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WO2013051672A1 - Medicinal agent comprising thiazolidine derivative or salt thereof as active ingredient - Google Patents

Medicinal agent comprising thiazolidine derivative or salt thereof as active ingredient Download PDF

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Publication number
WO2013051672A1
WO2013051672A1 PCT/JP2012/075857 JP2012075857W WO2013051672A1 WO 2013051672 A1 WO2013051672 A1 WO 2013051672A1 JP 2012075857 W JP2012075857 W JP 2012075857W WO 2013051672 A1 WO2013051672 A1 WO 2013051672A1
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Prior art keywords
methylene
phenyl
thiazolidine
dione
imidazo
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French (fr)
Japanese (ja)
Inventor
淳博 安倍
竜太 山崎
俊雄 笹井
隆 八重樫
正人 長岡
陽光 高木
松崎　健
理之 前
卓弥 杉本
恒之 小林
西山　裕之
諭一 澤口
由紀子 西山
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Yakult Honsha Co Ltd
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Yakult Honsha Co Ltd
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Priority to JP2013537559A priority Critical patent/JP6057907B2/en
Publication of WO2013051672A1 publication Critical patent/WO2013051672A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D417/14—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the present invention relates to a compound having Pim kinase inhibition (hereinafter referred to as Pim inhibition) and useful as a medicament such as an anticancer agent, and a medicament containing the same.
  • Protein kinases play an important role in the control of information transmission within and between cells and are involved in various diseases including cancer.
  • protein kinase targeting inhibitors such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib, Bcr-Abl tyrosine kinase inhibitor imatinib, and sorafenib that inhibits many types of protein kinases
  • EGFR epidermal growth factor receptor
  • Bcr-Abl tyrosine kinase inhibitor imatinib and sorafenib that inhibits many types of protein kinases
  • the drug is widely used clinically in the field of cancer treatment as a molecular targeted therapeutic agent, and has shown high effectiveness. It is said that there are more than 500 types of human protein kinases, and it is believed that they have great potential as targets for the development of new cancer molecular targeted therapeutics.
  • Pim-1 is a serine / threonine kinase that positively controls cell survival and proliferation by phosphorylating various intracellular factors that control cell cycle progression and apoptosis.
  • Pim-1 is known to be inactivated by phosphorylating BAD, which is a proapoptotic factor, and to act as an anti-apoptotic factor.
  • BAD phosphorylating BAD
  • Pim-1 increases phosphatase activity by phosphorylating CDC25A and CDC25C that positively control cell cycle progression, and inactive by phosphorylating p21 that negatively regulates cell cycle progression. To accelerate cell cycle progression.
  • Pim-1 is known to increase protein synthesis and promote cell growth by phosphorylating 4E-BP1, which is a protein synthesis regulator.
  • Pim-1 is known to have two types of isozymes, Pim-2 and Pim-3, which are highly homologous, and, like Pim-1, also partially share the above functions. It is believed that.
  • Pim-1, Pim-2 and Pim-3 are involved in the control of the activity of various factors involved in cell survival and proliferation, and diseases characterized by abnormal cell proliferation such as cancer Is thought to be deeply involved in In fact, Pim has been reported to be involved in the development of various cancers such as hematological cancers including acute myeloid leukemia, and solid cancers including prostate cancer. Patent Documents 1 to 5). In addition, it has been suggested to be involved in angiogenesis (Non-patent Document 6) and resistance to anticancer drugs in chemotherapy (Non-patent Document 7), and Pim is considered an attractive molecular target in cancer treatment. And compounds that inhibit it are expected as new cancer therapeutics. Furthermore, Pim's involvement extends to areas other than cancer.
  • Non-patent Document 8 For example, Pim has been reported to enhance the action of inflammatory cytokines and increase production (Non-patent Document 8), and is a molecular target for the treatment of inflammatory diseases such as rheumatoid arthritis. It is thought to get. Some Pim inhibitors have been reported so far (Non-Patent Documents 9 to 12).
  • an object of the present invention is to provide a compound having an excellent Pim inhibitory action and useful as a medicine.
  • the present inventors have synthesized various thiazolidine derivatives and studied their Pim inhibitory action.
  • the thiazolidine skeleton represented by the following general formula (1) and an amino group, a monosubstituted amino group, a disubstituted amino group, Or a compound having a nitrogen-containing saturated heterocyclic group which may have a substituent has an excellent Pim inhibitory action and has an excellent pharmacological action such as a strong cancer cell growth inhibitory action.
  • the present invention has been completed.
  • the present invention has the general formula (1)
  • X represents O, S or NH
  • R 3 represents a hydrogen atom or an alkyl group
  • the dashed line indicates that at least one is a double bond
  • Z 1 , Z 2 and Z 6 each independently represent C, CH or N
  • Z 3 , Z 4 , Z 5 , Z 7 and Z 8 each independently represent C, CH, N, NH, Indicates O or S
  • Y has at least one C 6-14 aromatic hydrocarbon group, and may have an ether bond between a terminal or a carbon-carbon bond or may have a substituent.
  • Am represents an amino group, a monosubstituted amino group, a disubstituted amino group, or a nitrogen-containing saturated heterocyclic group which may have a substituent;
  • R 1 and R 2 are each independently a hydrogen atom, halogen atom, alkyl group, alkoxy group, thioalkoxy group, hydroxy group, amino group, monosubstituted amino group, disubstituted amino group, halogenoalkyl group, cyano group Nitro group, thioalkyl group, thiohalogenoalkyl group, halogenoalkoxy group, acyl group, carboxyl group, alkylamino group, alkoxyalkyl group, or al
  • this invention provides the Pim inhibitor containing the thiazolidine derivative represented by the said General formula (1), or its salt. Moreover, this invention provides the pharmaceutical containing the thiazolidine derivative represented by the said General formula (1), or its salt.
  • the present invention also provides a thiazolidine derivative represented by the above general formula (1) or a salt thereof for Pim inhibition or cancer treatment. Moreover, this invention provides use of the thiazolidine derivative represented by the said General formula (1) or its salt for Pim inhibitor or anticancer agent manufacture.
  • the present invention also provides a method for treating cancer, comprising administering an effective amount of a thiazolidine derivative represented by the above general formula (1) or a salt thereof.
  • the thiazolidine derivative represented by the general formula (1) or a salt thereof has an excellent Pim inhibitory action, a cancer cell growth inhibitory action, an apoptosis inducing action, etc., and various diseases caused by the action of Pim For example, it is useful as a preventive and therapeutic agent for cancer, rheumatoid arthritis and the like.
  • the dose dependence of the inhibitory action with respect to Pim-1, Pim-2 and Pim-3 of the compound of the present invention is shown.
  • the dose dependence of the growth inhibitory effect with respect to A549 cell, HT29 cell, and HCT116 cell of this invention compound is shown.
  • the effect of the compounds of the present invention on phosphorylation of 4E-BP1 and BAD is shown.
  • the apoptosis-inducing action of the compound of the present invention is shown.
  • the thiazolidine derivative of the present invention is represented by the general formula (1).
  • X represents O, S or NH, and is preferably O or S, and is particularly O from Pim-2 inhibition, cancer cell growth suppression, high metabolic stability, and the like. Is preferred.
  • R 3 represents a hydrogen atom or an alkyl group, and particularly preferably a hydrogen atom.
  • a broken line indicates that at least one of the broken lines is a double bond.
  • the condensed bicycle containing Z 1 to Z 8 is preferably an aromatic ring.
  • Z 1 , Z 2 and Z 6 each independently represent C, CH or N
  • Z 3 , Z 4 , Z 5 , Z 7 and Z 8 each independently represent C, CH, N , NH, O or S.
  • Z 1 to Z 8 , 3 to 7 are C or CH, the remaining 1 to 5 are C, CH, N, NH, O or S, and at least one is N, NH, O or S S, especially N, NH or O is preferred.
  • Z 4 , Z 5 and Z 6 are preferably C or CH.
  • more preferred structures are those in which Z 4 , Z 5 and Z 6 are C or CH.
  • Z 1 , Z 2 represent C, CH or N
  • Z 3 , Z 7 and Z 8 represent C, CH, N, NH, O or S
  • Z 1 , Z 2 , Z 3 , At least one of Z 7 and Z 8 is N, NH, O or S
  • Z 1 is preferably C, CH or N
  • Z 2 is preferably C or N
  • Z 3 , Z 7 and Z 8 are C, CH, N, NH, O or S
  • Z 1 , Among Z 2 , Z 3 , Z 7 and Z 8 , 1 to 3 are preferably N, NH, O or S, and 1 to 3 are particularly preferably N, NH or O.
  • at least one of the broken lines is a double bond
  • the (Aa) ring is preferably an aromatic ring.
  • the structure (A) include the following structures (A-1) to (A-21), of which (A-1), (A-2), (A-3), (A-5), (A-6), (A-7), (A-8), (A-9), (A-11), (A-12), (A-13), (A -14), (A-16), (A-17), (A-18), (A-19), (A-20) and (A-21) are more preferred, and (A-1), ( A-5), (A-6), (A-7) and (A-16) are more preferred.
  • Y has at least one C 6-14 aromatic hydrocarbon group and may have an ether bond (—O—) between the terminal or carbon-carbon bonds.
  • a divalent hydrocarbon group which may have a group, a substituent which may have an ether bond, an alkylene group or an alkylene group which has an ether bond between a terminal or a carbon-carbon bond
  • Preferred aromatic heterocyclic group may divalent which are.
  • the divalent hydrocarbon group includes an aliphatic hydrocarbon group, an aromatic hydrocarbon group, and a group in which an aliphatic hydrocarbon group and an aromatic hydrocarbon group are connected.
  • Examples of the divalent hydrocarbon group which may have an ether bond between the terminal or carbon-carbon bond include (1) -hydrocarbon-, (2) -O-hydrocarbon-, (3) -hydrocarbon -O-, (4) -hydrocarbon-O-hydrocarbon-, (5) -O-hydrocarbon-O-hydrocarbon-, (6) -hydrocarbon-O-hydrocarbon-O-, or (7 ) -O-hydrocarbon-O-hydrocarbon-O-.
  • aromatic hydrocarbon group examples include an aromatic hydrocarbon group having 6 to 14 carbon atoms (arylene group) such as a phenylene group and a naphthylene group.
  • arylene group such as a phenylene group and a naphthylene group.
  • aliphatic hydrocarbon group examples include a C 1-12 aliphatic hydrocarbon group, and examples thereof include C 1-12 alkylene, C 2-12 alkenylene, and C 2-12 alkynylene.
  • Examples of the divalent hydrocarbon group which may have a terminal or a carbon-carbon ether bond include a C 1 -C 12 alkylene group, a C 2 -C 12 alkenylene group, and a C 2 -C 12 alkynylene group.
  • the divalent hydrocarbon groups at least one C 6-14 aromatic hydrocarbon group may be present, and an ether bond may be present between the terminal or carbon-carbon bonds.
  • the divalent hydrocarbon group that may be contained include C 6 -C 14 arylene, C 6 -C 14 arylene-C 1 -C 12 alkylene, C 6 -C 14 arylene-C 2 -C 12 alkynylene, C 6 -C 14 arylene-O—, C 6 -C 14 arylene-O—C 1 -C 12 alkylene, C 6 -C 14 arylene-C 1 -C 12 alkylene-O—, C 1 -C 12 alkylene- C 6 -C 14 arylene, C 1 -C 12 alkylene-C 6 -C 14 arylene-O—, C 1 -C 12 alkylene-C 6 -C 14 arylene, C 1 -C 12 alkylene-C 6 -C 14 arylene-O—, C 1 -C 12 alky
  • a divalent hydrocarbon group which has at least one C 6-14 aromatic hydrocarbon group and may have an ether bond between a terminal or a carbon-carbon bond and may have a substituent; Among them, phenylene, phenylene-C 1 -C 6 alkylene, phenylene-C 2 -C 6 alkynylene, phenylene-O—, phenylene-O—C 1 -C 6 alkylene, phenylene-C 1 -C 6 alkylene-O— C 1 -C 6 alkylene-phenylene, C 1 -C 6 alkylene-phenylene-O—, C 1 -C 6 alkylene-phenylene-O—C 1 -C 6 alkylene, C 1 -C 6 alkylene-phenylene-C 1- C 6 alkylene, C 1 -C 6 alkylene-phenylene-C 1 -C 6 alkylene-O-, C 1 -C 6 alkylene-phenylene-C 1 -C 6 More
  • a divalent hydrocarbon group which has at least one C 6-14 aromatic hydrocarbon group and may have an ether bond between a terminal or a carbon-carbon bond and may have a substituent; More preferred specific examples of phenylene, phenylene-O—, phenylene-CH 2 —, phenylene- (CH 2 ) 2 —, phenylene- (CH 2 ) 3 —, phenylene-C ⁇ C—CH 2 —, phenylene -C ⁇ C- (CH 2) 2 -, phenylene -C ⁇ C- (CH 2) 3 -, phenylene -C ⁇ C- (CH 2) 4 -, phenylene -O-CH 2 -, phenylene -O- (CH 2 ) 2- , phenylene-CH 2 -O-, phenylene- (CH 2 ) 2 -O-, -CH 2 -phenylene-,-(CH 2 ) 2 -phenylene, -CH 2 -pheny
  • Examples of groups that can be substituted with these divalent hydrocarbon groups include halogen atoms, halogenoalkyl groups, alkoxy groups, halogenoalkoxy groups, hydroxy groups, oxo groups, amino groups, cyano groups, alkyl groups, thioalkoxy groups, halogeno groups.
  • a thioalkoxy group etc. are mentioned.
  • halogen atom halogen atom, halogeno-C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, halogeno C 1 -C 6 alkoxy group, hydroxy group, oxo group, amino group, cyano group, C 1 -C 6 alkyl group, a halogeno -C 1 -C 6 thioalkoxy group.
  • substituents include fluorine atom, chlorine atom, bromine atom, iodine atom, oxo group, trifluoromethyl group, trifluoromethoxy group, difluoromethoxy group, trifluoromethylthio group, cyano group, and methyl group.
  • Ethyl group isopropyl group, tert-butyl group, methoxy group and the like.
  • These substituents may have 1 to 5 substituents on the hydrocarbon group.
  • Examples of the divalent aromatic heterocyclic group optionally having an ether bond, an alkylene group, or an alkylene group having an ether bond between the terminal or carbon-carbon bonds include an aromatic heterocyclic group and an aromatic heterocyclic ring.
  • an aromatic heterocyclic group, an aromatic heterocycle —O—C 1 -C 12 alkylene and an aromatic heterocycle —C 1 -C 12 alkylene are preferred.
  • the alkylene group is more preferably a C 1 -C 6 alkylene group.
  • aromatic heterocyclic group examples include monocyclic or bicyclic aromatic heterocyclic groups having a heteroatom selected from N, S and O, and a heteroatom selected from N, S and O Monocyclic or bicyclic aromatic heterocyclic groups having 1 to 4 are preferred.
  • the monocyclic aromatic heterocyclic group is preferably a 5- to 6-membered one.
  • divalent aromatic heterocyclic group examples include aromatic heterocycle, aromatic heterocycle-O—, aromatic heterocycle-O—CH 2 —, aromatic heterocycle-O— (CH 2 ).
  • aromatic heterocycle —CH 2 —, aromatic heterocycle — (CH 2 ) 2 —, aromatic heterocycle —CH 2 —O—, aromatic heterocycle — (CH 2 ) 2 —O—, — CH 2 -aromatic heterocycle —CH 2 — and the like can be mentioned.
  • Examples of groups that can be substituted with these divalent aromatic heterocyclic groups or alkylene groups include halogen atoms, halogenoalkyl groups, alkoxy groups, halogenoalkoxy groups, hydroxy groups, amino groups, cyano groups, alkyl groups, and thioalkoxy groups. Group, a halogenothioalkoxy group, and the like.
  • halogen atom halogen atom, halogeno-C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, halogeno C 1 -C 6 alkoxy group, hydroxy group, amino group, cyano group, C 1 -C A 6- alkyl group and a halogeno-C 1 -C 6 thioalkoxy group are preferred.
  • substituents include fluorine atom, chlorine atom, bromine atom, iodine atom, trifluoromethyl group, trifluoromethoxy group, difluoromethoxy group, trifluoromethylthio group, cyano group, methyl group, ethyl group. , Isopropyl group, methoxy group and the like.
  • substituents may have 1 to 5 substituents on the aromatic heterocyclic group or alkylene group.
  • Examples of the divalent C 2-12 aliphatic hydrocarbon group include a linear or branched alkylene group having 2 to 12 carbon atoms, a linear or branched alkenylene group having 2 to 12 carbon atoms, and a carbon number of 2 A -12 linear or branched alkynylene group, a cycloalkylene group having 3 to 12 carbon atoms, and the like. More specifically, an alkylene group having 2 to 6 carbon atoms such as an ethylene group, an n-propylene group, an isopropylene group, an n-butylene group, an n-pentylene group, and an n-hexylene group; an ethenylene group, a propenylene group, etc.
  • alkenylene group having 2 to 6 carbon atoms an alkynylene group having 2 to 6 carbon atoms such as ethynylene group, propynylene group and hexynylene; 3 to 6 carbon atoms such as cyclopropylene group, cyclobutylene group, cyclopentylene group and cyclohexylene group Of the cycloalkylene group.
