CN109721563A

CN109721563A - Sulphonyl thiazolium compounds and its preparation method and application

Info

Publication number: CN109721563A
Application number: CN201811643257.3A
Authority: CN
Inventors: 周成合; 扈圆圆; 李铁军
Original assignee: Southwest University
Current assignee: Southwest University
Priority date: 2018-12-29
Filing date: 2018-12-29
Publication date: 2019-05-07

Abstract

The present invention relates to sulphonyl thiazolium compounds and its preparation method and application, belong to chemosynthesis technical field, sulphonyl thiazolium compounds is as shown in general formula I-II, such compound has certain inhibitory activity to gram positive bacteria, gram-negative bacteria and fungi, it can be used for preparing antibacterium and/or antifungal drug, to provide more drug candidates efficiently, safe for clinical antimicrobial treatment, facilitate the clinical treatments such as the drug resistance for solving the problems, such as to be on the rise, obstinate invasive organism and emerging harmful microorganism.And it prepares that raw material is simple, and cheap and easy to get, synthetic route is short, is of great significance to the application of anti-infective aspect.

Description

Sulphonyl thiazolium compounds and its preparation method and application

Technical field

The invention belongs to chemosynthesis technical fields, and in particular to sulphonyl thiazolium compounds and its preparation method and application.

Background technique

Domain of Abuse Antibiotics and the antibiotic resistance accelerated has become the global challenges that public health faces.In the past Decades in, drug resistance caused by antibiotic, so that the quantity of human disease bacterium sharply increases.Therefore, design synthesis has The novel antibacterial drug of anti-drug resistance bacterial strain becomes abnormal urgent, more especially has efficiently, less toxic and low drug resistance The research and development of antimicrobial, it has also become a more and more active topic.Wherein, high incidence caused by germ infects and the death rate are Through to the mankind health and existence pose a serious threat.Sulfa drugs as the artificial synthesized antimicrobial of the first kind, to its Further exploitation has caused to pay high attention in biology and medical domain.So far, largely there are various pharmacological activities Sulfanilamide (SN) and sulphonyl amine system drug are widely used to clinic, such as antiviral anpunave and tipranavir, and antiparasitic agent is yellow Grass disappears, carbonic anhydrase inhibitor acetazolamide and methazolamide, hypoglycemic glibenclamide and Dibatrol etc..Especially exist Antibiosis, many sulphadiazine class antibacterials, such as mafenide, sulfadimethoxine, sulfapryidine, sulphathiazole, Sulfamethoxazole, sulfamethyldiazine etc. have played important function in the treatment of infectious diseases.However, antibacterials Drug resistance caused by abusing and side effects of pharmaceutical drugs limit their clinical application.Therefore, research has hypotoxicity and height Active novel sulfonamides compound has become the hot spot of research.

Thiazole ring is a kind of important 5-membered aromatic heterocycle, containing nitrogen and sulfur heteroatom, with electronics abundant.This knot Structure imparts many special performances of thiazole compound, has in numerous areas such as chemistry, pharmacy, biology and material science Wide application prospect shows huge Development volue, receives significant attention.Especially in antibacterial field, more and more thiophenes Azole drug treats bacterium and fungal infection in clinic, such as anti-bacterial drug cephalosporins cefotaxime, cephalo department oxime and Cephalo amidoxime, antifungal drug Abafungin etc..Studies have shown that the introducing of thiazole segment is most important for antibacterial activity and has Hope the novel anti-infection drug for obtaining high activity.

Summary of the invention

In view of this, one of the objects of the present invention is to provide sulphonyl thiazolium compounds and its officinal salts；The second purpose It is to provide the preparation method of sulphonyl thiazolium compounds and its officinal salt；The third purpose be to provide sulphonyl thiazolium compounds and Application of its officinal salt in preparation antibacterium and/or antifungal drug；The fourth purpose is to provide containing sulphonyl thiazole Close the preparation of object and its officinal salt.

In order to achieve the above objectives, the invention provides the following technical scheme:

1, sulphonyl thiazolium compounds and its officinal salt, structure is as shown in general formula I-II:

In formula,

R¹, R²For hydrogen, alkyl, allyl, propargyl, benzyl, halogen benzyl, cyano, acyl group or ethoxy.

Preferably,

R¹For hydrogen or acetyl group；

R²For hydrogen, alkyl, allyl, propargyl, benzyl or halogen benzyl.

Preferably, it is any one of following compounds:

Preferably, the officinal salt is hydrochloride, nitrate or acetate.

2, the preparation method of the sulphonyl thiazolium compounds and its officinal salt, described method includes following steps:

A, the preparation of intermediate III:

Using acetyl thiazole as starting material, in acetum, substitution reaction occurs to get in bromine under the conditions of 50 DEG C Mesosome III；

B, the preparation of sulphonyl thiazolium compounds shown in general formula I:

1) sulfonating reaction occurs and obtains N-acetylsulfanilyl chloride by starting material and chlorosulfonic acid of antifebrin, then pass through Salt-forming reaction obtains cosaprin, and finally and intermediate III is with acetonitrile as solvents, is reacted at 80 DEG C up to structure Sulphonyl thiazolium compounds shown in Formulas I -1；

2) sulphonyl thiazolium compounds shown in structural formula I-1 and brominated alkanes, propargyl bromide, bromopropene or benzyl chloride are with N, N- bis- Methylformamide makees solvent, and potassium hydroxide does alkali, is reacted under room temperature up to sulphonyl thiazole shown in structural formula I-2 to I-15 Close object；

3) sulphonyl thiazolium compounds shown in structural formula I-1 to I-15 hydrolyzes anti-under the conditions of hydrochloric acid catalysis and alcohol reflux It should be to get sulphonyl thiazolium compounds shown in structural formula I-16 to I-30；

C, the preparation of sulphonyl thiazolium compounds shown in general formula II:

Sulphonyl thiazolium compounds shown in structural formula I-16 to I-30 makees the item of solvent in sodium borohydride catalyzing and methylene chloride It is reacted at room temperature under part up to sulphonyl thiazolium compounds shown in formula II -1 to II-15；

D, the preparation of the officinal salt of sulphonyl thiazolium compounds shown in general formula II:

Sulphonyl thiazolium compounds shown in general formula II is dissolved in organic solvent, pharmaceutically acceptable acid is added and reacts to without precipitating generation Until to get sulphonyl thiazolium compounds shown in general formula II officinal salt.

Preferably,

In step b, in step 1), the temperature of the sulfonating reaction is 0-60 DEG C；Salt-forming reagent is in the salt-forming reaction Sodium sulfite or sodium bicarbonate, solvent are water；In step 2), sulphonyl thiazolium compounds and hydroxide shown in the structural formula I-1 The ratio between amount of substance of potassium is 1:3；In step 3), the temperature of the hydrolysis is 78 DEG C；

In step c, the amount of the substance of sulphonyl thiazolium compounds shown in the structural formula I-16 to I-30 and sodium borohydride it Than for 1:5；

In step d, the organic solvent is at least one of chloroform, acetone, acetonitrile, ether or tetrahydrofuran；It is described Pharmaceutically acceptable acid is hydrochloric acid or sulfuric acid.

3, the sulphonyl thiazolium compounds and its officinal salt answering in preparation antibacterium and/or antifungal drug With.

Preferably, the bacterium is staphylococcus aureus, methicillin-resistant staphylococcus aureus, Krebs pneumonia At least one of bacillus, Escherichia coli, enterococcus faecalis, Acinetobacter bauamnnii or pseudomonas aeruginosa；The fungi is the torrid zone At least one of candidiasis, aspergillus fumigatus, Candida albicans or Candida parapsilosis bacterium.

4, the preparation of the sulphonyl thiazolium compounds and its officinal salt, which is characterized in that the preparation is tablet, glue One of wafer, granule, injection, powder-injection, eye drops, liniment, suppository, ointment or aerosol.

The beneficial effects of the present invention are: the present invention designs principle of hybridization using drug, introduces thiazole in sulphonyl structure And amido is modified, design has synthesized a series of sulphonyl thiazolium compounds of structure novels, these compounds are through external Antimicrobial acivity detection discovery is to gram-positive bacteria (methicillin-resistant staphylococcus aureus, enterococcus faecalis, golden yellow Portugal Grape coccus, staphylococcus aureus ATCC25923, staphylococcus aureus ATCC29213), Gram-negative bacteria (Krebs Pneumobacillus, Escherichia coli, pseudomonas aeruginosa, pseudomonas aeruginosa ATCC27853, Escherichia coli ATCC25922, Bao Man are not Lever bacterium) and fungi (Candida albicans, Candida tropicalis, aspergillus fumigatus, Candida albicans ATCC90023, nearly smooth vacation Silk saccharomycete ATCC20019) there is certain inhibitory activity, it can be used for preparing antibacterium and/or antifungal drug, thus to face Bed antimicrobial therapy provides more drug candidates efficiently, safe, facilitates the drug resistance for solving to be on the rise, obstinate cause The clinical treatments problem such as characteristic of disease microorganism and emerging harmful microorganism.And its simple, cheap and easy to get, synthesis for preparing raw material Route is short, is of great significance to the application of anti-infective aspect.

Detailed description of the invention

In order to keep the purpose of the present invention, technical scheme and beneficial effects clearer, the present invention provides following attached drawing and carries out Illustrate:

Fig. 1 is compound I-21 and I-22 and reference drug Norfloxacin and sulphathiazole to methicillin-resistant staphylococcus Portugal The drug resistance reference of grape coccus (MRSA).

Specific embodiment

Below by a preferred embodiment of the present invention will be described in detail.

Embodiment 1

The preparation of intermediate III

Bibliography " J.M.Keith, L.A.Gomez, A.J.Barbier, S.J.Wilson, J.D.Boggs, B.Lord, C.Mazur,L.Aluisio,T.W.Lovenberg and N.I.Carruthers,Pyrrolidino- tetrahydroisoquinolines Bearing Pendant Heterocycles as Potent dual H3Antagonist and Serotonin Transporter Inhibitors,Bioorg Med Chem Lett,2007, It is prepared by method disclosed in 17,4374-4377. ".Obtain 12.2g intermediate III, yield 75.3%；Light yellow solid.

The preparation of embodiment 2, compound I-1

By acetparaminosalol benzene sulfonyl sodium (10.00g, 45.00mmol), intermediate III (9.30g, 45.00mmol) and The acetonitrile as solvents of 30mL is added in 250mL round-bottomed flask in 80 DEG C of reflux 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, cooling It to room temperature, is separated after acetonitrile is evaporated under reduced pressure by silica gel column chromatography, drying obtains compound IV (3.20g), yield is 21.80%；Light yellow solid；Fusing point is 204-206 DEG C；¹H NMR(600MHz,DMSO-d₆)δ:10.42(s,1H,NH), 8.30 (d, J=2.8Hz, 1H, thiazole-5-H), 8.15 (d, J=2.9Hz, 1H, thiazole-4-H), 7.81 (d, J= 9.0Hz, 2H, Ph-2,6-H), 7.79 (d, J=9.2Hz, 2H, Ph-3,5-H), 5.23 (s, 2H, SO₂CH₂),2.10(s,3H, COCH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:182.3,169.7,165.6,146.0,144.8,133.1,130.4, 129.9,119.0,62.4,24.6ppm.

