KR100491100B1 - Terephthalate Amide Derivatives - Google Patents

Abstract

The present invention relates to a novel terephthalic acid amide derivative, and more particularly, a novel terephthalic acid amide derivative represented by the following formula (1) and its pharmaceutically acceptable which is effective as an antiviral agent due to its excellent anti-proliferative effect of various viruses including HIV and HBV. Salts and methods for their preparation.

[Formula 1]

In Chemical Formula 1,

R ₁ , R ₂ and R ₃ are as described in the detailed description of the invention.

Description

New Terephthalate Amide Derivatives

The present invention relates to a novel terephthalic acid amide derivative, and more particularly, a novel terephthalic acid amide derivative represented by the following formula (1) and its pharmaceutically acceptable which is effective as an antiviral agent due to its excellent anti-proliferative effect of various viruses including HIV and HBV. Salts and methods for their preparation.

Formula 1

In Formula 1 above:

R ₁ and R ₂ are the same as or different from each other, a hydrogen atom; Phenyl group; Benzyl groups; An alkyl group of C ₁ to C ₆ ; Di (C ₁ ~ C ₄ alkyl) amino group or an acetylamino group is a substituted alkyl group of C ₁ ~ C _4; A C ₁ to C ₄ alkyl group substituted with a 4 to 7 membered heterocycle containing 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur; C ₁ ~ C ₅ hydroxyalkyl group; Phenyl group, benzyl group, C ₁ ~ C ₄ alkyl group and a hydroxy-C ₁ ~ is a substituent selected from the group of C ₇ 1 ~ 2 gae hydroxy alkyl group-substituted C ₁ ~ C _4; C ₂ ~ C ₆ Alkoxyalkyl group; C ₂ to C ₆ dialkoxyalkyl group; C ₂ -C _{5 represents} a (hydroxyalkoxy) alkyl group; However, except that when R ₁ and R ₂ are hydrogen atoms at the same time, when one of R ₁ and R ₂ is a hydrogen atom may represent a stereospecificity of the form (R)-or (S)-,

In addition, R ₁ and R ₂ may be bonded together with 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur to form a 5- or 6-membered heterocycle, wherein the heterocyclic ring is an alkyl group of C ₁ to C ₅ . , a C ₃ ~ C ₆ cycloalkyl group, C ₃ ~ C ₅ a (hydroxy-alkoxy) of the alkyl group, C ₂ ~ C ₅ hydroxy alkyl, C ₁ ~ C ₃ with C ₁ ~ C ₄ substituted with an alkyl group of hydroxyl hydroxy alkyl group, C ₁ ~ C ₄ dihydroxy alkyl group, or C ₁ ~ C ₃ may be substituted with a di-hydroxy alkyl group of the optionally substituted C ₁ ~ C ₄ alkyl groups and in the;

R ₃ represents an alkyl group of C ₁ to C ₄ ;

In addition, the above-mentioned alkyl group is a linear alkyl group or a pulverized alkyl group or includes a cycloalkyl group.

Hepatitis B virus (HBV) is a major pathogen of hepatitis with an infection of about 300 million people worldwide. It not only invades humans and causes acute or chronic hepatitis, but also cirrhosis or liver cancer. It is well known to be involved in the transition. Much research has been conducted on HBV due to its association with liver disease and molecular biological characteristics of the virus. However, only preventive vaccines for hepatitis B have been developed so far, and no obvious treatment has been developed.

For some time, some of the Nucleosides compounds, which have been developed primarily for the treatment of Acquired immune deficiency syndrome (AIDS), have been reported to be effective as HBV inhibitors [J. Org. Chem., 1992, Vol. 57, 2217], these nucleic acid compounds are known to be limited in the development of a desirable hepatitis B therapeutic agent due to the high cost of treatment and inherent side effects and toxicity of the nucleic acid compounds.

Therefore, there is an urgent need for development of a hepatitis B therapeutic agent having excellent antiviral action against HBV as a non-nucleic acid compound, and recently, a quinolone compound [European Patent Publication Nos. 563732, 563734] and an iridoid compound [ Korean Patent Publication No. 94-1886] and the like have been applied for a patent, but until now, no clear development result is known.

The present inventors have conducted continuous research to solve the side effects and toxicity problems and to develop non-nucleic acid compounds with excellent antiviral action against HBV. As a result, the terephthalic acid amide derivative represented by Chemical Formula 1 is a non-nucleosides compound having a unique structure as well as other viruses including a human immunodeficiency virus (HIV) as well as HBV proliferation inhibitory effect. The present invention has been completed by knowing that the antiproliferative effect is strong. For example, HBV and HIV are different viruses, but they have a common replication process, namely reverse transcription from viral RNA to DNA, and the cleavage of the RNA portion of the resulting RNA-DNA hybrid. In addition, the terephthalic acid amide derivative represented by the general formula (1) of the present invention has a mechanism of inhibiting such a process, and thus can be developed as a growth inhibitor of various viruses including HBV, HIV and the like.

Accordingly, an object of the present invention is to provide a novel terephthalate amide derivative, a pharmaceutically acceptable salt thereof, and a method for preparing the same, which have strong anti-proliferative effects of various viruses including HBV and HIV.

The present invention is characterized by the novel terephthalic acid amide derivative represented by the following formula (1) and its pharmaceutically acceptable salts.

Formula 1

In Formula 1, R ₁ , R ₂ and R ₃ are as described above, respectively.

Referring to the present invention in more detail as follows.

In the terephthalic acid amide derivative represented by the formula (1) according to the present invention is preferably as follows:

_One of R ₁ and R ₂ is a hydrogen atom, the other is a C ₁ ~ C ₃ Alkoxy C ₁ ~ C ₄ Alkyl group; C ₂ ~ C ₅ dialkoxy C ₁ ~ C ₄ Alkyl group; 1,3-dioxolan-2-yl-methyl group; Tetrahydrofuran-2-yl-methyl group; 2- (morpholin-4-yl) ethyl group; 3- (morpholin-4-yl) propyl group; 2- (piperidin-1-yl) ethyl group; Di (C ₁ -C ₃ alkyl) amino C ₁ -C ₃ alkyl groups; 2- (acetylamino) ethyl group; 2-hydroxyethyl group; Or a 2-hydroxyethyl group substituted with one or two or the same or different substituents selected from a phenyl group, a benzyl group, a C ₁ to C ₃ hydroxyalkyl group and a C ₁ to C ₅ alkyl group,

Any one of R ₁ and R ₂ is an alkyl group of C ₁ to C ₃ , and the other is an alkyl group of C ₁ to C ₃ dialkoxy C ₂ to C ₃ ; 1,3-dioxolan-2-yl-methyl group; Tetrahydrofuran-2-yl-methyl group; 2- (morpholin-4-yl) ethyl group; 3- (morpholin-4-yl) propyl group; 2- (piperidin-1-yl) ethyl group; 2-hydroxyethyl group; Di (C ₁ -C ₃ alkyl) amino C ₁ -C ₃ alkyl groups; Or 2- (acetylamino) ethyl group,

When R ₁ and R ₂ are simultaneously C ₁ to C ₃ alkyl, hydroxyethyl or 2-hydroxypropyl groups, and

R ₁ and R ₂ combine with one or two heteroatoms selected from nitrogen, oxygen, and sulfur to form a hetero ring such as morpholine, thiomorpholine, pyrrolidine, piperidine, or piperazine, and in particular, If the heterocycle is piperazine optionally dihydroxy represents a hydrogen atom, C ₁ ~ C ₅ alkyl group, C ₃ ~ C ₅ cycloalkyl group, C ₁ ~ C ₅ hydroxyalkyl group, C ₂ ~ C ₅ of the, C ₂ -C ₅ (hydroxyalkoxy) alkyl group, C ₁ -C ₃ alkyl substituted C ₁ -C ₄ hydroxyalkyl group, (2R) -3-hydroxy-2-methylpropyl group or (2S) When substituted with a 3-hydroxy-2-methylpropyl group.

More preferred in the terephthalic acid amide derivative represented by the formula (1) according to the present invention are as follows.

When R ₁ is a 2-hydroxyethyl group and R ₂ is a hydrogen atom, a methyl group, an ethyl group or an isopropyl group,

When both R ₁ and R ₂ are 2-hydroxyethyl group, 2-hydroxypropyl group, ethyl group or isopropyl group,

2-hydroxyethyl group wherein R ₁ is a hydrogen atom and R ₂ is substituted, in particular a methyl group, ethyl group, isopropyl group, phenyl group, benzyl group or hydroxymethyl group in the 1- or 2-position as a substituent, and (R)- Or a 2-hydroxyethyl group substituted with (S)-form stereospecificity, or 2-hydroxyethyl group substituted with two or more substituents selected from methyl, ethyl and hydroxymethyl groups at 1-position; If is

When R ₁ is a hydrogen atom or a 2-methoxyethyl group and R ₂ is a 2-methoxyethyl group, 3-methoxypropyl group, 3-ethoxypropyl group or 3-isopropoxypropyl group,

R ₂ is a hydrogen atom or a methyl group while R ₂ is a 2,2-dimethoxyethyl group, a 2,2-diethoxyethyl group, a 1,3-dioxolan-2-yl-methyl group, a tetrahydrofuran-2-yl-methyl group , 2- (morpholin-4-yl) ethyl group, 3- (morpholin-4-yl) propyl group, or 2- (piperidin-1-yl) ethyl group,

R ₂ is a hydrogen atom, a methyl group or an ethyl group, and R ₂ is a 2- (dimethylamino) ethyl group, 2- (diethylamino) ethyl group, 3- (dimethylamino) propyl group, 3- (diethylamino) propyl group or 2 -(Acetylamino) ethyl group,

When R ₁ and R ₂ together with the nitrogen atom form a heterocycle such as morpholine, thiomorpholine, pyrrolidine, piperidine or piperazine, and the like, and

R ₁ and R ₂ form a piperazine ring together with the nitrogen atom, and methyl, ethyl, isopropyl, cyclopropyl, cyclopentyl, 2-hydroxyethyl, and 3-hydroxypropyl groups in the 4-position nitrogen atom. , 2,3-dihydroxypropyl group, 2,2-dimethyl-3-hydroxypropyl group, (2R) -3-hydroxy-2-methylpropyl group, (2S) -3-hydroxy-2- It is the case where a methylpropyl group or 2- (2-hydroxyethoxy) ethyl group is substituted.

Especially preferably, it is a case where R <_1> and R <_2> are mentioned above, and R <_3> is an isopropyl group.

Representative examples of the terephthalic acid amide derivative represented by Formula 1 according to the present invention are as follows:

1- [N- (2-hydroxyethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound No. 1 ),

1- [N- (3-hydroxypropyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound No. 2 ),

1- [N- (4-hydroxybutyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound No. 3 ),

1- [N- (5-hydroxypentyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound No. 4 ),

1- [N- (2-hydroxyethyl) -N-methylcarbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound number 5),

1- [N-ethyl-N- (2-hydroxyethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound number 6),

1- [N- (2-hydroxyethyl) -N-propylcarbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound number 7),

1- [N- (2-hydroxyethyl) -N- (1-methylethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl -Carbonyl] benzene (Compound No. 8),

1- [N-butyl-N- (2-hydroxyethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound number 9),

1- [N-benzyl-N- (2-hydroxyethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound number 10),

1- [N- (2-hydroxyethyl) -N-phenylcarbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound number 11),

1- [N, N-bis (2-hydroxyethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene ( Compound number 12),

1- [N, N-diethylcarbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound No. 13),

1- [N, N-bis (1-methylethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (compound Number 14),

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- (N-methyl-N-propylcarbamoyl) benzene (Compound No. 15),

1- [N, N-bis (2-hydroxypropyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene ( Compound number 16),

1- [N- [2- (2-hydroxyethoxy) ethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl Benzene (Compound No. 17),

1- [N-ethyl-N- (2-hydroxyethyl) carbamoyl] -4- [1- [3- (ethylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene ( Compound number 18),

1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] piperazine (Compound No. 19),

1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4-methylpiperazin (Compound No. 20),

4-ethyl-1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] piperazine (Compound No. 21),

4-cyclopentyl-1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] piperazine (Compound No. 22),

1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4-propylpiperazine (Compound No. 23),

1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (1-methylethyl) piperazine (Compound No. 24) ,

4-cyclopropyl-1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] piperazine (Compound No. 25),

4- (2-hydroxyethyl) -1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] piperazine (Compound No. 26 ),

4- (3-hydroxypropyl) -1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] piperazine (Compound No. 27 ),

4-[(2R) -3-hydroxy-2-methylpropyl] -1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] Benzoyl] piperazine (Compound No. 28),

4-[(2S) -3-hydroxy-2-methylpropyl] -1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] Benzoyl] piperazine (Compound No. 29),

4- (2,2-dimethyl-3-hydroxypropyl) -1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] Piperazine (Compound No. 30),

