WO2006006610A1 - Oxopiperazine derivative - Google Patents

Abstract

A compound represented by the formula (I) (wherein R1 represents linear or branched lower alkoxy, etc.; R2 represents halogeno, lower alkyl, cyano, nitro, alkoxy, etc.; R3 represents hydrogen, halogeno, or lower alkyl; and X1 represents phenyl, 6-membered heteroaryl having one or two nitrogen atoms in the ring, etc.) or a pharmaceutically acceptable salt of the compound. The compound and salt have mGluR1 inhibitory activity and are useful for the treatment and/or prevention of convulsion, acute pains, brain disorders such as brain infarction or transient cerebral ischemic attack, mental-function disorders such as schizophrenia, anxiety, drug dependence, or Parkinson's disease.

Description

 Akira Ita

 Oxopiperazine derivatives

Technical field

 The present invention relates to an oxopiperazine derivative.

Background art

Glutamate is a neurotransmitter that mediates excitatory transmission in the central nervous system. In addition to various neurotransmitter effects, glutamate has many important brain functions such as neuronal survival and death, differentiation and proliferation, nerve and glial cell development, maturation or plastic changes in neurotransmission efficiency of the developing brain. Related to function (eg, Annual Review of Biophysics and Biomolecular Structures, 23, 3 1 9 (1 994))).

 Based on pharmacological and molecular biological studies, glutamate receptors in the central nervous system of mammals are classified into two types: ion channel glutamate receptors and metabotropic glutamate receptors (hereinafter referred to as “mG 1 uR”). ing. An ion channel glutamate receptor is an ion channel that is composed of a complex of different subunit proteins and is opened and closed by the binding of ligands. On the other hand, mG l uR is coupled to GTP-binding protein and acts by regulating intracellular second messenger production or ion channel activity via GTP-binding protein (for example, B rain Research R evi ew s), 26 卷, p. 230 (1998)).

Previous studies have reported that mG 1 uR exists as eight different subtypes of mG 1 uR 1-8. These fall into three subgroups according to amino acid sequence homology, signal transduction, and pharmacological properties. Group I (mG l uR l and 5) is a phospholipase for intracellular signaling. By activating C, group II (mG 1 uR 2 and 3) and group III (mG 1 uR4, 6, 7 and 8) regulate cyclic adenosine 1 phosphate by modulating adenylate cyclase activity ( cAMP) suppresses forskolin-stimulated accumulation. In addition, Group II is selectively activated by LY 354740 described in, for example, Journal of Medicinal Chemistry, 42 卷, page 1027 (1999). III is selectively activated by L-AP 4. Furthermore, various receptors are expressed in a wide range of brain and nervous system, except for mG 1 uR6, which exists specifically in the retina. It has a characteristic distribution in the brain, and it is thought that each receptor plays a different physiological role (for example, Neurochemistry International (Neuroch em istry I nternationa 1), 24 卷, 439 ( 1 994) Eopyo Ichibanbian Joura Nore off, 'Eu ropean Journal of Pharmacology, 375 卷, 277 (1999) etc.).

 In addition, as a compound approximate to the compound according to the present invention, for example, a compound represented by the formula (A)

 A compound represented by (A) is described (WOO 3/026652).

The compound (A) has one NH—S (O) ₂ — Ph on the oxopiperazine ring, and has a benzyloxycarbonyl group at the 4-position on the oxopiperazine ring. It is structurally different from the compound according to the present invention.

Disclosure of the invention Accordingly, an object of the present invention is to provide a novel substance having an mG 1 uR 1 inhibitory action.

 The present inventors have found that a specific oxopiperazine derivative has an mG 1 uR l inhibitory action, and completed the present invention.

 That is, the present invention provides the following compounds (1) to (7) or a pharmaceutically acceptable salt thereof in order to achieve the above object.

 (1) Formula (I)

[Where R ¹ is

 (a) a straight or branched lower alkoxy group, a cycloalkoxy group or a straight chain or branched lower alkyl group, or

 (b) Formula (I I)

In the formula, R ⁴ and R ⁵ are each independently a hydrogen atom, a linear or branched lower alkyl group or a cycloalkyl group, or a nitrogen atom in the formula (II), R ⁴ and R ⁵ together. Therefore, a 4- to 7-membered nitrogen-containing aliphatic heterocyclic group to be formed (the heterocyclic group may have one oxygen atom as a constituent atom of the ring),

R ² may have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group, a cyano group, a nitro group, an alkoxy group, a lower alkylsulfonyl group and a hydroxy group in the ring. Les A 5- to 6-membered unsaturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms in the ring selected from the group consisting of a phenyl group, a nitrogen atom, a sulfur atom and an oxygen atom Or a branched alkyl group having 3 to 10 carbon atoms, R ³ represents a hydrogen atom, a halogen atom or a lower alkyl group,

Represents a phenyl group or a 6-membered heteroaryl group having 1 or 2 nitrogen atoms in the ring ring, or a condensed ring formed by combining R ² with R ² ]. Or a pharmaceutically acceptable salt thereof.

(2) R ² has 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group, a cyano group, a nitro group, a lower alkoxy group, a lower alkylsulfonyl group and a hydroxy group in the ring. Or a pharmaceutically acceptable salt thereof, which is a 6-membered heteroaryl group having 1 or 2 phenyl groups or nitrogen atoms in the ring.

(3) The compound according to the above (1) or a pharmaceutically acceptable salt thereof, wherein R ² is a branched lower alkyl group having 3 to 10 carbon atoms.

(4) One Xi—R ² in formula (I) is

[Wherein A to A ₅ each independently represent a methine group, or any one or two of A to A ₅ is a nitrogen atom, and the remaining 3 or 4 is a _{10 to} A ₄₀ represents a chin group. To A ₄ . Any one or two of them is a nitrogen atom, the remaining 2 or 3 is a methine group, and R ⁶ , R ^6G and R ⁶¹ are independently a hydrogen atom, a halogen atom, The compound according to the above (1) or a pharmaceutically acceptable salt thereof, which is a group represented by the following: a lower alkyl group, a cyano group, a nitro group, a lower alkoxy group, a lower alkylsulfonyl group or a hydroxy group. (5) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (4), wherein R ¹ is a linear or branched lower alkyl group or a cycloalkoxy group.

(6) R ¹ is the formula (II) ー

R ⁵

 (Π)

The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (5), which is a group represented by:

 (7) The compound represented by the formula (I) is 4— (2′-fluoro-bibiphenyl-2-yl) _ 3—oxopiperazine 1 _carboxylic acid tert-butyl ester, 4- (biphenyl 1 3 —Yl) 1-oxopiperazine 1 _carboxylic acid tert-butinoresestenole,

 4— (2′-methyl-1-biphenyl-1-3-yl) 1-oxo-1-piperazine 1-carboxylic acid tert-butynole ester,

 4— (2′—chloro-bibiphenyl-1-3-yl) -3-oxo-1-piperazine 1-carboxylic acid ter t-ptyl ester,

 3-Oxo 4- (3-Pyridine 1- 2-Inole 1-phenyl) 1 Piperazine 1 1 1 Force Rubonic acid tert-butyl ester,

 3-Oxo 4- (3-T er t-Butyl monophenol)-Piperazine 1-Carbonic acid ter t-Butyl ester,

4-Naphthalene 1- 2-yl 3-oxo-1piperazine 1-carboxylic acid t e r t

—Bucinore Estenore,

 3-Oxo 1- (3-Pyridine 1 3-Roylenyl) 1 Piperazine 1 1-Force Norebonic acid tert-butyl ester,

3—Oxo 4— (6—Phenyl 1—Pyridine 2— ^ T) 1 Piperazine 1—Power Rubonic acid ter t_butyl ester, or

3-oxo 4- (5-phenyl pyridine 3-yl) monopiperazine 1-power rubonic acid A compound which is tert-butyl ester or a pharmaceutically acceptable salt thereof. The compounds of the above (1) to (7) or pharmaceutically acceptable salts thereof have mG luR l inhibitory action. That is, the present invention provides an _m G 1 uR 1 inhibitor comprising the compound according to (1) to (7) or a pharmaceutically acceptable salt thereof.

 3, 5-dihydroxyphenyglycine (DHPG), a selective agonist for Group I, has been reported to cause convulsions when administered intraventricularly (eg, Journal of Neuroscience Research). (J ournalof Neuroscience Research),

5 See page 1, page 339 (1998), etc.).

On the other hand, in the test using mG 1 uR 1 selective antagonist, R 1—am inoindan— 丄, o-dicarboxylicacid (hereinafter referred to as AI DA) in the pentylenetetrazole-induced convulsions model widely used for evaluating the effects of anticonvulsants. In addition to exhibiting a dose-dependent anticonvulsant effect (for example, New mouth pharmaco-mouth disease (see Neuropha rma cology, 37 卷, page 1465 (1998), etc.), it is genetically easily convulsive. Has an inhibitory effect on sound stimulation-induced convulsions in mice and rats (eg, Eu ropean Journal of Pharmacology, 368 、, 17 pages (1 999 In addition, LY456236, another selective antagonist, reduces convulsion duration and severity in kindled rats of the amygdala known as the model of hemorrhoid spasm Reported to let (See, for example, Neuropharmacology, 43, 308 (2002)) These findings indicate that mG 1 uR 1 inhibitors are useful for the prevention or treatment of convulsions. Suggest. Therefore, the compounds described in the above (1) to (7) having an mG 1 uR 1 inhibitory action or pharmaceutically acceptable salts thereof are considered to be effective in preventing or treating convulsions. Also, when DHPG is administered intrathecally, allodynia and hypersensitivity to mechanical stimuli or hypersensitivity to thermal stimuli occur in rats (for example, Neuroreport, 9 1, 1 1 69 ( 1 998)). On the other hand, in studies using antagonists, the pain threshold increases when AIDA is administered into the brain (for example, The Journal of Pharmacology and Dexperimentorole Therapeutics (Th e J ournalof Pharmorology & Xperi me ntalfherapeutics), 28 1, 721 (1 997), etc.), spinal cord injury hyperalgesia model (eg, Journal of Neurology) by administration of AI DA into the spinal cavity. Trauma (J ournalof N eurotrauma), 19 卷, p. 23 (2002), etc.) and arthritis models (eg, The Journal of Pharmacologic and Xperimentanore Therapeutics) rma cology & experimenta 1 Therapeutics), 300, p. 149 (2002) etc.).

