CXCR4 / HDAC dual inhibitors and their preparation and application

Abstract

The present invention discloses a class of CXCR4 / HDAC dual inhibitors, their preparation methods, and applications. These dual CXCR4 / HDAC inhibitors are compounds having the structures represented by formula (I) or (II) and / or pharmaceutically acceptable salts thereof: #imgabs0# In formulas (I) and (II): R1 is selected from #imgabs1, R2 is selected from #imgabs2, and L is empty or a saturated or unsaturated aliphatic hydrocarbon chain with a C1-C6 range, preferably a C1-C4 range. These dual CXCR4 / HDAC inhibitors exhibit both CXCR4 antagonism and HDAC inhibition, and are multi-target derivatives that can synergistically achieve anti-tumor, anti-inflammatory, and anti-depressant effects.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a class of CXCR4 / HDAC dual inhibitors and a preparation method and application thereof. Background Art

[0002] CXC Chemokine Receptor 4 (CXCR4) is the primary receptor for CXC Chemokine 12 (CXCL12). It participates in multiple downstream signaling pathways and plays an important role in tumor invasion and metastasis, HIV infection, and inflammatory responses. CXCR4 antagonists can block the CXCR4 / CXCL12 signaling pathway, thereby inhibiting tumor cell invasion and inflammatory cell chemotaxis. Currently, several CXCR4 antagonists are in the clinical research stage for anti-tumor and anti-inflammatory effects. In addition, CXCR4 antagonists have also demonstrated good antidepressant activity. Therefore, CXCR4 is a potential effective target for anti-tumor metastasis, anti-inflammatory, and anti-depression. The applicant has previously researched and developed a variety of CXCR4 antagonists. For details, please refer to the patent specifications with publication numbers CN113845439A and CN117624140A.

[0003] Histone deacetylases (HDACs) are a class of epigenetic enzymes that mediate transcriptional repression by catalyzing the deacetylation of lysine residues on histones and other proteins. They are closely associated with abnormal gene expression in humans and the development of various cancers. HDAC inhibitors have attracted considerable attention in cancer treatment. Appropriate use of HDAC inhibitors can disrupt the cell cycle, differentiation, and apoptosis of tumor cells while remaining relatively well tolerated by normal cells. Currently, five HDAC inhibitors are clinically used to treat malignant tumors. Furthermore, HDACs are involved in the regulation of multiple inflammatory signaling pathways, influencing the expression of numerous inflammatory factors. Furthermore, HDCA inhibitors can modulate neurotransmitter levels in the central nervous system and exhibit potent antidepressant activity, even comparable to that of traditional clinically used antidepressants. Therefore, HDACs are also a promising target for anti-metastatic, anti-inflammatory, and anti-depressant drugs.

[0004] In summary, the development of small molecule inhibitors with dual CXCR4 and HDAC inhibitory activity using pharmacophore fusion and multi-target design strategies has the potential to become a novel therapeutic strategy for anti-tumor, anti-inflammatory, and anti-depressant drugs. Currently, there is limited research on this topic, but it holds great research significance and translational value. Summary of the Invention

[0005] In response to the above technical problems and deficiencies in the art, the present invention provides a class of CXCR4 / HDAC dual inhibitors, which have both CXCR4 antagonistic and HDAC inhibitory effects and are multi-target derivatives that can synergistically achieve anti-tumor, anti-inflammatory and anti-depressant effects.

[0006] The CXCR4 / HDAC dual inhibitor is a compound having a structure represented by general formula (I) or (II) and / or a pharmaceutically acceptable salt thereof:

[0007]

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

[0009] R1 is selected from

[0010] R2 is selected from

[0011] L is empty or a saturated or unsaturated aliphatic hydrocarbon chain of C1-C6, preferably C1-C4. When L is empty, it means that the benzene ring in formula (I) is directly connected to -C(=O)NHOH, and R1R2N- in formula (II) is directly connected to -C(=O)NHOH.

[0012] Furthermore, in the CXCR4 / HDAC dual inhibitor, L may be empty or selected from the following structures:

[0013] In some embodiments, the CXCR4 / HDAC dual inhibitor may be compounds Ia-Ip, IIa-IIp and / or pharmaceutically acceptable salts thereof having the following structures:

[0014]

[0015] The present invention also provides a method for preparing the CXCR4 / HDAC dual inhibitor.

[0016] When the CXCR4 / HDAC dual inhibitor is a compound having a structure represented by general formula (I), its synthetic route is:

[0017]

[0018] The preparation method comprises: performing a reductive amination reaction on raw material 1 or raw material 2 with raw material 3 to generate intermediate 4, then performing a reductive amination reaction on raw material 5 to generate intermediate 6, deprotecting intermediate 6 to obtain intermediate 7, performing nucleophilic substitution or reductive amination reaction on intermediate 7 with raw material 9, 10, 11 or 12 to obtain intermediate 8, and finally performing an amine ester exchange reaction on intermediate 8 to obtain a compound having a structure represented by general formula (I).

[0019] When the CXCR4 / HDAC dual inhibitor is a compound having a structure represented by general formula (II), its synthetic route is:

[0020]

[0021] The preparation method comprises: raw material 1 or raw material 2 is subjected to a reductive amination reaction with raw material 3 to generate intermediate 4; intermediate 4 is deprotected to obtain intermediate 13; intermediate 13 is subsequently subjected to a nucleophilic substitution reaction with raw material 14 to obtain intermediate 15; intermediate 15 is subjected to a nucleophilic substitution or reductive amination reaction with raw material 9, 10, 11 or 12 to obtain intermediate 16; and finally intermediate 16 is subjected to an amine ester exchange reaction to obtain a compound having a structure represented by general formula (II).

[0022] The present invention also provides the use of the CXCR4 / HDAC dual inhibitor in the preparation of a drug for preventing and treating related diseases by antagonizing CXC chemokine receptor 4 and / or inhibiting histone deacetylase. Further, the diseases include cancer, inflammation, depression, etc.

[0023] As a general inventive concept, the present invention also provides a pharmaceutical composition comprising at least one of a carrier and an excipient and the CXCR4 / HDAC dual inhibitor, wherein the carrier and the excipient can be commonly used materials in the art.

[0024] Compared with the prior art, the present invention has the following beneficial effects: the CXCR4 / HDAC dual inhibitor of the present invention has both CXCR4 antagonistic effect and HDAC inhibitory effect, and is a multi-target derivative that can synergistically achieve anti-tumor, anti-inflammatory and anti-depressant effects. DETAILED DESCRIPTION

[0025] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The operating methods in the following examples where no specific conditions are specified are generally performed under conventional conditions or as recommended by the manufacturer.

[0026] Example 1: Preparation of (S)-4-((((1H-benzo[d]imidazol-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)-N-hydroxybenzamide (Compound Ia)

[0027]

[0028] To a 100 mL round-bottom flask equipped with a magnetic stirrer, add starting materials 1 (6 mmol), 3 (6.6 mmol), glacial acetic acid (12 mmol), and 1,2-dichloroethane (20 mL). Stir at room temperature for 1 hour. Then, add half the amount of sodium triacetoxyborohydride (4.5 mmol). After the reaction is continued for 1 hour, add the remaining half of the amount of sodium triacetoxyborohydride (4.5 mmol), and stir at room temperature for 6 hours. Monitor the reaction progress by TLC using a 3:1 ratio of petroleum ether to ethyl acetate, 0.5% aqueous ammonia as the developing solvent. After the reaction, remove the 1,2-dichloroethane by distillation under reduced pressure. Adjust the pH with saturated sodium bicarbonate solution until no bubbles form, then extract with dichloromethane (20 mL x 3). Combine the carbon dichloride layers and wash with saturated brine (20 mL x 2). The residue was then dried over anhydrous sodium sulfate for half an hour, and the solvent was removed by distillation under reduced pressure to obtain a crude product, which was then purified by column chromatography using petroleum ether:ethyl acetate (3:1, v / v) as eluent to obtain yellow-green solid intermediate 4 in a yield of 74%.

