Sulfamide derivatives and preparation method and use thereof

Abstract

The present invention discloses a compound shown in formula I or a stereoisomer, pharmaceutically acceptable salt, crystal form, solvate or isotopologue thereof. The compound of the present invention shows excellent inhibition activity against histone deacetylases, has remarkable inhibition effects on cancer cells, and provides a new choice of drugs used for the clinic treatment and diseases related to the abnormal activity of histone deacetylases. ##STR00001##

Claims

1. A compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, crystal form, solvate or isotopologue thereof: ##STR00140## wherein X.sub.1 is CR.sub.6 or N; R.sub.1, R.sub.2, R.sub.3 and R.sub.6 are each independently selected from H, halogen, hydroxyl, sulfydryl, amino, phenyl, C.sub.1-C.sub.6 alkyl, halogen-substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy or halogen-substituted C.sub.1-C.sub.6 alkoxy; R.sub.4 is ##STR00141## wherein m and n are each independently an integer selected from 1 or 2; R.sub.41 is hydroxyl, sulfydryl, amino, epoxyketone, phenyl or substituted phenyl; and R.sub.5 is ##STR00142## wherein R.sub.1b to R.sub.5b are each independently selected from H, halogen, hydroxyl, —C(═O)N(R.sub.21b)(R.sub.22b), C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, piperazinyl, substituted piperazinyl, amino or substituted amino; wherein R.sub.21b and R.sub.22b are independently H, C.sub.1-C.sub.6 alkyl, dimethylamino-substituted C.sub.1-C.sub.6 alkyl or diethylamino-substituted C.sub.1-C.sub.6 alkyl; wherein R.sub.1c, R.sub.2c and R.sub.3c are each independently H, halogen, C.sub.1-C.sub.6 alkyl, halogen-substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy or halogen-substituted C.sub.1-C.sub.6 alkoxy; and R.sub.4c is 5- to 7-membered optionally substituted heterocyclyl having a heteroatom selected from N, O or S.

2. The compound according to claim 1, wherein only one of Rib to R.sub.5b is selected from hydroxyl, —C(═O)N(R.sub.21b)(R.sub.22b), C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, piperazinyl, substituted piperazinyl, amino or substituted amino.

3. The compound according to claim 2, wherein, when R.sub.3b is hydroxyl, the compound is represented by formula IIb1: ##STR00143##

4. The compound according to claim 2, wherein, when R.sub.3b is —C(═O)N(R.sub.21b)(R.sub.22b), the compound is represented by formula IIb2: ##STR00144##

5. The compound according to claim 4, wherein R.sub.21b is H, and R.sub.22b is C.sub.1-C.sub.3 alkyl, dimethylamino-substituted C.sub.1-C.sub.3 alkyl or diethylamino-substituted C.sub.1-C.sub.3 alkyl.

6. The compound according to claim 5, wherein the compound of formula IIb2 is: ##STR00145##

7. The compound according to claim 1, wherein the compound is represented by formula IIb31, IIb32 or IIb33: ##STR00146## wherein a is an integer from 0 to 6; R.sub.31b and R.sub.32b are independently H, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl having a substituent group of C.sub.1-C.sub.6 alkoxy or C.sub.1-C.sub.6 alkyl-substituted amino, or 5- to 7-membered optionally substituted heterocyclyl having a heteroatom selected from N, O or S; or, R.sub.31b and R.sub.32b are linked to form 5- to 7-membered optionally substituted heterocyclyl; and R.sub.33b is H, and R.sub.34b is C.sub.1-C.sub.6 alkyl.

8. The compound according to claim 7, wherein R.sub.31b and R.sub.32b are independently 6-membered heterocyclyl; or, R.sub.31b and R.sub.32b are linked to form 6-membered heterocyclyl.

9. The compound according to claim 7, wherein a is an integer from 0 to 3; R.sub.31b and R.sub.32b are independently H, methyl, ethyl, methoxyethyl, dimethylaminoethyl or ##STR00147## or, R.sub.31b and R.sub.32b are linked to form ##STR00148## and, R.sub.34b is C.sub.1-C.sub.3 alkyl; wherein R.sub.35b and R.sub.36b are independently C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkoxy-substituted C.sub.1-C.sub.6 alkyl.

10. The compound according to claim 9, wherein R.sub.35b and R.sub.36b are independently C.sub.1-C.sub.4 alkyl, methoxy-substituted C.sub.1-C.sub.4 alkyl or ethoxy-substituted C.sub.1-C.sub.4 alkyl.

11. The compound according to claim 7, wherein the compound of formula IIb31, IIb32 or IIb33 is: ##STR00149## ##STR00150##

12. The compound according to claim 2, wherein, when one of R.sub.2b and R.sub.3b is selected from piperazinyl or substituted piperazinyl, the compound is represented by formula IIb4 or IIb5: ##STR00151## wherein R.sub.41b, R.sub.42b, R.sub.44b and R.sub.45b are independently H or C.sub.1-C.sub.6 alkyl; and R.sub.43b is H, C.sub.1-C.sub.6 alkyl, methoxy-substituted C.sub.1-C.sub.6 alkyl, ethoxy-substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 acyl or C.sub.3-C.sub.6 cycloalkyl.

13. The compound according to claim 12, wherein R.sub.41b, R.sub.42b, R.sub.44b and R.sub.45b are independently H, methyl or ethyl; and, R.sub.43b is H, methyl, ethyl, methoxy-substituted C.sub.2-C.sub.4 alkyl, ethoxy-substituted C.sub.2-C.sub.4 alkyl, acetyl or cyclopropyl.

14. The compound according to claim 13, wherein the compound of formula IIb4 or IIb5 is: ##STR00152##

15. The compound according to claim 1, wherein the compound is represented by formula IIc: ##STR00153##

16. The compound according to claim 15, wherein R.sub.1c, R.sub.2c and R.sub.3c are independently H, F, Cl, methyl, trifluoromethyl, methoxy or trifluoromethoxy; and, R.sub.4c is 6- or 7-membered optionally substituted heterocyclyl containing at most two heteroatoms.

17. The compound according to claim 16, wherein R.sub.4c is ##STR00154## wherein R.sub.5c and R.sub.6c are independently selected from C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkoxy-substituted C.sub.1-C.sub.6 alkyl.

18. The compound according to claim 17, wherein the compound of formula IIc is: ##STR00155##

19. The compound according to claim 1, wherein the compound is represented by formula IV: ##STR00156## wherein X.sub.3 is CR.sub.39 or N; R.sub.31 is hydroxyl or sulfydryl; R.sub.32 to R.sub.34 are independently H, halogen, C.sub.1-C.sub.6 alkyl, halogen-substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy or halogen-substituted C.sub.1-C.sub.6 alkoxy; R.sub.35 to R.sub.39 are independently H, halogen, C.sub.1-C.sub.6 alkyl, or halogen-substituted C.sub.1-C.sub.6 alkyl; and R.sub.311 is H, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy-substituted C.sub.1-C.sub.6 alkyl.

20. The compound according to claim 19, wherein R.sub.32 to R.sub.34 are independently H, F, Cl, methyl, trifluoromethyl, methoxy or trifluoromethoxy; R.sub.35 to R.sub.39 are independently H, F, Cl, methyl, or trifluoromethyl; and R.sub.311 is methyl or ethyl.

21. The compound according to claim 20, wherein the compound of the formula IV is: ##STR00157##

22. A method for inhibiting histone deacetylase, comprising providing to a cell in need thereof the compound or a stereoisomer, pharmaceutically acceptable salt, crystal form, solvate or isotopologue thereof according to claim 1, and inhibiting one or more of HDAC1, HDAC3 and HDAC6.

23. A method for treating liver cancer, comprising administering to a patient in need thereof the compound or stereoisomers, pharmaceutically acceptable salts, crystal forms, solvates or isotopologues thereof according to claim 1.

24. A pharmaceutical composition comprising the compound or stereoisomer, pharmaceutically acceptable salt, crystal form, solvate or isotopologue thereof according to claim 1, and pharmaceutically acceptable adjuvants or auxiliary ingredients.

25. The pharmaceutical composition according to claim 24, wherein the composition is an oral preparation, a sublingual preparation, a buccal preparation, a transdermal absorption preparation or an injectable preparation.

26. The compound of claim 17, wherein R.sub.5c and R.sub.6c are independently selected from C.sub.1-C.sub.3 alkyl, methoxy-substituted C.sub.1-C.sub.3 alkyl or ethoxy-substituted C.sub.1-C.sub.3 alkyl.

Description

DETAILED DESCRIPTION OF THE PRESENT INVENTION

(1) All raw materials and facilities used in the specific implementations of the present invention are known products and commercially available products.

Embodiment 1: Preparation of N-hydroxyl-1-((4-(1-(piperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

1. Preparation of ethyl 1,2,3,6-tetrahydropyridine-4-formate

(2) ##STR00078##

(3) Ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate (10.0 g, 39.2 mmol, produced by Nanjing Ailikaide Chemical Co., Ltd.) was dissolved in 50.0 mL of dichloromethane solution in an ice bath, then added dropwise with 50.0 mL of trifluoroacetic acid and stirred. The mixture was slowly heated to the room temperature and then continuously stirred for 2 h. Subsequently, the reaction solution was condensed to obtain yellow oily ethyl 1,2,3,6-tetrahydropyridine-4-formate (5.80 g, 37.4 mmol, 96% yield).

(4) MS (ESI) m/z 156 (M+1)+.

2. Preparation of ethyl 1-((4-bromophenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formate

(5) ##STR00079##

(6) Ethyl 1,2,3,6-tetrahydropyridine-4-formate (2.00 g, 5.40 mmol) and triethylamine (1.09 g, 10.8 mmol) were dissolved in dichloromethane (20.0 ml), and 4-bromophenyl-1-sulfonylchloride (1.38 g, 5.40 mmol) was added in the reaction solution at the room temperature. The reaction solution was stirred for 2 h at the room temperature and condensed to remove the solvent, and the crude product was purified by column chromatography to obtain white solid ethyl 1-((4-bromophenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formate (1.51 g, 4.05 mmol, 75% yield).

(7) MS (ESI) m/z 374 (M+1)+.

