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

Tolylthiophene sulfamide compound and its production and use Download PDF

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CN103450149B
CN103450149B CN201210179644.2A CN201210179644A CN103450149B CN 103450149 B CN103450149 B CN 103450149B CN 201210179644 A CN201210179644 A CN 201210179644A CN 103450149 B CN103450149 B CN 103450149B
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phenyl
ethyl
sulphonyl amine
thienyl sulphonyl
thienyl
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CN103450149A (en
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王任小
王慧
马大为
杨成文
刘真
张政希
周宓
巴乾
李井泉
李嫣
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Shanghai Institute of Organic Chemistry of CAS
Shanghai Institute of Nutrition and Health of CAS
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Shanghai Institute of Organic Chemistry of CAS
Shanghai Institutes for Biological Sciences SIBS of CAS
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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

Tolylthiophene sulfamide compound and its production and use
Technical field
The present invention relates to pharmaceutical chemistry and pharmaceutical research achievement, be specifically related to tolylthiophene sulfamide compound and its production and use.
Background technology
In pharmaceutical chemistry research, thiophene, based on fragrant and shape and benzene similarity, usually by the bioisostere as benzene, maintains again enough structural differences simultaneously, may bring different physics and biological characteristics.Vitamin H and vitamin H all contain tetramethylene sulfide structure, and this shows that thiophene-structure plays an important role in organism.Compound containing thiophene result has the biological activity of wide spectrum, such as some thiophene derivants have powerful analgesia, anticonvulsion, anti-inflammatory, antibacterial, bring down a fever, antitumor, parasiticide, sterilization, antihistaminic agent, anxiety, arrhythmia and 5-hydroxytryptamine antagonist effect.Aromatic base thiophene and polyacetylene link together, and are used for livestock industry as insect repellent.
Sulfonamides compound also has important effect in organism.Uncle's sulfanilamide (SN) and bioisostere such as thionamic acid fat, sulfamide compound are all typical carbonic anhydrase inhibitor.Many sulfonamides compounds are used as diuretic(s) and the glaucomatous medicament for the treatment of clinical.Nearest research finds, this compounds also have potential anticonvulsion, anti-obesity is anticancer, analgesia, the effect such as anti-infective.Aromatic sulfonamide or assorted aromatic sulfonamide by number of ways as upset G1 phase, microtubules, inhibiting angiogenesis, and can suppress activating transcription factor NF-Y etc., and wherein the most significant mechanism suppresses carbonic anhydrase isozyme as tumor inhibitor.
Chemical structure and urea groups (or thioureido) with tolylthiophene sulphonamide couples together by compound that the present invention describes by rights, and the preparation method of this type compound and potential application have no forefathers and report.Our experimental result shows that this compounds has obvious lethal effect to people's lung cancer and liver cancer cell, has the potentiality that preparation becomes new type antineoplastic medicine.
Summary of the invention
An object of the present invention is to provide the new tolylthiophene sulfamide compound of a class, and its general structure is as shown in figure (I) and (II).
Two of object of the present invention is to provide the preparation method of above-mentioned tolylthiophene sulfamide compound.
Three of object of the present invention is to provide the purposes of above-mentioned tolylthiophene sulfamide compound, recommends the antitumor drug for the preparation for the treatment of lung cancer and liver cancer.Compound described in the invention adopts tumor cell line and its antitumous effect of normal cell strain experiment test, multiple tumor cell line proves it has stronger inhibition tumor cell active, finds that this compounds aligns the toxicity of normal cell very little simultaneously.
The class tolylthiophene sulfamide compound that the present invention describes, specifically comprise tolylthiophene sulphonamide N-alkyl (sulphur) carbamide compounds (structural formula as: I), a class tolylthiophene sulphonamide N-alkylamide compound (structural formula as: II), tolylthiophene sulphonamide N-alkyl (sulphur) carbamide compounds of the present invention represents the general designation of tolylthiophene sulphonamide N-alkyl urea compounds and tolylthiophene sulphonamide N-alkyl thiourea compounds.Above-claimed cpd has following structural formula:
In above structural formula (I) and (II):
R 1be selected from Z replaces or aromatic base Ar, Z of not replacing replace or do not replace heteroaryl or cyclohexyl; Described aromatic base Ar or heteroaryl be selected from 5-7 unit aromatic base, 5-7 unit heteroaryl and close 5-7 unit heteroaryl 5-7 unit aromatic base; Heteroatoms in described heterocyclic aryl is N, O or S, and contained heteroatomic number is 1,2 or 3; Described Z substituting group is selected from: halogen, C 1-C 4alkoxyl group, nitro, C 1-C 6the C that straight or branched alkyl, hydroxyl, hydroxyl replace 1-C 6straight or branched alkyl, C 3-C 7saturated or undersaturated cycloalkyl; The substituent number of Z is 1-4; R 1oxygen base and the thienyl group be connected on same phenyl ring can be in ortho position, a position or contraposition; Position or ortho position between phenyl in thiphene ring and sulfuryl substituting group are in;
X is O, S or NH;
R 2, R 3be selected from H, halogen, C 1-C 6straight or branched alkyl, hydroxyl, C 1-C 4alkoxyl group, carboxyl, C 1-C 4ester group, cyano group, nitro, amino, methylol, trifluoromethyl, trifluoromethoxy, methoxyl group, hydrogen atom, sulfydryl or C 1-C 4acyl group; R 2, R 3for identical or different group; R 4and R 5for H or be jointly selected from-(CH 2) m-, i.e. ring diamine structures, wherein m is the integer of 0-2; R 6for ethanoyl or trifluoroacetyl group or 4-nitrophenylsulfonyl;
N is the integer of 0-4.
Tolylthiophene sulfamide compound of the present invention can be more specifically described as follows:
1, described tolylthiophene sulphonamide N-alkyl (sulphur) carbamide compounds I refers to 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-phenyl urea groups) ethyl)-2-thienyl sulphonyl aminated compounds: 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(4-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(3, 5-dichlorophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(4-chloro-phenyl-) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(3, 5-3,5-dimethylphenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(3, 5-bis-trifluoromethyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(3-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(3-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(3, 5-bis-trifluoromethyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(3-chloro-phenyl-) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(4-chloro-phenyl-) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(3-aminomethyl phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine,
2, described tolylthiophene sulphonamide N-alkyl (sulphur) carbamide compounds refers to 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-phenyl urea groups) propyl group)-2-thienyl sulphonyl amine: 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(4-nitrophenyl) urea groups) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(3, 5-dichlorophenyl) urea groups) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(4-chloro-phenyl-) urea groups) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(4-p-methoxy-phenyl) urea groups) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(3, 5-3,5-dimethylphenyl) urea groups) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(4-p-methoxy-phenyl) thioureido) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(3-nitrophenyl) thioureido) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(3, 5-bis-trifluoromethyl) thioureido) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(3-chloro-phenyl-) thioureido) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(3-p-methoxy-phenyl) thioureido) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(4-chloro-phenyl-) thioureido) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(4-nitrophenyl) thioureido) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(3-aminomethyl phenyl) thioureido) propyl group)-2-thienyl sulphonyl amine,
3, described tolylthiophene sulphonamide N-alkyl (sulphur) carbamide compounds refers to 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3,5-dichlorophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(4-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3-aminomethyl phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-phenylthiourea base) ethyl)-2-thienyl sulphonyl amine,
4, described tolylthiophene sulphonamide N-alkyl (sulphur) carbamide compounds refers to 3-(2-sesame phenolic group phenyl)-N-(2-(3-(3,5-dichlorophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(4-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(4-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(3-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(3-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(4-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(3-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(3-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(3-aminomethyl phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-phenylthiourea base) ethyl)-2-thienyl sulphonyl amine,
5, described tolylthiophene sulphonamide N-alkyl (sulphur) carbamide compounds refers to 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3,5-dichlorophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine,
6, described tolylthiophene sulphonamide N-alkyl (sulphur) carbamide compounds refers to 3-(2-(3, 4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(3, 5-bis-trifluoromethyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(3, 5-dichlorophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(3-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(3, 5-bis-trifluoromethyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dimethoxy phenoxy group) phenyl)-N-(2-(3-phenylthiourea base) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(3-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine,
7, described tolylthiophene sulphonamide N-alkyl (sulphur) carbamide compounds refers to 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3, 5-bis-trifluoromethyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(4-nitro base phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3, 5-dichlorophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3, 5-bis-trifluoromethyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine,
8, described tolylthiophene sulphonamide N-alkyl (sulphur) carbamide compounds can also refer to 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(3,5-dichloroanilino) formyl piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(4-anisole amido) formyl piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(3,5-bis-trifluoromethylbenzene amido) formyl piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(4-anisole amido) thioformyl piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(4-anisole amido) thioformyl piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(3-oil of mirbane amido) thioformyl piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(3,5-bis-trifluoromethylbenzene amido) thioformyl piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(3-anisole amido) thioformyl piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(4-oil of mirbane amido) thioformyl piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(3-toluidine) thioformyl piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-anilino thioformyl piperazine,
9, tolylthiophene sulphonamide N-alkylamide compound (II) as claimed in claim 1 refers to 3-(2 (2,4-dichlorophenoxy) phenyl)-N-amido alkyl-2-thienyl sulphonyl amine: 3-(2-(2,4-dichlorophenoxy) phenyl)-N-(2-trifluoroacetyl amido ethyl)-2-thienyl sulphonyl amine, 3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(4-nitrobenzene sulphonyl amido) ethyl)-2-thienyl sulphonyl amine;
10, described tolylthiophene sulphonamide N-alkylamide compound refers to 3-(2-(2,4-dichlorophenoxy) phenyl)-N-(3-acetamido propyl group)-2-thienyl sulphonyl amine, 3-(2-(2,4-dichlorophenoxy) phenyl)-N-(3-trifluoroacetyl amido propyl group)-2-thienyl sulphonyl amine, 3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-(4-nitrobenzene sulphonyl amido) propyl group)-2-thienyl sulphonyl amine;
11, described tolylthiophene sulphonamide N-alkylamide compound refers to 3-(2-(1-naphthols base) phenyl)-N-(2-acetamido ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(4-nitrobenzene sulphonyl amido) ethyl)-2-thienyl sulphonyl amine;
12, described tolylthiophene sulphonamide N-alkylamide compound refers to 3-(2-sesame phenolic group phenyl)-N-(2-acetamido ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(4-nitrobenzene sulphonyl amido) ethyl)-2-thienyl sulphonyl amine;
13, described tolylthiophene sulphonamide N-alkylamide compound refers to 3-(2-(3,4-dimethoxy phenoxy group) phenyl)-N-(2-(acetamido ethyl)-2-thienyl sulphonyl amine, 3-(2-(3,4-dimethoxy phenoxy group) phenyl)-N-(2-(4-nitrobenzene sulphonyl amido) ethyl)-2-thienyl sulphonyl amine;
14, described tolylthiophene sulphonamide N-alkylamide compound refers to 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-Acetylpiperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-trifluoroacetyl group piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-4-nitrobenzenesulfonyl piperazine;
15, described tolylthiophene sulphonamide N-alkylamide compound can also refer to 3-(2-(3,4-dihydroxyl phenoxy group) phenyl)-N-(2-acetamidoethyl)-2-thienyl sulphonyl amine
The preparation method of tolylthiophene sulfamide compound of the present invention is as follows:
Wherein R 1, R 2, R 3, R 4, R 5and R 6definition as previously mentioned:
R 1be selected from Z replaces or aromatic base Ar, Z of not replacing replace or do not replace heteroaryl or cyclohexyl; Described aromatic base Ar or heteroaryl be selected from 5-7 unit aromatic base, 5-7 unit heteroaryl and close 5-7 unit heteroaryl 5-7 unit aromatic base; Heteroatoms in described heterocyclic aryl is N, O or S, and contained heteroatomic number is 1,2 or 3; Described Z substituting group is selected from: halogen, C 1-C 4alkoxyl group, nitro, C 1-C 6the C that straight or branched alkyl, hydroxyl, hydroxyl replace 1-C 6straight or branched alkyl, C 3-C 7saturated or undersaturated cycloalkyl; The substituent number of Z is 1-4; R 1oxygen base and the thienyl group be connected on same phenyl ring can be in ortho position, a position or contraposition; Position or ortho position between phenyl in thiphene ring and sulfuryl substituting group are in; X is O, S or NH;
R 2, R 3be selected from H, halogen, C 1-C 6straight or branched alkyl, hydroxyl, C 1-C 4alkoxyl group, carboxyl, C 1-C 4ester group, cyano group, nitro, amino, methylol, trifluoromethyl, trifluoromethoxy, methoxyl group, hydrogen atom, sulfydryl or C 1-C 4acyl group; R 2, R 3for identical or different group; R 4and R 5for H or be jointly selected from-(CH 2) m-, i.e. ring diamine structures, wherein m is the integer of 0-2; R 6for ethanoyl or trifluoroacetyl group or 4-nitrophenylsulfonyl;
N is the integer of 0-4.
Specifically can respectively by following steps (8), or (7) and (8), or (6), and (8), or (5) (7), (6), and (8), or (4) (7), (6), and (8), or (4) (7), (5), (6), and (8), or (3) (7), (4), (5), (6), and (8), or (2) (7), (3), (4), (5), (6), and (8), or (1) (7), (2), (3), (4), (5), (6), and (8) (7), or (15), or (14) and (15), or (13), and (15), or (12) (14), (13), and (15), or (5) (14), (13), and (15), or (11) (14), (12), (5), (13), and (15), or (10) (14), (11), (12), (5), (13), and (15), or (3) (14), (10), (11), (12), (5), (13), and (15), or (2) (14), (3), (10), (11), (12), (5), (13), and (15), or (1) (14), (2), (3), (10), (11), (12), (5), (13), (14) tolylthiophene sulphonamide N-alkyl (sulphur) carbamide compounds and (15), is obtained,
By following steps (9), or (7) and (9), or (6), and (9), or (5) (7), (6), and (9), or (4) (7), (6), and (9), or (4) (7), (5), (6), and (9), or (3) (7), (4), (5), (6), and (9), or (2) (7), (3), (4), (5), (6), and (9), or (1) (7), (2), (3), (4), (5), (6), and (9) (7), or (16), or (14) and (16), or (13), and (16), or (12) (14), (13), and (16), or (5) (14), (13), and (16), or (11) (14), (12), (5), (13), and (16), or (10) (14), (11), (12), (5), (13), and (16), or (3) (14), (10), (11), (12), (5), (13), and (16), or (2) (14), (3), (10), (11), (12), (5), (13), and (16), or (1) (14), (2), (3), (10), (11), (12), (5), (13), (14) tolylthiophene sulphonamide N-alkylamide compound and (16), is obtained.
(1) in organic solvent, oxy-compound, K 2cO 3, NaH and fluoronitrobenzene mol ratio be followed successively by 1: (0 ~ 5): (0 ~ 2): (0.8 ~ 2), 10 ~ 200 DEG C of reactions 2 ~ 10 hours
Compd A;
Described oxy-compound can typical compound be example as follows:
The structural formula of described compd A is as follows:
(2) in organic solvent, compd A, Pd/C, NH 2nH 2h 2the mol ratio of O is followed successively by 1: (0.01 ~ 0.1): (1 ~ 5), within 2 ~ 10 hours, obtains compd B 10 ~ 200 DEG C of reactions; Or the mol ratio of compd A, zinc powder and hydrochloric acid is followed successively by 1: (1 ~ 5): (2 ~ 10), within 2 ~ 10 hours, obtain compd B 10 ~ 200 DEG C of reactions;
The structural formula of described compd B is as follows:
(3) in a solvent, compd B, H 2sO 4, NaNO 2, Kl mol ratio be followed successively by 1: (1 ~ 3): (1 ~ 2): (1 ~ 2) ,-5 ~ 10 DEG C reaction 2 ~ 10 hours Compound C;
The structural formula of described Compound C is as follows:
(4) in a solvent, the mol ratio of Compound C, n-Butyl Lithium, trimethyl borate is followed successively by 1: (1 ~ 2): (1 ~ 2), within 1 ~ 5 hour, obtains Compound D-78 ~ 0 DEG C of reaction;
The structural formula of described Compound D is as follows:
(5) in organic solvent, the mol ratio of the yellow acyl chlorides of the bromo-2-thienyl of 3-, 1-N-Boc diamines, triethylamine is followed successively by 1: (1 ~ 2): (1 ~ 2), within 2 ~ 5 hours, obtains compd E 0 ~ 200 DEG C of reaction;
The structural formula of described compd E is as follows:
(6) in a solvent, compd E, Compound D, triphenylphosphine or Sphos, K 3pO 4be followed successively by 1 with the mol ratio of palladium: (1 ~ 1.5): (0.05 ~ 0.2): (1 ~ 3): (0.02 ~ 0.1), within 2 ~ 15 hours, obtain compound F 17-hydroxy-corticosterone 10 ~ 200 DEG C of reactions;
The structural formula of described compound F 17-hydroxy-corticosterone is as follows:
(7) in a solvent, the mol ratio of compound F 17-hydroxy-corticosterone, trifluoroacetic acid is followed successively by 1: (1 ~ 3), within 2 ~ 15 hours, obtains compound G 10 ~ 200 DEG C of reactions;
The structural formula of described compound G is as follows:
(8) in organic solvent, the mol ratio of compound G, isocyanic ester or lsothiocyanates is 1: (1 ~ 1.5), within 2 ~ 12 hours, obtains compound H 10 ~ 200 DEG C of reactions;
The structural formula of described compound H is as follows:
Described solvent is: THF, DMF, toluene, CH 2cl 2, CHCl 3, Isosorbide-5-Nitrae-dioxane, ethanol, water, methyl alcohol, acetonitrile;
(9) in a solvent, the mol ratio of compound G, acyl chlorides and triethylamine is followed successively by 1: (1 ~ 1.5): (1 ~ 3), within 2 ~ 15 hours, obtains Compound I 10 ~ 200 DEG C of reactions;
The structural formula of described Compound I is as follows:
(10) in a solvent, the mol ratio of Compound C 6, boron tribromide is 1: (1 ~ 3), within 2 ~ 5 hours, obtains compound J at-78 DEG C ~ room temperature reaction,
The structural formula of described compound J is as follows:
(11) in a solvent, the mol ratio of compound J, TBSCl, imidazoles or triethylamine is 1: (1 ~ 3): (1 ~ 3), within 2 ~ 15 hours, obtains Compound C 7 at 0 ~ room temperature reaction; Described TBSCl represents TERT-BUTYL DIMETHYL CHLORO SILANE; The structural formula of described Compound C 7 is as follows:
(12) in a solvent, the mol ratio of Compound C 7, n-Butyl Lithium, trimethyl borate is followed successively by 1: (1 ~ 2): (1 ~ 2), within 1 ~ 5 hour, obtains Compound D 7-78 ~ 0 DEG C of reaction;
The structural formula of described Compound D 7 is as follows:
(13) in a solvent, compd E, Compound D 7, triphenylphosphine or Sphos, K 3pO 4be followed successively by 1 with the mol ratio of palladium: (1 ~ 1.5): (0.05 ~ 0.2): (1 ~ 3): (0.02 ~ 0.1), within 2 ~ 15 hours, obtain compound F 17-hydroxy-corticosterone 7 10 ~ 200 DEG C of reactions;
The structural formula of described compound F 17-hydroxy-corticosterone 7 is as follows:
(14) in a solvent, the mol ratio of compound F 17-hydroxy-corticosterone 7, trifluoroacetic acid is followed successively by 1: (1 ~ 3), within 2 ~ 15 hours, obtains compound G7 10 ~ 200 DEG C of reactions; The structural formula of described compound G7 is as follows:
(15) in organic solvent, the mol ratio of compound G7, isocyanic ester or lsothiocyanates and hydrofluoric acid is 1: (1 ~ 1.5): (2 ~ 20), within 2 ~ 12 hours, obtains compound H 7 at room temperature reaction;
The structural formula of described compound H 7 is as follows:
(16) in a solvent, the mol ratio of compound G7, acyl chlorides and triethylamine is followed successively by 1: (1 ~ 1.5): (1 ~ 3), within 2 ~ 15 hours, obtains Compound I 7 10 ~ 200 DEG C of reactions;
The structural formula of described Compound I 7 is as follows:
The concrete preparation method of compound described above can comprise the following steps:
(1) the phenol 10g replaced, is placed in 250ml pear shape bottle, adds inert solvent DMF 60ml or THF 60ml, then adds K 2cO 3or 60%NaH 2 molar equivalent, then adding o-fluoronitrobenzene 1.0 molar equivalent, stirring heating refluxes, stirring heating is stopped after 2 ~ 4 hours, after cooling, add water 200ml, extraction into ethyl acetate three times, each 200ml, combined ethyl acetate extraction liquid, anhydrous sodium sulfate drying, filters, concentrated, obtain liquid or solid shape compd A.