4- (2,3-dihydroxypropyl) -1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] piperazine ( Compound number 31),

Propylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] piperazin (Compound No. 32),

1- [4- [1- [3- (ethylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (2-hydroxyethyl) piperazine (Compound No. 33) ,

1- [N- (1,1-dimethyl-2-hydroxyethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl ] Benzene (compound number 34),

1- [N-[(1S) -2-hydroxy-1-methylethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl- Carbonyl] benzene (Compound No. 35),

1- [N-[(1R) -2-hydroxy-1-methylethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl- Carbonyl] benzene (Compound No. 36),

1- [N- (2-hydroxy-1-methylethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound number 37),

1- [N-[(1S) -2-hydroxy-1- (1-methylethyl) ethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazine -4-yl-carbonyl] benzene (Compound No. 38),

1- [N-[(1R) -2-hydroxy-1- (1-methylethyl) ethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazine -4-yl-carbonyl] benzene (Compound No. 39),

1- [N- [2-hydroxy-1- (1-methylethyl) ethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl -Carbonyl] benzene (Compound No. 40),

1- [N-[(1S) -1-ethyl-2-hydroxyethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl- Carbonyl] benzene (Compound No. 41),

1- [N-[(1R) -1-ethyl-2-hydroxyethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl- Carbonyl] benzene (Compound No. 42),

1-[[N- (1-ethyl-2-hydroxyethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] Benzene (Compound No. 43),

1- [N-[(1S) -2-hydroxy-1- (2-methylpropyl) ethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazine -4-yl-carbonyl] benzene (Compound No. 44),

1- [N-[(1R) -2-hydroxy-1- (2-methylpropyl) ethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazine -4-yl-carbonyl] benzene (Compound No. 45),

1- [N-[(1S) -2-hydroxy-1- (1-methylpropyl) ethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazine -4-yl-carbonyl] benzene (Compound No. 46),

1- [N-[(1S) -1- (cyclohexylmethyl) -2-hydroxyethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazine- 4-yl-carbonyl] benzene (Compound No. 47),

1- [N-[(1S) -2-hydroxy-1-phenylethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl- Carbonyl] benzene (Compound No. 48),

1- [N-[(1R) -2-hydroxy-1-phenylethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl- Carbonyl] benzene (Compound No. 49),

1- [N-[(1S) -1-benzyl-2-hydroxyethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl- Carbonyl] benzene (Compound No. 50),

1- [N-[(1R) -1-benzyl-2-hydroxyethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl- Carbonyl] benzene (Compound No. 51),

1- [N- [bis (hydroxymethyl) methyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (compound Number 52),

1- [N- [1,1-bis (hydroxymethyl) ethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl Benzene (Compound No. 53),

1- [N- [1,1-bis (hydroxymethyl) propyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl Benzene (Compound No. 54),

1- [N- [tris (hydroxymethyl) methyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (compound Number 55),

1- [N-[(2S) -2-hydroxypropyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound number 56),

1- [N-[(2R) -2-hydroxypropyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound number 57),

1- [N- (2-hydroxypropyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound No. 58 ),

1- [N- (2-hydroxy-2-phenylethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound number 59),

1- [N- (2,3-dihydroxypropyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene ( Compound number 60),

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- [N- (2-methoxyethyl) carbamoyl] benzene (Compound No. 61 ),

1- [N, N-bis (2-methoxyethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene ( Compound number 62),

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- [N- (2-methoxy-1-methylethyl) carbamoyl] benzene (Compound number 63),

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- [N- (3-methoxypropyl) carbamoyl] benzene (Compound No. 64 ),

1- [N- (3-ethoxypropyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound No. 65 ),

1- [N- (3-isopropoxypropyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound No. 66),

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- [N- [3- (vinyloxy) propyl] carbamoyl] benzene (compound Number 67),

1- [N- (2,2-dimethoxyethyl) -N-methylcarbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl Benzene (Compound No. 68),

1- [N- (2,2-dimethoxyethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (compound Number 69),

1- [N- (2,2-diethoxyethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (compound Number 70),

1- [N-[(1,3-dioxolan-2-yl) methyl] -N-methylcarbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazine -4-yl-carbonyl] benzene (Compound No. 71),

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- [N-[(tetrahydrofuran-2-yl) methyl] carbamoyl] Benzene (Compound No. 72),

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- [N-[[(2R) -tetrahydrofuran-2-yl] methyl ] Carbamoyl] benzene (Compound No. 73),

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- [N-[[(2S) -tetrahydrofuran-2-yl] methyl ] Carbamoyl] benzene (Compound No. 74),

1- [N-[(furan-2-yl) methyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene ( Compound number 75),

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- (morpholin-4-yl-carbonyl) benzene (Compound No. 76),

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- (thiomorpholin-4-yl-carbonyl) benzene (Compound No. 77) ,

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- (thiazolidin-3-yl-carbonyl) benzene (Compound No. 78) ,

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- [N- [2- (morpholin-4-yl) ethyl] carbamoyl Benzene (Compound No. 79),

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- [N- [3- (morpholin-4-yl) propyl] carbamoyl Benzene (Compound No. 80),

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- [4- [2- (piperidin-1-yl) ethyl] carba Mole] benzene (Compound No. 81),

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- [N- [2- (pyrrolidin-1-yl) ethyl] carba Mole] benzene (Compound No. 82),

1- [N- [2- (dimethylamino) ethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (compound Number 83),

1- [N- [2- (dimethylamino) ethyl] -N-methylcarbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl Benzene (Compound No. 84),

1- [N- [2- (dimethylamino) ethyl] -N-ethylcarbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl Benzene (Compound No. 85),

1- [N- [2- (diethylamino) ethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene ( Compound number 86),

1- [N- [2- (diethylamino) ethyl] -N-methylcarbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbo Nil] benzene (Compound No. 87),

1- [N- [2- (diethylamino) ethyl] -N-ethylcarbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbo Nil] benzene (Compound No. 88),

1- [N- [3- (dimethylamino) propyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (compound Number 89),

1- [N- [3- (dimethylamino) propyl] -N-methylcarbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl Benzene (Compound No. 90),

1- [N- [3- (diethylamino) propyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene ( Compound number 91),

1- [N- [2- (acetylamino) ethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (compound Number 92),

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- (piperidin-1-yl-carbonyl) benzene (Compound No. 93) ,

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- (pyrrolidin-1-yl-carbonyl) benzene (Compound No. 94) .

In addition, the terephthalic acid amide derivative represented by Chemical Formula 1 according to the present invention may form a pharmaceutically acceptable acid addition salt according to a conventional method in the art. Examples may be salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, citric acid, maleic acid, methanesulfonic acid and the like.

The terephthalic acid amide derivative represented by Chemical Formula 1 according to the present invention can be used as a clinically useful hepatitis B therapeutic agent and AIDS therapeutic agent because HBV and HIV proliferation inhibitory effect is strong.

Accordingly, the present invention includes a pharmaceutical composition containing the terephthalic acid amide derivative represented by Chemical Formula 1 and a pharmaceutically acceptable salt thereof as an active ingredient.

In clinical use of the pharmaceutical composition of the present invention, it is combined with a conventional carrier in the pharmaceutical field, and is a conventional agent in the pharmaceutical field, for example, an oral preparation such as tablets, capsules, troches, solutions, suspensions, and the like. ; Injectable preparations in the form of injectable solutions or suspensions, or ready-to-use injectable dry powders which can be prepared and used as injectable distilled water at the time of injection; It can be formulated into various preparations such as topical preparations such as ointments, creams, liquids and the like.

Carriers that can be used in the pharmaceutical composition of the present invention are conventional in the pharmaceutical field, for example, in the case of oral preparations, binders, suspending agents, disintegrants, excipients, compatibilizers, dispersants, stabilizers, suspending agents, Pigments, perfumes, and the like; Injectables include preservatives, analgesics, solubilizers, stabilizers and the like; In the case of topical administration, there are bases, excipients, lubricants, and preservatives. The pharmaceutical preparations thus prepared can be administered orally or parenterally, for example, intravenously, subcutaneously, intraperitoneally or topically. In addition, in order to prevent the drug from being degraded by gastric acid during oral administration, an antacid may be used in combination, or may be formulated into a formulation coated with an oral administration solid preparation such as tablets.

In addition, the dosage of the terephthalic acid amide derivative represented by Formula 1 according to the present invention to the human body depends on the absorption rate, inactivation rate and excretion rate of the active ingredient in the body, the age, sex and condition of the patient, the severity of the disease to be treated, etc. Although appropriately selected, generally an adult is administered with an amount of 10 to 500 mg, preferably 50 to 300 mg per day. Therefore, when preparing the pharmaceutical composition of the present invention in unit dosage form, each unit dosage form is 10 to 500 mg, preferably 50 to 300, of the terephthalic acid amide derivative represented by Formula 1 in consideration of the above-mentioned effective dosage range. It may be formulated to contain mg. The unit dosage form thus formulated uses a specialized dosage method according to the judgment of the expert who monitors or observes the administration of the drug as needed and the needs of the individual, or several times, preferably one to six times at regular time intervals. May be administered.

The present invention includes a method for preparing the terephthalic acid amide derivative represented by Chemical Formula 1, and the terephthalic acid amide derivative represented by Chemical Formula 1 according to the present invention may be prepared by the following Schemes 1, 2 and 3.

The following Reaction Scheme 1 briefly illustrates a method for preparing a terephthalic acid derivative represented by Formula 1 by using the compound represented by Formula 2 as a starting material and reacting it with an amine compound.

Scheme 1

In Scheme 1, R ₁ , R ₂ and R ₃ are as defined above, respectively.

According to Scheme 1, the terephthalic acid derivative represented by Chemical Formula 2 is reacted with an acid chloride such as pivaloyl chloride to generate a highly reactive acid anhydride, and then reacted with an amine compound represented by Chemical Formula 3 to react as the target compound. The terephthalic acid amide derivative represented by general formula (1) is obtained. This reaction is triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine, N, N-dimethylaniline, 2,6-lutidine, It is completed within 6 hours at 0 ° C to 30 ° C in the presence of a general tertiary base such as pyridine and the like. The solvent used here is a single selected from chloroform, methylene chloride, acetonitrile, tetrahydrofuran, dioxane, dioxolane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, and the like. It is preferable to use a solvent or a mixed solvent.

As another preparation method, a method of directly preparing a terephthalic acid derivative represented by Chemical Formula 1 by reacting an amine compound with a compound represented by Chemical Formula 4, which is a precursor of the compound represented by Chemical Formula 2, used in Scheme 1 below Its preparation process is shown in the following scheme 2. That is, this method has the advantage of shortening the manufacturing process of the used starting material by one step.

Scheme 2

In Scheme 2, R ₁ , R ₂ and R ₃ are each as defined above.

According to the reaction scheme 2, the amine compound represented by the formula (3) is carried out by directly nucleophilic substitution reaction of the methyl ester group of the terephthalic acid ester derivative represented by the formula (4), this reaction is the reaction used in the preparation method of Scheme 1 Since the reactivity is relatively lower than good acid anhydride, stronger reaction conditions are required. The nucleophilic substitution reaction is carried out using an alcohol solvent such as methanol, ethanol, propanol, isopropanol, butanol, or a polar organic solvent such as acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidone. It is completed in 20 hours within the temperature range of 40 degreeC-90 degreeC using.

In addition, the amine compound represented by Chemical Formula 3 used in Schemes 1 and 2 is a substance for introducing substituents R ₁ and R ₂ to the terephthalic acid amide derivative represented by Chemical Formula 1, which is appropriate according to the required substituents. An amine compound is selected, which can be easily selected and used by those of ordinary skill in the art.

In addition, when R ₁ and R ₂ in the compound represented by Chemical Formula 1 combine with a nitrogen atom to form a piperazine ring, it may be prepared by the following Reaction Scheme 3 in addition to the method of the above Reaction Scheme 1 and Scheme 2. .

Scheme 3

In Scheme 3,

R ₃ is as defined in Formula 1;

R ₄ is a hydrogen atom, a C ₁ to C ₅ alkyl group, C ₃ to C ₅ cycloalkyl group, C ₁ to C ₅ hydroxyalkyl group, C ₂ to C ₅ dihydroxyalkyl group, C ₂ to C ₅ (Hydroxyalkoxy) alkyl group, C ₁ -C ₃ alkyl substituted C ₁ -C ₄ hydroxyalkyl group, (2R) -3-hydroxy-2-methylpropyl group or (2S) -3-hydroxy- 2-methylpropyl group;

X represents a halogen atom.