3. Preparation of ethyl 1-((4-(1-(piperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formate

(8) ##STR00080##

(9) Ethyl 1-((4-bromophenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formate (500 mg, 1.34 mmol), tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentaborane-2-yl)-1H-pyrazol-1-yl]piperidine-1-formate (506 mg, 1.34 mmol, produced by Nanjing Ailikaide Chemical Co., Ltd.), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (49.0 mg, 67.0 μmol) and sodium carbonate (284 mg, 2.68 mmol) were dissolved in N,N-dimethylformamide (12.0 ml). Under the atmosphere of nitrogen, the reaction solution was heated to 80° C. and stirred overnight. At the end of reaction, the reaction solution was condensed to remove the solvent. The crude product was dissolved in water (40.0 ml) and extracted with ethyl acetate (40.0 ml×3). The organic phases were combined, then condensed to remove the solvent and purified by column chromatography to obtain white solid. The white solid was dissolved in dichloromethane (3.00 ml) and then added dropwise with trifluoroacetic acid (3.00 ml) in an ice bath. After the dropwise addition is completed, the reaction system was heated to the room temperature and reacted for 1 h, and condensed at a reduced pressure to remove the solvent to obtain ethyl 1-((4-(1-(piperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formate (202 mg, 456 μmol, 34% yield).

(10) MS (ESI) m/z 445 (M+1)+.

4. Preparation of N-hydroxyl-1-((4-(1-(piperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(11) ##STR00081##

(12) Ethyl 1-((4-(1-(piperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formate (202 mg, 456 μmol) was dissolved in dichloromethane (3.00 ml) and methanol (3.00 ml), and then added with hydroxylamine aqueous solution (505, 2.00 mL) and NaOH (83.1 mg, 2.10 mmol) while stirring. The mixture was slowly heated to the room temperature and then continuously stirred for 2 h. The reaction system was condensed to remove the solvent, and the crude product was purified by preparative liquid chromatography to obtain white solid N-hydroxyl-1-((4-(1-(piperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-form amide (14.4 mg, 33.3 μmol, 7.3% yield).

(13) MS (ESI) m/z 432 (M+1)+.

(14) .sup.1HNMR (400 MHz, DMSO) δ=8.44 (s, 1H), 8.31 (s, 1H), 8.06 (s, 1H), 7.86-7.84 (d, J=8.4 Hz, 2H), 7.75-7.73 (d, J=8.4 Hz, 2H), 6.35 (s, 1H), 4.39-4.37 (m, 1H), 3.64-3.63 (d, J=2.8 Hz, 2H), 3.23-3.21 (d, J=8.8 Hz, 2H), 2.87-2.83 (m, 2H), 2.29 (br, 2H), 2.10-2.09 (s, 2H), 2.02-1.97 (m, 2H).

Embodiment 2: Preparation of N-hydroxyl-1-((4′-hydroxyl-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(15) ##STR00082##

(16) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and 4-hydroxyphenylboronic acid as raw materials, white solid N-hydroxyl-1-((4′-hydroxyl-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (3.4% total yield) was prepared by steps similar to those in Embodiment 1.

(17) MS (ESI) m/z 375 (M+1)+.

(18) .sup.1HNMR (400 MHz, DMSO) δ=9.80 (s, 1H), 7.85-7.83 (m, 2H), 7.79-7.77 (m, 2H), 7.61-7.59 (d, J=8.7, 2H), 6.90-6.88 (d, J=8.6, 2H), 6.36 (s, 1H), 3.64-3.63 (d, J=2.6, 2H), 3.14-3.11 (t, J=5.6, 2H), 2.32-2.28 (m, 2H).

Embodiment 3: Preparation of N-hydroxyl-1-((3′-fluoro-4′-(4-methylpiperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

1. Preparation of 1-(4-bromo-2-fluorophenyl)-4-methylpiperazine

(19) ##STR00083##

(20) 3-fluoro-4-(4-methylpiperazine-1-yl)aniline (2.00 g, 9.56 mmol) was dissolved in 5.00 ml of water in an ice bath, then added with 2.00 ml of solution of hydrobromic acid in acetic acid and sodium nitrite (663 mg, 10.5 mmol), stirred for half an hour, and added with cuprous bromide (4.11 g, 28.7 mmol). The reaction system was reacted for 2 h, then added with solid potassium carbonate to adjust the pH of the solution as 9 to 10, and extracted with dichloromethane (100 ml×5). The organic phases were combined, dried, condensed and purified by column chromatography to obtain brown oily 1-(4-bromo-2-fluorophenyl)-4-methylpiperazine (600 mg, 2.20 mmol, 23% yield).

(21) MS (ESI) m/z 273 (M+1)+.

2. Preparation of 3-fluoro-4-(4-methylpiperazine-1-yl)-phenylboronic acid pinacol ester

(22) ##STR00084##

(23) 1-(4-bromo-2-fluorophenyl)-4-methylpiperazine (500 mg, 1.83 mmol) was dissolved in 1,4-dioxane (10.0 ml) at the room temperature, and added with potassium acetate (128 mg, 1.35 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (50.0 mg, 183 μmol) and bis(pinacolato)diboron (465 mg, 1.83 mmol). Nitrogen replacement was performed for three times, and the reaction system was heated to 90° C. and reacted for 2 h. The reaction solution was condensed and purified by column chromatography to obtain brown oily 3-fluoro-4-(4-methylpiperazine-1-yl)-phenylboronic acid pinacol ester (300 mg, 937 μmol, 51% yield).

3. Preparation of N-hydroxyl-1-((3′-fluoro-4′-(4-methylpiperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(24) ##STR00085##

(25) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate (10.0 g, 39.2 mmol), 4-bromophenyl-1-sulfonylchloride (1.38 g, 5.40 mmol) and 3-fluoro-4-(4-methylpiperazine-1-yl)-phenylboronic acid pinacol ester (319 mg, 1.34 mmol) as raw materials, white solid N-hydroxyl-1-((3′-fluoro-4′-(4-methylpiperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (22.2 mg, 46.9 μmol, 3.5% total yield) was prepared by steps similar to those in Embodiment 1.

(26) MS (ESI) m/z 475 (M+1)+.

(27) .sup.1HNMR (400 MHz, DMSO) δ=8.25 (s, 1H), 7.92 (d, J=7.6 Hz, 2H), 7.81 (d, J=8.8 Hz, 2H), 7.63-7.53 (m, 2H), 7.14 (t, J=8.8 Hz, 1H), 6.36 (s, 1H), 3.66 (s, 2H), 3.6-3.09 (m, 6H), 2.32 (s, 2H), 2.24 (s, 3H).

Embodiment 4: Preparation of N-hydroxyl-1-((4′-(4-(2-methoxyethyl)piperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

1. Preparation of 4-(4-bromophenyl)benzenesulfonic acid

(28) ##STR00086##

(29) 4-bromobiphenyl (10.0 g, 42.9 mmol) was dissolved in dichloromethane (100 mL) in an ice bath, and then slowly added dropwise with chlorosulfonic acid (6.53 g, 55.8 mmol). The reaction system was heated to the room temperature and then reacted for 1 h. The reaction solution was filtered to obtain white solid 4-(4-bromophenyl)benzenesulfonic acid (11.5 g, 36.7 mmol, 86% yield).

2. Preparation of 4-(4-bromophenyl)benzenesulfonyl chloride

(30) ##STR00087##

(31) 4-(4-bromophenyl)benzenesulfonic acid (10.5 g, 33.5 mmol) was dissolved in thionyl chloride (60.0 mL). The reaction system was heated to 80° C. and then reacted for 4 h. The reaction solution was added dropwise in icy water (300 mL), and extracted with ethyl acetate (100 mL×2). The organic layer was dried with anhydrous sodium sulfate and condensed to obtain white solid 4-(4-bromophenyl)benzenesulfonyl chloride (11.5 g, 34.7 mmol, 100% yield).

3. Preparation of ethyl 1-(4-(4-bromophenyl)phenyl)sulfonyl-1,2,3,6-tetrahydropyridine-4-formate

(32) ##STR00088##

(33) Ethyl 1,2,3,6-tetrahydropyridine-4-formate (5.38 g, 34.7 mmol) was dissolved in tetrahydrofuran (80.0 mL) and water (80.0 mL), and then added with solid sodium bicarbonate (11.9 g, 139 mmol) and 4-(4-bromophenyl)benzenesulfonyl chloride (11.5 g, 34.7 mmol). The reaction system was stirred and reacted for 1 h. The reaction solution was condensed, and extracted with ethyl acetate (100 mL×2). The organic layer was combined, dried with anhydrous sodium sulfate and condensed to obtain white solid ethyl 1-(4-(4-bromophenyl)phenyl)sulfonyl-1,2,3,6-tetrahydropyridine-4-formate (10.5 g, 13.3 mmol, 67% yield).

4. Preparation of ethyl 1-[4-[4-[4-(2-methoxyethyl)piperazine-1-yl]phenyl]phenyl]sulfony-1,2,3,6-tetrahydropyridine-4-formate

(34) ##STR00089##

(35) Ethyl 1-(4-(4-bromophenyl)phenyl)sulfonyl-1,2,3,6-tetrahydropyridine-4-formate (3.00 g, 6.66 mmol) was dissolved in methylbenzene (30.0 mL), and added with solid cesium carbonate (3.25 g, 9.99 mmol), 2-dicyclohexylphosphonio-2,4,6-triisopropyl biphenyl (200 mg, 6.66 mmol), tris(dibenzylideneacetone)dipalladium (200 mg, 6.66 mmol) and 4-(2-methoxyethyl)piperazine (1.44 g, 9.99 mmol). The reaction system was heated to 100° C. and reacted for 4 h in the atmosphere of nitrogen. The reaction solution was filtered, and the filtrate was condensed and purified by column chromatography to obtain light yellow solid ethyl 1-[4-[4-[4-(2-methoxyethyl)piperazine-1-yl]phenyl]phenyl]sulfony-1,2,3,6-tetrahydropyridine-4-formate (2.50 g, 4.62 mmol, 69% yield).

