Novel hydroxamic acid derivative as well as preparation method and application thereof

Abstract

The invention relates to a novel hydroxamic acid derivative and application thereof, the derivative is a compound as shown in a structural general formula I, or a stereoisomer or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, and R1, R2, W1, W2, W3, Y, Z1, Z2, Z3, Cy, m and p have meanings given in the specification. In addition, the invention also discloses application of the derivatives in preparation of drugs for treating diseases caused by abnormal expression of HDACs, especially application in preparation of drugs for treating and / or preventing cancers. .

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and particularly relates to a novel class of hydroxamic acid derivatives, a preparation method and application thereof, and their use in inhibiting histone deacetylases (HDACs) and treating HDACs-related diseases (especially cancer). Background Art

[0002] The occurrence and development of cancer is associated with a variety of endogenous and exogenous factors. Epigenetic modification is another important endogenous factor in tumor development, in addition to genetic factors. Epigenetic modification refers to a reversible or heritable process that regulates gene expression without changing the DNA nucleotide sequence. It affects gene expression through DNA demethylation and methylation, histone modification, and RNA interference, thereby influencing processes such as cancer cell proliferation, metabolism, and apoptosis.

[0003] Epigenetic regulation refers to the process of controlling gene expression without altering the genomic DNA sequence through specific mechanisms such as DNA methylation, histone modification, noncoding RNA regulation, and transcription factors. These epigenetic modifications precisely regulate cellular activities by modulating the function and expression levels of nucleic acids and proteins. DNA methylation and histone modification are the two most common epigenetic modifications. The acetylation regulatory mechanism of histones and non-histone proteins plays a central role in maintaining normal cellular life, particularly in key biological processes such as cell differentiation, proliferation, and apoptosis. At the molecular level, histone deacetylases (HDACs) and histone acetyltransferases (HATs), as families of antagonistic enzymes, dynamically regulate the acetylation levels of histones and non-histone proteins, forming a crucial regulatory network for maintaining cellular homeostasis. Dysregulation of acetylation significantly increases the risk of diseases such as cancer. HDACs are enzymes that catalyze the removal of acetyl groups from lysine residues in the tails of histones, leading to chromatin remodeling. Relevant data show that abnormal expression of HDACs is closely associated with tumor cell proliferation, apoptosis, DNA damage repair, metastasis, and autophagy. Given the close relationship between HDACs and cancer, they have become one of the effective targets for cancer targeted therapy. The development of effective HDAC inhibitors has become a key research direction for targeted anticancer drugs. Summary of the Invention

[0004] The present invention aims to design and synthesize a novel class of hydroxamic acid derivatives or their stereoisomers or optical isomers, or their pharmaceutically acceptable salts, and pharmaceutical compositions containing the compounds, which mainly exert their anti-tumor effects by inhibiting histone deacetylase.

[0005] Specifically, the first aspect of the present invention provides a heterocyclic compound represented by general formula I or a stereoisomer or optical isomer thereof, or a pharmaceutically acceptable salt thereof,

[0006] Where, Y is none, CONH, CONHNH, CONHCH2 or NH; Z1, Z2, Z3 are N or CH; m, p are 0 or 1; R1 and R2 are none, a halogen atom, –(C1-C2 alkyl), –(C1-C3 alkoxy), or –(C1-C2 haloalkyl); Cy is 、 、 、 or , wherein R3 is hydrogen, methyl or halogen atom; W1 is hydrogen, a 3-6 membered cycloalkyl group, a 6-10 membered aryl group, a 5-10 membered heterocyclic group, -(C1-C3 haloalkyl), one -(C1-C4 alkyl) group or two identical or different -(C1-C4 alkyl) groups. The above heterocyclic ring may contain 1-3 identical or different nitrogen, sulfur or oxygen atoms. The aryl and heterocyclic groups may be unsubstituted or substituted with 1-2 -(C1-C2 alkyl), -(C1-C2 alkoxy), halogen atoms, trifluoromethyl, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2 or hydroxyl groups; W2 is a 4-6 membered cycloalkyl, a 4-10 membered (fused) heterocycle, a 6-10 membered aryl-(C1-C3 alkyl) or a -(C1-C3 alkyl) 1-2 N(C1-C3 alkyl), the above heterocyclic ring may contain 1-3 identical or different nitrogen, sulfur or oxygen atoms, and may be unsubstituted or substituted with 1-3 –(C1-C2 alkyl), –(C1-C2 alkoxy), –(C1-C2 acyl), halogen atoms, trifluoromethyl or –NH(C1-C3 alkyl); W3 is none, or , wherein X is O, S or NHCO, and n is 5, 6 or 7.

[0007] In another preferred embodiment, the compound is selected from at least one of the following compounds:

[0008] The second aspect of the present invention provides a pharmaceutical composition comprising the compound according to the first aspect or its stereoisomer or optical isomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0009] The third aspect of the present invention provides use of the compound of the first aspect or its stereoisomers or optical isomers, or pharmaceutically acceptable salts thereof, in the preparation of a medicament for treating or preventing HDACs-mediated diseases or inhibiting HDACs.

[0010] In another preferred embodiment, the disease mediated by HDACs is cancer.

[0011] In another preferred embodiment, the cancer is: leukemia, T-cell lymphoma, non-small cell lung cancer, small cell lung cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, gastric cancer or multiple myeloma, etc.

[0012] According to some common methods in the field to which the present invention belongs, the heterocyclic compound of general formula I in the present invention can form a pharmaceutically acceptable salt with an acid. Pharmaceutically acceptable addition salts include inorganic acid addition salts and organic acid addition salts. Salts formed with the following acids are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid and benzoic acid.

[0013] In the present invention, "halogen atom" refers to fluorine or chlorine; "alkyl" refers to a linear or branched alkyl; and "ring" refers to a monocyclic or condensed ring.

[0014] The active compound of the present invention, or its pharmaceutically acceptable salt or solvate thereof, can be used alone as the sole anti-tumor agent, or in combination with currently marketed anti-tumor drugs (such as bortezomib, osimertinib, cisplatin, irinotecan, cetuximab, docetaxel, sabutinib, and canertinib). Combination therapy can be achieved by administering the individual therapeutic components simultaneously, sequentially, or separately. DETAILED DESCRIPTION

[0015] The following synthetic schemes summarize and describe the preparation of the Formula I derivatives of the present invention. All starting materials are prepared by the methods depicted in these schemes, by methods well known to those skilled in the art of organic chemistry, or are commercially available. All final derivatives of the present invention are prepared by the methods depicted in these schemes or by methods analogous thereto, which are well known to those skilled in the art of organic chemistry. All variables used in these schemes are as defined below or in the claims.

[0016] According to the present invention, the compounds of formula I can be prepared according to the methods of routes 1 to 7. Wherein, R1, R2, W1, W2, W3, Y, Z1, Z2, Z3, Cy, m and p in the compounds are as defined in the claims.

[0017] More specifically, when Cy is When Y is absent, the compound can be prepared by the method of route 1. Methyl 5-bromo-2-(bromomethyl)benzoate (1) reacts with a methyl carboxylate derivative (2) in the presence of DIEA to form isoindolinone 3. Intermediate 3 is hydrolyzed to obtain intermediate 4. Carboxylic acid 4 is condensed with different amino substituents in the presence of HATU and DIEA to obtain intermediate 5. Intermediate 5 is subjected to Suzuki coupling reaction to obtain intermediate 6. The acid 7 obtained by hydrolysis of intermediate 6 is reacted with O -(tetrahydro-2 H -pyran-2-yl)hydroxylamine condensation to obtain intermediate 8, intermediate 8 is depyranyloxy under acidic conditions to obtain the target compound.

[0018] Route 1: .

[0019] More specifically, when Cy is 、 、 or When Y does not exist, the compound can be prepared by the method of route 2. d ]Isoxazole-3(2 H )-ketone, bromoindazole and bromobenzo[ d ]isothiazole-3(2 H )-ketone-1,1-dioxo compound (10) and bromocarboxylate (11) react with cesium carbonate to produce intermediate 12 through nucleophilic substitution reaction. Ester 12 is hydrolyzed to produce acid 13. Acid 13 is condensed with amino substituent to produce amide 14. Amide 14 is converted into intermediate 15 through Suzuki coupling reaction. Intermediate 15 is hydrolyzed to produce acid 16. Acid 16 is reacted with O -(tetrahydro-2 H -pyran-2-yl)hydroxylamine condensation to give intermediate 17, intermediate 17 is depyranyloxy under acidic conditions to give the target compound.

[0020] Route 2: .

[0021] More specifically, when Y is NH, the compound can be prepared using route 3. Intermediate 5 or 14 is subjected to a Buchwald-Hartwig coupling reaction to obtain intermediate 19, which is hydrolyzed to obtain acid 20, which is then reacted with O-(tetrahydro-2 H -pyran-2-yl)hydroxylamine condensation to give intermediate 21, intermediate 21 is depyranyloxy under acidic conditions to give the target compound.

[0022] Route 3: .

[0023] More specifically, when Y is CONH, CONHNH, or CONHCH2, the compounds can be prepared using Routes 4–7. Under palladium catalysis, intermediate 14 is converted to carboxylic acid 23. Intermediate 23 undergoes condensation to produce intermediate 24. Intermediate 24 is hydrolyzed to produce acid 25. Intermediate 25 is then depyranoxylated under acidic conditions to yield the target compound (Route 4). Acid 23 undergoes condensation to produce hydrazide 27. Intermediate 17 is then hydrolyzed, condensed, and depyranoxylated to yield the target compound (Route 5). Intermediate 23 undergoes condensation to produce intermediate 30. Intermediate 30 is then hydrolyzed, condensed, and depyranoxylated to yield the target compound (Route 6). Nitrate 33 is reduced with ferric acid to produce amine 34. Intermediate 34 undergoes condensation to produce intermediate 35. Intermediate 35 is then hydrolyzed, condensed, and depyranoxylated to yield the target compound (Route 7).

[0024] Route 4: .

[0025] Route 5: .

[0026] Route 6: .

[0027] Route 7: .

[0028] The following examples and preparations are provided to further illustrate and illustrate the compounds of the present invention and their preparation methods. It should be understood that the scope of the following examples and preparations does not limit the scope of the present invention in any way.

[0029] The examples are intended to illustrate rather than limit the scope of the present invention. The H NMR spectra of the compounds were determined using a Bruker ARX-600, and the high-resolution mass spectra were determined using a Thermo Fisher triple quadrupole liquid chromatography-mass spectrometry instrument. All reagents used were commercially available analytical grade or chemically pure.

[0030] Example 1 N Synthesis of 7-hydroxy-7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isothiazolin-5-yl)phenoxy)heptylamide (1) Synthesis of methyl 2-(6-bromo-1-oxoisoindolin-2-yl)-2-phenylacetate (3-1)

[0031] Methyl 5-bromo-2-bromomethylbenzoate (6.00 g, 19.5 mmol) was dissolved in 45 mL of DMF at 0°C. Methyl 2-amino-2-phenylacetate hydrochloride (6.46 g, 21.3 mmol) and DIEA (7.63 g, 58.8 mmol) were added. After stirring until completely dissolved, the mixture was reacted at 110°C for 14 h. The reaction solution was cooled to room temperature and poured into 150 mL of ice water. Filtering afforded 9.80 g of a yellow solid, which was then purified by column chromatography to afford 7.23 g of a light yellow solid.

[0032] (2) Synthesis of 2-(6-bromo-1-oxoisoindolin-2-yl)-2-phenylacetic acid (4-1)

[0033] At room temperature, intermediate 3-1 (7.00 g, 19.5 mmol) was added to 50 mL of methanol / water, followed by the addition of LiOH (0.72 g, 29.2 mmol). Stirring was continued for 5 h. The reaction mixture was evaporated to dryness, and the residue was added to 30 mL of water. The pH was adjusted to 3 with concentrated hydrochloric acid, and the mixture was filtered to obtain 5.5 g of a light yellow solid.

[0034] (3) 2-(6-bromo-1-oxoisoindolin-2-yl)-2-phenyl- N Synthesis of -(thiazol-2-yl)acetamide (5-1)

[0035] Intermediate 4-1 (5.0 g, 14.5 mmol) was dissolved in 40 mL of DMF. HATU (9.9 g, 26.1 mmol) and DIEA (4.1 g, 31.9 mmol) were added. After stirring at room temperature for 30 min, 2-aminothiazole (1.7 g, 17.4 mmol) was added and the reaction continued at room temperature for 4 h. The reaction solution was poured into an appropriate amount of ice water, stirred, and filtered to obtain 5.7 g of the crude product.