(2) 7g compd A is placed in the there-necked flask of 1L, add the zinc powder of 5 molar equivalents, 80ml ethanol, under mechanical stirring, slowly add the hydrochloric acid soln 500ml of 2mol/L, stir 12 ~ 24 hours, the extraction into ethyl acetate aqueous solution 3 times, each 300ml, combined ethyl acetate solution, saturated common salt water washing, ethyl acetate solution anhydrous sodium sulfate drying, filter, concentrated, obtain product liquid B; Or add 100ml ethanol, then add 0.7g Pd/C, finally slowly add hydrazine hydrate 5.0 molar equivalent, after question response heat release, reflux 2 ~ 5 hours, stops stirring, filtered on buchner funnel, underpressure distillation is except desolventizing, and add water 200ml, extraction into ethyl acetate three times, each 200ml, combined ethyl acetate, adds anhydrous sodium sulfate drying, filter, concentrate to obtain liquid benzene amine compound B.
(3) 6g compd B adds in 500ml there-necked flask, and add sulphuric acid soln 3 molar equivalent of 3mol/L, there-necked flask puts into-5 ~ 5 DEG C of ice-water baths, slowly adds the NaNO of 0.4mol/L under stirring 2solution 1.5 molar equivalent, stir after one hour, slowly add Kl solution 1.5 molar equivalent of 0.8mol/L under stirring, stir after one hour in-5 ~ 5 DEG C of ice-water baths, be placed in stirred at ambient temperature and stop after 3 hours stirring, extraction into ethyl acetate three times, each 100ml, combined ethyl acetate solution and with saturated sodium thiosulfate washing, saturated common salt water washing, ethyl acetate solution anhydrous sodium sulfate drying, filter, concentrate to obtain liquid or solid product Compound C.
(4) 2.8g Compound C is placed in 250ml eggplant-shape bottle, fully dewater after deoxygenation, under argon shield, add 40ml anhydrous tetrahydro furan, be placed in-78 DEG C of dry ice acetone bath, add n-butyllithium solution 1.2 molar equivalent of 2.5mol/L again, trimethyl borate 1.2 molar equivalent is added after one hour, under afterwards eggplant-shape bottle being placed in room temperature after an hour again, stirring at room temperature is after 3 hours, add the hydrochloric acid soln cancellation of 1mol/L, underpressure distillation is except desolventizing, add extraction into ethyl acetate three times, each 50ml, combined ethyl acetate solution, saturated nacl aqueous solution washs, ethyl acetate solution anhydrous sodium sulfate drying, filter, concentrated, column chromatography Compound D.
(5) the yellow acyl chlorides of the bromo-2-thienyl of 2.5g compound 3-adds in 50ml eggplant-shape bottle, adds 15ml methylene dichloride, adds triethylamine, each 1.2 molar equivalents of 1-N-Boc diamines again, stirring at room temperature, after 5 hours, stops stirring, add water 50ml, dichloromethane extraction three times, each 50ml, combined dichloromethane solution, saturated nacl aqueous solution washs, dichloromethane solution anhydrous sodium sulfate drying, filters, and concentrates to obtain compd E.
(6) Compound D 1.4g, compd E 1.9g, Sphos 0.1 molar equivalent, K 3pO 42 molar equivalents, palladium 0.05 molar equivalent once add in 100ml Shrek pipe, after substituting argon gas, add THF25ml; water 5ml, starts heated and stirred under argon shield, 5 hours; stop stirring, add water 50ml, extraction into ethyl acetate three times; each 50ml, combined ethyl acetate solution also washs with saturated nacl aqueous solution, ethyl acetate solution anhydrous sodium sulfate drying; filter; concentrated, column chromatography, obtains compound F 17-hydroxy-corticosterone.
(7) 1.3g compound F 17-hydroxy-corticosterone is placed in 25ml eggplant-shape bottle, adds 10ml methylene dichloride, then adds 3ml trifluoroacetic acid, stirring at room temperature 12 hours, add in saturated sodium bicarbonate solution and produce to bubble-free with trifluoroacetic acid, add water 50ml, dichloromethane extraction three times, each 50ml, combined dichloromethane solution also uses saturated common salt water washing, dichloromethane solution anhydrous sodium sulfate drying, filters, concentrated, obtain compound G.
(8) 60mg compound G is placed in 25ml pear shape bottle, and adds methylene dichloride 3ml in pear shape bottle, is adding isocyanic ester or lsothiocyanates 1.1 molar equivalent, stirring at room temperature 5 hours, and concentrated, column chromatography obtains compound H.
(9) 60mg compound G is placed in 25ml pear shape bottle, and methylene dichloride 3ml is added in pear shape bottle, adding Acetyl Chloride 98Min. or trifluoroacetic anhydride (TFAA) or this yellow acyl chlorides of 4-nitro and each 1.1 molar equivalents of triethylamine, stirring at room temperature 5 hours, add water 20ml, dichloromethane extraction three times, each 25ml, combined dichloromethane solution also uses saturated common salt water washing, dichloromethane solution anhydrous sodium sulfate drying, filter, concentrated, column chromatography obtains Compound I.
(10) 3.0g Compound C 6 is placed in 100ml pear shape bottle, adds methylene dichloride 25ml, pear shape bottle is placed in ice bath, and add Boron tribromide solution 2 molar equivalent of 1mol/L, slowly rise to stirring at room temperature 5 hours, slowly add water 50ml cancellation.Dichloromethane extraction three times, each 50ml, combined dichloromethane solution also uses saturated common salt water washing, dichloromethane solution anhydrous sodium sulfate drying, filters, and concentrated, column chromatography obtains compound J.
(11) 2.0g compound J is placed in 100ml pear shape bottle, adds methylene dichloride 40ml, pear shape bottle is placed in ice bath, and add imidazoles and each 2 molar equivalents of TBSCl, slowly rise to stirring at room temperature 5 hours, add water 50ml cancellation.Dichloromethane extraction three times, each 50ml, combined dichloromethane solution also uses saturated common salt water washing, dichloromethane solution anhydrous sodium sulfate drying, filters, and concentrated, column chromatography obtains Compound C 7.
(12) 2.8g Compound C 7 is placed in 250ml eggplant-shape bottle, fully dewater after deoxygenation, under argon shield, add 40ml anhydrous tetrahydro furan, be placed in-78 DEG C of dry ice acetone bath, add n-butyllithium solution 1.2 molar equivalent of 2.5mol/L again, trimethyl borate 1.2 molar equivalent is added after one hour, under afterwards eggplant-shape bottle being placed in room temperature after an hour again, stirring at room temperature is after 3 hours, add the hydrochloric acid soln cancellation of 1mol/L, underpressure distillation is except desolventizing, add extraction into ethyl acetate three times, each 50ml, combined ethyl acetate solution, saturated nacl aqueous solution washs, ethyl acetate solution anhydrous sodium sulfate drying, filter, concentrated, column chromatography compound D7.
(13) 1.4g Compound D 7, compd E 1.0 molar equivalent, Sphos 0.1 molar equivalent, K 3pO 42 molar equivalents, palladium 0.05 molar equivalent once add in 100ml Shrek pipe, after substituting argon gas, add THF 25ml; water 5ml, starts heated and stirred under argon shield, 5 hours; stop stirring, add water 50ml, extraction into ethyl acetate three times; each 50ml, combined ethyl acetate solution also washs with saturated nacl aqueous solution, ethyl acetate solution anhydrous sodium sulfate drying; filter; concentrated, column chromatography, obtains compound F 17-hydroxy-corticosterone 7.
(14) 1.3g compound F 17-hydroxy-corticosterone 7 is placed in 25ml eggplant-shape bottle, adds 10ml methylene dichloride, then adds 3ml trifluoroacetic acid, stirring at room temperature 12 hours, add in saturated sodium bicarbonate solution and produce to bubble-free with trifluoroacetic acid, add water 50ml, dichloromethane extraction three times, each 50ml, combined dichloromethane solution also uses saturated common salt water washing, dichloromethane solution anhydrous sodium sulfate drying, filters, concentrated, obtain compound G7.
(15) 60mg compound G7 is placed in 25ml pear shape bottle, and adds methylene dichloride 3ml in pear shape bottle, is adding isocyanic ester or lsothiocyanates 1.1 molar equivalent, stirring at room temperature 5 hours, and concentrated, column chromatography obtains compound H 7.
(16) 60mg compound G7 is placed in 25ml pear shape bottle, and methylene dichloride 3ml is added in pear shape bottle, adding Acetyl Chloride 98Min. or trifluoroacetic anhydride (TFAA) or this yellow acyl chlorides of 4-nitro and each 1.1 molar equivalents of triethylamine, stirring at room temperature 5 hours, add water 20ml, dichloromethane extraction three times, each 25ml, combined dichloromethane solution also uses saturated common salt water washing, dichloromethane solution anhydrous sodium sulfate drying, filter, concentrated, column chromatography obtains Compound I 7.
Described Sphos represent 2-dicyclohexyl phosphine-2 ', 6 '-dimethoxy-1,1 '-biphenyl;
Described organic solvent is; Tetrahydrofuran THF, DMF (DMF), toluene toluene, CH 2cl 2, CHCl 3, Isosorbide-5-Nitrae-dioxane, ethanol, methyl alcohol, acetonitrile, toluene or its mixing solutions.
Described solvent is: tetrahydrofuran THF, DMF (DMF), toluene toluene, CH 2cl 2, CHCl 3, Isosorbide-5-Nitrae-dioxane, ethanol, water, methyl alcohol, acetonitrile, toluene or its mixing solutions.
Above (1)-(15) illustrate described in inert solvent comprise tetrahydrofuran (THF), methylene dichloride, chloroform, dioxane and toluene, wherein preferred tetrahydrofuran (THF)
Embodiment
The present invention will be illustrated further below in an example.These embodiments only for illustration of the present invention, but do not limit the present invention in any way.Unless otherwise specified, the explanation below in all embodiments is all that the room temperature mentioned refers to 20 DEG C-30 DEG C with quality (gram) for unit.
Embodiment 1
2-(2,4 dichloro benzene oxygen base) oil of mirbane (A1)
2,4 dichloro phenol 28g (171.8mmol) is added, o-fluoronitrobenzene 19.572g (138.8mmol), K in 250ml egg type bottle 2cO 323.848g, DMF60ml, backflow 5h.Stop heating, add 500ml ethyl acetate, water 200ml × 3 are washed, dry, filter, concentrated, PE: ethyl acetate=10: 1 column chromatography, obtains salmon liquid 36.789g, productive rate 93.3%. 1h NMR (400MHz, CDCl 3) δ 8.00 (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); 13c NMR (100MHz, CDCl 3) δ 145.7,145.4,136.4,130.2,126.5,126.4,124.1,122.5,121.7,119.6,117.4,115.1; EI-MSm/z, 283 (M) +; EI-HRMS calculated value (calcd for) C 12h 7nO 3cl 2 +(M) +282.9803, measured value (observed) 282.9801.
Embodiment 2
2-(2,4 dichloro benzene oxygen base) amino-benzene (B1)
2-(2 is added in the four-hole bottle of 2L, 4-dichlorophenoxy) oil of mirbane 36.563g (128.7mmol), ethanol 300ml, and add a little ethyl acetate hydrotropy, add 30g (461.5mmol) zinc powder, the hydrochloric acid 20ml of 1N is slowly dripped, to the grey decoloration of zinc powder under mechanical stirrer stirring at room temperature.Stop stirring.Add 500ml ethyl acetate, 200ml × 3 are washed, dry, filter, and concentrated, PE: ethyl acetate=10: 1 column chromatography, obtains salmon liquid 36.789g, productive rate 94.6%. 1H 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)； 13C 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 forC 12H 9NOCl 2 +(M) +253.0062，observed 253.0061.
Embodiment 3
2-(2,4 dichloro benzene oxygen base) iodobenzene (C1)
500ml there-necked flask is placed in ice bath, adds 2-(2,4 dichloro benzene oxygen base) amino-benzene 10.7g (42.1mmol), vitriol oil 7ml wherein and adds after 45ml water dilution cooling, slowly add NaNO under mechanical stirring 23.9533g (57.3mmol) water (16ml) solution, adds for ten minutes, then adds Kl11.5542g (69.6mmol) water (10ml) solution, moves to stirred at ambient temperature after half hour.Stop after room temperature reaction 4h, add water 200ml, use CH 2cl 2300ml × 3 extract, then are merged, and use saturated Na 2s 2o 3washing once.Dry, filter, concentrated, column chromatography, obtains nearly colourless liquid 13.0956g, and productive rate is 85.2%. 1H 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)； 13C 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(M-H) -；EI-HRMS calcd for C 12H 7OCl 2l +(M) +363.8919，observed 363.8922.
Embodiment 4
2-(2,4 dichloro benzene oxygen base) phenyl-boron dihydroxide (D1)
2-(2 is added in 100ml reaction tubes; 4-dichlorophenoxy) iodobenzene 2.4743g (6.8mmol) substitutes gas; anhydrous THF32ml is added under argon shield; slowly n-Butyl Lithium 3.2ml is dripped in-78 DEG C of cryostats; react after 1 hour; add trimethyl borate 14ml at-78 DEG C, after 2h, reaction tubes is moved to stirring at room temperature.Add 1ml concentrated hydrochloric acid after 1h, extraction into ethyl acetate, dry, filter, concentrated after white solid 1.4978g, productive rate is 78.3%. 1H 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)； 13C 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 forC 12H 9O 3Cl 2B +(M) +282.0022，observed 282.0020.
Embodiment 5
The bromo-N-of 3-(2-(N-Boc amido) ethyl)-2-thienyl sulphonyl amine (E1)
In 20ml egg type bottle, add N-Boc protect 2-aminoethyl 138.6mg (0.86mmol), CH 2cl 23ml, triethylamine 0.16ml (1.12mmol), slowly add 3-bromine, 2-thienyl chlorination sulfone 200.8mg (0.77mmol) under ice bath stirs.Stirring at room temperature one hour is moved to after 5 minutes.Stop stirring.Add water 50ml, CH 2cl 2100ml × 3 extract, dry, filter, concentratedly to obtain faint yellow solid 290.1mg, and productive rate is 98.1%. 1H 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) +.
Embodiment 6
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(N-Boc is amino) ethyl)-2-thienyl sulphonyl amine (F1-1)
The bromo-N-of 3-(2-(N-Boc amido) ethyl)-2-thienyl sulphonyl amine 1.8521g (4.8mmol) is added in 250ml reaction tubes, 2-(2,4-dichlorophenoxy) phenyl-boron dihydroxide 1.3600g (4.8mmol), Sphos109mg (0.27mmol), palladium 57.4mg (0.26mmol), K 3pO 43.1012g (14.6mmol), adds THF25ml after substituting gas, refluxes 8 hours, stops heated and stirred.Add water 100ml, and ethyl acetate 250ml × 2 extract, dry, filter, concentrated, PE: ethyl acetate=2.5: 1 column chromatography, obtains yellow floss 1.3117g, and productive rate is 50.2%, and reclaim, 2-(3 bromo thiophene base) sulfoamido N-Boc ethamine 670.8mg. 1H 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)； 13CNMR(100MHz，CDCl 3)δ156.2，153.5，151.0，139.8，137.1，132.4，131.7，130.5，130.4，129.4，129.0，128.3，126.0，125.1，123.9，121.2，117.6，79.7，43.5，40.4，28.4；ESI-MS m/z，565.2(M+Na) +；ESI-H RMS acalcd forC 23H 25N 2O 5Cl 2S 2Na(M+Na) +565.0396，observed 565.0399.
Embodiment 7
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine (G1-1)
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(N-Boc is amino) ethyl)-2-thienyl sulphonyl amine 1.3117g (2.35mmol) is added, CH in 50ml egg type bottle 2cl 215ml, CF 3cO 2h 5ml, stirring at room temperature 1 hour.Add in salt of wormwood and CF 3cO 2h, to alkalescence, adds water, CH 2cl 2200ml × 3 extract, dry, filter, concentratedly to obtain faint yellow solid 992.1mg, productive rate 95.1%. 1H 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 18H 17N 2O 3Cl 2S 2(M+H) +443.0052，observed443.0052.
Embodiment 83-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(3-(4-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H1-1)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 63.8mg, 4-nitrophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 85.9mg, productive rate 98.2%.Y37： 1H 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＝8.8，2.4Hz，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)； 13C NMR(100MHz，Acetone-d 6)δ155.7，154.5，152.2，147.8，142.4，140.6，138.9，133.4，132.8，131.1，130.9，130.0，129.6，129.4，126.6，126.3，125.7，124.6，122.5，118.4，118.1，44.2，40.6；IR(film)3365.9，1694.4，1614.1，1557.0，1505.1，1472.9，1329.2，1153.4，1109.5，850.1，751.4，587.9；ESI-MSm/z 607.2(M+H) +；ESI-HRMS calcd for C 25H 20N 4O 6Cl 2S 2Na(M+Na) +629.0104，observed 629.0094.
Embodiment 9
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(3-(3,5-dichlorophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H1-2)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 57.0mg, 3,5-dichlorophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 76.7mg, productive rate 93.7%.Y38： 1H 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)； 13CNMR(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；IR(film)3361.0，2925.0，1667.1，1588.0，1544.4，1473.2，1447.8，1256.6，1153.9，1100.9，836.3，742.8，587.8；ESI-MSm/z 628.4(M-H) -；ESI-HRMS calcd for C 25H 18N 3O 4Cl 4S 2(M-H) -627.94929，observed 627.9498.
Embodiment 10
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(3-(4-chloro-phenyl-) urea groups) ethyl)-2-thienyl sulphonyl amine (H1-3)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 60.3mg, 4-chlorophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 74.0mg, productive rate 87.2%.Y39： 1H 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＝8.8，2.4Hz，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)， 13C 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；IR(film)3401.5，2924.6，1659.6，1548.4，1491.7，1473.0，1446.8，1398.9，1307.1，1256.9，1233.9，1154.1，1099.8，828.3，588.7；ESI-MS m/z 594.4(M-H) -；ESI-HRMS calcd for C 25H 19N 3O 4Cl 3S 2-(M-H) -693.9888，observed 693.9888.
