PYRROLIC AMIDE COMPOUND AND PREPARATION METHOD AND APPLICATION THEREOF

Abstract

The present invention discloses a pyrrolic amide compound shown as a formula I, or crystal forms thereof, and pharmaceutically acceptable salts, hydrates or solvates, wherein R.sub.1 is selected from hydrogen, hydroxyl, cyano, halogen, carboxyl, C.sub.1-C.sub.6 alkyl and the like; R.sub.2 is selected from hydrogen, hydroxyl, cyano, halogen and the like; R.sub.3 is selected from hydroxyl and the like; X is selected from

##STR00001##

group, m is equal to 0, 1, 2 or 3, and n is equal to 0, 1 or 2. The novel compound shown as the formular I provided by the present invention has high deacetylase inhibitory viability; and meanwhile, a method for preparing the novel compound in the present invention has the advantages of fewer steps, simple and convenient operation, safety, environment friendliness, high yield and the like and is very suitable for industrial application.

##STR00002##

Claims

1. A pyrrolic amide compound shown as a formula I, or crystal forms thereof, and pharmaceutically acceptable salts, hydrates or solvates: ##STR00076## wherein R.sub.1 is selected from hydrogen, hydroxyl, cyano, halogen, carboxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 acylamino, C.sub.2-C.sub.6 aminoacyl, C.sub.3-C.sub.6 heterocyclic radical, C.sub.3-C.sub.6 heterocyclic, alkenyl or phenoxy; R.sub.2 is selected from hydrogen, hydroxyl, cyano, halogen, carboxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 acylamino, C.sub.2-C.sub.6 aminoacyl, C.sub.3-C.sub.6 heterocyclic radical, C.sub.3-C.sub.6 heterocyclic alkenyl, phenoxy, phenyl or substituted phenyl; R.sub.3 is selected from hydroxyl, amino-substituted phenyl, thiol or epoxy ketone groups; X is selected from ##STR00077## group, m is equal to 0, 1, 2 or 3, and n is equal to 0, 1 or 2.

2. The pyrrolic amide compound or crystal forms thereof, and pharmaceutically acceptable salts, hydrates or solvates according to claim 1, wherein R.sub.1 is selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentalkoxy, hexalkoxy, formamido, acetamido, n-propionamido, isopropylamino, n-butyramido, isobutyramido, tert-butyramido, pentaneamide, hexaneamide, methylaminoacyl, ethyaminoacyl, n-propylaminoacyl, isopropylaminoacyl, n-butylaminoacyl, isobutylaminoacyl, tert-butylaminoacyl, pentylaminoacyl, hexylaminoacyl, C.sub.3 N-heterocyclic radical, C.sub.4 N-heterocyclic radical, C.sub.5 N-heterocyclic radical, C.sub.6 N-heterocyclic radical, C.sub.3 N-heterocyclic alkenyl, C.sub.4 N-heterocyclic alkenyl, C.sub.5 N-heterocyclic alkenyl, C.sub.6 N-heterocyclic alkenyl or phenoxy; R.sub.2 is selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentalkoxy, hexalkoxy, formamido, acetamido, n-propionamido, isopropylamide, n-butyramido, isobutyramido, tert-butyramido, pentaneamide, hexaneamide, methylaminoacyl, Ethylaminoacyl, n-propylaminoacyl, isopropylaminoacyl, n-butylaminoacyl, isobutylaminoacyl, tert-butylaminoacyl, pentylaminoacyl, hexylaminoacyl, C.sub.3 N-heterocyclic radical, C.sub.4 N-heterocyclic radical, C.sub.5 N-heterocyclic radical, C.sub.6 N-heterocyclic radical, C.sub.3 N-heterocyclic alkenyl, C.sub.4 N-heterocyclic alkenyl, C.sub.5 N-heterocyclic alkenyl, C.sub.6 N-heterocyclic alkenyl, phenoxy, phenyl or substituted phenyl; R.sub.1 and R.sub.2 are not simultaneously hydrogen; R.sub.3 is selected from hydroxyl, amino-substituted phenyl or thiol; m is equal to 1 or 2, and n is equal to 1 or 2.

3. The pyrrolic amide compound or crystal forms thereof, and pharmaceutically acceptable salts, hydrates or solvates according to claim 1, wherein the compound shown as the formula I refers to: ##STR00078## ##STR00079## ##STR00080##