[0036] (4) Synthesis of methyl 7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-yl)ethyl)isoindolin-5-yl)phenoxy)heptanoate (6-1)

[0037] Intermediate 5-1 (0.5 g, 1.2 mmol) was dissolved in 10 mL of 1,4-dioxane, and methyl 7-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)heptanoate (0.6 g, 1.8 mmol), 2 N A 1 mL aqueous Na₂CO₃ solution was ultrasonically degassed for 5 minutes. After preheating at 100°C for 20 minutes, PdCl₂(dppf)₂ (0.07 mmol) and X-phos (0.11 mmol) were added and the reaction continued for 10 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to yield 0.3 g of a yellow solid.

[0038] (5) 7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isothiazolin-5-yl)phenoxy)- N -((Tetrahydro-2 H Synthesis of 2-pyran-2-yl)oxy)heptylamide (8-1)

[0039] At room temperature, intermediate 6-1 (0.3 g, 0.5 mmol) was added to 3 mL of methanol / water, followed by the addition of LiOH (0.8 mmol) and continued stirring for 5 h. The reaction solution was evaporated to dryness, and the residue was added to 2 mL of water. The pH was adjusted to 3 with concentrated hydrochloric acid and filtered to obtain 0.2 g of a light yellow solid. The above solid was added to 2 mL of DMF, and HATU (0.6 mmol) and DIEA (0.7 mmol) were added. After stirring at room temperature for 30 min, the mixture was added. O -(tetrahydro-2 H 2-pyran-2-yl)hydroxylamine (0.5 mmol) was added and the reaction was continued at room temperature for 3 h. The reaction solution was poured into an appropriate amount of ice water, stirred, and filtered to obtain 0.2 g of a yellow solid.

[0040] (6) N Synthesis of hydroxy-7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isothiazolin-5-yl)phenoxy)heptylamide (Example 1)

[0041] 90.0 mg of intermediate 8-1 was added to 3 mL of methanol, followed by an appropriate amount of dilute hydrochloric acid. The mixture was allowed to react at room temperature for 2 h. The pH was adjusted to 6 with saturated aqueous sodium bicarbonate solution, filtered, and the solid was separated and purified by column chromatography to obtain 25.0 mg of the title compound. 1 H NMR (600 MHz, DMSO- d6) δ 12.68 (br, 1H), 10.35 (s, 1H), 8.67 (s, 1H), 7.89 (s, 1H),7.87 (m, 1H), 7.67(d, J =8.4 Hz, 2H), 7.62 (m, 1H), 7.47 (m, 3H), 7.44–7.41 (m,1H), 7.39 (m, 2H), 7.24 (br, 1H), 7.04 (d, J =8.4 Hz, 2H), 6.31 (s, 1H), 4.83(m, 1H), 4.02–3.99 (m, 3H), 1.97 (m, 2H), 1.74–1.70 (m, 2H), 1.54–1.49 (m,2H), 1.44–1.39 (m, 2H), 1.33–1.28 (m, 2H); 13 C NMR (151 MHz, DMSO- d 6) δ 169.57,169.28, 168.15, 159.07, 141.22, 140.44, 138.16, 135.37, 132.73, 132.06,130.38, 130.13, 129.50 (2C), 129.26 (2C), 129.06, 128.51 (2C), 124.63,120.52, 115.46 (2C), 114.10, 67.95, 58.91, 48.85, 32.67, 29.03, 28.80, 25.72,25.56. HRMS (ESI) m / z : 585.2170 [M+H] + , Calcd for 585.2172.

[0042] Example 2 N 1 -Hydroxy- N 7 Synthesis of -(4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenyl)pimelanediamide (1) Synthesis of methyl 7-oxo-7-((4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenyl)amino)heptanoate (6-2)

[0043] Intermediate 5-1 (0.50 g, 1.2 mmol) was dissolved in 10 mL of 1,4-dioxane, and methyl 7-oxo-7-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)heptanoate (1.8 mmol), 2 N A 1 mL aqueous Na₂CO₃ solution was ultrasonically degassed for 5 minutes. After preheating at 100°C for 20 minutes, PdCl₂(dppf)₂ (0.07 mmol) and X-phos (0.11 mmol) were added and the reaction continued for 10 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to yield 0.2 g of a yellow solid.

[0044] (2) Synthesis of 7-oxo-7-((4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenyl)amino)heptanoic acid (7-2)

[0045] At room temperature, intermediate 6-2 (0.5 mmol) was added to 3 mL of methanol / water, followed by the addition of LiOH (0.8 mmol), and stirring continued for 5 h. The reaction solution was evaporated to dryness, and the residue was added to 2 mL of water. The pH was adjusted to 3 with concentrated hydrochloric acid, and the product was filtered to obtain 0.2 g of a light yellow solid.

[0046] (3) N 1 -(4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-amino)ethyl)isoindolin-5-yl)phenyl)- N 7 -((Tetrahydro-2 H Synthesis of 2-pyran-2-yl)oxy)pimelanediamide (8-2)

[0047] The above solid was added to 2 mL DMF, HATU (0.6 mmol) and DIEA (0.7 mmol) were added, and the mixture was stirred at room temperature for 30 min and then added. O -(tetrahydro-2 H 2-pyran-2-yl)hydroxylamine (0.5 mmol) was added and the reaction was continued at room temperature for 3 h. The reaction solution was poured into an appropriate amount of ice water, stirred, and filtered to obtain 0.15 g of a yellow solid.

[0048] (4) N 1 -Hydroxy- N 7Synthesis of -(4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenyl)pimelamide (Example 2)

[0049] 0.1 g of intermediate 8-2 was added to 3 mL of methanol, followed by an appropriate amount of dilute hydrochloric acid. The mixture was allowed to react at room temperature for 2 h. The pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was filtered. Purification by column chromatography afforded 45.0 mg of the title compound. 1 H NMR (600 MHz, DMSO- d 6) δ 10.29 (br, 1H), 9.94 (s, 1H), 8.59 (br, 1H), 7.92 (s, 1H), 7.88 (m,1H), 7.72 (d, J =8.4 Hz, 2H), 7.68 (d, J =8.4 Hz, 2H), 7.63 (m, 1H), 7.46–7.44(m, 3H), 7.42–7.38 (m, 3H), 7.18 (br, 1H), 6.30 (s, 1H), 4.87 (d, J =18.0 Hz,1H), 4.03 (d, J =18.0 Hz, 1H), 2.33–2.31 (m, 2H), 1.97–1.95 (m, 2H), 1.63–1.58(m, 2H), 1.56–1.51 (m, 2H), 1.31–1.27 (m, 2H); HRMS (ESI) m / z: 598.2127 [M+H] + ,Calcd for 598.2124.

[0050] Example 3: N -(7-(hydroxyamino)-7-oxoheptyl)-4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)benzamide

[0051] The intermediate 5-1 and 7-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide)heptanoic acid methyl ester were prepared by the synthesis method of Example 1. 1 H NMR (600 MHz, DMSO- d6) δ 10.29 (br, 1H),8.60 (br, 1H), 8.46 (m, 1H), 8.01 (m, 1H), 7.96 (m, 3H), 7.83 (d, 2H), 7.68(m, 1H), 7.43–7.41 (m, 2H), 7.37–7.35 (m, 4H), 7.00 (br, 1H), 6.23 (s, 1H), 5.02 (d, J =18.0 Hz, 1H), 4.06 (d, J =18.0 Hz, 1H), 1.96 (m, 2H), 1.56–1.48 (m,4H), 1.32–1.26 (m, 6H); HRMS (ESI) m / z : 612.2281 [M+H] + , Calcd for 612.2281.

[0052] Example 4: N -hydroxy-8-(4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenoxy)octanamide

[0053] The intermediate 5-1 and 8-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenoxy)octanoic acid methyl ester were prepared by the synthesis method of Example 1. 1 H NMR (600 MHz, DMSO- d 6) δ 12.70 (br, 1H), 10.34 (s, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.87–7.85 (m, 1H), 7.66 (d, J =8.4Hz, 1H), 7.62 (m, 1H), 7.49–7.46 (m, 3H), 7.44–7.42 (m, 1H), 7.40–7.38 (m,2H), 7.27 (br, 1H), 7.04 (d, J =8.4 Hz, 1H), 6.32 (s, 1H), 4.81 (d, J=18.0 Hz,1H), 4.02–3.99 (m, 3H), 1.96–1.93 (m, 2H), 1.75–1.70 (m, 2H), 1.52–1.48 (m,2H), 1.44–1.39 (m, 2H), 1.35–1.30 (m, 2H), 1.29–1.25 (m, 2H). HRMS (ESI) m / z :599.2324[M+H] + , Calcd for 599.2328.

[0054] Example 5 N -hydroxy-6-(4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenoxy)hexanamide

[0055] The intermediate 5-1 and 8-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenoxy)hexanoic acid methyl ester were prepared by the synthesis method of Example 1. 1 H NMR (600 MHz, DMSO- d 6) δ 12.69 (br, 1H), 10.40 (s, 1H), 8.71 (s, 1H), 7.90 (s, 1H), 7.87 (d, J =7.8 Hz, 1H), 7.67 (d, J =8.4Hz, 2H), 7.62 (d, J =7.8 Hz, 1H), 7.49–7.46 (m, 3H), 7.45–7.42 (m, 1H), 7.40(m, 2H), 7.27 (br, 1H), 7.04, (d, J =8.4 Hz, 2H). 6.32 (s, 1H), 4.81 (d, J =17.4Hz, 1H), 4.03–3.99 (m, 3H), 2.04–2.02 (m, 2H), 1.74–1.70 (m, 2H), 1.68–1.64(m, 2H); 13 C NMR (151 MHz, DMSO- d6) δ 169.39, 169.03, 168.19, 159.03, 141.22,140.46, 138.24, 135.07, 132.67, 132.09, 130.43, 130.13, 129.55 (2C), HRMS (ESI) m / z : 557.1857 [M+H] + , Calcd for 557.1859.

[0056] Example 6, 7-(2-fluoro-4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide

[0057] The intermediate 5-1 and methyl 7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenoxy)heptanoate were prepared by the synthesis method of Example 1. 1 H NMR (600 MHz, DMSO- d 6) δ 12.35 (br,1H), 10.33 (s, 1H), 8.68 (s, 1H), 7.89 (s, 1H), 7.87 (m, 1H), 7.62 (m, 3H),7.47 (m, 3H), 7.44–7.41 (m, 1H), 7.39 (m, 2H), 7.24 (br, 1H), 6.31 (s, 1H), 4.83 (m, 1H), 4.02–3.99 (m, 3H), 1.97 (m, 2H), 1.74–1.70 (m, 2H), 1.54–1.49(m, 2H), 1.44–1.39 (m, 2H), 1.33–1.28 (m, 2H). HRMS (ESI) m / z : 603.2069 [M+H] + ,Calcd for 603.2077.

[0058] Example 7 N-hydroxy-7-(3-methyl-4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenoxy)heptylamide

[0059] Prepared from intermediate 5-1 and methyl 7-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)heptanoate using the synthetic method of Example 1. HRMS (ESI) m / z : 599.2322 [M+H] + , Calcdfor 599.2328.

[0060] Example 8 N -hydroxy-7-(3-methoxy-4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenoxy)heptylamide

[0061] Prepared from intermediate 5-1 and methyl 7-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)heptanoate using the synthetic method of Example 1. HRMS (ESI) m / z : 615.2264 [M+H] + ,Calcd for 615.2277.

[0062] Example 9: N -hydroxy-7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)-2-(trifluoromethyl)phenoxy)heptylamide

[0063] Prepared from intermediate 5-1 and methyl 7-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-2-(trifluoromethyl)phenoxy)heptanoate using the synthetic method of Example 1. HRMS (ESI) m / z : 653.2038 [M+H] + ,Calcd for 653.2046.

[0064] Example 10 N -hydroxy-7-(4-(2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)heptylamide (1) 2-(6-bromo-2 H Synthesis of methyl 2-indazol-2-yl)-2-phenylacetate (12-1)

[0065] Dissolve 10-1 (2.3 g, 10.0 mmol) in an appropriate amount of acetonitrile, add Cs2CO3 (3.9 g, 12.0 mmol) and 4-bromoindazole (2.1 g, 11.0 mmol), and react in an ice bath for 0.5 h and then at room temperature for 2 h. Filter, rinse the solid with a small amount of acetonitrile, and concentrate the filtrate under reduced pressure. Purify by column chromatography to obtain 1.9 g of intermediate 12-1.

[0066] (2) 2-(6-bromo-2 H Synthesis of 2-indazol-2-yl)-2-phenylacetic acid (13-1)

[0067] At room temperature, intermediate 12-1 (1.9 g, 5.5 mmol) was added to 20 mL of methanol / water, followed by the addition of LiOH (0.2 g, 8.3 mmol). Stirring was continued for 5 h. The reaction mixture was evaporated to dryness, and the residue was added to 15 mL of water. The pH was adjusted to 3 with concentrated hydrochloric acid, and the mixture was filtered to obtain 1.3 g of a light yellow solid.

