CXCR4 antagonist with hydroxamic acid structure as well as preparation and application of CXCR4 antagonist

Abstract

The invention discloses a CXCR4 antagonist with a hydroxamic acid structure as well as preparation and application of the CXCR4 antagonist. The invention discloses a compound with a structure as shown in a general formula (II) or a pharmaceutically acceptable salt of the compound. In the formula (II), R1 is selected from # imgabs1, R2 is selected from # imgabs2, and L is an empty or C1-C6 saturated or unsaturated aliphatic hydrocarbon chain. The compound with the structure as shown in the general formula (II) and / or the pharmaceutically acceptable salt thereof are / is a multi-target derivative capable of synergistically realizing anti-tumor, anti-inflammatory and anti-depression effects.

Description

[0001] This application is a divisional application of "CXCR4 / HDAC Dual Inhibitor and Its Preparation and Application". The filing date of the original application is June 4, 2024, and the application number of the original application is 202410714277.4. Technical Field

[0002] The present invention relates to the field of medicinal chemistry, and specifically relates to a class of CXCR4 antagonists with hydroxamic acid structure, and their preparation methods and applications. Background Art

[0003] C-X-C chemokine receptor 4 (CXCR4) is the main receptor of C-X-C chemokine 12 (CXCL12), participates in a variety of 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 and thus play a role in inhibiting tumor cell invasion and inflammatory cell chemotaxis. Currently, multiple CXCR4 antagonists are in the stage of anti-tumor and anti-inflammatory clinical research. In addition, CXCR4 antagonists also exhibit good antidepressant activity. Therefore, CXCR4 is a potential effective target for anti-tumor metastasis, anti-inflammation, and anti-depression. The applicant has previously developed a variety of CXCR4 antagonists, specifically, reference can be made to the patent specifications with publication numbers CN113845439A and CN117624140A, etc.

[0004] Histone deacetylase (HDAC) is a class of epigenetic enzymes that mediate transcriptional repression by catalyzing the deacetylation of lysine residues of histones and other proteins, and is closely related to abnormal human gene expression and the development of various cancers. HDAC inhibitors have attracted 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, HDAC also participates in the regulation of multiple inflammatory signaling pathways and affects the expression of various inflammatory factors. In addition, HDCA inhibitors can also regulate the levels of neurotransmitters in the central nervous system and exhibit good antidepressant activity, and the antidepressant effect is comparable to that of traditional antidepressant drugs used in clinical practice. Therefore, HDAC is also a potential effective target for anti-tumor metastasis, anti-inflammation, and anti-depression.

[0005] The present invention utilizes pharmacophore fusion and multi-target design strategies to develop novel CXCR4 antagonists. Meanwhile, a hydroxamic acid structure is introduced into its structure. Through structural optimization, the compound shows high activity against CXCR4. The compounds of the present invention have the potential to become novel therapeutic strategies for anti-tumor, anti-inflammatory, and anti-depressant treatments. Currently, there is relatively little relevant research, which has great research significance and translational value. Summary of the Invention

[0006] In view of 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 effect and HDAC inhibitory effect, and are multi-target derivatives that can synergistically achieve anti-tumor, anti-inflammatory, and anti-depressant effects.

[0007] The CXCR4 / HDAC dual inhibitor is a compound having the structure shown in general formula (I) or (II) and / or its pharmaceutically acceptable salt:

[0008]

[0009] In formula (I) and (II):

[0010] R1 is selected from

[0011] R2 is selected from

[0012] L is empty or a saturated or unsaturated aliphatic hydrocarbon chain of C1-C6, preferably C1-C4. When L is empty, it means that in formula (I), the benzene ring is directly connected to -C(=O)NHOH, and in formula (II), R1R2N- is directly connected to -C(=O)NHOH.

[0013] Furthermore, for the CXCR4 / HDAC dual inhibitor, L can be empty or selected from the following structures:

[0014] In some embodiments, the CXCR4 / HDAC dual inhibitor can be compounds Ia-Ip, IIa-IIp having the following structures and / or their pharmaceutically acceptable salts:

[0015]

[0016] The present invention also provides a preparation method for the CXCR4 / HDAC dual inhibitor.

[0017] When the CXCR4 / HDAC dual inhibitor is a compound having the structure shown in general formula (I), its synthetic route:

[0018]

[0019] The preparation method includes: raw material 1 or raw material 2 and raw material 3 undergo reductive amination reaction to generate intermediate 4, and then react with raw material 5 through reductive amination reaction to obtain intermediate 6. Intermediate 6 is deprotected to obtain intermediate 7. Intermediate 7 reacts with raw materials 9, 10, 11 or 12 through nucleophilic substitution or reductive amination reaction to obtain intermediate 8. Finally, intermediate 8 undergoes amine transesterification reaction to obtain the compound with the structure shown in general formula (I).

[0020] When the CXCR4 / HDAC dual inhibitor is a compound with the structure shown in general formula (II), its synthetic route is as follows:

[0021]

[0022] The preparation method includes: raw material 1 or raw material 2 and raw material 3 undergo reductive amination reaction to generate intermediate 4. Intermediate 4 is deprotected to obtain intermediate 13, and then reacts with raw material 14 through nucleophilic substitution reaction to obtain intermediate 15. Intermediate 15 reacts with raw materials 9, 10, 11 or 12 through nucleophilic substitution or reductive amination reaction to obtain intermediate 16. Finally, intermediate 16 undergoes amine transesterification reaction to obtain the compound with the structure shown in general formula (II).

[0023] The present invention also provides the application of the described CXCR4 / HDAC dual inhibitor in the preparation of drugs for preventing and treating related diseases by antagonizing C-X-C chemokine receptor 4 and / or inhibiting histone deacetylase. Further, the diseases include cancer, inflammation, depression, etc.