The terephthalic acid derivative represented by Formula 2 used as a starting material in Scheme 1 is reacted with an acid chloride such as pivaloyl chloride to generate an acid anhydride having high reactivity, followed by reaction with a piperazine compound represented by Formula 5 The desired terephthalic acid amide derivative represented by the general formula (1a) is obtained. This reaction is used in excess of the piperazine compound represented by the formula (5) or triethylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, It is completed within 6 hours at 0 ° C. to 30 ° C. in the presence of a general tertiary base such as 2,6-lutidine and the like, and methylene chloride, chloroform, acetonitrile and the like are preferable.

And, if you want to introduce another substituent at the 4-position of the piperazine ring, a substitution reaction using a halogen compound represented by the formula (6) to the terephthalic acid amide derivative represented by the formula (1a). The substitution reaction is preferably carried out in a polar solvent such as methanol, ethanol, isopropanol, butanol, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, and the like. It proceeds quantitatively within 50 hours at 50-110 ° C in the presence of a higher organic base such as ethylamine, N-methylmorpholine, N-methylpiperidine, 2,6-lutidine and the like.

In addition, each compound represented by Formula 2 or Formula 4 used as a starting material in the method for preparing a compound represented by Formula 1 according to Scheme 1 and Scheme 2 can be prepared and used by the following Scheme 4.

Scheme 4

In Scheme 4, R ₃ is as defined in the formula (1).

Basic raw materials used in Scheme 4, for example, 2-chloro-3-nitropyridine represented by the formula (7), piperazine represented by the formula (5), monomethyl terephthalate represented by the formula (9) are all Commercially available materials are readily available. In addition, the pyridylpiperazine derivative represented by Chemical Formula 8 is a known substance introduced in various literatures, and known methods [J. Med. Chem., 1994, Vol. 37, 999-1014] can be easily prepared and used.

First, the monomethyl terephthalate represented by Chemical Formula 9 is reacted with an acid chloride such as pivaloyl chloride to generate a highly reactive acid anhydride, and then reacted with a pyridylpiperazine derivative represented by Chemical Formula 8 to the chemical formula The terephthalic ester derivative including the nitropyridyl group represented by 10 is obtained. This reaction is completed within 5 hours at 0 ° C. to 30 ° C. in the presence of a tertiary organic base. At this time, a non-polar solvent such as methylene chloride and chloroform is mainly used.

Hydrogen reduction reaction of the obtained compound represented by the formula (9) yields a derivative including the aminopyridyl group represented by the formula (11). This hydrogen reduction reaction proceeds well if pressurized using hydrofoam in the presence of small amounts of active metal catalysts such as nickel, palladium-activated carbon, which are widely used in the reduction reaction. In this case, various solvents such as methanol, ethanol, methylene chloride, chloroform and ethyl acetate can be used.

In addition, the obtained derivative including the aminopyridyl group represented by the formula (11) is subjected to a reduction alkylation reaction with acetone or acetaldehyde under acidic conditions in the presence of a selective reducing agent such as sodium cyanoborohydride in isopropyl represented by the formula (4) The terephthalic acid ester derivative containing an amino group or an ethylamino group is obtained. The reaction proceeds well in the presence of organic acids such as acetic acid and usually uses lower alcohol solvents such as methanol and ethanol.

Hydrolysis of the obtained terephthalic acid ester derivative represented by the formula (4) yields a terephthalic acid derivative represented by the formula (2). In this case, a mixed solvent in which water is added to lower alcohols such as methanol, ethanol and isopropanol is used as the solvent. This hydrolysis reaction is completed within 3 hours at 40 占 폚 or lower.

Such the present invention will be described in more detail based on the following Preparation Examples and Examples, but the present invention is not limited thereto.

Preparation Example 1 Preparation of 1- (3-nitro-2-pyridyl) piperazine (Formula 8)

Dissolve anhydrous piperazine (Formula 5, 60 g) in methylene chloride (400 mL), then slowly add 2-chloro-3-nitropyridine (Formula 7, 40 g) at 10 ° C to 20 ° C and 2 hours at 20 ° C. Reacted for a while. After completion of the reaction, the methylene chloride solution was washed three times with water (300 mL) and the layers were separated and the organic layer was concentrated under reduced pressure. The resulting precipitate was washed with water and a small amount of ethanol and dried in vacuo to give 46 g (yield 87.5%) of the title compound.

m.p. : 79 to 82 ° C

¹ H-NMR (CDCl ₃ ), ppm: δ 1.93 (s, 1H), 2.95 (m, 4H), 3.41 (m, 4H), 6.71 (m, 1H), 8.10 (m, 1H), 8.30 ( m, 1H)

Preparation Example 2 Preparation of 4- [1- (3-nitro-2-pyridyl) piperazin-4-yl-carbonyl] benzoic acid methyl ester (Formula 10)

Monomethyl terephthalate (Formula 9, 20 g) was added to methylene chloride (380 mL), and triethylamine (18.2 mL) was added to dissolve it. After cooling, pivaloyl chloride (15 mL) was added at 0 ° C to 5 ° C, and stirred at 5 ° C for 2 hours. 1- (3-nitro-2-pyridyl) piperazine (Formula 8, 21.3 g) and triethylamine (18.6 mL) obtained in Preparation Example 1 were added sequentially, followed by reaction at 5 ° C to 10 ° C for 2 hours. The reaction solution was washed twice with an aqueous sodium hydrogen carbonate solution and water, and the layered organic layer was concentrated under reduced pressure. The resulting yellow solid was treated with ether (250 mL) for 1 hour, filtered and dried to give 17.2 g (yield 91%) of light yellow crystals of the title compound.

m.p. : 149-152 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ 3.38 (m, 2H), 3.53 (m, 4H), 3.92 (m, 5H), 6.81 (m, 1H), 7.48 (m, 2H), 8.08 ( m, 2H), 8.17 (m, 1H), 8.35 (m, 1H)

Preparation Example 3: Preparation of 4- [1- (3-amino-2-pyridyl) piperazin-4-yl-carbonyl] benzoic acid methyl ester (Formula 11)

4- [1- (3-nitro-2-pyridyl) piperazin-4-yl-carbonyl] benzoic acid methyl ester (Formula 10, 5 g) obtained in Preparation Example 2 was added to methanol (80 g) in a pressurized reaction vessel. ㎖) and methylene chloride (60 mL) were dissolved in a mixed solvent, and about 1 g of Ranickel (50% slurry aqueous solution) was added thereto, followed by hydrogen reduction to carry out hydrogen reduction at 50 to 60 psi for 4 hours. After completion of the reaction, diatomaceous earth (celite) was laid and filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was treated with hexane and ether to crystallize, filtered, washed and dried to obtain 4.05 g (yield 88%) of the title compound.

m.p. : 144 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ 3.15 (m, 4H), 3.47 (m, 2H), 3.82-3.91 (m, 7H), 6.87 (m, 1H), 6.97 (m, 1H), 7.48 (m, 2H), 7.78 (m, 1H), 8.07 (m, 2H)

Preparation Example 4 Preparation of 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid methyl ester (Formula 4, R ₃ = isopropyl)

To methanol (90 mL) was added 4- [1- (3-amino-2-pyridyl) piperazin-4-yl-carbonyl] benzoic acid methyl ester (Formula 11, 4 g) obtained in Preparation Example 3. Acetone (2 mL), acetic acid (5 mL) and sodium cyanoborohydride (2.4 g) were added sequentially at 10 ° C, followed by reaction at 10 ° C for 4 hours, heating, and further reaction at 20 ° C to 25 ° C for 1 hour. . An aqueous solution of 3N-sodium hydroxide was added to neutralize (pH = -8), and excess water was gradually added to precipitate crystals. After stirring for 1 hour, the mixture was filtered, washed with water, methanol and ether sequentially and dried to obtain 3.5 g (yield 78%) of the title compound as white crystals.

m.p. : 116-118 degreeC

¹ H-NMR (CDCl ₃ ), ppm: δ 1.24 (d, 6H), 3.12 (m, 4H), 3.53 (m, 3H), 3.91 (m, 5H), 4.14 (m, 1H), 7.02 ( m, 1H), 7.08 (m, 1H), 7.49 (m, 1H), 7.76 (m, 1H), 8.08 (m, 2H)

Preparation Example 5 Preparation of 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid (Formula 2, R ₃ = isopropyl)

In methanol (47 mL), 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid methyl ester (Formula 4, 3 g) obtained in Preparation Example 4 was used. ) Was added, and 1N aqueous sodium hydroxide solution (16 mL) was added slowly to hydrolyze at 20 ° C-25 ° C for 3 hours. When 2N hydrochloric acid is gradually added to neutralize (pH = -5), crystalline powder precipitates. Filtration, washing with water and methanol and drying gave 2.7 g (yield 93%) of the title compound.

m.p. : 215-217 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ 1.24 (d, 6H), 3.17 (m, 4H), 3.56 (m, 3H), 3.93 (m, 2H), 6.91 (m, 1H), 7.03 ( m, 1H), 7.56 (m, 2H), 7.87 (m, 1H), 8.16 (m, 2H)

Preparation Example 6 Preparation of 4- [1- [3- (ethylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid methyl ester (Formula 4, R ₃ = ethyl)

To methanol (80 ml) was added 4- [1- (3-amino-2-pyridyl) piperazin-4-yl-carbonyl] benzoic acid methyl ester (Formula 11, 4 g) obtained in Preparation Example 3. Acetaldehyde (1.7 mL) and acetic acid (4 mL) were added at 0 ° C. and stirred at 0 ° C. for 30 minutes. Sodium cyanoborohydride (2.2 g) was added and further reacted at 0 ° C to 5 ° C for 2 hours. Excess water was added slowly and neutralized (pH = -8) by adding 3N-sodium hydroxide aqueous solution at 10 ° C to 15 ° C. After stirring for 1 hour, the solid obtained by filtration was recrystallized with methanol and ether to obtain 3.51 g (yield 81%) of the title compound.

m.p. : 96-97 degreeC

¹ H-NMR (CDCl ₃ ), ppm: δ 1.28 (t, 3H), 3.12 (m, 6H), 3.52 (m, 2H), 3.92 (m, 5H), 4.18 (m, 1H), 6.85 ( m, 1H), 6.96 (m, 1H), 7.48 (m, 2H), 7.70 (m, 1H), 8.06 (m, 2H)

Preparation Example 7 Preparation of 4- [1- [3- (ethylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid (Formula 2, R ₃ = ethyl)

From 4- [1- [3- (ethylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid methyl ester obtained in Preparation Example 6, hydrolysis was carried out in the same manner as in Preparation Example 5 The compound was prepared.

Yield: 91%

m.p. : 208-209 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ 1.30 (t, 3H), 3.16 (m, 6H), 3.48 (m, 2H), 3.94 (m, 2H), 6.95 (m, 1H), 7.05 ( m, 1H), 7.56 (m, 2H), 7.91 (m, 1H), 8.15 (m, 2H)

Example 1 1- [N- (2-hydroxyethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound No. 1)

Methylene chloride (50 mL) in 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid obtained in 5 for preparation above (Formula 2, 1.5 g) To this was added triethylamine (0.7 mL) and dissolved. After cooling, pivaloyl chloride (0.58 mL) was slowly added at 0 ° C to 5 ° C, and reacted at 5 ° C for 2 hours. Triethylamine (0.7 mL) and 2-aminoethanol (0.27 g) were added sequentially, followed by reaction at 0 ° C. to 5 ° C. for 2 hours, and gradually heated to further react at 20 ° C. to 25 ° C. for 30 minutes. The reaction solution was washed twice with water and the solvent was concentrated under reduced pressure. The concentrated residue was treated with ether to crystallize, recrystallized from isopropanol and ether, filtered and dried to obtain 1.34 g (yield 80%) of the title compound as a white powder.

m.p. : 182-184 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ 1.20 (d, 6H), 3.07 (m, 4H), 3.51 (m, 3H), 3.58 (m, 2H), 3.76 (m, 2H), 3.85 ( m, 2H), 6.83 (m, 1H), 6.94 (m, 1H), 7.07 (m, 1H), 7.36 (m, 2H), 7.63 (m, 1H), 7.77 (m, 2H)

Example 2: 1- [N- (3-hydroxypropyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound No. 2)

The above-mentioned implementation using 3-amino-1-propanol from 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid obtained in Preparation Example 5 above Synthesis by the method of Example 1 and recrystallized with ethyl acetate and ether to prepare the target compound.

Yield: 76%

m.p. : 110-111 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ1.23 (d, 6H), 1.80 (m, 2H), 3.11 (m, 4H), 3.50 (m, 3H), 3.59 (m, 2H), 3.72 ( m, 2H), 3.90 (m, 2H), 4.15 (m, 1H), 6.86 (m, 1H), 6.97 (m, 1H), 7.12 (m, 1H), 7.44 (m, 2H), 7.67 (m , 1H), 7.78 (m, 2H)

Example 3: 1- [N- (4-hydroxybutyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound No. 3)

From 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid obtained in Preparation Example 5 described above, 4-amino-1-butanol was used. Synthesis by the method of Example 1 and recrystallized with ethyl acetate and isopropyl ether to prepare the target compound.