  • Am represents an amino group, a monosubstituted amino group, a disubstituted amino group, or a nitrogen-containing saturated heterocyclic group which may have a substituent.
  • the same effect can be obtained by using a phthalimide group.
  • the substituent of the monosubstituted amino group or the disubstituted amino group include an alkyl group, an aminoalkyl group, an aminocycloalkyl group, an N-alkyl-azacycloalkyl group, an alkylaminoalkyl group, a dialkylaminoalkyl group, an alkoxyalkyl group, Examples thereof include a hydroxyalkyl group and a thioalkoxyalkyl group.
  • Preferred examples of the monosubstituted amino group include a C 1 -C 6 alkylamino group, an amino-C 1 -C 6 alkylamino group, an amino-C 3 -C 7 cycloalkylamino group, and an N—C 1 -C 6 alkyl group.
  • -C 2 -C 6 azacycloalkylamino group and the like specifically, methylamino group, ethylamino group, isopropylamino group, aminocyclohexylamino group, aminomethylamino group, aminoethylamino group, aminopropylamino Group, aminobutylamino group, and N-methylpiperidinoamino group.
  • disubstituted amino group examples include a di-C 1 -C 6 alkylamino group, a di (amino-C 1 -C 6 alkyl) amino group, and (C 1 -C 6 alkylamino-C 1 -C 6 alkyl).
  • (C 1 -C 6 alkyl) amino group (di-C 1 -C 6 alkylamino-C 1 -C 6 alkyl) (C 1 -C 6 alkyl) amino group, di (C 1 -C 6 alkoxy-C 1 -C 6 alkyl) amino group and the like, specifically, dimethylamino group, diethylamino group, diisopropylamino group, (ethyl) (n-propyl) amino group, di (aminoethyl) amino group, (dimethylamino Ethyl) (methyl) amino, (diethylaminoethyl) (methyl) amino, (diethylaminoethyl) (ethyl) amino, di (aminopropyl) amino, di (amino) ) Amino group, and the like.
  • Examples of the nitrogen-containing saturated heterocyclic group include 5- to 7-membered saturated heterocyclic groups which have 1 or 2 nitrogen atoms and may further have an oxygen atom or a sulfur atom.
  • Preferred examples of the saturated heterocyclic group include pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, 1,1-dioxidethiomorpholinyl group, homopiperazinyl group, ketopiperazinyl group, diketopiperazinyl group. Groups and the like. Of these, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, 1,1-dioxidethiomorpholinyl group, homopiperazinyl group and the like are preferable.
  • Examples of the group that can be substituted with the nitrogen-containing saturated heterocyclic group include an alkyl group, a cycloalkyl group, an amino group, an aminoalkyl group, an alkoxyalkyl group, a hydroxyalkyl group, a hydroxy group, an oxo group, a piperidinyl group, a pyrrolidinyl group, Examples include morpholinyl group, cyano group, cyanoalkyl group, halogen atom, halogenoalkyl group, halogenoalkoxy group, alkylsulfonyl group, acyl group, alkyloxycarbonyl group, acyloxyalkyl group and the like.
  • substituents include C 1 -C 10 alkyl group, C 3 -C 6 cycloalkyl group, amino group, amino-C 1 -C 6 alkyl group, C 1 -C 6 alkoxy-C 1- C 6 alkyl group, hydroxy-C 1 -C 6 alkyl group, hydroxy group, oxo group, piperidinyl group, pyrrolidinyl group, morpholinyl group, cyano group, cyano-C 1 -C 6 alkyl group, halogen atom, halogeno-C 1 -C 6 alkyl group, halogeno-C 1 -C 6 alkoxy group, C 1 -C 6 alkylsulfonyl group, C 1 -C 6 acyl group, C 1 -C 6 alkyloxycarbonyl group, C 1 -C 6 acyloxy- Examples thereof include C 1 -C 6 alkyl groups.
  • substituents include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, n-hexyl group, n-decyl group.
  • cyclopentyl group cyclohexyl group, amino group, aminoethyl group, methoxyethyl group, ethoxyethyl group, hydroxyethyl group, hydroxy group, oxo group, piperidinyl group, pyrrolidinyl group, morpholinyl group, cyano group, cyanomethyl group, fluorine atom Chlorine atom, bromine atom, trifluoromethyl group, trifluoromethoxy group, methylsulfonyl group, ethylsulfonyl group, acetyl group, t-butoxycarbonyl group, and acetyloxyethyl group.
  • substituents may have 1 to 5 on the nitrogen-containing saturated heterocyclic group.
  • R 1 and R 2 are each independently a hydrogen atom, halogen atom, alkyl group, alkoxy group, thioalkoxy group, hydroxy group, amino group, monosubstituted amino group, disubstituted amino group, halogenoalkyl group, cyano group Nitro group, thioalkyl group, thiohalogenoalkyl group, halogenoalkoxy group, acyl group, carboxyl group, alkylamino group, alkoxyalkyl group, or alkoxycarbonyl group.
  • R 1 and R 2 are more preferably hydrogen atom, halogen atom, C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, C 1 -C 6 thioalkoxy group, hydroxy group, amino group, C 1 -C 6 alkylamino group, di-C 1 -C 6 alkylamino group, halogeno-C 1 -C 6 alkyl group, cyano group, nitro group, thio C 1 -C 6 alkyl group, thio-halogeno C 1 -C 6 alkyl group Halogeno-C 1 -C 6 alkoxy group, C 1 -C 6 alkanoyl group, carboxyl group, C 1 -C 6 alkylamino group, C 1 -C 6 alkoxy-C 1 -C 6 alkyl group, C 1 -C 6 alkoxycarbonyl group and the like. More specifically, a hydrogen atom and a methyl group are exemplified.
  • Y is a divalent C 6-14 aromatic hydrocarbon group which may have a substituent, or a divalent C 1-10 aliphatic which may have a substituent.
  • Hydrocarbon-C 6-14 aromatic hydrocarbon group optionally having divalent C 6-14 aromatic hydrocarbon-C 1-10 aliphatic hydrocarbon group, having substituent Divalent C 6-14 aromatic hydrocarbon-O— which may be optionally substituted, Divalent C 6-14 aromatic hydrocarbon-O—C 1-10 aliphatic hydrocarbon group which may have a substituent
  • a divalent C 6-14 aromatic hydrocarbon-C 1-10 aliphatic hydrocarbon group-O- which may have a substituent, N, S and O which may have a substituent
  • a divalent monocyclic or bicyclic aromatic heterocyclic group having 1 to 4 selected heteroatoms, a substituent selected from optionally substituted N, S and O From a divalent monocyclic or bicyclic aromatic heterocyclic ring having 1 to 4 rhoatoms- C 1-12 aliphatic hydrocarbon group, or
  • said Y has prescribed
  • the divalent C 6-14 aromatic hydrocarbon-O— the divalent C 6-14 aromatic hydrocarbon-O—Am which may have a substituent is obtained.
  • the structure represented by (A) in the general formula (1) is (A-1), (A-2), (A-3), (A-5), (A-6), (A-7). ), (A-8), (A-9), (A-11), (A-12), (A-13), (A-14), (A-16), (A-17), (A-18), (A-19), (A-20) or (A-21);
  • Y is a divalent C 6-14 aromatic hydrocarbon group optionally having substituent (s) , Divalent C 6-14 aromatic hydrocarbon-C 1-10 aliphatic hydrocarbon group which may have a substituent, divalent C 6-14 aromatic group which may have a substituent Hydrocarbon-O—, divalent C 6-14 aromatic hydrocarbon-O—C 1-10 aliphatic hydrocarbon group optionally having substituent (s), divalent optionally having substituent (s) C 6-14 aromatic hydrocarbon -C 1-10 aliphatic hydrocarbons -O-, a divalent monocyclic or bicyclic aromatic heterocyclic group having 1 to 4 heteroatoms selected from N, S and O which
  • the structure represented by Y in the general formula (1) is a divalent C 6-14 aromatic hydrocarbon group which may have a substituent, or a substituent.
  • Divalent C 6-14 aromatic hydrocarbon-C 1-6 aliphatic hydrocarbon group which may have, Divalent C 6-14 aromatic hydrocarbon-O which may have a substituent -, An optionally substituted divalent C 6-14 aromatic hydrocarbon-O—C 1-6 aliphatic hydrocarbon group, an optionally substituted divalent C 6- 14 aromatic hydrocarbon-C 1-6 aliphatic hydrocarbon group-O-, divalent monocyclic having 1 to 4 heteroatoms selected from optionally substituted N, S and O Or a bivalent aromatic heterocyclic group, a divalent monocyclic group having 1 to 4 heteroatoms selected from optionally substituted N, S and O Bicyclic aromatic heterocyclic -C 1-6 aliphatic hydrocarbon group, or it may have a substituent group N, 2 divalent monocyclic the chromatic 1 to 4 hetero atoms selected
  • the compound (1) of the present invention is particularly preferred compounds for reasons such as Pim inhibitory action, cancer cell growth inhibitory action, high metabolic stability, and the like. It is as follows. (1) 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 1) (2) 5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one ( Compound 3) (3) 5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 4) (4) 5-((2-Methyl-1
  • Examples of the salt of the compound (1) of the present invention include inorganic acid salts such as hydrochloric acid, sulfuric acid and nitric acid, and organic acid salts such as acetic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, methanesulfonic acid and paratoluenesulfonic acid. Hydrochloric acid, methanesulfonic acid and sulfuric acid are preferred. Specific examples include the following compounds.
  • the compound (1) of the present invention or a salt thereof includes solvates such as hydrates.
  • the compound of the present invention has an isomer due to the presence of a double bond, and includes both a Z-form and an E-form. Moreover, when an asymmetric carbon atom is contained in this invention compound, those optical isomers and a racemate are also contained.
  • the compound (1) of the present invention can be produced, for example, according to the following reaction formula.
  • the salt of the compound (1) of the present invention can be produced from the compound (1) of the present invention by a known method.
  • this invention compound (1) is obtained by making the aldehyde represented by Formula (2) react with the compound represented by Formula (3).
  • the reaction of aldehyde (2) with compound (3) includes (A) a reaction in the presence of acetic acid and ammonium acetate, (B) a reaction in the presence of piperidine and pyrrolidine, (C) presence of acetic acid and piperidine. It can carry out by the method of making it react below. More specifically, aldehyde (2) and compound (3) are heated and refluxed in the presence of (A) acetic acid and sodium bicarbonate; (B-1) heated in an alcohol such as ethanol in the presence of piperidine.
  • the method (A) uses, for example, 0.8 to 1.2 equivalents of aldehyde (2) and 2.5 equivalents of ammonium acetate with respect to compound (3) in acetic acid at 100 ° C. for 18 It is preferable to heat to reflux for a period of time.
  • the method (B) 0.8 to 1.2 equivalents of aldehyde (2) and 0.2 to 0.5 equivalents of piperidine or pyrrolidine are used with respect to compound (3) at 70 ° C. for 20 hours. It is preferable to heat to reflux for a period of time.
  • the method (C) is based on 0.8 to 1.2 equivalents of aldehyde (2), 0.05 to 0.5 equivalents of piperidine and 0.05 to 0.5 equivalents relative to compound (3). It is preferable to heat and reflux for 20 hours under reflux conditions using an amount of acetic acid.
  • the raw material aldehyde (2) can be produced by known means.
  • the aldehyde (2a) having the structure (A-1) can be synthesized, for example, according to the following formula.
  • reaction from compound (4) to compound (5) is carried out, for example, by first reacting compound (4) with oxalyl chloride or the like to give the corresponding acid chloride and then reacting with dimethylhydroxylamine.
  • the reaction between the compound (5) and the amine compound (H 2 N—Y—Am) is carried out by heating in the presence of a base.
  • a base potassium carbonate, N, N-diisopropylethylamine or the like is used.
  • the reaction solvent N, N-dimethylformamide, N-methyl-2-pyrrolidone or the like is preferably used.
  • the reaction may be performed at about 80 ° C.-100 ° C. for about 12 hours.
  • the reduction reaction of the compound (6) is carried out by a catalytic hydrogenation reaction in the presence of a catalyst such as palladium-activated carbon or platinum-activated carbon. Moreover, you may heat using iron powder and ammonium chloride, and you may heat in the presence of tin chloride and ammonium acetate.
  • a catalyst such as palladium-activated carbon or platinum-activated carbon.
  • the cyclization reaction of the compound (7) is performed by reacting triethyl orthoformate or the like in the presence of an acid catalyst.
  • an acid catalyst hydrochloric acid, acetic acid, paratoluenesulfonic acid, pyridinium paratoluenesulfonate, or the like is used.
  • the reaction from the compound (8) to the aldehyde (2a) is carried out by reacting the compound (8) with biscyclopentadienylzirconium (IV) chloride hydride, lithium aluminum hydride or the like.
  • the aldehyde (2a) can also be synthesized according to the following reaction formula.
  • W is a functional group such as a halogen atom, a hydroxy group, a protected hydroxy group, a protected hydroxyalkyl group, an alkoxycarbonyl group, a formyl group, a formylalkyl group, and Y and Am are the same as above)
  • Compound (5) is reacted with amine compound (H 2 N—Y—W) in the same manner as in the reaction from compound (5) to compound (6) to give compound (9).
  • Compound (11) is obtained by performing a reaction similar to the reaction from Compound (6) to Compound (8) on Compound (9).
  • a compound (12) is obtained by performing reaction similar to the reaction from the said compound (8) to an aldehyde (2a) with respect to a compound (11). Am is introduced into compound (12) to obtain aldehyde (2a).
  • compound (12) is acetal protected to give compound (13), then Am is reacted to obtain compound (14), and the acetal group of compound (14) is deprotected to remove aldehyde (2a ) Is obtained.
  • compound (15) can be obtained by introducing Am into compound (11), and then the amide moiety of compound (15) can be converted from compound (8) by the same method as aldehyde (2a). (2a) is obtained.
  • the compound (12) when W is a protected hydroxyalkyl group, the compound (12) is reacted with methanesulfonyl chloride after deprotecting W of the compound (12) to form a hydroxyalkyl group.
  • W is a protected hydroxyalkyl group
  • the compound (12) is reacted with methanesulfonyl chloride after deprotecting W of the compound (12) to form a hydroxyalkyl group.
  • the acetal protection of the compound (12) is performed by reacting ethylene glycol, 1,3-propanediol or the like in the presence of an acid catalyst.
  • Conversion of compound (13) to compound (14) can be achieved when W is halogen, for example, by Backward-Hartwig-cross coupling, for example, palladium acetate as a palladium catalyst, cesium carbonate as a base, 2,2 as a ligand. It is carried out by heating using '-bis (diphenylphosphino) -1,1'-binaphthyl.
  • W is a formyl group or a formylalkyl group
  • compound (14) can be synthesized by reacting Am with a reducing agent such as triacetoxyborohydride in the presence of an acid such as acetic acid.
  • W is a protected hydroxyalkyl group
  • W is deprotected to form a hydroxyalkyl group, then oxidized to formylalkyl group, and Am is a reducing agent such as triacetoxyborohydride in the presence of an acid such as acetic acid.
  • Am is a reducing agent such as triacetoxyborohydride in the presence of an acid such as acetic acid.
  • the deprotection reaction of the acetal group of compound (14) is performed with an acid.
  • an acid hydrochloric acid or the like is used.
  • Examples of the reaction from compound (11) to compound (15) include the following.
  • W is a protected hydroxy group, it can be synthesized by deprotecting W of compound (11) to form a hydroxy group and then an alkylation reaction in which an alkyl halide is reacted in the presence of a base.
  • W is a protected hydroxyalkyl group
  • W is deprotected to form a hydroxyalkyl group, then reacted with methanesulfonyl chloride or the like, and then reacted with Am to obtain compound (15).
  • W is a protected hydroxyalkyl group
  • W is deprotected to form a hydroxyalkyl group and then oxidized to formylalkyl group.
  • Am is a reducing agent such as triacetoxyborohydride in the presence of an acid such as acetic acid. You may make it react.
  • W is an alkoxycarbonyl group, it is hydrolyzed to give a carboxylic acid, and then O- (1H-6-chlorobenzotriazol-1-yl) -N, N, N ′, N′-tetra Compound (15) can also be obtained by condensation with Am using a condensing agent such as methyluronium tetrafluoroborate.
  • W is a formyl group or a formylalkyl group
  • Am can be reacted with a reducing agent such as triacetoxyborohydride in the presence of an acid such as acetic acid to synthesize compound (15).
  • W is halogen, for example, by Backwald-Hartwig-cross coupling, palladium acetate as the palladium catalyst, cesium carbonate as the base, and 2,2′-bis (diphenylphosphino) -1,1 as the ligand
  • Am can be introduced to obtain compound (15).
  • a terminal alkyne having Am is reacted by a Sonogashira coupling reaction in the presence of an amine such as diisopropylamine, a copper catalyst such as copper iodide, and a palladium catalyst such as palladium dichlorobistriphenylphosphine to convert the compound (15).