 These findings suggest that mGluRl inhibitors may have analgesic effects not only on acute pain but also on inflammatory and chronic pain.

 Therefore, the compounds of the above (1) to (7) having mG 1 uR 1 inhibitory activity or pharmaceutically acceptable salts thereof are considered useful for the prevention or treatment of acute pain, inflammatory pain or chronic pain. Be

In addition, the inhibitory effect of AI DA on the delayed neuronal death of the hippocampus observed in the transient global cerebral ischemia-reperfusion model (eg, Neuropharmacology, 38 卷, 1607 ( 1 999) and the Neuroscience Letters, 29 3 卷, 1 (2000), etc.), mG 1 uR 1 selective antagonist (3 a S, 6 a S) — 6 a— naphta 1 en— 2— y 1 methy 1— 5— me thy 1 iden— hexahydro— eye 1 openta [c] furan— 1— one (hereinafter referred to as “B AY 36— 7620”) reduces the cortical infarct volume in the rat subdural hemorrhage model (for example, In the European Journal of Pharmacology (see Eu ropean Journal of Pharmorology), 428 卷, 203 (2001), etc.) and other selective antagonists R 1 28494, rat middle cerebral artery ligation There is a decrease in the total infarct volume in the model (see, for example, Neuropharmacology 43, 295 (2002)).

 These findings suggest that niGluRl inhibitors may have a protective effect against cerebral disorders such as cerebral infarction or transient ischemic attack.

 Therefore, the compounds of the above (1) to (7) having a mG 1 uR 1 inhibitory action or pharmaceutically acceptable salts thereof are useful for the prevention or treatment of cerebral disorders such as cerebral infarction or transient ischemic attack. It is considered useful.

In addition, administration of DHPG into the nucleus accumbens showed an increase in locomotor activity, and the effect was similar to the response when a dopamine receptor stimulant was administered (for example, Bibija Bianja Nanole). European Journal of Neuroscience 1 3 卷, 2 1 pp. 57 (20 01) etc.), for example, P sychophar macology, 141 卷, 405 (1 999 ), Etc., prepulse inhibition disorder observed in experimental animal models and schizophrenic patients occurred when DHPG was administered into the nucleus accumbens. These reactions caused by DHPG are similar to those observed with dopamine receptor stimulants such as apomorphine or dopamine-releasing drugs such as amphetamine and methamphetamine. On the other hand, existing antipsychotic drugs suppress overexcited dopamine nerves. It is considered to exert an effect.

 The fact that DHPG showed a similar response to dopamine stimulation suggests that mG 1 uR l and mG 1 u R 5 are involved in mental dysfunction in the nucleus accumbens. This suggests the possibility of improving the symptoms.

 Therefore, the compounds of the above (1) to (7) having a mG 1 uR 1 inhibitory action or pharmaceutically acceptable salts thereof are considered useful for the prevention or treatment of mental dysfunction such as schizophrenia. .

 In addition, it was reported that the selective antagonist R 1 28494 increased drinking water with punishment in the Voge type 1 conflict test using rats, which is widely used as an evaluation system capable of detecting the anxiolytic effects of drugs. (See, for example, Neuropharmacology, 43, 295 (2002)).

 This finding suggests that mG 1 uR 1 inhibitors may have anxiolytic effects. Therefore, the compounds (1) to (7) or pharmaceutically acceptable salts thereof are considered useful for the prevention or treatment of anxiety.

 Further, in Non-Patent Document 16 described above, B which is an mG 1 u R 1 selective antagonist

There is a description that AY 36 — 7620 suppresses brain self-stimulation promoted by MK — 801, which is an NMD A receptor antagonist. Since many NMDA receptor antagonists have been clinically clarified to cause dependence, this test system is considered to be a model that reflects part of the dependence due to MK-801. Yes.

 These findings suggest that selective antagonists of mG 1 u R 1 receptors may be drug-dependent preventive or therapeutic agents.

 Therefore, the compounds (1) to (7) or pharmaceutically acceptable salts thereof are considered useful for prevention or treatment of drug dependence.

In addition, in an experiment in which extracellular potentials were recorded using brain slices containing rat hypothalamic nuclei, an increase in the frequency of action potentials was observed by local application of DHPG (for example, Brain Research (B rain R esearch), 766 卷, 1 62 (1 997)) suggests that activation of the subthalamic nucleus is caused by mG l uR 1 or mG 1 uR 5. It is well known that the excitation of the subthalamic nucleus is characteristic of Parkinson's disease.

 These findings suggest that mGluRl inhibitors may be preventive or therapeutic agents for Parkinson's disease.

 Therefore, the compounds (1) to (7) or pharmaceutically acceptable salts thereof are considered useful for the prevention or treatment of Parkinson's disease. Reflux esophagitis (GERD) is the most common upper gastrointestinal disorder. Current drug therapy aims to suppress gastric acid secretion or neutralize gastric acid in the esophagus. The main mechanism involved in reflux has been thought to be due to chronic tension decline in the lower esophageal sphincter. However, for example, in the report of Gastroenterol Clinical North America (Gastroenterol Clin. No rth Am.) 19 p. 51 p. Pp. 1 535 (1 990), the temporary relaxation of lower esophageal sphincter It has been shown that most reflux episodes are caused by TLESR s), ie relaxations other than swallowing. In addition, normal gastric acid secretion in GERD patients has been found to be normal. The lower esophageal sphincter (LE S) tends to relax intermittently. As a result, when the sphincter is relaxed, the mechanical barrier is temporarily lost, so that gastric fluid can flow into the esophagus. This phenomenon is defined as “reflux”.

 The word “TLE SR”, which indicates the temporary relaxation of the lower esophageal sphincter, is defined according to Gastroenterology (Gastroen tetrology), 109 (2), 601 pp. 1 6 10 (1 995).

The term “reflux” is defined as gastric juice that can flow from the stomach into the esophagus. This is because the mechanical barrier is temporarily lost in such a state. The word “GERD”, which indicates reflux esophagitis, is the veilers clinical gastroente This is a definition according to J. Kazuichi Kuchiguchi (Baillier e's Clinical Ga stroenterology), 14 pp. 759 pp. 774 (2000). Due to the physiological and pathophysiological significance described above, the compounds (1) to (7) or pharmaceutically acceptable salts thereof are considered useful for the prevention or treatment of gastrointestinal disorders.

BEST MODE FOR CARRYING OUT THE INVENTION

The meanings of terms used in the present specification are explained below, and the compounds according to the present invention are further explained.

The meanings of terms used in the present specification are explained below, and the compounds according to the present invention are further explained.

 The “aryl group” means a hydrocarbon ring aryl group having 6 to 14 carbon atoms, and examples thereof include a phenyl group and a naphthyl group.

 “Lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group. Tert-butyl group, pentyl group, isoamyl group, neopentyl group, isopentyl group, 1,1-dimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, Isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3 —Dimethylbutyl group, 2,3-dimethylbutyl group,

Examples include 3,3-dimethylbutyl group, 1_ethylbutyl group, 2-ethylbutyl group, 1,2,2-trimethylpropyl group, 1-ethyl-2-methylpropyl group and the like.

 “Cycloalkyl group” means a cycloalkyl group having 3 to 9 carbon atoms, such as cyclopropyl group, cyclobutyl group, cyclopentyl pentyl group, cyclohexyl hexyl group, cycloheptyl group, cyclooctyl group, cyclononyl. Groups.

“Alkoxy group” means that a hydrogen atom of a hydroxy group is substituted with the lower alkyl group. For example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, hexyloxy group, And an isohexyloxy group.

 “Halogen atom” means, for example, fluorine atom, chlorine atom, bromine atom, iodine atom and the like.

 The “alkylsulfonyl group” means a group in which the alkyl group and the sulfonyl group are bonded. For example, a methylsulfonyl group, an ethylsulfonyl group, a propylsulfoninore group, an isopropylsulphoninole group, a butylsulfoninore group, Etc. The compound according to the present invention has an mG 1 uR 1 inhibitory action. Here, the “mG 1 uR l inhibitory action” may be any substance that inhibits the function of mG 1 uR 1, for example, mG 1 uR 1 inhibitory action. Those having 1 uR 1 antagonistic activity and those that are non-antagonistic and have mG 1 uR 1 receptor antagonistic activity are included.

 In order to more specifically disclose the formula (I) according to the present invention, the formula (I)

 (I)

Various symbols used in will be described with specific examples.

Examples of the “linear or branched lower alkoxy group” represented by R ¹ include a methoxy group, an ethoxy group, an _n -propoxy group, an isopropoxy group, an n-butoxy group, and a tert-butoxy group. Of these, n-propoxy group, isopropoxy group, tert-butoxy group and the like are preferable.

Examples of the “straight chain or branched lower alkyl group” represented by R ¹ include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, 1-methyl-pro And a pyrrole group, a tert-butyl group, a 1-ethynolepropyl group, and the like. Among these, an isopropyl group, a butyl tert-group, a 1-methyl-propyl group, a 1-ethylloop pill group, and the like are preferable. A group or a tert-butyl group is more preferred.

Examples of the “cycloalkoxy group” represented by R ¹ include a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, and the like. A propyloxy group, a cyclobutyloxy group, cyclopentyloxy and the like are preferable, and a cyclopropyloxy group is more preferable.

Formula represented by R ¹ (II)

N

 /

R ⁵

 (Π)

Will be described.

