WO2007086584A1 - NOVEL INHIBITOR OF FabK AND FabI/K - Google Patents

NOVEL INHIBITOR OF FabK AND FabI/K Download PDF

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Publication number
WO2007086584A1
WO2007086584A1 PCT/JP2007/051523 JP2007051523W WO2007086584A1 WO 2007086584 A1 WO2007086584 A1 WO 2007086584A1 JP 2007051523 W JP2007051523 W JP 2007051523W WO 2007086584 A1 WO2007086584 A1 WO 2007086584A1
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Prior art keywords
group
hydrogen atom
alkyl
halogen atom
chemical
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PCT/JP2007/051523
Other languages
French (fr)
Japanese (ja)
Inventor
Hideo Kitagawa
Tomohiro Ozawa
Maiko Iida
Takashi Watanabe
Sho Takahata
Mototsugu Yamada
Yasuo Yamamoto
Original Assignee
Meiji Seika Kaisha, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Priority claimed from JP2006021372A external-priority patent/JP2009091251A/en
Priority claimed from JP2006243953A external-priority patent/JP2009091252A/en
Application filed by Meiji Seika Kaisha, Ltd. filed Critical Meiji Seika Kaisha, Ltd.
Publication of WO2007086584A1 publication Critical patent/WO2007086584A1/en

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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Definitions

  • the present invention relates to a compound that inhibits fatty acid synthase FabK or FablZK and is useful for the treatment of bacterial infection and is pharmaceutically promising.
  • Fatty acid biosynthesis in bacteria is carried out by a series of enzymes called type II fatty acid synthase (FAS) systems.
  • type II fatty acid synthase FOS
  • the biosynthesis of fatty acids is catalyzed by a single multifunctional enzyme called the Type I FAS system, which is very different from the fatty acid biosynthesis system of bacteria. Therefore, compounds that inhibit the FAS enzymes of Type II, possibly as selective and novel antimicrobial agent is suggested (Prog. L ipid Res. ( 2001), 40,467-497) o
  • a fatty acid biosynthetic system of bacteria four enzyme reactions proceed sequentially to form a cycle, and a long-chain saturated fatty acid is biosynthesized through multiple cycles.
  • the first step of the cycle is a condensation reaction with
  • j8-ketosyl-ACP synthase I or II condenses malo-roux ACP and facile ACP.
  • a reduction reaction occurs with NADPH-dependency-ketocil ACP reductase (FabG).
  • FabG NADPH-dependency-ketocil ACP reductase
  • j8-hydroxyacyl-ACP dehydrase ⁇ & 1) & 1 ⁇ to obtain dehydrated transformer, 2 enol, 1 ACP.
  • it is reduced by enol-one ACP reductase (Fabl, FabK, or FabL) to yield isacyl ACP.
  • Fabl, FabK, or FabL enol-one ACP reductase
  • Enolulu ACP reductase is the rate-limiting enzyme in the fatty acid synthesis pathway of bacteria, and is an important regulatory point of overall fatty acid biosynthesis in bacteria.
  • Fabl is a target for the broad-spectrum antibiotic triclosan.
  • the complex crystal structure of NAD and triclosan and E. coli-derived Fabl has also been studied, and it has been shown that triclosan acts as a highly specific inhibitor of Fabl by mimicking its natural substrate. .
  • Conformational data on the Fabl-NAD and triclosan complex provides important information in the design of specific inhibitors. Based on this information, it has been found that inhibitors designed in this way may be useful in the treatment of bacterial infections (Nature (1998) 394,531-532, J. Biol. Chem. (1998), 273). , 30316-3032 0, Nature (1999) 398,383-384, and J. Med. Chem. (2003), 46, 1627-1635).
  • FabK is essential for growth in Streptococcus pneumoniae and has been clarified to be a flavin protein having FMN as a coenzyme at a molar concentration ratio of 1: 1 (Bioche m. J (2003)). , 370, 1055-1062) o
  • compounds that inhibit FabK even though it is weak, but there are reports of compounds that strongly inhibit FabK and three-dimensional structures of FabK. (Special Table 2003-511448, J. Med. Chem. (2003), 46,1627-1635, and Antimicrob. Agents. Chem., 46, 3118, (2002)).
  • drugs that inhibit FabK, as well as both Fabl and FabK enzymes are ideal antibacterial agents having a broad antibacterial spectrum and are expected.
  • Streptococcus pneumoniae which is a clinically important pathogen, has only Fa bK as an enoyl ACP reductase, and Pseudomonas aeruginosa and enterococci have both Fabl and FabK.
  • Conventional targeted inhibitors cannot be broader antimicrobial active agents and need to inhibit not only Fabl but also FabK.
  • reports of compounds that inhibit FabK included improvements to be made, such as the fact that most conventional FabK inhibitors are not necessarily lipid-specific, because their inhibitory ability is low. Therefore, creation of compounds having inhibitory activity against Fabl and FabK, particularly Fab K, is desired.
  • the present inventors have now found a compound of formula (I) that inhibits FabK or both Fabl and FabK enzymes and is useful in the treatment of bacterial infections.
  • a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier and an inhibitor for FabK or both Fabl and FabK enzymes.
  • an object of the present invention is to provide a compound of formula (I) that is useful in the treatment of bacterial infections.
  • the present invention provides a compound represented by the following formula (I), a salt thereof, or a solvate thereof:
  • a ′ represents a hydrogen atom or a force representing a C 1-6 alkyl group, or together with an adjacent nitrogen atom and A, the following formula (II):
  • a ' represents a hydrogen atom or a halogen atom
  • R a is a hydrogen atom, hydroxyl group, halogen atom, cyano group, nitro group, C1-6 alkyl group, C1-6 alkoxy group, trifluoromethyl group, trifluoromethyloxy group, carboxyl group, aryl Oxycarbol group, C1 6 alkyloxycarbol group, C1 6 alkylcarboloxy group, C1 6 alkylsulfol group, sulfamoyl group, —OC H CH N, 1 OCH CH NHCOCH, 1 COOCH CH OH, I COOCH CH NH
  • R b represents a hydrogen atom, a halogen atom, a C1 6 alkyl group, a C1-6 alkoxy group, a C1-6 alkyloxycarbon group, or COOCH CH N (SO 2 CH 3),
  • R e is a hydrogen atom, a halogen atom, a C16 alkyl group, a C2-6 alkyl group, a C2 6 alkyl group, a hydroxycarboromethyl group, a C1 6 alkyloxycarbonyl group, a C16 alkyl group.
  • Xyloxycarbonyl group C16 alkyl carbonyl group, naphthyl group, C16 alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C16 alkylsulfol group, C2-6 alkyl -Sulfol group, C2-6 alkylsulfol group, C1 6 alkylsulfur group, C2-6 alkylsulfur group Fier group, C2-6 alkyl sulfier group, pyridyl group, pyridylthio group, lysylthio group, morpholinomethyl group, piperidino group,
  • R ea represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a strong rubamoyl group, or one OC (CH) COOCH CH;
  • R eb represents a hydrogen atom, a halogen atom, a carboxyl group, a nitro group, a C1 6 alkyloxy levono vinyl group, or CONHCH CH OH,
  • R ⁇ represents a hydrogen atom, a halogen atom, a C16 alkyl group, or a -tro group
  • R d represents a hydrogen atom, a phenyl group, a —SO phenyl group (one to two on the phenyl group).
  • R e is also Yogu here have a number of R e radicals is a hydrogen atom, Shiano group or - represents a represents a Toro group).
  • R f represents a hydrogen atom, a hydroxyl group, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a phenol group, a nitro group, or an amino group,
  • R ga is a hydrogen atom, a halogen atom , C1-6 alkyl group, C1 6 alkoxy group, hydroxy carboxymethyloxy group, C1-6 alkyl carboxymethyloxy group, rubamoylmethyloxy group, C1 6 alkyloxy carboxylethyl group, OCH CONHCH CH OH, — OCH CONHPh
  • R h represents a hydrogen atom or an amino group
  • Ri represents a hydrogen atom or a C16 alkyl group
  • R j represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a trifluoromethyl group
  • R k group is
  • the R ka group is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a phenol group, a trifluoromethyl group, an amino group, a nitro group, a —SO 2 H group, or a C 1-6 alkyloxycarbon group.
  • the R kb group represents a hydrogen atom or a acetyl group
  • R ke group represents a hydrogen atom or a nitro group
  • R 1 group is
  • the compound of the present invention inhibited both Fabl and FabK enzymes and showed very strong antibacterial activity against Streptococcus pneumoniae. Therefore, the present invention can be used for the treatment of bacterial infections such as S. pneumoniae, Pseudomonas aeruginosa, or enterococci.
  • C1-6 alkyl group or “C1-6 alkoxy group”, “C1-6 alkyloxycarbonyl group”, “C1 6 alkylcarboxoxy group”, “hydroxy C1 6 alkyl group”, “C1—
  • the “alkyl group” in the substituents such as “6 alkylthio group”, “C 1-6 alkyl sulfol group”, and “Cl-6 alkyl sulfiel group” represents an alkyl group having 16 carbon atoms, and is a chain. It may be any of a shape, a branch, or a ring.
  • alkyl having 14 carbon atoms Preferably, it is alkyl having 14 carbon atoms, and examples thereof include a methyl group, an ethyl group, an n propyl group, an isopropyl group, a cyclopropyl group, an n butyl group, a t butyl group, and an isobutyl group.
  • C2-6 alkenyl group refers to a straight chain, branched or cyclic alkenyl group having 26 carbon atoms, such as a bule group or a 1-probe group.
  • 2—Probing Group isopropylene group, 2-methyl-1 propylene group, 3-methyl-1 propellyl group, 2-methyl-2 propellyl group, 3-methyl-2 propellyl group, 1-butur Group, 2 Butyl Group, 3 Butyl Group, 1 Pentyl Group, 2 Pental Group, 3 Pentul Group, 4 Pental Group, Cyclopental Group, 1 Hexane Group, 2 Hexane Group A 4-hexyl group, a 4-hexyl group, a 5-hexyl group, a cyclohexyl group, or the like.
  • bur group, 1 probe group, 2 probe group isoprop group, 2-methyl 1 prop group, 3-methyl 1 prop group, 2-methyl group 2-Propyl group, 3-Methyl- 2-Propyl group, 1-Butur group, 2--Butur group, 3-Butul group, 1-Pental group, 2-Pental group, 3-Pental group, or 4 A pentenyl group and the like.
  • C2-6 alkyl group means a straight or branched alkyl group having 2 to 6 carbon atoms, such as an ethur group, a 1 propyl group, a 2-propyl group.
  • an ethur group such as an ethur group, a 1-propyl group, a 2-propyl group, a 1-butur group, a 2-butur group, or a 3-butur group
  • C1-6 alkylthio group means a linear, branched or cyclic alkylthio group having 1 to 6 carbon atoms, and examples thereof include a methylthio group, an ethylthio group, and an n-propylthio group.
  • examples include a xylthio group or a cyclohexylthio group.
  • it is alkyl having 1 to 4 carbon atoms, such as methylthio group, ethylthio group, n propylthio group, isopropylthio group, cyclopropylthio group, n-butylthio group, t-butylthio group, or isobutylthio group. More preferably, it is an alkyl group having 13 carbon atoms, and is a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, or a cyclopropyl group. Such as a ruthio group.
  • C2-6 alkenylthio group means a linear, branched, or cyclic alkarylthio group having 2 to 6 carbon atoms.
  • C2-6 alkylthio group means a linear or branched alkylthio group having 2 to 6 carbon atoms, including 1 ethylthio group, 1 propylthio group.
  • Preferable examples include 1-ethylthio group, 1-propylthio group, 2-propylthio group, 1-butylthio group, 2-butynylthio group
  • C16 alkylsulfol group means a linear, branched, or cyclic alkylsulfol group having 1 to 6 carbon atoms, such as a methanesulfol group, an ethylsulfol group, or a 1propylsulfol group.
  • a methanesulfol group an ethylsulfol group ⁇ ⁇ 1-propinolesnoreno-nore group, 2-propinolesnoreno-nore group, 2-methinoreol 1-propinosoleol group, 3-methyl 1-propylsulfol group, 2-methyl-2-propylsulfol group, 3-methyl-2-propylsulfol group, 1-butylsulfol group, 2-butylsulfol group, 3-butylsulfol group, 1 pentylsulfo group Group, 2-pentylsulfol group, 3-pentylsulfol group, or 4-pentylsulfol group.
  • C2-6 alkaryl sulfonyl group refers to a linear, branched, or cyclic arnolekenino lesnorenonole group having 2 to 6 carbon atoms.
  • 2-Methinore 1 propeninores norehoninore group 3-Methinore 1 propeninores norehoninore group
  • 2-Methinore-2 propeninores norehoninole group 3-methinore-2 propeninores norehoninore group
  • 1-butenylsulfol group 2 butenylsulfol group, 3 butenylsulfol group
  • 1 penteninoresnorenonoreno group 2 penteninoresnorenorenoreno group, 3 penteninoresnorenorenoor group, or 4 A pentylsulfol group.
  • C2-6 alkynylsulfol group represents a straight or branched alkyninolesnorehoninore group having 2 to 6 carbon atoms, 1-ethyninoresnorehoninore group, 1 propyninole group Sunolehoninole group, 2-propyninoresnorehonoreno group, 1-butyninoresnorehoninole group, 2-butyninoresnorehoninore group, 3-butylpropyl group, 3-methyl-1-propynylsulfol group, 1 1-pentyl-nolesnorehonore group, 2-penti-noresnorehonore group, 3-penti-norethnorehoninore group, 4-penti-noresnorehonore group, 1-hexinolesnorehoninole group, 2 hexinolesnor
  • C16 alkyl sulfiel group refers to a linear, branched, or cyclic alkyl sulfiel group having 1 to 6 carbon atoms, such as a methyl sulfyl group, an ethyl sulfyl group, a 1 propyl sulfiel group.
  • 2-propyl sulfier group 2-methyl-1 propyl sulfier group, 3-methyl-1-propyl sulfier group, 2-methyl-2 propyl sulfier group, 3-methyl-2-propyl sulfier group, 1-butyl Sulfiel group, 2-butyl sulfier group, 3 butyl sulfier group, 1 pentyl sulfier group, 2 pentyl sulfier group, 3 pentyl sulfier group, 4 pentyl sulfinyl group, cyclopentyl sulfyl group, 1-Hexylsulfyl group, 2-Hexylsulfuryl group, 3-Hexylsulfier group, 4-Hexylsulfuryl group To 5 alkoxy Rusurufi - group or cyclohexylene, means such as cyclohexyl sulfide El group.
  • C2-6 alkaryl sulfier group refers to a straight, branched or cyclic alkenyl sulfier group having 2 to 6 carbon atoms, including a vinyl sulfier group and a 1-propyl sulfenyl group.
  • sulfulfiel group 1-propeninoresnorefinolole group, 2-propeninoresnorefininole group, isopropenenolesnorefier group, 1-butenylsulfuryl group, 2 butenylsulfiel group, Such as 3-butersulfyl group, 1-pentylsulfuric group, 2-pentylsulfuryl group, 3-pentylsulfuryl group, or 4-pentylsulfuryl group.
  • the "C2-6 alkynylsulfier group” represents a straight-chain or branched alkyninolesnorefinol group having 2 to 6 carbon atoms, and includes a 1-ethyninoresnorephinore group, 1-propynino Resnorefinole group, 2-propynyl sulfier group, 1-butyl sulfier group, 2-pentyl sulfier group, 3-pentyl sulfier group, 3-methyl-1 propynyl sulfier group, 1-methyl —3 propynyl sulfiel group, 1—pentyl sulfyl group, 2 pentyl-norethnorephi-noreth group, 3—penty-norethnorephi-noreth group, 4-penty-norethnorephinor group, 1—hexylsulfier group 2 hex
  • the term “optionally substituted” means that a certain group may have one or more substituents, and preferably 1 to 6, More preferably, it means that it may have 1 to 3 substituents.
  • substituents include a hydroxyl group, a halogen atom, an amino group, a mono-substituted amino group, a di-substituted amino group, an azide group, a C 1-6 alkyl group, a C 3-7 cyclic alkyl group, a C 16 alkoxy group, C3-7 cyclic alkoxy group, hydroxy C1 6 alkyl group, amide group, N-substituted amide group, N, N-disubstituted amide group, amino carbonyl group, carboxyl group, C16 alkyl carboxy group, phenol Group, phenyl group, substituted phenol group, benzyl group, substituted benzyl group, benzoyl group, C16 alkyl Examples
  • halogen atom includes a chlorine atom, a bromine atom, a fluorine atom, or an iodine atom.
  • heterocycle means one or two selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and a 5- to 14-membered member containing 1 to 4 heteroatoms. Examples thereof include monocyclic to tricyclic heterocycles, and preferably include 5 to 10-membered monocyclic or bicyclic heterocycles containing 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms.
  • Ph and Me represent a phenyl group and a methyl group, respectively.
  • PG represents a protecting group, and desorption of the protecting group is performed as necessary during the production process.
  • the protective si is used in accordance with the protective group described in Protective groups in organic synthesis, 2nd ecu, (John Wiley & 3 ⁇ 4 ons Inc., 1991) and the method described. Further, as necessary, a known method, an experimental chemistry course (edited by the Chemical Society of Japan, Maruzen), or the like can be applied as a method for substituting the substituents on the side chain and side chain as necessary.
  • the compound according to the present invention is a compound represented by the formula (I).
  • V represents CH or a nitrogen atom
  • Y represents hydrogen
  • Aa represents a hydrogen atom, a C16 alkyl group, a hydroxy C1-6 alkyl group, a mono (CH) Ph group,
  • R a represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethyloxy group, a carboxyl group.
  • COOCH N represents, R b is a hydrogen atom, a halogen atom, a C1 6 alkyl group, a C 1-6 al
  • R e is a hydrogen atom, a halogen atom, C1 6 alkyl, C2- 6 Aruke - Le group
  • C2-6 alkyl group hydroxycarboromethyl group, C1-6 alkyloxycarboro group, C1 6 alkyloxycarboromethyl group, C1 6 alkylcarboxyloxy group, naphthyl group, C1 6 alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C1 6 alkylsulfol group, C2-6 alkylsulfol group, C2-6 alkylsulfol group, C 1 —6 alkyl sulfiel groups, C2-6 alkyl sulfyl groups, C2-6 alkyl sulfiel groups, pyridyl groups, pyridylthio groups, nitropyridylthio groups, morpholinomethyl groups, piperidino groups,
  • R ea is hydrogen atom, halogen atom, C1 6 alkyl, C1 6 alkoxy group, a force Rubamoiru group, or - represents OC (CH) COOCH CH, R eb is hydrogen, halo
  • R ⁇ is a hydrogen atom, halogen atom, C1-6 alkyl group
  • R d represents a hydrogen atom, a phenol group, a -SO phenol group
  • R e groups may be present on the phenyl group
  • R e represents a hydrogen atom, a cyan group, or a -tro group
  • B a is
  • R f represents a hydrogen atom, a hydroxyl group, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a phenyl group, a nitro group, or an amino group, and represents a hydrogen atom, a halogen atom, or a phenyl group
  • Hue - Le group is a hydrogen atom
  • Yogu R ga be one to three amino substituents at R ga, halogen atom, C1 6 alkyl group, C1- 6 alkoxy group, hydroxycarbonated - Rumechiruokishi group, C1 6 alkyl Oxycarboxymethyloxy group, strong rubamoyl methyloxy group, C16 alkyloxycarboruethyl group, —OCH CONHCH
  • R h represents a hydrogen atom or an amino group
  • Ri represents a hydrogen atom or a C 1-6 alkyl group
  • R j represents a hydrogen atom, a halogen atom, C1 6 alkyl or triflates Ruo Russia methyl group, . ].
  • Y represents a hydrogen atom or a methyl group
  • R a is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, a C1-6 alkyl group, a C16 alkoxy group, a trifluoromethyl group, a trifluoromethyloxy group, a carboxyl group, an aryloxycarbo Group, C1 6 alkyloxycarbonyl group, C1 6 alkylcarboxoxy group, C1 6 alkylsulfonyl group, sulfamoyl group, —OCH CH N, 1 OCH CH NHCOCH, 1 COOCH CH OH, 1 COOCH CH NHC
  • R b represents a hydrogen atom, a halogen atom, a C1 6 alkyl group, a C1 6 alkoxy group, a C1-6 alkylcarbonyl group, or COOCH CH N (SO 2 CH 3),
  • R ca represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C1-6 alkoxy group, a carbamoyl group, or —OC (CH 2) COOCH CH,
  • R eb represents a hydrogen atom, a halogen atom, a carboxyl group, a nitro group, a C1-6 alkyloxy group norboninole group, or CONHCH CH OH,
  • R ⁇ represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a -tro group
  • R d is a hydrogen atom, a phenyl group, a —SO phenyl group (one or two on the phenyl group)
  • R g represents a hydrogen atom, a halogen atom, or a phenyl group, and the phenyl group may be substituted by 1 to 3 of R ga .
  • R ga is a hydrogen atom, halogen atom, C1 6 alkyl group, C1-6 alkoxy group, hydroxy carboxymethyloxy group, C1 6 alkyloxy carboxymethyloxy group, force
  • R 1 represents a hydrogen atom or a CI 6 alkyl group.
  • B a is
  • R g represents a phenylene group
  • the Hue alkenyl group is one to three amino substituents at R ga, at best, the R ga a hydrogen atom, a halogen atom, C1- 6 alkyl group, C1- 6 alkoxy group, hydroxy Cycarboxylmethyloxy group, C16 alkyloxycarboxylmethyl group, force Rubamoylmethyloxy group, C16 alkyloxycarboxyl group, OCH C
  • Still another preferred embodiment of the present invention is the above formula (Iaa), wherein A a is
  • Another preferred embodiment of the present invention provides a compound represented by the following formula (lab), a salt thereof, or a solvate thereof:
  • X represents a halogen atom
  • IT represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C2-6 alkyl group, a C2-6 alkyl group, a hydroxycarbonmethyl group, a C1-6 alkyl group.
  • R ea is hydrogen atom, halogen atom, C1 6 alkyl, C1 6 alkoxy group, a force Rubamoiru group, or - represents OC (CH) COOCH CH
  • R eb is hydrogen, halogen
  • R ⁇ represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a -tro group, and these may have a substituent.
  • X represents a halogen atom
  • R e is a C1-6 alkyl group, a C2-6 alkyl group, a C2-6 alkyl group, C 1-6 Alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C16 alkylsulfol group, C2-6 alkylsulfol group, C2-6 alkylsulfol group, C1-6 alkylsulfur group Represents a Fiel group, a C2-6 alkylsulfuryl group, or a C2-6 alkylsulfuryl group, which is provided with an optionally substituted compound, a salt thereof, or a solvent thereof.
  • Another embodiment of the present invention provides a compound represented by the following formula (lb), a salt thereof, or a solvate thereof:
  • a ′ represents a hydrogen atom, a C1-6 alkyl group, or an adjacent nitrogen atom, A b together with the following formula (II),
  • a ′ ′ represents a hydrogen atom or a halogen atom
  • a b is
  • R a is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, a C1-6 alkyl group, a C16 alkoxy group, a trifluoromethyl group, a trifluoromethyloxy group, a carboxyl group, an aryloxycarbo Group, C1 6 alkyloxycarbonyl group, C1 6 alkylcarboxoxy group, C1 6 alkylsulfonyl group, sulfamoyl group, —OCH CH N, 1 OCH CH NHCOCH, 1 COOCH CH OH, 1 COOCH CH NHC
  • R b represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a C1-6 alkyl carboxy group, or COOCH CH N (SO CH);
  • R ca represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C1-6 alkoxy group, a carbamoyl group, or —OC (CH 2) COOCH CH,
  • R eb represents a hydrogen atom, a halogen atom, a carboxyl group, a nitro group, a C1-6 alkyloxy group norboninole group, or CONHCH CH OH,
  • R ⁇ represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a -tro group
  • R d is a hydrogen atom, a phenyl group, a —SO phenyl group (one or two on the phenyl group)
  • B b is a C 1-6 alkyloxycarboluminomethyl group, CH—S—R k group, CH—
  • R f represents a hydrogen atom, a hydroxyl group, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a phenyl group, a nitro group, or an amino group,
  • R h represents a hydrogen atom or an amino group
  • R ka group is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a phenyl group, a trifluoromethyl group, an amino group, a nitro group, a SOH group, or a C16 alkyloxycarbon group.
  • R kb group represents a hydrogen atom or a acetyl group
  • R ke group represents a hydrogen atom or -tro group
  • R 1 group is
  • a ′ represents a hydrogen atom
  • a b represents [Chemical Formula 35] 1-3
  • B b is a compound representing a —CH—S—R k group, a salt thereof, or a solvate thereof.
  • Another embodiment provides a compound represented by the following formula (Ic), a salt thereof, or a solvate thereof:
  • NA, -CO-CH O— N C (B,) one or
  • a ′ represents a hydrogen atom, a C1-6 alkyl group, or an adjacent nitrogen atom, A e together with the following formula (II):
  • a ′ ′ represents a hydrogen atom or a halogen atom
  • a e is a hydrogen atom, a C16 alkyl group
  • Ra is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, a C1-6 alkyl group, a C1-6 alkoxy group, a trifluoromethyl group, a trifluoromethyloxy group, a carboxyl group, an arylo group.
  • R b represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a C1-6 alkyloxycarbon group, or COOCH CH N (SO CH);
  • R e is a hydrogen atom, a halogen atom, a C16 alkyl group, a C2-6 alkyl group, a C2-6 alkyl group, a hydroxycarboromethyl group, a C16 alkyloxycarbon group, a C16 alkyl group Xyloxymethyl group, C16 alkyl carbonyl group, naphthyl group, C16 alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C1-6 alkylsulfol group, C2 — 6-alkylsulfol group, C2— 6-alkynylsulfol group, C1-6 alkylsulfuryl group, C2—6-alkylsulfuryl group, C2—6-alkylsulfuryl group, pyridylthio group, morpholinomethyl Group, piperidino group,
  • R ea represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a strong rubamoyl group, or one OC (CH) COOCH CH;
  • R eb represents a hydrogen atom, a halogen atom, a carboxyl group, a nitro group, a C16 alkyloxycarbon group, or CONHCH CHOH,
  • R ⁇ represents a hydrogen atom, a halogen atom, a C16 alkyl group, or a -tro group
  • R d represents a hydrogen atom, a phenyl group, a —SO phenyl group (on the phenyl group, 1 to 2 Having a number of R e groups,
  • B e is a naphthyl group
  • R f represents a hydrogen atom, a hydroxyl group, a halogen atom, a C1 6 alkyl group, a C1-6 alkoxy group, a phenyl group, a nitro group, or an amino group,
  • R h represents a hydrogen atom or an amino group, NR,
  • Ri represents a hydrogen atom or a C16 alkyl group.
  • a ′ represents a hydrogen atom
  • Another aspect is a pharmaceutical composition
  • a pharmaceutical composition comprising the above-described compound or a salt thereof as an active ingredient, preferably a FabK inhibitor comprising the above-described compound or a salt thereof as an active ingredient, or Fabl and The compound or salt thereof as described above, which inhibits FabK.
  • the compound according to the present invention can be obtained, for example, by a method represented by the following reaction formula or a method analogous thereto.
  • the compounds according to the present invention are not limited to the following production methods, and salts and reagents are exemplified for the sake of convenience, and are not limited thereto.
  • PG represents a protective group, and the protective group is desorbed as necessary during the production process.
  • Protective groups are used in accordance with the protective groups described in Protective groups in organic synthesis, 2nd ed., (John Wiley & Sons Inc., 1991) and the methods described above.
  • a known method for substituting the side chain and the substituent on the side chain as necessary a known method, an experimental chemistry course (edited by the Chemical Society of Japan, Maruzen), etc. can be applied.
  • urea-type derivatives can be produced according to Scheme I or II, or a method via isocyanate.
  • the obtained compound of the formula (2) is used as it is or after purification, and in the presence of a suitable base as necessary (as the organic base, diisopropylethylamine, diazabicyclo [2, 2, 2] undecene,
  • a suitable base as necessary
  • examples of inorganic bases such as 2,6-lutidine include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and preferably diisopropylethyl.
  • a suitable solvent acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether, hexane, N, N-dimethylformamide, dimethyl sulfoxide, (Toluene, benzene, methanol, ethanol, hexamethylphosphoric triamide, etc., or a mixed solvent thereof may be mentioned, preferably tetrahydrofuran, N, N-dimethylformamide, etc.). be able to.
  • the reaction temperature is preferably 0 to 150 ° C., more preferably 20 to 50 ° C.
  • the reaction time is preferably 0.5 to 24 hours, more preferably 0.5 to 18 hours.
  • the reaction solvent may be inert to the halogenating agent.
  • the halogenating agent for example, dichloromethane, chloroform, carbon tetrachloride, carbon disulfide, N , N-dimethylformamide, benzene, toluene, xylene, hexane, or octane, preferably dichloromethane.
  • the reaction temperature is 0 to: LOO ° C is preferably 0 to 30 ° C, and the reaction time is preferably 0.5 to 24 hours, more preferably 0.5 to 13 hours. .
  • the step of reacting the formulas (5) and (6) is carried out in the presence of a suitable base (for example, diisopropylpyrutamine, diazabicyclo [2, 2, 2] undecene, or 2,6-lutidine as the organic base
  • a suitable base for example, diisopropylpyrutamine, diazabicyclo [2, 2, 2] undecene, or 2,6-lutidine
  • the inorganic base include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, and preferably diisopropyl etheramine.
  • reaction solvent is inert to the halogenating agent, for example, dichloromethane, chloroform, carbon tetrachloride, disulfide Carbonized carbon, N, N-dimethylformamide, benzene, toluene, xylene, hexane, octane, etc. are preferable, and dichloromethane is preferable.
  • the reaction temperature is 0 to: LO 0 ° C is preferred, more preferably 0 to 30 ° C, and the reaction time is preferably 0.5 to 24 hours, more preferably 0.5 to 6 hours.
  • the acetophenone represented by the formula (8) which is available as a commercial product or obtained by the method described in J. Macromol. Sci. Chem., (1977),, (3), 507, is converted to an appropriate halogen An agent (eg, J. Am. Chem. So, (1964), 29, 3459, J. Het. Chem “(1988), 25,337, J. Am. Chem. Soc, (1980), 102, 2838, Biorg Med. Chem. Lett., (1996), 6 (3), 253, J. Med. Chem "(1988), 31 (10), 1910, J. Am. Chem. Soc., (1999), 121,248 , J. Macro mol. Sci.
  • a suitable solvent eg acetone, acetonitrile, dichloromethane, chloroform
  • 1,2-dichloroethane 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether, hexane, N, N-dimethylformamide, dimethyl sulfoxide, toluene, benzene, methanol, ethanol To Kisamechirurin triamide, etc.
  • reaction temperature is -10 ⁇ 1 00 ° C is preferable, and 0 to 30 ° C is more preferable.
  • reaction time is preferably 0.5 to 24 hours. More preferably, it is 1 to 6 hours.
  • a suitable base for example, triethylamine, diiso
  • the inorganic base examples include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, or cesium carbonate, preferably sodium methoxide.
  • the ammonium salt eg, ammonium nitrate, salty ammonium, odorous ammonia, ammonium sulfate, or ammonium acetate.
  • salt salt ammonium or bromide ammonium and converted to amidines represented by formula (10).
  • the reaction temperature is ⁇ 10 to: L00 ° C is preferable, and more preferably 0 to 30 ° C.
  • the reaction time is preferably 0.5 to 24 hours. More preferably, it is 0.5 to 4 hours.
  • the obtained amidine (10) and the formula (9) are combined with a suitable base (for example, triethylamine, diisopropylethylamine, diazabicyclo [2,2,2] undecene, or 2,6 as the organic base).
  • a suitable base for example, triethylamine, diisopropylethylamine, diazabicyclo [2,2,2] undecene, or 2,6 as the organic base.
  • — Lutidine and the like, and inorganic bases include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, or cesium carbonate, preferably calcium carbonate
  • the 2-aminomethylimidazo complex can be obtained by reacting in the presence.
  • the reaction temperature is preferably 0 to: L0 0 ° C, more preferably 20 to 70 ° C.
  • the reaction time is preferably 0.5 to 24 hours. More preferably, it is 1-3 hours.
  • Acid salts hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc. as inorganic acids, acetic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, etc. as organic acids
  • formula (3-2) A compound is obtained.
  • the 2-aminothiazole compound represented by the formula (13) is also available as a commercial product.
  • halogenated alkyl (F) and thiourea in a suitable solvent (aceton, acetonitrinol, dichloromethane, chlorohonolem, 1,2-dichloroethane, ethynole acetate, tetrahydrofuran, dioxane, jetyl ether , Isopropyl ether, hexane, N, N-dimethylformamide, dimethyl sulfoxide, toluene, benzene, methanol, ethanol, hexamethylphosphoric triamide, or a mixed solvent thereof, preferably in ethanol)
  • a suitable solvent aceton, acetonitrinol, dichloromethane, chlorohonolem, 1,2-dichloroethane, ethynole acetate, tetrahydrofuran, dioxane, jetyl ether , Isopropyl ether,
  • the reaction temperature is preferably -10 to 100 ° C, more preferably 50 to 80 ° C.
  • the reaction time is preferably 0.5 to 24 hours, more preferably 0.5 to 1 hour.
  • Suitable bases for commercially available 2-amino-5 bromothiazole halides (D) and (E) for example, triethylamine, diisopropylethylamine, diazabicyclo [2, 2, 2] undecene as organic bases
  • the inorganic base includes sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc., preferably hydroxide Quaternary ammonium salts (for example, tetraptyl ammonium fluoride, benzyl dimethyl phenol ammonium chloride, benzyl tributyl ammonium chloride, phenol triethyl) Ammo-um chloride, tetraptyl ammo
  • the reaction temperature is -10 ⁇ : LOO ° C is preferred More preferably, it is 25 to 50 ° C.
  • the reaction time is preferably 0.5 to 48 hours, more preferably 24 to 30 hours.
  • the 2-aminothiazole compound represented by the formula (13) is mixed in a suitable solvent (for example, acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, Examples thereof include jetyl ether, isopropyl ether, hexane, N, N dimethylformamide, dimethyl sulfoxide, toluene, benzene, hexamethylphosphoric triamide, etc., or a mixed solvent thereof, preferably tetrahydrofuran, etc.
  • a suitable solvent for example, acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane
  • a suitable solvent for example, acetone, acetonitrile, dichloromethane, chlor
  • CDI 1, 1'-carbonyldiimidazole
  • the reaction temperature is preferably 0 to 100 ° C. More preferably, it is 10 to 40 ° C.
  • the reaction time is preferably 0.5 to 24 hours, more preferably 1 to 12 hours. .
  • the reaction between the formulas (2-2) and (3-2) is carried out in the presence of a suitable base (for example, triethylamine, diisopropylethylamine, diazabicyclo [2,2,2] undecene as the organic base, or 2, 6-lutidine and the like, and the inorganic base includes sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc. Is diisopropylethylamine, etc.
  • a suitable base for example, triethylamine, diisopropylethylamine, diazabicyclo [2,2,2] undecene
  • the inorganic base includes sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc. Is diisopropylethylamine, etc.
  • a suitable solvent for example, acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether, Hexane, N, N dimethylformamide, dimethyl sulfoxide, toluene, benzene, hexamethylphosphorus (Examples include triamide and the like, or a mixed solvent thereof, and preferably tetrahydrofuran, etc.)
  • a compound represented by the formula (42) was obtained.
  • the reaction temperature was 0 to: LOO ° C is more preferably 10 to 40 ° C.
  • the reaction time is preferably 0.5 to 24 hours, more preferably 1 to 12 hours.
  • the formula (1) or (3) such as triphosgene is an isocyanate compound, and in the case of the isocyanate compound of the formula (1), the formula (3) is replaced by the formula (3).
  • the formula (4) can be obtained by reacting the formula (1).
  • the compound represented by the formula (4) obtained by Scheme I, the formula (7) obtained by Scheme II, and the formula (4 2) obtained by Scheme III may have a side chain as necessary. You can also convert The order of response can be changed as necessary.
  • the compound of the present invention corresponding to the formula (16) can be produced by Eur. J. Med. Chem., (2003), 38, 10 25, J. Med. Chem., (1999), 42, 3458. Chem. Pharm. Bull. (2001), 49.
  • the amine represented by the formula (17) is a halogenated acetyl chloride (for example, chloroacetyl chloride) and a suitable solvent (acetone, acetonitrile, dichloromethane, Form, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether, hexane, N, N-dimethylformamide, dimethyl sulfoxide, toluene, benzene, methanol, ethanol, hexamethyl phosphate triamide Or a mixed solvent thereof, preferably benzene, etc.
  • a suitable solvent acetone, acetonitrile, dichloromethane, Form, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether, hexane
  • a halogenated acetamide of formula (14) is obtained by reaction.
  • the reaction temperature is preferably -10 to 100 ° C, more preferably 40 to 80 ° C.
  • the reaction time is preferably 0.5 to 24 hours. More preferably, it is 0.5 to 2 hours.
  • the oxime compound represented by formula (15) can be synthesized with formula (14) in the presence of a suitable base (for example, triethylamine, diisopropylethylamine, diazabicyclo [2, 2, 2] undecene, or 2 , 6-lutidine, and the like, and inorganic bases include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, or cesium carbonate, preferably Is potassium carbonate) in a suitable solvent (acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether).
  • a suitable base for example, triethylamine, diisopropylethylamine, diazabicyclo [2, 2, 2] undecene, or 2 , 6-lutidine, and the like
  • the reaction temperature is preferably ⁇ 10 to 100 ° C., more preferably 0 to 30 ° C.
  • the reaction time is preferably 0.5 to 24 hours. More preferably, it is 0.5 to 3 hours.
  • the oxime compound represented by the formula (15) is mixed with an a-halogenoacetate ester represented by the formula (20) in the presence of an appropriate base (for example, triethylamine, diisopropylethylamine, diazabicyclo [2, 2, 2] undecene, 2,6-lutidine and the like, and inorganic bases include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, Or cesium carbonate, etc., preferably sodium hydride, etc.) in a suitable solvent (acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, Jetyl ether, isopropyl ether, hexane, N, N dimethylformamide, dimethylsulfate (E.g., amide, toluene,
  • an appropriate base for example
  • the reaction temperature is preferably 10 to: L0 0 ° C, more preferably 0 to 30 ° C.
  • the reaction time is preferably 0.5 to 24 hours. More preferably, it is 0.5 to 3 hours.
  • Formula (22) can be manufactured by the method of Tetrahedron (2001), 57,1551 or Tetrahedron (1999), 55,13159.
  • the obtained compound represented by the formula (22) is converted into a suitable halogenating agent such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, acetic acid, salt oxalil, or N , ⁇ '-dicyclohexylcarbodiimide, ⁇ -hydroxyphthalimide, ⁇ -hydroxysuccinimide, or HOBT (l- Hydroxybenzotriazole hydrate) ⁇ WS (Water soluble carbodnmide nydro chloride, 1— Ethyl— «3— (3— dimethylaminopropyl ) carbodiimide hydrochloride) and other suitable solvents (acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, isopropyl ether, hexane,
  • the reaction temperature is preferably 10 to 100 ° C, more preferably 10 to 50 ° C.
  • the reaction time is preferably 0.5 to 24 hours. More preferably, it is 1 to 6 hours.
  • the obtained compound represented by the formula (18) and the amine represented by the formula (17) are present in the presence of an appropriate base (as the organic base, triethylamine, diisopropylethylamine, diazabicyclo [2] , 2, 2] undecene, or 2,6-lutidine, and the inorganic bases include sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, or potassium carbonate, cesium carbonate.
  • an appropriate base as the organic base, triethylamine, diisopropylethylamine, diazabicyclo [2] , 2, 2] undecene, or 2,6-lutidine
  • the inorganic bases include sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, or potassium carbonate, cesium carbonate.
  • Etc. preferably diisopropylethylamine, triethylamine, etc.
  • a suitable solvent acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl
  • Ether isopropyl ether, hexane, N, N dimethylformamide, dimethylsulfoxy , Toluene, benzene, methanol, ethanol, hexamethylphosphoric triamide, etc., or a mixed solvent thereof, preferably benzene, etc.
  • the reaction temperature is — 10-100 ° C is preferred, more preferably 10-50 ° C.
  • the reaction time is preferably 0.5-24 hours. More preferably, it is 1 to 6 hours.
  • the compound of formula (22) can be obtained from the formula (16) obtained by reacting with the formula (17) using the condensing agent for peptide synthesis.
  • formula (24) is obtained by peptide-bonding formula (17) and formula (23) using the condensing agent for peptide synthesis usually used by those skilled in the art. .
  • the formula (23), which is commercially available, is converted into an appropriate solvent (acetone, acetonitrile, dichloromethane, chloroform, 1, 2, -dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, Examples thereof include isopropyl ether, hexane, N, N dimethylformamide, dimethyl sulfoxide, toluene, benzene, methanol, ethanol, hexamethylphosphoric acid triamide, or a mixed solvent thereof, preferably tetrahydrofuran or N, N dimethylformamide.
  • the compound (24) is obtained by reacting with the peptide synthesis condensing agent and the compound represented by the formula (17).
  • the reaction temperature is preferably 10 to 100, more preferably 10 to 50 ° C.
  • the reaction time is preferably 0.5 to 24 hours! /. More preferably, it is 1 to 6 hours.
  • the compound represented by the formula (14) is added in the presence of a suitable base
  • the organic base is Ethylamine, diisopropylethylamine, diazabicyclo [2,2,2] undecene, 2,6-lutidine and the like
  • inorganic bases include sodium hydroxide, potassium hydroxide, sodium bicarbonate, carbonate Examples include potassium hydrogen, sodium carbonate, potassium carbonate, cesium carbonate, and preferably sodium methoxide. ), Commercially available, or Acta Chem.
  • a compound according to the present invention in which the salt is preferably a pharmaceutically acceptable salt may be provided as the salt.
  • the salt examples include alkali metals, alkaline earth metals, ammonium, organic bases, etc., preferably lithium, sodium, potassium, magnesium, calcium, ammonium, ethanolamine, triethanolamine, trimethyl. And amine, triethylamine, diisopropylamine and the like.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, kenate, camphorate, camphorsulfone.
  • Acid salt cyclopentanepropionate, didarconate, dodecyl sulfate, ethane sulfonate, fumarate, darcoheptanoate, glycephosphate, hemisulfate, heptanoate, hexaneate, Hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, Pamoate, pectate, persulfate, 3-phenolpropionate, picrate, bivalinate, propionate, succinate, tartrate, thiocyanate, Examples include tosylate and undecanoate.
  • the compounds (I) or ( ⁇ ⁇ ⁇ ) to (V) according to the present invention are hydrates or non-hydrates. Also good. These compounds or salts thereof may have asymmetric carbon and geometric isomerism in the molecule. Each of them or mixtures thereof are included in the present invention.
  • solvates may include water, methanol, ethanol, isopropanol, butanol, acetone, ethyl acetate, Or black mouth form etc. are mentioned.
  • the medicament provided by the present invention comprises a compound represented by the general formula (I) and a physiologically acceptable salt thereof, and a group force that is a solvate power thereof as an active ingredient. It is characterized by containing.
  • the medicament of the present invention can be administered orally or parenterally. Examples of parenteral administration include intranasal, eye drop, ear drop, transdermal, respiratory tract, intrarectal, intraurinary, subcutaneous, intramuscular, and intravenous routes.
  • parenteral administration include intranasal, eye drop, ear drop, transdermal, respiratory tract, intrarectal, intraurinary, subcutaneous, intramuscular, and intravenous routes.
  • the above-mentioned substance as an active ingredient may be administered as it is, but generally, a pharmaceutical composition is produced using one or two or more pharmaceutical additives (carriers). It is desirable to invest.
  • preparations suitable for oral administration include, for example, tablets, granules, fine granules, powders, syrups, solutions, capsules, wearables, suspensions, etc.
  • suitable formulations include, for example, injections, drops, inhalants, sprays, suppositories, vaginal suppositories, transdermal absorption agents, transmucosal absorption agents, eye drops, ear drops, nasal drops, or A patch etc. can be mentioned.
  • Liquid preparations such as injections and infusions are provided as powdered pharmaceutical compositions in lyophilized form, and water or other suitable media (for example, physiological saline, glucose infusion solution, buffer solution, etc.) can be mentioned at the time of use. )) Or dissolved in suspension.
  • the additive for the formulation can be appropriately selected depending on the form of the pharmaceutical composition, and the type thereof is not particularly limited, but for example, a stabilizer, a surfactant, a plasticizer, a lubricant, a solubilizing agent.
  • Agent buffering agent, sweetener, base, adsorbent, flavoring agent, binder, suspending agent, brightening agent, coating agent, flavoring agent, fragrance, wetting agent, wetting regulator, filler, extinguishing agent foams, chews, fresheners, wearing colorant, dragees, tonicity agents, P H modifiers, softeners, emulsifiers, adhesives, adhesion enhancer, viscous agents, thickening agents, foaming agents , Excipients, dispersants, propellants, disintegrants, disintegration aids, fragrances, desiccants, preservatives, preservatives, soothing agents, solvents, solubilizers, solubilizers, fluidizing agents, etc.
  • the pharmaceutical composition of a desired form can be manufactured according to a method generally used in this field.
  • the pharmaceutical composition can be prepared so that the substance as an active ingredient is 1.0 to 100% (W / W), preferably 1.0 to 60% (W / W). wear.
  • the compounds described herein are inhibitors of FabK or Fabl / FabK and are useful for the treatment of bacterial infections.
  • these compounds include upper respiratory tract infections (eg, otitis media, bacterial tracheitis, acute pharyngitis, or thyroiditis), lower respiratory tract infections (eg, empyema or lung abscess).
  • Heart infection eg, infection endocarditis
  • gastrointestinal infection eg, secretory diarrhea, spleen abscess, or retroperitoneal abscess
  • CNS infection eg, cerebrum
  • eye infections eg, conjunctivitis, keratitis, endophthalmitis, anterior septum, blepharitis and orbital cellulitis, or lacrimal cystitis
  • kidney and ureteral infections for example, accessory testicularitis, intrarenal and perirenal abscess, or toxic shock syndrome
  • skin infections eg, impetigo, folliculitis, skin abscess, cellulitis, wound infection, or bacterial myositis As well as bone And joint infections (e.g., septic arthritis or osteomyelitis, and the like.) are effective in the treatment of bacterial infections, such as.
  • the compounds of the present invention are also useful as antifungal agents, and the compounds can be used in combination with known antibiotics.
  • the dose and frequency of administration of the medicament of the present invention are not particularly limited, but it is appropriately administered according to various conditions such as the purpose of treatment or prevention, the type of disease, the age, weight, or symptoms of the patient.
  • the amount and number of administrations can be determined. In the case of oral administration, it can be administered once or several times per day so that the amount of active ingredient per day for adults is 0.1 to 1000 mg / kg.In the case of parenteral administration, 0.001 to 500 mg / kg It is preferable to administer once or several times a day.
  • Example 30 The compound of Example 30 was produced in the same manner as in Example 25.
  • Example 30 The compound obtained in Example 30 22.5 mg, 28% aqueous ammonia 5 L, using the above Example 2
  • Example 41 N— (2 Hydroxyethyl) 4 (2— (3 — ((4 ferro- 1H imidazole-2 yl) methyl) ureido) thiazole-5-ylthio) benzamide
  • Example 30 Using 22.5 mg of the compound obtained in 1 above and 5 L of aminoethanol, 8.9 mg of the title compound was obtained in the same manner as in Example 26.
  • Example 56 was prepared in the same manner as in Example 302 described later, the compound of Example 57 was treated in the same manner as in Example 55, and the compounds of Examples 58 to 62 were synthesized in the same manner as in Example 29. In the same manner, the compounds of Examples 63 to 64 were produced in the same manner as in Example 302 described later.
  • Example 66 was prepared by the same method as in Example 65, the compound of Example 67 was prepared by the same method as in Example 29, and the compound of Example 68 was prepared by the same method as in Example 25.
  • Examples 69 to 70 The compounds were prepared in the same manner as in Example 29.
  • Example 72 The compound of Example 72 was produced in the same manner as in Example 29.
  • the compound of this example was produced in the same manner as in Example 29.
  • the compound of this example was produced in the same manner as in Example 29.
  • Example 80 The compound of Example 79 was produced in the same manner as in Example 302 described later. [0119] [Example 80]
  • Example 77 Using 10.6 mg of the compound obtained in Example 77, 6. lmg of the title compound was obtained in the same manner as in Example 25.
  • Example 83 The compound of Example 83 was produced in the same manner as in Example 84 described later.
  • N- (5-Methylthiothiazol-2-yl) -1H-imidazole-1 Carboxamide 12 mg (0. O50 mmol) was dissolved in 1 mL of tetrahydrofuran, and (4- (4 bromophenol) -1H-imidazole-2-yl) Methylamine hydrochloride 18 mg (0. 55 mmol), N 2, ⁇ , -diisopropylethylamine 19 L (0. 1 mmol) was added and stirred at room temperature overnight. Saturated saline was added to the mixed solution, extracted with black mouth form, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol 10 Zl) to obtain the title compound (21 mg, 99%) o
  • Example 90 The compound of Example 90 was produced in the same manner as in Example 29.
  • Example 98 The compound of Example 98 was produced in the same manner as in Example 29.
  • Example 101 to 102 were produced in the same manner as in Example 29, and Example 103 was produced in the same manner as in Example 302 described later.
  • Example 108 to 197 were the same as in Example 29, Example 198 was the same as Example 302 described later, and Examples 199 to 215 were the same as Example 29.
  • Example 216 was produced in the same manner as Example 302 described later, and Examples 217 to 231 were produced in the same manner as in Example 29.
  • Example 233 to 256 were the same as in Example 29, the compound of Example 257 was the same as Example 302 described later, and the compounds of Examples 258 to 276 were In the same manner as in Example 29, the compound of Example 277 was prepared in the same manner as in Example 302 described later, and the compounds of Examples 278 to 301 were prepared in the same manner as in Example 29.
  • N— (6-Methoxybenzo [d] thiazol-2-yl) -1H-imidazole 1-carboxamide 27 mg is dissolved in 1 mL of tetrahydrofuran, and 2-aminomethyl 4-phenol — 1H-imidazole hydrochloride 30 mg, N , N, -Diisopropylethylamine 41 ⁇ L was added and stirred overnight at room temperature. The reaction system was concentrated under reduced pressure, and the residue was purified by ⁇ -TLC (black mouth form ⁇ methanol 20 Zl) to obtain the title compound.
  • Example 400 was produced in the same manner as in Example 401 described later.
  • the extract was concentrated under reduced pressure, and the resulting solid was recrystallized and purified with a mixed solution of ethyl acetate and methanol. The resulting crystals were collected by filtration with a Kiriyama funnel and washed with methanol to give the title compound. (23.4 mg, 30%).
  • Example 408 to 414 are the same as in Example 401, the compounds of Examples 415 to 501 are the same as in Example 669 described later, and the compound of Example 502 is described later.
  • Example 671 the compounds of Examples 503 to 668 were prepared in the same manner as in Example 669 described later.
  • Example 735 to 737 were produced in the same manner as in Example 734, and the compounds of Examples 738 to 750 were produced in the same manner as in Example 703.
  • Tables 2 and 3 are compounds represented by the formulas (3-2) and (13) in the schemelll described above.
  • Benzyl 2 amino-2-iminoethylcarbamate hydrobromide 86 4 mg (3. Om mol) dissolved in 30 mL of a mixed solution of tetrahydrofuran / water 10/1, potassium carbonate 41 5 mg (3. Ommol), 2 Promo 1 One (4 bromophenol) Ethanone 584mg (2. lmm ol) was added and stirred at 80 ° C. for 30 minutes. Saturated brine was added to the mixed solution, extracted with methyl chloride, and dried over sodium sulfate. The solid obtained by concentration under reduced pressure was washed with black mouthform to obtain the title compound (232 mg, 20%).
  • the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure.
  • the title compound was obtained (4. Omg, 43%).
  • N- (5 thiocyanatothiazole-2-yl) acetamide lllmg (0.56 mmol) was dissolved in 8 mL of methanol, and 171 mg (l.llmmol) of dithiothreitol was added and stirred at room temperature for 2 hours.
  • the mixed solution was concentrated under reduced pressure, replaced with argon, and redissolved in 8 mL of N, N, -dimethylformamide.

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Abstract

Disclosed is a compound which can inhibit both of FabI and FabK which are fatty acid synthases to show a wide antibacterial spectrum including Streptococcus pneumoniae, Pseudomonas aeruginosa and Enterococcus faecalis, and therefore can be used for the treatment of a bacterial infection.

Description

明 細 書  Specification
新規 FabKおよび FablZK阻害剤  New FabK and FablZK inhibitors
発明の背景  Background of the Invention
[0001] 発明の分野 [0001] Field of the Invention
本発明は、脂肪酸シンターゼ FabKまたは FablZKを阻害し、細菌感染治療に有 用で医薬上有望な化合物に関する。  The present invention relates to a compound that inhibits fatty acid synthase FabK or FablZK and is useful for the treatment of bacterial infection and is pharmaceutically promising.
[0002] 背景枝術 [0002] Background branching
細菌における脂肪酸の生合成はタイプ IIの脂肪酸シンターゼ (FAS)系と呼ばれる 一連の酵素群により行われている。一方、哺乳動物などの真核生物においては、脂 肪酸の生合成はタイプ Iの FAS系と呼ばれる、単一の多機能酵素により触媒されて おり、細菌の脂肪酸生合成系とは大きく異なる。そのため、タイプ IIの FAS系酵素を 阻害する化合物は、選択的かつ新規な抗菌剤としての可能性が示唆される（Prog. L ipid Res. (2001),40,467-497) o Fatty acid biosynthesis in bacteria is carried out by a series of enzymes called type II fatty acid synthase (FAS) systems. On the other hand, in eukaryotes such as mammals, the biosynthesis of fatty acids is catalyzed by a single multifunctional enzyme called the Type I FAS system, which is very different from the fatty acid biosynthesis system of bacteria. Therefore, compounds that inhibit the FAS enzymes of Type II, possibly as selective and novel antimicrobial agent is suggested (Prog. L ipid Res. ( 2001), 40,467-497) o
[0003] 細菌の脂肪酸生合成系では四つの酵素反応が順次進行してサイクルを形成し、複 数回のサイクルを経て、長鎖の飽和脂肪酸が生合成される。サイクルの第 1工程は |8 ーケトァシルー ACPシンターゼによる縮合反応で、はじめのサイクルでは j8—ケトァ シル— ACPシンターゼ III (FabH)がマロ-ルー ACPとァセチルー CoAとを縮合す る。二回目以降のサイクルでは j8—ケトァシル— ACPシンターゼ Iまたは II (FabBま たは FabF)がマロ-ルー ACPとァシル ACPとを縮合する。第 2工程では NADPH —依存性 —ケトァシル ACPレダクターゼ (FabG)による還元反応が起こる。第 3 工程で j8—ヒドロキシァシル— ACPデヒドラーゼ ^&1)八または？&1^)により脱水され 、トランス一 2 エノィル一 ACPが得られる。第 4工程において、エノィル一 ACPレダ クターゼ（Fabl、 FabK,または FabL)により還元されて、ァシル ACPを生ずる。一 サイクル当たり二個の炭素原子が付加され、最終的にパルミトイル— ACP (16C)が 得られる力 このサイクルは主にパルミトイルー ACPによるエノィルー ACPレダクタ一 ゼのフィードバック阻害を介して停止する（Escherichia coli and Salmonella： Cellular and Molecular Biology i 99bノ, 612—り《3り, American society for Microbiology.Wa shington D. C.および J. Biol. Chem. (1996),271, 1833- 836)。 [0004] すなわち、エノィルー ACPレダクターゼが細菌の脂肪酸合成経路の律速酵素であ り、細菌における脂肪酸生合成全体の重要な調節ポイントである。 [0003] In a fatty acid biosynthetic system of bacteria, four enzyme reactions proceed sequentially to form a cycle, and a long-chain saturated fatty acid is biosynthesized through multiple cycles. The first step of the cycle is a condensation reaction with | 8-ketoacyl-ACP synthase, and in the first cycle j8-ketosyl-ACP synthase III (FabH) condenses malo-roux ACP with acetyl-CoA. In the second and subsequent cycles, j8-ketosyl-ACP synthase I or II (FabB or FabF) condenses malo-roux ACP and facile ACP. In the second step, a reduction reaction occurs with NADPH-dependency-ketocil ACP reductase (FabG). In the third step, j8-hydroxyacyl-ACP dehydrase ^ & 1) & 1 ^) to obtain dehydrated transformer, 2 enol, 1 ACP. In the fourth step, it is reduced by enol-one ACP reductase (Fabl, FabK, or FabL) to yield isacyl ACP. The force that adds two carbon atoms per cycle and ultimately yields palmitoyl- ACP (16C). This cycle is stopped primarily by feedback inhibition of Enolulu ACP reductase by Palmitoire ACP (Escherichia coli and Salmonella: Cellular and Molecular Biology i 99b, 612—R, American Society for Microbiology. Washington DC and J. Biol. Chem. (1996), 271, 1833-836). [0004] That is, Enolulu ACP reductase is the rate-limiting enzyme in the fatty acid synthesis pathway of bacteria, and is an important regulatory point of overall fatty acid biosynthesis in bacteria.
[0005] また、大腸菌（Escherichia coli)や黄色ブドウ球菌（Staphylococcus aureus)などに 存在するエノィルー ACPレダクターゼである Fablは生育に必須な酵素であることが 大腸菌の Fabl温度感受性変異株の解析から明らかにされた (J. Biol. Chem. (1995) ,270,26538-26542) oしたがって、エノィルー ACPレダクターゼを阻害することにより 抗菌作用が発現されると考えられるから、抗菌剤の標的として重要なタンパク質であ るといえる。  [0005] In addition, analysis of Fabl temperature-sensitive mutants of Escherichia coli revealed that Fabl, an enoleu ACP reductase present in Escherichia coli and Staphylococcus aureus, is an essential enzyme for growth. (J. Biol. Chem. (1995), 270,26538-26542) o Therefore, it is thought that the antibacterial action is expressed by inhibiting Enolulu ACP reductase. I can say that.
[0006] また、 Fablが広域スペクトル抗生物質トリクロサンの標的であることも明らかにされて いる。 NADおよびトリクロサンと、大腸菌由来 Fablとの複合体結晶構造についても研 究されており、その天然基質を模倣することで、トリクロサンが特異性の高い Fablの 阻害剤として作用することが示されている。 Fablと NADおよびトリクロサンの複合体 に関する立体構造データは特異的な阻害剤設計において重要な情報を提供する。 この情報に基づ 、て設計した阻害剤が、細菌感染症の治療に有用である可能性が 見出されている（Nature (1998) 394,531-532、 J. Biol. Chem. (1998) ,273,30316- 3032 0、 Nature (1999) 398,383-384、および J. Med. Chem. (2003) ,46, 1627- 1635)。  [0006] It has also been shown that Fabl is a target for the broad-spectrum antibiotic triclosan. The complex crystal structure of NAD and triclosan and E. coli-derived Fabl has also been studied, and it has been shown that triclosan acts as a highly specific inhibitor of Fabl by mimicking its natural substrate. . Conformational data on the Fabl-NAD and triclosan complex provides important information in the design of specific inhibitors. Based on this information, it has been found that inhibitors designed in this way may be useful in the treatment of bacterial infections (Nature (1998) 394,531-532, J. Biol. Chem. (1998), 273). , 30316-3032 0, Nature (1999) 398,383-384, and J. Med. Chem. (2003), 46, 1627-1635).
[0007] ゲノム解析研究により、大腸菌や黄色ブドウ球菌などのほとんどの細菌はエノィル 一 ACPレダクターゼとして Fablを有して!/、ることが知られて!/、るが、 、くつかの菌種 では Fablの代わりに FabKが存在して!/、ることが明らかにされて!/、る。とりわけ臨床上 重要な病原菌である肺炎連鎖球菌（Streptococcus pneumoniae)はエノィルー ACPレ ダクターゼとして FabKのみを有しており、緑膿菌（Pseudomonas aeruginosa)、腸球 菌（Enterococcus faecalis)では Fablと FabKの両方を有していることが明らかになつ ている（Nature (2000) ,406, 145-146)。そのため、より広範な抗菌活性を有する抗菌 剤を創出するには、 Fablだけでなく FabKを阻害する必要がある。  [0007] Genome analysis studies have shown that most bacteria such as Escherichia coli and Staphylococcus aureus have Fabl as an enoyl-ACP reductase! /, But there are several bacterial species Then, it was revealed that FabK existed instead of Fabl! /. In particular, Streptococcus pneumoniae, a clinically important pathogen, has only FabK as an enoleu ACP reductase, and both Fabl and FabK in Pseudomonas aeruginosa and Enterococcus faecalis. (Nature (2000), 406, 145-146). Therefore, it is necessary to inhibit not only Fabl but also FabK in order to create an antibacterial agent having a broader antibacterial activity.
[0008] さらに、 FabKは肺炎連鎖球菌において生育に必須であり、補酵素として FMNを 1 ： 1のモル濃度比で有するフラビンタンパク質であることが明らかにされている（Bioche m. J (2003) ,370, 1055-1062) oその他、 FabKを弱いながらも阻害する化合物の報告 はあるが、 FabKを強く阻害する化合物の報告や FabKの立体構造に関する報告は ない（特表 2003— 511448号、 J. Med. Chem. (2003) ,46,1627— 1635、および Antim icrob. Agents.Chem.,46, 3118, (2002) )。 [0008] Furthermore, FabK is essential for growth in Streptococcus pneumoniae and has been clarified to be a flavin protein having FMN as a coenzyme at a molar concentration ratio of 1: 1 (Bioche m. J (2003)). , 370, 1055-1062) o In addition, there are reports of compounds that inhibit FabK even though it is weak, but there are reports of compounds that strongly inhibit FabK and three-dimensional structures of FabK. (Special Table 2003-511448, J. Med. Chem. (2003), 46,1627-1635, and Antimicrob. Agents. Chem., 46, 3118, (2002)).
[0009] それゆえ、 FabKさらには Fabl、 FabK両酵素を阻害する薬剤は広範囲にわたり優 れた抗菌スペクトラムを有する理想的な抗菌剤であり、期待されている。  [0009] Therefore, drugs that inhibit FabK, as well as both Fabl and FabK enzymes, are ideal antibacterial agents having a broad antibacterial spectrum and are expected.
[0010] 臨床上重要な病原菌である肺炎連鎖球菌はエノィルー ACPレダクターゼとして Fa bKのみを有しており、緑膿菌、腸球菌では Fablと FabKの両方を有しているため、 F ablのみを標的とした従来の阻害剤ではより広範な抗菌活性剤には成り得ず、 Fabl だけでなく FabKを阻害する必要がある。しかし、 FabKを阻害する化合物の報告は ほとんどなぐ従来の FabK阻害剤ではその阻害能が低ぐ脂質特異的とは必ずしも 言えないなどの改良すべき点を含んでいた。そのため、 Fablおよび FabK、特に Fab Kに対して阻害活性を有する化合物の創出が望まれている。  [0010] Streptococcus pneumoniae, which is a clinically important pathogen, has only Fa bK as an enoyl ACP reductase, and Pseudomonas aeruginosa and enterococci have both Fabl and FabK. Conventional targeted inhibitors cannot be broader antimicrobial active agents and need to inhibit not only Fabl but also FabK. However, reports of compounds that inhibit FabK included improvements to be made, such as the fact that most conventional FabK inhibitors are not necessarily lipid-specific, because their inhibitory ability is low. Therefore, creation of compounds having inhibitory activity against Fabl and FabK, particularly Fab K, is desired.
発明の概要  Summary of the Invention
[0011] 本発明者らは、今般、 FabKもしくは、 Fablおよび FabK両酵素を阻害し、細菌感染 症の治療に有用である式 (I)の化合物を見出した。また、式 (I)の化合物および医薬 上許容される担体を含む医薬組成物および FabKもしくは Fablおよび FabK両酵素 に対する阻害剤も見出した。  [0011] The present inventors have now found a compound of formula (I) that inhibits FabK or both Fabl and FabK enzymes and is useful in the treatment of bacterial infections. We have also found a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier and an inhibitor for FabK or both Fabl and FabK enzymes.
[0012] 従って、本発明は細菌感染の治療に有用である式 (I)の化合物の提供をその目的 としている。  [0012] Accordingly, an object of the present invention is to provide a compound of formula (I) that is useful in the treatment of bacterial infections.
[0013] 本発明は、下記式 (I)で表される化合物、その塩、またはそれらの溶媒和物が提供 される：  [0013] The present invention provides a compound represented by the following formula (I), a salt thereof, or a solvate thereof:
[化 1]  [Chemical 1]
A - Z - B ( I ) A-Z-B (I)
[式中、 [Where
Zは、  Z is
-NH-CO-NY-CH  -NH-CO-NY-CH
2  2
(ここで、 Yは水素原子またはメチル基を表す）、  (Where Y represents a hydrogen atom or a methyl group),
[化 2] -W [Chemical 2] -W
NH-CO-N  NH-CO-N
(ここで、 Vは CHまたは窒素原子を表し、 Wは C = 0または—CH を表す）、 (Where V represents CH or a nitrogen atom, W represents C = 0 or —CH),
2  2
NA，一 CO— CH O— N = C (B，）一、  NA, one CO— CH O— N = C (B,) one,
2  2
-O-CO-CH O— N = C (B，）一、または  -O-CO-CH O— N = C (B,) one, or
2  2
NA，一 CO—  NA, one CO—
を表し、 Represents
上己に^ ヽ飞、  To my self ^ ヽ 飞
A'は、水素原子または C 1—6アルキル基を表す力 または隣接する窒素原子およ び Aと一緒になつて下記式 (II)：  A ′ represents a hydrogen atom or a force representing a C 1-6 alkyl group, or together with an adjacent nitrogen atom and A, the following formula (II):
[化 3]
Figure imgf000006_0001
[Chemical 3]
Figure imgf000006_0001
(ここで、 A'，は水素原子またはハロゲン原子を表す） (Here, A ', represents a hydrogen atom or a halogen atom)
を表し、 Represents
B'は水素原子または 2—ピリジル基を表す力 または隣接する =Cおよび Bと一緒 になってシクロへキシリデンを表す。  B 'represents a hydrogen atom or a force representing a 2-pyridyl group or cyclohexylidene together with adjacent = C and B.
Aは、  A is
水素原子、  Hydrogen atom,
C1 6アルキル基、  C1 6 alkyl group,
ヒドロキシ C 1 - 6アルキル基、一（CH ) - Ph基、  Hydroxy C 1-6 alkyl group, mono (CH) -Ph group,
2 1-3 2 1-3
Figure imgf000007_0001
Figure imgf000007_0001
Figure imgf000007_0002
を表し、
Figure imgf000007_0002
Represents
上記にねい"""  Above "" "
Raは、水素原子、水酸基、ハロゲン原子、シァノ基、ニトロ基、 C1— 6アルキル基、 C1— 6アルコキシ基、トリフルォロメチル基、トリフルォロメチルォキシ基、カルボキシ ル基、ァリルォキシカルボ-ル基、 C1 6アルキルォキシカルボ-ル基、 C1 6アル キルカルボ-ルォキシ基、 C1 6アルキルスルホ-ル基、スルファモイル基、—OC H CH N 、 一 OCH CH NHCOCH 、 一 COOCH CH OH、 一 COOCH CH NHR a is a hydrogen atom, hydroxyl group, halogen atom, cyano group, nitro group, C1-6 alkyl group, C1-6 alkoxy group, trifluoromethyl group, trifluoromethyloxy group, carboxyl group, aryl Oxycarbol group, C1 6 alkyloxycarbol group, C1 6 alkylcarboloxy group, C1 6 alkylsulfol group, sulfamoyl group, —OC H CH N, 1 OCH CH NHCOCH, 1 COOCH CH OH, I COOCH CH NH
2 2 3 2 2 3 2 2 2 22 2 3 2 2 3 2 2 2 2
COCH 、 -COOCH CH N (SO CH ) 、 -COOCH CH NH、または COOCCOCH, -COOCH CH N (SO CH), -COOCH CH NH, or COOC
3 2 2 2 3 2 2 2 2 3 2 2 2 3 2 2 2 2
H Nを表し、  H N represents
2 3  twenty three
Rbは、水素原子、ハロゲン原子、 C1 6アルキル基、 C1— 6アルコキシ基、 C1— 6アルキルォキシカルボ-ル基、または COOCH CH N (SO CH )を表し、 R b represents a hydrogen atom, a halogen atom, a C1 6 alkyl group, a C1-6 alkoxy group, a C1-6 alkyloxycarbon group, or COOCH CH N (SO 2 CH 3),
2 2 2 3 2  2 2 2 3 2
Reは、水素原子、ハロゲン原子、 C1 6アルキル基、 C2— 6ァルケ-ル基、 C2 6アルキ-ル基、ヒドロキシカルボ-ルメチル基、 C1 6アルキルォキシカルボ-ル 基、 C1 6アルキルォキシカルボ-ルメチル基、 C1 6アルキルカルボ-ルォキシ 基、ナフチル基、 C1 6アルキルチオ基、 C2— 6ァルケ-ルチオ基、 C2— 6アルキ -ルチオ基、 C1 6アルキルスルホ-ル基、 C2— 6ァルケ-ルスルホ-ル基、 C2— 6アルキ-ルスルホ -ル基、 C1 6アルキルスルフィエル基、 C2— 6ァルケ-ルスル フィエル基、 C2— 6アルキ-ルスルフィエル基、ピリジル基、ピリジルチオ基 リジルチオ基、モルフオリノメチル基、ピペリジノ基、 R e is a hydrogen atom, a halogen atom, a C16 alkyl group, a C2-6 alkyl group, a C2 6 alkyl group, a hydroxycarboromethyl group, a C1 6 alkyloxycarbonyl group, a C16 alkyl group. Xyloxycarbonyl group, C16 alkyl carbonyl group, naphthyl group, C16 alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C16 alkylsulfol group, C2-6 alkyl -Sulfol group, C2-6 alkylsulfol group, C1 6 alkylsulfur group, C2-6 alkylsulfur group Fier group, C2-6 alkyl sulfier group, pyridyl group, pyridylthio group, lysylthio group, morpholinomethyl group, piperidino group,
[化 5]
Figure imgf000008_0001
[Chemical 5]
Figure imgf000008_0001
(ここで、 (here,
Reaは、水素原子、ハロゲン原子、 C1 6アルキル基、 C1 6アルコキシ基、力ルバ モイル基、または一 OC (CH ) COOCH CHを表し、 R ea represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a strong rubamoyl group, or one OC (CH) COOCH CH;
3 2 2 3  3 2 2 3
Rebは、水素原子、ハロゲン原子、カルボキシル基、ニトロ基、 C1 6アルキルォキ シカノレボニノレ基、または CONHCH CH OHを表し、 R eb represents a hydrogen atom, a halogen atom, a carboxyl group, a nitro group, a C1 6 alkyloxy levono vinyl group, or CONHCH CH OH,
2 2  twenty two
R∞は、水素原子、ハロゲン原子、 C1 6アルキル基、または-トロ基を表す） を表し、 R ∞ represents a hydrogen atom, a halogen atom, a C16 alkyl group, or a -tro group)
Rdは、水素原子またはフエニル基、—SO フエ-ル基 (フエ-ル基上に一〜二 R d represents a hydrogen atom, a phenyl group, a —SO phenyl group (one to two on the phenyl group).
(0-2)  (0-2)
個の Re基を有していてもよぐここで Reは水素原子、シァノ基、または-トロ基を表す） を表す。 R e is also Yogu here have a number of R e radicals is a hydrogen atom, Shiano group or - represents a represents a Toro group).
