JP4799408B2 - Use of novel 2-oxoheterocyclic compounds and pharmaceutical compositions containing them - Google Patents

Description

The present invention relates to the use of a novel 2-oxoheterocyclic compound having anticancer activity and a pharmaceutical composition containing the same.

Cancer is characterized by the formation of cell aggregates called tumors due to abnormal and uncontrollable cell growth that spread to adjacent tissues and, in severe cases, metastasis to other tissues called neoplasia. More than 20 million people worldwide are afflicted with cancer each year, and 6 million of them die from the disease each year. The origin of cancer is classified into internal factors such as genetic factors, immune factors, and external factors such as various chemicals, radiation, and virus. Cancer can occur when the balance between oncogenes and tumor suppressor genes is disrupted by the above factors.
Histone is a nuclear protein that binds to the DNA nucleus, and the reversible acetylation reaction of histone occurs reversibly at the positively charged lysine tail ε-amino group. Since the response is related to the formation of advanced tissue in chromatin, it has been documented to be related to cell cycle regulation and gene expression with non-histone proteins.

The balance of acetylation state is sustained by regulation of two enzyme complexes, histone acetyltransferase (HAT) and histone deacetylase (HDAC), and changes in acetylation levels are described as essential to changes in gene expression. ing. Therefore, the acetylation state of histone has a structure such as (1) butyrate having a short chain fatty acid structure (Newmark et al., Cancer Lett, 78, 1-5, 1994), (2) Tricostatin A, Suberoylanilide Hydroxamic acid (SAHA) and Oxamflatin with hydroxamic acid structure (Tsuji et al., J. Antibiot. (Tokyo) 29, 1-6, 1976; Richon et al., Proc. Natl. Acad. Sci USA, 95, 3003-3007, 1998; Kim et al., Oncogene 18, 2461-2470, 1999), (3) 2-amino-8-oxo-9,10-epoxy-decanoyl (AOE) ) Containing cyclic tetrapeptide structure; trapoxin A (Kijima et al., J. Biol. Chem. 268, 22429-22453, 1993), (4) cyclic tetrapeptide structure containing AOE; FR901228 and apicidin (Nakajima) Exp. Cell Res. 241. l26-33, 1998; Darkin-Rattray et al., Proc. Natl. Acad. Sci. USA, 93, 13143-13147, 1996 ), (5) benzamide structure; MS-27-275 (Saito et al., Proc. Natl. Acad. Sci. USA, 96. 4592-4597, 1999) can be controlled by a compound that suppresses HDAC activity. .

 These compounds cause high expression of certain proteins such as tumors that suppress HDAC enzymes, induce hyperacetylation of histone proteins, suppress elements, and suppress the growth of cancer cells leading to cancer cell death It becomes. Thus, compounds that selectively inhibit HDACs can be developed into promising candidate drugs that inhibit cancer cells and induce cell death.

However, the disclosure has neither described nor disclosed a novel oxopiperidine compound exhibiting a strong inhibitory effect on HDAC activity and anticancer activity in any of the above-mentioned documents cited here as a reference.

In order to investigate a novel compound having a novel oxopiperidine skeleton exhibiting a strong inhibitory effect on HDAC activity and an anticancer activity, the inventors of the present invention intensively performed in vitro experiments on the inhibitory effect on HDAC enzyme. As a result of investigation, the present inventors finally completed the present invention by confirming that the novel compound of the present invention inhibits the HDAC enzyme. And it can be useful as an anticancer agent.
The present invention also provides the use of novel 2-oxoheterocyclic compounds and pharmacologically acceptable salts thereof for the manufacture of a pharmaceutical composition for treating or preventing cancer.
The present invention provides a pharmaceutical composition containing a novel 2-oxoheterocyclic compound and a pharmacologically acceptable salt thereof as an active ingredient and containing an amount effective for treating or preventing cancer.

Thus, the present invention provides a novel compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof or an isomer thereof for the manufacture of a pharmaceutical composition for treating or preventing cancer. Provide the use of.
In the formula, X represents a hydroxyl group, —NHOH, —NHOCH ₂ Ph,
Or
And
A is hydrogen, A1 group or
And
A1 is a lower alkyl, lower alkenyl, lower alkynyl, or lower allyl group having C1 to C5 carbon atoms, and is a heterocyclic group or an aromatic aryl group, preferably a thiopenyl group, a naphthyl group, a pyrrolyl group, a furyl group, and A group selected from a biphenyl group,
In the formula, Y is a lower alkyl group, a lower alkoxy group, nitro, halogen, amine, acetamide, carbonamide or sulfonamide group,
M is a lower alkyl group or a phenyl group substituted by R ′, R ′ is hydrogen, lower alkyl or lower alkoxy group, and m and r are each independently an integer of 1 to 5 in the A2 residue. is there.
p is an integer of 0, 1 or 2;
n is an integer from 1 to 5;
Broken line
Means a single bond or a double bond.

In a preferred embodiment, the present invention also provides a novel compound represented by the following general formula (II) and a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating or preventing cancer, Alternatively, use of the isomer is provided.
In the formula, X represents a hydroxyl group, —NHOH, —NHOCH ₂ Ph,
Or
And
Y is a lower alkyl group, lower alkoxy group, nitro, halogen, amine, acetamide, carbonamide or sulfonamide group;
M is a lower alkyl group or a phenyl group substituted with R ′, and R ′ is hydrogen, a lower alkyl or a lower alkoxy group;
m and r are each independently an integer of 1 to 5;
n is an integer from 1 to 5;
Broken line
Means a single bond or a double bond.

Preferred compounds of general formula (II) are one selected from the group consisting of:
3- [1- (2,4-dimethoxybenzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxypropionamide,
3- (1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxypropionamide,
N-hydroxy-3- (2-oxo-1-phenethyl-2,5-dihydro-1H-pyrrol-3-yl) -propionamide,
N-hydroxy-3- [2-oxo-1- (3-phenylpropyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
N-hydroxy-3- [2-oxo-1- (4-phenylbutyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
N-hydroxy-3- [1- (2-methyl-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
N-hydroxy-3- [1- (3-methyl-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
N-hydroxy-3- [1- (4-methyl-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
N-hydroxy-3- [1- (2-methoxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
N-hydroxy-3- [1- (3-methoxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
N-hydroxy-3- [1- (4-methoxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
3- [1- (4-bromo-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxypropionamide,
3- [1- (4-chloro-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxypropionamide,
3- [1- (4-benzyloxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxypropionamide,
N-hydroxy-3- [1- (4-nitro-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
3- [1- (2,4-dimethoxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxypropionic acid,
3- (1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -propionic acid,
N- {4- [3- (2-hydroxycarbamoyl-ethyl) -2-oxo-2,5-dihydro-pyrrol-1-yl-methyl] -phenyl} -benzamide
N-hydroxy-3- {2-oxo-1- [4- (toluene-4-sulfonylamino) -benzyl] -2,5-dihydro-1H-pyrrol-3-yl} -propionamide,
2- (1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -N-hydroxy-acetamide,
2- [1- (2,4-dimethoxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxy-acetamide,
N-hydroxy-2- (2-oxo-1-phenethyl-2,5-dihydro-1H-pyrrol-3-yl) -acetamide,
N-hydroxy-2-[(2-oxo-1 (4-phenyl-butyl) -2,5-dihydro-1H-pyrrol-3-yl) -acetamide,
2- [1- (4-benzyloxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxy-acetamide,
2- (1-benzyl-2-oxo-pyrrolidin-3-yl) -N-hydroxy-acetamide,
2- [1- (2,4-dimethoxy-benzyl) -2-oxo-pyrrolidin-3-yl] -N-hydroxy-acetamide,
N-hydroxy-2- (2-oxo-1-phenethyl-pyrrolidin-3-yl) -acetamide,
3- {1- [2- (2-fluoro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide,
3- {1- [2- (3-fluoro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide,
3- {1- [2- (4-fluoro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide,
N-hydroxy-3- {1- [2- (2-nitro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide,
N-hydroxy-3- {1- [2- (3-nitro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide,
N-hydroxy-3- {1- [2- (4-nitro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide,
3- {1- [2- (2-bromo-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide,
3- {1- [2- (4-bromo-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide,
N-hydroxy-3- {1- [2- (2-methoxy-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide,
N-hydroxy-3- {1- [2- (3-methoxy-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide,
N-hydroxy-3- {1- [2- (4-methoxy-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide,
N-hydroxy-3- [2-oxo-1- (2-p-tolyl-ethyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
N-hydroxy-3- {1- [3- (4-methoxy-phenyl) -propyl] -2,5-dihydro-1H-pyrrol-3-yl} -propionamide,
N-hydroxy-3- [2-oxo-1- (3-o-tolyl-propyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
N-hydroxy-3- [2-oxo-1- (3-m-tolyl-propyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
N-hydroxy-3- {1- [3- (4-isopropyl-phenyl) -propyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide,
3- {1- [3- (4-bromo-phenyl) -propyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide,
3- {1- [3- (4-chloro-phenyl) -propyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide,
N-hydroxy-3- {1- [3- (4-methoxy-phenyl) -propyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide,
N-hydroxy-3- {1- [3- (2-methoxy-phenyl) -propyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide,
N-hydroxy-3- {1- [3- (3-methoxy-phenyl) -propyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide.

In a preferred embodiment, the present invention also provides a novel compound represented by the following general formula (III) and a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating or preventing cancer, Alternatively, use of the isomer is provided.
In the formula, X represents a hydroxyl group, —NHOH, —NHOCH ₂ Ph,
Or
And
R is a lower alkyl, lower alkenyl, lower alkynyl, lower allyl group having C1 to C5 carbon atoms, a heterocyclic group or an aromatic aryl group, preferably a thiopenyl group, a naphthyl group, a pyrrolyl group, a furyl group, and A group selected from a biphenyl group,
n is an integer from 1 to 5;
Broken line
Means a single bond or a double bond.

Preferred compounds of general formula (III) are one selected from the group consisting of:
N-hydroxy-3- (1-naphthalen-2-ylmethyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -propionamide,
N-hydroxy-3- (1-methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -propionamide,
3- (1-allyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -N-hydroxy-propionamide,
N-hydroxy-3- [1- (2-naphthalen-1-yl-ethyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
N-hydroxy-3- [1- (2-naphthalen-2-yl-ethyl) -2-oxo-2,5-dihydro-1H-pyrrol-1-yl] -propionamide,
N-hydroxy-3- [2-oxo-1- (2-thiophen-2-yl-ethyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
3- [1- (3-biphenyl-4-yl-propyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -N-hydroxy-propionamide,
N-hydroxy-3- [1- (3-naphthalen-2-yl-propyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide.

In a preferred embodiment, the present invention also provides a novel compound represented by the following general formula (IV) and a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating or preventing cancer, Alternatively, use of the isomer is provided.
In the formula, X represents a hydroxyl group, —NHOH, —NHOCH ₂ Ph,
Or
And
Y is a lower alkyl group, lower alkoxy group, nitro, halogen, amine, acetamide, carbonamide or sulfonamide group;
M is a lower alkyl group or a phenyl group substituted with R ′, and R ′ is hydrogen, a lower alkyl or a lower alkoxy group;
m and r are each independently an integer of 1 to 5;
n is an integer from 1 to 5;
Broken line
Means a single bond or a double bond.

Preferred compounds of general formula (IV) are one selected from the group consisting of:
3- [1- (2,4-dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydropyridin-3-yl} -N-hydroxypropionamide,
N-hydroxy-3- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid,
N-hydroxy-3- [1- (4-nitro-benzyl) -2-oxo-1,2,5,6-tetrahydropyridin-3-yl] -propionamide,
3- (1-Benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-hydroxypropionamide,
N-hydroxy-3- [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide,
N-hydroxy-3- (2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide,
3- [1- (2,4-dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid,
3- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid,
3- [1- (4-nitro-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid,
3- [2-oxo-1- (4-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid,
3- [2-oxo- (4-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid,
3- (2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid,
3- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-pyridin-2-yl-propionamide,
N- (2-amino-phenyl) -3- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide,
N- (2-amino-phenyl) -3- [1- (2-methyl-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide,
N- (2-amino-phenyl) -3- [1- (2-methyl-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide,
N-benzyloxy-3- (2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide,
3- [1- (4-acetylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide,
N-4- [5- (2-hydroxycarbamoyl-ethyl) -6-oxo-3,6-dihydro-2-pyridin-1-yl-methyl] -phenyl-benzamide,
N-hydroxy-3- [1- (4-dimethylsulfonylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide,
N-hydroxy-3-2-oxo-1- [4- (toluene-4-sulfonylamino) -benzyl-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide,
3- [1- (4-acetylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid,
3- [1- (4-benzoylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid,
3-2-oxo-1- [4- (toluene-4-sulfonylamino) -benzyl] -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid,
N-hydroxy-3- (2-oxo-1-phenethyl-piperidin-3-yl) -propionamide,
2- [1- (2,4-dimethoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -hydroxy-acetamide,
2- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-hydroxy-acetamide,
N-hydroxy-2- [1- (4-nitro-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-acetamide,
N-hydroxy-2- [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-acetamide,
N-hydroxy-2- [2-oxo-1- (4-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-acetamide,
[1- (2,4-dimethoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -acetic acid,
(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -acetic acid,
(2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -acetic acid,
[2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -acetic acid,
[2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -acetic acid,
2- [1- (2,4-dimethoxy-benzyl) -2-oxo-piperidin-3-yl] -N-hydroxy-acetamide,
(2-oxo-1-phenethyl-piperidin-3-yl) -acetic acid,
[2-oxo-1- (3-phenyl-propyl) -piperidin-3-yl] -acetic acid,
4- [1- (4-methoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-butyramide,
4- (1-phenethyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-hydroxy-butyramide,
N-hydroxy-4- [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -butyramide,
N-hydroxy-4- [2-oxo-1- (3-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -butyramide.

In a preferred embodiment, the present invention also provides a novel compound represented by the following general formula (V) and a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating or preventing cancer, Alternatively, use of the isomer is provided.
In the formula, X represents a hydroxyl group, —NHOH, —NHOCH ₂ Ph,
Or
And
R is a lower alkyl, lower alkenyl, lower alkynyl or lower allyl group having C1 to C5 carbon atoms, a heterocyclic group or an aromatic aryl group, preferably a thiopenyl group, a naphthyl group, a pyrrolyl group, a furyl group and a biphenyl group. A group selected from
n is an integer from 1 to 5;
Broken line
Means a single bond or a double bond.

Preferred compounds of general formula (V) are one selected from the group consisting of:
3- (2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid,
N-benzyloxy-3- (2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide,
3- (1-allyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -N-hydroxy-propionamide,
N-hydroxy-3- (1-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide,
N-hydroxy-3- [1- (naphthalen-2-yl-methyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide,
N-hydroxy-3- [2-oxo-1- (2-thiophen-2-yl-ethyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide.

In a preferred embodiment, the present invention also provides a novel compound represented by the following general formula (VI) and a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating or preventing cancer, Alternatively, the isomers and their uses are provided.
In the formula, X represents a hydroxyl group, —NHOH, —NHOCH ₂ Ph,
Or
And
R is selected from lower alkyl, lower alkenyl, lower alkynyl, lower allyl having C1 to C5 carbon atoms, heterocyclic group or aromatic aryl group, preferably thiopenyl group, naphthyl group, pyrrolyl group, furyl group and biphenyl group. Group,
n is an integer from 1 to 5;
Broken line
Means a single bond or a double bond.

Preferred compounds of general formula (VI) are one selected from the group consisting of:
N-3- (1-benzyl-2-oxo-2,5,6,7-tetrahydro-1H-azepin-3-yl) -N-hydroxy-propionamide,
N-hydroxy-3- [2-oxo-1- (3-phenyl-ethyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] -propionamide,
N-hydroxy-3- [2-oxo-1- (3-phenyl-propyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] -propionamide,
N-hydroxy-3- [2-oxo- (3-phenyl-butyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] -propionamide.