Examples of the “linear or branched lower alkyl group” represented by R ⁴ or R ⁵ include, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, and 1_methylol. —Propyl group, 1-ethyl-butyl group and the like can be mentioned, and among these, methyl group, ethyl group, isopropyl group, tert-butyl group and the like are preferable, and methyl group, isopropyl group and tert-butyl group are more preferable.

Examples of the “cycloalkyl group” represented by R ⁴ or R ⁵ include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like, and a cyclopropyl group or a cyclobutyl group is preferable. A cyclopropyl group is more preferable.

1 ⁴及Pi 1 ^5, when a lower alkyl group or a cycloalkyl group, R ³及beauty R ⁴ may be the same or different.

Further, R ⁴ and R ⁵ are formed together with the nitrogen atom in the formula (II). Examples of the `` to 7-membered nitrogen-containing aliphatic heterocyclic group '' include a pyrrolidine 1-1yl group, a piperidine 1-1yl group, and a homopiperidine 1-1yl group. Among these, pyrrolidine A _ 1 _yl group or a piperidine 1-1-yl group is preferable, and a pyrrolidine 1-1-yl group is more preferable.

 In addition, one of the methylene groups constituting the 4- to 7-membered nitrogen-containing aliphatic heterocyclic group may be substituted with an oxygen atom. For example, morpholine-1 monoyl group or oxazolidine-1-i Among them, morpholine 1-yl group and the like are preferable.

R ¹ may be an alkoxy group, a cycloalkoxy group or a formula (II)-

R ⁵

 (Π)

 [Wherein each symbol is the same as defined above] is preferable.

R ² represents a “5- to 6-membered unsaturated heterocycle having 1 to 3 heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen” in the ring. For example, furyl group, enyl group, pyrrolyl group, imidazolyl group, triazolyl group, pyrazolyl group, thiazolyl group, thiadiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, pyridinyl group, pyrimidinyl group, pyridazinyl group, And pyridyl group. Among these, a pyridinyl group, a phenyl group, a birazinyl group, a pyrimidinyl group, and the like are preferable, a pyridinyl group and a phenyl group are more preferable, and a pyridinyl group is particularly preferable.

Examples of the “partially unsaturated heterocycle having 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom” in R ² include the following formulas: (III)

The group represented by these is preferable.

R ² is a phenyl group or a 5- to 6-membered unsaturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms in the ring selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom In this case, a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a cyano group, a nitro group, an alkoxy group, an alkylsulfonyl group and a hydroxy group is substituted with the phenyl group or the unsaturated or partially substituted group. 1 to 3 may be present on the unsaturated polycyclic ring.

When R ² has 2 or 3 substituents, these may be the same or different.

 The “halogen atom” of the substituent is, for example, preferably a fluorine atom, a chlorine atom, a bromine atom.

 The “lower alkyl group” for the substituent is, for example, preferably a methyl group, an ethyl group, an isopropyl group.

 Examples of the “alkoxy group” of the substituent include a methoxy group, an ethoxy group, and n

—Propoxy group, isopropoxy group and the like are preferable.

The “branched alkyl group having 3 to 10 carbon atoms” represented by R ² is, for example, the following formula (IV)

(IV)

Group represented by the above.

From the above, as R ² , more specifically, for example, a tert-butyl group, a phenyl group, a fluorophenyleno group, a methinophenyl group, a cyanphenyl group, a nitrophenyl group, a methoxyphenyl group, a hydroxyphenyl group, a pyridinyl group Of these, tert-butyl, phenyl, fluorophenyl, and pyridinyl are preferred.

As the “halogen atom” represented by R ³ , for example, a fluorine atom, a chlorine atom, or an aromatic atom can be mentioned, and among these, a fluorine atom or a chlorine atom is preferable.

Examples of the “lower alkyl group” represented by R ³ include a methyl group, an ethyl group, an isopropyl group, and an n-propyl group, and among these, a methyl group is preferable. Next, will be described.

Specific examples of the 6-membered heteroaryl group having 1 or 2 nitrogen atoms in the ring include a pyridinyl group, a pyradyl group, a pyrimidinyl group, and a pyridazinyl group. , Pyridinyl group, pyrimidinyl group, etc. Is preferred.

Of the “naphthyl group, quinolinyl group, isoquinolinyl group, quinazolinyl group, quinoxalinyl group, or cinnolinyl group formed by combining X and R ² together”, a naphthyl group, a quinolinyl group, an isoquinolinyl group, and the like are preferable.

When R ² and R ² together form a naphthyl group, quinolinyl group, isoquinolinyl group, quinazolinyl group, quinoxalinyl group or cinnolinyl group, a halogen atom or lower alkyl group as a substituent of the group 1 to 3 may be included. When R ² has 2 or 3 substituents, these may be the same or different.

From the above, more specifically, as the condensed ring formed by combining R ² and R ¹ which may be substituted with 1 to 3 halogen atoms or lower alkyl groups, for example, a naphthyl group, A quinolinyl group, an isoquinolinyl group, etc. are mentioned, Among these, a naphthyl group etc. are preferable.

Therefore, one Xi—R ² in the formula (I) is, for example, the following formula (V)

 (V)

[Wherein A to A ₅ each independently represent a methine group, or any one or two of A b to A ₅ is a nitrogen atom, and the remaining 3 or 4 Indicates a methine group. To A ₄ . Is To A ₄ . Any one or two of them is a nitrogen atom, the remaining 2 or 3 is a methine group, and R ⁶ , R ^6G and R ⁶¹ are independently a hydrogen atom, a halogen atom, A lower alkyl group, a cyano group, a nitro group, a lower alkoxy group, a lower alkylsulfonyl group or a hydroxy group] is preferred. From the above, the formula (I) according to the present invention

[In the formula, each symbol is the same as above] Specifically, for example, 4— (2′—fluoro-biphenyl 2-3-f) 1-oxopiperazine 1-Strong Norevonic acid tert-Butyl ester, 4- (Bifinole _ 3—Inole)-3-oxopiperazine 1 _Strong Norebonic acid tert-Butinore Estenole, 4— (2'-Methyl monobiphenyl) 3—yl) 1 3-oxopiperazine 1-carboxylic acid tert-butinoreestenole, 4-(2 '-black-one bifue-nore 1 3-inole) 1 3-oxo 1-piperazine 1 1-carvone Acid tert-butyl ester, 3 _oxo 4- (3-pyridine-1--2-yl monophenyl) monopiperazine mono 1-carboxylic acid tert-butyl ester, 3-oxo 4- (3-tert-butyl monophenyl) ) —Piperazine mono 1-carboxylic acid tert-butynole ester, 4 1-Naphthalene 2-I-yl 3-Oxo-piperazine 1-Carboxylic acid tert-Butyl ester, 3-Oxo 4- (3-Pyridine 1-yl-phenyl) One Piperazine 1-Strength Rubon Acid tert-butyl ester, 3 _oxo _4 _ (6-phenolinopyridin-2-yl) monopiperazine _ 1-carboxylic acid tert-butyl ester or 3 -oxo 1- (5-phenyl monopyridine) 1 3 f) 1 Piperazine 1 1 1 Carbonic acid tert-Ptyl ester, etc. Among them, 4- (2′-Fluoro bibienyl 1 3-yl) 1 3-Oxopiperazine 1 1-Carboxylic acid tert-butyl ester, 4- (Biphenyl _ 3— ^ f) 1 3-oxopiperazine — 1—Strength of levonic acid tert—Butinore estenole, 4— (2 '-Metinorebihue-nore — 3 —1) 1—Oxo 1 Piperazine 1—Cal Phosphate tert- Puchiruesu ether or 4- (2 '- chloro port one biphenyl one 3-I le) Single 3 Okiso one piperazine 1-Forced norebonic acid tert-butyl ester is preferred.

 The compound (I) according to the present invention can be produced using a known reaction means or according to a method known per se. The compound (I) according to the present invention can be produced not only by a synthesis method in a normal liquid phase but also by a method using a solid phase such as a combinatorial synthesis method or a parallel synthesis method, which has been developed in recent years. it can.

The (1-1), (1-2), (1-3) or (1-4) included in the compound (I) according to the present invention can be produced, for example, by the following method.

 (1) Process-Process 2

 [Where each symbol is the same as above]

 (Process I)

This step is a process for producing compound (3) by reacting 4-Boc-piperazinone (I) with I-mouthed 3-benzene benzene (2) in the presence of a base and a catalyst. It is.

 Examples of the base used in this step include potassium phosphate, sodium carbonate, potassium carbonate and the like.

 The amount of the base used in this step is usually 1 to 100 equivalents, preferably 2 to 10 equivalents, relative to 1 equivalent of compound (1).

 The amount of the compound (2) used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 0.1 equivalent of the compound (1).

 Instead of the compound (2), the reaction can be carried out using 1,3-dibromobenzene, 1,3-jodobenzene, or the like.

 Examples of the catalyst used include copper iodide, copper chloride (1), and copper acetate (I I). Of these, copper iodide is preferred.

 The amount of the catalyst used is 1% mol to 200% mol, preferably 5% mol to 20% mol, relative to 1 equivalent of the compound (1).

 The reaction solvent used in this step is not particularly limited as long as it does not interfere with the reaction. Specific examples include DMF, N-methylpyrrolidone, dioxane, THF, DMS O, and water. Of these, DMF, N-methylpyrrolidone or dioxane is preferred.

 The reaction temperature in this step is usually 0 ° C to 150 ° C, preferably 50 ° C to 120 ° C.

 The reaction time in this step is usually 30 minutes to 7 days, preferably 6 hours to

1 2 hours.

 The compound (3) thus obtained can be isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be attached to the next process.

 (Process 2)

This step is a combination of the compound (3) obtained in Step 1 in the presence of a catalyst and a base. This is a method for producing the compound (I-1) according to the present invention by reacting the product (4). The reaction in this step is a so-called Suzuki coupling reaction. The amount of compound (3) used is usually 1 to 1 per 1 equivalent of compound (4).

