Amide / sulfonamide-based CXCR4 / HDAC dual inhibitors and their preparation methods and uses

Abstract

The present invention discloses a class of amide / sulfonamide CXCR4 / HDAC dual inhibitors, their preparation methods and applications. Based on the principle of rational drug design, the present invention designs and synthesizes novel small-molecule compounds with multi-targets having CXCR4 and HDAC inhibitory activities, and having potential anti-tumor, anti-inflammatory and anti-depressant activities. The compounds of the present invention introduce a hydroxamic acid structure that can improve anti-tumor, anti-inflammatory and anti-depressant activities, improve anti-tumor, anti-inflammatory and anti-depressant activities, and have good improvement on the disadvantages of long treatment time and large side effects of currently used anti-tumor, anti-inflammatory and anti-depressant compounds. The CXCR4 / HDAC dual inhibitors of the present invention have both CXCR4 antagonistic effect and HDAC inhibitory effect, and are a class of multi-target hydroxamic acid derivatives that achieve anti-tumor, anti-inflammatory and anti-depressant effects synergistically with benzamide / benzenesulfonamide groups and hydroxamic acid.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and particularly relates to a class of amide / sulfonamide CXCR4 / HDAC dual inhibitors, their preparation methods and applications. Background Art

[0002] CXC chemokine receptor 4 (CXCR4) is a class of seven-transmembrane G protein-coupled receptors. By binding to CXC chemokine ligand 12 (CXCL12) of the CXC family, it participates in a variety of downstream signaling pathways and plays an important role in tumor invasion and metastasis, human immunodeficiency virus (HIV) infection, and inflammatory responses. Research shows that CXCR4 antagonists can block the CXCR4 / CXCL12 signaling pathway, thereby inhibiting the invasion of tumor cells and the chemotaxis of inflammatory cells. Currently, several CXCR4 antagonists are in the clinical research stage for anti-tumor and anti-inflammatory treatments. In addition, there is also research indicating that CXCR4 can mediate the occurrence of depression by regulating the release of neurotransmitters on the presynaptic membrane of neurons. Therefore, CXCR4 is a potential effective target for anti-tumor, anti-inflammatory, and anti-depressant treatments.

[0003] Histone deacetylases (HDACs) are a class of epigenetic enzymes that jointly regulate the acetylation level of histones with histone acetyltransferases (HATs). In vivo, the dysregulation of acetylation levels can affect cell proliferation and differentiation, as well as the normal function of the immune system, thereby triggering various diseases such as cancer and inflammation. HDAC inhibitors have received much attention in cancer treatment. Rational use of HDAC inhibitors can interfere with the cell cycle, differentiation, and apoptosis of tumor cells while normal cells are relatively tolerant. Currently, five HDAC inhibitors have been clinically used for the treatment of malignant tumors. In addition, HDACs also participate in the regulation of multiple inflammatory signaling pathways and affect the expression of various inflammatory factors. Moreover, experiments have shown that HDAC can change the epigenetics in the central nervous system and affect brain activities. According to a large amount of preclinical data and research on animal depression models, HDAC inhibitors can play an important role in the pathophysiological process of depression. For example, the classic HDAC inhibitor vorinostat can effectively reduce the depressive-like behavior of mice, counteract the inflammatory response caused by depression, and reverse the level of coenzyme Q10 in the hippocampus. Therefore, HDACs are a potential anti-tumor, anti-inflammatory, and anti-depressant target. The applicant has previously developed some multi-target inhibitors that can act on HDAC. For details, please refer to the patent specifications with publication numbers CN118084732A, CN117924217A, and CN113956182A, etc.

[0004] As introduced above, CXCR4 and HDAC are two anti-tumor, anti-inflammatory and antidepressant targets with great prospects. Therefore, by integrating the pharmacophores of CXCR4 antagonists and HDAC inhibitors according to the principles of rational drug design, the development of novel small molecule inhibitors with dual CXCR4 / HDAC inhibitory effects is expected to open up new directions for anti-tumor, anti-inflammatory and antidepressant treatments. Currently, there is relatively little relevant research, which has great research significance and translational value. Summary of the Invention

[0005] In view of the above technical problems and deficiencies in the art, the present invention provides a class of amide / sulfonamide CXCR4 / HDAC dual inhibitors, which are expected to improve the deficiencies of single-target anti-tumor, anti-inflammatory and antidepressant drugs and enhance their biological activities simultaneously.

[0006] The amide / sulfonamide CXCR4 / HDAC dual inhibitors are compounds having the structures shown in formula (I) or (II) and / or their pharmaceutically acceptable salts:

[0007]

[0008] In formula (I) and (II):

[0009] R1 is selected from the following structures:

[0010] R2 is selected from H, C1-C4 alkyl;

[0011] R3 is selected from the following structures:

[0012] R4 is selected from the following structures: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, where n is an integer from 1 to 4, represents the site connected to R3.

[0013] Furthermore, the amide / sulfonamide CXCR4 / HDAC dual inhibitors can be compounds having the following structures and / or their pharmaceutically acceptable salts:

[0014]

[0015]

[0016]

[0017] The present invention also provides a method for preparing the amide / sulfonamide CXCR4 / HDAC dual inhibitor, and the synthetic route includes:

[0018]

[0019] The preparation method includes:

[0020] 4-Bromomethylbenzenesulfonyl chloride or 4-chloromethylbenzoyl chloride is subjected to a condensation reaction with compound 11 to obtain intermediate 2 or 7;

[0021] Intermediate 2 or 7 is subjected to a nucleophilic substitution reaction with compound 12 to obtain intermediate 3 or 8;

[0022] Intermediate 3 or 8 is deprotected by Boc (tert-butoxycarbonyl) to generate intermediate 4 or 9;

[0023] Intermediate 4 or 9 is subjected to a substitution or condensation reaction with compound 13 to obtain intermediate 5 or 10;

[0024] Intermediate 5 or 10 undergoes an amine-ester exchange reaction to obtain the amide / sulfonamide CXCR4 / HDAC dual inhibitor.

[0025] The present invention also provides the use of the amide / sulfonamide CXCR4 / HDAC dual inhibitor in the preparation of a drug for preventing and treating related diseases by antagonizing CXCR4 and / or inhibiting HDAC. Further, the diseases may include cancer, inflammation, depression, etc.

[0026] As a general inventive concept, the present invention also provides a pharmaceutical composition containing a safe and effective amount of the amide / sulfonamide CXCR4 / HDAC dual inhibitor.

[0027] The pharmaceutical composition may further include at least one of a pharmaceutically acceptable excipient, carrier, and auxiliary material.

[0028] The pharmaceutical composition can prevent and treat related diseases by antagonizing CXCR4 and / or inhibiting HDAC. Further, the diseases may include cancer, inflammation, depression, etc.

[0029] Compared with the prior art, the beneficial effects of the present invention are:

[0030] Based on the principle of rational drug design, the present invention designs and synthesizes a novel small molecule compound with multi-targets having CXCR4 and HDAC inhibitory activities and having potential anti-tumor, anti-inflammatory, and anti-depressant activities.

[0031] The compounds of the present invention are superior to previous CXCR4 compounds in the design strategy. An isohydroxamic acid structure that can enhance anti-tumor, anti-inflammatory, and antidepressant activities is introduced, improving the anti-tumor, anti-inflammatory, and antidepressant activities, and having a good improvement on the disadvantages of long treatment time and large side effects of currently used anti-tumor, anti-inflammatory, and antidepressant compounds.

[0032] The CXCR4 / HDAC dual inhibitor of the present invention, which has both CXCR4 antagonistic effect and HDAC inhibitory effect, is a class of multi-target isohydroxamic acid derivatives that achieve anti-tumor, anti-inflammatory, and antidepressant effects synergistically with benzamide / benzenesulfonamide groups and isohydroxamic acid. Detailed implementation manners

[0033] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The operation methods without specific conditions noted in the following embodiments are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer.

[0034] Preparation of Intermediate 2, Reaction Scheme 1:

[0035]

[0036] Reaction reagents and conditions: 4-dimethylaminopyridine (DMAP), dichloromethane (DCM), 0 °C - room temperature.

[0037] As shown in Reaction Scheme 1, to a 125 mL round-bottom flask equipped with a magnetic stirrer, raw material 1 (10 mmol), DMAP (2 mmol), and DCM (40 mL) were added in sequence. Stir at 0 °C for 5 min, then add N-methylbenzylamine (15 mmol), continue to react at 0 °C for 30 min, and then move to room temperature and continue to stir for 2 - 3 h. Monitor the reaction process by TLC, and the developing agent is dichloromethane: petroleum ether (volume ratio 4:1). After the reaction is completed, add DCM (30 mL) to the round-bottom flask for dilution, wash with 10% dilute hydrochloric acid solution (50 mL × 2), and then wash with saturated brine (60 mL × 2). Combine the organic liquids, dry over anhydrous sodium sulfate, distill off the solvent under reduced pressure, and purify by silica gel column chromatography. The eluent is dichloromethane: petroleum ether (volume ratio 2:1), and finally obtain a white solid, namely Intermediate 2a (85%).

[0038] According to Reaction Scheme 1 and the same method above, replace the reactants to prepare Intermediates 2b - 2n.

[0039] Preparation of Intermediate 7, Reaction Scheme 2:

[0040]

[0041] Reaction reagents and conditions: Triethylamine (TEA), DCM, 0 °C.

[0042] As shown in Reaction Scheme 2, add N-methylbenzylamine (4 mmol), TEA (10 mmol) and DCM (15 mL) to a 50 mL round-bottom flask equipped with a magnetic stir bar, stir at 0 °C for 5 min, and then slowly add a solution of 4-(chloromethyl)benzamide (5 mmol) in DCM (15 mL) dropwise using a constant pressure dropping funnel. Continue to stir the reaction at 0 °C for 1 - 2 h. Monitor the reaction progress by TLC, with the eluent being dichloromethane. After the reaction is complete, add water (30 mL × 2) to wash the reaction solution, collect the organic layer, wash it with saturated brine (20 mL), then dry it over anhydrous sodium sulfate, remove the solvent by rotary evaporation under reduced pressure, and purify it by silica gel column chromatography with dichloromethane as the eluent to finally obtain a white solid, namely Intermediate 7a (70 - 85%).

[0043] According to Reaction Scheme 2 and the same method above, change the reactants to prepare Intermediates 7b - 7o.

[0044] Preparation of Intermediates 3 and 8, Reaction Scheme 3:

[0045]

[0046] Reaction reagents and conditions: N,N-Diisopropylethylamine (DIPEA), acetonitrile (MeCN), 50 °C.