[0024] As a general inventive concept, the present invention also provides a pharmaceutical composition, which contains at least one of a carrier, an excipient and the described CXCR4 / HDAC dual inhibitor. Among them, the carrier and the excipient can be commonly used materials in the art.

[0025] 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. Specific Embodiments

[0026] The following combines specific embodiments to further elaborate the present invention. 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.

[0027] 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)

[0028]

[0029] To a 100 mL round-bottom flask equipped with a magnetic stir bar, add starting material 1 (6 mmol), 3 (6.6 mmol), glacial acetic acid (12 mmol) and 1,2-dichloroethane (20 mL), and stir at room temperature for 1 h. Subsequently, add half of the sodium triacetoxyborohydride (4.5 mmol), continue the reaction for 1 h, then add the remaining half of the sodium triacetoxyborohydride (4.5 mmol), and continue to stir at room temperature for 6 h. Monitor the reaction progress by TLC, and the eluent is petroleum ether: ethyl acetate (3:1, 0.5% ammonia water). After the reaction is completed, distill off 1,2-dichloroethane under reduced pressure. First, adjust the pH to no bubbles in the solution with saturated sodium bicarbonate solution, then extract with dichloromethane (20 mL × 3), combine the dichloromethane layers, and wash the dichloromethane layers with saturated brine solution (20 mL × 2). Then dry over anhydrous sodium sulfate for half an hour, distill off the solvent under reduced pressure to obtain the crude product, and purify by column chromatography. The eluent is petroleum ether: ethyl acetate (3:1, v / v), and finally obtain a yellow-green solid intermediate 4 with a yield of 74%.

[0030] To a 100 mL round-bottom flask equipped with a magnetic stir bar, add intermediate 4 (4.7 mmol), raw material 5 (4.7 mmol), glacial acetic acid (9.0 mmol) and 1,2-dichloroethane (20 mL), and stir at room temperature for 1 h. Subsequently, add half of the sodium triacetoxyborohydride (4.5 mmol), continue the reaction for 1 h, then add the remaining half of the sodium triacetoxyborohydride (4.5 mmol), and continue to stir at room temperature for 6 h. Monitor the reaction progress by TLC, and the eluent is petroleum ether: ethyl acetate (3:1, 0.5% ammonia water). After the reaction is completed, distill off 1,2-dichloroethane under reduced pressure. First, adjust the pH to no bubbles in the solution with saturated sodium bicarbonate solution, then extract with dichloromethane (20 mL × 2) times, combine the dichloromethane layers, and wash the dichloromethane layers with saturated brine solution (20 mL × 2). Then dry over anhydrous sodium sulfate for half an hour, distill off the solvent under reduced pressure to obtain the crude product, and purify by column chromatography. The eluent is petroleum ether: ethyl acetate (5:1, v / v), and finally obtain a colorless transparent liquid intermediate 6 with a yield of 57%.

[0031] To a 100 mL round-bottom flask equipped with a magnetic stir bar, add intermediate 6 (1.28 mmol) and 5 mL of anhydrous dichloromethane. Stir for 10 min in an ice bath, then slowly add a mixed solution of trifluoroacetic acid (4 mL) and anhydrous dichloromethane (5 mL) dropwise to the reaction flask using a constant-pressure dropping funnel. Continue stirring for 8 h in an ice bath environment. Monitor the reaction progress by TLC, with the eluent being petroleum ether:ethyl acetate (3:1, 0.5% ammonia water). After the reaction is complete, slowly add saturated sodium bicarbonate solution to the reaction mixture to remove the excess trifluoroacetic acid and adjust the pH to 7 - 8. Then extract with dichloromethane (10 mL × 4). Combine the dichloromethane layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to remove dichloromethane to obtain the crude product. Purify by column chromatography, with the eluent being ethyl acetate, and finally obtain the pale yellow liquid intermediate 7 with a yield of 89%.

[0032] To a 100 mL round-bottom flask equipped with a magnetic stir bar, sequentially add intermediate 7 (0.68 mmol), starting material 9 (0.75 mmol), N,N-diisopropylethylamine (1.36 mmol), and acetonitrile (15 mL). Heat to 60 °C and react. Monitor the reaction progress by TLC, with the eluent being petroleum ether:ethyl acetate (3:1, 0.5% ammonia water). After the reaction is complete, cool the reaction mixture to room temperature and concentrate under reduced pressure to remove acetonitrile. Add 15 mL of water and shake to dissolve the mixture. Extract with dichloromethane (15 mL × 2). Combine the dichloromethane layers, wash the dichloromethane layer with saturated brine (30 mL × 1), dry over anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent, and purify by column chromatography, with the eluent being petroleum ether:ethyl acetate (3:1, v / v). Finally, obtain the white solid intermediate 8 with a yield of 42%.

[0033] Weigh 0.24 mmol of intermediate 8 and dissolve it in dichloromethane (2 mL) and methanol (4 mL). Add sodium hydroxide solid (2.4 mmol) and aqueous hydroxylamine solution (7.04 mmol) under ice bath conditions and react for 0.5 - 1 h. Monitor the reaction progress by TLC, with the eluent being dichloromethane:methanol (5:1, 0.5% ammonia water). After the reaction is complete, adjust the pH to 7 - 8 with 10% hydrochloric acid solution. Distill off dichloromethane and methanol under reduced pressure to obtain the crude product. Purify by preparative TLC to obtain the white solid target compound Ia. The yield is 43%, and the melting point is 151.2 - 151.8 °C. 11H NMR (500 MHz, Methanol-d4) δ 8.59 (dd, J = 4.9, 1.7 Hz, 1H), 7.54 (dd, J = 13.8, 7.9 Hz, 3H), 7.49–7.43 (m, 4H), 7.25 (dd, J = 7.7, 4.8 Hz, 1H), 7.16 (dd, J = 6.0, 3.1 Hz, 2H), 4.15–4.08 (m, 2H), 3.98 (d, J = 15.3 Hz, 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 13C NMR (125 MHz, DMSO-d6) δ 163.2, 157.6, 155.7, 148.4, 147.0, 146.1, 145.3, 136.3, 135.9, 133.4, 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。