0 equivalents, preferably 1 to 3 equivalents.

The catalyst to be used, for _{example, P d (PPh 3) 4} , P d 2 (dba) 3, P d C 1 2 (dppf) 2 and the like.

 The amount of the catalyst used is usually 1 to 200% mole, preferably 5 to 20% mole, relative to 1 equivalent of the compound (4).

 Examples of the base used include sodium carbonate and potassium carbonate.

 The amount of the base used is usually 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (4).

 Examples of the compound (4) used include 2_pyridine boric acid, 3-pyridin boric acid, 4 monopyridine boric acid, and pyrimidine 1 5_boric acid. Any solvent can be used as long as it does not interfere with the reaction. For example, toluene, N, N-dimethylformamide (hereinafter referred to as “DMF”), N —Methylpyrrolidone (hereinafter referred to as “NMP”), dioxane, tetrahydrofuran (hereinafter referred to as “THF”), dimethyl sulfoxide (hereinafter referred to as “D MSO”), water, etc. Toluene, DMF and NMP are preferred.

 The reaction temperature is generally 0 ° C to 150 ° C, preferably 50 ° C to 120 ° C. The reaction time is usually 30 minutes to 7 days, preferably 6 to 12 hours. The compound (1-1) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, reprecipitation, chromatography, etc., or in the next step. Can be attached.

(Process 3) This step is a method for producing a compound (5) by removing the B oc group of the compound (I-1) obtained in the above step 2.

 This reaction can be performed using methods described in the literature (for example, Protective Groups in Organic Synthesis, TW G reen, 2 te, John W i 1 ey & Sons, 1 991 Year, etc.), a method according to it, or a combination thereof with a conventional method, specifically, for example, monoethanol hydrochloride or TFA.

 The amount of hydrochloric acid monomethanol or TFA used is 1 to the amount of solvent. The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include chlorohonolem, THF, jetyl ethereol, tonoleene, hexane, pyridine, DMF, NMP, methanol, ethanol, and the like. Of these, black mouth form, THF, methanol are preferred.

 The reaction temperature is usually from 78 ° C to 100 ° C, preferably from 0 ° O to 30 ° C.

 The reaction time is usually 10 minutes to 2 days, preferably 10 minutes to 2 hours.

 The compound (5) thus obtained can be isolated or purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. or without isolation and purification. It can be attached to the next process.

 (Process 4_ 1)

 This step is a process for producing the compound (1-2) according to the present invention by reacting the compound (5) obtained in the step 3 with a carboxylic acid compound (6-1) or a reactive derivative thereof. It is.

This reaction is a method described in the literature (eg, peptide synthesis fundamentals and experiments, Nobuo Izumiya et al., Maruzen, 1983, Comprehensive Organic Synthesis (C omp r ehensive Organic Synthesis), No. 6, Pergamon Press, 1 99, 1), etc., or a combination of these and conventional methods to perform normal amide formation reactions. In other words, it can be carried out by using a condensing agent known to those skilled in the art, or by an ester activation method, a mixed acid anhydride method, an acid chloride method, a carbodiimide method, etc. available to those skilled in the art. You can. Examples of such amide-forming reagents include thionyl chloride, oxalyl chloride, N, N-dicyclohexylcarbodiimide, 1-methyl-2-bromopyridinium iodide, N, N′-carboninoresidimidazole, diphenyl. Phospholinole chloride, diphenylphosphoryl azide, Ν, Ν '—disuccinimidinole canolebonate, N, N' —disuccimidyloxalate, 1-ethyl-1-3- (3-dimethylaminopropyl) Examples thereof include carbodiimide hydrochloride, chloroethyl formate, chlorobutyl isobutyl formate or benzotriazo-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, and examples thereof include thiol chloride, 1 _Ethyl_3_ (3-Dimethylaminopropyl) carbodiimide hydrochloride, Ν, Ν-di Preferred is hexylcarbodiimide or benzotriazo 1-yloxytris (dimethylamino) phosphonium hexafluorophosphate. In the amide formation reaction, a base and a condensation aid may be used together with the amide formation reagent.

Examples of the base used include trimethylamine, triethylamine, Ν, Ν-diisopropylethylamine, Ν-methylmorpholine, Ν-methylpyrrolidine, Ν-methylbiperidine, Ν, Ν-dimethylaniline, 1,8_diazabicycle Mouth [5. 4. 0] Third-class aliphatic amines such as 7-hen (DBU), 1, 5-azabicyclo [4. 3. 0] non-5-hen (DBN); Aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline or isoquinoline, etc. are mentioned. Among them, for example, tertiary aliphatic amines are preferred, and particularly, for example, triethylamine or N, N— Disopropylethylamine is preferred. is there.

 Condensation aids used include, for example, N-hydroxybenzotriazole hydrate, N-hydroxysuccinimide, N-hydroxy-5-norbornene-2,3-dicarboxyimide, or 3-hydroxyl-3 , 4-dihydro 4-oxo-1,2,3-benzotriazole and the like, among which N-hydroxybenzotriazole and the like are preferable.

 The amount of compound (6-1) or reactive derivative used varies depending on the type of compound and solvent used and other reaction conditions, but usually 1 to 50 equivalents, preferably 1 to 50 equivalents per 1 equivalent of compound (5) Is 2 to 10 equivalents.

 The amount of the amide-forming reagent used varies depending on the type of compound and solvent used and other reaction conditions, but usually 1 to 50 equivalents, preferably 2 to 10 equivalents, per 1 equivalent of the normal compound (5) It is.

 The amount of the condensation aid used varies depending on the compound used, the type of solvent and other reaction conditions, but is usually 1 to 50 equivalents, preferably 2 to 10 equivalents, relative to 1 equivalent of compound (5).

 The amount of base used varies depending on the compound used, the type of solvent, and other reaction conditions, but is usually 1 to 50 equivalents, preferably 2 to 5 equivalents, relative to 1 equivalent of normal compound (5). .

 The reaction solvent used in this step is not particularly limited. Specifically, for example, chlorohonolem, salt methylene chloride, THF, jetyl ether, DMF,

NMP, dioxane, DMSO, toluene, benzene, xylene and the like can be mentioned. Among these, for example, black mouth form, methylene chloride, THF, jetyl ether, DMF, NMP, toluene, benzene or xylene are preferable.

 The reaction temperature in this step is usually from 78 ° C to 150 ° C, preferably 0 ° C to 50 ° C.

The reaction time in this step is usually 30 minutes to 7 days, preferably 30 minutes to 1 2 hours.

 The base, amide-forming reagent and condensation aid used in this step can be used alone or in combination.

 The compound (1-2) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, and the like.

 (Process 4-2)

 This step is a method for producing the compound (I-3) according to the present invention by reacting the compound (5) obtained in the above step 3 with the compound (6-2) in the presence of a base. Examples of the base used in this step include trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylbiperidine, N, N-dimethylaniline, 1, 8—Jazabicyclo [5. 4. 0] Wunde force 7—Yen (DBU), 1, 5—Zazabicyclo [4. 3. 0] Nonah 1—5-Nen (DBN), etc. A class of aliphatic amines; for example, aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline or isoquinoline, etc., among which, for example, tertiary aliphatic amines are preferred. Triethylamine, N, N-diisopropylethylamine, pyridine and the like are preferable.

 The amount of the base used is usually 1 to the amount of solvent with respect to 1 equivalent of compound (5).

 Examples of the compound (6-2) used in this step include t tert -butyl isocyanate, isopropyl cyanate, or isobutyl cyanate.

 The amount of the compound (6-2) used is usually 1 to 50 equivalents, preferably 2 to 10 equivalents, relative to 1 equivalent of the compound (5).

The reaction solvent used in this step is not particularly limited as long as the reaction is not hindered. Specifically, for example, black form, methylene chloride, THF, dimethyl ether, DMF, NMP, dioxane, DMSO, toluene, benzene, xylene, etc., among these, black form, chloride Preference is given to methylene, THF, jetyl ether, DMF, NMP, toluene, benzene or xylene.

 The reaction temperature in this step is 178 ° C to 150 ° C, preferably 0 ° C to 50 ° C.

 The reaction time in this step is usually 30 minutes to 7 days, preferably 30 minutes to 12 hours.

 The thus obtained compound (1-3) according to the present invention can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. Can do.

 (Process 4-3)

 This step is a method for producing the compound (I-3) according to the present invention by reacting the compound (5) with the compound (6-3).

 Examples of the compound (6-3) used in this step include dimethylcarbamoyl chloride, jetylcarbamoyl chloride, diisopropyl-powered rubamoyl chloride, isopropylmethylcarbamoyl chloride, 1-pyrrolidine-powered ruba moinole chloride, and 1-pipid. Examples include peridinecarbamoyl chloride, 4-morpholine-carbamoyl chloride, and the like.

 The amount of (6-3) used is usually 1 to 50 equivalents, preferably 2 to 10 equivalents, relative to 1 equivalent of compound (5).

 Further, the reaction in this step may be performed using a base.

Examples of the base used include trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylolpyrrolidine, N-methylbiperidine, N, N-dimethylaniline, 1,8- Jazabisik Mouth [5. 4. 0] Third-class aliphatic amines such as Wunde 7-Yen (DBU), 1, 5-Azabicyclo [4. 3. 0] Nona 5-Yen (DBN), etc .; Examples thereof include aromatic amines such as pyridine, 4_dimethylaminopyridine, picoline, lutidine, quinoline or isoquinoline, among which tertiary aliphatic amines and the like are preferable, and particularly, for example, triethylamine or N, N-diisopropylethylamine. Min, pyridine and the like are preferable. '

 The reaction solvent used in this step is not particularly limited as long as it does not interfere with the reaction. Specifically, for example, black mouth form, methylene chloride, THF, ethynole ether, DMF, NMP, dioxane, DMSO, Toluene, pyridine, benzene, xylene and the like can be mentioned, and among these, pyridine, chloroform, methylene chloride, THF, jetyl ether, DMF, NMP, toluene, benzene or xylene are preferable. The reaction temperature in this step is usually −78 ° C. to 150 ° C., preferably 0 ° C. to 50 ° C.

