HK1118015A

HK1118015A - Inhibitors against the production and release of inflammmatory cytokines

Info

Publication number: HK1118015A
Application number: HK08109112.6A
Authority: HK
Inventors: 武藤进; 永野辰夫; 早乙女智美; 板井昭子
Original assignee: 株式会社医药分子设计研究所
Priority date: 2000-12-18
Filing date: 2004-08-19
Publication date: 2009-01-30

Description

Inflammatory cytokine production dissociation inhibitor

The present application is a divisional application filed on the application date of 2001, 12/18/2001, under the name of 01822716.3, entitled "inhibitor of inflammatory cytokine production release".

Technical Field

The present invention relates to a drug having an inhibitory effect on the dissociation of the production of inflammatory cytokines such as Interleukins (IL) -1, IL-6, IL-8, tumor necrosis factor (TNF-alpha), etc., and an inhibitory effect on NF- κ B activation.

Background

Inflammation is the fundamental body defense response to various kinds of invasion, and inflammatory cytokines, Interleukin (IL) -1 and TNF- α (tumor necrosis factor), are known to play an important role in this defense response. As the gene analysis of inflammatory cytokines and inflammatory cell adhesion factors proceeds, it is known that these factors are controlled by a common transcription factor (also referred to as a transcription regulatory factor). These transcription factors are proteins known as NF-. kappa.B (sometimes also referred to as NF-. kappa.B) (Clark B.D. et al, Nucl. acids Res., 14, 7898 (1984); Nedosposasov S.A. et al, Cold Spring Harb. Symp. Quant. biol., 51, 611 (1986)).

The NF-. kappa.B is a heterodimer (also known as a complex) of p65 (also known as Rel A) and p50 (also known as NF-. kappa.B-1), and usually binds to I-. kappa.B in the absence of external stimuli and exists in the cytoplasm as an inert form. I-. kappa.B is phosphorylated by various external stimuli (oxidative stress, cytokines, lipopolysaccharides, viruses, UV, free radicals, protein kinase C, etc.), ubiquitinated, and then decomposed by proteasomes (Verma I.M., Stevenson J.K., et al, Genes Dev., 9, 2723-2735 (1995)). NF-. kappa.B separated from I-. kappa.B rapidly migrates into the nucleus, binds to a promoter region having a recognition sequence of NF-. kappa.B, and functions as a transcription factor.

After 1997, phosphorylases (called IKB kinases, IKK for short) associated with the phosphorylation of I-. kappa.B were identified (DiDonation J., Hayakawa M. et al, Nature, 388, 548-383 (1997); Regnier C.H., Song H.Y. et al, Cell, 90, 373-383 (1997)). It is known that there are very similar IKK-alpha (also known as IKK1) and IKK-beta (also known as IKK2) in IKK, which form complexes that bind directly to IkB, phosphorylate it (Woronicz J.D. et al, Science, 278, 866-869 (1997); Zandi, E. et al, Cell, 91243-252 (1997)).

It is known that, recently, for aspirin which has been widely used as an anti-inflammatory agent, a mechanism of action other than the inhibition of cyclooxygenase is conceived, and this action is achieved by inhibiting NF-. kappa.B activation (Kopp E. et al, Science, 265, 956-959 (1994)). Moreover, it has been shown that aspirin competes with ATP for reversible binding to the I κ B kinase IKK- β, inhibiting phosphorylation of I κ B, and thus inhibiting the liberation, activation of NF- κ B (Yin m.j. et al, Nature, 396, 77-80 (1998)). However, aspirin must be administered in a large dose in order to sufficiently inhibit NF- κ B activation, and side effects such as gastrointestinal disorders due to inhibition of prostaglandin synthesis and increased bleeding tendency due to anti-blood coagulation are likely to occur, and therefore, it is not suitable for long-term use.

In addition to aspirin, drugs which have been clarified to have an inhibitory effect on NF- κ B activation are also known. Glucocorticoids (steroid hormones) such as dexamethasone are known to activate NF- κ B by binding to their receptors (called glucocorticoid receptors) (Scheinman r.i. et al, Science, 270, 283(1995)), but are not suitable for long-term use due to serious side effects such as exacerbation of infection, development of peptic ulcer, reduction of bone density, central action, and the like. The immunosuppressant isoxazole drug leflunomide also has NF-. kappa.B inhibitory action (Manna S. et al, J.Immunol., 164, 2095-2102(1999)), but is also not suitable for long-term use due to serious side effects. Further, as NF-. kappa.B activation inhibitors, substituted pyrimidine derivatives (Japanese patent application laid-open No. 11-512399, Japanese patent application laid-open No. 11-512399, J.Med.chem., 41, 413(1998)), xanthine derivatives (Japanese patent application laid-open No. 9-227561), isoquinoline derivatives (Japanese patent application laid-open No. 10-87491), indane derivatives (WO 00/05234), epiquinomycin C, D and derivatives thereof (Japanese patent application laid-open No. 10-45738, bioorg.Med.chem.Lett., 10, 865-Astro 869(2000)) are known, but the mechanism of action and the receptor or protein acting to inhibit NF-. kappa.B activation are not yet known.

DISCLOSURE OF THE INVENTION

IKK-beta specific inhibitory compounds were found with IKK-beta directly causing phosphorylation of IkB as a target, and it was expected that the compounds had no influence on other signal transduction pathways, i.e., showed no serious side effects, and showed desired effects of inhibiting the release of inflammatory cytokines and inflammatory cell adhesion molecules. Further, it is considered that the above-mentioned external stimulus activates NF- κ B, and expresses proteins such as inflammatory cytokines, and among the inflammatory cytokines, particularly TNF- α and interleukin (I L) -1, the gene expression itself is positively controlled by NF- κ B to form a positive feedback loop [ TNF- α → NF- κ B → TNF- α ], and the compound plays a part of the chronic inflammation (18 th day of the society of inflammation, "mechanism of action and progress of antirheumatic drug", tokyo, 2000), and therefore, the specific inhibitory compound targeting IKK- β is expected to be a useful drug for chronic-mediated inflammatory diseases and diseases caused by TNF- α and IL-1.

Accordingly, an object of the present invention is to provide a drug useful for the prevention and/or treatment of inflammatory diseases in which inflammatory cytokines are involved, autoimmune diseases such as chronic rheumatic arthritis, and bone diseases such as osteoporosis. Another object of the present invention is to provide an inhibitor of inflammatory cytokine production release which can specifically inhibit IKK-beta to avoid side effects and has an inhibitory activity on NF-kappa B activation.

In order to solve the above problems, the present inventors have searched for compounds that inhibit NF-. kappa.B activation by selectively inhibiting IKK-. beta.by a molecular design technique using a computer. An appropriate substance having high homology to IKK- β is selected from a protein kinase having a structure registered in PDB (protein database), a three-dimensional structure model of IKK- β is constructed by a method for creating a homology model using the appropriate substance as a template, and the binding pattern of aspirin and the ATP-binding region of IKK- β and the characteristic intermolecular interaction are analyzed by using an automatic search program for the binding pattern of a drug molecule to a protein. Based on the results, compounds capable of becoming IKK- β specific inhibitors were screened from compounds posted in commercial compound databases by Waqiaru (ヴア - チヤル) screening using an automatic search program for compound three-dimensional databases based on the protein three-dimensional structures of ligands, and the inhibitory activity of NF- κ B activation under TNF-. alpha.stimulation was confirmed by reporter gene analysis for the compounds. The present inventors have completed the present invention by analyzing the binding pattern and interaction with IKK- β of a compound having a strong activity, and searching and synthesizing from a compound database of analogs based on the result.

The medicine of the invention is

(1) A drug having NF- κ B activation inhibition effect contains a substance selected from compounds represented by the following general formula (I) and pharmaceutically acceptable salts thereof, hydrates thereof and solvates thereof as an active ingredient,

(in the formula, wherein,

x represents a linking group (which may have a substituent) having 2 to 4 carbon atoms of the main chain,

a represents a hydrogen atom or an acetyl group,

e represents an aryl group which may have A substituent or A heteroaryl group which may have A substituent, and the ring Z represents an arene which may further have A substituent in addition to the groups represented by the formulA-O-A (wherein A is the same as the above definition) and the formulA-X-E (wherein X and E are the same as the above definition), or A heteroarene which may further have A substituent in addition to the groups represented by the formulA-O-A (wherein A is the same as the above definition) and the formulA-X-E (wherein X and E are the same as the above definition).

Among them, the preferred drugs are as follows:

(2) a drug having an NF- κ B activation inhibitory action, comprising as an active ingredient a compound wherein X is a group selected from the following linked group α (these groups may have a substituent), a pharmaceutically acceptable salt thereof, and a hydrate or solvate thereof, [ linked group α ] having the formula:

(in the formula, the left bond is bonded to ring Z, and the right bond is bonded to E);

(3) a drug having an NF- κ B activation inhibitory action, which comprises a compound wherein X is a group represented by the formula (the group may have a substituent), a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof as an active ingredient,

(4) a drug having NF- κ B activation inhibition effect contains a substance selected from compounds in which X is a group represented by the following formula, pharmaceutically acceptable salts thereof, hydrates thereof and solvates thereof as an active ingredient,

(5) a drug having an NF- κ B activation inhibitory action, comprising a substance selected from a compound wherein A is a hydrogen atom, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof as an active ingredient;

(6) a medicine with NF-kB activation inhibiting effect contains C from ring Z₆～C₁₀An aromatic hydrocarbon which may further have A substituent in addition to the group represented by the formulA-O-A (wherein A is as defined in the general formulA (I)) and the formulA-X-E (wherein X and E are as defined in the general formulA (I)), or A6 to 13-membered heteroaromatic hydrocarbon which may further have A substituent in addition to the group represented by the formulA-O-A (wherein A is as defined in the general formulA (I)) and the formulA-X-E (wherein X and E are as defined in the general formulA (I)), and pharmaceutically acceptable salts thereof, hydrates thereof, and solvates thereof as an effective ingredient;

(7) A drug having an NF- κ B activation inhibitory action, which comprises, as an active ingredient, A compound selected from compounds wherein ring Z is A ring selected from ring group β (the ring may further have A substituent other than the group represented by formulA-O-A (wherein A is as defined in general formulA (I)) and formulA-X-E (wherein X and E are as defined in general formulA (I)), pharmaceutically acceptable salts thereof, hydrates thereof and solvates thereof,

[ ring group beta ] benzene ring, naphthalene ring, pyridine ring, indole ring, quinoxaline ring, carbazole ring;

(8) a drug having an NF- κ B activation inhibitory action, which comprises as an active ingredient A compound selected from the group consisting of compounds wherein ring Z is A benzene ring which may further have A substituent in addition to the groups represented by the formulA-O-A (wherein A is as defined in the general formulA (I)) and the formulA-X-E (wherein X and E are as defined in the general formulA (I)), pharmaceutically acceptable salts thereof, hydrates thereof and solvates thereof;

(9) a drug having an NF- κ B activation inhibitory action, which comprises, as an active ingredient, A compound selected from the group consisting of A compound wherein ring Z is A benzene ring which may further have A substituent selected from the group consisting of substituents γ -1Z in addition to the groups represented by the formulA-O-A (wherein A is as defined in the general formulA (I)) and the formulA-X-E (wherein X and E are as defined in the general formulA (I)), A pharmaceutically acceptable salt thereof, A hydrate thereof and A solvate thereof,

[ substituent group γ -1z ] a halogen atom, a nitro group, a cyano group, a hydroxyl group which may have a substituent, an amino group which may have a substituent, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, an acyl group which may have a substituent, a ureido group which may have a substituent, a thioureido group which may have a substituent, a diazenyl group which may have a substituent;

(10) a drug having an NF- κ B activation inhibitory action, which comprises a substance selected from the group consisting of a compound represented by the following partial structural formula (IZ-1) including ring Z in the general formula (I) and the following formula (IZ-2) and pharmaceutically acceptable salts thereof, hydrates thereof and solvates thereof as an active ingredient,

(in the formula, R^zRepresents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group which may have a substituent, an amino group which may have a substituent, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, an acyl group which may have a substituent, an ureido group which may have a substituent, a thioureido group which may have a substituent, a diazenyl group which may have a substituent);

(11) a drug having NF- κ B activation inhibitory effect, containing compound R^zIs a hydrogen atom, a halogen atom, a nitro group, a cyano group, or C which may have a substituent ₁～C₆Alkoxy, di (C)₁～C₆Alkyl) -amino, C₆～C₁₀Aryl-carbonyl-amino group, optionally substituted C₁～C₆Alkyl group, C which may have a substituent₁～C₆Haloalkyl group, optionally substituted C₂～C₆Alkenyl, C which may have a substituent₂～C₆Alkynyl group, C which may have a substituent₆～C₁₀Aryl group, C which may have a substituent₇～C₁₆Aralkyl group, 5-to 6-membered heteroaryl group which may have a substituent, carbamoyl group which may have a substituent, sulfamoyl group which may have a substituent, C which may have a substituent₁～C₆Alkyl-carbonyl, C which may have a substituent₁～C₆An alkoxy-carbonyl group, a 5-membered heteroaryl-sulfonyl group which may have a substituent, a 6-membered non-aromatic heterocyclic-sulfonyl group which may have a substituent, or a diazenyl group which may have a substituent, and pharmaceutically acceptable salts thereof, hydrates thereof, and solvates thereof as an active ingredient;

(12) a drug having NF- κ B activation inhibitory effect, containing compound R^zIs a hydrogen atom, a halogen atom, a nitro group, a cyano group, a methoxy group, a dimethylamino group, a benzoylamino group, a methyl group, a tert-butyl group, a 1-hydroxyethyl group, a 1- (methoxyimino) ethyl group, a 1- [ (phenylmethoxy) imino ] ethyl group, a trifluoromethyl group, a pentafluoroethyl group, a phenyl group, a 4- (trifluoromethyl) phenyl group, a 4-fluorophenyl group, a 2, 4-difluorophenyl group, a 2-styryl-1-yl group, a 2, 2-dicyanoethyl-1-yl group, a 2-cyano-2- (methoxycarbonyl) ethen-1-yl group, a 2-carboxy-2-cyanoethen-1-yl group, an ethynyl group, a phenylethynyl group, (trimethylsilyl) ethynyl group, a phenyl group, a 2-phenethyl group, a 2-thienyl group, a, A compound selected from the group consisting of 3-thienyl, 1-pyrrolyl, 2-methylthiazol-4-yl, 2-pyridyl, N- [ 3, 5-bis (trifluoromethyl) phenyl ] carbamoyl, dimethylcarbamoyl, dimethylsulfamoyl, acetyl, isobutyryl, methoxycarbonyl, piperidinocarbonyl, 4-benzylpiperidino, (pyrrol-1-yl) sulfonyl, 3-phenylureido, (3-phenyl) thioureido, (4-nitrophenyl) diazenyl and { [ (4-pyridin-2-yl) sulfamoyl ] phenyl } diazenyl, and pharmaceutically acceptable salts thereof, and hydrates thereof and solvates thereof as an active ingredient;

(13) Drug having NF- κ B activation inhibitory effect, containing R^zCompounds being halogen atoms and their usePharmaceutically acceptable salts, and hydrates and solvates thereof as an active ingredient;

(14) a medicine with NF-kB activation inhibiting effect contains E as C which may have substituent₆～C₁₀An aryl group, or a 5-to 13-membered heteroaryl group which may have a substituent, and pharmaceutically acceptable salts thereof, and hydrates and solvates thereof as an active ingredient;

(15) a medicine with NF-kB activation inhibiting effect contains E as C which may have substituent₆～C₁₀Aryl compounds and pharmaceutically acceptable salts thereof, hydrates thereof, and solvates thereof as an active ingredient;

(16) a drug having an NF- κ B activation inhibitory action, which contains a substance selected from a compound in which E is a phenyl group which may have a substituent, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof as an active ingredient;

(17) a medicine with NF-kB activation inhibiting effect contains 2C molecules from E₁～C₆Haloalkyl-substituted phenyl (said phenyl being divided by 2C)₁～C₆May further have a substituent other than the haloalkyl group) and pharmaceutically acceptable salts thereof, hydrates thereof, and solvates thereof as an active ingredient;

(18) A medicine with NF-kB activation inhibiting effect contains 2C molecules from E₁～C₆A halogenated alkyl-substituted phenyl compound and a pharmaceutically acceptable salt thereof, and a hydrate thereof and a solvate thereof as an active ingredient;

(19) a medicament having an NF- κ B activation inhibitory action, comprising a substance selected from a compound in which E is 3, 5-bis (trifluoromethyl) phenyl or 2, 5-bis (trifluoromethyl) phenyl and pharmaceutically acceptable salts thereof, hydrates thereof and solvates thereof as an active ingredient;

(20) a drug having an NF- κ B activation inhibitory action, comprising a substance selected from a compound in which E is 3, 5-bis (trifluoromethyl) phenyl and a pharmaceutically acceptable salt thereof, and a hydrate thereof and a solvate thereof as an active ingredient;

(21) a medicine with NF-kB activation inhibiting effect contains 1C from E₁～C₆Haloalkyl-substituted phenyl (said phenyl being divided by 1C)₁～C₆May further have a substituent other than the haloalkyl group (however, C₁～C₆Halogenated alkyl group) and pharmaceutically acceptable salts thereof, and hydrates thereof and solvates thereof as an active ingredient;

(22) a medicine with NF-kB activation inhibiting effect contains 1C from E ₁～C₆Haloalkyl-substituted phenyl (said phenyl being divided by 1C)₁～C₆A compound having a group selected from the following substituent group γ -1 e) in addition to the haloalkyl group, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof as an active ingredient,

[ substituent group γ -1e ] a halogen atom, a nitro group, a cyano group, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted sulfanyl group (スルフアニル);

(23) a medicine with NF-kB activation inhibiting effect contains 1C from E₁～C₆Haloalkyl-substituted phenyl (said phenyl being divided by 1C)₁～C₆A compound having a group selected from the following substituent group γ -2 e) in addition to the haloalkyl group, and pharmaceutically acceptable salts thereof, hydrates thereof, and solvates thereof as an active ingredient,

[ substituent group [ gamma-2 e ] halogen atom, nitro group, cyano group, C which may have a substituent₁～C₆An alkyl group, a 5-to 6-membered non-aromatic heterocyclic group which may have a substituent, a heterocyclic group which may have a substituentC of substituent group₁～C₆Alkoxy group, optionally substituted C₁～C₆Alkyl-sulfanyl;

(24) a drug having an NF- κ B activation inhibitory action, which comprises a compound selected from the group consisting of E is 2- (trifluoromethyl) phenyl, 3- (trifluoromethyl) phenyl, 4- (trifluoromethyl) phenyl, 2-fluoro-3- (trifluoromethyl) phenyl, 2-chloro-4- (trifluoromethyl) phenyl, 2-fluoro-5- (trifluoromethyl) phenyl, 2-chloro-5- (trifluoromethyl) phenyl, 3-fluoro-5- (trifluoromethyl) phenyl, 3-bromo-5- (trifluoromethyl) phenyl, 4-chloro-2- (trifluoromethyl) phenyl, 4-fluoro-3- (trifluoromethyl) phenyl, 4-chloro-3- (trifluoromethyl) phenyl, 2-nitro-5- (trifluoromethyl) phenyl, N-phenylcarbamoyl-p-amino-phenyl, N-phenylcarbamoyl-p-methyl-amino-4-fluoro-5- (trifluoromethyl) phenyl, N-phenylcarbamoyl-p-amino-methyl-phenyl, N-methyl-4-chloro-3, 4-nitro-3- (trifluoromethyl) phenyl, 4-cyano-3- (trifluoromethyl) phenyl, 2-methyl-5- (trifluoromethyl) phenyl, 4-methyl-3- (trifluoromethyl) phenyl, 2-methoxy-5- (trifluoromethyl) phenyl, 3-methoxy-5- (trifluoromethyl) phenyl, 4-methoxy-3- (trifluoromethyl) phenyl, 2- (methylsulfanyl) -5- (trifluoromethyl) phenyl, 2- (1-pyrrolidinyl (ピロリジノ)) -5- (trifluoromethyl) phenyl, or 2-morpholino-5- (trifluoromethyl) phenyl, and pharmaceutically acceptable salts thereof, And hydrates thereof and solvates thereof as an active ingredient;

(25) A drug having an NF- κ B activation inhibitory action, which comprises as an active ingredient a substance selected from compounds wherein E is 2-chloro-5- (trifluoromethyl) phenyl, 4-chloro-3- (trifluoromethyl) phenyl, 2-methoxy-5- (trifluoromethyl) phenyl or 3-methoxy-5- (trifluoromethyl) phenyl, pharmaceutically acceptable salts thereof, hydrates thereof and solvates thereof;

(26) a drug having an NF- κ B activation inhibitory action, comprising a substance selected from a compound in which E is 2-chloro-5- (trifluoromethyl) phenyl, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof as an active ingredient;

(27) a medicine with NF- κ B activation inhibiting effect contains E as optional substituent (wherein, C₁～C₆Halogenated alkyl group excluded) and pharmaceutically acceptable salts thereof, and water thereofA compound selected from the group consisting of a salt thereof and a solvate thereof as an active ingredient;

(28) a drug having an NF- κ B activation inhibitory action, comprising as an active ingredient a substance selected from the group consisting of a compound in which E is a phenyl group which may have a group selected from the following substituent groups γ -3E, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof,

[ substituent group γ -3e ] a halogen atom, a nitro group, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted acyl group;

(29) A drug having an NF- κ B activation inhibitory action, comprising as an active ingredient a substance selected from the group consisting of a compound in which E is a phenyl group substituted by a group selected from the following substituent group γ -4E, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof,

[ substituent group [ gamma-4 e ] halogen atom, nitro group, hydroxy group, optionally substituted C₁～C₆Alkyl group, C which may have a substituent₆～C₁₀Aryl group, C which may have a substituent₁～C₆Alkylene group, C which may have a substituent₁～C₆Alkoxy group, optionally substituted C₁～C₆Alkylcarbonyl group, C which may have a substituent₁～C₆An alkoxycarbonyl group;

(30) a drug having an NF- κ B activation inhibitory activity, which comprises a compound selected from the group consisting of E phenyl, 3-chlorophenyl, 4-chlorophenyl, 2, 5-dichlorophenyl, 3, 4-dichlorophenyl, 3, 5-difluorophenyl, 3, 5-dichlorophenyl, 3, 4, 5-trichlorophenyl, pentafluorophenyl, 3, 5-dinitrophenyl, 3, 5-dichloro-4-hydroxyphenyl, 2, 5-dimethoxyphenyl, 3, 5-dimethylphenyl, 2, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl, 3, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl, 5- (1, 1-dimethyl) ethyl-2-methoxyphenyl, 3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydronaphthalen-2-yl, biphenyl-3-yl, 4-methoxybiphenyl-3-yl, 3-acetylphenyl or 3, 5-di (methoxycarbonyl) phenyl compounds and pharmaceutically acceptable salts thereof, and hydrates and solvates thereof as an active ingredient;

(31) A medicament having an NF- κ B activation inhibitory action, which comprises as an active ingredient a compound selected from the group consisting of a compound wherein E is 2, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl, 3, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl or 5- (1, 1-dimethyl) ethyl-2-methoxyphenyl, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof;

(32) a drug having an NF- κ B activation inhibitory action, comprising a substance selected from a compound in which E is a 5-to 13-membered heteroaryl group which may have a substituent, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof as an active ingredient;

(33) a drug having an NF- κ B activation inhibitory action, which comprises as an active ingredient a compound selected from the group consisting of a thienyl group which may have a substituent, a pyrazolyl group which may have a substituent, an oxazolyl group which may have a substituent, a thiazolyl group which may have a substituent, a thiadiazolyl group which may have a substituent, a pyridyl group which may have a substituent, a pyrimidinyl group which may have a substituent, an indolyl group which may have a substituent, a quinolyl group which may have a substituent or a carbazolyl group which may have a substituent, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof;

(34) A drug having an NF- κ B activation inhibitory action, comprising a substance selected from a compound in which E is a thiazolyl group which may have a substituent, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof as an active ingredient;

(35) a drug having an NF- κ B activation inhibitory action, comprising as an active ingredient a compound selected from the group consisting of compounds in which E is a thiazolyl group which may have a group selected from the following substituent group γ -5E, pharmaceutically acceptable salts thereof, hydrates thereof and solvates thereof,

[ substituent group γ -5e ] a halogen atom, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted acyl group;

(36) a drug having an NF- κ B activation inhibitory action, comprising as an active ingredient a compound selected from the group consisting of compounds in which E is a thiazolyl group which may have a group selected from the following substituent group γ -6E, pharmaceutically acceptable salts thereof, hydrates thereof and solvates thereof,

[ substituent group-. gamma. -6e ] halogen atom, cyano group, optionally substituted C₁～C₆Alkyl group, C which may have a substituent₁～C₆Haloalkyl group, optionally substituted C₆～C₁₀Aryl group, C which may have a substituent ₇～C₁₆Aralkyl group, 6-membered non-aromatic heterocyclic group which may have substituent, C which may have substituent₁～C₆Alkyl-carbonyl, C which may have a substituent₆～C₁₀Aryl-carbonyl group, optionally substituted C₁～C₆Alkoxy-carbonyl;

(37) a medicament having NF- κ B activation inhibitory activity comprising a compound selected from the group consisting of E5-bromo-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 5-bromo-4- (trifluoromethyl) thiazol-2-yl, 5-cyano-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 5-phenyl-4- (trifluoromethyl) thiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-ethylthiazol-2-yl, 5-methyl-4-phenylthiazol-2-yl, 4-isopropyl-5-phenylthiazol-2-yl, N-methyl-4-phenylthiazol-2-yl, N-methyl-4-ethyl-thiazol-2-yl, N- β -methyl-2-yl, N-methyl-4-ethyl-5, 4-benzyl-5-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl, 5-acetyl-4-phenylthiazol-2-yl, 5-benzoyl-4-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- (ethoxycarbonyl) thiazol-2-yl, 5-ethoxycarbonyl-4- (trifluoromethyl) thiazol-2-yl, 5-ethoxycarbonyl-4-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-piperidinothiazol-2-yl, methyl-5-yl, ethyl-5-piperidinothiazol-2-yl, methyl-yl, ethyl-5-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-morpholinothiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- (4-phenylpiperidin-1-yl) thiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- (4-methylpiperidin-1-yl) thiazol-2-yl, 4, 5-diphenylthiazol-2-yl, 4-phenylthiazol-2-yl, 4, 5-dimethylthiazol-2-yl, 2-thiazolyl, 5-methylthiazol-2-yl, 4-ethyl-5-phenylthiazol-2-yl, 5-carboxymethyl-4-phenylthiazol-2-yl, methyl-4-phenylthiazol-2-yl, methyl-2, 5-methylcarbamoyl-4-phenylthiazol-2-yl, 5-ethylcarbamoyl-4-phenylthiazol-2-yl, 5-isopropylcarbamoyl-4-phenylthiazol-2-yl, 5- (2-phenylethyl) carbamoyl-4-phenylthiazol-2-yl, a compound selected from the group consisting of 4- (n-butyl) -5-phenylthiazol-2-yl, 4-methyl-5- [ (3-trifluoromethyl) phenyl ] thiazol-2-yl and 5- (4-fluorophenyl) -4-methylthiazol-2-yl, pharmaceutically acceptable salts thereof, hydrates thereof and solvates thereof as an active ingredient;

(38) A drug having an NF- κ B activation inhibitory action, comprising a compound having E of 4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl group, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof as an active ingredient.

The drug of the present invention can be used as a gene expression inhibitor for 1 or 2 or more substances selected from the following substance group delta,

[ group delta ] Tumor Necrosis Factor (TNF), interleukin-1, interleukin-2, interleukin-6, interleukin-8, granulocyte colony stimulating factor, interferon beta, cell adhesion factor ICAM-1, VCAM-1, ELAM-1, nitric oxide synthase, major histocompatibility class I antigen, major histocompatibility class II antigen, beta 2-microglobulin, immunoglobulin light chain, serum amyloid A component, angiotensinogen, complement B, complement C4, C-myc, a transcription product derived from HIV gene, a transcription product derived from HTLV-1 gene, a transcription product derived from monkey virus 40 gene, a transcription product derived from cytomegalovirus gene, and a transcription product derived from adenovirus gene.

The drug of the present invention can be used as an inhibitor of the release of inflammatory cytokines or as an immunosuppressant. The agent of the present invention can be used as an agent for preventing and/or treating 1 or 2 or more diseases selected from the following disease group ε -2 caused by activation of NF-. kappa.B or excessive production of inflammatory cytokines,

[ group of diseases Epsilon-1 ] inflammatory diseases, autoimmune diseases, allergic diseases, cancers such as tumors and sarcomas, metabolic diseases, circulatory diseases, vascular proliferative diseases, septic diseases, and viral diseases,

[ group of diseases ε -2 ] chronic rheumatic arthritis, osteoarthritis, systemic lupus erythematosus, systemic scleroderma, polymyositis, Sjoegren's disease, vasculitis syndrome, antiphospholipid antibody syndrome, Still's disease, Behcet's disease, periarteritis nodosa, ulcerative colitis, Crohn's disease, chronic active hepatitis, glomerulonephritis and other autoimmune diseases, chronic nephritis, chronic pancreatitis, gout, atherosclerosis, multiple sclerosis, arteriosclerosis, vascular intimal hypertrophy, psoriasis, psoriatic arthritis, contact dermatitis, atopic dermatitis, pollinosis and other allergic diseases, asthma, bronchitis, interstitial pneumonia, lung disease with granuloma, chronic obstructive pulmonary disease, chronic pulmonary thromboembolism, pulmonary embolism, systemic lupus erythematosus, systemic sclerosis, multiple sclerosis, Behcet's disease, multiple sclerosis, multiple, Inflammatory colitis, insulin resistance, obesity, diabetes and its complications (nephropathy, retinopathy, neuropathy, hyperinsulinemia, arteriosclerosis, hypertension, peripheral vascular occlusion, etc.), hyperlipidemia, retinopathy and other diseases with abnormal vascular proliferation, pneumonia, Alzheimer's disease, encephalomyelitis, acute hepatitis, chronic hepatitis, drug-toxicity liver disorder, alcoholic hepatitis, viral hepatitis, jaundice, liver cirrhosis, liver failure, atrial myxoma, キヤツスルマン syndrome, glomerulonephritis, kidney cancer, lung cancer, liver cancer, breast cancer, uterine cancer, pancreatic cancer, other solid tumors, sarcoma, osteosarcoma, metastatic infiltration of cancer, canceration of inflammatory lesions, cancer cachexia, cancer metastasis, acute myeloblastic leukemia and other leukemia, multiple myeloma, レンネルト lymphoma, malignant lymphoma, anticancer agent resistance of cancer, canceration of focus such as viral hepatitis and liver cirrhosis, cancer of large intestine polyp, cerebroma, neuroma, endotoxin shock, septicemia, cytomegalovirus pneumonia, cytomegalovirus retinopathy, adenovirus cold, adenovirus blood stasis (pool) fever, adenovirus ophthalmia, conjunctivitis, AIDS, uveitis, other diseases or complications caused by infection with bacteria, viruses, fungi, etc., complications after surgical operation such as systemic inflammatory syndrome, etc., reperfusion disorder after opening of vascular occlusion such as restenosis after percutaneous transluminal coronary angioplasty, ischemia reperfusion disorder, etc., rejection reaction and reperfusion disorder after transplantation of heart, liver, kidney, etc., pruritus, anorexia, tiredness, chronic fatigue syndrome, osteoporosis, chronic fatigue, chronic, Metabolic bone diseases such as pain in bone cancer and organ deterioration during organ preservation before transplantation

From another viewpoint, the present invention provides use of the above-mentioned various substances for the preparation of the above-mentioned medicaments (1) to (38).

Further, according to the present invention, there is provided a method for inhibiting NF- κ B activation in a mammal, including a human, comprising administering the agents of (1) to (38) above to the mammal, including the human; a method for inhibiting gene expression of 1 or 2 or more substances selected from the group δ for mammals including humans, which comprises administering the drugs of the above (1) to (38) to mammals including humans; a method for inhibiting the release of inflammatory cytokines in a mammal including a human, which comprises administering the drugs of the above (1) to (38) to the mammal including the human; a method for suppressing immunity of a mammal including a human, which comprises administering the above-mentioned drugs (1) to (38) to a mammal including a human; a method for preventing and/or treating 1 or 2 or more diseases selected from the group consisting of ε -1, which comprises administering the drugs of (1) to (38) above to a mammal including a human; and a method for preventing and/or treating 1 or more than 2 diseases selected from the group consisting of epsilon-2 of the above-mentioned disease group caused by NK-kappa B activation or excessive production of inflammatory cytokines, which comprises administering the drugs of the above-mentioned (1) to (38) to mammals including humans.

Furthermore, the present invention also provides a method for producing,

(1) a compound represented by the following general formula (I-1) or a salt thereof, or a hydrate thereof or a solvate thereof.

(in the formula, wherein,

Z¹represents a 2-hydroxyphenyl group which may have a substituent at the 5-position, or a 2-acetoxyphenyl group which may have a substituent at the 5-position,

E¹is represented by 2C₁～C₆Haloalkyl-substituted phenyl (said phenyl being divided by 2C)₁～C₆Haloalkyl group may further have a substituent))

(except for the following compounds, however,

n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxybenzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-chloro-2-hydroxybenzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-bromo-2-hydroxybenzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-iodobenzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-nitrobenzamide

2-hydroxy-N- [ 2, 3, 5-tris (trifluoromethyl) phenyl ] benzamide)

It is preferable to provide that,

(2)E¹is covered by 2C₁～C₆Phenyl substituted by alkyl, said alkyl being substituted by more than 1 fluorine atom (the phenyl being divided by 2C's substituted by more than 1 fluorine atom₁～C₆A compound which may further have a substituent other than an alkyl group) or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof;

(3)E¹Is covered by 2C₁～C₆Phenyl substituted by alkyl, said alkyl being substituted by more than 3 fluorine atoms (the phenyl being divided by 2C substituted by more than 3 fluorine atoms₁～C₆A compound which may further have a substituent other than an alkyl group) or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof;

(4)E¹is covered by 2C₁～C₆A phenyl group substituted with an alkyl group, a compound in which the alkyl group is substituted with 3 or more fluorine atoms or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof;

(5)E¹a compound of the formula or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof,

(in the formula, wherein,

R^1e2and R^1e3One of them represents a hydrogen atom, and the other represents C substituted with 3 or more fluorine atoms₁～C₆An alkyl group, a carboxyl group,

R^1e5represents C substituted by 3 or more fluorine atoms₁～C₆Alkyl groups);

(6)E¹a compound which is 3, 5-bis (trifluoromethyl) phenyl or 2, 5-bis (trifluoromethyl) phenyl, or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof;

(7)E¹a compound which is 2, 5-bis (trifluoromethyl) phenyl or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof;

(8)Z¹a compound of the formula or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof,

(in the formula, wherein,

A¹represents a hydrogen atom or an acetyl group,

R^1zrepresents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group which may have a substituent, an amino group which may have a substituent, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, an acyl group which may have a substituent, an ureido group which may be particularly substituted, a thioureido group which may have a substituent, a diazenyl group which may have a substituent);

(9)A¹a compound which is a hydrogen atom or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof;

(10)R^1zis a hydrogen atom, a halogen atom, a nitro group, a cyano group, or C which may have a substituent₁～C₆Alkoxy, di (C)₁～C₆Alkyl) -amino, C which may have a substituent₁～C₆Alkyl group, C which may have a substituent₁～C₆Haloalkyl group, optionally substituted C₂～C₆Alkenyl, C which may have a substituent₂～C₆Alkynyl group, C which may have a substituent₆～C₁₀Aryl group, C which may have a substituent₇～C₁₆Aralkyl group, 5-to 6-membered heteroaryl group which may have a substituent, C which may have a substituent₁～C₆Alkyl-carbonyl, C which may have a substituent₁～C₆Compound of alkoxy-carbonyl group, 5-membered heteroaryl-sulfonyl group which may have a substituent, or diazenyl group which may have a substituent, or a pharmaceutically acceptable salt thereof, or its derivative Hydrates thereof or solvates thereof;

(11)R^1zis a halogen atom, may have a substituent C₁～C₆Alkyl or C which may have a substituent₁～C₆A haloalkyl compound or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof;

(12)R^1za compound which is a halogen atom or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof.

Most preferably, the following compounds or pharmaceutically acceptable salts thereof, or hydrates thereof or solvates thereof are provided.

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-fluoro-2-hydroxybenzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-cyano-2-hydroxybenzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-methylbenzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5- (1, 1-dimethyl) ethyl-2-hydroxybenzamide

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

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (1, 1, 2, 2, 2-pentafluoroethyl) benzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (2-phenylethen-1-yl) benzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5- (2, 2-dicyanoethylene-1-yl) -2-hydroxybenzamide

3- ({3- [ 3, 5-bis (trifluoromethyl) phenyl ] carbamoyl } -4-hydroxyphenyl) -2-cyanoacrylic acid methyl ester

3- ({3- [ 3, 5-bis (trifluoromethyl) phenyl ] carbamoyl } -4-hydroxyphenyl) -2-cyanoacrylic acid

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-ethynyl-2-hydroxybenzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (phenylethynyl) benzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- [ (trimethylsilyl) ethynyl ] benzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -4-hydroxybiphenyl-3-carboxamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (2-phenylethyl) benzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (3-thienyl) benzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (1-pyrrolyl) benzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (2-methyl-thiazol-4-yl) benzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (2-pyridyl) benzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-dimethylamino-2-hydroxybenzamide

5-benzoylamino-N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxybenzamide

·N³- [ 3, 5-bis (trifluoromethyl) phenyl ] -4-hydroxy-N¹，N¹-dimethyl isophthalamide

·N¹，N³-bis [ 3, 5-bis (trifluoromethyl) phenyl ] -4-hydroxyisophthalamide

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

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

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

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

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

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-isobutyrylbenzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -4-hydroxym-benzenedicarboxamic acid methyl ester

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- [ (4-nitrophenyl) diazenyl ] benzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- ({ [ (4-pyridin-2-yl) sulfamoyl ] phenyl } diazenyl) benzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- [ (3-phenyl) ureido ] benzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- [ (3-phenyl) thioureido ] benzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (1-hydroxyethyl) benzamide

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

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- [ 1- (methoxyimino) ethyl ] benzamide

5- {1- [ (Phenylmethoxy) imino ] ethyl) -N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxybenzamide

N- [ 2, 5-bis (trifluoromethyl) phenyl ] -5-chloro-2-hydroxybenzamide

N- [ 2, 5-bis (trifluoromethyl) phenyl ] -5-bromo-2-hydroxybenzamide

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

2-acetoxy-N- [ 2, 5-bis (trifluoromethyl) phenyl ] -5-chlorobenzamide

2-acetoxy-N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-chlorobenzamide

Furthermore, the present invention also provides a method for producing,

(1) a compound represented by the following general formula (I-2) or a salt thereof, or a hydrate thereof or a solvate thereof.

(in the formula, wherein,

Z²represents a 2-hydroxyphenyl group which may have a substituent at the 5-position, or a 2-acetoxyphenyl group which may have a substituent at the 5-position,

E²denotes that the 3 or 5 position is C₁～C₆Haloalkyl-substituted phenyl (said phenyl being substituted by C in position 3 or 5 ₁～C₆The alkyl group may further have a substituent (wherein the substituent is C)₁～C₆Where haloalkyl groups do not exist)))

(except for the following compounds, however,

5-chloro-2-hydroxy-N- [ 3- (trifluoromethyl) phenyl ] benzamide

5-bromo-2-hydroxy-N- [ 3- (trifluoromethyl) phenyl ] benzamide

2-hydroxy-5-iodo-N- [ 3- (trifluoromethyl) phenyl ] benzamide

5-chloro-N- [ 4-chloro-3- (trifluoromethyl) phenyl ] -2-hydroxybenzamide

5-chloro-N- [ 5-chloro-3- (trifluoromethyl) phenyl ] -2-hydroxybenzamide

5-chloro-2-hydroxy-N- [ 4-nitro-3- (trifluoromethyl) phenyl ] benzamide

5-fluoro-2-hydroxy-N- [ 2- (2, 2, 2-trifluoroethoxy) -5- (trifluoromethyl) phenyl ] benzamide

5-fluoro-2-hydroxy-N- [ 2- (6, 6, 6-trifluorohexyloxy) -5- (trifluoromethyl) phenyl ] benzamide

5-chloro-2-hydroxy-N- (3-trifluoromethyl-4- { [ 4- (trifluoromethyl) sulfanyl ] phenoxy) phenyl) benzamide

N- [ 4- (benzothiazol-2-yl) sulfanyl-3- (trifluoromethyl) phenyl ] -5-chloro-2-hydroxy-benzamide

5-chloro-N- [ 2- (4-chlorophenoxy) -5- (trifluoromethyl) phenyl ] -2-hydroxybenzamide

5-chloro-2-hydroxy-N- [ 2- (4-methylphenoxy) -5- (trifluoromethyl) phenyl ] benzamide

5-chloro-N- [ 2- (4-chlorophenyl) sulfanyl-5- (trifluoromethyl) phenyl ] -2-hydroxybenzamide

5-chloro-2-hydroxy-N- [ 2- (1-naphthyloxy) -5- (trifluoromethyl) phenyl ] benzamide

5-chloro-2-hydroxy-N- [ 2- (2-naphthyloxy) -5- (trifluoromethyl) phenyl ] benzamide. )

It is preferable to provide that,

(2)E²is phenyl, and the 3-or 5-position of the phenyl group is C substituted by more than 1 fluorine atom₁～C₆Alkyl (C substituted by 1 or more fluorine atoms except 3-or 5-position of the phenyl group)₁～C₆The alkyl group may further have a substituent (wherein the substituent is C)₁～C₆Except for the case of haloalkyl)) or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof;

(3)E²is phenyl, and the 3-or 5-position of the phenyl group is C substituted by more than 3 fluorine atoms₁～C₆Alkyl (C substituted by more than 3 fluorine atoms except 3 or 5 position of the phenyl group₁～C₆The alkyl group may further have a substituent (wherein the substituent is C)₁～C₆Except for the case of haloalkyl)) or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof;

(4)E²is phenyl, and the 3-or 5-position of the phenyl group is C substituted by more than 3 fluorine atoms₁～C₆Alkyl (C substituted by more than 3 fluorine atoms except 3 or 5 position of the phenyl group ₁～C₆A compound having a group selected from the following substituent group γ -7 e) in addition to the alkyl group, or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof,

[ substituent group-. gamma. -7e ] halogen atom, nitro group, cyano group, and optionally substituted C₁～C₆Alkyl group, 5 to 6-membered non-aromatic heterocyclic group which may have substituent, C which may have substituent₁～C₆Alkoxy group, optionally substituted C₁～C₆Alkyl-sulfanyl;

(5)E²a phenyl group having a trifluoromethyl group at the 3-position or 5-position (the phenyl group may further have a group selected from the following substituent group γ -7e in addition to the trifluoromethyl group at the 3-position or 5-position), a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof,

[ substituent group-. gamma. -7e ] halogen atom, nitro group, cyano group, and optionally substituted C₁～C₆Alkyl group, 5 to 6-membered non-aromatic heterocyclic group which may have substituent, C which may have substituent₁～C₆Alkoxy group which may have a substituentC of (A)₁～C₆Alkyl-sulfanyl;

(6)E²is 3- (trifluoromethyl) phenyl, 2-fluoro-5- (trifluoromethyl) phenyl, 2-chloro-5- (trifluoromethyl) phenyl, 3-fluoro-5- (trifluoromethyl) phenyl, 3-bromo-5- (trifluoromethyl) phenyl, 4-fluoro-3- (trifluoromethyl) phenyl, 4-chloro-3- (trifluoromethyl) phenyl, 2-nitro-5- (trifluoromethyl) phenyl, 4-nitro-3- (trifluoromethyl) phenyl, 4-cyano-3- (trifluoromethyl) phenyl, 2-methyl-5- (trifluoromethyl) phenyl, a compound of 4-methyl-3- (trifluoromethyl) phenyl, 2-methoxy-5- (trifluoromethyl) phenyl, 3-methoxy-5- (trifluoromethyl) phenyl, 4-methoxy-3- (trifluoromethyl) phenyl, 2- (methylsulfanyl) -5- (trifluoromethyl) phenyl, 2- (1-pyrrolidinyl) -5- (trifluoromethyl) phenyl, or 2-morpholino-5- (trifluoromethyl) phenyl, or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof;

(7)Z²A compound of the formula or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof,

(in the formula, wherein,

A²represents a hydrogen atom or an acetyl group,

R^2zrepresents a halogen atom, C₁～C₆Alkyl or C₁～C₆Haloalkyl);

(8)A²a compound which is a hydrogen atom or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof;

(9)R^2za compound which is a halogen atom or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof.

5-chloro-N- [ 2-fluoro-3- (trifluoromethyl) phenyl ] -2-hydroxybenzamide

5-chloro-N- [ 2-fluoro-5- (trifluoromethyl) phenyl ] -2-hydroxybenzamide

5-chloro-N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2-hydroxybenzamide

5-bromo-N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2-hydroxybenzamide

2-acetoxy-5-chloro-N- [ 2-chloro-5- (trifluoromethyl) phenyl ] benzamide

N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2-hydroxy-5-methylbenzamide

5-chloro-N- [ 3-fluoro-5- (trifluoromethyl) phenyl ] -2-hydroxybenzamide

5-bromo-N- [ 3-bromo-5- (trifluoromethyl) phenyl ] -2-hydroxybenzamide

5-chloro-N- [ 3-fluoro-5- (trifluoromethyl) phenyl ] -2-hydroxybenzamide

5-chloro-N- [ 4-fluoro-3- (trifluoromethyl) phenyl ] -2-hydroxybenzamide

5-bromo-N- [ 4-chloro-3- (trifluoromethyl) phenyl ] -2-hydroxybenzamide

N- [ 4-chloro-3- (trifluoromethyl) phenyl ] -2-hydroxy-5-methylbenzamide

5-chloro-2-hydroxy-N- [ 2-nitro-5- (trifluoromethyl) phenyl ] benzamide

5-bromo-N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -2-hydroxybenzamide

5-chloro-2-hydroxy-N- [ 2-methyl-3- (trifluoromethyl) phenyl ] benzamide

5-chloro-2-hydroxy-N- [ 2-methyl-5- (trifluoromethyl) phenyl ] benzamide

2-hydroxy-5-methyl-N- [ 2-methyl-5- (trifluoromethyl) phenyl ] benzamide

5-chloro-2-hydroxy-N- [ 4-methyl-3- (trifluoromethyl) phenyl ] benzamide

2-hydroxy-5-methyl-N- [ 4-methyl-3- (trifluoromethyl) phenyl ] benzamide

5-bromo-2-hydroxy-N- [ 2-methoxy-5- (trifluoromethyl) phenyl ] benzamide

5-chloro-2-hydroxy-N- [ 2-methoxy-5- (trifluoromethyl) phenyl ] benzamide

2-hydroxy-N- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -5-methylbenzamide

5-bromo-2-hydroxy-N- [ 3-methoxy-5- (trifluoromethyl) phenyl ] benzamide

5-chloro-2-hydroxy-N- [ 4-methoxy-3- (trifluoromethyl) phenyl ] benzamide

2-hydroxy-N- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -5-methylbenzamide

5-chloro-2-hydroxy-N- [ 2-methylsulfanyl-5- (trifluoromethyl) phenyl ] benzamide

5-chloro-2-hydroxy-N- [ 2- (1-pyrrolidinyl) -5- (trifluoromethyl) phenyl ] benzamide

5-chloro-2-hydroxy-N- [ 2-morpholino-5- (trifluoromethyl) phenyl ] benzamide

Furthermore, the present invention also provides a method for producing,

(1) a compound represented by the following general formula (I-3) or a salt thereof, or a hydrate thereof or a solvate thereof,

(in the formula, wherein,

Z³represents a 2-hydroxyphenyl group which may have a substituent at the 5-position, or a 2-acetoxyphenyl group which may have a substituent at the 5-position,

E³is represented by the following formula,

(in the formula, wherein,

R^3e2and R^3e3The same or different, represents a hydrogen atom, a hydrocarbon group which may have a substituent, or a hydroxyl group which may have a substituent (wherein R is^3e2And R^3e3While being a hydrogen atom) R^3e5Represents optionally substituted C₂～C₆A hydrocarbon group)).

It is preferable to provide that,

(2)R^3e2and R^3e3C which may be the same or different and is a hydrogen atom₁～C₆Alkyl or C which may have a substituent₁～C₆Alkoxy (wherein, R^3e2And R^3e3Except where both are hydrogen atoms), and R^3e5Is C which may have a substituent₂～C₆A compound of an alkyl group or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof;

(3)E³A compound which is 2, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl, 3, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl or 5- (1, 1-dimethyl) ethyl-2-methoxyphenyl or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof;

(4)Z³a compound of the formula or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof,

(in the formula, wherein,

A³represents a hydrogen atom or an acetyl group,

R^3zrepresents a halogen atom, C₁～C₆Alkyl or C₁～C₆Haloalkyl);

(5)A³a compound which is a hydrogen atom or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof;

(6)R^3za compound which is a halogen atom or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof.

N- {2, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl } -5-chloro-2-hydroxybenzamide

N- {2, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl } -2-hydroxy-5-methylbenzamide

N- {3, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl } -5-chloro-2-hydroxybenzamide

N- {3, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl } -5-bromo-2-hydroxybenzamide

N- {3, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl } -2-hydroxy-5-methylbenzamide

2-acetoxy-N- {3, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl } -5-chlorobenzamide

5-chloro-N- [ 5- (1, 1-dimethyl) ethyl-2-methoxyphenyl ] -2-hydroxybenzamide

N- [ 5- (1, 1-dimethyl) ethyl-2-methoxyphenyl ] -2-hydroxy-5-methylbenzamide

2-acetoxy-5-chloro-N- [ 5- (1, 1-dimethyl) ethyl-2-methoxyphenyl ] benzamide.

There is also provided, in accordance with the present invention,

(1) a compound represented by the following general formula (I-4) or a salt thereof, or a hydrate thereof or a solvate thereof,

(in the formula, wherein,

Z⁴represents a 2-hydroxyphenyl group which may have a substituent at the 5-position, or a 2-acetoxyphenyl group which may have a substituent at the 5-position,

E⁴is represented by the following formula,

(in the formula, wherein,

R^4e4represents a hydrocarbon group which may have a substituent(s),

R^4e5represents a halogen atom, a cyano group, an acyl group which may have a substituent, or a heterocyclic group which may have a substituent).

It is preferable to provide that,

(2)R^4e4is C which may have a substituent₁～C₆Alkyl group, C which may have a substituent₁～C₆Haloalkyl or C which may have a substituent₆～C₁₀Aryl, and R^4e5Is a halogen atom, a cyano group, or C which may have a substituent ₁～C₆Alkyl-carbonyl, C which may have a substituent₆～C₁₀Aryl-carbonyl group, optionally substituted C₁～C₆A compound of an alkoxy-carbonyl group or a 6-membered non-aromatic heterocyclic group which may have a substituent, or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof;

(3)E⁴is 5-bromo-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 5-bromo-4- (trifluoromethyl) thiazol-2-yl, 5-cyano-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl, 5-acetyl-4-phenylthiazol-2-yl, 5-benzoyl-4-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- (ethoxycarbonyl) thiazol-2-yl, 5-ethoxycarbonyl-4- (trifluoromethyl) thiazol-2-yl, methyl-2-yl, ethyl-5-, 5-ethoxycarbonyl-4-phenylthiazol-2-yl, 5-ethoxycarbonyl-4- (pentafluorophenyl) thiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-piperidinothiazol-2-yl, a compound of 4- (1, 1-dimethyl) ethyl-5-morpholinothiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- (4-methylpiperidin-1-yl) thiazol-2-yl or 4- (1, 1-dimethyl) ethyl-5- (4-phenylpiperidin-1-yl) thiazol-2-yl, or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof;

(4)E⁴A compound which is 4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof;

(5)Z⁴a compound of the formula or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof,

(in the formula, wherein,

A⁴represents a hydrogen atom or an acetyl group,

R^4zrepresents a halogen atom, optionally substituted C₆～C₁₀Aryl or 5-membered heteroaryl);

(6)A⁴a compound which is a hydrogen atom or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof;

(7)R^4za compound which is a halogen atom or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof.

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

5-bromo-N- { 5-bromo-4- (trifluoromethyl) thiazol-2-yl } -2-hydroxybenzamide

5-chloro-N- { 5-cyano-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl } -2-hydroxybenzamide

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

5-chloro-N- {4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl } -2-hydroxybenzamide

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

N- (5-acetyl-4-phenylthiazol-2-yl) -5-bromo-2-hydroxybenzamide

N- (5-benzoyl-4-phenylthiazol-2-yl) -5-bromo-2-hydroxybenzamide

Ethyl 2- (5-bromo-2-hydroxybenzoyl) amino-4- [ (1, 1-dimethyl) ethyl ] thiazole-5-carboxylate

2- (5-bromo-2-hydroxybenzoyl) amino-4- (trifluoromethyl) thiazole-5-carboxylic acid ethyl ester

2- (5-chloro-2-hydroxybenzoyl) amino-4-phenylthiazole-5-carboxylic acid ethyl ester

2- (5-bromo-2-hydroxybenzoyl) amino-4-phenylthiazole-5-carboxylic acid ethyl ester

Ethyl 2- [ (4-hydroxybiphenyl) -3-carbonyl ] amino-4-phenylthiazole-5-carboxylate

Ethyl 2- [ (4' -fluoro-4-hydroxybiphenyl) -3-carbonyl ] amino-4-phenylthiazole-5-carboxylate

Ethyl 2- [ (2 ', 4' -difluoro-4-hydroxybiphenyl) -3-carbonyl ] amino-4-phenylthiazole-5-carboxylate

Ethyl 2- { [ 4-hydroxy-4' - (trifluoromethyl) biphenyl ] -3-carbonyl } amino-4-phenylthiazole-5-carboxylate

Ethyl 2- [ 2-hydroxy-5- (1-pyrrolyl) benzoyl ] amino-4-phenylthiazole-5-carboxylate

2- [ 2-hydroxy-5- (1-thienyl) benzoyl ] amino-4-phenylthiazole-5-carboxylic acid ethyl ester

Ethyl 2- (5-bromo-2-hydroxybenzoyl) amino-4- (pentafluorophenyl) thiazole-5-carboxylate

5-bromo-N- [ 4- (1, 1-dimethyl) ethyl-5-piperidinothiazol-2-yl ] -2-hydroxybenzamide

5-bromo-N- [ 4- (1, 1-dimethyl) ethyl-5-morpholinothiazol-2-yl ] -2-hydroxybenzamide

5-bromo-N- [ 4- (1, 1-dimethyl) ethyl-5- (4-methylpiperidin-1-yl) thiazol-2-yl ] -2-hydroxybenzamide

5-bromo-N- [ 4- (1, 1-dimethyl) ethyl-5- (4-phenylpiperidin-1-yl) thiazol-2-yl ] -2-hydroxybenzamide.

