Benzothiazole compound or its salt, preparation method and application thereof

Abstract

The present invention discloses a class of benzothiazole compounds or salts thereof, preparation methods and applications thereof. The benzothiazole compounds have a structure as shown in formula (I), wherein R1, R2 are at least independently selected from hydrogen, halogen, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, aryl, heteroaryl or heterocyclic group, and n is 1 to 7. The benzothiazole compounds or pharmaceutically acceptable salts thereof can be used to prepare drugs for treating proliferative diseases, etc. In particular, the benzothiazole compounds can target HDAC6 to treat autosomal dominant polycystic kidney disease (ADPKD), have a good inhibitory effect on MDCK cells, and when the dosage is 1 mg / kg, the inhibitory activity on ADPKD mice is comparable to Tolvaptan, providing a new path for the treatment and prevention of autosomal dominant polycystic kidney disease.

Description

Technical Field

[0001] The present invention specifically relates to a class of benzothiazole compounds or salts thereof, a preparation method and pharmaceutical use thereof, and belongs to the technical field of pharmaceutical compounds. Background Art

[0002] Histone deacetylases (HDACs) catalyze the removal of acetyl groups from lysine residues at the amino termini of histones, leading to chromatin condensation and transcriptional repression. Eighteen HDACs have been identified in humans and are divided into four classes based on their homology to yeast HDACs, subcellular localization, and enzymatic activity. Class I HDACs (1, 2, 3, and 8) are homologous to the yeast RPD3 protein, are normally detected in the nucleus, and are ubiquitously expressed in various human cell lines and tissues. Class II HDACs (4, 5, 6, 7, 9, and 10) have homology to the yeast Hda1 protein and can shuttle between the nucleus and cytoplasm. Class IIb HDACs, HDAC6 and 10, are present in the cytoplasm and contain two deacetylase domains. HDAC6 has a unique substrate specificity, with an α-tubulin deacetylase (TDAC) domain that is specific for the cytoskeletal protein α-tubulin. Class III HDACs (SIRT1, 2, 3, 4, 5, 6, and 7) are homologs of the yeast protein Sir2 and require NAD + SIRT1 is a class of HDACs that regulates gene expression in response to changes in the cellular redox state. SIRT1 has been shown to interact with and deacetylate p53, thereby inhibiting p53-mediated transcriptional activity. HDAC11 is the only member of class IV HDACs. It has sequence similarity to the catalytic core regions of class I and class II enzymes, but not strong enough identity to be classified into any class.

[0003] Studies have shown that HDACs antagonists have a positive effect in the treatment of multiple myeloma, acute myeloid leukemia, diffuse large B-cell lymphoma, Alzheimer's disease, breast tumors, non-Hodgkin's lymphoma, colorectal tumors, cutaneous T-cell lymphoma, glioblastoma, HIV infection, inflammatory diseases, pancreatic tumors, peripheral T-cell lymphoma and autosomal dominant polycystic kidney disease. Vorinostat, romidepsin, belinostat, panobinostat, etc. are approved by the US FDA for the clinical treatment of peripheral T-cell lymphoma, cutaneous T-cell lymphoma and multiple myeloma; tucidinostat / chidamide is approved by my country's NMPA for the treatment of peripheral T-cell lymphoma and breast cancer. The development of these HDACs inhibitors has become a hot topic in the research and development of drugs for the treatment of the above diseases. These compounds have the activity of antagonizing histone deacetylase receptors and can therefore be used to treat the above diseases.

[0004] Most of the HDACs inhibitors currently on the market are non-selective inhibitors, which have defects such as large side effects and many adverse reactions. Studies have shown that mice with HDAC6 knockout can survive and HDAC6 selective inhibitors can be used to treat ADPKD. Currently, the only effective ADPKD treatment drug certified by the FDA (U.S. Food and Drug Administration) is tolvaptan, but in clinical trials, while tolvaptan slowed down the decline in patients' renal function, the serum liver transaminase of some patients rose to more than three times the normal level, indicating that the use of tolvaptan can cause liver damage. Therefore, it is necessary to develop new HDAC6 selective inhibitors and develop drugs with better therapeutic effects and less toxic side effects to alleviate the occurrence of the disease. Summary of the invention

[0005] One of the purposes of the present invention is to provide a class of benzothiazole compounds or salts thereof, which can be used as effective HDAC6 kinase inhibitors to treat proliferation-related diseases mediated by HDAC6 kinase, have the characteristics of high response rate, low side effects, and few adverse reactions, meet the needs of clinical medication, and thus overcome the defects of the prior art.

[0006] The second object of the present invention is to provide the use of the benzothiazole compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing and / or treating a proliferative disease.

[0007] The third object of the present invention is to provide a method for preparing the benzothiazole compound or its salt.

[0008] In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical solutions:

[0009] The first aspect of the present invention provides a benzothiazole compound or a salt thereof, wherein the benzothiazole compound has a structure shown in formula (I):

[0010]

[0011] Wherein R1 and R2 are at least independently selected from any one of hydrogen, halogen, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, aryl, heteroaryl and heterocyclic group, and n is any integer from 1 to 7.

[0012] Wherein, if the benzothiazole group in the definition formula (I) is the A unit, the benzene ring group connected to the benzothiazole group is the B unit, and the group connected to the B unit through an ether bond is the C unit, then R2 in the B unit is connected to the 2, 3 or 6 position of the benzene ring, and the C unit is connected to the 4 or 5 position of the benzene ring in the B unit.

[0013] In one embodiment, R1 is selected from hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy, and R2 is selected from hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy.

[0014] Preferably, R1 is selected from hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy, and R2 is selected from hydrogen, halogen, methoxy, ethoxy or methyl.

[0015] More preferably, R1 is hydrogen, and R2 is selected from any one of hydrogen, halogen, methoxy, ethoxy or methyl.

[0016] Preferably, R1 is hydrogen, and R2 is selected from any one of hydrogen, halogen, methoxy, ethoxy or methyl.

[0017] Preferably, R1 is hydrogen, and R2 is selected from any one of hydrogen, halogen, methoxy, ethoxy or methyl.

[0018] Among them, the halogen is preferably fluorine or chlorine.

[0019] More preferably, R1 is halogen and R2 is selected from hydrogen or methoxy.

[0020] More preferably, R1 is fluorine or chlorine, and R2 is selected from hydrogen or methoxy.

[0021] More preferably, R1 is a C1-6 alkyl group, and R2 is selected from hydrogen or methoxy.

[0022] More preferably, R1 is methyl and R2 is selected from hydrogen or methoxy.

[0023] More preferably, R1 is a C1-6 alkoxy group, and R2 is selected from hydrogen or methoxy.

[0024] More preferably, R1 is methoxy and R2 is selected from hydrogen or methoxy.

[0025] In one embodiment, the benzothiazole compounds include 2-(4-(benzo[d]thiazol-2-yl)phenoxy)-N-hydroxyacetamide, 6-(4-(benzo[d]thiazol-2-yl)phenoxy)-N-hydroxyhexanamide, 7-(4-(benzo[d]thiazol-2-yl)phenoxy)-N-hydroxyheptanamide, 8-(4-(benzo[d]thiazol-2-yl)phenoxy)-N-hydroxyoctanamide, 7-(4-(benzo[d]thiazol-2-yl)-2-fluorophenoxy)-N-hydroxyheptanamide, 7-(4-(benzo[d]thiazol-2-yl)-2-methylphenoxy)- N-hydroxyheptylamide, 7-(4-(benzo[d]thiazol-2-yl)-2-chlorophenoxy)-N-hydroxyheptylamide, 7-(4-(benzo[d]thiazol-2-yl)-2-methoxyphenoxy)-N-hydroxyheptylamide, 7-(4-(benzo[d]thiazol-2-yl)-2-ethoxyphenoxy)-N-hydroxyheptylamide, 7-(4-(benzo[d]thiazol-2-yl)-3-chlorophenoxy)-N-hydroxyheptylamide, 7-(4-(benzo[d]thiazol-2-yl)-3-fluorophenoxy)-N-hydroxyheptylamide, 7-(4-(benzo[d]thiazol-2-yl)-2,6-(3-(Benzo[d]thiazol-2-yl)phenoxy)-N-hydroxyheptylamide, 2-(3-(Benzo[d]thiazol-2-yl)phenoxy)-N-hydroxyacetamide, 4-(3-(Benzo[d]thiazol-2-yl)phenoxy)-N-hydroxybutyramide, 5-(3-(Benzo[d]thiazol-2-yl)phenoxy)-N-hydroxypentanamide, 6-(3-(Benzo[d]thiazol-2-yl)phenoxy)-N-hydroxyhexanamide, 7-(3-(Benzo[d]thiazol-2-yl)phenoxy)-N-hydroxyheptylamide, 8-(3-(Benzo[d]thiazol-2-yl)phenoxy)-N-hydroxybutyramide ]thiazol-2-yl)phenoxy)-N-hydroxyoctanamide, 7-(3-(benzo[d]thiazol-2-yl)-2-chlorophenoxy)-N-hydroxyheptylamide, 7-(5-(benzo[d]thiazol-2-yl)-2-methoxyphenoxy)-N-hydroxyheptylamide, N-hydroxy-7-(2-methoxy-5-(6-methoxybenzo[d]thiazol-2-yl)phenoxy)heptylamide, 7-(5-(6-chlorobenzo[d]thiazol-2-yl)-2-methoxyphenoxy)-N-hydroxyheptylamide, 7-(5-(6-fluoro benzo[d]thiazol-2-yl)-2-methoxyphenoxy)-N-hydroxyheptylamide, N-hydroxy-7-(2-methoxy-5-(6-methylbenzo[d]thiazol-2-yl)phenoxy)heptylamide, 7-(5-(5-chlorobenzo[d]thiazol-2-yl)-2-methoxyphenoxy)-N-hydroxyheptylamide, N-hydroxy-7-(4-(6-methoxybenzo[d]thiazol-2-yl)phenoxy)heptylamide, 7-(4-(6-fluorobenzo[d]thiazol-2-yl)phenoxy)-N-hydroxyheptylamide, 7- Any one of (4-(6-chlorobenzo[d]thiazol-2-yl)phenoxy)-N-hydroxyheptylamide, N-hydroxy-7-(4-(6-methylbenzo[d]thiazol-2-yl)phenoxy)heptylamide, 7-(4-(5-chlorobenzo[d]thiazol-2-yl)phenoxy)-N-hydroxyheptylamide, 8-(5-(benzo[d]thiazol-2-yl)-2-methoxyphenoxy)-N-hydroxyoctanamide and 7-(3-(benzo[d]thiazol-2-yl)-2-fluorophenoxy)-N-hydroxyheptylamide, but not limited to this. ,