The preparation of embodiment 3, compound I-2

By compound I-1 (0.30g, 1.00mmol), the N of potassium hydroxide (0.17g, 3.00mmol) and 5mL, N- dimethyl Formamide makees that 0.5h is stirred at room temperature in solvent addition 25mL round-bottomed flask, adds iodomethane (0.07mL, 1.10mmol) continuation Stir 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and system is instilled in ice water solution, and solid is precipitated, and is filtered, by what is be collected into Product vacuum is dry, obtains compound I-2 (0.2g), yield 59.6%；Light yellow solid；Fusing point is 180-182 DEG C；¹H NMR(600MHz,DMSO-d₆) δ: 8.29 (d, J=1.9Hz, 1H, thiazole-5-H), 8.13 (d, J=2.5Hz, 1H, ), thiazole-4-H 7.52 (d, J=8.6Hz, 2H, Ph-2,6-H), 6.62 (d, J=8.7Hz, 2H, Ph-3,5-H), 5.12 (s,2H,SO₂-CH₂), 2.73 (d, J=4.9Hz, 3H, N-CH₃),1.80(s,3H,COCH₃)ppm；¹³C NMR(150MHz, DMSO-d₆)δ:182.2,169.1,164.5,152.6,145.9,130.1,129.8,121.2,111.0,61.5,29.8, 23.0ppm.

The preparation of embodiment 4, compound I-3

By compound I-1 (0.30g, 1.00mmol), the N of potassium hydroxide (0.17g, 3.00mmol) and 5mL, N- dimethyl Formamide makees that 0.5h is stirred at room temperature in solvent addition 25mL round-bottomed flask, adds bromoethane (0.08mL, 1.10mmol) continuation Stir 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and system is instilled in ice water solution, and solid is precipitated, and is filtered, by what is be collected into Product vacuum is dry, obtains compound I-3 (0.23g), yield 64.2%；Light yellow solid；Fusing point is 210-212 DEG C；¹H NMR(600MHz,DMSO-d₆)δ:8.30(s,1H,thiazole-5-H),8.11(s,1H,thiazole-4-H),7.93(d,J =7.0Hz, 2H, Ph-2,6-H), 7.56 (d, J=7.6Hz, 2H, Ph-3,5-H), 5.35 (s, 2H, SO₂CH₂), 3.69 (d, J= 6.7Hz,2H,N-CH₂CH₃),1.80(s,3H,COCH₃),0.99(s,3H,N-CH₂CH₃)ppm；¹³C NMR(150MHz,DMSO- d₆)δ:182.2,168.9,165.4,148.1,145.9,130.5,130.0,129.1,62.2,43.9,23.0,13.5ppm.

The preparation of embodiment 5, compound I-4

By compound I-1 (0.30g, 1.00mmol), the N of potassium hydroxide (0.17g, 3.00mmol) and 5mL, N- dimethyl Formamide makees that 0.5h is stirred at room temperature in solvent addition 25mL round-bottomed flask, adds N-Propyl Bromide (0.10mL, 1.10mmol) continuation Stir 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and system is instilled in ice water solution, and solid is precipitated, and is filtered, by what is be collected into Product vacuum is dry, obtains compound I-4 (0.25g), yield 67.2%；Light yellow solid；Fusing point is 204-206 DEG C；¹H NMR(600MHz,DMSO-d₆) δ: 8.30 (d, J=2.7Hz, 1H, thiazole-5-H), 8.11 (d, J=2.8Hz, 1H, ), thiazole-4-H 7.92 (d, J=8.4Hz, 2H, Ph-2,6-H), 7.56 (d, J=8.4Hz, 2H, Ph-3,5-H), 5.35 (s,2H,SO₂CH₂), 3.63 (t, J=7.4Hz, 2H, N-CH₂CH₂CH₃),1.81(s,3H,COCH₃), 1.36 (dd, J=14.7, 7.4Hz,2H,N-CH₂CH₂CH₃), 0.81 (t, J=7.4Hz, 3H, N-CH₂CH₂CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆) δ:182.2,169.1,165.4,148.3,145.9,138.0,130.5,130.0,129.0,62.2,50.4,23.1,21.2, 11.5ppm.

The preparation of embodiment 6, compound I-5

By compound I-1 (0.30g, 1.00mmol), the N of potassium hydroxide (0.17g, 3.00mmol) and 5mL, N- dimethyl Formamide makees that 0.5h is stirred at room temperature in solvent addition 25mL round-bottomed flask, adds bromobutane (0.12mL, 1.10mmol) continuation Stir 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and system is instilled in ice water solution, and solid is precipitated, and is filtered, by what is be collected into Product vacuum is dry, obtains compound I-5 (0.26g), yield 67.2%；Yellow solid；Fusing point is 112-114 DEG C；¹H NMR(600MHz,DMSO-d₆) δ: 8.30 (d, J=2.9Hz, 1H, thiazole-5-H), 8.11 (d, J=2.9Hz, 1H, ), thiazole-4-H 7.93 (d, J=8.6Hz, 2H, Ph-2,6-H), 7.56 (d, J=8.6Hz, 2H, Ph-3,5-H), 5.36 (s,2H,SO₂CH₂),3.68–3.65(m,2H,N-CH₂(CH₂)₂CH₃),1.80(s,3H,COCH₃), 1.33 (dt, J=14.9, 7.4Hz,2H,N-CH₂CH₂CH₂CH₃), 1.23 (dd, J=14.9,7.4Hz, 2H, N- (CH₂)₂CH₂CH₃), 0.83 (t, J= 7.3Hz,3H,N-(CH₂)₃CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:182.2,169.1,165.4,148.3, 145.9,138.0,130.5,130.0,129.1,62.1,48.4,30.0,23.1,19.8,14.1ppm.

The preparation of embodiment 7, compound I-6

By compound I-1 (0.30g, 1.00mmol), the N of potassium hydroxide (0.17g, 3.00mmol) and 5mL, N- dimethyl Formamide makees that 0.5h is stirred at room temperature in solvent addition 25mL round-bottomed flask, adds bromo pentane silane (0.14mL, 1.10mmol) continuation Stir 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and system is instilled in ice water solution, and solid is precipitated, and is filtered, by what is be collected into Product vacuum is dry, obtains compound I-6 (0.26g), yield 66.2%；White solid；Fusing point is 110-112 DEG C；¹H NMR(600MHz,DMSO-d₆) δ: 8.30 (d, J=2.8Hz, 1H, thiazole-5-H), 8.11 (d, J=2.8Hz, 1H, ), thiazole-4-H 7.93 (d, J=8.4Hz, 2H, Ph-2,6-H), 7.56 (d, J=8.4Hz, 2H, Ph-3,5-H), 5.36 (s,2H,SO₂CH₂), 3.65 (t, J=7.4Hz, 2H, N-CH₂(CH₂)₃CH₃),1.80(s,3H,COCH₃),1.38–1.32(m, 2H,N-CH₂CH₂(CH₂)₂CH₃),1.25–1.18(m,4H,N-CH₂CH₂(CH₂)₂CH₃), 0.82 (t, J=7.0Hz, 3H, N- (CH₂)₄CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:182.2,169.0,165.4,148.3,145.9,138.0, 130.5,130.0,129.0,62.1,48.7,28.7,27.5,23.1,22.2,14.3ppm.

The preparation of embodiment 8, compound I-7

By compound I-1 (0.30g, 1.00mmol), the N of potassium hydroxide (0.17g, 3.00mmol) and 5mL, N- dimethyl Formamide makees that 0.5h is stirred at room temperature in solvent addition 25mL round-bottomed flask, adds bromohexane (0.18mL, 1.10mmol) continuation Stir 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and system is instilled in ice water solution, and solid is precipitated, and is filtered, by what is be collected into Product vacuum is dry, obtains compound I-7 (0.28g), yield 68.7%；Light yellow solid；Fusing point is 124-126 DEG C；¹H NMR(600MHz,DMSO-d₆) δ: 8.30 (d, J=2.4Hz, 1H, thiazole-5-H), 8.11 (d, J=2.4Hz, 1H, ), thiazole-4-H 7.93 (d, J=8.3Hz, 2H, Ph-2,6-H), 7.56 (d, J=8.3Hz, 2H, Ph-3,5-H), 5.36 (s,2H,SO₂CH₂), 3.66 (t, J=7.4Hz, 2H, N-CH₂(CH₂)₄CH₃),1.80(s,3H,COCH₃), 1.34 (d, J= 6.8Hz,2H,N-CH₂CH₂(CH₂)₃CH₃), 1.22 (dd, J=15.9,8.6Hz, 6H, N- (CH₂)₂(CH₂)₃CH₃),0.83(t,J =6.6Hz, 3H, N- (CH₂)₅CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:182.2,169.0,165.4,148.3, 145.9,138.0,130.5,123.0,129.0,62.1,48.7,31.3,27.9,26.2,23.1,22.4,14.3ppm.

The preparation of embodiment 9, compound I-8

By compound I-1 (0.30g, 1.00mmol), the N of potassium hydroxide (0.17g, 3.00mmol) and 5mL, N- dimethyl Formamide makees that 0.5h is stirred at room temperature in solvent addition 25mL round-bottomed flask, adds heptyl bromide (0.17mL, 1.10mmol) continuation Stir 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and system is instilled in ice water solution, and solid is precipitated, and is filtered, by what is be collected into Product vacuum is dry, obtains compound I-8 (0.29g), yield 68.2%；White solid；Fusing point is 120-122 DEG C；¹H NMR(600MHz,DMSO-d₆) δ: 8.30 (d, J=2.9Hz, 1H, thiazole-5-H), 8.11 (d, J=2.9Hz, 1H, ), thiazole-4-H 7.93 (d, J=8.5Hz, 2H, Ph-2,6-H), 7.56 (d, J=8.4Hz, 2H, Ph-3,5-H), 5.36 (s,2H,SO₂CH₂), 3.65 (t, J=7.4Hz, 2H, N-CH₂(CH₂)₅CH₃),1.80(s,3H,COCH₃),1.37–1.32(m, 2H,N-CH₂CH₂(CH₂)₄CH₃),1.25–1.18(m,8H,N-(CH₂)₂(CH₂)₄CH₃), 0.83 (t, J=7.0Hz, 3H, N- (CH₂)₆CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:182.2,169.0,165.4,148.3,145.9,138.0, 130.5,130.0,129.0,62.1,48.7,31.6,28.8,27.9,26.5,23.1,22.4,14.3ppm.

The preparation of embodiment 10, compound I-9

By compound I-1 (0.30g, 1.00mmol), the N of potassium hydroxide (0.17g, 3.00mmol) and 5mL, N- dimethyl Formamide makees that 0.5h is stirred at room temperature in solvent addition 25mL round-bottomed flask, adds bromooctane (0.19mL, 1.10mmol) continuation Stir 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and system is instilled in ice water solution, and solid is precipitated, and is filtered, by what is be collected into Product vacuum is dry, obtains compound I-9 (0.29g), yield 66.2%；White solid；Fusing point is 122-124 DEG C；¹H NMR(600MHz,DMSO-d₆) δ: 8.30 (d, J=2.9Hz, 1H, thiazole-5-H), 8.11 (d, J=2.9Hz, 1H, ), thiazole-4-H 7.93 (d, J=8.5Hz, 2H, Ph-2,6-H), 7.56 (d, J=8.5Hz, 2H, Ph-3,5-H), 5.36 (s,2H,SO₂CH₂),3.67–3.63(m,2H,N-CH₂(CH₂)₆CH₃),1.80(s,3H,COCH₃),1.35(s,2H,N-CH₂CH₂ (CH₂)₅CH₃),1.20(s,10H,N-(CH₂)₂(CH₂)₅CH₃), 0.84 (t, J=7.0Hz, 3H, N- (CH₂)₇CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:182.2,169.1,165.4,148.3,145.9,138.0,130.5,130.0,129.1, 62.1,48.7,31.6,29.0,27.9,26.5,23.1,22.5,14.4ppm.