[0034] 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)

[0035]

[0036] Replace 2-chloromethylbenzimidazole with 3,5-dimethyl-2-chloromethylpyridine, and obtain Compound Ib according to the synthesis method of Example 1, white solid, yield 59%, melting point: 106.7 - 107.2 °C. 1 1H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.83 (s, 1H), 8.49 (d, J = 4.1 Hz, 1H), 8.07 (s, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 7.9 Hz, 2H), 7.14 (s, 1H), 7.06 (dd, J = 7.7, 4.7 Hz, 1H), 4.12–3.84 (m, 4H), 3.63 (d, J = 13.6 Hz, 1H), 2.75 (d, J = 11.1 Hz, 1H), 2.63 (d, J = 16.3 Hz, 1H), 2.26 (s, 3H), 2.17 (s, 3H), 2.10–1.87 (m, 3H), 1.52 (m, 1H).13 CNMR(125MHz, DMSO-d6) δ 164.7, 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。

[0037] Example 3: Preparation of (S)-4-((((3-chloropyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)-N-hydroxybenzamide (Compound Ic)

[0038]

[0039] Replace 2-chloromethylbenzimidazole with 3-chloropyridine-2-carbaldehyde, and obtain Compound Ic according to the synthesis method of Example 1. It is a white solid with a yield of 57% and a melting point of 147.5 - 148.2 °C. 1 H NMR(500MHz, DMSO-d6) δ 11.23(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) δ 164.6, 158.6, 156.8, 147.4, 147.0, 145.3, 137.6, 137.0, 134.5, 131.8, 131.2, 128.1, 126.7, 124.1, 122.1, 62.0, 56.9, 56.0, 29.5, 29.0, 21.9。

[0040] Example 4: Preparation of (S)-N-hydroxy-4-(((isoquinolin-1-ylmethyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)benzamide (Compound Id)

[0041]

[0042] Replace 2-chloromethylbenzimidazole with 1-isoquinolinecarboxaldehyde, and obtain compound Id as a white solid according to the synthesis method of Example 1, 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=16.6,11.1,5.0Hz,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)δ163.2,157.6,155.7,148.4,147.0,145.3,136.3,136.1,135.9,134.2,133.4,132.0,131.5,130.8,130.1,127.1,126.7,124.1,122.1,62.0,56.9,56.0,28.3,27.9,20.8.

[0043] 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)

[0044]

[0045] Replace 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine, and obtain compound Ie as a white solid according to the synthesis method of Example 1, with a yield of 53% and a melting point of 151.7 - 152.5 °C. 11H NMR (500 MHz, Methanol-d4) δ 8.59 (dd, J = 4.9, 1.7 Hz, 1H), 7.54 (dd, J = 13.8, 7.9 Hz, 3H), 7.49–7.43 (m, 4H), 7.25 (dd, J = 7.7, 4.8 Hz, 1H), 7.16 (dd, J = 6.0, 3.1 Hz, 2H), 4.15–4.08 (m, 2H), 3.98 (d, J = 15.3 Hz, 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 13C NMR (125 MHz, DMSO-d6) δ 163.1, 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。

[0046] Example 6: Preparation of (S)-4-((((3,5-dimethylpyridin-2-yl)methyl)(1-(4-methylpyridin-2-yl)ethyl)amino)methyl)-N-hydroxybenzamide (Compound If)

[0047]

[0048] Replace 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine, and obtain Compound If according to the synthesis method of Example 2. It is a white solid with a yield of 57% and a melting point of 86.2 - 87.0 °C. 1 1H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.41 (d, J = 5.0 Hz, 1H), 8.12 (s, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.25 (dd, J = 26.3, 18.3 Hz, 4H), 7.13–7.10 (m, 1H), 3.93–3.81 (m, 2H), 3.65 (dd, J = 27.5, 13.6 Hz, 2H), 3.52 (d, J = 14.4 Hz, 1H), 2.32 (s, 3H), 2.19 (s, 3H), 2.09 (s, 3H), 1.45 (d, J = 6.8 Hz, 3H). 1313C NMR (125 MHz, DMSO-d6) δ 164.6, 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.

[0049] Example 7: Preparation of (S)-4-((((3-chloropyridin-2-yl)methyl)(1-(4-methylpyridin-2-yl)ethyl)amino)methyl)-N-hydroxybenzamide (Compound Ig)

[0050]

[0051] Replace 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine, and obtain Compound Ig according to the synthesis method of Example 3. It is a white solid with a yield of 49% and a melting point of 175.3 - 175.8 °C. 1 1H NMR (500 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.41 (d, J = 5.0 Hz, 1H), 8.12 (s, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.25 (dd, J = 26.3, 18.3 Hz, 4H), 7.13–7.10 (m, 1H), 3.93–3.81 (m, 2H), 3.65 (dd, J = 27.5, 13.6 Hz, 2H), 3.52 (d, J = 14.4 Hz, 1H), 2.32 (m, 1H), 2.19 (m, 1H), 2.09 (m, 1H), 1.45 (d, J = 6.8 Hz, 3H). 13 13C NMR (125 MHz, DMSO-d6) δ 164.6, 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.

[0052] Example 8: Preparation of (S)-N-hydroxy-4-(((isoquinolin-1-ylmethyl)(1-(4-methylpyridin-2-yl)ethyl)amino)methyl)benzamide (Compound Ih)

[0053]

[0054] Replace 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine, and obtain compound Ih as a white solid with a yield of 56% and a melting point of 123.4 - 124.0 °C according to the synthesis method of Example 4. 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=16.6,11.1,5.0Hz,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.