 The reaction time in this step is usually 30 minutes to 7 days, preferably 30 minutes to 12 hours.

 The thus obtained compound (1_4) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

 The compound (I-11) according to the present invention can also be produced by the following method.

 [Wherein R represents a lower alkyl group, and other symbols are the same as above]

(Process 2-1) This step is a method for producing the compound (1-1) according to the present invention by reacting the compound (3) obtained in the above step 1 with (4a) in the presence of a catalyst.

 The reaction in this step is a so-called S t i 1 1 e coupling reaction. R in the compound (4a) represents a lower alkyl group, and for example, a methyl group, an ethyl group, a propyl group, a butyl group and the like are preferable.

 Specific examples of the compound (4a) to be used include, for example, 4-tributylstannyl pyridine, 2-tributylstanninopyridine, 2_tributylstanninothiophene, 2-tributinorestandifuran, 2_tributylstane Ninolepyrazine, 2-tributylstannylpyrimidine, trimethylphenyltin, trimethyl (2-pyridyl) tin, and the like.

 The amount of the compound (4a) used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the compound (3).

Examples of the catalyst used include P d (PP h ₂ ) ₄ and P d ₂ (dba) ₂ .

 The amount of the catalyst used is usually 1 to 200% mol, preferably 5 to 20% mol, relative to 1 equivalent of compound (3).

 The reaction solvent is not particularly limited as long as it does not interfere with the reaction. Examples thereof include toluene, DMF, NMP, THF, DMSO and the like. Among these, toluene, DMF, NMP and the like are preferable.

 The reaction temperature is usually 0 to 150 ° C, preferably 50 to 120 ° C. The reaction time is usually 30 minutes to 7 days, preferably 6 to 12 hours. The compound (1_1) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be attached to the next process without doing.

 In addition, the compounds (I 15), (1-6),

(I_7) or (I-8) can be produced, for example, by the following method.

Process

 (1-5) (5-1)

(1-6)

(1-8)

[Wherein R ^{2 G} represents a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a cyano group, a nitro group, a lower alkoxy group, a lower alkylsulfonyl group and a hydroxy group in the ring. 3 may have a fuunyl group or nitrogen atom, sulfur A 5- to 6-membered unsaturated heterocycle having 1 to 3 heteroatoms selected from the group consisting of atoms and oxygen atoms, the other symbols are the same as above]

 (Process 5)

 This step is a method for producing a compound (3-1) by reacting a 4-Boc-piperazinone (1) with a compound (2-1) in the presence of a base and a catalyst.

 Examples of the base used in this step include potassium phosphate, sodium carbonate or carbonated lithium.

 The amount of the base used in this step is usually 1 to 100 equivalents, preferably 2 to 10 equivalents, relative to 1 equivalent of compound (1).

 Examples of the compound (2-1) used include 2, 6_dibromopyridine,

3, 5_dibromopyridine, 3_bromo-5_iodopyridine, 2_bromo_4—iodopyridine and the like.

 The amount of the compound (2-1) used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the compound (1).

 Examples of the catalyst used include copper iodide, copper chloride (1), and copper acetate (I I). Of these, copper iodide is preferred.

 The amount of the catalyst used is 1% mol to 200% mol, preferably 5% mol to 20% mol, per 1 equivalent of the compound (1).

 The reaction solvent used in this step is not particularly limited as long as it does not interfere with the reaction. Specifically, for example, DMF, NMP, dioxane, THF,

Examples thereof include DMS O or water, and among these, DMF, NMP or dioxane is preferred.

 The reaction temperature in this step is usually 0 ° C to 150 ° C, preferably 50 ° C to 120 ° C.

 The reaction time in this step is usually 30 minutes to 7 days, preferably 6 hours to

12 hours. The compound (3_1) thus obtained is isolated and purified or isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be attached to the next process without any problems.

 (Process 6)

 In this step, the compound (3-1) obtained in the step 5 and the compound (4-1) are reacted in the presence of a catalyst and a base to produce the compound (1-5) according to the present invention. It is a method.

 The reaction in this step is a so-called Suzuki coupling reaction. The amount of the compound (3-1) used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the compound (4-1).

 Specific examples of the compound (4_1) to be used include, for example, ferroboric acid, methoxyphenyl borenolic acid, methino feneno borenoic acid, bromo phen eno boroboric acid, black feneno boroboric acid, nitro phen eno boroboric acid, acetyl thiophene. Noreboric acid, Thiophene-2-boric acid, Thiophene_3_Boric acid, Pyridine-1-2-boric acid, Pyridine-1-3-boric acid, Pyridine-1-4-boric acid, Furan-1-2-boric acid, Furan-1-3-boron Acid, pyrimidine-1-2 boric acid, pyrimidine 1-4-boric acid, pyrimidine 15-boric acid and the like.

The catalyst to be used, for _{example, P d (PP h 3)} 4, P d 2 (dba) 3, P d C 1 2 (dppf) 2 and the like.

 The amount of the catalyst to be used is generally 1 to 200% mol, preferably 5 to 20% mol, relative to 1 equivalent of compound (4-1).

 Examples of the base used include sodium carbonate and potassium carbonate.

 The amount of the base used is usually 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of the compound (4-1).

Any reaction solvent can be used as long as it does not interfere with the reaction. For example, toluene, DMF, NMP, dioxane, THF, DMSO, water and the like can be mentioned. Of these, toluene, DMF and NMP are preferable. The reaction temperature is generally 0 ° C to 150 ° C, preferably 50 ° C to 120 ° C. The reaction time is usually 30 minutes to 7 days, preferably 6 to 12 hours. The compound (1-5) according to the present invention thus obtained is isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, reprecipitation, chromatography, etc. Or it can attach to the next process, without isolating and purifying.

 (Process 7)

 This step is a method for producing the compound (5-1) by removing the Boc group of the compound (I 1-5) obtained in the step 6.

 The reaction in this process is the method described in the literature (for example, Protective Group Organic Synthesis, TW G reen, 2nd fe, John Wiley & Sons, 1991, etc. ), A method according to it, or a combination thereof with a conventional method, specifically, for example, hydrochloric acid monomethanol or TFA, etc., and the same method as in step 2, It is possible to carry out the same methods or a combination of these with conventional methods.

 (Process 8-1)

 In this step, the compound (5-1) obtained in the step 7 is reacted with the carboxylic acid derivative (6-1) or a reactive derivative thereof to produce the compound (I-6) according to the present invention. It is a method to do. '

 The reaction in this step can be carried out by the same method as in Step 4-11, a method analogous thereto, or a combination of these with conventional methods.

The ichigo compound (1-6) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. it can. This step is a method for producing the compound (I-7) according to the present invention by reacting the compound (I-15) obtained in the step 5 with the compound (6-2).

 The reaction in this step can be carried out by the same method as in Step 4-12, a method analogous thereto, or a combination of these with conventional methods.

 The thus obtained compound (I-16) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

 (Process 8-3)

 This step is a method for producing the compound (I-7) according to the present invention by reacting the compound (5) obtained in the above step 5 with the compound (6-3).

 The reaction in this step can be carried out by the same method as in Step 4-13, a method analogous thereto, or a combination of these with conventional methods.

 The thus obtained compound (I-18) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

 In addition, the compound (I_5) can also be produced by the following method.

[Wherein R ^G represents a lower alkyl group, and other symbols are the same as above]

 (Process 6-1)

This step is a method for producing the compound (I-15) according to the present invention by reacting the compound (3-1) with the compound (4-1b) in the presence of a catalyst. The reaction in this step is a so-called S tille coupling reaction. Specific examples of the compound (4b) used include, for example, 4 monotributyls Tandirubiridine, 2_tributylstannylrubiridine, 2-tributylstanninorethiophene, 2-tribiti ^ / stanninolefuran, 2_tribhistanninorepyrazine, 2-tributylstannylpyrimidine, trimethylphenyltin, trimethyl ( 2-pyridyl) tin and the like.

^RG in the compound (4b) represents a lower alkyl group, and for example, a methyl group, an ethyl group, a propyl group, a butyl group and the like are preferable.

 The amount of the compound (4b) used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the compound (3-1).

Examples of the catalyst used include P d (PPh ₂ ) ₄ and P d ₂ (dba) ₂ .

 The amount of the catalyst to be used is generally 1 to 200% mol, preferably 5 to 20% mol, relative to 1 equivalent of compound (3-1).

 The reaction solvent is not particularly limited as long as it does not interfere with the reaction. Examples thereof include toluene, DMF, NMP, THF, DMSO and the like. Among these, toluene, DMF, NMP and the like are preferable.

The reaction temperature is usually 0 ° C to 150 ° C, preferably 50 ° C to 120 ° C. The reaction time is usually 30 minutes to 7 days, preferably 6 to 12 hours. The compound (1_5) thus obtained should be isolated and purified or isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography, etc. It can be attached to the next process. In addition, the compounds (I-9), (1-9-1), (1-9-2), (1-9-3), (1-10) included in the compound (I) according to the present invention , (1-1 0-1), (1-10-2) or (I-1 0-3) can be produced, for example, by the following method.

I,

R ^! Or R ¹

 Process 11 -3 t-Bu

 (1-9-3) (1-10-3)

 [Wherein t _Bu represents a t e r t _butyl group, and other declarations are the same as above] (Step 9) '

 In this step, 4-B oc-piperazinone (1) and compound (2-2) or (2-3) are reacted to give compound (I 1 9) or (I 1 10) according to the present invention. It is a manufacturing method.

 The reaction in this step can be carried out by the same method as in Step 1, a method analogous thereto, or a combination of these and conventional methods.

The compound (1-9) or (1-10) thus obtained can be obtained by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography. It can be isolated and purified by the same method or can be subjected to the next step without isolation and purification.