[0068] (3) 2-(6-bromo-2 H -indazol-2-yl)-2-phenyl- N Synthesis of -(thiazol-2-yl)acetamide (14-1)

[0069] Intermediate 13-1 (1.2 g, 3.6 mmol) was dissolved in 10 mL of DMF. HATU (2.0 g, 5.4 mmol) and DIEA (0.9 g, 7.2 mmol) were added. After stirring at room temperature for 30 min, 2-aminothiazole (0.4 g, 4.3 mmol) was added and the reaction continued at room temperature for 5 h. The reaction solution was poured into an appropriate amount of ice water, stirred, and filtered to obtain 1.1 g of intermediate 14-1.

[0070] (4) 7-(4-(2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2 H Synthesis of methyl (15-1)-indazol-6-yl)phenoxy)heptanoate

[0071] Intermediate 14-1 (1.0 g, 2.4 mmol) was dissolved in 15 mL of 1,4-dioxane, and methyl 7-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)heptanoate (1.2 g, 3.6 mmol), 2 N A 2 mL aqueous Na₂CO₃ solution was ultrasonically degassed for 5 minutes. After preheating at 100°C for 20 minutes, PdCl₂(dppf)₂ (0.14 mmol) and X-phos (0.22 mmol) were added and the reaction continued for 13 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to yield 0.7 g of a yellow solid.

[0072] (5) 7-(4-(2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2 H Synthesis of 6-indazol-6-yl)phenoxy)heptanoic acid (16-1)

[0073] At room temperature, intermediate 15-1 (0.5 g, 0.9 mmol) was added to 10 mL of methanol / water, followed by the addition of LiOH (0.04 g, 1.4 mmol). Stirring was continued for 5 h. The reaction solution was evaporated to dryness, and the residue was added to 11 mL of water. The pH was adjusted to 3 with concentrated hydrochloric acid, and the mixture was filtered to obtain 0.3 g of a light yellow solid.

[0074] (6) 7-(4-(2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)- N -((Tetrahydro-2 H Synthesis of 2-pyran-2-yl)oxy)heptylamide (17-1)

[0075] 16-1 (0.3 g, 0.5 mmol) was added to 2 mL DMF, and HATU (0.3 g, 0.8 mmol) and DIEA (0.1 g, 0.8 mmol) were added. After stirring at room temperature for 30 min, the mixture was added. O -(tetrahydro-2 H 2-pyran-2-yl)hydroxylamine (0.06 g, 0.5 mmol) was added and the reaction was continued at room temperature for 3 h. The reaction solution was poured into an appropriate amount of ice water, stirred, and filtered to obtain 0.2 g of a brown solid.

[0076] (7) N -hydroxy-7-(4-(2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2H Synthesis of 6-indazol-6-yl)phenoxy)heptylamide (Example 10)

[0077] 0.1 g of intermediate 17-1 was added to 2 mL of methanol, followed by an appropriate amount of dilute hydrochloric acid. The mixture was allowed to react at room temperature for 2 h. The pH was adjusted to 6 with saturated aqueous sodium bicarbonate solution, and the solid was filtered. Purification by column chromatography afforded 32.0 mg of the title compound. 1 H NMR (600 MHz, DMSO- d 6) δ 12.46 (br, 1H), 10.30 (s, 1H), 8.68 (s, 1H), 7.89 (s, 1H), 7.87(m, 1H), 7.67 (d, J =8.4 Hz, 2H), 7.62 (m, 1H), 7.47 (m, 3H), 7.44–7.41 (m,1H), 7.40 (m, 2H), 7.22 (br, 1H), 7.04 (d, J =8.4 Hz, 2H), 6.31 (s, 1H), 4.83(m, 1H), 4.02–3.99 (m, 3H), 1.97 (m, 2H), 1.74–1.70 (m, 2H), 1.54–1.48 (m,2H), 1.44–1.39 (m, 2H), 1.33–1.28 (m, 2H). HRMS (ESI) m / z : 570.2169 [M+H] + ,Calcd for 570.2175.

[0078] Example 11, 7-(4-(4-chloro-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)- N -Hydroxyheptylamide

[0079] The intermediate 14-1 and methyl 7-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)heptanoate were used as raw materials and prepared by the synthesis method of Example 10. HRMS (ESI) m / z : 604.1778 [M+H] + ,Calcd for 604.1785.

[0080] Example 12 N-hydroxy-7-(4-(2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenoxy)heptylamide

[0081] Prepared from methyl 2-bromo-2-phenylacetate and 4-bromoisoindoline using the synthesis method of Example 10. HRMS (ESI) m / z : 571.2372 [M+H] + , Calcd for 571.2379.

[0082] Example 13: N -hydroxy-7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2,3-dihydrobenzo[ d ]isoxazol-5-yl)phenoxy)heptylamide

[0083] With 2-bromo-2-phenylacetic acid methyl ester and 5-bromobenzo[ d ]Isoxazole-3(2 H )-ketone as raw material, and prepared by the synthesis method of Example 10. 1 H NMR (600 MHz, DMSO- d 6) δ 12.25 (br, 1H), 10.21 (s, 1H), 8.65(s, 1H), 7.89 (s, 1H), 7.87 (m, 1H), 7.67(d, J =8.4 Hz, 2H), 7.62 (m, 1H), 7.47(m, 3H), 7.44–7.41 (m, 1H), 7.39 (m, 2H), 7.24 (br, 1H), 7.05 (d, J =8.4 Hz,2H), 6.31 (s, 1H), 4.01 (m, 2H), 1.97 (m, 2H), 1.74–1.69 (m, 2H), 1.54–1.49 (m, 2H), 1.43–1.39 (m, 2H), 1.33–1.27 (m, 2H). HRMS (ESI) m / z : 587.1959 [M+H] + ,Calcd for 587.1964.

[0084] Example 14, 7-(4-(7-fluoro-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2H -indazol-6-yl)phenoxy)- N -Hydroxyheptylamide

[0085] 2-Bromo-2-phenylacetic acid methyl ester and 6-bromo-7-fluoro-2 H -indazole was used as the raw material and prepared by the synthesis method of Example 10. HRMS (ESI) m / z : 588.2073 [M+H] + , Calcd for 588.2081.

[0086] Example 15, 7-(4-(4-chloro-2-(1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-2 H -indazol-6-yl)phenoxy)- N -Hydroxyheptylamide

[0087] 2-bromo-methyl propionate and 4-chloro-6-bromo-2 H -indazole was used as the raw material and prepared by the synthesis method of Example 10. HRMS (ESI) m / z : 604.1776 [M+H] + , Calcd for 604.1785.

[0088] Example 16: N -hydroxy-7-(4-(4-methyl-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)heptylamide

[0089] 2-bromo-2-phenylacetic acid methyl ester and 6-bromo-4-methyl-2 H -indazole was used as the raw material and prepared by the synthesis method of Example 10. HRMS (ESI) m / z : 584.2324 [M+H] + , Calcd for 584.2332.

[0090] Example 17: N -hydroxy-7-(4-(2-(2-methyl-1-oxo-1-(thiazol-2-ylamino)butan-2-yl)-3-oxoisoindolin-5-yl)phenoxy)heptylamide

[0091] Prepared using the synthesis method of Example 1 using 5-bromo-2-bromomethylbenzoic acid methyl ester and 2-amino-2-methylbutyric acid methyl ester hydrochloride as raw materials. HRMS (ESI) m / z : 551.2322 [M+H] + , Calcd for 551.2328.

[0092] Example 18, 7-(4-(3-fluoro-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)- N -Hydroxyheptylamide

[0093] 2-Bromo-2-phenylacetic acid methyl ester and 6-Bromo-3-fluoro-2 H -indazole was used as the starting material and prepared by the synthesis method of Example 10. HRMS (ESI) m / z: 588.2073 [M+H] + , Calcd for 588.2081.

[0094] Example 19: N -hydroxy-7-(4-(3-methyl-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)heptylamide

[0095] 2-Bromo-2-phenylacetic acid methyl ester and 6-Bromo-3-methyl-2 H -indazole was used as the starting material and prepared by the synthesis method of Example 10. HRMS (ESI) m / z: 584.2325 [M+H] + , Calcd for 584.2332.

[0096] Example 20 N -hydroxy-7-(4-(3-oxo-2-(1-oxo-1-(thiazol-2-ylamino)butan-2-yl)isoindolin-5-yl)phenoxy)heptylamide

[0097] Prepared from methyl 5-bromo-2-bromomethylbenzoate and methyl 2-aminobutyrate hydrochloride using the synthesis method of Example 1. HRMS (ESI) m / z: 537.2163 [M+H] + , Calcd for 537.2172.

[0098] Example 21N -hydroxy-7-(4-(2-(1-(naphthalen-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-3-oxoisoindolin-5-yl)phenoxy)heptylamide

[0099] Prepared from methyl 5-bromo-2-bromomethylbenzoate and methyl 2-amino-2-(naphthalen-1-yl)acetate hydrochloride using the synthesis method of Example 1. HRMS (ESI) m / z: 635.2320 [M+H] + , Calcd for 635.2328.

[0100] Example 22 N -hydroxy-7-(4-(2-(2-methyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-oxoisoindolin-5-yl)phenoxy)heptylamide

[0101] The product was prepared by the synthesis method of Example 1 using 5-bromo-2-bromomethylbenzoic acid methyl ester and 2-amino-2-methylpropionic acid methyl ester hydrochloride as raw materials. 1 H NMR (600 MHz, DMSO- d 6) δ 12.26 (br, 1H), 10.36 (s, 1H), 8.68 (s, 1H), 7.89 (s, 1H), 7.87 (m, 1H), 7.66(d, J =8.4 Hz, 2H), 7.62 (m, 1H), 7.47 (m, 1H), 7.44–7.41 (m, 1H), 7.06 (d, J =8.4 Hz, 2H), 4.84 (m, 1H), 4.02–3.99 (m, 3H), 1.97 (m, 2H), 1.74–1.70 (m, 2H), 1.54–1.49 (m, 2H), 1.44–1.40(m, 2H), 1.37 (s, 6H), 1.33–1.28 (m, 2H); HRMS (ESI) m / z : 537.2163 [M+H] + ,Calcd for 537.2172.

[0102] Example 23, 7-(4-(2-(1-(furan-2-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-2 H-indazol-6-yl)phenoxy)- N -Hydroxyheptylamide

[0103] 2-Bromo-2-(furan-2-yl)acetic acid methyl ester and 6-bromo-2 H -indazole was used as the starting material and prepared by the synthesis method of Example 10. HRMS (ESI) m / z: 560.1959 [M+H] + , Calcd for 560.1968.

[0104] Example 24 N -hydroxy-7-(4-(2-(2-oxo-1-(pyridin-3-yl)-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)heptylamide

[0105] 2-Bromo-2-(pyridin-3-yl)acetic acid methyl ester and 6-bromo-2 H -indazole was used as the starting material and prepared by the synthesis method of Example 10. HRMS (ESI) m / z: 571.2120 [M+H] + , Calcd for 571.2127.

[0106] Example 25, 7-(4-(2-(1-(2-fluorophenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide

[0107] The product was prepared using methyl 2-bromo-2-(2-fluorophenyl)acetate and 5-bromoisoindoline as raw materials and the synthesis method of Example 10. 1 H NMR (600 MHz, DMSO- d 6) δ 12.64 (br, 1H), 10.30 (s, 1H), 8.67 (s,1H), 7.87 (s, 1H), 7.85 (m, 1H), 7.67(d, J =8.4 Hz, 2H), 7.62 (m, 1H), 7.47 (m,3H), 7.39 (m, 2H), 7.24 (br, 1H), 7.04 (d, J=8.4 Hz, 2H), 6.30 (s, 1H), 4.83(m, 1H), 4.02–3.99 (m, 3H), 3.86 (m, 2H), 1.97 (m, 2H), 1.74–1.70 (m, 2H), 1.54–1.49 (m, 2H), 1.43–1.39 (m, 2H), 1.33–1.27 (m, 2H); HRMS (ESI) m / z :589.2276 [M+H] + , Calcd for 589.2285.

[0108] Example 26, 7-(4-(2-(1-((2-(dimethylamino)ethyl)(methyl)amino)-1-oxopropan-2-yl)-3-oxoisoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide

[0109] The product was prepared by the synthesis method of Example 1 using 5-bromo-2-bromomethylbenzoic acid methyl ester and 2-amino-2-methylpropionic acid methyl ester hydrochloride as raw materials. 1 H NMR (600 MHz, DMSO- d 6) δ 10.35 (br, 1H), 8.69 (br, 1H), 7.87–7.85 (m, 2H), 7.67–7.64 (m, 3H), 7.04 (d, 2H), 5.32–5.27 (m, 1H), 4.58–4.47 (m, 2H), 4.02–4.00 (t, J =6.0 Hz, 2H), 3.66–3.55 (m, 1H), 3.22–3.18 (m,1H), 2.97(s, 2H), 2.84 (s, 1H), 2.38–2.27 (m, 2H), 2.17–2.12(m, 6H), 1.97–1.95 (t, J =6.0 Hz, 2H), 1.73–1.71 (m, 2H), 1.54–1.50 (m, 2H), 1.43–1.38 (m,3H), 1.35–1.30 (m, 4H). HRMS (ESI) m / z : [M+H] + , Calcd for 525.3077.