4. A method for preparing the pyrrolic amide compound shown as the formula I, comprising the following synthetic routes: ##STR00081## ##STR00082## ##STR00083## R.sub.1 is selected from hydrogen, hydroxyl, cyano, halogen, carboxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 acylamino, C.sub.2-C.sub.6 aminoacyl, C.sub.3-C.sub.6 heterocyclic radical, C.sub.3-C.sub.6 heterocyclic alkenyl or phenoxy; is selected from hydrogen, hydroxyl, cyano, halogen, carboxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 acylamino, C.sub.2-C.sub.6 aminoacyl, C.sub.3-C.sub.6 heterocyclic radical, C.sub.3-C.sub.6 heterocyclic alkenyl, phenoxy, phenyl or substituted phenyl; R.sub.5 is selected from halogen; X is selected from ##STR00084## group, m is equal to 0, 1, 2 or 3, and n is equal to 0, 1 or 2; comprising the following steps: a, after stirring, a compound IM-4, lithium hydroxide and a mixed solvent of ether solvents or water at a temperature of 20° C.-30° C. to react for 1-6 hours, removing an organic solvent, adding water for diluting, regulating the pH value to 3-6, separating out solids, filtering to obtain solids; washing the solids with water and drying the solids, thereby obtaining N-t-butyloxycarboryl-2,5-dihydro-1H-pyrrole-3-formic acid, wherein a molar ratio of the compound IM-4 to the lithium hydroxide is (1):(1-10); a mass-volume ratio of the compound IM-4 to the mixed solvent is (1):(7-20) (m:v); and a volume ratio of the ether solvents to the water in the mixed solvent is (1-2):1; b, dissolving the N-t-butyloxycarboryl-2,5-dihydro-1H-pyrrole-3-formic acid in the step a in a halocarbon solvent at a temperature of 0° C.-5° C., adding trifluoroacetic acid, and stirring at the temperature of 20° C.-30° C. to react for 2-12 hours to obtain a reaction solution; and concentrating the reaction solution to obtain a yellow oily matter, that is, a compound IM-3, wherein a mass-volume ratio of the 1-t-butyloxycarboryl-25-dihydro-1H-pyrrole-3-formic acid to the halocarbon solvent to the trifluoroacetic acid is (1):(5-20):(2-10)(m:v:v); c, after stirring the compound IM-3 in the step b, sodium carbonate, fluorenone formyl chloride and the mixed solvent of the ether solvents and the water at the temperature of 20° C.-30° C. to react for 12-16 hours, adding water for diluting, regulating the pH value to 1-3, extracting with the ester solvents, merging an organic phase, and drying, filtering and concentrating the organic phase to obtain a compound IM-2, wherein a molar ratio of the compound IM-3 to the sodium carbonate to the fluorenone formyl chloride is (1):(1-5):(0.9-1.5); mass-volume ratio of the compound IM-3 to the mixed solvent is (1):(10-25); and a volume ratio of the ether solvents to the water in the mixed solvent is (1-2):(1); d, after stirring the compound IM-2 in the step c, O-(tetrahydro-2H-pyran-2-yl) hydramine, 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N-ethyldiisopropylamine and halocarbon solvents at a temperature of 25° C.-30° C. to react for 12-16 hours, adding water for diluting, extracting with the ester solvents, merging the organic phase, and drying, filtering and concentrating the organic phase to obtain a crude product, purifying the crude product through column chromatography, thereby obtaining a compound IM-1, wherein a molar ratio of the compound IM-2 to the O-(tetrahydro-2H-pyran-2-yl) hydramine to the 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate to the N,N-ethyldiisopropylamine is (1):(1-2):(1-2):(2-4); and a mass-volume ratio of the compound IM-2 to the halocarbon solvents is (1):(9-20):(m:v); e, after stilling the compound IM-1 in the step d, piperidine and nitrogen-containing solvents at the temperature of 25° C.-30° C. to react for 4-6 hours, adding water for diluting, extracting with the ester solvents, merging the organic phase, and drying, filtering and concentrating the organic phase, thereby obtaining a compound IM, wherein a mass-volume ratio of the compound IM-1 to the piperidine to the nitrogen-containing solvents is (1):(1-4):(5-20); f, after stirring the compound IM in the step e, triethylamine, ##STR00085## and the halocarbon solvents at the temperature of 25° C.-30° C. to react for 1-10 hours, removing the solvents to obtain a crude product, purifying the crude product through the column chromatography, thereby obtaining a compound TM-1(a), wherein a molar ratio of the compound IM to the triethylamine to ##STR00086## is (1):(1-5);(1-2), and a mass-volume ratio of the compound IM to the halocarbon solvents is or after stirring the compound IM in the step e, the triethylamine, ##STR00087## and the halocarbon solvents at the temperature of 25° C.-30° C. to react for 1-10 hours, removing the solvents to obtain a crude product, purifying the crude product through the column chromatography, thereby obtaining, a compound TM-1(b), wherein a molar ratio of the compound IM to the triethylamine to ##STR00088## is (1):(1-5):(1-2), and a mass-volume ratio of the compound IM to the halocarbon solvents is (1):(50-100):(m:v); and g, after dissolving the compound TM-1(a) in the step f in the halocarbon solvents at the temperature of 0° C.-5° C., adding the trifluoroacetic acid and stirring at the temperature of 25° C.-30° C. to react for 1-12 hours, removing the solvents to obtain a crude product, purifying the crude product through preparative high performance liquid chromatography, thereby obtaining a compound TM(a), wherein a mass-volume ratio of the compound TM-1(a) to the halocarbon solvents to the trifluoroacetic acid is (1);(50-100):(10-50)(m:v:v); or alter dissolving the compound TM-1(b) in the step fin the halocarbon solvents at the temperature of 0° C.-5° C., adding the trifluoroacetic acid and stirring at the temperature of 25° C.-30° C. to react for 1-12 hours, removing the solvents to obtain a crude product, purifying the crude product through the preparative high performance liquid chromatography, thereby obtaining a compound TM(b), wherein a mass-volume lotto of the compound TM-1(b) to the halocarbon solvents to the trifluoroacetic acid is (1):(50-100): (10-50)(m:v:v).

5. The preparation method according to claim 4, wherein the preparation method comprises the following steps: a, after stirring the compound IM-4, the lithium hydroxide and the mixed solvent of the ether solvents and water at a temperature of 25° C. to react for 2 hours, removing the organic solvent, adding water for diluting, regulating the pH value to 5, separating out solids, filtering to obtain solids: washing the solids with water and drying the solids thereby obtaining N-t-butyloxycarboryl-2,5-dihydro-1H-pyrrole-3-formic acid, wherein a molar ratio of the compound IM-4 to the lithium hydroxide is (1):(4.5-5); a mass-volume ratio of the compound IM-4 to the mixed solvent is (1):(10-12) (m:v); and a volume ratio of the ether solvents to the water in the mixed solvent is 2:1; b, dissolving the N-t-butyloxycarboryl-2,5-dihydro-1H-pyrrole-3-formic acid in the step a in a halocarbon solvent at a temperature of 0° C., adding trifluoroacetic acid, and stirring at the temperature of 25° C. to react for 2 hours to obtain a reaction solution; and concentrating the reaction solution to obtain a yellow oily matter, that is, the compound IM-3, wherein a mass-volume ratio of the N-t-butyloxycarboryl-2,5-dihydro-1H-pyrrole-3-formic acid to the halocarbon solvent to the trifluoroacetic acid is (1);(10):(4-5)(m:v:v); c, after stirring the compound IM-3 in the step h, sodium carbonate, fluorenone formyl chloride and the mixed solvent of the ether solvents and the water and stirring at the temperature of 25° C. for 12-16 hours, adding water for diluting, regulating the pH value to extracting with the ester solvents, merging an organic phase, and drying, filtering and concentrating the organic phase to obtain the compound IM-2, wherein a molar ratio of the compound IM-3 to the sodium carbonate to the fluorenone formyl chloride is 1:3:1; a mass-volume ratio of the compound IM-3 to the mixed solvent is 1:20; and a volume ratio of the ether solvents to the water in the mixed solvent is 5:3; d, after stirring the compound IM-2 in the step c, O-(tetrahydro-2H-pyran-2-yl) hydramine, 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N-ethyldiisopropylamine and halocarbon solvents at a temperature of 25° C. to react for 12-16 hours, adding water for diluting, extracting with the ester solvents, merging the organic phase, and drying, filtering and concentrating the organic phase to obtain a crude product, purifying the crude product through column chromatography, thereby obtaining the compound IM-1, wherein a molar ratio of the compound IM-2 to the O-(tetrahydro-2H-pyran-2-yl) hydramine to the 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate to the N,N-ethyldiisopropylamine is (1):(1.1):(1.2):(3); and a mass-volume ratio of the compound IM-2 to the halocarbon solvents is (1):(9-10):(m:v); e, after stirring the compound IM-1 in the step d, piperidine and nitrogen-containing solvents at the temperature of 25° C. to react for 4-6 hours, adding water for diluting, extracting with the ester solvents, merging the organic phase, and drying, filtering and concentrating the organic phase, thereby obtaining the compound wherein a mass-volume ratio of the compound IM-1 to the piperidine to the nitrogen-containing solvents is 1;2:10; f, after stirring the compound IM in the step e, triethylamine, ##STR00089## and the halocarbon solvents at the temperature of 25° C. to react for 2 hours, removing the solvents to obtain a crude product, purifying the crude product through the column chromatography, thereby obtaining, the compound TM-1(a), wherein a molar ratio of the compound IM to the triethylamine to ##STR00090## is (1):(1.4):(1-1.2), and a mass-volume ratio of the compound IM to the halocarbon solvents is (1):(80):(m:v), or after stirring the compound IM in the step e, the triethylamine, ##STR00091## and the halocarbon solvents at the temperature of 25° C. to react for 2 hours, removing the solvents to obtain a crude product, purifying the crude product through the column chromatography, thereby obtaining a compound TM-1(b), wherein a molar ratio of the compound IM to the triethylamine to ##STR00092## is (1):(1.4):(1-1.2), and a mass-volume ratio of the compound IM to the halocarbon solvents is (1):(80):(m:v); and g, after dissolving the compound TM-1(a) in the step f in the halocarbon solvents at the temperature of 0° C., adding the trifluoroacetic acid and stirring at the temperature of 25° C. to react for 2 hours, removing the solvents to obtain a crude product, and purifying the crude product through preparative high performance liquid chromatography, thereby obtaining the compound TM(a), wherein a mass-volume ratio of the compound TM-1(a) to the halocarbon solvents to the trifluoroacetic acid is (1):(60-65): (25)(m:v:v); or after dissolving the compound TM-1(b) in the step f in the halocarbon solvents at the temperature of 0° C., adding the trifluoroacetic acid and stirring at the temperature of 25° C. to react for 2 hours, removing the solvents to obtain a crude product, and purifying the crude product through the preparative high performance liquid chromatography, thereby obtaining the compound TM(b), wherein a mass-volume ratio of the compound TM-1(b) to the halocarbon solvents to the trifluoroacetic acid is (1):(60-65): (25)(m:v:v),