Embodiment 11
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H1-4)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 60.3mg, 4-methoxyphenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 74.0mg, productive rate 90.4%.Y40： 1H 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)； 13C NMR(100MHz，Acetone-d 6)δ157.0，156.0，154.5，152.2，140.5，139.0，134.3，133.4，132.7，131.1，130.8，129.8，129.6，129.4，126.6，126.4，124.6，122.7，121.2，118.3，114.7，55.7，45.0，40.5；IR(film)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(M-H) -；ESI-HRMS calcd forC 26H 22N 3O 5Cl 2S 2-(M-H) -590.0395，observed 590.0383.
Embodiment 12
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(3-(3,5-3,5-dimethylphenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H1-5)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 64.0mg, 3,5-dimethylphenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 54.2mg, productive rate 63.6%.Y41： 1H 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)； 13C NMR(100MHz，Acetone-d 6)δ156.7，154.5，152.2，141.2，140.5，139.0，138.8，133.4，132.7，131.1，130.8，129.8，129.6，129.4，126.7，126.3，124.5，124.2，122.7，118.3，117.1，44.9，40.5，21.5；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(M-H) -；ESI-H RMS calcd for C 27H 27N 3O 4Cl 2S 2-(M-H) -588.0596，observed 588.0591.
Embodiment 13
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H1-6)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 40mg, 3,5-bis-trifluoromethylbenzene based isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 52.9mg, productive rate 84%.
1H 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＝8.2Hz，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.forC 27H 19N 3O 4F 6S 2Cl 2Na(M+Na) +719.9990，observed 719.9981.
Embodiment 14
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(3-(3-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H1-7)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 40mg, 3-nitrophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 44mg, productive rate 81%. 1H 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)； 13C 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 25H 30N 4O 6S 2Cl 2Na (M+Na) +629.0094，observed 629.0077.
Embodiment 15
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H1-8)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 40mg, 3-methoxyphenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 42mg, productive rate 79%. 1H 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)； 13C NMR(100MHz，CDCl 3)δ160.2，156.2，153.6，150.8，140.2，140.0，136.6，132.2，131.8，130.5，130.4，129.7，129.5，129.3，128.3，126.1，124.8，123.8，121.5，117.3，112.3，108.9，105.8，55.2，43.8，39.9；ESI-MS m/z591.9(M+H) +，614.2(M+Na) +；MALDI-HRMS calcd.for C 26H 24N 3O 5S 2Cl 2(M+H) +592.0529，observed 592.0514.
Embodiment 16
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H1-9)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 60.5mg, 4-p-methoxy-phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 79.8mg, productive rate 96.1%.Y42： 1H 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)； 13C 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；IR(film)3363.6，2927.2，1539.6，1510.0，1473.0，1332.4，1247.9，1154.7，1099.9，832.2，587.7；ESI-MS m/z 606.5(M-H) -；ESI-HRMScalcd for C 26H 22N 3O 4Cl 2S 3-(M-H) -606.0159，observed 606.0155.
Embodiment 17
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(3-(3-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H1-10)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 58.3mg, 3-nitro phenylisothiocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 78.0mg, productive rate 95.1%.
Y43： 1H 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)； 13CNMR(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；IR(film)3355.1，2924.5，1527.4，1472.9，1346.5，1257.0，1153.4，1099.2，740.2，586.9；ESI-MS m/z621.4(M-H) -；ESI-HRMS calcd for C 25H 19N 2O 5Cl 3S 3-(M-H) -620.9914，observed 620.9900.
Embodiment 18
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H1-11)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 57.5mg, 3,5-bis-trifluoromethyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 90.1mg, productive rate 97.2%.
Y44： 1H 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)； 13C 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；IR(film)3349.9，3217.3，1556.6，1473.7，1382.6，1330.8，1277.7，1130.9，887.7，588.4；ESI-MS m/z 712.5(M-H) -；ESI-H RMScalcd for C 27H 18N 3O 3Cl 2S 3F 6-(M-H) -711.9789，observed 711.9797.
Embodiment 19
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(3-(3-chloro-phenyl-) thioureido) ethyl)-2-thienyl sulphonyl amine (H1-12)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 58.5mg, 3-chlorophenyl isothiocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 79.2mg, productive rate 97.9%.Y45： 1H NMR(400MHz，Acetone-d 6)δ3.07(q，J＝6.0Hz，2H)，3.62(q，J＝6.0Hz，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)； 13C 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；ESI-MS m/z 610.4(M-H) -；ESI-HRMS calcd for C 25H 19N 3O 3Cl 3S 3-(M-H) -609.9657，observed 609.9660.
Embodiment 20
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H1-13)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 57.7mg, 3-p-methoxy-phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 79.2mg, productive rate 100%.
Y46： 1H 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)； 13C NMR(100MHz，Acetone-d 6)δ182.5，161.4，154.5，152.2，140.6，140.2，138.9，133.5，132.8，131.1，130.9，130.0，129.6，129.4，126.7，126.4，124.0，122.6，118.4，117.0，112.1，110.5，55.7，55.7，44.9，43.5；IR(film)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(M-H) -；ESI-H RMS calcd for C 26H 22N 3O 4Cl 2S 3-(M-H) -606.0149，observed 606.0155.
Embodiment 21
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(3-(4-chloro-phenyl-) thioureido) ethyl)-2-thienyl sulphonyl amine (H1-14)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 60.9mg, 4-chlorophenyl isothiocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 84.2mg, productive rate 100%.
Y47： 1H NMR(400MHz，Acetone-d 6)δ3.06(q，J＝6.0Hz，2H)，3.62(q，J＝5.9Hz，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)； 13C NMR(100MHz，Acetone-d 6)δ181.4，153.1，150.8，139.2，137.4，137.1，132.0，131.3，129.7，129.5，129.2，128.6，128.3，128.2，128.0，125.2，125.1，123.2，121.1，117.0，43.4，41.9；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(M-H) -；ESI-HRMS calcd for C 25H 19N 3O 3Cl 3S 3-(M-H) -609.9655，observed 609.9660.
Embodiment 22
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H1-15)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 59.8mg, 4-nitro phenylisothiocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 84.1mg, productive rate 100%.Y48： 1H NMR(400MHz，Acetone-d 6)δ3.10(q，J＝6.0Hz，2H)，3.64(q，J＝5.9Hz，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)； 13C NMR(100MHz，Acetone-d 6)δ182.2，154.5，152.2，146.7，144.0，140.8，138.7，133.5，132.8，131.2，130.9，130.1，129.7，129.4，126.6，126.3，125.2，124.6，122.5，122.3，118.4，44.8，42.9；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(M-H) -；ESI-H RMS calcd for C 25H 19N 4O 5Cl 2S 3-(M-H)-620.9913，observed 620.9900.
Embodiment 23
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(3-(3-aminomethyl phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H1-16)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 63.6mg, 3-aminomethyl phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 85.0mg, productive rate 100%.
Y49： 1H 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)； 13C 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；IR(film)3360.5，2923.6，1538.0，1472.9，1335.2，1257.1，1154.3，1099.4，744.1，587.0；ESI-MS m/z 590.4(M-H) -；ESI-HRMS calcd for C 26H 22N 3O 3Cl 2S 3-(M-H) -590.0205，observed 590.0206.
Embodiment 24
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-trifluoroacetyl amido ethyl)-2-thienyl sulphonyl amine (I1-1)
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 60.5mg is added, trifluoroacetic anhydride (TFAA) 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 48.8mg, productive rate 63.5%.Y50： 1H 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)； 13C 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+H) +，561.3(M+Na) +；ESI-HRMS calcd for C 20H 15N 2O 4F 3Cl 2S 2Na +(M+Na) +560.9689，observed 560.9695.
Embodiment 25
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(4-nitrobenzene sulphonyl amido) ethyl)-2-thienyl sulphonyl amine (I1-2)
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 63.2mg is added, this yellow acyl chlorides 1.1 molar equivalent of 4-nitro, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 49.6mg, productive rate 55.4%.
Y51： 1H 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)； 13C 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；IR(film)3357.4，3276.8，2922.0，1529.0，1473.4，1335.5，1258.6，1157.4，1099.4，856.9，592.6；ESI-MS m/z 626.4(M-H) -；ESI-HRMS calcd for C 24H 19N 3O 7Cl 2S 3Na +(M+Na) +649.9656，observed 649.9654.
Embodiment 26
The bromo-N-of 3-(3-(N-Boc amido) propyl group)-2-thienyl sulphonyl amine (E2)
Under ice bath stirs, in 20ml egg type bottle, add N-Boc protect amino propylamine 1.3g (7.46mmol) of 3-, CH 2cl 210ml, triethylamine 1ml, slowly drip 3-bromine, 2-thienyl chlorination sulfone 1.8467g (7.06mmol).Stirring at room temperature is moved to one hour after adding.Add 200ml water, CH 2cl 2200ml × 3 extract, dry, filter, concentratedly to obtain faint yellow solid 2.6831g, and productive rate is 95.2%. 1H 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 12H 19BrN 2O 4S 2Na +420.9862(M+Na) +，observed 420.9881.
Embodiment 27
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-(N-Boc is amino) propyl group)-2-thienyl sulphonyl amine (F1-2)
The bromo-N-of 3-(3-(N-Boc amido) propyl group)-2-thienyl sulphonyl amine 1.5781g (4.8mmol) is added in 250ml reaction tubes, 2-(2,4-dichlorophenoxy) phenyl-boron dihydroxide 1.5183g (5.4mmol), Sphos 140.1mg (0.47mmol), palladium 105.5mg (0.34mmol), K 3pO 43.0693g (14.5mmol), adds THF25ml after substituting gas, refluxes 8 hours, stops heated and stirred.Add water 100ml, and ethyl acetate 250ml × 2 extract, dry, filter, concentrated, PE: ethyl acetate=2.5: 1 column chromatography, obtains yellow floss 1.3117g, and productive rate is 55.5%.
1H 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)； 13CNMR(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 forC 24H 26N 2O 5Cl 2S 2Na +(M+Na) +579.0544，observed 579.0552.
Embodiment 28
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-aminopropyl)-2-thienyl sulphonyl amine (G1-2)
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-(1-N-Boc is amino) propyl group)-2-thienyl sulphonyl amine 1.4015g (2.51mmol) is added, CH in 50ml egg type bottle 2cl 215ml, CF 3cO 2h 5ml, stirring at room temperature 1 hour.Add in salt of wormwood and CF 3cO 2h, to alkalescence, adds water, CH 2cl 2200ml × 3 extract, dry, filter, concentratedly to obtain faint yellow solid 1.1183g, productive rate 97.3%. 1H 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)； 13C 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 19H 19ClN 2O 3S 2457.0209(M+H) +，observed 457.0218.
Embodiment 29
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-(3-(4-nitrophenyl) urea groups) propyl group)-2-thienyl sulphonyl amine (H1-17)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(3-aminopropyl)-2-thienyl sulphonyl amine 62.5mg, 4-nitrophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 67.6mg, productive rate 79.6%.
1H 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)； 13C NMR(100MHz，Acetone-d 6)δ155.7，154.4，152.3，147.9，142.4，140.5，139.3，133.5，132.8，131.1，130.8，129.8，129.5，129.3，126.6，126.5，125.7，124.6，122.4，118.5，118.1，41.4，37.6，31.1；IR(film)3364.8，2925.6，1682.5，1552.6，1473.1，1329.1，1232.8，1153.4，1111.0，751.3，588.0；ESI-MS m/z 619.5(M-H) -；MALDI/DHB-HRMS calcd forC 26H 22N 4O 5C1 2S 2Na +(M+Na) +643.0245，observed 643.0250.
Embodiment 30
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-(3-(3,5-dichlorophenyl) urea groups) propyl group)-2-thienyl sulphonyl amine (H1-18)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(3-aminopropyl)-2-thienyl sulphonyl amine 61.1mg, 3,5-dichlorophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 76.9mg, productive rate 89.2%.
1H 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)； 13C NMR(100MHz，Acetone-d 6)δ156.0，154.4，152.3，144.0，140.4，139.3，135.4，133.5，132.7，131.1，130.9，129.7，129.5，129.3，126.6，126.5，124.6，122.4，121.5，118.5，117.0，41.3，37.5，31.2；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(M-H) -；MALDI/DHB-H RMS calcd for C 26H 21N 3O 4Cl 4S 2Na +(M+Na) +665.9608，observed 665.9620.
Embodiment 31
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-(3-(4-chloro-phenyl-) urea groups) propyl group)-2-thienyl sulphonyl amine (H1-19)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(3-aminopropyl)-2-thienyl sulphonyl amine 67.3mg, 4-chlorophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 81.2mg, productive rate 90.0%.
1H 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)； 13C NMR(100MHz，Acetone-d 6)δ156.5，154.4，152.3，140.5，139.4，133.5，132.7，131.1，130.9，129.7，129.5，129.3，126.6，126.5，124.6，122.3，120.5，118.5，41.3，37.4，31.4；IR(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(M-H) -；MALDI/DHB-HRMS calcd for C 26H 22N 3O 4Cl 3S 2Na +(M+Na) +632.0010，observed 632.0003.
Embodiment 32
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-(3-(4-p-methoxy-phenyl) urea groups) propyl group)-2-thienyl sulphonyl amine (H1-20)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(3-aminopropyl)-2-thienyl sulphonyl amine 66.8mg, 4-methoxyphenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 80.0mg, productive rate 90.3%.
1H 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＝9.8，3.0Hz，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)； 13C 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(M-H) -；MALDI/DHB-HRMS calcd for C 27H 25N 3O 5Cl 2S 2Na +(M+Na) +628.0518，observed 628.0505.
Embodiment 33
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-(3-(4-p-methoxy-phenyl) thioureido) propyl group)-2-thienyl sulphonyl amine (H1-21)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(3-aminopropyl)-2-thienyl sulphonyl amine 64.0mg, 4-p-methoxy-phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 73.2mg, productive rate 84.0%.
1H 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＝7.8，1.4Hz，1H)，7.63(d，J＝4.8Hz，1H)，8.47(s，1H)； 13C 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；IR(film)3340.0，2926.7，1708.1，1537.7，1510.3，1331.7，1247.5，1153.7，1100.2，743.6，586.9；ESI-MS m/z 620.5(M-H) -；MALDI/DHB-HRMScalcd for C 27H 25N 3O 4Cl 2S 3Na +(M+Na) +644.0267，observed 644.0277.
Embodiment 34
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-(3-(3-nitrophenyl) thioureido) propyl group)-2-
Thienyl sulphonyl amine (H1-22)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(3-aminopropyl)-2-thienyl sulphonyl amine 65.9mg, 3-nitro phenylisothiocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 89.3mg, productive rate 97.2%.
1H 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＝5.2Hz，1H)，7.75(d，J＝7.6Hz，1H)，7.84(d，J＝8.0Hz，1H)，8.46(s，1H)，9.09(s，1H)； 13CNMR(100MHz，Acetone-d 6)δ182.6，154.4，152.3，149.2，141.8，140.5，139.2，133.5，132.8，131.1，130.9，130.5，129.9，129.6，129.4，126.6，126.5，124.6，122.4，119.5，119.4，118.6，118.5，42.3，41.4，30.6；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(M-H) -；ESI-HRMS calcd for C 26H 21N 4O 5Cl 2S 3-(M-H) -635.0062，observed 623.0057.
Embodiment 35
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-(3-(3,5-bis-trifluoromethyl) thioureido) propyl group)-2-thienyl sulphonyl amine (H1-23)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(3-aminopropyl)-2-thienyl sulphonyl amine 66.2mg, 3,5-bis-trifluoromethyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 100.9mg, productive rate 95.7%.
1H 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)； 13C NMR(100MHz，Acetone-d 6)δ182.5，154.5，152.3，142.9，140.5，139.1，133.5，132.8，132.1，131.8，131.1，130.9，129.9，129.6，129.3，126.6，126.5，125.8，124.6，123.1，122.4，118.5，42.2，41.4，30.4；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(M-H) -；ESI-HRMS calcd for C 28H 20N 3O 3Cl 2F 3S 3-(M-H) -725.9951，observed725.9954.
Embodiment 36
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-(3-(3-chloro-phenyl-) thioureido) propyl group)-2-thienyl sulphonyl amine (H1-24)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(3-aminopropyl)-2-thienyl sulphonyl amine 64.9mg, 3-chlorophenyl isothiocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 72.1mg, productive rate 81.0%.
1H 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)； 13C NMR(100MHz，Acetone-d 6)δ182.4，154.4，152.3，141.4，140.4，139.3，134.6，133.5，132.7，131.2，131.1，130.9，129.8，129.5，129.4，126.6，126.5，125.5，124.6，124.4，122.9，122.4，118.5，42.3，41.3，30.6；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(M-H) -；MALDI/DHB-HRMS calcd for C 26H 22N 3O 3Cl 3S 3Na +(M+Na) +647.9770，observed 647.9781.
Embodiment 37
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-(3-(3-p-methoxy-phenyl) thioureido) propyl group)-2-thienyl sulphonyl amine (H1-25)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(3-aminopropyl)-2-thienyl sulphonyl amine 66.2mg, 3-p-methoxy-phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 57.7mg, productive rate 64.0%.
1H 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)； 13C NMR(100MHz，Acetone-d 6)δ180.8，160.0，153.0，150.9，139.0，138.9，138.0，132.1，131.3，129.7，129.5，128.3，128.1，128.0，125.2，125.1，123.2，121.0，117.1，115.6，110.6，109.2，54.2，41.0，39.9，28.9；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(M-H) -；ESI-H RMS calcd for C 27H 24N 3O 4Cl 2S 3-(M-H) -620.0303，observed 620.0312.
Embodiment 38
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-(3-(4-chloro-phenyl-) thioureido) propyl group)-2-thienyl sulphonyl amine (H1-26)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(3-aminopropyl)-2-thienyl sulphonyl amine 62.5mg, 4-chlorophenyl isothiocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 64.1mg, productive rate 74.8%.
1H 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)； 13C NMR(100MHz，Acetone-d 6)δ181.1，153.0，150.9，139.0，137.8，137.2，132.1，131.3，129.7，129.5，129.1，128.4，128.3，128.1，128.0，127.9，125.2，123.2，121.0，119.1，117.1，40.9，39.9，28.9；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(M-H) -；ESI-HRMS calcd for C 26H 21N 3O 3Cl 3S 3-(M-H) -623.9806，observed 623.9816.
Embodiment 39
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-(3-(4-nitrophenyl) thioureido) propyl group)-2-thienyl sulphonyl amine (H1-27)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(3-aminopropyl)-2-thienyl sulphonyl amine 62.9mg, 4-nitro phenylisothiocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 62.8mg, productive rate 71.6%.
1H 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)； 13C NMR(100MHz，Acetone-d 6)δ182.0，154.5，152.3，146.9，143.9，140.5，139.1，133.5，132.8，131.1，130.9，129.9，129.6，129.4，126.4，126.5，125.3，124.6，122.4，122.2，118.5，42.3，41.5，29.8；IR(film)3334.2，2924.7，1597.2，1510.3，1472.8，1328.7，1256.6，1153.0，1101.0，748.7，587.5；ESI-MS m/z 635.4(M-H) -；ESI-HRMS calcd for C 26H 21N 4O 5Cl 2S 3-(M-H) -635.0064，observed 637.0057.