Yield: 84%

¹ H-NMR (CDCl ₃ ), ppm: δ1.22 (d, 6H), 1.51 (m, 2H), 1.62 (m, 2H), 3.10 (m, 4H), 3.51 (m, 5H), 3.73 ( m, 2H), 3.92 (m, 2H), 4.13 (m, 1H), 6.84 (m, 1H), 6.95 (m, 1H), 7.11 (m, 1H), 7.45 (m, 2H), 7.64 (m , 1H), 7.79 (m, 2H)

Example 4: 1- [N- (5-hydroxypentyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound No. 4)

The target compound was obtained by the same preparation method as in Example 1.

Yield: 74%

¹ H-NMR (CDCl ₃ ), ppm: δ1.22 (d, 6H), 1.42-1.51 (m, 6H), 3.10 (m, 4H), 3.50 (m, 5H), 3 71 (m, 2H) , 3.91 (m, 2H), 4.13 (m, 1H), 6.82 (m, 1H), 6.94 (m, 1H), 7.10 (m, 1H), 7.44 (m, 2H), 7.64 (m, 1H), 7.77 (m, 2 H)

Example 5: 1- [N- (2-hydroxyethyl) -N-methylcarbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl- Carbonyl] benzene (Compound No. 5)

The target compound was obtained by the same preparation method as in Example 1.

Yield: 77%

m.p. : 131-132 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ1.21 (d, 6H), 3.02 (s, 3H), 3.11 (m, 4H), 3.53 (m, 3H), 3.72 (m, 2H), 3.89 ( m, 3H), 4.15 (m, 1H), 6.84 (m, 1H), 6.95 (m, 1H), 7.48 (m, 4H), 7.68 (m, 1H)

Example 6: 1- [N-ethyl-N- (2-hydroxyethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl- Carbonyl] benzene (Compound No. 6)

The above-mentioned operation using 2- (ethylamino) ethanol from 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid obtained in Preparation Example 5 above Synthesized by the method of Example 1, recrystallized with ethyl acetate and petroleum ether, filtered and dried to prepare the target compound as a white crystals.

Yield: 86%

m.p. : 115 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ1.11 (t, 3H), 1.20 (d, 6H), 3.06 (m, 4H), 3.31 (m, 2H), 3.52 (m, 4H), 3.68 ( m, 2H), 3.87 (m, 3H), 4.14 (m, 1H), 6.83 (m, 1H), 6.93 (m, 1H), 7.45 (m, 4H), 7.66 (m, 1H)

Example 7: 1- [N- (2-hydroxyethyl) -N-propylcarbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl- Carbonyl] benzene (Compound No. 7)

The target compound was obtained by the same preparation method as in Example 6.

Yield: 82%

m.p. : 79 to 82 ° C

¹ H-NMR (CDCl ₃ ), ppm: δ 0.77 (t, 3H), 1.23 (d, 6H), 1.56 (m, 2H), 3.14-3.24 (m, 6H), 3.53 (m, 4H), 3.70 (m, 2H), 3.89 (m, 3H), 4.15 (m, 1H), 6.91 (m, 1H), 6.98 (m, 1H), 7.46 (m, 4H), 7.70 (m, 1H)

Example 8 1- [N- (2-hydroxyethyl) -N- (1-methylethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazine -4-yl-carbonyl] benzene (Compound No. 8)

The target compound was obtained by the same preparation method as in Example 6.

Yield: 85%

¹ H-NMR (CDCl ₃ ), ppm: δ1.21 (m, 12H), 3.06 (m, 4H), 3.51 (m, 6H), 3.80 (m, 2H), 3.91 (m, 2H), 4.13 ( m, 1H), 6.90 (m, 1H), 6.97 (m, 1H), 7.47 (m, 4H), 7.70 (m, 1H)

Example 9: 1- [N-butyl-N- (2-hydroxyethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl- Carbonyl] benzene (Compound No. 9)

The target compound was obtained by the same preparation method as in Example 6.

Yield: 75%

¹ H-NMR (CDCl ₃ ), ppm: δ 0.97 (t, 3H), 1.21 (d, 6H), 1.48 (m, 4H), 3.20 (m, 6H), 3.52 (m, 4H), 3.70 ( m, 2H), 3.88 (m, 3H), 4.13 (m, 1H), 6.90 (m, 1H), 6.97 (m, 1H), 7.45 (m, 4H), 7.70 (m, 1H)

Example 10 1- [N-benzyl-N- (2-hydroxyethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl- Carbonyl] benzene (Compound No. 10)

From Example 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid obtained in Preparation Example 5, using Example 2- (benzylamino) ethanol Synthesis by the method of 1, recrystallized with isopropanol and isopropyl ether, filtered and dried to prepare the target compound.

Yield: 81%

m.p. : 99 ~ 101 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ1.22 (d, 6H), 3.11 (m, 4H), 3.53 (m, 3H), 3.69 (m, 2H), 3.81 (m, 2H), 3.89 ( m, 2H), 4.58 (s, 2H), 6.87 (m, 1H), 6.96 (m, 1H), 7.16 (m, 2H), 7.28 (m, 1H), 7.35 (m, 2H), 7.44-7.52 (m, 4H), 7.68 (m, 1H)

Example 11 1- [N- (2-hydroxyethyl) -N-phenylcarbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl- Carbonyl] benzene (Compound No. 11)

The target compound was obtained by the same preparation method as in Example 10.

Yield: 76%

m.p. : 71-72 degreeC

¹ H-NMR (CDCl ₃ ), ppm: δ1.21 (d, 6H), 3.08 (m, 4H), 3.42 (m, 2H), 3.53 (m, 1H), 3.84 (m, 2H), 4.21 ( m, 2H), 6.88 (m, 1H), 6.96 (m, 1H), 7.07 (m, 2H), 7.16 (m, 1H), 7.25 (m, 4H), 7.36 (m, 2H), 7.68 (m , 1H)

Example 12 1- [N, N-bis (2-hydroxyethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbo Nyl] benzene (Compound No. 12)

The target compound was obtained by the same preparation method as in Example 10.

Yield: 83%

m.p. : 161-162 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ1.22 (d, 6H), 3.13 (m, 4H), 3.41 (m, 2H), 3.56 (m, 3H), 3.70 (m, 5H), 3.96 ( m, 3H), 6.89 (m, 1H), 6.97 (m, 1H), 7.49 (m, 2H), 7,55 (m, 2H), 7.68 (m, 1H)

Example 13: 1- [N, N-diethylcarbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzene (Compound No. 13)

The target compound was obtained by the same preparation method as in Example 1.

Yield: 80%

m.p. : 78-80 degreeC

¹ H-NMR (CDCl ₃ ), ppm: δ1.08 (t, 3H), 1.22 (m, 9H), 3.11 (m, 4H), 3.21 (m, 2H), 3.53 (m, 5H), 3.91 ( m, 2H), 4.15 (m, 1H), 6.84 (m, 1H), 6.95 (m, 1H), 7.39 (m, 2H), 7.44 (m, 2H), 7.68 (m, 1H)

Example 14 1- [N, N-bis (1-methylethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl ] Benzene (Compound No. 14)

The target compound was obtained by the same preparation method as in Example 1.

Yield: 72%

m.p. : 152-153 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ 1.16 (m, 6H), 1.24 (d, 6H), 1.50 (m, 6H), 3.14 (m, 4H), 3.53 (m, 3H), 3.87 ( m, 4H), 6.90 (m, 1H), 6.97 (m, 1H), 7.36 (m, 2H), 7.48 (m, 2H), 7.69 (m, 1H)

Example 15 1- [N, N-bis (2-hydroxypropyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbo Nil] benzene (Compound No. 16)

The target compound was obtained by the same preparation method as in Example 10.

Yield: 77%

m.p. : 73 to 75 ° C

¹ H-NMR (CDCl ₃ ), ppm: δ1.11 (d, 3H), 1.21 (d, 9H), 3.05 (m, 4H), 3.51 (m, 5H), 3.80 (m, 4H), 4.10 ( m, 2H), 6.82 (m, 1H), 6.93 (m, 1H), 7.46 (m, 4H), 7.66 (m, 1H)

Example 16: 1- [N- [2- (2-hydroxyethoxy) ethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4- Yl-carbonyl] benzene (Compound No. 17)

The target compound was obtained by the same preparation method as in Example 1.

Yield: 82%

m.p. : 116 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ1.21 (d, 6H), 3.10 (m, 4H), 3.51 (m, 3H), 3.60 (m, 2H), 3.68 (m, 4H), 3.76 ( m, 2H), 3.90 (m, 2H), 4.16 (m, 1H), 6.84 (m, 1H), 6.95 (m, 2H), 7.44 (m, 2H), 7.67 (m, 1H), 7.80 (m , 2H)

Example 17 1- [N-ethyl-N- (2-hydroxyethyl) carbamoyl] -4- [1- [3- (ethylamino) -2-pyridyl] piperazin-4-yl-carbo Nyl] benzene (Compound No. 18)

Example 1 using 2- (ethylamino) ethanol from 4- [1- [3- (ethylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid obtained in Preparation Example 7 It was synthesized by the method of and recrystallized with ethyl acetate and hexane to prepare the target compound.

Yield: 72%

m.p. : 106 ~ 108 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ 1.12 (t, 3H), 1.26 (t, 3H), 3.12 (m, 6H), 3.30 (m, 2H), 3.53 (m, 3H), 3.69 ( m, 2H), 3.89 (m, 3H), 4.19 (m, 1H), 6.84 (m, 1H), 6.95 (m, 1H), 7.48 (m, 4H), 7.70 (m, 1H)

Example 18 1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] piperazine (Compound No. 19)

To methylene chloride (50 mL) was added 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid (Formula 2, 1.5 g) obtained in Preparation Example 5. Triethylamine (0.7 mL) was added thereto and dissolved. After cooling, pivaloyl chloride (0.58 mL) was slowly added at 0 ° C to 5 ° C, and reacted at 5 ° C for 2 hours. Piperazine (0.9 g) was added and reacted at 5 ° C to 10 ° C for 3 hours. The reaction solution was washed with water and aqueous sodium bicarbonate solution and the solvent was concentrated under reduced pressure. The concentrated residue was treated with ether to crystallize, recrystallized from isopropanol and ether, filtered and dried to give 1.48 g (yield 83%) of the title compound as white crystals.

m.p. : 175-176 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ1.21 (d, 6H), 2.51 (m, 1H), 2.84 (m, 2H), 3.03 (m, 6H), 3.52 (m, 5H), 3.80 ( m, 2H), 3.90 (m, 2H), 4.13 (m, 1H), 6.80 (m, 1H), 6.93 (m, 1H), 7.47 (m, 4H), 7.66 (m, 1H)

Example 19 1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4-methylpiperazin (Compound No. 20)

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid (Formula 2, 1.2 g) obtained in Preparation Example 5 in methylene chloride (40 ml). Was added, and triethylamine (0.6 mL) was added to dissolve it. After cooling, pivaloyl chloride (0.46 mL) was slowly added at 0 ° C to 5 ° C, and reacted at 5 ° C for 2 hours. Triethylamine (0.6 mL) and 1-methylpiperazine (0.38 g) were added thereto, reacted at 5 ° C. for 2 hours, and gradually heated to further react at 20 ° C. for 30 minutes. The reaction solution was washed with water and aqueous sodium bicarbonate solution and the solvent was concentrated under reduced pressure. The concentrated residue was crystallized by treatment with hexane and ether, recrystallized with ethyl acetate and isopropyl ether, filtered, washed and dried to obtain 1.15 g (yield 78%) of the title compound as a white powder.

m.p. : 158-160 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ 1.20 (d, 6H), 2.33 (m, 5H), 2.54 (m, 2H), 3.05 (m, 4H), 3.47 (m, 5H), 3.85 ( m, 4H), 4.12 (m, 1H), 6.82 (m, 1H), 6.90 (m, 1H), 7.45 (m, 4H), 7.65 (m, 1H)

Example 20 4-ethyl-1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] piperazine (Compound No. 21)

In the same manner as in Example 19, the target compound was obtained.