[0026] In one embodiment, the salt of the benzothiazole compound includes any one of hydrochloride, p-toluenesulfonate, sulfate, succinate, maleate, fumarate, acetate, phosphate, citrate, methanesulfonate, and sodium salt.

[0027] The second aspect of the present invention provides a method for preparing a benzothiazole compound, which comprises:

[0028] S1. Using the compound represented by formula (II) as a starting material, reacting with the compound represented by formula (IV) in a first reaction system to form a first intermediate represented by formula (V), wherein the first reaction system comprises sodium dithionite, ethanol and water. Among them, the equivalent ratio of the compound represented by formula (II), the compound represented by formula (IV) and sodium dithionite can be 1 to 2: 1 to 2: 2 to 4, preferably about 1: 1: 2. The reaction temperature can be 50 to 100° C., preferably about 80° C. Ethanol and water are mainly used as solvents, and the volume ratio of ethanol to water can be about 5: 1 to 2, preferably about 8: 3.

[0029] S2. The first intermediate (1 eq) is reacted in a second reaction system to obtain a second intermediate represented by formula (VI), wherein the second reaction system comprises boron tribromide and dichloromethane. The equivalent ratio of the first intermediate to boron tribromide can be about 1:3 to 8, preferably about 1:6. Dichloromethane is mainly used as a solvent. The reaction can be first carried out at about 0°C for about 0.5h, and then at room temperature for about 6 to 12h.

[0030] S3, react the second intermediate and the bromoalkyl ester compound shown in formula (VII) in a third reaction system to obtain the third intermediate shown in formula (VIII), wherein the third reaction system includes potassium carbonate, potassium iodide and N, N-dimethylformamide or acetonitrile. Wherein, the equivalent ratio of the second intermediate, the bromoalkyl ester compound shown in formula (VII), potassium carbonate and potassium iodide can be 1-2: 1-2: 2-4: 0.1-0.5, preferably about 1: 1.5: 2: 0.1. N, N-dimethylformamide or acetonitrile is mainly used as a solvent. The temperature of the reaction can be 50-100°C, preferably about 80°C, and the time can be about 8-12h.

[0031] S4, reacting the third intermediate in a fourth reaction system to obtain a benzothiazole compound of formula (I), wherein the fourth reaction system comprises a methanol solution of hydroxylamine. The equivalent ratio of the third intermediate to hydroxylamine may be 1:3 to 3:1. The reaction temperature may be room temperature, and the reaction time may be about 1-2 hours.

[0032]

[0033]

[0034] Wherein R1 and R2 are at least independently selected from any one of hydrogen, halogen, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, aryl, heteroaryl and heterocyclic group, n is any integer from 1 to 7, the value of n1 is 1, 3, 4, 5, 6 or 7, and the value of n2 is 0 or 1.

[0035] The third aspect of the present invention provides a pharmaceutical composition comprising:

[0036] A therapeutically effective amount of the benzothiazole compound or a pharmaceutically acceptable salt thereof;

[0037] and, one or more pharmaceutically acceptable carriers.

[0038] The fourth aspect of the present invention provides use of the benzothiazole compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of an HDAC6 kinase inhibitor.

[0039] The fifth aspect of the present invention provides use of the benzothiazole compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of a medicament for preventing and / or treating a proliferative disease.

[0040] In one embodiment, the proliferative disease includes any one of acute myeloid leukemia, chronic myeloid leukemia, thyroid cancer, gastric cancer, gastrointestinal stromal tumors, colorectal cancer, prostate cancer, breast cancer, ovarian cancer, pancreatic cancer, lung cancer, non-small cell lung cancer, lymphoma, renal cancer, autosomal dominant polycystic kidney disease and myeloma, and is not limited thereto.

[0041] The sixth aspect of the present invention provides use of the benzothiazole compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of a targeted drug for preventing and / or treating autosomal dominant polycystic kidney disease.

[0042] The benzothiazole compounds or pharmaceutically acceptable salts thereof provided by the present invention, when used as HDAC6 kinase inhibitors, have a good inhibitory effect on MDCK cells and tissue embryonic kidney experiments, and when the dosage is 1 mg / kg, the inhibitory activity on ADPKD mice is comparable to that of Tolvaptan, thereby providing a new class of lead compounds for the treatment and prevention of autosomal dominant polycystic kidney disease. DETAILED DESCRIPTION

[0043] The present invention is further described in detail below in conjunction with embodiments.

[0044] Specific embodiments are further illustrated by the following synthesis schemes and examples, which should not be considered as limiting in any way. The experimental procedures used to generate the data will be discussed in detail below. For all preparations here, multiple doses can be proportioned according to techniques known in the art.

[0045] The preparation method of the benzothiazole compound 1-32 in the following embodiment of the present invention comprises:

[0046] First, 2-aminobenzenethiol with different substitutions as starting materials is reacted with methoxybenzaldehyde with different substitutions in a system of sodium dithionite, ethanol and water to obtain a first intermediate;

[0047] Then, the first intermediate is reacted in a system of boron tribromide and dichloromethane to obtain a second intermediate;

[0048] Then, the second intermediate and bromoalkyl ester compounds with different carbon chain lengths are reacted in a potassium carbonate, potassium iodide and N,N-dimethylformamide or acetonitrile system to obtain a third intermediate;

[0049] Finally, the third intermediate is reacted with a methanol solution of hydroxylamine to obtain the benzothiazole compound.

[0050] The specific reaction principle of the preparation method is as follows:

[0051]

[0052] Example 1

[0053] The preparation method of 2-(4-(benzo[d]thiazol-2-yl)phenoxy)N-hydroxyacetamide (Compound 1) comprises the following steps:

[0054] Step 1: The preparation method of 4-(benzo[d]thiazol-2-yl)phenol (second intermediate) comprises:

[0055]

[0056] 2-Aminobenzenethiol (2.0 g, 15.98 mmol) was dissolved in ethanol (16 ml), 4-hydroxybenzaldehyde (1.95 g, 15.98 mmol) was added and stirred, then sodium dithionite (5.56 g, 31.95 mmol) was added to water (6 ml), and then quickly added to the above mixture, and stirred at 80°C for 8 hours. The solvent was evaporated under reduced pressure, 1M hydrochloric acid was added to acidic state and stirred for 30 minutes, and filtered, the filter cake was first washed three times with water, and finally washed once with PE to obtain the second intermediate as a yellow solid (3.56 g, yield: 98%). 1 H NMR (400MHz, DMSO-d6) δ10.19 (s, 1H), 8.06-7.92 (m, 2H), 7.92-7.85 (m, 2H), 7.50-7.32 (m, 2H), 6.93-6.84 (m, 2H).MS (ESI) calculated for C 13 H 10 NOS + [M+H] + 228.0;Found:227.9.

[0057] Step 2: The preparation method of ethyl 2-(4-(benzo[d]thiazol-2-yl)phenoxy)acetate (third intermediate) comprises:

[0058]

[0059] The second intermediate (0.5 g, 2.2 mmol) was dissolved in acetonitrile (20 ml), potassium carbonate (0.61 g, 4.4 mmol) and a catalytic amount of potassium iodide were added and stirred, and finally ethyl 2-bromoacetate (0.55 g, 3.3 mmol) was added and stirred at 80°C for 8 hours. The solvent was evaporated under reduced pressure, diluted with water (100 ml), extracted three times with ethyl acetate (50 ml), the organic phases were combined, and the solvent was evaporated under reduced pressure. The solid residue was purified by silica gel column chromatography (eluent: PE / EA = 10:1) to obtain a light yellow third intermediate (0.6 g, yield: 87%). 1 H NMR (400MHz, CDCl3) δ8.07-7.99 (m, 3H), 7.87 (d, J=7.9, 1.0Hz, 1H), 7.46 (t, J=8.3, 7.2, 1.3Hz, 1H), 7.35 (t, J=8.1 , 7.2, 1.2Hz, 1H), 7.03-6.97 (m, 2H), 4.69 (s, 2H), 4.28 (q, J=7.1Hz, 2H), 1.30 (t, J=7.1Hz, 3H).MS (ESI) calculated for C 17 H 16 NO3S + [M+H] + 314.1;Found:314.0.