Another object of the present invention is to provide an effective amount of a compound represented by the general formulas (I) to (VI) or a pharmaceutically acceptable salt of the general formula (VI) according to claim 12 as an active ingredient. It is to provide a pharmaceutical composition containing in an amount effective to treat or prevent cancer with a pharmaceutically acceptable carrier or diluent.

The compounds of the invention represented by general formulas (I) to (VI) can be converted into their pharmacologically acceptable salts and solvates by conventional methods well known in the art. As salts, acid addition salts formed with pharmacologically acceptable acids are useful and can be prepared by conventional methods. For example, after dissolving the compound in an excess of an acid solution, the salt is precipitated with a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile to prepare its acid addition salt, and further water or alcohols such as An equivalent mixture of acid and compound diluted with glycol monomethyl ether can be heated and then evaporated to dryness or filtered under reduced pressure to give the salt in dried form.

Organic acids or inorganic acids can be used as the free acid in the above process. For example, organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, Glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonyl acid, vanillic acid, hydroiodic acid and the like, and inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like may be used here.

In addition, pharmaceutically acceptable salt forms of the compounds of the invention can be prepared using bases. The alkali metal or alkaline earth metal salt is retained by conventional methods, for example, by dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution and then filtering the insoluble salt. It can be prepared by evaporating the filtrate to obtain its metal salt. Sodium, potassium or calcium salts are pharmacologically suitable as the metal salts of the present invention, and the corresponding silver salts are prepared by reacting an alkali metal salt or alkaline earth metal salt with a suitable silver salt such as silver nitrate. Can be done.

The pharmacologically acceptable salts of the compounds represented by the general formulas (I) to (VI) include all acidic or basic salts, which are a plurality of unless otherwise specified herein. It may be a compound. For example, pharmacologically acceptable salts of the compounds of the present invention include hydroxyl group salts such as the sodium, calcium and potassium salts; amino group salts such as hydrobromide, sulfate, hydrogen sulfate, Phosphate, hydrogen phosphate, dihydrophosphate, acetate, oxalate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), p-toluenesulfonate (tosylate), etc. Which can be made by conventional methods well known in the art.

Since the compounds of the general formulas (I) to (VI) have asymmetric centers, they may exist in the form of optically different diastereomers, and therefore all the compounds of the present invention are optically active. Consisting of isomers, R or S stereoisomers and mixtures thereof. The present invention also consists of all uses of racemic mixtures, one or more optically active isomers or mixtures thereof, as well as methods for the preparation or isolation of diastereomers well known in the art.

The compounds of the present invention of general formulas (I)-(VI) may be chemically prepared by the methods illustrated in the following reaction schemes below, but they are merely exemplary and in no way limit the invention. The reaction scheme shows steps for preparing representative compounds of the invention, and other compounds can also be prepared by the following steps, with appropriate changes in starting materials and reagents, as would be expected by one skilled in the art.

General Synthesis Procedure Scheme 1
As represented in Scheme 1 above, the scheme describes a method of preparing a hydroxamic acid compound (e) comprising 4 steps;
In the first step, compound (a) is reacted with 1-bromo-3-butene in the presence of a Hunig base in an organic solvent to synthesize compound (b). In this step, an organic solvent such as acetonitrile, dichloromethane or the like is preferred, and diethylisopropylamine can be used as the Hunig base in an amount of 2-3 equivalents relative to compound (a). The reaction is preferably performed at a temperature of 0 ° C. to room temperature (RT).
In the second step, the compound (b) obtained in Step 1 is reacted with a monoacid in the presence of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (EDC) in an organic solvent. The In this step, an organic solvent such as dichloromethane, THF or the like is preferable, and a monoacid such as 2-methylenepentanedioic acid-5-methyl ester in an amount of 1 to 1.2 equivalents relative to the compound (b) is preferable. The reaction is preferably performed at a temperature of 0 ° C. to RT.
In the third step, compound (c) obtained in step 2 is converted to compound (d) in the presence of a Grubbs (I) catalyst such as a ruthenium catalyst in an organic solvent. In this step, it is preferable to use the catalyst in an amount of 0.02 to 0.1 equivalent to the compound (c) at a temperature of 0 ° C. to RT.
In the fourth step, the compound (d) obtained in step 3 is reacted with an amine salt to synthesize the hydroxamic acid compound (e) in the general formula I where X is NHOH. In this step, it is preferable to use potassium hydroxamide (KONH ₂ ) in an amount of 2 to 3 equivalents relative to compound (d) at a temperature of 0 ° C. to RT.

Scheme 2
As represented in Scheme 2 above, the ester compound (d) is reacted with a metal hydroxide salt in an organic solvent such as THF to synthesize the carboxylic acid (f). In this reaction, it is preferred to use LiOH in an amount of 2 to 3 equivalents relative to compound (d) at a temperature of 0 ° C. to RT.

Scheme 3
As represented in Scheme 3 above, the carboxylic acid compound (f) obtained in Scheme 2 is present in the presence of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (EDC) in an organic solvent. below, benzyloxyamine (BnONH _2), is reacted with pyridylamine or diaminobenzene, X is benzyloxy amine (BnONH _2), to synthesize a pyridylamine or amide compound is a diaminobenzene group. In this reaction, it is preferable to use benzyloxyamine (BnONH ₂ ), pyridylamine or diaminobenzene in an amount of 1 to 1.5 equivalents relative to compound (f) at a temperature of 0 ° C. to RT.

Scheme 4
As shown in Scheme 4 above, hydroxamide compound (j) and carboxylic acid compound (k) are prepared from ester compound (d) by the following procedure;
In the first step, compound (d) obtained from Scheme 2 is reacted with zinc powder in an organic solvent to synthesize compound (h). In this step, the zinc is preferably used in an amount of 2 to 5 equivalents relative to compound (h).
In the second step, compound (h) obtained in step 1 is reacted with (AcO) ₂ O, PhCOCl, MsCl or TsCl to synthesize compound (i). In this step, (AcO) ₂ O, PhCOCl, MsCl or TsCl is preferably used in an amount of 1 to 3 equivalents relative to compound (h).
In the third step, compound (i) obtained in step 2 is reacted with an amine salt in an organic solvent such as methanol to synthesize compound (j), ie a compound of general formula I where X is NHOH. [In this case, the amine salt is preferably used in an amount of 2 to 3 equivalents relative to compound (i)] or reacted with a metal hydroxide salt such as LiOH in an organic solvent such as THF to give compound (k ), Ie a compound of the general formula I in which X is OH [in this case the metal salt is preferably used in an amount of 2 to 3 equivalents relative to the compound (i)].

Scheme 5
As shown in Scheme 5 above, the 1,2,5,6-dihydropyridine compound (d) is prepared by adding palladium-carbon (Pd) in an amount of 0.1 to 0.2 equivalents of the compound (d) in an alcohol solvent. / C) and reduced to the piperidine compound (l), and the piperidine compound (l) is further reacted with KONH _{2 in} MeOH to synthesize the compound (m). In this reaction, the amine salt is preferably used in an amount of 1 to 1.5 equivalents relative to the compound (m) at a temperature of 0 ° C. to RT.

Scheme 6
As shown in Scheme 6 above, benzyl compound (d) is reacted with trifluoroacetic acid (TFA) in the presence of an amount of 1-1.5 equivalents of compound (d) to prepare compound (l). . Compound (l) is further reacted with sodium hexamethyldisilazide (NaHMDS) in a THF solvent, and then reacted with RX (R: allyl, methyl, etc .; X: halogen atom) to give compound (m) Manufacturing. In this reaction, NaHMDS is preferably used in an amount of 1 to 1.5 equivalents relative to compound (l).

Scheme 7
As shown in Scheme 7 above, compound (b) as a starting material is prepared by the following procedure;
In the first step, compound (z), which is conventionally available on the market or at a chemical company, is reacted with a Wittig reagent in an organic solvent such as dichloromethane to synthesize compound (aa). In this step, the Wittig reagent is preferably used in an amount of 1.5 to 2 equivalents relative to compound (z) at a temperature of 60 to 70 ° C.
In the second step, the compound (aa) obtained in step 1 is reacted with 0.1 to 0.2 equivalent amount of Pd / C of the compound (aa) in an H ₂ atmosphere in an ethyl alcohol solvent. Compound (ab) is synthesized.
In the third step, compound (ab) obtained in step 2 is reacted with lithium hydride (LAH) in an organic solvent such as THF at 0 ° C. to produce compound (ac).
In the fourth step, compound (ac) is then washed with p-toluene in the presence of diisopropylethylamine or 4- (dimethylamino) pyridine in an amount of 0.1-0.2 equivalents of compound (aa) in an ethyl alcohol solvent. Reaction with sulfonyl chloride synthesizes compound (ad).
In the fifth step, both allylamine and a Hunig base are added to the compound (ad) dissolved in acetonitrile, mixed and stirred at 80 ° C. for a time, and the compound (ae), which is one of the compounds (b), is added. Synthesize.

The present invention also treats an effective amount of a compound represented by the general formulas (I) to (VI) or a pharmacologically acceptable salt thereof as an active ingredient together with a pharmacologically acceptable carrier to treat cancer. A pharmaceutical composition is provided that contains an amount effective to inhibit

The compounds of general formulas (I) to (VI) according to the present invention can provide a pharmaceutical composition containing a pharmacologically acceptable carrier, adjuvant or diluent. For example, the compounds of the present invention can be dissolved in oils, propylene glycol or other solvents that are commonly used to produce injectables. Suitable examples of the carrier include, but are not limited to, physiological saline, polyethylene glycol, ethanol, vegetable oil, isopropyl myristate, and the like. For topical administration, the compounds of the invention may be formulated in the form of ointments and creams.

The pharmaceutical composition comprising the compound of the present invention includes, for example, lung cancer, osteosarcoma, pancreatic cancer, skin cancer, head and neck cancer, skin or recurrent intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer or anal cancer , Gastric cancer, colon cancer, breast cancer, gynecological tumors (eg uterine fleshy, fallopian tube carcinoma, uterine mucosal carcinoma, cervical cancer, vaginal carcinoma or vulvar carcinoma), Hodgkin's disease, esophageal cancer, small intestine cancer Cancer, endocrine cancer (eg, thyroid, parathyroid or adrenal cancer), soft tissue fleshy, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, childhood solid tumor, lymphocyte lymphoma, Cancers such as bladder cancer, renal or ureteral cancer (eg, renal cell carcinoma, renal pelvic carcinoma), or central nervous system carcinoma (eg, primary central nervous system lymphoma, spinal axis tumor, brainstem glioma or pituitary adenoma) Treat or prevent

The compounds of the present invention have potent anticancer activity and the pharmaceutical compositions of the present invention can therefore be used to treat or prevent cancer.

The present invention also provides a method for preventing or treating cancer. In such prevention or treatment, the method comprises using a compound selected from the group of compounds of general formulas (I) to (VI) or a pharmacologically acceptable salt thereof as an anticancer agent, the salt or the pharmacology thereof. Administration of a therapeutically effective amount of a pharmaceutically acceptable hydrate.

In the following, the following formulation methods and excipients are merely illustrative and do not limit the present invention in any way.

The compounds of the present invention in pharmaceutical dosage form may be used in the form of their pharmaceutically acceptable salts, alone or in appropriate combinations, as well as in combination with other pharmacologically active compounds. May be used

The compounds of the present invention dissolve or suspend them in an aqueous solvent such as saline, 5% dextrose, or a non-aqueous solvent such as vegetable oil, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol. It can be formulated into an injectable preparation by turbidity or emulsification. The formulation may contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives.

The desired dosage of the compounds of the present invention will vary depending on the subject and severity of the administration, severity, formulation form, route of administration and duration and can be selected by one skilled in the art. However, in order to obtain the desired effect, it is generally recommended to administer the compounds of the invention in an amount of 0.0001-100 mg / kg, preferably 0.001-100 mg / kg, weight / day. . Administration may be a single dose per day or may be divided into several doses. With respect to the composition, the compound should be present in an amount of 0.0001 to 10% by weight, preferably 0.0001 to 1% by weight, based on the total weight of the composition.

The pharmaceutical composition of the present invention can be administered to a subject animal such as a mammal (rat, mouse, domestic animal or human) by various administration routes. All aspects of administration are contemplated, for example, administration can be performed orally, rectally, or by intravenous, intramuscular, subcutaneous, subarachnoid, epidural or intracerebroventricular injection.

The invention is more specifically described by the following examples. However, it should be understood that the present invention is not limited to these examples in any way.

It will be apparent to those skilled in the art that various modifications and variations can be made in the composition, use and preparation of the present invention without departing from the spirit or scope of the invention.

The invention is more specifically described by the following examples. However, it should be understood that the present invention is not limited to these examples in any way.

EXAMPLES The following reference examples, examples and experimental examples are intended to illustrate the present invention without limiting its scope.

Preparation of 3- [1- (2,4-dimethoxybenzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxypropionamide (1e)

Step 1: Preparation of allyl- (2,4-dimethoxybenzyl) amine (1b) Allyl bromide was added to a reaction solution containing 500 mg (3.33 mmol) of 2,4-dimethoxybenzylamine dissolved in methylene chloride. Of 0.32 ml (3.66 mmol) and 0.7 ml (3.99 mmol) of diisopropylethylamine were added with stirring and the solution was allowed to stand at room temperature. After the reaction mixture was neutralized with 10% NaOH solution, the mixture was extracted with chloroform, washed with saturated NaCl solution, dried over MgSO ₄ , filtered and concentrated in vacuo. The obtained compound was purified by column chromatography on silica gel using a mixed solvent of methanol and chloroform (1: 9) as an eluent to obtain 276 mg of allyl- (2,4-dimethoxybenzyl) amine (1b). (Yield: 40%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.12 (d, J = 8.1 Hz, 1H), 6.44-6.39 (m, 2H), 5.99-5.86 (m, 1H), 5.21-5.09 (m, 2H) 3.79 (d, J = 6.0 Hz, 6H), 3.74 (s, 2H), 3.23 (d, J = 6.0 Hz, 2H)

Step 2: Preparation of 4- [allyl- (2,4-dimethoxy-benzyl) -carbamoyl] -pent-4-enoic acid methyl ester (1c) Reaction in which compound (1b) prepared in Step 1 is dissolved To 0.5M of the solution was added 253 mg (1.6 mmol) of 2-methylene-pentanedioic acid 5-methyl ester, 331 mg (1.73 mmol) of [3- (dimethylamino) propyl] -3-ethylcarbodiimide. And 48 mg (0.39 mmol) of 4- (dimethylamino) pyridine were added and the mixture was stirred at room temperature for 10 hours. After the resulting mixture was washed with 5% HCl solution (10 ml), the mixture was extracted with ethyl acetate and washed with saturated NaCl. The extract was then washed with 10 ml of saturated NaHCO ₃ solution and NaCl solution and separated into organic and aqueous layers. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The product was purified by column chromatography on silica gel using a mixed solvent of EtOH and hexane (1: 2) as eluent to give 4- [allyl- (2,4-dimethoxy-benzyl) -carbamoyl] -pent. 324 mg of 4-enoic acid methyl ester (1c) was obtained (yield: 70%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.14 (s, 1H), 6.44 (d, 2H), 5.72 (s, 1H), 5.12 (s, 4H), 4.56-4.81 (m, 2H), 3.91 -3.83 (m, 2H), 3.78 (d, J = 5.3Hz, 6H), 3.65 (d, J = 1.4Hz, 3H), 2.63 (t, J = 5.7Hz, 2H), 2.54 (t, J = 5.4Hz, 2H)

Step 3: Preparation of 3- [1- (2,4-dimethoxybenzyl) -2-oxo-1H-pyrrol-3-yl] -propionic acid methyl ester (1d) dissolved in 93 ml of CH ₂ Cl ₂ To a catalyst solution containing 74 mg (0.09 mmol) of ruthenium, 324 mg (0.933 mmol) of compound (1c) prepared in Step 2 above was added. The mixture was then stirred at room temperature for 24 hours, filtered and concentrated in vacuo. The product was purified by column chromatography on silica gel using a mixed solvent of EtOH and hexane (1: 1) as eluent to give 3- [1- (2,4-dimethoxybenzyl) -2-oxo-1H. 268 mg of -pyrrol-3-yl] -propionic acid methyl ester (1d) were obtained (yield: 90%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.11 (d, J = 9.0 Hz, 1H), 6.61 (br t, 1H), 6.43 (s, 1H), 6.40 (d, J = 2.7 Hz, 1H) , 4.56 (s, 2H), 3.78 (d, J = 5.4Hz, 9H), 3.65 (s, 2H), 2.61 (s, 4H)

Step 4: Preparation of 3- [1- (2,4-dimethoxybenzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxypropionamide (1e) Step 3 above 100 mg of the compound (d) prepared in step 1 was dissolved in a methanol solution (0.313 mmol) and then a 1.7 M methanolic suspension containing NH ₂ OK (0.27 ml, 0.47 mmol) was obtained. To this was added at 0 ° C. and the resulting mixture was stirred at room temperature for 10 hours. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with a methanol / chloroform solution, filtered and concentrated in vacuo. The obtained compound was purified by column chromatography on silica gel using a mixed solvent of methanol and chloroform (1: 9) as an eluent to give 3- [1- (2,4-dimethoxybenzyl) -2-oxo- 50 mg of 2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxypropionamide (1e) was obtained (yield: 50%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.04 (d, J = 8.1 Hz, 1H), 6.83 (s, 1H), 6.53-6.44 (m, 2H), 4.54 (s, 2H), 3.81 (t , J = 2.0 Hz, 6H), 2.56 (t, J = 7.2 Hz, 2H), 2.34 (t, J = 7.4 Hz, 2H), 1.9 (s, 3H)

Preparation of 3- (1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -N-hydroxypropionamide (2e) In a procedure similar to that described in Example 1 above, 3- (1-Benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -N-hydroxypropionamide (2e) was prepared (see Table 1a).

