WO2001036386A1 - Diabetic remedy containing dipiperazine derivative - Google Patents

Abstract

A remedy for diabetes which contains a dipiperazine derivative represented by formula (1) or a pharmacologically acceptable salt thereof. [In said formula, Ar?1 and Ar2¿ each represents optionally substituted phenyl, etc.; A?1 and A2¿ each represents optionally substituted alkylene or carbonyl (provided that not both of A?1 and A2¿ are carbonyl); A represents methylene or ethylene; Y?1, Y2, Y3, and Y4¿ each represents hydrogen or alkyl; L represents -L?3-X1-L1-X2-L2-X3-L4-; L3 and L4¿ each represents carbonyl or sulfonyl; X?1 and X3¿ each represents a single bond, NR1, etc.; R1 represents hydrogen or alkyl; X2 represents a single bond, optionally substituted alkylene, etc.; R?2, R3, R4, and R5¿ each represents hydrogen or alkyl; and L?1 and L2¿ each represents a single bond, alkylene, etc.]

Description

 Description Anti-diabetic drug containing dipidazine derivative

 The present invention relates to dipiperazine derivatives useful as medicaments such as hypoglycemic agents.

Background art

 In recent years, the number of diabetic patients has increased remarkably due to westernization of dietary habits and increase in social stress. Diabetes is a disease characterized by chronic hyperglycemia and is caused by a deficiency of insulin or an excess of factors that inhibit its action. That is, diabetes is characterized by an absolute or deficient insulin action. Clinically, diabetes is divided into insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM). In the treatment of diabetes, exercise therapy and diet therapy are first performed, but if these therapies also result in inadequate blood glucose lowering, pharmacotherapy is performed.Sulfonylurea (SU) as an oral diabetes treatment However, it is known that its effect is to promote insulin secretion in the cerebral glands, and that it causes hypoglycemia as a side effect. Fatigue causes secondary ineffectiveness In recent years, biguanides, which are being re-evaluated, are able to control blood glucose as a drug to improve peripheral tissue insulin sensitivity. However, it is well known that lactic acidosis develops as a side effect, and thiazolidinedione-based diabetes drugs ("Diabetes 2": Japanese clinical studies, Vol. 725, pp. 125-145 (Heisei Heisei) 9 years)) has an effect of improving peripheral insulin resistance and is capable of good blood sugar control, but serious side effects such as liver damage have been reported as side effects, and there is a problem in safety.

 Therefore, there is a strong need for a therapeutic agent for diabetes capable of controlling blood sugar well. Disclosure of the invention

The problem to be solved by the present invention is to provide a therapeutic agent for diabetes useful for improving insulin resistance. Means for Solving the Problems As a result of diligent studies, the present inventors have found that dipiperazine derivatives improve insulin resistance, improve hyperglycemia, and are useful for treating diabetes, and completed the present invention.

 That is, the present invention is as follows.

[1] Equation 1:

Y ¹ Y ³

[Wherein, A r ¹ and A r ² each represent an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted heterocyclyl group.

A ¹ and A ² each represent an alkylene group or a carbonyl group which may be substituted. However, A ¹ and A ² do not simultaneously represent a carbonyl group.

 A represents a methylene group or a dimethylene group.

Υ ² , Υ ³ and Υ ⁴ each represent a hydrogen atom or an alksole group.

L represents a group represented by the formula: one L ³ — X ¹ — L ¹ — X ² — L ² — X ³ — L ⁴ —.

L ³ and L ⁴ each represent a carbonyl group or a sulfonyl group.

X ¹ and X ³ each represent a single bond, ^one NR group or an oxygen atom. However, when L ³ or L ⁴ represents a sulfonyl group, each represents! Or ^ does not represent an oxygen atom.

R ¹ represents a hydrogen atom or an alkyl group.

X ² is a single bond, an optionally substituted alkylene group, an optionally substituted heteroarylene group, an optionally substituted phenylene group, an optionally substituted cycloalkylidene group, an optionally substituted cycloalkylene group An optionally substituted divalent aliphatic heterocyclic group, an optionally substituted vinylene group, an ethynylene group, a sulfur atom, an oxygen atom or a formula: 1 N (R ² ) 1 C (= 0) —, One N (R ³ ) One C (= 0) — N (R ⁴ ) —, One N (R ² ) One C (= 0 ) One O—, One O— C (= 0) — O—, -OC (= 0) One, One C (= 0) One, or — N [-C (= 0) -R ⁵ ] — Represents a group represented by

R ² , R ³ , R ⁴ and R ⁵ each represent a hydrogen atom or an alkyl group.

L ¹ and L ² each represent a single bond, an alkylene group, a vinylene group or a phenylene group which may be substituted.

Provided that X ² is a single bond, an optionally substituted vinylene group, an ethynylene group, a sulfur atom, an oxygen atom or a formula: one N (R ² ) one C (= 0) —, -N (R ³ ) -C ( = 0) — N (R ⁴ ) —, one N (R ² ) -C (= 0) — O—, -0-C (= 0) — 0—, -OC (= 0) —, — C ( = 0)-or-N [-C (= 0) -R ⁵ ]-does not form a L ¹ or L ² force single bond. When L ¹ or L ² is a vinylene group, X ¹ or X ³ is a single bond, respectively. ]

For the treatment of diabetes containing a dipyrazine derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof:

[2] The therapeutic agent for diabetes according to [1], wherein A ¹ and A ² are both methylene groups.

[3] The diabetes treatment according to [1] or [2], wherein Ar ¹ and Ar ² are substituted phenyl groups.

[4] Ar ¹ and Ar ² are para-substituted phenyl groups [1] to [3].

[5] The diabetes according to any one of [1] to [4], wherein the substituents of Ar ¹ and Ar ² are a halogen atom, an alkyl group, a trifluoromethinole group or a trifluoromethoxy group, respectively.

In [6] L, the sum of the atoms of the shortest chain of atoms extending from X ¹ to X ³ is Ru 1-7 der [1:] to [5], diabetes drug according to any misalignment.

[7] The therapeutic drug for diabetes according to any one of [1] to [6:], wherein —X ¹ —L ¹ —X ² —L ² —X ³ — is an amino-1,4-phenylene group.

[8] The therapeutic drug for diabetes according to any one of [1] to [6], wherein one X ¹ —L ¹ —X ² —L ² —X ³ — is a substituted alkylene group. [9] The antidiabetic agent according to [1] to [6], wherein X ¹ — LX ² — L ² — X ³ — is a 1,1-dimethyl-1,2-dimethylene group.

[10] The therapeutic drug for diabetes according to any one of [1] to [6], wherein X ¹ —L ¹ —X ² —L ² —X ³ — is a 1,2-cyclopentylene group.

[1 1] — X ¹ — L ¹ — X ² — L ² — X ³ — is 1, 3-dimethylene (2-oxo-1,

The drug for treating diabetes according to any one of [1] to [6], which is a 3-imidazolidine) group.

[12] — X ¹ — L] — X ² — L ² — X ³ — is 1-alkoxycarbonylethyl — 1, 3

—The therapeutic agent for diabetes according to any one of [1] to [6], which is a trimethylene group.

[13] The antidiabetic agent according to any one of [1] to [6], wherein one X ¹ —L] _X ² —L ² —X ³ — is a 1-alkoxycarbonyldiethyl-1,2 dimethylene group.

[14] —X ¹ — L ¹ — X ² — L ² — X ³ — is a 3-dialkylaminocarbonyl—1,5 monopentamethylene group [1] to [6]. Therapeutic drugs.

[15] The therapeutic agent for diabetes according to any one of [1] to [6], wherein X ¹ —L ¹ —X ² —L ² —X ³ — is a 2,2-dimethyl-1,3-trimethylene group.

[16] One of L ³ or L ⁴ is a carbonyl group, the other is a sulfonyl group, and one X ¹ — L ¹ — X ² — L ² — X ³ — is a methylene group [1] to [6] No, Diabetes treatment described

[17] One of L ³ or L ⁴ is a carbonyl group and the other is a sulfonyl group, and — X】 _ Li—X ² — L ² — X ³ — is a phenylene group [1] to [6]. Any of the above-mentioned antidiabetic drugs.

[18] The therapeutic drug for diabetes according to any one of [1] to [6], wherein L ³ and L ⁴ are sulfonyl groups, and one X] —L ¹ —X ² —L ² _X ³ — is a dimethylene group. .

[19] The diabetes treatment according to [7], wherein L ³ is a carbonyl group and L ⁴ is a sulfonyl group.

[20] The therapeutic agent for diabetes according to [15], wherein L ³ and L ⁴ are sulfonyl groups.

[21] Expression: Y ¹ Y ³

[Wherein, Ar ¹ and Ar ² each represent a substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted heterocyclyl group.

A ¹ and A ² each represent an alkylene group or a carbonyl group which may be substituted. However, A ¹ and A ² do not simultaneously represent a carbonyl group.

 A represents a methylene group or a dimethylene group.

Y Υ ² , Υ ³ and Υ ⁴ each represent a hydrogen atom or an alkoxy group.

L represents a group represented by the formula: _L ³ — X ¹ — L ¹ — X ² — L ² _X ³ — L ⁴ —.

L ³ and L ⁴ each represent a carbonyl group or a sulfonyl group.

X ¹ and X ³ each represent a single bond, ^one NR group or an oxygen atom. However, when L ³ or L ⁴ represents a sulfonyl group, X ^{1 and} X ³ each do not represent an oxygen atom.

R ¹ represents a hydrogen atom or an alkyl group. '

X ² is a single bond, an optionally substituted alkylene group, an optionally substituted heteroarylene group, an optionally substituted phenylene group, an optionally substituted cycloalkylidene group, an optionally substituted cycloalkylene group An optionally substituted divalent aliphatic heterocyclic group, an optionally substituted vinylene group, an ethynylene group, a sulfur atom, an oxygen atom or a formula: —N (R ² ) —C (= 0) -N (R ³ ) one C (= 0) one N (R ⁴ ) one, one N (R ² ) one C (= 0) one 0-, one 0-C (= 0) one O--, -OC (= 0) represents a group represented by one, one C (= 0)-or — N [-C (= 0)-R ⁵ ] —.

R ² , R ³ , R ⁴ and R ⁵ each represent a hydrogen atom or an alkyl group.

L ¹ and L ² each represent a single bond, an alkylene group, a vinylene group or a phenylene group which may be substituted. However, when (1) L ³ and L ⁴ represent a carbonyl group, and —X ¹ —L] X ² —L ² —X ³ — represents an alkylene group, the alkylene group has 3 to 3 carbon atoms. (2) X ² is a single bond, an optionally substituted vinylene group, an ethynylene group, a sulfur atom, an oxygen atom or a formula: —N ( R ² ) -C (= 0) one, one N (R ³ ) one C (= 0) -N (R ⁴ ) —, — N (R ² ) — C (= 0) one-, one 0- C (= 0) —0—, -OC (= 0) —, one C (= 0) —, or one N [-C (= 0) -R ⁵ ] Or L ² is not a single bond, or (3) When L ¹ or L ² is a vinylene group, X ¹ or X ³ is a single bond, respectively. ]

Or a pharmaceutically acceptable salt thereof.

[22] The dipiperazine derivative according to [21], wherein A ¹ and A ² are both methylene groups, or a pharmaceutically acceptable salt thereof.

[23] The dipirazine derivative or the pharmaceutically acceptable salt thereof according to [21] or [22], wherein Ar ¹ and Ar ² are substituted phenyl groups.

[24] The dipiperazine derivative or the pharmaceutically acceptable salt thereof according to any one of [21 :! to [23], wherein Ar ¹ and Ar ² are para-substituted feninole groups.

[25] The dipiperazine derivative according to any one of [21] to [24], wherein the substituents of Ar ′ and Ar ² are a halogen atom, an alkyl group, a trifluoromethyl group or a trifluoromethoxy group, respectively. Its pharmaceutically acceptable salts.

[26] The dipiperazine derivative or the pharmaceutically acceptable salt thereof according to any one of [21] to [25], wherein in L, the total number of atoms in the shortest atom chain from X ¹ to X ³ is 1 to 7.

[27]-The dipiperazine derivative or the pharmaceutical preparation thereof according to any one of [21] to [26], wherein X ¹ — L ¹ — X ² — L ² — X ³ — is an amino-1,4-phenylene group. Above acceptable salts.

[28] The dipiperazine derivative or the pharmaceutically acceptable salt thereof according to any one of [21] to [26], wherein X ¹ —L ¹ —X ² —L ² _X ³ _ is a substituted alkylene group.

[29] —X ¹ — L'_X ² — L ² — X ³ — is 1,1-dimethyl—1, .2-dimethylene group [21] The dipiperazine derivative or a pharmaceutically acceptable salt thereof according to any one of [21] to [: 26].

[30] — X ¹ — L ¹ — X ² — L ² — X ³ — is a 1,2-cyclopentylene group [21] to [26]. Or a pharmaceutically acceptable salt thereof.

[3 1] — X ¹ — L'— X ² — L ² — X ³ — is a 1,3-dimethylene (2-oxo-1,3-imidazolidine) group [21] to [26] The dipiperazine derivative according to any one of the above, or a pharmaceutically acceptable salt thereof.

[32] —X′— I ^ —X ² — L ² — X ³ — is a monoalkoxycarborletyl-1,3-trimethylene group or the dipiperazine derivative according to any one of [21] to [26]. Pharmaceutically acceptable salts.

[33] —X ¹ —! ^ ¹ — X ² — L ² — X ³ — is a 1-alkoxycarbonyldiethyl-1,2—dimethylene group The dipiperazine derivative according to any one of [21] to [26] Or a pharmaceutically acceptable salt thereof.

[34] — X〗 — L〗 _X ² — L ² — X ³ — is a 3-dialkylaminocarboxy-1,5-pentamethylene group The dipiperazine derivative according to any one of [21] to [26] Or a pharmaceutically acceptable salt thereof.

[35] — X ¹ — L ¹ — X ² — L ² — X ³ — is a 2,2-dimethyl-1,3-trimethylene group, or the dipiperazine derivative according to any of [21] to [26] or A pharmaceutically acceptable salt thereof.

[36] One of L ³ or L ⁴ is a carbonyl group, the other is a sulfonyl group, and one X ¹ — L ¹ — X ² — L ² — X ³ — is a methylene group [21] to [26] ] Or the pharmaceutically acceptable salt thereof.

[37] One of L ³ or L ^{4 is} a carbinole group, the other is a sulfonyl group, and one X ¹ — L] — X ² — L ² _ X ³ — is a phenylene group [21] to [ 26] The dipiperazine derivative or the pharmaceutically acceptable salt thereof according to any one of the above.

[38] The dipiperazine according to any one of [21] to [26], wherein L ³ and L ⁴ are sulfonyl groups, and — X′— L′—X ² — L ² — X ³ — is a dimethylene group. Derivative or its drug A scientifically acceptable salt.

[39] The dipyrazine derivative or the pharmaceutically acceptable salt thereof according to [27], wherein L ³ is a carbonyl group and L ⁴ is a sulfonyl group.

[40] The dipiperazine derivative or the pharmaceutically acceptable salt thereof according to [35], wherein L ³ and L ⁴ are sulfonyl groups.

 [41] Use of the dipiperazine derivative or the pharmaceutically acceptable salt thereof according to any one of [1] to [20] in the manufacture of a therapeutic agent for diabetes.

 [42] A method for treating diabetes in a patient, comprising administering a therapeutically effective amount of the dipiperazine derivative or the pharmaceutically acceptable salt thereof according to any of [1:] to [20]. The "heterocyclyl group" of the optionally substituted heterocyclyl group includes, for example, a 5- to 7-membered monocyclic ring containing 1 to 3 nitrogen, oxygen and Z or sulfur atoms, or a monocyclic ring thereof. And a benzene ring fused to a two-ring heterocyclyl group. Specifically, pyridyl, virazyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, chenyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, pyrazinyl, isothiazolyl, trithiazolyl, trithiazolyl, trithiazolyl Monocyclic heterocyclyl groups such as zolinone-yl and vilanyl, and indolyl, chromenyl, quinolyl, isoquinolyl, quinolinyl, benzofuryl, benzochenyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl , Benzotriazolinole, benzimidazolyl, 1,3-benzodioxolyl, 2,3-dihide mouth-1,4 And a heterocyclyl group on the ring.

As the `` substituent '' in the optionally substituted phenyl group, the optionally substituted naphthinole group, the optionally substituted heterocyclyl group, the optionally substituted heteroarylene group, and the optionally substituted phenylene group Is, for example, the following substituents, which may be substituted with one or more optional substituents. Substituents: hydroxyl group, halogen atom, amino group, cyano group, nitro group, alkyl group, alkoxy group, carbamoyl group, sulfamoyl group, alkanoyl group, alkanoyloxy group, alkanoylamino group, alkoxycarbonyl group, Alkoxycarbonylamino group, alkylsulfonyl group, alkylthio group, ureido group, halogen-substituted alkyl group, halogen-substituted alkoxy group, alkyl-substituted rubamoisole group, etc. (Note that these substituents are other substituents described herein. May be replaced by Preferred examples of the “substituent” include a halogen atom, a cyano group, a halogen-substituted alkyl group and a nodogen-substituted alkoxy group, an alkyl group, an alkoxy group, a carbamoyl group, and an alkyl-substituted carbamoyl group.

 Examples of the alkylene group include a linear or branched alkylene group i ′ having 1 to 6 carbon atoms. Specifically, methylene, dimethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylmethylene, dimethylmethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1-methyltrimethylene, 2-methyl Trimethylene, 1,1-dimethyltrimethylene, 1,2-dimethinoletrimethylene, 1,3-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1-ethyltrimethylene, 2-ethylimethylene Power.

 Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

 The halogen-substituted alkyl group and the nitrogen-substituted alkoxy group mean an alkyl group and an alkoxy group each substituted by one or more halogen atoms. Preferred examples thereof include trifluoromethyl, trifluoromethyl and trifluoromethyl. Methoxy and the like can be mentioned.

 Examples of the alkyl group include a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, 2-methyl-2-propyl, 2 —Butyl, 2-methyl-2-butyl, 3-methyl-2-butyl, pentyl, hexyl and the like.

Examples of the alkoxy group include linear or branched alkoxy having 1 to 6 carbon atoms. Methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 3-methylbutoxy, hexoxy, 4-methylpen Toxic and the like.

 Examples of the alkanoyl group include straight-chain or branched-chain alkenyl groups having 1 to 6 carbon atoms, and specific examples thereof include formyl, acetyl, propanol, n-butanol, and vivacotyl. .

 Specific examples of the alkyl-substituted rubamoyl group include mono- or dialkyl-substituted rubamoyl S such as ethylcarbamoyl and dimethyllrubamoyl.

Examples of the “substituent” of the alkylene group which may be substituted in A ¹ and A ² include, for example, an alkoxycarbonyl group, a monoalkylaminocarbonyl group, a dialkylaminocarbonyl group, a carbamoyl group and the like.

 Examples of the “substituent” of the optionally substituted cycloalkylidene group and the optionally substituted cycloalkylene group include a hydroxyl group, an alkoxy group, an oxo group and the like.

Examples of the “substituent” of the alkylene group which may be substituted in X ² include a substituted alkyl group having 1 to 4 carbon atoms (eg, substituted methyl, substituted 2-ethyl, substituted 3-propyl, substituted 3-butyl) , Substituted 4-butyl, etc.), an alkoxy group having 1 to 4 carbon atoms (eg, methoxy, ethoxy, propyloxy, butoxy, etc. ^), and an alkanoyloxy group having 1 to 4 carbon atoms. (For example, formyloxy, acetyloxy, propanoyloxy, butanoyloxy, etc.), a cyano group, a carboxy group, an alkoxycarbonyl group having 1 to 4 carbon atoms, a carbamoyl group, an alkylaminocarbonyl group (for example, carbon Aminocarbyl group S substituted with an alkyl group having a number of 1 to 6 Luminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, 2-propylaminocarbonyl, butylaminocarbonyl, pentylaminocarbonyl, hexylaminocarbonyl, etc.), dialkylaminocarbonyl group (for example, having the same or different carbon number 1) And 6 is an aminocarbonyl group substituted with an alkyl group, specifically, dimethylamino. Carbonyl, getylaminocarbonyl, ethylmethylaminocarbonyl, dipropylaminocarbonyl, methylpropylaminocarbonyl, di-2-propylaminocarbonyl, dibutylaminocarbonyl, dipentylaminocarbonyl, dihexylamino Carbonyl and the like. Further, dialkyl groups may be bonded to each other or may be bonded to each other via an oxygen atom to form a saturated heterocyclic ring having 2 to 6 carbon atoms. Examples of the saturated hetero ring include 1-pyrrolidinyl, 1-piperidinyl, and 1-morpholinyl. Examples of such a dialkylaminocarbonyl group include 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-morpholinylcarbonyl and the like. ), Amino group, alkylamino group, substituted alkylamino group, dialkylamino group (even if the alkyl group is bonded to each other or via an oxygen atom to form a saturated heterocyclic ring having 2 to 6 carbon atoms) Saturated heterocycles include 1-pyrrolidinyl, 1-piberidinyl, 1-morpholinyl, etc.), oxo groups, hydroxyimino groups, alkoxyimino groups having 1 to 4 carbon atoms, and 1 carbon atom. To 4 substituted alkoxyimino groups. Examples of the substituent of the substituted alkoxyimino group having 1 to 4 carbon atoms include an alkoxycarbonyl group having 1 to 4 carbon atoms and a carboxy group. Examples of the substituent of the substituted alkylamino group include an alkoxycarbonyl group having 1 to 4 carbon atoms and a carboxyl group.

Examples of the substituent of the substituted alkyl group having 1 to 4 carbon atoms (for example, substituted methyl, substituted ethyl, substituted 3-propyl, substituted 4-butyl, etc.) include an alkoxy group having 1 to 4 carbon atoms (for example, , Methoxy, ethoxy, propyloxy, butoxy, etc.), a hydroxyl group, an alkanoyloxy group having 1 to 4 carbon atoms (for example, formyloxy, acetyloxy, propanoyloxy, butanoyloxy and the like). Group, carboxy group, alkoxycarbonyl group having 1 to 4 carbon atoms, carbamoyl group, alkylaminocarbonyl group (for example, an aminocarbonyl group substituted with an alkyl group having 1 to 6 carbon atoms, and specifically, , For example, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarboni , 2-propyl aminocarbonyl, butyl § amino carbonyl, pliers Rua Mino Cal Bonyl, hexylaminocarbonyl and the like. ), A dialkylaminocarbonyl group (for example, an aminocarbonyl group substituted with the same or different alkyl group having 1 to 6 carbon atoms, specifically, dimethylaminocarbonyl, methylaminocarbonyl, Dialkylaminocarbonyl, dipropylaminocarbonyl, methylpropylaminocarbonyl, di-2-propylaminocarbonyl, dibutylaminocarbonyl, dipentylaminocarbonyl, dihexylaminocarbonyl, and the like. The groups may be bonded to each other or may be bonded across an oxygen atom to form a saturated heterocyclic ring having 2 to 6 carbon atoms, such as 1-pyrrolidinyl, 1-piberidinyl, 1-morpholinyl And such a dialkylaminocarbonyl group. Is 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-morpholinylcarbonyl, etc.), amino group, alkylamino group, substituted alkylamino group, dialkyamino group (dialkyl group is Or a bond with an oxygen atom interposed therebetween to form a saturated heterocyclic ring having 2 to 6 carbon atoms.Examples of the saturated heterocyclic ring include 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl and the like.) And oxo groups, hydroxyimino groups, alkoxyimino groups having 1 to 4 carbon atoms, and substituted alkoxyimino groups having 1 to 4 carbon atoms. Examples of the substituent of the substituted alkoxyimino group having 1 to 4 carbon atoms include an alkoxycarbonyl group having 1 to 4 carbon atoms and a carboxyl group. Examples of the substituent of the substituted alkylamino group include an alkoxycarbonyl group having 1 to 4 carbon atoms and a carboxyl group.

 Examples of the “substituent” of the optionally substituted vinylene group include an alkynole group and a halogen atom. Examples of the vinylene group include cis- and trans-vinylene groups.

 Examples of the naphthyl group include a 1-naphthyl group and a 21-naphthyl group.

 The phenylene group includes 1,2-phenylene group, 1,3-phenylene group, and 1,4-phenylene group.

The heteroarylene group is selected from, for example, a nitrogen atom, an oxygen atom and a sulfur atom. And a monocyclic 5- to 6-membered heteroarylene group containing 1 to 2 heteroatoms. Specifically, a monocyclic 6-membered heteroarylene containing only one or two nitrogen atoms as a heteroatom such as pyridine-diyl, pyrazinedyl, pyrimidine-diyl, etc .; and isothiazoyl-diyl, pyrrole Rings of 1-Ruzil, Fran-Zir, Thofen-Zir, Tiazo-Ruzil, Imidazo-Rizil, Thyadiaz-Ruzil, Pyrazol-Zil, Oxazo-Ruzil, Isoxazo-Ruzil, Imidazolon-Zil, Rings of Imidazolon-Zil, etc. And a 5-membered heteroarylene group.

 Examples of the divalent aliphatic bicyclic group include, for example, a 5-membered ring or a 6-membered ring containing 1 to 3 heteroatoms arbitrarily selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. A divalent aliphatic heterocyclic group or the like can be used. Specific examples of the divalent 5-membered aliphatic heterocyclic group include, for example, nitrogen such as pyrrolidine-diyl, pyrroline-diyl, imidazolidine-diyl, villazolidinediyl, tetrahydrofuran-diyl, tetrahydrothiophenidyl, dioxolan-diyl and the like. And a divalent 5-membered aliphatic heterocyclic group containing 1 or 2 atoms independently and arbitrarily selected from the group consisting of an atom, a sulfur atom and an oxygen atom. Specific examples of the divalent 6-membered aliphatic heterocyclic group include a nitrogen atom such as piperidine-diyl, piperazine-diyl, morpholine-diyl, tetrahydropyran-diyl, and dioxan-diyl, and a sulfur atom. And a divalent 6-membered aliphatic heterocyclic group containing 1 or 2 atoms independently and arbitrarily selected from the group consisting of oxygen atoms. Examples of the “substituent” of the divalent aliphatic heterocyclic group which may be substituted include an alkyl group and an oxo group.

 Examples of the cycloalkylidene group include a cycloalkylidene group having 3 to 6 carbon atoms such as a cyclopropylidene group, a cyclobutylidene group, a cyclopentylidene group, and a cyclohexylidene group.

Examples of the cycloalkylene group include a cyclopropylene group, a cyclobutylene group, a 1,2-cyclopentylene group, a 1,3-cyclopentylene group, a 1,2-cyclohexylene group, and a 1,2-cyclohexylene And cycloalkylene groups having 3 to 6 carbon atoms such as 1,3-cyclohexylene group and 1,4-cyclohexylene group. In the present specification, when a part of the group described herein (for example, alkyl, alkanoyl, alkoxy, etc.) constitutes a part of the group, the same examples as the groups mentioned here can be mentioned.

 The compound of the present invention may have one or more asymmetric centers. The invention includes all pure optical isomers, partially purified optical isomers, racemic mixtures, and pure diastereomers, partially purified diastereomers, mixtures thereof, and the like. .

 Pharmaceutically acceptable salts of the compounds of the present invention include, for example, acid addition salts. Examples of the acid addition salt include, for example, inorganic acid salts such as hydrochloride, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, maleate, and citrate Organic acid salts such as malonate, methanesulfonate and the like.

 The dipiperazine derivative of the formula 1 can be used as a hypoglycemic agent, and is useful, for example, as a therapeutic agent for diabetes.

The dipiperazine derivative of the formula 1 can be produced, for example, according to the following production method. (However, L ³ and L ⁴ both represent a carbinole group.)

Force equivalent to A r A ¹ and A r ² _A ²

Manufacturing method (1)

(Wherein, Ar ¹ , A ¹ , L, A, YYY ³ and Y ⁴ have the same meanings as in the above formula 1. Y is a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, toluene Represents a leaving group such as sulfonyloxy, trifluoromethanesulfonyloxy, etc. Z represents a hydroxyl group or a hydrogen atom, and P g represents a protecting group.)

A compound of formula 12 is obtained by condensing the compound of formula 11 with a Z-acid group in formula 10 and the compounds of formulas 11-1 and 11-2 in the presence of a dehydrating condensing agent. The condensation reaction here can be carried out in an organic solvent such as, for example, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran (ΤHF) or dimethylformamide (DMF). Reaction temperatures range from 10 ° C to 60 ° C. Examples of the dehydrating condensing agent include hexylcarbodiimide and 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, which are used together with a reaction aid. Examples of the reaction aid include N-hydroxybenztriazole, N, N-dimethyl-4-aminoviridine and the like. Further, as a dehydrating condensing agent, for example, Ν, Ν-bis (2-oxo-13-oxazolidinyl) phosphinic acid chloride is used as an organic salt such as triethylamine. It can be used in combination with a group.

 In the case where Z is a hydrogen atom in the formula 10, the compounds of the formulas 11 and 11 are condensed with the compound of the formula 10 in the presence of an organic base such as, for example, triethylamine to form the formula 12 Can lead to a compound. The condensation reaction can be carried out in an organic solvent such as, for example, dichloromethane, chloroform, ethyl acetate, THF or dimethylformamide. The reaction temperature ranges from 110 ° C to 60 ° C.

 As the protecting group represented by P g in the formula, any commonly used protecting group can be used. For example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc. Protective groups, amide-type protective groups such as N-acetyl and N-benzoyl, and benzyl, nitro, p-toluenesulfonyl, and methanesulfonyl. Subsequently, the compound of formula 13 is obtained by removing the protecting group Pg. Removal of the protecting group is carried out by a general method (for example, TW Greene and PGM Wuts, "Protective Groups in Organic Synthes is", 2nd Ed., John Wiley and Sons, inc., New York (1991), p. 315). -362).

A compound of formula 15 can be produced by reacting a piperazine derivative of formula 13 with a compound of formula 14 in the presence of a base. The reaction can be carried out according to the conditions of a conventional N-alkylation reaction. Specifically, examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal amides such as sodium amide and lithium amide; alkalis such as potassium t-butoxide and sodium methoxide. Metal alkoxides, carbonates such as potassium carbonate and sodium carbonate, and organic bases such as triethylamine. The amount of the base to be used is, for example, 2 to 10 equivalents, preferably 3 to 5 equivalents, relative to the derivative of the formula 13, provided that the compound represented by the formula 13 is a salt such as hydrochloride. In this case, it is necessary to add an excess of the base in an amount equivalent to the amount of the salt. The amount of the compound represented by the formula 14 is, for example, 2 to 6 equivalents, preferably 2.2 to 2 equivalents to the derivative of the formula 13. Examples of the reaction solvent include an inert organic solvent such as THF and DMF. The reaction temperature includes, for example, 0 ° C to the boiling point of the reaction solvent, and preferably ranges from room temperature to 80 ° C. I can do it.

Manufacturing method (2)

13 + Ar'-A ⁰ -CO-R ¹⁰

 18

(In the formula, Ar L, A, YYY ³ and Y ⁴ have the same meanings as in the above formula 1. R ¹⁰ represents a hydrogen atom or an alkyl group, and has the formula: —A ° —C (R ¹⁰ ) H The group represented by — corresponds to the case where A ^{1 in the} above formula ¹ is an alkylene group.)

 The compound of the formula 17 contained in the compound of the present invention can be obtained by using the compound of the formula 13 and the aldehyde compound or the ketone compound of the formula 18 in the presence of sodium borohydride, sodium cyanoborohydride or the like. It can also be synthesized by a reductive amination reaction at room temperature in an alcohol solvent such as alcohol, or a reductive amination reaction at room temperature in a halogenated hydrocarbon such as sodium acetoborohydride and dichloroethane. Manufacturing method (3)

Y ¹ Υ 3

— 15

(Wherein, L, Αν Α Α, Υ 1, Υ 2, Υ 3 and Upsilon ⁴ is represented. Zeta the same meaning as in the formula 1 represents a hydroxyl group or a chlorine atom.) The compound 15 of the present invention is obtained by condensing the compound of the formula 10 with the piperazine derivative of the formulas 16-1 and 16-0 under the same conditions as the condensation reaction with the compounds 10, 11-1 and 11-2 described above. Can also be synthesized.

Manufacturing method (4)

.

-CO-Y ⁰

Η-Χ ^Ί ■ ¹ -X ² -L ² -X ³ -H 19-1

 Fifteen

CO (OCCI ₃ ) ₂ 19-1

 11-1- 12

(Wherein, Ar ¹ , AX ¹ , X ² , X ³ , LL ² , Α, Υ ¹ and Υ ² represent the same meaning as in the above formula 1. However, X ¹ or X ³ is a single bond. unless in the above I匕合was 12 and 15, except when L is a Okisarinore group or force carbonyl group Y ^G is a chlorine atom or -.. represents an O-CC 1 _3).

When X ¹ and X ³ are NR ¹ or an oxygen atom, hexachlorodimethylcarbonate (triphosgene) is allowed to act on the piperazine derivative of the formula 16-1 to form an active intermediate of the formula 20-1. Then, the compound of the formula 19-1 is reacted with a compound of the formula 15-1 in the presence of a base to obtain the compound of the formula 15 or the compound of the formula 11-1 is treated with hexachlorodimethylcarbonate (triphosgene). The protected piperazine derivative of formula 12 can be obtained by reacting the compound of formula 19-11 with a base. Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride; alkali amides such as sodium amide and lithium amide; alkali metal alkoxides such as potassium t-butoxide and sodium methoxide; potassium carbonate; Carbonates such as sodium, organic bases such as triethylamine, and the like. As a reaction solvent for the reaction of the compound of the formula 16-1 or the compound of the formula 11-1 with hexachlorodimethyl carbonate (triphosgene) and the subsequent reaction with the compound of the formula 19-11, for example, THF, DMF And the like. The reaction temperature of the reaction with hexachlorodimethyl carbonate (triphosgene) is, for example, in the range of 0 ° C to room temperature. The reaction temperature of the reaction with the compound of the formula 19-1 is from 0 ° C. to the boiling point of the reaction solvent, preferably from room temperature to 80 ° C.

 Compounds of the invention can be derived from protected piperazine derivatives of formula 12 by the methods described above.

 The above can be similarly produced when the compounds of formulas 16-1 and 16-0, and 11-1 and 11-12 are non-equivalent, indicating that they are equivalent.

Manufacturing method (5)

CO (OCCI ₃ ) ₂

HX -L ¹ -X ² -L ² -X ³ -H ► 16-1

 Fifteen

 19-1

CO (OCCI ₃ ) ₂

Η-Χ ^Ί . ¹ -X ² -L ² -X ³ -H ► 11-1

 12

 19-1

(Wherein, X ¹ , X ² , X ³ , L ¹ and L ² have the same meanings as in the above formula 1. However, when X ¹ or X ³ is a single bond. In 12 and 15, the case where L is an oxalyl group or a carbonyl group is excluded.)

When X ¹ and X ³ are NR ¹ or an oxygen atom, a compound of the formula 19-1 is treated with hexachlorodimethylcarbonate (triphosgene) to obtain a compound of the formula Y. — CO— X′— L ¹ -X ² -L ² -X ³ -CO-Y ° (Y ⁰ has the same meaning as above) Reacting with a compound of formula 16-1 in the presence of a compound of formula 15 to obtain an inventive compound of formula 15, or reacting an active intermediate with a compound of formula 11-1 in the presence of a base to protect the compound of formula 12 The obtained piperazine derivative can be obtained.

Examples of the base include the same examples as in the above production method (4). Examples of the reaction solvent for the reaction between the compound of the formula 19_1 and hexachlorodimethyl carbonate (triphosgene) include an inert organic solvent such as THF and DMF. The reaction temperature is, for example, 0. ° C to room temperature.

 The above shows the case where the compounds of the formulas 16-1 and 16-0, and 11-1 and 11-2 are equivalent. However, when the compounds are not equivalent, they can be produced similarly.

Manufacturing method (6)

_{1 1.} ^ CO (CCI ₃ ) 2 16-1

HO-CO-X ¹ -L ⁿ -X "-L ² -X ³ -H ^

HO-CO—

 16-0

 Fifteen

(In the formula, Ar AXX ² , X ³ , LLA, Y ¹ and Y ² have the same meanings as in the above formula 1. However, unless X ¹ or X ³ is a single bond. In the case of 15, excluding the case where L is an oxalinole group or a carbonyl group.) When a compound in which X ³ is NR ¹ or an oxygen atom in the formula 21 is used as a starting material, the compound of the formula 21 is first converted to a compound of the formula 21 The compound of formula 22-1 is obtained by reacting xachlorodimethylcarbonate (triphosgene) to form an active intermediate and then reacting with the compound of formula 16-1 in the presence of a base. Here, the conditions for the action of hexachlorodimethylcarbonate (triphosgene) and the conditions for the reaction in the presence of the compound of Formula 16-1 and the base are the same as described above. The compound of the formula 15-1 is obtained by condensing the compound of the formula 22-1 and the compound of the formula 16-0 under the aforementioned condensation conditions. In this series of reactions, if the compound of the formula 11-1 and 11-2 is used in place of the compound of the formula 16 -1 and 16-0 after deprotection, the compound of the formula 13 is obtained. Obtainable. Compounds of formula 13 can lead to compounds of formula 15 according to the invention as described above.

Ar '—Α ¹ and Ar ² _A ² are unequal: Manufacturing method

(Wherein, Ar ¹ , A Ar ² , A ² , A, Y \ YY ³ and Y ⁴ have the same meanings as in the above formula 1. Y is a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy And leaving groups such as toluenesulfonyloxy and trifluoromethanesulfonyloxy. Y ⁰ represents a chlorine atom or a 0- CC 1 _3. However, in the above production methods (3) and (4), cases where X ¹ or X ³ is a single bond and cases where L is an oxalyl group or a carbonyl group are excluded. )

 For example,

(1) The present invention of formula 1 can be obtained by reacting one equivalent of Ar ¹ —A ¹ —Y on the compound of formula 13 and then further reacting one equivalent of Ar ² —A ² —Y on the product. A compound can be obtained. As the reaction conditions, the conditions for N-alkylation described above can be used.

(2) One equivalent of the compound of the formula 16-1 is reacted with the compound of the formula 10, and then one more equivalent of the compound of the formula 16-2 is reacted with the product, whereby the compound of the present invention of the formula 1 is reacted. Can be obtained. As the reaction conditions, the above-described conditions for the condensation reaction can be used.

(3) In formula 19, when X ¹ and X ³ are NR ¹ or an oxygen atom, the compound of formula 19 is reacted with an active intermediate of formula 20-1 in the presence of an organic base such as triethylamine, followed by The compound of the present invention of the formula 1 can be obtained by reacting the active intermediate of the formula 20-12. Examples of the reaction solvent include an inert organic solvent such as THF and DMF. The reaction temperature may be 0 ° C to the boiling point of the reaction solvent, preferably room temperature to 80 ° C. The method for generating the active intermediates of the formulas 20-1 and 20-2 is the same as that of the compound of the formula 20.

(4) When a compound in which X ³ is NR ¹ or an oxygen atom in the formula 21 is used as a starting material, first, hexachlorodimethylcarbonate (triphosgene) is allowed to act to form an active I intermediate. Subsequently, the compound of the formula 16-1 is reacted with a compound of the formula 16-1 to obtain a compound of the formula 22-1. Here, the conditions for the action of hexachlorodimethyl carbonate (triphosgene) and the conditions for the reaction of the compound of formula 16-1 with a base in the presence of a base are the same as described above. The compound of the formula 1 is obtained by condensing the compound of the formula 22_1 with the compound of the formula 16-2 using the aforementioned condensation conditions.

In Formulas 1) to 3) above, when Formula 13 is asymmetric, the compound of Formula 1 is purified by column chromatography, and is obtained as a mixture of such asymmetric compounds. Each compound can be separated and purified by a conventional method such as a purification method by distillation, a distillation method, or a recrystallization method.

In order to obtain compounds of the invention in which Ar ¹ —A ¹ and Ar 2 —A ² are unequal, it may be preferable to use conventional protection and deprotection techniques. Conventional protective deprotection techniques are described in detail in TW Greene and PGMWuts, "Protective Groups in Organic Synthesis", 2nd Ed., John Wiley and Sons, inc., New York (1991). Further, when synthesizing the compound of the present invention, the technique of protection and deprotection can be used whenever necessary. The dipiperazine derivative of the formula 100 can be produced, for example, according to the following production method.

(Wherein, Ar], AA, YYX ¹ , LX ² , LX ³ , Y ³ , YA ² and Ar ² have the same meanings as in the above formula 1. L ³ and L ⁴ are both sulfonyl groups ).

Ar ¹ — A ¹ and Ar ² — A ² , Y ¹ and Y ³ , Υ ² and Υ ⁴

Manufacturing method (1)

Υ ¹ 102

_{, -Ι Λ -S0 2 - X 1-} L i- X 2- tooth 2- _x 3.S0 ₂ - ₂

Ar ¹ — A ¹ — N NH

 101 no

Υ ²

Υ 'Y'

/ ^Α一 | Λ / ^Α_ ΙΛ

Ar ¹ — Α ¹ -Ν N-S0 ₂ -X ¹ -L ¹ -X ² -L ² -X ³ -S0 ₂ -N Ν— A ¹ — Ar ¹

103 (In the formula, Ar AX ¹ , X ² , X ³ , Y ^] , Y ² , Α, L ¹ and L ² have the same meaning as in the above formula 1.。 represents a chlorine atom.)

