KR20050019739A - Remedies for neurodegenerative diseases - Google Patents

Abstract

Formula I:

<Formula I>

(In formula,

A represents a hydrogen atom or an acetyl group,

E is a 2,5-disubstituted or 3,5-disubstituted phenyl group, or a monocyclic or condensed polycyclic heteroaryl group which may have a substituent, provided that the heteroaryl group is directly connected to the -CONH- group in (I). Is a benzene ring condensed polycyclic heteroaryl group, (2) unsubstituted thiazol-2-yl group, and (3) unsubstituted benzothiazol-2-yl group).

Ring Z is an arene which may further have a substituent in addition to the group represented by the formula -OA (wherein A is the same as defined above) and formula -CONH-E (wherein E is the same as defined above); Or heteroarene which may further have a substituent in addition to the group represented by the formula -OA (wherein A is the same as defined above) and the formula -CONH-E (wherein E is the same as defined above). A pharmaceutical for the prophylaxis and / or treatment of neurodegenerative diseases such as Alzheimer's disease, comprising as an active ingredient a compound represented by the compound) and a pharmacologically acceptable salt thereof, a hydrate thereof, and a solvate thereof.

Description

Neurodegenerative diseases

The present invention relates to a medicament for the prevention and / or treatment of neurodegenerative diseases such as Alzheimer's disease or epilepsy.

Alzheimer's disease is a neurodegenerative disease that includes senile dementia. The characteristic pathological changes of the brain of the patient include atrophy of the brain due to neuronal dropouts, neuronal fibrous changes that accumulate fibrous substances in neurons, and cerebral cortex. In the wider part of the world is the accumulation of plaques called senile plaques. At present, since the protein accumulated in the senile plaque is Aβ (β-amyloid), it is said that accumulation by any cause of Aβ is the cause of Alzheimer's disease (amyloid hypothesis). That is, the concentration of A [beta] in the brain is increased to form cohesive deposits, so that senile plaques are formed, and the aggregated A [beta] acts on nerve cells to cause neuronal cell death and neuronal fiber changes. In fact, Aβ has been reported to cause apoptosis in neurons (The Journal of Neuroscience: the official journal of the society for neuroscience). , (US), 2001, Vol. 21, No. 1, RC118). Therefore, the prevention of neuronal cell death and neuronal fiber change by accumulation of Aβ can be expected to be an effective means of treating Alzheimer's disease.

In the brain of patients with Alzheimer's disease, the activity of the promoter regions of COX (cyclooxygenase) and Aβ precursor protein is raised, and the increase is thought to be due to activation of NF-κB (Nuclear Factor-κB). An increase in COX in the brain causes inflammation, and an increase in the activity of the promoter region of the A [beta] proprotein is thought to cause A [beta] expression to proliferate and cause cell death. In addition, since NF-κB is thought to be deeply involved in the plasticity of neurons, it is thought that NF-κB is deeply involved in the development of Alzheimer's disease, and thus, anti-inflammatory agents and drugs having an NF-κB inhibitory effect. Treatment of Alzheimer's disease is also under consideration (Journal of Pain and Symptom Management, USA), 2002, Vol. 23, No. 4 (extra), p.S35-40 ; Neuroreport, (UK), 2001, Vol. 12, No. 7, p.1449-1452; The Journal of Clinical Investigation, (US , 2001, Vol. 107, No. 2, pp.135-142).

However, the action of Aβ on neurons has been reported to activate AP-1 (Activated Protein-1) in addition to NF-κB (The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. Neuroscience: the official journal of the society for neuroscience, '' (US), 2001, Vol. 21, No. 1, RC118). In addition, recent studies suggest that AP-1 activation causes apoptosis, and NF-κB Since activation of is thought to protect cells and inhibit cell death, selective inhibition of NF-κB may promote apoptosis and lead to worsening of symptoms of Alzheimer's disease ("The Journal of Clinical"). The Journal of Clinical Investigation, (US), 2001, Vol. 107, No. 3, p.247-254; Cell and Tissue Research, (Germany), 2000, Vol. 301, No. 1, p.1 73-187; The Journal of Biological Chemistry, (US), 2000, Vol. 275, No. 20, p. 15114-15124. Therefore, in order to accumulate Aβ and to prevent neuronal cell death and neuronal fiber change caused by Aβ, it is considered that it is necessary to simultaneously suppress not only NF-κB but also AP-1 activation. In fact, inhibition of AP-1 activation has been reported to inhibit apoptosis by UV irradiation or oxidative stimulation (The Journal of Biological Chemistry, 2001). Vol. 276, No. 16, p.12697-12701; Molecular and Cellular Biology, (US), 2001, Vol. 21, No. 9, p. 3012-3024) , It is expected that inhibition of activation of AP-1 is also effective in suppressing apoptosis of neurons by Aβ.

Similar to Alzheimer's disease, epilepsy, a disease related to the brain, is thought to cause seizures caused by abnormal cerebral excitation due to a breakdown of the balance of glutamic acid acting on excitability in the brain and γ-aminobutyric acid acting on inhibitory effects. At that time, AP-1 is thought to be active in the hippocampus and cerebral cortex (`` Pharmacy Magazine: Journal of the Pharmacy Society of Japan (Yakugaku Zasshi: Journal of The Pharmaceutical Society) of Japan), 1999, Vol. 119, No. 7, p.510-518). Also, NF-κB was administered to rats or mice when kainic acid, an agonist of glutamic acid receptors, was administered to rats or mice. Since it is reported to be activated in the hippocampus (Neuroscience, (US), 1999, Vol. 94, No. 1, p.83-91), NF-κB and AP-1 inhibitors It is believed to be effective for the prevention and / or treatment of seizures of epilepsy.

On the other hand, the N-phenylsalicylamide derivative is disclosed as a plant growth inhibitor in US Patent No. 4358443, and as a medicine, European Patent No. 0221211, Japanese Patent Laid-Open No. 62-99329 and US Patent 6117859 discloses an anti-inflammatory agent. In addition, International Publication No. 99/65499 pamphlet, International Publication No. 02/49632 pamphlet and International Publication No. 02/076918 pamphlet are disclosed as NF-κB inhibitors, and International Publication No. 99/65499 pamphlet and international publication pamphlet. The 02/49632 pamphlet also suggests the use as an anti-Alzheimer's drug. However, the publication does not show any direct data indicating that N-phenylsalicylamide derivatives are effective for the prevention or treatment of Alzheimer's disease, and also describes a technique for inhibiting the activation of AP-1 (Activated Protein-1). none. In addition, International Publication No. 02/051397 pamphlet discloses N-phenylsalicylamide derivatives as cytokine production inhibitors.

Disclosure of the Invention

An object of the present invention is to provide a medicament for preventing and / or treating Alzheimer's disease or epilepsy. The inventors of the present invention have shown that various N-arylsalicylamide derivatives and hydroxyaryl derivatives thereof, which are flexible bodies thereof, inhibit NF-κB activation under TNF-α stimulation and AP-1 under TNF-α stimulation. As a result of examining the activation inhibitory activity by a reporter assay, it was found that the compound of the present invention had AP-1 activation inhibitory activity in addition to the NF-κB inhibitory activity. Based on this fact, the inventors have confirmed the effectiveness of the compound in Alzheimer's and epilepsy model animals and have completed the present invention.

That is, the present invention

(1) Formula (I):

(In formula,

A represents a hydrogen atom or an acetyl group,

E is a 2,5-disubstituted or 3,5-disubstituted phenyl group, or a monocyclic or condensed polycyclic heteroaryl group which may have a substituent, provided that the heteroaryl group is directly connected to the -CONH- group in (I). Is a benzene ring condensed polycyclic heteroaryl group, (2) unsubstituted thiazol-2-yl group, and (3) unsubstituted benzothiazol-2-yl group).

Ring Z is an arene which may further have a substituent in addition to the group represented by the formula -OA (wherein A is the same as defined above) and formula -CONH-E (wherein E is the same as defined above); Or heteroarene which may further have a substituent in addition to the group represented by the formula -OA (wherein A is the same as defined above) and the formula -CONH-E (wherein E is the same as defined above). It is to provide a medicament for preventing and / or treating Alzheimer's disease, comprising as an active ingredient a compound represented by) and a pharmacologically acceptable salt thereof, a hydrate thereof, and a substance selected from the group consisting of solvates thereof. Also, according to the present invention, the prevention and / or treatment of epilepsy comprising a compound represented by the above formula (I) and a pharmacologically acceptable salt thereof, a hydrate thereof and a solvate thereof as an active ingredient. Medications are also provided.

As a preferable medicine of this invention,

(2) the medicament comprising a compound wherein A is a hydrogen atom and a pharmacologically acceptable salt thereof, a hydrate thereof and a solvate thereof as an active ingredient,

(3) ring Z is an arene of C ₆ -C ₁₀ wherein the arene is -OA (wherein A is the same as defined in Formula I) and the formula -CONH-E (wherein E is It may have a substituent in addition to the group represented by the same as the definition in), or a 5-10 membered heteroarene (The said heteroarene is a formula -OA (wherein A is a definition in general formula (I).) And pharmacologically acceptable salts thereof, and a compound represented by the formula -CONH-E, wherein E may have a substituent in addition to the group represented by the formula (I). The medicament comprising a substance selected from the group consisting of hydrates and solvates thereof as an active ingredient,

(4) Ring Z is represented by the formula -OA (wherein A is the same as defined in formula I) and formula -CONH-E (wherein E is the same as defined in formula I). A benzene ring which may further have a substituent in addition to the group, or the formula -OA (wherein A is the same as defined in the formula (I)) and the formula -CONH-E (wherein E is the definition in the formula (I) The above medicament comprising as an active ingredient a compound selected from the group consisting of a compound which is a naphthalene ring which may further have a substituent in addition to the group represented by the above), and a pharmacologically acceptable salt thereof, their hydrate and their solvate. ,

(5) Ring Z is represented by the formula -OA (wherein A is the same as defined in formula I) and formula -CONH-E (wherein E is the same as defined in formula I). The above medicament comprising as an active ingredient a compound selected from the group consisting of a compound which is a benzene ring further having a halogen atom in addition to the group and pharmacologically acceptable salts thereof, hydrates thereof and solvates thereof,

(6) Ring Z is represented by formula -OA (wherein A is the same as defined in Formula I) and formula -CONH-E (wherein E is the same as defined in Formula I). The above medicament comprising as an active ingredient a compound selected from the group consisting of a compound which is a naphthalene ring which may further have a substituent, and pharmacologically acceptable salts thereof, hydrates thereof and solvates thereof;

(7) the above-mentioned compound comprising a compound wherein E is a 2,5-disubstituted or 3,5-disubstituted phenyl group, and a substance selected from the group consisting of pharmacologically acceptable salts, hydrates thereof and solvates thereof as an active ingredient. medicine,

(8) A compound in which E is a 2,5-disubstituted phenyl group (at least one of the substituents is a trifluoromethyl group) or a 3,5-disubstituted phenyl group (at least one of the substituents is a trifluoromethyl group) And a pharmacologically acceptable salt thereof, a hydrate thereof and a solvate thereof, wherein the medicament comprises a substance selected from the group consisting of

(9) the above medicament comprising as an active ingredient a compound wherein E is a 3,5-bis (trifluoromethyl) phenyl group and a substance selected from the group consisting of pharmacologically acceptable salts thereof, their hydrates and their solvates,

(10) A monocyclic or condensed polycyclic heteroaryl group in which E may have a substituent, provided that the heteroaryl group is a benzene ring in which the ring directly connected to the -CONH- group in (I) is benzene ring; Substituted thiazol-2-yl group, and ③ unsubstituted benzothiazol-2-yl group), and pharmacologically acceptable salts thereof, their hydrates and their solvates. The medicament comprising the substance as an active ingredient,

(11) A compound wherein E is a 5-membered monocyclic heteroaryl group which may have a substituent, except that the heteroaryl group is an unsubstituted thiazol-2-yl group, and pharmacologically acceptable salts thereof , The medicament comprising a substance selected from the group consisting of hydrates and solvates thereof as an active ingredient

Can be mentioned.

In another aspect, the present invention provides the use of each of the above substances for the manufacture of a medicament of (1) to (11). The present invention also provides a method for preventing and / or treating Alzheimer's disease, the method comprising administering to the mammalian animal including a human an effective amount for preventing and / or treating each substance and a method for preventing and / or treating epilepsy. As a method, there is provided a method comprising administering a prophylactic and / or therapeutically effective amount of each of these substances to a mammal, including a human.

Brief description of the drawings

Fig. 1 is a diagram showing the effect of suppressing memory formation in Alzheimer's model animals of the medicine (compound No. 4) of the present invention.

Best Mode for Carrying Out the Invention

It is useful to refer to the disclosure of "International Publication No. 02/49632 Pamphlet" for the understanding of the present invention. The disclosure of this International Publication No. 02/49632 pamphlet is incorporated herein by reference in its entirety.

The meaning of the term used in this specification is as follows.

As a "halogen atom", unless otherwise mentioned, you may use any of a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

As a "hydrocarbon group", an aliphatic hydrocarbon group, an aryl group, an arylene group, an aralkyl group, a crosslinkable hydrocarbon group, a spiro cyclic hydrocarbon group, a terpene hydrocarbon, etc. are mentioned, for example.

Examples of the "aliphatic hydrocarbon group" include linear or branched monovalent or divalent acyclic hydrocarbon groups such as alkyl groups, alkenyl groups, alkynyl groups, alkylene groups, alkenylene groups, and alkylidene groups; Saturated or unsaturated monovalent or divalent alicyclic hydrocarbon groups, such as a cycloalkyl group, a cycloalkenyl group, a cycloalkanedenyl group, a cycloalkyl-alkyl group, a cycloalkylene group, and a cycloalkenylene group, etc. are mentioned. .

As an "alkyl group", for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, Neopentyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2- Dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-ethylbutyl, 1-ethyl-1-methylpropyl, C ₁ -C ₁₅ straight chain such as n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadedecyl Or a branched alkyl group.

As an "alkenyl group", for example, vinyl, propa-1-en-1-yl, allyl, isopropenyl, buta-1-en-1-yl, buta-2-en-1-yl, buta-3 -En-1-yl, 2-methylpropa-2-en-1-yl, 1-methylpropa-2-en-1-yl, penta-1-en-1-yl, penta-2-ene -1-yl, penta-3-en-1-yl, penta-4-en-1-yl, 3-methylbuta-2-en-1-yl, 3-methylbuta-3-en-1-yl , Hexa-1-en-1-yl, hexa-2-en-1-yl, hexa-3-en-1-yl, hexa-4-en-1-yl, hexa-5-en-1-yl , 4-methylpenta-3-en-1-yl, 4-methylpenta-3-en-1-yl, hepta-1-en-1-yl, hepta-6-en-1-yl, octa-1 -En-1-yl, octa-7-en-1-yl, nona-1-en-1-yl, nona-8-en-1-yl, deca-1-en-1-yl, deca-9 -En-1-yl, undeka-1-en-1-yl, undeka-10-en-1-yl, dodeca-1-en-1-yl, dodeca-11-en-1-yl , Trideca-1-en-1-yl, trideca-12-en-1-yl, tetradeca-1-en-1-yl, tetradeca-13-en-1-yl, pentadeca-1- en-1-one, 14-penta-deca-en-1-yl, such as C ₂ ~ C ₁₅ linear or branched chain alkenyl of shape It may be a group.

As an "alkynyl group", for example, ethynyl, propa-1-yn-1-yl, propa-2-yn-1-yl, buta-1-yn-1-yl, buta-3-yn-1 -Yl, 1-methylpropa-2-yn-1-yl, penta-1-yn-1-yl, penta-4-yn-1-yl, hexa-1-yn-1-yl, hexa-5 -Yn-1-yl, hepta-1-yn-1-yl, hepta-6-yn-1-yl, octa-1-yn-1-yl, octa-7-yn-1-yl, nona-1 -Yn-1-yl, nona-8-yn-1-yl, deca-1-yn-1-yl, deca-9-yn-1-yl, undeka-1-yn-1-yl, undeca -10-yn-1-yl, dodeca-1-yn-1-yl, dodeca-11-yn-1-yl, trideca-1-yn-1-yl, trideca-12-yne-1 C ₂ , such as -yl, tetradeca-1-yn-1-yl, tetradeca-13-in-1-yl, pentadeca-1-yn-1-yl, pentadeca-14-in-1-yl ~ it may be mentioned C ₁₅ linear or branched alkynyl groups of shapes.

As the "alkylene group", for example, methylene, ethylene, ethane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-2,2-diyl, butane-1,4- C ₁ to C ₈ straight or branched chains such as diyl, pentane-1,5-diyl, hexane-1,6-diyl, 1,1,4,4-tetramethylbutane-1,4-diyl Alkylene group is mentioned.

As an "alkenylene group", for example, ethene-1,2-diyl, propene-1,3-diyl, buta-1-ene-1,4-diyl, buta-2-ene-1,4-diyl, C ₁ to C ₆ linear or branched chains, such as 2-methylpropene-1,3-diyl, penta-2-ene-1,5-diyl, hexa-3-ene-1,6-diyl Alkenylene group is mentioned.

As the "alkylidene group", for example, C ₁ to C ₆ linear or branched alkylidene such as methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene and hexylidene The group can be mentioned.

"Cycloalkyl group" includes, for example there may be mentioned a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The cycloalkyl group of C ₃ ~ C ₈ of.

In addition, the "cycloalkyl group" may be condensed with a benzene ring, a naphthalene ring and the like, for example, 1-indanyl, 2-indanyl, 1,2,3,4-tetrahydronaphthalene And groups such as -1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl and the like.

As a "cycloalkenyl group", for example, 2-cyclopropen-1-yl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, and 2-cyclohexene And C ₃ to C ₆ cycloalkenyl groups such as -1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl, and 1-cyclopenten-1-yl.

In addition, the said "cycloalkenyl group" may be condensed with a benzene ring, a naphthalene ring, etc., for example, 1-indanyl, 2-indanyl, 1,2,3,4-tetrahydronaphthalen-1-yl, 1 And groups such as 2,3,4-tetrahydronaphthalen-2-yl, 1-indenyl, and 2-indenyl.

Such as "cycloalkane diethoxy group" includes, for example 2,4-cyclopentane-dien-1-yl, 2,4-cyclohexane-dien-1-yl, 2,5-cyclohexane-dien-1-yl C ₅ ~ cycloalkyl of C ₆ may be an alkane dienyl.

Moreover, the said "cycloalkanedienyl group" may be condensed with a benzene ring, a naphthalene ring, etc., For example, groups, such as 1-indenyl and 2-indenyl, are mentioned.

Examples of the "cycloalkyl-alkyl group" include a group in which one hydrogen element of the "alkyl group" is substituted with a "cycloalkyl group". For example, cyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 3-cyclo Propylpropyl, 4-cyclopropylbutyl, 5-cyclopropylpentyl, 6-cyclopropylhexyl, cyclobutylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylpropyl, cyclohexylbutyl, cyclo And C ₄ -C ₁₄ cycloalkyl-alkyl groups such as heptylmethyl, cyclooctylmethyl and 6-cyclooctylhexyl.

As a "cycloalkylene group", for example, cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, cyclobutane-1, 3-diyl, cyclopentane-1,1-diyl, cyclopentane-1,2-diyl, cyclopentane-1,3-diyl, cyclohexane-1,1-diyl, cyclohexane-1,2-diyl, cyclo Hexane-1,3-diyl, cyclohexane-1,4-diyl, cycloheptan-1,1-diyl, cycloheptan-1,2-diyl, cyclooctane-1,1-diyl, cyclooctane-1,2 - there may be mentioned C ₃ ~ C ₈ cycloalkylene groups such as a-diyl.

As a "cycloalkenylene group", for example, 2-cyclopropene-1,1-diyl, 2-cyclobutene-1,1-diyl, 2-cyclopentene-1,1-diyl, 3-cyclopentene-1 , 1-diyl, 2-cyclohexene-1,1-diyl, 2-cyclohexene-1,2-diyl, 2-cyclohexene-1,4-diyl, 3-cyclohexene-1,1-diyl, 1 And C ₃ to C ₆ cycloalkenylene groups such as -cyclobutene-1,2-diyl, 1-cyclopentene-1,2-diyl and 1-cyclohexene-1,2-diyl.

Examples of the "aryl group" include monocyclic or condensed polycyclic aromatic hydrocarbon groups, and examples thereof include phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl, acenaphthylenyl, and the like. An aryl group of C ₆ to C ₁₄ can be mentioned.

Further, the above-described "aryl group" is the "C ₃ ~ C ₈ cycloalkyl group", "C ₃ ~ C ₆ of the cycloalkenyl group", or "cycloalkyl of C ₅ ~ C ₆ alkane diethoxy group" is optionally axis bright as 4-indanyl, 5-indanyl, 1,2,3,4-tetrahydronaphthalen-5-yl, 1,2,3,4-tetrahydronaphthalen-6-yl, 3-acenaph Tenyl, 4-acenaphthenyl, inden-4-yl, inden-5-yl, inden-6-yl, inden-7-yl, 4-phenalenyl, 5-phenalenyl, 6-phenalenyl, And groups such as 7-phenalenyl, 8-phenalenyl, and 9-phenalenyl.

As an "arylene group", for example, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, naphthalene-1,2-diyl, naphthalene-1,3-diyl, naphthalene -1,4-diyl, naphthalene-1,5-diyl, naphthalene-1,6-diyl, naphthalene-1,7-diyl, naphthalene-1,8-diyl, naphthalene-2,3-diyl, naphthalene-2 C ₆ to C, such as, 4-diyl, naphthalene-2,5-diyl, naphthalene-2,6-diyl, naphthalene-2,7-diyl, naphthalene-2,8-diyl, anthracene-1,4-diyl The arylene group of ₁₄ is mentioned.

Examples of the "aralkyl group" include groups in which one hydrogen atom of the "alkyl group" is substituted with an "aryl group". For example, benzyl, 1-naphthylmethyl, 2-naphthylmethyl, anthracenylmethyl, phenanthrenylmethyl , Acenaphthylenylmethyl, diphenylmethyl, 1-phenethyl, 2-phenethyl, 1- (1-naphthyl) ethyl, 1- (2-naphthyl) ethyl, 2- (1-naph Tyl) ethyl, 2- (2-naphthyl) ethyl, 3-phenylpropyl, 3- (1-naphthyl) propyl, 3- (2-naphthyl) propyl, 4-phenylbutyl, 4- (1-naphth Tyl) butyl, 4- (2-naphthyl) butyl, 5-phenylpentyl, 5- (1-naphthyl) pentyl, 5- (2-naphthyl) pentyl, 6-phenylhexyl, 6- (1-naph And aralkyl groups of C ₇ to C ₁₆ , such as butyl) hexyl and 6- (2-naphthyl) hexyl.

As a "crosslinkable hydrocarbon group", for example, bicyclo [2. 1.0] pentyl, bicyclo [2. 2. 1] heptyl, bicyclo [2. 2. 1] octyl, adamantyl and the like.

As a "spirocyclic hydrocarbon group", for example, spiro [3. [4] octyl, spiro [4. 5] groups, such as deca-1,6-dienyl, are mentioned.

Examples of the "terpene hydrocarbon group" include groups such as geranyl, neryl, linalyl, phytyl, menthyl, and bornyl.

Examples of the "halogenated alkyl group" include groups in which one hydrogen atom of the "alkyl group" is substituted with a "halogen atom". For example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloro Methyl, bromomethyl, dibromomethyl, tribromomethyl, iodinemethyl, diiomethyl, triiomethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-tri C ₁ -C ₆ straight or branched chain halogenated alkyl groups substituted with 1 to 13 halogen atoms such as fluoropropyl, heptafluoropropyl, heptafluoroisopropyl, nonafluorobutyl, and perfluorohexyl Can be mentioned.

The "heterocyclic group" is, for example, a monocyclic or condensed atom containing at least one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom as an atom (ring atom) constituting a ring system. A monocyclic or condensed polycyclic non-aromatic heterocyclic group containing at least one heteroatom selected from an oxygen atom, a sulfur atom, a nitrogen atom, and the like as an atom (ring atom) constituting a polycyclic heteroaryl group and a ring system Can be mentioned.

As the "monocyclic heteroaryl group", for example, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3- Pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-thiazolyl, 4-thia Zolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imida Zolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, (1,2,3-oxadiazole) -4-yl, (1,2,3 -Oxadiazole) -5-yl, (1,2,4-oxadiazol) -3-yl, (1,2,4-oxadiazole) -5-yl, (1,2,5-oxa Diazol) -3-yl, (1,2,5-oxadiazol) -4-yl, (1,3,4-oxadiazol) -2-yl, (1,3,4-oxadiazole ) -5-yl, furazanyl, (1,2,3-thiadiazole) -4-yl, (1,2,3-thiadiazole) -5-yl, (1, 2,4-thiadiazole) -3-yl, (1,2,4-thiadiazole) -5- , (1,2,5-thiadiazol) -3-yl, (1,2,5-thiadiazol) -4-yl, (1,3,4-thiadiazolyl) -2-yl, ( 1,3,4-thiadiazolyl) -5-yl, (1H-1,2,3-triazole) -1-yl, (1H-1,2,3-triazole) -4- 1, (1H-1,2,3-triazole) -5-yl, (2H-1,2,3-triazol) -2-yl, (2H-1,2,3-triazole) -4 -Yl, (1H-1,2,4-triazol) -1-yl, (1H-1,2,4-triazol) -3-yl, (1H-1,2,4-triazole)- 5-yl, (4H-1,2,4-triazol) -3-yl, (4H-1,2,4-triazol) -4-yl, (1H-tetrazole) -1- 1, (1H-tetrazol) -5-yl, (2H-tetrazol) -2-yl, (2H-tetrazol) -5-yl, 2-pyridyl, 3-pyridyl, 4- Pyridyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, (1, 2,3-triazine) -4-yl, (1,2,3-triazine) -5-yl, (1,2,4-triazine) -3-yl, (1,2, 4-triazine) -5-yl, (1,2,4-triazine) -6-yl, (1,3,5-triazine) -2-yl, 1-azinyl, 1 -Azinyl, 2-azinyl, 3- Zefinyl, 4-azinyl, (1,4-oxazepine) -2-yl, (1,4-oxazepine) -3-yl, (1,4-oxazepine) -5-yl , (1,4-oxazepine) -6-yl, (1,4-oxazepine) -7-yl, (1,4-thiazepine) -2-yl, (1,4-thiazepine 5-7 members such as) -3-yl, (1,4-thiazepine) -5-yl, (1,4-thiazepine) -6-yl, (1,4-thiazepine) -7-yl And monocyclic heteroaryl group.

As a "condensed polycyclic heteroaryl group", for example, 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 1- Isobenzofuranyl, 4-isobenzofuranyl, 5-isobenzofuranyl, 2-benzo [b] thienyl, 3-benzo [b] thienyl, 4-benzo [b] thienyl, 5-benzo [ b] thienyl, 6-benzo [b] thienyl, 7-benzo [b] thienyl, 1-benzo [c] thienyl, 4-benzo [c] thienyl, 5-benzo [c] thienyl, 1-Indolyl, 1-Indolyl, 2-Indolyl, 3-Indolyl, 4-Indolyl, 5-Indolyl, 6-Indolyl, 7-Indolyl, (2H-isoindole) -1-yl , (2H-isoindole) -2-yl, (2H-isoindole) -4-yl, (2H-isoindole) -5-yl, (1H-indazol) -1-yl, (1H-indazole ) -3-yl, (1H-indazol) -4-yl, (1H-indazol) -5-yl, (1H-indazol) -6-yl, (1H-indazol) -7day, ( 2H-indazol) -1-yl, (2H-indazol) -2-yl, (2H-indazol) -4-yl, (2H-indazol) -5-yl, 2-benzooxazolyl, 2 -Benzooxazolyl, 4-benzooxazolyl, 5-benzooxazolyl, 6-benzooxazolyl, 7-benzooxa Reel, (1,2-benzoisoxazol) -3-yl, (1,2-benzoisoxazol) -4-yl, (1,2-benzoisoxazol) -5-yl, (1,2-benzoy Oxazol) -6-yl, (1,2-benzoisoxazol) -7-yl, (2,1-benzoisoxazol) -3-yl, (2,1-benzoisoxazol) -4-yl, (2,1-benzoisoxazol) -5-yl, (2,1-benzoisoxazol) -6-yl, (2,1-benzoisoxazol) -7-yl, 2-benzothiazolyl, 4- Benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl, (1,2-benzoisothiazol) -3-yl, (1,2-benzoisothiazole) -4- 1, (1,2-benzoisothiazol) -5-yl, (1,2-benzoisothiazol) -6-yl, (1,2-benzoisothiazol) -7-yl, (2, 1-benzoisothiazol) -3-yl, (2,1-benzoisothiazol) -4-yl, (2,1-benzoisothiazol) -5-yl, (2,1-benzoisothia Sol) -6-yl, (2,1-benzoisothiazol) -7-yl, (1,2,3-benzooxadiazole) -4-yl, (1,2,3-benzooxadiazole ) -5-yl, (1,2,3-benzooxadiazole) -6-yl, (1,2,3-benzooxadiazole) -7-yl, (2,1,3-benzooxadia Sol) -4-yl , (2,1,3-benzooxadiazole) -5-yl, (1,2,3-benzothiadiazol) -4-yl, (1,2,3-benzothiadiazole) -5- 1, (1,2,3-benzothiadiazole) -6-yl, (1,2,3-benzothiadiazole) -7-yl, (2,1,3-benzothiadiazole) -4 -Yl, (2,1,3-benzothiadiazol) -5-yl, (1H-benzotriazol) -1-yl, (1H-benzotriazol) -4-yl, (1H-benzotriazole ) -5-yl, (1H-benzotriazole) -6-yl, (1H-benzotriazole) -7-yl, (2H-benzotriazol) -2-yl, (2H-benzotriazole)- 4-yl, (2H-benzotriazole) -5-yl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl , 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl, 3-cinnolinyl ), 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl, 2-quinazolinyl, 4-quinazolinyl, 5-quina Zolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl, 2-quinoxalinyl , 5-quinoxalinyl, 6-quinoxalinyl, 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl, 2-naphthyridinyl, 3-naphthyridinyl, 4 -Naphthyridinyl, 2-purinyl, 6-purinyl, 7-furinyl, 8-purinyl, 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7 -Putridinyl, 1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl, 9-carbazolyl, 2- (α-carbolinyl), 3- (α-carbolinyl), 4- (α-carbolinyl), 5- (α-carbolinyl), 6- (α-carbolinyl), 7- (α-carbolinyl), 8- (α-carbolinyl), 9- (α-carbolinyl), 1- (β-carbolinyl), 3- (β-carbolinyl), 4- (β-carbolinyl), 5- (β-carbolinyl), 6- (β-carbolinyl), 7- (β-carbolinyl), 8- (β-carbolinyl), 9- (β-carbolinyl), 1- (γ-carbolinyl), 2- (γ-carbolinyl), 4- (γ-carbolinyl), 5- (γ-carbolinyl), 6- (γ-carbolinyl), 7- (γ-carbolinyl), 8- (γ-carbolinyl), 9- (γ-carbolinyl), 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl, 1-phenoxazinyl ), 2-phenoxazinyl, 3-phenoxazinyl, 4-phenoxazinyl, 10-phenoxazinyl, 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4-pheno Thiazinyl, 10-phenothiazinyl, 1-phenazinyl, 2-phenazinyl, 1-phenanthridinyl, 2-phenanthridinyl, 3-phenanthridinyl, 4-phenanthtridinyl, 6 -Phenantridinyl, 7-phenantridinyl, 8-phenantridinyl, 9-phenantridinyl, 10-phenantridinyl, 2-phenanthrolinyl, 3-phenanthrolinyl, 4-phenanthrolinyl, 5-phenanthrolinyl, 6-phenanthrolinyl, 7-phenanthrolinyl, 8-phenanthrolinyl, 9-phenanthrolinyl, 10-phenanthrolinyl, 1-thianthrenyl, 2-thiaanthrenyl , 1-indolizinyl, 2-indolizinyl, 3-indolizinyl, 5-indolizinyl, 6-indolizide , 7-indolizinyl, 8-indolizinyl, 1-phenoxathiinyl, 2-phenoxatiinyl, 3-phenoxatiinyl, 4-phenoxatiinyl, thieno [2,3 -b] furyl, pyrollo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [11,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a And 8 to 14 membered condensed polycyclic heteroaryl groups such as] pyridyl and 1,2,4-triazolo [4,3-a] pyridazinyl.

As a "monocyclic non-aromatic heterocyclic group", for example, 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl , 2-tetrahydrofuryl, 3-tetrahydrofuryl, thiolanyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolidinyl ( pyrazolidinyl), 3-pyrazolidinyl, 4-pyrazolidinyl, 1- (2-pyrrolinyl), 1- (2-imidazolinyl), 2- (2-imidazolinyl), 1- ( 2-pyrazolinyl), 3- (2-pyrazolinyl), piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-homopiperidinyl, 2 3- to 7-membered saturated or unsaturated monocyclic non-aromatics such as tetrahydropyranyl, morpholino, (thiomorpholin) -4-yl, 1-piperazinyl, 1-homopiperazinyl, etc. Heterocyclic group etc. are mentioned.