Embodiment 40
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-(3-(3-aminomethyl phenyl) thioureido) propyl group)-2-thienyl sulphonyl amine (H1-28)
3-(2-(2 is added in 25ml egg type bottle, 4-dichlorophenoxy) phenyl)-N-(3-aminopropyl)-2-thienyl sulphonyl amine 62.7mg, 3-aminomethyl phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 58.5mg, productive rate 70.3%.
1H 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)； 13C NMR(100MHz，Acetone-d 6)δ182.3，154.4，152.3，140.4，140.0，139.4，139.0，133.5，132.7，131.1，130.9，130.0，129.7，129.5，129.4，127.1，126.6，126.5，125.8，124.7，122.4，122.3，118.5，42.4，41.2，30.9；IR(film)3334.1，2924.5，1537.8，1473.1，1257.0，1099.7，744.3，587.0；ESI-MS m/z 604.4([M-H] -)；ESI-HRMScalcd for C 27H 24N 3O 3Cl 2S 3-(M-H) -604.0382，observed 604.0362.
Embodiment 41
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-trifluoroacetyl amido propyl group)-2-thienyl sulphonyl amine (I1-3)
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-aminopropyl)-2-thienyl sulphonyl amine 65.2mg is added, trifluoroacetic anhydride (TFAA) 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 48.9mg, productive rate 62.0%.
1H 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)； 13C 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；IR(film)3331.1，3104.1，2930.7，1712.5，1473.9，1333.5，1157.4，1101.0，741.1，588.7；ESI-MS m/z 551.1(M-H) -；ESI-HRMS calcd for C 21H 16N 2O 4Cl 2F 3S 2-(M-H) -550.9873，observed550.9886.
Embodiment 42
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-(4-nitrobenzene sulphonyl amido) propyl group)-2-thienyl sulphonyl amine (I1-4)
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-aminopropyl)-2-thienyl sulphonyl amine 68mg is added, yellow acyl chlorides 1.1 molar equivalent of 4-oil of mirbane, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 45.7mg, productive rate 47.9%.
1H 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＝8.8，2.4Hz，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＝8.8Hz，2H)，8.43(d，J＝8.8Hz，2H)； 13C 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(M-H) -；ESI-HRMS calcd for C 25H 20N 3O 7Cl 2S 3-(M-H) -639.9852，observed 639.9846.
Embodiment 43
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-acetamido propyl group)-2-thienyl sulphonyl amine (I1-5)
3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-aminopropyl)-2-thienyl sulphonyl amine 63.2mg is added, aceticanhydride 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 66.4mg, productive rate 96%.
1H 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)； 13CNMR(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(film)3288.0，3104.4，1621.7，1574.0，1473.4，1259.3，1146.7，802.0，589.2；ESI-MS m/z 497.2(M-H) -；ESI-HRMS calcd forC 21H 19N 2O 4Cl 2S 2-(M-H) -497.0172，observed 497.0169.
Embodiment 44
2-(1-naphthols base) oil of mirbane (A4)
1-naphthols 10.104g is added, o-fluoronitrobenzene 10.137g, K in 250ml egg type bottle 2cO 311.744g, DMF 46ml, backflow 5h.Stop heating, add 500ml ethyl acetate, water 200ml × 3 are washed, dry, filter, concentrated, obtain salmon liquid 18.590g, productive rate 100%.
1H 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)； 13C 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 16H 11NO 3Na(M+Na) +288.0632，observed 288.0632.
Embodiment 45
2-(1-naphthols base) amino-benzene (B4)
Add 2-(1-naphthols base) oil of mirbane 18.590g, ethanol 20ml in 1L eggplant-shape bottle, and add a little ethyl acetate hydrotropy, add 20g zinc powder, slowly drip the hydrochloric acid 360ml of 1mol/L under mechanical stirrer stirring at room temperature, to the grey decoloration of zinc powder.Stop stirring.Add 500ml ethyl acetate, 200ml × 3 are washed, dry, filter, concentrated, obtain salmon liquid 16.48g, productive rate 100%.
1H 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)；
Embodiment 46
2-(1-naphthols base) iodobenzene (C4)
500ml there-necked flask is placed in ice bath, adds 2-(1-naphthols base) amino-benzene 10.318g, vitriol oil 7ml wherein and adds after 170ml water dilution cooling, slowly add NaNO under mechanical stirring 24.069g water (60ml) solution, adds for ten minutes, adds Kl 9.929g water (40ml) solution again, move to stirred at ambient temperature after half hour after 1 hour.Stop after room temperature reaction 4h, add water 200ml, use CH 2cl 2300ml × 3 extract, then are merged, and use saturated Na 2s 2o 3washing once.Dry, filter, concentrated, column chromatography, obtains nearly colourless liquid 13.093g, and productive rate is 75.3%.
EI-MS m/z 346(M+H) +；EI-HRMS calcd.for C 16H11OI(M) +345.9855，observed 345.9859；
Embodiment 47
2-(1-naphthols base) phenyl-boron dihydroxide (D4)
2-(1-naphthols base) iodobenzene 3.073g is added in 100ml reaction tubes; under argon shield, anhydrous THF 32ml is added after abundant deoxygenation dewaters; 2.5mol/L n-butyllithium solution 4.2ml is slowly dripped in-78 DEG C of cryostats; react after 1 hour; add trimethyl borate 1.4ml at-78 DEG C, after 2h, reaction tubes is moved to stirring at room temperature.Add 1ml concentrated hydrochloric acid after stirring at room temperature 2h, extraction into ethyl acetate, dry, filter, concentrated after white solid 1.498g, productive rate is 64%.
1H 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 16H 13BO 3(M) +263.0994，observed 263.0989.
Embodiment 48
3-(2-(1-naphthols base) phenyl)-N-(2-(N-Boc amido) ethyl)-2-thienyl sulphonyl amine (F4)
The bromo-N-of 3-(2-(N-Boc amido) ethyl)-2-thienyl sulphonyl amine 0.810g, 2-(1-naphthols base) phenyl-boron dihydroxide 1.92g, Sphos 126mg is added, palladium 48mg, K in 250ml Shrek pipe 3pO 40.889g, adds THF50ml after after abundant deoxygenation, refluxes 8 hours, stops heated and stirred.Add water 100ml, and ethyl acetate 100ml × 2 extract, dry, filter, concentrated, column chromatography, obtains yellow floss 700mg, and productive rate is 43.5%.ESI-MS m/z 525.0(M+H) +；
Embodiment 49
3-(2-(1-naphthols base) phenyl)-N-(2-amido ethyl)-2-thienyl sulphonyl amine (G4)
3-(2-(1-naphthols base) phenyl)-N-(2-(N-Boc amido) ethyl)-2-thienyl sulphonyl amine 700mg, CH is added in 25ml egg type bottle 2cl 26ml, CF 3cO 2h 1.5ml, stirring at room temperature 12 hours.Add in salt of wormwood and CF 3cO 2h, to alkalescence, adds water, CH 2cl 260ml × 3 extract, dry, filter, concentratedly to obtain yellow solid 539mg, productive rate 95.2%.
ESI-MS m/z 425.0(M+H) +；ESI-HRMS calcd.for C 16H 11NO 3Na 425.0988(M+H) +，observed 425.0092；
Embodiment 50
3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3,5-dichlorophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H4-1)
3-(2-(1-naphthols base) phenyl)-N-(2-amido ethyl)-2-thienyl sulphonyl amine 39.5mg is added, 3,5-dichlorophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 49.6mg, productive rate 87%.
1H 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)； 13C NMR(100MHz，Acetone-d 6)δ155.9，155.7，153.8，143.9，141.2，138.7，135.9，135.5，133.2，132.9，131.0，129.8，128.7，127.6，127.4，126.9，126.8，126.7，124.2，124.0，122.7，121.6，119.2，117.0，114.0，44.3，40.6；
Embodiment 51
3-(2-(1-naphthols base) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H4-2)
3-(2-(1-naphthols base) phenyl)-N-(2-amido ethyl)-2-thienyl sulphonyl amine 40.1mg is added, 4-methoxyphenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 50.6mg, productive rate 93.4%.
1H 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)； 13CNMR(100MHz，Acetone-d 6)δ157.0，155.9，155.7，153.8，141.1，138.8，135.9，134.4，133.2，132.8，131.0，129.7，128.6，127.5，127.4，126.9，126.8，126.7，124.2，124.1，122.8，121.2，119.3，114.7，114.0，55.7，45.0，40.5；
Embodiment 52
3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H4-3)
3-(2-(1-naphthols base) phenyl)-N-(2-amido ethyl)-2-thienyl sulphonyl amine 40.4mg is added in 25ml egg type bottle, 3,5-bis-trifluoromethylbenzene based isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 58.4mg, productive rate 90.3%.
1H 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)； 13C 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；
Embodiment 53
3-(2-(1-naphthols base) phenyl)-N-(2-(3-(4-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H4-4)
3-(2-(1-naphthols base) phenyl)-N-(2-amido ethyl)-2-thienyl sulphonyl amine 40mg is added, 4-nitrophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 48.3mg, productive rate 87%.
1H 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 29H 24N 4O 6S 2Na(M+Na) +611.1030，observed611.1038.
Embodiment 54
3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3-nitrophenyl) urea groups) ethyl)-2-thienyl sulphur
Acid amides (H4-5)
3-(2-(1-naphthols base) phenyl)-N-(2-amido ethyl)-2-thienyl sulphonyl amine 40mg is added, 4-nitrophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 48.3mg, productive rate 87%.
1H 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)； 13C NMR(100MHz，CDCl 3)δ155.6，154.7，152.6，148.3，141.2，140.4，135.8，134.9，132.1，131.9，130.5，129.6，129.4，127.9，126.8，126.4，126.2，125.8，125.1，124.5，123.8，123.4，121.6，118.6，116.9，113.3，113.1，43.7，39.7；ESI-MS m/z 589.3(M+H) +，611.2(M+Na) +；MALDI-HRMS calcd.for C 29H 24N 4O 6S 2Na(M+Na) +611.1030，observed611.1044.
Embodiment 55
3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H4-6)
3-(2-(1-naphthols base) phenyl)-N-(2-amido ethyl)-2-thienyl sulphonyl amine 40mg is added, 3-methoxyphenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 50mg, productive rate 93%.
1H 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)； 13C NMR(100MHz，CDCl 3)δ160.2，156.2，154.6，152.8，140.8，140.1，136.4，134.9，132.0，131.9，130.4，129.7，129.2，127.8，126.8，126.4，126.2，125.8，125.3，123.6，123.4，121.7，118.7，113.0，112.2，108.9，105.6，43.8，39.8；ESI-MS m/z 574.3(M+H) +，596.1(M+Na) +；MALDI-HRMScalcd.for C 30H 27N 3O 5S 2Na(M+Na) +596.1284，observed 596.1288.
Embodiment 56
3-(2-(1-naphthols base) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H4-7)
3-(2-(1-naphthols base) phenyl)-N-(2-amido ethyl)-2-thienyl sulphonyl amine 40.8mg is added in 25ml egg type bottle, 4-p-methoxy-phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 51.3mg, productive rate 90.5%. 1H 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)； 13C 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；
Embodiment 57
3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H4-7)
3-(2-(1-naphthols base) phenyl)-N-(2-amido ethyl)-2-thienyl sulphonyl amine 40.0mg is added, 3-nitro phenylisothiocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 54.0mg, productive rate 94.7%.
1H 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)； 13C 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；
Embodiment 58
3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H4-8)
3-(2-(1-naphthols base) phenyl)-N-(2-amido ethyl)-2-thienyl sulphonyl amine 40.2mg is added in 25ml egg type bottle, 3,5-bis-trifluoromethyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 59.3mg, productive rate 90.0%.
1H 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)； 13C NMR(100MHz，Acetone-d 6)δ182.8，155.8，153.8，142.8，141.4，138.5，135.9，133.2，133.0，132.2，131.9，131.0，130.0，128.7，127.6，127.4，127.0，126.8，126.7，125.7，124.2，124.0，123.7，122.7，119.3，114.0，44.8，42.9；
Embodiment 59
3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H4-9)
3-(2-(1-naphthols base) phenyl)-N-(2-amido ethyl)-2-thienyl sulphonyl amine 39.9mg is added in 25ml egg type bottle, 3-p-methoxy-phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 49.7mg, productive rate 89.7%.
1H 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)； 13C NMR(100MHz，Acetone-d 6)δ182.4，155.7，153.8，161.4，141.2，140.2，138.7，135.9，133.2，132.9，131.0，130.9，129.9，128.6，127.6，127.4，127.0，126.9，126.9，126.8，124.2，124.1，122.8，119.3，116.9，114.0，112.1，110.5，55.7，44.9，43.5；
Embodiment 60
3-(2-(1-naphthols base) phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H4-10)
3-(2-(1-naphthols base) phenyl)-N-(2-amido ethyl)-2-thienyl sulphonyl amine 39.5mg is added, 4-nitro phenylisothiocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 52.5mg, productive rate 93.3%.
1H 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)； 13C 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；
Embodiment 61
3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3-aminomethyl phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H4-11)
3-(2-(1-naphthols base) phenyl)-N-(2-amido ethyl)-2-thienyl sulphonyl amine 39.7mg is added, 3-aminomethyl phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 49.2mg, productive rate 91.6%.
1H 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)； 13C 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；
Embodiment 62
3-(2-(1-naphthols base) phenyl)-N-(2-(3-phenylthiourea base) ethyl)-2-thienyl sulphonyl amine (H4-12)
3-(2-(1-naphthols base) phenyl)-N-(2-amido ethyl)-2-thienyl sulphonyl amine 39.6mg is added, PITC 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 19.7mg, productive rate 38%.
1H 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)； 13C NMR(100MHz，Acetone-d 6)δ182.6，155.7，153.8，141.3，138.7，135.9，133.2，132.9，131.0，130.0，129.9，128.6，127.6，127.4，127.0，126.9，126.8，126.2，125.1，125.0，124.2，124.1，122.8，119.3，114.0，44.9，43.5；
Embodiment 63
3-(2-(1-naphthols base) phenyl)-N-(2-(4-nitrobenzene sulphonyl amido) ethyl)-2-thienyl sulphonyl amine (I4-1)
3-(2-(1-naphthols base) phenyl)-N-(2-amido ethyl)-2-thienyl sulphonyl amine 39.2mg is added, 4-nitrobenzene sulfonyl chloride 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 45.2mg, productive rate 80.3%.
1H 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)； 13C NMR(100MHz，Acetone-d 6)δ155.8，153.7，150.9，147.3，141.4，138.6，135.9，133.2，133.0，131.0，130.0，129.2，128.7，127.6，127.4，127.0，126.8，126.5，125.3，124.3，123.9，122.7，119.1，114.3，43.7；
Embodiment 64
3-(2-(1-naphthols base) phenyl)-N-(2-acetamido ethyl)-2-thienyl sulphonyl amine (I4-2)
3-(2-(1-naphthols base) phenyl)-N-(2-amido ethyl)-2-thienyl sulphonyl amine 39.9mg is added, aceticanhydride 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 45.8mg, productive rate 95.8%.ESI-MS m/z 509.0 (M+H) +; Synthetic route:
Embodiment 65
2-hexamethylene alcohol radical oil of mirbane (A2)
Hexalin 10.054g is added, o-fluoronitrobenzene 14.180g, K in 250ml egg type bottle 2cO 313.962g, DMF 46ml, backflow 5h.Stop heating, add 500ml ethyl acetate, water 200ml × 3 are washed, dry, filter, concentrated, obtain salmon liquid 9.730g, productive rate 44%.ESI-MS m/z 222.0(M+H) +；
Embodiment 66
2-hexamethylene alcohol radical amino-benzene (B2)
Add 2-hexamethylene alcohol radical oil of mirbane 4.587g in 1L eggplant-shape bottle, ethanol 100ml, Pd/C 0.450g, finally adds hydrazine hydrate 6.9ml, stirring at room temperature 5 hours.Filter, after underpressure distillation solvent, add 200ml ethyl acetate, 100ml × 2 are washed, dry, filter, concentrated, obtain salmon liquid 3.569g, productive rate 90%.ESI-MS m/z 192.0(M+H) +；
Embodiment 67
2-hexamethylene alcohol radical iodobenzene (C2)
500ml there-necked flask is placed in ice bath, adds 2-hexamethylene alcohol radical amino-benzene 3.9g wherein, and vitriol oil 3.25ml adds after 80ml water dilution cooling, slowly adds NaNO under mechanical stirring 21.7g water (25ml) solution, adds for ten minutes, adds Kl 4.29g water (40ml) solution again, move to stirred at ambient temperature after half hour after 1 hour.Stop after room temperature reaction 4h, add water 200ml, use CH 2cl 2100ml × 3 extract, then are merged, and use saturated Na 2s 2o 3washing once.Dry, filter, concentrated, column chromatography, obtains nearly colourless liquid 4.84g, and productive rate is 78.6%.
1H 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 12H 15IO(M)302.1068，observed302.1070.
Embodiment 68
2-hexamethylene alcohol radical phenyl-boron dihydroxide (D2)
2-hexamethylene alcohol radical iodobenzene 3.241g is added in 100ml reaction tubes; under argon shield, anhydrous THF 50ml is added after abundant deoxygenation dewaters; 2.5mol/L n-butyllithium solution 5.3ml is slowly dripped in-78 DEG C of cryostats; react after 1 hour; add trimethyl borate 2.1ml at-78 DEG C, after 2h, reaction tubes is moved to stirring at room temperature.Add 1ml concentrated hydrochloric acid after stirring at room temperature 2h, extraction into ethyl acetate, dry, filter, concentrated after white solid 2.2167g, productive rate is 94%.
1H 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 12H 17BO 3(M)219.1307，observed 219.1311.
Embodiment 69
1-N-((the bromo-2-thienyl of 3-) sulfuryl)-4-N-Boc piperazine (E3)
Ice bath adds 1-N-Boc piperazine 0.985g, CH under stirring in 20ml egg type bottle 2cl 230ml, triethylamine 1ml, slowly drip 3-bromine, 2-thienyl chlorination sulfone 1.309g.Stirring at room temperature is moved to one hour after adding.Add 100ml water, CH 2cl 2100ml × 3 extract, dry, filter, concentratedly to obtain faint yellow solid 1.645g, and productive rate is 80%.
1H 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/z433.1(M+Na) +；ESI-HRMS calcd.for C 13H 19BrN 2O 4S 2Na(M+Na) +432.9862，observed 432.9848.
Embodiment 70
1-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-4-N-Boc piperazine (F2)
1-N-((the bromo-2-thienyl of 3-) sulfuryl)-4-N-Boc piperazine 0.555g is added, 2-hexamethylene alcohol radical phenyl-boron dihydroxide 0.900g, Sphos 94mg, palladium 28mg, K in 250ml Shrek pipe 3pO 40.939g, adds THF 50ml after after abundant deoxygenation, reflux 8 hours, stops heated and stirred.Add water 100ml, and ethyl acetate 100ml × 2 extract, dry, filter, concentrated, column chromatography, obtains yellow floss 875mg, and productive rate is 78.9%.
1H 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.forC 25H 34N 2O 5S 2Na(M+Na) +529.1801，observed 529.1814.