The preparation of embodiment 11, compound I-10

By compound I-1 (0.30g, 1.00mmol), the N of potassium hydroxide (0.17g, 3.00mmol) and 5mL, N- dimethyl Formamide makees that 0.5h is stirred at room temperature in solvent addition 25mL round-bottomed flask, adds bromopropene (0.10mL, 1.10mmol) continuation Stir 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and system is instilled in ice water solution, and solid is precipitated, and is filtered, by what is be collected into Product vacuum is dry, obtains compound I-10 (0.11g), yield 30.2%；Light yellow solid；Fusing point is 140-142 DEG C；¹H NMR(600MHz,DMSO-d₆) δ: 8.30 (d, J=2.9Hz, 1H, thiazole-5-H), 8.12 (d, J=2.9Hz, 1H, ), thiazole-4-H 7.91 (d, J=8.5Hz, 2H, Ph-2,6-H), 7.56 (d, J=8.5Hz, 2H, Ph-3,5-H), 5.82- 5.74(m,1H,CH₂CHCH₂),5.34(s,2H,CH₂CHCH₂),5.12–5.06(m,2H,NHCH₂), 4.31 (d, J=5.1Hz, 2H,SO₂CH₂),1.88(s,3H,COCH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:182.2,165.4,148.2, 145.9,137.8,134.0,130.5,129.8,128.6,117.7,62.2,51.6,23.0ppm.

The preparation of embodiment 12, compound I-11

By compound I-1 (0.30g, 1.00mmol), the N of potassium hydroxide (0.17g, 3.00mmol) and 5mL, N- dimethyl Formamide makees that 0.5h is stirred at room temperature in solvent addition 25mL round-bottomed flask, adds propargyl bromide (0.13mL, 1.10mmol) continuation Stir 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and system is instilled in ice water solution, and solid is precipitated, and is filtered, by what is be collected into Product vacuum is dry, obtains compound I-11 (0.18g), yield 50.2%；White solid；Fusing point is 165-167 DEG C；¹H NMR(600MHz,DMSO-d₆) δ: 8.30 (d, J=2.8Hz, 1H, thiazole-5-H), 8.12 (d, J=2.9Hz, 1H, ), thiazole-4-H 7.96 (d, J=8.4Hz, 2H, Ph-2,6-H), 7.62 (d, J=8.4Hz, 2H, Ph-3,5-H), 5.37 (s,2H,SO₂CH₂),4.51(s,2H,NHCH₂),3.22(s,1H,C-CH),1.87(s,3H,COCH₃)ppm；¹³C NMR (150MHz,DMSO-d₆)δ:182.2,169.1,165.4,147.4,145.9,138.5,130.5,129.9,128.8,79.9, 75.5,62.2,38.2,22.8ppm.

The preparation of embodiment 13, compound I-12

By compound I-1 (0.30g, 1.00mmol), the N of potassium hydroxide (0.17g, 3.00mmol) and 5mL, N- dimethyl Formamide makees that 0.5h is stirred at room temperature in solvent addition 25mL round-bottomed flask, adds benzyl chloride (0.13mL, 1.10mmol) continuation Stir 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and system is instilled in ice water solution, and solid is precipitated, and is filtered, by what is be collected into Product vacuum is dry, obtains compound I-12 (0.25g), yield 60.4%；Light yellow solid；Fusing point is 150-152 DEG C；¹H NMR(600MHz,DMSO-d₆) δ: 8.27 (d, J=2.4Hz, 1H, thiazole-5-H), 8.03 (d, J=2.7Hz, 1H, ), thiazole-4-H 7.86 (d, J=8.4Hz, 2H, Ph-2,6-H), 7.52 (d, J=8.4Hz, 2H, N-CH₂-Ph-2,6- ), H 7.30 (d, J=7.4Hz, 2H, N-CH₂- Ph-3,5-H), 7.24 (d, J=7.2Hz, 1H, N-CH₂-Ph-4-H),7.19(d, J=7.4Hz, 2H, Ph-3,5-H), 5.32 (s, 2H, NHCH₂),4.95(s,2H,SO₂-CH₂),1.92(s,3H,COCH₃)ppm ；¹³C NMR(150MHz,DMSO-d₆)δ:182.1,169.7,165.4,148.1,145.9,137.7,130.5,129.8, 128.8,128.0,127.6,119.0,62.1,52.2,23.0ppm.

The preparation of embodiment 14, compound I-13

By compound I-1 (0.30g, 1.00mmol), the N of potassium hydroxide (0.17g, 3.00mmol) and 5mL, N- dimethyl Formamide make solvent be added 25mL round-bottomed flask in 0.5h is stirred at room temperature, add to fluorine benzyl chloride (0.13mL, 1.10mmol) after Continuous stirring 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and system is instilled in ice water solution, and solid is precipitated, and is filtered, will be collected into Product vacuum it is dry, obtain compound I-13 (0.24g), yield 55.2%；Yellow solid；Fusing point is 125-127 DEG C；¹H NMR(600MHz,DMSO-d₆) δ: 8.28 (d, J=2.1Hz, 1H, thiazole-5-H), 8.06 (s, 1H, thiazole-4- ), H 7.87 (d, J=8.2Hz, 2H, Ph-2,6-H), 7.49 (d, J=8.2Hz, 2H, N-CH₂-Ph-2,6-H),7.23–7.20 (m,2H,N-CH₂- Ph-3,5-H), 7.11 (t, J=8.2Hz, 2H, Ph-3,5-H), 5.32 (s, 2H, NHCH₂),4.91(s,2H, SO₂CH₂),1.89(s,3H,COCH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:182.1,169.6,165.4,162.6, 161.0,148.0,145.9,130.4,130.1,129.9,128.9,115.7,115.6,62.1,51.5,23.0ppm.

The preparation of embodiment 15, compound I-14

By compound I-1 (0.30g, 1.00mmol), the N of potassium hydroxide (0.17g, 3.00mmol) and 5mL, N- dimethyl Formamide make solvent be added 25mL round-bottomed flask in 0.5h is stirred at room temperature, add to benzyl chloride chlorine (0.14mL, 1.10mmol) after Continuous stirring 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and system is instilled in ice water solution, and solid is precipitated, and is filtered, will be collected into Product vacuum it is dry, obtain compound I-14 (0.27g), yield 60.3%；Light yellow solid；Fusing point is 165-167 ℃；¹H NMR(600MHz,DMSO-d₆) δ: 8.27 (d, J=2.8Hz, 1H, thiazole-5-H), 8.05 (s, 1H, ), thiazole-4-H 7.87 (d, J=7.1Hz, 2H, Ph-2,6-H), 7.51 (d, J=7.7Hz, 2H, N-CH₂-Ph-2,6- ), H 7.35 (d, J=7.6Hz, 3H, N-CH₂- Ph-3,5-H), 7.21 (d, J=8.2Hz, 3H, Ph-3,5-H, NH), 5.32 (s, 2H,NHCH₂),4.92(s,2H,SO₂CH₂),1.89(s,3H,COCH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:182.1, 169.7,165.4,145.8,138.6,136.8,132.3,130.4,129.7,128.9,111.8,62.1,45.5, 23.0ppm.

The preparation of embodiment 16, compound I-15

By compound I-1 (0.30g, 1.00mmol), the N of potassium hydroxide (0.17g, 3.00mmol) and 5mL, N- dimethyl Formamide make solvent be added 25mL round-bottomed flask in 0.5h is stirred at room temperature, add 2,4- dichloro benzyl chloride (0.15mL, 1.10mmol) continue to stir 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and system is instilled in ice water solution, and solid is precipitated, and is taken out Filter, the product vacuum being collected into is dry, obtain compound I-15 (0.3g), yield 67.2%；Light yellow solid；Fusing point is 156–158℃；¹H NMR(600MHz,DMSO-d₆)δ:8.27(s,1H,thiazole-5-H),8.06(s,1H,thiazole- 4-H), 7.89 (d, J=7.9Hz, 2H, Ph-2,6-H), 7.63 (d, J=1.9Hz, 1H, N-CH₂- Ph-3-H), 7.56 (d, J= 8.4Hz,2H,N-CH₂- Ph-5,6-H), 7.37 (dd, J=8.4,1.8Hz, 2H, Ph-3,5-H), 5.33 (s, 2H, NHCH₂), 4.66(s,2H,SO₂CH₂),1.92(s,3H,COCH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:169.8,147.8, 145.9,135.1,133.6,131.4,130.5,129.2,128.8,127.9,69.1,43.4,23.0ppm.

The preparation of embodiment 17, compound I-16

25mL round-bottomed flask is added in the ethyl alcohol of compound I-1 (0.16g, 0.50mmol) and 5mL, it is dense that 2mL is then added dropwise In 78 DEG C of reflux 8h after hydrochloric acid.Thin-layer chromatography, which tracks to reaction, to be terminated, and is stopped heating, is cooled to room temperature.Revolving removes ethyl alcohol, will System instills in saturated sodium bicarbonate solution, and solid is precipitated, and filters, and the product vacuum being collected into is dry, obtains compound I- 16 (0.10g), yield 70.9%；Yellow solid；Fusing point is 165-167 DEG C；¹H NMR(600MHz,DMSO-d₆)δ:8.28 (d, J=2.9Hz, 1H, thiazole-5-H), 8.14 (d, J=2.9Hz, 1H, thiazole-4-H), 7.43 (d, J= 8.7Hz, 2H, Ph-2,6-H), 6.59 (d, J=8.7Hz, 2H, Ph-3,5-H), 6.21 (s, 2H, NH₂),5.05(s,2H, SO₂CH₂)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:182.6,165.9,154.5,145.9,130.5,130.1,124.4, 113.0,62.9ppm.

The preparation of embodiment 18, compound I-17

25mL round-bottomed flask is added in the ethyl alcohol of compound I-2 (0.17g, 0.50mmol) and 5mL, it is dense that 2mL is then added dropwise In 78 DEG C of reflux 8h after hydrochloric acid.Thin-layer chromatography, which tracks to reaction, to be terminated, and is stopped heating, is cooled to room temperature.Revolving removes ethyl alcohol, will System instills in saturated sodium bicarbonate solution, and solid is precipitated, and filters, and the product vacuum being collected into is dry, obtains compound I- 17 (0.08g), yield 56.6%；Light yellow solid；Fusing point is 190-192 DEG C；¹H NMR(600MHz,DMSO-d₆)δ:8.28 (d, J=1.9Hz, 1H, thiazole-5-H), 8.14 (d, J=2.5Hz, 1H, thiazole-4-H), 7.50 (d, J= 8.6Hz, 2H, Ph-2,6-H), 6.78 (d, J=4.3Hz, 1H, NH), 6.59 (d, J=8.7Hz, 2H, Ph-3,5-H), 5.07 (s,2H,SO₂CH₂), 2.73 (d, J=4.9Hz, 3H, N-CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:182.6, 165.9,154.6,145.9,130.4,130.1,124.2,111.0,62.9,29.6ppm.