[0055] 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)

[0056]

[0057] Replace methyl 4-formylbenzoate with methyl 4-formylcinnamate, and obtain compound Ii as a white solid with a yield of 46% and a melting point of 102.6 - 103.3 °C according to the synthesis method of Example 1. 11H NMR (500 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.60 (d, J = 4.6 Hz, 2H), 7.44 (s, 1H), 7.39 (d, J = 15.8 Hz, 2H), 7.22 (dd, J = 7.7, 4.7 Hz, 2H), 7.11 (dt, J = 23.2, 7.1 Hz, 4H), 6.39 (d, J = 15.8 Hz, 2H), 3.76 (d, J = 14.4 Hz, 2H), 2.83–2.76 (m, 2H), 2.21–2.14 (m, 2H), 2.00–1.89 (m, 5H), 1.58 (d, J = 10.7 Hz, 2H). 13 13C NMR (125 MHz, DMSO-d6) δ 162.3, 161.6, 157.6, 155.7, 148.4, 147.2, 145.3, 141.5, 138.9, 137.8, 136.7, 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。

[0058] 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)

[0059]

[0060] Replace methyl 4-formylbenzoate with methyl 4-formylcinnamate, and obtain Compound Ij according to the synthesis method of Example 2. It is a white solid with a yield of 59% and a melting point of 90.6 - 91.3 °C. 1 1H NMR (500 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.50 (d, J = 4.6 Hz, 1H), 8.11 (s, 1H), 7.52–7.25 (m, 7H), 7.18 (s, 1H), 6.41 (d, J = 15.7 Hz, 1H), 3.93 (d, J = 17.7 Hz, 4H), 2.81–2.71 (m, 1H), 2.64 (d, J = 16.4 Hz, 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) δ 164.6, 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。

[0061] 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)

[0062]

[0063] Replace methyl 4-formylbenzoate with methyl 4-formylcinnamate, and obtain Compound Ik by referring to the synthesis method of Example 3. It is a white solid with a yield of 53% and a melting point of 163.4 - 164.0 °C. 1 H NMR(500MHz, DMSO-d6) δ 9.87(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) δ 163.3, 158.6, 156.9, 147.3, 147.0, 143.5, 138.6, 137.6, 136.9, 134.5, 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。

[0064] 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 Il)

[0065]

[0066] Methyl 4-formylcinnamate was used to replace methyl p-formylbenzoate, and compound Il was obtained by referring to the synthesis method of Example 4. It was 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=16.6,11.1,5.0Hz,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)δ162.3,158.2,156.5,155.6,148.3,147.2,144.2,142.7,137.8,136.4,135.2,134.9,133.7,132.4,131.9,130.8,130.1,127.2,126.7,121.2,119.1,67.2,62.0,56.9,28.4,28.0,20.9.

[0067] 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)

[0068]

[0069] 2-Acetyl-4-methylpyridine was used to replace 6,7-dihydro-5H-quinolin-8-one, and methyl 4-formylcinnamate was used to replace methyl p-formylbenzoate. Compound Im was obtained by referring to the synthesis method of Example 1. It was a white solid with a yield of 57% and a melting point of 126.3 - 127.0 °C. 11H NMR (500 MHz, DMSO-d6) δ 12.21 (s, 1H), 10.73 (s, 1H), 9.02 (s, 1H), 8.42 (d, J = 5.0 Hz, 1H), 7.58–7.40 (m, 7H), 7.36 (s, 1H), 7.19–7.09 (m, 3H), 6.42 (d, J = 15.7 Hz, 1H), 4.05–3.92 (m, 2H), 3.72 (dd, J = 14.7, 7.2 Hz, 2H), 3.53 (d, J = 14.5 Hz, 1H), 2.34 (s, 3H), 1.45 (d, J = 6.8 Hz, 3H). 13 13C NMR (125 MHz, DMSO-d6) δ 162.2, 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。

[0070] 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)

[0071]

[0072] Replace 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine and methyl 4-formylbenzoate with methyl 4-formylcinnamate, and obtain Compound In by referring to the synthesis method of Example 2. It is a white solid with a yield of 37% and a melting point of 112.3 - 113.0 °C. 1 1H NMR (500 MHz, DMSO-d6) δ 8.40 (d, J = 5.0 Hz, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.40 (dd, J = 23.1, 11.7 Hz, 3H), 7.27 (d, J = 2.1 Hz, 1H), 7.24–7.17 (m, 3H), 7.10 (d, J = 5.0 Hz, 1H), 6.40 (d, J = 15.7 Hz, 1H), 3.87 (q, J = 6.8 Hz, 1H), 3.78 (d, J = 12.4 Hz, 1H), 3.59 (dd, J = 13.4, 10.0 Hz, 2H), 3.44 (d, J = 14.3 Hz, 1H), 2.31 (s, 3H), 2.18 (s, 3H), 2.08 (s, 3H), 1.43 (d, J = 6.8 Hz, 3H). 1313C NMR (125 MHz, DMSO-d6) δ 163.4, 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.

[0073] 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)

[0074]

[0075] Replace 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine, and methyl 4-formylbenzoate with methyl 4-formylcinnamate. Compound Io was obtained according to the synthesis method of Example 3. It was a white solid with a yield of 53% and a melting point of 152.4 - 153.0 °C. 1 1H NMR (500 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.43 (dd, J = 4.7, 1.6 Hz, 1H), 8.38 (d, J = 5.0 Hz, 1H), 7.80 (dd, J = 8.0, 1.5 Hz, 1H), 7.43–7.34 (m, 2H), 7.32–7.20 (m, 4H), 7.08 (dd, J = 5.1, 1.8 Hz, 1H), 6.40 (dd, J = 15.9, 3.7 Hz, 1H), 4.04–3.95 (m, 2H), 3.80–3.65 (m, 2H), 3.60 (d, J = 14.8 Hz, 1H), 2.31 (s, 3H), 1.46 (d, J = 6.9 Hz, 3H). 13 13C NMR (125 MHz, DMSO-d6) δ 161.6, 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.