Yield: 85%

m.p. : 130-131 degreeC

¹ H-NMR (CDCl ₃ ), ppm: δ1.07 (t, 3H), 1.20 (d, 6H), 2.51 (m, 6H), 3.05 (m, 4H), 3.51 (m, 5H), 3.89 ( m, 4H), 4.13 (m, 1H), 6.81 (m, 1H), 6.93 (m, 1H), 7.46 (m, 4H), 7.66 (m, 1H)

Example 21 4-cyclopentyl-1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] piperazine (Compound No. 22)

1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid] piperazine (Formula 1a, 0.5 g) obtained in Example 18 was prepared. It was dissolved in acetonitrile (25 mL), N-methylmorpholine (0.17 mL) and cyclopentyl bromide (0.3 mL) were added, followed by heating and reaction at 65 ° C to 75 ° C for 20 hours. The solvent was concentrated under reduced pressure, the residue was dissolved in chloroform (40 mL), washed twice with water, and the solvent was concentrated under reduced pressure. The concentrated residue was crystallized by treating with ether and hexane, recrystallized with ethanol and isopropyl ether, filtered, washed and dried to obtain 0.41 g (yield 71%) of the title compound.

m.p. : 181 to 182 ° C

¹ H-NMR (CDCl ₃ ), ppm: δ1.22 (d, 6H), 1.41 (m, 2H), 1.53 (m, 2H), 1.69 (m, 1H), 1.85 (m, 2H), 2.42 ( m, 2H), 2.57 (m, 2H), 3.04 (m, 4H), 3.43 (m, 2H), 3.51 (m, 3H), 3.81 (m, 4H), 4.14 (m, 1H), 6.81 (m , 1H), 6.91 (m, 1H), 7.45 (m, 4H), 7.66 (m, 1H)

Example 22 4- (2-hydroxyethyl) -1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] piperazine (Compound No. 26)

1- (2-hydroxyethyl from 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid (Formula 2) obtained in Preparation Example 5. ) Using the piperazine was synthesized by the method of Example 19 and recrystallized with isopropanol and ether to prepare the target compound.

Yield: 82%

m.p. : 148-149 degreeC

¹ H-NMR (CDCl ₃ ), ppm: δ1.23 (d, 6H), 2.49 (m, 2H), 2.62 (m, 4H), 3.05 (m, 4H), 3.52 (m, 5H), 3.65 ( m, 2H), 3.84 (m, 4H), 4.11 (m, 1H), 6.80 (m, 1H), 6.91 (m, 1H), 7.45 (m, 4H), 7.66 (m, 1H)

Example 23 4- (3-hydroxypropyl) -1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] piperazine (Compound No. 27)

1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] piperazine (obtained in Example 18 above in anhydrous ethanol (25 ml) Formula 1a, 0.5 g) was added, triethylamine (0.3 mL) and 3-bromo-1-propanol (0.5 g) were added followed by heating to reflux for 12 hours. The solvent was concentrated under reduced pressure, and the residue was dissolved in chloroform (50 mL) and washed twice with water. Water (40 mL), methanol (5 mL) and 10% aqueous sodium hydroxide solution (10 mL) were added to the chloroform solution. The mixture was stirred for 1 hour, then separated and the organic layer was washed with water, and the solvent was concentrated under reduced pressure. The concentrated residue was crystallized by treating with ether, recrystallized with ethyl acetate and ether, filtered and dried to obtain 0.44 g (yield 78%) of the title compound as white crystals.

m.p. : 129 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ1.22 (d, 6H), 1.76 (m, 2H), 2.50 (m, 2H), 2.68 (rn, 4H), 3.04 (m, 4H), 3.51 ( m, 5H), 3.80 (m, 6H), 4.12 (m, 1H), 6.80 (m, 1H), 6.91 (m, 1H), 7.47 (m, 4H), 7.65 (m, 1H)

Example 24 4-[(2R) -3-hydroxy-2-methylpropyl] -1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl -Carbonyl] benzoyl] piperazine (Compound No. 28)

The target compound was obtained in the same manner as in Example 23.

Yield: 75%

¹ H-NMR (CDCl ₃ ), ppm: δ 1.01 (d, 3H), 1.20 (d, 6H), 2.00 (m, 1H), 2.50 (m, 2H), 2.67 (m, 4H), 3.05 ( m, 4H), 3.51 (m, 5H), 3.79 (m, 6H), 4.11 (m, 1H), 6.81 (m, 1H), 6.91 (m, 1H), 7.45 (m, 4H), 7.66 (m , 1H)

Example 25 4-[(2S) -3-hydroxy-2-methylpropyl] -1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl -Carbonyl] benzoyl] piperazine (Compound No. 29)

The target compound was obtained in the same manner as in Example 23.

Yield: 72%

¹ H-NMR (CDCl ₃ ), ppm: δ 1.02 (d, 3H), 1.21 (d, 6H), 2.01 (m, 1H), 2.50 (m, 2H), 2.67 (m, 4H), 3.06 ( m, 4H), 3.50 (m, 5H), 3.79 (m, 6H), 4.10 (m, 1H), 6.80 (m, 1H), 6.90 (m, 1H), 7.47 (m, 4H), 7.66 (m , 1H)

Example 26 4- (2,2-dimethyl-3-hydroxypropyl) -1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbo Nyl] benzoyl] piperazine (Compound No. 30)

The target compound was obtained in the same manner as in Example 23.

Yield: 80%

¹ H-NMR (CDCl ₃ ), ppm: δ 1.04 (s, 6H), 1.20 (d, 6H), 2.51 (m, 2H), 2.68 (m, 4H), 3.06 (m, 4H), 3.50 ( m, 5H), 3.79 (m, 6H), 4.10 (m, 1H), 6.80 (m, 1H), 6.90 (m, 1H), 7.47 (m, 4H), 7.66 (m, 1H)

Example 27 4- (2,3-dihydroxypropyl) -1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl Piperazine (Compound No. 31)

From 1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] piperazine (Formula 1a) obtained in Example 18, 3- Bromo-1,2-propanediol was synthesized in the same manner as in Example 23, and recrystallized from isopropanol and isopropyl ether to prepare a target compound.

Yield: 71%

m.p. : 158 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ1.22 (d, 6H), 2.47 (m, 2H), 2.70 (m, 6H), 3.09 (m, 4H), 3.51 (m, 5H), 3.75 ( m, 1H), 3.88 (m, 6H), 4.13 (m, 1H), 6.81 (m, 1H), 6.91 (m, 1H), 7.48 (m, 4H), 7.66 (m, 1H)

Example 28 4- [2- (2-hydroxyethoxy) ethyl] -1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbo Nyl] benzoyl] piperazine (Compound No. 32)

A target compound was obtained by the same preparation method as in Example 19.

Yield: 80%

m.p. : 92-93 ° C

¹ H-NMR (CDCl ₃ ), ppm: δ1.21 (d, 6H), 2.55 (m, 4H), 3.09 (m, 4H), 3.52 (m, 5H), 3.59 (m, 4H), 3.69 ( m, 4H), 3.89 (m, 4H), 4.12 (m, 1H), 6.80 (m, 1H), 6.91 (m, 1H), 7.43 (m, 4H), 7.66 (m, 1H)

Salcy Example 29 1- [4- [1- [3- (ethylamino) -2-pyridyl] piperazin-4-yl-carbonyl] banzoyl] -4- (2-hydroxyethyl) piperazine (Compound No. 33)

1- (2-hydroxyethyl) piperazine was used from 4- [1- [3- (ethylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid obtained in the above preparation. Synthesis was carried out by the method of Example 19, and recrystallized with ethyl acetate and hexane to prepare the target compound.

Yield: 76%

m.p. : 152-153 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ 1.29 (t, 3H), 2.51 (m, 2H), 2.63 (m, 4H), 3.12 (m, 6H), 3.45 (m, 4H), 3.70 ( m, 2H), 3.87 (m, 4H), 4.18 (m, 1H), 6.92 (m, 1H), 6.97 (m, 1H), 7.46 (m, 4H), 7.68 (m, 1H)

Example 30 1- [N- (1,1-dimethyl-2-hydroxyethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4- Yl-carbonyl] benzene (Compound No. 34)

Methylene chloride (45 mL) in 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid obtained in Preparation Example 5 (Formula 2, 1.5 g) To this was added triethylamine (0.73 mL) and dissolved. After cooling, pivaloyl chloride (0.58 mL) was slowly added at 0 ° C to 5 ° C, and reacted at 5 ° C for 2 hours. Pyridine (0.65 mL) and 2-amino-2-methyl-1-propanol (0.4 g) were added sequentially, followed by reaction at 0 ° C. to 5 ° C. for 2 hours, and then slowly heated to further react at 20 ° C. for 1 hour. The reaction solution was washed twice with water, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The concentrated residue was treated with ether to crystallize, recrystallized from ethyl acetate and ether, filtered and dried to give 1.5 g (yield 84%) of the title compound.

m.p. : 113 to 115 ℃

¹ H-NMR (CDCl ₃ ) ppm: δ1.22 (d, 6H), 1.41 (s, 6H), 3.10 (m, 4H), 3.52 (m, 3H), 3.68 (s, 2H), 3.90 (m , 2H), 4.14 (s, 1H), 6.31 (s, 1H), 6.85 (m, 1H), 6.96 (m, 1H), 7.45 (m, 2H), 7.67 (m, 1H), 7.77 (m, 2H)

Example 31 1- [N-[(1S) -2-hydroxy-1-methylethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazine- 4-yl-carbonyl] benzene (Compound No. 35)

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid methyl ester (1.8 g) and (S)-(+) in methanol (30 mL) 2-amino-1-propanol (0.71 g) was added sequentially and heated to reflux for 12 hours. After cooling slightly, excess water was gradually added and precipitated at 40 ° C., and then cooled slowly and stirred at 20 ° C. for 1 hour, followed by filtration and washing with water. The filtered solid was recrystallized with isopropanol and ether, filtered and dried to obtain 1.66 g (yield 83%) of the title compound.

m.p. : 132-133 degreeC

¹ H-NMR (CDCl ₃ ), ppm: δ1.21 (d, 6H), 1.29 (d, 3H), 3.05 (m, 4H), 3.49 (m, 3H), 3.63 (m, 1H), 3.78 ( m, 1H), 3.89 (m, 2H), 4.13 (In, 1H), 4.25 (m, 1H), 6.67 (m, 1H), 6.85 (m, 1H), 6.95 (m, 1H), 7.40 (m , 2H), 7.66 (m, 1H), 7.78 (m, 2H)

Example 32 1- [N-[(1R) -2-hydroxy-1-methyl-ethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazine -4-yl-carbonyl] benzene (Compound No. 36)

The target compound was obtained by the same preparation method as in Example 31.

Yield: 75%

¹ H-NMR (CDCl ₃ ), ppm: δ 1.20 (d, 6H), 1.29 (d, 3H), 3.05 (m, 4H), 3.50 (m, 3H), 3.63 (m, 1H), 3.78 ( m, 1H), 3.90 (m, 2H), 4.13 (m, 1H), 4.24 (m, 1H), 6.67 (m, 1H), 6.86 (m, 1H), 6.95 (m, 1H), 7.40 (m , 2H), 7.66 (m, 1H), 7.79 (m, 2H)

Example 33 1- [N-[(1S) -2-hydroxy-1- (1-methylethyl) ethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyri Dill] piperazin-4-yl-carbonyl] benzene (Compound No. 38)

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid, (S)-(+)-2-amino-3-methyl-1 Synthesis was carried out by the method of Example 30 using butanol and recrystallized from ethanol and isopropyl ether to prepare a target compound.

Yield: 80%

m.p. : 82 ~ 83 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ 0.98 (d, 6H), 1.21 (d, 6H), 2.01 (m, 1H), 3.08 (m, 4H), 3.53 (m, 3H), 3.82 ( m, 2H), 3.93 (m, 3H), 4.14 (m, 1H), 6.70 (m, 1H), 6.85 (m, 1H), 6.95 (m, 1H), 7.39 (m, 2H), 7.66 (m) , 1H), 7.77 (m, 2H)

Example 34 1- [N-[(1S) -2-hydroxy-1- (1-methylethyl) ethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyri Dill] piperazin-4-yl-carbonyl] benzene (Compound No. 39)

The target compound was obtained by the same preparation method as in Example 33.

Yield: 72%

m.p. : 86 ~ 88 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ 0.99 (d, 6H), 1.21 (d, 6H), 2.02 (m, 1H), 3.06 (m, 4H), 3.51 (m, 3H), 3.80 ( m, 2H), 3.92 (m, 3H), 4.13 (m, 1H), 6.68 (m, 1H), 6.83 (m, 1H), 6.96 (m, 1H), 7.40 (m, 2H), 7.65 (m , 1H), 7.78 (m, 2H)

Example 35 1- [N-[(1S) -1-ethyl-2-hydroxyethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazine- 4-yl-carbonyl] benzene (Compound No. 41)

(S)-(+)-2-amino-1-butanol from 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid methyl ester Synthesis was carried out in the same manner as in Example 31, and recrystallized with acetonitrile and isopropan ether to prepare a target compound.

Yield: 79%

¹ H-NMR (CDCl ₃ ), ppm: δ 0.97 (t, 3H), 1.21 (d, 6H), 1.73 (m, 1H), 1.85 (m, 1H), 3.06 (m, 4H), 3.51 ( m, 3H), 3.81 (m, 2H), 3.92 (m, 2H), 4.11 (m, 2H), 6.69 (m, 1H), 6.84 (m, 1H), 6.97 (m, 1H), 7.41 (m) , 2H), 7.65 (m, 1H), 7.79 (m, 2H)

Example 36 1- [N-[(1R) -1-ethyl-2-hydroxyethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazine- 4-yl-carbonyl] benzene (Compound No. 42)

The target compound was obtained in the same manner as in Example 35.