[0047] As shown in Reaction Scheme 3, successively add Intermediate 2 (6 mmol), 1-(tert-butoxycarbonyl)piperazine (7.2 mmol), DIPEA (12 mmol) and acetonitrile (30 mL) to a 100 mL round-bottom flask equipped with a magnetic stir bar, and stir the reaction at 50 °C. Monitor the reaction progress by TLC, with the eluent being n-hexane:ethyl acetate (volume ratio 1:1). After the reaction is complete, cool to room temperature, concentrate the reaction solvent under reduced pressure, add water (30 mL), extract with DCM (30 mL × 2), combine the organic layers, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, remove the solvent by rotary evaporation under reduced pressure, and purify it by silica gel column chromatography with petroleum ether:ethyl acetate (2:1) as the eluent to finally obtain a white solid, namely Intermediate 3a (90%).

[0048] According to Reaction Scheme 3 and the same method above, change the reactants to prepare Intermediates 3b - 3c, 8a - 8c.

[0049] Preparation of Intermediates 4 and 9, Reaction Scheme 4:

[0050]

[0051] Reaction reagents and conditions: CF3COOH, DCM, 0 °C.

[0052] As shown in Reaction Formula 4, add intermediate 3 (3 mmol) and DCM (9 mL) to a 100 mL round-bottom flask equipped with a magnetic stir bar, stir at 0 °C for 10 min, and then slowly add a solution of trifluoroacetic acid (9 mL) in DCM (9 mL) dropwise to the reaction flask through a constant pressure dropping funnel. Continue to stir and react at 0 °C for 0.5 - 1 h. Monitor the reaction progress by TLC, and the developing solvent is dichloromethane:methanol (volume ratio 9:1). After the reaction is completed, add saturated sodium bicarbonate solution to the reaction solution to adjust the pH value to 7 - 8. Then add water (10 mL), extract with DCM (30 mL × 5), combine the organic layers, dry over anhydrous sodium sulfate, distill off the solvent under reduced pressure, and then recrystallize with n-hexane and DCM to precipitate a solid. Filter and dry to finally obtain a white solid, namely intermediate 4 (80%).

[0053] According to Reaction Formula 4 and the same method as above, change the reactants to prepare intermediate 9.

[0054] Preparation of intermediates 5 and 10, Reaction Formula 5:

[0055]

[0056] Reaction reagents and conditions: Cs2CO3, tetrabutylammonium iodide (TBAI), CH3CN, 60 °C, 4 - 6 h.

[0057] As shown in Reaction Formula 5, add intermediate 4 (0.3 mmol), cesium carbonate (0.45 mmol), tetrabutylammonium iodide (0.03 mmol), acetonitrile (9 mL) and the corresponding p-bromomethyl phenyl ester (0.45 mmol) to a 50 mL round-bottom flask equipped with a magnetic stir bar, heat to 60 °C and react for 4 - 6 h. Monitor the reaction progress by TLC, and the developing solvent is dichloromethane:methanol (volume ratio 50:1). After the reaction is completed, cool to room temperature, concentrate under reduced pressure to remove the solvent, then add water (10 mL) to the reaction solution, extract with DCM (10 mL × 2), combine the organic layers, dry over anhydrous sodium sulfate, distill off the solvent under reduced pressure, and purify by silica gel column chromatography. The eluent is dichloromethane:methanol (volume ratio 100:1) to finally obtain a pale yellow liquid, namely intermediate 5a (45 - 72%)

[0058] According to Reaction Formula 5 and the same method as above, change the reactants to prepare intermediates 5c, 10a and 10c.

[0059] To a 50 mL round-bottom flask equipped with a magnetic stir bar, add intermediate 4 (0.5 mmol) and DCM (9 mL), stir at 0 °C for 15 min, then add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (0.6 mmol) and 1-hydroxybenzotriazole (HOBT) (0.6 mmol), stir at 0 °C for 15 min, then add triethylamine (1.0 mmol), stir for 15 min, and finally add methyl malonate. Transfer to room temperature and continue the reaction for 6 - 8 h. Monitor the reaction progress by TLC, and the developing solvent is dichloromethane:methanol (volume ratio 20:1). After the reaction is completed, dilute the reaction solution with DCM (15 mL), wash the organic solution with water (15 mL × 2), collect the organic solution, wash it with saturated brine (15 mL), dry over anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, purify by silica gel column chromatography, and the eluent is dichloromethane:methanol (volume ratio 100:1). Finally, a pale yellow liquid is obtained, which is intermediate 5b (68 - 80%).

[0060] According to Reaction Scheme 5 and the same method as above, replace the reactants to prepare intermediate 10b.

[0061] Preparation of CXCR4 / HDAC dual inhibitors end products (Ⅰ) and (Ⅱ), Reaction Scheme 6:

[0062]

[0063] Reaction reagents and conditions: NH2OH, NaOH, DCM, MeOH, 0 °C, 0.5 - 1 h.

[0064] As shown in Reaction Scheme 6, add intermediate 5 or 10 (0.3 mmol), DCM (3 mL) and methanol (6 mL) to a 50 mL round-bottom flask equipped with a magnetic stir bar, stir at 0 °C for 10 min, then successively add sodium hydroxide (3.0 mmol) and hydroxylamine aqueous solution (9.0 mmol), and continue to stir and react at 0 °C for 0.5 - 1 h. Monitor the reaction progress by TLC, and the developing solvent is dichloromethane:methanol (volume ratio 9:1). After the reaction is completed, slowly add 10% hydrochloric acid solution to the reaction solution at 0 °C to adjust the pH value to 7 - 8. Remove the organic solvent by distillation under reduced pressure, purify by thin layer chromatography, and finally recrystallize with n-hexane and DCM to precipitate a solid. Filter and dry to finally obtain a white solid, which is the target compound (50 - 89%).

[0065] Each intermediate and end product used can be prepared according to the above process, which will not be elaborated here.

[0066] Example 1: Preparation of 2-(4-(4-(N-benzyl-N-methylsulfonyl)benzyl)piperazin-1-yl)-N-hydroxyacetamide (Compound A-1)

[0067]

[0068] The intermediate 5a (0.3 mmol), DCM (3 mL) and methanol (6 mL) were stirred at 0 °C for 10 min. Subsequently, sodium hydroxide (3.0 mmol) and aqueous hydroxylamine solution (9.0 mmol) were added successively, and the reaction was continued to stir at 0 °C for 0.5 - 1 h. The reaction progress was monitored by TLC, and the developing agent was dichloromethane:methanol (volume ratio 9:1). After the reaction was completed, 10% hydrochloric acid solution was slowly added dropwise to the reaction solution at 0 °C to adjust the pH value to 7 - 8. The organic solvents were removed by distillation under reduced pressure, purified by thin-layer chromatography, and finally recrystallized with n-hexane and DCM to precipitate a solid, which was filtered and dried to obtain compound A-1 (62.5%), a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.76 (s, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.38–7.33 (m, 2H), 7.30 (t, J = 6.7 Hz, 3H), 4.13 (s, 2H), 3.58 (s, 2H), 2.87 (s, 2H), 2.54 (s, 3H), 2.44 (d, J = 25.8 Hz, 8H). 13C NMR (125 MHz, DMSO-d6) δ 166.14, 144.44, 136.50, 136.00, 129.93, 129.00, 128.62, 128.14, 127.66, 61.71, 59.51, 53.74, 53.21, 52.94, 34.92. HRMS calculated for C21H29N4O4S 433.1904 [M + H]+, found 433.1982.

[0069] Example 2: Preparation of 3-(4-(4-(N-benzyl-N-methylsulfonyl)benzyl)piperazin-1-yl)-N-hydroxypropanamide (Compound A-2)

[0070]

[0071] The preparation method was basically the same as that of Example 1. In this example, compound A-2 (60.6%) was obtained, a white solid. 11H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.71 (s, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.38–7.27 (m, 5H), 4.13 (s, 2H), 3.57 (s, 2H), 2.54 (s, 4H), 2.39 (s, 8H), 2.11 (t, J = 7.2 Hz, 2H). 13C NMR (125 MHz, DMSO-d6) δ 168.45, 144.43, 136.50, 136.00, 129.94, 129.00, 128.62, 128.14, 127.65, 61.74, 54.30, 53.74, 53.08, 52.93, 34.92, 30.77. HRMS calcd for C22H31N4O4S 447.2061 [M+H]+, found 447.2135.

[0072] Example 3: Preparation of 4-(4-(4-(N-Benzyl-N-methylsulfonyl)benzyl)piperazin-1-yl)-N-hydroxybutanamide (Compound A-3)

[0073]

[0074] The preparation method was basically the same as that in Example 1. In this example, Compound A-3 (88.9%) was obtained as a white solid. 1 1H NMR (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.65 (s, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.38–7.33 (m, 2H), 7.30 (t, J = 6.9 Hz, 3H), 4.13 (s, 2H), 3.57 (s, 2H), 2.54 (s, 3H), 2.34 (d, J = 57.6 Hz, 8H), 2.24 (s, 2H), 1.96 (t, J = 7.4 Hz, 2H), 1.63 (p, J = 7.3 Hz, 2H). 13C NMR (125 MHz, DMSO-d6) δ 169.05, 143.96, 136.03, 135.53, 129.48, 128.53, 128.15, 127.67, 127.18, 61.31, 57.19, 53.27, 52.68, 39.52, 34.44, 30.23, 22.42. HRMS calcd for C23H33N4O4S 461.2217 [M+H]+, found 461.2276.

[0075] Example 4: Preparation of 5-(4-(4-(N-benzyl-N-methylsulfonyl)benzyl)piperazin-1-yl)-N-hydroxypentanamide (Compound A-4)

[0076]

[0077] The preparation method was basically the same as that in Example 1. In this example, Compound A-4 (50.2%) was obtained as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.65 (s, 1H), 7.79 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.38–7.33 (m, 2H), 7.30 (t, J = 7.0 Hz, 3H), 4.13 (s, 2H), 3.57 (s, 2H), 2.54 (s, 3H), 2.40 (s, 8H), 2.26 (s, 2H), 1.95 (t, J = 7.2 Hz, 2H), 1.48 (p, J = 7.2 Hz, 2H), 1.38 (p, J = 7.1, 6.7 Hz, 2H). 13C NMR (125 MHz, DMSO-d6) δ 169.03, 143.99, 136.03, 135.53, 129.46, 128.53, 128.15, 127.67, 127.19, 61.30, 57.41, 53.27, 52.72, 52.68, 39.52, 34.45, 32.10, 25.77, 23.05. HRMS calcd for C24H35N4O4S 475.2374 [M+H]+, found 475.2436.

