Hz, 1H), 4.86(t, J=4.0Hz, 1H), 3.85(s, 3H), 3.81(d, J =1.6Hz, 6H), 3.70(q, J=5.7Hz, 2H), 3.14(q, J=5.9Hz, 2H); ¹³ CNMR(100MHz, CDCl ₃ ) δ181.6, 159.0, 155.2, 150.3, 150.1 , 145.7, 140.9, 136.2, 131.9, 131.7, 130.3, 129.1, 128.4, 127.6, 124.8, 122.9, 117.8, 115.4, 111.9, 110.4, 104.3, 56.3, 56.1, 55.6, 44.5, 40.8/z MS6 (M+H) ⁺ , 622.4(M+Na) ⁺ ; MALDI-HRMS calcd. for C ₂₈ H ₃₀ N ₃ O ₆ S ₃ (M+H) ⁺ 600.1291, observed 600.1295.

Example 135

3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)thioureido)ethyl) -2-Thienylsulfonamide (H6-7)

Add 42.7mg of 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 3,5 - Ditrifluoromethylphenyl isothiocyanate 1.1 molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 66.0 mg, yield 95.1%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.98(brs, 1H), 7.88(s, 2H), 7.64(s, 1H), 7.55(d, J=4.8Hz, 1H), 7.41(d, J= 7.6Hz, 1H), 7.33(t, J=7.8Hz, 1H), 7.15-7.13(m, 2H), 6.91(d, J=8.4Hz, 1H), 6.78(d, J=8.4Hz, 2H) , 6.53(d, J=2.8Hz, 1H), 6.47(dd, J=8.8, 2.8Hz, 1H), 5.07(d, J=5.6Hz, 1H), 3.84(s, 3H), 3.78(s, 3H), 3.72(q, J=5.3Hz, 2H), 3.16(q, J=5.6Hz, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ181.5, 155.2, 150.1, 145.8, 141.7, 140.0, 134.8, 132.2, 132.1, 131.8, 131.5, 130.5, 130.0, 124.6, 123.5, 123.0, 121.7, 118.4, 118.0, 112.1, 110.4, 104.2, 56.3, 56.1, 44.0, 42.6; ESI-MS m/z 7 H) ⁺ , 628.4(M+Na) ⁺ ; MALDI-HRMS calcd. for C ₂₉ H ₂₅ N ₃ O ₅ F ₆ S ₃ Na(M+Na) ⁺ 728.0753, observed 728.0767.

Example 136

3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(3-(4-nitrophenyl)thioureido)ethyl)-2-thienyl Sulfonamide (H6-8)

Add 41.9mg of 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 4-nitro 1.1 molar equivalents of phenyl isothiocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 57.7 mg, yield 97.3%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.18(dd, J=7.2, 2.0Hz, 1H), 8.06(brs, 1H), 7.56(d, J=5.2Hz, 1H), 7.51(d, J= 9.2Hz, 2H), 7.43(dd, J=7.6, 1.6Hz, 1H), 7.35(td, J=7.9, 1.8Hz, 1H), 7.17-7.12(m, 2H), 6.91(d, J=8.4 Hz, 1H), 6.87(t, J=5.2Hz, 1H), 6.79(d, J=8.8Hz, 1H), 6.54(d, J=2.8Hz, 1H), 6.47(dd, J=8.8, 2.8 Hz, 1H), 5.08(t, J=6.0Hz, 1H), 3.85(s, 3H), 3.79(s, 3H), 3.73(q, J=5.7Hz, 2H), 3.19(q, J=5.6 Hz, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ180.7, 155.2, 150.2, 150.1, 145.8, 144.0, 143.9, 141.6, 135.1, 132.2, 131.6, 130.5, 129.9, 124.9, 124.6, 123.0, 122. 117.9, 112.1, 110.4, 104.2, 56.4, 56.2, 44.2, 42.6; ESI-MS m/z 615.4(M+H) ⁺ , 637.3(M+Na) ⁺ ; MALDI _- HRMS _{calcd.for C27H26N4O 7} S ₃ Na(M+Na) ⁺ 637.0856, observed 637.0845.

Example 137

3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(3-phenylthioureido)ethyl)-2-thienylsulfonamide (H6-9 )

Add 42.5mg of 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, phenyliso Thiocyanate 1.1 molar equivalent, dichloromethane 3ml, stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 55.5 mg, the yield was 99.6%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.61(s, 1H), 7.51(d, J=5.2Hz, 1H), 7.47-7.41(m, 3H), 7.36-7.28(m, 2H), 7.19( d, J=7.6Hz, 2H), 7.15(td, J=7.5, 1.1Hz, 1H), 7.11(d, J=5.2Hz, 1H), 6.89(dd, J=8.0, 1.0Hz, 1H), 6.79(d, J=8.8Hz, 1H), 6.57(d, J=2.8Hz, 1H), 6.49(dd, J=8.8, 2.8Hz, 1H), 6.38(t, J=5.2Hz, 1H), 4.85(t, J=6.0Hz, 1H), 3.85(s, 3H), 3.81(s, 3H), 3.72(q, J=5.7Hz, 2H), 3.16(q, J=5.9Hz, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ181.1, 155.2, 150.3, 150.1, 145.7, 140.9, 136.1, 131.9, 131.7, 130.3, 130.1, 129.2, 127.3, 127.2, 125.1, 124.8, 122.9, 1104.0, , 104.3; ESI-MS m/z 570.5(M+H) ⁺ , 592.3(M+Na) ⁺ ; MALDI-HRMS calcd. for C ₂₇ H ₂₈ N ₃ O ₅ S ₃ (M+H) ⁺ 570.1186, observed 570.1189.

Example 138

3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(3-(3-nitrophenyl)thioureido)ethyl)-2-thienyl Sulfonamide (H6-10)

Add 40.7mg of 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 3-nitro 1.1 molar equivalents of phenyl isocyanate, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 56.1 mg, the yield was 97.4%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.17(s, 1H), 8.05(dd, J=8.4, 2.0Hz, 1H), 7.81(s, 1H), 7.69(d, J=8.0Hz, 1H) , 7.55-7.51(m, 2H), 7.43(dd, J=7.8, 1.8Hz, 1H), 7.37-7.31(m, 1H), 7.15(td, J=7.5, 1.1Hz, 1H), 7.11(d , J=4.8Hz, 1H), 6.91(dd, J=8.4, 1.2Hz, 1H), 6.79(d, J=8.4Hz, 1H), 6.68(s, 1H), 6.54(d, J=2.8Hz , 1H), 6.47(dd, J=8.4, 2.8Hz, 1H), 4.98(t, J=5.8Hz, 1H), 3.85(s, 3H), 3.80(s, 3H), 3.72(q, J= 5.5Hz, 2H), 3.16 (q, J=5.7Hz, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ181.4, 155.2, 150.2, 150.1, 148.4, 145.7, 141.4, 139.0, 135.2, 132.1, 131.6 , 130.4, 130.0, 129.9, 129.8, 124.6, 123.0, 120.2, 118.8, 117.9, 112.0, 110.4, 104.2, 56.4, 56.2, 44.3, 42.6; ESI-MS m/z 615.3(M+H) ⁺ , 637.2(M +Na) ⁺ ; MALDI-H RMS calcd. for C ₂₇ H ₂₆ N ₄ O ₇ S ₃ Na 637.0856(M+Na) ⁺ , observed 637.0849.

Example 139

3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(4-nitrobenzenesulfonamido)ethyl)-2-thienylsulfonamide (I6- 1)

Add 43.0mg of 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide to a 25ml egg-shaped bottle, 4-nitro 1.1 molar equivalents of phenylsulfonyl chloride and triethylamine each, 3 ml of dichloromethane, and stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 59.4 mg, the yield was 96.7%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.33(d, J=9.2Hz, 2H), 7.98(d, J=8.8Hz, 2H), 7.55(d, J=5.2Hz, 1H), 7.44(d , J=7.6Hz, 1H), 7.36(t, J=8.4Hz, 1H), 7.17(t, J=7.6Hz, 1H), 7.11(d, J=5.2Hz, 1H), 6.92(d, J =8.0Hz, 1H), 6.80(d, J=8.8Hz, 1H), 6.56(d, J=2.4Hz, 1H), 6.48(dd, J=8.8, 2.8Hz, 1H), 5.10(t, J =5.8Hz, 1H), 4.76(t, J=5.8Hz, 1H), 3.87(s, 3H), 3.81(s, 3H), 3.06(t, J=6.0Hz, 2H), 3.03(t, J =5.8Hz, 2H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ156.7, 151.4, 151.2, 150.9, 147.3, 147.0, 141.7, 138.3, 133.2, 132.9, 130.8, 130.1, 129.2, 125.7, 125.3, 123.1, 117.9, 113.5, 111.7, 105.8, 56.6, 56.2, 43.8, 43.7; ESI-MSm/z 620.3(M+H) ⁺ , 642.1(M+Na) ⁺ ; MALDI-HRMS calcd.for C ₂₆ H ₂₅ N ₃ O ₉ S ₃ Na(M+Na) ⁺ 642.0645, observed 642.0646.