As the "condensed polycyclic non-aromatic heterocyclic group", for example, 2-quinuclidinyl, 2-chromanyl, 3-chromenyl, 4-chromenyl, 5-chromenyl, 6-chromenyl, 7-chromenyl, 8-chromenyl, 1-isochromenyl, 3-isochromenyl, 4-isochromenyl, 5-isochromenyl, 6-isochromenyl, 7-isochromenyl, 8-isochrome Nyl, 2-thiochromenyl, 3-thiochromenyl, 4-thiochromenyl, 5-thiochromenyl, 6-thiochromenyl, 7-thiochromenyl, 8-thiochromenyl, 1-isothiochromenyl , 3-isothiochromenyl, 4-isothiochromenyl, 5-isothiochromenyl, 6-isothiochromenyl, 7-isothiochromenyl, 8-isothiochromenyl, 1-indolinyl, 2- Indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, 1-isoindolinyl, 2-isoindolinyl, 4-isoindolinyl, 5 Isoindolinyl, 2- (4H-chromenyl), 3- (4H-chromenyl), 4- (4H- Lomenyl), 5- (4H-chromenyl), 6- (4H-chromenyl), 7- (4H-chromenyl), 8- (4H-chromenyl), 1-isochromenyl, 3-isochrome Menyl, 4-isochromenyl, 5-isochromenyl, 6-isochromenyl, 7-isochromenyl, 8-isochromenyl, 1- (1H-pyrrolidinyl), 2- (1H-pyrrolidinyl ), 8- to 10-membered saturation such as 3- (1H-pyrrolidinyl), 5- (1H-pyrrolidinyl), 6- (1H-pyrrolidinyl), 7- (1H-pyrrolidinyl), or An unsaturated condensed polycyclic non-aromatic heterocyclic group can be mentioned.

Of the above "heterocyclic groups", a monocyclic or condensed polycyclic compound which may have one to three kinds of hetero atoms selected from oxygen atoms, sulfur atoms, nitrogen atoms, etc. in addition to nitrogen atoms having a binding number as atoms (ring atoms) constituting the ring system. Monocyclic or condensed polycyclic which may have 1 to 3 kinds of heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, in addition to a cyclic heteroaryl group and a nitrogen atom having a binding number as an atom (ring atom) constituting the ring system Non-aromatic heterocyclic group is called "cyclic amino group", for example, 1-pyrrolidinyl, 1-imidazolidinyl, 1-pyrazolidinyl, 1-oxazolidinyl, 1-thiazolidinyl, piperidino , Morpholino, 1-piperazinyl, thiomorpholin-4-yl, 1-homopiperidinyl, 1-homopiperazinyl, 2-pyrrolin-1-yl, 2-imidazoline-1- 1, 2-pyrazolin-1-yl, 1-indolinyl, 2-isoindolinyl, 1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, 1 -Groups, such as indolyl, 1-indazolyl, and 2-isoindoleyl, are mentioned.

Said "cycloalkyl group", "cycloalkenyl group", "cycloalkanedienyl group", "aryl group", "cycloalkylene group", "cycloalkenylene group", "arylene group", "crosslinkable hydrocarbon group", " Spiro cyclic hydrocarbon group "and" heterocyclic group "are collectively called" cyclic group. " Among the above-mentioned "cyclic groups", "aryl group", "arylene group", "monocyclic heteroaryl group" and "condensed polycyclic heteroaryl group" are collectively referred to as "aromatic group".

Examples of the "hydrocarbon-oxy group" include groups in which a hydrogen atom of the "hydroxy group" is substituted with a "hydrocarbon group", and examples of the "hydrocarbon" include the same groups as those of the "hydrocarbon group". As a "hydrocarbon-oxy group", for example, aliphatic hydrocarbons such as an alkoxy group (alkyl-oxy group), an alkenyl-oxy group, an alkynyl-oxy group, a cycloalkyl-oxy group and a cycloalkyl-alkyl-oxy group Time; Aryl-oxy group; Aralkyl-oxy group; Alkylene-deoxy group etc. are mentioned.

As an "alkoxy group (alkyl-oxy group)", for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyl Oxy, isopentyloxy, 2-methylbutoxy, 1-methylbutoxy, neopentyloxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy, 3- Methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1, 3-dimethylbutoxy, 2,3-dimethylbutoxy, 2-ethylbutoxy, 1-ethylbutoxy, 1-ethyl-1-methylpropoxy, n-heptyloxy, n-octyloxy, n-nonyloxy , C ₁ to C ₁₅ straight chain such as n-decyloxy, n-undecyloxy, n-dodecyloxy, n-tridecyloxy, n-tetradecyloxy, n-pentadedecyloxy, or A branched chain alkoxy group is mentioned.

As an "alkenyl-oxy group", for example, vinyloxy, (propa-1-en-1-yl) oxy, aryloxy, isopropenyloxy, (buta-1-en-1-yl) oxy, ( Buta-2-en-1-yl) oxy, (buta-3-en-1-yl) oxy, (2-methylpropa-2-en-1-yl) oxy, (1-methylpropa-2 -En-1-yl) oxy, (penta-1-en-1-yl) oxy, (penta-2-en-1-yl) oxy, (penta-3-en-1-yl) oxy, (penta -4-en-1-yl) oxy, (3-methylbuta-2-en-1-yl) oxy, (3-methylbuta-3-en-1-yl) oxy, (hexa-1-ene- 1-yl) oxy, (hexa-2-en-1-yl) oxy, (hexa-3-en-1-yl) oxy, (hexa-4-en-1-yl) oxy, (hexa-5- En-1-yl) oxy, (4-methylpenta-3-en-1-yl) oxy, (4-methylpenta-3-en-1-yl) oxy, (hepta-1-en-1-yl ) Oxy, (hepta-6-en-1-yl) oxy, (octa-1-en-1-yl) oxy, (octa-7-en-1-yl) oxy, (nona-1-ene-1 -Yl) oxy, (nona-8-en-1-yl) oxy, (deca-1-en-1-yl) oxy, (deca-9-en-1-yl) oxy, (undeca-1- En-1-yl) oxy, (undeca-10-en-1-yl) oxy, (dodeca-1-en-1- ) Oxy, (dodeca-11-en-1-yl) oxy, (trideca-1-en-1-yl) oxy, (trideca-12-en-1-yl) oxy, (tetradeca-1 -En-1-yl) oxy, (tetradeca-13-en-1-yl) oxy, (pentadeca-1-en-1-yl) oxy, (pentadeca-14-en-1-yl) oxy such as the C ₂ ~ C ₁₅ straight-chain shape or a branched shape seen in the alkenyl-oxy group may be mentioned.

As an "alkynyl-oxy group", for example, ethynyloxy, (propa-1-yn-1-yl) oxy, (propa-2-yn-1-yl) oxy, (buta-1-yn- 1-yl) oxy, (buta-3-yn-1-yl) oxy, (1-methylpropa-2-yn-1-yl) oxy, (penta-1-yn-1-yl) oxy, ( Penta-4-yn-1-yl) oxy, (hexa-1-yn-1-yl) oxy, (hexa-5-yn-1-yl) oxy, (hepta-1-yn-1-yl) oxy , (Hepta-6-yn-1-yl) oxy, (octa-1-yn-1-yl) oxy, (octa-7-yn-1-yl) oxy, (nona-1-yn-1-yl ) Oxy, (nona-8-yn-1-yl) oxy, (deca-1-yn-1-yl) oxy, (deca-9-yn-1-yl) oxy, (undeca-1-yne- 1-yl) oxy, (undeca-10-yn-1-yl) oxy, (dodeca-1-yn-1-yl) oxy, (dodeca-11-yn-1-yl) oxy, (tri Deca-1-yn-1-yl) oxy, (trideca-12-yn-1-yl) oxy, (tetradeca-1-yn-1-yl) oxy, (tetradeca-13-yn-1- yl) oxy, (penta-deca-1-yl) oxy, (1-penta-deca-14-a-yl) oxy, etc. of C ₂ ~ C ₁₅ linear or branched chain shape alkynyl-oxy The group can be mentioned.

Include oxy groups - "cycloalkyl-oxy group" includes, for example cycloalkyl-propoxy, cyclopropyl-butoxy, cyclopentyloxy, cyclohexyloxy, cyclo-heptyloxy, cyclopropyl octyloxy, etc. of C ₃ ~ C ₈ cycloalkyl have.

As a "cycloalkyl-alkyl-oxy group", for example, cyclopropylmethoxy, 1-cyclopropylethoxy, 2-cyclopropylethoxy, 3-cyclopropylpropoxy, 4-cyclopropylbutoxy, 5-cyclopropyl Pentyloxy, 6-cyclopropylhexyloxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, 2-cyclohexylethoxy, 3-cyclohexylpropoxy, And C ₄ -C ₁₄ cycloalkyl-alkyl-oxy groups such as ₄ -cyclohexylbutoxy, cycloheptylmethoxy, cyclooctylmethoxy and 6-cyclooctylhexyloxy.

As the "aryl-oxy group", for example, C ₆ -C ₁₄ aryl-oxy groups such as phenoxy, 1-naphthyloxy, 2-naphthyloxy, anthryloxy, phenanthryloxy, acenaphthylenyloxy and the like Can be mentioned.

As an "aralkyl-oxy group", for example, benzyloxy, 1-naphthyl methoxy, 2-naphthyl methoxy, anthracenyl methoxy, phenanthrenyl methoxy, acenaphthylenyl methoxy, diphenyl methoxy, 1- pe Netyloxy, 2-phenethyloxy, 1- (1-naphthyl) ethoxy, 1- (2-naphthyl) ethoxy, 2- (1-naphthyl) ethoxy, 2- (2-naphthyl) Ethoxy, 3-phenylpropoxy, 3- (1-naphthyl) propoxy, 3- (2-naphthyl) propoxy, 4-phenylbutoxy, 4- (1-naphthyl) butoxy, 4- (2-naphthyl) butoxy, 5-phenylpentyloxy, 5- (1-naphthyl) pentyloxy, 5- (2-naphthyl) pentyloxy, 6-phenylhexyloxy, 6- (1-naph there may be mentioned oxy group - naphthyl) hexyloxy, 6- (2-naphthyl) hexyloxy, etc. of C ₇ ~ C ₁₆ aralkyl.

Examples of the "alkylenedioxy group" include groups such as methylenedioxy, ethylenedioxy, 1-methylmethylenedioxy, and 1,1-dimethylmethylenedioxy.

Examples of the "halogenated alkoxy group (halogenated alkyl-oxy group)" include groups in which a hydrogen atom of a "hydroxy group" is substituted with a "halogenated alkyl group". For example, fluoromethoxy, difluoromethoxy, chloromethoxy, bromomethoxy , Iodinemethoxy, trifluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 3,3,3-trifluoropropoxy, heptafluoropropoxy, And C ₁ -C ₆ linear or branched halogenated alkoxy groups substituted with 1 to 13 halogen atoms such as heptafluoroisopropoxy, nonafluorobutoxy, and perfluorohexyloxy.

Examples of the "heterocyclic-oxy group" include groups in which a hydrogen atom of a "hydroxy group" is substituted with a "heterocyclic group", and examples of the "heterocycle" include the same groups as those of the "heterocyclic group". Examples of the "heterocyclic-oxy group" include monocyclic heteroaryl-oxy groups, condensed polycyclic heteroaryl-oxy groups, monocyclic non-aromatic heterocyclic-oxy groups, and condensed polycyclic non-aromatic heterocyclic-oxy groups. Can be mentioned.

As a "monocyclic heteroaryl-oxy group", for example, 3-thienyloxy, (isoxazole-3-yl) oxy, (thiazol-4-yl) oxy, 2-pyridyloxy, 3 And groups such as -pyridyloxy, 4-pyridyloxy and (pyrimidin-4-yl) oxy.

Examples of the "condensed polycyclic heteroaryl-oxy group" include groups such as 5-indolyloxy, (benzimidazol-2-yl) oxy, 2-quinolyloxy, 3-quinolyloxy, and 4-quinolyloxy. have.

Examples of the "monocyclic non-aromatic heterocyclic-oxy group" include groups such as 3-pyrrolidinyloxy and 4-piperidinyloxy.

Examples of the "condensed polycyclic non-aromatic heterocyclic-oxy group" include groups such as 3-indolinyloxy and 4-chromanyloxy.

Examples of the "hydrocarbon-sulfanyl group" include a group in which a hydrogen atom of the "sulfanyl group" is substituted with a "hydrocarbon group". Examples of the "hydrocarbon" include the same groups as those of the "hydrocarbon group". Examples of the "hydrocarbon-sulfanyl group" include aliphatic hydrocarbon-sulfanyl groups such as alkyl-sulfanyl group, alkenyl-sulfanyl group, alkynyl-sulfanyl group, cycloalkyl-sulfanyl group and cycloalkyl-alkyl-sulfanyl group; Aryl-sulfanyl group, an aralkyl-sulfanyl group, etc. are mentioned.

As the "alkyl-sulfanyl group", for example, methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfa Nyl, n-pentylsulfanyl, isopentylsulfanyl, (2-methylbutyl) sulfanyl, (1-methylbutyl) sulfanyl, neopentylsulfanyl, (1,2-dimethylpropyl) sulfanyl, (1- Ethylpropyl) sulfanyl, n-hexylsulfanyl, (4-methylpentyl) sulfanyl, (3-methylpentyl) sulfanyl, (2-methylpentyl) sulfanyl, (1-methylpentyl) sulfanyl, (3 , 3-dimethylbutyl) sulfanyl, (2,2-dimethylbutyl) sulfanyl, (1,1-dimethylbutyl) sulfanyl, (1,2-dimethylbutyl) sulfanyl, (1,3-dimethylbutyl) Sulfanyl, (2,3-dimethylbutyl) sulfanyl, (2-ethylbutyl) sulfanyl, (1-ethylbutyl) sulfanyl, (1-ethyl-1-methylpropyl) sulfanyl, n-heptylsulfanyl , n-octylsulfanyl, n-nonylsulfanyl, n-decylsulfanyl, n-undecylsulfanyl, n-dodecylsulfanyl, n-tridecylsulfanyl, n-tetradecylsulfanyl, n-penta Decyl Isoquinoline, etc. of C ₁ ~ C ₁₅ linear or branched chain-like alkyl-sulfanyl group can be given.

As an "alkenyl-sulfanyl group", for example, vinylsulfanyl, (propano-1-en-1-yl) sulfanyl, allylsulfanyl, isopropenylsulfanyl, (buta-1-en-1-yl ) Sulfanyl, (buta-2-en-1-yl) sulfanyl, (buta-3-en-1-yl) sulfanyl, (2-methylpropa-2-en-1-yl) sulfanyl, (1-methylpropan-2-en-1-yl) sulfanyl, (penta-1-en-1-yl) sulfanyl, (penta-2-en-1-yl) sulfanyl, (penta-3 -En-1-yl) sulfanyl, (penta-4-en-1-yl) sulfanyl, (3-methylbuta-2-en-1-yl) sulfanyl, (3-methylbuta-3-ene -1-yl) sulfanyl, (hexa-1-en-1-yl) sulfanyl, (hexa-2-en-1-yl) sulfanyl, (hexa-3-en-1-yl) sulfanyl, (Hexa-4-en-1-yl) sulfanyl, (hexa-5-en-1-yl) sulfanyl, (4-methylpenta-3-en-1-yl) sulfanyl, (4-methylpenta -3-en-1-yl) sulfanyl, (hepta-1-en-1-yl) sulfanyl, (hepta-6-en-1-yl) sulfanyl, (octa-1-en-1-yl ) Sulfanyl, (octa-7-en-1-yl) sulfanyl, (nona-1-en-1-yl) sulfanyl, (nona-8-en-1-yl) sulfanyl, (deca-1 -En-1-yl) sulfanyl, (deca-9-en-1-yl) Panyl, (Undeca-1-en-1-yl) sulfanyl, (Undeca-10-en-1-yl) sulfanyl, (dodeca-1-en-1-yl) sulfanyl, (dodeca -11-en-1-yl) sulfanyl, (trideca-1-en-1-yl) sulfanyl, (trideca-12-en-1-yl) sulfanyl, (tetradeca-1-ene- 1-yl) sulfanyl, (tetradeca-13-en-1-yl) sulfanyl, (pentadeca-1-en-1-yl) sulfanyl, (pentadeca-14-en-1-yl) sulfa carbonyl, such as alkenyl of C ₂ ~ C ₁₅ linear or branched seen the shape of the - can be given an sulfanyl.

As the "alkynyl-sulfanyl group", for example, ethynylsulfanyl, (propa-1-yn-1-yl) sulfanyl, (propa-2-yn-1-yl) sulfanyl, (buta-1) -Yn-1-yl) sulfanyl, (buta-3-yn-1-yl) sulfanyl, (1-methylpropane-2-yn-1-yl) sulfanyl, (penta-1-yne-1 -Yl) sulfanyl, (penta-4-yn-1-yl) sulfanyl, (hexa-1-yn-1-yl) sulfanyl, (hexa-5-yn-1-yl) sulfanyl, (hepta -1-yn-1-yl) sulfanyl, (hepta-6-yn-1-yl) sulfanyl, (octa-1-yn-1-yl) sulfanyl, (octa-7-yn-1-yl ) Sulfanyl, (nona-1-yn-1-yl) sulfanyl, (nona-8-yn-1-yl) sulfanyl, (deca-1-yn-1-yl) sulfanyl, (deca-9 -Yn-1-yl) sulfanyl, (undeca-1-yn-1-yl) sulfanyl, (undec-10-yn-1-yl) sulfanyl, (dodeca-1-yn-1- Yl) sulfanyl, (dodeca-11-yn-1-yl) sulfanyl, (trideca-1-yn-1-yl) sulfanyl, (trideca-12-yn-1-yl) sulfanyl, (Tetradeca-1-yn-1-yl) sulfanyl, (tetradeca-13-in-1-yl) sulfanyl, (pentadeca-1-in-1-yl) sulfanyl, (pentadeca-14 -In-1-yl) sulfanyl and the like C ₂ ~ C ₁₅ And linear or branched alkynyl-sulfanyl groups.

"Cycloalkyl-sulfanyl group" includes, for example cyclopropyl sulfanyl, cyclobutyl sulfanyl, cyclopentyl sulfanyl, cyclohexyl sulfanyl, cycloheptyl sulfanyl, cyclooctyl sulfanyl such as the C of ₃ ~ C ₈ cycloalkyl -Sulfanyl group.

As a "cycloalkyl-alkyl-sulfanyl group", for example, (cyclopropylmethyl) sulfanyl, (1-cyclopropylethyl) sulfanyl, (2-cyclopropylethyl) sulfanyl, (3-cyclopropylpropyl) sulfanyl , (4-cyclopropylbutyl) sulfanyl, (5-cyclopropylpentyl) sulfanyl, (6-cyclopropylhexyl) sulfanyl, (cyclobutylmethyl) sulfanyl, (cyclopentylmethyl) sulfanyl, (cyclobutyl Methyl) sulfanyl, (cyclopentylmethyl) sulfanyl, (cyclohexylmethyl) sulfanyl, (2-cyclohexylethyl) sulfanyl, (3-cyclohexylpropyl) sulfanyl, (4-cyclohexylbutyl) sulfanyl And C ₄ -C ₁₄ cycloalkyl-alkyl-sulfanyl groups such as (cycloheptylmethyl) sulfanyl, (cyclooctylmethyl) sulfanyl, and (6-cyclooctylhexyl) sulfanyl.

Examples of the "aryl-sulfanyl group" include C ₆ to C, such as phenylsulfanyl, 1-naphthylsulfanyl, 2-naphthylsulfanyl, anthrylsulfanyl, phenanthrylsulfanyl, and acenaphthylenylsulfanyl. The aryl-sulfanyl group of ₁₄ is mentioned.

Examples of the "aralkyl-sulfanyl group" include benzylsulfanyl, (1-naphthylmethyl) sulfanyl, (2-naphthylmethyl) sulfanyl, (anthracenylmethyl) sulfanyl, and (phenanthrenylmethyl) sulfa Neyl, (acenaphthylenylmethyl) sulfanyl, (diphenylmethyl) sulfanyl, (1-phenethyl) sulfanyl, (2-phenethyl) sulfanyl, (1- (1-naphthyl) ethyl) sulfa Neyl, (1- (2-naphthyl) ethyl) sulfanyl, (2- (1-naphthyl) ethyl) sulfanyl, (2- (2-naphthyl) ethyl) sulfanyl, (3-phenylpropyl) Sulfanyl, (3- (1-naphthyl) propyl) sulfanyl, (3- (2-naphthyl) propyl) sulfanyl, (4-phenylbutyl) sulfanyl, (4- (1-naphthyl) butyl ) Sulfanyl, (4- (2-naphthyl) butyl) sulfanyl, (5-phenylpentyl) sulfanyl, (5- (1-naphthyl) pentyl) sulfanyl, (5- (2-naphthyl) pentyl) sulfanyl, (6-phenyl-hexyl) sulfanyl, (6- (1-naphthyl) hexyl) sulfanyl, (6- (2-naphthyl) hexyl) sulfanyl, etc. of a C ₇ ~ C ₁₆ aralkyl And a kill-sulfanyl group.

Examples of the "halogenated alkyl-sulfanyl group" include groups in which a hydrogen atom of the "sulfanyl group" is substituted with a "halogenated alkyl group". For example, (fluoromethyl) sulfanyl, (chloromethyl) sulfanyl, (bro) Momethyl) sulfanyl, (iodinemethyl) sulfanyl, (difluoromethyl) sulfanyl, (trifluoromethyl) sulfanyl, (trichloromethyl) sulfanyl, (2,2,2-trifluoroethyl ) Sulfanyl, (pentafluoroethyl) sulfanyl, (3,3,3-trifluoropropyl) sulfanyl, (heptafluoropropyl) sulfanyl, (heptafluoroisopropyl) sulfanyl, (nonnafluoro may include groups sulfanyl-butyl) sulfanyl, (perfluoro-hexyl) sulfanyl, such as 1 to 13 halogen atoms substituted C ₁ ~ C ₆ linear or branched alkyl halide of the shape of the.

 Examples of the "heterocyclic-sulfanyl group" include groups in which a hydrogen atom of the "sulfanyl group" is substituted with a "heterocyclic group", and examples of the "heterocyclic group" include the same groups as the "heterocyclic group". Examples of the "heterocyclic-sulfanyl group" include monocyclic heteroaryl-sulfanyl group, condensed polycyclic heteroaryl-sulfanyl group, monocyclic non-aromatic heterocyclic-sulfanyl group, and condensed polycyclic non-aromatic heterocyclic-sulfanyl group. Can be mentioned.

 As the "monocyclic heteroaryl-sulfanyl group", for example, (imidazol-2-yl) sulfanyl, (1,2,4-triazol-2-yl) sulfanyl, (pyridin-2-yl) sulfanyl And groups such as (pyridin-4-yl) sulfanyl and (pyrimidin-2-yl) sulfanyl.

 Examples of the "condensed polycyclic heteroaryl-sulfanyl group" include groups such as (benzimidazol-2-yl) sulfanyl, (quinolin-2-yl) sulfanyl, and (quinolin-4-yl) sulfanyl.

 Examples of the "monocyclic non-aromatic heterocyclic sulfanyl group" include groups such as (3-pyrrolidinyl) sulfanyl and (4-piperidinyl) sulfanyl.

 Examples of the "condensed polycyclic non-aromatic heterocyclic sulfanyl group" include groups such as (3-indolinyl) sulfanyl and (4-chromanyl) sulfanyl.

 Examples of the "acyl group" include formyl group, glyoxyloyl group, thioformyl group, carbamoyl group, thiocarbamoyl group, sulfamoyl group, sulfinamoyl group, carboxy group, sulfo group, Phosphono group and the following formula:

^Wherein R ^a1 and R ^b1 are the same or different and represent a hydrocarbon group or a heterocyclic group, or R ^a1 and R ^b1 become one and represent a cyclic amino group together with the nitrogen atom to which they are bonded. The group can be mentioned.

In the definition of "acyl group",

In the group represented by the formula (ω-1A), a group in which R ^a1 is a hydrocarbon group is a "hydrocarbon-carbonyl group" (specific examples: acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl ( pivaloyl, lauroyl, miristoil, palmitoil, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, cyclo A group such as hexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, 1-naphthoyl, 2-naphthoyl, phenylacetyl), or a group in which R ^a1 is a heterocyclic group (heterocyclic-carbonyl group) (specific example: 2-tenoyl) (tenoyl), 3-proyl (nicoyl), nicotinoyl, and isonicotinoyl).

In the group represented by the formula (ω-2A), a group in which R ^a1 is a hydrocarbon group includes a "hydrocarbon-oxy-carbonyl group" (specific examples: methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, etc.). Group which R <^a1> is heterocyclic group is called "heterocyclic-oxy-carbonyl group" (specific example: group, such as 3-pyridyloxycarbonyl).

In the group represented by the formula (ω-3A), a group in which R ^a1 is a hydrocarbon group is a "hydrocarbon-carbonyl-carbonyl group" (specific example: a group such as pyruvoyl), and a group in which R ^a1 is a heterocyclic group is "hetero." Ring-carbonyl-carbonyl group ”.

In the group represented by the formula (ω-4A), a group in which R ^a1 is a hydrocarbon group is a "hydrocarbon-oxy-carbonyl-carbonyl group" (specific examples: groups such as methoxalyl, ethoxalyl, etc.), R ^a1 The group which is this heterocyclic group is called "heterocyclic-oxy-carbonyl-carbonyl group."

In the group represented by the formula (ω-5A), a group in which R ^a1 is a hydrocarbon group is referred to as a "hydrocarbon-sulfanyl-carbonyl group" and a group in which R ^a1 is a heterocyclic group.

In the group represented by the formula (ω-6A), a group in which R ^a1 is a hydrocarbon group is referred to as a "hydrocarbon-thiocarbonyl group" and a group in which R ^a1 is a heterocyclic group is referred to as a "heterocyclic-thiocarbonyl group".

In the group represented by the formula (ω-7A), a group in which R ^a1 is a hydrocarbon group is referred to as a "hydrocarbon-oxy-thiocarbonyl group" and a group in which R ^a1 is a heterocyclic group.

In the group represented by the formula (ω-8A), a group in which R ^a1 is a hydrocarbon group is referred to as a "hydrocarbon-sulfanyl-thiocarbonyl group" and a group in which R ^a1 is a heterocyclic group.

In the group represented by the formula (ω-9A), a group in which R ^a1 is a hydrocarbon group is selected from the group "N-hydrocarbon-carbamoyl group" (specific examples: groups such as N-methylcarbamoyl) and R ^a1 is a heterocyclic group. N-heterocyclic-carbamoyl group ".

In the group represented by the formula (ω-10A), a group in which R ^a1 and R ^b1 are hydrocarbon groups is represented by a group such as "N, N-di (hydrocarbon) -carbamoyl group" (specific examples: N, N-dimethylcarbamoyl, etc.). ), A group in which R ^a1 and R ^b1 are a heterocyclic group is an "N, N-di (heterocyclic) -carbamoyl group", a group in which R ^a1 is a hydrocarbon group and R ^b1 is a heterocyclic group is "N-hydrocarbon-N-hetero" A ring-substituted carbamoyl group ”, R ^a1 and R ^b1 , and a group which is a cyclic amino group together with the nitrogen atom to which they are bonded; a“ cyclic amino-carbonyl group ”(specific examples: groups such as morpholinocarbonyl) It is called.

In the group represented by the formula (ω-11A), a group in which R ^a1 is a hydrocarbon group is referred to as a "N-hydrocarbon-thiocarbamoyl group" and a group in which R ^a1 is a heterocyclic group is referred to as a "N-heterocyclic-thiocarbamoyl group".

In the group represented by the formula (ω-12A), a group in which R ^a1 and R ^b1 is a hydrocarbon group is represented by "N, N-di (hydrocarbon) -thiocarbamoyl group", and a group in which R ^a1 and R ^b1 are heterocyclic groups is represented by "N, N-di (heterocyclic) -thiocarbamoyl group ", R ^a1 is a hydrocarbon group, R ^b1 is a heterocyclic group," N-hydrocarbon-N-heterocyclic-thiocarbamoyl group ", R ^a1 and R ^b1 are The group which becomes one, and which is a cyclic amino group with the nitrogen atom to which they couple | bond is called "cyclic amino- thiocarbonyl group."

In the group represented by the formula (ω-13A), a group in which R ^a1 is a hydrocarbon group is referred to as "N-hydrocarbon-sulfamoyl group" and a group in which R ^a1 is a heterocyclic group is referred to as "N-heterocyclic sulfamoyl group".

In the group represented by the formula (ω-14A), a group in which R ^a1 and R ^b1 are hydrocarbon groups is "N, N-di (hydrocarbon) -sulfamoyl group" (specific examples: groups such as N, N-dimethylsulfamoyl) , A group in which R ^a1 and R ^b1 are heterocyclic groups is an "N, N-di (heterocycle) -sulfamoyl group", a group in which R ^a1 is a hydrocarbon group and R ^b1 is a heterocyclic group is selected from an "N-hydrocarbon-N-heterocycle" A sulfamoyl group, R ^a1 and R ^b1 , and a group having a cyclic amino group together with the nitrogen atom to which they are bonded are referred to as a "cyclic amino-sulfonyl group" (specific examples: groups such as 1-pyrrolylsulfonyl) It is called.

In the group represented by the formula (ω-15A), a group in which R ^a1 is a hydrocarbon group is referred to as a "N-hydrocarbon-sulfinamoyl group" and a group in which R ^a1 is a heterocyclic group is referred to as a "N-heterocyclic sulfinamoyl group".

In the group represented by the formula (ω-16A), a group in which R ^a1 and R ^b1 is a hydrocarbon group is "N, N-di (hydrocarbon) -sulfinamoyl group", and a group in which R ^a1 and R ^b1 are heterocyclic groups is "N, N -Di (heterocyclic) -sulfinamoyl group ", R ^a1 is a hydrocarbon group, R ^b1 is a heterocyclic group," N-hydrocarbon-N-heterocyclic-sulfinamoyl group ", R ^a1 and R ^b1 become one A group which is a cyclic amino group together with the nitrogen atom to which they are bonded is called "cyclic amino-sulfinyl group".

In the group represented by the formula (ω-17A), a group in which R ^a1 is a hydrocarbon group is referred to as a "hydrocarbon-oxy-sulfonyl group" and a group in which R ^a1 is a heterocyclic group.

In the group represented by the formula (ω-18A), a group in which R ^a1 is a hydrocarbon group is referred to as a "hydrocarbon-oxy-sulfinyl group" and a group in which R ^a1 is a heterocyclic group.

In the group represented by the formula (ω-19A), a group in which R ^a1 and R ^b1 is a hydrocarbon group is represented by "O, O'-di (hydrocarbon) -phosphono group", and a group in which R ^a1 and R ^b1 are heterocyclic groups is represented by "O, O'-di (heterocyclic) -phosphono group "and a group in which R ^a1 is a hydrocarbon group and R ^b1 is a heterocyclic group are referred to as"O-hydrocarbon-O'-heterocyclic-phosphono group ".

In the group represented by the formula (ω-20A), a group in which R ^a1 is a hydrocarbon group is a "hydrocarbon-sulfonyl group" (specific examples: groups such as methanesulfonyl and benzenesulfonyl), and a group in which R ^a1 is a heterocyclic group is a "heterocyclic group." -Sulfonyl group ".

In the group represented by the formula (ω-21A), a group in which R ^a1 is a hydrocarbon group is a "hydrocarbon-sulfinyl group" (specific examples: groups such as methylsulfinyl, benzenesulfinyl, etc.), and a group in which R ^a1 is a heterocyclic group is a "heterocyclic group." -Sulfinyl group ".

Examples of the "hydrocarbon" in the group represented by the formulas (ω-1A) to (ω-21A) include the same groups as those of the "hydrocarbon group". For example, as a "hydrocarbon-carbonyl group" represented by the formula (ω-1A), an alkyl-carbonyl group, an alkenyl-carbonyl group, an alkynyl-carbonyl group, a cycloalkyl-carbonyl group, a cycloalkenyl-carbonyl group, a cycloalkanedenyl-carbonyl group Aliphatic hydrocarbon-carbonyl groups such as cycloalkyl-alkyl-carbonyl group; Aryl-carbonyl group; Aralkyl-carbonyl groups; Cross-linked hydrocarbon-carbonyl group; Spiro cyclic hydrocarbon-carbonyl group; Terpene-type hydrocarbon-carbonyl group is mentioned. Hereinafter, the airway shown by Formula (ω-2A)-Formula (ω-21A) is the same.

Examples of the "heterocycle" in the group represented by the formulas (ω-1A) to (ω-21A) include the same groups as the above "heterocyclic groups". For example, as the "heterocyclic-carbonyl group" represented by the formula (ω-1A), for example, a monocyclic heteroaryl-carbonyl group, a condensed polycyclic heteroaryl-carbonyl group, a monocyclic non-aromatic heterocyclic-carbonyl group, or a condensed poly Cyclic non-aromatic heterocyclic-carbonyl group is mentioned. The same also applies to the formulas (ω-2A) to (ω-21A) below.

Examples of the "cyclic amino" in the group represented by the formulas (ω-10A) to (ω-16A) include the same groups as the above-mentioned "cyclic amino group".

In this specification, in the case of "you may have a substituent" in any functional group, except when specifically mentioned, the functional group may have one or two or more "functional groups" in the chemically possible position. Means that. The kind of substituents present in the functional group, the number of substituents and the position of substitution are not particularly limited, and when two or more substituents are present, they may be the same or different. As the "substituent" present in the functional group, for example, a halogen atom, an oxo group, a thioxo group, a nitro group, a nitroso group, a cyano group, an isocyano group, a cyanato group, a thiocyanato group, Isocyanato group, isothiocyanato, hydroxy group, sulfanyl group, carboxyl group, sulfanylcarbonyl group, oxalo group, mesooxalo group, thiocarboxyl group, dithiocarboxyl group, carbamoyl group, thiocarbamoyl group, sulfonyl group Aeration, sulfamoyl group, sulfino group, sulfinamoyl group, sulfeno group, sulfenamoyl group, phosphono group, hydroxyphosphonyl group, hydrocarbon group, heterocyclic group, hydrocarbon-oxy group, heterocyclic-oxy group, hydrocarbon-sulfa Nyl group, heterocyclic-sulfanyl group, acyl group, amino group, hydrazino group, hydrazono group, diazenyl group, diagenyl group, ureido group, thiouido group, guanidino group Carbamomidoyl group (amidino group), Azido group, imino group, hydroxyamino group, hydroxyimino group, aminooxy group, diazo group, semicarbodidino group, semicarbazono group, allophanyl group, hydantoyl group, Phosphano groups, phosphorososo groups, phospho groups, bolyl groups, silyl groups, stannyl groups, selanyl groups, oxide groups and the like.