[0076] 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)

[0077]

[0078] Replace 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine, and replace methyl 4-formylbenzoate with methyl 4-formylcinnamate. According to the synthesis method of Example 4, compound Ip was obtained 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=16.6,11.1,5.0Hz,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。

[0079] Example 17: Preparation of (S)-4-(((1H-benzo[d]imidazol-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)-N-hydroxybutyramide (Compound IIa)

[0080]

[0081] Replace methyl 4-formylbenzoate with methyl 4-bromobutyrate. According to the synthesis method of Example 1, compound IIa was obtained as a colorless transparent liquid with a yield of 43%. 11H NMR (500 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.51 (dd, J = 4.7, 1.7 Hz, 1H), 7.51 (dd, J = 5.6, 3.6 Hz, 3H), 7.20 (dd, J = 7.7, 4.7 Hz, 1H), 7.12 (dd, J = 6.0, 3.2 Hz, 2H), 4.15 (d, J = 15.7 Hz, 1H), 3.97 (dd, J = 10.2, 5.9 Hz, 1H), 3.92 (d, J = 15.7 Hz, 1H), 2.78 (ddd, J = 16.4, 10.8, 5.1 Hz, 1H), 2.67 (dt, J = 13.2, 5.2 Hz, 2H), 2.58 (dt, J = 13.2, 7.0 Hz, 1H), 2.09 (s, 2H), 1.91 (t, J = 7.3 Hz, 3H), 1.85–1.75 (m, 1H), 1.61 (dt, J = 13.8, 6.8 Hz, 3H). 13 13C NMR (125 MHz, DMSO-d6) δ 169.9, 162.3, 148.4, 147.2, 146.8, 146.4, 141.5, 138.9, 136.7, 132.4, 131.6, 124.1, 123.3, 59.5, 55.7, 49.6, 32.5, 29.4, 27.7, 23.6, 21.1。

[0082] Example 18: Preparation of (S)-4-(((3,5-dimethylpyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)-N-hydroxybutanamide (Compound IIb)

[0083]

[0084] Replace methyl 4-formylbenzoate with methyl 4-bromobutyrate, and obtain Compound IIb by referring to the synthesis method of Example 2. It is a colorless transparent liquid with a yield of 41%. 1 1H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.42 (dd, J = 4.7, 1.8 Hz, 1H), 8.13 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.36 (s, 1H), 7.17 (dd, J = 7.7, 4.6 Hz, 1H), 4.14–3.90 (m, 3H), 3.63–3.55 (m, 2H), 2.76 (td, J = 11.2, 5.6 Hz, 1H), 2.66 (d, J = 16.7 Hz, 2H), 2.34 (s, 3H), 2.23 (s, 3H), 1.97 - 1.74 (m, 6H), 1.55 (d, J = 55.8 Hz, 3H). 1313C NMR (125 MHz, DMSO-d6) δ 168.2, 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.

[0085] Example 19: Preparation of (S)-4-(((3-chloropyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)-N-hydroxybutanamide (Compound IIc)

[0086]

[0087] Methyl 4-bromobutyrate was used instead of methyl 4-formylbenzoate, and Compound IIc was obtained by referring to the synthesis method of Example 3. It was a colorless transparent liquid with a yield of 46%. 1 1H NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), δ 8.47 (dd, J = 4.5, 2.0 Hz, 1H), δ 8.09 (d, J = 8.0 Hz, 1H), δ 7.52 (t, J = 7.5 Hz, 1H), δ 7.40 (s, 1H), δ 7.22 (dd, J = 7.5, 4.5 Hz, 1H), δ 4.10 - 3.85 (m, 3H), δ 3.70 - 3.60 (m, 2H), δ 2.81 (td, J = 11.5, 5.5 Hz, 1H), δ 2.70 (d, J = 17.0 Hz, 2H), δ 2.39 (s, 3H), δ 2.28 (s, 3H), δ 1.94 - 1.69 (m, 6H), δ 1.51 (d, J = 56.0 Hz, 3H). 13 13C NMR (125 MHz, DMSO-d6): δ 168.5, 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.

[0088] Example 20: Preparation of (S)-N-hydroxy-4-((isoquinolin-1-ylmethyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)butanamide (Compound IId)

[0089]

[0090] Methyl 4-bromobutyrate was used instead of methyl 4-formylbenzoate, and Compound IId was obtained by referring to the synthesis method of Example 4. It was a colorless transparent liquid with a yield of 49%.1 1H NMR (500 MHz, DMSO-d6) δ 10.50 (s, 1H), δ 8.55 (dd, J = 4.8, 1.9 Hz, 1H), δ 7.55 (dd, J = 5.7, 3.7 Hz, 3H), δ 7.25 (dd, J = 7.8, 4.8 Hz, 1H), δ 7.15 (dd, J = 6.1, 3.3 Hz, 2H), δ 4.20 (d, J = 15.8 Hz, 1H), δ 4.00 (dd, J = 10.3, 6.0 Hz, 1H), δ 3.95 (d, J = 15.8 Hz, 1H), δ 2.80 (ddd, J = 16.5, 11.0, 5.2 Hz, 1H), δ 2.70 (dt, J = 13.3, 5.3 Hz, 2H), δ 2.60 (dt, J = 13.3, 7.1 Hz, 1H), δ 2.10 (s, 2H), δ 1.93 (t, J = 7.4 Hz, 3H), δ 1.88 - 1.78 (m, 1H), δ 1.65 (dt, J = 13.9, 6.9 Hz, 3H). 13 13C NMR (125 MHz, DMSO-d6): δ 169.5, 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。