[0060] Step 3: The preparation method of 2-(4-(benzo[d]thiazol-2-yl)phenoxy)-N-hydroxyacetamide (Compound 1) comprises:

[0061]

[0062] The third intermediate (0.15 g, 0.48 mmol) was dissolved in dichloromethane (2 ml), and a methanol solution of hydroxylamine (6 ml, 6.6 g potassium hydroxide was dissolved in 20 ml methanol, and 4.67 g hydroxylamine hydrochloride was slowly added to 20 ml methanol solution under ice bath) was added, and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, 20 ml methanol was added, 1 M hydrochloric acid was added to adjust the pH to 7-8, stirred for 10 minutes, filtered, and the filter cake was washed three times with water and finally washed once with PE to obtain compound 1 (134 mg, yield: 93.1%) as a white solid. 1HNMR (400MHz, DMSO-d6) δ10.93 (s, 1H), 9.02 (s, 1H), 8.07 (d, J=8.1Hz, 1H), 8.03-7.96 (m, 3H), 7 .48 (t, J=7.7Hz, 1H), 7.39 (t, J=7.6Hz, 1H), 7.13-7.07 (m, 2H), 4.56 (s, 2H).MS (ESI) calculated for C 15 H 13 N2O3S + [M+H] + 301.1;Found:300.9.

[0063] Example 2

[0064] The preparation method of 6-(4-(benzo[d]thiazol-2-yl)phenoxy)-N-hydroxyhexanamide (Compound 2) comprises:

[0065]

[0066] The ethyl 2-bromoacetate in step 2 of Example 1 was replaced with methyl 6-bromohexanoate, and the remaining raw materials, reagents and preparation methods were the same as those in Example 1, and finally compound 2 was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.39 (s, 1H), 8.67 (s, 1H), 8.06 (d, J=7.9, 1.2Hz, 1H), 8 .01-7.93(m, 3H), 7.47(t, J=8.3, 7.2, 1.3Hz, 1H), 7.38(t, J=8.2, 7.2, 1.2Hz, 1H ), 7.09-6.97 (m, 2H), 4.00 (t, J=6.5Hz, 2H), 1.95 (t, J=7.3Hz, 2H), 1.69 (p, J=6. 6Hz, 2H), 1.52 (p, J=7.3Hz, 2H), 1.36 (p, J=9.7, 5.9Hz, 2H).MS (ESI) calculated for C 19 H 21 N2O3S + [M+H] + 357.1;Found:357.0.

[0067] Example 3

[0068] The preparation method of 7-(4-(benzo[d]thiazol-2-yl)phenoxy)-N-hydroxyheptylamide (Compound 3) comprises:

[0069]

[0070] The ethyl 2-bromoacetate in step 2 of Example 1 was replaced by ethyl 7-bromoheptanoate, and the remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain compound 3 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.64 (s, 1H), 8.07 (d, 1H), 8.01-7.93 (m, 3H) , 7.48 (t, J=8.3, 7.2, 1.3Hz, 1H), 7.38 (t, J=8.2, 7.2, 1.2Hz, 1H), 7.12-6.98 (m, 2H ), 4.01 (t, J=6.5Hz, 2H), 1.92 (t, J=7.3Hz, 2H), 1.69 (p, J=6.7Hz, 2H), 1.48 (p, J=7 .4Hz, 2H), 1.38 (p, J=7.1Hz, 2H), 1.26 (p, J=7.6, 3.4Hz, 2H).HRMS(ESI)calculated for C20H 23 N2O3S + [M+H] + 371.1;Found:371.0.

[0071] Example 4

[0072] The preparation method of 8-(4-(benzo[d]thiazol-2-yl)phenoxy)-N-hydroxyoctanamide (Compound 4) comprises:

[0073]

[0074] The ethyl 2-bromoacetate in step 2 of Example 1 was replaced by ethyl 8-bromooctanoate, and the remaining raw materials, reagents and preparation methods were the same as those in step 5 of Example 1 to obtain compound 4 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.64 (s, 1H), 8.06 (d, J=6.9Hz, 1H), 8.00-7.93(m, 3H), 7.52-7.43(m, 1H), 7.42-7.33(m, 1H), 7.05(d, J=8.9Hz , 2H), 4.00 (t, J=6.5Hz, 2H), 1.91 (t, J=7.4Hz, 2H), 1.76-1.61 (m, 2H), 1.51-1.41 (m, 2H), 1.41-1.32 (m, 2H), 1.32-1.17 (m, 4H).MS (ESI) calculated forC 21 H 24 N2NaO3S + [M+Na] +Found:407.1;Found:406.7.

[0075] Example 5

[0076] The preparation method of 7-(4-(benzo[d]thiazol-2-yl)-2-fluorophenoxy)-N-hydroxyheptylamide (Compound 5) comprises:

[0077]

[0078] The 4-hydroxybenzaldehyde in step 1 of Example 1 was replaced by 3-fluoro-4-hydroxybenzaldehyde, and the ethyl 2-bromoacetate in step 2 was replaced by ethyl 7-bromoheptanoate. The remaining raw materials, reagents and preparation methods were the same as those in steps 1-3 of Example 1 to obtain compound 5 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.34 (s, 1H), 8.64 (s, 1H), 8.08 (d, J=8.0Hz, 1H), 7.98 (d, J=7. 1Hz, 1H), 7.89-7.82 (m, 1H), 7.79 (d, J=8.6Hz, 1H), 7.49 (t, J=8.3Hz, 1H), 7.40 (t, J=8. 2Hz, 1H), 7.27 (t, J=8.6Hz, 1H), 4.08 (t, J=6.5Hz, 2H), 1.92 (t, J=7.4Hz, 2H), 1.75-1.6 6(m, 2H), 1.53-1.42(m, 2H), 1.43-1.32(m, 2H), 1.32-1.22(m, 2H).MS(ESI)calculated for C 20 H 21 FN2KO3S + [M+K] + :427.1;found:426.6.

[0079] Example 6

[0080] The preparation method of 7-(4-(benzo[d]thiazol-2-yl)-2-methylphenoxy)-N-hydroxyheptylamide (Compound 6) comprises:

[0081]

[0082] The 4-hydroxybenzaldehyde in step 1 of Example 1 was replaced by 4-hydroxy-3-methylbenzaldehyde, and the ethyl 2-bromoacetate in step 2 was replaced by ethyl 7-bromoheptanoate. The remaining raw materials, reagents and preparation methods were the same as those in steps 1-3 of Example 1 to obtain compound 6 as a white solid. 1H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.64 (s, 1H), 8.05 (d, J=8.1Hz, 1H), 7.95 (d, J=7.0Hz, 1H), 7.86-7.80 (m, 2H), 7.51-7.43 (m, 1H), 7.41-7.33 (m, 1H), 7.02 (d, J=8 .4Hz, 1H), 4.00 (t, J=6.4Hz, 2H), 2.20 (s, 3H), 1.93 (t, J=7.4Hz, 2H), 1.75-1.66 (m , 2H), 1.53-1.44(m, 2H), 1.44-1.35(m, 2H), 1.33-1.22(m, 2H).MS(ESI)calculated for C 21 H 25 N2O3S + [M+H] + 385.2; Found: 384.7.

[0083] Example 7

[0084] The preparation method of 7-(4-(benzo[d]thiazol-2-yl)-2-chlorophenoxy)-N-hydroxyheptylamide (Compound 7) comprises:

[0085]

[0086] The 4-hydroxybenzaldehyde in step 1 of Example 1 was replaced by 3-chloro-4-hydroxybenzaldehyde, and the ethyl 2-bromoacetate in step 2 was replaced by ethyl 7-bromoheptanoate. The remaining raw materials, reagents and preparation methods were the same as those in steps 1-3 of Example 1 to obtain compound 7 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.36 (s, 1H), 8.64 (s, 1H), 8.08 (d, J = 6.8Hz, 1H), 8.06 (d, J = 2.3Hz, 1 H), 7.98 (d, J=7.1Hz, 1H), 7.93 (d, J=8.6, 2.2Hz, 1H), 7.49 (t, J=8.3, 7.2, 1.3Hz, 1H), 7.40 (t, J=8.3, 7.2, 1.2Hz, 1H), 7.25 (d, J=8.7Hz, 1H), 4.09 (t, J=6.4Hz, 2H), 1.93 (t, J=7.3Hz, 2H), 1. 76-1.66(m, 2H), 1.53-1.45(m, 2H), 1.44-1.35(m, 2H), 1.33-1.23(m, 2H).MS(ESI)calculated for C 20 H 21ClN2NaO3S + [M+Na] + 427.1; Found:426.6.

[0087] Example 8

[0088] The preparation method of 7-(4-(benzo[d]thiazol-2-yl)-2-methoxyphenoxy)-N-hydroxyheptylamide (Compound 8) comprises:

[0089]

[0090] The 4-hydroxybenzaldehyde in step 1 of Example 1 was replaced by 4-hydroxy-3-methoxybenzaldehyde, and the ethyl 2-bromoacetate in step 2 was replaced by ethyl 7-bromoheptanoate. The remaining raw materials, reagents and preparation methods were the same as those in steps 1-3 of Example 1 to obtain compound 8 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.32 (s, 1H), 8.64 (s, 1H), 8.05 (d, J=8.4Hz, 1H), 7.98 (d, J=7.6H z, 1H), 7.60 (d, J=2.1Hz, 1H), 7.55 (d, J=8.4Hz, 1H), 7.48 (t, J=7.0Hz, 1H), 7.42-7.35 (m, 1 H), 7.06 (d, J=8.4Hz, 1H), 3.99 (t, J=6.5Hz, 2H), 3.85 (s, 3H), 1.92 (t, J=7.3Hz, 2H), 1.74- 1.65(m,2H),1.53-1.43(m,2H),1.42-1.32(m,2H),1.32-1.23(m,2H).MS(ESI)calculated for C 21 H 24 N2NaO4S + [M+Na] + 423.1; Found:422.7.