Preparation of N-hydroxy-3- (2-oxo-1-phenethyl-2,5-dihydro-1H-pyrrol-3-yl) -propionamide (3e) In a procedure similar to that described in Example 1 above, N -Hydroxy-3- (2-oxo-1-phenethyl-2,5-dihydro-1H-pyrrol-3-yl) -propionamide (3e) was prepared (see Table 1a).

Preparation of N-hydroxy-3- [2-oxo-1- (3-phenyl-propyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide (4e) As described in Example 1 above In a similar procedure, N-hydroxy-3- [2-oxo-1- (3-phenyl-propyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide (4e) was prepared (4e) Table 1a).

Preparation of N-hydroxy-3- [2-oxo-1- (4-phenylbutyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide (5e) Same as described in Example 1 above N-hydroxy-3- [2-oxo-1- (4-phenylbutyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide (5e) was prepared by the procedure of (Table 1a). reference).

Preparation of N-hydroxy-3- [1- (2-methyl-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide (6e) As described in Example 1 above In a similar procedure, N-hydroxy-3- [1- (2-methyl-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide (6e) was prepared (6e) Table 1a).

Preparation of N-hydroxy-3- [1- (3-methyl-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide (7e) As described in Example 1 above In a similar procedure, N-hydroxy-3- [1- (3-methyl-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide (7e) was prepared (7e) ( Table 1a).

Preparation of N-hydroxy-3- [1- (4-methyl-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide (8e) As described in Example 1 above In a similar procedure, N-hydroxy-3- [1- (4-methyl-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide (8e) was prepared (8e) ( Table 1a).

Preparation of N-hydroxy-3- [1- (2-methoxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide (9e) As described in Example 1 above In a similar procedure, N-hydroxy-3- [1- (2-methoxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide (9e) was prepared (9e) See Table 1b).

Preparation of N-hydroxy-3- [1- (3-methoxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide (10e) As described in Example 1 above In a similar procedure, N-hydroxy-3- [1- (3-methoxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide (10e) was prepared (10e) ( See Table 1b).

Preparation of N-hydroxy-3- [1- (4-methoxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide (11e) As described in Example 1 above In a similar procedure, N-hydroxy-3- [1- (4-methoxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide (11e) was prepared (11e) See Table 1b).

Preparation of 3- [1- (4-Bromo-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxypropionamide (12e) As described in Example 1 above. 3- [1- (4-Bromo-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxypropionamide (12e) was prepared by a procedure similar to (See Table 1b).

Preparation of 3- [1- (4-Chloro-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxypropionamide (13e) As described in Example 1 above. 3- [1- (4-Chloro-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxypropionamide (13e) was prepared by a procedure similar to (See Table 1b).

Preparation of 3- [1- (4-benzyloxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxypropionamide (14e) described in Example 1 above In a similar procedure as described above, 3- [1- (4-benzyloxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxypropionamide (14e) was (See Table 1b).

Preparation of N-hydroxy-3- [1- (4-nitro-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide (15e) As described in Example 1 above In a similar procedure, N-hydroxy-3- [1- (4-nitro-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide (15e) was prepared (15e) See Table 1b).
(Table 1a)
(Table 1b)

Preparation of 3- [1- (2,4-dimethoxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxypropionic acid
THF containing 55 mg (0.17 mmol) of 3- [1- (2,4-dimethoxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionic acid methyl ester To 0.86 ml of the solution, 10.8 mg (0.25 mmol) of LiOH · H ₂ O solution was added dropwise at 0 ° C. The reaction mixture was stirred at 0 ° C. for 2 hours and 5% HCl was added until the pH was 1. The mixture was then extracted 3 times with 10 ml of ethyl acetate and the organic layer was washed with saturated NaCl solution, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The obtained compound was purified by column chromatography on silica gel using a mixed solvent of methanol and chloroform (1: 9) as an eluent to give 3- [1- (2,4-dimethoxy-benzyl) -2-oxo. 41 mg of -2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxypropionic acid (16f) was obtained (yield: 80%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.11 (d, J = 9.0 Hz, 1H), 6.65 (br t, 1H), 6.41 (ab, J = 6.5 Hz, 2H), 4.57 (s, 2H) , 3.81-3.76 (m, 8H), 2.63 (s, 4H)

Preparation of 3- (1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -propionic acid (17f) In a similar procedure as described in Example 16 above, 3- (1 -Benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -propionic acid (17f) was prepared (see Table 2).
(Table 2)

Preparation of N- {4- [3- (2-hydroxycarbamoyl-ethyl) -2-oxo-2,5-dihydro-pyrrol-1-yl-methyl] -phenyl} -benzamide (18j)

Step 1: Preparation of 3- [1- (4-amino-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionic acid methyl ester (h)
90 mg (0.3 mmol) of 3- [1- (4-nitro-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionic acid methyl ester in methanol at room temperature It was dissolved in. Then 290 mg (4.44 mmol) of Zn and 0.02 ml (0.3 mmol) of acetic acid were added thereto and the mixture was stirred at room temperature for 48 hours. The resulting compound was purified by silica gel column chromatography using acetic acid as eluent to give 3- [1- (4-amino-benzyl) -2-oxo-2,5-dihydro-1H-pyrrole-3- 20 mg of yl] -propionic acid methyl ester (h) was obtained (yield: 25%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.01 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 1.8 Hz, 2H), 6.60 (br t, 1H), 4.48 (s, 2H) 3.68 (d, J = 1.2 Hz, 3H), 3.65 (s, 4H), 2.66-2.58 (m, 4H)

Step 2: Preparation of 3- [1- (4-Benzoylamino-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionic acid methyl ester (i) Prepared in Step 1 above 10 mg of the prepared 3- [1- (4-amino-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionic acid methyl ester (h) at room temperature in methylene chloride solution ( 0.04 mmol). Then 8.5 μl (0.07 mmol) of benzyl chloride and 19.1 μl (0.11 mmol) of diisopropylamine were added thereto and the mixture was stirred at 0 ° C. for 2 hours. The reaction was quenched with methanol and the mixture was extracted 3 times with 10 ml of ethyl acetate. The organic layer was washed with saturated NaCl solution, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on silica gel using a mixed solvent of ethyl acetate and hexane (1: 2) as an eluent to give 3- [1- (4-benzoylamino-benzyl) -2-oxo. 12 mg of -2,5-dihydro-1H-pyrrol-3-yl] -propionic acid methyl ester (i) was obtained (yield: 87%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.88-7.83 (m, 3H), 7.62-7.47 (m, 6H), 6.68 (br t, 1H), 4.62 (s, 2H), 3.75 (d, 2H) ), 3.68 (s, 3H), 2.67-2.64 (m, 4H)

Step 3: Preparation of N- {4- [3- (2-hydroxycarbamoyl-ethyl) -2-oxo-2,5-dihydro-pyrrol-1-yl-methyl] -phenyl} -benzamide (j) Step 2 7 mg of compound (i) prepared in step 1 was dissolved in a methanol solution (0.02 mmol), then a 1.7 M methanolic suspension containing NH ₂ OK (0.4 ml, 0.68 mmol) was dissolved. To this was added at 0 ° C. and the resulting mixture was stirred at room temperature for 8 hours. The resulting mixture was neutralized with 0.01 ml of acetic acid, diluted with a 10% methanol / chloroform solution, filtered and concentrated in vacuo. The obtained compound was purified by column chromatography on silica gel using a mixed solvent of methanol and chloroform (1: 9) as an eluent to give 3N- {4- [3- (2-hydroxycarbamoyl-ethyl) -2 3.2 mg of -oxo-2,5-dihydro-pyrrol-1-yl-methyl] -phenyl} -benzamide (j) was obtained (yield: 46%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.86 (d, J = 6.6 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.53-7.39 (m, 4H), 7.17 (d, J = 8.4 Hz, 2 H), 6.77 (br t, 1 H), 4.57 (s, 2 H), 3.77 (s, 2 H), 2.58 (t, J = 7.3 Hz, 2 H), 2.31 (t, J = 7.2 Hz, 2H)

Preparation of N-hydroxy-3- {2-oxo-1- [4- (toluene-4-sulfonylamino) -benzyl] -2,5-dihydro-1H-pyrrol-3-yl} -propionamide (19j) In a similar procedure as described in Example 18, N-hydroxy-3- {2-oxo-1- [4- (toluene-4-sulfonylamino) -benzyl] -2,5-dihydro-1H-pyrrole- 3-yl} -propionamide (19j) was prepared (see Table 3).
(Table 3)

Preparation of 2- (1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -N-hydroxy-acetamide (20q)

Step 1: Preparation of 3- (allyl-benzyl-carbamoyl) -but-3-enoic acid methyl ester (o) 300 mg (2.04 mmol) of allylbenzylamine dissolved in methylene chloride solution (0.5 M). To the reaction solution contained, 587 mg (4.07 mmol) of 2-methylenesuccinic acid 4-methyl ester, 781 mg (4.07 mmol) of 1- [3- (dimethylamino) -propyl-3-ethylcarbodiimide, And 75 mg (0.61 mmol) of 4- (dimethylamino) pyridine was added with stirring at room temperature for 10 hours. After the resulting mixture was washed with 5% HCl solution (10 ml), the mixture was diluted with ethyl acetate, washed with 10 ml of a solution mixture of saturated NaHCO ₃ solution and saturated NaCl solution, and the organic and aqueous layers And separated. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The product was purified by column chromatography on silica gel using a mixed solvent of EtOAc and hexane (1: 1) as eluent to give 3- (allyl-benzyl-carbamoyl) -but-3-enoic acid methyl ester (o ) (272 mg) was obtained (yield: 49%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.30-7.22 (m, 5H), 5.84-5.71 (m, 1H), 5.37-5.15 (m, 4H), 4.75-4.65 (m, 2H), 4.02 ( s, 2H), 3.63 (s, 3H), 3.48 (s, 2H)

Step 2: Preparation of (1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -acetic acid methyl ester (p) Grubbs such as ruthenium dissolved in CH ₂ Cl ₂ (I ) To a catalyst solution containing 36 mg of catalyst, 234 mg (0.1) of 3- (allyl-benzyl-carbamoyl) -but-3-enoic acid methyl ester (o) prepared in Step 1 above under Ar atmosphere. Mmol) was added. The mixture was then stirred at room temperature for 24 hours, filtered and concentrated in vacuo. The product was purified by column chromatography on silica gel using a mixed solvent of EtOAc and hexane (1: 2) as eluent to give (1-benzyl-2-oxo-2,5-dihydro-1H-pyrrole-3 180 mg of (yl) -acetic acid methyl ester (p) were obtained (yield: 85%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.33-7.18 (m, 5H), 6.94 (t, J = 1.5 Hz, 1H), 4.61 (s, 2H), 3.79 (d, J = 0.7 Hz, 2H ), 3.70 (s, 3H), 3.37 (d, J = 1.5Hz, 2H)

Step 3: Preparation of 2- (1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -N-hydroxy-acetamide (q) Prepared in step 2 above (1-benzyl 2-Oxo-2,5-dihydro-1H-pyrrol-3-yl) -acetic acid methyl ester (p) 24 mg was dissolved in methanol solution (0.1 mmol) and then NH ₂ OK (0.4 ml , 0.68 mmol) was added to this at 0 ° C. and the resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with a 10% methanol / chloroform solution, filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on silica gel using a mixed solvent of methanol and chloroform (1: 9) as eluent to give 2- (1-benzyl-2-oxo-2,5-dihydro-1H 12 mg of (pyrrol-3-yl) -N-hydroxy-acetamide (q) were obtained (yield: 48%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.35-7.21 (m, 5H), 7.05 (br t, 1H), 4.63 (s, 2H), 3.90 (s, 2H), 3.30 (t, J = 1.5 Hz, 1H), 3.13 (s, 2H)

Preparation of 2- [1- (2,4-dimethoxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxy-acetamide (21q) described in Example 20 above In a similar procedure to 2- [1- (2,4-dimethoxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxy-acetamide (21q) Prepared (see Table 4).

Preparation of N-hydroxy-2- (2-oxo-1-phenethyl-2,5-dihydro-1H-pyrrol-3-yl) -acetamide (22q) In a similar procedure as described in Example 20 above, N -Hydroxy-2- (2-oxo-1-phenethyl-2,5-dihydro-1H-pyrrol-3-yl) -acetamide (22q) was prepared (see Table 4).

Preparation of N-hydroxy-2-[(2-oxo-1 (4-phenyl-butyl) -2,5-dihydro-1H-pyrrol-3-yl) -acetamide (23q) As described in Example 20 above In a similar procedure, N-hydroxy-2-[(2-oxo-1 (4-phenyl-butyl) -2,5-dihydro-1H-pyrrol-3-yl) -acetamide (23q) was prepared ( (See Table 4).

Preparation of 2- [1- (4-benzyloxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxy-acetamide (24q) As described in Example 20 above. 2- [1- (4-Benzyloxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxy-acetamide (24q) was prepared by a procedure similar to (See Table 4).
(Table 4)

Preparation of 2- (1-benzyl-2-oxo-pyrrolidin-3-yl) -N-hydroxy-acetamide (25s)

Step 1: Preparation of (2-oxo-1-phenethyl-pyrrolidin-3-yl) -acetic acid methyl ester (25r)
30 mg of 1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -acetic acid methyl ester was dissolved in a methanol solution (0.12 mmol) under a nitrogen stream. Then 2.6 mg (0.02 mmol) of Pd—C was added and hydrogenated under a hydrogen balloon at room temperature for 1-2 hours. The reaction mixture was filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on silica gel using a mixed solvent of EtOAc and hexane (1: 1) as eluent to give (2-oxo-1-phenethyl-pyrrolidin-3-yl) -methyl acetate The ester (25r) was obtained (yield: 95%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.34–7.19 (m, 5H), 4.44 (ab, J = 19.8 Hz, 7.4 Hz, 2H), 3.67 (s, 3H), 3.21-3.16 (m, 2H) ), 2.96 (m, 2H), 2.43 (dd, J = 8.7 Hz, 7.9 Hz, 1H), 2.34-2.23 (m, 1H), 1.76-1.65 (m, 1H)

Step 2: Preparation of 2- (1-benzyl-2-oxo-pyrrolidin-3-yl) -N-hydroxy-acetamide (25s) (2-oxo-1-phenethyl-pyrrolidine-3 prepared in Step 1 above ) -Ill) -acetic acid methyl ester (25r) 12 mg dissolved in methanol solution (0.04 mmol), then 1.7 M methanolic suspension containing NH ₂ OK (0.07 ml, 0.12 mmol) The liquid was added to this at 0 ° C. and the resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with a 10% methanol / chloroform solution, filtered and concentrated in vacuo. The obtained compound was purified by column chromatography on silica gel using a mixed solvent of methanol and chloroform (1: 9) as an eluent to give 2- (1-benzyl-2-oxo-pyrrolidin-3-yl)- 1.6 mg of N-hydroxy-acetamide (25s) was obtained (yield: 8%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.34–7.19 (m, 5H), 4.46 (d, J = 8.1 Hz, 2H), 3.35-3.20 (m, 2H), 3.01-2.71 (m, 2H) 2.66-2.44 (m, 2H), 2.35-2.22 (m, 2H), 1.81-1.58 (m, 2H)

Preparation of 2- [1- (2,4-dimethoxy-benzyl) -2-oxo-pyrrolidin-3-yl] -N-hydroxy-acetamide (26s) In a similar procedure as described in Example 25 above, -[1- (2,4-Dimethoxy-benzyl) -2-oxo-pyrrolidin-3-yl] -N-hydroxy-acetamide (26s) was prepared (see Table 5).

