Diphenyl oxadiazole compound or salt thereof, and preparation method and application thereof

Abstract

A class of biphenyl oxadiazole compounds or salts thereof, and a preparation method and application thereof, the biphenyl oxadiazole compounds have a structure as shown in formula (I), R1 is at least independently selected from hydrogen, halogen, cyano, nitryl, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, aryl, heteroaryl or heterocyclic radical, and n is 1-7. The bis-phenyl oxadiazolidine compound or the pharmaceutically acceptable salt thereof can be used for preparing a medicine for preventing and / or treating pain. Particularly, the biphenyl oxadiazole compound can target HDAC6 to treat pain and has an inhibition effect on proinflammatory factors, and when the administration dosage is 30 mg / kg, the inhibition activity on a pain model mouse is equivalent to that of ACY-1215; a new path is provided for treatment and prevention of moderate to severe pain, acute pain, chronic pain, neuralgia, inflammatory pain, nociceptive pain, cancer pain, hyperalgesia and visceral pain.

Description

Technical Field

[0001] This invention specifically relates to a class of diphenyloxadiazole compounds or their salts, their preparation methods and pharmaceutical uses, belonging to the field of pharmaceutical compound technology. Background Technology

[0002] Pain is a distressing experience encompassing sensory, emotional, cognitive, and social dimensions, associated with tissue damage or potential tissue damage. It is an innate, instinctive, protective response of the body, enabling people to avoid harm or detect potential illnesses. If pain persists, it gradually evolves into chronic pain. Modern medicine considers acute pain a symptom, while chronic pain is a disease. Chronic pain has become a major public health challenge, as significant as any other common, intractable, and prevalent chronic disease (such as diabetes and cancer). The etiology of chronic pain is complex, its developmental mechanisms are not yet fully understood, and effective treatments are currently lacking in clinical practice.

[0003] Recent studies have shown a correlation between epigenetic regulation and the development of chronic pain. Chronic pain or the chronication of acute pain is often the result of the interaction between environmental factors and genes. A deeper understanding of the relationship between epigenetic regulatory components and chronic pain, and the search for biomarkers (such as epigenetic regulation-related markers) that are closely related to the development and efficacy of pain, especially chronic pain, and drug treatment, will enable the diagnosis of chronic pain susceptibility and the evaluation of drug treatment effects. Ultimately, this will help promote the development of personalized analgesia and precision medicine for pain.

[0004] Histone deacetylases (HDACs) remove acetyl groups from histones, thereby inhibiting nuclear chromatin activity and the expression of their target genes. The HDAC family is currently known to include four classes (HDAC I to HDAC IV), containing 18 members. Among these, 11 are zinc-dependent subtypes, sharing the same enzymatic mechanism but differing in their biological functions, possibly related to the different signal regulation functions performed by each subtype. HDACs have been found to be closely associated with various major and intractable human diseases such as cancer, heart disease, neurodegenerative diseases, and autoimmune diseases. Currently, a few small-molecule HDAC inhibitors are used clinically, primarily targeting HDAC subtypes I, II, and IV. However, extensive research is still needed to explore their potential clinical applications in diseases including pain. Recent studies have also indicated that HDACs can participate in pain regulation processes.

[0005] Studies have shown that HDAC inhibitors can alleviate inflammatory pain. Subcutaneous administration of the HDAC inhibitor MS-275 alone or in combination with the histone deacetylase inhibitor (SAHA) can increase the expression of metabolite glutamate receptor 2 (mGluR2) in DRG and reduce formalin-induced acute binomial pain behavior. However, further research is needed on HDAC acetylation and its intrinsic expression levels in DRG neurons in this model. Chronic inflammatory pain in CFA can also increase the expression levels of type IIa HDACs in the dorsal horn of the spinal cord, including HDAC4, HDAC5, HDAC7, and HDAC9, but has no effect on the expression of type I HDACs, including HDAC1, HDAC2, and HDAC3. Conversely, intrathecal injection of type I and II HDAC inhibitors such as SAHA, trichosin (TSA), and the histone deacetylase inhibitor LAQ824, or type IIa HDAC inhibitors valproic acid (VPA) and phenyl 4-butyrate (4-PB), can significantly delay the development of inflammatory pain in CFA. This suggests that HDAC is closely related to the occurrence of inflammatory pain, and its inhibitors may be a more effective analgesic tool, but the effective targets for its action still need further research. HDAC can also participate in pain regulation through related areas of the higher central brain.

[0006] Studies have shown that mice with HDACs, especially HDAC6 knockout, can survive, and selective HDAC6 inhibitors can be used to treat moderate to severe pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, cancer pain, hyperalgesia, and visceral pain. Therefore, developing new selective HDAC6 inhibitors and creating drugs with better therapeutic effects and fewer side effects to alleviate pain is of great significance. Summary of the Invention

[0007] One objective of this invention is to provide a class of biphenyloxadiazole compounds or their salts, which can serve as effective HDAC6 kinase inhibitors for the treatment of moderate to severe pain, acute pain, chronic pain, neuralgia, inflammatory pain, nociceptive pain, cancer pain, hyperalgesia, and visceral pain-related diseases mediated by HDAC6 kinase. These compounds have the characteristics of high response rate, few side effects, and few adverse reactions, thus meeting the needs of clinical medication and overcoming the shortcomings of existing technologies.

[0008] A second objective of this invention is to provide the use of the aforementioned diphenyloxadiazole compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for the prevention and / or treatment of moderate to severe pain, acute pain, chronic pain, neuralgia, inflammatory pain, nociceptive pain, cancer pain, hyperalgesia, and visceral pain-related diseases.

[0009] A third objective of this invention is to provide a method for preparing the aforementioned diphenyloxadiazole compounds or their salts.

[0010] To achieve the above-mentioned objectives, the present invention adopts the following technical solution:

[0011] The first aspect of the present invention provides a class of bisphenyloxadiazole compounds or salts thereof, said bisphenyloxadiazole compounds having the structure shown in formula (I).

[0012]

[0013] R1 is selected independently from at least one of hydrogen, halogen, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, aryl, heteroaryl and heterocyclic, and n is any integer from 1 to 7.

[0014] In the definition (Ⅰ), if the diphenyloxadiazole group is the A unit, the benzene ring group connected to the diphenyloxadiazole group is the B unit, and the group connected to the B unit through an ether bond is the C unit, the C unit is connected to the 4th or 5th position of the benzene ring in the B unit.

[0015] In one embodiment, R1 is selected from hydrogen, halogen, C1-6 alkyl, or C1-6 alkoxy.

[0016] More preferably, R1 is hydrogen.

[0017] More preferably, R1 is a halogen; even more preferably, the halogen is fluorine or chlorine.

[0018] More preferably, R1 is a C1-6 alkyl group; even more preferably, R1 is a methyl group.

[0019] More preferably, R1 is a C1-6 alkoxy group; even more preferably, R1 is a methoxy group.