6. The preparation method according to claim 4, wherein R.sub.1 is selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentalkoxy, hexalkoxy, formamido, acetamido, n-propionamido, isopropylamide, n-butyramido, isobutyramido tert-butyramido, pentaneamide, hexaneamide, methylaminoacyl, Ethylaminoacyl, n-propylaminoacyl, isopropylaminoacyl, n-butylaminoacyl, isobutylaminoacyl, tert-butylaminoacyl, pentylaminoacyl, hexylaminoacyl, C.sub.3 N-heterocyclic radical, C.sub.4 N-heterocyclic radical, C.sub.5 N-heterocyclic radical, C.sub.6 N-heterocyclic radical, C.sub.3 N-heterocyclic alkenyl, C.sub.4 N-heterocyclic alkenyl, C.sub.5 N-heterocyclic alkenyl, C.sub.6 N-heterocyclic alkenyl or phenoxy; R.sub.2 is selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentalkoxy, hexalkoxy, formamido, acetamido, n-propionamido, isopropylamide, n-butyramido, isobutyramido, tert-butyramido, pentaneamide, hexaneamide, methylaminoacyl, Ethylaminoacyl, n-propylaminoacyl, isopropylaminoacyl, n-butylaminoacyl, isobutylaminoacyl, tert-butylaminoacyl, pentylaminoacyl, hexylaminoacyl, C.sub.3 N-heterocyclic radical, C.sub.4 N-heterocyclic radical, C.sub.5 N-heterocyclic radical, C.sub.6 N-heterocyclic radical, C.sub.3 N-heterocyclic alkenyl, C.sub.4 N-heterocyclic alkenyl, C.sub.5 N-heterocyclic alkenyl, C.sub.6 N-heterocyclic alkenyl, phenoxy, phenyl or substituted phenyl; R1 and R.sub.2 are not simultaneously hydrogen; R.sub.3 is selected from fluorine, chlorine, bromine or iodine; m is equal to 1 or 2, and n is equal to 1 or 2.

7. The preparation method according to claim 6, wherein the ##STR00093## refers to: ##STR00094##

8. The preparation method according to claim 4, wherein in the steps a-g, the ether solvents refer to any one or more of tetrahydrofuran, diethyl ether, tert-butyl methyl ether, isopropyl ether and butyl ether; the halocarbon solvents refer to any one or more of dichloromethane, chloroethane, dichloroethane, trichloromethane and carbon tetrachloride; the ester solvents refer to any one or more of ethyl acetate and ethyl formate; and the nitrogen-containing solvents refer to any one or more of N,N-dimethylformamide, N,N-dimethyl-acetamide, acetonitrile and pyridine.

9. An application of the pyrrolic amide compound or crystal forms thereof and the pharmaceutically acceptable salts, hydrates or solvates according to claim 1 in preparation of histone deacetylase inhibitor medicines.

10. The application according to claim 9, wherein the histone deacetylase inhibitor medicines refer to medicines for treating diseases caused by histone deacetylase viability abnormality.

11. The application according to claim 10, wherein the diseases refer to any one or mote of cell proliferative diseases, autoimmune diseases, inflammations, neurodegenerative diseases or viral diseases.

12. The application according to claim 11, wherein the diseases refer to cancers.

13. A pharmaceutical composition for inhibiting the histone deacetylase viability, referring to a preparation prepared by taking the pyrrolic amide compound or crystal forms thereof and the pharmaceutically acceptable salts, hydrates or solvates according to claim 1 as active ingredients and adding pharmaceutically common excipients or auxiliary ingredients.

14. The pharmaceutical composition according to claim 13, wherein the preparation comprises an oral administration preparation, a sublingual administration preparation, a buccal administration preparation, a transdermal absorption preparation or an injection preparation.

Description

DETAILED DESCRIPTION

[0138] Raw materials and devices used in specific embodiments of the present invention are known products and are obtained by purchasing commercially-available products.

Embodiment 1

Preparation of 1-(4-cyanobenzene)sulfonyl)-N-hydroxy-2,5-dihydro-1H-pyrrole-3-formamide

1. Preparation of 2,5-dihydro-1H-pyrrole-3-formic acid

[0139] ##STR00050##

[0140] comprising the following steps: dissolving N-t-butyloxcarboryl-2,5-dihydro-1H-pyrrole-3-ethyl formate (8.5 g, 36 mmol; manufacturer: Accela ChemBio Co. Ltd.) in a mixed solution of 60 mL of tetrahydrofuran and 30 mL of water, and then adding lithium hydroxide (4.2 g, 176 mmol); after stirring at a temperature of 25° C. to react for 2 hours, removing an organic solvent in vacuum to obtain residues; adding a proper amount of water into the residues for diluting, regulating the pH value to 5 by using IN of hydrochloric acid, separating out solids, and filtering to obtain solids; washing the solids with water and thereby obtaining white solid N-t-butyloxycarboryl-2,5-dihydro-1H-pyrrole-3-formic acid (7.0 g, 93% yield);

[0141] MS(ESI)m/z214(m+1).sup.+.