When two or more "substituents" in the definition of "having a substituent" are present, the two or more substituents may be one with the atoms to which they are bonded to form a cyclic group. The cyclic group may contain one or three or more heteroatoms selected from oxygen, sulfur and nitrogen atoms as the atoms (ring atoms) constituting the ring system, and at least one substituent is present on the ring. You may be. The ring may be either monocyclic or condensed polycyclic, or may be either aromatic or nonaromatic.

The "substituent" in the definition of "having a substituent" may be substituted by said "substituent" at a position that is chemically possible on the substituent. The kind of substituent, the number of substituents and the position of substitution are not particularly limited, and when substituted with two or more substituents, they may be the same or different. As such examples, for example, halogenated alkyl-carbonyl groups (specific examples: groups such as trifluoroacetyl), halogenated alkyl-sulfonyl groups (specific examples: groups such as trifluoromethanesulfonyl), acyl-oxy groups, acyl Sulfanyl group, N-hydrocarbon group-amino group, N, N-di (hydrocarbon) -amino group, N-heterocyclic-amino group, N-hydrocarbon-N-heterocyclic-amino group, acyl-amino group, di (acyl) -amino group Etc. are mentioned. In addition, "substitution" on the said "substituent" may be repeated several times.

Examples of the "acyl-oxy group" include groups in which a hydrogen atom of a "hydroxy group" is substituted with an "acyl group". For example, a formyloxy group, a glyoxyloyloxy group, a thioformyloxy group, a carbamoyloxy group, and a thiocar Bamoyloxy group, sulfamoyloxy group, sulfinamoyloxy group, carboxyoxy group, sulfooxy group, phosphonooxy group and the following formula:

( ^Wherein R ^a2 and R ^b2 are the same or different and represent a hydrocarbon group or a heterocyclic group, or R ^a2 and R ^b2 become one and represent a cyclic amino group together with the nitrogen atom to which they are bonded) The group displayed is mentioned.

In the definition of the "acyl-oxy group",

In the group represented by the formula (ω-1B), a group in which R ^a2 is a hydrocarbon group is a "hydrocarbon-carbonyl-oxy group" (specific examples: groups such as acetoxy, benzoyloxy), and a group in which R ^a2 is a heterocyclic group is "hetero." Ring-carbonyl-oxy group ”.

In the group represented by the formula (ω-2B), a group in which R ^a2 is a hydrocarbon group is a "hydrocarbon-oxy-carbonyl-oxy group" group in which "hydrocarbon-oxy-carbonyl-oxy group" and R ^a2 are a heterocyclic group It is called.

In the group represented by the formula (ω-3B), a group in which R ^a2 is a hydrocarbon group is a "hydrocarbon-carbonyl-carbonyl-oxy group" and a group in which R ^a2 is a heterocyclic group is a "heterocyclic-carbonyl-carbonyl-oxy group" It is called.

In the group represented by the formula (ω-4B), a group in which R ^a2 is a hydrocarbon group is a "hydrocarbon-oxy-carbonyl-carbonyl-oxy group" and a group in which R ^a2 is a heterocyclic group is "heterocyclic-oxy-carbonyl-carbon" Carbonyl-oxy group ”.

In the group represented by the formula (ω-5B), a group in which R ^a2 is a hydrocarbon group is a "hydrocarbon-sulfanyl-carbonyl-oxy group" and a group in which R ^a2 is a heterocyclic group is a "heterocyclic-sulfanyl-carbonyl-oxy group" It is called.

In the group represented by the formula (ω-6B), a group in which R ^a2 is a hydrocarbon group is referred to as a "hydrocarbon-thiocarbonyl-oxy group" and a group in which R ^a2 is a heterocyclic group.

In the group represented by the formula (ω-7B), a group in which R ^a2 is a hydrocarbon group is a "hydrocarbon-oxy-thiocarbonyl-oxy group" and a group in which R ^a2 is a heterocyclic group is a "heterocyclic-oxy-thiocarbonyl-oxy group" It is called.

In the group represented by the formula (ω-8B), a group in which R ^a2 is a hydrocarbon group is a "hydrocarbon-sulfanyl-thiocarbonyl-oxy group", and a group in which R ^a2 is a heterocyclic group is "heterocyclic-sulfanyl-thiocarbonyl- Oxygen ”.

In the group represented by the formula (ω-9B), a group in which R ^a2 is a hydrocarbon group is a "N-hydrocarbon-carbamoyl-oxy group" and a group in which R ^a2 is a heterocyclic group is an "N-heterocyclic-carbamoyl-oxy group. It is called.

In the group represented by the formula (ω-10B), a group in which R ^a2 and R ^b2 are a hydrocarbon group is represented by "N, N-di (hydrocarbon) -carbamoyl-oxy group", a group in which R ^a2 and R ^b2 are heterocyclic groups N, N-di (heterocyclic) -carbamoyl-oxy group ", a group in which R ^a2 is a hydrocarbon group and R ^b2 is a heterocyclic group" N-hydrocarbon-N-heterocyclic-carbamoyl-oxy group ", A group in which R ^a2 and R ^b2 are one and the cyclic amino group together with the nitrogen atom to which they are bonded is referred to as "cyclic amino-carbonyl-oxy group".

In the group represented by the formula (ω-11B), a group in which R ^a2 is a hydrocarbon group is an "N-hydrocarbon-thiocarbamoyl-oxy group" and a group in which R ^a2 is a heterocyclic group is "N-heterocyclic-thiocarbamoyl- Oxygen ”.

In the group represented by the formula (ω-12B), a group in which R ^a2 and R ^b2 are a hydrocarbon group is represented by "N, N-di (hydrocarbon) -thiocarbamoyl-oxy group", and a group in which R ^a2 and R ^b2 are heterocyclic groups "N, N-di (heterocyclic) -thiocarbamoyl-oxy group", a group in which R ^a2 is a hydrocarbon group and R ^b2 is a heterocyclic group is represented by "N-hydrocarbon-N-heterocyclic-thiocarbamoyl-jade A group which is a cyclic amino group together with the nitrogen atom to which R <^a2> and R <^b2> become one, and is couple | bonded is called "cyclic amino- thiocarbonyl-oxy group."

In the group represented by the formula (ω-13B), a group in which R ^a2 is a hydrocarbon group is referred to as "N-hydrocarbon-sulfamoyl-oxy group" and a group in which R ^a2 is a heterocyclic group is referred to as "N-heterocyclic-sulfamoyl-oxy group". It is called.

In the group represented by the formula (ω-14B), a group in which R ^a2 and R ^b2 is a hydrocarbon group is represented by "N, N-di (hydrocarbon) -sulfamoyl-oxy group", and a group in which R ^a2 and R ^b2 are heterocyclic groups is "N , N-di (heterocyclic) -sulfamoyl-oxy group ", a group in which R ^a2 is a hydrocarbon group and R ^b2 is a heterocyclic group," N-hydrocarbon-N-heterocyclic-sulfamoyl-oxy group ", R ^a2 and A group in which R ^b2 becomes one and is a cyclic amino group together with the nitrogen atom to which they are bonded is called a "cyclic amino-sulfonyl-oxy group".

In the group represented by the formula (ω-15B), a group in which R ^a2 is a hydrocarbon group is a "N-hydrocarbon-sulfinamoyl-oxy group" and a group in which R ^a2 is a heterocyclic group is a "N-heterocyclic sulfinamoyl-oxy group". It is called.

In the group represented by the formula (ω-16B), a group in which R ^a2 and R ^b2 are a hydrocarbon group is represented by "N, N-di (hydrocarbon) -sulfinamoyl-oxy group", and a group in which R ^a2 and R ^b2 are heterocyclic groups is " N, N-di (heterocyclic) -sulfinamoyl-oxy group ", a group in which R ^a2 is a hydrocarbon group and R ^b2 is a heterocyclic group," N-hydrocarbon-N-heterocyclic-sulfinamoyl-oxy group ", A group in which R ^a2 and R ^b2 become one and the cyclic amino group together with the nitrogen atom to which they are bonded is referred to as "cyclic amino-sulfinyl-oxy group".

In the group represented by the formula (ω-17B), a group in which R ^a2 is a hydrocarbon group is a "hydrocarbon-oxy-sulfonyl-oxy group" and a group in which R ^a2 is a heterocyclic group is called a "heterocyclic-oxy-sulfonyl-oxy group". It is called.

In the group represented by the formula (ω-18B), a group in which R ^a2 is a hydrocarbon group is a "hydrocarbon-oxy-sulfinyl-oxy group" and a group in which R ^a2 is a heterocyclic group is called a "heterocyclic-oxy-sulfinyl-oxy group". It is called.

In the group represented by the formula (ω-19B), a group in which R ^a2 and R ^b2 are a hydrocarbon group is selected from the group "O, O'-di (hydrocarbon) -phosphono-oxy group", and a group in which R ^a2 and R ^b2 are heterocyclic groups O, O'-di (heterocyclic) -phosphono-oxy group ", a group in which R ^a2 is a hydrocarbon group and R ^b2 is a heterocyclic group" O-hydrocarbon substituted-O'- heterocyclic substituted phosphono-oxy group " It is called.

In the group represented by the formula (ω-20B), a group in which R ^a2 is a hydrocarbon group is referred to as a "hydrocarbon-sulfonyl-oxy group" and a group in which R ^a2 is a heterocyclic group.

In the group represented by the formula (ω-21B), a group in which R ^a2 is a hydrocarbon group is referred to as a "hydrocarbon-sulfinyl-oxy group" and a group in which R ^a2 is a heterocyclic group.

Examples of the "hydrocarbon" in the group represented by the formulas (ω-1B) to (ω-21B) include the same groups as those described above for the "hydrocarbon group". For example, as the "hydrocarbon-carbonyl-oxy group" represented by the formula (ω-1B), an alkyl-carbonyl-oxy group, an alkenyl-carbonyl-oxy group, an alkynyl-carbonyl-oxy group, or cyclo Aliphatic hydrocarbon-carbonyl-oxy groups such as alkyl-carbonyl-oxy group, cycloalkenyl-carbonyl-oxy group, cycloalkanedienyl-carbonyl-oxy group, and cycloalkyl-alkyl-carbonyl-oxy group; Aryl-carbonyl-oxy group; Aralkyl-carbonyl-oxy groups; Cross-linked hydrocarbon-carbonyl-oxy group; Spirocyclic hydrocarbon-carbonyl-oxy groups; And terpene hydrocarbon-carbonyl-oxy groups. Hereinafter, the airway shown by Formula (ω-2B)-Formula (ω-21B) is also the same.

Examples of the "heterocycle" in the group represented by the formulas (ω-1B) to (ω-21B) include the same groups as the above "heterocyclic group". For example, as the "heterocyclic-carbonyl group" represented by the formula (ω-1B), for example, a monocyclic heteroaryl-carbonyl group, a condensed polycyclic heteroaryl-carbonyl group, a monocyclic non-aromatic heterocyclic-carbonyl group, or a condensed poly Cyclic non-aromatic heterocyclic-carbonyl group is mentioned. The same also applies to the formulas (ω-2B) to (ω-21B).

Examples of the "cyclic amino group" in the group represented by the formulas (ω-10B) to (ω-16B) include the same groups as the above-mentioned "cyclic amino group".

Said "acyl-oxy group", "hydrocarbon-oxy group", and "heterocyclic-oxy group" are collectively called "substituted oxy group". In addition, these "substituted oxy groups" and "hydroxy group" are collectively called "hydroxy group which may have a substituent".

Examples of the "acyl-sulfanyl group" include a group in which the hydrogen atom of the "sulfanyl group" is substituted with an "acyl group". For example, a formylsulfanyl group, glyoxyloylsulfanyl group, thioformylsulfanyl group, carbamoyl. Sulfanyl group, thiocarbamoylsulfanyl group, sulfamoylsulfanyl group, sulfinamoylsulfanyl group, carboxylfanyl group, sulfosulfanyl group, phosphonosulfanyl group and the following formula:

( ^Wherein R ^a3 and R ^b3 are the same or different and represent a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, or R ^a3 and R ^b3 become one and the nitrogen to which they are bonded The group represented by the cyclic amino group which may have a substituent with the atom) is mentioned.

In the definition of said "acyl sulfanyl group",

In the group represented by the formula (ω-1C), a group in which R ^a3 is a hydrocarbon group is referred to as a "hydrocarbon-carbonyl-sulfanyl group" and a group in which R ^a3 is a heterocyclic group.

In the group represented by the formula (ω-2C), a group in which R ^a3 is a hydrocarbon group is referred to as a "hydrocarbon-oxy-carbonyl-sulfanyl group" and a group in which R ^a3 is a heterocyclic group. It is called.

In the group represented by the formula (ω-3C), a group in which R ^a3 is a hydrocarbon group is a "hydrocarbon-carbonyl-carbonyl-sulfanyl group" and a group in which R ^a3 is a heterocyclic group is a "heterocyclic-carbonyl-carbonyl-sulfanyl group" It is called.

In the group represented by the formula (ω-4C), a group in which R ^a3 is a hydrocarbon group is a "hydrocarbon-oxy-carbonyl-carbonyl-sulfanyl group" and a group in which R ^a3 is a heterocyclic group is "heterocyclic-oxy-carbonyl-car Carbonyl-sulfanyl group ”.

In the group represented by the formula (ω-5C), a group in which R ^a3 is a hydrocarbon group is a "hydrocarbon-sulfanyl-carbonyl-sulfanyl group" and a group in which R ^a3 is a heterocyclic group is a "heterocyclic-sulfanyl-carbonyl-sulfanyl group" It is called.

In the group represented by the formula (ω-6C), a group in which R ^a3 is a hydrocarbon group is referred to as a "hydrocarbon- thiocarbonyl-sulfanyl group" and a group in which R ^a3 is a heterocyclic group.

In the group represented by the formula (ω-7C), a group in which R ^a3 is a hydrocarbon group is a "hydrocarbon-oxy-thiocarbonyl-sulfanyl group" and a group in which R ^a3 is a heterocyclic group is a "heterocyclic-oxy-thiocarbonyl-sulfanyl group" It is called.

In the group represented by the formula (ω-8C), a group in which R ^a3 is a hydrocarbon group is a "hydrocarbon-sulfanyl-thiocarbonyl-sulfanyl group" and a group in which R ^a3 is a heterocyclic group is "heterocyclic-sulfanyl-thiocarbonyl- Sulfanyl group ”.

In the group represented by the formula (ω-9C), a group in which R ^a3 is a hydrocarbon group is a "N-hydrocarbon-carbamoyl-sulfanyl group" and a group in which R ^a3 is a heterocyclic group is a "N-heterocyclic-carbamoyl-sulfanyl group". It is called.

In the group represented by the formula (ω-10C), a group in which R ^a3 and R ^b3 is a hydrocarbon group is represented by "N, N-di (hydrocarbon) -carbamoyl-sulfanyl group" and a group in which R ^a3 and R ^b3 are heterocyclic groups N, N-di (heterocyclic) -carbamoyl-sulfanyl group ", R ^a3 is a hydrocarbon group, and R ^b3 is a heterocyclic group," N-hydrocarbon-N-heterocyclic-carbamoyl-sulfanyl group ", A group in which R ^a3 and R ^b3 are one and the cyclic amino group together with the nitrogen atom to which they are bonded is called a "cyclic amino-carbonyl-sulfamoyl group".

In the group represented by the formula (ω-11C), a group in which R ^a3 is a hydrocarbon group is "N-hydrocarbon-thiocarbamoyl-sulfanyl group" and a group in which R ^a3 is a heterocyclic group is "N-heterocyclic-thiocarbamoyl- Sulfanyl group ”.

In the group represented by the formula (ω-12C), a group in which R ^a3 and R ^b3 is a hydrocarbon group is a group in which "N, N-di (hydrocarbon) -thiocarbamoyl-sulfanyl group" and R ^a3 and R ^b3 are heterocyclic groups. "N, N-di (heterocyclic) -thiocarbamoyl-sulfanyl group", a group in which R ^a3 is a hydrocarbon group and R ^b3 is a heterocyclic group is represented by "N-hydrocarbon-N-heterocyclic-thiocarbamoyl-sulfa" The group which is a cyclic amino group with the nitrogen atom to which R <^3> and R <^a3> and R <^b3> become one, and is couple | bonded is called "cyclic amino- thiocarbonyl-sulfanyl group."

In the group represented by the formula (ω-13C), a group in which R ^a3 is a hydrocarbon group is referred to as "N-hydrocarbon-sulfamoyl-sulfanyl group" and a group in which R ^a3 is a heterocyclic group is referred to as "N-heterocyclic-sulfamoyl-sulfanyl group". It is called.

In the group represented by the formula (ω-14C), a group in which R ^a3 and R ^b3 is a hydrocarbon group is "N, N-di (hydrocarbon) -sulfamoyl-sulfanyl group", and a group in which R ^a3 and R ^b3 are heterocyclic groups is "N , N-di (heterocyclic) -sulfamoyl-sulfanyl group ", wherein R ^a3 is a hydrocarbon group and R ^b3 is a heterocyclic group," N-hydrocarbon-N-heterocyclic sulfamoyl-sulfanyl group ", R ^a3 and R ^{A group in which b3} becomes one and is a cyclic amino group together with the nitrogen atom to which they are bonded is called a "cyclic amino-sulfonyl-sulfanyl group".

In the group represented by the formula (ω-15C), a group in which R ^a3 is a hydrocarbon group is a "N-hydrocarbon-sulfinamoyl-sulfanyl group" and a group in which R ^a3 is a heterocyclic group is a "N-heterocyclic-sulfinamoyl-sulfanyl group". It is called.

In the group represented by the formula (ω-16C), a group in which R ^a3 and R ^b3 is a hydrocarbon group is represented by "N, N-di (hydrocarbon) -sulfinamoyl-sulfanyl group", and a group in which R ^a3 and R ^b3 are heterocyclic groups is " N, N-di (heterocyclic) -sulfinamoyl-sulfanyl group ", wherein R ^a3 is a hydrocarbon group and R ^b3 is a heterocyclic group," N-hydrocarbon-N-heterocyclic-sulfinamoyl-sulfanyl group ", A group in which R ^a3 and R ^b3 are one and the cyclic amino group together with the nitrogen atom to which they are bonded is called a "cyclic amino-sulfanyl-sulfanyl group".

In the group represented by the formula (ω-17C), a group in which R ^a3 is a hydrocarbon group is a "hydrocarbon-oxy-sulfonyl-sulfanyl group" and a group in which R ^a3 is a heterocyclic group is called a "heterocyclic-oxy-sulfonyl-sulfanyl group". It is called.

In the group represented by the formula (ω-18C), a group in which R ^a3 is a hydrocarbon group is a "hydrocarbon-oxy-sulfinyl-sulfanyl group" and a group in which R ^a3 is a heterocyclic group is called a "heterocyclic-oxy-sulfinyl-sulfanyl group". It is called.

In the group represented by the formula (ω-19C), a group in which R ^a3 and R ^b3 is a hydrocarbon group is represented by "O, O'-di (hydrocarbon) -phosphono-sulfanyl group", and a group in which R ^a3 and R ^b3 are heterocyclic groups O, O'-di (heterocyclic) -phosphono-sulfanyl group ", a group in which R ^a3 is a hydrocarbon group and R ^b3 is a heterocyclic group is called"O-hydrocarbon-O'-heterocyclic-phosphono-sulfanyl group " It is called.

In the group represented by the formula (ω-20C), a group in which R ^a3 is a hydrocarbon group is called a "hydrocarbon-sulfonyl-sulfanyl group" and a group in which R ^a3 is a heterocyclic group is called a "heterocyclic-sulfonyl-sulfanyl group".

In the group represented by the formula (ω-21C), a group in which R ^a3 is a hydrocarbon group is called a "hydrocarbon-sulfinyl-sulfanyl group" and a group in which R ^a3 is a heterocyclic group is called a "heterocyclic-sulfinyl-sulfanyl group".

Examples of the "hydrocarbon" in the group represented by the formulas (ω-1C) to (ω-21C) include the same groups as those described above for the "hydrocarbon group". For example, as the "hydrocarbon-carbonyl-sulfanyl group" represented by the formula (ω-1C), an alkyl-carbonyl-sulfanyl group, an alkenyl-carbonyl-sulfanyl group, alkynyl-carbonyl-sulfanyl group, cyclo Aliphatic hydrocarbon-carbonyl-sulfanyl groups such as alkyl-carbonyl-sulfanyl group, cycloalkenyl-carbonyl-sulfanyl group, cycloalkanedienyl-carbonyl-sulfanyl group, and cycloalkyl-alkyl-carbonyl-sulfanyl group; Aryl-carbonyl-sulfanyl group; Aralkyl-carbonyl-sulfanyl groups; Cross-linked hydrocarbon-carbonyl-sulfanyl group; Spirocyclic hydrocarbon-carbonyl-sulfanyl groups; And terpene hydrocarbon-carbonyl-sulfanyl groups. Hereinafter, the airway represented by Formula (ω-2C)-Formula (ω-21C) is also the same.

Examples of the "heterocycle" in the group represented by the formulas (ω-1C) to (ω-21C) include the same groups as the above "heterocyclic groups". For example, as the "heterocyclic-carbonyl-sulfanyl group" represented by the formula (ω-1C), for example, a monocyclic heteroaryl-carbonyl-sulfanyl group, a condensed polycyclic heteroaryl-carbonyl-sulfanyl group, Monocyclic non-aromatic heterocyclic-carbonyl-sulfanyl group and condensed polycyclic non-aromatic heterocyclic-carbonyl-sulfanyl group. The same also applies to the formulas (ω-2C) to (ω-21C) below.

Examples of the "cyclic amino group" in the group represented by the formulas (ω-10C) to (ω-16C) include the same groups as those of the "cyclic amino group".

Said "acyl-sulfanyl group", "hydrocarbon-sulfanyl group", and "heterocyclic-sulfanyl group" are collectively called "substituted sulfanyl group." In addition, these "substituted sulfanyl groups" and "sulfanyl groups" are collectively called "sulfanyl group which may have a substituent".

Examples of the "N-hydrocarbon-amino group" include groups in which one hydrogen atom of the "amino group" is substituted with a "hydrocarbon group". For example, an N-alkyl-amino group, an N-alkenyl-amino group, or an N-alkynyl-amino group. , N-cycloalkyl-amino group, N-cycloalkyl-alkyl-amino group, N-aryl-amino group, N-aralkyl-amino group and the like.

Examples of the "N-alkyl-amino group" include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, Isopentylamino, (2-methylbutyl) amino, (1-methylbutyl) amino, neopentylamino, (1,2-dimethylpropyl) amino, (1-ethylpropyl) amino, n-hexylamino, (4- Methylpentyl) amino, (3-methylpentyl) amino, (2-methylpentyl) amino, (1-methylpentyl) amino, (3,3-dimethylbutyl) amino, (2,2-dimethylbutyl) amino, ( 1,1-dimethylbutyl) amino, (1,2-dimethylbutyl) amino, (1,3-dimethylbutyl) amino, (2,3-dimethylbutyl) amino, (2-ethylbutyl) amino, (1- Ethylbutyl) amino, (1-ethyl-1-methylpropyl) amino, n-heptylamino, n-octylamino, n-nonylamino, n-decylamino, n-undecylamino, n-dodecylamino, n -Tridecylamino, n-tetradecylamino, n-pentadede Such as amino-C ₁ ~ C ₁₅ linear or branched chain of shape N- alkyl-amino group may be mentioned.

Examples of the "N-alkenyl-amino group" include vinylamino, (propa-1-en-1-yl) amino, allylamino, isopropenylamino, (buta-1-en-1-yl) amino, (Buta-2-en-1-yl) amino, (buta-3-en-1-yl) amino, (2-methylpropa-2-en-1-yl) amino, (1-methylpropa- 2-en-1-yl) amino, (penta-1-en-1-yl) amino, (penta-2-en-1-yl) amino, (penta-3-en-1-yl) amino, ( Penta-4-en-1-yl) amino, (3-methylbuta-2-en-1-yl) amino, (3-methylbuta-3-en-1-yl) amino, (hexa-1-ene -1-yl) amino, (hexa-2-en-1-yl) amino, (hexa-3-en-1-yl) amino, (hexa-4-en-1-yl) amino, (hexa-5 -En-1-yl) amino, (4-methylpenta-3-en-1-yl) amino, (4-methylpenta-3-en-1-yl) amino, (hepta-1-en-1- Yl) amino, (hepta-6-en-1-yl) amino, (octa-1-en-1-yl) amino, (octa-7-en-1-yl) amino, (nona-1-ene- 1-yl) amino, (nona-8-en-1-yl) amino, (deca-1-en-1-yl) amino, (deca-9-en-1-yl) Amino, (undeca-1-en-1-yl) amino, (undec-10-en-1-yl) amino, (dodeca-1-en-1-yl) amino, (dodeca-11- En-1-yl) amino, (trideca-1-en-1-yl) amino, (trideca-12-en-1-yl) amino, (tetradeca-1-en-1-yl) amino, Straight chain of C ₂ to C ₁₅ such as (tetradeca-13-en-1-yl) amino, (pentadeca-1-en-1-yl) amino, (pentadeca-14-en-1-yl) amino Or a branched N-alkenyl-amino group.

As an "N-alkynyl-amino group", for example, ethynylamino, (propa-1-yn-1-yl) amino, (propa-2-yn-1-yl) amino, (buta-1-yne) -1-yl) amino, (buta-3-yn-1-yl) amino, (1-methylpropa-2-yn-1-yl) amino, (penta-1-yn-1-yl) amino, (Penta-4-yn-1-yl) amino, (hexa-1-yn-1-yl) amino, (hexa-5-yn-1-yl) amino, (hepta-1-yn-1-yl) Amino, (hepta-6-yn-1-yl) amino, (octa-1-yn-1-yl) amino, (octa-7-yn-1-yl) amino, (nona-1-yn-1- Yl) amino, (nona-8-yn-1-yl) amino, (deca-1-yn-1-yl) amino, (deca-9-yn-1-yl) amino, (undeca-1-yne -1-yl) amino, (undeca-10-yn-1-yl) amino, (dodeca-1-yn-1-yl) amino, (dodeca-11-yn-1-yl) amino, ( Trideca-1-yn-1-yl) amino, (trideca-12-yn-1-yl) amino, (tetradeca-1-yn-1-yl) amino, (tetradeca-13-yne-1 -yl) amino, (penta-deca-1-yl) amino, (14-a, such as penta-deca-1-yl) amino-C ₂ ~ C _And linear or branched N-alkynyl-amino groups of ₁₅ .

As the "N-cycloalkyl-amino group", for example, C ₃ to C ₈ N-cycloalkyl-amino groups such as cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino and cyclooctylamino Can be mentioned.

Examples of the "N-cycloalkyl-alkyl-amino group" include (cyclopropylmethyl) amino, (1-cyclopropylethyl) amino, (2-cyclopropylethyl) amino, (3-cyclopropylpropyl) amino, (4 -Cyclopropylbutyl) amino, (5-cyclopropylpentyl) amino, (6-cyclopropylhexyl) amino, (cyclobutylmethyl) amino, (cyclopentylmethyl) amino, (cyclobutylmethyl) amino, (cyclopentylmethyl ) Amino, (cyclohexylmethyl) amino, (2-cyclohexylethyl) amino, (3-cyclohexylpropyl) amino, (4-cyclohexylbutyl) amino, (cycloheptylmethyl) amino, (cyclooctylmethyl) amino And C ₄ to C ₁₄ N-cycloalkyl-alkyl-amino groups such as (6-cyclooctylhexyl) amino.

As the "N-aryl-amino group", for example, C ₆ to C ₁₄ N-mono such as phenylamino, 1-naphthylamino, 2-naphthylamino, anthrylamino, phenanthrylamino, acenaphthylenylamino, etc. -Arylamino group is mentioned.

Examples of the "N-aralkyl-amino group" include benzylamino, (1-naphthylmethyl) amino, (2-naphthylmethyl) amino, (anthracenylmethyl) amino, (phenanthrenylmethyl) amino, and (ace) Naphthylenylmethyl) amino, (diphenylmethyl) amino, (1-phenethyl) amino, (2-phenethyl) amino, (1- (1-naphthyl) ethyl) amino, (1- (2-naph Tyl) ethyl) amino, (2- (1-naphthyl) ethyl) amino, (2- (2-naphthyl) ethyl) amino, (3-phenylpropyl) amino, (3- (1-naphthyl) propyl ) Amino, (3- (2-naphthyl) propyl) amino, (4-phenylbutyl) amino, (4- (1-naphthyl) butyl) amino, (4- (2-naphthyl) butyl) amino, (5-phenylpentyl) amino, (5- (1-naphthyl) pentyl) amino, (5- (2-naphthyl) pentyl) amino, (6-phenylhexyl) amino, (6- (1-naphthyl) And C ₇ -C ₁₆ N-aralkyl-amino groups such as) hexyl) amino and (6- (2-naphthyl) hexyl) amino.

Examples of the "N, N-di (hydrocarbon) -amino group" include a group in which two hydrogen atoms in the "amino group" are substituted with a "hydrocarbon group". For example, N, N-dimethylamino, N, N-diethylamino , N-ethyl-N-methylamino, N, N-di-n-propylamino, N, N-diisopropylamino, N-allyl-N-methylamino, N- (propa-2-yn-1 -Yl) -N-methylamino, N, N-dicyclohexylamino, N-cyclohexyl-N-methylamino, N-cyclohexylmethylamino-N-methylamino, N, N-diphenylamino, N- And groups such as methyl-N-phenylamino, N, N-dibenzylamino and N-benzyl-N-methylamino.

Examples of the "N-heterocyclic-amino group" include groups in which one hydrogen atom in the "amino group" is substituted with a "heterocyclic group". Examples thereof include (3-pyrrolidinyl) amino, (4-piperidinyl) amino, (2-tetrahydropyranyl) amino, (3-indolinyl) amino, (4-chromenyl) amino, (3-thienyl) amino, (3-pyridyl) amino, (3-quinolyl) amino, Groups, such as (5-indolyl) amino, are mentioned.

Examples of the "N-hydrocarbon-N-heterocyclic-amino group" include groups in which two hydrogen atoms in the "amino group" are substituted one by one with a "hydrocarbon group" and a "heterocyclic group". For example, N-methyl-N- ( 4-piperidinyl) amino, N- (4-chromenyl) -N-methylamino, N-methyl-N- (3-thienyl) amino, N-methyl-N- (3-pyridyl) amino, And groups such as N-methyl-N- (3-quinolyl) amino.

Examples of the "acyl-amino group" include groups in which one hydrogen atom in the "amino group" is substituted with an "acyl group". For example, formylamino group, glyoxyloylamino group, thioformylamino group, carbamoylamino group, thio Carbamoylamino group, sulfamoylamino group, sulfinamoylamino group, carboxyamino group, sulfoamino group, phosphonoamino group and the following formula:

( ^Wherein R ^a4 and R ^b4 are the same or different and represent a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, or R ^a4 and R ^b4 become one and the nitrogen to which they are bonded And cyclic amino groups which may have a substituent together with an atom).

In the definition of said "acyl-amino group",

In the group represented by the formula (ω-1D), a group in which R ^a4 is a hydrocarbon group is referred to as a "hydrocarbon-carbonyl-amino group" and a group in which R ^a4 is a heterocyclic group.

In the group represented by the formula (ω-2D), a group in which R ^a4 is a hydrocarbon group is referred to as a "hydrocarbon-oxy-carbonyl-amino group" and a group in which R ^a4 is a heterocyclic group.

In the group represented by the formula (ω-3D), a group in which R ^a4 is a hydrocarbon group is a "hydrocarbon-carbonyl-carbonyl-amino group" group in which "hydrocarbon-carbonyl-carbonyl-amino group" and R ^a4 are heterocyclic groups It is called.

In the group represented by the formula (ω-4D), a group in which R ^a4 is a hydrocarbon group is a "hydrocarbon-oxy-carbonyl-carbonyl-amino group" and a group in which R ^a4 is a heterocyclic group is "heterocyclic-oxy-carbonyl-carbonyl -Amino group ".

In the group represented by the formula (ω-5D), a group in which R ^a4 is a hydrocarbon group is a "hydrocarbon-sulfanyl-carbonyl-amino group" and a group in which R ^a4 is a heterocyclic group is called a "heterocyclic-sulfanyl-carbonyl-amino group". It is called.

In the group represented by the formula (ω-6D), a group in which R ^a4 is a hydrocarbon group is referred to as a "hydrocarbon-thiocarbonyl-amino group" and a group in which R ^a4 is a heterocyclic group.

In the group represented by the formula (ω-7D), a group in which R ^a4 is a hydrocarbon group is a "hydrocarbon-oxy-thiocarbonyl-amino group" and a group in which R ^a4 is a heterocyclic group is called a "heterocyclic-oxy-thiocarbonyl-amino group". It is called.

In the group represented by the formula (ω-8D), a group in which R ^a4 is a hydrocarbon group is a "hydrocarbon-sulfanyl-thiocarbonyl-amino group", a group in which R ^a4 is a heterocyclic group is a "heterocyclic-sulfanyl-thiocarbonyl-amino group" It is called.

In the group represented by the formula (ω-9D), a group in which R ^a4 is a hydrocarbon group is referred to as a "N-hydrocarbon-carbamoyl group" and a group in which R ^a4 is a heterocyclic group is referred to as a "N-heterocyclic-carbamoyl-amino group".