  • the Sonogashira coupling reaction is performed using a terminal alkyne having a halogen instead of a terminal alkyne having Am, and Am is then reacted in the presence of a base such as potassium carbonate to obtain (15). it can.
  • the triple bond of the product obtained by the Sonogashira coupling reaction can be reduced by catalytic hydrogenation in the presence of a catalyst such as palladium-activated carbon.
  • reaction from compound (15) to aldehyde (2a) is carried out in the same manner as the reaction from compound (8) to aldehyde (2a).
  • the terminal of Am is an amino group, it may be synthesized using a protective group as appropriate, and a substituent may be introduced after deprotection.
  • the aldehyde (2a) can also be synthesized according to the following reaction formula.
  • Compound (4) is esterified to give compound (16), and compound (19) is obtained in the same manner as in the reaction from compound (5) to compound (8). Reduction of the ester of compound (19) to an alcohol followed by oxidation gives aldehyde (2a).
  • the compound (19) is H 2 N-Y-W ( W instead of H 2 N-Y-Am in compound (16) is a halogen atom, hydroxy group, protected hydroxy group or protected hydroxy group, A functional group such as an alkoxycarbonyl group, a formyl group, a formylalkyl group, etc.) is reacted, reduced, and cyclized, and then obtained in the same manner as the method for introducing Am into the compound (11). .
  • the terminal of Am is an amino group, it may synthesize
  • the esterification reaction of the compound (4) is performed by heating in the presence of an acid in an alcohol solvent such as methanol.
  • an acid such as methanol.
  • hydrochloric acid, sulfuric acid or the like is used as the acid.
  • the reduction reaction of the compound (19) is performed, for example, with lithium aluminum hydride or diisobutylaluminum hydride.
  • the oxidation reaction of the compound (20) is carried out by using an oxidizing agent such as Dess-Martin periodinane or manganese dioxide.
  • the aldehyde (2a) can also be synthesized, for example, according to the following reaction formula.
  • V represents a functional group such as a halogen atom
  • Y and Am are the same as described above.
  • Compound (21) is benzoylated to give compound (22), and then reacted with thionyl chloride to give compound (23).
  • Compound (23) and known compound (24) are reacted to obtain compound (25), and then heated to obtain compound (26).
  • Compound (28) is obtained by deprotecting the benzoyl group of compound (26) and carrying out a reaction similar to the reaction from compound (6) to compound (8).
  • the compound (28) is subjected to a reaction similar to the reaction from the compound (13) to the aldehyde (2a) to obtain the aldehyde (2a).
  • the benzoylation reaction of compound (21) is performed by reacting benzoyl chloride or the like in the presence of a base. Sodium hydroxide or the like is used as the base.
  • the reaction between compound (22) and thionyl chloride is carried out by heating.
  • Thionyl chloride is preferably used in an excess amount as a reaction solvent.
  • the reaction between the compound (23) and the compound (24) is performed in the presence of a base.
  • a base sodium hydride or the like is used.
  • the rearrangement reaction of compound (25) is performed by heating.
  • the reaction is preferably carried out at about 180 ° C. for 8 hours.
  • the deprotection of the compound (26) is preferably performed in the presence of alkali.
  • alkali potassium hydroxide or the like is used.
  • the aldehyde (2b) having the structure (A-2) can be synthesized, for example, according to the following formula.
  • the amide moiety of the compound (30) is converted by the same method as the reaction from the compound (8) to the aldehyde (2a). 2b) is obtained.
  • the cyclization reaction of the compound (7) is performed by reacting trimethyl orthoacetate or the like in the presence of an acid catalyst.
  • an acid catalyst acetic acid or the like is preferable.
  • the aldehyde (2c) having the structure (A-20) can be synthesized, for example, according to the following formula.
  • Compound (31) is obtained by cyclization reaction of compound (7), and the amide moiety of compound (31) is converted in the same manner as in the reaction from compound (8) to aldehyde (2a) to obtain aldehyde (2c). Is obtained.
  • the cyclization reaction of the compound (7) is performed by reacting sodium nitrite or the like in the presence of an acid catalyst.
  • Acetic acid or the like is used as the acid catalyst.
  • the aldehyde (2d) having the structure (A-3) can be synthesized, for example, according to the following formula.
  • V represents a functional group such as a halogen atom
  • Y and Am are the same as described above.
  • the reaction from the compound (32) to the compound (33) is performed by heating using, for example, copper iodide as a copper catalyst and tripotassium phosphate as a base.
  • the compound (33) can also be obtained by an alkylation reaction in which an alkyl halide is reacted in the presence of a base.
  • the reduction reaction of the compound (33) is performed, for example, with diisobutylaluminum hydride or the like.
  • compound (33) is obtained by replacing VY-Am with VYW (W is a halogen atom, a hydroxy group, a protected hydroxy group, a protected hydroxyalkyl group, an alkoxycarbonyl group, formyl instead of VY-Am. Group, a functional group such as formylalkyl group, etc.) is reacted, and then Am can be introduced by a method similar to the method for introducing Am into compound (11).
  • the aldehyde (2e) having the structure (A-5) can be synthesized, for example, according to the following formula.
  • Compound (36) is obtained from Compound (34) by a known method (Non-Patent Document 13).
  • Compound (36) and QY-Am are reacted by Suzuki-Miyaura coupling to give compound (37), and aldehyde (2e) is obtained by carbon monoxide insertion reaction of compound (37).
  • Suzuki-Miyaura coupling reaction between compound (36) and QY-Am is carried out by using tetrakis (triphenylphosphine) palladium (0) or 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) as a palladium catalyst. ) Using a dichloride-dichloromethane complex and using sodium carbonate or potassium carbonate as a base.
  • the carbon monoxide insertion reaction of the compound (37) is performed, for example, by using tris (dibenzylideneacetone) dipalladium (0) as a catalyst and reacting with sodium formate.
  • Aldehyde (2e) is QYW instead of QY-Am (W is halogen atom, hydroxy group, protected hydroxy group, protected hydroxyalkyl group, alkoxycarbonyl group, formyl group, formylalkyl) Or a functional group such as a group) is reacted with the compound (36), and then Am is introduced into the compound (11) by a method similar to the method for introducing Am. it can.
  • Aldehyde (2e) can be synthesized according to the following formula.
  • Q is a functional group such as boronic acid or boronic acid ester
  • W is a halogen atom, hydroxy group, protected hydroxy group, protected hydroxyalkyl group, alkoxycarbonyl group, formyl group, formylalkyl group, etc. Indicates a functional group, Y and Am are the same as above)
  • Compound (40) is obtained from Compound (38) by a known method (Patent Document 1 and Non-Patent Document 14).
  • Compound (40) and QYW are reacted in the same manner as in the reaction from Compound (36) to Compound (37) to give Compound (41), which is the same as the method for introducing Am into Compound (11).
  • the compound (42) is obtained by the method of The compound (42) is subjected to a reaction similar to the reaction from the compound (19) to the compound (2a) to obtain the aldehyde (2e).
  • the aldehyde (2f) having the structure (A-6) can be synthesized, for example, according to the following formula.
  • Compound (44) and QY-Am are reacted in the same manner as in the reaction from Compound (36) to Compound (37) to give Compound (45).
  • a vinyl group is introduced into compound (45) to form compound (46), and the vinyl group of compound (46) is oxidatively cleaved to obtain aldehyde (2f).
  • the vinylation reaction of the compound (45) is performed by reacting tributylvinyltin, 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane, etc. in the presence of a palladium catalyst. .
  • the double bond cleavage reaction of the compound (46) is performed by using, for example, osmium tetroxide as a catalyst and sodium periodate as a reoxidant.
  • aldehyde (2f) having a condensed bicyclic ring at Y can be synthesized, for example, according to the following formula.
  • a vinyl group is introduced into compound (44) to form compound (47), and the vinyl group of compound (47) is oxidatively cleaved to obtain aldehyde (48).
  • the vinylation reaction of compound (44) is carried out by reacting tributylvinyltin, 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane, etc. in the presence of a palladium catalyst. .
  • the double bond cleavage reaction of compound (47) is carried out, for example, by using osmium tetroxide as a catalyst and sodium periodate as a reoxidant.
  • Compound (48) is reacted with 2-aminophenol to give compound (49).
  • the compound (49) is subjected to a reaction similar to the reaction from the compound (45) to the aldehyde (2f) to obtain the aldehyde (2f).
  • the reaction between compound (48) and 2-aminophenols is carried out by adding activated carbon and heating in the presence of oxygen.
  • Xylene is used as the reaction solvent, and the reaction temperature is preferably around 120 ° C.
  • Aldehyde (2f) is QYW instead of QY-Am (W is halogen atom, hydroxy group, protected hydroxy group, protected hydroxyalkyl group, alkoxycarbonyl group, formyl group, formylalkyl, Or a functional group such as a group), and then reacting with the compound (44) and then introducing Am into the compound (11) in the same manner as described above. it can.
  • W is halogen atom, hydroxy group, protected hydroxy group, protected hydroxyalkyl group, alkoxycarbonyl group, formyl group, formylalkyl, Or a functional group such as a group
  • Compound (45) can also be synthesized by a known method (Non-patent Document 15).
  • the terminal of Am is an amino group, it may be synthesized using a protective group as appropriate, and a substituent may be introduced after deprotection.
  • the aldehyde (2g) having the structure (A-21) can be synthesized, for example, according to the following formula.
  • the aldehyde (2 g) is obtained by performing the same reaction as the reaction from the compound (51) to the aldehyde (2f) using the compound (44) and QY-Am.
  • the aldehyde (2h) having the structure (A-8) can be synthesized, for example, according to the following formula.
  • Compound (54) is converted to Compound (60) by a known method (Non-patent Document 16 and Patent Document 2).
  • Compound (61) is obtained by reacting compound (60) with QY-Am in the same manner as in the reaction from compound (36) to compound (37).
  • Compound (61) is deprotected to give compound (62), and then oxidized in the same manner as in the reaction from compound (20) to aldehyde (2a) to give aldehyde (2h).
  • the aldehyde (2i) having the structure (A-9) can be synthesized, for example, according to the following formula.
  • Compound (63) is converted to Compound (67) by a known method (Non-Patent Documents 14 and 16).
  • Compound (68) is obtained by reacting compound (67) with QY-Am in the same manner as in the reaction from compound (36) to compound (37).
  • the compound (68) is subjected to a reaction similar to the reaction from the compound (19) to the aldehyde (2a) to obtain the aldehyde (2i).
  • the aldehyde (2j) having the structure (A-14) can be synthesized, for example, according to the following formula.
  • Compound (70) is converted to Compound (75) by a known method (Non-patent Documents 17-19).
  • Compound (76) is obtained by reacting compound (75) with QY-Am in the same manner as in the reaction from compound (36) to compound (37).
  • Compound (76) is reduced by a method similar to the reaction from compound (33) to aldehyde (2d) to give aldehyde (2j).
  • the aldehyde (2k) having the structure (A-12) can be synthesized, for example, according to the following formula.
  • Compound (78) is obtained by reacting compound (77) with QY-Am in the same manner as in the reaction from compound (36) to compound (37). Compound (78) is converted from compound (45) to compound (80) in the same manner as aldehyde (2f), and compound (80) is deprotected to give aldehyde (2k).
  • Compound (80) can be deprotected with an acid such as trifluoroacetic acid.
  • the aldehyde (2l) having the structure of (A-13) can be synthesized, for example, according to the following formula.
  • Compound (81) is converted to Compound (84) by a known method (Non-Patent Document 14).
  • Compound (85) is obtained by reacting compound (84) with QY-Am in the same manner as in the reaction from compound (36) to compound (37).
  • the compound (85) is subjected to a reaction similar to the reaction from the compound (19) to the aldehyde (2a) to obtain the aldehyde (2l).
  • the aldehyde (2m) having the structure (A-18) can be synthesized, for example, according to the following formula.
  • the aldehyde (2n) having the structure (A-7) can be synthesized, for example, according to the following formula.
  • compound (89) is reacted with an amine compound (H 2 N—Y—Am) to give compound (90).
  • compound (92) is obtained by cyclization reaction.
  • the compound (92) is subjected to a reaction similar to the reaction from the compound (37) to the aldehyde (2e) to obtain the aldehyde (2n).
  • the aldehyde (2n) can be obtained by carrying out a reaction similar to the reaction from the compound (45) to the aldehyde (2f) on the compound (92).
  • reaction of compound (89) with amine compound (H 2 N—Y—Am) is carried out in the presence of a base in a solvent such as ethanol.
  • a base such as ethanol.
  • triethylamine, N, N-diisopropylethylamine and the like are preferable.
  • the reduction reaction of the compound (90) is performed by heating with, for example, iron powder and ammonium chloride.
  • the cyclization reaction of compound (91) is performed by using formamidine acetate or the like.
  • the aldehyde (2n) is H 2 N-Y-Am H 2 N-Y-W (W is a halogen atom in place of a hydroxy group, protected hydroxy group or protected hydroxy group, an alkoxycarbonyl group, formyl A functional group such as a formylalkyl group, etc.), and then reacting with the compound (44) and then introducing Am in the same manner as the method for introducing Am into the compound (11). Can also be obtained.
  • the terminal of Am is an amino group, it may be synthesized using a protective group as appropriate, and a substituent may be introduced after deprotection.
  • the aldehyde (2o) having the structure (A-16) can be synthesized, for example, according to the following formula.
  • the aldehyde (2p) having the structure (A-11) can be synthesized, for example, according to the following formula.
  • the aldehyde (2p) is obtained by performing a reaction similar to the reaction from the compound (89) to the aldehyde (2n) with respect to the compound (96).
  • the terminal of Am is an amino group
  • synthesis may be performed using a protective group as appropriate, and the substituent may be introduced after deprotection.
  • the aldehyde (2q) having the structure (A-19) can be synthesized, for example, according to the following formula.
  • V represents a functional group such as a halogen atom
  • Y and Am are the same as described above.
  • the compound (101) and the hydrazine compound (H 2 N—NH—Y—V) are reacted to obtain the compound (102), and the same method as that for introducing Am into the compound (11) is obtained in the compound (102) Introducing Am yields compound (103).
  • the compound (103) is subjected to a reaction similar to the reaction from the compound (45) to the aldehyde (2f) to obtain the aldehyde (2q).
  • the reaction between the compound (101) and the hydrazine compound (H 2 N—NH—YV) is carried out by heating in the presence of cesium carbonate.
  • the aldehyde (2r) having the structure (A-10) can be synthesized, for example, according to the following formula.
  • V represents a functional group such as a halogen atom
  • Y and Am are the same as described above.
  • Compound (105) is reacted with hydrazine compound (H 2 N—NH—Y—V) to obtain compound (106), and then cyclization reaction is performed to obtain compound (107).
  • the compound (107) is subjected to a reaction similar to the reaction from the compound (102) to the aldehyde (2q) to obtain the aldehyde (2r).