[0029] To a 100 mL round-bottom flask equipped with a magnetic stirrer, intermediate 4 (4.7 mmol), starting material 5 (4.7 mmol), glacial acetic acid (9.0 mmol), and 1,2-dichloroethane (20 mL) were added and stirred at room temperature for 1 hour. Half the amount of sodium triacetoxyborohydride (4.5 mmol) was then added. After the reaction continued for 1 hour, the remaining half of the sodium triacetoxyborohydride (4.5 mmol) was added and stirring continued at room temperature for 6 hours. The reaction progress was monitored by TLC using a 3:1 ratio of petroleum ether to ethyl acetate, 0.5% aqueous ammonia as the developing solvent. After completion of the reaction, the 1,2-dichloroethane was removed by distillation under reduced pressure. The solution was first adjusted to a pH of no bubbles with saturated sodium bicarbonate solution, then extracted with dichloromethane (20 mL x 2). The carbon dichloride layers were combined and washed with saturated brine (20 mL x 2). The product was then dried over anhydrous sodium sulfate for half an hour, and the solvent was removed by distillation under reduced pressure to obtain a crude product, which was then purified by column chromatography using petroleum ether:ethyl acetate (5:1, v / v) as the eluent to obtain a colorless, transparent liquid intermediate 6 with a yield of 57%.

[0030] To a 100 mL round-bottom flask equipped with a magnetic stirrer, intermediate 6 (1.28 mmol) and 5 mL of anhydrous dichloromethane were added. The mixture was stirred in an ice bath for 10 minutes. A mixture of trifluoroacetic acid (4 mL) and anhydrous dichloromethane (5 mL) was then slowly added dropwise to the reaction flask using a constant pressure dropping funnel. Stirring was continued in an ice bath for 8 hours. The reaction progress was monitored by TLC using a 3:1 ratio of petroleum ether to ethyl acetate, 0.5% aqueous ammonia as the developing solvent. After the reaction, saturated sodium bicarbonate solution was slowly added dropwise to the reaction mixture to remove excess trifluoroacetic acid and adjust the pH to 7-8. The mixture was then extracted with dichloromethane (10 mL x 4). The combined dichloromethane layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the dichloromethane to obtain the crude product. The crude product was purified by column chromatography using ethyl acetate as the eluent to obtain intermediate 7, a pale yellow liquid in 89% yield.

[0031] To a 100 mL round-bottom flask equipped with a magnetic stirrer were added intermediate 7 (0.68 mmol), starting material 9 (0.75 mmol), N,N-diisopropylethylamine (1.36 mmol), and acetonitrile (15 mL) in sequence. The mixture was heated to 60°C and allowed to react. The reaction progress was monitored by TLC using a 3:1 ratio of petroleum ether to ethyl acetate, 0.5% aqueous ammonia. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the acetonitrile. 15 mL of water was added and the mixture was shaken to dissolve. The mixture was then extracted with dichloromethane (15 mL x 2). The carbon dichloride layers were combined and washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The product was purified by column chromatography using a 3:1 ratio of petroleum ether to ethyl acetate (v / v) to obtain intermediate 8 as a white solid in a 42% yield.

[0032] Weigh 0.24 mmol of intermediate 8 and dissolve it in dichloromethane (2 mL) and methanol (4 mL). Add solid sodium hydroxide (2.4 mmol) and aqueous hydroxylamine (7.04 mmol) in an ice bath and allow to react for 0.5-1 h. Monitor the reaction progress by TLC using a 5:1 ratio of dichloromethane to methanol, 0.5% aqueous ammonia. After completion of the reaction, adjust the pH to 7-8 with 10% hydrochloric acid. Remove the dichloromethane and methanol by distillation under reduced pressure to obtain the crude product, which is then purified by TLC to yield the title compound Ia as a white solid. Yield: 43%, melting point: 151.2-151.8°C. 1H NMR(500MHz,Methanol-d4)δ8.59(dd,J=4.9,1.7Hz,1H),7.54(dd,J=13.8,7.9Hz,3H ),7.49–7.43(m,4H),7.25(dd,J=7.7,4.8Hz,1H),7.16(dd,J=6.0,3.1Hz,2H),4.15– 4.08(m,2H),3.98(d,J=15.3Hz,1H),3.70–3.63(m,2H),2.87(ddd,J=16.6,11.1,5.0 Hz,1H),2.78–2.70(m,1H),2.31–2.23(m,1H),2.09–2.01(m,2H),1.71–1.62(m,1H). 13 C NMR (125MHz, DMSO-d6) δ163.2,157.6,155.7,148.4,147.0,146.1,145.3,136.3,135.9,13 3.4,130.8,130.1,128.0,127.1,126.7,124.1,122.1,62.0,56.9,56.0,28.4,27.9,20.9.

[0033] Example 2: Preparation of (S)-4-((((3,5-dimethylpyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)-N-hydroxybenzamide (Compound Ib)

[0034]

[0035] 2-Chloromethylbenzimidazole was replaced with 3,5-dimethyl-2-chloromethylpyridine, and the synthesis method according to Example 1 was used to obtain compound Ib as a white solid with a yield of 59% and a melting point of 106.7-107.2°C. 1 H NMR(500MHz,DMSO-d6)δ11.10(s,1H),8.83(s,1H),8.49(d,J=4.1Hz,1H),8.07(s,1H) ,7.48(d,J=8.0Hz,2H),7.35(d,J=7.7Hz,1H),7.23(d,J=7.9Hz,2H),7.14(s,1H),7.06 (dd,J=7.7,4.7Hz,1H),4.12–3.84(m,4H),3.63(d,J=13.6Hz,1H),2.75(d,J=11.1Hz, 1H), 2.63 (d, J = 16.3Hz, 1H), 2.26 (s, 3H), 2.17 (s, 3H), 2.10–1.87 (m, 3H), 1.52 (m, 1H).13 CNMR(125MHz,DMSO-d6)δ164.7,158.0,154.5,147.1,146.1,144.4,138.9,137.0,134.7, 132.9,131.8,131.4,128.7,126.9,122.1,60.5,56.3,55.2,29.0,26.9,21.9,18.3,17.8.

[0036] Example 3: Preparation of (S)-4-((((3-chloropyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)-N-hydroxybenzamide (Compound Ic)

[0037]

[0038] Substituting 2-chloromethylbenzimidazole with 3-chloropyridine-2-carboxaldehyde, the compound Ic was obtained according to the synthesis method of Example 1 as a white solid with a yield of 57% and a melting point of 147.5-148.2°C. 1 H NMR (500MHz, DMSO-d6) δ11.23(s,1H),8.41(d,J=5.0Hz,1H),8.12(s,1H),7.62(d,J=8.3Hz,2H),7.25(dd,J=26.3,18.3Hz,4H),7.13–7.10(m ,1H),3.93–3.81(m,2H),3.65(dd,J=27.5,13.6Hz,2H),3.52(d,J=14.4Hz,1H),2.32(m,1H),2.19(m,1H),2.09(m,1H),1.45(d,J=6.8Hz,3H). 13 C NMR(125MHz,DMSO-d6)δ164.6,158.6,156.8,147.4,147.0,145.3,137.6,137.0,13 4.5,131.8,131.2,128.1,126.7,124.1,122.1,62.0,56.9,56.0,29.5,29.0,21.9.