Yield: 73%

¹ H-NMR (CDCl ₃ ), ppm: δ 0.98 (t, 3H), 1.21 (d, 6H), 1.75 (m, 1H), 1.84 (m, 1H), 3.05 (m, 4H), 3.51 ( m, 3H), 3.80 (m, 2H), 3.93 (m, 2H), 4.11 (m, 2H), 6.69 (m, 1H), 6.84 (m, 1H), 6.98 (m, 1H), 7.41 (m) , 2H), 7.65 (m, 1H), 7.80 (m, 2H)

Example 37 1- [N- (1-ethyl-2-hydroxyethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl- Carbonyl] benzene (Compound No. 43)

The target compound was obtained in the same manner as in Example 35.

Yield: 84%

¹ H-NMR (CDCl ₃ ), ppm: δ 0.98 (t, 3H), 1.21 (d, 6H), 1.76 (m, 1H), 1.84 (m, 1H), 3.06 (m, 4H), 3.51 ( m, 3H), 3.81 (m, 2H), 3.92 (m, 2H), 4.11 (m, 2H), 6.69 (m, 1H), 6.84 (m, 1H), 6.97 (m, 1H), 7.40 (m , 2H), 7.66 (m, 1H), 7.79 (m, 2H)

Example 38 1- [N-[(1S) -1- (cyclohexylmethyl) -2-hydroxyethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl ] Piperazin-4-yl-carbonyl] benzene (Compound No. 47)

To methylene chloride (60 mL) was added 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid (1.5 g) and triethylamine (0.7 mL). It was dissolved by addition. After cooling, pivaloyl chloride (0.58 mL) was slowly added at 0 ° C to 5 ° C, and reacted at 5 ° C for 2 hours. Triethylamine (1.7 mL) and (S)-(+)-2-amino-3-cyclohexyl-1-propanol hydrochloride (0.87 g) were added sequentially, reacted at 0 ° C. for 3 hours, and gradually heated to 20 ° C. The reaction was further reacted for 1 hour. The reaction solution was washed twice with water and the solvent was concentrated under reduced pressure. The concentrated residue was recrystallized from isopropanol and ether, filtered and dried to yield 2.07 g (yield 80%) of the title compound.

m.p. : 139 ~ 140 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ 0.99-1.01 (m, 2H), 1.22 (m, 9H), 1.34 (m, 1H), 1.45 (m, 2H), 1.71 (m, 4H), 1.81 (m, 1H), 3.10 (m, 4H), 3.51 (m, 3H), 3.61 (m, 1H), 3.76 (m, 1H), 3.89 (m, 2H), 4.13 (m, 1H), 4.26 (m, 1H), 6.59 (m, 1H), 6.83 (m, 1H), 6.95 (m, 1H), 7.40 (m, 2H), 7.67 (m, 1H), 7.77 (m, 2H)

Example 39 1- [N-[(1S) -2-hydroxy-1-phenylethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazine- 4-yl-carbonyl] benzene (Compound No. 48)

(S)-(+)-2-amino-2-phenylethanol from 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid Synthesis by the method of Example 30 and recrystallized with ethanol and petroleum ether to give the target compound.

Yield: 77%

m.p. : 93-95 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ1.21 (d, 6H), 3.10 (m, 4H), 3.51 (m, 3H), 3.88 (m, 2H), 3.96 (m, 2H), 4.14 ( m, 1H), 5.20 (m, 1H), 6.84 (m, 1H), 6.94 (m, 1H), 7.31-7.39 (m, 8H), 7.65 (m, 1H), 7.80 (m, 2H)

Example 40 1- [N-[(1R) -2-hydroxy-1-phenylethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] furperazine -4-yl-carbonyl] benzene (Compound No. 49)

The target compound was obtained by the same preparation method as in Example 39.

Yield: 75%

¹ H-NMR (CDCl ₃ ), ppm: δ 1.20 (d, 6H), 3.09 (m, 4H), 3.50 (m, 3H), 3.88 (m, 2H), 3.96 (m, 2H), 4.13 ( m, 1H), 5.20 (m, 1H), 6.84 (m, 1H), 6.95 (m, 1H), 7.30-7.39 (m, 8H), 7.65 (m, 1H), 7.80 (m, 1H)

Example 41 1- [N- [bis (hydroxymethyl) methyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl ] Benzene (Compound No. 52)

The above example using 2-amino-1,3-propanediol from 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid methyl ester Synthesis by the method of 31 and recrystallized with ethyl acetate and ether to give the target compound.

Yield: 79%

m.p. : 147-149 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ1.21 (d, 6H), 3.06 (m, 4H), 3.49 (m, 3H), 3.90 (m, 6H), 4.11 (m, 2H), 6.85 ( m, 1H), 6.96 (m, 1H), 7.38 (m, 3H), 7.65 (m, 1H), 7.80 (m, 2H)

Example 42 1- [N]-[1,1-bis (hydroxymethyl) propyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazine-4 -Yl-carbonyl] benzene (Compound No. 54)

The target compound was obtained by the same preparation method as in Example 41.

Yield: 82%

¹ H-HMR (CDCl ₃ ), ppm: δ 0.99 (t, 3H), 1.21 (d, 6H), 1.91 (m, 2H), 3.06 (m, 4H), 3.50 (m, 3H), 3.90 ( m, 6H), 4.11 (m, 1H), 6.86 (m, 1H), 6.95 (m, 1H), 7.38 (m, 3H), 7.66 (m, 1H), 7.80 (m, 2H)

Example 43 1- [N-[(2S) -2-hydroxypropyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl- Carbonyl] benzene (Compound No. 56)

(S)-(+)-1-Amino-2-propanol from 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid methyl ester Synthesis was carried out in the same manner as in Example 31, and recrystallized from isopropanol and tetrahydrofuran to prepare a target compound.

Yield: 81%

¹ H-NMR (CDCl ₃ ), ppm: δ1.21 (m, 6H), 1.29 (d, 3H), 3.05 (m, 4H), 3.50 (m, 3H), 3.59 (m, 1H), 3.72 ( m, 2H), 3.90 (m, 2H), 4.13 (m, 1H), 4.25 (m, 1H), 6.67 (m, 1H), 6.85 (m, 1H), 6.95 (m, 1H), 7.40 (m , 2H), 7.66 (m, 1H), 7.78 (m, 2H)

Example 44 1- [N-[(2R) -2-hydroxypropyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl- Carbonyl] benzene (Compound No. 57)

The target compound was obtained in the same manner as in Example 43.

Yield: 74%

¹ H-HMR (CDCl ₃ ), ppm: δ 1.20 (m, 6H), 1.29 (d, 3H), 3.04 (m, 4H), 3.50 (m, 3H), 3.60 (m, 1H), 3.73 ( m, 2H), 3.91 (m, 2H), 4.11 (m, 1H), 4.25 (m, 1H), 6.67 (m, 1H), 6.85 (m, 1H), 6.95 (m, 1H), 7.40 (m , 2H), 7.66 (m, 1H), 7.78 (m, 2H)

Example 45 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- [N- (2-methoxyethyl) carbamoyl] benzene (Compound No. 61)

Dissolve 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid methyl ester (1.6 g) in methanol (35 mL) and 2-methoxyethylamine (0.68 g) was added followed by heating to reflux for 10 hours. After cooling slightly, excess water was gradually added and precipitated at 35 ° C. to 40 ° C., and the mixture was slowly cooled, stirred at 10 ° C. for 1 hour, filtered, and washed with a mixed solvent of water and methanol (4: 1 v / v). The filtered solid was recrystallized with isopropanol and ether, filtered and dried to obtain 1.39 g (yield 78%) of the title compound.

m.p. : 120 to 121 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ1.23 (d, 6H), 3.15 (m, 4H), 3.38 (s, 3H), 3.55 (m, 5H), 3.64 (m, 2H), 3.91 ( m, 2H), 6.55 (m, 1H), 6.90 (m, 1H), 6,99 (m, 1H), 7.49 (m, 2H), 7.70 (m, 1H), 7.81 (m, 2H)

Example 46 1- [N, N-bis (2-methoxyethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbo Nyl] benzene (Compound No. 62)

To methylene chloride (45 mL) add 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid (1.5 g) and triethylamine (0.7 mL) It was dissolved by addition. After cooling, pivaloyl chloride (0.58 mL) was slowly added at 0 ° C to 5 ° C, and reacted at 5 ° C for 2 hours. N, N-diisopropylethylamine (0.8 mL) and bis (2-methoxyethyl) amine (0.6 g) were added sequentially, followed by reaction at 0 ° C. to 5 ° C. for 2 hours, and gradually heated to 20 ° C. to 25 ° C. It was further reacted for 30 minutes. The reaction solution was washed twice with water, washed once with 5% aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the concentrated residue was crystallized by treating with ether, recrystallized with ethyl acetate and ether, filtered and dried to obtain 1.65 g (yield 84%) of the title compound.

m.p. : 82 ~ 83 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ1.21 (d, 6H), 3.08 (m, 4H), 3.25 (s, 3H), 3.36 (m, 5H), 3.52 (m, 5H), 3.64 ( m, 2H), 3.74 (m, 2H), 3.90 (m, 2H), 4.15 (m, 1m), 6.82 (m, 1H), 6.91 (m, 1H), 7.44 (m, 4H), 7.66 (m) , 1H)

Example 47 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- [N- (3-methoxypropyl) carbamoyl] benzene (Compound No. 64)

The target compound was obtained in the same manner as in Example 45.

Yield: 75%

¹ H-NMR (CDCl ₃ ), ppm: δ1.22 (d, 6H), 1.80 (m, 3H), 3.13 (m, 4H), 3.39 (s, 3H), 3.53 (m, 5H), 3.63 ( m, 2H), 3.91 (m, 2H), 6.55 (m, 1H), 6.90 (m, 1H), 6.96 (m, 1H), 7.49 (m, 2H), 7.71 (m, 1H), 7.80 (m , 2H)

Example 48 1- [N- (2,2-dimethoxyethyl) -N-methylcarbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazine-4- Yl-carbonyl] benzene (Compound No. 68)

Synthesis by the method of Example 46 above using methylaminoacetaldehyde dimethyl acetal from 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid and aceto The target compound was prepared by recrystallization with nitrile and ether.

Yield: 80%

¹ H-NMR (CDCl ₃ ), ppm: δ1.21 (d, 6H), 3.01 (s, 3H), 3.14 (m, 4H), 3.38 (s, 3H), 3.41 (s, 3H), 3.51 ( m, 5H), 3.91 (m, 2H), 4.82 (m, 1H), 6.87 (m, 1H), 6.94 (m, 1H), 7.46 (m, 4H), 7.67 (m, 1H)

Example 49 1- [N- (2,2-diethoxyethyl) carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl ] Benzene (Compound No. 70)

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid by the method of Example 46 using 2,2-diethoxyethylamine Synthesized and recrystallized from ethanol and isopropyl ether to prepare the target compound.

Yield: 76%

¹ H-NMR (CDCl ₃ ), ppm: δ1.22 (m, 12H), 3.15 (m, 4H), 3.50 (m, 5H), 3.57 (m, 2H), 3.80 (m, 2H), 3.92 ( m, 2H), 4.85 (m, 1H), 6.87 (m, 1H), 6.93 (m, 1H), 7.45 (m, 4H), 7.67 (m, 1H)

Example 50 1- [N-[(1,3-dioxolan-2-yl) methyl] -N-methylcarbamoyl] -4- [1- [3- (isopropylamino) -2-pyri Dill] piperazin-4-yl-carbonyl] benzene (Compound No. 71)

The target compound was obtained by the same preparation method as in Example 46.

Yield: 81%

m.p. : 102 to 104 ° C

¹ H-NMR (CDCl ₃ ), ppm: δ1.22 (d, 6H), 3.12 (m, 7H), 3.42 (m, 1H), 3.54 (m, 3H), 3.72 (m, 1H), 3.90 ( m, 6H), 4.15 (m, 1H), 5.01 (m, 1H), 6.87 (m, 2H), 7.46 (m, 4H), 7.69 (m, 1H)

Example 51 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- [N-[(tetrahydrofuran-2-yl) methyl ] Carbamoyl] benzene (Compound No. 72)

Synthesis from 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid methyl ester by the method of Example 45 using tetrahydroperfurylamine And recrystallized with ethyl acetate and hexane to prepare the target compound.

Yield: 83%

m.p. : 146-147 degreeC

¹ H-NMR (CDCl ₃ ), ppm: δ1.21 (d, 6H), 1.61 (m, 1H), 1.94 (m, 2H), 2.02 (m, 1H), 3.11 (m, 4H), 3.33 ( m, 1H), 3.52 (m, 3H), 3.76 (m, 2H), 3.86 (m, 3H), 4.05 (m, 1H), 4.12 (m, 1H), 6.53 (m, 1H), 6.87 (m , 1H), 6.95 (m, 1H), 7.49 (m, 2H), 7.68 (m, 1H), 7.81 (m, 2H)

Example 52 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- [N-[[(2R) -tetrahydrofuran-2 -Yl] methyl] carbamoyl] benzene (Compound No. 73)

The target compound was obtained by the same preparation method as in Example 51.