Bは、  B
ナフチル基、  A naphthyl group,
C1 6アルキルォキシカルボ-ルァミノメチル基、  C1 6 alkyloxycarboluminomethyl group,
CH— S— Rk基、または CH—S—R k group, or
2  2
— CH— O— R1基、 — CH— O— R 1 group,
2 2
Figure imgf000009_0001
Figure imgf000009_0001
を表し、 Represents
上記にねい"""  Above "" "
Rfは、水素原子、水酸基、ハロゲン原子、 C1 6アルキル基、 C1 6アルコキシ基 、フエ-ル基、ニトロ基、またはアミノ基を表し、 R f represents a hydrogen atom, a hydroxyl group, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a phenol group, a nitro group, or an amino group,
は、水素原子、ハロゲン原子、またはフエ二ル基を表し、該フヱ-ル基は、 Rgaに て一〜三個置換されていてもよく（ここで、 Rgaは水素原子、ハロゲン原子、 C1— 6ァ ルキル基、 C1 6アルコキシ基、ヒドロキシカルボ-ルメチルォキシ基、 C1— 6アル キルォキシカルボ-ルメチルォキシ基、力ルバモイルメチルォキシ基、 C1 6アルキ ルォキシカルボ-ルェチル基、 OCH CONHCH CH OH、— OCH CONHPh Represents a hydrogen atom, a halogen atom or a phenylene group,, the full We - le groups may be hand one to three amino substituents in R ga (wherein, R ga is a hydrogen atom, a halogen atom , C1-6 alkyl group, C1 6 alkoxy group, hydroxy carboxymethyloxy group, C1-6 alkyl carboxymethyloxy group, rubamoylmethyloxy group, C1 6 alkyloxy carboxylethyl group, OCH CONHCH CH OH, — OCH CONHPh
2 2 2 2  2 2 2 2
、—OCH CONHCH Ph、—OCH CONHCH、フエ-ル CI— 6アルキル基、  , —OCH CONHCH Ph, —OCH CONHCH, phenol CI—6 alkyl group,
2 2 2 3 2 2 2 3
Figure imgf000010_0001
を表す)、
Figure imgf000010_0001
Represents
Rhは、水素原子またはアミノ基を表し、 R h represents a hydrogen atom or an amino group,
Riは、水素原子または C1 6アルキル基を表し、  Ri represents a hydrogen atom or a C16 alkyl group,
Rjは、水素原子、ハロゲン原子、 C1— 6アルキル基、またはトリフルォロメチル基を 表し、 R j represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a trifluoromethyl group,
Rk基は、 R k group is
[化 8] [Chemical 8]
Figure imgf000010_0002
Figure imgf000010_0002
(ここで、 Rka基は、水素原子、ハロゲン原子、 C1— 6アルキル基、フエ-ル基、トリフ ルォロメチル基、アミノ基、ニトロ基、—SO H基、または C 1—6アルキルォキシカル (Here, the R ka group is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a phenol group, a trifluoromethyl group, an amino group, a nitro group, a —SO 2 H group, or a C 1-6 alkyloxycarbon group.
3  Three
ボニノレ基を表し、 Represents a boninole group,
Rkb基は、水素原子またはァセチル基を表し、 The R kb group represents a hydrogen atom or a acetyl group;
Rke基は、水素原子またはニトロ基を表す） を表し、 R ke group represents a hydrogen atom or a nitro group) Represents
R1基は、 R 1 group is
[化 9]  [Chemical 9]
Figure imgf000011_0001
を表す]。
Figure imgf000011_0001
Represents].
[0014] 本発明の化合物は、 Fablおよび FabKの両酵素を阻害し、肺炎連鎖球菌に対して 非常に強い抗菌活性を示した。従って、本発明は肺炎連鎖球菌、緑膿菌、または腸 球菌などの細菌感染の治療に活用できる。  [0014] The compound of the present invention inhibited both Fabl and FabK enzymes and showed very strong antibacterial activity against Streptococcus pneumoniae. Therefore, the present invention can be used for the treatment of bacterial infections such as S. pneumoniae, Pseudomonas aeruginosa, or enterococci.
発明の具体的説明  Detailed description of the invention
[0015]  [0015]
「C1— 6アルキル基」または「C1— 6アルコキシ基」、「C1— 6アルキルォキシカル ボ-ル基」、「C1 6アルキルカルボ-ルォキシ基」「ヒドロキシ C1 6アルキル基」、「 C1— 6アルキルチオ基」、「C 1—6アルキルスルホ-ル基」、および「Cl— 6アルキル スルフィエル基」など置換基中の「アルキル基」とは、炭素数 1 6のアルキル基を表 し、鎖状、分岐、または環状のいずれでもよい。例えば、メチル基、ェチル基、 n—プ 口ピル基、イソプロピル基、シクロプロピル基、 n ブチル基、 t ブチル基、イソプチ ル基、 n ペンチル基、イソペンチル基、ネオペンチル基、シクロペンチル基、 n キシル基、イソへキシル基、およびシクロへキシル基などが挙げられる。好ましくは、 炭素数 1 4のアルキルであり、例えば、メチル基、ェチル基、 n プロピル基、イソプ 口ピル基、シクロプロピル基、 n ブチル基、 t ブチル基、またはイソブチル基などが 挙げられ、さらに好ましくは炭素数 1 3のアルキル基であり、メチル基、ェチル基、 n プロピル基、イソプロピル基、またはシクロプロピル基などである。  “C1-6 alkyl group” or “C1-6 alkoxy group”, “C1-6 alkyloxycarbonyl group”, “C1 6 alkylcarboxoxy group”, “hydroxy C1 6 alkyl group”, “C1— The “alkyl group” in the substituents such as “6 alkylthio group”, “C 1-6 alkyl sulfol group”, and “Cl-6 alkyl sulfiel group” represents an alkyl group having 16 carbon atoms, and is a chain. It may be any of a shape, a branch, or a ring. For example, methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, n butyl group, t butyl group, isopropyl group, n pentyl group, isopentyl group, neopentyl group, cyclopentyl group, n xyl group , An isohexyl group, a cyclohexyl group, and the like. Preferably, it is alkyl having 14 carbon atoms, and examples thereof include a methyl group, an ethyl group, an n propyl group, an isopropyl group, a cyclopropyl group, an n butyl group, a t butyl group, and an isobutyl group. Preferred is an alkyl group having 13 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, or a cyclopropyl group.
[0016] 本明細書において「C2— 6アルケニル基」とは、炭素数 2 6の直鎖、分岐状、また は環状のァルケ-ル基を示し、例えばビュル基、 1—プロべ-ル基、 2—プロべ-ル 基、イソプロぺ-ル基、 2—メチルー 1 プロぺ-ル基、 3—メチルー 1 プロぺ-ル 基、 2—メチルー 2 プロぺ-ル基、 3—メチルー 2 プロぺ-ル基、 1ーブテュル基 、 2 ブテュル基、 3 ブテュル基、 1 ペンテ-ル基、 2 ペンテ-ル基、 3 ペン テュル基、 4 ペンテ-ル基、シクロペンテ-ル基、 1一へキセ -ル基、 2 へキセ- ル基、 3—へキセ -ル基、 4一へキセ -ル基、 5—へキセ -ル基、またはシクロへキセ -ル基などを意味する。好ましくは、ビュル基、 1 プロべ-ル基、 2—プロべ-ル基 、イソプロぺ-ル基、 2—メチルー 1 プロぺ-ル基、 3—メチルー 1 プロぺ-ル基、 2—メチルー 2 プロぺ-ル基、 3—メチルー 2 プロぺ-ル基、 1ーブテュル基、 2— ブテュル基、 3 ブテュル基、 1 ペンテ-ル基、 2 ペンテ-ル基、 3 ペンテ-ル 基、または 4 ペンテニル基などである。 In the present specification, the “C2-6 alkenyl group” refers to a straight chain, branched or cyclic alkenyl group having 26 carbon atoms, such as a bule group or a 1-probe group. 2—Probing Group, isopropylene group, 2-methyl-1 propylene group, 3-methyl-1 propellyl group, 2-methyl-2 propellyl group, 3-methyl-2 propellyl group, 1-butur Group, 2 Butyl Group, 3 Butyl Group, 1 Pentyl Group, 2 Pental Group, 3 Pentul Group, 4 Pental Group, Cyclopental Group, 1 Hexane Group, 2 Hexane Group A 4-hexyl group, a 4-hexyl group, a 5-hexyl group, a cyclohexyl group, or the like. Preferably, bur group, 1 probe group, 2 probe group, isoprop group, 2-methyl 1 prop group, 3-methyl 1 prop group, 2-methyl group 2-Propyl group, 3-Methyl- 2-Propyl group, 1-Butur group, 2--Butur group, 3-Butul group, 1-Pental group, 2-Pental group, 3-Pental group, or 4 A pentenyl group and the like.
[0017] 本明細書において「C2— 6アルキ-ル基」とは炭素数 2〜6の直鎖または分岐状の アルキ-ル基、例えばェチュル基、 1 プロピ-ル基、 2—プロピ-ル基、 1 プチ- ル基、 2 ブチュル基、 3 ブチュル基、 3—メチルー 1 プロピ-ル基、 1 メチル 3 プロピ-ル基、 1 ペンチ-ル基、 2 ペンチ-ル基、 3 ペンチ-ル基、 4 ペンチ-ル基、 1一へキシュル基、 2 へキシュル基、 3 へキシュル基、 4一へキシ -ル基、 5 へキシュル基などを表す。好ましくは、ェチュル基、 1 プロピ-ル基、 2 プロピ-ル基、 1ーブチュル基、 2 ブチュル基、または 3 ブチュル基などである In the present specification, the “C2-6 alkyl group” means a straight or branched alkyl group having 2 to 6 carbon atoms, such as an ethur group, a 1 propyl group, a 2-propyl group. Group, 1-pentyl group, 2-buturyl group, 3-buturyl group, 3-methyl-1-propyl group, 1-methyl-3-propyl group, 1-pentyl group, 2-pentyl group, 3-pentyl group 4 pentyl group, 1 hexyl group, 2 hexyl group, 3 hexyl group, 4 hexyl group, 5 hexyl group, and the like. Preferably, such as an ethur group, a 1-propyl group, a 2-propyl group, a 1-butur group, a 2-butur group, or a 3-butur group
[0018] 本明細書において「C1— 6アルキルチオ基」とは炭素数 1〜6の直鎖、分岐状、ま たは環状のアルキルチオ基を示し、例えば、メチルチオ基、ェチルチオ基、 n—プロ ピルチオ基、イソプロピルチオ基、シクロプロピルチオ基、 n プチルチオ基、 tーブ チルチオ基、イソブチルチオ基、 n ペンチルチオ基、イソペンチルチオ基、ネオペ ンチルチオ基、シクロペンチルチオ基、 n—へキシルチオ基、イソへキシルチオ基、ま たはシクロへキシルチオ基などが挙げられる。好ましくは、炭素数 1—4のアルキルで あり、例えば、メチルチオ基、ェチルチオ基、 n プロピルチオ基、イソプロピルチオ 基、シクロプロピルチオ基、 n—ブチルチオ基、 tーブチルチオ基、またはイソブチル チォ基などが挙げられ、さらに好ましくは炭素数 1 3のアルキル基であり、メチルチ ォ基、ェチルチオ基、 n プロピルチオ基、イソプロピルチオ基、またはシクロプロピ ルチオ基などである。 In the present specification, the “C1-6 alkylthio group” means a linear, branched or cyclic alkylthio group having 1 to 6 carbon atoms, and examples thereof include a methylthio group, an ethylthio group, and an n-propylthio group. Group, isopropylthio group, cyclopropylthio group, n-ptylthio group, tert-butylthio group, isobutylthio group, n pentylthio group, isopentylthio group, neopentylthio group, cyclopentylthio group, n-hexylthio group, isohexyl group Examples include a xylthio group or a cyclohexylthio group. Preferably, it is alkyl having 1 to 4 carbon atoms, such as methylthio group, ethylthio group, n propylthio group, isopropylthio group, cyclopropylthio group, n-butylthio group, t-butylthio group, or isobutylthio group. More preferably, it is an alkyl group having 13 carbon atoms, and is a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, or a cyclopropyl group. Such as a ruthio group.
[0019] 本明細書において「C2— 6アルケニルチオ基」とは、炭素数 2〜6の直鎖、分岐状、 または環状のァルケ-ルチオ基を表し、ビ-ルチオ基、 1 プロべ-ルチオ基、 2— プロべ-ルチオ基、イソプロべ-ルチオ基、 2—メチルー 1 プロべ-ルチオ基、 3— メチルー 1 プロべ-ルチオ基、 2—メチルー 2 プロべ-ルチオ基、 3—メチルー 2 プロべ-ルチオ基、 1 ブテ-ルチオ基、 2 ブテニルチオ基、 3 ブテ-ルチオ 基、 1 ペンテ-ルチオ基、 2 ペンテ-ルチオ基、 3 ペンテ-ルチオ基、 4 ペン テ-ルチオ基、シクロペンテ-ルチオ基、 1一へキセ-ルチオ基、 2—へキセ -ルチ ォ基、 3—へキセ-ルチオ基、 4一へキセ-ルチオ基、 5—へキセ-ルチオ基、また はシクロへキセ-ルチオ基などを意味する。好ましくは、ビニルチオ基、 1—プロべ- ルチオ基、 2—プロべ-ルチオ基、イソプロべ-ルチオ基、 2—メチルー 1 プロべ- ルチオ基、 3—メチルー 1 プロべ-ルチオ基、 2—メチルー 2 プロべ-ルチオ基、 3—メチルー 2 プロべ-ルチオ基、 1 ブテニルチオ基、 2 ブテ-ルチオ基、また は 3—ブテ-ルチオ基などである。  In the present specification, the “C2-6 alkenylthio group” means a linear, branched, or cyclic alkarylthio group having 2 to 6 carbon atoms. Group, 2-probethio group, iso-probethio group, 2-methyl-1 probethio group, 3-methyl-1 probethio group, 2-methyl-2 probethio group, 3-methyl-2 Probelthio group, 1-Butenylthio group, 2 Butenylthio group, 3 Butylthio group, 1 Pentylthio group, 2 Pentylthio group, 3 Pentylthio group, 4 Pentylthio group, Cyclopente group 1-hexylthio group, 2-hexylthio group, 3-hexylthio group, 4-1-hexylthio group, 5-hexylthio group, or cyclohexene group -Luthio group and the like. Preferably, a vinylthio group, 1-probethio group, 2-probethio group, iso-probethio group, 2-methyl-1 probethio group, 3-methyl-1 probethio group, 2- Examples thereof include a methyl-2-propylthio group, a 3-methyl-2 probethio group, a 1-butenylthio group, a 2-butenylthio group, and a 3-butenylthio group.
[0020] 本明細書において「C2— 6アルキ-ルチオ基」とは、炭素数 2〜6の直鎖または分 岐状のアルキ-ルチオ基を示し、 1 ェチ-ルチオ基、 1 プロピ-ルチオ基、 2— プロピ-ルチオ基、 1 ブチニルチオ基、 2 プチ-ルチオ基、 3 ブチニルチオ基 、 3—メチルー 1 プロピ-ルチオ基、 1ーメチルー 3 プロピ-ルチオ基、 1 ペンチ 二ルチオ基、 2 ペンチ-ルチオ基、 3 ペンチ-ルチオ基、 4 ペンチ-ルチオ基 、 1一へキシュルチオ基、 2 へキシュルチオ基、 3 へキシュルチオ基、 4一へキシ 二ルチオ基、または 5 へキシニルチオ基などを意味する。好ましくは、 1ーェチュル チォ基、 1 プロピ-ルチオ基、 2—プロピ-ルチオ基、 1 プチ-ルチオ基、 2—ブ チニルチオ基、または 3—プチ二ルチオ基などである。  In the present specification, “C2-6 alkylthio group” means a linear or branched alkylthio group having 2 to 6 carbon atoms, including 1 ethylthio group, 1 propylthio group. Group, 2-propylthio group, 1 butynylthio group, 2 butylthio group, 3 butynylthio group, 3-methyl-1 propylthio group, 1-methyl-3 propylthio group, 1 pentyl dithio group, 2 pentylthio group Group, 3 pentylthio group, 4 pentylthio group, 1 hexylthio group, 2 hexylthio group, 3 hexylthio group, 4 hexyl dithio group, or 5 hexynylthio group. Preferable examples include 1-ethylthio group, 1-propylthio group, 2-propylthio group, 1-butylthio group, 2-butynylthio group, and 3-butyldithio group.
[0021] 「C1 6アルキルスルホ-ル基」とは炭素数 1〜6の直鎖、分岐状、または環状のァ ルキルスルホ-ル基を表し、メタンスルホ-ル基、ェチルスルホ -ル基、 1 プロピル スルホ-ル基、 2 プロピルスルホ-ル基、 2—メチルー 1 プロピルスルホ-ル基、 3 メチル 1 プロピルスルホ-ル基、 2 メチル 2 プロピルスルホ-ル基、 3— メチルー 2—プロピルスルホ-ル基、 1ーブチルスルホ -ル基、 2—ブチルスルホ -ル 基、 3 ブチルスルホ -ル基、 1 ペンチルスルホ -ル基、 2 ペンチルスルホ -ル 基、 3—ペンチルスルホ -ル基、 4 ペンチルスルホ -ル基、シクロペンチルスルホ- ル基、 1一へキチルスルホ -ル基、 2 へキシルスルホ -ル基、 3 へキシルスルホ- ル基、 4一へキシルスルホ -ル基、 5—へキシルスルホ -ル基、またはシクロへキシル スルホ-ル基などを意味する。好ましくは、メタンスルホ-ル基、ェチルスルホ -ル基 ゝ 1—プロピノレスノレホ -ノレ基、 2—プロピノレスノレホ -ノレ基、 2—メチノレ一 1—プロピノレス ルホ-ル基、 3 -メチル 1 プロピルスルホ-ル基、 2 -メチル 2 プロピルスル ホ-ル基、 3—メチルー 2 プロピルスルホ-ル基、 1ーブチルスルホ -ル基、 2 ブ チルスルホ-ル基、 3 ブチルスルホ -ル基、 1 ペンチルスルホ -ル基、 2 ペン チルスルホ-ル基、 3—ペンチルスルホ -ル基、または 4 ペンチルスルホ -ル基な どである。 [0021] The "C16 alkylsulfol group" means a linear, branched, or cyclic alkylsulfol group having 1 to 6 carbon atoms, such as a methanesulfol group, an ethylsulfol group, or a 1propylsulfol group. Group, 2-propylsulfol group, 2-methyl-1-propylsulfol group, 3-methyl-1-propylsulfol group, 2-methyl-2-propylsulfol group, 3-methyl-2-propylsulfol group, 1-butylsulfol group, 2-butylsulfol Group, 3 butylsulfol group, 1 pentylsulfol group, 2 pentylsulfol group, 3-pentylsulfol group, 4 pentylsulfol group, cyclopentylsulfol group, 1 hexylsulfol group 2 hexylsulfol group, 3 hexylsulfol group, 4 hexylsulfol group, 5-hexylsulfol group, cyclohexylsulfol group and the like. Preferably, a methanesulfol group, an ethylsulfol group プ ロ 1-propinolesnoreno-nore group, 2-propinolesnoreno-nore group, 2-methinoreol 1-propinosoleol group, 3-methyl 1-propylsulfol group, 2-methyl-2-propylsulfol group, 3-methyl-2-propylsulfol group, 1-butylsulfol group, 2-butylsulfol group, 3-butylsulfol group, 1 pentylsulfo group Group, 2-pentylsulfol group, 3-pentylsulfol group, or 4-pentylsulfol group.
[0022] 「C2— 6ァルケ-ルスルホ-ル基」とは、炭素数 2〜6の直鎖、分岐状、または環状 のァノレケニノレスノレホニノレ基を表し、 1ーェテニノレスノレホニノレ基、 1 プロぺニノレスノレ ホニノレ基、 2—プロぺニノレスノレホ二ノレ基、 2—メチノレー 1 プロぺニノレスノレホ二ノレ基、 3—メチノレ 1 プロぺニノレスノレホニノレ基、 2—メチノレ—2 プロぺニノレスノレホニノレ基 、 3—メチル—2—プロべ-ルスルホ-ル基、 1—ブテニルスルホ -ル基、 2 ブテ- ルスルホ -ル基、 3 ブテ-ルスルホ-ル基、 1—ペンテ-ルスルホ-ル基、 2 ペン テュルスルホ-ル基、 3—ペンテ-ルスルホ-ル基、 4—ペンテ-ルスルホ-ル基、シ クロペンテニノレスノレホニノレ基、 1一へキセニノレスノレホニノレ基、 2—へキセニノレスノレホ二 ル基、 3—へキセ-ルスルホ-ル基、 4—へキセ-ルスルホ-ル基、 5—へキセ-ルス ルホニル基、またはシクロへキセニルスルホ -ル基などを意味する。好ましくは、 2— メチノレー 1 プロぺニノレスノレホ二ノレ基、 3—メチノレー 1 プロぺニノレスノレホ二ノレ基、 2 ーメチノレ—2 プロぺニノレスノレホニノレ基、 3—メチノレ—2 プロぺニノレスノレホニノレ基、 1ーブテニルスルホ -ル基、 2 ブテニルスルホ -ル基、 3 ブテニルスルホ -ル基、 1 ペンテニノレスノレホ二ノレ基、 2 ペンテニノレスノレホ二ノレ基、 3 ペンテニノレスノレホ二 ル基、または 4 ペンテ-ルスルホ-ル基などである。  [0022] "C2-6 alkaryl sulfonyl group" refers to a linear, branched, or cyclic arnolekenino lesnorenonole group having 2 to 6 carbon atoms. Ninore group, 1-propeninoresnore Honinole group, 2-propeninoresnorehoninore group, 2-methinole 1 propeninoresnorehoninore group, 3-methinore 1 propeninoresnorehoninore group, 2-methinore-2 propenore Snorhononole group, 3-Methyl-2-probesulfol group, 1-Butenylsulfol group, 2-Butylsulfol group, 3 Butylsulfol group, 1-Pentylsulfol group Group, 2-pentylsulfol group, 3-pentylsulfol group, 4-pentylsulfol group, cyclopenteninoresnorehoninore group, 1-hexeninoresnorehoninole group, 2 —Hexeninoles norephonyl group, 3—Hexels E - group, the 4-xenon - Rusuruho - group, the 5-xenon - Luz Ruhoniru group or cyclohexylene, Kisenirusuruho - and the like Le group. Preferably, 2-Methinore 1 propeninores norehoninore group, 3-Methinore 1 propeninores norehoninore group, 2-Methinore-2 propeninores norehoninole group, 3-methinore-2 propeninores norehoninore group, 1-butenylsulfol group, 2 butenylsulfol group, 3 butenylsulfol group, 1 penteninoresnorenonoreno group, 2 penteninoresnorenorenoreno group, 3 penteninoresnorenorenoor group, or 4 A pentylsulfol group.
[0023] 「C2— 6アルキニルスルホ -ル基」とは炭素数 2〜6の直鎖または分岐状のアルキ ニノレスノレホニノレ基を表し、 1ーェチニノレスノレホニノレ基、 1 プロピニノレスノレホニノレ基、 2—プロピニノレスノレホ二ノレ基、 1ーブチニノレスノレホ二ノレ基、 2—ブチニノレスノレホ二ノレ 基、 3—プチ-ルスルホ-ル基、 3—メチルー 1 プロピニルスルホ -ル基、 1ーメチ ノレ一 3 プロピ-ノレスノレホ-ノレ基、 1 -ペンチ-ノレスノレホニノレ基、 2 -ペンチ-ノレス ノレホニノレ基、 3 ペンチ-ノレスノレホニノレ基、 4 ペンチ-ノレスノレホニノレ基、 1—へキ シニノレスノレホニノレ基、 2 へキシニノレスノレホニノレ基、 3 へキシニノレスノレホニノレ基、 4 一へキシュルスルホ -ル基、または 5—へキシュルスルホ-ル基などを意味する。好 ましくは、 1 ェチ-ルスルホ -ル基または 1 プロピ-ルスルホ -ル基などである。 [0023] "C2-6 alkynylsulfol group" represents a straight or branched alkyninolesnorehoninore group having 2 to 6 carbon atoms, 1-ethyninoresnorehoninore group, 1 propyninole group Sunolehoninole group, 2-propyninoresnorehonoreno group, 1-butyninoresnorehoninole group, 2-butyninoresnorehoninore group, 3-butylpropyl group, 3-methyl-1-propynylsulfol group, 1 1-pentyl-nolesnorehonore group, 2-penti-noresnorehonore group, 3-penti-norethnorehoninore group, 4-penti-noresnorehonore group, 1-hexinolesnorehoninole group, 2 hexinolesnorehoninole group, 3 hexinonolesnorehoninole group, 4 monohexylsulfol group, 5-hexylsulfol group, etc. . A 1-ethylsulfol group or a 1-propylsulfol group is preferred.
[0024] 「C1 6アルキルスルフィエル基」とは炭素数 1〜6の直鎖、分岐状、または環状の アルキルスルフィエル基を示し、メチルスルフィ-ル基、ェチルスルフィ-ル基、 1 プロピルスルフィエル基、 2—プロピルスルフィエル基、 2—メチルー 1 プロピルスル フィエル基、 3—メチル—1—プロピルスルフィエル基、 2—メチル—2 プロピルスル フィエル基、 3—メチルー 2 プロピルスルフィエル基、 1ーブチルスルフィエル基、 2 ーブチルスルフィエル基、 3 ブチルスルフィエル基、 1 ペンチルスルフィエル基、 2 ペンチルスルフィエル基、 3 ペンチルスルフィエル基、 4 ペンチルスルフィ二 ル基、シクロペンチルスルフィ-ル基、 1一へキチルスルフィ-ル基、 2—へキシルス ルフィ-ル基、 3—へキシルスルフィエル基、 4—へキシルスルフィエル基、 5—へキシ ルスルフィ-ル基、またはシクロへキシルスルフィエル基などを意味する。好ましくは、 メチルスルフィ-ル基、ェチルスルフィ-ル基、 1 プロピルスルフィエル基、 2—プロ ピルスルフィエル基、 2—メチル—1—プロピルスルフィエル基、 3—メチル—1—プロ ピルスルフィエル基、 2—メチル—2 プロピルスルフィエル基、 3—メチル—2 プロ ピルスルフィエル基、 1ーブチルスルフィ-ル基、 2 ブチルスルフィエル基、 3 ブ チルスルフィ-ル基、 1 ペンチルスルフィ-ル基、 2 ペンチルスルフィエル基、 3 ペンチルスルフィ-ル基、または 4 ペンチルスルフィエル基などである。  [0024] The "C16 alkyl sulfiel group" refers to a linear, branched, or cyclic alkyl sulfiel group having 1 to 6 carbon atoms, such as a methyl sulfyl group, an ethyl sulfyl group, a 1 propyl sulfiel group. , 2-propyl sulfier group, 2-methyl-1 propyl sulfier group, 3-methyl-1-propyl sulfier group, 2-methyl-2 propyl sulfier group, 3-methyl-2-propyl sulfier group, 1-butyl Sulfiel group, 2-butyl sulfier group, 3 butyl sulfier group, 1 pentyl sulfier group, 2 pentyl sulfier group, 3 pentyl sulfier group, 4 pentyl sulfinyl group, cyclopentyl sulfyl group, 1-Hexylsulfyl group, 2-Hexylsulfuryl group, 3-Hexylsulfier group, 4-Hexylsulfuryl group To 5 alkoxy Rusurufi - group or cyclohexylene, means such as cyclohexyl sulfide El group. Preferably, a methylsulfyl group, an ethylsulfyl group, a 1 propylsulfiel group, a 2-propylsulfiel group, a 2-methyl-1-propylsulfiel group, a 3-methyl-1-propylsulfiel group, 2-methyl-2 propyl sulfiel group, 3-methyl-2 propyl sulfiel group, 1-butyl sulfyl group, 2 butyl sulfiel group, 3 butyl sulfyl group, 1 pentyl sulfyl group, 2 pentyl A sulfiel group, a 3-pentylsulfyl group, or a 4-pentylsulfiel group.
[0025] 「C2— 6ァルケ-ルスルフィエル基」とは、炭素数 2〜6の直鎖、分岐状、または環 状のアルケニルスルフィエル基を示し、ビニルスルフィエル基、 1—プロべ-ルスルフ ィ-ル基、 2—プロべ-ルスルフィ-ル基、イソプロべ-ルスルフィ-ル基、 2—メチル —1—プロべ-ルスルフィエル基、 3—メチル 1—プロべ-ルスルフィエル基、 2—メ チル 2 プロべ-ルスルフィ-ル基、 3 メチル 2 プロべ-ルスルフィ-ル基、 1—ブテニルスルフィエル基、 2 ブテニルスルフィエル基、 3 ブテニルスルフィ二 ル基、 1—ペンテ-ルスルフィエル基、 2 ペンテ-ルスルフィエル基、 3 ペンテ- ルスルフィ-ル基、 4—ペンテ-ルスルフィエル基、シクロペンテ-ルスルフィ-ル基、 1—へキセ-ノレスノレフィ-ノレ基、 2 へキセ-ノレスノレフィ-ノレ基、 3 へキセ-ノレスノレ フィエル基、 4—へキセ-ルスルフィ-ル基、 5—へキセ-ルスルフィ-ル基、または シクロへキセニルスルフィ-ル基などを意味する。好ましくは、ビュルスルフィエル基、 1 プロぺニノレスノレフィニノレ基、 2—プロぺニノレスノレフィニノレ基、イソプロぺニノレスノレ フィエル基、 1ーブテニルスルフィ-ル基、 2 ブテニルスルフィエル基、 3 ブテュル スルフィエル基、 1 ペンテ-ルスルフィ-ル基、 2 ペンテ-ルスルフィエル基、 3— ペンテ-ルスルフィ-ル基、または 4 ペンテ-ルスルフィエル基などである。 [0025] The "C2-6 alkaryl sulfier group" refers to a straight, branched or cyclic alkenyl sulfier group having 2 to 6 carbon atoms, including a vinyl sulfier group and a 1-propyl sulfenyl group. Group, 2-propylsulfuryl group, isopropylsulfuryl group, 2-methyl-1-probesulfuryl group, 3-methyl1-probesulfuryl group, 2-methyl-2 Probe sulfyl group, 3 methyl 2-propyl sulfyl group, 1-butenyl sulfiel group, 2 butenyl sulfiel group, 3 butenyl sulfinyl group, 1-pentyl sulfier group, 2 pentyl sulfier group, 3 pentyl sulfiel group, 4-pentyl sulfier group, cyclopente -Rulsulfyl group, 1-hexenolesnorefi-nore group, 2hexenolesnorephinore group, 3hexenolesnorefier group, 4-hexylsulfuryl group, 5-hexylsulfi group Or a cyclohexenylsulfyl group. Preferably, sulfulfiel group, 1-propeninoresnorefinolole group, 2-propeninoresnorefininole group, isopropenenolesnorefier group, 1-butenylsulfuryl group, 2 butenylsulfiel group, Such as 3-butersulfyl group, 1-pentylsulfuric group, 2-pentylsulfuryl group, 3-pentylsulfuryl group, or 4-pentylsulfuryl group.
[0026] 「C2— 6アルキニルスルフィエル基」とは炭素数 2〜6の直鎖または分岐状のアルキ ニノレスノレフィ-ノレ基を表し、 1—ェチニノレスノレフィ-ノレ基、 1—プロピニノレスノレフィ-ノレ 基、 2—プロピニルスルフィエル基、 1—プチ-ルスルフィエル基、 2—プチ-ルスルフ ィ-ル基、 3—プチ-ルスルフィエル基、 3—メチルー 1 プロピニルスルフィエル基、 1—メチル—3 プロピニルスルフィエル基、 1—ペンチ-ルスルフィ-ル基、 2 ペン チ-ノレスノレフィ-ノレ基、 3—ペンチ-ノレスノレフィ-ノレ基、 4—ペンチ-ノレスノレフィ-ノレ 基、 1—へキシュルスルフィエル基、 2 へキシュルスルフィエル基、 3 へキシュル スルフィ-ル基、 4—へキシュルスルフィ-ル基、または 5—へキシュルスルフィ-ル 基などを意味する。好ましくは、 1—ェチニルスルフィエル基または 1—プロピニルス ルフィ-ル基などである。 [0026] The "C2-6 alkynylsulfier group" represents a straight-chain or branched alkyninolesnorefinol group having 2 to 6 carbon atoms, and includes a 1-ethyninoresnorephinore group, 1-propynino Resnorefinole group, 2-propynyl sulfier group, 1-butyl sulfier group, 2-pentyl sulfier group, 3-pentyl sulfier group, 3-methyl-1 propynyl sulfier group, 1-methyl —3 propynyl sulfiel group, 1—pentyl sulfyl group, 2 pentyl-norethnorephi-noreth group, 3—penty-norethnorephi-noreth group, 4-penty-norethnorephinor group, 1—hexylsulfier group 2 hexulsulfiel group, 3 hexulsulfyl group, 4-hexylsulfyl group, 5-hexylsulfyl group, and the like. Preferably, it is a 1-ethynylsulfyl group or a 1-propynylsulfyl group.
[0027] 本明細書中、「置換されていてもよい」との語は、ある基が一またはそれ以上の置換 基を有していてもよいことを意味し、好ましくは 1—6個、さらに好ましくは 1—3個の置 換基を有していてもよいことを意味する。「置換基」の例としては、水酸基、ハロゲン原 子、アミノ基、モノ置換アミノ基、ジ置換アミノ基、アジド基、 C 1—6アルキル基、 C3— 7環状アルキル基、 C1 6アルコキシ基、 C3— 7環状アルコキシ基、ヒドロキシ C1 6アルキル基、アミド基、 N 置換アミド基、 N, N—ジ置換アミド基、ァミノカルボ-ル 基、カルボキシル基、 C1 6アルキルォキシカルボ-ル基、フエ-ル基、フエ-ルォ キシ基、置換フエ-ル基、ベンジル基、置換べンジル基、ベンゾィル基、 C1 6アル キルカルボ-ル基、置換 C1 6アルキルカルボ-ル基、カルボ-ル基、または複素 環などが挙げられる。 In the present specification, the term “optionally substituted” means that a certain group may have one or more substituents, and preferably 1 to 6, More preferably, it means that it may have 1 to 3 substituents. Examples of the “substituent” include a hydroxyl group, a halogen atom, an amino group, a mono-substituted amino group, a di-substituted amino group, an azide group, a C 1-6 alkyl group, a C 3-7 cyclic alkyl group, a C 16 alkoxy group, C3-7 cyclic alkoxy group, hydroxy C1 6 alkyl group, amide group, N-substituted amide group, N, N-disubstituted amide group, amino carbonyl group, carboxyl group, C16 alkyl carboxy group, phenol Group, phenyl group, substituted phenol group, benzyl group, substituted benzyl group, benzoyl group, C16 alkyl Examples thereof include a kill carbo yl group, a substituted C16 alkyl carbo ol group, a carbo ol group, and a heterocyclic ring.
[0028] 「ハロゲン原子」とは、塩素原子、臭素原子、フッ素原子、またはヨウ素原子などであ る。  The “halogen atom” includes a chlorine atom, a bromine atom, a fluorine atom, or an iodine atom.
[0029] 本明細書にぉ 、て、「複素環」とは窒素原子、酸素原子、および硫黄原子から選ば れた一種または二種、一ないし四個のへテロ原子を含む 5〜 14員の単環式ないし三 環性複素環等が挙げられ、好ましくは、窒素原子、酸素原子、または硫黄原子を一 〜四個含む、 5〜10員の単環または二環性複素環が挙げられる。さらに好ましくは、 テトラヒドロフラン、フラン、ピロリジン、ピぺリジン、ビラゾリジン、イミダゾリジン、ピペラ ジン、モルホリン、チオモルホリン、ピロール、チォフェン、ォキサゾール、イソォキサ ゾール、チアゾール、イソチアゾール、イミダゾール、ピラゾール、ピリジン、ピリダジン 、ピリミジン、ピラジン、トリァゾール、テトラゾール、チアジアゾール、ァゼチジン、チア ゾリン、キヌタリジン、トリアジン、イソべンゾフラン、インドール、インドリジン、クロメン、 キノリン、イソキノリン、シンノリン、キナゾリン、キノキサリン、フタラジン、プリン、または プテリジンなどを表す。  In the present specification, the term “heterocycle” means one or two selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and a 5- to 14-membered member containing 1 to 4 heteroatoms. Examples thereof include monocyclic to tricyclic heterocycles, and preferably include 5 to 10-membered monocyclic or bicyclic heterocycles containing 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms. More preferably, tetrahydrofuran, furan, pyrrolidine, piperidine, virazolidine, imidazolidine, piperazine, morpholine, thiomorpholine, pyrrole, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine , Pyrazine, triazole, tetrazole, thiadiazole, azetidine, thiazoline, quinutaridin, triazine, isobenzofuran, indole, indolizine, chromene, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, purine, or pteridine.
[0030] 本明細書中、 Phと Meは、それぞれフエニル基とメチル基を表す。  In the present specification, Ph and Me represent a phenyl group and a methyl group, respectively.
[0031] 本明細書中、ペプチドおよび化学分野にて共通して使用される略号および符号を 利用している。一般に、アミノ酸の略号は Eur. J. Biochem., 9, 158, (1984)に記載さ れるよつ【こ、 IUPAC— IUB Joint Commission on Biocnemical Nomenclature【こ従つ。  [0031] In this specification, abbreviations and symbols commonly used in the peptide and chemical fields are used. In general, amino acid abbreviations are described in Eur. J. Biochem., 9, 158, (1984). IUPAC—IUB Joint Commission on Biocnemical Nomenclature.
[0032] 本明細書中、 PGは保護基を表し、製造工程中に保護基の脱着は必要に応じて行 つ。保 si としては、 Protective groups in organic synthesis, 2nd ecu, (John Wiley & ¾ ons Inc., 1991)記載の保護基、および、記載の方法に準じて利用する。また必要に 応じて側鎖、側鎖上の置換基を置換してもよぐその方法は公知の方法、実験化学 講座（日本化学会編、丸善)などを適用できる。  [0032] In the present specification, PG represents a protecting group, and desorption of the protecting group is performed as necessary during the production process. The protective si is used in accordance with the protective group described in Protective groups in organic synthesis, 2nd ecu, (John Wiley & ¾ ons Inc., 1991) and the method described. Further, as necessary, a known method, an experimental chemistry course (edited by the Chemical Society of Japan, Maruzen), or the like can be applied as a method for substituting the substituents on the side chain and side chain as necessary.
[0033] 式（I)の化合物  [0033] Compound of formula (I)
本発明による化合物は、前記式 (I)で表される化合物である。  The compound according to the present invention is a compound represented by the formula (I).
[0034] 本発明の好ま 、別の態様によれば、下記式 (la)で表される化合物、その塩、また はそれらの溶媒和物が提供される： [化 10] [0034] According to another aspect of the present invention, there is provided a compound represented by the following formula (la), a salt thereof, or a solvate thereof: [Chemical 10]
Aa— Z a— B a ( l a ) A a — Z a — B a (la)
[式中、 Zaは— NH— CO— NY— CH—または [Where Z a is — NH— CO— NY— CH— or
2  2
[化 11]
Figure imgf000018_0001
を表し、 Vは CHまたは窒素原子を表し、 Wは C = 0または— CH—を表し、 Yは水素 [Chemical 11]
Figure imgf000018_0001
V represents CH or a nitrogen atom, W represents C = 0 or —CH—, Y represents hydrogen
2  2
原子またはメチル基を表し、 Aaは水素原子、 C1 6アルキル基、ヒドロキシ C1— 6ァ ルキル基、一（CH ) Ph基、 Aa represents a hydrogen atom, a C16 alkyl group, a hydroxy C1-6 alkyl group, a mono (CH) Ph group,
2 1-3  2 1-3
[化 12]  [Chemical 12]
Figure imgf000018_0002
を表し、 Raは水素原子、水酸基、ハロゲン原子、シァノ基、ニトロ基、 C 1—6アルキル 基、 C1— 6アルコキシ基、トリフルォロメチル基、トリフルォロメチルォキシ基、カルボ キシル基、ァリルォキシカルボ-ル基、 C1 6アルキルォキシカルボ-ル基、 C1 6 アルキルカルボ-ルォキシ基、 C1 6アルキルスルホ-ル基、、スルファモイル基、 一 OCH CH N 、 一 OCH CH NHCOCH 、 一 COOCH CH OH、 一 COOCH C
Figure imgf000018_0002
R a represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethyloxy group, a carboxyl group. , Allyloxycarbonyl group, C1 6 alkyloxycarbol group, C1 6 alkylcarboxoxy group, C1 6 alkylsulfol group, sulfamoyl group, 1 OCH CH N, 1 OCH CH NHCOCH, COOCH CH OH, COOCH C
2 2 3 2 2 3 2 2 22 2 3 2 2 3 2 2 2
H NHCOCH 、 -COOCH CH N (SO CH ) 、 -COOCH CH NH、またはH NHCOCH, -COOCH CH N (SO CH), -COOCH CH NH, or
2 3 2 2 2 3 2 2 2 2 2 3 2 2 2 3 2 2 2 2
COOCH Nを表し、 Rbは水素原子、ハロゲン原子、 C1 6アルキル基、 C 1—6アル COOCH N represents, R b is a hydrogen atom, a halogen atom, a C1 6 alkyl group, a C 1-6 al
2 3  twenty three
コキシ基、 C1 6アルキルォキシカルボ-ル基、または COOCH CH N (SO CH )を表し、 Reは水素原子、ハロゲン原子、 C1 6アルキル基、 C2— 6ァルケ-ル基Coxy group, C1 6 alkyloxycarbol group, or COOCH CH N (SO CH ) Represents, R e is a hydrogen atom, a halogen atom, C1 6 alkyl, C2- 6 Aruke - Le group
3 2 3 2
、 C2— 6アルキ-ル基、ヒドロキシカルボ-ルメチル基、 C1— 6アルキルォキシカル ボ-ル基、 C1 6アルキルォキシカルボ-ルメチル基、 C1 6アルキルカルボ-ル ォキシ基、ナフチル基、 C1 6アルキルチオ基、 C2— 6ァルケ-ルチオ基、 C2— 6 アルキ-ルチオ基、 C1 6アルキルスルホ-ル基、 C2— 6ァルケ-ルスルホ -ル基 、 C2— 6アルキ-ルスルホ -ル基、 C 1—6アルキルスルフィエル基、 C2— 6ァルケ- ルスルフィ-ル基、 C2— 6アルキ-ルスルフィエル基、ピリジル基、ピリジルチオ基、 ニトロピリジルチオ基、モルフオリノメチル基、ピペリジノ基、  C2-6 alkyl group, hydroxycarboromethyl group, C1-6 alkyloxycarboro group, C1 6 alkyloxycarboromethyl group, C1 6 alkylcarboxyloxy group, naphthyl group, C1 6 alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C1 6 alkylsulfol group, C2-6 alkylsulfol group, C2-6 alkylsulfol group, C 1 —6 alkyl sulfiel groups, C2-6 alkyl sulfyl groups, C2-6 alkyl sulfiel groups, pyridyl groups, pyridylthio groups, nitropyridylthio groups, morpholinomethyl groups, piperidino groups,
[化 13]
Figure imgf000019_0001
[Chemical 13]
Figure imgf000019_0001
を表し、 Reaは水素原子、ハロゲン原子、 C1 6アルキル基、 C1 6アルコキシ基、 力ルバモイル基、または— OC (CH ) COOCH CHを表し、 Rebは水素原子、ハロ The stands, R ea is hydrogen atom, halogen atom, C1 6 alkyl, C1 6 alkoxy group, a force Rubamoiru group, or - represents OC (CH) COOCH CH, R eb is hydrogen, halo
3 2 2 3  3 2 2 3
ゲン原子、カルボキシル基、ニトロ基、 C1 6アルキルォキシカルボ-ル基、または - CONHCH CH OHを表し、 R∞は、水素原子、ハロゲン原子、 C1— 6アルキル基 Represents a gen atom, carboxyl group, nitro group, C1 6 alkyloxycarbonyl group, or -CONHCH CH OH, R ∞ is a hydrogen atom, halogen atom, C1-6 alkyl group
2 2  twenty two
、または-トロ基を表し、 Rdは、水素原子、またはフエ-ル基、 - SO フエ-ル基（ Or -tro group, R d represents a hydrogen atom, a phenol group, a -SO phenol group (
(0-2)  (0-2)
フエニル基上に、一〜二個の Re基を有していてもよい）を表し、 Reは水素原子、シァ ノ基、または-トロ基を表し、 Baは、 1 to 2 R e groups may be present on the phenyl group), R e represents a hydrogen atom, a cyan group, or a -tro group, and B a is
[化 14] [Chemical 14]
Figure imgf000020_0001
Figure imgf000020_0001
Rfは水素原子、水酸基、ハロゲン原子、 C1 6アルキル基、 C1 6アルコキシ基、フ ェニル基、ニトロ基、またはアミノ基を表し、 は水素原子、ハロゲン原子、またはフエ -ル基を表し、該フエ-ル基は Rgaにて一〜三個置換されていてもよぐ Rgaとは水素 原子、ハロゲン原子、 C1 6アルキル基、 C1— 6アルコキシ基、ヒドロキシカルボ- ルメチルォキシ基、 C1 6アルキルォキシカルボ-ルメチルォキシ基、力ルバモイル メチルォキシ基、 C1 6アルキルォキシカルボ-ルェチル基、—OCH CONHCH R f represents a hydrogen atom, a hydroxyl group, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a phenyl group, a nitro group, or an amino group, and represents a hydrogen atom, a halogen atom, or a phenyl group, Hue - Le group is a hydrogen atom and Yogu R ga be one to three amino substituents at R ga, halogen atom, C1 6 alkyl group, C1- 6 alkoxy group, hydroxycarbonated - Rumechiruokishi group, C1 6 alkyl Oxycarboxymethyloxy group, strong rubamoyl methyloxy group, C16 alkyloxycarboruethyl group, —OCH CONHCH
2 2 twenty two
CH OH、 一 OCH CONHPh、 一 OCH CONHCH Ph、 一 OCH CONHCH、フCH OH, OCH CONHPh, OCH CONHCH Ph, OCH CONHCH, O
2 2 2 2 2 3 ェ-ル C 1 6アルキル基、 2 2 2 2 2 3 Well C 1 6 alkyl group,
[化 15]
Figure imgf000021_0001
[Chemical 15]
Figure imgf000021_0001
を表し、 Rhは水素原子またはアミノ基を表し、 Riは水素原子または C 1—6アルキル基 を表し、 Rjは水素原子、ハロゲン原子、 C1 6アルキル基、またはトリフルォロメチル 基を表す。〕。 The stands, R h represents a hydrogen atom or an amino group, Ri represents a hydrogen atom or a C 1-6 alkyl group, R j represents a hydrogen atom, a halogen atom, C1 6 alkyl or triflates Ruo Russia methyl group, . ].
好ましくは、下記式 (Iaa)で表される化合物、その塩、またはそれらの溶媒和物が提 供され、  Preferably, a compound represented by the following formula (Iaa), a salt thereof, or a solvate thereof is provided,
Aa-NH-CO-NY-CH Ba (laa) A a -NH-CO-NY-CH B a (laa)
2  2
式中、 Aaは、 Where A a is
[化 16] [Chemical 16]
Figure imgf000021_0002
を表し、
Figure imgf000021_0002
Represents
Baは、 B a
[化 17]
Figure imgf000021_0003
を表し、 [Chemical 17]
Figure imgf000021_0003
Represents
Yは水素原子またはメチル基を表し、  Y represents a hydrogen atom or a methyl group,
Raは水素原子、水酸基、ハロゲン原子、シァノ基、ニトロ基、 C1— 6アルキル基、 C1 6アルコキシ基、トリフルォロメチル基、トリフルォロメチルォキシ基、カルボキシル 基、ァリルォキシカルボ-ル基、 C1 6アルキルォキシカルボ-ル基、 C1 6アルキ ルカルボ-ルォキシ基、 C1 6アルキルスルホ-ル基、、スルファモイル基、—OCH CH N 、 一 OCH CH NHCOCH 、 一 COOCH CH OH、 一 COOCH CH NHCR a is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, a C1-6 alkyl group, a C16 alkoxy group, a trifluoromethyl group, a trifluoromethyloxy group, a carboxyl group, an aryloxycarbo Group, C1 6 alkyloxycarbonyl group, C1 6 alkylcarboxoxy group, C1 6 alkylsulfonyl group, sulfamoyl group, —OCH CH N, 1 OCH CH NHCOCH, 1 COOCH CH OH, 1 COOCH CH NHC
2 2 3 2 2 3 2 2 2 22 2 3 2 2 3 2 2 2 2
OCH 、 -COOCH CH N (SO CH )、または一 COOCH CH NHを表し、Represents OCH, -COOCH CH N (SO CH), or one COOCH CH NH;
3 2 2 2 3 2 2 2 2 3 2 2 2 3 2 2 2 2
Rbは水素原子、ハロゲン原子、 C1 6アルキル基、 C1 6アルコキシ基、 C1— 6ァ ルキルォキシカルボ-ル基、または COOCH CH N (SO CH ) 、を表し、 R b represents a hydrogen atom, a halogen atom, a C1 6 alkyl group, a C1 6 alkoxy group, a C1-6 alkylcarbonyl group, or COOCH CH N (SO 2 CH 3),
2 2 2 3 2  2 2 2 3 2
は水素原子、ハロゲン原子、 C1 6アルキル基、 C2— 6ァルケ-ル基、 C2— 6ァ ルキ-ル基、ヒドロキシカルボ-ルメチル基、 C1 6アルキルォキシカルボ-ル基、 C 1 6アルキルォキシカルボ-ルメチル基、 C1 6アルキルカルボ-ルォキシ基、ナ フチル基、 C1 6アルキルチオ基、 C2— 6ァルケ-ルチオ基、 C2— 6アルキ-ルチ ォ基、 C1 6アルキルスルホ-ル基、 C2— 6ァルケ-ルスルホ-ル基、 C2— 6アル キニルスルホ -ル基、 C1 6アルキルスルフィエル基、 C2— 6ァルケ-ルスルフィ- ル基、 C2— 6アルキ-ルスルフィエル基、ピリジルチオ基、モルフオリノメチル基、ピ ペリジノ基、  Is a hydrogen atom, halogen atom, C1 6 alkyl group, C2-6 alkyl group, C2-6 alkyl group, hydroxycarboromethyl group, C1 6 alkyloxycarboxyl group, C 16 alkyl group Xyloxymethyl group, C16 alkylcarbonyl group, naphthyl group, C16 alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C16 alkylsulfol group, C2— 6-alkylsulfonyl group, C2-6 alkynylsulfol group, C1 6 alkylsulfuryl group, C2-6 alkylsulfuryl group, C2-6 alkylsulfuryl group, pyridylthio group, morpholinomethyl group , Piperidino group,
[化 18]
Figure imgf000022_0001
を表し、 [Chemical 18]
Figure imgf000022_0001
Represents
Rcaは水素原子、ハロゲン原子、 C1 6アルキル基、 C 1—6アルコキシ基、カルバモ ィル基、または— OC (CH ) COOCH CHを表し、 R ca represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C1-6 alkoxy group, a carbamoyl group, or —OC (CH 2) COOCH CH,
3 2 2 3  3 2 2 3
Rebは水素原子、ハロゲン原子、カルボキシル基、ニトロ基、 C1— 6アルキルォキシ力 ノレボニノレ基、または CONHCH CH OHを表し、 R eb represents a hydrogen atom, a halogen atom, a carboxyl group, a nitro group, a C1-6 alkyloxy group norboninole group, or CONHCH CH OH,
2 2  twenty two
R∞は水素原子、ハロゲン原子、 C 1—6アルキル基、または-トロ基を表し、 Rdは水素原子またはフエ-ル基、—SO フエニル基 (フエニル基上に、一〜二個 R ∞ represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a -tro group, R d is a hydrogen atom, a phenyl group, a —SO phenyl group (one or two on the phenyl group)
(0-2)  (0-2)
の Re基を有して 、てもよ 、）を表し、 Having a R e group of
Rgは水素原子、ハロゲン原子、またはフエ-ル基を表し、該フエニル基は、 Rgaにて一 〜三個置換されていてもよぐ R g represents a hydrogen atom, a halogen atom, or a phenyl group, and the phenyl group may be substituted by 1 to 3 of R ga .
Rgaとは水素原子、ハロゲン原子、 C1 6アルキル基、 C1— 6アルコキシ基、ヒドロキ シカルボ-ルメチルォキシ基、 C1 6アルキルォキシカルボ-ルメチルォキシ基、力R ga is a hydrogen atom, halogen atom, C1 6 alkyl group, C1-6 alkoxy group, hydroxy carboxymethyloxy group, C1 6 alkyloxy carboxymethyloxy group, force
,、/R NN- ルバモイルメチルォキシ基 i、 C1 6アルキルォキシカルボ-ルェチル基、 OCH C  ,, / R NN- Rubamoylmethyloxy group i, C16 alkyloxycarboruethyl group, OCH C
2 2
ONHCH CH OH Q ONHCH CH OH Q
、 一 OCH CONHPh、 一 OCH CONHCH Ph、 一 OCH CON , OCH CONHPh, OCH CONHCH Ph, OCH CON
2 2 twenty two
HCH、  HCH,
3  Three
[化 19]  [Chemical 19]
—— OCH —— OCH
Figure imgf000023_0001
を表し、 R1は水素原子または CI 6アルキル基を表す。
Figure imgf000023_0001
R 1 represents a hydrogen atom or a CI 6 alkyl group.
さらに好ましくは、前記式 (Iaa)で表される化合物の式中、 Baが、 More preferably, in the formula of the compound represented by the formula (Iaa), B a is
[化 20] [Chemical 20]
を表し、 Represents
Rgはフエ二ル基を表し、該フエ二ル基は Rgaにて一〜三個置換されて 、てもよく、 Rgaとは水素原子、ハロゲン原子、 C1— 6アルキル基、 C1— 6アルコキシ基、ヒドロキ シカルボ-ルメチルォキシ基、 C1 6アルキルォキシカルボ-ルメチルォキシ基、力 ルバモイルメチルォキシ基、 C1 6アルキルォキシカルボ-ルェチル基、 OCH C R g represents a phenylene group, the Hue alkenyl group is one to three amino substituents at R ga, at best, the R ga a hydrogen atom, a halogen atom, C1- 6 alkyl group, C1- 6 alkoxy group, hydroxy Cycarboxylmethyloxy group, C16 alkyloxycarboxylmethyl group, force Rubamoylmethyloxy group, C16 alkyloxycarboxyl group, OCH C
2 2
ONHCH CH OH OCH CONHPh OCH CONHCH Ph OCH CON ONHCH CH OH OCH CONHPh OCH CONHCH Ph OCH CON
2 2  twenty two
HCH  HCH
3  Three
[化 21]  [Chemical 21]
Figure imgf000024_0001
を表す化合物、その塩、またはそれらの溶媒和物が提供される。
Figure imgf000024_0001
Or a salt thereof, or a solvate thereof is provided.
またさらに本発明の好ましい別の態様は、前記式 (Iaa)において、 Aaが、 Still another preferred embodiment of the present invention is the above formula (Iaa), wherein A a is
[化 22]
Figure imgf000024_0002
を表し、 Baが、 [Chemical 22]
Figure imgf000024_0002
B a
[化 23]
Figure imgf000024_0003
[Chemical 23]
Figure imgf000024_0003
を表し、 はフエ二ル基を表し、該フヱ-ル基が Rgaにて一個置換されており、 Rgaは、
Figure imgf000025_0001
を表す化合物、その塩、またはそれらの溶媒和物が提供される。 Represents, represents a phenylene group, the full We - Le group are one substituted by R ga, R ga is
Figure imgf000025_0001
Or a salt thereof, or a solvate thereof is provided.
さらに好ましい本発明の別の態様は下記式 (lab)で表される化合物、その塩、また はそれらの溶媒和物が提供される：  Furthermore, another preferred embodiment of the present invention provides a compound represented by the following formula (lab), a salt thereof, or a solvate thereof:
[化 25] [Chemical 25]
Figure imgf000025_0002
Figure imgf000025_0002
[式中、 Xはハロゲン原子を表し、 ITは水素原子、ハロゲン原子、 C1 6アルキル基、 C2— 6ァルケ-ル基、 C2— 6アルキ-ル基、ヒドロキシカルボ-ルメチル基、 C1— 6 アルキルォキシカルボ-ル基、 C1 6アルキルォキシカルボ-ルメチル基、 C1 6 アルキルカルボ-ルォキシ基、ナフチル基、 C1 6アルキルチオ基、 C2— 6ァルケ 二ルチオ基、 C2— 6アルキ-ルチオ基、 C1 6アルキルスルホ-ル基、 C2— 6アル ケニルスルホ -ル基、 C2— 6アルキニルスルホ -ル基、 C1 6アルキルスルフィエル 基、 C2— 6ァルケ-ルスルフィエル基、 C 2— 6アルキ-ルスルフィエル基、ピリジル チォ基、モルフオリノメチル基、ピペリジノ基、 [In the formula, X represents a halogen atom, IT represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C2-6 alkyl group, a C2-6 alkyl group, a hydroxycarbonmethyl group, a C1-6 alkyl group. Oxycarbonyl group, C1 6 alkyloxycarboxyl methyl group, C1 6 alkylcarboxoxy group, naphthyl group, C1 6 alkylthio group, C2—6 alkylthio group, C2—6 alkylthio group, C1 6 alkylsulfol group, C2-6 alkenylsulfol group, C2-6 alkynylsulfol group, C1 6 alkylsulfier group, C2-6 alkylsulfuryl group, C2-6 alkylsulfier group, pyridyl Thio group, morpholinomethyl group, piperidino group,
[化 26]
Figure imgf000025_0003
[Chemical 26]
Figure imgf000025_0003
を表し、 Reaは水素原子、ハロゲン原子、 C1 6アルキル基、 C1 6アルコキシ基、力 ルバモイル基、または— OC (CH ) COOCH CHを表し、 Rebは水素原子、ハロゲ The stands, R ea is hydrogen atom, halogen atom, C1 6 alkyl, C1 6 alkoxy group, a force Rubamoiru group, or - represents OC (CH) COOCH CH, R eb is hydrogen, halogen
3 2 2 3  3 2 2 3
ン原子、カルボキシル基、ニトロ基、 C 1—6アルキルォキシカルボ-ル基、または— C ONHCH CH OHを表し、 R∞は水素原子、ハロゲン原子、 C 1—6アルキル基、または-トロ基を表し、これらは 置換基を有していてもよい。 ]。 Represents a carbon atom, a carboxyl group, a nitro group, a C 1-6 alkyloxycarbonyl group, or —C ONHCH CH OH, R∞ represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a -tro group, and these may have a substituent. ].
下記式 (lab)でさらに好ましくは、式中、 Xはハロゲン原子を表し、 Reは C1— 6アル キル基、 C2— 6ァルケ-ル基、 C2— 6アルキ-ル基、 C 1—6アルキルチオ基、 C2— 6ァルケ-ルチオ基、 C2— 6アルキ-ルチオ基、 C1 6アルキルスルホ-ル基、 C2 6ァルケ-ルスルホ-ル基、 C2— 6アルキ-ルスルホ -ル基、 C1 6アルキルスル フィエル基、 C2— 6ァルケ-ルスルフィエル基、または C2— 6アルキ-ルスルフィ- ル基を表し、これらは置換基を有していてもよい化合物、その塩、またはそれらの溶 媒和物が提供される。 More preferably, in the following formula (lab), X represents a halogen atom, R e is a C1-6 alkyl group, a C2-6 alkyl group, a C2-6 alkyl group, C 1-6 Alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C16 alkylsulfol group, C2-6 alkylsulfol group, C2-6 alkylsulfol group, C1-6 alkylsulfur group Represents a Fiel group, a C2-6 alkylsulfuryl group, or a C2-6 alkylsulfuryl group, which is provided with an optionally substituted compound, a salt thereof, or a solvent thereof. The
[化 27]  [Chemical 27]
Figure imgf000026_0001
さらに本発明の別の態様としては、下記式 (lb)で表される化合物、その塩、または それらの溶媒和物が提供される：
Figure imgf000026_0001
Furthermore, another embodiment of the present invention provides a compound represented by the following formula (lb), a salt thereof, or a solvate thereof:
[化 28] [Chemical 28]
Ab— N A， 一 C O— B b ( l b ) A b — NA, one CO— B b (lb)
〔式中、 A'は水素原子、 C1— 6アルキル基、または隣接する窒素原子、 Abと共に下 記式 (II)を表し、 [In the formula, A ′ represents a hydrogen atom, a C1-6 alkyl group, or an adjacent nitrogen atom, A b together with the following formula (II),
[化 29]
Figure imgf000026_0002
[Chemical 29]
Figure imgf000026_0002
A' 'は水素原子またはハロゲン原子を表し、  A ′ ′ represents a hydrogen atom or a halogen atom,
Abは、 A b is
[化 30]
Figure imgf000027_0001
を表し、 [Chemical 30]
Figure imgf000027_0001
Represents
Raは水素原子、水酸基、ハロゲン原子、シァノ基、ニトロ基、 C1— 6アルキル基、 C1 6アルコキシ基、トリフルォロメチル基、トリフルォロメチルォキシ基、カルボキシル 基、ァリルォキシカルボ-ル基、 C1 6アルキルォキシカルボ-ル基、 C1 6アルキ ルカルボ-ルォキシ基、 C1 6アルキルスルホ-ル基、、スルファモイル基、—OCH CH N 、 一 OCH CH NHCOCH 、 一 COOCH CH OH、 一 COOCH CH NHCR a is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, a C1-6 alkyl group, a C16 alkoxy group, a trifluoromethyl group, a trifluoromethyloxy group, a carboxyl group, an aryloxycarbo Group, C1 6 alkyloxycarbonyl group, C1 6 alkylcarboxoxy group, C1 6 alkylsulfonyl group, sulfamoyl group, —OCH CH N, 1 OCH CH NHCOCH, 1 COOCH CH OH, 1 COOCH CH NHC
2 2 3 2 2 3 2 2 2 22 2 3 2 2 3 2 2 2 2
OCH 、 -COOCH CH N (SO CH ) 、 -COOCH CH NH、または COOCHOCH, -COOCH CH N (SO CH), -COOCH CH NH, or COOCH
3 2 2 2 3 2 2 2 2 3 2 2 2 3 2 2 2 2
Nを表し、  N
2 3  twenty three
Rbは水素原子、ハロゲン原子、 C1 6アルキル基、 C1 6アルコキシ基、 C1— 6ァ ルキルォキシカルボ-ル基、または COOCH CH N (SO CH )を表し、 R b represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a C1-6 alkyl carboxy group, or COOCH CH N (SO CH);
2 2 2 3 2  2 2 2 3 2
は水素原子、ハロゲン原子、 C1 6アルキル基、 C2— 6ァルケ-ル基、 C2— 6ァ ルキ-ル基、ヒドロキシカルボ-ルメチル基、 C1 6アルキルォキシカルボ-ル基、 C 1 6アルキルォキシカルボ-ルメチル基、 C1 6アルキルカルボ-ルォキシ基、ナ フチル基、 C1 6アルキルチオ基、 C2— 6ァルケ-ルチオ基、 C2— 6アルキ-ルチ ォ基、 C1 6アルキルスルホ-ル基、 C2— 6ァルケ-ルスルホ-ル基、 C2— 6アル キニルスルホ -ル基、 C1 6アルキルスルフィエル基、 C2— 6ァルケ-ルスルフィ- ル基、 C2— 6アルキ-ルスルフィエル基、ピリジルチオ基、モルフオリノメチル基、ピ ペリジノ基、  Is a hydrogen atom, halogen atom, C1 6 alkyl group, C2-6 alkyl group, C2-6 alkyl group, hydroxycarboromethyl group, C1 6 alkyloxycarboxyl group, C 16 alkyl group Xyloxymethyl group, C16 alkylcarbonyl group, naphthyl group, C16 alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C16 alkylsulfol group, C2— 6-alkylsulfonyl group, C2-6 alkynylsulfol group, C1 6 alkylsulfuryl group, C2-6 alkylsulfuryl group, C2-6 alkylsulfuryl group, pyridylthio group, morpholinomethyl group , Piperidino group,
[化 31] [Chemical 31]
Figure imgf000027_0002
を表し、
Figure imgf000027_0002
Represents
Rcaは水素原子、ハロゲン原子、 C1 6アルキル基、 C 1—6アルコキシ基、カルバモ ィル基、または— OC (CH ) COOCH CHを表し、 R ca represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C1-6 alkoxy group, a carbamoyl group, or —OC (CH 2) COOCH CH,
3 2 2 3  3 2 2 3
Rebは水素原子、ハロゲン原子、カルボキシル基、ニトロ基、 C1— 6アルキルォキシ力 ノレボニノレ基、または CONHCH CH OHを表し、 R eb represents a hydrogen atom, a halogen atom, a carboxyl group, a nitro group, a C1-6 alkyloxy group norboninole group, or CONHCH CH OH,
2 2  twenty two
R∞は水素原子、ハロゲン原子、 C 1—6アルキル基、または-トロ基を表し、 R ∞ represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a -tro group,
Rdは水素原子またはフエ-ル基、—SO フエニル基 (フエニル基上に、一〜二個 R d is a hydrogen atom, a phenyl group, a —SO phenyl group (one or two on the phenyl group)
(0-2)  (0-2)
の Re基を有して 、てもよ 、）を表し、 Having a R e group of
Bbは C 1—6アルキルォキシカルボ-ルァミノメチル基、 CH— S— Rk基、 CH -B b is a C 1-6 alkyloxycarboluminomethyl group, CH—S—R k group, CH—
2 2twenty two
O— R1基、 O—R 1 group,
[化 32] [Chemical 32]
Figure imgf000028_0001
Figure imgf000028_0001
Rfは水素原子、水酸基、ハロゲン原子、 C1 6アルキル基、 C1 6アルコキシ基、フ ェニル基、ニトロ基、またはアミノ基を表し、 R f represents a hydrogen atom, a hydroxyl group, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a phenyl group, a nitro group, or an amino group,
Rhは水素原子またはアミノ基を表し、 R h represents a hydrogen atom or an amino group,
Rk基とは、 Rk group is
[化 33] [Chemical 33]
Figure imgf000029_0001
を表し、
Figure imgf000029_0001
Represents
Rka基とは水素原子、ハロゲン原子、 C1— 6アルキル基、フエニル基、トリフルォロメチ ル基、アミノ基、ニトロ基、 SO H基、または C1 6アルキルォキシカルボ-ル基を R ka group is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a phenyl group, a trifluoromethyl group, an amino group, a nitro group, a SOH group, or a C16 alkyloxycarbon group.
3  Three
表し、 Represent,
Rkb基とは水素原子またはァセチル基を表し、 R kb group represents a hydrogen atom or a acetyl group;
Rke基とは水素原子または-トロ基を表し、 R ke group represents a hydrogen atom or -tro group,
R1基とは、 R 1 group is
[化 34] [Chemical 34]
Figure imgf000029_0002
を表す。〕。
Figure imgf000029_0002
Represents. ].
好ましくは、前記式 (lb)で表される化合物の式中、 A'は水素原子を表し、 Abは、 [化 35]
Figure imgf000029_0003
1-3 を表し、 Preferably, in the formula of the compound represented by the formula (lb), A ′ represents a hydrogen atom, and A b represents [Chemical Formula 35]
Figure imgf000029_0003
1-3
Bbは—CH— S—Rk基を表すィ匕合物、その塩、またはそれらの溶媒和物が提供され る。 B b is a compound representing a —CH—S—R k group, a salt thereof, or a solvate thereof. The
もう一つの態様は下記式 (Ic)で表される化合物、その塩、またはそれらの溶媒和物 が提供される：  Another embodiment provides a compound represented by the following formula (Ic), a salt thereof, or a solvate thereof:
[化 36] [Chemical 36]
( I c ) ( I c )
[式中、 Zeは、 [Where Z e is
NA， -CO-CH O— N = C (B，）一または  NA, -CO-CH O— N = C (B,) one or
2  2
-O-CO-CH O— N=C (B，）一  -O-CO-CH O— N = C (B,)
2  2
を表し、  Represents
A'は水素原子、 C1— 6アルキル基、または隣接する窒素原子、 Aeと共に下記式 (I I)を表し、 A ′ represents a hydrogen atom, a C1-6 alkyl group, or an adjacent nitrogen atom, A e together with the following formula (II):
A' 'は水素原子またはハロゲン原子を表し、  A ′ ′ represents a hydrogen atom or a halogen atom,
B'は水素原子、 2—ピリジル基、または隣接する =C、および Beと共にシクロへキシ リデンを表し、 B 'represents a hydrogen atom, a 2-pyridyl group or a carboxy isopropylidene adjacent = C, and with B e cycloheteroalkyl,
[化 37]
Figure imgf000030_0001
[Chemical 37]
Figure imgf000030_0001
Aeは水素原子、 C1 6アルキル基、 A e is a hydrogen atom, a C16 alkyl group,
[化 38]  [Chemical 38]
Figure imgf000030_0002
を表し、
Figure imgf000030_0002
Represents
Raは水素原子、水酸基、ハロゲン原子、シァノ基、ニトロ基、 C1— 6アルキル基、 C 1—6アルコキシ基、トリフルォロメチル基、トリフルォロメチルォキシ基、カルボキシル 基、ァリルォキシカルボ-ル基、 C1 6アルキルォキシカルボ-ル基、 C1 6アルキ ルカルボ-ルォキシ基、 C1 6アルキルスルホ-ル基、スルファモイル基、—OCH Ra is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, a C1-6 alkyl group, a C1-6 alkoxy group, a trifluoromethyl group, a trifluoromethyloxy group, a carboxyl group, an arylo group. XiCarbon group, C16 alkyloxycarbonyl group, C16 alkylcarbonyl group, C16 alkylsulfol group, sulfamoyl group, —OCH
2 2
CH N 、 一 OCH CH NHCOCH 、 一 COOCH CH OH、 一 COOCH CH NHCCH N, I OCH CH NHCOCH, I COOCH CH OH, I COOCH CH NHC
2 3 2 2 3 2 2 2 22 3 2 2 3 2 2 2 2
OCH 、 -COOCH CH N (SO CH ) 、または一 COOCH CH NHを表し、 Represents OCH, -COOCH CH N (SO CH), or one COOCH CH NH;
3 2 2 2 3 2 2 2 2  3 2 2 2 3 2 2 2 2
Rbは水素原子、ハロゲン原子、 C1 6アルキル基、 C1 6アルコキシ基、 C1— 6 アルキルォキシカルボ-ル基、または COOCH CH N (SO CH )を表し、 R b represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a C1-6 alkyloxycarbon group, or COOCH CH N (SO CH);
2 2 2 3 2  2 2 2 3 2
Reは水素原子、ハロゲン原子、 C1 6アルキル基、 C2— 6ァルケ-ル基、 C2-6 アルキ-ル基、ヒドロキシカルボ-ルメチル基、 C1 6アルキルォキシカルボ-ル基 、 C1 6アルキルォキシカルボ-ルメチル基、 C1 6アルキルカルボ-ルォキシ基、 ナフチル基、 C1 6アルキルチオ基、 C2— 6ァルケ-ルチオ基、 C2— 6アルキ-ル チォ基、 C 1—6アルキルスルホ-ル基、 C2— 6ァルケ-ルスルホ-ル基、 C2— 6ァ ルキニルスルホ -ル基、 C1 6アルキルスルフィエル基、 C2— 6ァルケ-ルスルフィ -ル基、 C2— 6アルキ-ルスルフィエル基、ピリジルチオ基、モルフオリノメチル基、 ピペリジノ基、 R e is a hydrogen atom, a halogen atom, a C16 alkyl group, a C2-6 alkyl group, a C2-6 alkyl group, a hydroxycarboromethyl group, a C16 alkyloxycarbon group, a C16 alkyl group Xyloxymethyl group, C16 alkyl carbonyl group, naphthyl group, C16 alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C1-6 alkylsulfol group, C2 — 6-alkylsulfol group, C2— 6-alkynylsulfol group, C1-6 alkylsulfuryl group, C2—6-alkylsulfuryl group, C2—6-alkylsulfuryl group, pyridylthio group, morpholinomethyl Group, piperidino group,
[化 39]
Figure imgf000031_0001
を表し、 [Chemical 39]
Figure imgf000031_0001
Represents
Reaは水素原子、ハロゲン原子、 C1 6アルキル基、 C1 6アルコキシ基、力ルバ モイル基、または一 OC (CH ) COOCH CHを表し、 R ea represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a strong rubamoyl group, or one OC (CH) COOCH CH;
3 2 2 3  3 2 2 3
Rebは水素原子、ハロゲン原子、カルボキシル基、ニトロ基、 C1 6アルキルォキシ カルボ-ル基、または CONHCH CH OHを表し、 R eb represents a hydrogen atom, a halogen atom, a carboxyl group, a nitro group, a C16 alkyloxycarbon group, or CONHCH CHOH,
2 2  twenty two
R∞は水素原子、ハロゲン原子、 C1 6アルキル基、または-トロ基を表し、 R∞ represents a hydrogen atom, a halogen atom, a C16 alkyl group, or a -tro group,
Rdは水素原子またはフエ-ル基、—SO フエニル基 (フエニル基上に、一〜二 個の Re基を有して 、てもよ 、）を表し、 R d represents a hydrogen atom, a phenyl group, a —SO phenyl group (on the phenyl group, 1 to 2 Having a number of R e groups,
Beはナフチル基、 B e is a naphthyl group,
[化 40]  [Chemical 40]
Figure imgf000032_0001
Figure imgf000032_0001
Rfは水素原子、水酸基、ハロゲン原子、 C1 6アルキル基、 C1— 6アルコキシ基、 フエニル基、ニトロ基、またはアミノ基を表し、 R f represents a hydrogen atom, a hydroxyl group, a halogen atom, a C1 6 alkyl group, a C1-6 alkoxy group, a phenyl group, a nitro group, or an amino group,
Rhは水素原子またはアミノ基を表し、 N R, R h represents a hydrogen atom or an amino group, NR,
Riは水素原子または C1 6アルキル基を表す。  Ri represents a hydrogen atom or a C16 alkyl group.