[0078] Example 5: Preparation of 6-(4-(4-(N-benzyl-N-methylsulfonyl)benzyl)piperazin-1-yl)-N-hydroxyhexanamide (Compound A-5)

[0079]

[0080] The preparation method was basically the same as that in Example 1. In this example, Compound A-5 (66.8%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.65 (s, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.38–7.33 (m, 2H), 7.30 (t, J = 6.8 Hz, 3H), 4.13 (s, 2H), 3.57 (s, 2H), 2.54 (s, 3H), 2.39 (s, 8H), 2.23 (s, 2H), 1.93 (t, J = 7.4 Hz, 2H), 1.48 (p, J = 7.4 Hz, 2H), 1.39 (p, J = 7.5 Hz, 2H), 1.22 (dt, J = 15.1, 7.5 Hz, 2H). 13C NMR (125 MHz, DMSO-d6) δ 169.06, 144.00, 136.03, 135.53, 129.47, 128.53, 128.15, 127.67, 127.18, 61.32, 57.79, 53.28, 52.78, 52.70, 39.52, 34.45, 32.25, 26.54, 26.02, 25.08. HRMS calcd for C25H37N4O4S 489.2530 [M+H]+, found 489.2584.

[0081] Example 6: Preparation of 4-((4-(4-(N-Benzyl-N-methylsulfonyl)benzyl)piperazin-1-yl)methyl)-N-hydroxybenzamide (Compound A-6)

[0082]

[0083] The preparation method was basically the same as that in Example 1. In this example, Compound A-6 (30.2%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.99 (s, 1H), 7.79 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.35 (t, J = 7.3 Hz, 4H), 7.29 (t, J = 7.1 Hz, 3H), 4.13 (s, 2H), 3.58 (s, 2H), 3.51 (s, 2H), 2.53 (s, 3H), 2.41 (s, 8H). 13C NMR (125 MHz, DMSO-d6) δ 164.12, 143.95, 141.54, 136.02, 135.53, 131.48, 129.46, 128.66, 128.53, 128.14, 127.66, 127.19, 126.79, 61.54, 61.23, 53.26, 52.57, 39.52, 34.44. HRMS calcd for C27H33N4O4S 509.2217 [M+H]+, found 509.2273.

[0084] Example 7: Preparation of 3-(4-(4-(N-Benzyl-N-methylsulfonyl)benzyl)piperazin-1-yl)-N-hydroxy-3-oxopropanamide (Compound A-7)

[0085]

[0086] The preparation method was basically the same as that in Example 1. Compound A-7 (%) was obtained in this example as a white solid. 1 1H NMR (500 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.89 (s, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 8.3 Hz, 2H), 7.38–7.33 (m, 2H), 7.30 (t, J = 6.7 Hz, 3H), 4.14 (s, 2H), 3.61 (s, 2H), 3.50 (dd, J = 11.3, 6.3 Hz, 4H), 3.16 (s, 2H), 2.55 (s, 3H), 2.44–2.37 (m, 2H), 2.37–2.30 (m, 2H). 13 13C NMR (125 MHz, DMSO-d6) δ 165.98, 164.24, 143.78, 136.37, 136.10, 130.31, 129.10, 128.62, 128.27, 127.66, 61.45, 53.80, 53.07, 52.58, 46.18, 41.75, 39.52, 34.96. LCMS (ESI) m / z: 461.0 [M+H]+.

[0087] Example 8: Preparation of 4-(4-(4-(N-Benzyl-N-methylsulfonyl)benzyl)piperazin-1-yl)-N-hydroxy-4-oxobutanamide (Compound A-8)

[0088]

[0089] The preparation method was basically the same as that of Example 1. In this example, Compound A-8 (66.8%) was obtained as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.64 (s, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 7.40–7.33 (m, 2H), 7.30 (t, J = 6.7 Hz, 3H), 4.14 (s, 2H), 3.61 (s, 2H), 3.46 (s, 4H), 2.54 (d, J = 7.8 Hz, 5H), 2.40 (s, 2H), 2.36–2.31 (m, 2H), 2.19 (t, J = 7.1 Hz, 2H). 13C NMR (125 MHz, DMSO-d6) δ 170.02, 169.00, 144.09, 136.50, 136.13, 130.02, 129.01, 128.62, 128.15, 127.71, 61.55, 53.75, 53.27, 52.83, 45.15, 41.57, 40.49, 40.41, 40.32, 40.24, 40.15, 40.08, 39.99, 39.91, 39.82, 39.65, 39.49, 34.93, 28.09, 27.96. HRMS calcd for C23H31N4O5S 475.2010 [M+H]+, found 475.2057.

[0090] Example 9: Preparation of 5-(4-(4-(N-Benzyl-N-methylsulfonyl)benzyl)piperazin-1-yl)-N-hydroxy-5-oxopentanamide (Compound A-9)

[0091]

[0092] The preparation method was basically the same as that of Example 1. In this example, Compound A-9 (56.1%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.66 (s, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.36 (td, J = 7.0, 1.5 Hz, 2H), 7.30 (t, J = 6.7 Hz, 3H), 4.14 (s, 2H), 3.61 (s, 2H), 3.49–3.42 (m, 4H), 2.55 (s, 3H), 2.41–2.37 (m, 2H), 2.35–2.32 (m, 2H), 2.28 (t, J = 7.4 Hz, 2H), 1.98 (t, J = 7.3 Hz, 2H), 1.70 (p, J = 7.4 Hz, 2H). 13C NMR (125 MHz, DMSO-d6) δ 170.11, 168.89, 143.61, 136.04, 135.68, 129.57, 128.56, 128.17, 127.70, 127.25, 61.09, 53.30, 52.92, 52.40, 44.85, 40.98, 39.52, 34.48, 31.60, 20.91. HRMS calcd for C24H33N4O5S 489.2166 [M+H]+, found 489.2217.

[0093] Example 10: Preparation of 6-(4-(4-(N-Benzyl-N-methylsulfonyl)benzyl)piperazin-1-yl)-N-hydroxy-6-oxohexanamide (Compound A-10)

[0094]

[0095] The preparation method was basically the same as that in Example 1. In this example, Compound A-10 (80.2%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.66 (s, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.38–7.33 (m, 2H), 7.30 (t, J = 7.2 Hz, 3H), 4.14 (s, 2H), 3.61 (s, 2H), 3.49–3.43 (m, 4H), 2.55 (s, 3H), 2.42–2.37 (m, 2H), 2.35–2.31 (m, 2H), 2.28 (t, J = 7.1 Hz, 2H), 1.95 (t, J = 6.9 Hz, 2H), 1.53–1.42 (m, 4H). 13C NMR (125 MHz, DMSO-d6) δ 170.44, 168.99, 143.63, 136.04, 135.68, 129.58, 128.57, 128.17, 127.70, 127.26, 61.10, 53.31, 52.98, 52.43, 44.93, 40.99, 39.52, 34.48, 32.13, 31.95, 24.89, 24.39. HRMS calcd for C25H35N4O5S 503.2323 [M+H]+, found 503.2371.

[0096] Example 11: Preparation of 3-((2-((4-(N-Benzyl-N-methylsulfamoyl)benzyl)(methyl)amino)ethyl)(methyl)amino)-N-hydroxypropanamide (Compound A-11)

[0097]

[0098] The preparation method was basically the same as that of Example 1. In this example, Compound A-11 (63.0%) was obtained as a yellow liquid. 11H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.70 (s, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.39–7.27 (m, 5H), 4.12 (s, 2H), 3.60 (s, 2H), 2.56 (t, J = 7.1 Hz, 2H), 2.53 (s, 3H), 2.47 (s, 4H), 2.15 (s, 3H), 2.13 (s, 3H), 2.11 (t, J = 7.1 Hz, 2H). 13C NMR (125 MHz, MeOD) δ 171.49, 145.39, 137.51, 137.32, 131.20, 129.67, 129.44, 128.92, 128.62, 62.85, 55.62, 55.52, 55.13, 54.15, 49.00, 42.75, 42.15, 34.84, 31.44. HRMS calcd for C22H33N4O4S 449.2217 [M+H]+, found 449.2284.

[0099] Example 12: Preparation of 5-((2-((4-(N-Benzyl-N-methylsulfamoyl)benzyl)(methyl)amino)ethyl)(methyl)amino)-N-hydroxypentanamide (Compound A-12)

[0100]

[0101] The preparation method was basically the same as that in Example 1. In this example, Compound A-12 (56.1%) was obtained as a yellow liquid. 11H NMR (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.66 (s, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 7.39–7.27 (m, 5H), 4.12 (s, 2H), 3.60 (s, 2H), 2.53 (s, 3H), 2.45 (s, 4H), 2.27 (d, J = 14.2 Hz, 2H), 2.15 (s, 3H), 2.11 (s, 3H), 1.94 (t, J = 7.3 Hz, 2H), 1.51–1.43 (m, 2H), 1.35 (dt, J = 12.3, 6.2 Hz, 2H). 13C NMR (125 MHz, DMSO-d6) δ 169.09, 145.06, 136.06, 135.36, 129.39, 128.58, 128.17, 127.71, 127.17, 61.13, 57.13, 55.22, 54.88, 53.33, 42.34, 42.16, 40.02, 39.95, 39.86, 39.69, 39.61, 39.52, 39.44, 39.35, 39.19, 39.02, 34.47, 32.15, 26.27, 23.05. HRMS calcd for C24H37N4O4S 447.2530 [M+H]+, found 447.2575.

[0102] Example 13: Preparation of 6-((2-((4-(N-Benzyl-N-methylsulfonyl)benzyl)(methyl)amino)ethyl)(methyl)amino)-N-hydroxyhexanamide (Compound A-13)

[0103]

[0104] The preparation method was basically the same as that of Example 1. In this example, Compound A-13 (89.3%) was obtained as a yellow liquid. 11H NMR (500 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.64 (s, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.38–7.33 (m, 2H), 7.32–7.27 (m, 3H), 4.12 (s, 2H), 3.60 (s, 2H), 2.53 (s, 3H), 2.46 (s, 4H), 2.26 (t, J = 7.2 Hz, 2H), 2.16 (s, 3H), 2.12 (s, 3H), 1.92 (t, J = 7.4 Hz, 2H), 1.48 (p, J = 7.4 Hz, 2H), 1.37 (p, J = 7.5 Hz, 2H), 1.23–1.18 (m, 2H). 13C NMR (125 MHz, DMSO-d6) δ 169.03, 145.05, 136.04, 135.34, 129.35, 128.54, 128.14, 127.68, 127.14, 61.12, 57.38, 55.24, 54.86, 53.31, 42.34, 42.18, 39.52, 34.44, 32.26, 26.46, 25.07. HRMS calcd for C25H39N4O4S 491.2687 [M+H]+, found 491.2732.