  • the reaction between the compound (105) and the hydrazine compound (H 2 N—NH—YV) is carried out by heating in the presence of a base.
  • a base N, N-diisopropylethylamine or the like is used.
  • the cyclization reaction of the compound (106) is performed by heating in the presence of cesium carbonate.
  • the aldehyde (2s) having the structure (A-4) can be synthesized, for example, according to the following formula.
  • V represents a functional group such as a halogen atom
  • Y and Am are the same as described above.
  • Compound (111) is obtained by reacting compound (110) with hydrazine compound (H 2 N—NH—CO—YV). The compound (111) is subjected to a reaction similar to the reaction from the compound (102) to the aldehyde (2q) to obtain the aldehyde (2s).
  • reaction of the compound (110) and the hydrazine compound (H 2 N—NH—CO—YV) is carried out by heating in the presence of triethylamine hydrochloride or the like.
  • reaction solvent xylene or the like is preferably used.
  • the aldehyde (2t) having the structure (A-15) can be synthesized, for example, according to the following formula.
  • Compound (114) is converted to hydrazine and then reacted with aldehyde (OHC-Y-Am) to obtain compound (116).
  • Compound (116) is oxidatively cyclized to obtain compound (117).
  • Compound (117) is subjected to a reaction similar to the reaction from compound (45) to aldehyde (2f) to give aldehyde (2t). can get.
  • the cyclization reaction of the compound (116) is performed using an oxidizing agent.
  • an oxidizing agent chloramine T or the like is used.
  • the aldehyde (2u) having the structure (A-17) can be synthesized, for example, according to the following formula.
  • Compound (119) is converted to thiol, then cyclized and brominated to give compound (121).
  • Compound (122) is obtained by reacting compound (121) with QY-Am in the same manner as in the reaction from compound (36) to compound (37). The compound (122) is subjected to a reaction similar to the reaction from the compound (45) to the aldehyde (2f) to obtain the aldehyde (2u).
  • Conversion of compound (119) to thiol is performed by using sodium sulfide or the like.
  • the cyclization reaction and bromination of the compound (120) are simultaneously performed using bromine.
  • the compound (1) of the present invention or a salt thereof has an excellent Pim inhibitory action, as shown in Examples below, and has an inhibitory action on cancer cell proliferation and an apoptosis-inducing action. It is useful as a medicine such as a drug, an angiogenesis inhibitor, an anticancer drug resistance-resolving agent, and an anticancer drug effect enhancer.
  • the Pim inhibitory action may be effective for any one of Pim-1, Pim-2, or Pim-3 isozymes, but it is more preferable that all of the isozymes are effective.
  • the Pim inhibitory action is preferably such that the inhibitory action against Pim (IC 50 ) (concentration of the compound that inhibits Pim activity by 50%) determined by the method described later (Test Example 1) is 1 ⁇ M or less.
  • the cancer cell growth inhibitory action has a growth inhibitory action (IC 50 ) (concentration of a compound that inhibits cell growth by 50%) determined by the method described later (Test Example 2) of 1 ⁇ M or less for at least one kind of cancer cell.
  • IC 50 concentration of a compound that inhibits cell growth by 50%
  • Metabolic stability refers to, for example, the stability of a compound in liver microsomes, and higher stability is preferred.
  • the compound (1) of the present invention can be administered as it is, but within a range not reducing the effect, it is mixed with a carrier such as a dispersion aid, excipient, etc., which is usually used for formulation, It can be used in the form of oral preparations such as liquids, capsules, suspensions, emulsions, syrups, elixirs, granules, pills, tablets, troches and limonades, or injections.
  • a carrier such as a dispersion aid, excipient, etc.
  • Examples of such a carrier include water-soluble monosaccharides or oligosaccharides or polysaccharides such as mannitol, lactose, and dextran; for example, gel-forming or water-soluble celluloses such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose; Water-absorbing and poorly water-soluble celluloses such as crystalline cellulose, ⁇ -cellulose, crosslinked sodium carboxymethylcellulose, and derivatives thereof; for example, hydroxypropyl starch, carboxymethyl starch, crosslinked starch, amylose, amylopectin, pectin and the like Water-absorbing and poorly water-soluble polysaccharides such as derivatives thereof; water-absorbing and poorly water-soluble gums such as gum arabic, tragacanth gum, glycomannan and derivatives thereof; Examples include crosslinked vinyl polymers such as bridged polyacrylic acid and salts thereof, crosslinked polyvinyl alcohol, polyhydroxyethyl methacrylate and derivatives thereof; and lipid
  • a solubilization treatment can be performed.
  • a solubilization treatment a method that can be generally applied to a medicine, for example, a method of adding a surfactant such as polyoxyethylene alcohol ethers, polyoxyethylene acyl esters, sorbitan acyl esters, polyoxyethylene sorbitan acyl esters, Examples thereof include a method using a water-soluble polymer such as polyethylene glycol. Further, if necessary, a method of forming a soluble salt, a method of forming an inclusion compound using cyclodextrin, and the like can be used.
  • the dosage of the pharmaceutical agent of the present invention may be appropriately adjusted according to the administration method, patient's symptoms, etc., but the compound (1) or a salt thereof of the present invention is 1 mg to 10 g, more preferably 100 mg to 10 g, in particular, 500 mg to 10 g is preferably administered.
  • the Pim inhibitor of the present invention can be used not only as a pharmaceutical preparation as described above but also as a food or drink.
  • the compound (1) or a salt thereof of the present invention may be contained in food or drink as it is or with various nutritional components added.
  • These foods and drinks can be used as health foods or food materials useful for the improvement and prevention of cancer metastasis and decoration, rheumatoid arthritis, etc., and these foods and drinks or containers thereof have the effects described above. An indication may be attached.
  • an additive that can be used as a food or drink is appropriately used, and a form suitable for food using conventional means, for example, granular or granular , Tablets, capsules, pastes, etc., and various foods such as processed meat products such as ham and sausage, fishery products such as kamaboko and chikuwa, bread, confectionery, butter, milk powder, lactic acid bacteria beverages, You may add and use for fermented foods and drinks, such as fermented milk and fermented soymilk.
  • the food and drink includes animal feed.
  • N-methoxy-N-methyl-1- (3-morpholinopropyl) -1H-benzo [d] imidazole-6-carboxamide is synthesized in the same manner as N-methoxy-N-methyl-3-((1- Methylpiperidin-4-yl) amino) -4-nitrobenzamide (0.42 g, 1.30 mmol) was used to obtain the title compound (0.17 g, 41%).
  • N-methoxy-N-methyl-1- (3-morpholinopropyl) -1H-benzo [d] imidazole-6-carboxamide is synthesized in the same manner as N-methoxy-N-methyl-3- (4- ( Using 4-methylpiperazin-1-yl) phenylamino) -4-nitrobenzamide (0.57 g, 1.4 mmol), the title compound (0.26 g, 49%) was obtained.
  • reaction mixture was returned to room temperature, 1N hydrochloric acid (1.5 mL, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hr. While the reaction mixture was cooled in an ice bath, 1N sodium hydroxide (2 mL, 2 mmol) was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (0.02 g, 20%).
  • Step 6 5-((1- (3- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 6)
  • N-methylpiperazine 100 mg, 1 mmol was added to the reaction mixture, and the mixture was stirred in an ice bath for 2 hours and at room temperature overnight.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform.
  • the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (0.09 g, 61%).
  • Step 6 5-((1- (3-((4-methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one ( Compound 7)
  • N-methoxy-N-methyl-1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazole-6-carboxamide (340 mg, 0.86 mmol) in tetrahydrofuran ( 10 mL)
  • biscyclopentadienylzirconium (IV) chloride hydride (335 mg, 1.30 mmol)
  • Process 1 1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazole-6-carbaldehyde (77 mg, 0.23 mmol), 2,4-thiazolidinedione (26 mg, 0.22 mmol) Piperidine (4 mg, 0.04 mmol) was added to the ethanol (2 mL) solution, and the mixture was stirred at 80 ° C. overnight. Ethyl acetate was added to the reaction solution to precipitate crystals, followed by filtration and washing with ethyl acetate and ethanol to obtain the title compound (21 mg, 23%).
  • 4-nitrobenzyl alcohol (3.06 g, 20 mmol) was dissolved in methylene chloride (60 mL) under an argon atmosphere. Thereto were added pyridinium paratoluenesulfonate (0.20 g) and dihydropyran (5.0 g, 60 mmol), and the mixture was stirred at 40 ° C. for 1 hour. To the reaction solution was added an aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform.
  • N-methylpiperazine (385 mg, 3.85 mmol) was added to the reaction mixture, and the mixture was stirred in an ice bath for 3 hours and at room temperature overnight.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform.
  • the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.41 g, 1.04 mmol, 61%).
  • Step 6 1- (4-((4-Methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde
  • N-methylpiperazine (145 mg, 1.45 mmol) was added to the reaction mixture, followed by stirring in an ice bath for 3 hours and at room temperature for 3 days.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform.
  • the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.07 g, 0.18 mmol, 28%).
  • N-ethylpiperazine (228 mg, 2 mmol) was added to the reaction mixture, and the mixture was stirred in an ice bath for 3 hours and at room temperature for 3 days.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform.
  • the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.36 g, 0.88 mmol, 98%).
  • Methyl 4-amino-3-((3- (2-morpholinoethoxy) phenyl) amino) benzoate (833 mg, 2.24 mmol) was dissolved in ethanol (10 mL) under an argon atmosphere. Triethyl orthoformate (3.73 mL, 22.4 mmol) and acetic acid (256 ⁇ L, 4.48 mL) were added thereto, and the mixture was stirred at 50 ° C. for 18 hours. The reaction mixture was concentrated, ethyl acetate was added, and the mixture was washed with saturated multilayered water, water and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated.
  • (+)-Sodium potassium tartrate aqueous solution was added, and the mixture was warmed to room temperature and stirred for 1 hour.
  • the reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • the obtained residue was purified by silica gel column chromatography (NH column, hexane / ethyl acetate) to obtain the title compound (388 mg, 71%).
  • Process 1 (4- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (18 mg, 0.05 mmol) is dissolved in ethanol (0.50 mL) and thiazolidine-2,4-dione (5 mg, 0.045 mmol) and piperidine (2 ⁇ L, 0.025 mmol) were added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (3 mg, 15%, 0.007 mmol).
  • Methyl 3-fluoro-4-nitrobenzoate (1.9 g, 10 mmol) in N-methyl-2-pyrrolidone (10 mL) solvent, 4-bromoaniline (2.19 g, 10 mmol), and N-ethyl-N -Isopropylpropan-2-amine (3.04 mL, 18 mmol) was added. The mixture was stirred at 85 ° C. for 5 days and allowed to cool to room temperature. Then, ethyl acetate and saturated brine were added to extract the organic layer, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Lithium aluminum hydride (31 mg, 0.81 mmol) in a solution of methyl 1- (4-morpholinophenyl) -1H-benzo [d] imidazole-6-carboxylate (92 mg, 0.27 mmol) in tetrahydrofuran (1 mL) ) was added at 0 ° C. under an argon atmosphere. After warming to room temperature and stirring for 3 hours, an aqueous ammonium chloride solution was added, ethyl acetate and saturated brine were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Process 1 4-([1,4'-bipiperidin] -1'-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (26 mg, 0.067 mmol) was dissolved in ethanol (1.5 mL). , Thiazolidine-2,4-dione (8 mg, 0.067 mmol) and piperidine (1.3 ⁇ L, 6.69 ⁇ mol) were added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (4 mg, 12%, 0.008 mmol).
  • Process 1 4- (4- (4-Methyl-1,4-diazepan-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (30 mg, 0.09 mmol) in ethanol (2.0 mL), tetrahydrofuran (1.0 mL), thiazolidine-2,4-dione (11 mg, 0.09 mmol) and piperidine (0.9 ⁇ L, 0.009 mmol) were added, and the mixture was stirred overnight under reflux conditions.
  • Process 1 4-((2- (dimethylamino) ethyl) (methyl) amino) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (35 mg, 0.11 mmol) was added to ethanol (1.0 mL), tetrahydrofuran (2.0 mL), thiazolidine-2,4-dione (13 mg, 0.11 mmol) and piperidine (1.08 ⁇ L, 0.01 mmol) were added, and the mixture was stirred overnight under reflux conditions.
  • Step 6 3- (3- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde
  • Step 7 5-((1- (3- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4- ON (compound 41)
  • Process 1 1- (3- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (19 mg, 0.05 mmol) was dissolved in ethanol (1.0 mL). , Thiazolidine-2,4-dione (6 mg, 0.05 mmol) and piperidine (1.0 ⁇ L, 0.01 mmol) were added and stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (4 mg, 17%, 0.008 mmol).
  • the obtained crude product was dissolved in methylene chloride (10 mL) and methanol (5 mL), and 37% aqueous formaldehyde solution, acetic acid (66 mg) and sodium triacetoxyborohydride (290 mg, 1.37 mmol) were added. Stir at room temperature for 1 hour. Saturated multistory water was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.33 g, 0.91 mmol, quant.).
  • Methyl 1- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-6-carboxylate (0.33 g, 0.9 mmol) in tetrahydrofuran (20 mL) and ethanol Dissolve in (20 mL), add calcium chloride (222 mg, 2 mmol), stir in an ice bath for 15 minutes, and then add sodium borohydride. (151 mg, 4 mmol) was added, and the mixture was stirred in an ice bath for 1 hour and further at room temperature for 22 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform.
  • Process 1 1- (4- (4-Methylpiperazinyl) benzyl) -1H-indole-6-carbaldehyde (83 mg, 0.23 mmol), 2,4-thiazolidinedione (27 mg, 0.22 mmol) in ethanol (5 mL ) Piperidine (4 mg, 0.04 mmol) was added to the solution and stirred overnight at 80 ° C. Ethyl acetate was added to the reaction solution to precipitate crystals, followed by filtration and washing with ethyl acetate and ethanol to obtain the title compound (54 mg, 54%).
  • 6-bromoimidazo [1,2-a] pyridine (1.02 g, 5.16 mmol) was dissolved in acetonitrile (15 mL) under an argon atmosphere.
  • N-iodosuccinimide (1.16 g, 5.16 mmol) was added thereto, and the mixture was stirred at room temperature for 17 hours under light shielding.
  • the resulting precipitate was collected by filtration, washed with acetonitrile, and dried under vacuum to obtain the title compound (1.39 g, 84%).
  • reaction solution was quenched by adding saturated aqueous ammonium chloride solution, and extracted with ethyl acetate.
  • the ethyl acetate layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated.
  • the obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (501 mg, 85%).
  • 6-bromo-3-iodoimidazo [1,2-a] pyridine 350 mg, 1.08 mmol was suspended in 1,4-dioxane (9 mL) and water (3 mL).
  • 1-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine 360 mg, 1.12 mmol
  • 1,1 ' -Bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex 88 mg, 0.11 mmol
  • potassium carbonate 597 mg, 4.32 mmol
  • the inside of the reaction vessel was evacuated and purged with argon. This operation was repeated 3 times, followed by stirring at 100 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (NH column, hexane / ethyl acetate) to obtain the title compound (226 mg, 56%).
  • 6-Bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine 183 mg, 0.493 mmol
  • dichlorobis (triphenylphosphine) palladium (6.9 mg, 9.86 ⁇ mol)
  • sodium formate 50 mg, 0.740 mmol
  • N, N-dimethylformamide (1 mL) was added there, and it stirred at 110 degreeC for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • reaction solution was quenched by adding saturated aqueous ammonium chloride solution, and extracted with ethyl acetate.
  • the ethyl acetate layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated.
  • the obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (166 mg, 45%).