Best mode for carrying out the invention

The meanings of the terms used in the present specification are as follows.

The "halogen atom" may be any of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom unless otherwise specified.

Examples of the "hydrocarbon group" include aliphatic hydrocarbon groups, aryl groups, arylene groups, aralkyl groups, bridged hydrocarbon groups, spiro hydrocarbon groups, and terpene-based hydrocarbons.

Examples of the "aliphatic hydrocarbon group" include linear or branched acyclic hydrocarbon groups having a valence of 1 or 2, such as an alkyl group, an alkenyl group, an alkynyl group, an alkylene (alkylene), an alkenylene group, and an alkylene (alkylene); and saturated or unsaturated 1-or 2-valent alicyclic hydrocarbon groups such as cycloalkyl, cycloalkenyl, cycloalkadienyl, cycloalkyl-alkyl, cycloalkylene, and cycloalkenylene.

Examples of the "alkyl group" include 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-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1-ethyl-1-methylpropyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-decyl, and the like, C such as n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl and the like₁～C₁₅The linear or branched alkyl group of (3).

Examples of the "alkenyl group" include vinyl, prop-1-en-1-yl, allyl, isopropenyl, but-1-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, 2-methylprop-2-en-1-yl, 1-methylprop-2-en-1-yl, pent-1-en-1-yl, pent-2-en-1-yl, pent-3-en-1-yl, pent-4-en-1-yl, 3-methylbut-2-en-1-yl, 3-methylbut-3-en-1-yl, allyl, isopropenyl, but-1-yl, but-2-en-1-yl, and the like, Hex-1-en-1-yl, hex-2-en-1-yl, hex-3-en-1-yl, hex-4-en-1-yl, hex-5-en-1-yl, 4-methylpent-3-en-1-yl Hept-1-en-1-yl, hept-6-en-1-yl, oct-1-en-1-yl, oct-7-en-1-yl, non-1-en-1-yl, non-8-en-1-yl, dec-1-en-1-yl, dec-9-en-1-yl, undec-1-en-1-yl, undec-10-en-1-yl, dodec-1-en-1-yl, dodec-11-en-1-yl, tridec-1-en-1-yl, tridec-12-en-1-yl, tridec-1-en-1-yl, and mixtures thereof, C such as tetradec-1-en-1-yl, tetradec-13-en-1-yl, pentadec-1-en-1-yl, pentadec-14-en-1-yl₂～C₁₅The linear or branched alkenyl group of (3).

As "alkynyl" there may be mentioned, for example, ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, but-1-yn-1-yl, but-3-yn-1-yl, 1-methylpropan-2-yn-1-yl, pent-1-yn-1-yl, pent-4-yn-1-yl, hex-1-yn-1-yl, hex-5-yn-1-yl, hept-1-yn-1-yl, hept-6-yn-1-yl, oct-1-yn-1-yl, oct-7-yn-1-yl, non-1-yn-1-yl, non-8-alkyn-1-yl, dec-1-alkyn-1-yl, dec-9-alkyn-1-yl, undec-1-alkyn-1-yl, undec-10-alkyn-1-yl, dodec-1-alkyn-1-yl, dodec-11-alkyn-1-yl, tridec-1-alkyn-1-yl, tridec-12-alkyn-1-yl, tetradec-1-alkyn-1-yl, tetradec-13-alkyn-1-yl, pentadec-1-alkyn-1-yl, pentadec-14-alkyn-1-yl and the like C ₂～C₁₅The straight-chain or branched alkynyl group of (1).

Examples of the "alkylene (alkylene)" include a C group such as methylene, ethylene, ethane-1, 1-diyl, propane-1, 3-diyl, propane-1, 2-diyl, propane-2, 2-diyl, butane-1, 4-diyl, pentane-1, 5-diyl, hexane-1, 6-diyl and 1, 1, 4, 4-tetramethylbutane-1, 4-diyl₁～C₈The linear or branched alkylene group of (3).

Examples of the "alkenylene group" include C such as ethylene-1, 2-diyl, propylene-1, 3-diyl, but-1-en-1, 4-diyl, but-2-en-1, 4-diyl, 2-methylpropene-1, 3-diyl, pent-2-en-1, 5-diyl and hex-3-en-1, 6-diyl₁～C₆The linear or branched alkenylene group of (4).

As "alkylene (alkylene)", there are mentioned, for example, methylene, ethylene, propylene, isopropylene, butylenePentyl, hexylene, etc. C₁～C₆The linear or branched alkylene group of (3).

Examples of the "cycloalkyl group" include C such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl₃～C₈A cycloalkyl group of (a).

The "cycloalkyl group" may be condensed with a benzene ring, a naphthalene ring, etc., and examples thereof include 1-indanyl group, 2-indanyl group, 1, 2, 3, 4-tetrahydronaphthalen-1-yl group, and 1, 2, 3, 4-tetrahydronaphthalen-2-yl group.

Examples of the "cycloalkenyl group" include C such as 2-cyclopropen-1-yl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl and 1-cyclopenten-1-yl₃～C₆The cycloalkenyl group of (1).

The "cycloalkenyl group" may be fused with a benzene ring, a naphthalene ring, etc., and examples thereof include groups such as 1-indanyl, 2-indanyl, 1, 2, 3, 4-tetrahydronaphthalen-1-yl, 1, 2, 3, 4-tetrahydronaphthalen-2-yl, 1-indenyl, and 2-indenyl.

Examples of the "cycloalkadienyl group" include C such as 2, 4-cyclopentanedien-1-yl group, 2, 4-cyclohexanedien-1-yl group, 2, 5-cyclohexanedien-1-yl group₅～C₆Cycloalkadienyl groups.

The "cycloalkadienyl group" may be condensed with a benzene ring, a naphthalene ring, or the like, and examples thereof include a 1-indenyl group, a 2-indenyl group, and the like.

Examples of the "cycloalkyl-alkyl group" may include groups in which 1 hydrogen atom of the "alkyl group" is replaced with a "cycloalkyl group", such as a C group (e.g., cyclopropylmethyl group, 1-cyclopropylethyl group, 2-cyclopropylethyl group, 3-cyclopropylpropyl group, 4-cyclopropylbutyl group, 5-cyclopropylpentyl group, 6-cyclopropylhexyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclohexylpropyl group, cyclohexylbutyl group, cycloheptylmethyl group, cyclooctylmethyl group, 6-cyclooctylhexyl group, etc.) ₁～C₁₄Cycloalkyl-alkyl of (a).

As the "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, C3-C8 cycloalkylene groups such as cyclohexane-1, 1-diyl, cyclohexane-1, 2-diyl, cyclohexane-1, 3-diyl, cyclohexane-1, 4-diyl, cycloheptane-1, 1-diyl, cycloheptane-1, 2-diyl, cyclooctane-1, 1-diyl and cyclooctane-1, 2-diyl.

Examples of the "cycloalkenylene group" include C such as 2-cyclopropene-1, 1-diyl, 2-cyclobutene-1, 1-diyl, 2-cyclopentene-1, 1-diyl, 3-cyclopentene-1, 1-diyl, 2-cyclohexene-1, 2-diyl, 2-cyclohexene-1, 4-diyl, 3-cyclohexene-1, 1-diyl, 1-cyclobutene-1, 2-diyl, 1-cyclopentene-1, 2-diyl and 1-cyclohexene-1, 2-diyl₃～C₆The cycloalkenylene group of (1).

Examples of the "aryl" may include monocyclic or condensed polycyclic aromatic hydrocarbon groups, for example, C such as phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl, acenaphthenyl and the like₆～C₁₄Aryl group of (1).

The "aryl" may be substituted with the "C" mentioned above ₃～C₈Cycloalkyl group "," C₃～C₆Cycloalkenyl radical "or" C₅～C₆Cycloalkadienyl "and the like, for example, groups such as 4-indanyl, 5-indanyl, 1, 2, 3, 4-tetrahydronaphthalen-5-yl, 1, 2, 3, 4-tetrahydronaphthalen-6-yl, 3-acenaphthenyl, 4-acenaphthenyl, inden-4-yl, inden-5-yl, inden-6-yl, inden-7-yl, 4-phenanthryl (フエナレニル), 5-phenanthryl, 6-phenanthryl, 7-phenanthryl, 8-phenanthryl, 9-phenanthryl and the like.

Examples of the "arylene group" include a 1, 2-phenylene group, a 1, 3-phenylene group, a 1, 4-phenylene group, a naphthalene-1, 2-diyl group, a naphthalene-1, 3-diyl group, a naphthalene-1, 4-diyl group, a naphthalene-1, 5-diyl group, a naphthalene-1, 6-diyl group, a naphthalene-1, 7-diyl group, a naphthalene-1, 8-diyl group, a naphthalene-2, 3-diyl group, a naphthalene-2, 4-diyl group, a naphthalene-2, 5-diyl group, a naphthalene-2, 6-diyl group and a naphthalene-2, 7-diyl groupC such as naphthalene-2, 8-diyl and anthracene-1, 4-diyl₆～C₁₄An arylene group of (a).

Examples of the "aralkyl group" may include groups in which 1 hydrogen atom of the "alkyl group is substituted with an" aryl group ", such as benzyl, 1-naphthylmethyl, 2-naphthylmethyl, anthrylmethyl, phenanthrylmethyl, acenaphthenylmethyl, diphenylmethyl, 1-phenylethyl, 2-phenylethyl, 1- (1-naphthyl) ethyl, 1- (2-naphthyl) ethyl, 2- (1-naphthyl) ethyl, 2- (2-naphthyl) ethyl, 3-phenylpropyl, 3- (1-naphthyl) propyl, 3- (2-naphthyl) propyl, 4-phenylbutyl, 4- (1-naphthyl) butyl, 4- (2-naphthyl) butyl, 5-phenylpentyl, 5- (1-naphthyl) pentyl, 5- (2-naphthyl) pentyl, etc, C such as 6-phenylhexyl, 6- (1-naphthyl) hexyl, 6- (2-naphthyl) hexyl ₇～C₁₆An aralkyl group.

Examples of the "bridged hydrocarbon group" include a bicyclo [ 2.1.0 ] pentyl group, a bicyclo [ 2.2.1 ] heptyl group, a bicyclo [ 2.2.1 ] octyl group, an adamantyl group and the like.

Examples of the "spiro hydrocarbon group" include spiro [ 3.4 ] octyl, spiro [ 4.5 ] decan-1, 6-dienyl and the like.

Examples of the "terpene hydrocarbon" include geranyl, neryl, linalyl, phytyl, menthyl, bornyl and the like.

Examples of the "haloalkyl group" may include groups in which 1 hydrogen atom of the "alkyl group" is substituted by a "halogen atom", for example, a C group substituted by 1 to 13 halogen atoms such as a fluoromethyl group, difluoromethyl group, trifluoromethyl group, chloromethyl group, dichloromethyl group, trichloromethyl group, bromomethyl group, dibromomethyl group, tribromomethyl group, iodomethyl group, diiodomethyl group, triiodomethyl group, 2, 2, 2-trifluoroethyl group, pentafluoroethyl group, 3, 3, 3-trifluoropropyl group, heptafluoropropyl group, heptafluoroisopropyl group, nonafluorobutyl group, perfluorohexyl group and the like₁～C₆The linear or branched haloalkyl group of (1).

As the "heterocyclic group", there may be mentioned a monocyclic or condensed polycyclic heteroaryl group containing at least 1 to 3 kinds of hetero atoms selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like as atoms (ring atoms) constituting the ring system, and a monocyclic or condensed polycyclic non-aromatic heterocyclic group containing at least 1 to 3 kinds of hetero atoms selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like as atoms (ring atoms) constituting the ring system.

Examples of the "monocyclic heteroaryl group" include a 2-furyl group, 3-furyl group, 2-thienyl group, 3-thienyl group, 1-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, 1-pyrazolyl group, 3-pyrazolyl group, 4-pyrazolyl group, 5-pyrazolyl group, (1, 2, 3-oxadiazol) -4-yl group, and the like, (1, 2, 3-oxadiazol) -5-yl, (1, 2, 4-oxadiazol) -3-yl, (1, 2, 4-oxadiazol) -5-yl, (1, 2, 5-oxadiazol) -3-yl, (1, 2, 5-oxadiazol) -4-yl, (1, 3, 4-oxadiazol) -2-yl, (1, 3, 4-oxadiazol) -5-yl, furazanyl, (1, 2, 3-thiadiazol) -4-yl, (1, 2, 3-thiadiazol) -5-yl, (1, 2, 4-thiadiazol) -3-yl, (1, 2, 4-thiadiazol) -5-yl, (1, 2, 5-thiadiazol) -3-yl, methyl ethyl methyl propyl methyl, (1, 2, 5-thiadiazole) -4-yl, (1, 3, 4-thiadiazole) -2-yl, (1, 3, 4-thiadiazole) -5-yl, (1H-1, 2, 3-triazole) -1-yl, (1H-1, 2, 3-triazole) -4-yl, (1H-1, 2, 3-triazole) -5-yl, (2H-1, 2, 3-triazole) -2-yl, (2H-1, 2, 3-triazole) -4-yl, (1H-1, 2, 4-triazole) -1-yl, (1H-1, 2, 4-triazole) -3-yl, (1H-1, 2, 4-triazol-5-yl, (4H-1, 2, 4-triazol) -3-yl, (4H-1, 2, 4-triazol) -4-yl, (1H-tetrazol-1-yl, (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-triazin-4-yl, (1, 2, 3-triazin-5-yl, (1, 2, 4-triazin-3-yl group, (1, 2, 4-triazin) -5-yl group, (1, 2, 4-triazin) -6-yl group, (1, 3, 5-triazin) -2-yl group, 1-aza * -yl group, 1-aza * -yl group, 2-aza * -yl group, 3-aza * -yl group, 4-aza * -yl group, (1, 4-oxa *) -2-yl group, (1, 4-oxa *) -3-yl group, (1, 4-oxa *) -5-yl group, (1, 4-oxa *) -6-yl group, (1, 4-oxa *) -7-yl group, (1, 4-thia *) -2-yl group, (1, 4-thia *) -3-yl group, 3-aza-yl group, 5-to 7-membered monocyclic heteroaryl groups such as (1, 4-thiazepine *) -5-yl, (1, 4-thiazepine *) -6-yl, (1, 4-thiazepine *) -7-yl and the like.

As the "fused 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, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, (2H-isoindol) -1-yl, (2H-isoindol) -2-yl, (2H-isoindol) -4-yl, (2H-isoindol) -5-yl, (1H-indazol) -1-yl, (1H-indazol) -3-yl, (1H-indazol) -4-yl, (1H-indazol) -5-yl, (1H-indazol) -6-yl, (1H-indazol) -7-yl, (2H-indazol) -1-yl, (2H-indazol) -2-yl, (2H-indazol) -4-yl, o, (2H-indazol) -5-yl, 2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 7-benzoxazolyl, (1, 2-benzisoxazole) -3-yl, (1, 2-benzisoxazole) -4-yl, (1, 2-benzisoxazole) -5-yl, (1, 2-benzisoxazole) -6-yl, (1, 2-benzisoxazole) -7-yl, (2, 1-benzisoxazole) -3-yl, (2, 1-benzisoxazole) -4-yl, (2, 1-benzisoxazole) -5-yl, (2, 1-benzisoxazole) -6-yl, (2, 1-benzisoxazole) -7-yl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl, (1, 2-benzisothiazole) -3-yl, (1, 2-benzisothiazole) -4-yl, (1, 2-benzisothiazole) -5-yl, (1, 2-benzisothiazole) -6-yl, (1, 2-benzisothiazole) -7-yl, (2, 1-benzisothiazole) -3-yl, (2, 1-benzisothiazole) -4-yl, (2, 1-benzisothiazole) -5-yl, (2, 1-benzisothiazol) -6-yl, (2, 1-benzisothiazol) -7-yl, (1, 2, 3-benzoxadiazol) -4-yl, (1, 2, 3-benzoxadiazol) -5-yl, (1, 2, 3-benzoxadiazol) -6-yl, (1, 2, 3-benzoxadiazol) -7-yl, (2, 1, 3-benzoxadiazol) -4-yl, (2, 1, 3-benzoxadiazol) -5-yl, (1, 2, 3-benzothiadiazol) -4-yl, (1, 2, 3-benzothiadiazol) -5-yl, (1, 2, 3-benzothiadiazol) -6-yl, (1, 2, 3-benzothiadiazole) -7-yl, (2, 1, 3-benzothiadiazole) -4-yl, (2, 1, 3-benzothiadiazole) -5-yl, (1H-benzotriazole) -1-yl, (1H-benzotriazole) -4-yl, (1H-benzotriazole) -5-yl, (1H-benzotriazole) -6-yl, (1H-benzotriazole) -7-yl, (2H-benzotriazole) -2-yl, (2H-benzotriazole) -4-yl, (2H-benzotriazole) -5-yl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, quinoline-4-yl, and a pharmaceutically acceptable salt thereof, 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-quinazolinyl, 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 group, 6-purinyl group, 7-purinyl group, 8-purinyl group, 2-pteridine, 4-pteridinyl group, 6-pteridinyl group, 7-pteridinyl group, 1-carbazolyl group, 2-carbazolyl group, 3-carbazolyl group, 4-carbazolyl group, 9-carbazolyl group, 2- (. alpha. -carbolinyl), 3- (. alpha. -carbolinyl), 4- (. alpha. -carbolinyl), 5- (. alpha. -carbolinyl), 6- (. alpha. -carbolinyl), 7- (. alpha. -carbolinyl), 8- (. alpha. -carbolinyl), 9- (. alpha. -carbolinyl), 1- (. beta. -carbolinyl), 3- (. beta. -carbolinyl), 4- (. beta. -carbolinyl), 5- (. beta. -carbolinyl),. beta. -6- (. beta. -carbolinyl),. beta. -7- (. beta. -carbolinyl),. 8- (. beta. -carbolinyl),. beta. -9- (. beta. -carbolinyl),. 1- (. gamma. -carbolinyl),. 2- (. gamma. -carbolinyl),. 4- (. gamma. -carbolinyl), 5- (. gamma. -carbolinyl),. gamma. -6- (. gamma. -carbolinyl),. 7- (. gamma. -carbolinyl),. 8- (. gamma. -carbolinyl),. gamma. -9- (. gamma. -carbolinyl),. 1-acridinyl,. 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl, 1-phenoxazinyl, 2-phenoxazinyl, 3-phenoxazinyl, 4-phenoxazinyl, 10-phenothiazinyl, 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4-phenothiazinyl, 10-phenothiazinyl, 1-phenazinyl, 2-phenazinyl, 1-phenanthridinyl, 2-phenanthridinyl, 3-phenanthridinyl, 4-phenanthridinyl, 6-phenanthridinyl, 7-phenanthridinyl, 8-phenanthridinyl, 9-phenanthridinyl, 10-phenanthridinyl, 2-phenanthrolinyl, 3-phenanthrolinyl, 4-phenanthrolinyl, 5-phenanthrolinyl, 6-phenanthrolinyl, 7-phenanthrolinyl, 8-phenanthrolinyl, 9-phenanthrolinyl, 10-phenanthrolinyl, 1-thianthrenyl, 2-thianthrenyl, 1-indolizinyl, 2-indolizinyl, 3-phenothiazinyl, 4-phenanthridinyl, 7-phenanthridinyl, 8-phenanthridinyl, 9-phenanthrolinyl, 10-phenanthrolinyl, 1-thianthrenyl, 2-thianthrenyl, 1-indolizinyl, 2-indoli, An 8-to 14-membered fused heteroaryl group such as 3-indolizinyl, 5-indolizinyl, 6-indolizinyl, 7-indolizinyl, 8-indolizinyl, 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4-phenothiazinyl, thieno [ 2, 3-b ] furyl, pyrrolo [ 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 ] pyridyl, 1, 2, 4-triazolo [ 4, 3-a ] pyridazinyl and the like.

Examples of the "monocyclic non-aromatic heterocyclic group" include a 1-aziridinyl group, a 1-azetidinyl group, a 1-pyrrolidinyl group, a 2-pyrrolidinyl group, a 3-pyrrolidinyl group, a 2-tetrahydrofuryl group, a 3-tetrahydrofuryl group, a tetrahydrothienyl group, a 1-imidazolidinyl group, a 2-imidazolidinyl group, a 4-imidazolidinyl group, a 1-pyrazolidinyl group, a 3-pyrazolidinyl group, a 4-pyrazolidinyl group, a 1- (2-pyrrolinyl group), a 1- (2-imidazolinyl group), a 2- (2-imidazolinyl group), a 1- (2-pyrazolinyl group), a 3- (2-pyrazolinyl group), a piperidino group, a 2-piperidyl group, a 3-piperidyl group, a 4-piperidyl group, a 1-homopiperidinyl group, a piperidine group, 3-to 7-membered saturated or unsaturated monocyclic non-aromatic heterocyclic group such as 2-tetrahydropyranyl group, morpholino group, (thiomorpholin) -4-yl group, 1-piperazinyl group, 1-homopiperazinyl group and the like.

As the "fused polycyclic non-aromatic heterocyclic group", for example, 2-quinuclidinyl group, 2-chromanyl group, 3-chromanyl group, 4-chromanyl group, 5-chromanyl group, 6-chromanyl group, 7-chromanyl group, 8-chromanyl group, 1-isochromanyl group, 3-isochromanyl group, 4-isochromanyl group, 5-isochromanyl group, 6-isochromanyl group, 7-isochromanyl group, 8-isochromanyl group, 2-thiochromanyl group, 3-thiochromanyl group, 4-thiochromanyl group, 5-thiochromanyl group, 6-thiochromanyl group, 7-thiochromanyl group, 8-thiochromanyl group, 1-isochromanyl group, 3-isochromanyl group, 4-isochromanyl group, 5-isochromanyl group, 6-isochromanyl group, 7-isochromanyl group, 8-isochromanyl group, 1-indolinyl group, 2-indolinyl group, 3-indolinyl group, 4-indolinyl group, 5-indolinyl group, 6-indolinyl group, 7-indolinyl group, 1-isoindolinyl group, 2-isoindolinyl group, 4-isoindolinyl group, 5-isoindolinyl group, 3- (4H-benzopyranyl) group, 4- (4H-benzopyranyl), 5- (4H-benzopyranyl), 6- (4H-benzopyranyl), 7- (4H-benzopyranyl), 8- (4H-benzopyranyl), 1-isochromanyl, 3-isochromanyl, 4-isochromanyl, 5-isochromanyl, 6-isochromanyl, 7-isochromanyl, 8-isochromanyl, 1- (1H-pyrrolidinyl), 2- (1H-pyrrolidinyl), 3- (1H-pyrrolidinyl), 5- (1H-pyrrolidinyl), 6- (1H-pyrrolidinyl), 7- (1H-pyrrolidinyl), And the like 8 to 10-membered saturated or unsaturated condensed polycyclic non-aromatic heterocyclic groups.

Among the above-mentioned "heterocyclic groups", a monocyclic or condensed polycyclic heteroaryl group which may have 1 to 3 kinds of hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom as atoms (ring atoms) constituting a ring system other than the nitrogen atom having a bond, and a monocyclic or condensed polycyclic non-aromatic heterocyclic group which may have 1 to 3 kinds of hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom as atoms (ring atoms) constituting a ring system other than the nitrogen atom having a bond are referred to as "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-imidazolin-1-yl, 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-indolyl, 1-indazolyl, 2-isoindolyl and the like.

Examples of the "hydrocarbon-oxy group" may include a group in which a hydrogen atom of a "hydroxyl group" is substituted with a "hydrocarbon group", and examples of the "hydrocarbon" may include the same groups as those described above for the "hydrocarbon group". The "hydrocarbyloxy group" includes, for example, an aliphatic hydrocarbyloxy group such as an alkoxy group (alkyloxy group), an alkenyloxy group, an alkynyloxy group, a cycloalkoxy group, or a cycloalkylalkoxy group; an aryloxy group; an aralkyloxy group; alkylenedioxy, and the like.

As the "alkoxy (alkyloxy)", there may be mentioned methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, 1-methylbutoxy, neopentoxy, 1, 2-dimethylpropoxy, 1-ethylpropoxy, n-hexoxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-dimethylbutoxy, 2-dimethylbutoxy, 1-dimethylbutoxy, 1, 2-dimethylbutoxy, 1, 3-dimethylbutoxy, 2-ethylbutoxy, 1-ethyl-1-methylpropoxy, 1-ethylbutoxy, 1-methylpropoxy, n-butoxy, i-butoxy, C such as n-heptyloxy, n-octyloxy, n-nonyloxy, n-decyloxy, n-undecyloxy, n-dodecyloxy, n-tridecyloxy, n-tetradecyloxy, n-pentadecyloxy₁～C₁₅The linear or branched alkoxy group of (3).

As the "alkenyloxy group", there may be mentioned, for example, vinyloxy, (prop-1-en-1-yl) oxy, allyloxy, isopropenyloxy, (but-1-en-1-yl) oxy, (but-2-en-1-yl) oxy, (but-3-en-1-yl) oxy, (2-methylprop-2-en-1-yl) oxy, (1-methylprop-2-en-1-yl) oxy, (pent-1-en-1-yl) oxy, (pent-2-en-1-yl) oxy, (pent-3-en-1-yl) oxy, (pent-4-en-1-yl) oxy, (3-methylbut-2-en-1-yl) oxy, etc, (3-methylbut-3-en-1-yl) oxy, (hex-1-en-1-yl) oxy, (hex-2-en-1-yl) oxy, (hex-3-en-1-yl) oxy, (hex-4-en-1-yl) oxy, (hex-5-en-1-yl) oxy, (4-methylpent-3-en-1-yl) oxy, (hept-1-en- 1-yl) oxy, (hept-6-en-1-yl) oxy, (oct-1-en-1-yl) oxy, (oct-7-en-1-yl) oxy, (non-1-en-1-yl) oxy, (non-8-en-1-yl) oxy, (dec-1-en-1-yl) oxy, (dec-9-en-1-yl) oxy, (undec-1-en-1-yl) oxy, (undec-10-en-1-yl) oxy, (dodec-1-en-1-yl) oxy, (dodec-11-en-1-yl) oxy, (tridec-1-en-1-yl) oxy, and mixtures thereof, (tridec-12-en-1-yl) oxy, (tetradec-1-en-1-yl) oxy, (tetradec-13-en-1-yl) oxy, (pentadec-1-en-1-yl) oxy, (pentadec-14-en-1-yl) oxy, and the like₂～C₁₅Linear or branched alkenyloxy groups.

As the "alkynyloxy group", there are exemplified ethynyloxy, (prop-1-yn-1-yl) oxy, (prop-2-yn-1-yl) oxy, (but-1-yn-1-yl) oxy, (but-3-yn-1-yl) oxy, (1-methylprop-2-yn-1-yl) oxy, (pent-1-yn-1-yl) oxy, (pent-4-yn-1-yl) oxy, (hex-1-yn-1-yl) oxy, (hex-5-yn-1-yl) oxy, (hept-1-yn-1-yl) oxy, (hept-6-yn-1-yl) oxy, (oct-1-yn-1-yl) oxy, and, (oct-7-yn-1-yl) oxy, (non-1-yn-1-yl) oxy, (non-8-yn-1-yl) oxy, (dec-1-yn-1-yl) oxy, (dec-9-yn-1-yl) oxy, (undec-1-yn-1-yl) oxy, (undec-10-yn-1-yl) oxy, (dodec-1-yn-1-yl) oxy, (dodec-11-yn-1-yl) oxy, (tridec-1-yn-1-yl) oxy, (tridec-12-yn-1-yl) oxy, (tetradec-1-yn-1-yl) oxy, and mixtures thereof, (tetradec-13-yn-1-yl) oxy, (pentadec-1-yn-1-yl) oxy, (pentadec-14-yn-1-yl) oxy, and the like ₂～C₁₅The linear or branched alkynyloxy group of (1).

Examples of the "cycloalkoxy group" include C such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy₃～C₈Cycloalkoxy group of (1).

As the "cycloalkylalkoxy group", for example, cyclopropylmethoxy group, 1-cyclopropylethoxy group, 2-cyclopropylethoxy group, 3-cyclopropylpropoxy group, 4-cyclopropylbutoxy group, 5-cyclopropylpentyloxy group, 6-cyclopropylhexyloxy group, cyclobutylmethoxy group, cyclopentylmethoxy group, cyclohexylmethoxy group, 2-cyclohexylethoxy group, 3-cyclohexylpropoxy group, 4-cyclohexylbutoxy group, cycloheptylmethoxy group, cyclooctylmethoxy group, 6-cyclooctylhexyloxy groupOxy radicals and the like C₄～C₁₄Cycloalkylalkoxy group of (a).

Examples of the "aryloxy group" include a phenoxy group, 1-naphthoxy group, 2-naphthoxy group, anthracenoxy group, phenanthrenoxy group, acenaphthenyloxy group and the like₆～C₁₄An aryloxy group of (1).

As the "aralkyloxy group", for example, benzyloxy, 1-naphthylmethoxy, 2-naphthylmethoxy, anthracenylmethoxy, phenanthrenylmethoxy, acenaphthenylmethoxy, diphenylmethoxy, 1-phenethyloxy, 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-phenylpentoxy, 5- (1-naphthyl) pentyloxy, 5- (2-naphthyl) pentyloxy, m, C such as 6-phenylhexyloxy group, 6- (1-naphthyl) hexyloxy group, 6- (2-naphthyl) hexyloxy group ₇～C₁₆An aralkyloxy group of (a).

As the "alkylenedioxy group", there are mentioned methylenedioxy group, ethylenedioxy group, 1-methylmethylenedioxy group, 1-dimethylmethylenedioxy group and the like.

Examples of the "haloalkoxy (haloalkyloxy)" may include a group in which a hydrogen atom of a "hydroxyl group" is substituted with a "haloalkyl", and examples thereof include a C1 to 13 halogen atoms substituted with a fluoromethoxy group, difluoromethoxy group, chloromethoxy group, bromomethoxy group, iodomethoxy group, trifluoromethoxy group, trichloromethoxy group, 2, 2, 2-trifluoroethoxy group, pentafluoroethoxy group, 3, 3, 3-trifluoropropoxy group, heptafluoropropoxy group, heptafluoroisopropoxy group, nonafluorobutoxy group, perfluorohexyloxy group and the like₁～C₆The linear or branched halogenoalkoxy group of (1).

Examples of the "heterocyclic-oxy group" may include a group in which a hydrogen atom of the "hydroxy group" is replaced with a "heterocyclic group", and examples of the "heterocyclic group" may include the same ones as those described above for the "heterocyclic group". Examples of the "heterocycle-oxy group" include monocyclic heteroaryloxy group, condensed polycyclic heteroaryloxy group, monocyclic non-aromatic heterocycle-oxy group, condensed polycyclic non-aromatic heterocycle-oxy group and the like.

As "monocyclic heteroaryloxy", there are illustrated 3-thienyloxy, (isoxazol-3-yl) oxy, (thiazol-4-yl) oxy, 2-pyridyloxy, 3-pyridyloxy, 4-pyridyloxy, (pyrimidin-4-yl) oxy, and the like groups.

As "fused polycyclic heteroaryloxy", for example, a group such as 5-indolyloxy, (benzimidazol-2-yl) oxy, 2-quinolinyloxy, 3-quinolinyloxy, 4-quinolinyloxy, etc.

Examples of the "monocyclic non-aromatic heterocyclic-oxy group" include a 3-pyrrolidinyloxy group, a 4-piperidinyloxy group and the like.

As "fused polycyclic non-aromatic heterocyclic-oxy", for example, a 3-indolinyloxy group, a 4-chromanyloxy group and the like are mentioned.

Examples of the "hydrocarbon-sulfanyl group" may include a group in which a hydrogen atom of the "sulfanyl group" is substituted with a "hydrocarbon group", and examples of the "hydrocarbon" may include the same groups as those of the "hydrocarbon group". The "hydrocarbon-sulfanyl group" includes, for example, an aliphatic hydrocarbon-sulfanyl group such as an alkyl-sulfanyl group, an alkenyl-sulfanyl group, an alkynyl-sulfanyl group, a cycloalkyl-sulfanyl group, and a cycloalkyl-alkyl-sulfanyl group; aryl-sulfanyl, aralkyl-sulfanyl, and the like.

Examples of the "alkyl-sulfanyl group" include methylsulfanyl group, ethylsulfanyl group, n-propylsulfanyl group, isopropylsulfanyl group, n-butylsulfanyl group, isobutylsulfanyl group, sec-butylsulfanyl group, tert-butylsulfanyl group, n-pentylsulfanyl group, isopentylsulfanyl group, (2-methylbutyl) sulfanyl group, (1-methylbutyl) sulfanyl group, neopentylthanyl group, (1, 2-dimethylpropyl) sulfanyl group, (1-ethylpropyl) sulfanyl group, n-hexylsulfanyl group, (4-methylpentyl) sulfanyl group, (3-methylpentyl) sulfanyl group, (2-methylpentyl) sulfanyl group, (1-methylpentyl) sulfanyl group, (3, 3-dimethylbutyl) sulfanyl group, (2, 2-dimethylbutyl) sulfanyl group, (1, 1-dimethylbutyl) sulfanyl group, isopropylsulfanyl group, n-butylsulfanyl group, isobutylsulfanyl group, sec-, (1, 2-dimethylbutyl) sulfanyl, (1, 3-dimethylbutyl) sulfanyl, (2, 3-dimethylbutyl) sulfur C such as alkyl, (2-ethylbutyl) sulfanyl, (1-ethyl-1-methylpropyl) sulfanyl, n-heptylthio, n-octylsulfanyl, n-nonylthio, n-decylthioalkyl, n-undecylsulfanyl, n-dodecylsulfanyl, n-tridecylthio, n-tetradecylthio, n-pentadecylthio and the like₁～C₁₅The linear or branched alkyl-sulfanyl group of (3).

As the "alkenyl-sulfanyl group", there are mentioned, for example, vinylsulfanyl, (prop-1-en-1-yl) sulfanyl, allylsulfanyl, isopropenylsulfanyl, (but-1-en-1-yl) sulfanyl, (but-2-en-1-yl) sulfanyl, (but-3-en-1-yl) sulfanyl, (2-methylprop-2-en-1-yl) sulfanyl, (1-methylprop-2-en-1-yl) sulfanyl, (pent-1-en-1-yl) sulfanyl, (pent-2-en-1-yl) sulfanyl, (pent-3-en-1-yl) sulfanyl, (pent-4-en-1-yl) sulfanyl, and the like, (3-methylbut-2-en-1-yl) sulfanyl, (3-methylbut-3-en-1-yl) sulfanyl, (hex-1-en-1-yl) sulfanyl, (hex-2-en-1-yl) sulfanyl, (hex-3-en-1-yl) sulfanyl, (hex-4-en-1-yl) sulfanyl, (hex-5-en-1-yl) sulfanyl, (4-methylpent-3-en-1-yl) sulfanyl, (hept-1-en-1-yl) sulfanyl, (hept-6-en-1-yl) sulfanyl, (oct-1-en-1-yl) sulfanyl, (oct-7-en-1-yl) sulfanyl, (non-1-en-1-yl) sulfanyl, (non-8-en-1-yl) sulfanyl, (dec-1-en-1-yl) sulfanyl, (dec-9-en-1-yl) sulfanyl, (undec-1-en-1-yl) sulfanyl, (undec-10-en-1-yl) sulfanyl, (dodec-1-en-1-yl) sulfanyl, (dodec-11-en-1-yl) sulfanyl, (tridec-1-en-1-yl) sulfanyl, and mixtures thereof, C such as (tridec-12-en-1-yl) sulfanyl, (tetradec-1-en-1-yl) sulfanyl, (tetradec-13-en-1-yl) sulfanyl, (pentadec-1-en-1-yl) sulfanyl, and (pentadec-14-en-1-yl) sulfanyl ₂～C₁₅The linear or branched alkenyl-sulfanyl group of (3).

As "alkynyl-sulfanyl group", for example, ethynylsulfanyl, (prop-1-yn-1-yl) sulfanyl, (prop-2-yn-1-yl) sulfanyl, (but-1-yn-1-yl) sulfanyl, (but-3-yn-1-yl) sulfanyl, (1-methylprop-2-yn-1-yl) sulfanyl(pent-1-yn-1-yl) sulfanyl, (pent-4-yn-1-yl) sulfanyl, (hex-1-yn-1-yl) sulfanyl, (hex-5-yn-1-yl) sulfanyl, (hept-1-yn-1-yl), (hept-6-yn-1-yl) sulfanyl, (oct-1-yn-1-yl) sulfanyl, (oct-7-yn-1-yl) sulfanyl, (non-1-yn-1-yl) sulfanyl, (non-8-yn-1-yl) sulfanyl, (dec-1-yn-1-yl) sulfanyl, (dec-9-yn-1-yl) sulfanyl, C.C.sub.1-yn-1-yl) sulfanyl, (undec-10-yn-1-yl) sulfanyl, (dodec-1-yn-1-yl) sulfanyl, (dodec-11-yn-1-yl) sulfanyl, (tridec-1-yn-1-yl) sulfanyl, (tridec-12-yn-1-yl) sulfanyl, (tetradec-1-yn-1-yl) sulfanyl, (tetradec-13-yn-1-yl) sulfanyl, (pentadec-1-yn-1-yl) sulfanyl, (pentadec-14-yn-1-yl) sulfanyl, and the like₂～C₁₅The straight-chain or branched alkynyl-sulfanyl group of (3).

Examples of the "cycloalkyl-sulfanyl group" include C such as cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopentylsulfanyl, cyclohexylsulfanyl, cycloheptylsulfanyl and cyclooctylsulfanyl ₃～C₈Cycloalkyl-sulfanyl groups of (a).

Examples of the "cycloalkyl-alkyl-sulfanyl group" include (cyclopropylmethyl) sulfanyl group, (1-cyclopropylethyl) sulfanyl group, (2-cyclopropylethyl) sulfanyl group, (3-cyclopropylpropyl) sulfanyl group, (4-cyclopropylbutyl) sulfanyl group, (5-cyclopropylpentyl) sulfanyl group, (6-cyclopropylhexyl) sulfanyl group, (cyclobutylmethyl) sulfanyl group, (cyclopentylmethyl) sulfanyl group, a C such as a (cyclobutylmethyl) sulfanyl group, a (cyclopentylmethyl) sulfanyl group, a (cyclohexylmethyl) sulfanyl group, a (2-cyclohexylethyl) sulfanyl group, a (3-cyclohexylpropyl) sulfanyl group, a (4-cyclohexylbutyl) sulfanyl group, a (cycloheptylmethyl) sulfanyl group, a (cyclooctylmethyl) sulfanyl group, or a (6-cyclooctylhexyl) sulfanyl group.₄～C₁₄Cycloalkyl-alkyl-sulfanyl.

Examples of the "aryl-sulfanyl group" include C such as phenylsulfanyl, 1-naphthylsulfanyl, 2-naphthylsulfanyl, anthrylsulfanyl, phenanthrylsulfanyl, and acenaphthenylsulfanyl₆～C₁₄Aryl-sulfanyl groups of (a).

As"aralkyl-sulfanyl group" includes, for example, benzylsulfanyl group, (1-naphthylmethyl) sulfanyl group, (2-naphthylmethyl) sulfanyl group, (anthracenylmethyl) sulfanyl group, (phenanthrenyl methyl) sulfanyl group, (acenaphthenylmethyl) sulfanyl group, (diphenylmethyl) sulfanyl group, (1-phenethyl) sulfanyl group, (2-phenethyl) sulfanyl group, (1- (1-naphthyl) ethyl) sulfanyl group, (1- (2-naphthyl) ethyl) sulfanyl group, (2- (1-naphthyl) ethyl) sulfanyl group, (2- (2-naphthyl) ethyl) sulfanyl group, (3-phenylpropyl) sulfanyl group, (3- (1-naphthyl) propyl) sulfanyl group, (3- (2-naphthyl) propyl) sulfanyl group, (4-phenylbutyl) sulfanyl group, c-such as (4- (1-naphthyl) butyl) sulfanyl, (4- (2-naphthyl) butyl) sulfanyl, (5-phenylpentyl) sulfanyl, (5- (1-naphthyl) pentyl) sulfanyl, (5- (2-naphthyl) pentyl) sulfanyl, (6-phenylhexyl) sulfanyl, (6- (1-naphthyl) hexyl) sulfanyl, and (6- (2-naphthyl) hexyl) sulfanyl ₇～C₁₆Aralkyl-sulfanyl groups of (a).

Examples of the "haloalkyl-sulfanyl group" may include groups in which the hydrogen atom of the "sulfanyl group" is substituted by a "haloalkyl group", such as a C (C) haloalkyl group substituted by 1 to 13 halogen atoms, e.g., (fluoromethyl) sulfanyl group, (chloromethyl) sulfanyl group, (bromomethyl) sulfanyl group, (iodomethyl) sulfanyl group, (difluoromethyl) sulfanyl group, (trifluoromethyl) sulfanyl group, (trichloromethyl) sulfanyl group, (2, 2, 2-trifluoroethyl) sulfanyl group, (pentafluoroethyl) sulfanyl group, (3, 3, 3-trifluoropropyl) sulfanyl group, (heptafluoropropyl) sulfanyl group, (heptafluoroisopropyl) sulfanyl group, (nonafluorobutyl) sulfanyl group, and (perfluorohexyl) sulfanyl group₁～C₆The straight-chain or branched haloalkyl-sulfanyl group of (3).

Examples of the "heterocycle-sulfanyl group" may include a group in which a hydrogen atom of the "sulfanyl group" is substituted with a "heterocyclic group", and examples of the "heterocycle" may include the same groups as those of the "heterocyclic group". Examples of the "heterocycle-sulfanyl group" include monocyclic heteroaryl-sulfanyl group, fused polycyclic heteroaryl-sulfanyl group, monocyclic non-aromatic heterocycle-sulfanyl group, and fused polycyclic non-aromatic heterocycle-sulfanyl group.

Examples of the "monocyclic heteroaryl-sulfanyl group" include (imidazol-2-yl) sulfanyl, (1, 2, 4-triazol-2-yl) sulfanyl, (pyridin-4-yl) sulfanyl, and (pyrimidin-2-yl) sulfanyl groups.

Examples of the "fused polycyclic heteroaryl-sulfanyl group" include a (benzimidazol-2-yl) sulfanyl group, a (quinolin-2-yl) sulfanyl group, and a (quinolin-4-yl) sulfanyl group.

Examples of the "monocyclic non-aromatic heterocyclic-sulfanyl group" include a (3-pyrrolidinyl) sulfanyl group, a (4-piperidinyl) sulfanyl group and the like.

Examples of the "fused polycyclic non-aromatic heterocyclic-sulfanyl group" include a (3-indolinyl) sulfanyl group, a (4-chromanyl) sulfanyl group and the like.

As the "acyl group", for example, formyl group, glyoxyl group, thioaldehyde group and a group represented by the following formula,

(in the formula, R^a1And R^b1Identical or different, denotes a hydrocarbon group or a heterocyclic group, or R^a1And R^b1Taken together, together with the nitrogen atom to which they are bound, represent a cyclic amino group).

In the definition of the above-mentioned "acyl group",

in the group represented by the formula (. omega. -1A), R^a1The group which is a hydrocarbon group is called "hydrocarbon-carbonyl group" (specific examples: acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, lauroyl, myristoyl, palmitoyl, acryloyl, propioloyl, methacryloyl, crotonyl, isocrotonyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, 1-naphthoyl, 2-naphthoyl, phenylacetyl and the like), R ^a1A group which is a heterocyclic group is referred to as "heterocyclic-carbonyl" (specific examples: 2-thenoyl, 3-furoyl, nicotinoyl, etc.),Isonicotinyl, etc.).

In the group represented by the formula (. omega. -2A), R^a1The group which is a hydrocarbon group is referred to as "hydrocarbon-oxy-carbonyl" (specific examples: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, benzyloxycarbonyl, etc. groups), R^a1A group which is a heterocyclic group is referred to as "heterocycle-oxy-carbonyl" (specific examples: 3-pyridyloxycarbonyl and the like groups).

In the group represented by the formula (. omega. -3A), R^a1The group being a hydrocarbon group is referred to as "hydrocarbon-carbonyl" (specific examples: pyruvoyl and the like groups), R^a1A group that is a heterocyclic group is referred to as "heterocycle-carbonyl.

In the group represented by the formula (. omega. -4A), R^a1The group which is a hydrocarbon group is referred to as "hydrocarbon-oxy-carbonyl" (specific examples: oxalyl, etc. groups), R^a1A group that is a heterocyclic group is referred to as "heterocycle-oxy-carbonyl.

In the group represented by the formula (. omega. -5A), R^a1The radical being a hydrocarbon radical is known as "hydrocarbon-sulfanyl-carbonyl", R^a1A group that is a heterocyclic group is referred to as a "heterocycle-sulfanyl-carbonyl".

In the group represented by the formula (. omega. -6A), R^a1The radical being a hydrocarbon radical is known as "hydrocarbon-thiocarbonyl", R ^a1A group that is a heterocyclic group is referred to as a "heterocyclic-thiocarbonyl".

In the group represented by the formula (. omega. -7A), R^a1The radicals being hydrocarbon radicals are known as "hydrocarbon-oxy-thiocarbonyl", R^a1A group that is a heterocyclic group is referred to as a "heterocyclic-oxy-thiocarbonyl".

In the group represented by the formula (. omega. -8A), R^a1The radicals being hydrocarbon radicals are known as "hydrocarbon-sulfanyl-thiocarbonyl", R^a1A group that is a heterocyclic group is referred to as "heterocycle-sulfanyl-thiocarbonyl".

In the group represented by the formula (. omega. -9A), R^a1The group which is a hydrocarbon group is referred to as "N-hydrocarbon-carbamoyl" (specific example: N-methylamino)Formyl, etc.), R^a1A group that is a heterocyclic group is referred to as an "N-heterocyclic-carbamoyl".

In the group represented by the formula (. omega. -10A), R^a1And R^b1The group which is a hydrocarbon group is referred to as "N, N-di (hydrocarbon) -carbamoyl" (specific examples: N, N-dimethylcarbamoyl and the like), R^a1And R^b1A group that is a heterocyclic group is referred to as "N, N-di (heterocyclic) -carbamoyl", R^a1Is a hydrocarbon radical and R^b1A group that is a heterocyclic group is referred to as "N-hydrocarbon-N-heterocycle-substituted carbamoyl", R^a1And R^b1The group which is linked together to form a cyclic amino group together with the nitrogen atom to which they are bonded is referred to as "cyclic amino-carbonyl" (specific examples: morpholinocarbonyl and the like).

In the group represented by the formula (. omega. -11A), R^a1The radical being a hydrocarbon radical is known as "N-hydrocarb-thiocarbamoyl", R^a1A group that is a heterocyclic group is referred to as an "N-heterocyclic-thiocarbamoyl".

In the group represented by the formula (. omega. -12A), R^a1And R^b1The radical being a hydrocarbon radical is known as "N, N-di (hydrocarbon) -thiocarbamoyl", R^a1And R^b1A group that is a heterocyclic group is referred to as "N, N-di (heterocyclic) -thiocarbamoyl", R^a1Is a hydrocarbon radical and R^b1A group which is a heterocyclic group is referred to as "N-Hydrocarbon-N-heterocycle-thiocarbamoyl", R^a1And R^b1Groups that are taken together to form a cyclic amino group together with the nitrogen atom to which they are bound are referred to as "cyclic amino-thiocarbonyl".

In the group represented by the formula (. omega. -13A), R^a1The radical being a hydrocarbon radical, known as "N-Hydrocarbon-sulfamoyl", R^a1A group that is a heterocyclic group is referred to as an "N-heterocyclic-sulfamoyl group".

In the group represented by the formula (. omega. -14A), R^a1And R^b1The group which is a hydrocarbon group is referred to as "N, N-di (hydrocarbon) -sulfamoyl" (specific example: N, N-dimethylsulfamoyl and the like group), R^a1And R^b1Is a heterocyclic radicalThe radical of the group is designated "N, N-di (heterocyclic) -sulfamoyl", R^a1Is a hydrocarbon radical and R^b1A group which is a heterocyclic group is referred to as "N-hydrocarbon-N-heterocyclic-sulfamoyl", R ^a1And R^b1The group which is linked together to form a cyclic amino group together with the nitrogen atom to which they are bonded is referred to as "cyclic amino-sulfonyl" (specific examples: 1-pyrrolylsulfonyl and the like groups).

In the group represented by the formula (. omega. -15A), R^a1The group which is a hydrocarbon group is referred to as "N-hydrocarbonsulfenamide group (スルフイナモイル)", R^a1A group that is a heterocyclic group is referred to as an "N-heterocyclic-sulfamoyl group".

In the group represented by the formula (. omega. -16A), R^a1And R^b1The radical being a hydrocarbon radical is known as "N, N-di (hydrocarbon) -sulfamoyl", R^a1And R^b1A group that is a heterocyclic group is referred to as "N, N-di (heterocyclic) -sulfamoyl", R^a1Is a hydrocarbon radical and R^b1A group which is a heterocyclic group is referred to as "N-hydrocarbon-N-heterocyclic-sulfamoyl", R^a1And R^b1Groups which, taken together, form a cyclic amino group together with the nitrogen atom to which they are bound are referred to as "cyclic amino-sulfinyl".

In the group represented by the formula (. omega. -17A), R^a1The radical being a hydrocarbon radical, known as "hydrocarbyl-oxy-sulfonyl", R^a1A group that is a heterocyclic group is referred to as "heterocycle-oxy-sulfonyl".

In the group represented by the formula (. omega. -18A), R^a1The radicals being hydrocarbon radicals being known as "hydrocarbyl-oxy-sulfinyl", R^a1A group that is a heterocyclic group is referred to as "heterocycle-oxy-sulfinyl".

In the group represented by the formula (. omega. -19A), R^a1And R^b1The group being a hydrocarbon radical is referred to as "O, O-di (hydrocarbon) -phosphono", R^a1And R^b1A group that is a heterocyclic group is referred to as "O, O-di (heterocyclic) -phosphonyl", R^a1Is a hydrocarbon radical and R^b1A group that is a heterocyclic group is referred to as an "O-hydrocarbon-O' -heterocyclic-phosphonyl group".

In the group represented by the formula (. omega. -20A), R^a1The group which is a hydrocarbon group is referred to as "hydrocarbon-sulfonyl" (specific examples: methanesulfonyl, benzenesulfonyl and the like groups), R^a1A group that is a heterocyclic group is referred to as "heterocycle-sulfonyl".

In the group represented by the formula (. omega. -21A), R^a1The group which is a hydrocarbon group is referred to as "hydrocarbon-sulfinyl" (specific examples: methanesulfinyl, benzenesulfinyl, etc. groups), R^a1A group that is a heterocyclic group is referred to as "heterocycle-sulfinyl".

Examples of the "hydrocarbon" in the groups represented by the above formulae (. omega. -1A) to (. omega. -21A) may include the same groups as those mentioned for the "hydrocarbon group". Examples of the "hydrocarbon-carbonyl group" represented by the formula (. omega. -1A) include aliphatic hydrocarbon-carbonyl groups such as alkyl-carbonyl group, alkenyl-carbonyl group, alkynyl-carbonyl group, cycloalkyl-carbonyl group, cycloalkenyl-carbonyl group, cycloalkadienyl-carbonyl group, and cycloalkyl-alkyl-carbonyl group; aryl-carbonyl; aralkyl-carbonyl; bridged hydrocarbon-carbonyl; spiro hydrocarbon-carbonyl; a terpene hydrocarbon-carbonyl group. The same applies to the groups represented by the formulae (. omega. -2A) to (. omega. -21A) below.

Examples of the "heterocyclic ring" in the groups represented by the above formulae (ω -1A) to (ω -21A) may include the same groups as those described above for the "heterocyclic group". Examples of the "heterocyclic-carbonyl group" represented by the formula (. omega. -1A) include monocyclic heteroaryl-carbonyl group, fused polycyclic heteroaryl-carbonyl group, monocyclic non-aromatic heterocyclic-carbonyl group and fused polycyclic non-aromatic heterocyclic-carbonyl group. The same applies to the groups represented by the formulae (. omega. -2A) to (. omega. -21A) below.

Examples of the "cyclic amino group" in the groups represented by the above formulae (. omega. -10A) to (. omega. -16A) may include the same groups as the "cyclic amino group" described above.

The above-mentioned "acyl group", "carbamoyl group", "thiocarbamoyl group", "sulfamoyl group" and "sulfamoyl group" are collectively referred to as "acyl group which may have a substituent".

In the present specification, the case where "may have a substituent" is referred to for some functional groups, unless otherwise mentioned, means that these functional groups may or may not have 1 or 2 or more "substituents" at chemically possible positions. The kind of the substituent present on the functional group, the number of the substituents and the substitution position are not particularly limited, and when 2 or more substituents are present, these substituents may be the same or different. As the "substituent" present on the functional group, there may be mentioned, for example, a halogen atom, oxo, thio, nitro, nitroso, cyano, isocyano, cyanato, thiocyanato, isocyano, isothiothio, hydroxyl, sulfanyl, carboxyl, thioalkylcarbonyl, oxalyl, methoxalyl, thiocarboxyl, dithiocarboxyl, carbamoyl, thiocarbamoyl, sulfo, sulfamoyl, sulfino, sulfenamo, sulfeno, sulfenamoyl, phosphonyl, hydroxyphosphono, hydrocarbyl, heterocyclic, hydrocarbonoxy, heterocyclic-oxy, hydrocarbonsulfanyl, heterocyclic-sulfanyl, acyl, amino, hydrazino, hydrazone, diazenyl, ureido, thioureido, guanidino, methionyl (carbamoimido), azido, imino, hydroxyamino, hydroxyimino, aminooxy, diazo, Urealyl (semicarbazo), ureaformaldoyl, urealyl, phosphano, oxyphosphoryl, phospho, boryl, silyl, スタニル, セラニル, oxy, and the like.

When 2 or more "substituents" exist in the definition of "may have a substituent", the 2 or more substituents may form a cyclic group together with the atom to which they are bonded. Such a cyclic group may contain 1 or more kinds of hetero atoms selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like as atoms (ring atoms) constituting the ring system, and 1 or more substituents may be present on the ring. The ring may be monocyclic or fused polycyclic, and may be aromatic or non-aromatic.

The "substituent" in the definition of "may have a substituent" described above may also be substituted with the "substituent" described above at a chemically possible position on the substituent. The kind of the substituent, the number of the substituent and the substitution position are not particularly limited, and when 2 or more substituents are substituted, these substituents may be the same or different. Examples thereof include a haloalkyl-carbonyl group (specific examples: a group such as trifluoroacetyl group), a haloalkyl-sulfonyl group (specific examples: a group such as trifluoromethanesulfonyl group), an acyloxy group, an acyl-sulfanyl group, an N-hydrocarbon-amino group, an N, N-di (hydrocarbon) -amino group, an N-heterocyclic-amino group, an N-hydrocarbon-N-heterocyclic amino group, an acylamino group, a di (acyl) amino group, and the like. The "substitution" in the "substituent" may be repeated several times.