[0091] Example 9

[0092] The preparation method of 7-(4-(benzo[d]thiazol-2-yl)-2-ethoxyphenoxy)-N-hydroxyheptylamide (Compound 9) comprises:

[0093]

[0094] The 4-hydroxybenzaldehyde in step 1 of Example 1 was replaced by 3-ethoxy-4-hydroxybenzaldehyde, and the ethyl 2-bromoacetate in step 2 was replaced by ethyl 7-bromoheptanoate. The remaining raw materials, reagents and preparation methods were the same as those in steps 1-3 of Example 1 to obtain compound 9 as a white solid.1 H NMR (400MHz, DMSO-d6) δ10.34 (s, 1H), 8.64 (s, 1H), 8.05 (d, J=7.9Hz, 1H), 7.97 (d, J=7. 6Hz, 1H), 7.59 (s, 1H), 7.54 (d, J=8.3Hz, 1H), 7.48 (t, J=7.7Hz, 1H), 7.38 (t, J=7.6Hz, 1H ), 7.07 (d, J=8.5Hz, 1H), 4.10 (q, J=6.9Hz, 2H), 3.99 (t, J=6.6Hz, 2H), 1.92 (t, J=7.4Hz , 2H), 1.75-1.65(m, 2H), 1.53-1.43(m, 2H), 1.42-1.24(m, 7H).MS(m / z)(ESI): calcdfor C 22 H 26 N2NaO4S + [M+Na] + :437.2;found:422.7.

[0095] Example 10

[0096] The preparation method of 7-(4-(benzo[d]thiazol-2-yl)-3-chlorophenoxy)-N-hydroxyheptylamide (Compound 10) comprises:

[0097]

[0098] The 4-hydroxybenzaldehyde in step 1 of Example 1 was replaced by 2-chloro-4-hydroxybenzaldehyde, and the ethyl 2-bromoacetate in step 2 was replaced by ethyl 7-bromoheptanoate. The remaining raw materials, reagents and preparation methods were the same as those in steps 1-3 of Example 1 to obtain compound 10 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.36 (s, lH), 8.64 (s, 1H), 8.21-8.08 (m, 2H), 8.0 3(d, J=7.7Hz, 1H), 7.56-7.48 (m, 1H), 7.44 (t, J=7.6Hz, 1H), 7.19 (d, J=2.5 Hz, 1H), 7.11-7.04 (m, 1H), 4.03 (t, J=6.5Hz, 2H), 1.93 (t, J=7.4Hz, 2H), 1.74-1.62 (m, 2H), 1.54-1.31 (m, 4H), 1.31-1.20 (m, 2H).MS (ESI) calculated for C 20 H 21 ClN2KO3S + [M+K] +:443.1; found:442.6.

[0099] Embodiment 11

[0100] The preparation method of 7-(4-(benzo[d]thiazol-2-yl)-3-fluorophenoxy)-N-hydroxyheptylamide (Compound 11) comprises:

[0101]

[0102] The 4-hydroxybenzaldehyde in step 1 of Example 1 was replaced by 2-fluoro-4-hydroxybenzaldehyde, and the ethyl 2-bromoacetate in step 2 was replaced by ethyl 7-bromoheptanoate. The remaining raw materials, reagents and preparation methods were the same as those in steps 1-3 of Example 1 to obtain compound 11 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.36 (s, 1H), 8.65 (s, 1H), 8.22 (t, J=8.9Hz, 1H), 8.13-7.97 (m, 2H), 7.54-7.35 (m, 2H), 7.08-6.90 (m, 2H), 4.02 (t, J=6.5Hz, 2H), 1.92 (t, J=7.4Hz, 2H), 1.74-1.63 (m, 2H), 1.54-1.43 (m, 2H), 1.42-1.31 (m, 2H), 1.31-1.21 (m, 2H).MS (ESI) calculated for C 20 H 21 FN2NaO3S + [M+Na] + :411.1; found:411.7.

[0103] Example 12

[0104] The preparation method of 7-(4-(benzo[d]thiazol-2-yl)-2,6-dimethoxyphenoxy)-N-hydroxyheptylamide (Compound 12) comprises:

[0105]

[0106] The 4-hydroxybenzaldehyde in step 1 of Example 1 was replaced by 4-hydroxy-3,5-dimethoxybenzaldehyde, and the ethyl 2-bromoacetate in step 2 was replaced by ethyl 7-bromoheptanoate. The remaining raw materials, reagents and preparation methods were the same as those in steps 1-3 of Example 1 to obtain compound 12 as a white solid. 1H NMR (400MHz, DMSO-d6) δ10.30 (s, 1H), 8.62 (s, 1H), 8.09 (d, J = 7.2Hz, 1H), 8.02 (d, J = 7.7Hz, 1H), 7.53-7.48 (m, 1H), 7.46-7.39 (m, 1H), 7.29 (s, 2H), 3.92-3.84(m, 8H), 1.92(t, J=7.4Hz, 2H), 1.65-1.56(m, 2H), 1.53-1.43(m, 2H), 1.43-1.33(m, 2H), 1.30-1.19(m, 2H).MS (ESI) calculated for C 22 H 26 N2NaO5S + [M+Na] + :453.1; found:452.7.

[0107] Example 13

[0108] The preparation method of 2-(3-(benzo[d]thiazol-2-yl)phenoxy)-N-hydroxyacetamide (Compound 13) comprises:

[0109]

[0110] The 4-hydroxybenzaldehyde in step 1 of Example 1 was replaced by 3-hydroxybenzaldehyde, and the remaining raw materials, reagents and preparation methods were the same as those in steps 1-3 of Example 1 to obtain compound 13 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.89 (s, 1H), 8.99 (s, 1H), 8.13 (d, J = 8.0Hz, 1H), 8.04 (d, J = 8.1Hz, 1H) ,7.69-7.62(m,2H),7.56-7.41(m,3H),7.15(d,J=8.3Hz,1H),4.58(s,2H).MS(ESI)calculated forC 15 H 13 N2O3S + [M+H] + :301.1; found:301.0.

[0111] Embodiment 14

[0112] The preparation method of 4-(3-(benzo[d]thiazol-2-yl)phenoxy)-N-hydroxybutyramide (Compound 14) comprises:

[0113]

[0114] The 4-hydroxybenzaldehyde in step 1 of Example 1 was replaced by 3-hydroxybenzaldehyde, and the ethyl 2-bromoacetate in step 2 was replaced by methyl 4-bromobutyrate. The remaining raw materials, reagents and preparation methods were the same as those in steps 1-3 of Example 1 to obtain compound 14 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.43 (s, 1H), 8.72 (s, 1H), 8.11 (d, J = 8.0Hz, 1H), 8.04 (d, J = 7.1Hz, 1H), 7.60 (d, J = 7.9Hz, 1H), 7.57 (s, 1H), 7.52 (t, J = 7.0Hz, 1H), 7.47-7.41 (m, 2H), 7.11 (d, J=10.7Hz, 1H), 4.04 (t, J=6.3Hz, 2H), 2.14 (t, J=7.4Hz, 2H), 1.95 (p, J=6.8Hz, 2H).MS (ESI) calculated for C 17 H 17 N2O3S + [M+H] + :329.1; found:329.0.

[0115] Embodiment 15

[0116] The preparation method of 5-(3-(benzo[d]thiazol-2-yl)phenoxy)-N-hydroxypentanamide (Compound 15) comprises:

[0117]

[0118] The 4-hydroxybenzaldehyde in step 1 of Example 1 was replaced by 3-hydroxybenzaldehyde, and the ethyl 2-bromoacetate in step 2 was replaced by methyl 5-bromovalerate. The remaining raw materials, reagents and preparation methods were the same as those in steps 1-3 of Example 1 to obtain compound 15 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.37 (s, 1H), 8.69 (s, 1H), 8.11 (d, J = 7.4Hz, 1H), 8.04 (d, J = 7.6Hz, 1H), 7.60 (d, J = 8.3Hz, 1H), 7.57 (s, 1H), 7.5 2(t, 1H), 7.47-7.41 (m, 2H), 7.11 (d, J=9.9Hz, 1H), 4.05 (t, J=6.0Hz, 2H), 2.01 (t, J=7.0Hz, 2H), 1.76-1.61 (m, 4H).MS (ESI) calculated for C 18 H 19 N2O3S + [M+H]+ :343.1; found:343.0.

[0119] Example 16

[0120] The preparation method of 6-(3-(benzo[d]thiazol-2-yl)phenoxy)-N-hydroxyhexanamide (Compound 16) comprises:

[0121]

[0122] The 4-hydroxybenzaldehyde in step 1 of Example 1 was replaced by 3-hydroxybenzaldehyde, and the ethyl 2-bromoacetate in step 2 was replaced by methyl 6-bromohexanoate. The remaining raw materials, reagents and preparation methods were the same as those in steps 1-3 of Example 1 to obtain compound 16 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.35 (s, 1H), 8.68 (s, 1H), 8.10 (d, J=6.7Hz, 1H), 8.03 ( d, J=7.7Hz, 1H), 7.59 (d, J=7.8Hz, 1H), 7.56 (s, 1H), 7.51 (t, 1H), 7.46-7.41 (m, 2H), 7.10 (d, J=8.3Hz, 1H), 4.02 (t, J=6.4Hz, 2H), 1.95 (t, J=7.3Hz, 2H), 1.70 (p , J=7.0Hz, 2H), 1.53 (p, J=7.4Hz, 2H), 1.39 (p, J=8.6Hz, 2H).MS (ESI) calculated forC 19 H 21 N2O3S + [M+H] + :357.1; found:356.9.