[0020] In one embodiment, the diphenyloxadiazole compound includes N-hydroxy-2-(3-(3-phenyl-1,2,4-oxadiazole-5-yl)phenoxy)acetamide, N-hydroxy-4-(3-(3-phenyl-1,2,4-oxadiazole-5-yl)phenoxy)butyramide, N-hydroxy-5-(3-(3-phenyl-1,2,4-oxadiazole-5-yl)phenoxy)pentanamide, N-hydroxy-6-(3-(3-phenyl-1,2,4-oxadiazole-5-yl)phenoxy)hexamamide, N-hydroxy-7-(3-(3-phenyl-1,2,4-oxadiazole-5-yl)phenoxy)heptanamide, 5-(3-(3-(4-fluorophenyl)-1,2,4-oxadiazole-5-yl)phenoxy) -N-hydroxypentanamide, 6-(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyhexamamide, 7-(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyheptanamide, 5-(3-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxypentanamide, 6-(3-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyhexamamide, 7-(3-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyheptanamide, N-hydroxy-5-(3-(3-(p-tolyl)-1,2 ...-(4-chlorophenyl)-1,2-(4-chlorophenyl)-1,2-(4-chlorophenyl)-1,2-(4-chlorophenyl)-1,2-(4-chlorophenyl)-1,2-(4-chlorophenyl)-1,2-(4-chlorophenyl)-1,2-(4-chlorophenyl)-1,2-(4-chlorophenyl)-1,2-(4-chlorophenyl)-1,2-(4-chlorophenyl) 4-Oxadiazol-5-yl)phenoxy)pentanamide, N-hydroxy-6-(3-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)phenoxy)hexamamide, N-hydroxy-7-(3-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)phenoxy)heptanamide, N-hydroxy-4-(3-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)butanamide, N-hydroxy-5-(3-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)pentanamide, N-hydroxy-6-(3-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)hexamamide, N-hydroxy-7-( 3-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)heptamide, N-hydroxy-2-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)acetamide, N-hydroxy-4-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)butamide, N-hydroxy-5-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)pentanamide, N-hydroxy-6-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)hexamamide, N-hydroxy-7-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)heptamide, 5-(4-(3-(4-fluorophenyl)-1,2,4-Oxadiazol-5-yl)phenoxy)-N-hydroxypentanamide, 6-(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyhexamamide, 7-(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyheptanamide, 5-(4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxypentanamide, 6-(4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)- The following are possible combinations of N-hydroxyhexamamide, 7-(4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyheptamide, N-hydroxy-5-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)phenoxy)pentanamide, N-hydroxy-6-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)phenoxy)hexamamide, and N-hydroxy-7-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)phenoxy)heptamide, but not limited thereto.

[0021] In one embodiment, the salt of the biphenyloxadiazole compound includes any one of hydrochloride, p-toluenesulfonate, sulfate, succinate, maleate, fumarate, acetate, phosphate, citrate, methanesulfonate, and sodium salt.

[0022] A second aspect of the present invention provides a method for preparing a class of diphenyloxadiazole compounds, comprising:

[0023] S1. Using the compound shown in formula (II) as the starting material, react with hydroxylamine hydrochloride in a first reaction system to form the first intermediate shown in formula (III). The first reaction system contains anhydrous sodium carbonate, ethanol, and water. The equivalent ratio of the compound shown in formula (II), hydroxylamine hydrochloride, and anhydrous sodium carbonate can be 1–2:1–2:2–4, preferably around 1:1:2. The reaction temperature can be 50–100°C, preferably around 80°C. Ethanol and water are mainly used as solvents, and the volume ratio of ethanol to water can be around 5:1–2, preferably around 5:3.

[0024] S2. The first intermediate (1 eq) is reacted in the second reaction system with the substrate (IV) to obtain the second intermediate shown in formula (V). The second reaction system contains EDCI, HOBT, triethylamine, and DMF. The equivalence ratio of the first intermediate to EDCI can be approximately 1:1 to 7, preferably approximately 1:1. DMF is mainly used as a solvent. The reaction can be carried out at approximately 0°C for about 0.5 h initially, followed by at room temperature for about 6 to 12 h.

[0025] S3. The second intermediate and the brominated alkyl ester compound of formula (VI) are reacted in a third reaction system to obtain the third intermediate of formula (VII). The third reaction system includes potassium carbonate, potassium iodide, and N,N-dimethylformamide or acetonitrile. The equivalent ratio of the second intermediate, the brominated alkyl ester compound of formula (VI), potassium carbonate, and potassium iodide can be 1–2:1–2:1–4:0.1–0.5, preferably around 1:1.5:1.5:0.1. N,N-dimethylformamide or acetonitrile is mainly used as a solvent. The reaction temperature can be 50–100°C, preferably around 80°C, and the reaction time can be around 8–12 hours.

[0026] S4. React the third intermediate in a fourth reaction system to obtain the bisphenyloxadiazole compound shown in formula (I), wherein the fourth reaction system includes a methanol solution of hydroxylamine. The equivalent ratio of the third intermediate to hydroxylamine can be 1:3 to 3:1. The reaction can be carried out at room temperature for approximately 1-2 hours.

[0027]

[0028]

[0029] R1 is selected independently from at least one of hydrogen, halogen, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, aryl, heteroaryl and heterocyclic, n is any integer from 1 to 7, n1 is 1, 3, 4, 5, 6 or 7, and n2 is 0 or 1.

[0030] A third aspect of the present invention provides a pharmaceutical composition comprising:

[0031] A therapeutically effective amount of the aforementioned biphenyloxadiazole compound or a pharmaceutically acceptable salt thereof;

[0032] And one or more pharmaceutically acceptable carriers.

[0033] A fourth aspect of the invention provides the use of the aforementioned diphenyloxadiazole compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in the preparation of an HDAC6 kinase inhibitor.

[0034] A fifth aspect of the invention provides the use of the said biphenyloxadiazole compound or a pharmaceutically acceptable salt thereof, or the said pharmaceutical composition, in the preparation of a medicament for the prevention and / or treatment of pain.

[0035] In one embodiment, the pain includes moderate to severe pain; the pain is acute or chronic pain; the pain includes any one of neuralgia, inflammatory pain, nociceptive pain, cancer pain, hyperalgesia, and visceral pain.

[0036] A sixth aspect of the invention provides the use of the said biphenyloxadiazole compound or a pharmaceutically acceptable salt thereof, or the said pharmaceutical composition, in the preparation of a targeted medicament for the prevention and / or treatment of neuropathic pain and inflammatory pain.

[0037] The present invention provides a class of biphenyloxadiazole compounds or pharmaceutically acceptable salts thereof, which, when used as HDAC6 kinase inhibitors, have inhibitory effects on pro-inflammatory factors. At a dose of 30 mg / kg, their inhibitory activity in pain model mice is comparable to that of ACY-1215. This provides a novel class of lead compounds for the treatment and prevention of moderate to severe pain, acute pain, chronic pain, neuralgia, inflammatory pain, nociceptive pain, cancer pain, hyperalgesia, and visceral pain.

[0038] Attachment title

[0039] Figure 1 The diagram shows the relevant experimental results of carrageenan-induced inflammatory pain model. Among them, (A) is the analgesic time-effect curve of compound 8 in carrageenan-treated mice, (B) the time-effect relationship of compound 8 represented by the AUC plot, (C) the analgesic time-effect curve of compound 31 in carrageenan-treated mice, and (D) the time-effect relationship of compound 31 represented by the AUC plot.