Examples of the "acyloxy group" may include a group in which the hydrogen atom of the "hydroxy group" is substituted by an "acyl group", such as formyloxy, glyoxyloxy, thioaldoxy, and a group represented by the following formula.

(in the formula, R^a2And R^b2Identical or different, denotes a hydrocarbon group or a heterocyclic group, or R^a2And R^b2Taken together, together with the nitrogen atom to which they are bound, represent a cyclic amino group).

In the definition of the "acyloxy group" mentioned above,

in the group represented by the formula (. omega. -1B), R^a2The group which is a hydrocarbon group is referred to as "hydrocarbon-carbonyl-oxy" (specific examples: acetoxy, benzoyloxy, etc. group), R^a2A group that is a heterocyclic group is referred to as "heterocycle-carbonyl-oxy".

In the group represented by the formula (. omega. -2B), R^a2The radical being a hydrocarbon radical being known as "hydrocarbon-oxy-carbonyl-oxy", R^a2A group that is a heterocyclic group is referred to as "heterocycle-oxy-carbonyl-oxy".

In the group represented by the formula (. omega. -3B), R^a2The radical being a hydrocarbon radical being known as "hydrocarbon-carbonyl-oxy", R^a2A group that is a heterocyclic group is referred to as "heterocycle-carbonyl-oxy".

In the group represented by the formula (. omega. -4B), R^a2The radical being a hydrocarbon radical being known as "hydrocarbon-oxy-carbonyl-oxy", R^a2A group that is a heterocyclic group is referred to as "heterocycle-oxy-carbonyl-oxy".

In the group represented by the formula (. omega. -5B), R^a2The radical being a hydrocarbon radical being known as "hydrocarbon-sulfanyl-carbonyl-oxy", R^a2A group that is a heterocyclic group is referred to as "heterocycle-sulfanyl-carbonyl-oxy".

In the group represented by the formula (. omega. -6B), R^a2The radical being a hydrocarbon radical being known as "hydrocarbon-thiocarbonyl-oxy", R^a2A group that is a heterocyclic group is referred to as "heterocycle-thiocarbonyl-oxy".

In the group represented by the formula (. omega. -7B), R^a2The radicals being hydrocarbon radicals being known as "hydrocarbon-oxy-thiocarbonyl-oxy", R^a2A group that is a heterocyclic group is referred to as "heterocycle-oxy-thiocarbonyl-oxy".

In the group represented by the formula (. omega. -8B), R^a2The radicals being hydrocarbon radicals being known as "hydrocarbon-sulfanyl-thiocarbonyl-oxy", R^a2A group that is a heterocyclic group is referred to as "heterocycle-sulfanyl-thiocarbonyl-oxy".

In the group represented by the formula (. omega. -9B), R^a2The radical being a hydrocarbon radical is known as "N-hydrocarben-carbamoyl-oxy", R^a2A group that is a heterocyclic group is referred to as "N-heterocyclic-carbamoyl-oxy".

In the group represented by the formula (. omega. -10B), R^a2And R^b2The radical being a hydrocarbon radical is known as "N, N-di (hydrocarbon) -carbamoyl-oxy", R^a2And R^b2A group that is a heterocyclic group is referred to as "N, N-di (heterocyclic) -carbamoyl-oxy", R ^a2Is a hydrocarbon radical and R^b2A group that is a heterocyclic group is referred to as "N-Hydrocarbon-N-heterocycle-carbamoyl-oxy", R^a2And R^b2Groups taken together to form a cyclic amino group together with the nitrogen atom to which they are bound are referred to as "cyclic amino-carbonyl-oxy".

In the group represented by the formula (. omega. -11B), R^a2The radical being a hydrocarbon radical is known as "N-hydrocarbonthio-carbamoyl-oxy", R^a2A group that is a heterocyclic group is referred to as "N-heterocycle-thiocarbamoyl-oxy".

In the group represented by the formula (. omega. -12B), R^a2And R^b2The radical being a hydrocarbon radical is known as "N, N-di (hydrocarbon) -thiocarbamoyl-oxy", R^a2And R^b2A group that is a heterocyclic group is referred to as "N, N-bis (heterocyclic) -thiocarbamoyl-oxy", R^a2Is a hydrocarbon radical and R^b2A group that is a heterocyclic group is referred to as "N-Hydrocarbon-N-heterocycle-Thiocarbamoyl-oxy", R^a2And R^b2Groups that are taken together to form a cyclic amino group together with the nitrogen atom to which they are bound are referred to as "cyclic amino-thiocarbonyl-oxy".

In the group represented by the formula (. omega. -13B), R^a2The radical being a hydrocarbon radical being known as "N-hydrocarbonaminosulfonyloxy", R^a2A group that is a heterocyclic group is referred to as "N-heterocycle-sulfamoyl-oxy".

In the group represented by the formula (. omega. -14B), R ^a2And R^b2The radical being a hydrocarbon radical is known as "N, N-di (hydrocarbon) -sulfamoyl-oxy", R^a2And R^b2A group that is a heterocyclic group is referred to as "N, N-di (heterocyclic) -sulfamoyl-oxy", R^a2Is a hydrocarbon radical and R^b2A group that is a heterocyclic group is referred to as "N-Hydrocarbon-N-heterocycle-sulfamoyl-oxy", R^a2And R^b2Groups that are taken together to form a cyclic amino group together with the nitrogen atom to which they are bound are referred to as "cyclic amino-sulfonyl-oxy".

In the group represented by the formula (. omega. -15B), R^a2The radical being a hydrocarbon radical being known as "N-hydrocarbonsulphinylsulphonideoxy", R^a3A group that is a heterocyclic group is referred to as "N-heterocyclic-sulfamoyl-oxy".

In the group represented by the formula (. omega. -16B), R^a2And R^b2The radical being a hydrocarbon radical being known as "N, N-di (hydrocarbon) -sulfamoyl radical-oxy ", R^a2And R^b2A group that is a heterocyclic group is referred to as "N, N-bis (heterocyclic) -sulfamoyl-oxy", R^a2Is a hydrocarbon radical and R^b2A group that is a heterocyclic group is referred to as "N-hydrocarbon-N-heterocycle-sulfamoyl-oxy", R^a2And R^b2Groups which, taken together, form a cyclic amino group together with the nitrogen atom to which they are bound are referred to as "cyclic amino-sulfinyl-oxy".

In the group represented by the formula (. omega. -17B), R^a2The radical being a hydrocarbon radical being known as "hydrocarbon-oxy-sulfonyl-oxy", R ^a2A group that is a heterocyclic group is referred to as "heterocycle-oxy-sulfonyl-oxy".

In the group represented by the formula (. omega. -18B), R^a2The radical being a hydrocarbon radical being known as "hydrocarbyl-oxy-sulfinyl-oxy", R^a2A group that is a heterocyclic group is referred to as "heterocycle-oxy-sulfinyl-oxy".

In the group represented by the formula (. omega. -19B), R^a2And R^b2The group being a hydrocarbon radical is referred to as "O, O' -di (hydrocarbon) -phosphono-oxy", R^a2And R^b2A group that is a heterocyclic group is referred to as "O, O' -di (heterocyclic) -phosphono-oxy", R^a2Is a hydrocarbon radical and R^b2A group that is a heterocyclic group is referred to as an "O-hydrocarbon substituted-O' -heterocyclic substituted phosphono-oxy group".

In the group represented by the formula (. omega. -20B), R^a2The radical being a hydrocarbon radical being known as "hydrocarbon-sulfonyl-oxy", R^a2A group that is a heterocyclic group is referred to as "heterocycle-sulfonyl-oxy".

In the group represented by the formula (. omega. -21B), R^a2The radical being a hydrocarbon radical being known as "hydrocarbyl-sulfinyl-oxy", R^a2A group that is a heterocyclic group is referred to as "heterocycle-sulfinyl-oxy".

Examples of the "hydrocarbon" in the groups represented by the above formulae (. omega. -1B) to (. omega. -21B) may include the same groups as those mentioned for the "hydrocarbon group". Examples of the "hydrocarbon-carbonyl-oxy group" represented by the formula (. omega. -1B) include aliphatic hydrocarbon-carbonyl-oxy groups such as alkyl-carbonyl-oxy group, alkenyl-carbonyl-oxy group, alkynyl-carbonyl-oxy group, cycloalkyl-carbonyl-oxy group, cycloalkenyl-carbonyl-oxy group, cycloalkadienyl-carbonyl-oxy group, and cycloalkyl-alkyl-carbonyl-oxy group; aryl-carbonyl-oxy; aralkyl-carbonyl-oxy; bridged hydrocarbon-carbonyl-oxy; spiro hydrocarbon-carbonyl-oxy; a terpene hydrocarbon-carbonyl-oxy. The same applies to the groups represented by the formulae (. omega. -2B) to (. omega. -21B) below.

Examples of the "heterocyclic ring" in the groups represented by the above formulae (ω -1B) to (ω -21B) may include the same groups as those described above for the "heterocyclic group". Examples of the "heterocyclic-carbonyl group" represented by the formula (. omega. -1B) include monocyclic heteroaryl-carbonyl group, fused polycyclic heteroaryl-carbonyl group, monocyclic non-aromatic heterocyclic-carbonyl group and fused polycyclic non-aromatic heterocyclic-carbonyl group. The same applies to the groups represented by the formulae (. omega. -2B) to (. omega. -21B) below.

Examples of the "cyclic amino group" in the groups represented by the above formulae (. omega. -10B) to (. omega. -16B) may include the same groups as the "cyclic amino group" described above.

The above "acyloxy group", "hydrocarbon-oxy group" and "heterocyclic-oxy group" are collectively referred to as "substituted oxy group". In addition, these "substituted oxy" and "hydroxy" are collectively referred to as "hydroxy which may have a substituent".

Examples of the "acyl-sulfanyl group" may include groups in which the hydrogen atom of the "sulfanyl group" is substituted by an "acyl group", such as formylsulfanyl group, glyoxylsulfanyl group, thioaldehyde sulfanyl group, and groups represented by the following formula.

(in the formula, R^a3And R^b3The same or different, represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, or R ^a3And R^b3Taken together, together with the nitrogen atom to which they are bound may haveA cyclic amino group having a substituent).

In the definition of "acyl-sulfanyl" above,

in the group represented by the formula (. omega. -1C), R^a3The radical being a hydrocarbon radical being known as "hydrocarbon-carbonyl-sulfanyl", R^a3A group that is a heterocyclic group is referred to as "heterocycle-carbonyl-sulfanyl".

In the group represented by the formula (. omega. -2C), R^a3The radicals being hydrocarbon radicals being termed "hydrocarbon-oxy-carbonyl-sulfanyl", R^a3A group that is a heterocyclic group is referred to as "heterocycle-oxy-carbonyl-sulfanyl".

In the group represented by the formula (. omega. -3C), R^a3The radical being a hydrocarbon radical being known as "hydrocarbon-carbonyl-sulfanyl", R^a3A group that is a heterocyclic group is referred to as "heterocycle-carbonyl-sulfanyl".

In the group represented by the formula (. omega. -4C), R^a3The radical being a hydrocarbon radical being known as "hydrocarbon-oxy-carbonyl-sulfanyl", R^a3A group that is a heterocyclic group is referred to as "heterocycle-oxo-carbonyl-sulfanyl".

In the group represented by the formula (. omega. -5C), R^a3The radicals being hydrocarbon radicals being termed "hydrocarbon-sulfanyl-carbonyl-sulfanyl", R^a3A group that is a heterocyclic group is referred to as "heterocycle-sulfanyl-carbonyl-sulfanyl".

In the group represented by the formula (. omega. -6C), R^a3The radicals being hydrocarbon radicals being known as "hydrocarbon-thiocarbonyl-sulfanyl", R ^a3A group that is a heterocyclic group is referred to as "heterocycle-thiocarbonyl-sulfanyl".

In the group represented by the formula (. omega. -7C), R^a3The radicals being hydrocarbon radicals being known as "hydrocarbon-oxy-thiocarbonyl-sulfanyl", R^a3A group that is a heterocyclic group is referred to as "heterocycle-oxy-thiocarbonyl-sulfanyl".

In the group represented by the formula (. omega. -8C), R^a3The radicals being hydrocarbon radicals being known as "hydrocarbon-sulfanyl-thiocarbonyl-sulfanyl", R^a3Radicals being heterocyclic radicalsThe group is referred to as "heterocycle-sulfanyl-thiocarbonyl-sulfanyl".

In the group represented by the formula (. omega. -9C), R^a3The radical being a hydrocarbon radical is known as "N-hydrocarban-carbamoyl-sulfanyl", R^a3A group that is a heterocyclic group is referred to as "N-heterocyclic-carbamoyl-sulfanyl".

In the group represented by the formula (. omega. -10C), R^a3And R^b3The radical being a hydrocarbon radical is called "N, N-di (hydrocarbon) -carbamoyl-sulfanyl", R^a3And R^b3A group that is a heterocyclic group is referred to as "N, N-di (heterocyclic) -carbamoyl-sulfanyl", R^a3Is a hydrocarbon radical and R^b3A group that is a heterocyclic group is referred to as "N-Hydrocarbon-N-heterocycle-carbamoyl-sulfanyl", R^a3And R^b3Groups that are taken together to form a cyclic amino group together with the nitrogen atom to which they are bound are referred to as "cyclic amino-carbonyl-sulfamoyl".

In the group represented by the formula (. omega. -11C), R ^a3The radical being a hydrocarbon radical is known as "N-hydrocarbyl-thiocarbamoyl-sulfanyl", R^a3A group that is a heterocyclic group is referred to as "N-heterocycle-thiocarbamoyl-sulfanyl".

In the group represented by the formula (. omega. -12C), R^a3And R^b3The radical being a hydrocarbon radical is known as "N, N-di (hydrocarbon) -thiocarbamoyl-sulfanyl", R^a3And R^b3A group that is a heterocyclic group is referred to as "N, N-di (heterocyclic) -thiocarbamoyl-sulfanyl", R^a3Is a hydrocarbon radical and R^b3A group that is a heterocyclic group is referred to as "N-Hydrocarbon-N-heterocycle-Thiocarbamoyl-sulfanyl", R^a3And R^b3Groups that are taken together to form a cyclic amino group together with the nitrogen atom to which they are bound are referred to as "cyclic amino-thiocarbonyl-sulfanyl".

In the group represented by the formula (. omega. -13C), R^a3The radical being a hydrocarbon radical being referred to as "N-hydrocarbon-sulfamoyl-sulfanyl", R^a3A group that is a heterocyclic group is referred to as "N-heterocycle-sulfamoyl-sulfanyl".

In the group represented by the formula (. omega. -14C), R^a3And R^b3The radical being a hydrocarbon radical is called "N, N-di (hydrocarbon) -sulfamoyl-sulfanyl", R^a3And R^b3A group that is a heterocyclic group is referred to as "N, N-di (heterocyclic) -sulfamoyl-sulfanyl", R^a3Is a hydrocarbon radical and R^b3A group that is a heterocyclic group is referred to as "N-Hydrocarbon-N-heterocyclic sulfamoyl-sulfanyl", R ^a3And R^b3Groups that are taken together to form a cyclic amino group together with the nitrogen atom to which they are bound are referred to as "cyclic amino-sulfonyl-sulfanyl".

In the group represented by the formula (. omega. -15C), R^a3The radical being a hydrocarbon radical being referred to as "N-hydrocarbonene-iminosulfonyl-sulfanyl", R^a3A group that is a heterocyclic group is referred to as "N-heterocyclic-sulfamoyl-sulfanyl".

In the group represented by the formula (. omega. -16C), R^a3And R^b3The radical being a hydrocarbon radical is known as "N, N-di (hydrocarbon) -sulfamoyl-sulfanyl", R^a3And R^b3A group that is a heterocyclic group is referred to as "N, N-di (heterocyclic) -sulfamoyl-sulfanyl", R^a3Is a hydrocarbon radical and R^b3A group which is a heterocyclic group is referred to as "N-hydrocarbon-N-heterocyclic-sulfamoyl-sulfanyl", R^a3And R^b3Groups which, taken together, form a cyclic amino group together with the nitrogen atom to which they are bound are referred to as "cyclic amino-sulfanyl".

In the group represented by the formula (. omega. -17C), R^a3The radical being a hydrocarbon radical, being called "hydrocarbyl-oxy-sulfonyl-sulfanyl", R^a3A group that is a heterocyclic group is referred to as "heterocycle-oxy-sulfonyl-sulfanyl".

In the group represented by the formula (. omega. -18C), R^a3The radical being a hydrocarbon radical being known as "hydrocarbyloxy-sulfinyl-sulfanyl", R^a3A group that is a heterocyclic group is referred to as "heterocycle-oxy-sulfinyl-sulfanyl".

In the group represented by the formula (. omega. -19C), R^a3And R^b3The group being a hydrocarbyl group is referred to as "O, O' -di (hydrocarbon) -phosphono-sulfanyl", R^a3And R^b3A group that is a heterocyclic group is referred to as "O, O' -di (heterocyclic) -phosphono-sulfanyl", R^a3Is a hydrocarbon radical and R^b3A group that is a heterocyclic group is referred to as "O-hydrocarbon-O' -heterocyclic-phosphono-sulfanyl".

In the group represented by the formula (. omega. -20C), R^a3The radical being a hydrocarbon radical being known as "hydrocarbon-sulfonyl-sulfanyl", R^a3A group that is a heterocyclic group is referred to as "heterocycle-sulfonyl-sulfanyl".

In the group represented by the formula (. omega. -21C), R^a3The radical being a hydrocarbon radical being known as "hydrocarbyl-sulfinyl-sulfanyl", R^a3A group that is a heterocyclic group is referred to as "heterocycle-sulfinyl-sulfanyl".

Examples of the "hydrocarbon" in the groups represented by the above formulae (. omega. -1C) to (. omega. -21C) may include the same groups as those mentioned for the "hydrocarbon group". Examples of the "hydrocarbon-carbonyl-sulfanyl group" represented by the formula (. omega. -1C) include aliphatic hydrocarbon-carbonyl-sulfanyl groups such as alkyl-carbonyl-sulfanyl group, alkenyl-carbonyl-sulfanyl group, alkynyl-carbonyl-sulfanyl group, cycloalkyl-carbonyl-sulfanyl group, cycloalkenyl-carbonyl-sulfanyl group, cycloalkadienyl-carbonyl-sulfanyl group, and cycloalkyl-alkyl-carbonyl-sulfanyl group; aryl-carbonyl-sulfanyl; aralkyl-carbonyl-sulfanyl; bridged hydrocarbon-carbonyl-sulfanyl; spiro hydrocarbon-carbonyl-sulfanyl; a terpene hydrocarbon-carbonyl-sulfanyl. The same applies to the groups represented by the formulae (. omega. -2C) to (. omega. -21C) below.

Examples of the "heterocyclic ring" in the groups represented by the above formulae (. omega. -1C) to (. omega. -21C) may include the same ones as the "heterocyclic group" described above. Examples of the "heterocycle-carbonyl-sulfanyl group" represented by the formula (. omega. -1C) include monocyclic heteroaryl-carbonyl-sulfanyl group, fused polycyclic heteroaryl-carbonyl-sulfanyl group, monocyclic non-aromatic heterocycle-carbonyl-sulfanyl group, and fused polycyclic non-aromatic heterocycle-carbonyl-sulfanyl group. The same applies to the groups represented by the formulae (. omega. -2C) to (. omega. -21C) below.

Examples of the "cyclic amino group" in the groups represented by the above formulae (. omega. -10C) to (. omega. -16C) may include the same groups as the "cyclic amino group" described above.

The above-mentioned "acyl-sulfanyl", "hydrocarbon-sulfanyl" and "heterocycle-sulfanyl" are collectively referred to as "substituted sulfanyl". In addition, these "substituted sulfanyl group" and "sulfanyl group" are collectively referred to as "sulfanyl group which may have a substituent".

Examples of the "N-hydrocarbonamino group" may include groups in which 1 hydrogen atom of the "amino group" is substituted with a "hydrocarbon group", such as N-alkyl-amino group, N-alkenyl-amino group, N-alkynyl-amino group, N-cycloalkyl-alkyl-amino group, N-aryl-amino group, and N-aralkyl-amino group.

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, C-amino group such as (2, 3-dimethylbutyl) amino group, (2-ethylbutyl) amino group, (1-ethyl-1-methylpropyl) amino group, n-heptylamino group, n-octylamino group, n-nonylamino group, n-decylamino group, n-undecylamino group, n-dodecylamino group, n-tridecylamino group, n-tetradecylamino group, n-pentadecylamino group₁～C₁₅The straight-chain or branched-chain N-alkyl-amino group of (1).

As "N-alkenyl-amino group", for example, vinylamino, (prop-1-en-1-yl) amino, allylamino, isopropenylamino, (but-1-en-1-yl) amino, (but-2-en-1-yl) amino, (but-3-en-1-yl) amino, (2-methylprop-2-en-1-yl) amino, (1-methylprop-2-en-1-yl) amino, (pent-1-en-1-yl) amino, (pent-2-en-1-yl) amino, (pent-3-en-1-yl) amino, and (pent-4-ene). -1-yl) amino, (3-methylbut-2-en-1-yl) amino, (3-methylbut-3-en-1-yl) amino, (hex-1-en-1-yl) amino, (hex-2-en-1-yl) amino, (hex-3-en-1-yl) amino, (hex-4-en-1-yl) amino, (hex-5-en-1-yl) amino, (4-methylpent-3-en-1-yl) amino, (hept-1-en-1-yl) amino, (hept-6-en-1-yl) amino, amino, (oct-1-en-1-yl) amino, (oct-7-en-1-yl) amino, (non-1-en-1-yl) amino, (non-8-en-1-yl) amino, (dec-1-en-1-yl) amino, (dec-9-en-1-yl) amino, (undec-1-en-1-yl) amino, (undec-10-en-1-yl) amino, (dodec-1-en-1-yl) amino, (dodec-11-en-1-yl) amino, (tridec-1-en-1-yl) amino, (tridec-12-en-1-yl) amino, C such as (tetradec-1-en-1-yl) amino, (tetradec-13-en-1-yl) amino, (pentadec-1-en-1-yl) amino, (pentadec-14-en-1-yl) amino₂～C₁₅The straight-chain or branched-chain N-alkenyl-amino group of (1).

As "N-alkynyl-amino group", for example, ethynylamino, (prop-1-yn-1-yl) amino, (prop-2-yn-1-yl) amino, (but-1-yn-1-yl) amino, (but-3-yn-1-yl) amino, (1-methylprop-2-yn-1-yl) amino, (pent-1-yn-1-yl) amino, (pent-4-yn-1-yl) amino, (hex-1-yn-1-yl) amino, (hex-5-yn-1-yl) amino, (hept-1-yn-1-yl) amino, (hept-6-yn-1-yl) amino, and the like, (oct-1-yn-1-yl) amino, (oct-7-yn-1-yl) amino, (non-1-yn-1-yl) amino, (non-8-yn-1-yl) amino, (dec-1-yn-1-yl) amino, (dec-9-yn-1-yl) amino, (undec-1-yn-1-yl) amino, (undec-10-yn-1-yl) amino, (dodec-1-yn-1-yl) amino, (dodec-11-yn-1-yl) amino, (tridec-1-yn-1-yl) amino, (tridec-12-yn-1-yl) amino, and mixtures thereof, C such as (tetradec-1-yn-1-yl) amino, (tetradec-13-yn-1-yl) amino, (pentadec-1-yn-1-yl) amino, or (pentadec-14-yn-1-yl) amino ₂～C₁₅The straight-chain or branched-chain N-alkynyl-amino group of (1).

Examples of the "N-cycloalkyl-amino group" include a C group such as cyclopropylamino group, cyclobutylamino group, cyclopentylamino group, cyclohexylamino group, cycloheptylamino group, and cyclooctylamino group₃～C₈N-cycloalkyl-amino of (a).

Examples of the "N-cycloalkyl-alkyl-amino group" include C.sub.C.sub.i. (cyclopropylmethyl) amino, (1-cyclopropylethyl) amino, (2-cyclopropylethyl) amino, (3-cyclopropylpropyl) amino, (4-cyclopropylbutyl) amino, (5-cyclopropylpentyl) amino, (6-cyclopropylhexyl) amino, (cyclobutylmethyl) amino, (cyclopentylmethyl) amino, (cyclohexylmethyl) amino, (2-cyclohexylethyl) amino, (3-cyclohexylpropyl) amino, (4-cyclohexylbutyl) amino, (cycloheptylmethyl) amino, (cyclooctylmethyl) amino, (6-cyclooctylhexyl) amino and the like₄～C₁₄N-cycloalkyl-alkyl-amino of (a).

Examples of the "N-aryl-amino group" include a C group such as phenylamino, 1-naphthylamino, 2-naphthylamino, anthrylamino, phenanthrylamino, acenaphthenylamino₆～C₁₄N-monoarylamino of (1).

Examples of the "N-aralkyl-amino group" include a benzylamino group, a (1-naphthylmethyl) amino group, a (2-naphthylmethyl) amino group, an (anthracenylmethyl) amino group, a (phenanthrenyl) amino group, an (acenaphthenylethyl) amino group, a (diphenylmethyl) amino group, a (1-phenylethyl) amino group, a (2-phenylethyl) amino group, a (1- (1-naphthyl) ethyl) amino group, a (1- (2-naphthyl) ethyl) amino group, a (2- (1-naphthyl) ethyl) amino group, a (3-phenylpropyl) amino group, a (3- (1-naphthyl) propyl) amino group, a (3- (2-naphthyl) propyl) amino group, a (4-phenylbutyl) amino group, a (4- (1-naphthyl) butyl) amino group, a (1-naphthyl) butyl, C-such as (4- (2-naphthyl) butyl) amino, (5-phenylpentyl) amino, (5- (1-naphthyl) pentyl) amino, (5- (2-naphthyl) pentyl) amino, (6-phenylhexyl) amino, (6- (1-naphthyl) hexyl) amino, (6- (2-naphthyl) hexyl) amino ₇～C₁₆N-aralkyl-amino of (a).

Examples of the "N, N-di (hydrocarbon) -amino group" may include groups in which 2 hydrogen atoms of the "amino group" are substituted with a "hydrocarbon group", such as N, N-dimethylamino group, N-diethylamino group, N-ethyl-N-methylamino group, N-di-N-propylamino group, N-diisopropylamino group, N-allyl-N-methylamino group, N- (prop-2-yn-1-yl) -N-methylamino group, N-dicyclohexylamino group, N-cyclohexyl-N-methylamino group, N-cyclohexylmethylamino-N-methylamino group, N-diphenylamino group, N-methyl-N-phenylamino group, N-diphenylmethylamino group, N-diisopropyl, N-benzyl-N-methylamino, and the like.

Examples of the "N-heterocyclic-amino group" may include groups in which 1 hydrogen atom of the "amino group" is substituted with a "heterocyclic group", such as (3-pyrrolidinyl) amino, (4-piperidinyl) amino, (2-tetrahydropyranyl) amino, (3-indolinyl) amino, (4-chromanyl) amino, (3-thienyl) amino, (3-pyridyl) amino, (3-quinolyl) amino, and (5-indolyl) amino.

Examples of the "N-hydrocarbon-N-heterocyclic-amino group" may include groups in which 2 hydrogen atoms of the "amino group" are substituted with a "hydrocarbon group" and a "heterocyclic group", respectively, and groups such as an N-methyl-N- (4-piperidyl) amino group, an N- (4-chromanyl) -N-methylamino group, an N-methyl-N- (3-thienyl) amino group, an N-methyl-N- (3-pyridyl) amino group, and an N-methyl-N- (3-quinolyl) amino group.

Examples of the "acylamino group" may include a group in which the hydrogen atom of the "amino group" is substituted with an "acyl group", such as a formylamino group, a glyoxylamido group, a thioaldolamino group and a group represented by the following formula.

(in the formula, R^a4And R^b4The same or different, represents a hydrocarbon group which may have a substituent or a heterocyclic group which may be exemplified by a substituent, or R^a4And R^b4Taken together, together with the nitrogen atom to which they are bound represent a cyclic amino group which may have a substituent).

In the definition of "amido" as described above,

in the group represented by the formula (. omega. -1D), R^a4The radicals being hydrocarbon radicals are known as "hydrocarbon-carbonyl-amino", R^a4A group that is a heterocyclic group is referred to as "heterocycle-carbonyl-amino".

In the group represented by the formula (. omega. -2D), R^a4The radicals being hydrocarbon radicals are known as "hydrocarbon-oxy-carbonyl-amino", R^a4A group that is a heterocyclic group is referred to as "heterocycle-oxy-carbonyl-amino".

In the group represented by the formula (. omega. -3D), R^a4The radicals being hydrocarbon radicals are known as "hydrocarbon-carbonyl-amino", R^a4A group that is a heterocyclic group is referred to as "heterocycle-carbonyl-amino".

In the group represented by the formula (. omega. -4D), R^a4The radical being a hydrocarbon radical is known as "hydrocarbon-oxy-carbonyl-amino", R^a4A group that is a heterocyclic group is referred to as "heterocycle-oxy-carbonyl-amino".

In the group represented by the formula (. omega. -5D), R^a4The radicals being hydrocarbon radicals being known as "hydrocarbon-sulfanyl-carbonyl-amino", R^a4A group that is a heterocyclic group is referred to as "heterocycle-sulfanyl-carbonyl-amino".

In the group represented by the formula (. omega. -6D), R^a4The radicals being hydrocarbon radicals being known as "hydrocarbon-thiocarbonyl-amino", R^a4A group that is a heterocyclic group is referred to as "heterocycle-thiocarbonyl-amino".

In the group represented by the formula (. omega. -7D), R^a4The radicals being hydrocarbon radicals being known as "hydrocarbon-oxy-thiocarbonyl-amino", R^a4A group that is a heterocyclic group is referred to as "heterocycle-oxy-thiocarbonyl-amino".

In the group represented by the formula (. omega. -8D), R^a4The radicals being hydrocarbon radicals being known as "hydrocarbon-sulfanyl-thiocarbonyl-amino", R^a4A group that is a heterocyclic group is referred to as "heterocycle-sulfanyl-thiocarbonyl-amino".

In the group represented by the formula (. omega. -9D), R^a4The radical being a hydrocarbon radical is known as "N-hydrocarb-carbamoyl", R^a4A group that is a heterocyclic group is referred to as "N-heterocyclic-carbamoyl-amino".

In the group represented by the formula (. omega. -10D), R^a4And R^b4The radical being a hydrocarbon radical is referred to as "N, N-di (hydrocarbon) -carbamoyl-amino", R^a4And R^b4A group that is a heterocyclic group is referred to as "N, N-bis (heterocyclic) -carbamoyl-amino", R^a4Is a hydrocarbon radical and R ^b4A group that is a heterocyclic group is referred to as "N-Hydrocarbon-N-heterocycle-carbamoyl-amino", R^a4And R^b4Groups that are taken together to form a cyclic amino group together with the nitrogen atom to which they are bound are referred to as "cyclic amino-carbonyl-amino".

In the group represented by the formula (. omega. -11D), R^a4The radical being a hydrocarbon radical is known as "N-hydrocarbonthio-carbamoyl-amino", R^a4A group that is a heterocyclic group is referred to as "N-heterocyclic-thiocarbamoyl-amino".

In the group represented by the formula (. omega. -12D), R^a4And R^b4The radical being a hydrocarbon radical is known as "N, N-di (hydrocarbon) -thiocarbamoyl-amino", R^a4And R^b4A group that is a heterocyclic group is referred to as "N, N-bis (heterocyclic) -thiocarbamoyl-amino", R^a4Is a hydrocarbon radical and R^b4A group that is a heterocyclic group is referred to as "N-Hydrocarbon-N-heterocycle-Thiocarbamoyl-amino", R^a4And R^b4Groups that are taken together to form a cyclic amino group together with the nitrogen atom to which they are bound are referred to as "cyclic amino-thiocarbonyl-amino".

In the group represented by the formula (. omega. -13D), R^a4The radical being a hydrocarbon radical is called "N-Hydrocarbon-sulfamoyl-amino", R^a4A group that is a heterocyclic group is referred to as "N-heterocyclic-sulfamoyl-amino".

In the group represented by the formula (. omega. -14D), R^a4And R^b4The radical being a hydrocarbon radical is known as "di (hydrocarbon) sulfamoyl-amino", R ^a4And R^b4A group that is a heterocyclic group is referred to as "N, N-di (heterocyclic) sulfamoyl-amino", R^a4Is a hydrocarbon radical and R^b4A group that is a heterocyclic group is referred to as "N-Hydrocarbon-N-heterocycle-sulfamoyl-amino", R^a4And R^b4Is connected toTogether with the nitrogen atom to which they are bound, a group forming a cyclic amino group is referred to as "cyclic amino-sulfonyl-amino".

In the group represented by the formula (. omega. -15D), R^a4The radical being a hydrocarbon radical is known as "N-hydrocarbyl-iminosulfonyl-amino", R^a4A group that is a heterocyclic group is referred to as "N-heterocyclic-sulfamoyl-amino".

In the group represented by the formula (. omega. -16D), R^a4And R^b4The radical being a hydrocarbon radical is referred to as "N, N-di (hydrocarbon) -sulfamoyl-amino", R^a4And R^b4A group that is a heterocyclic group is referred to as "N, N-bis (heterocyclic) -sulfamoyl-amino", R^a4Is a hydrocarbon radical and R^b4A group that is a heterocyclic group is referred to as "N-Hydrocarbon-N-heterocycle-sulfamoyl-amino", R^a4And R^b4Groups which, taken together, form a cyclic amino group together with the nitrogen atom to which they are bound are referred to as "cyclic amino-sulfinyl-amino".

In the group represented by the formula (. omega. -17D), R^a4The radical being a hydrocarbon radical is called "hydrocarbyl-oxy-sulfonyl-amino", R^a4A group that is a heterocyclic group is referred to as "heterocycle-oxy-sulfonyl-amino".

In the group represented by the formula (. omega. -19D), R^a4The radical being a hydrocarbon radical being known as "hydrocarbyl-oxy-sulfinyl-amino", R^a4A group that is a heterocyclic group is referred to as "heterocycle-oxy-sulfinyl-amino".

In the group represented by the formula (. omega. -19D), R^a4And R^b4The group being a hydrocarbon radical is referred to as "O, O' -di (hydrocarbon) -phosphono-amino", R^a4And R^b4A group that is a heterocyclic group is referred to as "O, O' -di (heterocyclic) -phosphono-amino", R^a4Is a hydrocarbon radical and R^b4A group that is a heterocyclic group is referred to as "O-hydrocarbon-O' -heterocyclic-phosphono-amino".

In the group represented by the formula (. omega. -20D), R^a4The radical being a hydrocarbon radical being known as "hydrocarbon-sulfonyl-amino", R^a4Radicals being heterocyclic radicals, denoted "heterocycle-sulfonyl-amino"。

In the group represented by the formula (. omega. -21D), R^a4The radicals being hydrocarbon radicals being termed "hydrocarbenyl-sulfinyl-amino", R^a4A group that is a heterocyclic group is referred to as "heterocycle-sulfinyl-amino".

Examples of the "hydrocarbon" in the groups represented by the above formulae (. omega. -1D) to (. omega. -21D) may include the same groups as those mentioned for the "hydrocarbon group". Examples of the "hydrocarbon-carbonyl-amino group" represented by the formula (. omega. -1D) include aliphatic hydrocarbon-carbonyl-amino groups such as alkyl-carbonyl-amino group, alkenyl-carbonyl-amino group, alkynyl-carbonyl-amino group, cycloalkyl-carbonyl-amino group, cycloalkenyl-carbonyl-amino group, cycloalkadienyl-carbonyl-amino group, and cycloalkyl-alkyl-carbonyl-amino group; aryl-carbonyl-amino; aralkyl-carbonyl-amino; bridged hydrocarbon-carbonyl-amino; spiro hydrocarbon-carbonyl-amino; a terpene hydrocarbon-carbonyl-amino. The same applies to the groups represented by the formulae (. omega. -2D) to (. omega. -21D) below.

Examples of the "heterocyclic ring" in the groups represented by the above formulae (. omega. -1D) to (. omega. -21D) may include the same ones as the "heterocyclic group" described above. Examples of the "heterocyclic-carbonyl-amino group" represented by the formula (. omega. -1D) include monocyclic heteroaryl-carbonyl-amino group, fused polycyclic heteroaryl-carbonyl-amino group, monocyclic non-aromatic heterocyclic-carbonyl-amino group and fused polycyclic non-aromatic heterocyclic-carbonyl-amino group. The same applies to the groups represented by the formulae (. omega. -2D) to (. omega. -21D) below.

Examples of the "cyclic amino group" in the groups represented by the above formulae (. omega. -10D) to (. omega. -16D) may include the same groups as the "cyclic amino group" described above.

Examples of the "di (acyl) -amino group" may include groups in which 2 hydrogen atoms of the "amino group" are substituted with the "acyl group" as defined in the "substituent(s)" of the above-mentioned "substituent(s)", such as di (formyl) amino group, di (glyoxyl) amino group, di (thioaldehyde) amino group and a group represented by the following formula.

(in the formula, R^a5And R^b5The same or different, represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may be exemplified by a substituent, or R^a5And R^b5Taken together, together with the nitrogen atom to which they are bound represent a cyclic amino group which may have a substituent).

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

in the group represented by the formula (. omega. -1E), R^a5The radical being a hydrocarbon radical is known as "di (hydrocarbon-carbonyl) -amino", R^a5A group that is a heterocyclic group is referred to as "di (heterocyclic-carbonyl) -amino".

In the group represented by the formula (. omega. -2E), R^a5The radical being a hydrocarbon radical is known as "di (hydrocarbon-oxy-carbonyl) -amino", R^a5A group that is a heterocyclic group is referred to as "di (heterocycle-oxy-carbonyl) -amino".

In the group represented by the formula (. omega. -3E), R^a5The radical being a hydrocarbon radical is known as "di (hydrocarbon-carbonyl) -amino", R^a5A group that is a heterocyclic group is referred to as "bis (heterocyclic-carbonyl) -amino".

In the group represented by the formula (. omega. -4E), R^a5The radical being a hydrocarbon radical is known as "di (hydrocarbon-oxy-carbonyl) -amino", R^a5A group that is a heterocyclic group is referred to as "bis (heterocycle-oxy-carbonyl) -amino".

In the group represented by the formula (. omega. -5E), R^a5The radical being a hydrocarbon radical is called "di (hydrocarbon-sulfanyl-carbonyl) -amino", R^a5A group that is a heterocyclic group is referred to as "di (heterocycle-sulfanyl-carbonyl) -amino".

In the group represented by the formula (. omega. -6E), R^a5The radical being a hydrocarbon radical is known as "di (hydrocarbon-thiocarbonyl) -amino", R^a5A group that is a heterocyclic group is referred to as "bis (heterocyclic-thiocarbonyl) -amino".

In the group represented by the formula (. omega. -7E), R^a5The radical being a hydrocarbon radical is known as "di (hydro-oxy-thiocarbonyl) -amino", R^a5A group that is a heterocyclic group is referred to as "bis (heterocycle-oxy-thiocarbonyl) -amino".

In the group represented by the formula (. omega. -8E), R^a5The group being a hydrocarbon radical is referred to as "di (hydrocarbon-sulfanyl-thiocarbonyl) -amino", R^a5A group that is a heterocyclic group is referred to as "di (heterocycle-sulfanyl-thiocarbonyl) -amino".

In the group represented by the formula (. omega. -9E), R^a5The radical being a hydrocarbon radical is known as "di (N-hydrocarb-carbamoyl) amino", R^a5A group that is a heterocyclic group is referred to as "di (N-heterocyclic-carbamoyl) -amino".

In the group represented by the formula (. omega. -10E), R^a5And R^b5Radicals which are hydrocarbon radicals are known as "di [ N, N-di (hydrocarbon) -carbamoyl ] -amino", R^a5And R^b5Radicals which are heterocyclic radicals are referred to as "di [ N, N-di (heterocyclic) -carbamoyl ] -amino", R^a5Is a hydrocarbon radical and R^b5A group that is a heterocyclic group is referred to as "di (N-hydrocarbyl-N-heterocyclic-carbamoyl) -amino", R^a5And R^b5Groups that are taken together to form a cyclic amino group together with the nitrogen atom to which they are bound are referred to as "di (cyclic amino-carbonyl) -amino".

In the group represented by the formula (. omega. -11E), R^a5The group being a hydrocarbyl radical is referred to as "di (N-hydrocarbyl-thiocarbamoyl) -amino", R ^a5A group that is a heterocyclic group is referred to as "di (N-heterocycle-thiocarbamoyl) -amino".

In the group represented by the formula (. omega. -12E), R^a5And R^b5Radicals which are hydrocarbon radicals are known as "di [ N, N-di (hydrocarbon) -thiocarbamoyl ] -amino", R^a5And R^b5A group which is a heterocyclic group is referred to as "bis [ N, N-bis (heterocyclic) -thiocarbamoyl ] -amino", R^a5Is a hydrocarbon radical and R^b5Groups which are heterocyclic groups are referred to as "di (N-hydrocarbon-N-heterocyclic-thioamines)Carbamoyl) -amino', R^a5And R^b5Groups that are taken together to form a cyclic amino group together with the nitrogen atom to which they are bound are referred to as "bis (cyclic amino-thiocarbonyl) -amino".

In the group represented by the formula (. omega. -13E), R^a5The radical being a hydrocarbon radical is known as "di (N-hydrocarbyl-sulfamoyl) -amino", R^a5A group that is a heterocyclic group is referred to as "di (N-heterocycle-sulfamoyl) -amino".

In the group represented by the formula (. omega. -14E), R^a5And R^b5Radicals which are hydrocarbon radicals are known as "bis [ N, N-di (hydrocarbon) -sulfamoyl ] -amino", R^a5And R^b5A group which is a heterocyclic group is referred to as "bis [ N, N-bis (heterocyclic) -sulfamoyl ] -amino", R^a5Is a hydrocarbon radical R^b5A group that is a heterocyclic group is referred to as "di (N-hydrocarbon-N-heterocyclic-sulfamoyl) -amino", R^a5And R^b5Groups that are taken together to form a cyclic amino group together with the nitrogen atom to which they are bound are referred to as "bis (cyclic amino-sulfonyl) -amino".

In the group represented by the formula (. omega. -15E), R^a5The radical being a hydrocarbon radical is known as "di (N-hydrocarbyl-sulfamoyl) -amino", R^a5A group that is a heterocyclic group is referred to as "bis (N-heterocycle-sulfamoyl) -amino".

In the group represented by the formula (. omega. -16E), R^a5And R^b5Radicals which are hydrocarbon radicals are known as "bis [ N, N-di (hydrocarbon) -sulfamoyl ] -amino", R^a5And R^b5A group which is a heterocyclic group is referred to as "bis [ N, N-bis (heterocyclic) -sulfamoyl ] -amino", R^a5Is a hydrocarbon radical and R^b5A group that is a heterocyclic group is referred to as "di (N-hydrocarbon-N-heterocycle-sulfamoyl) -amino", R^a5And R^b5Groups which, taken together, form a cyclic amino group together with the nitrogen atom to which they are bound are referred to as "di (cyclic amino-sulfinyl) -amino".

In the group represented by the formula (. omega. -17E), R^a5The radical being a hydrocarbon radical is known as "di (hydro-oxy-sulfonyl) -amino", R^a5A group that is a heterocyclic group is referred to as "bis (heterocycle-oxy-sulfonyl) -amino".

In the group represented by the formula (. omega. -18E), R^a5The radical being a hydrocarbon radical is known as "di (hydro-oxy-sulfinyl) -amino", R^a5A group that is a heterocyclic group is referred to as "di (heterocycle-oxy-sulfinyl) -amino".

In the group represented by the formula (. omega. -19E), R^a5And R^b5Radicals which are hydrocarbon radicals are known as "di [ O, O' -di (hydrocarbon) -phosphonyl ] -amino", R ^a5And R^b5A group which is a heterocyclic group is referred to as "bis [ O, O' -bis (heterocyclic) -phosphonyl ] -amino", R^a5Is a hydrocarbon radical and R^b5A group that is a heterocyclic group is referred to as "di (O-hydrocarbon-O' -heterocyclic-phosphonyl) -amino".

In the group represented by the formula (. omega. -20E), R^a5The radical being a hydrocarbon radical is known as "di (hydrocarbon-sulfonyl) -amino", R^a5A group that is a heterocyclic group is referred to as "bis (heterocycle-sulfonyl) -amino".

In the group represented by the formula (. omega. -21E), R^a5The radical being a hydrocarbon radical being known as "di (hydro-sulfinyl) -amino", R^a5A group that is a heterocyclic group is referred to as "di (heterocycle-sulfinyl) -amino".

Examples of the "hydrocarbon" in the groups represented by the above formulae (. omega. -1E) to (. omega. -21E) may include the same groups as those mentioned for the "hydrocarbon group". For example, the "di (hydrocarbon-carbonyl) -amino group" represented by the formula (ω -1E) may include a di (aliphatic hydrocarbon-carbonyl) -amino group such as a di (alkyl-carbonyl) -amino group, a di (alkenyl-carbonyl) -amino group, a di (alkynyl-carbonyl) -amino group, a di (cycloalkyl-carbonyl) -amino group, a di (cycloalkenyl-carbonyl) -amino group, a di (cycloalkadienyl-carbonyl) -amino group, or a di (cycloalkyl-alkyl-carbonyl) -amino group; bis (aryl-carbonyl) -amino; bis (aralkyl-carbonyl) -amino; bis (bridged hydrocarbon-carbonyl) -amino; bis (spirocyclic hydrocarbon-carbonyl) -amino; bis (terpene hydrocarbons-carbonyl) -amino. The same applies to the groups represented by the formulae (. omega. -2E) to (. omega. -21E) below.

Examples of the "heterocyclic ring" in the groups represented by the above formulae (. omega. -1E) to (. omega. -21E) may include the same ones as the "heterocyclic group" described above. Examples of the "di (heterocyclic-carbonyl) -amino group" represented by the formula (. omega. -1E) include di (monocyclic heteroaryl-carbonyl) -amino group, di (fused polycyclic heteroaryl-carbonyl) -amino group, di (monocyclic non-aromatic heterocyclic-carbonyl) -amino group and di (fused polycyclic non-aromatic heterocyclic-carbonyl) -amino group. The same applies to the groups represented by the formulae (. omega. -2E) to (. omega. -21E) below.

Examples of the "cyclic amino group" in the groups represented by the above formulae (. omega. -10E) to (. omega. -16E) may include the same groups as the "cyclic amino group" described above.

The above "acyl-amino" and "di (acyl) -amino" are collectively referred to as "acyl-substituted amino". In addition, the above-mentioned "N-hydrocarbon-amino", "N, N-di (hydrocarbon) -amino", "N-heterocyclic-amino", "N-hydrocarbon-N-heterocyclic-amino", "cyclic amino", "acyl-amino" and "di (acyl) -amino" are collectively referred to as "substituted amino". Further, these "substituted amino group" and "amino group" are collectively referred to as "amino group which may have a substituent".

The compounds represented by the above general formulae (I), (I-1), (I-2), (I-3) and (I-4) will be specifically described below.

The "linking group having 2 to 4 atoms in the main chain" in the definition of X means a linking group in which 2 to 4 main chain atoms are linked between the rings Z and E. The above-mentioned "number of atoms of main chain" is independent of the presence or absence of hetero atoms, and the number of atoms present between the rings Z and E is minimized in the counting. For example, the number of atoms of the 1, 2-cyclopentenylene group is 2, the number of atoms of the 1, 3-cyclopentenylene group is 3, the number of atoms of the 1, 4-phenylene group is 4, and the number of atoms of the 2, 6-pyridinediyl group is 3.

The above-mentioned "linking group having 2 to 4 atoms in the main chain" is formed by 1 group selected from xi-1, which is the group of 2-valent groups described below, or by combining 1 to 4 groups selected from xi-2, which is the group of 2-valent groups described below.

[ group xi-1 of valence 2 ] is represented by the following formula:

[ group xi-2 of valency 2 ] the following formula:

when 2 or more of the 2-valent groups are combined, the groups may be the same or different.

The "linking group having 2 to 4 atoms in the main chain" is preferably a group selected from the following linking group α.

[ linker group α ] the following formula:

(in the formula, the bond on the left side is bonded to the ring Z, and the bond on the right side is bonded to the ring E)

Most preferred are groups represented by the following formula.

Examples of the "substituent" which may have a substituent "for the" linking group having 2 to 4 atoms in the main chain "in the definition of the" linking group which may have a substituent "may include the same ones as the" substituent "in the definition of the" may have a substituent ", and C is preferable₁～C₆Alkyl, more preferably methyl. The substituent may be bonded to the substituent on the ring Z or E, and together with the atom bonded to the substituent, a cyclic group which may have a substituent may be formed. Examples of the compound include compounds represented by the following formula (I).

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

The "aromatic hydrocarbon" of the "aromatic hydrocarbon which may have a substituent(s)" in the definition of the ring Z may be, for example, a monocyclic or condensed polycyclic aromatic hydrocarbon, such as a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, an acenaphthylene ring, etc. Preferably C such as benzene ring, naphthalene ring and the like₆～C₁₀More preferably a benzene ring and a naphthalene ring, and most preferably a benzene ring.

When ring Z is A benzene ring, "A substituent which may further have A substituent" in addition to the groups represented by the formulA-O-A (wherein A is as defined in the general formulA (I)) and the formulA-X-E (wherein X and E are as defined in the general formulA (I)), is preferably present in the case where R in the following partial structural formulA (IZ-1) including ring Z in the general formulA (I) is represented by the following formulA (IZ-2) ^zThe position of (a).

Examples of the "heteroarene" of the "heteroarene which may have a substituent(s)" in the definition of the ring Z include monocyclic or condensed polycyclic aromatic heterocycles containing at least 1 to 3 kinds of hetero atoms selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like as atoms (ring atoms) constituting the ring system, for example, furan rings, thiophene rings, pyrrole rings, oxazole rings, isoxazole rings, thiazole rings, isothiazole rings, imidazole rings, pyrazole rings, 1, 2, 3-oxadiazole rings, 1, 2, 3-thiadiazole rings, 1, 2, 3-triazole rings, pyridine rings, pyridazine rings, pyrimidine rings, pyrazine rings, 1, 2, 3-triazine rings, 1, 2, 4-triazine rings, 1H-aza * rings, 1, 4-oxa * rings, 1, 4-thia monocyclic rings, benzofuran rings, isobenzofuran rings, benzo [ b ] thiophene rings, benz [ b ] rings, Benzo [ c ] thiophene ring, indole ring, 2H-isoindole ring, 1H-indazole ring, 2H-indazole ring, benzoxazole ring, 1, 2-benzisoxazole ring, 2, 1-benzisoxazole ring, benzothiazole ring, 1, 2-benzisothiazole ring, 2, 1-benzisothiazole ring, 1, 2, 3-benzoxazole ring, 2, 1, 3-benzoxazole ring, 1, 2, 3-benzisothiazole ring, 2, 1, 3-benzisothiazole ring, 1H-benzotriazole ring, 2H-benzotriazol ring, quinoline ring, isoquinoline ring, cinnoline ring, quinazoline ring, quinoxaline ring, phthalazine ring, naphthyridine ring, 1H-1, 5-benzodiazepine * ring, carbazole ring, alpha-carboline ring, beta-carboline ring, gamma-carboline ring, 5-to 14-membered monocyclic or fused polycyclic aromatic heterocycles such as an acridine ring, a phenoxazine ring, a phenothiazine ring, a phenazine ring, a phenanthridine ring, a phenanthroline ring, a thianthrene ring, a indolizine ring, and a phenothiazine ring. Preferably a 6 to 13 membered monocyclic or fused polycyclic aromatic heterocycle, more preferably a pyridine ring, an indole ring, a quinoxaline ring and a carbazole ring.

As the "substituent(s)" which may further have A substituent(s) in addition to the group(s) represented by the formulA-O-A (wherein A is as defined in the general formulA (I)) and the group(s) represented by the formulA-X-E (wherein X and E are as defined in the general formulA (I)), there may be mentioned the same groups as the "substituent(s)" in the above-mentioned definition of "substituent(s)", and when the ring Z is A "benzene ring which may further have A substituent(s) in addition to the group(s) represented by the formulA-O-A (wherein A is as defined in the general formulA (I)) and the group(s) represented by the formulA-X-E (wherein X and E are as defined in the general formulA (I)", preferred as the substituent(s) are A halogen atom, A nitro group, A cyano group, A hydroxyl group which may have A substituent(s) ", and the group, An amino group which may have a substituent, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, an acyl group which may have a substituent, a ureido group which may have a substituent, a thioureido group which may have a substituent, a diazenyl group which may have a substituent.

"hydroxyl group which may have substituent(s)" in the definition of the substituent group γ -1z, and R^zThe "hydroxyl group which may have a substituent" in the definition of (1) may be the same as the "hydroxyl group which may have a substituent" in the definition of the above "may have a substituent", and the substituent may be the same as the "substituent" in the definition of the above "may have a substituent". The "optionally substituted hydroxyl group" is preferably an optionally substituted hydrocarbon-oxy group, more preferably an optionally substituted C ₁～C₆Alkoxy, particularly preferably methoxy.

"amino group which may have substituent(s)" in the definition of the substituent group γ -1z, and R^zThe "amino group which may have a substituent" in the definition of (1) may be the same as the "amino group which may have a substituent" in the definition of "may have a substituent", and the substituent may be the same as the "substituent" in the definition of "may have a substituent". The "amino group which may have a substituent(s)" is preferably a di (hydrocarbon) -amino group or a hydrocarbon-carbonyl-amino group, and more preferably a di (C)₁～C₆Alkyl) -amino and C₆～C₁₀Aryl-carbonyl-amino, particularly preferably dimethylamino and benzoylamino.

The "substituent" of the "hydrocarbon group which may have a substituent" in the definition of the substituent group γ -1z, and R^zExamples of the "substituent" of the "hydrocarbon group which may have a substituent" in the above definition may include the same ones as those of the "substituent" in the above definition of the "hydrocarbon group which may have a substituent". As the "hydrocarbon group which may have a substituent", C which may have a substituent is preferable₁～C₆Alkyl group, C which may have a substituent₁～C₆Haloalkyl group, optionally substituted C ₂～C₆Alkenyl, C which may have a substituent₂～C₆Alkynyl group, C which may have a substituent₆～C₁₀Aryl group and C which may have a substituent₇～C₁₆Aralkyl, more preferably methyl group, t-butyl group, 1-hydroxyethyl group, 1- (methoxyimino) ethyl group, 1- [ (phenylmethoxy) imino ] ethyl group, trifluoromethyl group, pentafluoroethyl group, phenyl group, 4- (trifluoromethyl) phenyl group, 4-fluorophenyl group, 2, 4-difluorophenyl group, 2-phenylethen-1-yl group, 2-dicyanoethylene-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, phenyl group and 2-phenylethyl group.