Compound (103) can be synthesized according to a method known per se, for example, the method described in Shin-Experimental Research Institute, 14- [ΠΙ], pp. 803-1808 (issued by Maruzen Co., Ltd., 1978). be able to. The reaction of reacting the sulfonyl chloride with the amine is carried out in the presence of an organic base such as triethylamine or pyridine or an inorganic base such as alkali hydroxide or potassium carbonate, for example, dichloromethane, chloroform, ethyl acetate, or the like. It can be performed in an organic solvent such as tetrahydrofuran, toluene, acetone, dioxane or dimethylformamide. The reaction temperature ranges from -10 ° C to 60 ° C. Compound (102) can be prepared by a method known per se, for example, New Experimental Chemistry Lecture, 14— [III], Vol. 1, pp. 1784-1808 (Maruzen Co., Ltd., published in 1978), Experimental Chemistry Lecture, Fourth Edition, Vol. 127 pages (Maruzen Co., Ltd., published in 1992), or the method described in the literature, for example, Org. Synth., I, 84 (1941), Synthesis, 852 (1986), J. Am. C Hem. Soc., 60, 1486 (1938) and Chem. Lett., 1483 (1992).

Ar '— A ¹ and Ar ² — A ² are unequal and Y ¹ and Y ³ , Υ ² and Υ ⁴ are equivalent: Production method (2)

Pg

Ar ² — A ² -Y

(Wherein, Ar A ′, Ar ² , A ² , XX ² , X ³ , YY ² , A, L ¹ and L ² represent the same meaning as in the above formula 1. Y represents a chlorine atom, a bromine atom, Represents a leaving group such as iodine atom, methanesulfonyloxy, toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc. Z represents a chlorine atom, and P g represents a protecting group.)

Compound (105) can be obtained by reacting compound (104) with compound (102) under the same conditions as in production method (1). Compound (105) can be converted to compound (106) by removing the protecting group Pg. The removal of the protecting group here is performed by a general method (for example, TWGreene and PGMWuts, "Protective Groups in Organic Synthesis", 2nd Ed., John Wiley and Sons, inc., New York (1991), p.315- 362). As the protecting group represented by P g, any of various commonly used protecting groups can be used. For example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc. Protecting groups, amide-type protecting groups such as N-acetyl and N-benzoyl; benzyl, nitro, p-toluenesulfonyl, methanesulfonyl and the like. Compound (106) can be reacted with Ar ¹ —A′_Y in the presence of a base to produce compound (107). The reaction can be carried out under the conditions of a conventional N_alkylidene reaction. Specifically, examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal amides such as sodium amide and lithium amide; alkali metal amides such as potassium t-butoxide and sodium methoxide. Carbonates such as alkoxides, potassium carbonate and sodium carbonate; and organic bases such as triethylamine. The amount of the base to be used is 0.5 to 5 equivalents, preferably 0.8 to 1.2 equivalents to the compound (106). If it is a salt, it is necessary to add an excess of base in an amount equivalent to the salt. The amount of A r A ¹ —Y to be used is, for example, 0.5 to 5 equivalents, preferably 0.8 to 1.2 equivalents, relative to compound (106). Examples of the reaction solvent include an inert organic solvent such as dimethylformamide, tetrahydrofuran, acetonitrile, and acetone. The reaction temperature is, for example, 0 ° C. to the boiling point S of the reaction solvent, and preferably a force in the range of room temperature to 80 ° C. The compound (107) of the present invention can be produced by reacting the compound (107) with Ar ² —A ² —Y in the presence of a base. The reaction can be carried out under the conditions of a conventional N_alkylidene reaction. Specifically, examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal amides such as sodium amide and lithium amide; alkali metal alkoxides such as potassium t-butoxide and sodium methoxide; Carbonates such as potassium acid and sodium carbonate; and organic bases such as triethylamine. The amount of the base used is, for example, 1 to 5 equivalents, preferably 1 to 2 equivalents to the compound (107). However, the compound (107) is a salt such as a hydrochloride. In such a case, it is necessary to add an excess of the base by an equivalent amount of the salt. The amount of Ar ² —A ² —Y used is, for example, 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound (107). As the reaction solvent, for example, dimethyl Examples include inert organic solvents such as formamide, tetrahydrofuran, acetonitrile, and acetone. The reaction temperature is, for example, from o ° C to the boiling point of the reaction solvent, and preferably from room temperature to 80 ° C. Ar A ¹ and Ar ² — A ² , Y ¹ and Y ³ , Υ ² and Υ ⁴ are unequal

Manufacturing method (3-1)

Υ ¹ 109 Y ¹

Α- | _Λ Ζ- S0 ₂ — _Χ 1 _L 1 1 _X 2- _L 2- _X 3— _Z1 / A—

Pg— Ν NH Pg— Ν N-S0 ₂ -X -L ¹ — x ² -L ² -X ^3-

104

Y ² | 2 no

Y ¹ Y ¹

^{Pg- N N- S0 2 - X 1} - L 1 - X 2 - L 2 - X 3 - H Pg- N N-S0 2 - X 1_ L 1- X 2- L 2- X 3. S o 2 one _z

1 ²⁸

Y ² 112

Y ³

HN N— A ² — Ar ² Y ¹ Y ³

| ノ 4 113 / ^A- ichi

Pg— N ¹ Λ N-S0 ₂ -X ¹ - _L I_X ² -L ² -X ³ -S0 ₂ -N / N— A -Ar ²

| ₂ 114 ^ 4

Y ¹ Y ³

HN 'Λ N-S0 ₂ - _X I_L ¹ -X ² -L ² -X ³ S0 ₂ -N, 1 ¹ Λ N— A ² -A

 115

Y ² Y ⁴

Y ¹ Y ³

_Ar , one _A 1_ _Y

1 A ¹ -N ^{,, Α_Ι} Λ

_{- Ar N-S0 2 - x} 1 - tooth ¹ one X ² - teeth _{^{2 - X 3 -S0 2 - NN-}} A 2 - Ar 2

HY ² He Y ノ⁴

(Wherein, Ar ′, A ¹ , Ar ² , AXXX ³ , YY ² , YYA, L ¹ and L ² have the same meanings as in the above formula 1. X ¹ — L ¹ — X ² — L ² Y represents a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, toluenesulfonyloxy, or triflurine, which represents an optionally substituted phenylene group or an optionally substituted heteroarylene group. Represents a leaving group such as fluoromethanesulfonyloxy. Z represents a chlorine atom. Pg and Z ¹ represent a protecting group. )

Compound (110) can be obtained by reacting compound (104) with compound (109) under the same conditions as in production method (1). As the protecting group represented by P g, various types of protecting groups that are commonly used can be used. For example, a force that can be used, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, or the like, a lubamate type And amide-type protecting groups such as N-acetyl and N-benzoyl; benzyl, nitro, p-toluenesulfonyl, methanesulfonyl and the like. Compound (109) can be prepared by a method known per se, for example, New Experimental Chemistry Course, 14— [III], Vol. 1, pp. 784-1808 (Maruzen Co., Ltd., published in 1978), Experimental Chemistry Lecture, Fourth Edition, Vol. 22, Vol. 11, 5-127 pages (Maruzen Co., Ltd., published in 1999), or the method described in the literature, for example, Org. Synth., I, 84 (1941), Synthesis, 852 (1986) , J. Am. Chem. Soc., 60, 1486 (1938) and Chem. Lett., 1483 (1992).

Compound (1 10) may be converted into the compound by removing the protecting group Z ¹ (1 28). The removal of the protecting group here can be carried out by a general method (for example, TWGreene and PGM Uts, "Protective Groups in Organic Synthesis", 2na Ed., John Wiley and Sons, inc., New York (1991), p.315- 362).

Compound (128) can be prepared by a method known per se, for example, New Experimental Chemistry Course 141-1 [一] Vol. 1 790 (Maruzen Co., Ltd., published in 1978), or a method described in the literature, for example, Chem. Compound (112) can be synthesized according to the method described in Ber., 841, 851 (1957) and Chem. Ber., 2728, 2733 (1909). The reaction here is a method of synthesizing sulfonyl chloride using, for example, a metal catalyst such as copper chloride after converting into diazonium salt using sodium nitrite. The reaction for obtaining the diazonium salt is carried out by subjecting compound (128) to acidic conditions such as an aqueous hydrochloric acid solution, in this case, adding 1 to 5 equivalents of acid to compound (128), preferably It can be obtained by reacting sodium nitrite in the range of 0.5 to 2 equivalents, preferably about 1 equivalent. The reaction temperature may be from 15 ° C to 50 ° C, preferably from 0 ° C to 5 ° C. Examples of the reaction solvent include a water-soluble solvent such as hydrochloric acid and acetic acid sulfate, acetic acid and an inert organic solvent such as dioxane or tetrahydrofuran, and a non-aqueous solvent such as propionic acid. The diazodium salt prepared here is reacted in the presence of a metal catalyst such as copper chloride, for example, in a sulfur dioxide-containing solution such as hydrogen sulphite to obtain the compound (111). Can be done. The reaction temperature includes −5 ° C. to 80 ° C., preferably 10 ° C .; Compound (114) can be synthesized by reacting compound (112) with compound (113) in the same manner as in production method (1). Compound (114) can be converted to compound (115) by removing the protecting group Pg. The removal of the protecting group here is carried out by a general method (for example, TWG Greene and PGM Uts, "Protective Groups in Organic Syntnesis", 2nd Ed., John Wiley and Sons, inc., New York (1991), p.315-). 362).

The compound (1 16) of the present invention can be produced by reacting the compound (1 15) with Ar A ¹ —Y in the presence of a base. The reaction can be carried out by a method similar to production method (2).

L ³ and L ⁴ are sulfonyl groups and X ³ is a single bond:

Manufacturing method (3-2)

Y ¹ 109 Y ¹

Al Λ -S0 ₂ -x ¹ one cog ¹ - x ² - teeth ² - X ³ -

_{Pg- N NH Pg- N-S0 2} - x i eleven _X 2- _L 2_ _X 3 one ₂

 104

Y ² ) 2 110

(In the formula, Ar ′, A Ar ² , A ² , X ¹ , X ² , YY ² , Y ³ , Y ⁴ , A, L ¹ and L ² represent the same meaning as in the above formula 1. X ¹ — L ¹ — X ² _L ² — X ³ represents a group other than an optionally substituted phenylene group or an optionally substituted heteroarylene group X ³ represents a single bond Y represents a chlorine atom , Bromine, iodine, methanesulfonyloxy, toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc. Z represents a chlorine atom Z ¹ represents a chlorine atom, toluenesulfonyloxy, etc. Z ² represents a sulfonic acid group and its sodium salt, potassium salt, etc. Pg represents a protecting group.)

Compound (1 10) is compound (104) and compound (109) in the same manner as in production method (1). It can be obtained by reacting under conditions. As the protecting group represented by Pg, various commonly used protecting groups can be used. For example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl Compound (109), which includes a protecting group of a bamba type such as amide, a protecting group of an amide such as N-acetyl or N-benzoyl, benzyl, nitro, p-toluenesulfonyl, methanesulfonyl, etc. , For example, Shin-Keikaku-Danigaku Course 141-1 [III] Vol. 1 784-1808 (Maruzen Co., Ltd., published in 1978), Experimental Chemistry Course, 4th edition, Vol. 22, Vol. 11 15-127 (Maruzen Co., Ltd.) , Published in 992).

 Compound (110) can be prepared according to a method known per se, for example, the method described in Shin-Jikken Kagaku Koza Vol. 14 [III], Vol. 17, pp. 773-1809 (issued by Maruzen Co., Ltd., 1978). 1 1 2) can be synthesized. The reaction here is a method of converting the compound (110) into a sulfonate of the compound (111), and then synthesizing the sulfonyl chloride of the compound (111). The compound (.110) can be prepared according to a method known per se, for example, the method described in Shin-Jikken Kagaku Koza 14- [III], pp. 1773-1784 (issued by Maruzen Co., Ltd., 1978). Compound (11) can be used. The reaction here may be carried out in an aqueous sodium sulfite solution at a temperature ranging from 0 ° C to the boiling point of the solvent, preferably from 80 ° C to the boiling point of the solvent. Compound (1 11) is reacted with a chlorinating agent such as pentachloride or phosphoryl chloride under a solvent-free condition at a temperature of 50 ° C to 200 ° C to give compound (1 1 1). 1 2) can be led. Compound (114) can be synthesized by reacting compound (112) with compound (113) in the same manner as in production method (1).

Compound (114) can be led to compound (115) by removing the protecting group Pg. The removal of the protecting group here is carried out by a general method (for example, TWG Greene and PGM Uts, "Protective Groups m Organic Synthesis", 2nd Ed., John Wiley and Sons, inc., New York (1991), p.315). -362). The compound (1 16) of the present invention can be produced by reacting the compound (1 15) with Ar A ¹ —Y in the presence of a base. The reaction can be carried out by a method similar to production method (2). When L ³ and L ⁴ are sulfonyl groups and X ³ is NR ¹ :

Manufacturing method (3-3)

Y ¹ 109

-S0 ₂ - _X i- _L ¹ -x ² -L ² -X ³ -2 / ^{A- 1}

Pg— Ν NH Pg— Λ N-S0 ₂ -X ¹ -L -X ² — then ² — X ^3-

104) NO 2 Y ² 110

Pg— Ν N-S0 ₂ -x ¹ -L ¹ -X ² -L ² -X ³ -H

 128

Υ ²

Υ ¹ Υ ³

 Α

ΗΝ Ν-S0 ₂ -χ ¹ — ι. ¹ -X ² -L ² -X ³ -S0 ₂ - _N -Κ-A ² -Ar ²

 No

Υ ² 115 γ

Υ ¹ γ ³

Ar ¹ — A ¹ — Ν N-S0 ₂ - _X ¹ _L ¹ — χ ² — | _ ^2- ) <3-30 ₂ NA ² -Ar ²

 2 116

(In the formula, Ar A ¹ , Ar ² , A ² , X ¹ , X ² , Y ¹ , Y ² , YY ⁴ , A, L ¹ and L ² have the same meanings as in the above formula 1. X ³ is NR ¹ (R ¹ is a hydrogen atom or Represents a kill group. ). Y represents a leaving group such as a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, toluenesulfonyloxy and trifluoromethanesulfonyloxy. Z represents a chlorine atom. P g represents a protecting group. ∑ ¹ ? Represents a protecting group different from ₈ . )

Compound (110) can be obtained by reacting compound (104) with compound (109) under the same conditions as in production method (1). Pg, the protecting group represented by Z ^1, it is possible to use various protective groups generally used force e.g., Metokishika carbonyl, ethoxycarbonyl, tert- butoxycarbonyl, protection force Rubameto types such Benjiruokishika carbonyl Groups, amide-type protecting groups such as N-acetyl and N-benzoyl, benzyl, nitro, p-toluenesulfonyl, methanesulfonyl and the like.

 The compound (109) can be prepared by a method known per se, for example, Shin-Jikken-Dojigaku Koza 14- [III], Vol. 1, pp. 784-1808 (issued by Maruzen Co., Ltd., 1978), Experimental Chemistry Kogaku, 4th edition, Vol. 22 Pages 115 to 127 (Maruzen Co., Ltd., published in 1999) or a method described in the literature, for example, Org. Synth., I, 84 (1941), Synthesis, 852 (1986) ), J. Am. Chem. SoC., 60, 1486 (1938) and Chem. Lett., 1483 (1992).

Compound (1 10) may be converted into the compound by removing the protecting group Z ¹ (1 28). The removal of the protecting group here is carried out by a general method (for example, TWGreene and PGM Uts, "Protective Groups in Organic Synthesis", 2nd Ed., John Wiley and Sons, inc., New York (1991), p.315-). 362).

The reaction for obtaining the compound (114) is performed by reacting the compound (113) with sulfuryl chloride to generate an active intermediate, and then reacting the compound (128) with the compound (128) in the presence of a base. Compound (114) can be obtained by obtaining 114) or by reacting compound (128) with thiosulfuryl salt and then reacting with compound (113) in the presence of a base. Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride; alkali amides such as sodium amide and lithium amide; alkali metal alkoxides such as potassium t-butoxide and sodium methoxide; potassium carbonate; Carbonates such as sodium, and organic bases such as triethylamine.

 Examples of the reaction solvent for the reaction between the compound (128), the compound (113) and sulfuryl chloride include inert organic solvents such as dichloromethane, chloroform, and carbon tetrachloride. Examples of the reaction temperature for the reaction with the salt of sulfurylfuryl include the range of 1 to 100 ° C to room temperature, and preferably the range of 178 to 0 ° C. From the compound (114), the invention compound can be derived by the above-mentioned method.

[Wherein, Ar], AA, Y>, Y ² , XLX ² , L ² , X ³ , Y ³ , Y ⁴ , A ² and Ar ² have the same meaning as in the above formula 1. One of L ³ and L ⁴ is a sulfonyl group, and the other is a carbonyl group.)

When L ³ is a sulfonyl group, L ⁴ is a carbonyl group, and X ³ is NR ¹ (R ¹ is a hydrogen atom or an alkyl group) or an oxygen atom

Manufacturing method (4) Y ¹ 109 Y ¹

-S0 ₂ - _X, one LI one _X 2_ | _2 one _χ 3- Ak

Pg—N NH Pg—N _N -S0 ₂ -x ¹ -L ¹ -X ² -L ² -X ^3- \ _l

104 γ | no 2 Y ² 110

(Wherein, Ar ¹ A Ar ² , A ² , XX ² , YΥ ² , Υ ³ , Υ Α, L ¹ and L ² have the same meaning as in the above formula 1. Υ is a chlorine atom, Represents a leaving group such as bromine atom, iodine atom, methanesulfonyloxy, toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc. Ζ represents a chlorine atom, Pg represents a protecting group, and Pg represents a protecting group. X ³ represents NR ¹ (R ¹ is a hydrogen atom or an alkyl group) or an oxygen atom.

Compound (110) can be obtained by reacting compound (104) with compound (109) under the same conditions as in production method (1). As a protecting group represented by ZP g Is a force capable of using various commonly used protecting groups such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like, and a rubamate-type protecting group, N-acetyl, N-benzoyl, etc. And benzyl-type protecting groups, benzyl, nitro, p-toluenesulfonyl, methanesulfonyl and the like.

 The compound (109) can be prepared by a method known per se, for example, Shin-Jikken-Ji-Dogaku Koza 14- [III], Vol. 1, pp. 784-1808 (Maruzen Co., Ltd., published in 1978), Experimental Chemistry Kogaku, 4th edition, Vol. 22, 1 15-127 (Maruzen Co., Ltd., published in 1999), or the method described in the literature, for example, Org. Synth., I, 84 (1941), Synthesis, 852 (1 986), J. Am. Chem. Soc., 60, 1486 (1938) and Chem. Lett., 1483 (1992). .

Compound (1 1 0) can be converted into the compound by removing the protecting group Z ¹ (1 28). The removal of the protecting group here is carried out by a general method (for example, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 2nd Ed., John Wiley and Sons, inc., New York (1991), p. 315-362).

 Compound (128) is prepared by reacting compound (113) with hexachlorodimethylcarbonate (triphosphogen) to form an active intermediate, followed by compound (128) in the presence of a base. The compound (1 20) is obtained by reacting the compound (1 20) with hexachlorodimethyl carbonate (triphosgene) and then reacted with the compound (1 13) in the presence of a base. (1 20) can be obtained. Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride; alkali amides such as sodium amide and lithium amide; alkali metal alkoxides such as potassium t-butoxide and sodium methoxide; potassium carbonate; Carbonates such as sodium, organic bases such as triethylamine, and the like.

The reaction solvent for the reaction of compound (128) with compound (113) and hexachlorodimethylcarbonate (for example, as an inert organic solvent such as THF and DMF) And the like. The reaction temperature of the reaction with hexachlorodimethylcarbonate (triphosgene) is, for example, in the range of 0 ° C to room temperature.

From the compound (120), the compound of the present invention can be derived by the aforementioned method. When L ³ is a sulfonyl group, L ⁴ is a carbonyl group, X ^^ 'NR ¹ (R ¹ is a hydrogen atom or an alkyl group)

(Ar A ¹ and Ar ² — A ² , Y ¹ and Y ³ , Υ ² and Υ ⁴ are equivalent):

Manufacturing method (5)

Υ ¹ 117

Α- "'Λ Z-S0 ₂ - _X 1- _L 1— _X 2_ _L 2—

Ar ¹ — A ¹ -N NH

 V do

101 γ ²

(Wherein, Ar ¹ , AX ¹ , X ² , YΎA, L ¹ and L ² represent the same meaning as in the above formula 1. Y is a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy, Represents a leaving group such as toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc. Z represents a chlorine atom R ^{1 (5} represents an alkyl group) Compound (118) can be synthesized according to a method known per se, for example, the method described in Shin-Jikken-Ji-Dogaku Koza 14- [III], pp. 1803-1808 (Maruzen Co., Ltd., published in 1978). Can be. The reaction of reacting the sulfonyl chloride with the amine is carried out, for example, in the presence of an organic base such as triethylamine or pyridine, for example, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, toluene, acetone, dioxane or dimethylformamide. In an organic solvent. Reaction temperatures range from 10 ° C to 60 ° C.

Compound (1 18) the presence of a base, R ¹⁰ - is reacted with Y, it is possible to produce the compound (1 1 9). The reaction can be carried out according to the conditions of a conventional N_alkylich reaction. Specifically, examples of the base include alkali metal hydrides such as sodium heptahydride and potassium hydride, alkali metal amides such as sodium amide and lithium amide, and alkali metals such as potassium t-butoxide and sodium methoxide. Metal alkoxide and the like can be mentioned. The amount of the base used is, for example, 1 to 10 equivalents, preferably 1 to 2 equivalents to the compound (118), provided that the compound (118) is a salt such as a force hydrochloride. In this case, it is necessary to add an excess of the base in an amount equivalent to the amount of the salt. The amount of R ^{1 (3} — Y to be used is, for example, 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound (118). As the reaction solvent, for example, THF, The reaction temperature may be, for example, 0 ° C. to the boiling point of the reaction solvent, and preferably the room temperature to 80 ° C. The sulfonyl group, L ⁴ Is a carbonyl group and X ³ is a single bond

A r, one A] and A r ² — A ² , Y ¹ and Y ³ , Υ ² and Υ ⁴ force equivalent:

Manufacturing method (6) one two Three

 Y '

A— I Λ -S0 ₂ - _X I_L -X ² -L ² -X ³ -CO-

Ar ¹ — A ¹ -N NH

 101

Y 'Y ¹

 A- A

Ar ¹ — A ¹ — N N-S0 ₂ - _X 1-L ¹ -X ² -L ² -X ³ -CO-N N—A, one Ar

 124

Υ '125

-S0 ₂ - _X 1— _L 1- _X 2— _L 2—x3. _CO - _OH

Ar ¹ — A ¹ -N NH

 101

Y ¹ Y ¹

 A- Λ

Ar'—A'-N N-S0 ₂ -X ¹ -L ¹ — x ² -L ² -X ³ -CO-N, N—A ¹ — Ar ¹

 ノ | ノ

 γ2 124 γ2

(In the formula, Ar AX ¹ , X ² , YY ² , A, L ¹ and L ² have the same meanings as in the above formula 1. Z represents a chlorine atom. X ³ represents a single bond.)

Compound (124) can be synthesized under the same conditions as in Production method (1). Compound (124) can be obtained by reacting compound (101) with compound (125) under the same conditions as in production method (1), and then condensing in the presence of a dehydrating condensing agent. The condensation reaction here can be carried out by adding an organic solvent such as dichloromethane, chloroform, ethyl acetate, tetrahydrofuran or dimethylformamide to the reaction system. The reaction temperature may be in the range of -10 ° C to 60 ° C. Examples of the dehydrating condensing agent include dicyclohexylcarbodiimide and 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, which are used together with a reaction aid. Examples of the reaction assistant include ヒ ド ロ キ シ -hydroxybenztriazole, Ν, Ν-dimethyl-aminoviridine and the like. Also, as a dehydrating condensing agent, for example, N, N-bis (2-oxo-13-oxazolidinyl) phosphinic chloride can be used in combination with an organic base such as, for example, triethylamine.

When L ³ is a sulfonyl group, L ⁴ carboxyl group, and X ³ is a single bond

Ar A ¹ and Ar ² — If A ² , Y ¹ and Y ³ , Υ ² and Υ ⁴ are unequal:

Manufacturing method (7)

Y ¹ 125

A- -S0 ₂ - _X 1-X ² -X ³ -CO-OH

Ar'— Α ¹ — Ν ΝΗ

 101

Y ¹ Α 一

A- HN N— A ² -Ar ²

^{Ar 1 - A 1 - N N} -S0 2 -X -L - X 2 - L 2 - -CO- .OH \ - \ J 113

 NO 26

Y ¹

 A-l A- Λ

Ar ¹ — AN I NS-S0 ₂ -xL ¹ -X ² -L ² -X ³ -CO-N N— A ² -Ar ²

 -\ J \ _l

 127

(Wherein, Ar ¹ A ¹ , Ar ² , A ² , XX ² , YY ² , Y ³ , YA, L ¹ and L ² represent the same meaning as in the above formula 1. Z represents a chlorine atom X ³ represents a single bond.)

Compound (126) can be synthesized under the same reaction conditions as in the aforementioned method for synthesizing compound (124). The reaction here is performed by reacting the compound (125) with an equivalent of the compound (101) having a range of about 0.5 to about 2.0 equivalents, preferably about 1 equivalent, with a power of about 1 equivalent. 126) is synthesized, isolated and purified. As a method for isolation and purification, for example, a recrystallization method, a purification method using column chromatography, and the like can be used. The isolated and purified compound (126) is condensed with the compound (113) in the presence of a dehydrating condensing agent. Thus, the desired compound can be obtained. The condensation reaction here can be synthesized under the same conditions as in the method for synthesizing the compound (124) described above. The dipiperazine derivative of the formula 1 can be converted to a salt by mixing with a pharmaceutically acceptable acid such as hydrochloric acid, oxalic acid, methanesulfonic acid or the like in a solvent such as water, methanol, ethanol or acetone. it can.

 Compound (1) or an intermediate for producing the same can be purified by a usual method. ίIf it is in sequence, it can be purified by column chromatography, recrystallization, etc. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as getyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as toluene and acetone. Ketone solvents, hydrocarbon solvents such as hexane, aprotic solvents such as acetonitrile, and the like, or mixed solvents thereof.

 In carrying out the above reaction, if necessary, protection and deprotection techniques can be used. Regarding the technology of protection and deprotection, see (T. W. Greene and P. G. M. Wuts, "Pro- tecting Groups in Organizing Synthes is", 1990).

When the compound (100) has a substituent having an asymmetric carbon, optical isomers exist, and a mixture or an isolated optical isomer is included in the compound (100). As a method for obtaining such an optical isomer purely, for example, there is an optical resolution power. As the optical resolution method, for example, the compound (100) is dissolved in an inert solvent (for example, an alcohol solvent such as methanol, ethanol, or 2-propanol, an ether solvent such as geethyl ether, or an ester solvent such as ethyl acetate). Solvents, aromatic hydrocarbon solvents such as toluene, acetonitrile, etc., optically active acids (eg, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, lactic acid, tartaric acid, o-diisopropylidene) Dicarboxylic acids such as tartaric acid and malic acid, sulfonic acids such as camphorsulfonic acid and bromocamphorsulfonic acid) or optically active amines (eg, organic amines such as α-phenethylamine, quinine, quinidine, cinchonidine, cinchonidine, strychnine) To form a salt and can be separated.

 The temperature for forming the salt includes a range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to increase the temperature to near the boiling point of the solvent. Before filtering out the precipitated salt, it can be cooled if necessary to improve the yield. The amount of the optically active acid or amine used is in the range of about 0.5 to about 2.0 equivalents, preferably about 1 equivalent, per substrate. If necessary, the crystals are placed in an inert solvent (for example, alcohol solvents such as methanol, ethanol, and 2-propanol; ether solvents such as dimethyl ether; ester solvents such as ethyl acetate; and aromatic hydrocarbons such as toluene. Recrystallization with a hydrogen-based solvent, acetonitrile, etc.) can also provide high-purity optically active salts. If necessary, the obtained salt can be treated with a base in a usual manner to obtain a free form.The dipiperazine derivative of the formula 1 or a pharmaceutically acceptable salt thereof is used in the treatment. It can be administered orally or parenterally (eg, intravenously, subcutaneously, or intramuscularly, topically, rectally, transdermally, or nasally). Examples of compositions for oral administration include tablets, capsules, pills, granules, powders, solutions, suspensions, and the like. Examples of compositions for parenteral administration include injections Aqueous preparations, oily preparations, ointments, creams, lotions, aerosols, suppositories, patches and the like can be mentioned. These preparations can be prepared using conventionally known techniques, and can contain nontoxic and inert carriers or excipients usually used in the field of preparation. Such a dosage form can be produced by mixing a pharmaceutically acceptable usual carrier, excipient, binder, stabilizer, buffer, dissolution aid, isotonic agent and the active ingredient of the present invention. Can be.

The dose and frequency of administration vary depending on the patient's symptoms, medical history, age, weight, dosage form, and the like.For example, when orally administered to an adult (body weight 60 kg), usually 1 to 3000 mg per day, preferably 5 to The dosage can be adjusted as appropriate within the range of 50 mg, and can be administered once or in several divided doses. Example

 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Reference example 1

Synthesis of N_ [3- (topiperazinylcarbonyl) phenyl] -1-piperazinecarboxamide Reference Example 1-1

 1 Synthesis of tert-butyl 1-pyrazinecarboxylate

A solution of piperazine (200.6 g, 2.33 mmol) in isopropanol (1000 ml) was stirred at 0 ° C. To this, Boc ₂₀ (100.2 g, 459 t ol) was added dropwise over 2 hours. The mixture was stirred at 0 ° C for 1 hour, returned to room temperature, and stirred overnight. The solvent was distilled off, the residue was dissolved in ethyl acetate (1 000 ml), and the insoluble matter was separated by filtration. The filtrate was washed with water to remove the raw material piperazine. The ethyl acetate layer was separated and washed with saturated aqueous sodium hydrogen carbonate, and the solvent was distilled off. The residue was dissolved in t-butanol (700 ml), allowed to stand overnight, and the white precipitate was filtered off. By concentrating the filtrate, 67.77 g of the title compound was obtained as a white solid. (79%)

Reference Example 1-1

4-[(3- {[4- (tert-butoxycarbonyl) -topiperazinyl] carbonyl} anilino) carbonyl] -1-piperazine tert-butyl rubnate and 3- ({[4- ( Synthesis of tert-butoxycarbonyl) -topidazinyl] carbonyl} amino) benzoic acid

To a solution of triphosgene (5.0 g, 16.8 mmol) in THF (20 ml) was added dropwise a solution of 3-aminobenzoic acid (2.4 g, 17.5 mmol) in THF (120 ml) under ice-cooling over 1.5 hours. This reaction solution was stirred at 0 to 5 ° C for 30 minutes. THF (80 ml) was added, and the mixture was further stirred at 5 ° C for 1 hour and at 20 ° C for 30 minutes. Under ice-cooling, a solution of tert-butyl 1-piperazinecarboxylate (9.8 g, 52.6 mmol) in THF (50 ml) was added to the reaction mixture, and the mixture was added at 5 ° C for 15 minutes and then at 20 ° C for 30 minutes. Stirred for minutes. The reaction was quenched with a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Obtained residue (hexane: ethyl acetate = 1: 2 → 1: 9 )), And purified by tert-butyl 4-[(3-{[4- (tert-butoxycarbonyl) -1-piperazinyl] -l-propane, di} arilino) carbonyl] -tripiperazinecarboxylate (2.22 g, 25%). The separated aqueous layer was made acidic (around PH3) with aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dried under vacuum to obtain 3-({[4- (tert-butoxycarbonyl) -1-piperazinyl] carbonyl} amino) benzoic acid (3.78 g, yield 62%). .

 4-[(3-{[4- (tert-butoxycarbonyl) -piperazinyl] -capillonyl} anilino) -rubonyl] -topidazine tert-butylrubonate

_{Ή MR (CDC1 3, 270 MHz} ) 57.44 (s, 1 H), 7.43 - 7.26 (m, 2 H), 7.05 (dt, 1 H, J = 7.3, 1.3 Hz), 6.71 (s, 1 H), 3.8-3.35 (m, 16 H), 1.48 (s, 9 H), 1.47 (s, 9 H).

3-({[4- (ter t-butoxycarbonyl)-1 -piperazinyl] capillonyl} amino) benzoic acid ^] H NMR (DMS 0-d ₆ , 270 MHz) 8 12.8 (br, 1 H), 8.77 (s , 1 H), 8.08 (t, 1 H, J = 1.7 Hz), 7.78-7.71 (m, 1 H), 7.58 (dd, 1 H, J = 7.6, 1,3 Hz), 7.35 (t, 1 H, J = 7.9 Hz), 3.45-3.35 (m, 8H), 1.42 (s, 9H).

Reference Example 1-3

 From 3-({[4- (tert-butoxycarbonyl) -1-piperazinyl] carbonyl} amino) benzoic acid to 4-[(3-{[4- (tert-butoxycarbonyl) -topiperazinyl] Synthesis of tert-butyl carbonyl carbonate

To a solution of 3-({[4- (tert-butoxycarbonyl) -1-piperazinyl] carbonyl} amino) benzoic acid (3.77 g, 10.8 bandol) in DMF (20 ml) was added 1-pidazinecarboxylic acid. tert-butyl (2.4 g, 12.9 ol), triethylamine (1.6 g, 15.8 ol), 1-hydroxybenzotriazole (HOBt) (1.79 g, 13.2 ol), triethyl-3- (3 dimethyla) Minopropyl) carposimide (WSC) · hydrochloride (2.6 g, 13.6 mmol) was added, and the reaction solution was stirred at room temperature for 19 hours. Tert-butyl 1-piperazinecarboxylate (0.5 g, 2.7 mmol) and WSC-hydrochloride (0.44 g, 2.3 mol) were added, and the mixture was further stirred at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. After washing the organic layer with water and saturated saline, magnesium sulfate The extract was dried over sodium hydroxide and the solvent was distilled off under reduced pressure. The obtained residue is separated and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 3 → ethyl acetate) to give 4-[(3-{[4- (tert-butoxycarbonyl) -topiperazinyl]. [Carbonyl} anilino) carbonyl] -1-tert-butyl-1-piperazinecarboxylate (5.55 g, yield 99%) was obtained.

Reference Examples 1-4

 Synthesis of N- [3- (l-pirazinylcarbonyl) phenyl] -1-piperazinecarboxamide

 4-[(3-{[4- (tert-Butoxycarbonyl) -topiperazinyl] carbonyl} anilino) force of tert-butyl rubonyl] -1-piperazinecarboxylate (2.2 g, 4.25 mmol) A 4N hydrogen chloride Z dioxane solution (10 ml) was added to the dioxane (10 ml) solution, and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution was added a 4N hydrogen chloride Z-dioxane solution (10 ml), and the mixture was further stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure and dried under vacuum to obtain the title compound (1.9 g).

'Η NMR (DMSO—d ₆ , 270 MHz) δ 9.4-9.1 (br, 4 Η), 9.05 (s, 1 Η), 7.63 (s, 1 Η), 7.56 (d, 1 Η, J = 8.3 Hz ), 7.34 (t, 1 H, J = 7.9 Hz), 7.04 (d, 1 H, J = 7.9 Hz), 3.8-3.6 (m, 8 H), 3.3—3.2 (m, 8 H).

Reference example 2

 Synthesis of N- [4- (1-piperazinylcarbonyl) phenyl] -1-pidazinecarboxamide Reference Example 2-1

 Synthesis of 4-[(1-piperazinylcarbonyl) amino] benzoic acid

 Dissolve triphosgene (2.97 g, 10.0 mmol) in THF (10 ml), stir at 0 ° C, and add dropwise a solution of p-aminobenzoic acid (2.74 g, 20.0 mmol) in THF (180 ml) over 1 hour. did . After stirring at 0 ° C. for 1 hour as it was, teri-butyl 1-piperazinecarboxylate (5.60 g, 30.0 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction was terminated by adding saturated aqueous layer water, and the 7j layer was washed with ethyl acetate. The aqueous layer was added with concentrated hydrochloric acid little by little to ρΗ3-4 and extracted with THF. The THF layer was washed with 1N diluted hydrochloric acid and dried over magnesium sulfate. Evaporation of the solvent gave the title compound as a white solid (5.08 g, 14.5 mmol, 72.7%).

_{'Η NMR (CDC1 3, 300} MHz) δ 8.92 (s, 1 H), 7.82 (d, 2 H, J = 8.8 Hz), 7.58 (d , 2H, J = 8.8 Hz), 3.45-3.43 (m, 4H), 3.37-3.35 (m, 4H), 1.42 (s, 9H).

Reference Example 2-2

 41 Synthesis of tert-butyl [4-({[4- (tert-butoxycarbonyl) -1-piperazinyl] carbonyl} amino) benzoyl] -1-piperazine

 4-[(Topiperazinylcarbonyl) amino] benzoic acid (5.06 g, 14.5 t ol) was dissolved in DMF (60 ml), and tert-butyl piperazinecarboxylate (2.98 g, 15.9 mmol), WSCI-hydrochloride ( 3.34 g, 17.4 mmol), HOBt (2.35 g, 17.4 mmol), and triethylamine (2.4 ml, 17 mmol) were sequentially added, and the mixture was stirred at room temperature for 27 hours. The reaction was terminated by the addition of saturated aqueous layer water, and the mixture was extracted with ethyl acetate. This was washed with saturated aqueous layer water and dried over anhydrous magnesium sulfate. The concentrated residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1 → 3: 1) to give 4.90 g (9.47 mino 1, 65.3%) of the title compound as a white solid.

'Eta Awakening: _{(CDC1 3, 300 MHz) 5} 7.41 - 7.34 (m, 4 H), 6.53 (s, 1 H), 3.51 - 3.44 (m, 16 H), 1.48 (s, 9 H), 1.47 (s , 9H).

Reference Example 2-3

 Synthesis of N- [4- (1-piperazinylcarbonyl) phenyl] -topiperazine-forced ruboxamide

4- [4-({[4- (tert-Butoxycarbonyl) -1-piperazinyl] -capillonyl} amino) benzoyl] -tert-butyl-1-piperazinecarboxylate (4.90 g, 9.47 mmol) After dissolving in acetic acid (60 ml), 4N hydrogen chloride dioxane (20 ml) was added thereto, and the mixture was stirred at 50 ° C for 30 minutes. The title compound was obtained as a white solid (4.46 g, 11.4 bandol, 100%) by distilling off the solvent and azeotropically distilling off acetic acid with toluene and methanol several times.

Reference example 3

 Synthesis of N- {4-[(Topiperazinylcarbonyl) amino] phenyl} -1-pidazine

Reference Example 3-1

4-{[4- ({[4- (ter t-butoxycarbonyl)-1 -pirazinyl] potassium} amino) anili [No] Cyrubonyl} -Synthesis of tert-butyl topiperazine chelate

 Dissolve triphosgene (1.39 g, 4.69 mraol) in THF (5 ml) and stir at 0 ° C to give p-phenylenediamine dihydrochloride (1.21 g, 6.70 nunol), triethylamine (1.0 ml, 7.37 mmol) And a solution of THF (200 ml) was added dropwise over 1 hour. After stirring at room temperature for 1 hour, tert-butyl 1-piperazinecarboxylate (3.13 g, 16.8 mmol) obtained in Reference Example 1-1 was added, and the mixture was stirred overnight. The reaction was terminated by the addition of saturated aqueous layer water, and the THF layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with 1N diluted hydrochloric acid and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel gel chromatography (ethyl acetate) to give the title compound (95.3 mg, 0.179 mol, 2.7%) as a white solid.

_{Ή NMR (CDC1 3, 300 MHz} ) 8 7.28 (s, 4 H), 6.29 (s, 2 H), 3.48 (bs, 16 H), 1. 48 (s, 18 H).

Reference example 3-2

 Synthesis of N- {4-[(1-Piperazinylcarbonyl) amino] phenyl} -topiperazinecarboxamide

 4-tert-butyl 4-[{4-({[4- (tert-butoxycarbonyl) -1-piperazinyl] capillonyl} amino) anilino] carbonyl} -1-piperazinecarboxylate (95.3 mg, 0.179 iranol) was dissolved in acetic acid (30 ml), 4N hydrogen chloride / dioxane (10 ml) was added, and the mixture was stirred at 50 ° C for 30 minutes. The solvent was distilled off, and the acetic acid was distilled off azeotropically with toluene to give the title compound (74.5 mg, 0.184%, 100%) as a white solid.

_{Ή NMR (CDC1 3, 300 MHz} ) δ 9.13 (s, 4 H), 8.66 (s, 2 H), 7.32 (s, 4 H), 3.66

(m, 8 H), 3.11 (m, 8 H).

Reference example 4

 Synthesis of N- (4-ethylbenzyl) pidazine

Reference Example 4-1-1 Synthesis

 4-ethylbenzyl alcohol

To a suspension of lithium aluminum hydride (380 mg, 10.0 mmol) in THF (5 ml) was added 4- A solution of tyl benzoic acid (1.50 g, 9.99 mmol) in THF (10 ml) was added dropwise, and the reaction solution was stirred at room temperature for 17 hours. Water (0.38 ml), 15% aqueous sodium hydroxide (0.38 ml) and water (1.1 ml) were sequentially added dropwise to the reaction solution, and the reaction solution was stirred at room temperature for 30 minutes and at 40 ° C for 30 minutes. . The reaction solution was diluted with ether, the insolubles were removed by filtration, and the filtrate was concentrated and dried under vacuum to obtain the title compound (1.35 g, yield 99%).