Embodiment 71
1-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-piperazine (G2)
1-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-4-N-Boc piperazine 835mg, CH is added in 25ml egg type bottle 2cl 210ml, CF 3cO 2h 1.5ml, stirring at room temperature 12 hours.Add in salt of wormwood and CF 3cO 2h, to alkalescence, adds water, CH 2cl 260ml × 3 extract, dry, filter, concentratedly to obtain yellow solid 670mg, productive rate 100%.
ESI-MS m/z 407.3(M+H) +；MALDI-HRMS calcd.for C 20H 27N 2O 3S 2(M+H) +407.1458，observed 407.1472.
Embodiment 72
4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1 one N-(3,5-dichloroanilino) formyl piperazine (H2-1)
1-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-piperazine 41mg is added in 25ml egg type bottle, 3,5-dichlorophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 60mg, productive rate 100%.
1H 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)； 13C 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/z616.4(M+H) +；HRMS calcd.forC 27H 29N 3O 4S 2Cl 2Na(M+Na) +616.0869，observed 616.0857；
Embodiment 73
4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(4-anisole amido) formyl piperazine (H2-2)
1-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-piperazine 41mg is added in 25ml egg type bottle, 4-methoxyphenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 50.8mg, productive rate 90.7%.
1H 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＝8.0Hz，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)； 13C 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；ESIMS m/z 556.5(M+H) +；HRMS calcd.for C 28H 33N 3O 5S 2Na(M+Na) +578.1754，observed578.1762；
Embodiment 74
4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(3,5-bis-trifluoromethylbenzene amido) formyl piperazine (H2-3)
1-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-piperazine 41mg is added in 25ml egg type bottle, 3,5-bis-trifluoromethylbenzene based isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 66.7mg, productive rate 100%.
1H 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)； 13CNMR(100MHz，CDCl 3)δ155.0，153.6，143.2，140.5，133.2，132.9，132.9，132.3，132.0，130.2，129.1，123.3，119.6，119.3，116.3，112.3，75.2，45.2，43.7，31.8，25.4，23.5；ESIMS m/z 684.5(M+Na) +；HRMS calcd.forC 29H 29N 3O 4S 2F 6Na(M+Na) +684.1396，observed 684.1401；
Embodiment 75
4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(4-anisole amido) thioformyl piperazine (H2-4)
1-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-piperazine 42.3mg is added in 25ml egg type bottle, 4-p-methoxy-phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 59.5mg, productive rate 100%.
1H 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)； 13C 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.forC 28H 33N 3O 4S 3Na(M+Na) +594.1525，observed 594.1507；
Embodiment 76
4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(3-oil of mirbane amido) thioformyl piperazine (H2-5)
1-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-piperazine 42.4mg is added in 25ml egg type bottle, 3-nitro phenylisothiocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 61.2mg, productive rate 100%.
1H 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)； 13C 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.forC 27H 30N 4O 5S 3Na(M+Na) +609.1271，observed 609.1277；
Embodiment 77
4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(3,5-bis-trifluoromethylbenzene amido) thioformyl piperazine (H2-6)
1-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-piperazine 45.0mg is added in 25ml egg type bottle, 3,4-bis-trifluoromethyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 68mg, productive rate 90.7%.
1H 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)； 13CNMR(100MHz，CDCl 3)δ182.2，155.0，143.6，141.2，132.8，132.2，132.0，131.7，130.3，129.4，124.4，123.7，123.1，121.7，119.6，112.3，75.2，48.1，44.9，31.8，25.4，23.6；ESIMS m/z 687.5(M+H) +；HRMS calcd.forC 29H 29N 3O 3S 3F 6Na(M+Na) +700.1167，observed 700.1190；
Embodiment 78
4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(3-anisole amido) thioformyl piperazine (H2-7)
1-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-piperazine 42.1mg is added in 25ml egg type bottle, 3-p-methoxy-phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 57.7mg, productive rate 97.5%.
1H 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)； 13C 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 28H 33N 3O 4S 3Na(M+Na) +594.1525，observed 594.1519；
Embodiment 79
4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(4-oil of mirbane amido) thioformyl piperazine (H2-8)
1-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-piperazine 42.4mg is added in 25ml egg type bottle, 4-nitro phenylisothiocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 59.0mg, productive rate 96.4%.
1H 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)； 13C NMR(100MHz，CDCl 3)δ182.1，154.9，145.8，143.5，143.5，133.3，132.8，132.4，130.3，129.3，124.8，123.1，121.6，119.6，112.3，75.2，48.6，44.9，31.8，25.5，23.6；ESIMS m/z 587.5(M+H) +；HRMS calcd.for C 27H 30N 4O 5S 3Na(M+Na) +609.1271，observed 609.1264；
Embodiment 80
4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(3-toluidine) thioformyl piperazine (H2-9)
1-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-piperazine 43.0mg is added in 25ml egg type bottle, 3-aminomethyl phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 55.0mg, productive rate 93.5%.
1H 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)； 13C 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 28H 33N 3O 3S 3Na(M+Na) +578.1576，observed 578.1571；
Embodiment 81
4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-anilino thioformyl piperazine (H2-10)
1-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-piperazine 42.7mg is added, PITC 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 56.3mg, productive rate 98.9%.
1H 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)； 13C 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) +；HRMS calcd.for C 27H 31N 3O 3S 3Na(M+Na) +564.1420，observed564.1437；
Embodiment 82
4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-4-nitrobenzenesulfonyl piperazine (I2-1)
1-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl) this yellow acyl chlorides 1.1 molar equivalent of-piperazine 42.3mg, 4-nitro is added, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 44.3mg, productive rate 76%.
1H 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)； 13CNMR(100MHz，CDCl 3)δ154.9，150.4，143.0，141.6，133.2，133.1，133.0，130.1，129.0，128.8，124.5，123.2，119.6，112.1，75.0，45.6，44.9，31.8，25.5，23.6；ESIMS m/z 614.4(M+Na) +；HRMS calcd.for C 26H 29N 3O 7S 3Na(M+Na) +614.1060，observed 614.1059；
Embodiment 83
4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-Acetylpiperazine (I2-2)
1-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-piperazine 42.0mg is added in 25ml egg type bottle, 4-p-methoxy-phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 32.4mg, productive rate 70%.
1H 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)； 13C 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.forC 22H 28N 2O 4S 2Na(M+Na) +471.1383，observed 471.1386；
Embodiment 84
4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-trifluoroacetyl group piperazine (I2-3)
1-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-piperazine 41mg is added in 25ml egg type bottle, 4-p-methoxy-phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 39.0mg, productive rate 77%.
1H 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)； 13C 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/z525.4(M+H) +；HRMS calcd.for C 22H 25N 2O 4F 3S 2Na(M+Na) +525.1100，observed 525.1120；
Embodiment 85
2-sesame phenolic group oil of mirbane (A5)
Sesamol 7.749g is added, o-fluoronitrobenzene 7.5g, the NaH 3.0g of 85%, anhydrous tetrahydro furan 50ml, backflow 5h in 250ml egg type bottle.Add 500ml ethyl acetate, water 200ml × 3 are washed, dry, filter, concentrated, obtain khaki color solid 11.103g, productive rate 80.5%.
1H 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)；
Embodiment 86
2-sesame phenolic group amino-benzene (B5)
Add 2-sesame phenolic group oil of mirbane 6.052g in 1L eggplant-shape bottle, ethanol 100ml, Pd/C 0.700g, finally adds hydrazine hydrate 8ml, stirring at room temperature 5 hours.Filter, after underpressure distillation solvent, add 200ml ethyl acetate, 100ml × 2 are washed, dry, filter, concentrated, obtain salmon liquid 5.056g, productive rate 94.5%.
1H 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)；
Embodiment 87
2-sesame phenolic group iodobenzene (C5)
500ml there-necked flask is placed in ice bath, adds 2-sesame phenolic group amino-benzene 3.092g wherein, and vitriol oil 2.2ml adds after 52ml water dilution cooling, slowly adds NaNO under stirring 21.246g water (18ml) solution, adds for ten minutes, adds Kl 2.883g water (18ml) solution again, move to stirred at ambient temperature after half hour after 1 hour.Stop after room temperature reaction 4h, add water 100ml, use CH 2cl 2100ml × 3 extract, then are merged, and use saturated Na 2s 2o 3washing once.Dry, filter, concentrated, column chromatography, obtains nearly colourless liquid 3.032g, and productive rate is 66.1%.
1H 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)； 13C 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 13H 9lO 3(M)339.9596，observed 339.9593.
Embodiment 88
2-sesame phenolic group phenyl-boron dihydroxide (D5)
2-sesame phenolic group iodobenzene 2.980g is added in 100ml reaction tubes; under argon shield, anhydrous THF50ml is added after abundant deoxygenation dewaters; 2.5mol/L n-butyllithium solution 4.0ml is slowly dripped in-78 DEG C of cryostats; react after 1 hour; add trimethyl borate 1.4ml at-78 DEG C, after 2h, reaction tubes is moved to stirring at room temperature.Add 1ml concentrated hydrochloric acid after stirring at room temperature 2h, extraction into ethyl acetate, dry, filter, concentrated after white solid 2.261g, productive rate is 100%.
1H 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)；
Embodiment 89
3-(2-sesame phenolic group phenyl)-N-(2-(N-Boc is amino) ethyl)-2-thienyl sulphonyl amine (F5)
The bromo-N-of 3-(2-(N-Boc amido) ethyl)-2-thienyl sulphonyl amine 1.038g is added, 2-sesame phenolic group phenyl-boron dihydroxide 0.772g, Sphos 120mg, palladium 49mg, K in 250ml Shrek pipe 3pO 40.855g, adds THF 50ml after after abundant deoxygenation, water 10ml, refluxes 8 hours, stops heated and stirred.Add water 100ml, and ethyl acetate 100ml × 2 extract, dry, filter, concentrated, column chromatography, obtains yellow floss 1.139g, and productive rate is 73.4%.
Embodiment 90
3-(2-sesame phenolic group phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine (G5)
3-(2-sesame phenolic group phenyl)-N-(2-(N-Boc is amino) ethyl)-2-thienyl sulphonyl amine 877mg, CH is added in 25ml egg type bottle 2cl 210ml, CF 3cO 2h 1.5ml, stirring at room temperature 12 hours.Add in salt of wormwood and CF 3cO 2h, to alkalescence, adds water, CH 2cl 260ml × 3 extract, dry, filter, concentratedly to obtain yellow solid 487.4mg, productive rate 68.9%.
1H 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)； 13C 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 19H 19N 2O 5S 2(M+H) +419.0730，observed 419.0720.
Embodiment 91
3-(2-sesame phenolic group phenyl)-N-(2-(3-(3,5-dichlorophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H5-1)
3-(2-sesame phenolic group phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 40.2mg is added, 3,5-dichlorophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 58.3mg, productive rate 100%.
1H 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＝7.6，2.0Hz，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)； 13C NMR(100MHz，Acetone)δ156.5，155.9，152.2，149.5，144.9，143.9，141.4，138.5，135.5，133.0，132.9，130.8，129.9，126.0，123.3，121.6，118.1，117.0，112.8，109.0，102.9，102.6，44.3，40.5；
Embodiment 92
3-(2-sesame phenolic group phenyl)-N-(2-(3-(4-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H5-2)
3-(2-sesame phenolic group phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 39.4mg is added, 4-methoxyphenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 53.4mg, productive rate 100%.
1H 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)； 13CNMR(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；
Embodiment 93
3-(2-sesame phenolic group phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H5-3)
3-(2-sesame phenolic group phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 39.7mg is added, 3,5-bis-trifluoromethylbenzene based isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 55.1mg, productive rate 86.2%.
1H 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)； 13C 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，
Embodiment 94
3-(2-sesame phenolic group phenyl)-N-(2-(3-(4-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H5-4)
3-(2-sesame phenolic group phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 39.4mg is added, 4-nitrophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 51.8mg, productive rate 94.5%.
1H 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 26H 22N 4O 8S 2Na(M+Na) +605.0771，observed 605.0775.
Embodiment 95
3-(2-sesame phenolic group phenyl)-N-(2-(3-(3-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H5-5)
3-(2-sesame phenolic group phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 40.3mg is added, 3-nitrophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 49.3mg, productive rate 87.9%.
1H 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)； 13C 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.forC 26H 22N 4O 8S 2Na(M+Na) +605.0771，observed 605.0767.
Embodiment 96
3-(2-sesame phenolic group phenyl)-N-(2-(3-(3-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H5-6)
3-(2-sesame phenolic group phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 39.4mg is added, 3-methoxyphenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 46.1mg, productive rate 86.3%.
1H 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)； 13C 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；ESI-MSm/z 568.3(M+H) +，590.3(M+Na) +；MALDI-HRMS calcd.forC 27H 25N 3O 7S 2Na(M+Na) +590.1026，observed 590.1013.
Embodiment 97
3-(2-sesame phenolic group phenyl)-N-(2-(3-(4-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H5-7)
3-(2-sesame phenolic group phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 39.0mg is added, 4-p-methoxy-phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 54.4mg, productive rate 100%.
1H 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，J＝8.4，2.4Hz，1H)，6.00(s，2H)，3.79(s，3H)，3.74(q，J＝6.0Hz，2H)，3.16(q，J＝5.9Hz，2H)； 13C NMR(100MHz，Acetone)δ183.0，158.9，156.4，152.3，149.5，144.9，141.4，138.5，133.0，132.9，130.8，129.9，127.9，127.8，126.2，123.5，118.2，115.4，112.8，109.1，102.8，102.6，55.8，44.8，43.7；
Embodiment 98
3-(2-sesame phenolic group phenyl)-N-(2-(3-(3-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H5-8)
3-(2-sesame phenolic group phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 39.6mg is added, 3-nitro phenylisothiocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 56.6mg, productive rate 100%.
1H 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＝8.8Hz，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)； 13C 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；
Embodiment 99
3-(2-sesame phenolic group phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H5-9)
3-(2-sesame phenolic group phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 38.5mg is added, 3,5-bis-trifluoromethyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 63.4mg, productive rate 100%. 1H 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)； 13C NMR(100MHz，Acetone)δ182.7，156.5，152.2，149.5，144.9，142.8，141.6，138.2，133.1，132.9，132.2，131.8，130.8，130.1，126.1，125.7，123.7，123.4，123.0，118.2，112.8，109.0，102.8，102.6，44.7，42.9；
Embodiment 100
3-(2-sesame phenolic group phenyl)-N-(2-(3-(3-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H5-10)
3-(2-sesame phenolic group phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 38.7mg is added, 3-p-methoxy-phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 54.0mg, productive rate 100%.
1H 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)； 13C 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；
Embodiment 101
3-(2-sesame phenolic group phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H5-11)
3-(2-sesame phenolic group phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 39.7mg is added, 4-nitro phenylisothiocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 49.6mg, productive rate 87.3%.
1H 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)； 13C NMR(100MHz，Acetone)δ181.9，156.5，152.2，149.5，146.7，144.9，143.9，141.6，138.2，133.0，132.9，130.9，130.1，126.0，125.2，123.4，122.0，118.2，112.8，109.1，102.8，102.6，44.7，42.8；
Embodiment 102
3-(2-sesame phenolic group phenyl)-N-(2-(3-(3-aminomethyl phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H5-12)
3-(2-sesame phenolic group phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 38.6mg is added, 3-aminomethyl phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 52.4mg, productive rate 100%.
1H 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)； 13C NMR(100MHz，Acetone)δ182.5，156.4，152.3，149.5，144.9，141.5，140.0，138.9，138.4，133.0，132.9，130.8，130.0，129.9，127.2，126.1，125.8，123.5，122.3，118.2，112.8，109.1，102.8，102.6，44.8，43.5；
Embodiment 103
3-(2-sesame phenolic group phenyl)-N-(2-(3-phenylthiourea base) ethyl)-2-thienyl sulphonyl amine (H5-13)
3-(2-sesame phenolic group phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 36.8mg is added, PITC 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 48.7mg, productive rate 100%.
1H 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)； 13CNMR(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；
Embodiment 104
3-(2-sesame phenolic group phenyl)-N-(2-(4-nitrobenzene sulphonyl amido) ethyl)-2-thienyl sulphonyl amine (I5-1)
3-(2-sesame phenolic group phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 43.5mg is added, each 1.1 molar equivalents of 4-nitrobenzene sulfonyl chloride, triethylamine, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 54.0mg, productive rate 86.1%.
1H 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)； 13C 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；
Embodiment 105
3-(2-sesame phenolic group phenyl)-N-(2-acetamido ethyl)-2-thienyl-N-alkylsulfonyl ethanamide (I5-2)
3-(2-sesame phenolic group phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 40mg is added, each 1.1 molar equivalents of aceticanhydride, triethylamine, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 44.3mg, productive rate 92.3%.
1H 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)； 13C NMR(100MHz，Acetone)δ170.3，170.3，157.0，151.4，149.6，145.4，143.6，137.7，133.1，132.6，132.5，131.5，124.4，123.2，117.1，113.5，109.1，103.3，102.7，46.4，38.7；
Embodiment 106
2-(beta naphthal base) oil of mirbane (A3)
Beta naphthal 4.071g is added, o-fluoronitrobenzene 3.690g, the NaH 2.558g of 60%, anhydrous tetrahydro furan 50ml, backflow 5h in 250ml egg type bottle.Removing tetrahydrofuran (THF), adds 200ml ethyl acetate, and water 200ml × 3 are washed, dry, filter, concentrated, product 5.0g, productive rate 72.0%.
Embodiment 107
2-(beta naphthal base) amino-benzene (B3)
Add 2-(beta naphthal base) oil of mirbane 5.0g in 250ml eggplant-shape bottle, ethanol 60ml, Pd/C 0.450g, finally adds hydrazine hydrate 7ml, stirring at room temperature 5 hours.Filter, after underpressure distillation solvent, add 200ml ethyl acetate, 100ml × 2 are washed, dry, filter, concentrated, obtain faint yellow solid 3.965g, productive rate 89.4%.
1H 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)； 13C 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；
Embodiment 108
2-(beta naphthal base) iodobenzene (C3)
500ml there-necked flask is placed in ice bath, adds 2-(beta naphthal base) amino-benzene 3.965g wherein, and vitriol oil 2.8ml adds after 70ml water dilution cooling, slowly adds NaNO under stirring 21.415g water (20ml) solution, adds for ten minutes, adds Kl 3.943g water (20ml) solution again, move to stirred at ambient temperature after half hour after 1 hour.Stop after room temperature reaction 4h, add water 100ml, use CH 2cl 2100ml × 3 extract, then are merged, and use saturated Na 2s 2o 3washing once.Dry, filter, concentrated, column chromatography, obtains nearly colourless liquid 2.009g, and productive rate is 34.4%.
1H 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＝2.3Hz，1H)，6.97(dd，J＝8.2，1.3Hz，1H)，6.92(td，J＝7.8，1.4Hz，1H)； 13C 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；
Embodiment 109
2-(beta naphthal base) phenyl-boron dihydroxide (D3)
2-(beta naphthal base) iodobenzene 1.819g is added in 100ml reaction tubes; under argon shield, anhydrous THF 50ml is added after abundant deoxygenation dewaters; 2.5mol/L n-butyllithium solution 2.5ml is slowly dripped in-78 DEG C of cryostats; react after 1 hour; add trimethyl borate 1.2ml at-78 DEG C, after 2h, reaction tubes is moved to stirring at room temperature.Add 1ml concentrated hydrochloric acid after stirring at room temperature 2h, extraction into ethyl acetate, dry, filter, concentrated after white solid 0.902g, productive rate is 65%.