[0040] Figure 2 The diagram shows the experimental model of paclitaxel-induced neuropathic pain. Among them, (A) is the analgesic time-effect curve of ACY-215 in paclitaxel-treated mice, (B) the time-effect relationship of ACY-215 represented by the AUC plot, (C) the analgesic time-effect curve of compound 8 in paclitaxel-treated mice, (D) the time-effect relationship of compound 8 represented by the AUC plot, (E) the analgesic time-effect curve of compound 31 in paclitaxel-treated mice, and (F) the time-effect relationship of compound 31 represented by the AUC plot. Detailed Implementation

[0041] The present invention will be further described in detail below with reference to the embodiments.

[0042] The following synthetic schemes and examples further illustrate the specific implementation methods, which should not be considered as limitations in any way. The experimental procedures used to generate data will be discussed in detail below. For all formulations and multiple dosages herein, proportions can be made according to techniques known in the art.

[0043] The preparation methods of the diphenyloxadiazole compounds 1-32 in the following embodiments of the present invention include:

[0044] The first intermediate was obtained by reacting benzonitrile with different substituted starting materials with hydroxylamine hydrochloride in anhydrous sodium carbonate, ethanol and water.

[0045] Subsequently, the first intermediate was reacted with substrate (IV) in a system of EDCI, HOBT, triethylamine and DMF to give the second intermediate;

[0046] Then, the second intermediate and brominated alkyl esters of different carbon chain lengths are reacted in a system of potassium carbonate, potassium iodide and N,N-dimethylformamide or acetonitrile to obtain the third intermediate;

[0047] Finally, the third intermediate is reacted with a methanol solution of hydroxylamine to prepare the diphenyloxadiazole compound.

[0048] The specific reaction principle of the preparation method is as follows:

[0049]

[0050] Example 1

[0051] The preparation method of N-hydroxy-2-(3-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)acetamide (compound 1) includes the following steps:

[0052] Step 1: The preparation method of N'-hydroxybenzomidine (first intermediate) includes:

[0053]

[0054] Benzonitrile (5.15 g, 50 mmol) and hydroxylamine hydrochloride (6.9 g, 100 mmol) were dissolved in 30 mL of water and 100 mL of ethanol. Sodium carbonate solution (10.6 g, 100 mmol) was carefully added, and the resulting solution was stirred and heated at 70 °C for 8 hours. After cooling, the solution was concentrated, followed by the addition of 200 mL of saturated sodium chloride solution and extraction with ethyl acetate (3 times, 100 mL each). The organic phase was dried over magnesium sulfate and then evaporated. The residue was recrystallized from ethyl acetate (5.6 g, yield 82.3%). 1 H NMR(400MHz,DMSO-d6)δ9.62(s,1H),7.72–7.61(m,2H),7.41–7.31(m,3H),5.79(s,2H).MS(m / z)(ESI):calcd for C7H9N2O + [M+H] + :137.1; found:137.3.

[0055] Step 2: The preparation method of 3-(3-phenyl-1,2,4-oxadiazol-5-yl)phenol (second intermediate) includes:

[0056]

[0057] 3-Hydroxybenzoic acid (2.15 g, 15.6 mmol) was dissolved in anhydrous DMF (30 mL), followed by the addition of EDCI (3.50 g, 18.3 mmol), HOBt (2.50 g, 18.5 mmol), and 0.2 mL of triethylamine (TEA). The first intermediate (2.50 g, 18.4 mmol) was added, and the mixture was sonicated until completely dissolved. After reflux for 3–6 hours, the mixture was cooled to room temperature, and 100 mL of distilled water was added. The resulting solution was extracted with ethyl acetate (3 times, 20 mL each time), washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. This crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the second intermediate (yield 73.2%). 1 H NMR(400MHz,DMSO-d6)δ10.17(s,1H),8.13–8.07(m,2H),7.67–7.60(m,4H),7.60 –7.55(m,1H),7.48(t,J=8.0Hz,1H),7.15–7.10(m,1H).MS(m / z)(ESI):calcdfor C 14 H 11 N2O2 + [M+H] + :239.1; found:239.1.

[0058] Step 3: The preparation method of ethyl acetate 2-(3-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy) (third intermediate) includes:

[0059]

[0060] In a stirred suspension of the second intermediate (2.0 mmol) with potassium carbonate (3.0 mmol) and potassium iodide (0.2 mmol) in DMF (10 mL), ethyl 2-bromoacetic acid (3.0 mmol) was added. After reacting at 80 °C for 6 hours, the mixture was quenched with water and extracted three times with 100 mL of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to give the third intermediate (yield 85.3%). 1H NMR(400MHz, DMSO-d6)δ8.15–8.06(m,2H),7.82(d,J=7.8Hz,1H),7.69–7.56(m,5H),7.37–7 .30(m,1H),4.97(s,2H),4.26–4.14(m,2H),1.24(t,J=7.2Hz,3H).MS(m / z)(ESI):calcdfor C 18 H 16 N2NaO4 + [M+Na] + :347.1; found:347.1.

[0061] Step 4: The preparation method of 2-(4-(benzo[d]thiazol-2-yl)phenoxy)-N-hydroxyacetamide (compound 1) includes:

[0062]

[0063] First, hydroxylamine hydrochloride (9.34 g, 134 mmol) was dissolved in 40 mL of methanol, and then 40 mL of 5 M potassium hydroxide solution was added dropwise at 0 °C. The reaction mixture was kept at 0 °C for 30 minutes, and after filtration, solution A was obtained. Next, the third intermediate (0.20 g) was dissolved in solution A (10-15 mL), and stirred at room temperature for 1-2 hours. Subsequently, the mixture was neutralized with 1 M hydrochloric acid to pH 7-8. Filtration yielded a white precipitate, which was the target compound. 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),9.02(s,1H),8.06(d,2H),7.77(d,J=7.8Hz,1H),7.70(s ,1H),7.61–7.53(m,4H),7.29(d,J=8.2Hz,1H),4.60(s,2H).MS(m / z)(ESI)[M+H]found:312.2.

[0064] Example 2

[0065] The preparation method of N-hydroxy-4-(3-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)butyramide (compound 2) includes:

[0066]

[0067] In Example 1, step 3, ethyl 2-bromoacetate was replaced with methyl 4-bromobutyrate. The remaining raw materials, reagents, and preparation methods were the same as in Example 1, and compound 2, a white solid, was finally obtained. 1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.75(s,1H),8.18–8.05(m,2H),7.82–7.70(m,1H),7.69–7.56(m,5H),7 .37–7.26(m,1H),4.10(t,J=6.2Hz,2H),2.18(t,J=7.4Hz,2H),2.11–1.94(m,2H).MS(ESI)[M+H]Found:340.2.

[0068] Example 3

[0069] The preparation method of N-hydroxy-5-(3-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)pentanamide (compound 3) includes:

[0070]

[0071] Replace ethyl 2-bromoacetate in step 3 of Example 1 with methyl 5-bromopentanoate. The other required raw materials, reagents and preparation methods are the same as in Example 1, to obtain compound 3, which is a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H),8.74(s,1H),8.15–8.07(m,2H),7.80–7.74(m,1H),7.67–7.54(m,5H),7. 34–7.28(m,1H),4.11(t,J=6.2Hz,2H),2.05(t,J=7.0Hz,2H),1.82–1.62(m,4H).HRMS(ESI)[M+H]found:354.3.