_{¾ NM (CDC1 3, 270 MHz} ) 57.29 (d, 2 H, J = 8.3 Hz), 7.19 (d, 2 H, J = 8.3 H z), 4.65 (d, 2 H, J = 5.9 Hz), 2.65 (q, 2 H, J = 7.6 Hz), 1.61 (t, 1 H, J = 5.9 Hz), 1.24 (t, 3 H, J = 7.6 Hz).

Reference Example 4-2

Synthesis of tri (4-ethylbenzyl) piperazine

 To a solution of 4-ethylbenzyl alcohol (3.0 g, 22.0 ol) in THF (30 ml) was added triethylamine (3.0 g, 29.6 mmol) and methanesulfonyl chloride (3.0 g, 26.2 t) under ice-cooling. The reaction solution was stirred at 0 ° C for 1 hour. This reaction solution was added dropwise at 50 ° C to a suspension of piperazine (6.0 g, 69.7 mmol), potassium carbonate (5.3 g, 38.3 tmol) in acetonitrile (50 ml), and DMF (10 ml). This reaction solution was stirred at 50 ° C for 1 hour. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was extracted four times with aqueous sodium dihydrogen phosphate, and the obtained aqueous layer was washed with ethyl acetate and then made alkaline with sodium hydroxide. This was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dried under vacuum to give the title compound (3.23 g, yield 72%).

¾ thigh _{(CDC1 3, 300 MHz) δ} 7.23 (d, 2 H, J = 8.0 Hz), 7.15 (d, 2 H, J = 8.0 Hz), 3.46 (s, 2 H), 2.88 (bt, 4 H , J = 4.8 Hz), 2.63 (q, 2 H, J = 7.5 Hz), 2.35 — 2.5 (m, 4 H), 1.23 (t, 3 H, J = 7.5 Hz).

Reference example 5

Synthesis of N- (4-methoxybenzyl) pidazine

In a suspension of piperazine (10.1 g, 117 mmol) in acetonitrile (50 ml) and DMF (10 ml), potassium carbonate (7.7 g, 55.7 mmol), 4-methoxybenzyl chloride at 40 ° C (5.0 g, 31.9), and the reaction solution was stirred at 50 ° C for 2 hours. Dilute hydrochloric acid and aqueous sodium hydroxide were added to the reaction mixture to adjust the pH to around 4, and the mixture was washed with ethyl acetate. The aqueous layer was made alkaline with sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dried under vacuum to give the title compound (6.06 g, yield 92%).

_{¾ NMR (CDC1 3, 300 MHz} ) δ 7.23 (d, 2 H, J = 8.6 Hz), 6.85 (d, 2 H, J = 8.6 Hz), 3.80 (s, 3 H), 3.44 (s, 2 H ), 2.87 (bt, 4 H, J = 4.9 Hz), 2.3-2.5 (m, 4 H).

Reference example 6

Synthesis of N- (3,4-dichlorobenzyl) piperazine

 Potassium carbonate (11 g, 79.6 mmol) was added to a solution of piperazine (15.0 g, 174 ol) in acetonitrile (100 ml) and DMF (20 ml). Dichlorobenzyl chloride (9.0 g, 46.0 mmol) was added dropwise. The reaction solution was stirred at 50 ° C for 2 hours. Dilute hydrochloric acid and aqueous sodium dihydrogen phosphate were added to the reaction solution, and acetonitrile was distilled off. The residue was diluted with ethyl acetate and extracted with aqueous sodium dihydrogen phosphate. The resulting aqueous layer was made alkaline with aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (10.2 g, yield 90%).

_{Ή NMR (CDC1 3, 400 MHz} ) §7.44 (d, 1 H, J = 1.9 Hz), 7.37 (d, 1 H, J = 8.2 H z), 7.16 (dd, 1 H, J = 8.2, 1.9 Hz ), 3.43 (s, 2 H), 2.89 (brt., 4 H, J = 4.9 Hz), 2.35-2.45 (br., 4 H).

Reference Example 7

Synthesis of l- [4- (trifluoromethyl) benzyl] pidazine

While stirring a suspension of anhydrous piperazine (91.3 g, 1.06 mmol) and potassium carbonate (27.7 g, 200 mmol) in acetonitrile (700 ml) at 60 ° C, 4- (trifluoromethyl) benzyl bromide was stirred. A solution of (45.8 g, 192 mmol) in acetonitrile (80 ml) was added dropwise over 1 hour. After further stirring at 60 ° C for 4 hours, the solvent was distilled off under reduced pressure, and water was added to the obtained residue. In addition, it was extracted with black-mouthed form. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (chloroform-form → chloroform: methanol: triethylamine = 20: 1: 1). The title compound (43.5 g, 92.7%) was obtained as a pale yellow oil.

¾ thigh _{(CDC1 3, 300 MHz) 8} 7.57 (d, 2 H, J = 8.0 Hz), 7.45 (d, 2 H, J = 8.0 Hz), 3.53 (s, 2 H), 2.89 (t, 4 H , J = 4.9 Hz), 2.42 (t, 4 H, J = 4.9 Hz). Similarly to Reference Example 7, the following compounds of Reference Examples 8 to 11 were synthesized.

Reference Example 8

Synthesis of 1- (4-chlorobenzyl) pidazine

_{¾ NMR (CDC1 3, 300 MHz} ) δ 7.32 - 7.24 (m, 4 H), 3.45 (s, 2 H), 2.88 (t, 4 H, J = 4.9 Hz), 2.40 (t, 4 H, J = 4.9 Hz).

Reference Example 9

 Synthesis of 1- (3,4-dimethylbenzyl) piperazine

_{Ή NMR (CDC1 3, 300 MHz} ) δ 7.09- 7.02 (m, 3 H), 3.43 (s, 2 H), 2.90 - 2.84 (m, 4 H), 2.40 (s, 3 H), 2.29- 2.24 ( m, 5 H), 1.65-1.70 (m, 2 H).

Reference Example 10

Synthesis of l- [4- (trifluoromethoxy) benzyl] pirazine

¾ thigh _{(CDC1 3, 300 MHz) δ} 7.35 (d, 2 H, J = 8.3 Hz), 7.15 (d, 2 H, J = 8.3 Hz), 3.48 (s, 2 H), 2.96 (s, 1 H ), 2.89 (t, 4 H, J = 4.1 Hz), 2.41 (t, 4 H, J = 4.1 Hz).

Reference example 1 1

 1- [4- (trifluoromethyl) benzyl] -1,4-diazepan

_{'H NMR (CDC1 3, 400} MHz) 8 7.56 (d, 2 H, J = 8.1 Hz), 7.47 (d, 2 H, J = 8.0 Hz), 3.71 (s, 2 H), 2.97 (t, 2 H, J = 6.1 Hz), 2.88-2.92 (m, 2 H), 2.63-2.71 (m, 4 H), 1.74-1.82 (m, 3 H).

Example 1 Synthesis of 4- (4-trifluoromethylbenzyl) -N- (3-{[4- (4-trifluoromethylbenzyl) -tripiperazinyl] carbonyl} phenyl) -topiperazinecarboxamide

 The N- [3- (l-piperazinylcarbonyl) phenyl] -topiperazinecarboxamide (80.2 mg, 0.205 tmol) obtained in Reference Example 1 was suspended in acetonitrile (3 ml), and potassium carbonate (3 ml) was added. 175 mg, 1.27 t ol) and 4- (trifluoromethyl) benzyl bromide (279 mg, 1.17 t ol) were sequentially added, and the mixture was stirred at room temperature overnight. The reaction was terminated by adding a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-toluene (2: 1). Take the organic layer into a test tube,

The solvent was distilled off at 50 ° C under a nitrogen stream. A part of the obtained residue was separated by HPLC, and the fraction was analyzed by LC-MS to confirm that it was the desired product. The conditions for preparative and analytical procedures are as follows.

HP LC preparative conditions:

Solvent: Elution with a gradient using a mixed solvent of solution A 0.035% acetonitrile trifluoroacetate solution and solution B 0.05% aqueous trifluoroacetic acid

Gradient conditions:

 0 → 1 3 minutes Solution A 10% → 95%,

 13 → 15 minutes A solution 95% (—constant)

Column: YMC Combi Prep ^TM (75x3 Omm, S-5 μπι)

Flow velocity: 35 m1 / min

Detection: UV 220 nm, 254 nm

Uses GIL SON215 ' ^1M HPLC system

 LC-MS analysis conditions:

Solvent: Elution with a gradient using a mixed solvent of solution A 0.035% acetonitrile trifluoroacetate and solution B 0.05% aqueous trifluoroacetic acid

Gradient conditions:

 0 → 0.5 minutes A solution 10% (constant),

 0.5 → 4.2 min Solution A 10% → 99%,

4.2 → 4.4 minutes A solution 99% (constant) Column: YMC Combi S creen ™ OD S—A (50 x .6 mm, S—5 μm)

Flow rate: 3.5ml / min

Detection: UV 220 nm, 254 nm

 The following compounds were synthesized in the same manner as in Example 1.

Example 2

 4 -— (3,4-Dichlorobenzyl) —N— (3 -— [[4- (3,4-Dichlorobenzene) —1-piperazinyl] carbonyl} phenyl) —1-piperazinecarboxamide Example 3

4— (2-Naphthylmethyl) — N— (3 — {[4- (2-Naphthylmethyl) —1-piperazinyl] carbonyl} phenyl) — 1-pidazinecarboxamide

Example 4

 4 -— (3,4-difluorobenzyl) — N— (3 — {[4- (3,4-difluorobenzoyl) 1-1-piperazinyl] carbonyl} phenyl) —1-piperazinecarboxamide ,

Example 5

 4- (4-tert-butylbenzyl) — N— (3-{[4- (4-tert-butylbenzyl) — 1-piperazinyl] carbonyl} phenyl) — 1-pidazinecarboxamide 6

4- (3,4-dimethylbenzyl) —N— (3-{[4- (3,4-dimethylbenzyl) _1-piperazinyl] carbonyl} phenyl) -11-pidazinecarboxamide Example 7

 4- (4-fluorobenzyl) -1-N- (3-{[4- (4-fluorobenzyl) -1-piperazinyl] carbonyl} phenyl) — 1-pidazinecarboxamide

Example 8

4- (4-Brozen benzyl) — N— (3-{[4- (4-Brozenyl benzyl) — 1-piperazinyl] carbonyl} phenyl) 1 1-Piperazine ruboxamide Example 9

 4- (4-Bromobenzyl) —N— (3-{[4- (4-Bromobenzyl) —1-piperazinyl] carbonyl} phenyl) 1-pidazinecarboxamide

Example 10

4— [3— (1,3-benzodioxol-5-yl) propyl] —N— [3-({4-1- [3-(1,3-benzodioxol_5—yl) Propyl] — 1-piperazinyl} carbonyl) phenyl] — 1-piperazinecarboxamide

Example 1 1

 4 -— (3,4-dimethoxybenzyl) -N- (3-{[4- (3,4-dimethoxybenzyl) —1-piperazinyl] carbonyl} phenyl) —1—pidazinecarboxa K

 To a solution of N- [3- (1-piperazinylcarbonyl) phenyl] -1-piperazinecarboxamide (80 mg, 0.2 Ommo 1) obtained in Reference Example 1 in methanol (2 ml) was added 3,3 4-Dimethoxybenzaldehyde (90 mg, 0.45 mmo 1) and sodium cyanoborohydride (30 mg, 0.477 mmo 1) were added, and acetic acid (0.3 ml) was added, followed by stirring at room temperature for 5 hours. 3,4-Dimethoxybenzaldehyde (30 mg, 0.18 mmo 1), sodium cyanoborohydride (4 Omg, 0.0.64 mmo 1) and acetic acid (0.2 ml) were added to the reaction mixture, and the reaction mixture was added. Was stirred at room temperature for 66 hours. Saturated sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with a mixture of THF (0.5 ml) and toluene (1 ml). The organic layer was taken into a test tube, and the solvent was blown off by blowing a stream of nitrogen at 40 to 50 ° C. A part of the obtained residue was fractionated by HPLC, and the fraction was analyzed by LC-MS to confirm that it was the desired product. The preparative and analytical conditions are as described above.

Example 1 2

Synthesis of 4- (2-quinolylmethyl) 1N— (3 — {[4- (2-quinolylmethyl) 1-1-piperazinyl] carbonyl} phenyl) —1-piperazinecarboxamide

N- [3- (1-piperazinylcarbonyl) phenyl] obtained in Reference Example 1 To a suspension of azinecarboxamide (80 mg, 0.20 mmol) in 1,2-dichloroethane (2.5 ml), add 2-quinolinecarboxaldehyde (75 mg, 0.48 mmol) to a calo at room temperature. Stirred for 10 minutes. NaBH (OAc) ₃ (120 mg, 0.57 mmo 1) was added, and the mixture was stirred at room temperature for 3 hours. Saturated sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with a mixed solution of THF (0.5 ml), toluene (1 ml) and ethyl acetate (2 ml). The organic layers were combined and concentrated, and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate → ethyl acetate: methanol = 2: 1) to give the title compound (72 mg, yield 60%). Was.

^! H-NMR (acetone-d ₆ , 270 MHz) δ 8.27 (dd, 2Η, J = 8.6, 2.6 Hz), 8.11 (brs, 1H), 8.01-7.98 (m, 2H), 7.91 (ddd , 2 H, J = 7.9, 3.0, 1.0 Hz), 7.75-7.68 (m, 4 H), 7.63-7.51 (m, 4 H), 7.26 (t, 1 H, J = 7.6 Hz), 6.98 (dt , 1 H, J = 7.6, 1.3 Hz), 3.84 (s, 2 H), 3.83 (s, 2 H), 3.57 (t, 8 H, J = 5.0 Hz), 2.54 (t, 8 H, J = 5.0 Hz).

 The following compounds were synthesized in the same manner.

Example 13

 4-[(5-Methyl-2-Chenyl) methyl] -1-N- [3-({4-[(5-Methyl-2-Chenyl) methyl] -1-Piperazinyl} carbonyl) phenyl] — 1-piperazine Carboxamide

_{^{J H-NMR (CDC1 3,}} 270 MHz) δ 7.43 (ddd, 1 H, J = 7.6, 2.3, 1.0 Hz), 7.33 (brs, 1H), 7.29 (d, 1 H, J = 7.6 Hz), 7.00 (d, 1 H, J = 7.6 Hz), 6.68 (dd, 2

H, J = 6.0, 3.3 Hz), 6.6 (br, 1 H), 6.58 (ddd, 2 H, J = 5.0, 3.3, 1.0 Hz), 3.7 (br, 2 H), 3.67 (s, 2 H) , 3.65 (s, 2 H), 3.50 (t, 6 H, J = 5.0 Hz), 2.51

(t, 6 H, J = 5.0 Hz), 2.46 (d, 3 H, J = 3.0 Hz), 2.45 (d, 3 H, J = 3.3 Hz),

2.4 (br, 2H).

Example 14

4- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -N- (3-{[4- (2,3-dihydro-1,4-benzodioxin-6- ^ T-methyl) -1 —Piperazinyl] carbonyl} phenyl) — 1-piperazinecarboxamide

Example 15

 4- [3-(1,3-benzodioxo-1-yl 5-propyl) propyl] —N— [3- ({4- [3-(1, 3-benzodioxo-1-yl 5-propyl) propyl] ― 1 —Piperazinyl} carbonyl) phenyl] Synthesis of 1-piperazinecarboxamide

Example 15-1

 Synthesis of 3- (1,3-benzodioxol _ 5-yl) — 1-propanol

(3,4-Methylenedioxy) phenylpropionic acid (387 mg, 1.96 mmol) was dissolved in THF (lml) and stirred at 0 ° C. To this, 1N BH ₃ —THF complex salt ZTHF solution (2.5 ml, 2.5 mmol 1) was added dropwise over 5 minutes. After stirring at 0 ° C for another 30 minutes, the mixture was returned to room temperature and stirred for 1 hour. The solution was set to 0 again, methanol was added to terminate the reaction, and the solvent was distilled off. A saturated sodium bicarbonate solution was added to the residue, extracted with ethyl acetate, and washed with a saturated sodium bicarbonate solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound (341 _mg , 1.89 _mmol , 96.5%) as a white solid.

_{¾ NMR (CDC1 3, 300 MHz} ) δ 6.74 - 6.62 (m, 3 H), 3.66 (t, 2 H, J = 6 Hz), 2. 63 (t, 2 H, J = 7.3 Hz), 1.89- 1.80 (ra, 2 H).

Example 15-2

Methanesulfonic acid 3- (1,3-benzodioxol-5-yl) propyl

3- (1,3-Benzodoxyl-5-yl) -11-propanol (34 Omg, 1.89 mmol) was dissolved in THF (5 ml) and stirred at 0 ° C. To this was added triethylamine (0.79 ml, 5.7 mmo 1) and methanesulfonyl chloride (325 mg, 2.84 mmo 1) in small portions. After stirring was continued for 1 hour at 0 ° C, a saturated aqueous sodium hydrogen carbonate solution was added to terminate the reaction. The mixture was extracted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound (470 mg, 1.97 mmol, 100%) as a pale yellow oil. _{¾ NMR (CDC1 3, 300 MHz} ) δ 6.75 - 6.62 (m, 3 H), 5.93 (s, 2 H), 4.21 (t, 2 H , J = 6.4 Hz), 3.0 (s, 3 H), 2.67 (t, 2 H, J = 7.9 Hz), 2.07-1.98 (m, 2 H) Example 15-3

 4-[3— (1,3_Benzodoxyl—5T) propyl] —N— [3-({4- [3— (1,3—Benzodoxyl—5—yl) propyl ] ― 1-piperazinyl} carbonyl) phenyl] _ Synthesis of 1-piperazinecarboxamide

 N- [3- (1-Piperazinylcarbonyl) phenyl] -11-piperazinecarboxamide (52.lmg, 0.133 mmo 1) obtained in Reference Example 1 was dissolved in acetonitrile (3 m 1) and carbonated. Potassium (87.2 mg, 0.631 mmol) and the compound obtained in Example 15-2 (91.5 mg, 0.384 mmol) were sequentially added, and the mixture was stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate-toluene (2: 1). After distilling off the solvent and dissolving the residue in methanol: acetonitrile (2: 1), the title compound was fractionated from a part of the solution as HPF using the HPLC.

Example 16

4 -— (1,3-Benzodoxyl-5-ylmethyl) —N— (4-{[4- (1,3-Benzodoxyl-5-ylmethyl) 1-1-piperazinyl] carbonyl} phenyl) one Synthesis of 1-piperazinecarboxamide

Example 16-1

 4-({[4- (1,3-Benzodoxyl-5-ylmethyl) -1-1-piperazinyl] carbonyl} amino) Synthesis of benzoic acid

Dissolve triphosgene (331 mg, 1.12 mmol) in THF (1 ml), stir at 0 ° C, and add p-aminobenzoic acid (219 mg, 1.59 mmol) in THF (8 ml). ) The solution was added dropwise over 30 minutes. The mixture was stirred at 0 ° C for 1 hour, 1-pironylpyrazine (737 mg, 3.35 mmol) was added, and the mixture was returned to room temperature and stirred for 1 hour. The reaction was terminated by adding saturated aqueous sodium hydrogen carbonate, and the 7j layer was washed with ethyl acetate. Concentrated hydrochloric acid was gradually added to the 7j layer to adjust the pH to 4 to 5, and the mixture was extracted several times with ethyl acetate. This was washed with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent gives the title compound (160 mg, 0.417 mmol, 26.2%) was obtained as a white solid.

Example 16-2

 4 -— (1,3_benzodioxol-5-ylmethyl) — N— (4 — {[4- (1,3_benzodioxo-1-yl 5-ylmethyl) —1-piperazinyl] carbonyl} phenyl 1) Synthesis of 1-piperazinecarboxamide

 Example 16 The compound (160 mg, 0.417 mmol) obtained in 6-1 was dissolved in DMF (15 ml), and 1-piperonylpiperazine (110 mg, 0.501 mmol), WSC I-HC 1 (96 mg, 0.5 Ommo 1), HOBt (68 mg, 0.50 mmo 1) and triethylamine (0.14 ml, 0.83 mmol) were sequentially added and stirred for 5 hours. . The reaction was quenched by adding saturated aqueous layer water, and extracted with ethyl acetate. Toluene was added to the extracted solution in approximately equal amounts, washed with saturated aqueous layer water, and dried over anhydrous magnesium sulfate. Purification by silica gel column chromatography (ethyl acetate: methanol = 20: 1 → 10: 1) gave the title compound (93 mg, 0.16 mmo1, 38%) as a white solid.

_{¾ MR (CDC1 3, 300 MHz} ) δ 7.32 (d, 2 H, J = 8.8 Hz), 7.24 (d, 2 H, J = 8.6 Hz), 7.12 (s, 1 H), 6.84 (s, 2 H ), 6.77-6.71 (m, 4 H), 5.94 (s, 2 H), 3.70-3.42 (m, 12 H), 2.44-2.40 (m, 8 H).

Example 17

 4- [4- (Trifluoromethyl) benzyl] — N— [4-({4-—4- (Trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) phenyl] Synthesis of 1-1-pirazinecarboxamide

N- [4- (1-piperazinylcarbonyl) phenyl] -11-piperazinecarboxamide (110 mg, 0.282 mmo 1) obtained in Reference Example 2 was dissolved in DMF (6 ml). Add potassium carbonate (195 mg, 1.41 mmo1) and 4- (trifluoromethyl) benzylbromide (270 mg, 1.13 mmo1), stir at 50 ° C for 5 hours, and Stirred overnight. The reaction was terminated by adding water, and extracted with ethyl acetate. The extract was washed with saturated aqueous layer water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Leftovers The title compound (69.7 mg, 0.11 Ommo 1, 39.0) was dissolved in chloroform and purified by silica gel column chromatography (ethyl acetate: methanol = 20: 1 → 10: 1). %) Was obtained as a white solid.

'Eta testimony _{(CDC1 3, 300 MHz) δ} 7.60 - 7.57 (m, 4 H), 7.47 - 7.43 (m, 4 H), 7.37 - 7.27 (m, 4 H), 6.88 (s, 1 H), 3.58 -3.51 (m, 12 H), 2.49-2.46 (m, 8 H).

 Synthesis of 4- (4-cyclopentyl) -1-N- (4-{[4- (4-cyclobenzyl) —1-piperazinyl] carbonyl} phenyl) 1-piperazinecarboxamide

 In the same manner as in Example 17, the 4- (1- (1-)-N- [4- (1-) obtained in Reference Example 2 was replaced by 4-benzyl benzyl bromide instead of 4- (trifluoromethyl) benzyl bromide. Piperazinylcarbonyl) phenyl] 1-piperazinecarboxamide (108 mg, 0.277 mmo 1) to give the title compound as a white solid (84.4 mg, 0.149 mmo 1, 53.8%).

_{'Η NMR (CDC1 3, 300} MHz) δ 7.37 - 7.23 (m, 12 H), 6.72 (s, 1 H), 3.52 - 3.48 (m, 12 H), 2.47- 2.44 (m, 8 H).

Example 19

 4- [4- (Trifluoromethyl) benzyl] -1-N— {4-[({4-—4- (Trifluoromethyl) benzyl] —1-piperazinyl} carbonyl) amino] phenyl}-1-piperazine Synthesis of carboxamide

N- {4-([1-piperazinylcarbonyl) amino] phenyl} obtained in Reference Example 3 was replaced with 1-piperazinecarboxamide (22.7 mg, 0.056 Ommo 1) in acetonitrile (2 m 1), add potassium carbonate (48.3 mg, 0.349 mmo 1) and 4- (trifluoromethyl) benzyl bromide (72.3 mg, 0.302 mmo 1) and stir at room temperature overnight. did. The reaction was terminated by adding water, and extracted with ethyl acetate. The extract was washed with saturated aqueous layer water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. A part of the residue was dissolved in chloroform and purified by silica gel column chromatography (ethyl acetate: methanol = 20: 1 → 10: 1) to give the title compound (7. 5 mg) was obtained as a white solid.

'.Eta. thigh _{(DMS0-d 6, 300MHz)} δ 8.67 (brs, 2 Η), 8.31 (s, 2 Η), 7.95 (s, 2 Η), 7. 87 (m, 4 Η), 7.30 (s , 4Η), 4.46 (m, 8Η), 4.19 (m, 8Η), 4.04 (s, 2Η), 4.01 (s, 2Η).

Example 20

 4-(4 -Cross benzyl) — Ν— [4-({[4-(4 -Cross benzyl) 1-1 piperazinyl] carbonyl} amino) phenyl] — Synthesis of 1-piperazinecarboxamide

 In the same manner as in Example 19, synthesis was performed using the compound of Reference Example 2 (11.6 mg, 0.0286 mmo 1), and a part of the reaction product was purified by HP LC. The title compound (1.9 mg) was obtained as ditrifluoroacetate.

LC—MS analysis results

Compound Retention time (min) Molecular weight MS (m, / z) Example 2 3.6 6 6 3 5.4 6 36.2 (M + H) + Example 3 3.64 5 9 7.75 9 8.6 (M + H) + Example 4 3.3 3 2 5 6 9.6 5 7 0.3 (M + H) + Example 5 3.95 6 0 9. 8 6 1 0.4 ( (M + H) + Example 6 3.5 1 5 5 3.7.5 5 54.4 (M + H) + Example 7 3.1.8 5 3 3.6.5 5 34.5 (M + H) + Example Example 8 3.44 5 6 6.5 5 6 6.4 M +

 Example 9 3.6 1 6 5 5. 4 6 5 6.3 (M + H) + Example 1 0 3.5 5 6 7 3. 8 6 74.6 (M + H) + Example 20 3.4 7 5 8 1.5 5 8 1.5 M +

Example 1 1 3.09 6 1 7.76 18.5 (M + H) + Example 14 3.20 6 1 3.7 6 14.3 (M + H) ⁺ Example 2 1

 4 -— (1,3-Benzodoxyl-5-ylmethyl) —N— (3 — {[4- (1,3-Benzodoxyl-5-ylmethyl) —1-piperazinyl] carbonyl} phenyl) one Synthesis of 1-piperazinecarboxamide

Example 2 1 1 1

 Synthesis of methyl 3-aminobenzoate

 m-Aminobenzoic acid (1.65 g, 12.0 tmol) was dissolved in methanol (100 ml) and stirred under ice-cooling. To this solution, 5 equivalents of thionyl chloride (4.3 ml, 60 t) were added dropwise. Thereafter, the temperature was raised to room temperature, and the mixture was stirred for 2.5 hours. After the solvent was distilled off, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and dried over magnesium sulfate. The solvent was distilled off to obtain the title compound (920 mg, 6.09 mmol) as a yellow amorphous. (Yield 50.8%)

_{'H-NMR (CDC1 3,} 300 MHz) δ 7.44 - 7.41 (m, 1 H), 7.35 (t, 1 H, J = 1.9 Hz), 7 .21 (t, 1 H, J = 7.9 Hz), 6.88-6.84 (m, 1 H), 3.89 (s, 3 H), 3.64 (brs, 2 H).

Example 2 1 -2

 Synthesis of methyl 3-tert-butoxycarbonylaminobenzoate

Methyl 3-aminobenzoate (920 mg, 6.09 mmol) was dissolved in ethyl acetate (50 ml), and 2 equivalents of (Boc) ₂₀ (2.8 ml, 12 t ol) was added dropwise with stirring. After stirring for 1.5 hours, the solvent was distilled off and used for the next reaction.

Example 2 1 -3

 Synthesis of 3-t-butoxycarbonylamino benzoic acid

To a solution of the crude methyl 3-t-butoxycarbonylaminobenzoate obtained above, THF (30 ml) and methanol (30 ml), with stirring, a 1N aqueous solution of sodium dimethyl sodium hydroxide (30 ml) was added little by little. . After stirring overnight, add 5% aqueous potassium hydrogen sulfate while cooling with ice. In addition, when the solution was acidified, crystals were precipitated. The crystals were separated by filtration to obtain the title compound (1.14 g, 4.81 mmol) as a white solid. (78.9% yield)

'H-NMR (DMS0-d ₆ , 300ΜΗζ) δ 9.54 (s, 1 H), 8.14 (s, 1 H), 7.62 (d, 1 H, J = 8.6 Hz), 7.53 (d, 1 H , J = 7.7 Hz), 7.36 (t, 1 H, J = 7.9 Hz), 1.48 (s, 9 H).

 3-{{4- (1,3-Benzodoxol-1-5-methyl) -1-piperazinyl] carbonyl} Synthesis of tert-butyl phenylcarbamate

Methyl 3-t-butoxycarbonylaminobenzoate (1.07 g, 4.51 mmol) was dissolved in DMF (80 ml) and, with stirring, 1 equivalent of 1-piperonylbiperazine (6.85 g, 31.1 mmol), 1 .2 equivalents of WSCI'HCl (1.04 g, 5.41 mmol), 1.2 equivalents of HOBt (731 mg, 5.41 mmol), 1.2 equivalents of triethylamine (0.75 ml, 5.4 mmol) were added sequentially. 2.5 hours later, a saturated aqueous sodium hydrogen carbonate solution was added to terminate the reaction, and the mixture was extracted with ethyl acetate-toluene (2: 1). The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over magnesium sulfate. The solvent was distilled off to obtain the title compound (1.27 g, 2.89 ol) as a white compound. (64.1% yield) ¾- thigh _{(CDC1 3, 300 MHz) δ} 7.40 (d, 2 H), 7.03 (td, 1H J = 1.6, 7.5 Hz), 6.85 (s, 1 H), 6.74 (s, 2H), 6.51 (s, 1H), 5.95 (s, 2H), 3.76 (s, 2H), 3.44 (s, 4H), 2.49 (s, 4H), 1.52 (s, 9H) ).

Example 2 1 -5

 3-{[4- (1,3-benzodioxo-l-5-ylmethyl) -1-1-piperazinyl] carbonyl} Synthesis of aniline

 Example 2 The compound (656 mg, 1.93 tmol) obtained in 1-4 was dissolved in acetic acid (25 ml), and 5 ml of 4N salted hydrogen Z dioxane was removed with stirring and stirring. After stirring for 1 hour, the solvent was distilled off, and a saturated aqueous solution of sodium bicarbonate was added while cooling with ice to make the solution alkaline. The mixture was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, and dried over magnesium sulfate. The solvent was distilled off and azeotroped with toluene to give the title compound (442 mg, 1.30 mol) as a yellow amorphous. (Yield 67.5%)

E - thigh _{(CDC1 3, 300 MHz) 8} 7.28 - 7.12 (m, 2 H), 6.85 (s, 1 H), 6.76 - 6.68 ( Example 2 1-6 m, 4 H), 5.94 (s, 2 H), 3.74 (brs, 2 H), 3.43 (s, 4 H), 2.48 (brs, 4 H).

 4- (1,3-benzodioxo-l-5-ylmethyl) —N— (3 — {[4— (1,3-benzodioxol-5-ylmethyl) 1-1—piperazinyl] carbonyl} phenyl) Synthesis of 1-piperazinecarboxamide

 Dissolve triphosgene (230 mg, 0.755 mmol) in THF (1 ml), and stir at 0 ° C., and add a solution of the compound (239 mg, 0.704 tmol) obtained in Example 21-5 in 12 ml of THF. It was added dropwise over a period of 20 minutes. After stirring at 0 ° C for 40 minutes as it was, 1-pironylpyrazine (171 mg, 0.775 mmol) was added to the mixture, and triethylamine was further added until the mixture became basic. After returning to room temperature and stirring for 1 hour, the mixture was heated to 50 ° C. and further stirred for 1 hour. The temperature was returned to room temperature again, the reaction was terminated by adding saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. This was washed with saturated aqueous sodium hydrogen carbonate and dried over magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (ethyl acetate: methanol = 20: 1, and when the title compound eluted, ethyl acetate: methanol = 10: 1). Recrystallization was performed with ethyl acetate-hexane (10: 1), and hexane was added to the filtrate to cause reprecipitation. This was filtered off to give the title compound (193 mg, 0.330 bandol). (Yield 46.8%)

 'H-NMR (CDC1, 300 MHz) 8 7.42-7.37 (m, 2 H), 7.31-7.26 (m, 1 H), 7.04-7.01 (m, 1 H), 6.86-6.84 (m, 2 H) , 6.74 (d, 4 H, J = 5.86 Hz), 6.54 (s, 1 H), 5.95 (s, 2 H), 5.94 (s, 2 H), 3.75 (brs, 2 H), 3.51-3.43 ( m, 10 H), 2.48-2.36 (m, 8 H).

Example 22

 1 _ (1,3-benzodioxo-1-5-methyl)-4-(3-{[4-(1, 3-benzodioxo-1-5-methyl)-1-piperazinyl] carbonyl) benzoyl) Synthesis of azine

Isophthalic acid (108 mg, 0.655 mol) was dissolved in DMF (4 ml) and 2.0 equivalents of 1-piperonylbiperazine (294 mg, 1.33 mmol), 2.5 equivalents of WSCI'HCl (312 mg, 1.63 mol) ), 2.5 equivalents of HOBt (220 mg, 1.63 mmol) and 2.5 equivalents of triethylamine (0.23 ml, I.61M0I) was added sequentially. After stirring at room temperature for 3 hours, saturated aqueous sodium hydrogen carbonate was added to terminate the reaction, and the mixture was extracted with ethyl acetate-toluene (2: 1). This was washed with saturated aqueous sodium hydrogen carbonate and dried over magnesium sulfate. After evaporating the solvent, the residue was purified by column chromatography (ethyl acetate, ethyl acetate: methanol = 10: 1) to obtain the title compound (273 mg, 0.478 mmol) as a white solid. (Yield 73.6%)

_{¾- NMR (CDC1 3 300MHz) δ} 8.44 - 7.41 (m, 4 H), 6.84 (s, 2 H), 6.76 - 6.70 (m, 4 H), 5.95 (s, 4 H), 3.77 (brs, 4 H), 3.43 (s, 4H), 3.41 (brs, 4H), 2.95 (brs, 4H), 2.35 (brs, 4H).

Example 23, Example 24

N— (3 — {[4- (1,3-benzodioxo-l-5-methyl) _1-piperazinyl] carbonyl} phenyl) 1-4-1-phenyl-2-piperazinecarboxamide and N— (3— { [4- (1,3-Benzodoxyl-5-ylmethyl) — 1-piperazinyl] carbonyl} phenyl) — 4 _benzyl-1-pidazine Carboxamide

 Triphosgene (151 mg, 0.510 mol) was dissolved in THF (2 ml) and stirred under ice-cooling. A solution of the compound obtained in Example 21-5 (345 mg, 1.02 mol) in THF (10 ml) was added dropwise thereto over 30 minutes. After dropping, stirring was continued for 1 hour under ice cooling. 1-phenylbiperazine (165 mg, 1.02 mmol) [Example 23] and 1-benzylpiperazine (180 mg, 1.02 mol) [Example 24] were prepared in flasks, respectively. One portion was added and triethylamine was added until the solution was basic. Saturated aqueous sodium bicarbonate was added to each of the two reaction solutions to terminate the reaction, and extracted with ethyl acetate. These were each washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The concentrated residues were each purified as follows.

Example 23

N— (3 — {[4- (1,3-benzodioxo-1-yl 5-ylmethyl) 1-1-piperazinyl] carbonyl) phenyl) —4-1-phenyl-2—1-pyrazinecarboxamide Column chromatography (ethyl acetate : Methanol = 25: 1) Thus, the title compound (134 mg, 0.254 mmol) was obtained as a white solid.

_{'H- MR (CDC1 3, 300MHz} ) δ 7.46 (d, 1 H, J = 7.33 Hz), 7.37 (t, 1 H), 7.33 - 7 .27 (m, 3 H), 7.04 (d, 1 H , J = 7.69 Hz), 6.96-6.89 (m, 3 H), 6.84 (s, 1 H), 6.76-6.69 (m, 3 H), 5.94 (s, 2 H), 3.74 (brs, 2 H) , 3.68-3.65 (m, 4 H), 3.43 (brs, 4 H), 3.25-3.22 (m, 4 H), 2.48 (brs, 2 H), 2.37 (brs, 2 H).

 N— (3-{[4- (1,3-benzodioxole-5-ylmethyl) -1-1-piperazinyl] carbonyl} phenyl) -1-4-benzyl-1-piperazinecarboxamide column The title compound (124 mg, 0.229 mol) was obtained as a white solid by purification by chromatography (ethyl acetate: methanol = 20: 1).

_{'H-NMR (CDC1 3,} 300MHz) δ 7.43 (d, 1 H, J = 8.05 Hz), 7.35 - 7.25 (m, 7 H), 7 .01 (d, 1 H, J = 7.51 Hz), 6.84 (s, 1 H), 6.74 (d, 1 H, J-7.87 Hz), 6.71 (d, 1 H, J = 8.08 Hz), 6.59 (s, 1 H), 5.94 (s, 2 H), 3.74 (brs, 2 H), 3.54-3.42 (m, 10 H), 2.49-2.36 (m, 8 H)

Example 2 5

 4-(1,3-Benzodoxyl-5-ylmethyl) — N— [3 — ({[4- (1,3-Benzodoxyl-5-ylmethyl) 1-1-1—Piperazinyl] carbonyl} amino ) Phenyl] Synthesis of 1-piperazinecarboxamide

 Triphosgene (608 mg, 2.05 mmol) was dissolved in THF (3 ml) and stirred under ice cooling. To this was added a solution of m-phenylenediamine (222 mg, 2.05 bandol) dissolved in THF (40 ml) dropwise over 30 minutes. After the dropwise addition, stirring was continued for 1 hour while keeping the mixture under ice-cooling, and after adding topidronyl biperazine (1.35 g, 6.15 mmol), the temperature was returned to room temperature. One hour later, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. This was washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by column chromatography (form: methanol = 20: 1) to give the title compound (225 mg, 0.404 mol) as a red oil. (Yield: 19.7)

- Yuzuru _{(CDC1 3, 300MHz) δ 7.50} (s, 1 H), 7.16 (t, 1 H, J = 7.3 Hz), 7.02 (d, 2 H, J = 7.5 Hz), 6.86 (s, 2 H), 6.76 (d, 2 H, J = 7.8 Hz), 6.72 (d, 2 H, J = 7.8 Hz), 6.42 (brs, 1 H) , 6.40 (brs, 1 H), 5.95 (s, 4 H), 3.48 — 3.45 (m, 8 H), 3.44 (s, 4 H), 2.46-2.43 (m, 8 H).

Example 26

4- (1,3_Benzodioxo-l-5T) —N— {3 — [(4-Benzyl-1-l-pirazinyl) caprulbonyl] phenyl} Synthesis of 1-piperazinecylboxamide Example 26 -1

 3-({[4- (1,3-Benzodoxyl-l-5-ylmethyl) — 1-piperazinyl] carbonyl} amino) Synthesis of methyl benzoate

 Triphosgene (2.01 g, 6.78 mmol) was dissolved in THF (5 ml) and stirred under ice-cooling. A solution of the compound obtained in Example 21-1 (2.05 g, 13.6 mmol) in THF (300 ml) was added dropwise thereto over 1 hour. After dropping, stirring was continued for 1 hour under ice-cooling. Topironyl piperazine (2.24 g, 10.2 ramol) was added to the solution, and triethylamine was added until the solution became basic. . After 1.5 hours, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. This was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by column chromatography (form: methanol = 30: 1 → 20: 1) to give the title compound (3.47 g, 8.73 mmol) as a white solid. (Yield: 64.2%)

 ¾-NMR (CDCI3, 300 MHz) δ 9.07 (s, 1 H), 8.12 (s, 1 H), 7.77 (d, 1 H, J = 8.2 Hz), 7.56 (d, 1 H, J = 7.7 Hz), 7.40 (t, 1 H, J = 8.1 Hz), 7.24 (s, 1 H), 7.02-6.97 (m, 2 H), 6.07 (s, 2 H), 4.24 (brs, 4 H) , 3.84 (s, 3H), 3.33 (m, 6H)

Example 26-2

 Synthesis of 3-({[4- (1,3-benzodioxo-l-5-methyl)-1-piperazinyl] carbonyl} amino) benzoic acid

The compound (202 mg, 0.508 tmol) obtained in Example 26-1 was suspended in concentrated hydrochloric acid (15 mL) and gradually dissolved when stirred. After heating to 60 ° C and stirring for 2.5 hours, the hydrochloric acid was decompressed. The title compound (203 mg, 0.483 mmol) was obtained as a white solid by distillation and azeotropic distillation with toluene. (Yield: 95.1 »

丽_{(DMS0- d 6, 300MHz) δ} 9.00 (s, 1 H), 8.07 (s, 1 H), 7.73 (d, 1 H, J = 9 .0 Hz), 7.54 (d, 1 H, J = 7.5 Hz), 7.36 (t, 1 H, J = 7.9 Hz), 7.22 (s, 1 H), 7.05-6.92 (m, 2 H), 6.80 (s, 1 H), 6.07 (s, 2 H) , 4.24 (brs, 4 H), 3.43-3.30 (m, 6 H).

Example 26-3

 4- (1,3-benzodioxo-l-5T) 1-N— {3-((4-benzyl-1-piperazinyl) carbonyl] phenyl} —Synthesis of 1-pidazinecarboxamide In Example 26-2 The obtained compound (63.3 mg, 0.151 t ol) was dissolved in DMF (lml), and 1-benzylpiperazine (22.7 mg, 0.151 t ol), WSC I-HC1 (34.7 mg, 0.181 mmol), HOBt (24.5 t) mg, 0.181 t) and triethylamine (0.10 ml, 0.76 mmol) were added in that order, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added, extracted with ethyl acetate acetate (2: 1), and washed with saturated aqueous sodium hydrogen carbonate. After drying over anhydrous magnesium sulfate, the concentrated residue was purified by column chromatography (ethyl acetate: methanol = 10: 1) to give the title compound (14.6 mg, 27.0 μηιο1) as a white amorphous. (Yield: 17.9%)

 -丽 (CDC1.3, 300 MHz) 8 7.44 (d, 1 H, J = 8.2 Hz), 7.34-7.24 (m, 7 H), 6.99 (d, 1 H, J = 7.5 Hz), 6.86 (s , 2 H), 6.75 (s, 2 H), 5.95 (s, 2 H), 3.75 (brs, 2 H), 3.52-3.26 (m, 10 H), 2.47-2.40 (m, 8 H).