The preparation of embodiment 19, compound I-18

25mL round-bottomed flask is added in the ethyl alcohol of compound I-3 (0.18g, 0.50mmol) and 5mL, it is dense that 2mL is then added dropwise In 78 DEG C of reflux 8h after hydrochloric acid.Thin-layer chromatography, which tracks to reaction, to be terminated, and is stopped heating, is cooled to room temperature.Revolving removes ethyl alcohol, will System instills in saturated sodium bicarbonate solution, and solid is precipitated, and filters, and the product vacuum being collected into is dry, obtains compound I- 18 (0.11g), yield 68.8%；White solid；Fusing point is 142-144 DEG C；¹H NMR(600MHz,DMSO-d₆)δ:8.28 (s, 1H, thiazole-5-H), 8.14 (s, 1H, thiazole-4-H), 7.48 (d, J=8.3Hz, 2H, Ph-2,6-H), 6.73 (s, 1H, NH), 6.60 (d, J=8.4Hz, 2H, Ph-3,5-H), 5.06 (s, 2H, SO₂CH₂),3.13–3.07(m,2H,N- CH₂CH₃), 1.16 (t, J=7.0Hz, 3H, N-CH₂CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:182.6,165.9, 153.7,145.9,130.4,130.0,124.1,111.2,62.9,37.3,14.5ppm.

The preparation of embodiment 20, compound I-19

25mL round-bottomed flask is added in the ethyl alcohol of compound I-4 (0.18g, 0.50mmol) and 5mL, it is dense that 2mL is then added dropwise In 78 DEG C of reflux 8h after hydrochloric acid.Thin-layer chromatography, which tracks to reaction, to be terminated, and is stopped heating, is cooled to room temperature.Revolving removes ethyl alcohol, will System instills in saturated sodium bicarbonate solution, and solid is precipitated, and filters, and the product vacuum being collected into is dry, obtains compound I- 19 (0.11g), yield 68.5%；Yellow solid；Fusing point is 88-90 DEG C；¹H NMR(600MHz,DMSO-d₆)δ:8.27(d,J =2.5Hz, 1H, thiazole-5-H), 8.13 (d, J=2.7Hz, 1H, thiazole-4-H), 7.47 (d, J=8.6Hz, 2H, ), Ph-2,6-H 6.76 (t, J=4.7Hz, 1H, NH), 6.61 (d, J=8.7Hz, 2H, Ph-3,5-H), 5.05 (s, 2H, SO₂CH₂), 3.03 (dd, J=12.7,6.6Hz, 2H, N-CH₂CH₂CH₃),1.58–1.52(m,2H,N-CH₂CH₂CH₃),0.93 (t, J=7.4Hz, 3H, N-CH₂CH₂CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:182.6,165.9,153.8, 145.9,130.4,130.0,124.0,111.2,62.9,44.5,22.1,12.0ppm.

The preparation of embodiment 21, compound I-20

25mL round-bottomed flask is added in the ethyl alcohol of compound I-5 (0.19g, 0.50mmol) and 5mL, it is dense that 2mL is then added dropwise In 78 DEG C of reflux 8h after hydrochloric acid.Thin-layer chromatography, which tracks to reaction, to be terminated, and is stopped heating, is cooled to room temperature.Revolving removes ethyl alcohol, will System instills in saturated sodium bicarbonate solution, and solid is precipitated, and filters, and the product vacuum being collected into is dry, obtains compound I- 20 (0.11g), yield 62.3%；Light yellow solid；Fusing point is 90-92 DEG C；¹H NMR(600MHz,DMSO-d₆)δ:8.28 (s, 1H, thiazole-5-H), 8.14 (s, 1H, thiazole-4-H), 7.47 (d, J=8.2Hz, 2H, Ph-2,6-H), 6.76 (s, 1H, NH), 6.61 (d, J=8.3Hz, 2H, Ph-3,5-H), 5.06 (s, 2H, SO₂CH₂), 3.06 (d, J=5.7Hz, 2H, N- CH₂(CH₂)₂CH₃),1.54–1.50(m,2H,N-CH₂CH₂CH₂CH₃), 1.37 (dd, J=14.9,7.4Hz, 2H, N- (CH₂)₂CH₂CH₃), 0.91 (t, J=7.3Hz, 3H, N- (CH₂)₃CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:182.6, 165.9,153.8,145.9,130.4,130.1,124.0,111.2,62.9,42.4,30.9,20.2,14.2ppm.

The preparation of embodiment 22, compound I-21

25mL round-bottomed flask is added in the ethyl alcohol of compound I-6 (0.20g, 0.50mmol) and 5mL, it is dense that 2mL is then added dropwise In 78 DEG C of reflux 8h after hydrochloric acid.Thin-layer chromatography, which tracks to reaction, to be terminated, and is stopped heating, is cooled to room temperature.Revolving removes ethyl alcohol, will System instills in saturated sodium bicarbonate solution, and solid is precipitated, and filters, and the product vacuum being collected into is dry, obtains compound I- 21 (0.11g), yield 62.2%；Yellow solid；Fusing point is 174-176 DEG C；¹H NMR(600MHz,DMSO-d₆)δ:8.28 (d, J=2.5Hz, 1H, thiazole-5-H), 8.14 (d, J=2.6Hz, 1H, thiazole-4-H), 7.47 (d, J= 8.7Hz, 2H, Ph-2,6-H), 6.74 (s, 1H, NH), 6.60 (d, J=8.7Hz, 2H, Ph-3,5-H), 5.05 (s, 2H, SO₂CH₂), 3.05 (dd, J=12.4,6.5Hz, 2H, N-CH₂(CH₂)₃CH₃),1.33(d,6H,N-CH₂CH₂(CH₂)₂CH₃), 0.88 (d, J=6.6Hz, 3H, N- (CH₂)₄CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:177.3,151.0,143.2, 130.4,127.7,121.3,110.6,62.9,43.0,29.2,28.5,22.4,14.4ppm.

The preparation of embodiment 23, compound I-22

25mL round-bottomed flask is added in the ethyl alcohol of compound I-7 (0.18g, 0.50mmol) and 5mL, it is dense that 2mL is then added dropwise In 78 DEG C of reflux 8h after hydrochloric acid.Thin-layer chromatography, which tracks to reaction, to be terminated, and is stopped heating, is cooled to room temperature.Revolving removes ethyl alcohol, will System instills in saturated sodium bicarbonate solution, and solid is precipitated, and filters, and the product vacuum being collected into is dry, obtains compound I- 22 (0.11g), yield 60.2%；Yellow solid；Fusing point is 86-88 DEG C；¹H NMR(600MHz,DMSO-d₆)δ:8.28(d,J =2.4Hz, 1H, thiazole-5-H), 8.14 (d, J=2.4Hz, 1H, thiazole-4-H), 7.47 (d, J=8.6Hz, 2H, ), Ph-2,6-H 6.75 (s, 1H, NH), 6.61 (d, J=8.7Hz, 2H, Ph-3,5-H), 5.06 (s, 2H, SO₂CH₂),3.07– 3.04(m,2H,N-CH₂(CH₂)₄CH₃), 1.34 (d, J=6.8Hz, 2H, N-CH₂CH₂(CH₂)₃CH₃),1.29(s,6H,N- (CH₂)₂(CH₂)₃CH₃), 0.87 (d, J=6.5Hz, 3H, N- (CH₂)₅CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ: 182.6,165.9,153.8,145.9,130.5,130.2,127.7,124.0,111.2,62.9,42.7,31.5,28.8, 26.7,22.6,14.4ppm.

The preparation of embodiment 24, compound I-23

25mL round-bottomed flask is added in the ethyl alcohol of compound I-8 (0.21g, 0.50mmol) and 5mL, it is dense that 2mL is then added dropwise In 78 DEG C of reflux 8h after hydrochloric acid.Thin-layer chromatography, which tracks to reaction, to be terminated, and is stopped heating, is cooled to room temperature.Revolving removes ethyl alcohol, will System instills in saturated sodium bicarbonate solution, and solid is precipitated, and filters, and the product vacuum being collected into is dry, obtains compound I- 23 (0.11g), yield 58.5%；Brown solid；Fusing point is 203-205 DEG C；¹H NMR(600MHz,DMSO-d₆)δ:8.30 (s, 1H, thiazole-5-H), 8.16 (s, 1H, thiazole-4-H), 7.61 (d, J=8.6Hz, 2H, Ph-2,6-H), 6.77 (d, J=8.7Hz, 2H, Ph-3,5-H), 6.51 (s, 1H, NH), 5.08 (s, 2H, SO₂CH₂),3.07(s,2H,N-CH₂(CH₂)₅CH₃),1.30(s,10H,N-CH₂(CH₂)₅CH₃),0.88(s,3H,N-CH₂(CH₂)₅CH₃)ppm；¹³C NMR(150MHz, DMSO-d₆)δ:182.6,166.0,154.0,130.4,127.7,111.1,110.6,62.9,42.9,42.4,31.8,29.0, 27.0,22.5,14.4ppm.

The preparation of embodiment 25, compound I-24

25mL round-bottomed flask is added in the ethyl alcohol of compound I-9 (0.22g, 0.50mmol) and 5mL, it is dense that 2mL is then added dropwise In 78 DEG C of reflux 8h after hydrochloric acid.Thin-layer chromatography, which tracks to reaction, to be terminated, and is stopped heating, is cooled to room temperature.Revolving removes ethyl alcohol, will System instills in saturated sodium bicarbonate solution, and solid is precipitated, and filters, and the product vacuum being collected into is dry, obtains compound I- 24 (0.12g), yield 59.4%；Light yellow solid；Fusing point is 85-87 DEG C；¹H NMR(600MHz,DMSO-d₆)δ:8.27 (d, J=3.0Hz, 1H, thiazole-5-H), 8.13 (d, J=3.0Hz, 1H, thiazole-4-H), 7.47 (d, J= 9.0Hz, 2H, Ph-2,6-H), 6.61 (d, J=9.0Hz, 2H, Ph-3,5-H), 5.06 (s, 2H, SO₂CH₂), 3.05 (t, J= 7.0Hz,2H,N-CH₂(CH₂)₆CH₃),1.55–1.51(m,2H,N-CH₂CH₂(CH₂)₅CH₃),1.34(s,2H,N-(CH₂)₂CH₂ (CH₂)₄CH₃), 1.27 (dd, J=10.5,4.3Hz, 8H, N- (CH₂)₃(CH₂)₄CH₃), 0.86 (t, J=7.0Hz, 3H, N- (CH₂)₇CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:182.6,165.9,153.8,145.9,130.4,130.0, 124.0,111.2,62.9,42.7,31.7,29.2,28.8,27.0,22.5,14.4ppm.

The preparation of embodiment 26, compound I-25

25mL round-bottomed flask is added in the ethyl alcohol of compound I-10 (0.18g, 0.50mmol) and 5mL, it is dense that 2mL is then added dropwise In 78 DEG C of reflux 8h after hydrochloric acid.Thin-layer chromatography, which tracks to reaction, to be terminated, and is stopped heating, is cooled to room temperature.Revolving removes ethyl alcohol, will System instills in saturated sodium bicarbonate solution, and solid is precipitated, and filters, and the product vacuum being collected into is dry, obtains compound I- 25 (0.06g), yield 40.4%；Yellow solid；Fusing point is 101-103 DEG C；¹H NMR(600MHz,DMSO-d₆)δ:8.28 (s, 1H, thiazole-5-H), 8.13 (s, 1H, thiazole-4-H), 7.48 (d, J=8.2Hz, 2H, Ph-2,6-H), 6.99 (s, 1H, NH), 6.62 (d, J=8.1Hz, 2H, Ph-3,5-H), 5.90-5.82 (m, 1H, CH₂CHCH₂), 5.16 (dd, J= 34.8,13.6Hz,2H,CH₂CHCH₂),5.06(s,2H,SO₂CH₂),3.76(s,2H,NHCH₂)ppm；¹³C NMR(150MHz, DMSO-d₆)δ:182.6,165.9,153.6,145.8,135.3,133.2,131.2,130.3,116.3,111.6,62.9, 44.9ppm.