 (Process 10)

 This step is a method for producing the compound (5-2) or (5-3) by removing the B oc group of the compound (1_9) or (1-10) obtained in the step 9 above. . The reaction in this step is performed according to the method described in the literature (for example, Protective Group Organic Organic Synthesis, T. W, Green 2nd edition, John Wiley & Sons, 199 1 , Etc.), a method according to it, or a combination thereof with a conventional method, specifically, for example, hydrochloric acid monomethanol or TFA, etc., and the same method as in step 2, this Or a combination of these and conventional methods.

 The compound (5-2) or (5-3) thus obtained can be isolated and purified by known separation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, chromatography, etc. Or it can attach to the next process, without isolating and purifying.

 (Process 1 1— 1)

 This step comprises reacting the compound (5-2) or (5-3) obtained in the step 10 with a carboxylic acid compound (6-1) or a reactive derivative thereof, to thereby obtain the compound according to the present invention. This is a method for producing (I — 9-1) or (I — 1 0 — 1).

 The reaction in this step can be carried out by the same method as in Step 4-11, a method analogous thereto, or a combination of these with conventional methods.

 Thus obtained compounds according to the present invention (I 1 9 1 1) or (1-10_

1) can be isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like.

 (Process 1 1 1 2)

This step consists of compound (5-2) or (5-3) and compound obtained in step 10 above. (6-2) is a method for producing a compound (1-9-2) or (1-10-2) according to the present invention.

 The reaction in this step can be carried out by the same method as in step 4-2, a method analogous thereto, or a combination of these with conventional methods.

 The thus obtained compound (26) can be isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. it can.

 (Process 1 1 1 3)

 In this step, the compound (5_2) or (5-3) obtained in the step 10 is reacted with the compound (6-3) to give the compound (1-9-3) or (1— Ten

-3).

 The reaction in this step can be carried out by the same method as in Step 4-13, a method analogous thereto, or a combination of these with conventional methods.

 The compound (1-9-3) or (1-10-3) thus obtained can be obtained by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be isolated and purified.

 The compound according to the present invention can be converted into a pharmaceutically acceptable salt or ester by a conventional method, and the salt or ester is obtained by using the compound included in the compound (I) or (I) according to the invention. It can be produced according to a conventional method.

 Specifically, when the compound (I) has a basic group derived from, for example, an amino group or a pyridinyl group in the molecule, the compound is treated with an acid. Can be converted into the corresponding pharmaceutically acceptable salts.

Examples of the acid addition salt include hydrohalides such as hydrochloride, hydrofluoride, hydrobromide, and hydroiodide; nitrate, perchlorate, sulfate, phosphate, carbon Inorganic acid salts such as acid salts; lower alkyl sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; benzene sulfonate, p- Aryl sulfonates such as toluene sulfonate; organic acid salts such as fumarate, succinate, citrate, tartrate, oxalate, maleate; and glutamate, aspartate Examples thereof include acid addition salts which are organic acids such as amino acids such as salts.

 In addition, when the compound of the present invention has an acidic group in the group, for example, a carboxyl group or the like, the corresponding pharmacology can also be obtained by treating the compound with a base. Can be converted into a salt which is acceptable to the environment. Examples of the base addition salt include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, salts with organic bases such as guanidine, triethylamine, and dicyclohexylamine. Is mentioned.

 Furthermore, the compound of the present invention may exist as any hydrate or solvate of a free compound or a salt thereof. '

 Conversely, conversion from a salt or ester to a free compound can be carried out according to a conventional method.

 Further, the compound according to the present invention may have a stereoisomer or a tautomer such as an optical isomer, a diastereoisomer, or a geometric isomer depending on the mode of the substituent. Needless to say, all of these isomers are included in the compounds of the present invention. Furthermore, it goes without saying that any mixture of these isomers is also encompassed by the compounds according to the present invention.

The compound according to the present invention, the aromatic hydrogen in the compound tritium, a methylation group ³ H ₃ C, ^{1 4} CH _3, in Ita_〇_Ita _3, fluorine in ^{1 8} F, the carbonyl group It can also be used as Rajioraberu body by conversion to isotopes of ^{1 1} C etc. carbon.

When the compound of the present invention is used clinically, it may be formulated by adding a pharmaceutically acceptable additive according to the administration form. As additives at that time, various additives usually used in the pharmaceutical field can be used. For example, gelatin, Lactose, Sucrose, Titanium oxide, Starch, Crystalline cellulose, Hydroxypropylmethylenocellulose, Carboxymethyl cenololose, Corn starch, Microcrystalline wax, White petrolatum, Magnesium aluminate metasilicate, Hydrous calcium phosphate, Quenic acid, Quenic acid Trisodium, hydroxypropylsenololose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, hydrogenated castor oil, polybylpyrrolidone, magnesium stearate, light anhydrous keic acid, talc, vegetable oil Benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, hydroxypropylcyclodextrin, etc. Is mentioned. The mixture of the compound of the present invention and the above-mentioned additives should be used as a solid preparation (tablets, capsules, condyles, powders, suppositories, etc.) or a liquid preparation (syrup, elixir, injection, etc.) Can do. These preparations can be prepared according to usual methods in the pharmaceutical field. The liquid preparation may be dissolved or suspended in water or other appropriate medium at the time of use. In particular, in the case of injections, they may be dissolved or suspended in physiological saline or budu sugar solution as necessary, and buffering agents or preservatives may be added. These preparations can contain the compound of the present invention in a proportion of 1.0 to 100% by weight, preferably 1.0 to 60% by weight.

 For example, the compound of the present invention can be formulated according to the following formulation examples. (Formulation Example 1)

 10 parts of the compound of Example 1, which will be described later, 15 parts of heavy magnesium oxide and 75 parts of lactose are uniformly mixed to obtain a powdery or finely divided powder of 3500 / xm or less. This powder is put into a capsule enamel to make a capsule.

 (Formulation example 2)

After uniformly mixing 5 parts of the compound of Example 1 described below, 5 parts of starch, 6 parts of lactose, 1 part of crystalline cellulose, 2 parts of crystalline cellulose, 3 parts of polybulal alcohol and 30 parts of distilled water, the mixture is crushed and granulated. Granulate with a diameter of 1 4 1 0 to 1 7 7 / zm And

 (Formulation example 3)

 After preparing granules by the same method as in Formulation Example 2, add 96 parts of calcium stearate to 96 parts of this granule and compress it to prepare tablets with a diameter of 1 Omm.

 (Formulation example 4)

 To 90 parts of the granule obtained by the method of Formulation Example 2, 10 parts of crystalline cellulose and 3 parts of calcium stearate were added and compression-molded to form tablets with a diameter of 8 mm. Add the precipitating calcium carbonate mixed suspension to make a sugar-coated tablet.

 When the compound of the present invention is used in a clinical setting, the dose and frequency of administration vary depending on the sex, age, weight, symptom of the patient, and the type and range of the desired treatment effect. In general, in the case of oral administration, 0.01 to 100 mg / kg, preferably 0.0 S lmgZkg per adult is administered in divided doses from Γ to several times. In the case of parenteral administration, 0.001 to: 1 OmgZkg, preferably 0.001 to 0 · lmgZkg, is administered in 1 to several divided doses.

 Ordinary physicians, veterinarians or clinicians can easily determine the amount of effective drug needed to prevent, inhibit or stop disease progression.

 (Example)

 The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to these examples.

In the examples, Wakogel (registered trademark) C-300 manufactured by Wako Pure Chemical Industries, Ltd. or KP-Si1 (registered trademark) Silica prepacked column manufactured by Biotage Corporation was used for the Siri-force gel force ram chromatography. For the preparative thin layer chromatography, Kiese 1 ge 1 ™ 60 F ₂₅₄ , Art. 5744 manufactured by Merck was used. Basic silica gel column chromatography is Chromatorex (registered trademark) NH (1 00—250me sh or 200—350me s manufactured by Fuji Silicon Chemical Co., Ltd. h) was used.

 Mass spectra were measured by electrospray ionization (ESI) or atmospheric pressure chemical ionization (APC I) using microsass ZQ manufactured by Watters.

 The NMR spectrum uses dimethyl sulfoxide as an internal standard when measuring with deuterated dimethyl sulfoxide solution, and Gemini-200 (20 OMH z;

V a r i a n), Gem i n i—300 (30 OMH z; V r i a n), Mer c u r y 400 (400 MHz; V a r i a n) or I n o v a 400 (400

MHz; V ari 'a n) spectrometer was used, and all δ values were expressed as p p m.

 The meaning of the abbreviation in the below-mentioned Example is shown below.

 i -B u: Isobutyl group

n -B u: n-butyl group

 t-Bu: t-butyl group

M e: methyl group

 E t: Ethyl group

 P h: Phenyl group

 i -P r: Isopropyl group

n -P r: n-propyl group

CDC 13: Deuterated chloroform

CD ₃ OD: Deuterated methanol

 DMS 0-d 6: heavy dimethyl sulfoxide

 The meanings of the abbreviations in the nuclear magnetic resonance spectrum are shown below.

 s: Sync'let

d: Doublet

dd: Dub Nore doublet t: triplet

m: Manople plate

b r: Broad

q ： Power noteette

 J: Coupling constant

 H z: Hertz

Example 1

 4— (2 — Funoleo mouth bibienyl 1 3-yl) 1 3-oxopiperazine _ 1— carboxylic acid t rt t butyl ester

1) 4- (3-Bromophenyl) 1 3-oxopiperazine 1 1-Carboxylic acid t tert -Butyl ester

Under nitrogen atmosphere, 3-year-old xisopiperazine _ 1 _ carboxylic acid tert-butyl ester 4 g of dioxane 2 Om 1 solution 3-bromo-benzene benzene 1 1 g, phosphoric acid tritium 1 3 g, Copper (I) 200 mg, trans-1,2-diaminocyclohexane 0.5 ml 1 were sequentially added, and the mixture was stirred at 90 ° overnight. After adding water, the product was extracted with ethyl acetate, and the organic layer was washed with water and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to obtain 3.7 g of the title compound as a white solid.