[0110] Example 27, 7-(4-(2-(1-(4-fluorophenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide

[0111] Prepared from methyl 2-bromo-2-(4-fluorophenyl)acetate and 5-bromoisoindoline using the synthesis method of Example 10. HRMS (ESI) m / z: 589.2278 [M+H] + , Calcd for 589.2285.

[0112] Example 28, 7-(4-(2-(1-(4-chloro-2-fluorophenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)- N -Hydroxyheptylamide

[0113] Prepared from methyl 2-bromo-2-(4-chloro-2-fluorophenyl)acetate and 6-bromoindazole using the synthesis method of Example 10. HRMS (ESI) m / z: 622.1684 [M+H] + , Calcd for 622.1691.

[0114] Example 29 N -hydroxy-7-(4-(2-(2-oxo-2-(thiazol-2-ylamino)-1-(3-(trifluoromethyl)phenyl)ethyl)-2- H -indazol-6-yl)phenoxy)heptylamide

[0115] Prepared from methyl 2-bromo-2-(3-trifluoromethylphenyl)acetate and 6-bromoindazole using the synthesis method of Example 10. HRMS (ESI) m / z: 638.2042 [M+H] + , Calcd for 638.2049.

[0116] Example 30 N -hydroxy-7-(4-(2-(1-(3-(methylamino)phenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)heptylamide

[0117] Prepared from methyl 2-bromo-2-(3-methylaminophenyl)acetate and 6-bromoindazole using the synthesis method of Example 10. HRMS (ESI) m / z: 638.2042 [M+H] + , Calcd for 638.2049.

[0118] Example 31 N -hydroxy-7-(4-(2-(2-oxo-1-(thiazol-2-yl)-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)heptylamide

[0119] Prepared from methyl 2-bromo-2-(thiazol-2-yl)acetate and 6-bromoindazole using the synthesis method of Example 10. HRMS (ESI) m / z: 577.1685 [M+H] + , Calcd for 577.1692.

[0120] Example 32, 7-(4-(2-(2-((1,3,4-thiadiazol-2-yl)amino)-2-oxo-1-phenylethyl)-3-oxoisoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide

[0121] The intermediate 4-1 and 2-amino-1,3,4-thiadiazole were used as raw materials and the synthesis method of Example 1 was used to prepare the product. 1 HNMR (600 MHz, DMSO- d 6) δ 10.34 (s, 1H), 9.07 (br, 1H), 8.66 (s, 1H), 7.89 (s,1H), 7.86 (d, J =7.8 Hz, 1H), 7.67 (d, J =8.4 Hz, 2H), 7.62 (d, J =7.8 Hz, 1H),7.46–7.38 (m, 5H), 7.04 (d, J =8.4 Hz, 2H), 6.26 (s, 1H), 4.85 (m, 1H), 4.03(m, 3H), 1.97 (m, 2H), 1.73 (m, 2H), 1.54–1.50 (m, 2H), 1.43–1.40 (m, 2H),1.35–1.30 (m, 2H); 13C NMR (151 MHz, DMSO- d 6) δ 171.08, 169.60, 168.07, 159.05,150.89, 150.04, 148.20, 141.25, 140.37, 132.91, 132.10, 130.28, 129.35 (2C),129.32 (2C), 128.79, 128.50 (2C), 124.57, 120.50, 115.46 (2C), 67.95, 59.79,48.76, 32.67, 29.03, 28.80, 25.72, 25.55; HRMS (ESI) m / z : 586.2122 [M+H] + ,Calcd for 586.2124.

[0122] Example 33 N -hydroxy-7-(4-(2-(1-(2-hydroxyphenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)heptylamide

[0123] Prepared from methyl 2-bromo-2-(2-hydroxyphenyl)acetate and 6-bromoindazole using the synthesis method of Example 10. HRMS (ESI) m / z: 586.2120 [M+H] + , Calcd for 586.2124.

[0124] Example 34, 7-(4-(6-fluoro-2-(1-(3-fluorophenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide

[0125] Prepared from methyl 2-bromo-2-(3-fluorophenyl)acetate and 5-bromo-6-fluoroisoindoline using the synthesis method of Example 10. HRMS (ESI) m / z: 607.2186 [M+H] + , Calcd for 607.2191.

[0126] Example 35 N -hydroxy-7-(4-(2-(2-oxo-2-(thiazol-2-ylamino)-1-(2-(trifluoromethoxy)phenyl)ethyl)-2- H-indazol-6-yl)phenoxy)heptylamide

[0127] Prepared from methyl 2-bromo-2-(2-trifluoromethoxyphenyl)acetate and 5-bromo-6-fluoroisoindoline using the synthesis method of Example 10. HRMS (ESI) m / z: 654.1993 [M+H] + , Calcd for 654.1998.

[0128] Example 36, 7-(4-(2-(2-(cyclobutylamino)-2-oxo-1-phenylethyl)-3-oxoisoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide

[0129] Prepared from intermediate 4-1 and cyclobutylamine using the synthesis method of Example 1. HRMS (ESI) m / z: 556.2800 [M+H] + , Calcd for 556.2811.

[0130] Example 37 N -hydroxy-7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-((4,5,6,7-tetrahydrobenzo[ d ]thiazol-2-yl)amino)ethyl)isoindolin-5-yl)phenoxy)heptylamide

[0131] With intermediate 4-1 and 4,5,6,7-tetrahydrobenzo[ d ] Thiazole-2-amine was used as raw material and the synthesis method of Example 1 was adopted to prepare the product. 1 H NMR (600 MHz, DMSO- d 6) δ 10.36 (br, 1H), 8.69 (br, 1H), 7.89 (s,1H), 7.86 (m, 1H), 7.66 (m, 2H), 7.61 (m, 1H), 7.44–7.41 (m, 3H), 7.35 (m,2H), 7.04 (m, 2H), 6.23 (s, 1H), 4.86 (m, 1H), 4.01–3.96 (m, 3H), 2.62 (m,2H), 1.96 (m, 2H), 1.75 (m, 6H), 1.52 (m, 2H), 1.42 (m, 2H), 1.31 (m, 2H); 13CNMR (151 MHz, DMSO- d 6) δ 169.55, 169.11, 168.09, 159.07, 144.29, 141.23,140.42, 135.73, 132.79, 132.08, 130.34, 129.92, 129.44 (2C), 129.19 (2C),128.94, 128.51 (2C), 124.60, 121.72, 120.52, 115.46 (2C), 114.84, 67.95,48.78, 32.69, 29.04, 28.81, 26.46, 25.73, 25.56, 23.45, 23.12, 22.83; HRMS(ESI) m / z : 639.2641 [M+H] + , Calcd for 639.2641.

[0132] Example 38 N -hydroxy-7-(4-(3-oxo-2-(2-oxo-2-((4-oxo-4,5-dihydrothiazol-2-yl)amino)-1-phenylethyl)isoindolin-5-yl)phenoxy)heptylamide

[0133] Intermediate 4-1 and 2-aminothiazole-4(5 H )-ketone as raw material, prepared by the synthesis method of Example 1. HRMS (ESI) m / z : 639.2641 [M+H] + , Calcd for 639.2641.

[0134] Example 39 N -hydroxy-7-(4-(3-oxo-2-(1-oxo-3-phenyl-1-(thiazol-2-ylamino)propan-2-yl)isoindolin-5-yl)phenoxy)heptylamide

[0135] The product was prepared by using 5-bromo-2-bromomethylbenzoic acid methyl ester and 2-amino-3-phenylpropionic acid methyl ester hydrochloride as raw materials and the synthesis method of Example 1. 1 H NMR (600 MHz, DMSO- d6) δ 10.35 (br, 1H), 8.69 (br, 1H), 7.83 (m, 1H), 7.76 (s, 1H), 7.63 (m, 3H), 7.38 (br, 1H), 7.33 (m, 2H), 7.26–7.23 (m, 2H), 7.16–7.13 (m, 1H), 7.02 (m, 3H), 5.39 (m, 1H), 4.83 (d, J =18.0Hz, 1H), 4.55 (d, J =18.0 Hz, 1H), 4.00 (m, 2H), 3.50–3.47 (m, 1H), 3.24–3.19(m, 1H), 1.97–1.94 (m, 2H), 1.72–1.70 (m, 2H), 1.54–1.49 (m, 2H), 1.44–1.39(m, 2H), 1.33–1.29(m, 2H); 13 C NMR (151 MHz, DMSO- d 6) δ 170.15, 169.57,168.35, 159.04, 141.07, 140.32, 138.13, 137.71, 132.84, 132.04, 130.29,129.14 (2C), 128.87 (2C), 128.47 (2C), 127.07, 124.38, 120.46, 115.44 (2C),114.14, 114.12, 67.94, 55.91, 48.22, 40.39, 40.25, 40.11, 39.97, 39.84,39.70, 39.56, 35.74, 32.67, 29.03, 28.80, 25.71, 25.55; HRMS (ESI) m / z :599.2323 [M+H] + , Calcd for 599.2328.

[0136] Example 40, 7-(4-(2-(1-cyclopropyl-2-oxo-2-(thiazol-2-ylamino)ethyl)-3-oxoisoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide

[0137] The product was prepared using methyl 5-bromo-2-bromomethylbenzoate and methyl 2-amino-2-cyclopropylacetate hydrochloride as raw materials and the synthesis method of Example 1. 1 H NMR (600 MHz, DMSO- d 6) δ 12.35 (br, 1H), 10.35 (br,1H), 8.69 (br, 1H), 7.90 (d, J =7.8 Hz, 1H), 7.85 (s, 1H), 7.72 (d, J =7.8 Hz,1H), 7.67 (d, J =8.4 Hz, 2H), 7.48 (m, 1H), 7.20 (s, 1H), 7.04 (d, J =8.4 Hz,2H), 5.00 (d, J =18.0 Hz, 1H), 4.84 (d, J =18.0 Hz, 1H), 4.28 (d, 1H), 4.02 (m,2H), 1.97 (m, 2H), 1.73 (m, 2H), 1.54–1.49 (m, 2H), 1.46–1.39 (m, 2H), 1.33–1.28 (m, 2H), 0.88–0.84 (m, 1H), 0.68 (m, 2H), 0.32 (m, 2H); 13 C NMR (151 MHz, DMSO- d 6) δ 170.29, 169.54, 168.04, 159.05, 158.77, 141.41, 140.38, 138.16,133.01, 132.10, 130.24, 128.49 (2C), 124.53, 120.39, 115.46 (2C), 114.11,67.94, 59.71, 48.52, 32.68, 29.03, 28.80, 25.72, 25.55, 12.57, 4.53, 4.44; HRMS (ESI) m / z : 549.2164 [M+H] + , Calcd for 549.2172.

[0138] Example 41, 1-(6-(4-((7-(hydroxyamino)-7-oxoheptyl)oxy)phenyl)-1-oxoisoindolin-2-yl)- N-(thiazol-2-yl)cyclopentane-1-amide

[0139] The product was prepared by using 5-bromo-2-bromomethylbenzoic acid methyl ester and 1-amino-1-cyclopentanecarboxylic acid methyl ester as raw materials and the synthesis method of Example 1. 1 H NMR (600 MHz, DMSO- d 6) δ 11.94 (br, 1H), 10.35 (br, 1H), 8.69 (br, 1H), 7.89 (d, J =7.8 Hz, 1H), 7.77 (s, 1H), 7.69 (d, J =7.8 Hz, 1H),7.65 (d, J =8.4 Hz, 2H), 7.38 (s, 1H), 7.12 (s, 1H), 7.03 (d, J =8.4 Hz, 2H),4.74 (s, 2H), 4.01 (m, 2H), 2.41 (m, 2H), 2.17 (m, 2H), 1.97–1.94 (m, 2H),1.74–1.70 (m, 7H), 1.53–1.49 (m, 2H), 1.44–1.39 (m, 2H), 1.33–1.29 (m, 2H); 13 CNMR (151 MHz, DMSO- d 6) δ 172.67, 169.54, 168.34, 160.41, 159.03, 141.84,140.16, 137.74, 133.89, 132.19, 130.05, 128.44 (2C), 124.19, 120.12, 115.48(2C), 113.38, 69.49, 67.94, 63.27, 49.08, 35.45, 32.67, 29.02, 28.80, 25.71,25.55, 24.38 (2C); HRMS (ESI) m / z : 563.2324 [M+H] + , Calcd for 563.2328.