[0123] Embodiment 17

[0124] The preparation method of 7-(3-(benzo[d]thiazol-2-yl)phenoxy)-N-hydroxyheptylamide (Compound 17) comprises:

[0125]

[0126] The 4-hydroxybenzaldehyde in step 1 of Example 1 was replaced by 3-hydroxybenzaldehyde, and the ethyl 2-bromoacetate in step 2 was replaced by ethyl 7-bromoheptanoate. The remaining raw materials, reagents and preparation methods were the same as those in steps 1-3 of Example 1 to obtain compound 17 as a white solid. 1H NMR (400MHz, DMSO-d6) δ10.32 (s, 1H), 8.64 (s, 1H), 8.10 (d, J=8.0Hz, 1H), 8.03 (d, J= 8.1Hz, 1H), 7.59 (d, J=7.8Hz, 1H), 7.56 (s, 1H), 7.51 (t, 1H), 7.43 (t, J=7.7Hz, 2H), 7. 10 (d, J=8.3Hz, 1H), 4.02 (t, J=6.4Hz, 2H), 1.93 (t, J=7.3Hz, 2H), 1.70 (p, J=7.3Hz, 2H ), 1.49 (p, 2H), 1.40 (p, J = 7.8Hz, 2H), 1.28 (p, J = 8.0, 7.5Hz, 2H).MS (ESI) calculated for C 20 H 22 N2NaO3S + [M+Na] + :393.1; found:392.8.

[0127] Embodiment 18

[0128] The preparation method of 8-(3-(benzo[d]thiazol-2-yl)phenoxy)-N-hydroxyoctanamide (Compound 18) comprises:

[0129]

[0130] The 4-hydroxybenzaldehyde in step 1 of Example 1 was replaced by 3-hydroxybenzaldehyde, and the ethyl 2-bromoacetate in step 2 was replaced by ethyl 8-bromooctanoate. The remaining raw materials, reagents and preparation methods were the same as those in steps 1-3 of Example 1 to obtain compound 18 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.31 (s, 1H), 8.63 (s, 1H), 8.17-7.97 (m, 2H), 7.65-7.48 (m, 3H), 7.48-7.36 (m, 2H), 7.10 (d, J=8.3, 2.5Hz, 1H), 4. 03 (t, J=6.5Hz, 2H), 1.91 (t, J=7.4Hz, 2H), 1.76-1.65 (m, 2H), 1.53-1.42 (m, 2H), 1.42-1.34 (m, 2H), 1.34-1.18 (m, 4H).MS (ESI) calculated for C 21 H 25 N2O3S + [M+H] + :385.2; found:384.7.

[0131] Embodiment 19

[0132] The preparation method of 7-(3-(benzo[d]thiazol-2-yl)-2-chlorophenoxy)-N-hydroxyheptylamide (Compound 19) comprises:

[0133]

[0134] The 4-hydroxybenzaldehyde in step 1 of Example 1 was replaced by 2-chloro-3-hydroxybenzaldehyde, and the ethyl 2-bromoacetate in step 2 was replaced by ethyl 7-bromoheptanoate. The remaining raw materials, reagents and preparation methods were the same as those in steps 1-3 of Example 1 to obtain compound 19 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.32 (s, 1H), 8.66 (s, 1H), 8.19-8.04 (m, 2H), 7.6 8(d, J=7.9, 1.4Hz, 1H), 7.55 (t, J=8.2, 7.7, 1.4Hz, 1H), 7.51-7.40 (m, 2H), 7.30 (d, J=8.3, 1.5Hz, 1H), 4.09 (t, J=6.4Hz, 2H), 1.93 (t, J=7.4Hz, 2H), 1.79-1.67 (m, 2H), 1.54-1.36 (m, 4H), 1.34-1.22 (m, 2H).MS (ESI) calculated for C 20 H 21 ClN2NaO3S + [M+Na] + :427.1;found:426.6.

[0135] Embodiment 20

[0136] The preparation method of 7-(5-(benzo[d]thiazol-2-yl)-2-methoxyphenoxy)-N-hydroxyheptylamide (Compound 20) comprises:

[0137]

[0138] The 4-hydroxybenzaldehyde in step 1 of Example 1 was replaced by 3-hydroxy-4-methoxybenzaldehyde, and the ethyl 2-bromoacetate in step 2 was replaced by ethyl 7-bromoheptanoate. The remaining raw materials, reagents and preparation methods were the same as those in steps 1-3 of Example 1 to obtain compound 20 as a white solid. 1H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.64 (s, 1H), 8.08-7.90 (m, 2H), 7.61-7.53 ( m, 2H), 7.48 (t, J=8.3, 7.2, 1.3Hz, 1H), 7.38 (t, J=8.2, 7.2, 1.2Hz, 1H), 7.07 (d, J=8 .4Hz, 1H), 4.02(t, J=6.5Hz, 2H), 3.81(s, 3H), 1.93(t, J=7.4Hz, 2H), 1.76-1.66(m , 2H), 1.54-1.44(m, 2H), 1.44-1.35(m, 2H), 1.33-1.23(m, 2H).MS(ESI)calculated for C 21 H 24 N2NaO4S + [M+Na] + :423.1; found:423.0.

[0139] Embodiment 21

[0140] The preparation method of N-hydroxy-7-(2-methoxy-5-(6-methoxybenzo[d]thiazol-2-yl)phenoxy)heptylamide (Compound 21) comprises:

[0141]

[0142] Step 1: The preparation method of 2-amino-5-methoxybenzenethiol comprises:

[0143]

[0144] Dissolve 6-methoxybenzo[d]thiazol-2-amine (2.0 g, 11.11 mmol) in water (20 ml), add potassium hydroxide (6.23 g, 110.1 mmol) and stir at 120°C for 18 hours. Add 1M hydrochloric acid until a large amount of solid precipitates, filter with suction, wash the filter cake three times with water, and finally wash once with PE to obtain a solid compound (1.1 g, yield: 64%).

[0145] Step 2: The preparation method of 2-methoxy-5-(6-methoxybenzo[d]thiazol-2-yl)phenol (second intermediate) comprises:

[0146]

[0147] 2-Amino-5-methoxybenzenethiol (0.5 g, 3.22 mmol) was dissolved in ethanol (8 ml), 3-hydroxy-4-methoxybenzaldehyde (0.49 g, 3.22 mmol) was added and stirred, then sodium dithionite (1.2 g, 6.44 mmol) was added to water (3 ml), and the mixture was quickly added to the mixture and stirred at 80°C for 8 hours. The solvent was evaporated under reduced pressure, 1 M hydrochloric acid was added to acidic state and stirred for 30 minutes, and filtered, the filter cake was first washed with water three times, and finally washed with PE once, to obtain the second intermediate as a yellow solid (0.85 g, yield: 91.4%).

[0148] 1 H NMR (400MHz, DMSO-d6) δ9.49 (s, 1H), 7.87-7.80 (m, 1H), 7.63 (d, J=2.5Hz, 1H), 7.47-7.36 (m, 2H), 7.09-6.99 (m, 2H), 3.80 (s, 6H).MS (ESI) calculated for C 15 H 14 NO3S + [M+H] + :288.1;found:287.9.

[0149] Step 3: The preparation method of ethyl 7-(2-methoxy-5-(6-methoxybenzo[d]thiazol-2-yl)phenoxy)heptanoate (third intermediate) comprises:

[0150]

[0151] The second intermediate (0.5 g, 1.74 mmol) was dissolved in DMF (20 ml), potassium carbonate (0.48 g, 3.5 mmol) and a catalytic amount of potassium iodide were added and stirred, and finally ethyl 7-bromoheptanoate (0.62 g, 2.6 mmol) was added and stirred at 80°C for 8 hours. The solvent was evaporated under reduced pressure, diluted with water (100 ml), extracted three times with ethyl acetate (50 ml), the organic phases were combined, and the solvent was evaporated under reduced pressure. The solid residue was purified by silica gel column chromatography (eluent: PE / EA = 10:1) to obtain a light yellow third intermediate (0.7 g, yield: 90.9%).

[0152] 1H NMR (400MHz, CDCl3) δ7.92 (d, J=8.9, 0.8Hz, 1H), 7.65 (s, 1H), 7.53 (d, J=8.4, 2.1, 0.8Hz , 1H), 7.35-7.32 (m, 1H), 7.07 (d, J=9.0, 2.6, 0.8Hz, 1H), 6.93 (d, J=8.5, 0.8Hz, 1H), 4.18 -4.09(m, 4H), 3.94(s, 3H), 3.89(s, 3H), 2.32(t, 2H), 1.95-1.87(m, 2H), 1.73-1.64(m, 2 H), 1.57-1.49 (m, 2H), 1.46-1.38 (m, 2H), 1.26 (t, J=7.1, 0.8Hz, 3H).MS (ESI) calculated for MS(m / z)(ESI):calcd for C 24 H 30 NO5S + [M+H] + :444.2;found:444.1.