Example 27

 4 -— (1,3-benzodioxoyl-5-ylmethyl) -1-N— (4-{[4- (1,3-benzodioxo-1-lu-5-ylmethyl) 1-1-piperazinyl] carbonyl} phenyl) 1 1 Synthesis of piperazinecarboxamide

The compound (54.lmg, 0.129mmol) obtained in Example 26-2 was dissolved in 1ml of DMF, and 1-phenylpiperazine (20.9mg, 0.129mmol), WSCI-HC1 (29.7mg, 0.155 fraction 1), HOBt (20.9 mg, 0.155 t ol) and triethylamine (0.09 ml, 0.6 ramol). Then, the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added, extracted with ethyl acetate-toluene (2: 1), and washed with saturated aqueous sodium bicarbonate. After drying over anhydrous magnesium sulfate, the concentrated residue was purified by column chromatography (ethyl acetate: methanol = 10: 1) to give the title compound (22.4 mg, 42.5 mol) as a white amorphous. (Yield: 32.9%) Ή-NMR ( CDC1 3, 300 MHz) δ 7.44 - 7.42 (in, 2 H), 7.35 - 7.25 (m, 2 H), 7.09 (d, 1 H, J = 7.54 Hz) , 6.94-6.86 (m, 5 H), 6.75 (s, 2 H), 6.48 (s, 1 H), 5.95 (s, 2 H), 3.78 (m, 2 H), 3.63 (m, 2 H), 3.50-3.49 (m, 4 H), 3.45 (s, 2 H), 3.17 (m, 4 H), 2.47 (m, 4 H).

Example 28

 1— (1,3-benzodioxol—5-ylmethyl) —4 — [(1 — {[4— (1,3-benzodioxo-l-u—5-t-methyl) _1-piperazinyl] carbonyl} Synthesis of cyclobutyl) carbonyl] pidazine

 1,1-cyclobutanedicarboxylic acid (72 mg, 0.5 mmol), 1-pironinolepiperazine (264 mg, 1.2 mmol 1), WSC I hydrochloride (24 Omg, 1.25 mmol 1) and HOB After dissolving t (153 mg, 1. Ommo 1) in DMF (4 ml), the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with a mixed solvent of toluene Z-ethyl acetate (1/1) (40 ml) and washed twice with a saturated aqueous solution of potassium hydrogen carbonate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain the title compound (274 mg, 0.5 mmo 1). For the hydrochloride, dissolve this in chloroform-ether, add 4 N 1,4-dioxane solution of hydrogen chloride, evaporate the solvent, wash the residual solid with ether, filter and dry. Gave the title compound. (100% yield)

_{'H-NMR (CDC1 3,} 270 MHz) δ 6.82 (s, 2 H), 6.75 (d, 2 H, J = 7.9 Hz), 6.70 (d, 2 H, J = 7.9 Hz), 5.94 (s, 4H), 3.55-3.68 (m, 4H), 3.39 (s, 4H), 3.30-3.40 (m, 4H), 2.20-2.80 (m, 12H), 1.82-1.93 (m, 2H ).

 Similarly, the compounds of Example 29 to Example 44 below were synthesized.

Example 29 1— (1,3-benzodioxoyl-5-ylmethyl) — 4- [((1 R *, 2 R *) —2— {[4— (1,3 _benzodioxol—5-ylmethyl ) — 1-piperazinyl] carbonyl] cyclopentyl) carbonyl] piperazine

_{Ή- MR (CDC1 3, 270 MHz} ) δ 6.84 (s, 2 H), 6.75 (d, 2 H, J = 7.9Hz), 6.72 (d, 2 H, J = 7.9Hz), 5.94 (s, 4 H) 3.50-3.68 (m, 10 H), 3.41 (s, 4 H), 2.30-2.50 (m, 8 H), 2.00-2.10 (m, 2 H), 1.62-1.82 (m, 4 H).

Example 30

 1— (1,3_Benzodoxyl-5-ylmethyl) —4 _ [((1R *, 2S *)-2-{[4- (1,3_Benzodoxyl-5-ylmethyl) 1 1-piperazinyl] carbonyl] cyclohexyl) carbonyl] piperazine

_{• H-NMR (CDC1 3,} 270 MHz) δ 6.85 (s, 2 H), 6.73 (s, 4 H), 5.94 (s, 4 H), 3.62 one 3.90 (m, 2 H), 3.35- 3.55 ( m, 4 H), 3.41 (s, 4 H), 2.78-2.85 (m, 2 H), 2.20-2.62 (m, 8 H), 1.86-1.90 (m, 2 H), 1.48-1.70 (m, 4 H), 1.32-1.48 (m, 2 H).

Example 3 1

 1— (1,3—Benzodoxol—5-ylmethyl) —4 — {(2E) —4-1- [4- (1,3_benzodioxol-1-5-methyl) 1-1-piperazinyl] — 4—Kiso 1—Butenyl} Pirazine

_{Ή-NMR (CDC1 3, 270} MHz) δ 7.38 (s, 2 H), 6.84 (s, 2 H), 6.74 (s, 4 H), 5.95 (s, 4 H), 3.65 - 3.76 (m, 4 H), 3.53-3.64 (m, 4H), 3.42 (s, 4H), 2.31-2.54 (m, 8H).

Example 32

 1— (1,3—Benzodoxyl—5-ylmethyl) —4 — [((1R *, 2R *) 1 2 — {[4— (1,3_Benzodoxyl-5-ylmethyl) ) — 1-piperazinyl] carbonyl] cyclobutyl) carbonyl] piperazine

_{'H-NMR (CDC1 3,} 270 MHz) δ 6.84 (s, 2 H), 6.73 (s, 4 H), 5.94 (s, 4 H), 3.72 - 3.77 (m, 2 H), 3.57 - 3.60 ( m, 4 H), 3.43-3.47 (m, 4 H), 3.40 (s, 4 H), 2.30-2.48 (m, 4 H), 2.09-2.12 (m, 4 H).

Example 33

 1- (1,3-benzodioxoyl-5-ylmethyl) — 4-— ((1-{[4 -— (1,3-benzodioxo-1-yl 5-ylmethyl) —1-piperazinyl] carbonyl} cyclopropyl ) Carbonyl] piperazine

¾- Anonymous _{(CDC1 3, 270 MHz) δ} 6.84 (s, 2 H), 6.75 (d, 2 H, J - 7.9 Hz), 6.71 (d, 2 H, J = 7.9 Hz), 5.94 (s, 4 H), 3.66 (br, 4 H), 3.57 (br, 4 H), 3.41 (s, 4 H), 2.35 (br, 8 H), 1.25 (br, 4 H).

Example 34

 1— (1,3-benzodioxol—5-ylmethyl) —4— {5— [4 -— (1,3—benzodioxo-l-5-ylmethyl) —1-piperazinyl] _3,3-dimethyl— 5-oxopentanoyl} piperazine

_{'H-NMR (CDC1 3,} 270 MHz) 8 6.84 (s, 2 H), 6.75 (d, 2 H, J = 7.9 Hz) 6.71 (d,

2 H, J = 7.9 Hz), 5.94 (s, 4 H), 3.59 (brt, 4 H, J-5.0 Hz), 3.52 (brt, 4 H, J = 5.0 Hz), 3.41 (s, 4 H) , 2.51 (s, 4 H), 2.36-2.39 (m, 8 H), 1.15 (s,

6 H).

Example 35

 1— (1,3—Benzodoxyl—5 f-methyl) 1 4— (4-{[4— (1,

3-benzodioxo-5-ylmethyl) -1-piperazinyl] carbonyl] benzyl) pidazine

 ¾—thigh (CDC1- ,, 270 MHz) δ 7.42 (s, 4 H), 6.84 (s, 2 H), 6.75 (d, 2 H, J = 7.9 Hz), 6.72 (d, 2 H, J = 7.9 Hz), 5.95 (s, 4H), 3.70-3.88 (br, 4H), 3.4

4 (s, 4 H), 3.32-3.44 (br, 4 H), 2.45-2.58 (br, 4 H), 2.30-2.45 (br, 4 H).

Example 36

1— (1,3-Benzodoxyl-5-ylmethyl) — 4 — [(4—1 [[4— (1,3—Benzodoxyl-l-5-permethyl) —1—piperazinyl] carbonyl} Chlohexyl) carbonyl] piperazine

_{Ή-NMR (CDC1 3, 270} MHz) δ 6.85 (s, 2 H), 6.75 (d, 2 H, J = 7.9 Hz), 6.72 (d, 2 H, J = 7.9 Hz), 5.94 (s, 4 H), 3.55-3.65 (br, 4 H), 3.41 (s, 4 H), 3.4

0-3.55 (br, 4 H), 2.55-2.65 (br, 2 H), 2.39 (brt, 8 H, J = 5.0 Hz), 1.95-2.08 (m, 4 H), 1.50-1.65 (m, 4 H).

Example 37

 1— (1,3-Benzodoxyl-5-ylmethyl) —4— [(2-{2- [4-1 (1,3-Benzodoxyl-l-u—5— ^ Tlmethyl) 1-1-piperazinyl] -1-2- Cisethyl} phenyl) acetyl] piperazine

_{Ή-NMR (CDC1 3, 270} MHz) δ 7.20 - 7.28 (m, 2 H), 7.10 - 7.18 (m, 2 H), 6.83 (s, 2 H) 6.69 - 6.76 (m, 4 H), 5.94 ( s, 4 H), 5.94 (s, 4 H), 3.69 (s, 4 H), 3.64 (brt, 4 H, J = 4.6 Hz), 3.47 (brt, 4 H, J = 4.6 Hz), 3.40 ( s, 4 H), 2.4 1 (brt, 4 H, J = 4.6 Hz), 2.33 (brt, 4 H, J = 4.6 Hz).

Example 38

 1— (1,3—Benzodoxyl — 5-permethyl) —4— [(2 E) —3— (4 — {(1E) —1 ——— 4- (1,3—Benzodoxyl 5 T 1-piperazinyl] 13-oxo- 1-propenyl} phenyl) 1- 2-propynyl] piperazine

- thigh _{(CDC1 3, 270 MHz) 8} 7.64 (d, 2 H, J = 15.5 Hz), 7.50 (s, 4 H), 6.86 (s, 2 H), 6.88 (d, 2 H, J = 15.5 Hz ), 6.75 (s, 4 H), 3.70-3.80 (br, 4 H), 3.60-3.70 (br, 4 H), 3.45 (s, 4 H), 2.47 (brt, 8 H, J = 5 Hz).

Example 39

 1- (1,3-benzodioxo-l-5-ylmethyl) 1-4-1 [3- (3- (3- {3- [4-(1,3_benzodioxo-l-uyl 5-ylmethyl) 1-1-piperazinyl] —3— Oxopropyl} phenyl) propanoyl] pidazine

_{Ή-NMR (CDC1 3, 270} MHz) δ 7.19 (d, 1 H, J = 7.3 Hz), 7.03 - 7.06 (m, 3 H), 6.83 (s, 2 H), 6.75 (d, 2 H, J = 7.9 Hz), 6.71 (d, 2 H, J = 7.9 Hz), 5.94 (s , 4H), 3.62 (brt, 4H, J = 5.0 Hz), 3.39 (s, 4H), 3.38 (brt, 4H, J = 5.0 Hz), 2.93 (dd, 4H, J = 7.3, 8.3 Hz), 2.59 (dd, 4 H, J = 7.3, 8.3 Hz), 2.37 (brt, 4 H, J = 5.0 Hz), 2.29 (brt, 4 H, J = 5.0 Hz).

Example 40

 1- (1,3-benzodioxo-l-5T-methyl) —4— [3 -— (4- {3— [4 -— (1,3-benzodioxo-l—5-ylmethyl) —1-piperazinyl] 1— Oxopropyl} phenyl) propanoyl] pidazine

'H-NMR (DMS0-d ₆₎ 270 MHz) δ 11.20-11.00 (br, 2 H), 7.21 (s, 2 H), 7.13 (s, 4 H), 7.00 (s, 4 H), 6.07 ( s, 4H), 4.40-4.51 (m, 2H), 4.21 (br, 4H), 4.00-4.11 (m, 2H), 3.20-3.50 (m, 8H), 2.55-3.11 (m, 12 H).

Example 4 1

 1— (1,3-Benzodoxyl—5T-methyl) —4— [(3— {2— [4— (1,3—Benzodoxyl—5—ylmethyl) —1-Piperazinyl] —2—o Cisethyl} phenyl) acetyl] piperazine

_{Ή-NMR (CDC1 3, 270} MHz) δ 7.22 - 7.28 (m, 1 H), 7.09 - 7.11 (m, 3 H), 6.81 (s, 2 H), 6.71 (d, 2 H, J = 7.9 Hz ), 6.70 (d, 2 H, J = 7.9 Hz), 5.92 (s, 4 H), 3.69 (s, 4 H), 3.63 (brt, 4 H, J = 5.0 Hz), 3.41 (brt, 4 H , J = 5.0 Hz), 3.36 (s, 4 H), 2.37 (brt, 4 H, J = 5.0 Hz), 2.24 (brt, 4 H, J = 5.0 Hz).

 1— (1,3—Benzodoxyl — 5-permethyl) —4-1 (4- {1,2,3- [1,3-Benzodoxyl-5-ylmethyl) -1-1-piperazinyl] —1,2-oxoethyl } Benzyl) piperazine

-丽_{(CDC1 3, 270 MHz) δ} 7.36 (d, 2 H, J = 8.3 Hz), 7.26 (d, 2 H, J = 8.3 Hz), 6.85 (s, 1 H), 6.82 (s, 1 H ), 6.77-6.68 (m, 4 H), 5.94 (s, 2 H), 5.93 (s, 2 H), 3.70-3.88 (br, 2 H), 3.73 (s, 2 H), 3.64 (brt, 2 H, J = 5.0 Hz), 3.38 — 3.44 (m, 8 H), 2.25-2.58 (m, 8 H).

Example 43 1 _ [4-1 (2-oxo-2-{4 _ [4-(trifluoromethyl) benzyl] _ 1-piperazinyl} ethyl) benzoyl]-4-[4-(trifluoromethyl) benzyl ] Pirazine

_{Ή-NMR (CDC1 3, 270} MHz) 8 7.54 - 7.59 (m, 4 H), 7.35- 7.48 (m, 6 H), 7.25 - 7.28 (m, 2 H), 3.61 (brt, 4 H, J = 5.0 Hz), 3.47 (s, 4 H), 3.45 (brt, 4 H, J = 5.0 Hz), 2.37-2.41 (m, 8 H), 2.30 (brt, 4 H, J = 7.9 Hz), 1.55- 1.70 (m, 4 H), 1.30-1.43 (m, 4 H).

Example 44

 1-[4-(Trifluoromethyl) benzyl] —4— {[1 — ({4- [4- (trifluoromethyl) benzyl] — 1-piperazinyl} carbonyl) cyclopropyl] force rubonyl} piperazine

¾- thigh _{(CDC1 3, 270 MHz) δ} 7.59 (d, 4 H, J = 7.9 Hz), 7,44 (d, 4 H, J = 7.9H z), 3.65 one 3.75 (br, 4 H), 3.55 (s, 4 H), 3.55-3.65 (br, 4 H), 2.30-2.45 (br, 8 H), 1.26 (br, 4 H).

Example 45

 4- [4- (Trifluoromethyl) benzyl] —N— {5-(({4_ [4- (trifluoromethyl) benzyl] —1-piperazinyl} carbonyl) amino] pentyl} -1-piperazinecarboxamide Synthesis

To a solution of triphosgene (70 mg, 0.236 mmo 1) in THF (1 m 1), p-Trifluoromethylbenzylpiperazine hydrochloride (16 Omg, 0.52 mmo 1), diisobutyl A suspension of ethylamine (135 mg, 1.04 mmol) and THF (3 ml) was added at -70-160 ° C over 10 minutes. The reaction solution was heated to room temperature over 1 hour under stirring. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue were added pentamethylenediamine (22 mg, 0.215 mmol), triethylamine (60 mg, 0.593 mmol) and THF (lml). After stirring at room temperature for 2 hours, pentamethylenediamine (10 mg, 0.098 mmo 1), and the mixture was further heated and stirred at 40 ° C. for 10 minutes. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (black-mouthed form → black-mouthed form: methanol = 20: 1 → 5: 1) to obtain the title compound. The dihydrochloride was obtained by adding a dioxane hydrochloride solution thereto and distilling off the solvent under reduced pressure. (Yield 42%)

2-hydrochloride:

_{Ή-NMR (DMS0- d 6,} 270 MHz) δ 11.2 (br, 2 H), 8,32 (s, 8 H), 6.75 (brs, 2 H), 4.42 (s, 4 H), 4.05 - 4.01 (m, 4H), 3.35-2.86 (m, 16H), 1.45-1.20 (m, 6H).

 Similarly, the following compounds of Example 46 to Example 48 were synthesized.

Example 46

 4- [4- (trifluoromethyl) benzyl] {4-(({4- [4- (trifluoromethyl) benzyl] -11-piperazinyl} carbonyl) amino] butyl} -1-piperazinecarboxamide

_{'H-NMR (CDC1 3,} 270 MHz) δ 7.58 (d, 4 H, J = 8.3 Hz), 7.45 (d, 4 H, J = 8.3 Hz), 4.79 (br, 2 H), 3.56 (s, 4H), 3.37 (t, 8H, J = 5.0 Hz), 3.28-3.24 (m, 4H), 2.42 (t, 8H, J = 5.0 Hz), 1.57-1.52 (m, 4H).

Example 47

4- [1- (trifluoromethyl) benzyl] —N— {3— [({4- [4- (trifluoromethyl) benzyl] -11-piperazinyl} carbonyl) amino] propyl}-1-piperazinecarboxamide

- thigh _{(CDC1 3, 270 MHz) δ} 7.58 (d, 4 H, J = 8.3 Hz), 7.45 (d, 4 H, J = 8.3 Hz), 5.4 (br, 2 H), 3.56 (s, 4 H ), 3.40 (t, 8 H, J = 5.0 Hz), 3.35-3.28 (m, 4 H), 2.43 (t, 8 H, J = 5.0 Hz), 1.65-1.60 (m, 4 H).

Example 48

4-1 [4-1 (trifluoromethyl) benzyl] — N— {2 _ [({4- [4- (tri Fluoromethyl) benzyl] 1-piperazinyl} carbonyl) amino] ethyl}-1-piperazine

_{Ή-NMR (CDC1 3, 270} MHz) δ 7.58 (d, 4 H, J = 7.9 Hz), 7.45 (d, 4 H, J = 7.9 Hz), 5.56 (br, 2 H), 3.56 (s, 4 H), 3.37 (t, 8 H, J = 5.0 Hz), 3.36-3.33 (m, 4 H), 2.42 (t, 8 H, J-5.0 Hz).

Example 49

 Synthesis of 1,3-bis (2-oxo-1-2- {4- [4- (trifluoromethyl) benzyl]-1-piperazinyl} ethyl) — 2-imidazolidinone

Example 49-1

 [3- (2-tert-butoxy 2-oxoethyl) _2-oxo-11-imidazolidinyl] Synthesis of tert-butyl acetate

Ethylene urea (43 Omg, 5.Ommo 1) is dissolved in THF (24 ml), 60% sodium hydride (440 mg, 11 mmo 1) is added little by little, and the mixture is heated at 40-50 ° C for 30 minutes. Stirred. A solution of bromoacetic acid t-butyl ester (2.05 g) in THF (3 ml) was added dropwise, and the mixture was stirred at 60 ° C for 3 hours. After adding water (50 ml), the mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with saturated saline. It was dried with anhydrous magnesium sulfate. The solvent was distilled off, and 1.1 g of the crude product was purified by silica gel column chromatography (developing solvent: hexane ethyl acetate = 31 to 11) to obtain the title compound (510 _mg , 1.6 mmo 1). . (Yield 32.4%)

_{- NMR (CDC1 3, 270 MHz} ) δ 3.89 (s, 4 H), 3.50 (s, 4 H), 1.46 (s, 18 H).

Example 49-2

 Synthesis of 3-(Carboxymethyl) -1-2oxo- 1-imidazolidinyl] acetic acid

The compound (50 Omg, 1.6 mmo 1) obtained in Example 49-1 was dissolved in 1,4-dioxane (20 ml), and then dissolved in 4 N hydrogen chloride / 1,4-dioxane (20 ml). And acetic acid (20 ml) were added, and the mixture was stirred at 40 ° C for 7 hours. After the solvent was distilled off, the remaining acetic acid was azeotropically dried with toluene. The title compound (3'23 mg, 1.6 mmol) was obtained. (100% yield) ¾-NMR (DMSO-dg, 270 MHz) δ 12.67 (br, 2 H), 3.81 (s, 4 H), 3.38 (s, 4 H).

 Synthesis of 1,3-bis (2-oxo-1-2- {4- (4- (trifluoromethyl) benzyl)-1-piperazinyl} ethyl) -1-2-imidazolidinone

Compound obtained in Example 49-2 (101 mg, 0.5 mmol), N- (4-trifluorobenzyl) pidazine (293 mg, 1.2 mmol), WSC I hydrochloride (240 mg , 1.25 mmo 1) and HOB t (153 mg, 1. Ommo 1) were dissolved in DMF (4 ml) and stirred at room temperature for 48 hours. The reaction solution was diluted with a mixed solvent (40 ml) of toluene Z-ethyl acetate (1/1) and washed twice with a saturated aqueous solution of hydrogencarbonate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (developing solvent: chloroform / methanol = 50Z1 to 30/1) to obtain the title compound (283 mg, 0.43 mMol). For the dihydrochloride, dissolve the title compound in chloroform-ether, add 4N hydrogen chloride Zl, 4-dioxane solution, evaporate the solvent, wash the residual solid with ether, filter, and dry. I got it. (Yield: 80.0%)

¾- thigh _{(CDC1 3, 270 MHz) δ} 7.58 (d, 2 H, J = 7.9 Hz), 7.44 (d, 2 H, J = 7.9 Hz), 4.02 (s, 4 H), 3.61 (brt, 4 H, J = 5.0 Hz), 3.56 (s, 4H), 3.52 (s, 4H), 3.48 (brt, 4H, J = 5.0 Hz, 2.50-2.40 (m, 8H).

In the same manner as in Example 49, the compounds of Examples 50 to 55 were synthesized.

Example 50

 Synthesis of 1,3-bis (2-oxo-2- {4- [4- (trifluoromethoxy) benzyl] -1-piperazinyl} ethyl) -2-imidazolidinone

_{¾ NMR (CDC1 3, 300 MHz} ) δ 7.34 (d, 4 H, J = 8.4 Hz), 7.16 (d, 4 H, J = 8.4 Hz), 4,02 (s, 4 H), 3.60 (t, 4 H, J = 4.8 Hz), 3.52 (s, 4 H), 3.50 (s, 4 H), 3.47 (t, 4 H, J = 4.8 Hz), 2.39-2.46 (m, 8 H).

Example 5 1

1,3-bis {2- [4- (4-ethylbenzyl) -1-piperazinyl] -2-oxoethyl}-2-imidazo Rizinon

'Eta Anonymous _{(CDC1 3, 300 MHz) δ} 7.21 (d, 4 H, J = 8.1 Hz), 7.15 (d, 4 H, J = 8.1 Hz), 4.01 (s, 4 H), 3.59 (t, 4 H, J = 4.9 Hz), 3.51 (s, 4 H), 3.48 (s, 4 H),

3.46 (t, 4 H, J = 4.9 Hz), 2.64 (q, 4 H, J = 7.6 Hz), 2.38-2.46 (m, 8 H), 1.23 (t, 6 H, J = 7.6 Hz).

Example 52

 1,3-bis {2- [4- (3,4-dimethylbenzyl) -1-piperazinyl] -2-oxoethyl} -2-imidazolidinone

_{¾ NMR (CDC1 3, 300 MHz} ) δ 7.09 - 7.00 (m, 6 H), 4.00 (s, 4 H), 3.59 (t, 4 H, J = 4.8 Hz), 3.51 (s, 4 H), 3.45 (t, 4 H, J = 4.8 Hz), 3.45 (s, 4 H), 2.38-2.46 (m, 8 H), 2.25 (s, 6 H), 2.24 (s, 6 H).

Example 5 3

 1,3-bis {2- [4- (4-methoxybenzyl) -1-piperazinyl] -2-oxoethyl} _2-imidazolidinone

_{lti NMR (CDC1 3, 300 MHz} ) δ 7.21 (d, 4 H, J = 8.6 Hz), 6.85 (d, 4 H, J = 8.6 Hz), 4.01 (s, 4 H), 3.80 (s, 6 H ), 3.59 (t, 4 H, J = 4.8 Hz), 3.51 (s, 4 H),

3.47-3.43 (m, 8 H), 2.38-2.46 (m, 8 H).

Example 54

 1,3-bis {2- [4_ (1,3-benzodioxoyl-5-ylmethyl) -1-pyrazinyl] -2-oxoethyl} -2-imidazolidinone

_{¾ NMR (CDC1 3, 300 MHz} ) δ 6.84 (s, 2 H), 6.70 - 6.77 (m, 4 H), 5.94 (s, 4 H), 4.01 (s, 4 H), 3.59 (t, 4 H , J = 4.8 Hz), 3.52 (s, 4 H), 3.46 (t, 4 H, J = 4.8 Hz), 3.42 (s, 4 H), 2.35-2.44 (m, 8 H).

Example 55

Synthesis of 1,3-bis {2- [4- (4-chlorobenzyl) -1-piperazinyl] -2-oxoethyl} -2-imidazolidinone

_{'H NMR (CDC1 3, 400} MHz) δ 7.30 - 7.24 (ra, 8 H), 4.01 (s, 4 H), 3.64 - 3.59 (m, 4H), 3.52 (s, 4H), 3.49-3.45 (m, 4H), 3.47 (s, 4H), 2.44-2.39 (m, 8H).

Example 56

 1- {2- [4- (1,3-benzodioxoyl-5-ylmethyl) -topidrazinyl] -2-oxoethyl}-3- (2-oxo-2- {4-[4- (trifur Synthesis of 1-piperazinyl} ethyl) -2-imidazolidinone

Example 56-1

 Synthesis of methyl [2-oxo-3- (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl) -reimidazolidinyl] acetate

 [3- (Carboxymethyl) -2-oxo-1-imidazolidinyl] acetic acid (105 mg, 0.519 iranol) was suspended in dimethylene chloride (10 ml), and 1- [4- (trifluoromethyl) benzyl] piぺ Add azine (127 mg, 0.519 mmol), triethylamine (220 µl, 1.6 t ol), N, N-bis (2-oxo-3-oxazolidinyl) phosphinic chloride (132 mg, 0.519 ol) and add 3 Stirred at room temperature for hours. Thionyl chloride (190 μ1, 2.6 mmol) and methanol (10 ml) were added to the solution, and the mixture was further stirred at room temperature for 3 hours. After terminating the reaction with a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with chloroform. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1 → chloroform: methanol = 10: 1) to give the title compound (144 mg, 62.7%) as a yellow oil. Was.

_{¾ NMR (CDC1 3, 300 MHz} ) 8 7.59 (d, 2 H, J = 8.1 Hz), 7.47 (d, 2 H, J = 8.1 Hz), 4.03 (s, 2 H), 4.00 (s, 2 H ), 3.73 (s, 3 H), 3.68-3.60 (m, 2 H), 3.61

(s, 2H), 3.55-3.48 (m, 2H), 3.52 (s, 4H), 2.52-2.45 (m, 4H).

Example 56-2

l- {2- [4- (1,3-benzodioxoyl-5-ylmethyl) -topidrazinyl] -2-oxoethyl}-3- (2-oxo-2- {4- [4- ( Synthesis of Oromethyl) benzyl] -Topiperazinyl} ethyl) -2-Imidazolidinone

[2-oxo-3- (2-oxo-2-4- [4- (trifluoromethyl) benzyl] -topiperazinyl} (Ethyl) -triimidazolidinyl] acetate (53.0 mg, 0.120 mmol) was dissolved in THF (3 ml), sodium methoxide (25.9 mg, 0.479 mmol) was added, and the mixture was stirred at 60 ° C for 1.5 hours. After allowing to cool to room temperature, 1-piperonylbiperazine (29.1 mg, 0.132 mmol) and N, N-bis (2-oxo-3-oxazolidinyl) phosphinic chloride (33.6 mg, 0.132 ramol) were added. Stirred at room temperature for hours. The reaction was terminated by adding water, and the mixture was extracted with black-mouthed form. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1 → chloroform: methanol = 10: 1) to give the title compound (52.7 mg, 69.7%).

_{¾ NMR (CDC1 3, 300 MHz} ) δ 7.58 (d, 2 H, J = 8.1 Hz), 7.44 (d, 2 H, J = 8.1 Hz), 6.84 (s, 1 H), 6.74 (s, 2 H ), 5.94 (s, 2 H), 4.02 (s, 2 H), 4.01 (s, 2 H), 3.61-3.56 (m, 4 H), 3.52 (s, 4 H), 3.50-3.44 (m, 4H), 3.42 (s, 4H), 2.44-2.41 (m, 8H).

In the same manner as in Example 56, the compounds of Example 57 and Example 58 were synthesized.

Example 57

Tri (2-oxo-2- {4- [4- (trifluoromethoxy) benzyl] -1-piperazinyl} ethyl) -3- (2-oxo-2- {4- [4- (trifluoromethyl ) Benzyl] -topiperazinyl} ethyl) -2-y Synthesis of midazolidinone

_{¾ NMR (CDC1 3, 300 MHz} ) δ 7.58 (d, 2 H, J = 8.1 Hz), 7.44 (d, 2 H, J = 8.1 Hz), 7.34 (d, 2 H, J = 8.2 Hz), 7.16 (d, 2 H, J = 8.2 Hz), 4.02 (s, 4 H), 3.65-3.55 (m, 4 H), 3.56 (s, 2 H), 3.52 (s, 4 H), 3.50 ( s, 2 H), 3.55-3.45 (in, 4 H), 2.46-2.43 (m, 8 H).

Example 58

l- {2- [4- (4-Methoxybenzyl) -topidrazinyl] -2-oxoethyl} -3- (2-oxo-2-{4- [4- (trifluoromethyl) benzyl] -Synthesis of 1-piperazinyl} ethyl) -2-imidazolidinone

H NMR (CDCL, 300 MHz) δ 7.58 (d, 2 H, J = 8.2 Hz), 7.44 (d, 2 H, J = 8.2 Hz), 7.21 (d, 2 H, J = 8.6 Hz), 6.85 (d, 2 H, J = 8.6 Hz), 4.02 (s, 2 H), 4.01 (s, 2 H), 3.80 (s , 3H), 3.62-3.55 (m, 4H), 3.52 (s, 4H), 3.50-3.42 (m, 4H), 3.45 (s, 4H), 2.46-2.39 (m, 8H ).

Example 59

 Synthesis of 1,3-bis (3-oxo-3- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} propyl) -2-imidazolidinone

Example 59-1

 Synthesis of tert-butyl 3- [3- (3-tert-butoxy-3-oxopropyl) -2-oxo-trimidazolidinyl] propanoate

 Ethylene urea (1.20 g, 13.9 mmol) was dissolved in DMF (200 ml), potassium carbonate (3.85 g, 27.9 mmol), tert-butyl acrylate (5, 34 g, 41.7 mmol), triethyl chloride benzylammonium (633 mg, 2.78 mmol) were added sequentially, and the mixture was stirred at 80 ° C for 7.5 hours. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate-toluene (3: 1). The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound (3.07 g, 64.5%) as a colorless oil.

_{¾ NMR (CDC1 3, 400 MHz} ) 5 3.45 (t, 4 H, J = 6.8 Hz), 3.31 (s, 4 H), 2.45 (t, 4 H, J = 6.8 Hz), 1.44 (s, 18 H ).

Example 59-2

 Synthesis of 3- [3- (2-carboxyethyl) -2-oxo-1-imidazolidinyl] propanoic acid

 Dissolve tert-butyl 3- [3- (3-tert-butoxy-3-oxopropyl) _2-oxo-trimidazolidinyl] propanoate (2.82 g, 8.23 band01) in acetic acid (10 ml) and add 4N hydrochloric acid. —Dioxane (10 ml) was added, and the mixture was stirred at 40 ° C. for 3 hours. The solvent was distilled off under reduced pressure and azeotroped with toluene to obtain the title compound (1.89 g, quant.) As a white powder.

_{* H NMR (DMS0- d 6,} 400 MHz) δ 12.23 (s, 2 H), 3.27 (t, 4 H, J = 7.2 Hz), 3.23

(s, 4H), 2.39 (t, 4H, J = 7.2 Hz).

Example 59-3 Synthesis of 1,3-bis (3-oxo-3- {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} propyl) -2-imidazolidinone

Dissolve 3- [3- (2-carboxyethyl) -2-oxo-1-imidazolidinyl] propanoic acid (820 mg, 3.56 olol) in DMF (50 ml) and add tri [4- (trifluoromethyl) ) Benzyl] piperazine (1.83 g, 7.48 t ol), WSC (1.43 g, 7.48 mmol), HOBt (1.01 g, 7.48 t ol) were sequentially added, and the mixture was stirred at 40 ° C for 5 hours. After the reaction solution was cooled to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added to terminate the reaction. After extraction with ethyl acetate-toluene (3: 1), the organic layer was washed with saturated aqueous sodium hydrogen carbonate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The title compound (2.16 g, 88.9%) was obtained as a colorless amorphous by purifying by silica gel column chromatography (form: methanol = 10: 1). Ή thigh _{(CDC1 3, 400 MHz) δ} 7.58 (d, 4 H, J = 8.1 Hz), 7.44 (d, 4 H, J = 8.1 Hz), 3.62 (t, 4 H, J = 4.8 Hz), 3.56 (s, 4 H), 3.49 (t, 4 H, J = 4.8 Hz), 3.46 (t, 4 H, J = 6.8 Hz), 3.38 (s, 4 H), 2.57 (t, 4 H, J = 6.8 Hz), 2.42 (quint, 8 H, J = 4.8 Hz).

Compounds of Examples 60 to 65 were synthesized in the same manner as in Example 59.

Example 60

 Synthesis of 1,3-bis {3- [4- (4-cyclobenzyl) -1-piperazinyl] -3-oxopropyl} -2-imidazolidinone

_{Ή NMR (CDC1 3, 400 MHz} ) 5 7.31 - 7.25 (m, 8 H), 3.62 (brs, 4 H), 3.47 - 3.5 5 (m, 8 H), 3.46 (t, 4 H, J = 6.8 Hz ), 3.37 (s, 4 H), 2.57 (t, 4 H, J = 6.8 Hz), 2.38-2.48 (m, 8 H).

Example 6 1

 Synthesis of 1,3-bis (3-oxo-3- {4- [4- (trifluoromethoxy) benzyl] -1-piperazinyl} pulpyl) -2-imidazolidinone

Ή thigh _{(CDC1 3, 400 MHz) 8} 7.34 (d, 4 H, J = 8.0 Hz), 7.17 (d, 4 H, J = 8.0 Hz), 3.61 (t, 4 H, J = 4.8 Hz), 3.50 (s, 4 H), 3.48-3.45 (m, 4 H), 3.46 (t, 4 H, J = 7.2 Hz), 3,37 (s, 4 H), 2.57 (t, 4 H, J = 7.2 Hz), 2.43-2.36 (m , 8H).

Example 62

 Synthesis of 1,3-bis {3- [4- (4-methoxybenzyl) -topiperazinyl] -3-oxopropyl} -2-imidazolidinone

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.21 (d, 4 H, J = 8.8 Hz), 6.86 (d, 4 H, J = 8.8 Hz), 3.80 (s, 6 H), 3.60 (t, 4 H , J = 4.8 Hz), 3.48-3.44 (m, 12 H), 3.36 (s, 4 H), 2.56 (t, 4 H, J = 7.2 Hz), 2.41-2.36 (in, 8 H).

Example 63

 Synthesis of 1,3-bis {3- [4- (4-ethylbenzyl) -topiperazinyl] -3-oxopropyl} -2-imidazolidinone

¾ thigh _{(CDC1 3, 400 MHz) δ} 7.22 (d, 4 H, J = 8.0 Hz), 7.16 (d, 4 H, J = 8.0 Hz), 3.61 (brs, 4 H), 3.48 (s, 4 H ), 3.48-3:44 (m, 4 H), 3.46 (t, 4 H, J = 7.2 Hz), 3.36 (s, 4 H), 2.64 (q, 4 H, J = 7.6 Hz), 2.56 ( t, 4 H, J = 7.2 Hz), 2.37-2.46 (m, 8 H), 1.24 (t, 6 H, J = 7.6 Hz).

Example 64

 Synthesis of 1,3-bis {3- [4- (3,4-dichlorobenzyl) -topiperazinyl] -3-oxopropyl} -2-ymidazolidinone

¾ thigh _{(CDC1 3, 400 MHz) 8} 7.44 - 7.46 (m, 2 H), 7.40 (d, 2 H, J = 8.2 Hz), 7.19 (d, 2 H, J = 8.2 Hz), 3.64 (brs, 4H), 3.54-3.45 (m, 4H), 3.49 (s, 4H), 3.46 (t, 4H, J = 6.9 Hz), 3.38 (s, 4H), 2.57 (t, 4H, J = 6.9 Hz), 2.40-2.51 (m, 8 H).

Example 65

 Synthesis of 1,3-bis (3-oxo-3- {4- [4- (trifluoromethyl) benzyl: H-piperazinyl} propyl) tetrahydro-2 (1H) _pyrimidinone

Example 65-1

Synthesis of tert-butyl 3- [3- (3-tert-butoxy-3-oxopropyl) -2-oxotetrahydrido-1 (2H) -pyrimidinyl] propanoate ¾ NMR (CDCI3, 400 MHz) δ 3.54 (t, 4 H, J = 7.0 Hz), 3.29 (t, 4 H, J = 5.9 Hz), 2.49 (t, 4 H, J = 7.0 Hz), 1.91 ( quint, 2 H, J = 5.9 Hz), 1.44 (s, 18 H).

Example 65-2

Synthesis of 3- [3- (2_Carboxyethyl) -2-oxotetrahydro-1 (2H) -pyrimidinyl] propanoic acid

 Tert-Butyl 3- [3- (3-tert-butoxy-3-oxopropyl) -2-oxotetrahydro-1 (2H) -pyrimidinyl] propanoate (100 mg, 0.281 t) was added to acetic acid (5 ml). And 4N hydrochloric acid-dioxane (2.5 ml) was added thereto, followed by stirring at 60 ° C for 3 hours. After evaporating the solvent under reduced pressure, the title compound (67.1 mg, quant.) Was obtained as a white powder by azeotropic distillation with toluene.

_{¾ NMR (DMS0- d 6, 400} MHz) δ 12.18 (s, 2 H), 3.38 (t, 4 H, J = 7.2 Hz), 3.22 (t, 4 H, J = 5.6 Hz), 2.39 (t, 4 H, J = 7.2 Hz), 1.81 (quint, 2 H, J = 5.6 Hz).

Example 65-3

 Synthesis of 1,3-bis (3-oxo-3- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} propyl) tetrahydro-2 (1H) -pyrimidinone

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.58 (d, 4 H, J = 8.1 Hz), 7.44 (d, 4 H, J = 8.1 Hz), 3.61 (t, 4 H, J = 4.8 H), 3.55 (s, 4 H), 3.55-3.52 (ra, 8 H), 3.33 (t, 4 H, J = 6.0 Hz), 2.61 (t, 4 H, J = 7.0 Hz), 2.37-2.45 (m, 8 H), 1.91 (qu int, 2 H, J = 6.0 Hz).

The compounds of Example 66 and Example 67 were synthesized in the same manner as in Example 59 and Example 65. Example 66

 Synthesis of 1,3-bis {3- [4- (4-chlorobenzyl) -topiperazinyl] -3-oxopropyl} tetrahydro-2 (1H) -pyrimidinone

¾ thigh _{(CDC1 3, 400 MHz) δ} 7.29 (d, 4 H, J = 8.5 Hz), 7.24 (d, 4 H, J = 8.5 Hz), 3.61 (t, 4 H, J = 5.2 Hz), 3.55 -3.50 (m, 8 H), 3.47 (s, 4 H), 3.33 (t , 4 H, J = 6.0 Hz), 2.60 (t, 4 H, J = 7.2 Hz), 2.39 (quint, 8 H, J = 5.2 Hz), 1.90 (quint, 2 H, J = 6.0 Hz).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.29 (d, 4 H, J = 8.5 Hz), 7.24 (d, 4 H, J = 8.5 Hz), 3.61 (t, 4 H, J = 5.2 Hz), 3.55 -3.50 (m, 8 H), 3.47 (s, 4 H), 3.33 (t, 4 H, J = 6.0 Hz), 2.60 (t, 4 H, J = 7.2 Hz), 2.36-2.44 (m, 8 H), 1.90 (q uint, 2 H, J = 6.0 Hz).