[0140] Example 42, 7-(4-(2-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)-3-oxoisoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide

[0141] The intermediate 4-1 and cyclohexylamine were used as raw materials and the synthesis method of Example 1 was used to prepare the compound. 1 H NMR (600 MHz, DMSO- d 6) δ 10.35 (br, 1H), 8.67 (br, 1H), 8.40 (d, J =7.8 Hz, 1H), 7.88(s, 1H), 7.84–7.82 (m, 1H), 7.66 (d, J =9.0 Hz, 2H), 7.60 (d, J =7.8 Hz, 1H),7.43–7.41 (m, 2H), 7.37–7.35 (m, 1H), 7.32–7.30 (m, 2H), 7.04 (d, J =9.0 Hz,2H), 6.08 (s, 1H), 4.87 (d, J =18.0 Hz, 2H), 4.02 (t, J =6.6 Hz, 2H), 3.96 (d, J =9.0 Hz, 2H), 3.66–3.61 (m, 1H), 1.96 (t, J =6.6 Hz, 2H), 1.79–1.65 (m, 6H), 1.56–1.50 (m, 3H), 1.45–1.40 (m, 2H), 1.33–1.30 (m, 2H), 1.28–1.23 (m, 2H), 1.22–1.19 (m, 1H), 1.16–1.08 (m, 2H).

[0142] Example 43 N -hydroxy-7-(4-(2-(2-(4-methylpiperazin-1-yl)-2-oxo-1-phenylethyl)-3-oxoisoindolin-5-yl)phenoxy)heptylamide

[0143] The intermediate 4-1 and 1-methylpiperazine were used as raw materials and the synthesis method of Example 1 was used to prepare the product. 1 H NMR (600 MHz, DMSO- d 6) δ 10.37 (br, 1H), 8.70 (br, 1H), 7.87 (s, 1H), 7.84 (d, J=7.8Hz, 1H), 7.66 (d, J =8.4 Hz, 2H), 7.58 (d, J =7.8 Hz, 1H), 7.48 (m, 1H), 7.42 (m,1H), 7.40 (m, 2H), 7.04 (d, J =8.4 Hz, 1H), 6.42 (s, 1H), 4.77 (d, J =17.4 Hz,1H), 4.00 (m, 2H), 3.80 (d, J =17.4 Hz, 1H), 3.61 (m, 1H), 3.45 (m, 2H), 3.23(m, 1H), 2.32 (m, 1H), 2.20 (m, 2H), 2.10 (s, 3H), 1.96 (m, 2H), 1.82 (m,1H), 1.73 (m, 2H), 1.52 (m, 2H), 1.41 (m, 2H), 1.31 (m, 2H). HRMS (ESI) m / z :585.3072 [M+H] + , Calcd for 585.3077.

[0144] Example 44, 7-(4-(2-(1-(3-fluoroazetidin-1-yl)-1-oxopropyl-2-yl)-3-oxoisoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide

[0145] The product was prepared by using 5-bromo-2-bromomethylbenzoic acid methyl ester and 2-aminopropionic acid methyl ester as raw materials and the synthesis method of Example 1. 1 H NMR (600 MHz, DMSO- d6) δ 10.35 (br, 1H), 8.68 (br, 1H), 7.86 (m,2H), 7.66 (m, 3H), 7.04 (m, 1H), 5.42–5.32 (m, 1H), 4.96 (m, 1H), 4.54–4.45(m, 3H), 4.39–4.33 (m, 1H), 4.19 (m, 1H), 4.01 (s, 2H), 3.95–3.89 (m, 1H), 1.96 (t, 2H), 1.72 (s, 2H) 1.52 (m, 2H), 1.42–1.38 (m, 5H), 1.32 (m, 2H).HRMS (ESI) m / z : 498.2392 [M+H] + , Calcd for 498.2404.

[0146] Example 45 N -hydroxy-7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-((thiazol-2-ylmethyl)amino)ethyl)isoindolin-5-yl)phenoxy)heptylamide

[0147] The intermediate 4-1 and thiazol-2-ylmethylamine were used as raw materials and the synthesis method of Example 1 was used to prepare the compound. 1 H NMR (600 MHz, DMSO- d 6) δ 10.35 (br, 1H), 9.35 (m, 1H), 8.67 (br, 1H), 7.89 (m,1H), 7.85–7.83 (m, 1H), 7.73 (m, 1H), 7.66–7.64 (m, 3H), 7.61 (m, 1H), 7.45–7.42 (m, 2H), 7.40–7.38 (m, 3H), 7.04 (m, 2H), 6.14 (s, 1H), 4.81 (d, J =17.4Hz, 1H), 4.69–4.60 (m, 2H), 4.01 (m, 2H), 3.98 (d, J =17.4 Hz, 1H), 1.96 (m,2H), 1.75–1.70 (m, 2H), 1.55–1.50 (m, 2H), 1.45–1.40 (m, 2H), 1.33–1.28 (m,2H). HRMS (ESI) m / z: 599.2323 [M+H] + , Calcd for 599.2328.

[0148] Example 46 N -hydroxy-7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-(phenylamino)ethyl)isoindolin-5-yl)phenoxy)heptylamide

[0149] The intermediate 4-1 and aniline were used as raw materials and the synthesis method of Example 1 was used to prepare the product. 1 H NMR (600 MHz, DMSO- d 6) δ 10.57 (s, 1H), 10.36 (s, 1H), 8.67 (s, 1H), 7.90 (s, 1H), 7.86 (m,1H), 7.67 (d, J =9.0 Hz, 2H), 7.64 (m, 3H), 7.48 (m, 2H), 7.43–7.40 (m, 3H), 7.34–7.32 (m, 2H), 7.10–7.07 (m, 1H), 7.04 (d, J =9.0 Hz, 2H), 6.27 (s, 1H), 4.88 (d, J =17.4 Hz, 1H), 4.02-3.98 (m, 3H), 1.97–1.95 (m, 2H), 1.75–1.70 (m,2H), 1.55–1.50 (m, 2H), 1.45–1.39 (m, 2H), 1.33–1.28 (m, 2H). HRMS (ESI) m / z :578.2649 [M+H] + , Calcd for 578.2655.

[0150] Example 47 N -hydroxy-7-(4-(2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-3-oxoisoindolin-5-yl)phenoxy)heptylamide

[0151] The product was prepared by using 5-bromo-2-bromomethylbenzoic acid methyl ester and 2-aminopropionic acid methyl ester as raw materials and the synthesis method of Example 1. 1 H NMR (600 MHz, DMSO- d6) δ 7.88–7.85 (m, 2H), 7.67–7.65 (m, 3H), 7.04(m, 2H), 5.33–5.29 (m, 1H), 4.57–4.46 (m, 2H), 4.02 (t, J =6.0 Hz, 2H), 3.52(m, 2H), 3.39 (m, 2H), 2.33–2.29 (m, 2H), 2.18–2.15 (m, 1H), 2.12 (s, 3H),2.09 (m, 1H), 1.97 (t, J =6.0 Hz, 2H), 1.73–1.71 (m, 2H), 1.54–1.50 (m, 2H), 1.43–1.38 (m, 2H), 1.36 (d, 3H), 1.33–1.31 (m, 2H). HRMS (ESI) m / z : 523.2914[M+H] + , Calcd for 523.2920.

[0152] Example 48 N -hydroxy-7-((5-(2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-3-oxoisoindolin-5-yl)pyridin-2-yl)oxy)heptylamide

[0153] The product was prepared using the synthesis method of Example 1 using 5-bromo-2-bromomethylbenzoic acid methyl ester and 2-aminopropionic acid methyl ester as raw materials. HRMS (ESI) m / z : 524.2867 [M+H] + , Calcd for 524.2873.

[0154] Example 49 N -hydroxy-7-(4-(3-oxo-2-(1,1,1-trifluoro-3-(4-methylpiperazin-1-yl)-3-oxopropan-2-yl)isoindolin-5-yl)phenoxy)heptylamide

[0155] The product was prepared using 5-bromo-2-bromomethylbenzoic acid methyl ester and 2-amino-3,3,3-trifluoropropionic acid methyl ester as raw materials and the synthesis method of Example 1. HRMS (ESI) m / z : 523.2915 [M+H] + , Calcd for 523.2920.

[0156] Embodiment 50 N -hydroxy-7-(4-((2-(2-(methylamino)-2-oxo-1-phenylethyl)-2 H -indazol-6-yl)amino)phenoxy)heptylamide (1) 2-(6-bromo-2 H -indazol-2-yl)- N Synthesis of methyl-2-phenylacetamide (14-2)

[0157] Intermediate 13-1 (1.2 g, 3.6 mmol) was dissolved in 10 mL of DMF. HATU (2.0 g, 5.4 mmol) and DIEA (0.9 g, 7.2 mmol) were added. After stirring at room temperature for 30 min, methylamine hydrochloride (0.6 g, 7.2 mmol) was added and the reaction continued at room temperature for 8 h. The reaction solution was poured into an appropriate amount of ice water, stirred, and filtered to obtain 0.4 g of intermediate 14-2.

[0158] (2) 7-(4-((2-(2-(methylamino)-2-oxo-1-phenylethyl)-2 H Synthesis of methyl (19-1)-indazol-6-yl)amino)phenoxy)heptanoate

[0159] Intermediate 14-2 (0.4 g, 1.2 mmol), methyl 7-(4-aminophenoxy)heptanoate (0.6 g, 2.3 mmol), and potassium carbonate (0.5 g, 3.5 mmol) were added to 5 mL of 2-butanol and heated to 100°C. Under nitrogen, Pd2(dba)3 (0.1 g, 0.12 mmol) and Xphos (0.8 g, 1.7 mmol) were added, and the reaction was continued for 7 h. The solvent was evaporated, and the residue was purified by column chromatography to obtain 0.3 g of intermediate 19-1.

[0160] (3) 7-(4-((2-(2-(methylamino)-2-oxo-1-phenylethyl)-2 H Synthesis of methyl (2-indazol-6-yl)amino)phenoxy)heptanoate (20-1)

[0161] At room temperature, the intermediate 19-1 obtained above was added to 5 mL of methanol / water, followed by an appropriate amount of LiOH, and stirring was continued for 5 h. The reaction solution was evaporated to dryness, and the residue was added to 5 mL of water. The pH was adjusted to 3 with concentrated hydrochloric acid, and the mixture was filtered to obtain 0.2 g of a white solid.

[0162] (4) 7-(4-((2-(2-(methylamino)-2-oxo-1-phenylethyl)-2 H -indazol-6-yl)amino)phenoxy)- N -((Tetrahydro-2 H Synthesis of 2-pyran-2-yl)oxy)heptylamide (21-1)

[0163] Intermediate 20-1 (0.2 g, 0.4 mmol) was added to 2 mL of DMF, and HATU (0.3 g, 0.7 mmol) and DIEA (0.1 g, 0.7 mmol) were added. After stirring at room temperature for 30 min, the mixture was added. O -(tetrahydro-2 H 2-pyran-2-yl)hydroxylamine (0.06 g, 0.5 mmol) was added and the reaction was continued at room temperature for 3 h. The reaction solution was poured into an appropriate amount of ice water, stirred, and filtered to obtain 0.2 g of a yellow solid.

[0164] (5) N -hydroxy-7-(4-((2-(2-(methylamino)-2-oxo-1-phenylethyl)-2 H Synthesis of (-indazol-6-yl)amino)phenoxy)heptylamide (Example 50)

[0165] The crude product was added to 2 mL of methanol and an appropriate amount of dilute hydrochloric acid. The mixture was allowed to react at room temperature for 2 h. The pH was adjusted to 6 with saturated sodium bicarbonate solution, filtered, and the solid was purified by column chromatography to obtain 59.0 mg of the title compound. HRMS (ESI) m / z :516.2600 [M+H] + , Calcd for 516.2611.

[0166] Example 51 N -hydroxy-4-(2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-3-oxoisoindolin-5-yl)benzamide

[0167] The product was prepared using the synthesis method of Example 1 using 5-bromo-2-bromomethylbenzoic acid methyl ester and 2-aminopropionic acid methyl ester as raw materials. HRMS (ESI) m / z : 423.2027 [M+H] + , Calcd for 423.2032.

[0168] Example 52N -hydroxy-3-(4-(2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-3-oxoisoindolin-5-yl)phenyl)acrylamide

[0169] The product was prepared using the synthesis method of Example 1 using 5-bromo-2-bromomethylbenzoic acid methyl ester and 2-aminopropionic acid methyl ester as raw materials. HRMS (ESI) m / z : 449.2194 [M+H] + , Calcd for 449.2198.