5: Preparation of N-hydroxyl-1-((4′-(4-(2-methoxyethyl)piperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(36) ##STR00090##

(37) Ethyl 1-[4-[4-[4-(2-methoxyethyl)piperazine-1-yl]phenyl]phenyl]sulfony-1,2,3,6-tetrahydropyridine-4-formate (2.00 g, 3.89 mmol) was dissolved in methanol (20.0 mL) and dichloromethane (20.0 mL), then added with hydroxylamine aqueous solution (6.19 g, 117 mmol), stirred for 10 min, and added with solid sodium hydroxide (779 mg, 19.5 mmol). The reaction system was reacted for 1.5 h at the room temperature. The reaction solution was added with 20 mL of water, and extracted with dichloromethane (50 ml×5). The organic phases were combined, dried, condensed and purified by column chromatography to obtain white solid N-hydroxyl-1-((4′-(4-(2-methoxyethyl)piperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (800 mg, 1.60 mmol, 41.08% yield).

(38) MS (ESI) m/z 502 (M+1)+.

(39) .sup.1HNMR (400 MHz, DMSO) δ=10.67 (br, 1H), 8.82 (br, 1H), 8.14 (s, 0.5H), 7.89-7.87 (m, 2H), 7.80-7.78 (m, 2H), 7.68-7.66 (m, 2H), 7.09 (d, J=8.8 Hz, 2H), 6.36 (s, 1H), 3.46 (s, 4H), 3.27 (s, 3H), 3.14-3.10 (m, 2H), 2.94-2.91 (m, 6H), 2.28 (s, 2H).

Embodiment 5: Preparation of N-hydroxyl-1-(4-(6-(4-methylpiperazine-1-yl)pyridine-3-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(40) ##STR00091##

(41) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and 2-(4-methylpiperazine-1-yl)pyridine-5-boronic acid pinacol ester (produced by Nanjing Ailikaide Chemical Co., Ltd.) as raw materials, white solid N-hydroxyl-1-(4-(6-(4-methylpiperazine-1-yl)pyridine-3-yl)phenyl)sulfonyl)-1,2, 3,6-tetrahydropyridine-4-formamide (18% total yield) was prepared by steps similar to those in Embodiment 1.

(42) MS (ESI) m/z 458 (M+1)+.

(43) .sup.1HNMR (400 MHz, DMSO) δ=10.80 (br, 1H), 8.57 (d, J=2.4 Hz, 1H), 8.15 (s, 2H), 7.99 (d, J=2.8 Hz, 2H), 7.91 (d, J=9.2 Hz, 2H), 7.80 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 6.36 (s, 1H), 3.65 (s, 6H), 3.14 (t, J=1.6 Hz, 2H), 2.62-2.60 (m, 4H), 2.36-2.32 (m, 4H).

Embodiment 6: Preparation of N-hydroxyl-1-(4′-(4-ethylpiperazine-1-yl)-[1, t-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(44) ##STR00092##

(45) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and 1-((4′-4-methylethylpiperazine-1-yl)phenylboronic acid pinacol ester (produced by Shanghai Shuya Chemical Science and Technology Co., Ltd.) as raw materials, white solid N-hydroxyl-1-(4′-(4-ethylpiperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-form amide (13% total yield) was prepared by steps similar to those in Embodiment 1.

(46) MS (ESI) m/z 471 (M+1)+.

(47) .sup.1HNMR (400 MHz, DMSO) δ=10.67 (br, 1H), 8.82 (br, 1H), 8.15 (s, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.80 (d, J=3.6 Hz, 2H), 7.67 (d, J=8.8 Hz, 2H), 7.10 (d, J=8.8 Hz, 2H), 6.37 (s, 1H), 3.64 (s, 2H), 3.40 (s, 4H), 3.12 (t, J=5.6 Hz, 2H), 3.03 (s, 4H), 2.88 (d, J=7.2 Hz, 2H), 2.28 (s, 2H), 1.18 (t, J=7.2 Hz, 2H).

Embodiment 7: Preparation of N-hydroxyl-1-((2-fluoro-4′-(4-methylpiperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(48) ##STR00093##

(49) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromo-3-fluorophenyl-1-sulfonylchloride and (4-(4-methylpiperazine-1-yl)phenyl)boronic acid pinacol ester (produced by Shanghai Accela ChemBio Co., Ltd.) as raw materials, white solid N-hydroxyl-1-((2-fluoro-4′-(4-methylpiperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (2.6% total yield) was prepared by steps similar to those in Embodiment 1.

(50) MS (ESI) m/z 475 (M+1)+.

(51) .sup.1HNMR (400 MHz, DMSO) δ=10.63 (br, 1H), 8.75 (s, 1H), 7.77 (t, J=2 Hz, 1H), 7.64 (t, J=6 Hz, 2H), 7.53 (d, J=1.6 Hz, 2H), 7.51 (d, J=1.2 Hz, 2H), 7.08 (d, J=9.2 Hz, 2H), 6.38 (s, 1H), 3.70 (d, J=2.4 Hz, 2H), 3.37-3.20 (m, 4H), 3.20 (t, J=5.6 Hz, 2H), 2.64-2.63 (m, 4H), 2.35 (s, 3H), 2.34-2.32 (m, 2H).

Embodiment 8: Preparation of N-hydroxyl-1-((4′-((dimethylamino)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(52) ##STR00094##

(53) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and 4-(N,N-dimethylaminomethyl)phenylboronic acid pinacol ester (produced by J&K Scientific LTD.) as raw materials, white solid N-hydroxyl-1-((4′-((dimethylamino)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (20.1% total yield) was prepared by steps similar to those in Embodiment 1.

(54) MS (ESI) m/z 416 (M+1)+.

(55) .sup.1HNMR (400 MHz, DMSO) δ=8.27 (s, 1H), 7.93 (d, J=7.6 Hz, 2H), 7.85 (d, J=8.8 Hz, 2H), 7.76 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 6.33 (s, 1H), 3.67 (d, J=2.4 Hz, 2H), 3.14 (t, J=5.6 Hz, 2H), 2.44 (s, 6H), 2.27 (s, 2H).

Embodiment 9: Preparation of N-hydroxyl-1-((4′-(3,4-dimethylpiperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(56) ##STR00095##

(57) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and (4-(3,4-dimethylpiperazine-1-yl)phenyl)boronic acid (produced by Nanjing Ailikaide Chemical Co., Ltd.) as raw materials, white solid N-hydroxyl-1-((4′-(3,4-dimethylpiperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (5.6% total yield) was prepared by steps similar to those in Embodiment 1.

(58) MS (ESI) m/z 471 (M+1)+.

(59) .sup.1HNMR (400 MHz, DMSO) δ=8.21 (s, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.8 Hz, 2H), 6.33 (s, 1H), 3.72-3.64 (m, 4H), 3.12 (t, J=5.6 Hz, 2H), 2.61 (s, 3H), 2.42 (s, 3H), 2.28 (s, 2H), 1.16 (s, 3H).

Embodiment 10: Preparation of N-hydroxyl-1-((4′-(piperazine-1-yl)-[1, t-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(60) ##STR00096##

(61) By using

(62) ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and (4-(piperazine-1-yl)phenyl)boronic acid pinacol ester (produced by Nanjing Ailikaide Chemical Co., Ltd.) as raw materials, white solid N-hydroxyl-1-((4′-(piperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (11.3% total yield) was prepared by steps similar to those in Embodiment 1.

(63) MS (ESI) m/z 443 (M+1)+.

(64) .sup.1HNMR (400 MHz, DMSO) δ=8.21 (s, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.8 Hz, 2H), 6.33 (s, 1H), 3.72-3.64 (m, 4H), 3.12 (t, J=5.6 Hz, 2H), 2.61 (s, 3H), 2.42 (s, 3H), 2.28 (s, 2H), 1.16 (s, 3H).

Embodiment 11: Preparation of N-hydroxyl-1-((4′-(4-cyclopropylpiperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(65) ##STR00097##

(66) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and (4-(4-cyclopropylpiperazine-1-yl)phenyl)boronic acid (produced by Nanjing Ailikaide Chemical Co., Ltd.) as raw materials, white solid N-hydroxyl-1-((4′-(4-cyclopropylpiperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (7.4% total yield) was prepared by steps similar to those in Embodiment 1.

(67) MS (ESI) m/z 483 (M+1)+.

(68) .sup.1HNMR (400 MHz, DMSO) δ=7.86 (d, J=8.6, 2H), 7.78 (d, J=8.0, 2H), 7.64 (d, J=8.9, 2H), 7.05 (d, J=8.9, 2H), 6.36 (s, 1H), 3.65-3.64 (m, 2H), 3.21-3.16 (m, 4H), 3.14-3.12 (t, J=5.7, 2H), 2.69-2.67 (m, 4H), 3.42-3.29 (m, 2H), 1.68-1.65 (m, 1H), 0.46-0.44 (m, 2H), 0.37-0.35 (m, 2H).

Embodiment 12: Preparation of N-hydroxyl-1-((4′-(2-(dimethylamino)ethyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

1. Preparation of 2-(4-bromophenyl)-N,N-dimethylacetamide

(69) ##STR00098##

(70) 4-bromophenylacetic acid (2.00 g, 9.30 mmol) was dissolved in dichloromethane (50.0 mL), then added with N,N-diisopropylethylamine (3.61 g, 27.9 mmol, 4.87 mL), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.57 g, 18.6 mmol), 1-hydroxybenzotriazole (1.21 g, 18.6 mmol) and dimethylamine (2.10 g, 46.5 mmol). The reaction system was stirred and reacted for 2 h. The reaction solution was poured into 50.0 mL of water, and extracted for two times with dichloromethane. The organic phases were combined, condensed and purified by column chromatography to obtain colorless oily 2-(4-bromophenyl)-N,N-dimethylacetamide (2.00 g, 8.26 mmol, 88.82% yield).

2. Preparation of 2-(4-bromophenyl)-N,N-dimethylethylamide

(71) ##STR00099##

(72) 2-(4-bromophenyl)-N,N-dimethylacetamide (2.00 g, 8.26 mmol) was dissolved in tetrahydrofuran (50.0 mL) in an ice bath, added with lithium aluminum hydride (245 mg, 6.44 mmol) and reacted for 1 h.1N NaOH was added to quench the reaction, and the reaction solution was filtered. The filtrate was condensed and purified by column chromatography to obtain colorless oily 2-(4-bromophenyl)-N,N-dimethylethylamide (800 mg, 3.51 mmol, 65.30% yield).