Example 140

3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(acetamidoethyl)-2-thienyl-N-sulfonylacetamide (I6-2 )

Add 43.3mg of 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide, acetic anhydride, 1.1 molar equivalents of triethylamine and 3 ml of dichloromethane were stirred at room temperature for 5 hours. PE: ethyl acetate = 1:2 column chromatography, the product was collected to obtain 51.7 mg, and the yield was 100%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.65(d, J=4.8Hz, 1H), 7.36-7.29(m, 2H), 7.14-7.10(m, 2H), 6.80(d, J=8.4Hz, 1H), 6.77(d, J=8.0Hz, 1H), 6.58(d, J=2.8Hz, 1H), 6.50(dd, J=8.6, 2.6Hz, 1H), 5.82(s, 1H), 3.86( s, 3H), 3.84 (s, 3H), 3.32-3.27 (m, 4H), 2.16 (s, 3H), 1.94 (s, 3H); ¹³ C NMR (100MHz, CDCl ₃ ) δ170.6, 170.4, 156.0, 150.1, 149.3, 146.1, 143.1, 136.2, 132.2, 131.7, 131.1, 130.8, 122.8, 122.3, 116.2, 111.8, 111.4, 104.9, 56.3, 56.1, 45.5, 38.9, 24.5, 23.2;

Example 141

2-(3,4-Dihydroxyphenoxy)iodobenzene (J)

Add 2.899 g of 2-(3,4-dimethoxyphenoxy) iodobenzene and 100 ml of dichloromethane into a 250 ml eggplant-shaped bottle, place the eggplant-shaped bottle in an ice bath, and slowly add 1 mol of /L of boron tribromide solution, rose to room temperature after the dropwise addition, and stirred for 6 hours. Slowly add 100ml of water to quench the reaction. Dichloromethane extraction, each 50ml. Dichloromethane was washed with saturated brine, dried, filtered, concentrated, and column chromatographed to obtain 2.671 g of an orange-yellow oily liquid with a yield of 100%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.87-7.80(m, 1H), 7.25-7.21(m, 1H), 6.87-6.78(m, 3H), 6.58(d, J=2.7Hz, 1H), 6.46(dd, J=8.6, 2.8Hz, 1H), 5.44(s, 1H), 5.07(s, 1H);

Example 142

2-(3,4-bis(tert-butyldimethylsilyloxy)phenoxy)iodobenzene (C7)

Add 2.671g of 2-(3,4-dihydroxyphenoxy)iodobenzene, 40ml of dichloromethane, 2.0g of imidazole, and 3.524g of 3,4-tert-butyldimethylsilyl chloride into a 100ml eggplant-shaped bottle, and stir at room temperature After 3 hours, add 100ml of water, extract twice with dichloromethane, 75ml each time, combine the dichloromethane solution, wash with saturated brine, dry, filter, concentrate, and column chromatography to obtain 4.189g of orange-red oily liquid, yield 92.5%

¹ H NMR (400MHz, CDCl ₃ ) δ7.83(dd, J=7.8, 1.5Hz, 1H), 7.25-7.20(m, 1H), 6.84-6.75(m, 3H), 6.48(dt, J=8.5 , 2.8Hz, 2H), 0.99(s, 9H), 0.96(s, 9H), 0.19(s, 6H), 0.17(s, 6H); ¹³ C NMR (100MHz, CDCl ₃ ) δ157.5, 150.3, 147.6, 143.5, 139.8, 129.5, 124.6, 121.3, 118.1, 112.7, 111.9, 87.9, 26.0, 25.9, 18.4, -4.1, -4.1;

Example 143

2-(3,4-Bis(tert-butyldimethylsilyloxy)phenoxy)phenylboronic acid (D7)

Add 2-(3,4-bis(tert-butyldimethylsilyloxy)phenoxy)iodobenzene 2.462g into a 100ml reaction tube, add anhydrous THF 50ml under the protection of argon after fully removing oxygen and water 2.3ml of 2.5mol/L n-butyllithium solution was slowly added dropwise in a cold bath at -78°C. After reacting for 1 hour, 0.9ml of trimethyl borate was added at -78°C. After 2h, the reaction tube was moved to room temperature and stirred. After stirring at room temperature for 2 h, 1 ml of concentrated hydrochloric acid was added, extracted with ethyl acetate, dried, filtered, and concentrated to obtain 2.0271 g of a yellow solid, with a yield of 96.6%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.89(dd, J=7.4, 1.8Hz, 1H), 7.38-7.31(m, 1H), 7.08(td, J=7.3, 0.8Hz, 1H), 6.82( d, J=8.5Hz, 1H), 6.67(d, J=8.3Hz, 1H), 6.57(dt, J=8.5, 2.8Hz, 2H), 5.69(s, 2H), 1.00(s, 9H), 0.96(s, 9H), 0.21(s, 6H), 0.18(s, 6H);

Example 144

3-(2-(3,4-bis(tert-butyldimethylsilyloxy)phenoxy)phenyl)-N-(2-(N-Bocamino)ethyl)-2-thienylsulfonyl Amide (F7)

Add 0.843g of 3-bromo-N-(2-(N-Bocamino)ethyl)-2-thienylsulfonamide, 2-(3,4-di(tert-butyldimethyl Silyloxy)phenoxy)phenylboronic acid 1.097g, triphenylphosphine 248mg, palladium acetate 85mg, K ₃ PO ₄ 1.049g, add THF 30ml, water 5ml, reflux for 8 hours, stop heating Stir. Add 100ml of water, extract with 100ml of ethyl acetate x 2, dry, filter, concentrate, and perform column chromatography to obtain 1.128g of yellow floc with a yield of 70.1%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.48(dd, J=9.9, 3.4Hz, 2H), 7.37-7.30(m, 1H), 7.18-7.12(m, 1H), 7.06(d, J=5.1 Hz, 1H), 6.89(d, J=8.0Hz, 1H), 6.75(d, J=8.6Hz, 1H), 6.44(dt, J=8.6, 2.9Hz, 2H), 4.74(s, 2H), 3.13(d, J=5.4Hz, 2H), 3.04(t, J=5.8Hz, 2H), 1.41(s, 9H), 0.98(s, 9H), 0.95(s, 9H), 0.18(s, 6H ), 0.15(s, 6H); ESI-MS m/z 757.4(M+Na) ⁺ ; ESI-HRMS calcd. for C ₃₅ H ₅₄ N ₂ O ₇ S ₂ Si ₂ Na 757.2803(M+Na) ⁺ , observed 757.2796.

Example 145

3-(2-(3,4-bis(tert-butyldimethylsilyloxy)phenoxy)phenyl)-N-(2-aminoethyl)-2-thienylsulfonamide (G7)

Add 3-(2-(3,4-bis(tert-butyldimethylsilyloxy)phenoxy)phenyl)-N-(2-(N-Bocamino)ethyl) to a 25ml egg-shaped bottle - 411 mg of 2-thienylsulfonamide, 5 ml of CH ₂ Cl ₂ , 0.6 ml of CF ₃ CO ₂ H, stirred at room temperature for 12 hours. Add potassium carbonate to neutralize CF ₃ CO ₂ H to make it alkaline, add water, extract with CH ₂ Cl ₂ 60ml×3, dry, filter, and concentrate to obtain 354mg of yellow solid with a yield of 100%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.53-7.47(m, 2H), 7.34-7.29(m, 1H), 7.14(td, J=7.5, 1.0Hz, 1H), 7.08(d, J=5.1 Hz, 1H), 6.87(dd, J=8.3, 0.8Hz, 1H), 6.75(d, J=8.6Hz, 1H), 6.48(d, J=2.9Hz, 1H), 6.44(dd, J=8.6 , 2.9Hz, 1H), 2.97-2.90(m, 2H), 2.76-2.63(m, 2H), 0.98(s, 9H), 0.95(s, 9H), 0.18(s, 6H), 0.16(s, 6H);

Example 146

3-(2-(3,4-dihydroxyphenoxy)phenyl)-N-(2-(3-(4-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide (H7-1)

Add 3-(2-(3,4-bis(tert-butyldimethylsilyloxy)phenoxy)phenyl)-N-(2-aminoethyl)-2-thienyl to a 25ml egg-shaped bottle Sulfonamide 70.5mg, 4-methoxyphenyl isocyanate 1.1 molar equivalent, dichloromethane 3ml, after stirring at room temperature for 5 hours, dichloromethane was distilled off under reduced pressure, acetonitrile 2ml was added to the system, and then 40% hydrogen fluoride aqueous solution was added 0.1ml, react at room temperature for 12 hours. PE: ethyl acetate = 1:1 column chromatography, the product was collected to obtain 55.5 mg, and the yield was 90.0%.