Example 67

 Synthesis of 1,3-bis {3- [4- (3,4-dichlorobenzyl) -1-piperazinyl] -3-oxopropyl} tetrahydro-2 (1H) -pyrimidinone

_{Ή NMR (CDC1 3, 400 MHz} ) δ 7.45 (m, 2 H), 7.40 (d, 2 H, J = 8.2 Hz), 7.19 (d, 2 H, J = 8.2 Hz), 3.70 - 3.50 (m, 8 H), 3.53 (t, 4 H, J = 7.2 Hz), 3.49 (s, 4 H), 3.33 (t, 4 H, J = 5.8 Hz), 2.61 (t, 4 H, J = 7.2 Hz) , 2.37-2.52 (m, 8 H), 1.92 (quint, 2 H, J = 5.8 Hz).

Example 68

 N- (4-{[4- (1,3-benzodioxol-5-ylmethyl) -1-piperazinyl] carbonyl} phenyl) -4- [4- (trifluoromethyl) benzyl] Synthesis of -topiperazinecarboxamide Example 68-1

 Synthesis of methyl 4-[({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) amino] benzoate

Triphosgene (3.83 g, 12.9 mmol) was dissolved in THF (5 ml) and stirred at 0 ° C. While maintaining the temperature at 0 ° C, a solution of methyl 4-aminobenzoate (4.49 g, 29.7 mmol) dissolved in THF (220 ml) was added dropwise over 1.5 hours. After stirring at 0 ° C. for 30 minutes, the mixture was stirred at room temperature for 3 hours. Subsequently, 1- [41- (trifluoromethyl) benzyl] piperazine (10.9 g, 44.6 mmol) was added, and the mixture was stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution to terminate the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is dissolved in chloroform and purified by silica gel chromatography (chloroform: ethyl acetate = 10: 1 → ethyl acetate) to give a white color. The title compound (5.54 g, 44.3%) was obtained as a solid.

Ή thigh _{(CDC1 3, 300 MHz) δ} 7.87 - 7.96 (m, 2 H), 7.59 (d, 2 H, J = 8.0 Hz), 7.40 - 7.49 (in, 4 H), 6.96 (s, 1 H) , 3.87 (s, 3 H), 3.57 (s, 2 H), 3.53 (t, 4 H, J = 4.9 Hz), 2.46 (t, 4 H, J = 4.9 Hz).

Example 68-2

 Synthesis of 4-[({4- [4- (trifluoromethyl) benzyl] -topiperazinyl} carbonyl) amino] benzoic acid hydrochloride

 4 _ [({4- [4- (Trifluoromethyl) benzyl] -topiperazinyl} carbonyl) amino] Methyl benzoate (5.54 g, 13.1 ol) was suspended in concentrated hydrochloric acid (300 ml), and 60 ° The mixture was stirred at 〇 for 3.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. Acetonitrile was added to the obtained residue and azeotroped to give the title compound (5.85 g, quant.) As a white solid.

_{¾ NMR (DMS0- d 6, 300} MHz) 8 9.92 (s, 1 H), 7.86- 7.82 (m, 5 H), 7.84 (d, 2 H, J = 8.7 Hz), 7.59 (d, 2 H, J = 8.7 Hz), 4.45 (s, 2 H), 4.26 (m, 2 H), 3.33 (m, 4 H), 3.08 (m, 2 H).

Example 68-3

Ν- (4-{[4- (1,3-Benzodioxol-5-ylmethyl) -topiperazinyl] potubonyl} phenyl) -4- [4- (trifluoromethyl) benzyl]- Synthesis of piperazinecarboxamide 4-[(4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) amino] Benzoic acid (102 mg, 0.230 mol) was dissolved in DMF (3 ml). , 1-piperonilpiperazine (68.2 mg, 0.310 mmol), WSC (56.1 mg, 0.293 mmol), HOBt (42.2 mg, 0.312 mmol), and triethylamine (80μ1) were added sequentially, and the mixture was added at 40 ° C for 3 hours. It was stirred. After cooling to room temperature and stirring overnight, saturated aqueous sodium hydrogen carbonate was added to the reaction solution to terminate the reaction. The mixture was extracted with ethyl acetate-toluene (2: 1) and washed with saturated aqueous sodium hydrogen carbonate. Then, after drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 20: 1 → 10: 1), and the resulting white amorphous was dissolved in chloroform (2 ml) and 4N monohydroxane hydrochloride (2 ml) Add I got it. The solvent of this suspension was distilled off under reduced pressure, and azeotroped with toluene to obtain the title compound (87 mg, 55%) as a white solid.

_{Ή NMR (CDC1 3, 300 MHz} ) δ 7.59 (d, 2 H, J = 8.1 Hz), 7.46 (d, 2 H, J = 8.1 Hz), 7.36 (d, 2 H, J = 8.9 Hz), 7.32 (d, 2 H, J = 8.9 Hz), 6.85 (s, 1 H), 6.75 (d, 1 H, J = 9.0 Hz), 6.72 (d, 1 H, J = 9.0 Hz), 6.55 ( s, 1H), 5.95 (s, 2H), 3.85-3.43 (m, 4H), 3.59 (s, 2H), 3.52 (t, 4H, J = 5.1 Hz), 3.43 (s, 2H) H), 2.55-2.30 (m, 4 H), 2.49 (t, 4 H, J = 5.1 Hz).

The compound of Example 69 was synthesized in the same manner as in Example 68-3.

Example 6 9

Synthesis of N- (4-{[4- (4-chlorobenzyl) -topiperazinyl] carbonyl} phenyl) -4- [4- (trifluoromethyl) benzyl] -topiperazine

_{¾ NMR (CDC1 3, 300 MHz} ) δ 7.59 (d, 2 H, J = 8.1 Hz), 7.46 (d, 2 H, J = 8.1 Hz), 7.36 - 7.24 (m, 8H), 6.73 (s, 1 H), 3.90-3.45 (m, 6H), 3.59 (s, 2H), 3.52 (t, 4H, J = 5.1 Hz), 2.60-2.35 (m, 4H), 2.48 (t, 4H, J = 5.1 Hz). In the same manner as in Example 68, the compounds of Examples 70 to 73 were synthesized.

Example 70

 Ν- (3-{[4- (1,3-Benzodoxyl-5-ylmethyl) -1-piperazinyl] carbonyl} phenyl) -4- [4- (trifluoromethyl) benzyl] -1 Example 70-1 Synthesis of -Pirazinecarboxamide

Synthesis of methyl 3-[[{{[4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) amino] benzoate

¾飄_{(CDC1 3, 300 MHz) δ} 7.88 (t, 1 H, J = 1.9 Hz), 7.76 one 7.69 (m, 2 H), 7.60 (d, 2 H, J = 8.1 Hz), 7.47 (d, 2H, J = 8.1 Hz), 7.36 (t, 1H, J = 8.0 Hz), 6.46 (s, 2H), 3.89 (s, 3H), 3.60 (s, 2H), 3.53 (t, 4 H, J = 5.0 Hz), 2.51 (t, 4 H, J = 5.0 Hz).

Example 70-2

3-[({4- [4-[(trifluoromethyl) benzyl] -topiperazinyl] carbonyl) amino] Synthesis of benzoic acid hydrochloride

Ή thigh _{(DMSO- d 6, 300 MHz)} δ 9.01 (s, 1 H), 8.01 - 8.11 (m, 1 H), 7,85 - 7.6 5 (m, 6 H), 7.53 (d, 1 H, J = 6.2 Hz), 7.42-7.33 (m, 1H), 4.44 (s, 2H), 4.26-4.22 (m, 2H), 3.20-3.40 (m, 4H), 3.00-3.11 (m, 2H) .

Example 70-3

N- (3-{[4- (1,3-Benzodoxyl-5-ylmethyl) -1-piperazinyl] carbonyl} phenyl) _4- [4- (trifluoromethyl) benzyl] -1- synthesis Ή墮the pin Pera Jin carboxamide _{(CDC1 3, 300 MHz) 8} 7.59 (d, 2 H, J = 8.1 Hz), 7.46 (d, 2 H, J = 8.1 Hz), 7.42 - 7.35 (m, 1 H ), 7.28-7,21 (m, 2H), 7.00-6.91 (m, 2H), 6.84 (s, 1H), 6.76-6.73 (m, 2H), 5.94 (s, 2H), 3.76 (brs, 4H), 3.57 (s, 2H), 3.50 (t, 4H, J = 5.0 Hz), 3.43 (s, 2H), 2.46 (t, 4H, J = 5.0 Hz), 2.30 -2.42 (m, 4H).

Example 7 1

 Synthesis of N- (3-{[4- (4-cyclobenzyl) -topiperazinyl] carbonyl} phenyl) -4- 4- [4- (trifluoromethyl) benzyl] -topiperazinecarboxamide

'Eta丽_{(CDC1 3, 300 MHz) δ} 7.59 (d, 2 H, J = 8.2 Hz), 7.46 (d, 2 H, J = 8.2 Hz), 7.43 - 7.23 (m, 7 H), 6.99 (d , 1 H, J = 7.5 Hz), 6.83 (s, 1 H), 3.75 (m, 4 H), 3.58 (s, 2 H), 3.50 (t, 4 H, J = 5.0 Hz), 3.48 (s , 2H), 2.46 (t, 4H, J = 5.0 Hz), 2.36 (m, 4H).

Example 72

 4- (l, 3-benzodioxol-5-ylmethyl) -N- [3-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) phenyl] -1 Synthesis of -pirazinecarboxamide Example 72-1

 Synthesis of methyl 3-({[4- (1,3-benzodioxol-5-ylmethyl) -1-piperazinyl] carbonyl} amino) benzoate

'.Eta. thigh _{(CDC1 3, 300MHz) δ 9.07} (s, 1 H), 8.12 (s, 1 H), 7.74 - 7.80 (m, 1 H), 7.56 (d, 1 H, J = 7.7 Hz), 7.40 (t, 1 H, J = 8.1 Hz), 7.24 (s, 1 H), 7.02 6.97 (m, 2 H), 6.07 (s, 2 H), 4.24 (brs, 4 H), 3.84 (s, 3 H), 3.33 (s, 6 H).

 Synthesis of 3-({[4- (1,3-benzodioxol-5-ylmethyl) -1-pidrazinyl] -pyrubonyl} amino) benzoate hydrochloride

'Η-thigh (DMS0-, 300 MHz) 5 9.00 (s, 1 H), 8.07 (s, 1 H), 7.70-7.76 (m, 1 H), 7.54 (d, 1 H, J = 9.0 Hz), 7.36 (t, 1 H, J = 7.9 Hz), 7.22 (s, 1 H), 7.05-6.92 (m, 2 H), 6.80 (s, 1 H), 6.07 (s, 2 H), 4.24 (brs , 4 H), 3.43-3.30 (m, 6 H).

Example 72-3

4- (l, 3-benzodioxoyl-5-ylmethyl) -N- [3-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) phenyl] -1-pi Pera Jin carboxamide synthesis ¾ thigh _{(CDC1 3, 300 MHz) δ} 7.57 (d, 2 H, J = 8.0 Hz), 7.44 (d, 2 H, J = 8.0 Hz), 7.40 - 7.38 (m, 2 H) , 7.30-7.25 (m, 1 H), 7.01 (d, 1 H, J = 7.3 Hz), 6.86 (s, 1 H), 6.78-6.68 (m, 3 H), 5.95 (s, 2 H), 3.76 (brs, 4H), 3.57 (s, 2H), 3.49 (t, 4H, J = 5.0 Hz), 3.44 (s, 2H), 2.34-2.55 (m, 8H).

Example 73

 4- (1,3-benzodioxol-5-ylmethyl) -N- (3-{[4- (4-chlorobenzoyl) -1-piperazinyl] butyarbonyl} phenyl)- Synthesis of piperazine potato ruboxamide

_{¾ NMR (CDC1 3, 300 MHz} ) δ 7.41 (d, 1 H, J = 7.4 Hz), 7.33 - 7.36 (m, 1 H), 7.30 - 7.23 (m, 5 H), 6.99 (d, 1 H, J = 7.4 Hz), 6.85 (d, 2 H, J = 6.8 Hz), 6.77-6.74 (m, 2 H), 5.95 (s, 2 H), 3.74 (brs, 4 H), 3.48 (t, 4 H, J = 5.0 Hz), 3.47 (s, 2 H), 3.44 (s, 2 H), 2.44 (t, 4 H, J = 5.0 Hz), 2.36-2.43 (m, 4H).

Example 7

4- [4- (Trifluoromethyl) benzyl] -N- [6-({4- [4- (trifluoromethyl) benzyl] -topiperazinyl} pyrubonyl) -3-pyridinyl] -1-piperazine Example 74-1 Synthesis of Capsuleboxamide Synthesis of 6-({4- [4- (trifluoromethyl) benzyl]-1-piperazinyl} carbonyl) nicotinic acid

 Dissolve 2,5-pyridinedicarboxylic acid (2.34 g, 14.0 mmol) in DMF (35 ml), WSC (2.68 g, 14.0 mmol), HOBt (1.89 g, 14.0 mmol), triethylamine (7.8 ml, 56 mmol), [4- (Trifluoromethyl) benzyl] piperazine (3.42 g, 14.0 mmol) was sequentially added, and the mixture was stirred overnight. The reaction was terminated by adding water, and extracted with ethyl acetate-toluene (2: 1). The resulting aqueous layer was acidified by adding concentrated hydrochloric acid little by little to adjust the pH to about 3, and extracted several times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give the title compound (1.78 g, 32.3%) as a white solid.

_{MR (DMS0- d 6, 300 MHz} ) δ 9.04 (d, 1 H, J = 2.0 Hz), 8.36 (dd, 1 H, J = 2 .0, 8.4 Hz), 7.97 (d, 1 H, J = 8.4 Hz), 7.69 (d, 2 H, J = 8.0 Hz), 7.56 (d, 2 H, J = 8.0 Hz), 3.67 (m, 4 H), 3.62 (s, 2 H), 2.47 (brs, 2 H), 2.37-2.52 (m, 2 H).

Example 74-2

4- [4- (Trifluoromethyl) benzyl] -N- [6 _ ({4- [4- (Trifluoromethyl) benzyl] -topiperazinyl} pyrubonyl) -3-pyridinyl] -topiperazinecarboxamide Synthesis 6- (4- [4- (Trifluoromethyl) benzyl] -topiperazinyl} carbonyl) nicotinic acid (198 mg, 0.503 mmol) was dissolved in toluene (10 ml), and DPPA (277 mg, 1.01 tmol) was dissolved. , And triethylamine (140 μ1, 1.0 mmol) were added, and the mixture was stirred at 100 ° C. for 4.5 hours. [4- (Trifluoromethyl) benzyl] piperazine (147 mg, 0.604 mmol) was added, and the mixture was stirred at 100 ° C for 2 hours. After cooling to room temperature, the reaction was quenched with a saturated aqueous solution of sodium bicarbonate, and extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (form: methanol = 20: 1) to give the title compound (110 mg, 34.5%) as a white amorphous. 'Η NMR (DMS0-d ₆ , 300 MHz) 8 8.42 (d, 1 H, J = 2.3 Hz), 7.80 (dd, 1 H, J = 2.3, 8.4 Hz), 7.59 (d, 2 H, J = 8.0 Hz), 7.58 (d, 2 H, J = 8.0 Hz), 7.48-7.45 (m, 5 H), 7.41 (d, 1 H, J = 8.4 Hz), 3.76-3.82 (br, 2 H), 3.53-3.65 (m, 10 H), 2.53-2.43 (m, 8 H).

Example 75

 4- [4- (trifluoromethyl) benzyl] -N- [6-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) -3-pyridazinyl] -1-pi Synthesis of Perazinecarboxamide Example 75-1

 Synthesis of 6-amino-3-pyridazinecarbonitrile

 3-Amino-6-chloropyridazine (3.70 g, 28.6 t ol) was dissolved in DMF (30 ml), and 60% zinc cyanide (6.15 g, 31.4 mmol), tetrakis (triphenylphosphine) palladium (6.61 g) was dissolved. g, 5.72 mmol) and stirred for 21 hours at 80 ° C. The reaction solution was allowed to cool to room temperature, added to ice-cooled saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate-toluene (3: 1). The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give a white powder. To give the title compound (2.17 g, 63.2%).

_{¾ NMR (DMS0-d 6,} 400 MHz) δ 7.66 (d, 1 H, J = 9.3 Hz), 7.38 (brs, 2 H), 6.7 5 (d, 1 H, J = 9.3 Hz).

Example 75-2

Synthesis of 6-amino-3-pyridazine dicarboxylic acid

 6-Amino-3-pyridazine dirubonitrile (28.8 mg, 0.240 mmol) was suspended in 480 μl of 2% aqueous sodium hydroxide solution and stirred at 100 ° C. for 4 hours. After allowing to cool to room temperature, concentrated hydrochloric acid was added little by little to adjust the pH to about 1. The reaction mixture was stirred under ice-cooling, and solid power was precipitated. The solid was separated by filtration and dried to give the title compound (27.8 mg, 83.3%) as a white solid.

¾ thigh _{(DMS0- d 6, 400 MHz)} 8 8.49 (brs, 2 H), 7.88 (d, 2 H, J = 9.5 Hz), 7.2 3 (d, 2 H, J = 9.5 Hz). Example 75-3

 Synthesis of 6-({4- [4- (trifluoromethyl) benzyl] -topiperazinyl} carbonyl) -3-pyridazinamine

 6-Amino-3-pyridazinecarboxylic acid (22.7 mg, 0.163 mmol) was dissolved in 3 ml of DMF (3 ml), and WSC (37.5 mg, 0.196 mmol), HOBt (26.5 mg, 0.196 mmol), and [4] -(Trifluoromethyl) benzyl] piperazine (47.9 mg, 0.196 mmol) was sequentially added, and the mixture was stirred at room temperature for 1 day. Saturated aqueous sodium bicarbonate was added to the reaction mixture to terminate the reaction, and the mixture was extracted with ethyl acetate-toluene (3: 0. The organic layer was washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. After evaporation, the residue was purified by silica gel column chromatography (ethyl acetate → ethyl acetate: methanol = 10: 1) to obtain the title compound (41.2 mg, 69.2%) as a white powder.

_{¾ NMR (CDC1 3 ,, 400 MHz} ) δ 7.69 (d, 1 H, J - 9.2 Hz), 7.62 (d, 2 H, J = 8.0 Hz), 7.56 (d, 2 H, J = 8.0 Hz), 6.85 (d, 1 H, J = 9.2 Hz), 5.14 (brs, 2 H), 3.85-4.05 (m, 4 H), 3.74 (brs, 2 H), 2.70 (brs, 4 H).

Example 75-4

4- [4- (trifluoromethyl) benzyl] -N- [6-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) -3-pyridazinyl] -1-pi Synthesis of perazinecarboxamide 6- (4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) -3-pyridinamine (31.7 mg, 0.0868 mmol) was dissolved in DMF (3 ml). Then, triphosgene (12.9 mg, 0.0434 mmol) and triphetamine (481, 0.35 mmol) were added, and the mixture was stirred at 80 ° C for 1.5 hours. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate-toluene (3: 1). The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was dissolved in 2 ml of DMF (2 ml), and 1- [4- (trifluoromethyl) benzyl] pirazine (10.5 mg, 0,0430 麵 ol), a catalytic amount of NaH was added and the mixture was stirred at 80 ° C for 6 hours. After allowing to cool to room temperature, the reaction was terminated by adding saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate-toluene (3: 1). The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the silica gel column The product was purified by chromatography (ethyl acetate: methanol = 10: 1). The title compound (100 mg, 18.3%) was obtained as a white powder.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.72 (s, 1 H), 7.73 (d, 1 H, J = 8.9 Hz), 7.58 - 7.63 (m, 4 H), 7.46 - 7.63 (m, 4 H) , 7.16 (d, 1 H, J = 8.9 Hz), 3.84-3.94 (m, 6 H), 3.63 (brs, 4 H), 3.52-3.57 (m, 2 H), 2.53-2.63 (m, 8 H ).

Example 76

 4-oxo-2- (2-oxo- 2- {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} ethyl)-4- {4- [4- (trifluoromethyl) benzyl ] Synthesis of methyl -1 -piperazinyl} butanoate

Example 76-1

 Synthesis of 1,2,2,3-propanetetracarboxylic acid 1,3-ditert-butyl 2,2-dimethyl

 Dimethyl malonate (2.04 g, 15.4 mmol) was dissolved in DMF (20 ml), sodium hydride (1.36 g, 34.0 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. To this solution was added dropwise a solution of ethyl bromoacetate (7.21 g, 37.0 tmol) in DMF (5 ml), and the mixture was stirred at 80 ° C for 1 hour. The reaction was terminated by adding water, and extracted with ethyl acetate-toluene (3: 1). The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 → hexane: ethyl acetate = 3: 1) to give the title compound as a pale yellow oil. (5.08 g, 91.5%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 3.75 (s, 6 H), 3.04 (s, 4 H), 1.43 (s, 18 H).

Example 76-2

 Synthesis of 3,3-bis (methoxycarbonyl) pentannic acid

 1,2,2,3-Propanetetracarboxylic acid 1,3-ditert-butyl 2,2-dimethyl (3.72 g, 10.3 bandol) was dissolved in benzene (60 ml) and trifluoroacetic acid (60 ml) was added. ml) was added. After stirring at 50 ° C for 30 minutes, the solvent was distilled off under reduced pressure. The residue was azeotroped three times with toluene. The title compound (2.55 g, quant.) Was obtained as a white solid.

¾ thigh _{(DMS0- d 6, 400 MHz)} δ 12.55 (brs, 2 H), 3.63 (s, 6 H), 2.99 (s, 4 H). Example 76-3

 Synthesis of dimethyl 2,2-bis (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl) maphate

 3,3-Bis (methoxycarbonyl) pentanedioic acid (2.31 g, 9.31 ramol) was dissolved in DMF (30 ml) and 1- [4- (trifluoromethyl) benzyl] piperazine (5.00 g, 20.5 mmol) ), WSC (3.75 g, 19.6 mmol) and HOBt (2.65 g, 19.6 ramol) were added, and the mixture was stirred at room temperature for 5 hours and then at 50 ° C for 2 hours. The reaction was terminated by adding a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-toluene (3: 1). The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel gel column chromatography ((form of black mouth → form of methanol: methanol = 50: 1)) to give the title compound (2,20) as a pale brown oil. g, 33.7%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.59 (d, 4 H, J = 7.2 Hz), 7.46 (brs, 4 H), 3.73 (s, 6 H), 3.57 (s, 4 H), 3.46 - 3.64 (m, 8H), 3.36 (s, 4H), 2.35-2.51 (m, 8H).

Example 76-4

 4-oxo-2- (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl)-4- {4- [4- (trifluoromethyl) Synthesis of methyl [benzyl] -topiperazinyl} butanoate

 Dimethyl 2,2-bis (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl) malonate (10.4 g, 14.8 mmol) in DMS0 (100 ml) Then, sodium chloride (2.60 g, 44.5 mmol) and water (1 ml) were added, and the mixture was stirred at 180 ° C for 5 hours. The reaction was quenched by the addition of saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate-toluene (3: 1). The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (form: methanol = 50: 1). The title compound (3.02 g, 31.8%) was obtained as a light brown oil.

Ή thigh _{(CDC1 3, 400 MHz) δ} 7.59 (d, 4 H, J = 7.8 Hz), 7.46 (brs, 4 H), 3.70 (s, 3 H), 3.58- 3.67 (brm, 8 H), 3.50 (s, 4 H), 3.31 (quint, 1 H, J = 6.1 H z), 2.84-2.66 (m, 4 H), 2.43 (brs, 8 H).

The compound of Example 77 was synthesized in the same manner as in Example 76.

Example 7 7

 4- [4- (3,4-dichlorobenzyl) -1-piperazinyl] -2- {2- [4- (3,4-dichlorobenzyl) -1-piperazinyl] -2-oxoethyl} -4- Synthesis of methyl oxobutanoate

Example 7 7-1

 Synthesis of dimethyl 2,2-bis {2- [4- (3,4-dicyclopentyl) -topiperazinyl] -2-oxoethyl} maproate

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7,43 - 7.46 (m, 2 H), 7.40 (d, 2 H, J = 8.2 Hz), 7.17 (dd, 2 H, J = 1.7, 8.2 Hz), 3.73 (s, 6 H), 3.35-3.62 (m, 16 H), 2.36-2.46 (m, 8 H).

Example 7 7-2

 4- [4- (3,4-dichlorobenzyl) -1-piperazinyl] -2- {2- [4- (3,4-dichlorobenzyl) -1-piperazinyl] -2-oxoethyl} -4-oxobutanoic acid Synthesis of methyl

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.44 (d, 2 H, J = 1.9 Hz), 7.39 (d, 2 H, J = 4.0 Hz), 7.16 (dd, 2 H, J = 1.9, 4.0 Hz) , 3.70 (s, 3 H), 3.64-3.56 (m, 4 H), 3.52-3.46 (m, 4 H), 3.46 (s, 4 H), 3.31 (quint, 1 H, J = 6.0 Hz ), 2.85-2.66

(m, 4 H), 2.46-2.43 (m, 8 H).

Example 8

4-oxo- 2- (2-oxo- 2- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl)-4- {4- [4- (trifluoromethyl) Benzyl] -1-piperazinyl} butanoic acid

4-oxo-2- (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} ethyl)-4- {4- [4- (trifluoromethyl) benzyl] Methyl -topiperazinyl} butanoate (493 mg, 0.767 mmol) was dissolved in a 2N aqueous methanol-THF (1: 1: 1) solution (30 ml) and stirred at 50 ° C for 1 hour. Saturated sodium dihydrogen phosphate solution was added to bring the solution pH to 4-5. The organic layer was extracted with ethyl acetate and washed with saturated sodium dihydrogen phosphate solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Yellow oil As a result, the title compound (406 mg, 84.2%) was obtained.

Thigh _{(DMS0- d 6, 400 MHz)} δ 7.69 (d, 4 H, J = 8.1 Hz), 7.55 (d, 4 H, J = 8. 1 Hz), 3.58 (s, 3 H), 3.43 - 3.34 (m, 12 H), 3.02 (quint, 1 H, J = 6.4 Hz), 2.68-2.46 (m, 4 H), 2.36-2.31 (m, 8 H).

Example 79

 N, N-dimethyl-4-oxo-2- (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl) -4- {4- [4- Synthesis of (trifluoromethyl) benzyl] -topiperazinyl} butanamide

4-oxo-2- (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl)-4- {4- [4- (trifluoromethyl) benzyl ] -Topiperazinyl} butanoic acid (103 mg, 0.147 mmol) was dissolved in DMF (1 ml) and dimethylamine hydrochloride (30.0 _mg , 0.367 mmol), WSC (59.2 g, 0.309 mmol), HOBt (41.8 mg, 0.309 mmol) and triethylamine (103 μl, 0.735 tmol) were added, and the mixture was stirred at room temperature for 4 hours and then at 50 ° C. for 3 hours. The reaction was terminated by adding a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate-toluene (3: 1). The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (black-mouthed form → black-eared form: methanol = 20: 1). The title compound (8 9.3 mg, 92.7%) was obtained as a pale brown oil.

¾ thigh _{(CDC1 3, 400 MHz) δ} 7.59 (d, 4 H, J = 7.8 Hz), 7.47 (brd, 4 H), 3.76 (quint, 1 H, J = 6.4 Hz), 3.59 (m, 8 H ), 3.48 (s, 4 H), 3.22 (s, 3 H), 2.95 (s, 3 H), 2.78-2.66 (m, 2 H), 2.49-2.43 (m, 10 H).

In the same manner as in Example 79, the compounds of Examples 80 to 82 were synthesized.

Example 80

 4- [4- (3,4-dichlorobenzyl) -1-piperazinyl] -2-[4- (3,4-dichlorobenzyl) -1-piperazinyl] -2-oxoethyl} -N, N-dimethyl- Synthesis of 4-oxobutanamide

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.43 (d, 2 H, J = 1.8 Hz), 7.39 (d, 2 H, J = 8.2 Hz), 7.15 (dd, 2 H, J = 1.8, 8.2 Hz) , 3.76 (m, 1 H), 3.59 (brt, 4 H), 3.45 ( m, 8 H), 3.23 (s, 3 H), 2.96 (s, 3 H), 2.80-2.68 (m, 2 H), 2.55-2.37 (m,

10 H).

Example 8 1

 4-Oxo-2- (2-oxo-2--2- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl) -N, N-dipropyl-4- {4- [4- Synthesis of (Trifluoromethyl) benzyl] -1-piperazinyl} butanamide

Ή thigh _{(CDC1 3, 400 MHz) δ} 7.59 (d, 4 H, J = 8.1 Hz), 7.46 (d, 4 H, J = 8.1 Hz), 3.66 (quint, 1 H, J = 6.8 Hz), 3.58 One 3.48 (m, 12 H), 3.38 (t, 2 H, J = 7.5 Hz), 3.27 (t, 2 H, J = 7.5 Hz), 2.69-2.50 (m, 4 H), 2.43 (brt, 8 H), 1.69 (quint, 2 H, J = 7.5 Hz), 1.54 (quint, 2 H, J = 7.5 Hz).

¾ thigh _{(CDC1 3, 400 MHz) 5} 7.59 (d, 4 H, J = 8.1 Hz), 7.46 (d, 4 H, J = 8.1 Hz), 3.66 (quint, 1 H, J = 6.8 Hz), 3.58 ― 3.48 (m, 12 H), 3.38 (t, 2 H, J = 7.5 Hz), 3.27 (t, 2 H, J = 7.5 Hz), 2.69-2.50 (m, 4 H), 2.43 (brs, 8 H), 1.75-1.50 (m, 2 H), 0.93 (t, 3 H, J = 7.5 Hz), 0.87 (t, 3 H, J = 7.5 Hz).

Tri (5-oxo-3- (topiperidinylcarbonyl) -5- {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} pentanoyl) -4- [4- (trifluoromethyl ) Synthesis of benzyl] piperazine

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.59 (d, 4 H, J = 7.9 Hz), 7.47 (brs, 4 H), 3.80 (quint, 1 H, J = 6.4 Hz), 3.60 - 3.49 (m, 16H), 2.73-2.67 (m, 2H), 2.49-2.43 (m, 10H), 1.64 (brs, 4H), 1.53 (brs, 2H).

Example 83

 4-oxo-2--2- (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} ethyl) -4- {4- [4- (trifluoromethyl) benzyl ] -Topiperazinil} -Synthesis of topbutanol

4-oxo-2- (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl) -4- {4- [4- (trifluoromethyl) benzyl ]-Toppiperazinyl methyl butanoate (4.44 g, 6.91 mmol) was dissolved in THF (20 ml), and anhydrous sodium chloride (733 mg, 17.3 ramol) and sodium borohydride (733 mg, 17.3 mmol) were added. Further, ethanol (20 ml) was added little by little, and the mixture was stirred at room temperature for 3 hours. The reaction was terminated by adding 10% aqueous hydrochloric acid, and this was added to saturated aqueous sodium hydrogen carbonate to make the solution basic. Extracted with black-mouthed form and washed with saturated aqueous sodium bicarbonate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography. The title compound (3.04 g, 71.6%) was obtained as a colorless amorphous.

¾ thigh _{(CDC1 3, 400 MHz) δ} 7.58 (d, 4 H, J = 8.0 Hz), 7.45 (d, 4 H, J = 8.0 Hz), 3.72 - 3.52 (m, 15 H), 2.57 - 2.40 ( m, 13H).

Example 84

 4-oxo-2- (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} ethyl) -4- {4- [4- (trifluoromethyl) benzyl Synthesis of -1-piperazinyl} butanal 4-oxo-2- (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl) -4_ {4- [4- (Trifluoromethyl) benzyl] -topiperazinyl} -Tobutanol (950 mg, 1.55 mmol) was dissolved in methylene chloride (5 ml), and triethylamine (640 μl) was dissolved.

1, 4.6 mmol) was added. While stirring at 0 ° C., a solution of sulfur trioxide ′ pyridine (738 mg, 4.64 mmol) in DMS0 (5 ml) was added dropwise. The mixture was stirred at 0 ° C. for 30 minutes, and further stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate-toluene (3: 1). The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel gel chromatography (clophore: methanol = 50: 1). The title compound (939 mg, qua nt.) Was obtained as a pale yellow amorphous.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 9.79 (s, 1 Η), 7.59 (d, 4 Η, J = 8.0 Hz), 7.45 (d, 4 H, J = 8.0 Hz), 3.62 - 3.49 (m, 8H), 3.58 (s, 4H), 3.15 (quint, 1H, J = 5.8 Hz), 2.97-2.91 (m, 2H), 2.71-2.65 (m, 2H), 2,45-2.42 (m, 8H) Example 85 (1Ε) -4-oxo-2- (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl)-4- {4- [4- (trifur Oromethyl) benzyl] -1-piperazinyl} butanaloxime

 4-oxo-2- (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl) -4- {4- [4- (trifluoromethyl) benzyl ] -1-Piperazinyl} butanal (187 mg, 0.299 tmol) was dissolved in ethanol (2 ml), and sodium chloride (41.5 mg, 0.597 mmol) and sodium acetate (81.2 mg, 0.597 mmol) were added. In addition, the mixture was stirred at room temperature for 30 minutes, and further stirred for 1 hour at 4 (TC). The reaction was terminated by adding saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (163 mg, 86.9%) as a pale-yellow amorphous.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.63 (d, 4 H, J = 8.1 Hz), 7.55 (d, 4 H, J = 8.1 Hz), 7.42 (d, 1 H, J = 5.7 Hz), 3.62 -3.58 (m, 12 H), 3.22-3.17 (m, 1 H), 2.69-2.55 (m, 4 H), 2.48-2.43 (m, 8 H).

Example 86

 (2E) -6-oxo-4- (2-oxo-2_ {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl) -6- {4- [4- (trifluoro Synthesis of l-methyl) benzyl] -1-piperazinyl}-2-ethylhexenoate

4-oxo-2- (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl) -4- {4- [4- (trifluoromethyl) benzyl ] -1 -Piperazinyl} butanal (475 mg, 0.775 mmol) was dissolved in DMF (4 ml), and sodium hydride (34.1 _mg , 0.853 mmol) and ethyl phosphonoacetate (174 mg, 0.775 mmol) were added. In addition, after stirring at room temperature for 30 minutes, the mixture was stirred at 50 ° C for 1 hour. Water was added, and saturated aqueous sodium hydrogen carbonate was added to terminate the reaction. The mixture was extracted with ethyl acetate-toluene (3: 1), washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1). The title compound (321 mg, 60.7%) was obtained as a colorless amorphous. ¾ NMR (CDCI3, 400 MHz) δ 7.58 (d, 4 H, J = 7.8 Hz), 7.45 (d, 4 H, J = 7.8 Hz), 6.97 (dd, 1 H, J = 8.1, 15.7 Hz), 5.87 (d, 1 H, J = 15.7 Hz), 4.17 (q, 2 H, J = 7.1 Hz), 3.61-3.51 (m, 12 H), 3.24 (m, 1 H), 2.67-2.62 (m, 2 H), 2.50-2.41 (m, 10 H), 1.28 (t, 3 H, J = 7.1 Hz).

Example 87

 Synthesis of 1,3-bis (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl) -2,4 (1H, 3H) -pyrimidinedione

Example 87_1

 Synthesis of 1- (chloroacetyl) -4- [4- (trifluoromethyl) benzyl] pirazine

 1 Dissolve [4- (trifluoromethyl) benzyl] piperazine (3.07 g, 12.6 mmol) in T HF (20 ml), add triethylamine (3.5 ml, 25 mmol) and add 0 ° C. Stirred for 30 minutes. Chloroacetyl chloride (1.42 g, 12.6 mmol) was added dropwise and stirred for 1 hour, and chloroacetyl chloride (1.42 g, 12.6 mmol) was further added dropwise and stirred for 1.5 hours. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1). The title compound (3.02 g, 74.7%) was obtained as a brown oil.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.60 (brd, 2 H), 7.47 (brd, 2 H), 4.06 (s, 2 H),

3.65-3.64 (m, 6 H), 2.48 (m, 4 H).

Example 87-2

 Synthesis of 1,3-bis (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} ethyl) -2,4 (1H, 3H) -pyrimidinedione

 Dissolve peracil (123 mg, 1.10 mmol) in DMF (3 ml) and add sodium hydride (92

.4 mg, 2.31 mmol) and stirred at room temperature for 30 minutes. A solution of tri (chloroacetyl) -4- [4- (trifluoromethyl) benzyl] pirazine (742 mg, 2.31 tmol) in DMF (2 ml) was added, and the mixture was stirred at 80 ° C for 4 hours. The reaction was terminated by the addition of saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate-toluene (3: 1). The organic layer is washed with a saturated aqueous solution of sodium bicarbonate, The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give the title compound (405 mg, 54.1%) as a pale yellow solid.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.59 - 7.63 (brd, 4 H), 7.46 (brs, 4 H), 7.17 (d, 1 H, J = 7.9 Hz), 5.82 (d, 1 H, J = 7.9 Hz), 4.75 (s, 2 H), 4.55 (s, 2 H), 3.68-3.43 (m, 12 H), 2.56-2.37 (m, 8 H).

The compound of Example 88 was synthesized in the same manner as in Example 87.

Example 88

 5-methyl-1,3-bis (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl) -2,4 (1H, 3H) -pyrimidine Synthesis of dione

_{¾ NMR (CDC1 3, 400 MHz} ) 8 7.63 - 7.56 (m, 4 H), 7.46 (brs, 4 H), 7.02 (s, 1 H), 4.77 (s, 1 H), 4.53 (brs, 2 H ), 3.63-3.45 (m, 12 H), 2.55-2.40 (m, 8 H), 1.94 (s, 3 H).

Example 89

{{[卜 (2-oxo_2- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl) cyclohexyl] acetyl} -4- [4- (trifluoromethyl) benzyl ] Pyrazine synthesis

1,1-Cyclohexyldiacetic acid (146 mg, 0.729 mmol) was dissolved in DMF (3 ml), and WSC (293 mg, 1.53 mmol), HOBt (207 mg, 1.53 mmol), [4- (trifluoro (Rmethyl) benzyl] piperazine (392 mg, 1.60 mmol) was added successively, and the mixture was stirred at room temperature overnight. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-toluene (3: 1). The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate. The product was purified by silica gel column chromatography (chloroform: methanol = 50: 1). The title compound (411 mg, 86.4%) was obtained as a colorless amorphous.

Analysis by LC-MS was performed using the following conditions.

Solvent: Elution with a gradient using a mixed solvent of solution A 0.035% acetonitrile trifluoroacetate solution and solution B 0.05% trifluoroacetic acid aqueous solution

'conditions: 0 → 0.5 minutes A solution 10% (—constant)

 0.5 → 4.2 min A solution 10% → 99%,

 4.2 → 4.4 minutes A solution 99% (constant)

Column: Mightysil RP-18 GP 5 m 4.6 x 50 mm

Flow rate: 3.5ml / min

Detection: UV 220nm, 254 dishes

 LC-MS analysis result: retention time 3.30 minutes, molecular weight 652,7, MS (m / z) 653.5 (M + H) + In the same manner as in Example 89, compounds from Example 90 to Example 94 were synthesized.

Example 90

 1- (3-Ethyl-3-methyl-5-oxo-5- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} pentanoyl)-4- [4- (trifluoromethyl ) Synthesis of benzyl] pidazine The analysis was performed using the same LC-MS analysis conditions as in Example 89.

LC-MS analysis result: retention time 4.47 minutes, molecular weight 626.7, MS (m / z) 627.5 (M + H) + Example 9 1

 1- (3-Methyl-5-oxo-5- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ぺ tannoyl)-4-[4- (trifluoromethyl) benzyl] pi Perazine synthesis

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.58 (d, 4 H, J = 8.0 Hz), 7.46 (d, 4 H, J = 8.0 Hz), 3.65 - 3.51 (m, 12 H), 2.51 - 2.38 ( m, 11 H), 2.20-2.15 (m, 2 H), 1.05 (d, 3 H, J = 6.5 Hz).

Example 92

1-{[(2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -1--1-piperazinyl} ethyl) cyclopentyl] acetyl} -4- [4- (trifluoromethyl) benzyl ] piperidines Rajin synthesis ¾ NMR of _{(CDC1 3, 400 MHz) δ} 7.59 (brd. 4 H), 7.46 (brd, 4 H), 3.57 (m, 12 H), 2.64 (s, 4 H), 2.41 ( m, 8 H), 1.69-1.58 (m, 8 H).

Example 93

Tri (5-oxo-3-phenyl-5- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} Pentanoiru) -4- [4- (Torifuruo port methyl) benzyl] Synthesis of piperidines Rajin _{Ή NMR (CDC1 3, 400 MHz} ) δ 7.59 (d, 4 H, J = 7.9 Hz), 7.46 (brs, 4 H) , 7.32-7.21 (m, 5 H), 3.63 (quint, 1 H, J = 7.0 Hz), 3.69-3.35 (m, 12 H), 2.89-2.78 (m, 2 H), 2.69-2.59 (m, 2 H), 2.37 (m, 8 H).

Example 9

l- [4- (Trifluoromethyl) benzyl] -4-{[(1R, 3S) -1,2,2-trimethyl-3-({4- [4- (trifluoromethyl) benzyl]-1- Synthesis of Piperazinyl} Rubonyl) cyclopentyl] Rubonyl} piperazine

_{lH NMR (CDC1 3, 400 MHz} ) δ 7.62 - 7.57 (m, 4 H), 7.48 (brs, 4 H), 3.77 - 3.5 9 (m, 12 H), 3.10 - 3.00 (m, 1 H), 2.43 ― 2.29 (m, 8 H), 1.80-1.68 (m, 2 H), 1.58 (brs, 2 H), 1.32 (s, 3 H), 1.25 (s, 3 H), 0.97 (s, 3 H) .