[0105] Example 14: Preparation of N-benzyl-4-((4-(5-(hydroxyamino)-5-oxopentyl)piperazin-1-yl)methyl)-N-methylbenzamide (Compound A-14)

[0106]

[0107] The preparation method was basically the same as that of Example 1. In this example, Compound A-14 (47.7%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.64 (s, 1H), 7.33 (d, J = 30.8 Hz, 8H), 7.17 (s, 1H), 4.57 (d, J = 95.7 Hz, 2H), 3.48 (s, 2H), 2.85 (d, J = 15.8 Hz, 3H), 2.35 (s, 7H), 2.24–2.18 (m, 2H), 1.93 (t, J = 7.2 Hz, 2H), 1.46 (q, J = 7.3 Hz, 2H), 1.36 (q, J = 7.1 Hz, 2H). 13C NMR (125 MHz, DMSO) δ 169.51, 140.32, 135.31, 129.10, 128.06, 127.64, 127.33, 127.24, 127.22, 127.03, 127.01, 62.15, 57.92, 53.24, 53.17, 32.58, 26.29, 23.53. HRMS calcd for C25H35N4O3 439.2704 [M+H]+, found 439.2733.

[0108] Example 15: Preparation of N-benzyl-4-((4-(2-(hydroxyamino)-2-oxoethyl)piperazin-1-yl)methyl)benzamide (Compound A-15)

[0109]

[0110] The preparation method was basically the same as that of Example 1. In this example, Compound A-15 (45.2%) was obtained as a white solid. 1 1H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.99 (t, J = 6.0 Hz, 1H), 8.74 (s, 1H), 7.87–7.83 (m, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.34–7.29 (m, 4H), 7.23 (tt, J = 5.6, 2.7 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.50 (d, J = 4.7 Hz, 2H), 2.85 (s, 2H), 2.44 (s, 4H), 2.38 (s, 4H). 13 13C NMR (125 MHz, DMSO) δ 39.52, 42.73, 52.61, 52.94, 59.28, 61.75, 126.86, 127.33, 127.36, 128.42, 128.75, 133.18, 139.91, 141.92, 165.88, 166.22. HRMS calcd for C 21 H 27N4O3 383.2078[M+H] + , found 383.2090.

[0111] Example 16: Preparation of N-benzyl-4-((4-(5-(hydroxyamino)-5-oxopentyl)piperazin-1-yl)methyl)benzamide (Compound A-16)

[0112]

[0113] The preparation method was basically the same as that of Example 1. In this example, Compound A-16 (59.3%) was obtained as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.99 (t, J = 5.9 Hz, 1H), 8.65 (s, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.34–7.29 (m, 4H), 7.24 (dt, J = 8.2, 4.2 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.49 (s, 2H), 2.35 (s, 8H), 2.22 (t, J = 7.2 Hz, 2H), 1.93 (t, J = 7.2 Hz, 2H), 1.47 (p, J = 7.2 Hz, 2H), 1.36 (q, J = 7.5 Hz, 2H). 13 C NMR (125 MHz, DMSO) δ 23.53, 26.30, 32.58, 43.02, 53.18, 53.22, 57.92, 62.12, 127.15, 127.63, 127.64, 128.71, 129.05, 133.47, 140.21, 142.26, 166.52, 169.50. HRMS calcd for C 24 H 33 N4O3 425.2547[M+H] + , found 425.2567.

[0114] Example 17: Preparation of N-benzyl-4-((4-(2-(hydroxyamino)-2-oxoethyl)piperazin-1-yl)methyl)-N-methylbenzamide (Compound A-17)

[0115]

[0116] The preparation method was basically the same as that of Example 1. In this example, Compound A-17 (47.8%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.77 (s, 1H), 7.33 (d, J = 40.7 Hz, 8H), 7.16 (s, 1H), 4.57 (d, J = 95.0 Hz, 2H), 3.48 (s, 2H), 2.84 (s, 5H), 2.47 (d, J = 34.1 Hz, 9H). 13C NMR (125 MHz, DMSO) δ 166.11, 140.27, 135.32, 129.08, 128.05, 127.67, 127.30, 62.06, 59.56, 53.25, 52.90, 39.74. HRMS calcd for C22H29N4O3 397.2234 [M+H]+, found 397.2257.

[0117] Example 18: Preparation of N-benzyl-4-((4-(3-(hydroxyamino)-3-oxopropyl)piperazin-1-yl)methyl)-N-methylbenzamide (Compound A-18)

[0118]

[0119] The preparation method was basically the same as that of Example 1. In this example, Compound A-18 (21.3%) was obtained as a white solid. 1 1H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.72 (s, 1H), 7.46–7.24 (m, 8H), 7.17 (s, 1H), 4.67 (s, 1H), 4.48 (s, 1H), 3.49 (s, 2H), 2.85 (d, J = 19.1 Hz, 3H), 2.56–2.51 (m, 1H), 2.37 (s, 7H), 2.10 (t, J = 7.0 Hz, 2H). 13C NMR (125 MHz, DMSO) δ 168.43, 140.20, 135.34, 129.12, 128.06, 127.79, 127.69, 127.30, 127.26, 127.16, 126.98, 62.06, 54.28, 52.99, 52.92, 30.73. HRMS calcd for C23H31N4O3 411.2391 [M+H]+, found 411.2410.

[0120] Example 19: Preparation of N-benzyl-4-((4-(4-(hydroxyamino)-4-oxobutyl)piperazin-1-yl)methyl)-N-methylbenzamide (Compound A-19)

[0121]

[0122] The preparation method was basically the same as that of Example 1. In this example, compound A-19 (62.1%) was obtained as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.64 (s, 1H), 7.33 (d, J = 41.0 Hz, 8H), 7.17 (s, 1H), 4.57 (d, J = 95.7 Hz, 2H), 3.48 (s, 2H), 2.85 (d, J = 17.5 Hz, 3H), 2.42 (d, J = 69.8 Hz, 8H), 2.21 (s, 2H), 1.94 (t, J = 7.4 Hz, 2H), 1.61 (p, J = 7.1 Hz, 2H). 13C NMR (125 MHz, DMSO) δ 166.11, 140.27, 135.32, 129.08, 128.05, 127.67, 127.30, 127.24, 127.17, 127.08, 127.00, 62.06, 59.56, 53.25, 52.90, 39.74. HRMS calcd for C24H33N4O3 425.2547 [M+H]+, found 425.2578.

[0123] Example 20: Preparation of N-benzyl-4-((4-(6-(hydroxyamino)-6-oxohexyl)piperazin-1-yl)methyl)-N-methylbenzamide (Compound A-20)

[0124]

[0125] The preparation method was basically the same as that of Example 1. In this example, compound A-20 (38.0%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.64 (s, 1H), 7.34 (d, J = 32.9 Hz, 8H), 7.16 (s, 1H), 4.57 (d, J = 95.9 Hz, 2H), 3.48 (s, 2H), 2.85 (d, J = 17.5 Hz, 3H), 2.35 (s, 7H), 2.24–2.16 (m, 2H), 1.92 (t, J = 7.3 Hz, 2H), 1.52–1.43 (m, 2H), 1.37 (d, J = 13.9 Hz, 2H), 1.21 (d, J = 14.7 Hz, 2H). 13C NMR (125 MHz, DMSO) δ 169.50, 140.31, 135.32, 129.09, 128.07, 127.67, 127.31, 62.14, 58.28, 53.28, 53.15, 50.30, 32.71, 27.00, 26.51, 25.55. HRMS calcd for C 26 H 37 N4O3 453.2860 [M+H] + , found 453.2896.

[0126] Example 21: Preparation of N-Benzyl-4-((4-(4-(hydroxyformamido)benzyl)piperazin-1-yl)methyl)-N-methylbenzamide (Compound A-21)

[0127]

[0128] The preparation method was basically the same as that in Example 1. In this example, Compound A-21 (26.2%) was obtained as a yellow solid. 1 1H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.98 (s, 1H), 7.70 (s, 2H), 7.33 (d, J = 27.1 Hz, 10H), 7.17 (s, 1H), 4.57 (d, J = 97.6 Hz, 2H), 3.49 (s, 5H), 2.84 (d, J = 16.2 Hz, 3H), 2.38 (s, 8H). 13 13C NMR (126 MHz, DMSO) δ 164.60, 142.04, 140.24, 135.31, 131.90, 129.09, 128.05, 127.73, 127.24, 62.04, 53.07. HRMS calcd for C 28 H 33 N4O3 473.2547 [M+H] + , found 473.2569.

[0129] Example 22: Preparation of N-benzyl-4-((4-(3-(hydroxyamino)-3-oxopropyl)piperazin-1-yl)methyl)benzamide (Compound A-22)

[0130]

[0131] The preparation method was basically the same as that of Example 1. In this example, Compound A-22 (76.0%) was obtained as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.99 (t, J = 6.0 Hz, 1H), 8.71 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 5.7 Hz, 4H), 7.26–7.21 (m, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.49 (s, 2H), 2.48 (s, 2H), 2.36 (s, 8H), 2.10 (t, J = 7.1 Hz, 2H). 13 C NMR (125 MHz, DMSO) δ 30.77, 43.03, 52.93, 53.03, 54.30, 62.06, 127.16, 127.63, 128.72, 129.07, 133.48, 140.20, 142.18, 166.52, 168.46. HRMS calcd for C 22 H 29 N4O3 397.2234 [M+H] + , found 397.2250.

[0132] Example 23: Preparation of N-benzyl-4-((4-(4-(hydroxyamino)-4-oxobutyl)piperazin-1-yl)methyl)benzamide (Compound A-23)

[0133]

[0134] The preparation method was basically the same as that of Example 1. In this example, Compound A-23 (57.0%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.00 (t, J = 6.0 Hz, 1H), 8.65 (s, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 6.3 Hz, 4H), 7.27–7.22 (m, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.51 (d, J = 6.3 Hz, 2H), 2.37 (s, 8H), 2.23 (t, J = 7.1 Hz, 2H), 1.96 (t, J = 7.4 Hz, 2H), 1.62 (p, J = 7.3 Hz, 2H). 13 13C NMR (125 MHz, DMSO) δ 169.06, 166.05, 141.73, 139.74, 133.01, 128.61, 128.25, 127.16, 126.69, 61.63, 57.19, 54.91, 52.63, 42.56, 39.52, 30.22, 22.41. HRMS calcd for C 23 H 31 N4O3 411.2391 [M+H] + , found 411.2402.

[0135] Example 24: Preparation of N-Benzyl-4-((4-(6-(hydroxyamino)-6-oxohexyl)piperazin-1-yl)methyl)benzamide (Compound A-24)

[0136]

[0137] The preparation method was basically the same as that of Example 1. In this example, Compound A-24 (79.5%) was obtained as a white solid. 1 1H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.99 (t, J = 6.0 Hz, 1H), 8.64 (s, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 7.35–7.28 (m, 4H), 7.23 (tt, J = 5.6, 2.7 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.49 (s, 2H), 2.35 (s, 7H), 2.24–2.19 (m, 2H), 1.92 (t, J = 7.3 Hz, 2H), 1.48 (q, J = 7.4 Hz, 2H), 1.38 (p, J = 7.6 Hz, 2H), 1.20 (d, J = 7.8 Hz, 2H). 1313C NMR(125MHz,DMSO)δ169.51,166.52,142.26,140.20,133.46,129.05,128.72,127.64,127.63,127.16,62.12,58.28,53.27,53.17,43.02,32.71,27.00,26.52,25.55.HRMS calcd for C 25 H 35 N4O3 439.2704[M+H] + ,found 439.2729.