Preparation of N-hydroxy-2- (2-oxo-1-phenethyl-pyrrolidin-3-yl) -acetamide (2s) In a similar procedure as described in Example 25 above, N-hydroxy-2- (2- Oxo-1-phenethyl-pyrrolidin-3-yl) -acetamide (27s) was prepared (see Table 5).
(Table 5)

Preparation of 3- {1- [2- (2-fluoro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide (28y)

Step 1: Preparation of toluene-4-sulfonic acid-2- (2-fluoro-phenyl) -ethyl ester (u) 500 mg of 2- (2-fluoro-phenyl) -ethanol dissolved in methylene chloride solution (3. 57 ml) was added to a reaction solution (3.57 mmol), 1.02 g (5.35 mM) of p-toluenesulfonyl chloride, 1.24 ml (7.13 mmol) of diisopropylethylamine and 4- (dimethylamino). 86 mg (0.71 mmol) of pyridine was added with stirring at 0 ° C. under Ar atmosphere for 6 hours, and then the reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was neutralized with ammonium chloride, extracted with ethyl acetate, washed with saturated NaCl solution, and separated into an organic layer and an aqueous layer. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The product was purified by column chromatography on silica gel using a mixed solvent of methanol and chloroform (1: 7) as eluent to give toluene-4-sulfonic acid-2- (2-fluoro-phenyl) -ethyl ester. 740 mg of (u) was obtained (yield: 70%).

Step 2: Preparation of allyl- [2- (2-fluoro-phenyl) -ethyl] -amine (v) Toluene-4-sulfonic acid-2- (2) prepared in Step 1 above, dissolved in acetonitrile. To a reaction solution (1.2 mmol) containing 350 mg of -fluoro-phenyl) -ethyl ester (u) was added 0.89 ml (11.9 mmol) of allylamine and 0.31 ml (1.78 mM) of diisopropylethylamine. Added with stirring at 80 ° C. for 6 hours. After the reaction mixture was neutralized with 10% NaOH solution, the mixture was extracted with chloroform, washed with saturated NaCl solution, dried over MgSO ₄ , filtered and concentrated in vacuo. The product was purified by column chromatography on silica gel using a mixed solvent of methanol and chloroform (1: 9) as eluent to give allyl- [2- (2-fluoro-phenyl) -ethyl] -amine (v ) Was obtained (yield: 66%).

Step 3: Preparation of 4- {allyl- [2- (3-fluoro-phenyl) -ethyl] -carbamoyl} -pent-4-enoic acid methyl ester (w) Allyl- [2-prepared in Step 2 above To a reaction solution (0.56 mmol) in which 100 mg of (2-fluoro-phenyl) -ethyl] -amine (v) was dissolved in methylene chloride was added 2-methylene-pentane-dioic acid-5-methyl ester. 106 mg (0.67 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide 139 mg (0.73 mmol) and 4- (dimethylamino) pyridine 20 mg (0.17 mmol) The mixture was added and stirred at room temperature for 10 hours. After the resulting mixture was washed with 5% HCl solution (10 ml), the mixture was extracted with ethyl acetate and washed with saturated NaCl. The extract was then washed with 10 ml of saturated NaHCO ₃ solution and NaCl solution and separated into organic and aqueous layers. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The product was purified by column chromatography on silica gel using a mixed solvent of EtOH and hexane (1: 2) as eluent to give 4- {allyl- [2- (3-fluoro-phenyl) -ethyl]- 128 mg of carbamoyl} -pent-4-enoic acid methyl ester (w) was obtained (yield: 72%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.19-7.09 (m, 1H), 7.04-6.94 (m, 3H), 5.84-5.57 (m, 1H), 5.13 (t, J = 10.7 Hz, 4H) , 5.06-4.94 (m, 2H), 3.79 (s, 2H), 3.62 (s, 4H), 3.53 (d, J = 5.4Hz, 3H), 2.89 (d, J = 6.0Hz, 3H)

Step 4: Preparation of 3- {1- [2- (2-Fluoro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionic acid methyl ester (x) A catalyst solution containing 27 mg (0.03 mmol) of the ruthenium catalyst dissolved in 3.13 ml of CH ₂ Cl ₂ was added to the 4- {allyl- [2- 100 mg (0.31 mmol) of (3-fluoro-phenyl) -ethyl] -carbamoyl} -pent-4-enoic acid methyl ester (w) was added. The mixture was then stirred at room temperature for 24 hours, filtered and concentrated in vacuo. The product was purified by column chromatography on silica gel using a mixed solvent of EtOAc and hexane (1: 2) as eluent to give 3- {1- [2- (2-fluoro-phenyl) -ethyl] -2 69 mg of -oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionic acid methyl ester (x) was obtained (yield: 75%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.16-7.12 (m, 2H), 7.03-6.93 (m, 2H), 6.59 (brt, 1H), 3.67-3.65 (m, 4H), 3.62 (s , 3H), 2.89 (t, J = 7.3 Hz, 2H), 2.56 (s, 4H)

Step 5: of 3- {1- [2- (2-Fluoro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide (28y) Preparation 3- {1- [2- (2-Fluoro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionic acid methyl ester prepared in step 4 above 38 mg of (x) was dissolved in a methanol solution (0.13 mmol), then a 1.7M methanolic suspension containing NH ₂ OK (0.38 ml, 0.65 mmol) was added to this at 0 ° C. The resulting mixture was stirred at room temperature for 8 hours. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with a 10% methanol / chloroform solution, filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on silica gel using a mixed solvent of methanol and chloroform (1: 9) as eluent to give 3- {1- [2- (2-fluoro-phenyl) -ethyl] 25 mg of -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide (28y) was obtained (yield: 65%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.19-7.08 (m, 2H), 7.02-6.92 (m, 2H), 6.69 (br t, 1H), 3.69 (s, 2H), 3.63 (t, J = 7.0Hz, 2H), 2.87 (t, J = 7.0Hz, 2H), 2.51 (t, J = 7.0Hz, 2H), 2.25 (t, J = 7.3Hz, 2H)

Preparation of 3- {1- [2- (3-fluoro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide (29y) In a similar procedure as described in Example 28, 3- {1- [2- (3-fluoro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N -Hydroxy-propionamide (29y) was prepared (see Table 6).

Preparation of 3- {1- [2- (4-fluoro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide (30y) In a similar procedure as described in Example 28, 3- {1- [2- (4-fluoro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N -Hydroxy-propionamide (30y) was prepared (see Table 6).

Preparation of N-hydroxy-3- {1- [2- (2-nitro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide (31y) In a similar procedure as described in Example 28, N-hydroxy-3- {1- [2- (2-nitro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrole-3- IL} -propionamide (31y) was prepared (see Table 6).

Preparation of N-hydroxy-3- {1- [2- (3-nitro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide (32y) In a similar procedure as described in Example 28, N-hydroxy-3- {1- [2- (3-nitro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrole-3- IL} -propionamide (32y) was prepared (see Table 6).

Preparation of N-hydroxy-3- {1- [2- (4-nitro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide (33y) In a similar procedure as described in Example 28, N-hydroxy-3- {1- [2- (4-nitro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrole-3- IL} -propionamide (33y) was prepared (see Table 6).

Preparation of 3- {1- [2- (2-bromo-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide (34y) In a similar procedure as described in Example 28, 3- {1- [2- (2-bromo-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N -Hydroxy-propionamide (34y) was prepared (see Table 6).

Preparation of 3- {1- [2- (4-Bromo-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide (35y) In a similar procedure as described in Example 28, 3- {1- [2- (4-bromo-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N -Hydroxy-propionamide (35y) was prepared (see Table 6).

Preparation of N-hydroxy-3- {1- [2- (2-methoxy-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide (36y) In a similar procedure as described in Example 28, N-hydroxy-3- {1- [2- (2-methoxy-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrole-3- IL} -propionamide (36y) was prepared (see Table 6).

Preparation of N-hydroxy-3- {1- [2- (3-methoxy-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide (37y) In a similar procedure as described in Example 28, N-hydroxy-3- {1- [2- (3-methoxy-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrole-3- IL} -propionamide (37y) was prepared (see Table 6).

Preparation of N-hydroxy-3- {1- [2- (4-methoxy-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide (38y) In a similar procedure as described in Example 28, N-hydroxy-3- {1- [2- (4-methoxy-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrole-3- IL} -propionamide (38y) was prepared (see Table 6).

Preparation of N-hydroxy-3- [2-oxo-1- (2-p-tolyl-ethyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide (39y) described in Example 28 above In a similar procedure to N-hydroxy-3- [2-oxo-1- (2-p-tolyl-ethyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide (39y) Prepared (see Table 6).
(Table 6)

Preparation of N-hydroxy-3- {1- [3- (4-methoxy-phenyl) -propyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide (40ah)

Step 1: Preparation of 3-p-tolyl-acrylic acid methyl ester (40aa) 1 g of p-tolualdehyde and 4.16 g (12.45 mmol) of triphenylphosphanylideneacetic acid methyl ester were dissolved in methylene chloride, The reaction solution was stirred at 90 ° C. overnight. The resulting mixture was concentrated under reduced pressure and a mixed solvent of EtOAc and hexane (1: 7) was added to it with stirring for 1 hour, then the white solid was removed on the filter and the residue was filtered And concentrated in vacuo to give 1.39 g of 3-p-tolyl-acrylic acid methyl ester (40aa) (yield: 95%).

Step 2: Preparation of 3-p-tolyl-propionic acid methyl ester (40ab) 1.39 g of 3-p-tolyl-acrylic acid methyl ester (40aa) prepared in Step 1 above was dissolved in a methanol solution ( 7.9 mmol). Pd-C was then added to it and hydrogenated under a hydrogen balloon at room temperature for 1-2 hours. The reaction mixture was filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on silica gel using a mixed solvent of EtOAc and hexane (1:10) as eluent to give 1.24 g of 3-p-tolyl-propionic acid methyl ester (40ab). Obtained (yield: 95%).

Step 3: Preparation of 3-p-tolyl-propan-1-ol (40ac) 1.24 g of 3-p-tolyl-propionic acid methyl ester (40ab) prepared in Step 2 above was dissolved in tetrahydrofuran under argon atmosphere. Dissolved in 100 ml. Next, 27 ml of lithium aluminum hydride was added thereto with stirring at 0 ° C. for 2 hours. To the reaction mixture was sequentially added 3 ml of distilled water, 3 ml of NaOH (1N) and 9 ml of distilled water, and the mixture was stirred for 30 minutes, filtered using Celite in a glass filter, and concentrated in vacuo. It was. The product was purified by column chromatography on silica gel using a mixed solvent of methanol and chloroform (1: 2) as eluent to give 971 mg of 3-p-tolyl-propan-1-ol (40ac). (Yield: 93%).

Step 4: Preparation of toluene-4-sulfonic acid-3-p-tolyl-propyl ester (40ad) 3-p-tolyl-propan-1-ol ( 40ac) prepared in Step 3 above dissolved in methylene chloride ) In a reaction solution (6.46 mmol) containing 971 mg, 2.46 g (13 mmol) of tosyl chloride, 3.4 ml (19.4 mmol) of diisopropylethylamine and 158 mg of 4- (dimethylamino) pyridine ( 1.29 mmol) was added with stirring at 0 ° C. under Ar atmosphere for 6 hours, and then the reaction mixture was stirred at room temperature for 12 hours. After the reaction mixture was neutralized with ammonium chloride, the mixture was extracted with ethyl acetate, washed with saturated NaCl solution, dried over MgSO ₄ , filtered and concentrated in vacuo. The product was purified by column chromatography on silica gel using a mixed solvent of methanol and chloroform (1: 7) as eluent to give toluene-4-sulfonic acid-3-p-tolyl-propyl ester (40ad). 1.3 g was obtained (yield: 70%).

Step 5: Preparation of allyl- (3-p-tolyl-propyl) -amine (40ae) Allyl- (3-p-tolyl-propyl) -amine (40ae) prepared in step 4 above dissolved in acetonitrile To a reaction solution containing 1.3 g of (4.27 mmol), 1.6 ml (21.4 mmol) of allylamine and 0.97 ml (5.5 mM) of diisopropylethylamine were added with stirring at 100 ° C. for 6 hours. It was. After the reaction mixture was neutralized with 10% NaOH solution, the mixture was extracted with chloroform, washed with saturated NaCl solution, dried over MgSO ₄ , filtered and concentrated in vacuo. The product was purified by column chromatography on silica gel using a mixed solvent of methanol and chloroform (1: 9) as eluent to obtain 687 mg of allyl- (3-p-tolyl-propyl) -amine (40ae). Obtained (yield: 85%).

Step 6: Preparation of 4- [allyl- (3-p-tolyl-propyl) -carbamoyl] -pent-4-enoic acid methyl ester (40af) Prepared in Step 5 above in 0.5M of methylene chloride solution. To a reaction solution (3.62 mmol) in which 687 mg of allyl- (3-p-tolyl-propyl) -amine (40ae) was dissolved, 683 mg (4.3 of 2-methylene-pentanedioic acid-5-methyl ester was added. Mmol), 902 mg (4.7 mmol) of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide and 133 mg (1.09 mmol) of 4- (dimethylamino) pyridine were added under Ar atmosphere. And the mixture was stirred at room temperature for 10 hours. After the resulting mixture was washed with 5% HCl solution (10 ml), the mixture was extracted with ethyl acetate and washed with saturated NaCl. The extract was then washed with 10 ml of saturated NaHCO ₃ solution and NaCl solution and separated into organic and aqueous layers. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The product was purified by column chromatography on silica gel using a mixed solvent of EtOAc and hexane (1: 2) as eluent to give 4- [allyl- (3-p-tolyl-propyl) -carbamoyl] -pento. 797 mg of 4-enoic acid methyl ester (40af) was obtained (yield: 73%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.05 (s, 4H), 5.70 (s, 1H), 5.16-5.07 (m, 4H), 3.94 (s, 2H), 3.64 (t, J = 3.3 Hz , 3H), 3.36 (s, 2H), 2.67-2.15 (m, 6H), 2.28 (s, 3H), 1.83 (t, J = 7.7Hz, 2H)

Step 7: Preparation of 3- [2-oxo-1- (3-p-tolyl-propyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionic acid methyl ester (40ag) CH ₂ Cl ₂ To the catalyst solution containing 180 mg (0.1 mmol) of the ruthenium catalyst dissolved in 200 ml of 4- [allyl- (3-p-tolyl-propyl) -carbamoyl]-prepared in step 6 above. 797 mg (2.6 mmol) of pent-4-enoic acid methyl ester (40af) was added under Ar atmosphere. The mixture was then stirred at room temperature for 24 hours, filtered and concentrated in vacuo. The product was purified by column chromatography on silica gel using a mixed solvent of EtOH and hexane (1: 1) as eluent to give 3- [2-oxo-1- (3-p-tolyl-propyl)- 391 mg of 2,5-dihydro-1H-pyrrol-3-yl] -propionic acid methyl ester (40ag) was obtained (yield: 50%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.96 (s, 4H), 6.56 (s, 1H), 3.67 (s, 2H), 3.55 (s, 3H), 3.37 (t, J = 7.2 Hz, 2H ), 2.48 (t, J = 8.2 Hz, 6H), 2.19 (s, 3H), 1.76 (t, J = 7.6 Hz, 2H)

Step 8: Preparation of N-hydroxy-3- [2-oxo-1- (3-p-tolyl-propyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide (40ah) Step 7 above Of 100 mg of 3- [2-oxo-1- (3-p-tolyl-propyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionic acid methyl ester (40ag) prepared in 1 1.7M methanolic suspension dissolved in (0.33 mmol) and then containing NH ₂ OK (0.82 ml, 5.0 mmol) was added to it at 0 ° C. and the resulting mixture was Stir at room temperature for 8 hours. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with a 10% methanol / chloroform solution, filtered and concentrated in vacuo. The obtained compound was purified by column chromatography on silica gel using a mixed solvent of methanol and chloroform (1: 9) as an eluent to give N-hydroxy-3- [2-oxo-1- (3-p- 50 mg of (tolyl-propyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide (40ah) was obtained (yield: 50%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.21 (s, 4H), 6.95 (s, 1H), 3.96 (s, 2H), 3.60 (s, 2H), 2.72 (s, 5H), 2.45 (s , 3H), 1.99 (s, 2H)

Preparation of N-hydroxy-3- [2-oxo-1- (3-o-tolyl-propyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide (41ah) described in Example 40 above In a similar procedure to N-hydroxy-3- [2-oxo-1- (3-o-tolyl-propyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide (41ah) Prepared (see Table 7).