[0142] dissolving N-t-butyloxycarboryl-2,5-dihydro-1H-pyrrole-3-formic acid (7 g, 36 mmol) in 70 mL of dichloromethane solution in an ice bath, dripping 30 mL of trifluoroacetic acid, stirring, slowly rising to the temperature of 25° C., and continuously stirring to react for 2 hours to obtain a reaction solution; and concentrating the reaction solution, thereby obtaining a yellow oily matter 2,5-dihydro-1H-pyrrole-3-formic acid(4.0 g, 99% yield);

[0143] MS(ESI)m/z114(M+1).sup.+.

2, Preparation of N-fluorenyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-formic acid

[0144] ##STR00051##

[0145] comprising the following steps: dissolving 2,5-dihydro-1H-pyrrole-3-formic acid (4.0 g, 35.4 mmol) it 50 mL of tetrahydrofuran and 30 mL of water; then adding sodium carbonate (11.2 g, 106 mmol) and fluorenone formyl chloride (9.2 g, 35.4 mmol; manufacturer; Alfa Aesar (China) Chemical Co., Ltd.); stirring at a temperature of 25° C. to react and stay overnight (“to react and stay overnight” in the present invention refers to that the reaction time is more than 8 hours at least); and adding 200 mL of water for diluting after reaction completion, regulating the pH value to 1 by using 2N of hydrochloric acid, extracting with ethyl acetate, merging an organic phase, drying, the organic phase, filtering and performing vacuum concentration, thereby obtaining white solid N-fluorenyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-formic acid (11.0 g, 92% yield);

[0146] MS (EST) m/z336(M+1).sup.+.

3, Preparation of N-fluorenyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide

[0147] ##STR00052##

[0148] comprising Ire following steps: dissolving N-fluorenyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-formic acid (11.0 g, 32.8 mmol) in 100 mL of dichloromethane, sequentially adding O-(tetrahydro-2H-pyran-2-yl)hydramine (4.2 g, 36 mmol), HATU (1.5 g, 39.4 mmol), DIEA (12.8 g, 98.4 mmol; manufacturer; J&K Scientific LTD.), stirring at a temperature of 25° C. to react and stay overnight to obtain a reaction solution; adding 50 mL of water into the reaction solution for diluting, extracting with ethyl acetate (50 mL×2), merging an ethyl acetate phase, drying the ethyl acetate phase, and filtering and concentrating to obtain a crude product; and purifying the crude product through column chromatography, thereby obtaining white solid N-fluorenyloxycarbonyl-2,5-dihydro-1H-pyrrole-3 -(tetrahydropyrane-2-oxo)-formamide(12 g, 48% yield);

[0149] MS (ESI) m/z435(M+1).sup.−.

4. Preparation of 2,5-dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide

[0150] ##STR00053##

[0151] comprising the following steps: dissolving

[0152] N-fluorenyloxycarbonyl-2,5-dihydro-1H-pyrrole-3 -(tetrahydropyrane-2-oxo)-formamide (10 g, 23 mmol) in 100 mL of DMF; then adding 20 mL of piperidine, stirring at a temperature of 25° C. to react for 4 hours, adding 800 mL of water for diluting, extracting with ethyl acetate, and merging an organic phase; and drying, filtering and concentrating the organic phase, thereby obtaining white solid 2,5-dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide(4.5 g, 92% yield);

[0153] MS (ESI) m/z213(M+1).sup.−.

5. Preparation of 1-((4-cyanobenzene)sulfonyl)-N-hydroxy-2,5-dihydro-1H-pyrrole-3-formamide

[0154] ##STR00054##

[0155] comprising the following steps: Dissolving 2,5-dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide(100 mg,0.5 mmol) and triethylamine (66 mg, 0.7 mmol) in dichloromethane (8 mL), adding 4-cyanobenzene-1-sulfonyl chloride(125 mg, 0 5 mmol; manufacturer: J&K Scientific LTD.) into a reaction solution at a temperature of 25° C.; after stirring at the temperature of 25° C. to react for 2 hours, concentrating to remove a solvent to obtain crude product; and purifying the crude product through column chromatography, thereby obtaining white solid 1 -((4-cyanobenzene)sulfonyl)-N-((tetrahydro-2H-pyran-2-y)oxo)-2,5-dihydro-1H-pyrrole-3-formamide(80 mg, 39% yield);

[0156] dissolving 1-((4-cyanobenzene)sulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxo)-2,5 -dihydro-1H-pyrrole-3-formamide(80 mg, 0.3 mmol) in 5 mL of dichloromethane solution in an ice bath, dripping 2 mL of trifluoroacetic acid, stirring, slowly rising to a temperature of 25° C., and continuously stirring to react for 2 hours, concentrating to remove a solvent to obtain a crude product; and purifying the crude product through preparative high performance liquid chromatography, thereby obtaining white solid 1-((4-cyanobenzene)sulfonyl)-N-hydroxy-2,5-dihydro-1H-pyrrole-3-formamide (13 mg, 25% yield).

[0157] MS (ESI)m/z294(M+1).sup.+.

[0158] 1HNMR (400 MHz. DMSO-d6) δ10.80 (br s. 1H). 8.13-8.11 (m, 2H), 8.02-8.00 (m, 2H), 6.32 (s, 1H). 422-4.21 (d, J=2.4 Hz. 4H).

Embodiment 2

Preparation of N-hydroxy-1-(benzenesulfonyl)-2,5-dihydro-1H-pyrrole-3-formamide

[0159] ##STR00055##

[0160] comprising the following step: preparing white solid N-hydroxy-1-(benzenesulfonyl)-2,5-dihydro-1H-pyrrole-3-formamide(18 mg, 14% yield) according to similar steps in embodiment 1 by taking 2,5-dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide (100 mg, 0 5 mmol) and benzene sulfonyl chloride (100 mg, 0.6 mmol; manufacturer: J&K Scientific LTD.) as raw materials;

[0161] MS (ESI)m/z269(M+1).sup.+.

[0162] .sup.1HNMR (400 MHz, DMSO-d.sub.6)δ10.80(br s, 1H),9.0(br s, 1H), 7.84-7.82(d,J=7.6 Hz,2H), 7.74-7.70(m, 1H), 7.66-7.62(m, 2H), 6.30 (s, 1H), 4.17(s, 4H).

Embodiment 3

Preparation of N-hydroxy-1((4-phenoxyphenyl)sulfonyl)-2,5-dihydro-1H-pyrrole-3-formamide

[0163] ##STR00056##

[0164] comprising the following step: preparing white solid N -hydroxy-1((4-(trifluoromethoxy)phenyl)sulfonyl)-2,5-dihydro-1H-pyrrole-3 -formamide (26 mg 16 yield) according to similar steps in embodiment 1 by taking 2,5-dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide (100 mg 0.5 mmol) and 4-phenoxybenzenesulfonyl chloride (125 mg, 0.6 mmol; manufacturer: J&K Scientific LTD.) as raw materials;

[0165] MS (ESI) m/z361 (M+1).sup.+.