Yield: 77%

¹ H-NMR (CDCl ₃ ), ppm: δ1.22 (d, 6H), 1.60 (m, 1H), 1.93 (m, 2H), 2.02 (m, 1H), 3.11 (m, 4H), 3.31 ( m, 1H), 3.51 (m, 3H), 3.77 (m, 2H), 3.86 (m, 3H), 4.06 (m, 1H), 4.13 (m, 1H), 6.52 (m, 1H), 6.87 (m , 1H), 6.95 (m, 1H), 7.50 (m, 2H), 7.68 (m, 1H), 7.82 (m, 2H)

Example 53 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- [N-[[(2S) -tetrahydrofuran-2 -Yl] methyl] carbamoyl] benzene (Compound No. 74)

The target compound was obtained by the same method as in Example 51 at all times.

Yield: 79%

¹ H-NMR (CDCl ₃ ), ppm: δ1.21 (d, 6H), 1.61 (m, 1H), 1.93 (m, 20), 2.03 (m, 1H), 3.12 (m, 4H), 3.32 ( m, 1H), 3.52 (m, 3H), 3.77 (m, 2H), 3.86 (m, 3H), 4.06 (m, 1H), 4.12 (m, 1H), 6.53 (m, 1H), 6.87 (m , 1H), 6.94 (m, 1H), 7.49 (m, 2H), 7.68 (m, 1H), 7.81 (m, 2H)

Example 54 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- (morpholin-4-yl-carbonyl) benzene (compound Number 76)

To methylene chloride (45 mL) add 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid (1.5 g) and triethylamine (0.7 mL) It was dissolved by addition. After cooling, pivaloyl chloride (0.58 mL) was slowly added at 0 ° C to 5 ° C, and reacted at 5 ° C for 2 hours. Morpholine (0.91 g) was slowly added and reacted at 0 ° C to 5 ° C for 3 hours. The reaction solution was washed twice with water, washed once with 1% aqueous acetic acid solution and 5% aqueous sodium bicarbonate solution, and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, the concentrated residue was treated with ether to crystallize, recrystallized from methanol and hexane, filtered and dried to obtain 1.52 g (yield 85%) of the title compound.

m.p. : 139 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ1.23 (d, 6H), 3.10 (m, 4H), 3.41 (m, 2H), 3.53 (m, 5H), 3.77 (m, 4H), 3.90 ( m, 2H), 4.14 (m, 1H), 6.85 (m, 1H), 6.96 (m, 1H), 7.48 (m, 4H), 7.67 (m, 1H)

Example 55 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- (thiomorpholin-4-yl-carbonyl) benzene ( Compound number 77)

The target compound was obtained by the same preparation method as in Example 54.

Yield: 76%

m.p. : 163-164 degreeC

¹ H-NMR (CDCl ₃ ), ppm: δ1.21 (d, 6H), 2.53 (m, 2H), 2.72 (m, 2H), 3.10 (m, 4H), 3.52 (m, 3H), 3.63 ( m, 2H), 3.91 (m, 2H), 4.01 (m, 2H), 4.14 (m, 1H), 6.85 (m, 1H), 6.93 (m, 1H), 7.41 (m, 2H), 7.46 (m , 2H), 7.67 (m, 1H)

Example 56 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- [N- [2- (morpholin-4-yl) Ethyl] carbamoyl] benzene (Compound No. 79)

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid methyl ester in a mixed solvent of ethanol (10 mL) and acetonitrile (20 mL) g) was dissolved, and 4- (2-aminoethyl) morpholine (0.82 g) was added thereto, followed by heating to reflux for 15 hours. After cooling, excess water was gradually added to precipitate at 30 ° C., stirred for 1 hour, and then cooled slowly, stirred for 2 hours at 10 ° C. to 15 ° C., filtered, and washed with water at 40 ° C. The filtered crystals were recrystallized from isopropanol and ether, filtered and dried to obtain 1.22 g (yield 81%) of the title compound.

m.p. : 114-116 degreeC

¹ H-NMR (CDCl ₃ ), ppm: δ1.22 (d, 6H), 2.59 (m, 4H), 2.68 (m, 2H), 3.04 (m, 4H), 3.57 (m, 5H), 3.77 ( m, 4H), 3.90 (m, 2H), 4.12 (m, 1H), 6.81 (m, 1H), 6.92 (m, 1H), 7.10 (m, 1H), 7.48 (m, 2H), 7.65 (m , 1H), 7.85 (m, 2H)

Example 57 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- [N- [3- (morpholin-4-yl) Propyl] carbamoyl] benzene (Compound No. 80)

The target compound was obtained by the same preparation method as in Example 56.

Yield: 74%

m.p. : 103 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ1.21 (d, 6H), 1.85 (m, 2H), 2.62 (m, 6H), 3.05 (m, 4H), 3.53 (m, 5H), 3.75 ( m, 4H), 3.91 (m, 2H), 4.12 (m, 1H), 6.81 (m, 1H), 6.92 (m, 1H), 7.51 (m, 2H), 7.66 (m, 1H), 7.87 (m , 2H), 8.13 (m, 1H)

Example 58 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] -1- [N- [2- (piperidin-1-yl ) Ethyl] carbamoyl] benzene (Compound No. 81)

From 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid methyl ester, using 1- (2-aminoethyl) piperidine It synthesize | combined by the method of Example 56, and recrystallized with acetonitrile and hexane to produce the target compound.

Yield: 70%

m.p. : 106-107 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ1.22 (d, 6H), 1.46 (m, 2H), 1.61 (m, 4H), 2.47 (m, 4H), 2.58 (m, 2H), 3.06 ( m, 4H), 3.54 (m, 5H), 3.90 (m, 2H), 4.12 (m, 1H), 6.81 (m, 1H), 6.91 (m, 1H), 7.14 (m, 1H), 7.48 (m , 2H), 7.66 (m, 1H), 7.83 (m, 2H)

Example 59 1- [N- [2- (dimethylamino) ethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbo Nyl] benzene (Compound No. 83)

The process of Example 45 above using N, N-dimethylethylenediamine from 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid methyl ester It synthesize | combined and the recrystallized with ethanol and isopropyl ether, and prepared the target compound.

Yield: 79%

m.p. : 133 ℃

¹ H-NMR (CDCl ₃ ), ppm: δ1.22 (d, 6H), 2.31 (s, 6H), 2.57 (m, 2H), 3.09 (m, 4H), 3.53 (m, 5H), 3.91 ( m, 2H), 4.13 (m, 1H), 6.80 (m, 1H), 6.91 (m, 1H), 7.04 (m, 1H), 7.48 (m, 2H), 7.66 (m, 1H), 7.86 (m , 2H)

Example 60 1- [N- [2- (dimethylamino) ethyl] -N-methylcarbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazine-4- Yl-carbonyl] banzen (Compound No. 84)

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid using N, N, N'-trimethylethylenediamine as in Example 46 above. It was synthesized by the method, and recrystallized with isopropanol and ether to prepare the target compound.

Yield: 80%

¹ H-NMR (CDCl ₃ ), ppm: δ1.22 (d, 6H), 2.31 (s, 6H), 2.58 (m, 2H), 3.01 (s, 3H), 3.10 (m, 4H), 3.53 ( m, 5H), 3.90 (m, 2H), 4.12 (m, 1H), 6.80 (m, 1H), 6.92 (m, 1H), 7.48 (m, 2H), 7.67 (m, 1H), 7.86 (m , 2H)

Example 61 1- [N- [2- (dimethylamino) ethyl] -N-ethylcarbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazine-4- Yl-carbonyl] benzene (Compound No. 85)

The target compound was obtained by the same preparation method as in Example 60.

Yield: 74%

¹ H-NMR (CDCl ₃ ), ppm: δ 1.10 (t, 3H), 1.22 (d, 6H), 2.30 (s, 6H), 2.59 (m, 2H), 3.11 (m, 4H), 3.52 ( m, 7H), 3.91 (m, 2H), 4.12 (m, 1H), 6.81 (m, 1H), 6.92 (m, 1H), 7.49 (m, 2H), 7.67 (m, 1H), 7.87 (m , 2H)

Example 63 1- [N- [2- [diethylamino) ethyl] carbamoyl] -4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbo Nyl] benzene (Compound No. 86)

4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid methyl ester of Example 45 using N, N-diethylethylenediamine It was synthesized by the method, and recrystallized with isopropanol and hexane to prepare the target compound.

Yield: 76%

¹ H-NMR (CDCl ₃ ), ppm: δ 1.02 (t, 6H), 1.22 (d, 6H), 2.60 (m, 6H), 3.11 (m, 4H), 3.51 (m, 5H), 3.90 ( m, 2H), 4.13 (m, 1H), 6.18 (m, 1H), 6.92 (m, 1H), 7.05 (m, 1H), 7.49 (m, 2H), 7.67 (m, 1H), 7.87 (m , 2H)

Experimental Example 1 In vitro Inhibitory Activity Test of Hepatitis B Virus Polymerase

Recently, the present inventors have filed a patent application by expressing and separating the recombinant polymerase protein of hepatitis B virus in E. coli and measuring the enzyme activity thereof (Korean Patent Application Nos. 94-3918 and 96-33998). The inventors have established a method for measuring reverse transcriptase activity of hepatitis B virus polymerase in vivo using this enzyme. The basic principle is the same as the enzyme-immunological method (ELISA), and the reaction is performed by incorporating biotin- and DIG-modified nucleotides into the substrate, and then using the anti-DIG antibody attached to the polymerized substrate. Recognition method was used. 20 μl of hepatitis B virus polymerase, 20 μl of reaction mixture and 20 μl of sample were mixed and reacted at 14 ° C. to 30 ° C. for 18 to 24 hours, and compared with the result of control experiment without sample. Reverse transcriptase inhibitory activity was confirmed. The inhibitory activity results of each sample are shown in Table 1 below.

TABLE 1

Table 1 (continued)

Table 1 (continued)

Table 1 (continued)

0

0

Experimental Example 2

1) Expression and purification of recombinant RNase H enzyme protein derived from HBV polymerase

E. coli NM522 strain was transformed with the recombinant plasmid pMRH and the transformants were inoculated in LB medium and incubated overnight at 37 ° C. This was inoculated again by diluting 1: 100 in glucose-added medium (glucoserich) at 37 ° C and incubating at 37 ° C. When the absorbance at the wavelength of 600 nm reached 0.5, IPTG (isopropylthiogalactoside) was added so that the final concentration was 0.5mM for 16 hours at 20 ° C. During further cultures to express the recombinant RNase H enzyme protein.

The culture solution obtained above was centrifuged at 3,000 rpm for 10 minutes, followed by washing the cell pellet with 10 ml of TNE column buffer (10 mM Tris-hydrochloric acid, pH 8.0, 200 mM sodium chloride, 1 mM EDTA), and then again with 10 ml TNE buffer. Suspended in. After freezing and thawing the cell suspension (freeze and thaw) was repeated four times, cells were crushed using three sonications for 10 seconds to prepare crude cell eluate. The crude cell eluate prepared in the above process was centrifuged at 13,000 rpm for 30 minutes at 4 ° C., and then the supernatant was separated, and this process was repeated twice, and the supernatant was passed through amylose resin. After passing all of the supernatant, the resin was washed with 50-fold column buffer, and the recombinant RNase H enzyme protein in the form of a fusion protein was isolated with a buffer containing 10 mM maltose.

Since the RNase H enzyme protein produced from the expression plasmid pMRH has a histidine label at the carboxy terminus of the protein, it was isolated and purified using a histidine labeled affinity column. Resin (Ni-NTA, QIAGEN) used in histidine-labeled affinity column was activated with sonication buffer solution (50 mM sodium phosphate, pH 8.0, 300 mM sodium chloride), and then the activated resin was about 1 cm in diameter. To a volume of 4-5 ml. The protein sample obtained above was passed through the column at a flow rate of 0.1 ml / min, and then the column was washed with a wash buffer solution (50 mM sodium phosphate, pH 6.0, 300 mM sodium chloride, 10% glycerol) corresponding to a volume of 100 to 200 times the protein sample. Rinse enough. Then, the recombinant protein was eluted by preparing a washing buffer containing an imidazole reagent having a concentration gradient of 0.01-0.5 M and sequentially passing the column.

As a result, the RNase H enzyme protein of the HBV polymerase was freed from the histidine-labeled affinity column at an imidazole 30mM concentration and separated and purified. The eluted sample was removed at imidazole and mixed with 50% glycerol and stored at -20 ° C. The purified RNase H protein of HBV polymerase was used to search for inhibitors.