好ましくは、前記式 (Ic)で表される化合物の式中、  Preferably, in the formula of the compound represented by the formula (Ic),
Zcは NA，一 CO— CH O— N = C (B，）一を表し、 Z c represents NA, one CO—CH 2 O—N = C (B,) one,
2  2
A'は水素原子を表し、  A ′ represents a hydrogen atom,
B'は水素原子、 2—ピリジル基、または隣接する =C、および Beと共にシクロへキシ リデンを表し、 B 'represents a hydrogen atom, a 2-pyridyl group or a carboxy isopropylidene adjacent = C, and with B e cycloheteroalkyl,
Acは、 A c
[化 41]
Figure imgf000032_0002
を表す化合物、その塩、またはそれらの溶媒和物が提供される。 [Chemical 41]
Figure imgf000032_0002
Or a salt thereof, or a solvate thereof is provided.
[0044] また別の態様としては、前記記載の化合物またはその塩を有効成分とする医薬組 成物であり、好ましくは前記記載の化合物またはその塩を有効成分とする FabK阻害 剤、または Fablおよび FabKを阻害することを特徴とする、前記記載の化合物または その塩である。 [0044] Another aspect is a pharmaceutical composition comprising the above-described compound or a salt thereof as an active ingredient, preferably a FabK inhibitor comprising the above-described compound or a salt thereof as an active ingredient, or Fabl and The compound or salt thereof as described above, which inhibits FabK.
[0045] 本発明の具体的な化合物は以下に示される。  [0045] Specific compounds of the present invention are shown below.
ウレァ漏 ：  Urea leakage:
1, 3 ビス（（1H ベンゾ [d]イミダゾールー 2—ィル)メチル)ゥレア（実施例 1参照 ) 1,3 bis ((1H benzo [d] imidazol-2-yl) methyl) urea (see Example 1) )
N— (2- (2- (3—（（1H べンゾ [d]イミダゾールー 2 ィル)メチル）ウレイド）ベ ンゾ [d]チアゾール 6 ィルォキシ)ェチル)ァセトアミド（実施例 23参照）  N— (2- (2- (3 -— ((1H-benzo [d] imidazole-2-yl) methyl) ureido) benzo [d] thiazole-6-yloxy) ethyl) acetamide (see Example 23)
1一（（4一（4 （（エトキシカルボ-ル)メチルォキシ）フエ-ル） 1H—イミダゾー ルー 2 ィル）メチル）ー3—（6 （メチルスルフォ -ル）ベンゾ [d]チアゾールー 2— ィル)ゥレア（実施例 24参照）  1 1 ((4 1 (4 ((ethoxycarbol) methyloxy) phenyl) 1H-imidazole 2 yl) methyl) -3- (6 (methylsulfol) benzo [d] thiazole 2-yl ) Urea (see Example 24)
2- (4一（2—（（3—（6 （メチルスルフォ -ル）ベンゾ [d]チアゾールー 2 ィル）ゥ レイド)メチル） 1H イミダゾールー 4 ィル）フエノキシ）酢酸（実施例 25参照） 2- (4-1 (2-((3- (6 (methylsulfoyl) benzo [d] thiazole-2-yl) ureid) methyl) 1H imidazole-4-yl) phenoxy) acetic acid (see Example 25)
1一（6 （メチルスルフォ -ル）ベンゾ [d]チアゾールー 2 ィル）一 3—（（4一（4一 ( (モルフォリノカルボ-ル）メチルォキシ）フエ-ル） 1H—イミダゾールー 2—ィル） メチル)ゥレア（実施例 26参照） 1- (6 (methylsulfo) benzo [d] thiazol-2-yl) 1-3-(((4- (4-((morpholinocarbon) methyloxy) phenol) 1H-imidazole-2-yl) Methyl) urea (see Example 26)
1一（6 （メチルスルフォ -ル）ベンゾ [d]チアゾールー 2 ィル） 3—（（4一（4 （（フエ-ルカルバモイル）メチルォキシ）フエ-ル）—1H—イミダゾールー 2—ィル） メチル)ゥレア（実施例 27参照）  1- (6 (Methylsulfol) benzo [d] thiazol-2-yl) 3-((4 ((((2-carbcarbyl) methyloxy) phenol) -1H-imidazol-2-yl) methyl) urea (See Example 27)
1 （5—（4ーメトキシカルボ-ルフエ-ルチオ）チアゾールー 2 ィル）ー3—（（4 —フエ-ル— 1H—イミダゾール— 2—ィル)メチル）ゥレア（実施例 28参照）  1 (5- (4-Methoxycarbophenylthio) thiazole-2-yl) -3-(((4-phenol-1H-imidazol-2-yl) methyl) urea (see Example 28)
1一（（4一（4 （（エトキシカルボ-ル)メチルォキシ）フエ-ル） 1H—イミダゾー ルー 2 ィル)メチル）ー3—（5 （ピリジン 2—ィルチオ）チアゾールー 2 ィル）ゥ レア（実施例 29参照）  1 1 ((4 1 (4 ((Ethoxycarbol) methyloxy) phenyl) 1H-imidazole 2 yl) methyl) -3 (5 (pyridine 2-ylthio) thiazole 2 yl) urea ( (See Example 29)
2- (4一（2— ( (3—（5 （ピリジン 2—ィルチオ）チアゾールー 2 ィル）ゥレイ ド)メチル） 1H—イミダゾールー 4 ィル)フエノキシ)酢酸ナトリウム塩（実施例 31 参照）  2- (4-1 (2-((3- (5 (pyridine-2-ylthio) thiazole-2-yl) ureidomethyl) 1H-imidazole-4-yl) phenoxy) acetic acid sodium salt (see Example 31)
1— (5— (ベンジルチオ）チアゾール—2—ィル）—3— ( (4 フエ-ルー 1H—イミ ダゾールー 2 ィル)メチル)ゥレア（実施例 42参照）  1— (5— (Benzylthio) thiazol-2-yl) —3— ((4 Ferro- 1H—imidazole-2-yl) methyl) urea (see Example 42)
1— (5— (フエネチルチオ）チアゾール—2—ィル）—3— ( (4 フエ-ルー 1H— イミダゾール— 2—ィル)メチル)ゥレア（実施例 43参照）  1— (5— (Phenethylthio) thiazole-2-yl) —3— ((4 Phenol 1H—imidazol-2-yl) methyl) urea (see Example 43)
1一（5 ブチルチアゾールー 2 ィル） 3—（（4 フエ-ル） 1H—イミダゾール —2—ィル)メチル)ゥレア（実施例 44参照） 1— (5— (ピリジン— 2—ィルチオ）チアゾール—2—ィル） - 3 - ( (4- (ピリジン— 3 ィル） 1H—イミダゾールー 2 ィル)メチル）ゥレア（実施例 49参照） 1- (5-Butylthiazole-2-yl) 3-((4 phenol) 1H-imidazole-2-yl) methyl) urea (see Example 44) 1— (5— (Pyridine-2-ylthio) thiazole-2-yl)-3-((4- (Pyridine-3-yl) 1H-imidazole-2-yl) methyl) urea (see Example 49)
2- (4 (2- ( (3- (5 （モルフオリノメチル）チアゾールー 2 ィル）ウレイド)メチ ル）— 1H—イミダゾール— 4—ィル)フエノキシ)酢酸ナトリウム塩（実施例 54参照） 2- (4 (2- ((3- (5 (morpholinomethyl) thiazole-2-yl) ureido) methyl)-1H-imidazole-4-yl) phenoxy) acetic acid sodium salt (see Example 54)
1— ( (4—フエ-ルー 1H—イミダゾールー 2—ィル)メチル）—3 プロピルウレァ（ 実施例 55参照） 1— ((4-Fer-Lu 1H-imidazole-2-yl) methyl) —3 propylurea (see Example 55)
1 -メチル 3— ( (4 フエ-ル 1 H イミダゾール 2 ィル)メチル）ゥレア（実 施例 65参照）  1-Methyl 3-— ((4 Phenol 1 H Imidazole 2-yl) methyl) urea (see Example 65)
1 （（4 フエ-ルー 1H—イミダゾールー 2 ィル）メチル）ー3—（3 （フエ-ルチ ォ)プロピル)ゥレア（実施例 71参照）  1 (((4) 1H-imidazole-2-yl) methyl) -3- (3 (phenol) propyl) urea (see Example 71)
1— ( (4— (4 ブロモフエ-ル）— 1H—イミダゾールー 2—ィル）メチル）—3— (5 - (ピリジン— 2—ィルチオ)チアゾール 2—ィル)ゥレア（実施例 73参照）  1— ((4— (4 Bromophenol) — 1H—imidazol-2-yl) methyl) —3— (5- (Pyridine-2-ylthio) thiazole 2-yl) urea (see Example 73)
1一（（4一（3 （（エトキシカルボ-ル)メチルォキシ）フエ-ル） 1H—イミダゾー ルー 2 ィル)メチル）ー3—（5 （ピリジン 2—ィルチオ）チアゾールー 2 ィル）ゥ レア (実施例 77参照）  1 1 ((4 1 (3 ((ethoxycarbol) methyloxy) phenol) 1H-imidazole 2 yl) methyl) -3 (5 (pyridine 2-ylthio) thiazole 2 yl) urea ( (See Example 77)
1— ( (4— (3—メトキシフエ-ル）— 1H—イミダゾール— 2—ィル)メチル）—3— ( 5— (ピリジン— 2—ィルチオ)チアゾール 2—ィル）ゥレア（実施例 78参照）  1— ((4— (3-Methoxyphenol) — 1H-imidazole-2-yl) methyl) —3— (5- (Pyridine-2-ylthio) thiazole 2-yl) urea (see Example 78) )
2- (3—（2— ( (3—（5 （ピリジン 2—ィルチオ）チアゾールー 2 ィル）ゥレイ ド)メチル） 1H—イミダゾールー 4 ィル)フエノキシ)酢酸ナトリウム塩（実施例 80 参照）  2- (3— (2— ((3— (5 (pyridine 2-ylthio) thiazole-2-yl) ureidomethyl) 1H-imidazole-4-yl) phenoxy) acetic acid sodium salt (see Example 80)
1— ( (4— (4— (2— (tert—ブトキシカルボ-ル）ェチル）フエ-ル） 1H—イミダ ゾールー 2 ィル)メチル）ー3—（5 （ピリジン 2—ィルチオ）チアゾールー 2—ィ ル)ゥレア（実施例 81参照）  1— ((4— (4— (2— (tert-Butoxycarbole) ethyl) phenol) 1H—Imidazole-2-yl) methyl) -3— (5 (Pyridin-2-ylthio) thiazole-2- Il) Urea (see Example 81)
1— ( (4— (3 ブロモフエ-ル）— 1H—イミダゾールー 2—ィル）メチル）—3— (5 - (ピリジン— 2—ィルチオ)チアゾール 2—ィル)ゥレア（実施例 82参照）  1— ((4— (3 Bromophenol) — 1H—Imidazole-2-yl) methyl) —3— (5- (Pyridine-2-ylthio) thiazol 2-yl) urea (see Example 82)
(E)-l- (5-ブロモチアゾール -2-ィル) -3- ((4- (4- (2- (3- (2,6-ジクロロベンジル) -2-メ チル- 4-ォキソピリジン- 1(4H)-ィル）ビュル）フエ-ル) -1H-イミダゾール -2-ィル）メ チル）ゥレア (実施例 84参照） 1一（5 ブロモチアゾールー 2 ィル）ー3—（（4 （4— (3— (3— (2, 6 ジクロ口 ベンジル） 2—メチルー 4 ォキソピリジン 1 (4H) ィル）プロピル）フエ-ル） 1H—イミダゾール— 2—ィル)メチル)ゥレア（実施例 85参照） (E) -l- (5-bromothiazol-2-yl) -3- ((4- (4- (2- (3- (2,6-dichlorobenzyl) -2-methyl-4-oxopyridine) -1 (4H) -yl) bul) fehl) -1H-imidazole-2-yl) methyl) urea (see Example 84) 1- (5 Bromothiazole-2 yl)-3-((4 (4— (3— (3— (2, 6 Dichloro benzyl) 2-methyl-4 oxopyridine 1 (4H) yl) propyl) L) 1H-imidazole-2-yl) methyl) urea (see Example 85)
(E)- 1- ((4- (4- (3- (3- (2,6-ジクロロベンジル) -2-メチル -4-ォキソピリジン- 1(4H)-ィル )プロプ - 1-ェ -ル)フエ-ル)- 1H-イミダゾール -2-ィル)メチル )-3-(5- (メチルチオ)チ ァゾール- 2-ィル)ゥレア（実施例 86参照）  (E)-1- ((4- (4- (3- (3- (2,6-dichlorobenzyl) -2-methyl-4-oxopyridine-1 (4H) -yl) prop-1-e- L) phenol) -1H-imidazole-2-yl) methyl) -3- (5- (methylthio) thiazol-2-yl) urea (see Example 86)
1 - ( (4- (4—ブロモフエ-ル）— 1H—イミダゾールー 2—ィル）メチル）—3— (5 ーメチルチオチアゾールー 2 ィル)ゥレア（実施例 87参照）  1-((4- (4-Bromophenol) — 1H-imidazole-2-yl) methyl) —3— (5-methylthiothiazol-2-yl) urea (see Example 87)
(E)- 1- ((4- (4- (2- (3- (2,6-ジクロロベンジル) -2-メチル -4-ォキソピリジン- 1(4H)-ィル )ビ -ル)フエ-ル) -1H-イミダゾール -2-ィル)メチル )- 3-(5- (ピリジン- 2-ィルチオ)チア ゾール -2-ィル)ゥレア（実施例 88参照）  (E)-1- ((4- (4- (2- (3- (2,6-dichlorobenzyl) -2-methyl-4-oxopyridine-1 (4H) -yl) vinyl) ) -1H-imidazol-2-yl) methyl))-3- (5- (pyridin-2-ylthio) thiazol-2-yl) urea (see Example 88)
1一（5 ブロモチアゾールー 2 ィル）ー3—（（4 （4— (2— (3— (2, 6 ジクロ口 ベンジル） 2—メチル 4—ォキソピリジン一 1 (4H)—ィル）ェチル）フエ二ル）一 1 H—イミダゾール— 2—ィル)メチル)ゥレア（実施例 89参照）  1- (5 Bromothiazol-2 yl) -3 — ((4 (4 -— (2 -— (3-— (2,6 Dichloro-benzyl) 2-methyl-4-oxopyridine-1 1 (4H) —yl) ethyl ) Phenyl) 1 1 H-imidazole-2-yl) methyl) urea (see Example 89)
1 - ( (4- (4—ブロモフエ-ル）— 1—メチル—1H—イミダゾールー 2—ィル）メチ ル）ー3—（5 （ピリジンー2—ィルチオ）チアゾールー 2 ィル）ゥレア（実施例 91参 照）  1-((4- (4-Bromophenol) — 1-methyl-1H-imidazole-2-yl) methyl) -3— (5 (pyridine-2-ylthio) thiazole-2-yl) urea (Example 91 (See)
1— (5 ブロモチアゾール—2—ィル）—3— ( (4— (4— (4 フエ-ルブチル）フエ -ル）― 1H—イミダゾィル— 2—ィル)メチル）ゥレア（実施例 92参照）  1— (5 Bromothiazole—2-yl) —3— ((4— (4 — (4 Phenylbutyl) phenol) — 1H—Imidazol—2-yl) methyl) urea (see Example 92) )
(E) 3—（4一（2— ( (3—（5 ブロモチアゾールー 2 ィル）ウレイド）メチル）一 1 H—イミダゾル—4—ィル）フエ-ル） N—メチル N— ( (1—メチル— 1H—インド 一ノレ 3—ィル)メチル)アタリノレアミド (実施例 93参照）  (E) 3— (4 1 (2— ((3— (5 Bromothiazole-2 yl) ureido) methyl) 1 1 H—Imidazol-4-yl) phenol) N—Methyl N— (( 1-Methyl- 1H-Indo 1-nore 3-yl) methyl) attalinoleamide (see Example 93)
1— ( (4— (3, 4 ジクロロフエ-ル）— 1H—イミダゾール— 2—ィル）メチル）—3— (5— (ピリジン— 2—ィル)チォ)チアゾール 2—ィル)ゥレア（実施例 97参照） 1— ((4— (3, 4 Dichlorophenol) — 1H—Imidazole-2-yl) methyl) —3— (5- (Pyridine-2-yl) thio) thiazole 2-yl) urea (See Example 97)
1— (5 ブロモチアゾール—2—ィル）—3— ( (4— (3, 4 ジクロロフエ-ル）— 1 H—イミダゾール— 2—ィル)メチル)ゥレア（実施例 99参照） 1— (5 Bromothiazol-2-yl) —3— ((4— (3,4 Dichlorophenol) — 1 H-imidazole-2-yl) methyl) urea (see Example 99)
1- (5-ブロモチアゾール -2-ィル) -3- ((4- (4- ((3- (2,6-ジクロロベンジル) -2-メチル- 4-ォキソピリジン- 1(4H)-ィル）メチル）フエ-ル) -1H-イミダゾール -2-ィル)メチル)ゥ レア（実施例 100参照） 1- (5-bromothiazol-2-yl) -3-((4- (4-((3- (2,6-dichlorobenzyl) -2-methyl-4-oxopyridine-1 (4H)- L) Methyl) Fuel) -1H-imidazole-2-yl) Methyl) Rare (see Example 100)
1 - ( (4- (4— (2- (3 - (2, 6 ジクロロベンジル） 2—メチノレ一 4—ォキソピリジ ン— 1 (4H)—ィル）ェチル）フエ-ル）— 1H—イミダゾールー 2—ィル）メチル）—3— (5— (ピリジン— 2—ィルチオ)チアゾール—2—ィル）ゥレア（実施例 104参照） 1-((4- (4— (2- (3-(2, 6 dichlorobenzyl) 2-methylolene 1-oxopyridin-1 (4H) -yl) ethyl) phenol)-1H-imidazole 2 —Yl) methyl) —3— (5— (pyridine-2-ylthio) thiazole-2-yl) urea (see Example 104)
1— ( (4— (4— (2— (3— (2, 6 ジクロロベンジル） 2—メチノレ一 4—ォキソピリジ ン— 1 (4H)—ィル）ェチル）フエ-ル）— 1H—イミダゾールー 2—ィル）メチル）—3— (1H—イミダゾールー 2—ィル)ゥレア（実施例 105参照） 1— ((4— (4— (2— (3— (2, 6 dichlorobenzyl) 2-methylolene 1-oxopyridin-1 (4H) -ethyl) ethyl) phenol) — 1H-imidazole 2 —Yl) methyl) —3— (1H-imidazole-2-yl) urea (see Example 105)
1— ( (4— (4— (2— (3— (2, 6 ジクロロベンジル） 2—メチノレ一 4—ォキソピリジ ン— 1 (4H)—ィル）ェチル）フエ-ル）— 1H—イミダゾールー 2—ィル）メチル）—3— (6 （メチルスルフォ -ル）ベンゾ [d]チアゾールー 2 ィル）ゥレア（実施例 106参照 )  1— ((4— (4— (2— (3— (2, 6 dichlorobenzyl) 2-methylolene 1-oxopyridin-1 (4H) -ethyl) ethyl) phenol) — 1H-imidazole 2 —Yl) methyl) —3— (6 (methylsulfol) benzo [d] thiazol-2-yl) urea (see Example 106)
1— ( (4— (4— (2— (3— (2, 6 ジクロロベンジル） 2—メチノレ一 4—ォキソピリジ ン— 1 (4H)—ィル）ェチル）フエ-ル）— 1H—イミダゾールー 2—ィル）メチル）—3— (5 （メチルスルフォ -ル）チアゾールー 2 ィル）ゥレア（実施例 107参照）  1— ((4— (4— (2— (3— (2, 6 dichlorobenzyl) 2-methylolene 1-oxopyridin-1 (4H) -ethyl) ethyl) phenol) — 1H-imidazole 2 —Yl) methyl) —3— (5 (methylsulfol) thiazol-2-yl) urea (see Example 107)
1— (5— (ァリルスルフォ -ル）チアゾール—2—ィル）—3— ( (4— (4 ブロモフエ -ル） 1H—イミダゾールー 2 ィル)メチル）ゥレア（実施例 108参照）  1— (5— (arylsulfol) thiazole-2-yl) —3— ((4— (4 bromophenol) 1H-imidazole-2-yl) methyl) urea (see Example 108)
1 （6 （メチルスルフォ -ル）ベンゾ [d]チアゾールー 2 ィル）ー3—（（4—フエ -ル— 1H—イミダゾールー 2—ィル)メチル）ゥレア（実施例 232参照）  1 (6 (methylsulfol) benzo [d] thiazol-2-yl) -3-(((4-phenol-1H-imidazol-2-yl) methyl) urea (see Example 232)
N— (2, 3ジクロロフエ-ル）一 4— (2, 4—ジクロロフエ-ル）一 3—ォキソピペラジ ンー 1一力ノレボキシアミド（実施例 302参照）  N— (2,3 dichlorophenol) 1 4-— (2, 4-dichlorophenyl) 1 3-oxopiperazine 1 Stretch norboxamide (see Example 302)
キシム ί本  Kissim ί 本
Ν— (6—メトキシカルボ-ル）ベンゾ [d]チアゾールー 2—ィルー 2—（3 -トロべ ンジリデンアミノォキシ)ァセトアミド（実施例 399参照）  Ν— (6-Methoxycarbol) benzo [d] thiazole-2-yl-2- (3-trobenzylideneaminooxy) acetoamide (see Example 399)
N— (6—メトキシベンゾ [d]チアゾールー 2 ィル）ー2—（3 -トロベンジリデン アミノォキシ)ァセトアミド（実施例 401参照）  N— (6-methoxybenzo [d] thiazol-2-yl) -2- (3-trobenzylideneaminooxy) acetamide (see Example 401)
N—(6—tert ブチルー 4, 5, 6, 7—テトラヒドロべンゾ [d]チアゾールー 2—ィル ) - 2- (4 -トロべンジリデンアミノォキシ)ァセトアミド (実施例 406参照）  N— (6-tert-butyl-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) -2- (4-trobenzylideneaminooxy) acetamide (see Example 406)
N— (6— tert ブチル 4, 5, 6, 7—テトラヒドロべンゾ [d]チアゾール 2—ィル） — 2— (3 -トロベンジリデンアミノォキシ)ァセトアミド (実施例 407参照） N— (6-tert-butyl 4, 5, 6, 7-tetrahydrobenzo [d] thiazole 2-yl) — 2— (3-Trobenzylideneaminooxy) acetamide (see Example 407)
N- (4ーメトキシベンゾ [d]チアゾールー 2 ィル）ー2—（3 -トロベンジリデンァ ミノォキシ)ァセトアミド (実施例 669参照）  N- (4-Methoxybenzo [d] thiazol-2-yl) -2- (3-trobenzylidene minoxy) acetamide (see Example 669)
N— (6 トロベンゾ [d]チアゾールー 2 ィル）ー2—（3 トロベンジリデンァ ミノォキシ)ァセトアミド (実施例 670参照）  N— (6 trobenzo [d] thiazol-2-yl) -2- (3 trobenzylidene minoxy) acetamide (see Example 670)
N- (6 エトキシベンゾ [d]チアゾールー 2 ィル）ー2—（3 -トロベンジリデンァ ミノォキシ)ァセトアミド (実施例 671参照）  N- (6 ethoxybenzo [d] thiazol-2-yl) -2- (3-trobenzylidene minoxy) acetamide (see Example 671)
アミド纏 ί本 Amido Summary ί 本
2—（1H—イミダゾールー 2—ィルチオ）—N—(6—tert ブチルー 4, 5, 6, 7—テ トラヒドロべンゾ [d]チアゾール 2—ィル)ァセトアミド（実施例 695参照）  2- (1H-imidazole-2-ylthio) -N- (6-tert butyl-4,5,6,7-tetrahydrobenzo [d] thiazol 2-yl) acetamide (see Example 695)
2- (4 エトキシカルボ-ルー 1H—イミダゾールー 2—ィルチオ） N— (6—メト キシカルボ-ルペンゾ [d]チアゾールー 2 ィル）ァセトアミド（実施例 703参照） 2- (4 ethoxycarboru 1H-imidazole-2-ylthio) N— (6-methoxycarbolpenzo [d] thiazole-2-yl) acetamide (see Example 703)
2- (5 アミノー 1H ベンゾイミダゾールー 2—ィルチオ） N— (6— tert ブチ ルー 4, 5, 6, 7—テトラヒドロべンゾ [d]チアゾールー 2 ィル）ァセトアミド（実施例 7 05参照） 2- (5 Amino-1H benzimidazole-2-ylthio) N— (6-tert-butyl 4, 5, 6, 7-tetrahydrobenz [d] thiazol-2-yl) acetamide (see Example 700)
2— (1H—イミダゾールー 2—ィルチオ）— N— (6— n—プロピル— 4, 5, 6, 7— テトラヒドロべンゾ [d]チアゾール 2—ィル)ァセトアミド（実施例 722参照）  2— (1H—imidazole-2-ylthio) —N— (6—n-propyl— 4, 5, 6, 7— tetrahydrobenzo [d] thiazol 2-yl) acetamide (see Example 722)
2- (6 アミノー 1H ベンゾ [d]イミダゾールー 2—ィルチオ） N— 2— (6—メト キシカルボ-ルペンゾ [d]チアゾール 2—ィル）ァセトアミド（実施例 728参照） 2- (6 Amino-1H benzo [d] imidazole-2-ylthio) N— 2— (6-Methoxycarborpenzo [d] thiazol 2-yl) acetamide (see Example 728)
N— (ベンゾ [d]チアゾールー 2 ィル） 3 フエ-ルイソキサゾールー 5 カル ボキサミド (実施例 734参照） N— (benzo [d] thiazole-2-yl) 3 phenol isoxazole-5 carboxamide (see Example 734)
1— ( (4— (4 ブロモフエ-ル）— 1H—イミダゾールー 2—ィル）メチル）—3— (5 ェチ-ルチアゾールー 2 ィル）ゥレア（実施例 775参照）  1— ((4— (4 Bromophenol) — 1H—Imidazole-2-yl) methyl) —3— (5 Ethylthiazol-2-yl) urea (see Example 775)
1— ( (4— (4 ブロモフエ-ル）— 1H—イミダゾールー 2—ィル）メチル）—3— (5 - (ペントー 4 -ェ-ルチオ）チアゾール - 2 ィル）ゥレア（実施例 776参照）  1— ((4— (4 Bromophenyl) — 1H—imidazole-2-yl) methyl) —3— (5- (pento-4-ethylthio) thiazole-2-yl) urea (see Example 776)
1 - ( (4- (4 ブロモフエ-ル）— 1H—イミダゾールー 2—ィル）メチル）—3— (5 イソプロピルチオ）チアゾールー 2 ィル）ゥレア（実施例 777参照）  1-((4- (4 bromophenol) — 1H-imidazole-2-yl) methyl) —3— (5 isopropylthio) thiazol-2-yl) urea (see Example 777)
1— ( (4— (4 ブロモフエ-ル）— 1H—イミダゾールー 2—ィル）メチル）—3— (5 - (ペントー 4 -ェニルスルホ -ル）チアゾール - 2 ィル）ゥレア（実施例 778参照）1— ((4— (4 Bromophenyl) — 1H—imidazole-2-yl) methyl) —3— (5 -(Pentho 4 -enylsulfoyl) thiazole-2 yl) urea (see Example 778)
1 - ( (4- (4 ブロモフエ-ル）— 1H—イミダゾールー 2—ィル）メチル）—3— (5 （ブト 3 ェ-ルチオ）チアゾールー 2 ィル）ゥレア（実施例 779参照）1-((4- (4 bromophenol) — 1H-imidazole-2-yl) methyl) —3— (5 (but-3-ethylthio) thiazole-2-yl) urea (see Example 779)
1— ( (4— (4 ブロモフエ-ル）— 1H—イミダゾールー 2—ィル）メチル）—3— (5 （ブト 3 ェニルスルホ -ル）チアゾールー 2 ィル）ゥレア（実施例 780参照）1— ((4— (4 Bromophenol) — 1H—imidazole-2-yl) methyl) —3— (5 (but-3-enylsulfoyl) thiazol-2-yl) urea (see Example 780)
(E)— 1— ( (4— (4 ブロモフエ-ル）— 1H—イミダゾールー 2—ィル）メチル）—3 一（5 （ペントー 2 ェ-ルチオ）チアゾールー 2 ィル）ゥレア（実施例 781参照）(E) — 1— ((4— (4 bromophenol) — 1H-imidazole-2-yl) methyl) —3 1 (5 (pento-2-ethylthio) thiazole-2-yl) urea (see Example 781) )
(E)— 1— ( (4— (4 ブロモフエ-ル）— 1H—イミダゾールー 2—ィル）メチル）—3 一（5 （ペントー 2 ェニルスルホ -ル）チアゾールー 2 ィル）ゥレア（実施例 782 参照） (E) — 1— ((4— (4 bromophenol) — 1H-imidazole-2-yl) methyl) —3 mono (5 (pento-2-enylsulfoyl) thiazole-2-yl) urea (see Example 782) )
[0048] 式 (I)の化合物の製诰  [0048] Production of compound of formula (I)
以下に、本発明による化合物の製造法について述べる。本発明による化合物は、 例えば以下の反応式で示される方法、またはこれに準じた方法などにより得られる。 本発明による化合物は、下記製造法に限定されものではなぐまた塩や試薬などは 便宜上例示したものであって、それに限定されるものではな 、。  Below, the manufacturing method of the compound by this invention is described. The compound according to the present invention can be obtained, for example, by a method represented by the following reaction formula or a method analogous thereto. The compounds according to the present invention are not limited to the following production methods, and salts and reagents are exemplified for the sake of convenience, and are not limited thereto.
[0049] 下記反応式中の各記号は前記と同義を示す。 PGは保護基を表し、製造工程中に 保護基の脱着は必要に応じて行う。保護基としては Protective groups in organic syn thesis, 2nd ed., (John Wiley & Sons Inc., 1991)記載の保護基および前記記載の方 法に準じて利用する。また必要に応じて側鎖、側鎖上の置換基を置換してもよぐそ の方法は公知の方法、実験化学講座（日本化学会編、丸善)などを適用できる。  [0049] Each symbol in the following reaction formula has the same meaning as described above. PG represents a protective group, and the protective group is desorbed as necessary during the production process. Protective groups are used in accordance with the protective groups described in Protective groups in organic synthesis, 2nd ed., (John Wiley & Sons Inc., 1991) and the methods described above. Moreover, as a method for substituting the side chain and the substituent on the side chain as necessary, a known method, an experimental chemistry course (edited by the Chemical Society of Japan, Maruzen), etc. can be applied.
[0050] 1)ウレァ型誘導体合成（Z=— NH— CO— NY— CH—または  [0050] 1) Urea type derivative synthesis (Z = —NH—CO—NY—CH— or
2  2
[化 42] 厂 W  [Chemical 42] 厂 W
— NH—CO— N V—  — NH—CO— N V—
\ _ / を表す化合物群）  \ _ / Represents a compound group)
ウレァ型誘導体の製造は、一般的には Scheme Iまたは II、もしくはイソシアナート経 由の方法に準じて製造することが出来る。  In general, urea-type derivatives can be produced according to Scheme I or II, or a method via isocyanate.
[化 43] Scheme I [Chemical 43] Scheme I
A A
Figure imgf000039_0001
Figure imgf000039_0001
Scheme II  Scheme II
(1) (1)
Figure imgf000039_0002
Figure imgf000039_0002
(5) (7)  (5) (7)
市販品として入手可能、もしくは以下に記載の方法: J. Med. Chem. (1999) ,42,28 29、 J. Med. Chem. (1999) ,42,2887、 J. Med. Chem. (2001) ,44,749, Chem. Pharm . Bull. (1962) , 10,376、 J. Org. Chem. (1984) ,49,569、 J. Org. Chem. (2000) ,65,11 02、 J. Org. Chem. (2004) ,69,2381、 Biorg. Med. Chem. Lett. (1998) ,8,3153、 Bior g. Med. Chem. Lett. (1999) ,9,957、特表平 10— 504542号、特表 2001— 51766 7号、 EP518,731、および EP611,766)により合成した式（1)の化合物を、適当な 溶媒下（アセトン、ァセトニトリル、ジクロロメタン、クロ口ホルム、 1, 2-ジクロロエタン、 酢酸ェチノレ、テトラヒドロフラン、ジォキサン、ジェチノレエーテノレ、イソプロピノレエーテ ル、へキサン、 N, N—ジメチルホルムアミド、ジメチルスルホキシド、トルエン、ベンゼ ン、メタノール、エタノール、へキサメチルリン酸トリアミド等、またはこれらの混合溶媒 が挙げられ、好ましくはテトラヒドロフラン、 N, N—ジメチルホルムアミドなどである。 ) 、 CDI ( 1 , 1 ' -カルボ-ルジイミダゾール）と反応させ式（2)で示される活性化された 化合物へと変換する。反応温度は— 20〜： L00°Cが好ましぐさらに好ましくは 20〜5 0°Cである。反応時間は 0. 5〜7二時間が好ましい。さらに好ましくは 0. 5〜24時間 である。  Available commercially or as described below: J. Med. Chem. (1999), 42, 28 29, J. Med. Chem. (1999), 42, 2887, J. Med. Chem. (2001 ), 44,749, Chem. Pharm. Bull. (1962), 10,376, J. Org. Chem. (1984), 49,569, J. Org. Chem. (2000), 65, 1102, J. Org. Chem. 2004), 69,2381, Biorg. Med. Chem. Lett. (1998), 8,3153, Biorg. Med. Chem. Lett. (1999), 9,957, JP 10-504542, JP 2001— 51766 No. 7, EP518,731, and EP611,766) are synthesized in a suitable solvent (acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethynole acetate, tetrahydrofuran, Dioxane, Jetinoreethenole, Isopropinoleate, Hexane, N, N-Dimethylformamide, Dimethylsulfoxide, Toluene, Benzene, Methanol, Ethanol, Hexamethylphosphoric triamide , Or a mixed solvent thereof, preferably tetrahydrofuran, N, N-dimethylformamide, etc.)), CDI (1,1′-carbodidiimidazole) and the activation represented by the formula (2) It is converted into the compound. The reaction temperature is −20 to: L00 ° C. is more preferable, and 20 to 50 ° C. is more preferable. The reaction time is preferably 0.5-7 hours. More preferably, it is 0.5 to 24 hours.
得られた式 (2)の化合物は、そのまま、もしくは、精製した後、必要に応じて適当な 塩基存在下 (有機塩基としては、ジイソプロピルェチルァミン、ジァザビシクロ [2, 2, 2]ゥンデセン、 2, 6—ルチジン等、無機塩基としては、水酸化ナトリウム、水酸化カリ ゥム、炭酸水素ナトリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシ ゥム等が挙げられ、好ましくはジイソプロピルェチルァミンなどが挙げられる。）、適当 な溶媒中（アセトン、ァセトニトリル、ジクロロメタン、クロ口ホルム、 1, 2—ジクロロエタ ン、酢酸ェチル、テトラヒドロフラン、ジォキサン、ジェチルエーテル、イソプロピルェ 一テル、へキサン、 N, N—ジメチルホルムアミド、ジメチルスルホキシド、トルエン、ベ ンゼン、メタノール、エタノール、へキサメチルリン酸トリアミド等、またはこれらの混合 溶媒が挙げられ、好ましくはテトラヒドロフラン、 N, N—ジメチルホルムアミドなどが好 まし 、)反応させることにより式 (4)を得ることができる。反応温度は 0〜150°Cが好ま しぐさらに好ましくは 20〜50°Cであり、反応時間は 0. 5〜24時間が好ましぐさらに 好ましくは 0. 5〜 18時間である。 The obtained compound of the formula (2) is used as it is or after purification, and in the presence of a suitable base as necessary (as the organic base, diisopropylethylamine, diazabicyclo [2, 2, 2] undecene, Examples of inorganic bases such as 2,6-lutidine include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and preferably diisopropylethyl. Amamine etc.), suitable In a suitable solvent (acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether, hexane, N, N-dimethylformamide, dimethyl sulfoxide, (Toluene, benzene, methanol, ethanol, hexamethylphosphoric triamide, etc., or a mixed solvent thereof may be mentioned, preferably tetrahydrofuran, N, N-dimethylformamide, etc.). be able to. The reaction temperature is preferably 0 to 150 ° C., more preferably 20 to 50 ° C., and the reaction time is preferably 0.5 to 24 hours, more preferably 0.5 to 18 hours.
[0052] Zが以下の化合物の場合には、前記 Scheme IIに準じて製造することが出来る。 [0052] When Z is the following compound, it can be produced according to Scheme II.
[化 44] 厂 W  [Chemical 44] 厂 W
— NH-CO-N V—  — NH-CO-N V—
\ _ / 式（1)の化合物をホスゲンや、トリホスゲン (炭酸ビストリクロロメチル)などハロゲ ン化剤と反応させたのち、得られた式 (5)と式 (6)を反応させることにより式 (7)の化 合物を得ることが出来る。  \ _ / After reacting the compound of formula (1) with a halogenating agent such as phosgene or triphosgene (bistrichloromethyl carbonate), the resulting formula (5) is reacted with formula (6) to formula ( The compound of 7) can be obtained.
[0053] 式（1)から（5)への工程において、反応溶媒はハロゲン化剤に対して不活性なもの であればよぐ例えばジクロロメタン、クロ口ホルム、四塩化炭素、二硫化炭素、 N, N ージメチルホルムアミド、ベンゼン、トルエン、キシレン、へキサン、またはオクタン等を 挙げられ、好ましくは、ジクロロメタンなどである。反応温度は 0〜： LOO°Cが好ましぐさ らに好ましくは 0〜30°Cであり、反応時間は 0. 5〜24時間が好ましぐさらに好ましく は 0. 5〜十三時間である。  [0053] In the process from formulas (1) to (5), the reaction solvent may be inert to the halogenating agent. For example, dichloromethane, chloroform, carbon tetrachloride, carbon disulfide, N , N-dimethylformamide, benzene, toluene, xylene, hexane, or octane, preferably dichloromethane. The reaction temperature is 0 to: LOO ° C is preferably 0 to 30 ° C, and the reaction time is preferably 0.5 to 24 hours, more preferably 0.5 to 13 hours. .
[0054] 式 (5)と (6)とを反応させる工程は、適当な塩基存在下 (有機塩基としてはジイソプ 口ピルェチルァミン、ジァザビシクロ [2, 2, 2]ゥンデセン、または 2, 6—ルチジン等、 無機塩基としては水酸ィ匕ナトリウム、水酸ィ匕カリウム、炭酸水素ナトリウム、炭酸水素 カリウム、炭酸ナトリウム、炭酸カリウム、または炭酸セシウム等が挙げられ、好ましくは ジイソプロピルェチルァミンなどが挙げられる。）、反応溶媒はハロゲン化剤に対して 不活性なものであればよぐ例えばジクロロメタン、クロ口ホルム、四塩化炭素、ニ硫 化炭素、 N, N—ジメチルホルムアミド、ベンゼン、トルエン、キシレン、へキサン、ま たはオクタン等を挙げられ、好ましくは、ジクロロメタンなどである。反応温度は 0〜： LO 0°Cが好ましぐさらに好ましくは 0〜30°Cであり、反応時間は 0. 5〜24時間が好まし ぐさらに好ましくは 0. 5〜6時間である。 [0054] The step of reacting the formulas (5) and (6) is carried out in the presence of a suitable base (for example, diisopropylpyrutamine, diazabicyclo [2, 2, 2] undecene, or 2,6-lutidine as the organic base, Examples of the inorganic base include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, and preferably diisopropyl etheramine. It is sufficient if the reaction solvent is inert to the halogenating agent, for example, dichloromethane, chloroform, carbon tetrachloride, disulfide Carbonized carbon, N, N-dimethylformamide, benzene, toluene, xylene, hexane, octane, etc. are preferable, and dichloromethane is preferable. The reaction temperature is 0 to: LO 0 ° C is preferred, more preferably 0 to 30 ° C, and the reaction time is preferably 0.5 to 24 hours, more preferably 0.5 to 6 hours.
A=チアゾールタイプ B=イミダゾールタイプの式（4)の製造法は以下の通りであ る。  The production method of formula (4) of A = thiazole type B = imidazole type is as follows.
[化 45]  [Chemical 45]
Scheme III A=チアゾール夕ィプ B=イミダゾ一ル夕ィプの例  Scheme III A = thiazole type B = Imidazol type
Figure imgf000041_0001
Figure imgf000041_0001
市販品として入手可能、もしくは J. Macromol. Sci. Chem., (1977) ,ΑΙΙ, (3) ,507記 載の方法により得ることができる式 (8)で示されるァセトフヱノン類を、適当なハロゲン 化剤（例えば、 J. Am. Chem. So ，（1964) ,29, 3459、 J. Het. Chem" (1988) ,25,337、 J. Am. Chem. Soc, (1980) ,102, 2838、 Biorg. Med. Chem. Lett., (1996) ,6 (3) ,253、 J. Med. Chem" (1988) ,31 (10) , 1910、 J. Am. Chem. Soc., (1999) ,121,248、 J. Macro mol. Sci. Chem., (1977) , All, (3) ,507,および Synthesis, (1985) ,406)を用い、適当 な溶媒下（例えばアセトン、ァセトニトリル、ジクロロメタン、クロ口ホルム、 1, 2—ジクロ ロェタン、酢酸ェチル、テトラヒドロフラン、ジォキサン、ジェチルエーテル、イソプロピ ルエーテル、へキサン、 N, N—ジメチルホルムアミド、ジメチルスルホキシド、トルェ ン、ベンゼン、メタノール、エタノール、へキサメチルリン酸トリアミド等、またはこれらの 混合溶媒、好ましくは酢酸ェチルまたはジクロロメタンなどが挙げられる。）反応させる ことにより、式（9)で示される a—ハロゲンィ匕ケトンに変換する。反応温度は— 10〜1 00°Cが好ましぐさらに好ましくは 0〜30°Cである。反応時間は 0. 5〜24時間が好ま しい。さらに好ましくは 1〜6時間である。 The acetophenone represented by the formula (8), which is available as a commercial product or obtained by the method described in J. Macromol. Sci. Chem., (1977),, (3), 507, is converted to an appropriate halogen An agent (eg, J. Am. Chem. So, (1964), 29, 3459, J. Het. Chem "(1988), 25,337, J. Am. Chem. Soc, (1980), 102, 2838, Biorg Med. Chem. Lett., (1996), 6 (3), 253, J. Med. Chem "(1988), 31 (10), 1910, J. Am. Chem. Soc., (1999), 121,248 , J. Macro mol. Sci. Chem., (1977), All, (3), 507, and Synthesis, (1985), 406), in a suitable solvent (eg acetone, acetonitrile, dichloromethane, chloroform) 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether, hexane, N, N-dimethylformamide, dimethyl sulfoxide, toluene, benzene, methanol, ethanol To Kisamechirurin triamide, etc. or solvent mixtures thereof, and preferably by.) The reaction and the like acetic Echiru or dichloromethane, converted to a- Harogeni spoon ketone of formula (9). Reaction temperature is -10 ~ 1 00 ° C is preferable, and 0 to 30 ° C is more preferable. The reaction time is preferably 0.5 to 24 hours. More preferably, it is 1 to 6 hours.
[0056] また、市販品として入手可能なアミノアセトニトリル（11)を酸塩である場合には適当 な塩基 (例えば有機塩基としてはジイソプロピルェチルァミン、ジァザビシクロ [2, 2, 2]ゥンデセン、 2, 6—ルチジン等、無機塩基としては水酸ィ匕ナトリウム、水酸化力リウ ム、炭酸水素ナトリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシゥ ム等、好ましくは炭酸水素ナトリウムなどが挙げられる。）を用いて中和した後、ァミノ に保 (PG )を ¾入し (Protective groups in organic synthesis, 2nd ed., (Joh n Wiley & Sons Inc., 1991)を参照）、式（12)で示される化合物に変換する。式（12) で示される化合物の-トリルを適当な塩基、（例えば有機塩基としてはトリェチルアミ ン、ジイソプロピルェチルァミン、ジァザビシクロ [2, 2, 2]ゥンデセン、 2, 6—ルチジ ン、またはナトリウムメトキシドなどが挙げられ、無機塩基としては水酸ィ匕ナトリウム、水 酸ィ匕カリウム、炭酸水素ナトリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸カリウム、 または炭酸セシウム等、好ましくはナトリウムメトキシドなどが挙げられる。）を用いてィ ミデートまで導き、アンモ-ゥム塩 (例えば、硝酸アンモ-ゥム、塩ィ匕アンモ-ゥム、臭 化アンモ-ゥム、硫酸アンモ-ゥム、または酢酸アンモ-ゥムなどが挙げられ、好まし くは塩ィ匕アンモ-ゥムまたは臭化アンモ-ゥムなどが挙げられる）と作用させ式（10) で示されるアミジン類に変換させる。反応温度は— 10〜： L00°Cが好ましぐさらに好 ましくは 0〜30°Cである。反応時間は 0. 5〜24時間が好ましい。さらに好ましくは 0. 5〜4時間である。 [0056] When aminoacetonitrile (11), which is commercially available, is an acid salt, an appropriate base (for example, diisopropylethylamine, diazabicyclo [2,2,2] undecene, 2 , 6-lutidine, etc., inorganic bases such as sodium hydroxide, lithium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, preferably sodium hydrogen carbonate )), And then added (PG) to the amino (see Protective groups in organic synthesis, 2nd ed., (John Wiley & Sons Inc., 1991)), formula (12) Is converted into a compound represented by -Tolyl of the compound represented by the formula (12) is replaced with a suitable base (for example, triethylamine, diisopropylethylamine, diazabicyclo [2,2,2] undecene, 2,6-lutidine, or sodium as an organic base). Examples of the inorganic base include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, or cesium carbonate, preferably sodium methoxide. To the imidate, and the ammonium salt (eg, ammonium nitrate, salty ammonium, odorous ammonia, ammonium sulfate, or ammonium acetate). , Preferably salt salt ammonium or bromide ammonium), and converted to amidines represented by formula (10). Make. The reaction temperature is −10 to: L00 ° C is preferable, and more preferably 0 to 30 ° C. The reaction time is preferably 0.5 to 24 hours. More preferably, it is 0.5 to 4 hours.
[0057] 得られたアミジン（10)と、式（9)とを適当な塩基 (例えば有機塩基としてはトリェチ ルァミン、ジイソプロピルェチルァミン、ジァザビシクロ [2, 2, 2]ゥンデセン、または 2 , 6—ルチジン等が挙げられ、無機塩基としては水酸ィ匕ナトリウム、水酸ィ匕カリウム、 炭酸水素ナトリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸カリウム、または炭酸セ シゥム等が挙げられ、好ましくは炭酸カルシウムなどが挙げられる。）存在下、反応さ せることで 2—アミノメチルイミダゾ一ルイ匕合物を得ることができる。反応温度は 0〜： L0 0°Cが好ましぐさらに好ましくは 20〜70°Cである。反応時間は 0. 5〜24時間が好ま しい。さらに好ましくは 1〜3時間である。そして保護基を除去した後、必要に応じて 酸塩 (無機酸としては塩酸、硫酸、硝酸、燐酸等、有機酸としては酢酸、シユウ酸、メ タンスルホン酸、 p—トルエンスルホン酸、またはカンファースルホン酸等）とし式（3— 2)の化合物を得る。 [0057] The obtained amidine (10) and the formula (9) are combined with a suitable base (for example, triethylamine, diisopropylethylamine, diazabicyclo [2,2,2] undecene, or 2,6 as the organic base). — Lutidine and the like, and inorganic bases include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, or cesium carbonate, preferably calcium carbonate The 2-aminomethylimidazo complex can be obtained by reacting in the presence. The reaction temperature is preferably 0 to: L0 0 ° C, more preferably 20 to 70 ° C. The reaction time is preferably 0.5 to 24 hours. More preferably, it is 1-3 hours. And after removing the protecting group, if necessary Acid salts (hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc. as inorganic acids, acetic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, etc. as organic acids) and formula (3-2) A compound is obtained.
また、式（13)で示される 2—ァミノチアゾールイ匕合物は、市販品としても入手可能 であるが、以下に列挙する文献記載の方法: J. Med. Chem. (1999) ,42,2829、 J. Me d. Chem. (1999) ,42, 2887、 J. Med. Chem. (2001) ,44,749, Chem. Pharm. Bull. ( 1962) , 10,376、 J. Org. Chem. (1984) ,49,569、 J. Org. Chem. (2000) ,65,1102、 J. O rg. Chem. (2004) ,69,2381、 Biorg. Med. Chem. Lett. (1998) ,8,3153、 Biorg. Med. Chem. Lett. (1999) ,9,957、特表平 10— 504542号、特表 2001— 517667号、 EP 518,731、および EP611,766)、または、下記記載の特表 2003— 525872号に記 載の方法により得ることができる。  In addition, the 2-aminothiazole compound represented by the formula (13) is also available as a commercial product. However, the methods described in the literature listed below: J. Med. Chem. (1999), 42 , 2829, J. Med. Chem. (1999), 42, 2887, J. Med. Chem. (2001), 44, 749, Chem. Pharm. Bull. (1962), 10,376, J. Org. Chem. (1984) ), 49, 569, J. Org. Chem. (2000), 65, 1102, J. Org. Chem. (2004), 69, 2381, Biorg. Med. Chem. Lett. (1998), 8, 3153, Biorg Med. Chem. Lett. (1999), 9,957, JP 10-504542, JP 2001-517667, EP 518,731, and EP 611,766), or JP 2003-525872 described below. It can be obtained by the method described.
[化 46] [Chem 46]
Scheme IV Scheme IV
Figure imgf000043_0001
Figure imgf000043_0001
RX + (H2N)2CS RX + (H 2 N) 2 CS
(F) 市販品として入手可能なハロゲンィ匕アルキル (F)とチォ尿素を適当な溶媒下 (ァセ トン、ァセトニトリノレ、ジクロロメタン、クロロホノレム、 1, 2—ジクロロェタン、酢酸ェチノレ 、テトラヒドロフラン、ジォキサン、ジェチルエーテル、イソプロピルエーテル、へキサン 、 N, N—ジメチルホルムアミド、ジメチルスルホキシド、トルエン、ベンゼン、メタノー ル、エタノール、へキサメチルリン酸トリアミド等、またはこれらの混合溶媒、好ましくは エタノール中）反応させ、式（E)で示される S—アルキルチォゥレアのハロゲン化水素 塩を得る。反応温度は— 10〜100°Cが好ましぐさらに好ましくは 50〜80°Cである。 反応時間は 0. 5〜24時間が好ましぐさらに好ましくは 0. 5〜1時間である。次に、 市販品として入手可能な 2 ァミノ 5 ブロモチアゾールのハロゲンィ匕水素塩 (D) および (E)に適当な塩基 (有機塩基としてはトリエチルァミン、ジイソプロピルェチル ァミン、ジァザビシクロ [2, 2, 2]ゥンデセン、または 2, 6—ルチジン等が挙げられ、 無機塩基としては水酸ィ匕ナトリウム、水酸ィ匕カリウム、炭酸水素ナトリウム、炭酸水素 カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等、好ましくは水酸ィ匕ナトリウム などが挙げられる。）を加え、第四級アンモ-ゥム塩 (例えば、テトラプチルアンモ-ゥ ムフルオライド、ベンジルジメチルフエ-ルアンモ -ゥムクロリド、ベンジルトリブチルァ ンモ -ゥムクロリド、フエ-ルトリェチルアンモ -ゥムクロリド、テトラプチルアンモ -ゥム クロリド、テトラエチルアンモ -ゥムクロリド、ベンジルジメチルフエ-ルアンモ-ゥムブ 口ミド、ベンジルトリブチルアンモ-ゥムブロミド、フエ-ルトリェチルアンモ -ゥムブロミ ド、テトラプチルアンモ-ゥムブロミド、テトラエチルアンモ-ゥムブロミド、ベンジルジメ チルフエ-ルアンモ-ゥムョージド、ベンジルトリブチルアンモ-ゥムョージド、フエ二 ルトリェチルアンモ-ゥムョージド、テトラプチルアンモ-ゥムョージド、テトラエチルァ ンモ-ゥムョ一ジド、ベンジルジメチルフエ-ルアンモ -ゥムハイドロォキシド、ベンジ ルトリプチルアンモ -ゥムハイドロォキシド、フヱ-ルトリエチルアンモ -ゥムハイドロォ キシド、テトラプチルアンモ -ゥムハイドロォキシド、テトラエチルアンモ -ゥムハイド口 ォキシド、テトラプチルアンモ -ゥムアジド、テトラプチルアンモ -ゥムボロヒドリド、テト ラブチルアンモ -ゥムへキサフルォロホスフェート、テトラプチルアンモ -ゥムハイド口 ゲンスルフェート、テトラプチルアンモ -ゥムパーク口レート、テトラプチルアンモ -ゥム テトラフルォロボレート、テトラプチルアンモ-ゥムテトラフヱ-ルポレート、テトラプチ ルアンモ-ゥムトリブ口ミド、テトラプチルアンモ-ゥムトリヨージドなどが挙げられ、好 ましくはテトラブチルアンモ -ゥムハイドロゲンスルフェートなどが挙げられる。 )存在 下、水と適当な溶媒（アセトン、ァセトニトリル、ジクロロメタン、クロ口ホルム、 1, 2—ジ クロロェタン、酢酸ェチル、テトラヒドロフラン、ジォキサン、ジェチルエーテル、イソプ 口ピルエーテル、へキサン、 N, N—ジメチルホルムアミド、ジメチルスルホキシド、トル ェン、ベンゼン、メタノール、エタノール、へキサメチルリン酸トリアミド等、またはこれら の混合溶媒、好ましくはトルエン）との任意の混合比 (好ましくは 1対 1)で作用させ、 式（13)で示されるチアゾール類に変換させる。反応温度は— 10〜： LOO°Cが好ましく 、さらに好ましくは 25〜50°Cである。反応時間は 0. 5〜48時間が好ましぐさらに好 ましくは 24〜30時間である。 (F) Commercially available halogenated alkyl (F) and thiourea in a suitable solvent (aceton, acetonitrinol, dichloromethane, chlorohonolem, 1,2-dichloroethane, ethynole acetate, tetrahydrofuran, dioxane, jetyl ether , Isopropyl ether, hexane, N, N-dimethylformamide, dimethyl sulfoxide, toluene, benzene, methanol, ethanol, hexamethylphosphoric triamide, or a mixed solvent thereof, preferably in ethanol) The hydrogen halide salt of S-alkylthiourea is obtained. The reaction temperature is preferably -10 to 100 ° C, more preferably 50 to 80 ° C. The reaction time is preferably 0.5 to 24 hours, more preferably 0.5 to 1 hour. next, Suitable bases for commercially available 2-amino-5 bromothiazole halides (D) and (E) (for example, triethylamine, diisopropylethylamine, diazabicyclo [2, 2, 2] undecene as organic bases) Or 2, 6-lutidine and the like, and the inorganic base includes sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc., preferably hydroxide Quaternary ammonium salts (for example, tetraptyl ammonium fluoride, benzyl dimethyl phenol ammonium chloride, benzyl tributyl ammonium chloride, phenol triethyl) Ammo-um chloride, tetraptyl ammo chloride, tetraethyl ammo-umcro Lido, benzyldimethylformum mouth amide, benzyltributylammonium bromide, feltylethylammum bromide, tetraptylammonium bromide, tetraethylammonium bromide, benzyldimethylmethylammonium bromide, benzyltributylammonium Humouzid, phenyltriammonum, tetraptylammoumide, tetraethylammoumide, benzyldimethylphenol ammohydride, benzyltriptylammoum hydroxide, fumar -Rutriethylammo-muhydroxide, tetraptylammo-muhydroxide, tetraethylammo-muhydride mouth oxide, tetraptylammo-muazide, tetraptylammo-um Rhohydride, Tetrabutylammonium-Hexafluorophosphate, Tetraptylammo-umhide mouth Gensulfate, Tetraptylammo-umpark mouth rate, Tetraptylammo-um Tetrafluoroborate, Tetraptylammo-umtetraph In this case, water and an appropriate solvent (acetone, acetonitrile, etc.) can be used, for example, tetrabutylammonium trisulfide, and tetrabutylammonium hydrogen sulfate. , Dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether, hexane, N, N-dimethylformamide, dimethyl sulfoxide, toluene , Benzene, methanol, ethanol, hexamethylphosphoric triamide, etc., or a mixed solvent thereof, preferably toluene) at an arbitrary mixing ratio (preferably 1 to 1), and the thiazoles represented by formula (13) Convert it. The reaction temperature is -10 ~: LOO ° C is preferred More preferably, it is 25 to 50 ° C. The reaction time is preferably 0.5 to 48 hours, more preferably 24 to 30 hours.
[0059] 式（13)で示される 2 ァミノチアゾールイ匕合物を適当な溶媒中（例えばアセトン、ァ セトニトリル、ジクロロメタン、クロ口ホルム、 1, 2—ジクロロエタン、酢酸ェチル、テトラ ヒドロフラン、ジォキサン、ジェチルエーテル、イソプロピルエーテル、へキサン、 N, N ジメチルホルムアミド、ジメチルスルホキシド、トルエン、ベンゼン、へキサメチルリ ン酸トリアミド等、またはこれらの混合溶媒が挙げられ、好ましくはテトラヒドロフランな どが挙げられる。 CDI (1, 1 ' -カルボニルジイミダゾール）と反応させることにより式 (2— 2)で示される化合物へと変換した後、式（3— 2)と反応させる。反応温度は 0〜 100°Cが好ましぐさらに好ましくは 10〜40°Cである。反応時間は 0. 5〜24時間が 好まし 、。さらに好ましくは 1〜 12時間である。  [0059] The 2-aminothiazole compound represented by the formula (13) is mixed in a suitable solvent (for example, acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, Examples thereof include jetyl ether, isopropyl ether, hexane, N, N dimethylformamide, dimethyl sulfoxide, toluene, benzene, hexamethylphosphoric triamide, etc., or a mixed solvent thereof, preferably tetrahydrofuran, etc. CDI ( 1, 1'-carbonyldiimidazole) to form a compound represented by formula (2-2) and then react with formula (3-2). The reaction temperature is preferably 0 to 100 ° C. More preferably, it is 10 to 40 ° C. The reaction time is preferably 0.5 to 24 hours, more preferably 1 to 12 hours. .
[0060] 式 (2— 2)と（3— 2)との反応は適当な塩基存在下 (例えば有機塩基としてはトリエ チルァミン、ジイソプロピルェチルァミン、ジァザビシクロ [2, 2, 2]ゥンデセン、または 2, 6—ルチジン等が挙げられ、無機塩基としては水酸ィ匕ナトリウム、水酸ィ匕カリウム、 炭酸水素ナトリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸カリウム、または炭酸セ シゥム等が挙げられ、好ましくはジイソプロピルェチルァミンなどである。 適当な溶 媒中（例えばアセトン、ァセトニトリル、ジクロロメタン、クロ口ホルム、 1, 2—ジクロロェ タン、酢酸ェチル、テトラヒドロフラン、ジォキサン、ジェチルエーテル、イソプロピルェ 一テル、へキサン、 N, N ジメチルホルムアミド、ジメチルスルホキシド、トルエン、ベ ンゼン、へキサメチルリン酸トリアミド等、またはこれらの混合溶媒が挙げられ、好まし くはテトラヒドロフランなどが挙げられる。）反応させることにより式 (4 2)で示される化 合物を得た。反応温度は 0〜： LOO°Cが好ましぐさらに好ましくは 10〜40°Cである。 反応時間は 0. 5〜24時間が好ましい。さらに好ましくは 1〜12時間である。  [0060] The reaction between the formulas (2-2) and (3-2) is carried out in the presence of a suitable base (for example, triethylamine, diisopropylethylamine, diazabicyclo [2,2,2] undecene as the organic base, or 2, 6-lutidine and the like, and the inorganic base includes sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc. Is diisopropylethylamine, etc. In a suitable solvent (for example, acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether, Hexane, N, N dimethylformamide, dimethyl sulfoxide, toluene, benzene, hexamethylphosphorus (Examples include triamide and the like, or a mixed solvent thereof, and preferably tetrahydrofuran, etc.) By reacting, a compound represented by the formula (42) was obtained.The reaction temperature was 0 to: LOO ° C is more preferably 10 to 40 ° C. The reaction time is preferably 0.5 to 24 hours, more preferably 1 to 12 hours.
[0061] また前記の方法以外にもトリホスゲンなど式（1)または（3)をイソシァネートイ匕合物と し、式（1)のイソシァネート体の場合には式（3)を、式（3)のイソシァネート体の場合 には式（1)を反応させることにより、式 (4)を得ることが出来る。  [0061] In addition to the above method, the formula (1) or (3) such as triphosgene is an isocyanate compound, and in the case of the isocyanate compound of the formula (1), the formula (3) is replaced by the formula (3). In the case of an isocyanate, the formula (4) can be obtained by reacting the formula (1).
[0062] Scheme Iで得られた式（4)、 Scheme IIで得られた式（7)、および Scheme IIIで得られ た式 (4 2)で示される化合物は、必要に応じて、側鎖の変換を行ってもよぐまた反 応の順番も必要に応じて前後することも可能である。 [0062] The compound represented by the formula (4) obtained by Scheme I, the formula (7) obtained by Scheme II, and the formula (4 2) obtained by Scheme III may have a side chain as necessary. You can also convert The order of response can be changed as necessary.
[0063] 2)ォキシム型誘導体（Z=— NA， 一 CO— CH O—  [0063] 2) Oxime-type derivatives (Z = —NA, one CO—CH 2 O—
2  2
-CH O— N = C (B，）一を表す化合物群）  -CH 2 O— N = C (B,) a compound group representing one)
2  2
[化 47]  [Chemical 47]
Figure imgf000046_0001
Figure imgf000046_0001
[0064] 式（16)に相当する本発明の化合物の製造は、 Eur.J. Med. Chem. , (2003) ,38,10 25、 J. Med. Chem. , (1999) ,42,3458、 Chem. Pharm. Bull. (2001) ,49記載の方法に より製造することが出来る。  [0064] The compound of the present invention corresponding to the formula (16) can be produced by Eur. J. Med. Chem., (2003), 38, 10 25, J. Med. Chem., (1999), 42, 3458. Chem. Pharm. Bull. (2001), 49.
[0065] 式（17)は、市販品として入手可能か、もしくは J. Med. Chem. (1999) ,42,2829、 J.  [0065] Formula (17) is available as a commercial product, or J. Med. Chem. (1999), 42, 2829, J.
Med. Chem. (1999) ,42,2887、 J. Med. Chem. (2001) ,44,749, Chem. Pharm. Bull. (1962) , 10,376、 J. Org. Chem. (1984) ,49,569、 J. Org. Chem. (2000) ,65,1102、 J. Org. Chem. (2004) ,69,2381、 Biorg. Med. Chem. Lett. (1998) ,8,3153、 Biorg. Med . Chem. Lett. (1999) ,9,957、特表平 10— 504542号、特表 2001— 517667号、 E P518,731、および EP611, 766記載の方法により得る。  Med. Chem. (1999), 42, 2887, J. Med. Chem. (2001), 44, 749, Chem. Pharm. Bull. (1962), 10, 376, J. Org. Chem. (1984), 49, 569, J. Org. Chem. (2000), 65,1102, J. Org. Chem. (2004), 69,2381, Biorg. Med. Chem. Lett. (1998), 8,3153, Biorg. Med. Chem. Lett. (1999), 9,957, JP-T 10-504542, JP-T 2001-517667, EP 518,731, and EP 611,766.
[0066] 式（17)で示されるアミン類を Scheme Vに示すように、ハロゲン化ァセチルハライド（ 例えばクロロアセチルクロリドなどが挙げられる）と適当な溶媒中（アセトン、ァセトニト リル、ジクロロメタン、クロ口ホルム、 1, 2—ジクロロエタン、酢酸ェチル、テトラヒドロフ ラン、ジォキサン、ジェチルエーテル、イソプロピルエーテル、へキサン、 N, N—ジメ チルホルムアミド、ジメチルスルホキシド、トルエン、ベンゼン、メタノール、エタノール 、へキサメチルリン酸トリアミド等、またはこれらの混合溶媒、好ましくはベンゼンなど が挙げられる）、反応させることにより式（14)で示される a ハロゲンィ匕ァセトアミドを 得る。反応温度は— 10〜100°Cが好ましぐさらに好ましくは 40〜80°Cである。反応 時間は 0. 5〜24時間が好ましい。さらに好ましくは 0. 5〜2時間である。 [0066] As shown in Scheme V, the amine represented by the formula (17) is a halogenated acetyl chloride (for example, chloroacetyl chloride) and a suitable solvent (acetone, acetonitrile, dichloromethane, Form, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether, hexane, N, N-dimethylformamide, dimethyl sulfoxide, toluene, benzene, methanol, ethanol, hexamethyl phosphate triamide Or a mixed solvent thereof, preferably benzene, etc. A halogenated acetamide of formula (14) is obtained by reaction. The reaction temperature is preferably -10 to 100 ° C, more preferably 40 to 80 ° C. The reaction time is preferably 0.5 to 24 hours. More preferably, it is 0.5 to 2 hours.
[0067] 市販品として入手可能、もしくは Synthesis (1996) ,8,991、 J. Org. Chem. (1980) ,45 ,3917、 J. Med. Chem. (1990) ,33, 313記載の方法により得た式（15)で示されるォキ シム化合物を式（14)と適当な塩基存在下 (有機塩基としてはトリエチルァミン、ジイソ プロピルェチルァミン、ジァザビシクロ [2, 2, 2]ゥンデセン、または 2, 6—ルチジン 等が挙げられ、無機塩基としては水酸ィ匕ナトリウム、水酸ィ匕カリウム、炭酸水素ナトリ ゥム、炭酸水素カリウム、炭酸ナトリウム、炭酸カリウム、または炭酸セシウム等が挙げ られ、好ましくは炭酸カリウムなどである）、適当な溶媒中（アセトン、ァセトニトリル、ジ クロロメタン、クロ口ホルム、 1, 2—ジクロロエタン、酢酸ェチル、テトラヒドロフラン、ジ ォキサン、ジェチルエーテル、イソプロピルエーテル、へキサン、 N, N ジメチルホ ルムアミド、ジメチルスルホキシド、トルエン、ベンゼン、メタノール、エタノール、へキ サメチルリン酸トリアミド等、またはこれらの混合溶媒が挙げられ、好ましくは N、 N-ジメ チルホルムアミドなどが挙げられる）、反応させることにより、式（16)を得る。反応温度 は— 10〜100°Cが好ましぐさらに好ましくは 0〜30°Cである。反応時間は 0. 5〜24 時間が好ましい。さらに好ましくは 0. 5〜3時間である。  [0067] Available as a commercial product or obtained by the method described in Synthesis (1996), 8,991, J. Org. Chem. (1980), 45, 3917, J. Med. Chem. (1990), 33, 313 The oxime compound represented by formula (15) can be synthesized with formula (14) in the presence of a suitable base (for example, triethylamine, diisopropylethylamine, diazabicyclo [2, 2, 2] undecene, or 2 , 6-lutidine, and the like, and inorganic bases include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, or cesium carbonate, preferably Is potassium carbonate) in a suitable solvent (acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether). Hexane, N, N dimethylformamide, dimethyl sulfoxide, toluene, benzene, methanol, ethanol, hexamethylphosphoric triamide, etc., or a mixed solvent thereof, preferably N, N-dimethylformamide, etc. To give the formula (16). The reaction temperature is preferably −10 to 100 ° C., more preferably 0 to 30 ° C. The reaction time is preferably 0.5 to 24 hours. More preferably, it is 0.5 to 3 hours.
[0068] また、式（15)で示されるォキシム化合物を、式（20)で示される a ーハロゲノ酢酸ェ ステルと、適当な塩基存在下 (有機塩基としてはトリエチルァミン、ジイソプロピルェチ ルァミン、ジァザビシクロ [2, 2, 2]ゥンデセン、または 2, 6—ルチジン等が挙げられ 、無機塩基としては水酸ィ匕ナトリウム、水酸ィ匕カリウム、炭酸水素ナトリウム、炭酸水素 カリウム、炭酸ナトリウム、炭酸カリウム、または炭酸セシウム等が挙げられ、好ましくは 水素化ナトリウムなどが挙げられる。）、適当な溶媒中（アセトン、ァセトニトリル、ジクロ ロメタン、クロ口ホルム、 1 , 2—ジクロロエタン、酢酸ェチル、テトラヒドロフラン、ジォキ サン、ジェチルエーテル、イソプロピルエーテル、へキサン、 N, N ジメチルホルム アミド、ジメチルスルホキシド、トルエン、ベンゼン、メタノール、エタノール、へキサメチ ルリン酸トリアミド等、またはこれらの混合溶媒などが挙げられ、好ましくは N、 N-ジメ チルホルムアミド等が挙げられる）、反応させ、必要に応じ脱エステル、または脱保護 を行い、式（22)で示されるカルボン酸化合物へと変換する。反応温度は 10〜： L0 0°Cが好ましぐさらに好ましくは 0〜30°Cである。反応時間は 0. 5〜24時間が好ま しい。さらに好ましくは 0. 5〜3時間である。また、式（22)は、 Tetrahedron (2001) ,57, 1551または Tetrahedron (1999) , 55,13159記載の方法により製造することが出来る。 [0068] In addition, the oxime compound represented by the formula (15) is mixed with an a-halogenoacetate ester represented by the formula (20) in the presence of an appropriate base (for example, triethylamine, diisopropylethylamine, diazabicyclo [2, 2, 2] undecene, 2,6-lutidine and the like, and inorganic bases include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, Or cesium carbonate, etc., preferably sodium hydride, etc.) in a suitable solvent (acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, Jetyl ether, isopropyl ether, hexane, N, N dimethylformamide, dimethylsulfate (E.g., amide, toluene, benzene, methanol, ethanol, hexamethylphosphoric triamide, etc., or mixed solvents thereof, preferably N, N-dimethylformamide, etc.). Or deprotection To convert to a carboxylic acid compound represented by the formula (22). The reaction temperature is preferably 10 to: L0 0 ° C, more preferably 0 to 30 ° C. The reaction time is preferably 0.5 to 24 hours. More preferably, it is 0.5 to 3 hours. Moreover, Formula (22) can be manufactured by the method of Tetrahedron (2001), 57,1551 or Tetrahedron (1999), 55,13159.