3. Preparation of 4-((N,N-dimethylamino)ethyl)phenylboronic acid pinacol ester

(73) ##STR00100##

(74) 2-(4-bromophenyl)-N,N-dimethylethylamide (800 mg, 3.51 mmol) was added in 1,4-dioxane (10.0 mL) at the room temperature, and then added with bis(pinacolato)diboron (891 mg, 3.51 mmol), potassium acetate (369 mg, 5.27 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (80.0 mg, 3.51 mmol). The reaction system was heated to 90° C. and reacted for 2 h in the atmosphere of nitrogen. The reaction solution was condensed and purified by column chromatography to obtain brown oily 4-((N,N-dimethylamino)ethyl)phenylboronic acid pinacol ester (500 mg, 1.82 mmol, 51.76% yield).

4. Preparation of N-hydroxyl-1-((4′-(2-(dimethylamino)ethyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(75) ##STR00101##

(76) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate (10.0 g, 39.2 mmol), 4-bromophenyl-1-sulfonylchloride (1.38 g, 5.40 mmol) and (4-(2-(dimethylamino)ethyl-phenylboronic acid pinacol ester (369 mg, 1.34 mmol) as raw materials, white solid N-hydroxyl-1-((4′-(2-(dimethylamino)ethyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (30.5 mg, 71.0 μmol, 5.3% total yield) was prepared by steps similar to those in Embodiment 1.

(77) MS (ESI) m/z 430 (M+1)+.

(78) .sup.1HNMR (400 MHz, DMSO) δ=8.29 (s, 0.7H), 7.91 (d, J=8.8 Hz, 2H), 7.84 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 6.34 (s, 1H), 3.76-3.66 (m, 4H), 3.13 (t, J=5.2 Hz, 2H), 3.02-2.90 (m, 4H), 2.59 (s, 6H), 2.28 (s, 2H).

Embodiment 13: Preparation of N-hydroxyl-1-(6-(4-(4-methylpiperazine-1-yl)phenyl)pyridine-3-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(79) ##STR00102##

(80) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 6-bromopyridyl-3-sulfonylchloride and 4-(4-methylpiperazine-1-yl)phenylboronic acid pinacol ester (produced by Shanghai Accela ChemBio Co., Ltd.) as raw materials, white solid N-hydroxyl-1-(6-(4-(4-methylpiperazine-1-yl)phenyl)pyridine-3-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (12.6% total yield) was prepared by steps similar to those in Embodiment 1.

(81) MS (ESI) m/z 458 (M+1)+.

(82) .sup.1HNMR (400 MHz, DMSO) δ=8.87 (s, 1H), 8.24 (s, 1H), 8.14-8.02 (m, 3H), 7.06 (d, J=9.2 Hz, 2H), 6.34 (s, 1H), 3.71 (s, 2H), 3.33 (s, 4H), 3.19 (t, J=5.2 Hz, 2H), 2.67 (s, 4H), 2.59-2.34 (m, 3H), 2.27 (s, 2H).

Embodiment 14: Preparation of N-hydroxyl-1-((4-(1-(1-methylpiperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

1. Preparation of ethyl 1-((4-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formate

(83) ##STR00103##

(84) Ethyl 1-((4-bromophenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formate (1.00 g, 2.67 mmol) was dissolved in DMF (12.0 mL) and water (4.00 mL), and then added with tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentaborane-2-yl)-1H-pyrazol-1-yl)piperidine-1-formate (1.00 mg, 2.67 mmol, produced by Nanjing Ailikaide Chemical Co., Ltd.), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride. The reaction system was stirred and reacted for 3 h at 80° C. in the atmosphere of nitrogen. The reaction solution was added with ethyl acetate (60.0 mL) and water (40.0 mL) to extract the organic layer, and then extracted with ethyl acetate (40.0 mL×2). The organic layer was combined, dried with anhydrous sodium sulfate, and evaporated to remove the solvent. The crude product was purified by column chromatography to obtain ethyl 1-((4-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formate (1.45 g, 2.17 mmol, 81% yield).

2. Preparation of ethyl 1-((4-(1-(piperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formate hydrochloride

(85) ##STR00104##

(86) Ethyl 1-((4-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formate (1.45 g, 2.17 mmol) was dissolved in dichloromethane (20.0 mL), then added with 5.00 mL of concentrated hydrochloric acid (12N), and stirred for 1 h at the room temperature. The reaction solution was evaporated to remove the solvent so as to obtain ethyl 1-((4-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formate hydrochloride (1.22 g, 2.54 mmol, 95% yield).

3. Preparation of ethyl 1-((4-(1-(1-methylpiperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formate

(87) ##STR00105##

(88) Ethyl 1-((4-(1-(piperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formate hydrochloride (400 mg, 900 μmol) was dissolved in 1,2-dichloroethane (12.0 mL). The mixture was added with formaldehyde aqueous solution (40%, 338 mg, 4.50 mmol) and sodium triacetylborohydride (936 mg, 4.50 mmol), and stirred and reacted for 3 h at the room temperature. The reaction solution was added with ethyl acetate (40.0 mL) and water (20.0 mL) to extract the organic layer, and then extracted with dichloromethane (20 mL×2). Subsequently, the organic phase was washed with saturated salt water, dried with anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain the resulting product ethyl 1-((4-(1-(1-methylpiperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-format e (345 mg, 87.0 μmol, 11.5% yield).

4. Preparation of 1-((4-(1-(1-methylpiperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-(N-hydroxyl)formamide

(89) ##STR00106##

(90) Ethyl 1-((4-(1-(1-methylpiperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-format e (345 mg, 750 μmol) was dissolved in dichloromethane (5.00 mL) and methanol (5.00 mL). The reaction system was cooled to 0° C., added with hydroxylamine aqueous solution (50%, 20.0 mL) and sodium hydroxide (150 mg, 3.76 mmol), heated to the room temperature and stirred for 3 h. The reaction solution was adjusted with hydrochloric acid (1N) until the pH is neutral, and the resulting product was spin-dried and dissolved in methanol. The solution was condensed to obtain high performance liquid phase, and the high performance liquid phase was purified to obtain the resulting product 1-((4-(1-(1-methylpiperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-(N-hydroxyl)formamide (44.5 mg, 200 μmol, 7.28% yield).

(91) MS (ESI) m/z 446 (M+1)+.

(92) .sup.1HNMR (400 MHz, DMSO) δ=8.18 (s, 1H), 8.04 (s, 1H), 7.85-7.83 (d, J=8.4 Hz, 2H), 7.75-7.73 (d, J=8.8 Hz, 2H), 6.36 (s, 1H), 4.20-4.15 (m, 1H), 3.64-3.63 (d, J=2.8 Hz, 2H), 3.13-3.10 (t, J=6.0 Hz, 2H), 2.94-2.91 (d, J=11.6 Hz, 2H), 2.27-2.25 (m, 2H), 2.20 (s, 3H), 2.18-2.04 (m, 2H), 2.04-1.98 (m, 4H).

Embodiment 15: Preparation of N-hydroxyl-1-((4′-(4-methylpiperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,4-tetrahydropyridine-4-formamide

(93) ##STR00107##

(94) By using ethyl N-t-butyloxycarboryl-1,2,3,4-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and 4-(4-methylpiperazine-1-yl)phenyl)boronic acid pinacol ester (produced by Shanghai Accela ChemBio Co., Ltd.) as raw materials, white solid N-hydroxyl-1-((4′-(4-methylpiperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,4-tetrahydropyridine-4-formamide (6.1% total yield) was prepared by steps similar to those in Embodiment 1.

(95) MS (ESI) m/z 457 (M+1)+.

(96) .sup.1HNMR (400 MHz, DMSO) δ=7.87-7.85 (d, J=8.4 Hz, 2H), 7.84-7.82 (d, J=9.2 Hz, 2H), 7.79-7.77 (d, J=8.4 Hz, 2H), 7.06-7.04 (d, J=8.8 Hz, 2H), 6.73-6.71 (m, 1H), 4.93-4.90 (m, 1H), 3.46-3.37 (m, 2H), 3.26-3.23 (m, 4H), 2.75-2.73 (m, 1H), 2.52-2.50 (m, 4H), 2.26 (s, 3H), 1.83-1.79 (m, 1H), 1.64-1.61 (m, 1H).

Embodiment 16: Preparation of N-hydroxyl-1-((4-(1-acetylpiperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(97) ##STR00108##

(98) By using ethyl 1-((4-(1-(piperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formate hydrochloride and acetic anhydride as raw materials, white solid N-hydroxyl-1-((4-(1-acetylpiperidine-4-yl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (14.9% total yield) was prepared by steps similar to those in Embodiment 14.

(99) MS (ESI) m/z 474 (M+1)+.

(100) .sup.1HNMR (400 MHz, DMSO) δ=8.45 (s, 1H), 8.05 (s, 1H), 7.84-7.83 (d, J=8.4, 1H), 7.75-7.73 (d, J=8.4 Hz, 2H), 6.36 (s, 1H), 4.26-4.20 (m, 1H), 3.64-3.63 (d, J=2.8 Hz, 2H), 3.12-3.10 (t, J=2.4 Hz, 2H), 3.02-2.99 (d, J=11.6 Hz, 2H), 2.43 (s, 3H), 2.36-2.23 (m, 4H), 2.28-2.05 (m, 4H).

Embodiment 17: Preparation of N-hydroxyl-1-((4-(6-(4-(2-methoxyethyl)piperazine-1-yl)pyridine-3-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide 1. Preparation of 1-(5-bromopyridine-2-yl)-4-(2-methoxyethyl)piperazine

(101) ##STR00109##

(102) 5-bromo-2-chloropyridine (1.00 g, 5.19 mmol), 1-(2-methoxyethyl)piperazine (899 mg, 6.23 mmol) and potassium carbonate (1.08 g, 8.00 mmol) were dissolved in N,N-dimethylformamide. The reaction solution was heated to 70° C., stirred overnight, evaporated to remove the solvent and purified by column chromatography to obtain 1-(5-bromopyridine-2-yl)-4-(2-methoxyethyl) piperazine (500 mg, 1.66 mmol, 32% yield).

(103) MS (ESI) m/z 300 (M+1)+.