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Abstract

Provided is a compound having an excellent Pim inhibition activity and useful as a medicinal agent. A thiazolidine derivative represented by general formula (1) (wherein X represents O, S or NH; R3 represents a hydrogen atom or an alkyl group; at least one of the dotted lines is a double bond; Z1, Z2 and Z6 independently represent C, CH or N; Z3, Z4, Z5, Z7 and Z8 independently represent C, CH, N, NH, O or S; Y represents a bivalent hydrocarbon group which has at least one C6-14 aromatic hydrocarbon group and may have a substituent, a bivalent aromatic heterocyclic group which may have a substituent, or a bivalent C2-12 aliphatic hydrocarbon group; Am represents an amino group, a mono-substituted amino group, a di-substituted amino group, or a nitrogenated saturated heterocyclic group which may have a substituent; and R1 and R2 independently represent a hydrogen atom, a halogen atom, an alkoxy group, a halogenoalkoxy group, or the like) or a salt thereof.

Description

チアゾリジン誘導体又はその塩を有効成分とする医薬品Pharmaceuticals containing thiazolidine derivatives or their salts as active ingredients

　本発明は、Ｐｉｍキナーゼ阻害（以下、Ｐｉｍ阻害という）作用を有し、抗がん剤等の医薬として有用な化合物及びそれを含有する医薬に関する。 The present invention relates to a compound having Pim kinase inhibition (hereinafter referred to as Pim inhibition) and useful as a medicament such as an anticancer agent, and a medicament containing the same.

　プロテインキナーゼは、細胞内や細胞間での情報伝達の制御に重要な役割を果たしており、がんをはじめとする様々な疾患に関与している。近年では、上皮細胞増殖因子受容体（ＥＧＦＲ）チロシンキナーゼ阻害剤のゲフィチニブやエルロチニブ、Ｂｃｒ－Ａｂｌチロシンキナーゼ阻害剤のイマチニブや、多種類のプロテインキナーゼを阻害するソラフェニブなど、プロテインキナーゼを標的とした阻害剤が分子標的治療薬としてがんの治療分野で広く臨床使用されており、高い有効性が示されている。ヒトのプロテインキナーゼは５００種類以上あるとも言われており、今後も新しいがん分子標的治療薬の開発を目的としたターゲットとして大きな可能性を秘めているものと考えられる。 Protein kinases play an important role in the control of information transmission within and between cells and are involved in various diseases including cancer. In recent years, protein kinase targeting inhibitors such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib, Bcr-Abl tyrosine kinase inhibitor imatinib, and sorafenib that inhibits many types of protein kinases The drug is widely used clinically in the field of cancer treatment as a molecular targeted therapeutic agent, and has shown high effectiveness. It is said that there are more than 500 types of human protein kinases, and it is believed that they have great potential as targets for the development of new cancer molecular targeted therapeutics.