[0069] 得られた式（22)で示される化合物を、適当なハロゲン化剤、例えば塩酸、臭化水 素酸、フッ化水素酸、硫酸、リン酸、酢酸、塩ィ匕オギザリル、もしくは N, Ν' -ジシクロ へキシルカルボジイミド、 Ν-ヒドロキシフタルイミド、 Ν-ヒドロキシスクシンイミド、もしく は HOBT(l— Hydroxybenzotriazole hydrate) ^ WSし (Water soluble carbodnmide nydro chloride, 1— Ethyl— «3— (3— dimethylaminopropyl) carbodiimide hydrochloride)などのぺ プチド合成用縮合剤存在下、適当な溶媒 (アセトン、ァセトニトリル、ジクロロメタン、ク ロロホルム、 1 , 2—ジクロロエタン、酢酸ェチル、テトラヒドロフラン、ジォキサン、ジェ チルエーテル、イソプロピルエーテル、へキサン、 N, N ジメチルホルムアミド、ジメ チルスルホキシド、トルエン、ベンゼン、メタノール、エタノール、へキサメチルリン酸ト リアミド等、またはこれらの混合溶媒）、好ましくはジクロロメタン中、反応させること〖こよ り、式（18)で示される化合物へと変換する。反応温度は 10〜100°Cが好ましぐさ らに好ましくは 10〜50°Cである。反応時間は 0. 5〜24時間が好ましい。さらに好ま しくは 1〜6時間である。 [0069] The obtained compound represented by the formula (22) is converted into a suitable halogenating agent such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, acetic acid, salt oxalil, or N , Ν'-dicyclohexylcarbodiimide, Ν-hydroxyphthalimide, Ν-hydroxysuccinimide, or HOBT (l- Hydroxybenzotriazole hydrate) ^ WS (Water soluble carbodnmide nydro chloride, 1— Ethyl— «3— (3— dimethylaminopropyl ) carbodiimide hydrochloride) and other suitable solvents (acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, isopropyl ether, hexane, N, N dimethylformamide, dimethyl sulfoxide, toluene, benzene, methanol, ethanol , To Kisamechirurin Santo polyamide, etc. or a mixed solvent), preferably in dichloromethane, Ri child stranded 〖be reacted to convert to a compound represented by the formula (18). The reaction temperature is preferably 10 to 100 ° C, more preferably 10 to 50 ° C. The reaction time is preferably 0.5 to 24 hours. More preferably, it is 1 to 6 hours.
[0070] 得られた式（18)で示される化合物と、式（17)で示されるァミンとを、適当な塩基存 在下 (有機塩基としてはトリエチルァミン、ジイソプロピルェチルァミン、ジァザビシクロ [2, 2, 2]ゥンデセン、または 2, 6—ルチジン等が挙げられ、無機塩基としては水酸 化ナトリウム、水酸ィ匕カリウム、炭酸水素ナトリウム、炭酸水素カリウム、炭酸ナトリウム 、または炭酸カリウム、炭酸セシウム等が挙げられ、好ましくはジイソプロピルェチル ァミン、トリェチルァミンなどである）、適当な溶媒下 (アセトン、ァセトニトリル、ジクロロ メタン、クロ口ホルム、 1, 2—ジクロロェタン、酢酸ェチル、テトラヒドロフラン、ジォキサ ン、ジェチルエーテル、イソプロピルエーテル、へキサン、 N, N ジメチルホルムアミ ド、ジメチルスルホキシド、トルエン、ベンゼン、メタノール、エタノール、へキサメチル リン酸トリアミド等、またはこれらの混合溶媒などが挙げられ、好ましくはベンゼンなど が挙げられる。）、反応させることにより式（16)で示される化合物を得る。反応温度は — 10〜100°Cが好ましぐさらに好ましくは 10〜50°Cである。反応時間は 0. 5〜24 時間が好まし 、。さらに好ましくは 1〜6時間である。 [0070] The obtained compound represented by the formula (18) and the amine represented by the formula (17) are present in the presence of an appropriate base (as the organic base, triethylamine, diisopropylethylamine, diazabicyclo [2] , 2, 2] undecene, or 2,6-lutidine, and the inorganic bases include sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, or potassium carbonate, cesium carbonate. Etc., preferably diisopropylethylamine, triethylamine, etc.) in a suitable solvent (acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl) Ether, isopropyl ether, hexane, N, N dimethylformamide, dimethylsulfoxy , Toluene, benzene, methanol, ethanol, hexamethylphosphoric triamide, etc., or a mixed solvent thereof, preferably benzene, etc.), and reacting to obtain the compound represented by the formula (16) . The reaction temperature is — 10-100 ° C is preferred, more preferably 10-50 ° C. The reaction time is preferably 0.5-24 hours. More preferably, it is 1 to 6 hours.
[0071] また、式 (22)化合物は、前記ペプチド合成用縮合剤を用いて、式（17)と反応させ ること〖こより得られる式（16)力らち得ることが出来る。  [0071] Further, the compound of formula (22) can be obtained from the formula (16) obtained by reacting with the formula (17) using the condensing agent for peptide synthesis.
[0072] 3)アミド型誘導体 (Z =— NA '— CO を表す化合物群）  [0072] 3) Amide derivatives (compounds representing Z = — NA '— CO)
[化 48]  [Chemical 48]
Scheme VI  Scheme VI
Figure imgf000049_0001
Figure imgf000049_0001
[0073] 式（24)または式（25)に相当する本発明の化合物の製造は、 Eur. J. Med. Chem.  [0073] The production of the compound of the present invention corresponding to the formula (24) or the formula (25) can be carried out according to Eur. J. Med. Chem.
, (1981) ,4,383、 Indian J. Pharm. Sci., (1980) ,42,133、 Indian Journal of Heterocyclic Chemistry (2001) , 10,231、または J. Indian Chem. Soc., (1981) LVIII,687記載の方法 により製造することが出来る。  , (1981), 4,383, Indian J. Pharm. Sci., (1980), 42,133, Indian Journal of Heterocyclic Chemistry (2001), 10,231, or J. Indian Chem. Soc., (1981) LVIII, 687 Can be manufactured.
[0074] 一般的には、当業者において通常使用される前記ペプチド合成用縮合剤を用いて 式（ 17)と式（23)とをペプチド結合させることにより、式（24)を得て 、る。  [0074] Generally, formula (24) is obtained by peptide-bonding formula (17) and formula (23) using the condensing agent for peptide synthesis usually used by those skilled in the art. .
[0075] 市販品として入手可能な式 (23)を、適当な溶媒下 (アセトン、ァセトニトリル、ジクロ ロメタン、クロ口ホルム、 1, 2、 -ジクロロェタン、酢酸ェチル、テトラヒドロフラン、ジォキ サン、ジェチルエーテル、イソプロピルエーテル、へキサン、 N, N ジメチルホルム アミド、ジメチルスルホキシド、トルエン、ベンゼン、メタノール、エタノール、へキサメチ ルリン酸トリアミド等、またはこれらの混合溶媒が挙げられ、好ましくはテトラヒドロフラ ンまたは N, N ジメチルホルムアミドなどである）、前記ペプチド合成用縮合剤ととも に式（17)で示される化合物と反応させることにより、式（24)を得る。反応温度は 1 0〜100でカ 子ましく、さらに好ましくは 10〜50°Cである。反応時間は 0. 5〜24時間 が好まし!/、。さらに好ましくは 1〜6時間である。  [0075] The formula (23), which is commercially available, is converted into an appropriate solvent (acetone, acetonitrile, dichloromethane, chloroform, 1, 2, -dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, Examples thereof include isopropyl ether, hexane, N, N dimethylformamide, dimethyl sulfoxide, toluene, benzene, methanol, ethanol, hexamethylphosphoric acid triamide, or a mixed solvent thereof, preferably tetrahydrofuran or N, N dimethylformamide. The compound (24) is obtained by reacting with the peptide synthesis condensing agent and the compound represented by the formula (17). The reaction temperature is preferably 10 to 100, more preferably 10 to 50 ° C. The reaction time is preferably 0.5 to 24 hours! /. More preferably, it is 1 to 6 hours.
[0076] また、前記式（14)で示される化合物を、適当な塩基存在下 (有機塩基としてはトリ ェチルァミン、ジイソプロピルェチルァミン、ジァザビシクロ [2, 2, 2]ゥンデセン、 2, 6—ルチジン等が挙げられ、無機塩基としては水酸ィ匕ナトリウム、水酸ィ匕カリウム、炭 酸水素ナトリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等 が挙げられ、好ましくはナトリウムメトキシドなどが挙げられる。）、市販品として入手可 能、もしくは Acta Chem. Scsand,20,57, (1966) ,Sandstrom記載の方法により得た Rk— SHまたは R1— OHで示されるチオール類、またはアルコール類と、適当な溶媒中（ァ セトン、ァセトニトリル、ジクロロメタン、クロ口ホルム、 1, 2—ジクロロエタン、酢酸ェチ ル、テトラヒドロフラン、ジォキサン、ジェチルエーテル、イソプロピルエーテル、へキ サン、 N, N—ジメチルホルムアミド、ジメチルスルホキシド、トルエン、ベンゼン、メタノ ール、エタノール、へキサメチルリン酸トリアミド等、またはこれらの混合溶媒などが挙 げられ、好ましくは N, N—ジメチルホルムアミドなどが挙げられる。）、反応させること により式 (25)で示される化合物を得ることができる。 [0076] In addition, the compound represented by the formula (14) is added in the presence of a suitable base (the organic base is Ethylamine, diisopropylethylamine, diazabicyclo [2,2,2] undecene, 2,6-lutidine and the like, and inorganic bases include sodium hydroxide, potassium hydroxide, sodium bicarbonate, carbonate Examples include potassium hydrogen, sodium carbonate, potassium carbonate, cesium carbonate, and preferably sodium methoxide. ), Commercially available, or Acta Chem. Scsand, 20, 57, (1966), thiols or alcohols represented by R k — SH or R 1 — OH obtained by the method described in Sandstrom, In a suitable solvent (acetone, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether, hexane, N, N-dimethylformamide, dimethyl Examples thereof include sulfoxide, toluene, benzene, methanol, ethanol, hexamethylphosphoric triamide, or a mixed solvent thereof, preferably N, N-dimethylformamide, etc.) The compound represented by 25) can be obtained.
[0077] 化 ·の ffl /  [0077] chemistry · ffl /
塩とは医薬的に許容される塩であることが好ましぐ本発明による化合物は、その塩 として提供されてよい。例えばアルカリ金属、アルカリ土類金属、アンモ-ゥム、有機 塩基等が挙げられ、好ましくは、リチウム、ナトリウム、カリウム、マグネシウム、カルシゥ ム、アンモ-ゥム、エタノールァミン、トリエタノールァミン、トリメチルァミン、トリェチル ァミン、ジイソプロピルアミン等が挙げられる。また、酸付加塩の例としては、酢酸塩、 アジピン酸塩、アルギン酸塩、ァスパラギン酸塩、安息香酸塩、ベンゼンスルホン酸 塩、重硫酸塩、酪酸塩、クェン酸塩、樟脳酸塩、カンファースルホン酸塩、シクロペン タンプロピオン酸塩、ジダルコン酸塩、ドデシル硫酸塩、エタンスルホン酸塩、フマル 酸塩、ダルコヘプタン酸塩、グリセ口リン酸塩、へミ硫酸塩、ヘプタン酸塩、へキサン 酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、 2—ヒドロキシエタンスルホン酸塩、 乳酸塩、マレイン酸塩、メタンスルホン酸塩、 2—ナフタレンスルホン酸塩、ニコチン酸 塩、シユウ酸塩、パモ酸塩、ぺクチン酸塩、過硫酸塩、 3—フエ-ルプロピオン酸塩、 ピクリン酸塩、ビバリン酸塩、プロピオン酸塩、コハク酸塩、酒石酸塩、チォシアン酸 塩、トシル酸塩、およびゥンデカン酸塩等が挙げられる。  A compound according to the present invention in which the salt is preferably a pharmaceutically acceptable salt may be provided as the salt. Examples include alkali metals, alkaline earth metals, ammonium, organic bases, etc., preferably lithium, sodium, potassium, magnesium, calcium, ammonium, ethanolamine, triethanolamine, trimethyl. And amine, triethylamine, diisopropylamine and the like. Examples of acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, kenate, camphorate, camphorsulfone. Acid salt, cyclopentanepropionate, didarconate, dodecyl sulfate, ethane sulfonate, fumarate, darcoheptanoate, glycephosphate, hemisulfate, heptanoate, hexaneate, Hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, Pamoate, pectate, persulfate, 3-phenolpropionate, picrate, bivalinate, propionate, succinate, tartrate, thiocyanate, Examples include tosylate and undecanoate.
[0078] また、本発明による化合物 (I)または (Π)〜 (V)は水和物または非水和物であって もよい。これらの化合物またはその塩は、分子内に不斉炭素、幾何異性を有すること もある。それら各々、またはそれらの混合物のいずれも本発明に含まれる。 [0078] The compounds (I) or (ま た は) to (V) according to the present invention are hydrates or non-hydrates. Also good. These compounds or salts thereof may have asymmetric carbon and geometric isomerism in the molecule. Each of them or mixtures thereof are included in the present invention.
[0079] さらに、本発明による化合物およびそれらの塩は、「溶媒和物」とされてもよぐ溶媒 和物の溶媒としては、水、メタノール、エタノール、イソプロパノール、ブタノール、ァ セトン、酢酸ェチル、またはクロ口ホルム等が挙げられる。  [0079] Further, the compounds of the present invention and salts thereof may be referred to as "solvates". Solvents of solvates may include water, methanol, ethanol, isopropanol, butanol, acetone, ethyl acetate, Or black mouth form etc. are mentioned.
[0080] 本発明により提供される医薬は、一般式 (I)で表される化合物および生理学的に許 容されるその塩、ならびにそれらの溶媒和物力 なる群力 選ばれる物質を有効成 分として含有することを特徴として 、る。本発明の医薬は経口的または非経口的に投 与することができる。非経口投与としては鼻腔内、点眼、点耳、経皮、気道内、直腸 内、泌尿器内、皮下、筋肉内、および静脈内等の投与経路を挙げることができる。本 発明の医薬としては、有効成分である前記の物質をそのまま投与してもよいが、一般 的には、一または二以上の製剤用添加物 (担体)を用いて医薬組成物を製造して投 与することが望ましい。経口投与に適する製剤の例としては、例えば、錠剤、顆粒剤 、細粒剤、散剤、シロップ剤、溶液剤、カプセル剤、チユアブル剤、または懸濁剤等を 挙げることができ、非経口投与に適する製剤の例としては、例えば、注射剤、点滴剤 、吸入剤、噴霧剤、坐剤、膣座剤、経皮吸収剤、経粘膜吸収剤、点眼剤、点耳剤、 点鼻剤、または貼付剤等を挙げることができる。注射剤や点滴剤等の液体製剤を例 えば凍結乾燥形態の粉末状医薬組成物として提供し、用時に水または他の適当な 媒体 (例えば生理食塩水、ブドウ糖輸液、または緩衝液等が挙げられる。）に溶解ま たは懸濁させて用いてもょ 、。  [0080] The medicament provided by the present invention comprises a compound represented by the general formula (I) and a physiologically acceptable salt thereof, and a group force that is a solvate power thereof as an active ingredient. It is characterized by containing. The medicament of the present invention can be administered orally or parenterally. Examples of parenteral administration include intranasal, eye drop, ear drop, transdermal, respiratory tract, intrarectal, intraurinary, subcutaneous, intramuscular, and intravenous routes. As the medicament of the present invention, the above-mentioned substance as an active ingredient may be administered as it is, but generally, a pharmaceutical composition is produced using one or two or more pharmaceutical additives (carriers). It is desirable to invest. Examples of preparations suitable for oral administration include, for example, tablets, granules, fine granules, powders, syrups, solutions, capsules, wearables, suspensions, etc. Examples of suitable formulations include, for example, injections, drops, inhalants, sprays, suppositories, vaginal suppositories, transdermal absorption agents, transmucosal absorption agents, eye drops, ear drops, nasal drops, or A patch etc. can be mentioned. Liquid preparations such as injections and infusions are provided as powdered pharmaceutical compositions in lyophilized form, and water or other suitable media (for example, physiological saline, glucose infusion solution, buffer solution, etc.) can be mentioned at the time of use. )) Or dissolved in suspension.
[0081] 製剤用添加物は医薬組成物の形態に応じて適宜選択可能であり、その種類は特 に限定されないが、例えば、安定化剤、界面活性剤、可塑剤、滑沢剤、可溶化剤、 緩衝剤、甘味剤、基剤、吸着剤、矯味剤、結合剤、懸濁化剤、光沢化剤、コーティン グ剤、着香剤，香料、湿潤剤、湿潤調節剤、充填剤、消泡剤、咀嚼剤、清涼化剤、着 色剤、糖衣剤、等張化剤、 PH調節剤、軟化剤、乳化剤、粘着剤、粘着増強剤、粘稠 剤、粘稠化剤、発泡剤、賦形剤、分散剤、噴射剤、崩壊剤、崩壊補助剤、芳香剤、 防湿剤、防腐剤、保存剤、無痛化剤、溶剤、溶解剤、溶解補助剤、または流動化剤 等を挙げることができ、これらを二種以上組み合わせて用いてもよい。これらの製剤 用添加物の具体例は、例えば、医薬品添加物事典（日本医薬品添加剤協会編集、 薬事日報社発行）に説明されているので、当業者は医薬組成物の形態に応じて適宜 の製剤用添加物を選択し、当業界で汎用の方法に従って所望の形態の医薬組成物 を製造することができる。一般的には、前記の医薬組成物は有効成分である前記の 物質を 1.0〜1 00% (W/W)、好ましくは 1.0〜60% (W/W)となるように調製することがで きる。 [0081] The additive for the formulation can be appropriately selected depending on the form of the pharmaceutical composition, and the type thereof is not particularly limited, but for example, a stabilizer, a surfactant, a plasticizer, a lubricant, a solubilizing agent. Agent, buffering agent, sweetener, base, adsorbent, flavoring agent, binder, suspending agent, brightening agent, coating agent, flavoring agent, fragrance, wetting agent, wetting regulator, filler, extinguishing agent foams, chews, fresheners, wearing colorant, dragees, tonicity agents, P H modifiers, softeners, emulsifiers, adhesives, adhesion enhancer, viscous agents, thickening agents, foaming agents , Excipients, dispersants, propellants, disintegrants, disintegration aids, fragrances, desiccants, preservatives, preservatives, soothing agents, solvents, solubilizers, solubilizers, fluidizing agents, etc. These may be used in combination of two or more. These preparations Specific examples of excipients are described in, for example, the Pharmaceutical Additives Encyclopedia (edited by the Japan Pharmaceutical Additives Association, published by Yakuji Nippo Co., Ltd.). The pharmaceutical composition of a desired form can be manufactured according to a method generally used in this field. Generally, the pharmaceutical composition can be prepared so that the substance as an active ingredient is 1.0 to 100% (W / W), preferably 1.0 to 60% (W / W). wear.
[0082] より具体的には、ゼラチン、乳糖、白糖、酸化チタン、デンプン、結晶セルロース、ヒ ドロキシプロピノレメチノレセノレロース、カノレボキシメチノレセノレロース、トウモロコシデンプ ン、マイクロクリスタルワックス、白色ワセリン、メタケイ酸アルミン酸マグネシウム、無水 リン酸カルシウム、クェン酸、クェン酸三ナトリウム、ヒドロキシプロピルセルロース、ソ ルビトール、ソルビタン脂肪酸エステル、ポリイソべート、ショ糖脂肪酸エステル、ポリ ォキシエチレン硬化ヒマシ油、ポリビュルピロリドン、ステアリン酸マグネシウム、軽質 無水ケィ酸、タルク、植物油、ベンジルアルコール、アラビアゴム、プロピレングリコー ル、ポリアルキレングリコール、シクロデキストリン、またはヒドロキシプロビルシクロデキ ストリン等の製剤用添加物を用いることができるが、これらに限定されることはない。  [0082] More specifically, gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropinoremethinoresenorelose, canoleoxymethinoresenorelose, corn starch, microcrystal wax, white Petrolatum, magnesium aluminate metasilicate, anhydrous calcium phosphate, citrate, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polyisobate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polybutyropyrrolidone, Magnesium stearate, light anhydrous carboxylic acid, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, or hydroxypropyl cyclo Can be used pharmaceutical additives such as key string, it is not limited thereto.
[0083] 本明細書記載の化合物は FabKまたは Fabl/FabKの阻害剤であり、細菌性感染 症の治療に有用である。例えば、これらの化合物は上気道感染症 (例えば、中耳炎、 細菌性気管炎、急性咽頭蓋炎、または甲状腺炎が挙げられる。）、下気道感染症 (例 えば、蓄膿症または肺膿瘍が挙げられる。）、心臓感染症 (例えば、感染症心内膜炎 が挙げられる。）、胃腸感染症 (例えば、分泌性下痢、脾臓膿瘍、または腹膜後膿瘍 が挙げられる。）、 CNS感染症 (例えば、大脳膿瘍が挙げられる。）、眼感染症 (例え ば、結膜炎、角膜炎、眼内炎、前中隔、眼瞼炎および眼窩蜂巣炎、または涙嚢炎が 挙げられる。）、腎および尿管感染症 (例えば、副睾丸炎、腎内および腎周囲膿瘍、 またはトキシックショック症候群が挙げられる。）、皮膚感染症 (例えば、膿痂疹、毛嚢 炎、皮膚膿瘍、蜂巣炎、創傷感染、または細菌性筋炎が挙げられる。）、ならびに骨 および関節感染症 (例えば、敗血症性関節炎または骨髄炎が挙げられる。）などの細 菌性感染症の治療に有効である。また本発明の化合物は抗真菌剤としても有用であ り、該化合物は既知の抗生物質と組み合わせて用いることも出来る。 [0084] 本発明の医薬の投与量および投与回数は特に限定されないが、治療または予防 の目的、疾患の種類、患者の年齢、体重、または症状等の種々の条件に応じて、適 宜の投与量および投与回数を決定することができる。経口投与の場合には、成人一 日当たり有効成分量として 0.1〜1000mg/kgとなるように、一日当たり一回または数回 投与することができ、非経口投与の場合は、 0.001〜500mg/kgを一日あたり一回また は数回に分けて投与するのが好ましい。 [0083] The compounds described herein are inhibitors of FabK or Fabl / FabK and are useful for the treatment of bacterial infections. For example, these compounds include upper respiratory tract infections (eg, otitis media, bacterial tracheitis, acute pharyngitis, or thyroiditis), lower respiratory tract infections (eg, empyema or lung abscess). ), Heart infection (eg, infection endocarditis), gastrointestinal infection (eg, secretory diarrhea, spleen abscess, or retroperitoneal abscess), CNS infection (eg, cerebrum) Abscesses), eye infections (eg, conjunctivitis, keratitis, endophthalmitis, anterior septum, blepharitis and orbital cellulitis, or lacrimal cystitis), kidney and ureteral infections ( For example, accessory testicularitis, intrarenal and perirenal abscess, or toxic shock syndrome), skin infections (eg, impetigo, folliculitis, skin abscess, cellulitis, wound infection, or bacterial myositis As well as bone And joint infections (e.g., septic arthritis or osteomyelitis, and the like.) Are effective in the treatment of bacterial infections, such as. The compounds of the present invention are also useful as antifungal agents, and the compounds can be used in combination with known antibiotics. [0084] The dose and frequency of administration of the medicament of the present invention are not particularly limited, but it is appropriately administered according to various conditions such as the purpose of treatment or prevention, the type of disease, the age, weight, or symptoms of the patient. The amount and number of administrations can be determined. In the case of oral administration, it can be administered once or several times per day so that the amount of active ingredient per day for adults is 0.1 to 1000 mg / kg.In the case of parenteral administration, 0.001 to 500 mg / kg It is preferable to administer once or several times a day.
実施例  Example
[0085] 以下、本発明による化合物を実施例により説明する。ただし、本発明は下記実施 例に限定されるものではない。  Hereinafter, the compounds according to the present invention will be described with reference to Examples. However, the present invention is not limited to the following examples.
[0086] ゥレア誘導体  [0086] Urea derivatives
[実施例 1 ] 1 , 3 ビス（（ 1H ベンゾ [d]イミダゾール 2 ィル)メチル）ゥレア [Example 1] 1,3 bis ((1H benzo [d] imidazole2yl) methyl) urea
2 アミノメチルベンゾイミダゾール塩酸塩 30mg (0. 14mmol)を N, N ジメチル ホルムアミド 0. 9mLに溶解し、 N, N，—ジイソプロピルェチルァミン 46 L (0. 27m mol)、 1 , 1，—カルボ-ルビス— 1H—イミダゾール 22mg (0. 14mmol)をカ卩え、室 温にて三十分間攪拌した。続いて、 2 アミノー 6—メトキシカルボ-ルペンゾチアゾ ール 28mg (0. 14mmol)をカ卩え、室温にて三十分間、 60°Cにて一時間攪拌した。 反応系を減圧濃縮後、クロ口ホルム Zメタノール Zへキサン Z酢酸ェチルを加え析 出した固体をろ過した。ろ液を放置、ろ取して、標記化合物（3mg、 6. 9%)を得た。2 Dissolve 30 mg (0.14 mmol) of aminomethylbenzimidazole hydrochloride in 0.9 mL of N, N dimethylformamide, and add N, N, -diisopropylethylamine 46 L (0.27 mmol), 1, 1, — Carbonol-bis-1H-imidazole (22 mg, 0.14 mmol) was added and stirred at room temperature for 30 minutes. Subsequently, 28 mg (0.14 mmol) of 2 amino-6-methoxycarborpenezothiazol was added and stirred at room temperature for 30 minutes and at 60 ° C for 1 hour. After the reaction system was concentrated under reduced pressure, Kuroguchi form Z methanol Z hexane Z ethyl acetate was added and the precipitated solid was filtered. The filtrate was left standing and collected by filtration to obtain the title compound (3 mg, 6.9%).
— NMR (DMSO— d ) : 6 7. 51— 7. 49 (4H, m) , 7. 16— 7. 13 (4H, m) ,  — NMR (DMSO— d): 6 7. 51— 7. 49 (4H, m), 7. 16— 7. 13 (4H, m),
6  6
6. 88— 6. 84 (2H, m) , 4. 48 (4H, d, J =4. 8 Hz) , MS (FAB+)： 321 (M+ + 1) 6. 88— 6. 84 (2H, m), 4. 48 (4H, d, J = 4.8 Hz), MS (FAB + ): 321 (M + + 1)
[0087] 実施例 2〜22の化合物は後記する実施例 29と同様の方法で製造した。  [0087] The compounds of Examples 2 to 22 were produced in the same manner as in Example 29 described later.
[0088] [実施例 23] N—（2—（2—（3—（（1H べンゾ [d]イミダゾールー 2 ィル)メチル） ウレイド）ベンゾ [d]チアゾーノレ 6—ィルォキシ）ェチノレ）ァセトアミド [0088] [Example 23] N- (2- (2- (3-((1H benzo [d] imidazole-2-yl) methyl) ureido) benzo [d] thiazolole 6-yloxy) ethinole) acetoamide
実施例 22で得たィ匕合物 20mg (0. 049mmol)をテトラヒドロフラン Z水に溶解し、ト リフエ-ルホスフィン 14mg (0. 054mmol)をカロえ、 60°Cにて 3. 5時間攪拌した。反 応系【こピリジン 5. 9 μ L· (0. 074mmol)、無水醉酸 5. l μ L· (0. 054mmol)をカロ免 て、室温にてさらに二時間攪拌した。混合溶液に水を加え、クロ口ホルムで抽出後、 硫酸ナトリウムにて乾燥した。減圧濃縮後、残渣を P— TLC (クロ口ホルム Zメタノー ル =8Zl)にて精製し、標記化合物を得た (6mg、 29%) o20 mg (0.049 mmol) of the compound obtained in Example 22 was dissolved in tetrahydrofuran Z water, and 14 mg (0.054 mmol) of triphenylphosphine was prepared and stirred at 60 ° C. for 3.5 hours. . The reaction system [this pyridine 5.9 μL · (0.074 mmol) and succinic anhydride 5. l μL · (0.054 mmol) was calorie free and stirred at room temperature for another 2 hours. After adding water to the mixed solution and extracting with black mouth form, Dried with sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol = 8 Zl) to obtain the title compound (6 mg, 29%) o
— NMR(CDC1 /CD OD)： δ 7. 57 (2Η, d, J = 8. 8 Hz), 7. 29— 7. 24 (  — NMR (CDC1 / CD OD): δ 7.57 (2Η, d, J = 8.8 Hz), 7. 29— 7. 24 (
3 3  3 3
4H, m), 7. 00(1H, dd, J = 9. 0 Hz, J = 2. 7 Hz), 4. 71 (2H, s), 4. 08 (2H , t, J = 5. 3 Hz), 3. 62(2H, t, J = 5. 3 Hz), 2. 00 (3H, s)、 MS (ESI+) :42 5(M+ + 1)  4H, m), 7.00 (1H, dd, J = 9.0 Hz, J = 2.7 Hz), 4.71 (2H, s), 4.08 (2H, t, J = 5.3) Hz), 3.62 (2H, t, J = 5.3 Hz), 2.00 (3H, s), MS (ESI +): 42 5 (M + + 1)
[0089] [実施例 24] 1—（（4一（4 （（エトキシカルボ-ル)メチルォキシ）フエ-ル） 1H— イミダゾールー 2 ィル）メチル） 3—（6 （メチルスルフォ -ル）ベンゾ [d]チアゾー ルー 2—ィル）ゥレア  [Example 24] 1-((4 ((4 ((ethoxycarbol) methyloxy) phenol) 1H-imidazole-2-yl) methyl) 3- (6 (methylsulfol) benzo [d ] Chiazoru 2—Il) Urea
N— (6—（メチルスルフォ -ル）ベンゾ [d]チアゾールー 2—ィル）—1H—イミダゾ 一ルー 1—カルボキシアミド 64mg (0. 20mmol)をテトラヒドロフラン 2mLに溶解し、 (4一（4 （（エトキシカルボ-ル)メチルォキシ）フエ-ル）—1H—イミダゾールー 2— ィル)メチルァミン塩酸塩 77mg(0. 22mmol)、N, N，—ジイソプロピルェチルァミン 75μL·(0. 44mmol)を加え、室温で終夜、続いて 40°Cで三時間攪拌した。混合溶 液をろ取し、標記化合物を得た (40mg、 38%)。 N— (6- (Methylsulfo-) benzo [d] thiazol-2-yl) —1H—imidazo One-Lou 1-Carboxamide 64 mg (0.20 mmol) is dissolved in 2 mL of tetrahydrofuran and (4 (4 (( Ethoxycarbol) methyloxy) phenol) -1H-imidazole-2-yl) methylamine hydrochloride 77 mg (0.22 mmol), N, N, -diisopropylethylamine 75 μL (0.44 mmol) were added, The mixture was stirred at room temperature overnight and then at 40 ° C for 3 hours. The mixed solution was collected by filtration to give the title compound (40 mg, 38%).
— NMR(DMSO d ) : 68. 54(1H, d, J=l. 7 Hz), 7. 88— 7. 80 (2H,  — NMR (DMSO d): 68. 54 (1H, d, J = l. 7 Hz), 7. 88— 7. 80 (2H,
6  6
m), 7. 70-7. 63 (2H, br), 7.45— 7. 33 (2H, m), 6. 91 (2H, d, J = 7. 8 H z), 4. 77 (2H, s), 4.45 (2H, d, J = 5. 4 Hz), 4. 16 (2H, q, J = 7. 1 Hz), 3 . 22 (3H, s), 1. 21 (3H, t, J=7. 1 Hz)、 MS(ESI+) :530(M+ + 1)  m), 7. 70-7. 63 (2H, br), 7.45— 7. 33 (2H, m), 6. 91 (2H, d, J = 7.8 H z), 4. 77 (2H, s), 4.45 (2H, d, J = 5.4 Hz), 4.16 (2H, q, J = 7.1 Hz), 3.22 (3H, s), 1.21 (3H, t, J = 7.1 Hz), MS (ESI +): 530 (M ++ 1)
[0090] [実施例 25] 2—（4一（2—（（3—（6 （メチルスルフォ -ル）ベンゾ [d]チアゾールー 2 ィル）ウレイド）メチル） 1H—イミダゾールー 4 ィル）フヱノキシ）酢酸 [0090] [Example 25] 2- (4- (2-((3- (6 (methylsulfol) benzo [d] thiazole-2-yl) ureido) methyl) 1H-imidazole-4-yl) phenoxy) acetic acid
1一（（4一（4 （（エトキシカルボ-ル)メチルォキシ）フエ-ル） 1H—イミダゾー ルー 2 ィル）メチル）ー3—（6 （メチルスルフォ -ル）ベンゾ [d]チアゾールー 2— ィル）ゥレア llmg(0. 020mmol)を N, N，—ジメチルホルムアミド lmLに溶解し、 1 N水酸ィ匕ナトリウム水溶液 200 L(0. 20mmol)を加え、室温で二時間攪拌した。 混合溶液を減圧濃縮後、塩酸 Z酢酸ェチル、水で洗い、標記化合物を得た (6. 7m g、 67%) o 1 1 ((4 1 (4 ((ethoxycarbol) methyloxy) phenyl) 1H-imidazole 2 yl) methyl) -3- (6 (methylsulfol) benzo [d] thiazole 2-yl ) Urea llmg (0.020 mmol) was dissolved in 1 mL of N, N, -dimethylformamide, 200 L (0.20 mmol) of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours. The mixed solution was concentrated under reduced pressure, washed with hydrochloric acid Z ethyl acetate and water to give the title compound (6.7 mg, 67%) o
— NMR(DMSO d ) : 68. 54(1H, s), 7. 89— 7. 79 (2H, m), 7. 66— 7 . 55 (3H, m) , 7. 34 (1H, brs) , 6. 88 (2H, d, J = 8. 0 Hz) , 4. 59 (2H, brs) , 4. 44 (2H, d, J = 5. 6 Hz) , 3. 23 (3H, s)、 MS (FAB+) : 502 (M+ + 1) — NMR (DMSO d): 68. 54 (1H, s), 7. 89— 7. 79 (2H, m), 7. 66— 7 55 (3H, m), 7. 34 (1H, brs), 6. 88 (2H, d, J = 8.0 Hz), 4. 59 (2H, brs), 4. 44 (2H, d, J = 5.6 Hz), 3.23 (3H, s), MS (FAB +): 502 (M + + 1)
[0091] [実施例 26] 1—（6 （メチルスルフォ -ル）ベンゾ [d]チアゾールー 2 ィル） 3— ( [0091] [Example 26] 1— (6 (methylsulfol) benzo [d] thiazole-2-yl) 3— (
(4一（4一（（モルフォリノカルボ-ル）メチルォキシ）フエ-ル）一 1H—イミダゾールー 2—ィル)メチル）ゥレア  (4 1 (4 ((morpholinocarbol) methyloxy) phenol) 1 1H-imidazole-2-yl) methyl) urea
2- (4一（2—（（3—（6 （メチルスルフォ -ル）ベンゾ [d]チアゾールー 2 ィル）ゥ レイド）メチル） 1H—イミダゾールー 4—ィル）フエノキシ）酢酸 50mg (0. lOmmol) を N, N，—ジメチルホルムアミド 2mLに溶解し、 1—ヒドロキシベンゾトリアゾール水和 物 23mg (0. 15mmol)、 1—ェチル—3— (3 ジメチルァミノプロピル）—カルボジィ ミド塩酸塩 29mg (0. 15mmol)、モルフォリン 13 L (0. 15mmol)をカ卩え、室温で 三時間攪拌した。混合溶液に半飽和重曹水、酢酸ェチルを加え、フェーズセパレー ターにより有機層を分取した。減圧濃縮後、残渣を P— TLC (クロ口ホルム Zメタノー ル =8Zl)にて精製し、標記化合物を得た（23mg、 39%) o 2- (4-((2-((3- (6 (methylsulfol) benzo (d) thiazol-2-yl) ureid) methyl) 1H-imidazole-4-yl) phenoxy) acetic acid 50mg (0. lOmmol) 1-hydroxybenzotriazole hydrate 23 mg (0.15 mmol), 1-ethyl-3- (3 dimethylaminopropyl) -carbodiimide hydrochloride 29 mg (0. 15 mmol) and morpholine 13 L (0.15 mmol) were added and stirred at room temperature for 3 hours. Semi-saturated aqueous sodium hydrogen carbonate and ethyl acetate were added to the mixed solution, and the organic layer was separated using a phase separator. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol = 8 Zl) to obtain the title compound (23 mg, 39%) o
— NMR(CD OD)： δ 8. 43 (1Η, d, J= l. 7 Hz) , 7. 91 (1H, dd, J = 6. 0  — NMR (CD OD): δ 8. 43 (1Η, d, J = l. 7 Hz), 7. 91 (1H, dd, J = 6.0
3  Three
Hz, J= l. 7 Hz) , 7. 78 (1H, d, J = 6. 0 Hz) , 7. 61 (2H, d, J = 8. 8 Hz) , 7. 24 (1H, s) , 6. 97 (2H, d, J = 8. 8 Hz) , 4. 57 (2H, s) , 3. 69— 3. 62 (10 H, m) , 3. 15 (3H, s)、 MS (ESI+) : 571 (M+ + 1)  Hz, J = l. 7 Hz), 7. 78 (1H, d, J = 6.0 Hz), 7. 61 (2H, d, J = 8.8 Hz), 7. 24 (1H, s) , 6. 97 (2H, d, J = 8.8 Hz), 4. 57 (2H, s), 3. 69—3.62 (10 H, m), 3. 15 (3H, s), MS (ESI +): 571 (M + + 1)
[0092] [実施例 27] 1—（6 （メチルスルフォ -ル）ベンゾ [d]チアゾールー 2 ィル） 3— ( [0092] [Example 27] 1— (6 (methylsulfol) benzo [d] thiazole-2-yl) 3— (
(4一（4 （（フエ-ルカルバモイル）メチルォキシ）フエ-ル）—1H—イミダゾールー 2 ィル)メチル）ゥレア  (4 (4 ((Fercarbamoyl) methyloxy) phenol) —1H-imidazole-2-yl) methyl) urea
2- (4一（2—（（3—（6 （メチルスルフォ -ル）ベンゾ [d]チアゾールー 2 ィル）ゥ レイド）メチル） 1H—イミダゾールー 4—ィル）フエノキシ）酢酸 50mg (0. lOmmol) を N, N，—ジメチルホルムアミド 2mLに溶解し、 1—ヒドロキシベンゾトリアゾール水和 物 23mg (0. 15mmol)、 1—ェチル—3— (3 ジメチルァミノプロピル）—カルボジィ ミド塩酸塩 29mg (0. 15mmol)、ァ-リン 14 1^ (0. 15mmol)をカ卩え、室温で三時 間攪拌した。混合溶液に半飽和重曹水、酢酸ェチルを加え、フェーズセパレーター により有機層を分取した。減圧濃縮後、残渣を P— TLC (クロ口ホルム Zメタノール = 8/1)にて精製し、標記化合物を得た (33mg、 57%) o H— NMR(CD OD)： δ 8.43(1H, m), 7.92(1H, dd, J=8.8 Hz, J=l.6 2- (4-((2-((3- (6 (methylsulfol) benzo (d) thiazol-2-yl) ureid) methyl) 1H-imidazole-4-yl) phenoxy) acetic acid 50mg (0. lOmmol) 1-hydroxybenzotriazole hydrate 23 mg (0.15 mmol), 1-ethyl-3- (3 dimethylaminopropyl) -carbodiimide hydrochloride 29 mg (0. 15 mmol) and Alin 14 1 ^ (0.15 mmol) were added and stirred at room temperature for 3 hours. Semi-saturated aqueous sodium hydrogen carbonate and ethyl acetate were added to the mixed solution, and the organic layer was separated using a phase separator. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol = 8/1) to obtain the title compound (33 mg, 57%) o H—NMR (CD OD): δ 8.43 (1H, m), 7.92 (1H, dd, J = 8.8 Hz, J = l.6
3  Three
Hz), 7.79(1H, d, J = 8.8 Hz), 7.65 (2H, d, J = 8.8 Hz), 7.60 (2H, d , J = 7.6 Hz), 7.33 (2H, dd, J=7.6 Hz, J = 7.2 Hz), 7.26 (1H, s), 7. 13 (1H, t, J = 7.2 Hz), 7.07 (2H, d, J = 8.8 Hz), 4.57 (2H, s), 4.69(2 H, s), 3.13 (3H, s)、 MS(ESI+) :577(M+ + 1)  Hz), 7.79 (1H, d, J = 8.8 Hz), 7.65 (2H, d, J = 8.8 Hz), 7.60 (2H, d, J = 7.6 Hz), 7.33 (2H, dd, J = 7.6 Hz, J = 7.2 Hz), 7.26 (1H, s), 7.13 (1H, t, J = 7.2 Hz), 7.07 (2H, d, J = 8.8 Hz), 4.57 (2H, s), 4.69 (2 H , s), 3.13 (3H, s), MS (ESI +): 577 (M ++ 1)
[0093] [実施例 28] 1—（5—（4ーメトキシカルボ-ルフエ-ルチオ）チアゾールー 2 ィル） — 3— ( (4 フエ-ル - 1H イミダゾール一 2 ィル）メチル）ゥレア [0093] [Example 28] 1- (5- (4-Methoxycarbophenylthio) thiazole-2-yl) — 3— ((4-phenol-1H imidazole-2-yl) methyl) urea
N- (5—（4ーメトキシカルボ-ルフエ-ルチオ）チアゾールー 2 ィル） 1H—イミ ダゾールー 1 カルボキシアミド 300mg (0.83mmol)をテトラヒドロフラン 9mLに溶 解し、（4 -フエ-ル - 1H イミダゾール― 2 ィル)メチルァミン塩酸塩 210mg (0. 86mmol)、 N, N，—ジイソプロピルェチルァミン 311 L(l.8mmol)を加え、室温 で終夜攪拌した。混合溶液に水を加え、酢酸ェチルで抽出後、硫酸ナトリウムにて乾 燥した。減圧濃縮して得られる固体をクロ口ホルム Zメタノール混合溶液で洗浄し、 標記化合物を得た（281mg、 73%) o N- (5- (4-Methoxycarbophenylthio) thiazole-2-yl) 1H-imidazole-1 Carboxamide 300 mg (0.83 mmol) was dissolved in 9 mL of tetrahydrofuran to give (4-phenol-1H imidazole-2 (L) Methylamine hydrochloride (210 mg, 0.86 mmol) and N, N, -diisopropylethylamine (311 L, l.8 mmol) were added, and the mixture was stirred at room temperature overnight. Water was added to the mixed solution, extracted with ethyl acetate, and dried over sodium sulfate. The solid obtained by concentration under reduced pressure was washed with Kuroguchi Form Z methanol mixed solution to obtain the title compound (281 mg, 73%) o
— NMR(DMSO— d ): 67.88 (2H, d, J = 8.4 Hz), 7.76 (2H, d, J = 8  — NMR (DMSO— d): 67.88 (2H, d, J = 8.4 Hz), 7.76 (2H, d, J = 8
6  6
.0 Hz), 7.69 (1H, s), 7.55 (1H, brs), 7.35— 7.31 (2H, m), 7.26 (2H , d, J = 8.4 Hz), 7.19-7.11 (2H, m), 4.40 (2H, d, J = 5.4 Hz), 3.82 (3H, s)、 MS(ESI+) :466(M+ + 1)  .0 Hz), 7.69 (1H, s), 7.55 (1H, brs), 7.35— 7.31 (2H, m), 7.26 (2H, d, J = 8.4 Hz), 7.19-7.11 (2H, m), 4.40 (2H, d, J = 5.4 Hz), 3.82 (3H, s), MS (ESI +): 466 (M + + 1)
[0094] [実施例 29] 1—（（4一（4 （（エトキシカルボ-ル)メチルォキシ）フエ-ル） 1H— イミダゾール 2 ィル)メチル） 3— ( 5 (ピリジン— 2 ィルチオ）チアゾール - 2 ィル）ゥレア [Example 29] 1 — ((4 ((4 ((ethoxycarbol) methyloxy) phenol) 1H—imidazole 2 yl) methyl) 3— (5 (pyridine—2 thio) thiazole- 2) Urea
N- (5 （ピリジン 2—ィルチオ）チアゾールー 2 ィル） 1H—イミダゾールー 1 —カルボキシアミド 200mg(0.66mmol)をテトラヒドロフラン 6mLに溶解し、（4— (4 （（エトキシカルボ-ル）メチルォキシ）フエ-ル）—1H—イミダゾールー 2—ィル）メ チルァミン塩酸塩 253mg(0.73mmol)、N, N，—ジイソプロピルェチルァミン 247 μL·(l.45mmol)を加え、室温で終夜攪拌した。混合溶液に飽和食塩水を加え、酢 酸ェチルで抽出後、硫酸ナトリウムにて乾燥した。減圧濃縮後、残渣をシリカゲルクロ マトグラフィー（クロ口ホルム Zメタノール = 10/1)にて精製し、標記化合物を得た（1 24mg、 37%)。N- (5 (pyridine 2-ylthio) thiazole-2-yl) 1H-imidazole 1 —carboxamide 200 mg (0.66 mmol) was dissolved in 6 mL of tetrahydrofuran, and (4- (4 ((ethoxycarbol) methyloxy) phenol- L) -1H-imidazole-2-yl) methylamine hydrochloride 253 mg (0.73 mmol) and N, N, -diisopropylethylamine 247 μL (l.45 mmol) were added, and the mixture was stirred at room temperature overnight. Saturated saline was added to the mixed solution, and the mixture was extracted with ethyl acetate and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (black mouth form Z methanol = 10/1) to obtain the title compound (1 24 mg, 37%).
— NMR(DMSO— d ) : 68.41— 8. 39(1H, m), 7. 72— 7. 63 (4H, m),  — NMR (DMSO— d): 68.41— 8. 39 (1H, m), 7. 72— 7. 63 (4H, m),
6  6
7. 42(1H, brs), 7. 19— 7. 15(1H, m), 7. 11(1H, brs), 7. 03(1H, d, J = 8 . 0 Hz), 6. 90 (2H, d, J = 7. 8 Hz), 4. 77 (2H, s), 4. 39 (2H, d, J = 5.4 Hz), 4. 17(2H, q, J = 7. 1 Hz), 1. 22(3H, t, J = 7. 1 Hz)、 MS (ESI+) : 51 1(M+ + 1)  7. 42 (1H, brs), 7. 19— 7. 15 (1H, m), 7. 11 (1H, brs), 7. 03 (1H, d, J = 8.0 Hz), 6. 90 (2H, d, J = 7.8 Hz), 4. 77 (2H, s), 4. 39 (2H, d, J = 5.4 Hz), 4. 17 (2H, q, J = 7.1 Hz ), 1.22 (3H, t, J = 7.1 Hz), MS (ESI +): 51 1 (M ++ 1)
[0095] 実施例 30の化合物は前記実施例 25と同様の方法で製造した。  [0095] The compound of Example 30 was produced in the same manner as in Example 25.
[0096] [実施例 31]2— (4— (2-((3- (5— (ピリジン— 2—ィルチオ)チアゾール—2—ィ ル）ウレイド)メチル） 1H—イミダゾールー 4 ィル）フエノキシ）酢酸ナトリウム塩[0096] [Example 31] 2- (4- (2-((3- (5- (Pyridine-2-ylthio) thiazole-2-yl) ureido) methyl) 1H-imidazole-4-yl) phenoxy) Acetate sodium salt
1一（（4一（4 （（エトキシカルボ-ル)メチルォキシ）フエ-ル） 1H—イミダゾー ルー 2 ィル)メチル）ー3—（5 （ピリジン 2—ィルチオ）チアゾールー 2 ィル）ゥ レア 41mg(0. 080mmol)をエタノール lmLに溶解し、 5N水酸化ナトリウム水溶液 8 OμL·(0. 40mmol)を加え、室温で二時間攪拌した。混合溶液を減圧濃縮後、 HP —20にて精製し、標記化合物を得た（35mg、 86%) o1 1 ((4 1 (4 ((Ethoxycarbol) methyloxy) phenyl) 1H-imidazole 2 yl) methyl) -3 (5 (pyridine 2-ylthio) thiazole 2 yl) urea 41 mg (0. 080 mmol) was dissolved in 1 mL of ethanol, 5 N aqueous sodium hydroxide solution 8 O μL · (0.40 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixed solution was concentrated under reduced pressure and purified with HP-20 to give the title compound (35 mg, 86%) o
— NMR(CD OD)： δ 8. 36— 8. 33(1H, m), 7. 67(1Η, ddd, J = 8. 0 H  — NMR (CD OD): δ 8. 36— 8. 33 (1H, m), 7. 67 (1Η, ddd, J = 8.0 H
3  Three
z, J = 7. 8 Hz, J=l. 7 Hz), 7. 57— 7. 54 (3H, m), 7. 19— 7. 13 (2H, m) z, J = 7.8 Hz, J = l. 7 Hz), 7.57—7.54 (3H, m), 7.19—7.13 (2H, m)
, 7. 07(1H, d, J = 8. 0 Hz), 6. 94 (2H, d, J = 8. 8 Hz), 4. 52 (2H, s), 4., 7. 07 (1H, d, J = 8. 0 Hz), 6. 94 (2H, d, J = 8.8 Hz), 4. 52 (2H, s), 4.
39 (2H, s)、 MS(ESI+) :483(M+ + 1) 39 (2H, s), MS (ESI +): 483 (M ++ 1)
[0097] 実施例 32〜39の化合物は前記実施例 26と同様の方法で製造した。 [0097] The compounds of Examples 32-39 were produced in the same manner as in Example 26.
[0098] [実施例 40] 4—（2— (3— ((4 フエ-ルー 1H—イミダゾールー 2 ィル)メチル） ウレイド）チアゾールー 5—ィルチオ）ベンズアミド [Example 40] 4— (2— (3— ((4 Ferulu 1H-imidazole-2-yl) methyl) ureido) thiazole-5-ylthio) benzamide
実施例 30で得たィ匕合物 22. 5mg、 28%アンモニア水 5 Lを用い、前記実施例 2 The compound obtained in Example 30 22.5 mg, 28% aqueous ammonia 5 L, using the above Example 2
6と同様の方法で、標記化合物 10mgを得た。 In the same manner as in 6, 10 mg of the title compound was obtained.
[0099] [実施例 41]N—（2 ヒドロキシェチル） 4一（2—（3—（（4 フエ-ルー 1H イミ ダゾールー 2 ィル）メチル）ウレイド）チアゾールー 5—ィルチオ）ベンズアミド 実施例 30で得たィ匕合物 22. 5mg、アミノエタノール 5 Lを用い、前記実施例 26と 同様の方法で、標記化合物 8. 9mgを得た。 [Example 41] N— (2 Hydroxyethyl) 4 (2— (3 — ((4 ferro- 1H imidazole-2 yl) methyl) ureido) thiazole-5-ylthio) benzamide Example 30 Using 22.5 mg of the compound obtained in 1 above and 5 L of aminoethanol, 8.9 mg of the title compound was obtained in the same manner as in Example 26.
[0100] 以下の実施例 42〜44の化合物は、前記実施例 24〜29または前記実施例 31と同 様の方法で製造した。 [0100] The compounds of Examples 42 to 44 below are the same as those of Examples 24 to 29 or Example 31. It was manufactured by the method of
[0101] [実施例 42]1—（5 （ベンジルチオ）チアゾールー 2 ィル） 3—（（4 フエ-ル  [0101] [Example 42] 1- (5 (benzylthio) thiazole-2-yl) 3-((4 phenol
1H—イミダゾールー 2—ィル）メチル）ゥレア 1H-imidazole-2-yl) methyl) urea
— NMR(CDC1 ): 67.55 (2H, brs), 7.12— 7.30(10H, complex) , 4  — NMR (CDC1): 67.55 (2H, brs), 7.12— 7.30 (10H, complex), 4
3  Three
.48 (2H, brs), 3.82 (2H, s)、 MS(ESI+) :422(M+ + 1)  .48 (2H, brs), 3.82 (2H, s), MS (ESI +): 422 (M +++ 1)
[0102] [実施例 43] 1—（5 （フエネチルチオ）チアゾールー 2 ィル） 3—（（4 フエ- ル一 1 H イミダゾール 2—ィル）メチル）ゥレア[0102] [Example 43] 1- (5 (Phenethylthio) thiazole-2-yl) 3-(((4-Phenol 1 H Imidazole-2-yl) methyl) urea
— NMR(CDC1 ): 67.58 (2H, brs), 7.10— 7.32(10H, complex) , 4  — NMR (CDC1): 67.58 (2H, brs), 7.10— 7.32 (10H, complex), 4
3  Three
.53 (2H, brs), 2.86 (4H, m)、 MS(ESI+) :436(M+ + 1)  .53 (2H, brs), 2.86 (4H, m), MS (ESI +): 436 (M +++ 1)
[0103] [実施例 44] 1— (5 ブチルチアゾールー 2 ィル）ー3—（（4 フエ-ル） 1H— イミダゾールー 2—ィル）メチル）ゥレア[Example 44] 1— (5 Butylthiazole-2-yl) -3 — ((4 phenol) 1H-imidazole-2-yl) methyl) urea
— NMR(CD OD)： δ 7.67 (2Η, d, J = 7.8 Hz), 7.35 (2H, t, J = 8.3  — NMR (CD OD): δ 7.67 (2Η, d, J = 7.8 Hz), 7.35 (2H, t, J = 8.3
3  Three
Hz), 7.33(1H, brs), 7.22(1H, t, J = 8. 1 Hz), 4.53 (2H, s), 2.73(2 H, t, J = 7.6 Hz), 1.61 (2H, m)l.39 (2H, m), 0.94 (3H, m)、 MS(ESI+ ) :355(M+)  Hz), 7.33 (1H, brs), 7.22 (1H, t, J = 8.1 Hz), 4.53 (2H, s), 2.73 (2 H, t, J = 7.6 Hz), 1.61 (2H, m) l.39 (2H, m), 0.94 (3H, m), MS (ESI +): 355 (M +)
[0104] 実施例 45〜48の化合物は前記実施例 29と同様の方法で製造した。  [0104] The compounds of Examples 45 to 48 were produced in the same manner as in Example 29.
[0105] [実施例 49]1一（5 （ピリジン 2—ィルチオ）チアゾールー 2 ィル） 3—（（4 [0105] [Example 49] 1 (5 (Pyridine 2-ylthio) thiazole-2-yl) 3-((4
(ピリジン— 3—ィル）― 1H—イミダゾール— 2—ィル)メチル）ゥレア  (Pyridine-3-yl) -1H-imidazole-2-yl) methyl) urea
N— (5—（ピリジンー2—ィルチオ）チアゾールー 2—ィル）—1H—イミダゾール — 1—カルボキシアミド 30mg(0. lOmmol)をテトラヒドロフラン lmLに溶解し、（4— (ピリジンー3 ィル）—1H—イミダゾールー 2 ィル)メチルァミン塩酸塩 34mg(0. 12mmol)、 N, N，—ジイソプロピルェチルァミン 61 L(0.36mmol)を加え、室温 で終夜攪拌した。混合溶液に飽和食塩水を加え、クロ口ホルムで抽出後、硫酸ナトリ ゥムにて乾燥した。減圧濃縮後、残渣を P—TLC (クロ口ホルム Zメタノール Zアンモ ニァ水 = 5ZlZO.1)にて精製し、標記化合物を得た（5.5mg、 13%)。 N— (5- (Pyridin-2-ylthio) thiazol-2-yl) -1H-imidazole — 1-carboxamide 30 mg (0. lOmmol) is dissolved in 1 mL of tetrahydrofuran to give (4- (Pyridine-3-yl) -1H -Imidazole-2-yl) methylamine hydrochloride 34 mg (0.12 mmol), N, N, -diisopropylethylamine 61 L (0.36 mmol) was added, and the mixture was stirred at room temperature overnight. Saturated saline was added to the mixed solution, followed by extraction with black mouth form, followed by drying over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol Z ammonia water = 5 ZlZO.1) to obtain the title compound (5.5 mg, 13%).
— NMR(CD OD)： δ 8.91 (1Η, s) , 8.38— 8.33 (2H, m), 8.15(1H, d  — NMR (CD OD): δ 8.91 (1Η, s), 8.38— 8.33 (2H, m), 8.15 (1H, d
3  Three
, J = 8.0 Hz), 7.67(1H, dd, J=7.6 Hz, J = 7.6 Hz), 7.56— 7.54 (2H , m), 7.43(1H, dd, J = 8.3 Hz, J = 5.0 Hz), 7.14(1H, dd, J = 8.0 Hz , J = 7. 6 Hz), 7. 08(1H, d, J = 8. 3 Hz), 4. 55 (2H, s)、 MS(ESI+) :410( M+ + 1) , J = 8.0 Hz), 7.67 (1H, dd, J = 7.6 Hz, J = 7.6 Hz), 7.56— 7.54 (2H, m), 7.43 (1H, dd, J = 8.3 Hz, J = 5.0 Hz), 7.14 (1H, dd, J = 8.0 Hz , J = 7.6 Hz), 7.08 (1H, d, J = 8.3 Hz), 4.55 (2H, s), MS (ESI +): 410 (M ++ 1)
[0106] 実施例 50〜51の化合物は前記実施例 29と同様の方法で、実施例 52〜53は実 前記施例 25と同様の方法で製造した。  [0106] The compounds of Examples 50 to 51 were produced in the same manner as in Example 29, and Examples 52 to 53 were produced in the same manner as in Example 25.
[0107] [実施例 54]2—（4 (2-((3- (5 （モルフオリノメチル）チアゾールー 2 ィル）ゥ レイド)メチル）— 1H—イミダゾール— 4—ィル）フヱノキシ）酢酸ナトリウム塩  [Example 54] 2- (4 (2-((3- (5 (morpholinomethyl) thiazole-2-yl) ureido) methyl)-1H-imidazole-4-yl) phenoxy) acetic acid Sodium salt
1一（（4一（4一（（エトキシカルボ-ル)メチルォキシ）フエ-ル）一 1H—イミダゾー ルー 2—ィル)メチル）—3— (5— (モルフオリノメチル）チアゾール—2—ィル）ゥレア 2 lmg(0. 042mmol)をエタノール lmLに溶解し、 1N水酸化ナトリウム水溶液 210 L(0. 21mmol)を加え、室温で三時間攪拌した。混合溶液を減圧濃縮後、 HP— 20 にて精製し、標記化合物を得た（12mg、 59%) o  1 1 ((4 1 (4 ((ethoxycarbol) methyloxy) phenol) 1 1H-imidazole 2-yl) methyl) —3— (5— (morpholinomethyl) thiazole—2— 2 lmg (0.042 mmol) of yl) urea was dissolved in 1 mL of ethanol, 210 L (0.21 mmol) of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 3 hours. The mixed solution was concentrated under reduced pressure and purified with HP-20 to obtain the title compound (12 mg, 59%).
'H-NMRCDMSO-d ) : 67. 74(1H, br), 7. 54 (2H, d, J = 8. 5 Hz), 7.  'H-NMRCDMSO-d): 67. 74 (1H, br), 7. 54 (2H, d, J = 8.5 Hz), 7.
6  6
18(1H, s), 7. 10(1H, s), 6. 79 (2H, d, J = 8. 5 Hz), 4. 36 (2H, d, J = 8. 5 18 (1H, s), 7.10 (1H, s), 6. 79 (2H, d, J = 8.5 Hz), 4.36 (2H, d, J = 8.5
Hz), 4. 32 (2H, s), 3. 56 (6H, br), 2. 35 (4H, br)、 MS(ESI+) :473 (M+ +1) Hz), 4.32 (2H, s), 3.56 (6H, br), 2.35 (4H, br), MS (ESI +): 473 (M + +1)
[0108] [実施例 55] 1— ((4 フエ-ルー 1H—イミダゾールー 2—ィル)メチル）—3 プロ ピルウレァ  [Example 55] 1 — (((4 FE-LUE 1H-imidazol-2-yl) methyl) -3 propylurea
(4 フエ-ルー 1H—イミダゾールー 2 ィル)メチルァミン塩酸塩 9. 3mg(0. 038 mmol)をテトラヒドロフランに溶解し、プロピルイソシアナ一ト 2.4μL·(0. 025mmol )、 N, N，—ジイソプロピルェチルァミン 13 1^(0. 075mmol)を加え、室温にて三 時間攪拌した。混合溶液に飽和食塩水を加え、酢酸ェチルで抽出後、硫酸ナトリウ ムにて乾燥した。減圧濃縮後、残渣を P— TLC (クロ口ホルム Zメタノール =10Zl) にて精製し、標記化合物を得た（8. 6mg、 quant. )0 MS (EI+)： 258 (M+) Dissolve 9.3 mg (0.038 mmol) of (4 ferro- 1H-imidazole-2-yl) methylamine hydrochloride in tetrahydrofuran, 2.4 μL propyl isocyanate (0.025 mmol), N, N, -diisopropyl Ethylamine 13 1 ^ (0. 075 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Saturated saline was added to the mixed solution, and the mixture was extracted with ethyl acetate and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P—TLC (black mouth form Z methanol = 10 Zl) to obtain the title compound (8.6 mg, quant.) 0 MS (EI +): 258 (M +)
[0109] 実施例 56の化合物は後記する実施例 302と同様の方法により、実施例 57の化合 物は前記実施例 55と同様の方法により、実施例 58〜62の化合物は前記実施例 29 と同様の方法により、実施例 63〜64の化合物は後記する実施例 302と同様の方法 により製造した。 [0109] The compound of Example 56 was prepared in the same manner as in Example 302 described later, the compound of Example 57 was treated in the same manner as in Example 55, and the compounds of Examples 58 to 62 were synthesized in the same manner as in Example 29. In the same manner, the compounds of Examples 63 to 64 were produced in the same manner as in Example 302 described later.
[0110] [実施例 65]1—メチルー 3—（（4 フエ-ルー 1H イミダゾールー 2 ィル)メチル） ゥレア [0110] [Example 65] 1-Methyl-3-(((4 ferro- 1H imidazole-2 yl) methyl) Urea
トリホスゲン 9. 8mg(0. O33mmol)を塩化メチレンに溶解し、（4 フエ-ル— 1H —イミダゾールー 2—ィル)メチルァミン塩酸塩 24. 6mg(0. lOmmol)及び N, N，— ジイソプロピルェチルァミン 58 μ L (0. 35mmol)の塩化メチレン溶液を滴下し、室温 にて五分間攪拌した。混合溶液に 2Mメチルァミン Zテトラヒドロフラン溶液 75 L(0 . 15mmol)を加え、室温にて四時間攪拌し、再度 2Mメチルァミン/テトラヒドロフラ ン溶液 150 1^(0. 30mmol)をカ卩え、室温にて終夜攪拌した。混合溶液に飽和食 塩水を加え、クロ口ホルムで抽出後、硫酸ナトリウムにて乾燥した。減圧濃縮後、残渣 を P— TLC (クロ口ホルム Zメタノール =5Zl)にて精製し、標記化合物を得た（7. 0 mg、 30%) o MS(ESI+) :231(M+ + 1)  Dissolve 9.8 mg (0. O33 mmol) of triphosgene in methylene chloride and add 24.6 mg (0. lOmmol) of (4 phenol-1H -imidazole-2-yl) methylamine hydrochloride and N, N,-diisopropylethyl. A solution of 58 μL of amine (0.35 mmol) in methylene chloride was added dropwise, and the mixture was stirred at room temperature for 5 minutes. Add 75 L (0.15 mmol) of 2M methylamine Z tetrahydrofuran solution to the mixed solution, stir at room temperature for 4 hours, and again add 2M methylamine / tetrahydrofuran solution 150 1 ^ (0.30 mmol) at room temperature overnight. Stir. Saturated saline was added to the mixed solution, extracted with black mouth form, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol = 5Zl) to obtain the title compound (7.0 mg, 30%) o MS (ESI +): 231 (M ++ 1)
[0111] 実施例 66の化合物は前記実施例 65と同様の方法により、実施例 67化合物は前 記実施例 29と同様の方法により、実施例 68化合物は前記実施例 25と同様の方法 により、実施例 69〜70化合物は前記実施例 29と同様の方法により製造した。  [0111] The compound of Example 66 was prepared by the same method as in Example 65, the compound of Example 67 was prepared by the same method as in Example 29, and the compound of Example 68 was prepared by the same method as in Example 25. Examples 69 to 70 The compounds were prepared in the same manner as in Example 29.
[0112] [実施例 71] 1—（（4 フエ-ルー 1H—イミダゾールー 2 ィル)メチル）ー3—（3 （フエ-ルチオ）プロピル）ゥレア  [0112] [Example 71] 1-(((4 FE-LUE 1H-imidazole-2-yl) methyl) -3-((3 (FE-thio) propyl) urea)
前記実施例 66で得た化合物 7. 8mg(0. 0284mmol)をテトラヒドロフランに溶解し 、 0。Cにて、トリブチルホスフィン 21. 2μL·(0. 0852mmol)、ァゾジカルボン酸ジェ チル 10. 3μL·(0. 0568mmol)、ジフエ-ルジスルフイド 9. 3mg(0. 0427mmol) を加え、室温にて三時間攪拌した。混合溶液を減圧濃縮して得られる残渣を P—TL C (クロ口ホルム Zメタノール =20Z1X3回）にて精製し、標記化合物を得た（5.4m g、 52%) o 7.8 mg (0.0284 mmol) of the compound obtained in Example 66 was dissolved in tetrahydrofuran. In C, add 21.2 μL of tributylphosphine (0.0852 mmol), 10.3 μL of azodicarboxylate (0.0568 mmol), and 9.3 mg (0.0427 mmol) of diphenyl disulfide, and stir at room temperature for 3 hours. did. The residue obtained by concentrating the mixed solution under reduced pressure was purified by P-TL C (black mouth form Z methanol = 20Z1X3 times) to obtain the title compound (5.4 mg, 52%) o
— NMR(CDC1 ) : 67. 62 (2H, d, J = 7. 6 Hz), 7. 38— 7. 14 (9H, m)、  — NMR (CDC1): 67. 62 (2H, d, J = 7.6 Hz), 7. 38— 7. 14 (9H, m),
3  Three
4. 32(2H, s)、 3. 26(2H, t, J = 6. 6 Hz)、 2. 90(2H, t, J = 7. 1 Hz), 1. 81 4.32 (2H, s), 3.26 (2H, t, J = 6. 6 Hz), 2.90 (2H, t, J = 7.1 Hz), 1. 81
—1. 75 (2H, m)、 MS(EI+) :366(M+) —1.75 (2H, m), MS (EI +): 366 (M +)
[0113] 実施例 72の化合物は前記実施例 29と同様の方法で製造した。 [0113] The compound of Example 72 was produced in the same manner as in Example 29.
[0114] [実施例 73]1—（（4一（4 ブロモフエ-ル） 1H イミダゾールー 2 ィル)メチ ル）ー3—（5 （ピリジン 2—ィルチオ）チアゾールー 2 ィル）ゥレア [0114] [Example 73] 1-((4 (4-bromophenol) 1H imidazole-2-yl) methyl) -3- (5 (pyridine-2-ylthio) thiazole-2-yl) urea
N— (5—（ピリジンー2—ィルチオ）チアゾールー 2—ィル）—1H—イミダゾール — 1—カルボキシアミド 30mg(0. lOmmol)をテトラヒドロフラン lmLに溶解し、（4— (4 ブロモフエ-ル） 1H—イミダゾール 2 ィル）メチルァミン塩酸塩 36mg (0. llmmol)、 N, N，—ジイソプロピルェチルァミン 37 L(0.22mmol)を加え、室温 で終夜攪拌した。混合溶液に飽和食塩水を加え、クロ口ホルムで抽出後、硫酸ナトリ ゥムにて乾燥した。減圧濃縮して得られる固体をクロ口ホルム Zメタノール混合溶液 で洗浄し、標記化合物を得た（17mg、 34%) oN— (5- (Pyridine-2-ylthio) thiazole-2-yl) —1H-imidazole — Dissolve 30 mg (0.1 mmol) of 1-carboxamide in 1 mL of tetrahydrofuran, and add (4— (4 bromophenol) 1H-imidazole 2 yl) methylamine hydrochloride 36 mg (0.1 mmol), N, N, —diisopropyl Ethylamine 37 L (0.22 mmol) was added, and the mixture was stirred at room temperature overnight. Saturated saline was added to the mixed solution, followed by extraction with black mouth form, followed by drying over sodium sulfate. The solid obtained by concentration under reduced pressure was washed with Kuroguchi Form Z methanol mixed solution to obtain the title compound (17 mg, 34%) o
— NMR(CDC1 /CD OD)： δ 8.38— 8.36 (1Η, m), 7.58— 7.49 (6H,  — NMR (CDC1 / CD OD): δ 8.38— 8.36 (1Η, m), 7.58— 7.49 (6H,
3 3  3 3
m), 7.23 (1H, s), 7.09 (1H, ddd, J = 8.2 Hz, J = 7.6 Hz, J = 0.6 Hz), 7.01 (1H, dd, J = 8.2 Hz, J = 0.6 Hz), 4.47 (2H, s)、 MS (FAB+) :487( M+ + 1)  m), 7.23 (1H, s), 7.09 (1H, ddd, J = 8.2 Hz, J = 7.6 Hz, J = 0.6 Hz), 7.01 (1H, dd, J = 8.2 Hz, J = 0.6 Hz), 4.47 (2H, s), MS (FAB +): 487 (M ++ 1)
[0115] 実施例 74〜75の化合物は前記実施例 29と同様の方法で、実施例 76の化合物は 実前記施例 25と同様の方法で製造した。  [0115] The compounds of Examples 74 to 75 were prepared in the same manner as in Example 29, and the compound of Example 76 was actually prepared in the same manner as in Example 25.
[0116] [実施例 77] 1—（（4一（3 （（エトキシカルボ-ル）メチルォキシ）フエ-ル） 1H イミダゾールー 2 ィル)メチル） 3—（5 （ピリジン 2—ィルチオ）チアゾール 2—ィル）ゥレア [0116] [Example 77] 1-((4 (3 ((ethoxycarbol) methyloxy) phenol) 1H imidazole-2-yl) methyl) 3- (5 (pyridine 2-ylthio) thiazole 2— Ill) Urea
本実施例の化合物は前記実施例 29と同様の方法で製造した。  The compound of this example was produced in the same manner as in Example 29.
'H-NMRCCD OD)： δ 8.33 (1Η, m), 7.64 (1H, m), 7.54 (1H, s), 7.  'H-NMRCCD OD): δ 8.33 (1Η, m), 7.64 (1H, m), 7.54 (1H, s), 7.