The preparation of embodiment 27, compound I-26

25mL round-bottomed flask is added in the ethyl alcohol of compound I-11 (0.18g, 0.50mmol) and 5mL, it is dense that 2mL is then added dropwise In 78 DEG C of reflux 8h after hydrochloric acid.Thin-layer chromatography, which tracks to reaction, to be terminated, and is stopped heating, is cooled to room temperature.Revolving removes ethyl alcohol, will System instills in saturated sodium bicarbonate solution, and solid is precipitated, and filters, and the product vacuum being collected into is dry, obtains compound I- 26 (0.09g), yield 54.5%；Brown liquid；¹H NMR(600MHz,DMSO-d₆)δ:8.28(s,1H,thiazole-5- ), H 8.13 (s, 1H, thiazole-4-H), 7.55 (d, J=7.2Hz, 3H, Ph-2,6-H, NH), 6.71 (d, J=7.1Hz, 2H,Ph-3,5-H),5.10(s,2H,SO₂CH₂),3.96(s,3H,NHCH₂,C-CH)ppm；¹³C NMR(150MHz,DMSO-d₆) δ:182.6,165.8,152.8,145.9,130.3,125.6,113.1,112.2,81.4,74.0,62.8,32.0ppm.

The preparation of embodiment 28, compound I-27

25mL round-bottomed flask is added in the ethyl alcohol of compound I-12 (0.21g, 0.50mmol) and 5mL, it is dense that 2mL is then added dropwise In 78 DEG C of reflux 8h after hydrochloric acid.Thin-layer chromatography, which tracks to reaction, to be terminated, and is stopped heating, is cooled to room temperature.Revolving removes ethyl alcohol, will System instills in saturated sodium bicarbonate solution, and solid is precipitated, and filters, and the product vacuum being collected into is dry, obtains compound I- 27 (0.12g), yield 64.5%；Yellow solid；Fusing point is 130-132 DEG C；¹H NMR(600MHz,DMSO-d₆)δ:8.27 (d, J=2.9Hz, 1H, thiazole-5-H), 8.09 (d, J=2.9Hz, 1H, thiazole-4-H), 7.47 (d, J= 9.0Hz,2H,Ph-2,6-H),7.37–7.32(m,5H,N-CH₂- Ph-2,3,4,5,6-H), 7.26 (t, J=6.9Hz, 1H, ), NH 6.65 (d, J=8.8Hz, 2H, Ph-3,5-H), 5.06 (s, 2H, SO₂CH₂),4.36(s,2H,NHCH₂)ppm；¹³C NMR (150MHz,DMSO-d₆)δ:182.6,165.8,153.6,145.8,139.5,130.4,128.9,127.6,127.4, 124.6,113.2,111.7,62.9,46.2ppm.

The preparation of embodiment 29, compound I-28

25mL round-bottomed flask is added in the ethyl alcohol of compound I-13 (0.22g, 0.50mmol) and 5mL, it is dense that 2mL is then added dropwise In 78 DEG C of reflux 8h after hydrochloric acid.Thin-layer chromatography, which tracks to reaction, to be terminated, and is stopped heating, is cooled to room temperature.Revolving removes ethyl alcohol, will System instills in saturated sodium bicarbonate solution, and solid is precipitated, and filters, and the product vacuum being collected into is dry, obtains compound I- 28 (0.11g), yield 55.7%；Yellow solid；Fusing point is 130-132 DEG C；¹H NMR(600MHz,DMSO-d₆)δ:8.27 (d, J=2.9Hz, 1H, thiazole-5-H), 8.10 (d, J=2.9Hz, 1H, thiazole-4-H), 7.47 (d, J= 8.9Hz,2H,N-CH₂- Ph-2,6-H), 7.36 (dd, J=8.3,5.7Hz, 3H, Ph-2,6-H, NH), 7.18 (t, J= 8.8Hz,2H,N-CH₂- Ph-3,5-H), 6.64 (d, J=8.8Hz, 2H, Ph-3,5-H), 5.06 (s, 2H, SO₂CH₂),4.34 (d, J=5.9Hz, 2H, NHCH₂)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:182.6,165.8,162.6,160.9, 153.4,145.8,135.6,130.4,130.0,129.6,124.8,115.7,115.6,111.7,62.9,45.5ppm.

The preparation of embodiment 30, compound I-29

25mL round-bottomed flask is added in the ethyl alcohol of compound I-14 (0.22g, 0.50mmol) and 5mL, it is dense that 2mL is then added dropwise In 78 DEG C of reflux 8h after hydrochloric acid.Thin-layer chromatography, which tracks to reaction, to be terminated, and is stopped heating, is cooled to room temperature.Revolving removes ethyl alcohol, will System instills in saturated sodium bicarbonate solution, and solid is precipitated, and filters, and the product vacuum being collected into is dry, obtains compound I- 29 (0.12g), yield 61.2%；Light yellow solid；Fusing point is 126-128 DEG C；¹H NMR(600MHz,DMSO-d₆)δ:8.27 (d, J=2.9Hz, 1H, thiazole-5-H), 8.09 (d, J=2.9Hz, 1H, thiazole-4-H), 7.47 (d, J= 8.9Hz,2H,N-CH₂- Ph-2,6-H), 7.41 (d, J=8.4Hz, 2H, N-CH₂- Ph-3,5-H), 7.38 (d, J=6.2Hz, 1H, NH), 7.34 (d, J=8.4Hz, 2H, Ph-2,6-H), 6.63 (d, J=8.8Hz, 2H, Ph-3,5-H), 5.06 (s, 2H, SO₂CH₂), 4.35 (d, J=6.0Hz, 2H, NHCH₂)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:182.6,165.8, 153.4,145.8,138.6,131.9,130.4,130.1,129.4,128.9,124.9,111.8,62.9,45.5ppm.

The preparation of embodiment 31, compound I-30

25mL round-bottomed flask is added in the ethyl alcohol of compound I-15 (0.24g, 0.50mmol) and 5mL, it is dense that 2mL is then added dropwise In 78 DEG C of reflux 8h after hydrochloric acid.Thin-layer chromatography, which tracks to reaction, to be terminated, and is stopped heating, is cooled to room temperature.Revolving removes ethyl alcohol, will System instills in saturated sodium bicarbonate solution, and solid is precipitated, and filters, and the product vacuum being collected into is dry, obtains compound I- 30 (0.13g), yield 59.6%；Light yellow solid；Fusing point is 180-182 DEG C；¹H NMR(600MHz,DMSO-d₆)δ:8.28 (d, J=3.0Hz, 1H, thiazole-5-H), 8.11 (d, J=3.0Hz, 1H, thiazole-4-H), 7.65 (d, J= 2.1Hz, 1H, Ph-2,6-H), 7.50 (d, J=9.0Hz, 2H, N-CH₂-Ph-3-H),7.47–7.42(m,2H,N-CH₂-Ph-5, 6-H), 7.35 (t, J=5.9Hz, 1H, NH), 6.63 (d, J=8.8Hz, 2H, Ph-3,5-H), 5.07 (s, 2H, SO₂CH₂), 4.39 (d, J=5.9Hz, 2H, NHCH₂)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:182.5,165.8,153.1,145.8, 135.5,135.1,133.8,132.9,131.3,130.5,130.1,129.3,129.2,127.9,62.8,43.8ppm.

The preparation of embodiment 32, compound II-1

25mL round-bottomed flask is added in the methylene chloride of compound I-16 (0.08g, 0.28mmol) and 5mL, is then added Sodium borohydride (0.05g, 1.40mmol) is in room temperature reaction 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and is filtered and is removed hydroboration Sodium, is separated after methylene chloride is evaporated under reduced pressure by silica gel column chromatography, and drying obtains compound II-1 (0.06g), yield is 75.9%；Yellow solid；Fusing point is 138-140 DEG C；¹H NMR(600MHz,DMSO-d₆) δ: 8.28 (d, J=3.0Hz, 1H, ), thiazole-5-H 8.14 (d, J=3.0Hz, 1H, thiazole-4-H), 7.43 (s, 2H, Ph-2,6-H), 6.60 (d, J= 8.8Hz,2H,Ph-3,5-H),6.21(s,2H,NH₂), 5.19 (ddd, J=9.1,6.6,2.7Hz, 1H, OH), 3.64 (dd, J =14.5,2.6Hz, 1H, SO₂CH₂), 3.53 (dd, J=14.5,9.0Hz, 1H, SO₂CH₂)ppm；¹³C NMR(150MHz, DMSO-d₆)δ:174.8,154.5,145.9,130.5,130.2,121.0,113.0,66.7,62.9ppm.

The preparation of embodiment 33, compound II-2

25mL round-bottomed flask is added in the methylene chloride of compound I-17 (0.08g, 0.28mmol) and 5mL, is then added Sodium borohydride (0.05g, 1.40mmol) is in room temperature reaction 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and is filtered and is removed hydroboration Sodium, is separated after methylene chloride is evaporated under reduced pressure by silica gel column chromatography, and drying obtains compound II-2 (0.04g), yield is 52.7%；Colourless liquid；¹H NMR(600MHz,DMSO-d₆) δ: 7.71 (d, J=3.2Hz, 1H, thiazole-5-H), 7.64 (d, J=3.2Hz, 1H, thiazole-4-H), 7.58 (d, J=8.8Hz, 2H, Ph-2,6-H), 6.69 (d, J=4.9Hz, 1H, ), NH 6.63 (d, J=8.9Hz, 2H, Ph-3,5-H), 5.20-5.17 (m, 1H, OH), 3.65 (dd, J=1Hz, 4.5,2.5Hz, 1H,SO₂CH₂),3.56–3.52(m,1H,SO₂CH₂), 2.74 (d, J=4.9Hz, 3H, N-CH₃).ppm；¹³C NMR(150MHz, DMSO-d₆)δ:174.8,154.3,142.9,130.1,125.0,121.0,111.2,66.7,62.9,29.6ppm.

The preparation of embodiment 34, compound II-3

25mL round-bottomed flask is added in the methylene chloride of compound I-18 (0.11g, 0.28mmol) and 5mL, is then added Sodium borohydride (0.05g, 1.40mmol) is in room temperature reaction 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and is filtered and is removed hydroboration Sodium, is separated after methylene chloride is evaporated under reduced pressure by silica gel column chromatography, and drying obtains compound II-3 (0.07g), yield is 63.2%；White solid；Fusing point is 116-118 DEG C；¹H NMR(600MHz,DMSO-d₆) δ: 7.71 (d, J=3.2Hz, 1H, ), thiazole-5-H 7.64 (d, J=3.2Hz, 1H, thiazole-4-H), 7.57 (d, J=8.9Hz, 2H, Ph-2,6-H), 6.65 (d, J=8.9Hz, 2H, Ph-3,5-H), 6.61 (d, J=6.6Hz, 1H, NH), 5.20 (ddd, J=9.1,6.6, 2.7Hz,1H,OH),4.10–4.07(m,2H,N-CH₂CH₃), 3.65 (dd, J=14.6,2.7Hz, 1H, SO₂CH₂),3.54 (dd, J=14.6,9.0Hz, 1H, SO₂CH₂), 3.12 (d, J=1.8Hz, 1H, CHOH), 1.17 (t, J=7.2Hz, 3H, N- CH₂CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:174.8,153.4,142.9,130.2,124.8,121.0,111.3, 66.7,62.9,37.3,14.5ppm.