1H 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)； 13C 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 16H 13BO 3(M) +263.0994，observed 263.0998.
Embodiment 110
3-(2-(beta naphthal base) phenyl)-N-(2-(N-Boc is amino) ethyl)-2-thienyl sulphonyl amine (F3)
The bromo-N-of 3-(2-(N-Boc amido) ethyl)-2-thienyl sulphonyl amine 0.375g, 2-(beta naphthal base) phenyl-boron dihydroxide 0.375g, Sphos 58mg is added, palladium 17mg, K in 250ml Shrek pipe 3pO 40.458g, adds THF 50ml after after abundant deoxygenation, water 5ml, refluxes 8 hours, stops heated and stirred.Add water 100ml, and ethyl acetate 100ml × 2 extract, dry, filter, concentrated, column chromatography, obtains yellow floss 0.312g, and productive rate is 61.2%.
1H 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)； 13C NMR(100MHz，CDCl 3)δ156.9，156.0，155.2，141.1，139.0，135.3，133.2，132.8，131.2，131.0，130.8，129.8，128.6，128.1，127.5，127.3，125.6，124.3，120.6，120.0，114.7，79.0，44.2，41.1；ESI-MS m/z 547.4(M+Na) +；MALDI-HRMS calcd.for C 27H 28N 2O 5S 2Na(M+Na) +547.1332，observed 547.1340.
Embodiment 111
3-(2-(beta naphthal base) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine (G3)
3-(2-(beta naphthal base) phenyl)-N-(2-(N-Boc is amino) ethyl)-2-thienyl sulphonyl amine 312mg, CH is added in 25ml egg type bottle 2cl 210ml, CF 3cO 2h 1.0ml, stirring at room temperature 12 hours.Add in salt of wormwood and CF 3cO 2h, to alkalescence, adds water, CH 2cl 260ml × 3 extract, dry, filter, concentratedly to obtain yellow solid 238.4mg, productive rate 94.4%.
1H 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 C 22H 21N 2O 3S 2(M+H) +425.0988，observed 425.0988.
Embodiment 112
3-(2-(beta naphthal base) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H3-1)
3-(2-(beta naphthal base) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 39.3mg is added, 4-methoxyphenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 46.2mg, productive rate 87%.
1H 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)； 13C NMR(100MHz，CDCl 3)δ156.8，156.2，154.9，153.9，136.5，134.2，140.5，132.2，131.8，131.1，130.4，130.1，129.1，127.8，127.2，126.7，126.0，124.9，123.9，123.6，119.5，119.4，114.4，113.6，55.5，43.9，39.8；
Embodiment 113
3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H3-2)
3-(2-(beta naphthal base) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 38.7mg is added in 25ml egg type bottle, 3,5-bis-trifluoromethylbenzene based isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 52mg, productive rate 89%.
1H 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)； 13C 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；
Embodiment 114
3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H3-3)
3-(2-(beta naphthal base) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 41.3mg is added, 3-nitrophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 57.3mg, productive rate 100%.
1H 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)； 13C 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 29H 24N 4O 6S 2Na(M+Na) +611.1030，observed 611.1040.
Embodiment 115
3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H3-4)
3-(2-(beta naphthal base) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 42.0mg is added, 3-methoxyphenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 56.8mg, productive rate 100%.
1H 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)； 13C NMR(100MHz，CDCl 3)δ160.2，156.1，154.9，154.0，140.8，140.2，136.4，134.2，132.1，131.8，130.5，130.1，129.7，129.2，127.8，127.2，126.7，125.9，124.9，123.8，119.5，119.4，113.7，112.2，108.9，105.6，55.2，43.8，39.8；ESI-MS m/z 574.3(M+H) +，596.3(M+Na) +；MALDI-HRMScalcd.for C 30H 27N 3O 5S 2Na(M+Na) +596.1284，observed 596.1275.
Embodiment 116
3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3,5-dichlorophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H3-5)
3-(2-(beta naphthal base) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 41.3mg is added, 3,5-dichlorophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 58.5mg, productive rate 98.2%.
1H 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.forC 29H 23N 3O 4S 2Cl 2Na(M+Na) +634.0399，observed 634.0388.
Embodiment 117
3-(2-(beta naphthal base) phenyl)-N-(2-(3-(4-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H3-6)
3-(2-(beta naphthal base) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 40.7mg is added, 3-nitrophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 56.4mg, productive rate 100%.
1H 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＝6.6，3.8Hz，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)； 13C 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 29H 24N 4O 6S 2Na(M+Na) +611.1030，observed 611.1048.
Embodiment 118
3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H3-7)
3-(2-(beta naphthal base) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 41.5mg is added, 3-nitro phenylisothiocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours in 25ml egg type bottle.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 57.5mg, productive rate 97.3%.
1H 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)； 13C NMR(100MHz，CDCl 3)δ181.3，154.7，154.0，148.4，141.2，138.9，135.4，134.2，132.0，132.0，130.6，130.3，130.2，130.1，129.9，129.8，127.8，127.1，126.9，125.7，125.1，123.9，120.3，119.6，119.2，119.0，113.7，44.3，42.6；ESI-MS m/z 605.3(M+H)+，627.3(M+Na) +；MALDI-HRMScalcd.for C 29H 24N 4O 5S 3Na(M+Na) +627.0801，observed 627.0816.
Embodiment 119
3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H3-8)
3-(2-(beta naphthal base) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 40.7mg is added in 25ml egg type bottle, 3-p-methoxy-phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 56.5mg, productive rate 100%.
1H 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＝8.3，2.3Hz，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)； 13C 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) +；MALDI-HRMScalcd.for C 30H 28N 3O 4S 3(M+H) +590.1237，observed 590.1249.
Embodiment 120
3-(2-(beta naphthal base) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H3-9)
3-(2-(beta naphthal base) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 39.4mg is added in 25ml egg type bottle, 4-p-methoxy-phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 49mg, productive rate 90%.
1H 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)； 13C 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.
Embodiment 121
3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H3-10)
3-(2-(beta naphthal base) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 40.2mg is added in 25ml egg type bottle, 3,5-bis-trifluoromethyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 58.9mg, productive rate 89%.
1H 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)； 13C 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.
Embodiment 122
3-(2-(beta naphthal base) phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H3-11)
3-(2-(beta naphthal base) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 38.9mg is added in 25ml egg type bottle, 4-nitro base PITC 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 50mg, productive rate 91%.
1H 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＝5.9Hz，2H)，3.20(q，J＝6.1Hz，2H)； 13C 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.
Embodiment 123
2-(3,4-dimethoxy phenoxy group) oil of mirbane (A6)
3,4-syringol 4.920g is added, o-fluoronitrobenzene 4.130g, the NaH 2.022g of 60%, anhydrous tetrahydro furan 50ml, backflow 5h in 250ml egg type bottle.Removing tetrahydrofuran (THF), adds 200ml ethyl acetate, and water 200ml × 3 are washed, dry, filter, concentrated, product yellow liquid 8.063g, productive rate 100%.
1H 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 14H 13NO 5(M)275.0794，observed 275.0797.
Embodiment 124
2-(3,4-dimethoxy phenoxy group) amino-benzene (B6)
Add 2-(3,4-dimethoxy phenoxy group) oil of mirbane 4.508g in 250ml eggplant-shape bottle, ethanol 60ml, Pd/C 0.450g, finally adds hydrazine hydrate 7ml, stirring at room temperature 5 hours.Filter, after underpressure distillation solvent, add 200ml ethyl acetate, 100ml × 2 are washed, dry, filter, concentrated, obtain faint yellow solid 4.017g, productive rate 100%.
1H 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)； 13C 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.
Embodiment 125
2-(3,4-dimethoxy phenoxy group) iodobenzene (C6)
500ml there-necked flask is placed in ice bath, adds 2-(3,4-dimethoxy phenoxy group) amino-benzene 4.095g, vitriol oil 2.8ml wherein and adds after 70ml water dilution cooling, slowly add NaNO under stirring 21.415g water (20ml) solution, adds for ten minutes, adds Kl 3.943g water (20ml) solution again, move to stirred at ambient temperature after half hour after 1 hour.Stop after room temperature reaction 4h, add water 100ml, use CH 2cl 2100ml × 3 extract, then are merged, and use saturated Na 2s 2o 3washing once.Dry, filter, concentrated, column chromatography, obtains nearly colourless liquid 3.654g, and productive rate is 61.5%.
1H 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＝2.7Hz，1H)，6.50(dd，J＝8.7，2.7Hz，1H)，3.87(s，3H)，3.85(s，3H)； 13C 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 C 14H 13lO 3(M)355.9909，observed355.9906.
Embodiment 126
2-(3,4-dimethoxy phenoxy group) phenyl-boron dihydroxide (D6)
2-(3 is added in 100ml reaction tubes; 4-dimethoxy phenoxy group) iodobenzene 1.958g; under argon shield, anhydrous THF 50ml is added after abundant deoxygenation dewaters; 2.5mol/L n-butyllithium solution 2.8ml is slowly dripped in-78 DEG C of cryostats; react after 1 hour; add trimethyl borate 1.2ml at-78 DEG C, after 2h, reaction tubes is moved to stirring at room temperature.Add 1ml concentrated hydrochloric acid after stirring at room temperature 2h, extraction into ethyl acetate, dry, filter, concentrated after white solid 0.827g, productive rate is 54.9%.
1H 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＝7.4，0.8Hz，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)；
Embodiment 127
3-(2-(3,4-dimethoxy phenoxy group) phenyl)-N-(2-(N-Boc is amino) ethyl)-2-thienyl sulphonyl amine (F6)
The bromo-N-of 3-(2-(N-Boc amido) ethyl)-2-thienyl sulphonyl amine 0.789g, 2-(3,4-dimethoxy phenoxy group) phenyl-boron dihydroxide 0.613g is added, triphenylphosphine 112mg, palladium 37mg, K in 250ml Shrek pipe 3pO 40.886g, adds THF 50ml after after abundant deoxygenation, water 5ml, refluxes 8 hours, stops heated and stirred.Add water 100ml, and ethyl acetate 100ml × 2 extract, dry, filter, concentrated, column chromatography, obtains yellow floss 0.769g, and productive rate is 70.2%.
1H 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 25H 30N 2O 7S 2Na(M+Na) +557.1387，observed 557.1391.
Embodiment 128
3-(2-(3,4-dimethoxy phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine (G6)
3-(2-(3,4-dimethoxy phenoxy group) phenyl)-N-(2-(N-Boc is amino) ethyl)-2-thienyl sulphonyl amine 745mg, CH is added in 25ml egg type bottle 2cl 210ml, CF 3cO 2h 1.0ml, stirring at room temperature 12 hours.Add in salt of wormwood and CF 3cO 2h, to alkalescence, adds water, CH 2cl 260ml × 3 extract, dry, filter, concentratedly to obtain yellow solid 545mg, productive rate 90%.
1H 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/z435.4(M+H) +；MALDI-H RMS calcd.for C 20H 23N 2O 5S 2(M+H) +435.1043，observed 435.1038.
Embodiment 129
3-(2-(3,4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H6-1)
3-(2-(3 is added in 25ml egg type bottle, 4-dimethoxy phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 43.0mg, 4-methoxyphenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 52.9mg, productive rate 91.5%.
1H 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)； 13C NMR(100MHz，CDCl 3)δ156.8，156.2，155.3，150.4，150.0，145.6，140.9，136.4，131.9，131.7，131.4，130.2，129.1，124.9，123.0，122.9，117.7，114.3，111.9，110.5，104.3，56.3，56.1，55.5，43.9，39.9；ESI-MS m/z584.4(M+H) +，606.4(M+Na) +；MALDI-HRMS calcd.for C 28H 29N 3O 7S 2Na(M+Na) +606.1339，observed 606.1335.
Embodiment 130
3-(2-(3,4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H6-2)
3-(2-(3 is added in 25ml egg type bottle, 4-dimethoxy phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 42.7mg, 3,5-bis-trifluoromethylbenzene based isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 59.1mg, productive rate 87.2%.
1H 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＝5.3Hz，2H)，3.09(q，J＝5.5Hz，2H)； 13C 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 29H 25N 3O 6F 6S 2Na(M+Na) +712.0981，observed 712.0989.
Embodiment 131
3-(2-(3,4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(3-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H6-3)
3-(2-(3 is added in 25ml egg type bottle, 4-dimethoxy phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 41.0mg, 3-nitrophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 54.5mg, productive rate 96.5%.
1H 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)； 13C NMR(100MHz，CDCl 3)δ155.4，155.2，150.3，150.0，148.4，145.7，141.4，140.5，135.6，132.1，131.6，130.4，129.6，129.4，124.7，124.4，122.9，117.8，116.8，113.2，112.0，110.5，104.3，56.3，56.1，43.8，39.7；ESI-MS m/z 599.3(M+H) +，621.4(M+Na) +；MALDI-HRMS calcd.forC 27H 26N 4O 8S 2Na(M+Na) +621.1084，observed 621.1074.
Embodiment 132
3-(2-(3,4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(3,5-dichlorophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H6-4)
3-(2-(3 is added in 25ml egg type bottle, 4-dimethoxy phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 40.1mg, 3,5-dichlorophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 52.2mg, productive rate 91.3%.
1H 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)； 13C 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.forC 27H 25N 3O 6S 2Cl 2Na(M+Na) +644.0454，observed 644.0460.
Embodiment 133
3-(2-(3,4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(4-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H6-5)
3-(2-(3 is added in 25ml egg type bottle, 4-dimethoxy phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 41.7mg, 4-nitrophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 53.9mg, productive rate 93.7%.
1H 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＝8.8Hz，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＝6.2Hz，1H)，3.83(s，3H)，3.77(s，3H)，3.30(q，J＝5.3Hz，2H)，3.09(q，J＝5.5Hz，2H)； 13C NMR(100MHz，CDCl 3)δ155.2，154.9，150.2，150.1，145.8，141.8，141.5，135.4，132.2，131.6，130.4，129.7，125.1，124.7，123.0，117.9，117.4，112.0，110.5，104.3，56.3，56.1，43.7，39.7；ESI-MS m/z 599.2(M+H) +，621.2(M+Na) +；MALDI-HRMS calcd.for C 27H 26N 4O 8S 2Na (M+Na) +621.1084，observed 621.1094.
Embodiment 134
3-(2-(3,4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H6-6)
3-(2-(3 is added in 25ml egg type bottle, 4-dimethoxy phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 41.8mg, 4-p-methoxy-phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 45.6mg, productive rate 79.0%.
1H 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)； 13CNMR(100MHz，CDCl 3)δ181.6，159.0，155.2，150.3，150.1，145.7，140.9，136.2，131.9，131.7，130.3，129.1，128.4，127.6，124.8，122.9，117.8，115.4，111.9，110.4，104.3，56.3，56.1，55.6，44.5，42.8；ESI-MS m/z 600.4(M+H) +，622.4(M+Na) +；MALDI-HRMS calcd.for C 28H 30N 3O 6S 3(M+H) +600.1291，observed 600.1295.
Embodiment 135
3-(2-(3,4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H6-7)
3-(2-(3 is added in 25ml egg type bottle, 4-dimethoxy phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 42.7mg, 3,5-bis-trifluoromethyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 66.0mg, productive rate 95.1%.
1H 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)； 13C 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 706.4(M+H) +，628.4(M+Na) +；MALDI-HRMS calcd.for C 29H 25N 3O 5F 6S 3Na(M+Na) +728.0753，observed728.0767.
Embodiment 136
3-(2-(3,4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H6-8)
3-(2-(3 is added in 25ml egg type bottle, 4-dimethoxy phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 41.9mg, 4-nitro phenylisothiocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 57.7mg, productive rate 97.3%.
1H 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＝8.4Hz，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＝8.8，2.8Hz，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＝5.6Hz，2H)； 13C NMR(100MHz，CDCl 3)δ180.7，155.2，150.2，150.1，145.8，144.0，143.9，141.6，135.1，132.2，131.6，130.5，129.9，124.9，124.6，123.0，122.0，117.9，112.1，110.4，104.2，56.4，56.2，44.2，42.6；ESI-MS m/z 615.4(M+H) +，637.3(M+Na) +；MALDI-HRMS calcd.forC 27H 26N 4O 7S 3Na(M+Na) +637.0856，observed 637.0845.
Embodiment 137
3-(2-(3,4-dimethoxy phenoxy group) phenyl)-N-(2-(3-phenylthiourea base) ethyl)-2-thienyl sulphonyl amine (H6-9)
3-(2-(3 is added in 25ml egg type bottle, 4-dimethoxy phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 42.5mg, PITC 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 55.5mg, productive rate 99.6%.
1H 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)； 13C NMR(100MHz，CDCl 3)δ181.1，155.2，150.3，150.1，145.7，140.9，136.1，131.9，131.7，130.3，130.1，129.2，127.3，127.2，125.1，124.8，122.9，117.8，112.0，110.4，104.3；ESI-MS m/z 570.5(M+H) +，592.3(M+Na) +；MALDI-HRMS calcd.for C 27H 28N 3O 5S 3(M+H) +570.1186，observed 570.1189.
Embodiment 138
3-(2-(3,4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(3-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H6-10)
3-(2-(3 is added in 25ml egg type bottle, 4-dimethoxy phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 40.7mg, 3-nitrophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 56.1mg, productive rate 97.4%.
1H 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)； 13C 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 27H 26N 4O 7S 3Na 637.0856(M+Na) +，observed 637.0849.
Embodiment 139
3-(2-(3,4-dimethoxy phenoxy group) phenyl)-N-(2-(4-nitrobenzene sulphonyl amido) ethyl)-2-thienyl sulphonyl amine (I6-1)
3-(2-(3 is added in 25ml egg type bottle, 4-dimethoxy phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 43.0mg, each 1.1 molar equivalents of 4-nitrobenzene sulfonyl chloride, triethylamine, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 59.4mg, productive rate 96.7%.
1H 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)； 13C 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.forC 26H 25N 3O 9S 3Na(M+Na) +642.0645，observed 642.0646.
Embodiment 140
3-(2-(3,4-dimethoxy phenoxy group) phenyl)-N-(2-(acetamido ethyl)-2-thienyl-N-alkylsulfonyl ethanamide (I6-2)
3-(2-(3 is added in 25ml egg type bottle, 4-dimethoxy phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 43.3mg, each 1.1 molar equivalents of aceticanhydride, triethylamine, methylene dichloride 3ml, stirring at room temperature 5 hours.PE: ethyl acetate=1: 2 column chromatographies, collect product, obtain 51.7mg, productive rate 100%.
1H 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)； 13C 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；
Embodiment 141
2-(3,4-dihydroxyl phenoxy group) iodobenzene (J)
Add 2-(3,4-dimethoxy phenoxy group) iodobenzene 2.899g in 250ml eggplant-shape bottle, methylene dichloride 100ml, is placed in ice bath by eggplant-shape bottle, in eggplant-shape bottle, slowly drips the Boron tribromide solution of 1mol/L, rise to room temperature after dripping, and stirs 6 hours.The 100ml cancellation that slowly adds water is reacted.Dichloromethane extraction, each 50ml.Methylene dichloride saturated common salt water washing, dry, filter, concentrated, column chromatography obtains orange-yellow oily liquids 2.671g, productive rate 100%.