In the same manner as in Example 17, the compounds of Examples 95 to 99 were synthesized.

Example 9 5

 4- (4-iodobenzyl) -N- (4-{[4- (4-iodobenzyl) -1-piperazinyl] caphylcarbonyl) phenyl) -1-pidazinecarboxamide

_{'Η NMR (CDC1 3, 270} MHz) §7.66 (d, 2 H, J = 8.3 Hz), 7.64 (d, 2 H, J = 8.3 H z), 7.32 - 7.40 (m, 4 H), 7.09 ( d, 2 H, J = 8.3 Hz), 7.07 (d, 2 H, J = 8.3 Hz), 6.42 (brs, 1 H), 3.52 (s, 2 H), 3.50 (s, 2 H), 3.3 -3.9 (m, 8H), 2.35-2.55 (m, 8H).

Example 9 6

4- [4- (trifluoromethoxy) benzyl] -N- [4-({4- [4- (trifluoromethoxy) benzyl] -topiperazinyl} carbonyl) phenyl] -topiperazinecarboxamidini hydrochloride ¾ Yuzuru _{(DMSO- d 6, 300 MHz)} δ 11.2 - 11.4 (br, 2 H), 9.11 (brs, 1 H), 7.7 - 7.8 (m, 4 H), 7.55 (d, 2 H, J = 8.7 Hz), 7.4 — 7.5 (m, 4 H), 7.36 (d, 2 H, J = 8.7 Hz), 4.2 — 4.45 (m, 8 H), 2.9-3.5 (m, 12 H).

Example 9 7

4-(4-Ethylbenzyl) -N- (4-{[4- (4-ethylbenzyl) -1-piperazinyl] carbonyl} Fenil)-1-pidazine lipoxamide dihydrochloride

Ή NMR (DMS0-d ₆ , 300 MHz) δ 10.8 -11 (br, 2 H), 9.10 (brs, 1 H), 7.55 (d, 2 H, J = 8.7 Hz), 7.43-7.51 (m, 4 H), 7.37 (d, 2 H, J = 8.7 Hz), 7.25 — 7.3

3 (m, 4 H), 4.15-4.35 (m, 8 H), 2.9-3.5 (m, 12 H), 2.55-2.70 (m, 4 H), 1.184 (t, 3 H, J = 7.5 Hz) , 1.176 (t, 3 H, J = 7.5 Hz).

Example 98

 4- (4-Methoxybenzyl) -N- (4-{[4- (4-methoxybenzyl) -topiperazinyl] potassyl} phenyl) -topiperazine potash

_{¾ NMR (CDC1 3, 300 MHz} ) δ 7.18 - 7.40 (m, 8 H), 6.8 - 6.9 (m, 4 H), 6.51 (br s, 1 H), 3.809 (s, 3 H), 3.802 (s , 3 H), 3.47 (s, 2 H), 3.45 (s, 2 H), 3.45 — 3.7 (m, 6 H), 3.25 (brt, 2 H), 2.3-2.55 (m, 8 H).

Example 9 9

 4-[(5-Couguchi-2-Chenyl) methyl] -N- [4-({4-[(5-Couguchi-2-Chenyl) methyl] -1 -piperazinyl} carbonyl) phenyl] -Topipeperazinecarboxamide

_{¾ NMR (CDC1 3, 400 MHz} ) 57.36 (d, 2 H, J = 8.2 Hz), 7.34 (d, 2 H, J = 8.2 H z), 6.75 (d, 1 H, J = 3.7 Hz), 6.73 (d, 1 H, J = 3.7 Hz), 6.69 (brd., 1 H, J = 3.7 Hz), 6.67 (brd, 1 H, J = 3.7 Hz), 6.39 (brs, 1 H), 3.66 (s , 2H), 3.6

4 (s, 2 H), 3.53 (brt, 4 H, J = 5.0 Hz), 3.4-3.8 (m, 4 H), 2.54 (brt, 4 H, J = 5.0 Hz), 2.35-2.6 (m, 4H). In the same manner as in Example 1, the compounds of Example 100 and Example 101 were synthesized. For purification, ordinary silica gel column chromatography was used.

).

Example 100

4- (4-Ethylbenzyl) -N- (3-{[4- (4-Ethylbenzyl) -topiperazinyl] butyarbonyl} phenyl) -1-pidazinecarboxamide

¾ NMR (CDC1, 300 MHz) 57.45 — 7.29 (m, 3 H), 7.24 (d, 2 H, J = 8.0 Hz), 7 .21 (d, 2 H, J = 8.0 Hz), 7.17 (d, 2 H, J = 8.0 Hz), 7.15 (d, 2 H, J = 8.0 Hz), 7.03 (d, 1 H, J = 7.3 Hz), 6.42 (brs, 1 H), 3.7 — 3.8 (m, 2 H), 3.52 (s, 2 H), 3.49 (s, 2 H), 3.40-3.55 (m, 6 H), 2.65 ( q, 2 H, J = 7.7 Hz), 2.63 (q, 2 H, J = 7.7 Hz), 2.48 (brt, 6 H, J = 5.0 Hz), 2.30-2.45 (m, 2 H), 1.2 4 ( t, 3 H, J = 7.7 Hz), 1.23 (t, 3 H, J = 7.7 Hz).

Example 1 01

 4-[(5-Couguchi-2-Chenyl) methyl] -N- [3-({4-[(5-Couguchi-2-Chenyl) methyl]-1-piperazinyl} carbonyl) phenyl] -1-piperazinecarboxamide

Ή thigh _{(CDC1 3, 400 MHz) 57.38} - 7.42 (m, 2 H), 7.29 - 7.33 (m, 1 H), 7.30 - 7.60 (m, 1 H), 6.74 (d, 1 H, J = 3.7 Hz ), 6.73 (d, 1 H, J = 3.7 Hz), 6.69 (brd, 1 H, J = 3.7 Hz), 6.66 (brd, 1 H, J = 3.7 Hz), 6.38 (brs, 1 H), 3.4 -3.8 (m, 4 H), 3.66 (s, 2 H), 3.64 (s, 2 H), 3.51 (brt, 4 H, J = 5.0 Hz), 2.45

(brt, 4 H, J = 5.0 Hz), 2.35-2.6 (m, 4 H).

Example 102

4- (1,3-benzodioxoyl-5-ylmethyl) -N- (4-{[4- (4-ethylbenzyl) -topiperazinyl] carbonyl} phenyl) -1-pidazinecarboxamidini hydrochloride Salt synthesis

Example 102-1

 Synthesis of 4-({[4- (1,3-benzodioxoyl-5-ylmethyl) -1-piperazinyl] carbonyl} amino) benzoic acid

To a solution of triphosgene (3.3 g, 11.1 mmol) in THF (5 ml) was added dropwise a solution of 4-aminobenzoic acid (3.0 g, 21.9 mmol) in THF (30 ml) under ice cooling, and the reaction solution was brought to 0 ° C. And stirred for 1 hour. To this reaction solution, Bokupipe b piperazine (7.3 g, 33.1 mmol) THF (20 ml) dissolved solution, Toryechiruamin (4.2 g, 41.5 negation ₀ 1) the Karoe was stirred 65 hours at room temperature. Ethyl acetate and aqueous sodium hydrogen carbonate were added to the reaction solution, and the mixture was extracted with aqueous sodium hydroxide. The aqueous layer was washed with ethyl acetate, and then made acidic (pHpH4) by adding aqueous hydrochloric acid. This was extracted with ethyl acetate: THF (3: 1). The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography. The residue was purified by separation (ethyl acetate → chloroform: methanol = 20 _: 1 → 5: 1) to give the title compound (4.50 g, yield 54%).

¾ thigh _{(DMSO- d 6, 300 MHz)} §8.84 (s, 1 H), 7.79 (d, 2 H, J = 9.0 Hz), 7.56 (d, 2 H, J = 9.0 Hz), 6.87 (s, 1H), 6.85 (d, 1 H, J = 7.9 Hz), 6.76 (d, 1 H, J = 7.9 Hz), 5.98 (s, 2 H), 3.4—3.5 (m, 4 H), 3.41 ( s, 2 H), 2.3-2.4 (m, 4 H).

Example 102-2

 4- (1,3-benzodioxoyl-5-ylmethyl) -N- (4-{[4- (4-ethylbenzyl) -tripiperazinyl] carbonyl} phenyl) -1-pidazinecarboxamide Synthesis of dihydrochloride

 Example 10 4-({[4- (1,3-Benzodoxyl-5-ylmethyl) -topidazinyl] carbonyl} amino) benzoic acid obtained in 02-1 (67 mg, 0.175 t ol) ), N- (4-ethylbenzyl) pidazine dihydrochloride (55 mg, 0.198 mmol), triethylamine (40 mg, 0.395 dandelionol), HOBt (25 mg, 0.185 t, o WSC hydrochloride (40 mg, (0.209 mmol) in DMF (1.5 ml) was stirred at room temperature for 18 hours, aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The residue was separated and purified by silica gel column chromatography (ethyl acetate → ethyl acetate: methanol = 20: 1), and treated with dioxane hydrochloride solution. The dihydrochloride (90 mg) was obtained.

Thigh (DMS0-d ₆ , 300 MHz) 510.8 -11.1 (br, 2 H), 9.11 (brs, 1 H), 7.55 (d, 2 H, J = 8.6 Hz), 7.48 (d, 2 H, J = 8.1 Hz), 7.37 (d, 2 H, J = 8.6 Hz), 7.29 (d, 2 H, J = 8.1 Hz), 7.21 (s, 1 H), 6.98-7.03 (m, 2 H), 6, 07 (s, 2 H), 4.15-4.35 (m, 8 H), 2.9-3.5 (m, 12 H), 2.62 (q, 2 H, J = 7.5 Hz), 1.17 (t, 3 H, J = 7.5 Hz).

In the same manner as in Example 102, compounds from Example 103 to Example 105 were synthesized. Example 1 03

4- (1,3-benzodioxol-5-ylmethyl) -N- (4-{[4- (4-methoxybenzyl)-1-pyrazinyl 1carbonyl) phenyl) -1- Piperazinecarboxamidini hydrochloride _{Ή NMR (DMSO- d 6, 300} MHz) 510.9 -11.2 (br, 2 H), 9.14 (brs, 1 H), 7.55 (d, 2 H, J = 8.5 Hz), 7.49 (d, 2 H, J = 8.8 Hz), 7.36 (d, 2 H, J = 8.5 Hz), 7.24 (s, 1 H), 6.98-7.05 (m, 4 H), 6.07 (s, 2 H), 4.18-4.35 (m , 8H), 3.77 (s, 3H), 3.7-3.95 (m, 4H), 3.2-3.4 (m, 6H), 2.9-3.15 (m, 2H).

Example 10

 4- (1,3-benzodioxol-5-ylmethyl) -N- [4-({4- [4_ (trifluoromethoxy) benzyl] -topiperazinyl} carbonyl) phenyl] -1-piぺ Razinecarboxamidini hydrochloride

'H corrupt (DMS0-d ₆ , 300 MHz) δ 11.2 -11.4 (br, 1 H), 10.8 -11.1 (br, 1 H), 9, 1 1 (brs, 1 H), 7.73 (d, 2 H , J = 8.2 Hz), 7.55 (d, 2 H, J = 8.7 Hz), 7.47 (d, 2 H, J = 8.2 Hz), 7.36 (d, 2 H, J = 8.7 Hz), 7.22 (s, 1H), 6.95-7.05 (m, 2H), 6.07 (s, 2H), 4.2-4.4 (m, 8H), 2.9-3.5 (ra, 12H).

Example 1 05

 4- (1,3-benzodioxoyl-5-ylmethyl) -N- [4-({4- [4- (hydroxymethyl) benzyl] -topiperazinyl} carbonyl) phenyl] -1-pidazinecarboxamide Dihydrochloride

¾ thigh _{(DMS0 - d 6, 300 MHz} ) 511.1 -11.3 (br, 2 H), 9.15 (brs, 1 H), 7.56 (d, 2 H, J = 8.5 Hz), 7.53 (d, 2 H, J = 7.9 Hz), 7.38 (d, 2H, J = 7.9 Hz), 7.3

6 (d, 2 H, J = 8.5 Hz), 7.25 (s, 1 H), 6.97-7.05 (m, 2 H), 6.06 (s, 2 H),

4.51 (s, 2 H), 3.9-4.4 (m, 8 H), 2.9 — 3.5 (m, 12 H).

Example 1 06

 Synthesis of 1,7-Dioxo-1,7-bis {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} -4-heptanone

N- [4- (Trifluoromethyl) benzyl] piperazine (810 mg, 3.32 mmol), HOBt (420 mg, 3.11 mmol) in a solution of 4-ketopimelic acid (253 mg, 1.45 mmol) in DMF (5 ml) , WSC · hydrochloride (620 mg, 3.23 Band01) was added, and the reaction solution was stirred at room temperature for 86 hours. Aqueous sodium bicarbonate was added to the reaction solution, and extracted with ethyl acetate: toluene (2: 1). The organic layer is washed with saturated saline, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. did. The obtained residue was separated and purified by silica gel column chromatography (chloroform: methanol = 50: 1 → 20: 1) to give the title compound (770 mg, yield 85%).

_{¾ MR (CDC1 3, 400 MHz} ) δ 7.58 (d, 4 H, J = 8.1 Hz), 7.45 (d, 4 H, J = 8.1 Hz), 3.60 (brt, 4 H, J = 5.0 Hz), 3.56 (s, 4 H), 3.50 (brt, 4 H, J = 5.0 Hz), 2.84 (t, 4 H, J = 6.2 Hz), 2.63 (t, 4 H, J = 6.2 Hz), 2.44 (brt, 4 H, J = 5.0 Hz), 2.40 (brt, 4 H, J = 5.0 Hz).

In the same manner as in Example 106, compounds from Example 107 to Example 120 were synthesized. Example 1 07

Tri ((2S) -2-acetylamino-5-oxo-5- {4_ [4- (trifluoromethyl) benzyl] -1-piperazinyl} pentanoyl) -4- [4- (trifluoromethyl) benzyl ] Pirazine

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.58 (d, 4 H, J = 8.0 Hz), 7.45 (d, 4 H, J = 8.0 Hz), 6.57 (d, 1 H, J = 7.9 Hz), 4.90 -4.98 (m, 1 H), 3.6-3.84 (m, 6 H), 3.56 (s, 4 H), 3.38-3.5 (m, 2 H), 2.35-2.58 (m, 9 H), 2.26 (dt, 1 H, J = 16.6, 5.6 Hz), 2.08-2.18 (m, 1 H), 2.00 (s, 3 H), 1.62-1.70 (m, 1 H).

 1- (3,3-Dimethyl-5-oxo-5- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} pentanoyl) -4- 4- [4- (trifluoromethyl) benzyl] Perazine

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.58 (d, 4 H, J = 8.0 Hz), 7.44 (d, 4 H, J = 8.0 Hz), 3.61 (brt, 4 H, J = 4.7 Hz), 3.55 (s, 4H), 3.52-3.57 (m, 4H), 2.52 (s, 4H), 2.38-2.45 (m, 8H), 1.15 (s, 6H).

Example 1 09

l- (2,2-dimethyl-4-oxo-4- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} butanoyl)-4- [4- (trifluoromethyl) benzyl ] Pirazine

_{¾ NMR (CDC1 3, 400 MHz} ) 57.58 (d, 4 H, J = 7.9 Hz), 7.45 (d, 4 H, J = 7.9 H z), 3.59 one 3.68 (m, 6 H), 3.55 (s, 4H), 3.48-3.52 (m, 2H), 2.61 (s, 2H), 2,39-2.46 (m, 8H), 1.41 (s, 6H). Example 1 1 0

 1- (2-Methyl-4-oxo-4- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} butanoyl) -4- [4- (trifluoromethyl) benzyl] pi Perazine

_{'Η NMR (CDC1 3, 400} MHz) 57.58 (d, 4 H, J = 8.0 Hz), 7.45 (d, 2 H, J = 8.0 H z), 7.44 (d, 2 H, J = 8.0 Hz), 3.48-3.70 (m, 8 H), 3.55 (s, 2 H), 3.53 (s, 2 H), 3.26-3.36 (m, 1 H), 2.94 (dd, 1 H, J = 8.8, 6.2 Hz) , 2.35-2.59 (m, 8 H), 2.25 (dd, 1 H, J = 6.2, 4.6 Hz), 1.13 (d, 3 H, J = 7.1 Hz).

Example 1 1 1

1- [4- (Trifluoromethyl) benzyl] -4-{[(1R, S, 2R, S) -2-({4- [4- (trifluoromethyl) benzyl] -topiperazinyl} carbonyl) cyclo mouth butyl] carbonitrile sulfonyl} piperidines Rajin Ή thigh _{(CDC1 3, 400 MHz) §7.57} (d, 4 H, J = 8.1 Hz), 7.43 (d, 4 H, J = 8.1 H z), 3.73 - 3.79 (m, 2 H), 3.57-3.63 (m, 4 H), 3.55 (s, 4 H), 3.39-3.52 (m, 4 H), 2.33-2.46 (m, 8 H), 2.08-2.15 (m , 4H).

Example 1 1 2

1- [4- (Trifluoromethyl) benzyl] -4- 4-[[(1R, S, 2R, S) -2-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) Pentyl] carbonyl} piperazine

_{¾ NMR (CDC1 3, 400 MHz} ) 57.58 (d, 4 H, J = 8.0 Hz), 7.44 (d, 4 H, J = 8.0 H z), 3.5 - 3.68 (m, 10 H), 3.55 (s, 4H), 2.36-2.51 (m, 8H), 1.98-2.07 (m, 2H), 1.72-1.80 (m, 2H), 1.60-1.70 (m, 2H).

Example 1 1 3

 1- (4-oxo-2-phenyl-4- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} butanoyl) -4- [4- (trifluoromethyl) benzyl] pi Razine

_{] H NMR (CDC1 3, 400} MHz) 57.57 (d, 2 H, J = 8.1 Hz), 7.53 (d, 2 H, J = 8.1 H z), 7.42 (d, 2 H, J = 8.1 Hz), 7.37 (d, 2 H, J = 8.1 Hz), 7.22-7.33 (m, 5 H), 4.42 (dd, 1 H, J = 4.1 Hz), 3.70-3.79 (m, 1 H), 3.52 (s, 2H), 3.44 (s, 2H), 3.28-3.70 (m, 8H), 2.40-2.50 (m, 4H), 2.28-2.38 (m, 2H), 2. 18-1 2.27 (m, 2 H), 1.77-1.84 (m, 1 H).

Example 1 14

l- [4- (Trifluoromethyl) benzyl]-4-{[5-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) -3-pyridinyl] carbonyl } Pirazine

_{¾ NMR (CDC1 3, 400 MHz} ) 58.67 (d, 2 H, J = 2.1 Hz), 7.80 (t, 1 H, J = 2.1 H z), 7.59 (d, 4 H, J = 8.0 Hz), 7.45 (d, 4 H, J = 8.0 Hz), 3.75-3.85 (br, 4 H), 3.59 (s, 4 H), 3.4-3.5 (br, 4 H), 2.35-2.65 (br, 8 H).

Example 1 1 5

l- [4- (Trifluoromethyl) benzyl]-4-{[6-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) -2-pyridinyl] carbo Two} piperazine

¾ thigh _{(CDC1 3, 400 MHz) 57.90} (t, 1 H, J = 7.8 Hz), 7.68 (d, 2 H, J = 7.8 H z), 7.59 (d, 4 H, J = 8.0 Hz), 7.45 (d, 4 H, J = 8.0 Hz), 3.82 (brt, 4 H, J = 5.0 Hz), 3.58 (s, 4 H), 3.57 (brt, 4 H, J = 5.0 Hz), 2.54 (brt, 4 H, J = 5.0 Hz), 2.42 (brt, 4 H, J = 5.0 Hz).

Example 1 1 6

 1- [4- (Trifluoromethyl) benzyl] -4- [3-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} pyrbonyl) benzoyl] pidazine

_{¾ NMR (CDC1 3, 400 MHz} ) 57.58 (d, 4 H, J = 8.1 Hz), 7.41 - 7.46 (m, 8 H, J = 8.0 Hz), 3.7 - 3.85 (br, 4 H), 3.58 (s , 4 H), 3.35-3.5 (br, 4 H), 2.3-2.6 (br, 8 H).

Example 1 1 7

l- [2-methoxy-5-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) benzoyl] -4- [4- (trifluoromethyl) benzyl] pi Perazine

_{¾ NMR (CDC1 3, 400 MHz} ) 57.579 (d, 2 H, J = 8.1 Hz), 7.575 (d, 2 H, J = 8.1 Hz), 7.42 one 7.47 (m, 5 H), 7.31 (d, 1 H, J = 2.1 Hz), 6.91 (d, 1 H, J = 8.6

Hz), 3.85 (s, 3H), 3.57 (s, 4H), 3.4-3.9 (br, 6H), 3.2-3.3 (m, 2H),

2.25-2.65 (m, 8 H). Example 1 18

1, 7-bis [4- (4-black port benzyl) - Bok piperazinyl] -1,7 Jiokiso - 4-heptanone _{Ή NMR (CDC1 3, 400 MHz} ) §7.29 (d, 4 H, J = 8.4 Hz ), 7.25 (d, 4 H, J = 8.4 Hz), 3.58 (brt, 4 H, J = 5.0 Hz), 3.48 (brt, 4 H, J = 5.0 Hz), 3.47 (s, 4 H), 2.83 (t, 4 H, J = 6.3 Hz), 2.61 (t, 4 H, J = 6.3 Hz), 2.41 (brt, 4 H, J = 5.0 Hz), 2.38 (brt, 4 H, J = 5.0 Hz).

Example 1 1 9

1, 7-bis [4- (3, 4-dichlorobenzyl) -1-piperazinyl] -1, 7-Jiokiso - 4-heptanone _{Ή NMR (CDC1 3, 400 MHz} ) δ 7.43 (d, 2 H, J = 1.9 Hz), 7.39 (d, 2 H, J = 8.2 Hz), 7.15 (dd, 2 H, J = 8.2, 1.9 Hz), 3.59 (brt, 4 H, J = 5.0 Hz), 3.49 (brt, 4 H, J = 5.0 Hz), 3.45 (s, 4 H), 2.84 (t, 4 H, J = 6.3 Hz), 2.61 (t, 4 H, J = 6.3 Hz), 2.43 (brt, 4 H, J = 5.0 Hz), 2.38 (brt, 4 H, J = 5.0 Hz).

Example 1 20

 1 (3,4-Dimethyl benzyl) -4- {5- [4- (3,4-Dimethyl benzyl) -topiperazinyl] -3,3-dimethyl-5-oxopentanoisole} piperazine

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.43 (d, 2 H, J = 1.9 Hz), 7.39 (d, 2 H, J = 8.2 Hz), 7.15 (dd, 2 H, J = 8.2, 1.9 Hz) , 3.61 (brt, 4H, J = 4.8 Hz), 3.54 (brt, 4H, J = 4.8 Hz), 3.45 (s, 4H), 2.52 (s, 4H), 2.36-2.42 (m, 8 H), 1.15 (s, 6 H).

Example 1 2 1

 5-oxo-2- (3-oxo-3- {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} pulp) -5- {4-[4- (trifluoromethyl) Synthesis of methyl benzyl] -1-piperazinyl} pentanoate

Example 1 22

Methyl 7-oxo-7- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} -4-(({4- [4- (trifluoromethyl) benzyl] -topiperazinyl} carbonyl) heptanoic acid Example 1 23 1- (5-oxo-2-(3-oxo-3- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} propyl)-5- {4- [4- (trifluoro Methyl) benzyl: Synthesis of H-piperazinyl} pentanoyl) -4- [4- (trifluoromethyl) benzyl] piperazine

 To a solution of 1,3,5-pentanetricarboxylic acid (0.40 g, 1.96 mmol) in DMF (10 ml) was added N- [4- (trifluoromethyl) benzyl] piperazine (1.0 g , 4.09 mmol), HOBt (0.55 g, 4.07 mmol) and WSC · hydrochloride (0.83 g, 4.33 mmol), and the reaction solution was stirred at room temperature for 40 hours. did. An aqueous solution of sodium dihydrogen phosphate was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.

The obtained residue was dissolved in methanol (30 ml), and thionyl chloride (0.75 g, 6.30 mmol) was added dropwise. The reaction solution was stirred at room temperature for 20 minutes and at 60 ° C for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and part of the solvent was distilled off. The residue was extracted with ethyl acetate, and the organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (form: methanol = 100: 1 → 20: 1) and (ethyl acetate: methanol = 50: 1 → 5: 1) to give 5-oxo_2 -(3-oxo-3- {4- [4- (Trifluoromethinole) benzyl] -1-piperazinyl} propyl) -5- {4- [4- (Trifluoromethyl) benzyl] -1- Methyl piperazinyl} pentanoate (189 mg, 1% 14%), 7-oxo-7- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} -4-({4- Methyl [4-[(trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) heptanoate (125 mg, 10% yield), tri (5-oxo-2- (3-oxo-3- {4- [4- (Trifluoromethyl) benzyl] -topiperazinyl} propyl)-5- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} pentanoyl)-4- [4- (trifluoromethyl) Le) benzyl] Pipera Jin (180 m _g, 10% yield).

Example 1 Compound of 21

5-oxo- 2- (3-oxo-3- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} -pyr) -5- {4- [4- (trifluoromethyl ) Benzyl] -Topiperazinyl} methyl pentanoate ¾ NMR (CDCI3, 400 MHz) δ 7.58 (d, 4 H, J = 8.0 Hz), 7.45 (d, 4 H, J = 8.0 Hz), 3.67 (s, 3 H), 3.61 (brt, 4 H, J = 4.8 Hz), 3.56 (s, 4 H), 3.45 (brt, 4 H, J = 4.8 Hz), 2.46-2.55 (m, 1 H), 2.38-2.45 (m, 8 H), 2.25-2.36 (m, 4 H), 1.82-2.00 (m, 4 H).

Example 1 Compound of 22

 7-oxo-7- {4- [4- (Trifluoromethyl) benzyl] -1-piperazinyl} -4-({4_ [4- (Trifluoromethyl) benzyl] -tripiperazinyl} carbonyl) methyl heptanoate

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.58 (d, 4 H, J = 8.1 Hz), 7.44 (d, 4 H, J = 8.1 Hz), 3.65 (s, 3 H), 3.56 (s, 2 H ), 3.55 (s, 2 H), 3.50-3.71 (m, 6 H), 3.39-3.50 (m, 2 H), 2.86-2.94 (m, 1 H), 2.34-2.47 (m, 10 H), 2.13-2.30 (m, 2H), 1.88-2.00 (m, 2H), 1.68-1.80 (m, 2H).

Example 1 Compound of 23

Tri (5-oxo-2- (3-oxo-3- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} propyl) -5- {4- [4- (trifluoromethyl ) Benzyl] -1-piperazinyl} pentanoyl) -4-C4- (trifluoromethyl) benzyl] pidazine

_{¾ NMR (CDC1 3, 400 MHz} ) 57.58 (d, 6 H, J = 8.0 Hz), 7.44 (d, 6 H, J = 8.0 H z), 3.60 - 3.70 (m, 6 H), 3.56 (s, 4 H), 3.55 (s, 2 H), 3.40-3.54 (m, 6 H), 2.90 (quint, 1 H, J = 6.8 Hz), 2.35-2.50 (m, 14 H), 2.15-2.25 (m , 2H), 1.85-2.00 (m, 2H), 1.67-1.78 (m, 2H).

Example 1 24

4- [4- (Trifluoromethyl) benzyl] -N- [5-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) -2-pyridinyl] -1 Synthesis of 2-pirazazinecarboxamide In a solution of triphosgene (200 mg, 0.674 mmol) in THF (2 ml), add 6-aminoaminonicotinic acid (100 mg, 0.724 bandol) in THF (5 ml) under ice-cooling, and tryptilamine ( A solution of 140 mg, 1.38 mmol) in THF (5 ml) was added dropwise, and the reaction solution was stirred at 0 ° C for 20 minutes and at room temperature for 2.5 hours. A solution of N- [4- (trifluoromethyl) benzyl] piperazine (0.50 g, 2.05 mmol) in THF (5 ml) and a solution of triethylamine (0.5 g, 4.94 mmol) in THF (3 ml) The solution was added and stirred at room temperature for 15 hours. Aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: methanol = 50: 1 → 5: 1) to obtain SSG-5960 (243 mg, yield 53%).

Ή thigh _{(CDC1 3, 400 MHz) §8.49} (s, 1 H), 8.33 (d, 1 H, J = 2.3 Hz), 7.62 (dd, 1 H, J = 8.3, 2.3 Hz), 7.59 (d, 2H, J = 8.0 Hz), 7.58 (d, 2H, J = 8.0 Hz), 7.47 (d, 2H, J = 8.0 Hz), 7.45 (d, 2H, J = 8.0 Hz), 6.92 ( d, 1 H, J = 8.3 Hz), 3.6-3.85 (m, 4 H), 3.60 (s, 2 H), 3.59 (s, 2 H), 3.45-3.60 (m, 4 H), 2.4 -2.6 (m, 8 H).

Example 1 25

 Synthesis of 1,7-Dioxo-1,7-bis {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} -4-heptanoisole

 1,7-Dioxo-1,7-bis {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} -4-heptanone (296 mg, 0.472 mmol) obtained in Example 106 in ethanol (296 mg To the solution (3 ml) was added sodium borohydride (23 mg, 0.608 mmol), and the reaction solution was stirred at room temperature for 40 minutes. To the reaction solution was added 1N aqueous hydrochloric acid, and the mixture was stirred at room temperature for 10 minutes. To this was added sodium bicarbonate water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and dried under vacuum to obtain the title compound (273 mg, yield: 92%).

_{¾ NMR (CDC1 3, 400 MHz} ) 8 7.59 (d, 4 H, J = 8.1 Hz), 7.45 (d, 4 H, J = 8.1 Hz), 4.21 (d, 1 H, J = 4.2 Hz), 3.58 -3.70 (m, 5 H), 3.56 (s, 4 H), 3.50 (b rt, 4 H, J = 5.0 Hz), 2.47-2.56 (m, 4 H), 2.37-2.47 (m, 8 H) , 1.80 — 1.90 (m, 2 H), 1.70-1.80 (m, 2 H).

Example 1 26

Synthesis of 1,7-Dioxo-1,7-bis {4- [4- (trifluoromethyl) benzyl: H-piperazinyl}-4-heptanone oxime 1,7-Dioxo-1,7-bis {4_ [4- (trifluoromethyl) benzyl] -topiperazinyl} -4-heptanone (80 mg, 0.128 mmol) obtained in Example 106, hydroxylamine hydrochloride A solution of the salt (15 mg, 0.216 bandol) and sodium acetate trihydrate (25 mg, 0.186 mmol) in ethanol (2 ml) was stirred at room temperature for 4 hours. Aqueous sodium hydrogen carbonate was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was dried under reduced pressure to give the title compound (85 mg).

_{■ H NMR (CDC1 3, 400} MHz) δ 7.6 - 7.9 (brs, 1 H), 7.58 (d, 4 H, J = 8.1 Hz), 7.45 (d, 4 H, J = 8.1 Hz), 3.62 (brt , 4 H, J = 4.9 Hz), 3.56 (s, 4 H), 3.49 (brt, 4 H, J = 4.9 Hz), 2.54-2.66 (m, 8 H), 2.39-2.45 (m, 8 H) .

Example 1 27

 {[(4-oxo-3- (3-oxo-3- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} pulpyl) -4- {4- [4- (trifluoro Synthesis of tert-butyl l-methyl) benzyl]-1-piperazinyl} butylidene) amino

Synthesis of 1,7-Dioxo-1,7-bis {4_ [4- (trifluoromethyl) benzyl] -topiperazinyl} -4-heptanone oxime (80 mg, 0.125 mmol) obtained in Example 26 Sodium hydride (60%, 10 mg, 0.25 mmol) was added to a THF (1 ml) solution, and the reaction solution was stirred at 40 ° C for 15 minutes. To this reaction solution was added tert-butyl bromoacetate (30 mg, 0.154 mmol), and the mixture was stirred at 40 ° C for 5 hours. Sodium hydride (60%, 6 mg) was added, and the mixture was further stirred at 40 ° C for 1 hour. An aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (chloroform-form → clopeform-form: methanol = 20: 1) to give the title compound (72 mg, yield 77%). Ή thigh _{(CDC1 3, 400 MHz) δ} 7.58 (d, 4 H, J = 8.0 Hz), 7.45 (d, 4 H, J = 8.0 Hz), 4.43 (s, 2 H), 3.60 - 3.65 (br, 4H), 3.56 (s, 4H), 3.46-3.53 (m, 4H), 2.52-2.64 (m, 8H), 2.38-2.45 (br, 8H), 1.44 (s, 9H).

The compound of Example 128 was synthesized in the same manner as in Example 127.

Example 1 28 {[(4-oxo-3- (3-oxo-3- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} propyl)-4- {4- [4- (trifluoromethyl ) Benzyl] -1-piperazinyl} phenylidene) amino] oxy} ethyl acetate

Ή丽_{(CDC1 3, 400 MHz) δ} 7.58 (d, 4 H, J = 8.0 Hz), 7.45 (d, 4 H, J = 8.0 Hz), 4.54 (s, 2 H), 4.17 (q, 2 H , J = 7.1 Hz), 3.60-3.70 (br, 4H), 3.56 (s, 4H), 3.46-3.52 (m, 4H), 2.51-2.68 (m, 8H), 2.38-2.48 (br , 8 H), 1.26 (t, 3 H, J = 7.1 Hz).

Example 1 29

 {[(4-oxo-l- (3-oxo-3--3- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} propyl) -4- {4- [4- (trifluoro Methyl) benzyl] -topiperazinyl} butylidene) amino] oxy} acetic acid

 {[(4-oxo-1- (3-oxo-3- {4- [4- (trifluoromethyl) benzyl]]-topiperazinyl} propyl) -4- {4- [4- (Trifluoromethyl) benzyl] -1-pirazinyl} butylidene) amino] oxy} ethyl acetate (42 mg, 0.058 mmol), ethanol solution (1 ml), THF (1 ml), IN hydroxylation A mixture of sodium water (1 ml) was stirred at room temperature for 2 hours. Aqueous sodium dihydrogen phosphate was added to the reaction solution to make it weakly acidic (around pH 4), and extracted with ethyl acetate. The organic layer was distilled off under reduced pressure, and the obtained residue was dried under vacuum to obtain the title compound (42 mg).

_{¾ MR (CDC1 3, 400 MHz} ) δ 7.59 (d, 4 H, J = 8.0 Hz), 7.46 (d, 2 H, J = 8.0 Hz), 7.44 (d, 2 H, J = 8.0 Hz), 4.59 (s, 2 H), 3.60-3.66 (m, 4 H), 3.60 (s, 2 H), 3.59 (s, 2 H), 3.47-3.53 (m, 4 H), 2.67 (s, 4 H) , 2.55 (s, 4 H), 2.42-2.48 (m, 8 H).

Example 1 30

 Synthesis of 1,7-Dioxo-1,7-bis {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} -4-heptanamine

Sodium borohydride (3 mg, 0.079 mmol) was added to a methanol (5 ml) solution of salted nickel pentahydrate (10 mg, 0.042 mmol), and the reaction solution was stirred at room temperature for 15 minutes. . 1,7-Dioxo-1,7-bis {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} -4-heptanone oxime (40 mg, 0.062) obtained in Example 126 was added to the reaction mixture. mmol) of methanol (1.5 ml) and sodium borohydride (9 mg, 0.238 mmol), and the mixture was stirred at room temperature for 30 minutes. Then, while checking the progress of the reaction by TLC, sodium borohydride was added little by little until the raw materials disappeared (total 16 mg, 0.423 mmoK at room temperature for 4 hours). The insoluble material was removed by filtration through celite, and the filtrate was concentrated. The residue was treated with 1N aqueous hydrochloric acid, and further made alkaline with aqueous ammonia. This was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off to obtain the title compound (33 mg, yield 85%).

_{'Η NMR (CDC1 3, 400} MHz) δ 7.58 (d, 4 Η, J = 8.0 Hz), 7.45 (d, 4 H, J = 8.0 Hz), 3.56- 3.68 (m, 4 H), 3.56 (s , 4H), 3.49 (brt, 4H, J = 4.9 Hz), 2.73-2.80 (m, 1H), 2.37-2.50 (m, 12H), 1.75-1.85 (m, 2H), 1.56- 1.64 (m, 2H).

Example 1 3 1

4-oxo- 4-[(4-oxo-l- (3-oxo-3_ {4- [4- (trifluoromethyl) benzyl] -1 -piperazinyl} propyl)-4- {4- [4 Synthesis of methyl (-(trifluoromethyl) benzyl] -1-piperazinyl} butyl) amino] butanoate

 1,7-Dioxo-1,7-bis {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} -4-heptanamine (27 mg, 0.043 mmol) obtained in Example 30 To a solution of triethylamine (10 mg, 0.1 bandol) in THF (3 ml) was added dropwise a solution of 3-carbomethoxypropionyl chloride (9 mg, 0.060 mmol) in THF (0.5 ml) under ice-cooling. The mixture was stirred at 0 ° C for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (chloroform: methanol = 100: 1 → 10: 1) to give the title compound (25 mg, yield 78%).

¾ thigh _{(CDC1 3, 400 MHz) §7.58} (d, 4 H, J = 8.0 Hz), 7.44 (d, 4 H, J = 8.0 H z), 6.22 (d, 1 H, J = 8.7 Hz), 3.83-3.94 (m, 1 H), 3.62 (s, 3 H), 3.58-3 .66 (m, 4 H), 3.56 (s, 4 H), 3.45 (brt, 4 H, J = 4.9 Hz), 2.63 (t, 2 H, J = 6.7 Hz), 2.38-2.45 (m, 8 H), 2.29-2.38 (m, 6 H), 1.75-1.93 (m, 4 H).

 4-oxo-4-[(4-oxo-1- (3-oxo-3- {4_ [4- (trifluoromethyl) benzyl] -topiperazinyl} propyl)-4- {4- [4- Synthesis of ((trifluoromethyl) benzyl] -topiperazinyl} butyl (amino) butanoic acid

 4-oxo-4-[(4-oxo-tri (3-oxo-3- {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} propyl) -4- {obtained in Example 13 Methyl 4- [4- (trifluoromethyl) benzyl] -topiperazinyl} butyl) amino] butanoate (20 mg, 0.027 mmol) in aqueous lithium hydroxide (1 ml), THF (0.5 ml), The methanol (0.5 ml) solution was stirred at room temperature for 30 minutes. The reaction solution was charged with sodium dihydrogen phosphate water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then dried under vacuum to obtain the title compound (Π mg, yield: 87%).

Ή thigh _{(CDC1 3, 400 MHz) 57.58} (d, 4 H, J = 8.0 Hz), 7.45 (d, 4 H, J = 8.0 H z), 6.98 - 7.02 (br, 1 H), 3.85 - 3.94 ( in, 1 H), 3.57 (s, 4 H), 3.55-3.70

(m, 4 H), 3.46 (brt, 4 H, J = 4.9 Hz), 2.61-2.66 (m, 2 H), 2.39-2.50 (m, 12 H), 2.27-2.39 (m, 2 H), 1.76-1.91 (m, 4 H).

Example 1 33.

 N, N-dimethyl-5-oxo-2- (3-oxo-3--3- {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} propyl) -5- {4- [4- ( Synthesis of trifluoromethyl) benzyl] -topiperazinyl} tantanamide

 Example 12 5-oxo-2- (3-oxo-3- {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} propyl) obtained in 21) -5- {4- [4 -(Trifluoromethyl) benzyl] -topiperazinyl} methyl pentanoate was subjected to alkaline hydrolysis in the same manner as in Example 132, followed by a condensation reaction with dimethylamine in the same manner as in Example 106 to obtain the title compound. Was.

¾ thigh _{(CDC1 3, 400 MHz) δ7.58} (d, 4 H, J = 8.0 Hz), 7.44 (d, 4 H, J = 8.0 H z), 3.56 (s, 4 H), 3.56- 3.67 ( m, 4 H), 3.41 ― 3.52 (m, 4 H), 3.10 (s, 3 H) , 2.94 (s, 3 H), 2.87-2.94 (m, 1 H), 2.36-2.45 (m, 10 H), 2.16-2.25 (m, 2 H), 1.88-1.98 (m, 2 H), 1.70 ― 1.80 (m, 2 H).

Example 13

 1-{[1- (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} ethyl) -3-piperidinyl] carbonyl}-4- [4- (trifur Synthesis of (Oromethyl) benzyl] piperazine

Example 1 34-1

 Synthesis of 1- (tert-butoxycarbonyl) -3-piperidinecarboxylic acid

Boc ₂₀ (7.5 g, 34.4 mmol) was added dropwise to a THF (30 ml) solution of ethyl heptyl dipecotate (5.07 g, 32.2 mraol) and triethylamine (3.6 g, 35.6 t o), and the reaction solution was brought to room temperature. And stirred for 5 hours. The reaction solution was charged with sodium dihydrogen phosphate water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a mixture of Boc-ethyl ester of dipecotinic acid (9.1 g).

The above mixture was dissolved in THF (10 ml) and ethanol (10 ml), 1N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was stirred at room temperature for 2 hours. Lithium hydroxide dihydrate (2.0 g) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hour. A part of the solvent of the reaction solution was distilled off, and the residue was diluted with water and washed with ethyl ether. The aqueous layer was made acidic (pH 3-4) with aqueous hydrochloric acid and aqueous sodium dihydrogen phosphate, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and then dried under vacuum to obtain the title compound (7.25 g, yield in two steps: 98%).