　Ｐｉｍ－１は、細胞周期の進行やアポトーシスを制御する種々の細胞内因子をリン酸化することにより、細胞の生存や増殖を正に制御するセリン・スレオニンキナーゼである。例えば、Ｐｉｍ－１は、アポトーシス促進因子であるＢＡＤをリン酸化することにより不活性化し、抗アポトーシス因子として働くことが知られている。また、Ｐｉｍ－１は、細胞周期の進行を正に制御するＣＤＣ２５ＡやＣＤＣ２５Ｃをリン酸化することによりホスファターゼ活性を上昇させるとともに、細胞周期の進行を負に制御するｐ２１をリン酸化することにより不活性化させて、細胞周期の進行を加速させることが報告されている。さらにＰｉｍ－１は、蛋白質の合成制御因子である４Ｅ－ＢＰ１をリン酸化することにより蛋白合成を増加させ、細胞の増殖を促進させることが知られている。Ｐｉｍ－１には、相同性の高いＰｉｍ－２とＰｉｍ－３の２種類のアイソザイムが知られているが、これらについてもＰｉｍ－１と同様に、上記の機能を部分的に共有していると考えられている。 Pim-1 is a serine / threonine kinase that positively controls cell survival and proliferation by phosphorylating various intracellular factors that control cell cycle progression and apoptosis. For example, Pim-1 is known to be inactivated by phosphorylating BAD, which is a proapoptotic factor, and to act as an anti-apoptotic factor. In addition, Pim-1 increases phosphatase activity by phosphorylating CDC25A and CDC25C that positively control cell cycle progression, and inactive by phosphorylating p21 that negatively regulates cell cycle progression. To accelerate cell cycle progression. Furthermore, Pim-1 is known to increase protein synthesis and promote cell growth by phosphorylating 4E-BP1, which is a protein synthesis regulator. Pim-1 is known to have two types of isozymes, Pim-2 and Pim-3, which are highly homologous, and, like Pim-1, also partially share the above functions. It is believed that.

　以上のように、Ｐｉｍ－１、Ｐｉｍ－２およびＰｉｍ－３は、細胞の生存や増殖に関わる様々な因子の活性制御に関与しており、がんなどの細胞の異常増殖を特徴とする疾患に深く関与していると考えられている。実際に、Ｐｉｍは、急性骨髄性白血病をはじめとする血液がんや、前立腺がんをはじめとする固形がんなど、種々のがんの進展に関与していることが報告されている（非特許文献１～５）。また、血管新生（非特許文献６）や化学療法における抗がん剤に対する耐性（非特許文献７）にも関与することが示唆されており、Ｐｉｍはがん治療において魅力的な分子標的と考えられ、それを阻害する化合物は新しいがんの治療薬として期待される。さらに、Ｐｉｍの関与はがん以外の領域にも及んでいる。例えば、Ｐｉｍは、炎症性サイトカインの作用を増強させるとともに、産生量を増加させることが報告されており（非特許文献８）、関節リウマチなどの炎症性疾患の治療を目的とした分子標的になり得ると考えられる。
　これまでに幾つかのＰｉｍ阻害剤が報告されている（非特許文献９～１２）。 As described above, Pim-1, Pim-2 and Pim-3 are involved in the control of the activity of various factors involved in cell survival and proliferation, and diseases characterized by abnormal cell proliferation such as cancer Is thought to be deeply involved in In fact, Pim has been reported to be involved in the development of various cancers such as hematological cancers including acute myeloid leukemia, and solid cancers including prostate cancer. Patent Documents 1 to 5). In addition, it has been suggested to be involved in angiogenesis (Non-patent Document 6) and resistance to anticancer drugs in chemotherapy (Non-patent Document 7), and Pim is considered an attractive molecular target in cancer treatment. And compounds that inhibit it are expected as new cancer therapeutics. Furthermore, Pim's involvement extends to areas other than cancer. For example, Pim has been reported to enhance the action of inflammatory cytokines and increase production (Non-patent Document 8), and is a molecular target for the treatment of inflammatory diseases such as rheumatoid arthritis. It is thought to get.
Some Pim inhibitors have been reported so far (Non-Patent Documents 9 to 12).

Hammerman PS et al., Blood, 105, 4477-83 (2005)Hammerman PS et al., Blood, 105, 4477-83 (2005) Amson R et al., Proc Natl Acad Sci U S A, 86, 8857-61 (1989)Amson R et al., Proc Natl Acad Sci U S A, 86, 8857-61 (1989) Nieborowska-Skorska M et al., Blood, 99, 4531-9 (2002).Nieborowska-Skorska M et al., Blood, 99, 4531-9 (2002). Dhanasekaran SM et al., Nature, 412, 822-6 (2001)Dhanasekaran SM et al., Nature, 412, 822-6 (2001) Ellwood-Yen K et al., Cancer Cell, 4, 223-38 (2003)Ellwood-Yen K et al., Cancer Cell, 4, 223-38 (2003) Zhang P et al., J Cell Physiol, 220, 82-90 (2009)Zhang P et al., J Cell Physiol, 220, 82-90 (2009) Xie Y et al., Mol Pharmacol, 78, 310-18 (2010)Xie Y et al., Mol Pharmacol, 78, 310-18 (2010) Yang J et al., Immunology, 131, 174-82 (2010)Yang J et al., Immunology, 131, 174-82 (2010) Mumenthaler SM et al., Mol Cancer Ther, 8, 2882-93 (2009)Mumenthaler SM et al., Mol Cancer Ther, 8, 2882-93 (2009) Li Y-Y et al., Int J Cancer, 127, 474-84 (2010)Li Y-Y et al., Int J Cancer, 127, 474-84 (2010) Holder S et al., Mol Cancer Ther, 6, 163-72 (2007)Holder S et al., Mol Cancer Ther, 6, 163-72 (2007) Blanco-Aparicio C et al., Cancer Lett, 300, 145-53 (2011)Blanco-Aparicio C et al., Cancer Lett, 300, 145-53 (2011)

　しかしながら、これまで報告されているＰｉｍ阻害剤のＰｉｍ阻害作用及び具体的な薬理作用は十分なものでなく、さらに強力なＰｉｍ阻害剤が望まれている。
　従って、本発明の課題は、優れたＰｉｍ阻害作用を有し、医薬として有用な化合物を提供することにある。 However, the Pim inhibitory action and specific pharmacological action of the Pim inhibitor reported so far are not sufficient, and a more powerful Pim inhibitor is desired.
Accordingly, an object of the present invention is to provide a compound having an excellent Pim inhibitory action and useful as a medicine.

　そこで本発明者は、種々のチアゾリジン誘導体を合成し、そのＰｉｍ阻害作用を検討してきたところ、下記一般式（１）で表されるチアゾリジン骨格とアミノ基、一置換アミノ基、二置換アミノ基、又は置換基を有していてもよい窒素含有飽和複素環式基とを有する化合物が、優れたＰｉｍ阻害作用を示し、かつ強いがん細胞増殖抑制作用等の優れた薬理作用を有することを見出し、本発明を完成した。 Therefore, the present inventors have synthesized various thiazolidine derivatives and studied their Pim inhibitory action. As a result, the thiazolidine skeleton represented by the following general formula (1) and an amino group, a monosubstituted amino group, a disubstituted amino group, Or a compound having a nitrogen-containing saturated heterocyclic group which may have a substituent has an excellent Pim inhibitory action and has an excellent pharmacological action such as a strong cancer cell growth inhibitory action. The present invention has been completed.

　すなわち、本発明は、一般式（１） That is, the present invention has the general formula (1)

Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005

（式中、Ｘは、Ｏ、Ｓ又はＮＨを示し；
Ｒ３は水素原子またはアルキル基を示し；
破線は、少なくとも一つが二重結合であることを示し；
Ｚ1、Ｚ2及びＺ6は、それぞれ独立してＣ、ＣＨ又はＮを示し、Ｚ3、Ｚ4、Ｚ5、Ｚ7及びＺ8は、それぞれ独立してＣ、ＣＨ、Ｎ、ＮＨ、Ｏ又はＳを示し；
Ｙは、Ｃ６－１４芳香族炭化水素基を少なくとも一つ有し、かつ末端若しくは炭素－炭素結合間にエーテル結合を有していてもよく置換基を有していてもよい２価の炭化水素基、置換基を有していてもよくエーテル結合、アルキレン基又は末端若しくは炭素－炭素結合間にエーテル結合を有するアルキレン基を有していてもよい２価の芳香族複素環式基、又は２価のＣ２－１２脂肪族炭化水素基を示し；
Ａｍは、アミノ基、一置換アミノ基、二置換アミノ基、又は置換基を有していてもよい窒素含有飽和複素環式基を示し；
Ｒ1及びＲ2は、それぞれ独立して、水素原子、ハロゲン原子、アルキル基、アルコキシ基、チオアルコキシ基、ヒドロキシ基、アミノ基、一置換アミノ基、二置換アミノ基、ハロゲノアルキル基、シアノ基、ニトロ基、チオアルキル基、チオハロゲノアルキル基、ハロゲノアルコキシ基、アシル基、カルボキシル基、アルキルアミノ基、アルコキシアルキル基、又はアルコキシカルボニル基を示す。）
で表されるチアゾリジン誘導体又はその塩を提供するものである。 Wherein X represents O, S or NH;
R 3 represents a hydrogen atom or an alkyl group;
The dashed line indicates that at least one is a double bond;
Z 1 , Z 2 and Z 6 each independently represent C, CH or N, and Z 3 , Z 4 , Z 5 , Z 7 and Z 8 each independently represent C, CH, N, NH, Indicates O or S;
Y has at least one C 6-14 aromatic hydrocarbon group, and may have an ether bond between a terminal or a carbon-carbon bond or may have a substituent. A hydrogen group, an optionally substituted ether group, an alkylene group, or a divalent aromatic heterocyclic group optionally having an alkylene group having an ether bond between the terminal or carbon-carbon bonds, or Represents a divalent C 2-12 aliphatic hydrocarbon group;
Am represents an amino group, a monosubstituted amino group, a disubstituted amino group, or a nitrogen-containing saturated heterocyclic group which may have a substituent;
R 1 and R 2 are each independently a hydrogen atom, halogen atom, alkyl group, alkoxy group, thioalkoxy group, hydroxy group, amino group, monosubstituted amino group, disubstituted amino group, halogenoalkyl group, cyano group Nitro group, thioalkyl group, thiohalogenoalkyl group, halogenoalkoxy group, acyl group, carboxyl group, alkylamino group, alkoxyalkyl group, or alkoxycarbonyl group. )
The thiazolidine derivative represented by these, or its salt is provided.

　また本発明は、上記一般式（１）で表されるチアゾリジン誘導体又はその塩を含有するＰｉｍ阻害剤を提供するものである。
　また本発明は、上記一般式（１）で表されるチアゾリジン誘導体又はその塩を含有する医薬を提供するものである。
　また本発明は、Ｐｉｍ阻害又はがん治療のための、上記一般式（１）で表されるチアゾリジン誘導体又はその塩を提供するものである。
　また本発明はＰｉｍ阻害剤又は抗がん剤製造のための、上記一般式（１）で表されるチアゾリジン誘導体又はその塩の使用を提供するものである。
　また本発明は、上記一般式（１）で表されるチアゾリジン誘導体又はその塩の有効量を投与することを特徴とするがんの治療方法を提供するものである。 Moreover, this invention provides the Pim inhibitor containing the thiazolidine derivative represented by the said General formula (1), or its salt.
Moreover, this invention provides the pharmaceutical containing the thiazolidine derivative represented by the said General formula (1), or its salt.
The present invention also provides a thiazolidine derivative represented by the above general formula (1) or a salt thereof for Pim inhibition or cancer treatment.
Moreover, this invention provides use of the thiazolidine derivative represented by the said General formula (1) or its salt for Pim inhibitor or anticancer agent manufacture.
The present invention also provides a method for treating cancer, comprising administering an effective amount of a thiazolidine derivative represented by the above general formula (1) or a salt thereof.

　一般式（１）で表されるチアゾリジン誘導体又はその塩は、優れたＰｉｍ阻害作用を有し、かつがん細胞増殖抑制作用、アポトーシス誘導作用等を有し、Ｐｉｍの働きに起因する種々の疾患、例えばがん、関節リウマチ等の予防及び治療薬として有用である。 The thiazolidine derivative represented by the general formula (1) or a salt thereof has an excellent Pim inhibitory action, a cancer cell growth inhibitory action, an apoptosis inducing action, etc., and various diseases caused by the action of Pim For example, it is useful as a preventive and therapeutic agent for cancer, rheumatoid arthritis and the like.

本発明化合物のＰｉｍ－１、Ｐｉｍ－２及びＰｉｍ－３に対する阻害作用の用量依存性を示す。The dose dependence of the inhibitory action with respect to Pim-1, Pim-2 and Pim-3 of the compound of the present invention is shown. 本発明化合物のＡ５４９細胞、ＨＴ２９細胞及びＨＣＴ１１６細胞に対する増殖抑制作用の用量依存性を示す。The dose dependence of the growth inhibitory effect with respect to A549 cell, HT29 cell, and HCT116 cell of this invention compound is shown. 本発明化合物の４Ｅ－ＢＰ１およびＢＡＤのリン酸化に対する作用を示す。The effect of the compounds of the present invention on phosphorylation of 4E-BP1 and BAD is shown. 本発明化合物のアポトーシス誘導作用を示す。The apoptosis-inducing action of the compound of the present invention is shown.