3  Three
34 (1H, s), 7.24-7.30 (3H, complex) , 7.14 (1H, m), 7.06 (1H, m), 6 .79(1H, m), 4.71 (2H, s), 4.53 (2H, s), 4.24 (2H, q, J = 7.1 Hz), 1.2 7(3H, t, J = 7.1 Hz)、 MS(FAB+) :511(M+ + 1)  34 (1H, s), 7.24-7.30 (3H, complex), 7.14 (1H, m), 7.06 (1H, m), 6.79 (1H, m), 4.71 (2H, s), 4.53 (2H, s), 4.24 (2H, q, J = 7.1 Hz), 1.2 7 (3H, t, J = 7.1 Hz), MS (FAB +): 511 (M + + 1)
[0117] [実施例 78]1— ((4— (3—メトキシフエ-ル）— 1H—イミダゾール— 2—ィル)メチ ル）ー3—（5 （ピリジン 2—ィルチオ）チアゾールー 2 ィル）ゥレア [0117] [Example 78] 1- ((4- (3-Methoxyphenyl)-1H-imidazole-2-yl) methyl) -3- (5 (pyridine-2-ylthio) thiazole-2-yl) Urea
本実施例の化合物は前記実施例 29と同様の方法で製造した。  The compound of this example was produced in the same manner as in Example 29.
一 NMR(CD OD)： δ 8.34 (1Η, m) , 7.65 (1H, m), 7.54 (1H, s), 7.  NMR (CD OD): δ 8.34 (1Η, m), 7.65 (1H, m), 7.54 (1H, s), 7.
3  Three
33 (1H, s), 7.23-7.27 (3H, complex) , 7.14(1H, dd, J = 7.6 Hz, J=l. 0 Hz), 7.07(1H, dt, J = 7. 1 Hz, J = 0.9 Hz), 6.79(1H, m), 4.53 (2H , s), 3.82 (3H, s)、 MS(ESI+) :439(M+ + 1)  33 (1H, s), 7.23-7.27 (3H, complex), 7.14 (1H, dd, J = 7.6 Hz, J = l. 0 Hz), 7.07 (1H, dt, J = 7.1 Hz, J = 0.9 Hz), 6.79 (1H, m), 4.53 (2H, s), 3.82 (3H, s), MS (ESI +): 439 (M ++ 1)
[0118] 実施例 79の化合物は後記する実施例 302と同様の方法で製造した。 [0119] [実施例 80] [0118] The compound of Example 79 was produced in the same manner as in Example 302 described later. [0119] [Example 80]
2- (3— (2-((3- (5 （ピリジン 2—ィルチオ）チアゾールー 2 ィル）ウレイド) メチル） 1H—イミダゾールー 4 ィル）フエノキシ）酢酸ナトリウム塩  2- (3-— (2-((3- (5 (pyridine 2-ylthio) thiazole-2-yl) ureido) methyl) 1H-imidazole-4-yl) phenoxy) acetic acid sodium salt
前記実施例 77で得た化合物 10.6mgを用い、前記実施例 25と同様の方法で標 記化合物 6. lmgを得た。 Using 10.6 mg of the compound obtained in Example 77, 6. lmg of the title compound was obtained in the same manner as in Example 25.
— NMR(CD OD)： δ 8.25 (1H, m) , 7.60 (1H, m), 7.45 (1H, s), 7.  — NMR (CD OD): δ 8.25 (1H, m), 7.60 (1H, m), 7.45 (1H, s), 7.
3  Three
25 (1H, s), 7.09-7.19 (4H, complex) , 6.98 (1H, d, J = 7.3 Hz), 6.72 (1H, m)4.45 (2H, s), 4.32 (2H, s)、 MS (FAB+) : 505 (M+ + 1)  25 (1H, s), 7.09-7.19 (4H, complex), 6.98 (1H, d, J = 7.3 Hz), 6.72 (1H, m) 4.45 (2H, s), 4.32 (2H, s), MS ( FAB +): 505 (M + + 1)
[0120] [実施例 81] l-((4-(4-(2- (tert ブトキシカルボ-ル）ェチル）フエ-ル） 1H—イミダゾールー 2 ィル)メチル）ー3—（5 （ピリジン 2—ィルチオ）チアゾー ルー 2—ィル）ゥレア [0120] [Example 81] l-((4- (4- (2- (tert-butoxycarbol) ethyl) phenol) 1H-imidazole-2-yl) methyl) -3- (5 (pyridine 2 —Ilchio) thiazo ru 2—il) urea
1— ((1— ((2 トリメチルシリル)エトキシ)メチル）—4— (4— (2— (tert—ブトキ シカルボ-ル）ェチル）フエ-ル）— 1H—イミダゾールー 2—ィル）メチル）—3— (5— (ピリジン— 2—ィルチオ）チアゾール—2—ィル）ゥレア 18mg(0.27mmol)をテトラ ブチルアンモ -ゥムフロリド Zテトラヒドロフラン（1M溶液） 0.53mL(0.53mmol)に 溶解し、 80°Cにて五時間攪拌した。混合溶液に飽和塩化アンモ-ゥム溶液を加え、 酢酸ェチルで抽出後、硫酸ナトリウムにて乾燥した。減圧濃縮後、残渣を P— TLC( クロ口ホルム Zメタノール =10Zl)にて精製し、標記化合物を得た（13mg、 90%) o — NMR(CDC1 /CD OD)： δ 8.39— 8.37(1Η, m), 7.56— 7.52 (4Η,  1 — ((1 — ((2 trimethylsilyl) ethoxy) methyl) —4— (4— (2— (tert-butoxycarbonyl) ethyl) phenol) — 1H-imidazole-2-yl) methyl) — 3- (5- (Pyridin-2-ylthio) thiazol-2-yl) urea 18mg (0.27mmol) was dissolved in tetrabutylammonium fluoride Ztetrahydrofuran (1M solution) 0.53mL (0.53mmol) at 80 ° C And stirred for 5 hours. Saturated ammonium chloride solution was added to the mixed solution, extracted with ethyl acetate, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P—TLC (black mouth form Z methanol = 10 Zl) to obtain the title compound (13 mg, 90%) o—NMR (CDC1 / CD OD): δ 8.39— 8.37 (1Η) , m), 7.56— 7.52 (4Η,
3 3  3 3
m), 7.22 (2Η, d, J = 8.1 Hz), 7.08— 7.06 (1H, m), 7.00(1H, d, J = 8. 2 Hz), 4.46 (2H, s), 2.91 (2H, t, J = 7.8 Hz), 2.56(2H, t, J = 7.8 Hz )、 MS(ESI+) :537(M+ + 1)  m), 7.22 (2Η, d, J = 8.1 Hz), 7.08— 7.06 (1H, m), 7.00 (1H, d, J = 8.2 Hz), 4.46 (2H, s), 2.91 (2H, t , J = 7.8 Hz), 2.56 (2H, t, J = 7.8 Hz), MS (ESI +): 537 (M + + 1)
[0121] [実施例 82]1—（（4一（3 ブロモフエ-ル） 1H イミダゾールー 2 ィル)メチ ル）ー3—（5 （ピリジン 2—ィルチオ）チアゾールー 2 ィル）ゥレア [0121] [Example 82] 1-((4 (3-bromophenol) 1H imidazole-2-yl) methyl) -3- (5 (pyridine-2-ylthio) thiazole-2-yl) urea
N— (5—（ピリジンー2—ィルチオ）チアゾールー 2—ィル）—1H—イミダゾール — 1—カルボキシアミド 15mg(0.050mmol)をテトラヒドロフラン lmLに溶解し、 （4 - (3 ブロモフエ-ル）— 1H—イミダゾール— 2—ィル)メチルァミン塩酸塩 18mg( 0.055mmol)、N, N，—ジイソプロピルェチルァミン 19 L(0. llmmol)をカロえ、 室温で五時間攪拌した。混合溶液に飽和塩化アンモ-ゥム溶液を加え、クロ口ホル ムで抽出後、硫酸ナトリウムにて乾燥した。減圧濃縮後、残渣をシリカゲルクロマトグ ラフィー（クロ口ホルム Zメタノール =15Zl)にて精製し、標記化合物を得た（llmg 、45%)。N— (5- (Pyridin-2-ylthio) thiazol-2-yl) -1H-imidazole 1-carboxamide 15 mg (0.050 mmol) was dissolved in 1 mL of tetrahydrofuran, and (4- (3 bromophenol) — 1H— Imidazole-2-yl) methylamine hydrochloride 18 mg (0.055 mmol), N, N, -diisopropylethylamine 19 L (0. llmmol) Stir at room temperature for 5 hours. Saturated ammonium chloride solution was added to the mixed solution, extracted with chloroform, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (black mouth form Z methanol = 15 Zl) to obtain the title compound (llmg, 45%).
— NMR(CDC1 /CD OD)： δ 8.39— 8.37(1Η, m), 7.82(1Η, brs), 7  — NMR (CDC1 / CD OD): δ 8.39— 8.37 (1Η, m), 7.82 (1Η, brs), 7
3 3  3 3
.58-7.52 (3Η, m), 7.39— 7.37(1Η, m), 7.27— 7.23 (2Η, m), 7.08 -7.06 (1H, m), 7.00(1H, d, J = 8.3 Hz), 4.46 (2H, s)、 MS(FAB+) :4 87(M+ + 1) .58-7.52 (3Η, m), 7.39— 7.37 (1Η, m), 7.27— 7.23 (2Η, m), 7.08 -7.06 (1H, m), 7.00 (1H, d, J = 8.3 Hz), 4.46 (2H, s), MS ( FAB +): 4 87 (M + + 1)
[0122] 実施例 83の化合物は後記する実施例 84と同様の方法で製造した。  [0122] The compound of Example 83 was produced in the same manner as in Example 84 described later.
[0123] [実施例 84](E)-1- (5-ブロモチアゾール -2-ィル) -3- ((4- (4- (2- (3- (2,6-ジクロロべ ンジル )-2-メチル -4-ォキソピリジン- 1(4H)-ィル）ビニル）フエ-ル) -1H-イミダゾー ル -2-ィル）メチル）ゥレア [Example 84] (E) -1- (5-Bromothiazol-2-yl) -3-((4- (4- (2- (3- (2,6-dichlorobenzen)) -2-methyl-4-oxopyridine-1 (4H) -yl) vinyl) phenol) -1H-imidazole-2-yl) methyl) urea
N— (5—ブロモチアゾール—2—ィル） 1H—イミダゾールー 1—カルボキシアミ ド 14mg(0.050mmol)に（4—(4—((1Ε)—2—(3—(2, 6 ジクロ口ベンジル） 2—メチル 4—ォキソピリジン一 1 (4H)—ィル）ビュル）フエ-ル） 1H—イミダゾー ルー 2 ィル）メチルァミンの N, N ジメチルホルムアミド溶液（0.5mL + 0.5mL) を加え、室温で一時間攪拌した。混合溶液にへキサン Z酢酸ェチルをカ卩え、ろ取し 、へキサン Z酢酸ェチルで洗浄し、標記化合物を得た（22mg、 63%) o N— (5-Bromothiazole-2-yl) 1H-imidazole 1-carboxyamide 14 mg (0.050 mmol) to (4- (4 -— ((1Ε) —2— (3 -— (2, 6 Diclonal benzyl) ) 2-Methyl 4-oxopyridine 1 (4H) -yl) Bue) Fuel) 1H-Imidazolu 2 yl) Add N, N dimethylformamide solution (0.5 mL + 0.5 mL) of methylamine at room temperature. Stir for 1 hour. To the mixed solution was added hexane Z ethyl acetate, filtered and washed with hexane Z ethyl acetate to obtain the title compound (22 mg, 63%).
— NMR(DMSO— d )： δ 7.90(1H, d, J = 7.6 Hz), 7.76 (2H, d, J = 8  — NMR (DMSO— d): δ 7.90 (1H, d, J = 7.6 Hz), 7.76 (2H, d, J = 8
6  6
.0 Hz), 7.64— 7.52 (4H, m), 7.41— 7.38 (3H, m), 7.23(1H, t, J = 8. 0 Hz), 7.10(1H, br), 6.82(1H, d, J=13.6 Hz), 6. 10(1H, d, J = 7.6 Hz) , 4.39 (1H, d, J=4.8 Hz) , 4.16 (2H, s) , 2.23 (3H, s)、 MS (FAB+) :669(M+ + 1)  .0 Hz), 7.64— 7.52 (4H, m), 7.41— 7.38 (3H, m), 7.23 (1H, t, J = 8.0 Hz), 7.10 (1H, br), 6.82 (1H, d, J = 13.6 Hz), 6.10 (1H, d, J = 7.6 Hz), 4.39 (1H, d, J = 4.8 Hz), 4.16 (2H, s), 2.23 (3H, s), MS (FAB +) : 669 (M ++ 1)
[0124] [実施例 85] 1—（5 ブロモチアゾールー 2 ィル） 3—（（4一（4一（3—（3—（2, 6 ジクロロベンジル） 2—メチル 4—ォキソピリジン一 1 (4H)—ィル）プロピル） フエ-ル） 1H—イミダゾールー 2—ィル）メチル）ゥレア  [0124] [Example 85] 1— (5 Bromothiazole-2-yl) 3 — ((4 1 (4 1 (3— (3— (2, 6 dichlorobenzyl) 2 —methyl 4-oxopyridine 1 1 ( 4H) —yl) propyl) file) 1H—imidazole 2—yl) methyl) urea
N— (5—ブロモチアゾール—2—ィル）—1H—イミダゾールー 1—カルボキシアミド 11.4mg(0.042mmol)を N, N—ジメチルホルムアミド lmLに溶解し、（4— (4— ( 3- (3- (2, 6 ジクロロベンジル） 2—メチル 4—ォキソピリジン一 1(4H)—ィ ル）プロピル）フエ-ル） 1H—イミダゾールー 2 ィル)メチルァミン塩酸塩 27mg (0 .046mmol)、N, N，—ジイソプロピルェチルァミン 29 L(0.168mmol)を加え、 室温で 1.5時間攪拌した。混合溶液に飽和食塩水を加え、クロ口ホルムで抽出後、 硫酸ナトリウムにて乾燥した。減圧濃縮後、残渣を P— TLC (クロ口ホルム Zメタノー ル Zアンモニア水 = 5ZlZ0.05)にて精製し、標記化合物を得た（20mg、 71%) — NMR(CD OD)： δ 7.90(1H, s) , 7.69(1Η, d, J = 7.6 Hz), 7.59(2 N— (5-Bromothiazole-2-yl) —1H—imidazole 1-carboxamide 11.4 mg (0.042 mmol) is dissolved in 1 mL of N, N-dimethylformamide, and (4— (4— ( 3- (3- (2,6dichlorobenzyl) 2-methyl 4-oxopyridine 1 (4H) -yl) propyl) phenol) 1H-imidazole-2-yl) methylamine hydrochloride 27 mg (0.046 mmol), N, N, -Diisopropylethylamine 29 L (0.168 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. Saturated saline was added to the mixed solution, extracted with black mouth form, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol Z ammonia water = 5ZlZ0.05) to obtain the title compound (20 mg, 71%) — NMR (CD OD): δ 7.90 ( 1H, s), 7.69 (1Η, d, J = 7.6 Hz), 7.59 (2
3  Three
H, d, J=8.4 Hz), 7.33-7.29 (3H, m), 7.25(1H, s), 7. 19— 7.15(3H , m), 6.35 (2H, d, J = 7.6 Hz), 4.51 (2H, s), 4.32 (2H, s), 3.99 (2H, t , J = 7.2 Hz), 2.62 (2H, t, J = 7.2 Hz), 2.08 (3H, s), 2.05— 1.97 (2H , m)、 MS (FAB+)： 685 (M+ + 1)  H, d, J = 8.4 Hz), 7.33-7.29 (3H, m), 7.25 (1H, s), 7. 19— 7.15 (3H, m), 6.35 (2H, d, J = 7.6 Hz), 4.51 (2H, s), 4.32 (2H, s), 3.99 (2H, t, J = 7.2 Hz), 2.62 (2H, t, J = 7.2 Hz), 2.08 (3H, s), 2.05— 1.97 (2H, m), MS (FAB +): 685 (M ++ 1)
[実施例 86](E)-1- ((4- (4- (3- (3- (2,6-ジクロロベンジル) -2-メチル -4-ォキソピリジン -1(4H)-ィル)プロプ- 1-ェ -ル)フエ-ル)- 1H-イミダゾール- 2-ィル)メチル )-3- (5- (メ チルチオ)チアゾール -2-ィル)ゥレア  [Example 86] (E) -1-((4- (4- (3- (3- (2,6-dichlorobenzyl) -2-methyl-4-oxopyridine-1 (4H) -yl) prop -1-phenyl) phenol) -1H-imidazol-2-yl) methyl) -3- (5- (methylthio) thiazol-2-yl) urea
N- (5—メチルチオチアゾールー 2—ィル）—1H—イミダゾールー 1 カルボキ シアミド 10mg(0.042mmol)をテトラヒドロフラン、塩化メチレン、 N, N，一ジメチル ホルムアミドの混合溶液 2mLに溶解し、 (4-(4-((1Ε)-(3-(2, 6 ジクロロべ ンジル） 2—メチル 4—ォキソピリジン一 1(4H)—ィル）プロプ一 1—ェニル）フエ -ル）—1H—イミダゾールー 2 ィル）メチルァミン塩酸塩 27mg(0.046mmol)、 N , Ν，—ジイソプロピルェチルァミン 43 L(0.25mmol)をカ卩え、室温で 1.5時間攪 拌した。混合溶液に飽和食塩水を加え、酢酸ェチルで抽出後、硫酸ナトリウムにて乾 燥した。減圧濃縮後、残渣を P—TLC (クロ口ホルム Zメタノール Zアンモニア水 =5 /1/0.05)にて精製し、標記化合物を得た（10mg、 37%) o 10 mg (0.042 mmol) of N- (5-methylthiothiazol-2-yl) -1H-imidazole-1 carboxamide was dissolved in 2 mL of a mixed solution of tetrahydrofuran, methylene chloride, N, N, and dimethylformamide, and (4- ( 4-((1Ε)-(3- (2,6 dichlorobenzyl) 2-methyl 4-oxopyridine 1 (4H) -yl) prop 1-enyl) phenol) -1H-imidazole 2 yl ) Methylamine hydrochloride 27 mg (0.046 mmol), N 2, Ν, -diisopropylethylamine 43 L (0.25 mmol) were added and stirred at room temperature for 1.5 hours. Saturated saline was added to the mixed solution, extracted with ethyl acetate, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol Z aqueous ammonia = 5/1 / 0.05) to obtain the title compound (10 mg, 37%) o
— NMR(CD OD)： δ 7.76 (1Η, d, J = 7.4 Hz), 7.63 (2H, d, J = 8.4  — NMR (CD OD): δ 7.76 (1Η, d, J = 7.4 Hz), 7.63 (2H, d, J = 8.4
3  Three
Hz), 7.36-7.27 (6H, m), 7.14(1H, t, J = 8.0 Hz), 6.41 (1H, d, J = 7 .4 Hz), 6.33 (1H, dt, J=16 Hz, J=4.8 Hz), 6.18 (1H, d, J=16 Hz) , 4.80-4.78 (2H, m), 4.52 (2H, s), 4.37 (2H, s), 2.38 (3H, s), 2.20 ( 3H, s)、 MS(ESI+) :651(M+ + 1) Hz), 7.36-7.27 (6H, m), 7.14 (1H, t, J = 8.0 Hz), 6.41 (1H, d, J = 7.4 Hz), 6.33 (1H, dt, J = 16 Hz, J = 4.8 Hz), 6.18 (1H, d, J = 16 Hz), 4.80-4.78 (2H, m), 4.52 (2H, s), 4.37 (2H, s), 2.38 (3H, s), 2.20 ( 3H, s), MS (ESI +): 651 (M ++ 1)
[0126] [実施例 87]1—（（4一（4 ブロモフエ-ル） 1H—イミダゾールー 2 ィル)メチル） [Example 87] 1-(((4- (4-bromophenol) 1H-imidazole-2-yl) methyl)
3—（5—メチルチオチアゾールー 2 ィル）ゥレア  3— (5-Methylthiothiazole-2 yl) urea
N— (5—メチルチオチアゾールー 2—ィル）—1H—イミダゾールー 1 カルボキシ アミド 12mg(0. O50mmol)をテトラヒドロフラン lmLに溶解し、（4— (4 ブロモフエ -ル）—1H—イミダゾールー 2 ィル）メチルァミン塩酸塩 18mg(0. O55mmol)、 N , Ν，—ジイソプロピルェチルァミン 19 L(0. llmmol)をカ卩え、室温で終夜攪拌し た。混合溶液に飽和食塩水を加え、クロ口ホルムで抽出後、硫酸ナトリウムにて乾燥 した。減圧濃縮後、残渣を P— TLC (クロ口ホルム Zメタノール =10Zl)にて精製し 、標記化合物を得た（21mg、 99%) o  N- (5-Methylthiothiazol-2-yl) -1H-imidazole-1 Carboxamide 12 mg (0. O50 mmol) was dissolved in 1 mL of tetrahydrofuran, and (4- (4 bromophenol) -1H-imidazole-2-yl) Methylamine hydrochloride 18 mg (0. 55 mmol), N 2, Ν, -diisopropylethylamine 19 L (0. 1 mmol) was added and stirred at room temperature overnight. Saturated saline was added to the mixed solution, extracted with black mouth form, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol = 10 Zl) to obtain the title compound (21 mg, 99%) o
'H-NMRCDMSO-d )： δ 7.71 (2Η, d, J = 8.0 Hz) , 7.61 (1H, brs) , 7  'H-NMRCDMSO-d): δ 7.71 (2Η, d, J = 8.0 Hz), 7.61 (1H, brs), 7
6  6
.51 (2H, d, J = 8.0 Hz), 7.34(1H, s), 7.12(1H, brs), 4.39 (2H, d, J = 5.2 Hz), 2.37(3H, s)、 MS(FAB+) :424(M+ + 1)  .51 (2H, d, J = 8.0 Hz), 7.34 (1H, s), 7.12 (1H, brs), 4.39 (2H, d, J = 5.2 Hz), 2.37 (3H, s), MS (FAB +) : 424 (M +++ 1)
[0127] [実施例 88](E)-1- ((4- (4- (2- (3- (2,6-ジクロロベンジル) -2-メチル -4-ォキソピリジン- 1(4H)-ィル)ビュル)フエ-ル)- 1H-イミダゾール- 2-ィル)メチル )-3- (5- (ピリジン- 2-ィ ルチオ)チアゾール -2-ィル)ゥレア [Example 88] (E) -1-((4- (4- (2- (3- (2,6-dichlorobenzyl) -2-methyl-4-oxopyridine-1 (4H) -i B) Buyl) Fuel) -1H-imidazol-2-yl) methyl))-3- (5- (Pyridin-2-ylthio) thiazol-2-yl) urea
N- (5 （ピリジン 2—ィルチオ）チアゾールー 2 ィル） 1H—イミダゾールー 1 —カルボキシアミド 12mg(0. O38mmol)を N, N，—ジメチルホルムアミド lmLに溶 解し、 (4-(4-((1Ε)-(3-(2, 6 ジクロロベンジル） 2—メチル 4—ォキソピ リジン—1(4H) ィル）プロプー 1ーェ -ル）フエ-ル） 1H—イミダゾールー 2—ィ ル)メチルァミン塩酸塩 25mg(0.042mmol)、N, N, ジイソプロピルェチルァミン 26/zL(0. 15mmol)を加え、室温で二時間攪拌した。混合溶液に飽和食塩水を加 え、クロ口ホルムで抽出後、硫酸ナトリウムにて乾燥した。減圧濃縮後、残渣を P— TL C (クロ口ホルム Zメタノール Zアンモニア水 = 5ZlZO.05)にて精製し、標記化合 物を得た（21mg、 76%) o N- (5 (pyridine 2-ylthio) thiazole-2-yl) 1H-imidazole 1 —carboxamide 12 mg (0. O38 mmol) is dissolved in 1 mL of N, N, -dimethylformamide and (4- (4-(( 1Ε)-(3- (2,6 dichlorobenzyl) 2-methyl 4-oxopyridine-1 (4H) yl) prop 1-l) phenol) 1H-imidazol-2-yl) methylamine hydrochloride 25 mg (0.042 mmol), N, N, diisopropylethylamine 26 / zL (0.15 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Saturated saline was added to the mixed solution, extracted with black mouth form, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TL C (black mouth form Z methanol Z ammonia water = 5ZlZO.05) to obtain the title compound (21 mg, 76%) o
— NMR(CD OD)： δ 8.35— 8.33(1H, m), 7.77(1Η, d, J = 7.6 Hz)  — NMR (CD OD): δ 8.35— 8.33 (1H, m), 7.77 (1Η, d, J = 7.6 Hz)
3  Three
, 7.68-7.63 (3H, m), 7.55(1H, s), 7.37— 7.32 (5H, m), 7.17— 7.1 3(2H, m), 7.08 (1H, d, J = 8.4 Hz), 6.42(1H, d, J = 7.6 Hz), 6.34(1 H, dt, J=16 Hz, J=4. 8 Hz), 6. 18 (1H, d, J=16 Hz), 4. 80—4. 78(2 H, m), 4. 53 (2H, s), 4. 37 (2H, s), 2. 20 (3H, s)、 MS(FAB+) :714(M+ + 1) , 7.68-7.63 (3H, m), 7.55 (1H, s), 7.37— 7.32 (5H, m), 7.17— 7.1 3 (2H, m), 7.08 (1H, d, J = 8.4 Hz), 6.42 ( 1H, d, J = 7.6 Hz), 6.34 (1 H, dt, J = 16 Hz, J = 4.8 Hz), 6. 18 (1H, d, J = 16 Hz), 4. 80—4.78 (2 H, m), 4. 53 (2H , s), 4.37 (2H, s), 2.20 (3H, s), MS (FAB +): 714 (M ++ 1)
[0128] [実施例 89] 1—（5 ブロモチアゾールー 2 ィル） 3—（（4一（4一（2—（3—（2, 6 ジクロロベンジル） 2—メチル 4—ォキソピリジン一 1 (4H)—ィル）ェチル）フ ェ -ル） 1H—イミダゾールー 2—ィル）メチル）ゥレア  [0128] [Example 89] 1— (5 Bromothiazole-2-yl) 3 — ((4 1 (4 1 (2— (3— (2, 6 dichlorobenzyl) 2 —Methyl 4-oxopyridine 1 1 ( 4H) —yl) ethyl) phenol) 1H—imidazole-2-yl) methyl) urea
N— (5—ブロモチアゾール—2—ィル）—1H—イミダゾールー 1—カルボキシアミド 3. 9mg(0. 014mmol)を N, N，—ジメチルホルムアミド 0. 5mLに溶解し、（4— (4 - (2- (3- (2, 6 ジクロロベンジル） 2—メチル 4—ォキソピリジン一 1(4H) - ィル）ェチル）フエ-ル）—1H—イミダゾールー 2 ィル)メチルァミン塩酸塩 8. 2mg (0. 014mmol)、N, N，—ジイソプロピルェチルァミン 9. 7 μL·(0. 057mmol)をカロ え、室温で三時間攪拌した。混合溶液に飽和食塩水を加え、クロ口ホルムで抽出後、 硫酸ナトリウムにて乾燥した。減圧濃縮後、残渣を P— TLC (クロ口ホルム Zメタノー ル Zアンモニア水 = 5ZlZ0.05)にて精製し、標記化合物を得た（5.4mg、 57% N— (5-Bromothiazole-2-yl) —1H—imidazole 1-carboxamide 3.9 mg (0.014 mmol) is dissolved in 0.5 mL of N, N, -dimethylformamide, and (4— (4 − (2- (3- (2, 6 dichlorobenzyl) 2-methyl 4-oxopyridine 1 (4H) -yl) ethyl) phenol) —1H-imidazole-2-yl) methylamine hydrochloride 8.2 mg (0 014 mmol), N, N, -diisopropylethylamine 9.7 μL · (0.057 mmol) was added and stirred at room temperature for 3 hours. Saturated saline was added to the mixed solution, extracted with black mouth form, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol Z aqueous ammonia = 5ZlZ0.05) to obtain the title compound (5.4 mg, 57%
)o) o
— NMR(CD OD)： δ 7. 56 (2Η, d, J = 7. 6 Hz), 7. 51 (2H, d, J = 8. 0  — NMR (CD OD): δ 7. 56 (2Η, d, J = 7. 6 Hz), 7. 51 (2H, d, J = 8.0
3  Three
Hz), 7. 30— 7. 21 (4H, m), 7. 01 (2H, d, J = 8. 2 Hz), 6. 94(1H, t, J = 8 . 2 Hz), 6. 29(1H, d, J = 7. 6 Hz), 4. 52 (2H, s), 4. 27—4. 22 (4H, m), 2. 99 (2H, t, J = 6. 2 Hz), 1. 86 (3H, s)、 MS(FAB+) :671(M+ + 1)  Hz), 7.30—7.21 (4H, m), 7.01 (2H, d, J = 8.2 Hz), 6.94 (1H, t, J = 8.2 Hz), 6. 29 (1H, d, J = 7.6 Hz), 4.52 (2H, s), 4.27—4.22 (4H, m), 2.99 (2H, t, J = 6.2 Hz ), 1.86 (3H, s), MS (FAB +): 671 (M ++ 1)
[0129] 実施例 90の化合物は前記実施例 29と同様の方法で製造した。  [0129] The compound of Example 90 was produced in the same manner as in Example 29.
[0130] [実施例 91]  [0130] [Example 91]
(1— ((4一（4 ブロモフエ-ル）ー1ーメチルー 1H—イミダゾールー 2 ィル）メチル )3— (5— (ピリジン— 2—ィルチオ）チアゾール—2—ィル）ゥレア  (1 — ((4 (4-bromophenol) -1-methyl-1H-imidazole-2-yl) methyl) 3— (5- (pyridine-2-ylthio) thiazole-2-yl) urea
N— (5 （ピリジン 2—ィルチオ）チアゾールー 2 ィル） 1H—イミダゾールー 1 —カルボキシアミド 10. lmg(0. 003mmol)をテトラヒドロフラン lmLに溶解し、（4— (4 ブロモフエ-ル） 1ーメチルー 1H—イミダゾールー 2 ィル）メチルァミン塩酸 塩 10mg(0. 003mmol)、N, N, ジイソプロピルェチルァミン 5. 6μL·(0. 003m mol)を加え、室温で 0. 5時間攪拌した。混合溶液に飽和塩化アンモ-ゥム溶液を加 え、クロ口ホルムで抽出後、無水硫酸マグネシウムにて乾燥した。減圧濃縮後、残渣 をシリカゲルクロマトグラフィー（クロ口ホルム Zメタノール =ιο/ι)にて精製し、標記 化合物を得た（9. 9mg、 60%) oN— (5 (pyridine 2-ylthio) thiazole-2-yl) 1H-imidazole 1 —carboxamide 10. lmg (0.003 mmol) was dissolved in 1 mL of tetrahydrofuran, and (4- (4 bromophenol) 1-methyl-1H— Imidazole-2-yl) methylamine hydrochloride 10 mg (0.003 mmol), N, N, diisopropylethylamine 5.6 μL · (0.003 mmol) were added, and the mixture was stirred at room temperature for 0.5 hour. Add saturated ammonium chloride solution to the mixed solution. After extraction with black mouth form, it was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (black mouth form Z methanol = ιο / ι) to obtain the title compound (9.9 mg, 60%) o
— NMR(CDC1 /CD OD)： δ 8. 39— 8. 37(1Η, m), 7. 52 (6Η, m), 7.  — NMR (CDC1 / CD OD): δ 8. 39— 8. 37 (1Η, m), 7. 52 (6Η, m), 7.
3 3  3 3
30 (1Η, s), 7.01 (2H, m), 4. 53 (2H, d, J=4.4 Hz), 3. 78 (1H, s)、 MS( FAB+) :501(M+ + 1)  30 (1Η, s), 7.01 (2H, m), 4.53 (2H, d, J = 4.4 Hz), 3.78 (1H, s), MS (FAB +): 501 (M + + 1)
[0131] [実施例 92] 1— (5 ブロモチアゾールー 2 ィル）ー3—（（4一（4一（4 フエ-ル ブチル）フエ-ル） 1H—イミダゾィル一 2—ィル）メチル）ゥレア [Example 92] 1— (5 Bromothiazole-2-yl) -3 — ((4 (4 (butyl) phenyl) 1H-imidazolyl-2-yl) methyl ) Urea
1) (4— (4一（4—フ ニルブチル）フ ニル） 1 （（2 （トリメチルシリル）エトキシ） メチル） 1H—イミダゾールー 2—ィル）メチルァミン  1) (4- (4 (4-phenylbutyl) phenyl) 1 ((2 (trimethylsilyl) ethoxy) methyl) 1H-imidazol-2-yl) methylamine
後記する実施例 769の 1)で得た化合物 103mg(0. 20mmol)を N、 N ジメチル ホルムアミド 4mLに溶解し、ブチル 3
Figure imgf000067_0001
24mmol)、トリ ス（ジベンジリデンアセトン）ジパラジウム 36.6mg(0.04mmol)、トリ（tert—ブチル )ホスフィン 20 μL·(0.08mmol)、ジシクロへキシルメチルァミン 85 μL·(0.4mmol) を加え、 80°Cにて一時間攪拌した。混合溶液に飽和食塩水を加え、塩化メチレンで 抽出後、硫酸ナトリウムにて乾燥した。減圧濃縮後、残渣を P— TLC (へキサン Z酢 酸ェチル =3,2)にて精製し、ォレフィン体を得た。続いて、得られたォレフィン体を 、メタノール Z10%塩酸混合液に溶解し、 10 wt%PdZC (48mg、 30 wt%)をカロ え、水素雰囲気下、室温にて二時間攪拌した。混合液をセライトろ過し、ろ液を減圧 濃縮した。得られた残渣を P— TLC (クロ口ホルム Zメタノール =10Zl)にて精製し 、標記化合物を得た（51. lmg、 59%) o103 mg (0.20 mmol) of the compound obtained in 1) of Example 769 described later was dissolved in 4 mL of N, N dimethylformamide, and butyl 3
Figure imgf000067_0001
24 mmol), tris (dibenzylideneacetone) dipalladium 36.6 mg (0.04 mmol), tri (tert-butyl) phosphine 20 μL · (0.08 mmol), dicyclohexylmethylamine 85 μL · (0.4 mmol) Stir at 80 ° C. for 1 hour. To the mixed solution was added saturated brine, extracted with methylene chloride, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (hexane Z ethyl acetate = 3,2) to obtain an olefin body. Subsequently, the obtained olefin body was dissolved in a methanol Z10% hydrochloric acid mixed solution, 10 wt% PdZC (48 mg, 30 wt%) was added, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by P-TLC (black mouth form Z methanol = 10 Zl) to obtain the title compound (51. lmg, 59%) o
— NMR(CDC1 ): 67.66 (2H, d, J = 8.0 Hz), 7. 27— 7. 15 (8H, m),  — NMR (CDC1): 67.66 (2H, d, J = 8.0 Hz), 7. 27— 7. 15 (8H, m),
3  Three
5. 31 (2H, s), 4.00 (2H, s), 3. 56 (2H, t, J = 8.0 Hz), 2.68— 2.64 (4H , m), 1. 73— 1. 70 (4H, m), 0. 93 (2H, t, J = 8.0 Hz)、 MS(FAB+) :436 ( M+ + 1)  5. 31 (2H, s), 4.00 (2H, s), 3. 56 (2H, t, J = 8.0 Hz), 2.68— 2.64 (4H, m), 1. 73— 1. 70 (4H, m ), 0.93 (2H, t, J = 8.0 Hz), MS (FAB +): 436 (M ++ 1)
[0132] 2) (4一（4一（4一フエ-ルブチル）フエ-ル）—1H—イミダゾールー 2 ィル)メチル ァミン塩酸塩  [0132] 2) (4 1 (4 1 butyl butyl) -1H-imidazole 2 yl) methylamine hydrochloride
1)で得た化合物 52mgを 5N塩酸 1. 5mLとテトラヒドロフラン 1. OmLの混合溶液 に溶解し、 80°Cにて一時間攪拌した。混合液を減圧濃縮後、飽和重そう水を加え、 塩化メチレンにて抽出後、硫酸ナトリウムにて乾燥した。減圧濃縮後、残渣を P— TL C (クロ口ホルム Zメタノール Zアンモニア水 = 5ZlZ0.05)にて精製し、標記化合 物を得た（19. lmg、46%)。52 mg of the compound obtained in 1) 5N hydrochloric acid 1.5mL and tetrahydrofuran 1. OmL mixed solution And stirred at 80 ° C. for 1 hour. The mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate was added, extracted with methylene chloride, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol Z aqueous ammonia = 5 ZlZ0.05) to obtain the title compound (19. lmg, 46%).
— NMR(CD OD)： δ 7.87(1H, s) , 7.66 (2Η,  — NMR (CD OD): δ 7.87 (1H, s), 7.66 (2Η,
3 d, J = 8.4 Hz), 7.33(2 3 d, J = 8.4 Hz), 7.33 (2
H, d, J=8.4 Hz), 7.22 (2H, d, J = 7.6 Hz), 7. 15— 7.11 (3H, m), 4.5 0(2H, s), 2.70 (2H, t, J = 7.2 Hz), 2.64 (2H, t, J = 7.2 Hz), 1.68— 1 .64 (4H, m)、 MS(FAB+) :306(M+ + 1) H, d, J = 8.4 Hz), 7.22 (2H, d, J = 7.6 Hz), 7. 15— 7.11 (3H, m), 4.5 0 (2H, s), 2.70 (2H, t, J = 7.2 Hz), 2.64 (2H, t, J = 7.2 Hz), 1.68— 1.64 (4H, m), MS (FAB +): 306 (M ++ 1)
[0133] 3) 1— (5 ブロモチアゾール 2—ィル） 3— ((4— (4— (4—フエ-ルブチル）フ ェ -ル） - 1H—イミダゾィルー 2—ィル）メチル）ゥレア [0133] 3) 1— (5 Bromothiazole 2-yl) 3— ((4— (4— (4-Fe-butyl) phenyl)-1H—imidazolyl 2-yl) methyl) urea
2)で得た化合物 15.6mg(0.041mmol)を THFlmLに溶解し、 N、 N，—ジイソ プロピルェチルァミン 19 /zL O. lllmmol)、 N— (5 ブロモチアゾール—2—ィル )—1Η—イミダゾール— 1—カルボキシアミド 10.2mg(0.037mmol)を加え、室温 にて終夜攪拌した。混合溶液に飽和食塩水を加え、クロ口ホルムにて抽出後、硫酸 ナトリウムにて乾燥した。減圧濃縮後、残渣を P— TLC (クロ口ホルム Zメタノール Z へキサン Z酢酸ェチル =10ZlZ5.5/5.5X3回）にて精製し、標記化合物を得 た（5.9mg、 31%)。 15.6 mg (0.041 mmol) of the compound obtained in 2) is dissolved in THFlmL, and N, N, -diisopropylethylamine 19 / zL O. lllmmol), N— (5 bromothiazol-2-yl) — 1Η-imidazole-1-carboxyamide 10.2 mg (0.037 mmol) was added, and the mixture was stirred overnight at room temperature. Saturated saline was added to the mixed solution, extracted with black mouth form, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol Z hexane Z ethyl acetate = 10ZlZ5.5 / 5.5X3 times) to obtain the title compound (5.9 mg, 31%).
— NMR(CD OD)： δ 7.56 (2Η, d, J = 8.0 Hz), 7.27— 7.21(4H、m)  — NMR (CD OD): δ 7.56 (2Η, d, J = 8.0 Hz), 7.27— 7.21 (4H, m)
3  Three
、 7.17-7.14(5H、 m)、 4.59 (2H, brs)、 4.51 (2H, s)、 2.65— 2.61 (4H, m)、 1.66-1.63 (4H, m)、 MS(ESI+) :510(M+ + 1)  7.17-7.14 (5H, m), 4.59 (2H, brs), 4.51 (2H, s), 2.65—2.61 (4H, m), 1.66-1.63 (4H, m), MS (ESI +): 510 (M + + 1)
[0134] [実施例 93] (E)— 3— (4— (2— ((3— (5 ブロモチアゾール—2—ィル）ウレイド )メチル） 1 H イミダゾル 4 ィル）フエ-ル） N メチル N— ( ( 1 メチル 1H インドール一 3 ィル)メチル）アクリルアミド [0134] [Example 93] (E) — 3— (4— (2— ((3— (5 Bromothiazole-2-yl) ureido) methyl) 1 H imidazole 4 yl) phenol) N Methyl N— ((1 methyl 1H indole 1 3 yl) methyl) acrylamide
N— (5—ブロモチアゾール—2—ィル）—1H—イミダゾールー 1—カルボキシアミド 8.2mg(0.030mmol)を N, N ジメチルホルムアミド 0.5mLに溶解し、（E)— 3— (4一（2 （アミノエチル） 1H—イミダゾールー 4 ィル）フエ-ル）アクリル酸塩酸 塩 10.4mg(0.033mmol)、N, N，—ジイソプロピルェチルァミン 12 L(0.066m mol)を加え、室温にて四時間攪拌した。続けて、反応系に 1—ェチル—3— (3 ジ メチルァミノプロピル）—カルポジイミド塩酸塩 8.6mg(0.045mmol)、 1—ヒドロキ シベンゾトリアゾール水和物 6. lmg(0.045mmol)、N—メチルー 1ー（1 メチル — 1H—インドール— 3—ィル）メチルァミン 7.8mg(0.045mmol)をカ卩えて、室温 にてさらに 2.5時間攪拌した。混合溶液に飽和食塩水を加え、クロ口ホルムにて抽出 後、硫酸ナトリウムにて乾燥した。減圧濃縮後、残渣を P— TLC (クロ口ホルム Zメタノ ール =8Z1X2回）にて精製し、標記化合物を得た（3.6mg、 20%)。 MS(FAB+) :604(M+ + 1) N— (5-Bromothiazole-2-yl) —1H—imidazole 1-carboxamide 8.2 mg (0.030 mmol) was dissolved in 0.5 mL of N, N dimethylformamide, and (E) — 3— (4 (Aminoethyl) 1H-imidazole-4-yl) phenol) acrylic acid salt 10.4 mg (0.033 mmol), N, N, -diisopropylethylamine 12 L (0.066 mmol) were added, and the mixture was added at room temperature. Stir for hours. Next, 1-ethyl-3- (3 di Methylaminopropyl) -carpositimide hydrochloride 8.6 mg (0.045 mmol), 1-hydroxybenzotriazole hydrate 6. lmg (0.045 mmol), N-methyl-1- (1 methyl — 1H-indole-3-yl ) Methylamine 7.8 mg (0.045 mmol) was added, and the mixture was further stirred at room temperature for 2.5 hours. Saturated saline was added to the mixed solution, extracted with black mouth form, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol = 8Z1 × 2 times) to obtain the title compound (3.6 mg, 20%). MS (FAB +): 604 (M +++ 1)
[0135] 実施例 94〜96の化合物は前記実施例 29と同様の方法で製造した。  [0135] The compounds of Examples 94 to 96 were produced in the same manner as in Example 29.
[0136] [実施例 97] 1—（（4 (3, 4ージクロ口フエ-ル） 1H—イミダゾールー 2 ィル） メチル） 3— (5— (ピリジン一 2—ィル）チォ）チアゾール 2—ィル）ゥレア  [Example 97] 1 — ((4 (3,4-Dichlorodiethyl) 1H-imidazole-2-yl) methyl) 3-— (5- (pyridine-2-yl) thio) thiazole 2— Ill) Urea
N— (5 （ピリジン 2—ィルチオ）チアゾールー 2 ィル） 1H—イミダゾールー 1 N— (5 (Pyridine 2-ylthio) thiazole-2-yl) 1H-imidazole-1
—カルボキサミド 11.5mg、（4— (3, 4 ジクロロフエ-ル）— 1H—イミダゾールー 2 ィル)メチルァミン塩酸塩 11.9mgを用い、前記実施例 29と同様の方法で標記化 合物 3. lmgを得た。-Carboxamide 11.5 mg, (4- (3,4 Dichlorophenol)-1H-imidazole-2-yl) methylamine hydrochloride 11.9 mg was used and the title compound 3. lmg was obtained in the same manner as in Example 29. It was.
— NMR(CDC1 /CD OD)： δ 8.38 (1Η, m), 7.76 (1H, s), 7.46— 7.5  — NMR (CDC1 / CD OD): δ 8.38 (1Η, m), 7.76 (1H, s), 7.46—7.5
3 3  3 3
6(4H, complex) , 7.23 (1H, s), 7.06 (1H, m), 7.00 (1H, d, J = 8. 1 Hz) , 4.45 (2H, s)、 MS(FAB+) :477(M+ + 1) 6 (4H, complex), 7.23 (1H, s), 7.06 (1H, m), 7.00 (1H, d, J = 8.1 Hz), 4.45 (2H, s), MS (FAB +): 477 (M + + 1)
[0137] 実施例 98の化合物は前記実施例 29と同様の方法で製造した。 [0137] The compound of Example 98 was produced in the same manner as in Example 29.
[0138] [実施例 99] 1 （5 ブロモチアゾールー 2 ィル）ー3—（（4一（3、 4ージクロロフ ェ -ル） 1H—イミダゾールー 2—ィル）メチル）ゥレア [Example 99] 1 (5 Bromothiazole-2-yl) -3-(((4- (3,4-dichlorophenyl) 1H-imidazol-2-yl) methyl) urea
前記実施例 29と同様に製造した。 The same production as in Example 29 was performed.
— NMR(CDC1 /CD OD)： δ 7.76 (1Η, m), 7.49 (1H, m), 7.48(1  — NMR (CDC1 / CD OD): δ 7.76 (1Η, m), 7.49 (1H, m), 7.48 (1
3 3  3 3
H, brs), 7.28 (1H, s), 7.22(1H, s), 4.50 (2H, s)、 MS(FAB+) :446 (M+ +1)  H, brs), 7.28 (1H, s), 7.22 (1H, s), 4.50 (2H, s), MS (FAB +): 446 (M + +1)
[0139] [実施例 100] 1- (5-ブロモチアゾール -2-ィル) -3- ((4- (4- ((3- (2,6-ジクロロべンジル )-2-メチル -4-ォキソピリジン- 1(4H)-ィル）メチル）フエ-ル) -1H-イミダゾール -2-ィ ル)メチル)ゥレア  [Example 100] 1- (5-Bromothiazol-2-yl) -3-((4- (4-((3- (2,6-dichlorobenzyl))-2-methyl-4 -Oxopyridine-1 (4H) -yl) methyl) phenol) -1H-imidazole-2-yl) methyl) urea
N— (5—ブロモチアゾール—2—ィル） 1H—イミダゾールー 1—カルボキシアミ ド 4.6mg(0.017mmol)を N, N ジメチルホルムアミド 0.6mLに溶解し、（4— (4 - (2- (3- (2, 6 ジクロロベンジル） 2—メチル 4—ォキソピリジン一 1(4H) - ィル)メチル）フエ-ル）—1H—イミダゾールー 2 ィル)メチルァミン塩酸塩 9.4mg( 0.017mmol)、N, N，—ジイソプロピルェチルァミン 11 L(0.067mmol)を加え 、室温で四時間攪拌した。混合溶液に飽和食塩水を加え、クロ口ホルムで抽出後、 硫酸ナトリウムにて乾燥した。減圧濃縮後、残渣を P— TLC (クロ口ホルム Zメタノー ル Zアンモニア水 = 5ZlZ0.05)にて精製し、標記化合物を得た (4.9mg、 45%N— (5-Bromothiazole-2-yl) 1H-imidazole 1-carboxyami 4.6 mg (0.017 mmol) was dissolved in 0.6 mL of N, N dimethylformamide, and (4- (4- (2- (3- (2, 6 dichlorobenzyl) 2-methyl 4-oxopyridine) 1 (4H)- Yl) methyl) phenol) —1H-imidazole-2-yl) methylamine hydrochloride 9.4 mg (0.017 mmol), N, N, -diisopropylethylamine 11 L (0.067 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Stir. Saturated saline was added to the mixed solution, extracted with black mouth form, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol Z ammonia water = 5ZlZ0.05) to obtain the title compound (4.9 mg, 45%
)o) o
— NMR(CD OD)： δ 7.85(1Η, d, J = 7.6 Hz), 7.67 (2H, d, J = 8.0  — NMR (CD OD): δ 7.85 (1Η, d, J = 7.6 Hz), 7.67 (2H, d, J = 8.0
3  Three
Hz), 7.37(1H, s), 7.28 (2H, d, J = 7.8 Hz), 7.25(1H, s), 7.12(1H, t , J = 7.8 Hz), 7.03(2H, d, J = 8.0 Hz), 6.43 (2H, d, J = 7.6 Hz), 5.2 6 (2H, s), 4.51 (2H, s) , 4.33 (2H, s) , 2.06 (3H, s)、 MS (FAB+)： 657 (M + + 1)  Hz), 7.37 (1H, s), 7.28 (2H, d, J = 7.8 Hz), 7.25 (1H, s), 7.12 (1H, t, J = 7.8 Hz), 7.03 (2H, d, J = 8.0 Hz), 6.43 (2H, d, J = 7.6 Hz), 5.2 6 (2H, s), 4.51 (2H, s), 4.33 (2H, s), 2.06 (3H, s), MS (FAB +): 657 (M ++ 1)
[0140] 実施例 101〜102の化合物は前記実施例 29と同様の方法で、実施例 103は後記 する実施例 302と同様の方法で製造した。  [0140] The compounds of Examples 101 to 102 were produced in the same manner as in Example 29, and Example 103 was produced in the same manner as in Example 302 described later.
[0141] [実施例104]1—（（4ー（4ー（2—（3—（2, 6 ジクロ口べンジル）ー2—メチルー 4 ォキソピリジン 1 (4H) ィル）ェチル）フエ-ル） 1H—イミダゾールー 2—ィル )メチル) -3- (5- (ピリジン一 2—ィルチオ）チアゾール 2—ィル）ゥレア  [0141] [Example 104] 1-((4- (4- (2- (3- (2,6 Diclonal benzyl) -2-methyl-4-oxopyridine 1 (4H) yl) ethyl) ) 1H-Imidazole-2-yl) methyl) -3- (5- (pyridine-2-ylthio) thiazole 2-yl) urea
N— (5—（ピリジンー2—ィルチオ）チアゾールー 2—ィル）—1H—イミダゾール —1—カルボキシアミド 4.2mg(0.014mmol)を N, N ジメチルホルムアミド 0.5m Lに溶解し、（4— (4— (2— (3— (2, 6 ジクロロベンジル）—2—メチル—4—ォキソ ピリジンー1 (4H) ィル）ェチル）フエ-ル）—1H—イミダゾールー 2 ィル)メチル ァミン塩酸塩 8. lmg(0.014mmol)、N, N，—ジイソプロピルェチルァミン 9.5 L (0.056mmol)を加え、室温で四時間攪拌した。混合溶液に飽和食塩水を加え、ク ロロホルムで抽出後、硫酸ナトリウムにて乾燥した。減圧濃縮後、残渣を P— TLC (ク ロロホルム Zメタノール Zアンモニア水 = 5ZlZ0.05)にて精製し、標記化合物を 得た（4.2mg、 43%) o N— (5- (Pyridin-2-ylthio) thiazol-2-yl) -1H-imidazole-1-carbonamide 4.2 mg (0.014 mmol) was dissolved in N, N dimethylformamide 0.5 mL, and (4— (4 — (2— (3— (2, 6 Dichlorobenzyl) —2-Methyl-4-oxopyridine-1 (4H) yl) ethyl) phenol) —1H-imidazole-2-yl) methylamine hydrochloride 8. lmg (0.014 mmol), N, N, -diisopropylethylamine 9.5 L (0.056 mmol) were added, and the mixture was stirred at room temperature for 4 hours. Saturated saline was added to the mixed solution, and the mixture was extracted with chloroform and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (chloroform Z methanol Z aqueous ammonia = 5ZlZ0.05) to give the title compound (4.2mg, 43%) o
— NMR(CD OD)： δ 8.34— 8.32(1H, m), 7.64(1Η, ddd, J = 8.0 H z, J = 8.0 Hz, J = 2.0 Hz), 7.58(1H, d, J = 7.4 Hz), 7.55(1H, s), 7. 51 (2H, d, J = 8.0 Hz), 7.28 (1H, s), 7.21 (2H, d, J = 8.0 Hz), 7.05— 6.99 (3H, m), 6.91 (1H, t, J = 8.0 Hz), 6.31 (1H, d, J = 7.4 Hz), 4.5 3(2H, s), 4.26-4.22 (4H, m), 2.99 (2H, d, J = 6.4 Hz), 1.83 (3H, s) 、 MS (FAB+)： 702 (M+ + 1) — NMR (CD OD): δ 8.34— 8.32 (1H, m), 7.64 (1Η, ddd, J = 8.0 H z, J = 8.0 Hz, J = 2.0 Hz), 7.58 (1H, d, J = 7.4 Hz), 7.55 (1H, s), 7.51 (2H, d, J = 8.0 Hz), 7.28 (1H, s), 7.21 (2H, d, J = 8.0 Hz), 7.05—6.99 (3H, m), 6.91 (1H, t, J = 8.0 Hz), 6.31 (1H, d, J = 7.4 Hz), 4.5 3 (2H, s), 4.26-4.22 (4H, m), 2.99 (2H, d, J = 6.4 Hz), 1.83 (3H, s), MS (FAB +): 702 (M + + 1)
[0142] [実施例105]1—（（4ー（4ー（2—（3—（2, 6 ジクロ口べンジル）ー2—メチルー 4 ォキソピリジン 1 (4H) ィル）ェチル）フエ-ル） 1H—イミダゾールー 2—ィル )メチル) -3- (1H—イミダゾール一 2—ィル）ゥレア [0142] [Example 105] 1-((4- (4- (2- (3- (2, 6 Diclonal benzyl) -2-methyl-4-oxopyridine 1 (4H) yl) ethyl) ) 1H-imidazole-2-yl) methyl) -3- (1H-imidazole-2-yl) urea
N— (1H—イミダゾールー 2—ィル）—1H—イミダゾールー 1—カルボキシアミド 2. 5mg(0.014mmol)を N, N ジメチルホルムアミド 0.5mLに溶解し、（4— (4— (2 - (3- (2, 6 ジクロロベンジル） 2—メチル 4—ォキソピリジン一 1(4H)—ィル )ェチル）フエ-ル）—1H—イミダゾールー 2 ィル)メチルァミン塩酸塩 8. lmg(0. 014mmol)、N, N，—ジイソプロピルェチルァミン 9.5uL(0.056mmol)を加え、 室温で四時間攪拌した。混合溶液に飽和食塩水を加え、クロ口ホルムで抽出後、硫 酸ナトリウムにて乾燥した。減圧濃縮後、残渣を P— TLC (クロ口ホルム Zメタノール Zアンモニア水 = 5ZlZ0.05)にて精製し、標記化合物を得た（5.3mg、 66%)。 N— (1H—imidazole-2-yl) —1H—imidazole-1-carboxyamide 2.5 mg (0.014 mmol) was dissolved in 0.5 mL of N, N dimethylformamide, and (4— (4— (2-(3- (2,6 dichlorobenzyl) 2-methyl 4-oxopyridine 1 (4H) -yl) ethyl) phenol) -1H-imidazole-2-yl) methylamine hydrochloride 8. lmg (0.014 mmol), N, N, -Diisopropylethylamine 9.5 uL (0.056 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Saturated saline was added to the mixed solution, and the mixture was extracted with black form and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol Z aqueous ammonia = 5 ZlZ0.05) to obtain the title compound (5.3 mg, 66%).
— NMR(CD OD)： δ 7.56(1H, d, J = 7.6 Hz), 7.52 (2H, d, J = 8.0  — NMR (CD OD): δ 7.56 (1H, d, J = 7.6 Hz), 7.52 (2H, d, J = 8.0
3  Three
Hz), 7.28 (1H, brs), 7.22 (2H, d, J = 8.0 Hz), 7.01 (2H, d, J = 7.8 Hz ), 6.94(1H, t, J = 7.8 Hz), 6.72 (2H, s), 6.30(1H, d, J = 7.6 Hz), 4. 51 (2H, s), 4.27-4.23 (4H, m), 2.07 (2H, t, J = 5.2 Hz), 1.87 (3H, s )、 MS (FAB+)： 576 (M+ + 1)  Hz), 7.28 (1H, brs), 7.22 (2H, d, J = 8.0 Hz), 7.01 (2H, d, J = 7.8 Hz), 6.94 (1H, t, J = 7.8 Hz), 6.72 (2H, s), 6.30 (1H, d, J = 7.6 Hz), 4. 51 (2H, s), 4.27-4.23 (4H, m), 2.07 (2H, t, J = 5.2 Hz), 1.87 (3H, s ), MS (FAB +): 576 (M ++ 1)
[0143] [実施例106]1—（（4ー（4ー（2—（3—（2, 6 ジクロ口べンジル）ー2—メチルー 4 ォキソピリジン 1 (4H) ィル）ェチル）フエ-ル） 1H—イミダゾールー 2—ィル )メチル）ー3—（6 （メチルスルフォ -ル）ベンゾ [d]チアゾールー 2 ィル）ゥレア N— (6—（メチルスルフォ -ル）ベンゾ [d]チアゾールー 2—ィル）—1H—イミダゾ 一ルー 1—カルボキシアミド 4.4mg(0.014mmol)を N, N ジメチルホルムアミド 0 .2mLに溶解し、（4— (4— (2— (3— (2, 6 ジクロロベンジル）—2—メチル—4— ォキソピリジンー1 (4H) ィル）ェチル）フエ-ル）—1H—イミダゾールー 2 ィル)メ チルァミン塩酸塩 7. 8mg(0. 014mmol)及び N, N，—ジイソプロピルェチルァミン 9. 2μL·(0. 054mmol)の N, N ジメチルホルムアミド溶液（0. 3mL)をカ卩え、室温 で四時間攪拌した。混合溶液に飽和食塩水を加え、クロ口ホルムで抽出後、硫酸ナト リウムにて乾燥した。減圧濃縮後、残渣を P—TLC (クロ口ホルム Zメタノール Zアン モニァ水 = 5ZlZO.05)にて精製し、標記化合物を得た (4.6mg、 47%)。[Example 106] 1-((4- (4- (2- (3- (2,6 Diclonal benzyl) -2-methyl-4-oxopyridine 1 (4H) yl) ethyl) phenol) ) 1H-imidazole-2-yl) methyl) -3- (6 (methylsulfol) benzo [d] thiazole-2-yl) urea N- (6- (methylsulfol) benzo [d] thiazol-2-yl ) —1H—Imidazo One-Lou 1-Carboxamide 4.4 mg (0.014 mmol) is dissolved in 0.2 mL of N, N dimethylformamide, and (4— (4— (2— (3— (2, 6 dichlorobenzyl) — 2—Methyl—4—oxopyridine-1 (4H) yl) ethyl) phenol) —1H—imidazole-2 ethyl) Prepare a solution of tilamine hydrochloride 7.8 mg (0.014 mmol) and N, N, -diisopropylethylamine 9.2 μL (0.054 mmol) in N, N dimethylformamide (0.3 mL) at room temperature. Stir for 4 hours. Saturated saline was added to the mixed solution, followed by extraction with black mouth form, followed by drying over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol Z ammonia water = 5 ZlZO.05) to obtain the title compound (4.6 mg, 47%).
— NMR(CD OD)： δ 8.43(1H, d, J=l. 8 Hz), 7. 92(1H, dd, J = 8. 6  — NMR (CD OD): δ 8.43 (1H, d, J = l. 8 Hz), 7. 92 (1H, dd, J = 8.6
3  Three
Hz, J=l. 8 Hz), 7. 80(1H, d, J = 8. 6 Hz), 7. 57— 7. 51 (3H, m), 7. 3 0(1H, s), 7. 22 (2H, d, J = 8. 0 Hz), 7. 01 (2H, d, J = 8.4 Hz), 6. 94(1 H, t, J = 8.4 Hz), 6. 29(1H, d, J = 7. 2 Hz), 4. 58 (2H, s), 4. 26—4. 22 (4H, m), 3. 14 (3H, m), 2. 99 (2H, t, J = 6.4 Hz)l. 86 (3H, s)、 MS(FA B+) :721(M+ + 1)  Hz, J = l. 8 Hz), 7. 80 (1H, d, J = 8.6 Hz), 7. 57—7.51 (3H, m), 7. 3 0 (1H, s), 7 22 (2H, d, J = 8. 0 Hz), 7. 01 (2H, d, J = 8.4 Hz), 6. 94 (1 H, t, J = 8.4 Hz), 6. 29 (1H, d, J = 7.2 Hz), 4.58 (2H, s), 4.26—4.22 (4H, m), 3.14 (3H, m), 2.99 (2H, t, J = 6.4 Hz) l. 86 (3H, s), MS (FA B +): 721 (M + + 1)
[実施例107]1—（（4ー（4ー（2—（3—（2, 6 ジクロ口べンジル）ー2—メチルー 4 ォキソピリジン 1 (4H) ィル）ェチル）フエ-ル） 1H—イミダゾールー 2—ィル )メチル）ー3—（5 （メチルスルフォ -ル）チアゾールー 2 ィル）ゥレア [Example 107] 1-((4- (4- (2- (3- (2,6 dichroic benzyl) -2-methyl-4-oxopyridine 1 (4H) yl) ethyl) phenol) 1H— Imidazole-2-yl) methyl) -3- (5 (methylsulfol) thiazole-2-yl) urea
N— (5 （メチルスルフォ -ル）チアゾールー 2 ィル） 1H—イミダゾールー 1 力ノレボキシアミド 3. 5mg(0. 0128mmol)を N, N ジメチノレホノレムアミド 0. 2mLに 溶解し、（4— (4— (2— (3— (2, 6 ジクロロベンジル）—2—メチル—4—ォキソピリ ジンー1 (4H) ィル）ェチル）フエ-ル）—1H—イミダゾールー 2 ィル）メチルアミ ン塩酸塩 7. 8mg(0. 0135mmol)及び N, N，—ジイソプロピルェチルァミン 9. 2μ L(0. 054mmol)の N, N，ージメチルホルムアミド溶液（0. 3mL)をカ卩え、室温で四 時間攪拌した。混合溶液に飽和食塩水を加え、クロ口ホルムで抽出後、硫酸ナトリウ ムにて乾燥した。減圧濃縮後、残渣を P—TLC (クロ口ホルム Zメタノール Zアンモ- ァ水 = 5ZlZ0.05)にて精製し、標記化合物を得た (4. 3mg、 50%)。 N— (5 (Methylsulfol) thiazol-2-yl) 1H—imidazole-1 force norevoxamide 3.5 mg (0.0128 mmol) was dissolved in 0.2 mL of N, N-dimethinorenolemamide to give (4— (4— (2- (3- (2,6-dichlorobenzyl) -2-methyl-4-oxopyridine-1 (4H) yl) ethyl) phenol) -1H-imidazole-2-yl) methylamine hydrochloride 7.8 mg (0.0135 mmol) and N, N, -diisopropylethylamine 9.2 μL (0.054 mmol) in N, N, -dimethylformamide solution (0.3 mL) were added and stirred at room temperature for 4 hours. . Saturated saline was added to the mixed solution, extracted with black mouth form, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol Z ammonia water = 5 ZlZ 0.05) to obtain the title compound (4.3 mg, 50%).
— NMR(CD OD)： δ 7. 88 (1Η, s) , 7. 56 (1H, d, J = 7. 6 Hz), 7. 52(1  — NMR (CD OD): δ 7. 88 (1Η, s), 7. 56 (1H, d, J = 7.6 Hz), 7. 52 (1
3  Three
H, d, J=8. 0 Hz), 7. 29 (1H, s), 7. 23 (2H, d, J = 8. 0 Hz), 7. 01 (2H, d , J = 8. 2 Hz), 6. 94(1H, t, J = 8. 2 Hz), 6. 29(1H, d, J = 7. 6 Hz), 4. 5 5(2H, s), 4. 26—4. 22 (4H, m), 3. 21 (3H, s), 2. 99 (2H, t, J = 6. 4 Hz) , 1. 86 (3H, s)、 MS(ESI+) :671(M+ + 1) [0145] [実施例 108]1—（5 （ァリルスルフォ -ル）チアゾールー 2 ィル）ー3—（（4一（4 ブロモフエ-ル） 1H—イミダゾールー 2—ィル）メチル）ゥレア H, d, J = 8.0 Hz), 7. 29 (1H, s), 7. 23 (2H, d, J = 8. 0 Hz), 7. 01 (2H, d, J = 8.2 Hz), 6.94 (1H, t, J = 8.2 Hz), 6.29 (1H, d, J = 7.6 Hz), 4.5 5 (2H, s), 4. 26—4 22 (4H, m), 3.21 (3H, s), 2.99 (2H, t, J = 6.4 Hz), 1.86 (3H, s), MS (ESI +): 671 (M + + 1) [Example 108] 1— (5 (arylsulfol) thiazole-2-yl) -3-(((4-bromophenol) 1H-imidazole-2-yl) methyl) urea
N— (5 （ァリルスルフォ -ル）チアゾールー 2 ィル） 1H—イミダゾールー 1 カルボキシアミド 83mg(0.28mmol)を N, N ジメチルホルムアミド 3mLに溶解し、 (4一（4 ブロモフエ-ル） 1H—イミダゾールー 2 ィル)メチルァミン塩酸塩 109 mg(0.34mmol)、N, N，—ジイソプロピルェチルァミン 123 L(0.72mmol)をカロ え、室温で 2.5時間攪拌した。混合溶液に飽和食塩水を加え、クロ口ホルムで抽出 後、硫酸ナトリウムにて乾燥した。減圧濃縮後、残渣を P— TLC (クロ口ホルム Zメタノ ール =10Zl)にて精製し、標記化合物を得た (60mg、 39%) o N— (5 (arylsulfol) thiazole-2-yl) 1H-imidazole-1 Carboxamide 83 mg (0.28 mmol) was dissolved in 3 mL of N, N dimethylformamide, (L) Methylamine hydrochloride 109 mg (0.34 mmol) and N, N, -diisopropylethylamine 123 L (0.72 mmol) were added and stirred at room temperature for 2.5 hours. Saturated saline was added to the mixed solution, extracted with black mouth form, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol = 10 Zl) to obtain the title compound (60 mg, 39%) o
— NMR(DMSO— d ): 67.85 (1H, s), 7.71 (2H, d, J = 7.6 Hz), 7.6  — NMR (DMSO— d): 67.85 (1H, s), 7.71 (2H, d, J = 7.6 Hz), 7.6
6  6
1(1H, brs), 7.52 (2H, d, J = 7.6 Hz), 7.25(1H, br), 5.75 (1H, ddt, J = 17 Hz, J=ll Hz, J = 7. 1 Hz), 5.37(1H, d, J=ll Hz), 5.29(1H, d, J =17 Hz), 4.42 (2H, d, J=4.9 Hz), 4.13(2H, d, J = 7.1 Hz) , MS (ES 1+) :482(M+ + 1)  1 (1H, brs), 7.52 (2H, d, J = 7.6 Hz), 7.25 (1H, br), 5.75 (1H, ddt, J = 17 Hz, J = ll Hz, J = 7.1 Hz), 5.37 (1H, d, J = ll Hz), 5.29 (1H, d, J = 17 Hz), 4.42 (2H, d, J = 4.9 Hz), 4.13 (2H, d, J = 7.1 Hz), MS ( ES 1+): 482 (M ++ 1)
[0146] 実施例 108〜197の化合物は前記実施例 29と同様の方法で、実施例 198は後記 する実施例 302と同様の方法で、実施例 199〜215は前記実施例 29と同様の方法 で、実施例 216は後記する実施例 302と同様の方法で、実施例 217〜231は前記 実施例 29と同様方法で製造した。  [0146] The compounds of Examples 108 to 197 were the same as in Example 29, Example 198 was the same as Example 302 described later, and Examples 199 to 215 were the same as Example 29. Example 216 was produced in the same manner as Example 302 described later, and Examples 217 to 231 were produced in the same manner as in Example 29.
[0147] [実施例 210]1—（（1H べンゾ [d]イミダゾールー 2 ィル)メチル） 3—（6 （メ チルスルフォ -ル）ベンゾ [d]チアゾール 2—ィル）ゥレア  [Example 210] 1-(((1H benzo [d] imidazol-2-yl) methyl) 3- (6 (methylsulfol) benzo [d] thiazole-2-yl) urea
N— (6—（メチルスルフォ -ル）ベンゾ [d]チアゾールー 2—ィル）—1H—イミダゾ 一ルー 1—カルボキサミド 128mgをテトラヒドロフラン 5mLに溶解し、（1H ベンゾ [d ]イミダゾールー 2—ィル)メチルァミン塩酸塩 108mg、 N, N，—ジイソプロピルェチ ルァミン 164 Lを加え、室温にて終夜攪拌した。反応系に水、酢酸ェチルを加え、 フェーズセパレーターにて有機層を分取した。硫酸ナトリウムで乾燥後、減圧濃縮し た。残渣をクロ口ホルム、メタノール、へキサン、酢酸ェチル、エーテルの混合溶媒か ら再結晶精製し、標記化合物 92.3mgを得た。 N— (6- (Methylsulfol) benzo [d] thiazol-2-yl) —1H-imidazo Iru 1-carboxamide 128 mg was dissolved in 5 mL of tetrahydrofuran, and (1H benzo [d] imidazol-2-yl) methylamine 108 mg of hydrochloride, 164 L of N, N, -diisopropylethylamine were added, and the mixture was stirred overnight at room temperature. Water and ethyl acetate were added to the reaction system, and the organic layer was separated with a phase separator. The extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was recrystallized and purified from a mixed solvent of chloroform, methanol, hexane, ethyl acetate, and ether to obtain 92.3 mg of the title compound.
— NMR(DMSO— d )： δ 8.50(1H, s), 7.85(1H, d, J = 8.4 Hz), 7.7 8(1H, d, J = 8.4 Hz), 7. 57 (2H, br), 7.46 (1H, br), 7. 16 (2H, br), 4. 6 4(2H, d, J = 5. 2 Hz), 3. 22 (3H, s) — NMR (DMSO— d): δ 8.50 (1H, s), 7.85 (1H, d, J = 8.4 Hz), 7.7 8 (1H, d, J = 8.4 Hz), 7.57 (2H, br), 7.46 (1H, br), 7.16 (2H, br), 4. 6 4 (2H, d, J = 5. 2 Hz), 3.22 (3H, s)
[0148] [実施例 232] 1—（6 （メチルスルフォ -ル）ベンゾ [d]チアゾールー 2 ィル） 3 [0148] [Example 232] 1— (6 (methylsulfol) benzo [d] thiazole-2-yl) 3
- ( (4—フエ-ル— 1H—イミダゾール— 2—ィル）メチル）ゥレア  -((4-Fel— 1H-imidazole-2-yl) methyl) urea
N- (6 （メチルスルフォ -ル）ベンゾ [d]チアゾールー 2 ィル）—1H—イミダゾ ール一 1—カルボキシアミド 113mg (0. 35mmol)をテトラヒドロフラン 4mLに溶解し 、（4 フエ-ルー 1H—イミダゾールー 2 ィル)メチルァミン塩酸塩 95mg(0. 39m mol)、 N, N，—ジイソプロピルェチルァミン 149 μL·(0. 88mmol)を加え、室温で 三日間攪拌した。混合溶液に飽和食塩水を加え、クロ口ホルムで抽出後、硫酸ナトリ ゥムにて乾燥した。減圧濃縮後、残渣をシリカゲルクロマトグラフィー（クロ口ホルム z メタノール）にて精製し、標記化合物の粗精製品を得た。メタノールより再結晶を行い 113 mg (0.35 mmol) of N- (6 (methylsulfo) benzo [d] thiazole-2-yl) -1H-imidazole 1-carboxamide was dissolved in 4 mL of tetrahydrofuran to give (4 phenol 1H-imidazole). 2-yl) methylamine hydrochloride (95 mg, 0.39 mmol), N, N, -diisopropylethylamine (149 μL · 0.88 mmol) was added, and the mixture was stirred at room temperature for 3 days. Saturated saline was added to the mixed solution, followed by extraction with black mouth form, followed by drying over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (Kuroguchi Form z methanol) to obtain a crude product of the title compound. Recrystallize from methanol
、標記化合物を得た（50mg、 33%)。The title compound was obtained (50 mg, 33%).