[0039] Example 4: Preparation of (S)-N-hydroxy-4-(((isoquinolin-1-ylmethyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)benzamide (Compound Id)

[0040]

[0041] Substituting 2-chloromethylbenzimidazole with 1-isoquinolinecarboxaldehyde, the compound Id was obtained according to the synthesis method of Example 1 as a white solid with a yield of 49% and a melting point of 169.3-170.0°C. 1 H NMR(500MHz,Methanol-d4)δ8.53(dd,J=4.9,1.7Hz,1H),7.53(dd,J=13.8,7.9Hz,3H ),7.48–7.42(m,4H),7.24(dd,J=7.7,4.8Hz,2H),7.15(dd,J=6.0,3.1Hz,2H),4.14– 4.09(m,2H),3.87(d,J=15.3Hz,1H),3.69–3.62(m,2H),2.77(ddd,J=16.6,11.1,5.0 Hz,1H),2.76–2.68(m,1H),2.30–2.22(m,1H),2.10–2.02(m,2H),1.60–1.61(m,1H). 13 C NMR (125MHz, DMSO-d6) δ163.2,157.6,155.7,148.4,147.0,145.3,136.3,136.1,135.9,134.2,13 3.4,132.0,131.5,130.8,130.1,127.1,126.7,124.1,122.1,62.0,56.9,56.0,28.3,27.9,20.8.

[0042] Example 5: Preparation of (S)-4-((((1H-benzo[d]imidazol-2-yl)methyl)(1-(4-methylpyridin-2-yl)ethyl)amino)methyl)-N-hydroxybenzamide (Compound Ie)

[0043]

[0044] Substituting 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine, the compound Ie was obtained according to the synthesis method of Example 1 as a white solid with a yield of 53% and a melting point of 151.7-152.5°C. 1H NMR(500MHz,Methanol-d4)δ8.59(dd,J=4.9,1.7Hz,1H),7.54(dd,J=13.8,7.9Hz,3H ),7.49–7.43(m,4H),7.25(dd,J=7.7,4.8Hz,1H),7.16(dd,J=6.0,3.1Hz,2H),4.15– 4.08(m,2H),3.98(d,J=15.3Hz,1H),3.70–3.63(m,2H),2.87(ddd,J=16.6,11.1,5.0 Hz,1H),2.78–2.70(m,1H),2.31–2.23(m,1H),2.09–2.01(m,2H),1.71–1.62(m,1H). 13 C NMR (125MHz, DMSO-d6) δ163.1,157.5,155.7,148.5,147.2,146.1,145.3,136.4,135.9 ,133.3,130.7,130.1,128.1,127.0,126.8,124.1,122.2,59.7,54.2,48.7,21.1,15.7.

[0045] Example 6: Preparation of (S)-4-((((3,5-dimethylpyridin-2-yl)methyl)(1-(4-methylpyridin-2-yl)ethyl)amino)methyl)-N-hydroxybenzamide (Compound If)

[0046]

[0047] Substituting 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine, the compound If was obtained according to the synthesis method of Example 2 as a white solid with a yield of 57% and a melting point of 86.2-87.0°C. 1 H NMR (500MHz, DMSO-d6) δ11.12(s,1H),8.41(d,J=5.0Hz,1H),8.12(s,1H),7.62(d,J=8.3Hz,2H),7.25(dd,J=26.3,18.3Hz,4H),7.13–7.10(m ,1H),3.93–3.81(m,2H),3.65(dd,J=27.5,13.6Hz,2H),3.52(d,J=14.4Hz,1H),2.32(s,3H),2.19(s,3H),2.09(s,3H),1.45(d,J=6.8Hz,3H). 13C NMR (125MHz, DMSO-d6) δ164.6,160.9,154.0,148.6,147.3,146.1,133.7,139.2,132. 7,132.0,131.6,128.8,127.0,124.5,123.6,59.6,54.5,53.8,21.1,17.9,17.8,14.0.

[0048] Example 7: Preparation of (S)-4-((((3-chloropyridin-2-yl)methyl)(1-(4-methylpyridin-2-yl)ethyl)amino)methyl)-N-hydroxybenzamide (Compound Ig)

[0049]

[0050] Substituting 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine, the compound Ig was obtained according to the synthesis method of Example 3 as a white solid with a yield of 49% and a melting point of 175.3-175.8°C. 1 H NMR (500MHz, DMSO-d6) δ11.23(s,1H),8.41(d,J=5.0Hz,1H),8.12(s,1H),7.62(d,J=8.3Hz,2H),7.25(dd,J=26.3,18.3Hz,4H),7.13–7.10(m ,1H),3.93–3.81(m,2H),3.65(dd,J=27.5,13.6Hz,2H),3.52(d,J=14.4Hz,1H),2.32(m,1H),2.19(m,1H),2.09(m,1H),1.45(d,J=6.8Hz,3H). 13 CNMR(125MHz,DMSO-d6)δ164.6,160.9,154.0,148.6,147.3,146.1,143.7,139.2 ,132.7,132.0,131.6,128.8,127.1,124.5,123.6,59.6,54.5,21.1,17.8,14.0.

[0051] Example 8: Preparation of (S)-N-hydroxy-4-(((isoquinolin-1-ylmethyl)(1-(4-methylpyridin-2-yl)ethyl)amino)methyl)benzamide (Compound Ih)

[0052]

[0053] Substituting 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine, the compound Ih was obtained according to the synthesis method of Example 4 as a white solid with a yield of 56% and a melting point of 123.4-124.0°C. 1 H NMR(500MHz,Methanol-d4)δ8.53(dd,J=4.9,1.7Hz,1H),7.53(dd,J=13.8,7.9Hz,3H ),7.48–7.42(m,4H),7.24(dd,J=7.7,4.8Hz,2H),7.15(dd,J=6.0,3.1Hz,2H),4.14– 4.09(m,2H),3.87(d,J=15.3Hz,1H),3.69–3.62(m,2H),2.77(ddd,J=16.6,11.1,5.0 Hz,1H),2.76–2.68(m,1H),2.30–2.22(m,1H),2.10–2.02(m,2H),1.60–1.61(m,1H). 13 C NMR (125MHz, DMSO-d6) δ162.9,157.3,155.1,148.4,147.2,145.4,136.6,136.4,136.1,134.6 ,133.5,132.0,131.3,130.5,130.0,127.3,126.2,124.1,122.3,56.9,56.0,28.2,27.9,20.8.