_{Ή NMR (CDC1 3, 400 MHz} ) δ 3.95 - 4.30 (br, 1 H), 3.84- 3.93 (m, 1 H), 2.95 - 3.20 (br, 1 H), 2.81 - 2.91 (m, 1 H), 2.45-2.55 (m, 1 H), 2.03-2.12 (m, 1 H), 1.60-1.77 (m, 2 H), 1.46 (s, 9 H), 1.45-1.55 (m, 1 H).

Example 134-2

Synthesis of tert-butyl 3-({4- [4- (trifluoromethyl) benzyl] -topiperazinyl} carbonyl) -1-piperidinecarboxylate

Tri (tert-butoxycarbonyl) -3-piperidinecarboxylic acid obtained in Example 134-1 ( 0.24 g, 1.05 mmol), a solution of triethylamine (120 mg, 1.19 mmol) in dichloromethane (5 ml), N- [4- (trifluoromethyl) benzyl] piperazine (330 mg, 1.35 t1), B0P-C1 (0.30 g, 1.18 mmol) was added, and the reaction solution was stirred at room temperature for 98 hours. Aqueous sodium dihydrogen phosphate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (cloth form: methanol = 200: 1 → 20: 1) to give the title compound (410 mg, yield 86%).

_{¾ NMR (CDC1 3, 400 MHz} ) §7.59 (d, 2 H, J = 8.0 Hz), 7.45 (d, 2 H, J = 8.0 H z), 3.90 - 4.30 (m, 2 H), 3.57 (s , 2H), 3.45-3.75 (m, 4H), 2.50-3.00 (m, 3H), 2.35-2.50 (m, 4H), 1.80-1.90 (m, 1H), 1.65-1.80 (m , 2 H), 1.45 (s, 9 H), 1.40-1.50 (m, 1 H).

Example 1 34-3

 Synthesis of 1- (3-piperidinylcarbonyl) -4- [4- (trifluoromethyl) benzyl] piperazine

 Example 1 tert-butyl 3-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) -topiperidinecarboxylate (0.40 g, 0.878 mmol) obtained in 34-2, A mixture of 4N dioxane hydrochloride solution (2 ml), acetic acid (1 ml), and dioxane (1 ml) was stirred at room temperature for 1.5 hours. The reaction solution was concentrated, the residue was suspended in toluene, and the solvent was distilled off. The obtained residue was dried under vacuum to give the title compound (348 mg, yield 93%).

Example 1 34-4

{{1- (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl) -3-piperidinyl] carbonyl} -4- [4- (trifluryl Synthesis of (Oromethyl) benzyl] piperazine

To a solution of N- [4- (trifluoromethyl) benzyl] pidazine (298 mg, 1.22 mmol) and triethylamine (150 mg, 1.48 mmol) in THF (3 ml) was added chloroacetyl chloride ( A solution of 130 mg, 1.15 mmol) in THF (2 ml) was added dropwise, and the reaction solution was stirred under ice-cooling for 20 minutes. Add sodium dihydrogen phosphate water to the reaction solution Extracted. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.

 The obtained residue was dissolved in DMF, and 1/5 of the solution was heated at 45 ° C. at 45 ° C. to obtain 1- (3-piperidinylcarbonyl) -4- [4- (trifluoro (Oromethyl) benzyl] piperazine (101 mg, 0.236 mmol) and potassium carbonate (0.15 g, 1.09 mmol) were added to a suspension in DMF (2 ml). The reaction solution was stirred at 50 ° C for 5 hours. Aqueous sodium dihydrogen phosphate was added to the reaction mixture, and the mixture was extracted with ethyl acetate: toluene (4: 1). The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (form: form: methanol = 50: 1 → 5: 1) to give the title compound (99 mg, yield 66%).

_{¾ MR (CDC1 3, 400 MHz} ) §7.58 (d, 4 H, J = 8.0 Hz), 7.45 (d, 2 H, J = 8.0 H z), 7.44 (d, 2 H, J = 8.0 Hz), 3.56 (s, 2 H), 3.55 (s, 2 H), 3.48-3.70 (m, 8 H), 3.18 (d, 1 H, J = 14.5 Hz), 3.16 (d, 1 H, J = 14.5 Hz ), 2.86-2.96 (m, 2 H), 2.74-2.84 (m, 1 H), 2.35-2.50 (m, 8 H), 2.24 (t, 1 H, J = 10.9 Hz), 2.00-2.10 (m , 1 H), 1.70-1.81 (m, 2 H), 1.6-1.70 (m, 1 H), 1.44-1.56 (m, 1 H).

In the same manner as in Example 134, the compounds of Example 135 and Example 136 were synthesized.

Example 1 35

 1- (4-chlorobenzyl) -4-[(3-{[4- (4-chlorobenzyl) -topiperazinyl] -capillonyl} -1-piperidinyl) acetyl] pidazine

¾ thigh _{(CDC1 3, 400 MHz) δ} 7.30 (d, 4 H, J = 8.1 Hz), 7.25 (d, 2 H, J = 8.1 H z), 7.24 (d, 2 H, J = 8.1 Hz), 3.47 (s, 2H), 3.46 (s, 2H), 3.45-3.70 (m, 8H), 3.17 (s, 2H), 2.85-2.95 (m, 2H), 2.74-2.83 (m, 1 H), 2.35-2.4

5 (m, 8 H), 2.22 (t, 1 H, J = 10.9 Hz), 2.00-2.08 (m, 1 H), 1.69-1.80 (m, 2 H), 1.6-1.65 (m, 1 H) , 1.46-1.56 (m, 1 H).

Example 1 36

{{[((2-oxo-2- {4_ [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl) - 4 - piperidines lysinyl] force carbonyl} -4- [4- (triflate Ruo ii) benzyl] piperidines Rajin ¾ NMR (CDC1 _3, 400丽z) 57.59 (d, 4 H , J = 8.1 Hz), 7.46 (d, 2 H, J = 8.1 Hz), 7.45 (d, 2 H, J = 8.1 Hz), 3.58-3.68 (m, 6 H), 3.57 (s, 2 H), 3.55 (s, 2 H), 3.47 ― 3.53 (m, 2 H), 3.15 (s, 2 H), 2.86-2.93 (m, 2 H), 2.37 — 2,5 0 (m, 9 H), 2.05-2.14 (m, 2H) 2H), 1.76-1.90 (m, 2H), 1.63-1.71 (m, 2H)

 Synthesis of dimethyl 2,2-bis (3-oxo-3- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} propyl) maproate

Example 1 37-1

 Synthesis of tetramethyl 1,3,3,5-pentanetetracarboxylate

 To a solution of dimethyl malonate (2.0 g, 15.1 mmol) in methanol (20 ml), add a 28% sodium methoxide methanol solution (2.9 g, 15.0 mmol) and methanol (5 ml), and cool the reaction mixture to 50 ° C. For 1 hour. A solution of methyl acrylate (1.3 g, 15.1 mmol) in methanol (5 ml) was added, and the mixture was stirred at 50 ° C for 2 hours, and further heated under reflux for 16 hours. Dilute hydrochloric acid and subsequently aqueous sodium hydrogen carbonate were added to the reaction solution, and methanol was distilled off. The residue was extracted with ethyl acetate, and the organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 2: 1) to give the title compound (0.55 g, yield 24% based on methyl acrylate). Obtained.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 3.73 (s, 6 H), 3.68 (s, 6 H), 2.29 - 2.35 (m, 4 H), 2.18 - 2.25 (m, 4 H).

Example 1 37 -2

 Synthesis of dimethyl 2,2-bis (3-oxo-3-{4- [4- (trifluoromethyl) benzyl] -topiperazinyl} propyl) malonate

Example 1 To a solution of tetramethyl 1,3,3,5-pentanetetracarboxylate (520 mg, 1.71 acetylol) obtained in 37-1 in methanol (2 ml) was added sodium hydroxide (145 mg, 3.63 ol). ) Was added and dissolved, and the reaction solution was stirred at room temperature for 7 hours. Dilute hydrochloric acid was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a carboxylic acid mixture (538 mg). This was dissolved in DMF (5 ml), and N- [4- (trifluoromethyl) benzyl] piperazine (440 mg, 1.80 t ol), HOBt (290 mg, 2.15 ol), WSC hydrochloride (440 mg, 2.56 tmol) was added and the reaction solution was stirred at room temperature for 70 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol (15 ml), and thionyl chloride (250 mg, 2.10 mol) was added dropwise, followed by stirring at room temperature for 30 minutes. Aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (cloth form: methanol = 100: 1 → 20: 1) to give the title compound (196 mg, yield 16%).

_{¾ NM (CDC1 3, 400 MHz} ) δ 7.59 (d, 4 H, J - 8.0 Hz), 7.45 (d, 4 H, J = 8.0 Hz), 3.72 (s, 6 H), 3.61 (brt, 4 H , J = 4.9 Hz), 3.56 (s, 4 H), 3.46 (brt, 4 H, J = 4.9 Hz), 2.38-2.45 (m, 8 H), 2.28-2.35 (m, 4 H), 2.19- 2.26 (m, 4 H).

Example 1 38

 6-oxo-6- {4- [4- (Trifluoromethyl) benzyl] -1-piperazinyl}-3-({4- [4- (Trifluoromethyl) benzyl] -1-piperazinyl} carbonyl ) Synthesis of tert-butyl hexanoate

Example 138-1

Synthesis of methyl 3- (2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl) propanoate To a solution of Meldrum's acid (3.0 g, 20.8 t) in acetonitrile (25 ml) Potassium carbonate (2.9 g, 21.0 tmol) and benzyltriethylammonium chloride (4.75 g, 20.9 mmol) were added, and the reaction solution was stirred at room temperature for 20 minutes. A solution of methyl acrylate (2.58 g, 30.0 mmol) in acetonitrile (10 ml) was added to the reaction solution, and the mixture was stirred at 60 ° C for 8 hours. Water was added to the reaction solution, which was washed with getyl ether. Acidify the aqueous layer with dilute hydrochloric acid (pH 1- After 2), extraction was performed with getyl ether. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dried under vacuum to give the title compound (2.41 g, yield 50%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 3.93 (t, 1 H, J = 5.6 Hz), 3.68 (s, 3 H), 2.66 (t, 2 H, J = 7.1 Hz), 2.40 (dt, 2 H , J = 7.1, 5.6 Hz), 1.82 (s, 3H), 1.78 (s, 3H).

Example 1 38-2

 Synthesis of methyl 3- [5- (261-1: -butoxy-2-oxoethyl) -2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl] propanoate

 Example 1 Acetonitrile of methyl 3- (2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl) propanoate (432 mg, 1.88 mmol) obtained in 38-1 (5 ml) ) The solution was charged with potassium carbonate (270 mg, 1.95 mmol) and benzyltriethylammonium chloride (430 mg, 1.89 mmol), and the reaction solution was stirred at 40 ° C for 10 minutes. The reaction solution was charged with tert-butyl bromoacetate (730 mg, 3.74 mmol) and stirred at 60 ° C for 7 hours. Dilute hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography.

(Hexane: ethyl acetate = 5: 1 → 3: 1) to give the title compound (627 mg, yield 97%).

_{¾ NMR (CDC1 3, 400 MHz} ) 53.68 (s, 3 H), 3.09 (s, 2 H), 2.47 (t, 2 H, J = 7. 9 Hz), 2.23 (t, 2 H, J = 7.9 Hz), 1.93 (s, 3H), 1.84 (s, 3H), 1.41 (s, 9H).

Example 1 38-3, 1 38-4

Example 1 38-3

 Synthesis of 1-tert-butyl 6-methyl 3-({4- [4- (trifluoromethyl) benzyl] -topiperazinyl} carbonyl) hexandioate

Example 1 38-4

6-oxo- 6- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl}-3-({4- [4- ( Synthesis of tert-butyl trifluoromethyl) benzyl] -1-pirazinyl} carbonyl) hexanoate

 Example 1 3- [5- (2-tert-butoxy-2-oxoethyl) -2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl] propane obtained in 38-2 To a solution of methyl acid (1.38 g, 4.01 mmol) in THF (8 ml) and methanol (8 ml) was added a 1 N aqueous solution of lithium hydroxide (7.9 ml), and the reaction solution was stirred at room temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, the resulting residue was

(10 ml) solution. This DMS0 solution was heated and stirred at 160 ° C. for 2 hours. A 5% aqueous solution of potassium hydrogen sulfate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a monocarboxylic acid mixture (940 mg).

 The above monocarboxylic acid mixture (465 mg, 3- [5- (2-tert-butoxy-2-oxoethyl) -2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl] propane 1.79 t) was dissolved in DMF (5 ml), and N- [4- (trifluoromethyl) benzyl] pidazine (0.90 g, 3.68 t) was dissolved in DMF (5 ml). , HOBt (0.49 g, 3.63 mmol), WSC hydrochloride (0.70 g, 3.65 mmol), and triethylamine (0.30 g, 2.96 mmol) were added, and the mixture was stirred at room temperature for 10 days. Aqueous sodium hydrogen carbonate was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate → ethyl acetate: methanol = 20: 1 → 5: 1) to give 3-({4- [4- (trifluoromethyl) benzene). Tert-butyl 6-methyl hexane) dioxane (419 mg, yield 3 48%), 6-oxo-6- {4- [4- (trifluoromethylinole) benzyl ] Tert-Butyl -1-piperazinyl} -3-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) hexanoate (260 mg, yield 21% over 3 steps) Was.

Example 1 Compound of 38-3

1-tert-butyl 6-methyl 3-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) hexanedioate

_{¾ NMR (CDC1 3, 400 MHz} ) 57.58 (d, 2 H, J = 8.0 Hz), 7.45 (d, 2 H, J = 8.0 H z), 3.69 (s, 3H), 3.62 (brt, 2H, J = 4.9 Hz), 3.56 (s, 2H), 3.45 (brt, 2H, J = 4.9 Hz), 2.79-1.87 (m , 1H), 2.65 (dd, 1H, J = 16.4, 8.9 Hz), 2.28-2.45 (m, 7H), 1.84-1.98 (m, 2H), 1.42 (s, 9H).

Example 1 Compound of 38-4

To 6-oxo-6- {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} -3-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) hexanoic acid tert- butyl ¾ MR (CDC1 _3, 400顧z) 57.58 (d, 4 H , J = 8.0 Hz), 7.44 (d, 4 H, J = 8.0 H z), 3.56 (s, 4 H), 3.35-3.70 (m, 8 H), 3.23-3.30 (m, 1 H), 2.70 (dd, 1 H, J = 16.3, 9.0 Hz), 2.50-2.61 (m, 1 H), 2.18-2.48 (m , 10 H), 1.86-1.98 (m, 1 H), 1.69-1.80 (m, 1 H), 1.41 (s, 9 H).

Example 1 39

 6-oxo-6- {4- [4- (Trifluoromethyl) benzyl] -1-piperazinyl} -3-({4- [4- (Trifluoromethyl) benzyl] -topidrazinyl} carbonyl) Synthesis of methyl xanate 6-oxo-6- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} obtained in Example 1 38} -3-({4- [4- (trifluoro A solution of tert-butyl hexane (250 mg, 0.358 mmol) in trifluoroacetic acid (1.5 ml) and benzene (2 ml) in chloroform (2 ml) was stirred at room temperature for 3.5 hours. did. After the reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in methanol (5 ml). Thionyl chloride (110 mg, 0.925 mmol) was added dropwise to this solution, and the mixture was stirred at room temperature for 2 hours. Aqueous sodium hydrogen carbonate was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate → ethyl acetate: methanol = 20: 1 → chloroform: methanol = 20: 1) to give the title compound (145 mg, yield 63% over two steps). Obtained.

_{NMR (CDC1 3, 400 MHz)} δ 7.58 (d, 4 H, J = 7.8 Hz), 7.44 (d, 4 H, J = 7.8 Hz), 3.64 (s, 3 H), 3.56 (s, 4 H) , 3.50-3.72 (m, 6 H), 3.40-3.49 (m, 2 H), 3.30-3.40 (m, 1 H), 2.83 (dd, 1 H, J = 16.7, 9.4 Hz), 2.49-2.62 ( m, 1 H), 2.29-2.48 (m, 9 H), 2.19-2.29 (m, 1 H), 1.88-1.98 (m, 1 H), 1.71 -1.81 (m, 1 H).

Example 140

6-oxo-6- {4- [4- (Trifluoromethyl) benzyl] -1-piperazinyl} -4-({4- [4- (Trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) hexane Example 1 Synthesis of 3-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) hexanedioate obtained in Example 38-3 tert-butyl 6-methyl ( A solution of 285 mg (0.586 t) of trifluoroacetic acid (1.5 ml) and benzene (2 ml) was stirred at room temperature for 2.5 hours. After the reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in DMF (5 ml). N- [4- (Trifluoromethyl) benzyl] piperazine (200 mg, 0.819 mmol), HOBt (110 mg, 0.814 mmol), WSC hydrochloride (170 mg, 0.887 mmol), triethylamine (180 mg, 1.78 mmol) and stirred at room temperature for 13 hours and at 40 ° C for 2 hours. Aqueous sodium bicarbonate was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (chloroform: methanol = 50 _: 1 → 20: 1) to give the title compound (327 mg, yield 85% over two steps).

 Thigh (CDC1, 400 MHz) δ 7.58 (d, 4 H, J = 8.0 Hz), 7.44 (d, 4 H, J = 8.0 Hz), 3.69 (s, 3 H), 3.56--3.66 (m, 4H), 3.56 (s, 4H), 3.41-3.49 (m, 4H), 2.88-2.97 (m, 1H), 2.79 (dd, 1H, J = 16.0, 9.0 Hz), 2.34-2.48 (m, 1 1 H), 1.88-1.95 (m, 2 H).

Example 14 1

 6-oxo-6- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl}-4-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) hexane Acid synthesis

6-oxo-6- {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} -4-({4- [4- (trifluoromethyl) benzyl]-obtained in Example 140 Methyl 1-piperazinyl} carbonyl) hexanoate was subjected to alkaline hydrolysis in the same manner as in Example 132 to give the title compound. _{¾ NMR (CDC1 3, 400 MHz} ) δ 7.59 (d, 4 H, J = 7.7 Hz), 7.46 (d, 4 H, J = 7.7 Hz), 3,45- 3.75 (m, 12 H), 2.88 - 2.98 (m, 1 H), 2.81 (dd, 1 H, J = 16.7, 8 .6 Hz), 2.62-2.71 (m, 1 H), 2.35-2.60 (m, 10 H), 1.75-1,81 (m, 2 H).

 -Dimethyl-6-oxo-6- {4- [4- (trifluoromethyl) benzyl] -topiperazinyl}-4-({4- [4- (trifluoromethyl) benzyl] -tripiperazinyl} carbonyl ) Synthesis of hexaneamide

 6-oxo-6- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} -4-({4- [4- (trifluoromethyl) obtained in Example 1 Benzyl] -topiperazinyl} carbonyl) hexanoic acid and dimethylamine were subjected to a condensation reaction in the same manner as in Example 106 to give the title compound.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.58 (d, 4 H, J = 7.9 Hz), 7.44 (d, 4 H, J = 7.9 Hz), 3.57- 3.64 (m, 4 H), 3.56 (s, 2H), 3.55 (s, 2H), 3.34-3.50 (m, 5H), 3.17 (s, 3H), 2.95 (s, 3H), 2.90 (dd, 1H, J = 16.1, 9.7 Hz), 2.35-2.4 6 (m, 8 H), 2.22-2.33 (m, 3 H), 1.76-1.95 (m, 2 H) ..

Example 13

l- [5-oxo ·-2- (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} ethyl) -5- (1 -piperidinyl) pentanoyl]- Synthesis of 4- [4- (trifluoromethyl) benzyl] piperazine

 Example 14 6-oxo-6- {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} -4-({4- [4- (trifluoromethyl) benzyl) obtained in 41 ] -Topiperazinyl} carbonyl) Hexanoic acid and piperidine were subjected to a condensation reaction in the same manner as in Example 106 to obtain the title compound.

¾ Anonymous _{(CDC1 3, 400 MHz) δ} 7.58 (d, 4 H, J = 8.0 Hz), 7.42 one 7.49 (br, 4 H), 3.38 - 3.70 (m, 17 H), 2.89 (dd, 1 H, J = 15.6, 9.3 Hz), 2.20-2.55 (m, 11 H), 1.75-1.96 (m, 2 H), 1.4-1.7 (m, 6 H).

Example 1 44

6- [4- (3,4-dichlorobenzyl)-1-piperazinyl] -3- 3-[[4- (3,4-dichlorobenzyl) -1-piperazinyl] butyarbonyl} -6-oxohexanoic acid Synthesis of tert-butyl The title compound was obtained in the same manner as in Example 138.

Ή organ _{(CDC1 3, 400 MHz) 57.44} (brs, 2 H), 7.39 (d, 1 H, J = 8.2 Hz), 7.38 (d, 1 H, J = 8.2 Hz), 7.15 (brd, 2 H, J = 8.2 Hz), 3.45 (s, 4 H), 3.35-3.71 (m, 8 H), 3.23-3,31 (m, 1 H), 2.71 (dd, 1 H, J = 16.4, 9.0 Hz) , 2.49-2.60 (m, 1 H), 2.17-2.47 (m, 10 H), 1.86-1.98 (m, 1 H), 1.70-1.80 (m, 1 H), 1.41 (s, 9 H) .

Example 1 45

 6- [4- (3,4-dichlorobenzyl) -1-pidrazinyl] -4-{[4- (3,4-dichlorobenzyl) -1-piperazinyl] carbonyl} -6-oxohexane Of Methyl Acid

 The title compound was obtained in the same manner as in Example 140.

_{¾ NMR (CDC1 3, 400 MHz} ) 57.43 (d, 2 H, J = 1.8 Hz), 7.39 (d, 2 H, J =., 8.2 H z), 7.15 (d, 2 H, J = 8.2, 1.8 Hz), 3.69 (s, 3 H), 3.54-3.65 (m, 4 H), 3.45 (s, 4 H), 3.42-3.49 (m, 4 H), 2.89-2.97 (m, 1 H), 2.79 (dd, 1 H, J = 1 6.1, 9.1 Hz), 2.33-2.48 (m, 11 H), 1.88-1.96 (m, 2 H).

Example 1 46

 N- [2-methyl-5-({4- [4- (trifluoromethyl) benzyl] -topiperazinyl} carbonyl) phenyl]-4- [4- (trifluoromethyl) benzyl] -topiperazinecarboxamide Synthesis of

 The title compound was obtained in the same manner as in Example 124.

_{¾ NMR (CDC1 3, 400 MHz} ) 57.69 (d, 1 H, J = 1.6 Hz), 7.59 (d, 2 H, J = 8.3 H z), 7.57 (d, 2 H, J = 8.3 Hz), 7.47 (d, 2 H, J = 8.3 Hz), 7.44 (d, 2 H, J = 8.3 Hz), 7.18 (d, 1 H, J = 7.7 Hz), 7.06 (dd, 1 H, J = 7.7, 1.6 Hz), 6.21 (b rs, 1 H), 3.7-3.8 (br, 2 H), 3.60 (s, 2 H), 3.57 (s, 2 H), 3.52 (brt, 6 H, J = 5.0 Hz) , 2.51 (brt, 6 H, J = 5.0 Hz), 2.35-2.5 (br, 2 H), 2.24 (s, 3 H).

Example 1 47

N- [2-methoxy-5-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbodi Synthesis of 4- (4- (trifluoromethyl) benzyl) -1-piperazinecarboxamide

Example 147-1

 Synthesis of methyl 4-methoxy-3-[({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) amino] benzoate

 To a solution of triphosgene (45 mg, 0.152 mmol) in THF (2 ml) was added, under ice-cooling, methyl 3-amino-4-methylbenzoate (75 mg, 0.414 mmol) and triethylamine (70 mg, 0.692 mmol) in THF. (2 ml) The solution was added dropwise, and the reaction solution was stirred at 0 ° C for 10 minutes and at room temperature for 20 minutes. A solution of N- [4- (trifluoromethyl) benzyl] piperazine (103 mg, 0.414 mmol) in THF (1 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 15 hours. Hydrogen carbonate-water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sulfuric acid and toluene, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (chloroform: methanol = 50: 1 → 30: 1) to give the title compound (201 mg).

¾ thigh _{(CDC1 3, 400 MHz) 58.78} (d, 1 H, J = 2.1 Hz), 7.73 (dd, 1 H, J = 8.6, 2.1 Hz), 7.59 (d, 2 H, J = 8.1 Hz), 7.45 (d, 2 H, J = 8.1 Hz), 7.04 (brs, 1 H), 6.88 (d, 1 H, J = 8.6 Hz), 3.93 (s, 3 H), 3.86 (s, 3 H), 3.60 (s, 2 H), 3.54 (brt, 4 H, J = 5.0 Hz), 2.51 (brt, 4 H, J = 5.0 Hz).

Example 147-2

N- [2-methoxy-5-({4- [4- (trifluoromethyl) benzyl]: H-piperazinyl} carbonyl) phenyl] -4- [4- (trifluoromethyl) benzyl] -1 -Pirazinecarboxamide synthesis

 Methyl 4-methoxy-3-[[({4- [4- (trifluoromethyl) benzyl] -1-pirazinyl} -capillonyl) amino] benzoate obtained in Example 147-1 was used. After hydrolysis in the same manner as in 132, the obtained carboxylic acid was subjected to a condensation reaction in the same manner as in Example 106 to obtain the title compound.

_{¾ NMR (CDC1 3, 400 MHz} ) 58.21 (d, 1 H, J = 2.0 Hz), 7.59 (d, 2 H, J = 8.5 H z), 7.57 (d, 2 H, J = 8.5 Hz), 7.47 (d, 2 H, J = 8.5 Hz), 7.45 (d, 2 H, J = 8.5 Hz), 7.12 (dd, 1 H, J -8.4, 2.0 Hz), 7.08 (brs, 1 H), 6.87 (d, 1 H, J = 8.4 Hz), 3.89 (s, 3 H), 3.65 — 3.8 (br, 2H), 3.60 (s, 2 H), 3.57 (s, 2 H), 3.52 (brt, 6 H, J = 5.0 Hz), 2.50 (brt, 6 H, J = 5.0 Hz), 2.35-2.5 (br, 2 H).

Example 148

 N- [2-Methoxy-4-({4- [4- (trifluoromethyl) benzyl]-1-piperazinyl} carbonyl) phenyl] -4- [4- (trifluoromethyl) benzyl]- Synthesis of 1-piperazinecarboxamide

Example 148-1

 Synthesis of methyl 3-methoxy-4-di-benzoate

 To a suspension of 3-hydroxy-4-nitrobenzoic acid (0.63 g, 3.44 mmol) in acetone (10 ml) was added potassium carbonate (1.62 g, 11.7 mmol) and dimethyl sulfate (0.88 g, 6.98 mmol). The liquid was heated to reflux for 3 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (691 mg, yield 95%).

_{¾ NMR (CDC1 3, 400 MHz} ) 57.84 (d, 1 H, J = 8.3 Hz), 7.76 (d, 1 H, J = 1.6 H z), 7.70 (dd, 1 H, J = 8.3, 1.6 Hz) , 4.02 (s, 3 H), 3.97 (s, 3 H).

Example 148-2

Synthesis of methyl 4-amino-3-methoxybenzoate

 Methyl 3-methoxy-4-methoxybenzoate obtained in Example 148-1 (0.69 g, 3.27 mmol

), A suspension of 50% wet 10% palladium on carbon (0.20 g) in THF (10 ml) under a hydrogen atmosphere

The mixture was stirred at room temperature for 1 hour. The palladium carbon was removed by filtration, and the filtrate was concentrated under reduced pressure and dried under vacuum to obtain the title compound (0.60 g).

_{¾ NMR (CDC1 3, 400 MHz} ) §7.54 (dd, 1 H, J = 8.1, 1.7 Hz), 7.45 (d, 1 H, J = 1.7 Hz), 6.66 (d, 1 H, J = 8.1 Hz) , 4.21 (brs, 2 H), 3.90 (s, 3 H), 3.86 (s

, 3H). Example 18-3

 N- [2-methoxy-4-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) phenyl] -4- [4- (trifluoromethyl) benzyl ] -Synthesis of Topiperazine Carboxamide

 The methyl 4-amino-3-methoxybenzoate obtained in Example 148-2 was synthesized in the same manner as in! J147 to give the title compound.

'Thigh (CDC1 ₃₎ 400 MHz) 58.15 (d, 1 H, J = 8.3 Hz), 7.59 (d, 2 H, J = 8.2 Hz), 7.58 (d, 2 H, J = 8.2 Hz), 7.46 (d, 2 H, J = 8.2 Hz), 7.45 (d, 2 H, J = 8.2 Hz), 7.17 (s, 1 H), 7.01 (d, 1 H, J = 1.7 Hz), 6.96 (dd , 1 H, J = 8.3, 1.7 Hz), 3.89 (s, 3 H), 3.60-3.80 (br, 4 H), 3.60 (s, 2 H), 3.58 (s, 2 H), 3.53 ( brt, 4 H, J = 5.0 Hz), 2.50 (brt, 4 H, J = 5.0 Hz), 2.35-2.5 (br, 4 H).

Example 149

 N- [2-Hydroxy-4-({4- [4- (trifluoromethyl) benzyl] -topiperazinyl} carbonyl) phenyl] -4- [4- (trifluoromethyl) benzyl] -topiperazine Synthesis of carboxamide

 N- [2-Methoxy-4-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) phenyl] -4- [4- (trifluoro) obtained in Example 148 To a solution of (romethyl) benzyl] -1-piperazinecarboxamide (93 mg, 0.140 mmol) in dichloromethane (2 ml) was added a solution of boron tribromide in dichloromethane (0.91 M, 0.4 ml, 0.36 mmol) and the mixture was added at room temperature. Stir for 3 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was stirred for 15 minutes, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (cloth form: methanol = 100: 1 → 20: 1) to give the title compound (58 mg, yield 64%).

'Eta thigh _{(CDC1 3, 400 MHz) 59.42} (s, 1 H), 7.59 (d, 2 H, J = 7.9 Hz), 7.58 (d, 2 H, J = 7.9 Hz), 7.46 (d, 2 H , J = 7.9 Hz), 7.44 (d, 2H, J = 7.9 Hz), 7.0 8 (d, 1 H, J = 8.0 Hz), 6.99 (d, 1 H, J = 1.9 Hz), 6.82 (dd, 1 H, J = 8.0, 1.9 Hz), 6.81 (s, 1 H) , 3.7-3.9 (br, 2 H), 3.60 (s, 2 H), 3.57 (s, 2 H), 3.55 (brt, 4 H, J = 5.0 Hz), 3.40-3.52 (br, 2 H ), 2.51 (brt, 4 H, J = 5,0 Hz), 2.3-2.5 (br, 4 H).

Example 1 50

 N- [2-hydroxy-5-({4- [4- (trifluoromethyl) benzyl] -topiperazinyl} carbonyl) phenyl] -4- [4- (trifluoromethyl) benzyl] -topiperazine Synthesis of carboxamide

 Run {N- [2-methoxy-5-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) phenyl obtained in column 147] -4- [4- (trifluoro Methyl) benzyl] -1-Pyrazinecarboxamide was synthesized in the same manner as in Example 149 to obtain the title compound.

_{¾ NMR (CDC1 3, 400 MHz} ) 59.69 (s, 1 H), 7.53 (d, 2 H, J = 8.4 Hz), 7.51 (d, 2 H, J - 8.4 Hz), 7.40 (d, 2 H, J = 8.4 Hz), 7.38 (d, 2 H, J = 8.4 Hz), 7.0 2 (d, 1 H, J = 8.5 Hz), 7.01 (s, 1 H), 6.90 (d, 1 H, J = 8.5 Hz), 6.55 (s, 1 H), 3.54 (s, 2 H), 3.51 (s, 2 H), 3.48 (brt, 4 H, J = 5.0 Hz), 3.35-3.67 (m, 4 H) , 2.45 (brt, 4 H, J = 5.0 Hz), 2.30-2.42 (m, 4 H).

Example 1 51

 N- [4- (2-oxo- 2- {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} ethyl)-1,3-thiazol-2-yl] _4-[4 Synthesis of [-(trifluoromethyl) benzyl] -1-piperazinecarboxamide

Example 1 5 1-1

 Synthesis of [2-({[4- (tert-butoxycarbonyl) -topiperazinyl] carbonyl} amino) -1,3-thiazol-4-yl] acetic acid

To a solution of triphosgene (260 mg, 0.876 mmol) in THF (3 ml) was added dropwise a solution of ethyl (2-amino-4-thiazolyl) acetate (0.40 g, 2.15 mmol) in THF (8 ml) under ice-cooling. The liquid was stirred at 0 ° C for 30 minutes and at room temperature for 1 hour. To the reaction mixture was added a solution of tert-butyl topiperazinecarboxylate (0.55 g, 2.95 bandol) in THF (6 ml), and triethylamine (0.43 g, 4.25 m). mol) and stirred at room temperature for 16 hours. Aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was separated by silica gel column chromatography (hexane: ethyl acetate = 3: 2 → 1: 1) to obtain a urea mixture (0.36 g).

 To a solution of the above urea mixture in THF (3 ml) and ethanol (3 ml) was added a 1N aqueous solution of hydroxide hydroxide (5 ml), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with water and ethyl acetate, extracted with aqueous sodium hydrogen carbonate, and the aqueous layer was washed with ethyl acetate. Aqueous hydrochloric acid was added to the aqueous layer to adjust the pH to around pH 4, and the mixture was extracted with ethyl acetate: THF (2: 1). The organic layer was washed with brine, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and dried under vacuum to obtain the title compound (0.16 g, two-step yield 20%).

¾ Awakening: _{(DMS0-d 6, 300 MHz} ) δ 6.75 (brs, 1 H), 3.53 (s, 2 H), 3.42 - 3.49 (m, 4 H), 3.28 - 3.36 (m, 4 H), 1.40 ( s, 9H).

Example 1 51 -2

4-({[4- (2-oxo-2--2- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl) -1, 3-thiazolyl-2-yl] amino Synthesis of tert-Butyl (Irbonyl) -1-pidazine Potassium Rubonate

 Example 15 [2-({[4- (tert-Butoxycarbonyl) -topiperazinyl] potassium propyl] amino) -1,3-thiazol-4-yl] acetic acid obtained in 111 Then, a condensation reaction was carried out in the same manner as in Example 106 to obtain the title compound.

¾ thigh _{(CDC1 3, 300 MHz) 57.57} (d, 2 H, J = 8.0 Hz), 7.43 (d, 2 H, J = 8.0 H z), 6.75 (s, 1 H), 3.71 (s, 2 H ), 3.65 (brt, 2 H, J = 5.0 Hz), 3.53 (s, 2 H), 3.44-3.54 (m, 10 H), 2.41 (brt, 2 H, J = 5.0 Hz), 2.34 (brt, 2 H, J = 5.0 Hz), 1.48 (s, 9 H).

Example 15 1 3

N- [4- (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} ethyl)-1,3-thiazolyl-2-yl]-4- [ 4- (trifluoromethyl) benzyl] -1-piperazinecarbo Synthesis of oxamide

 Example 1 4-({[4- (2-oxo-2- {4- [4- (trifluoromethyl) benzyl] -topidrazinyl} ethyl) obtained in 51-12) -1,3 -Thiazol-2-yl] amino} aminocarbonyl) -tert-butyl topirazinecarboxylate (235 mg, 0.394 ol) was dissolved in a solution of acetic acid (1 ml) and methanol (1 ml) in 4N. Dioxane hydrochloride solution (3 ml) was added, and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and dried under vacuum to obtain a Boc-removed mixture (250 mg).

 To a suspension of the above de-Boc mixture (30 mg, 0.053 mol ol by proportional calculation) and potassium carbonate (25 mg, 0.18 t ol) in DMF (1 ml) was added 4- (trifluoromethyl) benzyl bromide (1 (4 mg, 0.058 mmol), and the reaction solution was stirred at room temperature for 21 hours. Aqueous sodium bicarbonate was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (chloroform: methanol = 50: 1 → 10: 1) to give the title compound (20 mg, yield 58%).

¾ thigh _{(CDC1 3, 400 MHz) δ} 7.59 (d, 2 H, J = 8.4 Hz), 7.57 (d, 2 H, J = 8.4 Hz), 7.46 (d, 2 H, J = 8.4 Hz), 7.43 (d, 2 H, J = 8.4 Hz), 6.58 (s, 1 H), 3.71 (s, 2 H), 3.65 (brt, 2 H, J = 4.8 Hz), 3.58 (s, 2 H) , 3.53 (s, 2 H), 3.50-3.57 (m, 4 H), 3.48 (brt, 2 H, J = 5.0 Hz), 2.49 (brt, 4 H, J = 5.0 Hz), 2.41 (brt, 2 H, J = 5.0 Hz), 2.33 (brt, 2 H, J = 4.8 Hz).

Example 1 52

{{1- (2-Oxo-2- {4- [4- (trifluoromethyl) benzyl] -topiperazinyl} ethyl) -1H-imidazoyl-4-yl] carbonyl} -4 Synthesis of-[4- (trifluoromethyl) benzyl] piperazine

Example 1 52-1

Synthesis of tri (1H-imidazole-4-ylcarbonyl) -4- [4- (trifluoromethyl) benzyl] pyrazine

The condensation reaction was carried out from 4-imidazolecarboxylic acid in the same manner as in Example 106 to obtain the title compound. _{¾ NMR (CDC1 3, 400 MHz} ) δ 9.9 - 10.6 (. Brs, 1 H), 7.67 - 7.80 (br, 1 H), 7. 60 (brs, 1 H), 7.59 (d, 2 H, J = 8.0 Hz), 7.47 (d, 2 H, J = 8.0 Hz), 4.20-4.35 (br, 1 H), 3.7-3.9 (br, 3 H), 3.60 (s, 2 H), 2.53 (brt, 4 H, J = 5.0 Hz).

Example 152-2

 Synthesis of ethyl [4 _ ({4- [4- (trifluoromethyl) benzyl] -topiperazinyl} carbonyl) -1H-imidazol-1-yl] acetate

 Example 1 1- (1H-imidazol-4-ylcarbonyl) -4- [4- (trifluoromethyl) benzyl] pidazine (1.69 g, 5.0 mmol) obtained in 52-1, potassium carbonate ( Ethyl acetate (0.62 g, 5.06 mmol) was added to a suspension of 0.85 g (6.15 t) in DMF (10 ml), and the reaction solution was stirred at 50 ° C for 6 hours. Aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate: toluene (2: 1). The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (cloform form → cloform form: methanol = 5: 1) to obtain the title compound (1.577 g, yield 74%).

 'Η NMR (CDCI3, 400 MHz) δ 7.58 (d, 2Η, J = 8.0 Hz), 7.56 (d, 1H, J = 1.5 Hz), 7.46 (d, 2H, J = 8.0 Hz), 7.45 (d, 1 H, J = 1.5 Hz), 4.70 (s, 2 H), 4.25-4.35 (br, 2 H), 4.26 (q, 2 H, J = 7.1 Hz), 3.7-3.85 (br , 2H), 3.58 (s, 2H), 2.51 (brt, 4H, J = 5.0 Hz), 1.30 (t, 3H, J = 7.1 Hz).

Example 1 52-3

{{[1- (2-oxo-2--2- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl)-1H-imidazoyl-4-yl] carbonyl}- Synthesis of 4- [4- (trifluoromethyl) benzyl] piperazine

Example 1 [4-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) -1H-imidazoyl-1-yl] acetic acid obtained in 52-2 After hydrolyzing the ethyl with alkali as in Example 132, the obtained carboxylic acid was subjected to a condensation reaction as in Example 106 to obtain the title compound. 'Eta thigh _{(CDC1 3, 400 MHz) 5} 7.59 (d, 2 H, J = 8.1 Hz), 7.58 (d, 2 H, J = 8.1 Hz), 7.52 (d, 1 H, J = 1.3 Hz), 7.46 (d, 2 H, J = 8.1 Hz), 7.45 (d, 2 H, J = 8.1 Hz), 7.44 (d, 1 H, J = 1.3 Hz), 4.78 (s, 2 H), 4.2-4.4 (br, 2 H), 3.7-3.85 (br, 2 H), 3.67 (brt, 2 H, J = 4.9 Hz), 3.60 (s, 2 H), 3.58 (s, 2 H), 3.48 (brt, 2 H, J = 4.9 Hz), 2.45-2.55 (m, 8 H).

Example 1 53

 4- [4- (trifluoromethyl) benzyl] -N- [4-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} sulfonyl) phenyl] -1-pidazinecarboxamide

 4- (Trifluoromethyl) benzylpiperazine (269 mg, 0.5 l ol) and triethylamine (0.09 ml, 0.6 marl ol) were dissolved in THF (5 ml) and stirred at room temperature. The solution was charged with 4- (chlorosulfonyl) phenylisocyanate (109 mg, 0.5 t ol) and stirred at room temperature for 4 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, filtered, and the solvent was distilled off. This was purified by column chromatography (cloth form: methanol = 40: 1) to obtain 297 mg of the title compound as a colorless oil. (89% yield)

_{Ή NMR (CDC1 3, 400 MHz} ) 8 7.59 - 7.65 (m, 4 H), 7.49 - 7.55 (m, 4 H), 7.47 (d, J = 8.0 Hz, 2 H), 7.36 (d, J = 8.0 Hz, 2 H), 6.65 (s, 1 H), 3.61 (s, 2 H), 3.51-3.57 (m, 6 H), 3.00 (brs, 4 H), 2.51 (brs, 8 H).