[0166] .sup.1HNMR(400 MHz, DMSO-d.sub.6) δ 10.82(br s, 1H), 9.02(br s, 1H), 7.84-7.82(m, 2H), 7.50-7.46(m, 2H),7.30-7.26(m, 1H), 7.18-7.12(m, 4H), 6.34(s, 1H), 4.16(s, 4H).

Embodiment 4

Preparation of N-hydroxy-1-((4-acetamido-3-chlorphenyl)sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide

[0167] ##STR00057##

[0168] comprising the following step: preparing white solid N -hydroxy-1-((4-acetamido-3-chlorphenyl)sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide (47 mg, 10.7% yield) according to similar steps in embodiment 1 by taking 2,5-dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide (100 mg, 0.5 mmol) and 4-acetamido-3-chlorobenzenesulfonyl chloride (150 mg, 0.6 mmol; manufacturer J&K. Scientific LTD.) as raw materials;

[0169] MS (ESI) m/z360(M+1).sup.+.

[0170] .sup.1HNMR(400 MHz, CD.sub.2OD) δ 8.25-8.23(d, J=8.8 Hz, 1H), 7.74(d, J=0.8 Hz, 1H), 7.80-7.78(m, 1H), 6.38(s, 1H), 4.28(s, 4H),2.25(s, 3H).

Embodiment 5

Preparation of N-hydroxy-1-((2,3-dihydrobenzo[b][1,4]dioxin)-6-sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide

[0171] ##STR00058##

[0172] comprising the following step: preparing white solids N-hydroxy-1-((2,3-dihydrobenzo[b][1,4]dioxin)-6-sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide (12 mg., 8.0% yield) according to similar steps in embodiment 1 by taking 2,5-dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide (100 mg, 0.5 mmol) and 2,3-dihydrobenzo[b][1,4]dioxin-6-sulfonyl chloride (132 mg, 0.6 mmol; manufacturer: J&K Scientific LTD.) as raw materials;

[0173] MS (ESI) m/z327(M+1).sup.+.

[0174] .sup.1HNMR(400 MHz, DMSO-d.sub.6) δ 10.80(s, 1H), 9,05(br s, 1H), 7.31-7,26(m, 2H), 7.09-7.07(d, J=8.4 Hz, 1H), 632 (s, 1H), 4.34-43.1(m, 4H),4.14(s, 4H).

Embodiment 6

Preparation of N-hydroxy-1-((2,3-dihydrobenzofuran)-6-Sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide

[0175] ##STR00059##

[0176] comprising the following step: preparing white solid N-hydroxy-1-((2,3-dihydrobenzofuran)-6-sulfonyl)2, 5-dihydro-1H-pyrrole:-3-formamide (10 mg 6.8% yield) according to similar steps in embodiment 1 by taking 2,5-dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide (100 mg, 0.5 mmol) and 2,3-dihydrobenzofuran-6-sulfonylchloride (123 mg, 0.6 mmol; manufacturer: J&K Scientific LTD.) as raw materials;

[0177] MS (ESI) m/z311(M+1).sup.+.

[0178] .sup.1HNMR(400 MHz, DMSO-d.sub.6) δ 10.82(s, 1H), 9,05(br s, 1H), 7.69(d, J=1.6 Hz, 1H),7.59-7.57(m, 1H),6.96-6.94(d, J=8.4 Hz, 1H),6.31 (s, 1H),4.67-4.62(t, J=8.8 Hz, 2H)4.13(s, 4H), 3.29-3.24), (t, J=8.8 Hz, 2H).

Embodiment 7

Preparation of N-hydroxy-1-((4-formyl)-benzenesulfonyl)2,5-dihydro-1H-pyrrole-3-formamide

[0179] ##STR00060##

[0180] comprising the following step: preparing white solid N-hydroxy-1-((4-formyl)-benzenesulfonyl)2,5-dihydro-1H-formamide (116 mg, 79% yield) according to similar steps in embodiment 1 by taking 2,5-dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide (100 mg, 0.5 mmol) and 4-(chlorosulfonyl) benzoic acid (124 mg, 0.6 mmol; manufacturer: J&K Scientific LTD.) as raw materials;

[0181] MS (ESI) m/z313(M+1).sup.+.

[0182] .sup.1HNMR(400 MHz, DMSO-d.sub.6) δ 10.81 (br s, 1H), 9.05(br s, 1H),8.16-8.14 (d, J=8.4 Hz, 2H), 7.96-7.94(d, J=8.4 Hz, 3H), 6.32(s, 1H), 4.40 (s, 4H).

Embodiment 8

Preparation of N-hydroxy-1-((4-(tert-butyl)phenyl)sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide

[0183] ##STR00061##

[0184] comprising the following step: preparing white solid N-hydroxy-1-((4-(tert-butyl)phenyl)sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide (10 mg, 6% yield) according to similar steps in embodiment 1 taking 2,5 -dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide (100 mg, 0.5 mmol) and 4-(tert-butyl)phenyl)sulfonyl chloride (130 mg, 0.6 mmol; manufacturer J&K Scientific LTD.) as raw materials;

[0185] MS (ESI) m/z325(M+1).sup.+.

[0186] .sup.1HNMR(400 Hz, CD.sub.3OD) δ 7.81-7.79(m, 2H), 7.69-7.67(m, 2H), 6.36(s, 1H), 4.26(s, 4H), 1.37(s, 9H).

Embodiment 9

Preparation of N-hydroxy-1-((4-(methylamine carbonyl)phenyl)sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide

[0187] ##STR00062##

[0188] comprising the following step: preparing white solid N-hydroxy-((4-methylamine carbonyl)phenyl)sulfonyl)2,5 -dihydro-1H-pyrrole-3-formamide(25 mg 16% yield) according to similar steps in embodiment 1 by taking 2,5-dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide (100 mg, 0.5 mmol) and 4-(methylamine carbonyl) benzene sulfonyl chloride (128 mg, 0.6 mmol; manufacturer: J&K Scientific LTD.) as raw materials;

[0189] MS (ESI) m/z326(M+1).sup.+.

[0190] .sup.1HNMR(400 MHz, DMSO-d.sub.6)δ 11.81(br s, 1H), 9.05(br s, 1H)8.67(br s, 1H), 8.04-8.02 (d, J=8.4 Hz. 2H), 7.93-7.91(d, J=8.4 Hz, 3H), 6.32(s, 1H), 4.20 (s, 4H).