[0054] Example 9: Preparation of (S,E)-3-(4-((((1H-benzo[d]imidazol-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)phenyl)-N-hydroxyacrylamide (Compound Ii)

[0055]

[0056] By replacing methyl p-formylbenzoate with methyl 4-formylcinnamate, the synthesis method of Example 1 was referred to to obtain compound Ii as a white solid with a yield of 46% and a melting point of 102.6-103.3°C. 1H NMR (500MHz, DMSO-d6) δ12.54(s,1H),8.60(d,J=4.6Hz,2H),7.44(s,1H),7.39(d,J=15.8Hz,2H),7.22(dd,J=7.7,4.7Hz,2H),7.11(dt,J=23. 2,7.1Hz,4H),6.39(d,J=15.8Hz,2H),3.76(d,J=14.4Hz,2H),2.83–2.7 6(m,2H),2.21–2.14(m,2H),2.00–1.89(m,5H),1.58(d,J=10.7Hz,2H). 13 CNMR(125MHz,DMSO-d6)δ162.3,161.6,157.6,155.7,148.4,147.2,145.3,141.5,138.9,137.8,1 36.7,136.0,133.4,130.8,130.1,127.1,126.7,124.1,122.1,62.0,56.9,56.0,28.4,28.0,20.9.

[0057] Example 10: Preparation of (S,E)-3-(4-((((3,5-dimethylpyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)phenyl)-N-hydroxyacrylamide (Compound Ij)

[0058]

[0059] By replacing methyl p-formylbenzoate with methyl 4-formylcinnamate, the synthesis method of Example 2 was referred to to obtain compound Ij, a white solid with a yield of 59% and a melting point of 90.6-91.3°C. 1 H NMR (500MHz, DMSO-d6) δ10.77(s,1H),8.50(d,J=4.6Hz,1H),8.11(s,1H),7.52–7.25(m,7H),7.18(s,1H),6.41(d,J=15.7Hz,1H),3.93(d,J=17.7H z,4H),2.81–2.71(m,1H),2.64(d,J=16.4Hz,1H),2.26(s,3H),2.18(s,3H ),2.08(s,1H),2.00–1.89(m,2H),1.75(s,1H),1.55(s,1H),1.22(s,1H). 13CNMR(125MHz,DMSO-d6)δ164.6,158.6,156.8,147.4,147.0,145.3,138.2,137.6,137.0,135.6, 134.5,131.8,131.2,128.1,126.7,124.1,122.1,62.1,56.9,56.4,29.5,29.0,21.9,18.3,19.1.

[0060] Example 11: Preparation of (S,E)-3-(4-((((3-chloropyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)phenyl)-N-hydroxyacrylamide (Compound Ik)

[0061]

[0062] By replacing methyl p-formylbenzoate with methyl 4-formylcinnamate, the synthesis method according to Example 3 was used to obtain compound Ik as a white solid with a yield of 53% and a melting point of 163.4-164.0°C. 1 H NMR(500MHz,DMSO-d6)δ9.87(s,1H),8.46(dd,J=4.7,1.7Hz,1H),8.36(dd,J=4.7,1.5Hz,1H ),7.74(dd,J=8.1,1.5Hz,1H),7.50–7.11(m,9H),6.37(d,J=15.8Hz,1H),4.16(d,J=13.1Hz, 1H),4.07(dd,J=30.5,14.2Hz,3H),3.76(d,J=15.2Hz,1H),2.73(td,J=13.2,10.7,4.5Hz,1H ),2.63(d,J=16.4Hz,1H),2.09–2.01(m,1H),1.93(q,J=10.5Hz,2H),1.54(d,J=10.4Hz,1H). 13 C NMR (125MHz, DMSO-d6) δ163.3,158.6,156.9,147.3,147.0,143.5,138.6,137.6,136.9,13 4.5,133.3,131.8,128.8,127.4,124.1,122.1,118.6,61.9,56.9,56.1,29.5,29.0,21.9.

[0063] Example 12: Preparation of (S,E)-N-hydroxy-3-(4-(((isoquinolin-1-ylmethyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)phenyl)acrylamide (Compound I1)

[0064]

[0065] By replacing methyl p-formylbenzoate with methyl 4-formylcinnamate, the synthesis method of Example 4 was referred to to obtain compound I1 as a white solid with a yield of 61% and a melting point of 97.1-98.0°C. 1 H NMR(500MHz,DMSO-d6)δ8.53(dd,J=4.9,1.7Hz,1H),7.53(dd,J=13.8,7.9Hz,3H),7 .48–7.42(m,4H),7.24(dd,J=7.7,4.8Hz,4H),7.15(dd,J=6.0,3.1Hz,2H),4.14–4. 09(m,2H),3.87(d,J=15.3Hz,1H),3.69–3.62(m,2H),2.77(ddd,J=16.6,11.1,5.0H z,1H),2.76–2.68(m,1H),2.30–2.22(m,1H),2.10–2.02(m,2H),1.60–1.61(m,1H). 13 C NMR (125MHz, DMSO-d6) δ162.3,158.2,156.5,155.6,148.3,147.2,144.2,142.7,137.8,136.4,135.2,13 4.9,133.7,132.4,131.9,130.8,130.1,127.2,126.7,121.2,119.1,67.2,62.0,56.9,28.4,28.0,20.9.

[0066] Example 13: Preparation of (S,E)-3-(4-((((1H-benzo[d]imidazol-2-yl)methyl)(1-(4-methylpyridin-2-yl)ethyl)amino)methyl)phenyl)-N-hydroxyacrylamide (Compound Im)

[0067]

[0068] The 6,7-dihydro-5H-quinolin-8-one was replaced by 2-acetyl-4-methylpyridine, and methyl p-formylbenzoate was replaced by methyl 4-formylcinnamate. The synthesis method of Example 1 was referred to to obtain compound Im as a white solid with a yield of 57% and a melting point of 126.3-127.0°C. 1H NMR(500MHz,DMSO-d6)δ12.21(s,1H),10.73(s,1H),9.02(s,1H),8.42(d,J=5.0Hz,1H),7.58–7.40(m,7H),7.36(s,1H),7.19–7.09(m,3 H),6.42(d,J=15.7Hz,1H),4.05–3.92(m,2H),3.72(dd,J=14.7,7.2Hz,2H),3.53(d,J=14.5Hz,1H),2.34(s,3H),1.45(d,J=6.8Hz,3H). 13 C NMR (125MHz, DMSO-d6) δ162.2,156.5,155.7,148.0,147.7,146.9,145.3,141.5,138.9,136.4 ,135.9,133.3,130.7,130.1,127.1,126.6,124.0,122.9,115.2,62.0,56.9,56.0,28.2,20.8.

[0069] Example 14: Preparation of (S,E)-3-(4-((((3,5-dimethylpyridin-2-yl)methyl)(1-(4-methylpyridin-2-yl)ethyl)amino)methyl)phenyl)-N-hydroxyacrylamide (Compound In)

[0070]

[0071] The 6,7-dihydro-5H-quinolin-8-one was replaced by 2-acetyl-4-methylpyridine, and the methyl p-formylbenzoate was replaced by methyl 4-formylcinnamate. The compound In was obtained according to the synthesis method of Example 2 as a white solid with a yield of 37% and a melting point of 112.3-113.0°C. 1 H NMR(500MHz,DMSO-d6)δ8.40(d,J=5.0Hz,1H),8.10(d,J=2.1Hz,1H),7.40(dd,J=23.1, 11.7Hz,3H),7.27(d,J=2.1Hz,1H),7.24–7.17(m,3H),7.10(d,J=5.0Hz,1H),6.40(d,J= 15.7Hz,1H),3.87(q,J=6.8Hz,1H),3.78(d,J=12.4Hz,1H),3.59(dd,J=13.4,10.0Hz,2H ),3.44(d,J=14.3Hz,1H),2.31(s,3H),2.18(s,3H),2.08(s,3H),1.43(d,J=6.8Hz,3H). 13C NMR (125MHz, DMSO-d6) δ163.4,157.5,156.7,149.0,147.9,146.3,138.9,137.4,136.9,134. 3,131.7,131.1,128.1,127.6,125.0,123.1,122.5,63.2,57.7,57.2,27.1,28.8,21.6,18.3.