¹ H NMR (400MHz, Acetone) δ8.28(s, 1H), 7.81(s, 1H), 7.75(d, J=4.8Hz, 1H), 7.62(s, 1H), 7.47(dd, J=7.6 , 1.6Hz, 1H), 7.33-7.28(m, 3H), 7.20(d, J=4.8Hz, 1H), 7.07(td, J=7.5, 1.1Hz, 1H), 6.83-6.80(m, 3H) , 6.77(d, J=8.8Hz, 1H), 6.60(d, J=3.2Hz, 1H), 6.49(t, J=6.0Hz, 1H), 6.41(dd, J=8.8, 2.8Hz, 1H) , 5.89(t, J=5.4Hz, 1H), 3.74(s, 3H), 3.29(q, J=6.0Hz, 2H), 3.01(q, J=6.0Hz, 2H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ156.5, 155.9, 155.4, 149.4, 146.0, 141.8, 140.7, 137.5, 132.9, 132.2, 132.0, 129.8, 128.8, 124.9, 122.1, 121.1, 117.1, 115.5, 117.6, 103.9, 10 , 43.9, 39.6; ESI-MS m/z 556.3(M+H) ⁺ , 578.2(M+Na) ⁺ ; HRMS calcd. for C ₂₆ H ₂₅ N ₃ O ₇ S ₂ Na(M+Na) ⁺ 578.1046 , observed 578.1026.

Example 147

3-(2-(3,4-dihydroxyphenoxy)phenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)ureido)ethyl)-2- Thienylsulfonamide (H7-2)

Add 3-(2-(3,4-bis(tert-butyldimethylsilyloxy)phenoxy)phenyl)-N-(2-aminoethyl)-2-thienyl to a 25ml egg-shaped bottle Sulfonamide 85.2 mg, 3,5-ditrifluoromethylphenyl isocyanate 1.1 molar equivalent, dichloromethane 3ml, after stirring at room temperature for 5 hours, dichloromethane was distilled off under reduced pressure, 2ml of acetonitrile was added to the system, and then 1mol /L tetrahydrofuran aqueous solution of n-butylamine fluoride 0.2ml, react at room temperature for 12 hours. PE: ethyl acetate = 1:1 column chromatography, the product was collected to obtain 25 mg, and the yield was 28.2%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.64(s, 2H), 7.56(d, J=4.8Hz, 1H), 7.52(s, 1H), 7.43(s, 2H), 7.36(dd, J= 7.6, 1.6Hz, 1H), 7.26-7.22(m, 1H), 7.15(d, J=5.2Hz, 1H), 7.06(td, J=7.5, 1.5Hz, 1H), 6.87(d, J=7.6 Hz, 1H), 6.74(d, J=8.4Hz, 1H), 6.49(d, J=2.8Hz, 1H), 6.30(dd, J=8.6, 2.6Hz, 1H), 5.73(t, J=5.8 Hz, 2H), 5.37(t, J=6.4Hz, 1H), 3.30(q, J=5.5Hz, 2H), 3.05(q, J=5.9Hz, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ155.7, 154.9, 149.3, 144.8, 142.0, 140.9, 140.1, 134.3, 132.5, 132.2, 131.8, 131.5, 130.4, 130.0, 124.6, 123.0, 121.8, 118.7, 115.7, 110.3, 430.7, IES MS m/z 662.4(M+H) ⁺ , _684.4 ( _M +Na) ⁺ ; HRMS calcd. for _{C27H21N3O6F6S2Na} (M ₊ Na) ⁺ _684.0668 , observed _684.0682 .

Example 148

3-(2-(3,4-dihydroxyphenoxy)phenyl)-N-(2-(3-(4-nitrophenyl)ureido)ethyl)-2-thienylsulfonamide ( H7-3)

Add 3-(2-(3,4-bis(tert-butyldimethylsilyloxy)phenoxy)phenyl)-N-(2-aminoethyl)-2-thienyl to a 25ml egg-shaped bottle Sulfonamide 70.5 mg, 4-nitrophenyl isocyanate 1.1 molar equivalent, dichloromethane 3ml, after stirring at room temperature for 5 hours, dichloromethane was distilled off under reduced pressure, acetonitrile 2ml was added to the system, and 40% hydrogen fluoride aqueous solution 0.1 ml, react at room temperature for 12 hours. PE: ethyl acetate = 1:1 column chromatography, the product was collected to obtain 22.3 mg, the yield was 35.2%.

¹ H NMR (400MHz, Acetone) δ8.73(s, 1H), 8.14(d, J=9.2Hz, 2H), 8.07(s, 1H), 7.80(s, 1H), 7.76(d, J=4.8 Hz, 1H), 7.70(d, J=9.6Hz, 2H), 7.47(dd, J=7.4, 1.4Hz, 1H), 7.33-7.28(m, 1H), 7.20(d, J=4.8Hz, 1H ), 7.08(t, J=7.6Hz, 1H), 6.82(d, J=8.4Hz, 1H), 6.78(d, J=8.8Hz, 1H), 6.59(d, J=2.8Hz, 1H), 6.46(t, J=6.2Hz, 1H), 6.42(dd, J=8.4, 2.8Hz, 1H), 6.18(s, 1H), 3.33(q, J=5.9Hz, 2H), 3.06(q, J =6.0Hz, 2H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ155.9, 154.8, 149.4, 146.9, 146.0, 141.7, 141.6, 140.8, 137.4, 132.2, 131.9, 129.8, 128.9, 124.9, 124.8, 122.0, 117.3, 117.0, 115.5, 110.7, 107.6, 43.3, 39.6; ESI-MS m/z _571.4 (M+H) ⁺ , 593.4(M ₊ Na) ⁺ ; _{HRMS calcd.forC25H22N4O8F 6} S ₂ Na(M+Na) ⁺ 593.0774, observed 593.0771.

Example 149

3-(2-(3,4-dihydroxyphenoxy)phenyl)-N-(2-(3-(3,5-dichlorophenyl)ureido)ethyl)-2-thienylsulfonyl Amide (H7-4)

Add 3-(2-(3,4-bis(tert-butyldimethylsilyloxy)phenoxy)phenyl)-N-(2-aminoethyl)-2-thienyl to a 25ml egg-shaped bottle Sulfonamide 70.9 mg, 3,5-dichlorophenyl isocyanate 1.1 molar equivalent, dichloromethane 3ml, after stirring at room temperature for 5 hours, dichloromethane was distilled off under reduced pressure, 2ml of acetonitrile was added to the system, and then 40% hydrogen fluoride was added Aqueous solution 0.1ml, react at room temperature for 12 hours. PE: ethyl acetate = 1:1 column chromatography, the product was collected to obtain 45.9 mg, the yield was 69.1%.

¹ H NMR (400MHz, Acetone) δ8.37(s, 1H), 8.07(s, 1H), 7.76(d, J=5.2Hz, 2H), 7.52(d, J=2.0Hz, 2H), 7.47( dd, J=7.6, 1.6Hz, 1H), 7.33-7.27(m, 1H), 7.19(d, J=5.2Hz, 1H), 7.08(td, J=7.5, 1.1Hz, 1H), 7.00(t , J=2.0Hz, 1H), 6.82(dd, J=8.4, 0.8Hz, 1H), 6.78(d, J=8.4Hz, 1H), 6.58(d, J=2.8Hz, 1H), 6.47-6.40 (m, 2H), 6.07(s, 1H), 3.30(q, J=5.7Hz, 2H), 3.04(q, J=6.0Hz, 2H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ155. 9, 155.1, 149.5, 146.0, 142.9, 141.7, 140.8, 137.4, 134.6, 132.2, 131.9, 129.8, 128.9, 124.9, 122.0, 120.8, 117.1, 116.3, 115.6, 110.7, 107.6, 93.5 m; /z 594.3(M+H) ⁺ , 616.3(M+Na) ⁺ ; HRMS calcd. for C ₂₅ H ₂₁ N ₃ O ₆ S ₂ ClNa (M+Na) ⁺ 616.0146, observed 616.0141.

Example 150

3-(2-(3,4-dihydroxyphenoxy)phenyl)-N-(2-(3-(3-nitrophenyl)ureido)ethyl)-2-thienylsulfonamide ( H7-5)

Add 3-(2-(3,4-bis(tert-butyldimethylsilyloxy)phenoxy)phenyl)-N-(2-aminoethyl)-2-thienyl to a 25ml egg-shaped bottle Sulfonamide 71.8mg, 3-nitrophenyl isocyanate 1.1 molar equivalent, dichloromethane 3ml, after stirring at room temperature for 5 hours, dichloromethane was distilled off under reduced pressure, acetonitrile 2ml was added to the system, and 40% hydrogen fluoride aqueous solution 0.1 ml, react at room temperature for 12 hours. PE: ethyl acetate = 1:1 column chromatography, the product was collected to obtain 53.1 mg, the yield was 82.3%.