In the group represented by the formula (ω-10D), a group in which R ^a4 and R ^b4 is a hydrocarbon group is represented by "N, N-di (hydrocarbon) -carbamoyl-amino group", and a group in which R ^a4 and R ^b4 are heterocyclic groups is "N , N-di (heterocyclic) -carbamoyl-amino group '', a group in which R ^a4 is a hydrocarbon group and R ^b4 is a heterocyclic group, "N-hydrocarbon-N-heterocyclic-carbamoyl-amino group", R ^a4 and A group in which R ^b4 becomes one and is a cyclic amino group together with the nitrogen atom to which they are bonded is called a "cyclic amino-carbonyl-amino group".

In the group represented by the formula (ω-11D), a group in which R ^a4 is a hydrocarbon group is a "N-hydrocarbon-thiocarbamoyl-amino group" and a group in which R ^a4 is a heterocyclic group is a "N-heterocyclic-thiocarbamoyl-amino group" It is called.

In the group represented by the formula (ω-12D), a group in which R ^a4 and R ^b4 is a hydrocarbon group is represented by "N, N-di (hydrocarbon) -thiocarbamoyl-amino group", and a group in which R ^a4 and R ^b4 are heterocyclic groups is " N, N-di (heterocyclic) -thiocarbamoyl-amino group ", a group in which R ^a4 is a hydrocarbon group and R ^b4 is a heterocyclic group" N-hydrocarbon-N-heterocyclic-thiocarbamoyl-amino group ", A group in which R ^a4 and R ^b4 become one and is a cyclic amino group together with the nitrogen atom to which they are bonded is referred to as "cyclic amino-thiocarbonyl-amino group".

In the group represented by the formula (ω-13D), a group in which R ^a4 is a hydrocarbon group is referred to as "N-hydrocarbon-sulfamoyl-amino group" and a group in which R ^a4 is a heterocyclic group is referred to as "N-heterocyclic-sulfamoyl-amino group".

In the group represented by the formula (ω-14D), a group in which R ^a4 and R ^b4 is a hydrocarbon group is a "di (hydrocarbon) sulfamoyl-amino group", and a group in which R ^a4 and R ^b4 is a heterocyclic group is "N, N-di (hetero) Ring) sulfamoyl-amino group ", R ^a4 is a hydrocarbon group, and R ^b4 is a heterocyclic group," N-hydrocarbon-N-heterocyclic-sulfamoyl-amino group ", R ^a4 and R ^b4 are one, and they are bonded The group which is a cyclic amino group with the nitrogen atom which exists is called "cyclic amino-sulfonyl-amino group."

In the group represented by the formula (ω-15D), a group in which R ^a4 is a hydrocarbon group is referred to as "N-hydrocarbon-sulfinamoyl-amino group" and a group in which R ^a4 is a heterocyclic group is referred to as "N-heterocyclic sulfinamoyl-amino group". It is called.

In the group represented by the formula (ω-16D), a group in which R ^a4 and R ^b4 is a hydrocarbon group is represented by "N, N-di (hydrocarbon) sulfinamoyl-amino group", and a group in which R ^a4 and R ^b4 is a heterocyclic group is represented by "N, N-di (heterocyclic) -sulfinamoyl-amino group ", wherein R ^a4 is a hydrocarbon group and R ^b4 is a heterocyclic group," N-hydrocarbon-N-heterocyclic-sulfinamoyl-amino group ", R ^a4 and R ^{The group which b4} becomes one and is a cyclic amino group with the nitrogen atom to which they couple | bond is called "cyclic amino-sulfinyl-amino group."

In the group represented by the formula (ω-17D), a group in which R ^a4 is a hydrocarbon group is referred to as a "hydrocarbon-oxy-sulfonyl-amino group" and a group in which R ^a4 is a heterocyclic group.

In the group represented by the formula (ω-18D), a group in which R ^a4 is a hydrocarbon group is referred to as a "hydrocarbon-oxy-sulfinyl-amino group" and a group in which R ^a4 is a heterocyclic group.

In the group represented by the formula (ω-19D), a group in which R ^a4 and R ^b4 is a hydrocarbon group is represented by "O, O'-di (hydrocarbon) -phosphono-amino group", and a group in which R ^a4 and R ^b4 are heterocyclic groups is "O" , O'-di (heterocyclic) -phosphono-amino group ", a group in which R ^a4 is a hydrocarbon group and R ^b4 is a heterocyclic group, is referred to as"O-hydrocarbon-O'-heterocyclic-phosphono-amino group ".

In the group represented by the formula (ω-20D), a group in which R ^a4 is a hydrocarbon group is referred to as a "hydrocarbon-sulfonyl-amino group" and a group in which R ^a4 is a heterocyclic group.

In the group represented by the formula (ω-21D), a group in which R ^a4 is a hydrocarbon group is referred to as a "hydrocarbon-sulfinyl-amino group" and a group in which R ^a4 is a heterocyclic group.

Examples of the "hydrocarbon" in the group represented by the formulas (ω-1D) to (ω-21D) include the same groups as those described above for the "hydrocarbon group". For example, as a "hydrocarbon-carbonyl-amino group" represented by the formula (ω-1D), an alkyl-carbonyl-amino group, an alkenyl-carbonyl-amino group, an alkynyl-carbonyl-amino group, cycloalkyl-carbonyl Aliphatic hydrocarbon-carbonyl-amino groups such as -amino group, cycloalkenyl-carbonyl-amino group, cycloalkanedienyl-carbonyl-amino group, and cycloalkyl-alkyl-carbonyl-amino group; Aryl-carbonyl-amino group; Aralkyl-carbonyl-amino groups; Cross-linked hydrocarbon-carbonyl-amino group; Spirocyclic hydrocarbon-carbonyl-amino groups; And terpene hydrocarbon-carbonyl-amino groups. Hereinafter, the airway shown by Formula (ω-2D)-Formula (ω-21D) is also the same.

Examples of the "heterocycle" in the group represented by the formulas (ω-1D) to (ω-21D) include the same groups as the above "heterocyclic group". For example, as the "heterocyclic-carbonyl-amino group" represented by the formula (ω-1D), for example, a monocyclic heteroaryl-carbonyl-amino group, a condensed polycyclic heteroaryl-carbonyl-amino group, or a monocyclic ratio Aromatic heterocyclic-carbonyl-amino group and a condensed polycyclic non-aromatic heterocyclic-carbonyl-amino group are mentioned. The same also applies to the formulas (ω-2D) to (ω-21D) below.

Examples of the "cyclic amino group" in the group represented by the formulas (ω-10D) to (ω-16D) include the same groups as the above-mentioned "cyclic amino group".

Examples of the "di (acyl) -amino group" include a group in which two hydrogen atoms in the "amino group" are substituted with an "acyl group" in the definition of the "substituent" in the "substituent" above. (Formyl) -amino group, di (glyoxyloyl) -amino group, di (thioformyl) -amino group, di (carbamoyl) -amino group, di (thiocarbamoyl) -amino group, di (sulfamoyl) -Amino group, di (sulfinamoyl) -amino group, di (carboxy) -amino group, di (sulfo) -amino group, di (phosphono) -amino group and the following formula:

(Wherein, R ^a5 and R ^b5 are the same or different and represent a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent, or R ^a5 and R ^b5 become one and combine And a cyclic amino group which may have a substituent together with the nitrogen atom in question.

In the definition of said "di (acyl) -amino group",

In the group represented by the formula (ω-1E), a group in which R ^a5 is a hydrocarbon group is referred to as a "bis (hydrocarbon-carbonyl) -amino group" and a group in which R ^a5 is a heterocyclic group is called a "bis (heterocyclic-carbonyl) -amino group". .

In the group represented by the formula (ω-2E), a group in which R ^a5 is a hydrocarbon group is a "bis (hydrocarbon-oxy-carbonyl) -amino group" and a group in which R ^a5 is a heterocyclic group is "bis (heterocyclic-oxy-carbonyl)- Amino group ”.

In the group represented by the formula (ω-3E), a group in which R ^a5 is a hydrocarbon group is a "bis (hydrocarbon-carbonyl-carbonyl) -amino group", and a group in which R ^a5 is a heterocyclic group is "bis (heterocyclic-carbonyl-carbonyl) ) -Amino group ”.

In the group represented by the formula (ω-4E), a group in which R ^a5 is a hydrocarbon group is a "bis (hydrocarbon-oxy-carbonyl-carbonyl) -amino group" and a group in which R ^a5 is a heterocyclic group is "bis (heterocyclic-oxy-car) Carbonyl-carbonyl) -amino group ”.

In the group represented by the formula (ω-5E), a group in which R ^a5 is a hydrocarbon group is a "bis (hydrocarbon-sulfanyl-carbonyl) -amino group" and a group in which R ^a5 is a heterocyclic group is "bis (heterocyclic-sulfanyl-carbonyl) ) -Amino group ”.

In the group represented by the formula (ω-6E), a group in which R ^a5 is a hydrocarbon group is a "bis (hydrocarbon-thiocarbonyl) -amino group", and a group in which R ^a5 is a heterocyclic group is "bis (heterocyclic-thiocarbonyl) -amino group" It is called.

In the group represented by the formula (ω-7E), a group in which R ^a5 is a hydrocarbon group is a "bis (hydrocarbon-oxy-thiocarbonyl) -amino group" and a group in which R ^a5 is a heterocyclic group is selected from a group of "bis (heterocyclic-oxy-thiocarbonyl). ) -Amino group ”.

In the group represented by the formula (ω-8E), a group in which R ^a5 is a hydrocarbon group is a "bis (hydrocarbon-sulfanyl-thiocarbonyl) -amino group" and a group in which R ^a5 is a heterocyclic group is "bis (heterocyclic-sulfanyl-thio) Carbonyl) -amino group ”.

In the group represented by the formula (ω-9E), a group in which R ^a5 is a hydrocarbon group is a "bis (N-hydrocarbon-carbamoyl) -amino group" and a group in which R ^a5 is a heterocyclic group is "bis (N-heterocyclic-carbamoyl). ) -Amino group ”.

The group represented by the formula (ω-10E) is a group in which R ^a5 and R ^b5 are hydrocarbon groups such as "bis [N, N-di (hydrocarbon) -carbamoyl] -amino group" and R ^a5 and R ^b5 are heterocyclic groups. "Bis (N, N-di (heterocyclic) -carbamoyl] -amino group", a group in which R ^a5 is a hydrocarbon group and R ^b5 is a heterocyclic group is selected from "bis (N-hydrocarbon-N-heterocyclic-carbamoyl) ) ^-Amino group ", R <^a5> and R <^b5> become one, and group which is a cyclic amino group with the nitrogen atom which they couple is called" bis (cyclic amino-carbonyl) -amino group. "

In the group represented by the formula (ω-11E), a group in which R ^a5 is a hydrocarbon group is a "bis (N-hydrocarbon-thiocarbamoyl) -amino group" and a group in which R ^a5 is a heterocyclic group is "bis (N-heterocyclic-thiocar) Barmoyl) -amino group ”.

In the group represented by the formula (ω-12E), a group in which R ^a5 and R ^b5 is a hydrocarbon group is a "bis [N, N-di (hydrocarbon) -thiocarbamoyl] -amino group", and R ^a5 and R ^b5 are heterocyclic groups. Group is a "bis [N, N-di (heterocyclic) -thiocarbamoyl] -amino group", a group in which R ^a5 is a hydrocarbon group and R ^b5 is a heterocyclic group is selected from "bis (N-hydrocarbon-N-heterocyclic-thio) Carbamoyl) -amino group ", R ^a5 and R ^b5 become one and group which is a cyclic amino group with the nitrogen atom to which they couple | bond is called" bis (cyclic amino- thiocarbonyl) -amino group. "

In the group represented by the formula (ω-13E), a group in which R ^a5 is a hydrocarbon group is a "bis (N-hydrocarbon-sulfamoyl) -amino group" and a group in which R ^a5 is a heterocyclic group is "bis (N-heterocyclic-sulfamoyl)- Amino group ”.

In the group represented by the formula (ω-14E), a group in which R ^a5 and R ^b5 is a hydrocarbon group is a "bis [N, N-di (hydrocarbon) -sulfamoyl] -amino group" group and a group in which R ^a5 and R ^b5 are heterocyclic groups is " A bis [N, N-di (heterocyclic) -sulfamoyl] -amino group, a group in which R ^a5 is a hydrocarbon group and R ^b5 is a heterocyclic group, represents a "bis (N-hydrocarbon-N-heterocyclic-sulfamoyl) -amino group And a group in which R ^a5 and R ^b5 become one and are a cyclic amino group together with the nitrogen atom to which they are bonded are referred to as a "bis (cyclic amino-sulfonyl) -amino group".

In the group represented by the formula (ω-15E), a group in which R ^a5 is a hydrocarbon group is a "bis (N-hydrocarbon-sulfinamoyl) -amino group", and a group in which R ^a5 is a heterocyclic group is "bis (N-heterocyclic-sulfamomoyl). ) -Amino group ”.

The group represented by the formula (ω-16E) is a group in which R ^a5 and R ^b5 are hydrocarbon groups, a group of "bis [N, N-di (hydrocarbon) -sulfinamoyl] -amino group", and R ^a5 and R ^b5 are heterocyclic groups. "Bis (N, N-di (heterocycle) -sulfinamoyl] -amino group", a group in which R ^a5 is a hydrocarbon group and R ^b5 is a heterocyclic group, is selected from "bis (N-hydrocarbon-N-heterocyclic-sulfinamoyl) ) ^-Amino group ", R <^a5> and R <^b5> become one, and group which is a cyclic amino group with the nitrogen atom to which they couple is called" bis (cyclic amino-sulfinyl) -amino group. "

In the group represented by the formula (ω-17E), a group in which R ^a5 is a hydrocarbon group is a "bis (hydrocarbon-oxy-sulfonyl) -amino group" and a group in which R ^a5 is a heterocyclic group is "bis (N-heterocyclic-oxy-sulfonyl) ) -Amino group ”.

In the group represented by the formula (ω-18E), a group in which R ^a5 is a hydrocarbon group is a "bis (hydrocarbon-oxy-sulfinyl) -amino group" and a group in which R ^a5 is a heterocyclic group is "bis (heterocyclic-oxy-sulfinyl)- Amino group ”.

A group represented by the formula (ω-19E), wherein a group in which R ^a5 and R ^b5 is a hydrocarbon group is a "bis [O, O'-di (hydrocarbon) -phosphono] -amino group" group and a group in which R ^a5 and R ^b5 are heterocyclic groups "Bis (O, O'-di (heterocyclic) -phosphono] -amino group", a group in which R ^a5 is a hydrocarbon group and R ^b5 is a heterocyclic group is selected from "bis (O-hydrocarbon-O'-heterocyclic-phosphono) ) -Amino group ”.

In the group represented by the formula (ω-20E), a group in which R ^a5 is a hydrocarbon group is referred to as a "bis (hydrocarbon-sulfonyl) -amino group" and a group in which R ^a5 is a heterocyclic group is referred to as a "bis (heterocyclic-sulfonyl) -amino group". .

In the group represented by the formula (ω-21E), a group in which R ^a5 is a hydrocarbon group is referred to as a "bis (hydrocarbon-sulfinyl) -amino group" and a group in which R ^a5 is a heterocyclic group is called a "bis (heterocyclic-sulfinyl) -amino group". .

Examples of the "hydrocarbon" in the group represented by the formulas (ω-1E) to (ω-21E) include the same groups as those described above for the "hydrocarbon group". For example, as a "bis (hydrocarbon-carbonyl) -amino group" represented by the formula (ω-1E), a bis (alkyl-carbonyl) -amino group, a bis (alkenyl-carbonyl) -amino group, and a bis (alkynyl) -Carbonyl) -amino group, bis (cycloalkyl-carbonyl) -amino group, bis (cycloalkenyl-carbonyl) -amino group, bis (cycloalkanedienyl-carbonyl) -amino group, bis (cycloalkyl-alkyl- Bis (aliphatic hydrocarbon-carbonyl) -amino groups such as carbonyl) -amino group; Bis (aryl-carbonyl) -amino group; Bis (aralkyl-carbonyl) -amino group; Bis (cross-substituted hydrocarbon-carbonyl) -amino group; Bis (spirocyclic hydrocarbon-carbonyl) -amino group; And bis (terpene hydrocarbon-carbonyl) -amino groups. Hereinafter, the airway represented by Formula (ω-2E)-Formula (ω-21E) is also the same.

Examples of the "heterocycle" in the group represented by the formulas (ω-1E) to (ω-21E) include the same groups as the above "heterocyclic groups". For example, as a "bis (heterocyclic-carbonyl) -amino group" represented by a formula (ω-1E), for example, a bis (monocyclic heteroaryl-carbonyl) -amino group and a bis (condensed polycyclic heteroaryl) -Carbonyl) -amino group, bis (monocyclic non-aromatic heterocyclic-carbonyl) -amino group, and bis (condensed polycyclic non-aromatic heterocyclic-carbonyl) -amino group. The same also applies to the formulas (ω-2E) to (ω-21E) below.

Examples of the "cyclic amino group" in the group represented by the formulas (ω-10E) to (ω-16E) include the same groups as those of the "cyclic amino group".

Said "acyl-amino group" and "di (acyl) -amino group" are collectively called "acyl substituted amino group." In addition, said "N-hydrocarbon-amino group", "N, N-di (hydrocarbon) -amino group", "N-heterocyclic-amino group", "N-hydrocarbon-N-heterocyclic-amino group", "cyclic amino group" "" Acyl-amino group "and" di (acyl) -amino group "are collectively referred to as" substituted amino group ".

Hereinafter, the compound represented by the formula (I) will be described in detail.

In the above formula (I), A may be a hydrogen atom or an acetyl group, and is preferably a hydrogen atom.

In the definition of the ring Z, in addition to the group represented by the formula "OA (wherein A is the same as defined above) and formula -CONH-E (wherein E is the same as defined above), a substituent is further added. Examples of the "arene" of the arene which may have a monocyclic or condensed polycyclic aromatic hydrocarbon include a benzene ring, a naphthalene ring, anthracene ring, phenanthrene ring, acenaphthylene ring and the like. It is suitably C ₆ -C ₁₀ arene, such as a benzene ring and a naphthalene ring, More preferably, it is a benzene ring and a naphthalene ring, Most preferably, it is a benzene ring.

In addition to the group represented by the formula "OA (wherein A is the same as defined above) and formula -CONH-E (wherein E is the same as defined above) in the definition of the ring Z, a substituent is further provided. Examples of the "substituent" of the arene which may have a group include the same group as the "substituent" in the definition of the "substituted device". The substitution position on the arene of the substituent is not particularly limited. In addition, when two or more said substituents exist, they may be same or different.

In addition to the group represented by the formula "OA (wherein A is the same as defined above) and formula -CONH-E (wherein E is the same as defined above) in the definition of the ring Z, a substituent is further provided. In addition to the group represented by the formula "OA (wherein A is the same as defined above) and the formula -CONH-E (wherein E is the same as defined above), In the case of the benzene ring you may have, the group represented by the formula -OA (wherein A is the same as defined above) and the formula -CONH-E (wherein E is the same as defined above) is preferred. In addition, a benzene ring having 1 to 3 substituents '', and more preferably, "Formula -A (wherein A is the same as defined above) and Formula -CONH-E (wherein E is as defined above and Benzene ring having one substituent in addition to the group represented by the same). In this case, the substituent is preferably a group selected from the following "substituent group γ-1z", more preferably a halogen atom and a tert-butyl group [(1,1-dimethyl) ethyl group], most preferably It is a halogen atom.

[Substituent Group γ-1z] Halogen atom, nitro group, cyano group, hydroxy group, methoxy group, methyl group, isopropyl group, tert-butyl group, 1,1,3,3-tetramethylbutyl group, 2-phenylethene -1-yl group, 2,2-dicyanoethen-1-yl group, 2-cyano-2- (methoxycarbonyl) ethen-1-yl group, 2-carboxy-2-cyanoethen-1- Diary, ethynyl group, phenylethynyl group, (trimethylsilyl) ethynyl group, trifluoromethyl group, pentafluoroethyl group, phenyl group, 4- (trifluoromethyl) phenyl group, 4-fluorophenyl group, 2,4-di Fluorophenyl group, 2-phenethyl group, 1-hydroxydiethyl group, 1- (methoxyimino) ethyl group, 1-[(benzyloxy) imino] ethyl group, 2-thienyl group [thiophen-2-yl group], 3-thienyl group [thiophen-3-yl group], 1-pyrrolyl group [pyrrole-1-yl group], 2-methylthiazol-4-yl group, imidazo [1,2-a] pyridin-2-yl group, 2-pyridyl group [pyridin-2-yl group], acetyl group, isobutyryl group, piperidinocarbonyl group, 4-benzyl piperidinocarbonyl group, (pyrrole -1-yl) sulfonyl group, carboxyl group, methoxycarbonyl group, N- [3,5-bis (trifluoromethyl) phenyl] carbamoyl group, N, N-dimethylcarbamoyl group, sulfamoyl group, N- [ 3,5-bis (trifluoromethyl) phenyl] sulfamoyl group, N, N-dimethylsulfamoyl group, amino group, N, N-dimethylamino group, acetylamino group, benzoylamino group, methanesulfonylamino group, benzenesulfonylamino group , 3-phenyl ureido group, (3-phenyl) thio ureido group, (4-nitrophenyl) diagenyl group, {[4- (pyridin-2-yl) sulfamoyl] phenyl} diagenyl group

In addition to the group represented by the formula "OA (wherein A is the same as defined above) and formula -CONH-E (wherein E is the same as defined above) in the definition of the ring Z, a substituent is further provided. In addition to the group represented by the formula "OA (wherein A is the same as defined above) and the formula -CONH-E (wherein E is the same as defined above), In the case of the benzene ring which may have ”, the following partial structural formula (Iz-1) containing one substituent and containing ring Z in formula (I):

The following formula Iz-2:

It is most preferably present in the position of R ^z, if represented by. At this time, the substituent may be defined as R ^z . R ^z is preferably a group selected from the following "substituent group γ-2z", more preferably a halogen atom and a tert-butyl group, and most preferably a halogen atom.

[Substituent Group γ-2z] Halogen atom, nitro group, cyano group, methoxy group, methyl group, isopropyl group, tert-butyl group, 1,1,3,3-tetramethylbutyl group, 2-phenylethene-1 -Group, 2,2-dicyanoethen-1-yl group, 2-cyano-2- (methoxycarbonyl) ethen-1-yl group, 2-carboxy-2-cyanoethen-1-yl group, Ethynyl group, phenylethynyl group, (trimethylsilyl) ethynyl group, trifluoromethyl group, pentafluoroethyl group, phenyl group, 4- (trifluoromethyl) phenyl group, 4-fluorophenyl group, 2,4-difluoro Phenyl group, 2-phenethyl group, 1-hydroxyethyl group, 1- (methoxyimino) ethyl group, 1-[(benzyloxy) imino] ethyl group, 2-thienyl group, 3-thienyl group, 1-pyrrolyl group, 2 -Methylthiazol-4-yl group, imidazo [1,2-a] pyridin-2-yl group, 2-pyridyl group, acetyl group, isobutyryl group, piperidinocarbonyl group, 4-benzylpiperidinocarbonyl group, ( Pyrrole-1-yl) sulfonyl group, carboxyl group, methoxycarbonyl group, N- [3,5-bis (trifluoro) Butyl) phenyl] carbamoyl group, N, N-dimethylcarbamoyl group, sulfamoyl group, N- [3,5-bis (trifluoromethyl) phenyl] sulfamoyl group, N, N-dimethylsulfamoyl group, Amino group, N, N-dimethylamino group, acetylamino group, benzoylamino group, methanesulfonylamino group, benzenesulfonylamino group, 3-phenylureido group, (3-phenyl) thioureido group, (4-nitrophenyl) diagenyl group , {[4- (pyridin-2-yl) sulfamoyl] phenyl} diagenyl group

In addition to the group represented by the formula "OA (wherein A is the same as defined above) and formula -CONH-E (wherein E is the same as defined above) in the definition of Z, a substituent is further provided. Arene which may have a substituent in addition to the group represented by the formula "OA (wherein A is the same as defined above) and formula -CONH-E (wherein E is the same as defined above). Naphthalene ring ”, the naphthalene ring is preferable.

In addition to the group represented by the formula "OA (wherein A is the same as defined above) and formula -CONH-E (wherein E is the same as defined above) in the definition of Z, a substituent is further provided. As the "heteroarene" of "heteroarene which may have," monocyclic or condensation containing at least one heteroatom selected from oxygen, sulfur and nitrogen atoms as an atom (ring atom) constituting a ring system Examples of the polycyclic aromatic heterocycle include, for example, furan ring, thiophene ring, pyrrole ring, oxazol ring, isoxazole ring, thiazole ring, isothiazol ring, imidazole ring, pyrazole ring, 1 , 2,3-oxadiazole ring, 1,2,3-thiadiazol ring, 1,2,3-triazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, 1,2,3 Triazine ring, 1,2,4-triazine ring, 1H-azepine ring, 1,4-oxepin ring, 1,4-thiazepine ring, benzofuran Ring, isobenzofuran ring, benzo [b] thiophene ring, benzo [c] thiophene ring, indole ring, 2H-isoindole ring, 1H-indazole ring, 2H-indazole ring, benzoxazole ring, 1 , 2-benzoisoxazole ring, 2,1-benzoisoxazole ring, benzothiazole ring, 1,2-benzoisothiazole ring, 2,1-benzoisothiazole ring, 1,2,3-benzooxa Diazole ring, 2,1,3-benzooxadiazole ring, 1,2,3-benzothiadiazole ring, 2,1,3-benzothiadiazole ring, 1H-benzotriazole ring, 2H-benzo Triazole ring, quinoline ring, isoquinoline ring, cinnoline ring, quinazoline ring, quinoxaline ring, phthalazine ring, naphthyridine ring, 1H-1,5-benzodiazepine ring, carbazole ring, α-carboline ( carboline ring, β-carboline ring, γ-carboline ring, acridine ring, phenoxazine ring, phenothiazine ring, phenazine ring, phenanthridine ring , Phenanthroline And 5 to 14 membered monocyclic or condensed polycyclic aromatic heterocycles such as ring, thianthrene ring, indolizine ring, and phenoxathiine ring. Suitably a 5-10 membered monocyclic or condensed polycyclic aromatic heterocycle, more preferably a thiophene ring, a pyridine ring, an indole ring and a quinoxaline ring.

In addition to the group represented by the formula "OA (wherein A is the same as defined above) and formula -CONH-E (wherein E is the same as defined above) in the definition of the ring Z, a substituent is further provided. Examples of the "substituent" of "heteroarene" which may have a group similar to the "substituent" in the definition of said "substituent may be mentioned". The position of substitution on the heteroarene of the substituent is not particularly limited. In addition, when two or more said substituents exist, they may be same or different.

In addition to the group represented by the formula "OA (wherein A is the same as defined above) and formula -CONH-E (wherein E is the same as defined above) in the definition of the ring Z, a substituent is further provided. As a "substituent" of "heteroarene which may have," it is preferably a halogen atom.

Examples of the "substituent" of the "2,5-disubstituted phenyl group" in the definition of E include the same group as the "substituent" in the definition of the "substituent" above.

As a specific example of the suitable group of the "2, 5- di-substituted phenyl group" in the definition of said E, group shown by the following "substituent group δ-1e" is mentioned.

[Substituent group δ-1e] 2,5-dimethoxyphenyl group, 2-chloro-5- (trifluoromethyl) phenyl group, 2,5-bis (trifluoromethyl) phenyl group, 2-fluoro-5- ( Trifluoromethyl) phenyl group, 2-nitro-5- (trifluoromethyl) phenyl group, 2-methyl-5- (trifluoromethyl) phenyl group, 2-methoxy-5- (trifluoromethyl) phenyl group, 2-methylsulfanyl-5- (trifluoromethyl) phenyl group, 2- (1-pyrrolidinyl) -5- (trifluoromethyl) phenyl group, 2-morpholino-5- (trifluoromethyl) Phenyl group, 2,5-dichlorophenyl group, 2,5-bis [(1,1-dimethyl) ethyl] phenyl group, 5-[(1,1-dimethyl) ethyl] -2-methoxyphenyl group, 4-methoxybiphenyl -3-yl group, 2-bromo-5- (trifluoromethyl) phenyl group, 2- (2-naphthyloxy) -5- (trifluoromethyl) phenyl group, 2- (2,4-dichlorophenoxy ) -5- (trifluoromethyl) phenyl group, 2- [4- (trifluoromethyl) piperidin-1-yl] -5- (trifluoromethyl) phenyl group, 2- (2,2,2 -Trifluoroethoxy) -5- (triflu Romethyl) phenyl group, 2- (2-methoxyphenoxy) -5- (trifluoromethyl) phenyl group, 2- (4-chloro-3,5-dimethylphenoxy) -5- (trifluoromethyl) Phenyl group, 2-piperidino-5- (trifluoromethyl) phenyl group, 2- (4-methylphenoxy) -5- (trifluoromethyl) phenyl group, 2- (4-chlorophenoxy) -5- (Trifluoromethyl) phenyl group, 5-isopropyl-2-methylphenyl group, 2,5-diethoxyphenyl group, 2,5-dimethylphenyl group, 5-chloro-2-cyano group, 5-diethylsulfamoyl-2 -Methoxyphenyl group, 2-chloro-5-nitrophenyl group, 2-methoxy-5- (phenylcarbamoyl) phenyl group, 5-acetylamino-2-methoxyphenyl group, 5-methoxy-2-methylphenyl group, 2,5-dibutoxyphenyl group, 2,5-diisopentyloxy group, 5-carbamoyl-2-methoxyphenyl group, 5-[(1,1-dimethyl) propyl] -2-phenoxyphenyl group, 2 -Hexyloxy-5-methanesulfonyl, 5- (2,2-dimethylpropionyl) -2-methylphenyl group, 5-methoxy-2- (1-pyrrolyl) phenyl group, 5-chloro-2- ( p-toluenesulfonyl) phenyl group, 2-chloro-5- (p- Toluenesulfonyl) phenyl group, 2-fluoro-5-methanesulfonyl group, 2-methoxy-5-phenoxy group, 2-methoxy-5- (1-methyl-1-phenylethyl) phenyl group, 5-morpholi No-2-nitrophenyl group, 5-fluoro-2- (1-imidazolyl) phenyl group, 2-butyl-5-nitrophenyl group, 5-[(1,1-dimethyl) propyl] -2-hydroxyphenyl group , 2-methoxy-5-methylphenyl group, 2,5-difluorophenyl group, 2-benzoyl-5-methylphenyl group, 2- (4-cyanophenoxy) -5- (trifluoromethyl) phenyl group, 2- (4-methoxyphenoxy) -5- (trifluoromethyl) phenyl group

As "2,5-disubstituted phenyl" in the definition of E, more preferably "2,5-disubstituted phenyl group (where at least one of the substituents is a trifluoromethyl group)", in particular More preferably, it is group selected from the following "substituent group δ-2e", Most preferably, it is a 2, 5-bis (trifluoromethyl) phenyl group.

[Substituent group δ-2e] 2-Chloro-5- (trifluoromethyl) phenyl group, 2,5-bis (trifluoromethyl) phenyl group, 2-fluoro-5- (trifluoromethyl) phenyl group, 2 -Nitro-5- (trifluoromethyl) phenyl group, 2-methyl-5- (trifluoromethyl) phenyl group, 2-methoxy-5- (trifluoromethyl) phenyl group, 2-methylsulfanyl-5- (Trifluoromethyl) phenyl group, 2- (1-pyrrolidinyl) -5- (trifluoromethyl) phenyl group, 2-morpholino-5- (trifluoromethyl) phenyl group, 2-bromo-5 -(Trifluoromethyl) phenyl group, 2- (2-naphthyloxy) -5- (trifluoromethyl) phenyl group, 2- (2,4-dichlorophenoxy) -5- (trifluoromethyl) phenyl group , 2- [4- (trifluoromethyl) piperidin-1-yl] -5- (trifluoromethyl) phenyl group, 2- (2,2,2-trifluoroethoxy) -5- ( Trifluoromethyl) phenyl group, 2- (2-methoxyphenoxy) -5- (trifluoromethyl) phenyl group, 2- (4-chloro-3,5-dimethylphenoxy) -5- (trifluoro Methyl) phenyl group, 2-piperi No-5- (trifluoromethyl) phenyl group, 2- (4-methylphenoxy) -5- (trifluoromethyl) phenyl group, 2- (4-chlorophenoxy) -5- (trifluoromethyl) Phenyl group, 2- (4-cyanophenoxy) -5- (trifluoromethyl) phenyl group, 2- (4-methoxyphenoxy) -5- (trifluoromethyl) phenyl group

Examples of the "substituent" of the "3,5-disubstituted phenyl group" in the definition of E include the same group as the "substituent" in the definition of the "substituent group".

As a specific example of the suitable group of "3, 5- di-substituted phenyl group" in the definition of said E, group shown by the following "substituent group δ-3e" is mentioned.

[Substituent group δ-3e] 3,5-bis (trifluoromethyl) phenyl group, 3,5-dichlorophenyl group, 3,5-bis [(1,1-dimethyl) ethyl] phenyl group, 3-fluoro-5 -(Trifluoromethyl) phenyl group, 3-bromo-5- (trifluoromethyl) phenyl group, 3-methoxy-5- (trifluoromethyl) phenyl group, 3,5-difluorophenyl group, 3, 5-dinitrophenyl group, 3,5-dimethylphenyl group, 3,5-dimethoxyphenyl group, 3,5-bis (methoxycarbonyl) phenyl group, 3-methoxycarbonyl-5- (trifluoromethyl) phenyl group , 3-carboxy-5- (trifluoromethyl) phenyl group, 3,5-dicarboxyphenyl group

As the "3,5-disubstituted phenyl group" in the definition of E, more preferably "3,5-disubstituted phenyl group (where at least one of the substituents is a trifluoromethyl group)", in particular More preferably, it is group selected from the following "substituent group delta-4e", Most preferably, it is a 3, 5-bis (trifluoromethyl) phenyl group.