[0072] Example 4

[0073] The preparation method of N-hydroxy-6-(3-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)hexamamide (compound 4) includes:

[0074]

[0075] Replace ethyl 2-bromoacetate in step 3 of Example 1 with methyl 6-bromohexanoate. The other required raw materials, reagents and preparation methods are the same as in Example 1, to obtain compound 4, which is a white solid. 1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.73(s,1H),8.15–8.07(m,2H),7.80–7.73(m,1H),7.67–7.54(m,5H),7.34–7.27(m,1H),4 .09(t,J=6.4Hz,2H),1.99(t,J=7.2Hz,2H),1.81–1.71(m,2H),1.63–1.52(m,2H),1.48–1.36(m,2H).MS(ESI)[M+H]found:368.1.

[0076] Example 5

[0077] The preparation method of N-hydroxy-7-(3-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)heptamide (compound 5) includes:

[0078]

[0079] Replace ethyl bromoacetate in step 32 of Example 1 with ethyl 7-bromoheptanoate, and use the same raw materials, reagents and preparation methods as in Example 1 to obtain compound 5, which is a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.70(s,1H),8.13–8.07(m,2H),7.78–7.74(m,1H),7.67–7.55(m,5H),7.33–7.28(m,1H),4.09(t ,J=6.4Hz,2H),1.97(t,J=7.2Hz,2H),1.81–1.70(m,2H),1.58–1.49(m,2H),1.49–1.40(m,2H),1.37–1.28(m,2H).MS(ESI)calculated for C 20 H 21 FN2KO3S + [M+Na] + :found:404.1590.

[0080] Example 6

[0081] The preparation method of 5-(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxypentanamide (compound 6) includes:

[0082]

[0083] In Example 1, the benzonitrile in step 1 was replaced with 4-fluorobenzonitrile, and the ethyl 2-bromoacetate in step 3 was replaced with methyl 5-bromopentanoate. The other required raw materials, reagents and preparation methods were the same as in Example 1, and a white solid compound 6 was obtained. 1 HNMR(400MHz,DMSO-d6)δ10.41(s,1H),8.73(s,1H),8.19–8.11(m,2H),7.80–7.73(m,1H),7.68–7.63(m,1H),7.62–7.54(m ,1H),7.49–7.40(m,2H),7.34–7.27(m,1H),4.10(t,J=6.0Hz,2H),2.05(t,J=7.0Hz,2H),1.81–1.63(m,4H).MS(ESI)[M+H] + :found:372.2.

[0084] Example 7

[0085] The preparation method of 6-(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyhexanoamide (compound 7) includes:

[0086]

[0087] In Example 1, the benzonitrile in step 1 was replaced with 4-fluorobenzonitrile, and the ethyl 2-bromoacetate in step 3 was replaced with methyl 6-bromohexanoate. The other required raw materials, reagents and preparation methods were the same as in Example 1, and a white solid compound 7 was obtained. 1 HNMR(400MHz,DMSO-d6)δ10.40(s,1H),8.71(s,1H),8.20–8.11(m,2H),7.77–7.71(m,1H),7.68–7.61(m,1H),7.60–7.54(m,1H),7.49–7.40(m ,2H),7.34–7.26(m,1H),4.08(t,J=6.4Hz,2H),2.00(t,J=7.2Hz,2H),1.82–1.69(m,2H),1.64–1.52(m,2H),1.51–1.36(m,2H).MS(ESI)[M+H] + :found:386.2.

[0088] Example 8

[0089] The preparation method of 7-(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyheptanamide (compound 8) includes:

[0090]

[0091] In Example 1, benzonitrile in step 1 was replaced with 4-fluorobenzonitrile, and ethyl 2-bromoacetate in step 3 was replaced with ethyl 7-bromoheptanoate. The other required raw materials, reagents and preparation methods were the same as in Example 1, and compound 8, a white solid, was obtained. 1 HNMR(400MHz,DMSO-d6)δ10.37(s,1H),8.68(s,1H),8.20–8.11(m,2H),7.78 –7.72(m,1H),7.66–7.62(m,1H),7.57(t,J=8.0Hz,1H),7.49–7.41(m,2H),7. 34–7.27(m,1H),4.09(t,J=6.4Hz,2H),1.97(t,J=7.2Hz,2H),1.79–1.71(m, 2H),1.58–1.49(m,2H),1.48–1.40(m,2H),1.39–1.28(m,2H).MS(ESI)[M+Na] + :found:422.1485.

[0092] Example 9

[0093] The preparation method of 5-(3-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxypentanamide (compound 9) includes:

[0094]

[0095] In Example 1, benzonitrile in step 1 was replaced with 4-chlorobenzonitrile, and ethyl 2-bromoacetate in step 3 was replaced with methyl 5-bromopentanoate. The other required raw materials, reagents and preparation methods were the same as in Example 1, and compound 9 in white solid form was obtained. 1 HNMR(400MHz,DMSO-d6)δ10.43(s,1H),8.73(s,1H),8.14–8.06(m,2H),7.78–7.72(m,1H),7.71–7.63(m,3H),7.61– 7.54(m,1H),7.36–7.27(m,1H),4.10(t,J=6.2Hz,2H),2.05(t,J=7.0Hz,2H),1.83–1.60(m,4H).MS(m / z)(ESI)[M+H] + Found: 388.1052.

[0096] Example 10

[0097] The preparation method of 6-(3-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyhexanoamide (compound 10) includes:

[0098]

[0099] In Example 1, benzonitrile in step 1 was replaced with 4-chlorobenzonitrile, and ethyl 2-bromoacetate in step 3 was replaced with methyl 6-bromohexanoate. The other required raw materials, reagents and preparation methods were the same as in Example 1, and compound 10 in white solid form was obtained. 1 HNMR(400MHz,DMSO-d6)δ10.38(s,1H),8.71(s,1H),8.14–8.05(m,2H),7.78–7.53(m,5H),7.33–7.26(m,1H),4.0 9(t,J=6.4Hz,2H),1.99(t,J=7.2Hz,2H),1.81–1.71(m,2H),1.63–1.53(m,2H),1.48–1.37(m,2H).MS(ESI)[M+H] + :found:402.2.

[0100] Example 11

[0101] The preparation method of 7-(3-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyheptanamide (compound 11) includes:

[0102]

[0103] In Example 1, benzonitrile in step 1 was replaced with 4-chlorobenzonitrile, and ethyl 2-bromoacetate in step 3 was replaced with ethyl 7-bromoheptanoate. The other required raw materials, reagents and preparation methods were the same as in Example 1, and compound 11 in white solid form was obtained. 1 HNMR(400MHz,DMSO-d6)δ10.36(s,1H),8.69(s,1H),8.23–7.15(m,8H),4.14–3.98( m,2H),1.97(t,J=7.2Hz,2H),1.83–1.68(m,2H),1.61–1.25(m,6H).MS(ESI)[M+Na] + :found:438.1198.