"substituent" of "heterocyclic group which may have substituent" in the definition of substituent group γ -1z, and R^zExamples of the "substituent" of the "heterocyclic group which may have a substituent" in the above definition may include the same ones as those of the "substituent" in the above definition of the "may have a substituent". As the "heterocyclic group which may have a substituent", a heteroaryl group which may have a substituent is preferable, a 5-to 6-membered heteroaryl group which may have a substituent is further preferable, and a 2-thienyl group, a 3-thienyl group, a 1-pyrrolyl group, a 2-methylthiazol-4-yl group and a 2-pyridyl group are particularly preferable.

"acyl group which may have substituent(s)" in the definition of the substituent group γ -1z, and R^zThe "acyl group which may have a substituent" in the definition of (1) may, for example, be the same as the group exemplified in the definition of the "acyl group which may have a substituent" mentioned above, and the substituent may, for example, be the same as the "substituent" mentioned in the definition of the "acyl group which may have a substituent" mentioned above. The "acyl group which may have a substituent" is preferably a carbamoyl group which may have a substituent, a sulfamoyl group which may have a substituent, a hydrocarbon-carbonyl group which may have a substituent, a hydrocarbon-oxy-carbonyl group which may have a substituent, a heterocyclic-carbonyl group which may have a substituent, or a heterocyclic-sulfonyl group which may have a substituent, more preferably a carbamoyl group which may have a substituent, a sulfamoyl group which may have a substituent, or C which may have a substituent₁～C₆Alkyl-carbonyl, C which may have a substituent₁～C₆Alkoxy-carbonyl, 5-membered heteroaryl-sulfonyl which may have a substituent, and 6-membered non-aromatic heterocyclic-sulfonyl which may have a substituent, with [ 3, 5-bis (trifluoromethyl) phenyl ] carbamoyl, dimethylcarbamoyl, dimethylsulfamoyl, acetyl, isobutyryl, methoxycarbonyl, piperidinocarbonyl, 4-benzylpiperidinocarbonyl, and (pyrrol-1-yl) sulfonyl being particularly preferable.

The "substituent" of "ureido group which may have substituent" in the definition of the substituent group γ -1z, and R^zExamples of the "substituent" of the "ureido group which may have a substituent" in the definition of (1) may include the same ones as those of the "substituent" in the definition of the "ureido group which may have a substituent" mentioned above. As the "ureido group which may have a substituent(s)", a 3-phenylureido group is preferable.

The "substituent" of the "thioureido group which may have a substituent" in the definition of the substituent group γ -1z, and R^zExamples of the "substituent" of the "thioureido group which may have a substituent" in the definition of (1) may include the same ones as those of the "substituent" in the definition of the "substituent which may have a substituent" mentioned above. As the "thioureido group which may have a substituent", a (3-phenyl) thioureido group is preferable.

The "substituent" of the "diazenyl group which may have a substituent" in the definition of the substituent group γ -1z, and R^zThe "substituent" of the "optionally substituted diazenyl" in the definition of (1) above may, for example, be the same as the "substituent" in the definition of the "optionally substituted" above. As the "diazenyl group which may have a substituent(s)", preferred are a (4-nitrophenyl) diazenyl group and a { [ (4-pyridin-2-yl) sulfamoyl ] phenyl } diazenyl group.

As R^zExamples thereof may include a hydrogen atom, a halogen atom, a nitro group, a cyano group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted acyl group, an optionally substituted ureido group, an optionally substituted halogen atom, a nitro group, a cyano group, an optionally substituted hydroxyl group, an optionally substituted hydrocarbylA thioureido group which may have a substituent and a diazenyl group which may have a substituent, most preferably a halogen atom.

Examples of the "aryl" of the "aryl group which may have a substituent(s)" in the definition of E may include the same ones as those of the "aryl" in the definition of the "hydrocarbon group", and C such as phenyl, 1-naphthyl and 2-naphthyl is preferable₆～C₁₀Most preferably phenyl.

Examples of the "substituent" of the "aryl group which may have a substituent" in the definition of E may include the same ones as those of the "substituent" in the definition of the "aryl group which may have a substituent" described above.

Preferred modes of "phenyl group which may have a substituent" in the definition of E are:

(1) is covered with 2 pieces of C₁～C₆Haloalkyl-substituted phenyl (said phenyl being divided by 2C)₁～C₆The alkyl group may further have a substituent in addition to the haloalkyl group

(2) Is covered with 1C₁～C₆Haloalkyl-substituted phenyl (said phenyl being divided by 1C)₁～C₆The alkyl group may further have a substituent (wherein, C) ₁～C₆Except for haloalkyl))

(3) May have a substituent (wherein, C₁～C₆Except haloalkyl) of (a).

As defined for E "by 2C₁～C₆Haloalkyl-substituted phenyl (said phenyl being divided by 2C)₁～C₆"C" which may further have a substituent(s) "in addition to the haloalkyl group₁～C₆Haloalkyl ", may be exemplified by the above-mentioned" C₁～C₆Haloalkyl "is defined as a group exemplified in the definition of" alkyl ". As the "quilt 2C₁～C₆Haloalkyl-substituted phenyl (said phenyl being divided by 2C)₁～C₆The "substituent" which may further have a substituent "other than the haloalkyl group may be mentionedThe same groups as the "substituents" in the definition of "may have substituents" are mentioned. As "the" is covered by 2C₁-C₆Haloalkyl-substituted phenyl (said phenyl being divided by 2C)₁-C₆The "haloalkyl group" may further have a substituent(s) ", preferably" substituted with 2 carbon atoms₁～C₆Haloalkyl-substituted phenyl ", 3, 5-bis (trifluoromethyl) phenyl and 2, 5-bis (trifluoromethyl) phenyl are further preferred, 3, 5-bis (trifluoromethyl) phenyl being most preferred.

As defined for E "by 1C₁～C₆Haloalkyl-substituted phenyl (said phenyl being divided by 1C)₁～C₆The alkyl group may further have a substituent (wherein, C) ₁～C₆Examples of "the substituent" other than the haloalkyl group of (a)) "may include the same groups as the" substituent "in the definition of" the substituent(s) "as described above (wherein, C is₁～C₆Except haloalkyl group), a halogen atom, a nitro group, a cyano group, a hydroxyl group which may have a substituent, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, a sulfanyl group which may have a substituent, as defined as substituent group γ -1e, are preferable.

The "optionally substituted hydroxyl group" in the definition of the substituent group γ -1e may be the same as the "optionally substituted hydroxyl group" in the definition of the above "optionally substituted group", and the substituent may be the same as the "optionally substituted group" in the definition of the above "optionally substituted group". The "hydroxyl group which may have a substituent(s)" is preferably a hydrocarbon-oxy group which may have a substituent(s), and more preferably C which may have a substituent(s) and is defined as a substituent group γ -2e₁～C₆Alkoxy, particularly preferably methoxy.

Examples of the "substituent" of the "hydrocarbon group which may have a substituent" in the definition of the substituent group γ -1e may include the same ones as those of the "substituent" in the definition of the "hydrocarbon group which may have a substituent" described above. The "hydrocarbon group which may have a substituent" is preferably a substituent C which may have a substituent defined by the substituent group γ -2e₁～C₆Alkyl groups, more preferably methyl groups.

The "substituent" of the "heterocyclic group which may have a substituent" in the definition of the substituent group γ -1e may be the same as the "substituent" in the definition of the "may have a substituent" described above. As the "heterocyclic group which may have a substituent", a 5 to 6-membered non-aromatic heterocyclic group which may have a substituent defined as γ -2e is preferable, and 1-pyrrolidinyl group and morpholino group are further preferable.

The "sulfamoyl group which may have a substituent" in the definition of the substituent group γ -1e may be the same as the "sulfamoyl group which may have a substituent" in the definition of the above "may have a substituent", and the substituent may be the same as the "substituent" in the definition of the above "may have a substituent". The "optionally substituted thioalkyl group" is preferably an optionally substituted hydrocarbon-thioalkyl group, more preferably an optionally substituted C as defined for the substituent γ -2e₁～C₆Alkyl-sulfanyl, particularly preferably methylsulfanyl.

As defined for E "by 1C ₁～C₆Haloalkyl-substituted phenyl (said phenyl being divided by 1C)₁～C₆The alkyl group may further have a substituent (wherein, C)₁～C₆Except haloalkyl group of (a)) "" C₁～C₆Haloalkyl ", may be exemplified by the above-mentioned" C₁～C₆Haloalkyl "same group, preferably C substituted by 1 or more fluorine atoms₁～C₆Alkyl, more preferably C substituted with 3 or more fluorine atoms₁～C₆Alkyl, most preferably trifluoromethyl.

As defined for E "by 1C₁～C₆Haloalkyl-substituted phenyl (said phenyl being divided by 1C)₁～C₆The alkyl group may further have a substituent (wherein, C)₁～C₆With the exception of haloalkyl group (s)) ", preferably 2- (trifluoromethyl) phenyl, 3- (trifluoromethyl) phenyl, 4- (trifluoromethyl) phenyl, 2-fluoro-3- (trifluoromethyl) phenyl, 2-chloro-4- (trifluoromethyl) phenyl, 2-fluoro-5- (trifluoromethyl) phenyl, 2-chloro-5- (trifluoromethyl) phenyl, 3-fluoro-5- (trifluoromethyl) phenyl, 3-bromo-5- (trifluoromethyl) phenyl, 4-chloro-2- (trifluoromethyl) phenyl, 4-fluoro-3- (trifluoromethyl) phenyl, 4-chloro-3- (trifluoromethyl) phenyl, 2-nitro-5- (trifluoromethyl) phenyl, methyl-ethyl-phenyl, ethyl-, 4-nitro-3- (trifluoromethyl) phenyl, 4-cyano-3- (trifluoromethyl) phenyl, 2-methyl-5- (trifluoromethyl) phenyl, 4-methyl-3- (trifluoromethyl) phenyl, 2-methoxy-5- (trifluoromethyl) phenyl, 3-methoxy-5- (trifluoromethyl) phenyl, 4-methoxy-3- (trifluoromethyl) phenyl, 2- (methylsulfanyl) -5- (trifluoromethyl) phenyl, 2- (1-pyrrolidinyl) -5- (trifluoromethyl) phenyl, and 2-morpholino-5- (trifluoromethyl) phenyl, further preferred are 2-chloro-5- (trifluoromethyl) phenyl, 4-chloro-3- (trifluoromethyl) phenyl, 2-methoxy-5- (trifluoromethyl) phenyl and 3-methoxy-5- (trifluoromethyl) phenyl, most preferred is 2-chloro-5- (trifluoromethyl) phenyl.

As the definition of E, "may have a substituent (wherein, C₁～C₆Examples of the "substituent" of the "phenyl group" other than the haloalkyl group "may include the same groups as the" substituent "in the definition of the" may have a substituent ", and preferably include a halogen atom, a nitro group, a hydroxyl group which may have a substituent, a hydrocarbon group which may have a substituent, and an acyl group which may have a substituent, as defined in the substituent group γ -3 e.

The "optionally substituted hydroxyl group" in the definition of the substituent group γ -3e may be the same as the "optionally substituted hydroxyl group" in the definition of the above "optionally substituted group", and the substituent may be the same as the "optionally substituted group" in the definition of the above "optionally substituted group". The "hydroxyl group which may have a substituent(s)" is preferably an unsubstituted hydroxyl group or a hydrocarbon-oxy group which may have a substituent(s), and more preferably an unsubstituted hydroxyl group as defined in the substituent group γ -4eAnd C which may have a substituent₁～C₆Alkoxy, particularly preferably unsubstituted hydroxy and methoxy.

Examples of the "substituent" of the "hydrocarbon group which may have a substituent" in the definition of the substituent group γ -3e may include the same ones as those of the "substituent" in the definition of the "hydrocarbon group which may have a substituent" described above. As the "hydrocarbon group which may have a substituent", C which may have a substituent defined as the substituent group γ -4e is preferable ₁～C₆Alkyl group, C which may have a substituent₆～C₁₀Aryl group and C which may have a substituent₁～C₆Alkylene, further preferably methyl, tert-butyl, phenyl and 1, 1, 4, 4-tetramethylbutane-1, 4-diyl.

The "acyl group which may have a substituent" in the definition of the substituent group γ -3e may, for example, be the same as the group exemplified in the definition of the "acyl group which may have a substituent" mentioned above, and the substituent may, for example, be the same as the group exemplified in the "substituent" in the definition of the "acyl group which may have a substituent" mentioned above. The "acyl group which may have a substituent" is preferably a hydrocarbon-carbonyl group which may have a substituent and a hydrocarbon-oxy-carbonyl group which may have a substituent, and more preferably C which may have a substituent as defined in the substituent group γ -4e₁～C₆Alkyl-carbonyl group, and C which may have a substituent₁～C₆Alkoxy-carbonyl, particularly preferably acetyl and methoxycarbonyl.

As the definition of E, "may have a substituent (wherein, C₁～C₆With the exception of the haloalkyl group) is preferably a phenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, a 2, 5-dichlorophenyl group, a 3, 4-dichlorophenyl group, a 3, 5-difluorophenyl group, a 3, 5-dichlorophenyl group, a 3, 4, 5-trichlorophenyl group, a pentafluorophenyl group, a 3, 5-dinitrophenyl group, a 3, 5-dichloro-4-hydroxyphenyl group, a 2, 5-dimethoxyphenyl group, a 3, 5-dimethylphenyl group, a 2, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl group, a 3, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl group, a 5- (1, 1-dimethyl) ethyl ] phenyl group A group-2-methoxyphenyl group, a 3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydronaphthalen-2-yl group, a biphenyl-3-yl group, a 4-methoxybiphenyl-3-yl group, a 3-acetylphenyl group and a 3, 5-di (methoxycarbonyl) phenyl group, further preferably a 2, 5-di [ (1, 1-dimethyl) ethyl ] phenyl group, a 3, 5-di [ (1, 1-dimethyl) ethyl ] phenyl group and a 5- (1, 1-dimethyl) ethyl-2-methoxyphenyl group.

Examples of the "heteroaryl" of the "heteroaryl group which may have a substituent" in the definition of E may include the same groups as those of the "monocyclic heteroaryl" and the "condensed polycyclic heteroaryl" in the definition of the "heterocyclic group" described above. Preferably 5 to 13 membered heteroaryl, further preferably thienyl, pyrazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, indolyl and carbazolyl, most preferably thiazolyl.

Examples of the "substituent" of the "heteroaryl group which may have a substituent" in the above definition of E may include the same ones as the "substituent" in the above definition of the "heteroaryl group which may have a substituent".

Examples of the "substituent" of the "thiazolyl which may have a substituent" in the above definition of E may include the same ones as the "substituent" in the above definition of the "thiazolyl which may have a substituent". A halogen atom defined as a substituent γ -5e, a cyano group, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, and an acyl group which may have a substituent are preferable.

Examples of the "substituent" of the "hydrocarbon group which may have a substituent" in the definition of the substituent group γ -5e may include the same ones as those of the "substituent" in the definition of the "hydrocarbon group which may have a substituent" described above. As the "hydrocarbon group which may have a substituent", C which may have a substituent defined as the substituent group γ -6e is preferable₁～C₆Alkyl group, C which may have a substituent₁～C₆Haloalkyl group, optionally substituted C₆～C₁₀Aryl group and C which may have a substituent₇～C₁₆Aralkyl, more preferably methyl, ethyl, isoPropyl, n-butyl, tert-butyl, carboxymethyl, trifluoromethyl, phenyl, 4-fluorophenyl, 3- (trifluoromethyl) phenyl, pentafluorophenyl and benzyl.

The "substituent" of the "heterocyclic group which may have a substituent" in the definition of the substituent group γ -5e may be the same as the "substituent" in the definition of the "may have a substituent" described above. As the "heterocyclic group which may have a substituent", a 6-membered non-aromatic heterocyclic group which may have a substituent defined as substituent group γ -6e is preferable, and piperidino, morpholino, 4-methylpiperidin-1-yl and 4-phenylpiperidin-1-yl are further preferable.

The "acyl group which may have a substituent" in the definition of the substituent group γ -5e may, for example, be the same as the group exemplified in the definition of the "acyl group which may have a substituent" mentioned above, and the substituent may, for example, be the same as the group exemplified in the "substituent" in the definition of the "acyl group which may have a substituent" mentioned above. The "acyl group which may have a substituent(s)" is preferably a hydrocarbon-carbonyl group which may have a substituent(s), a carbamoyl group which may have a substituent(s), and a hydrocarbon-oxy-carbonyl group which may have a substituent(s), more preferably a carbamoyl group which may have a substituent(s) and C which may have a substituent(s) as defined in the substituent group γ -6e₁～C₆Alkyl-carbonyl, C which may have a substituent₆～C₁₀Aryl-carbonyl group, and C which may have a substituent₁～C₆Alkoxy-carbonyl, particularly preferably N-methylcarbamoyl, N-ethylcarbamoyl, N-isopropylcarbamoyl, N- (2-phenylethyl) carbamoyl, acetyl, pivaloyl, benzoyl and ethoxycarbonyl.

As the "thiazolyl group which may have a substituent(s) in the definition of E", 5-bromo-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 5-bromo-4- (trifluoromethyl) thiazol-2-yl, 5-cyano-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 5-phenyl-4- (trifluoromethyl) thiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-ethylthiazol-2-yl, 5-methyl-4-phenylthiazol-2-yl, 4-isopropyl-5-phenylthiazol-2-yl, m, 4-benzyl-5-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl, 5-acetyl-4-phenylthiazol-2-yl, 5-benzoyl-4-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- (ethoxycarbonyl) thiazol-2-yl, 5-ethoxycarbonyl-4- (trifluoromethyl) thiazol-2-yl, 5-ethoxycarbonyl-4-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-piperidinothiazol-2-yl, methyl-5-yl, ethyl-5-piperidinothiazol-2-yl, methyl-yl, ethyl-5-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-morpholinothiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- (4-phenylpiperidin-1-yl) thiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- (4-methylpiperidin-1-yl) thiazol-2-yl, 4, 5-diphenylthiazol-2-yl, 4-phenylthiazol-2-yl, 4, 5-dimethylthiazol-2-yl, 2-thiazolyl, 5-methylthiazol-2-yl, 4-ethyl-5-phenylthiazol-2-yl, 5-carboxymethyl-4-phenylthiazol-2-yl, methyl-4-phenylthiazol-2-yl, methyl-2, 5-methylcarbamoyl-4-phenylthiazol-2-yl, 5-ethylcarbamoyl-4-phenylthiazol-2-yl, 5-isopropylcarbamoyl-4-phenylthiazol-2-yl, 5- (2-phenylethyl) carbamoyl-4-phenylthiazol-2-yl, 4- (n-butyl) -5-phenylthiazol-2-yl, 4-methyl-5- [ (3-trifluoromethyl) phenyl ] thiazol-2-yl or 5- (4-fluorophenyl) -4-methylthiazol-2-yl, further preferably 4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl.

In the above general formula (I-1), Z¹Is a 2-hydroxyphenyl group which may have a substituent at the 5-position or a 2-acetoxyphenyl group which may have a substituent at the 5-position.

As E¹In the definition of (1)' by 2C₁～C₆Haloalkyl-substituted phenyl (said phenyl being divided by 2C)₁～C₆"C" which may further have a substituent(s) "in addition to the haloalkyl group₁～C₆Haloalkyl ", may be exemplified by the above-mentioned" C₁～C₆Haloalkyl "is defined as a group exemplified in the definition of" alkyl ". As the group "(the phenyl group is substituted by 2C)₁～C₆Examples of the "substituent" which may further have a substituent "other than the haloalkyl group include those mentioned above as the" substituent(s) "The "substituents" in the definition are the same groups. As the "quilt 2C₁～C₆Haloalkyl-substituted phenyl (said phenyl being divided by 2C)₁～C₆The "may further have a substituent(s)" other than the haloalkyl group, preferably substituted by 2C₁～C₆Phenyl substituted by alkyl, said alkyl being substituted by more than 1 fluorine atom (the phenyl being divided by 2C's substituted by more than 1 fluorine atom₁～C₆May further have a substituent in addition to the alkyl group), and is more preferably substituted by 2C₁～C₆Phenyl substituted by alkyl, said alkyl being substituted by more than 3 fluorine atoms (the phenyl being divided by 2C substituted by more than 1 fluorine atom ₁～C₆May further have a substituent in addition to the alkyl group), and particularly preferably 2C₁～C₆Phenyl substituted with an alkyl group, said alkyl group being substituted with 3 or more fluorine atoms. The 2 substituents are preferably substituted at the 2 and 5 positions, or the 3 and 5 positions, of the phenyl group.

As R^1e2、R^1e3And R^1e5In the definition of (1)' C substituted by 3 or more fluorine atoms₁～C₆Alkyl ", most preferably trifluoromethyl.

E¹Preferably 3, 5-bis (trifluoromethyl) phenyl or 2, 5-bis (trifluoromethyl) phenyl, most preferably 2, 5-bis (trifluoromethyl) phenyl.

A¹Is a hydrogen atom or an acetyl group, preferably a hydrogen atom.

As R^1zThe "hydroxyl group which may have a substituent" in the definition of (1) may be the same as the "hydroxyl group which may have a substituent" in the definition of the above "may have a substituent", and the substituent may be the same as the "substituent" in the definition of the above "may have a substituent". The "optionally substituted hydroxyl group" is preferably an optionally substituted hydrocarbon-oxy group, more preferably an optionally substituted C₁～C₆Alkoxy, particularly preferably methoxy.

As R^1zThe "amino group which may have a substituent" in the definition of (1) may be the same as the "amino group which may have a substituent" in the definition of "may have a substituent", and the substituent may be the same as the "substituent" in the definition of "may have a substituent". The "amino group which may have a substituent(s)" is preferably a di (hydrocarbon) -amino group or a hydrocarbon-carbonyl-amino group, and more preferably a di (C) ₁～C₆Alkyl) -amino and C₆～C₁₀Aryl-carbonyl-amino, particularly preferably dimethylamino and benzoylamino.

As R^1zExamples of the "substituent" of the "hydrocarbon group which may have a substituent" in the above definition may include the same ones as those of the "substituent" in the above definition of the "hydrocarbon group which may have a substituent". As the "hydrocarbon group which may have a substituent", C which may have a substituent is preferable₁～C₆Alkyl group, C which may have a substituent₁～C₆Haloalkyl group, optionally substituted C₂～C₆Alkenyl, C which may have a substituent₂～C₆Alkynyl group, C which may have a substituent₆～C₁₀Aryl group and C which may have a substituent₇～C₁₆Aralkyl, more preferably methyl group, t-butyl group, 1-hydroxyethyl group, 1- (methoxyimino) ethyl group, 1- [ (phenylmethoxy) imino ] ethyl group, trifluoromethyl group, pentafluoroethyl group, phenyl group, 4- (trifluoromethyl) phenyl group, 4-fluorophenyl group, 2, 4-difluorophenyl group, 2-phenylethen-1-yl group, 2-dicyanoethylene-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, phenyl group and 2-phenylethyl group.

As R^1zExamples of the "substituent" of the "heterocyclic group which may have a substituent" in the above definition may include the same ones as those of the "substituent" in the above definition of the "may have a substituent". The "heterocyclic group which may have a substituent" is preferably a heteroaryl group which may have a substituent, and more preferably 5 to 5 which may have a substituent 6-membered heteroaryl, particularly preferably 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-methylthiazol-4-yl and 2-pyridyl.

As R^1zThe "acyl group which may have a substituent" in the definition of (1) may, for example, be the same as the group exemplified in the definition of the "acyl group which may have a substituent" mentioned above, and the substituent may, for example, be the same as the "substituent" mentioned in the definition of the "acyl group which may have a substituent" mentioned above. The "acyl group which may have a substituent" is preferably a carbamoyl group which may have a substituent, a sulfamoyl group which may have a substituent, a hydrocarbon-carbonyl group which may have a substituent, a hydrocarbon-oxy-carbonyl group which may have a substituent, a heterocyclic-carbonyl group which may have a substituent, or a heterocyclic-sulfonyl group which may have a substituent, more preferably a carbamoyl group which may have a substituent, a sulfamoyl group which may have a substituent, or C which may have a substituent₁～C₆Alkyl-carbonyl, C which may have a substituent₁～C₆Alkoxy-carbonyl, 5-membered heteroaryl-sulfonyl which may have a substituent, and 6-membered non-aromatic heterocyclic-sulfonyl which may have a substituent, with [ 3, 5-bis (trifluoromethyl) phenyl ] carbamoyl, dimethylcarbamoyl, dimethylsulfamoyl, acetyl, isobutyryl, methoxycarbonyl, piperidinocarbonyl, 4-benzylpiperidinocarbonyl, and (pyrrol-1-yl) sulfonyl being particularly preferable.

As R^1zExamples of the "substituent" of the "ureido group which may have a substituent" in the definition of (1) may include the same ones as those of the "substituent" in the definition of the "ureido group which may have a substituent" mentioned above. As the "ureido group which may have a substituent(s)", a 3-phenylureido group is preferable.

As R^1zExamples of the "substituent" of the "thioureido group which may have a substituent" in the definition of (1) may include the same ones as those of the "substituent" in the definition of the "substituent which may have a substituent" mentioned above. As the "thioureido group which may have a substituent", a (3-phenyl) thioureido group is preferable.

AsR^1zThe "substituent" of the "optionally substituted diazenyl" in the definition of (1) above may, for example, be the same as the "substituent" in the definition of the "optionally substituted" above. As the "diazenyl group which may have a substituent(s)", preferred are a (4-nitrophenyl) diazenyl group and a { [ (4-pyridin-2-yl) sulfamoyl ] phenyl } diazenyl group.

As R^1zExamples thereof may include a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group which may have a substituent, an amino group which may have a substituent, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, an acyl group which may have a substituent, an ureido group which may have a substituent, a thioureido group which may have a substituent and a diazenyl group which may have a substituent, preferably a halogen atom, a C group which may have a substituent ₁～C₆Alkyl group and optionally substituted C₁～C₆Haloalkyl groups, most preferably halogen atoms.

The compounds defined by the above general formula (I-1) or pharmaceutically acceptable salts thereof, or hydrates thereof or solvates thereof (wherein 6 compounds are excluded) are all novel compounds, and the use of the compounds based on the present invention is not particularly limited.

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

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-chloro-2-hydroxybenzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-bromo-2-hydroxybenzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-iodobenzamide

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-nitrobenzamide

2-hydroxy-N- [ 2, 3, 5-tris (trifluoromethyl) phenyl ] benzamide)

In the above-mentioned general formula (I-2),Z²is a 2-hydroxyphenyl group which may have a substituent at the 5-position or a 2-acetoxyphenyl group which may have a substituent at the 5-position.

As E²In the definition of (1), "3-or 5-position" is C₁～C₆Phenyl of haloalkyl (the phenyl being substituted by the C in position 3 or 5₁～C₆The alkyl group may further have a substituent (wherein the substituent is C)₁～C₆Where haloalkyl is not present), "C ₁～C₆Haloalkyl ", may be exemplified by the above-mentioned" C₁～C₆The same groups as those exemplified for the "haloalkyl" are preferably C substituted with 1 or more fluorine atoms₁～C₆Alkyl, more preferably C substituted with 3 or more fluorine atoms₁～C₆Alkyl, most preferably trifluoromethyl. As the group "(the phenyl group is substituted by C at the 3-or 5-position)₁～C₆The alkyl group may further have a substituent (wherein the substituent is C)₁～C₆Examples of "substituent" other than the case of haloalkyl group) include the same groups as those of the "substituent" in the definition of "may have substituent" described above, and preferably a halogen atom, a nitro group, a cyano group, or C which may have substituent as defined in the substituent group γ -7e₁～C₆Alkyl group, 5 to 6-membered non-aromatic heterocyclic group which may have substituent, C which may have substituent₁～C₆Alkoxy group, optionally substituted C₁～C₆Alkyl-sulfanyl, more preferably halogen atom, nitro, cyano, methoxy, methyl, 1-pyrrolidinyl, morpholino, methylsulfanyl.

As E²In the definition of (1), "3-or 5-position" is C₁～C₆Phenyl of haloalkyl (the phenyl being substituted by the C in position 3 or 5₁～C₆The alkyl group may further have a substituent (wherein the substituent is C) ₁～C₆Except for the case of haloalkyl)) ", preferably 3- (trifluoromethyl) phenyl, 2-fluoro-5- (trifluoromethyl) phenyl, 2-chloro-5- (trifluoromethyl)Phenyl, 3-fluoro-5- (trifluoromethyl) phenyl, 3-bromo-5- (trifluoromethyl) phenyl, 4-fluoro-3- (trifluoromethyl) phenyl, 4-chloro-3- (trifluoromethyl) phenyl, 2-nitro-5- (trifluoromethyl) phenyl, 4-nitro-3- (trifluoromethyl) phenyl, 4-cyano-3- (trifluoromethyl) phenyl, 2-methyl-5- (trifluoromethyl) phenyl, 4-methyl-3- (trifluoromethyl) phenyl, 2-methoxy-5- (trifluoromethyl) phenyl, 3-methoxy-5- (trifluoromethyl) phenyl, methyl-3- (trifluoromethyl) phenyl, methyl-5- (trifluoromethyl) phenyl, methyl-3-trifluoromethyl) phenyl, methyl-5- (trifluoromethyl) phenyl, 4-methoxy-3- (trifluoromethyl) phenyl, 2- (methylsulfanyl) -5- (trifluoromethyl) phenyl, 2- (1-pyrrolidinyl) -5- (trifluoromethyl) phenyl, and 2-morpholino-5- (trifluoromethyl) phenyl.

A²Is a hydrogen atom or an acetyl group, preferably a hydrogen atom.

As R^2zExamples thereof may include a halogen atom and C₁～C₆Alkyl and C₁～C₆Haloalkyl groups, preferably halogen atoms, methyl groups, tert-butyl groups, trifluoromethyl groups and pentafluoroethyl groups.

The compounds defined by the above general formula (I-2) or pharmaceutically acceptable salts thereof, or hydrates thereof or solvates thereof (wherein 15 compounds are excluded) are all novel compounds, and the use of the compounds based on the present invention is not particularly limited.

5-chloro-2-hydroxy-N- [ 3- (trifluoromethyl) phenyl ] benzamide

5-bromo-2-hydroxy-N- [ 3- (trifluoromethyl) phenyl ] benzamide

2-hydroxy-5-iodo-N- [ 3- (trifluoromethyl) phenyl ] benzamide

5-chloro-N- [ 4-chloro-3- (trifluoromethyl) phenyl ] -2-hydroxybenzamide

5-chloro-N- [ 5-chloro-3- (trifluoromethyl) phenyl ] -2-hydroxybenzamide

5-chloro-2-hydroxy-N- [ 4-nitro-3- (trifluoromethyl) phenyl ] benzamide

5-chloro-2-hydroxy-N- [ 2- (2-naphthyloxy) -5- (trifluoromethyl) phenyl ] benzamide

In the above general formula (I-3), Z³Is a 2-hydroxyphenyl group which may have a substituent at the 5-position or a 2-acetoxyphenyl group which may have a substituent at the 5-position.

As R^3e2、R^3e3Examples of the "substituent" of the "hydrocarbon group which may have a substituent" in the above definition may include the same ones as those of the "substituent" in the above definition of the "hydrocarbon group which may have a substituent". As the "hydrocarbon group which may have a substituent", C is preferable₁～C₆Alkyl, most preferably tert-butyl.

As R^3e2、R^3e3Examples of the "substituent" of the "optionally substituted hydroxyl group" in the above definition may include the same ones as those of the "substituent" in the above definition of the "optionally substituted group". As the "can haveHydroxy group of substituent group ", preferably C₁～C₆Alkoxy, most preferably methoxy.

As R^3e5In the definition of (1)₂～C₆Examples of the "substituent" of the hydrocarbon group include the same ones as the "substituent" in the above definition of "may have a substituent". As the "may have a substituent C₂～C₆Hydrocarbyl radical ", preferably C₂～C₆Alkyl, most preferably tert-butyl.

E³Preferred are 2, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl, 3, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl and 5- (1, 1-dimethyl) ethyl-2-methoxyphenyl.

A³Is a hydrogen atom or an acetyl group, preferably a hydrogen atom.

As R^3zExamples thereof may include a halogen atom and C₁～C₆Alkyl and C₁～C₆Haloalkyl groups, preferably halogen atoms, methyl groups, tert-butyl groups, trifluoromethyl groups and pentafluoroethyl groups.

The compounds defined by the above general formula (I-3) or pharmaceutically acceptable salts thereof, or hydrates thereof or solvates thereof are all novel compounds, and the use of the compounds based on the present invention is not particularly limited.

In the above general formula (I-4), Z⁴2-hydroxyphenyl which may have a substituent at the 5-position, and 2-acetoxyphenyl which may have a substituent at the 5-position.

As R^4e4Examples of the "substituent" of the "hydrocarbon group which may have a substituent" in the above definition may include the same ones as those of the "substituent" in the above definition of the "hydrocarbon group which may have a substituent". As the "hydrocarbon group which may have a substituent", C which may have a substituent is preferable₁～C₆Alkyl group, C which may have a substituent₁～C₆Haloalkyl and C which may have a substituent₆～C₁₀Aryl radical, orMethyl, isopropyl, tert-butyl, phenyl and pentafluorophenyl are preferred.

As R^4e5Examples of the "substituent" of the "acyl group which may have a substituent" in the above definition may include the same ones as those of the "substituent" in the above definition of the "acyl group which may have a substituent". The "acyl group which may have a substituent" is preferably C which may have a substituent ₁～C₆Alkyl-carbonyl, C which may have a substituent₆～C₁₀Aryl-carbonyl group, optionally substituted C₁～C₆Alkoxy-carbonyl, further preferably acetyl, pivaloyl and benzoyl.

As R^4e5Examples of the "substituent" of the "heterocyclic group which may have a substituent" in the above definition may include the same ones as those of the "substituent" in the above definition of the "may have a substituent". The "heterocyclic group which may have a substituent" is preferably a 6-membered non-aromatic heterocyclic group which may have a substituent, and more preferably a piperidino group, a morpholino group, a 4-methylpiperazin-1-yl group or a 4-phenylpiperazin-1-yl group.

E⁴Preferably 5-bromo-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 5-bromo-4- (trifluoromethyl) thiazol-2-yl, 5-cyano-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl, 5-acetyl-4-phenylthiazol-2-yl, 5-benzoyl-4-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- (ethoxycarbonyl) thiazol-2-yl, 5-ethoxycarbonyl-4- (trifluoromethyl) thiazol-2-yl, m, 5-ethoxycarbonyl-4-phenylthiazol-2-yl, 5-ethoxycarbonyl-4- (pentafluorophenyl) thiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-piperidinothiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-morpholinothiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- (4-methylpiperidin-1-yl) thiazol-2-yl and 4- (1, 1-dimethyl) ethyl-5- (4-phenylpiperidin-1-yl) thiazol-2-yl, most preferably 4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl.

A⁴Is a hydrogen atom orAcetyl group, preferably hydrogen atom.

As R^4zExamples of the "halogen atom" may include a halogen atom and optionally substituted C₆～C₁₀Aryl and 5-membered heteroaryl, preferably a halogen atom, phenyl, 4-fluorophenyl, 2, 4-difluorophenyl, 4- (trifluoromethyl) phenyl, 1-pyrrolyl and 2-thienyl.

The compounds defined by the above general formula (I-4) or pharmaceutically acceptable salts thereof, or hydrates thereof or solvates thereof are all novel compounds, and the use of the compounds based on the present invention is not particularly limited.

The compounds represented by the above general formulae (I), (I-1), (I-2), (I-3) and (I-4) may form salts. The pharmaceutically acceptable salt may, when an acidic group is present, be a metal salt such as a lithium salt, a sodium salt, a potassium salt, a magnesium salt, a calcium salt, or the like, or an ammonium salt such as an ammonium salt, a methylammonium salt, a dimethylammonium salt, a trimethylammonium salt, or a dicyclohexylammonium salt, and when a basic group is present, may be an inorganic acid salt such as a hydrochloride, a hydrobromide, a sulfate, a nitrate, or a phosphate, or an organic acid salt such as a methanesulfonate, a benzenesulfonate, a p-toluenesulfonate, an acetate, a propionate, a tartrate, a fumarate, a maleate, a malate, an oxalate, a succinate, a citrate, a benzoate, a mandelate, a cinnamate, or a lactate. Salts may be 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 compounds represented by the above general formulae (I), (I-1), (I-2), (I-3) and (I-4) or salts thereof may exist as hydrates or solvates. Any of the above substances can be used as the active ingredient of the drug of the present invention. Further, the compounds represented by the general formulae (I), (I-1), (I-2), (I-3) and (I-4) may have 1 or more chiral carbons and thus may exist as stereoisomers such as optically active isomers or diastereomers. As the active ingredient of the drug of the present invention, stereoisomers in pure form, arbitrary mixtures of optical enantiomers or diastereomers, racemates, and the like can be used. When the compounds represented by the general formulae (I), (I-1), (I-2), (I-3) and (I-4) have an olefinic double bond, the arrangement may be either Z arrangement or E arrangement, and any geometrical isomer or mixture thereof may be used as the active ingredient of the medicament of the present invention.

The compounds which are preferable as the active ingredient of the drug of the present invention will be exemplified below, but the active ingredient of the drug of the present invention is not limited to the following compounds. In the tables, Me represents a methyl group and Et represents an ethyl group.

The compound represented by the general formula (I) can be produced, for example, by the following method.

< method 1>

In the general formula (I), the compound wherein X is represented by-CONH- (wherein the hydrogen atom on the nitrogen may be substituted), can be produced, for example, by the method represented by reaction scheme 1.

Reaction scheme 1

(in the formula, A)¹⁰¹A protecting group for a hydrogen atom or a hydroxyl group (preferably an alkyl group such as a methyl group, an aralkyl group such as a benzyl group, an acetyl group, an alkoxyalkyl group such as a methoxymethyl group, a substituted silyl group such as a trimethylsilyl group), R¹⁰¹Represents a hydrogen atom, C₁～C₆Alkyl and the like, E¹⁰¹Represents E in the definition of the general formula (I) or a precursor of E, and G represents a hydroxyl group, a halogen atom (preferably a chlorine atom), a hydrocarbyloxy group (preferably an aryloxy group which may be substituted with a halogen atom), an acyloxy group, an imidoyloxy group or the like. )

(step 1)

The amide (3) can be produced by dehydrating condensation of the carboxylic acid derivative (1) with the amine (2). The reaction is carried out in the presence of an acid halide or a dehydration condensation agent, in the presence or absence of a base, in the absence of a solvent or in an aprotic solvent, at a reaction temperature of 0 ℃ to 180 ℃.

The reaction is carried out in the presence of an acid halide or a dehydration condensation agent, in the presence or absence of a base, in the absence of a solvent or in an aprotic solvent, at a reaction temperature of 0 ℃ to 180 ℃.

As the acid halide, for example, thionyl chloride, thionyl bromide, sulfuryl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride and the like, A ¹⁰¹In the case of a hydrogen atom, phosphorus trichloride, A is preferred¹⁰¹In the case of acetyl group, phosphorus oxychloride is preferred. Examples of the dehydration condensation agent include N, N' -dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and diphenylphosphoramide. Examples of the base include inorganic salts such as sodium carbonate, potassium carbonate and sodium hydrogencarbonate, and organic bases such as pyridine, triethylamine and N, N' -diethylaniline. Examples of the aprotic solvent include dichloromethane, dichloroethane, chloroform, tetrahydrofuran, 1, 4-dioxane, benzene, toluene, monochlorobenzene, o-dichlorobenzene, N' -dimethylformamide, N-methylpyrrolidone, and the like, and when the reaction is carried out in the presence of an acid halide, toluene, monochlorobenzene, and o-dichlorobenzene are particularly preferable.

Alternatively, the acid chlorides may be prepared in advance from carboxylic acids, isolated, and then reacted with a compound having E, using, for example, the method described in J.Med.chem., 1998, 41, 2939, and the methods based thereon¹⁰¹To produce the desired amide.

(step 2)

When the amide (3) has a protecting group and/or has a substituent which is advantageous for modification of a functional group (for example, an amino group and a protecting entity or precursor thereof; a carboxyl group and a protecting entity or precursor thereof; a hydroxyl group and a protecting entity or precursor thereof, etc.), the compound (4) which is the final target product can be produced by performing deprotection reaction and/or functional group modification reaction in this step. Various known methods can be used for the reaction, and as the deprotection reaction and the functional group modification reaction, for example, methods described in "Protective Groups in Organic Syntheses" (P.G.M.Wuts, eds. T.Green, 3 rd edition, 1999, Wiley, the journal of John & Sons), "Handbook of reagent for Organic Syntheses" (L.A.Patent, Vol.4, 1999, Wiley, the journal of John & Sons), etc. can be used, and as the functional group modification reaction, for example, "Palladium Reagents in Organic Syntheses" (R.F.heck, 1985, Academic Press), "Palladium Reagents and Catalysts: innovations in Organic Synthesis (J.Tsuji, 1999, Wiley, John & Sons), and the like.

Even when X is other linking group (e.g., -SO)₂NH-、-NHCO-、-NHSO₂-、-CONHCH₂-、-CONHCH₂CH₂-; the hydrogen atom in the linking group may be substituted), the above-mentioned method can be applied by appropriately combining the raw materials.

< method 2>

In the general formula (I), X is-CH₂The NH-represented compound can be prepared, for example, by the method represented by reaction equation 2.

Reaction equation 2

(wherein A and E are as defined in the general formula (I))

First, the aldehyde (5) and the amine (6) are subjected to dehydration condensation to prepare the compound of formula (7) (R)¹～R⁴And B is as defined for formula (I). The reaction is carried out in a solvent at a reaction temperature of 0 ℃ to 100 ℃ in the presence or absence of a dehydrating agent. Examples of the dehydrating agent include anhydrous magnesium sulfate and a molecular sieve. The solvent may, for example, be a non-reactive solvent, preferably tetrahydrofuran, 1, 4-dioxane, methanol or ethanol.

Even when X is another linking group (for example, -CONHN ═ CH;, the hydrogen atom on the linking group may be substituted), the above-mentioned method can be applied by appropriately combining the raw materials.

Then, the imine derivative (7) is reduced to prepare the target compound (8). The reaction is carried out in a solvent in the presence of a reducing agent at a reaction temperature of 0 ℃ to 100 ℃. Examples of the reducing agent include sodium borohydride, lithium borohydride and the like. The solvent may, for example, be a non-reactive solvent, preferably tetrahydrofuran, 1, 4-dioxane, methanol or ethanol. In addition, the reaction may be carried out by a catalytic hydrogenation method. Examples of the catalyst include palladium on carbon, platinum on carbon, palladium hydroxide, and palladium black. The solvent may, for example, be a non-reactive solvent, preferably tetrahydrofuran, 1, 4-dioxane, methanol, ethanol or water. The reaction is carried out at a reaction temperature of 0 ℃ to 200 ℃ and under the condition that the hydrogen pressure is normal pressure or pressurization.

< method 3>

In the general formula (I), the compound in which X is represented by — CH ═ CH (the hydrogen atom in the linking group may be substituted), can be produced, for example, by the method represented by reaction formula 3.

Reaction equation 3

(wherein A and E represent the same meanings as defined in the general formula (I) and W represents O, O' -dihydrocarbyl-phosphonyl or triaryl * group)

The objective compound (11) can be produced by dehydrating condensation of the aldehyde (9) and the phosphorus compound (10). The reaction is carried out in the presence of a base at a reaction temperature of from 0 ℃ to the boiling point of the solvent. Examples of the base include inorganic bases such as sodium carbonate, potassium carbonate and sodium hydrogencarbonate, and organic bases such as pyridine, triethylamine and N, N' -diethylaniline. Examples of the solvent include non-reactive solvents, preferably tetrahydrofuran, 1, 4-dioxane, methanol, ethanol, and water.

< method 4>

In the general formula (I), X is-COCH ═ CH-and-COCH₂CH₂The compound represented by (the hydrogen atom of the linking group may be substituted), for example, can be prepared by the method represented by reaction formula 4.

Reaction equation 4

Ketene (14) which is the target compound can be produced by dehydration condensation of ketone (12) and aldehyde (13). The reaction is carried out in the presence of a base at a reaction temperature of from 0 ℃ to the boiling point of the solvent. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium hydrogencarbonate, and organic bases such as pyridine, triethylamine and N, N' -diethylaniline. Examples of the solvent include non-reactive solvents, preferably tetrahydrofuran, 1, 4-dioxane, methanol, ethanol, and water.

Subsequently, the target compound (15) can be produced by reducing the enone (14). The reaction is carried out in a solvent in the presence of a reducing agent at a reaction temperature of 0 ℃ to 100 ℃. Examples of the reducing agent include sodium borohydride, lithium borohydride and the like. The solvent may, for example, be a non-reactive solvent, preferably tetrahydrofuran, 1, 4-dioxane, methanol or ethanol. In addition, the reaction may be carried out by a catalytic hydrogenation method. Examples of the catalyst include palladium on carbon, platinum on carbon, palladium hydroxide, and palladium black. The solvent may, for example, be a non-reactive solvent, preferably tetrahydrofuran, 1, 4-dioxane, methanol, ethanol or water. The reaction is carried out at a reaction temperature of 0 ℃ to 200 ℃ and under the condition that the hydrogen pressure is normal pressure or pressurization.

In the examples of the present specification, a method for producing a representative compound contained in the general formula (I) is specifically described. Therefore, those skilled in the art can prepare any compound included in the general formula (I) by selecting appropriate reaction materials, reaction reagents, and reaction conditions and appropriately modifying or changing these methods as necessary, with reference to the above general description of the preparation method and the description of the specific preparation method of the examples.

The compound represented by the general formula (I) has an NF- κ B activation inhibitory action and an inflammatory cytokine production dissociation inhibitory action, and is useful as an active ingredient of a drug such as an NF- κ B activation inhibitor and an inflammatory cytokine production dissociation inhibitor. The above-mentioned drugs can be used as gene expression inhibitors of 1 or 2 or more substances selected from the group consisting of, the substances include Tumor Necrosis Factor (TNF), interleukin-1, interleukin-2, interleukin-6, interleukin-8, granulocyte colony stimulating factor, interferon beta, cell adhesion factors ICAM-1 and VCAM-1 and ELAM-1, nitric oxide synthase, major histocompatibility class I antigen, major histocompatibility class II antigen, beta 2-microglobulin, immunoglobulin light chain, serum amyloid A component, angiotensinogen, complement B, complement C4, C-myc, a transcription product derived from HIV gene, a transcription product derived from HTLV-1 gene, a transcription product derived from simian virus 40 gene, a transcription product derived from cytomegalovirus gene, and a transcription product derived from adenovirus gene. In addition, the above-mentioned drugs are useful as drugs for preventing and/or treating diseases caused by NF- κ B activation and diseases caused by excessive production of inflammatory cytokines.

More specifically, the drug of the present invention is useful for the prevention and/or treatment of diseases considered to be associated with NF-. kappa.B activation and/or inflammatory cytokines as described below, such as chronic rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, systemic scleroderma, polymyositis, Sjogren's syndrome, vasculitis syndrome, antiphospholipid antibody syndrome, Still's disease, Behcet's disease, periarteritis nodosa, ulcerative colitis, Crohn's disease, autoimmune diseases such as chronic active hepatitis and glomerulonephritis, chronic nephritis, chronic pancreatitis, gout, atherosclerosis, multiple sclerosis, arteriosclerosis, intimal hypertrophy, psoriasis, psoriatic arthritis, contact dermatitis, atopic dermatitis, and the like, Allergic diseases such as pollinosis, asthma, bronchitis, interstitial pneumonia, lung diseases accompanied by granuloma, chronic obstructive lung disease, chronic pulmonary thromboembolism, inflammatory colitis, insulin resistance, obesity, diabetes and its accompanying complications (nephropathy, retinopathy, neuropathy, hyperinsulinemia, arteriosclerosis, hypertension, peripheral vascular occlusion, etc.), hyperlipemia, retinopathy, and other diseases accompanied by abnormal vascular proliferation, pneumonia, Alzheimer's disease, encephalomyelitis, acute hepatitis, chronic hepatitis, drug-toxicity liver disorder, alcoholic hepatitis, viral hepatitis, jaundice, liver cirrhosis, liver failure, atrial myxoma, キヤツスルマン syndrome, glomerulonephritis, kidney cancer, lung cancer, liver cancer, breast cancer, uterine cancer, pancreatic cancer, other solid tumors, sarcoma, and the like, Osteosarcoma, metastasis and infiltration of cancer, canceration of inflammatory lesions, cancer cachexia, cancer metastasis, leukemia such as acute myeloblastic leukemia, multiple myeloma, レンネルト lymphoma, malignant lymphoma, resistance to anticancer agents for cancer, canceration of lesions such as viral hepatitis and liver cirrhosis, canceration of polyp of large intestine, cerebroma, neuroma, endotoxin shock, septicemia, cytomegalovirus pneumonia, cytomegalovirus retinopathy, adenovirus cold, adenovirus blood stasis (pool) fever, adenovirus ophthalmia, conjunctivitis, AIDS, uveitis, other diseases or complications caused by infection with bacteria, viruses, fungi, etc., complications after surgical operation such as systemic inflammatory syndrome, restenosis after percutaneous transluminal coronary angioplasty, reperfusion disorder after opening of blood vessel occlusion such as ischemia reperfusion disorder, etc, Rejection after transplantation of organs such as heart, liver or kidney, reperfusion disorder, pruritus, anorexia, listlessness, and chronic fatigue syndrome. In addition, since inflammatory cytokines and NF-. kappa.B are involved in the differentiation and activation of osteoclasts, the drug of the present invention is also useful for the prevention and/or treatment of metabolic bone diseases such as osteoporosis and bone cancer pain. Can also be used for preventing organ deterioration during organ preservation before transplantation.

As the active ingredient of the drug of the present invention, 1 or 2 or more selected from the compounds represented by the general formula (I) and pharmaceutically acceptable salts thereof, and hydrates and solvates thereof can be used. The above-mentioned substance itself can be used as the drug of the present invention, but it is preferable that the drug of the present invention is provided in the form of a pharmaceutical composition containing the above-mentioned substance as an active ingredient and 1 or 2 or more pharmaceutically acceptable additives for pharmaceutical preparations. In the above pharmaceutical composition, the proportion of the active ingredient relative to the additive for formulation is 1 to 90% by weight.

The drug of the present invention can be administered as a pharmaceutical composition for oral administration such as granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, and solutions, or as a pharmaceutical composition for non-oral administration such as an injection for intravenous administration, intramuscular administration, or subcutaneous administration, an infusion solution, a suppository, a transdermal absorbent, a transmucosal absorbent, a nasal drop, an ear drop, an eye drop, and an inhalant. The pharmaceutical composition in powder form can also be dissolved at the time of use and used as an injection or infusion solution.

In the preparation of the pharmaceutical composition, solid or liquid additives for formulation may be used. The additive for the preparation may be an organic additive or an inorganic additive. That is, in the case of preparing an oral solid preparation, an excipient is added to a main ingredient, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, and the like are added, followed by preparing into a preparation in the form of a tablet, a coated tablet, a granule, a powder, a capsule, and the like according to a conventional method. Examples of the excipient to be used include lactose, sucrose, white sugar, glucose, corn starch, talc, sorbitol, crystalline cellulose, dextrin, kaolin, calcium carbonate, and silica. Examples of the binder include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, calcium citrate, dextrin, pectin and the like. Examples of the lubricant include magnesium stearate, talc, polyethylene glycol, silicon dioxide, hardened vegetable oil, and the like. The colorant may be any colorant that is generally acceptable for addition to a pharmaceutical product. As flavoring agent, cocoa powder, menthol, aromatic acid, oleum Menthae Dementholatum, Borneolum Syntheticum, cortex Cinnamomi Japonici powder, etc. can be used. These tablets, granules may be sugar-coated, gelatin-coated, or other suitable coatings as desired. Further, preservatives, antioxidants and the like may be added as required.

In the preparation of liquid preparations for oral administration, such as emulsions, syrups, suspensions, solutions, inert diluents commonly used, such as water or vegetable oils, can be used. In these preparations, in addition to the inert diluent, an auxiliary such as a wetting agent, a suspending aid, a sweetener, an aromatic, a coloring agent, or a preservative may be blended. After being formulated into a liquid preparation, the preparation may be filled into a capsule containing an absorbable material such as gelatin. As a solvent or suspending agent for preparing a preparation for non-oral administration, for example, an injection, a suppository or the like, for example, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin, etc. As the base for preparing suppositories, for example, cacao butter, emulsified cacao butter, lauryl butter, ウイテツプゾ - ル are exemplified. The method for preparing the preparation is not particularly limited, and any method widely used in the art can be used.

When making into injection, water, ethanol, polyethylene glycol, propylene glycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid, and sodium hydroxide can be used as carrier; pH regulators and buffers such as sodium citrate, sodium acetate and sodium phosphate; stabilizers such as sodium metabisulfite, ethylenediaminetetraacetic acid, thioglycolic acid, mercaptopropionic acid, and the like. In this case, a sufficient amount of common salt, glucose, mannitol or glycerin may be added to the preparation to prepare an isotonic solution, and a conventional dissolution aid, analgesic, local anesthetic, or the like may be used.

When the composition is prepared into an ointment, for example, a paste, cream or gel, it may be mixed with a base, a stabilizer, a moisturizer, a preservative, etc. which are generally used, if necessary, and the components may be mixed according to a conventional method to prepare a preparation. As the base, for example, white vaseline, polyethylene, paraffin, glycerin, cellulose derivative, polyethylene glycol, silicone, bentonite, and the like can be used. As the preservative, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, or the like can be used. In the form of a patch, the ointment, cream, gel, paste, or the like can be applied to a conventional support according to a conventional method. As the support, woven or nonwoven fabrics made of cotton, chemical short fibers, and chemical fibers; a film or a foam sheet of soft vinyl chloride, polyethylene, polyurethane, or the like.

The dose of the drug of the present invention is not particularly limited, and in the case of oral administration, it is usually 0.01 to 5000mg per day for an adult based on the weight of the compound of the present invention. The dose is preferably increased or decreased as appropriate according to the age, condition and symptoms of the patient. The daily dose may be administered once, 2 to 3 times a day at appropriate intervals, or several days at intervals. When the compound of the present invention is used as an injection, the daily dose for an adult is about 0.001 to 100mg based on the weight of the compound of the present invention.