[Substituent group δ-4e] 3,5-bis (trifluoromethyl) phenyl group, 3-fluoro-5- (trifluoromethyl) phenyl group, 3-bromo-5- (trifluoromethyl) phenyl group, 3-methoxy-5- (trifluoromethyl) phenyl group, 3-methoxycarbonyl-5- (trifluoromethyl) phenyl group, 3-carboxy-5- (trifluoromethyl) phenyl group

"A monocyclic or condensed polycyclic heteroaryl group which may have a substituent," in the definition of E, provided that the ring in which said heteroaryl group is directly linked to the -CONH- group in (I) is a benzene ring; (Except for "unsubstituted thiazol-2-yl group and ③ unsubstituted benzothiazol-2-yl group)") "substituent" in the definition of "you may have a substituent" above And the same group as ". The position of substitution on the heteroaryl group of the substituent is not particularly limited. In addition, when two or more said substituents exist, they may be same or different.

As a "monocyclic heteroaryl group" of the "monocyclic or condensed polycyclic heteroaryl group which may have a substituent" in the definition of E, "monocyclic heteroaryl group" in the definition of the "heterocyclic group" The same group as can be mentioned.

As a "condensed polycyclic heteroaryl group" of the "monocyclic or condensed polycyclic heteroaryl group which may have a substituent" in the definition of E, "condensed polycyclic heteroaryl" in the definition of "heterocyclic group" Group "can be mentioned.

As the "monocyclic or condensed polycyclic heteroaryl group which may have a substituent" in the definition of E above, (1) A condensed polycyclic heteroaryl group in which the ring directly connected to the -CONH- group in formula (I) is a benzene ring, and (2) unsubstituted. The thiazol-2-yl group and (3) unsubstituted benzothiazol-2-yl group are excluded.

As the "monocyclic or condensed polycyclic heteroaryl group" of the "monocyclic or condensed polycyclic heteroaryl group which may have a substituent" in the definition of E is preferably a 5- to 10-membered monocyclic or condensed group. A cyclic heteroaryl group, and specific examples of suitable groups at this time include thiazolyl group, thienyl group, pyrazolyl group, oxazolyl group, 1,3,4-thiadiazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group and Quinolyl group.

As the "monocyclic or condensed polycyclic heteroaryl group" of the "monocyclic or condensed polycyclic heteroaryl group which may have a substituent" in the definition of E is more preferably a 5-membered monocyclic heteroaryl group. More particularly, thiazolyl group, thienyl group, pyrazolyl group, oxazolyl group and 1,3,4-thiadiazolyl group, most preferably thiazolyl group.

Here, as the "monocyclic or condensed polycyclic heteroaryl group which may have a substituent" in the definition of E, since "unsubstituted thiazol-2-yl group is excluded", said "substituent group Monocyclic or condensed polycyclic heteroaryl groups which may be used &quot; are most preferably substituted thiazolyl groups.

When the "monocyclic or condensed polycyclic heteroaryl group which may have a substituent" in the definition of E is a "substituted thiazolyl group", "mono-substituted thiazol-2-yl group" and "disubstituted" are preferable. Thiazol-2-yl group ”, and more preferably a“ disubstituted thiazol-2-yl group ”.

When the "monocyclic or condensed polycyclic heteroaryl group which may have a substituent" in the definition of E is a "disubstituted thiazol-2-yl group", the following "substituent group δ-5e" is more particularly suitable. Group, and most preferably 4-[(1,1-dimethyl) ethyl] -5-[(2,2-dimethyl) propionyl] thiazol-2-yl group.

[Substituent Group δ-5e] 5-Bromo-4-[(1,1-dimethyl) ethyl] thiazol-2-yl group, 5-bromo-4- (trifluoromethyl) thiazol-2-yl group , 5-cyano-4-[(1,1-dimethyl) ethyl] thiazol-2-yl group, 5-methylthiazol-2-yl group, 4,5-dimethylthiazol-2-yl group, 5-methyl 4-phenylthiazol-2-yl group, 5- (4-fluorophenyl) -4-methylthiazol-2-yl group, 4-methyl-5- [3- (trifluoromethyl) phenyl] thiazole -2-yl group, 4-[(1,1-dimethyl) ethyl] -5-ethylthiazol-2-yl group, 4-ethyl-5-phenylthiazol-2-yl group, 4-isopropyl-5-phenyl Thiazol-2-yl group, 4-butyl-5-phenylthiazol-2-yl group, 4-[(1,1-dimethyl) ethyl] -5-[(2,2-dimethyl) propionyl] thiazole- 2-yl group, 4-[(1,1-dimethyl) ethyl] -5- (ethoxycarbonyl) thiazol-2-yl group, 4-[(1,1-dimethyl) ethyl] -5-piperidino Thiazol-2-yl group, 4-[(1,1-dimethyl) ethyl] -5-morpholinothiazol-2-yl group, 4-[(1,1-dimethyl) ethyl] -5- (4-methyl Piperazin-1-yl) thiazol-2-yl group, 4-[(1,1-dimethyl) ethyl] -5- (4-phenylpiperazin-1-yl) thi Zol-2-yl, 5-carboxymethyl-4-phenylthiazol-2-yl, 4,5-diphenylthiazol-2-yl, 4-benzyl-5-phenylthiazol-2-yl, 5- Phenyl-4- (trifluoromethyl) thiazol-2-yl group, 5-acetyl-4-phenylthiazol-2-yl group, 5-benzoyl-4-phenylthiazol-2-yl group, 5-ethoxycar Bonyl-4-phenylthiazol-2-yl group, 5-ethoxycarbonyl-4- (pentafluorophenyl) thiazol-2-yl group, 5-methylcarbamoyl-4-phenylthiazol-2-yl group , 5-ethylcarbamoyl-4-phenylthiazol-2-yl group, 5-isopropylcarbamoyl-4-phenylthiazol-2-yl group, 5- (2-phenylethyl) carbamoyl-4- Phenylthiazol-2-yl group, 5-ethoxycarbonyl-4- (trifluoromethyl) thiazol-2-yl group, 5-carboxy-4-[(1,1-dimethyl) ethyl] thiazole-2 -Yl group, 5- (ethoxycarbonyl) methyl-4-phenylthiazol-2-yl group, 5-carboxy-4-phenylthiazol-2-yl group, 5-propylcarbamoyl-4-phenylthiazole- 2-diary

When the "monocyclic or condensed polycyclic heteroaryl group which may have a substituent" in the definition of E is a "mono-substituted thiazol-2-yl group", specific examples of the suitable group include the following "substituent group δ-6e" The group shown to is mentioned.

[Substituent group δ-6e] 4-[(1,1-dimethyl) ethyl] thiazol-2-yl group, 4-phenylthiazol-2-yl group, 4- [3,5-bis (trifluoromethyl) Phenyl] thiazol-2-yl group, 4- (2,4-dichlorophenyl) thiazol-2-yl group, 4- (3,4-dichlorophenyl) thiazol-2-yl group, 4- [4- (tri Fluoromethyl) phenyl] thiazol-2-yl group, 4- (2,5-difluorophenyl) thiazol-2-yl group, 4- (4-methoxyphenyl) thiazol-2-yl group, 4- [3- (trifluoromethyl) phenyl] thiazol-2-yl group, 4- (pentafluorophenyl) thiazol-2-yl group

As a compound represented by the said Formula (I), it is suitably a compound other than "substituted benzoic acid derivative represented by following formula (X-1)".

Wherein R ¹⁰⁰¹ is represented by the formula

Or Formula X-3:

(Wherein, R ¹⁰⁰³ , R ¹⁰⁰⁴ and R ¹⁰⁰⁵ are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, and R ¹⁰⁰⁹ and R ¹⁰¹⁰ are each independently a hydrogen atom, having 1 to C atoms An alkyl group of 6 or an acyl group having 2 to 11 carbon atoms;

R ¹⁰⁰² is a hydrogen atom, a lower alkyl group of 1 to 6 carbon atoms that may be substituted, an aryl group of 6 to 12 carbon atoms that may be substituted, a heteroaryl group of 4 to 11 carbon atoms that may be substituted, or a carbon number of 7 to 11 that may be substituted An aralkyl group of 14 or a heteroarylalkyl group of 5 to 13 carbon atoms which may be substituted, or an acyl group of 2 to 11 carbon atoms;

X ¹⁰⁰¹ represents a carboxyl group which may be esterified or amidated.)

The compound represented by Formula I may form a salt. Pharmacologically acceptable salts include acid salts, for example, metal salts such as lithium salts, sodium salts, potassium salts, magnesium salts and calcium salts, or ammonium salts, methylammonium salts, dimethylammonium salts, trimethylammonium salts and dicyclohexyl Ammonium salts such as ammonium salts, and when a basic group is present, for example, inorganic salts such as hydrochloride, bromate, sulfate, nitrate, phosphate, or methanesulfonate, benzenesulfonate, paratoluenesulfonate, acetate, propionate Organic salts such as tartarate, fumarate, maleate, malate, oxalate, succinate, citrate, benzoate, mandelic acid salt, cinnamon acid salt, and lactate salts. In some cases, salts are formed with amino acids such as glycine. As the active ingredient of the medicament of the present invention, pharmaceutically acceptable salts can also be suitably used.

The compound represented by the said general formula (I) or its salt may exist as a hydrate or a solvate. As the active ingredient of the medicament of the present invention, any of the above substances may be used. Furthermore, the compound represented by the formula (I) may have one or more subsidiary carbons, and may exist as stereoisomers such as an optically active substance and a diastereomer. As an active ingredient of the medicament of the present invention, any mixture of pure stereoisomers, enantiomers or diastereomers, racemates and the like may be used.

In addition, when the compound represented by general formula (I) has a 2-hydroxypyridine structure, for example, it exists as a 2-pyridone structure which is the tautomer. As an active ingredient of the medicament of the present invention, tautomers or mixtures thereof in pure form may be used. In addition, when the compound represented by general formula (I) has an olefinic double bond, the batch may be either a Z batch or an E batch, and as an active ingredient of the pharmaceutical of the present invention, any batch of geometric isomers or mixtures thereof may be used. You may also

Although the compound contained in General formula (I) as an active ingredient of the medicine of this invention is illustrated below, the active ingredient of the medicine of this invention is not limited to the following compound.

In addition, the meaning of the abbreviation used in the following table | surface is as follows.

Me: methyl group, Et: ethyl group

The compound represented by general formula (I) can be manufactured, for example by the method shown by the following reaction process formulas.

<Reaction Process Formula>

(Wherein A, rings Z and E are the same as defined in formula (I), and A ¹⁰¹ represents a hydrogen atom or a protecting group of a hydroxy group (preferably, an alkyl group such as methyl group; an aralkyl group such as benzyl group; acetyl group; Alkoxyalkyl groups such as methoxymethyl group; substituted silyl groups such as trimethylsilyl group), R and R ¹⁰¹ represent a hydrogen atom, an alkyl group of C ₁ to C ₆ , etc., and E ¹⁰¹ represents E in the definition of formula (I). Or a precursor of E, G represents a hydroxy group, a halogen atom (preferably a chlorine atom), a hydrocarbon-oxy group (preferably an aryl-oxy group which may be substituted with a halogen atom), an acyl-oxy group, an imide-jade Indicates the time, etc.)

(First process)

By dehydrating and condensing the carboxylic acid derivative (1) and the amine (2), the amide (3) can be produced. This reaction is carried out at a reaction temperature of 0 ° C to 180 ° C in the presence of an acid halogenating agent or a dehydrating condensing agent, in the presence or absence of a base, and in a solvent-free or aprotic solvent.

This reaction is carried out at a reaction temperature of 0 ° C to 180 ° C in the presence of an acid halogenating agent or a dehydrating condensing agent, in the presence or absence of a base, and in a solvent-free or aprotic solvent.

Examples of the acid halogenating agent include thionyl chloride, thionyl bromide, sulfuryl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, and the like, when A ¹⁰¹ is a hydrogen atom; When ^A101 is an acetyl group etc., phosphorus oxychloride is preferable. Examples of the dehydrating condensing agent include N, N'-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, diphenylphosphoryl azide and the like. Examples of the base include inorganic bases such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate, or organic bases such as pyridine, triethylamine and N, N-diethylaniline. As an aprotic solvent, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, 1,4-dioxane, benzene, toluene, monochlorobenzene, o-dichlorobenzene, N, N-dimethylformamide, N-methylpyrroli Toluene, monochlorobenzene, and o-dichlorobenzene are especially preferable when reacting in presence of an acid halogenating agent.

In addition, for example, by the method described in "Journal of Medicinal Chemistry", (US), 1998, Vol. 41, No. 16, p.2939-2945, and methods similar thereto. it is also possible to manufacture, was isolated (單離) an acid chloride from a pre-carboxylic acid, it was then prepared for the purpose of the amide by reaction with an amine having a E ^101.

As suitable reaction conditions when G is a hydroxy group, for example, the reaction described in "Archiv der Pharmazie", (Germany), 1998, Vol. 331, No. 1, p.3-6. Conditions can be used.

The kind of carboxylic acid derivative (1) and amine (2) is not specifically limited, It can synthesize | combine novelly with reference to a well-known manufacturing method suitably, or can obtain a commercial reagent, and can use for the said reaction.

(Second process)

When the amide (3) has a protecting group and / or has a substituent (e.g., an amino group and its protecting or precursor; carboxyl group and its protecting or precursor; hydroxy group and its protecting or precursor, etc.) advantageous for functional group modification. In this step, a deprotection reaction and / or a functional group modification reaction can be carried out to produce compound (4) as the final target. The reaction can use various known methods, and examples of deprotection reactions and functional group modification reactions are Theodora W. Green and Peter GM Wuts. Protected Groups in Organic Syntheses, (US), 3rd Edition, John Wiley & Sons, Inc., April 1999; Methods described in Handbook of Reagents for Organic Synthesis, USA, Vol. 4, John Wiley & Sons, Inc., June 1999, etc. of; Examples of functional group modification reactions include, for example, Richard F. Heck, Palladium Reagents in Organic Syntheses, USA, Academic Press, 1985; J. Tsuji, Palladium Reagents and Catalysts: Innovations in Organic Synthesis, USA, John Wiley & Inks Sons, Inc., 1999, etc. can be used.

The compound represented by the formula (I) prepared by the above method can be isolated and purified by methods well known to those skilled in the art, for example, extraction, precipitation, fraction chromatography, fractional crystallization, suspension washing, recrystallization, and the like. In addition, pharmacologically acceptable salts of the compounds of the present invention, their hydrates and solvates can also be prepared by methods well known to those skilled in the art, respectively.

In the examples herein, a method for preparing a representative compound included in Formula (I) is described in detail. Therefore, those skilled in the art can select appropriate reaction raw materials, reaction reagents and reaction conditions while referring to the description of the above general production methods and the specific production methods of the examples, and modify the formulas or modifications appropriate to these methods as necessary. By addition, all the compounds contained in general formula (I) can be manufactured.

The compound represented by the formula (I) has an activation inhibitory effect on both NF-κB and AP-1, so that the medicine for the prevention and / or treatment of Alzheimer's disease, or the medicine for the prevention and / or treatment of epilepsy Used as a component. In the present specification, the prevention and / or treatment of Alzheimer's disease should be interpreted most broadly, including inhibition of accumulation of Aβ, inhibition of neuronal cell death, inhibition of brain atrophy, inhibition of neuronal fiber change and dementia improvement, and the like. It should not be interpreted in a limited sense in any sense. In addition, in the present specification, the prevention and / or treatment of epilepsy is an epileptic seizure inhibitory action such as tonic seizure seizure, absence seizure, myoclonic seizure, and the like. It should be interpreted in the broadest sense, including the effect of inhibiting abnormal excitability of neurons in the cerebrum and nerve cell death in the hippocampus, and should not be interpreted in any limited way.

In addition, recent studies have shown that GSK3β (glycogen synthase kinase-3 beta) plays an important role in neurological diseases represented by Alzheimer's disease, Parkinson's disease, and Huntington's disease. It is suggested that the inhibitor of β may be a therapeutic drug for these diseases. Compound (4 μM) of compound No. 4 of the present invention increased the amount of phosphorylated GSK3β phosphorylated by GSK3β after 24 hours of action on MOLT-4F cells (human leukemia cells), and it is sufficient that the same phenomenon occurs in neurons. It is estimated. Since GSK3β is inactivated by phosphorylation, since an increase in the amount of phosphorylated GSK3β is considered to mean substantially inhibition of GSK3β, these results also indicate that the compounds of the present invention are effective in Alzheimer's disease, Parkinson's disease and Huntington's disease. It suggests that it is effective as a therapeutic drug (The Biochemical Journal, (UK), 2001, Vol. 359, No. PT1, p.1-16; "Current Opinion in Neurobiology (Current"). Opinion in Neurobiology '', (UK), 2002, Vol. 12, No. 3, p.275-278; Trends in Molecular Medicine, (UK), 2002, 1st Vol. 8, No. 3, p.126-132; Proceedings of The National Academy of Sciences of The United States of America, (USA , 1996, Vol. 93, No. 7, p.2719-2723; `` The National The Journal of Biological Chemistry, (US), 2002, Vol. 277, No. 44, p.42060-42065; Proceedings of the National Academy of Sciences of the United States Proceedings of The National Academy of Sciences of The United States of America, (USA), 2003, Vol. 100, No. 2, p.721-726; Analys of the New York Academy of Sciences (Annals of The New York Academy of Sciences), (US), 2000, Vol. 920, p.107-114; Nature, England, 2003, Vol. 423, 6938. , p.435-439; See Neuron, United States, 2003, Vol. 38, No. 4, p.555-565.). Furthermore, GSK3β is known to be inhibited by lithium, and it is already known that there is an antipressant action against lithium. If the antidepressant action of lithium is caused by the inhibition of GSK3β, the compound of the present invention can be used as an antidepressant.

As the active ingredient of the medicament of the present invention, one or two or more kinds of substances selected from the group consisting of the compounds represented by the formula (I) and their pharmacologically acceptable salts, their hydrates and their solvates can be used. Although the above-mentioned substance itself may be used as the medicament of the present invention, the medicament of the present invention is suitably provided in the form of a pharmaceutical composition containing the above-mentioned substance as an active ingredient and one or more pharmaceutically acceptable additives for the preparation. . In the said pharmaceutical composition, the ratio of the active ingredient with respect to the additive for formulation is about 1 weight%-about 90 weight%.

The pharmaceutical of the present invention may be administered, for example, as a pharmaceutical composition for oral administration such as granules, fine granules, powders, light capsules, lead capsules, syrups, emulsions, suspensions or solutions. Intravenous, intramuscular or subcutaneous injections, drops, suppositories, transdermal absorbents, transmucosal absorbents, nasal drops, ear drops, eye drops, inhalants, etc. It is also possible to administer. When using the preparation prepared as a pharmaceutical composition in powder form, it may be dissolved and used as an injection or drop. In the preparation of the pharmaceutical composition, additives for the preparation of solids or liquids may be used. The additive for preparation may be either organic or inorganic. In other words, in the preparation of oral solid preparations, excipients, additives, disintegrating agents, lubricants, coloring agents, colloids, and the like are added to the main medicine, and then tablets, coating tablets, granules, and powders are prepared in a general manner. , A capsule or the like can be prepared. Examples of the excipients to be used include lactose, sucrose, white sugar, glucose, corn starch, starch, talc, sorbet, crystalline cellulose, dextrin, kaolin, calcium carbonate, silicon dioxide and the like. Examples of the binder include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, calcium citrate, Dextrin, pectin, and the like. Examples of the lubricant include magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil, and the like. As a coloring agent, if it is normally permitted to add to a pharmaceutical, all can be used. Cocoa powder, peppermint brain, aromatic acid, peppermint oil, dragon brain, cinnamon powder, etc. can be used as a mating agent. These tablets and granules can be appropriately coated according to sugar, gelatin coating and other needs. Moreover, preservatives, antioxidants, etc. can be added as needed.

Inert diluents commonly used in the preparation of liquid preparations for oral administration, such as emulsions, syrups, suspensions, solutions, may be used, for example water or vegetable oils. In addition to the inert diluent, this preparation may be formulated with an adjuvant such as a wetting agent, suspending aid, sweetener, fragrance, colorant or preservative. After the liquid formulation is prepared, it may be filled into a capsule of absorbable material such as gelatin.

As a solvent or suspending agent used for preparation of a parenteral administration agent, for example, an injection or suppository, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin can be mentioned. As a base used for manufacture of a suppository, a cacao butter, an emulsified cacao butter, a laurin butter, and a witezol are mentioned, for example. The preparation method of the formulation is not particularly limited, and any method commonly used in the art can be used.

In the case of injectable preparations, for example, diluents such as water, ethylene alcohol, macrogol, propylene glycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid and sodium hydroxide; PH adjusters and buffers such as sodium citrate, sodium acetate and sodium phosphate; Stabilizers, such as sodium pyrosulfite, ethylenediamine tetraacetic acid, thioglycolic acid, and thio lactic acid, etc. can be used. In this case, in order to prepare an isotonic solution, a sufficient amount of salt, glucose, mannitol, or glycerin may be blended in the preparation, or a conventional dissolution aid, analgesic agent, or local anesthetic may be used. Do.

In the case of ointments such as pastes, creams, and gels, bases, stabilizers, wetting agents, preservatives, and the like, which are commonly used, can be blended as necessary, and the components can be mixed and formulated by a general method. As the base, for example, white petrolatum, polyethylene, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like can be used. Methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoic acid, etc. can be used as a preservative. When it is set as the form of a patch, the said ointment, cream, gel, paste, etc. can be apply | coated to a normal support body by a general method. Examples of the support include a woven or nonwoven fabric made of cotton, staple fibers and chemical fibers; Films or foam sheets such as soft vinyl chloride, polyethylene, and polyurethane can be suitably used.

The dosage of the medicament of the present invention is not particularly limited, but in the case of oral administration, it is usually 0.01 to 5,000 mg as the weight of the substance as an active ingredient per adult. It is preferable to appropriately increase or decrease this dosage depending on the age, condition and symptoms of the patient. The daily dose may be administered once or in two or three times a day at appropriate intervals or may be administered intermittently at intervals of several days. When used as an injection, the weight of the substance as an active ingredient per adult is about 0.001 to 100 mg.

Hereinafter, although an Example demonstrates this invention further more concretely, the scope of the present invention is not limited to the following Example. In an Example, a compound number corresponds to the number of the compound shown in the said table | surface. In addition, the present Example includes the compound which purchased a commercial reagent and provided for the test as it is. For such compounds, the code numbers listed in the salesman and catalog of the reagents are shown.

Example 1: Preparation of Compound of Compound No. 1

To a solution of O-acetylsalicyloyl chloride (345 mg, 1.7 mmol) in benzene (10 mL) under ice-cooling and argon atmosphere, 3,5-bis (trifluoromethyl) aniline (500 mg, 2.2 mmol) ), Pyridine (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain the title compound. A white solid (570 mg, 84.2%) was obtained.

Example 2: Preparation of Compound of Compound No. 2

To a solution of 2-acetoxy-N- [3,5-bis (trifluoromethyl) phenyl] benzamide (Compound No. 1; 100 mg, 0.25 mmol) in ethanol (5 mL), dilute sodium hydroxide aqueous solution (0.5) mL, 1 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from n-hexane / ethyl acetate to give the title compound as a white solid (40 mg, 45.1%). Got it.

Example 3: Preparation of Compound of Compound No. 3

5-fluorosalicylic acid (156 mg, 1 mmol), 3,5-bis (trifluoromethyl) aniline (229 mg, 1 mmol), phosphorus trichloride (44 μL, 0.5 mmol), monochlorobenzene (5 mL) The mixture was heated to reflux for 3 hours under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed sequentially with water and brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane). : Ethyl acetate = 6: 1) afforded the title compound as a white solid (215 mg, 58.7%).

When the method of Example 3 is cited in the following examples, phosphorus trichloride was used as the acid halogenating agent. As the reaction solvent, solvents such as monochlorobenzene and toluene were used.

Example 4: Preparation of Compound No. 4

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 85.5%

Example 5: Preparation of Compound No. 5

Tetrahydro of N- [3,5-bis (trifluoromethyl) phenyl] -5-chloro-2-hydroxybenzamide (Compound No. 4; 1.51 g, 3 mmol), pyridine (285 mg, 3.6 mmol) To furan (6 mL) solution, acetyl chloride (234 mg, 3.3 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, 2N hydrochloric acid was added to the obtained residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from n-hexane / ethyl acetate to obtain the title compound as a white solid (1.06 g, 83.0%). Got.

When the method of Example 5 is cited in the following examples, organic bases, such as pyridine and triethylamine, were used as a base. As the reaction solvent, solvents such as dichloromethane, tetrahydrofuran and benzene were used.

Example 6: Preparation of Compound No. 6

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 88.5%

This compound was obtained also by the following manufacturing method.

To a solution of carbon tetrachloride (8 mL) of 2-acetoxy-N- [3,5-bis (trifluoromethyl)] benzamide (Compound No. 1; 100 mg, 0.25 mmol), iron (30 mg, 0.54 mmol) Bromine (0.02 mL, 0.39 mmol) was added, followed by stirring at 50 ° C. for 4 hours. The reaction mixture was cooled to room temperature and poured into NaHSO ₄ water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain the title compound as a white solid (600 mg, 54.9%).

Example 7: Preparation of compound of compound No. 7

The title compound was obtained in the same manner as the Example 3 using 5-iodine salicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 62.2%

Example 8: Preparation of Compound No. 8

The title compound was obtained in the same manner as the Example 3 using 5-nitrosalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 57.2%

Example 9: Preparation of Compound No. 9

(1) 2-benzyloxy-5-formyl benzoic acid benzyl ester

A mixture of 5-formylsalicylic acid (4.98 g, 30 mmol), benzyl bromide (15.39 g, 90 mmol), potassium carbonate (16.59 g, 120 mmol) and methyl ethyl ketone (350 mL) was heated to reflux for 8 hours. After cooling, the solvent was distilled off under reduced pressure, 2N hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. It was washed with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1), and the residue was washed with heating under reflux with isopropyl ether to give the title compound as a white solid (5.98 g, 57.5%). )

(2) 2-benzyloxy-5-cyanobenzoic acid benzyl ester

A mixture of 2-benzyloxy-5-formylbenzoic acid benzyl ester (693 mg, 2 mmol), hydroxylamine hydrochloride (167 mg, 2.4 mmol) and N-methylpyrrolidone (3 mL) was added at 115 ° C. for 4 hours. Stirred. After cooling the reaction mixture, 2N hydrochloric acid (5 mL) and water (30 mL) were added, followed by extraction with ethyl acetate. The organic layer was washed with 2N aqueous sodium hydroxide solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was suspended and washed with isopropyl ether under heating under reflux to obtain the title compound as a white solid (527 mg, 76.7%).

(3) 5-cyanosalicylic acid

2-benzyloxy-5-cyanobenzoic acid benzyl ester (446 mg, 1.3 mmol) and 5% palladium-carbon (45 mg) were added to ethanol (10 mL) and tetrahydrofuran (10 mL), followed by hydrogen at room temperature for 2 hours. Added. After filtering off the insolubles, the solvent was distilled off under reduced pressure to obtain the title compound as a white solid (212 mg, 100.0%).

(4) N- [3,5-bis (trifluoromethyl) phenyl] -5-cyano-2-hydroxybenzamide (Compound No. 9)

The title compound was obtained in the same manner as the Example 3 using 5-cyanosalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 16.6%

Example 10: Preparation of the compound of Compound No. 10

The title compound was obtained in the same manner as the Example 3 using 5-methylsalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 54.9%

Example 11: Preparation of compound of Compound No. 11

(1) 5-[(1,1-dimethyl) ethyl] salicylic acid

To a solution of 5-[(1,1-dimethyl) ethyl] -2-hydroxybenzaldehyde (2.15 g, 12.1 mmol) in 1,4-dioxane (100 mL), water (40 mL), sulfamic acid (1.76 g) 18.1 mmol) and monosodium phosphate (7.33 g, 47 mmol) were added. An aqueous solution of sodium chlorite (1.76 g, 15.5 mmol) (10 mL) was added dropwise to the mixture under ice cooling, followed by stirring for 1 hour. Sodium sulfite (1.80 g, 14.3 mmol) was added to the mixture, followed by stirring for 30 minutes. Concentrated hydrochloric acid was added to the reaction mixture to pH 1. The residue obtained by distilling off 1,4-dioxane under reduced pressure was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was suspended and washed with n-hexane to obtain a white powder (1.81 g, 77.4%) as a title compound.

(2) N- [3,5-bis (trifluoromethyl) phenyl] -5-[(1,1-dimethyl) ethyl] -2-hydroxybenzamide (Compound No. 11)

The title compound was obtained in the same manner as the Example 3 using 5-[(1,1-dimethyl) ethyl] salicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 53.8%

Example 12: Preparation of the compound of Compound No. 12

(1) 5-acetyl-2-benzyloxybenzoic acid methyl ester

A mixture of 5-acetylsalicylic acid methyl ester (13.59 g, 70 mmol), benzyl bromide (17.96 g, 105 mmol), potassium carbonate (19.35 g, 140 mmol) and methyl ethyl ketone (350 mL) was heated to reflux for 8 hours. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure, 2N hydrochloric acid was added to the obtained residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from isopropyl ether to obtain a white solid (14.20 g, 71.4%) as a title compound.

(2) 5-acetyl-2-benzyloxybenzoic acid

To a methanol / tetrahydrofuran (20 mL + 20 mL) mixed solution of 5-acetyl-2-benzyloxybenzoic acid methyl ester (5.69 g, 20 mmol) was added 2 N sodium hydroxide (11 mL) and stirred for 8 hours. The solvent was distilled off under reduced pressure, 2N hydrochloric acid was added to the obtained residue, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was washed with isopropyl ether to obtain a white solid (4.92 g, 91.0%) as a title compound.

(3) 5-acetyl-2-benzyloxy-N- [3,5-bis (trifluoromethyl) phenyl] benzamide

5-acetyl-2-benzyloxybenzoic acid (4.87 g, 18 mmol), 3,5-bis (trifluoromethyl) aniline (4.54 g, 19.8 mmol), pyridine (5.70 g, 72 mmol) tetrahydrofuran / Phosphorous oxychloride (1.85 mL, 19.8 mmol) was added to the dichloromethane (72 mL + 36 mL) mixed solution under ice-cooling, followed by stirring at room temperature for 12 hours. The solvent was distilled off under reduced pressure, 1N hydrochloric acid (100 mL) was added to the obtained residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1-&gt; 2: 1). Purification gave a slightly yellow solid (5.47 g, 63.1%) as the title compound.

When the manufacturing method of Example 12 (3) is cited in the following Examples, phosphorus oxychloride was used as an acid halogenating agent. Pyridine was used as the base. In addition, as a reaction solvent, solvents, such as dichloromethane and tetrahydrofuran, were used individually or in mixture.

(4) 5-acetyl-N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxybenzamide (Compound No. 12)

5-acetyl-2-benzyloxy-N- [3,5-bis (trifluoromethyl) phenyl] benzamide (602 mg, 1.25 mmol), ethanol (6 mL) in 5% palladium carbon (60 mg), Tetrahydrofuran (72 mL) was added and stirred for 30 minutes at room temperature under hydrogen atmosphere. After filtering off the insoluble matter, the solvent was distilled off under reduced pressure and the obtained residue was recrystallized from n-hexane / ethyl acetate to obtain the title compound as a white solid (230 mg, 47.0%).

Example 13: Preparation of compound of Compound No. 13

Sodium borohydride in an ethanol (2 mL) suspension of 5-acetyl-N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxybenzamide (Compound No. 12; 50.5 mg, 0.13 mmol) (23.6 mg, 0.62 mmol) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was suspended and washed with isopropyl ether / n-hexane to give the title compound as a white powder (39.7 mg, 78.3%). Got it.

Example 14: Preparation of the compound of Compound No. 14

To a solution of 5-acetyl-N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxybenzamide (Compound No. 12; 100.0 mg, 0.26 mmol) in ethanol (3 mL), pyridine (45 μL, 0.56 mmol) and O-methylhydroxylamine hydrochloride (25.8 mg, 0.31 mmol) were added and heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, poured into diluted hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain the title compound, white crystals. (102.1 mg, 95.3%).

Example 15: Preparation of the compound of Compound No. 15

Operation similar to Example 14 using 5-acetyl-N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxybenzamide (Compound No. 12) and O-benzylhydroxylamine hydrochloride as raw materials To give the title compound.

Yield: 79.9%

Example 16: Preparation of Compound No. 16

(1) 5- (2,2-dicyanoethen-1-yl) -2-hydroxybenzoic acid

5-formylsalicylic acid (332 mg, 2 mmol) was added to a solution of malononitrile (132 mg, 2 mmol) in ethanol (6 mL), and benzylamine (0.1 mL) was added under ice cooling, followed by stirring at room temperature for 2 hours. . The precipitated yellow crystals were collected by filtration and recrystallized from ethanol to obtain the title compound as a pale yellow solid (139.9 mg, 32.7%).

(2) N- [3,5-bis (trifluoromethyl) phenyl] -5- (2,2-dicyanoethen-1-yl) -2-hydroxybenzamide (Compound No. 16)

The title compound was obtained in the same manner as the Example 3 using 5- (2,2-dicyanoethen-1-yl) -2-hydroxybenzoic acid and 3,5-bis (trifluoromethyl) aniline as starting materials. Got it.