— NMR(DMSO d )： δ 8. 52— 8. 51 (1Η, m), 7. 86(1H, dd, J = 8. 0  — NMR (DMSO d): δ 8. 52— 8. 51 (1Η, m), 7.86 (1H, dd, J = 8.0
6  6
Hz, J=l. 6 Hz), 7. 80— 7. 74 (3H, m), 7. 55 (1H, brs), 7.44— 7. 32(3 H, m), 7. 19— 7. 15(1H, m), 4.46 (2H, d, J = 5.4 Hz), 3. 22 (3H, s), 3 . 17(1H, d, J= 5.4Hz)、 MS(ESI+) :428(M+ + 1)  Hz, J = l. 6 Hz), 7. 80— 7. 74 (3H, m), 7. 55 (1H, brs), 7.44— 7. 32 (3 H, m), 7. 19— 7. 15 (1H, m), 4.46 (2H, d, J = 5.4 Hz), 3.22 (3H, s), 3.17 (1H, d, J = 5.4Hz), MS (ESI +): 428 (M + + 1)
[0149] 実施例 233〜256の化合物は前記実施例 29と同様の方法で、実施例 257の化合 物は後記する実施例 302と同様の方法で、実施例 258〜276の化合物は前記実施 例 29と同様の方法で、実施例 277の化合物は後記する実施例 302と同様の方法で 、実施例 278〜301の化合物は前記実施例 29と同様の方法で製造した。  [0149] The compounds of Examples 233 to 256 were the same as in Example 29, the compound of Example 257 was the same as Example 302 described later, and the compounds of Examples 258 to 276 were In the same manner as in Example 29, the compound of Example 277 was prepared in the same manner as in Example 302 described later, and the compounds of Examples 278 to 301 were prepared in the same manner as in Example 29.
[0150] [実施例 241] 1—（6—メトキシベンゾ [d]チアゾールー 2 ィル）ー3—（（4 フエ-ル  [0150] [Example 241] 1- (6-Methoxybenzo [d] thiazole-2-yl) -3-((4 phenol
1H—イミダゾールー 2—ィル）メチル）ゥレア  1H-imidazole-2-yl) methyl) urea
N— (6—メトキシベンゾ [d]チアゾール—2—ィル）—1H—イミダゾールー 1—カル ボキシアミド 27mgをテトラヒドロフラン lmLに溶解し、 2 -アミノメチル 4 フエ-ル — 1H—イミダゾール塩酸塩 30mg、 N, N，—ジイソプロピルェチルァミン 41 μ Lを加 え、室温にて終夜攪拌した。反応系を減圧濃縮し、残渣を Ρ— TLC (クロ口ホルム Ζメ タノール =20Zl)で精製し、標記化合物を得た。  N— (6-Methoxybenzo [d] thiazol-2-yl) -1H-imidazole 1-carboxamide 27 mg is dissolved in 1 mL of tetrahydrofuran, and 2-aminomethyl 4-phenol — 1H-imidazole hydrochloride 30 mg, N , N, -Diisopropylethylamine 41 μL was added and stirred overnight at room temperature. The reaction system was concentrated under reduced pressure, and the residue was purified by Ρ-TLC (black mouth form Ζ methanol = 20 Zl) to obtain the title compound.
[0151] [実施例 242] 1—（5—（4 -トロフエ-ルスルフォ -ル）チアゾールー 2 ィル）ー3 - ( (4—フエ-ル— 1H—イミダゾール— 2—ィル）メチル）ゥレア [0151] [Example 242] 1— (5— (4-Tropherylsulfol) thiazole-2-yl) -3 -((4-Fel— 1H-imidazole-2-yl) methyl) urea
N— (5- (4—二トロフエ-ルスルフォ -ル）チアゾール—2—ィル）—1H—イミダゾ 一ルー 1 カルボキシアミド 38mg、 2 アミノメチルー 4 フエ-ルー 1H—イミダゾー ル塩酸塩 30mgを用い、前記実施例 241と同様の方法で、標記化合物を得た。  N— (5- (4-Nitrophenylsulfol) thiazole-2-yl) —1H-imidazo One-Lou 1 Carboxamide 38 mg, 2 Aminomethyl-4 Phenol 1H-Imidazole hydrochloride 30 mg The title compound was obtained in the same manner as in Example 241.
[0152] [実施例 302]N— (2, 3ジクロロフエ-ル）ー4 (2, 4ージクロ口フエ-ル）ー3—ォ キソピペラジン一 1 力ノレボキシアミド [0152] [Example 302] N— (2,3 dichlorophenol) -4 (2,4-dichloromouth) -3-oxoxoperazine
トリホスゲン 10mg(0. O33mmol)を塩化メチレン（lmL)に溶解させ、この溶液に 2, 3 ジクロロア-リン 16. 2mg(0. 10mmol)、N, N，一ジイソプロピルェチルァミン 3 4. 4μL·(0. 20mmol)の塩化メチレン (0. 5mL)溶液を加え、室温で十分間攪拌し た。反応溶液に 1— (2, 4 ジクロロフエ-ル）ピぺラジン一 2—オン 29.4mg(0. 12 mmol)と N, N，—ジイソプロピルェチルァミン 43 μ L (0. 25mmol)を加え室温で終 夜撹拌した。反応液をシリカゲル薄層クロマトグラフィー（クロ口ホルム Zメタノール Z へキサン Z酢酸ェチル =10ZlZ5.5/5. 5)にて精製し、標記化合物を 29mg(0 . O33mmol, 67%)得た。 10 mg (0. 33 mmol) of triphosgene was dissolved in methylene chloride (1 mL). To this solution, 16.2 mg (0. 10 mmol) of 2, 3 dichloroaline, N, N, monodiisopropylethylamine 3 4.4 μL · A solution of (0.20 mmol) in methylene chloride (0.5 mL) was added, and the mixture was stirred for a while at room temperature. To the reaction solution was added 1— (2,4 dichlorophenyl) piperazine-2-one 29.4 mg (0.12 mmol) and N, N, -diisopropylethylamine 43 μL (0.25 mmol) at room temperature. And stirred overnight. The reaction solution was purified by silica gel thin layer chromatography (black mouth form Z methanol Z hexane Z ethyl acetate = 10ZlZ5.5 / 5. 5) to obtain 29 mg (0.033 mmol, 67%) of the title compound.
— NMR(CDC1 )： δ 8. 12(1H, dd, J = 7. 6 Hz, J=l. 6 Hz), 7. 52(1H,  — NMR (CDC1): δ 8. 12 (1H, dd, J = 7.6 Hz, J = l. 6 Hz), 7. 52 (1H,
3  Three
d, J = 2. 4 Hz), 7. 33(1H, dd, J = 8.4 Hz, J = 2. 0 Hz), 7. 17— 7. 24(2 H, m), 7. 16 (1H, dd, J = 8.4Hz, 1. 6Hz), 7. 06 (1H, brs), 4. 34 (2H, d, J =3. 2 Hz), 4. 06 (1H, m), 3. 91 (1H, m), 3.46 (2H, m)、 MS(FAB+) :43 1(M+ + 1)  d, J = 2.4 Hz), 7.33 (1H, dd, J = 8.4 Hz, J = 2. 0 Hz), 7. 17— 7. 24 (2 H, m), 7. 16 (1H , dd, J = 8.4Hz, 1. 6Hz), 7. 06 (1H, brs), 4. 34 (2H, d, J = 3.2 Hz), 4. 06 (1H, m), 3. 91 (1H, m), 3.46 (2H, m), MS (FAB +): 43 1 (M ++ 1)
[0153] 実施例 303〜393の化合物は前記実施例 29と同様の方法で製造した。  [0153] The compounds of Examples 303 to 393 were produced in the same manner as in Example 29.
[0154] [実施例 345] 1—（6 ブロモベンゾ [d]チアゾールー 2 ィル）ー3—（（4 フエ-ル [Example 345] 1— (6 Bromobenzo [d] thiazole-2-yl) -3 — ((4 phenol
1H—イミダゾールー 2—ィル）メチル）ゥレア  1H-imidazole-2-yl) methyl) urea
N— (6—ブロモベンゾ [d]チアゾール—2—ィル）—1H—イミダゾールー 1—カルボ キシアミド 32mg、 2 アミノメチルー 4—フエ-ルー 1H—イミダゾール塩酸塩 30mg を用い、前記実施例 241と同様の方法で、標記化合物を得た。  N- (6-Bromobenzo [d] thiazol-2-yl) -1H-imidazole 1-carboxamide 32 mg, 2-aminomethyl-4-phenol- 1H-imidazole hydrochloride 30 mg, and the same method as in Example 241 To give the title compound.
[0155] [実施例 348]1—（（4 フエ-ルー 1H—イミダゾールー 2 ィル)メチル）ー3— (5 （フエ-ルチオ）チアゾールー 2—ィル）ゥレア [Example 348] 1-(((4 ferro-lH-imidazole-2-yl) methyl) -3)-(5 (phenol-thio) thiazol-2-yl) urea
N— (5 （フエ-ルチオ）チアゾールー 2 ィル） 1H—イミダゾールー 1 カルボ キシアミド 30mg、 2 アミノメチルー 4—フエ-ルー 1H—イミダゾール塩酸塩 30mg を用い、前記実施例 241と同様の方法で、標記化合物を得た。 N— (5 (Phenolthio) thiazole-2 yl) 1H—imidazole-1 carbo The title compound was obtained in the same manner as in Example 241 using 30 mg of xyamide and 30 mg of 2 aminomethyl-4-phenol 1H-imidazole hydrochloride.
[0156] [実施例 370] 1— (5— (2, 5 ジクロロフエノキシ）チアゾール 2—ィル） 3— ( ( 4—フエ-ルー 1H—イミダゾールー 2—ィル）メチル）ゥレア [0156] [Example 370] 1— (5- (2,5 dichlorophenoxy) thiazole 2-yl) 3— ((4-phenol- 1H-imidazole-2-yl) methyl) urea
N— (5— (2, 5 ジクロロフエノキシ）チアゾール 2—ィル） 1H—イミダゾール — 1 カルボキシアミド 36mg、 2 -アミノメチル 4—フエ-ル - 1H イミダゾール塩 酸塩 30mgを用い、前記実施例 241と同様の方法で、標記化合物を得た。  N- (5- (2,5 dichlorophenoxy) thiazole 2-yl) 1H-imidazole — 1 Carboxamide 36 mg, 2-aminomethyl 4-phenol-1H imidazole hydrochloride 30 mg The title compound was obtained in the same manner as in Example 241.
[0157] [実施例 371] 1—（5— (3, 4 ジクロ口フエ-ルチオ）チアゾールー 2—ィル）ー3 [0157] [Example 371] 1— (5- (3, 4 Diclonal thiolthio) thiazole-2-yl) -3
- ( (4—フエ-ル— 1H—イミダゾール— 2—ィル）メチル）ゥレア  -((4-Fel— 1H-imidazole-2-yl) methyl) urea
N— (5- (3, 4 ジクロロフエ-ルチオ）チアゾール—2—ィル）—1H—イミダゾー ルー 1—カルボキシアミド 37mg、 2 アミノメチルー 4—フエ-ルー 1H—イミダゾール 塩酸塩 30mgを用い、前記実施例 241と同様の方法で、標記化合物を得た。  N— (5- (3,4-dichlorophenyl-thio) thiazole-2-yl) —1H—imidazole 1-carboxamide 37 mg, 2 aminomethyl-4-phenol 1H-imidazole hydrochloride 30 mg The title compound was obtained in a similar manner to 241.
[0158] [実施例 372] 1—（5—（3 クロ口フエ-ルチオ）チアゾールー 2 ィル） 3—（（4 フエ-ルー 1H—イミダゾールー 2—ィル）メチル）ゥレア [Example 372] 1— (5- (3 black mouth thio) thiazole-2-yl) 3 — ((4 benzene 1H-imidazol-2-yl) methyl) urea
N— (5—（3 クロ口フエ-ルチオ）チアゾールー 2 ィル） 1H—イミダゾールー 1 カルボキシアミド 34mg、 2 アミノメチルー 4 フエ-ルー 1H—イミダゾール塩酸 塩 30mgを用い、前記実施例 241と同様の方法で、標記化合物を得た。  N— (5- (3 black mouth thio) thiazole-2-yl) 1H-imidazole-1 carboxamide 34 mg, 2 aminomethyl-4 felt 1H-imidazole hydrochloride 30 mg in the same manner as in Example 241 To give the title compound.
[0159] [実施例 373] 1—（（4 フエ-ルー 1H—イミダゾールー 2 ィル)メチル）ー3— (5 （ピリジン 2—ィルチオ）チアゾールー 2—ィル）ゥレア [Example 373] 1-((4 FE-LUE 1H-imidazole-2-yl) methyl) -3- (5 (pyridine-2-ylthio) thiazol-2-yl) urea
N— (5 （ピリジン 2—ィルチオ）チアゾールー 2 ィル） 1H—イミダゾールー 1 カルボキシアミド 30mg、 2 アミノメチルー 4 フエ-ルー 1H—イミダゾール塩酸 塩 30mgを用い、前記実施例 241と同様の方法で、標記化合物を得た。 N- (5 (pyridine 2-ylthio) thiazole-2-yl) 1H-imidazole-1 carboxamide 30 mg, 2 aminomethyl-4 felt 1H-imidazole hydrochloride 30 mg in the same manner as in Example 241 Got.
— NMR(DMSO— d ) : 6 8. 41 (1H, m) , 7. 77— 7. 68 (3H, m) , 7. 64 (1  — NMR (DMSO— d): 6 8. 41 (1H, m), 7. 77— 7. 68 (3H, m), 7. 64 (1
6  6
H, s) , 7. 55 (1H, br) , 7. 36— 7. 32 (2H, m) , 7. 19— 7. 10 (3H, m) , 7. 03 (1H, d, J = 8. 0 Hz, J = 0. 7 Hz) , 4. 41 (2H, d, J = 5. 4 Hz)  H, s), 7. 55 (1H, br), 7. 36— 7. 32 (2H, m), 7. 19— 7. 10 (3H, m), 7. 03 (1H, d, J = 8.0 Hz, J = 0.7 Hz), 4.41 (2H, d, J = 5.4 Hz)
[0160] ォキシム誘導体  [0160] Oxime derivatives
実施例 394〜398の化合物は後記する実施例 669と同様の方法で製造した。  The compounds of Examples 394 to 398 were produced in the same manner as in Example 669 described later.
[0161] [実施例 399]N—（6—メトキシカルボ-ル）ベンゾ [d]チアゾールー 2—ィルー 2— ( 3— -トロベンジリデンアミノォキシ）ァセトアミド [0161] [Example 399] N— (6-Methoxycarbol) benzo [d] thiazole-2-yl 3— -Trobenzylideneaminooxy) acetamide
後記する実施例 401と同様に製造した。 It was produced in the same manner as Example 401 described later.
— NMR(DMSO d )： δ 12.79 (1Η, s), 8.66(1H, d, J=l.7 Hz), 8.  — NMR (DMSO d): δ 12.79 (1Η, s), 8.66 (1H, d, J = l.7 Hz), 8.
6  6
62(1H, s), 8.45(1H, m), 8.27(1H, m), 8.07(1H, d, J = 7.8 Hz), 8.0 1(1H, dd, J = 8.6 Hz, J=l.7 Hz), 7.83(1H, d, J = 8.6 Hz), 7.72(1H , t, J = 8.0 Hz), 5.01 (2H, s), 3.86 (3H, s)、 MS(FAB+) :415(M+ + 1) [0162] 実施例 400の化合物は後記する実施例 401と同様の方法で製造した。  62 (1H, s), 8.45 (1H, m), 8.27 (1H, m), 8.07 (1H, d, J = 7.8 Hz), 8.0 1 (1H, dd, J = 8.6 Hz, J = l.7 Hz), 7.83 (1H, d, J = 8.6 Hz), 7.72 (1H, t, J = 8.0 Hz), 5.01 (2H, s), 3.86 (3H, s), MS (FAB +): 415 (M ++ 1) [0162] The compound of Example 400 was produced in the same manner as in Example 401 described later.
[0163] [実施例 401]N— (6—メトキシベンゾ [d]チアゾールー 2 ィル）ー2—（3 -トロ ベンジリデンアミノォキシ)ァセトアミド [0163] [Example 401] N— (6-Methoxybenzo [d] thiazol-2-yl) -2- (3-trobenzylideneaminooxy) acetamide
室温下（（（（3 -トロフエ-ル)メチレン）ァミノ）ォキシ）ァセチルクロリド 48.5mg (0.20mmol)をベンゼン 2mLに溶解し、 6—メトキシベンゾチアゾール 2—ィルァ ミン 32.4mg(0.18mmol)をカ卩ぇ撹拌した。反応溶液を五時間、加熱還流した後、 室温まで冷却し、飽和炭酸水素ナトリウム水溶液を加え反応を停止した。酢酸ェチル にて抽出後、抽出液を無水硫酸マグネシウムにて乾燥した。乾燥剤を除去した後、 抽出液を減圧濃縮し、得られた固体を酢酸ェチル Zメタノール混合溶液にて再結晶 精製し、生じた結晶を桐山ロートにてろ取し、メタノール洗浄により標記化合物を得た (23.4mg、 30%)。 Dissolve 48.5mg (0.20mmol) acetyl chloride in 2mL of benzene at room temperature ((((3-trifluorophenyl) methylene) amino) oxy) oxy) and add 6-methoxybenzothiazole 2-ylamine 32.4mg (0.18mmol) Stirring. The reaction solution was heated to reflux for 5 hours, then cooled to room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction. After extraction with ethyl acetate, the extract was dried over anhydrous magnesium sulfate. After removing the desiccant, the extract was concentrated under reduced pressure, and the resulting solid was recrystallized and purified with a mixed solution of ethyl acetate and methanol. The resulting crystals were collected by filtration with a Kiriyama funnel and washed with methanol to give the title compound. (23.4 mg, 30%).
— NMR(DMSO d )： δ 12.5(1H, brs), 8.68 (1Η, s), 8.53 (1H, br  — NMR (DMSO d): δ 12.5 (1H, brs), 8.68 (1Η, s), 8.53 (1H, br
6  6
s), 8.34(1H, dt, J = 8.3 Hz, J=l.0 Hz), 8.14(1H, d, J = 8.0 Hz), 7 .79(1H, t, J = 8.3 Hz), 7.71 (1H, d, J = 8.7 Hz), 7.64(1H, d, J = 2.5 Hz), 7.10(1H, dd, J = 8.7 Hz, J = 2.7 Hz), 5.04 (2H, s), 3.87 (3H, s)、 MS (FAB+)： 387 (M+ + 1)  s), 8.34 (1H, dt, J = 8.3 Hz, J = l.0 Hz), 8.14 (1H, d, J = 8.0 Hz), 7.79 (1H, t, J = 8.3 Hz), 7.71 ( 1H, d, J = 8.7 Hz), 7.64 (1H, d, J = 2.5 Hz), 7.10 (1H, dd, J = 8.7 Hz, J = 2.7 Hz), 5.04 (2H, s), 3.87 (3H, s), MS (FAB +): 387 (M ++ 1)
[0164] 実施例 402〜405の化合物は前記実施例 401と同様の方法で製造した。  [0164] The compounds of Examples 402 to 405 were produced in the same manner as in Example 401.
[0165] 以下、前記実施例 401と同様の方法で製造した。  [0165] The following production method was carried out in the same manner as in Example 401.
[0166] [実施例 406]N—（6 tert ブチルー 4, 5, 6, 7—テトラヒドロベンゾ [d]チアゾー ルー 2 ィル） -2- (4 -トロべンジリデンアミノォキシ）ァセトアミド [Example 406] N— (6 tert-butyl-4,5,6,7-tetrahydrobenzo [d] thiazolol 2-yl) -2- (4-trobenzylideneaminooxy) acetamide
— NMR(CDC1 ): 68.23 (2H, m), 7.98 (1H, s), 7.64 (2H, m), 4.85  — NMR (CDC1): 68.23 (2H, m), 7.98 (1H, s), 7.64 (2H, m), 4.85
3  Three
(2H, s), 2.74 (2H, m), 2.56(1H, m), 2.42(1H, m), 2.04 (1H, m), 1. 50 (1H, m), 1.30(1H, m), 0.93 (9H, s)、 MS(ESI+) :416(M+ + 1) (2H, s), 2.74 (2H, m), 2.56 (1H, m), 2.42 (1H, m), 2.04 (1H, m), 1. 50 (1H, m), 1.30 (1H, m), 0.93 (9H, s), MS (ESI +): 416 (M ++ 1)
[0167] [実施例 407]N—（6— tert ブチルー 4, 5, 6, 7—テトラヒドロベンゾ [d]チアゾー ルー 2—ィル） -2- (3—二トロべンジリデンアミノォキシ）ァセトアミド[0167] [Example 407] N- (6-tert-butyl-4,5,6,7-tetrahydrobenzo [d] thiazol 2-yl) -2- (3-dibenzylideneaminooxy) Acetamide
— NMR(CDC1 )： δ 8.34 (1H, t, J = 2.0 Hz), 8.25(1H, m), 7.97(1  — NMR (CDC1): δ 8.34 (1H, t, J = 2.0 Hz), 8.25 (1H, m), 7.97 (1
3  Three
H, s), 7.84 (1H, m), 7.58 (1H, t, J = 8.0 Hz), 4.82 (2H, s), 2.74 (2H , m), 2.56(1H, m), 2.41 (1H, m), 2.03(1H, m), 1.40(1H, m), 1.30 ( 1H, m), 0.93 (9H, s)、 MS(ESI+) :416(M+ + 1)  H, s), 7.84 (1H, m), 7.58 (1H, t, J = 8.0 Hz), 4.82 (2H, s), 2.74 (2H, m), 2.56 (1H, m), 2.41 (1H, m ), 2.03 (1H, m), 1.40 (1H, m), 1.30 (1H, m), 0.93 (9H, s), MS (ESI +): 416 (M ++ 1)
[0168] 実施例 408〜414の化合物は前記実施例 401と同様の方法で、実施例 415〜50 1の化合物は後記する実施例 669と同様の方法で、実施例 502の化合物は後記す る実施例 671と同様の方法で、実施例 503〜668の化合物は後記する実施例 669と 同様の方法で製造した。  The compounds of Examples 408 to 414 are the same as in Example 401, the compounds of Examples 415 to 501 are the same as in Example 669 described later, and the compound of Example 502 is described later. In the same manner as in Example 671, the compounds of Examples 503 to 668 were prepared in the same manner as in Example 669 described later.
[0169] [実施例 665]N—（6 （メチルスルフォ -ル）ベンゾ [d]チアゾール -2 ィル） 2—  [Example 665] N— (6 (methylsulfoyl) benzo [d] thiazole-2yl) 2—
(2— -トロベンジリデンアミノォキシ）ァセトアミド  (2-—Trobenzylideneaminooxy) acetamide
N— (6—（メチルスルフォ -ル）ベンゾ [d]チアゾールー 2—ィル）—1H—イミダゾ 一ルー 1—カルボキサミド 32mgを N, N ジメチルホルムアミド 0.5mLに溶解し、 1 —ヒドロキシベンゾトリアゾール水和物 23mg、 1—ェチル 3— (3 ジメチルアミノプ 口ピル）—カルボジイミド塩酸塩 29mgを加えた。続いて、 2— (2 -トロべンジリデン アミノォキシ）酢酸 24mgの N, N ジメチルホルムアミド溶液 0.5mLを加え、室温に て終夜攪拌した。反応系にへキサン Z酢酸ェチル =2Z3(4mL)を加え、ろ取し、標 記化合物を得た。  1—hydroxybenzotriazole hydrate by dissolving 32 mg of N— (6- (methylsulfo-) benzo [d] thiazol-2-yl) —1H—imidazo 1-ro 1-carboxamide in 0.5 mL of N, N dimethylformamide 23 mg, 1-ethyl 3- (3 dimethylaminopropyl) -carbodiimide hydrochloride 29 mg was added. Subsequently, 2- (2-trobenzylideneaminoxy) acetic acid (24 mg) in N, N dimethylformamide solution (0.5 mL) was added, and the mixture was stirred at room temperature overnight. Hexane Z ethyl acetate = 2Z3 (4 mL) was added to the reaction system, and the mixture was collected by filtration to give the title compound.
[0170] [実施例 669]N— (4—メトキシベンゾ [d]チアゾールー 2 ィル）ー2—（3 -トロべ ンジリデンアミノ才キシ)ァセトアミド  [0170] [Example 669] N— (4-Methoxybenzo [d] thiazol-2-yl) -2- (3-trobenzylideneamino-gen-oxy) acetoamide
室温下（（（（3 -トロフエ-ル)メチレン）ァミノ）ォキシ）酢酸 22.4mg(0. lOmmo 1)、 2 ァミノ一 4—メトキシベンゾチアゾール 19.8mg(0. llmmol)、 1—ェチル一 3— (3 ジメチルァミノプロピル）カルボジイミド塩酸塩 (WSC—HC1) 28.8mg(0. 15mmol)、 1—ヒドロキシ一 1H べォゾトリァゾーノレ（HOBt)20.3mg(0.15mmo 1)を N, N'—ジメチルホルムアミド lmLに加え撹拌した。終夜攪拌後、反応溶液に水 を加え反応を停止し、塩化メチレンで抽出後、抽出液を無水硫酸マグネシウムにて 乾燥した。乾燥剤を除去した後、抽出液を減圧濃縮し、得られた残渣をへキサン Z 酢酸ェチル（1Z1)を用いて TLC精製し、標記化合物を得た (6.8mg、 18%)。At room temperature ((((3-trifluoro) methylene) amino) oxy) acetic acid 22.4 mg (0. lOmmo 1), 2-amino 4-methoxybenzothiazole 19.8 mg (0. llmmol), 1-ethyl 3- (3 Dimethylaminopropyl) carbodiimide hydrochloride (WSC—HC1) 28.8 mg (0.15 mmol), 1-hydroxy 1H benzotriazolone (HOBt) 20.3 mg (0.15 mmo 1) N, N′— Dimethylformamide was added to 1 mL and stirred. After stirring overnight, water was added to the reaction solution to stop the reaction. After extraction with methylene chloride, the extract was washed with anhydrous magnesium sulfate. Dried. After removing the desiccant, the extract was concentrated under reduced pressure, and the resulting residue was purified by TLC using hexane Z ethyl acetate (1Z1) to obtain the title compound (6.8 mg, 18%).
— NMR(DMSO— d ): 68.48 (1H, s), 8.03 (1H, m), 7.65 (1H, t, J =  — NMR (DMSO— d): 68.48 (1H, s), 8.03 (1H, m), 7.65 (1H, t, J =
6  6
8. 1 Hz), 7.44(1H, d, J = 8.0 Hz), 7.28 (1H, t, J = 8.0 Hz), 7.16(1 H, m), 7.03(1H, t, J = 8. 1 Hz), 7.00(1H, m), 6.85(1H, d, J = 8.3 H z), 3.97 (2H, s), 3.91 (3H, s)、 MS(ESI+) :387(M+ + 1)  8.1 Hz), 7.44 (1H, d, J = 8.0 Hz), 7.28 (1H, t, J = 8.0 Hz), 7.16 (1 H, m), 7.03 (1H, t, J = 8.1 Hz ), 7.00 (1H, m), 6.85 (1H, d, J = 8.3 H z), 3.97 (2H, s), 3.91 (3H, s), MS (ESI +): 387 (M + + 1)
[0171] [実施例 670]N— (6 -トロベンゾ [d]チアゾールー 2 ィル）ー2—（3 -トロべ ンジリデンアミノ才キシ)ァセトアミド [0171] [Example 670] N— (6-Trobenzo [d] thiazol-2-yl) -2- (3-trobenzylideneamino-oxygen) acetoamide
前記実施例 669と同様の方法で製造した。  It was produced in the same manner as in Example 669.
'H-NMRCDMSO-d ): 69.29(1H, d, J = 2.7 Hz), 8.85(1H, s), 8.  'H-NMRCDMSO-d): 69.29 (1H, d, J = 2.7 Hz), 8.85 (1H, s), 8.
6  6
68 (1H, s), 8.49 (2H, m), 8.29(1H, d, J = 8.0 Hz), 8.13(1H, d, J = 8. 8 Hz), 7.94(1H, t, J = 8.0 Hz), 5.26(2H, s)、 MS(ESI+) :402(M+ + 1) [0172] [実施例 671]N— (6 エトキシベンゾ [d]チアゾールー 2 ィル）ー2—（3 -トロ ベンジリデンアミノォキシ)ァセトアミド  68 (1H, s), 8.49 (2H, m), 8.29 (1H, d, J = 8.0 Hz), 8.13 (1H, d, J = 8.8 Hz), 7.94 (1H, t, J = 8.0 Hz) ), 5.26 (2H, s), MS (ESI +): 402 (M ++ 1) [0172] [Example 671] N— (6 ethoxybenzo [d] thiazol-2-yl) -2- (3-trobenzylidene Aminooxy) acetamide
室温下（（（（3 -トロフエ-ル)メチレン）ァミノ）ォキシ）酢酸 22.4mg(0. 10mm ol)、 2 アミノー 6 エトキシベンゾチアゾール 22. Omg(0. llmmol)、 4— (4, 6 —ジメトキシ一 1, 3, 5 トリァジン一 2—ィル） 4—メチルモルフオリ-ゥムクロリド（ DMTMM) 30.4mg(0. llmmol)をテトラヒドロフラン lmLに加え撹拌した。終夜 攪拌後、反応溶液に水を加え反応を停止し、塩化メチレンで抽出後、抽出液を無水 硫酸マグネシウムにて乾燥した。乾燥剤を除去した後、抽出液を減圧濃縮し、得られ た残渣をへキサン Z酢酸ェチル（1Z1)を展開溶媒として、 TLCにて精製し、標記化 合物を得た（2.3mg、 34%) o  At room temperature ((((3-trifluoro) methylene) amino) oxy) acetic acid 22.4 mg (0. 10 mmol), 2 amino-6 ethoxybenzothiazole 22. Omg (0. llmmol), 4- (4, 6 — Dimethoxy-1,3,5 triazine-2-yl) 4-methylmorpholine chloride (DMTMM) 30.4 mg (0. llmmol) was added to tetrahydrofuran 1 mL and stirred. After stirring overnight, water was added to the reaction solution to stop the reaction. After extraction with methylene chloride, the extract was dried over anhydrous magnesium sulfate. After removing the desiccant, the extract was concentrated under reduced pressure, and the resulting residue was purified by TLC using hexane Z ethyl acetate (1Z1) as a developing solvent to obtain the title compound (2.3 mg, 34 %) o
'H-NMRCDMSO-d )： δ 8.70(1H, s), 8.53(1H, d, J = 8.1 Hz), 8.  'H-NMRCDMSO-d): δ 8.70 (1H, s), 8.53 (1H, d, J = 8.1 Hz), 8.
6  6
35 (1H, d, J = 8.1 Hz), 8. 15(1H, d, J = 8.1 Hz), 7.80(1H, t, J = 8. 1 Hz), 7.70(1H, d, J = 8.8 Hz), 7.63(1H, s), 7.09(1H, d, J=8.0 Hz) , 5.04 (2H, s), 4.13(2H, q, J = 7. 1 Hz), 1.40(3H, t, J = 7.1 Hz)、 MS (ESI+) :401(M+ + 1)  35 (1H, d, J = 8.1 Hz), 8.15 (1H, d, J = 8.1 Hz), 7.80 (1H, t, J = 8.1 Hz), 7.70 (1H, d, J = 8.8 Hz) ), 7.63 (1H, s), 7.09 (1H, d, J = 8.0 Hz), 5.04 (2H, s), 4.13 (2H, q, J = 7.1 Hz), 1.40 (3H, t, J = 7.1 Hz), MS (ESI +): 401 (M ++ 1)
[0173] アミド誘導体 実施例 672〜694は後記する実施例 703と同様の方法で製造した。 [0173] Amide derivatives Examples 672 to 694 were produced in the same manner as Example 703 described later.
[0174] [実施例 695]2—（1H—イミダゾールー 2—ィルチオ） N— (6—tert ブチルー 4 , 5, 6, 7—テトラヒドロべンゾ [d]チアゾールー 2 ィル）ァセトアミド [Example 695] 2— (1H-imidazole-2-ylthio) N— (6-tert butyl-4,5,6,7-tetrahydrobenzo [d] thiazole-2-yl) acetamide
後記する実施例 703と同様の方法で製造した。 It was produced in the same manner as in Example 703 described later.
— NMR(CDC1 ): 63.72 (2H, s), 2.64— 2.73 (2H, complex) , 2.49 (  — NMR (CDC1): 63.72 (2H, s), 2.64— 2.73 (2H, complex), 2.49 (
3  Three
IH, m), 2.36 (IH, m), 1.95 (IH, m), 1.45 (IH, m), 1.33 (IH, m), 0.8 8(9H, s)、 MS(FAB+) :351(M+ + 1)  IH, m), 2.36 (IH, m), 1.95 (IH, m), 1.45 (IH, m), 1.33 (IH, m), 0.8 8 (9H, s), MS (FAB +): 351 (M ++ 1)
[0175] 実施例 696〜702の化合物は後記する実施例 703と同様の方法で製造した。 [0175] The compounds of Examples 696 to 702 were produced in the same manner as in Example 703 described later.
[0176] [実施例 703] 2—（4 エトキシカルボ-ルー 1H イミダゾールー 2—ィルチオ） N—（6—メトキシカルボ-ルペンゾ [d]チアゾールー 2 ィル）ァセトアミド [0176] [Example 703] 2— (4 Ethoxycarbo-Lu 1H Imidazole-2-ylthio) N— (6-Methoxycarbolpenzo [d] thiazole-2-yl) acetamide
4 エトキシカルボ-ル— 2—メルカプトイミダゾール 27mg(0.16mmol)を N, N ，—ジメチルホルムアミド 0.3mLに溶解し、ナトリウムメトキシド 8.3mg(0.16mmol) 、 N— (6—メトキシカルボ-ルペンゾ [d]チアゾール—2—ィル）—2 クロロアセトァ ミド 40mg(0.14mmol)を加え、室温で五時間攪拌した。混合溶液に飽和塩化アン モ -ゥム溶液を加え、クロ口ホルムで抽出後、飽和食塩水にて洗浄、有機層を硫酸ナ トリウムにて乾燥した。減圧濃縮後得られた固体をクロ口ホルム Zメタノール混合溶媒 にて洗浄し、標記化合物を得た（32mg、 54%)。 4 Ethoxycarbol-2-mercaptoimidazole 27 mg (0.16 mmol) was dissolved in 0.3 mL of N, N, -dimethylformamide, 8.3 mg (0.16 mmol) of sodium methoxide, N- (6-methoxycarbolpenzo [d ] Thiazole-2-yl) -2 chloroacetamide 40 mg (0.14 mmol) was added and stirred at room temperature for 5 hours. A saturated ammonium chloride solution was added to the mixed solution, extracted with chloroform, washed with saturated brine, and the organic layer was dried over sodium sulfate. The solid obtained after concentration under reduced pressure was washed with Kuroguchi Form Z methanol mixed solvent to obtain the title compound (32 mg, 54%).
— NMR(DMSO d ): 68.65(1H, m), 8.01 (IH, dd, J = 8.4 Hz, J=  — NMR (DMSO d): 68.65 (1H, m), 8.01 (IH, dd, J = 8.4 Hz, J =
6  6
2.0 Hz), 7.84— 7.82 (2H, m), 4.23—4. 16 (4H, m), 3.88 (3H, s), 1. 2.0 Hz), 7.84—7.82 (2H, m), 4.23—4. 16 (4H, m), 3.88 (3H, s), 1.
23 (3H, t, J = 7.2 Hz)、 MS(FAB+) :421(M+ + 1) 23 (3H, t, J = 7.2 Hz), MS (FAB +): 421 (M +++ 1)
[0177] 以下、実施例 704〜733の化合物は前記実施例 703と同様の方法で製造した。 Hereinafter, the compounds of Examples 704 to 733 were produced in the same manner as in Example 703.
[0178] [実施例 705]2—（5 アミノー 1H べンゾイミダゾールー 2—ィルチオ） N—（6— tert ブチルー 4, 5, 6, 7—テトラヒドロべンゾ [d]チアゾールー 2 ィル）ァセトアミド — NMR(CDC1 )： δ 7.10 (IH, brs), 6.38 (2H, dd, J = 8.5 Hz, J=l.9 [Example 705] 2- (5 amino-1H benzoimidazole-2-ylthio) N- (6-tert-butyl-4,5,6,7-tetrahydrobenzo [d] thiazole-2-yl) Acetamide — NMR (CDC1): δ 7.10 (IH, brs), 6.38 (2H, dd, J = 8.5 Hz, J = l.9
3  Three
Hz), 3.90 (2H, s), 2.74 (2H, m), 2.53 (IH, m), 2.42 (IH, m), 2.00 ( IH, m), 1.50 (IH, m), 1.37(1H, m), 0.93 (9H, s)、 MS(FAB+) :416 (M + + 1)  Hz), 3.90 (2H, s), 2.74 (2H, m), 2.53 (IH, m), 2.42 (IH, m), 2.00 (IH, m), 1.50 (IH, m), 1.37 (1H, m ), 0.93 (9H, s), MS (FAB +): 416 (M ++ 1)
[0179] [実施例 722]2—（IH—イミダゾールー 2—ィルチオ） N— (6—11ープロピルー4 , 5, 6, 7—テトラヒドロべンゾ [d]チアゾールー 2 ィル）ァセトアミド[0179] [Example 722] 2- (IH-imidazole-2-ylthio) N- (6-11-propyl-4 , 5, 6, 7-Tetrahydrobenzo [d] thiazole-2-yl) acetamide
— NMR(CDC1 ): 67.01 (2H, brs), 3.79 (2H, s), 2.79(1H, dd, J=l  — NMR (CDC1): 67.01 (2H, brs), 3.79 (2H, s), 2.79 (1H, dd, J = l
3  Three
5.8 Hz, J=4.6 Hz), 2.70(1H, m), 2.60(1H, m), 2.29(1H, m), 1.9 4(1H, m), 1.78 (1H, brs), 1.38 (4H, m), 0.93 (3H, t, J = 6.4 Hz) , MS (ESI+) :336(M+ + 1)  5.8 Hz, J = 4.6 Hz), 2.70 (1H, m), 2.60 (1H, m), 2.29 (1H, m), 1.9 4 (1H, m), 1.78 (1H, brs), 1.38 (4H, m ), 0.93 (3H, t, J = 6.4 Hz), MS (ESI +): 336 (M + + 1)
[0180] [実施例 728]2—（6 アミノー 1H べンゾ [d]イミダゾールー 2—ィルチオ） N— 2 一（6—メトキシカルボ-ルペンゾ [d]チアゾールー 2 ィル）ァセトアミド  [0180] [Example 728] 2- (6 amino-1H benzo [d] imidazole-2-ylthio) N-2 mono (6-methoxycarborpenezo [d] thiazol-2-yl) acetamide
室温下、 6 アミノー 1H ベンゾイミダゾールー 2 チオール 49.6mg(0.30mm ol)、ナトリウムメトキシド 16.2mg(0.3mmol)を N, N ジメチルホルムアミド lmLに 加え三十分間撹拌した。上記溶液にメチルー 2—（2—クロロアセトアミド)ベンゾチア ゾール—6—カルボキシレートをカ卩えた。終夜攪拌後、反応溶液に水、酢酸ェチルを 加え反応を停止し、フェーズセパレーター (Whatman (登録商標） )を用いて有機層 を分離し、減圧濃縮した。得られた残渣に酢酸ェチル、メタノールを加え、溶け残つ た固体を桐山ロートにてろ取し、さらにメタノールにて洗浄した。得られた固体を減圧 下、 50°Cにて乾燥し、標記化合物を得た（18.4mg、 27%)。 At room temperature, 6 amino-1H benzimidazole-2 thiol 49.6 mg (0.30 mmol) and sodium methoxide 16.2 mg (0.3 mmol) were added to 1 mL of N, N dimethylformamide and stirred for 30 minutes. Methyl-2- (2-chloroacetamido) benzothiazole-6-carboxylate was added to the above solution. After stirring overnight, water and ethyl acetate were added to the reaction solution to stop the reaction, and the organic layer was separated using a phase separator (Whatman (registered trademark)) and concentrated under reduced pressure. Ethyl acetate and methanol were added to the resulting residue, and the solid that remained undissolved was collected by filtration with a Kiriyama funnel and further washed with methanol. The obtained solid was dried at 50 ° C. under reduced pressure to obtain the title compound (18.4 mg, 27%).
— NMR(CD OD)： δ 8.54(1H, m), 8.06 (1Η, dd, J=8.5 Hz, J=l.7  — NMR (CD OD): δ 8.54 (1H, m), 8.06 (1Η, dd, J = 8.5 Hz, J = l.7
3  Three
Hz), 7.78 (1H, d, J = 8.5 Hz), 7.32(1H, d, J = 8.9 Hz), 6.92(1H, d , J= 1.9), 6.76(1H, dd, J = 8.5 Hz, J=l.9 Hz), 4.20 (1H, s), 3.92 (3H, s)、 MS(ESI+) :414(M+ + 1)  Hz), 7.78 (1H, d, J = 8.5 Hz), 7.32 (1H, d, J = 8.9 Hz), 6.92 (1H, d, J = 1.9), 6.76 (1H, dd, J = 8.5 Hz, J = l.9 Hz), 4.20 (1H, s), 3.92 (3H, s), MS (ESI +): 414 (M +++ 1)
[0181] [実施例 734] N—(ベンゾ [d]チアゾールー 2—ィル）ー3 フエ-ルイソキサゾー ルー 5—カルボキサミド [0181] [Example 734] N— (Benzo [d] thiazol-2-yl) -3 phenol isoxazol® 5-carboxamide
1)3 フエ二ルイソキサゾール 5 カルボニルクロリド  1) 3 phenyl isoxazole 5 carbonyl chloride
市販の 3 フエ-ルイソキサゾール—5—カルボン酸 150mg(0.79mmol)をテトラ ヒドロフラン 4.5mLに溶解し、ォキザリルクロリド 102 1^(1.19mmol)を加え、室温 にて三十分間攪拌した。さらに、ォキザリルクロライド 102/^(1.19mmol)をカロえ、 80°Cにて二時間攪拌した。混合溶液を減圧濃縮し、標記化合物をクルードとして得 た（136mg、 83%) o  150 mg (0.79 mmol) of commercially available 3-phenylisoxazole-5-carboxylic acid was dissolved in 4.5 mL of tetrahydrofuran, oxalyl chloride 102 1 ^ (1.19 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Further, oxalyl chloride 102 / ^ (1.19 mmol) was prepared and stirred at 80 ° C. for 2 hours. The mixed solution was concentrated under reduced pressure to give the title compound as crude (136 mg, 83%) o
[0182] 2)N— (ベンゾ [d]チアゾール 2—ィル） 3 フエ-ルイソキサゾール 5—カル ボキサミド [0182] 2) N— (Benzo [d] thiazole 2-yl) 3 Phenol isoxazole 5-Cal Boxamide
市販の 2—ァミノべンゾ [d]チアゾール 13.2mgをテトラヒドロフラン 0.6mLに溶解 し、ピリジン 12 （0. 144mmol)、 1)で得たィ匕合物 20mg(0. O96mmol)をカロえ、 室温にて三時間攪拌した。混合溶液をろ取し、得られた固体を、 P—TLC (へキサン Z酢酸ェチル =5Z2)にて精製し、標記化合物を得た（7mg、 25%) o Commercially available 2-aminobenzo [d] thiazole 13.2 mg was dissolved in 0.6 mL of tetrahydrofuran, and 20 mg (0.96 mmol) of the compound obtained with pyridine 12 (0.144 mmol), 1) was prepared at room temperature. For 3 hours. The mixed solution was collected by filtration, and the obtained solid was purified by P-TLC (hexane Z ethyl acetate = 5Z2) to obtain the title compound (7 mg, 25%) o
— NMR(CDC1 ): 67.87— 7.84(4H、 m)、 7.54— 7.51(4H、 m)、 7.39  — NMR (CDC1): 67.87— 7.84 (4H, m), 7.54—7.51 (4H, m), 7.39
3  Three
-7.36(1H、 m)、 7.11(1H, s)、 MS(ESI+) :322(M+ + 1)  -7.36 (1H, m), 7.11 (1H, s), MS (ESI +): 322 (M ++ 1)
[0183] 実施例 735〜737の化合物は前記実施例 734と同様の方法で、実施例 738〜750 の化合物は前記実施例 703と同様の方法で製造した。 [0183] The compounds of Examples 735 to 737 were produced in the same manner as in Example 734, and the compounds of Examples 738 to 750 were produced in the same manner as in Example 703.
[0184] 中間体 [0184] Intermediate
上記化合物の合成に用いた中間体の構造を示せば、以下の通りである。なお、表 2 および表 3は前述の schemelllにおける式 (3-2)および式 (13)で表される化合物である  The structure of the intermediate used in the synthesis of the above compound is as follows. Tables 2 and 3 are compounds represented by the formulas (3-2) and (13) in the schemelll described above.
[0185] [表 1] [0185] [Table 1]
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000083_0001
Figure imgf000084_0001
CZSTS0/.00Zdf/X3d 38 1?8δ980/.00Ζ OAV 3] CZSTS0 / .00Zdf / X3d 38 1? 8δ980 / .00Ζ OAV 3]
Figure imgf000085_0001
Figure imgf000085_0001
[実施例 751]ベンジル （4一（4 ブロモフエニル） 1H—イミダゾールー 2 ィル） メチルカーバメート [Example 751] Benzyl (4-bromophenyl) 1H-imidazole-2-yl) Methyl carbamate
ベンジル 2 アミノー 2—イミノエチルカーバメート臭化水素酸塩 864mg (3. Om mol)をテトラヒドロフラン/水 = 10/1の混合溶液 30mLに溶解し、炭酸カリウム 41 5mg (3. Ommol)、 2 プロモー 1一（4一ブロモフエ-ル)エタノン 584mg (2. lmm ol)を加え、 80°Cにて三十分間攪拌した。混合溶液に飽和食塩水を加え、塩化メチ レンで抽出後、硫酸ナトリウムにて乾燥した。減圧濃縮して得られる固体をクロ口ホル ムで洗浄し、標記化合物を得た（232mg、 20%) oBenzyl 2 amino-2-iminoethylcarbamate hydrobromide 86 4 mg (3. Om mol) dissolved in 30 mL of a mixed solution of tetrahydrofuran / water = 10/1, potassium carbonate 41 5 mg (3. Ommol), 2 Promo 1 One (4 bromophenol) Ethanone 584mg (2. lmm ol) was added and stirred at 80 ° C. for 30 minutes. Saturated brine was added to the mixed solution, extracted with methyl chloride, and dried over sodium sulfate. The solid obtained by concentration under reduced pressure was washed with black mouthform to obtain the title compound (232 mg, 20%).
— NMR(CDC1 )： δ 7.60 (2Η, d, J = 8.5 Hz), 7.47 (2H, d, J = 8.5  — NMR (CDC1): δ 7.60 (2Η, d, J = 8.5 Hz), 7.47 (2H, d, J = 8.5
3  Three
Hz), 7.37-7.32 (5H, m), 7.22(1H, s), 5.63(1H, br), 5.15 (2H, s), 4 .41 (2H, d, J = 6.1 Hz)、 MS(FAB+) :386(M+ + 1)  Hz), 7.37-7.32 (5H, m), 7.22 (1H, s), 5.63 (1H, br), 5.15 (2H, s), 4.41 (2H, d, J = 6.1 Hz), MS (FAB + ): 386 (M ++ 1)
[0189] 以下、前記実施例 751と同様の方法で製造した。 [0189] Then, the same method as in Example 751 was produced.
[0190] [実施例 752]ベンジル（4一 （4一（（エトキシカルボ-ル)メトキシ）フエ-ル）一 1H イミダゾール— 2—ィル）メチルカーバメート [0190] [Example 752] Benzyl (4 (4 (((ethoxycarbol) methoxy) phenol) 1) 1H imidazole-2-yl) methyl carbamate
— NMR(CDC1 ): 67.57 (2H, d, J = 8.8 Hz), 7.31— 7.37 (5H, m)  — NMR (CDC1): 67.57 (2H, d, J = 8.8 Hz), 7.31— 7.37 (5H, m)
3  Three
, 7.12(1H, s), 6.89 (2H, d, J = 8.8 Hz), 5.97(1H, br), 5. 13 (2H, s), 4.62 (2H, s), 4.39 (2H, d, J = 6.1 Hz), 4.27 (2H, q, J = 7.2 Hz), 1.3 0(3H, t, J = 7.2 Hz)、 MS(FAB+) :310(M+ + 1)  , 7.12 (1H, s), 6.89 (2H, d, J = 8.8 Hz), 5.97 (1H, br), 5.13 (2H, s), 4.62 (2H, s), 4.39 (2H, d, J = 6.1 Hz), 4.27 (2H, q, J = 7.2 Hz), 1.3 0 (3H, t, J = 7.2 Hz), MS (FAB +): 310 (M + + 1)
[0191] [実施例 753]ベンジル（4— (3 ブロモフエ-ル) 1H イミダゾール— 2—ィル） メチルカーバメート[0191] [Example 753] benzyl (4- (3 bromophenol) 1H imidazole-2-yl) methyl carbamate
— NMR(CDC1 ): 67.85 (1H, brs), 7.59— 7.61 (1H, m), 7.20— 7.  — NMR (CDC1): 67.85 (1H, brs), 7.59— 7.61 (1H, m), 7.20— 7.
3  Three
38 (8H, m), 5.68 (1H, br), 5.15 (2H, s), 4.42 (2H, d, J = 6.4 Hz) , MS (FAB+) :386(M+ + 1)  38 (8H, m), 5.68 (1H, br), 5.15 (2H, s), 4.42 (2H, d, J = 6.4 Hz), MS (FAB +): 386 (M + + 1)
[0192] [実施例 754]ベンジル（4— (3 ((エトキシカルボ-ル)メトキシ）フエ-ル） 1H イミダゾール— 2—ィル）メチルカーバメート [Example 754] Benzyl (4- (3 ((ethoxycarbol) methoxy) phenol) 1H imidazole-2-yl) methylcarbamate
1 ブロモ 2 (3— ( (エトキシカルボ-ル）メトキシ）フエ-ル）プロノ ノン 365mg ( 1.21mmol)、ベンジルアミドメチルカルバメート塩酸塩 296mg(l.21mmol)と炭 酸カリウム 168mg(l.21mmol)を N, N，—ジメチルホルムアミド溶液（5mL)に加え 、室温下で二時間攪拌した。反応懸濁液をセライトにてろ過し、ろ液に飽和食塩水を 加え、酢酸ェチルで抽出後、無水硫酸マグネシウムにて乾燥した。減圧濃縮して得 られる固体をシリカゲル薄層クロマトグラフィー（クロ口ホルム Zメタノール 10/1)に て標記化合物を 117mg (24%)得た。 1 Bromo 2 (3-((ethoxycarbol) methoxy) phenol) prononone 365 mg (1.21 mmol), benzylamidomethylcarbamate hydrochloride 296 mg (l.21 mmol) and potassium carbonate 168 mg (l.21 mmol) To the N, N, -dimethylformamide solution (5 mL), the mixture was stirred at room temperature for 2 hours. The reaction suspension was filtered through celite, saturated brine was added to the filtrate, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solid obtained by concentration under reduced pressure was subjected to silica gel thin layer chromatography (Kuroguchi Form Z methanol 10/1) to obtain 117 mg (24%) of the title compound.
— NMR(CDC1 ): 67.20— 7.34 (9H, complex) , 7.14(1H, brs), 6. 75 (IH, brs), 6.54 (IH, brs), 5.05 (2H, s), 4.58 (2H, s), 4.36 (2H, d, J = 6. 1 Hz), 4.23 (2H, q, J = 7.3 Hz), 1.26(3H, t, J = 7.3 Hz)、 MS (EI +) :409 (M+) — NMR (CDC1): 67.20— 7.34 (9H, complex), 7.14 (1H, brs), 6. 75 (IH, brs), 6.54 (IH, brs), 5.05 (2H, s), 4.58 (2H, s), 4.36 (2H, d, J = 6.1 Hz), 4.23 (2H, q, J = 7.3 Hz), 1.26 (3H, t, J = 7.3 Hz), MS (EI +): 409 (M +)
[0193] [実施例 755]ベンジル（4— (3、 4 ジクロロフエ-ル) IH イミダゾール— 2— ィル）メチルカーバメート [0193] [Example 755] Benzyl (4- (3,4-dichlorophenol) IH imidazole-2-yl) methyl carbamate
— NMR(CDC1 /CD OD)： δ 7.73(1H, d, J = 2 Hz), 7.30— 7.47(8  — NMR (CDC1 / CD OD): δ 7.73 (1H, d, J = 2 Hz), 7.30— 7.47 (8
3 3  3 3
H, complex) , 5.10 (2H, s), 4.33 (2H, s)、 MS (FAB+) : 376 (M+ + 1)  H, complex), 5.10 (2H, s), 4.33 (2H, s), MS (FAB +): 376 (M + + 1)
[0194] [実施例 756]ベンジル（4一（3—メトキシフエ-ル) 1H イミダゾールー 2—ィル )メチルカーバメート[Example 756] Benzyl (4- (3-methoxyphenol) 1H imidazole-2-yl) methyl carbamate
— NMR(CDC1 ): 67. 19— 7.30(10H, complex) , 6.77(1Η, m), 6.  — NMR (CDC1): 67. 19— 7.30 (10H, complex), 6.77 (1Η, m), 6.
3  Three
39 (IH, m) , 5.09 (2H, s) , 4.38 (2H, d, J = 6. 1 Hz) , 3.78 (3H, s)、 MS ( FAB+) :338(M+ + 1)  39 (IH, m), 5.09 (2H, s), 4.38 (2H, d, J = 6.1 Hz), 3.78 (3H, s), MS (FAB +): 338 (M + + 1)
[0195] [実施例 757]ベンジル（4 （ピリジンー3 ィル） 1H—イミダゾールー 2 ィル） メチルカーバメート[0195] [Example 757] Benzyl (4 (pyridine-3-yl) 1H-imidazole-2 yl) Methyl carbamate
— NMR(CDC1 ): 68.94 (IH, brs), 8.47(1H, d, J=4.8 Hz), 7.99  — NMR (CDC1): 68.94 (IH, brs), 8.47 (1H, d, J = 4.8 Hz), 7.99
3  Three
—8.01 (IH, m), 7.32— 7.36 (5H, m), 7.28— 7.31 (3H, m), 5.16 (2H, brs), 4.44 (2H, d, J = 6.0 Hz)、 MS (FAB+) : 308 (M+)  —8.01 (IH, m), 7.32— 7.36 (5H, m), 7.28— 7.31 (3H, m), 5.16 (2H, brs), 4.44 (2H, d, J = 6.0 Hz), MS (FAB +): 308 (M +)
[0196] [実施例 758]ベンジル（4 フエ-ルー IH イミダゾールー 2 ィル)メチルカーバメ ート[0196] [Example 758] Benzyl (4-ferro-IH imidazole-2-yl) methyl carbamate
— NMR(CDC1 ): 67.34— 7.39 (8H, m), 7.22— 7.24 (3H, m)5.15(  — NMR (CDC1): 67.34— 7.39 (8H, m), 7.22— 7.24 (3H, m) 5.15 (
3  Three
2H, s), 4.43 (2H, d, J = 6.4 Hz)  2H, s), 4.43 (2H, d, J = 6.4 Hz)
[0197] [実施例 759]4—（4 ブロモフエ-ルー IH—イミダゾールー 2 ィル)メチルァミン 塩酸塩 [0197] [Example 759] 4- (4 Bromoferro-IH-imidazole-2-yl) methylamine hydrochloride
ベンジル （4 -フエ-ル 1 H イミダゾール 2 ィル）メチルカーノ メート 39mg (0. lOmmol)を 4N—塩酸 Zジォキサン Z水の混合溶液 5mLに溶解し 100°Cで 1. 5時間攪拌した。混合液をエーテルで洗浄後、水層を減圧濃縮し、標記化合物を得 た（28mg、 86%) o 39 mg (0.1 mmol) of benzyl (4-phenol 1 H imidazole 2 yl) methylcarnamate was dissolved in 5 mL of a mixed solution of 4N-hydrochloric acid Z dioxane Z water and stirred at 100 ° C for 1.5 hours. The mixture was washed with ether, and the aqueous layer was concentrated under reduced pressure to give the title compound (28 mg, 86%).
— NMR(CD OD)： δ 8.04 (IH, br) , 7.74— 7.71 (4H, m), 4.57 (2H, br)、 MS (FAB+)： 252 (M+ + 1) — NMR (CD OD): δ 8.04 (IH, br), 7.74— 7.71 (4H, m), 4.57 (2H, br), MS (FAB +): 252 (M ++ 1)
[0198] [実施例 760] (4— (4 エトキシカルボ-ルメトキシフエ-ル) 1H イミダゾール [0198] [Example 760] (4- (4 ethoxycarboromethoxyphenyl) 1H imidazole
2—ィル)メチルァミン塩酸塩  2-yl) methylamine hydrochloride
後記する実施例 762と同様の方法で製造した。 It was produced in the same manner as in Example 762 described later.
— NMR(CD OD)： δ 7. 63 (2Η, d, J = 8. 8 Hz) , 7. 35 (1H, s) , 6. 95 (  — NMR (CD OD): δ 7. 63 (2Η, d, J = 8.8 Hz), 7. 35 (1H, s), 6. 95 (
3  Three
1H, d, J = 8. 8 Hz) , 4. 72. (2H, s) , 4. 25 (2H, q, J = 7. 3 Hz) , 1. 29 (3H , t, J = 7. 3 Hz)  1H, d, J = 8.8 Hz), 4. 72. (2H, s), 4.25 (2H, q, J = 7.3 Hz), 1.29 (3H, t, J = 7. (3 Hz)
[0199] [実施例 761] (4— (3 ブロモフエ-ル) 1H イミダゾール— 2—ィル)メチルァ 塩酸塩  [0199] [Example 761] (4- (3 Bromophenol) 1H imidazole-2-yl) methyla hydrochloride
前記実施例 759と同様の方法で製造した。 The same method as in Example 759 was used.
— NMR(CD OD)： δ 8. 18 (2Η, m) , 7. 77 (1Η, d, J = 8. 0 Hz) , 7. 62  — NMR (CD OD): δ 8. 18 (2Η, m), 7. 77 (1Η, d, J = 8.0 Hz), 7. 62
3  Three
(1H, d, J = 7. 6 Hz) , 7. 44. (1H, dd, J = 8. 0 Hz, 7. 6 Hz) , 4. 53 (2H, s )、 MS (FAB+)： 252 (M+ + 1)  (1H, d, J = 7.6 Hz), 7. 44. (1H, dd, J = 8.0 Hz, 7.6 Hz), 4. 53 (2H, s), MS (FAB +): 252 (M +++ 1)
[0200] [実施例 762] 4— (3— ( (エトキシカルボ-ル）メトキシ）フエ-ル) 1H イミダゾ 一ルー 2—ィル)メチルァミン塩酸塩 [0200] [Example 762] 4— (3 — ((Ethoxycarbol) methoxy) phenol) 1H imidazo 1-ru 2-yl) methylamine hydrochloride
ベンジル（5— (3 ( (エトキシカルボ-ル)メトキシ）フエ-ル) 1H イミダゾー ルー 2—ィル）メチルカーバメート 95mg (0. 23mmol)をメタノール（5mL)、 10%メタ ノール塩酸溶液 (0. 5mL)の混液に溶かし、 10%パラジウム/炭素触媒 28mgをカロえ た。室温、水素雰囲気下、一時間撹拌後アルゴンガス置換して反応を停止した。反 応懸濁液をセライトにてろ過、メタノールで洗浄し、減圧濃縮にて標記化合物を 72m g (90%)得た。 Benzyl (5- (3 ((ethoxycarbol) methoxy) phenol) 1H imidazole 2-yl) methylcarbamate 95 mg (0.23 mmol) in methanol (5 mL), 10% methanolic hydrochloric acid solution (0. 5 mL), and 28 mg of 10% palladium / carbon catalyst was added. After stirring for 1 hour at room temperature in a hydrogen atmosphere, the reaction was stopped by replacing with argon gas. The reaction suspension was filtered through celite, washed with methanol, and concentrated under reduced pressure to obtain 72 mg (90%) of the title compound.
— NMR(DMSO)： δ 8. 69 (2Η, brs) , 7. 84 (1Η, s) , 7. 42 (2H, m) , 7 . 34 (1H, t, J = 8. 3 Hz) , 6. 86 (1H, m) , 4. 81 (2H, s) , 4. 26 (2H, brs) , 4 . 17 (2H, q, J = 7. 1 Hz) , 1. 21 (3H, t, J = 7. 1 Hz)、 MS (EI+) : 275 (M+) [0201] [実施例 763] (4— (3、 4 ジクロロフエ-ル) 1H イミダゾール— 2—ィル)メチ ルァミン塩酸塩  — NMR (DMSO): δ 8.69 (2Η, brs), 7.84 (1Η, s), 7.42 (2H, m), 7.34 (1H, t, J = 8.3 Hz), 6.86 (1H, m), 4.81 (2H, s), 4.26 (2H, brs), 4.17 (2H, q, J = 7.1 Hz), 1.21 (3H, t , J = 7.1 Hz), MS (EI +): 275 (M +) [0201] [Example 763] (4— (3,4 Dichlorophenol) 1H imidazole-2-yl) methylamine hydrochloride
前記実施例 759と同様の方法で製造した。 The same method as in Example 759 was used.
— NMR(DMSO)： δ 8. 52 (2Η, brs) , 8. 07 (1H, m) , 7. 91 (1H, brs) , 7. 78 (1H, m), 7. 67(1H, d, J = 8. 5 Hz), 4. 16 (2H, s)、 MS (EI+) : 241 ( M+) — NMR (DMSO): δ 8. 52 (2Η, brs), 8. 07 (1H, m), 7. 91 (1H, brs), 7.78 (1H, m), 7.67 (1H, d, J = 8.5 Hz), 4.16 (2H, s), MS (EI +): 241 (M +)
[0202] [実施例 764] (4—（3—メトキシフエ-ル) 1H イミダゾールー 2 ィル)メチルァ 塩酸塩  [0202] [Example 764] (4- (3-Methoxyphenol) 1H imidazole-2-yl) methyl hydrochloride
前記実施例 762と同様の方法で製造した。 This was prepared in the same manner as in Example 762.
— NMR(DMSO)： δ 8. 50 (2Η, brs), 7. 29— 7.40 (4H, complex) , 6. 8 2(1Η, m), 4. 14 (2Η, s), 3. 82 (3Η, s)、 MS(FAB+) :204(Μ+ + 1)  — NMR (DMSO): δ 8. 50 (2Η, brs), 7. 29— 7.40 (4H, complex), 6. 8 2 (1Η, m), 4. 14 (2Η, s), 3. 82 ( 3Η, s), MS (FAB +): 204 (Μ ++ 1)
[0203] [実施例 765] (4— (ピリジン— 3—ィル) 1H イミダゾールー 2—ィル)メチルアミ ン塩酸塩 [0203] [Example 765] (4- (Pyridine-3-yl) 1H imidazole-2-yl) methylamine hydrochloride
前記実施例 762と同様の方法で製造した。 This was prepared in the same manner as in Example 762.