4-(2 Fluorobibienol 3-yl) 1-Oxopiperazine Production of rubonic acid ter _t-butyl ester

Under a nitrogen atmosphere, 0.5 ml of water was added to a 1.5 ml solution of 38 mg of the ethylene glycol dimethyl ether compound obtained in 1) above, and then 17 mg of 2-fluorophenylboronic acid, 33 mg of sodium carbonate, 1,1′-Bis (diphenylphosphino) phenocene] dichloropalladium (3 mg) was added, and the mixture was stirred at 90 ° overnight. After adding water, the product was extracted with ethyl acetate, and the organic layer was washed with water and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by preparative thin-layer silica gel chromatography (hexane: ethyl acetate = 3: 1) to obtain 33 mg of the title compound as a white solid.

_{^{J HNMR (400MHz, CDC 1 3}} ) δ: 1. 50 (9 H, s), 3. 79 (4 H, s), 4. 26 (2H, s), 7. 10- 7. 50 (8H, m)

E S I—MS Found: m / z 37 1. 3 [M + H] + Example 2

4— (biphenyl 2 _ 3) _ 3—oxopiperazine 1 1 strength rubonic acid tert-butinoreestenole 3-nitrosopiperazine 1 1 strength rubonic acid tert-butylester 20 Add 235 mg of 3-bromobiphenyl, 420 mg of tripotassium phosphate, 10 mg of copper (I) iodium, trans-1,2,2-diaminocyclohexane 0.01 5 m 1 to Omg dioxane lm 1 solution 90 Stir at rt overnight. Add water After that, the product was extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by preparative thin layer silica gel chromatography (hexane: ethyl acetate = 3: 1) to obtain 2 Omg of the title compound as a white solid. .

^ NMR (40 OMH z, CDC l ₃ ) δ: 1.5 1 (9H, s), 3. 79 (4 H, brs), 4. 27 (2H, s), 7. 30-7.60 ( 9 H, m)

E S I -MS Fo und: m / z 353. 3 [M + H] + Example 3

4- (2 Methyl 1-biphenyl 1-yl) 1 3-Oxo 1-piperazine 1-Carboxylic acid tert 1-butyl ester 4 _ (3 _Bromophenyl) _3 obtained in 1) of Example 1 under nitrogen atmosphere —Oxopiperazine mono 1-carboxylic acid tert-petite / resestenole 380 mg of ethylene glycol dimethyl ether 15 5 ml of water is added with 5 ml of water, then 2-methylphenylboronic acid 140 mg, sodium carbonate 33 Omg, [1, 1 ' —Bis (diphenylphosphino) phenocene] Dichloropalladium 3 Omg was added and stirred at 90 ° overnight. After adding water, the product was extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by preparative thin layer silica gel chromatography (hexane: ethyl acetate = 3: 1) to obtain 96 mg of the title compound as a white solid. ^J HNMR (40 OMH z _N CDC ") 5: 1. 50 (9 H, s), 2. 22 (3 H, s), 3. 80 (4H, brs), 4. 24 (2 H, s) , 7.1 5—7.55 (8H, m)

ES I—MS Found: m / z 367. 3 [M + H] + Example 4

 4- (2'-chlorobiphenyl-1 3 Tl) 1 3-oxo-1piperazine 1-strength norebonic acid tert-butinoresestenole 4 _ (obtained in Example 1 1) under nitrogen atmosphere 3-Bromophenyl) 1 3-oxopiperazine 1 1-carboxylic acid tert-butylesterol 38 Omg of ethylene glycol dimethyl ether 15 Add 5 ml of water to 5 ml solution, then 2-chlorophenylboronic acid 1 60 mg, sodium carbonate 33 Omg, [1,1'-bis (diphenylphosphino) fecene] dichloropalladium 3 Omg was added and stirred at 90 degrees overnight. After adding water, the product was extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (hexane: ethyl acetate = 3: 1) to obtain 72 mg of the title compound as a white solid.

^X HNMR (400 MHz, CDC 1 ₃ ) δ: 1. 50 (9 H, s), 3. 78 (4 H, brs), 4. 26 (2H, s), 7. 23— 7. 50 (8H, m) ESI-MS Found: m / z 3 8 7. 3 [M + H] + Example 5

3-Oxo 1- (3-Pyridine 1- 2-yl 1-phenyl) 1-Piperazine 1-Power Norebonic acid tert-Butyl ester 4- (3-Bromophenyl) obtained in 1 of Example 1 under nitrogen atmosphere ) _ 3-oxopiperazine 1-strong norevonic acid tert-butinoreestenole 3 8 mg of ethylene glycol dimethyl ether 1.5 ml of water is added 0.5 ml of water and pyridine-

15 mg of 3-boronic acid, 3 mg of sodium carbonate, and 3 mg of [1,1'-bis (diphenylphosphino) feuccene] dichloropalladium were added, and the mixture was stirred overnight at 90 ° C. After adding water, the product was extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (hexane: ethyl acetate = 3: 1) to obtain 1 Omg of the title compound as a white solid.

'HNMR (40 OMH z, CDC l ₃ ) δ: 3. 8 1 (4 H, s), 4.2 7 (2 H, s), 7. 2 0-7. 2 5 (1 H, m ), 7. 3 2— 7. 3 7 (1 H, m), 7.5 0 (1 H, t), 7. 6 8-7. 8 0 (2 H, m), 7. 8 2— 7. 8 7 (1 H, m), 7. 9 5 (1 H, brs), 8.6 4-8. 6 9 (1 H, m)

ESI -MS Found: m / z 3 5 4. 3 [M + H] + Example 6

 3-Oxo 4-- (3-Tert-butyl monophenyl)-Piperazine 1-Carbonic acid tert-Butinoreestenole 3-N-oxopiperazine 1-carboxylic acid tert-Butyl estenole 200 mg 1_tert-Butyl 3-Ododobenzene 20 Omg, 1 trillion tritium phosphate 420mg, copper iodide (I) 10mg, trans-l, 2-diaminocyclohexane 0.020m 1 was added sequentially, and the mixture was stirred at 90 ° overnight. After adding water, the product was extracted with ethyl acetate, and the organic layer was washed with water and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by preparative thin layer silica gel chromatography (hexane: ethyl acetate = 3: 1) to obtain 62 mg of the title compound as a white solid.

^ NMR (400MHz, CDC 1 ₃ ) δ: 1. 32 (9 Η, s), 1. 50 (9 Η, s), 3. 70-3. 8 1 (4 Η, m), 4. 24 ( 2 Η, s), 7.03-7.35 (4 Η, m)

Ε SI-MS Found: / z 333.3 [M + H] + Example 7

4-Naphthalene-2-yl 3-Oxopiperazine 1-Carboxylic acid tert-Butinore Estenole 3-Nixopiperazine 1 in 1 nitrogen tert-Butylester 20 Omg To the dioxane lm 1 solution, add 2-bromonaphthalene (210 mg), tritium phosphate (420 mg), copper (I) oxalate (10 mg), trans-1, 2-diaminocyclohexane (0.02 Om 1) in this order at 90 degrees. Stir overnight. After adding water, the product was extracted with ethyl acetate, and the organic layer was washed with water and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by preparative thin layer silica gel chromatography (hexane: ethyl acetate = 3: 1) to obtain 72 mg of the title compound as a white solid.

^ NMR (40 OMH z, CDC l ₃ ) δ: 1.51 (9H, s), 3.82 (4 H, s), 4.29 (2H, s), 7. 36— 7.89 ( (7 H, m)

E S I -MS F o u n d: m / z 327.3 [M + H] +

Example 8

 3-Oxo 1-(3-Pyridine 1 3-yl 1-phenyl) 1 Piperazine 1 1-Force Rubonic acid t e r t-Butyl ester

1) 1) 4 1 (4, 4, 5, 5—Tetramethyl 1 [1, 3, 2] Dioxaborane —Inole) 1 3-Oxopiperazine _ 1—Strengthen of levonolic acid tert-butinoreester Manufacturing

In a nitrogen atmosphere, 4- (3-bromophenyl) 1-3-oxopiperazine 1 1 obtained in 1) of Example 1 1 rubonic acid tert-butylesterol 2.6 g of dimethyl sulfoxide 1 Om 1 in solution Bispinacholate diborane 74 Omg, acetic acid power 800 mg, [1,1'-bis (diphenylphosphino) phenocene] dichloropalladium 65mg was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through celite, the solvent was distilled off, water was added to the residue, and the product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography (hexane: ethyl acetate = 5: 1) to obtain 67 Omg of the title compound as a white solid.

2) 3-Oxo 1-4-1 (3-Pyridine 1 3_yl 1-phenyl) 1 Piperazine 1 1 Production of rubonic acid ter t-butyl ester

In a nitrogen atmosphere, in a solution of 2 Omg of the compound obtained in 1) above in dimethylformamide lm 1 2-bromopyridine 3 lmg, potassium carbonate 42 mg, [1, 1'-bis (dipheninorephosphino) Kuchisen] 3 mg of dichloropalladium was added and stirred at 90 ° C. for 6 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to obtain 5 mg of the title compound as a white solid.