[0091] Example 21: Preparation of (S)-4-(((1H-benzo[d]imidazol-2-yl)methyl)(1-(4-methylpyridin-2-yl)ethyl)amino)-N-hydroxybutanamide (Compound IIe)

[0092]

[0093] Replace 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine and methyl 4-formylbenzoate with methyl 4-bromobutyrate, and obtain Compound IIe according to the synthesis method of Example 1. It is a colorless transparent liquid with a yield of 51%. 1HNMR(500 MHz, DMSO-d6) δ 10.20 (s, 1H), δ 8.64–8.58 (m, 1H), δ 8.48 (d, J = 4.5 Hz, 1H), δ 8.43 (dd, J = 4.8, 1.9 Hz, 1H), δ 7.81 (d, J = 8.2 Hz, 1H), δ 7.49 (d, J = 7.5 Hz, 1H), δ 7.38–7.31 (m, 1H), δ 7.19 (t, J = 6.5 Hz, 1H), δ 4.26 (d, J = 13.5 Hz, 1H), δ 4.05 (dd, J = 36.7, 23.6 Hz, 2H), δ 2.90–2.63 (m, 3H), δ 1.92 (d, J = 33.1 Hz, 3H), δ 1.79 (t, J = 7.4 Hz, 2H), δ 1.65 (s, 1H), δ 1.45–1.15 (m, 5H). 13 C NMR(125 MHz, DMSO-d6): δ 168.0, 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。

[0094] Example 22: Preparation of (S)-4-(((3,5-dimethylpyridin-2-yl)methyl)(1-(4-methylpyridin-2-yl)ethyl)amino)-N-hydroxybutanamide (Compound IIf)

[0095]

[0096] Replace 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine and methyl 4-formylbenzoate with methyl 4-bromobutyrate, and obtain Compound IIf according to the synthesis method of Example 2. It is a colorless transparent liquid with a yield of 47%. 1 HNMR(500 MHz, DMSO-d6) δ 12.00 (s, 1H), δ 10.25 (d, J = 4.5 Hz, 1H), δ 8.75 (d, J = 5.0 Hz, 1H), δ 8.40 (d, J = 5.0 Hz, 1H), δ 7.55–7.35 (m, 3H), δ 7.30 (s, 1H), 7.10–6.95 (m, 2H), δ 4.00–3.90 (m, 2H), δ 3.70 (d, J = 14.0 Hz, 1H), δ 2.30 (s, 4H), δ 1.80 (d, J = 7.0 Hz, 2H), δ 1.35 (t, J = 7.0 Hz, 3H), δ 1.25 (s, 3H). 1313C NMR (125 MHz, DMSO-d6): δ 168.0, 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.

[0097] Example 23: Preparation of (S)-4-(((3-chloropyridin-2-yl)methyl)(1-(4-methylpyridin-2-yl)ethyl)amino)-N-hydroxybutanamide (Compound IIg)

[0098]

[0099] Replace 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine and methyl 4-formylbenzoate with methyl 4-bromobutyrate, and obtain Compound IIg by referring to the synthesis method of Example 3. It is a colorless transparent liquid with a yield of 41%. 1 1H NMR (500 MHz, DMSO-d6) δ 10.62 (s, 1H), δ 8.39 (dd, J = 4.5, 2.0 Hz, 1H), δ 8.10 (d, J = 8.0 Hz, 1H), δ 7.34 (t, J = 7.5 Hz, 1H), δ 7.36 (s, 1H), δ 7.31 (dd, J = 7.5, 4.5 Hz, 1H), δ 4.10 - 3.85 (m, 3H), δ 3.70 - 3.60 (m, 2H), δ 2.81 (td, J = 11.5, 5.5 Hz, 1H), δ 2.70 (d, J = 17.0 Hz, 2H), δ 2.39 (s, 3H), δ 2.28 (s, 3H), δ 1.94 - 1.69 (m, 6H), δ 1.50 (d, J = 56.0 Hz, 3H). 13 13C NMR (125 MHz, DMSO-d6): δ 168.3, 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.

[0100] Example 24: Preparation of (S)-N-hydroxy-4-((isoquinolin-1-ylmethyl)(1-(4-methylpyridin-2-yl)ethyl)amino)butanamide (Compound IIh)

[0101]

[0102] Replace 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine and methyl 4-formylbenzoate with methyl 4-bromobutyrate. Compound IIh was obtained according to the synthesis method of Example 4. It is 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(dd,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。

[0103] 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)

[0104]

[0105] Replace methyl 4-formylbenzoate with methyl 5-bromovalerate. Compound IIi was obtained according to the synthesis method of Example 1. It is a colorless transparent liquid with a yield of 52%. 11H NMR (500 MHz, DMSO-d6) δ 12.13 (s, 1H), 10.34 (d, J = 4.4 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 8.38 (d, J = 4.9 Hz, 1H), 7.61–7.41 (m, 2H), 7.37 (s, 1H), 7.17–7.04 (m, 3H), 4.03–3.94 (m, 2H), 3.75 (d, J = 15.2 Hz, 1H), 2.32 (s, 4H), 1.85 (d, J = 6.9 Hz, 2H), 1.40 (t, J = 6.8 Hz, 7H), 1.23 (s, 1H). 13 13C NMR (125 MHz, DMSO-d6) δ 169.1, 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。

[0106] Example 26: Preparation of (S)-5-(((3,5-dimethylpyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)-N-hydroxypentanamide (Compound IIj)

[0107]