[0170] Embodiment 53 N -hydroxy-2-((2-(1-(4-methylpiperazin-1-yl)-1-oxopropyl-2-yl)-3-oxoisoindolin-5-yl)amino)pyrimidine-5-amide

[0171] Prepared using methyl 5-bromo-2-bromomethylbenzoate and methyl 2-aminopropionate as raw materials using the synthetic method of Example 50. HRMS (ESI) m / z : 440.2041 [M+H] + , Calcd for 440.2046.

[0172] Example 54 N -hydroxy-3-(4-((2-(1-(4-methylpiperazin-1-yl)-1-oxopropyl-2-yl)-3-oxoisoindolin-5-yl)amino)phenyl)acrylamide

[0173] Prepared using methyl 5-bromo-2-bromomethylbenzoate and methyl 2-aminopropionate as raw materials using the synthetic method of Example 50. HRMS (ESI) m / z : 464.2292 [M+H] + , Calcd for 464.2298.

[0174] Example 55 N -hydroxy-7-(4-(2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-4-(trifluoromethyl)-2 H -indazol-6-yl)phenoxy)heptylamide

[0175] 6-bromo-4-(trifluoromethyl)-2 H-indazole and methyl 2-bromopropionate were used as raw materials and prepared by the synthesis method of Example 10. HRMS (ESI) m / z : 576.2793 [M+H] + , Calcd for 576.2798.

[0176] Example 56 N -hydroxy-7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-(((5-(trifluoromethyl)thiazol-2-yl)methyl)amino)ethyl)isoindolin-5-yl)phenoxy)heptylamide

[0177] Prepared using intermediate 4-1 and (5-(trifluoromethyl)thiazol-2-yl)methylamine as raw materials using the synthesis method of Example 1. HRMS (ESI) m / z : 667.2197 [M+H] + , Calcd for 667.2202.

[0178] Example 57 N -hydroxy-7-(4-(4-methoxy-2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-2 H -indazol-6-yl)phenoxy)heptylamide

[0179] 6-bromo-4-methoxy-2 H -indazole and methyl 2-bromopropionate were used as raw materials and prepared by the synthesis method of Example 10. HRMS (ESI) m / z : 538.3024 [M+H] + , Calcd for 538.3029.

[0180] Example 58, 3-(3-chloro-4-(2-(1-(4-methylpiperazin-1-yl)-1-oxopropyl-2-yl)-3-oxoisoindolin-5-yl)phenyl)- N -Hydroxyacrylamide

[0181] The product was prepared using the synthesis method of Example 1 using 5-bromo-2-bromomethylbenzoic acid methyl ester and 2-aminopropionic acid methyl ester as raw materials. HRMS (ESI) m / z : 483.1792 [M+H] + , Calcd for 483.1799.

[0182] Example 59N -hydroxy-7-(4-((2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-1,1-dioxide-3-oxo-2,3-dihydrobenzo[ d ]isothiazol-5-yl)amino)phenoxy)heptylamide

[0183] 5-bromobenzo[ d ]isothiazole-3(2 H )-ketone-1,1-dioxo compound and methyl 2-bromopropionate were used as raw materials and prepared by the synthesis method of Example 50. HRMS (ESI) m / z : 588.2484 [M+H] + , Calcd for 588.2492.

[0184] Example 60 N -hydroxy-7-(4-(2-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-3-oxoisoindolin-5-yl)phenoxy)heptylamide

[0185] The product was prepared using 5-bromo-2-bromomethylbenzoic acid methyl ester and 2-aminoacetic acid methyl ester as raw materials and the synthesis method of Example 1. 1 H NMR (600 MHz, DMSO- d 6) δ 10.36 (s, 1H), 8.67 (s, 1H), 7.86 (m, 2H), 7.67 (m, 3H), 7.04 (m, 2H), 4.50 (m, 2H), 4.46 (m, 2H), 4.01 (m, 2H), 3.50(m, 2H), 3.45 (m, 2H), 2.35 (m, 2H), 2.28 (m, 2H), 2.20 (s, 3H), 1.96 (m,2H), 1.72 (m, 2H), 1.52 (m, 2H), 1.42 (m, 2H), 1.31 (m, 2H). HRMS (ESI) m / z :509.2759 [M+H] + , Calcd for 509.2764.

[0186] Example 61 N -hydroxy-7-(4-(2-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)-3-oxoisoindolin-5-yl)phenoxy)heptylamide

[0187] The product was prepared by using 5-bromo-2-bromomethylbenzoic acid methyl ester and 3-aminopropionic acid methyl ester as raw materials and the synthesis method of Example 1. 1 H NMR (600 MHz, DMSO- d 6) δ 10.35 (s, 1H), 8.67 (br, 1H), 7.84 (m, 2H), 7.65 (m, 2H), 7.04 (m, 2H), 4.54 (s, 2H), 4.01 (t, J =6.0 Hz, 2H), 3.76 (m,2H), 3.44 (m, 4H), 2.72 (m, 2H), 2.28 (m, 2H), 2.23 (m, 2H), 2.16 (s, 3H),1.97 (t, J =6.0 Hz, 2H), 1.74–1.70 (m, 2H), 1.55–1.50 (m, 2H), 1.44–1.39 (m,2H), 1.33–1.28 (m, 2H). HRMS (ESI) m / z : 523.2914 [M+H] + , Calcd for 523.2920.

[0188] Example 62 N -hydroxy-8-((4-(2-(1-((1-methylpiperazin-4-yl)amino)-1-oxopropan-2-yl)-2 H -indazol-6-yl)phenyl)thio)octanamide

[0189] 6-Bromo-2 H -indazole and methyl 2-bromopropionate were used as raw materials and prepared by the synthesis method of Example 10. HRMS (ESI) m / z : 552.3001 [M+H] + , Calcd for 552.3008.

[0190] Example 63 N -hydroxy-7-(4-(2-(2-(((5-methoxythiazol-2-yl)methyl)amino)-2-oxo-1-phenylethyl)-3-oxoisoindolin-5-yl)phenoxy)heptylamide

[0191] Prepared using intermediate 4-1 and (5-methoxythiazol-2-yl)methylamine as raw materials using the synthesis method of Example 1. HRMS (ESI) m / z : 629.2421 [M+H] + , Calcd for 629.2434.

[0192] Example 64, 7-(4-(2-(2-((5-fluorothiazol-2-yl)amino)-2-oxo-1-phenylethyl)-3-oxoisoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide

[0193] The intermediate 4-1 and 5-fluorothiazol-2-amine were used as raw materials and the synthesis method of Example 1 was used to prepare the product. HRMS (ESI) m / z : 603.2071 [M+H] + , Calcd for 603.2077.

[0194] Example 65 N -hydroxy-7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-((4-(trifluoromethyl)thiazol-2-yl)aminoethyl)isoindolin-5-yl)phenoxy)heptylamide

[0195] Prepared using intermediate 4-1 and 4-(trifluoromethyl)thiazol-2-amine as raw materials using the synthesis method of Example 1. HRMS (ESI) m / z : 653.2041 [M+H] + , Calcd for 653.2046.

[0196] Example 66 N -hydroxy-7-(4-(2-(1-((4-(methylamino)phenyl)amino-1-oxopropan-2-yl)-2 H -indazol-6-yl)phenoxy)heptylamide

[0197] 6-Bromo-2 H -indazole and methyl 2-bromopropionate were used as raw materials and prepared by the synthesis method of Example 10. HRMS (ESI) m / z : 530.2761 [M+H] + , Calcd for 530.2767.

[0198] Example 67, 7-(4-(2-(1-((4-acetylthiazol-2-yl)amino)-1-oxopropan-2-yl)-2 H -indazol-6-yl)phenoxy)- N -Hydroxyheptylamide

[0199] 6-Bromo-2 H -indazole and methyl 2-bromopropionate were used as raw materials and prepared by the synthesis method of Example 10. HRMS (ESI) m / z : 550.2119 [M+H] + , Calcd for 550.2124.

[0200] Example 68 N -hydroxy-7-(4-(2-(1-((3-methoxyphenyl)amino)-1-oxopropan-2-yl)-2 H -indazol-6-yl)phenoxy)heptylamide

[0201] 6-Bromo-2 H -indazole and methyl 2-bromopropionate were used as raw materials and prepared by the synthesis method of Example 10. HRMS (ESI) m / z : 531.2601 [M+H] + , Calcd for 531.2607.

[0202] Example 69, 7-(4-(2-(2-benzo[ d ]thiazol-2-ylamino)-2-oxo-1-phenylethyl)-3-oxoisoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide

[0203] With intermediate 4-1 and benzo[ d ] Thiazole-2-amine was used as raw material and the synthesis method of Example 1 was adopted to prepare the product. 1 H NMR (600 MHz, DMSO- d 6) δ 12.95 (br, 1H), 10.35 (s, 1H), 8.67 (s, 1H), 7.95 (br,1H), 7.90 (s, 1H), 7.88 (d, J =7.8 Hz,1H), 7.67–7.64 (m, 3H), 7.62 (d, J=7.8 Hz,1H), 7.48–7.46 (m, 2H), 7.43–7.41 (m, 4H), 7.28 (m, 1H), 7.04 (d, 2H), 6.31(s, 1H), 4.85 (m, 1H), 4.04–4.00 (m, 3H), 1.97 (m, 2H), 1.73–1.70 (m, 2H), 1.54–1.50 (m, 2H), 1.43–1.39 (m, 2H), 1.33–1.28 (m, 2H); 13 C NMR (151 MHz, DMSO- d 6) δ 170.73, 169.57, 168.17, 159.07, 149.15, 141.25, 140.45, 135.34,132.77, 132.14, 132.07, 130.39, 129.50 (2C), 129.36 (2C), 129.07, 128.51(2C), 126.42, 124.64, 123.80, 122.08, 120.77, 120.58, 120.54, 115.46 (2C),67.95, 59.43, 48.87, 32.68, 29.03, 28.80, 25.72, 25.55; HRMS (ESI) m / z :635.2326 [M+H] + , Calcd for 635.2328.

[0204] Embodiment 70 N -hydroxy-7-(4-(3-oxo-2-(2-oxo-2-((7-oxo-4,5,6,7-tetrahydrobenzo[ d ]thiazol-2-yl)amino)-1-phenylethyl)isoindolin-5-yl)phenoxy)heptylamide

[0205] With intermediate 4-1 and 2-amino-5,6-dihydrobenzo[ d ]thiazole-7(4 H )-ketone as raw material, and prepared by the synthesis method of Example 1. 1 H NMR (600 MHz, DMSO- d 6) δ 13.20 (br, 1H), 10.34 (s, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.67 (d, J =8.4 Hz, 2H), 7.62 (d, J =7.8 Hz, 1H), 7.47–7.42 (m, 3H), 7.37 (m, 2H), 7.04 (d, J =8.4 Hz, 2H), 6.25(s, 1H), 4.81 (m, 1H), 4.02–3.99 (m, 3H), 2.82 (m, 2H), 2.47 (m, 2H), 2.06(m, 2H), 1.97 (m, 2H), 1.74–1.70 (m, 2H), 1.54–1.50 (m, 2H), 1.44–1.39 (m,2H), 1.35–1.28 (m, 2H); 13 C NMR (151 MHz, DMSO- d 6) δ 192.27, 170.93, 169.57,168.17, 164.87, 159.07, 141.23, 140.45, 135.10, 132.70, 132.05, 130.41,130.14, 129.51 (2C), 129.34 (2C), 129.11, 128.51 (2C), 124.63, 123.68,120.53, 115.46 (2C), 67.95, 59.52, 48.85, 37.73, 32.68, 29.03, 28.80, 26.90,25.72, 25.55, 23.13; HRMS (ESI) m / z : 653.2431 [M+H] + , Calcd for 653.2434.

[0206] Example 71 N -(4-((7-(hydroxyamino)-7-oxoheptyl)oxy)phenyl)-2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-3-oxoisoindolin-5-amide (1) Synthesis of 2-(1-(4-methylpiperazin-1-yl)-1-oxopropyl-2-yl)-3-oxoisoindoline-5-carboxylic acid (23-1)

[0207] Under nitrogen, Pd(OAc)2 (33.7 mg, 0.15 mmol) and Xantphos (86.8 mg, 0.15 mmol) were added to 10 mL of DMF. Formic acid (35.0 mmol), 6-bromo-2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)isoindolin-1-one (1.8 g, 5.0 mmol), DCC (2.1 g, 10.0 mmol), and Et3N (1.0 g, 10.0 mmol) were then added. The mixture was reacted at 80°C for 13 h. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 0.8 g of intermediate 23-1.