^J HNMR (40 OMH z, CDC l ₃ ) δ: 1.51 (9H, s), 3.80 (4 H, brs), 4.28 (2 H, s), 7. 30—7.55 (5H, m), 7. 83 (1 H, dt, J = 2. 0, 8. 0Hz), 8. 58 (1 H, dd, J = 1. 4, 4. 6Hz), 8.8 1 (1 H, d, J = 2.0 H z)

ESI -MS Found: m / z 354. 3 [M + H] +

 3-Oxo 1- (6-Phenol 1-Pyridine 1- 2-yl) 1 Piperazine 1 1-Power Norebonic acid t e r t-Butylesterol

 4- (6-Bromopyridine 1- 2-yl) 1 3-oxo 1 Piperazine 1 1-Carbonate t rt -Butinore Estenole

 3-Oxopiperazine 1-Carboxylic acid tert-Butinoreestenole 1 80 mg 2,6 _Dibromopyridine 238 mg, Cesium carbonate 4 10 mg, Catalytic amount of tris (dibenzylideneacetone) Di-palladium (0), A catalytic amount of 4,5-bis (diphenylphosphino) _9,9-dithiolxanthene in 1,4-dioxane 5 ml suspension was stirred at 100 ° C for 5 hours. The reaction solution was diluted with ethyl acetate, washed with water and then saturated Japanese brine, and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by preparative thin layer silica gel chromatography (hexane: ethyl acetate = 7: 3) to give 95.3 mg of the title compound as a colorless oil. .

_{'HNMR (300MHz, CDC 1 3} ) δ:. 1. 49 (9 H, s), 3. 73- 3. 76 (2H, m), 4. 1 1 -4 1 5 (2 H, m), 4. 28 (2H, s), 7. 28-7.30 (1 H, m), 7.54—7.59 (1 H, m), 8. 05 (1 H, d, J = 8. 2 H z)

ES I -MS F o n d: m / z 358. 0 [+ H] +

3-Oxo 1- (6-Phenyl 1-Pyridine 1- 2-yl) 1 Piperazine 1-Strength Rubonic acid tert-butyl ester W

4- (6-Bromopyridine 1- 2-yl) 1 3-oxo 1-piperazine 1 1 Monocarboxylic acid tert-Butyl ester 9 2. 7 mg, Phenonoboronic acid 7 0.4 mg, Carbonate 2 1 4 mg, a catalytic amount of tetrakis (triphenylphosphine) paradium 1,4-dioxane 3 ml 1 suspension was heated to reflux for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and then saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by preparative thin layer silica gel chromatography (hexane: ethyl acetate = 7: 3) to give 82.3 mg of the title compound as a colorless oil. Obtained.

'HNMR (300 MHz, CDC 1 ₃ ) δ: 1.5 1 (9 H, s), 3. 7 8— 3. 8 1 (2 H, m), 4. 2 6-4. 2 8 (2 H, m), 4.3 0 (2 H, s), 7. 4 0-7.5 50 (3 H, m), 7.5 5 6-7.5 9 (1 H, m), 7. 7 5— 7. 8 1 (1 H, m), 7. 9 5— 8. 0 1 (3 H, m)

 E S I -MS Fo und: m / z 3 5 4. 2 [M + H] +

 3-Oxo 1 _ (5-Phenyl 1-Pyridine 1- 3-yl) 1 Piperazine 1 1—Power Rubonic acid t er t-Butinore Estenole

 Using 2,5-dibromopyridine instead of 2,6-dibromopyridine, 144 mg of the title compound was obtained as a colorless oil in the same manner as in Example 9.

! HNMR (3 0 MHz, CDC 1 ₃ ) δ: 1.5 1 (9 H, s), 3. 8 4 (4 Η, s), 4. 3 1 (2 Η, s), 7.4 0— 7. 6 0 (5 Η, m), 7. 8 8 (1 H, s), 8.5 6 (1 H, s), 8. 7 5 (1 H, s) ESI-MS Found: m / z 3 54.2 [M + H] + Examples of pharmacological tests conducted using the compounds according to the present invention as test compounds are shown below. (Pharmacological test example 1: mG 1 u R 1 inhibitory action)

 Using the compound of Example 1 according to the present invention, mG 1 u R 1 inhibitory action was measured.

 (Cell culture)

Using LI POFECTAM I NE (manufactured by Gibco BRL), transfer the cDNA of glutamate receptor 1a (mG lu R la) to CHO cells and mG 1 uR 1 aStable expression strain was obtained. CHO cells expressing mG 1 uR 1 a are 10% dialyzed fetal bovine clot, 1% proline, 100 units / m 1 penici 1 1 in _s 0.1 mg / m 1 strept omy cinsulfate, 2 mM The cells were cultured in a DMEM medium containing glutamine.

 (Measurement of intracellular calcium concentration)

 On the day before the measurement, 9 6-well black plate (Packard, View P 1 ate) mG 1 u R 1 a-expressing CHO cells plated with 5 000 0 cells, 4 / MF 1 uo— 3 Was incubated for 1 hour in a CO 2 incubator. Next, after washing the cells 4 times with an HB SS solution containing 20 mM HE PE S and 2.5 mM Probenecid, the cells were submerged using a fluorescence imaging late reader (FLIPR, manufactured by Molecular Devices). The calcium concentration was measured. The test compound and dartamic acid were prepared using an HBSS solution containing 20 mM HEPES, 2.5 mM P robenecide. The test compound was added 5 minutes before the agonist stimulation, and 10 μΜ glutamic acid was used as the agonist.

As a result, with respect to mG 1 u R 1, the compound according to the present invention described in Example 1 below did not show agonism until 10; uM. 10 μΜ glutamic acid The increase in calcium was suppressed in a dose-dependent manner. Its IC 50 value was 38 ηΜ.

Industrial applicability ''

 According to the present invention, a novel substance having an mG 1 uR l inhibitory action is provided.

 The dialyl-substituted hetero 5-membered ring derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof provided by the present invention has a potent mG lUR l inhibitory action, convulsions, acute pain, It is useful for the prevention or treatment of inflammatory pain, chronic pain, cerebral infarction or transient ischemic attack, mental dysfunction such as schizophrenia, anxiety, drug dependence, Parkinson's disease or gastrointestinal disorders.

Claims

Claim: (I) [where R1 is

 (1) represents a linear or branched lower alkoxy group, a cycloalkoxy group or a linear or branched lower alkyl group, or

 (2) Formula (I I)

In the formula, R ⁴ and R ⁵ are each independently a hydrogen atom, a linear or branched lower alkyl group or a cycloalkyl group, or a nitrogen atom in the formula (II), 1 ^ ⁴ and! ¾ ⁵ Together, it forms a 4- to 7-membered nitrogen-containing aliphatic heterocyclic group (which may have one oxygen atom as a constituent atom of the ring),

R ² may have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group, a cyano group, a nitro group, an alkoxy group, a lower alkylsulfonyl group and a hydroxyl group in the ring. 5- to 6-membered unsaturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms in the ring selected from the group consisting of a phenol group or a nitrogen atom, a sulfur atom and an oxygen atom Or a branched alkyl group having 3 to 10 carbon atoms,

R ³ represents a hydrogen atom, a halogen atom or a lower alkyl group,

Xi represents a phenyl group or a 6-membered heteroaryl group having 1 or 2 nitrogen atoms in the ring ring, or a naphthyl group formed by combining R ² with A group selected from the group consisting of a norinyl group, an isoquinolinyl group, a quinazolinyl group, a quinoxalinyl group, and a cinnolinyl group], or a pharmaceutically acceptable salt thereof.

2. R ² is substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group, a cyano group, a nitro group, a lower alkoxy group, a lower alkylsulfonyl group and a hydroxy group. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a 6-membered heteroaryl group having 1 or 2 phenyl groups or nitrogen atoms in the ring.

3. The compound according to claim 1, wherein R ² is a branched lower alkyl group having 3 to 10 carbon atoms, or a pharmaceutically acceptable salt thereof.

4. One X — R ^{2 in} formula (I) is

 (V)

[Wherein A to A ₅ each independently represent a methine group, or any one or two of A b to A ₅ are nitrogen atoms, and the remaining 3 or 4 are Indicates methine group. To A ₄ . Is To A ₄ . Any one or two of them is a nitrogen atom, the remaining 2 or 3 represents a methine group, and R ⁶ and R ⁶ R ⁶¹ are independently a hydrogen atom, a halogen atom, 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is a group represented by the following: an alkyl group, a cyano group, a nitro group, a lower alkoxy group, a lower alkylsulfonyl group or a hydroxy group.

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R ¹ is a linear or branched lower alkyl group or a cycloalkoxy group.

6. R ¹ is the formula (II) _{/ N} —

R ⁵

 (Π)

The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, which is a group represented by the formula:

 7. The formula (I) is 4— (2′-fluorobiphenyl-1-3-f f) -1-oxopiperazine-1- 1-carboxylic acid tert-butynole ester,

 4-(Bihuenil 3-yl) 1 3-oxopiperazine 1 1 rubonic acid t e r t-butinore Estenole,

 4— (2′-methyl-1-biphenyl-1-3-yl) 1-oxo-1-piperazine 1-strength norebonic acid t e r t-butinoresestenole,

 4— (2′—Chromatic mouth biphenyl 1—3-yl) 1—Oxo 1—piperazine 1—Carboxylic acid ter t-butyl ester,

 3-Oxo-4 1 (3-Pyridine 1 2-yl 1-Phenyl) 1 Piperazine 1 1-Power Norebonic acid t er t-Butinore Estenole,

 3-Oxo 4- (3-T er t-Butyl monophenyl) One piperazine 1-Strengthen boronic acid t er t-Butinore Estenole,

 4—Naphthalene 1 —Inole 3 —Oxo 1 Piperazine 1 —Strengthen norebonic acid

 3-Oxo 4- (3-Pyridine _ 3-yl monophenyl) 1 Piperazine 1 1-power Norebonic acid t e r t-Butinore Estenole,

 3-oxo-4-1 (6-phenol pyridine 2-yl) 1 piperazine 1 1 force rubonic acid t er t 1 butyl ester or

 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is 3-oxo-4- (5-phenyl monopyridine 1-3-yl) monopiperazine mono 1-power rubonic acid tert-butyl ester.

5 hours

8. An m G 1 u R 1 inhibitor comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.

 9. Convulsions, acute pain, inflammatory pain, chronic pain, cerebral infarction or transient brain comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient Therapeutic and / or prophylactic agent for ischemic stroke brain damage, mental dysfunction such as schizophrenia, anxiety, drug dependence and / or Parkinson's disease.