　本発明のチアゾリジン誘導体は、上記一般式（１）で表される。
　一般式（１）中、Ｘは、Ｏ、Ｓ又はＮＨを示し、Ｏ又はＳであるのが好ましく、Ｐｉｍ－２阻害、がん細胞増殖抑制、代謝安定性の高さ等より特にＯであるのが好ましい。また、一般式（１）中、Ｒ３は水素原子またはアルキル基を示し、特に水素原子であるのが好ましい。 The thiazolidine derivative of the present invention is represented by the general formula (1).
In the general formula (1), X represents O, S or NH, and is preferably O or S, and is particularly O from Pim-2 inhibition, cancer cell growth suppression, high metabolic stability, and the like. Is preferred. In the general formula (1), R 3 represents a hydrogen atom or an alkyl group, and particularly preferably a hydrogen atom.

　一般式（１）中、破線は、当該破線の少なくとも一つが二重結合であることを示す。このうち、Ｚ１～Ｚ８を含む縮合二環は芳香族環であるのが好ましい。また、Ｚ１、Ｚ２及びＺ６は、それぞれ独立して、Ｃ、ＣＨ又はＮを示し、Ｚ３、Ｚ４、Ｚ５、Ｚ７及びＺ８は、それぞれ独立してＣ、ＣＨ、Ｎ、ＮＨ、Ｏ又はＳを示す。Ｚ１～Ｚ８のうち、３～７個がＣ又はＣＨであり、残りの１～５個はＣ、ＣＨ、Ｎ、ＮＨ、Ｏ又はＳであり、少なくとも１個はＮ、ＮＨ、Ｏ又はＳ、特にＮ、ＮＨ又はＯであるのが好ましい。また、Ｚ4、Ｚ5及びＺ6はＣ又はＣＨであるのが好ましい。 In the general formula (1), a broken line indicates that at least one of the broken lines is a double bond. Of these, the condensed bicycle containing Z 1 to Z 8 is preferably an aromatic ring. Z 1 , Z 2 and Z 6 each independently represent C, CH or N, and Z 3 , Z 4 , Z 5 , Z 7 and Z 8 each independently represent C, CH, N , NH, O or S. Of Z 1 to Z 8 , 3 to 7 are C or CH, the remaining 1 to 5 are C, CH, N, NH, O or S, and at least one is N, NH, O or S S, especially N, NH or O is preferred. Z 4 , Z 5 and Z 6 are preferably C or CH.

　一般式（１）中の In general formula (1)

Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006

で表される構造のうち、より好ましい構造としては、Ｚ4、Ｚ5及びＺ6がＣ又はＣＨである式（Ａａ） Among the structures represented by formula (Aa), more preferred structures are those in which Z 4 , Z 5 and Z 6 are C or CH.

Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007

（式中、Ｚ１、Ｚ２はＣ、ＣＨ又はＮを示し、Ｚ３、Ｚ７及びＺ８はＣ、ＣＨ、Ｎ、ＮＨ、Ｏ又はＳを示し、Ｚ１、Ｚ２、Ｚ３、Ｚ７及びＺ８のうち少なくとも１個はＮ、ＮＨ、Ｏ又はＳである）
で示される構造が挙げられる。ここで、Ｚ１はＣ、ＣＨ又はＮが好ましく、Ｚ２はＣ又はＮが好ましく、Ｚ３、Ｚ７及びＺ８はＣ、ＣＨ、Ｎ、ＮＨ、Ｏ又はＳであって、Ｚ１、Ｚ２、Ｚ３、Ｚ７及びＺ８のうち１～３個がＮ、ＮＨ、Ｏ又はＳであるのが好ましく、１～３個がＮ、ＮＨ又はＯであるのが特に好ましい。ここで破線の少なくとも一つは二重結合であり、（Ａａ）環は芳香族環であるのが好ましい。 (In the formula, Z 1 , Z 2 represent C, CH or N, Z 3 , Z 7 and Z 8 represent C, CH, N, NH, O or S, and Z 1 , Z 2 , Z 3 , At least one of Z 7 and Z 8 is N, NH, O or S)
The structure shown by is mentioned. Here, Z 1 is preferably C, CH or N, Z 2 is preferably C or N, and Z 3 , Z 7 and Z 8 are C, CH, N, NH, O or S, and Z 1 , Among Z 2 , Z 3 , Z 7 and Z 8 , 1 to 3 are preferably N, NH, O or S, and 1 to 3 are particularly preferably N, NH or O. Here, at least one of the broken lines is a double bond, and the (Aa) ring is preferably an aromatic ring.

　前記構造（Ａ）の具体例としては、次の（Ａ－１）～（Ａ－２１）の構造が挙げられ、このうち（Ａ－１）、（Ａ－２）、（Ａ－３）、（Ａ－５）、（Ａ－６）、（Ａ－７）、（Ａ－８）、（Ａ－９）、（Ａ－１１）、（Ａ－１２）、（Ａ－１３）、（Ａ－１４）、（Ａ－１６）、（Ａ－１７）、（Ａ－１８）、（Ａ－１９）、（Ａ－２０）及び（Ａ－２１）がより好ましく、（Ａ－１）、（Ａ－５）、（Ａ－６）、（Ａ－７）及び（Ａ－１６）がさらに好ましい。 Specific examples of the structure (A) include the following structures (A-1) to (A-21), of which (A-1), (A-2), (A-3), (A-5), (A-6), (A-7), (A-8), (A-9), (A-11), (A-12), (A-13), (A -14), (A-16), (A-17), (A-18), (A-19), (A-20) and (A-21) are more preferred, and (A-1), ( A-5), (A-6), (A-7) and (A-16) are more preferred.

Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008

　一般式（１）中、Ｙは、Ｃ6-14芳香族炭化水素基を少なくとも一つ有し、かつ末端若しくは炭素－炭素結合間にエーテル結合（－Ｏ－）を有していてもよく置換基を有していてもよい２価の炭化水素基、置換基を有していてもよくエーテル結合、アルキレン基又は末端若しくは炭素－炭素結合間にエーテル結合を有するアルキレン基を有していてもよい２価の芳香族複素環式基、又は２価のＣ2-12脂肪族炭化水素基であるが、このうち、Ｃ6-14芳香族炭化水素基を少なくとも一つ有し、かつ末端若しくは炭素－炭素結合間にエーテル結合を有していてもよく置換基を有していてもよい２価の炭化水素基、又は置換基を有していてもよくエーテル結合、アルキレン基又は末端若しくは炭素－炭素結合間にエーテル結合を有するアルキレン基を有していてもよい２価の芳香族複素環式基が好ましい。ここで、２価の炭化水素基には、脂肪族炭化水素基、芳香族炭化水素基、及び、脂肪族炭化水素基と芳香族炭化水素基が連結した基を含む。末端若しくは炭素－炭素結合間にエーテル結合を有していてもよい２価の炭化水素基としては、（１）－炭化水素－、（２）－Ｏ－炭化水素－、（３）－炭化水素－Ｏ－、（４）－炭化水素－Ｏ－炭化水素－、（５）－Ｏ－炭化水素－Ｏ－炭化水素－、（６）－炭化水素－Ｏ－炭化水素－Ｏ－、又は（７）－Ｏ－炭化水素－Ｏ－炭化水素－Ｏ－のような結合形態が挙げられる。 In general formula (1), Y has at least one C 6-14 aromatic hydrocarbon group and may have an ether bond (—O—) between the terminal or carbon-carbon bonds. A divalent hydrocarbon group which may have a group, a substituent which may have an ether bond, an alkylene group or an alkylene group which has an ether bond between a terminal or a carbon-carbon bond A good divalent aromatic heterocyclic group or a divalent C 2-12 aliphatic hydrocarbon group, of which at least one C 6-14 aromatic hydrocarbon group has A divalent hydrocarbon group which may have an ether bond between carbon-carbon bonds and may have a substituent, or an ether bond, alkylene group or terminal or carbon which may have a substituent -Having an alkylene group having an ether bond between carbon bonds Preferred aromatic heterocyclic group may divalent which are. Here, the divalent hydrocarbon group includes an aliphatic hydrocarbon group, an aromatic hydrocarbon group, and a group in which an aliphatic hydrocarbon group and an aromatic hydrocarbon group are connected. Examples of the divalent hydrocarbon group which may have an ether bond between the terminal or carbon-carbon bond include (1) -hydrocarbon-, (2) -O-hydrocarbon-, (3) -hydrocarbon -O-, (4) -hydrocarbon-O-hydrocarbon-, (5) -O-hydrocarbon-O-hydrocarbon-, (6) -hydrocarbon-O-hydrocarbon-O-, or (7 ) -O-hydrocarbon-O-hydrocarbon-O-.

　前記の芳香族炭化水素基としては、炭素数６～１４の芳香族炭化水素基（アリーレン基）、例えばフェニレン基、ナフチレン基等が挙げられる。前記脂肪族炭化水素基としてはＣ1-12脂肪族炭化水素基が挙げられ、Ｃ1-12アルキレン、Ｃ２-12アルケニレン、Ｃ２-12アルキニレンが挙げられる。 Examples of the aromatic hydrocarbon group include an aromatic hydrocarbon group having 6 to 14 carbon atoms (arylene group) such as a phenylene group and a naphthylene group. Examples of the aliphatic hydrocarbon group include a C 1-12 aliphatic hydrocarbon group, and examples thereof include C 1-12 alkylene, C 2-12 alkenylene, and C 2-12 alkynylene.

　末端若しくは炭素－炭素間にエーテル結合を有していてもよい２価の炭化水素基の例としては、Ｃ１－Ｃ１２アルキレン基、Ｃ２－Ｃ１２アルケニレン基、Ｃ２－Ｃ１２アルキニレン基、Ｃ３－Ｃ１２シクロアルキレン基、Ｃ６－Ｃ１４アリーレン基、Ｃ１－Ｃ１２アルキレン－Ｃ３－Ｃ１２シクロアルキレン基、Ｃ１－Ｃ１２アルキレン－Ｃ６－Ｃ１４アリーレン基、Ｃ３－Ｃ１２シクロアルキレン－Ｃ１－Ｃ１２アルキレン基、Ｃ６－Ｃ１４アリーレン－Ｃ１－Ｃ１２アルキレン基、Ｃ６－Ｃ１４アリーレン－Ｃ２－Ｃ１２アルキニレン基、Ｃ１－Ｃ１２アルキレン－Ｃ６－Ｃ１４アリーレン－Ｃ１－Ｃ１２アルキレン基、Ｃ１－Ｃ１２アルキレン－Ｏ－、Ｃ３－Ｃ１２シクロアルキレン－Ｏ－、Ｃ６－Ｃ１４アリーレン－Ｏ－、Ｃ１－Ｃ１２アルキレン－Ｃ３－Ｃ１２シクロアルキレン－Ｏ－、Ｃ１－Ｃ１２アルキレン－Ｃ６－Ｃ１４アリーレン－Ｏ－、Ｃ３－Ｃ１２シクロアルキレン－Ｃ１－Ｃ１２アルキレン－Ｏ－、Ｃ６－Ｃ１４アリーレン－Ｃ１－Ｃ１２アルキレン－Ｏ－、Ｃ６－Ｃ１４アリーレン－Ｃ２－Ｃ１２アルキニレン－Ｏ－、Ｃ６－Ｃ１４アリーレン－Ｏ－Ｃ１－Ｃ１２アルキレン、Ｃ１－Ｃ１２アルキレン－Ｏ－Ｃ６－Ｃ１４アリーレン、Ｃ１－Ｃ１２アルキレン－Ｏ－Ｃ１－Ｃ１２アルキレン、Ｃ１－Ｃ１２アルキレン－Ｏ－Ｃ３－Ｃ１２シクロアルキレン、Ｃ１－Ｃ１２アルキレン－Ｃ６－Ｃ１４アリーレン－Ｃ１－Ｃ１２アルキレン－Ｏ－、Ｃ１－Ｃ１２アルキレン－Ｃ６－Ｃ１４アリーレン－Ｃ１－Ｃ１２アルキレン－Ｏ－Ｃ１－Ｃ１２アルキレン、Ｃ１－Ｃ１２アルキレン－Ｃ６－Ｃ１４アリーレン－Ｏ－Ｃ１－Ｃ１２アルキレン等が挙げられる。 Examples of the divalent hydrocarbon group which may have a terminal or a carbon-carbon ether bond include a C 1 -C 12 alkylene group, a C 2 -C 12 alkenylene group, and a C 2 -C 12 alkynylene group. C 3 -C 12 cycloalkylene group, C 6 -C 14 arylene group, C 1 -C 12 alkylene-C 3 -C 12 cycloalkylene group, C 1 -C 12 alkylene-C 6 -C 14 arylene group, C 3- C 12 cycloalkylene-C 1 -C 12 alkylene group, C 6 -C 14 arylene-C 1 -C 12 alkylene group, C 6 -C 14 arylene-C 2 -C 12 alkynylene group, C 1 -C 12 alkylene -C 6 -C 14 arylene -C 1 -C 12 alkylene group, C 1 -C 12 alkylene -O-, C 3 -C 12 cycloalkylene -O , C 6 -C 14 arylene -O-, C 1 -C 12 alkylene -C 3 -C 12 cycloalkylene -O-, C 1 -C 12 alkylene -C 6 -C 14 arylene -O-, C 3 -C 12 cycloalkylene-C 1 -C 12 alkylene-O—, C 6 -C 14 arylene-C 1 -C 12 alkylene-O—, C 6 -C 14 arylene-C 2 -C 12 alkynylene-O—, C 6 -C 14 arylene-O-C 1 -C 12 alkylene, C 1 -C 12 alkylene-O-C 6 -C 14 arylene, C 1 -C 12 alkylene-O-C 1 -C 12 alkylene, C 1 -C 12 alkylene -O-C 3 -C 12 cycloalkylene, C 1 -C 12 alkylene -C 6 -C 14 arylene -C 1 -C 12 alkylene -O-, C 1 -C 1 Include alkylene -C 6 -C 14 arylene -C 1 -C 12 alkylene -O-C 1 -C 12 alkylene, C 1 -C 12 alkylene -C 6 -C 14 arylene -O-C 1 -C 12 alkylene or the like It is done.