Embodiment 10

Preparation of N-hydroxy-1-((4-acetamidophenyl)sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide

[0191] ##STR00063##

[0192] comprising the following step: preparing white solid N-hydroxy-1((4-acetamidophenyl)sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide (15 mg, 9.6% yield) according to similar steps in embodiment 1 by taking 2,5-dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide (100 mg, 0.5 mmol) and 4-(acetamido) benzene sulfonyl chloride (128 mg, 0.6mmol; manufacturer: J&K Scientific LTD.) as raw materials;

[0193] MS (ESI) m/z326(M+1).sup.−.

[0194] .sup.1HNMR(400 MHz, CD3OD) δ 7.82(s, 4H), 6.38(s, 1H),4.25(s, 4H), 2.17 (s, 3H).

Embodiment 11

Preparation of N-hydroxy-1-((4-fluorophenyl)sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide

[0195] ##STR00064##

[0196] comprising the following step: preparing white solid N-hydroxy-1-((4-fluorophenyl)sulfonyl)2,5-dihydro-1H-pyrrole-3 -formamide (33 mg,25% yield) according to similar steps in embodiment 1 by taking 2,5 -dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide (100 mg, 0.5 mmol) and 4-fluoro-benzene-sulfonyl chloride (109 mg, 0.6 mmol; manufacturer: J&K Scientific LTD.) as raw materials;

[0197] MS (ESI) m/z 287(M+1).sup.+.

[0198] .sup.1HNMR(400 Hz.,CD3OD) δ 7.96-7.93(d, J=4.8, 8.0 Hz, 2H),7.39-7.35(m, 2H), 6.4(s, 1H), 4.3(s, 4H).

Embodiment 12

Preparation of N-hydroxy-1-((3-fluorophenyl)sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide

[0199] ##STR00065##

[0200] comprising the following step: preparing white solid N-hydroxy-1-((3-fluorophenyl)sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide (33 mg,25% yield) according to similar steps in embodiment 1 by taking 2,5-dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide (100 mg,0.5 mmol) and 3-fluorobenzenesulfonyl chloride (109 mg, 0.6 mmol; manufacturer: J&K Scientific LTD.) as raw materials:

[0201] MS (ESI) m/z 287(M+1).sup.+.

[0202] .sup.1HNMR(400 Hz, CD3OD) δ 8.17-8.12 (m, J=8.0 Hz, 2H), 8.03-8.01(d, 1H), 7.89-7.85(m, 1H), 6.38(s, 1H) 4.31(s, 4H).

Embodiment 13

Preparation of N-hydroxy-1-((4-methoxyphenyl)sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide

[0203] ##STR00066##

[0204] comprising the following step: preparing white solid N-hydroxy-1-((4-methoxyphenyl)sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide (34 mg, 23% yield) according to similar steps in embodiment 1 by taking 2,5-dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide (100 mg, 0.5 mmol) and 4-methoxybenzenesulfonyl chloride (123 mg, 0.6 mmol; manufacturer: J&K Scientific LTD.) as raw materials;

[0205] MS (ESI) m/z 299(M+1).sup.+.

[0206] .sup.1HNMR(400 Hz, CD3OD) δ=7.828-7.805(d, J=8 Hz, 2H), 7.145-7.123(d, J=8.8 Hz), 2H),6.432(s, 1H), 4.242(s, 4H), 3.896(s, 3H),

Embodiment 14

Preparation of N-hydroxy-1-((3-methoxyphenyl)sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide

[0207] ##STR00067##

[0208] comprising the following steps: preparing white solid N-hydroxyl-1-((3-methoxyphenyl)sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide (36 mg, 24% yield) according to similar steps m embodiment 1 by taking 2,5-dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide (100 mg, 0.5 mmol) and 3-methoxybenzenesulfonyl chloride (123 mg, 0.6 mmol; manufacturer: J&K Scientific LTD.) as raw materials;

[0209] LC-MS(ESI) m/z 299 (M+H).sup.+.

[0210] .sup.1HNMR (400 Hz, DMSO-D.sub.6) δ 10.80(s, 1H), 9.02(s, 1H), 7.59-7.55(m, 1H), 7.41-7.39(d, J=8 Hz, 1H), 7.30-7.27(m, 2H), 6.35(s, 1H), 4.19(s, 4H), 3.85(s, 3H).

Embodiment 15

Preparation of N-hydroxy-1-((4-methylphenyl)sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide

[0211] ##STR00068##

[0212] comprising the following steps: preparing white solid N-hydroxy-1-((4-methylphenyl)sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide (26 mg, 19% yield) according to similar steps in embodiment 1 by taking 2,5 -dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide (100 mg,0.5 mmol) and 4-toluene sulfonyl chloride (114 mg, 0.6 mmol; manufacturer: J&K Scientific LTD.) as raw materials;

[0213] MS (ESI) m/z 283(M+1 ).sup.+.

[0214] .sup.1HNMR (400 MHz, CD.sub.3OD) δ=7.76 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 635 (s, 1H), 4.25 (s, 4H), 2.45 (s, 3H).

Embodiment 16

Preparation of N-hydroxy-1-((3-methylphenyl)sulfonyl)2,5-dihydro-1H-pyrrole-1H-3-formamide

[0215] ##STR00069##

[0216] comprising the following step: preparing white solid N-hydroxy-1-((3-methylphenyl)sulfonyl)2,5-dihydro-1H -pyrrole-3 -formamide (24 mg, 18% yield) according to similar steps in embodiment 1 by taking 2,5-dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide (100 mg,0.5 mmol) and 3-toluene sulfonyl chloride (114 mg, 0.6 mmol; manufacturer: J&K Scientific LTD.) as raw materials;

[0217] MS (ESI) m/z 283(M+1).sup.+.

[0218] .sup.1HNMR (400 MHz, CD.sub.3OD) δ=7.70-7.66 (m, 2H), 7.52-7.51 (m, 2H), 6.36 (s, 1H), 4.26 (s. 4H), 2.46 (s, 3H).

Embodiment 17

Preparation of N-hydroxy-1-(3, 4-dimethoxyphenyl)sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide

[0219] ##STR00070##

[0220] comprising the following step: preparing white solid N-hydroxy-1-((3, 4-dimethoxyphenyl)sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide (24 mg, 18% yield) according to similar steps in embodiment 1 by taking 2,5-dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide (100 mg, 0.5 mmol) and 3,4-dimethoxybenzenesulfonyl chloride (114 mg, 0.6 mmol; manufacturer: J&K Scientific LTD.) as raw materials;

[0221] MS (ESI) m/z 329(M+1).sup.+.

[0222] .sup.1HNMR(400 Hz, DMSO-D.sub.6) δ=10.80(s, 1H), 9.13(s, 1H), 7.50-7.48(m, 1H), 7.31-7.24(m, 2H), 6.38(s, 1H), 4.24(s, 4H), 3.92(s, 3H).