— NMR(CD OD)： δ 9. 25(1H, s) , 9. 00(1Η, d, J = 8. 2 Hz), 8. 70(1  — NMR (CD OD): δ 9. 25 (1H, s), 9.00 (1Η, d, J = 8.2 Hz), 8. 70 (1
3  Three
H, d, J=6. 2 Hz), 8. 10. (1H, dd, J = 8. 5 Hz, 6. 2 Hz), 7. 37(1H, br) , 4. 32 (2H, s)  H, d, J = 6.2 Hz), 8. 10. (1H, dd, J = 8.5 Hz, 6.2 Hz), 7. 37 (1H, br), 4. 32 (2H, s )
[0204] [実施例 766] (4—（4一（2—（3— (2, 6 ジクロ口ベンジル）ー2—メチルー 4ーォキ ソピリジンー1 (4H) ィル)メチル）フエ-ル）—1H—イミダゾールー 2 ィル)メチル ァミン塩酸塩  [0204] [Example 766] (4— (4— (2— (3— (2,6 Diclonal Benzyl) -2-methyl-4-oxopyridine-1 (4H) yl) methyl) phenol) —1H —Imidazole-2-yl) methylamine hydrochloride
1)ベンジル （4— (4— (2 （tert ブトキシカルボ-ル）ェテュルブロモフエ-ル） —1— ((2— (トリメチルシリル）エトキシ)メチル）— 1H—イミダゾール— 2—ィル)メチ ノレカーノメート  1) Benzyl (4— (4— (2 (tert-butoxycarbol) ether bromophenol) —1— ((2- (trimethylsilyl) ethoxy) methyl) — 1H-imidazole-2-yl) methyl Nore Carnomate
ベンジル （4— (4 ブロモフエ-ル）— 1— ((2— (トリメチルシリル）エトキシ）メチ ル）— 1H—イミダゾールー 2—ィル）メチルカーバメート 258mg(0. 50mmol)を N, N，—ジメチルホルムアミド 5mLに溶解し、ァクリル酸 61^—ブチル87 μL·(0. 60mm ol)、トリス（ジベンジリデンアセトン）ジパラジウム 92mg (0. lOmmol)、トリ（tert—ブ チル）フォスフィン 50 μ L (0. 20mmol)、ジシクロへキシルメチルァミン 212 μL·(l. Ommol)を加え、 80°Cにて 1. 5時間攪拌した。混合液に飽和食塩水を加え、塩化メ チレンで抽出後、硫酸ナトリウムにて乾燥した。減圧濃縮後、残渣をシリカゲルクロマ トグラフィー（へキサン Z酢酸ェチル =2Zl)にて精製し、標記化合物を得た（242m gゝ 86%)。 H-NMR(CDC1 ): 67.74 (2H, d, J = 8.3 Hz), 7.58(1H, d, J=16 Hz Benzyl (4- (4 bromophenol) — 1— ((2- (trimethylsilyl) ethoxy) methyl) — 1H-imidazole-2-yl) methyl carbamate 258 mg (0.50 mmol) N, N, dimethylformamide Dissolved in 5 mL, acrylic acid 61 ^ -butyl 87 μL · (0.60 mmol), tris (dibenzylideneacetone) dipalladium 92 mg (0.1 mmol), tri (tert-butyl) phosphine 50 μL (0. 20 mmol) and dicyclohexylmethylamine 212 μL · (l. Ommol) were added, and the mixture was stirred at 80 ° C. for 1.5 hours. Saturated brine was added to the mixture, and the mixture was extracted with methyl chloride and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (hexane Z ethyl acetate = 2Zl) to obtain the title compound (242 mg ゝ 86%). H-NMR (CDC1): 67.74 (2H, d, J = 8.3 Hz), 7.58 (1H, d, J = 16 Hz
3  Three
), 7.51 (2H, d, J = 8.3 Hz), 7.37— 7.27 (6H, m), 6.36(1H, d, J=16 Hz), 5.34 (2H, brs), 5. 14 (2H, brs), 4.54 (2H, d, J = 5.4 Hz), 3.54(2 H, t, J = 8.4 Hz), 1.54 (9H, s), 0.92 (2H, t, J = 8.4 Hz), 0.01 (9H, m )  ), 7.51 (2H, d, J = 8.3 Hz), 7.37— 7.27 (6H, m), 6.36 (1H, d, J = 16 Hz), 5.34 (2H, brs), 5. 14 (2H, brs) , 4.54 (2H, d, J = 5.4 Hz), 3.54 (2 H, t, J = 8.4 Hz), 1.54 (9H, s), 0.92 (2H, t, J = 8.4 Hz), 0.01 (9H, m )
[0205] 2)ベンジル（4— (4 ホルミルフエ-ル）— 1 ((2— (トリメチルシリル）エトキシ)メチ ル） 1H—イミダゾールー 2—ィル）メチルカーバメート  [0205] 2) Benzyl (4- (4 formylphenol) — 1 ((2- (trimethylsilyl) ethoxy) methyl) 1H-imidazole-2-yl) methyl carbamate
ベンジル （4一（4一（2 (tert ブトキシカルボ-ル）ェテュルブロモフエ-ル） —1— ((2— (トリメチルシリル）エトキシ)メチル）— 1H—イミダゾール— 2—ィル)メチ ルカーバメート 33mg(0. O59mmol)をアセトン Z水 = 3Zlの混合溶液 1.2mLに 溶解し、四酸化オスミウム（4wt%水溶液） 19/zL(0. O030mmol)、過ヨウ素酸ナトリ ゥム 44mg(0.21mmol)を加え、室温で五時間攪拌した。混合液をろ過し、ろ液に 飽和食塩水を加え、クロ口ホルムで抽出後、硫酸ナトリウムにて乾燥した。減圧濃縮 後、残渣を P—TLC (へキサン Z酢酸ェチル =1Z1)にて精製し、標記化合物を得 た（22mg、 78%) o Benzyl (4 (2 (tert-butoxycarbol) ethylbromophenol) —1— ((2- (trimethylsilyl) ethoxy) methyl) — 1H-imidazole-2-yl) methyl carbamate 33 mg (0. O59 mmol) was dissolved in 1.2 mL of a mixed solution of acetone Z water = 3 Zl, and osmium tetroxide (4 wt% aqueous solution) 19 / zL (0. O030 mmol) and sodium periodate 44 mg (0.21 mmol) were dissolved. The mixture was filtered and the mixture was filtered, saturated brine was added to the filtrate, extracted with chloroform, dried over sodium sulfate, concentrated under reduced pressure, and the residue was filtered with P-TLC (hexane. Z ethyl acetate = 1Z1) to obtain the title compound (22 mg, 78%) o
— NMR(CDC1 )： δ 10.0(1H, s) , 7.90— 7.88 (4H, m), 7.40— 7.30  — NMR (CDC1): δ 10.0 (1H, s), 7.90— 7.88 (4H, m), 7.40— 7.30
3  Three
(6H, m), 5.37 (2H, s), 4.56 (2H, d, J = 5.6 Hz), 3.56 (2H, t, J = 8.0 Hz), 0.93 (2H, t, J=8.0 Hz), 0.01 (9H, m)、 MS(FAB+) :466(M+ + 1) [0206] 3)ベンジル （4— (4— (ヒドロキシメチル）フエ-ル） 1 ( (2— (トリメチルシリル）ェ トキシ）メチル） 1H—イミダゾールー 2—ィル）メチルカーバメート  (6H, m), 5.37 (2H, s), 4.56 (2H, d, J = 5.6 Hz), 3.56 (2H, t, J = 8.0 Hz), 0.93 (2H, t, J = 8.0 Hz), 0.01 (9H, m), MS (FAB +): 466 (M + + 1) [0206] 3) Benzyl (4- (4- (hydroxymethyl) phenol) 1 ((2- (trimethylsilyl) ethoxy) methyl) 1H-imidazole-2-yl) methyl carbamate
ベンジル （4— (4 ホルミルフエ-ル） 1 ( (2— (トリメチルシリル）エトキシ)メチ ル）一 1H—イミダゾールー 2—ィル）メチルカーバメート 12mg(0.026mmol)をエタ ノール 0.5mLに溶解し、水素化ホウ素ナトリウム 1. Omg(0.026mmol)を加え、室 温で三十分間攪拌した。混合液に酢酸を加え反応を停止させた。混合液に飽和重 そう水を加え、クロ口ホルムで抽出後、硫酸ナトリウムにて乾燥した。減圧濃縮後、残 渣を P— TLC (クロ口ホルム Zメタノール =ιοΖΐ)にて精製し、標記化合物を得た（1 lmgゝ 90%) o Benzyl (4- (4 formylphenol) 1 ((2- (trimethylsilyl) ethoxy) methyl) 1 1H-imidazole-2-yl) methylcarbamate 12 mg (0.026 mmol) is dissolved in 0.5 mL of ethanol and hydrogenated. Sodium boron 1. Omg (0.026 mmol) was added, and the mixture was stirred for 30 minutes at room temperature. Acetic acid was added to the mixture to stop the reaction. Saturated sodium bicarbonate water was added to the mixture, and the mixture was extracted with black mouth form and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified with P-TLC (black mouth form Z methanol = ιοΖΐ) to obtain the title compound (1 lmg ゝ 90%) o
— NMR(CDC1 ): 67.72 (2H, d, J = 8.0 Hz), 7.39— 7.26 (8H, m), 5.35 (2H, s), 5.15 (2H, brs), 4.70 (2H, s), 4.55 (2H, d, J = 5.4 Hz), 3 .55(2H, t, J = 8.0 Hz), 0.93(2H, t, J = 8.0 Hz) , 0.01 (9H, m)、 MS (E 1+) :467(M+) — NMR (CDC1): 67.72 (2H, d, J = 8.0 Hz), 7.39— 7.26 (8H, m), 5.35 (2H, s), 5.15 (2H, brs), 4.70 (2H, s), 4.55 (2H, d, J = 5.4 Hz), 3.55 (2H, t, J = 8.0 Hz), 0.93 (2H , t, J = 8.0 Hz), 0.01 (9H, m), MS (E 1+): 467 (M + )
[0207] 4)ベンジル （4— (4— (クロロメチル）フエ-ル） 1 ( (2— (トリメチルシリル）エトキシ )メチル） 1 H イミダゾール 2—ィル）メチルカーバメート  [0207] 4) Benzyl (4- (4- (chloromethyl) phenol) 1 ((2- (trimethylsilyl) ethoxy) methyl) 1 H imidazole 2-yl) methyl carbamate
ベンジル （4— (4— (ヒドロキシメチル）フエ-ル） 1 ( (2— (トリメチルシリル）ェトキ シ）メチル） 1H—イミダゾールー 2 ィル）メチルカーバメート 4.2mg(0.0090m mol)をテトラヒドロフラン 0.3mLに溶解し、塩化チォ -ル 2.0 Lを加え、室温で一 時間攪拌した。混合液を減圧濃縮し、飽和重そう水を加え、クロ口ホルムで抽出後、 硫酸ナトリウムにて乾燥した。減圧濃縮し、標記化合物を得た（3.6mg、 82%) o — NMR(CDC1 ): 67.74 (2H, d, J = 8.1 Hz), 7.41— 7.33 (8H, m),  Benzyl (4- (4- (hydroxymethyl) phenol) 1 ((2- (trimethylsilyl) ethoxy) methyl) 1H-imidazole-2-yl) methylcarbamate 4.2 mg (0.0090 mmol) dissolved in tetrahydrofuran 0.3 mL Then, 2.0 L of chlorochloride was added and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, saturated sodium bicarbonate water was added, extracted with black mouth form, and dried over sodium sulfate. Concentration under reduced pressure gave the title compound (3.6 mg, 82%) o —NMR (CDC1): 67.74 (2H, d, J = 8.1 Hz), 7.41—7.33 (8H, m),
3  Three
5.35 (2H, s), 5.13 (2H, s), 4.62 (2H, s), 4.56 (2H, d, J = 5.4 Hz), 3. 55 (2H, t, J = 8.1 Hz), 0.93 (2H, t, J = 8.1 Hz), 0.01 (9H, m), MS(F AB+) :486(M+ + 1)  5.35 (2H, s), 5.13 (2H, s), 4.62 (2H, s), 4.56 (2H, d, J = 5.4 Hz), 3.55 (2H, t, J = 8.1 Hz), 0.93 (2H , t, J = 8.1 Hz), 0.01 (9H, m), MS (F AB +): 486 (M + + 1)
[0208] 5)ベンジル （4— (4— (ョードメチル）フエ-ル） 1 ( (2— (トリメチルシリル）ェトキ シ）メチル） 1H—イミダゾールー 2—ィル）メチルカーバメート  [0208] 5) Benzyl (4- (4- (iodomethyl) phenol) 1 ((2- (trimethylsilyl) ethoxy) methyl) 1H-imidazole-2-yl) methyl carbamate
ベンジル （4— (4— (クロロメチル）フエ-ル） 1 ( (2— (トリメチルシリル）エトキシ )メチル） 1H—イミダゾールー 2—ィル）メチルカーバメート 21mg(0.043mmol) をアセトン 0.5mLに溶解し、ヨウィ匕ナトリウム 13mg(0.086mmol)を加え、室温で 四時間攪拌した。混合液に飽和食塩水を加え、クロ口ホルムで抽出後、硫酸ナトリウ ムにて乾燥した。減圧濃縮し、標記化合物を得た（21mg、 85%) o Dissolve 21 mg (0.043 mmol) of benzyl (4- (4- (chloromethyl) phenol) 1 ((2- (trimethylsilyl) ethoxy) methyl) 1H-imidazol-2-yl) methylcarbamate in 0.5 mL of acetone, Yowisodium 13 mg (0.086 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Saturated saline was added to the mixture, extracted with black mouth form, and dried over sodium sulfate. Concentrated under reduced pressure to give the title compound (21 mg, 85%) o
— NMR(CDC1 ): 67.67 (2H, d, J = 8.1 Hz), 7.41— 7.33 (8H, m),  — NMR (CDC1): 67.67 (2H, d, J = 8.1 Hz), 7.41— 7.33 (8H, m),
3  Three
5.34 (2H, s), 5.15 (2H, s), 4.55 (2H, d, J = 5.4 Hz), 4.51 (2H, s), 3. 54 (2H, t, J = 8.0 Hz), 0.93(2H, t, J = 8.0 Hz), 0.01 (9H, m)、 MS (F AB+) :578(M+ + 1)  5.34 (2H, s), 5.15 (2H, s), 4.55 (2H, d, J = 5.4 Hz), 4.51 (2H, s), 3.54 (2H, t, J = 8.0 Hz), 0.93 (2H , t, J = 8.0 Hz), 0.01 (9H, m), MS (F AB +): 578 (M + + 1)
[0209] 6)ベンジル（4一（4一（2—（3— (2, 6 ジクロ口ベンジル）ー2—メチルー 4ーォキ ソピリジン一 1 (4H)—ィル)メチル）フエ-ル） 1 ( (2— (トリメチルシリル）エトキシ)メ チノレ） 1H—イミダゾーノレ 2—ィノレ）メチノレカーバメート 3- (2, 6 ジクロロベンジル） 2—メチルピリジン一 4 (1H)—オン 9.4mg(0.0 35mmol)をテトラヒドロフラン 0.3mLに溶解し、水素化ナトリウム 0.84mg(0.035 mmol)を加えた。反応溶液に、ベンジル (4- (4- (ョードメチル）フエ-ル） 1 ( ( 2- (トリメチルシリル）エトキシ)メチル）— 1H—イミダゾールー 2—ィル)メチルカーバ メート 20mg(0. O35mmol)をカ卩え、室温で 3.5時間攪拌した。混合液に飽和食塩 水を加え、クロ口ホルムで抽出後、硫酸ナトリウムにて乾燥した。減圧濃縮後、残渣を P— TLC (クロ口ホルム Zメタノール =10Zl)にて精製し、標記化合物を得た（11m g、 45%) o[0209] 6) Benzyl (4 1 (4 1 (2— (3— (2, 6 Diclonal Benzyl) -2-methyl-4-oxopyridine 1 (4H) -yl) methyl) phenol) 1 ( (2— (Trimethylsilyl) ethoxy) methylol) 1H—imidazole 2—inore) methinorecarbamate 9.4 mg (0.0 35 mmol) of 3- (2, 6 dichlorobenzyl) 2-methylpyridine 1 4 (1H) -one was dissolved in 0.3 mL of tetrahydrofuran, and 0.84 mg (0.035 mmol) of sodium hydride was added. To the reaction solution, 20 mg (0. O35 mmol) of benzyl (4- (4- (iodomethyl) phenol) 1 ((2- (trimethylsilyl) ethoxy) methyl) — 1H-imidazole-2-yl) methylcarbamate was added. The mixture was stirred at room temperature for 3.5 hours. Saturated saline was added to the mixture, and the mixture was extracted with black mouth form and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol = 10 Zl) to obtain the title compound (11 mg, 45%) o
— NMR(CDC1 ): 67.72 (2H, d, J = 8.3 Hz), 7.54— 7.25 (9H, m),  — NMR (CDC1): 67.72 (2H, d, J = 8.3 Hz), 7.54— 7.25 (9H, m),
3  Three
7.06-6.98 (3H, m), 6.41 (1H, d, J = 7.6 Hz), 5.35 (2H, s), 5.14 (2H , s), 5.02 (2H, s), 4.55 (2H, d, J = 5.6 Hz), 4.36 (2H, s), 3.55 (2H, t , J = 8.0 Hz), 2.01 (3H, s), 0.93(2H, t, J = 8.0 Hz), 0.01 (9H, m) [0210] 7) (4— (4— (2- (3- (2, 6 ジクロロベンジル） 2—メチル 4—ォキソピリジン — 1 (4H)—ィル)メチル）フエ-ル）— 1H—イミダゾールー 2—ィル)メチルァミン塩 酸塩  7.06-6.98 (3H, m), 6.41 (1H, d, J = 7.6 Hz), 5.35 (2H, s), 5.14 (2H, s), 5.02 (2H, s), 4.55 (2H, d, J = 5.6 Hz), 4.36 (2H, s), 3.55 (2H, t, J = 8.0 Hz), 2.01 (3H, s), 0.93 (2H, t, J = 8.0 Hz), 0.01 (9H, m) (0210 ] 7) (4— (4— (2- (3- (2, 6 dichlorobenzyl) 2-methyl 4-oxopyridine — 1 (4H) -yl) methyl) phenyl) — 1H-imidazole 2- M) Methylamine hydrochloride
ベンジル （4— (4— (2— (3— (2, 6 ジクロロベンジル） 2—メチル 4—ォキ ソピリジン一 1 (4H)—ィル)メチル）フエ-ル） 1 ( (2— (トリメチルシリル）エトキシ)メ チル）—1H—イミダゾールー 2 ィル）メチルカーバメート 14mg(0.020mmol)を 4 N—塩酸 Zジォキサン Z水の混合溶液 0.6mLに溶解し 100°Cで 1.5時間攪拌した 。混合液を減圧濃縮し、残渣を P—TLC (クロ口ホルム Zメタノール Zアンモニア水 = 5/1/0.05)にて精製し、塩酸 Z酢酸ェチルにて処理、減圧濃縮し、標記化合物 を得た（9.4mg、 84%) o Benzyl (4— (4— (2— (3— (2, 6 dichlorobenzyl) 2-methyl 4-oxopyridine 1 (4H) -yl) methyl) phenol) 1 ((2— (trimethylsilyl ) Ethoxy) methyl) -1H-imidazole-2-yl) methylcarbamate 14 mg (0.020 mmol) was dissolved in 0.6 mL of a mixed solution of 4 N-hydrochloric acid Z dioxane Z water and stirred at 100 ° C. for 1.5 hours. The mixture was concentrated under reduced pressure, and the residue was purified by P-TLC (black mouth form Z methanol Z ammonia water = 5/1 / 0.05), treated with hydrochloric acid Z ethyl acetate, and concentrated under reduced pressure to obtain the title compound. (9.4mg, 84%) o
— NMR(CD OD)： δ 8.63(1H, d, J = 6.8 Hz), 7.87 (2H, m), 7.36 (  — NMR (CD OD): δ 8.63 (1H, d, J = 6.8 Hz), 7.87 (2H, m), 7.36 (
3  Three
2H, d, J = 8.0 Hz), 7.29— 7.19 (5H, m), 5.77 (2H, s), 4.54—4.50(4 H, m), 2.53 (3H, m)、 MS(FAB+) :453(M+ + 1)  2H, d, J = 8.0 Hz), 7.29— 7.19 (5H, m), 5.77 (2H, s), 4.54—4.50 (4 H, m), 2.53 (3H, m), MS (FAB +): 453 M ++ 1)
[0211] [実施例 767] (4—（4一（2—（3— (2, 6 ジクロ口ベンジル）ー2—メチルー 4ーォ キソピリジン— 1 (4H)—ィル）ビュル）フエ-ル）— 1H—イミダゾールー 2—ィル)メチ ルァミン塩酸塩 1)ベンジル （4一（4 (2- (3— (2, 6 ジクロ口ベンジル）ー2—メチルー 4ーォキ ソピリジン 1 (4H) ィル）ビュル）フエ-ル） 1 ( (2 （トリメチルシリル）エトキシ)メ チノレ） 1H—イミダゾーノレ 2—ィノレ）メチノレカーバメート [0211] [Example 767] (4- (4- (2- (3- (2,6 Dichloro-benzyl))-2-methyl-4-oxopyridine-1 (4H) -yl) bulu) ) — 1H-imidazole-2-yl) methylamine hydrochloride 1) Benzyl (41 (4 (2- (3— (2, 6 Diclonal Benzyl)-2-Methyl-4-oxopyridine 1 (4H) yl) butyl) pheyl) 1 ((2 (trimethylsilyl) ethoxy ) Minole) 1H—Imidazonore 2-—Nole) Metinorecarbamate
ベンジル （4— (4 ブロモフエ-ル）— 1— ((2— (トリメチルシリル）エトキシ）メチ ル）— 1H—イミダゾールー 2—ィル）メチルカーバメート 400mg(0.77mmol)、 3— ( 2, 6 ジクロロベンジル） 2—メチル 1—ビュルピリジン一 4(1H)—オン 216mg( 0.74mmol)を N, N，—ジメチルホルムアミド 15mLに溶解し、トリス（ジベンジリデン アセトン）ジパラジウム 142mg(0.16mmol)、トリ（tert—ブチル）フォスフィン  Benzyl (4- (4 bromophenol) — 1— ((2- (trimethylsilyl) ethoxy) methyl) — 1H-imidazole-2-yl) methyl carbamate 400 mg (0.77 mmol), 3— (2, 6 dichlorobenzyl ) 216 mg (0.74 mmol) of 2-methyl 1-butylpyridine 1 (4H) -one was dissolved in 15 mL of N, N, -dimethylformamide, 142 mg (0.16 mmol) of tris (dibenzylideneacetone) dipalladium, —Butyl) phosphine
(0.31mmol)、ジシクロへキシルメチルァミン 329 Ι^(1.6mmol)を加え、 80°Cに て二時間攪拌した。混合液に飽和食塩水を加え、塩化メチレンで抽出後、硫酸ナトリ ゥムにて乾燥した。減圧濃縮後、残渣を P— TLC (クロ口ホルム Zメタノール =20Zl )にて粗精製、 LH— 20(塩化メチレン Ζメタノール =1Ζ1)にて精製し、標記化合物 を ΖΖΕ=約 7Z1の異性体混合物として得た（121mg、 23%)。(0.31 mmol) and dicyclohexylmethylamine 329Ι (1.6 mmol) were added, and the mixture was stirred at 80 ° C for 2 hours. Saturated brine was added to the mixture, and the mixture was extracted with methylene chloride and dried over sodium sulfate. After concentration under reduced pressure, the residue was roughly purified with P-TLC (black mouth form Zmethanol = 20Zl) and purified with LH-20 (methylene chlorideΖmethanol = 1Ζ1). The title compound was isomer mixture of ΖΖΕ = about 7Z1. (121 mg, 23%).
— NMR(CDC1 )： δ 7.74 (2Η, d, J = 8.4 Hz), 7.55 (1H, d, J = 7.8  — NMR (CDC1): δ 7.74 (2Η, d, J = 8.4 Hz), 7.55 (1H, d, J = 7.8
3  Three
Hz), 7.36— 7.27(10H, m), 7.17(1H, d, J=14 Hz), 7.07(1H, t, J = 7 .6 Hz), 6.63 (1H, d, J=14 Hz), 6.38 (1H, d, J = 7.8 Hz), 5.35 (2H, s), 5.13 (2H, s), 4.54 (2H, d, J = 5.6 Hz), 4.38 (2H, s), 3.54 (2H, t, J =8.0 Hz), 2.16 (3H, s), 0.92 (2H, t, J = 8.0 Hz), 0.01 (9H, m)、 MS (FAB+) :729(M+ + 1)  Hz), 7.36— 7.27 (10H, m), 7.17 (1H, d, J = 14 Hz), 7.07 (1H, t, J = 7.6 Hz), 6.63 (1H, d, J = 14 Hz), 6.38 (1H, d, J = 7.8 Hz), 5.35 (2H, s), 5.13 (2H, s), 4.54 (2H, d, J = 5.6 Hz), 4.38 (2H, s), 3.54 (2H, t , J = 8.0 Hz), 2.16 (3H, s), 0.92 (2H, t, J = 8.0 Hz), 0.01 (9H, m), MS (FAB +): 729 (M + + 1)
2) (4— (4— (2— (3— (2, 6 ジクロロベンジル） 2—メチル 4—ォキソピリジン - 1 (4H) ィル）ビュル）フエ-ル） 1H—イミダゾールー 2 ィル)メチルァミン塩 酸塩  2) (4— (4— (2— (3— (2, 6 dichlorobenzyl) 2-methyl 4-oxopyridine-1 (4H) yl) bur)) 1H-imidazole 2 yl) methylamine salt Acid salt
ベンジル （4— (4— (2— (3— (2, 6 ジクロロベンジル） 2—メチル 4—ォキ ソピリジン 1 (4H) ィル）ビュル）フエ-ル） 1 ( (2 （トリメチルシリル）エトキシ)メ チル）—1H—イミダゾールー 2 ィル）メチルカーバメート 21mg(0.029mmol)を 4 N—塩酸 Zジォキサン Z水の混合溶液 0.9mLに溶解し 100°Cで 1.5時間攪拌した 。混合液をエーテルで洗浄後、水層を減圧濃縮した。残渣をクロ口ホルム Zメタノー ルカも結晶化を行い、標記化合物を得た (4. lmg、 25%) o H— NMR(CD OD)： δ 8.63 (1H, d, J = 7.2 Hz), 8.01 (1H, s), 7.94— Benzyl (4— (4— (2— (3— (2, 6 dichlorobenzyl) 2-methyl 4-oxopyridine 1 (4H) yl) butyl) phenol) 1 ((2 (trimethylsilyl) ethoxy) Methyl) -1H-imidazole-2-yl) methylcarbamate 21 mg (0.029 mmol) was dissolved in 0.9 mL of 4 N-hydrochloric acid Z-dioxane Z-water mixed solution and stirred at 100 ° C. for 1.5 hours. The mixture was washed with ether, and the aqueous layer was concentrated under reduced pressure. The residue was also crystallized with black mouth form Z methanol to give the title compound (4. lmg, 25%) o H—NMR (CD OD): δ 8.63 (1H, d, J = 7.2 Hz), 8.01 (1H, s), 7.94—
3  Three
7.89 (3H, m), 7.80 (2H, d, J = 8.4 Hz), 7.41 (2H, d, J = 8.0 Hz), 7.2 9-7.19 (3H, m), 4.54 (4H, m), 2.68 (3H, m)、 MS(FAB+) :465(M+ + 1 )  7.89 (3H, m), 7.80 (2H, d, J = 8.4 Hz), 7.41 (2H, d, J = 8.0 Hz), 7.2 9-7.19 (3H, m), 4.54 (4H, m), 2.68 ( 3H, m), MS (FAB +): 465 (M ++ 1)
[0213] [実施例 768] (4—（4一（2—（3— (2, 6 ジクロ口ベンジル）ー2—メチルー 4ーォ キソピリジンー1 (4H) ィル）ェチル）フエ-ル）—1H—イミダゾールー 2 ィル)メチ ルァミン塩酸塩  [0213] [Example 768] (4— (4— (2— (3— (2,6 Dichlorobiethyl)-2-methyl-4-oxopyridine-1 (4H) yl) ethyl) phenol) — 1H-imidazole-2-yl) methylamine hydrochloride
(4一（4一（2—（3— (2, 6 ジクロ口ベンジル）ー2—メチルー 4 ォキソピリジン - 1 (4H) ィル）ビュル）フエ-ル） 1H—イミダゾールー 2 ィル)メチルァミン塩 酸塩 25mg(0.044mmol)を塩酸/メタノール混合溶液 1. lmLに溶解し、含水パ ラジウム Zカーボン 2.5mgをカ卩え、水素雰囲気下、室温にて 4.5時間攪拌した。反 応液をセライトろ過し、ろ液を減圧濃縮後、残渣を P—TLC (クロ口ホルム Zメタノー ル Zアンモニア水 = 5ZlZ0.1)にて精製し、塩酸 Ζ酢酸ェチルにて処理、減圧濃 縮し、標記化合物を得た（llmg、 44%)。 (4 1 (4— (2— (3— (2,6 Diclonal benzyl) -2-methyl-4-oxopyridine-1 (4H) yl) butyl) phenol) 1H-imidazole-2 yl) methylamine hydrochloride 25 mg (0.044 mmol) of the salt was dissolved in 1 mL of a hydrochloric acid / methanol mixed solution, 2.5 mg of hydrous palladium Z-carbon was added, and the mixture was stirred at room temperature for 4.5 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by P-TLC (black mouth form Z methanol Z ammonia water = 5ZlZ0.1), treated with hydrochloric acid and ethyl acetate, and concentrated under reduced pressure. Shrink to give the title compound (llmg, 44%).
— NMR(CD OD)： δ 8.21 (2Η, d, J = 7.2 Hz), 7.65 (2H, d, J = 8.2  — NMR (CD OD): δ 8.21 (2Η, d, J = 7.2 Hz), 7.65 (2H, d, J = 8.2
3  Three
Hz), 7.59(1H, s), 7.35 (2H, d, J = 8.2 Hz), 7.18— 7. 12(3H, m), 6.9 7(2H, d, J = 7.2 Hz ), 4.68(2H, t, J = 6.8 Hz), 4.44 (2H, s), 4.32(2 H, s), 3. 18 (2H, t, J = 6.8 Hz), 2.43 (3H, s)  Hz), 7.59 (1H, s), 7.35 (2H, d, J = 8.2 Hz), 7.18— 7. 12 (3H, m), 6.9 7 (2H, d, J = 7.2 Hz), 4.68 (2H, t, J = 6.8 Hz), 4.44 (2H, s), 4.32 (2 H, s), 3.18 (2H, t, J = 6.8 Hz), 2.43 (3H, s)
[0214] [実施例 769] (4—（4一（（IE)—（3— (2, 6 ジクロ口ベンジル）ー2—メチルー 4 —ォキソピリジン一 1 (4H) ィル）プロプ一 1 ェ -ル）フエ-ル） 1H—イミダゾー ルー 2—ィル)メチルァミン塩酸塩 [0214] [Example 769] (4— (4 ((IE) — (3— (2, 6 Diclonal benzyl) -2-methyl-4 —oxopyridine 1 1 (4H) yl) prop 1- 1) —Imidazolu® 2—yl) methylamine hydrochloride
1)ベンジル （4— (4 ブロモフエ-ル）— 1— ((2— (トリメチルシリル）エトキシ)メチ ル） 1H—イミダゾールー 2—ィル）メチルカーバメート  1) Benzyl (4- (4 Bromophenyl)-1- ((2- (Trimethylsilyl) ethoxy) methyl) 1H-imidazole-2-yl) methyl carbamate
ベンジル （4— (4 ブロモフエ-ル） 1H—イミダゾールー 2—ィル）メチルカ一 ノメート 386mg(l. Ommol)をテトラヒドロフラン 8mLに溶解し、水素化ナトリウム 24 mg(l. Ommol) , (2— (クロロメトキシ）ェチル）トリメチルシラン 175 L(l. Ommol) を加え室温にて二時間、続いて 40°Cにて一時間攪拌した。混合液に飽和食塩水を 加え、塩化メチレンで抽出後、硫酸ナトリウムにて乾燥した。減圧濃縮後、残渣をシリ 力ゲルクロマトグラフィー（へキサン Z酢酸ェチル =2Zl)にて精製し、標記化合物 を得た（312mg、 60%) oBenzyl (4- (4 bromophenol) 1H-imidazole-2-yl) methyl cyanate 386 mg (l. Ommol) was dissolved in tetrahydrofuran 8 mL, and sodium hydride 24 mg (l. Ommol), (2- (chloro Methoxy) ethyl) trimethylsilane (175 L, l.Ommol) was added, and the mixture was stirred at room temperature for 2 hours and then at 40 ° C for 1 hour. Saturated saline was added to the mixture, and the mixture was extracted with methylene chloride and dried over sodium sulfate. After concentration under reduced pressure, Purification by force gel chromatography (hexane Zethyl acetate = 2Zl) gave the title compound (312 mg, 60%) o
— NMR(CDC1 )： δ 7.62 (2Η, d, J = 8.3 Hz), 7.49 (2H, d, J = 8.3  — NMR (CDC1): δ 7.62 (2Η, d, J = 8.3 Hz), 7.49 (2H, d, J = 8.3
3  Three
Hz), 7.38-7.33 (5H, m), 5.34 (2H, brs), 5.15 (2H, brs), 4.54 (2H, d , J = 5.6 Hz), 3.55(2H, t, J = 8.2 Hz), 0.93(2H, t, J = 8.2 Hz)、MS( FAB+) :516(M+ + 1)  Hz), 7.38-7.33 (5H, m), 5.34 (2H, brs), 5.15 (2H, brs), 4.54 (2H, d, J = 5.6 Hz), 3.55 (2H, t, J = 8.2 Hz), 0.93 (2H, t, J = 8.2 Hz), MS (FAB +): 516 (M ++ 1)
[0215] 2) (E)—ベンジル （4— (4— (3— (3— (2, 6 ジクロロベンジル） 2—メチル一 4—ォキソピリジン一 1(4H)—ィル）プロプ一 1—ェ -ル）フエ-ル）一 1— ((2— (トリ メチルシリル）エトキシ）メチル） 1 H イミダゾール 2—ィル）メチルカーバメート ベンジル（4— (4 ブロモフエ-ル）— 1— ((2— (トリメチルシリル）エトキシ）メチ ル）— 1H—イミダゾールー 2—ィル）メチルカーバメート 26mg(0.050mmol)、 1— ァリル一 3— (2, 6 ジクロロベンジル） 2—メチルピリジン一 4(1H) オン 15mg( 0.050mmol)を N, N，—ジメチルホルムアミド lmLに溶解し、トリス（ジベンジリデン アセトン）ジパラジウム 9.2mg(0. Olmmol) 、トリ（tert—ブチル）フォスフィン 5.0 μ L (0.020mmol)、ジシクロへキシノレメチノレ ミン 21 μ L (0. lOmmol)をカ卩免、 80 °Cにて二時間攪拌した。混合液に飽和食塩水を加え、塩化メチレンで抽出後、硫酸 ナトリウムにて乾燥した。減圧濃縮後、残渣を P— TLC (クロ口ホルム Zメタノール =2 0/1)にて精製し、標記化合物を得た (31mg、 84%) o[0215] 2) (E) —Benzyl (4— (4— (3— (3— (2, 6 dichlorobenzyl) 2-methyl-1, 4-oxopyridine 1 (4H) —yl) prop 1— 1-((2— (trimethylsilyl) ethoxy) methyl) 1 H imidazole 2—yl) methyl carbamate benzyl (4- (4 bromophenol) — 1— ((2— ( Trimethylsilyl) ethoxy) methyl)-1H-imidazol-2-yl) methyl carbamate 26 mg (0.050 mmol), 1-aryl-1- (2, 6 dichlorobenzyl) 2-methylpyridine 4- (1H) on 15 mg (0.050 mmol) is dissolved in 1 mL of N, N, -dimethylformamide, 9.2 mg (0. Olmmol) of tris (dibenzylideneacetone), 5.0 μL (0.020 mmol) of tri (tert-butyl) phosphine, dicyclohexylenoretinolemine 21 μL (0. lOmmol) was stirred at 80 ° C. for 2 hours. Saturated brine was added to the mixture, and the mixture was extracted with methylene chloride and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol = 20/1) to give the title compound (31 mg, 84%) o
— NMR(CDC1 )： δ =7.70 (2Η, d, J = 8.4 Hz), 7.37— 7.23(10H,  — NMR (CDC1): δ = 7.70 (2Η, d, J = 8.4 Hz), 7.37— 7.23 (10H,
3  Three
m), 7.04 (1H, t, J = 8.0 Hz), 6.39(1H, d, J = 7.2 Hz), 6.19 (2H, m), 5.34 (2H, brs), 5.13 (2H, brs), 4.56—4.53 (4H, m), 4.40 (2H, s), 3. 54 (2H, t, J = 8.0 Hz), 2.12(3H, s), 0.92(2H, t, J = 8.0 Hz) , MS (ESI +) :743(M+ + 1)  m), 7.04 (1H, t, J = 8.0 Hz), 6.39 (1H, d, J = 7.2 Hz), 6.19 (2H, m), 5.34 (2H, brs), 5.13 (2H, brs), 4.56— 4.53 (4H, m), 4.40 (2H, s), 3.54 (2H, t, J = 8.0 Hz), 2.12 (3H, s), 0.92 (2H, t, J = 8.0 Hz), MS (ESI +): 743 (M ++ 1)
[0216] 3) (4— (4— ((IE) - (3— (2, 6 ジクロロベンジル） 2—メチル 4—ォキソピリ ジンー1 (4H) ィル）プロプー 1ーェ -ル）フエ-ル） 1H—イミダゾールー 2—ィル )メチルァミン塩酸塩  [0216] 3) (4— (4— ((IE)-(3— (2, 6 Dichlorobenzyl) 2-methyl 4-oxopyridine 1 (4H)) Propol 1-L) ) 1H-imidazole-2-yl) methylamine hydrochloride
(E)—ベンジル （5— (4— (3— (3— (2, 6 ジクロロベンジル） 2—メチル 4 —ォキソピリジン一 1 (4H)—ィル）プロプ一 1 ェ -ル）フエ-ル） 1— ( (2— (トリメ チルシリル）エトキシ)メチル）— 1 H イミダゾール— 2—ィル)メチルカーバメート 10 mg (0.013mmol)を 4N—塩酸 Zジォキサン Z水の混合溶液 5mLに溶解し 100°C で一時間攪拌した。混合液をエーテルで洗浄後、水層を減圧濃縮し、残渣を P— TL C (クロ口ホルム Zメタノール Zアンモニア水 = 10ZlZ0. 1)にて精製し、塩酸 Ζ酢 酸ェチルにて処理、減圧濃縮し、標記化合物を得た（7. Omg、 95%) o (E) —Benzyl (5— (4— (3— (3— (2, 6 dichlorobenzyl) 2-methyl 4 —oxopyridine 1 1 (4H) —yl) prop 1 1))) 1— ((2— (trim Tylsilyl) ethoxy) methyl)-1 H imidazol-2-yl) methylcarbamate 10 mg (0.013 mmol) was dissolved in 5 mL of a mixed solution of 4N-hydrochloric acid Z dioxane Z water and stirred at 100 ° C for 1 hour. After washing the mixture with ether, the aqueous layer was concentrated under reduced pressure, and the residue was purified with P-TLC (black mouth form Z methanol Z ammonia water = 10ZlZ0.1), treated with hydrochloric acid and ethyl acetate and reduced pressure. Concentration gave the title compound (7. Omg, 95%) o
'H-NMRCCD OD)： δ =7.78 (1Η, d, J = 7.4 Hz), 7.63 (2H, d, J = 8.  'H-NMRCCD OD): δ = 7.78 (1Η, d, J = 7.4 Hz), 7.63 (2H, d, J = 8.
3  Three
3 Hz), 7.38-7.32(5H, m), 7.15(1H, t, J = 7.8 Hz), 6.43(1H, d, J =7.4 Hz), 6.36(1H, dt, J=16 Hz, J=4.9 Hz), 6.19(1H, d, J=16 Hz) , 4.81-4.79 (2H, m) , 4.37 (2H, s) , 3.92 (2H, s) , 2.21 (3H, s)、 M S(ESI+) :479(M+ + 1) 3 Hz), 7.38-7.32 (5H, m), 7.15 (1H, t, J = 7.8 Hz), 6.43 (1H, d, J = 7.4 Hz), 6.36 (1H, dt, J = 16 Hz, J = 4.9 Hz), 6.19 (1H, d, J = 16 Hz), 4.81-4.79 (2H, m), 4.37 (2H, s), 3.92 (2H, s), 2.21 (3H, s), MS (ESI +) : 479 (M ++ 1)
[0217] [実施例 770] (4—（4一（3—（3— (2, 6 ジクロ口ベンジル）ー2—メチルー 4ーォ キソピリジン— 1 (4H)—ィル）プロピル）フエ-ル）— 1H—イミダゾールー 2—ィル)メ チルァミン塩酸塩 [0217] [Example 770] (4- (4- (3- (3- (2,6 Diclonal Benzyl) -2-methyl-4-oxopyridine-1 (4H) -yl) propyl) phenol) ) — 1H-imidazole-2-yl) methylamine hydrochloride
(4— (4— ((1E) - (3- (2, 6 ジクロロベンジル） 2—メチル 4—ォキソピリ ジンー1 (4H) ィル）プロプー 1ーェ -ル）フエ-ル） 1H—イミダゾールー 2—ィル )メチルァミン塩酸塩 9.3mg(0.016mmol)をメタノール lmLに溶解し、含水パラジ ゥム/カーボン 1.9mg、ジフエ-ルスルフイド 0.27 μ\.{0.0016mmol)を加え、水 素雰囲気下、室温にて終夜攪拌した。反応液をセライトろ過し、ろ液を減圧濃縮後、 残渣を P—TLC (クロ口ホルム Zメタノール Zアンモニア水 = 5ZlZ0.1)にて精製 し、塩酸 Ζ酢酸ェチルにて処理、減圧濃縮し、標記化合物を得た (4. Omg、 43%)。 (4— (4— ((1E)-(3- (2, 6 dichlorobenzyl) 2-methyl 4-oxopyridin-1 (4H) yl) prop 1-mol) 2) 1H-imidazole 2 -Il) Dissolve 9.3 mg (0.016 mmol) of methylamine hydrochloride in 1 mL of methanol, add 1.9 mg of hydrous palladium / carbon, diphenylsulfide 0.27 μ \. {0.0016 mmol), and bring it to room temperature under a hydrogen atmosphere. And stirred overnight. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure.The residue was purified with P-TLC (black mouth form Z methanol Z aqueous ammonia = 5ZlZ0.1), treated with hydrochloric acid and ethyl acetate, and concentrated under reduced pressure. The title compound was obtained (4. Omg, 43%).
— NMR(CD OD)： δ =8.48 (1Η, d, J = 7.2 Hz), 7.96 (1H, s), 7.76  — NMR (CD OD): δ = 8.48 (1Η, d, J = 7.2 Hz), 7.96 (1H, s), 7.76
3  Three
(2H, d, J = 6.4 Hz), 7.44-7.37 (4H, m), 7.25(1H, t, J = 7.6 Hz), 7 . 10(1H, d, J = 7.2 Hz), 4.57 (2H, s), 4.47—4.44 (4H, m), 2.80 (2H, t, J = 7.6 Hz), 2.23-2.18 (2H, m)、 MS(FAB+) :481(M+ + 1)  (2H, d, J = 6.4 Hz), 7.44-7.37 (4H, m), 7.25 (1H, t, J = 7.6 Hz), 7.10 (1H, d, J = 7.2 Hz), 4.57 (2H, s), 4.47—4.44 (4H, m), 2.80 (2H, t, J = 7.6 Hz), 2.23-2.18 (2H, m), MS (FAB +): 481 (M + + 1)
[0218] [実施例 771]2 ァミノ一 5— (2, 5—ジクロロフエノキシ）チアゾール [0218] [Example 771] 2 amino 5- (2,5-dichlorophenoxy) thiazole
2, 5 ジクロロフエノール 0.94 g(5.8mmol)を N, N，一ジメチルホルムアミド 5 mLに溶解し、 0°C攪拌下、 tert—ブトキシカリウム 0.65 g(5.8mmol)、 N, N， - ジイソプロピルアミン 0.66mL(3.9mmol)、 2 アミノー 5 ブロモチアゾール臭化 水素酸塩 1. 0 g(3. 9mmol)を加え、室温、続いて 50°Cで終夜攪拌した。混合溶 液を 1N塩酸に溶解し、エーテルにて洗浄した。水層を飽和重そう水で中和、酢酸ェ チルにて抽出し、硫酸ナトリウムにて乾燥した。減圧濃縮し、標記化合物を得た (0. 9 0 g、88%)。Dissolve 0.94 g (5.8 mmol) of 2,5 dichlorophenol in 5 mL of N, N, monodimethylformamide and stir at 0 ° C. 0.65 g (5.8 mmol) of tert-butoxypotassium, N, N, -diisopropylamine 0.66 mL (3.9 mmol), 2 amino-5 bromothiazole bromide Hydrogenate 1.0 g (3.9 mmol) was added and stirred at room temperature followed by 50 ° C overnight. The mixed solution was dissolved in 1N hydrochloric acid and washed with ether. The aqueous layer was neutralized with saturated sodium bicarbonate water, extracted with ethyl acetate, and dried over sodium sulfate. Concentration in vacuo gave the title compound (0.90 g, 88%).
— NMR(CDC1 )： δ 7. 33 (1Η, d, J = 8. 6 Hz), 7. 08 (1H, d, J = 2. 0  — NMR (CDC1): δ 7. 33 (1Η, d, J = 8.6 Hz), 7. 08 (1H, d, J = 2.0
3  Three
Hz), 7. 03 (1H, dd, J = 8. 6 Hz, 2. 0 Hz), 6. 81 (1H, s), 5. 23. (2H, br) [0219] 以下、前記実施例 771と同様の方法で製造した。  Hz), 7.03 (1H, dd, J = 8.6 Hz, 2.0 Hz), 6.81 (1H, s), 5.23 (2H, br) [0219] It was produced in the same manner as 771.
[0220] [実施例 772] 2 アミノー 5—（（4ーメトキシカルボ-ル）フエ-ル）チォチアゾール 塩酸塩 [0220] [Example 772] 2 Amino-5-((4-methoxycarbol) phenol) thothiazole hydrochloride
— NMR(CD OD)： δ 7. 95 (2Η, d, J = 6.4 Hz), 7.44 (1H, s), 7. 34(2  — NMR (CD OD): δ 7. 95 (2Η, d, J = 6.4 Hz), 7.44 (1H, s), 7. 34 (2
3  Three
H, d, J=6.4 Hz), 3. 88. (3H, s)、 MS(FAB+) :267(M+ + 1)  H, d, J = 6.4 Hz), 3. 88. (3H, s), MS (FAB +): 267 (M ++ 1)
[0221] [実施例 773] 2 ァミノ 5 フエネチルチオチアゾール塩酸塩 [Example 773] 2-amino-5-phenethylthiothiazole hydrochloride
2 フエ-ルエタンチオール 1.4 g(10mmol)と tert—ブトキシカリウム 1. 1 g(l Ommol)を N, N，ージメチルホルムアミド 10mLに加え室温下、三十分間撹拌した。 N, N，一ジイソプロピノレアミン 1. lmL(6. 7mmol)と 2 アミノー 5 ブロモチアゾー ル 1. 7 g(6. 7mmol)を加え、 60°Cの油浴にて四時間攪拌した。反応容器を室温 に戻し、 1N塩酸を加え反応を停止した。酢酸ェチルにて二回抽出後、有機層を水、 飽和食塩水洗浄し無水硫酸マグネシウムにて乾燥した。減圧濃縮後、標記化合物を 得た（622mg、 26%) o 2 Phenylethanethiol (1.4 g, 10 mmol) and tert-butoxypotassium (1.1 g, lOmmol) were added to N, N, dimethylformamide (10 mL), and the mixture was stirred at room temperature for 30 minutes. N, N, monodiisopropylinolamine (1 mL) (6.7 mmol) and 2-amino-5-bromothiazol (1.7 g, 6.7 mmol) were added, and the mixture was stirred in an oil bath at 60 ° C for 4 hours. The reaction vessel was returned to room temperature, and 1N hydrochloric acid was added to stop the reaction. After extraction twice with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration in vacuo, the title compound was obtained (622 mg, 26%) o
— NMR(CDC1 ) : 68. 02(1H, brs), 7. 12— 7. 31 (5H, m), 5. 30 (2H  — NMR (CDC1): 68. 02 (1H, brs), 7. 12— 7. 31 (5H, m), 5. 30 (2H
3  Three
, brs), 3. 30 (2H, m), 3. 00 (2H, m)、 MS(ES+) :237(M+ + 1)  , brs), 3.30 (2H, m), 3.00 (2H, m), MS (ES +): 237 (M ++ 1)
[0222] [実施例 774]5 （ァリルスルフォ -ル）チアゾールー 2 ァミン [Example 774] 5 (Arylsulfoyl) thiazole-2-amine
1)N— (5 （ァリルチオ）チアゾールー 2 ィル）ァセトアミド  1) N— (5 (Arylthio) thiazole-2-yl) acetamide
N— (5 チオシアナートチアゾール—2—ィル）ァセトアミド lllmg(0. 56mmol) をメタノール 8mLに溶解し、ジチオトレイトール 171mg(l. llmmol)をカ卩え、室温で 二時間攪拌した。混合溶液を減圧濃縮後、アルゴンにて置換し、 N, N，—ジメチル ホルムアミド 8mLに再び溶解した。炭酸カリウム 92mg(0. 67mmol)、ァリルブロマイ ド 47 (0. 56mmol)をカ卩え、室温で二時間攪拌した。混合溶液に飽和食塩水を 加え、クロ口ホルムで抽出後、硫酸ナトリウムにて乾燥した。減圧濃縮後、残渣を P— TLC (へキサン Z酢酸ェチル =1Z2)にて精製し、標記化合物を得た（104mg、 87 %)。 N- (5 thiocyanatothiazole-2-yl) acetamide lllmg (0.56 mmol) was dissolved in 8 mL of methanol, and 171 mg (l.llmmol) of dithiothreitol was added and stirred at room temperature for 2 hours. The mixed solution was concentrated under reduced pressure, replaced with argon, and redissolved in 8 mL of N, N, -dimethylformamide. Potassium carbonate 92 mg (0.67 mmol) and allyl bromide 47 (0.56 mmol) were added and stirred at room temperature for 2 hours. Add saturated saline to the mixed solution In addition, it was extracted with black mouth form and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by P-TLC (hexane Z ethyl acetate = 1Z2) to obtain the title compound (104 mg, 87%).
'H-NMRCCDCl ): 67.38 (1H, s), 5.83 (1H, ddt, J=17 Hz, J=10 H  'H-NMRCCDCl): 67.38 (1H, s), 5.83 (1H, ddt, J = 17 Hz, J = 10 H
3  Three
z, J = 7.3 Hz), 5.06 (1H, dd, J=10 Hz, J=l.0 Hz), 4.94(1H, dd, J = 17 Hz, J=l.0 Hz), 3.33(2H, d, J = 7.3 Hz), 2.31 (3H, s)、 MS (EI+) : 214(M+)  z, J = 7.3 Hz), 5.06 (1H, dd, J = 10 Hz, J = l.0 Hz), 4.94 (1H, dd, J = 17 Hz, J = l.0 Hz), 3.33 (2H, d, J = 7.3 Hz), 2.31 (3H, s), MS (EI +): 214 (M +)
[0223] 2)N- (5 （ァリルスルフォ -ル）チアゾールー 2 ィル）ァセトアミド  [0223] 2) N- (5 (arylsulfonyl) thiazole-2-yl) acetamide
N— (5— (ァリルチオ）チアゾール—2—ィル）ァセトアミド 94mg(0.44mmol)を テトラヒドロフラン/水 = 1/1の混合溶液 6mLに溶解し、氷冷下、ォキソン 593mg( 0.97mmol)を加え、 0°C〜室温で二時間攪拌した。混合溶液を濃縮後、飽和重そ う水を加え、クロ口ホルムにて抽出、硫酸ナトリウムにて乾燥した。減圧濃縮し、標記 化合物を得た（100mg、 93%) o 94 mg (0.44 mmol) of N- (5- (allylthio) thiazol-2-yl) acetamide was dissolved in 6 mL of a mixed solution of tetrahydrofuran / water = 1/1, and 593 mg (0.97 mmol) of oxone was added under ice cooling. The mixture was stirred at 0 ° C to room temperature for 2 hours. After the mixed solution was concentrated, saturated heavy water was added, extracted with black mouth form, and dried over sodium sulfate. Concentrated under reduced pressure to give the title compound (100 mg, 93%) o
— NMR(DMSO— d ): 67.99(1H, s), 5.77(1H, ddt, J=17 Hz, J=l  — NMR (DMSO— d): 67.99 (1H, s), 5.77 (1H, ddt, J = 17 Hz, J = l
6  6
0 Hz, J = 7.3 Hz), 5.36 (1H, d, J=10 Hz), 5.28 (1H, d, J=17 Hz), 4 . 19 (2H, d, J = 7.3 Hz), 2.20 (3H, s)、 MS (EI+) : 246 (M+)  0 Hz, J = 7.3 Hz), 5.36 (1H, d, J = 10 Hz), 5.28 (1H, d, J = 17 Hz), 4.19 (2H, d, J = 7.3 Hz), 2.20 (3H , s), MS (EI +): 246 (M +)
[0224] 3)5- (ァリルスルフォ -ル）チアゾール—2 ァミン [0224] 3) 5- (Arylsulfol) thiazole-2-amine
N— (5- (ァリルスルフォ -ル）チアゾール—2—ィル）ァセトアミド 97mg(0.39m mol)を 4N—塩酸 Zジォキサン Z水の混合溶液 5mLに溶解し 80°Cで 1.5時間攪 拌した。混合液を濃縮後、飽和重そう水を加え、クロ口ホルムにて抽出、硫酸ナトリウ ムにて乾燥した。減圧濃縮し、標記化合物を得た（75mg、 93%) o 97 mg (0.39 mmol) of N- (5- (arylsulfol) thiazol-2-yl) acetamide was dissolved in 5 mL of a mixed solution of 4N-hydrochloric acid Z dioxane Z water, and the mixture was stirred at 80 ° C for 1.5 hours. After the mixture was concentrated, saturated sodium bicarbonate water was added, extracted with black mouth form, and dried with sodium sulfate. Concentrated under reduced pressure to give the title compound (75 mg, 93%) o
— NMR(CDC1 ): 67.60 (1H, s), 5.86 (1H, ddt, J=17.2 Hz, 10.4  — NMR (CDC1): 67.60 (1H, s), 5.86 (1H, ddt, J = 17.2 Hz, 10.4
3  Three
Hz,7.6 Hz), 5.49 (2H, br), 5.44 (1H, d, J=10.4 Hz), 5.30 (1H, d, J = 17.2 Hz), 3.87(2H, d, J = 7.6 Hz)、 MS(EI+) :204(M+)  Hz, 7.6 Hz), 5.49 (2H, br), 5.44 (1H, d, J = 10.4 Hz), 5.30 (1H, d, J = 17.2 Hz), 3.87 (2H, d, J = 7.6 Hz), MS (EI +): 204 (M +)
[0225] ゥレア誘導体 [0225] Urea derivatives
[実施例 775] 1—（（4一（4 ブロモフエ-ル） 1H—イミダゾールー 2 ィル)メチ ル）ー3—（5 ェチ-ルチアゾールー 2 ィル）ゥレア  [Example 775] 1-((4 (4-bromophenol) 1H-imidazole-2-yl) methyl) -3 ((5-ethyl-thiazole-2-yl) urea
1)2-ァミノ 5 ェチ-ルチアゾール 2 アミノー 5 ブロモチアゾール臭化水素酸塩 2. 5 g (9. 6mmol)を炭酸力リウ ム水溶液で中和、酢酸ェチルで抽出した。有機層を減圧濃縮し、 2 アミノー 5 ブ ロモチアゾールをクルードで 1. 6 g得た。このうち、 1. 5 gをキシレン 30mLに溶解 し、ェチュルトリブチルチン 2. 9mL (10mmol)、塩化トリフエ-ルホスフィンパラジゥ ム 590mg (0. 84mmol)を加え、 110°Cにて一時間攪拌した。混合溶液を減圧濃縮 後、残渣をシリカゲルクロマトグラフィーにて精製し、標記化合物を得た（38mg、 3. 7 %)。 MS (ESI+) : 125 (M+ + 1) 1) 2-amino-5-ethylthiazole 2 Amino-5 bromothiazole hydrobromide 2.5 g (9.6 mmol) was neutralized with an aqueous carbonate power solution and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain 1.6 g of 2 amino-5-bromothiazole. Of these, 1.5 g was dissolved in 30 mL of xylene, 2.9 mL (10 mmol) of ethyl tributyltin and 590 mg (0.84 mmol) of triphenylphosphine chloride were added, and the mixture was stirred at 110 ° C for 1 hour. did. After the mixed solution was concentrated under reduced pressure, the residue was purified by silica gel chromatography to obtain the title compound (38 mg, 3.7%). MS (ESI +): 125 (M + + 1)
[0226] 2) N- (5—ェチ-ルチアゾールー 2 ィル）—1H—イミダゾールー 1 カルボキシ アミド [0226] 2) N- (5-Ethyl-thiazole-2-yl) —1H-imidazole-1 Carboxamide
2 アミノー 5 ェチ-ルチアゾール 38mg (0. 3 lmmol)をテトラヒドロフラン 1. 2m Lに溶解し、 1、 1，—カルボ-ルジイミダゾール 230mg (l. 4mmol)を加え、室温で 終夜攪拌した。反応液をろ取し、標記化合物をクルードで 15mg得た。  2 Amino-5-ethylthiazole (38 mg, 0.3 lmmol) was dissolved in tetrahydrofuran (1.2 mL), 1,1, -carbodiimidazole (230 mg, l.4 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was collected by filtration, and 15 mg of the title compound was obtained.
[0227] 3) 1 - ( (4- (4 ブロモフエ-ル） 1H—イミダゾールー 2 ィル)メチル）ー3— (5 ェチ-ルチアゾールー 2—ィル）ゥレア [0227] 3) 1-((4- (4 Bromophenol) 1H—imidazole-2-yl) methyl) -3— (5-ethylthiazol-2-yl) urea
2)で得たクルード化合物 15mg (0. 070mmol)をテトラヒドロフラン 0. 5mLに溶解 し、 （4一（4 ブロモフエ-ル） 1H—イミダゾールー 2 ィル)メチルァミン塩酸塩 2 7mg (0. 084mmol)、N, N，—ジイソプロピルェチルァミン 31 L (0. 18mmol)を 加え、室温で終夜攪拌した。混合溶液にメタールを加え、減圧濃縮後、残渣を P— T LC (クロ口ホルム Zメタノール = 10Zl)にて精製し、標記化合物を得た（9. 2mg、 3 3%) 0 15 mg (0.070 mmol) of the crude compound obtained in 2) is dissolved in 0.5 mL of tetrahydrofuran, and (4 mono (4-bromophenol) 1H-imidazole-2-yl) methylamine hydrochloride 2 7 mg (0.084 mmol), N , N, -Diisopropylethylamine 31 L (0.18 mmol) was added and stirred at room temperature overnight. After adding methanol to the mixed solution and concentrating under reduced pressure, the residue was purified by P-TLC (black mouth form Z methanol = 10 Zl) to obtain the title compound (9.2 mg, 33%) 0
— NMR(CDC1 /CD OD)： δ 7. 72— 7. 46 (6H, m) , 4. 49 (2H, s) , 3. 5  — NMR (CDC1 / CD OD): δ 7. 72— 7. 46 (6H, m), 4. 49 (2H, s), 3.5
3 3  3 3
1 (1H, s) 、 MS (FAB+) :402 (M+ + 1)  1 (1H, s), MS (FAB +): 402 (M + + 1)
[0228] [実施例 776] 1—（（4一（4 ブロモフエ-ル） 1H イミダゾールー 2 ィル)メチ ル）ー3—（5 （ペントー 4ーェ-ルチオ）チアゾールー 2 ィル）ゥレア [0228] [Example 776] 1 — ((4 (4-bromophenol) 1H imidazole-2-yl) methyl) -3— (5 (pentau-4-ylthio) thiazole-2-yl) urea
1) 2- (ペントー 4ーェ -ル)イソチォゥレア  1) 2- (Pentau 4-Le) Isothiourea
市販の 97%純度の 5 ブロモー 1 ペンテン 2. 01 g (13. lmmol)を脱水ェチ ルアルコール 13mLに溶解し、チォゥレア 995. 8mg (13. lmmol)を加え、加熱還 流下、 1. 5時間攪拌した。反応溶液を室温に戻し、減圧濃縮を行い、標記化合物を 黄色オイル状のクルードで得た。 Commercially available 97% pure 5-bromo-1-pentene (2.01 g, 13. lmmol) is dissolved in 13 mL of dehydrated ethyl alcohol, and 99.58 mg (13. lmmol) of thiourea is added, and heated under reflux for 1.5 hours. Stir. The reaction solution is returned to room temperature and concentrated under reduced pressure to give the title compound. Obtained with a yellow oily crude.
[0229] 2) ァミノ 5—（4 ペンテ-ルチオ）チアゾール  [0229] 2) Amino 5 -— (4 Pentylthio) thiazole
1)で得たクルードの内 2. 9 gを取り、水酸ィ匕ナトリウム 4. 72 g(13. lmmol)、水 25mL、トルエン 25mLを加え攪拌し、さらにテトラ— n—ブチルアンモ -ゥム硫酸水 素塩 75. 6mg(0. 22mmol)、 2 アミノー 5 ブロモチアゾール臭化水素酸塩 3.4 g(13. lmmol)を加え室温で終夜攪拌した。混合溶液に水、酢酸ェチルを加え反 応を停止し、酢酸ェチルにて二回抽出し、有機層を無水硫酸マグネシウムにて乾燥 、減圧濃縮し標記化合物をクルードで得た。  2.9 g of the crude product obtained in 1) is taken, and 4.72 g (13. lmmol) of sodium hydroxide, 25 mL of water and 25 mL of toluene are added and stirred, and tetra-n-butylammonium sulfate is further added. Hydrogen salt 75.6 mg (0.22 mmol) and 2 amino-5 bromothiazole hydrobromide 3.4 g (13. lmmol) were added and stirred at room temperature overnight. Water and ethyl acetate were added to the mixed solution to stop the reaction, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound as crude.
[0230] 3)N— (5—（4 ペンテ-ルチオ）チアゾールー 2 ィル） 1H—イミダゾールー 1 一力ノレボキシアミド [0230] 3) N— (5— (4 Pentylthio) thiazole-2-yl) 1H-imidazole-1
2)で得たクルードの内 2. 08 gを脱水テトラヒドロフラン 20mLに溶かし、 1, 1，一力 ルポ-ルビス 1H—イミダゾール 3. 37 g(20. 8mmol)をカ卩ぇ室温で約三時間攪 拌した。混合溶液に水、酢酸ェチルを加え反応を停止し、酢酸ェチルにて二回抽出 、減圧濃縮し、標記化合物をクルードで得た。  Dissolve 2.08 g of the crude product obtained in 2) in 20 mL of dehydrated tetrahydrofuran, and mix 1,1,1 force bis-lbis 1H-imidazole 3.37 g (20.8 mmol) at room temperature for about 3 hours. Stir. Water and ethyl acetate were added to the mixed solution to stop the reaction, and the mixture was extracted twice with ethyl acetate and concentrated under reduced pressure to obtain the title compound as crude.
[0231] 4)1- ((4- (4 ブロモフエ-ル） 1H—イミダゾールー 2 ィル)メチル）ー3— (5 一（4 ペンテ-ルチオ）チアゾールー 2 ィル）ゥレア  [0231] 4) 1- ((4- (4 Bromophenol) 1H—Imidazole-2-yl) methyl) -3— (5 (4-Pentelthio) thiazole-2-yl) urea
3)で得たクルードの内 56. 8mgをテトラヒドロフラン 3mLに溶解し、（4— (4 ブロ モフエ-ル）— 1H—イミダゾールー 2—ィル）メチルァミン塩酸塩 82. 6mg(0. 25m mol)、N, N，—ジイソプロピルェチルァミン 86. 5μL·(0. 51mmol)をカ卩え、室温で 終夜攪拌した。混合溶液に水、酢酸ェチルを加え反応を停止し、酢酸ェチルにて二 回抽出後、有機層を減圧濃縮し、残渣を P— TLC (クロ口ホルム Zメタノール =ιοΖ 1)にて精製し、標記化合物を得た（33mg、 33%)。 36.8 mg of the crude product obtained in 3) was dissolved in 3 mL of tetrahydrofuran, and (4— (4 bromphenol) —1H-imidazole-2-yl) methylamine hydrochloride 82.6 mg (0.25 mol) N, N, -diisopropylethylamine 86.5 μL (0.51 mmol) was added and stirred at room temperature overnight. Water and ethyl acetate are added to the mixed solution to stop the reaction. After extraction twice with ethyl acetate, the organic layer is concentrated under reduced pressure, and the residue is purified by P-TLC (black form Z methanol = ιοΖ 1). The title compound was obtained (33 mg, 33%).
— NMR(CDC1 /CD OD)： δ 7. 58 (2Η, m), 7.48 (2Η, m), 7. 33 (1H  — NMR (CDC1 / CD OD): δ 7. 58 (2Η, m), 7.48 (2Η, m), 7. 33 (1H
3 3  3 3
, s), 7. 27(1H, s), 5. 76 (1H, m), 5. 05—4. 94 (2H, m), 4. 53 (2H, s), 2 . 69 (2H, t, J=7. 1Hz), 2. 16 (2H, m), 1. 67 (2H, m)、 MS(ES+) :478 (M+ +1) , s), 7.27 (1H, s), 5.76 (1H, m), 5. 05--4.94 (2H, m), 4. 53 (2H, s), 2.69 (2H, t, J = 7.1 Hz), 2.16 (2H, m), 1.67 (2H, m), MS (ES +): 478 (M + +1)
[0232] [実施例 777] 1—（（4一（4 ブロモフエ-ル） 1H イミダゾールー 2 ィル)メチ ル）ー3—（5 イソプロピルチオ）チアゾールー 2 ィル）ゥレア 1)2-ァミノ 5 (イソプロピルチオ）チアゾール塩酸塩 [0232] [Example 777] 1 — ((4- (4-bromophenol) 1H imidazole-2-yl) methyl) -3- (5 isopropylthio) thiazole-2-yl) urea 1) 2-amino-5 (isopropylthio) thiazole hydrochloride
市販の 90%純度の 2 プロパンチォレートナトリウム塩 1. 13 g(ll. 5mmol)を脱 水 N, N ジメチルホルムアミド 10mLに加え、懸濁化し、 N, N，—ジイソプロピルェ チルァミン 1. 31mL(7.69mmol)、 2 アミノー 5 ブロモチアゾール臭化水素酸 塩 2 g(7.69mmol)の脱水 N, N ジメチルホルムアミド 5mL溶液を加え、室温で 終夜攪拌した。混合溶液に 1N塩酸水溶液、酢酸ェチルを加え反応を停止し、水層 を酢酸ェチルにて二回、ジクロロメタンにて一回洗净後、減圧濃縮し、生じた白色沈 殿をろ取し減圧下、 50°Cにて乾燥し、標記化合物をクルードで得た。  Commercially available 90% pure 2-propantolate sodium salt 1.13 g (ll. 5 mmol) is added to 10 mL of dehydrated N, N dimethylformamide, suspended, and N, N, -diisopropylethylamine 1.31 mL (7.69 mmol), 2 amino-5 bromothiazole hydrobromide 2 g (7.69 mmol) in dehydrated N, N dimethylformamide 5 mL was added and stirred at room temperature overnight. 1N aqueous hydrochloric acid and ethyl acetate were added to the mixed solution to stop the reaction. The aqueous layer was washed twice with ethyl acetate and once with dichloromethane and then concentrated under reduced pressure. The resulting white precipitate was collected by filtration and subjected to reduced pressure. And dried at 50 ° C. to give the title compound as a crude.
[0233] 2)N-(5- (イソプロピルチオ）チアゾール—2—ィル）—1H—イミダゾールー 1—力 ノレボキシアミド [0233] 2) N- (5- (Isopropylthio) thiazole-2-yl) -1H-imidazole 1-force Norevoxamide
1)で得たクルードの内 2 gを脱水テトラヒドロフラン 20mLに溶かし、 1, 1， 一カルボ 二ルビス— 1H—イミダゾール 3. 1 g(19mmol)を加え室温で終夜攪拌した。混合 溶液に水、ジクロロメタンを加え反応を停止し、有機層を水にて洗浄後、減圧濃縮し 2 g of the crude product obtained in 1) was dissolved in 20 mL of dehydrated tetrahydrofuran, 3.1 g (19 mmol) of 1,1, monocarborubis-1H-imidazole was added, and the mixture was stirred at room temperature overnight. Water and dichloromethane were added to the mixed solution to stop the reaction, and the organic layer was washed with water and concentrated under reduced pressure.
、標記化合物をクルードで 337. 6mg得た。 The title compound was obtained by crude.
[0234] 3)1- ((4- (4 ブロモフエ-ル） 1H—イミダゾールー 2 ィル)メチル）ー3— (5 イソプロピルチオ）チアゾールー 2—ィル）ゥレア [0234] 3) 1- ((4- (4 Bromophenol) 1H-imidazole-2-yl) methyl) -3- (5 isopropylthio) thiazole-2-yl) urea
2)で得たクルードの内 85mgをテトラヒドロフラン 4mLに溶解し、（4— (4 ブロモフ ェ -ル） 1H—イミダゾールー 2 ィル)メチルァミン塩酸塩 123.4mg(0. 38mmol )、 N, N，—ジイソプロピルェチルァミン 129 μL·(0. 76mmol)を加え、室温で終夜 攪拌した。混合溶液に水、酢酸ェチルを加え反応を停止し、酢酸ェチルにて二回抽 出後、有機層を減圧濃縮し、残渣を P— TLC (クロ口ホルム Zメタノール =10Zl)に て精製し、標記化合物を得た（21mg、 15%)。 85 mg of the crude product obtained in 2) is dissolved in 4 mL of tetrahydrofuran, and 123.4 mg (0. Ethylamine 129 μL · (0.776 mmol) was added and stirred at room temperature overnight. Water and ethyl acetate are added to the mixed solution to stop the reaction. After extraction twice with ethyl acetate, the organic layer is concentrated under reduced pressure, and the residue is purified by P-TLC (black form Z methanol = 10 Zl). The title compound was obtained (21 mg, 15%).
— NMR(CDC1 /CD OD)： δ 7. 57 (2Η, m), 7.48 (2Η, m), 7. 31 (1H  — NMR (CDC1 / CD OD): δ 7. 57 (2Η, m), 7.48 (2Η, m), 7. 31 (1H
3 3  3 3
, s), 7. 26 (1H, s), 4. 53 (2H, s), 3.05 (1H, m), 1. 26 (6H, d, J = 6.8 Hz ), MS(ES+) :452(M+ + 1)  , s), 7.26 (1H, s), 4.53 (2H, s), 3.05 (1H, m), 1.26 (6H, d, J = 6.8 Hz), MS (ES +): 452 ( M ++ 1)
[0235] [実施例 778] 1—（（4一 （4一ブロモフエ-ル）一 1H イミダゾールー 2 ィル)メチ ル）—3— (5— (ペントー 4 ェ-ルスルホ -ル）チアゾール—2—ィル）ゥレア 前記実施例 775— 777と同様の方法で製造し、標記化合物を得た（36. 2mg、 44% （ / — s— /— 、 ^ ( / / エー 4ベ ） -9)— ε— [0235] [Example 778] 1 — ((4 (4 bromophenyl) 1 1H imidazole-2 yl) methyl) —3— (5— (Pentose 4 ethylsulfol) thiazole—2— Yl) urea Prepared in the same manner as in Example 775-777 to give the title compound (36.2 mg, 44% (/ — S— / —, ^ (/ / A 4) -9) — ε—
(1 + (1 +
+W)SL^- (+S3)SPV (ui 'UZ)L9 Ί ' 'UZ)9l 'Ζ '(ΖΗ I ·Ζ = Γ 'HS)6 + W) SL ^-( + S3) SPV (ui 'UZ) L9 Ί''UZ)9l' Ζ '( Ζ Η I · Ζ = Γ' HS) 6
9 'Ζ '(s 'HS)S9 ' '(m 'HS) 6 ー SO '9 '(^ 'HI)9Z '9 '(s 'HI)ZS ' L '( s 'Ηΐ)εε ' L ' ( ¾s)8 ' L ' ( 'HS)89 ' L 9 : (αο^ο/^οαο) H N - HX
Figure imgf000102_0001
9 'Ζ' ( s ' HS) S9 '' (m 'HS) 6 ー SO' 9 '(^' HI) 9Z '9' ( s ' HI) ZS 'L' ( s ' Ηΐ) εε 'L' (¾s) 8 'L'('HS)89' L 9: (αο ^ ο / ^ οαο) HN-H X
Figure imgf000102_0001
/ — S— /— 、^^ — HI— ( / ェ ） ）） (3) [ΐ8Ζί^¾ϊ第] [8S20] / — S— / —, ^^ — HI— (/ é))) (3) [ΐ8Ζί ^ ¾ϊ 第] [8S20]
{l + +W) LV- (+S3) SPV (ui 'HS)Z9 Ί '(^ 'HS)9I '(ΖΗ I 'Ζ = Γ (l + + W) LV- ( + S3) SPV (ui 'HS) Z9 Ί' (^ 'HS) 9I' ( Ζ Η I 'Ζ = Γ
"\ 'HS)69 '(s 'HS)S9 ' '(^ 'HS) 6 ー SO '9 '(^ 'HI)9Z '9 '(s 'HI) "\ 'HS) 69' ( s 'HS) S9''(^' HS) 6 ー SO '9' (^ 'HI) 9Z' 9 '( s ' HI)
LZ ' L '(s 'ΗΙ)εε ' L '(m 'HS)8 ' L '(^ 'HS)89 ' L 9 : (CIO aO)H N-Hx LZ 'L' ( s 'ΗΙ) εε' L '(m' HS) 8 'L' (^ 'HS) 89' L 9: (CIO aO) H NH x
°(  ° (
Figure imgf000102_0002
[ εεο]
Figure imgf000102_0002
[εεο]
(1 +  (1 +
+W) LV- (+S3)SPV (ui 'HS)Z9 Ί '(^ 'HS)9I 'Ζ '(ΖΗ I ·Ζ = Γ 'HS)6 + W) LV- ( + S3) SPV (ui 'HS) Z9 Ί' (^ 'HS) 9I' Ζ '( Ζ Η I · Ζ = Γ' HS) 6
9 'Z '(s 'HS)S9 '（m 'HS) 6 ー SO '9 '(^ 'HI)9Z '9 '(s 'HI)ZS ' L '( s 'Ηΐ)εε ' L ' ( ¾s)8 ' L ' ( 'HS)89 ' L 9 : (ao^o/^oao) H N - HX 9 'Z' ( s 'HS) S9' (m 'HS) 6 ー SO' 9 '(^' HI) 9Z '9' ( s 'HI) ZS' L '( s ' Ηΐ) εε 'L' ( ¾s) 8 'L'('HS)89' L 9: (ao ^ o / ^ oao) HN-H X
°(  ° (
Figure imgf000102_0003
Figure imgf000102_0003
(1+ , )8 ^: (,S3)SPV (UI 'HS)Z9 Ί '(m 'HS)9I '(ΖΗ I 'Ζ = Γ (1+,) 8 ^: (, S3) SPV (UI 'HS) Z9 Ί' (m 'HS) 9I' ( Ζ Η I 'Ζ = Γ
' 'HS)69 'Ζ '(s 'HS)S9 '(^ 'HS) 6 ー SO '9 '(^ 'HI)9Z '9 '(s 'HI) '' HS) 69 'Ζ' ( s ' HS) S9 '(^' HS) 6 ー SO '9' (^ 'HI) 9Z' 9 '( s ' HI)
LZ ' L '(s 'ΗΙ)εε ' L '(m 'HS)8 ' L '(^ 'HS)89 ' L 9 : (CIO aO)H N-Hx LZ 'L' ( s 'ΗΙ) εε' L '(m' HS) 8 'L' (^ 'HS) 89' L 9: (CIO aO) H NH x
°(  ° (
CZSTS0/.00Zdf/X3d 001· 178S980/.00Z OAV 前記実施例 775— 777と同様の方法で製造し、標記化合物を得た（27.6mg、 34%CZSTS0 / .00Zdf / X3d 001 · 178S980 / .00Z OAV Prepared in the same manner as in Examples 775-777 to give the title compound (27.6 mg, 34%
)。).
— NMR(CDC1 ): 67.80(1H, s), 7.52 (4H, m), 7.26 (IH, s), 5.74(1  — NMR (CDC1): 67.80 (1H, s), 7.52 (4H, m), 7.26 (IH, s), 5.74 (1
3  Three
H, m), 5.47(1H, m), 3.86 (2H, m), 2.09 (2H, m), 0.98 (3H, m)、 MS( FAB+) :510(M+ + 1)  H, m), 5.47 (1H, m), 3.86 (2H, m), 2.09 (2H, m), 0.98 (3H, m), MS (FAB +): 510 (M + + 1)
合成された化合物の構造を示せば、以下の表に示された通りである。  The structure of the synthesized compound is shown in the following table.