2. Preparation of 1-((4-(6-(2-methoxyethyl)piperazine-1-yl)pyridine-3-yl)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxo)-1,2,3,6-tetrahydropyridine-4-formamide

(104) ##STR00110##

(105) 1-(5-bromopyridine-2-yl)-4-(2-methoxyethyl)piperazine (450 mg, 1.50 mmol) was dissolved in 15.0 mL of ethanol, and added with chloro[4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2-aminobiphenyl)]palladium (II) (45.8 mg), potassium acetate (441 mg, 4.50 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (28.6 mg, 60.0 μmol). The reaction system was heated to 80° C. and reacted for 2 h in the atmosphere of nitrogen. The reaction system was added with ethyl 1-((4-bromophetnyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formate (655 mg, 1.47 mmol) and potassium carbonate (610 mg, 4.41 mmol), heated to 100° C. and reacted overnight. At the end of reaction, the reaction solution was evaporated to remove the solvent, and purified by column chromatography to obtain 1-((4-(6-(2-methoxyethyl)piperazine-1-yl)pyridine-3-yl)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxo)-1,2,3,6-tetrahydropyridine-4-formamide (170 mg, 290 μmol, 20% yield).

(106) MS (ESI) m/z 586 (M+1)+.

3. Preparation of N-hydroxyl-1-((4-(6-(4-(2-methoxyethyl)piperazine-1-yl)pyridine-3-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(107) ##STR00111##

(108) 1-((4-(6-(2-methoxyethyl)piperazine-1-yl)pyridine-3-yl)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxo)-1,2,3,6-tetrahydropyridine-4-formamide (170 mg, 290 μmol) was added with hydrochloric acid (0.1N, 10.0 mL), and stirred overnight at the room temperature to obtain high performance liquid phase. The high performance liquid phase was purified to obtain white solid N-hydroxyl-1-((4-(6-(4-(2-methoxyethyl)piperazine-1-yl)pyridine-3-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (25.6 mg, 46.8 μmol, 16.1%).

(109) MS (ESI) m/z 502 (M+1)+.

(110) .sup.1HNMR (400 MHz, DMSO) δ=8.52 (d, J=2.6 Hz, 1H), 7.95 (dd, J=2.6, 8.9 Hz, 1H), 7.86 (d, J=8.6, 2H), 7.78 (d, J=8.6, 2H), 6.96 (d, J=9.0, 1H), 6.32 (m, 1H), 3.65-3.61 (m, 6H), 3.54-3.52 (t, J=5.48, 2H), 3.25 (s, 3H), 3.11 (t, J=5.5, 2H), 2.79-2.77 (m, 6H), 2.28-2.25 (m, 2H).

Embodiment 18: Preparation of N-hydroxyl-1-((4′-((diethylamino)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(111) ##STR00112##

(112) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and (4-((diethylamino)methyl)phenyl)boronic acid pinacol ester (produced by Shanghai Bide Pharmatech Ltd.) as raw materials, white solid N-hydroxyl-1-((4′-((diethylamino)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-form amide (7.1% total yield) was prepared by steps similar to those in Embodiment 1.

(113) MS (ESI) m/z 444 (M+1)+.

(114) .sup.1HNMR (400 MHz, DMSO) δ=8.25 (s, 0.4H), 7.95-7.93 (m, 2H), 7.87-7.85 (m, 2H), 7.81-7.79 (m, 2H), 7.61-7.59 (m, 2H), 6.33 (s, 1H), 4.14 (s. 2H), 3.66 (d, J=4.0 Hz, 2H), 3.14 (t, J=4.0 Hz, 2H), 2.95-2.90 (m, 4H), 2.27 (s, 2H), 1.16 (t, J=8.0 Hz, 6H).

Embodiment 19: Preparation of N-hydroxyl-1-((4′-(piperidine-1-yl-methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(115) ##STR00113##

(116) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and 4-(piperidylmethyl)phenylboronic acid pinacol ester (produced by J&K Scientific LTD.) as raw materials, white solid N-hydroxyl-1-((4′-(piperidine-1-yl-methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (5.1% total yield) was prepared by steps similar to those in Embodiment 1.

(117) MS (ESI) m/z 456 (M+1)+.

(118) .sup.1HNMR (400 MHz, DMSO) δ=8.4 (s, 1H), 7.93 (d, J=8.2 Hz, 2H), 7.84 (d, J=8.0 Hz, 2H), 7.71 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 1H), 6.36 (s, 1H), 3.66 (m, 4H), 3.14 (t, J=6.0 Hz, 2H), 2.32-2.35 (m, 6H), 1.49-1.52 (m, 4H), 1.39-1.41 (m, 2H).

Embodiment 20: Preparation of N-hydroxyl-1-((4′-((4-methylpiperazine-1-yl)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(119) ##STR00114##

(120) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and 4-(4-methyl-1-piperazinylmethyl)phenylboronic acid pinacol ester (produced by Nanjing Ailikaide Chemical Co., Ltd.) as raw materials, white solid N-hydroxyl-1 ((4′-((4-methylpiperazine-1-yl)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (5.5% total yield) was prepared by steps similar to those in Embodiment 1.

(121) MS (ESI) m/z 471 (M+1)+.

(122) .sup.1HNMR (400 MHz, DMSO) δ=7.93 (d, J=8.0 Hz, 2H), 7.84 (d, J=8.0 Hz, 2H), 7.71 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 6.36 (s, 1H), 3.66-3.67 (d, J=4.0 Hz, 2H), 3.52 (s, 1H), 3.14-3.17 (m, 2H), 2.4-2.42 (m, 6H), 2.32-2.37 (m, 4H), 2.19 (s, 3H).

Embodiment 21: Preparation of N-hydroxyl-1-((4′-(morpholinylmethyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(123) ##STR00115##

(124) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and 4-(4-morpholinylmethyl)phenylboronic acid pinacol ester (produced by Nanjing Ailikaide Chemical Co., Ltd.) as raw materials, white solid N-hydroxyl-1-((4′-(morpholinylmethyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (6.3% total yield) was prepared by steps similar to those in Embodiment 1.

(125) MS (ESI) m/z 458 (M+1)+.

(126) .sup.1HNMR (400 MHz, DMSO) δ=7.93 (d, J=8.0 Hz, 2H), 7.84 (d, J=8.0 Hz, 2H), 7.72 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 6.36 (s, 1H), 3.66 (s, 1H), 3.57-3.60 (m, 4H), 3.52 (s, 4H), 3.13-3.16 (m, 2H), 2.38 (m, 4H), 2.31 (s, 2H).

Embodiment 22: Preparation of N-hydroxyl-1-((4′-((2-(dimethylamino)ethyl)aminoformyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(127) ##STR00116##

(128) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and ((((dimethylamino)ethyl)aminoformyl)phenyl)boronic acid (produced by Nanjing Ailikaide Chemical Co., Ltd.) as raw materials, white solid N-hydroxyl-1-((4′-((2-(dimethylamino)ethyl)aminoformyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (7.8% total yield) was prepared by steps similar to those in Embodiment 1.

(129) MS (ESI) m/z 473 (M+1)+.

(130) .sup.1HNMR (400 MHz, DMSO) δ=8.6 (s, 1H), 7.98-8.01 (m, 4H), 7.86-7.89 (m, 4H), 6.37 (s, 1H), 3.67 (m, 2H), 3.40-3.43 (m, 2H), 3.14-3.17 (m, 2H), 2.56-2.58 (m, 2H), 2.29-2.31 (m, 8H).

Embodiment 23: Preparation of N-hydroxyl-1-((3′-(4-methylpiperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(131) ##STR00117##

(132) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and (3-(4-methylpiperazine-1-yl)phenyl)boronic acid (produced by Shanghai Accela ChemBio Co., Ltd.) as raw materials, white solid N-hydroxyl-1-((3′-(4-methylpiperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (1.6% total yield) was prepared by steps similar to those in Embodiment 1.

(133) MS (ESI) m/z 457 (M+1)+.

(134) .sup.1HNMR (400 MHz, DMSO) δ=8.16 (s, 1H), 7.92-7.89 (m, 2H), 7.34 (d, J=8.0 Hz, 1H), 7.19-7.23 (m, 1H), 6.99-7.05 (dd, J=8.0, 2.0 Hz, 1H), 6.36 (s, 1H), 3.65 (d, J=3.2, 2H), 3.26-3.24 (m, 5H), 3.13 (t, J=5.6 Hz, 2H), 2.48-2.44 (m, 3H), 2.36-2.28 (m, 2H), 2.23 (s, 3H).

Embodiment 24: Preparation of N-hydroxyl-1-((4-(6-(4-methyl-1,4-diazaheptane-1-yl)pyridine-3-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(135) ##STR00118##

(136) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride, 1-methyl-1,4-diazaheptane and 2,5-dibromopyridine as raw materials, white solid N-hydroxyl-1-((4-(6-(4-methyl-1,4-diazaheptane-1-yl)pyridine-3-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (7.8% total yield) was prepared by steps similar to those in Embodiment 17.

(137) MS (ESI) m/z 472 (M+1)+.

(138) .sup.1H NMR (400 MHz, DMSO) δ=8.53 (d, J=2.1 Hz, 1H), 8.24 (s, 1.4H), 7.92 (d, J=9.1 Hz, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.4 Hz, 2H), 6.76 (d, J=9.0 Hz, 1H), 6.36 (s, 1H), 3.83 (s, 2H), 3.65 (d, J=6.5 Hz, 4H), 3.12 (t, J=5.5 Hz, 2H), 2.73 (s, 2H), 2.61 (s, 2H), 2.33 (t, J=8.4 Hz, 5H), 1.96 (s, 2H).

Embodiment 25: Preparation of N-hydroxyl-1-((2′-((dimethylamino)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(139) ##STR00119##

(140) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and 2-(N,N-dimethylmethylene)phenylboronic acid (produced by Nanjing Ailikaide Chemical Co., Ltd.) as raw materials, white solid N-hydroxyl-1-((2′-((dimethylamino)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (5.9% total yield) was prepared by steps similar to those in Embodiment 1.

(141) MS (ESI) m/z 416 (M+1)+.

(142) .sup.1H NMR (400 MHz, DMSO) δ=10.70 (s, 1H), 8.14 (s, 0.8H), 7.84 (d, J=8.4 Hz, 2H), 7.74-7.52 (m, 3H), 7.44 (td, J=13.0, 7.3 Hz, 2H), 7.30 (d, J=7.1 Hz, 1H), 6.37 (s, 1H), 3.70 (d, J=2.5 Hz, 2H), 3.53 (s, 2H), 3.18 (t, J=5.7 Hz, 2H), 2.30 (s, 2H), 2.17 (s, 6H).