1H 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)；
Embodiment 142
2-(3,4-bis-(tertiary butyl dimethyl Si base) phenoxy group) iodobenzene (C7)
2-(3,4-dihydroxyl phenoxy group) iodobenzene 2.671g, methylene dichloride 40ml is added in 100ml eggplant-shape bottle, imidazoles 2.0g, 3,4-TERT-BUTYL DIMETHYL CHLORO SILANE 3.524g, stirring at room temperature 3 hours, add water 100ml, dichloromethane extraction twice, each 75ml, combined dichloromethane solution, saturated common salt water washing, dry, filter, concentrated, column chromatography obtains orange/red oil 4.189g, productive rate 92.5%
1H 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)； 13C 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；
Embodiment 143
2-(3,4-bis-(tertiary butyl dimethyl Si base) phenoxy group) phenyl-boron dihydroxide (D7)
2-(3 is added in 100ml reaction tubes; 4-bis-(tertiary butyl dimethyl Si base) phenoxy group) iodobenzene 2.462g; under argon shield, anhydrous THF 50ml is added after abundant deoxygenation dewaters; 2.5mol/L n-butyllithium solution 2.3ml is slowly dripped in-78 DEG C of cryostats; react after 1 hour; add trimethyl borate 0.9ml at-78 DEG C, after 2h, reaction tubes is moved to stirring at room temperature.Add 1ml concentrated hydrochloric acid after stirring at room temperature 2h, extraction into ethyl acetate, dry, filter, concentrated after yellow solid 2.0271g, productive rate is 96.6%.
1H 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)；
Embodiment 144
3-(2-(3,4-bis-(tertiary butyl dimethyl Si base) phenoxy group) phenyl)-N-(2-(N-Boc is amino) ethyl)-2-thienyl sulphonyl amine (F7)
The bromo-N-of 3-(2-(N-Boc amido) ethyl)-2-thienyl sulphonyl amine 0.843g is added in 250ml Shrek pipe, 2-(3,4-bis-(tertiary butyl dimethyl Si base) phenoxy group) phenyl-boron dihydroxide 1.097g, triphenylphosphine 248mg, palladium 85mg, K 3pO 41.049g, adds THF 30ml after after abundant deoxygenation, water 5ml, refluxes 8 hours, stops heated and stirred.Add water 100ml, and ethyl acetate 100ml × 2 extract, dry, filter, concentrated, column chromatography, obtains yellow floss 1.128g, and productive rate is 70.1%.
1H 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＝5.1Hz，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.forC 35H 54N 2O 7S 2Si 2Na 757.2803(M+Na) +，observed 757.2796.
Embodiment 145
3-(2-(3,4-bis-(tertiary butyl dimethyl Si base) phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine (G7)
3-(2-(3,4-bis-(tertiary butyl dimethyl Si base) phenoxy group) phenyl)-N-(2-(N-Boc is amino) ethyl)-2-thienyl sulphonyl amine 411mg, CH is added in 25ml egg type bottle 2cl 25ml, CF 3cO 2h0.6ml, stirring at room temperature 12 hours.Add in salt of wormwood and CF 3cO 2h, to alkalescence, adds water, CH 2cl 260ml × 3 extract, dry, filter, concentratedly to obtain yellow solid 354mg, productive rate 100%.
1H 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＝5.1Hz，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)；
Embodiment 146
3-(2-(3,4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H7-1)
3-(2-(3 is added in 25ml egg type bottle, 4-bis-(tertiary butyl dimethyl Si base) phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 70.5mg, 4-methoxyphenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature is after 5 hours, and underpressure distillation removing methylene dichloride, adds acetonitrile 2ml in system, add the aqueous hydrogen fluoride solution 0.1ml of 40% again, room temperature reaction 12 hours.PE: ethyl acetate=1: 1 column chromatography, collects product, obtains 55.5mg, productive rate 90.0%.
1H 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)； 13C NMR(100MHz，Acetone-d 6)δ156.5，155.9，155.4，149.4，146.0，141.8，140.7，137.5，132.9，132.2，132.0，129.8，128.8，124.9，122.1，121.1，117.1，115.5，113.9，110.6，107.6，54.8，43.9，39.6；ESI-MS m/z556.3(M+H) +，578.2(M+Na) +；HRMS calcd.for C 26H 25N 3O 7S 2Na(M+Na) +578.1046，observed 578.1026.
Embodiment 147
3-(2-(3,4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H7-2)
3-(2-(3 is added in 25ml egg type bottle, 4-bis-(tertiary butyl dimethyl Si base) phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 85.2mg, 3,5-bis-trifluoromethylbenzene based isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature is after 5 hours, underpressure distillation removing methylene dichloride, acetonitrile 2ml is added in system, add the tetrahydrofuran aqueous solution 0.2ml fluoridizing n-butylamine of 1mol/L again, room temperature reaction 12 hours.PE: ethyl acetate=1: 1 column chromatography, collects product, obtains 25mg, productive rate 28.2%.
1H 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＝7.6Hz，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＝5.8Hz，2H)，5.37(t，J＝6.4Hz，1H)，3.30(q，J＝5.5Hz，2H)，3.05(q，J＝5.9Hz，2H)； 13C NMR(100MHz，CDCl 3)δ155.7，154.9，149.3，144.8，142.0，140.9，140.1，134.3，132.5，132.2，131.8，131.5，130.4，130.0，124.6，123.0，121.8，118.7，115.7，110.7，106.7，43.3，39.7；ESI-MS m/z 662.4(M+H) +，684.4(M+Na) +；HRMS calcd.for C 27H 21N 3O 6F 6S 2Na(M+Na) +684.0668，observed 684.0682.
Embodiment 148
3-(2-(3,4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(4-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H7-3)
3-(2-(3 is added in 25ml egg type bottle, 4-bis-(tertiary butyl dimethyl Si base) phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 70.5mg, 4-nitrophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature is after 5 hours, and underpressure distillation removing methylene dichloride, adds acetonitrile 2ml in system, add the aqueous hydrogen fluoride solution 0.1ml of 40% again, room temperature reaction 12 hours.PE: ethyl acetate=1: 1 column chromatography, collects product, obtains 22.3mg, productive rate 35.2%.
1H 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＝4.8Hz，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)； 13C 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.forC 25H 22N 4O 8F 6S 2Na(M+Na) +593.0774，observed 593.0771.
Embodiment 149
3-(2-(3,4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3,5-dichlorophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H7-4)
3-(2-(3 is added in 25ml egg type bottle, 4-bis-(tertiary butyl dimethyl Si base) phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 70.9mg, 3,5-dichlorophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature is after 5 hours, underpressure distillation removing methylene dichloride, in system, add acetonitrile 2ml, then add the aqueous hydrogen fluoride solution 0.1ml of 40%, room temperature reaction 12 hours.PE: ethyl acetate=1: 1 column chromatography, collects product, obtains 45.9mg, productive rate 69.1%.
1H 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)； 13C NMR(100MHz，Acetone-d 6)δ155.9，155.1，149.5，146.0，142.9，141.7，140.8，137.4，134.6，132.2，131.9，129.8，128.9，124.9，122.0，120.8，117.1，116.3，115.6，110.7，107.6，43.5，39.6；ESI-MS m/z 594.3(M+H) +，616.3(M+Na) +；HRMS calcd.for C 25H 21N 3O 6S 2ClNa (M+Na) +616.0146，observed 616.0141.
Embodiment 150
3-(2-(3,4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H7-5)
3-(2-(3 is added in 25ml egg type bottle, 4-bis-(tertiary butyl dimethyl Si base) phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 71.8mg, 3-nitrophenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature is after 5 hours, and underpressure distillation removing methylene dichloride, adds acetonitrile 2ml in system, add the aqueous hydrogen fluoride solution 0.1ml of 40% again, room temperature reaction 12 hours.PE: ethyl acetate=1: 1 column chromatography, collects product, obtains 53.1mg, productive rate 82.3%.
1H 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)； 13C NMR(100MHz，Acetone-d 6)δ155.9，155.3，149.5，148.8，146.0，141.8，141.7，140.8，137.4，132.2，131.9，129.8，129.7，128.9，124.9，124.9，123.9，122.1，117.1，116.0，115.6，112.5，110.7，107.6，43.5，39.6；ESI-MS m/z 571.3(M+H) +，593.3(M+Na) +；HRMS calcd.for C 25H 22N 4O 8S 2Na (M+Na) +593.0786，observed 593.0771.
Embodiment 151
3-(2-(3,4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine (H7-6)
3-(2-(3 is added in 25ml egg type bottle, 4-bis-(tertiary butyl dimethyl Si base) phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 71.1mg, 3-methoxyphenyl isocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature is after 5 hours, and underpressure distillation removing methylene dichloride, adds acetonitrile 2ml in system, add the aqueous hydrogen fluoride solution 0.1ml of 40% again, room temperature reaction 12 hours.PE: ethyl acetate=1: 1 column chromatography, collects product, obtains 40.8mg, productive rate 65.6%.
1H 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)； 13C NMR(100MHz，Acetone-d 6)δ160.3，155.9，149.4，146.0，141.7，141.5，140.8，137.5，132.2，131.9，129.8，129.3，128.9，124.9，122.0，117.1，115.6，110.8，110.6，107.6，107.4，104.4，54.5，43.8，39.5，ESI-MS m/z556.3(M+H) +，578.3(M+Na) +；HRMS calcd.for C 26H 25N 3O 7S 2Na(M+Na) +578.1044，observed 578.1026.
Embodiment 152
3-(2-(3,4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H7-7)
3-(2-(3 is added in 25ml egg type bottle, 4-bis-(tertiary butyl dimethyl Si base) phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 40.1mg, 4-p-methoxy-phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature is after 5 hours, and underpressure distillation removing methylene dichloride, adds acetonitrile 2ml in system, add the aqueous hydrogen fluoride solution 0.1ml of 40% again, room temperature reaction 12 hours.PE: ethyl acetate=1: 1 column chromatography, collects product, obtains 16.2mg, productive rate 45%.
1H 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 C 26H 26N 3O 6S 3(M+H) +572.0997，observed 572.0978.
Embodiment 153
3-(2-(3,4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H7-8)
3-(2-(3 is added in 25ml egg type bottle, 4-bis-(tertiary butyl dimethyl Si base) phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 83.1mg, 4-nitro phenylisothiocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature is after 5 hours, and underpressure distillation removing methylene dichloride, adds acetonitrile 2ml in system, add the aqueous hydrogen fluoride solution 0.1ml of 40% again, room temperature reaction 12 hours.PE: ethyl acetate=1: 1 column chromatography, collects product, obtains 53mg, productive rate 69%.
1H 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.forC 25H 23N 4O 7S 3(M+H) +587.0723，observed 587.0705.
Embodiment 154
3-(2-(3,4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H7-9)
3-(2-(3 is added in 25ml egg type bottle, 4-bis-(tertiary butyl dimethyl Si base) phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 83.1mg, 3,5-bis-trifluoromethyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature is after 5 hours, underpressure distillation removing methylene dichloride, in system, add acetonitrile 2ml, then add the aqueous hydrogen fluoride solution 0.1ml of 40%, room temperature reaction 12 hours.PE: ethyl acetate=1: 1 column chromatography, collects product, obtains 76.4mg, productive rate 85.6%.
1H 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 27H 21N 3O 5F 6S 3Na(M+Na) +700.0451，observed 700.0440.
Embodiment 155
3-(2-(3,4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H7-10)
3-(2-(3 is added in 25ml egg type bottle, 4-bis-(tertiary butyl dimethyl Si base) phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 83.1mg, 3-nitro phenylisothiocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature is after 5 hours, and underpressure distillation removing methylene dichloride, adds acetonitrile 2ml in system, add the aqueous hydrogen fluoride solution 0.1ml of 40% again, room temperature reaction 12 hours.PE: ethyl acetate=1: 1 column chromatography, collects product, obtains 36.8mg, productive rate 57.4%.
1H 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)； 13C NMR(100MHz，Acetone-d 6)δ182.0，155.9，149.5，148.3，146.0，141.6，140.9，140.9，137.3，132.2，131.9，129.8，129.6，129.0，124.9，122.1，118.7，118.7，117.8，117.0，115.6，110.7，107.6，43.9，42.2；ESI-MS m/z 587.2(M+H) +，609.2(M+Na) +；HRMS calcd.for C 25H 22N 4O 7S 3Na(M+Na) +609.0556，observed 609.0543.
Embodiment 156
3-(2-(3,4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine (H7-11)
3-(2-(3 is added in 25ml egg type bottle, 4-bis-(tertiary butyl dimethyl Si base) phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 69.4mg, 3-p-methoxy-phenyl lsothiocyanates 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature is after 5 hours, and underpressure distillation removing methylene dichloride, adds acetonitrile 2ml in system, add the aqueous hydrogen fluoride solution 0.1ml of 40% again, room temperature reaction 12 hours.PE: ethyl acetate=1: 1 column chromatography, collects product, obtains 24.5mg, productive rate 39.2%.
1H 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)； 13CNMR(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 26H 25N 3O 6S 3Na(M+Na) +594.0788，observed 594.0798.
Embodiment 157
3-(2-(3,4-dihydroxyl phenoxy group) phenyl)-N-(2-acetamidoethyl)-2-thienyl sulphonyl amine (I7-1)
3-(2-(3 is added in 25ml egg type bottle, 4-bis-(tertiary butyl dimethyl Si base) phenoxy group) phenyl)-N-(2-amino-ethyl)-2-thienyl sulphonyl amine 53.4mg, 4-nitro phenylisothiocyanate 1.1 molar equivalent, methylene dichloride 3ml, stirring at room temperature is after 5 hours, and underpressure distillation removing methylene dichloride, adds acetonitrile 2ml in system, add the aqueous hydrogen fluoride solution 0.1ml of 40% again, room temperature reaction 12 hours.PE: ethyl acetate=1: 1 column chromatography, collects product, obtains 29.7mg, productive rate 70.2%.
1H 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).
Embodiment 158
The part of compounds stated in the present invention measures the inhibit activities of liver cancer cell
Choose the compound of the present invention's statement, adopt cell proliferation-toxicity detection test kit (Cell CountingKit-8, CCK-8) measure the inhibit activities that it grows human hepatoma cell strain Hep3B and BEL-7404 human hepatocellular cells, in this test, select the Human normal hepatocyte strain HL-7702 of immortalization in addition in contrast.
The concrete steps of experiment are:
● get and be in exponential phase of growth, cell in good condition, add 0.25% tryptic digestive juice, digestion makes attached cell come off, counting 4 × 10 4individual/mL, makes cell suspension;
● obtained cell suspension is inoculated on 96 orifice plates, and 100 μ l/ holes, put constant temperature CO 2overnight incubation in incubator;
● choose testing compound, add in cell culture fluid and make its final concentration be respectively 0 μM, 1 μM, 10 μMs, 50 μMs, often organize concentration and establish 3 multiple holes, process cell 48h;
● added by CCK-8 in 96 orifice plates, 10 μ l/ holes, react 3h in incubator;
● use the multi-functional microplate reader of SpectraMax 190 at wavelength for 450nm place measures every hole light absorption value, by following formulae discovery cell inhibitory rate.
● for often kind of test-compound, use Microsoft Office Excel software to carry out Fitting Analysis according to the cell survival rate recorded under three kinds of concentration, obtain the medium effective concentration value (IC that this compounds on cell growth suppresses 50).
In above experiment, the hepatoma cell strain used is all purchased from American Type CultureCollection (ATCC, Manassas, VA), and the Human normal hepatocyte strain of immortalization is purchased from Chinese Academy of Sciences's cell bank (Shanghai).Cell Counting Kit-8 (CK-04) test kit is purchased from Dojindo company (Kumamoto, Japan).
Test result on three kinds of cell strains that above compound describes in the present embodiment is in table 1.
The part of compounds stated in table 1, the present invention is to the inhibit activities measurement result of liver cancer cell
Embodiment 159
The part of compounds stated in the present invention measures the inhibit activities of lung carcinoma cell
Choose the compound of the present invention's statement, adopt cell proliferation-toxicity detection test kit (Cell CountingKit-8, CCK-8) measure the inhibit activities that it grows human lung carcinoma cell line A549 and human lung carcinoma cell line H1299, in this test, select people's normal lung epithelial cell BEAS-2B of immortalization in addition in contrast.
The concrete steps of experiment are:
● get and be in exponential phase of growth, cell in good condition, add 0.25% tryptic digestive juice, digestion makes attached cell come off, counting 4 × 10 4individual/mL, makes cell suspension;
● obtained cell suspension is inoculated on 96 orifice plates, and 100 μ l/ holes, put constant temperature CO 2overnight incubation in incubator;
● choose testing compound, add in cell culture fluid and make its final concentration be respectively 0 μM, 1 μM, 10 μMs, 50 μMs, often organize concentration and establish 3 multiple holes, process cell 48h;
● added by CCK-8 in 96 orifice plates, 10 μ l/ holes, react 3h in incubator;
● use the multi-functional microplate reader of SpectraMax 190 at wavelength for 450nm place measures every hole light absorption value, by following formulae discovery cell inhibitory rate.
● for often kind of test-compound, use Microsoft Office Excel software to carry out Fitting Analysis according to the cell survival rate recorded under three kinds of concentration, obtain the medium effective concentration value (IC that this compounds on cell growth suppresses 50).
In above experiment, the lung cancer cell line used is all purchased from American Type CultureCollection (ATCC, Manassas, VA), and people's normal lung epithelial cell strain is purchased from Chinese Academy of Sciences's cell bank (Shanghai).Cell Counting Kit-8 (CK-04) test kit is purchased from Dojindo company (Kumamoto, Japan).
Test result on three kinds of cell strains that above compound describes in the present embodiment is in table 2.
The part of compounds stated in table 2, the present invention is to the inhibit activities measurement result of lung carcinoma cell
Active and purposes is summed up:
1. part of compounds (the such as compound: H4-1, H4-4, H4-5, H4-6, H4-9 described in the present invention, 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) at least one human liver cancer cell, there is obvious lethal effect (IC 50< 20 μMs), part of compounds is simultaneously on the very little (IC of the impact of normal cell proliferation 50> 100 μMs), there is good selectivity.These compounds have the potentiality being developed to new type antineoplastic medicine, recommend the medicine for the preparation of Hepatoma therapy.
2. part of compounds (the such as compound: H4-3, H4-4, H4-5, H4-6, H4-8, H4-9 described in the present invention, 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) at least one human lung carcinoma cell, there is obvious lethal effect (IC 50< 20 μMs), part of compounds is simultaneously on the very little (IC of the impact of normal pneumonocyte 50> 100 μMs), there is good selectivity.These compounds have the potentiality being developed to new type antineoplastic medicine, recommend the medicine for the preparation for the treatment of lung cancer.