Embodiment 18

Preparation of N-hydroxy-1-((4-(1,2,36-tetrahydropyridine-4-yl)phenyl)sulfonyl)2,5-dihydro-1H -pyrrole-3-formamide

[0223] ##STR00071##

[0224] comprising the following step: preparing white solid N-hydroxy-1((4-(1,2,36-tetrahydropyridine-4-yl)phenyl)sulfonyl)2,5-dihydro-1H-pyrrole-3-formamide (26 mg, 15% yield) according to similar steps in embodiment 1 by taking 2,5-dihydro-1H-pyrrole-3-(tetrahydropyrane-2-oxo)-formamide (1000 mg,0.5 mmol) and 4-(1,2,36-tetrahydropyridine-4-yl)phenyl) sulfonyl chloride (114 mg, 0.6 mmol; manufacturer: J&K Scientific LTD.) as raw materials:

[0225] MS (ESI) m/z 350(M+1).sup.+.

Embodiment 19

Preparation of N-(2-aminophenyl)-1-(benzenesulfonyl)-2,5-dihydro-1H-pyrrole-3-formamide

1. Preparation of 2,5-dihydro-1H-pyrrole-3-ethyl formate

[0226] ##STR00072##

[0227] comprising the following steps: dissolving N-t-butyloxycarboryl-2,5-dihydro-1H-pyrrole-3-ethyl formate (250 mg, 1.1 mmol) in 5 mL of dichloromethane solution in an ice bath, dripping 2 mL of trifluoroacetic acid, stirring, slowly rising to the temperature of 25° C., and continuously stirring to react for 2 hours to obtain a reaction solution; and concentrating the reaction solution to obtain a yellow oily matter 2,5-dihydro-1H-pyrrole-3-ethyl formate (150 mg, 99% yield).

[0228] MS (EST) m/z 142(M+1)+.

2. Preparation of 1-phenyl sulfonyl-2,5-dihydro-1H-pyrrole-3-ethyl formate

[0229] ##STR00073##

[0230] comprising the following steps: slowly adding benzene sulfonyl chloride (222 mg, 1.3 mmol) into a dichloromethane (10 mL) solution of 2,5-dihydro-1H-pyrrole-3-ethyl formate (150 mg, 1.1 mmol) and triethylamine (310 mg, 3.1 mmol) in an ice bath, slowly rising to the temperature of 25° C., and after continuously stirring to react for 2 hours, adding 10 mL of water to carry out a quenching reaction to obtain a reaction solution; extracting with ethyl acetate (50 mL+2), merging an organic phase, washing with a saturated salt solution (10 mL+2), and drying, filtering and concentrating the organic phase to obtain a crude product; and purifying the crude product through column chromatography (silica gel, a ratio of petroleum ether to ethyl acetate is 6:1), thereby obtaining a white solid compound 1-phenyl sulfonyl-2,5-dihydro-1H-pyrrole-3-ethyl formate (280 mg, 94% yield).

[0231] MS (ESI) m/z 281(M+1).sup.+.

3. Preparation of 1-phenyl sulfonyl-2,5-dihydro-1H-pyrrole-3-formic acid

[0232] ##STR00074##

[0233] comprising the following steps: adding LiOH (179 mg, 4.5 mmol) into a solution of tetrahydrofuran (12 mL) and water (4 mL) of 1-phenyl sulfonyl-2,5-dihydro-1H-pyrrole-3-ethyl formate (280 mg, 1.0 mmol) at a temperature of 25° C. and stirring to stay overnight to obtain a reaction solution; then regulating the pH value of the reaction solution to 2 in an ice bath by using IN of hydrochloric acid, extracting with ethyl acetate (10 mL×3), and merging an organic phase; and drying, filtering and concentrating the organic phase, thereby obtaining 1-phenyl sulfonyl-2,5-dihydro-1H-pyrrole-3-formic acid (223 mg, 64% yield), wherein the obtained product does not need to be further purified and is directly used for the next reaction step.

[0234] MS (ESI) m/z 267(M+1).sup.+.

4. Preparation of N-(2-aminophenyl)-1-(benzenesulfonyl)-2,5-dihydro-1H-pyrrole-3-formamide

[0235] ##STR00075##

[0236] comprising the following steps: dissolving 1-phenyl sulfonyl-2,5-dihydro-1H-pyrrole-3,formic acid (223 mg, 0.6 mmol) 10 mL of dichloromethane, sequentially adding 1,2-diaminobenzene (104 mg, 0.9 mmol), HATU (338 mg 0.9 mmol) and DIEA (229 mg, 1.8 mmol) into the solution, and stirring at a temperature of 25° C. to stay overnight to obtain a reaction solution; diluting the reaction solution with 20 mL of water, extracting with ethyl acetate (50 mL×2), and merging an organic phase; drying, filtering and concentrating the organic phase to obtain a crude product and purifying the crude product through preparative high performance liquid chromatography, thereby obtaining N-(2-aminophenyl)-1-(benzenesulfonyl)-2,5-dihydro-1H-pyrrole-3-formamide (52 mg, 22% yield).

[0237] MS (EST) m/z 344(M+1).sup.+.

[0238] .sup.1HNMR(400 MHz, CD3OD). δ9.5(br s, 1H),7.9-7.8(m, 2H),7.7-7.6(m, 3H), 7.1-7.0(m, 4H), 6.7(s, 1H), 4.3(s, 4H).

[0239] In order to describe the beneficial effects of the present invention, the present invention provides the following test examples:

Test example 1 Detection of biological viability

[0240] HDAC inhibitory viabilities of the compounds in the present invention are detected in detection of substrate deacetylation.

[0241] A: Detection of enzyme viability of histone deacetylase 6 (#50076, BPS Bioscience):

[0242] Acetyl of HDAC 6 on a substrate is removed, so that the substrate is activated and can be affected by a subsequently added developing solution, and fluorophore is released. The size of a fluorescence signal reflects the viability of the HDAC 6. An IC50 detection method of the enzyme is disclosed in Chuping Xu, Elisabetta Soragni improved Histone Deacetylase Inhibitors as Therapeutics for the Neurdegenerative DiseaseEriedreich's Ataxia: A New Synthetic Route. A total reaction system (100 μL/well) contains 0.35 ng/μL of HDAC 6, 20 μM of substrate and compounds of different concentrations. The fluorescence signal is measured within 30 minutes after incubation at a temperature of 37° C., inhibitory effects of the compounds are determined from the obtained data and mapped with the compound concentrations to obtain a concentration response curve, and the IC50 value is fitted according to a four-parameter model.