Yield: 9.1%

Example 17: Preparation of the compound of Compound No. 17

(1) 5-[(2-cyano-2-methoxycarbonyl) ethen-1-yl] -2-hydroxybenzoic acid

A mixture of 5-formylsalicylic acid (332 mg, 2 mmol), cyanoacetic acid methyl ester (198 mg, 2 mmol), acetic acid (6 mL) and triethylamine (0.2 ml) was heated to reflux for 5 hours. The reaction mixture was cooled to room temperature, poured into water, and the precipitated crystals were collected by filtration and recrystallized from n-hexane to obtain a pale yellow solid (327.7 mg, 66.3%) as a title compound.

(2) 3-({N- [3,5-bis (trifluoromethyl) phenyl] carbamoyl} -4-hydroxyphenyl) -2-cyanoacrylic acid methyl ester (Compound No. 17)

The same as Example 3 using 5-[(2-cyano-2-methoxycarbonyl) ethen-1-yl] -2-hydroxybenzoic acid and 3,5-bis (trifluoromethyl) aniline as starting materials The operation was carried out to obtain the title compound.

Yield: 66.3%

Example 18: Preparation of the compound of Compound No. 18

3-({N- [3,5-bis (trifluoromethyl) phenyl] carbamoyl} -4-hydroxyphenyl) -2-cyanoacrylic acid methyl ester (Compound No. 17; 50 mg, 0.11 mmol) Sodium hydroxide (0.11 ml, 0.22 mmol) was added to the ethanol (5 mL) solution, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethyl acetate to obtain a pale yellow solid (13.5 mg, 30.4%) as a title compound.

Example 19: Preparation of the compound of Compound No. 19

N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-5-iodinebenzamide (Compound No. 7; 475 mg, 1 mmol), styrene (130 mg, 1.25 mmol), palladium acetate (4.5 mg, 0.02 mmol), a mixture of tris (ortho-tolyl) phosphine (12.2 mg, 0.04 mmol), diisopropylamine (388 mg, 3 mmol), N, N-dimethylformamide (2 mL) It was heated to reflux for 8 hours. After cooling the reaction mixture to room temperature, water was added, followed by extraction with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: isopropyl ether = 2: 1-1: 1). Purified with to give the title compound as a pale yellow solid (173 mg, 38.3%).

Example 20: Preparation of the compound of Compound No. 20

N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-5-iodinebenzamide (Compound No. 7; 950 mg, 2 mmol), trimethylsilylacetylene (246 mg, 2.5 mmol), To an N, N-dimethylformamide (4 mL) solution of triethylamine (2 mL), tetrakis (triphenylphosphine) palladium (23 mg, 0.02 mmol), cuprous iodide (4 mg, 0.02 mmol) was added and stirred at 40 ° C for 2 hours. The reaction mixture was cooled to room temperature, poured into ethyl acetate (100 mL) and 1N citric acid (100 mL) and stirred, followed by celite filtration. The ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (n-hexane: ethyl acetate = 19: 1), and n Crystallization with -hexane gave the title compound as white crystals (286 mg, 32.1%).

Example 21: Preparation of the compound of Compound No. 21

N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-5-[(trimethylsilyl) ethynyl] benzamide (Compound No. 20; 233 mg, 0.5 mmol) in methanol (1 mL 2) Sodium hydroxide (1 mL) was added to the solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethanol / water to obtain an off-white crystal (67 mg, 35.9%) as a title compound.

Example 22: Preparation of the compound of Compound No. 22

The title compound was obtained in the same manner as the Example 20 using N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-5-iodinebenzamide (Compound No. 7) and phenylacetylene as starting materials. Got it.

Yield: 40.8%

Example 23: Preparation of the compound of Compound No. 23

1,2-dimethoxyethane (3 mL) of N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-5-iodinebenzamide (Compound No. 7; 200 mg, 0.42 mmol) To the solution, tetrakis (triphenylphosphine) palladium (16 mg, 0.0014 mmol) was added under argon atmosphere, followed by stirring at room temperature for 5 minutes. Dihydroxyphenylborane (57 mg, 0.47 mmol) and 1 mol / L aqueous sodium carbonate solution (1.3 mL) were then added and heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, poured into diluted hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 6: 1-&gt; 3: 1). To give the title compound white crystals (109 mg, 61.1%).

Example 24: Preparation of the compound of Compound No. 24

The same operation as in Example 12 (4) was carried out using N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-5- (phenylethynyl) benzamide (Compound No. 22) as a starting material. To give the title compound.

Yield: 86.2%

Example 25: Preparation of the compound of Compound No. 25

The title compound was obtained in the same manner as the Example 3 using 2-hydroxy-5- (trifluoromethyl) benzoic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 44.7%

[2-Hydroxy-5- (trifluoromethyl) benzoic acid: "Chemical & Pharmaceutical Bulletin", 1996, Vol. 44, No. 4, p.734- 745 references]

Example 26: Preparation of the compound of Compound No. 26

The title compound was obtained in the same manner as the Example 3 using 2-hydroxy-5- (pentafluoroethyl) benzoic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 65.7%

[2-Hydroxy-5- (pentafluoroethyl) benzoic acid: "Chemical & Pharmaceutical Bulletin", 1996, Vol. 44, No. 4, p.734- 745 references]

Example 27: Preparation of the compound of Compound No. 27

The title compound was obtained in the same manner as the Example 3 using 2-hydroxy-5- (pyrrole-1-yl) benzoic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 57.8%

Example 28: Preparation of the compound of Compound No. 28

The same operation as in Example 23 was carried out using N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-5-iodinebenzamide (Compound No. 7) and 2-thiophenboronic acid as starting materials. To give the title compound.

Yield: 44.4%

Example 29: Preparation of the compound of Compound No. 29

The same procedure as in Example 23 was carried out using N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-5-iodinebenzamide (Compound No. 7) and 3-thiophenboronic acid as starting materials. To give the title compound.

Yield: 38.7%

Example 30: Preparation of the compound of Compound No. 30

(1) 2-benzyloxy-5- (2-bromoacetyl) -N- [3,5-bis (trifluoromethyl) phenyl] benzamide

Tetrahydrofuran (30 ml) of 5-acetyl-2-benzyloxy-N- [3,5-bis (trifluoromethyl) phenyl] benzamide (compound of Example 12 (3); 4.81 g, 10 mmol) Phenyltrimethylammonium tribromide (3.75 g, 10 mmol) was added to the solution, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with an aqueous sodium hydrogen sulfite solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and then the residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 4: 1). Purified by ethyl acetate and recrystallized from ethyl acetate / n-hexane to give the title compound as a white solid (2.39 g, 42.7%).

(2) 2-benzyloxy-N- [3,5-bis (trifluoromethyl) phenyl] -5- (2-methylthiazol-4-yl) benzamide

2-benzyloxy-5- (2-bromoacetyl) -N- [3,5-bis (trifluoromethyl) phenyl] benzamide (280 mg, 0.5 mmol), thioacetamide (41 mg, 0.55 mmol ), A mixture of sodium bicarbonate (50 mg, 0.60 mmol) and ethanol (15 mL) was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, poured into water, neutralized with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain the title compound. Phosphorus white solid (181 mg, 67.5%) was obtained.

(3) N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-5- (2-methylthiazol4-yl) benzamide (Compound No. 30)

2-benzyloxy-N- [3,5-bis (trifluoromethyl) phenyl] -5- (2-methylthiazol4-yl) benzamide (160 mg, 0.3 mmol), 10% palladium-carbon ( Ethanol (10 ml) was added to 240 mg), and the mixture was stirred for 3.5 hours under a hydrogen atmosphere. The reaction mixture was filtered and the solvent was distilled off under reduced pressure to obtain the title compound as a white solid (103.4 mg, 79.2%).

Example 31: Preparation of the compound of Compound No. 31

2-benzyloxy-5- (2-bromoacetyl) -N- [3,5-bis (trifluoromethyl) phenyl] benzamide (compound of Example 12 (3); 280 mg, 0.5 mmol), 2 A mixture of aminopyridine (51.8 mg, 0.55 mmol), sodium bicarbonate (50 mg, 0.6 mmol) and ethanol (10 mL) was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, poured into an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 2) to give a white solid. (130.3 mg) was obtained. Then a mixture of this solid (108 mg, 0.19 mmol), 10% palladium-carbon (11 mg), ethanol (8 mL) and ethyl acetate (8 mL) was stirred under hydrogen atmosphere for 7 hours. The reaction mixture was filtered, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 3) to obtain a white solid (18.3 mg, 20.2%) as a title compound.

Example 32: Preparation of the compound of Compound No. 32

(1) N- [3,5-bis (trifluoromethyl) phenyl] -5-iodine-2-methoxymethoxybenzamide

N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-5-iodinebenzamide (Compound No. 7; 4.75 g, 10 mmol), chloromethylmethyl ether (1.14 ml, 15 mmol) A mixture of potassium carbonate (2.76 g, 20 mmol) and acetone (50 mL) was heated to reflux for 8 hours. The reaction mixture was cooled to room temperature, poured into diluted hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1), and n Recrystallization from -hexane / ethyl acetate gave the title compound as a white solid (3.96 g, 76.3%).

(2) N- [3,5-bis (trifluoromethyl) phenyl] -2-methoxymethoxy-5- (pyridin-2-yl) benzamide

To a solution of N- [3,5-bis (trifluoromethyl) phenyl] -5-iodine-2-methoxymethoxybenzamide (0.20 g, 0.39 mmol) in N, N-dimethylformamide (8 ml) , Tri-n-butyl (2-pyridyl) tin (0.13 ml, 0.41 mmol) and dichlorobis (triphenylphosphine) palladium (32.1 mg, 0.05 mmol) were added thereto, followed by stirring at 100 ° C for 1.5 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1-&gt; 1: 1). The white compound (37.9 mg, 20.8%) was obtained as the title compound.

(3) N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-5- (pyridin-2-yl) benzamide (Compound No. 32)

N- [3,5-bis (trifluoromethyl) phenyl] -2-methoxymethoxy-5- (pyridin-2-yl) benzamide (37.9 mg, 0.08 mmol) in methanol (3 ml), concentrated Hydrochloric acid (0.5 ml) was added and heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain the title compound. White powder (16.2 mg, 47.2%) was obtained.

Example 33: Preparation of the compound of Compound No. 33

The title compound was obtained in the same manner as the Example 3 using 5-methoxysalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 56.8%

Example 34: Preparation of the compound of Compound No. 34

(1) 5-acetyl-2-methoxybenzoic acid methyl ester

To a mixture of 5-acetylsalicylic acid methyl ester (5.00 g, 25.7 mmol), potassium carbonate (7.10 g, 51.4 mmol), N, N-dimethylformamide (25 mL), methyl iodide (2.5 mL, 40.1 mmol) under ice-cooling Was added and stirred at room temperature for 3 hours. The reaction mixture was poured into water, neutralized with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was suspended and washed (isopropyl ether / n-hexane) to give the title compound as white crystals (5.17 g, 96.5). %) Was obtained.

(2) 5-isobutyryl-2-methoxybenzoic acid methyl ester

To a mixture of 5-acetyl-2-methoxybenzoic acid methyl ester (0.50 g, 2.40 mmol), tert-butoxy potassium (0.81 g, 7.22 mmol) and tetrahydrofuran (10 mL), methyl iodide (0.5 mL) under ice-cooling , 8.03 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was poured into water, neutralized with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1-&gt; 2: 1). The pale yellow oil (143.1 mg, 25.2%) was obtained as the title compound.

(3) 5-isobutyryl-2-methoxybenzoic acid

To a methanol (5 mL) solution of 5-isobutyryl-2-methoxybenzoic acid methyl ester (143.1 mg, 0.60 mmol) was added, a bimodal sodium hydroxide solution (1 mL) was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, poured into dihydrogen hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain white crystals (134 mg, quantitative) as the title compound.

(4) 5-isobutyryl-N- [3,5-bis (trifluoromethyl) phenyl] -2-methoxybenzamide

The title compound was obtained in the same manner as the Example 3 using 5-isobutyryl-2-methoxybenzoic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 61.4%

(5) N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-5-isobutyrylbenzamide (Compound No. 34)

5-isobutyryl-N- [3,5-bis (trifluoromethyl) phenyl] -2-methoxybenzamide (143.4 mg, 0.33 mmol), 2,4,6-collidine (3 ml), A mixture of lithium iodide (53.1 mg, 0.40 mmol) was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, poured into dihydrogen hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1), and ethyl acetate / isopropyl ether Crystallization was carried out to give the title compound as white crystals (90.3 mg, 65.3%).

Example 35: Preparation of the compound of Compound No. 35

The title compound was obtained in the same manner as the Example 3 using 4-hydroxyisophthalic acid-1-methylester and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 91.5%

[4-Hydroxyisophthalic acid-1-methyl ester: See Journal of the Chemical Society, UK, 1956, p. 3099-3107.

Example 36: Preparation of the compound of Compound No. 36

Methanol / tetrahydrofuran (14 mL + 14 mL) of N- [3,5-bis (trifluoromethyl) phenyl] -4-hydroxyisophthalamic acid methyl ester (Compound No. 35; 2.85 g, 7 mmol) 2) Aqueous sodium hydroxide solution (14 mL) was added to the suspension, and the mixture was heated to reflux for 2 hours. After cooling the reaction mixture to room temperature, 2N hydrochloric acid (20 mL) was added, and the precipitated solid was collected by filtration, washed with water and dried to obtain white crystals (2.68 g, 97.4%) as a title compound.

When the method of Example 36 was cited in the following examples, inorganic bases such as sodium hydroxide and potassium carbonate were used as the base. In addition, as a reaction solvent, solvents, such as water, methanol, ethanol, and tetrahydrofuran, were used individually or in mixture.

Example 37: Preparation of the compound of Compound No. 37

4-hydroxyisophthalic acid (182 mg, 1 mmol), 3,5-bis (trifluoromethyl) aniline (687 mg, 3 mmol), phosphorus trichloride (87 μL; 1 mmol), toluene (10 mL) In the same manner as in Example 3, the title compound was obtained as white crystals (151 mg, 25.0%).

Example 38: Preparation of the compound of Compound No. 38

(1) 4-benzyloxy-N- [3,5-bis (trifluoromethyl) phenyl] isophthalamic acid methyl ester

To a suspension of N, N-dimethylformamide (100 mL) in sodium hydride (60%; 1.04 g, 26 mmol) was dissolved N- [3,5-bis (trifluoromethyl) phenyl] -4-hydroxy under ice cooling. A N, N-dimethylformamide (100 mL) solution of sophthalamic acid methyl ester (Compound No. 35; 8.15 g, 20 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. Then, a solution of benzyl bromide (4.45 g, 26 mmol) in N, N-dimethylformamide (10 mL) was added thereto, and the mixture was stirred at 60 ° C for 3 hours. The reaction mixture was cooled to room temperature, poured into ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethyl acetate / n-hexane to give the title compound as a white solid (5.38 g, 54.1%). Got.

(2) 4-benzyloxy-N- [3,5-bis (trifluoromethyl) phenyl] isophthalamine acid

The title compound was obtained in the same manner as the Example 36 using 4-benzyloxy-N- [3,5-bis (trifluoromethyl) phenyl] isophthalamic acid methyl ester as a starting material.

Yield: 79.7%

(3) 4-benzyloxy-N ^3- [3,5-bis (trifluoromethyl) phenyl] -N ¹ , N ¹ -dimethylisophthalamide

4-benzyloxy-N- [3,5-bis (trifluoromethyl) phenyl] isophthalamic acid (242 mg, 0.50 mmol), dimethylamine hydrochloride (41 mg, 0.50 mmol), triethylamine (51 mg , 0.50 mmol) in tetrahydrofuran (5 mL) solution under ice-cooling, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (hereinafter abbreviated as WSCHCl; 95 mg, 0.50 mmol) Was added and stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with dilute hydrochloric acid, water, and saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4). A white solid (165 mg, 64.9%) was obtained as a compound.

When the method of Example 38 (3) was cited in the following examples, organic bases such as pyridine and triethylamine were used as the base. In addition, as a reaction solvent, solvents, such as dichloromethane and tetrahydrofuran, were used individually or in mixture.

(4) N ^3- [3,5-bis (trifluoromethyl) phenyl] -4-hydroxy-N ¹ , N ¹ -dimethylisophthalamide (Compound No. 38)

4-benzyloxy-N ^3- [3,5-bis (trifluoromethyl) phenyl] -N ¹ , N ¹ -dimethylisophthalamide (141 mg, 0.28 mmol), 5% palladium-carbon (14 mg ), Ethanol (5 ml) and ethyl acetate (5 ml) were stirred for 1 hour at room temperature under hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was distilled off under reduced pressure to obtain a white solid (106 mg, 91.2%) as a title compound.

Example 39: Preparation of the compound of Compound No. 39

(1) 2-benzyloxy-N- [3,5-bis (trifluoromethyl) phenyl] -5- (piperidine-1-carbonyl) benzamide

The same as Example 38 (3) using 4-benzyloxy-N- [3,5-bis (trifluoromethyl) phenyl] isophthalamic acid (compound of Example 38 (2)) and piperidine as starting materials The operation was carried out to obtain the title compound.

Yield: 56.4%

(2) N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-5- (piperidine-1-carbonyl) benzamide (Compound No. 39)

The same operation as in Example 38 (4) was carried out using 2-benzyloxy-N- [3,5-bis (trifluoromethyl) phenyl] -5- (piperidine-1-carbonyl) benzamide as a starting material. To give the title compound.

Yield: 96.3%, white solid

Example 40: Preparation of the compound of Compound No. 40

(1) 2-benzyloxy-5- (4-benzylpiperidine-1-carbonyl) -N- [3,5-bis (trifluoromethyl) phenyl] benzamide

Example 38 (3) using 4-benzyloxy-N- [3,5-bis (trifluoromethyl) phenyl] isophthalamic acid (compound of Example 38 (2)) and 4-benzylpiperidine as starting materials In the same manner as), the title compound was obtained.

Yield: 76.7%

(2) N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-5- (4-benzylpiperidine-1-carbonyl) benzamide (Compound No. 40)

Example 38 (4) and 2-benzyloxy-5- (4-benzylpiperidine-1-carbonyl) -N- [3,5-bis (trifluoromethyl) phenyl] benzamide were used as starting materials. The same operation was carried out to obtain the title compound.

Yield: 54.3%, white solid

Example 41: Preparation of the compound of Compound No. 41

(1) 2-methoxy-5-sulfamoyl benzoic acid

To a methanol (30 mL) solution of methyl 2-methoxy-5-sulfamoylbenzoate (4.91 g, 20 mmol) was added dihydrogen sodium hydroxide solution (30 mL, 60 mmol) and stirred at room temperature for 1 hour. The reaction mixture was poured into 2N hydrochloric acid, and the precipitated solid was collected by filtration to obtain the title compound as a white solid (4. 55 g, 98.3%).

(2) N- [3,5-bis (trifluoromethyl) phenyl] -2-methoxy-5-sulfamoylbenzamide

The title compound was obtained in the same manner as the Example 12 (3) using 2-methoxy-5-sulfamoylbenzoic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 24.2%

(3) N- [3,5-bis (trifluoromethyl) phenyl] -5-dimethylsulfamoyl-2-methoxybenzamide

N- [3,5-bis (trifluoromethyl) phenyl] -2-methoxy-5-sulfamoylbenzamide (442 mg, 1.0 mmol), methyl iodide (710 mg, 5.0 mmol), potassium carbonate (415 mg, 3.0 mmol) and acetonitrile (10 mL) were heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from n-hexane / ethyl acetate to obtain the title compound as a white solid (207 mg, 44.1%). Got.

(4) N- [3,5-bis (trifluoromethyl) phenyl] -5-dimethylsulfamoyl-2-hydroxybenzamide (Compound No. 41)

The title compound was obtained in the same manner as the Example 34 (5) using N- [3,5-bis (trifluoromethyl) phenyl] -5-dimethylsulfamoyl-2-methoxybenzamide as a starting material.

Yield: 45.5%

Example 42: Preparation of the compound of Compound No. 42

(1) N- [3,5-bis (trifluoromethyl) phenyl] -2-methoxy-5- (pyrrole-1-sulfonyl) benzamide

N- [3,5-bis (trifluoromethyl) phenyl] -2-methoxy-5-sulfamoylbenzamide (Compound of Example 41 (2); 442 mg, 1 mmol), 2,5-dimethoxy A mixture of tetrahydrofuran (159 mg, 1.2 mmol) and acetic acid (5 mL) was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 2). ) To give the title compound as a white solid (436.5 mg, 88.6%).

(2) N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-5- (pyrrole-1-sulfonyl) benzamide (Compound No. 42)

The same operation as in Example 34 (5) was carried out using N- [3,5-bis (trifluoromethyl) phenyl] -2-methoxy-5- (pyrrole-1-sulfonyl) benzamide as a starting material. The compound was obtained.

Yield: 79.4%

Example 43: Preparation of the compound of Compound No. 43

The title compound was obtained in the same manner as the Example 38 (4) using N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-5-nitrobenzamide (Compound No. 8) as a starting material. Got it.

Yield: 98.0%

Example 44: Preparation of the compound of Compound No. 44

The title compound was obtained in the same manner as the Example 3 using 5-dimethylaminosalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 28.8%

Example 45: Preparation of the compound of Compound No. 45

5-amino-N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxybenzamide (Compound No. 43; 364 mg, 1 mmol), pyridine (95 mg, 1.2 mmol) under argon atmosphere To the mixture of tetrahydrofuran (10 mL), benzoyl chloride (155 mg, 1.1 mmol) was added under ice cooling, followed by stirring for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain the title compound. Phosphorus white solid (121 mg, 25.7%) was obtained.

Example 46: Preparation of the compound of Compound No. 46

To a solution of 5-amino-N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxybenzamide (Compound No. 43; 100.2 mg, 0.28 mmol) in acetonitrile (4 ml), 4- Dimethylaminopyridine (3 mg) and phenyl isocyanate (30 μL, 0.28 mmol) were added and stirred at 60 ° C. for 5 minutes. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give a pale brown solid (54.8 mg, 41.2%) as a title compound.

Example 47: Preparation of the compound of Compound No. 47

The same operation as in Example 46 was carried out using 5-amino-N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxybenzamide (Compound No. 43) and phenylisothiocyanate as starting materials. The title compound was obtained.

Yield: 66.3%

Example 48: Preparation of the compound of Compound No. 48

The title compound was obtained in the same manner as the Example 3 using 5-[(4-nitrophenyl) diazenyl] salicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 11.3%

Example 49: Preparation of the compound of Compound No. 49

The title compound was obtained in the same manner as the Example 3 using 5-({[(4-pyridin-2-yl) sulfamoyl] phenyl} diagenyl) salicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials Got.

Yield: 7.9%

Example 50: Preparation of the compound of Compound No. 50

(1) 4-acetylamino-5-chloro-2-methoxybenzoic acid

The title compound was obtained in the same manner as the Example 36 using 4-acetylamino-5-chloro-2-methoxybenzoic acid methyl ester as a starting material.

Yield: 88.0%

(2) 4-acetylamino-N- [3,5-bis (trifluoromethyl) phenyl] -5-chloro-2-methoxybenzamide

The title compound was obtained in the same manner as the Example 12 (3) using 4-acetylamino-5-chloro-2-methoxybenzoic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 23.8%

(3) 4-acetylamino-N- [3,5-bis (trifluoromethyl) phenyl] -5-chloro-2-hydroxybenzamide (Compound No. 50)

The title compound was obtained in the same manner as the Example 34 (5) using 4-acetylamino-N- [3,5-bis (trifluoromethyl) phenyl] -5-chloro-2-methoxybenzamide as a starting material. Got it.

Yield: 72.8%

Example 51: Preparation of the compound of Compound No. 51

The title compound was obtained in the same manner as the Example 3 using 4-chlorosalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 55.8%

Example 52: Preparation of the compound of Compound No. 52

The title compound was obtained in the same manner as the Example 3 using 6-hydroxysalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 86.9%

Example 53: Preparation of the compound of Compound No. 53

The title compound was obtained in the same manner as the Example 3 using 4-methylsalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 42.9%

Example 54: Preparation of the compound of Compound No. 54

The title compound was obtained in the same manner as the Example 3 using 5-bromo-4-hydroxysalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 82.4%

Example 55: Preparation of the compound of Compound No. 55

The title compound was obtained in the same manner as the Example 3 using 4-hydroxysalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 29.9%

Example 56: Preparation of the compound of Compound No. 56

The title compound was obtained in the same manner as the Example 3 using 3,5-dichlorosalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 44.8%

Example 57: Preparation of the compound of Compound No. 57

The title compound was obtained in the same manner as the Example 3 using 3-hydroxysalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 22.7%

Example 58: Preparation of the compound of Compound No. 58

The title compound was obtained in the same manner as the Example 3 using 3-methylsalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 54.9%

Example 59: Preparation of the compound of Compound No. 59

The title compound was obtained in the same manner as the Example 3 using 3-methoxysalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 34.6%

Example 60: Preparation of the compound of Compound No. 60

The title compound was obtained in the same manner as the Example 3 using 5-[(1,1,3,3-tetramethyl) butyl] salicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield 64.2%

Example 61: Preparation of the compound of Compound No. 61

The title compound was obtained in the same manner as the Example 3 using 3,5,6-trichlorosalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 26.2%

Example 62: Preparation of the compound of Compound No. 62

The title compound was obtained in the same manner as the Example 3 using 3,5-bis [(1,1-dimethyl) ethyl] salicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 65.0%

Example 63: Preparation of the compound of Compound No. 63

The title compound was obtained in the same manner as the Example 3 using 6-fluorosalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 35.9%

Example 64: Preparation of the compound of Compound No. 64

The title compound was obtained in the same manner as the Example 3 using 3-chlorosalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 61.3%

Example 65: Preparation of the compound of Compound No. 65

The title compound was obtained in the same manner as the Example 3 using 4-methoxysalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 14.2%

Example 66: Preparation of the compound of Compound No. 66

The title compound was obtained in the same manner as the Example 3 using 6-methoxysalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 63.1%

Example 67: Preparation of the compound of Compound No. 67

The same operation as in Example 45 was carried out using 5-amino-N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxybenzamide (Compound No. 43) and methanesulfonylchloride as starting materials, to give the title The compound was obtained.

Yield: 22.6%

Example 68: Preparation of the compound of Compound No. 68

The title compound was obtained in the same manner as the Example 45 using 5-amino-N- [3,5-bis (trifluoromethyl) phenyl-2-hydroxybenzamide (Compound No. 43) and benzenesulfonylchloride as starting materials. Got.

Yield: 45.3%

Example 69: Preparation of the compound of Compound No. 69

The title compound was obtained in the same manner as the Example 45 using 5-amino-N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxybenzamide (Compound No. 43) and acetyl chloride as starting materials. Got it.

Yield: 44.8%

Example 70: Preparation of the compound of Compound No. 70

Using N- [3,5-bis (trifluoromethyl) phenyl] -2-methoxy-5-sulfamoylbenzamide (compound of Example 41 (2)), the same operation as in Example 34 (5) The title compound was obtained.

Yield: 59.9%

Example 71: Preparation of the compound of Compound No. 71

The title compound was obtained in the same manner as the Example 3 using 1-hydroxynaphthalene-2-carboxylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 65.5%

Example 72: Preparation of the compound of Compound No. 72

The title compound was obtained in the same manner as the Example 3 using 3-hydroxynaphthalene-2-carboxylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 46.9%

Example 73: Preparation of the compound of Compound No. 73

The title compound was obtained in the same manner as the Example 3 using 2-hydroxynaphthalene-1-carboxylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 30.2%

Example 74: Preparation of the compound of Compound No. 74

(1) 4-bromo-3-hydroxythiophene-2-carboxylic acid

Methyl 4-bromo-3-hydroxythiophene-2-carboxylic acid methyl ester (500 mg, 2.1 mmol) and sodium hydroxide (261 mg, 6.3 mmol) were mixed with methanol / water (2.5 mL + 2.5 mL). It was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL) at pH 1 with 2N hydrochloric acid. The ethyl acetate solution was washed sequentially with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain red brown powder (326 mg, 69.4%) as a title compound.

(2) 4-bromo-3-hydroxy-N- [3,5-bis (trifluoromethyl) phenyl] thiophene-2-carboxamide (Compound No. 74)

The title compound was obtained in the same manner as the Example 3 using 4-bromo-3-hydroxythiophene-2-carboxylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 82.4%

Example 75: Preparation of the compound of Compound No. 75

5-chloro-2-hydroxynicotinic acid (174 mg, 1 mmol), 3,5-bis (trifluoromethyl) aniline (275 mg, 1.2 mmol), pyridine (316 mg, 4 mmol) tetrahydrofuran / Phosphorous oxychloride (0.112 ml, 1.2 mmol) was added to a dichloromethane (20 mL + 10 mL) solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ethyl acetate (100 mL) and 0.2 N hydrochloric acid (100 mL), stirred for 30 minutes, filtered through Celite, and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were washed successively with water and brine, dried over anhydrous magnesium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1-1: 1). Purification and suspension washing with ethanol gave the title compound as white crystals (183 mg, 47.6%).

Melting Point: ＞ 270 ℃

When the manufacturing method of Example 75 was quoted in the following Examples, phosphorus oxychloride was used as a condensing agent (acid halogenating agent). Pyridine was used as the base. In addition, as a reaction solvent, solvents, such as dichloromethane and tetrahydrofuran, were used individually or in mixture.

Example 76: Preparation of the compound of Compound No. 76

The title compound was obtained in the same manner as the Example 75 using 3-hydroxypyridine-2-carboxylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 45.0%

Example 77: Preparation of the compound of Compound No. 77

To a tetrahydrofuran (5 mL) solution of 3,5-bis (trifluoromethyl) phenylisocyanate (255 mg, 1.0 mmol), tetrahydrofuran (184 mg, 1.1 mmol) tetrahydro of 6-chloro-oxyindole under argon atmosphere Furan (5 ml) solution and triethylamine (0.3 mL) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain the title compound as a peach solid (172.2 mg, 40.7%).

Example 78: Preparation of the compound of Compound No. 78

The title compound was obtained in the same manner as the Example 77 using 3,5-bis (trifluoromethyl) phenylisocyanate and oxyindole as starting materials.

Yield: 44.8%

Example 79: Preparation of the compound of Compound No. 79

The title compound was obtained in the same manner as the Example 77 using 3,5-bis (trifluoromethyl) phenylisocyanate and 5-chlorooxyindole as starting materials.

Yield: 31.1%

Example 80: Preparation of the compound of Compound No. 80

The title compound was obtained in the same manner as the Example 3 using 3-hydroxyquinoxaline-2-carboxylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 2.7%

Example 81: Preparation of the compound of Compound No. 81

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 3.6%

Example 82: Preparation of the compound of Compound No. 82

The title compound was obtained in the same manner as the Example 5 using N- [2,5-bis (trifluoromethyl) phenyl] -5-chloro-2-hydroxybenzamide (Compound No. 81) and acetyl chloride as starting materials. Got it.

Yield: 6.6%

Example 83: Preparation of a compound of Compound No. 83

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 2,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 24.0%

Example 84: Preparation of the compound of Compound No. 84

The title compound was obtained in the same manner as the Example 3 using 5-methylsalicylic acid and 2,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 1.5%

Example 85: Preparation of the compound of Compound No. 85

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 3-fluoro-5- (trifluoromethyl) aniline as starting materials.

Yield: 62.0%

Example 86: Preparation of the compound of Compound No. 86

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 3-bromo-5- (trifluoromethyl) aniline as starting materials.

Yield: 73.3%

Example 87: Preparation of the compound of Compound No. 87

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-fluoro-5- (trifluoromethyl) aniline as starting materials.

Yield: 77.9%

Example 88: Preparation of the compound of Compound No. 88

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-chloro-5- (trifluoromethyl) aniline as starting materials.

Yield: 49.1%

Example 89: Preparation of the compound of Compound No. 89

The title compound was obtained in the same manner as the Example 5 using 5-chloro-N- [2-chloro-5- (trifluoromethyl) phenyl] -2-hydroxybenzamide (Compound No. 88) and acetyl chloride as starting materials. Got.

Yield: 34.0%

Example 90: Preparation of the compound of Compound No. 90

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 2-chloro-5- (trifluoromethyl) aniline as starting materials.

Yield: 34.2%

Example 91: Preparation of the compound of Compound No. 91

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-nitro-5- (trifluoromethyl) aniline as starting materials.

Yield: 8.1%

Example 92: Preparation of the compound of Compound No. 92

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-methyl-5- (trifluoromethyl) aniline as starting materials.

Yield: 73.3%

Example 93: Preparation of the compound of Compound No. 93

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 3-methoxy-5- (trifluoromethyl) aniline as starting materials.

Yield: 58.8%

Example 94: Preparation of the compound of Compound No. 94

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 2-methoxy-5- (trifluoromethyl) aniline as starting materials.

Yield: 71.3%

Example 95: Preparation of the compound of Compound No. 95

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-methoxy-5- (trifluoromethyl) aniline as starting materials.

Yield: 83.4%

Example 96: Preparation of the compound of Compound No. 96

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-methylsulfanyl-5- (trifluoromethyl) aniline as starting materials.

Yield: 79.2%

Example 97: Preparation of the compound of Compound No. 97

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 2- (1-pyrrolidinyl) -5- (trifluoromethyl) aniline as starting materials.

Yield: 44.5%

Example 98: Preparation of the compound of Compound No. 98

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 2-morpholino-5- (trifluoromethyl) aniline as starting materials.

Yield: 65.9%

Example 99: Preparation of the compound of Compound No. 99

The title compound was obtained in the same manner as the Example 3 using 5-nitrosalicylic acid and 2-chloro-5- (trifluoromethyl) aniline as starting materials.