¹ H NMR (400MHz, Acetone) δ8.56(t, J=2.0Hz, 1H), 8.52(s, 1H), 8.07(s, 1H), 7.80-7.72(m, 4H), 7.52-7.46(m , 2H), 7.32-7.28(m, 1H), 7.19(d, J=5.2Hz, 1H), 7.08(td, J=7.2, 0.9Hz, 1H), 6.82(dd, J=8.4, 0.8Hz, 1H), 6.77(d, J=8.8Hz, 1H), 6.58(d, J=2.8Hz, 1H), 6.46(t, J=6.0Hz, 1H), 6.42(dd, J=8.4, 2.8Hz, 1H), 6.09(s, 1H), 3.33(q, J=6.0Hz, 2H), 3.06(q, J=6.0Hz, 2H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ155.9, 155.3 , 149.5, 148.8, 146.0, 141.8, 141.7, 140.8, 137.4, 132.2, 131.9, 129.8, 129.7, 128.9, 124.9, 124.9, 123.9, 122.1, 117.1, 116.0, 115.6, 112.5, 41.6, 110.7; ES -MS m/z _571.3 (M+H) ⁺ , 593.3(M ₊ Na) ⁺ ; HRMS calcd. for _{C25H22N4O8S2Na} (M ₊ Na) ⁺ _593.0786 , observed 593.0771.

Example 151

3-(2-(3,4-dihydroxyphenoxy)phenyl)-N-(2-(3-(3-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide (H7-6)

Add 3-(2-(3,4-bis(tert-butyldimethylsilyloxy)phenoxy)phenyl)-N-(2-aminoethyl)-2-thienyl to a 25ml egg-shaped bottle Sulfonamide 71.1mg, 3-methoxyphenyl isocyanate 1.1 molar equivalent, dichloromethane 3ml, after stirring at room temperature for 5 hours, dichloromethane was distilled off under reduced pressure, acetonitrile 2ml was added to the system, and then 40% hydrogen fluoride aqueous solution was added 0.1ml, react at room temperature for 12 hours. PE: ethyl acetate = 1:1 column chromatography, the product was collected to obtain 40.8 mg, the yield was 65.6%.

¹ H NMR (400MHz, Acetone) δ8.18(s, 1H), 8.01(s, 1H), 7.75(d, J=5.2Hz, 1H), 7.69(d, J=4.4Hz, 1H), 7.47( dd, J=7.4, 1.4Hz, 1H), 7.32-7.27(m, 1H), 7.22(t, J=2.0Hz, 1H), 7.19(d, J=5.2Hz, 1H), 7.13-7.05(m , 2H), 6.89(dd, J=8.0, 1.2Hz, 1H), 6.82(d, J=8.4Hz, 1H), 6.77(d, J=8.8Hz, 1H), 6.60(d, J=2.8Hz , 1H), 6.51(dd, J=8.2, 2.2Hz, 1H), 6.47(t, J=5.8Hz, 1H), 6.41(dd, J=8.4, 2.8Hz, 1H), 5.95(s, 1H) , 3.74(s, 3H), 3.30(q, J=5.9Hz, 2H), 3.03(q, J=5.9Hz, 2H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ160.3, 155.9, 149.4 I z556.3(M+H) ⁺ , 578.3(M+Na) ⁺ ; HRMS calcd. for C ₂₆ H ₂₅ N ₃ O ₇ S ₂ Na(M+Na) ⁺ 578.1044, observed 578.1026.

Example 152

3-(2-(3,4-dihydroxyphenoxy)phenyl)-N-(2-(3-(4-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonyl Amide (H7-7)

Add 3-(2-(3,4-bis(tert-butyldimethylsilyloxy)phenoxy)phenyl)-N-(2-aminoethyl)-2-thienyl to a 25ml egg-shaped bottle Sulfonamide 40.1mg, 4-methoxyphenyl isothiocyanate 1.1 molar equivalent, dichloromethane 3ml, after stirring at room temperature for 5 hours, dichloromethane was distilled off under reduced pressure, acetonitrile 2ml was added to the system, and then 40 % hydrogen fluoride aqueous solution 0.1ml, react at room temperature for 12 hours. PE: ethyl acetate = 1:1 column chromatography, the product was collected to obtain 16.2 mg, the yield was 45%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.55(s, 1H), 7.50(d, J=5.2Hz, 1H), 7.45(dd, J=7.6, 1.6Hz, 1H), 7.36(td, J= 8.0, 1.3Hz, 1H), 7.17(td, J=7.6, 1.1Hz, 1H), 7.12(d, J=5.2Hz, 1H), 7.04(d, J=8.8Hz, 2H), 6.96(d, J=8.4Hz, 1H), 6.91(dd, J=6.8, 2.0Hz, 2H), 6.80(d, J=8.8Hz, 1H), 6.57(d, J=2.8Hz, 1H), 6.32(dd, J=8.8, 2.8Hz, 1H), 6.15(t, J=5.4Hz, 1H), 4.95(t, J=6.8Hz, 1H), 3.82(s, 3H), 3.71(q, J=6.0Hz, 2H), 3.11(q, J=6.3Hz, 2H); ESI-MS m/z 572.5(M+H) ⁺ , 594.5( _M +Na) ⁺ _; HRMS _{calcd.for C26H26N3O6S 3} (M+H) ⁺ 572.0997, observed 572.0978.

Example 153

3-(2-(3,4-dihydroxyphenoxy)phenyl)-N-(2-(3-(4-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide (H7-8)

Add 3-(2-(3,4-bis(tert-butyldimethylsilyloxy)phenoxy)phenyl)-N-(2-aminoethyl)-2-thienyl to a 25ml egg-shaped bottle Sulfonamide 83.1mg, 4-nitrophenyl isothiocyanate 1.1 molar equivalent, dichloromethane 3ml, after stirring at room temperature for 5 hours, dichloromethane was distilled off under reduced pressure, 2ml of acetonitrile was added to the system, and then 40% Hydrogen fluoride aqueous solution 0.1ml, react at room temperature for 12 hours. PE: ethyl acetate = 1:1 column chromatography, the product was collected to obtain 53 mg, the yield was 69%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.18(dd, J=7.2, 2.0Hz, 1H), 8.08(s, 1H), 7.56(d, J=5.2Hz, 1H), 7.45(d, J= 8.4Hz, 2H), 7.39(dd, J=7.8, 1.8Hz, 1H), 7.34(td, J=7.7, 1.5Hz, 1H), 7.15(d, J=7.0Hz, 1H), 7.12(d, J=5.2Hz, 1H), 6.92(d, J=7.6Hz, 1H), 6.86(s, 1H), 6.78(d, J=8.4Hz, 1H), 6.50(d, J=2.8Hz, 1H) , 6.33(dd, J=8.8, 2.8Hz, 1H), 5.51(s, 1H), 5.12(s, 1H), 3.71(q, J=5.5Hz, 2H), 3.16(q, J=5.7Hz, 2H); ESI-MS m/z 587.4 (M+H) ⁺ ; HRMS calcd. for C ₂₅ H ₂₃ N ₄ O ₇ S ₃ (M+H) ⁺ 587.0723, observed 587.0705.

Example 154

3-(2-(3,4-dihydroxyphenoxy)phenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)thioureido)ethyl)-2 -Thienylsulfonamide (H7-9)

Add 3-(2-(3,4-bis(tert-butyldimethylsilyloxy)phenoxy)phenyl)-N-(2-aminoethyl)-2-thienyl to a 25ml egg-shaped bottle Sulfonamide 83.1mg, 3,5-ditrifluoromethylphenyl isothiocyanate 1.1 molar equivalent, dichloromethane 3ml, after stirring at room temperature for 5 hours, dichloromethane was distilled off under reduced pressure, and acetonitrile 2ml was added to the system , and then added 0.1 ml of 40% hydrogen fluoride aqueous solution, and reacted at room temperature for 12 hours. PE: ethyl acetate = 1:1 column chromatography, the product was collected to obtain 76.4 mg, the yield was 85.6%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.12(s, 1H), 7.81(s, 2H), 7.65(s, 1H), 7.56(d, J=5.2Hz, 1H), 7.36-7.29(m, 2H), 7.11(t, J=6.6Hz, 2H), 6.92(d, J=8.4Hz, 1H), 6.85(t, J=5.6Hz, 1H), 6.75(d, J=8.4Hz, 1H) , 6.49(d, J=2.8Hz, 1H), 6.31(dd, J=8.8, 2.8Hz, 1H), 5.30(t, J=6.2Hz, 1H), 3.69(d, J=4.8Hz, 2H) , 3.15 (d, J=5.2Hz, 2H); ESI-MS m/z 678.4 (M+H) ⁺ , 700.4 (M+Na) ⁺ ; HRMScalcd.for C ₂₇ H ₂₁ N ₃ O ₅ F ₆ S ₃ Na(M+Na) ⁺ 700.0451, observed 700.0440.

Example 155

3-(2-(3,4-dihydroxyphenoxy)phenyl)-N-(2-(3-(3-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide (H7-10)

Add 3-(2-(3,4-bis(tert-butyldimethylsilyloxy)phenoxy)phenyl)-N-(2-aminoethyl)-2-thienyl to a 25ml egg-shaped bottle Sulfonamide 83.1mg, 3-nitrophenyl isothiocyanate 1.1 molar equivalent, dichloromethane 3ml, after stirring at room temperature for 5 hours, dichloromethane was distilled off under reduced pressure, 2ml of acetonitrile was added to the system, and then 40% Hydrogen fluoride aqueous solution 0.1ml, react at room temperature for 12 hours. PE: ethyl acetate = 1:1 column chromatography, the product was collected to obtain 36.8 mg, yield 57.4%.