2) Preparation of Reaction Substrates of RNase H Enzyme Proteins

In order to confirm the activity of the RNase H enzyme protein, RNA-DNA complex used as a reaction substrate of the RNase H enzyme protein was prepared by in vitro transcription reaction using E. coli RNA polymerase. M13mp19 was used as a DNA template for the preparation of transcripts. E. coli was transformed with M13mp19, the transformants were cultured, and ssDNA was isolated and purified in large quantities. In vitro transcription reaction was performed using 4 μl 5 × reaction buffer solution (200 mM Tris-hydrochloric acid, pH 7.5, 30 mM magnesium chloride, 10 mM spermidine, 50 mM sodium chloride), 2 μl 100 mM DTT, 1 μl RNasin, single stranded M13mp19 2 to 5 μg. Place 1 μl, 1 μl 2.5 mM ATP, 1 μl 2.5 mM GTP, 1 μl 2.5 mM UTP, 2.4 μl 0.1 mM CTP, 5 μl [35P] CTP 50 μCi, 1 μl E.coli RNA polymerase into the test tube After mixing, the total reaction volume was 20 µl and reacted at 37 ° C. for 16 hours. Then, the unpolymerized nucleotides were removed using a QIAquick nucleotide removal kit (QIAGEN) and RNA / DNA complexes were separated.

3) Screening of Inhibitors of RNase H Enzyme Proteins

The activity of RNase H enzyme protein of HBV polymerase was measured using the isolated and purified RNase H enzyme protein and the radiolabeled RNA-DNA complex prepared above. 1 μg of RNase H enzyme protein was added under 40 mM Tris-HCl (pH 8.0), 4 mM Magnesium Chloride, 40 mM Potassium Chloride, and 2 mM DTT buffer, and the sample was subjected to pretreatment on ice for 10 minutes. After the pretreatment, RNA-DNA complex was added and reacted at 37 ° C. for 30 minutes. After the reaction, 7.5M ammonium acetate was added at a volume of 1/2 volume and ethanol 3 times to precipitate at -20 ° C for at least 2 hours. The supernatant was obtained by centrifugation at 4 ° C. for 15 minutes at 13,000 rpm, and the radioactivity was measured by mixing it with a scintillation cocktail. As a control, the reaction was performed by adding water instead of the sample, and the inhibitory activity was calculated by comparing the radioactivity intensity of each sample with the control.

The inhibitory activity results of each sample are shown in Table 2 below.

TABLE 2

Table 2 (continued)

Experimental Example 3 In vitro Inhibitory Activity Test of Immunodeficiency (AIDS) Virus Reverse Transcriptase (HIV RT)

In vitro inhibitory activity was measured using a non-radioactive reverse transcriptase assay kit (Boehringer Mannheim).

First, 20 μl (40 ng) of HIV-RT were placed in a well coated with streptavidin, template / primer hybrid poly (A) oligo (dT) ₁₅ and DIG- (digoxygenin). 20 μl of a reaction mixture containing -dUTP, biotin-dUTP, and TTP was added, and then 20 μl of the sample to measure activity was added and reacted at 37 ° C. for 1 hour. The activity was compared as a control without the sample. At this time, the DNA is produced by the action of HIV RT and because digoxigenin and biotin-labeled nucleotides are included together, it binds to streptavidin coated on the bottom of the well. After the reaction was completed, 250 μl of washing buffer solution (pH 7.0) was added to each well to remove remaining impurities, and washed five times for 30 seconds. 200 μl of anti-DIG-POD antibody was added thereto for 1 hour at 37 ° C. After reacting for a while, washed again with a washing buffer to remove impurities, and then reacted at room temperature for 30 minutes by adding 200 μl of ABTS ^TM , a substrate of POD (peroxidase), and then using an ELISA reader. Absorbance was measured at 405 nm to quantify reverse transcriptase activity and inhibitory activity.

Inhibitory activity of each sample is shown in Table 3 below.

TABLE 3

Table 3 (continued)

Table 3 (continued)

Table 3 (continued)

Experimental Example 4: Cytotoxicity Test

Cytotoxicity tests were performed to investigate the effects and toxicity of HBV and HIV inhibitory effects of the terephthalic acid amide derivative represented by Chemical Formula 1 and pharmaceutically acceptable salts thereof according to the present invention on cytotoxicity itself. HepG2 cells were used and performed in vitro. As a result, the terephthalic acid amide derivative represented by Chemical Formula 1 according to the present invention and its pharmaceutically acceptable salts were all CC ₅₀ ≧ ₂₀₀ μM and proved to be non-cytotoxic.

As described above, the terephthalic acid amide derivative represented by Chemical Formula 1 and a pharmaceutically acceptable salt thereof according to the present invention inhibit the replication of various viruses including a series of reverse transcription processes in their proliferation process, such as HBV and HIV. It is useful as an active ingredient of proliferation inhibitors of these viruses because it has a mechanism and is not particularly cytotoxic.

Claims (13)

The novel terephthalic acid amide derivative represented by the following formula (1) and a pharmaceutically acceptable salt thereof. Formula 1

In Formula 1 above: R ₁ and R ₂ are the same as or different from each other, a hydrogen atom; Phenyl group; Benzyl groups; An alkyl group of C ₁ to C ₆ ; Di (C ₁ ~ C ₄ alkyl) amino group or an acetylamino group is a substituted alkyl group of C ₁ ~ C _4; A C ₁ to C ₄ alkyl group substituted with a 4 to 7 membered heterocycle containing 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur; C ₁ ~ C ₅ hydroxyalkyl group; Phenyl group, benzyl group, C ₁ ~ C ₄ alkyl group and a hydroxy-C ₁ ~ is a substituent selected from the group of C ₇ 1 ~ 2 gae hydroxy alkyl group-substituted C ₁ ~ C _4; C ₂ ~ C ₆ Alkoxyalkyl group; C ₂ to C ₆ dialkoxyalkyl group; C ₂ -C _{5 represents} a (hydroxyalkoxy) alkyl group; However, except that when R ₁ and R ₂ are hydrogen atoms at the same time, when one of R ₁ and R ₂ is a hydrogen atom may represent a stereospecificity of the form (R)-or (S)-, In addition, R ₁ and R ₂ may be bonded together with one or two heteroatoms selected from nitrogen, oxygen, and sulfur to form a 5-membered or 6-membered heterocycle, wherein the heterocycle is an alkyl group of C ₁ to C ₅ , a C ₃ ~ C ₆ cycloalkyl group, C ₃ ~ C ₅ a (hydroxy-alkoxy) hydroxy in the alkyl group, C ₂ ~ C ₅ hydroxy alkyl, C ₁ ~ C ₃ with C ₁ ~ C ₄ substituted with an alkyl group of hydroxy alkyl group, C ₁ ~ C ₄ dihydroxy alkyl group, or C ₁ ~ C ₃ may be substituted with a di-hydroxy alkyl group of the optionally substituted C ₁ ~ C ₄ alkyl groups and in the; R ₃ represents an alkyl group of C ₁ to C ₄ ; In addition, the above-mentioned alkyl group is a linear alkyl group or a pulverized alkyl group or includes a cycloalkyl group. According to claim 1, wherein _one of R ₁ and R ₂ is a hydrogen atom, the other is C ₁ ~ C ₃ Alkoxy C ₁ ~ C ₄ Alkyl group; C ₂ -C ₅ dialkoxy C ₁ -C ₄ alkyl group, 1,3-dioxoran-2-yl-methyl group; Tetrahydrofuran-2-yl-methyl group; 2- (morpholin-4-yl) ethyl group; 3- (morpholin-4-yl) propyl group; 2- (piperidin-1-yl) ethyl group; Di (C ₁ -C ₃ alkyl) amino C ₁ -C ₃ alkyl groups; 2- (acetylamino) ethyl group; 2-hydroxyethyl group; Or a 2-hydroxyethyl group substituted with one or two or the same or different substituents selected from a phenyl group, a benzyl group, a C ₁ to C ₃ hydroxyalkyl group and a C ₁ to C ₅ alkyl group. . According to claim 1, wherein _one of R ₁ and R ₂ is an alkyl group of C ₁ ~ C ₃ , The other is a C ₁ ~ C ₃ dialkoxy C ₂ ~ C ₃ Alkyl group; 1,3-dioxolan-2-yl-methyl group; Tetrahydrofuran-2-yl-methyl group; 2- (morpholin-4-yl) ethyl group; 3- (morpholin-4-yl) propyl group; 2- (piperidin-1-yl) ethyl group; 2-hydroxyethyl group; Di (C ₁ -C ₃ alkyl) amino C ₁ -C ₃ alkyl groups; Or a 2- (acetylamino) ethyl group. The terephthalic acid amide derivative according to claim 1, wherein R ₁ and R ₂ are simultaneously C ₁ to C ₃ alkyl, hydroxyethyl or 2-hydroxypropyl groups. According to claim 1, wherein R ₁ and R ₂ is combined with one or two heteroatoms selected from nitrogen, oxygen, sulfur to form a morpholine, thiomorpholine, pyrrolidine, piperidine or piperazine ring Terephthalic acid amide derivative characterized by the above-mentioned. 6. The method of claim 5, The 4-position nitrogen atom of the piperazine ring a hydrogen atom, C ₁ ~ C ₅ alkyl group, C ₃ ~ C ₅ of the cycloalkyl group, C ₁ ~ C ₅ alkyl group of hydroxy, C ₂ ~ C ₅ dihydroxyalkyl group, C ₂ to C ₅ (hydroxyalkoxy) alkyl group, C ₁ to C ₃ alkyl substituted C ₁ to C ₄ hydroxyalkyl group, (2R) -3-hydroxy-2- Terephthalic acid amide derivative characterized by being substituted with a methylpropyl group or (2S) -3-hydroxy-2-methylpropyl group. A pharmaceutical composition for inhibiting virus growth, characterized in that it contains a terephthalic acid amide derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. Formula 1

In Formula 1: R ₁ , R ₂ and R ₃ are as defined in claim 1, respectively. A virus growth inhibitor, characterized in that it contains a terephthalic acid amide derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. Formula 1

In Formula 1: R ₁ , R ₂ and R ₃ are as defined in claim 1, respectively. 9. The virus growth inhibitor according to claim 8, wherein the virus is hepatitis B virus (HBV) or human immunodeficiency virus (HIV). A method for preparing a terephthalic acid amide derivative represented by the following Chemical Formula 1, which is prepared by reacting a compound represented by the following Chemical Formula 2 with an acid chloride to produce an acid anhydride, and then reacting it with an amine compound represented by the following Chemical Formula 3. . [Formula 2]

[Formula 3]

Formula 1

In the above formulas: R ₁ , R ₂ and R ₃ are each as defined in claim 1 above. A method for preparing a terephthalic acid amide derivative represented by the following formula (1), which is prepared by nucleophilic substitution reaction of a compound represented by the following formula (4) and an amine compound represented by the following formula (3). Formula 3

[Formula 4]

Formula 1

In the above formulas: R ₁ , R ₂ and R ₃ are each as defined in claim 1 above. A method for preparing a terephthalic acid amide derivative represented by the following Chemical Formula 1b, which is prepared by reacting a piperazine compound represented by the following Chemical Formula 1a with a halogen compound represented by the following Chemical Formula 7 in the presence of a tertiary organic base. [Formula 1a]

[Formula 7] R ₄ -X [Formula 1b]

In the above formulas: R ₃ is as defined in claim 1 above; R ₄ is a hydrogen atom, C ₁ ~ C ₅ lower alkyl group, C ₃ ~ C ₆ cycloalkyl group, C ₃ ~ C ₅ (hydroxyalkoxy) alkyl group, C ₂ ~ C ₅ hydroxyalkyl group, C ₁ ~ a C ₃ alkilga substituted C ₂ ~ C _4, a hydroxyalkyl group or a C ₂ ~ C represents a _{4-dihydroxy-alkyl} group; X represents a halogen atom. Next, a monomethyl terephthalate represented by Formula 9 is reacted with an acid chloride such as pivaloyl chloride to generate a highly reactive acid anhydride, and then reacted with a pyridylpiperazine derivative represented by Formula 8 to Formula 10 Obtaining a terephthalic acid ester derivative including the nitropyridyl group represented; Hydrogen reduction reaction of the obtained compound represented by Formula 10 to obtain a derivative including an aminopyridyl group represented by the following Formula 11; Obtaining a terephthalic acid ester derivative represented by the following Chemical Formula 4 by subjecting the obtained derivative including the aminopyridyl group represented by Chemical Formula 11 to acetone or acetaldehyde under acidic conditions in the presence of a reducing agent; And Method for producing a terephthalic acid derivative represented by the following formula (2) characterized in that the obtained by hydrolysis of the obtained terephthalic acid ester derivative represented by the formula (4). [Formula 8]

[Formula 9]

[Formula 10]

[Formula 11]

Formula 4

Formula 2

In the above formulas: R ₃ is as defined in claim 1 above.