Examples

The present invention will be described more specifically with reference to examples, but the scope of the present invention is not limited to the examples. In addition, in this example, compounds directly used for the test were included in commercially available reagents. For this compound, the numbers reported in the reagent's sales and in the catalogs are listed.

Example 1: preparation of N- { [ 3, 5-bis (trifluoromethyl) phenyl ] methyl } -5-bromo-2-hydroxybenzamide (Compound No. 1)

To a mixture of 5-bromosalicylic acid (217mg, 1mmol), 3, 5-bis (trifluoromethyl) benzylamine (243mg, 1mmol), 4-dimethylaminopyridine (12mg, 0.1mmol) and tetrahydrofuran (10ml) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (hereinafter abbreviated as WSC. HCl; 192mg, 1mmol) under an argon atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then distilled 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 (244.8mg, 55.4%).

¹H-NMR(DMSO-d₆)：δ4.69(2H，d，J＝5.7Hz)，6.93(1H，d，J＝8.7Hz)，7.56(1H，dd，J＝8.7，2.4Hz)，8.02(1H，d，J＝2.4Hz)，8.06(3H，s)，9.41(1H，t，J＝5.7Hz)，12.13(1H，s).

Example 2: 5-bromo-2-hydroxy-N- (2-phenylethyl) benzamide (Compound No. 2)

(1) 2-acetoxy-N- (2-phenylethyl) benzamide

O-acetylsalicyloyl chloride (0.20g, 1.00mmol) was dissolved in benzene (8mL), phenethylamine (0.12g, 1.00mmol) and pyridine (0.3mL) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate ═ 2: 1 → 1: 1) to obtain white crystals of the title compound (155.5mg, 54.9%).

¹H-NMR(CDCl₃)：δ2.09(3H，s)，2.92(2H，t，J＝6.8Hz)，3.71(2H，q，J＝6.8Hz)，6.32(1H，brs)，7.07(1H，dd，J＝8.4，1.2Hz)，7.23-7.35(6H，m)，7.44(1H，ddd，J＝8.0，7.6，1.6Hz)，7.73(1H，dd，J＝7.6，1.6H z).

(2) 2-hydroxy-N- (2-phenylethyl) benzamide

To 2-acetoxy-N- (2-phenylethyl) benzamide (155.5mg) were added methanol (5mL) and 2N sodium hydroxide (0.1mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to crystallize the obtained residue (dichloromethane/hexane) to obtain the title compound as a white solid (106.9mg, 80.7%).

¹H-NMR(DMSO-d₆)：δ2.86(2H，t，J＝7.6Hz)，3.52(1H，q，J＝7.6Hz)，6.84-6.88(2H，m)，7.18-7.31(5H，m)，7.37(1H，ddd，J＝8.4，7.2，1.6Hz)，7.80(1H，dd，J＝8.4，1.6Hz)，8.84(1H，s)，12.51(1H，s).

(3) 5-bromo-2-hydroxy-N- (2-phenylethyl) benzamide

To 2-hydroxy-N- (2-phenylethyl) benzamide (79.6mg, 0.33mmol) were added carbon tetrachloride (5mL), iron powder (0.03g), and bromine (25. mu.L, 0.48mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into an aqueous sodium bisulfite solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then distilled 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 of the title compound (62mg, 58.7%).

¹H-NMR(DMSO-d₆)：δ2.85(2H，t，J＝7.6Hz)，3.52(1H，q，J＝7.6Hz)，6.87(1H，d，J＝8.8Hz)，7.18-7.31(5H，m)，7.52(1H，dd，J＝8.8，2.4Hz)，8.01(1H，d，J＝2.4Hz)，8.90(1H，s)，12.51(1H，s).

Example 3: 5-bromo-2-hydroxy-N- [ 5- (morpholinocarbonyl) indan-2-yl ] benzamide (compound No. 3)

WSC & HCl (96mg, 0.5mmol) was added to a solution of 5-bromosalicylic acid (109mg, 0.5mmol), 2-amino-5- (morpholino) carbonyl indan (see chem. pharm. Bull., 2000, 48, 131.; 141mg, 0.5mmol), and triethylamine (70. mu.L, 0.5mmol) in dichloromethane (5mL), and the mixture was stirred at 40 ℃ for 1.5 hours. After cooling, the reaction mixture was diluted with ethyl acetate, washed with 2N hydrochloric acid, water and saturated brine in this order, dried over anhydrous magnesium sulfate, and concentrated, and then the residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 19: 1) to obtain the title compound as white crystals (26mg, 11.9%).

¹H-NMR(CDCl₃)：δ2.66(1H，dd，J＝16.2，7.2Hz)，2.82(1H，dd，J＝16.2，7.2Hz)，3.16-3.25(2H，m)，3.43-3.86(8H，m)，4.79-4.92(1H，m)，6.88(1H，d，J＝8.7Hz)，7.14-7.15(3H，m)，7.46(1H，dd，J＝8.7，2.4Hz)，7.74(1H，d，J＝7.8Hz)，7.84(1H，d，J＝2.4Hz).

Example 4: 3- (4-chlorophenyl) -1- (2, 6-dihydroxyphenyl) -3- (4-hydroxyphenyl) propan-1-one (Compound No. 4)

The present compounds are commercially available compounds.

And (4) selling places: apin Chemicals Inc

The catalog number of the commodity: N0100D

Example 5: 1- (5-chloro-2-hydroxyphenyl) -3- (4-methoxyphenyl) propan-1-one (Compound No. 5)

The present compounds are commercially available compounds.

And (4) selling places: specs corporation

The catalog number of the commodity: AI-233/31581024

Example 6: 1- (2-hydroxy-4-methoxyphenyl) -3- (2-methoxyphenyl) propen-1-one (Compound No. 6)

The present compounds are commercially available compounds.

And (4) selling places: maybridge Inc

The catalog number of the commodity: RJC 00106

Example 7: 3- (3, 4-dihydro-2H-benzo [ b ] [ 1, 4 ] dioxan * (ジオキセピン) -7-yl) -1- (2-hydroxy-5-methylphenyl) propen-1-one (Compound No. 7)

The present compounds are commercially available compounds.

And (4) selling places: maybridge Inc

The catalog number of the commodity: BTB 13230

Example 8: 3- (3, 4-dihydro-2H-benzo [ b ] [ 1, 4 ] dioxan * -7-yl) -1- [ 2-hydroxy-4- (methoxymethyl) phenyl ] propen-1-one (Compound No. 8)

The present compounds are commercially available compounds.

And (4) selling places: maybridge Inc

The catalog number of the commodity: BTB 114482

Example 9: 4-chloro-2- [ (4-chlorophenyl) ethen-2-yl ] phenol (Compound No. 9)

5-Chlorosalicaldehyde (313mg, 2mmol) and 4-chlorobenzyltriphenyl * chloride (847mg, 2mmol) were dissolved in N, N-dimethylformamide (20mL), and potassium carbonate (1.382g, 10mmol) was dissolved in water (10mL) and added, followed by heating and refluxing for 5 hours. After cooling, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then distilled 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 an off-white solid (44.6mg, 8.4%).

¹H-NMR(CDCl₃)：δ5.04(1H，s)，6.74(1H，d，J＝9.0Hz)，7.05(1H，d，J＝16.5Hz)，7.10(1H，dd，J＝8.4，2.4Hz)，7.26(1H，d，J＝16.5H z)，7.33(2H，d，J＝8.4Hz)，7.45(2H，d，J＝8.4Hz)，7.49(1H，d，J＝2.4Hz).

Example 10: 5-bromo-N- (3, 5-dichloro) phenyl-2-hydroxybenzenesulfonamide (Compound No. 10)

(1) 5-bromo-N- (3, 5-dichloro) phenyl-2-methoxybenzenesulphonamide

5-bromo-2-methoxybenzenesulfonyl chloride (857mg, 3mmol) was dissolved in dichloromethane (6mL), and 3, 5-dichloroaniline (510mg, 3.15mmol) and pyridine (261mg, 3.3mmol) were added dropwise in dichloromethane (2mL) under an ice-cold argon atmosphere, followed by stirring at room temperature for 6 hours. The reaction mixture was diluted with dichloromethane, washed successively with 2N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was crystallized from N-hexane-ethyl acetate to give white crystals of 5-bromo-2-methoxy-N- (3, 5-dichloro) benzenesulfonamide (900mg, 73.0%).

¹H-NMR(DMSO-d₆)：δ4.03(3H，s)，6.92(1H，d，J＝9.0Hz)，7.01(2H，d，J＝1.8Hz)，7.07-7.08(1H，m)，7.24(1H，brs)，7.63(1H，dd，J＝8.7，2.4Hz)，7.99(1H，d，J＝2.4Hz).

(2) 5-bromo-N- (3, 5-dichloro) phenyl-2-hydroxybenzenesulfonamide

A mixture of white crystals of 5-bromo-N- (3, 5-dichloro) phenyl-2-methoxybenzenesulfonamide (206mg, 0.5mmol), lithium iodide (134mg, 1mmol), 2, 4, 6-collidine (5mL) was heated at reflux for 30 minutes under an argon atmosphere. After the reaction mixture was cooled to room temperature, it was poured into 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine in this order, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was crystallized from n-hexane-ethyl acetate to obtain white crystals of the title compound (90mg, 45.3%).

mp158-159℃.

¹H-NMR(DMSO-d₆，δ)：6.92(1H，d，J＝8.7Hz)，7.11(2H，d，J＝2.1Hz)，7.21-7.22(1H，m)，7.62(1H，d d，J＝8.7，2.7Hz)，7.80(1H，d，J＝2.4Hz)，10.70(1H，br)，11.37(1H，br).

Example 11: 3, 5-bis (trifluoromethyl) -N- (2-hydroxyphenyl) benzamide (Compound No. 11)

2-aminophenol (120mg, 1.1mmol) was dissolved in dichloromethane (5mL), and a solution of 3, 5-bis (trifluoromethyl) benzoyl chloride (300mg, 1.1mmol) and dichloromethane (3mL), pyridine (0.5mL) was added dropwise under an ice-cold argon atmosphere, followed by stirring 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 with water and saturated brine in this order, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was dissolved in ethanol (5mL), and 2N sodium hydroxide (0.1mL, 0.2mmol) was added dropwise, followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into 2N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 4: 1) to obtain the title compound as pale pink crystals (288mg, 73.6%).

mp 183℃(dec.).

¹H-NMR(DMSO-d₆，δ)：6.83(1H，t d，J＝8.0，1.2Hz)，6.98(1H，dd，J＝8.0，1.2Hz)，7.08(1H，td，J＝8.0，1.6Hz)，7.50(1H，d，J＝8.0Hz)，8.35(2H，s)，9.61(1H，s)，10.15(1H，s).

Example 12: n- (5-chloro-2-hydroxyphenyl) -3, 5-dichlorobenzamide (compound No. 12)

2-amino-4-chlorophenol (316mg, 2.2mmol) and triethylamine (243mg, 2.4mol) were dissolved in dichloromethane (8mL), and a solution of 3, 5-dichlorobenzoyl chloride (419mg, 2mmol) in dichloromethane (2mL) was added dropwise under an ice-cold argon atmosphere, followed by stirring at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine in this order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate: 3: 1) to obtain a pale brown solid. This was washed in suspension with n-hexane-ethyl acetate under heating reflux to give the title compound as white crystals (205mg, 32.4%).

mp 251-252℃.

¹H-NMR(DMSO-d₆)：δ6.93(1H，d，J＝9.0Hz)，7.11(1H，dd，J＝8.7，2.7Hz)，7.67(2H，d，J＝2.7Hz)，7.86-7.87(1H，m)，7.97(1H，d，J＝1.8Hz)，9.85(1H，s)，10.03(1H，s).

Example 13: n- (5-chloro-2-hydroxyphenyl) -3, 5-dichlorobenzenesulfonamide (compound No. 13)

2-amino-4-chlorophenol (287mg, 2mmol) and 3, 5-dichlorobenzenesulfonyl chloride (540mg, 2.2mol) were dissolved in dichloromethane (4mL), and pyridine (1mL) was added dropwise under an ice-cold argon atmosphere, followed by stirring 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 with water and saturated brine in this order, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate ═ 3: 1 → 1: 1) to obtain a reddish brown solid. Crystallization from n-hexane-ethyl acetate gave the title compound as slightly brown crystals (445mg, 63.1%).

mp 190-191℃.

¹H-NMR(DMSO-d₆)：δ7.68(1H，d，J＝9.0Hz)，7.08(1H，dd，J＝8.7，2.7Hz)，7.17(1H，d，J＝2.4Hz)，7.70(2H，d，J＝1.8Hz)，7.95-7.96(1H，m)，10.00(1H，s)，10.06(1H，s).

Example 14: n- [ (5-bromo-2-hydroxyphenyl) methyl ] -3, 5-dichloroaniline (compound No. 14)

(1) 4-bromo-2- [ (3, 5-diphenylimino) methyl ] phenol

A mixture of 5-bromosalicylaldehyde (1.01g, 5mmol), 3, 5-dichloroaniline (810mg, 5mmol), and ethanol (25mL) was heated at reflux under argon for 1 hour. After the reaction mixture was cooled to room temperature, the precipitated crystals were collected by filtration to give orange crystals of 3, 5-dichloro-N- (5-bromo-2-hydroxybenzylidene) aniline (1.52g, 88.2%).

mp 161-163℃.¹H-NMR(CDC1₃，δ)：6.94(1H，d，J＝9.0Hz)，7.16(2H，d，J＝1.8Hz)，7.30-7.31(1H，m)，7.47-7.53(2H，m)，8.51(1H，s).

(2) N- [ (5-bromo-2-hydroxyphenyl) methyl ] -3, 5-dichloroaniline 3, 5-dichloro-N- (5-bromo-2-hydroxybenzylidene) aniline (1.04g, 3mmol) was dissolved in tetrahydrofuran (12mL) and ethanol (6mL), and sodium borohydride (113mg, 3mmol) was added under ice-cold argon atmosphere, followed by stirring at room temperature for 12 hours. Acetone (10mL) was added to the reaction mixture, the mixture was concentrated under reduced pressure, and water was added to the resulting residue to conduct extraction with methylene chloride. The dichloromethane layer was washed with water and saturated brine in this order, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 4: 1) to obtain a pale yellow viscous substance. Crystallization from n-hexane gave the title compound as white crystals (971mg, 93.3%).

mp 125-126℃.¹H-NMR(CDC1₃，δ)：δ4.31(2H，s)，6.64(2H，d，J＝1.8H z)，6.74-6.77(1H，m)，6.84-6.85(1H，m)，7.30-7.34(2H，m).

Example 15: 5-chloro-2-hydroxybenzoic acid (2, 4-dihydroxybenzylidene) hydrazide (compound No. 15)

The present compounds are commercially available compounds.

And (4) selling places: Sigma-Aldrich Co

The catalog number of the commodity: s3203-5

Example 16: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-chloro-2-hydroxy-N-methylbenzamide (Compound No. 16)

A mixture of 5-chlorosalicylic acid (173mg, 1mmol), 3, 5-bis (trifluoromethyl) -N-methylaniline (243mg, 1mmol), phosphorus trichloride (44. mu.l, 0.5mmol), and monochlorobenzene (5mL) was heated under reflux for 3 hours under an argon atmosphere. After the reaction mixture was cooled to room temperature, n-hexane (50mL) was added, and the precipitated crude crystals were collected by filtration and dissolved in ethyl acetate (50 mL). The ethyl acetate solution was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 2: 1) to obtain white crystals of the title compound (75mg, 18.9%).

¹H-NMR(CDCl₃)：δ6.59(1H，d，J＝2.4Hz)，6.94(1H，d，J＝9.0Hz)，7.21(1H，dd，J＝9.0，2.7Hz)，7.58(2H，s)，7.80(1H，s)，10.00(1H，brs).

Example 17: 1- (5-bromo-2-hydroxy) benzoyl-7- (trifluoromethyl) -1, 2, 3, 4-tetrahydroquinoline (Compound No. 17)

The same procedures used in example 16 were repeated using 5-bromosalicylic acid and 7- (trifluoromethyl) -1, 2, 3, 4-tetrahydroquinoline as starting materials to give the title compound.

Yield: 42.0 percent

¹H-NMR(CDCl₃)：δ2.08(2H，m)，2.92(2H，t，J＝6.6Hz)，3.95(2H，t，J＝6.6Hz)，6.91-6.94(2H，m)，7.14(1H，s)，7.32-7.35(2H，m)，7.40(1H，dd，J＝8.7，2.4Hz)，10.06(1H，s).

Example 18: n- (3, 5-dichlorophenyl) -2-hydroxy-1-naphthamide (Compound No. 18)

The same procedures used in example 16 were repeated except for using 2-hydroxynaphthalene-1-carboxylic acid and 3, 5-dichloroaniline as starting materials to give the title compound.

Yield: 51.2 percent

mp 246-248℃.

¹H-NMR(DMSO-d₆)：δ7.26(1H，d，J＝9.3Hz)，7.31-7.37(2H，m)，7.44-7.50(1H，m)，7.65-.68(1H，m)，7.85-7.90(4H，m)，10.23(1H，s)，10.74(1H，s).

Example 19: n- (3, 5-dichlorophenyl) -3-hydroxy-2-naphthamide (Compound No. 19)

The same procedures used in example 16 were repeated except for using 3-hydroxynaphthalene-2-carboxylic acid and 3, 5-dichloroaniline as starting materials to give the title compound.

mp 254-255℃.

¹H-NMR(DMSO-d₆)：7.34-7.39(3H，m)，7.49-7.54(1H，m)，7.76-7.79(1H，m)，7.89(2H，d，J＝1.8Hz)，7.92(1H，m)，8.39(1H，s)，10.75(1H，s)，11.01(1H，s).

Example 20: n- (3, 5-Dimethoxyphenyl) -3-hydroxy-2-naphthamide (Compound No. 20)

The present compounds are commercially available compounds.

And (4) selling places: Sigma-Aldrich Co

The catalog number of the commodity: s01361-8

Example 21: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -1-hydroxy-2-naphthamide (Compound No. 21)

The same operations as in example 16 were carried out using 1-hydroxynaphthalene-2-carboxylic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 65.5 percent

¹H-NMR(DMSO-d₆)：δ7.51(1H，d，J＝9.0Hz)，7.60(1H，td，J＝7.8，0.9Hz)，7.70(1H，td，J＝7.8，0.9Hz)，7.89(1H，s)，7.93(1H，d，J＝8.4Hz)，8.09(1H，d，J＝9.0Hz)，8.33(1H，d，J＝8.7Hz)，8.51(2H，s)，10.92(1H，s)，13.36(1H，s).

Example 22: { [ (1-Hydroxynaphthalen-2-yl) carbonyl ] amino) benzenesulfonyl fluoride (Compound No. 22)

The present compounds are commercially available compounds.

And (4) selling places: Sigma-Aldrich Co

The catalog number of the commodity: s58026-0

Example 23: 4- ({ [ 4- (2, 5-dichlorophenyl) azo-1-hydroxynaphthalen-2-yl ] carbonyl } amino) benzenesulfonyl fluoride (Compound No. 23)

The present compounds are commercially available compounds.

And (4) selling places: Sigma-Aldrich Co

The catalog number of the commodity: s63263-5

Example 24: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-chloro-2-hydroxypyridine-3-carboxamide (Compound No. 24)

5-chloro-2-hydroxynicotinic acid (174mg, 1mmol), 3, 5-bis (trifluoromethyl) aniline (275mg, 1.2mmol), and pyridine (316mg, 4mmol) were dissolved in tetrahydrofuran (20mL) and dichloromethane (10mL), and phosphorus oxychloride (0.112mL, 1.2mmol) was added, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into ethyl acetate (100mL) and 0.2N hydrochloric acid (100mL), stirred for 30 minutes, and then filtered through celite, and the aqueous layer of the filtrate was extracted with ethyl acetate. The combined ethyl acetate layer was washed with water and saturated brine in this order, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate ═ 2: 1 → 1: 1) to give a pale yellow solid. This was washed by suspension with ethanol under heating reflux to give the title compound as white crystals (183mg, 47.6%).

Melting point: > 270 DEG C

¹H-NMR(DMSO-d₆)：δ7.83(1H，s)，8.15(1H，d，J＝3.3Hz)，8.35(1H，d，J＝3.0Hz)，8.40(2H，s)，12.43(1H，s).

Example 25: n- [ 2-chloro-5- (trifluoromethyl) phenyl ] -5-chloro-2-hydroxynicotinamide (compound No. 25)

The same procedures used in example 24 were repeated using 5-chloro-2-hydroxynicotinic acid and 2-chloro-5- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 42.9 percent

¹H-NMR(DMSO-d₆)：δ7.52(1H，dd，J＝8.4，2.1Hz)，7，81(1H，d，J＝8.4Hz)，8.16(1H，s)，8.39(1H，d，J＝2.7Hz)，8.96(1H，d，J＝2.1Hz)，12.76(1H，s)，13.23(1H，s).

Example 26: n- {3, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl } -5-chloro-2-hydroxynicotinamide (Compound No. 26)

The same procedures used in example 24 were repeated except for using 5-chloro-2-hydroxynicotinic acid and 3, 5-di [ (1, 1-dimethyl) ethyl ] aniline as starting materials to give the title compound.

Yield: 59.1 percent

¹H-NMR(DMSO-d₆)：δ1.29(18H，s)，7.18(1H，t，J＝1.8Hz)，7.52(2H.d，J＝1.8Hz)，8.07(1H，d，J＝2.4Hz)，8.35(1H，d，J＝3.3Hz)，11.92(1H，s)，13.10(1H，s).

Example 27: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -3-hydroxypyridine-2-carboxamide (Compound No. 27)

The same operations as in example 24 were carried out using 3-hydroxy-pyridine-2-carboxylic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 45.0 percent

¹H-NMR(CDCl₃)：δ7.40(1H，dd，J＝8.4，1.8Hz)，7.46(1H，dd，J＝8.4，4.2Hz)，7.68(1H，s)，8.16(1H，dd，J＝4.2，1.2Hz)，8.25(2H，s)，10.24(1H，s)，11.42(1H，s).

Example 28: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -6-chloro-2-hydroxyindole-3-carboxamide (Compound No. 28)

3, 5-bis (trifluoromethyl) isocyanate (255mg, 1.0mmol) was dissolved in tetrahydrofuran (5mL) under an argon atmosphere, and a solution of 6-chloro-oxindole (184mg, 1.1mmol) in tetrahydrofuran (5mL) and triethylamine (0.3mL) were added to stir at room temperature for 4 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then distilled 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 pink solid (172.2mg, 40.7%).

¹H-NMR(DMSO-d₆)：δ3.97(2H，s)，7.29(1H，dd，J＝8.1，2.1Hz)，7.41(1H，d，J＝8.1Hz)，7.88(1H，s)，8.04(1H，d，J＝2.1Hz)，8.38(2H，s)，10.93(1H，s).

Example 29: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -3-hydroxyquinoxaline-2-carboxamide (Compound No. 29)

The same operations as in example 16 were carried out using 3-hydroxyquinoxaline-2-carboxylic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.

Yield: 2.7 percent

¹H-NMR(DMSO-d₆)：δ7.40-7.45(2H，m)，7.69(1H，td，J＝8.4，1.5Hz)，7.90-7.93(2H，m)，8.41(2H，s)，11.64(1H，s)，13.02(1H，s).

Example 30: n- (4-chlorophenyl) -2-hydroxy-9H-carbazole-3-carboxamide (Compound No. 30)

The present compounds are commercially available compounds.

And (4) selling places: Sigma-Aldrich Co

The catalog number of the commodity: s83846-2

Example 31: 2-hydroxy-N- (1-naphthyl) benzamide (compound number 31)

The present compounds are commercially available compounds.

And (4) selling places: maybridge Inc

The catalog number of the commodity: RDR 01818

Example 32: 5-chloro-2-hydroxy-N- (1-naphthyl) benzamide (Compound No. 32)

The title compound was obtained in the same manner as in example 16 using 5-chlorosalicylic acid and 1-naphthylamine as starting materials.

Yield: 65.0 percent

¹H-NMR(DMSO-d₆)：δ7.09(1H，d，J＝8.7Hz)，7.51-7.61(4H，m)，7.85(1H，d，J＝8.4Hz)，7.96(1H，d，J＝7.5Hz)，7.99-8.05(2H，m)，8.13(1H，d，J＝2.7Hz)，10.88(1H，s)，12.31(1H，s).

Example 33: 5-chloro-2-hydroxy-N- (4-methoxynaphthalen-2-yl) benzamide (Compound No. 33)

The same procedures used in example 16 were repeated using 5-aminosalicylic acid and 4-methoxy-1-naphthylamine as starting materials to give the title compound.

Yield: 84.3 percent

¹H-NMR(DMSO-d₆)：δ3.99(3H，s)，7.05(1H，d，J＝9.0Hz)，7.30(1H，d，J＝1.5Hz)，7.39-7.45(1H，m)，7.48-7.54(2H，m)，7.83(1H，d，J＝7.8Hz)，8.00(1H，s)，8.02(1H，d，J＝2.4Hz)，8.09(1H，d，J＝7.8Hz)，10.54(1H，s)，11.88(1H，s).

Example 34: 2-acetoxy-5-chloro-N- (4-methoxynaphthalen-2-yl) benzamide (Compound No. 34)

The same procedures used in example 24 were repeated using 2-acetoxy-5-chlorobenzoic acid and 4-methoxy-1-naphthylamine as starting materials to give the title compound (2-acetoxy-5-chlorobenzoic acid: see eur.j.med.chem., 1996, 31, 861.).

Yield: 39.9% Red solid

¹H-NMR(DMSO-d₆)：δ2.23(3H，s)，3.95(3H，s)，7.23(1H，d，J＝1.2Hz)，7.34(1H，d，J＝8.7Hz)，7.40(1H，dt，J＝8.1，1.2Hz)，7.50(1H，dt，J＝8.1，1.5Hz)，7.67(1H，dd，J＝8.7，2.7Hz)，7.81(1H，d，J＝8.7Hz)，8.72(1H，d，J＝3.0Hz)，8.02(1H，s)，8.08(1H，d，J＝8.7Hz)，10.58(1H，s).

Example 35: 2- (5-chloro-2-hydroxybenzoyl) amino-4, 5, 6, 7-tetrahydrobenzo [ b ] thiophene-3-carboxylic acid ethyl ester (Compound No. 35)

The same procedures used in example 16 were repeated using 5-chlorosalicylic acid and ethyl 2-amino-4, 5, 6, 7-tetrahydrobenzo [ b ] thiophene-3-carboxylate as starting materials to give the title compound.

Yield: 49.6 percent

¹H-NMR(DMSO-d₆)：δ1.32(3H，t，J＝7.2H z)，1.74(4H，br)，2.63(2H，br)，2.75(2H，br)，4.30(2H，q，J＝7.2Hz)，7.05(1H，d，J＝9.0H z)，7.50(1H，dd，J＝8.7，3.0Hz)，7.92(1H，d，J＝3.0Hz)，12.23(1H，s)，13.07(1H，s).

Example 36: 5-bromo-2-hydroxy-N- (5-phenylpyrazol-3-yl) benzamide (Compound No. 36)

The title compound was obtained in the same manner as in example 16 using 5-bromosalicylic acid and 3-amino-5-phenylpyrazole as starting materials.

Yield: 9.2 percent of

¹H-NMR(DMSO-d₆)：δ6.98(1H，d，J＝8.8Hz)，7.01(1H，s)，7.35(1H，t，J＝7.6Hz)，7.46(2H，t，J＝7.6Hz)，7.58(1H，dd，J＝8.8，2.8Hz)，7.74-7.76(2H，m)，8.19(1H，s)，10.86(1H，s)，12.09(1H，s)，13.00(1H，brs).

Example 37: 5-bromo-N- (4, 5-diethyloxazol-2-yl) -2-hydroxybenzamide (Compound No. 37)

(1) 2-amino-4, 5-diethyloxazole

Diethyl ketol (プロピオイン) (1.03g, 8.87mmol) was dissolved in ethanol (15mL), cyanamide (0.75g, 17.7mmol) and sodium ethoxide (1.21g, 17.7mmol) were added, 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 organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol 9: 1) to obtain a yellow amorphous form of the title compound (369.2mg, 29.7%).

¹H-NMR(DMSO-d₆)：δ1.04(3H，t，J＝7.5Hz)，1.06(3H，t，J＝7.5Hz)，2.20(2H，q，J＝7.5Hz)，2.43(2H，q，J＝7.5Hz)，6.15(2H，s).

(2) 2-acetoxy-5-bromo-N- (4, 5-diethyloxazol-2-yl) benzamide

The same procedures used in example 24 were repeated using 2-acetoxy-5-bromobenzoic acid and 2-amino-4, 5-diethyloxazole as starting materials to give the title compound (2-acetoxy-5-bromobenzoic acid: see Eur.J.Med.chem., 1996, 31, 861.).

Yield: 22.0 percent

¹H-NMR(CDCl₃)：δ1.22(3H，t，J＝7.5Hz)，1.23(3H，t，J＝7.5Hz)，2.48(2H，q，J＝7.5Hz)，2.57(2H，q，J＝7.5Hz)，6.96(1H，d，J＝8.7Hz)，7.58(1H，dd，J＝8.7，2.7Hz)，8.32(1H，s)，11.40(1H，br).

(3) 5-bromo-N- (4, 5-diethyloxazol-2-yl) -2-hydroxybenzamide

The same procedures as in example 2(2) were carried out using 2-acetoxy-5-bromo-N- (4, 5-diethyloxazol-2-yl) benzamide as a starting material to give the title compound.

Yield: 70.2 percent of

¹H-NMR(CDCl₃)δ：1.25(3H，t，J＝7.5Hz)，1.26(3H，t，J＝7.5Hz)，2.52(2H，q，J＝7.5Hz)，2.60(2H，q，J＝7.5Hz)，6.84(1H，d，J＝8.7Hz)，7.43(1H，dd，J＝8.7，3.0Hz)，8.17(1H，d，J＝3.0Hz)，11.35(1H，br)，12.83(1H，br).

Example 38: 5-bromo-N- (4, 5-diphenyloxazol-2-yl) -2-hydroxybenzamide (Compound No. 38)

The same procedures used in example 16 were repeated except for using 5-bromosalicylic acid and 2-amino-4, 5-diphenyloxazole as starting materials to give the title compound (2-amino-4, 5-diphenyloxazole: see Zh. org. Khim., 1980, 16, 2185.).

Yield: 32.6 percent

Melting point: 188 ℃ C. & 189 DEG C

¹H-NMR(DMSO-d₆，δ)：6.98(1H，d，J＝8.7Hz)，7.40-7.49(6H，m)，7.53-7.56(2H，m)，7.59-7.63(3H，m)，8.01(1H，d，J＝2.4Hz)，11.80(2H，brs).

Example 39: 5-bromo-N- [ 4, 5-bis (furan-2-yl) oxazol-2-yl ] -2-hydroxybenzamide (Compound No. 39)

(1) 2-amino-4, 5-bis (furan-2-yl) oxazole

Furoin (0.50g, 2.60mmol) was dissolved in ethanol (15ml), cyanamide (218.8mg, 5.20mmol) and sodium ethoxide (530.8mg, 7.80mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 1: 1 → 1: 2) to give the title compound as dark brown crystals (175.0mg, 31.1%).

¹H-NMR(DMSO-d₆)：δ6.59(1H，dd，J＝3.3，2.1Hz)，6.62(1H，dd，J＝3.3，2.1Hz)，6.73(1H，dd，J＝3.3，0.6Hz)，6.80(1H，dd，J＝3.3，0.9Hz)，7.05(2H，s)，7.75-7.76(2H，m).

(2) 5-bromo-N- [ 4, 5-bis (furan-2-yl) oxazol-2-yl ] -2-hydroxybenzamide

The same procedures used in example 16 were repeated except for using 5-bromosalicylic acid and 2-amino-4, 5-di (furan-2-yl) oxazole as starting materials to give the title compound.

Yield: 12.9 percent

¹H-NMR(DMSO-d₆)：δ6.65(1H，dd，J＝3.6，1.8Hz)，6.68(1H，dd，J＝3.6，1.8Hz)，6.75(1H，d，J＝8，7Hz)，6.92(1H，dd，J＝3.6，0.9Hz)，6.93(1H，d，J＝3.3Hz)，7.37(1H，dd，J＝8.7，2.7Hz)，7.80(1H，dd，J＝1.8，0.9Hz)，7.84(1H，dd，J＝1.8，0.9Hz)，7.92(1H，d，J＝3.0Hz)，14.88(2H，br).

Example 40: 2-hydroxy-N-5- [ (trifluoromethyl) -1, 3, 4-thiadiazol-2-yl ] benzamide (compound No. 40)

(1) 2-acetoxy-N-5- [ (trifluoromethyl) -1, 3, 4-thiadiazol-2-yl ] benzamide

The same procedures as in example 2(1) were carried out using o-acetylsalicyloyl chloride and 2-amino-5- (trifluoromethyl) -1, 3, 4-thiadiazole as starting materials to give the title compound.

Yield: 51.1 percent

¹H-NMR(DMSO-d₆，δ)：2.23(3H，s)，7.32(1H，dd，J＝8.0，1.2Hz)，7.45(1H，td，J＝7.6，1.2Hz)，7.69(1H，td，J＝8.0，2.0Hz)，7.87(1H，dd，J＝8.0，2.0Hz)，13.75(1H，brs).

(2) 2-hydroxy-N-5- [ (trifluoromethyl) -1, 3, 4-thiadiazol-2-yl ] benzamide

The same procedures used in example 2(2) were repeated except for using 2-acetoxy-N-5- [ (trifluoromethyl) -1, 3, 4-thiadiazol-2-yl ] benzamide as the starting material to give the title compound.

Yield: 92.9 percent

¹H-NMR(DMSO-d₆)：δ7.00(1H，td，J＝8.0，0.8Hz)，7.06(1H，d，J＝8.4Hz)，7.51(1H，ddd，J＝8.4，7.6，2.0Hz)，7.92(1H，dd，J＝8.0，1.6Hz)，12.16(1H，br).

Example 41: 5-bromo-2-hydroxy-N- [ 5- (trifluoromethyl) -1, 3, 4-thiadiazol-2-yl ] benzamide (compound No. 41)

The same procedures used in example 16 were repeated using 5-bromosalicylic acid and 2-amino-5- (trifluoromethyl) -1, 3, 4-thiadiazole as starting materials to give the title compound.

Yield: 80.2 percent

¹H-NMR(DMSO-d₆)：δ7.01(1H，d，J＝9.0Hz)，7.63(1H，dd，J＝8.7，2.7Hz)，7.97(1H，d，J＝2.4Hz).

Example 42: 5-chloro-N- (2-chloropyridin-4-yl) -2-hydroxybenzamide (Compound No. 42)

The same procedures as in example 16 were carried out using 5-chlorosalicylic acid and 4-amino-2-chloropyridine as starting materials to give the title compound.

Yield: 12.2 percent

¹H-NMR(DMSO-d₆)：δ7.04(1H，d，J＝9.0Hz)，7.49(1H，dd，J＝9.0，3.0Hz)，7.54(1H，d，J＝8.4Hz)，7.88(1H，d，J＝2.7Hz)，8.21(1H，dd，J＝8.7，2.7Hz)，8.74(1H，d，J＝2.7Hz)，10.62(1H，s)，11.57(1H，s).

Example 43: 5-chloro-N- (6-chloro-4-methoxypyrimidin-2-yl) -2-hydroxybenzamide (Compound No. 43)

The same operations as in example 16 were carried out using 5-chlorosalicylic acid and 2-amino-6-chloro-4-methoxypyrimidine as starting materials to give the title compound.

Yield: 2.2% white solid

¹H-NMR(DMSO-d₆)：δ3.86(3H，s)，6.85(1H，s)，7.01(1H，d，J＝9.0Hz)，7.47(1H，dd，J＝9.0，3.0Hz)，7.81(1H，d，J＝3.0Hz)，11.08(1H，s)，11.65(1H，s).

Example 44: 2-acetoxy-5-chloro-N- (indol-2-yl) benzamide (compound No. 44)

The title compound was obtained in the same manner as in example 24 using 2-acetoxy-5-chlorosalicylic acid and 2-aminoindole as starting materials.

Yield: 13.3 percent

¹H-NMR(DMSO-d₆)：δ2.20(3H，s)，6.41(1H，t，J＝2.1Hz)，7.27-7.36(4H，m)，7.63(1H，dd，J＝8.7，2.7Hz)，7.74(1H，d，J＝2.7Hz)，7.93(1H，s)，10.21(1H，s)，11.04(1H，s).

Example 45: 7- [ (2-Acetoxybenzoyl) amino ] indole-3-carboxylic acid ethyl ester (Compound No. 45)

The present compounds are commercially available compounds.

And (4) selling places: peakdale Inc

The catalog number of the commodity: PFC-0448

Example 46: 5-chloro-2-hydroxy-N- (quinolin-3-yl) benzamide (compound No. 46)

The title compound was obtained in the same manner as in example 16 using 5-chlorosalicylic acid and 2-aminoquinoline as starting materials.

Yield: 4.3 percent of

¹H-NMR(DMSO-d₆)：δ7.07(1H，d，J＝8.7Hz)，7.51(1H，dd，J＝9.0，3.0Hz)，7.61(1H，dt，J＝7.8，1.2Hz)，7.70(1H，dt，J＝7.8，1.5Hz)，7.98(2H，d，J＝3.0Hz)，8.01(1H，s)，8.82(1H，d，J＝2.4H z)，10.80(1H，s)，11.74(1H，s).

Example 47: n- (9-Ethylcarbazol-3-yl) -5-chloro-2-hydroxybenzamide (Compound No. 47)

The same operations as in example 16 were carried out using 5-aminosalicylic acid and 3-amino-9-ethylcarbazole as starting materials to obtain the title compound.

Yield: 64.6 percent

¹H-NMR(DMSO-d₆)：δ1.33(3H，t，J＝7.0Hz)，4.46(2H，q，J＝7.0Hz)，7.04(1H，d，J＝9.0Hz)，7.21(1H，t，J＝7.3Hz)，7.45-7.52(2H，m)，7.64-7.65(2H，m)，7.70(1H，d，J＝8.4，1.9Hz)，8.11-8.15(2H，m)，8.49(1H，d，J＝1.9Hz)，10.55(1H，s)，12.22(1H，s).

Example 48: 2-acetoxy- [ 3, 5-bis (trifluoromethyl) phenyl ] benzamide (Compound No. 95)

The same procedures as in example 2(1) were carried out using o-acetylsalicyloyl chloride and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 84.2 percent of

¹H-NMR(DMSO-d₆)：δ2.36(3H，s)，7.19(1H，dd，J＝8.0，1.2Hz)，7.39(1H，td，J＝7.6，1.2Hz)，7.57(1H，ddd，J＝8.0，7.6，1.6Hz)，7.65(1H，s)，7.83(1H，dd，J＝8.0，1.6Hz)，8.11(2H，s)，8.31(1H，s).

Example 49: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxybenzamide (Compound No. 48)

The same procedures as in example 2(2) were carried out using 2-acetoxy- [ 3, 5-bis (trifluoromethyl) phenyl ] benzamide as the starting material to give the title compound.

Yield: 45.1 percent of

¹H-NMR(DMSO-d₆)：δ6.96-7.02(2H，m)，7.45(1H，ddd，J＝8.0，7.2，1.6Hz)，7.81(1H，s)，7.87(1H，dd，J＝8.0，1.6Hz)，8.46(2H，s)，10.80(1H，s)，11.26(1H，s).

Example 50: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-fluoro-2-hydroxybenzamide (Compound No. 49)

The same operations as in example 16 were carried out using 5-fluorosalicylic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 58.7 percent

¹H-NMR(DMSO-d₆)：δ7.04(1H，ddd，J＝9.0，4.5，1.2Hz)，7.30-7.37(1H，m)，7.66(1H，ddd，J＝9.0，3.3，1.2Hz)，7.84(1H，s)，8.46(2H，s)，10.85(1H，s)，11.21(1H，brs).

Example 51: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-chloro-2-hydroxybenzamide (Compound No. 50)

The same operations as in example 16 were carried out using 5-chlorosalicylic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.

Yield: 85.5 percent

¹H-NMR(DMSO-d₆)：δ7.05(1H，d，J＝8.7Hz)，7.49(1H，dd，J＝8.7，2.7Hz)，7.85(1H，s)，7.87(1H，d，J＝2.7Hz)，8.45(2H，s)，10.85(1H，s)，11.39(1H，s).

Example 52: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-bromo-2-hydroxybenzamide (Compound No. 51)

The same procedures used in example 16 were repeated using 5-bromosalicylic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 88.5 percent

¹H-NMR(DMSO-d₆)：δ6.98(1H，d，J＝8.8Hz)，7.59(1H，dd，J＝8.8，2.8Hz)，7.83(1H，s)，7.98(1H，d，J＝2.8Hz)，8.43(2H，s)，10.82(1H，s)，11.37(1H，s).

Example 53: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-iodobenzamide (Compound No. 52)

The same operations as in example 16 were carried out using 5-iodosalicylic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 62.2 percent

¹H-NMR(DMSO-d₆)：δ6.86(1H，d，J＝8.4Hz)，7.74(1H，dd，J＝8.7，2.4Hz)，7.84(1H，s)，8.13(1H，d，J＝2.1Hz)，8.84(2H，s)，10.82(1H，s)，11.41(1H，s).

Example 54: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-nitrobenzamide (Compound No. 53)

The same procedures as in example 16 were carried out using 5-nitrosalicylic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 57.2 percent

¹H-NMR(DMSO-d₆)：7.18(1H，d，J＝9.0Hz)，7.86(1H，s)，8.81(1H，dd，J＝9.0，3.0Hz)，8.45(2H，s)，8.70(1H，d，J＝3.0Hz)，11.12(1H，s).

Example 55: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-cyano-2-hydroxybenzamide (Compound No. 54)

The same procedures as in example 16 were carried out using 5-cyanosalicylic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 16.6 percent

¹H-NMR(DMSO-d₆)：δ7.15(1H，d，J＝8.7Hz)，7.85(1H，s)，7.86(1H，dd，J＝8.7，2.1Hz)，8.22(1H，d，J＝2.4Hz)，8.43(2H，s)，10.93(1H，s)，12.00(1H，brs).

Example 56: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-methylbenzamide (Compound No. 55)

The same procedures as in example 16 were carried out using 5-methylsalicylic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 54.9 percent

¹H-NMR(DMSO-d₆)：δ6.92(1H，d，J＝8.7Hz)，7.28(1H，dd，J＝8.7，1.8Hz)，7.71(1H，d，J＝1.8Hz)，7.82(1H，s)，8.47(2H，s)，10.80(1H，s)，11.14(1H，s).

Example 57: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -5- (1, 1-dimethyl) ethyl-2-hydroxybenzamide (Compound No. 56)

The same procedures used in example 16 were repeated using 5- [ (1, 1-dimethyl) ethyl ] salicylic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound. Yield: 53.8 percent

¹H-NMR(DMSO-d₆)：δ1.30(9H，s)，6.96(1H，d，J＝8.7Hz)，7.50(1H，dd，J＝8.7，2.4Hz)，7.82(1H，d，J＝2.4Hz)，7.83(1H，s)，8.46(2H，s)，10.80(1H，s)11.12(1H，s).

Example 58: 5-acetyl-N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxybenzamide (Compound No. 78)

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

A mixture of methyl 5-acetylsalicylate (13.59g, 70mmol), benzyl bromide (17.96g, 105mmol), potassium carbonate (19.35g, 140mmol), and methyl ethyl ketone (350mL) was heated under reflux for 8 hours. After cooling, the solvent was distilled off under reduced pressure, and 2N hydrochloric acid was added to the residue to conduct extraction with ethyl acetate. After washing with water and saturated brine, drying over anhydrous magnesium sulfate and concentrating, the residue was recrystallized from isopropyl ether to give the title compound as a white solid (14.20g, 71.4%).

¹H-NMR(CDCl₃)：δ2.58(3H，s)，3.93(3H，s)，5.27(2H，s)，7.07(1H，d，J＝8.7Hz)，7.26-7.43(3H，m)，7.47-7.50(2H，m)，8.07(1H，dd，J＝8.7，2.4Hz)，8.44(1H，d，J＝2.4Hz).

(2) 5-acetyl-2-benzyloxy benzoic acid

Methyl 5-acetyl-2-benzyloxybenzoate (5.69g, 20mmol) was dissolved in a mixed solvent of methanol (20mL) and tetrahydrofuran (20mL), and 2N sodium hydroxide (11mL) was added dropwise thereto and the mixture was stirred for 8 hours. The solvent was distilled off under reduced pressure, and 2N hydrochloric acid was added to the residue to conduct extraction with methylene chloride. After washing with water and saturated brine, drying over anhydrous magnesium sulfate and concentration, the residue was washed with isopropyl ether to give the title compound as a white solid (4.92g, 91.0%).

¹H-NMR(DMSO-d₆)：δ2.55(3H，s)，5.32(2H，s)，7.30-7.43(4H，m)，7.49-7.52(2H，m)，8.09(1H，dd，J＝9.0，2.7Hz)，8.22(1H，d，J＝2.4Hz).

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

The same procedures used in example 24 were repeated using 5-acetyl-2-benzyloxybenzoic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound as a yellowish green solid (5.47g, 63.1%).

¹H-NMR(DMSO-d₆)：δ2.57(3H，s)，7.11(1H，d，J＝8.7Hz)，7.86(1H，s)，8.05(1H，dd，J＝8.4，2.1Hz)，8.44(1H，d，J＝2.1Hz)，8.47(2H，s)，10.96(1H，s)，11.97(1H，brs).

(4) Preparation of 5-acetyl-N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxybenzamide

To 5-acetyl-2-benzyloxy-N- [ 3, 5-bis (trifluoromethyl) phenyl ] benzamide (602mg, 1.25mmol) and 5% palladium on carbon (60mg) were added ethanol (6mL) and tetrahydrofuran (72mL), and the mixture was hydrogenated at room temperature for 30 minutes. After insoluble matter was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was recrystallized from n-hexane-ethyl acetate to give the title compound as a white solid (230mg, 47.0%).

¹H-NMR(DMSO-d₆)：δ2.59(3H，s)，5.35(2H，s)，7.32-7.36(3H，m)，7.43(1H，d，J＝8.7Hz)，7.52-7.55(2H，m)，7.82(1H，s)，8.16(1H，dd，J＝8.7，2.4Hz)，8.25(1H，d，J＝2.4Hz)，8.31(2H，s)，10.89(1H，s).

Example 59: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (1-hydroxyethyl) benzamide (compound No. 57)

5-acetyl-N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxybenzamide (50.5mg, 0.13mmol) was suspended in ethanol (2mL), and sodium borohydride (23.6mg, 0.62mmol) was added thereto, followed by stirring at room temperature for 12 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then distilled under reduced pressure, and the obtained residue was washed with isopropyl ether/n-hexane suspension to obtain a white powder of the title compound (39.7mg, 78.3%).

¹H-NMR(DMSO-d₆)：δ1.34(3H，d，J＝6.3Hz)，4.71(1H，q，J＝6.3Hz)，5.18(1H，brs)，6.97(1H，d，J＝8.4Hz)，7.44(1H，dd，J＝8.4，2.1Hz)，7.84(1H，s)，7.86(1H，d，J＝2.1Hz)，8.48(2H，s)，10.85(1H，s)，11.32(1H，s).

Example 60: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- [ (1-methoxyimino) ethyl ] benzamide (compound No. 58)

5-acetyl-N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxybenzamide (100.0mg, 0.26mmol) was dissolved in ethanol (3mL), pyridine (45. mu.L, 0.56mmol) and o-methylhydroxylamine hydrochloride (25.8mg, 0.31mmol) were added, and the mixture was refluxed for 1 hour. After cooling, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to obtain the title compound as white crystals (102.1mg, 95.3%).

¹H-NMR(DMSO-d₆)：δ2.19(3H，s)，3.91(3H，s)，7.05(1H，d，J＝8.7Hz)，7.77(1H，dd，J＝8.7，2.4Hz)，7.85(1H，s)，8.09(1H，d，J＝2.4Hz)，8.47(2H，s)，10.87(1H，s)，11.48(1H，s).

Example 61: 5- [ (1-Benzyloxyimino) ethyl ] -N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxybenzamide (Compound No. 59)

The same procedures as in example 60 were carried out using 5-acetyl- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxybenzamide and o-benzylhydroxylamine hydrochloride as starting materials to obtain the title compound.

Yield: 79.9 percent

¹H-NMR(DMSO-d₆)：δ2.24(3H，s)，5.20(2H，s)，7.04(1H，d，J＝8.7Hz)，7.29-7.47(5H，m)，7.76(1H，dd，J＝8.7，2.4Hz)，7.85(1H，s)，8.07(1H，d，J＝2.1Hz)，8.46(2H，s)，10.87(1H，s)，11.47(1H，s).

Example 62: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -5- (2, 2-dicyanoethylene-1-yl) -2-hydroxybenzamide (compound No. 60)

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

Malononitrile (132mg, 2mmol) was dissolved in ethanol (6mL), 5-formylsalicylic acid (332mg, 2mmol) was added, and after cooling in an ice bath, benzylamine (0.1mL) was added and stirred at room temperature for 2 hours. The precipitated yellow crystals were collected by filtration and recrystallized (ethanol) to give the title compound as a pale yellow solid (139.9mg, 32.7%).

¹H-NMR(DMSO-d₆)：δ7.12(1H，d，J＝8.7Hz)，8.09(1H，dd，J＝8.7，2.4Hz)，8.41(1H，s)，8.50(1H，d，J＝2.4Hz).

(2) N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5- (2, 2-dicyanoethylene-1-yl) -2-hydroxybenzamide

The same procedures used in example 16 were repeated using 5- (2, 2-dicyanoethylene-1-yl) -2-hydroxybenzoic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 9.1 percent of

¹H-NMR(DMSO-d₆)：δ7.13(1H，d，J＝9.0Hz)，7.83(1H，s)，8.04(1H，dd，J＝9.0，2.4Hz)，8.36(1H，s)，8.38(1H，d，J＝2.4Hz)，8.43(2H，s)，11.43(1H，s).

Example 63: methyl 3- ({ N- [ 3, 5-bis (trifluoromethyl) phenyl ] carbamoyl } -4-hydroxyphenyl) -2-cyanoacrylate (Compound No. 62)

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

Triethylamine (0.2mL) was added to a mixture of 5-formylsalicylic acid (332mg, 2mmol), methyl cyanoacetate (198mg, 2mmol 1) and acetic acid (6mL), and the mixture was refluxed for 5 hours. After cooling, the reaction mixture was poured into water, and the precipitated crystals were collected by filtration and recrystallized (n-hexane) to give the title compound as a pale yellow solid (327.7mg, 66.3%).

¹H-NMR(DMSO-d₆)：δ3.85(3H，s)，7.15(1H，d，J＝8.7Hz)，8.20(1H，dd，J＝8.7，2.4Hz)，8.37(1H，s)，8.66(1H，d，J＝2.4Hz).

(2)3- ({ N- [ 3, 5-bis (trifluoromethyl) phenyl ] carbamoyl } -4-hydroxyphenyl) -2-cyanoacrylic acid methyl ester

The same procedures used in example 16 were repeated using 5- [ (2-cyano-2-methoxycarbonyl) ethen-1-yl ] -2-hydroxybenzoic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 66.3 percent

Example 64: 3- ({ N- [ 3, 5-bis (trifluoromethyl) phenyl ] carbamoyl } -4-hydroxyphenyl) -2-cyanoacrylic acid (Compound No. 61)

Methyl 3- ({ N- [ 3, 5-bis (trifluoromethyl) phenyl ] carbamoyl } -4-hydroxyphenyl) -2-cyanoacrylate (50mg, 0.11mmol) was dissolved in ethanol (5mL), and 2N sodium hydroxide (0.11mL, 0.22mmol) was added and stirred at room temperature for 3 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure, and the obtained residue was recrystallized (ethyl acetate) to obtain the title compound as a pale yellow solid (13.5mg, 30.4%).

¹H-NMR(DMSO-d₆)：δ7.12(1H，d，J＝8.4Hz)，7.84(1H，s)，7.94(1H，dd，J＝8.4，2.1Hz)，8.38(1H，d，J＝2.1Hz)，8.45(2H，s)，9.87(1H，s)，11.41(1H，s).

Example 65: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (2-phenylethen-1-yl) benzamide (compound No. 63)

A mixture of N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-iodobenzamide (475mg, 1mmol), styrene (130mg, 1.25mmol), palladium acetate (4.5mg, 0.02mmol), tris (o-tolyl) phosphine (12.2mg, 0.04mmol), diisopropylamine (388mg, 3mmol), N-dimethylformamide (2mL) was added to reflux for 8 hours. After cooling, water was added and extracted with ethyl acetate. After washing with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated, the residue was purified by silica gel column chromatography (hexane-isopropyl ether: 2/1 → 1/1) to give the title compound as a pale yellow solid (173mg, 38.3%).

¹H-NMR(DMSO-d₆)：δ7.04(1H，d，J＝8.4Hz)，7.20-7.29(3H，m)，7.38(2H，t，J＝7.5Hz)，7.59(2H，d，J＝7.5Hz)，7.72(1H，dd，J＝8.4，2.1Hz)，7.86(1H，s)，8.07(1H，d，J＝2.1Hz)，8.49(2H，s)，10.89(1H，s)，11.33(1H，brs).

Example 66: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- [ (trimethylsilyl) ethynyl ] benzamide (compound No. 66)

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-iodobenzamide (950mg, 2mmol), trimethylsilylacetylene (246mg, 2.5mmol) were dissolved in triethylamine (2mL) and N, N-dimethylformamide (4mL), and tetrakis (triphenylphosphine) palladium (23mg, 0.02mmol) and cuprous iodide (4mg, 0.02mmol) were added under an argon atmosphere, followed by stirring at 40 ℃ for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into ethyl acetate (100mL) and 1N citric acid (100mL), and stirred, followed by filtration through celite. The ethyl acetate layer was washed with water and saturated brine in this order, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate: 19: 1) to obtain a light orange solid. Crystallization from n-hexane gave the title compound as white crystals (286mg, 32.1%).

¹H-NMR(DMSO-d₆)：δ0.23(9H，s)，7.00(1H，d，J＝8.7Hz)，7.54(1H，dd，J＝8.7，2.4Hz)，7.85(1H，s)，7.98(1H，d，J＝2.1Hz)，8.46(2H，s)，10.86(1H，s)，11.69(1H，s).

Example 67: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-ethynyl-2-hydroxybenzamide (compound No. 64)

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- [ (trimethylsilyl) ethynyl ] benzamide (233mg, 0.5mmol) was dissolved in methanol (1mL), and 2N sodium hydroxide (1mL) was added, followed by stirring 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 with water and saturated brine in this order, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was crystallized from ethanol-water to give the title compound as off-white crystals (67mg, 35.9%).