[表 4] [Table 4]
[S挲] [ so] [S 挲] [so]
Figure imgf000104_0001
Figure imgf000104_0001
fiSTS0//,00Zdf/X3d 1-8S980/ .00Z OAV
Figure imgf000105_0001
fiSTS0 //, 00Zdf / X3d 1-8S980 / .00Z OAV
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000106_0001
CZSTS0/Z.00Zdf/X3d 01 ^8S980/.00J OAV CZSTS0 / Z.00Zdf / X3d 01 ^ 8S980 / .00J OAV
Figure imgf000107_0001
Figure imgf000107_0001
CZSTS0/.00Zdf/X3d 901- 178S980/.00Z OAV [e [swo] CZSTS0 / .00Zdf / X3d 901- 178S980 / .00Z OAV [e [swo]
Figure imgf000108_0001
Figure imgf000108_0001
CZSTS0/.00Zdf/X3d 901· 178S980/.00Z OAV CZSTS0 / .00Zdf / X3d 901 · 178S980 / .00Z OAV
Figure imgf000109_0001
Figure imgf000109_0001
£ZSIS0/Z.00idf/X3d 101 ^8S980/Z.00∑ OAV
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
]
Figure imgf000113_0001
] m [TS20] £ ZSIS0 / Z.00idf / X3d 101 ^ 8S980 / Z.00∑ OAV
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
]
Figure imgf000113_0001
] m [TS20]
Figure imgf000114_0001
Figure imgf000114_0001
CZSTS0/.00Zdf/X3d s 178S980/.00Z OAV
Figure imgf000115_0001
]
Figure imgf000116_0001
]
Figure imgf000117_0001
]
Figure imgf000118_0001
] CZSTS0 / .00Zdf / X3d s 178S980 / .00Z OAV
Figure imgf000115_0001
]
Figure imgf000116_0001
]
Figure imgf000117_0001
]
Figure imgf000118_0001
]
Figure imgf000119_0001
]
Figure imgf000120_0001
]
Figure imgf000121_0001
]
Figure imgf000122_0001
]
Figure imgf000123_0001
4]
Figure imgf000124_0001
]
Figure imgf000125_0001
]
Figure imgf000126_0001
]
Figure imgf000127_0001
Figure imgf000119_0001
]
Figure imgf000120_0001
]
Figure imgf000121_0001
]
Figure imgf000122_0001
]
Figure imgf000123_0001
Four]
Figure imgf000124_0001
]
Figure imgf000125_0001
]
Figure imgf000126_0001
]
Figure imgf000127_0001
Figure imgf000127_0002
Figure imgf000127_0002
£ZSlS0/L00Zdr/13d 9ZV 178S980/Z.00Z; OAV
Figure imgf000128_0001
Figure imgf000128_0002
£ ZSlS0 / L00Zdr / 13d 9ZV 178S980 / Z.00Z; OAV
Figure imgf000128_0001
Figure imgf000128_0002
£ZSIS0/Z.00idf/X3d 921- ^8S980/Z.00∑ OAV
Figure imgf000129_0001
]
Figure imgf000130_0001
]
Figure imgf000131_0001
] £ ZSIS0 / Z.00idf / X3d 921- ^ 8S980 / Z.00∑ OAV
Figure imgf000129_0001
]
Figure imgf000130_0001
]
Figure imgf000131_0001
]
Figure imgf000132_0001
]
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000132_0001
]
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
]
Figure imgf000136_0001
] i Lz
Figure imgf000135_0001
]
Figure imgf000136_0001
] i Lz
Figure imgf000137_0001
Figure imgf000137_0001
CZSTS0/.00Zdf/X3d 9ε I. 1^8S980/.00Z OAV [6S挲] [SZ20] CZSTS0 / .00Zdf / X3d 9ε I. 1 ^ 8S980 / .00Z OAV [6S 挲] [SZ20]
Figure imgf000138_0001
Figure imgf000138_0001
fi£lS0/ .00idT/X3d 9ε ΐ- t8S980請 OAV
Figure imgf000139_0001
]
Figure imgf000140_0001
1] fi £ lS0 / .00idT / X3d 9ε ΐ- t8S980 contract OAV
Figure imgf000139_0001
]
Figure imgf000140_0001
1]
Figure imgf000141_0001
42]
Figure imgf000142_0001
Figure imgf000141_0001
42]
Figure imgf000142_0001
Figure imgf000142_0002
Figure imgf000142_0002
CZSTS0/.00Zdf/X3d OH 8S980/.00Z OAV
Figure imgf000143_0001
]
Figure imgf000144_0001
]
Figure imgf000145_0001
6]
Figure imgf000146_0001
]
Figure imgf000147_0001
]
Figure imgf000148_0001
CZSTS0 / .00Zdf / X3d OH 8S980 / .00Z OAV
Figure imgf000143_0001
]
Figure imgf000144_0001
]
Figure imgf000145_0001
6]
Figure imgf000146_0001
]
Figure imgf000147_0001
]
Figure imgf000148_0001
CZSTS0/.00ZdT/X3d 9 1^8S980/.00Z OAV vD O sslso-ooifcIdAV CZSTS0 / .00ZdT / X3d 9 1 ^ 8S980 / .00Z OAV vD O sslso-ooifcIdAV
Figure imgf000149_0001
Figure imgf000149_0001
s§os
Figure imgf000150_0001
1]
Figure imgf000151_0001
2] Ġ S¾95028 s§os
Figure imgf000150_0001
1]
Figure imgf000151_0001
2] Ġ S¾95028
Figure imgf000152_0001
Figure imgf000152_0001
Figure imgf000153_0001
4]
Figure imgf000154_0001
5] [9S挲] [Z6Z0]
Figure imgf000153_0001
Four]
Figure imgf000154_0001
Five] [9S 挲] [Z6Z0]
Figure imgf000155_0001
Figure imgf000155_0001
£ZSlS0/L00ZdF/lJd 891- t8S980婦 Z OAV
Figure imgf000156_0001
] [8S挲] [^620] £ ZSlS0 / L00ZdF / lJd 891- t8S980 Female Z OAV
Figure imgf000156_0001
] [8S 挲] [^ 620]
Figure imgf000157_0001
Figure imgf000157_0001
CZSTS0/.00Zdf/X3d 991- 178S980/.00Z OAV
Figure imgf000158_0001
] [09挲] [9620] CZSTS0 / .00Zdf / X3d 991- 178S980 / .00Z OAV
Figure imgf000158_0001
] [09 挲] [9620]
Figure imgf000159_0001
Figure imgf000159_0001
fi£lS0/ .00idT/X3d 19 V t8S980請 OAV
Figure imgf000160_0001
fi £ lS0 / .00idT / X3d 19 V t8S980 OAV
Figure imgf000160_0001
[表 61]
Figure imgf000161_0001
[Table 61]
Figure imgf000161_0001
0-0s8s98vuzfcd-oo. 0-0s8s98vuzfcd-oo.
Figure imgf000162_0001
Figure imgf000162_0001
u s§9ε us§9ε
Figure imgf000163_0001
4]
Figure imgf000164_0001
]
Figure imgf000165_0001
]
Figure imgf000166_0001
Figure imgf000167_0001
]
Figure imgf000168_0001
]
Figure imgf000169_0001
]
Figure imgf000170_0001
Figure imgf000163_0001
Four]
Figure imgf000164_0001
]
Figure imgf000165_0001
]
Figure imgf000166_0001
Figure imgf000167_0001
]
Figure imgf000168_0001
]
Figure imgf000169_0001
]
Figure imgf000170_0001
[0306] 肺炎逋鎖球菌 R6株由来のゲノム DNAの単離 [0306] Isolation of genomic DNA from Streptococcus pneumoniae strain R6
肺炎連鎖球菌（Streptococcus pneumoniae) R6株（ATCC49619)を血液寒天基礎 培地 (ベタトン'ディッキンソン社製)で二酸ィ匕炭素 5%、 37°Cの条件下で 18時間培 養し、低速遠心によって集菌した。得られた菌体から DNeasy Tissue Kit (QIAG EN社製)を用い、添付の説明書記載の方法に従って、ゲノム DNAを調製した。  Streptococcus pneumoniae (Streptococcus pneumoniae) R6 strain (ATCC49619) was cultured on blood agar basal medium (Betaton's Dickinson) for 18 hours under conditions of 5% carbon dioxide and 37 ° C and collected by low-speed centrifugation. Fungus. Genomic DNA was prepared from the obtained cells using DNeasy Tissue Kit (manufactured by QIAG EN) according to the method described in the attached instructions.
[0307] 肺炎連鎖球菌 R6株由来 FabK発現ベクターの構築 [0307] Construction of FabK expression vector derived from Streptococcus pneumoniae R6 strain
FabKをコードする DNAを単離するため以下のプライマーを設計した。  The following primers were designed to isolate DNA encoding FabK.
FabK-F. P. ： 5 ' -GGAATTCCATATGAAAACGCGTATTACAGAA- 3  FabK-F. P .: 5 '-GGAATTCCATATGAAAACGCGTATTACAGAA-3
His-FabK-R. P. : 5 ' - CCGCTCG AGGTCATTTCTTACAACTCCTGT 3， His-FabK-R. P.: 5 '-CCGCTCG AGGTCATTTCTTACAACTCCTGT 3,
[0308] 単離したゲノム DNAを铸型に、前記プライマーを用いて、 Pyrobest DNAPoly merase (タカラバイオ社製)でポリメラーゼ連鎖反応 (PCR)を添付の説明書に従 Vヽ 実施した。増幅した DNA断片は Ndelおよび Xholで消化した。この断片を予め Ndel および Xholで切断したベクター pET— 21b ( + ) (Novagen社製）に DNA Ligatio n Kit ver. 2 (TAKARA社製）を添付の説明書の方法に従い用い、サブクロー- ングした。得られた組換えプラスミドを大腸菌 COMPETENT high DH5 a (TOY OBO社製）に添付の説明書の方法に従い導入し、形質転換体を得た。形質転換体 を 50 /x g/mLのアンピシリンを含む LB agarプレート上にて、 37°Cでー晚培養し、 アンピシリン耐性コロニーを取得した。取得したコロニーから組換えプラスミド (His— FabKZpET— 21b ( + ) )を調製し DNA配列を確認し、 SWISSPROT Accessio n番号 Q8DR17に登録されている肺炎連鎖球菌 R6株由来 FabKをコードすることを 確認した。 [0308] The isolated genomic DNA was converted into a saddle shape, and a polymerase chain reaction (PCR) was performed with Pyrobest DNA Polymerase (manufactured by Takara Bio Inc.) using the above primers according to the attached instructions. The amplified DNA fragment was digested with Ndel and Xhol. This fragment was subcloned using a vector pET-21b (+) (Novagen) previously cleaved with Ndel and Xhol using DNA Ligation Kit ver. 2 (TAKARA) according to the method described in the attached instructions. The obtained recombinant plasmid was introduced into Escherichia coli COMPETENT high DH5 a (manufactured by TOY OBO) according to the method described in the attached instruction to obtain a transformant. Transformants were cultured at 37 ° C on LB agar plates containing 50 / xg / mL ampicillin, Ampicillin resistant colonies were obtained. A recombinant plasmid (His- FabKZpET-21b (+)) was prepared from the obtained colonies, the DNA sequence was confirmed, and it was confirmed that it encodes FabK derived from S. pneumoniae R6 strain registered in SWISSPROT Accession No. Q8DR17. .
[0309] flrtf 車 ϋ ¾iR6 fe FabKの^ E¾i 現.  [0309] Flrtf car ¾ ¾iR6 fe FabK ^ E¾i present.
得られた His— FabKZpET— 21b ( + )の組み換えプラスミドを大腸菌 BL21 (DE 3) (Novagen社製）に形質転換し、得られた形質転換体を 100 gZmLのアンピシ リンを含む SB培地（1. 2% (wZv) Bacto Tryptone, 2. 4% (w/v) Yeast Extra ct、 0. 5% (v/v)グジセ P—ノレ、 0. 072M ジン 素二カジクム、 0. 028Μ ジン 二水素カリウム含有） 5L中で 600nmにおける O. D. (吸光度）が 0. 6— 1. 0に達す るまで増殖させた。最終濃度 ImMのイソプロピル一 β—D チォガラタトピラノシド (I PTG)で三時間誘導後、遠心分離機によって集菌し、菌体をリン酸緩衝食塩水 (ΡΒ S) 200mLに懸濁した後、再度、遠心分離機によって集菌し、— 20°Cで凍結保存し た。保存した菌体を菌体破砕バッファー（50mMリン酸ナトリウム緩衝液 (pH8. 0) 、 300mM塩ィ匕ナトリウム、 5mMイミダゾール、 ImMフッ化フエ-ルメチルスルホ- ル、 ImMベンズアミジン、 ImM j8—メルカプトエタノール、 0. lmgZmLリゾチーム 含有）に懸濁し、氷上で 30分インキュベートした。次に 1分間の超音波処理を 5— 7回 行い、細胞を破砕した。遠心分離（30分間、 15000rpm)とそれに続く 0. の フィルターによって超音波処理の残渣を除去し、細胞抽出液を得た。  The obtained His-FabKZpET-21b (+) recombinant plasmid was transformed into E. coli BL21 (DE 3) (Novagen), and the resulting transformant was transformed into SB medium (1. 2% (wZv) Bacto Tryptone, 2.4% (w / v) Yeast Extra ct, 0.5% (v / v) Gujse P-Nole, 0.072M Contained) Grow in 5 L until OD (absorbance) at 600 nm reached 0.6—1.0. After induction with isopropyl-β-D thiogalatatopyranoside (I PTG) at a final concentration of ImM, the cells are collected by a centrifuge and the cells are suspended in 200 mL of phosphate buffered saline (ΡΒS). The cells were collected again by a centrifuge and stored frozen at -20 ° C. Preserved cells were disrupted with a cell disruption buffer (50 mM sodium phosphate buffer (pH 8.0), 300 mM sodium chloride, 5 mM imidazole, ImM fluorinated methyl chloride, ImM benzamidine, ImM j8-mercaptoethanol, 0 (containing lmgZmL lysozyme) and incubated on ice for 30 minutes. Next, sonication for 1 minute was performed 5-7 times to disrupt the cells. The sonication residue was removed by centrifugation (30 minutes, 15000 rpm) followed by a 0. filter to obtain a cell extract.
[0310] His - tag付き FabK (His - FabK)の精製  [0310] Purification of FabK (His-FabK) with His-tag
以下の精製操作はすべて 4°Cで行った。 His— FabKZpET—21b ( + )の組み換 え大腸菌から得られた細胞抽出液をァフィユティークロマトグラフィーで精製した。ァ フィ-ティークロマトグラフィーカラムは Ni— NTA Agarose (QIAGEN社製）を担体 として用い、取扱説明書に記載の方法でカラム容量 30mLのカラムを作製した。平衡 化バッファー（50mMリン酸ナトリウム緩衝液（pH 8. 0)、 300mM塩ィ匕ナトリウム、 5 mMイミダゾール、 ImMフッ化フエ-ルメチルスルホ -ル、 ImMベンズアミジン、 lm M β メルカプトエタノール含有)で平衡ィ匕した後、細胞抽出液を流速 lmLZmin でアプライし、 3カラム容量の洗浄バッファー（50mMリン酸ナトリウム緩衝液 (pH 8. 0)、 300mM塩ィ匕ナトリウム、 20mMイミダゾール、 ImMフッ化フエ-ルメチルスルホ -ル、 ImMベンズアミジン、 lmM jS—メルカプトエタノール含有）で洗浄した後、溶 出バッファー（50mMリン酸ナトリウム緩衝液（pH 8. 0)、 300mM塩ィ匕ナトリウム、 2 OOmMイミダゾール、 ImMフッ化フエ-ルメチルスルホ -ル、 ImMベンズアミジン、 ImM |8—メルカプトエタノール含有)で溶出した。 SDS— PAGEにより溶出画分を 確認し、 His— FabKの主要なフラクションをまとめて回収した。得られた His— FabK 溶液を透析バッファー（50mMトリス塩酸緩衝液 (pH 7. 5)、 50mM塩化アンモ- ゥム、 ImMフッ化フエ-ルメチルスルホ -ル、 ImMベンズアミジン、 ImMジチオスレ ィトール含有)で二時間透析し、酵素アツセィに使用した。 The following purification operations were all performed at 4 ° C. The cell extract obtained from Escherichia coli after recombination of His— FabKZpET-21b (+) was purified by affinity chromatography. For the affinity chromatography column, Ni-NTA Agarose (QIAGEN) was used as a carrier, and a column with a column volume of 30 mL was prepared by the method described in the instruction manual. Equilibration buffer (containing 50 mM sodium phosphate buffer (pH 8.0), 300 mM sodium chloride, 5 mM imidazole, ImM fluorinated methyl chloride, ImM benzamidine, lm M β mercaptoethanol) After that, the cell extract was applied at a flow rate of lmLZmin, and 3 column volumes of washing buffer (50 mM sodium phosphate buffer (pH 8. 0), 300mM sodium chloride, 20mM imidazole, ImM fluorinated methylmethylsulfol, ImM benzamidine, lmM jS-mercaptoethanol, and then elution buffer (50mM sodium phosphate buffer (pH 8. 0), 300 mM sodium chloride, 2 OO mM imidazole, ImM fluorinated methylmethylsulfol, ImM benzamidine, ImM | 8-mercaptoethanol). Elution fractions were confirmed by SDS-PAGE, and the major fractions of His-FabK were collected and collected. The resulting His-FabK solution was mixed with dialysis buffer (containing 50 mM Tris-HCl buffer (pH 7.5), 50 mM ammonium chloride, ImM fluoride methylsulfurol, ImM benzamidine, ImM dithiothreitol) for 2 hours. Dialyzed and used for enzyme assay.
[0311] FabK酵素アツセィ [0311] FabK enzyme assembly
FabK酵素アツセィは 96穴ハーフエリアプレートを用いて最終 100 μ Lの容量で実 施した。 FabK酵素活性は反応溶液中の NADHの減少を指標とし、 340nmの吸光 度 (OD )を測定した。基質 crotonoyl— CoA (最終濃度 0. 05mM)、補酵素 NA FabK enzyme assembly was performed in a final volume of 100 μL using a 96-well half area plate. FabK enzyme activity was measured by measuring the absorbance (OD) at 340 nm using the decrease in NADH in the reaction solution as an index. Substrate crotonoyl— CoA (final concentration 0.05 mM), coenzyme NA
340 340
DH (最終濃度 0. ImM)および阻害物質を酵素反応液 (最終 100mM2—（N— mo rpholino) ethanesulfonic acid (pH7. 0) - 100 mM NH4C1— 1 μ g/mL Fab K)に加え、室温で 5— 10分インキュベートし、反応前後の OD 値より差（AOD)を  Add DH (final concentration: 0. ImM) and inhibitor to the enzyme reaction solution (final 100 mM 2- (N- mo rpholino) ethanesulfonic acid (pH 7.0)-100 mM NH4C1- 1 μg / mL Fab K) at room temperature. Incubate for 5-10 minutes, and subtract the difference (AOD) from the OD value before and after the reaction.
340  340
求めた。陽性コントロールと比べて AOD値が 50%となる阻害物質の濃度を IC 値と  Asked. The concentration of the inhibitor that gives an AOD value of 50% compared to the positive control is the IC value.
50 し一 3¾し/こ。  50 to 1 3¾.
[0312] Fabl酵素アツセィ  [0312] Fabl enzyme assembly
Fabl酵素アツセィは 96穴ハーフエリアプレートを用いて最終 50 μ Lの容量で実施 した。 Fabl酵素活性は反応溶液中の NADHの減少を指標とし、 340nmの吸光度（ OD )を測定した。基質 crotonoyl— CoA (最終濃度 0. 25mM)、補酵素 NADH Fabl enzyme assembly was performed in a final 50 μL volume using 96-well half area plates. The Fabl enzyme activity was measured by measuring the absorbance (OD) at 340 nm using the decrease in NADH in the reaction solution as an index. Substrate crotonoyl— CoA (final concentration 0.25 mM), coenzyme NADH
340 340
(最終濃度 0. 4mM)および阻害物質を酵素反応液 (最終濃度 100 mMリン酸ナトリ ゥム（pH 7. 4) - 50 μ g/mL Fabl)にカロえ、室温で 5— 10分インキュベートし、反 応前後の OD 値より差（AOD)を求めた。陽性コントロールと比べて AOD値が 50  (Final concentration 0.4 mM) and inhibitors are added to the enzyme reaction solution (final concentration 100 mM sodium phosphate (pH 7.4)-50 μg / mL Fabl) and incubated at room temperature for 5-10 minutes. The difference (AOD) was calculated from the OD values before and after the reaction. 50 AOD compared to positive control
340  340
%となる阻害物質の濃度を IC 値として表した。  % Inhibitory substance concentration was expressed as IC value.
50  50
[0313] 上記実施例の化合物の FabK阻害活性は以下の表に示される通りであった。  [0313] The FabK inhibitory activities of the compounds of the above Examples were as shown in the following table.
[0314] [表 71] <FabK阻害活性 IG5。> [0314] [Table 71] <FabK inhibitory activity IG 5 . >
Figure imgf000173_0001
Figure imgf000173_0001
上記実施例の化合物の FabKおよび Fabl阻害活性は以下の表に示される通りで あった。 The FabK and Fabl inhibitory activities of the compounds of the above examples were as shown in the following table.
[表 72] [Table 72]
ぐ Fabl及び FabK阻害活性 IC50> Fabl and FabK inhibitory activity IC 50 >
Figure imgf000174_0001
Figure imgf000174_0001
[0316] 杭 ¾i活件測定 [0316] Pile ¾i activity measurement
最小発育阻止濃度（MIC)は NCCLS (National Committee for Clinical Labo ratory Standards)の勧告に準じた微量液体希釈法により測定した。 MIC測定には 当研究所保存の以下の菌株を使用した： Streptococcus pnemoniae 197 (S. Pneumo niae IP692)。 2%ゥマ溶血液添カ卩 Cation— adjusted Mueller—Hinton培地に試 験菌株を約 5 X 105CFUZmLとなるように接種し、 35°Cで 20— 24時間培養後、発 育を抑制する最小薬物濃度を MICと判定した。 The minimum inhibitory concentration (MIC) was measured by a micro liquid dilution method according to the recommendation of NCCLS (National Committee for Clinical Laboratory Standards). The following strains stored at our laboratory were used for MIC measurements: Streptococcus pnemoniae 197 (S. Pneumo niae IP692). Cation— adjusted Mueller—Hinton medium is inoculated with the test strain to about 5 X 10 5 CFUZmL, and growth is suppressed after incubation for 20-24 hours at 35 ° C. The minimum drug concentration was determined to be MIC.
[0317] 上記実施例化合物の Streptococcus pneumoniae 197(S. pneumoniae IP692)に対す る抗菌活性は以下の表に示される通りであった。  [0317] The antibacterial activity of the above Example compounds against Streptococcus pneumoniae 197 (S. pneumoniae IP692) was as shown in the following table.
[0318] [表 73] <抗菌活性 > [0318] [Table 73] <Antimicrobial activity>
MIC 197— MH- 実施例 No. 254LHB MIC 197— MH- Example No. 254LHB
73 0.125-0.2573 0.125-0.25
80 >3280> 32
82 1682 16
97 197 1
108 0.5108 0.5
401 1 6401 1 6
582 >32582> 32
665 16665 16
703 >32703> 32
722 32722 32
728 >32728> 32
775 4775 4
776 2776 2
778 0.1 25778 0.1 25
780 0.125 780 0.125

Claims

請求の範囲 The scope of the claims
下記式 (I)で表される化合物、その塩、またはそれらの溶媒和物：  A compound represented by the following formula (I), a salt thereof, or a solvate thereof:
[化 1] [Chemical 1]
A - Z - B ( I ) A-Z-B (I)
[式中、 [Where
zは、  z is
-NH-CO-NY-CH  -NH-CO-NY-CH
2  2
(ここで、 Yは水素原子またはメチル基を表す）、  (Where Y represents a hydrogen atom or a methyl group),
[化 2] 厂 W [Chemical 2] 厂 W
— NH-CO-N V—  — NH-CO-N V—
\ /  \ /
(ここで、 Vは CHまたは窒素原子を表し、 Wは C = 0または—CH を表す）、 (Where V represents CH or a nitrogen atom, W represents C = 0 or —CH),
2  2
NA，一 CO— CH O— N = C (B，）一、  NA, one CO— CH O— N = C (B,) one,
2  2
-O-CO-CH O— N = C (B，）一、または  -O-CO-CH O— N = C (B,) one, or
2  2
NA，一 CO—  NA, one CO—
を表し、 Represents
上己に^ ヽ飞、  To my self ^ ヽ 飞
A'は、水素原子または C 1—6アルキル基を表す力 または隣接する窒素原子およ び Aと一緒になつて下記式 (II)：  A ′ represents a hydrogen atom or a force representing a C 1-6 alkyl group, or together with an adjacent nitrogen atom and A, the following formula (II):
[化 3]
Figure imgf000176_0001
[Chemical 3]
Figure imgf000176_0001
(ここで、 A' 'は水素原子またはハロゲン原子を表す） (Where A '' represents a hydrogen atom or a halogen atom)
を表し、  Represents
B'は水素原子または 2—ピリジル基を表す力、または隣接する =Cおよび Bと一 緒になってシクロへキシリデンを表す。 Aは、 B ′ represents a hydrogen atom or a 2-pyridyl group, or cyclohexylidene together with ═C and B adjacent to each other. A is
水素原子、  Hydrogen atom,
CI 6アルキル基、  CI 6 alkyl group,
ヒドロキシ C1— 6アルキル基 (CH ) _Ph基、  Hydroxy C1-6 alkyl group (CH) _Ph group,
[化 4] [Chemical 4]
Figure imgf000177_0001
を表し、
Figure imgf000177_0001
Represents
上 C ^こお ヽて、  Top C ^
Raは、水素原子、水酸基、ハロゲン原子、シァノ基、ニトロ基、 C1— 6アルキル基、 C1— 6アルコキシ基、トリフルォロメチル基、トリフルォロメチルォキシ基、カルボキシ ル基、ァリルォキシカルボ-ル基、 C1 6アルキルォキシカルボ-ル基、 C1 6アル キルカルボ-ルォキシ基、 C1 6アルキルスルホ-ル基、スルファモイル基、—OC H CH N 、 一 OCH CH NHCOCH 、 一 COOCH CH OH、 一 COOCH CH NHR a is a hydrogen atom, hydroxyl group, halogen atom, cyano group, nitro group, C1-6 alkyl group, C1-6 alkoxy group, trifluoromethyl group, trifluoromethyloxy group, carboxyl group, aryl Oxycarbol group, C1 6 alkyloxycarbol group, C1 6 alkylcarboloxy group, C1 6 alkylsulfol group, sulfamoyl group, —OC H CH N, 1 OCH CH NHCOCH, 1 COOCH CH OH, I COOCH CH NH
2 2 3 2 2 3 2 2 2 22 2 3 2 2 3 2 2 2 2
COCH 、 -COOCH CH N (SO CH ) 、 -COOCH CH NH、または COOCCOCH, -COOCH CH N (SO CH), -COOCH CH NH, or COOC
3 2 2 2 3 2 2 2 2 3 2 2 2 3 2 2 2 2
H Nを表し、  H N represents
2 3  twenty three
Rbは、水素原子、ハロゲン原子、 C1 6アルキル基、 C1— 6アルコキシ基、 C1— 6アルキルォキシカルボ-ル基、または COOCH CH N (SO CH )を表し、 R b represents a hydrogen atom, a halogen atom, a C1 6 alkyl group, a C1-6 alkoxy group, a C1-6 alkyloxycarbon group, or COOCH CH N (SO 2 CH 3),
2 2 2 3 2  2 2 2 3 2
Reは、水素原子、ハロゲン原子、 C1 6アルキル基、 C2— 6ァルケ-ル基、 C2 6アルキ-ル基、ヒドロキシカルボ-ルメチル基、 C1 6アルキルォキシカルボ-ル 基、 C1 6アルキルォキシカルボ-ルメチル基、 C1 6アルキルカルボ-ルォキシ 基、ナフチル基、 C1 6アルキルチオ基、 C2— 6ァルケ-ルチオ基、 C2— 6アルキ -ルチオ基、 C1 6アルキルスルホ-ル基、 C2— 6ァルケ-ルスルホ-ル基、 C2— 6アルキ-ルスルホ -ル基、 C1 6アルキルスルフィエル基、 C2— 6ァルケ-ルスル フィエル基、 C2— 6アルキニルスルフィエル基、ピリジル基、ピリジルチオ基、ニトロピ リジルチオ基、モルフオリノメチル基、ピペリジノ基、 R e is a hydrogen atom, halogen atom, C1 6 alkyl group, C2-6 alkyl group, C2 6alkyl group, hydroxycarboromethyl group, C1 6 alkyloxycarboxyl group, C1 6 alkyloxycarboxyl group, C1 6 alkylcarboxoxy group, naphthyl group, C1 6 alkylthio group, C2— 6 alkylthio group, C2-6 alkylthio group, C1 6 alkylsulfol group, C2-6 alkylsulfonyl group, C2-6 alkylsulfol group, C1 6 alkylsulfur group, C2 — 6alkenylsulfier group, C2—6alkynylsulfier group, pyridyl group, pyridylthio group, nitropyridylthio group, morpholinomethyl group, piperidino group,
[化 5]
Figure imgf000178_0001
[Chemical 5]
Figure imgf000178_0001
(ここで、 (here,
Reaは、水素原子、ハロゲン原子、 C1 6アルキル基、 C1 6アルコキシ基、力ルバ モイル基、または一 OC (CH ) COOCH CHを表し、 R ea represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a strong rubamoyl group, or one OC (CH) COOCH CH;
3 2 2 3  3 2 2 3
Rebは、水素原子、ハロゲン原子、カルボキシル基、ニトロ基、 C1 6アルキルォキ シカノレボニノレ基、または CONHCH CH OHを表し、 R eb represents a hydrogen atom, a halogen atom, a carboxyl group, a nitro group, a C1 6 alkyloxy levono vinyl group, or CONHCH CH OH,
2 2  twenty two
Reeは、水素原子、ハロゲン原子、 C1 6アルキル基、または-トロ基を表す） を表し、 R ee represents a hydrogen atom, a halogen atom, a C16 alkyl group, or a -tro group)
Rdは、水素原子またはフエニル基、—SO フエ-ル基 (フエ-ル基上に一〜二 R d represents a hydrogen atom, a phenyl group, a —SO phenyl group (one to two on the phenyl group).
(0-2)  (0-2)
個の Re基を有していてもよぐここで Reは水素原子、シァノ基、または-トロ基を表す) を表す。 R e is also Yogu here have a number of R e radicals is a hydrogen atom, Shiano group or - represents a represents a Toro group).
Bは、  B
ナフチル基、  A naphthyl group,
C1 6アルキルォキシカルボ-ルァミノメチル基、  C1 6 alkyloxycarboluminomethyl group,
CH— S— Rk基、または CH—S—R k group, or
2  2
— CH— O— R1基、 — CH— O— R 1 group,
[化 6] [Chemical 6]
Figure imgf000179_0001
Figure imgf000179_0001
を表し、 Represents
上記にねい"""  Above "" "
Rfは、水素原子、水酸基、ハロゲン原子、 C1 6アルキル基、 C1 6アルコキシ基 、フエ-ル基、ニトロ基、またはアミノ基を表し、 R f represents a hydrogen atom, a hydroxyl group, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a phenol group, a nitro group, or an amino group,
は、水素原子、ハロゲン原子、またはフエ二ル基を表し、該フエニル基は、 Rgaに て一〜三個置換されていてもよく（ここで、 Rgaは水素原子、ハロゲン原子、 C1— 6ァ ルキル基、 C1 6アルコキシ基、ヒドロキシカルボ-ルメチルォキシ基、 C1— 6アル キルォキシカルボ-ルメチルォキシ基、力ルバモイルメチルォキシ基、 C1 6アルキ ルォキシカルボ-ルェチル基、 OCH CONHCH CH OH、— OCH CONHPh Represents a hydrogen atom, a halogen atom or a phenylene group,, said phenyl group may optionally be hand one to three amino substituents in R ga well (Again, R ga is a hydrogen atom, a halogen atom, C1- 6 alkyl groups, C1 6 alkoxy groups, hydroxy carboxymethyloxy groups, C1—6 alkyl carboxymethyloxy groups, strong rubamoylmethyloxy groups, C1 6 alkyloxycarboxyl groups, OCH CONHCH CH OH, — OCH CONHPh
2 2 2 2  2 2 2 2
、—OCH CONHCH Ph、—OCH CONHCH、フエ-ル CI— 6アルキル基、  , —OCH CONHCH Ph, —OCH CONHCH, phenol CI—6 alkyl group,
2 2 2 3  2 2 2 3
[化 7] [Chemical 7]
Figure imgf000180_0001
を表す)、
Figure imgf000180_0001
Represents
Rhは、水素原子またはアミノ基を表し、 R h represents a hydrogen atom or an amino group,
Riは、水素原子または C1 6アルキル基を表し、  Ri represents a hydrogen atom or a C16 alkyl group,
は、水素原子、ハロゲン原子、 C1— 6アルキル基、またはトリフルォロメチル基を 表し、  Represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a trifluoromethyl group,
Rk基は、 R k group is
[化 8] [Chemical 8]
Figure imgf000180_0002
Figure imgf000180_0002
(ここで、 Rka基は、水素原子、ハロゲン原子、 C1— 6アルキル基、フエ-ル基、トリフ ルォロメチル基、アミノ基、ニトロ基、—SO H基、または C 1—6アルキルォキシカル (Here, the R ka group is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a phenol group, a trifluoromethyl group, an amino group, a nitro group, a —SO 2 H group, or a C 1-6 alkyloxycarbon group.
3  Three
ボニノレ基を表し、 Represents a boninole group,
Rkb基は、水素原子またはァセチル基を表し、 Rke基は、水素原子または-トロ基を表す) を表し、 The R kb group represents a hydrogen atom or a acetyl group; R ke group represents a hydrogen atom or -tro group),
R1基は、 R 1 group is
[化 9] [Chemical 9]
Figure imgf000181_0001
Figure imgf000181_0001
を表す]。 Represents].
前記式 (I)において、  In the formula (I),
Zが、  Z is
-NH-CO-NY-CH  -NH-CO-NY-CH
-NA' -CO-CH O—  -NA '-CO-CH O—
2  2
NA，一 CO—  NA, one CO—
を表し、  Represents
Aが、  A
[化 10] [Chemical 10]
Figure imgf000181_0002
を表し、
Figure imgf000181_0002
Represents
Bが、 B
ナフチル基、 CH— S— Rk基、 Naphthyl group, CH—S—R k group,
2  2
[化 11] [Chemical 11]
Figure imgf000182_0001
を表す、請求項 1に記載の化合物、その塩、またはそれらの溶媒和物。 下記式 (la)で表される化合物、その塩、またはそれらの溶媒和物： [化 12]
Figure imgf000182_0001
The compound according to claim 1, a salt thereof, or a solvate thereof. A compound represented by the following formula (la), a salt thereof, or a solvate thereof: [Chemical Formula 12]
Aa-Za-Ba (la) A a -Z a -B a (la)
[式中、 [Where
zaは、 z a is
-NH-CO-NY-CH  -NH-CO-NY-CH
2  2
(ここで、 Yは水素原子またはメチル基を表す）、または  (Where Y represents a hydrogen atom or a methyl group), or
[化 13] 厂 W [Chemical 13] 厂 W
— NH-CO-N V—  — NH-CO-N V—
\ _ /  \ _ /
(ここで、 Vは CHまたは窒素原子を表し、 Wは C = 0または—CH—を: (Where V represents CH or a nitrogen atom, W represents C = 0 or —CH—:
2 を表す。  Represents 2.
Aaは、 A a is
水素原子、  Hydrogen atom,
C1 6アルキル基、  C1 6 alkyl group,
ヒドロキシ C1— 6アルキル基、  Hydroxy C1-6 alkyl group,
-(CH) — Ph基、  -(CH) — Ph group,
2 1-3  2 1-3
[化 14] [Chemical 14]
Figure imgf000183_0001
Figure imgf000183_0001
を表し、 Represents
上記にねい"""  Above "" "
Raは、水素原子、水酸基、ハロゲン原子、シァノ基、ニトロ基、 C1— 6アルキル基、 C1— 6アルコキシ基、トリフルォロメチル基、トリフルォロメチルォキシ基、カルボキシ ル基、ァリルォキシカルボ-ル基、 C1 6アルキルォキシカルボ-ル基、 C1 6アル キルカルボ-ルォキシ基、 C1 6アルキルスルホ-ル基、スルファモイル基、—OC H CH N 、 一 OCH CH NHCOCH 、 一 COOCH CH OH、 一 COOCH CH NHR a is a hydrogen atom, hydroxyl group, halogen atom, cyano group, nitro group, C1-6 alkyl group, C1-6 alkoxy group, trifluoromethyl group, trifluoromethyloxy group, carboxyl group, aryl Oxycarbol group, C1 6 alkyloxycarbol group, C1 6 alkylcarboloxy group, C1 6 alkylsulfol group, sulfamoyl group, —OC H CH N, 1 OCH CH NHCOCH, 1 COOCH CH OH, I COOCH CH NH
2 2 3 2 2 3 2 2 2 22 2 3 2 2 3 2 2 2 2
COCH 、 -COOCH CH N (SO CH ) 、 -COOCH CH NH、または COOCCOCH, -COOCH CH N (SO CH), -COOCH CH NH, or COOC
3 2 2 2 3 2 2 2 2 3 2 2 2 3 2 2 2 2
H Nを表し、  H N represents
2 3  twenty three
Rbは、水素原子、ハロゲン原子、 C1 6アルキル基、 C1— 6アルコキシ基、 C1— 6アルキルォキシカルボ-ル基、または COOCH CH N (SO CH )を表し、 R b represents a hydrogen atom, a halogen atom, a C1 6 alkyl group, a C1-6 alkoxy group, a C1-6 alkyloxycarbon group, or COOCH CH N (SO 2 CH 3),
2 2 2 3 2  2 2 2 3 2
Reは、水素原子、ハロゲン原子、 C1 6アルキル基、 C2— 6ァルケ-ル基、 C2 6アルキ-ル基、ヒドロキシカルボ-ルメチル基、 C1 6アルキルォキシカルボ-ル 基、 C1 6アルキルォキシカルボ-ルメチル基、 C1 6アルキルカルボ-ルォキシ 基、ナフチル基、 C1 6アルキルチオ基、 C2— 6ァルケ-ルチオ基、 C2— 6アルキ -ルチオ基、 C1 6アルキルスルホ-ル基、 C2— 6ァルケ-ルスルホ-ル基、 C2— 6アルキ-ルスルホ -ル基、 C1 6アルキルスルフィエル基、 C2— 6ァルケ-ルスル フィエル基、 C2— 6アルキニルスルフィエル基、ピリジル基、ピリジルチオ基、ニトロピ リジルチオ基、モルフオリノメチル基、ピペリジノ基、 R e is a hydrogen atom, a halogen atom, a C16 alkyl group, a C2-6 alkyl group, a C2 6 alkyl group, a hydroxycarboromethyl group, a C1 6 alkyloxycarbonyl group, a C16 alkyl group. Xyloxycarbonyl group, C16 alkyl carbonyl group, naphthyl group, C16 alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C16 alkylsulfol group, C2-6 alkyl -Sulfol group, C2-6 alkylsulfol group, C1 6 alkylsulfier group, C2-6 alkylsulfier group, C2-6 alkynylsulfier group, pyridyl group, pyridylthio group, nitropyridylthio group, Morpholinomethyl group, piperidino group,
[化 15]
Figure imgf000184_0001
s(O)0.2 Rcb、S(CH [Chemical 15]
Figure imgf000184_0001
s (O) 0 .2 R cb , S (CH
(ここで、 Rcaは水素原子、ハロゲン原子、 C1 6アルキル基、 C1 6アルコキシ基 、力ルバモイル基、または— OC (CH ) COOCH CHを表し、 (Where R ca represents a hydrogen atom, a halogen atom, a C 16 alkyl group, a C 16 alkoxy group, a force rubermoyl group, or —OC (CH) COOCH CH;
3 2 2 3  3 2 2 3
Rebは水素原子、ハロゲン原子、カルボキシル基、ニトロ基、 C1 6アルキルォキ シカルボ-ル基、または CONHCH CH OHを表し、 R eb represents a hydrogen atom, a halogen atom, a carboxyl group, a nitro group, a C16 alkyl carboxy group, or CONHCH CH OH,
2 2  twenty two
Reeは水素原子、ハロゲン原子、 C1 6アルキル基、または-トロ基を表す） を表し、 R ee represents a hydrogen atom, a halogen atom, a C16 alkyl group, or a -tro group)
Rdは、水素原子またはフエ-ル基、—SO フエ-ル基（フエ-ル基上に、一〜 R d represents a hydrogen atom, a phenyl group, a —SO phenol group (on the phenol group, 1 to
(0-2)  (0-2)
二個の Re基を有していてもよぐここで Reは水素原子、シァノ基、または-トロ基を表 す)を表す。 It may have two R e groups, where R e represents a hydrogen atom, a cyano group, or a -tro group).
Baは、 B a
[化 16] [Chemical 16]
Figure imgf000184_0002
を表し、 上記にねいて、
Figure imgf000184_0002
Represents As above
Rfは、水素原子、水酸基、ハロゲン原子、 C1 6アルキル基、 C1 6アルコキシ基 、フエ-ル基、ニトロ基、またはアミノ基を表し、 R f represents a hydrogen atom, a hydroxyl group, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a phenol group, a nitro group, or an amino group,
は、水素原子、ハロゲン原子、またはフエ二ル基を表し、該フヱ二ル基は Rgaに て一〜三個置換されていてもよく（ここで、 Rgaは水素原子、ハロゲン原子、 C1— 6ァ ルキル基、 C1 6アルコキシ基、ヒドロキシカルボ-ルメチルォキシ基、 C1— 6アル キルォキシカルボ-ルメチルォキシ基、力ルバモイルメチルォキシ基、 C1 6アルキ ルォキシカルボ-ルェチル基、 OCH CONHCH CH OH、— OCH CONHPh It represents a hydrogen atom, a halogen atom or an phenylene group, the full We sulfonyl group hand first to may be three substituents (wherein the R ga,, R ga is a hydrogen atom, a halogen atom, C1-6 alkyl group, C1 6 alkoxy group, hydroxycarboxylmethyloxy group, C1-6 alkyloxycarboxyloxy group, rubamoylmethyloxy group, C1 6 alkyloxycarboxyl group, OCH CONHCH CH OH, — OCH CONHPh
2 2 2 2  2 2 2 2
、—OCH CONHCH Ph、—OCH CONHCH、フエ-ル CI— 6アルキル基、  , —OCH CONHCH Ph, —OCH CONHCH, phenol CI—6 alkyl group,
2 2 2 3  2 2 2 3
[化 17]  [Chemical 17]
Figure imgf000185_0001
を表す)、
Figure imgf000185_0001
Represents
Rhは水素原子またはアミノ基を表し、 R h represents a hydrogen atom or an amino group,
Riは水素原子または C1 6アルキル基を表し、  Ri represents a hydrogen atom or a C16 alkyl group,
は水素原子、ハロゲン原子、 C1— 6アルキル基、またはトリフルォロメチル基を 表す]。  Represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a trifluoromethyl group.
下記式 (Iaa)で表される化合物、その塩、またはそれらの溶媒和物：  A compound represented by the following formula (Iaa), a salt thereof, or a solvate thereof:
Aa—NH— CO— NY—CH— Ba (Iaa) A a —NH— CO— NY—CH— B a (Iaa)
2  2
[式中、  [Where
Aaは、 [化 18] A a is [Chemical 18]
Figure imgf000186_0001
を表し、
Figure imgf000186_0001
Represents
Baは、 B a
[化 19]
Figure imgf000186_0002
を表し、 [Chemical 19]
Figure imgf000186_0002
Represents
Yは水素原子またはメチル基を表し、  Y represents a hydrogen atom or a methyl group,
上 d i ヽて、  D i up
Raは、水素原子、水酸基、ハロゲン原子、シァノ基、ニトロ基、 C1— 6アルキル基、 C1— 6アルコキシ基、トリフルォロメチル基、トリフルォロメチルォキシ基、カルボキシ ル基、ァリルォキシカルボ-ル基、 C1 6アルキルォキシカルボ-ル基、 C1 6アル キルカルボ-ルォキシ基、 C1 6アルキルスルホ-ル基、、スルファモイル基、—OC H CH N 、 一 OCH CH NHCOCH 、 一 COOCH CH OH、 一 COOCH CH NHR a is a hydrogen atom, hydroxyl group, halogen atom, cyano group, nitro group, C1-6 alkyl group, C1-6 alkoxy group, trifluoromethyl group, trifluoromethyloxy group, carboxyl group, aryl Oxycarbonyl group, C1 6 alkyl oxycarboxyl group, C1 6 alkyl carboxyloxy group, C1 6 alkyl sulphonyl group, sulfamoyl group, —OC H CH N, 1 OCH CH NHCOCH, 1 COOCH CH OH, one COOCH CH NH
2 2 3 2 2 3 2 2 2 22 2 3 2 2 3 2 2 2 2
COCH 、 -COOCH CH N (SO CH )、または一 COOCH CH NHを表し、Represents COCH, -COOCH CH N (SO CH), or one COOCH CH NH;
3 2 2 2 3 2 2 2 2 3 2 2 2 3 2 2 2 2
Rbは、水素原子、ハロゲン原子、 C1 6アルキル基、 C1— 6アルコキシ基、 C1— 6アルキルォキシカルボ-ル基、または COOCH CH N (SO CH )を表し、 R b represents a hydrogen atom, a halogen atom, a C1 6 alkyl group, a C1-6 alkoxy group, a C1-6 alkyloxycarbon group, or COOCH CH N (SO 2 CH 3),
2 2 2 3 2  2 2 2 3 2
Reは、水素原子、ハロゲン原子、 C1 6アルキル基、 C2— 6ァルケ-ル基、 C2 6アルキ-ル基、ヒドロキシカルボ-ルメチル基、 C1 6アルキルォキシカルボ-ル 基、 C1 6アルキルォキシカルボ-ルメチル基、 C1 6アルキルカルボ-ルォキシ 基、ナフチル基、 C1 6アルキルチオ基、 C2— 6ァルケ-ルチオ基、 C2— 6アルキ -ルチオ基、 C1 6アルキルスルホ-ル基、 C2— 6ァルケ-ルスルホ-ル基、 C2— 6アルキ-ルスルホ -ル基、 C1 6アルキルスルフィエル基、 C2— 6ァルケ-ルスル フィエル基、 C2— 6アルキ-ルスルフィエル基、ピリジルチオ基、モルフオリノメチル 基、ピペリジノ基、 R e is a hydrogen atom, a halogen atom, a C16 alkyl group, a C2-6 alkyl group, a C2 6 alkyl group, a hydroxycarboromethyl group, a C1 6 alkyloxycarbonyl group, a C16 alkyl group. Xyloxycarbonyl group, C16 alkyl carbonyl group, naphthyl group, C16 alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C16 alkylsulfol group, C2-6 alkyl -Lulsulfol group, C2— 6 alkylsulfol group, C1 6 alkylsulfier group, C2-6 alkylsulfier group, C2-6 alkylsulfier group, pyridylthio group, morpholinomethyl group, piperidino group,
[化 20]
Figure imgf000187_0001
[Chemical 20]
Figure imgf000187_0001
(ここで、 Rcaは水素原子、ハロゲン原子、 C1 6アルキル基、 C1 6アルコキシ基、 力ルバモイル基、または一 OC (CH ) COOCH CHを表し、 (Wherein R ca represents a hydrogen atom, a halogen atom, a C 16 alkyl group, a C 16 alkoxy group, a strong rubamoyl group, or one OC (CH) COOCH CH;
3 2 2 3  3 2 2 3
Rebは水素原子、ハロゲン原子、カルボキシル基、ニトロ基、 C1 6アルキルォキシ カルボ-ル基、または CONHCH CH OHを表し、 R eb represents a hydrogen atom, a halogen atom, a carboxyl group, a nitro group, a C16 alkyloxycarbon group, or CONHCH CHOH,
2 2  twenty two
R∞は水素原子、ハロゲン原子、 C1 6アルキル基、または-トロ基を表す） を表し、 R∞ represents a hydrogen atom, a halogen atom, a C16 alkyl group, or a -tro group)
Rdは、水素原子、または、フエ-ル基、—SO フエニル基 (該フエニル基上に、 R d represents a hydrogen atom, a phenyl group, a —SO phenyl group (on the phenyl group,
(0-2)  (0-2)
一〜二個の Re基を有していてもよぐここで Reは水素原子、シァノ基、または-トロ基 を表す)を表し、 It may have one or two R e groups, where R e represents a hydrogen atom, a cyano group, or a -tro group),
は、水素原子、ハロゲン原子、またはフエ二ル基を表し、該フエ-ル基は Rgaにて 一〜三個置換されていてもよく（ここで、 Rgaは水素原子、ハロゲン原子、 C 1—6アル キル基、 C1 6アルコキシ基、ヒドロキシカルボ-ルメチルォキシ基、 C1— 6アルキ ルォキシカルボ-ルメチルォキシ基、力ルバモイルメチルォキシ基、 C1 6アルキル ォキシカルボ-ルェチル基、 OCH CONHCH CH OH、— OCH CONHPh、 Represents a hydrogen atom, a halogen atom, or a phenyl group, and the phenyl group may be substituted with 1 to 3 groups of R ga (where R ga is a hydrogen atom, a halogen atom, C 1-6 alkyl group, C1 6 alkoxy group, hydroxycarboxylmethyloxy group, C1-6 alkyloxymethyl group, rubamoylmethyloxy group, C1 6 alkyloxycarboxyl group, OCH CONHCH CH OH, — OCH CONHPh,
2 2 2 2  2 2 2 2
一 OCH CONHCH Ph、一 OCH CONHCH、 OCH CONHCH Ph, OCH CONHCH,
2 2 2 3  2 2 2 3
[化 21]
Figure imgf000188_0001
を表す)、 [Chemical 21]
Figure imgf000188_0001
Represents
Riは、水素原子または CI 6アルキル基を表す。 ]。  Ri represents a hydrogen atom or a CI 6 alkyl group. ].
[5] 前記式（Iaa)において、 [5] In the formula (Iaa),
Baが、 B a
[化 22]  [Chemical 22]
Figure imgf000188_0002
Figure imgf000188_0002
(ここで、 Rgはフエ-ル基を表し、該フエ-ル基は Rgaにて一〜三個置換されていて もよく（ここで、 Rgaは水素原子、ハロゲン原子、 C1— 6アルキル基、 C1— 6アルコキシ 基、ヒドロキシカルボ-ルメチルォキシ基、 C1 6アルキルォキシカルボ-ルメチル ォキシ基、力ルバモイルメチルォキシ基、 C1 6アルキルォキシカルボ-ルェチル基 、 -OCH CONHCH CH OH、—OCH CONHPh、—OCH CONHCH Ph、一 (Wherein, R g Hue - represents a group, the Hue - Le groups being one to three amino substituents may (Again in R ga, R ga is a hydrogen atom, a halogen atom, C1- 6 Alkyl group, C1-6 alkoxy group, hydroxycarboxylmethyloxy group, C16 alkyloxycarboxylmethyloxy group, rubamoylmethyloxy group, C16 alkyloxycarboxyl group, -OCH CONHCH CHOH, —OCH CONHPh, —OCH CONHCH Ph, Ichi
2 2 2 2 2 2 2 2 2 2 2 2
OCH CONHCH、 OCH CONHCH,
[化 23] — OCH CO-N S— OCH,CO-N O — OCH2CO— N >— OH [Chemical 23] — OCH CO—N S— OCH, CO—N O — OCH 2 CO— N> — OH
2 \ _ / \ _ I \ 2 \ _ / \ _ I \
Figure imgf000189_0001
を表す)を表す、請求項 4に記載の化合物、その塩、またはそれらの溶媒和物。 目 |J 己式 (Iaa 【こお！ヽて、
Figure imgf000189_0001
The compound according to claim 4, or a salt thereof, or a solvate thereof. Eyes | J Self-style (Iaa [Koo!
Aaが、 A a
Figure imgf000189_0002
を表し、
Figure imgf000189_0002
Represents
Baが、 B a
[化 25] [Chemical 25]
Figure imgf000189_0003
Figure imgf000189_0003
(ここで、 はフエ-ル基を表し、該フエ-ル基が にて一個置換されており（ここで Rgaは、 (Wherein represents a phenyl group, and the phenyl group is substituted by one (where R ga is
[化 26]
Figure imgf000190_0001
を表す)を表す、請求項 4に記載の化合物、その塩、またはそれらの溶媒和物。 [Chemical 26]
Figure imgf000190_0001
The compound according to claim 4, or a salt thereof, or a solvate thereof.
下記式 (lab)で表される化合物、その塩、またはそれらの溶媒和物：  A compound represented by the following formula (lab), a salt thereof, or a solvate thereof:
[化 27] [Chemical 27]
Figure imgf000190_0002
Figure imgf000190_0002
[式中、 [Where
Xはハロゲン原子を表し、  X represents a halogen atom,
Reは、水素原子、ハロゲン原子、 C1 6アルキル基、 C2— 6ァルケ-ル基、 C2-6 アルキ-ル基、ヒドロキシカルボ-ルメチル基、 C1 6アルキルォキシカルボ-ル基 、 C1 6アルキルォキシカルボ-ルメチル基、 C1 6アルキルカルボ-ルォキシ基、 ナフチル基、 C1 6アルキルチオ基、 C2— 6ァルケ-ルチオ基、 C2— 6アルキ-ル チォ基、 C 1—6アルキルスルホ-ル基、 C2— 6ァルケ-ルスルホ-ル基、 C2— 6ァ ルキニルスルホ -ル基、 C1 6アルキルスルフィエル基、 C2— 6ァルケ-ルスルフィ -ル基、 C2— 6アルキ-ルスルフィエル基、ピリジルチオ基、モルフオリノメチル基、 ピペリジノ基、 R e is a hydrogen atom, a halogen atom, a C1 6 alkyl group, a C2-6 alkyl group, a C2-6 alkyl group, a hydroxycarboromethyl group, a C1 6 alkyloxycarbon group, a C1 6 alkyl group Oxycarboxyl group, C16 alkyl carboxy group, naphthyl group, C16 alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C1-6 alkylsulfol group, C2-6 alkyl sulfonyl group, C2-6 alkyl sulfonyl group, C1 6 alkyl sulfiel group, C2-6 alkyl sulfyl group, C2-6 alkyl sulfiel group, pyridylthio group, morpholino Methyl group, piperidino group,
[化 28]
Figure imgf000190_0003
[Chemical 28]
Figure imgf000190_0003
(ここで、 Rcaは水素原子、ハロゲン原子、 C1 6アルキル基、 C1 6アルコキシ基 、力ルバモイル基、または— OC (CH ) COOCH CHを表し、これら基は置換基を (Wherein R ca represents a hydrogen atom, a halogen atom, a C 16 alkyl group, a C 16 alkoxy group, a force rubermoyl group, or —OC (CH 2) 2 COOCH CH, and these groups represent substituents.
3 2 2 3  3 2 2 3
有していてもよぐ R は水素原子、ハロゲン原子、カルボキシル基、ニトロ基、 C1— 6アルキルォキ シカルボ-ル基、または一 CONHCH CH OHを表し、これら基は置換基を有して May have R represents a hydrogen atom, a halogen atom, a carboxyl group, a nitro group, a C1-6 alkyl carboxy group, or one CONHCH CH OH, and these groups have a substituent.
2 2  twenty two
いてもよく、 You may,
R∞は水素原子、ハロゲン原子、 C1 6アルキル基、または-トロ基を表し、これら 基は置換基を有していてもよい。 ) R∞ represents a hydrogen atom, a halogen atom, a C16 alkyl group, or a -tro group, and these groups may have a substituent. )
を表す]。 Represents].
下記式 (lab)で表される化合物、その塩、またはそれらの溶媒和物：  A compound represented by the following formula (lab), a salt thereof, or a solvate thereof:
[化 29] [Chemical 29]
Figure imgf000191_0001
Figure imgf000191_0001
[式中、 [Where
Xはハロゲン原子を表し、  X represents a halogen atom,
Rcは、 C1— 6アルキル基、 C2— 6ァルケ-ル基、 C2— 6アルキ-ル基、 C1— 6ァ ルキルチオ基、 C2— 6ァルケ-ルチオ基、 C2— 6アルキ-ルチオ基、 C1 6アルキ ルスルホ -ル基、 C2— 6ァルケ-ルスルホ-ル基、 C2— 6アルキニルスルホ -ル基 、 C1 6アルキルスルフィエル基、 C2— 6ァルケ-ルスルフィエル基、 C2— 6アルキ ニルスルフィ -ル基を表し、これら基は置換基を有していてもよい。 ]。  Rc is C1-6 alkyl group, C2-6 alkyl group, C2-6 alkyl group, C1-6 alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C1 6 Alkylsulfol group, C2-6 alkylsulfol group, C2-6 alkynylsulfol group, C16 alkylsulfier group, C2-6 alkylsulfuryl group, C2-6 alkenylsulfuryl group These groups may have a substituent. ].
下記式 (lb)で表される化合物、その塩、またはそれらの溶媒和物： A compound represented by the following formula (lb), a salt thereof, or a solvate thereof:
[化 30] [Chemical 30]
A b— N A , — C O— B b ( l b ) A b — NA, — CO— B b (lb)
[式中、 [Where
A'は、水素原子または C 1—6アルキル基を表す力 または隣接する窒素原子およ び Abと一緒になつて下記式 (II)： A ′ is a hydrogen atom or a force representing a C 1-6 alkyl group, or together with an adjacent nitrogen atom and A b , the following formula (II):
[化 31]
Figure imgf000191_0002
(ここで、 A'，は水素原子またはハロゲン原子を表す) [Chemical 31]
Figure imgf000191_0002
(Here, A ', represents a hydrogen atom or a halogen atom)
を表す。 Represents.
Abは、 A b is
[化 32] [Chemical 32]
Figure imgf000192_0001
を表し、
Figure imgf000192_0001
Represents
上記にねい"""  Above "" "
Raは、水素原子、水酸基、ハロゲン原子、シァノ基、ニトロ基、 C1— 6アルキル基、 C1— 6アルコキシ基、トリフルォロメチル基、トリフルォロメチルォキシ基、カルボキシ ル基、ァリルォキシカルボ-ル基、 C1 6アルキルォキシカルボ-ル基、 C1 6アル キルカルボ-ルォキシ基、 C1 6アルキルスルホ-ル基、、スルファモイル基、—OC H CH N 、 一 OCH CH NHCOCH 、 一 COOCH CH OH、 一 COOCH CH NHR a is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, a C1-6 alkyl group, a C1-6 alkoxy group, a trifluoromethyl group, a trifluoromethyloxy group, a carboxyl group, an aryl. Oxycarbon group, C16 alkyloxycarbonyl group, C16 alkylcarbonyl group, C16 alkylsulfonyl group, sulfamoyl group, —OC H CH N, OCH CH NHCOCH, COOCH CH OH, one COOCH CH NH
2 2 3 2 2 3 2 2 2 22 2 3 2 2 3 2 2 2 2
COCH 、 -COOCH CH N (SO CH ) 、 -COOCH CH NH、または COOCCOCH, -COOCH CH N (SO CH), -COOCH CH NH, or COOC
3 2 2 2 3 2 2 2 2 3 2 2 2 3 2 2 2 2
H Nを表し、  H N represents
2 3  twenty three
Rbは、水素原子、ハロゲン原子、 C1 6アルキル基、 C1— 6アルコキシ基、 C1— 6アルキルォキシカルボ-ル基、または COOCH CH N (SO CH )を表し、 R b represents a hydrogen atom, a halogen atom, a C1 6 alkyl group, a C1-6 alkoxy group, a C1-6 alkyloxycarbon group, or COOCH CH N (SO 2 CH 3),
2 2 2 3 2  2 2 2 3 2
Reは、水素原子、ハロゲン原子、 C1 6アルキル基、 C2— 6ァルケ-ル基、 C2 6アルキ-ル基、ヒドロキシカルボ-ルメチル基、 C1 6アルキルォキシカルボ-ル 基、 C1 6アルキルォキシカルボ-ルメチル基、 C1 6アルキルカルボ-ルォキシ 基、ナフチル基、 C1 6アルキルチオ基、 C2— 6ァルケ-ルチオ基、 C2— 6アルキ -ルチオ基、 C1 6アルキルスルホ-ル基、 C2— 6ァルケ-ルスルホ-ル基、 C2— 6アルキ-ルスルホ -ル基、 C1 6アルキルスルフィエル基、 C2— 6ァルケ-ルスル フィエル基、 C2— 6アルキ-ルスルフィエル基、ピリジルチオ基、モルフオリノメチル 基、ピペリジノ基、 R e is a hydrogen atom, a halogen atom, a C16 alkyl group, a C2-6 alkyl group, a C2 6 alkyl group, a hydroxycarboromethyl group, a C1 6 alkyloxycarbonyl group, a C16 alkyl group. Xyloxycarbonyl group, C16 alkyl carbonyl group, naphthyl group, C16 alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C16 alkylsulfol group, C2-6 alkyl -Sulfol group, C2-6 alkylsulfol group, C1 6 alkylsulfur group, C2-6 alkylsulfur group Fier group, C2-6 alkyl sulfier group, pyridylthio group, morpholinomethyl group, piperidino group,
[化 33]
Figure imgf000193_0001
[Chemical 33]
Figure imgf000193_0001
(ここで、 Rcaは水素原子、ハロゲン原子、 C1 6アルキル基、 C1 6アルコキシ基 、力ルバモイル基、または一 OC (CH ) COOCH CHを表し、 (Where R ca represents a hydrogen atom, a halogen atom, a C 16 alkyl group, a C 16 alkoxy group, a force rubermoyl group, or one OC (CH) COOCH CH;
3 2 2 3  3 2 2 3
Rcbは水素原子、ハロゲン原子、カルボキシル基、 -トロ基、 C1— 6アルキルォキ シカノレボニノレ基、または CONHCH CH OHを表し、 R cb represents a hydrogen atom, a halogen atom, a carboxyl group, a -tro group, a C1-6 alkyloxy decano vonore group, or CONHCH CH OH,
2 2  twenty two
Reeは水素原子、ハロゲン原子、 C1 6アルキル基、または-トロ基を表す）を表し Rdは、水素原子、またはフエ-ル基、—SO フエニル基 (フエニル基上に、 R ee represents a hydrogen atom, a halogen atom, a C16 alkyl group, or a -tro group) R d represents a hydrogen atom, a phenyl group, a —SO phenyl group (on the phenyl group,
(0-2) 一 (0-2) One
〜二個の Re基を有していてもよぐここで Reは水素原子、シァノ基、または-トロ基を 表す)を表す。 It may have two R e groups, where R e represents a hydrogen atom, a cyano group, or a -tro group.
Bbは、 C 1—6アルキルォキシカルボ-ルァミノメチル基、 CH— S— Rk基、 C B b is a C 1-6 alkyloxycarboluminomethyl group, CH—S—R k group, C
2  2
H O— R'基、  H O—R ′ group,
2  2
[化 34]  [Chemical 34]
Figure imgf000193_0002
を表し、
Figure imgf000193_0002
Represents
上 β己にぉ ヽ飞、  Above β
Rfは、水素原子、水酸基、ハロゲン原子、 C1 6アルキル基、 C1 6アルコキシ基 、フエ-ル基、ニトロ基、またはアミノ基を表し、 Rhは、水素原子またはアミノ基を表し、 R f represents a hydrogen atom, a hydroxyl group, a halogen atom, a C16 alkyl group, a C16 alkoxy group, a phenol group, a nitro group, or an amino group, R h represents a hydrogen atom or an amino group,
Rk基は、 R k group is
[化 35] [Chemical 35]
Figure imgf000194_0001
Figure imgf000194_0001
(ここで、 Rka基は、水素原子、ハロゲン原子、 C1— 6アルキル基、フエ-ル基、トリフ ルォロメチル基、アミノ基、ニトロ基、 SO H基、または C1 6アルキルォキシカル (Here, the R ka group is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a phenol group, a trifluoromethyl group, an amino group, a nitro group, a SO H group, or a C1 6 alkyloxy group.
3  Three
ボニノレ基を表し、 Represents a boninole group,
Rkb基とは水素原子またはァセチル基を表し、 R kb group represents a hydrogen atom or a acetyl group;
Rke基とは水素原子またはニトロ基を表す） R ke group represents a hydrogen atom or a nitro group)
を表し、  Represents
R1基は、 R 1 group is
[化 36] [Chemical 36]
Figure imgf000194_0002
を表す。 ]。
Figure imgf000194_0002
Represents. ].
前記式 (lb)において、  In the formula (lb),
A'が水素原子を表し、  A ′ represents a hydrogen atom,
Abが、 A b
[化 37]
Figure imgf000195_0001
[Chemical 37]
Figure imgf000195_0001
を表し、 Represents
Bbがー CH— S—Rk基を表す、請求項 9に記載の化合物、その塩、またはそれらの The compound according to claim 9, a salt thereof, or a group thereof, wherein B b represents a —CH—S—R k group
2  2
溶媒和物。 Solvate.
下記式 (Ic)で表される化合物、その塩、またはそれらの溶媒和物：  A compound represented by the following formula (Ic), a salt thereof, or a solvate thereof:
[化 38]  [Chemical 38]
Ac-Zc-Bc (I c) A c -Z c -B c (I c)
[式中、 [Where
zcは、 z c is
NA， -CO-CH O— N = C(B，）一または  NA, -CO-CH O— N = C (B,) one or
2  2
-O-CO-CH O— N = C(B，）一  -O-CO-CH O— N = C (B,)
2  2
(ここで、 A'は、水素原子または C1— 6アルキル基を表す力、または隣接する窒素 原子および Aeと一緒になつて下記式 (II)： (Where A ′ is a hydrogen atom or a C1-6 alkyl group, or together with an adjacent nitrogen atom and A e , the following formula (II):
[化 39]
Figure imgf000195_0002
[Chemical 39]
Figure imgf000195_0002
(ここで、 A' 'は水素原子またはハロゲン原子を表す）  (Where A '' represents a hydrogen atom or a halogen atom)
を表す)を表し、 Represents
B'は、水素原子、 2—ピリジル基、または隣接する =C、および Beと共にシクロ リデンを表す。 B 'represents a hydrogen atom, a 2-pyridyl group or a cycloalkyl isopropylidene adjacent = C, and with B e,.
Aeは、水素原子、 C1 6アルキル基、 A e is a hydrogen atom, a C16 alkyl group,
[化 40] [Chemical 40]
Figure imgf000196_0001
を表し、
Figure imgf000196_0001
Represents
Figure imgf000196_0002
Figure imgf000196_0002
Raは、水素原子、水酸基、ハロゲン原子、シァノ基、ニトロ基、 C1— 6アルキル基、 C1— 6アルコキシ基、トリフルォロメチル基、トリフルォロメチルォキシ基、カルボキシ ル基、ァリルォキシカルボ-ル基、 C1 6アルキルォキシカルボ-ル基、 C1 6アル キルカルボ-ルォキシ基、 C1 6アルキルスルホ-ル基、、スルファモイル基、—OC H CH N OCH CH NHCOCH COOCH CH OH COOCH CH NH R a is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, a C1-6 alkyl group, a C1-6 alkoxy group, a trifluoromethyl group, a trifluoromethyloxy group, a carboxyl group, an aryl. Oxycarbol group, C1 6 alkyloxycarbonyl group, C1 6 alkylcarboloxy group, C1 6 alkylsulfonyl group, sulfamoyl group, —OC H CH N OCH CH NHCOCH COOCH CH OH COOCH CH NH
2 2 3 2 2 3 2 2 2 2 2 2 3 2 2 3 2 2 2 2
COCH -COOCH CH N (SO CH ) 、または一 COOCH CH NHを表し、COCH-COOCH CH N (SO CH), or one COOCH CH NH,
3 2 2 2 3 2 2 2 2 3 2 2 2 3 2 2 2 2
Rbは、水素原子、ハロゲン原子、 C1 6アルキル基、 C1— 6アルコキシ基、 C1— 6アルキルォキシカルボ-ル基、または COOCH CH N (SO CH )を表し、 R b represents a hydrogen atom, a halogen atom, a C1 6 alkyl group, a C1-6 alkoxy group, a C1-6 alkyloxycarbon group, or COOCH CH N (SO 2 CH 3),
2 2 2 3 2  2 2 2 3 2
Reは、水素原子、ハロゲン原子、 C1 6アルキル基、 C2— 6ァルケ-ル基、 C2 6アルキ-ル基、ヒドロキシカルボ-ルメチル基、 C1 6アルキルォキシカルボ-ル 基、 C1 6アルキルォキシカルボ-ルメチル基、 C1 6アルキルカルボ-ルォキシ 基、ナフチル基、 C1 6アルキルチオ基、 C2— 6ァルケ-ルチオ基、 C2— 6アルキ -ルチオ基、 C1 6アルキルスルホ-ル基、 C2— 6ァルケ-ルスルホ-ル基、 C2— 6アルキ-ルスルホ -ル基、 C1 6アルキルスルフィエル基、 C2— 6ァルケ-ルスル フィエル基、 C2— 6アルキ-ルスルフィエル基、ピリジルチオ基、モルフオリノメチル 基、ピペリジノ基、 R e represents a hydrogen atom, a halogen atom, a C16 alkyl group, a C2-6 alkyl group, a C2 6 alkyl group, a hydroxycarboromethyl group, a C1 6 alkyloxycarboro group, a C16 alkyl group. Xyloxycarbonyl group, C16 alkyl carboxy group, naphthyl group, C16 alkylthio group, C2-6 alkylthio group, C2-6 alkylthio group, C16 alkylsulfol group, C2-6 alkyl -Sulfol group, C2-6 alkylsulfol group, C16 alkyl sulfier group, C2-6 alkyl sulfier group, C2-6 alkyl sulfier group, pyridylthio group, morpholinomethyl group, piperidino Group,
[化 41]
Figure imgf000197_0001
[Chemical 41]
Figure imgf000197_0001
(ここで、 Rcaは水素原子、ハロゲン原子、 C1 6アルキル基、 C1 6アルコキシ基 、力ルバモイル基、または一 OC (CH ) COOCH CHを表し、 (Where R ca represents a hydrogen atom, a halogen atom, a C 16 alkyl group, a C 16 alkoxy group, a force rubermoyl group, or one OC (CH) COOCH CH;
3 2 2 3  3 2 2 3
Rcbは水素原子、ハロゲン原子、カルボキシル基、 -トロ基、 C1— 6アルキルォキ シカノレボニノレ基、または CONHCH CH OHを表し、 R cb represents a hydrogen atom, a halogen atom, a carboxyl group, a -tro group, a C1-6 alkyloxy decano vonore group, or CONHCH CH OH,
2 2  twenty two
Reeは、水素原子、ハロゲン原子、 C1 6アルキル基、または-トロ基を表す） を表し、 R ee represents a hydrogen atom, a halogen atom, a C16 alkyl group, or a -tro group)
Rdは、水素原子またはフエニル基、—SO フエ-ル基 (フエ-ル基上に、一〜 R d represents a hydrogen atom, a phenyl group, a —SO phenyl group (on the phenyl group, 1 to
(0-2)  (0-2)
二個の Re基を有していてもよぐ ：で Reは水素原子、シァノ基、または-トロ基を表 す） It may have two R e groups: in which R e represents a hydrogen atom, a cyano group, or a -tro group)
を表す。  Represents.
Bcは、ナフチル基、 B c is a naphthyl group,
[化 42]  [Chemical 42]
Figure imgf000197_0002
Figure imgf000197_0002
(ここで、 Rは水素原子、水酸基、ハロゲン原子、 C1 6アルキル基、 C1— 6アルコ キシ基、フエニル基、ニトロ基、またはアミノ基を表し、 (Wherein R represents a hydrogen atom, a hydroxyl group, a halogen atom, a C16 alkyl group, a C1-6 alkoxy group, a phenyl group, a nitro group, or an amino group;
Rhは水素原子またはアミノ基を表し、 R h represents a hydrogen atom or an amino group,
Riは水素原子または C1 6アルキル基を表す）  Ri represents a hydrogen atom or a C16 alkyl group)
を表す]。  Represents].
[12] 前記式（Ic)において、  [12] In the formula (Ic),
Zcが NA， 一 CO— CH O— N = C (B，）一を表し、 Z c represents NA, one CO—CH 2 O—N = C (B,) one,
2  2
A'が水素原子を表し、  A ′ represents a hydrogen atom,
B'が水素原子または 2—ピリジル基を表す力 または隣接する =Cおよび Beと一緒 になってシクロへキシリデンを表し、 Acが、 B 'together with the force or adjacent = C and B e represents a hydrogen atom or a 2-pyridyl group represents a cyclohexylidene cyclohexane, A c
[化 43]
Figure imgf000198_0001
[Chemical 43]
Figure imgf000198_0001
を表す、請求項 11に記載の化合物、その塩、またはそれらの溶媒和物。  The compound according to claim 11, a salt thereof, or a solvate thereof.
[13] 請求項 1〜12のいずれか一項に記載の化合物、その塩、またはそれらの溶媒和物 を有効成分とする、医薬組成物。 [13] A pharmaceutical composition comprising the compound according to any one of claims 1 to 12, a salt thereof, or a solvate thereof as an active ingredient.
[14] 請求項 1〜12のいずれか一項に記載の化合物、その塩、またはそれらの溶媒和 物を有効成分とする、 FabKおよび Fablの阻害剤。 [14] An inhibitor of FabK and Fabl, comprising the compound according to any one of claims 1 to 12, a salt thereof, or a solvate thereof as an active ingredient.
[15] 請求項 1〜12のいずれか一項に記載の化合物、その塩、またはそれらの溶媒和物 の有効量を、ヒトを含む動物に投与することを含んでなる、細菌感染症の予防または 治療方法。 [15] Prevention of bacterial infection, comprising administering an effective amount of the compound according to any one of claims 1 to 12, a salt thereof, or a solvate thereof to an animal including a human. Or treatment method.
[16] 細菌感染症の予防または治療薬の製造のための、請求項 1〜12のいずれか一項 に記載の化合物、その塩、またはそれらの溶媒和物の使用。  [16] Use of the compound according to any one of claims 1 to 12, a salt thereof, or a solvate thereof for the manufacture of a preventive or therapeutic agent for a bacterial infection.
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