¹ H NMR (400MHz, Acetone) 68.63(s, 1H), 7.99-7.97(m, 1H), 7.90(d, J=8.4Hz, 1H), 7.78(d, J=5.2Hz, 1H), 7.59( t, J=8.2Hz, 1H), 7.47(dd, J=7.6, 1.6Hz, 1H), 7.35-7.31(m, 1H), 7.20(d, J=5.2Hz, 1H), 7.09(td, J =7.5, 0.9Hz, 1H), 6.85(dd, J=8.2, 0.6Hz, 1H), 6.78(d, J=8.8Hz, 1H), 6.58(d, J=2.8Hz, 1H), 6.42(dd , J=8.4, 2.8Hz, 1H), 3.75(t, J=5.4Hz, 2H), 3.20(t, J=6.0Hz, 2H); ¹³ C NMR (100MHz, Acetone-d ₆ ) δ182.0, 155.9, 149.5, 148.3, 146.0, 141.6, 140.9, 140.9, 137.3, 132.2, 131.9, 129.8, 129.6, 129.0, 124.9, 122.1, 118.7, 118.7, 117.8, 117.0, 115.6, 110.7 MS m/z 587.2(M+H) ⁺ , 609.2(M+Na) ⁺ ; HRMS calcd. for _{C25H22N4O7S3Na} ( _{M +} Na) ⁺ _609.0556 , observed _609.0543 .

Example 156

3-(2-(3,4-dihydroxyphenoxy)phenyl)-N-(2-(3-(3-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonyl Amide (H7-11)

Add 3-(2-(3,4-bis(tert-butyldimethylsilyloxy)phenoxy)phenyl)-N-(2-aminoethyl)-2-thienyl to a 25ml egg-shaped bottle Sulfonamide 69.4 mg, 3-methoxyphenyl isothiocyanate 1.1 molar equivalent, dichloromethane 3ml, after stirring at room temperature for 5 hours, dichloromethane was distilled off under reduced pressure, acetonitrile 2ml was added to the system, and then 40 % hydrogen fluoride aqueous solution 0.1ml, react at room temperature for 12 hours. PE: ethyl acetate = 1:1 column chromatography, the product was collected to obtain 24.5 mg, the yield was 39.2%.

¹ H NMR (400MHz, Acetone) δ8.90(s, 1H), 8.04(s, 1H), 7.76(d, J=4.8Hz, 2H), 7.47(dd, J=7.6, 1.6Hz, 1H), 7.34-7.30(m, 2H), 7.24(t, J=8.0Hz, 1H), 7.19(d, J=5.2Hz, 1H), 7.08(td, J=7.6, 1.1Hz, 1H), 7.02(d , J=2.4Hz, 1H), 6.89(d, J=8.8Hz, 1H), 6.83(d, J=8.4Hz, 1H), 6.79(d, J=8.4Hz, 1H), 6.74(dd, J =8.6, 1.8Hz, 1H), 6.59(d, J=2.8Hz, 1H), 6.50(t, J=5.4Hz, 1H), 6.42(dd, J=8.4, 2.8Hz, 1H), 3.78-3.74 (m, 5H), 3.18 (q, J=6.1Hz, 2H); ¹³ CNMR (100MHz, Acetone-d ₆ ) δ181.5, 160.5, 155.9, 149.5, 146.0, 141.7, 140.8, 139.3, 137.4, 132.1, 131.9, 130.0, 129.8, 128.9, 124.9, 122.0, 117.0, 116.1, 115.6, 111.3, 110.7, 109.6, 107.6, 54.8, 44.0, 42.6; ESI-MS m/z 572.3(M+H) ⁺ , 594.4(M+ Na) ⁺ ; HRMS calcd. for C ₂₆ H ₂₅ N ₃ O ₆ S ₃ Na(M+Na) ⁺ 594.0788, observed 594.0798.

Example 157

3-(2-(3,4-dihydroxyphenoxy)phenyl)-N-(2-acetylaminoethyl)-2-thienylsulfonamide (I7-1)

Add 3-(2-(3,4-bis(tert-butyldimethylsilyloxy)phenoxy)phenyl)-N-(2-aminoethyl)-2-thienyl to a 25ml egg-shaped bottle Sulfonamide 53.4mg, 4-nitrophenyl isothiocyanate 1.1 molar equivalent, dichloromethane 3ml, after stirring at room temperature for 5 hours, dichloromethane was distilled off under reduced pressure, 2ml of acetonitrile was added to the system, and then 40% Hydrogen fluoride aqueous solution 0.1ml, react at room temperature for 12 hours. PE: ethyl acetate = 1:1 column chromatography, the product was collected to obtain 29.7 mg, yield 70.2%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.55(d, J=5.52Hz, 1H), 7.51(dd, J=7.4, 1.4Hz, 1H), 7.33(td, J=7.7, 1.6Hz, 1H) , 7.14(t, J=6.2Hz, 1H), 7.08(d, J=5.2Hz, 1H), 6.93(d, J=8.0Hz, 1H), 6.72(d, J=8.8Hz, 1H), 6.37 (t, J=7.0Hz, 1H), 5.93(s, 1H), 3.36(t, J=8.0Hz, 1H), 3.15(d, J=8.2Hz, 1H).

Example 158

Determination of inhibitory activity of some compounds stated in the present invention to liver cancer cells

Choose the compound stated in the present invention, adopt cell proliferation-toxicity detection kit (Cell CountingKit-8, CCK-8) to measure its inhibitory activity to the growth of human liver cancer cell line Hep3B and human liver cancer cell line BEL-7404, in addition in this test The immortalized human normal liver cell line HL-7702 was used as the control.

The specific steps of the experiment are:

Take the cells in the exponential growth phase and in good condition, add 0.25% trypsin digestion solution, digest to make the adherent cells fall off, count ⁴ ×104 cells/mL, and make a cell suspension;

Take the cell suspension and inoculate it on a 96-well plate, 100 μl/well, and culture it overnight in a constant temperature CO ₂ incubator;

Select the compound to be tested and add it to the cell culture medium to make the final concentration of 0μM, 1μM, 10μM, 50μM respectively, set 3 duplicate wells for each concentration, and treat the cells for 48h;

●Add CCK-8 into 96-well plate, 10μl/well, and react in the incubator for 3h;

●Use SpectraMax 190 multifunctional microplate reader to measure the absorbance value of each well at the wavelength of 450nm, and calculate the cell inhibition rate according to the following formula.

● For each test compound, use Microsoft Office Excel software to conduct fitting analysis based on the cell viability measured at three concentrations, and obtain the half effective concentration value (IC ₅₀ ) of the compound for cell growth inhibition.

In the above experiments, the liver cancer cell lines used were purchased from American Type Culture Collection (ATCC, Manassas, VA), and the immortalized normal human liver cell lines were purchased from the Cell Bank of the Chinese Academy of Sciences (Shanghai). Cell Counting Kit-8 (CK-04) kit was purchased from Dojindo Company (Kumamoto, Japan).

See Table 1 for the test results of the above compounds on the three cell lines described in this example.

Table 1, the partial compound stated in the present invention is to the inhibitory activity determination result of liver cancer cell

Example 159

Determination of inhibitory activity of some compounds stated in the present invention to lung cancer cells

Select the compounds stated in the present invention, and use the cell proliferation-toxicity detection kit (Cell CountingKit-8, CCK-8) to measure its inhibitory activity to the growth of human lung cancer cell line A549 and human lung cancer cell line H1299. Immortalized human normal lung epithelial cells BEAS-2B served as a control.

The specific steps of the experiment are:

Take the cells in the exponential growth phase and in good condition, add 0.25% trypsin digestion solution, digest to make the adherent cells fall off, count ⁴ ×104 cells/mL, and make a cell suspension;

Take the cell suspension and inoculate it on a 96-well plate, 100 μl/well, and culture it overnight in a constant temperature CO ₂ incubator;

Select the compound to be tested and add it to the cell culture medium to make the final concentration of 0μM, 1μM, 10μM, 50μM respectively, set 3 duplicate wells for each concentration, and treat the cells for 48h;

●Add CCK-8 into 96-well plate, 10μl/well, and react in the incubator for 3h;

●Use SpectraMax 190 multifunctional microplate reader to measure the absorbance value of each well at the wavelength of 450nm, and calculate the cell inhibition rate according to the following formula.

● For each test compound, use Microsoft Office Excel software to conduct fitting analysis based on the cell viability measured at three concentrations, and obtain the half effective concentration value (IC ₅₀ ) of the compound for cell growth inhibition.

In the above experiments, the lung cancer cell lines used were purchased from American Type Culture Collection (ATCC, Manassas, VA), and the normal human lung epithelial cell lines were purchased from the Cell Bank of the Chinese Academy of Sciences (Shanghai). Cell Counting Kit-8 (CK-04) kit was purchased from Dojindo Company (Kumamoto, Japan).

Table 2 shows the test results of the above compounds on the three cell lines described in this example.