[0208] (2) Synthesis of methyl 7-(4-(2-(1-(4-methylpiperazin-1-yl)-1-oxopropyl-2-yl)-3-oxoisoindolin-5-amide)phenoxy)heptanoate (24-1)

[0209] Intermediate 23-1 (0.56 g, 1.0 mmol) was dissolved in 5 mL of DMF. HATU (0.6 g, 1.5 mmol) and DIEA (0.23 g, 1.8 mmol) were added. After stirring at room temperature for 30 min, methyl 7-(4-aminophenoxy)heptanoate (0.33 g, 1.3 mmol) was added and the reaction continued at room temperature for 5 h. The reaction solution was poured into an appropriate amount of ice water, stirred, and filtered to obtain 0.5 g of intermediate 24-1.

[0210] (3) N Synthesis of -(4-((7-(hydroxyamino)-7-oxoheptyl)oxy)phenyl)-2-(1-(4-methylpiperazin-1-yl)-1-oxopropyl-2-yl)-3-oxoisoindoline-5-amide (Example 71)

[0211] Prepared according to the preparation method of Example 50. HRMS (ESI) m / z : 566.2965 [M+H] + , Calcd for566.2979.

[0212] Example 72 N -(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)phenyl)-2-(1-(4-methylpiperazin-1-yl)-1-oxoprop-2-yl)-3-oxoisoindoline-5-amide

[0213] Prepared using methyl 5-bromo-2-bromomethylbenzoate and methyl 2-aminopropionate as raw materials using the synthetic method of Example 71. HRMS (ESI) m / z : 492.2234 [M+H] + , Calcd for 492.2247.

[0214] Example 73 N -(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-2-(1-(4-methylpiperazin-1-yl)-1-oxoprop-2-yl)-2 H -Indazole-6-carboxamide

[0215] 6-Bromo-2 H -indazole and methyl 2-bromopropionate were used as raw materials and prepared by the synthesis method of Example 71. HRMS (ESI) m / z : 491.2391 [M+H] + , Calcd for 491.2407.

[0216] Example 74, 3-(4-(2-(4-fluoro-2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-2 H -indazole-6-carbonyl)hydrazine)phenyl)- N -Hydroxyacrylamide

[0217] 6-bromo-4-fluoro-2 H -indazole and methyl 2-bromopropionate were used as raw materials and prepared by the synthesis method of Example 71. HRMS (ESI) m / z : 510.2253 [M+H] + , Calcd for 510.2265.

[0218] Example 75 N -(4-fluoro-2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-2 H -indazole-6-yl)-4-((7-(hydroxyamino)-7-oxoheptyl)oxy)benzamide (1) 2-(6-amino-4-fluoro-2 H Synthesis of 1-(4-methylpiperazin-1-yl)-1-indazol-2-yl)-1-(4-methylpiperazin-1-yl)propan-1-one (34-1)

[0219] Intermediate 33-1 (5.0 g, 14.9 mmol) was added to 50 mL of 90% ethanol. Reduced iron powder (2.5 g, 44.8 mL) and 1 drop of concentrated hydrochloric acid were added, and the mixture was refluxed for 3 h. The mixture was filtered while hot, and the filtrate was evaporated to dryness to obtain 3.9 g of a brown solid 34-1.

[0220] (2) 7-(4-((4-fluoro-2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-2 H Synthesis of methyl (35-1)-indazol-6-yl)carbamoyl)phenoxy)heptanoate

[0221] Intermediate 34-1 (3.0 g, 9.8 mmol) was added to 20 mL of DMF, followed by 4-((7-methoxy-7-oxoheptyl)oxy)benzoic acid (3.3 g, 11.8 mmol), HATU (5.6 g, 14.7 mmol), and DIEA (1.9 g, 14.7 mmol). The mixture was stirred at room temperature for 4 h. The reaction mixture was poured into 50 mL of ice water, stirred thoroughly, and filtered to obtain 4.7 g of intermediate 35-1.

[0222] (3) 7-(4-((4-fluoro-2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-2 H Synthesis of 6-indazol-6-yl)carbamoyl)phenoxy)heptanoic acid (36-1)

[0223] Intermediate 35-1 (1.0 g, 1.8 mmol) was added to 10 mL of methanol and 2 mL of water, followed by the addition of lithium hydroxide (0.2 g, 9.0 mmol). The mixture was allowed to react at 50°C for 2 h. The methanol was evaporated under reduced pressure, and 10 mL of water was added to the residue. The pH was adjusted to 3 with hydrochloric acid, and the mixture was filtered to obtain 0.7 g of intermediate 36-1.

[0224] (4) N -(4-fluoro-2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-2 H Synthesis of 6-(7-(hydroxyamino)-7-oxoheptyl)oxy)benzamide (Example 75)

[0225] Prepared using intermediate 36-1 as raw material by the method of Example 1. HRMS (ESI) m / z : 569.2876 [M+H] +, Calcd for 569.2888.

[0226] In vitro enzyme activity assay—fluorimetry The inhibitory activity of target compounds against HDACs was determined by fluorescence assay using SAHA as a positive control. The reaction system used assay buffer containing 50 mM Tris-HCl (pH 7.5), 0.01% (v / v) Tween-20, and 50 mM NaCl. A 10 mM stock solution of the test compound was diluted with DMSO to a 100-fold working concentration of the target concentration. Subsequently, 250 nL was accurately transferred to the assay plate using an Echo 650 acoustic pipetting system (Labcyte). The diluted compound was preincubated with 15 μL of recombinant human HDAC1 enzyme (final concentration 10 nM) in assay buffer for 15 minutes at room temperature (25 ± 2°C). The enzymatic reaction was initiated by the addition of 10 μL of a fluorogenic substrate solution containing the peptide Ac-LGK(Ac)-AMC (final concentration 8 μM) and trypsin (final concentration 0.05 μM). Fluorescence signals were monitored continuously for 30 min using a Paradigm multi-function microplate reader in kinetic mode (excitation wavelength 355 nm, emission wavelength 460 nm). Working solutions of the test compounds were prepared by a three-fold serial dilution in DMSO at five concentration points, and enzyme activity was determined as described above. Raw data were normalized to blank control wells containing only 1% DMSO. Concentration-response curves were fitted using a four-parameter nonlinear regression model, and the half-maximal inhibitory concentration (IC50) was calculated using MS Excel software with the XLFit plug-in. 50 ), the results are shown in Table 1 below.

[0227] Table 1:

[0228] In vitro antitumor activity assay—MTT assay NCI-H1975 cells, A549 cells, MV-4-11 cells, and HepG2 cells in the logarithmic growth phase were selected and digested with 0.25% trypsin to prepare single cell suspensions. The cell suspensions were counted using a platelet counter and diluted with complete medium to the desired density. Blank control wells, cell control wells, and experimental wells were set up in a 96-well plate. The diluted cell suspension was evenly inoculated into the cell control wells and experimental wells at a rate of 200 μL / well. The number of cells in each well was 3×10 3 –6×10 3 Then, they were placed in a 37°C, 5% CO2 incubator for 24 h. The starting concentration of the drug in both the experimental and positive control groups was 10.0 μg / mL, and a 3-fold gradient dilution was used to create five concentration gradients. After 24 h of incubation, the 96-well plate was removed, the cell culture medium discarded, and 170 μL / well of the drug solution at different concentrations was added to the experimental wells. Complete medium without drug was added to the cell control wells. The cells were then incubated in a 37°C, 5% CO2 incubator for 72 h. The 96-well plate cultured for 72 h was removed, the cell culture medium was discarded, and 100 μL of MTT solution (0.5 mg / mL) was added to each well under light-proof conditions. The plate was incubated in an incubator for another 4 h. The culture medium was removed, and 100 μL of DMSO was added to each well. The plate was shaken for 5 min. The OD value of each well at dual wavelengths of 490 nm and 630 nm was measured using a full-band microplate reader. The difference between the two values ​​was taken, and the half-maximal inhibitory concentration (IC) was calculated using GraphPadPrism 8.0. 50 values ​​(Table 2).

[0229] Table 2:

[0230] It can be clearly seen from the above test results that the compound of general formula I to be protected by the present invention has good in vitro anti-tumor activity and HDAC1 inhibitory activity, which is equivalent to or better than the marketed anticancer drug SAHA.

[0231] The compounds of general formula I of the present invention can be administered alone, but are usually administered in admixture with a pharmaceutical carrier. The choice of the pharmaceutical carrier should be based on the desired route of administration and standard pharmaceutical practice. The following uses the preparation methods of various pharmaceutical dosage forms of such compounds, such as tablets, capsules, injections, aerosols, suppositories and ointments, to illustrate their new applications in the pharmaceutical field.

[0232] Example 76: Tablets 10.0 g of a compound containing the compound of claim 1 (using the compound of Example 12 as an example) was added with 20.0 g of excipients and mixed uniformly according to a general pharmaceutical tableting method, and then compressed into 100 tablets, each weighing 300 mg.

[0233] Example 77: Capsules 10.0 g of the compound according to claim 1 (using the compound of Example 25 as an example) was mixed with 20.0 g of excipients according to the requirements of pharmaceutical capsules, and then filled into hollow capsules. Each capsule weighed 300 mg.

[0234] Example 78: Injection 10.0 g of the compound according to claim 1 (using the compound of Example 28 as an example) was adsorbed on activated carbon according to conventional pharmaceutical methods. After filtration through a 0.65 μm microporous filter membrane, the solution was filled into a nitrogen tank to prepare an aqueous injection preparation, each containing 2 mL, for a total of 100 bottles.

[0235] While the present invention has been described with reference to specific embodiments, modifications and equivalents will be apparent to those skilled in the art and are intended to fall within the scope of the present invention.

Claims

1. A novel hydroxamic acid derivative, characterized in that: The novel hydroxamic acid derivative is a compound having a structure shown in Formula I or a stereoisomer or an optical isomer or a pharmaceutically acceptable salt thereof. Where, Y is none, CONH, CONHNH, CONHCH2 or NH; Z1, Z2, Z3 are N or CH; m, p are 0 or 1; R1 and R2 are none, a halogen atom, –(C1-C2 alkyl), –(C1-C3 alkoxy), or –(C1-C2 haloalkyl); Cy is 、 、 、 or , wherein R3 is hydrogen, methyl or halogen atom; W1 is hydrogen, a 3-6 membered cycloalkyl group, a 6-10 membered aryl group, a 5-10 membered heterocyclic group, -(C1-C3 haloalkyl), one -(C1-C4 alkyl) group or two identical or different -(C1-C4 alkyl) groups. The above heterocyclic ring may contain 1-3 identical or different nitrogen, sulfur or oxygen atoms. The aryl and heterocyclic groups may be unsubstituted or substituted with 1-2 -(C1-C2 alkyl), -(C1-C2 alkoxy), halogen atoms, trifluoromethyl, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2 or hydroxyl groups; W2 is a 4-6 membered cycloalkyl, a 4-10 membered (fused) heterocycle, a 6-10 membered aryl-(C1-C3 alkyl) or a -(C1-C3 alkyl) 1-2 N(C1-C3 alkyl), the above heterocyclic ring may contain 1-3 identical or different nitrogen, sulfur or oxygen atoms, and may be unsubstituted or substituted with 1-3 –(C1-C2 alkyl), –(C1-C2 alkoxy), –(C1-C2 acyl), halogen atoms, trifluoromethyl or –NH(C1-C3 alkyl); W3 is none, or , wherein X is O, S or NHCO, and n is 5, 6 or 7.

2. The novel hydroxamic acid derivative according to claim 1, characterized in that The compound having the structure shown in Formula I forms a pharmaceutically acceptable salt with an acid; the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid or benzoic acid.

3. The novel hydroxamic acid derivative according to claim 2, characterized in that The halogen atom is fluorine or chlorine; the alkyl group is a straight chain or branched chain alkyl group; and the ring is a monocyclic ring or a condensed ring.