[0104] Example 12

[0105] The preparation method of N-hydroxy-5-(3-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)phenoxy)pentanamide (compound 12) includes:

[0106]

[0107] In Example 1, benzonitrile in step 1 was replaced with 4-methylbenzonitrile, and ethyl 2-bromoacetate in step 3 was replaced with methyl 5-bromopentanoate. The other required raw materials, reagents and preparation methods were the same as in Example 1, and compound 12 in white solid form was obtained. 1 HNMR(400MHz, DMSO-d6)δ10.42(s,1H),8.73(s,1H),8.03–7.95(m,2H),7.75(d,J=7.6Hz,1H),7.68–7.61(m,1H),7.61–7.52(m,1H), 7.41(d,J=7.8Hz,2H),7.33–7.26(m,1H),4.10(t,J=6.0Hz,2H),2.41(s,3H),2.05(t,J=7.0Hz,2H),1.80–1.63(m,4H).MS(ESI)[M+H] + :found:368.3.

[0108] Example 13

[0109] The preparation method of N-hydroxy-6-(3-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)phenoxy)hexamamide (compound 13) includes:

[0110]

[0111] In Example 1, benzonitrile in step 1 was replaced with 4-methylbenzonitrile, and ethyl 2-bromoacetate in step 3 was replaced with methyl 6-bromohexanoate. The other required raw materials, reagents and preparation methods were the same as in Example 1, and compound 13 in white solid form was obtained. 1 HNMR(400MHz,DMSO-d6)δ10.40(s,1H),8.72(s,1H),8.10(d,2H),7.97(d,2H),7.40(d,J=8.0Hz,2H),7.17(d,2H),4.08(t ,J=6.4Hz,2H),2.40(s,3H),2.00(t,J=7.2Hz,2H),1.80–1.69(m,2H),1.63–1.51(m,2H),1.48–1.36(m,2H).MS(ESI)[M+H] + :found:382.2

[0112] Example 14

[0113] The preparation method of N-hydroxy-7-(3-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)phenoxy)heptamide (compound 14) includes:

[0114]

[0115] In Example 1, benzonitrile in step 1 was replaced with 4-methylbenzonitrile, and ethyl 2-bromoacetate in step 3 was replaced with ethyl 7-bromoheptanoate. The other required raw materials, reagents and preparation methods were the same as in Example 1, and compound 14 in white solid form was obtained. 1 HNMR(400MHz,DMSO-d6)δ10.37(s,1H),8.70(s,1H),8.02–7.95(m,2H),7.76–7. 70(m,1H),7.66–7.60(m,1H),7.56(t,J=8.0Hz,1H),7.41(d,J=7.8Hz,2H),7.33– 7.25(m,1H),4.08(t,J=6.4Hz,2H),2.41(s,3H),1.97(t,J=7.2Hz,2H),1.80–1.6 9(m,2H),1.59–1.49(m,2H),1.49–1.39(m,2H),1.39–1.27(m,2H).MS(ESI)[M+H] + :found:396.2.

[0116] Example 15

[0117] The preparation method of N-hydroxy-4-(3-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)butyramide (compound 15) includes:

[0118]

[0119] In Example 1, benzonitrile in step 1 was replaced with 4-methoxybenzonitrile, and ethyl 2-bromoacetate in step 3 was replaced with methyl 4-bromobutyrate. The other required raw materials, reagents and preparation methods were the same as in Example 1, and compound 15 in white solid form was obtained. 1 H NMR(400MHz,DMSO-d6)δ10.46(s,1H),8.75(s,1H),8.08–7.98(m,2H),7.79–7.70(m,1H),7.66–7.53(m,2H),7.35–7.24 (m,1H),7.19–7.09(m,2H),4.10(t,J=6.2Hz,2H),3.86(s,3H),2.18(t,J=7.4Hz,2H),2.04–1.94(m,2H).MS(ESI)[M+H] +:found:370.3.

[0120] Example 16

[0121] The preparation method of N-hydroxy-5-(3-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)pentanamide (compound 16) includes:

[0122]

[0123] In Example 1, benzonitrile in step 1 was replaced with 4-methoxybenzonitrile, and ethyl 2-bromoacetate in step 3 was replaced with methyl 5-bromopentanoate. The other required raw materials, reagents and preparation methods were the same as in Example 1, and compound 16 in white solid form was obtained. 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),1.7 0(p,J=7.0Hz,2H),1.53(p,J=7.4Hz,2H),1.39(p,J=8.6Hz,2H).MS(ESI)[M+H] + :found:384.2.

[0124] Example 17

[0125] The preparation method of N-hydroxy-6-(3-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)hexamamide (compound 17) includes:

[0126]

[0127] In Example 1, benzonitrile in step 1 was replaced with 4-methoxybenzonitrile, and ethyl 2-bromoacetate in step 3 was replaced with methyl 6-bromohexanoate. The other required raw materials, reagents and preparation methods were the same as in Example 1, and compound 17 in white solid form was obtained. 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=7.3H z,2H),1.49(p,2H),1.40(p,J=7.8Hz,2H),1.28(p,J=8.0,7.5Hz,2H).MS(ESI)[M+H] + :found:398.2.

[0128] Example 18

[0129] The preparation method of N-hydroxy-7-(3-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)heptamide (compound 18) includes:

[0130]

[0131] In Example 1, benzonitrile in step 1 was replaced with 4-methoxybenzonitrile, and ethyl 2-bromoacetate in step 3 was replaced with ethyl 7-bromoheptanoate. The other required raw materials, reagents and preparation methods were the same as in Example 1, and compound 18 in white solid form was obtained. 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.68(s,1H),8.08–8.02(m,2H),7.78– 7.71(m,1H),7.66–7.61(m,1H),7.61–7.52(m,1H),7.33–7.27(m,1H),7.17– 7.10(m,2H),4.09(t,2H),3.86(s,3H),1.97(t,J=7.4Hz,2H),1.81–1.69(m, 2H),1.57–1.50(m,2H),1.50–1.39(m,2H),1.38–1.28(m,2H).MS(ESI)[M+H] + :found:412.3.

[0132] Example 19

[0133] The preparation method of N-hydroxy-2-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)acetamide (compound 19) includes:

[0134]

[0135] Replace 3-hydroxybenzoic acid in step 2 of Example 1 with 4-hydroxybenzoic acid. The other required raw materials, reagents and preparation methods are the same as in Example 1, and a white solid compound 19 is obtained. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),9.09(s,1H),8.18–8.13(m,2H),8.11–8. 07(m,2H),7.61(d,J=6.4Hz,3H),7.26–7.19(m,2H),4.64(s,2H).MS(ESI)[M+H] + :found:312.1.

[0136] Example 20

[0137] The preparation method of N-hydroxy-4-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)butyramide (compound 20) includes:

[0138]

[0139] Replace ethyl 2-bromoacetate in step 3 of Example 19 with methyl 4-bromobutyrate. The other required raw materials, reagents and preparation methods are the same as in Example 19, to obtain compound 20, which is a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.47(s,1H),8.77(s,1H),8.23–7.99(m,4H),7.61(d,J=6.4Hz,3H),7. 27–7.07(m,2H),4.10(t,J=6.2Hz,2H),2.17(t,J=7.4Hz,2H),2.04–1.92(m,2H).MS(ESI)[M+H] + :found:340.2.

[0140] Example 21

[0141] The preparation method of N-hydroxy-5-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)pentanamide (compound 21) includes:

[0142]

[0143] In step 3 of Example 19, ethyl 2-bromoacetate was replaced with methyl 5-bromopentanoate. The other required raw materials, reagents and preparation methods were the same as in Example 19, resulting in compound 21, which was a white solid. 1HNMR(400MHz,DMSO-d6)δ10.43(s,1H),8.75(s,1H),8.21–8.03(m,4H),7.72–7.49(m,3H),7.2 8–7.12(m,2H),4.11(t,J=6.2Hz,2H),2.04(t,J=7.2Hz,2H),1.82–1.62(m,4H).MS(ESI)[M+H] + :found:354.1.

[0144] Example 22

[0145] The preparation method of N-hydroxy-6-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)hexamamide (compound 22) includes:

[0146]

[0147] In Example 19, ethyl 2-bromoacetate in step 3 was replaced with ethyl 6-bromohexanoate. The other required raw materials, reagents and preparation methods were the same as in Example 19, resulting in compound 22, a white solid. 1 H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.73(s,1H),8.22–7.99(m,4H),7.70–7.47(m,3H),7.24–7.05(m,2H),4.0 9(t,J=6.4Hz,2H),1.99(t,J=7.2Hz,2H),1.82–1.69(m,2H),1.63–1.51(m,2H),1.47–1.35(m,2H).MS(ESI)[M+H] + :found:368.1.

[0148] Example 23

[0149] The preparation method of N-hydroxy-7-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)heptamide (compound 23) includes:

[0150]

[0151] In Example 19, ethyl 2-bromoacetate in step 3 was replaced with ethyl 7-bromoheptanoate. The other required raw materials, reagents and preparation methods were the same as in Example 19, resulting in compound 23, a white solid. 1H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.71(s,1H),8.20–8.04(m,4H),7.70–7.53(m,3H),7.25–7.08(m,2H),4.09(t,J=6. 4Hz,2H),1.96(t,J=7.2Hz,2H),1.80–1.68(m,2H),1.57–1.48(m,2H),1.47–1.37(m,2H),1.36–1.26(m,2H).MS(ESI)[M+H] + :found:382.1.

[0152] Example 24

[0153] The preparation method of 5-(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxypentanamide (compound 24) includes:

[0154]

[0155] In Example 19, benzonitrile in step 1 was replaced with 4-fluorobenzonitrile, and ethyl 2-bromoacetate in step 3 was replaced with methyl 5-bromopentanoate. The other required raw materials, reagents and preparation methods were the same as in Example 19, and compound 24 in white solid form was obtained. 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.73(s,1H),8.19–8.02(m,4H),7.44(t,J=8.8Hz,2H),7. 26–7.11(m,2H),4.11(t,J=6.2Hz,2H),2.04(t,J=7.2Hz,2H),1.85–1.59(m,4H).MS(ESI)[M+H] + :found:372.11.

[0156] Example 25

[0157] The preparation method of 6-(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyhexanoamide (compound 25) includes:

[0158]

[0159] In Example 19, benzonitrile in step 1 was replaced with 4-fluorobenzonitrile, and ethyl 2-bromoacetate in step 3 was replaced with ethyl 6-bromohexanoate. The other required raw materials, reagents and preparation methods were the same as in Example 19, and compound 25 in white solid form was obtained. 1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.71(s,1H),8.20–8.02(m,4H),7.53–7.35(m,2H),7.28–7.06(m,2H),4.0 9(t,J=6.4Hz,2H),1.99(t,J=7.2Hz,2H),1.80–1.70(m,2H),1.63–1.51(m,2H),1.46–1.34(m,2H).MS(ESI)[M+H] + :found:386.2

[0160] Example 26

[0161] The preparation method of 7-(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyheptamide (compound 26) includes:

[0162]

[0163] In Example 19, benzonitrile in step 1 was replaced with 4-fluorobenzonitrile, and ethyl 2-bromoacetate in step 3 was replaced with ethyl 7-bromoheptanoate. The other required raw materials, reagents and preparation methods were the same as in Example 19, resulting in compound 26, 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)[M+H] + :found:400.3.

[0164] Example 27

[0165] The preparation method of 5-(4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxypentanamide (compound 27) includes:

[0166]

[0167] In Example 19, benzonitrile in step 1 was replaced with 4-chlorobenzonitrile, and ethyl 2-bromoacetate in step 3 was replaced with methyl 5-bromopentanoate. The other required raw materials, reagents and preparation methods were the same as in Example 19, and compound 27 in white solid form was obtained. 1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.73(s,1H),8.22–7.99(m,4H),7.73–7.58(m,2H),7.2 9–7.03(m,2H),4.11(t,J=6.2Hz,2H),2.05(t,J=7.0Hz,2H),1.83–1.57(m,4H).MS(ESI)[M+H] + :found:388.1

[0168] Example 28

[0169] The preparation method of 6-(4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyhexanoamide (compound 28) includes:

[0170]

[0171] In Example 19, benzonitrile in step 1 was replaced with 4-chlorobenzonitrile, and ethyl 2-bromoacetate in step 3 was replaced with methyl 6-bromohexanoate. The other required raw materials, reagents and preparation methods were the same as in Example 19, and compound 28 in white solid form was obtained. 1 H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.71(s,1H),8.12–8.02(m,4H),7.72–7.59(m,2H),7.22–7.10(m,2H),4.0 8(t,J=6.4Hz,2H),2.00(t,J=7.2Hz,2H),1.81–1.68(m,2H),1.62–1.52(m,2H),1.48–1.36(m,2H).MS(ESI)[M+H] + :found:424.1.

[0172] Example 29

[0173] The preparation method of 7-(4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyheptamide (compound 29) includes:

[0174]

[0175] In Example 19, benzonitrile in step 1 was replaced with 4-chlorobenzonitrile, and ethyl 2-bromoacetate in step 3 was replaced with ethyl 7-bromoheptanoate. The other required raw materials, reagents and preparation methods were the same as in Example 19, resulting in compound 29, a white solid. 1H 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)[M+H] + :found:454.1.

[0176] Example 30

[0177] The preparation method of N-hydroxy-5-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)phenoxy)pentanamide (compound 30) includes:

[0178]

[0179] In Example 19, benzonitrile in step 1 was replaced with 4-methylbenzonitrile, and ethyl 2-bromoacetate in step 3 was replaced with methyl 5-bromopentanoate. The other required raw materials, reagents and preparation methods were the same as in Example 19, and compound 30 in white solid form was obtained. 1 HNMR (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=6.5H z,2H),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)[M+H] + :found:368.2.

[0180] Example 31

[0181] The preparation method of N-hydroxy-6-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)phenoxy)hexanoamide (compound 31) includes:

[0182]

[0183] In Example 19, benzonitrile in step 1 was replaced with 4-methylbenzonitrile, and ethyl 2-bromoacetate in step 3 was replaced with methyl 6-bromohexanoate. The other required raw materials, reagents and preparation methods were the same as in Example 19, and compound 31 in white solid form was obtained. 1 HNMR(400MHz,DMSO-d6)δ10.39(s,1H),8.70(s,1H),8.04–7.94(m,2H),7.77 –7.69(m,1H),7.67–7.60(m,1H),7.57(t,J=8.0Hz,1H),7.41(d,J=8.0Hz,2H) ,7.33–7.24(m,1H),4.09(t,J=6.4Hz,2H),2.41(s,3H),2.00(t,J=7.2Hz,2H ),1.82–1.70(m,2H),1.65–1.52(m,2H),1.49–1.36(m,2H).HRMS(ESI)[M+Na] + :found:404.1585.

[0184] Example 32

[0185] The preparation method of N-hydroxy-7-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)phenoxy)heptamide (compound 32) includes:

[0186]

[0187] In Example 19, benzonitrile in step 1 was replaced with 4-methylbenzonitrile, and ethyl 2-bromoacetate in step 3 was replaced with ethyl 7-bromoheptanoate. The other required raw materials, reagents and preparation methods were the same as in Example 19, and compound 32 in white solid form was obtained. 1 HNMR(400MHz, DMSO-d6)δ10.37(s,1H),8.70(s,1H),8.19–8.02(m,2H),8.04–7.82(m,2H),7.40(d,J=8.0Hz,2H),7.23–7.10(m,2H),4.07(t, J=6.4Hz,2H),2.40(s,3H),1.97(t,J=7.4Hz,2H),1.80–1.66(m,2H),1.60–1.48(m,2H),1.47–1.36(m,2H),1.37–1.25(m,2H).MS(ESI)[M+Na] + :found:418.1744.

[0188] Example 33

[0189] In vitro HDACs kinase inhibitory activity

[0190] Prepare a 10 mM stock solution of the test compound using DMSO, ensuring complete dissolution. Serially dilute the stock solution with buffer to obtain a series of concentrations. Add one of the following to a 96-well plate: Ac-Gly-Ala-Lys-AMC, recombinant human histone deacetylases (HDAC1, HDAC2, HDAC3, and HDAC6), and then add different concentrations of the test compound solution. Make up to 100 μL per well with reaction buffer to ensure a consistent reaction system. Incubate the 96-well plate on a shaker at low speed for 15 minutes to ensure complete hydrolysis of the fluorescent substrate. Use a microplate reader with excitation wavelength set to 360 nm and emission wavelength to 460 nm to measure and record the fluorescence intensity in each well. Vorinostat (SAHA) was used as a control. Calculate the inhibition rate using the following formula: Inhibition rate (%) = (Positive control fluorescence value - Compound fluorescence value) / (Positive control fluorescence value - Blank group fluorescence value) × 100%. The experimental data were fitted with dose-response curves using nonlinear regression analysis. Based on the fitted curves, the IC50 values ​​of the test compounds for HDAC1, HDAC2, HDAC3, and HDAC6 were calculated. 50 Value (i.e., the concentration of the compound required to inhibit 50% of enzyme activity).

[0191] Table 1 shows that compounds 3 and 20 exhibited superior inhibitory activity against HDAC6 kinase compared to SAHA. "++++" indicates IC50. 50 Values ​​less than 10 nM or inhibition rates of 80-100% indicate IC50. "++" indicates IC50. 50 Values ​​of 10-100 nM or inhibition rates of 60-80%, “++” indicates IC50 value. 50 Values ​​of 100-1000 nM or inhibition rates of 40-60%, with "+" indicating IC50. 50 Values ​​greater than 1000 nM or inhibition rates less than 40%.

[0192] Table 1. Inhibition of HDAC6 kinase by compounds 1-32 (IC50) 50 (nM))

[0193]

[0194]

[0195] Table 2 HDAC isoenzyme inhibitory activity of the compounds

[0196]

[0197] "++++" indicates IC 50 Values ​​less than 10 nM or inhibition rates of 80-100% indicate IC50. "++" indicates IC50. 50Values ​​of 10-100 nM or inhibition rates of 60-80%, “++” indicates IC50 value. 50 Values ​​of 100-1000 nM or inhibition rates of 40-60%, with "+" indicating IC50. 50 Values ​​greater than 1000 nM or inhibition rates less than 40%.

[0198] The results in Table 2 show that compounds 8 and 31 both exhibit some selectivity for HDAC6.

[0199] Example 35

[0200] Carrageenan-induced inflammatory pain model experiment

[0201] λ-carrageenan is a chemical substance that stimulates inflammation by releasing pro-inflammatory factors, including prostaglandins, leukotrienes, histamine, serotonin, bradykinin, and TNF-α. In mice, a paw injection of 20 μL of a 1% carrageenan solution induced a local inflammatory response (peaking at 3 hours and subsiding within 24–72 hours), such as tissue swelling, hyperemia, and hyperalgesia. Three hours after the carrageenan injection, the mechanical withdrawal threshold in mice was significantly lower than baseline, indicating successful induction of inflammatory pain. Figure 1 As shown, all compound dosage groups (15 mg / kg, 30 mg / kg, and 60 mg / kg) reduced carrageenan-induced inflammatory pain in a dose-dependent manner. Compound 8 (15 mg / kg, 30 mg / kg, and 60 mg / kg) showed analgesic inhibition rates of 24.24%, 43.71%, and 54.66% in inflammatory pain, respectively, with a median effective dose (ED50) of 45.76 mg / kg. Compound 31 (150 mg / kg, 300 mg / kg, and 60 mg / kg) showed analgesic inhibition rates of 24.81%, 45.84%, and 64.89% in inflammatory pain, respectively, with a median effective dose (ED50) of 35.66 mg / kg. Figure 1 ).

[0202] Example 36

[0203] Paclitaxel-induced neuropathic pain experimental model

[0204] Female ICR mice, weighing 22-30g, were randomly divided into a blank control group and various compound dosage groups (15mg / kg, 30mg / kg, and 60mg / kg), with six mice in each group. Mice were intraperitoneally injected with paclitaxel 2mg / kg (0.1mL / 10g) once daily for 5 consecutive days (days 1, 2, 3, 4, and 5, 14:00-16:00). Baseline mechanical thresholds were assessed the day before inducing neuropathic pain. Mechanosensitive behavior in mice was tested using the ZH-ZKL plantar tingling system and the ZHPAN801 automated pain analysis system. Three tests were performed on the right hind paw of each mouse to obtain baseline values. Each dosage group received a 0.01mg / kg solution prepared with physiological saline subcutaneously. The blank control group received an equal volume of physiological saline subcutaneously. Subsequently, the mechanical withdrawal threshold of mice was measured at 5, 15, 30, 45, and 60 minutes after drug administration. All compound dosage groups (15 mg / kg, 30 mg / kg, and 60 mg / kg) reversed paclitaxel-induced mechanical atopic pain in a dose-dependent manner. The analgesic inhibition rates of compound 8 at doses of 15 mg / kg, 30 mg / kg, and 60 mg / kg were 30.67%, 51.24%, and 64.11%, respectively, with an ED50% (half-maximal effective dose). 50 The concentration was 31.62 mg / kg; the analgesic inhibition rates of compound 31 at doses of 15 mg / kg, 30 mg / kg, and 60 mg / kg were 14.28%, 36.50%, and 73.21%, respectively, with an ED50% (half-maximal effective dose). 50 The analgesic inhibition rate of ACY-1215 at doses of 15 mg / kg, 30 mg / kg, and 60 mg / kg was 28.87%, 52.70%, and 60.43%, respectively, with an ED50% at the half-maximal effective dose. 50 33.58 mg / kg Figure 2 The analgesic effects of each compound were expressed as the percentage of maximum possible effect (%MPE): %MPE = (MWTm - MWTb) / (MWTn - MWTb) × 100%; where MWTm represents the maximum mechanical withdrawal threshold of mice after drug treatment, MWTb refers to the baseline threshold after 5 consecutive days of intraperitoneal injection of paclitaxel (baseline value after modeling), and MWTn refers to the baseline threshold of mice before receiving paclitaxel (baseline value before modeling); experimental data are expressed as mean ± standard error, and the obtained data were analyzed using GraphPad Prism 7 software.

[0205] In summary, the preferred compounds 8 and 31 both exhibited excellent analgesic activity in both carrageenan-induced inflammatory pain and paclitaxel-induced neuropathic pain models.

[0206] Although the invention has been described with reference to illustrative embodiments, those skilled in the art will understand that various other changes, omissions, and / or additions can be made without departing from the spirit and scope of the invention, and that elements of the described embodiments can be substituted with substantially equivalents. Furthermore, many modifications can be made without departing from the scope of the invention to adapt particular situations or materials to the teachings of the invention. Therefore, this invention is not intended to be limited to the specific embodiments disclosed for carrying out the invention, but rather is intended to encompass all embodiments falling within the scope of the appended claims.

Claims

1. A class of diphenyloxadiazole compounds or their salts, characterized in that, The diphenyloxadiazole compounds have the structure shown in formula (Ⅰ). R1 is selected independently from at least one of hydrogen, halogen, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, aryl, heteroaryl and heterocyclic, and n is any integer from 1 to 7.

2. The diphenyloxadiazole compound or its salt according to claim 1, characterized in that: R1 is selected from hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy; More preferably, R1 is hydrogen; More preferably, R1 is a halogen; even more preferably, the halogen is fluorine or chlorine; More preferably, R1 is a C1-6 alkyl group, and R1 is even more preferably methyl. More preferably, R1 is a C1-6 alkoxy group, and R1 is even more preferably a methoxy group.

3. The diphenyloxadiazole or its salt according to claim 1, characterized in that: The bisphenyloxadiazole compounds include N-hydroxy-2-(3-(3-phenyl-1,2,4-oxadiazole-5-yl)phenoxy)acetamide, N-hydroxy-4-(3-(3-phenyl-1,2,4-oxadiazole-5-yl)phenoxy)butyramide, N-hydroxy-5-(3-(3-phenyl-1,2,4-oxadiazole-5-yl)phenoxy)pentanamide, N-hydroxy-6-(3-(3-phenyl-1,2,4-oxadiazole-5-yl)phenoxy)hexamamide, N-hydroxy-7-(3-(3-phenyl-1,2,4-oxadiazole-5-yl)phenoxy)heptanamide, and 5-(3-(3-(4-fluorophenyl)-1,2,4-oxadiazole-5-yl)phenoxy)-N-hydroxypentanamide. Amides, 6-(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyhexamamide, 7-(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyheptamide, 5-(3-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxypentanamide, 6-(3-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyhexamamide, 7-(3-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyheptamide, N-hydroxy-5-(3-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyheptamide diazol-5-yl)phenoxy)pentanamide, N-hydroxy-6-(3-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)phenoxy)hexamamide, N-hydroxy-7-(3-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)phenoxy)heptanamide, N-hydroxy-4-(3-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)butanamide, N-hydroxy-5-(3-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)pentanamide, N-hydroxy-6-(3-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)hexamamide, N-hydroxy-7-(3-) (3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)heptamide, N-hydroxy-2-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)acetamide, N-hydroxy-4-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)butyramide, N-hydroxy-5-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)pentanamide, N-hydroxy-6-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)hexamamide, N-hydroxy-7-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)heptamide, 5-(4-(3-(4-fluorophenyl)-1,2,4-Oxadiazol-5-yl)phenoxy)-N-hydroxypentanamide, 6-(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyhexamamide, 7-(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyheptanamide, 5-(4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxypentanamide, 6-(4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)phenoxy The following are considered as an adjunct to N-hydroxyhexamamide: 7-(4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-hydroxyheptanamide, N-hydroxy-5-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)phenoxy)pentanamide, N-hydroxy-6-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)phenoxy)hexamamide, and N-hydroxy-7-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)phenoxy)heptanamide.

4. The diphenyloxadiazole compound or its salt according to any one of claims 1-3, characterized in that: The salts mentioned include any one of hydrochloride, p-toluenesulfonate, sulfate, succinate, maleate, fumarate, acetate, phosphate, citrate, methanesulfonate, and sodium salt.

5. A method for preparing a class of bisphenyloxadiazole compounds, characterized in that, include: S1. Using the compound shown in formula (II) as the starting material, react with hydroxylamine hydrochloride in a first reaction system at 80°C to form the first intermediate shown in formula (III), wherein the first reaction system contains anhydrous sodium carbonate, ethanol and water; S2. The first intermediate is reacted in a second reaction system with substrate (IV) to give a second intermediate as shown in formula (V), wherein the second reaction system contains EDCI, HOBT, triethylamine and DMF; S3. React the second intermediate and the brominated alkyl ester compound shown in formula (VI) in a third reaction system to obtain the third intermediate shown in formula (VII), wherein the third reaction system includes potassium carbonate, potassium iodide and N,N-dimethylformamide or acetonitrile; S4. React the third intermediate in a fourth reaction system to prepare a diphenyloxadiazole compound of formula (I), wherein the fourth reaction system includes a methanol solution of hydroxylamine; R1 is selected independently from at least one of hydrogen, halogen, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, aryl, heteroaryl and heterocyclic, n is any integer from 1 to 7, n1 is 1, 3, 4, 5, 6 or 7, and n2 is 0 or 1.

6. A pharmaceutical composition, characterized in that, include: A therapeutically effective amount of any one of claims 1-4, or a pharmaceutically acceptable salt thereof; And one or more pharmaceutically acceptable carriers.

7. Use of any one of the diphenyloxadiazole compounds of claims 1-4 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 6, in the preparation of an HDAC6 kinase inhibitor.

8. Use of any one of the diphenyloxadiazole compounds of claims 1-4 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 6, in the preparation of a medicament for the prevention and / or treatment of pain.

9. The use according to claim 8, characterized in that: The pain includes moderate to severe pain; the pain is acute or chronic pain; the pain includes any one of neuralgia, inflammatory pain, nociceptive pain, cancer pain, hyperalgesia, and visceral pain.

10. Use of any one of the diphenyloxadiazole compounds of claims 1-4 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 6, in the preparation of a targeted medicament for the prevention and / or treatment of neuropathic pain and inflammatory pain.

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