The preparation of embodiment 35, compound II-4

25mL round-bottomed flask is added in the methylene chloride of compound I-19 (0.09g, 0.28mmol) and 5mL, is then added Sodium borohydride (0.05g, 1.40mmol) is in room temperature reaction 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and is filtered and is removed hydroboration Sodium, is separated after methylene chloride is evaporated under reduced pressure by silica gel column chromatography, and drying obtains compound II-4 (0.05g), yield is 57.5%；White solid；Fusing point is 112-114 DEG C；¹H NMR(600MHz,DMSO-d₆) δ: 7.71 (d, J=3.2Hz, 1H, ), thiazole-5-H 7.64 (d, J=3.2Hz, 1H, thiazole-4-H), 7.56 (d, J=8.9Hz, 2H, Ph-2,6-H), 6.65 (d, J=8.9Hz, 2H, Ph-3,5-H), 6.61 (d, J=6.5Hz, 1H, NH), 5.19 (ddd, J=9.1,6.6, 2.7Hz, 1H, OH), 3.65 (dd, J=14.5,2.6Hz, 1H, SO₂CH₂), 3.54 (dd, J=14.5,9.0Hz, 1H, SO₂CH₂), 4.09 (q, J=5.2Hz, 1H, CHOH), 3.04 (dd, J=11.2,4.3Hz, 2H, N-CH₂CH₂CH₃),1.57(dd, J=14.4,7.2Hz, 2H, N-CH₂CH₂CH₃), 0.94 (t, J=7.4Hz, 3H, N-CH₂CH₂CH₃)ppm；¹³C NMR(150MHz, DMSO-d₆)δ:174.9,153.5,142.9,130.2,124.6,121.0,111.3,66.7,62.8,44.5,22.1, 12.0ppm.

The preparation of embodiment 36, compound II-5

25mL round-bottomed flask is added in the methylene chloride of compound I-20 (0.09g, 0.28mmol) and 5mL, is then added Sodium borohydride (0.05g, 1.40mmol) is in room temperature reaction 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and is filtered and is removed hydroboration Sodium, is separated after methylene chloride is evaporated under reduced pressure by silica gel column chromatography, and drying obtains compound II-5 (0.05g), yield is 56.4%；White solid；Fusing point is 100-102 DEG C；¹H NMR(600MHz,DMSO-d₆) δ: 7.71 (d, J=3.2Hz, 1H, ), thiazole-5-H 7.64 (d, J=3.2Hz, 1H, thiazole-4-H), 7.55 (d, J=8.9Hz, 2H, Ph-2,6-H), 6.65 (d, J=8.9Hz, 3H, Ph-3,5-H, NH), 5.19 (ddd, J=9.1,6.6,2.7Hz, 1H, OH), 3.65 (dd, J= 14.6,2.6Hz,1H,SO₂CH₂), 3.54 (dd, J=14.5,9.0Hz, 1H, SO₂CH₂),3.09–3.06(m,2H,N-CH₂ (CH₂)₂CH₃), 1.53 (dd, J=14.6,7.3Hz, 2H, N-CH₂CH₂CH₂CH₃), 1.38 (dd, J=15.0,7.4Hz, 2H, N- (CH₂)₂CH₂CH₃), 0.91 (t, J=7.4Hz, 3H, N- (CH₂)₂CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:174.8, 153.5,142.9,130.1,124.7,121.0,111.3,66.7,62.9,42.4,31.0,20.2,14.2ppm.

The preparation of embodiment 37, compound II-6

25mL round-bottomed flask is added in the methylene chloride of compound I-21 (0.10g, 0.28mmol) and 5mL, is then added Sodium borohydride (0.05g, 1.40mmol) is in room temperature reaction 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and is filtered and is removed hydroboration Sodium, is separated after methylene chloride is evaporated under reduced pressure by silica gel column chromatography, and drying obtains compound II-6 (0.04g), yield is 44.5%；Colourless liquid；¹H NMR(600MHz,DMSO-d₆) δ: 7.72 (d, J=2.4Hz, 1H, thiazole-5-H), 7.65 (s, 1H, thiazole-4-H), 7.57 (d, J=8.7Hz, 2H, Ph-2,6-H), 6.66 (d, J=8.4Hz, 3H, Ph-3,5-H, ), NH 5.21 (dd, J=7.4,5.1Hz, 1H, OH), 3.69-3.63 (m, 1H, SO₂CH₂), 3.55 (dd, J=14.5,9.0Hz, 1H,SO₂CH₂), 3.37 (s, 1H, CHOH), 3.08 (dd, J=12.1,6.1Hz, 2H, N-CH₂(CH₂)₃CH₃),1.59–1.53 (m,2H,N-CH₂CH₂(CH₂)₂CH₃),1.34(d,4H,N-(CH₂)₂(CH₂)₂CH₃), 0.90 (d, J=6.6Hz, 3H, N- (CH₂)₄CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:174.8,153.5,142.9,130.2,124.7,121.0,111.3, 66.7,62.9,42.7,29.2,28.6,22.4,14.4ppm.

The preparation of embodiment 38, compound II-7

25mL round-bottomed flask is added in the methylene chloride of compound I-22 (0.10g, 0.28mmol) and 5mL, is then added Sodium borohydride (0.05g, 1.40mmol) is in room temperature reaction 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and is filtered and is removed hydroboration Sodium, is separated after methylene chloride is evaporated under reduced pressure by silica gel column chromatography, and drying obtains compound II-7 (0.06g), yield is 58.5%；White solid；Fusing point is 108-110 DEG C；¹H NMR(600MHz,DMSO-d₆) δ: 7.71 (d, J=3.2Hz, 1H, ), thiazole-5-H 7.64 (d, J=3.2Hz, 1H, thiazole-4-H), 7.56 (d, J=8.9Hz, 2H, Ph-2,6-H), 6.65 (d, J=8.8Hz, 3H, Ph-3,5-H, NH), 5.19 (ddd, J=9.0,6.5,2.6Hz, 1H, OH), 3.65 (dd, J= 14.6,2.6Hz,1H,SO₂CH₂), 3.54 (dd, J=14.5,9.0Hz, 1H, SO₂CH₂),3.08–3.05(m,2H,N-CH₂ (CH₂)₄CH₃),1.56–1.53(m,2H,N-CH₂CH₂(CH₂)₃CH₃),1.38–1.34(m,2H,N-(CH₂)₂CH₂(CH₂)₂CH₃), 1.29 (d, J=3.4Hz, 4H, N- (CH₂)₃(CH₂)₂CH₃), 0.87 (d, J=6.9Hz, 3H, N- (CH₂)₅CH₃)ppm；¹³C NMR (150MHz,DMSO-d₆)δ:174.8,153.5,142.9,130.1,124.7,120.9,111.3,66.7,62.9,42.8, 31.5,28.8,26.7,22.5,14.3ppm.

The preparation of embodiment 39, compound II-8

25mL round-bottomed flask is added in the methylene chloride of compound I-23 (0.11g, 0.28mmol) and 5mL, is then added Sodium borohydride (0.05g, 1.40mmol) is in room temperature reaction 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and is filtered and is removed hydroboration Sodium, is separated after methylene chloride is evaporated under reduced pressure by silica gel column chromatography, and drying obtains compound II-8 (0.06g), yield is 59.8%；White solid；Fusing point is 106-108 DEG C；¹H NMR(600MHz,DMSO-d₆) δ: 7.71 (d, J=3.2Hz, 1H, ), thiazole-5-H 7.64 (d, J=3.2Hz, 1H, thiazole-5-H), 7.55 (d, J=8.9Hz, 2H, Ph-2,6-H), 6.65 (d, J=8.9Hz, 3H, Ph-3,5-H, NH), 5.19 (dd, J=8.9,2.4Hz, 1H, OH), 4.52 (d, J=2.2Hz, 1H, CHOH), 3.65 (dd, J=14.6,2.7Hz, 1H, SO₂CH₂), 3.53 (dd, J=14.6,9.0Hz, 1H, SO₂CH₂), 3.07 (dd, J=12.5,6.9Hz, 2H, N-CH₂(CH₂)₅CH₃), 1.54 (dd, J=14.5,7.2Hz, 2H, N-CH₂CH₂(CH₂)₄CH₃),1.30–1.23(m,8H,N-(CH₂)₂(CH₂)₄CH₃), 0.86 (t, J=6.9Hz, 3H, N- (CH₂)₂(CH₂)₄CH₃)ppm ；¹³C NMR(150MHz,DMSO-d₆)δ:174.9,153.5,142.9,130.2,124.6,121.0,111.3,66.7,62.9, 42.7,31.7,28.9,27.0,22.5,14.4ppm.

The preparation of embodiment 40, compound II-9

25mL round-bottomed flask is added in the methylene chloride of compound I-24 (0.11g, 0.28mmol) and 5mL, is then added Sodium borohydride (0.05g, 1.40mmol) is in room temperature reaction 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and is filtered and is removed hydroboration Sodium, is separated after methylene chloride is evaporated under reduced pressure by silica gel column chromatography, and drying obtains compound II-9 (0.06g), yield is 57.7%；White solid；Fusing point is 136-138 DEG C；¹H NMR(600MHz,DMSO-d₆) δ: 7.71 (d, J=3.2Hz, 1H, ), thiazole-5-H 7.64 (d, J=3.2Hz, 1H, thiazole-4-H), 7.55 (d, J=8.9Hz, 2H, Ph-2,6-H), 6.66-6.62 (m, 3H, Ph-3,5-H, NH), 5.20 (d, J=8.4Hz, 1H, OH), 4.10 (d, J=3.7Hz, 1H, CHOH), 3.65 (dd, J=14.5,2.7Hz, 1H, SO₂CH₂), 3.54 (dd, J=14.5,9.0Hz, 1H, SO₂CH₂), 3.18 (d, J= 2.5Hz,2H,N-CH₂(CH₂)₆CH₃), 3.07 (dd, J=12.6,6.8Hz, 2H, N-CH₂CH₂(CH₂)₅CH₃), 1.54 (dd, J= 14.5,7.3Hz,2H,N-(CH₂)₂CH₂(CH₂)₄CH₃),1.37–1.33(m,2H N-(CH₂)₃CH₂(CH₂)₃CH₃),1.29– 1.25(m,6H,N-(CH₂)₄(CH₂)₃CH₃), 0.86 (t, J=6.9Hz, 3H, N- (CH₂)₇CH₃)ppm；¹³C NMR(150MHz, DMSO-d₆)δ:174.9,153.5,142.9,130.2,124.7,121.0,111.3,66.7,62.9,42.8,31.7,29.2, 28.9,27.1,22.5,14.4ppm.