[0243] B: Detection of enzyme viability of histone deacetylase 3 (#50003, BPS Bioscience):

[0244] Acetyl of HDAC 3 on a substrate is removed, so that the substrate is activated and can be affected by the developing solution, and fluorophore is released. The size of a fluorescence signal reflects the viability of the HDAC 3. An IC50 detection method of the enzyme is disclosed in Chuping Xu, Elisabetta Soraeni Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurdegenerative DiseaseFriedreich's Ataxia: A New Synthetic Route. A total reaction system (100 μL/well) contains 0.16 ng/μL of HDAC 3, 10 μM of substrate and compounds of different concentrations. The fluorescence signal is detected at Ex/Em=360/460 on line, inhibitory effects of the compounds are determined from the obtained data and mapped with the compound concentrations to obtain a concentration response curve, and the IC50 value is fitted according to a four-parameter model.

[0245] The compounds 1-19 prepared in the embodiments are subjected to detection of enzyme viability of histone deacetylase 6 (i.e., HDAC6) according to the method above. Test results are shown in Table 2, wherein the measured IC50 values of the compounds are classified as specified, as shown in Table 2:

[0246] “+” indicates that the measured IC50 of HDAC6 is more than 500 nM;

[0247] “++” indicates that the IC50 of HDAC6 is less than 300 nM and more than 100 nM;

[0248] “+++” indicates that the IC50 of HDAC6 is less than 100 nM.

[0249] The compounds 1-19 prepared in the embodiments are subjected to detection of enzyme viability of histone deacetylase 3 (i.e., HDAC3) according to the method above. Test results are shown in Table 2, wherein the measured IC50 values of the compounds are classified as specified, as shown in Table 2:

[0250] “+” indicates that the measured IC50 of HDAC3 is more than 1000 nM;

[0251] “++” indicates that the IC50 of HDAC3 is mare than 100 nM and less than 1000 nM;

[0252] “+++” indicates that the IC50 of HDAC3 is less than 100 nM.

TABLE-US-00002 TABLE 2 Inhibitory Viabilities of Compounds an HDAC6 & HDAC3 Viability Compound Viability (HDAC6) (HDAC3) 1 ++ N.D. 2 +++ + 3 ++ ++ 4 +++ ++ 5 +++ + 6 +++ ++ 7 +++ N.D. 8 +++ ++ 9 +++ N.D. 10 +++ N.D. 11 +++ N.D. 12 +++ N.D. 13 +++ N.D. 14 +++ N.D. 15 +++ N.D. 16 +++ N.D. 17 ++ N.D. 18 ++ N.D. 19 + N.D. ND: data is in detection and analysis.

[0253] The tests indicate that the compounds 1-19 in the present invention have excellent histone deacetylase inhibitory viabilities and can be effectively used for treating diseases related to abnormal histone deacetylase viability.

Test example 2 Cell determination-determination of cell growth inhibition

[0254] Materials and reagents HepG2 cell strains, Hep3B cell strains, Huh7 cell strains and Li7 cell strains are purchased from Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences; DMEM high glucose media and MEM media are purchased from Hyclone; fetal calf serum is purchased from Gibco Company; trypsin is purchased from Invitrogen Shanghai; CCK-8 kits are purchased from Beyotime Institute of Biotechnology; and other consumables such as cell-culture dishes and the like are purchased from Corning China.

[0255] Cell preparation before compound effect

[0256] comprising the steps: digesting HepG2 cells, Hep3B Huh7 cells and Li7 cells in logarithmic phases by using the trypsin; after counting the cells by taking uniform cell suspension, adjusting cell density to 1500 cells/pore by using a culture medium containing 10% of serum, and re-inoculating into a 96-pore cell culture plate, wherein the culture volume is 200 μL; incubating in a 5% CO.sub.2 incubator at a temperature of 37° C.; and culturing for 24 hours for experiments.

[0257] Compound effect

[0258] comprising the steps: taking the cells cultured for 24 hours from the incubator, sucking culture solution in the pore plate, adding 200 μL of compound solution prepared by using a culture medium containing 10% of the fetal calf serum into each pore, enabling five pores of each concentration to be parallel, setting DMSO at negative control, and incubating in the 5% CO.sub.2 incubator at a temperature of 37° C. for 72 hours for performing CCK-8 detection.

[0259] CCK-8 detection

[0260] comprising the steps: taking a serum-free medium and a CCK-8 solution, and preparing a CCK-8 working solution according to a ratio of 10:1 (the process needs to be protected from light);

[0261] taking the cells cultured for 72 hours from the incubator, sucking culture solution in the pore plate, adding 120 μL of the CCK-8 working solution into each pore, adding 120 μL of the CCK-8 working solution into a cell-free pore plate to serve as blank control, and incubating in the 5% CO.sub.2 incubator at a temperature of 37° C. for one hour (the process needs to be protected from light ); and

[0262] taking the pore plate from the incubator, sucking 100 μL of solution from each pore into a new 96-pore plate, and reading absorbancy at 450 nm (the process needs to he protected from light).

[0263] Data processing:

[00001]$\%.Math..Math.\mathrm{Cell}.Math..Math.\mathrm{Viability}=\frac{100\times \left(\mathrm{Tx}-B\right)}{C-B}$

[0264] Tx: absorbancy measured in CCK-8 within 72 hours after compound effect

[0265] C: absorbancy measured m CCK-8 within 72 hours after culturing in negative control pores

[0266] B: absorbancy measured CCK-8 in blank control pores

[0267] The compounds 1-19 prepared in the embodiments are operated in the above determination, and test results are shown in Table 3, wherein the highest measured IC50 values of the various compounds during single or multiple operations are classified as specified, as shown in Table 3:

[0268] “+” indicates that the measured IC50 values of the compounds in cancer cells are more than 10 uM;

[0269] “++” indicates that the measured IC50 values of the compounds in the cancer cells are less than 10 uM;

TABLE-US-00003 TABLE 3 Inhibitory Viabilities of Compounds on Different Hepatoma Cells Compound HepG2 Huh-7 Li-7 Hep3B 1 + + + + 2 + + + + 3 + + + + 4 + + + + 5 + + + + 6 + + + + 7 + + + + 8 + + + + 9 + + + + 10 + + + + 11 + + + + 12 ++ + + + 13 ++ + ++ ++ 14 ++ + ++ ++ 15 ++ + ++ ++ 16 ++ + + + 17 + + + + 18 + + + + 19 + + + +

[0270] The tests indicate that the compounds 1-19 in the present invention have excellent inhibitory viabilities on different hepatoma carcinoma cells (HepG2, Huh-7, Li-7 and Hep3B).

[0271] In conclusion, the novel compound shown as the formula I disclosed in the present invention shows good histone deacetylase inhibitory viability, and a novel medicinal possibility is provided for clinically treating diseases related to abnormal histone deacetylase viability. Meanwhile, a method for preparing the novel compound in the present invention has the advantages of fewer steps, simple and convenient operation, safety, environment friendliness, high yield and the like and is very suitable for industrial application.