Yield: 31.1%

Example 100: Preparation of the compound of Compound No. 100

The title compound was obtained in the same manner as the Example 3 using 5-methylsalicylic acid and 2-chloro-5- (trifluoromethyl) aniline as starting materials.

Yield: 15.8%

Example 101: Preparation of the compound of Compound No. 101

The title compound was obtained in the same manner as the Example 3 using 5-methoxysalicylic acid and 2-chloro-5- (trifluoromethyl) aniline as starting materials.

Yield: 56.4%

Example 102: Preparation of the compound of Compound No. 102

The title compound was obtained in the same manner as the Example 3 using 5-methylsalicylic acid and 2-methyl-5- (trifluoromethyl) aniline as starting materials.

Yield: 14.2%, white solid

Example 103: Preparation of the compound of Compound No. 103

The title compound was obtained in the same manner as the Example 3 using 5-methylsalicylic acid and 2-methoxy-5- (trifluoromethyl) aniline as starting materials.

Yield: 77.9%

Example 104: Preparation of the compound of Compound No. 104

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 3-bromo-5- (trifluoromethyl) aniline as starting materials.

Yield: 37.1%

Example 105: Preparation of the compound of Compound No. 105

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 3-methoxy-5- (trifluoromethyl) aniline as starting materials.

Yield: 68.0%

Example 106: Preparation of the compound of Compound No. 106

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-morpholino-5- (trifluoromethyl) aniline as starting materials.

Yield: 64.8%

Example 107: Preparation of the compound of Compound No. 107.

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-bromo-5- (trifluoromethyl) aniline as starting materials.

Yield: 59.2%

Example 108: Preparation of the compound of Compound No. 108

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 3-amino-5-trifluoromethylbenzoic acid methyl ester as starting materials.

Yield: 67.0%

Example 109: Preparation of the compound of Compound No. 109

To a methanol (2.5 mL) suspension of 5-chloro-2-hydroxy-N- [3-methoxycarbonyl-5- (trifluoromethyl) phenyl] benzamide (Compound No. 108; 105 mg, 0.281 mmol) , 2N aqueous sodium hydroxide solution (0.6 mL) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was washed with ethyl acetate. Dilute hydrochloric acid was added to the aqueous layer to make it acidic, and then extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was crystallized with isopropyl ether to obtain a white solid (100 mg, 99.0%) as a title compound.

Example 110: Preparation of the compound of Compound No. 110

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2- (2-naphthyloxy) -5- (trifluoromethyl) aniline as starting materials.

Yield: 89.6%

Example 111: Preparation of the compound of Compound No. 111

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2- (2,4-dichlorophenoxy) -5- (trifluoromethyl) aniline as starting materials.

Yield: 4.7%

Example 112: Preparation of the compound of Compound No. 112

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-[(4-trifluoromethyl) piperidino] -5- (trifluoromethyl) aniline as starting materials.

Yield: 60.5%

Example 113: Preparation of a compound of Compound No. 113

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) aniline as starting materials.

Yield: 94.5%

Example 114: Preparation of the compound of Compound No. 114

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2- (2-methoxyphenoxy) -5- (trifluoromethyl) aniline as starting materials.

Yield: 80.6%

Example 115: Preparation of the compound of Compound No. 115

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2- (4-chloro-3,5-dimethylphenoxy) -5- (trifluoromethyl) aniline as starting materials.

Yield: 91.5%

Example 116: Preparation of a compound of Compound No. 116

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-piperidino-5- (trifluoromethyl) aniline as starting materials.

Yield: 73.7%

Example 117: Preparation of the compound of Compound No. 117

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2- (4-methylphenoxy) -5- (trifluoromethyl) aniline as starting materials.

Yield: 67.3%

Example 118: Preparation of the compound of Compound No. 118

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2- (4-chlorophenoxy) -5- (trifluoromethyl) aniline as starting materials.

Yield: 74.5%

Example 119: Preparation of the compound of Compound No. 119

The title compound was obtained in the same manner as the Example 75 using 5-chloro-2-hydroxynicotinic acid and 2-chloro-5- (trifluoromethyl) aniline as starting materials.

Yield: 42.9%

Example 120: Preparation of the compound of Compound No. 120

The title compound was obtained in the same manner as the Example 1 using O-acetylsalicylic acid chloride and 3,5-dichloroaniline as starting materials.

Yield: 73.5%

Example 121: Preparation of the compound of Compound No. 121

The title compound was obtained in the same manner as the Example 2 using 2-acetoxy-N- [3,5-dichlorophenyl) benzamide (Compound No. 121) as a starting material.

Yield: 60.3%

Example 122: Preparation of the compound of Compound No. 122

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2,5-dichloroaniline as starting materials.

Yield: 10.8%

Example 123: Preparation of a compound of Compound No. 123

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 3,5-difluoroaniline as starting materials.

Yield: 36.3%

Example 124: Preparation of the compound of Compound No. 124

The title compound was obtained in the same manner as the Example 3 using 5-fluorosalicylic acid and 3,5-dichloroaniline as starting materials.

Yield: 33.3%

Example 125: Preparation of the compound of Compound No. 125

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 3,5-dichloroaniline as starting materials.

Yield: 41.2%

Example 126: Preparation of the compound of Compound No. 126

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 3,5-dichloroaniline as starting materials.

Yield: 61.6%

Example 127: Preparation of a compound of Compound No. 127

The title compound was obtained in the same manner as the Example 3 using 5-iosalicylic acid and 3,5-dichloroaniline as starting materials.

Yield: 65.4%

Example 128: Preparation of the compound of Compound No. 128

The title compound was obtained in the same manner as the Example 3 using 3,5-dibromosalicylic acid and 3,5-dichloroaniline as starting materials.

Yield: 44.2%

Example 129: Preparation of the compound of Compound No. 129

The title compound was obtained in the same manner as the Example 3 using 4-chlorosalicylic acid and 3,5-dichloroaniline as starting materials.

Yield: 57.2%

Example 130: Preparation of the compound of Compound No. 130

The title compound was obtained in the same manner as the Example 3 using 5-nitrosalicylic acid and 3,5-dichloroaniline as starting materials.

Yield: 83.1%

Example 131: Preparation of a compound of Compound No. 131

The title compound was obtained in the same manner as the Example 3 using 5-methylsalicylic acid and 3,5-dichloroaniline as starting materials.

Yield: 71.0%

Example 132: Preparation of the compound of Compound No. 132

The title compound was obtained in the same manner as the Example 3 using 5-methoxysalicylic acid and 3,5-dichloroaniline as starting materials.

Yield: 29.8%

Example 133: Preparation of the compound of Compound No. 133

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 3,5-dinitroaniline as starting materials.

Yield: 32.2%

Example 134: Preparation of the compound of Compound No. 134

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2,5-bis [(1,1-dimethyl) ethyl] aniline as starting materials.

Yield: 75.7%

Example 135: Preparation of the compound of Compound No. 135

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 5-[(1,1-dimethyl) ethyl] -2-methoxyaniline as starting materials.

Yield: 89.5%

Example 136: Preparation of the compound of Compound No. 136

The same as Example 5 using 5-chloro-N- {5-[(1,1-dimethyl) ethyl] -2-methoxyphenyl} -2-hydroxybenzamide (Compound No. 135) and acetyl chloride as starting materials. The operation was carried out to obtain the title compound.

Yield: 87.5%

Example 137: Preparation of the compound of Compound No. 137

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 3,5-dimethylaniline as starting materials.

Yield: 58.1%

Example 138: Preparation of the compound of Compound No. 138

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 3,5-bis [(1,1-dimethyl) ethyl] aniline as starting materials.

Yield: 34.1%

Example 139: Preparation of a compound of Compound No. 139

The same operation as in Example 5 was carried out using N- {3,5-bis [(1,1-dimethyl) ethyl] phenyl} -5-chloro-2-hydroxybenzamide (Compound No. 138) and acetyl chloride as starting materials. To give the title compound.

Yield: 66.1%

Example 140: Preparation of the compound of Compound No. 140

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 3,5-bis [(1,1-dimethyl) ethyl] aniline as starting materials.

Yield: 45.2%

Example 141: Preparation of a compound of Compound No. 141

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 3-amino-4-methoxybiphenyl as starting materials.

Yield: 37.0%

Example 142: Preparation of the compound of Compound No. 142

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 2,5-dimethoxyaniline as starting materials.

Yield: 39.7%

Example 143: Preparation of the compound of Compound No. 143

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 3,5-dimethoxyaniline as starting materials.

Yield: 40.3%

Example 144: Preparation of a Compound of Compound No. 144

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 5-aminoisophthalic acid dimethyl ester as starting materials.

Yield: 74.1%

Example 145: Preparation of a compound of Compound No. 145

The title compound was obtained in the same manner as the Example 3 using 5-methylsalicylic acid and 2,5-bis [(1,1-dimethyl) ethyl] aniline as starting materials.

Yield: 61.1%

Example 146: Preparation of the compound of Compound No. 146

The title compound was obtained in the same manner as the Example 3 using 5-nitrosalicylic acid and 3,5-bis [(1,1-dimethyl) ethyl] aniline as starting materials.

Yield: 46.7%

Example 147: Preparation of the compound of Compound No. 147

The title compound was obtained in the same manner as the Example 3 using 5-methylsalicylic acid and 3,5-bis [(1,1-dimethyl) ethyl] aniline as starting materials.

Yield: 16.3%

Example 148: Preparation of the compound of Compound No. 148

The title compound was obtained in the same manner as the Example 3 using 5-methoxysalicylic acid and 3,5-bis [(1,1-dimethyl) ethyl] aniline as starting materials.

Yield: 12.7%

Example 149: Preparation of the compound of Compound No. 149

The title compound was obtained in the same manner as the Example 3 using 5-methylsalicylic acid and 5-[(1,1-dimethyl) ethyl] -2-methoxyaniline as starting materials.

Yield: 84.7%

Example 150: Preparation of the compound of Compound No. 150

The title compound was obtained in the same manner as the Example 109 using 5-bromo-2-hydroxy-N- [3,5-bis (methoxycarbonyl) phenyl] benzamide (Compound No. 144) as a starting material.

Yield: 89.0%

Example 151: Preparation of the compound of Compound No. 151

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-methyl-5-[(1-methyl) ethyl] aniline as starting materials.

Yield: 19.1%

Example 152: Preparation of a Compound of Compound No. 152

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2,5-diethoxyaniline as starting materials.

Yield: 59.2%

Example 153: Preparation of the compound of Compound No. 153

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2,5-dimethylaniline as starting materials.

Yield: 90.5%

Example 154: Preparation of the compound of Compound No. 154

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 5-chloro-2-cyanoaniline as starting materials.

Yield: 90.0%

Example 155: Preparation of a compound of Compound No. 155

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 5- (N, N-diethylsulfamoyl) -2-methoxyaniline as starting materials.

Yield: 44.8%

Example 156: Preparation of a compound of Compound No. 156

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-chloro-5-nitroaniline as starting materials.

Yield: 73.3%

Example 157: Preparation of a compound of Compound No. 157

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 5- (N-phenylcarbamoyl) -2-methoxyaniline as starting materials.

Yield: 40.3%

Example 158: Preparation of the compound of Compound No. 158

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2,5-dimethoxyaniline as starting materials.

Yield: 73.9%

Example 159: Preparation of the compound of Compound No. 159

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 5-acetylamino-2-methoxyaniline as starting materials.

Yield: 16.9%

Example 160: Preparation of the compound of Compound No. 160

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 5-methoxy-2-methylaniline as starting materials.

Yield: 100%

Example 161: Preparation of the compound of Compound No. 161

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2,5-dibutoxyaniline as starting materials.

Yield: 73.9%

Example 162: Preparation of a compound of Compound No. 162

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2,5-diisopentyloxyaniline as starting materials.

Yield: 59.7%

Example 163: Preparation of a compound of Compound No. 163

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 5-carbamoyl-2-methoxyaniline as starting materials.

Yield: 31.2%

Example 164: Preparation of a Compound of Compound No. 164

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 5-[(1,1-dimethyl) propyl] -2-phenoxyaniline as starting materials.

Yield: 65.2%

Example 165: Preparation of a compound of Compound No. 165

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-hexyloxy-5- (methylsulfonyl) aniline as starting materials.

Yield: 33.0%

Example 166: Preparation of the compound of Compound No. 163

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 3'-amino-2,2,4'-trimethylpropiophenone as starting materials.

Yield: 44.8%

Example 167: Preparation of the compound of Compound No. 167

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 5-methoxy-2- (1-pyrrolyl) aniline as starting materials.

Yield: 53.4%

Example 168: Preparation of the compound of Compound No. 168

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 5-chloro-2-tosylaniline as starting materials.

Yield: 8.0%

Example 169: Preparation of the compound of Compound No. 169

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-chloro-5-tosylaniline as starting materials.

Yield: 43.5%

Example 170: Preparation of the compound of Compound No. 170

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-fluoro-5- (methylsulfonyl) aniline as starting materials.

Yield: 28.8%

Example 171: Preparation of the compound of Compound No. 171

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-methoxy-5-phenoxyaniline as starting materials.

Yield: 77.0%

Example 172: Preparation of the compound of Compound No. 172

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 3-amino-4-methylbiphenyl as starting materials.

Yield: 47.7%

Example 173: Preparation of the compound of Compound No. 173

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 5- (α, α-dimethylbenzyl) -2-methoxyaniline as starting materials.

Yield: 89.0%

Example 174: Preparation of a compound of Compound No. 174

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 5-morpholino-2-nitroaniline as starting materials.

Yield: 4.1%

Example 175: Preparation of the compound of Compound No. 175

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 5-fluoro-2- (1-imidazolyl) aniline as starting materials.

Yield: 33.8%

Example 176: Preparation of a Compound of Compound No. 176

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-butyl-5-nitroaniline as starting materials.

Yield: 15.3%

Example 177: Preparation of the compound of Compound No. 177

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 5-[(1,1-dimethyl) propyl] -2-hydroxyaniline as starting materials.

Yield: 36.0%

Example 178: Preparation of the compound of Compound No. 178

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-methoxy-5-methylaniline as starting materials.

Yield 74.2%

Example 179: Preparation of the compound of Compound No. 179

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2,5-difluoroaniline as starting materials.

Yield: 81.5%

Example 180: Preparation of the compound of Compound No. 180

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 3,5-difluoroaniline as starting materials.

Yield: 82.0%

Example 181: Preparation of a compound of Compound No. 181

The title compound was obtained in the same manner as the Example 3 using 3-hydroxynaphthalene-2-carboxylic acid and 3,5-dichloroaniline as starting materials.

Yield: 44.3%

mp 254-255 ° C.

Example 182: Preparation of the compound of Compound No. 182

The title compound was obtained in the same manner as the Example 3 using 2-hydroxynaphthalene-1-carboxylic acid and 3,5-dichloroaniline as starting materials.

Yield: 51.2%

mp 246-248 ° C.

Example 183: Compound of Compound No. 183

This compound is a commercial compound.

Salesman: Sigma-Aldrich

Catalog Code: S01361-8

Example 184: Preparation of the compound of Compound No. 184

The title compound was obtained in the same manner as the Example 75 using 5-chloro-2-hydroxynicotinic acid and 3,5-bis [(1,1-dimethyl) ethyl] aniline as starting materials.

Yield: 59.1%

Example 185: Preparation of the compound of Compound No. 185

(1) 2-amino-4-[(1,1-dimethyl) ethyl] thiazole

A mixture of 1-bromo-3,3-dimethyl-2-butanone (5.03 g, 28.1 mmol), thiourea (2.35 g, 30.9 mmol) and ethanol (30 mL) was heated to reflux for 1.5 hours. The reaction mixture was cooled to room temperature, poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1-&gt; 1: 1). To give an off-white powder (3.99 g, 90.9%) as the title compound.

When the method of Example 185 (1) is cited in the following examples, a solvent such as ethanol was used as the reaction solvent.

(2) 2-acetoxy-5-bromo-N- {4-[(1,1-dimethyl) ethyl] thiazol-2-yl} benzamide

The title compound was obtained in the same manner as the Example 75 using 2-acetoxy-5-bromobenzoic acid and 2-amino-4-[(1,1-dimethyl) ethyl] thiazole as starting materials.

Yield: 59.4%

[2-Acetoxy-5-bromobenzoic acid: European Journal of Medicinal Chemistry, (France), 1996, Vol. 31, p. 861-874. For reference, the same operation as in Example 34 (1) was carried out using 5-bromosalicylic acid and acetic anhydride as starting materials. It carried out the same operation as Example 244 (1) mentioned later.]

(3) 5-bromo-N- {4-[(1,1-dimethyl) ethyl] thiazol-2-yl} -2-hydroxybenzamide (Compound No. 185)

Tetrahydrofuran (3 mL) solution of 2-acetoxy-5-bromo-N- {4-[(1,1-dimethyl) ethyl] thiazol-2-yl} benzamide (100.1 mg, 0.25 mmol) Sodium hydroxide (0.2 ml) was added to the mixture and stirred for 20 minutes at room temperature. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was crystallized from isopropyl ether / n-hexane to obtain a white powder (70.1 mg, 78.9%) as a title compound.

Example 186: Preparation of the compound of Compound No. 186

(1) 2-acetoxy-5-bromo-N- {5-bromo-4-[(1,1-dimethyl) ethyl] thiazol-2-yl} benzamide

2-acetoxy-5-bromo-N- {4-[(1,1-dimethyl) ethyl] thiazol-2-yl} benzamide (compound of Example 185 (2); 0.20 g, 0.50 mmol) of To acetonitrile (10 mL) solution was added N-bromohomozimic acid imide (97.9 mg, 0.55 mmol) and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain the title compound as a crude product.

(2) 5-bromo-N- {5-bromo-4-[(1,1-dimethyl) ethyl] thiazol-2-yl} -2-hydroxybenzamide (Compound No. 186)

The same operation as in Example 2 was carried out using 2-acetoxy-5-bromo-N- {5-bromo-4-[(1,1-dimethyl) ethyl] thiazol-2-yl} benzamide as a starting material To give the title compound.

Yield: 90.9% (2 steps)

Example 187: Preparation of the compound of Compound No. 187

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 2-amino-5-bromo-4- (trifluoromethyl) thiazole as starting materials.

Yield: 22.4%

mp 215 ° C. (dec.).

[2-Amino-5-bromo-4- (trifluoromethyl) thiazole: `` Journal of Heterocyclic Chemistry '', (US), 1991, Vol. 28, p.1017]

Example 188: Preparation of the compound of Compound No. 188

(1) α-bromo-pivaloylacetonitrile

To a carbon tetrachloride (15 mL) solution of pivaloyl acetonitrile (1.00 g, 7.99 mmol), N-bromohomozimid (1.42 g, 7.99 mmol) was added and heated to reflux for 15 minutes. After cooling the reaction mixture to room temperature, the insolubles were filtered off, the filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give the title compound a tan oil ( 1.43 g, 87.9%).

When the method of Example 188 (1) is cited in the following examples, N-bromosuccinimide was used as the bromoating agent. As the reaction solvent, a solvent such as carbon tetrachloride was used.

(2) Example 185 (1) using α-bromo-pivaloylacetonitrile and thiourea as 2-amino-5-cyano-4-[(1,1-dimethyl) ethyl] thiazole raw material The same operation as the above gave the title compound.

Yield: 66.3%

(3) 5-chloro-N- {5-cyano-4-[(1,1-dimethyl) ethyl] thiazol-2-yl} -2-hydroxybenzamide (Compound No. 188)

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-amino-5-cyano-4-[(1,1-dimethyl) ethyl] thiazole as starting materials.

Yield: 63.4%

Example 189: Preparation of the compound of Compound No. 189

The same procedure as in Example 3 was carried out using 5-bromosalicylic acid and 2-amino-5-cyano-4-[(1,1-dimethyl) ethyl] thiazole (compound of Example 188 (2)) as starting materials. The title compound was obtained.

Yield: 61.3%

Example 190: Preparation of the compound of Compound No. 190

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 2-amino-5-methylthiazole as starting materials.

Yield: 12.9%

Example 191: Preparation of the compound of Compound No. 191

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 2-amino-4,5-dimethylthiazole as starting materials.

Yield: 14.4%

Example 192: Preparation of the Compound of Compound No. 192

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 2-amino-5-methyl-4-phenylthiazole as starting materials.

Yield: 27.7%

mp 243-244 ° C.

[2-Amino-5-methyl-4-phenylthiazole: `` Pharmaceutical magazine: Journal of the Pharmaceutical Society of Japan '', 1961 , Vol. 81, p.1456]

Example 193: Preparation of the compound of Compound No. 193

The title compound was obtained in the same manner as the Examples 188 (1) to (3) using (4-fluorophenyl) acetone as a raw material.

Yield: 28.8% (3 steps)

(1) α-bromo- (4-fluorophenyl) acetone

(2) 2-amino-4-methyl-5- (4-fluorophenyl) thiazole

(3) 5-bromo-N- [4-methyl-5- (4-fluorophenyl) thiazol-2-yl] -2-hydroxybenzamide (Compound No. 193)

Example 194: Preparation of the compound of Compound No. 194

The title compound was obtained in the same manner as the Examples 188 (1) to (3) using 3- (trifluoromethyl) phenylacetone as a raw material.

Yield: 39.8% (3 steps)

(1) α-bromo-3- (trifluoromethyl) phenylacetone

(2) 2-amino-4-methyl-5- [3- (trifluoromethyl) phenyl] thiazole

(3) 5-bromo-N- {4-methyl-5- [3- (trifluoromethyl) phenyl] thiazol-2-yl} -2-hydroxybenzamide (Compound No. 194)

Example 195: Preparation of the compound of Compound No. 195

The title compound was obtained in the same manner as the Examples 188 (1) to (3) using 2,2-dimethyl-3-hexanone as a raw material.

Yield: 17.0% (3 steps)

(2) 2-amino-4-[(1,1-dimethyl) ethyl] -5-ethylthiazole

(3) 5-bromo-N- {4-[(1,1-dimethyl) ethyl] -5-ethylthiazol-2-yl} -2-hydroxybenzamide (Compound No. 195)

Example 196: Preparation of the compound of Compound No. 196

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 2-amino-4-ethyl-5-phenylthiazole as starting materials.

Yield: 17.4%

mp 224-225 ° C.

Example 197: Preparation of the compound of Compound No. 197

The title compound was obtained in the same manner as the Examples 188 (1) to (3) using benzylisopropyl ketone as a raw material.

Yield: 4.4% (3 steps)

(2) 2-amino-4-isopropyl-5-phenylthiazole

(3) 5-bromo-N- (4-isopropyl-5-phenylthiazol-2-yl) -2-hydroxybenzamide (Compound No. 197)

Example 198: Preparation of the compound of Compound No. 198

The title compound was obtained in the same manner as the Examples 188 (1) to (3) using 1-phenyl-2-hexanone as a raw material.

Yield: 52.6% (3 steps)

(1) α-bromo-1-phenyl-2-hexanone

(2) 2-amino-4-butyl-5-phenylthiazole

(3) 5-bromo-N- (4-butyl-5-phenylthiazol-2-yl) -2-hydroxybenzamide (Compound No. 198)

Example 199: Preparation of the compound of Compound No. 199

(1) 4-bromo-2,2,6,6-tetramethyl-3,5-heptanedione [α-bromo-dipivaloyl methane]

To a solution of carbon tetrachloride (10 mL) of 2,2,6,6-tetramethyl-3,5-heptanedione (dipivaloylmethane; 1.00 g, 5.42 mmol), N-bromohoxitate (965.8 mg, 5.42 mmol) was added and heated to reflux for 2 hours. After cooling the reaction mixture to room temperature, the insolubles were filtered off and the filtrate was distilled off under reduced pressure to obtain the title compound as white crystals (1.42 g, quantitative).

When the method of Example 199 (1) is cited in the following examples, N-bromohomo acid imide was used as a bromination agent. As the reaction solvent, a solvent such as carbon tetrachloride was used.

(2) 2-amino-4-[(1,1-dimethyl) ethyl] -5-[(2,2-dimethyl) propionyl] thiazole

4-bromo-2,2,6,6-tetramethyl-3,5-heptanedione (α-bromo-dipivaloylmethane; 1.42 g, 5.40 mmol), thiourea (451.8 mg, 5.94 mmol), The mixture of ethanol (15 mL) was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was crystallized with dichloromethane / n-hexane to give the title compound as white crystals (1.23 g, 94.5%). Got it.

(3) 5-chloro-N- {4-[(1,1-dimethyl) ethyl] -5-[(2,2-dimethyl) propionyl] thiazol-2-yl} -2-hydroxybenzamide (Compound No. 199)

5-chlorosalicylic acid (143.6 mg, 0.83 mmol), 2-amino-4-[(1,1-dimethyl) ethyl] ethyl-5-[(2,2-dimethyl) propionyl] thiazole (200.0 mg, 0.83 mmol), phosphorus trichloride (40 μL, 0.46 mmol) and chlorobenzene (4 mL) were heated to reflux for 3 h. After cooling the reaction mixture to room temperature, the solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain a white powder (159.1 mg, 48.4%) as a title compound.

When the method of Example 199 (3) is cited in the following examples, phosphorus trichloride was used as the acid halogenating agent. As the reaction solvent, solvents such as monochlorobenzene and toluene were used.

Example 200: Preparation of the compound of Compound No. 200

5-chloro-N- {4-[(1,1-dimethyl) ethyl] -5-[(2,2-dimethyl) propionyl] thiazol-2-yl} -2-hydroxybenzamide ( The title compound was obtained in the same manner as the Example 5 using compound No. 199) and acetyl chloride.

Yield: 65.3%

Example 201: Preparation of the compound of Compound No. 201

5-bromosalicylic acid and 2-amino-4-[(1,1-dimethyl) ethyl] -5-[(2,2-dimethyl) propionyl] thiazole (compounds of Example 199 (2)) as raw materials Using the same procedure as in Example 199 (3), the title compound was obtained.

Yield: 23.8%

Example 202: Preparation of the Compound of Compound No. 202

The title compound was obtained in the same manner as the Examples 199 (1) to (3) using pivaloyl acetate ethyl ester as a starting material.

Yield: 45.7% (3 steps)

(1) α-bromo-pivaloyl acetate ethyl ester

(2) 2-amino-4-[(1,1-dimethyl) ethyl] thiazole-5-carboxylic acid ethyl ester

(3) 2- (5-bromo-2-hydroxybenzoyl) amino-4-[(1,1-dimethyl) ethyl] thiazole-5-carboxylic acid ethyl ester (Compound No. 202)

Example 203: Preparation of the compound of Compound No. 203

Example 36 using 2- (5-bromo-2-hydroxybenzoyl) amino-4-[(1,1-dimethyl) ethyl] thiazole-5-carboxylic acid ethyl ester (Compound No. 202) as a starting material The title compound was obtained in the same manner as the title compound to obtain the title compound.

Yield: 85.5%

Example 204: Preparation of the compound of Compound No. 204

(1) 2-amino-5-bromo-4-[(1,1-dimethyl) ethyl] thiazole-2-amino-4-[(1,1-dimethyl) ethyl] thiazole (Example 185 (1 N-bromohoximide (1.00 g, 5.6 mmol) was added to the carbon tetrachloride (9 mL) solution of 0.87 g, 5.6 mmol), and it stirred at room temperature for 1 hour. Hexane was added to the reaction mixture to remove the insolubles. The filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give the title compound yellow gray powder (1.23). g, 93.7%)

(2) 2-amino-4-[(1,1-dimethyl) ethyl] -5-piperidinothiazole

2-amino-5-bromo-4-[(1,1-dimethyl) ethyl] thiazole (0.10 g, 0.42 mmol), piperidine (0.1 mL), potassium carbonate (0.20 g), acetonitrile (4 mL) was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain the title compound. Yellow crystals (80.7 mg, 79.3%) were obtained.

When the manufacturing method of Example 204 (2) is cited in the following examples, bases, such as sodium carbonate, were used as a base. As the reaction solvent, a solvent such as acetonitrile was used.

(3) 2-acetoxy-5-bromo-N- {4-[(1,1-dimethyl) ethyl] -5-piperidinothiazol-2-yl} benzamide

2-acetoxy-5-bromobenzoic acid (90.3 mg, 0.35 mmol), 2-amino-4-[(1,1-dimethyl) ethyl] -5-piperidinothiazole (80.7 mg, 0.34 under argon atmosphere mmol), pyridine (0.1 mL) and tetrahydrofuran (3 mL) were added phosphorus oxychloride (46 μL, 0.50 mmol), followed by stirring at room temperature for 2 hours. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain the title compound. Crude product (84.3 mg) was obtained.

When the manufacturing method of Example 204 (3) is cited in the following examples, phosphorus oxychloride was used as an acid halogenating agent. Pyridine was used as the base. As the reaction solvent, solvents such as dichloromethane and tetrahydrofuran were used.

(4) 5-bromo-N- {4-[(1,1-dimethyl) ethyl] -5-piperidinothiazol-2-yl} -2-hydroxybenzamide (Compound No. 204)

2-acetoxy-5-bromo-N- {4-[(1,1-dimethyl) ethyl] -5-piperidinothiazol-2-yl} benzamide (crude product, 84.3 mg) in ethanol ( 2 mL sodium hydroxide solution (0.1 mL) was added to the solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain the title compound. White powder (54.1 mg, 36.3%; 2 steps) was obtained.

When the manufacturing method of Example 204 (4) is cited in the following examples, inorganic bases, such as sodium hydroxide and potassium carbonate, were used as a base. In addition, as a reaction solvent, solvents, such as water, methanol, ethanol, and tetrahydrofuran, were used individually or in mixture.

Example 205: Preparation of the compound of Compound No. 205

Examples 204 (2) to (4) were prepared using 2-amino-5-bromo-4-[(1,1-dimethyl) ethyl] thiazole (compound of Example 204 (1)) and morpholine as starting materials. The same operation was carried out to obtain the title compound.

Yield: 17.1%

(2) 2-amino-4-[(1,1-dimethyl) ethyl] -5-morpholinothiazole

(3) 2-acetoxy-5-bromo-N- {4-[(1,1-dimethyl) ethyl] -5-morpholinothiazol-2-yl} benzamide

The crude product was used as such for the next reaction.

(4) 5-bromo-N- {4-[(1,1-dimethyl) ethyl] -5-morpholinothiazol-2-yl} -2-hydroxybenzamide (Compound No. 205)

Example 206: Preparation of the compound of Compound No. 206

Examples 204 (2)-(using 2-amino-5-bromo-4-[(1,1-dimethyl) ethyl] thiazole (compound of Example 204 (1)) and 4-methylpiperazine as raw materials The title compound was obtained in the same manner as the 4) to obtain the title compound.

Yield: 6.9%

(2) 2-amino-4-[(1,1-dimethyl) ethyl] -5- (4-methylpiperazin-1-yl) thiazole

(3) 2-acetoxy-N- {4-[(1,1-dimethyl) ethyl] -5- (4-methylpiperazin-1-yl) thiazol-2-yl} benzamide

The crude product was used as such for the next reaction.

(4) 5-bromo-N- {4-[(1,1-dimethyl) ethyl] -5- (4-methylpiperazin-1-yl) thiazol-2-yl} -2-hydroxybenz Amide (Compound No. 206)

Example 207: Preparation of the compound of Compound No. 207

Examples 204 (2)-(using 2-amino-5-bromo-4-[(1,1-dimethyl) ethyl] thiazole (compound of Example 204 (1)) and 4-phenylpiperazine as raw materials The title compound was obtained in the same manner as the 4) to obtain the title compound.

Yield: 6.9%

(2) 2-amino-4-[(1,1-dimethyl) ethyl] -5- (4-phenylpiperazin-1-yl) thiazole

(3) 2-acetoxy-5-bromo-N- {4-[(1,1-dimethyl) ethyl] -5- (4-phenylpiperazin-1-yl) thiazol-2-yl} benz amides

The crude product was used as such for the next reaction.

(4) 5-bromo-N- {4-[(1,1-dimethyl) ethyl] -5- (4-phenylpiperazin-1-yl) thiazol-2-yl} -2-hydroxybenz Amide (Compound No. 207)

Example 208: Preparation of a Compound of Compound No. 208

The title compound was obtained in the same manner as the Example 199 (3) using 5-bromosalicylic acid and 2-amino-4-phenylthiazole as starting materials.

Yield: 16.0%

mp 239 ° C. (dec.).

Example 209: Preparation of the compound of Compound No. 209

The title compound was obtained in the same manner as the Example 199 (3) using 5-bromosalicylic acid and 2-amino-4-phenylthiazole-5-acetic acid methyl ester as starting materials.

Yield: 32.1%

mp 288.5-229.5 ° C.

Example 210: Preparation of the compound of Compound No. 210

Methanol (5 mL) solution of {2-[(5-bromo-2-hydroxybenzoyl) amino] -4-phenylthiazol-5-yl} methyl ester (Compound No. 209; 75 mg, 0.17 mmol) Sodium hydroxide (0.5 mL, 1 mmol) was added to the mixture, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was suspended and washed with n-hexane / ethyl acetate to give the title compound pale yellow white crystals (56 mg, 77.3%). )

mp 284-286 ° C.

Example 211: Preparation of the compound of Compound No. 211

The title compound was obtained in the same manner as the Example 199 (3) using 5-bromosalicylic acid and 2-amino-4,5-diphenylthiazole as starting materials.

Yield: 25.9%

mp 262-263 ° C.

[2-Amino-4,5-diphenylthiazole: Nihon Kagaku Zasshi, 1962, Vol. 83, p. 209]

Example 212: Preparation of the compound of Compound No. 212

The title compound was obtained in the same manner as the Example 199 (3) using 5-bromosalicylic acid and 2-amino-4-benzyl-5-phenylthiazole as starting materials.

Yield: 28.1%

mp 198-200 ° C.

[2-Amino-4-benzyl-5-phenylthiazole: See Chemical & Pharmaceutical Bulletin, 1962, Vol. 10, p. 376.]