[0153] Step 4: The preparation method of N-hydroxy-7-(2-methoxy-5-(6-methoxybenzo[d]thiazol-2-yl)phenoxy)heptylamide (Compound 21) comprises:

[0154]

[0155] The third intermediate (0.15 g, 0.34 mmol) was dissolved in dichloromethane (2 ml), and a methanol solution of hydroxylamine (6 ml, 6.6 g potassium hydroxide was dissolved in 20 ml methanol, and 4.67 g hydroxylamine hydrochloride was slowly added to 20 ml methanol solution under ice bath) was added, and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, 20 ml methanol was added, 1 M hydrochloric acid was added to adjust the pH to 7-8, stirred for 10 minutes, filtered, and the filter cake was washed three times with water and finally washed once with PE to obtain compound 21 (140 mg, yield: 96.0%) as a white solid.

[0156] 1H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.66 (s, 1H), 7.86 (d, J = 8.9Hz, 1H), 7.63 (d, J = 2.6Hz, 1H), 7.57-7.45 (m, 2H), 7.10-7.00 (m, 2H), 4.01 (t, J =6.5Hz, 2H), 3.80 (s, 6H), 1.92 (t, J = 7.3Hz, 2H), 1.76-1.66 (m, 2H), 1.53-1.44 (m, 2H), 1.44-1.35 (m, 2H), 1.33-1.24 (m, 2H).MS (ESI) calculated for C 22 H 27 N2O5S+[M+H] + :431.2;found:431.0.

[0157] Embodiment 22

[0158] The preparation method of 7-(5-(6-chlorobenzo[d]thiazol-2-yl)-2-methoxyphenoxy)-N-hydroxyheptylamide (Compound 22) comprises:

[0159]

[0160] The 6-methoxybenzo[d]thiazol-2-amine in step 1 of Example 21 was replaced with 6-chlorobenzo[d]thiazol-2-amine, and the remaining required raw materials, reagents and preparation methods were the same as steps 1-4 of Example 21 to obtain compound 22 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.32 (s, 1H), 8.63 (s, 1H), 8.23 ​​(d, J = 2.1Hz, 1H), 7.97 (d, J = 8.7Hz, 1H), 7.61-7.47 (m, 3H), 7.09 (d, J = 9.0Hz, 1H), 4.02 (t, J=6.5Hz, 2H), 3.82 (s, 3H), 1.92 (t, J=7.3Hz, 2H), 1.77-1.64 (m, 2H), 1.53-1.44 (m, 2H), 1.43-1.35 (m, 2H), 1.32-1.24 (m, 2H).MS (ESI) calculated for C 21 H 24 ClN2O4S + [M+H] + :435.1;found:435.0.

[0161] Embodiment 23

[0162] The preparation method of 7-(5-(6-fluorobenzo[d]thiazol-2-yl)-2-methoxyphenoxy)-N-hydroxyheptylamide (Compound 23) comprises:

[0163]

[0164] The 6-methoxybenzo[d]thiazol-2-amine in step 1 of Example 21 was replaced with 6-fluorobenzo[d]thiazol-2-amine, and the remaining required raw materials, reagents and preparation methods were the same as steps 1-4 of Example 21 to obtain compound 23 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.65 (s, 1H), 8.04-7.95 (m, 2H), 7.60-7.51 (m, 2H), 7.35 (t, J = 9.3Hz, 1H), 7.09 (d, J = 8.3Hz, 1H), 4.03 (t, J =6.5Hz, 2H), 3.82 (s, 3H), 1.92 (t, J = 7.5Hz, 2H), 1.77-1.65 (m, 2H), 1.54-1.45 (m, 2H), 1.43-1.34 (m, 2H), 1.33-1.24 (m, 2H).MS (ESI) calculated for C 21 H 24 FN2O4S + [M+H] + :419.1;found:419.0.

[0165] Embodiment 24

[0166] The preparation method of N-hydroxy-7-(2-methoxy-5-(6-methylbenzo[d]thiazol-2-yl)phenoxy)heptylamide (Compound 24) comprises:

[0167]

[0168] The 6-methoxybenzo[d]thiazol-2-amine in step 1 of Example 21 was replaced with 6-methylbenzo[d]thiazol-2-amine, and the remaining required raw materials, reagents and preparation methods were the same as steps 1-4 of Example 21 to obtain compound 24 as a white solid. 1H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.64 (s, 1H), 7.87-7.80 (m, 2H), 7.57- 7.49 (m, 2H), 7.28 (d, J=8.4, 1.7Hz, 1H), 7.06 (d, J=8.4Hz, 1H), 4.01 (t, J=6.5 Hz, 2H), 3.81 (s, 3H), 2.40 (s, 3H), 1.93 (t, J=7.4Hz, 2H), 1.77-1.65 (m, 2H), 1.53-1.45(m, 2H), 1.44-1.34(m, 2H), 1.34-1.23(m, 2H).MS(ESI)calculated for C 22 H 27 N2O4S + [M+H] + :415.2;found:415.1.

[0169] Embodiment 25

[0170] The preparation method of 7-(5-(5-chlorobenzo[d]thiazol-2-yl)-2-methoxyphenoxy)-N-hydroxyheptylamide (Compound 25) comprises:

[0171]

[0172] The 6-methoxybenzo[d]thiazol-2-amine in step 1 of Example 21 was replaced with 5-chlorobenzo[d]thiazol-2-amine, and the remaining required raw materials, reagents and preparation methods were the same as steps 1-4 of Example 21 to obtain compound 25 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.64 (s, 1H), 8.14-8.02 (m, 2H), 7.6 3-7.54 (m, 2H), 7.44 (d, J=8.6, 2.2, 0.8Hz, 1H), 7.10 (d, J=8.3Hz, 1H), 4.02 (t, J=6.2Hz, 2H), 3.83 (s, 3H), 1.93 (t, J=7.3Hz, 2H), 1.77-1.66 (m, 2H), 1.53-1.44 (m, 2H), 1.43-1.34 (m, 2H), 1.33-1.25 (m, 2H).MS (ESI) calculated for C 21 H 23 ClN2KO4S + [M+K] + :473.1; found:472.8.

[0173] Embodiment 26

[0174] The preparation method of N-hydroxy-7-(4-(6-methoxybenzo[d]thiazol-2-yl)phenoxy)heptylamide (Compound 26) comprises:

[0175]

[0176] The 3-hydroxy-4-methoxybenzaldehyde in step 2 of Example 21 was replaced by 4-hydroxybenzaldehyde, and the remaining raw materials, reagents and preparation methods were the same as those in steps 1-4 of Example 21 to obtain compound 26 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.56 (s, 1H), 8.92 (s, 1H), 8.20-8.03 (m, 3H), 7.87 (s, 1H), 7.33-7.21 (m, 3H), 4.22 (t, J=6.8Hz, 2H), 4.03 (s, 3H), 2.15 (t, J=7.4Hz, 2H), 1.91 (s, 2H), 1.77-1.65 (m, 2H), 1.65-1.55 (m, 2H), 1.55-1.44 (m, 2H).MS (ESI) calculated for C 21 H 25 N2O4S + [M+H] + :401.2;found:401.0.

[0177] Embodiment 27

[0178] The preparation method of 7-(4-(6-fluorobenzo[d]thiazol-2-yl)phenoxy)-N-hydroxyheptylamide (Compound 27) comprises:

[0179]

[0180] The 6-methoxybenzo[d]thiazol-2-amine in step 1 of Example 21 was replaced by 6-fluorobenzo[d]thiazol-2-amine, and the 3-hydroxy-4-methoxybenzaldehyde in step 2 was replaced by 4-hydroxybenzaldehyde. The remaining required raw materials, reagents and preparation methods were the same as those in steps 1-4 of Example 21 to obtain compound 27 as a white solid. 1H NMR (400MHz, DMSO-d6) δ10.53 (s, 1H), 8.86 (s, 1H), 8.29-8.08 (m, 4H), 7.56 (t, J=9.1, 2.7Hz, 1H), 7.41-7.19 (m, 2H), 4.23 (t, J=6 .5Hz, 2H), 2.14(t, J=7.3Hz, 2H), 1.97-1.86(m, 2H), 1.74-1.66(m, 2H), 1.64-1.55(m, 2H), 1.54-1.44(m, 2H).MS(ESI)calculated for C 20 H 22 FN2O3S + [M+H] + :389.1;found:389.0.

[0181] Embodiment 28

[0182] The preparation method of 7-(4-(6-chlorobenzo[d]thiazol-2-yl)phenoxy)-N-hydroxyheptylamide (Compound 28) comprises:

[0183]

[0184] The 6-methoxybenzo[d]thiazol-2-amine in step 1 of Example 21 was replaced by 6-chlorobenzo[d]thiazol-2-amine, and the 3-hydroxy-4-methoxybenzaldehyde in step 2 was replaced by 4-hydroxybenzaldehyde. The remaining raw materials, reagents and preparation methods were the same as those in steps 1-4 of Example 21 to obtain compound 28 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.64 (s, 1H), 8.23 ​​(d, J=2.2Hz, 1H), 8.01-7.89 (m, 3H), 7.50 (d, J=8.7, 2.2Hz, 1H), 7.15-6.97 (m, 2H), 4 .01 (t, J=6.5Hz, 2H), 1.92 (t, J=7.4Hz, 2H), 1.74-1.61 (m, 2H), 1.55-1.43 (m, 2H), 1.42-1.32 (m, 2H), 1.31-1.22 (m, 2H).MS (ESI) calculated for C 20 H 22 ClN2O3S + [M+H] + :405.1;found:405.0.