[0138] Example 25: Preparation of N-Benzyl-4-((4-(4-hydroxyformamido)benzyl)piperazin-1-yl)methyl)benzamide (Compound A-25)

[0139]

[0140] The preparation method was basically the same as that in Example 1. In this example, Compound A-25 (28.9%) was obtained as a yellow solid. 1 1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),8.99(t,J = 5.8Hz,2H),7.84(d,J = 8.1Hz,2H),7.69(d,J = 8.1Hz,2H),7.39–7.28(m,8H),7.23(tt,J = 6.3,2.8Hz,1H),4.47(d,J = 5.9Hz,2H),3.50(d,J = 7.6Hz,4H),2.38(s,8H). 13 13C NMR(125MHz,DMSO)δ39.52,42.55,52.61,61.58,126.68,126.75,127.16,127.17,128.24,128.58,133.01,139.73,141.71,166.04.HRMScalcd for C 27 H 31 N4O3 459.2391[M+H] + ,found 459.2426.

[0141] Example 26: Preparation of 2-(4-(4-(N-Benzylsulfonamido)benzyl)piperazin-1-yl)-N-hydroxyacetamide (Compound A-26)

[0142]

[0143] The preparation method was basically the same as that of Example 1. Compound A-26 (35.2%) was obtained in this example as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.75 (s, 1H), 8.12 (t, J = 6.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 7.9 Hz, 2H), 7.28–7.16 (m, 5H), 3.99 (d, J = 6.0 Hz, 2H), 3.52 (s, 2H), 2.86 (s, 2H), 2.42 (d, J = 38.8 Hz, 8H). 13C NMR (125 MHz, DMSO-d6) δ 165.74, 143.12, 139.37, 137.64, 129.21, 128.17, 127.56, 127.06, 126.45, 61.32, 59.09, 52.75, 52.44, 46.13, 39.52. HRMS calcd for C20H27N4O4S 419.1748 [M+H]+, found 419.1779.

[0144] Example 27: Preparation of 3-(4-(4-(N-Benzylsulfonamido)benzyl)piperazin-1-yl)-N-hydroxypropanamide (Compound A-27)

[0145]

[0146] The preparation method was basically the same as that of Example 1. Compound A-27 (62.5%) was obtained in this example as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.73 (s, 1H), 8.14 (t, J = 6.4 Hz, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.28–7.15 (m, 5H), 3.99 (d, J = 6.3 Hz, 2H), 3.51 (s, 2H), 2.35 (s, 10H), 2.10 (t, J = 7.0 Hz, 2H). 13C NMR (125 MHz, DMSO-d6) δ 168.44, 143.55, 139.82, 138.09, 129.68, 128.62, 128.01, 127.52, 126.89, 61.78, 54.30, 53.02, 52.92, 46.57, 30.77. HRMS calcd for C21H29N4O4S 433.1904 [M+H]+, found 433.1951.

[0147] Example 28: Preparation of 4-(4-(4-(N-Benzylsulfonamido)benzyl)piperazin-1-yl)-N-hydroxybutanamide (Compound A-28)

[0148]

[0149] The preparation method was basically the same as that in Example 1. In this example, Compound A-28 (81.4%) was obtained as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.64 (s, 1H), 8.11 (t, J = 6.3 Hz, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.27–7.22 (m, 2H), 7.22–7.17 (m, 3H), 3.99 (d, J = 6.3 Hz, 2H), 3.51 (s, 2H), 2.49–2.19 (m, 10H), 1.95 (t, J = 7.4 Hz, 2H), 1.62 (p, J = 7.3 Hz, 2H). 13C NMR (125 MHz, DMSO-d6) δ 169.53, 143.56, 139.82, 138.09, 129.69, 128.62, 128.01, 127.52, 126.89, 61.83, 57.68, 53.16, 53.09, 46.58, 40.49, 40.41, 40.32, 40.25, 40.15, 40.07, 39.99, 39.90, 39.82, 39.65, 39.49, 30.71, 22.91. HRMS calcd for C22H31N4O4S 447.2061 [M+H]+, found 447.2110.

[0150] Example 29: Preparation of N-Hydroxy-5-((4-(4-(N-benzylsulfonyl)benzyl)piperazin-1-yl)-pentanamide (Compound A-29)

[0151]

[0152] The preparation method was basically the same as that in Example 1. In this example, Compound A-29 (48.3%) was obtained as a pale yellow solid. 1HNMR(400MHz, DMSO-d6) δ 10.33(s, 1H), 8.66(s, 1H), 8.13(t, J = 6.2Hz, 1H), 7.72(d, J = 8.1Hz, 2H), 7.45(d, J = 8.1Hz, 2H), 7.23(d, J = 6.0Hz, 2H), 7.20(d, J = 6.3Hz, 3H), 3.99(d, J = 6.2Hz, 2H), 3.51(s, 2H), 2.35(s, 8H), 2.26–2.20(m, 2H), 1.94(t, J = 7.1Hz, 2H), 1.48(dt, J = 14.3, 7.0Hz, 2H), 1.37(dt, J = 13.8, 7.5Hz, 2H). 13C NMR(125MHz, DMSO-d6) δ 169.01, 143.14, 139.34, 137.62, 129.20, 128.15, 127.54, 127.54, 127.05, 126.43, 126.43, 61.38, 57.47, 52.75, 52.75, 46.11, 39.85, 39.52, 32.11, 25.84, 23.08. HRMS calcd for C23H33N4O4S 461.2217[M + H]+, found 461.2262.

[0153] Example 30: Preparation of 6-(4-(4-(N-Benzylsulfonamido)benzyl)piperazin-1-yl)-N-hydroxyhexanamide (Compound A-30)

[0154]

[0155] The preparation method was basically the same as that in Example 1. In this example, Compound A-30 (60.8%) was obtained as a pale yellow solid. 1HNMR(500 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.65 (s, 1H), 8.11 (t, J = 6.3 Hz, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.27–7.22 (m, 2H), 7.22–7.17 (m, 3H), 3.99 (d, J = 6.2 Hz, 2H), 3.51 (s, 2H), 2.36 (s, 8H), 2.25–2.20 (m, 2H), 1.93 (t, J = 7.3 Hz, 2H), 1.48 (p, J = 7.4 Hz, 2H), 1.39 (p, J = 7.4 Hz, 2H), 1.22 (dt, J = 15.1, 7.4 Hz, 2H). 13C NMR(125 MHz, DMSO-d6) δ 169.04, 143.13, 139.34, 137.62, 129.19, 128.15, 127.54, 127.04, 126.42, 61.37, 57.81, 52.79, 52.66, 46.10, 39.52, 32.24, 26.54, 26.04, 25.08. HRMS calcd for C24H35N4O4S 475.2374 [M+H]+, found 475.2423.

[0156] Example 31: Preparation of 4-((4-(4-(N-Benzylsulfonamido)benzyl)piperazin-1-yl)methyl)-N-hydroxybenzamide (Compound A-31)

[0157]

[0158] The preparation method was basically the same as that in Example 1. In this example, Compound A-31 (35.3%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.99 (s, 1H), 8.11 (s, 1H), 7.71 (dd, J = 10.6, 8.3 Hz, 4H), 7.45 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 7.26–7.22 (m, 2H), 7.19 (d, J = 7.1 Hz, 3H), 3.98 (s, 2H), 3.52 (d, J = 8.5 Hz, 4H), 2.39 (s, 8H). 13C NMR (125 MHz, DMSO-d6) δ 164.14, 143.06, 141.57, 139.35, 137.62, 131.46, 129.19, 128.63, 128.14, 127.54, 127.03, 126.79, 126.43, 61.57, 61.29, 52.58, 46.10, 39.52. HRMS calcd for C26H31N4O4S 495.2061 [M+H]+, found 495.2108.

[0159] Example 32: Preparation of 4-((4-(4-(N-(2-Fluorobenzyl)sulfonamido)benzyl)piperazin-1-yl)methyl)-N-hydroxybenzamide (Compound A-32)

[0160]

[0161] The preparation method was basically the same as that in Example 1. In this example, Compound A-32 (66.7%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.99 (s, 1H), 8.15 (t, J = 6.2 Hz, 1H), 7.70 (dd, J = 8.2, 2.6 Hz, 4H), 7.44 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 7.29 (td, J = 7.9, 1.6 Hz, 1H), 7.24 (qd, J = 7.4, 6.5, 2.2 Hz, 1H), 7.10–7.03 (m, 2H), 4.03 (s, 2H), 3.51 (d, J = 4.6 Hz, 4H), 2.38 (s, 8H). 13C NMR (125 MHz, DMSO-d6) δ 161.27, 159.32, 143.60, 142.04, 139.58, 131.93, 130.67, 130.64, 129.79, 129.73, 129.63, 129.10, 127.26, 126.87, 124.90, 124.78, 124.66, 124.63, 115.36, 62.04, 61.75, 53.05. HRMS calcd for C26H30FN4O4S 513.1966 [M+H]+, found 513.1983.

[0162] Example 33: Preparation of 4-((4-(4-(N-(3-fluorobenzyl)sulfonamido)benzyl)piperazin-1-yl)methyl)-N-hydroxybenzamide (Compound A-33)

[0163]

[0164] The preparation method was basically the same as that of Example 1. In this example, Compound A-33 (63.5%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.99 (s, 1H), 8.20 (t, J = 6.4 Hz, 1H), 7.74–7.67 (m, 4H), 7.44 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 7.30–7.24 (m, 1H), 7.04 (d, J = 7.7 Hz, 1H), 7.02–6.96 (m, 2H), 4.03 (d, J = 6.2 Hz, 2H), 3.51 (d, J = 3.0 Hz, 4H), 2.38 (s, 8H). 13C NMR (125 MHz, DMSO-d6) δ 163.40, 161.47, 143.65, 142.04, 141.20, 141.14, 139.79, 131.92, 130.58, 130.52, 129.64, 129.10, 127.26, 126.88, 123.95, 123.93, 114.66, 114.49, 114.29, 114.12, 62.04, 61.76, 53.05, 45.93. HRMS calcd for C26H30FN4O4S 513.1966 [M+H]+, found 513.1985.