Example 213: Preparation of the compound of Compound No. 213

The title compound was obtained in the same manner as the Example 199 (3) using 5-bromosalicylic acid and 2-amino-5-phenyl-4- (trifluoromethyl) thiazole as starting materials.

Yield 33.2%

Example 214: Preparation of the compound of Compound No. 214

The title compound was obtained in the same manner as the Examples 199 (1) to (3) using 1-phenyl-1,3-butanedione as a starting material.

Yield: 8.9% (3 steps)

(1) α-bromo-1-phenyl-1,3-butanedione

(2) 2-amino-5-acetyl-4-phenylthiazole

(3) 5-bromo-N- (5-acetyl-4-phenylthiazol-2-yl) -2-hydroxybenzamide (Compound No. 214)

Example 215: Preparation of the compound of Compound No. 215

The title compound was obtained in the same manner as the Examples 199 (1) to (3) using 1,3-diphenyl-1,3-propanedione as a raw material.

Yield: 49.7%

(1) α-bromo-1,3-diphenyl-1,3-propanedione

(2) 2-amino-5-benzoyl-4-phenylthiazole

(3) 5-bromo-N- (5-benzoyl-4-phenylthiazol-2-yl) -2-hydroxybenzamide (Compound No. 215)

Example 216: Preparation of the compound of Compound No. 216

The title compound was obtained in the same manner as the Example 199 (3) using 5-bromosalicylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as starting materials.

Yield: 28.6%

mp 197-199 ° C.

Example 217: Preparation of the compound of Compound No. 217

The title compound was obtained in the same manner as the Example 36 using 2- (5-bromo-2-hydroxybenzoyl) amino-4-phenylthiazole-5-carboxylic acid ethyl ester (Compound No. 216).

Yield: 67.0%

Example 218: Preparation of the compound of Compound No. 218

The title compound was obtained in the same manner as the Example 199 (3) using 5-chlorosalicylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as starting materials.

Yield: 69.4%

Example 219: Preparation of the Compound of Compound No. 219

The title compound was obtained in the same manner as the Examples 199 (1) to (3) using pentafluorobenzoyl acetate ethyl ester as a starting material.

Yield: 40.0% (3 steps)

(1) α-bromo-pentafluorobenzoyl acetate ethyl ester

The crude product was used as such for the next reaction.

(2) 2-amino-4- (pentafluorophenyl) thiazole-5-carboxylic acid ethyl ester

(3) 2- (5-bromo-2-hydroxybenzoyl) amino-4- (pentafluorophenyl) thiazole-5-carboxylic acid ethyl (compound number 219)

Example 220: Preparation of the compound of Compound No. 220

2- (5-Bromo-2-hydroxybenzoyl) amino-4-phenylthiazole-5-carboxylic acid (Compound No. 217; 0.20 g, 0.48 mmol), methylamine 40% methanol solution (0.2 ml), A mixture of 1-hydroxybenzotriazole hydrate (96.7 mg, 0.72 mmol), WSC.HCl (137.2 mg, 0.72 mmol), tetrahydrofuran (15 mL) was stirred at room temperature for 18 hours. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 2) to obtain dichloromethane. Crystallization with / n-hexane afforded the title compound as a white powder (87.9 mg, 42.6%).

In the following examples, when the method of Example 220 was cited, WSC.HCl and 1-hydroxybenzotriazole hydrate were used as the dehydrating condensing agent. As the reaction solvent, a solvent such as tetrahydrofuran was used.

Example 221: Preparation of the compound of Compound No. 221

The same operation as in Example 202 was carried out using a 70% aqueous solution of 2- (5-bromo-2-hydroxybenzoyl) amino-4-phenylthiazole-5-carboxylic acid (Compound No. 217) and ethylamine as starting materials. To give the title compound.

Yield: 62.5%

Example 222: Preparation of a Compound of Compound No. 222

The title compound was obtained in the same manner as the Example 220 using 2- (5-bromo-2-hydroxybenzoyl) amino-4-phenylthiazole-5-carboxylic acid (Compound No. 217) and isopropylamine as starting materials. Got.

Yield: 23.9%

Example 223: Preparation of a Compound of Compound No. 223

The same operation as in Example 220 was carried out using 2- (5-bromo-2-hydroxybenzoyl) amino-4-phenylthiazole-5-carboxylic acid (Compound No. 217) and 2-phenethylamine as starting materials. The title compound was obtained.

Yield: 62.2%

Example 224: Preparation of a Compound of Compound No. 224

The title compound was obtained in the same manner as the Example 199 (3) using 5-bromosalicylic acid and 2-amino-4- (trifluoromethyl) thiazole-5-carboxylic acid ethyl ester as starting materials.

Yield: 88.7%

Example 225: Preparation of the compound of Compound No. 225

The title compound was obtained in the same manner as the Example 199 (3) using 4-hydroxybiphenyl-3-carboxylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as starting materials.

Yield: 61.7%

mp 207-208 ° C.

[4-hydroxybiphenyl-3-carboxylic acid: See Tetrahedron, (US), 1997, Vol. 53, p.11437]

Example 226: Preparation of the compound of Compound No. 226

The same as Example 199 (3) using (4'-fluoro-4-hydroxybiphenyl) -3-carboxylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as starting materials. The operation was carried out to obtain the title compound.

Yield: 62.7%

mp 237-238 ° C.

[(4'-Fluoro-4-hydroxybiphenyl) -3-carboxylic acid: See Tetrahedron, 1997, Vol. 53, p.11437]

Example 227: Preparation of the compound of Compound No. 227

Example 199 using (2 ', 4'-difluoro-4-hydroxybiphenyl) -3-carboxylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as starting materials The title compound was obtained in the same manner as the 3).

Yield: 45.6%

mp 206-207 ° C.

Example 228: Preparation of the compound of Compound No. 228

(1) [4-hydroxy-4 '-(trifluoromethyl) biphenyl] -3-carboxylic acid

5-bromosalicylic acid (500 mg, 2.30 mmol), dihydroxy-4- (trifluoromethyl) phenylborane (488 mg, 2.57 mmol), palladium acetate (10 mg, 0.040 mmol) and 1 mol / L sodium carbonate The mixture of aqueous solution (7 mL) was stirred at 80 ° C. for 1 hour. The reaction mixture was cooled to room temperature, poured into dihydrogen hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was subjected to methyl esterification with trimethylsilyldiazomethane and methanol according to the conventional method. Purification by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) gave a colorless liquid (563 mg). Sodium hydroxide (3 mL) was added to the methanol (10 mL) solution of this liquid and stirred at 60 ° C for 1 hour. The reaction mixture was cooled to room temperature, poured into dihydrogen hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was suspended and washed with n-hexane / dichloromethane to obtain the title compound as white crystals (458 mg, 70.4%). )

mp 185 ° C. (dec.).

(2) 2-{[4-hydroxy-4 '-(trifluoromethyl) biphenyl] -3-carbonyl} amino-4-phenylthiazole-5-carboxylic acid ethyl ester (Compound No. 228)

Example 199 ([4-hydroxy-4 '-(trifluoromethyl) biphenyl] -3-carboxylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester were used as starting materials. The title compound was obtained in the same manner as the 3).

Yield: 41.7%

mp 236-237 ° C.

Example 229: Preparation of the compound of Compound No. 229

The title compound was obtained in the same manner as the Example 199 (3) using 2-hydroxy-5- (1-pyrrolyl) benzoic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as starting materials. Got it.

Yield: 55.0%

Example 230: Preparation of the compound of Compound No. 230

(1) 2-hydroxy-5- (2-thienyl) benzoic acid

To a 5-bromosalicylic acid (500 mg, 2.30 mmol) solution of 1,2-dimethoxyethane (5 mL), tetrakis (triphenylphosphine) palladium (80 mg, 0.07 mmol) was added under argon atmosphere at room temperature. Stir for 10 minutes. Dihydroxy-2-thienylborane (324 mg, 2.53 mmol) and 1 mol / L aqueous sodium carbonate solution (7 mL) were then added and heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, poured into dihydrogen hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was subjected to methyl esterification with trimethylsilyldiazomethane and methanol according to the conventional method, followed by silica gel column chromatography. Purification by chromatography (n-hexane: ethyl acetate = 5: 1) gave a yellow liquid (277 mg). Sodium hydroxide (1.5 mL) was added to the methanol (5 mL) solution of this liquid and stirred at 60 ° C for 1 hour. The reaction mixture was cooled to room temperature, poured into dihydrogen hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was crystallized with n-hexane / dichloromethane to give the title compound as white crystals (58 mg). , 11.5%).

(2) 2- [2-hydroxy-5- (2-thienyl) benzoyl] amino-4-phenylthiazole-5-carboxylic acid ethyl ester (Compound No. 230)

The title compound was obtained in the same manner as the Example 199 (3) using 2-hydroxy-5- (2-thienyl) benzoic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as starting materials. Got it.

Yield: 58.2%

mp 213-214 ° C.

Example 231: Preparation of the compound of Compound No. 231

(1) 2-amino-4- [3,5-bis (trifluoromethyl) phenyl] thiazole

To a tetrahydrofuran (5 ml) solution of 3 ', 5'-bis (trifluoromethyl) acetophenone (0.51 g, 2.0 mmol) was added phenyltrimethylammonium tribromide (753 mg, 2 mmol), Stirred for time. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, ethanol (5 mL) and thiourea (152 mg, 2 mmol) were added to the obtained residue, and the mixture was heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature, poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1), and the mixture was suspended and washed with n-hexane. This gave the title compound pale yellow white crystals (520.1 mg, 83.3%).

(2) 5-chloro-2-hydroxy-N- {4- [3,5-bis (trifluoromethyl) phenyl] thiazol-2-yl} benzamide (Compound No. 231)

5-chlorosalicylic acid (172.6 mg, 1 mmol), 2-amino-4- [3,5-bis (trifluoromethyl) phenyl] thiazole (312.2 mg, 1 mmol), phosphorus trichloride (44 μL, 0.5 mmol) ), A mixture of monochlorobenzene (5 mL) was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1-&gt; 2: 1) to obtain the title compound. A pale yellow white powder (109.8 mg, 23.5%) was obtained.

Example 232: Preparation of the compound of Compound No. 232

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-amino-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylic acid ethyl ester as starting materials.

Yield: 49.6%

Example 233: Preparation of a compound of Compound No. 233

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 3-amino-5-phenylpyrazole as starting materials.

Yield: 9.2%

Example 234: Preparation of the compound of Compound No. 234

(1) 2-amino-4,5-diethyloxazole

Cyanamide (0.75 g, 17.7 mmol) and sodium ethoxide (1.21 g, 17.7 mmol) were added to a solution of propioin (1.03 g, 8.87 mmol) in ethanol (15 mL), and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 9: 1) to give the title compound yellow secret. Amorphous (369.2 mg, 29.7%) was obtained.

(2) 2-acetoxy-5-bromo-N- (4,5-diethyloxazol2-yl) benzamide

The title compound was obtained in the same manner as the Example 5 using 2-acetoxy-5-bromobenzoic acid and 2-amino-4,5-diethyloxazole as starting materials.

Yield: 22.0%

(3) 5-Bromo-N- (4,5-diethyloxazol2-yl) -2-hydroxybenzamide (Compound No. 234)

The title compound was obtained in the same manner as the Example 2 using 2-acetoxy-5-bromo-N- (4,5-diethyloxazol-2-yl) benzamide as a starting material.

Yield: 70.2%

Example 235: Preparation of a compound of Compound No. 235

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 2-amino-4,5-diphenyloxazole as starting materials.

Yield: 32.6%

mp 188-189 ° C.

[2-Amino-4,5-diphenyloxazole: 「Organic Organic Chesistry: Russian Journal of Organic Chemistry」, (Russia), 1980, 16th Vol., P.2185]

Example 236: Preparation of a compound of Compound No. 236

(1) 2-amino-4,5-bis (furan-2-yl) oxazole

To ethanol (15 ml) solution of furoin (0.50 g, 2.60 mmol), cyanamide (218.8 mg, 5.20 mmol) and sodium ethoxide (530.8 mg, 7.80 mmol) were added and stirred at room temperature for 2 hours. It was. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1-1: 2). The dark brown crystals (175.0 mg, 31.1%) were obtained as the title compound.

(2) 5-bromo-N- [4,5-bis (furan-2-yl) oxazol-2-yl] -2-hydroxybenzamide (Compound No. 236)

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 2-amino-4,5-bis (furan-2-yl) oxazole as starting materials.

Yield: 12.9%

Example 237: Preparation of a Compound of Compound No. 237

(1) 2-acetoxy-N- (5-trifluoromethyl-1,3,4-thiadiazol-2-yl) benzamide

The title compound was obtained in the same manner as the Example 1 using O-acetylsalicylic acid chloride and 2-amino-5-trifluoromethyl-1,3,4-thiadiazole as starting materials.

Yield: 51.1%

(2) 2-hydroxy-N- (5-trifluoromethyl-1,3,4-thiadiazol-2-yl) benzamide (Compound No. 237)

The title compound was obtained in the same manner as the Example 2 using 2-acetoxy-N- (5-trifluoromethyl-1,3,4-thiadiazol-2-yl) benzamide as a starting material.

Yield: 92.9%

Example 238: Preparation of the compound of Compound No. 238

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 2-amino-5-trifluoromethyl-1,3,4-thiadiazole as starting materials.

Yield: 80.2%

Example 239: Preparation of the compound of Compound No. 239

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 3-aminopyridine as starting materials.

Yield: 23.2%

Example 240: Preparation of the compound of Compound No. 240

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 5-amino-2-chloropyridine as starting materials.

Yield: 12.2%

Example 241: Preparation of a compound of Compound No. 241

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-amino-6-chloro-4-methoxypyrimidine as starting materials.

Yield: 2.2%, white solid

Example 242: Preparation of a compound of Compound No. 242

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 3-aminoquinoline as starting materials.

Yield: 4.3%

Example 243: Preparation of the compound of Compound No. 243

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-amino-6-bromopyridine as starting materials.

Yield: 12.3%

Example 244: Preparation of the compound of Compound No. 244

(1) 2-acetoxy-5-chlorobenzoic acid

Concentrated sulfuric acid (0.08 mL) was slowly added dropwise to a mixture of 5-chlorosalicylic acid (13.35 g, 77 mmol) and acetic anhydride (20 mL). After the reaction mixture solidified, it was poured into iced water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was suspended and washed with n-hexane to obtain white crystals (15.44 g, 93.0%) as the title compound.

(2) 2-acetoxy-5-chloro-N- (pyridazin-2-yl) benzamide

The title compound was obtained in the same manner as the Example 204 (3) using 2-acetoxy-5-chlorobenzoic acid and 2-aminopyridazine as starting materials.

Yield: 19.7%

(3) 5-Chloro-2-hydroxy-N- (pyridazin-2-yl) benzamide (Compound No. 244)

The title compound was obtained in the same manner as the Example 2 using 2-acetoxy-5-chloro-N- (pyridazin-2-yl) benzamide as a starting material.

Yield: 72.6%

Example 245: Preparation of the compound of Compound No. 245

The title compound was obtained in the same manner as the Example 3 using 5-bromosalicylic acid and 2-amino-5-bromopyrimidine as starting materials.

Yield: 10.3%

Example 246: Preparation of the compound of Compound No. 246

The title compound was obtained in the same manner as the Example 220 using 2- (5-bromo-2-hydroxybenzoyl) amino-4-phenylthiazole5-carboxylic acid (Compound No. 217) and propylamine as starting materials. .

Yield: 23.1%

Example 247: Preparation of a compound of Compound No. 247

Of 5-sulfosalicylic acid (218 mg, 1 mmol), 3,5-bis (trifluoromethyl) aniline (229 mg, 1 mmol), phosphorus trichloride (88 μL, 1 mmol), ortho-xylene (5 mL) The mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain the title compound as a white solid (29 mg, 9.2%).

Example 248: Preparation of the compound of Compound No. 248

5-chlorosalicylic acid (87 mg, 0.5 mmol), 2,2-bis (3-amino-4-methylphenyl) -1,1,1,3,3,3-hexafluoropropane (363 mg, 1 mmol) , A mixture of phosphorus trichloride (44 μL, 0.5 mmol) and toluene (4 mL) was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to obtain the title compound White (16 mg, 4.9%) (Example 251, compound No. 251 described later). The compound was obtained as a byproduct.)

Example 249: Preparation of the compound of Compound No. 249

The title compound was obtained in the same manner as the Example 3 using 3-phenylsalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 64.6%

Example 250: Preparation of the compound of Compound No. 250

The title compound was obtained in the same manner as the Example 3 using 4-fluorosalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 65.7%

Example 251: Preparation of a Compound of Compound No. 251

In Example 248 described above, a mixture with a compound of Compound No. 248 was obtained separately.

Yield: 9.4%

Example 252: Preparation of the compound of Compound No. 252

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 4- [2-amino-4- (trifluoromethyl) phenoxy] benzonitrile as starting materials.

Yield: 11.6%

Example 253: Preparation of the Compound of Compound No. 253

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 3-amino-4- (4-methoxyphenoxy) benzotrifluoride as starting materials.

Yield: 88.1%

Example 254: Preparation of the compound of Compound No. 254

The title compound was obtained in the same manner as the Example 3 using salicylic acid and 2,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 47.8%

Example 255: Preparation of the compound of Compound No. 255

(1) 2-amino-4- (2,4-dichlorophenyl) thiazole

The title compound was obtained in the same manner as the Example 231 (1) using 2 ', 4'-dichloroacetophenone and thiourea as starting materials.

Yield: 97.1%

(2) 5-chloro-2-hydroxy-N- [4- (2,4-dichlorophenyl) thiazol-2-yl] benzamide (Compound No. 255)

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-amino-4- (2,4-dichlorophenyl) thiazole as starting materials.

Yield: 8.0%

Example 256: Preparation of the compound of Compound No. 256

The title compound was obtained in the same manner as the Example 3 using 3-isopropylsalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 99.2%

Example 257: Preparation of the compound of Compound No. 257

Argon atmosphere in carbon tetrachloride (5 mL) solution of N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-3-isopropylbenzamide (Compound No. 256; 100 mg, 0.26 mmol). Bromine (14.4 μL, 0.28 mmol) and iron (1.7 mg, 0.03 mmol) were added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized with n-hexane / ethyl acetate to give the title compound as a white solid (110 mg, 91.5%).

Example 258: Preparation of the compound of Compound No. 258

Methanol / water (3: 1) mixed solution of N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-3-methylbenzamide (Compound No. 58; 150 mg, 0.41 mmol) ( 5 mL) was added to N-bromohoximide (88.2 mg, 0.50 mmol) and stirred for 10 minutes at room temperature. The reaction mixture was diluted with ethyl acetate. The ethyl acetate layer was washed sequentially with 10% aqueous sodium thiosulfate solution, water, and brine, 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 (n-hexane: ethyl acetate = 5: 1) to obtain a white powder (167 mg, 91.5%) as a title compound.

Example 259: Preparation of the compound of Compound No. 259

The title compound was obtained in the same manner as the Example 258 using N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-3-phenylbenzamide (Compound No. 249).

Yield: 67.5%

Example 260: Preparation of the compound of Compound No. 260

(1) 2-amino-4- (3,4-dichlorophenyl) thiazole

The title compound was obtained in the same manner as the Example 231 (1) using 3 ', 4'-dichloroacetophenone and thiourea as starting materials.

Yield: 77.8%

(2) 5-chloro-2-hydroxy-N- [4- (3,4-dichlorophenyl) thiazol-2-yl] benzamide (Compound No. 260)

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-amino-4- (3,4-dichlorophenyl) thiazole as starting materials.

Yield: 15.1%

Example 261: Preparation of the compound of Compound No. 261

(1) 2-amino-4- [4- (trifluoromethyl) phenyl] thiazole

The title compound was obtained in the same manner as the Example 231 (1) using 4 '-(trifluoromethyl) acetophenone and thiourea as starting materials.

Yield: 77.5%

(2) 5-chloro-2-hydroxy-N- {4- [4- (trifluoromethyl) phenyl] thiazol-2-yl} benzamide (Compound No. 261)

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-amino-4- [4- (trifluoromethyl) phenyl] thiazole as starting materials.

Yield: 16.0%

Example 262: Preparation of the compound of Compound No. 262

(1) Methyl 2-methoxy-4-phenylbenzoate

N, N-dimethylformamide (15 mL) of methyl 4-chloro-2-methoxybenzoate (904 mg, 4.5 mmol), phenylboronic acid (500 mg, 4.1 mmol), cesium carbonate (2.7 g, 8.2 mmol) Dichlorobis (triphenylphosphine) palladium (29 mg, 0.04 mmol) was added to the solution under argon atmosphere, and the mixture was stirred at 120 ° C for 8 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain a colorless oil (410 mg, 41.2%) as a title compound.

(2) 2-methoxy-4-phenylbenzoic acid

To a methanol (5 mL) solution of 2-methoxy-4-phenyl benzoate (410 mg, 1.69 mmol) was added 2 aqueous sodium hydroxide solution (5 mL) and heated to reflux for 1 hour. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. 2N hydrochloric acid was added to the obtained residue, and the precipitated crystals were collected by filtration to obtain a crude product (371 mg, 96.0%) as the title compound.

(3) N- [3,5-bis (trifluoromethyl) phenyl] -2-methoxy-4-phenylbenzamide

The title compound was obtained in the same manner as the Example 3 using 2-methoxy-4-phenylbenzoic acid and 3,5-bis (trifluoromethyl) aniline as starting materials.

Yield: 97.5%

(4) N- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-4-phenylbenzamide (Compound No. 262)

1M boron tribromide-dichloromethane in a solution of dichloromethane (5 mL) of N- [3,5-bis (trifluoromethyl) phenyl] -2-methoxy-4-phenylbenzamide (100 mg, 0.24 mmol) A solution (0.71 mL, 0.71 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed sequentially with water and brine, 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 (n-hexane: ethyl acetate = 5: 1) to obtain a white powder (69.3 mg, 71.6%) as a title compound.

Example 263: Preparation of the compound of Compound No. 263

(1) 2-amino-4- (2,5-difluorophenyl) thiazole

The title compound was obtained in the same manner as the Example 231 (1) using 2 ', 5'-difluoroacetophenone and thiourea as starting materials.

Yield: 77.8%

(2) 5-chloro-2-hydroxy-N- [4- (2,5-difluorophenyl) thiazol-2-yl] benzamide (Compound No. 263)

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-amino-4- (2,5-difluorophenyl) thiazole as starting materials.

Yield: 36.5%

Example 264 Preparation of the Compound of Compound No. 264

(1) 2-amino-4- (4-methoxyphenyl) thiazole

The title compound was obtained in the same manner as the Example 231 (1) using 4'-methoxyacetophenone and thiourea as starting materials.

Yield: 85.2%

(2) 5-chloro-2-hydroxy-N- [4- (4-methoxyphenyl) thiazol-2-yl] benzamide (Compound No. 264)

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-amino-4- (4-methoxyphenyl) thiazole as starting materials.

Yield: 16.4%

Example 265: Preparation of the compound of Compound No. 265

(1) 2-amino-4- [3- (trifluoromethyl) phenyl] thiazole

The title compound was obtained in the same manner as the Example 231 (1) using 3 '-(trifluoromethyl) acetophenone and thiourea as starting materials.

Yield: 94.1%

(2) 5-chloro-2-hydroxy-N- {4- [3- (trifluoromethyl) phenyl] thiazol-2-yl} benzamide (Compound No. 265)

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-amino-4- [3- (trifluoromethyl) phenyl] thiazole as starting materials.

Yield: 31.0%

Example 266: Preparation of the compound of Compound No. 266

(1) 2-amino-4- (2,3,4,5,6-pentafluorophenyl) thiazole

The title compound was obtained in the same manner as the Example 231 (1) using 2 ', 3', 4 ', 5', 6'-pentafluoroacetophenone and thiourea as starting materials.

Yield: 86.7%

(2) 5-chloro-2-hydroxy-N- [4- (2,3,4,5,6-pentafluorophenyl) thiazol-2-yl] benzamide (Compound No. 266)

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-amino-4- (2,3,4,5,6-pentafluorophenyl) thiazole as starting materials.

Yield: 23.8%

Example 267: Preparation of the compound of Compound No. 267

The title compound was obtained in the same manner as the Example 3 using 5-chlorosalicylic acid and 2-amino-4-methylbenzophenone as starting materials.

Yield: 8.7%

Example 268: Preparation of a Compound of Compound No. 268

To a solution of carbon tetrachloride (5 mL) of 2-hydroxy-N- [2,5-bis (trifluoromethyl) phenyl] benzamide (Compound No. 254; 175 mg, 0.5 mmol), iron (3 mg, 0.05 mmol) ) And bromine (129 µl, 2.5 mmol) were added and the mixture was stirred at 50 ° C for 12 hours. The reaction mixture was cooled to room temperature, washed with saturated sodium bicarbonate water, water and brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain white crystals (184.2 mg, 72.7%) as a title compound.

Test Example 1 Measurement of NF-κB Activation Inhibition

Inhibition of NF-κB activation was carried out with reference to Hill et al. (Cell, US, 1993, Vol. 73, No. 2, p. 395-406). A transfection reagent (pNFκB-Luc Reporter Plasmid: manufactured by STRATAGENE) in which an oligonucleotide linking five (in series) NF-κB binding sequences (TGGGGACTTTCCGC) was inserted upstream of the firefly luciferase gene (Luc). QIAGEN Co.) was transfected into human liver cancer cell line HepG2 according to QIAGEN's protocol and incubated for 6 to 24 hours. After 4 hours of incubation with TNF-α (40 ng / ml) in the presence or absence of the compound to be tested, the intracellular luciferase activity was determined by the Pickergin LT (manufactured by Toyo Ink Co.) and a chemiluminescence measuring device (SPECTRAFLUORPLUS). , Manufactured by TECAN Co., Ltd.). Inhibition rate was calculated | required by the ratio with respect to the luciferase activity value in the absence of the test compound. The inhibition rate of NF-κB activity in the presence of 10 μg / ml and 1 μg / ml of the test compound is shown in the table below.

 N. T. Not tested

Test Example 2 Measurement of AP-1 Activation Inhibition by TNFα Stimulation

Transfection reagent (pAP-1-Luc Reporter Plasmid: manufactured by STRATAGENE) in which an oligonucleotide having 7 linked (serial) AP-1 binding sequences (TGACTAA) is inserted upstream of the firefly luciferase gene (Luc) Effectene, manufactured by QIAGEN), was transfected into human uterine cancer-derived cell line HeLa according to QIAGEN's protocol, and cultured for 6 to 24 hours. After 4 hours of incubation with TNF-α (40 ng / ml) in the presence or absence of the compound to be tested, the luciferase activity in the cells was determined using the Pickergin LT (manufactured by Toyo Ink Co.) and a chemiluminescence measuring device (SPECTRAFLUORPLUS, It was measured using TECAN company). Inhibition rate was calculated | required by the ratio with respect to the luciferase activity value in the absence of the test compound. The inhibition rate of NF-κB activity in the presence of 10 μg / ml and 1 μg / ml of the test compound is shown in the table below.

NT: Not tested

Experimental Example 3: Measurement of Inhibition of Memory Dysfunction Using Alzheimer's Model Animals by Injecting Human β-amyloid into Rat Hippocampus

The micro-injection method was used to inject a 1: 1 mixture of Aβ1-40 and Aβ1-43 of human β-amyloid (Aβ) into several parts of the rat hippocampus for 7 consecutive days, and on the eighth day, the bipolar stimulating electrode was removed under urethane anesthesia. In the perforant path way, the recording electrodes were fixed to the hippocampal dentate gyrus. From the stimulation electrode, a mono-synaptic response is found by a test pulse of about 14-20 mV, and long-term potentiation (LTP: neurophysiology) by test stimulation and tetanic stimulation is found. By comparing the memory model phenomena, we examined the presence of memory dysfunction, a problem in Alzheimer's disease. The control group was physiological saline, and the administration group was administered intraperitoneally with the test compound administration group (30 mg / kg) once a day from 3 days before the start of β amyloid injection, and LTP was compared. The results are shown in FIG.

Test Example 4: Inhibition of epileptic seizures using epileptic model rats

Noda Epilepsy Rats (NER), a spontaneous large paroxysmal rat, were administered intraperitoneally with 0.5 ml of normal saline (control) or 30 mg / kg of the compound to be tested once daily for two weeks. Then, the urethane electrode under urine anesthesia was fixed in the through passage, and the recording electrode hippocampal tooth-shaped molecular layer was fixed, and the induced reaction by two consecutive paired pulses was compared. As a result, the control group recorded continuous spikes as seen in the epilepsy after stimulation, while the administration group showed the polar waves, but no continuous waveforms as in the control group were observed. These results indicate that the medicine of the present invention is useful for the prevention and / or treatment of epilepsy.

Test Example 5 Measurement of AP-1 Activation Inhibition by Forced Expression of MEKK-1

A plasmid (pAP-1-Luc Reporter Plasmid: manufactured by STRATAGENE) and MEKK-1, in which an oligonucleotide linked to seven AP-1 binding sequences (TGACTAA) is linked (in series) upstream of the firefly luciferase gene (Luc). An expression plasmid (pFCMEKK: manufactured by STRATAGENE) was transfected into a human hepatic cancer-derived cell line HepG2 using a transfection reagent (Effectene, manufactured by QIAGEN) according to QIAGEN's protocol and incubated for 20 to 24 hours. Thereafter, after 24 hours of incubation in the presence or absence of the compound to be tested, intracellular luciferase activity was measured using a Picker Gene LT (manufactured by Toyo Ink Co., Ltd.) and a chemiluminescence measuring device (Genios, TECAN Company). Inhibition rate was calculated | required by the ratio with respect to the luciferase activity value in the absence of the test compound. The inhibition rate of AP-1 activity in the presence of 1 μg / ml and / or 1 μM of the compound to be tested is shown in the table below.

N.T .: Not tested

The medicament of the present invention has an action of simultaneously inhibiting AP-1 and NF-κB activation, and based on the above action, can exhibit high effectiveness in the prevention and / or treatment of Alzheimer's disease and epilepsy.

Claims (12)

Formula I: <Formula I> (In formula, A represents a hydrogen atom or an acetyl group, E is a 2,5-disubstituted or 3,5-disubstituted phenyl group, or a monocyclic or condensed polycyclic heteroaryl group which may have a substituent, provided that the heteroaryl group is directly connected to the -CONH- group in (I). Is a benzene ring condensed polycyclic heteroaryl group, (2) unsubstituted thiazol-2-yl group, and (3) unsubstituted benzothiazol-2-yl group). Ring Z is an arene which may further have a substituent in addition to the group represented by the formula -OA (wherein A is the same as defined above) and formula -CONH-E (wherein E is the same as defined above); Or heteroarene which may further have a substituent in addition to the group represented by the formula -OA (wherein A is the same as defined above) and the formula -CONH-E (wherein E is the same as defined above). A medicament for the prevention and / or treatment of Alzheimer's disease comprising a compound represented by) and a pharmaceutically acceptable salt thereof, a hydrate thereof, and a substance selected from the group consisting of solvates thereof as an active ingredient. A medicament for the prevention and / or treatment of epilepsy comprising a compound represented by the formula (I) of claim 1 and a pharmacologically acceptable salt thereof, a hydrate thereof and a solvate thereof as an active ingredient. The pharmaceutical according to claim 1 or 2, wherein A is a hydrogen atom. The ring Z according to any one of claims 1 to 3, wherein ring Z is an arene of C ₆ to C ₁₀ , wherein the arene is a formula -OA (wherein A is the same as defined in Formula I) and a formula- In addition to the group represented by CONH-E (wherein E is the same as defined in the formula (I)), or may further have a substituent, or a 5-10 membered heteroarene (where the heteroarene is represented by the formula -OA ( In the formula, A may be identical to the definition in formula (I) and formula -CONH-E (wherein E is the same as definition in formula (I)) and may further have a substituent. Phosphorus. 5. The ring of claim 4 wherein ring Z is of the formula -OA wherein A is as defined in formula I and -CONH-E wherein E is as defined in formula I Benzene ring which may further have a substituent in addition to the group represented by the formula, or formula -OA (wherein A is the same as defined in formula I) and formula -CONH-E (wherein E is A medicament which is a naphthalene ring which may further have a substituent other than the group represented by the same definition as). The compound of claim 5, wherein ring Z is of the formula -OA, wherein A is as defined in formula I and -CONH-E, wherein E is as defined in formula I A pharmaceutical which is a benzene ring having a halogen atom in addition to the group represented by. The compound of claim 5, wherein ring Z is of the formula -OA, wherein A is as defined in formula I and -CONH-E, wherein E is as defined in formula I The pharmaceutical which is a naphthalene ring which may have a substituent further besides the group represented by. The medicament according to any one of claims 1 to 7, wherein E is a 2,5-disubstituted or 3,5-disubstituted phenyl group. The compound according to claim 8, wherein E is a 2,5-disubstituted phenyl group (at least one of the substituents is a trifluoromethyl group) or a 3,5-disubstituted phenyl group (at least one of the substituents is a trifluoromethyl group Medicine. The pharmaceutical according to claim 9, wherein E is a 3,5-bis (trifluoromethyl) phenyl group. The monocyclic or condensed polycyclic heteroaryl group according to any one of claims 1 to 7, wherein E may have a substituent, provided that the ring in which the heteroaryl group is directly connected to the -CONH- group in (I) is benzene. A fused polycyclic heteroaryl group which is a ring, ② unsubstituted thiazol-2-yl group, and ③ unsubstituted benzothiazol-2-yl group). The pharmaceutical according to claim 11, wherein E is a 5-membered monocyclic heteroaryl group which may have a substituent, except that the heteroaryl group is an unsubstituted thiazol-2-yl group.