[0108] Replace methyl 4-formylbenzoate with methyl 5-bromovalerate, and obtain Compound IIj by referring to the synthesis method of Example 2. It is a colorless transparent liquid with a yield of 53%. 1 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.61 (s, 1H), 8.41 (d, J = 4.7 Hz, 1H), 8.08 (s, 1H), 7.44 (d, J = 7.0 Hz, 1H), 7.31 (s, 1H), 7.13 (s, 1H), 4.08–3.77 (m, 3H), 2.75 (s, 1H), 2.63 (d, J = 20.1 Hz, 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). 1313C NMR (125 MHz, DMSO-d6) δ 168.3, 160.5, 147.5, 145.5, 145.1, 137.7, 131.3, 130.3, 124.4, 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。

[0109] Example 27: Preparation of (S)-5-(((3-chloropyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)-N-hydroxypentanamide (Compound IIk)

[0110]

[0111] Replace methyl 4-formylbenzoate with methyl 5-bromovalerate, and obtain Compound IIk by referring to the synthesis method of Example 3. It is a colorless transparent liquid with a yield of 37%. 1 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.62–8.56 (m, 1H), 8.45 (d, J = 4.7 Hz, 1H), 8.40 (dd, J = 4.7, 1.7 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.35–7.28 (m, 1H), 7.14 (t, J = 6.4 Hz, 1H), 4.21 (d, J = 13.2 Hz, 1H), 4.01 (dd, J = 36.6, 23.5 Hz, 2H), 2.87–2.59 (m, 3H), 1.89 (d, J = 32.9 Hz, 3H), 1.76 (t, J = 7.3 Hz, 2H), 1.60 (s, 1H), 1.40–1.12 (m, 5H). 13 13C NMR (125 MHz, DMSO-d6) δ 168.9, 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。

[0112] Example 28: Preparation of (S)-N-hydroxy-5-((isoquinolin-1-ylmethyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)pentanamide (Compound IIl)

[0113]

[0114] Methyl 4-formylbenzoate was replaced with methyl 5-bromovalerate, and compound III was obtained by referring to the synthesis method of Example 4. It is 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(dd,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.

[0115] Example 29: Preparation of (S)-5-(((1H-benzo[d]imidazol-2-yl)methyl)(1-(4-methylpyridin-2-yl)ethyl)amino)-N-hydroxypentanamide (Compound IIm)

[0116]

[0117] 6,7-Dihydro-5H-quinolin-8-one was replaced with 2-acetyl-4-methylpyridine, and methyl 4-formylbenzoate was replaced with methyl 5-bromovalerate. Compound IIm was obtained by referring to the synthesis method of Example 1. It is a colorless transparent liquid with a yield of 48%. 1HNMR(500MHz, DMSO-d6) δ 12.13(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, 1H), 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) δ 162.9, 161.5, 147.3, 146.9, 145.8, 144.4, 141.5, 139.1, 136.8, 132.3, 131.5, 124.5, 123.3, 59.6, 55.9, 49.5, 32.4, 29.6, 27.5, 23.6, 23.0。

[0118] Example 30: Preparation of (S)-5-(((3,5-dimethylpyridin-2-yl)methyl)(1-(4-methylpyridin-2-yl)ethyl)amino)-N-hydroxypentanamide (Compound IIn)

[0119]

[0120] Replace 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine and methyl 4-formylbenzoate with methyl 5-bromovalerate, and obtain Compound IIn according to the synthesis method of Example 2. It is a colorless transparent liquid with a yield of 51%. 1 HNMR(500MHz, DMSO-d6) δ 10.26(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, 1H), 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). 1313C NMR (125 MHz, DMSO-d6) δ 169.5, 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.

[0121] Example 31: Preparation of (S)-5-(((3-chloropyridin-2-yl)methyl)(1-(4-methylpyridin-2-yl)ethyl)amino)-N-hydroxypentanamide (Compound IIo)

[0122]

[0123] Replace 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine, and methyl 4-formylbenzoate with methyl 5-bromovalerate. Compound IIo was obtained by referring to the synthesis method of Example 3. It is a colorless transparent liquid with a yield of 42%. 1 1H NMR (500 MHz, DMSO-d6) δ 10.25 (d, J = 1.7 Hz, 1H), 8.62 (d, J = 1.9 Hz, 1H), 8.47 (dd, J = 4.7, 1.5 Hz, 1H), 8.34 (d, J = 4.9 Hz, 1H), 7.86 (dd, J = 8.1, 1.5 Hz, 1H), 7.39–7.26 (m, 2H), 7.05 (dd, J = 5.1, 1.7 Hz, 1H), 4.00 (q, J = 6.7 Hz, 1H), 3.88 (d, J = 13.0 Hz, 1H), 3.80 (d, J = 13.0 Hz, 1H), 2.38–2.31 (m, 1H), 2.29 (s, 3H), 1.77 (d, J = 7.0 Hz, 2H), 1.38 (d, J = 6.8 Hz, 3H), 1.27 (ddd, J = 18.5, 10.0, 5.7 Hz, 5H). 13 13C NMR (125 MHz, DMSO-d6) δ 169.6, 162.1, 148.4, 146.8, 146.4, 138.8, 136.4, 132.6, 131.8, 124.1, 123.4, 59.6, 32.7, 29.3, 27.2, 23.6, 21.0, 18.0, 17.8.

[0124] Example 32: Preparation of (S)-N-hydroxy-5-((1-isoquinolinylmethyl)(1-(4-methylpyridin-2-yl)ethyl)amino)pentanamide (Compound IIp)

[0125]

[0126] Replace 6,7-dihydro-5H-quinolin-8-one with 2-acetyl-4-methylpyridine and methyl 4-formylbenzoate with methyl 5-bromovalerate. Compound IIp was obtained according to the synthesis method of Example 4. It is 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,1H),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)δ167.2,161.3,158.2,157.7,148.8,146.0,146.4,142.7,136.8,132.9,131.3,127.2,124.5,122.4,119.1,59.8,56.2,51.0,32.0,29.7,27.3,23.3,21.5.