[0185] Embodiment 29

[0186] The preparation method of N-hydroxy-7-(4-(6-methylbenzo[d]thiazol-2-yl)phenoxy)heptylamide (Compound 29) comprises:

[0187]

[0188] The 6-methoxybenzo[d]thiazol-2-amine in step 1 of Example 21 was replaced by 6-methylbenzo[d]thiazol-2-amine, and the 3-hydroxy-4-methoxybenzaldehyde in step 2 was replaced by 4-hydroxybenzaldehyde. The remaining required raw materials, reagents and preparation methods were the same as those in steps 1-4 of Example 21 to obtain compound 29 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.35 (s, 1H), 8.67 (s, 1H), 7.99-7.75 (m, 4H), 7.29 (d, J=8.5Hz, 1H), 7.15-6.97 (m, 2H), 4.00 (t, J=6.5Hz, 2H) , 2.40 (s, 3H), 1.92 (t, J=7.3Hz, 2H), 1.74-1.64 (m, 2H), 1.54-1.43 (m, 2H), 1.42-1.31 (m, 2H), 1.31-1.22 (m, 2H).MS (ESI) calculated for C 21 H 25 N2O3S + [M+H] + :385.2; found:385.0.

[0189] Embodiment 30

[0190] The preparation method of 7-(4-(5-chlorobenzo[d]thiazol-2-yl)phenoxy)-N-hydroxyheptylamide (Compound 30) comprises:

[0191]

[0192] The 6-methoxybenzo[d]thiazol-2-amine in step 1 of Example 21 was replaced by 5-chlorobenzo[d]thiazol-2-amine, and the 3-hydroxy-4-methoxybenzaldehyde in step 2 was replaced by 4-hydroxybenzaldehyde. The remaining raw materials, reagents and preparation methods were the same as those in steps 1-4 of Example 21 to obtain compound 30 as a white solid. 1H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.65 (s, 1H), 8.14-7.94 (m, 4H), 7.43 (d, 1H), 7.11-7.02 (m, 2H), 4.01 (t, J=6.5Hz, 2 H), 1.92 (t, J=7.4Hz, 2H), 1.76-1.62 (m, 2H), 1.55-1.43 (m, 2H), 1.42-1.31 (m, 2H), 1.31-1.20 (m, 2H).MS (ESI) calculated for C 20 H 22 ClN2O3S + [M+H] + :405.1;found:405.0.

[0193] Embodiment 31

[0194] The preparation method of 8-(5-(benzo[d]thiazol-2-yl)-2-methoxyphenoxy)-N-hydroxyoctanamide (Compound 31) comprises:

[0195]

[0196] In Example 1, the 4-hydroxybenzaldehyde in step 1 was replaced by 3-hydroxy-4-methoxybenzaldehyde, and the ethyl 2-bromoacetate in step 2 was replaced by ethyl 8-bromooctanoate. The remaining raw materials, reagents and preparation methods were the same as those in steps 1-3 of Example 1 to obtain compound 31 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.34 (s, 1H), 8.65 (s, 1H), 8.14-7.91 (m, 2H), 7.62-7.5 4(m, 2H), 7.48(t, J=8.2, 7.2, 1.3Hz, 1H), 7.38(t, J=8.3, 7.1, 1.2Hz, 1H), 7.08( d, J=8.3Hz, 1H), 4.02 (t, J=6.5Hz, 2H), 3.81 (s, 3H), 1.92 (t, J=14.0, 6.7Hz, 2H) ,1.78-1.63(m,2H),1.51-1.35(m,4H),1.33-1.19(m,4H).HRMS(ESI)calculated forC 22 H 27 N2O4S + [M+H] + :415.2;found:415.0.

[0197] Embodiment 32

[0198] The preparation method of 7-(3-(benzo[d]thiazol-2-yl)-2-fluorophenoxy)-N-hydroxyheptylamide (Compound 32) comprises:

[0199]

[0200] The 4-hydroxybenzaldehyde in step 1 of Example 1 was replaced by 2-fluoro-3-hydroxybenzaldehyde, and the ethyl 2-bromoacetate in step 2 was replaced by ethyl 7-bromoheptanoate. The remaining raw materials, reagents and preparation methods were the same as those in steps 1-3 of Example 1 to obtain compound 32 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.53 (s, 1H), 8.89 (s, 1H), 8.35 (d, 1H), 8.27 (d, J= 8.2, 3.5Hz, 1H), 8.09-7.95 (m, 1H), 7.78-7.59 (m, 2H), 7.56-7.42 (m, 2H), 4 .25 (t, J=4.7, 3.2Hz, 2H), 2.11 (t, J=7.4, 3.4Hz, 2H), 1.96-1.84 (m, 2H), 1.76-1.63 (m, 2H), 1.62-1.53 ​​(m, 2H), 1.52-1.38 (m, 2H).MS (ESI) calculated for C 20 H 22 FN2O3S + [M+H] + :389.1;found:389.0.

[0201] Embodiment 33

[0202] In vitro HDAC inhibitory activity

[0203] Hela cells were cultured in MEM medium supplemented with 10% fetal bovine serum at 37°C and 5% CO2 atmosphere. Cells were lysed using a buffer solution (50mM Tris-HCl pH 7.4, 150mM NaCl, 1% Triton x-100). Hela cell extracts were subjected to enzymatic reaction at 37°C for 30 minutes. The 50μL reaction mixture contained 25mM Tris, pH 8.0, 1mMMgCl2, 0.1mg / ml BSA, 137mM NaCl, 2.7mM KCl, Hela extract and enzyme substrate (20μM Ac-leu-gly-lys(Ac)-AMC). The aforementioned example compounds 1-32 and SAHA were diluted with 10% DMSO, and 5μL of the diluent was added to the aforementioned 50μL reaction mixture, respectively, so that the final DMSO concentration in all reaction mixtures was 1%. The determination was completed by measuring the amount of fluorescent product in the solution after the enzyme reaction. After the enzymatic reaction was completed, 50 μL of 0.4 mg / ml Trypsin was added to each well and incubated for another 15 minutes at room temperature. The fluorescence was then analyzed on a Spectra Max M5 microtiter plate reader at an excitation wavelength of 350-360 nm and an emission wavelength of 450-460 nm. IC was calculated using nonlinear regression of normalized dose-response fit using Prism GraphPad software. 50 The results in Table 1 show that compounds 3 and 20 exhibited better inhibitory activity against HDACs kinases than SAHA. “++++” indicates IC 50 The value is less than 10 nM or the inhibition rate is 80-100%, and "+++" indicates IC 50 The value is 10-100 nM or the inhibition rate is 60-80%, and "++" indicates IC 50 Value 100-1000 nM or inhibition rate 40-60%, "+" indicates IC 50 The value was greater than 1000 nM or the inhibition rate was less than 40%.

[0204] Table 1 HDACs kinase inhibition test of compounds 1-32

[0205]

[0206]

[0207] Embodiment 34

[0208] HDAC isozyme inhibitory activity of selected compounds

[0209] All enzymatic reactions were carried out at 37°C for 30 minutes. The 50 μl reaction mixture contained 25 mM Tris, pH 8.0, 1 mM MgCl2, 0.1 mg / ml BSA, 137 mM NaCl, 2.7 mM KCl, HDAC and enzyme substrate. The aforementioned compounds 1-32 and SAHA were diluted with 10% dimethyl sulfoxide, and 5 μl of the dilution was added to the 50 μl reaction, so that the final concentration of dimethyl sulfoxide in all reactions was 1%. The determination was completed by measuring the amount of fluorescent product in the solution after the enzyme reaction. The fluorescence was then analyzed on a Spectra Max M5 microtiter plate reader with an excitation wavelength of 350-360 nm and an emission wavelength of 450-460 nm. IC was calculated using nonlinear regression of normalized dose-response fit using Prism GraphPad software. 50 "++++" means IC 50 The value is less than 10 nM or the inhibition rate is 80-100%, and "+++" indicates IC 50 The value is 10-100 nM or the inhibition rate is 60-80%, and "++" indicates IC 50 Value 100-1000 nM or inhibition rate 40-60%, "+" indicates IC 50 The value was greater than 1000 nM or the inhibition rate was less than 40%.

[0210] Table 2 HDAC isozyme inhibitory activity of compounds

[0211]

[0212] The results in Table 2 show that compounds 3 and 20 have certain selectivity for HDAC6.

[0213] Example 35 PKD vesicle experiment

[0214] MDCK cells were used to form vesicles similar to those in PKD under the action of the AC enzyme agonist forskolin, the occurrence and development of the disease were simulated, and a test compound (preferably compound 20) was administered to observe the effect of the test compound on the vesicles.

[0215] 1. Cell culture

[0216] MDCK cells were cultured at 37°C and 5% CO2 in DMEM F12 medium (available from Kangmei Co., Ltd.), with 10% fetal bovine serum and 1% double antibody added. After three days of cell culture, when the growth area was about 80-90%, the next step of the experiment was started.

[0217] 2. Prepare the matrix gel (single well) according to the following formula:

[0218]

[0219] 3. Digested cells were added to 24-well plates

[0220] While the Matrigel was recooling, the MDCK cells were digested and counted.

[0221] After pH adjustment, add cells and blow evenly, use a 1mL pipette tip to absorb 400μL of the prepared liquid and add it to a 24-well plate. The key points are as follows:

[0222] 1. The liquid should be sucked from the bottom to avoid sucking too many bubbles.

[0223] 2. When adding to a 24-well plate, the tip of the gun should be fixed and cannot be moved. Finally, the liquid at the tip of the gun should not be completely blown out.