[0165] Example 34: Preparation of 4-((4-(4-(N-(4-Fluorobenzyl)sulfamoyl)benzyl)piperazin-1-yl)methyl)-N-hydroxybenzamide (Compound A-34)

[0166]

[0167] The preparation method was basically the same as that of Example 1. In this example, Compound A-34 (32.6%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.99 (s, 1H), 8.14 (t, J = 6.3 Hz, 1H), 7.69 (dd, J = 8.3, 2.6 Hz, 4H), 7.44 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.22 (dd, J = 8.6, 5.6 Hz, 2H), 7.04 (t, J = 8.9 Hz, 2H), 3.98 (d, J = 6.1 Hz, 2H), 3.51 (d, J = 5.0 Hz, 4H), 2.38 (s, 8H). 13C NMR (125 MHz, DMSO-d6) δ 164.60, 162.67, 160.74, 143.56, 142.04, 134.30, 134.28, 131.91, 130.05, 129.98, 129.62, 129.10, 127.26, 126.88, 115.40, 115.23, 62.05, 61.77, 53.06, 45.81. HRMS calcd for C26H30FN4O4S 513.1966 [M+H]+, found 513.1987.

[0168] Example 35: Preparation of 4-((4-(4-(N-(3-chlorobenzyl)sulfonyl)phenyl)piperazin-1-yl)methyl)-N-hydroxybenzamide (Compound A-35)

[0169]

[0170] The preparation method was basically the same as that in Example 1. In this example, Compound A-35 (58.1%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.99 (s, 1H), 8.20 (t, J = 6.4 Hz, 1H), 7.70 (d, J = 8.0 Hz, 4H), 7.44 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 7.28–7.21 (m, 3H), 7.16 (d, J = 7.4 Hz, 1H), 4.03 (d, J = 6.3 Hz, 2H), 3.51 (d, J = 4.3 Hz, 4H), 2.38 (s, 8H). 13C NMR (125 MHz, DMSO-d6) δ 164.60, 143.67, 142.04, 140.75, 139.78, 133.28, 131.92, 130.46, 129.61, 129.10, 127.76, 127.38, 127.26, 126.87, 126.62, 62.04, 61.76, 53.06, 45.85. HRMS calcd for C26H30ClN4O4S 529.1671 [M+H]+, found 529.1688.

[0171] Example 36: Preparation of 4-((4-(4-(N-(4-chlorobenzyl)sulfamoyl)benzyl)piperazin-1-yl)methyl)-N-hydroxybenzamide (Compound A-36)

[0172]

[0173] The preparation method was basically the same as that in Example 1. In this example, Compound A-36 (35.4%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.02 (s, 1H), 8.18 (t, J = 6.3 Hz, 1H), 7.69 (d, J = 8.3 Hz, 4H), 7.44 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 3.99 (d, J = 6.2 Hz, 2H), 3.51 (d, J = 7.0 Hz, 4H), 2.39 (s, 8H). 13C NMR (125 MHz, DMSO-d6) δ 164.09, 143.16, 141.54, 139.32, 136.74, 131.62, 131.45, 129.36, 129.15, 128.64, 128.05, 126.78, 126.42, 61.58, 61.29, 52.60, 45.33, 39.52. HRMS calcd for C26H30ClN4O4S 529.1671 [M+H]+, found 529.1687.

[0174] Example 37: Preparation of N-Hydroxy-4-((4-(4-(N-(3-Methylbenzylsulfonyl)benzyl)piperazin-1-yl)methyl)benzamide (Compound A-37)

[0175]

[0176] The preparation method was basically the same as that in Example 1. In this example, Compound A-37 (41.7%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.99 (s, 1H), 8.07 (t, J = 6.3 Hz, 1H), 7.71 (t, J = 7.7 Hz, 4H), 7.45 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.14–7.09 (m, 1H), 7.03–6.96 (m, 3H), 3.94 (d, J = 6.3 Hz, 2H), 3.52 (d, J = 7.9 Hz, 4H), 2.39 (s, 8H), 2.21 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 164.63, 143.51, 142.02, 139.86, 137.90, 137.66, 131.93, 129.60, 129.11, 128.66, 128.53, 128.11, 127.27, 126.91, 125.13, 62.04, 61.78, 53.05, 46.58, 21.38. HRMS calculated for C27H33N4O4S 509.2217 [M+H]+, found 509.2237.

[0177] Example 38: Preparation of N-Hydroxy-4-((4-(4-(N-(4-methylbenzyl)sulfonyl)phenyl)piperazin-1-yl)methyl)benzamide (Compound A-38)

[0178]

[0179] The preparation method was basically the same as that in Example 1. In this example, Compound A-38 (53.6%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.02 (s, 1H), 8.05 (t, J = 6.3 Hz, 1H), 7.71 (t, J = 8.0 Hz, 4H), 7.45 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.05 (q, J = 8.2 Hz, 4H), 3.92 (s, 2H), 3.52 (d, J = 10.5 Hz, 4H), 2.39 (s, 8H), 2.22 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 164.58, 143.51, 142.01, 139.85, 136.62, 135.02, 131.93, 129.64, 129.15, 129.11, 127.99, 127.26, 126.91, 62.05, 61.78, 53.06, 46.37, 21.11. HRMS calcd for C27H33N4O4S 509.2217 [M+H]+, found 509.2238.

[0180] Example 39: Preparation of N-(2-Fluorobenzyl)-4-((4-(4-(Hydroxycarbonylamino)benzyl)piperazin-1-yl)methyl)benzamide (Compound A-39)

[0181]

[0182] The preparation method was basically the same as that of Example 1. In this example, Compound A-39 (54.8%) was obtained as a white solid. 1 1H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.99 (s, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 7.9 Hz, 2H), 7.42–7.27 (m, 6H), 7.17 (q, J = 8.5, 6.9 Hz, 2H), 4.51 (d, J = 5.5 Hz, 2H), 3.52 (s, 4H), 2.40 (s, 8H). 13 13C NMR (125 MHz, DMSO) δ 166.64, 161.43, 159.49, 133.30, 131.95, 129.85, 129.81, 129.25, 129.19, 129.10, 127.71, 127.28, 126.74, 126.62, 124.76, 124.74, 115.58, 115.41, 61.98, 53.01, 39.72, 36.85, 36.81. HRMS calcd for C 27 H 30FN4O3477.2296[M+H] + , found 477.2320.

[0183] Example 40: Preparation of N-(2-chlorobenzyl)-4-((4-(4-(hydroxycarbonylamino)benzyl)piperazin-1-yl)methyl)benzamide (Compound A-40)

[0184]

[0185] The preparation method was basically the same as that of Example 1. In this example, Compound A-40 (63.9%) was obtained as a white solid. 1 H NMR(500MHz, DMSO-d6) δ11.15(s, 1H), 9.00(t, J = 5.9Hz, 2H), 7.87(d, J = 8.3Hz, 2H), 7.69(d, J = 8.2Hz, 2H), 7.45(dd, J = 7.5, 1.6Hz, 1H), 7.39(d, J = 8.2Hz, 2H), 7.37–7.32(m, 3H), 7.32–7.26(m, 2H), 4.53(d, J = 5.8Hz, 2H), 3.51(d, J = 10.6Hz, 4H), 2.39(s, 8H). 13 C NMR(125MHz, DMSO) δ166.12, 163.94, 141.73, 141.44, 136.25, 132.58, 131.73, 131.29, 128.92, 128.45, 128.43, 128.34, 128.33, 127.09, 126.97, 126.62, 61.41, 52.45, 40.35, 39.52. HRMS calcd for C 27 H 30 ClN4O3 493.2001[M+H] + , found 493.2013.

[0186] Example 41: Preparation of N-(3-chlorobenzyl)-4-((4-(4-(hydroxycarbonylamino)benzyl)piperazin-1-yl)methyl)benzamide (Compound A-41)

[0187]

[0188] The preparation method was basically the same as that of Example 1. In this example, Compound A-41 (69.7%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.03 (t, J = 6.0 Hz, 1H), 8.98 (s, 1H), 7.84 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H), 7.37 (dd, J = 17.7, 7.9 Hz, 6H), 7.32–7.25 (m, 2H), 4.46 (d, J = 5.9 Hz, 2H), 3.50 (d, J = 8.0 Hz, 4H), 2.38 (s, 8H). 13 13C NMR (125 MHz, DMSO) δ 166.58, 164.57, 142.85, 133.38, 133.28, 131.95, 130.63, 129.12, 127.69, 127.48, 127.28, 127.13, 126.37, 61.96, 52.99, 42.57, 39.74. HRMS calcd for C 27 H 30 ClN4O3 493.2001 [M+H] + , found 493.2015.

[0189] Example 42: Preparation of N-Hydroxy-4-[(4-((4-((pyridin-2-ylmethyl)carbamoyl)benzyl)piperazin-1-yl)methyl)benzamide (Compound A-42)

[0190]

[0191] The preparation method was basically the same as that of Example 1. In this example, Compound A-42 (55.6%) was obtained as a white solid. 1 1H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.06 (t, J = 6.0 Hz, 1H), 8.99 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.74 (td, J = 7.7, 1.8 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 7.9 Hz, 1H), 7.25 (dd, J = 6.8, 5.1 Hz, 1H), 4.56 (d, J = 5.9 Hz, 2H), 3.51 (d, J = 10.0 Hz, 4H), 2.39 (s, 8H). 1313C NMR (125 MHz, DMSO) δ 166.69, 159.31, 149.27, 142.30, 142.08, 137.15, 133.34, 131.92, 129.08, 127.69, 127.26, 122.51, 121.33, 62.05, 53.09, 45.13. HRMS calcd for C 26 H 30 N5O3 460.2343 [M+H] + , found 460.2361.

[0192] Example 43: Preparation of 4-((5-(4-(N-Benzyl-N-methylsulfonyl)phenyl)hexahydrothieno[3,4-c]pyrrol-2(1H)-yl)methyl)N-hydroxybenzamide (Compound A-43)

[0193]

[0194] The preparation method was basically the same as that in Example 1. In this example, Compound A-43 (68.4%) was obtained as a white solid. 1 1H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.99 (s, 1H), 7.79 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.36 (dd, J = 14.1, 7.6 Hz, 4H), 7.30 (t, J = 5.5 Hz, 3H), 4.13 (s, 2H), 3.66 (s, 2H), 3.58 (s, 2H), 2.59 (dd, J = 15.8, 7.4 Hz, 6H), 2.54 (s, 3H), 2.33–2.25 (m, 4H). 13 13C NMR (125 MHz, DMSO) δ 34.44, 39.52, 41.45, 53.29, 58.17, 58.45, 59.20, 59.28, 126.78, 127.18, 127.66, 128.14, 128.17, 128.52, 129.06, 131.29, 135.36, 136.04, 142.59, 144.90, 164.10. HRMS calcd for C 29 H 35 N4O4S 535.2374 [M+H] + , found 535.2396.