The preparation of embodiment 41, compound II-10

25mL round-bottomed flask is added in the methylene chloride of compound I-25 (0.09g, 0.28mmol) and 5mL, is then added Sodium borohydride (0.05g, 1.40mmol) is in room temperature reaction 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and is filtered and is removed hydroboration Sodium, is separated after methylene chloride is evaporated under reduced pressure by silica gel column chromatography, and drying obtains compound II-10 (0.02g), yield is 20.6%；Yellow liquid；¹H NMR(600MHz,DMSO-d₆) δ: 7.71 (d, J=3.2Hz, 1H, thiazole-5-H), 7.64 (d, J=3.2Hz, 1H, thiazole-4-H), 7.57 (d, J=8.9Hz, 2H, Ph-2,6-H), 6.91 (t, J=5.7Hz, 1H, ), NH 6.67 (d, J=8.9Hz, 2H, Ph-3,5-H), 5.88 (ddt, J=17.1,10.2,5.0Hz, 1H, CH₂CHCH₂), 5.25–5.18(m,2H,CH₂CHCH₂), 5.14 (dd, J=10.3,1.6Hz, 1H, OH), 3.79-3.76 (m, 2H, NHCH₂), 3.67–3.64(m,1H,SO₂CH₂), 3.56 (dd, J=14.5,9.0Hz, 1H, SO₂CH₂)ppm；¹³C NMR(150MHz,DMSO- d₆)δ:182.6,165.9,153.6,145.8,135.3,133.2,131.2,130.3,116.3,111.6,62.9, 44.9ppm.

The preparation of embodiment 42, compound II-11

25mL round-bottomed flask is added in the methylene chloride of compound I-26 (0.09g, 0.28mmol) and 5mL, is then added Sodium borohydride (0.05g, 1.40mmol) is in room temperature reaction 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and is filtered and is removed hydroboration Sodium, is separated after methylene chloride is evaporated under reduced pressure by silica gel column chromatography, and drying obtains compound II-11 (0.05g), yield is 53.4%；Yellow liquid；¹H NMR(600MHz,DMSO-d₆) δ: 7.72 (d, J=3.2Hz, 1H, thiazole 5-H), 7.65 (d, J=3.2Hz, 1H, thiazole 4-H), 7.63 (d, J=8.8Hz, 2H, Ph-2,6-H), 7.08 (t, J=5.9Hz, 1H, ), NH 6.75 (d, J=8.9Hz, 2H, Ph-3,5-H), 5.21 (dd, J=9.0,2.7Hz, 1H, OH), 3.98 (dd, J=5.9, 2.3Hz,2H,SO₂CH₂), 3.67 (dd, J=14.6,2.7Hz, 1H, NHCH₂), 3.59 (dd, J=14.6,9.0Hz, 1H, NHCH₂), 3.16 (t, J=2.2Hz, 1H, C-CH) ppm；¹³C NMR(150MHz,DMSO-d₆)δ:174.8,152.4,142.9, 130.1,126.4,121.0,112.2,81.6,73.9,66.7,62.8,32.1ppm.

The preparation of embodiment 43, compound II-12

25mL round-bottomed flask is added in the methylene chloride of compound I-27 (0.10g, 0.28mmol) and 5mL, is then added Sodium borohydride (0.05g, 1.40mmol) is in room temperature reaction 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and is filtered and is removed hydroboration Sodium, is separated after methylene chloride is evaporated under reduced pressure by silica gel column chromatography, and drying obtains compound II-12 (0.07g), yield is 69.6%；Yellow liquid；¹H NMR(600MHz,DMSO-d₆) δ: 7.71 (d, J=3.1Hz, 1H, thiazole-5-H), 7.64 (d, J=3.1Hz, 1H, thiazole-4-H), 7.56 (d, J=8.8Hz, 2H, Ph-2,6-H), 7.38-7.33 (m, 5H, N- CH₂- Ph-2,3,4,5,6-H), 7.31 (t, J=5.7Hz, 1H, NH), 6.70 (d, J=8.7Hz, 2H, Ph-3,5-H), 5.20 (t, J=6.3Hz, 1H, OH), 4.37 (d, J=5.8Hz, 2H, NHCH₂), 3.65 (dd, J=14.5,2.1Hz, 1H, SO₂CH₂), 3.56 (dd, J=14.5,9.0Hz, 1H, SO₂CH₂)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:174.8,153.3,142.9, 140.0,130.1,128.9,127.7,127.4,125.5,121.0,66.7,62.8,46.3ppm.

The preparation of embodiment 44, compound II-13

25mL round-bottomed flask is added in the methylene chloride of compound I-28 (0.11g, 0.28mmol) and 5mL, is then added Sodium borohydride (0.05g, 1.40mmol) is in room temperature reaction 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and is filtered and is removed hydroboration Sodium, is separated after methylene chloride is evaporated under reduced pressure by silica gel column chromatography, and drying obtains compound II-13 (0.07g), yield is 61.5%；White solid；Fusing point is 154-156 DEG C；¹H NMR(600MHz,DMSO-d₆) δ: 7.70 (d, J=3.2Hz, 1H, ), thiazole5-H 7.63 (d, J=3.2Hz, 1H, thiazole 4-H), 7.55 (d, J=8.9Hz, 2H, Ph-2,6-H), 7.39 (dd, J=8.5,5.6Hz, 2H, N-CH₂- Ph-2,6-H), 7.29 (t, J=5.9Hz, 1H, NH), 7.17 (dd, J= 12.3,5.4Hz,2H,N-CH₂- Ph-3,5-H), 6.69 (d, J=8.9Hz, 2H, Ph-3,5-H), 5.19 (d, J=8.1Hz, 1H, OH), 4.35 (d, J=5.9Hz, 2H, NHCH₂), 3.64 (dd, J=14.5,2.7Hz, 1H, SO₂CH₂), 3.56 (dd, J= 14.6,8.9Hz,1H,SO₂CH₂)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:174.8,160.9,153.1,142.9, 135.7,130.1,129.6,125.6,121.0,115.7,115.6,111.8,66.6,62.8,45.6ppm.

The preparation of embodiment 45, compound II-14

25mL round-bottomed flask is added in the methylene chloride of compound I-29 (0.11g, 0.28mmol) and 5mL, is then added Sodium borohydride (0.05g, 1.40mmol) is in room temperature reaction 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and is filtered and is removed hydroboration Sodium, is separated after methylene chloride is evaporated under reduced pressure by silica gel column chromatography, and drying obtains compound II-14 (0.07g), yield is 63.2%；Colourless liquid；¹H NMR(600MHz,DMSO-d₆) δ: 7.70 (d, J=3.2Hz, 1H, thiazole-5-H), 7.63 (d, J=3.2Hz, 1H, thiazole-4-H), 7.55 (d, J=8.9Hz, 2H, N-CH₂- Ph-2,6-H), 7.38 (d, J= 10.0Hz,4H,N-CH₂- Ph-3,5-H, Ph-2,6-H), 7.30 (t, J=6.0Hz, 1H, NH), 6.68 (d, J=8.8Hz, 2H, ), Ph-3,5-H 5.19 (ddd, J=9.1,6.6,2.8Hz, 1H, OH), 4.36 (d, J=6.0Hz, 2H, NHCH₂),4.08(q,J =5.2Hz, 1H, CHOH), 3.65 (dd, J=14.5,2.7Hz, 1H, SO₂CH₂), 3.55 (dd, J=14.5,8.9Hz, 1H, SO₂CH₂)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:174.8,153.0,142.9,138.7,131.9,130.1,129.5, 128.9,125.7,121.0,111.8,66.6,62.8,45.6ppm.

The preparation of embodiment 46, compound II-15

25mL round-bottomed flask is added in the methylene chloride of compound I-30 (0.13g, 0.28mmol) and 5mL, is then added Sodium borohydride (0.05g, 1.40mmol) is in room temperature reaction 12h.Thin-layer chromatography, which tracks to reaction, to be terminated, and is filtered and is removed hydroboration Sodium, is separated after methylene chloride is evaporated under reduced pressure by silica gel column chromatography, and drying obtains compound II-15 (0.07g), yield is 58.5%；Yellow liquid；¹H NMR(600MHz,DMSO-d₆) δ: 7.76 (d, J=3.1Hz, 1H, thiazole 5-H), 7.68 (d, J=3.4Hz, 2H, thiazole 4-H, N-CH₂- Ph-3-H), 7.65 (d, J=8.9Hz, 2H, Ph-2,6-H), 7.46 (d, J=8.1Hz, 1H, N-CH₂- Ph-5-H), 7.42 (d, J=8.3Hz, 1H, N-CH₂- Ph-6-H), 7.37 (t, J=5.8Hz, 1H, NH), 6.73 (d, J=8.2Hz, 2H, Ph-3,5-H), 5.28 (s, 1H, OH), 4.71 (s, 1H, CHOH), 4.46 (d, J= 5.7Hz,2H,NHCH₂), 3.72 (dd, J=14.5,2.2Hz, 1H, SO₂CH₂), 3.63 (dd, J=14.6,9.0Hz, 1H, SO₂CH₂)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:174.8,152.8,142.9,135.6,133.8,131.3,130.6, 130.2,129.3,129.1,127.9,121.0,111.8,69.1,66.6,43.9ppm.

The in vitro anti-microbial activity of embodiment 47, sulphonyl thiazolium compounds

Using clinical trial standard (the Clinical and Laboratory for meeting United States National Committee's formulation Standards Institute, CLSI) 96 hole micro-dilution methods, sulphonyl thiazolium compounds made from testing example 2-46 To gram positive bacteria (methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus, staphylococcus aureus ATCC25923, staphylococcus aureus ATCC29213), gram-negative bacteria (K. pneumonia, Escherichia coli, verdigris Pseudomonad, pseudomonas aeruginosa ATCC27853, Escherichia coli ATCC25922, Acinetobacter bauamnnii) and fungi (Candida albicans Bacterium, Candida tropicalis, aspergillus fumigatus, Candida albicans ATCC90023, Candida parapsilosis bacterium ATCC20019) most Low inhibition concentration (MIC), a small amount of dimethyl sulfoxide of untested compound is dissolved, and adding water dilution and concentration is made is 1.28mg/mL Solution, then be diluted to 128 μ g/mL with culture solution, 35 DEG C are cultivated 24-72 hours, will sufficiently be shaken up on culture plate to oscillator Afterwards, MIC is measured at wavelength 490nm, the results are shown in Table 1-3.

The external anti-gram positive bacteria activity data (MIC, μ g/mL) of table 1, sulphonyl thiazolium compounds I-II

As it can be seen from table 1 compound I-II made from the embodiment of the present invention 2-46, shows one to the bacterium tested Fixed inhibiting effect, particularly, sulphonyl the thiazolium compounds I-21 and I-22 that bromo pentane silane and bromohexane replace show MRSA Higher antibacterial activity, MIC value are 1 μ g/mL.Part of compounds antibacterial activity can be with reference drug sulphathiazole, promise fluorine Husky astrology matches in excellence or beauty or even stronger.In addition, the reference drug Norfloxacin that compares it can be seen from drug resistance test result attached drawing 1 And sulphathiazole, compound I-21 and I-22 are basically unchanged the inhibitory activity of drug-fast bacteria MRSA.

The external anti-gram-negative bacteria activity data (MIC, μ g/mL) of table 2, sulphonyl thiazolium compounds I-II

From table 2 it can be seen that compound I-II made from the embodiment of the present invention 2-46, shows one to the bacterium tested Fixed inhibiting effect, particularly, sulphonyl the thiazolium compounds I-6 and I-7 that bromo pentane silane and bromohexane replace are to Acinetobacter bauamnnii Higher antibacterial activity is shown, MIC value is 8 μ g/mL.Part of compounds antibacterial activity can be with reference drug sulfanilamide (SN) thiophene Azoles, Norfloxacin compare favourably or even stronger.