Embodiment 26: Preparation of N-hydroxyl-1-(((4′-(4-(1-methoxy-2-methylpropane-2-yl)piperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(143) ##STR00120##

(144) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromobiphenyl and 1-(1-methoxy-2-methylpropane-2-yl)piperazine as raw materials, white solid N-hydroxyl-1-(((4′-(4-(1-methoxy-2-methylpropane-2-yl)piperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (8.4% total yield) was prepared by steps similar to those in Embodiment 4.

(145) MS (ESI) m/z 529 (M+1)+.

(146) .sup.1H NMR (400 MHz, DMSO) δ=10.73-10.62 (m, 1H), 8.88-8.78 (m, 1H), 8.14 (s, 0.7H), 7.87 (d, J=8.6 Hz, 2H), 7.78 (d, J=8.5 Hz, 2H), 7.66 (d, J=8.9 Hz, 2H), 7.06 (d, J=8.2 Hz, 2H), 6.36 (s, 1H), 3.64 (s, 2H), 3.32 (d, J=13.7 Hz, 12H), 3.12 (t, J=5.6 Hz, 3H), 2.31 (s, 2H), 1.15 (s, 6H).

Embodiment 27: Preparation of N-hydroxyl-1-((4′-((methylpiperidine-4-yl)amino)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(147) ##STR00121##

(148) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromobiphenyl and 1-methylpiperidine-4-amine as raw materials, white solid N-hydroxyl-1-((4′-((methylpiperidine-4-yl)amino)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (0.5% total yield) was prepared by steps similar to those in Embodiment 4.

(149) MS (ESI) m/z 471 (M+1)+.

(150) .sup.1H NMR (400 MHz, DMSO) δ=10.68 (s, 1H), 10.47 (s, 1H), 8.83 (s, 0.8H), 7.81 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.6 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 6.73 (d, J=7.6 Hz, 2H), 6.36 (s, 1H), 6.18 (s, 1H), 3.62 (s, 2H), 3.47 (d, J=50.1 Hz, 2H), 3.11 (t, J=5.6 Hz, 4H), 2.72 (s, 3H), 2.30 (s, 2H), 2.09 (d, J=13.0 Hz, 2H), 1.74 (d, J=9.7 Hz, 2H).

Embodiment 28: Preparation of N-hydroxyl-1 ((4′-((methylpiperidine-4-yl)amino)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,4-tetrahydropyridine-4-formamide

(151) ##STR00122##

(152) By using ethyl N-t-butyloxycarboryl-1,2,3,4-tetrahydropyridine-4-formate, 4-bromobiphenyl and 1-methylpiperidine-4-amine as raw materials, white solid N-hydroxyl-1-((4′-((methylpiperidine-4-yl)amino)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,4-tetrahydropyridine-4-formamide (2.7% total yield) was prepared by steps similar to those in Embodiment 4.

(153) MS (ESI) m/z 471 (M+1)+.

(154) .sup.1H NMR (400 MHz, DMSO) δ=10.47 (s, 1H), 8.25 (s, 1H), 7.79 (d, J=8.7 Hz, 2H), 7.73 (d, J=8.7 Hz, 2H), 7.52 (d, J=8.7 Hz, 2H), 6.70 (dd, J=13.8, 5.3 Hz, 3H), 5.96 (d, J=8.0 Hz, 1H), 4.90 (dd, J=8.4, 3.9 Hz, 1H), 3.51-3.21 (m, 4H), 2.85 (d, J=11.9 Hz, 2H), 2.73 (d, J=5.5 Hz, 1H), 2.27 (s, 3H), 2.21 (t, J=10.7 Hz, 2H), 1.92 (d, J=10.9 Hz, 2H), 1.79 (s, 1H), 1.66-1.56 (m, 1H), 1.46 (dd, J=20.8, 10.0 Hz, 2H).

Embodiment 29: Preparation of N-hydroxyl-1-((4′-(4-methylpiperazinyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(155) ##STR00123##

(156) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and 4-(4-methylpiperazinyl)phenylboronic acid pinacol ester (produced by Shanghai Accela ChemBio Co., Ltd.) as raw materials, white solid N-hydroxyl-1-((4′-(4-methylpiperazinyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (9.3% total yield) was prepared by steps similar to those in Embodiment 1.

(157) MS (ESI) m/z 457 (M+1)+.

(158) .sup.1HNMR (400 MHz, DMSO) δ=8.22 (s, 1H), 7.84 (d, J=8.0 Hz, 2H), 7.77 (d, J=8.0 Hz, 2H), 7.63 (d, J=8.0 Hz, 2H), 7.09 (d, J=8.0 Hz, 2H), 6.32 (s, 1H), 3.63 (s, 2H), 3.33-3.32 (m, 4H), 3.12-3.10 (t, 2H), 2.88-2.87 (m, 2H), 2.51 (s, 3H), 2.27 (s, 2H).

Embodiment 30: Preparation of N-hydroxyl-1-((4′-(4-(1-methoxyisopropyl)piperazinyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(159) ##STR00124##

(160) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and 4-(4-(1-methoxyisopropyl)piperazinyl)phenylboronic acid pinacol ester (produced by Shanghai Accela ChemBio Co., Ltd.) as raw materials, white solid N-hydroxyl-1-((4′-(4-(1-methoxyisopropyl)piperazinyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (0.93% total yield) was prepared by steps similar to those in Embodiment 1.

(161) MS (ESI) m/z 515 (M+1)+.

(162) .sup.1HNMR (400 MHz, DMSO) δ=10.6 (br, 1H), 8.8 (br, 1H), 7.84 (d, J=8.0 Hz, 2H), 7.77 (d, J=8.0 Hz, 2H), 7.63 (d, J=8.0 Hz, 2H), 7.03 (d, J=7.0 Hz, 2H), 6.35 (s, 1H), 3.63 (s, 2H), 3.60-3.31 (m, 2H), 3.29-3.25 (m, 3H), 3.22-3.21 (m, 4H), 3.12 (t, J=6.0 Hz, 2H), 2.84-2.82 (m, 1H), 2.71-2.70 (m, 4H), 2.30 (s, 2H), 1.01 (d, J=5.0 Hz, 3H).

Embodiment 31: Preparation of N-hydroxyl-1-((4′-(2-(diethylamino)ethyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(163) ##STR00125##

(164) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride, 4-bromophenylacetic acid and diethylamine hydrochloride as raw materials, white solid N-hydroxyl-1-((4′-(2-(diethylamino)ethyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (0.16% total yield) was prepared by steps similar to those in Embodiment 12.

(165) MS (ESI) m/z 458 (M+1)+.

(166) .sup.1HNMR (400 MHz, DMSO) δ=7.92 (d, J=8.0 Hz, 2H), 7.82 (d, J=8.0 Hz, 2H), 7.70 (d, J=8.0 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H), 6.36 (s, 1H), 3.65 (s, 2H), 3.14 (t, J=8.0 Hz, 2H), 2.99-2.86 (m, 8H), 2.31 (s, 2H), 1.12 (t, J=5.0 Hz, 6H).

Embodiment 32: Preparation of N-hydroxyl-1-((4-(2-(2-methoxyethyl)isoindoline-5-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(167) ##STR00126##

(168) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and 5-bromo-2-(2-methoxyethyl)isoindoline as raw materials, white solid N-hydroxyl-1-((4-(2-(2-methoxyethyl)isoindoline-5-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (4.9% total yield) was prepared by steps similar to those in Embodiment 3.

(169) MS (ESI) m/z 458 (M+1)+.

(170) .sup.1HNMR (400 MHz, DMSO) δ=7.91 (d, J=8.0 Hz, 2H), 7.85 (d, J=8.0 Hz, 2H), 7.74-7.70 (m, 2H), 7.50 (d, J=8.0 Hz, 2H), 6.33 (s, 1H), 4.59 (d, J=4.0 Hz, 4H), 3.70-3.66 (m, 4H), 3.51-3.49 (m, 2H), 3.33 (s, 3H), 3.13 (t, J=6.0 Hz, 2H), 2.28 (s, 2H).

Embodiment 33: Preparation of 1-((4′-(1-(dimethylamino)ethyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-N-hydroxyl-1,2,3,6-tetrahydropyridine-4-formamide

(171) ##STR00127##

(172) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and 4′-(1-(dimethylamino)ethylphenylboronic acid (produced by Nanjing Ailikaide Chemical Co., Ltd.) as raw materials, white solid 1-((4′-(1-(dimethylamino)ethyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-N-hydroxyl-1,2,3,6-tetrahydropyridine-4-formamide (6.0% total yield) was prepared by steps similar to those in Embodiment 1.

(173) MS (ESI) m/z 430 (M+1)+.

(174) .sup.1HNMR (400 MHz, DMSO) δ=7.95 (d, J=8.0 Hz, 2H), 7.86 (d, J=8.0 Hz, 2H), 7.78 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 6.33 (s, 1H), 3.99 (s, 1H) 3.66 (s, 2H), 3.53 (s, 2H), 3.14 (s, 2H), 2.27-2.42 (m, 8H), 1.48 (d, J=6.4 Hz, 3H).

Embodiment 34: Preparation of 1-((4′-((4-ethyl(2-methoxyethyl)amino)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-N-hydroxyl-1,2,3,6-tetrahydropyridine-4-formamide

(175) ##STR00128##

(176) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and 4-(ethyl(2-methoxyethyl)amino)methylphenylboronic acid (produced by Nanjing Ailikaide Chemical Co., Ltd.) as raw materials, white solid 1-((4′-((4-ethyl(2-methoxyethyl)amino)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-N-hydroxyl-1,2,3,6-tetrahydropyridine-4-formamide (1.5% total yield) was prepared by steps similar to those in Embodiment 1.

(177) MS (ESI) m/z 474 (M+1)+.

(178) .sup.1HNMR (400 MHz, DMSO) δ=7.94 (d, J=8.0 Hz, 2H), 7.86 (d, J=8.0 Hz, 2H), 7.73 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 6.36 (s, 1H), 3.66 (s, 2H), 3.64 (s, 2H), 3.43 (d, J=6.0 Hz, 2H), 3.32 (s, 3H), 3.14 (d, J=4.8 Hz 2H), 2.51-2.64 (m, 4H), 2.32 (s, 2H), 1.00 (t, J=6.8 Hz, 3H).