[0195] Example 44: Preparation of 4-((4-(4-(N-(2-chlorobenzyl)sulfonyl)benzyl)piperazin-1-yl)methyl)-N-hydroxybenzamide (Compound A-44)

[0196]

[0197] The preparation method was basically the same as that of Example 1. In this example, Compound A-44 (44.2%) was obtained as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.00 (s, 1H), 8.19 (t, J = 6.0 Hz, 1H), 7.71 (dd, J = 14.8, 8.2 Hz, 4H), 7.46 (d, J = 8.2 Hz, 2H), 7.40–7.32 (m, 4H), 7.24 (qd, J = 7.5, 3.6 Hz, 2H), 4.07 (d, J = 5.9 Hz, 2H), 3.52 (d, J = 9.1 Hz, 4H), 2.44 (d, J = 52.5 Hz, 8H). 13C NMR (125 MHz, DMSO-d6) δ 164.11, 143.20, 141.55, 139.05, 134.79, 132.08, 131.46, 129.76, 129.22, 129.02, 128.95, 128.63, 127.04, 126.79, 126.43, 64.91, 61.56, 61.27, 52.57, 43.55, 39.52. HRMS calcd for C26H30ClN4O4S 529.1671 [M+H]+, found 529.1705.

[0198] Example 45: Preparation of N-hydroxy-4-((4-(4-(N-(2-methylbenzyl)sulfonyl)benzyl)piperazin-1-yl)methyl)benzamide (Compound A-45)

[0199]

[0200] The preparation method was basically the same as that of Example 1. In this example, Compound A-45 (35.4%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.99 (s, 1H), 7.93 (t, J = 6.0 Hz, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 7.4 Hz, 1H), 7.13–7.04 (m, 3H), 3.94 (d, J = 6.0 Hz, 2H), 3.52 (d, J = 14.2 Hz, 4H), 2.40 (s, 8H), 2.17 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 164.14, 143.07, 141.57, 139.12, 135.98, 135.15, 131.46, 129.91, 129.20, 128.63, 127.32, 126.79, 126.45, 125.62, 61.56, 61.29, 52.58, 44.24, 40.02, 39.85, 39.52, 18.45. HRMS calcd for C27H33N4O4S 509.2217 [M+H]+, found 509.2257.

[0201] Example 46: Preparation of N-Hydroxy-4-((4-(4-(N-(2-Methoxybenzyl)sulfonyl)benzyl)piperazin-1-yl)methyl)benzamide (Compound A-46)

[0202]

[0203] The preparation method was basically the same as that in Example 1. In this example, Compound A-46 (30.1%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.00 (s, 1H), 7.91 (t, J = 6.2 Hz, 1H), 7.70 (d, J = 8.0 Hz, 4H), 7.44 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.22–7.13 (m, 2H), 6.88–6.79 (m, 2H), 3.94 (d, J = 6.2 Hz, 2H), 3.68 (s, 3H), 3.51 (d, J = 6.0 Hz, 4H), 2.39 (s, 8H). 13C NMR (125 MHz, DMSO-d6) δ 164.14, 156.40, 142.96, 141.57, 139.31, 131.46, 129.09, 128.63, 128.49, 128.43, 126.79, 126.40, 125.04, 119.93, 110.32, 64.91, 61.56, 61.30, 55.14, 52.58, 40.98, 39.52. HRMS calcd for C27H33N4O5S 525.2166 [M+H]+, found 525.2176.

[0204] Example 47: Preparation of N-Hydroxy-4-((4-(4-(N-(3-Methoxybenzyl)sulfonyl)benzyl)piperazin-1-yl)methyl)benzamide (Compound A-47)

[0205]

[0206] The preparation method was basically the same as that of Example 1. In this example, Compound A-47 (32.0%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.99 (s, 1H), 7.71 (dd, J = 8.1, 5.3 Hz, 4H), 7.45 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.14 (t, J = 7.7 Hz, 1H), 6.79–6.71 (m, 3H), 3.97 (d, J = 6.3 Hz, 2H), 3.66 (s, 3H), 3.51 (d, J = 4.1 Hz, 4H), 2.39 (s, 8H). 13C NMR (125 MHz, DMSO-d6) δ 164.61, 159.58, 143.55, 142.03, 139.87, 139.62, 131.94, 129.67, 129.61, 129.12, 127.27, 126.91, 120.12, 113.34, 113.15, 62.04, 61.77, 55.38, 53.06, 46.52. HRMS calcd for C27H33N4O5S 525.2166 [M+H]+, found 525.2195.

[0207] Example 48: Preparation of N-Hydroxy-4-((4-(4-(N-(4-Methoxybenzyl)sulfonyl)benzyl)piperazin-1-yl)methyl)benzamide (Compound A-48)

[0208]

[0209] The preparation method was basically the same as that in Example 1. In this example, Compound A-48 (30.1%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.98 (s, 1H), 8.02 (t, J = 6.3 Hz, 1H), 7.70 (dd, J = 8.2, 3.3 Hz, 4H), 7.45 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 8.7 Hz, 2H), 3.91 (d, J = 6.2 Hz, 2H), 3.67 (s, 3H), 3.51 (d, J = 8.4 Hz, 4H), 2.39 (s, 8H). 13C NMR (125 MHz, DMSO-d6) δ 165.90, 158.14, 141.61, 141.59, 133.10, 131.69, 128.60, 128.55, 128.53, 127.15, 126.78, 113.64, 61.56, 55.04, 52.60, 42.00, 39.85, 39.52. HRMS calcd for C27H33N4O5S 525.2166 [M+H]+, found 525.2185.

[0210] Example 49: Preparation of N-(4-chlorobenzyl)-4-((4-(4-(hydroxycarbonyl)benzyl)piperazin-1-yl)methyl)benzamide (Compound A-49)

[0211]

[0212] The preparation method was basically the same as that of Example 1. In this example, Compound A-49 (65.9%) was obtained as a white solid. 1 1H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.02 (t, J = 5.8 Hz, 1H), 8.98 (s, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 6.8 Hz, 5H), 7.35–7.28 (m, 3H), 4.45 (d, J = 5.8 Hz, 2H), 3.51 (d, J = 6.6 Hz, 4H), 2.39 (s, 8H). 13 13C NMR (125 MHz, DMSO) δ 166.09, 164.16, 141.74, 141.55, 138.79, 132.87, 131.46, 131.24, 129.06, 128.62, 128.20, 127.19, 126.79, 61.54, 61.54, 52.57, 52.57, 41.96, 41.96, 39.52. HRMS calcd for C27 H 30 ClN4O3 493.2001 [M+H] + , found 493.2032.

[0213] Example 50: Preparation of N-(3-fluorobenzyl)-4-((4-(4-(hydroxycarbonyl)benzyl)piperazin-1-yl)methyl)benzamide (Compound A-50)

[0214]

[0215] The preparation method was basically the same as that of Example 1. In this example, Compound A-50 (46.8%) was obtained as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.03 (t, J = 6.0 Hz, 1H), 8.98 (s, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 8.1 Hz, 2H), 7.37 (dd, J = 16.3, 8.1 Hz, 5H), 7.18–7.03 (m, 3H), 4.48 (d, J = 5.9 Hz, 2H), 3.50 (d, J = 8.0 Hz, 4H), 2.38 (s, 8H). 13 C NMR (125 MHz, DMSO) δ 166.15, 163.17, 161.23, 142.81, 142.75, 141.82, 141.59, 132.83, 131.45, 130.23, 130.16, 128.61, 127.20, 126.79, 123.13, 113.89, 113.72, 113.54, 113.37, 61.56, 52.60, 42.14, 39.52. HRMS calcd for C 27 H 30 FN4O3 477.2296 [M+H] + , found 477.2348.

[0216] Example 51: Preparation of N-(4-fluorobenzyl)-4-((4-(4-(hydroxycarbonyl)benzyl)piperazin-1-yl)methyl)benzamide (Compound A-51)

[0217]

[0218] The preparation method was basically the same as that of Example 1. In this example, Compound A-51 (44.3%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.00 (t, J = 5.9 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 7.36 (s, 2H), 7.34 (d, J = 6.0 Hz, 2H), 7.17–7.11 (m, 2H), 4.44 (d, J = 5.9 Hz, 2H), 3.51 (d, J = 5.3 Hz, 4H), 2.39 (s, 8H). 13 13C NMR (125 MHz, DMSO) δ 166.04, 164.16, 162.08, 160.16, 141.69, 141.55, 135.93, 135.91, 132.95, 131.47, 129.20, 129.13, 128.62, 128.61, 127.19, 126.80, 115.04, 114.87, 61.54, 52.57, 41.90, 39.69, 39.52. HRMS calcd for C 27 H 30 FN4O3 477.2296 [M+H] + , found 477.2339.

[0219] Example 52: Preparation of N-Hydroxy-4-((4-(4-((2-Methylbenzyl)carbamoyl)benzyl)piperazin-1-yl)methyl)benzamide (Compound A-52)

[0220]

[0221] The preparation method was basically the same as that of Example 1. In this example, Compound A-52 (51.5%) was obtained as a white solid. 1 1H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.99 (s, 1H), 8.85 (t, J = 5.8 Hz, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H), 7.36 (dd, J = 12.1, 8.2 Hz, 4H), 7.22 (q, J = 4.0, 3.4 Hz, 1H), 7.15 (dh, J = 7.0, 4.0, 3.4 Hz, 3H), 4.44 (d, J = 5.7 Hz, 2H), 3.50 (d, J = 7.1 Hz, 4H), 2.38 (s, 8H), 2.32 (s, 3H). 1313C NMR (125 MHz, DMSO) δ 166.03, 164.15, 141.66, 141.60, 137.19, 135.42, 133.04, 131.45, 129.84, 128.60, 128.56, 127.22, 126.79, 126.69, 125.68, 61.57, 52.61, 40.62, 39.52, 18.72. HRMS calcd for C 28 H 33 N4O3 473.2547 [M+H] + , found 473.2586.

[0222] Example 53: Preparation of N-Hydroxy-4-((4-(4-((3-Methylbenzyl)carbamoyl)benzyl)piperazin-1-yl)methyl)benzamide (Compound A-53)

[0223]

[0224] The preparation method was basically the same as that of Example 1. In this example, Compound A-53 (38.9%) was obtained as a white solid. 1 1H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.04–8.90 (m, 2H), 7.84 (d, J = 7.8 Hz, 2H), 7.69 (d, J = 7.8 Hz, 2H), 7.44–7.30 (m, 4H), 7.20 (t, J = 7.4 Hz, 1H), 7.14–7.07 (m, 2H), 7.04 (d, J = 7.2 Hz, 1H), 4.43 (d, J = 5.6 Hz, 2H), 3.50 (d, J = 6.0 Hz, 4H), 2.38 (s, 8H), 2.28 (s, 3H). 13 13C NMR (125 MHz, DMSO) δ 165.98, 164.12, 141.68, 141.60, 139.65, 137.28, 133.03, 131.45, 128.59, 128.17, 127.80, 127.32, 127.19, 126.79, 124.30, 61.58, 52.61, 42.53, 39.52, 21.04. HRMS calcd for C 28 H 33 N4O3 473.2547 [M+H] + , found 473.2582.