Table 2, the partial compound stated in the present invention is to the inhibitory activity determination result of lung cancer cell

Summary of activities and uses:

1. Some compounds described in the present invention (such as compounds: H4-1, H4-4, H4-5, H4-6, H4-9, H2-4, I2-3, H3-2, H3-3, H3 -5, H3-6, H3-7, H3-10, H3-11, H5-1, H5-4, H5-5, H5-11, H6-2, H6-4, H6-5, H6-7 , H6-8, H7-2, H7-4, H7-6, H7-9, H7-10, H1-6, H1-8) have obvious killing effect on at least one human liver cancer cell (IC ₅₀ <20μM ), some compounds have little effect on normal cell proliferation (IC ₅₀ >100 μM), and have good selectivity. These compounds have the potential to be developed into new antitumor drugs, and are recommended for preparing drugs for treating liver cancer.

2. Part of the compounds described in the present invention (such as compounds: H4-3, H4-4, H4-5, H4-6, H4-8, H4-9, I4-1, H1-2, H1-11, H1 -20, H1-22, H1-27, H1-6, I2-3, H3-2, H3-5, H3-6, H3-7, H3-10, H5-1, H5-3, H5-4 , H5-5, H5-6, H5-9, H5-11, H6-2, H6-4, H6-5, H6-7, H6-8, H6-10, H7-2, H7-9) pair At least one kind of human lung cancer cells has obvious killing effect (IC ₅₀ <20 μM), and some compounds have little effect on normal lung cells (IC ₅₀ >100 μM), and have good selectivity. These compounds have the potential to be developed into new antitumor drugs, and are recommended for preparing drugs for treating lung cancer.

Claims (9)