4. The novel hydroxamic acid derivative according to claim 1, characterized in that At least one selected from the following compounds: N -Synthesis of hydroxy-7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isothiazolin-5-yl)phenoxy)heptylamide; N 1 -Hydroxy- N 7 Synthesis of -(4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenyl)pimelanediamide; N -(7-(hydroxyamino)-7-oxoheptyl)-4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)benzamide; N -hydroxy-8-(4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenoxy)octanamide; N -hydroxy-6-(4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenoxy)hexanamide; 7-(2-fluoro-4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide; N -hydroxy-7-(3-methyl-4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenoxy)heptylamide; N -hydroxy-7-(3-methoxy-4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenoxy)heptylamide; N -hydroxy-7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)-2-(trifluoromethyl)phenoxy)heptylamide; N -hydroxy-7-(4-(2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)heptylamide; 7-(4-(4-chloro-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)- N -Hydroxyheptylamide; N -hydroxy-7-(4-(2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenoxy)heptylamide; N -hydroxy-7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2,3-dihydrobenzo[ d ]isoxazol-5-yl)phenoxy)heptylamide; 7-(4-(7-fluoro-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)- N -Hydroxyheptylamide; N -hydroxy-7-(4-(4-methyl-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)heptylamide; N -hydroxy-7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2,3-dihydrobenzo[ d ]isoxazol-5-yl)phenoxy)heptylamide; 7-(4-(7-fluoro-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)- N -Hydroxyheptylamide; 7-(4-(4-chloro-2-(1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-2 H -indazol-6-yl)phenoxy)- N -Hydroxyheptylamide; N -hydroxy-7-(4-(4-methyl-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)heptylamide; N -hydroxy-7-(4-(2-(2-methyl-1-oxo-1-(thiazol-2-ylamino)butan-2-yl)-3-oxoisoindolin-5-yl)phenoxy)heptylamide; 7-(4-(3-fluoro-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)- N -Hydroxyheptylamide; N -hydroxy-7-(4-(3-methyl-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)heptylamide; N -hydroxy-7-(4-(3-oxo-2-(1-oxo-1-(thiazol-2-ylamino)butan-2-yl)isoindolin-5-yl)phenoxy)heptylamide; N -hydroxy-7-(4-(2-(1-(naphthalen-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-3-oxoisoindolin-5-yl)phenoxy)heptylamide; N -hydroxy-7-(4-(2-(2-methyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-oxoisoindolin-5-yl)phenoxy)heptylamide; 7-(4-(2-(1-(furan-2-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)- N -Hydroxyheptylamide; N -hydroxy-7-(4-(2-(2-oxo-1-(pyridin-3-yl)-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)heptylamide; 7-(4-(2-(1-(2-fluorophenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide; 7-(4-(2-(1-((2-(dimethylamino)ethyl)(methyl)amino)-1-oxopropan-2-yl)-3-oxoisoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide; 7-(4-(2-(1-(4-fluorophenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide; 7-(4-(2-(1-(4-chloro-2-fluorophenyl)-2-oxo-2-thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)- N -Hydroxyheptylamide; N -hydroxy-7-(4-(2-(2-oxo-2-(thiazol-2-ylamino)-1-(3-(trifluoromethyl)phenyl)ethyl)-2- H -indazol-6-yl)phenoxy)heptylamide; N -hydroxy-7-(4-(2-(1-(3-(methylamino)phenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)heptylamide; N -hydroxy-7-(4-(2-(2-oxo-1-(thiazol-2-yl)-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)heptylamide; 7-(4-(2-(2-((1,3,4-thiadiazol-2-yl)amino)-2-oxo-1-phenylethyl)-3-oxoisoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide; N -hydroxy-7-(4-(2-(1-(2-hydroxyphenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-2 H -indazol-6-yl)phenoxy)heptylamide; 7-(4-(6-fluoro-2-(1-(3-fluorophenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide; N -hydroxy-7-(4-(2-(2-oxo-2-(thiazol-2-ylamino)-1-(2-(trifluoromethoxy)phenyl)ethyl)-2- H -indazol-6-yl)phenoxy)heptylamide; 7-(4-(2-(2-(cyclobutylamino)-2-oxo-1-phenylethyl)-3-oxoisoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide; N -hydroxy-7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-((4,5,6,7-tetrahydrobenzo[ d ]thiazol-2-yl)amino)ethyl)isoindolin-5-yl)phenoxy)heptylamide N -hydroxy-7-(4-(3-oxo-2-(2-oxo-2-((4-oxo-4,5-dihydrothiazol-2-yl)amino)-1-phenylethyl)isoindolin-5-yl)phenoxy)heptylamide; N -hydroxy-7-(4-(3-oxo-2-(1-oxo-3-phenyl-1-(thiazol-2-ylamino)propan-2-yl)isoindolin-5-yl)phenoxy)heptylamide; 7-(4-(2-(1-cyclopropyl-2-oxo-2-(thiazol-2-ylamino)ethyl)-3-oxoisoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide; 7-(4-(6-fluoro-2-(1-(3-fluorophenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)isoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide; N -hydroxy-7-(4-(2-(2-oxo-2-(thiazol-2-ylamino)-1-(2-(trifluoromethoxy)phenyl)ethyl)-2- H -indazol-6-yl)phenoxy)heptylamide; 7-(4-(2-(2-(cyclobutylamino)-2-oxo-1-phenylethyl)-3-oxoisoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide; N -hydroxy-7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-((4,5,6,7-tetrahydrobenzo[ d ]thiazol-2-yl)amino)ethyl)isoindolin-5-yl)phenoxy)heptylamide; N -hydroxy-7-(4-(3-oxo-2-(2-oxo-2-((4-oxo-4,5-dihydrothiazol-2-yl)amino)-1-phenylethyl)isoindolin-5-yl)phenoxy)heptylamide; N -hydroxy-7-(4-(3-oxo-2-(1-oxo-3-phenyl-1-(thiazol-2-ylamino)propan-2-yl)isoindolin-5-yl)phenoxy)heptylamide; 7-(4-(2-(1-cyclopropyl-2-oxo-2-(thiazol-2-ylamino)ethyl)-3-oxoisoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide; 1-(6-(4-((7-(hydroxyamino)-7-oxoheptyl)oxy)phenyl)-1-oxoisoindolin-2-yl)- N -(thiazol-2-yl)cyclopentane-1-carboxamide; 7-(4-(2-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)-3-oxoisoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide; N -hydroxy-7-(4-(2-(2-(4-methylpiperazin-1-yl)-2-oxo-1-phenylethyl)-3-oxoisoindolin-5-yl)phenoxy)heptylamide; 7-(4-(2-(1-(3-fluoroazetidin-1-yl)-1-oxopropan-2-yl)-3-oxoisoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide; N -hydroxy-7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-((thiazol-2-ylmethyl)amino)ethyl)isoindolin-5-yl)phenoxy)heptylamide; N -hydroxy-7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-(phenylamino)ethyl)isoindolin-5-yl)phenoxy)heptylamide; N -hydroxy-7-(4-(2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-3-oxoisoindolin-5-yl)phenoxy)heptylamide; N -hydroxy-7-((5-(2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-3-oxoisoindolin-5-yl)pyridin-2-yl)oxy)heptylamide; N -hydroxy-7-(4-(3-oxo-2-(1,1,1-trifluoro-3-(4-methylpiperazin-1-yl)-3-oxopropan-2-yl)isoindolin-5-yl)phenoxy)heptylamide; N -hydroxy-7-(4-((2-(2-(methylamino)-2-oxo-1-phenylethyl)-2 H -indazol-6-yl)amino)phenoxy)heptylamide; N -hydroxy-4-(2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-3-oxoisoindolin-5-yl)benzamide; N -hydroxy-3-(4-(2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-3-oxoisoindolin-5-yl)phenyl)acrylamide; N -hydroxy-2-((2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-3-oxoisoindolin-5-yl)amino)pyrimidine-5-amide; N -hydroxy-3-(4-((2-(1-(4-methylpiperazin-1-yl)-1-oxopropyl-2-yl)-3-oxoisoindolin-5-yl)amino)phenyl)acrylamide; N -hydroxy-7-(4-(2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-4-(trifluoromethyl)-2 H -indazole-6-yl)phenoxy)heptylamide; N -hydroxy-7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-(((5-(trifluoromethyl)thiazol-2-yl)methyl)amino)ethyl)isoindolin-5-yl)phenoxy)heptylamide; N -hydroxy-7-(4-(4-methoxy-2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-2 H -indazol-6-yl)phenoxy)heptylamide; 3-(3-chloro-4-(2-(1-(4-methylpiperazin-1-yl)-1-oxopropyl-2-yl)-3-oxoisoindolin-5-yl)phenyl)- N -hydroxyacrylamide; N -hydroxy-7-(4-((2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-1,1-dioxide-3-oxo-2,3-dihydrobenzo[ d ]isothiazol-5-yl)amino)phenoxy)heptylamide; N -hydroxy-7-(4-(2-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-3-oxoisoindolin-5-yl)phenoxy)heptylamide; N -hydroxy-7-(4-(2-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)-3-oxoisoindolin-5-yl)phenoxy)heptylamide; N -hydroxy-8-((4-(2-(1-((1-methylpiperazin-4-yl)amino)-1-oxopropan-2-yl)-2 H -indazol-6-yl)phenyl)thio)octanamide; N -hydroxy-7-(4-(2-(2-(((5-methoxythiazol-2-yl)methyl)amino)-2-oxo-1-phenylethyl)-3-oxoisoindolin-5-yl)phenoxy)heptylamide; 7-(4-(2-(2-((5-fluorothiazol-2-yl)amino)-2-oxo-1-phenylethyl)-3-oxoisoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide; N -hydroxy-7-(4-(3-oxo-2-(2-oxo-1-phenyl-2-((4-(trifluoromethyl)thiazol-2-yl)aminoethyl)isoindolin-5-yl)phenoxy)heptylamide; N -hydroxy-7-(4-(2-(1-((4-(methylamino)phenyl)amino-1-oxopropan-2-yl)-2 H -indazol-6-yl)phenoxy)heptylamide; 7-(4-(2-(1-((4-acetylthiazol-2-yl)amino)-1-oxopropan-2-yl)-2 H -indazol-6-yl)phenoxy)- N -Hydroxyheptylamide; N -hydroxy-7-(4-(2-(1-((3-methoxyphenyl)amino)-1-oxopropan-2-yl)-2 H -indazol-6-yl)phenoxy)heptylamide; 7-(4-(2-(2-benzo[ d ]thiazol-2-ylamino)-2-oxo-1-phenylethyl)-3-oxoisoindolin-5-yl)phenoxy)- N -Hydroxyheptylamide; N -hydroxy-7-(4-(3-oxo-2-(2-oxo-2-((7-oxo-4,5,6,7-tetrahydrobenzo[ d ]thiazol-2-yl)amino)-1-phenylethyl)isoindolin-5-yl)phenoxy)heptylamide; N -(4-((7-(hydroxyamino)-7-oxoheptyl)oxy)phenyl)-2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-3-oxoisoindolin-5-amide; N -(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)phenyl)-2-(1-(4-methylpiperazin-1-yl)-1-oxoprop-2-yl)-3-oxoisoindoline-5-amide; N -(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-2-(1-(4-methylpiperazin-1-yl)-1-oxoprop-2-yl)-2 H -indazole-6-carboxamide; 3-(4-(2-(4-fluoro-2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-2 H -indazole-6-carbonyl)hydrazine)phenyl)- N -hydroxyacrylamide; N -(4-fluoro-2-(1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-2 H -indazole-6-yl)-4-((7-(hydroxyamino)-7-oxoheptyl)oxy)benzamide.

5. A pharmaceutical composition comprising the novel hydroxamic acid derivative according to any one of claims 1 to 4 as an active ingredient and a pharmaceutically acceptable excipient.

6. Use of the novel hydroxamic acid derivative according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 5 in at least one of the following aspects: (1) Use in the preparation of drugs for treating and / or preventing proliferative diseases; (2) Use in the preparation of drugs for treating and / or preventing histone deacetylase-mediated diseases; (3) Application in the preparation of histone deacetylase inhibitors.

7. The use according to claim 6, characterized in that: The histone deacetylase-mediated disease is cancer.

8. The use according to claim 7, characterized in that: The cancer is leukemia, T-cell lymphoma, non-small cell lung cancer, small cell lung cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, gastric cancer or multiple myeloma.

9. The use according to claim 6, characterized in that: The novel hydroxamic acid derivative or pharmaceutical composition is used alone as the sole anti-tumor drug, or is used in combination with an anti-tumor drug currently on the market.

10. The method for preparing the novel hydroxamic acid derivative according to claim 1, characterized in that: (1) When Cy in Formula I is When Y does not exist, the target compound is prepared by using methyl 5-bromo-2-(bromomethyl)benzoate and a methyl carboxylate derivative as raw materials via synthetic route 1: ； (2) When Cy in Formula I is 、 、 or , and when Y does not exist, bromoisoindoline, bromobenzo[ d ]Isoxazole-3(2 H )-ketone, bromoindazole or bromobenzo[ d ]isothiazole-3(2 H )-ketone-1,1-dioxo compound and bromocarboxylate were used as raw materials to prepare the target compound via synthetic route 2: ； (3) When Y in the general formula I is NH, the intermediate 5 in (1) or the intermediate 14 in (2) is used as a starting material, and the target compound is prepared according to the synthetic route 3 through reactions such as Buchwald-Hartwig coupling: ； (4) When Y in Formula I is CONH, CONHNH or CONHCH2, the target compound is prepared using intermediate 14 as a starting material via synthetic route 4; ； Alternatively, intermediate 23 may be used as a raw material to prepare the target compound according to synthetic route 5, route 6 or route 7: Among them, Route 5: ； Route 6: ； Route 7: 。

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