[0072] Example 15: Preparation of (S,E)-3-(4-((((3-chloropyridin-2-yl)methyl)(1-(4-methylpyridin-2-yl)ethyl)amino)methyl)phenyl)-N-hydroxyacrylamide (Compound Io)

[0073]

[0074] The 6,7-dihydro-5H-quinolin-8-one was replaced by 2-acetyl-4-methylpyridine, and the methyl p-formylbenzoate was replaced by methyl 4-formylcinnamate. The synthesis method of Example 3 was referred to to obtain compound Io as a white solid with a yield of 53% and a melting point of 152.4-153.0°C. 1 H NMR (500MHz, DMSO-d6) δ10.73 (s, 1H), 8.43 (dd, J=4.7, 1.6Hz, 1H), 8.38 (d, J= 5.0Hz,1H),7.80(dd,J=8.0,1.5Hz,1H),7.43–7.34(m,2H),7.32–7.20(m,4H), 7.08(dd,J=5.1,1.8Hz,1H),6.40(dd,J=15.9,3.7Hz,1H),4.04–3.95(m,2H), 3.80–3.65(m,2H),3.60(d,J=14.8Hz,1H),2.31(s,3H),1.46(d,J=6.9Hz,3H). 13 C NMR (125MHz, DMSO-d6) δ161.6,156.2,148.6,147.5,147.0,142.4,138.7,137.8,133.6 ,131.8,131.7,129.1,127.6,124.3,124.2,123.4,118.8,60.2,54.1,54.0,21.1,14.8.

[0075] Example 16: Preparation of (S,E)-N-hydroxy-3-(4-(((isoquinolin-1-ylmethyl)(1-(4-methylpyridin-2-yl)ethyl)amino)methyl)phenyl)acrylamide (Compound Ip)

[0076]

[0077] The 6,7-dihydro-5H-quinolin-8-one was replaced by 2-acetyl-4-methylpyridine, and the methyl p-formylbenzoate was replaced by methyl 4-formylcinnamate. The synthesis method of Example 4 was referred to to obtain compound Ip as a white solid with a yield of 56% and a melting point of 97.1-98.0°C. 1 H NMR(500MHz,DMSO-d6)δ8.53(dd,J=4.9,1.7Hz,1H),7.53(dd,J=13.8,7.9Hz,3H),7 .48–7.42(m,4H),7.24(dd,J=7.7,4.8Hz,4H),7.15(dd,J=6.0,3.1Hz,2H),4.14–4. 09(m,2H),3.87(d,J=15.3Hz,1H),3.69–3.62(m,2H),2.77(ddd,J=16.6,11.1,5.0H z,1H),2.76–2.68(m,1H),2.30–2.22(m,1H),2.10–2.02(m,2H),1.60–1.61(m,1H). 13 C NMR (125MHz, DMSO-d6) δ163.2,157.9,155.7,155.4,148.0,147.5,144.3,143.0,137.6,135.5,135.2 ,134.9,133.7,132.6,132.2,130.8,130.2,127.3,126.8,121.3,119.0,62.0,56.9,56.0,28.0,20.9.

[0078] Example 17: Preparation of (S)-4-(((1H-benzo[d]imidazol-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)-N-hydroxybutanamide (Compound IIa)

[0079]

[0080] Substituting methyl p-formylbenzoate with methyl 4-bromobutyrate, the synthesis method according to Example 1 was followed to obtain Compound IIa, a colorless transparent liquid, with a yield of 43%. 1H NMR (500MHz, DMSO-d6) δ10.46(s,1H),8.51(dd,J=4.7,1.7Hz,1H),7.51(dd,J=5.6,3.6Hz,3H),7.20(d d,J=7.7,4.7Hz,1H),7.12(dd,J=6.0,3.2Hz,2H),4.15(d,J=15.7Hz,1H),3.97(dd,J=10.2,5.9Hz,1H) ,3.92(d,J=15.7Hz,1H),2.78(ddd,J=16.4,10.8,5.1Hz,1H),2.67(dt,J=13.2,5.2Hz,2H),2.58(dt,J =13.2,7.0Hz,1H),2.09(s,2H),1.91(t,J=7.3Hz,3H),1.85–1.75(m,1H),1.61(dt,J=13.8,6.8Hz,3H). 13 C NMR(125MHz,DMSO-d6)δ169.9,162.3,148.4,147.2,146.8,146.4,141.5,138.9,1 36.7,132.4,131.6,124.1,123.3,59.5,55.7,49.6,32.5,29.4,27.7,23.6,21.1.

[0081] Example 18: Preparation of (S)-4-(((3,5-dimethylpyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)-N-hydroxybutyramide (Compound IIb)

[0082]

[0083] Substituting methyl p-formylbenzoate with methyl 4-bromobutyrate, the synthesis method according to Example 2 was followed to obtain Compound IIb, a colorless transparent liquid, with a yield of 41%. 1 H NMR(500MHz,DMSO-d6)δ10.29(s,1H),8.42(dd,J=4.7,1.8Hz,1H),8.13(s,1 H),7.48(d,J=7.8Hz,1H),7.36(s,1H),7.17(dd,J=7.7,4.6Hz,1H),4.14–3. 90(m,3H),3.63–3.55(m,2H),2.76(td,J=11.2,5.6Hz,1H),2.66(d,J=16.7H z,2H),2.34(s,3H),2.23(s,3H),1.97-1.74(m,6H),1.55(d,J=55.8Hz,3H). 13C NMR(125MHz,DMSO-d6)δ168.2,160.6,147.4,145.7,145.3,137.6,136.2,132.6, 131.5,130.4,122.3,58.7,56.5,48.5,32.5,31.2,29.4,27.7,23.6,21.1,18.1.

[0084] Example 19: Preparation of (S)-4-(((3-chloropyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)-N-hydroxybutanamide (Compound IIc)

[0085]

[0086] Substituting methyl p-formylbenzoate with methyl 4-bromobutyrate, the synthesis method according to Example 3 was followed to obtain Compound IIc, a colorless transparent liquid, with a yield of 46%. 1 H NMR (500MHz, DMSO-d6) δ10.34 (s, 1H), δ8.47 (dd, J=4.5, 2.0Hz, 1H), δ8.09 (d, J=8. 0Hz, 1H), δ7.52 (t, J=7.5Hz, 1H), δ7.40 (s, 1H), δ7.22 (dd, J=7.5, 4.5Hz, 1H), δ4.1 0-3.85(m,3H), δ3.70-3.60(m,2H), δ2.81(td,J=11.5,5.5Hz,1H), δ2.70(d,J=17. 0Hz, 2H), δ2.39 (s, 3H), δ2.28 (s, 3H), δ1.94-1.69 (m, 6H), δ1.51 (d, J = 56.0Hz, 3H). 13 C NMR (125MHz, DMSO-d6): δ168.5,161.2,148.1,146.0,145.6,138.2,136.3, 132.2,131.2,130.9,123.5,59.2,57.1,49.3,33.3,31.5,30.2,24.1,22.0.