¹H-NMR(DMSO-d₆)：δ4.11(1H，s)，7.02(1H，d，J＝8.4Hz)，7.55(1H，dd，J＝8.4，2.1Hz)，7.85(1H，s)，7.98(1J，d，J＝2.1Hz)，8.46(2H，s)，8.46(2H，s)，10.86(1H，s)，11.62(1H，s).

Example 68: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (phenylethynyl) benzamide (compound number 65)

The same procedures used in example 66 were repeated using N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-iodobenzamide and phenylacetylene as starting materials to give the title compound.

¹H-NMR(DMSO-d₆)：δ7.06(1H，d，J＝8.4Hz)，7.42-7.46(3H，m)，7.53-7.57(2H，m)，7.64(1H，dd，J＝8.7，2.1Hz)，7.86(1H，s)，8.06(1H，d，J＝2.1H z)，8.48(2H，s)，10.94(1H，s)，11.64(1H，brs).

Example 69: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -4-hydroxybiphenyl-3-carboxamide (Compound No. 67)

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-iodobenzamide (200mg, 0.42mmol) was dissolved in 1, 2-dimethoxyethane (3mL), and tetrakis (triphenylphosphine) palladium (16mg, 0.0014mmol) was added under an argon atmosphere, followed by stirring at room temperature for 5 minutes. Next, dihydroxybenzylborane (57mg, 0.47mmol) and 1M sodium carbonate (1.3mL) were added, followed by heating and refluxing for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate ═ 6: 1 → 3: 1) to give the title compound as white crystals (109mg, 61.1%).

¹H-NMR(DMSO-d₆)：δ7.12(1H，d，J＝8.7Hz)，7.33-7.38(1H，m)，7.48(2H，t，J＝7.5Hz)，7.67-7.70(2H，m)，7.79(1H，dd，J＝8.4，2.4Hz)，7.87(1H，s)，8.17(1H，d，J＝2.4H z)，8.49(2H，s)，10.92(1H，s)，11.41(1H，s).

Example 70: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (2-phenylethyl) benzamide (compound number 68)

The title compound was obtained in the same manner as in example 58(4) using N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (phenylethynyl) benzamide as a starting material.

Yield: 86.2 percent

¹H-NMR(DMSO-d₆)：2.88(4H，s)，6.93(1H，d，J＝8.1Hz)，7.15-7.34(6H，m)，7.76(1H，d，J＝2.4Hz)，7.84(1H，s)，8.47(2H，s)，10.79(1H，s)，11.15(1H，s).

Example 71: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (trifluoromethyl) benzamide (compound No. 69)

The same procedures used in example 16 were repeated using 2-hydroxy-5- (trifluoromethyl) benzoic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound (2-hydroxy-5- (trifluoromethyl) benzoic acid: see chem. pharm. Bull, 1996, 44, 734.).

Yield: 44.7 percent

¹H-NMR(CDCl₃，δ)：7.17(1H，d，J＝9.0Hz)7.72-7.75(2H，m)，7.86(1H，s)，8.17(2H，s)，8.35(1H，s)11.88(1H，s).

Example 72: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (pentafluoroethyl) benzamide (compound No. 70)

The same procedures used in example 16 were repeated using 2-hydroxy-5- (pentafluoroethyl) benzoic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound (2-hydroxy-5- (pentafluoroethyl) benzoic acid: see chem. pharm. Bull, 1996, 44, 734.).

Yield: 65.7 percent

¹H-NMR(CDC1₃，δ)：7.19(1H，d，J＝9.0Hz)7.70(1H，dd，J＝8.7，2.1Hz)，7.81(1H，d，J＝2.1Hz)，8.17(2H，s)，8.37(1H，s)，11.92(1H，s).

Example 73: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (pyrrol-1-yl) benzamide (compound No. 71)

The same procedures used in example 16 were repeated using 2-hydroxy-5- (pyrrol-1-yl) benzoic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound. Yield: 57.8 percent

¹H-NMR(DMSO-d₆)：δ6.27(2H，dd，J＝2.4，1.8Hz)，7.10(1H，d，J＝9.0Hz)，7.29(2H，dd，J＝2.4，1.8Hz)，7.66(1H，dd，J＝9.0，2.7Hz)，7.86(1H，s)，7.98(1H，d，J＝2.4Hz)，8.47(2H，s)，10.89(1H，s)，11.24(1H，s).

Example 74: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (thien-2-yl) benzamide (compound number 72)

The same procedures used in example 69 were repeated using N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-iodobenzamide and 2-thiopheneboronic acid as starting materials to give the title compound.

¹H-NMR(DMSO-d₆)：δ7.08(1H，d，J＝8.4Hz)，7.14(1H，dd，J＝5.4，3.6Hz)，7.45(1H，dd，J＝3.6，1.2Hz)，7.51(1H，dd，J＝5.1，0.9Hz)，7.75(1H，dd，J＝8.4，2.4Hz)，7.59(1H，s)，8.08(1H，d，J＝2.4Hz)，8.48(2H，s)，10.91(1H，s)，11.38(1H，s).

Example 75: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (thien-3-yl) benzamide (compound No. 73)

The same procedures used in example 69 were repeated using N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-iodobenzamide and 3-thiopheneboronic acid as starting materials to give the title compound.

Yield: 38.7 percent

¹H-NMR(DMSO-d₆)：δ7.06(1H，d，J＝8.7Hz)，7.57(1H，dd，J＝4.8，1.5Hz)，7.66(1H，dd，J＝4.8，3.0Hz)，7.81-7.84(2H，m)，7.86(1H，s)，8.18(1H，d，J＝2.1Hz)，8.49(2H，s)，10.90(1H，s)，11.33(1H，s).

Example 76: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (2-methylthiazol-4-yl) benzamide (compound number 75)

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

5-acetyl-2-benzyloxy-N- [ 3, 5-bis (trifluoromethyl) phenyl ] benzamide (4.81g, 10mmol) was dissolved in THF (30ml), phenyltrimethylammonium tribromide (3.75g, 10mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium bisulfite solution, water and saturated brine, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1), followed by recrystallization (ethyl acetate/hexane), to give the title compound as a white solid (2.39g, 42.7%).

¹H-NMR(DMSO-d₆)：δ4.91(2H，s)，5.36(2H，s)，7.32-7.35(3H，m)，7.47(1H，d，J＝9.0Hz)，7.52-7.56(2H，m)，7.82(1H，s)，8.21(1H，dd，J＝8.7，2.4Hz)，8.29(1H，d，J＝2.4Hz)，8.31(2H，s)，10.91(1H，s).

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

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

¹H-NMR(DMSO-d₆)：δ2.72(3H，s)，5.29(2H，s)，7.33-7.36(3H，m)，7.40(1H，d，J＝9.0Hz)，7.54-7.57(2H，m)，7.81(1H，s)，7.94(1H，s)，8.12(1H，dd，J＝8.7，2.1Hz)，8.27(1H，d，J＝2.1Hz)，8.31(2H，s)，10.86(1H，s).

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

2-benzyloxy-N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5- (2-methylthiazol-4-yl) benzamide (160mg, 0.3mmol) and 10% Pd-C (240mg) were dissolved in ethanol (10ml), and the mixture was stirred under a hydrogen atmosphere for 3.5 hours. The reaction mixture was filtered, and the filtrate was distilled under reduced pressure to give the title compound as a white solid (103.4mg, 79.2%).

¹H-NMR(DMSO-d₆)：δ2.72(3H，s)，7.08(1H，d，J＝8.7Hz)，7.83(1H，s)，7.85(1H，s)，8.01(1H，dd，J＝8.7，2.4Hz)，8.42(1H，d，J＝2.1Hz)，8.50(2H，s)，10.96(1H，s)，11.40(1H，s).

Example 77: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (imidazo [ 1, 2-a ] pyridin-2-yl) benzamide (compound number 75)

A mixture of 2-benzyloxy-5- (2-bromoacetyl) -N- [ 3, 5-bis (trifluoromethyl) phenyl ] benzamide (280mg, 0.5mmol), 2-aminopyridine (51.8mg, 0.55mmol), sodium bicarbonate (50mg, 0.6mmol), and ethanol (10mL) was heated under reflux for 2 hours. After cooling, the reaction mixture was poured into an aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 1: 2) to obtain the title compound as a white solid (130.3mg, 46.9%). Subsequently, a mixture of the solid (108mg, 0.19mmol), 10% Pd-C (11mg), ethanol (8mL), and ethyl acetate (8mL) was stirred under hydrogen atmosphere for 7 hours. The reaction mixture was filtered, the filtrate was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate ═ 1: 3) to obtain the title compound as a white solid (18.3mg, 20.2%).

¹H-NMR(DMSO-d₆)：δ6.90(1H，dt，J＝6.6，0.9Hz)，7.10(1H，d，J＝8.7Hz)，7.25(1H，m)，7.57(1H，d，J＝9.0Hz)，7.86(1H，s)，8.04(1H，dd，J＝8.7，2.1Hz)，8.35(1H，s)，8.48-8.56(4H，m)，11.00(1H，s)，11.41(1H，s).

Example 78: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (pyridin-2-yl) benzamide (compound No. 76)

(1) N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-iodo-2-methoxymethyloxybenzamide

A mixture of N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-iodobenzamide (4.75g, 10mmol), chloromethyl methyl ether (1.14mL, 15mmol), potassium carbonate (2.76g, 20mmol), acetone (50mL) was heated under reflux for 8 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate: 3: 1), followed by recrystallization (hexane/ethyl acetate), to obtain the title compound as a white solid (3.96g, 76.3%).

¹H-NMR(DMSO-d₆)：δ3.38(3H，s)，5.28(2H，s)，7.12(1H，d，J＝9.0Hz)，7.81(1H，s)，7.82(1H，dd，J＝8.7，2.4Hz)，7.88(1H，d，J＝2.4Hz)，8.40(2H，s)，10.87(1H，s).

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

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-iodo-2-methoxymethyloxybenzamide (0.20g, 0.39mmol) was dissolved in N, N-dimethylformamide (8ml), and tri-N-butyl (2-pyridyl) tin (0.13ml, 0.41mmol) and dichlorobis (triphenylphosphine) palladium (32.1mg, 0.05mmol) were added to stir at 100 ℃ for 1.5 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate ═ 2: 1 → 1: 1) to obtain a white powder of the title compound (37.9mg, 20.8%).

¹H-NMR(CDCl₃)：δ3.64(3H，s)，5.53(2H，s)，7.23-7.28(1H，m)，7.36(1H，d，J＝8.7Hz)，7.65(1H，s)，7.77-7.84(2H，m)，8.20(2H，s)，8.31(1H，dd，J＝8.7，2.4Hz)，8.68-8.70(1H，m)，8.83(1H，d，J＝2.4Hz)，10.12(1H，s).

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

To N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-methoxymethyloxy-5- (pyridin-2-yl) benzamide (37.9mg, 0.08mmol) were added methanol (3ml) and concentrated hydrochloric acid (0.5ml), and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate: 2: 1) to obtain a white powder of the title compound (16.2mg, 47.2%).

¹H-NMR(DMSO-d₆)：δ7.13(1H，d，J＝8.4Hz)，7.33(1H，ddd，J＝7.5，6.3，1.2Hz)，7.86-7.91(2H，m)，7.97(1H，d，J＝7.8Hz)，8.20(1H，dd，J＝8.7，2.1Hz)，8.50(2H，s)，8.59(1H，d，J＝2.4Hz)，8.64-8.66(1H，m)，10.97(1H，s)，11.53(1H，s).

Example 79: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-methoxybenzamide (Compound No. 77)

The same procedures used in example 16 were repeated using 5-methoxysalicylic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 56.8 percent

¹H-NMR(DMSO-d₆)：δ3.77(3H，s)，6.97(1H，d，J＝9.0Hz)，7.10(1H，dd，J＝9.0，3.0Hz)，7.43(1H，d，J＝3.0Hz)，7.84(1H，s)，8.47(2H，s)，10.84(1H，s)，10.91(1H，s).

Example 80: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-isobutyrylbenzamide (Compound No. 79)

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

A mixture of methyl 5-acetylsalicylate (5.00g, 25.7mmol), potassium carbonate (7.10g, 51.4mmol) and N, N-dimethylformamide (25mL) was cooled in an ice bath, and methyl iodide (2.5mL, 40.1mmol) 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 organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then distilled under reduced pressure, and the obtained residue was washed with suspension (isopropyl ether/n-hexane) to obtain white crystals (5.17g, 96.5%) of the title compound.

¹H-NMR(CDCl₃)：δ2.59(3H，s)，3.92(3H，s)，3.99(3H，s)，7.04(1H，d，J＝8.7Hz)，8.12(1H，dd，J＝8.7，2.4Hz)，8.41(1H，d，J＝2.4Hz).

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

A mixture of methyl 5-acetyl-2-methoxybenzoate (0.50g, 2.40mmol), potassium tert-butoxide (0.81g, 7.22mmol) and tetrahydrofuran (10mL) was cooled in an ice bath, and methyl iodide (0.5mL, 8.03mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, neutralized with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 3: 1 → 2: 1) to give the title compound as a pale yellow oil (143.1mg, 25.2%).

¹H-NMR(CDCl₃)：δ1.22(6H，d，J＝6.9Hz)，3.52(1H，m)，3.92(3H，s)，3.98(3H，s)，7.05(1H，d，J＝8.7Hz)，8.13(1H，dd，J＝8.7，2.4Hz)，8.42(1H，d，J＝2.4Hz).

(3) 5-isobutyryl-2-methoxybenzoic acid

Methyl 5-isobutyryl-2-methoxybenzoate (143.1mg, 0.60mmol) was dissolved in methanol (5mL), and 2N sodium hydroxide solution (1mL) was added thereto, followed by heating and refluxing for 1 hour. After cooling, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to give the title compound as white crystals (134mg, yield: quantitative).

¹H-NMR(CDCl₃)：δ1.22(6H，d，J＝6.9Hz)，3.59(1H，m)，4.15(3H，s)，7.16(1H，d，J＝8.7Hz)，8.24(1H，dd，J＝8.7，2.4Hz)，8.73(1H，d，J＝2.1Hz).

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

The same procedures used in example 16 were repeated using 5-isobutyryl-2-methoxybenzoic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

¹H-NMR(CDC1₃)：δ1.23(6H，d，J＝6.9Hz)，3.64(1H，m)，4.20(3H，s)，7.18(1H，d，J＝8.7Hz)，7.65(1H，s)，8.19(2H，s)，8.22(1H，dd，J＝8.7，2.1Hz)，8.88(1H，d，J＝2.1Hz)，9.98(1H，s).

(5) N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-isobutyrylbenzamide

A mixture of 5-butyryl-N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-methoxybenzamide (143.4mg, 0.33mmol), 2, 4, 6-collidine (3ml) and lithium iodide (53.1mg, 0.40mmol) was heated under reflux for 1 hour. After cooling, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 3: 1) to crystallize (ethyl acetate/isopropyl ether), thereby obtaining white crystals of the title compound (90.3mg, 65.3%).

¹H-NMR(DMSO-d₆)：δ1.12(6H，d，J＝6.9Hz)，3.66(1H，m)，7.12(1H，d，J＝8.4Hz)，7.85(1H，s)，8.07(1H，dd，J＝8.4，2.4Hz)，8.45(1H，d，J＝2.4Hz)，8.47(2H，s)，10.93(1H，s)，11.95(1H，brs).

Example 81: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -4-hydroxym-benzenedicarboxamic acid methyl ester (Compound No. 81)

The same procedures used in example 16 were repeated except for using 1-methyl 4-hydroxyisophthalate and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 91.5 percent

¹H-NMR(DMSO-d₆)：δ3.85(3H，s)，7.12(1H，d，J＝8.4Hz)，7.86(1H，s)，8.02(1H，dd，J＝8.7，2.4Hz)，8.46-8.47(3H，m)，10.96(1H，s)，12.03(1H，brs).

Example 82: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -4-hydroxyisophthalic acid (Compound No. 80)

Methyl N- [ 3, 5-bis (trifluoromethyl) phenyl ] -4-hydroxyisophthalate (2.85g, 7mmol) was suspended in a mixed solvent of methanol (14mL) and tetrahydrofuran (14mL), and a 2N aqueous sodium hydroxide solution (14mL) was added dropwise, followed by heating and refluxing for 2 hours. After cooling, 2N hydrochloric acid (20ml) was added, and the precipitated solid was collected by filtration, washed with water, and dried to obtain the title compound as white crystals (2.68g, 97.4%).

¹H-NMR(DMSO-d₆)：δ7.10(1H，d，J＝8.7Hz)，7.82(1H，s)，7.86(1H，s)，8.01(1H，dd，J＝8.7，2.4Hz)，8.47(2H，s)，8.48(1H，d，J＝2.4Hz)，10.97(1H，s)，11.98(1H，brs).

Example 83: n is a radical of¹，N³-bis [ 3, 5-bis (trifluoromethyl) phenyl ] -4-hydroxyisophthalamide (Compound No. 82)

The same procedures used in example 16 were repeated except for using 4-hydroxyisophthalic acid (182mg, 1mmol), 3, 5-bis (trifluoromethyl) aniline (687mg, 3mmol), phosphorus trichloride (87. mu.l, 1mmol) and toluene (10mL) to give the title compound as white crystals (151mg, 25.0%).

¹H-NMR(DMSO-d₆)：δ7.18(1H，d，J＝8.7Hz)，7.82(1H，s)，7.86(1H，s)，8.11(1H，dd，J＝8.7，2.4Hz)，8.50(2H，s)，8.84(2H，s)，8.56(1H，d，J＝2.4Hz)，10.79(1H，s)，10.99(1H，s)，11.84(1H，brs).

Example 84: n is a radical of³- [ 3, 5-bis (trifluoromethyl) phenyl ] -4-hydroxy-N¹，N¹-dimethyl isophthalamide (Compound No. 83)

(1) 4-Phenylmethoxy-N- [ 3, 5-bis (trifluoromethyl) phenyl ] m-benzenedimethanoic acid methyl ester

Sodium hydride (60%; 1.04g, 26mmol) was washed with N-hexane, suspended in N, N-dimethylformamide (100mL), and a solution of methyl N- [ 3, 5-bis (trifluoromethyl) phenyl ] -4-hydroxyisophthalate (8.15g, 20mmol) in N, N-dimethylformamide (100mL) was added dropwise while cooling in an ice bath. After the completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour, and then a solution of benzyl bromide (4.45g, 26mmol) in N, N-dimethylformamide (10mL) was added thereto, followed by stirring at 60 ℃ for 3 hours. After cooling, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure, and the obtained residue was recrystallized (ethyl acetate/n-hexane) to obtain the title compound as a white solid (5.38g, 54.1%).

¹H-NMR(DMSO-d₆)：δ3.87(3H，s)，5.33(2H，s)，7.33-7.36(3H，m)，7.46(1H，d，J＝8.7H z)，7.53-7.56(2H，m)，7.82(1H，s)，8.15(1H，dd，J＝8.7，2.1Hz)，8.25(1H，d，J＝2.1Hz)8.28(2H，s)，10.87(1H，s).

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

The same procedures used in example 82 were repeated except for using 4-benzyloxy-N- [ 3, 5-bis (trifluoromethyl) phenyl ] m-xylylene diamine methyl ester as a starting material to give the title compound.

Yield: 79.7 percent

¹H-NMR(DMSO-d₆)：δ5.32(2H，s)，7.32-7.34(3H，m)，7.43(1H，d，J＝8.7Hz)，7.52-7.56(2H，m)，7.81(1H，s)，8.12(1H，dd，J＝8.7，2.1Hz)，8.22(1H，d，J＝2.1Hz)，8.28(2H，s)，10.85(1H，s)，13.81(1H，brs).

(3) 4-Phenylmethoxy-N³- [ 3, 5-bis (trifluoromethyl) phenyl ] -N¹，N¹-dimethyl isophthalamide

To a solution of 4-benzyloxy-N- [ 3, 5-bis (trifluoromethyl) phenyl ] isophthalic acid (242mg, 0.50mmol), dimethylamine hydrochloride (41mg, 0.50mmol) and triethylamine (51mg, 0.50mmol) in tetrahydrofuran (5mL) was added WSC. HCl (95mg, 0.50mmol) under ice-cooling, followed by stirring at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with diluted hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was then distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 1: 4) to obtain the title compound as a white solid (165mg, 64.9%).

¹H-NMR(DMSO-d₆)：δ2.99(6H，s)5.29(2H，s)，7.32-7.38(4H，m)，7.52-7.56(2H，m)，7.64(1H，dd，J＝8.7，2.1Hz)，7.73(1H，d，J＝2.1Hz)，7.80(1H，s)，8.28(2H，s)，10.83(1H，s).

(4)N³- [ 3, 5-bis (trifluoromethyl) phenyl ] -4-hydroxy-N¹，N¹-dimethyl isophthalamide

In hydrogen atmosphere, 4-benzyloxy-N ³- [ 3, 5-bis (trifluoromethyl) phenyl ] -N¹，N¹A mixed solution of (E) -dimethylisophthalamide (141mg, 0.28mmol), 5% Pd-C (14mg) in ethanol (5ml), and ethyl acetate (5ml) was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was distilled under reduced pressure to give the title compound as a white solid (106mg, 91.2%).

¹H-NMR(DMSO-d₆)：δ2.98(6H，s)，7.02(1H，d，J＝8.7Hz)，7.52(1H，dd，J＝8.7，2.1Hz)，7.84(1H，s)，7.95(1H，d，J＝2.1Hz)，8.46(2H，s)，11.10(1H，brs)，11.63(1H，brs).

Example 85: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (piperidine-1-carbonyl) benzamide

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

The same procedures used in example 84(3) were repeated except for using 4-benzyl-N- [ 3, 5-bis (trifluoromethyl) phenyl ] m-phenylalanine and piperidine as starting materials to give the titled compound.

Yield: 56.4 percent

¹H-NMR(CDCl₃)：δ1.53-1.70(6H，m)，3.44(2H，brs)，3.70(2H，brs)，5.26(2H，s)，7.24(1H，d，J＝8.7Hz)，7.26(1H，s)，7.52-7.58(5H，m)，7.66(2H，s)，7.74(1H，dd，J＝8.7，2.4Hz)，8.37(1H，d，J＝2.1Hz)，10.27(1H，s).

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

The title compound was obtained in the same manner as in example 84(4) using 2-benzyloxy-N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5- (piperidine-1-carbonyl) benzamide as a starting material.

Yield: 96.3% white solid

¹H-NMR(DMSO-d₆)：δ1.51(4H，brs)，1.60-1.65(2H，m)，3.47(4H，brs)，7.04(1H，d，J＝8.4Hz)，7.48(1H，dd，J＝8.4，2.1Hz)，7.85(1H，s)，7.92(1H，d，J＝2.1Hz)，8.46(2H，s)，10.99(1H，s)，11.64(1H，brs).

Example 86: 5- (4-Phenylmethylpiperidine-1-carbonyl) -N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxybenzamide

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

The same procedures used in example 84(3) were repeated except for using 4-benzyl-N- [ 3, 5-bis (trifluoromethyl) phenyl ] isophthalic acid and 4-benzylpiperidine as starting materials to give the titled compound.

Yield: 76.7 percent

¹H-NMR(CD₃0D)：δ1.18-1.38(2H，m)，1.67(1H，brs)，1.74(1H，brs)，1.84-1.93(1H，m)，2.60(2H，d，J＝7.2Hz)，2.83(1H，brs)，3.10(1H，brs)，3.78(1H，brs)，4.59(1H，brs)，5.34(2H，s)，7.15-7.18(3H，m)，7.24-7.28(2H，m)，7.40-7.46(4H，m)，7.57-7.63(3H，m)，7.65(1H，dd，J＝8.7，2.4Hz)，7.96(2H，s)，8.05(1H，d，J＝2.1Hz).

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

The same procedures used in example 84(4) were repeated except for using 2-benzyl-5- (4-benzylpiperidine-1-carbonyl) -N- [ 3, 5-bis (trifluoromethyl) phenyl ] benzamide as the starting material to obtain the title compound.

Yield: 54.3% white solid

¹H-NMR(DMSO-d₆)：δ1.08-1.22(2H，m)，1.59-1.62(2H，m)，1.77-1.80(1H，m)，2.50-2.55(2H，m)，2.87(2H，brs)，3.75(1H，br)，4.39(1H，br)，7.06(1H，d，J＝8.4Hz)，7.17-7.20(3H，m)，7.28(2H，t，J＝7.2Hz)，7.49(1H，dd，J＝8.4，2.1Hz)，7.84(1H，s)，7.93(1H，d，J＝2.1Hz)，8.47(2H，s)，10.89(1H，s)，11.65(1H，s).

Example 87: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-dimethylsulfamoyl-2-hydroxybenzamide

(1) 2-methoxy-5-sulfamoylbenzoic acid

Methyl 2-methoxy-5-sulfamoylbenzoate (4.91g, 20mmol) was dissolved in methanol (30mL), and 2N sodium hydroxide solution (30mL, 60mmol) was added 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 (4.55g, 98.3%).

¹H-NMR(DMSO-d₆)：δ3.89(3H，s)，7.30(1H，d，J＝8.7Hz)，7.32(2H，s)，7.92(1H，dd，J＝8.7，2.7H z)，8.09(1H，d，J＝2.7Hz)，13.03(1H，br).

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

The same procedures used in example 24 were repeated using 2-methoxy-5-sulfamoylbenzoic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 24.2 percent

¹H-NMR(DMSO-d₆)：δ3.97(3H，s)，7.38(2H，s)，7.39(1H，d，J＝8.7Hz)，7.85(1H，s)，7.96(1H，dd，J＝8.7，2.4Hz)，8.06(1H，d，J＝2.4Hz)，8.43(2H，s)，10.87(1H，s).

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

A suspension of N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-methoxy-5-sulfamoylbenzamide (442mg, 1.0mmol), methyl iodide (710mg, 5.0mmol) and potassium carbonate (415mg, 3.0mmol) in acetonitrile (10mL) was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from a mixed solvent of n-hexane and ethyl acetate (2: 1) to give the title compound as a white solid (207mg, 44.1%).

¹H-NMR(DMSO-d₆)：δ2.62(6H，s)，3.99(3H，s)，7.45(1H，d，J＝9.0Hz)，7.85(1H，s)，7.91(1H，dd，J＝8.7，2.4Hz)，7.95(1H，d，J＝2.4Hz)8.43(2H，s)，10.90(1H，s).

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

The title compound was obtained in the same manner as in example 80(5) using N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-dimethylsulfamoyl-2-methoxybenzamide as a starting material.

¹H-NMR(DMSO-d₆)：δ2.77(3H，d，J＝4.5Hz)，4.37(1H，brs)，6.70(1H，d，J＝3.6Hz)，7.04(2H，s).

Example 88: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- (pyrrole-1-sulfonyl) benzamide (compound No. 87)

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

A mixture of N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-methoxy-5-sulfamoylbenzamide (442mg, 1mmol), 2, 5-dimethoxytetrahydrofuran (159mg, 1.2mmol) and acetic acid (5mL) was heated under reflux for 2 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium bicarbonate solution and a saturated common salt solution, 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 obtain the title compound as a white solid (436.5mg, 88.6%).

¹H-NMR(DMSO-d₆)：δ3.96(3H，s)，6.36(2H，dd，J＝2.4，2.1Hz)，7.37(2H，dd，J＝2.4，2.1Hz)，7.42(1H，d，J＝9.0Hz)，7.85(1H，s)，8.80(1H，dd，J＝9.0，2.4Hz)8.18(1H，d，J＝2.7Hz)，8.38(2H，s)，10.92(1H，s).

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

The same procedures as in example 80(5) were carried out using N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-methoxy-5- (pyrrole-1-sulfonyl) benzamide as a starting material to obtain the title compound.

¹H-NMR(DMSO-d₆，δ)：6.36(2H，dd，J＝2.4，2.1Hz)，7.18(1H，d，J＝9.0Hz)，7.34(2H，d，J＝2.4，2.1Hz)，7.86(1H，s)，7.99(1H，dd，J＝9.0，2.7Hz)8.31(1H，d，J＝2.7Hz)，8.42(2H，s)，10.98(1H，s).

Example 89: 5-amino-N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxybenzamide (Compound No. 88)

The title compound was obtained in the same manner as in example 84(4) using N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-nitrobenzamide as a starting material.

Yield: 98.0 percent

¹H-NMR(DMSO-d₆)：δ4.79(2H，brs)，6.76(1H，d，J＝2.1Hz)，6.76(1H，s)，7.09(1H，dd，J＝2.1，1.2Hz)，7.80(1H，s)，8.4.5(2H，s)，10.30(1H，br)，10.84(1H，s).

Example 90: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-dimethylamino-2-hydroxybenzamide

The same procedures used in example 16 were repeated using 5-dimethylaminosalicylic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 28.8 percent

¹H-NMR(DMSO-d₆)：δ2.85(6H，s)，6.92(1H，d，J＝9.0Hz)，7.01(1H，dd，J＝8.7，3.0Hz)，7.22(1H，d，J＝3.0Hz)，7.84(1H，s)，8.47(2H，s)，10.62(1H，s)，10.83(1H，s).

Example 91: 5-benzoylamino-N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxybenzamide (Compound No. 90)

A mixture of 5-amino-N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxybenzamide (364mg, 1mmol), pyridine (95mg, 1.2mmol) and tetrahydrofuran (10mL) was cooled with ice under an argon atmosphere, benzoyl chloride (155mg, 1.1mmol) was added, and the mixture was stirred for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then distilled 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 (121mg, 25.7%).

¹H-NMR(DMSO-d₆)：δ7.04(1H，d，J＝8.7Hz)，7.51-7.62(3H，m)，7.81(1H，dd，J＝8.7，2.4Hz)，7.83(1H，s)，7.98(2H，d，J＝7.2Hz)，8.22(1H，d，J＝2.4Hz)，8.49(2H，s)，10.27(1H，s)，10.89(1H，s)，11.07(1H，s).

Example 92: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- [ (3-phenyl) ureido ] benzamide (compound No. 91)

5-amino-N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxybenzamide (100.2mg, 0.28mmol) was dissolved in acetonitrile (4ml), and 4-dimethylaminopyridine (3mg) and phenyl isocyanate (30. mu.l, 0.28mmol) were added thereto, followed by stirring at 60 ℃ for 5 minutes. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 1: 1) to give the title compound as a pale brown solid (54.8mg, 41.2%).

¹H-NMR(DMSO-d₆)：δ6.93-6.98(1H，m)，6.97(1H，d，J＝9.3Hz)，7.27(2H，t，J＝7.8Hz)，7.34-7.46(2H，m)，7.50(1H，dd，J＝9.0，2.4Hz)，7.83(1H，s)，7.88(1H，s)，8.47(2H，s)，8.56(1H，s)，8.63(1H，s)，10.87(1H，s)，10.89(1H，s).

Example 93: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- [ (3-phenyl) thioureido ] benzamide (compound No. 92)

The same procedures used in example 92 were repeated using 5-amino-N- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxybenzamide and phenyl isothiocyanate as starting materials to give the title compound.

Yield: 66.3 percent

¹H-NMR(DMSO-d₆)：δ7.00(1H，d，J＝8.4Hz)，7.13(1H，tt，J＝7.5，1.2Hz)，7.34(2H，t，J＝7.8Hz)，7.45-7.51(3H，m)，7.84(1H，s)，7.87(1H，d，J＝2.7H z)，8.47(2H，s)，9.65(1H，s)，9.74(1H，s)，10.84(1H，s)，11.32(1H，s).

Example 94: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- [ (4-nitrophenyl) diazenyl ] benzamide (compound No. 93)

The same procedures used in example 16 were repeated using 5- [ (4-nitrophenyl) diazenyl ] salicylic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 11.3 percent of

¹H-NMR(DMSO-d₆)：δ7.23(1H，d，J＝9.0Hz)，7.87(1H，s)，8.06(2H，d，J＝9.0Hz)，8.10(1H，dd，J＝9.0，2.4Hz)，8.44(2H，d，J＝9.0Hz)，8.50(2H，s)，8.53(1H，d，J＝2.4Hz)，11.13(1H，s)，12.14(1H，br)、

Example 95: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5- ({ [ (4-pyridin-2-yl) sulfamoyl ] phenyl } diazenyl) benzamide (Compound No. 94) the same procedure as in example 16 was carried out using 5- ({ [ (4-pyridin-2-yl) sulfamoyl ] phenyl } diazenyl) salicylic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 7.9 percent

¹H-NMR(DMSO-d₆)：δ6.87(1H，t，J＝6.0Hz)，7.22(1H，d，J＝8.7Hz)，7.21-7.23(1H，m)，7.77(1H，t，J＝8.4Hz)，7.87(1H，s)，7.95-7.98(3H，m)，8.03-8.07(4H，m)，8.47(1H，d，J＝2.4Hz)，8.49(2H，s)，11.14(1H，s)，12.03(1H，br).

Example 96: 2-acetoxy-N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-chlorobenzamide (Compound No. 96)

N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-chloro-2-hydroxybenzamide (1.51g, 3mmol) and pyridine (285mg, 3.6mmol) were dissolved in tetrahydrofuran (6mL), and acetyl chloride (234mg, 3.3mmol) was added dropwise under ice-cooling, followed by stirring at room temperature for 1 hour. The solvent was removed by distillation under the reduced pressure, and 2N hydrochloric acid was added to the residue to conduct extraction with ethyl acetate. After being washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated, the residue was recrystallized from n-hexane-ethyl acetate to give the title compound as a white solid (1.06g, 83.0%).

¹H-NMR(DMSO-d₆)：δ2.22(3H，s)，7.35(1H，d，J＝9.0Hz)，7.71(1H，dd，J＝8.7，2.7Hz)，7.85(1H，s)，7.88(1H，d，J＝2.7Hz)，8.37(2H，s)，11.05(1H，brs).

Example 97: 4-acetylamino-N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-chloro-2-hydroxybenzamide (Compound No. 97)

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

The same procedures used in example 82 were repeated except for using methyl 4-acetylamino-5-chloro-2-methoxybenzoate as a starting material to give the title compound.

Yield: 88.0 percent

¹H-NMR(DMSO-d₆)：δ2.16(3H，s)，3.78(3H，s)，7.72(1H，s)，7.77(1H，s)，9.57(1H，s)，12.74(1H，s).

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

The same procedures used in example 24 were repeated using 4-acetylamino-5-chloro-2-methoxybenzoic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 23.8 percent

¹H-NMR(DMSO-d₆)：δ2.17(3H，s)，3.89(3H，s)，7.77-7.82(3H，m)，8.45-8.49(2H，m)，9.66(1H，s)，10.68(1H，s).

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

The title compound was obtained in the same manner as in example 80 using 4-acetylamino-N- [ 3, 5-bis (trifluoromethyl) phenyl ] -5-chloro-2-methoxybenzamide as a starting material.

Yield: 72.8 percent

¹H-NMR(DMSO-d₆)：δ2.17(3H，s)，7.75(1H，s)，7.82(1H，s)，7.95(1H，s)，8.44(2H，s)，9.45(1H，s)，11.16(1H，brs)，11.63(1H，brs).

Example 98: n- [ 3, 5-bis (trifluoromethyl) phenyl ] -4-chloro-2-hydroxybenzamide (Compound No. 98)

The same operations as in example 16 were carried out using 4-chlorosalicylic acid and 3, 5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.

Yield: 55.8 percent

¹H-NMR(DMSO-d₆)：δ7.05-7.08(2H，m)，7.84-7.87(2H，m)，8.45(2H，s)，10.84(1H，s)11.64(1H.brs).

Example 99: n- [ 3, 5-bis (trifluoromethyl) -2-bromophenyl ] -5-chloro-2-hydroxybenzamide (Compound No. 99)

The same procedures used in example 16 were repeated using 5-chlorosalicylic acid and 3, 5-bis (trifluoromethyl) -2-bromoaniline as starting materials to give the title compound.

Yield: 14.5 percent

¹H-NMR(DMSO-d₆)：δ7.11(1H，d，J＝9.0Hz)，7.53(1H，dd，J＝9.0，2.7Hz)，7.91(1H，d，J＝1.8Hz)，7.98(1H，d，J＝2.7Hz)，9.03(1H，d，J＝1.8Hz)，11.26(1H，brs).

Example 100: n- [ 2, 5-bis (trifluoromethyl) phenyl ] -5-chloro-2-hydroxybenzamide (Compound No. 100)

The same operations as in example 16 were carried out using 5-chlorosalicylic acid and 2, 5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.

Yield: 3.6 percent

¹H-NMR(CDCl₃)：δ7.03(1H，d，J＝8.7Hz)，7.43-7.48(2H，m)，6.61(1H，d，J＝8.1Hz)，7.85(1H，d，J＝8.4Hz)，8.36(1H，brs)，8.60(1H，s)，11.31(1H，s).

Example 101: n- [ 2, 5-bis (trifluoromethyl) phenyl ] -5-bromo-2-hydroxybenzamide (Compound No. 101)

The same procedures used in example 16 were repeated using 5-bromosalicylic acid and 2, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 24.0 percent

¹H-NMR(DMSO-d₆)：δ7.03(1H，d，J＝8.7Hz)，7.65(1H，dd，J＝8.7，2.7Hz)，7.76(1H，d，J＝8.4Hz)，8.03(1H，d，J＝8.1Hz)8.11(1H，d，J＝2.7Hz)，8.74(1H，s)，11.02(1H，s)，12.34(1H，s).

Example 102: n- [ 2, 5-bis (trifluoromethyl) phenyl ] -2-hydroxy-5-methylbenzamide (Compound No. 102)

The same procedures as in example 16 were carried out using 5-methylsalicylic acid and 2, 5-bis (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 1.5 percent

¹H-NMR(CDCl₃)：δ2.36(3H，s)，6.97(1H，d，J＝8.4H z)，7.23(1H，s)，7.32(1H，dd，J＝8.4，1.5Hz)，7.57(1H，d，J＝8.4Hz)，7.83(1H，d，J＝8.4Hz)，8.46(1H，s)，8.69(1H，s)，11.19(1H，s).

Example 103: 2-acetoxy-N- [ 2, 5-bis (trifluoromethyl) phenyl ] -5-chlorobenzamide (Compound No. 103)

The title compound was obtained in the same manner as in example 96 using N- [ 2, 5-bis (trifluoromethyl) phenyl ] -5-chloro-2-hydroxybenzamide and acetyl chloride as starting materials.

Yield: 6.6 percent

¹H-NMR(CDCl₃)：δ2.25(3H，s)，7.17(1H，d，J＝8.7Hz)，7.54(1H，dd，J＝8.7，2.4Hz)，7.55(1H，d，J＝8.1Hz)，7.80(1H，d，J＝8.1Hz)，7.95(1H，d，J＝2.4Hz)，8.60(1H，s)，8.73(1H，s).

Example 104: 5-chloro-2-hydroxy-N- [ 2- (trifluoromethyl) phenyl ] benzamide (compound No. 104)

The same procedures as in example 16 were carried out using 5-chlorosalicylic acid and 2- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 58.0 percent

¹H-NMR(DMSO-d₆)：δ7.07(1H，d，J＝8.7Hz)，7.42(1H，t，J＝7.5Hz)，7.52(1H，d，J＝8.7，2.7Hz)，7.74(1H，t，J＝8.1Hz)，7.77(1H，t，J＝8.1Hz)，7.99(1H，d，J＝2.7Hz)，8.18(1H，d，J＝8.1Hz)，10.76(1H，s)，12.22(1H，s).

Example 105: 5-chloro-N- [ 4-chloro-2- (trifluoromethyl) phenyl ] -2-hydroxybenzamide (Compound No. 105)

The same procedures used in example 16 were repeated using 5-chlorosalicylic acid and 4-chloro-2- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 21.5 percent

¹H-NMR(DMSO-d₆)：δ7.07(1H，d，J＝8.7Hz)，7.52(1H，dd，J＝8.7，2.7Hz)，7.80-7.85(2H，m)，7.97(1H，d，J＝2.7Hz)，8.26(1H，d，J＝8.4Hz)，10.80(1H，s)，12.26(1H，s).

Example 106: 5-bromo-2-hydroxy-N- [ 3- (trifluoromethyl) phenyl ] benzamide (compound No. 106)

The title compound was obtained in the same manner as in example 16 using 5-bromosalicylic acid and 3- (trifluoromethyl) aniline as starting materials.

Yield: 50.3 percent of

¹H-NMR(DMSO-d₆，δ)：6.98(1H，d，J＝8.7Hz)，7.48-7.52(1H，m)，7.59(1H，dd，J＝8.7，2.7Hz)，7.62(1H，t，J＝8.1Hz)，7.92-7.96(1H，m)，8.02(1H，d，J＝2.4Hz)，8.20(1H，s)，10.64(1H，s)，11.60(1H，s).

Example 107: 5-chloro-N- [ 2-fluoro-3- (trifluoromethyl) phenyl ] -2-hydroxybenzamide (Compound No. 107)

The same procedures used in example 16 were repeated using 5-chlorosalicylic acid and 2-fluoro-3- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 71.7% white solid

¹H-NMR(DMSO-d₆)：δ7.07(1H，d，J＝9.0Hz)，7.46(1H，t，J＝7.8Hz)，7.52(1H，dd，J＝9.0，2.7Hz)，7.58(1H，t，J＝7.2Hz)，7.96(1H，d，J＝2.7Hz)，8.49(1H，t，J＝7.2Hz)，10.82(1H，s)，12.13(1H，brs).

Example 108: 5-chloro-N- [ 4-fluoro-3- (trifluoromethyl) phenyl ] -2-hydroxybenzamide (Compound No. 108)

The same procedures used in example 16 were repeated using 5-chlorosalicylic acid and 4-fluoro-3- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 72.1% white solid

¹H-NMR(DMSO-d₆)：7.03(1H，d，J＝9.0Hz)，7.48(1H，dd，J＝8.7，2.7Hz)，7.56(1H，d，J＝9.9Hz)，7.90(1H，d，J＝2.7Hz)，7.99-8.03(1H，m)，8.21(1H，dd，J＝6.6，2.4Hz)，10.63(1H，s)，11.58(1H，s).

Example 109: 5-bromo-N- [ 4-chloro-3- (trifluoromethyl) phenyl ] -2-hydroxybenzamide (Compound No. 109)

The same procedures used in example 16 were repeated using 5-bromosalicylic acid and 4-chloro-3- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 37.4 percent

¹H-NMR(DMSO-d₆)：δ6.98(1H，d，J＝8.7Hz)，7.59(1H，dd，J＝8.7，2.4Hz)，7.73(1H，d，J＝8.7Hz)，7.98(1H，d，J＝2.4Hz)，8.00(1H，dd，J＝8.7，2.4Hz)，8.31(1H，d，J＝2.4Hz)，10.68(1H，s)，11.52(1H，brs).

Example 110: 5-chloro-N- [ 3-fluoro-5- (trifluoromethyl) phenyl ] -2-hydroxybenzamide (Compound No. 110)

The same procedures used in example 16 were repeated using 5-chlorosalicylic acid and 3-fluoro-5- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 62.0 percent

¹H-NMR(DMSO-d₆)：δ7.04(1H，d，J＝8.7Hz)，7.42(1H，d，J＝8.4Hz)，7.48(1H，dd，J＝9.0，3.0Hz)，7.85(1H，d，J＝2.4Hz)，7.94(1H，dd，J＝11.4，2.1Hz)，7.99(1H，s)，10.73(1H，s)，11.46(1H，s).

Example 111: 5-bromo-N- [ 3-bromo-5- (trifluoromethyl) phenyl ] -2-hydroxybenzamide (Compound No. 111)

The same procedures used in example 16 were repeated using 5-bromosalicylic acid and 3-bromo-5- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 73.3 percent

¹H-NMR(DMSO-d₆)：δ6.99(1H，d，J＝9.0Hz)，7.60(1H，dd，J＝9.0，2.4Hz)，7.72(1H，s)，7.97(1H，d，J＝2.7Hz)，8.16(1H，s)，8.28(1H，s)，10.69(1H，s)，11.45(1H，s).

Example 112: 5-chloro-N- [ 2-fluoro-5- (trifluoromethyl) phenyl ] -2-hydroxybenzamide (Compound No. 112)

The same procedures used in example 16 were repeated using 5-chlorosalicylic acid and 2-fluoro-5- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 77.9 percent

¹H-NMR(DMSO-d₆)：57.07(1H，d，J＝9.0Hz)，7.52(1H，dd，J＝9.0，2.7Hz)，7.58-7.61(2H，m)，7.95(1H，d，J＝2.7Hz)，8，71(1H，d，J＝7.5Hz)，10.90(1H，s)，12.23(1H，s).

Example 113: 5-chloro-N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2-hydroxybenzamide (Compound No. 113)

The same operations as in example 16 were carried out using 5-chlorosalicylic acid and 2-chloro-5- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 49.1 percent

¹H-NMR(DMSO-d₆)：δ7.09(1H，d，J＝9.0Hz)，7.53(1H，dd，J＝9.0，3.0Hz)，7.55(1H，dd，J＝8.4，2.7Hz)，7.83(1H，d，J＝8.4Hz)，7.98(1H，d，J＝3.0Hz)，8.88(1H，d，J＝2.7Hz)，11.14(1H，s)，12.39(1H，s).

Example 114: 5-bromo-N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2-hydroxybenzamide (Compound No. 114)

The same procedures used in example 16 were repeated using 5-bromosalicylic acid and 2-chloro-5- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 34.2 percent

¹H-NMR(DMSO-d₆)：δ7.04(1H，d，J＝8.7Hz)，7.56(1H，ddd，J＝8.1，2.4，1.2Hz)，7.64(1H，dd，J＝8.7，2.7Hz)，7.83(1H，dd，J＝8.1，1.2Hz)，8.11(1H，d，J＝2.7Hz)，8.87(1H，d，J＝2.4Hz)，11.12(1H，s)，12.42(1H，s).

Example 115: 5-chloro-2-hydroxy-N- [ 4-nitro-3- (trifluoromethyl) phenyl ] benzamide (compound No. 115)

The same operations as in example 16 were carried out using 5-chlorosalicylic acid and 4-nitro-3- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 44.8 percent

¹H-NMR(DMSO-d₆)：δ7.04(1H，d，J＝9.0Hz)，7.49(1H，dd，J＝9.0，2.7Hz)，7.81(1H，d，J＝2.7Hz)，8.23-8.24(2H，m)，8.43(1H，d，J＝1.2Hz)，11.02(1H，s)，11.30(1H，br).

Example 116: 5-chloro-2-hydroxy-N- [ 2-nitro-5- (trifluoromethyl) phenyl ] benzamide (compound No. 116)

The same operations as in example 16 were carried out using 5-chlorosalicylic acid and 2-nitro-5- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 8.1 percent of

¹H-NMR(DMSO-d₆)：δ7.08(1H，d，J＝9.0Hz)，7.53(1H，dd，J＝8.7，2.7Hz)，7.73(1H，dd，J＝8.4，1.8Hz)，7.95(1H，d，J＝3.0Hz)，8.36(1H，d，J＝8.7Hz)，9.01(1H，d，J＝1.8Hz)，12.04(1H，s)，12.20(1H，s).

Example 117: 5-bromo-2-hydroxy-N- [ 4-nitro-3- (trifluoromethyl) phenyl ] benzamide (compound No. 117)

The same procedures used in example 16 were repeated using 5-bromosalicylic acid and 4-nitro-3- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 49.7 percent

¹H-NMR(DMSO-d₆)：δ6.99(1H，d，J＝8.7Hz)，7.60(1H，dd，J＝8.7，2.4Hz)，7.92(1H，d，J＝2.7Hz)，8.16(2H，s)，8.42(1H，s)，10.93(1H，s)，11.36(1H，s).

Example 118: 5-chloro-2-hydroxy-N- [ 2-methyl-3- (trifluoromethyl) phenyl ] benzamide (compound No. 118)

The same operations as in example 16 were carried out using 5-chlorosalicylic acid and 2-methyl-3- (trifluoromethyl) aniline as starting materials to obtain the title compound.

Yield: 14.5 percent

¹H-NMR(DMSO-d₆)：δ2.36(3H，d，J＝1.2Hz)，7.05(1H，d，J＝8.7Hz)，7.46(1H，t，J＝8.1Hz)，7.50(1H，dd，J＝8.7，2.7Hz)，7.60(1H，d，J＝7.2Hz)，7.99(1H，d，J＝7.2Hz)，8.00(1H，d，J＝2.4Hz)，10.43(1H，s)，12.08(1H，s).

Example 119: 5-chloro-2-hydroxy-N- [ 4-methyl-3- (trifluoromethyl) phenyl ] benzamide (compound No. 119)

The same operations as in example 16 were carried out using 5-chlorosalicylic acid and 4-methyl-3- (trifluoromethyl) aniline as starting materials to obtain the title compound.

Yield: 80.2 percent

¹H-NMR(DMSO-d₆)：δ7.01(1H，d，J＝8.7Hz)，7.44(1H，d，J＝8.4Hz)，7.47(1H，dd，J＝9.0，2.7Hz)，7.84(1H，dd，J＝8.4，2.1Hz)，7.92(1H，d，J＝2.7Hz)，8.13(1H，d，J＝2.1Hz)，10.65(1H，s)，11.68(1H，br).

Example 120: 5-chloro-2-hydroxy-N- [ 2-methyl-5- (trifluoromethyl) phenyl ] benzamide (compound No. 120)

The same operations as in example 16 were carried out using 5-chlorosalicylic acid and 2-methyl-5- (trifluoromethyl) aniline as starting materials to obtain the title compound.

Yield: 73.3 percent

¹H-NMR(DMSO-d₆)：δ2.39(3H，s)，7.07(1H，d，J＝8.7Hz)，7.44-7.54(3H，m)，7.99(1H，d，J＝3.0Hz)，8.43(1H，s)，10.52(1H，s)，12.17(1H，brs).

Example 121: 5-chloro-2-hydroxy-N- [ 4-methoxy-3- (trifluoromethyl) phenyl ] benzamide (compound No. 121)

The same procedures used in example 16 were repeated using 5-chlorosalicylic acid and 4-methoxy-3- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 79.1 percent

¹H-NMR(DMSO-d₆)：δ7.02(1H，d，J＝9.0Hz)，7.30(1H，d，J＝9.0Hz)，7.48(1H，dd，J＝9.0，3.0Hz)，7.92(1H，dd，J＝9.0，2.4Hz)，7.96(1H，d，J＝2.7Hz)，8.04(1H，d，J＝2.4Hz)，10.47(1H，s)，11.78(1H，s).

Example 122: 5-bromo-2-hydroxy-N- [ 3-methoxy-5- (trifluoromethyl) phenyl ] benzamide (compound number 122)

The same procedures used in example 16 were repeated using 5-bromosalicylic acid and 3-methoxy-5- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 58.8 percent

¹H-NMR(DMSO-d₆)：δ3.85(3H，s)，6.98(1H，d，J＝8.7Hz)，7.03(1H，s)，7.57-7.61(2H，m)，7.77(1H，s)，8.00(1H，d，J＝2.4Hz)，10.57(1H，s)，11.56(1H，s).

Example 123: 5-bromo-2-hydroxy-N- [ 2-methoxy-5- (trifluoromethyl) phenyl ] benzamide (compound No. 123)

The same procedures used in example 16 were repeated using 5-bromosalicylic acid and 2-methoxy-5- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 71.3 percent of

¹H-NMR(DMSO-d₆)：δ3.99(3H，s)，7.03(1H，d，J＝9.0Hz)，7.30(1H，d，J＝8.7Hz)，7.47-7.51(1H，m)，7.61(1H，dd，J＝9.0，2.4Hz)，8.10(1H，d，J＝2.4Hz)，8.82(1H，d，J＝2.1Hz)11.03(1H，s)，12.19(1H，s).

Example 124: 5-chloro-hydroxy-N- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -2-benzamide (compound No. 124)

The same procedures used in example 16 were repeated using 5-chlorosalicylic acid and 2-methoxy-5- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 83.4 percent

¹H-NMR(DMSO-d₆)：δ4.00(3H，s)，7.08(1H，d，J＝9.0Hz)，7.30(1H，d，J＝8.7Hz)，7.47-7.52(2H，m)，7.97(1H，d，J＝2.7Hz)，8.83(1H，d，J＝2.4Hz)，11.05(1H，s)

Example 125: 5-chloro-2-hydroxy-N- [ 2-methylsulfanyl-5- (trifluoromethyl) phenyl ] benzamide (compound No. 125)

Yield: 79.2 percent

¹H-NMR(DMSO-d₆)：δ2.57(3H，s)，7.07(1H，d，J＝8.7Hz)，7.52(1H，dd，J＝8.7，2.4Hz)，7.55(1H，dd，J＝8.4，1.5Hz)，7.63(1H，d，J＝8.1Hz)，8.00(1H，d，J＝2.4Hz)，8.48(1H，d，J＝1.5Hz)，10.79(1H，s)，12.26(1H，s).

Example 126: 5-bromo-2-hydroxy-N- [ 2- (1-pyrrolidinyl) -5- (trifluoromethyl) phenyl ] benzamide (compound No. 126)

The same procedures used in example 16 were repeated using 5-bromosalicylic acid and 2- (1-pyrrolidinyl) -5- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 44.5 percent

¹H-NMR(DMSO-d₆)：δ1.86-1.91(4H，m)，3.20-3.26(4H，m)，6.99(1H，d，J＝8.7Hz)，7.07(1H，d，J＝8.7Hz)，7.43(1H，dd，J＝8.7，2.1Hz)，7.62(1H，dd，J＝8.7，2.4Hz)，7.94(1H，d，J＝2.1Hz)，8.17(1H，d，J＝2.4Hz)，10.54(1H，s)，12.21(1H，s).

Example 127: 5-bromo-2-hydroxy-N- [ 2-morpholino-5- (trifluoromethyl) phenyl ] benzamide (compound No. 127)

The same procedures used in example 16 were repeated using 5-bromosalicylic acid and 2-morpholino-5- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 65.9 percent

¹H-NMR(DMSO-d₆)：δ2.90(4H，dd，J＝4.5，4.2Hz)，3.84(4H，dd，J＝4.8，4.2Hz)，7.09(1H，d，J＝8.4Hz)，7.48(2H，s)，7.61(1H，dd，J＝8.4，2.7Hz)，8.13(1H，d，J＝2.7Hz)，8.90(1H，s)，11.21(1H，s)，12.04(1H，s).

Example 128: 5-chloro-2-hydroxy-N- [ 4- (trifluoromethyl) phenyl ] benzamide (compound number 128)

The same procedures as in example 16 were carried out using 5-chlorosalicylic acid and 4- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 75.0% white solid

¹H-NMR(DMSO-d₆)：δ7.04(1H，d，J＝9.0Hz)，7.48(1H，dd，J＝8.7，2.7Hz)，7.74(2H，d，J＝8.7Hz)，7.90(1H，d，J＝2.7Hz)，7.95(2H，d，J＝9.0Hz)，10.65(1H，s)，11.59(1H，s).