[0225] Example 54: Preparation of N-Hydroxy-4-((4-(4-((4-Methylbenzyl)carbamoyl)benzyl)piperazin-1-yl)methyl)benzamide (Compound A-54)

[0226]

[0227] The preparation method was basically the same as that in Example 1. In this example, Compound A-54 (52.3%) was obtained as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.00 (s, 1H), 8.94 (t, J = 6.0 Hz, 1H), 7.83 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H), 7.36 (t, J = 8.5 Hz, 4H), 7.19 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 4.42 (d, J = 5.9 Hz, 2H), 3.50 (d, J = 5.3 Hz, 4H), 2.38 (s, 8H), 2.26 (s, 3H). 13 C NMR (125 MHz, DMSO) δ 165.97, 164.13, 141.64, 136.70, 135.69, 133.08, 131.45, 128.78, 128.60, 128.56, 127.17, 126.79, 61.57, 52.60, 42.31, 39.52, 20.67. HRMS calcd for C 28 H 33 N4O3 473.2547 [M + H] + , found 473.2581.

[0228] Example 55: Preparation of N-Hydroxy-4-((4-(4-((2-Methoxybenzyl)carbamoyl)benzyl)piperazin-1-yl)methyl)benzamide (Compound A-55)

[0229]

[0230] The preparation method was basically the same as that in Example 1. In this example, Compound A-55 (56.4%) was obtained as a white solid. 11H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.98 (s, 1H), 8.80 (t, J = 5.9 Hz, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H), 7.37 (dd, J = 13.0, 8.2 Hz, 4H), 7.23 (t, J = 8.5 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 4.44 (d, J = 5.8 Hz, 2H), 3.82 (s, 3H), 3.51 (d, J = 8.1 Hz, 4H), 2.39 (s, 8H). 13 13C NMR (125 MHz, DMSO) δ 166.65, 164.61, 156.98, 142.00, 133.57, 131.94, 129.09, 129.06, 128.30, 127.68, 127.62, 127.40, 127.27, 120.55, 110.86, 62.02, 55.79, 53.05, 38.02. HRMS calcd for C 28 H 33 N4O4 489.2496 [M + H] + , found 489.2524.

[0231] Example 56: Preparation of N-Hydroxy-4-((4-(4-((3-Methoxybenzyl)carbamoyl)benzyl)piperazin-1-yl)methyl)benzamide (Compound A-56)

[0232]

[0233] The preparation method was basically the same as that of Example 1. In this example, Compound A-56 (63.7%) was obtained as a white solid. 1 1H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.99 (s, 1H), 8.97 (d, J = 5.8 Hz, 1H), 7.84 (d, J = 7.9 Hz, 2H), 7.69 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 20.4 Hz, 4H), 7.23 (t, J = 7.9 Hz, 1H), 6.88 (d, J = 6.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 1H), 4.44 (d, J = 5.5 Hz, 2H), 3.72 (s, 3H), 3.50 (d, J = 6.8 Hz, 4H), 2.38 (s, 8H). 1313C NMR (125 MHz, DMSO) δ 166.06, 164.13, 159.27, 141.72, 141.61, 141.35, 133.02, 131.45, 129.32, 128.59, 127.18, 126.79, 119.33, 112.92, 111.99, 61.58, 54.95, 52.61, 42.51, 39.85, 39.69, 39.52. HRMS calcd for C 28 H 33 N4O4 489.2496 [M+H] + , found 489.2512.

[0234] Example 57: Preparation of N-Hydroxy-4-((4-(4-((4-Methoxybenzyl)carbamoyl)benzyl)piperazin-1-yl)methyl)benzamide (Compound A-57)

[0235]

[0236] The preparation method was basically the same as that of Example 1. In this example, Compound A-57 (58.1%) was obtained as a white solid. 1 1H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.99 (s, 1H), 8.92 (t, J = 5.4 Hz, 1H), 7.83 (d, J = 7.9 Hz, 2H), 7.70 (d, J = 7.9 Hz, 2H), 7.36 (t, J = 7.4 Hz, 4H), 7.23 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 4.39 (d, J = 5.7 Hz, 2H), 3.72 (s, 3H), 3.51 (s, 4H), 2.39 (s, 8H). 13 13C NMR (125 MHz, DMSO) δ 166.38, 164.63, 158.62, 142.07, 133.58, 132.17, 131.92, 129.08, 129.03, 129.01, 127.63, 127.26, 114.12, 62.02, 55.51, 53.06, 42.49. HRMS calcd for C 28 H 33 N4O4 489.2496 [M+H] + , found 489.2503.

[0237] Example 58: Preparation of N-Benzyl-4-((4-(7-(Hydroxyamino)-7-oxoheptyl)piperazin-1-yl)methyl)benzamide (Compound A-58)

[0238]

[0239] The preparation method was basically the same as that of Example 1. Compound A-58 (43.2%) was obtained in this example as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.99 (t, J = 6.0 Hz, 1H), 8.64 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.35–7.28 (m, 4H), 7.23 (ddd, J = 8.6, 6.4, 2.7 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 4.09 (d, J = 5.1 Hz, 2H), 3.51 (s, 2H), 3.17 (d, J = 4.5 Hz, 6H), 2.38 (s, 8H), 1.92 (t, J = 7.3 Hz, 2H), 1.47 (d, J = 7.1 Hz, 2H), 1.40 (s, 2H), 1.23 (s, 4H). 13 C NMR (125 MHz, DMSO) δ 25.52, 27.02, 28.92, 32.68, 40.49, 43.02, 49.07, 52.63, 53.01, 58.04, 61.93, 127.16, 127.63, 127.66, 128.72, 129.09, 133.52, 140.20, 142.04, 166.50, 169.54. HRMS calculated for C 26 H 37 N4O3 453.2860 [M+H] + , found 453.2901.

[0240] Pharmacodynamic experiments

[0241] 1. Determination of the inhibitory activity of the compound against HDAC1 / HDAC6

[0242] 1.1 Experimental method

[0243] The fluorescence detection method was used for the HDAC1 / HDAC6 inhibitory activity test. After the substrate Ac-Lys-Tyr-Lys(Ac)-AMC was deacetylated by HDAC1 / HDAC6, the product AMC obtained by hydrolysis with trypsin could be detected as a fluorescence signal under the emission light of a fluorescence detector. By measuring the changes in fluorescence signals of the blank group, control group, and experimental group over time, the inhibition rate of the test compound was calculated. Compounds with an inhibition rate greater than 50% were selected, and sample solutions with different concentrations were prepared and their inhibition rates were tested. The corresponding IC was calculated using GraphPad Prism software50 Value

[0244] 1.2 Experimental Results

[0245] Table 1 shows the inhibition rates and IC 50 Values of the compounds of Examples A-1 to A-58 against HDAC1 / HDAC6

[0246] Table 1

[0247]

[0248]

[0249]

[0250] As can be seen from Table 1, among all the compounds, Compound A-30 (IC 50 = 0.07 μM) and A-31 (IC 50 = 0.08 μM) showed the strongest inhibitory activity against HDAC6, approaching that of the positive control vorinostat (IC 50 = 0.07 μM). Among them, a total of 53 compounds had a certain selectivity for HDAC6. Some studies have shown that HDAC6 is deeply involved in the occurrence and development of inflammation, tumors, and depression. At the same time, among all the compounds, a total of 38 compounds had an inhibition rate of more than 50% against both HDAC1 and HDAC6

[0251] 2. Determination of the competitive affinity of the compounds for CXCR4

[0252] 2.1 Experimental Method

[0253] Since the natural ligand CXCL12 of CXCR4 has a relatively large molecular size and is not easy to synthesize and label, we selected TN14003 (a potent CXCR4 peptide antagonist) to mimic CXCL12 and labeled it with biotin. Biotin-labeled TN14003 can bind strongly to CXCR4 on the cell membrane surface of MDA-MB-231, showing a strong red fluorescence signal around the cells under a confocal microscope. After incubating the test compound with the cells for a period of time, and then adding biotin-labeled TN14003 for incubation, the fluorescence signal on the cell membrane was significantly weakened. Therefore, by quantifying the fluorescence signal and calculating according to the degree of fluorescence signal weakening, the affinity of the test compound for CXCR4 was calculated

[0254] 2.2 Experimental Results

[0255] Based on the inhibition rates and IC 50For the determination results of the values, we selected compounds with an inhibition rate (20 μM) of HDAC1 / HDAC6 both greater than 80% for the determination of the binding affinity to CXCR4. Table 2 shows the binding affinity of the compounds of the preferred embodiments to CXCR4.

[0256] Table 2

[0257]

[0258] As can be seen from Table 2, among the above-mentioned preferred compounds, a total of 12 compounds had a binding affinity to CXCR4 exceeding 50%, which was better than that of the positive control drug plerixafor. Among them, compound A-36 had the strongest binding affinity to CXCR4, reaching 86.90%, indicating that compound A-36 might play a good CXCR4 antagonistic role in vivo.

[0259] In summary, the inhibitory activity of compound A-36 on HDAC6 was close to that of the positive control drug vorinostat. More importantly, the binding affinity of compound A-36 to CXCR4 reached 86.90%, far higher than that of the positive control drug plerixafor (45.32%). Based on the above activity data, we have reason to speculate that compound A-36 might exert stronger anti-tumor, anti-inflammatory and anti-depressant effects than vorinostat and plerixafor in vivo and has good development potential.

[0260] In addition, it should be understood that after reading the above description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. Amide / sulfonamide CXCR4 / HDAC dual inhibitor, characterized in that: The compound having the following structure and its pharmaceutically acceptable salt:

2. Use of the amide / sulfonamide CXCR4 / HDAC dual inhibitor according to claim 1 in the preparation of drugs for preventing and treating related diseases by antagonizing CXCR4 and inhibiting HDAC.

3. The use according to claim 2, characterized in that: The diseases include cancer, inflammation, and depression.

4. A pharmaceutical composition, characterized in that Contains a safe and effective amount of the amide / sulfonamide CXCR4 / HDAC dual inhibitor according to claim 1.

5. The pharmaceutical composition according to claim 4, characterized in that The pharmaceutical composition further comprises pharmacologically acceptable excipients.

6. The pharmaceutical composition according to claim 5, characterized in that The auxiliary materials include excipients.

7. The pharmaceutical composition according to claim 5, characterized in that The auxiliary materials include carriers.

8. The pharmaceutical composition according to claim 4, characterized in that The pharmaceutical composition prevents and treats related diseases by antagonizing CXCR4 and inhibiting HDAC.

9. The pharmaceutical composition according to claim 8, characterized in that The diseases include cancer, inflammation, and depression.

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