Embodiment 35: Preparation of 1-((4′-(1-(diethylamino)ethyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-N-hydroxyl-1,2,3,6-tetrahydropyridine-4-formamide

(179) ##STR00129##

(180) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and 4′-(1-(diethylamino)ethylphenylboronic acid (produced by Nanjing Ailikaide Chemical Co., Ltd.) as raw materials, white solid 1-((4′-(1-(diethylamino)ethyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-N-hydroxyl-1,2,3,6-tetrahydropyridine-4-formamide (3.97% total yield) was prepared by steps similar to those in Embodiment 1.

(181) MS (ESI) m/z 458 (M+1)+.

(182) .sup.1HNMR (400 MHz, DMSO) δ=7.94 (d, J=8.0 Hz, 2H), 7.84 (d, J=8.0 Hz, 2H), 7.73 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 6.33 (s, 1H), 4.03 (d, J=6.68 Hz, 1H), 3.66 (s, 2H), 3.16 (t, J=5.36 Hz, 2H), 2.68-2.55 (m, 4H), 2.31 (s, 2H), 1.38 (d, J=6.64 Hz, 3H)), 1.01 (t, J=7.0 Hz, 6H).

Embodiment 36: Preparation of 1-((4′-(4-acetylpiperazine)-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-N-hydroxyl-1,2,3,6-tetrahydropyridine-4-formamide

(183) ##STR00130##

(184) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromobiphenyl and 4-acetylpiperazine as raw materials, white solid 1-((4′-(4-acetylpiperazine)-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-N-hydroxyl-1,2,3,6-tetrahydropyridine-4-formamide (5.6% total yield) was prepared by steps similar to those in Embodiment 4.

(185) MS (ESI) m/z 485 (M+1)+.

(186) .sup.1HNMR (400 MHz, DMSO) δ=7.84 (d, J=8.0 Hz, 2H), 7.77 (d, J=8.0 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.0 Hz, 2H), 6.33 (s, 1H), 4.03 (d, J=6.68 Hz, 1H), 3.66 (s, 2H), 3.64 (s, 2H), 3.57 (d, J=4 Hz, 4H), 3.24 (s, 2H), 3.18 (s, 2H), 3.10-3.12 (m, 2H), 2.27 (s, 2H), 2.04 (s, 3H).

Embodiment 37: Preparation of N-hydroxyl-1-((4-(2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(187) ##STR00131##

(188) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and 7-bromo-2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinoline as raw materials, white solid N-hydroxyl-1-((4-(2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)phenyl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (8.8% total yield) was prepared by steps similar to those in Embodiment 3.

(189) MS (ESI) m/z 472 (M+1)+.

(190) .sup.1HNMR (400 MHz, DMSO) δ=7.91 (d, J=8.0 Hz, 2H), 7.84 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.28 (d, J=8.4 Hz, 1H), 6.33 (s, 1H), 4.16 (s, 2H), 3.66-3.68 (m, 4H), 3.31 (s, 3H), 3.26 (s, 2H), 3.07-3.14 (m, 6H), 2.28 (s, 2H).

Embodiment 38: Preparation of N-hydroxyl-1-((4′-((4-(1-methoxy-2-methylpropane-2-yl)piperazine-1-yl)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide 1. Preparation of 4-((4-(1-methoxy-2-methylpropane-2-yl)piperazinyl)methyl)phenylboronic acid pinacol ester

(191) ##STR00132##

(192) 4-bromomethyl phenylboronic acid pinacol ester (1.14 g, 3.85 mmol) and 1-(1-methoxy-2-methylpropane-2-yl)piperazine (474 mg, 2.75 mmol) were dissolved in acetonitrile (20.0 mL), then added with sodium carbonate (874 mg, 8.25 mmol) and stirred overnight at the room temperature. The reaction solution was added with water (50.0 mL) and extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, evaporated at the reduced pressure to remove the solvent, and purified by column chromatography to obtain 4-((4-(1-methoxy-2-methylpropane-2-yl)piperazinyl)methyl)phenylboronic acid pinacol ester (800 mg, 2.06 mmol, 75% yield).

2. Preparation of N-hydroxyl-1-((4′-((4-(1-methoxy-2-methylpropane-2-yl)piperazine-1-yl)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(193) ##STR00133##

(194) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and 4-((4-(1-methoxy-2-methylpropane-2-yl)piperazinyl)methyl)phenylboronic acid pinacol ester as raw materials, N-hydroxyl-1-((4′-((4-(1-methoxy-2-methylpropane-2-yl)piperazine-1-yl)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (1.6% total yield) was prepared by steps similar to those in Embodiment 3.

(195) MS (ESI) m/z 543 (M+1)+.

(196) .sup.1HNMR (400 MHz, DMSO) δ=10.67 (s, 1H), 8.15 (s, 0.6H), 7.92 (d, J=8.5 Hz, 2H), 7.84 (d, J=8.5 Hz, 2H), 7.72 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H), 6.36 (s, 1H), 3.66 (s, 2H), 3.57 (s, 3H), 3.27 (d, J=7.8 Hz, 7H), 3.15 (t, J=5.5 Hz, 3H), 2.78 (s, 4H), 2.31 (s, 2H), 1.23-0.98 (m, 6H).

Embodiment 39: Preparation of N-hydroxyl-1-((4′-((4-(1-methoxy-2-methylpropane-2-yl)piperazine-1-yl)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,4-tetrahydropyridine-4-formamide

(197) ##STR00134##

(198) By using ethyl N-t-butyloxycarboryl-1,2,3,4-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride, 4-bromomethyl phenylboronic acid pinacol ester and 1-(1-methoxy-2-methylpropane-2-yl)piperazine as raw materials, N-hydroxyl-1-((4′-((4-(1-methoxy-2-methylpropane-2-yl)piperazine-1-yl)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,4-tetrahydropyridine-4-formamide (11% total yield) was prepared by steps similar to those in Embodiment 38.

(199) MS (ESI) m/z 543 (M+1)+.

(200) .sup.1HNMR (400 MHz, DMSO) δ=10.47 (s, 1H), 8.20 (s, 1.4H), 7.92 (d, J=8.6 Hz, 2H), 7.85 (d, J=8.6 Hz, 2H), 7.71 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.2 Hz, 2H), 6.73 (dd, J=8.3, 2.0 Hz, 1H), 4.92 (dd, J=8.4, 4.0 Hz, 1H), 3.50 (s, 2H), 3.43 (dd, J=10.6, 7.0 Hz, 2H), 3.23 (s, 3H), 3.20 (s, 2H), 2.74 (d, J=5.7 Hz, 1H), 2.57 (d, J=21.2 Hz, 4H), 2.38 (s, 4H), 1.79 (s, 1H), 1.62 (d, J=4.6 Hz, 1H), 0.97 (s, 6H).

Embodiment 40: Preparation of N-hydroxyl-1-((4′-(((2-(dimethylamino)ethyl)amino)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(201) ##STR00135##

(202) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride, 4-bromomethyl phenylboronic acid pinacol ester and N,N-dimethyl ethylenediamine as raw materials, N-hydroxyl-1-((4′-(((2-(dimethylamino)ethyl)amino)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (11% total yield) was prepared by steps similar to those in Embodiment 38.

(203) MS (ESI) m/z 459 (M+1)+.

(204) .sup.1HNMR (400 MHz, DMSO) δ=10.68 (s, 1H), 8.14 (s, 0.4H), 7.96 (d, J=8.4 Hz, 2H), 7.86 (d, J=8.4 Hz, 2H), 7.81 (d, J=8.1 Hz, 2H), 7.65 (d, J=8.0 Hz, 2H), 6.37 (s, 1H), 4.12 (s, 2H), 3.66 (s, 2H), 3.19-3.12 (m, 4H), 3.10 (s, 2H), 2.56 (s, 6H), 2.31 (s, 2H).

Embodiment 41: Preparation of N-hydroxyl-1-((4′-((methyl(1-methylpiperidine-4-yl)amino)methylene)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(205) ##STR00136##

(206) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride, 4-bromomethyl phenylboronic acid pinacol ester and N,1-dimethylpiperidyl-4-amine as raw materials, N-hydroxyl-1-((4′-((methyl(1-methylpiperidine-4-yl)amino)methylene)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (0.45% total yield) was prepared by steps similar to those in Embodiment 38.

(207) MS (ESI) m/z 499 (M+1)+.

(208) .sup.1HNMR (400 MHz, DMSO) δ=10.68 (s, 1H), 8.83 (s, 1H), 7.95 (d, J=8.0 Hz, 2H), 7.86 (d, J=8.0 Hz, 2H), 7.78 (s, 2H), 7.65 (br, 2H), 6.36 (s, 1H), 4.23 (m, 2H), 3.67 (s, 2H), 3.46 (m, 2H), 3.15 (t, J=6.0 Hz, 2H), 2.95 (m, 2H), 2.70 (s, 3H), 2.30-2.08 (m, 8H).

Embodiment 42: Preparation of N-hydroxyl-1-((4′-((4-(2-methoxyethyl)-1-piperazinyl)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide

(209) ##STR00137##

(210) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride and 4-bromomethyl phenylboronic acid pinacol ester and 4′-(4-(2-methoxyethyl)-1-piperazine (produced by Nanjing Ailikaide Chemical Co., Ltd.) as raw materials, white solid N-hydroxyl-1-((4′-((4-(2-methoxyethyl)-1-piperazinyl)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-1,2,3,6-tetrahydropyridine-4-formamide (1.9% total yield) was prepared by steps similar to those in Embodiment 38.

(211) MS (ESI) m/z 515 (M+1)+.

(212) .sup.1HNMR (400 MHz, DMSO) δ=7.93 (d, J=8.0 Hz, 2H), 7.84 (d, J=8.0 Hz, 2H), 7.71 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 6.33 (s, 1H), 3.66 (s, 2H), 3.53 (s, 2H), 3.42-3.45 (m, 2H), 3.20 (s, 3H) 3.13 (s, 2H), 2.46-2.60 (m, 8H), 2.27 (s, 2H).

Embodiment 43: Preparation of 1-((4′-((4-ethylpiperazine-1-yl)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-N-hydroxyl-1,2,3,6-tetrahydropyridine-4-formamide

(213) ##STR00138##

(214) By using ethyl N-t-butyloxycarboryl-1,2,3,6-tetrahydropyridine-4-formate, 4-bromophenyl-1-sulfonylchloride, 4-bromomethyl phenylboronic acid pinacol ester and N-ethylpiperazine as raw materials, 1-((4′-((4-ethylpiperazine-1-yl)methyl)-[1,1′-biphenyl]-4-yl)sulfonyl)-N-hydroxyl-1,2,3,6-tetrahydropyridine-4-formamide (2.2% total yield) was prepared by steps similar to those in Embodiment 38.