Example 129: 5-bromo-N- [ 2-chloro-4- (trifluoromethyl) phenyl ] -2-hydroxybenzamide (Compound No. 129)

The same procedures used in example 16 were repeated using 5-bromosalicylic acid and 2-chloro-4- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 34.9 percent

¹H-NMR(DMSO-d₆)：δ7.04(1H，d，J＝8.7Hz)，7.64(1H，dd，J＝8.7，2.7Hz)，7.79(1H，dd，J＝9.0，2.1Hz)，7.99(1H，d，J＝2.1Hz)，8.11(1H，d，J＝2.4Hz)，8.73(1H，d，J＝9.0Hz)，11.15(1H，s)，12.42(1H，s).

Example 130: 2-acetoxy-5-chloro-N- [ 2-chloro-5- (trifluoromethyl) phenyl ] benzamide (compound No. 130)

The same procedures used in example 96 were repeated using 5-chloro-N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2-hydroxybenzamide and acetyl chloride as starting materials to give the title compound.

Yield: 34.0 percent

¹H-NMR(CDCl₃)：δ2.39(3H，s)，7.16(1H，d，J＝8.7Hz)，7.37(1H，ddd，J＝8.7，2.4，0.6Hz)，7.51-7.56(2H，m)，7.97(1H，d，J＝＝3.0Hz)，8.85(1H，s)，8.94(1H，d，J＝1.8Hz).

Example 131: n- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2-hydroxy-5-nitrobenzamide (Compound No. 131)

The same procedures used in example 16 were repeated using 5-nitrosalicylic acid and 2-chloro-5- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 31.1 percent

¹H-NMR(DMSO-d₆)：δ6.98(1H，d，J＝9.3Hz)，7.52(1H，dd，J＝8.4，2.1Hz)，7.81(1H，d，J＝8.4Hz)，8.21(1H，dd，J＝9.0，3.3Hz)，8.82(1H，d，J＝3.0Hz)，8.93(1H，d，J＝2.4Hz)，12.18(1H，s).

Example 132: n- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2-hydroxy-5-methylbenzamide (compound No. 132)

The same procedures used in example 16 were repeated using 5-methylsalicylic acid and 2-chloro-5- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 15.8 percent

¹H-NMR(CDCl₃)：δ2.36(3H，s)，6.95(1H，d，J＝8.1Hz)，7.26-7.31(2H，m)，7.37(1H，dd，J＝8.4，1.8Hz)，7.56(1H，d，J＝8.4Hz)，8.65(1H，brs)，8.80(1H，d，J＝1.8Hz)，11.33(1H，brs).

Example 133: n- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2-hydroxy-5-methoxybenzamide (compound No. 133)

The same procedures used in example 16 were repeated using 5-methoxysalicylic acid and 2-chloro-5- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 56.4 percent

¹H-NMR(DMSO-d₆)：δ3.77(3H，s)，6.91(1H，d，J＝9.0Hz)，7.07(1H，dd，J＝8.7，3.0Hz)，7.20(1H，t，J＝1.8Hz)，7.52-7.54(3H，m)，10.33(1H，s)，11.44(1H，s).

Example 134: n- [ 4-chloro-3- (trifluoromethyl) phenyl ] -2-hydroxy-5-methylbenzamide (Compound No. 134)

The same procedures used in example 16 were repeated using 5-methylsalicylic acid and 4-chloro-3- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 70.4 percent

¹H-NMR(DMSO-d₆)：δ2.29(3H，s)，6.91(1H，d，J＝8.3Hz)，7.27(1H，ddd，J＝8.3，2.2，0.6Hz)，7.71(1H，d，J＝2.2Hz)，7.72(1H，d，J＝8.5Hz)，8.02(1H，dd，J＝8.5，2.5Hz)，8.33(1H，d，J＝2.5Hz)，10.64(1H，s)，11.25(1H，s).

Example 135: 2-hydroxy-5-methyl-N- [ 4-methyl-3- (trifluoromethyl) phenyl ] benzamide (compound No. 135)

The same procedures as in example 16 were carried out using 5-methylsalicylic acid and 4-methyl-3- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 63.7 percent

¹H-NMR(DMSO-d₆)：δ2.29(3H，s)，2.42(3H，s)，6，89(1H，d，J＝8.4Hz)，7.26(1H，ddd，J＝8.4，2.1，0.6Hz)，7.44(1H，d，J＝8.1Hz)，7.75(1H，d，J＝2.1Hz)，7.86(1H，dd，J＝8.4，1.8Hz)，8.13(1H.d，J＝2.1Hz)，10.50(1H，s)，11.42(1H，s).

Example 136: 2-hydroxy-5-methyl-N- [ 2-methyl-5- (trifluoromethyl) phenyl ] benzamide (compound No. 136)

The same procedures as in example 16 were carried out using 5-methylsalicylic acid and 2-methyl-5- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 14.2% white solid

¹H-NMR(DMSO-d₆)：δ2.29(3H，s)，2.38(3H，s)，6.94(1H，d，J＝8.4Hz)，7.27(1H，ddd，J＝8.4，2.4，0.6Hz)，7.44(1H，dd，J＝8.1，1.5Hz)，7.52(1H，d，J＝7.8Hz)，7.84(1H，d，J＝2.4Hz)，8.46(1H，d，J＝1.5Hz)，10.55(1H，s)，11.72(1H，s).

Example 137: 2-hydroxy-N- [ 4-methoxy-3- (trifluoromethyl) phenyl ] -5-methylbenzamide (Compound No. 137)

The same procedures used in example 16 were repeated using 5-methylsalicylic acid and 4-methoxy-3- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 65.1% yellowish solid

¹H-NMR(DMSO-d₆)：δ2.35(3H，s)，3.89(3H，s)，6.88(1H，d，J＝8.4Hz)，7.26(1H，dd，J＝8.1，1.8Hz)，7.30(1H，d，J＝8.4Hz)，7.77(1H，d，J＝2.1Hz)，7.92(1H，dd，J＝9.0，2.7Hz)，8.04(1H，d，J＝2.7Hz)，10.42(1H，s)，11.54(1H，s).

Example 138: 2-hydroxy-N- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -5-methylbenzamide (Compound No. 138)

The same procedures used in example 16 were repeated using 5-methylsalicylic acid and 2-methoxy-5- (trifluoromethyl) aniline as starting materials to give the title compound.

Yield: 77.9 percent

¹H-NMR(CDC1₃)：δ2.35(3H，s)，4.02(3H，s)，6.93(1H，d，J＝9.0Hz)，6.98(1H，d，J＝8.4Hz)，7.25-7.28(2H，m)，7.36(1H，ddd，J＝8.4，2.1，0.9Hz)，8.65(1H，brs)，8.73(1H，d，J＝2.1Hz)，11.69(1H，s).

Example 139: 5-bromo-2-hydroxy-N-phenylbenzamide (Compound No. 139)

The title compound was obtained in the same manner as in example 16 using 5-bromosalicylic acid and aniline as starting materials.

Yield: 68.8 percent of

mp 229-230℃.

¹H-NMR(DMSO-d₆)：δ6.96(1H，d，J＝9.0Hz)，7.12-7.18(1H，m)，7.35-7.41(2H，m)，7.58(1H，dd，J＝8.7，2.7Hz)，7.67-7.71(2H，m)，8.08(1H，d，J＝2.7Hz)，10.43(1H，s)，11.87(1H，s).

Example 140: 5-bromo-N- (3-chlorophenyl) -2-hydroxybenzamide (Compound No. 140)

The title compound was obtained in the same manner as in example 16 using 5-bromosalicylic acid and 3-chloroaniline as starting materials.

Yield: 63.1 percent

mp 231-232℃.

¹H-NMR(DMSO-d₆)：δ6.97(1H，d，J＝8.7Hz)，7.19-7.22(1H，m)，7.38-7.43(1H，m)，7.57-7.63(2H，m)，7.91-7.92(1H，m)，8.01(1H，d，J＝2.7Hz)，10.49(1H，s)，11.64(1H，s).

Example 141: 5-bromo-N- (4-chlorophenyl) -2-hydroxybenzamide (Compound No. 141)

The present compounds are commercially available compounds.

And (4) selling places: tokyo chemical society

The catalog number of the commodity: b0897

Example 142: 5-chloro-N- (2, 5-dichlorophenyl) -2-hydroxybenzamide (Compound No. 142)

The title compound was obtained in the same manner as in example 16 using 5-chlorosalicylic acid and 2, 5-dichloroaniline as starting materials.

Yield: 10.8 percent

¹H-NMR(DMSO-d₆)：δ7.08(1H，d，J＝9.0Hz)，7.24-7.28(1H，m)，7.50-7.54(1H，m)，7.61(1H，dd，J＝9.0，3.0Hz)，7.97(1H，d，J＝2.7Hz)，8.58(1H，d，J＝2.4Hz)，11.02(1H，s)，12.35(1H，brs).

Example 143: 5-bromo-N- (3, 4-dichlorophenyl) -2-hydroxybenzamide (Compound No. 143)

The title compound was obtained in the same manner as in example 16 using 5-bromosalicylic acid and 3, 4-dichloroaniline as starting materials.

Yield: 58.2 percent

mp 249-251℃.

¹H-NMR(DMSO-d₆)：δ6.97(1H，d，J＝8.7Hz)，7.57-7.70(3H，m)，7.98(1H，d，J＝2.7Hz)，8.10(1H，d，J＝2.4Hz)，10.54(1H，s)，11.55(1H，s).

Example 144: 5-bromo-N- (3, 5-difluorophenyl) -2-hydroxybenzamide (Compound No. 144)

The same procedures used in example 16 were repeated except for using 5-bromosalicylic acid and 3, 5-difluoroaniline as starting materials to give the title compound.

Yield: 36.3 percent

mp 259-261℃.

¹H-NMR(DMSO-d₆)：δ6.96-7.04(2H，m)，7.45-7.54(2H，m)，7.58(1H，dd，J＝8.7，2.7Hz)，7.94(1H，d，J＝2.7Hz)，10.60(1H，s)11.48(1H，s).

Example 145: 2-acetoxy-N- (3, 5-dichlorophenyl) benzamide (Compound No. 172)

The title compound was obtained in the same manner as in example 2(1) using o-acetylsalicyloyl chloride and 3, 5-dichloroaniline as starting materials.

Yield: 73.5 percent

mp 167--168℃.

¹H-NMR(CDCl₃)：δ2.35(3H，s)，7.14-7.18(2H，m)，7.35-7.40(1H，m)，7.52-7.57(3H，m)，7.81(1H，dd，J＝7.8，1.8Hz)，8.05(1H，brs).

Example 146: n- (3, 5-dichlorophenyl) -2-hydroxybenzamide (Compound No. 145)

The title compound was obtained in the same manner as in example 2(2) using 2-acetoxy-N- (3, 5-dichlorophenyl) benzamide as a starting material.

Yield: 60.3 percent

mp 218-219℃.

¹H-NMR(DMSO-d₆)：δ6.95-7.02(2H，m)，7.35-7.36(1H，m)，7.42-7.47(1H，m)，7.83-7.87(3H，m)，10.54(1H，s)，11.35(1H，s).

Example 147: n- (3, 5-dichlorophenyl) -5-fluoro-2-hydroxybenzamide (Compound No. 146)

The title compound was obtained in the same manner as in example 16 using 5-fluorosalicylic acid and 3, 5-dichloroaniline as starting materials.

Yield: 33.3 percent

mp 258-260℃.

¹H-NMR(DMSO-d₆)：δ7.00-7.05(1H，m)，7.28-7.37(2H，m)，7.63(1H，dd，J＝9.3，3.3Hz)，7.84(2H，d，J＝2.1Hz)，10.56(1H，s)，11.23(1H，s).

Example 148: 5-chloro-N- (3, 5-dichlorophenyl) -2-hydroxybenzamide (Compound No. 147)

The title compound was obtained in the same manner as in example 16 using 5-chlorosalicylic acid and 3, 5-dichloroaniline as starting materials.

Yield: 41.2 percent

¹H-NMR(DMSO-d₆)：δ7.03(1H，d，J＝9.0Hz)，7.36-7.37(1H，m)，7.48(1H，dd，J＝8.7，2.7Hz)，7.83-7.84(3H，m)，10.56(1H，s)，11.44(1H，s).

Example 149: 5-bromo-N- (3, 5-dichlorophenyl) -2-hydroxybenzamide (Compound No. 148)

The title compound was obtained in the same manner as in example 16 using 5-bromosalicylic acid and 3, 5-dichloroaniline as starting materials.

Yield: 61.6 percent

mp 243-244℃.

¹H-NMR(DMSO-d₆)：δ6.98(1H，d，J＝8.7Hz)，7.36-7.37(1H，m)，7.59(1H，dd，J＝9.0，2.4Hz)，7.83(2H，d，J＝1.8Hz)，7.95(1H，d，J＝2.4Hz)，10.56(1H，s)，11.46(1H，s).

Example 150: n- (3, 5-dichlorophenyl) -2-hydroxy-5-iodobenzamide (Compound No. 149)

The title compound was obtained in the same manner as in example 16 using 5-iodosalicylic acid and 3, 5-dichloroaniline as starting materials.

Yield: 65.4 percent

mp 244-245℃.

¹H-NMR(DMSO-d₆)：δ6.84(1H，d，J＝9.0Hz)，7.35-7.37(1H，m)，7.72(1H，dd，J＝9.0，2.1Hz)，7.83(2H，d，J＝1.8Hz)，8.09(1H，d，J＝2.1Hz)，10.55(1H，s)，11.45(1H，s).

Example 151: 3, 5-dibromo-N- (3, 5-dichlorophenyl) -2-hydroxybenzamide (Compound No. 150)

The title compound was obtained in the same manner as in example 16 using 3, 5-dibromosalicylic acid and 3, 5-dichloroaniline as starting materials.

Yield: 44.2 percent

mp 181-182℃.

¹H-NMR(DMSO-d₆)：δ7.42-7.43(1H，m)，7.80(2H，d，J＝1.8Hz)，8.03(1H，d，J＝2.1Hz)，8.17(1H，d，J＝2.1Hz)，10.82(1H，s).

Example 152: 4-chloro-N- (3, 5-dichlorophenyl) -2-hydroxybenzamide (Compound No. 151)

The title compound was obtained in the same manner as in example 16 using 4-chlorosalicylic acid and 3, 5-dichloroaniline as starting materials.

Yield: 57.2 percent

mp 255-256℃.

¹H-NMR(DMSO-d₆)：δ7.03-7.06(2H，m)，7.34-7.36(1H，m)，7.82-7.85(3H，m)，10.51(1H，s)，11.70(1H，brs).

Example 153: n- (3, 5-dichlorophenyl) -2-hydroxy-5-nitrobenzamide (Compound No. 152)

The title compound was obtained in the same manner as in example 16 using 5-nitrosalicylic acid and 3, 5-dichloroaniline as starting materials.

Yield: 83.1 percent

mp 232-233.

¹H-NMR(DMSO-d₆)：δ7.16(1H，d，J＝9.6Hz)，7.37-7.39(1H，m)，7.84(1H，d，J＝2.1Hz)，8.29(1H，dd，J＝9.0，3.0Hz)，8.65(1H，d，J＝3.0Hz)，10.83(1H，s).

Example 154: n- (3, 5-dichlorophenyl) -2-hydroxy-5-methylbenzamide (Compound No. 153)

The title compound was obtained in the same manner as in example 16 using 5-methylsalicylic acid and 3, 5-dichloroaniline as starting materials.

Yield: 71.0 percent

mp 216-217℃.

¹H-NMR(DMSO-d₆)：δ2.28(3H，s)，6.90(1H，d，J＝8.4Hz)，7.26(1H，dd，J＝8.7，1.8Hz)，7.34-7.36(1H，m)，7.67(1H，d，J＝1.5Hz)，7.85(2H，d，J＝1.8Hz)，10.52(1H，s)，11.15(1H，s).

Example 155: n- (3, 5-dichlorophenyl) -2-hydroxy-5-methoxybenzamide (Compound No. 154)

The title compound was obtained in the same manner as in example 16 using 5-methoxysalicylic acid and 3, 5-dichloroaniline as starting materials.

Yield: 29.8 percent

mp 230-232℃.

¹H-NMR(DMSO-d₆)：δ3.76(3H，s)，6.95(1H，d，J＝8.7Hz)，7.08(1H，dd，J＝9.0，3.0Hz)，7.35-7.36(1H，m)，7.40(1H，d，J＝3.0Hz)，7.85(2H，d，J＝1.5Hz)，10.55(1H，s)，10.95(1H，s).

Example 156: 5-bromo-2-hydroxy-N- (3, 4, 5-trichlorophenyl) benzamide (compound No. 155)

The title compound was obtained in the same manner as in example 16 using 5-bromosalicylic acid and 3, 4, 5-trichloroaniline as starting materials.

Yield: 78.6 percent

mp 297-299℃.

¹H-NMR(DMSO-d₆)：δ6.98(1H，d，J＝9.0Hz)，7.58(1H，dd，J＝8.4，2.4Hz)，7.95(1H，d，J＝2.4Hz)，8.03(1H，s)，10.58(1H，s)，11.49(1H，s).

Example 157: 5-bromo-2-hydroxy-N- (3, 5-dichloro-4-hydroxyphenyl) benzamide (compound No. 156)

The same procedures used in example 16 were repeated except for using 5-bromosalicylic acid and 3, 5-dichloro-4-hydroxyaniline as starting materials to give the title compound.

Yield: 22.5 percent

¹H-NMR(DMSO-d₆)：δ6.96(1H，d，J＝8.7Hz)，7.58(1H，dd，J＝8.7，2.4Hz)，7.76(2H，s)，8.01(1H，d，J＝2.4Hz)，10.03(1H，s)，10.36(1H，s)，11.67(1H，brs).

Example 158: 5-chloro-2-hydroxy-N- (2, 3, 4, 5, 6-pentafluorophenyl) benzamide (compound No. 157)

The same operations as in example 16 were carried out using 5-chlorosalicylic acid and 2, 3, 4, 5, 6-pentafluoroaniline as starting materials to give the title compound.

Yield: 58.6 percent

¹H-NMR(DMSO-d₆)：δ7.07(1H，d，J＝8.7Hz)，7.53(1H，dd，J＝8.7，2.7Hz)，7.91(1H，d，J＝2.7Hz)，10.38(1H，brs)，11.74(1H，brs).

Example 159: 5-bromo-N- (3, 5-dinitrophenyl) -2-hydroxybenzamide (Compound No. 158)

The title compound was obtained in the same manner as in example 16 using 5-bromosalicylic acid and 3, 5-dinitroaniline as starting materials.

Yield: 32.2 percent of

mp 258-260℃.

¹H-NMR(DMSO-d₆)：δ6.98-7.02(1H，m)，7.59-7.63(1H，m)，7.96-7.97(1H，m)，8.56-8.58(1H，m)，9.03-9.05(2H，m)，11.04(1H，s)，11.39(1H，brs).

Example 160: n- {2, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl) -5-chloro-2-hydroxybenzamide (Compound No. 159)

The same procedures used in example 16 were repeated except for using 5-chlorosalicylic acid and 2, 5-bis [ (1, 1-dimethyl) ethyl ] aniline as starting materials to give the title compound.

Yield: 75.7 percent

¹H-NMR(DMSO-d₆)：δ1.27(9H，s)，1.33(9H，s)，7.04(1H，d，J＝9.0Hz)，7.26(1H，dd，J＝8.4，2.1Hz)，7.35-7.38(2H，m)，7.49(1H，dd，J＝8.7，2.7Hz)，8.07(1H，d，J＝2.4Hz)，10.22(1H，s)，12.38(1H，brs).

Example 161: 5-chloro-N- [ 5- (1, 1-dimethyl) ethyl-2-methoxyphenyl ] -2-hydroxybenzamide (Compound No. 160)

The same procedures used in example 16 were repeated using 5-chlorosalicylic acid and 5- [ (1, 1-dimethyl) ethyl ] -2-methoxyaniline as starting materials to give the title compound.

Yield: 89.5 percent

¹H-NMR(DMSO-d₆)：δ1.28(9H，s)，3.33(3H，s)，7.01(1H，d，J＝8.7Hz)，7.05(1H，d，J＝9.0Hz)，7.11(1H，dd，J＝8.7，2.4Hz)，7.47(1H，dd，J＝9.0，3.0Hz)，7.99(1H，d，J＝3.0Hz)，8.49(1H，d，J＝2.4Hz)，10.78(1H，s)，12.03(1H，s).

Example 162: 5-bromo-N- (3, 5-dimethylphenyl) -2-hydroxybenzamide (Compound No. 161)

The title compound was obtained in the same manner as in example 16 using 5-bromosalicylic acid and 3, 5-dimethylaniline as starting materials.

Yield: 58.1 percent

mp 188-190℃.

¹H-NMR(DMSO-d₆)：δ2.28(6H，s)，6.80(1H，s)，6.96(1H，d，J＝8.7Hz)，7.33(2H，s)，7.58(1H，dd，J＝9.0，2.4Hz)，8.10(1H，d，J＝2.4Hz)，10.29(1H，s)，11.93(1H，brs).

Example 163: n- {3, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl } -5-chloro-2-hydroxybenzamide (Compound No. 162)

The same procedures used in example 16 were repeated except for using 5-chlorosalicylic acid and 3, 5-bis [ (1, 1-dimethyl) ethyl ] aniline as starting materials to give the title compound.

Yield: 34.1 percent

¹H-NMR(CDCl₃)：δ1.26(18H，s)，6.99(1H，d，J＝8.7Hz)，7.29(1H，t，J＝1.8Hz)，7.39(1、dd、J＝9.0，2.4Hz)，7.41(2H，d，J＝1.5Hz)，7.51(1H，d，J＝2.1Hz)，7.81(1H，brs)，12.01(1H，s).

Example 164: n- {3, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl } -5-bromo-2-hydroxybenzamide (Compound No. 163)

The same procedures used in example 16 were repeated except for using 5-bromosalicylic acid and 3, 5-bis [ (1, 1-dimethyl) ethyl ] aniline as starting materials to give the title compound.

Yield: 45.2 percent of

¹H-NMR(DMSO-d₆，δ)：1.30(18H，s)，6.95(1H，d，J＝8.7Hz)，7.20(1H，t，J＝1.5Hz)，7.56(2H，d，J＝1.5Hz)，7.58(1H，dd，J＝8.7，2.4Hz)，8.12(1H，d，J＝2.7Hz)，10.39(1H，s)，11.98(1H，s).

Example 165: 5-chloro-2-hydroxy- (3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydronaphthalen-2-yl) benzamide (compound No. 164)

The same procedures as in example 16 were carried out using 5-chlorosalicylic acid and 2-amino-3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydronaphthalene as starting materials to obtain the title compound.

Yield: 77.5 percent

¹H-NMR(DMSO-d₆)：δ1.23(6H，s)，1.24(6H，s)，1.64(4H，s)，2.19(3H，s)，7.13(1H，d，J＝9.0Hz)，7.20(1H，s)，7.49(1H，dd，J＝8.7，2.7Hz)，7.67(1H，s)，8.04(1H，d，J＝2.7Hz)，10.23(1H，s)，12.26(1H，s).

Example 166: n- (Biphenyl-3-yl) -5-chloro-2-hydroxybenzamide (Compound No. 165)

The title compound was obtained in the same manner as in example 16 using 5-chlorosalicylic acid and 3-aminobiphenyl as starting materials.

Yield: 75.6 percent

¹H-NMR(DMSO-d₆)：δ7.04(1H，d，J＝8.7Hz)，7.35-7.44(1H，m)，7.45-7.54(5H，m)，7.65-7.68(2H，m)，7.72(1H，dt，J＝7.2，1Hz).7.99(1H，d，J＝3.0Hz)，8.03(1H，m)，10.50(1H，s)，11.83(1H，brs).

Example 167: 5-chloro-2-hydroxy-N- (4-methoxybiphenyl-3-yl) benzamide (Compound No. 166)

The same procedures as in example 16 were carried out using 5-chlorosalicylic acid and 3-amino-4-methoxybiphenyl as starting materials to give the title compound.

Yield: 37.0 percent

¹H-NMR(DMSO-d₆)：δ3.95(3H，s)，7.08(1H，d，J＝8.7Hz)，7.20(1H，d，J＝8.4Hz).7.34(1H，t，J＝7.2Hz)，7.40-7.50(4H，m)，7.62(1H，d，J＝8.7Hz)，8.00(1H，d，J＝3.0Hz)，8.77(1H，d，J＝2.1Hz)，10.92(1H，s)，12.09(1H，s).

Example 168: 5-bromo-N- (2, 5-dimethoxyphenyl) -2-hydroxybenzamide (Compound No. 167)

The title compound was obtained in the same manner as in example 16 using 5-bromosalicylic acid and 2, 5-dimethoxyaniline as starting materials.

Yield: 39.7 percent

¹H-NMR(DMSO-d₆)：δ3.72(3H，s)，3.84(3H，s)，6.66(1H，ddd，J＝9.0，3.0，0.6Hz)，6.99-7.03(2H，m)，7.58(1H，ddd，J＝9.0，2.7，0.6Hz)，8.10(1H，dd，J＝2.4，0.6Hz)，8.12(1H，d，J＝3.0Hz)，10.87(1H，s)，12.08(1H，s).

Example 169: 5-bromo-N- (3, 5-dimethoxyphenyl) -2-hydroxybenzamide (Compound No. 168)

The title compound was obtained in the same manner as in example 16 using 5-bromosalicylic acid and 3, 5-dimethoxyaniline as starting materials.

Yield: 40.3 percent

mp 207-209℃.

¹H-NMR(DMSO-d₆)：δ3.75(6H，s)，6.30-6.32(1H，m)，6.94-6.97(3H，m)，7.57(1H，dd，J＝8.7，2.4Hz)，8.04(1H，d，J＝2.4Hz)，10.32(1H，s)，11.78(1H，s).

Example 170: 5-chloro-N- (3-acetylphenyl) -2-hydroxybenzamide (Compound No. 169)

The title compound was obtained in the same manner as in example 16 using 5-chlorosalicylic acid and 3-acetanilide as starting materials.

Yield: 80.0 percent

¹H-NMR(DMSO-d₆)：δ2.60(3H，s)，7.03(1H，d，J＝9.0Hz)，7.49(1H，dd，J＝9.0，3.0Hz)，7.54(1H，t，J＝8.1Hz)，7.76(1H，dq，J＝7.8，0.9Hz)，7.96-8.00(2H，m)，8.30(1H，t，J＝1.8Hz)，10.56(1H，s)，11.75(1H，s).

Example 171: dimethyl 5- { [ (5-bromo-2-hydroxy) benzoyl ] amino } isophthalate (Compound No. 170)

The title compound was obtained in the same manner as in example 16 using 5-bromosalicylic acid and dimethyl 5-aminoisophthalate as starting materials.

Yield: 74.1 percent

mp 254-256℃.

¹H-NMR(DMSO-d₆)：δ3.92(6H，s)，6.97(1H，d，J＝9.0Hz)，7.60(1H，dd，J＝9.0，2.4Hz)，8.06(1H，d，J＝2.4Hz)，8.24-8.25(1H，m)，8.62(2H，m)，10.71(1H，s)，11.57(1H，s).

Example 172: n- {4- [ 3- (2, 3-dichlorophenyl) thioureido ] phenyl } -2-hydroxybenzamide (Compound No. 171)

The present compounds are commercially available compounds.

And (4) selling places: maybridge Inc

The catalog number of the commodity: RDR 01434

Example 173: n- {2, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl } -2-hydroxy-5-methylbenzamide (Compound No. 173)

The same procedures used in example 16 were repeated except for using 5-methylsalicylic acid and 2, 5-bis [ (1, 1-dimethyl) ethyl ] aniline as starting materials to give the title compound.

Yield: 61.1 percent

¹H-NMR(DMSO-d₆)：δ1.27(9H，s)，1.33(9H，s)，2.28(3H，s)，6.89(1H，d，J＝8.1Hz)，7.24(1H，d，J＝2.1Hz)，7.27(1H，d，J＝2.1Hz)，7.32(1H，d，J＝2.4Hz)，7.37(1H，d，J＝8.4Hz)，7.88(1H，d，J＝1.5Hz)，10.15(1H，s)，11.98(1H，brs).

Example 174: 2-acetoxy-N- {3, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl } -5-chlorobenzamide (Compound No. 174)

The same procedures used in example 96 were repeated using N- {3, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl } -5-chloro-2-hydroxybenzamide and acetyl chloride as starting materials to give the title compound.

Yield: 66.1 percent

¹H-NMR(CDCl₃)：δ1.34(18H，s)，2.26(3H，s)，7.12(1H，d，J＝8.4Hz)，7.25(1H，d，J＝1.5Hz)，7.44(2H，d，J＝1.2Hz)，7.47(1H，dd，J＝8.7，2.7Hz)，7.87(1H，d，J＝2.4Hz)，7.98(1H，s).

Example 175: n- {3, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl } -2-hydroxy-5-nitrobenzamide (Compound No. 175)

The same procedures used in example 16 were repeated except for using 5-nitrosalicylic acid and 3, 5-bis [ (1, 1-dimethyl) ethyl ] aniline as starting materials to give the title compound.

Yield: 46.7 percent

¹H-NMR(CDCl₃)：δ1.37(18H，s)，7.13(1H，d，J＝9.3Hz)，7.32(1H，t，J＝1.8Hz)，7.46(2H，d，J＝1.8Hz)，8.07(1H，s)，8.33(1H，dd，J＝9.3，2.1Hz)，8.59(1H，d，J＝2.4Hz)，13.14(1H，s).

Example 176: n- {3, 5-bis [ (1, 1-dimethyl) ethyl ] phenyl } -2-hydroxy-5-methylbenzamide (Compound No. 176)

The same procedures used in example 16 were repeated except for using 5-methylsalicylic acid and 3, 5-bis [ (1, 1-methyl) ethyl ] aniline as starting materials to give the title compound.

Yield: 16.3 percent

¹H-NMR(CDCl₃)：δ1.35(18H，s)，2.35(3H，s)，6.94(1H，d，H＝8.4Hz)，7.23-7.28(2H，m)，7.31(1H，s)，7.42(1H，d，J＝1.8Hz)，7.88(1H，s)，11.86(1H，s).

Example 177: n- {3, 5-bis [ (1, 1 dimethyl) ethyl ] phenyl } -2-hydroxy-5-methoxybenzamide (compound No. 177)

The same procedures used in example 16 were repeated except for using 5-methoxysalicylic acid and 3, 5-di [ (1, 1 dimethyl) ethyl ] aniline as starting materials to give the title compound.

Yield: 12.7 percent

¹H-NMR(DMSO-d₆)：δ3.56(3H，s)，7.01(1H，d，J＝9.0Hz)，7.11(1H，dd，J＝9.0，3.0Hz)，7.52-7.56(2H，m)，7.83(1H，d，J＝8.1Hz)，8.95(1H，d，J＝1.5Hz)，11.29(1H，s)，11.63(1H，s).

Example 178: 2-acetoxy-5-chloro-N- [ 5- (1, 1-dimethyl) ethyl-2-methoxyphenyl ] benzamide (compound No. 178)

The same procedures used in example 96 were repeated using 5-chloro-N- [ 5- (1, 1-dimethyl) ethyl-2-methoxyphenyl ] -2-hydroxybenzamide and acetyl chloride as starting materials to give the title compound.

Yield: 87.5 percent

¹H-NMR(CDCl₃)：δ1.35(9H，s)，2.37(3H，s)，3.91(3H，s)，6.86(1H，d，J＝8.7Hz)，7.12(1H，dd，J＝8.7，2.4Hz)，7.13(1H，d，J＝9.0Hz)，7.47(1H，dd，J＝9.0，2.4Hz)，8.02(1H，d，J＝2.7Hz)，8.66(1H，d，J＝2.4Hz)，8.93(1H，s).

Example 179: n- [ 5- (1, 1-dimethyl) ethyl-2-methoxyphenyl ] -2-hydroxy-5-methylbenzamide (Compound No. 178)

The same procedures used in example 16 were repeated using 5-methylsalicylic acid and 5- (1, 1-dimethyl) ethyl-2-methoxyaniline as starting materials to give the title compound.

Yield: 84.7 percent

¹H-NMR(CDCl₃)：δ1.35(9H，s)，2.34(3H，s)，3.93(3H，s)，6.86(1H，d，J＝8.7Hz)，6.93(1H，d，J＝8.4Hz)，7.12(1H，dd，J＝8.7，2.4Hz)，7.24(1H，dd，J＝8.4，1.8Hz)，7.27(1H，brs)，8.48(1H，d，J＝2.4Hz)，8.61(1H，brs)，11.95(1H，s).

Example 180: 5-bromo-2-hydroxy-N- (thiazol-2-yl) benzamide (compound number 180)

The title compound was obtained in the same manner as in example 16 using 5-bromosalicylic acid and 2-aminothiazole as starting materials.

Yield: 12.0 percent

mp 212℃(dec.).

¹H-NMR(DMSO-d₆)：δ6.94(1H，brd，J＝8.0Hz)，7.25(1H，brd，J＝3.2Hz)，7.56(2H，m)，8.05(1H，d，J＝2.8Hz).

Example 181: 5-bromo-N- {4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl } -2-hydroxybenzamide (Compound No. 186)

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

A mixture of 1-bromo-3, 3-dimethyl-2-butanone (5.03g, 28.1mmol), thiourea (2.35g, 30.9mmol) and ethanol (30mL) was heated under reflux for 1.5 hours. After cooling, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 2: 1 → 1: 1) to obtain an off-white powder of the title compound (3.99g, 90.9%).

¹H-NMR(CDCl₃)：δ1.26(9H，s)，4.96(2H，brs)，6.09(1H，s).

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

The same procedures used in example 24 were repeated using 2-acetoxy-5-bromobenzoic acid and 2-amino-4- [ (1, 1-dimethyl) ethyl ] thiazole as starting materials to give the title compound.

Yield: 59.4 percent

¹H-NMR(CDCl₃)：δ1.31(9H，s)，2.44(3H，s)，6.60(1H，s)，7.13(1H，d，J＝8.4Hz)，7.68(1H，dd，J＝8.7，2.4Hz)，8.17(1H，d，J＝2.4Hz)，9.72(1H，brs).

(3) 5-bromo-N- {4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl } -2-hydroxybenzamide

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

¹H-NMR(DMSO-d₆)：δ1.30(9H，s)，6.80(1H，brs)，6.95(1H，brs)，7.57(1H，brs)，8.06(1H，d，J＝2.4Hz)，11.82(1H，brs)，13.27(1H，brs).

Example 182: 5-bromo-N- { 5-bromo-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl } -2-hydroxybenzamide (Compound No. 181)

(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 ] imidazol-2-yl } benzamide (0.20g, 0.50mmol) was dissolved in acetonitrile (10mL), N-bromosuccinimide (97.9mg, 0.55mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture 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 crude product of the title compound.

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

The same procedures used in example 2(2) were repeated except for 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 percent

¹H-NMR(DMSO-d₆)：δ1.42(9H，s)，6.99(1H，d，J＝8.7Hz)，7.61(1H，dd，J＝8.7，2.7Hz)，8.02(1H，d，J＝2.4Hz)，11.79(1H，brs)，12.00(1H，brs).

Example 183: 5-bromo-N- [ 5-bromo-4- (trifluoromethyl) thiazol-2-yl ] -2-hydroxybenzamide (Compound No. 182)

The same procedures used in example 16 were repeated using 5-bromosalicylic acid and 2-amino-5-bromo-4- (trifluoromethyl) thiazole as starting materials to give the title compound (2-amino-5-bromo-4- (trifluoromethyl) thiazole: cf. J.Heterococcus. chem., 1991, 28, 1017.).

Yield: 22.4 percent

mp 215℃(dec.).

¹H-NMR(DMSO-d₆)：δ7.00(1H，d，J＝8.8Hz)，7.61(1H，dd，J＝8.8，2.8Hz)，7.97(1H，d，J＝2.4Hz).

Example 184: 5-chloro-N- { 5-cyano-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl } -2-hydroxybenzamide

(1) Alpha-bromo-pivaloyl acetonitrile

Pivaloyl acetonitrile (1.00g, 7.99mmol) was dissolved in carbon tetrachloride (15mL), N-bromosuccinimide (1.42g, 7.99mmol) was added, and the mixture was refluxed for 15 minutes. After cooling, insoluble matter was removed by filtration, and the filtrate was distilled under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 4: 1) to give the title compound as a tan oil (1.43g, 87.9%).

¹H-NMR(CDCl₃)：δ1.33(9H，s)，5.10(1H，s).

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

The title compound was obtained in the same manner as in example 181(1) using α -bromopivaloyl acetonitrile and thiourea as starting materials.

Yield: 66.3 percent

¹H-NMR(CDCl₃)：δ1.41(9H，s)，5.32(2H，s).

(3) 5-chloro-N- { 5-cyano-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl } -2-hydroxybenzamide

The same procedures used in example 16 were repeated using 5-chlorosalicylic acid and 2-amino-5-cyano-4- [ (1, 1-dimethyl) ethyl ] thiazole as starting materials to give the title compound.

Yield: 63.4 percent

¹H-NMR(DMSO-d₆)：δ1.43(9H，s)，7.06(1H，d，J＝8.7Hz)，7.51(1H，dd，J＝8.7，3.0Hz)，7.85(1H，d，J＝2.7Hz)，12.31(2H，br).

Example 185: 5-bromo-N- { 5-cyano-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl } -2-hydroxybenzamide (Compound No. 184)

The same procedures used in example 16 were repeated using 5-bromosalicylic acid and 2-amino-5-cyano-4- [ (1, 1-dimethyl) ethyl ] thiazole as starting materials to give the title compound.

Yield: 61.3 percent

¹H-NMR(DMSO-d₆)：δ1.43(9H，s)，7.00(1H，d，J＝8.7Hz)，7.62(1H，dd，J＝8.7，2.7Hz)，7.97(1H，d，J＝2.7Hz)，11.75(1H，br)，12.43(1H，br).

Example 186: 5-bromo-2-hydroxy-N- (5-methylthiazol-2-yl) benzamide (Compound No. 185)

The title compound was obtained in the same manner as in example 16 using 5-bromosalicylic acid and 2-amino-5-methylthiazole as starting materials.

Yield: 12.9 percent

¹H-NMR(DMSO-d₆)：δ2.33(3H，s)，6.91(1H，d，J＝7.6Hz)，7.26(1H，s)，7.54(1H，d，J＝9.6Hz)，8.03(1H，d，J＝2.8Hz).

Example 187: 5-bromo-N- (4, 5-dimethylthiazol-2-yl) -2-hydroxybenzamide (Compound No. 187)

The title compound was obtained in the same manner as in example 16 using 5-bromosalicylic acid and 2-amino-4, 5-dimethylthiazole as starting materials.

Yield: 14.4 percent

¹H-NMR(DMSO-d₆)：δ2.18(3H，s)，2.22(3H，s)，6.89(1H，d，J＝8.8Hz)，7.51(1H，d，J＝6.8Hz)，8.02(1H，d，J＝2.8Hz)，13.23(1H，brs).

Example 188: 5-bromo-N- (5-methyl-4-phenylthiazol-2-yl) -2-hydroxybenzamide (Compound No. 188)

The same procedures used in example 16 were repeated using 5-bromosalicylic acid and 2-amino-5-methyl-4-phenylthiazole as starting materials to give the title compound (2-amino-5-methyl-4-phenylthiazole: see journal of pharmacy, 1961, 81, 1456.).

Yield: 27.7 percent

mp 243-244℃.

¹H-NMR(CD₃OD)：δ2.47(3H，s)，6.92(1H，d，J＝8.7Hz)，7.36-7.41(1H，m)，7.44-7.50(2H，m)，7.53(1H，dd，J＝9.0，2.7Hz)，7.57-7.61(2H，m)，8.16(1H，d，J＝2.7Hz).

Example 189: 5-bromo-N- [ 4-methyl-5- (4-fluorophenyl) thiazol-2-yl) -2-hydroxybenzamide (Compound No. 189)

The title compound was obtained in the same manner as in examples 184(1) to (3) using (4-fluorophenyl) acetone as a starting material.

Yield: 28.8% (3 steps)

(1) Alpha-bromo- (4-fluorophenyl) acetone

¹H-NMR(CDCl₃)：δ2.33(3H，s)，5.41(1H，s)，7.07(2H，t，J＝8.7Hz)，7.43(2H，dd，J＝8.7，5.1Hz).

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

¹H-NMR(CDCl₃)：δ2.27(3H，s)，4.88(2H，s)，7.07(2H，t，J＝8.7Hz)，7.32(2H，dd，J＝8.7，5.4Hz).

(3) 5-bromo-N- [ 4-methyl-5- (4-fluorophenyl) thiazol-2-yl) -2-hydroxybenzamide

¹H-NMR(DMSO-d₆)：δ2.36(3H，s)，6.95(1H，d，J＝8.4Hz)，7.33(2H，t，J＝8.7Hz)，7.52-7.59(3H，m)，8.06(1H，d，J＝3.0Hz)，12.01-13.65(2H，br).

Example 190: 5-bromo-N- { 4-methyl-5- [ 3- (trifluoromethyl) phenyl ] thiazol-2-yl } -2-hydroxybenzamide (Compound No. 190)

The title compound was obtained by carrying out the same operations as in examples 184(1) to (3) using 3- (trifluoromethyl) phenylacetone as a starting material.

Yield: 39.8% (3 steps)

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

¹H-NMR(CDCl₃)：δ2.38(3H，s)，5.43(1H，s)，7.52(1H，t，J＝7.8Hz)，7.61-7.66(2H，m)，7.69-7.70(1H，m).

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

¹H-NMR(CDCl₃)：δ2.32(3H，s)，4.95(2H，s)，7.46-7.56(3H，m)，7.59-7.61(1H，m).

(3) 5-bromo-N- { 4-methyl-5- [ 3- (trifluoromethyl) phenyl ] thiazol-2-yl } -2-hydroxybenzamide

¹H-NMR(DMSO-d₆)：δ2.40(3H，s)，6.97(1H，d，J＝8.7Hz)，7.59(1H，dd，J＝8.7，2.4Hz)，7.71-7.84(4H，m)，(2H，m)，8.06(1H，d，J＝2.4Hz)，12.09(1H，br)，12.91-13.63(1H，br).

Example 191: 5-bromo-N- {4- [ (1, 1-dimethyl) ethyl ] -5-ethylthiazol-2-yl } -2-hydroxybenzamide (Compound No. 191)

The title compound was obtained by carrying out the same operations as in examples 184(1) to (3) using 2, 2-dimethyl-3-hexanone as a starting material.

Yield: 17.0% (3 steps)

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

¹H-NMR(CDCl₃)：δ1.21(3H，t，J＝7.5Hz)，1.32(9H，s)，2.79(2H，q，J＝7.5Hz)，4.63(2H，brs).

(3) 5-bromo-N- {4- [ (1, 1-dimethyl) ethyl ] -5-ethylthiazol-2-yl } -2-hydroxybenzamide

¹H-NMR(CDCl₃)：δ1.32(3H，t，J＝7.5Hz)，1.41(9H，s)，2.88(2H，q，J＝7.5Hz)，6.84(1H，d，J＝9.0Hz)，7.44(1H，dd，J＝8.7，2.4Hz)，8.05(1H，d，J＝2.7Hz)，11.46(2H，br).

Example 192: 5-bromo-N- (4-ethyl-5-phenylthiazol-2-yl) -2-hydroxybenzamide (Compound No. 192)

The same procedures used in example 16 were repeated using 5-bromosalicylic acid and 2-amino-4-ethyl-5-phenylthiazole as starting materials to give the title compound.

Yield: 17.4 percent

mp 224-225℃.

¹H-NMR(DMSO-d₆)：δ1.24(3H，t，J＝7.6Hz)，2.70(2H，q，J＝7.6Hz)，6.95(1H，brd，J＝7.6Hz)，7.39-7.42(1H，m)，7.45-7.51(4H，m)，7.56(1H，brd，J＝8.0Hz)，8.06(1H，d，J＝2.8Hz)，11.98(1H，brs).

Example 193: 5-bromo-N- (4-ethyl-5-isopropylthiazol-2-yl) -2-hydroxybenzamide (Compound No. 193)

The title compound was obtained by carrying out the same operations as in examples 184(1) to (3) using benzyl isopropyl ketone as the starting material.

Yield: 4.4% (3 steps)

(2) 2-amino-4-ethyl-5-isopropylthiazole

¹H-NMR(CDCl₃)：δ1.23(6H，d，J＝6.6Hz)，3.05(1H，m)，4.94(2H，s)，7.28-7.41(5H，m).

(3) 5-bromo-N- (4-ethyl-5-isopropylthiazol-2-yl) -2-hydroxybenzamide

¹H-NMR(DMSO-d₆)：δ1.26(6H，d，J＝6.0Hz)，3.15(1H，m)，6.98(1H，brs)，7.43-7.53(5H，m)，7.59(1H，brs)，8.08(1H，d，J＝2.7Hz)，11.90(1H，brd)，13.33(1H，brd).

Example 194: 5-bromo-N- (4-butyl-5-phenylthiazol-2-yl) -2-hydroxybenzamide (Compound No. 194)

The title compound was obtained in the same manner as in examples 184(1) to (3) using 1-phenyl-2-hexanone as a starting material.

Yield: 52.6% (3 steps)

(1) Alpha-bromo-1-phenyl-2-hexanones

¹H-NMR(CDCl₃)：δ0.85(3H，t，J＝7.2Hz)，1.19-1.32(2H，m)，1，50-1.60(2H，m)，2.59(2H，td，J＝7.5，3.9Hz)，5.44(1H，s)，7.34-7.45(5H，m).

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

¹H-NMR(CDCl₃，δ)：0.89(3H，t，J＝7.5Hz)，1.28-1.41(2H，m)，1.61-1.71(2H，m)，2.56-2.61(2H，m)，4.87(2H，s)，7.25-7.40(5H，m).

(3) 5-bromo-N- (4-butyl-5-phenylthiazol-2-yl) -2-hydroxybenzamide

¹H-NMR(DMSO-d₆)：δ0.85(3H，t，J＝7.2Hz)，1.23-1.35(2H，m)，1.59-1.69(2H，m)，2.70(2H，t，J＝7.2Hz)，6.96(1H，d，J＝6.9Hz)，7.39-7.59(6H，m)，8.07(1H，d，J＝2.4Hz)，11.93(1H，br)，13.18-13.59(1H，br).

Example 195: 5-chloro-N- {4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl } -2-hydroxybenzamide (Compound No. 195) (1) α -bromodipivaloylmethane

Dipivaloylmethane (1.00g, 5.42mmol) was dissolved in carbon tetrachloride (10mL), N-bromosuccinimide (965.8mg, 5.42mmol) was added, and the mixture was refluxed for 2 hours. After cooling, insoluble matter was removed by filtration, and the filtrate was distilled under reduced pressure to give the title compound as white crystals (1.42g, quant).

¹H-NMR(CDCl₃，δ)：1.27(18H，s)，5.67(1H，s).

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

A mixture of α -bromodipivaloylmethane (1.42g), thiourea (451.8mg), ethanol (15mL) was heated under reflux for 2 hours. After cooling, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to crystallize the obtained residue (dichloromethane/hexane) to obtain white crystals of the title compound (1.23g, 94.5%).

¹H-NMR(CDCl₃，δ)：1.26(9H，s)，1.29(9H，s)，5.03(2H，s).

(3) 5-chloro-N- {4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl } -2-hydroxybenzamide

A mixture of 5-bromosalicylic acid (0.20g, 0.92mmol), 2-amino-4- [ (1, 1-dimethyl) ethyl ] -5- [ (2, 2-dimethyl) propionyl ] thiazole (221.5mg, 0.92mmol), phosphorus trichloride (40.1, 0.46mmol) and chlorobenzene (5mL) was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate: 2: 1) to obtain a white powder of the title compound (96.2mg, 23.8%).

¹H-NMR(CDCl₃)：δ1.33(9H，s)，1.35(9H，s)，6.94(1H，d，J＝8，7Hz)，7.55(1H，dd，J＝8.7，2.1Hz)，7.85(1H，d，J＝2.1Hz)，10.51(2H，br).

Example 196: 5-bromo-N- {4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl } -2-hydroxybenzamide (Compound No. 196)

The same procedures used in example 195(3) were repeated except for using 5-bromosalicylic acid and 2-amino-4- [ (1, 1-dimethyl) ethyl ] -5- [ (2, 2-dimethyl) propionyl ] thiazole as starting materials to give the title compound.

Yield: 23.8 percent

Example 197: ethyl 2- (5-bromo-2-hydroxybenzoyl) amino-4- [ (1, 1-dimethyl) ethyl ] thiazole-5-carboxylate (Compound No. 197)

The title compound was obtained in the same manner as in examples 195(1) to (3) using ethyl pivaloylacetate as a starting material.

Yield: 45.7% (3 steps)

(1) alpha-Bromopivalyl acetic acid ethyl ester

¹H-NMR(CDCl₃)：δ1.28(9H，s)，1.29(3H，t，J＝7.2Hz)，4.26(2H，q，J＝7.2Hz)，5.24(1H，s).

(2) 2-amino-4- [ (1, 1-dimethyl) ethyl ] thiazole-5-carboxylic acid ethyl ester

¹H-NMR(CDCl₃，δ)：1.32(3H，t，J＝7.2Hz)，1.43(9H，s)，4.24(2H，q，J＝7.2Hz)，5.18(2H，s).

(3)2- (5-bromo-2-hydroxybenzoyl) amino-4- [ (1, 1-dimethyl) ethyl ] thiazole-5-carboxylic acid ethyl ester

¹H-NMR(DMSO-d₆)：δ1.30(3H，t，J＝7.2Hz)，1.44(9H，s)，4.27(2H，q，J＝6.9Hz)，7.00(1H，d，J＝8.7Hz)，7.63(1H，dd，J＝8.7，2.7Hz)，8.02(1H，d，J＝2.4Hz)，11.80(1H，br)，12.12(1H，br).

Example 198: 5-bromo-N- [ 4- (1, 1-dimethyl) ethyl-5-piperidinothiazol-2-yl ] -2-hydroxybenzamide (Compound No. 198)

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

2-amino-4- [ (1, 1-dimethyl) ethyl ] thiazole (0.87g, 5.6mmol) was dissolved in carbon tetrachloride (9mL), and N-bromosuccinimide (1.00g, 5.6mmol) was added and the mixture was stirred at room temperature for 1 hour. Hexane was added to the reaction mixture, insoluble matter was removed by filtration, the filtrate was distilled under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 2: 1) to give the title compound as a yellow-gray powder (1.23g, 93.7%).

¹H-NMR(CDCl₃)：δ1.39(9H，s)，4.81(2H，brs).

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

A mixture of 2-amino-5-bromo-4- [ (1, 1-dimethyl) ethyl ] thiazole (0.10g, 0.42mmol), piperidine (0.1mL), potassium carbonate (0.20g) and acetonitrile (4mL) was heated under reflux for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 2: 1) to obtain yellow crystals (80.7mg, 79.3%) of the title compound.

¹H-NMR(CDCl₃)：δ1.32(9H，s)，1.64(4H，t，J＝5.7Hz)，1.71-1.77(2H，m)，2.35(2H，brs)，2.99(2H，brs)，4.68(2H，s).

(3) 2-acetoxy-5-bromo-N- [ 4- (1, 1-dimethyl) ethyl-5-piperidinothiazol-2-yl ] benzamide

Phosphorus oxychloride (46. mu.l, 0.50mmol) was added to a mixture of 2-acetoxy-5-bromobenzoic acid (J.Med. chem.31, 861-containing 8741996) (90.3mg, 0.35mmol), thiazole (80.7mg, 0.34mmol), pyridine (0.1mL), THF (3mL) under an argon atmosphere, and stirred at room temperature for 2 hours. The reaction mixture was poured into 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 3: 1) to obtain the crude product of the title compound (84.3 mg).

(4) 5-bromo-N- [ 4- (1, 1-dimethyl) ethyl-5-piperidinothiazol-2-yl ] -2-hydroxybenzamide

2-acetoxy-5-bromo-N- [ 4- (1, 1-dimethyl) ethyl-5-piperidinothiazol-2-yl ] benzamide (crude product, 84.3mg) was dissolved in ethanol (3mL), and 2N sodium hydroxide solution (0.1mL) was added to stir at room temperature for 1 hour. The reaction mixture was poured into 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 4: 1) to obtain a white powder of the title compound (54.1mg, 36.3%; 2 steps).

¹H-NMR(CDCl₃)：δ1.41(9H，s)，1.56(2H，brs)，1.67-1.74(4H，m)，2.79(4H，brs)，6.85(1H，d，J＝9.0Hz)，7.45(1H，dd，J＝9.0，2.4Hz)，8.06(1H，d，J＝2.4Hz)，11.70(2H，br).

Example 199: 5-bromo-N- [ 4- (1, 1-dimethyl) ethyl-5-morpholinothiazol-2-yl ] -2-hydroxybenzamide (Compound No. 199)

The title compound was obtained in the same manner as in examples 198(2) to (4) using morpholine as a starting material.

Yield: 17.1 percent

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

¹H-NMR(CDCl₃)：δ1.33(9H，s)，2.76(4H，brs)，3.79(4H，brs)，4.66(2H，s).

(3) 2-acetoxy-5-bromo-N- [ 4- (1, 1-dimethyl) ethyl-5-morpholinothiazol-2-yl ] benzamide

The crude product was used directly in the following reaction.

(4) 5-bromo-N- [ 4- (1, 1-dimethyl) ethyl-5-morpholinothiazol-2-yl ] -2-hydroxybenzamide

¹H-NMR(CDCl₃)：δ1.24(9H，s)，2.89(4H，dd，

J＝4.8，4.2Hz)，3.83(4H，dd，J＝4.5，4.2Hz)，6.89(1H，d，J＝9.0Hz)，7.49(1H，dd，J＝9.0，2.4Hz)，7.98(1H，d，J＝2.1Hz)，11.20(2H，br).

Example 200: 5-bromo-N- [ 4- (1, 1-dimethyl) ethyl-5- (4-methylpiperazin-1-yl) thiazol-2-yl ] -2-hydroxybenzamide (Compound No. 200)

The title compound was obtained in the same manner as in examples 198(2) to (4) using 4-methylpiperazine as a raw material.

Yield: 6.9 percent

(2) 2-amino-4- (1, 1-dimethyl) ethyl-5- (4-methylpiperazin-1-yl) thiazole

¹H-NMR(DMSO-d₆)：δ1.25(9H，s)，2.12(2H，brs)，2.19(3H，s)，2.57(2H，brs)，2.72(4H，brs)，6.51(2H，s).