Preparation of N-hydroxy-3- [2-oxo-1- (3-m-tolyl-propyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide (42ah) described in Example 40 above In a similar procedure to N-hydroxy-3- [2-oxo-1- (3-m-tolyl-propyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide (42ah) Prepared (see Table 7).

Preparation of N-hydroxy-3- {1- [3- (4-isopropyl-phenyl) -propyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide (43ah) In a similar procedure as described in Example 40, N-hydroxy-3- {1- [3- (4-isopropyl-phenyl) -propyl] -2-oxo-2,5-dihydro-1H-pyrrole-3- IL} -propionamide (43ah) was prepared (see Table 7).

Preparation of 3- {1- [3- (4-Bromo-phenyl) -propyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide (44ah) In a similar procedure as described in Example 40, 3- {1- [3- (4-bromo-phenyl) -propyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N -Hydroxy-propionamide (44ah) was prepared (see Table 7).

Preparation of 3- {1- [3- (4-chloro-phenyl) -propyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide (45ah) In a similar procedure as described in Example 40, 3- {1- [3- (4-chloro-phenyl) -propyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N -Hydroxy-propionamide (45ah) was prepared (see Table 7).

Preparation of N-hydroxy-3- {1- [3- (4-methoxy-phenyl) -propyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide (46ah) In a similar procedure as described in Example 40, N-hydroxy-3- {1- [3- (4-methoxy-phenyl) -propyl] -2-oxo-2,5-dihydro-1H-pyrrole-3- IL} -propionamide (46ah) was prepared (see Table 7).

Preparation of N-hydroxy-3- {1- [3- (2-methoxy-phenyl) -propyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide (47ah) In a similar procedure as described in Example 40, N-hydroxy-3- {1- [3- (2-methoxy-phenyl) -propyl] -2-oxo-2,5-dihydro-1H-pyrrole-3- IL} -propionamide (47ah) was prepared (see Table 7).

Preparation of N-hydroxy-3- {1- [3- (3-methoxy-phenyl) -propyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide (48ah) In a similar procedure as described in Example 40, N-hydroxy-3- {1- [3- (3-methoxy-phenyl) -propyl] -2-oxo-2,5-dihydro-1H-pyrrole-3- Il} -propionamide (48ah) was prepared (see Table 7).
(Table 7)

Preparation of N-hydroxy-3- (1-naphthalen-2-ylmethyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -propionamide (1e ′) As described in Example 1 above In a similar procedure, N-hydroxy-3- (1-naphthalen-2-ylmethyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -propionamide (1e ′) was prepared ( (See Table 8).
(Table 8)

Preparation of N-hydroxy-3- (1-methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -propionamide (2h ')

Step 1. Preparation of 3- (2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -propionic acid methyl ester (2f ) 0.1 ml of triethylsilane (0.63 mmol), 0.7 ml at 0 ° C [3- (1- (2,4-Dimethoxybenzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionic acid methyl ester (0.63 mmol) dissolved in trifluoroacetic acid solution Add to reaction solution containing 200 g. After the reaction, the mixture was heated for 1 hour, filtered to remove the solvent and concentrated in vacuo. Next, the obtained mixture was dissolved in 20 ml of chloroform solution and separated into an organic layer and an aqueous layer. The organic layer was washed with 5 ml of saturated NaHCO ₃ solution and 5 ml of saturated NaCl solution, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on silica gel eluting with a solvent mixture of EtOAc and hexane (19: 1) to give 3- (2-oxo-2,5-1H-pyrrol-3-yl) -50 mg of propionic acid methyl ester (2f) was obtained (yield: 47%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.76 (br t, 1H), 3.89 (d, J = 1.3 Hz, 2H), 3.63 (t, J = 1.9 Hz, 3H), 2.58 (s, 4H )

Step 2. Preparation of 3- (1-Methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -propionic acid methyl ester (2 g)
0.33 ml of NaHMDS solution (1.0 mol in THF, 0.33 mmol) was added to 50 mg of 3- (2-oxo-2,5-1H-pyrrol-3-yl) -propionic acid methyl ester (2f) prepared in step 1. (0.695 mmol) in 0.6 ml THF solution was added dropwise at −79 ° C. and stirred for 30 minutes. 0.3 ml of dimethyl sulfate (0.359 mmol) was added thereto, followed by stirring at 0 ° C. for 4 hours. The resulting mixture was then dissolved in 2 ml saturated NH ₄ Cl solution, extracted with 7 ml ethyl acetate and separated into organic and aqueous layers. The organic layer was washed with 2 ml saturated NaHCO ₃ solution and 2 ml saturated NaCl solution, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on silica gel using EtOAc as the eluent and 18 mg of 3- (1-methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -propion Acid methyl ester (2 g) was obtained (yield: 33%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.65 (br t, 1H), 3.81 (s, 1H), 3.64 (s, 3H), 3.01 (s, 3H), 2.60 (t, 4H).

Step 3. Preparation of N-hydroxy-3- (1-methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -propionamide (2h) 3- (1 -Methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -propionic acid methyl ester (2 g) 18 mg was dissolved in methanol solution (0.1 mmol) and then at 0 ° C. NH ₂ OK Add 1.7 moles of methanolic suspension containing (0.09 ml, 0.15 mmol). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was neutralized with 0.03 ml of acetic acid, diluted with 10% methanol / chloroform solution, filtered and concentrated in vacuo. The obtained compound was purified by column chromatography on silica gel using a mixed solvent of EtOAc and methanol (5: 2) as an eluent, and 11 mg of N-hydroxy-3- (1-methyl-2-oxo-2,5 -Dihydro-1H-pyrrol-3-yl) -propionamide (2h) was obtained (yield: 59%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.76 (br t, 1H), 3.84 (s, 2H), 3.00 (s, 3H), 2.59 (t, J = 7.2 Hz, 2H), 2.42 (t , J = 7.2 Hz, 2H)

Preparation of 3- (1-allyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -N-hydroxy-propionamide (3h ')
3- (1-allyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -N-hydroxy-propionamide (3h ′) was prepared in a manner similar to that described in Example 50 above. (See Table 9).
(Table 9)

Preparation of N-hydroxy-3- [1- (2-naphthalen-1-yl-ethyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide (4n ')
N-hydroxy-3- [1- (2-naphthalen-1-yl-ethyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide (4n ') Prepared by a similar procedure as described in 28 (see Table 10).

Preparation of N-hydroxy-3- [1- (2-naphthalen-2-yl-ethyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide (5n ')
N-hydroxy-3- [1- (2-naphthalen-2-yl-ethyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide (5n ′) Prepared by a procedure similar to that described in Example 28 (see Table 10).

Preparation of N-hydroxy-3- [2-oxo-1- (2-thiophen-2-yl-ethyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide (6n ')
N-hydroxy-3- [2-oxo-1- (2-thiophen-2-yl-ethyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide (6n ′) Prepared by the same procedure as described in 28 (see Table 10).
(Table 10)

Preparation of 3- [1- (3-biphenyl-4-yl-propyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxy-propionamide (7w ′)
3- [1- (3-Biphenyl-4-yl-propyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxy-propionamide (7w ′) was prepared from the above examples. Prepared by a similar procedure as described in 40 (see Table 11).

Preparation of N-hydroxy-3- [1- (3-naphthalen-2-yl-propyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide (8w ')
N-hydroxy-3- [1- (3-naphthalen-2-yl-propyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide (8w ′) was prepared as described above. Prepared by a similar procedure as described in Example 40 (see Table 11).
(Table 11)

Preparation of 3- [1- (2,4-dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydropyridin-3-yl] -N-hydroxypropionamide (e1)

Step 1. Preparation of but-3-enyl- (2,4-dimethoxybenzyl) amine (b)
0.5 ml 1-bromo-3-butene (4.926 mmol) and 0.94 ml diisopropylethylamine (5.396 mmol) were dissolved in 0.74 ml 2,4-dimethoxybenzylamine (a) (4.926 mmol) in methylene chloride. Add to the reaction solution with stirring. The mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated NaCl solution, dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on silica gel using EtOAc as an eluent to give 436 mg of pure title compound (b) (yield: 40%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.10 (d, J = 8.1 Hz, 1H), 6.41 (m, 2H), 5.75 (m, 1H), 5.01 (m, 2H), 3.78 (s, 3H), 3.77 (s, 3H), 3.70 (s, 2H), 2.63 (t, J = 7.5 Hz, 2H), 2.24 (m, 2H).

Step 2. Preparation of 4- [but-3-enyl- (2,4-dimethoxybenzyl) -carbamoyl] -pent-4-enoic acid methyl ester (c)
714 mg of 2-methylene-pentanedionate-5-methyl ester (4.519 mmol), 953 mg of EDC (4.971 mmol) and 110 mg of DMAP (0.9 mmol) were added to the compound (b) prepared in Step 1 above in methylene chloride. Add to the dissolved 0.5 molar reaction solution. The resulting mixture was diluted with ethyl acetate, washed with 5% HCl solution (10 ml) and 10 ml saturated NaHCO ₃ solution, and separated into organic and aqueous layers. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The obtained compound was purified by silica gel column chromatography using EtOAc and hexane (1: 2) mixed solvent as an eluent, and 1.39 g of 4- [but-3-enyl- (2,4-dimethoxybenzyl) was obtained. -Carbamoyl] -pent-4-enoic acid methyl ester (c) was obtained (yield: 40%).

Step 3. Preparation of 3- [1- (2,4-dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid methyl ester (d) 130 mg (0.360 mmol) of compound (c) prepared in ₂ was added to a catalyst solution in which 20 mg of ruthenium (0.024 mmol) was dissolved in CH ₂ Cl ₂ . The mixture was then stirred at room temperature for 24 hours, filtered and concentrated in vacuo. The obtained compound was purified by column chromatography on silica gel using a methanol / chloroform (1:10) mixed solvent as an eluent to obtain 108 g of the title compound (d) (yield: 90%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ7.17 (d, J = 8.9 Hz, 1H), 6.41 (m, 2H), 6.26 (t, J = 4.3 Hz, 1H), 4.53
(S, 2H), 3.77 (s, 3H), 3.76 (s, 3H), 3.62 (s, 3H), 3.28 (t, J = 7.1 Hz, 2H), 2.61-2.47 (m, 4H), 2.22 ( m, 2H).
¹³ C-NMR (75 MHz, CDCl ₃ ) δ 173.6, 164.8, 160.2, 158.5, 134.2, 133.9, 130.4, 118.0, 104.1, 98.3, 55.2, 51.3, 45.0, 44.3, 33.3, 26.6, 23.9

Step 4. Preparation of 3- [1- (2,4-dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydropyridin-3-yl] -N-hydropropionamide (e1) 46 mg of compound (d) prepared in 3 was dissolved in methanol solution (0.138 mmol), then at 0 ° C., 1.7 M methanol suspension containing NH ₂ OK (0.122 ml, 0.207 mmol) was added to the solution. The suspension was stirred at room temperature for 3 hours. The resulting mixture was neutralized with 0.02 ml acetic acid, diluted with 10 ml ethyl acetate solution, filtered and concentrated in vacuo. The obtained compound was purified by column chromatography on silica gel using a methanol / chloroform (1:10) mixed solvent as an eluent to obtain 32 mg of the title compound (d) (yield: 73%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ7.122 (d, J = 9.0 Hz, 1H), 6.415-6.331 (m, 3H), 4.505 (s, 2H), 3.750 (s, 3H), 3.744 ( s, 3H), 3.271 (t, J = 6.9Hz, 2H), 2.552 (m, 2H), 2.381 (m, 2H), 2.220 (m, 2H).
¹³ C-NMR (75 MHz, CDCl ₃ ) δ 170.1, 165.4, 160.2, 158.5, 135.8, 133.5, 130.4, 117.5, 104.2, 98.3, 55.3,44.9, 44.6, 32.8, 27.1, 23.8

Preparation of N-hydroxy-3- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid (e2)
N-hydroxy-3- (1-benzyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -propionic acid (e2) was prepared in the same manner as described in Example 57 above. (See Table 12).

Preparation of N-hydroxy-3- [1- (4-nitro-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide (e3)
N-hydroxy-3- [1- (4-nitro-benzyl) -2-oxo-1,2,5,6-tetrahydropyridin-3-yl) -propionamide (e3) was described in Example 57 above. It was prepared by the same procedure as that (see Table 12).

Preparation of 3- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-hydroxypropionamide (e4)
3- (1-Benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-hydroxypropionamide (e4) is similar to that described in Example 57 above. Prepared by manipulation (see Table 12).

Preparation of N-hydroxy-3- [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide (e5)
N-hydroxy-3- [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide (e5) is described in Example 57 above. Prepared by a similar procedure as described (see Table 12).

Preparation of N-hydroxy-3- (2-oxo-1-phenylethyl-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide (e6)
N-hydroxy-3- (2-oxo-1-phenylethyl-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide (e6) is similar to that described in Example 57 above. Prepared by manipulation (see Table 12).
(Table 12)

Preparation of 3- [1- (2,4-dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid (f1)

11 mg of LiOH.H ₂ O solution (0.262 mmol) was added at 0 ° C. with 3- [1- (2,4-dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydro-pyridine-3- Yl] -propionic acid methyl ester (d) (0.174 mmol) was added dropwise to a 0.75 ml THF solution containing 58 mg. The reaction mixture was stirred at 0 ° C. for 2 hours and at room temperature for 1 hour and then brought to pH 2 by addition of 5% HCl. The mixture was then extracted 3 times with 10 ml of ethyl acetate and the organic layer was washed with saturated NaCl solution, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The obtained compound was purified by silica gel column chromatography using a methanol / chloroform (1:10) mixed solvent as an eluent to obtain 44 mg of the title compound (f1) (yield: 80%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ7.16 (d, J = 8.9 Hz, 1H), 6.42 (m, 2H), 6.29 (t, J = 4.3 Hz, 1H), 4.54 (s, 2H) , 3.76 (s, 3H), 3.76 (s, 3H), 3.29 (t, J = 7.2 Hz, 2H), 2.56 (m, 4H), 2.22 (m, 2H).
¹³ C-NMR (75 MHz, CDCl ₃ ) δ177.7, 165.1, 160.1, 158.5, 134.6, 133.9, 130.5, 117.7, 104.1, 98.3, 55.2, 44.9, 44.5, 33.5, 26.3, 23.8

Preparation of 3- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid (f2)
3- (1-Benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid (f2) was prepared by a procedure similar to that described in Example 63 above. (See Table 13).