1. a class of phenylthiophene sulfonamide compounds is characterized in that the phenylthiophene sulfonamide N-alkylurea compound or phenylthiophene sulfonamide N-alkylthiourea compound I, phenylthiophene Sulfonamide N-alkylamides II: in: R ₁ is selected from Z substituted or unsubstituted aryl Ar, Z substituted or unsubstituted heteroaryl, or cyclohexyl; the aryl Ar or heteroaryl is selected from 5-7 membered aryl, naphthyl, A 5-7 membered heteroaryl group, a 5-7 membered aromatic group combined with a 5-7 membered heteroaryl group; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms contained is 1 , 2 or 3; the Z substituent is selected from: halogen, C ₁ -C ₄ alkoxy, nitro, C ₁ -C ₆ straight chain or branched hydrocarbon group, hydroxyl, hydroxyl substituted C ₁ -C ₆ Straight chain or branched chain hydrocarbon group, C ₃ -C ₇ saturated or unsaturated cycloalkyl group; the number of Z substituents is 1-4; R ₁ oxygen group and the thiophene group connected to the same benzene ring can be in the ortho position , meta or para position; the phenyl and sulfone substituents on the thiophene ring are in meta or ortho position; X is O or S; R ₂ and R ₃ are selected from H, halogen, C ₁ -C ₆ straight chain or branched hydrocarbon group, hydroxyl group, C ₁ -C ₄ alkoxy group, carboxyl group, C ₁ -C ₄ ester group, cyano group, nitro group, Amino, hydroxymethyl, trifluoromethyl, trifluoromethoxy, mercapto or C ₁ -C ₄ acyl; R ₂ and R ₃ are the same or different groups; R ₄ and R ₅ are H, acetyl or Trifluoroacetyl, or jointly selected from –(CH ₂ ) _m –, that is, a cyclic diamine structure; wherein m is an integer from 0 to 2; R ₆ is acetyl or trifluoroacetyl or 4-nitrophenylsulfone Acyl; n is an integer of 0-4; wherein m and n are not 0. 2. phenylthiophene sulfonamide compound as claimed in claim 1 is characterized in that a class of phenyl thiophene sulfonamide compound, described Ar substituent is phenyl, Z substituted phenyl or naphthyl; Described Z substituting group is as described in claim 1. 3. A class of phenylthiophene sulfonamide compounds, characterized by the following compounds: Phenylthiophenesulfonamide N-alkylurea compounds or phenylthiophenesulfonamide N-alkylthiourea compounds: 3-(2-(2,4-dichlorophenoxy)phenyl)-N-( 2-(3-Phenylureido)ethyl)-2-thienylsulfonamides: 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3 -(4-nitrophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-(3 -(3,5-dichlorophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2- (3-(4-chlorophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2-( 3-(4-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(2- (3-(3,5-Dimethylphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N- (2-(3-(3,5-Ditrifluoromethylphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)benzene base)-N-(2-(3-(3-nitrophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)benzene Base)-N-(2-(3-(3-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy) Phenyl)-N-(2-(3-(4-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy base)phenyl)-N-(2-(3-(3-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorobenzene Oxy)phenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-(2 ,4-dichlorophenoxy)phenyl)-N-(2-(3-(3-chlorophenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-(2 ,4-dichlorophenoxy)phenyl)-N-(2-(3-(3-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2- (2,4-dichlorophenoxy)phenyl)-N-(2-(3-(4-chlorophenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2- (2,4-dichlorophenoxy)phenyl)-N-(2-(3-(4-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2 -(2,4-dichlorophenoxy)phenyl)-N-(2-(3-(3-methylphenyl)thioureido)ethyl)-2-thienylsulfonamide; Phenylthiophenesulfonamide N-alkylurea compounds or phenylthiophenesulfonamide N-alkylthiourea compounds: 3-(2-(2,4-dichlorophenoxy)phenyl)-N-( 3-(3-phenylureido)propyl)-2-thienylsulfonamide: 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3-( 4-nitrophenyl)ureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3-( 3,5-dichlorophenyl)ureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3 -(4-chlorophenyl)ureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3- (4-methoxyphenyl)ureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-(3 -(3,5-Dimethylphenyl)ureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3 -(3-(4-methoxyphenyl)thioureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N- (3-(3-(3-nitrophenyl)thioureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N -(3-(3-(3,5-Ditrifluoromethylphenyl)thioureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy )phenyl)-N-(3-(3-(3-chlorophenyl)thioureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorophenoxy )phenyl)-N-(3-(3-(3-methoxyphenyl)thioureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorobenzene Oxy)phenyl)-N-(3-(3-(4-chlorophenyl)thioureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorobenzene Oxy)phenyl)-N-(3-(3-(4-nitrophenyl)thioureido)propyl)-2-thienylsulfonamide, 3-(2-(2,4-dichloro Phenyloxy)phenyl)-N-(3-(3-(3-methylphenyl)thioureido)propyl)-2-thienylsulfonamide; Phenylthiophenesulfonamide N-alkylurea compounds or phenylthiophenesulfonamide N-alkylthiourea compounds: 3-(2-(1-naphthyl)phenyl)-N-(2-(3 -(3,5-dichlorophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(1-naphthyl)phenyl)-N-(2-(3-( 4-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(1-naphthyl)phenyl)-N-(2-(3-(3,5 -Ditrifluoromethylphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(1-naphthyl)phenyl)-N-(2-(3-(4- Nitrophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(1-naphthyl)phenyl)-N-(2-(3-(3-methoxybenzene base) ureido) ethyl) -2-thienyl sulfonamide, 3-(2-(1-naphthyl) phenyl) -N-(2-(3-(3-nitrophenyl) ureido ) ethyl)-2-thienylsulfonamide, 3-(2-(1-naphthyl)phenyl)-N-(2-(3-(4-methoxyphenyl)thioureido)ethyl Base)-2-thienylsulfonamide, 3-(2-(1-naphthyl)phenyl)-N-(2-(3-(3-nitrophenyl)thioureido)ethyl)- 2-Thienylsulfonamide, 3-(2-(1-naphthyl)phenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)thioureido)ethyl )-2-thienylsulfonamide, 3-(2-(1-naphthyl)phenyl)-N-(2-(3-(3-methoxyphenyl)thioureido)ethyl)- 2-Thienylsulfonamide, 3-(2-(1-naphthyl)phenyl)-N-(2-(3-(4-nitrophenyl)thioureido)ethyl)-2-thiophene Sulfonamide, 3-(2-(1-naphthyl)phenyl)-N-(2-(3-(3-methylphenyl)thioureido)ethyl)-2-thienylsulfonamide , 3-(2-(1-naphthyl)phenyl)-N-(2-(3-phenylthioureido)ethyl)-2-thienylsulfonamide; Phenylthiophenesulfonamide N-alkylurea compounds or phenylthiophenesulfonamide N-alkylthiourea compounds: 3-(2-Sesamolylphenyl)-N-(2-(3-(3, 5-dichlorophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-sesaminolphenyl)-N-(2-(3-(4-methoxyphenyl) Urea group) ethyl)-2-thienyl sulfonamide, 3-(2-sesaminol phenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl) ureido) Ethyl)-2-thienylsulfonamide, 3-(2-sesaminolphenyl)-N-(2-(3-(4-nitrophenyl)ureido)ethyl)-2-thienyl Sulfonamide, 3-(2-sesaminolphenyl)-N-(2-(3-(3-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2 -Sesamolylphenyl)-N-(2-(3-(3-nitrophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-sesamolylphenyl)- N-(2-(3-(4-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-sesaminolphenyl)-N-(2-( 3-(3-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-sesaminolphenyl)-N-(2-(3-(3,5- Ditrifluoromethylphenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-sesaminolphenyl)-N-(2-(3-(3-methoxybenzene base) thioureido) ethyl) -2-thienyl sulfonamide, 3-(2-sesaminol phenyl) -N-(2-(3-(4-nitrophenyl) thioureido) ethyl Base)-2-thienylsulfonamide, 3-(2-sesaminolphenyl)-N-(2-(3-(3-methylphenyl)thioureido)ethyl)-2-thienyl Sulfonamide, 3-(2-sesaminolphenyl)-N-(2-(3-phenylthioureido)ethyl)-2-thienylsulfonamide; Phenylthiophenesulfonamide N-alkylurea compounds or phenylthiophenesulfonamide N-alkylthiourea compounds: 3-(2-(2-naphthyl)phenyl)-N-(2-(3 -(4-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2-naphthyl)phenyl)-N-(2-(3-(3 ,5-ditrifluoromethylphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2-naphthyl)phenyl)-N-(2-(3-( 3-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2-naphthyl)phenyl)-N-(2-(3-(3-nitro phenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(2-naphthyl)phenyl)-N-(2-(3-(3,5-dichlorobenzene base) ureido) ethyl) -2-thienylsulfonamide, 3-(2-(2-naphthyl)phenyl)-N-(2-(3-(4-methoxyphenyl)sulfur Ureado)ethyl)-2-thienylsulfonamide, 3-(2-(2-naphthyl)phenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl )thioureido)ethyl)-2-thienylsulfonamide, 3-(2-(2-naphthyl)phenyl)-N-(2-(3-(4-nitrophenyl)thiourea Base) ethyl) -2-thienylsulfonamide, 3-(2-(2-naphthyl)phenyl)-N-(2-(3-(3-nitrophenyl)thioureido)ethyl Base)-2-thienylsulfonamide, 3-(2-(2-naphthyl)phenyl)-N-(2-(3-(4-nitrophenyl)thioureido)ethyl)- 2-Thienylsulfonamide, 3-(2-(2-naphthyl)phenyl)-N-(2-(3-(3-methoxyphenyl)thioureido)ethyl)-2- Thienylsulfonamide; Phenylthiophenesulfonamide N-alkylurea compounds or phenylthiophenesulfonamide N-alkylthiourea compounds: 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N -(2-(3-(4-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4-dimethoxyphenoxy)phenyl )-N-(2-(3-(3,5-ditrifluoromethylphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4-dimethoxy phenyloxy)phenyl)-N-(2-(3-(3,5-dichlorophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4 -dimethoxyphenoxy)phenyl)-N-(2-(3-(3-nitrophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(3 ,4-dimethoxyphenoxy)phenyl)-N-(2-(3-(4-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-( 2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)thioureido)ethyl)-2- Thiphenylsulfonamide, 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(3-(4-nitrophenyl)thioureido)ethyl) -2-Thienylsulfonamide, 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(3-phenylthioureido)ethyl)-2- Thiphenylsulfonamide, 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(3-(3-nitrophenyl)thioureido)ethyl) -2-Thienylsulfonamide, 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2-(3-(4-nitrophenyl)thioureido) Ethyl)-2-thienylsulfonamide; , phenylthiophenesulfonamide N-alkylthiourea compounds or phenylthiophenesulfonamide N-alkyl (thio)urea compounds: 3-(2-(3,4-dihydroxyphenoxy)phenyl) -N-(2-(3-(4-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4-dihydroxyphenoxy)phenyl )-N-(2-(3-(3,5-ditrifluoromethylphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4-dihydroxybenzene Oxy)phenyl)-N-(2-(3-(4-nitrophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4-dihydroxy Phenyloxy)phenyl)-N-(2-(3-(3,5-dichlorophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4- Dihydroxyphenoxy)phenyl)-N-(2-(3-(3-nitrophenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4- Dihydroxyphenoxy)phenyl)-N-(2-(3-(3-methoxyphenyl)ureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4 -Dihydroxyphenoxy)phenyl)-N-(2-(3-(4-methoxyphenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-(3 ,4-dihydroxyphenoxy)phenyl)-N-(2-(3-(4-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-( 3,4-dihydroxyphenoxy)phenyl)-N-(2-(3-(3,5-ditrifluoromethylphenyl)thioureido)ethyl)-2-thienylsulfonamide, 3-(2-(3,4-Dihydroxyphenoxy)phenyl)-N-(2-(3-(3-nitrophenyl)thioureido)ethyl)-2-thienylsulfonamide , 3-(2-(3,4-dihydroxyphenoxy)phenyl)-N-(2-(3-(3-methoxyphenyl)thioureido)ethyl)-2-thienyl Sulfonamide; Phenylthiophenesulfonamide N-alkylthiourea compounds or phenylthiophenesulfonamide N-alkylthiourea compounds: 4-N-((3-(2-(cyclohexyl)phenyl)-2 -Thienyl)sulfone)-1-N-(3,5-dichloroanilino)formylpiperazine, 4-N-((3-(2-(cyclohexyl)phenyl)-2- Thienyl)sulfone)-1-N-(4-methoxyanilino)formylpiperazine, 4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl )sulfone)-1-N-(3,5-bistrifluoromethylanilino)formylpiperazine, 4-N-((3-(2-(cyclohexyl)phenyl)-2- Thienyl)sulfone)-1-N-(4-methoxyanilino)thioformylpiperazine, 4-N-((3-(2-(cyclohexyl)phenyl)-2- Thienyl)sulfone)-1-N-(4-methoxyanilino)thioformylpiperazine, 4-N-((3-(2-(cyclohexyl)phenyl)-2- Thienyl)sulfone)-1-N-(3-nitroanilino)thioformylpiperazine, 4-N-((3-(2-(cyclohexyl)phenyl)-2-thiophene Base) Sulfone)-1-N-(3,5-Ditrifluoromethylanilino)thioformylpiperazine, 4-N-((3-(2-(Cyclohexanyl)phenyl) -2-thienyl)sulfone)-1-N-(3-methoxyanilino)thioformylpiperazine, 4-N-((3-(2-(cyclohexyl)phenyl) -2-thienyl)sulfone)-1-N-(4-nitroanilino)thioformylpiperazine, 4-N-((3-(2-(cyclohexyl)phenyl)- 2-thienyl)sulfone)-1-N-(3-methylanilino)thioformylpiperazine, 4-N-((3-(2-(cyclohexyl)phenyl)-2 -thienyl)sulfone)-1-N-anilinothioformylpiperazine; Phenylthiophenesulfonamide N-alkylamides: 3-(2(2,4-dichlorophenoxy)phenyl)-N-amidoalkyl-2-thienylsulfonamide: 3-(2 -(2,4-dichlorophenoxy)phenyl)-N-(2-trifluoroacetamidoethyl)-2-thienylsulfonamide, 3-(2-(2,4-dichlorobenzene Oxy)phenyl)-N-(2-(4-nitrobenzenesulfonamido)ethyl)-2-thienylsulfonamide; Phenylthiophenesulfonamide N-Alkylamides: 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-acetamidopropyl)-2-thienylsulfonyl Amide, 3-(2-(2,4-dichlorophenoxy)phenyl)-N-(3-trifluoroacetamidopropyl)-2-thienylsulfonamide, 3-(2-(2 ,4-dichlorophenoxy)phenyl)-N-(3-(4-nitrobenzenesulfonamido)propyl)-2-thienylsulfonamide; Phenylthiophenesulfonamide N-alkylamides: 3-(2-(1-naphthyl)phenyl)-N-(2-acetamidoethyl)-2-thienylsulfonamide, 3- (2-(1-naphthyl)phenyl)-N-(2-(4-nitrobenzenesulfonamido)ethyl)-2-thienylsulfonamide; Phenylthiophenesulfonamide N-Alkylamides: 3-(2-Sesamolylphenyl)-N-(2-acetamidoethyl)-2-thienylsulfonamide, 3-(2-Sesame Phenylphenyl)-N-(2-(4-nitrobenzenesulfonamido)ethyl)-2-thienylsulfonamide; 3-(2-(3,4-dimethoxyphenoxy) Phenyl)-N-(2-(acetamidoethyl)-2-thienylsulfonamide, 3-(2-(3,4-dimethoxyphenoxy)phenyl)-N-(2 -(4-nitrobenzenesulfonamido)ethyl)-2-thienylsulfonamide; Phenylthiophenesulfonamide N-Alkylamides: 4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-1-N-acetylpiper oxazine, 4-N-((3-(2-(cyclohexyl)phenyl)-2-thienyl)sulfone)-1-N-trifluoroacetylpiperazine, 4-N-((3 -(2-(cyclohexyl)phenyl)-2-thienyl)sulfonyl)-1-N-4-nitrobenzenesulfonylpiperazine. 4. A method for preparing the compound as claimed in claim 1, characterized in that by following steps (8), or (7) and (8), or (6), (7) and (8), or ( 5), (6), (7) and (8), or (4), (6), (7) and (8), or (4), (5), (6), (7) and ( 8), or (3), (4), (5), (6), (7) and (8), or (2), (3), (4), (5), (6), ( 7) and (8), or (1), (2), (3), (4), (5), (6), (7) and (8), or (15), or (14) and (15), or (13), (14) and (15), or (12), (13), (14) and (15), or (5), (13), (14) and (15) , or (11), (12), (5), (13), (14) and (15), or (10), (11), (12), (5), (13), (14) and (15), or (3), (10), (11), (12), (5), (13), (14) and (15), or (2), (3), (10) , (11), (12), (5), (13), (14) and (15), or (1), (2), (3), (10), (11), (12), (5), (13), (14) and (15), obtain phenylthiophenesulfonamide N-alkylurea compound or phenylthiophenesulfonamide N-alkylthiourea compound; By following steps (9), or (7) and (9), or (6), (7) and (9), or (5), (6), (7) and (9), or (4) , (6), (7) and (9), or (4), (5), (6), (7) and (9), or (3), (4), (5), (6) , (7) and (9), or (2), (3), (4), (5), (6), (7) and (9), or (1), (2), (3) , (4), (5), (6), (7) and (9), or (16), or (14) and (16), or (13), (14) and (16), or ( 12), (13), (14) and (16), or (5), (13), (14) and (16), or (11), (12), (5), (13), ( 14) and (16), or (10), (11), (12), (5), (13), (14) and (16), or (3), (10), (11), ( 12), (5), (13), (14) and (16), or (2), (3), (10), (11), (12), (5), (13), (14 ) and (16), or (1), (2), (3), (10), (11), (12), (5), (13), (14) and (16), to obtain phenyl Thiophenesulfonamide N-alkylamides: (1) In the organic solvent, the molar ratio of hydroxyl compound, K ₂ CO ₃ , NaH and fluoronitrobenzene is 1:(0～5):(0～2):(0.8～2), in the order of 10～ Compound A was obtained by reacting at 200°C for 2 to 10 hours; Described hydroxyl compound has following structural formula: The structural formula of the compound A is as follows: ; (2) In an organic solvent, the molar ratio of compound A, Pd/C, NH ₂ NH ₂ ·H ₂ O is 1:(0.01～0.1):(1～5), reacting at 10～200℃ for 2 ～10 hours to obtain compound B; or the molar ratio of compound A, zinc powder and hydrochloric acid is 1:(1～5):(2～10) in turn, reacting at 10～200°C for 2～10 hours to obtain compound B; The structural formula of the compound B is as follows: (3) In the solvent, the molar ratio of compound B, H ₂ SO ₄ , NaNO ₂ , and KI is 1:(1~3):(1~2):(1~2), at -5~10°C React for 2 to 10 hours to obtain compound C; The structural formula of the compound C is as follows: (4) In the solvent, the molar ratio of compound C, n-butyllithium, and trimethyl borate is 1:(1~2):(1~2) in sequence, and react at -78~0°C for 1~5 hours to obtain Compound D; The structural formula of the compound D is as follows: (5) In the organic solvent, the molar ratios of 3-bromo-2-thienylsulfonyl chloride, 1-N-Boc diamine and triethylamine are 1:(1~2):(1~2), in Compound E was obtained by reacting at 0-200°C for 2-5 hours; The Boc represents a tert-butoxycarbonyl group; The structural formula of the compound E is as follows: (6) In the solvent, the molar ratio of compound E, compound D, triphenylphosphine or Sphos (2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl), K ₃ PO ₄ and palladium acetate The sequence is 1: (1~1.5): (0.05~0.2): (1~3): (0.02~0.1), react at 10~200°C for 2~15 hours to obtain compound F, The structural formula of the compound F is as follows: (7) In the solvent, the molar ratio of compound F and trifluoroacetic acid is 1: (1-3) in sequence, and react at 10-200° C. for 2-15 hours to obtain compound G; The structural formula of the compound G is as follows: (8) In an organic solvent, the molar ratio of compound G, isocyanate or isothiocyanate is 1:(1-1.5), reacting at 10-200°C for 2-12 hours to obtain compound H; The structural formula of the compound H is as follows: (9) In the solvent, the molar ratio of compound G, acid chloride and triethylamine is sequentially 1:(1-1.5):(1-3), react at 10-200°C for 2-15 hours to obtain compound I; The structural formula of the compound I is as follows: (10) In the solvent, the molar ratio of compound C6 and boron tribromide is 1: (1 ~ 3), react at -78°C ~ room temperature for 2 ~ 5 hours to obtain compound J, The structure of the compound J is as follows: (11) In the solvent, the molar ratio of compound J, TBSCl, imidazole or triethylamine is 1: (1-3): (1-3), react at 0-room temperature for 2-15 hours to obtain compound C7; Described TBSCl represents tert-butyldimethylsilyl chloride; The structural formula of described compound C7 is as follows: (12) In the solvent, the molar ratio of compound C7, n-butyllithium and trimethyl borate is 1:(1~2):(1~2) in turn, react at -78~0°C for 1~5 hours to obtain Compound D7; The structural formula of the compound D7 is as follows: (13) In the solvent, the molar ratio of compound E, compound D7, triphenylphosphine or Sphos, K ₃ PO ₄ and palladium acetate is 1: (1~1.5): (0.05~0.2): (1~3 ): (0.02～0.1), react at 10～200°C for 2～15 hours to obtain compound F7; The structural formula of the compound F7 is as follows: (14) In the solvent, the molar ratio of compound F7 and trifluoroacetic acid is 1: (1-3) sequentially, react at 10-200°C for 2-15 hours to obtain compound G7; The structural formula of the compound G7 is as follows: (15) In an organic solvent, the molar ratio of compound G7, isocyanate or isothiocyanate and hydrofluoric acid is 1:(1～1.5):(2～20), react at room temperature for 2～12 hours to obtain compound H7 ; The structural formula of the compound H7 is as follows: (16) In the solvent, the molar ratio of compound G7, acid chloride and triethylamine is 1:(1~1.5):(1~3), react at 10~200°C for 2~15 hours to obtain compound I7; The structural formula of the compound I7 is as follows: The organic solvent is: tetrahydrofuran, N,N-dimethylformamide, toluene, CH ₂ Cl ₂ , CHCl ₃ , 1,4-dioxane, ethanol, methanol, acetonitrile or a mixed solution thereof; the The solvents used are: tetrahydrofuran, N,N-dimethylformamide, toluene, CH ₂ Cl ₂ , CHCl ₃ , 1,4-dioxane, ethanol, water, methanol, acetonitrile or their mixed solutions; The Sphos means 2-bicyclohexylphosphine-2',6'-dimethoxy-1,1'-diphenyl. 5. the preparation method as claimed in claim 4 is characterized in that: the product described in step 1) carries out recrystallization purification or column chromatography after being concentrated; Step 2) described reaction product, after filtering, ethyl acetate Post-processing of extraction, drying, and concentration; the reverse temperature in step 3) is -5 to 5°C. After the reaction, the reaction solution is poured into water, extracted with an organic solvent, the organic layer is dried, filtered, and the solvent is evaporated under reduced pressure. The post-treatment of residue column chromatography separation; the reaction described in steps 4) and 12), the system must be anhydrous and oxygen-free, and start to drop n-butyllithium solution at a low temperature of -78～-20°C, after adding Add trimethyl borate half an hour to one hour after n-butyllithium is finished, and react at a low temperature of -78～-20°C for half an hour, then slowly rise to room temperature, and extract with ethyl acetate for post-treatment, and the organic layer is passed through Dry, filter, evaporate the solvent under reduced pressure or separate by column chromatography; step 5) after extraction, drying and concentration; the reaction system in step 6) and 13) is fully deoxygenated, and the ligand is Sphos or triphenyl Base phosphine, post-reaction treatment includes ethyl acetate extraction, drying, filtration, concentration and column chromatography; step 7), 14) described in the reaction removes Boc protecting group with trifluoroacetic acid, first neutralizes excessive acid, then carry out the post-reaction treatment of extraction, drying, filtration and concentration; the reaction product described in step 8) is evaporated to remove the solvent under reduced pressure, and the post-treatment of the residue column chromatography separation; step 9), 16) The reaction is post-treated by adding water, dichloromethane extraction, drying, filtration, concentration and column chromatography; after the reaction described in steps 10) and 11), slowly add water to quench, dichloromethane extraction, drying, filtration, concentration and column chromatography The post-processing of chromatography; the reaction product described in step 15) is evaporated to remove the solvent under reduced pressure, after adding hydrofluoric acid for sufficient reaction, adding water, extracting with ethyl acetate, drying, filtering, and concentrating, the residue is separated by column chromatography deal with. 6. Use of the phenylthiophenesulfonamide compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 in the preparation of antitumor drugs. 7. The application according to claim 6, characterized in that said antitumor drug is a drug for treating lung cancer or liver cancer. 8. The application of a class of phenylthiophene sulfonamide compounds in the preparation of antineoplastic drugs for the treatment of liver cancer, the phenyl thiophene sulfonamide compounds are as follows: 9. The application of a class of phenylthiophenesulfonamide compounds in the preparation of antitumor drugs for the treatment of lung cancer, the phenylthiophenesulfonamide compounds are as follows: