An HDAC6 inhibitor and its preparation method and application

Abstract

The present invention discloses a compound represented by formula (I), a preparation method and application thereof, or a pharmaceutically acceptable salt, stereoisomer, isotope-labeled substance, solvate, polymorph or prodrug thereof, which can effectively inhibit the catalytic activity of histone deacetylase 6, has a high selectivity gap for other subtypes, and has anti-proliferative ability against tumor cells. It can be used to prevent and / or treat cancer, has good effects, and has low toxic side effects.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to an HDAC6 inhibitor and a preparation method and application thereof. Background Art

[0002] The statements herein merely provide background information related to the present invention and do not necessarily constitute prior art.

[0003] Epigenetics refers to heritable variation independent of gene sequence. Post-translational modification of histones is a key area of ​​epigenetics. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) jointly regulate the degree of histone acetylation, and an imbalance in this mechanism is believed to be a contributing factor to a range of diseases, including cancer. Based on homology analysis with yeast proteins, the 18 mammalian HDAC family members are divided into four classes: Class I (HDACs 1-3 and 8), Class II (HDACs 4-7, 9, and 10), and Class IV (HDAC11). These three classes of histone deacetylases are zinc-dependent, while Class III HDACs (Sirtuins 1-7) rely on NAD+ for catalytic activity.

[0004] HDAC6 is a unique member of the HDAC family, possessing two independent catalytic domains. As a cytoplasmic protein, HDAC6 primarily influences cellular activity by interacting with various non-histone substrates, including α-tubulin, heat shock protein 90, and cortactin. Aberrant HDAC6 expression has been linked to various diseases, including cancer. HDAC6 promotes tumor cell invasion by reducing the acetylation of α-tubulin and cortactin. The interaction between HDAC6 and heat shock protein 90 is implicated in the normal function of various client proteins, including promoting the efficient degradation of misfolded proteins. HDAC6 also binds to dynein, transporting ubiquitinated proteins to vascular organizing centers for degradation via autophagy. HDAC6 has been shown to enhance the efficacy of other anti-cancer drugs by reducing drug resistance, enhancing immune signaling, and restoring apoptosis. HDAC6 inhibitors have been shown to cause mitotic arrest, likely due to impaired catalytic activity of HDAC6, which reduces microtubule dynamics and affects multiple mitotic processes, including centrosome localization. Selective HDAC6 inhibitors have anti-tumor activity.

[0005] Existing HDAC inhibitors are often HDAC pan-inhibitors with certain toxic side effects, such as cardiotoxicity and gastrointestinal adverse reactions. Therefore, how to improve the selectivity of HDAC inhibitors is an urgent problem to be solved. Summary of the Invention

[0006] In view of the shortcomings of the prior art, the purpose of the embodiments of the present invention is to provide an HDAC6 inhibitor and a preparation method and application thereof to solve at least one of the above problems.

[0007] The first aspect of the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, isotope-labeled substance, solvate, polymorph or prodrug thereof,

[0008]

[0009] Wherein, the quinoline in formula (I) is substituted at the 2-position, 3-position or 8-position;

[0010] In formula (I), R1 is one of the structural fragments of the following formula:

[0011] R@

[0012] R2 is a structural fragment of the following formula:

[0013] R2

[0014] In some embodiments, the compound is represented by formula (II):

[0015]

[0016] In some embodiments, the compound is represented by formula (III):

[0017]

[0018] R1 in the formula (III) is a structural fragment of the following formula:

[0019] R1

[0020] In some embodiments, the compound is one or more of the following compounds P1-P30:

[0021] In some embodiments, the compound is one or more of the above compounds P1, P5, P17, P21, and P30. In some embodiments, the compound is represented by formula (IV):

[0022]

[0023] The second aspect of the present invention provides a method for preparing the above compound.

[0024] In some embodiments, the preparation method of the compound of formula (II) comprises the following steps:

[0025] 8-Aminoquinoline and substituted phenyl formaldehyde / cyclohexane formaldehyde are used as reaction raw materials, DCM and AcOH are added for dissolution, NaBH(OAc)3 is added, and the reaction is carried out at room temperature to obtain intermediate 3. Intermediate 3 and a bromoaromatic ester containing R2 are used as reaction raw materials, K2CO3 and KI are added, ACN is dissolved, and the reaction is carried out at room temperature. Intermediate 4 is separated and purified. NH2OK methanol solution is added to intermediate 4, and the reaction is carried out at room temperature to obtain the compound of formula (II).

[0026] In some embodiments, the preparation method of the compound of formula (III) comprises the following steps:

[0027] (1,3-Dioxolane-2-yl)methyltriphenylphosphonium bromide is dissolved in tetrahydrofuran, potassium tert-butoxide is added, raw material 5 dissolved in THF is added dropwise, and the reaction is carried out at room temperature. HCl is added dropwise to hydrolyze the acetal to obtain intermediate 7; intermediate 7 is dissolved in methanol, NaBH4 is added, and the reaction is carried out under ice bath conditions to obtain intermediate 8; intermediate 8 is dissolved in ultra-dry tetrahydrofuran, phosphorus tribromide is added, and the reaction is carried out under ice bath conditions to obtain intermediate 9; intermediate 9 and R1-substituted 8-aminoquinoline, K2CO3 and KI are dissolved in ACN, and the reaction is carried out at room temperature to obtain intermediate 10; intermediate 10 is dissolved in NH2OK methanol solution and the reaction is carried out at room temperature to obtain a compound of formula (III).

[0028] In some embodiments, the preparation method of the compound of formula (IV) comprises the following steps:

[0029] 2-Aminoquinoline / 3-aminoquinoline and benzaldehyde were used as reaction raw materials, dissolved in DCM and AcOH, and NaBH(OAc)3 was added, and the reaction was carried out at room temperature to obtain intermediate 13; intermediate 13, methyl 4-bromomethylbenzoate, K2CO3 and KI were dissolved in ACN and reacted at room temperature to obtain intermediate 14; intermediate 14 was added with NH2OK methanol solution and reacted at room temperature to obtain the compound of formula (IV).

[0030] The third aspect of the present invention provides a pharmaceutical composition comprising the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, isotope label, solvate, polymorph, tautomer, metabolite or prodrug and a pharmaceutically acceptable carrier or excipient.

[0031] In some embodiments, the carrier is solid or liquid.

[0032] In some embodiments, the pharmaceutical composition is an oral preparation or a parenteral preparation.

[0033] In some embodiments, the pharmaceutical composition is a tablet, pill, capsule, or injection.

[0034] The fourth aspect of the present invention provides the use of the above-mentioned compound and its pharmaceutically acceptable salts, stereoisomers, isotope-labeled substances, solvates, polymorphs or prodrugs in the preparation of histone deacetylase (HDAC) inhibitors.

[0035] In some embodiments, the HDAC is histone deacetylase 6 (HDAC6).

[0036] In some embodiments, the application is application in the preparation of a drug for treating a disease associated with overexpression of the HDAC6 enzyme.

[0037] In some embodiments, the application is for preparing a drug for treating cancer caused by overexpression of the HDAC6 enzyme, wherein the disease is cancer.

[0038] One or more technical solutions provided in the embodiments of the present invention have at least the following technical effects or advantages:

[0039] 1. The compounds provided by the present invention solve the problem that the HDAC pan-inhibitors in the prior art have certain toxic side effects, and can effectively inhibit the activity of histone deacetylase 6, and have an IC of HDAC6. 50 It is 11.49nM, and has poor inhibitory ability against other HDACs, has good subtype selectivity, can significantly inhibit the proliferation of solid tumor cells, has anti-proliferative ability against tumor cells, and can be used to prevent and / or treat cancer.

[0040] 2. The preparation method provided by the present invention is simple and efficient, and the reagents and raw materials used are low in cost and low in toxicity, which is conducive to large-scale industrial production. DETAILED DESCRIPTION

[0041] As described herein, the term "treatment" refers to the possibility of recovering, alleviating, reducing development or suppressing the progress of a disease or disorder or one or more symptoms thereof. In some embodiments, treatment can be administered after one or more symptoms have developed, i.e., therapeutic treatment (therapeutic treatment). In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to susceptible individuals (e.g., according to symptom history and / or according to genetic factors or other predisposing factors) before the onset of symptoms, i.e., prophylactic treatment (prophylactic treatment). Treatment can also be continued after symptoms subside, for example, to prevent or delay its recurrence.

[0042] As described herein, the term "pharmaceutical composition" is generally safe, non-toxic and biologically desirable. The pharmaceutically acceptable carriers or excipients described in the present invention are non-toxic and safe, and their combination with the compounds described in the present invention is also non-toxic and safe.

[0043] The pharmaceutically acceptable carriers and excipients described herein are generally well known to those skilled in the art, or can be determined by those skilled in the art based on actual circumstances. Examples of suitable carriers and excipients include glucose, water, glycerol, ethanol, propylene glycol, corn starch, gelatin, lactose, sucrose, alginic acid, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, croscarmellose sodium, and sodium starch glycolate; polysorbate 80, polyethylene glycol 300, polyethylene glycol 400 cyclodextrin, or their derivatives, such as (2-hydroxypropyl)-cyclodextrin and (2-hydroxyethyl)-cyclodextrin, also known as HPCD, pegylated sesame oil, poloxamers (such as poloxamer 407 or 188); hydrophilic carriers, hydrophobic carriers, or combinations thereof. Hydrophobic carriers include, for example, fat emulsions, lipids, pegylated phospholipids, biocompatible polymers, lipid spheres, liposomes, vesicles, polymer matrices, particles, and the like. Furthermore, those skilled in the art will understand that diluents are included within the terms carrier and excipient.

[0044] The pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral administration, spray inhalation, rectal administration, nasal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or infusion, or by means of an explanted reservoir, wherein oral, intramuscular, intraperitoneal or intravenous administration is preferred. The pharmaceutical dosage form can be a liquid dosage form or a solid dosage form. The liquid dosage form can be a true solution, a colloid, a microgranular dosage form, an emulsion dosage form, or a mixed dosage form. Other dosage forms include tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, freeze-dried powder injections, inclusion compounds, implants, patches, liniments, etc.

[0045] As described in the background, HDAC inhibitors are relatively understudied, with no marketed drugs. Furthermore, existing HDAC inhibitors are often pan-inhibitors, often associated with toxic side effects. To address these technical challenges, the present invention proposes an HDAC6 inhibitor, its preparation method, and its use. The compounds of the present invention effectively inhibit the catalytic activity of histone deacetylase 6, exhibit high selectivity against other isoforms, and exhibit anti-proliferative properties against tumor cells, making them useful for the prevention and / or treatment of cancer.

[0046] The present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, isotope-labeled substance, solvate, polymorph or prodrug thereof,

[0047]

[0048] Wherein, the quinoline in formula (I) is substituted at the 2-position, 3-position or 8-position; and R1 in formula (I) is one of the structural fragments of the following formula:

[0049] R@

[0050] In formula (I), R2 is one of the structural fragments of the following formula:

[0051] R2

[0052] The second aspect of the present invention provides a method for preparing the above-mentioned compound. The inventors have found through research that the compounds of the present invention have different structures and substituents, and the preparation methods are divided into three routes according to different target products, as follows:

[0053] 1. Reaction route 1:

[0054]

[0055] Wherein, R1 is one of the following structures,

[0056] RI

[0057] R2 is one of the following structures,

[0058] R2

[0059] The preparation method of the compound of formula (II) comprises the following steps:

[0060] The corresponding formaldehyde represented by R1 in the structure of Raw Material 1 and Intermediate 3 (Raw Material 2) was used as a reaction raw material, dissolved in DCM and AcOH, and then NaBH(OAc)3 was added. The reaction was allowed to react at room temperature, and then separated and purified to obtain Intermediate 3. The corresponding bromoaryl ester represented by R2 in the structure of Intermediate 3 and Intermediate 4 was used as a reaction raw material, and K2CO3 and KI were added. The solution was dissolved in ACN, and the reaction was allowed to react at room temperature, and then separated and purified to obtain Intermediate 4. NH2OK methanol solution was added to Intermediate 4, and the reaction was allowed to react at room temperature. The pH was adjusted to 6-7 to precipitate a solid, which was separated, purified, and dried in vacuo to obtain the compound of Formula (II), i.e., the target compound represented by Formula A in the reaction scheme.

[0061] More specifically, they include:

[0062] 8-Aminoquinoline and substituted phenyl formaldehyde / cyclohexane formaldehyde were placed in a 100 mL eggplant-shaped reaction flask. An appropriate amount of dichloromethane was added to dissolve the mixture. A catalytic amount of glacial acetic acid was added as a catalyst. After stirring at room temperature for 0.5 h, sodium triacetoxyborohydride was added portionwise and the reaction continued at room temperature for 1-2 h. The reaction progress was monitored by TLC. The solvent was removed by rotary evaporation, the mixture was dissolved in water, the pH was adjusted to 10 with solid sodium hydroxide pellets, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated brine, dried over anhydrous magnesium sulfate for 30 min, filtered, and the solvent removed from the filtrate by vacuum evaporation. Column chromatography was performed to purify the product with 90% petroleum ether (10% ethyl acetate) to obtain Intermediate 3. Intermediate 3 was placed in an eggplant-shaped reaction flask, the bromide, anhydrous potassium carbonate, and potassium iodide were added, dissolved in an appropriate amount of acetonitrile, and the mixture was allowed to react at room temperature overnight. The reaction progress was monitored by TLC. The solvent was removed by rotary evaporation, dissolved in water, and extracted three times with dichloromethane. The combined organic phases were washed twice with saturated brine, dried over anhydrous magnesium sulfate for 30 minutes, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure. Column chromatography purification: 90% petroleum ether (10% ethyl acetate) was used to separate impurities and subsequently flush out the product to obtain Intermediate 4. Intermediate 4 was placed in an eggplant-shaped reaction flask, and NH2OK methanol solution was added. The reaction was stirred at room temperature for 1 hour. TLC was used to monitor the reaction progress. The solvent was evaporated under reduced pressure, and an appropriate amount of water was added to dissolve the product. 2M HCl was added to adjust the pH to 6-7. A solid precipitated and adhered to the bottom of the flask. The supernatant was discarded, and the solid in the flask was evaporated under reduced pressure using an oil pump to remove the solvent. Column chromatography purification: 97.5% dichloromethane (2.5% methanol) (0.1% AcOH) to 93.5% dichloromethane (6.5% methanol) was used to flush out the product. The product was dried under vacuum to obtain the compound of formula (II), which is the target compound shown in formula A in the reaction scheme.

[0063] 2. Reaction route 2:

[0064]

[0065] Wherein, R1 is one of the following structures,

[0066] R1

[0067] The preparation method of the compound of formula (III) comprises the following steps:

[0068] Dissolve raw material 6 in THF, add potassium tert-butoxide, and dropwise add raw material 5 dissolved in THF, and react at room temperature. Add 2M HCl dropwise to hydrolyze the acetal. Separate and purify to obtain intermediate 7. Dissolve intermediate 7 in methanol, add NaBH4, and react under ice bath conditions to obtain intermediate 8 without purification. Dissolve intermediate 8 in ultra-dry tetrahydrofuran, add phosphorus tribromide, and react under ice bath conditions, and separate and purify to obtain intermediate 9. Dissolve the corresponding intermediate 3, K2CO3, and KI represented by R1 in the structures of intermediates 9 and intermediate 10 in ACN, and react at room temperature. Separate and purify to obtain intermediate 10. Dissolve intermediate 10 in NH2OK methanol solution and react at room temperature. Separate and purify to obtain the compound of formula (III), i.e., the target compound represented by formula B.

[0069] More specifically, they include:

[0070] Dissolve (1,3-dioxolan-2-yl)methyltriphenylphosphonium bromide in tetrahydrofuran, add potassium tert-butoxide, and stir at room temperature for 15 minutes. Add methyl p-formylbenzoate dissolved in tetrahydrofuran dropwise, and react at room temperature for 30 minutes. Monitor the reaction progress by TLC. Add 2M HCl to hydrolyze the acetal, and react at room temperature for 1 hour. Monitor the reaction progress by TLC. Remove the tetrahydrofuran by rotary evaporation, add an appropriate amount of water, and extract three times with ethyl acetate. Combine the organic phases, wash twice with saturated brine, and dry over anhydrous magnesium sulfate for 30 minutes. Filter, concentrate the filtrate, and purify by column chromatography with 80% petroleum ether (20% ethyl acetate) to flush out the product, yielding intermediate 7. Dissolve intermediate 7 in an appropriate amount of methanol, add sodium borohydride under ice-cooling, and react at 0°C for 1 hour. Monitor the reaction progress by TLC. Remove the methanol by rotary evaporation, dissolve in water, and extract three times with ethyl acetate. Combine the organic phases, wash twice with saturated brine, and dry over anhydrous magnesium sulfate for 30 minutes. Filter, retain the filtrate, and remove the solvent by rotary evaporation to obtain intermediate 8 without purification. Dissolve intermediate 8 in an appropriate amount of ultra-dry tetrahydrofuran, purge with nitrogen, and add phosphorus tribromide under ice bath conditions. React at 0°C for 1 hour. Monitor the reaction progress by TLC. Remove tetrahydrofuran by rotary evaporation, dissolve with water, extract with ethyl acetate three times, combine the organic phases, wash twice with saturated brine, and dry over anhydrous magnesium sulfate for 30 minutes. Filter, and filter the filtrate under reduced pressure to remove the solvent. Purify by column chromatography: 96.7% petroleum ether (3.3% ethyl acetate) to flush out the product to obtain intermediate 9. Dissolve the corresponding intermediate 3 represented by R1 in the structure of intermediate 9 and intermediate 10, anhydrous potassium carbonate and potassium iodide in an appropriate amount of acetonitrile, react at room temperature overnight, and monitor the reaction progress by TLC. Remove the solvent by rotary evaporation, dissolve with water, extract with dichloromethane three times, combine the organic phases, wash twice with saturated brine, and dry over anhydrous magnesium sulfate for 30 minutes. The filtrate was filtered, and the solvent was evaporated. The product was purified by column chromatography using 90% petroleum ether (10% ethyl acetate) to separate impurities and flush out the product, yielding Intermediate 10. Intermediate 10 was placed in an eggplant-shaped reaction flask, and NH₂OK methanol solution was added. The reaction was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC. The solvent was evaporated under reduced pressure, and an appropriate amount of water was added to dissolve the product. The pH was adjusted to 6-7 with 2M HCl. A solid precipitated and adhered to the bottom of the flask. The supernatant was discarded, and the solvent was evaporated under reduced pressure using an oil pump. The product was then purified by column chromatography using 97.5% dichloromethane (2.5% methanol) (0.1% AcOH) to 93.5% dichloromethane (6.5% methanol) to flush out the product. The product was dried under vacuum to yield the compound of formula (III), the target compound shown in Formula B in the reaction scheme.

[0071] 3. Reaction route three: (IV)

[0072]

[0073] Wherein, quinoline is 2-substituted or 3-substituted.

[0074] The preparation method of the compound of formula (IV) comprises the following steps:

[0075] 2-Aminoquinoline / 3-aminoquinoline and benzaldehyde were used as reaction raw materials, dissolved in DCM and AcOH, and then NaBH(OAc)3 was added. The mixture was reacted at room temperature and separated and purified to obtain Intermediate 13. Intermediate 13, methyl 4-bromomethylbenzoate, K2CO3, and KI were dissolved in ACN, reacted at room temperature, and separated and purified to obtain Intermediate 14. A methanolic solution of NH2OK was added to Intermediate 14, reacted at room temperature, and the pH was adjusted to 6-7 to precipitate a solid. The solid was separated, purified, and dried in vacuo to obtain the compound of formula (IV), the target compound shown in formula C in the reaction scheme.

[0076] More specifically, they include:

[0077] Place 2-aminoquinoline or 3-aminoquinoline and benzaldehyde in a 100 mL eggplant-shaped reaction flask, dissolve in an appropriate amount of dichloromethane, and add a catalytic amount of glacial acetic acid as a catalyst. After stirring at room temperature for 0.5 h, sodium triacetoxyborohydride is added portionwise and the reaction is continued at room temperature for 1-2 h. Monitor the reaction progress by TLC. Remove the solvent by rotary evaporation, dissolve in water, adjust the pH to 10 with solid sodium hydroxide pellets, and extract three times with ethyl acetate. Combine the organic phases, wash twice with saturated brine, dry over anhydrous magnesium sulfate for 30 min, filter, and evaporate the filtrate to remove the solvent under reduced pressure. Purify by column chromatography: Wash out the product with 80% petroleum ether (20% ethyl acetate) to obtain intermediate 13. Place intermediate 13 in an eggplant-shaped reaction flask, add methyl 4-bromomethylbenzoate, anhydrous potassium carbonate, and potassium iodide, dissolve in an appropriate amount of acetonitrile, and react at room temperature overnight. Monitor the reaction progress by TLC. The solvent was removed by rotary evaporation, dissolved in water, and extracted three times with dichloromethane. The combined organic phases were washed twice with saturated brine, dried over anhydrous magnesium sulfate for 30 minutes, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure. Column chromatography purification: 80% petroleum ether (20% ethyl acetate) was used to flush out the product to obtain Intermediate 14. Intermediate 14 was placed in an eggplant-shaped reaction flask, and NH2OK methanol solution was added. The reaction was stirred at room temperature for 1 hour. TLC was used to monitor the reaction progress. The solvent was evaporated under reduced pressure, and an appropriate amount of water was added to dissolve the product. 2M HCl was added to adjust the pH to 6-7. A solid precipitated and adhered to the bottom of the flask. The supernatant was discarded, and the solid in the flask was evaporated under reduced pressure using an oil pump to remove the solvent. Column chromatography purification: 97.5% dichloromethane (2.5% methanol) (0.1% AcOH) to 93.5% dichloromethane (6.5% methanol) was used to flush out the product and dried under vacuum to obtain the compound of formula (IV), the target compound shown in formula C in the reaction scheme.

[0078] The present invention will be further described in detail below with reference to specific embodiments. It should be noted that the specific embodiments are intended to explain the present invention rather than to limit it.

[0079] It should be pointed out that the present invention uses some compounds as examples to synthesize and conduct effect experiments, and other compounds also have similar effects.

[0080] Example 1

[0081] Synthesis of target compounds P1-P30

[0082] 1. Synthesis of Intermediates 3a-3i and 13a-13b

[0083] Preparation of intermediate N-benzylquinolin-8-amine (3a)

[0084] 8-Aminoquinoline (1 g, 6.93 mmol) and benzaldehyde (0.58 g, 5.54 mmol) were weighed and placed in a 100 mL eggplant-shaped flask. 15 mL of dichloromethane was added for dissolution. 1 mL of glacial acetic acid was added as a catalyst. After stirring at room temperature for 0.5 h, sodium triacetoxyborohydride (1.47 g, 6.93 mmol) was added portionwise and the reaction continued at room temperature for 2 h. The reaction was monitored by thin-layer chromatography (TLC). Upon completion, the solvent was removed by distillation under reduced pressure. 20 mL of water was added to quench the reaction, and the pH was adjusted to 10 with solid sodium hydroxide pellets. The reaction was extracted three times with ethyl acetate (30 mL x 3). The organic phases were combined and extracted twice with saturated brine (50 mL x 2). The organic phases were dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to obtain a reddish-brown oil. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain C1, a yellow solid (0.9 g), in a yield of 69.4%.

[0085] Preparation of intermediate N-(4-chlorobenzyl)quinolin-8-amine (3b)

[0086] The method was the same as that of intermediate 3a, with 8-aminoquinoline and 4-chlorobenzaldehyde as substrates, and the yield was 53.1%.

[0087] Preparation of intermediate N-(4-bromobenzyl)quinolin-8-amine (3c)

[0088] The method was the same as that of intermediate 3a, with 8-aminoquinoline and 4-bromobenzaldehyde as substrates, and the yield was 78.0%.

[0089] Preparation of intermediate N-(3,5-dichlorobenzyl)quinolin-8-amine (3d)

[0090] The method was the same as that of intermediate 3a, with 8-aminoquinoline and 3,5-dichlorobenzaldehyde as substrates, and the yield was 49.5%.

[0091] Preparation of intermediate N-(3-chlorobenzyl)quinolin-8-amine (3e)

[0092] The method was the same as that of intermediate 3a, with 8-aminoquinoline and 3-chlorobenzaldehyde as substrates, and the yield was 59.1%.

[0093] Preparation of intermediate N-(4-fluorobenzyl)quinolin-8-amine (3f)

[0094] The method was the same as that of intermediate 3a, with 8-aminoquinoline and 4-fluorobenzaldehyde as substrates, and the yield was 71.5%.

[0095] Preparation of intermediate N-(4-methoxybenzyl)quinolin-8-amine (3 g)

[0096] The method was the same as that of intermediate 3a, with 8-aminoquinoline and 4-methoxybenzaldehyde as substrates, and the yield was 56.8%.

[0097] Preparation of intermediate N-(4-(trifluoromethyl)benzyl)quinolin-8-amine (3h)

[0098] The method was the same as that of intermediate 3a, with 8-aminoquinoline and 4-trifluoromethylbenzaldehyde as substrates, and the yield was 48.6%.

[0099] Preparation of intermediate N-(cyclohexanemethyl)quinolin-8-amine (3i)

[0100] The method was the same as that of intermediate 3a, with 8-aminoquinoline and cyclohexanecarboxaldehyde as substrates, and the yield was 56.4%.

[0101] Preparation of intermediate N-benzylquinolin-2-amine (13a)

[0102] The method was the same as that of intermediate 3a, and the product was purified by column chromatography (PE:EA=4:1). The substrates were 2-aminoquinoline and benzaldehyde, and the yield was 64.8%.

[0103] Preparation of intermediate N-benzylquinolin-3-amine (13b)

[0104] The method was the same as that of intermediate 3a, and the product was purified by column chromatography (PE:EA=4:1). The substrates were 3-aminoquinoline and benzaldehyde, and the yield was 60.1%.

[0105] Preparation of intermediate 7

[0106] (1,3-Dioxolan-2-yl)methyltriphenylphosphonium bromide (1.96 g, 4.57 mmol) was weighed and placed in a 100 mL eggplant-shaped flask. Dissolved in 5 mL of tetrahydrofuran. Potassium tert-butoxide (0.51 g, 4.57 mmol) was added to the solution and stirred at room temperature for 15 min. Methyl p-formylbenzoate (0.5 g, 3.05 mmol) was weighed and dissolved in 5 mL of tetrahydrofuran. This was added dropwise to the reaction system and stirred at room temperature for 30 min. The reaction was monitored by TLC. When the reaction ceased, 2M HCl solution was added to hydrolyze the acetal and stirring continued at room temperature for 1 h. The tetrahydrofuran was removed by distillation under reduced pressure. The reaction was quenched with water and extracted three times with ethyl acetate (30 mL x 3). The organic phases were combined and washed twice with saturated brine (100 mL x 2). The organic phases were dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to obtain a light yellow, transparent oil. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=4:1) to obtain a white solid (0.311 g). The yield was 53.6%.

[0107] Preparation of intermediate 8

[0108] Intermediate 7 (1 g, 5.26 mmol) was weighed into a 100 mL eggplant-shaped flask and dissolved in 30 mL of anhydrous methanol. Sodium borohydride (0.3 g, 7.93 mmol) was added in an ice bath and stirred for 1 h. The reaction was monitored for completion by TLC. Water was added to quench the reaction and the methanol in the solvent was removed by rotary evaporation. Extraction was performed three times with ethyl acetate (30 mL x 3). The combined organic phases were washed twice with saturated brine (100 mL x 2). The organic phase was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to obtain a white solid (0.65 g, 64.4% yield).

[0109] Preparation of intermediate 9

[0110] Intermediate 8 (3.9 g, 20.30 mmol) was weighed into a 100 mL two-necked flask and added to 10 mL of ultra-dry tetrahydrofuran. Under a nitrogen atmosphere, phosphorus tribromide (3.3 g, 12.18 mmol) was dissolved in 10 mL of ultra-dry tetrahydrofuran and injected into the reaction system. The mixture was stirred on ice for 1 h. The reaction was monitored for completion by TLC. Water was added to quench the reaction, and the tetrahydrofuran was removed by distillation under reduced pressure. The mixture was extracted three times with ethyl acetate (30 mL x 3). The combined organic phases were washed twice with saturated brine (100 mL x 2). The organic phases were dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to obtain a pale yellow solid. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 30:1) to obtain a white solid (1.91 g, 37.0% yield).

[0111] Synthesis of intermediates 4a-4t, 10a-10h, 14a-14b

[0112] Synthesis of the intermediate methyl 4-((benzyl(quinolin-8-yl)amino)methyl)benzoate (4a)

[0113] Compound 3a (0.9 g, 3.84 mmol), methyl 4-bromomethylbenzoate (1.056 g, 4.61 mmol), anhydrous potassium carbonate (0.63 g, 4.61 mmol), and potassium iodide (0.063 g, 0.384 mmol) were weighed into a 100 mL eggplant flask. 15 mL of acetonitrile was added and stirred at room temperature overnight. The reaction was monitored by TLC. When the reaction ceased, the acetonitrile was removed by vacuum distillation. The mixture was dissolved in water and extracted three times with dichloromethane (30 mL x 3). The organic phases were combined and washed twice with saturated brine (100 mL x 2). The organic phases were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated by vacuum distillation to obtain a reddish-brown oil. Column chromatography (petroleum ether:ethyl acetate = 10:1) afforded a light green oil (0.81 g, 55.2% yield).

[0114] Synthesis of the intermediate methyl 3-((benzyl(quinolin-8-yl)amino)methyl)benzoate (4b)

[0115] The method was the same as that of intermediate 4a, the substrates were intermediate 3a and methyl 3-bromomethylbenzoate, and the yield was 67.4%.

[0116] Synthesis of the intermediate methyl (E)-3-(4-((benzyl(quinolin-8-yl)amino)methyl)phenyl)acrylate (4c)

[0117] The method was the same as that of intermediate 4a. The substrates were intermediate 3a and methyl (E)-4-(bromomethyl)cinnamate. The yield was 42.1%.

[0118] Synthesis of the intermediate methyl 4-(((4-chlorobenzyl)(quinolin-8-yl)amino)methyl)benzoate (4d)

[0119] The method was the same as that of intermediate 4a, the substrates were intermediate 3b and methyl 4-bromomethylbenzoate, and the yield was 40.3%.

[0120] Synthesis of the intermediate methyl (E)-3-(4-(((4-chlorobenzyl)(quinolin-8-yl)amine)methyl)phenyl)acrylate (4e)

[0121] The method was the same as that of intermediate 4a, the substrates were intermediate 3b and methyl (E)-4-(bromomethyl)cinnamate, and the yield was 47.5%.

[0122] Synthesis of the intermediate methyl 4-(((4-bromobenzyl)(quinolin-8-yl)amino)methyl)benzoate (4f)

[0123] The method was the same as that of intermediate 4a, the substrates were intermediate 3c and methyl 4-bromomethylbenzoate, and the yield was 47.4%.

[0124] Synthesis of intermediate methyl (E)-3-(4(((4-bromobenzyl)(quinolin-8-yl)amine)methyl)phenyl)acrylate (4g)

[0125] The method was the same as that of intermediate 4a, the substrates were intermediate 3c and methyl (E)-4-(bromomethyl)cinnamate, and the yield was 59.5%.

[0126] Synthesis of the intermediate methyl (E)-4-(((3,5-dichlorobenzyl)(quinolin-8-yl)amine)methyl)benzoate (4h)

[0127] The method was the same as that of intermediate 4a, the substrates were intermediate 3d and methyl 4-bromomethylbenzoate, and the yield was 55.6%.

[0128] Synthesis of the intermediate methyl (E)-3-(4-(((3,5-dichlorobenzyl)(quinolin-8-yl)amine)methyl)phenyl)acrylate (4i)

[0129] The method was the same as that of intermediate 4a, the substrates were intermediate 3d and methyl (E)-4-(bromomethyl)cinnamate, and the yield was 49.8%.

[0130] Synthesis of the intermediate methyl 4-(((3-chlorobenzyl)(quinolin-8-yl)amino)methyl)benzoate (4j)

[0131] The method was the same as that of intermediate 4a, the substrates were intermediate 3e and methyl 4-bromomethylbenzoate, and the yield was 37.1%.

[0132] Synthesis of the intermediate methyl (E)-3-(4-(((3-chlorobenzyl)quinolin-8-yl)amine)methyl)phenyl)acrylate (4k)

[0133] The method was the same as that of intermediate 4a, the substrates were intermediate 3e and methyl (E)-4-(bromomethyl)cinnamate, and the yield was 57.6%.

[0134] Synthesis of the intermediate methyl 4-(((4-fluorobenzyl)(quinolin-8-yl)amino)methyl)benzoate (4l)

[0135] The method was the same as that of intermediate 4a, the substrates were intermediate 3f and methyl 4-bromomethylbenzoate, and the yield was 32.3%.

[0136] Synthesis of the intermediate methyl 3-(((4-fluorobenzyl)(quinolin-8-yl)amino)methyl)benzoate (4m)

[0137] The method was the same as that of intermediate 4a, the substrates were intermediate 3f and methyl 3-bromomethylbenzoate, and the yield was 44.1%.

[0138] Synthesis of the intermediate methyl (E)-3-(((4-fluorobenzyl)(quinolin-8-yl)amine)methyl)phenyl)acrylate (4n)

[0139] The method was the same as that of intermediate 4a, the substrates were intermediate 3f and methyl (E)-4-(bromomethyl)cinnamate, and the yield was 25.4%.

[0140] The synthesis method of intermediate methyl 4-(((4-methoxybenzyl)(quinolin-8-yl)amine)methyl)benzoate (4o) was the same as that of intermediate 4a. The substrates were intermediate 3g and methyl 4-bromomethylbenzoate. The yield was 46.6%.

[0141] The synthesis method of intermediate methyl 3-(((4-methoxybenzyl)(quinolin-8-yl)amine)methyl)benzoate (4p) was the same as that of intermediate 4a. The substrates were intermediate 3g and methyl 3-bromomethylbenzoate. The yield was 42.6%.

[0142] Synthesis of the intermediate methyl (E)-3-(4-(((4-methoxybenzyl)(quinolin-8-yl)amine)methyl)phenyl)acrylate (4q)

[0143] The method was the same as that of intermediate 4a. The substrates were intermediate 3g and methyl (E)-4-(bromomethyl)cinnamate. The yield was 44.0%.

[0144] Synthesis of the intermediate methyl 4-((quinolin-8-yl(4-(trifluoromethyl)benzyl)amine)methyl)benzoate (4r)

[0145] The method was the same as that of intermediate 4a, the substrates were intermediate 3h and methyl 4-bromomethylbenzoate, and the yield was 43.8%.

[0146] Synthesis of the intermediate methyl (E)-3-(4-((quinolin-8-yl(4-(trifluoromethyl)benzyl)amine)methyl)phenyl)acrylate (4s)

[0147] The method was the same as that of intermediate 4a, the substrates were intermediate 3h and methyl (E)-4-(bromomethyl)cinnamate, and the yield was 36.6%.

[0148] The synthesis method of intermediate methyl 4-(((cyclohexylmethyl)(quinolin-8-yl)amino)methyl)benzoate (4t) was the same as that of intermediate 4a. The substrates were intermediate 3i and methyl 4-bromomethylbenzoate. The yield was 52.8%.

[0149] Synthesis of the intermediate methyl (E)-4-(3-(benzyl(quinolin-8-yl)amino)prop-1-en-1-yl)benzoate (10a)

[0150] The method was the same as that of intermediate 4a, the substrates were intermediate 3a and intermediate 9, and the yield was 59.0%.

[0151] Synthesis of the intermediate methyl (E)-4-(3-((4-chlorobenzyl)(quinolin-8-yl)amino)prop-1-en-1-yl)benzoate (10b)

[0152] The method was the same as that of intermediate 4a, the substrates were intermediate 3b and intermediate 9, and the yield was 50.8%.

[0153] Synthesis of the intermediate methyl (E)-4-(3-((4-bromobenzyl)(quinolin-8-yl)amino)prop-1-en-1-yl)benzoate (10c)

[0154] The method was the same as that of intermediate 4a, the substrates were intermediate 3c and intermediate 9, and the yield was 47.8%.

[0155] Synthesis of the intermediate methyl (E)-4-(3-((3,5-dichlorobenzyl)(quinolin-8-yl)amino)prop-1-en-1-yl)benzoate (10d)

[0156] The method was the same as that of intermediate 4a, the substrates were intermediate 3d and intermediate 9, and the yield was 44.3%.

[0157] Synthesis of the intermediate methyl (E)-4-(3-((3-chlorobenzyl)(quinolin-8-yl)amino)prop-1-en-yl)benzoate (10e)

[0158] The method was the same as that of intermediate 4a, the substrates were intermediate 3e and intermediate 9, and the yield was 53.1%.

[0159] Synthesis of the intermediate methyl (E)-4-(3-((4-fluorobenzyl)(quinolin-8-yl)amino)prop-1-en-1-yl)benzoate (10f)

[0160] The method was the same as that of intermediate 4a, the substrates were intermediate 3f and intermediate 9, and the yield was 53.5%.

[0161] Synthesis of intermediate methyl (E)-4-(3-((4-methoxybenzyl)(quinolin-8-yl)amino)prop-1-en-1-yl)benzoate (10 g)

[0162] The method was the same as that of intermediate 4a, the substrates were intermediate 3g and intermediate 9, and the yield was 42.2%.

[0163] Synthesis of the intermediate methyl (E)-4-(3-(quinolin-8-yl(4-(trifluoromethyl)benzyl)phenyl)amino)prop-1-en-1-yl)benzoate (10h)

[0164] The method was the same as that of intermediate 4a, the substrates were intermediate 3h and intermediate 9, and the yield was 50.3%.

[0165] Synthesis of the intermediate methyl 4-((benzyl(quinolin-2-yl)amino)methyl)benzoate (14a)

[0166] The method was similar to that of intermediate 4a, and the product was purified by column chromatography (petroleum ether:ethyl acetate=4:1). The substrates were intermediate 13a and methyl 4-bromomethylbenzoate, and the yield was 44.3%.

[0167] Synthesis of the intermediate methyl 4-((benzyl(quinolin-3-yl)amino)methyl)benzoate (14b)

[0168] The method was similar to that of intermediate 4a, and the product was purified by column chromatography (petroleum ether:ethyl acetate=4:1). The substrates were intermediate 13b and methyl 4-bromomethylbenzoate, and the yield was 4.3%.

[0169] 2. Synthesis of target compounds P1-P30

[0170] Synthesis of the target compound 4-((benzyl(quinolin-8-yl)amine)methyl)-N-hydroxybenzamide (P1)

[0171] Weigh hydroxylamine hydrochloride (4.67 g, 67.2 mmol) into a 100 mL eggplant-shaped flask and dissolve in 24 mL of methanol to prepare solution a. Weigh potassium hydroxide (5.67 g, 101.1 mmol) and dissolve in 14 mL of methanol to prepare solution b. Add solution b dropwise to solution a in an ice bath and stir for 1 hour. Filter and retain the filtrate to obtain a potassium hydroxylamine alcoholate solution. Add 10 mL of the potassium hydroxylamine alcoholate solution to a 100 mL eggplant-shaped flask containing intermediate 4a (0.81 g, 2.12 mmol) and stir at room temperature for 1 hour. The reaction is complete as determined by TLC, and the solvent is removed by rotary evaporation under reduced pressure. 5 mL of water was added, and the pH was adjusted to 6-7 with 2 M HCl solution. A yellow precipitate formed and adhered to the bottom of the bottle. The supernatant was discarded, and the solvent was removed by oil pump. The product was purified by column chromatography: 97.5% dichloromethane (2.5% methanol) (0.1% AcOH) to 93.5% dichloromethane (6.5% methanol) was used to flush out the product to obtain a yellow solid with a yield of 21.6%. ESI-MS, m / z = 384.13 [M+H] + .MP:80-82℃. 1HNMR(600MHz,DMSO)δ11.14(s,1H),9.01(s,1H),8.93(dd,J=4.2,1.8Hz,1H),8.29(d d,J=8.3,1.9Hz,1H),7.66(d,J=8.1Hz,2H),7.53(dd,J=8.3,4.2Hz,1H),7.46(d,J=8 .0Hz,2H),7.44(d,J=8.1Hz,1H),7.37(d,J=7.6Hz,2H),7.31(t,J=7.9Hz,1H),7.26( t,J=7.5Hz,2H),7.19(t,J=7.4Hz,1H),7.03(d,J=7.7Hz,1H),4.69(d,J=13.5Hz,4H). 13 C NMR(151MHz,DMSO)δ164.68,148.33,146.52,143.04,139.40,137.09,131.85,129.96,1 29.92,128.63,128.46,128.34,127.26,126.85,121.67,121.09,118.68,56.79,56.26.

[0172] Preparation of the target compound 3-((benzyl(quinolin-8-yl)amine)methyl)-N-hydroxybenzamide (P2)

[0173] The method was the same as compound P1, the substrate was intermediate 4b, and the yield was 47.8%. ESI-MS, m / z=389.99[M+H] + .MP:160-161℃. 1 H NMR (400MHz, DMSO) δ11.13 (s, 1H), 8.96 (s, 1H), 8.92 (dd, J = 4.1, 1.7Hz, 1H), 8.29(dd,J=8.3,1.8Hz,1H),7.75(t,J=1.8Hz,1H),7.54(ddd,J=9.2,6.2,2.9 Hz,3H),7.43(d,J=8.5Hz,1H),7.37-7.30(m,4H),7.25(t,J=7.4Hz,2H),7.1 8(dd,J=8.2,6.1Hz,1H), 7.02(dd,J=7.7,1.3Hz,1H), 4.69(d,J=13.3Hz,4H). 13C NMR (151MHz, DMSO) δ164.91,148.28,146.55,142.84,139.97,139.37,137.09,133.27,131.20,1 29.92,128.61,128.47,127.40,127.24,126.86,125.70,121.65,121.05,118.69,56.53,56.50.

[0174] Synthesis of the target compound (E)-3-(4-((benzyl(quinolin-8-yl)amine)methyl)phenyl)-N-hydroxyacrylamide (P3)

[0175] The method was the same as compound P1, using intermediate 4c as the substrate, with a yield of 49.6%. ESI-MS, m / z = 410.01 [M+H]+. MP: 166-167°C. 1 H NMR (600MHz, DMSO) δ10.74 (s, 1H), 9.03 (s, 1H), 8.98-8.86 (m, 1H), 8.30 (d, J = 8.2 Hz,1H),7.54(dd,J=8.3,4.1Hz,1H),7.45(dd,J=11.7,8.0Hz,3H),7.43-7.39(m,3 H),7.37(d,J=7.5Hz,2H),7.32(t,J=7.8Hz,1H),7.26(t,J=7.5Hz,2H),7.19(t,J =7.2Hz, 1H), 7.03 (d, J = 7.6Hz, 1H), 6.40 (d, J = 15.8Hz, 1H), 4.67 (d, J = 4.1Hz, 4H). 13 C NMR (151MHz, DMSO) δ163.30,148.30,146.60,142.87,141.24,139.44,138.61,137.09,133.90,129. 92,129.01,128.61,128.48,127.83,127.25,126.85,121.66,121.05,119.00,118.72,56.66,56.33.

[0176] Synthesis of the target compound (E)-4-(3-(benzyl(quinolin-8-yl)amine)prop-1-en-1-yl)-N-hydroxybenzamide (P4)

[0177] The method was the same as compound P1, the substrate was intermediate 10a, and the yield was 36.9%. ESI-MS, m / z=410.00[M+H] + .MP:81-83℃. 1H NMR (600MHz, DMSO) δ8.90(d,J=3.7Hz,1H),8.28(d,J=8.0Hz,1H),7.68(d,J=8.1Hz ,2H),7.51(dt,J=11.1,5.5Hz,1H),7.44(d,J=8.0Hz,3H),7.38(d,J=7.6Hz,1H),7. 34(d,J=7.5Hz,2H),7.26(t,J=7.4Hz,2H),7.19(t,J=7.2Hz,1H),7.12(d,J=7.4Hz, 1H), 6.56 (s, 1H), 6.55 (d, J = 5.4Hz, 1H), 4.76 (s, 2H), 4.29 (dd, J = 14.3, 5.5Hz, 2H). 13 C NMR (151MHz, DMSO) δ164.16,148.06,147.05,142.66,139.82,139.46,137.02,131.90,131.42,129. 93,129.85,128.60,128.50,127.66,127.19,126.96,126.50,121.58,120.69,118.17,56.00,55.25.

[0178] Synthesis of the target compound 4-(((4-chlorobenzyl)(quinolin-8-yl)amine)methyl)-N-hydroxybenzamide (P5)

[0179] The method was the same as compound P1, the substrate was intermediate 4d, and the yield was 43.8%. ESI-MS, m / z=417.92[M+H] + .MP:84-86℃. 1 H NMR (600MHz, DMSO) δ11.07(s,1H),8.93(s,1H),8.92(dd,J=4.2,1.7Hz,1H),8.30(dd,J=8.4,1.8Hz,1H),7.63(d,J=8.1Hz,2H),7.53(d d,J=8.2,4.1Hz,1H),7.44(t,J=7.8Hz,3H),7.40(d,J=8.2Hz,2H),7.32(d,J=7.9Hz,3H),7.03(d,J=7.6Hz,1H),4.67(d,J=12.3Hz,4H). 13C NMR (151MHz, DMSO) δ164.65,148.45,146.22,142.87,142.84,138.52,137.13,131.85,131. 80,130.32,129.91,128.59,128.32,127.26,126.82,121.73,121.33,118.80,56.23,56.17.

[0180] Synthesis of the target compound (E)-3-(4-(((4-chlorobenzyl)(quinolin-8-yl)amine)methyl)phenyl)-N-hydroxyacrylamide (P6)

[0181] The method was the same as P1, the substrate was intermediate 4e, and the yield was 71.5%. ESI-MS, m / z=443.97[M+H] + .MP:180-182℃. 1 H NMR (600MHz, DMSO) δ10.69(s,1H),8.97(s,1H),8.92(dd,J=4.2,1.8Hz,1H),8.30(dd,J=8.4,1.8Hz,1H),7.53(dd,J=8.2,4.1Hz,1H),7.46-7.42( m,3H),7.41-7.39(m,4H),7.37(d,J=4.1Hz,1H),7.32(dt,J=7.7,3.6Hz, 3H), 7.03 (d, J = 7.6Hz, 1H), 6.38 (d, J = 15.8Hz, 1H), 4.65 (d, J = 3.3Hz, 4H). 13 C NMR (151MHz, DMSO) δ163.28,148.42,146.32,142.86,141.06,138.57,137.13,133.94,131.77,1 30.33,129.91,128.99,128.59,127.85,126.83,121.71,121.28,119.03,118.83,56.32,56.03.

[0182] Synthesis of the target compound (E)-4-(3-((4-chlorobenzyl)(quinolin-8-yl)amine)prop-1-en-1-yl)-N-hydroxybenzamide (P7)

[0183] The method was the same as compound P1, the starting material was intermediate 10b, and the yield was 41.2%. ESI-MS, m / z=443.97[M+H] + .MP:82-84℃. 1H NMR(600MHz,DMSO)δ8.89(dd,J=4.1,1.7Hz,1H),8.29(dd,J=8.3,1.8Hz,1H),7 .68(d,J=8.1Hz,2H),7.52(dd,J=8.3,4.1Hz,1H),7.44(t,J=8.6Hz,3H),7.39( dd,J=8.1,3.2Hz,3H),7.32(d,J=8.2Hz,2H),7.13(d,J=7.5Hz,1H),6.58(d,J= 16.1Hz,1H),6.52(dt,J=16.0,5.7Hz,1H),4.74(s,2H),4.27(d,J=5.7Hz,2H). 13 C NMR (151MHz, DMSO) δ148.20,146.75,142.60,142.46,139.73,137.07,133.34,131.89,131.56,130.46,1 29.93,129.57,128.22,127.64,127.18,127.12,126.98,126.51,121.66,120.95,118.18,55.58,55.35.

[0184] Synthesis of the target compound 4-(((4-bromobenzyl)(quinolin-8-yl)amine)methyl)-N-hydroxybenzamide (P8)

[0185] The method was the same as compound P1, the starting material was intermediate 4f, and the yield was 11.1%. ESI-MS, m / z=461.88[M+H] + .MP:77-78℃. 1 H NMR (600MHz, DMSO) δ11.08(s,1H),8.94(s,1H),8.91(dd,J=4.1,1.8Hz,1H),8.30(dd,J=8.3,1.8Hz,1H),7.63(d,J=8.2Hz,2H),7 .53(dd,J=8.3,4.1Hz,1H),7.48-7.40(m,5H),7.34(d,J=8.3Hz,2H),7.31(t,J=7.8Hz,1H),7.07-7.00(m,1H),4.70-4.61(m,4H). 13C NMR (151MHz, DMSO) δ164.62,148.45,146.21,142.83,138.96,137.14,131.88,131.52,1 30.70,129.92,128.31,127.27,126.82,121.73,121.32,120.31,118.78,56.25,56.21.

[0186] Synthesis of the target compound (E)-3-(4-(((4-bromobenzyl)(quinolin-8-yl)amine)methyl)benzyl)-N-hydroxyacrylamide (P9)

[0187] The method is the same as compound P1, the starting material is 4g of intermediate, and the yield is 35.1%. ESI-MS, m / z=488.01[M+H] + .MP:172-174℃. 1 H NMR (400MHz, DMSO) δ10.73(s,1H),9.02(s,1H),8.92(dd,J=4.1,1.9Hz,1H),8.30(dd,J=8.3,1.9Hz,1H),7.54(dd,J=8.4,4.2Hz,1 H),7.45(dd,J=8.4,2.9Hz,5H),7.35(td,J=16.1,8.3Hz,6H),7.02(d,J=7.6Hz,1H),6.38(d,J=15.8Hz,1H),4.64(d,J=9.3Hz,4H). 13 C NMR (151MHz, DMSO) δ163.28,148.42,146.29,142.84,141.05,139.00,138.58,137.13,133.94,131. 50,130.71,129.91,128.99,127.85,126.83,121.71,121.28,120.29,119.03,118.81,56.33,56.08.

[0188] Synthesis of the target compound (E)-4-(3-((4-bromobenzyl)(quinolin-8-yl)amine)prop-1-en-1-yl)-N-hydroxybenzamide (P10)

[0189] The method was the same as compound P1, the substrate was intermediate 10c, and the yield was 35.0%. ESI-MS, m / z=487.99[M+H] + .MP:76-78℃. 1H NMR (600MHz, DMSO) δ11.16(s,1H),8.96(d,J=18.0Hz,1H),8.89(dd,J=4.1,1.7Hz,1H) ,8.29(dd,J=8.3,1.8Hz,1H),7.68(d,J=8.1Hz,2H),7.51(dt,J=7.0,3.4Hz,1H),7.48 -7.41(m,5H),7.38(t,J=7.7Hz,1H),7.33(d,J=8.1Hz,2H),7.13(d,J=7.5Hz,1H),6.5 8(d,J=16.2Hz,1H),6.52(dt,J=16.2,5.8Hz,1H),4.72(s,2H),4.27(d,J=5.8Hz,2H). 13 C NMR (151MHz, DMSO) δ164.11,148.19,146.79,142.64,139.76,139.09,137.05,131.93,131.54,131. 49,130.72,129.93,129.63,127.64,126.96,126.52,121.64,120.92,120.20,118.24,55.43,55.29.

[0190] Synthesis of the target compound 4-(((3,5-dichlorobenzyl)(quinolin-8-yl)amine)methyl)-N-hydroxybenzamide (P11)

[0191] The method was the same as compound P1, starting from intermediate 4h, with a yield of 10.6%. ESI-MS, m / z = 451.79 [M+H]+. MP: 168-170°C. 1 H NMR (600MHz, DMSO) δ11.13(s,1H),9.00(s,1H),8.92(d,J=3.9Hz,1H),8.31(d,J=8.1Hz,1H),7.65(d,J=7.7Hz,2H),7.64(s,3H), 7.55(dd,J=8.3,4.0Hz,1H),7.46(dd,J=8.3,4.2Hz,3H),7.32(t,J=7.9Hz,1H),7.05(d,J=7.6Hz,1H),4.77(s,2H),4.72(s,2H). 13C NMR(151MHz,DMSO)δ164.61,148.49,146.14,144.63,142.79,137.15,131.92,129.95,1 29.09,128.31,127.29,126.84,125.71,125.53,121.77,121.38,118.67,56.48,56.43.

[0192] Synthesis of the target compound (E)-3-(4-(((3,5-dichlorobenzyl)(quinolin-8-yl)amine)methyl)phenyl)-N-hydroxyacrylamide (P12)

[0193] The method was the same as compound P1, the starting material was intermediate 4i, and the yield was 33.3%. ESI-MS, m / z=477.95[M+H] + .MP: 160-161℃. 1 H NMR (600MHz, DMSO) δ10.70(s,1H),8.97(s,1H),8.92(dd,J=4.2,1.8Hz,1H),8.31(dd,J=8.3,1.9Hz,1H),7.54(dd,J=8.3,4.1Hz,1H),7.47(q,J=3.2H z,3H),7.44(d,J=7.8Hz,2H),7.43-7.39(m,1H),7.35(dd,J=16.2,8.0Hz, 4H), 7.09 (d, J = 7.7Hz, 1H), 6.38 (d, J = 15.8Hz, 1H), 4.68 (d, J = 10.3Hz, 4H). 13 C NMR (151MHz, DMSO) δ163.28,148.55,146.01,144.52,142.73,140.83,138.55,137.19,134.24,133. 99,129.93,128.91,127.89,127.14,126.94,126.86,121.80,121.55,119.09,118.75,56.39,56.07.

[0194] Synthesis of the target compound (E)-4-(3-((3,5-dichlorobenzyl)(quinolin-8-yl)amine)prop-1-en-1-yl)-N-hydroxybenzamide (P13)

[0195] The method was the same as compound P1, the starting material was intermediate 10d, and the yield was 35.0%. ESI-MS, m / z=487.99[M+H] + MP: 84-86℃. 1H NMR (600MHz, DMSO) δ8.88(dd,J=4.1,1.8Hz,1H),8.31(dd,J=8.3,1.8Hz,1H),7.68(d,J=8.2Hz,2H),7.53(dd,J=8.3,4.1Hz,1H),7.50-7. 45(m,3H),7.45-7.39(m,4H),7.20(dd,J=7.7,1.3Hz,1H),6.58(d,J=16.0Hz,1H),6.55-6.48(m,1H),4.76(s,2H),4.28(d,J=5.9Hz,2H). 13 C NMR (151MHz, DMSO) δ164.22,148.27,146.57,144.68,142.56,139.72,137.07,134.26,131.93,131. 66,129.94,129.37,127.67,127.10,126.97,126.83,126.51,121.69,121.16,118.13,55.46,55.38.

[0196] Synthesis of the target compound 4-(((3-chlorobenzyl)(quinolin-8-yl)amine)methyl)-N-hydroxybenzamide (P14)

[0197] The method was the same as compound P1, the starting material was intermediate 4j, and the yield was 39.1%. ESI-MS, m / z=418.01[M+H] + .MP: 68-70℃. 1 H NMR (600MHz, DMSO) δ11.08(s,1H),8.94(s,1H),8.92(dd,J=4.2,1.7Hz,1H),8.30(dd,J=8.2,1.8Hz,1H),7.63(d,J=8.2Hz,2H),7.54(dd,J=8.2,4.1 Hz,1H),7.48-7.41(m,4H),7.34(dd,J=9.2,7.3Hz,2H),7.29(t,J=7.7Hz, 1H),7.26-7.23(m,1H),7.06(dd,J=7.7,1.2Hz,1H),4.70(d,J=3.6Hz,4H). 13C NMR (151MHz, DMSO) δ164.60,148.47,146.16,142.82,142.78,142.32,137.15,133.35,131.89,1 30.50,129.93,128.28,128.21,127.28,127.11,126.85,121.75,121.35,118.70,56.38,56.28.

[0198] Synthesis of the target compound (E)-3-(4-(((3-chlorobenzyl)(quinolin-8-yl)amine)methyl)phenyl)-N-hydroxyacrylamide (P15)

[0199] The method was the same as compound P1, the starting material was intermediate 4k, and the yield was 39.7%. ESI-MS, m / z=443.79[M+H] + .MP: 154-156℃. 1 H NMR (600MHz, DMSO) δ10.70(s,1H),8.97(s,1H),8.92(dd,J=4.2,1.8Hz,1H),8.30(dd,J=8.3,1.8Hz,1H),7.54(dd,J=8.3,4.2Hz,1H),7.47-7.43(m,4H ),7.41-7.36(m,3H),7.36-7.31(m,2H),7.29(t,J=7.7Hz,1H),7.27-7.22( m,1H),7.06(d,J=7.6Hz,1H),6.38(d,J=15.8Hz,1H),4.68(d,J=4.4Hz,4H). 13 C NMR (151MHz, DMSO) δ163.31,148.44,146.24,142.80,142.35,141.03,138.61,137.14,133.94,133.34,130. 48,129.92,128.96,128.21,127.87,127.26,127.12,126.85,121.74,121.33,119.02,118.75,56.38,56.25.

[0200] Synthesis of the target compound (E)-4-(3-((3-chlorobenzyl)(quinolin-8-yl)amine)prop-1-en-1-yl)-N-hydroxybenzamide (P16)

[0201] The method was the same as compound P1, the starting material was intermediate 10e, and the yield was 25%. ESI-MS, m / z=443.96[M+H] + .MP: 77-79℃.1 H NMR (600MHz, DMSO) δ8.91-8.87(m,1H),8.30(d,J=8.1Hz,1H),7.68(d,J=8. 1Hz,2H),7.52(dd,J=8.2,4.0Hz,1H),7.45(q,J=8.4Hz,4H),7.40(t,J=7.7H z,1H),7.32(t,J=6.5Hz,1H),7.29(d,J=7.5Hz,1H),7.25(d,J=7.6Hz,1H),7 .16(d,J=7.5Hz,1H),6.60-6.49(m,2H),4.77(s,2H),4.29(d,J=5.4Hz,2H). 13 C NMR (151MHz, DMSO) δ164.16,148.17,146.81,142.65,139.78,138.63,137.04,131.91,131.70,131. 52,130.32,129.93,129.65,128.56,127.65,126.95,126.52,121.62,120.91,118.25,55.39,55.26.

[0202] Synthesis of the target compound 4-(((4-fluorobenzyl)(quinolin-8-yl)amine)methyl)-N-hydroxybenzamide (P17)

[0203] The method was the same as compound P1, the starting material was intermediate 41, and the yield was 37.4%. ESI-MS, m / z=401.95[M+H] + .MP:84℃-86℃. 1 H NMR (600MHz, DMSO) δ8.91-8.87(m,1H),8.30(d,J=8.1Hz,1H),7.68(d,J=8. 1Hz,2H),7.52(dd,J=8.2,4.0Hz,1H),7.45(q,J=8.4Hz,4H),7.40(t,J=7.7H z,1H),7.32(t,J=6.5Hz,1H),7.29(d,J=7.5Hz,1H),7.25(d,J=7.6Hz,1H),7 .16(d,J=7.5Hz,1H),6.60-6.49(m,2H),4.77(s,2H),4.29(d,J=5.4Hz,2H). 13C NMR (151MHz, DMSO) δ164.63, 161.65 (d, J = 242.1Hz), 148.43, 146.33, 142.93, 142.89, 137.12, 135.55, 131.8 6,130.39,130.34,129.91,128.31,127.26,126.82,121.71,121.28,118.83,115.42,115.28,56.14,56.07.

[0204] Synthesis of the target compound 3-(((4-fluorobenzyl)(quinolin-8-yl)amine)methyl)-N-hydroxybenzamide (P18)

[0205] The method was the same as compound P1, the starting material was intermediate 4m, and the yield was 20.5%. ESI-MS, m / z=402.07[M+H] + .MP: 156-158℃. 1 H NMR(600MHz,DMSO)δ11.11(s,1H),8.94(s,1H),8.92(dd,J=4.1,1.8Hz,1H), 8.29(dd,J=8.4,1.8Hz,1H),7.74(d,J=1.8Hz,1H),7.56-7.51(m,3H),7.44( dd,J=8.1,1.2Hz,1H),7.42-7.36(m,2H),7.32(td,J=7.8,2.0Hz,2H),7.07( dd,J=10.0,7.7Hz,2H),7.03(dd,J=7.7,1.2Hz,1H),4.67(d,J=16.8Hz,4H). 13 C NMR (151MHz, DMSO) δ164.89,162.43,160.82,148.39,146.35,142.87,139.85,137.12,135.51,133.25,131.17,1 30.37,130.32,129.90,128.65,127.35,126.83,125.71,121.69,121.25,118.88,115.39,115.25,56.36,55.86.

[0206] Synthesis of the target compound (E)-3-(4-(((4-fluorobenzyl)quinolin-8-yl)amine)methyl)phenyl)-N-hydroxyacrylamide (P19)

[0207] The method was the same as compound P1, the starting material was intermediate 4n, and the yield was 84.8%. ESI-MS, m / z=427.96[M+H] +.MP: 166-168℃. 1 H NMR (400MHz, CDCl3) δ10.75 (s, 1H), 9.03 (s, 1H), 8.93 (dd, J = 4.1, 1.8Hz, 1H), 8.31 (dd,J=8.3,1.8Hz,1H),7.54(dd,J=8.3,4.1Hz,1H),7.50-7.43(m,3H),7.42(s,2H) ,7.37(d,J=7.4Hz,2H),7.31(d,J=8.0Hz,1H),7.27(t,J=7.4Hz,2H),7.20(d,J=7.2 Hz,1H),7.03(dd,J=7.7,1.3Hz,1H),6.39(d,J=15.8Hz,1H),4.67(d,J=2.6Hz,4H). 13 C NMR (151MHz, DMSO) δ163.31,162.45,160.84,148.40,146.41,142.90,141.13,138.62,137.11,135.57,133.92,1 30.39,130.34,129.91,128.99,127.85,126.83,121.69,121.24,119.02,118.86,115.40,115.26,56.15,56.00.

[0208] Synthesis of the target compound (E)-4-(3-((4-fluorobenzyl)(quinolin-8-yl)amine)prop-1-en-1-yl)-N-hydroxybenzamide (P20)

[0209] The method is the same as compound P1, the starting material is 10g of the intermediate, and the yield is 47.6%. ESI-MS, m / z=427.98[M+H] + .MP: 80-82℃. 1 H NMR (600MHz, DMSO) δ8.90(dd,J=4.0,1.8Hz,1H),8.29(dd,J=8.3,1.8Hz,1H),7.68(d,J=8.1Hz,2H),7.52(dd,J=8.2,4.1Hz,1H),7.44( t,J=8.4Hz,3H),7.41-7.36(m,3H),7.13(d,J=7.6Hz,1H),7.09(t,J=8.7Hz,2H),6.60-6.48(m,2H),4.73(s,2H),4.27(d,J=5.6Hz,2H). 13C NMR (151MHz, DMSO) δ164.22,162.42,160.81,148.14,146.92,142.71,139.81,137.02,135.60,131.91,131.47,1 30.39,130.34,129.93,129.72,127.67,126.94,126.50,121.59,120.88,118.30,115.37,115.23,55.34,55.10.

[0210] Synthesis of the target compound N-hydroxy-4-(((4-methoxybenzyl)(quinolin-8-yl)amine)methyl)benzamide (P21).

[0211] The method was the same as compound P1, the starting material was intermediate 4o, and the yield was 46.6%. ESI-MS, m / z=414.02[M+H] + .MP: 80℃-82℃. 1 H NMR (600MHz, DMSO) δ11.06(s,1H),8.93-8.91(m,2H),8.29(dd,J=8.3,1.9Hz,1H),7.64-7.60(m,2H),7.53(dd,J=8.2,4.2Hz,1H),7.45-7 .40(m,3H),7.31(t,J=7.9Hz,1H),7.26(d,J=8.4Hz,2H),7.02(d,J=7.6Hz,1H),6.85-6.79(m,2H),4.66(s,2H),4.60(s,2H),3.69(s,3H). 13 C NMR (151MHz, DMSO) δ164.67,158.66,148.32,146.57,143.10,142.91,137.08,131.81,131.11, 129.90,129.74,128.33,127.23,126.84,121.65,121.06,118.80,114.03,56.27,55.91,55.40.

[0212] Synthesis of the target compound N-hydroxy-3-(((4-methoxybenzyl)(quinolin-8-yl)amine)methyl)benzamide (P22)

[0213] The method was the same as compound P1, the intermediate was raw material 4p, and the yield was 42.5%. ESI-MS, m / z=414.04[M+H] + .MP: 155-157℃. 1H NMR (600MHz, DMSO) δ11.10(s,1H),8.93(s,1H),8.92(dd,J=4.1,1.8Hz,1H),8.29(dd,J=8.2,1.9Hz,1H),7.74(s,1H),7.56-7.50(m,3H),7.42(d,J= 8.1Hz,1H),7.31(td,J=7.8,4.7Hz,2H),7.24(d,J=8.3Hz,2H),7.01(d,J= 7.7Hz,1H),6.81(d,J=8.3Hz,2H),4.67(s,2H),4.60(s,2H),3.69(s,3H). 13 C NMR (151MHz, DMSO) δ164.95,158.64,148.26,146.63,142.92,140.04,137.06,133.27,131.19,131.08, 129.90,129.73,128.61,127.41,126.85,125.67,121.61,121.02,118.81,114.01,56.22,55.98,55.38.

[0214] Synthesis of the target compound (E)-N-hydroxy-3-(4-(((4-methoxybenzyl)(quinolin-8-yl)amine)methyl)phenyl)acrylamide (P23)

[0215] The method was the same as compound P1, the starting material was intermediate 4q, and the yield was 81.8%. ESI-MS, m / z=440.08[M+H] + .MP: 164-166℃. 1 H NMR (600MHz, DMSO) δ10.70 (s, 1H), 8.97 (s, 1H), 8.92 (dd, J = 4.1, 1.8Hz, 1H), 8.2 9(dd,J=8.2,1.8Hz,1H),7.53(dd,J=8.3,4.1Hz,1H),7.43(t,J=7.2Hz,3H),7.38 (d,J=8.0Hz,3H),7.31(t,J=7.9Hz,1H),7.26(d,J=8.4Hz,2H),7.01(d,J=7.6Hz ,1H),6.85-6.79(m,2H),6.38(d,J=15.9Hz,1H),4.66-4.57(m,4H),3.69(s,3H). 13CNMR(151MHz,DMSO)δ163.29,158.65,148.29,146.66,142.92,141.30,138.60,137.07,133.87,131.14, 129.90,129.74,129.00,127.81,126.84,121.63,121.02,118.99,118.82,114.02,56.14,55.99,55.40.

[0216] Synthesis of the target compound (E)-N-hydroxy-4-(3-((4-methoxybenzyl)(quinolin-8-yl)amine)prop-1-en-1-yl)benzamide (P24)

[0217] The method was the same as compound P1, the starting material was intermediate 10h, and the yield was 35.5%. ESI-MS, m / z=440.05[M+H] + .MP: 80-82℃. 1 H NMR (600MHz, DMSO) δ8.90 (dd, J=4.2, 1.8Hz, 1H), 8.28 (dd, J=8.3, 1.8Hz, 1H), 7.67(d,J=8.2Hz,2H),7.51(dd,J=8.2,4.1Hz,1H),7.43(d,J=8.0Hz,3H),7.4 1-7.34(m,2H),7.24(d,J=8.3Hz,2H),7.11(d,J=7.6Hz,1H),6.82(d,J=8.5Hz ,2H),6.54(d,J=13.0Hz,1H),4.67(s,2H),4.26(d,J=5.5Hz,2H),3.69(s,3H). 13 C NMR (151MHz, DMSO) δ164.19,158.61,148.06,147.12,142.72,139.83,137.00,131.90,131.37,131. 11,129.91,129.78,127.66,126.96,126.49,121.55,120.69,118.31,114.00,55.43,55.39,54.93.

[0218] Synthesis of the target compound N-hydroxy-4-((quinolin-8-yl(4-(trifluoromethyl)benzyl)amine)methyl)benzamide (P25)

[0219] The method was the same as compound P1, the starting material was intermediate 4r, and the yield was 44.2%. ESI-MS, m / z=451.94[M+H] + .MP: 76-78℃.1 H NMR (600MHz, DMSO) δ11.09(s,1H),8.95(s,1H),8.92(dd,J=4.1,1.7Hz,1H),8.31(dd,J=8.2,1.8Hz,1H),7.66-7.60(m,6H) ,7.54(dd,J=8.3,4.1Hz,1H),7.45(d,J=7.9Hz,3H),7.32(t,J=7.8Hz,1H),7.05(d,J=7.6Hz,1H),4.77(s,2H),4.72(s,2H). 13 CNMR(151MHz,DMSO)δ164.62,148.47,146.15,144.62,142.80,142.77,137.15,131.93,129.95, 129.09,128.31,128.08,127.87,127.30,126.83,125.51,121.76,121.38,118.67,56.49,56.44.

[0220] Synthesis of the target compound (E)-N-hydroxy-3-(4-((quinolin-8-yl(4-(trifluoromethyl)benzyl)amine)methyl)phenyl)acrylamide (P26)

[0221] The method was the same as for compound P1, using intermediate 4s as the starting material. The yield was 37.0%. ESI-MS, m / z = 478.01 [M+H]+. MP: 156-158°C. 1 H NMR (600MHz, DMSO) δ10.70(s,1H),8.92(dd,J=4.2,1.8Hz,1H),8.30(dd,J=8.3,1.8Hz,1H),7.63(s,4H),7.54(dd,J=8.2,4.1Hz,1H),7.45(dt, J=8.0,1.7Hz,3H),7.43-7.37(m,3H),7.32(t,J=7.9Hz,1H),7.05(dd,J=7.7,1.3Hz,1H),6.47-6.36(m,1H),4.76(s,2H),4.70(d,J=5.5Hz,2H). 13C NMR (151MHz, DMSO) δ148.47,146.24,144.69,142.81,140.97,137.15,134.00,129.95,129.11,129. 00,128.04,127.87,126.85,125.72,125.52,123.91,121.75,121.35,119.07,118.72,56.59,56.32.

[0222] Synthesis of the target compound (E)-N-hydroxy-4-(3-(quinolin-8-yl(4-trifluoromethyl)benzyl)amine)prop-1-en-1-yl)benzamide (P27)

[0223] The method was the same as compound P1, the starting material was intermediate 10h, and the yield was 38.0%. ESI-MS, m / z=477.95[M+H] + .MP: 80-82℃. 1 H NMR (600MHz, DMSO) δ8.88(dd,J=4.2,1.8Hz,1H),8.30(dd,J=8.2,1.8Hz,1H),7.67(d,J=8.2Hz,2H),7.63(s,2H),7.62(s,2H),7.52(dd,J=8.3,4.2 Hz,1H),7.46(dd,J=8.1,1.2Hz,1H),7.43(d,J=8.2Hz,2H),7.39(s,1H), 7.18-7.14(m,1H),6.62-6.50(m,2H),4.85(s,2H),4.30(d,J=5.8Hz,2H). 13 C NMR (151MHz, DMSO) δ164.20,148.21,146.74,144.85,142.61,139.77,137.06,131.89,131.58,129.96,129.59,129.10,128.62,1 27.96,127.75,127.64,127.54,126.97,126.53,125.74,125.49,125.46,125.43,123.94,121.66,120.94,118.08,55.75,55.53.

[0224] Synthesis of the target compound 4-(((cyclohexylmethyl)(quinolin-8-yl)amine)methyl)-N-hydroxybenzamide (P28)

[0225] The method was the same as compound P1, the starting material was intermediate 4t, and the yield was 23.4%. ESI-MS, m / z=390.02[M+H]+ .MP:81℃-83℃. 1 H NMR (600MHz, DMSO) δ11.10(s,1H),8.95(s,1H),8.86(dd,J=4.0,1.8Hz,1H),8.27(dd,J=8.3,1.8Hz,1 H),7.63(d,J=8.0Hz,2H),7.49(dd,J=8.2,4.0Hz,1H),7.45-7.42(m,2H),7.41(d,J=7.4Hz,2H),7.12 (dd,J=7.4,1.6Hz,1H),4.77(s,2H),3.25(d,J=6.9Hz,2H),1.78-1.74(m,1H),1.69(d,J=12.7Hz,2H) ,1.63(ddd,J=10.8,7.2,3.6Hz,1H),1.58-1.50(m,2H),1.04(d,J=8.2Hz,3H),0.76(d,J=11.9Hz,2H). 13 C NMR (151MHz, DMSO) δ164.70,147.95,147.42,143.62,142.97,137.00,131.71,130.03,12 8.50,127.11,126.99,121.53,120.55,118.29,58.53,58.44,35.51,31.32,26.62,25.90.

[0226] Synthesis of the target compound 4-((benzyl(quinolin-2-yl)amine)methyl)-N-hydroxybenzamide (P29)

[0227] The method was the same as compound P1, the starting material was intermediate 14a, and the yield was 40.4%. ESI-MS, m / z=384.11[M+H] + .MP: 78-81℃. 1 H NMR (400MHz, DMSO) δ9.01(s,1H),11.17(s,1H),7.99(d,J=9.1Hz,1H),7.68(dd,J=8.0,6.1Hz,3H),7.59-7.48(m,2H),7.36(d,J= 8.0Hz,2H),7.32(d,J=5.5Hz,4H),7.26(dd,J=5.9,2.8Hz,1H),7.24-7.18(m,1H),7.00(d,J=9.1Hz,1H),4.97(d,J=12.0Hz,4H). 13C NMR (151MHz, DMSO) δ164.52,156.84,147.84,142.58,139.02,138.03,131.94,129.95,128. 99,127.86,127.60,127.56,127.51,127.41,126.44,123.07,122.29,110.05,51.30,51.01.

[0228] Synthesis of the target compound 4-((benzyl(quinolin-3-yl)amine)methyl)-N-hydroxybenzamide (P30)

[0229] The method was the same as compound P1, the starting material was intermediate 14b, and the yield was 38.8%. ESI-MS, m / z=390.02[M+H] + .MP: 79-80℃. 1 H NMR (600MHz, DMSO) δ11.19(s,1H),9.04(s,1H),8.65(d,J=3.0Hz,1H),7.80-7.76(m,1H),7.73(d,J=8.0Hz,2H),7.62-7.59(m,1H),7.41(d,J=7 .9Hz,2H),7.38(ddd,J=7.3,5.4,1.6Hz,2H),7.35(d,J=6.2Hz,4H),7.29(d,J=3.0Hz,1H),7.26(tt,J=5.8,2.5Hz,1H),4.92(d,J=12.7Hz,4H). 13 C NMR (151MHz, DMSO) δ164.56,142.18,141.99,141.56,141.25,138.66,132.07,129.26,129. 11,128.78,127.70,127.48,127.32,127.23,127.18,126.58,125.28,112.78,54.66,54.33.

[0230] Example 2

[0231] In vitro HDACs and HDAC6 inhibitory activity test of compounds

[0232] In this example, HeLa cell nuclear extract (mainly containing HDAC1 and HDAC2) and HDAC6 were used as enzyme sources to perform preliminary HDAC enzyme inhibitory activity screening on the target compounds P1-P30 prepared in Example 1.

[0233] The HDAC fluorescence assay (two-step method) allows for rapid, convenient, and simple detection of HDAC activity. In the first step, an HDAC fluorescent substrate (containing an acetylated lysine residue, Boc-Lys(acetyl)-AMC) is incubated with a sample containing HDAC activity (e.g., HeLa cell nuclear extract, expressed HDAC6, etc.) to deacylate and activate the substrate. In the second step, Boc-Lys-AMC is hydrolyzed with trypsin to generate the AMC fluorescent group (or chromophore). Fluorescence intensity is measured at the excitation / emission wavelengths (390nm / 460nm).

[0234] Use a 100μL pipette to pipette 50μL of the test compound solution into a 96-well fluorescent plate, setting up three replicates. Add 50μL of HDAC buffer to each of the standard and blank groups. Then, add 10μL of the diluted enzyme solution to each of the experimental and standard groups. Add 10μL of buffer solution to the blank group. Incubate at 37°C on a shaker for 5 minutes.

[0235] Add 40 μL of prepared substrate solution to each well and incubate for 30-120 min under the same conditions.

[0236] After the substrate and enzyme have fully reacted, add 100 μL of the prepared stop solution and incubate for 20-30 minutes under the same conditions. After the reaction is complete, measure the fluorescence intensity at a set wavelength (390 nm / 460 nm).

[0237] The inhibition rate was calculated according to the following formula:

[0238] Inhibition rate (%) = (A1-A0) / (A1-A2)×100%

[0239] A1: 100% fluorescence intensity. A0: Fluorescence intensity of the experimental group. A2: Fluorescence intensity of the blank group.

[0240] Further concentration-inhibition rate curve was made by graphpad and IC was fitted. 50 The inhibition rate is shown in Table 1. It is found that 5 compounds have an inhibitory ability against HDAC6 close to or better than the lead compound MPT0G211, namely compounds P1, P5, P17, P21 and P30. The above compounds were then subjected to HDAC6 inhibitory activity experiments, and the IC 50 See Table 2 for values.

[0241] Table 1: Inhibitory activities of compounds P1-P30 in Example 1 on HDACs and HDAC6

[0242]

[0243]

[0244]

[0245] *In the table, MPT0G211 is a positive drug for histone deacetylase 6 inhibitors, and SAHA and PXD101 are positive drugs for histone deacetylase inhibitors. ND means not tested.

[0246] As shown in Table 1, there are five compounds with inhibitory abilities against HDAC6 close to or better than the lead compound MPT0G211, namely compounds P1, P5, P17, P21 and P30.

[0247] The target compound showed poor inhibition of the mixed enzyme extracted from HeLa cell nuclei, with a certain gap compared to the control drug. This suggests that the compound has similar properties to MPT0G211, namely, it has good activity only against HDAC6 and has no inhibitory ability against other HDACs in the cell nucleus. Based on the HDAC6 inhibition rate test data, we can complete the structure-activity analysis of the compounds considered in the design of the target compound.

[0248] First, the presence of compounds P1, P29, and P30 indicates that 8-substituted quinoline is the most active, while 2- and 3-substituted compounds reduce their inhibitory activity. Compound P28, in which the phenyl ring in the benzyl group of P1 is replaced with a cyclohexane, significantly reduces its inhibitory activity. This suggests that aromaticity of the side chain is essential for compound activity. The type of linker is crucial for compound activity. Compounds P21, P22, P23, and P24 share the same cap and ZBG structure, differing in linker length and angle. Replacing the para-substituted phenyl ring in P21 with a meta-substituted phenyl ring reduced the inhibition rate of P22 to 39.2%. Extending the linker also significantly reduced activity. This suggests that using para-substituted phenyl rings and methylene groups as linkers is a key step in designing selective HDAC6 inhibitors. This phenomenon is consistent with the structural characteristics of the HDAC6 catalytic pocket. We then selected eight compounds with identical linkers but different caps to examine the effect of different substituents on the branched phenyl ring on activity. Compounds P5, P17, and P21, obtained by adding substituents to the para position of the P1 branched benzene ring, showed no difference in their inhibitory activity. However, increasing the bulkiness of the electron-withdrawing group at the 4-position, as in P8 and P25, reduced their activity. Furthermore, converting the 4-position chlorine atom to a 3-position or 3,5-disubstituted chlorine atom impaired its activity.

[0249] Table 2: HDAC6 inhibitory activity (IC 50 , nM)

[0250]

[0251] *ACY-1215 in the table is a positive drug for histone deacetylase 6 inhibitor.

[0252] As shown in Table 2, compounds P1, P5, P17, and P21 have better inhibitory abilities against HDAC6 than the drug ACY1215 in clinical trials. Among them, compound P21 has the best activity, and its inhibitory ability against HDAC6 is 2.2 times that of the phase II drug ACY1215.

[0253] Example 3

[0254] This example is an in vitro anti-tumor cell proliferation experiment of compounds P8, P21 and P22

[0255] This experimental part adopts CCK-8 method for determination. Compared with the traditional MTT method, CCK-8 has the advantages of high reproducibility, simple operation and low toxicity. CCK-8 can be reduced to water-soluble formazan by succinate dehydrogenase in the mitochondria of living cells, which absorbs at a wavelength of 450nm. Its absorbance value is positively correlated with the number of living cells. Therefore, the number of living cells can be reflected by measuring the absorption value, and the inhibition rate of the compound on tumor cells can be calculated by the formula. According to the inhibition rate corresponding to different concentrations, the curve was fitted using Graphpad software to calculate the IC 50 value.

[0256] Remove frozen tumor cells from the ultra-low temperature freezer and rapidly thaw in a 37°C water bath. Transfer the cryovial to a 15mL cryovial and centrifuge at 1000 rpm for 5 minutes. Discard the supernatant and add 10mL of freshly prepared culture medium (45mL culture medium + 5mL fetal bovine serum + 0.5mL double-antibody). Gently pipette to resuspend the cells. Transfer the suspension to a T75 culture flask and culture the cells in a 5% CO2 incubator at 37°C.

[0257] Once the cells have grown confluently (change the culture medium promptly during this time), resuspend the cells in 4 mL of trypsin digestion buffer, add 8 mL of PBS buffer to stop digestion, transfer the cells to a 15 mL centrifuge tube, and centrifuge at 1000 rpm for 5 minutes. Discard the supernatant, add 10 mL of fresh culture medium, resuspend by pipetting, and divide equally between two T75 culture flasks, filling up to 12 mL of culture medium for cell passage.

[0258] Select cells in the logarithmic growth phase and resuspend them in 4 mL of trypsin digestion buffer. Add 8 mL of PBS buffer to stop digestion, transfer the cells to a 15 mL centrifuge tube, and centrifuge at 1000 rpm for 5 minutes. Discard the supernatant, add 5 mL of fresh culture medium, resuspend by pipetting, and count using a cell counter. Adjust the cell concentration to the desired level using fresh culture medium.

[0259] Add 100 μL of diluted cell suspension (approximately 5,000 to 8,000 cells) to each well. For the blank control group, add 100 μL of blank culture medium without cells. Incubate for 24 hours.

[0260] 100 μL of compound solution diluted with culture medium (DMSO content less than 1%) was added to each well, and 100 μL of blank culture medium was added to the blank control group and the positive control group, and the cells were incubated for 48 h.

[0261] The liquid was removed with a pipette, and 200 μL of CCK-8 (10%) diluted in culture medium was added to each well, and the cells were incubated for 0.5 to 2 hours. The absorbance at a wavelength of 450 nm was measured using a microplate reader.

[0262] The inhibition rate was calculated according to the following formula, and the curve was fitted using Graphpad software to calculate the IC 50 value.

[0263] Inhibition rate (%) = (A1-A0) / (A1-A2)×100%

[0264] A1: 100% fluorescence intensity, A0: fluorescence intensity of the experimental group, A2: fluorescence intensity of the blank group.

[0265] Graphpad software was used to fit the curve and calculate the IC 50 The results are shown in Table 3.

[0266] Table 3: Anti-tumor cell proliferation activity of some compounds (IC 50 , μM)

[0267]

[0268] In the table, MPT0G211, SAHA and PXD101 are positive drugs.

[0269] As shown in Table 3, compound P21 demonstrated the strongest anti-proliferative activity against tumor cells, outperforming the marketed drugs SAHA and PXD101 in HeLa and MDA-MB-468 cell lines. Compared to the lead compound MPT0G211, compound P21 exhibited significantly enhanced anti-proliferative activity against all five solid tumor cell lines, demonstrating the promising therapeutic potential of our invented compounds.

[0270] Example 4

[0271] This example is an experiment on the HDAC subtype selectivity of compound P21

[0272] Developing HDAC selective inhibitors can reduce the toxic side effects of pan-inhibitors. To test the subtype selectivity of target compounds, we selected compound P21 for subtype selectivity testing. The specific steps are as follows:

[0273] Recombinant HDAC enzymes were diluted to a working concentration of 0.5 μg / mL. In a 96-well black plate, 20 μL of the enzyme solution was mixed with various concentrations of the test compound (20 μL). After incubation at 30°C for 1 hour, 10 μL of 20 μM fluorescent substrates (Boc-Lys(Ac)-AMC (for HDACs 1, 2, 3, and 6), Boc-Lys(TFA)-AMC (for HDACs 4, 5, 7, 8, and 9), and ETDKmyr (for HDAC 11) were added. The substrates were purchased from Bachem AG, Switzerland. The mixture was incubated at 30°C for an additional 2 hours, after which the enzymatic reaction was terminated by the addition of 10 μL of a solution containing 35 mg / mL trypsin and 5 μM trichostatin A (TSA). After an additional 30-minute incubation, fluorescence intensity was measured using a microplate reader at an excitation wavelength of 360 nm and an emission wavelength of 460 nm. The deacetylation activity was calculated by reading the fluorescence intensity of the test wells relative to the control wells, and the IC was fitted using the “log (inhibitor) vs. normalized response-variable slope” function using GraphPad Prism 8.0 software. 50 curve.

[0274] The results are shown in Table 4. It can be seen that compound P21 has excellent subtype selectivity, with selectivity differences of approximately 300-fold for HDAC1, HDAC2, HDAC3, and HDAC8, 90-fold and 48.8-fold for HDAC4 and HDAC5, respectively, and more than 800-fold for HDAC7, HDAC9, and HDAC11. At the same time, compound P21 was verified to be an HDAC6 selective inhibitor.

[0275] Table 4: HDAC subtype selectivity data of compound P21

[0276]

[0277] The results of in vitro experiments showed that the compounds of the general structural formula (I) of the present invention have good biological activity. IC values ​​of compounds P1, P5, P17, P21 and P30 for HDAC6 inhibitory activity are 50 The value is below 100nM. Among them, compound P21 has the best activity, with an IC 50 The value is 11.49nM, which shows good selectivity to other HDAC isoforms. P21 has good anti-proliferative ability against 5 solid tumor cell lines.

[0278] The structures of the compounds described in the examples of this invention conform to the Y-conformation commonly used in HDAC6 inhibitor design strategies. Their quinoline ring and substituted benzyl groups may better fit into the L1 and L2 cavities on the surface of the HDAC6 catalytic pocket. The para-substituted benzyl ring in compound P21's structure is a key foundation for its HDAC6 inhibitory ability and subtype selectivity. The methoxy group on the benzyl group of compound P21 is not crucial for enzyme activity but is essential for maintaining cellular viability. This may be because the presence of the methoxy group improves the physicochemical properties of small molecule drugs, enabling them to better penetrate cell membranes and exert their effects.

[0279] Although the present invention describes specific implementation methods, it does not limit the scope of protection of the present invention. Those skilled in the art should understand that various modifications or variations that can be made by those skilled in the art on the basis of the technical solution of the present invention without creative work are still within the scope of protection of the present invention.

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, characterized in that: The compound is one or more of the following compounds P1, P5, P17, P21, P30: 。 2. A method for preparing the compound according to claim 1, characterized in that: The preparation method of compound P1, P5, P17, P21 or P30 comprises the following steps: Weigh 67.2 mmol of hydroxylamine hydrochloride into a 100 mL eggplant-shaped flask and dissolve it in 24 mL of methanol to prepare solution a. Weigh 101.1 mmol of potassium hydroxide and dissolve it in 14 mL of methanol to prepare solution b. Add solution b dropwise to solution a under ice-bath conditions and stir for 1 h. Filter and retain the filtrate to obtain a potassium hydroxylamine alcoholate solution. Add 10 mL of the potassium hydroxylamine alcoholate solution to a 100 mL eggplant-shaped flask containing 2.12 mmol of the intermediate and stir at room temperature for 1 h. After TLC, the reaction was complete and the solvent was removed by rotary evaporation under reduced pressure. Add 5 mL of water and adjust the pH to 6-7 with 2 M HCl solution. A yellow precipitate will form and adhere to the bottom of the flask. Discard the supernatant and remove the solvent by oil pump. Purify the product by column chromatography: 97.5% dichloromethane, 2.5% methanol, 0.1% acetic acid to 93.5% dichloromethane, 6.5% methanol to obtain the compound. When the intermediate is methyl 4-((benzyl(quinolin-8-yl)amine)methyl)benzoate, the obtained compound is P1; When the intermediate is methyl 4-(((4-chlorobenzyl)(quinolin-8-yl)amino)methyl)benzoate, the obtained compound is P5; When the intermediate is methyl 4-(((4-fluorobenzyl)(quinolin-8-yl)amino)methyl)benzoate, the obtained compound is P17; When the intermediate is methyl 4-(((4-methoxybenzyl)(quinolin-8-yl)amino)methyl)benzoate, the obtained compound is P21; When the intermediate is methyl 4-((benzyl(quinolin-3-yl)amino)methyl)benzoate, the obtained compound is P30.

3. A pharmaceutical composition, characterized in that The invention comprises the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

4. The pharmaceutical composition according to claim 3, wherein The carrier is solid or liquid.

5. The pharmaceutical composition according to claim 3, wherein The pharmaceutical composition is an oral preparation or a parenteral preparation.

6. The pharmaceutical composition according to claim 3, wherein The pharmaceutical composition is in the form of tablets, pills, capsules or injections.

7. Use of the compound according to claim 1 and a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to any one of claims 3 to 6 in the preparation of a histone deacetylase (HDAC) inhibitor.

8. The use according to claim 7, characterized in that The HDAC is HDAC6.

9. The use according to claim 7 or 8, characterized in that The application is in the preparation of drugs for treating diseases related to HDAC6 enzyme overexpression.

10. The use according to claim 9, characterized in that The disease is cancer.

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