Preparation of 3- [1- (4-nitro-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid (f3)
3- [1- (4-Nitro-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid (f3) is the same as described in Example 63 above. Prepared by a similar procedure (see Table 13).

Preparation of 3- [2-oxo- (3-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid (f4)
3- [2-Oxo- (3-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid (f4) is similar to that described in Example 63 above. Prepared by manipulation (see Table 13).

Preparation of 3- [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid (f5)
3- [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid (f5) is the same as described in Example 63 above. Prepared by a similar procedure (see Table 13).

Preparation of 3- (2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid (f6)
3- (2-Oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid (f6) was prepared by a procedure similar to that described in Example 63 above. (See Table 13).
(Table 13)

Preparation of 3- (1-benzyl-2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -N-pyridin-2-yl-propionamide (g1)
Pyridylamine was added to an organic solvent in which 30 mg of 3- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) propionic acid (0.12 mmol) was dissolved in EDC. The obtained compound was purified by column chromatography on silica gel using a methanol / chloroform (1:20) mixed solvent as an eluent to obtain 16 mg of the title compound (g1) (yield: 39%).

Preparation of N- (2-amino-phenyl) -3- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide (g2)

40 mg of 1,2-phenylenediamine (0.37 mmol), 77 mg of EDC (0.4 mmol) and 1 mg of DMAP (3 mol%) were prepared according to 3- (1-benzyl-2-oxo-1) prepared in Example 8 above. , 2,5,6-Tetrahydro-pyridin-3-yl) propionic acid was added to a reaction solution dissolved in 1 ml of methylene chloride under argon atmosphere. After the mixture was stirred at room temperature for 13 hours, the resulting mixture was diluted with ethyl acetate and washed with 10% NaOH solution (10 ml). It was then extracted with 50 ml of chloroform, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The obtained compound was purified by column chromatography on silica gel using a methanol / chloroform (1:20) mixed solvent as an eluent, and 96 mg of N- (2-amino-phenyl) -3- (1-benzyl-2 -Oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide (g2) was obtained (yield: 91%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ8.29 (s, 1H), 7.29-7.19 (m, 5H), 7.13 (d, 1H, J = 7.8 Hz), 6.99-6.94 (m, 1H), 6.68 (t, 2H, J = 7.9 Hz), 6.37 (t, 1H, J = 8.4 Hz), 4.57 (t, 2H, J = 7.4 Hz), 3.88 (s, 2H), 3.29-3.21 (m, 2H ), 2.68 (t, 2H, J = 6.5Hz), 2.59 (t, 2H, 6.5 Hz), 2.26-2.217 (m, 2H).

Preparation of N- (2-amino-phenyl) -3- [1- (2-methyl-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide (g3)
N- (2-amino-phenyl) -3- [1- (2-methyl-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide (g3) is Prepared by a similar procedure as described in Examples 69 and 70 above (see Table 14).

Preparation of N- (2-amino-phenyl) -3- [1- (2-methyl-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide (g4)
N- (2-amino-phenyl) -3- [1- (2-methyl-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide (g4) is Prepared by a similar procedure as described in Examples 69 and 70 above (see Table 14).
(Table 14)

Preparation of N-benzyloxy-3- (2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide (g5)

Benzyloxyamine was prepared by adding 30 mg (0.15 mmol) of 3- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid prepared in Example 12 above to EDC. It was added to the organic solvent dissolved therein. The obtained compound was purified by column chromatography on silica gel using an ethyl acetate / chloroform (1: 1) mixed solvent as an eluent to obtain 41 mg of the title compound (g5) (yield: 75%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ7.41-7.15 (m, 1H), 6.34 (br t, 1H), 4.88 (s, 2H), 3.58 (t, J = 7.4 Hz, 2H), 3.16 (t, J = 7.2 Hz, 2H), 2.82 (t, J = 7.2 Hz, 2H), 2.53 (t, J = 6.8 Hz, 2H), 2.26 (br s, 1H), 2.19 (dd, J = 11.4 , 7.1 Hz, 2H).

Preparation of 3- [1- (4-acetylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-hydroxy-propionamide (j1)

Step 1. Preparation of 3- [1- (4-amino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid methyl ester (h) Step 3 of Example 1 above 3- [1- (2,4-Dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid methyl ester (d) 50 mg (0.16 mmol) prepared in Was dissolved in methanol at room temperature. Next, 154 mg (2.36 mmol) Zn and 0.01 ml (0.16 mmol) acetic acid were added to it. The mixture was stirred at 80 ° C. for 20 hours. The obtained compound was purified by column chromatography on silica gel using a (1: 1) mixed solvent of ethyl acetate and hexane as an eluent, and 43 mg of 3- [1- (4-amino-benzyl) -2-oxo was obtained. -1,2,5,6-Tetrahydro-pyridin-3-yl] -propionic acid methyl ester (h) was obtained (yield: 92%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ8.22 (d, 1H, J = 8.4 Hz), 8.11 (d, 1H, J = 8.4 Hz), 7.37 (t, 2H, J = 8.3 Hz), 6.33 (t, 1H, J = 4.3 Hz), 4.66 (d, 2H, J = 7.5 Hz), 3.63 (s, 3H), 3.29 (t, 2H, J = 6.6 Hz), 2.63 (t, 2H, J = 6.9 Hz), 2.54 (, 2H, J = 6.6 Hz), 2.28 (t, 2H, J = 4.2 Hz)

Step 2. Preparation of 3- [1- (4-acetylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid methyl ester (i) 17.5 mg of 3- [1- (4-amino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid methyl ester (h) was dissolved in a methylene chloride solution. (0.06 mmol). And then 6 μmol (AcO) 2O (0.07 mmol), 0.01 mol triethylamine (0.08 mmol) and 1.0 mg DMAP (0.008 mmol) were added to it and the mixture was stirred at 0 ° C. for 3 hours. The reaction was stopped by adding methanol and the mixture was extracted three times with 10 ml of ethyl acetate. The organic layer was washed with saturated NaCl solution, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The obtained compound was purified by silica gel column chromatography using ethyl acetate as an eluent, and 46 mg of 3- [1- (4-acetylamino-benzyl) -2-oxo-1,2,5,6 -Tetrahydro-pyridin-3-yl] -propionic acid methyl ester (i) was obtained (yield: 44%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.34 (s, 1H), 7.40 (d, 2H, J = 8.4 Hz), 7.10 (d, 2H, J = 8.4 Hz), 6.29 (t, 1H, J = 4.2 Hz), 4.50 (s, 2H), 3.61 (s, 3H), 3.22 (t, 2H, J = 7.1 Hz), 2.59 (t, 2H, J = 7.1 Hz), 2.51 (d, 2H, J = 6.6 Hz), 2.22 (dd, 2H, J = 6.9 Hz), 2.09 (s, 3H)

Step 3. Preparation of 3- [1- (4-acetylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-propionamide (j1)

3- [1- (4-acetylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid methyl ester (i) prepared according to Step 2 above 3- [1- (4-acetylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-is dissolved in an organic solvent such as methanol and reacted with an amine salt. N-Hydroxy-propionamide (j1) was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.50 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 6.44 (br t, 1H), 4.57 (s, 2H ), 3.33 (t, J = 6.5 Hz, 6H), 2.57 (br t, 2H), 2.30-2.26 (m, 4H), 2.10 (s, 2H)

Preparation of N-4- [5- (2-hydroxycarbamoyl-ethyl) -6-oxo-3,6-dihydro-2-pyridin-1-yl-methyl] -phenyl-benzamide (j2)
N-4- [5- (2-Hydroxycarbamoyl-ethyl) -6-oxo-3,6-dihydro-2-pyridin-1-yl-methyl] -phenyl-benzamide (j2) is obtained in Example 74 above. Prepared by a similar procedure as described (see Table 15).

Preparation of N-2-hydroxy-3- [1- (4-dimethylsulfonylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] propionamide (j3)
N-2-Hydroxy-3- [1- (4-dimethylsulfonylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] propionamide (j3) Prepared by a similar procedure as described in 74 (see Table 15).

N-2-hydroxy-3-2-oxo-1- [4- (toluene-4-sulfonylamino) -benzyl-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide (j4) Preparation of
N-2-hydroxy-3-2-oxo-1- [4- (toluene-4-sulfonylamino) -benzyl-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide (j4) is Prepared by a similar procedure as described in Example 74 above (see Table 15).
(Table 15)

Preparation of 3- [1- (4-acetylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid (k)

3- [1- (4-Acetylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid methyl ester prepared by Step 2 of Example 18 above (I) is dissolved in an organic solvent such as tetrahydrofuran and reacted with LiOH to give 3- [1- (4-acetylamino-vanyl) -2-oxo-1,2,5,6-tetrahydro-pyridine-3- Yl] -propionic acid (k) was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.50 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 6.45 (t, J = 4.5 Hz, 1H), 4.58 (s, 2H), 3.32 (t, J = 7.5 Hz, 3H), 2.57 (t, J = 7.5 Hz, 2H), 2.46 (t, J = 7.5 Hz, 2H)

Preparation of 3- [1- (4-benzoylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid (k2)
3- [1- (4-Benzoylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid (k2) is as described in Example 788 above. (See Table 16).

3-2-oxo-1- [4- (toluene-4-sulfonylamino) -benzyl] -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid (k3) Preparation
3-2-Oxo-1- [4- (toluene-4-sulfonylamino) -benzyl] -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid (k3) is , And was adjusted by the same operation as described in Example 78 (see Table 16).
(Table 16)

Preparation of N-hydroxy-3- (2-oxo-1-phenethyl-piperidin-3-yl) -propionamide (m)

Step 1. Preparation of [1- (2-4-dimethoxy-benzyl) -2-oxo-piperidin-3-yl] -acetic acid methyl ester (l)
3- [1- (2-4-dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydro-piperidin-3-yl] -propionic acid methyl ester was dissolved in an alcohol solvent in a nitrogen atmosphere. Then Pd-C was added to it and the mixture was hydrogenated with a hydrogen balloon for 1-2 hours at room temperature. The reaction mixture was filtered and concentrated in vacuo. The obtained compound was purified by column chromatography on silica gel using an EtOAc / hexane (1: 1) mixed solvent as an eluent, and [1- (2-4-dimethoxy-benzyl) -2-oxo-piperidine- 3-Iyl] -acetic acid methyl ester (l) was obtained (yield: 74%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ7.13 (d, 1H, J = 8.4 Hz), 6.42 (d, 2H, J = 7.2 Hz), 4.51 (ab, 2H, J = 32.9, 7.4 Hz) , 3.76 (s, 6H), 3.66 (s, 3H), 3.24-3.18 (m, 2H), 2.93-2.72 (m, 2H), 2.56-2.43 (m, 1H), 1.98-1.55 (m, 4H)

Step 2. Preparation of N-hydroxy-3- (2-oxo-1-phenethyl-piperidin-3-yl) -propionamide (m)
[1- (2-4-Dimethoxy-benzyl) -2-oxo-piperidin-3-yl] -acetic acid methyl ester (l) prepared by Step 1 above was reacted with an amine salt to give N-hydroxy-3 -(2-Oxo-1-phenethyl-piperidin-3-yl) -propionamide (m) was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.267.17 (m5H), 3.61-3.44 (m 2H), 3.08-2.83 (m 4H), 2.56-2.16 (m 4H)

Preparation of 2- [1- (2,4-dimethoxy-benzyl) 2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-hydroxy-acetamide (p1)
Step 1. Preparation of 3- (Benzyl-3-butenyl-carbamoyl) -but-3-enoic acid methyl ester (n)
2-Methylene-pentanedioxane-5-methyl ester, EDC and DMAP, but-3-enyl- (2,4-dimethoxybenzyl) amine (b) prepared by Step 1 of Example 1 above to methylene chloride It was added to the dissolved reaction solution. The mixture was stirred at room temperature for 5 hours to give 3- (benzyl-but-3-enyl-carbamoyl) -but-3-enoic acid methyl ester (n).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.30-7.19 (m, 5H), 5.69 (br t, 1H), 5.23 (s, 2H), 5.00 (t, 2H, J = 12.6 Hz), 4.74 (s, 2H), 3.61 (s, 3H), 3.42 (s, 4H), 2.30 (q, 2H, J = 7.2 Hz)

Step 2. Preparation of [1- (2,4-dimethoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) acetic acid methyl ester (o) Prepared in step 1 above Solution of 3- (benzyl-but-3-enyl-carbamoyl) -but-3-enoic acid methyl ester (n) dissolved in a grub catalyst such as ruthenium in an organic solvent such as CH ₂ Cl ₂ In addition, [1- (2,4-dimethoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) acetic acid methyl ester (o) was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.17 (d, 1H, J = 6.2 Hz), 6.42-6.36 (m, 3H), 4.54 (s, 2H), 3.76 (d, 6H, J = 3.0 Hz), 3.66 (s, 3H), 3.35 (t, 2H, J = 6.9 Hz), 3.28 (s, 2H), 2.29 (ab, 2H, J = 11.3, 3.4 Hz)

Step 3. Preparation of 2- [1- (2,4-dimethoxy-benzyl) 2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-hydroxy-acetamide (p1)

[1- (2,4-Dimethoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) acetic acid methyl ester (o) prepared in Step 2 above was used as an alcohol solvent. Dissolve and react with amine salt to give 2- [1- (2,4-dimethoxy-benzyl) 2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-hydroxy-acetamide (p1) was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.14 (d, J = 8.7 Hz, 1H), 6.54 (br t, 1H) 6.44 (d, J = 6.0 Hz, 2H), 4.55 (s, 2H) , 3.78 (s, 6H), 3.41-3.32 (m, 2H), 3.20 (s, 2H), 2.0 (d, J = 4.5Hz, 2H)

Preparation of 2- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-hydroxy-acetamide (p2)
2- (1-Benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-hydroxy-acetamide (p2) was prepared in the same manner as described in Example 82 above. (See Table 17).

Preparation of N-hydroxy-2- [1- (4-nitro-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-acetamide (p3)
N-hydroxy-2- [1- (4-nitro-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-acetamide (p3) Prepared by a similar procedure as described in Example 82 (see Table 17).

Preparation of N-hydroxy-2- [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-acetamide (p4)
N-hydroxy-2- [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-acetamide (p4) Prepared by a similar procedure as described in Example 82 (see Table 17).

Preparation of N-hydroxy-2- [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-acetamide (p5)
N-hydroxy-2- [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-acetamide (p5) Prepared by a similar procedure as described in Example 82 (see Table 17).
(Table 17)

Preparation of [1- (2,4-dimethoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-acetamide (q1)

[1- (2,4-Dimethoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) acetic acid prepared by Step 2 of Example 26, dissolved in TFA The methyl ester (o) is reacted with LiOH to give [1- (2,4-dimethoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy- Acetamide (q1) was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.18 (d, J = 8.7 Hz, 1H), 6.54 (t, J = 4.3 Hz, 1H) 6.45 (d, J = 6.6 Hz, 2H), 4.60 ( s, 2H), 3.79 (s, 6H), 3.39 (t, J = 7.3 Hz, 2H), 3.34 (s, 2H), 2.32 (ab, J = 11.7 Hz, 3.6 Hz, 2H)

Preparation of (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -acetic acid (q2)
(1-Benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -acetic acid (q2) was prepared by a procedure similar to that described in Example 87 above (Table 18). reference).

Preparation of (2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -acetic acid (q3)
(2-Oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -acetic acid (q3) was prepared by a procedure similar to that described in Example 87 above (Table 18). reference).

Preparation of [2-oxo-1- (3-phenethyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl) -acetic acid (q4)
[2-Oxo-1- (3-phenethyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl) -acetic acid (q4) is the same procedure as described in Example 87 above. (See Table 18).