The extracorporeal antifungal activity data (MIC, μ g/mL) of table 3, sulphonyl thiazolium compounds I-II

From table 3 it can be seen that compound I-II made from the embodiment of the present invention 2-46, shows one to the fungi tested Fixed inhibiting effect, particularly, propargyl bromide and to benzyl chloride chlorine replace sulphonyl thiazolium compounds II-11 and II-14 to white read Pearl bacterium ATCC90023 shows higher antibacterial activity, and MIC value is 1 μ g/mL.The antifungal activity of part of compounds can be with Reference drug sulphathiazole, Fluconazole compare favourably or even stronger.

The pharmaceutical applications of embodiment 48, sulphonyl thiazolium compounds

According to above-mentioned antimicrobial acivity testing result, sulphonyl thiazolium compounds of the invention have preferable antibacterium, Antibacterium, antifungal drug can be made for clinical use in antifungal activity.These drugs either single preparations of ephedrine, such as It is made of the sulphonyl thiazolium compounds and pharmaceutically acceptable auxiliary material of a kind of structure；It is also possible to compound preparation, such as by one The sulphonyl thiazolium compounds of kind structure and existing antibacterium, Active antifungal compound (such as sulfamethoxazole, Fluconazole, phosphorus fluorine health Azoles, Itraconazole etc.) and pharmaceutically acceptable auxiliary material be made, or by different structure several sulphonyl thiazolium compounds with Pharmaceutically acceptable auxiliary material is made.The preparation type includes but is not limited to tablet, capsule, powder, granule, dripping pill Agent, injection, powder-injection, solution, suspension, emulsion, suppository, ointment, gelling agent, film, aerosol, Transdermal absorption patch The dosage forms such as agent and various slow-release controlled-release preparations and nanometer formulation.

1, the preparation of compound I-21 tablet

Prescription: compound I-21 10g, lactose 187g, cornstarch 50g, magnesium stearate 3.0g, concentration expressed in percentage by volume are 70% ethanol solution is appropriate, and 1000 are made altogether.

Preparation method: by cornstarch with 105 DEG C dry 5 hours it is spare；Compound I-21 is mixed with lactose, cornstarch Even, with 70% ethanol solution softwood, be sieved wet granular processed, adds magnesium stearate, tabletting to get；Every slice weight 250mg, Active component content is 10mg.

2, the preparation of compound I-21 capsule

Prescription: compound I-21 25g, modified starch (120 mesh) 12.5g, microcrystalline cellulose (100 mesh) 7.5g, low substitution Hydroxypropylcellulose (100 mesh) 2.5g, talcum powder (100 mesh) 2g, sweetener 1.25g, orange essence 0.25g, appropriate pigment, water are suitable Amount, is made 1000.

Preparation method: after the compound I-21 of recipe quantity is ground into superfine powder, with the modified starch of recipe quantity, micro- Crystalline cellulose, low-substituted hydroxypropyl cellulose, talcum powder, sweetener, orange essence and pigment mix, with water softwood, 12-14 mesh Sieve granulation, 40-50 DEG C of dryings, be sieved whole grain, be packed into capsulae vacuus to get；Every slice weight 50mg, active component content 25mg.

3, the preparation of compound I-22 granule

Prescription: compound I-22 26g, dextrin 120g, sucrose 280g.

Preparation method: compound I-22, dextrin, sucrose being uniformly mixed, wet granulation, 60 DEG C of dryings, packing to get.

4, the preparation of compound I-10 injection

Prescription: 1000mL is made in compound I-10 10g, propylene glycol 500mL, water for injection 500mL altogether.

Preparation method: propylene glycol and injection water, stirring and dissolving Weigh Compound I-10, is added, adds 1g active carbon, sufficiently stirs 15 minutes are stood after mixing, with 5 μm of stud filtering decarbonizations, then the miillpore filter refined filtration for being successively 0.45 μm and 0.22 μm with aperture, Last encapsulating in 10mL ampoule, 100 DEG C of circulation steam sterilizations 45 minutes to get.

5, the preparation of compound I-13 powder-injection

Preparation method: compound I-13 aseptic powdery aseptically dispense to get.

6, the preparation of compound I-13 eye drops

Prescription: compound I-13 3.78g, sodium chloride 0.9g, benzyl carbinol 3g, appropriate borate buffer solution, distilled water add to 1000mL。

Preparation method: Weigh Compound I-13, sodium chloride add in 500mL distilled water, use borate buffer solution after dissolution completely PH to 6.5 is adjusted, adds distilled water to 1000mL, stirs evenly, filtering with microporous membrane is filling, and sealing, 100 DEG C of circulation steams go out Bacterium 1 hour to get.

7, the preparation of compound I-14 liniment

Prescription: compound I-14 4g, SOFT SOAP 7.5g, camphor 5g, distilled water add to 100mL.

Preparation method: the ethanol solution that camphor concentration expressed in percentage by volume is 95% is dissolved, spare；SOFT SOAP is heats liquefied, Spare, potash fertilizer soap lye and camphor ethanol solution are added under constant stirring, then is gradually added into distilled water by Weigh Compound I-14, Emulsification completely after add distilled water to full dose to get.

8, the preparation of compound I-4 suppository

Prescription: compound I-4 4g, gelatin 14g, glycerol 70g, distilled water add to 100mL, and 100 pieces of metric system.

Preparation method: weighing gelatin and glycerol, adds distilled water to 100mL, and chemical combination is added when melting in the pasty state in 60 DEG C of heating of water-bath Object I-4, stirs evenly, and when nearly solidification pours into vaginal plug mold, cooled and solidified to get.

9, the preparation of compound I-11 ointment

Prescription: 0.5-2g of compound I-11,6-8g of hexadecanol, 8-10g of albolene, 8-19g of atoleine, monoglyceride 2-5g, 2-5g of polyoxyethylene (40) stearate, glycerol 5-10g, ethylparaben 0.1g, distilled water add to 100g.

Preparation method: hexadecanol, albolene, atoleine, monoglyceride and polyoxyethylene (40) stearate are heated complete It is mixed after dissolving, keeps the temperature 80 DEG C, it is mutually spare as oil；It is molten by ethylparaben addition glycerol and distilled water, being heated to 85 DEG C Solution, then oily phase is added under constant stirring, is added compound I-11 after emulsification, stirring it is cooling to get.

10, the preparation of compound I-12 and Fluconazole compound powder-injection

Prescription: compound I-12 50g, Fluconazole 50g, sodium benzoate 1g are made 100 bottles altogether.

Preparation method: taking compound I-12, Fluconazole and the sodium benzoate of recipe quantity, be uniformly mixed under aseptic conditions, packing 100 bottles to get.

11, the preparation of compound I-3 aerosol

Prescription: compound I-3 2.5g, Span20 3g, talcum powder (100 mesh) 4g, F-11 add in right amount.

Preparation method: compound I-3, Span20 and talcum powder are set into dry a few hours in vacuum oven respectively, set drier It is inside cooled to room temperature, is ground into micro mist with airslide disintegrating mill, then mix by recipe quantity, pours into closed container, trichlorine one is added Fluoromethane to specified amount to get.

Finally, it is stated that preferred embodiment above is only used to illustrate the technical scheme of the present invention and not to limit it, although logical It crosses above preferred embodiment the present invention is described in detail, however, those skilled in the art should understand that, can be Various changes are made to it in form and in details, without departing from claims of the present invention limited range.

Claims

1. sulphonyl thiazolium compounds and its officinal salt, which is characterized in that structure is as shown in general formula I-II:

In formula,

2. sulphonyl thiazolium compounds according to claim 1 and its officinal salt, which is characterized in that

R¹For hydrogen or acetyl group；

R²For hydrogen, alkyl, allyl, propargyl, benzyl or halogen benzyl.

3. sulphonyl thiazolium compounds according to claim 1 and its officinal salt, which is characterized in that in following compounds It is any:

4. sulphonyl thiazolium compounds according to claim 1 and its officinal salt, which is characterized in that the officinal salt is Hydrochloride, nitrate or acetate.

5. the preparation method of the described in any item sulphonyl thiazolium compounds of claim 1-4 and its officinal salt, which is characterized in that Described method includes following steps:

A, the preparation of intermediate III:

Using acetyl thiazole as starting material, in acetum, substitution reaction occurs to get intermediate with bromine under the conditions of 50 DEG C III；

1) sulfonating reaction occurs and obtains N-acetylsulfanilyl chloride by starting material and chlorosulfonic acid of antifebrin, then through at salt Reaction obtains cosaprin, and finally and intermediate III is with acetonitrile as solvents, is reacted at 80 DEG C up to structural formula I- Sulphonyl thiazolium compounds shown in 1；

2) sulphonyl thiazolium compounds shown in structural formula I-1 and brominated alkanes, propargyl bromide, bromopropene or benzyl chloride are with N, N- dimethyl Formamide makees solvent, and potassium hydroxide does alkali, is reacted under room temperature up to sulphonyl thiazole chemical combination shown in structural formula I-2 to I-15 Object；

3) hydrolysis under the conditions of hydrochloric acid catalysis and alcohol reflux of sulphonyl thiazolium compounds shown in structural formula I-1 to I-15, i.e., Obtain sulphonyl thiazolium compounds shown in structural formula I-16 to I-30；

Sulphonyl thiazolium compounds shown in structural formula I-16 to I-30 is in sodium borohydride catalyzing and under conditions of methylene chloride makees solvent It reacts at room temperature up to sulphonyl thiazolium compounds shown in formula II -1 to II-15；

Sulphonyl thiazolium compounds shown in general formula II is dissolved in organic solvent, addition pharmaceutically acceptable acid, which is reacted to no precipitating, to be generated as Only to get the officinal salt of sulphonyl thiazolium compounds shown in general formula II.

6. according to the method described in claim 5, it is characterized in that,

In step b, in step 1), the temperature of the sulfonating reaction is 0-60 DEG C；Salt-forming reagent is sulfurous in the salt-forming reaction Sour sodium or sodium bicarbonate, solvent are water；In step 2), sulphonyl thiazolium compounds shown in the structural formula I-1 and potassium hydroxide The ratio between amount of substance is 1:3；In step 3), the temperature of the hydrolysis is 78 DEG C；

In step c, the ratio between sulphonyl thiazolium compounds and the amount of substance of sodium borohydride shown in the structural formula I-16 to I-30 are 1:5；

In step d, the organic solvent is at least one of chloroform, acetone, acetonitrile, ether or tetrahydrofuran；It is described can medicine It is hydrochloric acid or sulfuric acid with acid.

7. the described in any item sulphonyl thiazolium compounds of claim 1-4 and its officinal salt in preparation antibacterium and/or resist true Application in bacterium drug.

8. application according to claim 7, which is characterized in that the bacterium is staphylococcus aureus, methicillin-resistant Staphylococcus aureus, K. pneumonia, Escherichia coli, enterococcus faecalis, Acinetobacter bauamnnii or pseudomonas aeruginosa At least one of；The fungi is in Candida tropicalis, aspergillus fumigatus, Candida albicans or Candida parapsilosis bacterium At least one.

9. the preparation containing the described in any item sulphonyl thiazolium compounds of claim 1-4 and its officinal salt, which is characterized in that The preparation is in tablet, capsule, granule, injection, powder-injection, eye drops, liniment, suppository, ointment or aerosol One kind.