[0087] Example 20: Preparation of (S)-N-hydroxy-4-((isoquinolin-1-ylmethyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)butanamide (Compound IId)

[0088]

[0089] Substituting methyl p-formylbenzoate with methyl 4-bromobutyrate, the synthesis method according to Example 4 was followed to obtain compound IId, a colorless transparent liquid, with a yield of 49%.1 H NMR (500MHz, DMSO-d6) δ10.50 (s, 1H), δ8.55 (dd, J=4.8, 1.9Hz, 1H), δ7.55 (dd, J=5.7, 3.7Hz, 3H), δ7.25 (d d,J=7.8,4.8Hz,1H), δ7.15(dd,J=6.1,3.3Hz,2H), δ4.20(d,J=15.8Hz,1H), δ4.00(dd,J=10.3,6.0Hz,1H), δ3.95(d,J=15.8Hz,1H), δ2.80(ddd,J=16.5,11.0,5.2Hz,1H), δ2.70(dt,J=13.3,5.3Hz,2H), δ2.60(dt,J= 13.3, 7.1Hz, 1H), δ2.10 (s, 2H), δ1.93 (t, J=7.4Hz, 3H), δ1.88-1.78 (m, 1H), δ1.65 (dt, J=13.9, 6.9Hz, 3H). 13 C NMR (125MHz, DMSO-d6): δ169.5,162.1,158.2,148.6,147.0,146.6,142.7,139.1,136.4, 132.6,131.8,129.6,127.2,124.3,123.5,59.7,55.9,49.8,32.7,29.6,27.9,23.8,21.3.

[0090] Example 21: Preparation of (S)-4-(((1H-benzo[d]imidazol-2-yl)methyl)(1-(4-methylpyridin-2-yl)ethyl)amino)-N-hydroxybutanamide (Compound IIe)

[0091]

[0092] Substituting 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine and methyl p-formylbenzoate with methyl 4-bromobutyrate, the synthesis method according to Example 1 was used to obtain Compound IIe, a colorless transparent liquid, with a yield of 51%. 1HNMR (500MHz, DMSO-d6) δ10.20 (s, 1H), δ8.64–8.58 (m, 1H), δ8.48 (d, J = 4.5Hz, 1H), δ8.43 ( dd,J=4.8,1.9Hz,1H),δ7.81(d,J=8.2Hz,1H),δ7.49(d,J=7.5Hz,1H),δ7.38–7.31(m,1H),δ 7.19(t,J=6.5Hz,1H), δ4.26(d,J=13.5Hz,1H), δ4.05(dd,J=36.7,23.6Hz,2H), δ2.90–2.63 (m, 3H), δ1.92 (d, J = 33.1Hz, 3H), δ1.79 (t, J = 7.4Hz, 2H), δ1.65 (s, 1H), δ1.45–1.15 (m, 5H). 13 C NMR (125MHz, DMSO-d6): δ168.0,162.2,148.6,147.5,146.7,146.3,141.2,139. 2,136.5,132.3,131.5,124.0,123.4,60.5,34.2,31.1,24.7,22.0,19.3,18.0.

[0093] Example 22: Preparation of (S)-4-(((3,5-dimethylpyridin-2-yl)methyl)(1-(4-methylpyridin-2-yl)ethyl)amino)-N-hydroxybutanamide (Compound IIf)

[0094]

[0095] Substituting 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine and methyl p-formylbenzoate with methyl 4-bromobutyrate, the compound IIf was obtained according to the synthesis method of Example 2. The compound IIf was a colorless transparent liquid with a yield of 47%. 1 HNMR (500MHz, DMSO-d6) δ12.00(s,1H), δ10.25(d,J=4.5Hz,1H), δ8.75(d,J=5.0Hz,1H), δ8.40(d,J=5.0Hz,1H), δ7.55–7.35(m,3H), δ7.30(s,1 H),7.10–6.95(m,2H),δ4.00–3.90(m,2H),δ3.70(d,J=14.0Hz,1H),δ2. 30(s,4H), δ1.80(d,J=7.0Hz,2H), δ1.35(t,J=7.0Hz,3H), δ1.25(s,3H). 13C NMR (125MHz, DMSO-d6): δ168.0,162.0,149.0,147.0,145.0,140.0,137.6,134 .0,132.0,126.0,122.0,60.0,56.0,50.0,33.0,30.0,28.0,24.0,22.0,20.3.

[0096] Example 23: Preparation of (S)-4-(((3-chloropyridin-2-yl)methyl)(1-(4-methylpyridin-2-yl)ethyl)amino)-N-hydroxybutanamide (Compound IIg)

[0097]

[0098] Substituting 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine and methyl p-formylbenzoate with methyl 4-bromobutyrate, the synthesis method according to Example 3 was used to obtain compound IIg, a colorless transparent liquid, with a yield of 41%. 1 HNMR (500MHz, DMSO-d6) δ10.62 (s, 1H), δ8.39 (dd, J=4.5, 2.0Hz, 1H), δ8.10 (d, J=8 .0Hz, 1H), δ7.34 (t, J=7.5Hz, 1H), δ7.36 (s, 1H), δ7.31 (dd, J=7.5, 4.5Hz, 1H), δ4.1 0-3.85(m,3H), δ3.70-3.60(m,2H), δ2.81(td,J=11.5,5.5Hz,1H), δ2.70(d,J=17. 0Hz, 2H), δ2.39 (s, 3H), δ2.28 (s, 3H), δ1.94-1.69 (m, 6H), δ1.50 (d, J = 56.0Hz, 3H). 13 C NMR (125MHz, DMSO-d6): δ168.3,161.5,148.2,146.3,145.7,138.3,136.3,134.2,132.4,131.0,123.4,59.3,49.4,33.5,31.3,30.6,28.2,24.3.

[0099] Example 24: Preparation of (S)-N-hydroxy-4-((isoquinolin-1-ylmethyl)(1-(4-methylpyridin-2-yl)ethyl)amino)butanamide (Compound IIh)

[0100]

[0101] Substituting 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine and methyl p-formylbenzoate with methyl 4-bromobutyrate, the synthetic method according to Example 4 was used to obtain compound IIh, a colorless transparent liquid, with a yield of 50%. 1 HNMR (500MHz, DMSO-d6) δ10.50 (s, 1H), δ8.55 (dd, J=4.8, 1.9Hz, 1H), δ7.55 (dd, J=5.7, 3.7Hz, 3H), δ7.25 (d d,J=7.8,4.8Hz,1H), δ7.15(dd,J=6.1,3.3Hz,2H), δ4.20(d,J=15.8Hz,1H), δ4.00(dd,J=10.3,6.0Hz,1H), δ3.95(d,J=15.8Hz,1H), δ2.80(ddd,J=16.5,11.0,5.2Hz,1H), δ2.70(dt,J=13.3,5.3Hz,2H), δ2.60(dt,J= 13.3, 7.1Hz, 1H), δ2.10 (s, 2H), δ1.93 (t, J=7.4Hz, 3H), δ1.88-1.78 (m, 1H), δ1.65 (dt, J=13.9, 6.9Hz, 3H). 13 C NMR (125MHz, DMSO-d6): δ169.5,162.1,158.2,157.7,148.6,147.0,146.6,142.7,139. 1,136.4,132.6,131.8,129.6,124.3,123.5,59.7,55.9,49.8,32.7,29.6,27.9,21.3.