[0127] Pharmacological experiment data

[0128] 1. Determination of the affinity of the compound for CXCR4

[0129] Competitive CXCR4 binding was carried out between biotinylated TN14003 (an effective CXCR4 peptide antagonist) and the compound, and the affinity of the compound for CXCR4 was tested by measuring the inhibition rate of the compound inhibiting the binding of TN14003 to CXCR4.

[0130] Experimental method: Digest MDA-MB-231 cells and inoculate them into a 96-well plate, with 1×10 5 cells per well. The next day, add the corresponding concentration of the compound (10 nM) according to the group setting and incubate for 10 min. Fix the cells with 4% paraformaldehyde for more than 30 min and wash them 3 times with PBS. Add 0.05 μg / mL of the polypeptide TN14003 and incubate at room temperature for 30 min, then wash 3 times with PBS. Add Streptavidin-Rhodamine (TRITC) (stock solution concentration 1 mg / mL) diluted 1:500, incubate at room temperature in the dark for 30 min, and wash 3 times with PBS. Add DAPI staining solution and incubate at room temperature in the dark for 5 min, then wash 3 times with PBS. Observe the expression under a confocal microscope and take pictures and save them in 3 highly expressed regions.

[0131] Table 1 shows the inhibitory rates of Examples 1 - 32 on the competitive binding affinity of CXCR4.

[0132] Table 1

[0133]

[0134] As can be seen from Table 1, at 10 nM, a total of 24 compounds had a competitive binding inhibition rate of more than 50% against CXCR4. Among them, 16 compounds had a competitive binding inhibition rate greater than 78%, approaching and being better than the positive control drug plerixafor (AMD3100) (78.24%). At the same time, the competitive binding inhibition rates of compounds If, IIf, IIh, IIi, IIl, and IIn reached 90%, indicating that the designed dual - target compounds retained a significant affinity for CXCR4. Among all the compounds, IIf, IIh, and IIi had the strongest competitive binding inhibition rates, all greater than 98%. Compared with the series I compounds, most of the compounds in series II had a competitive binding inhibition rate better than the positive control drug plerixafor.

[0135] 2. Determination of the inhibitory activity of compounds against HDAC

[0136] In the test, a fluorescence detection method was used 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 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 compound to be tested 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 50 value was calculated using GraphPad Prism software.

[0137] Table 2 shows the IC 50 values of Examples 1 - 32 on the inhibitory activity of HDAC1 / HDAC6.

[0138] Table 2

[0139]

[0140] As can be seen from Table 2, among all the compounds, a total of 15 compounds had a better inhibitory activity against HDAC6 than the positive control drug vorinostat (SAHA, IC 50= 0.55 μM), among which 14 compounds have certain selectivity for HDAC6. At the same time, among all the compounds, four compounds, Ik, Il, In, and Ip, have better inhibitory activities against HDAC1 and HDAC6 than SAHA (HDAC1: IC 50 = 0.26 μM; HDAC6: IC 50 = 0.55 μM). Compared with the compounds of Series I, the compounds of Series II have weaker inhibitory activities against HDAC1 and HDAC6 than SAHA. However, since HDAC inhibitors themselves have certain cytotoxicity, too strong inhibitory effects on HDAC may bring certain toxicity risks. Therefore, some compounds with weaker HDAC inhibitory activities than SAHA may also have the value of further development due to better safety. In summary, the compounds of both Series I and II have good development potential.

[0141] According to Table 2, the compounds of Series I perform significantly better than those of Series II in terms of HDAC inhibition. Among them, the four compounds, Ik, Il, In, and Ip, are the best, superior to the positive control drug vorinostat. Further combining with Table 1, the competitive binding inhibition rates of the two compounds, In and Ip, against CXCR4 are also superior to the positive control drug plerixafor.

[0142] 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. A compound having the structure shown in general formula (II) or a pharmaceutically acceptable salt thereof: In formula (II): R1 is selected from R2 is selected from L is empty or a saturated or unsaturated aliphatic hydrocarbon chain having 1 to 6 carbon atoms.

2. The compound having the structure shown by general formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, L is empty or a saturated or unsaturated aliphatic hydrocarbon chain having 1 to 4 carbon atoms.

3. The compound or its pharmaceutically acceptable salt having the structure shown in general formula (II) according to claim 2, characterized in that, L is empty or selected from the following structures:

4. The compound having the structure shown in general formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that, It is a compound IIa-IIp having the structure shown below or a pharmaceutically acceptable salt thereof:

5. The preparation method of the compound having the structure shown by the general formula (II) according to any one of claims 1 to 4, characterized in that, Synthetic route: The preparation method includes: raw material 1 or raw material 2 and raw material 3 undergo reductive amination reaction to generate intermediate 4, intermediate 4 is deprotected to obtain intermediate 13, and then it undergoes nucleophilic substitution reaction with raw material 14 to obtain intermediate 15. Intermediate 15 and raw material 9, 10, 11 or 12 undergo nucleophilic substitution or reductive amination reaction to obtain intermediate 16. Finally, intermediate 16 undergoes amine ester exchange reaction to obtain a compound having the structure shown in general formula (II).

6. Use of the compound having the structure shown in general formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the preparation of a drug for preventing and treating related diseases by antagonizing C-X-C chemokine receptor 4 and / or inhibiting histone deacetylase.

7. The application according to claim 6, characterized in that, The diseases include cancer, inflammation, and depression.

8. A pharmaceutical composition, characterized in that, It contains at least one of a carrier and an excipient, and the compound having the structure shown in general formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4.

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