In the same manner as in Example 153, compounds from Example 154 to Example 161 were synthesized.

Example 154

 4- (4-chlorobenzyl) -N- (4-{[4- (4-chlorobenzyl) -topiperazinyl] sulfonyl} phenyl) -1-piperazinecarboxamide

_{'Η NMR (CDC1 3, 400} MHz) δ 7.64 (d, J = 8.6 Hz, 2 H), 7.51 (d, J = 8.6 Hz, 2 H), 7.22 - 7.34 (ra, 6 H), 7.17 (d , J = 8.2 Hz, 2 H), 6.60 (s, 1 H), 3.50-3.55 (m, 6 H), 3.43 (s, 2 H), 2.99 (brs, 4 H), 2.49 (brs, 8 H ).

Example 1 55

4- (3,4-dichlorobenzyl) -N- (4-{[4- (3,4-dicyclohexyl) -topidrazinyl] sul Honyl} phenyl) -Topiperazine

¾ thigh _{(CDC1 3, 400 MHz) δ} 7.65 (d, J = 8.6 Hz, 2 H), 7.52 (d, J = 8.2 Hz, 2 H), 7.45 (d, J = 1.9 Hz, 1 H), 7.40 (d, J = 8.2 Hz, 1 H), 7.34 (d, J = 8.2

Hz, 2 H), 7.16 (d, J = 8.2 Hz, 1 H), 7.08 (d, J = 8.2 Hz, 1 H), 6.59 (s, 1 H)

), 3.54 (t, J = 5.0 Hz, 4 H), 3.50 (s, 2 H), 3.41 (s, 2 H), 3.00 (brs, 4 H), 2.48 (brs, 8 H).

Example 1 56

4- [4- (trifluoromethyl) benzyl] -N- [4-({4- [4- (trifluoromethyl) benzyl] -1, 4-diazepan-1-yl} capillonyl) phenyl ] - 1, 4-Jiazepan - 1 - carboxamide _{¾ NMR (CDC1 3, 400 MHz} ) δ 7.30 - 7.60 (m, 12 H), 6.44 (s, 1 H), 3.48 - 3.85

(m, 12H), 2.54-2.85 (m, 8H), 1.90-1.98 (m, 3H), 1.78 (br, 1H).

Example 1 57

4- [4- (trifluoromethyl) benzyl] -N- [3-({4- [4- (trifluoromethyl) benzyl] -1,4-diazenon-tolyl} force carbonyl) phenyl ] - 1, 4-Jiazepan - 1 - carboxamide _{¾ NMR (CDC1 3, 400 MHz} ) δ 7.26 - 7.60 (m, 11 H), 7.03 (t, 1 H, J = 7.1 Hz), 6.48 (d, 1 H , J = 3.2 Hz), 3.45-3.80 (m, 12 H), 2.55-2.82 (m, 8 H), 1.9

0-2.00 (m, 3 H), 1.75-1.80 (m, 1 H).

Example 1 58

4- [4- (trifluoromethyl) benzyl] -N- [4-({4- [4- (trifluoromethyl) benzyl] -1,4-diazepan-1-yl} sulfonyl) phenyl] - 1, 4-Jiazepan - 1-carboxamide _{¾ NMR (CDC1 3, 400 MHz} ) δ 7.69 (dd, 2 H, J = 8.7 Hz, 2.1 Hz), 7.50 - 7.60 (m, 6 H), 7.46 (d, 2 H, J = 8.0 Hz), 7.40 (d, 2 H, J = 8.0 Hz), 6.53 (s, 1 H), 3.60-3.71 (m, 8 H), 3.32-3.39 (m, 4 H), 2.61-2.79 (m, 8H), 1.92-1.99 (m, 2H), 1.75-1.85 (m, 2H).

Example 1 59

1- [4- (Trifluoromethyl) benzyl] -4-{[3-({4- [4- (trifluoromethyl) benzyl;]-tripiperazinyl} sulfonyl) phenyl] sulfonyl} piperazine ¾ NMR (CDCI3, 400 MHz) δ 8.11 (t, 1 H, J = 1.6 Hz), 7.98 (dd, 2 H, J = 7.8 Hz, 1.7 Hz), 7.74 (t, 1 H, J = 7.8 Hz) , 7.54 (d, 4 H, J = 8.1 Hz), 7.37 (d, 4 H, J = 8.1 Hz), 3.54 (s, 4 H), 3.08 (brs, 8 H), 2.51-2.55 (m, 8 H). Example 160

l- [4- (Trifluoromethyl) benzyl]-4-{[2-({4- [4- (trifluoromethyl) benzyl] 1-piperazinyl} sulfonyl) phenyl] sulfonyl} pidazine

_{Ή NMR (CDC1 3, 400 MHz} ) δ 8.12 - 8.19 (m, 2 H), 7.65- 7.72 (m, 2 H), 7.55 (d, 4 H, J = 8.1 Hz), 7.39 (d, 4 H, J = 8.1 Hz), 3.59 (s, 4 H), 3.30-3.35 (m, 8 H), 2.45-2.50 (m, 8 H).

Example 16 1

 ]-{[4-Chloro-2-fluoro-5-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) phenyl] sulfonyl} -4- [4- (Trifluoromethyl) benzyl] piperazine

_{Ή NMR (CDC1 3, 400 MHz} ) 8 7.77 (d, 1 H, J = 7.1 Hz), 7.53 - 7.60 (m, 4 H), 7.45 (d, 2 H, J = 8.0 Hz), 7.39 (d 2 H, J = 8.0 Hz), 7.31 (d, 1 H, J = 9.3 Hz), 3.82 (t, 2 H, J = 5.0 Hz), 3.59 (s, 2 H), 3.56 (s, 2 H), 3.20-3.29 (m, 6 H), 2.41-2.59 (brm, 8 H).

Example 1 62

[4- (Trifluoromethisole) benzyl] -4-{[4-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} carbonyl) phenyl] sulfonyl} pi} Razine

4- (Trifluoromethyl) benzylpiperazine (244 mg, 1 mol) and triethylamine (0.14 ml, 1 mmol) were dissolved in THF (2 ml) and stirred at room temperature. To this solution was added 4- (chlorosulfonyl) phenylbenzoic acid (88 mg, 0.4 ramol), and the mixture was stirred at room temperature for 2 hours. DMF (2 ml), HOBt (93 mg, 0.6 mmol) and WSC (153 mg, 0.8 mmol) were added to the reaction solution, and the mixture was further stirred at room temperature for 2 hours. After evaporating the solvent, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, filtered, and the solvent was distilled off. This is subjected to column chromatography (form: methanol = 40: 1) Purification afforded 261 mg of the title compound as a slightly yellow oil. (100% yield)

_{'Η MR (CDC1 3, 400} MHz) δ 7.79 (d, 2 Η, J = 8.3 Hz), 7.51 - 7.60 (m, 6 H), 7.45 (d, 2 H, J - 8.0 Hz), 7.37 (d , 2 H, J = 8.0 Hz), 3.82 (brs, 2 H), 3.60 (s, 2 H), 3.54 (s, 2 H), 3.39 (brs, 2 H), 3.04 (brs, 4 H), 2.50-2.56 (m, 6 H), 2.41 (brs, 2 H).

In the same manner as in Example 162, the compounds of Example 163 to Example 165 were synthesized.

Example 1 63

 1- [4- (Trifluoromethyl) benzyl]-4-{[3- ({4- [4- (Trifluoromethisole) benzyl

] -1-piperazinyl} carbonyl) phenyl] sulfonyl} pidazine

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.73 - 7.80 (m, 2 H), 7.60 - 7.65 (m, 2 H), 7.58

(d, 2 H, J = 8.1 Hz), 7.53 (d, 2 H, J = 8.1 Hz), 7.45 (d, 2 H, J = 8.1 Hz),

7.36 (d, 2 H, J = 8.1 Hz), 3.81 (br, 2 H), 3.59 (s, 2 H), 3.53 (s, 2 H), 3.3

9 (br, 2H), 3.05 (brs, 4H), 2.35-2.55 (brm, 8H).

Example 1 64

 1- (4-chlorobenzyl) -4-[(4-{[4- (4-chlorobenzyl) -topiperazinyl] potubonyl} phenyl) sulfonyl] pidazine

¾ thigh _{(CDC1 3, 400 MHz) δ} 7.78 (d, 2 H, J = 8.4 Hz), 7.54 (d, 2 H, J = 8.4 Hz), 7.24 - 7.31 (m, 6 H), 7.18 (d, 2H, J = 8.4 Hz), 3.81 (br, 2H), 3.51 (s, 2H), 3.45 (s, 2H), 3.37 (br, 2H), 3.03 (brs, 4H), 2.34 -2.55 (brm, 8 H).

Example 165

l- (3,4-dichlorobenzyl)-4-[(4-{[4- (3,4-dicyclopentylbenzyl) -topidrazinyl] force rubinyl} phenyl) sulfonyl] pidazine

_{Ή NMR (CDC1 3, 400 MHz} ) δ 7.79 (d, 2 H, J = 8.4 Hz), 7.56 (d, 2 H, J = 8.4 Hz), 7.32 - 7.42 (m, 4 H), 7.16 - 7.26 ( m, 1 H), 7.05-7.15 (m, 1 H), 3.82

(br, 2 H), 3.49 (s, 2 H), 3.43 (s, 2 H), 3.35-3.40 (brm, 2 H), 3.04 (brs,

4 H), 2.35-2.55 (brm, 8 H). Example 1 66

Tri (3,4-dichlorobenzyl) -4- [4-({4- [4- (trifluoromethyl) benzyl] -topiperazinyl} sulfonyl) benzoyl] pidazine

 4- (Trifluoromethyl) benzylpiperazine (244 mg, 1 mol) and triethylamine (0.14 ml, 1 mol) were dissolved in THF (2 ml) and stirred at room temperature. The solution was charged with 4- (chlorosulfonyl) phenylbenzoic acid (88 mg, 0.4 mmol) and stirred at room temperature for 2 hours. After evaporating the solvent, 1N aqueous hydrochloric acid and ethyl acetate were added, and the precipitated crystals were collected by filtration and dried under reduced pressure. The obtained crystals were dissolved in DMF (2 ml), and 3,4-dichlorobenzylpiperazine (38 mg, 0.15 mmol),

 HOBt (23 mg, 0.15 mmol) and WSC (38 mg, 0.2 mmol) were obtained, and the mixture was further stirred at room temperature for 2 hours. After evaporating the solvent, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, filtered, and the solvent was distilled off. The residue was purified by column chromatography (form: methanol = 50: 1) to give 93 mg of the title compound as a pale yellow oil. (35% yield)

_{¾ MR (CDC1 3, 400:} MHz) 5 7.79 (d, 2 H, J = 8.3 Hz), 7.51 - 7.58 (m, 4 H),

7.44 (d, 1 H, J = 1.9 Hz), 7.34-7.43 (m, 3 H), 7.12-7.18 (m, 1 H), 3.82 (br, 2 H), 3.54 (s, 2 H), 3.49 (s, 2H), 3.39 (br, 2H), 3.04 (brs, 4H), 2.35-2.55 (brra, 8H).

The compound of Example 167 was synthesized in the same manner as in Example 166.

Example 1 67

 1- (3,4-dichlorobenzyl)-4-{[4-({4- [4- (trifluoromethyl) benzyl] -topiperazinyl} carbonyl) phenyl] sulfonyl} pidazine

_{¾ NMR (CDC1 3, 400 MHz} ) 8 7.79 (d, 2 H, J = 8.4 Hz), 7.52 - 7.61 (m, 4 H),

7.45 (d, 2 H, J = 8.0 Hz), 7.31-7.38 (m, 2 H), 7.09 (dd, 1 H, J = 8.2 Hz, 1.9 Hz), 3.82 (br, 2 H), 3.60 (s , 2 H), 3.43 (s, 2 H), 3.35-3.41 (brm, 2 H

), 3.04 (brs, 4 H), 2.40-2.57 (brm, 8 H).

Example 1 68 l- [4- (Trifluoromethyl) benzyl]-4-{[2-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} sulfonyl) ethyl] sulfonyl} pi} Synthesis of azine

Example 1 68-1

 Synthesis of 1,2-ethanedisulfonic acid ninadium

 Add 1,2-dibromoethane (1.12 g, 5.96 ramol) to water (3 ml) and stir

Then, sodium sulfite (1.54 g, 12.2 orchid ol) was added to the mixture and heated under reflux for 8 hours. After returning to room temperature, the solvent was distilled off under reduced pressure, and the obtained residue was washed with ether. The title compound (1.14 g, 94.4%) was obtained as a white solid.

'Η NMR (D ₃₀ , 400 MHz) δ 3.20 (s, 4 Η).

Example 1 68-2

 Synthesis of 1,2-ethanedisulfonyl di-mouthride

 When 1,2-ethanedisulfonic acid (530 mg, 2.62 mmol) and phosphorus pentachloride (2.73 g, 13.1 mmol) remained in a solid state and the temperature was raised to 120 ° C with stirring, they melted with each other. While stirring at 120 ° C for 2 hours, the reaction vessel was returned to room temperature, and water was added little by little. After extraction with ethyl acetate, the organic layer was washed with water, washed with a saturated saline solution, and dried over anhydrous magnesium sulfate. The title compound (467 mg, 78.5%) was obtained as white crystals.

¾ thigh _{(CDC1 3, 400 MHz) δ} 4.27 (s, 4 H).

Example 1 68-3

l- [4- (Trifluoromethyl) benzyl] -4-{[2-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} sulfonyl) ethyl] sulfonyl} pi} Synthesis of azine

 To a solution of 1,2-ethanedisulfonyl dichloride (105 mg, 0.462 mmol) was added a solution of 1- [4- (trifluoromethyl) benzyl] piperazine (248 mg, 1.02 mmol) in THF (5 ml) little by little. And triethylamine (190 μl, 1.4 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (cloth form: methanol = 50: 1). The title compound (534 mg, 54.6%) was obtained as a yellow solid.

腿 Thigh (CDC1, 400 Hz) δ 7.58 (brd, 4 H), 7.45 (brd. 4 H), 3.59 (s, 4 H), 3.31 (m, 4 H), 3.12 (m, 2 H), 2.88 (m, 2 H), 2.68-2.42 (m, 12 H).

In the same manner as in Example 168, the compounds of Example 169 and Example 169 were synthesized.

Example 1 69

 1- [4- (Trifluoromethyl) benzyl]-4-{[3-({4- [4- (trifluoromethyl) benzyl] -topiperazinyl} sulfonyl) propisole] sulfonyl} pidazine Synthesis of

Example 1 69-1

 Synthesis of 1,3-propanedisulfonic acid sodium salt

¾ NMR (D ₃₀ , 400 MHz) δ 2.98 (t, 4 H, J = 7.7 Hz), 2.15 (quint, 2 H, J = 7.7 Hz).

Example 1 69-2

 Synthesis of 1,3-propanedisulfonyl dichloride

_{■ H NMR (CDC1 3, 400} MHz) δ 3.97 (t, 4 H, J = 7.0 Hz), 2.79 (quint, 2 H, J = 7.0 Hz).

Example 1 69-3

l- [4- (Trifluoromethyl) benzyl]-4-{[3-({4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} sulfonyl) propyl] sulfonyl} pi} Synthesis of azine

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.59 (d, 4 H, J = 8.0 Hz), 7,49 - 7.43 (brm, 4 H), 3.62 (brs, 4 H), 3.42 - 3.28 (m, 8 H), 3.13 (t, 4 H, J = 7.1 Hz), 2.62-2.52 (m, 8 H), 2.37 (quint, 4 H, J = 7.1 Hz).

Example 1 70

l-{[2,2-dimethyl-3-({4- [4- (trifluoromethyl) benzyl] -topiperazinyl} sulfonyl) propyl] sulfonyl}-4- [4- (trifluoro Synthesis of methyl) benzyl] piperazine

Example 1 70-1

Synthesis of Ninadium 2,2-Dimethyl-1,3-propanedisulfonate

_{¾ NMR (D 3 0, 400} MHz) 8 3.07 (s, 4 H), 1.20 (s, 6 H).

Example 1 70-2 Synthesis of 2,2-Dimethyl-1,3-propanedisulfonyl di-mouthride

_{Ή NMR (CDC1 3, 400 MHz} ) δ 4.16 (s, 4 H), 1.52 (s, 6 H).

Example 1 70-3

Tri [[2,2-dimethyl-3-({4- [4- (trifluoromethyl) benzyl] -topiperazinyl} sulfonyl) propyl] sulfonyl}-4- [4- (trifluoromethyl Synthesis of benzyl] piperazine

_{'Η NMR (CDC1 3, 400} MHz) δ 7.59 (d, 4 Η, J = 7.7 Hz), 7.47 (br, 4 H), 3.62 (s, 4 H), 3.34 (br, 8 H), 3.27 ( s, 4H), 2.58 (br, 8H), 1.36 (s, 6H).

Example 1 7 1

 1-[(2-Oxo-2- {4- [4- (trifluoromethyl) benzyl] -1-piperazinyl} ethyl) sulfonyl] -4- [4- (trifluoromethyl) benzyl] pi Synthesis of azine

 While stirring a solution of chlorosulfonylacetyl chloride (136 mg, 0.768 mmol) in THF (4 ml) at 0 ° C, 1- [4- (trifluoromethylinole) benzyl] piperazine (1.92 g, A solution of 7.88 mmol) and triethylamine (2.1 ml, 15 mmol) in THF (6 ml) was added dropwise. After the dropwise addition, the reaction temperature was raised to 50 ° C., and the mixture was stirred for 1 hour. After returning to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added to terminate the reaction. The mixture was extracted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was further washed with saturated saline, and dried over anhydrous magnesium sulfate. The product was purified by silica gel column chromatography (form: methanol = 30: 1). The title compound (693 mg, 31.2%) was obtained as pale yellow amalfas.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.59 (brd, 4 H), 7.47 (brd, 4 H), 4.07 (s, 2 H), 3.73 - 3.42 (m, 12 H), 2.54- 2.39 (m, 8 H). Example 1 72

 Investigation of glucose consumption promoting activity in culture medium using C2C12 myotube cells

Cell culture>

C2C12 cells (American Type Culture Collection) in 2xl0 ³ eel ls / wel 1 were seeded in 96-well plates that are gelatin-coated. Medium: 20% fetal bovine serum, 2 mM glutamine DMEM (Duldecco's modified Eagle's medium, High Glucose) was used. Two to three days later, after confirming that the cells had adhered to the bottom of the plate without any gap, the medium was replaced with a differentiation medium (DMEM (High Glucose) containing 2% horse serum and 2 mM glutamine). Thereafter, the medium was changed every two to three days, and the cells after the 7th were used.

Add drug>

The evaluation compound was diluted with a medium for fractionation immediately before use. The medium was removed from the cell plates and the diluted compound solution was added to each well. Then, it was carried out when 24 hours culture in C0 ₂ incubator scratch.

 <Measurement of glucose consumption in culture supernatant>

 After collecting the culture supernatant after 24 hours of culture, dilute it with saline containing 0.1% dodecyl sodium sulfate, and measure the amount of Darcos (Darcose CI I Test Co., Wako Pure Chemical Industries) Was used to determine the darkose concentration. The difference between the drug-free dalcos concentration and the drug-added glucose concentration is defined as the glucose consumption, and the activity is calculated assuming that the glucose consumption when adding 1 OmM metformin hydrochloride is 100%. did.

Result>

 [Table 2] Glucose consumption j 1 (% vs Metfosolemin (10 mM)) Test substance \ (concentration) (0. Ι μΜ) (Ι μΜ) (10 μΜ) (10 mM) Methoformin 100

 Example 1 3 9 8 9

 Example 1 7 4 7 9 2 8 9

 Example 1 8 2 3 4 9 9 0

 Example 4 2 4 9 8 0

 Example 4 6 1 8 1 8 6

Example 4 9 3 5 8 7 9 9 Example 7 6 1 a AQQ

 D Ό t O O

 Example 9 4 o O Ό

 Example] L 0 6 D VJ 7 Q t Q

 D O

 Example] L 0 8 Q Q

 U D y

 Example II-1 2 7 / I

 Example]. 18 O Q

 Δ O O

 Example]. 2 1 q p Q o

 y 丄

 Example 1.2 2 o U Q Q

 y b

 Example 1 3 3 Δ9 Δ9 Q Q

 丄 o y

 Example 1.40 mm ^ ± Q 1

 y O

 Example 1.4.6 V Q

 ό Ό / y y y

 Example 1 4 7 1 丄 Q y Q O 9 U

 Example 1 4 8 y y y b

 Example 1 5 0 Q Q

 O O 丄 D 丄

 Example 1 5 3 A Q Q O

 U o o

 Example 1 6 2 Q Q

 y b

 Example 1 6 6 Q

 Ο 丄 y Q u y y

 Example 16 9 8 6 1 0 0

 Example 1 7 0 4 6 8 6 1 0 5

 Example 1 7 1 2 3 4 9 8 7 Example 1 7 3

<Animals used>

 Six-week-old male C57BL / 6N mice were purchased and used for experiments at 6.5 weeks of age.

Inflammatory pathogenesis and grouping>

Mice were intraperitoneally administered streptozotocin (STZ) at a dose of 200 mg / kg once a day for two consecutive days. After that, the blood glucose level and body weight of all individuals were measured, and the blood glucose level of each group was measured. And body weight distribution, etc. (n = 8). Blood glucose was measured using a scalpel on the tail end of the mouse with a scalpel, taking a blood count of ^ 1, and using Antosense II (Bayer-Sankyo).

Preparation of chemical solution>

 The test substance was suspended in 0.5% CMC-saline (vehicle) so that the dose volume became 10 ml / kg, and used as a test substance administration liquid.

<Test substance administration and blood glucose measurement>

 Following the grouping, the blood glucose level (0 hour value) of the mice immediately before the administration of the drug solution was measured. Subsequently, the test substance was orally administered by gavage to 1 or 3 mg / kg (10 ml / kg). Immediately after that, insulin was administered (3 U / kg, s.c.). Four hours after the administration of the drug solution, the blood glucose level of each group of mice was measured.

<Result>

 [Table 3] Blood sugar level (mg / dL)

 Test substance \ time 0 hours 4 hours Insulin + Vehicle 410 ± 15 261 ± 92

 Insulin + Example 17 (1 mg / kg, p.o.) 408 ± 22 154 ± 32 **

 Insulin + Example 17 (3 mg / kg, p.o.) 404 ± 16 129 ± 43 **

**: P 0.01 vs Insulin + Vehicle Examples 1 to 15, 21, 23, 24, 26, 27

実施例 1 ： Ra = Rb = 4_トリフルォロメチルベンジル

Example 1: Ra = Rb = 4_trifluoromethylbenzyl

Example 2: Ra = Rb = 3,4-dichlorobenzyl

Example 3: Ra = Rb = 2 mono-naphthylmethyl

Example 4: Ra = Rb = 3,4-difluorobenzyl

Example 5: Ra = Rb = 4_tert-butylbenzyl

Example 6: Ra = Rb = 3,4-dimethylbenzyl

Example 7: R a = Rb = 4—Fluoroventil

Example 8: Ra = Rb = 4-black benzyl

Example 9: Ra = Rb = 4-bromobenzyl

Example 10: Ra = Rb = 3- (1,3-benzodioxoyl-5-yl) propyl Example 11 1: Ra = Rb = 3,4-dimethoxybenzyl

Example 12: R a = R b = 2-quinolylmethyl

Example 13 3: Ra = Rb = (5-Methyl-2-Chenyl) methyl

Example 14: Ra = Rb = 2,3-dihydro-1,4-benzodioxin-6-ylmethyl

Example 1 5: Ra = Rb = 3_ (1, 3- Benzojiokiso one rule 5 I) propyl Example _{2 1: R a = Rb =} l, 3- Benzojiokiso Ichiru - 5- Irumechiru

Example 23: Ra = phenyl, Rb = 1,3-benzodioxol-5-ylmethyl Example 24: Ra = benzyl, Rb = 1,3-benzodioxoyl-5-ylmethyl Example 26: Rb = 1,3-benzodioxo-1-ylmethyl, Ra dibenzyl Example 27: Rb = 1,3-benzodioxo-1-ylmethyl, Ra = phenyl Examples 16-20

Example 16: R = 1,3-benzodioxol-5-ylmethyl Example l7: R = 4- (triphneololomethyl) benzyl Example 18: R = 4_cyclopentyl

実施例 19 ： R = 4 _ (トリフルォロメチル） ベンジル 実施例 20 ： R=4—クロ口べンジル

Example 19: R = 4 _ (trifluoromethyl) benzyl Example 20: R = 4-cyclobenzene

Examples 22, 28 to 42

実施例 2 2 ： X = 実施例 3 6 ： X ： 実施例 2 8 ： X = 実施例 3 7 ： X ： 実施例 2 9 ： X = : 0ct <x 実施例 3 8 ： X ： 実施例 3 0 ： X = 実施例 3 9 ： X ：

実施例 3 1 ： X 0 0

Example 22: X = Example 36: X: Example 28: X = Example 37: X: Example 29: X =: 0ct <x Example 38: X: Example 30 : X = Example 39: X:

Example 31 1: X

Example 32: X Example 33: X Example 34: X

Example 35: X =

Example 43-49

0 0

Example 43: X Example 44: X

 H H

 Example 45: X =

 H

 Example 46: X =

 Ν *

Η Η Η

 Example 47: X = 'Ν Example 48: X

0 Example 49: X = Ν ^Α例 Example 50 to 55

実施例 56 ： X =Examples 56 to 58

Example 56: X =

Example 57: X =, CF ₃

Example 58: X =

Examples 59 to 64

Examples 65 to 67

 0 Ο Ο

Ν 'Ν

.N Ν,

X 'X Example 65: X Example 66: X Example 67: X

実施例 6 8, 6 9

Example 6 8, 6 9

実施例 70 ： X Examples 70 and 71

Example 70: X

¹ J-> Example 7 1: X

実施例 72 ： X = , Ci Examples 72, 73

Example 72: X =

CF ₃ Example 73: X =

Example 74 7 5

Example 7 7, 80

実施例 77 ： X =

Example 77: X =

 o "o Example 80: X =

実施例 7 6 78 7 9 8 1 94

Example 7 6 78 7 9 8 1 94

OO Λ ^Χ

N Example 7 S: X =

 ο Example 78: X

O ", to OH Λ _N Example 87: X =

 0 'Example 79: X =

 0 ', Ν,

 To 义 N = Example 81 1: X =

実施例 82 ： X =

Example 82: X =

Example 83: X = Example 84: X =

Example 85: X =

Examples 95 to 98

実施例 95 χ= |

Example 95 χ = |

Example 96 X = OCF ₃ 2HCI

Example 97 X = Et 2HCI

Example 98 X = OMe 2HCI

Example 100

Example 1 00 X = Et 2HCI Examples 102-105

Example 102 X = Et 2HCI

Example 1 03 X = OMe 2HCI

Example 104 X = OCF ₃ 2HCI

Example 1 05 X = CH ₂ OH 2HCI Example 99, 101

Examples 106-117, 121-134, 136-142, 146-152

9S1

S9080 / 00df / X3d 98C9C / T0 OAV Example 106: Example 107

Example 1 0 8

Example 1 10 卖 Example 1 110: Example 1 1 1: Example, 1 2: Example 1 1 3 Example Ί 1 4

S HNN H e 実施例 1 2 3 ： X

S HNN He Example 1 2 3: X

実施例 1 2 7 ： X 実施例 1 2 8 ： X ノ Actual 1 2 4: X Example 1 2 5: X Example 1 2 6: X

Example 1 2 7: X Example 1 2 8: X

Example 1 2 9: X

実施例 1 18、 135

Example 1 18, 135

o

o

Example 1 18: X =

 Example 1 35: X = N

Example 1 19, 120, 144, 15

Example 1 20: X =

Example 144: X =

Example 145: X =

実施例 1 5 3 ： X 実施例 1 6 1 ： X 実施例 1 6 2 ： X 実施例 1 6 3 ： XExamples 153, 161-163

Example 15 3: X Example 16 1: X Example 16 2: X Example 16 3: X

実施例 1 5 4、 1 6 4

Example 1 5 4, 1 6 4

実施例 1 5 5、 1 6 5

実施例 1 5 5 ： X

Example 1 5 5, 1 6 5

Example 1 55: X

Example 16: X

実施例 1 5 6〜 1 5 8

Example 15-6 to 15-8

Example 15 9 and 16 0

0 0 0 ゝ¹ , ιι, Ο

N: ^S- X Example 1 59: X = Example 1 60: X-=

実施例 1 6 6、 1 6 7

Example 1 6 6, 1 6 7

実施例 1 6 8 ： X Example 16-8 to 170

Example 16: X

Example 16 9: X =

実施例 1 7 1 ： X = 産業上の利用性 Example 17 0: X =, Example 1 7 1

Example 17 1: X = industrial applicability

 According to the present invention, a dipidazine derivative useful as a drug such as a hypoglycemic agent can be provided.

Claims

The scope of the claims  Expression Y, Υ 3

[Wherein, Ar ′ and Ar ² represent an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted heterocyclyl group, respectively. A ¹ and A ² each represent an alkylene group or a carbonyl group which may be substituted. However, A ¹ and A ² do not simultaneously represent a carbinole group.  A represents a methylene group or a dimethylene group. Υ ² , Υ ³ and Υ ⁴ each represent a hydrogen atom or an alkynole group. L represents a group represented by the formula: —L ³ —X ¹ —L ¹ —X ² —L ² —X ³ —L ⁴ — L ³ and L ⁴ each represent a carbonyl group or a sulfonyl group. X] and X ³ each represent a single bond, ^one NR group or an oxygen atom. However, when L ³ or L ⁴ represents a sulfonyl group, X ^{1 and} X ³ each do not represent an oxygen atom. R ¹ represents a hydrogen atom or an alkyl group. X ² is a single bond, an optionally substituted alkylene group, an optionally substituted heteroarylene group, an optionally substituted phenylene group, an optionally substituted cycloalkylidene group, an optionally substituted cycloalkylene group An optionally substituted divalent aliphatic heterocyclic group, an optionally substituted vinylene group, an ethynylene group, a sulfur atom, an oxygen atom or a formula: —N (R ² ) —C (= 0) One N (R ³ ) -C (= 0) — N (R ⁴ ) one, one N (R ² ) one C (= 0) one-one, -0-C (= 〇) one-one, one 0 — C (= 0) —, C (= 0) One, or one 一 [— C (= 0) — R ⁵ ] — represents a group represented by R ² , R ³ , R ⁴ and R ⁵ each represent a hydrogen atom or an alkyl group. 1 ^ OyoBishi ² each represents a single bond, an alkylene group, vinylene group or an optionally substituted phenylene group. Provided that X ² is a single bond, an optionally substituted vinylene group, an ethynylene group, a sulfur atom, an oxygen atom or a formula: one N (R ² ) -C (= 0)-, -N (R ³ ) — C ( = 0) — N (R ⁴ ) one, -N (R ² ) -C (= 0) — O_, -OC (= 0) — 0—, -0-C (= 0) —, — C (= 0) -, or - N [-C (= 0) -R 5] - is L ¹ or L ² months' does not become a single bond when a group represented by. When L ¹ or L ² is a vinylene group, X ¹ or X ³ is a single bond, respectively. ] A therapeutic agent for diabetes, comprising a dipiperazine derivative represented by the formula: or a pharmaceutically acceptable salt thereof. 2. The therapeutic agent for diabetes according to claim 1, wherein both A ¹ and A ² are methylene groups. 3. The diabetes treatment according to claim 1 or 2, wherein Ar ¹ and Ar ² are substituted phenyl groups. 4. The therapeutic agent for diabetes according to any one of claims 1 to 3, wherein Ar ¹ and Ar ² are para-substituted phenyl groups. 5. The therapeutic agent for diabetes according to any one of claims 1 to 4, wherein the substituents of Ar ¹ and Ar ² are a halogen atom, an alkyl group, a trifluoromethyl group or a trifluoromethoxy group, respectively. In 6. L, antidiabetic agents according to any one of claims 1-5 sum of the shortest chain of atoms atoms Ru 1-7 der extending from X ¹ to X ^3. 7. The therapeutic agent for diabetes according to any one of claims 1 to 6, wherein _X] 1 L ¹ — X ² — L ² — X ³ — is an amino-1,4-phenylene group. 8. The antidiabetic agent according to any one of claims 1 to 6, which is —X ¹ —i—X ² —L ² —X ³ —force ′ substituted alkylene group. 9. The therapeutic agent for diabetes according to any one of claims 1 to 6, wherein —X ¹ —L ¹ —X ² _L ² —X ³ — is a 1,1-dimethyl-1,2-dimethylene group. ^{10, -X 1 - L'- X 2} - L 2 - X 3 - 1, antidiabetic agents according to any one of claims 1 to 6 is 2-cyclopentylene group. 1 1. — X ¹ — L′—X ² — L ² — X ³ — is a 1,3-dimethylene-1 (2-oxo-1,3,3-imidazolidin) group. Antidiabetic drugs. 12. The therapeutic agent for diabetes according to any one of claims 1 to 6, wherein ——X ¹ —] ^ ¹ —X ² —L ² _X ³ — is a 1-alkoxycarbonylethyl-1,3-trimethylene group. ^{1 3. - X 1 - L'-} X 2 - L 2 - X 3 - diabetes therapeutic agent according to any one of claims 1 to 6 is 1-alkoxycarbonyl two Ruechiru 1, 2 one dimethylene group. 14. —A drug for treating diabetes according to claims 1 to 6, wherein L ¹ —X ² —L ² —X ³ — is a 3-dialkylaminocarbonyl—1,5-pentamethylene group. ^{15. - X 1 - L 1 -} X 2 - L 2 - X 3 - 2, 2-dimethyl one 1, antidiabetic agents according to any one of claims 1 to 6 is 3-trimethylene group. 16. The method according to claim 1, wherein one of L ^{3 and} L ⁴ is a carbonyl group, the other is a sulfonyl group, and —X ¹ —L ¹ —X ² —L ² —X ³ — is a methylene group. Antidiabetic drugs. 17. The method according to claim ¹ , wherein one of L ³ or L ⁴ is a carbonyl group, the other is a sulfonyl group, and one X ¹ —L′_X ² —L ² —X ³ — is a phenylene group. Diabetes 18. The therapeutic agent for diabetes according to any one of claims 1 to 6, wherein L ³ and L ⁴ are sulfonyl groups, and —X ¹ —L′—X ² —L ² —X ³ — is a dimethylene group. 19. The diabetes according to claim 7, wherein L ³ is a carbonyl group, and L ⁴ is a sulfonyl group. 20. antidiabetic agent of claim 15, wherein L ³ and L ⁴ are sulfonyl group. 21. Formula: Y ¹ Y 3

[Wherein, Ar ¹ and Ar ² each represent a substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted heterocyclyl group. A ¹ and A ² each represent an alkylene group or a carbonyl group which may be substituted. However, A ¹ and A ² do not simultaneously represent a carbonyl group.  A represents a methylene group or a dimethylene group. Y Υ ² , Υ ³ and Υ ⁴ each represent a hydrogen atom or an alkyl group. L represents a group represented by the formula: — Ls— X′— L ¹ — X ² — L ² — X ³ — L ⁴ —. L ³ and L ⁴ each represent a carbonyl group or a sulfonyl group. X ¹ and X ³ each represent a single bond, ^one NR group or an oxygen atom. However, when L ³ or L ⁴ represents a sulfonyl group, ¹ or ³ does not represent an oxygen atom, respectively. R ¹ represents a hydrogen atom or an alkynole group. X ² is a single bond, an optionally substituted alkylene group, an optionally substituted heteroarylene group, an optionally substituted phenylene group, an optionally substituted cycloalkylidene group, an optionally substituted cycloalkylene group An optionally substituted divalent aliphatic heterocyclic group, an optionally substituted vinylene group, an ethynylene group, a sulfur atom, an oxygen atom or a formula: _N (R ² ) 1 C (= 0) 1, 1 N (R ³ ) -C (= O) -N (R ⁴ ) —, -N (R ² ) -C (= 0) one O—, -OC (= 0) one 0—, -OC (= 0 ) —, One C (= 0) — or — N [— C (= 0) one R ⁵ ] —. R ² , R ³ , R ⁴ and R ⁵ each represent a hydrogen atom or an alkyl group. L ¹ and L ² each represent a single bond, an alkylene group, a vinylene group or a phenylene group which may be substituted. However, when (1) L ³ and L ⁴ represent a carbonyl group and one X ¹ —L ¹ —X ² —L ² —X ³ — represents an alkylene group, the alkylene group has 3 to 3 carbon atoms. 6 or is substituted with a substituent other than a hydroxyl group, and (2) X ² is a single bond, a vinylene group, an ethynylene group, an ethynylene group, a sulfur atom, an oxygen atom, or a formula: —N (R ² ) -C (= 0) one, -N (R ³ ) — C (= 0) — N (R ⁴ ) one, one N (R ² ) — C (= 0) — 0—, one OC (= 〇) one 0-, -OC (= 〇) Single, -C (= 0) primary, or single N [- C (= 0) -R 5] L 1 when a group represented by one Or L ² is not a single bond, or (3) When L ¹ or L ² is a vinylene group, X ¹ or X ³ is a single bond, respectively. ] Or a pharmaceutically acceptable salt thereof. 22. The dipiperazine derivative or the pharmaceutically acceptable salt thereof according to claim 21, wherein A ¹ and A ² are both methylene groups. 23. The dipidazine derivative or a pharmaceutically acceptable salt thereof according to claim 21 or 22, wherein Ar ¹ and Ar ² are substituted phenyl groups. 24. The dipidazine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 21 to 23, wherein Ar ¹ and Ar ² are para-substituted phenyl groups. 25. The dipiperazine derivative according to any one of claims 21 to 24 or a pharmaceutically acceptable salt thereof, wherein the substituents of Ar ¹ and Ar ² are each a halogen atom, an alkyl group, a trifluoromethyl group or a trifluoromethoxy group. Acceptable salt. In 26. L, Jipiperajin derivative or a pharmaceutically acceptable salt thereof according to any one of claims 21 to 25 total atoms in the shortest chain of atoms extending from X ¹ to X ³ is 1-7. 27. —The dipiperazine derivative according to any one of claims 21 to 26 or a pharmaceutically acceptable salt thereof, wherein —X ¹ —L ¹ —X ² —L ² —X ^3— is an amino-1,4_phenylene group. salt. 28. The dipidazine derivative or the pharmaceutically acceptable salt thereof according to any one of claims 21 to 26, wherein —X ¹ —L ¹ —X ² —L ² —X ³ — is a substituted alkylene group. 29. — X ¹ — L ¹ — X ² — L ² — X ³ — is a 1,1-dimethyl-1,2-dimethylene group The dipiperazine derivative according to any one of claims 21 to 26 or a pharmaceutically acceptable salt thereof. 30. —The dipiperazine derivative or the pharmaceutically acceptable salt thereof according to any one of claims 21 to 26, wherein —X ¹ —L ¹ —X ² —L ² —X ^3— is a 1,2-cyclopentylene group. . 31 1. The method according to any one of claims 21 to 26, wherein — — X ¹ — L ¹ — X ² — L ² — X ³ — is a 1,3-dimethylene-1 (2-oxo-1,1,3-imidazolidine) group. Or a pharmaceutically acceptable salt thereof. 32. The dipiperazine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 21 to 26, wherein 32, _X'_L X ² _L ² — X ³ — is 1-alkoxycarbonylethyl-1,3-trimethylene group. . 33. The dipiperazine derivative according to any one of claims 21 to 26 or a pharmaceutically acceptable salt thereof, wherein —X′—L′—X ² —L ² —X ³ — is a 1-alkoxycarbonylethyl-1,2—dimethylene group. Acceptable salt. 34. The dipiperazine derivative or the dipiperazine derivative according to any one of claims 1 to 26, wherein — X ¹ — L ¹ — X ² — L ² — X ³ — is a 3-dialkylaminocarbonyl — 1, 5-pentamethylene group. Its pharmaceutically acceptable salts. 35. The dipiperazine derivative according to any one of claims 21 to 26 or a pharmaceutically acceptable salt thereof, wherein —X ¹ —L ¹ —X ² —L ² —X ³ — is a 2,2-dimethyl-1,3-trimethylene group. Salt. 36. The di according to any one of claims 21 to 26, wherein one of L ^{3 and} L ⁴ is a carbonisole group, the other is a sulfonyl group, and — X ¹ — L ¹ — X ² _L ² _X ³ — is a methylene group. A piperazine derivative or a pharmaceutically acceptable salt thereof. 37. The method according to any one of claims 21 to 26, wherein one of L ^{3 and} L ⁴ is a carbonyl group, the other is a sulfonyl group, and one X ¹ —L ¹ —X ² —L ² —X ^3— is a phenylene group. Or a pharmaceutically acceptable salt thereof. 38. The dipiperazine derivative or a derivative thereof according to any one of claims 21 to 26, wherein L ³ and L ⁴ are a sulfonyl group, and — Xi_L '— X ² — L ² — X ³ — is a dimethylene group. Pharmaceutically acceptable salts. 3 9. L ³ is carbonyl, group, salt L ⁴ is acceptable di piperidines Rajin derivative or a pharmaceutically according to claim 2 7 wherein the sulfonyl group. 4 0. Jipiperajin derivative or a pharmaceutically acceptable salt thereof of L ³ and claim 3 5, wherein L ⁴ is a sulfonyl group.  41. Use of the dipiperazine derivative according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof in the manufacture of a therapeutic agent for diabetes.  42. A method for treating diabetes in a patient, comprising administering a therapeutically effective amount of the dipiperazine derivative of any one of claims 1-20 or a pharmaceutically acceptable salt thereof.