[0102] Example 25: Preparation of (S)-5-(((1H-benzo[d]imidazol-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)-N-hydroxypentanamide (Compound III)

[0103]

[0104] By replacing methyl p-formylbenzoate with methyl 5-bromovalerate, the synthesis method according to Example 1 was used to obtain Compound IIi, a colorless transparent liquid, with a yield of 52%. 1H NMR (500MHz, DMSO-d6) δ12.13(s,1H),10.34(d,J=4.4Hz,1H),8.67(d,J=5.6Hz,1H),8.38(d,J=4.9Hz,1H),7.61–7.41(m,2H),7.37(s,1 H),7.17–7.04(m,3H),4.03–3.94(m,2H),3.75(d,J=15.2Hz,1H),2.32(s,4H),1.85(d,J=6.9Hz,2H),1.40(t,J=6.8Hz,7H),1.23(s,1H). 13 C NMR(125MHz,DMSO-d6)δ169.1,161.8,148.1,146.9,146.5,141.5,138.7,132.6,131 .8,124.4,123.5,121.2,115.2,59.7,56.0,50.0,32.3,29.5,27.4,21.1,18.4,18.2.

[0105] Example 26: Preparation of (S)-5-(((3,5-dimethylpyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)-N-hydroxypentanamide (Compound IIj)

[0106]

[0107] Substituting methyl p-formylbenzoate with methyl 5-bromovalerate, the synthesis method according to Example 2 was followed to obtain compound IIj, a colorless transparent liquid, with a yield of 53%. 1 H NMR (500MHz, DMSO-d6) δ10.27(s,1H),8.61(s,1H),8.41(d,J=4.7Hz,1H),8.08(s,1H),7.44(d,J=7.0Hz,1H),7.31(s,1H),7.13(s,1H),4 .08–3.77(m,3H),2.75(s,1H),2.63(d,J=20.1Hz,2H),2.35(s,3H),2.25–2.19(m,3H),1.96–1.71(m,5H),1.55(s,1H),1.36–1.14(m,5H). 13C NMR(125MHz,DMSO-d6)δ168.3,160.5,147.5,145.5,145.1,137.7,131.3,130.3,12 4.4,123.6,122.5,58.8,56.7,48.4,32.8,31.6,29.5,23.5,21.3,18.2,18.0,13.8.

[0108] Example 27: Preparation of (S)-5-(((3-chloropyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)-N-hydroxypentanamide (Compound IIk)

[0109]

[0110] Substituting methyl p-formylbenzoate with methyl 5-bromovalerate, the synthesis method according to Example 3 was followed to obtain compound IIk, a colorless transparent liquid, with a yield of 37%. 1 H NMR(500MHz,DMSO-d6)δ10.25(s,1H),8.62–8.56(m,1H),8.45(d,J=4.7Hz,1H),8.40(d d,J=4.7,1.7Hz,1H),7.84(d,J=8.0Hz,1H),7.46(d,J=7.6Hz,1H),7.35–7.28(m,1H),7 .14(t,J=6.4Hz,1H),4.21(d,J=13.2Hz,1H),4.01(dd,J=36.6,23.5Hz,2H),2.87–2.59 (m,3H),1.89(d,J=32.9Hz,3H),1.76(t,J=7.3Hz,2H),1.60(s,1H),1.40–1.12(m,5H). 13 C NMR(125MHz,DMSO-d6)δ168.9,162.2,148.3,146.7,146.3,138.5,132.3,131 .6,124.2,123.3,121.4,59.7,33.8,32.2,30.3,27.6,24.0,23.3,21.3,18.4.

[0111] Example 28: Preparation of (S)-N-hydroxy-5-((isoquinolin-1-ylmethyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)pentanamide (Compound III)

[0112]

[0113] Substituting methyl p-formylbenzoate with methyl 5-bromovalerate, the compound II was obtained according to the synthesis method of Example 4 as a colorless transparent liquid with a yield of 43%. 1 H NMR (500MHz, DMSO-d6) δ10.50 (s, 1H), δ8.55 (dd, J=4.8, 1.9Hz, 1H), δ7.55 (dd, J=5.7, 3.7Hz, 3H), δ7.25 (d d,J=7.8,4.8Hz,1H), δ7.15(dd,J=6.1,3.3Hz,2H), δ4.20(d,J=15.8Hz,1H), δ4.00(dd,J=10.3,6.0Hz,1H), δ3.95(d,J=15.8Hz,2H), δ2.80(ddd,J=16.5,11.0,5.2Hz,2H), δ2.70(dt,J=13.3,5.3Hz,2H), δ2.60(dt,J= 13.3, 7.1Hz, 2H), δ2.10 (s, 2H), δ1.93 (t, J=7.4Hz, 3H), δ1.88-1.78 (m, 1H), δ1.65 (dt, J=13.9, 6.9Hz, 2H). 13 C NMR (125MHz, DMSO-d6): δ168.3,162.2,158.2,148.6,147.0,146.6,142.7,139.1,137.4,135 .4,131.8,129.6,127.2,124.3,123.5,59.7,55.9,49.8,32.7,31.2,29.6,27.9,23.8,20.3.

[0114] Example 29: Preparation of (S)-5-(((1H-benzo[d]imidazol-2-yl)methyl)(1-(4-methylpyridin-2-yl)ethyl)amino)-N-hydroxypentanamide (Compound IIm)

[0115]

[0116] Replace 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine, and replace methyl p-formylbenzoate with methyl 5-bromovalerate. Referring to the synthesis method of Example 1, compound IIm was obtained as a colorless transparent liquid with a yield of 48%. 1HNMR(500MHz,DMSO-d6)δ12.13(s,1H),10.34(d,J=4.4Hz,1H),8.67(d,J=5.6Hz,1H),8.38(d,J=4.9Hz,1H),7.61–7.41(m,2H),7.37(s,1 H),7.17–7.04(m,3H),4.03–3.94(m,2H),3.75(d,J=15.2Hz,1H),2.32(s,4H),1.85(d,J=6.9Hz,2H),1.40(t,J=6.8Hz,7H),1.23(s,1H). 13 C NMR(125MHz,DMSO-d6)δ162.9,161.5,147.3,146.9,145.8,144.4,141.5,139.1,1 36.8,132.3,131.5,124.5,123.3,59.6,55.9,49.5,32.4,29.6,27.5,23.6,23.0.

[0117] Example 30: Preparation of (S)-5-(((3,5-dimethylpyridin-2-yl)methyl)(1-(4-methylpyridin-2-yl)ethyl)amino)-N-hydroxypentanamide (Compound IIn)

[0118]

[0119] Substituting 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine and methyl p-formylbenzoate with methyl 5-bromovalerate, the compound IIn was obtained according to the synthesis method of Example 2 as a colorless transparent liquid with a yield of 51%. 1 HNMR(500MHz,DMSO-d6)δ10.26(s,1H),8.61(s,1H),8.35(d,J=4.9Hz,1H),8 .11(d,J=2.2Hz,1H),7.32(d,J=2.2Hz,1H),7.22(s,1H),7.06(d,J=5.0Hz,1 H),3.86(d,J=6.8Hz,1H),3.67(s,2H),2.42(s,1H),2.30(s,3H),2.22(d,J= 2.5Hz,7H),1.77(t,J=5.6Hz,2H),1.35(d,J=6.7Hz,3H),1.31–1.24(m,4H). 13C NMR(125MHz,DMSO-d6)δ169.5,162.0,154.9,148.5,146.9,146.3,138.9,132.7, 131.7,124.2,123.3,59.5,55.6,49.4,32.6,27.3,23.5,21.1,18.1,17.9,13.7.