[0224] 3. After adding all the glue, shake it gently clockwise to make it evenly distributed.

[0225] After the matrix gel was prepared, the well plate was placed in the incubator to stabilize for 90 minutes, and then 1.5 mL of cell culture medium containing 10 μM Forsklin and corresponding concentrations of drugs was added to each well, divided into a blank control group, an AMPK agonist (1 μM) group, and an AMPK agonist (10 μM) group. The culture was carried out for 10 days, the medium was changed every 12 hours, and photos were taken on the 4th, 6th, 8th, and 10th days. The photo area was selected and specific vesicles were tracked.

[0226] The vesicle diameters were compared on day 10 to evaluate the effects of the test compounds. The experimental results are shown in Table 9.

[0227] Table 9 PKD vesicle experiment

[0228]

[0229] The results of the vesicle experiment showed that compared with the control group, this type of compound can significantly inhibit the development of vesicles in PKD disease.

[0230] Example 36 Tissue Embryonic Kidney Experiment

[0231] The kidney of a 13.5-day embryonic mouse was placed in a transwell, and vesicles similar to those in PKD were formed under the stimulation of 8-Br-cAMP. The occurrence and development of the disease were simulated, and a test compound (preferably compound 20) was administered to observe the effect of the test compound on the kidney.

[0232] 1. Culture of embryonic kidney

[0233] The embryonic kidney was cultured at 37°C and 5% CO2 in DMEM F12 medium (available from Kangmei.com).

[0234] 8-Br-cAMP, insulin, transferrin, sodium selenite and double antibody were added. Drugs of corresponding concentrations were added to form a control group. The cells were cultured for 6 days, the medium was changed every 12 hours, and photos were taken on the 2nd, 4th and 6th days.

[0235] The vesicle areas were compared on day 6 to evaluate the effects of the test compounds. The experimental results are shown in Table 10.

[0236] Table 10 Tissue embryo kidney experiment

[0237]

[0238] The results of tissue embryonic kidney experiments showed that compared with the control group, this type of compound can significantly inhibit the development of vesicles in PKD disease.

[0239] Example 37 PKD mouse experiment

[0240] In this experiment, PKD1 gene knockout mice were used to evaluate the in vivo efficacy of the preferred compound 20.

[0241] Specific operations:

[0242] 1. Mouse number and gene identification: 3 days after birth, the mice were marked by clipping their toes and placed in pre-labeled EP tubes. After the toes were clipped and boiled, PCR was performed and then agarose electrophoresis was used for gene identification.

[0243] 2. Prepare the corresponding medicine: Use an electronic balance to accurately weigh the corresponding weight of the medicine and place it in a new EP tube. Then use a pipette to add the corresponding amount of HPMC to prepare the medicine of the required concentration. (Take 1mg / kg compound 20 as an example, weigh 1mg of compound 20, add 500uL HPMC, vortex for 30s (to suspend most of the medicine), then ultrasonicate for 15-20 minutes to crush the large pieces of medicine, and vortex for 30s again.)

[0244] 3. Dosing for mice: Dosing begins on the 6th or 5th day after birth (if the mouse is underweight, dosing begins on the 6th day, otherwise dosing begins on the 5th day), and the dosing time is fixed (e.g. 9 a.m.). Pinch the target mouse (back) with the index finger and thumb, weigh it, and use a microinjector to draw the corresponding amount of medicine, insert the injector from the middle of the bulge on the mouse's back (between the thumb and index finger), and perform subcutaneous injection.

[0245] 4. Mouse tissue extraction: Seven days after administration, the mice were killed and weighed accurately. The laparotomy was performed, and the left kidney was removed and weighed accurately. The kidney was placed in the horizontal line and photographed. After completion, it was placed in a numbered ep tube and temporarily stored on ice. The right kidney was then removed, weighed and photographed under the same conditions, and stored in a numbered ep tube in paraformaldehyde. The liver was removed and temporarily stored in an ep tube on ice. After the operation, the liver and left kidney were stored in a -80 degree refrigerator.

[0246] 5. Data processing: Calculate the total weight of left and right kidneys, kidney specific gravity, etc. The experimental results are shown in Table 11.

[0247] Table 11 PKD mouse experiment

[0248]

[0249] The results of animal experiments showed that compared with the control group, this type of compound exhibited comparable inhibitory activity to Tolvaptan in delaying the occurrence and development of PKD, which means that this type of compound has a good therapeutic effect on PKD.

[0250] Although the present invention has been described with reference to illustrative embodiments, it will be appreciated by those skilled in the art that various other changes, omissions and / or additions may be made and that elements of the described embodiments may be substituted with substantial equivalents without departing from the spirit and scope of the present invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the present invention without departing from the scope of the present invention. Therefore, it is not intended herein to limit the present invention to the specific disclosed embodiments for carrying out the present invention, but rather it is intended that the present invention will include all embodiments within the scope of the appended claims.

Claims

1. Use of a benzothiazole compound or a pharmaceutically acceptable salt thereof in the preparation of a targeted drug for preventing and / or treating autosomal dominant polycystic kidney disease, wherein the benzothiazole compound is selected from 2-(4-(benzo[ d ]thiazol-2-yl)phenoxy)-N-hydroxyacetamide, 6-(4-(benzo[ d ]thiazol-2-yl)phenoxy)-N-hydroxyhexanamide, 7-(4-(benzo[ d ]thiazol-2-yl)phenoxy)-N-hydroxyheptylamide, 8-(4-(benzo[ d ] thiazol-2-yl) phenoxy)-N-hydroxyoctanamide, 7-(4-(benzo[ d ]thiazol-2-yl)-2-fluorophenoxy)-N-hydroxyheptylamide, 7-(4-(benzo[ d ]thiazol-2-yl)-2-methylphenoxy)-N-hydroxyheptylamide, 7-(4-(benzo[ d ]thiazol-2-yl)-2-chlorophenoxy)-N-hydroxyheptylamide, 7-(4-(benzo[ d ]thiazol-2-yl)-2-methoxyphenoxy)-N-hydroxyheptylamide, 7-(4-(benzo[ d ] thiazol-2-yl)-2-ethoxyphenoxy)-N-hydroxyheptylamide, 7-(4-(benzo[ d ]thiazol-2-yl)-3-chlorophenoxy)-N-hydroxyheptylamide, 7-(4-(benzo[ d ]thiazol-2-yl)-3-fluorophenoxy)-N-hydroxyheptylamide, 7-(4-(benzo[ d ]thiazol-2-yl)-2,6-dimethoxyphenoxy)-N-hydroxyheptylamide, 2-(3-(benzo[ d ]thiazol-2-yl)phenoxy)-N-hydroxyacetamide, 4-(3-(benzo[ d ]thiazol-2-yl)phenoxy)-N-hydroxybutyramide, 5-(3-(benzo[ d ]thiazol-2-yl)phenoxy)-N-hydroxypentanamide, 6-(3-(benzo[ d ] thiazol-2-yl) phenoxy)-N-hydroxyhexanamide, 7-(3-(benzo[ d ]thiazol-2-yl)phenoxy)-N-hydroxyheptylamide, 8-(3-(benzo[ d ] thiazol-2-yl) phenoxy)-N-hydroxyoctanamide, 7-(3-(benzo[ d ]thiazol-2-yl)-2-chlorophenoxy)-N-hydroxyheptylamide, 7-(5-(benzo[ d ] thiazol-2-yl)-2-methoxyphenoxy)-N-hydroxyheptylamide, N-hydroxy-7-(2-methoxy-5-(6-methoxybenzo[ d ]thiazol-2-yl)phenoxy)heptylamide, 7-(5-(6-chlorobenzo[ d ]thiazol-2-yl)-2-methoxyphenoxy)-N-hydroxyheptylamide, 7-(5-(6-fluorobenzo[ d ] thiazol-2-yl)-2-methoxyphenoxy)-N-hydroxyheptylamide, N-hydroxy-7-(2-methoxy-5-(6-methylbenzo[ d ]thiazol-2-yl)phenoxy)heptylamide, 7-(5-(5-chlorobenzo[ d ]thiazol-2-yl)-2-methoxyphenoxy)-N-hydroxyheptylamide, N-hydroxy-7-(4-(6-methoxybenzo[ d ]thiazol-2-yl)phenoxy)heptylamide, 7-(4-(6-fluorobenzo[ d ]thiazol-2-yl)phenoxy)-N-hydroxyheptylamide, 7-(4-(6-chlorobenzo[ d ]thiazol-2-yl)phenoxy)-N-hydroxyheptylamide, N-hydroxy-7-(4-(6-methylbenzo[ d ]thiazol-2-yl)phenoxy)heptylamide, 7-(4-(5-chlorobenzo[ d ]thiazol-2-yl)phenoxy)-N-hydroxyheptylamide, 8-(5-(benzo[ d ]thiazol-2-yl)-2-methoxyphenoxy)-N-hydroxyoctanamide or 7-(3-(benzo[ d ]thiazol-2-yl)-2-fluorophenoxy)-N-hydroxyheptylamide.

2. The use according to claim 1, characterized in that: The salt includes any one of hydrochloride, p-toluenesulfonate, sulfate, succinate, maleate, fumarate, acetate, phosphate, citrate, methanesulfonate and sodium salt.

3. The use according to claim 1, characterized in that The targeted drug is a pharmaceutical composition, and comprises: A therapeutically effective amount of the benzothiazole compound or a pharmaceutically acceptable salt thereof; and, one or more pharmaceutically acceptable carriers.

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