Claims (9)

1. a class tolylthiophene sulfamide compound, is characterized in that tolylthiophene sulphonamide N-alkyl urea compounds or tolylthiophene sulphonamide N-alkyl thiourea compounds I, the tolylthiophene sulphonamide N-alkylamide compound II with following structural formula:
Wherein:
R 1be selected from Z replaces or aromatic base Ar, Z of not replacing replace or do not replace heteroaryl or cyclohexyl; Described aromatic base Ar or heteroaryl be selected from 5-7 unit aromatic base, naphthyl, 5-7 unit heteroaryl and close 5-7 unit heteroaryl 5-7 unit aromatic base; Heteroatoms in described heteroaryl is N, O or S, and contained heteroatomic number is 1,2 or 3; Described Z substituting group is selected from: halogen, C 1-C 4alkoxyl group, nitro, C 1-C 6the C that straight or branched alkyl, hydroxyl, hydroxyl replace 1-C 6straight or branched alkyl, C 3-C 7saturated or undersaturated cycloalkyl; The substituent number of Z is 1-4; R 1oxygen base and the thienyl group be connected on same phenyl ring can be in ortho position, a position or contraposition; Position or ortho position between phenyl in thiphene ring and sulfuryl substituting group are in;
X is O or S;
R 2, R 3be selected from H, halogen, C 1-C 6straight or branched alkyl, hydroxyl, C 1-C 4alkoxyl group, carboxyl, C 1-C 4ester group, cyano group, nitro, amino, methylol, trifluoromethyl, trifluoromethoxy, sulfydryl or C 1-C 4acyl group; R 2, R 3for identical or different group; R 4and R 5for H, ethanoyl or trifluoroacetyl group or common Xuan Zi – (CH 2) m–, i.e. ring diamine structures; Wherein m is the integer of 0-2; R 6for ethanoyl or trifluoroacetyl group or 4-nitrophenylsulfonyl; N is the integer of 0-4; Wherein m and n is not 0.
2. tolylthiophene sulfamide compound as claimed in claim 1, is characterized in that a class tolylthiophene sulfamide compound, the phenyl or naphthyl that described Ar substituting group is phenyl, Z replaces; Described Z substituting group as claimed in claim 1.
3. a class tolylthiophene sulfamide compound, is characterized in that following compound:
Tolylthiophene sulphonamide N-alkyl urea compounds or tolylthiophene sulphonamide N-alkyl thiourea compounds: 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-phenyl urea groups) ethyl)-2-thienyl sulphonyl aminated compounds: 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(4-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(3, 5-dichlorophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(4-chloro-phenyl-) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(3, 5-3,5-dimethylphenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(3, 5-bis-trifluoromethyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(3 – nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(3-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(3, 5-bis-trifluoromethyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(3-chloro-phenyl-) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(4-chloro-phenyl-) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(2-(3-(3-aminomethyl phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine,
Tolylthiophene sulphonamide N-alkyl urea compounds or tolylthiophene sulphonamide N-alkyl thiourea compounds: 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-phenyl urea groups) propyl group)-2-thienyl sulphonyl amine: 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(4-nitrophenyl) urea groups) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(3, 5-dichlorophenyl) urea groups) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(4-chloro-phenyl-) urea groups) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(4-p-methoxy-phenyl) urea groups) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(3, 5-3,5-dimethylphenyl) urea groups) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(4-p-methoxy-phenyl) thioureido) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(3-nitrophenyl) thioureido) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(3, 5-bis-trifluoromethyl) thioureido) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(3-chloro-phenyl-) thioureido) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(3-p-methoxy-phenyl) thioureido) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(4-chloro-phenyl-) thioureido) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(4-nitrophenyl) thioureido) propyl group)-2-thienyl sulphonyl amine, 3-(2-(2, 4-dichlorophenoxy) phenyl)-N-(3-(3-(3-aminomethyl phenyl) thioureido) propyl group)-2-thienyl sulphonyl amine,
Tolylthiophene sulphonamide N-alkyl urea compounds or tolylthiophene sulphonamide N-alkyl thiourea compounds: 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3,5-dichlorophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(4-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-(3-aminomethyl phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(3-phenylthiourea base) ethyl)-2-thienyl sulphonyl amine,
Tolylthiophene sulphonamide N-alkyl urea compounds or tolylthiophene sulphonamide N-alkyl thiourea compounds: 3-(2-sesame phenolic group phenyl)-N-(2-(3-(3,5-dichlorophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(4-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(4-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(3-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(3-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(4-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(3-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(3-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-(3-aminomethyl phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(3-phenylthiourea base) ethyl)-2-thienyl sulphonyl amine,
Tolylthiophene sulphonamide N-alkyl urea compounds or tolylthiophene sulphonamide N-alkyl thiourea compounds: 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3,5-dichlorophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3,5-bis-trifluoromethyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(beta naphthal base) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine,
Tolylthiophene sulphonamide N-alkyl urea compounds or tolylthiophene sulphonamide N-alkyl thiourea compounds: 3-(2-(3, 4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(3, 5-bis-trifluoromethyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(3, 5-dichlorophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(3-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(3, 5-bis-trifluoromethyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dimethoxy phenoxy group) phenyl)-N-(2-(3-phenylthiourea base) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(3-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dimethoxy phenoxy group) phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine,
, tolylthiophene sulphonamide N-alkyl thiourea compounds or tolylthiophene sulphonamide N-alkyl (sulphur) carbamide compounds: 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3, 5-bis-trifluoromethyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(4-nitro base phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3, 5-dichlorophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3-nitrophenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) urea groups) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(4-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(4-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3, 5-bis-trifluoromethyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3-nitrophenyl) thioureido) ethyl)-2-thienyl sulphonyl amine, 3-(2-(3, 4-dihydroxyl phenoxy group) phenyl)-N-(2-(3-(3-p-methoxy-phenyl) thioureido) ethyl)-2-thienyl sulphonyl amine,
Tolylthiophene sulphonamide N-alkyl thiourea compounds or tolylthiophene sulphonamide N-alkyl thiourea compounds: 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(3,5-dichloroanilino) formyl piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(4-anisole amido) formyl piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(3,5-bis-trifluoromethylbenzene amido) formyl piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(4-anisole amido) thioformyl piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(4-anisole amido) thioformyl piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(3-oil of mirbane amido) thioformyl piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(3,5-bis-trifluoromethylbenzene amido) thioformyl piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(3-anisole amido) thioformyl piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(4-oil of mirbane amido) thioformyl piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-(3-toluidine) thioformyl piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-anilino thioformyl piperazine,
Tolylthiophene sulphonamide N-alkylamide compound: 3-(2 (2,4-dichlorophenoxy) phenyl)-N-amido alkyl-2-thienyl sulphonyl amine: 3-(2-(2,4-dichlorophenoxy) phenyl)-N-(2-trifluoroacetyl amido ethyl)-2-thienyl sulphonyl amine, 3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(2-(4-nitrobenzene sulphonyl amido) ethyl)-2-thienyl sulphonyl amine;
Tolylthiophene sulphonamide N-alkylamide compound: 3-(2-(2,4-dichlorophenoxy) phenyl)-N-(3-acetamido propyl group)-2-thienyl sulphonyl amine, 3-(2-(2,4-dichlorophenoxy) phenyl)-N-(3-trifluoroacetyl amido propyl group)-2-thienyl sulphonyl amine, 3-(2-(2,4 dichloro benzene oxygen base) phenyl)-N-(3-(4-nitrobenzene sulphonyl amido) propyl group)-2-thienyl sulphonyl amine;
Tolylthiophene sulphonamide N-alkylamide compound: 3-(2-(1-naphthols base) phenyl)-N-(2-acetamido ethyl)-2-thienyl sulphonyl amine, 3-(2-(1-naphthols base) phenyl)-N-(2-(4-nitrobenzene sulphonyl amido) ethyl)-2-thienyl sulphonyl amine;
Tolylthiophene sulphonamide N-alkylamide compound: 3-(2-sesame phenolic group phenyl)-N-(2-acetamido ethyl)-2-thienyl sulphonyl amine, 3-(2-sesame phenolic group phenyl)-N-(2-(4-nitrobenzene sulphonyl amido) ethyl)-2-thienyl sulphonyl amine; 3-(2-(3,4-dimethoxy phenoxy group) phenyl)-N-(2-(acetamido ethyl)-2-thienyl sulphonyl amine, 3-(2-(3,4-dimethoxy phenoxy group) phenyl)-N-(2-(4-nitrobenzene sulphonyl amido) ethyl)-2-thienyl sulphonyl amine;
Tolylthiophene sulphonamide N-alkylamide compound: 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-Acetylpiperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-trifluoroacetyl group piperazine, 4-N-((3-(2-(hexamethylene alcohol radical) phenyl)-2-thienyl) sulfuryl)-1-N-4-nitrobenzenesulfonyl piperazine.
4. prepare a method for compound as claimed in claim 1, it is characterized in that respectively by following steps (8), or (7) and (8), or (6), and (8), or (5) (7), (6), and (8), or (4) (7), (6), and (8), or (4) (7), (5), (6), and (8), or (3) (7), (4), (5), (6), and (8), or (2) (7), (3), (4), (5), (6), and (8), or (1) (7), (2), (3), (4), (5), (6), and (8) (7), or (15), or (14) and (15), or (13), and (15), or (12) (14), (13), and (15), or (5) (14), (13), and (15), or (11) (14), (12), (5), (13), and (15), or (10) (14), (11), (12), (5), (13), and (15), or (3) (14), (10), (11), (12), (5), (13), and (15), or (2) (14), (3), (10), (11), (12), (5), (13), and (15), or (1) (14), (2), (3), (10), (11), (12), (5), (13), (14) and (15), tolylthiophene sulphonamide N-alkyl urea compounds or tolylthiophene sulphonamide N-alkyl thiourea compounds is obtained,
By following steps (9), or (7) and (9), or (6), and (9), or (5) (7), (6), and (9), or (4) (7), (6), and (9), or (4) (7), (5), (6), and (9), or (3) (7), (4), (5), (6), and (9), or (2) (7), (3), (4), (5), (6), and (9), or (1) (7), (2), (3), (4), (5), (6), and (9) (7), or (16), or (14) and (16), or (13), and (16), or (12) (14), (13), and (16), or (5) (14), (13), and (16), or (11) (14), (12), (5), (13), and (16), or (10) (14), (11), (12), (5), (13), and (16), or (3) (14), (10), (11), (12), (5), (13), and (16), or (2) (14), (3), (10), (11), (12), (5), (13), and (16), or (1) (14), (2), (3), (10), (11), (12), (5), (13), (14) tolylthiophene sulphonamide N-alkylamide compound and (16), is obtained:
(1) in organic solvent, oxy-compound, K 2cO 3, NaH and fluoronitrobenzene mol ratio be followed successively by 1:(0 ~ 5): (0 ~ 2): (0.8 ~ 2), 10 ~ 200 DEG C of reactions 2 ~ 10 hours compd A;
Described oxy-compound has following structural formula:
The structural formula of described compd A is as follows:
; (2) in organic solvent, compd A, Pd/C, NH 2nH 2h 2the mol ratio of O is followed successively by 1:(0.01 ~ 0.1): (1 ~ 5), obtains compd B in 2 ~ 10 hours 10 ~ 200 DEG C of reactions; Or the mol ratio of compd A, zinc powder and hydrochloric acid is followed successively by 1:(1 ~ 5): (2 ~ 10), obtain compd B in 2 ~ 10 hours 10 ~ 200 DEG C of reactions;
The structural formula of described compd B is as follows:
(3) in a solvent, compd B, H 2sO 4, NaNO 2, KI mol ratio be followed successively by 1:(1 ~ 3): (1 ~ 2): (1 ~ 2) ,-5 ~ 10 DEG C reaction 2 ~ 10 hours Compound C;
The structural formula of described Compound C is as follows:
(4) in a solvent, the mol ratio of Compound C, n-Butyl Lithium, trimethyl borate is followed successively by 1:(1 ~ 2): (1 ~ 2), obtains Compound D in 1 ~ 5 hour-78 ~ 0 DEG C of reaction;
The structural formula of described Compound D is as follows:
(5) in organic solvent, the mol ratio of 3-bromo-2-thienyl sulphonyl chlorine, 1-N-Boc diamines, triethylamine is followed successively by 1:(1 ~ 2): (1 ~ 2), obtains compd E in 2 ~ 5 hours 0 ~ 200 DEG C of reaction;
Described Boc represents tert-butoxycarbonyl;
The structural formula of described compd E is as follows:
(6) in a solvent, compd E, Compound D, triphenylphosphine or Sphos (2-dicyclohexyl phosphorus-2', 6'-dimethoxy-biphenyl), K 3pO 41:(1 ~ 1.5 are followed successively by with the mol ratio of palladium): (0.05 ~ 0.2): (1 ~ 3): (0.02 ~ 0.1), obtains compound F 17-hydroxy-corticosterone in 2 ~ 15 hours 10 ~ 200 DEG C of reactions,
The structural formula of described compound F 17-hydroxy-corticosterone is as follows:
(7) in a solvent, the mol ratio of compound F 17-hydroxy-corticosterone, trifluoroacetic acid is followed successively by 1:(1 ~ 3), within 2 ~ 15 hours, obtain compound G 10 ~ 200 DEG C of reactions;
The structural formula of described compound G is as follows:
(8) in organic solvent, the mol ratio of compound G, isocyanic ester or lsothiocyanates is 1:(1 ~ 1.5), within 2 ~ 12 hours, obtain compound H 10 ~ 200 DEG C of reactions;
The structural formula of described compound H is as follows:
(9) in a solvent, the mol ratio of compound G, acyl chlorides and triethylamine is followed successively by 1:(1 ~ 1.5): (1 ~ 3), obtains Compound I in 2 ~ 15 hours 10 ~ 200 DEG C of reactions;
The structural formula of described Compound I is as follows:
(10) in a solvent, the mol ratio of Compound C 6, boron tribromide is 1:(1 ~ 3), within 2 ~ 5 hours, obtain compound J at-78 DEG C ~ room temperature reaction,
The structure of described compound J is as follows:
(11) in a solvent, the mol ratio of compound J, TBSCl, imidazoles or triethylamine is 1:(1 ~ 3): (1 ~ 3), obtains Compound C 7 in 2 ~ 15 hours at 0 ~ room temperature reaction;
Described TBSCl represents TERT-BUTYL DIMETHYL CHLORO SILANE; The structural formula of described Compound C 7 is as follows:
(12) in a solvent, the mol ratio of Compound C 7, n-Butyl Lithium, trimethyl borate is followed successively by 1:(1 ~ 2): (1 ~ 2), obtains Compound D 7 in 1 ~ 5 hour-78 ~ 0 DEG C of reaction;
The structural formula of described Compound D 7 is as follows:
(13) in a solvent, compd E, Compound D 7, triphenylphosphine or Sphos, K 3pO 41:(1 ~ 1.5 are followed successively by with the mol ratio of palladium): (0.05 ~ 0.2): (1 ~ 3): (0.02 ~ 0.1), obtains compound F 17-hydroxy-corticosterone 7 in 2 ~ 15 hours 10 ~ 200 DEG C of reactions;
The structural formula of described compound F 17-hydroxy-corticosterone 7 is as follows:
(14) in a solvent, the mol ratio of compound F 17-hydroxy-corticosterone 7, trifluoroacetic acid is followed successively by 1:(1 ~ 3), within 2 ~ 15 hours, obtain compound G7 10 ~ 200 DEG C of reactions;
The structural formula of described compound G7 is as follows:
(15) in organic solvent, the mol ratio of compound G7, isocyanic ester or lsothiocyanates and hydrofluoric acid is 1:(1 ~ 1.5): (2 ~ 20), obtain compound H 7 in 2 ~ 12 hours at room temperature reaction;
The structural formula of described compound H 7 is as follows:
(16) in a solvent, the mol ratio of compound G7, acyl chlorides and triethylamine is followed successively by 1:(1 ~ 1.5): (1 ~ 3), obtains Compound I 7 in 2 ~ 15 hours 10 ~ 200 DEG C of reactions;
The structural formula of described Compound I 7 is as follows:
Described organic solvent is: tetrahydrofuran (THF), DMF, toluene, CH 2cl 2, CHCl 3, Isosorbide-5-Nitrae-dioxane, ethanol, methyl alcohol, acetonitrile or its mixing solutions; Described solvent is: tetrahydrofuran (THF), DMF, toluene, CH 2cl 2, CHCl 3, Isosorbide-5-Nitrae-dioxane, ethanol, water, methyl alcohol, acetonitrile or its mixing solutions;
Described Sphos represents 2-dicyclohexyl phosphine-2', 6'-dimethoxy-1,1'-biphenyl.
5. preparation method as claimed in claim 4, is characterized in that: step 1) described in product after concentrating, carry out recrystallization purifying or column chromatography; Step 2) described in reaction product, after filtration, extraction into ethyl acetate, drying, concentrated aftertreatment; Step 3) described in anti-temperature be-5 ~ 5 DEG C, reaction terminate in rear reaction solution impouring water, organic solvent extraction, organic layer drying, filter, remove solvent under reduced pressure, the aftertreatment of resistates column chromatography for separation; Step 4), 12) described in reaction, system palpus anhydrous and oxygen-free, and start to drip n-butyllithium solution at low temperatures-78 ~-20 DEG C carry out, after adding n-Butyl Lithium, half hour, added trimethyl borate by 1 hour, and slowly can rise to room temperature react half an hour at low temperature-78 ~-20 DEG C after, aftertreatment adopts extraction into ethyl acetate, organic layer drying, filter, remove solvent or column chromatography for separation under reduced pressure; Step 5) through extraction, dry and concentrated aftertreatment; Step 6), 13) described in the abundant deoxygenation of reaction system, part is Sphos or triphenylphosphine, and post-reaction treatment comprises extraction into ethyl acetate, drying, filtration, concentrated and column chromatography; Step 7), 14) described in reaction trifluoroacetic acid remove Boc protecting group, first neutralize wherein excessive acid after reaction, then carry out extracting, dry, filter and concentrated post-reaction treatment; Step 8) described in reaction product through removing solvent under reduced pressure, the aftertreatment of resistates column chromatography for separation; Step 9), 16) described in react through adding water, dichloromethane extraction, drying, filtration, concentrated and column chromatography aftertreatment; Step 10), 11) described in slowly to add water cancellation after reaction, the aftertreatment of dichloromethane extraction, drying, filtration, concentrated and column chromatography; Step 15) described in reaction product through removing solvent under reduced pressure, add after hydrofluoric acid fully reacts, add water, extraction into ethyl acetate, dry, filter, concentrated, the aftertreatment of resistates column chromatography for separation.
6. as the tolylthiophene sulfamide compound in claim 1 ~ 2 as described in any one or its pharmaceutically acceptable salt preparing the application in antitumor drug.
7. apply as claimed in claim 6, it is characterized in that described antitumor drug is the medicine for the treatment of lung cancer or liver cancer.
8. the application of class tolylthiophene sulfamide compound in the antitumor drug preparing Hepatoma therapy, described tolylthiophene sulfamide compound is as follows:
9. the application of a class tolylthiophene sulfamide compound in the antitumor drug of preparation treatment lung cancer, described tolylthiophene sulfamide compound is as follows:
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CN1058401A (en) * 1990-07-17 1992-02-05 伊莱利利公司 Anti-tumor compositions and methods of treatment
US5169860A (en) * 1992-03-13 1992-12-08 Eli Lilly And Company Antitumor compositions and methods of treatment
CN1575286A (en) * 2001-10-25 2005-02-02 伊莱利利公司 Thiophene-amd thiazolesulfonamides as antineoplastic agents

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CN1058401A (en) * 1990-07-17 1992-02-05 伊莱利利公司 Anti-tumor compositions and methods of treatment
US5169860A (en) * 1992-03-13 1992-12-08 Eli Lilly And Company Antitumor compositions and methods of treatment
CN1575286A (en) * 2001-10-25 2005-02-02 伊莱利利公司 Thiophene-amd thiazolesulfonamides as antineoplastic agents

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