[0120] Example 31: Preparation of (S)-5-(((3-chloropyridin-2-yl)methyl)(1-(4-methylpyridin-2-yl)ethyl)amino)-N-hydroxypentanamide (Compound IIo)

[0121]

[0122] Substituting 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine and methyl p-formylbenzoate with methyl 5-bromovalerate, the synthesis method according to Example 3 was followed to obtain Compound IIo, a colorless transparent liquid, with a yield of 42%. 1 HNMR(500MHz,DMSO-d6)δ10.25(d,J=1.7Hz,1H),8.62(d,J=1.9Hz,1H),8.47(dd,J=4.7,1.5Hz, 1H),8.34(d,J=4.9Hz,1H),7.86(dd,J=8.1,1.5Hz,1H),7.39–7.26(m,2H),7.05(dd,J=5.1,1.7H z,1H),4.00(q,J=6.7Hz,1H),3.88(d,J=13.0Hz,1H),3.80(d,J=13.0Hz,1H),2.38–2.31(m,1H) ,2.29(s,3H),1.77(d,J=7.0Hz,2H),1.38(d,J=6.8Hz,3H),1.27(ddd,J=18.5,10.0,5.7Hz,5H). 13 C NMR(125MHz,DMSO-d6)δ169.6,162.1,148.4,146.8,146.4,138.8,136.4,1 32.6,131.8,124.1,123.4,59.6,32.7,29.3,27.2,23.6,21.0,18.0,17.8.

[0123] Example 32: Preparation of (S)-N-hydroxy-5-((1-isoquinolylmethyl)(1-(4-methylpyridin-2-yl)ethyl)amino)pentanamide (Compound IIp)

[0124]

[0125] Substituting 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine and methyl p-formylbenzoate with methyl 5-bromovalerate, the synthetic method according to Example 4 was used to obtain Compound IIp, a colorless transparent liquid, with a yield of 53%. 1 HNMR(500MHz,DMSO-d6)δ12.13(s,1H),10.34(d,J=4.4Hz,1H),8.67(d,J=5.6Hz,1H),8.38(d,J=4.9Hz,1H),7.61–7.41(m,2H),7.37(s,1 H),7.17–7.04(m,3H),4.03–3.94(m,2H),3.75(d,J=15.2Hz,1H),2.32(s,4H),1.85(d,J=6.9Hz,2H),1.40(t,J=6.8Hz,7H),1.23(s,1H). 13 C NMR (125MHz, DMSO-d6) δ167.2,161.3,158.2,157.7,148.8,146.0,146.4,142.7,136.8,1 32.9,131.3,127.2,124.5,122.4,119.1,59.8,56.2,51.0,32.0,29.7,27.3,23.3,21.5.

[0126] Pharmacological experimental data

[0127] 1. Determination of compound affinity for CXCR4

[0128] Biotinylated TN14003 (an effective CXCR4 peptide antagonist) is used to compete with the compound for CXCR4 binding, and the affinity of the compound for CXCR4 is tested by measuring the inhibition rate of the compound in inhibiting the binding of TN14003 to CXCR4.

[0129] Experimental method: MDA-MB-231 cells were digested and seeded into 96-well plates, with 1×10 cells per well. 5 cells. The next day, the corresponding concentration of compound (10nM) was added according to the group settings and incubated for 10 minutes. Fix the cells with 4% paraformaldehyde for more than 30 minutes and wash 3 times with PBS. Add 0.05μg / mL of peptide TN14003 and incubate at room temperature for 30 minutes, and wash 3 times with PBS. Add Streptavidin-Rhodamine (TRITC) (stock concentration 1mg / mL) 1:500 dilution, incubate at room temperature for 30 minutes in the dark, and wash 3 times with PBS. Add DAPI staining solution and incubate at room temperature in the dark for 5 minutes, and wash 3 times with PBS. Observe the expression under a confocal microscope, and take pictures of 3 high expression areas for preservation.

[0130] Table 1 shows the competitive binding affinity inhibition rate (Inhibitory rate) of Examples 1-32 to CXCR4.

[0131] Table 1

[0132]

[0133] As shown in Table 1, at 10 nM, a total of 24 compounds exhibited competitive binding inhibition rates exceeding 50% against CXCR4, with 16 compounds exhibiting competitive binding inhibition rates exceeding 78%, approaching and exceeding the positive control drug plerixafor (AMD3100) (78.24%). Furthermore, compounds If, IIf, IIh, Ili, III, and IIn exhibited competitive binding inhibition rates exceeding 90%, demonstrating that the designed dual-target compounds retain significant affinity for CXCR4. Among all compounds, IIf, IIh, and III exhibited the strongest competitive binding inhibition rates, all exceeding 98%. Compared to Series I compounds, most compounds in Series II exhibited competitive binding inhibition rates superior to the positive control drug plerixafor.

[0134] 2. Determination of HDAC inhibitory activity of compounds

[0135] The test used a fluorescence detection method to test the inhibitory activity of HDAC1 / HDAC6. After the substrate Ac-Lys-Tyr-Lys(Ac)-AMC was deacetylated by HDAC1 / HDAC6, the product AMC obtained by trypsin hydrolysis was detected under the emission light of the fluorescence detector. By measuring the change in fluorescence signal over time in the blank group, control group and experimental group, the inhibition rate of the test compound was calculated. Compounds with an inhibition rate greater than 50% were selected, prepared into sample solutions of different concentrations and their inhibition rates were tested. The corresponding IC was calculated using GraphPad Prism software. 50 value.

[0136] Table 2 shows the IC values of the inhibitory activities of Examples 1-32 on HDAC1 / HDAC6. 50 value.

[0137] Table 2

[0138]

[0139] As shown in Table 2, among all the compounds, 15 compounds had better inhibitory activity against HDAC6 than the positive control drug vorinostat (SAHA, IC 50=0.55μM), 14 of which showed a certain selectivity for HDAC6. Meanwhile, among all the compounds, the inhibitory activities of Ik, Il, In and Ip on HDAC1 and HDAC6 were better than SAHA (HDAC1: IC 50 =0.26 μM; HDAC6:IC 50 =0.55μM). Compared to Series I compounds, Series II compounds exhibited weaker inhibitory activity against HDAC1 and HDAC6 than SAHA. However, since HDAC inhibitors themselves have some cytotoxicity, overly potent HDAC inhibition may pose a risk of toxicity. Therefore, compounds with weaker HDAC inhibitory activity than SAHA may be worth further development due to their improved safety profile. In summary, both Series I and Series II compounds have promising development potential.

[0140] According to Table 2, the performance of series I compounds in inhibiting HDAC is significantly better than that of series II compounds, among which compounds Ik, Il, In and Ip are the best and better than the positive control drug vorinostat. Further combined with Table 1, the competitive binding inhibition rate of compounds In and Ip on CXCR4 is also better than the positive control drug plerixafor.

[0141] In addition, it should be understood that after reading the above description of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A CXCR4 / HDAC dual inhibitor, characterized in that Compounds Ib to Ip and / or pharmaceutically acceptable salts thereof having the following structures:

2. Use of the CXCR4 / HDAC dual inhibitor according to claim 1 in the preparation of a drug for preventing and treating related diseases by antagonizing CXC chemokine receptor 4 and / or inhibiting histone deacetylase.

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

4. A pharmaceutical composition, characterized in that The invention comprises at least one of a carrier and an auxiliary material and the CXCR4 / HDAC dual inhibitor according to claim 1.

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