Preparation of [2-oxo-1- (3-phenethyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl) -acetic acid (q5)
[2-Oxo-1- (3-phenethyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl) -acetic acid (q5) was prepared in the same manner as described in Example 87 above. (See Table 18).
(Table 18)

Preparation of 2- [1- (2,4-dimethoxy-benzyl) -2-oxo-piperidin-3-yl) -N-hydroxy-acetamide (s1)

Step 1. Preparation of [1- (2,4-dimethoxy-benzyl) -2-oxo-piperidin-3-yl] -acetic acid methyl ester (r)
26 mg of [1- (2,4-dimethoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) acetic acid methyl ester (o) (0.08 mmol) in methanol under Ar atmosphere Dissolved in. Thereto was added 1.7 mg of 10% Pd—C, and the mixture was hydrogenated with a hydrogen balloon. The reaction mixture was stirred at room temperature for 5 hours, filtered and concentrated in vacuo. The obtained compound was purified by silica gel column chromatography to obtain 25 mg of [1- (2,4-dimethoxy-benzyl) -2-oxo-piperidin-3-yl] -acetic acid methyl ester (r). (Yield: 99%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.13 (d, J = 8.4 Hz, 2H), 6.41 (dd, J = 8.4 Hz, 2H), 6.41 (s, 1H), 4.51 (dd, J = 32.7Hz, 14.9Hz, 2H), 3.76 (s, 6H), 3.66 (s, 3H), 3.22 (dd, J = 7.5,4.6Hz, 2H), 2.90 (dd, J = 15.9, 5.1Hz, 1H) , 2.76 (m, 1H), 2.52 (dd, J = 16.2, 7.5 Hz, 2H), 1.98-1.55 (m, 4H).

Step 2. Preparation of [1- (2,4-dimethoxy-benzyl) -2-oxo-piperidin-3-yl] -N-hydroxy-acetamide (s1)
[1- (2,4-Dimethoxy-benzyl) -2-oxo-piperidin-3-yl] -acetic acid methyl ester (r) prepared by Step 1 is reacted with an amine salt to give [1- (2, 4-Dimethoxy-benzyl) -2-oxo-piperidin-3-yl] -N-hydroxy-acetamide (s1) was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.15 (d, J = 9.0 Hz, 1H), 6.46 (t, J = 4.65 Hz, 2H), 4.56 (q, J = 7.2, 23.7 Hz, 2H), 3.79 (s, 6H), 3.31-3.19 (m, 2H), 2.86-2.69 (m, 2H), 2.41 (d, J = 14.1Hz, 1H), 1.89-1.79 (m, 2H).

Preparation of (2-oxo-1-phenethyl-piperidin-3-yl) -N-hydroxy-acetamide (s2)
(2-Oxo-1-phenethyl-piperidin-3-yl) -N-hydroxy-acetamide (s2) was prepared by a procedure similar to that described in Example 92 above (see Table 19).

Preparation of [2-oxo-1- (3-phenyl-propyl) -piperidin-3-yl] -N-hydroxy-acetamide (s3)
[2-Oxo-1- (3-phenyl-propyl) -piperidin-3-yl] -N-hydroxy-acetamide (s3) was prepared by a procedure similar to that described in Example 92 above (Table 19). reference).
(Table 19)

Preparation of 4- [1- (4-Methoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydroxy-butyramide (v1)

Step 1. Preparation of 5-[(4-methoxy-benzyl) -3-butenyl-carbamoyl] -5-hexenoic acid methyl ester (t)
2-Methylene-pentanedionate-5-methyl ester, EDC and DMAP, and but-3-enyl- (2,4-dimethoxybenzyl) amine (b) prepared by Step 1 of Example 1 above into methylene chloride. Added to the dissolved reaction solution. The mixture was stirred at room temperature for 5 hours to give 5-[(4-methoxy-benzyl) -but-3-enyl-carbamoyl] -5-hexenoic acid methyl ester (t).

Step 2. Preparation of 4- [1- (4-methoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -butyric acid methyl ester (u) According to step 1 above Prepared 5-[(4-methoxy-benzyl) -but-3-enyl-carbamoyl] -5-hexenoic acid methyl ester (t), a rubbing catalyst such as ruthenium (I) as CH ₂ Cl ₂ In addition to the catalyst solution dissolved in an organic solvent, 4- [1- (4-methoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -butyric acid methyl ester ( u) got.
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.19 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.25 (t, J = 4.2 Hz, 1H), 4.54 (s, 2H), 3.77 (s, 3H), 3.65 (s, 3H), 3.25 (t, J = 6.9 Hz, 2H), 2.33 (t, J = 7.3 Hz, 4H), 2.24 (q, J = 4.5Hz, 2H), 1.80 (t, J = 7.2Hz, 2H), 1.56 (s, 2H)

Step 3. Preparation of 4- [1- (4-methoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydro-butyramide (v1)
4- [1- (4-Methoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -butyric acid methyl ester (u) prepared by Step 2 in an alcohol solvent Dissolve and react with amine salt to give 4- [1- (4-methoxy-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -N-hydro-butyramide ( v1) was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ7.19-7.15 (m, 2H), 6.83 (d, J = 7.8Hz, 2H), 6.28 (br t, 1H), 4.53 (s, 2H), 3.76 (s, 3H), 3.25 (dt, JA = 7.5Hz, JB = 1.8Hz, 2H), 2.38-2.23 (m, 6H), 1.85-1.76 (m, 2H).

Preparation of 4- (1-phenethyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-hydroxy-butyramide (v2)
4- (1-phenethyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-hydroxy-butyramide (v2) was prepared in the same manner as described in Example 95 above. (See Table 20).

Preparation of N-hydroxy-4- [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -butyramide (v3)
N-hydroxy-4- [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -butyramide (v3) is described in Example 95 above. Prepared by a similar procedure as described (see Table 20).

Preparation of N-hydroxy-4- [2-oxo-1- (3-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -butyramide (v4)
N-hydroxy-4- [2-oxo-1- (3-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -butyramide (v4) is described in Example 95 above. Prepared by a similar procedure as described (see Table 20).
(Table 20)

Preparation of 3- (2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid (g)
50 mg of 3- [1- (2,4-dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid (0.157 mmol) was added to 1 ml of trifluoroacetic acid solution. Dissolved. Then triethylsilane (0.465 mmol) was added to it and the mixture was heated at 80 ° C. for 20 minutes. The solvent is removed in vacuo and the residue is recrystallized with a mixed solution of methanol and ethyl acetate to give 3- (2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)]-propionic acid (G) 13 mg was obtained (yield: 50%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.51 (m, 1H), 3.31 (m, 2H), 2.50 (m, 4H), 2.32 (m, 2H)
¹³ C-NMR (75 MHz, CD ₃ OD), δ176.7, 168.6, 138.4, 134.5, 4.03, 34.1, 27.1, 25.0

Preparation of N-benzyloxy-3- (2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide (h)
29 mg of 3- (2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid (g) was dissolved in 0.5 ml of DMF (0.171 mmol). To it was added 30 mg BnONH ₂ · HCl (0.188 mmol), 0.033 ml diisopropylmethylamine (0.189 mmol), 43 mg EDC (0.224 mmol) and 5 mg DMAP (0.041 mmol) and the mixture was stirred at room temperature overnight. . The mixture was diluted with 7 ml of ethyl acetate and washed with 5% HCl (1 ml) and saturated NaHCO ₃ solution (1 ml). The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The obtained compound was purified by column chromatography on silica gel using a methanol / chloroform (1:20) mixed solvent as an eluent to obtain 126 mg of the title compound (h) (yield: 55%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.28 (s, br, 1H), 7.35 (m, 5H), 6.45 (s, br, 1H), 5.70 (s, br, 1H), 4.87 (s , 2H), 3.47 (s, br, 2H), 2.53 (m, 2H), 2.27 (m, 4H).
¹³ C-NMR (75 MHz, CDCL ₃ ) δ170.1, 166.9, 137.8, 135.6, 133.0, 129.1, 128.5, 78.0, 39.7, 32.8, 26.9, 24.1

Preparation of 3- (1-allyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-hydroxy-propioamide (j1)
Step 1. Preparation of 3- (2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid methyl ester (f)
3 ml of 310 mg 3- [1- (2,4-dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid methyl ester (d) (0.93 mmol) In trifluoroacetic acid solution. Then 0.222 ml of triethylsilane (1.395 mmol) was added to it and the mixture was heated at 80 ° C. for 20 minutes. The solvent was removed in vacuo and the residue was diluted with 20 ml of chloroform. The organic layer was washed with 5 ml saturated NaHCO ₃ solution and 5 ml saturated NaCl solution. The organic layer was then dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The obtained compound was purified by column chromatography on silica gel using EtOAc solvent as an eluent to obtain 126 mg of the title compound (f) (yield: 55%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ6.64 (s, br, 1H), 6.35 (t, J = 3.0 Hz, 1H), 3.59 (s, 3H), 3.31 (m, 2H), 2.48 ( m, 4H), 2.26 (m, 2H)
¹³ C-NMR (75 MHz, CDCL ₃ ) δ 173.4, 166.8, 136.1, 133.5, 51.4, 39.5, 33.1, 26.0, 24.0

Step 2. Preparation of 3- (1-allyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid methyl ester (i1) 3- (2-oxo-1 , 2,5,6-Tetrahydro-pyridin-3-yl) -propionic acid methyl ester in 0.5 ml THF solution, 0.220 ml NaHMDS solution (1.0 mol in THF, 0.22 mmol) − The mixture was added dropwise at 79 ° C, and the mixture was stirred at -79 ° C for 30 minutes. After adding 0.028 ml of allyl bromide (0.327 mmol) to the reaction mixture, the mixture was stirred at 0 ° C. for 3 hours. The reaction mixture was quenched with 2 ml saturated NH ₄ Cl and then the organic layer was extracted with 7 ml ethyl acetate. The combined organic layers were washed with 2 ml saturated NH ₄ Cl solution and 2 ml saturated NaCl solution. The organic layer was then dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The obtained compound was purified by column chromatography on silica gel using an EtOAc / hexane (1: 2) mixed solvent as an eluent to obtain 36 mg of the title compound (i1) (yield: 74%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ6.28 (m, 1H), 5.74 (m, 1H), 5.14 (m, 2H), 3.99 (d, J = 5.7 Hz 2H), 3.61 (s, 3H ), 3.27 (t, J = 6.9 Hz, 2H), 2.51 (m, 4H), 2.27 (m, 2H)
¹³ C-NMR (75 MHz, CDCl ₃ ) δ173.6, 164.6, 134.3, 134.1, 133.3, 117.1, 51.4, 49.0, 44.6, 33.3, 26.6, 23.8

Step 3. Preparation of 3- (1-allyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-hydroxy-propioamide (j1)
24 mg of 3- (1-allyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid methyl ester (i1) obtained from Step 2 was dissolved in a methanol solution ( 0.11 mmol). Next, 0.122 ml (0.207 mmol) of a 1.7 molar NH ₂ OK suspension was added thereto at 0 ° C., and the mixture was stirred at room temperature for 3 hours. The resulting mixture was neutralized with 0.02 ml acetic acid, diluted with 10 ml ethyl acetate solution, filtered and concentrated in vacuo. The obtained compound was purified by column chromatography on silica gel using a methanol / chloroform (1:10) mixed solvent as an eluent to obtain 11 mg of the title compound (j1) (yield: 48%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ6.39 (br t, 1H), 5.78-5.67 (m, 1H), 5.17 (d, J = 5.4 Hz 1H), 5.12 (s, 1H), 3.98 ( d, J = 5.4 Hz, 2H), 3.30 (t, J = 7.0 Hz, 2H), 2.54-2.28 (m, 6H)

Preparation of N-hydroxy-3- (1-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide (j2)

Step 1. Preparation of 3- (1-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid methyl ester (i2)
0.22 ml of 1.0 M NaHMDS in THF (0.22 mmol) was added to 3- (2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propion prepared in Step 1 of Example 3. To 0.5 ml of a THF solution containing 80 mg of acid methyl ester (f) (0.44 mmol) was added dropwise at −79 ° C., and then stirred for 30 minutes. To the reaction mixture 0.48 ml of methyl bromide (0.48 mmol) was added and the solution was stirred at 0 ° C. for 3 hours. The reaction mixture was quenched with 2 ml saturated NH ₄ Cl solution and then the organic layer was extracted with 7 ml ethyl acetate. The combined organic layers were washed with 2 ml of saturated NH ₄ Cl solution followed by 2 ml of saturated NaCl solution. The organic layer was then dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The obtained compound was purified by column chromatography on silica gel using EtOAc as an eluent to obtain 62 mg of the title compound (i2) (yield: 72%).

Step 2. Preparation of N-hydroxy-3- (1-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide (j2)
50 mg of 3- (1-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid methyl ester prepared in Step 1 was dissolved in a methanol solution (0.25 mmol). Then at 0 ° C., 0.122 ml (0.207 mmol) of 1.7 molar NH ₂ OK methanol suspension was added and the resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was neutralized with 0.02 ml acetic acid, diluted with 10 ml ethyl acetate, filtered and concentrated in vacuo. The resulting compound was purified by silica gel column chromatography using a methanol / chloroform (1:20) mixed solvent as an eluent to obtain 19 mg of the title compound (j2) (yield: 35%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ6.15 (t, J = 4.3 Hz, 1H), 3.41 (t, J = 7.2 Hz, 2H), 2.97 (s, 3H), 2.51 (t, J = 7.5 Hz, 2H), 2.35 (m, 2H), 2.22 (t, J = 7.5 Hz, 2H)

Preparation of N-hydroxy-3- (1-naphthalen-2-yl-methyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide
70 mg of 3- [1- (naphthyl-2-yl) methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid methyl ester was dissolved in methanol solution (0.22 mmol). ). And then, at 0 ° C., 0.64 ml (1.08 mmol) of 1.7 molar NH ₂ OK methanol suspension was added and the resulting mixture was stirred at room temperature for 5 hours. The resulting mixture was neutralized with 0.02 ml acetic acid and concentrated in vacuo. The obtained solid was filtered with a 10% methanol / chloroform mixed solvent and concentrated in vacuo. The obtained compound was purified by column chromatography on silica gel using a mixed solvent of methanol / chloroform (1: 9) as an eluent to obtain 61 mg of the title compound (j2) (yield: 95%) (Table 21).