(3) 2-acetoxy-N- [ 4- (1, 1-dimethyl) ethyl-5- (4-methylpiperazin-1-yl) thiazol-2-yl ] benzamide

The crude product was used directly in the following reaction.

(4) 5-bromo-N- [ 4- (1, 1-dimethyl) ethyl-5- (4-methylpiperazin-1-yl) thiazol-2-yl ] -2-hydroxybenzamide

¹H-NMR(CD₃OD)：δ1.41(9H，s)，2.55(3H，s)，2.87(4H，brs)，3.03(4H，brs)，6.88(1H，d，J＝8.7Hz)，7.49(1H，dd，J＝8.7，2.7Hz)，8.11(1H，d，J＝2.7Hz).

Example 201: 5-bromo-N- [ 4- (1, 1-dimethyl) ethyl-5- (4-phenylpiperazin-1-yl) thiazol-2-yl ] -2-hydroxybenzamide (Compound No. 201)

The title compound was obtained in the same manner as in examples 198(2) to (4) using 4-phenylpiperazine as a starting material.

Yield: 6.9 percent

(2) 2-amino-4- (1, 1-dimethyl) ethyl-5- (4-phenylpiperazin-1-yl) thiazole

¹H-NMR(CDCl₃)：δ1.34(9H，s)，2.80(2H，brs)，3.03(4H，brs)，3.55(2H，brs)，4.69(2H，s)，6.88(1H，tt，J＝7.2，1.2Hz)，6.95(2H，dd，J＝9.0，1.2Hz)，7.28(2H，dd，J＝8.7，7.2Hz).

(3) 2-acetoxy-5-bromo-N- [ 4- (1, 1-dimethyl) ethyl-5- (4-phenylpiperazin-1-yl) thiazol-2-yl ] benzamide

The crude product was used directly in the following reaction.

(4) 5-bromo-N- [ 4- (1, 1-dimethyl) ethyl-5- (4-phenylpiperazin-1-yl) thiazol-2-yl ] -2-hydroxybenzamide

¹H-NMR(DMSO-d₆)：δ1.39(9H，s)，2.97(4H，s)，3.30(4H，s)，6.82(1H，t，J＝7.5Hz)，6.97(2H，brs)，6.99(2H，t，J＝7.5Hz)，7.58(1H，brs)，8.05(1H，d，J＝2.4Hz)，11.69(1H，brs)，11.82(1H，brs).

Example 202: 5-bromo-N- (4-phenylthiazol-2-yl) -2-hydroxybenzamide (Compound No. 202)

The title compound was obtained in the same manner as in example 195(3) using 5-bromosalicylic acid and 2-amino-4-phenylthiazole as starting materials.

Yield: 16.0 percent

mp 239℃(dec.).

¹H-NMR(DMSO-d₆)：δ7.02(1H，d，J＝8.4Hz)，7.34(1H，t，J＝7.6Hz)，7.44(2H，t，J＝7.6Hz)，7.62(1H，dd，J＝8.4，2.8Hz)，7.67(1H，s)，7.92(2H，d，J＝7.2Hz)，8.08(1H，d，J＝2.8Hz)，11.88(1H，brs)，12.05(1H，brs).

Example 203: {2- [ (5-bromo-2-hydroxybenzoyl) amino ] -4-phenylthiazol-5-yl } acetic acid (compound No. 203)

(1) {2- [ (5-bromo-2-hydroxybenzoyl) amino ] -4-phenylthiazol-5-yl } acetic acid methyl ester

The same procedures used in example 195(3) were repeated except for using 5-bromosalicylic acid and methyl 2-amino-4-phenylthiazole-5-acetate as starting materials to give the title compound.

Yield: 32.1 percent of

mp 288.5-229.5℃.

¹H-NMR(DMSO-d₆)：δ3.66(3H，s)，3.95(2H，8)，6.99(1H，d，J＝8.0Hz)，7.42(1H，d，J＝6.0Hz)，7.48(2H，brt，J＝7.6Hz)，7.56-7.61(3H，m)，8.07(1H，d，J＝2.4Hz)，11.85(1H，brs)，11.98(1H，brs).

(2) {2- [ (5-bromo-2-hydroxybenzoyl) amino ] -4-phenylthiazol-5-yl } acetic acid

Methyl {2- [ (5-bromo-2-hydroxybenzoyl) amino ] -4-phenylthiazol-5-yl } acetate (75mg, 0.17mmol) was dissolved in methanol (5mL), and 2N sodium hydroxide (0.5mL, 1mmol) was added, followed by stirring 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 with water and saturated brine in this order, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was washed with n-hexane-ethyl acetate under reflux with heating to obtain pale yellow white crystals of the title compound (56mg, 77.3%).

mp 284-286℃.

¹H-NMR(DMSO-d₆)：δ3.84(2H，s)，6.98(1H，d，J＝8.8Hz)，7.42(1H，d，J＝6.8Hz)，7.49(2H，t，J＝7.6Hz)，7.58-7.61(3H，m)，8.07(1H，d，J＝2.8Hz)，12.25(H，brs).

Example 204: 5-bromo-N- (4, 5-diphenylthiazol-2-yl) -2-hydroxybenzamide (Compound No. 204)

The same procedures used in example 195(3) were repeated except for using 5-bromosalicylic acid and 2-amino-4, 5-diphenylthiazole as starting materials to give the title compound (2-amino-4, 5-diphenylthiazole: see Japanese journal of chemistry 1962, 83, 209.).

Yield: 25.9 percent

mp 262-26.3℃.

¹H-NMR(DMSO-d₆)：δ7.02(1H，d，J＝8.1Hz)，7.34-7.47(10H，m)，7.63(1H，d，J＝6.9Hz)，8.08(1H，d，J＝2.4Hz)，11.88(1H，brs)，12.08(1H，brs).

Example 205: 5-bromo-N- (4-benzyl-5-phenylthiazol-2-yl) -2-hydroxybenzamide (Compound No. 205)

The same procedures used in example 195(3) were repeated except for using 5-bromosalicylic acid and 2-amino-4-benzyl-5-phenylthiazole as starting materials to give the title compound (2-amino-4-benzyl-5-phenylthiazole: chem. pharm. Bull., 1962, 10, 376.).

Yield: 28.1 percent

mp 198-200℃.

¹H-NMR(DMSO-d₆)：δ4.08(2H，s)，6.95(1H，d，J＝8.8Hz)，7.15-7.22(3H，m)，7.30(2H，t，J＝7.6Hz)，7.38-7.43(1H，m)，7.47(4H，d，J＝4.4Hz)，7.57(1H，brd，J＝8.8Hz)，8.05(1H，d，J＝2.4Hz)，11.98(1H，brs).

Example 206: 5-bromo-N- [ 5-phenyl-4- (trifluoromethyl) thiazol-2-yl ] -2-hydroxybenzamide (Compound No. 206)

The title compound was obtained in the same manner as in example 195(3) using 5-bromosalicylic acid and 2-amino-5-phenyl-4- (trifluoromethyl) thiazole as starting materials.

Yield: 33.2 percent

mp 250℃(dec.).¹H-NMR(DMSO-d₆)：δ7.02(1H，d，J＝8.8Hz)，7.51(5H，s)，7.63(1H，dd，J＝8.8，2.4Hz)，8.02(1H，d，J＝2.8Hz)，12.38(1H，brs).

Example 207: 5-bromo-N- [ 5-acetyl-4-phenylthiazol-2-yl ] -2-hydroxybenzamide (Compound No. 207)

The title compound was obtained by carrying out the same operations as in examples 195(1), (3) and (1) using 1-phenyl-1, 3-butanedione as a starting material.

Yield: 8.9% (3 steps)

(1) Alpha-bromo-1-phenyl-1, 3-butanedione

¹H-NMR(CDCl₃)：δ2.46(3H，s)，5.62(1H，s)，7.48-7.54(2H，m)，7.64(1H，tt，J＝7.5，2.1Hz)，7.97-8.01(2H，m).

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

¹H-NMR(DMSO-d₆)：δ2.18(3H，s)，7.50-7.55(2H，m)，7.59-7.68(3H，m)，8.69(2H，brs).

(3) 5-bromo-N- [ 5-acetyl-4-phenylthiazol-2-yl ] -2-hydroxybenzamide

¹H-NMR(DMSO-d₆)：δ2.44(3H，s)，6.99(1H，d，J＝9.0Hz)，7.55-7.71(4H，m)，7.76-7.80(2H，m)，8.01(1H，d，J＝2.4Hz)，12.36(2H，br).

Example 208: 5-bromo-N- [ 5-benzoyl-4-phenylthiazol-2-yl ] -2-hydroxybenzamide (Compound No. 208)

The title compound was obtained by carrying out the same operations as in examples 195(1) - (3) using 1, 3-diphenyl-1, 3-propanedione as the starting material.

Yield: 49.7 percent

(1) Alpha-bromo-1, 3-diphenyl-1, 3-propanedione

¹H-NMR(CDCl₃，δ)：6.55(1H，s)，7.45-7.50(4H，m)，7.61(2H，tt，J＝7.2，2.1Hz)，7.98-8.01(4H，m).

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

¹H-NMR(DMSO-d₆)：δ7.04-7.18(5H，m)，7.22-7.32(3H，m)，7.35-7.38(2H，m)，8.02(2H，s).

(3) 5-bromo-N- [ 5-benzoyl-4-phenylthiazol-2-yl ] -2-hydroxybenzamide

¹H-NMR(DMSO-d₆)：δ7.03(1H，d，J＝8.7Hz)，7.17-7.30(5H，m)，7.39-7.47(3H，m)，7.57-7.60(2H，m)，7.64(1H，d d，J＝8.7，2.7Hz)，8.05(1H，d，J＝2.4Hz)，11.82(1H，brs)，12.35(1H，brs).

Example 209: 2- (5-chloro-2-hydroxybenzoyl) amino-4-phenylthiazole-5-carboxylic acid ethyl ester (Compound No. 209)

The same procedures as in example 195(3) were repeated using 5-chlorosalicylic acid and ethyl 2-amino-4-phenylthiazole-5-carboxylate as starting materials to give the title compound.

Yield: 69.4 percent

¹H-NMR(DMSO-d₆)：δ1.22(3H，t，J＝7.5Hz)，4.21(2H，q，J＝7.5Hz)，7.07(1H，d，J＝8.7Hz)，7.43-7.47(3H，m)，7.53(1H，dd，J＝8.7，2.4Hz)，7.70-7.74(2H，m)，7.92(1H，d，J＝3.0Hz)，11.88(1H，br)，12.29(1H，brs).

Example 210: 2- (5-bromo-2-hydroxybenzoyl) amino-4-phenylthiazole-5-carboxylic acid ethyl ester (Compound No. 210)

The same procedures used in example 195(3) were repeated except for using 5-bromosalicylic acid and ethyl 2-amino-4-phenylthiazole-5-carboxylate as starting materials to give the title compound.

Yield: 28.6 percent

mp 197-199℃.

¹H-NMR(DMSO-d₆)：δ1.21(3H，t，J＝6.8Hz)，4.20(2H，q，J＝6.8Hz)，7.01(1H，d，J＝8.8Hz)，7.43-7.48(3H，m)，7.63(1H，dd，J＝8.8，2.4Hz)，7.70-7.72(2H，m)，8.04(1H，d，J＝2.4Hz)，12.33(1H，brs).

Example 211: ethyl 2- (5-bromo-2-hydroxybenzoyl) amino-4- (pentafluorophenyl) thiazole-5-carboxylate (Compound No. 211)

The title compound was obtained in the same manner as in examples 195(1) to (3) using pentafluorobenzoylacetic acid as a starting material.

Yield: 40.0% (3 steps)

(1) Alpha-bromo-pentafluorobenzoylacetic acid ethyl ester

The crude product was used directly in the following reaction.

(2) 2-amino-4- (pentafluorophenyl) thiazole-5-carboxylic acid ethyl ester

¹H-NMR(CDCl₃)：δ1.23(3H，t，J＝7.2Hz)，4.21(2H，q，J＝7.2Hz)，5.41(2H，s).

(3)2- (5-bromo-2-hydroxybenzoyl) amino-4- (pentafluorophenyl) thiazole-5-carboxylic acid ethyl ester

¹H-NMR(DMSO-d₆)：δ1.20(3H，t，J＝7.2Hz)，2.51(2H，q，J＝7.2Hz)，7.02(1H，d，J＝8.7Hz)，7.64(1H，dd，J＝8.7，2.7Hz)，7.90(1H，d，J＝3.0Hz)，11.92(1H，br)，12.58(1H，br).

Example 212: [ 2- (5-bromo-2-hydroxybenzoyl) amino-4- (pentafluorophenyl) thiazol-5-yl ] -N-methylformamide (compound No. 212)

(1)2- (5-bromo-2-hydroxybenzoyl) amino-4- (pentafluorophenyl) thiazole-5-carboxylic acid

The same procedures used in example 82 were repeated except for using ethyl 2- (5-bromo-2-hydroxybenzoyl) amino-4- (pentafluorophenyl) thiazole-5-carboxylate to give the title compound.

(2) [ 2- (5-bromo-2-hydroxybenzoyl) amino-4- (pentafluorophenyl) thiazol-5-yl ] -N-methylformamide

A mixture of 2- (5-bromo-2-hydroxybenzoyl) amino-4- (pentafluorophenyl) thiazole-5-carboxylic acid (0.20g, 0.48mmol), methylamine in 40% methanol (0.2mL), 1-hydroxybenzotriazole hydrate (96.7mg, 0.72mmol), WSC & HCl (137.2mg, 0.72mmol), and tetrahydrofuran (15mL) was stirred at room temperature for 18 hours. The reaction mixture was poured into 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 1: 2) to crystallize (dichloromethane/n-hexane) to obtain a white powder of the title compound (87.9mg, 42.6%).

¹H-NMR(DMSO-d₆)：δ2.70(3H，d，J＝4.5Hz)，7.02(1H，d，J＝9.0Hz)，7.40-7.48(3H，m)，7.63(1H，dd，J＝9.0，2.4Hz)，7.68-7.71(2H，m)，8.06(1H，d，J＝2.4Hz)，8.16(1H，t，J＝4.5Hz)，11.88(1H，br)，12.15(1H，brs).

Example 213: [ 2- (5-bromo-2-hydroxybenzoyl) amino-4- (pentafluorophenyl) thiazol-5-yl ] -N-ethylformamide (compound No. 213)

The same procedures used in example 212(2) were repeated using 70% aqueous solution of 2- (5-bromo-2-hydroxybenzoyl) amino-4- (pentafluorophenyl) thiazole-5-carboxylic acid and ethylamine as starting materials to give the title compound.

Yield: 62.5 percent

¹H-NMR(DMSO-d₆)：δ1.05(3H，t，J＝6.9Hz)，3.15-3.24(2H，m)，7.02(1H，d，J＝8.7Hz)，7.40-7.47(3H，m)，7.63(1H，dd，J＝8.7，3.0Hz)，7.69-7.72(2H，m)，8.06(1H，d，J＝2.4Hz)，8.20(1H，t，J＝5.4Hz)，11.84(1H，br)，12.14(1H，brs).

Example 214: [ 2- (5-bromo-2-hydroxybenzoyl) amino-4- (pentafluorophenyl) thiazol-5-yl ] -N-isopropylcarboxamide (Compound No. 214)

The same procedures used in example 212(2) were repeated using 2- (5-bromo-2-hydroxybenzoyl) amino-4- (pentafluorophenyl) thiazole-5-carboxylic acid and isopropylamine as starting materials to give the title compound.

Yield: 23.9 percent

¹H-NMR(DMSO-d₆)：δ1.07(6H，d，J＝6.3Hz)，4.02(1H，m)，7.02(1H，d，J＝9.0Hz)，7.40-7.52(3H，m)，7.64(1H，dd，J＝8.7，2.7Hz)，7.69-7.73(2H，m)，8.06(1H，d，J＝2.7Hz)，11.89(1H，br)，12.14(1H，brs).

Example 215: [ 2- (5-bromo-2-hydroxybenzoyl) amino-4- (pentafluorophenyl) thiazol-5-yl ] -N- (2-phenylethyl) carboxamide (compound number 215)

The same procedures used in example 212 were repeated using 2- (5-bromo-2-hydroxybenzoyl) amino-4- (pentafluorophenyl) thiazole-5-carboxylic acid and 2-phenethylamine as starting materials to give the title compound.

Yield: 62.2 percent

¹H-NMR(DMSO-d₆)：δ2.78(2H，t，J＝7.5Hz)，3.43(2H，q，J＝7.5Hz)，7.02(1H，d，J＝9.0Hz)，7.19-7.24(3H，m)，7.27-7.33(2H，m)，7.39-7.41(3H，m)，7.61-7.65(3H，m)，8.06(1H，d，J＝2.4Hz)，8.25(1H，t，J＝6.0Hz)，11.85(1H，brs)，12.15(1H，brs).

Example 216: 2- (5-bromo-2-hydroxybenzoyl) amino-4- (trifluoromethyl) thiazole-5-carboxylic acid ethyl ester (compound No. 216)

The title compound was obtained in the same manner as in example 195(3) using 5-bromosalicylic acid and ethyl 2-amino-4- (trifluoromethyl) thiazole-5-carboxylate as starting materials. Yield: 88.7 percent

¹H-NMR(DMSO-d₆)：δ1.32(3H，t，J＝7.2Hz)，4.33(2H，q，J＝7.2Hz)，7.01(1H，d，J＝8.7Hz)，7.63(1H，dd，J＝8.7，2.7Hz)，7.98(1H，d，J＝2.4Hz)，12.64(1H，br).

Example 217: 2-acetoxy-5-chloro-N- {4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl } benzamide

The same procedures used in example 96 were repeated using 5-chloro-N- {4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl } -2-hydroxybenzamide and acetyl chloride as starting materials to give the title compound.

Yield: 65.3 percent

¹H-NMR(CDCl₃)：δ1.32(9H，s)，1.33(9H，s)，2.46(3H，s)，7.22(1H，d，J＝8.4Hz)，7.56(1H，dd，J＝8.7，2.4Hz)，8.05(1H，d，J＝2.7Hz)，9.82(1H，brs).

Example 218: 2- [ (4-Hydroxybiphenyl) -3-carbonyl ] amino-4-phenylthiazole-5-carboxylic acid ethyl ester (Compound No. 218)

The same procedures used in example 195 and 3 were repeated except for using 4-hydroxybiphenyl-3-carboxylic acid and ethyl 2-amino-4-phenylthiazole-5-carboxylate as starting materials to give the title compound (4-hydroxybiphenyl-3-carboxylic acid: see Tetrahedron, 1997, 53, 11437.).

Yield: 61.7 percent

mp 207-208℃.

¹H-NMR(DMSO-d₆)：δ1.23(3H，t，J＝7.2Hz)，4.22(2H，q，J＝7.2Hz)，7.16(1H，d，J＝8.7Hz)，7.36(1H，t，J＝7.5Hz)，7.45-7.50(5H，m)，7.69-7.76(4H，m)，7.85(1H，dd，J＝8.7，2.4Hz)，8.31(1H，d，J＝2.4Hz)，11.73(1H，brs)，12.60(1H，brs).

Example 219: ethyl 2- [ (4' -fluoro-4-hydroxybiphenyl) -3-carbonyl ] amino-4-phenylthiazole-5-carboxylate (compound No. 219)

The same procedures used in example 195 and 3 were repeated except for using (4 '-fluoro-4-hydroxybiphenyl) -3-carboxylic acid and ethyl 2-amino-4-phenylthiazole-5-carboxylate as starting materials to give the title compound ((4' -fluoro-4-hydroxybiphenyl) -3-carboxylic acid: see Tetrahedron, 1997, 53, 11437.).

Yield: 62.7 percent

mp 237-238℃.

¹H-NMR(DMSO-d₆)：δ1.22(3H，t，J＝7.2Hz)，4.21(2H，q，J＝7.2Hz)，7.13(1H，d，J＝8.4Hz)，7.28(2H，t，J＝8.8Hz)，7.44-7.45(3H，m)，7.71-7.75(4H，m)，7.81(1H，dd，J＝8.8，2.4Hz)，8.27(1H，d，J＝2.4Hz)，11.67(1H，brs)，12.58(1H，brs).

Example 220: ethyl 2- [ (2 ', 4' -difluoro-4-hydroxybiphenyl) -3-carbonyl ] amino-4-phenylthiazole-5-carboxylate (Compound No. 220)

The same procedures as in example 195(3) were carried out using (2 ', 4' -difluoro-4-hydroxybiphenyl) -3-carboxylic acid and ethyl 2-amino-4-phenylthiazole-5-carboxylate as starting materials to give the title compound.

Yield: 45.6 percent of

mp 206-207℃.

¹H-NMR(DMSO-d₆)：δ1.22(3H，t，J＝7.2Hz)，4.22(2H，q，J＝7，2Hz)，7.17(1H，d，J＝9.0Hz)，7.21(1H，td，J＝8.7，2.4Hz)，7.38(1H，ddd，J＝11.7，9.3，2.4Hz)，7.44-7.46(3H，m)，7.60-7.75(4H，m)，8.13-8.14(1H，m)，11.86(1H，brs)，12.46(1H，brs).

Example 221: ethyl 2- { [ 4-hydroxy-4' - (trifluoromethyl) biphenyl ] -3-carbonyl } amino-4-phenylthiazole-5-carboxylate (compound No. 221)

(1) [ 4' - (trifluoromethyl) -4-hydroxybiphenyl ] -3-carboxylic acid

A mixture of 5-bromosalicylic acid (500mg, 2.30mmol), dihydroxy-4- (trifluoromethyl) phenylborane (488mg, 2.57mmol), palladium acetate (10mg, 0.040mmol), and 1M sodium carbonate (7mL) was stirred at 80 ℃ for 1 hour. The reaction mixture was poured into 2N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was allowed to form a methyl ester using trimethylsilyldiazomethane and methanol according to a conventional method, followed by purification by silica gel column chromatography (n-hexane: ethyl acetate 5: 1),a colorless liquid (563mg) was obtained. This was dissolved in methanol (10mL), and 2N sodium hydroxide (3mL) was added, followed by stirring at 60 ℃ for 1 hour. After the reaction mixture was cooled to room temperature, it was poured into 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine in this order, and MgSO ₄After drying, the solvent was distilled off under reduced pressure. The obtained residue was washed with n-hexane-dichloromethane under reflux with heating to obtain white crystals of the title compound (458mg, 70.4%).

mp 185℃(dec.).

¹H-NMR(DMSO-d₆)：δ7.09(1H，d，J＝8.8Hz)，7.77(2H，d，J＝8.0Hz)，7.85(2H，d，J＝8.0Hz)，7.90(1H，dd，J＝8.8，2.0Hz)，8.10(1.H，d，J＝2.4Hz)，11.80(brs).

(2)2- { [ 4-hydroxy-4' - (trifluoromethyl) biphenyl ] -3-carbonyl } amino-4-phenylthiazole-5-carboxylic acid ethyl ester

The same procedures used in example 195(3) were repeated except for using [ 4' - (trifluoromethyl) -4-hydroxybiphenyl ] -3-carboxylic acid and ethyl 2-amino-4-phenylthiazole-5-carboxylate as starting materials to give the title compound.

Yield: 41.7 percent

mp 236-237℃.

¹H-NMR(DMSO-d₆)：δ1.22(3H，t，J＝7.2Hz)，4.21(2H，q，J＝7.2Hz)，7.18(1H，d，J＝8.8Hz)，7.44-7.45(3H，m)，7.72-7.74(2H，m)，7.81(2H，d，J＝8.4Hz)，7.91(1H，dd，J＝8.8，2.4Hz)，7.93(2H，d，J＝8.4Hz)，8.36(1H，d，J＝2.4Hz)，11.78(1H，brs)，12.62(1H，brs).

Example 222: 2- [ 2-hydroxy-5- (1-pyrrolyl) benzoyl ] amino-4-phenylthiazole-5-carboxylic acid ethyl ester (compound No. 222)

The same procedures as in example 195(3) were repeated using 2-hydroxy-5- (1-pyrrolyl) benzoic acid and ethyl 2-amino-4-phenylthiazole-5-carboxylate as starting materials to give the title compound.

Yield: 55.0 percent

¹H-NMR(DMSO-d₆)：δ1.22(3H，t，J＝7.2Hz)，4.22(2H，q，J＝7.2Hz)，6.26(2H，t，J＝2.1Hz)，7.13(1H，d，J＝8.7Hz)，7.32(2H，t，J＝2.1Hz)，7.43-7.47(3H，m)，7.70-7.75(3H，m)，8.09(1H，d，J＝2.7Hz)，11.58(1H，brs)，12.55(1H，brs).

Example 223: 2- [ 2-hydroxy-5- (2-thienyl) benzoyl ] amino-4-phenylthiazole-5-carboxylic acid ethyl ester (compound No. 223)

(1) 2-hydroxy-5- (2-thienyl) benzoic acid

5-Bromosalicylic acid (500mg, 2.30mmol) was dissolved in 1, 2-dimethoxyethane (5mL), and tetrakis (triphenylphosphine) palladium (80mg, 0.07mmol) was added under an argon atmosphere, followed by stirring at room temperature for 10 minutes. Next, dihydroxy-2-thienylborane (324mg, 2.53mmol) and 1M sodium carbonate (7mL) were added, and the mixture was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was formed into a methyl ester using trimethylsilyldiazomethane and methanol according to a conventional method, followed by purification by silica gel column chromatography (n-hexane: ethyl acetate: 5: 1) to give a yellow liquid (277 mg). This was dissolved in methanol (5mL), and 2N sodium hydroxide (1.5mL) was added, followed by stirring at 60 ℃ for 1 hour. After the reaction mixture was cooled to room temperature, it was poured into 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine in this order, dried over anhydrous magnesium sulfate, the solvent was then distilled off under reduced pressure, and the resulting residue was crystallized from n-hexane-dichloromethane to give the title compound as white crystals (58mg, 11.5%).

¹H-NMR(DMSO-d₆)：δ6.95(1H，d，J＝8.8Hz)，7.09(1H，dd，J＝4.8，3.6Hz)，7.37(1H，dd，J＝4.0，1.2Hz)，7.45(1H，dd，J＝5.2，1.2Hz)，7.74(1H，dd，J＝8.8，2.8Hz)，7.96(1H，d，J＝2.8Hz).

(2)2- [ 2-hydroxy-5- (2-thienyl) benzoyl ] amino-4-phenylthiazole-5-carboxylic acid ethyl ester

The same procedures as in example 195(3) were repeated using 2-hydroxy-5- (2-thienyl) benzoic acid and ethyl 2-amino-4-phenylthiazole-5-carboxylate as starting materials to give the title compound.

Yield: 58.2 percent

mp 213-214℃.

¹H-NMR(DMSO-d₆)：δ1.22(3H，t，J＝7.2Hz9，4.21(2H，q，J＝7.2Hz)，7.10(1H，d，J＝9.2Hz)，7.12(1H，dd，J＝4.8，3.6Hz)，7.44-7.46(4H，m)，7.50(1H，dd，J＝4.8，1.2Hz)，7.71-7.74(2H，m)，7.79(1H，dd，J＝8.8，2.4Hz)，8.21(1H，d，J＝2.4Hz)，11.78(1H，brs)，12.44(1H，brs).

Test example: NF-kB activation inhibition assay

NF-. kappa.B activation inhibition was determined by reference to the method of Hill et al (Hill C.S. et al, Cell, 73, 395-406 (1993)). An oligonucleotide was obtained by connecting (ligating) 5 NF-. kappa.B binding sequences (TGGGGACTTTCCGC) to each other to obtain an oligonucleotide, the obtained oligonucleotide was integrated upstream of a fluorite luciferase gene (Luc) to obtain a Plasmid (pNF-. kappa.B-Luc Reporter Plasmid, manufactured by STRATAGENE), the Plasmid was transfected into a cell line HepG2 derived from human liver cancer or a cell line HeLa derived from human uterine cancer using a transfection reagent (Effectene, manufactured by QIAGEN) according to the protocol of QIAGEN, and the cells were cultured for 6 to 24 hours. TNF-. alpha. (40ng/ml) was added in the presence or absence of the compound to be tested, and after 4 hours of incubation, luciferase activity in the cells was measured using ピツカジ - ン LT (manufactured by Toyo ink Co., Ltd.) and a chemiluminescence measuring apparatus (manufactured by TECAN Co., Ltd.). The inhibition rate was determined as the ratio of luciferase activity value in the absence of the test compound. The inhibition rates of NF- κ B activation of the tested compounds in the presence of 10 μ g/ml and 1 μ g/ml are shown in the following tables.

Compound number	NF-. kappa.B activation inhibition ratio (%)
	NF-. kappa.B activation inhibition ratio (%)		Drug concentration 10. mu.g/mL	Drug concentration 1. mu.g/mL
	1	54.4	Drug concentration 10. mu.g/mL	Drug concentration 1. mu.g/mL	-33.6
2	1	54.4	83.2	18.6	-33.6
2	3	68.4	83.2	18.6	54.2
4	3	68.4	94.1	42.9	54.2
4	5	98.0	94.1	42.9	33.3
6	5	98.0	61.9	27.8	33.3
6	7	68.7	61.9	27.8	30.4
8	7	68.7	59.9	35.3	30.4
8	9	99.2	59.9	35.3	21.9
10	9	99.2	78.6	7.1	21.9
10	11	44.1	78.6	7.1	28.4
12	11	44.1	87.3	68.6	28.4
12	13	63.8	87.3	68.6	-7.1
14	13	63.8	98.9	21.7	-7.1
14	15	70.4	98.9	21.7	15.2
16	15	70.4	91.6	36.4	15.2
16	17	96.5	91.6	36.4	19.9
18	17	96.5	90.2	85.3	19.9
18	19	95.1	90.2	85.3	-55.4
20	19	95.1	86.8	-12.1	-55.4
20	21	95.0	86.8	-12.1	89.6
22	21	95.0	92.9	37.0	89.6
22	23	96.6	92.9	37.0	75.7

24	82.2	58.1
24	82.2	58.1	25	86.9	85.4
27	47.3	68.5	25	86.9	85.4
27	47.3	68.5	28	41.7	16.3
29	73.0	46.3	28	41.7	16.3
29	73.0	46.3	30	98.1	76.5
31	93.2	13.3	30	98.1	76.5
31	93.2	13.3	32	96.3	89.3
33	99.5	95.1	32	96.3	89.3
33	99.5	95.1	34	98.5	90.5
35	85.4	88.2	34	98.5	90.5
35	85.4	88.2	36	84.7	26.6
37	63.1	29.1	36	84.7	26.6
37	63.1	29.1	38	81.8	-10.1
39	56.0	21.4	38	81.8	-10.1
39	56.0	21.4	40	81.9	3.9
41	90.3	26.1	40	81.9	3.9
41	90.3	26.1	42	92.3	14.3
43	78.9	25.5	42	92.3	14.3
43	78.9	25.5	44	65.8	36.7
45	91.3	61.7	44	65.8	36.7
45	91.3	61.7	46	85.7	-43.7
47	99.4	91.3	46	85.7	-43.7
47	99.4	91.3	48	95.6	93.3
49	94.3	81.5	48	95.6	93.3
49	94.3	81.5	50	99.5	96.3

51	98.6	94.9
51	98.6	94.9	52	85.4	86.6
53	99.2	92.0	52	85.4	86.6
53	99.2	92.0	54	99.6	92.2
55	99.4	95.8	54	99.6	92.2
55	99.4	95.8	56	98.3	92.9
57	96.0	76.8	56	98.3	92.9
57	96.0	76.8	58	98.3	94.7
59	99.2	94.5	58	98.3	94.7
59	99.2	94.5	60	99.4	42.7
61	98.5	59.7	60	99.4	42.7
61	98.5	59.7	62	99.1	74.9
63	96.9	95.5	62	99.1	74.9
63	96.9	95.5	64	90.1	53.3
65	97.1	83.9	64	90.1	53.3
65	97.1	83.9	66	94.9	91.1
67	96.8	91.8	66	94.9	91.1
67	96.8	91.8	68	98.3	92.3
69	99.6	96.4	68	98.3	92.3
69	99.6	96.4	70	95.4	93.3
71	97.9	93.8	70	95.4	93.3
71	97.9	93.8	72	97.8	79.5
73	92.9	81.7	72	97.8	79.5
73	92.9	81.7	74	95.3	82.1
76	99.0	90.4	74	95.3	82.1
76	99.0	90.4	77	97.0	30.7

78	99.2	86.3
78	99.2	86.3	79	98.7	90.7
81	96.4	88.2	79	98.7	90.7
81	96.4	88.2	82	94.5	-8.7
83	87.1	16.0	82	94.5	-8.7
83	87.1	16.0	84	82.2	23.7
85	96.0	44.9	84	82.2	23.7
85	96.0	44.9	86	95.9	42.2
87	98.1	84.4	86	95.9	42.2
87	98.1	84.4	89	67.5	-21.6
90	63.4	1.0	89	67.5	-21.6
90	63.4	1.0	91	88.4	20.5
92	97.2	51.8	91	88.4	20.5
92	97.2	51.8	93	98.7	96.2
94	89.1	19.4	93	98.7	96.2
94	89.1	19.4	95	97.1	90.9
96	99.2	96.5	95	97.1	90.9
96	99.2	96.5	97	96.0	69.9
98	98.2	90.5	97	96.0	69.9
98	98.2	90.5	101	98.3	95.7
104	96.9	76.2	101	98.3	95.7
104	96.9	76.2	105	93.9	89.6
106	93.3	80.7	105	93.9	89.6
106	93.3	80.7	107	95.0	92.3
108	97.6	94.7	107	95.0	92.3
108	97.6	94.7	109	88.8	83.0

110	98.9	94.7
110	98.9	94.7	111	98.7	96.7
112	95.9	93.1	111	98.7	96.7
112	95.9	93.1	113	97.1	94.8
114	94.1	88.9	113	97.1	94.8
114	94.1	88.9	115	94.3	89.0
116	96.7	86.3	115	94.3	89.0
116	96.7	86.3	117	93.0	89.2
118	96.3	94.1	117	93.0	89.2
118	96.3	94.1	119	91.7	88.1
120	97.9	93.8	119	91.7	88.1
120	97.9	93.8	121	96.5	85.5
122	97.2	84.5	121	96.5	85.5
122	97.2	84.5	123	93.4	76.6
125	99.1	94.6	123	93.4	76.6
125	99.1	94.6	126	97.8	95.8
127	86.4	81.8	126	97.8	95.8
127	86.4	81.8	128	95.0	87.2
129	85.8	75.4	128	95.0	87.2
129	85.8	75.4	139	60.2	-48.2
140	96.7	94.2	139	60.2	-48.2
140	96.7	94.2	141	96.4	83.3
142	96.9	95.1	141	96.4	83.3
142	96.9	95.1	143	93.8	91.6
144	96.8	91.8	143	93.8	91.6
144	96.8	91.8	145	95.5	92.9

146	97.0	94.2
146	97.0	94.2	147	96.8	84.5
148	92.8	77.1	147	96.8	84.5
148	92.8	77.1	149	97.1	85.4
150	95.1	91.4	149	97.1	85.4
150	95.1	91.4	151	71.8	-42.8
152	70.6	-56.8	151	71.8	-42.8
152	70.6	-56.8	153	88.7	49.1
154	48.2	-31.0	153	88.7	49.1
154	48.2	-31.0	155	94.1	85.6
156	74.9	7.3	155	94.1	85.6
156	74.9	7.3	157	98.1	86.2
158	95.6	91.0	157	98.1	86.2
158	95.6	91.0	159	96.3	89.1
160	99.2	86.2	159	96.3	89.1
160	99.2	86.2	161	92.6	86.3
163	82.0	70.9	161	92.6	86.3
163	82.0	70.9	164	98.6	94.9
165	95.1	88.2	164	98.6	94.9
165	95.1	88.2	166	97.9	82.4
167	95.7	32.4	166	97.9	82.4
167	95.7	32.4	168	96.8	38.3
169	88.1	14.5	168	96.8	38.3
169	88.1	14.5	170	56.4	-40.0
171	95.8	33.7	170	56.4	-40.0
171	95.8	33.7	172	97.5	88.6

180	42.8	-23.1
180	42.8	-23.1	181	98.7	96.5
182	94.4	85.3	181	98.7	96.5
182	94.4	85.3	183	92.4	92.6
184	93.8	20.0	183	92.4	92.6
184	93.8	20.0	185	69.7	-1.5
186	95.2	88.4	185	69.7	-1.5
186	95.2	88.4	187	67.2	4.6
188	94.4	83.6	187	67.2	4.6
188	94.4	83.6	189	82.0	-8.4
190	71.7	-32.4	189	82.0	-8.4
190	71.7	-32.4	191	98.1	90.5
192	87.6	28.8	191	98.1	90.5
192	87.6	28.8	193	96.1	70.1
194	88.7	46.1	193	96.1	70.1
194	88.7	46.1	195	98.3	95.7
196	97.5	86.8	195	98.3	95.7
196	97.5	86.8	197	92.4	84.5
198	97.8	93.6	197	92.4	84.5
198	97.8	93.6	199	96.8	87.8
200	89.6	36.3	199	96.8	87.8
200	89.6	36.3	201	95.9	92.5
202	78.8	-41.8	201	95.9	92.5
202	78.8	-41.8	203	72.1	2.4
204	67.0	-5.8	203	72.1	2.4
204	67.0	-5.8	205	95.0	79.7

206	89.4	85.1
206	89.4	85.1	207	95.9	70.2
208	97.3	90.7	207	95.9	70.2
208	97.3	90.7	209	82.8	55.8
210	94.2	80.7	209	82.8	55.8
210	94.2	80.7	211	96.0	82.2
212	58.6	50.8	211	96.0	82.2
212	58.6	50.8	213	84.0	51.9
214	91.3	49.6	213	84.0	51.9
214	91.3	49.6	215	60.4	33.3
216	96.5	87.6	215	60.4	33.3
216	96.5	87.6	217	97.7	95.0
218	78.6	34.6	217	97.7	95.0
218	78.6	34.6	219	85.8	45.0
220	90.3	31.8	219	85.8	45.0
220	90.3	31.8	221	90.0	66.9
222	90.1	74.0	221	90.0	66.9
222	90.1	74.0	223	84.8	40.8

Industrial applicability

The drug of the present invention has an inhibitory activity on the activation of transcription factor NF-. kappa.B and an inhibitory activity on the liberation of inflammatory cytokines, and is therefore useful as a prophylactic and/or therapeutic agent for diseases caused by the activation of NF-. kappa.B and diseases caused by the excess production of inflammatory cytokines.

Claims

1. Use of a substance selected from the group consisting of compounds represented by the following general formula (I) and pharmaceutically acceptable salts thereof, hydrates thereof and solvates thereof for the preparation of a medicament having an NF- κ B activation inhibitory effect,

in the formula (I), the compound is shown in the specification,

x represents

Wherein the left bond is bonded to ring Z and the right bond is bonded to E,

a represents a hydrogen atom or an acetyl group,

the following partial structural formula (IZ-1) containing ring Z in the general formula (I) is the following formula (IZ-2),

in the formula, R^zRepresents a halogen atom, C₆～C₁₀Aryl, 4- (trifluoromethyl) phenyl, 4-fluorophenyl, 2, 4-difluorophenyl, 1-pyrrolyl or 2-thienyl;

e represents 5-bromo-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 5-bromo-4- (trifluoromethyl) thiazol-2-yl, 5-cyano-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 5-phenyl-4- (trifluoromethyl) thiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-ethylthiazol-2-yl, 5-methyl-4-phenylthiazol-2-yl, 4-isopropyl-5-phenylthiazol-2-yl, methyl-ethyl-5-phenylthiazol-2-yl, methyl-4-ylt-butyl-ethyl-5-phenylthiazol-2-yl, methyl-4-ylt-butyl-yl, methyl-2-yl, methyl-4-, 4-benzyl-5-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl, 5-acetyl-4-phenylthiazol-2-yl, 5-benzoyl-4-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- (ethoxycarbonyl) thiazol-2-yl, 5-ethoxycarbonyl-4- (trifluoromethyl) thiazol-2-yl, 5-ethoxycarbonyl-4-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-piperidinothiazol-2-yl, methyl-5-yl, ethyl-5-piperidinothiazol-2-yl, methyl-yl, ethyl-5-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-morpholinothiazol-2-yl, 4, 5-diphenylthiazol-2-yl, 4-phenylthiazol-2-yl, 4, 5-dimethylthiazol-2-yl, 5-methylthiazol-2-yl, 4-ethyl-5-phenylthiazol-2-yl, 5-carboxymethyl-4-phenylthiazol-2-yl, 5-methylcarbamoyl-4-phenylthiazol-2-yl, 5-ethylcarbamoyl-4-phenylthiazol-2-yl, 5-isopropylcarbamoyl-4-phenylthiazol-2-yl, 5- (2-phenylethyl) carbamoyl-4-phenylthiazol-2-yl, 4- (n-butyl) -5-phenylthiazol-2-yl, 4-methyl-5- [ (3-trifluoromethyl) phenyl ] thiazol-2-yl, 5- (4-fluorophenyl) -4-methylthiazol-2-yl, 5-ethoxycarbonyl-4- (pentafluorophenyl) thiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- (4-phenylpiperazin-1-yl) thiazol-2-yl or 4- (1, 1-dimethyl) ethyl-5- (4-methylpiperazin-1-yl) thiazol-2-yl.

2. The use as claimed in claim 1, wherein

A is a hydrogen atom or an acetyl group;

R^zis a halogen atom;

3. The use as claimed in claim 2, wherein

A is a hydrogen atom or an acetyl group;

R^zis a chlorine atom or a bromine atom;

R^zwhen it is a bromine atom, E is 5-bromo-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 5-bromo-4- (trifluoromethyl) thiazol-2-yl, 4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 5-phenyl-4- (trifluoromethyl) thiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-ethylthiazol-2-yl, 5-methyl-4-phenylthiazol-2-yl, 4-benzyl-5-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl, or, 5-benzoyl-4-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- (ethoxycarbonyl) thiazol-2-yl, 5-ethoxycarbonyl-4- (trifluoromethyl) thiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-piperidinothiazol-2-yl, or 4- (1, 1-dimethyl) ethyl-5-morpholinothiazol-2-yl;

R^zwhen it is a chlorine atom, E is 5-bromo-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 5-bromo-4- (trifluoromethyl) thiazol-2-yl, 5-cyano-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 5-phenyl-4- (trifluoromethyl) thiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-ethylthiazol-2-yl, 5-methyl-4-phenylthiazol-2-yl, 4-benzyl-5-phenylthiazol-2-yl, m, 4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl, 5-benzoyl-4-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- (ethoxycarbonyl) thiazol-2-yl, 5-ethoxycarbonyl-4- (trifluoromethyl) thiazol-2-yl, 5-ethoxycarbonyl-4-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-piperidinothiazol-2-yl or 4- (1, 1-dimethyl) ethyl-5-morpholinothiazol-2-yl.

4. The use as claimed in claim 3, wherein

A is a hydrogen atom;

R^zis a chlorine atom or a bromine atom;

R^zwhen it is a bromine atom, E is 5-bromo-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 5-bromo-4- (trifluoromethyl) thiazol-2-yl, 4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 5-phenyl-4- (trifluoromethyl) thiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-ethylthiazol-2-yl, 5-methyl-4-phenylthiazol-2-yl, 4-benzyl-5-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl, m, 5-benzoyl-4-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- (ethoxycarbonyl) thiazol-2-yl, 5-ethoxycarbonyl-4- (trifluoromethyl) thiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-piperidinothiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-morpholinothiazol-2-yl;

5. The use as claimed in claim 2, wherein

A is a hydrogen atom;

R^zis a halogen atom;

e is 4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl.

6. The use as claimed in claim 4, wherein

A is a hydrogen atom;

R^zis a chlorine atom or a bromine atom;

e is 4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl.

7. Use of the substance according to any one of claims 1 to 6 for the preparation of a gene expression inhibitor of 1 or 2 or more substances selected from the group of substance δ,

substance group δ: tumor necrosis factor, interleukin-1, interleukin-2, interleukin-6, interleukin-8, granulocyte colony stimulating factor, interferon beta, cell adhesion factor ICAM-1, VCAM-1, ELAM-1, nitric oxide synthase, major histocompatibility class I antigen, major histocompatibility class II antigen, beta 2-microglobulin, immunoglobulin light chain, serum amyloid A component, angiotensinogen, complement B, complement C4, C-myc, a transcription product derived from HIV gene, a transcription product derived from HTLV-1 gene, a transcription product derived from simian virus 40 gene, a transcription product derived from cytomegalovirus gene, and a transcription product derived from adenovirus gene.

8. Use of the substance according to any one of claims 1 to 6 for the preparation of an inflammatory cytokine production free inhibitor or an immunosuppressant.

9. A compound represented by the following general formula (I-4) or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof,

in the formula (I), the compound is shown in the specification,

Z⁴represented by the formula

In the formula, A⁴Is a hydrogen atom or an acetyl group;

R^4zrepresents a halogen atom, C₆～C₁₀Aryl, 4-fluorophenyl, 2, 4-difluorophenyl, 4- (trifluoromethyl) phenyl, 1-pyrrolyl or 2-thienyl;

E⁴represented by the formula:

in the formula (I), the compound is shown in the specification,

R^4e4is represented by C₁～C₆Alkyl radical, C₁～C₆Haloalkyl, C₆～C₁₀Aryl or pentafluorophenyl, R^4e5Represents a halogen atom, a cyano group, C₁～C₆Alkyl-carbonyl, C₆～C₁₀Aryl-carbonyl, C₁～C₆Alkoxy-carbonyl, piperidino, morpholino, 4-methylpiperazin-1-yl or 4-phenylpiperazin-1-yl.

10. A compound according to claim 9 or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof, wherein

A⁴Is a hydrogen atom or an acetyl group;

R^4zis a halogen atom;

E⁴is 5-bromo-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 5-bromo-4- (trifluoromethyl) thiazol-2-yl, 5-cyano-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl, 5-acetyl-4-phenylthiazol-2-yl, 5-benzoyl-4-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- (ethoxycarbonyl) thiazol-2-yl, 5-ethoxycarbonyl-4- (trifluoromethyl) thiazol-2-yl, methyl-2-yl, ethyl-5-, 5-ethoxycarbonyl-4-phenylthiazol-2-yl, 5-ethoxycarbonyl-4- (pentafluorophenyl) thiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-piperidinothiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-morpholinothiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- (4-phenylpiperazin-1-yl) thiazol-2-yl or 4- (1, 1-dimethyl) ethyl-5- (4-methylpiperazin-1-yl) thiazol-2-yl -a radical.

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof, wherein

A⁴Is a hydrogen atom or an acetyl group;

R^4zis a chlorine atom or a bromine atom;

R^4zwhen it is a bromine atom, E⁴Is 5-bromo-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 5-bromo-4- (trifluoromethyl) thiazol-2-yl, 4- [ (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl]Thiazol-2-yl, 5-benzoyl-4-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- (ethoxycarbonyl) thiazol-2-yl, 5-ethoxycarbonyl-4- (trifluoromethyl) thiazol-2-yl, 5-ethoxycarbonyl-4- (pentafluorophenyl) thiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-piperidinothiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-morpholinothiazol-2-yl, or 4- (1, 1-dimethyl) ethyl-5- (4-phenylpiperazin-1-yl) thiazol-2-yl;

R^4zwhen it is a chlorine atom, E⁴Is 5-bromo-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 5-bromo-4- (trifluoromethyl) thiazol-2-yl, 5-cyano-4- [ (1, 1-dimethyl) ethyl ] thiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl, 5-benzoyl-4-phenylthiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5- (ethoxycarbonyl) thiazol-2-yl, 5-ethoxycarbonyl-4- (trifluoromethyl) thiazol-2-yl, methyl-ethyl-5- (ethoxycarbonyl) thiazol-2-yl, methyl-5-ethyl-4- (trifluoromethyl) thiazol-2-yl, methyl, 5-ethoxycarbonyl-4-phenylthiazol-2-yl, 5-ethoxycarbonyl-4- (pentafluorophenyl) thiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-piperidinothiazol-2-yl, 4- (1, 1-dimethyl) ethyl-5-morpholinothiazol-2-yl, or 4- (1, 1-dimethyl) ethyl-5- (4-phenylpiperazin-1-yl) thiazol-2-yl.

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof, wherein

A⁴Is a hydrogen atom;

R^4zis a chlorine atom or a bromine atom;

13. A compound according to claim 10 or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof, wherein

A⁴Is a hydrogen atom;

R^4zis a halogen atom;

E⁴is 4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl.

14. A compound according to claim 12 or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof, wherein

A⁴Is a hydrogen atom;

R^4zis a chlorine atom or a bromine atom;

E⁴is 4- (1, 1-dimethyl) ethyl-5- [ (2, 2-dimethyl) propionyl ] thiazol-2-yl.

15. Use of a substance selected from the group consisting of compounds represented by the following general formula (I) and pharmaceutically acceptable salts thereof, hydrates thereof and solvates thereof for the preparation of a medicament having an NF- κ B activation inhibitory effect,

in the formula (I), the compound is shown in the specification,

x represents

Wherein the left bond is bonded to ring Z and the right bond is bonded to E,

a represents a hydrogen atom or an acetyl group,

in the formula, R^zRepresents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a methyl group, a tert-butyl group, a 1- (methoxyimino) ethyl group, a 1- [ (phenylmethoxy) imino ] ethyl group, a trifluoromethyl group, a pentafluoroethyl group, a 2-phenylethen-1-yl group, a phenylethynyl group, a (trimethylsilyl) ethynyl group, a phenyl group, a 2-phenylethyl group, a 2-thienyl group, a 3-thienyl group, a 1-pyrrolyl group, a 2-methylthiazol-4-yl group, a 2-pyridyl group, an acetyl group, an isobutyryl group, a methoxycarbonyl group, a (pyrrol-1-yl) sulfonyl group or a (4-nitrophenyl) diazenyl group;

E represents a 3, 5-bis (trifluoromethyl) phenyl group, a 2, 5-bis (trifluoromethyl) phenyl group, a 3-fluoro-5- (trifluoromethyl) phenyl group, a 3-bromo-5- (trifluoromethyl) phenyl group, a 3-methoxy-5- (trifluoromethyl) phenyl group, a 2-fluoro-5- (trifluoromethyl) phenyl group, 2-chloro-5- (trifluoromethyl) phenyl, 2-nitro-5- (trifluoromethyl) phenyl, 2-methyl-5- (trifluoromethyl) phenyl, 2- (methylsulfanyl) -5- (trifluoromethyl) phenyl, 2- (1-pyrrolidinyl) -5- (trifluoromethyl) phenyl, or 2-morpholino-5- (trifluoromethyl) phenyl.

16. The use as claimed in claim 15, wherein

A represents a hydrogen atom or an acetyl group,

R^zrepresents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a methyl group, a tert-butyl group, a 1- (methoxyimino) ethyl group, a 1- [ (phenylmethoxy) imino ] ethyl group, a trifluoromethyl group, a pentafluoroethyl group, a 2-phenylethen-1-yl group, a phenylethynyl group, a (trimethylsilyl) ethynyl group, a phenyl group, a 2-phenylethyl group, a 2-thienyl group, a 3-thienyl group, a 1-pyrrolyl group, a 2-methylthiazol-4-yl group, a 2-pyridyl group, an acetyl group, an isobutyryl group, a methoxycarbonyl group, a (pyrrol-1-yl) sulfonyl group or a (4-nitrophenyl) diazenyl group;

e represents 3, 5-bis (trifluoromethyl) phenyl, 3-fluoro-5- (trifluoromethyl) phenyl, 3-bromo-5- (trifluoromethyl) phenyl or 3-methoxy-5- (trifluoromethyl) phenyl.

17. The use as claimed in claim 16, wherein

A represents a hydrogen atom, and A represents a hydrogen atom,

18. The use as claimed in claim 17, wherein

A represents a hydrogen atom, and A represents a hydrogen atom,

R^zrepresents a halogen atom, and is a halogen atom,

19. The use as claimed in claim 18, wherein

A represents a hydrogen atom, and A represents a hydrogen atom,

R^zrepresents a halogen atom, and is a halogen atom,

e represents 3, 5-bis (trifluoromethyl) phenyl.

20. The use as claimed in claim 19, wherein

A represents a hydrogen atom, and A represents a hydrogen atom,

R^zrepresents a chlorine atom, and represents a chlorine atom,

e represents 3, 5-bis (trifluoromethyl) phenyl.

21. The use as claimed in claim 17, wherein

A represents a hydrogen atom, and A represents a hydrogen atom,

R^zrepresents a tertiary butyl group, and is represented by,

e represents 3, 5-bis (trifluoromethyl) phenyl.

22. Use according to claim 16 or 17, wherein E represents 3, 5-bis (trifluoromethyl) phenyl.

23. Use of the substance according to any one of claims 16 to 22 for the preparation of a gene expression inhibitor of 1 or more than 2 substances selected from the group of substance δ,

24. Use of the substance of any one of claims 16 to 22 for the preparation of an inflammatory cytokine production free inhibitor or an immunosuppressant.

25. The use as claimed in claim 15, wherein

A represents a hydrogen atom or an acetyl group,

e represents 2, 5-bis (trifluoromethyl) phenyl, 2-fluoro-5- (trifluoromethyl) phenyl, 2-chloro-5- (trifluoromethyl) phenyl, 2-nitro-5- (trifluoromethyl) phenyl, 2-methyl-5- (trifluoromethyl) phenyl, 2- (methylsulfanyl) -5- (trifluoromethyl) phenyl, 2- (1-pyrrolidinyl) -5- (trifluoromethyl) phenyl or 2-morpholino-5- (trifluoromethyl) phenyl.

26. The use of claim 25, wherein

A represents a hydrogen atom, and A represents a hydrogen atom,

27. The use of claim 26, wherein

A represents a hydrogen atom, and A represents a hydrogen atom,

R^zrepresents a halogen atom;

28. The use of claim 27, wherein

A represents a hydrogen atom, and A represents a hydrogen atom,

R^zrepresents a halogen atom, and is a halogen atom,

e represents 2, 5-bis (trifluoromethyl) phenyl.

29. The use of claim 28, wherein

A represents a hydrogen atom, and A represents a hydrogen atom,

R^zrepresents a bromine atom, and is represented by,

e represents 2, 5-bis (trifluoromethyl) phenyl.

30. The use of claim 27, wherein

A represents a hydrogen atom, and A represents a hydrogen atom,

R^zrepresents a halogen atom, and is a halogen atom,

e represents 2, 5-bis (trifluoromethyl) phenyl.

31. Use according to claim 25 or 26, wherein E represents 2, 5-bis (trifluoromethyl) phenyl.

32. Use of the substance according to any one of claims 25 to 31 for the preparation of a gene expression inhibitor of 1 or more than 2 substances selected from the group of substance δ,

33. Use of the substance of any one of claims 25 to 31 for the preparation of an inflammatory cytokine production free inhibitor or an immunosuppressant.