(215) MS (ESI) m/z 485 (M+1)+.

(216) .sup.1HNMR (400 MHz, DMSO) δ=7.93 (d, J=8.0 Hz, 2H), 7.86 (d, J=8.0 Hz, 2H), 7.73 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 6.36 (s, 1H), 3.66 (s, 2H), 3.54 (s, 2H), 3.14 (d, J=4.8 Hz 2H), 2.31-2.51 (m, 8H), 1.48 (t, J=6.8 Hz, 3H).

Embodiment 44: Preparation of N-hydroxyl-1-((4′-(4-methylpiperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-2,3,6,7-tetrahydro-1H-aza-4-formamide

(217) ##STR00139##

(218) By using ethyl N-t-butyloxycarboryl-2,3,6,7-tetrahydro-1H-azepine-4-formate, 4-bromophenyl-1-sulfonylchloride and 4-(4-methylpiperazinyl)phenylboronic acid pinacol ester (produced by Shanghai Accela ChemBio Co., Ltd.) as raw materials, white solid N-hydroxyl-1-((4′-(4-methylpiperazine-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-2,3,6,7-tetrahydro-1H-aza-4-formamide (4.2% total yield) was prepared by steps similar to those in Embodiment 1.

(219) MS (ESI) m/z 471 (M+1)+.

(220) .sup.1HNMR (400 MHz, DMSO) δ=8.24 (s, 1H), 7.82 (d, J=8.0 Hz, 2H), 7.69 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.04 (d, J=8.0 Hz, 2H), 6.29 (s, 1H), 3.58 (s, 2H), 3.33-3.32 (m, 4H), 3.12-3.10 (t, 2H), 2.86-2.85 (m, 4H), 2.48 (s, 3H), 2.26 (s, 2H).

(221) In order to describe the beneficial effects of the present invention, the present invention provides the following test examples.

Test Example 1: Biological Activity Detection

(222) During the deacetylation detection of a substrate, the HDAC inhibition activity of the compound of the present invention was detected.

(223) A: Enzyme Activity Detection of Histone Deacetylase 6 (#50076, BPS Bioscience)

(224) Acetyl on the substrate was removed by the HDAC 6, so that the substrate was activated, and the developing liquid added subsequently could act on the substrate to release the fluorescent group. The size of the fluorescence signal reflected the activity of the HDAC 6. The IC50 detection method for this enzyme was disclosed in Chuping Xu, Elisabetta Soragni Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurdegenerative Disease Friedreich's Ataxia: A New Synthetic Route. The total reaction system (100 μL/well) contained 0.35 ng/μL of HDAC 6, 20 μM of the substrate and the compound in different concentrations. The reaction system was incubated for 30 min at 37° C., and the fluorescence signal was then measured. The inhibition effect of the compound was determined from the obtained data, a concentration response curve was obtained by using the inhibition effect and the concentration of the compound, and the value of IC50 was fitted according to a four-parameter model.

(225) B: Enzyme Activity Detection of Histone Deacetylase 3 (#50003, BPS Bioscience)

(226) Acetyl on the substrate was removed by the HDAC 3, so that the substrate was activated, and the developing liquid added subsequently could act on the substrate to release the fluorescent group. The size of the fluorescence signal reflected the activity of the HDAC 3. The IC50 detection method for this enzyme was disclosed in Chuping Xu, Elisabetta Soragni Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurdegenerative Disease Friedreich's Ataxia: A New Synthetic Route. The total reaction system (100 μL/well) contained 0.16 ng/μL of HDAC 3, 10 μM of the substrate and the compound in different concentrations. The fluorescence signal was detected online at Ex/Em=360/460. The inhibition effect of the compound was determined from the obtained data, a concentration response curve was obtained by using the inhibition effect and the concentration of the compound, and the value of IC.sub.50 was fitted according to a four-parameter model.

(227) C: Enzyme Activity Detection of Histone Deacetylase 1

(228) Acetyl on the substrate was removed by the HDAC 1, so that the substrate was activated, and the developing liquid added subsequently could act on the substrate to release the fluorescent group. The size of the fluorescence signal reflected the activity of the HDAC 1. The IC50 detection method for this enzyme was disclosed in Chuping Xu, Elisabetta Soragni Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurdegenerative Disease Friedreich's Ataxia: A New Synthetic Route. The total reaction system (100 μL/well) contained 0.28 ng/μL of HDAC 1, 10 μM of the substrate and the compound in different concentrations. The fluorescence signal was detected online at Ex/Em=360/460. The inhibition effect of the compound was determined from the obtained data, a concentration response curve was obtained by using the inhibition effect and the concentration of the compound, and the value of IC.sub.50 was fitted according to a four-parameter model.

(229) The activities of the compounds prepared in the embodiments against the histone deacetylases 1, 3 and 6 (i.e., HDAC 1, HDAC 3 and HDAC 6) were detected by the above methods, and the test results were shown in Table 2, where the measurements of IC50 of the compounds were classified according to the following description:

(230) “+” represents that the IC.sub.50 is measured to be greater than 500 nM;

(231) “++” represents that the IC.sub.50 is measured to be less than 500 nM but greater than 100 nM; and

(232) “+++” represents that the IC.sub.50 is measured to be less than 100 nM.

(233) TABLE-US-00002 TABLE 2 Inhibition activities of the compounds against HDAC 1, HDAC 3 and HDAC 6 Activity Compound (HDAC 1) Activity (HDAC 3) Activity (HDAC 6) 1 ND ++ +++ 2 ND ++ +++ 6 +++ ND ND 8 +++ ND ND 12 +++ ND ND 13 +++ ND ND 15 +++ ND ND 18 +++ ND ND 19 +++ ND +++ 29 +++ +++ +++ 44 ++ ++ +++

(234) where ND represents that the data is being detected and analyzed.

(235) The test results show that the compounds of the present invention have excellent inhibition activity against histone deacetylases and can be used for preventing and/or treating diseases caused by the abnormal activity of histone deacetylases, such as cell proliferation disorder diseases, autoimmune diseases, inflammations, neurodegenerative diseases or viral diseases.

Test Example 2: Cell Measurement-Cell Growth Inhibition Measurement

(236) Materials and Reagents

(237) A HepG2 cell strain and an HCT-116 cell strain were purchased from Shanghai Institutes for Biological Sciences; a DMEM high-sugar culture medium and an MEM culture medium were purchased from Hyclone; fetal calf serum was purchased from Gibco; trypsin was purchased from Invitrogen Shanghai; a CCK-8 kit was purchased from Beyotime Institute of Biotechnology; and, the remaining cell culture mediums and other consumables were purchased from Corning China.

(238) Cell Preparation Before Compound Action

(239) HepG2 cells and HCT-116 cells in the logarithmic growth phase were digested by trypsin. After the counting of uniform cell suspension, the cell density was adjusted as 1500 cells/well by a culture medium containing 10% serum. The cells were re-inoculated to a 96-well cell culture plate, and cultured to a volume of 200 μL at 37° C. in an incubator containing 5% CO.sub.2. The cells could be tested after being cultured for 24 h.

(240) Compound Action

(241) The cells cultured for 24 h were taken out from the incubator. The culture liquid in the well plate was sucked out, and 200 μL of compound solution prepared in the culture medium containing 10% fetal calf serum was added in each well. Five parallel mediums were provided for each concentration, and a DMSO culture medium was used as negative control. The culture mediums were cultured for 72 h at 37° C. in an incubator containing 5% CO.sub.2, and CCK-8 detection was performed.

(242) CCK-8 Detection

(243) A serum-free culture medium and CCK-8 solution were prepared, and CCK-8 working solution was prepared at a ratio of 10:1 (this process should be performed in dark place).

(244) The cells cultured for 72 h were taken out from the incubator. The culture liquid in the well plate was sucked out, and 120 μL of the CCK-8 working solution was added in each well. A well plate without cells was also added with 120 μL of the CCK-8 working solution to serve as blank control. The well plates were cultured for 1 h at 37° C. in an incubator containing 5% CO.sub.2 (this process should be performed in dark place).

(245) The well plates were taken out from the incubator, 100 μL of solution in each well was sucked out and added in a new 96-well plate, and the absorbance was measured at 450 nm (this process should be performed in dark place).

(246) Data Processing:

(247) $\%\mathrm{Cell}\mathrm{Viability}=\frac{100\times \left(\mathrm{Tx}-B\right)}{C-B}$

(248) where Tx is the absorbance of the CCK-8 after the compound acts for 72 h;

(249) C is the absorbance of the CCK-8 after the negative control wells are cultured for 72 h; and

(250) B is the absorbance of the CCK-8 in the blank control wells.

(251) The test results of the compounds prepared according to the embodiments during the measurement are shown in Table 3, wherein the measured highest EC.sub.50 of the compounds during one operation or multiple operations is classified according to the following description:

(252) “+” represents that EC.sub.50 of the compound is measured to be greater than 100 nM; and

(253) “++” represents that EC.sub.50 of the compound is measured to be less than 100 nM.

(254) TABLE-US-00003 TABLE 3 Inhibition activities of the compounds against cancer cells Compound HepG2 HCT-116 Compound HepG2 HCT-116 1 + ND 2 ++ ND 3 ++ ND 4 ++ ND 5 ++ ND 6 ++ ++ 7 ++ ++ 8 ++ ++ 9 ++ ND 10 ++ ND 11 ++ ND 12 ++ ++ 13 ++ ++ 14 + ND 15 ++ ++ 17 + ND 18 ++ ++ 19 ++ ++ 20 ++ ++ 21 ++ ++ 22 + ND 24 ++ ND 29 ++ ++ 44 + ND

(255) where ND represents that no test analysis has been conducted.

(256) The tests show that the compounds of the present invention have remarkable inhibition effects on cancer cells.

(257) In conclusion, the compound having a novel structure provided by the present invention shows excellent inhibition activity against histone deacetylases, has remarkable inhibition effects on cancer cells, and provides a new choice of drugs used for the clinic treatment and diseases related to the abnormal activity of histone deacetylases.