Preparation of N-hydroxy-3- [2-oxo-1- (2-thiophen-2-yl-ethyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide
60 mg of 3- [2-oxo-1- (2-thiophen-2-yl) -ethyl-1,2,5,6-tetrahydro-pyridin-3-yl] -propionic acid methyl ester is dissolved in methanol, To the 0.20 mmol solution was then added 0.6 ml (1.02 mmol) of 1.7 molar NH ₂ OK methanol suspension at 0 ° C. and the resulting mixture was stirred at room temperature for 5 hours. The resulting mixture was neutralized with 0.02 ml acetic acid and concentrated in vacuo. The obtained solid was filtered with a 10% methanol / chloroform mixed solvent and concentrated in vacuo. The obtained compound was purified by silica gel column chromatography using a methanol / chloroform (1: 9) mixed solvent as an eluent to obtain 44 mg of the title compound (yield: 73%) (see Table 21).
(Table 21)

Preparation of 3- (1-benzyl-2-oxo-2,5,6,7-tetrahydro-1H-azepin-3-yl) -hydroxy-propionamide (e1)

Step 1. Preparation of benzyl-pent-4-enyl-amine (b)
While stirring 0.397 ml of 5-bromo-1-pentene (3.35 mmol) and 0.67 ml of diisopropylethylamine (3.96 mmol) in 0.74 ml of benzylamine (a) (4.93 mmol) dissolved in acetonitrile, the reaction solution was stirred. Was added and the mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated NaCl solution, dried over MgSO ₄ , filtered and concentrated in vacuo. The obtained compound was purified by column chromatography on silica gel using EtOAc as an eluent to obtain 236 mg of the title compound (b) (yield: 44%).
¹ H-NMR (300MHz, CDCl ₃ ) δ7.35-7.24 (m, 5H), 5.92-5.78 (m, 1H), 5.09-4.98 (m, 2H), 3.80 (s, 2H), 2.67 (t, J = 7.5Hz,), 2.14 (q, J = 7.5Hz, 2H), 1.69-1.59 (m, 2H), 1.41 (br, 1H)

Step 2. Preparation of 4- (benzyl-pent-4-enyl-carbamoyl) -pent-4-enoic acid methyl ester (c)
320 g of 2-methylene-pentanedionate-5-methyl ester (2.02 mmol), 340 mg of EDC (2.02 mmol) and 50 mg of DMAP (0.405 mmol) Was added to 0.5 mol of the reaction solution dissolved in and the mixture was stirred for 5 hours at room temperature. The resulting mixture was diluted with ethyl acetate, washed with 5% HCl solution (10 ml) and 10 ml saturated NaHCO ₃ solution and separated into organic and aqueous layers. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The resulting product was purified by column chromatography on silica gel eluting with EtOAc / hexane (1: 2) to give 150 mg of 4- [but-3-enyl- (2.4-dimethoxybenzyl) -carbamoyl)] -Pent-4-enoic acid methyl ester (c) was obtained (yield: 35%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.31-7.14 (m, 5H), 5.81-5.64 (m, 1H), 5.12 (s, 1H), 5.04-4.97 (m, 3H), 3.65 (s, 2H), 3.56-3.46 (m, 3H), 3.42-3.36 (m, 1H), 3.33-3.31 (m, 1H), 2.85 (d, J = 3Hz, 2H), 2.65-2.45 (m, 4H), 2.07-2.01 (m, 2H), 1.69-1.59 (m, 2H)

Step 3.3- (1-Benzyl-2-oxo-2,5,6,7-tetrahydro-1H-azepin-3-yl) -propionic acid methyl ester (d)
150 mg of compound (c) (0.476 mmol) prepared in step 2 above was added to a catalyst solution containing 40 mg of ruthenium (0.047 mmol) dissolved in CH ₂ Cl ₂ . It was then stirred at room temperature for 24 hours, filtered and concentrated in vacuo. The obtained product was purified by column chromatography on silica gel using methanol / chloroform (1:10) mixed solvent as an eluent to obtain 108 mg of the title compound (d) (yield: 79%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.28-7.26 (m.5H), 5.99-5.94 (m, 1H), 4.63 (s, 2H), 3.60 (s, 2H), 3.21 (t, J = 6Hz, 2H), 2.65 (t, J = 7.2Hz, 2H), 2.48 (t, J = 6.9Hz, 2H), 2.08-2.01 (m, 2H), 1.67-1.57 (m, 2H)

Step 4. 3- (1-Benzyl-2-oxo-2,5,6,7-tetrahydro-1H-azepin-3-yl) -hydroxy-propionamide (e1)
108 mg of compound (d) (0.376 mmol) prepared in step 3 above was dissolved in methanol solution, and then 1.7 mol methanolic suspension containing NH ₂ OK (1.315 ml, 2.63 mmol) was added at 0 ° C. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was neutralized with 0.02 ml acetic acid, diluted with 10 ml ethyl acetate solution, filtered and concentrated in vacuo. The obtained product was purified by silica gel column chromatography using a methanol / chloroform (1:10) mixed solvent as an eluent to obtain 46 mg of the title compound (e1) (yield: 43%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.28-7.24 (m.5H), 6.20-6.02 (m, 2H), 4.65 (s, 2H), 3.26 (d, J = 3Hz, 2H), 2.66- 2.52 (m, 4H), 2.08-2.05 (m, 2H), 1.65-1.64 (m, 2H)

N-hydroxy-3- [2-oxo-1- (3-phenyl-ethyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] -propionamide (2e)
N-hydroxy-3- [2-oxo-1- (3-phenyl-ethyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] -propionamide (2e) was prepared as described in Example 105 above. (See Table 22).

N-hydroxy-3- [2-oxo-1- (3-phenyl-propyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] -propionamide (3e)
N-hydroxy-3- [2-oxo-1- (3-phenyl-propyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] -propionamide (3e) was prepared as described in Example 105 above. (See Table 22).

N-hydroxy-3- [2-oxo-1- (3-phenyl-butyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] -propionamide (4e)
N-hydroxy-3- [2-oxo-1- (3-phenyl-butyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] -propionamide (4e) was prepared as described in Example 105 above. (See Table 22).
(Table 22)

Experimental Example 1 Effect of Compounds of the Invention on HDAC To test the inhibitory effect of the compounds prepared from Examples 1-108 above on histone deacetylase (HDAC), an HDAC fluorescence activity assay / drug discovery kit was used as a HDAC source Used with nuclear extract of (HeLa) cells. A fluorogenic histone deacetylase lysyl substrate is used as a substrate for HDAC, and the test is based on the fact that removal of the acetyl group by HDAC activity results in an emission wavelength ranging from 360 nm to 460 nm.
Various concentrations of the compounds of the invention from 0.01 to 10 micromolar are HDA at 25 ° C. for 20 minutes.
Reacted with enzyme C, to which the same volume of developer was added. A fluorescence signal was detected at a wavelength of 350 nm to 460 nm using a fluorescence measuring instrument. IC ₅₀ values were defined as the concentration of sample required to reduce the fluorescence from half to half and the results are shown in Table 23.
As shown in Table 23, the compounds of the present invention showed a strong inhibitory effect on the activity of HDAC appeal.

Experimental Example 2. Effect of Compounds of the Invention on Cancer Cell Growth PC-3 cells (ATCC, US), a human prostate cancer cell line was cultured in RMPI 1640 supplemented with 10% fetal calf serum.
Cells of appropriate concentration (5 × 10 ⁴ cells / ml) cultured in RMPI 1640 supplemented with 5% FBS (Fetal Bovine Serum) were seeded in 96 well plates and 37% in 5% CO ₂ conditions. Cultured at 0 ° C. The day after culture, PC-3 cells were fixed to a time zero (T ₀ ) plate by adding 50 μl / well of 50% trichloroacetic acid, and the cell concentration was set to zero by fixing the cells. . In cells treated with test samples, 50% TCA was added to each well at 50 μl / well 48 hours later to fix the cells. The final concentrations of added test compounds were 0.01, 0.03, 0.1, 0.3 and 1 μg / ml, respectively. Each fixed plate was then washed, dried, and 0.4% reaction solution containing sulferodamine B (SRB) reagent dissolved in 0.1% acetic acid was added to it at 100 μl / well for staining. After 30 minutes, the cells were washed with 0.1% acetic acid, dried at room temperature, and 10 mM TRIS base (pH 10.5) was added to it to dissolve the reagent to be stained. Finally, the absorbance at 540 nm was measured and the value was converted to a percentage compared to that of the control group. IC ₅₀ (μg / ml), concentration of groups required to inhibit 50% growth of cancer cells is data (AA: IC ₅₀ 's <1, A: IC ₅₀ ' s <5, B: IC ₅₀ ' s <10 and C: calculated from IC ₅₀ 's> 10). In addition, the suppressive effect of cancer cells is various symbols according to the strength of the examples, for example, AA: almost equivalent to that of adriamycin used as a positive control group (1 to 2 times), A : Slightly weak (3-5 times), B: weak (5-10 times), C: very weak (10 times or more). The results are shown in Table 23.

As shown in Table 23, it was confirmed that the compound of the present invention directly inhibits HDAC and exhibits a strong inhibitory effect on cancer cell proliferation, particularly on the activity of PC-3 cancer cells.
(Table 23)

Experimental Example 3. Toxicity test

Methods An acute toxicity test was performed with the compound of Example 80 on ICR mice (average body weight 25 ± 5 g) and Sprague Dawley mice (235 ± 10 g, Jung-Ang Lab Animal Inc.). Four groups of 10 mice or 10 mice were orally administered with test samples of 4 mg / kg, 40 mg / kg, 400 mg / kg and 4,000 mg / kg or vehicle (0.2 ml), respectively. Observed for 2 weeks.

Results There were no treatment-related effects on mortality, clinical symptoms, body weight, or general findings in any group or any gender. These results indicated that the formulation provided in the present invention is powerful and safe.
In the following, the formation method and the type of excipient will be described. However, the present invention is not limited to these. Representative preparation examples are as described below.

Preparation of powder 50 mg of the compound of Example 80
Lactose 100mg
Talc 10mg
The preparation of the powder was carried out by mixing the above compounds and filling in a sealed package.

Preparation of tablet 50 mg of compound of example 80
Cornstarch 100mg
Lactose 100mg
Magnesium stearate 2mg
Tablets were prepared by mixing the above compounds into tablets.

Preparation of capsules 50 mg of the compound of Example 80
Cornstarch 100mg
Lactose 100mg
Magnesium stearate 2mg
Capsules were prepared by mixing the above compounds and filling them into gelatin capsules by conventional gelatin preparation methods.

Preparation of injection solution 50 mg of the compound of Example 80
Distilled water for injection Appropriate amount PH controller Preparation of the appropriate amount injection solution involves dissolving the active ingredient, controlling the pH to about 7.5, then filling all the ingredients into a 2 ml ampoule, and using the usual injection preparation method. Provided by sterilization.

Solution preparation 0.1-80 g of the compound of Example 80
5-10g sugar
Citric acid 0.05-0.3%
Caramel 0.005-0.02%
Vitamin C 0.1-1%
Distilled water 79-94%
CO ₂ gas 0.5 to 0.82 percent
Liquid preparation was provided by dissolving the active ingredient, filling all ingredients, and sterilizing by conventional liquid preparation methods.

Thus, while the invention has been described, it is clear that it can be varied in many ways. Such variations are not to be considered as departing from the spirit and scope of the present invention. Such modifications, which will be apparent to those skilled in the art, are intended to be included within the scope of the claims set forth below.

As described in the present invention, the 2-oxo ring compound of the present invention has a strong anti-cancer activity, and therefore it is, for example, lung cancer, osteosarcoma, pancreatic cancer, skin cancer, head and neck cancer, Skin or recurrent intraocular melanoma, uterine cancer, ovarian cancer, cancer of the rectum or anal region, stomach cancer, colon cancer, breast cancer, gynecological tumor, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, soft Treat cancers such as fleshy tissue, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, childhood solid tumors, lymphocyte lymphoma, bladder cancer, kidney or ureter cancer, or central nervous system carcinoma Or it can be used as a preventive treatment.

Claims (4)

Use of a compound and a pharmaceutically acceptable salt or isomer thereof for the preparation of a pharmaceutical composition for treating and preventing cancer comprising
The compounds are in the following groups:
3- [1- (2,4-dimethoxybenzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxypropionamide,
3- (1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -N-hydroxy-propionamide,
N-hydroxy-3- (2-oxo-1-phenethyl-2,5-dihydro-1H-pyrrol-3-yl) -propionamide,
N-hydroxy-3- [2-oxo-1- (3-phenyl-propyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
N-hydroxy-3- [1- (2-methyl-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
N-hydroxy-3- [1- (3-methyl-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
N-hydroxy-3- [1- (4-methyl-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
N-hydroxy-3- [1- (2-methoxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
N-hydroxy-3- [1- (3-methoxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
N-hydroxy-3- [1- (4-methoxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
3- [1- (4-bromo-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxy-propionamide,
3- [1- (4-chloro-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxy-propionamide,
3- [1- (4-benzyloxy-benzyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -N-hydroxypropionamide,
3- {1- [2- (2-fluoro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide,
3- {1- [2- (3-fluoro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide,
3- {1- [2- (4-fluoro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide,
N-hydroxy-3- {1- [2- (2-nitro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide,
N-hydroxy-3- {1- [2- (3-nitro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide,
N-hydroxy-3- {1- [2- (4-nitro-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide,
3- {1- [2- (2-bromo-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide,
3- {1- [2- (4-bromo-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -N-hydroxy-propionamide,
N-hydroxy-3- {1- [2- (2-methoxy-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide,
N-hydroxy-3- {1- [2- (3-methoxy-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide,
N-hydroxy-3- {1- [2- (4-methoxy-phenyl) -ethyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide,
N-hydroxy-3- [2-oxo-1- (2-p-tolyl-ethyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
N-hydroxy-3- {1- [3- (4-methoxy-phenyl) -propyl] -2,5-dihydro-1H-pyrrol-3-yl} -propionamide,
N-hydroxy-3- [2-oxo-1- (3-m-tolyl-propyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
N-hydroxy-3- {1- [3- (4-isopropyl-phenyl) -propyl] -2-oxo-2,5-dihydro-1H-pyrrol-3-yl} -propionamide,
N-hydroxy-3- (1-naphthalen-2-ylmethyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -propionamide,
N-hydroxy-3- (1-methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -propionamide,
3- (1-allyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -N-hydroxy-propionamide,
N-hydroxy-3- [1- (2-naphthalen-2-yl-ethyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
N-hydroxy-3- [2-oxo-1- (2-thiophen-2-yl-ethyl) -2,5-dihydro-1H-pyrrol-3-yl] -propionamide,
3- [1- (3-biphenyl-4-yl-propyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl) -N-hydroxy-propionamide,
N-hydroxy-3- [1- (3-naphthalen-2-yl-propyl) -2-oxo-2,5-dihydro-1H-pyrrol-3-yl] -propionamide.
3- [1- (2,4-dimethoxybenzyl) -2-oxo-1,2,5,6-tetrahydropyridin-3-yl} -N-hydroxypropionamide,
N-hydroxy-3- (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -propionic acid,
N-hydroxy-3- [1- (4-nitro-benzyl) -2-oxo-1,2,5,6-tetrahydropyridin-3-yl] -propionamide,
3- (1-Benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl) -N-hydroxypropionamide,
N-hydroxy-3- [2-oxo-1- (4-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide,
N-hydroxy-3- (2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl) -propionamide,
3- [1- (4-acetylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide,
N-4- [5- (2-hydroxycarbamoyl-ethyl) -6-oxo-3,6-dihydro-2-pyridin-1-yl-methyl] -phenyl-benzamide,
N-hydroxy-3- [1- (4-dimethylsulfonylamino-benzyl) -2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide,
N-hydroxy-3-2-oxo-1- [4- (toluene-4-sulfonylamino) -benzyl-1,2,5,6-tetrahydro-pyridin-3-yl] -propionamide,
N-hydroxy-3- (2-oxo-1-phenethyl-piperidin-3-yl) -propionamide,
N-hydroxy-4- [2-oxo-1- (3-phenyl-propyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -butyramide,
N-hydroxy-4- [2-oxo-1- (3-phenyl-butyl) -1,2,5,6-tetrahydro-pyridin-3-yl] -butyramide,
Use that is one selected from. The cancer is lung cancer, osteosarcoma, pancreatic cancer, skin cancer, head or neck cancer, skin or recurrent intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer or cancer of the anal region, stomach cancer, colon cancer, breast cancer, women Tumor, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, urethral cancer , penile cancer, prostate cancer, chronic or acute leukemia, solid tumor in children, lymphocyte lymphoma, bladder cancer, kidney or urine Use according to claim 1, consisting of ductal cancer and central nervous system carcinoma. The novel compound shown with the following general formula (VI), its pharmacologically acceptable salt, or its isomer.
Here, X is a hydroxyl group, -NHOH, -NHOCH ₂ Ph,
Or
And
R is independently a phenyl group (the phenyl group may be substituted with a halogen atom or a lower alkyl group) 1) an alkyl group having C1 to C4 carbon atoms, 2) from C1 An alkenyl group having a C4 carbon atom , 3) a group selected from an alkynyl group having a C1 to C4 carbon atom , and 4) an allyl group;
n is an integer from 1 to 5;
Broken line
Means a single bond or a double bond. The compound according to claim 3, wherein the compound is one selected from the following group.
N-3- (1-benzyl-2-oxo-2,5,6,7-tetrahydro-1H-azepin-3-yl) -N-hydroxy-propionamide,
N-hydroxy-3- [2-oxo-1- (3-phenyl-ethyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] -propionamide,
N-hydroxy-3- [2-oxo-1- (3-phenyl-propyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] -propionamide,
N-hydroxy-3- [2-oxo- (3-phenyl-butyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] -propionamide.