　また、前記の２価の炭化水素基のうち、Ｃ６－１４芳香族炭化水素基を少なくとも一つ有し、かつ末端若しくは炭素－炭素結合間にエーテル結合を有していてもよく置換基を有していてもよい２価の炭化水素基としては、Ｃ６－Ｃ１４アリーレン、Ｃ６－Ｃ１４アリーレン－Ｃ１－Ｃ１２アルキレン、Ｃ６－Ｃ１４アリーレン－Ｃ２－Ｃ１２アルキニレン、Ｃ６－Ｃ１４アリーレン－Ｏ－、Ｃ６－Ｃ１４アリーレン－Ｏ－Ｃ１－Ｃ１２アルキレン、Ｃ６－Ｃ１４アリーレン－Ｃ１－Ｃ１２アルキレン－Ｏ－、Ｃ１－Ｃ１２アルキレン－Ｃ６－Ｃ１４アリーレン、Ｃ１－Ｃ１２アルキレン－Ｃ６－Ｃ１４アリーレン－Ｏ－、Ｃ１－Ｃ１２アルキレン－Ｃ６－Ｃ１４アリーレン－Ｏ－Ｃ１－Ｃ１２アルキレン、Ｃ１－Ｃ１２アルキレン－Ｃ６－Ｃ１４アリーレン－Ｃ１－Ｃ１２アルキレン、Ｃ１－Ｃ１２アルキレン－Ｃ６－Ｃ１４アリーレン－Ｃ１－Ｃ１２アルキレン－Ｏ－、Ｃ１－Ｃ１２アルキレン－Ｃ６－Ｃ１４アリーレン－Ｃ１－Ｃ１２アルキレン－Ｏ－Ｃ１－Ｃ１２アルキレンが好ましい。これらの２価の炭化水素基のうち、Ｃ６－Ｃ１４アリーレン、Ｃ６－Ｃ１４アリーレン－Ｃ１－Ｃ１２アルキレン、Ｃ６－Ｃ１４アリーレン－Ｃ２－Ｃ１２アルキニレン、Ｃ６－Ｃ１４アリーレン－Ｏ－、Ｃ６－Ｃ１４アリーレン－Ｏ－Ｃ１－Ｃ１２アルキレン、Ｃ６－Ｃ１４アリーレン－Ｃ１－Ｃ１２アルキレン－Ｏ－、Ｃ１－Ｃ１２アルキレン－Ｃ６－Ｃ１４アリーレン、Ｃ１－Ｃ１２アルキレン－Ｃ６－Ｃ１４アリーレン－Ｏ－Ｃ１－Ｃ１２アルキレンがさらに好ましい。 Of the divalent hydrocarbon groups, at least one C 6-14 aromatic hydrocarbon group may be present, and an ether bond may be present between the terminal or carbon-carbon bonds. Examples of the divalent hydrocarbon group that may be contained include C 6 -C 14 arylene, C 6 -C 14 arylene-C 1 -C 12 alkylene, C 6 -C 14 arylene-C 2 -C 12 alkynylene, C 6 -C 14 arylene-O—, C 6 -C 14 arylene-O—C 1 -C 12 alkylene, C 6 -C 14 arylene-C 1 -C 12 alkylene-O—, C 1 -C 12 alkylene- C 6 -C 14 arylene, C 1 -C 12 alkylene-C 6 -C 14 arylene-O—, C 1 -C 12 alkylene-C 6 -C 14 arylene-O—C 1 -C 12 alkylene C 1 -C 12 alkylene-C 6 -C 14 arylene-C 1 -C 12 alkylene, C 1 -C 12 alkylene-C 6 -C 14 arylene-C 1 -C 12 alkylene-O—, C 1 -C 12 alkylene-C 6 -C 14 arylene-C 1 -C 12 alkylene-O—C 1 -C 12 alkylene is preferred. Among these divalent hydrocarbon groups, C 6 -C 14 arylene, C 6 -C 14 arylene-C 1 -C 12 alkylene, C 6 -C 14 arylene-C 2 -C 12 alkynylene, C 6 -C 14 arylene-O-, C 6 -C 14 arylene-O—C 1 -C 12 alkylene, C 6 -C 14 arylene-C 1 -C 12 alkylene-O—, C 1 -C 12 alkylene-C 6 -C More preferred are 14 arylene, C 1 -C 12 alkylene-C 6 -C 14 arylene-O—C 1 -C 12 alkylene.

　前記Ｃ６－１４芳香族炭化水素基を少なくとも一つ有し、かつ末端若しくは炭素－炭素結合間にエーテル結合を有していてもよく置換基を有していてもよい２価の炭化水素基のうち、フェニレン、フェニレン－Ｃ１－Ｃ６アルキレン、フェニレン－Ｃ２－Ｃ６アルキニレン、フェニレン－Ｏ－、フェニレン－Ｏ－Ｃ１－Ｃ６アルキレン、フェニレン－Ｃ１－Ｃ６アルキレン－Ｏ－、Ｃ１－Ｃ６アルキレン－フェニレン、Ｃ１－Ｃ６アルキレン－フェニレン－Ｏ－、Ｃ１－Ｃ６アルキレン－フェニレン－Ｏ－Ｃ１－Ｃ６アルキレン、Ｃ１－Ｃ６アルキレン－フェニレン－Ｃ１－Ｃ６アルキレン、Ｃ１－Ｃ６アルキレン－フェニレン－Ｃ１－Ｃ６アルキレン－Ｏ－、Ｃ１－Ｃ６アルキレン－フェニレン－Ｃ１－Ｃ６アルキレン－Ｏ－Ｃ１－Ｃ６アルキレンがさらに好ましい。これらの２価の炭化水素基のうち、フェニレン、フェニレン－Ｃ１－Ｃ６アルキレン、フェニレン－Ｃ２－Ｃ６アルキニレン、フェニレン－Ｏ－、フェニレン－Ｏ－Ｃ１－Ｃ６アルキレン、フェニレン－Ｃ１－Ｃ６アルキレン－Ｏ－、Ｃ１－Ｃ６アルキレン－フェニレン、Ｃ１－Ｃ６アルキレン－フェニレン－Ｏ－Ｃ１－Ｃ６アルキレンが特に好ましい。 A divalent hydrocarbon group which has at least one C 6-14 aromatic hydrocarbon group and may have an ether bond between a terminal or a carbon-carbon bond and may have a substituent; Among them, phenylene, phenylene-C 1 -C 6 alkylene, phenylene-C 2 -C 6 alkynylene, phenylene-O—, phenylene-O—C 1 -C 6 alkylene, phenylene-C 1 -C 6 alkylene-O— C 1 -C 6 alkylene-phenylene, C 1 -C 6 alkylene-phenylene-O—, C 1 -C 6 alkylene-phenylene-O—C 1 -C 6 alkylene, C 1 -C 6 alkylene-phenylene-C 1- C 6 alkylene, C 1 -C 6 alkylene-phenylene-C 1 -C 6 alkylene-O-, C 1 -C 6 alkylene-phenylene-C 1 -C 6 More preferred are alkylene-O—C 1 -C 6 alkylene. Of these divalent hydrocarbon groups, phenylene, phenylene-C 1 -C 6 alkylene, phenylene-C 2 -C 6 alkynylene, phenylene-O—, phenylene-O—C 1 -C 6 alkylene, phenylene-C 1 -C 6 alkylene -O-, C 1 -C 6 alkylene - phenylene, C 1 -C 6 alkylene - phenylene -O-C 1 -C 6 alkylene particularly preferred.

　前記Ｃ６－１４芳香族炭化水素基を少なくとも一つ有し、かつ末端若しくは炭素－炭素結合間にエーテル結合を有していてもよく置換基を有していてもよい２価の炭化水素基のより好ましい具体例としては、フェニレン、フェニレン－Ｏ－、フェニレン－ＣＨ２－、フェニレン－（ＣＨ２）２－、フェニレン－（ＣＨ２）３－、フェニレン－Ｃ≡Ｃ－ＣＨ２－、フェニレン－Ｃ≡Ｃ－（ＣＨ２）２－、フェニレン－Ｃ≡Ｃ－（ＣＨ２）３－、フェニレン－Ｃ≡Ｃ－（ＣＨ２）４－、フェニレン－Ｏ－ＣＨ２－、フェニレン－Ｏ－（ＣＨ２）２－、フェニレン－ＣＨ２－Ｏ－、フェニレン－（ＣＨ２）２－Ｏ－、－ＣＨ２－フェニレン－、－（ＣＨ２）２－フェニレン、－ＣＨ２－フェニレン－ＣＨ２－、－ＣＨ２－フェニレン－（ＣＨ２）２－、－（ＣＨ２）２－フェニレン－ＣＨ２－、－（ＣＨ２）２－フェニレン－（ＣＨ２）２－、－ＣＨ２－フェニレン－ＣＨ２－Ｏ－、－（ＣＨ２）２－フェニレン－（ＣＨ２）２－Ｏ－、－ＣＨ２－フェニレン－ＣＨ２－Ｏ－（ＣＨ２）２－、－ＣＨ２－フェニレン－Ｏ－、－（ＣＨ２）２－フェニレン－Ｏ－、－ＣＨ２－フェニレン－Ｏ－ＣＨ２－、－ＣＨ２－フェニレン－Ｏ－（ＣＨ２）２－、－ＣＨ２－フェニレン－ＣＨ２－Ｏ－ＣＨ２－、－ＣＨ２－フェニレン－ＣＨ２－Ｏ－（ＣＨ２）２－等が挙げられる。このうち、フェニレン、フェニレン－Ｏ－、フェニレン－ＣＨ２－、フェニレン－（ＣＨ２）２－、フェニレン－（ＣＨ２）３－、フェニレン－Ｃ≡Ｃ－ＣＨ２－、フェニレン－Ｃ≡Ｃ－（ＣＨ２）２－、フェニレン－Ｃ≡Ｃ－（ＣＨ２）３－、フェニレン－Ｃ≡Ｃ－（ＣＨ２）４－、フェニレン－Ｏ－ＣＨ２－、フェニレン－Ｏ－（ＣＨ２）２－、フェニレン－ＣＨ２－Ｏ－、フェニレン－（ＣＨ２）２－Ｏ－が特に好ましい。 A divalent hydrocarbon group which has at least one C 6-14 aromatic hydrocarbon group and may have an ether bond between a terminal or a carbon-carbon bond and may have a substituent; More preferred specific examples of phenylene, phenylene-O—, phenylene-CH 2 —, phenylene- (CH 2 ) 2 —, phenylene- (CH 2 ) 3 —, phenylene-C≡C—CH 2 —, phenylene -C≡C- (CH 2) 2 -, phenylene -C≡C- (CH 2) 3 -, phenylene -C≡C- (CH 2) 4 -, phenylene -O-CH 2 -, phenylene -O- (CH 2 ) 2- , phenylene-CH 2 -O-, phenylene- (CH 2 ) 2 -O-, -CH 2 -phenylene-,-(CH 2 ) 2 -phenylene, -CH 2 -phenylene-CH 2 -,- H 2 - phenylene - (CH 2) 2 -, - (CH 2) 2 - phenylene -CH 2 -, - (CH 2 ) 2 - phenylene - (CH 2) 2 -, - CH 2 - phenylene -CH 2 - O -, - (CH 2) 2 - phenylene - (CH 2) 2 -O - , - CH 2 - phenylene -CH 2 -O- (CH 2) 2 -, - CH 2 - phenylene -O -, - ( CH 2) 2 - phenylene -O -, - CH 2 - phenylene -O-CH 2 -, - CH 2 - phenylene -O- (CH 2) 2 -, - CH 2 - phenylene -CH 2 -O-CH 2 -, - CH 2 - phenylene -CH 2 -O- (CH 2) 2 - and the like. Of these, phenylene, phenylene-O—, phenylene-CH 2 —, phenylene- (CH 2 ) 2 —, phenylene- (CH 2 ) 3 —, phenylene-C≡C—CH 2 —, phenylene-C≡C— (CH 2 ) 2 —, phenylene-C≡C— (CH 2 ) 3 —, phenylene-C≡C— (CH 2 ) 4 —, phenylene-O—CH 2 —, phenylene-O— (CH 2 ) 2 —, Phenylene-CH 2 —O—, and phenylene- (CH 2 ) 2 —O— are particularly preferred.

　これらの２価の炭化水素基に置換し得る基としては、ハロゲン原子、ハロゲノアルキル基、アルコキシ基、ハロゲノアルコキシ基、ヒドロキシ基、オキソ基、アミノ基、シアノ基、アルキル基、チオアルコキシ基、ハロゲノチオアルコキシ基等が挙げられる。これらの置換基のうち、ハロゲン原子、ハロゲノ－Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、ハロゲノＣ１－Ｃ６アルコキシ基、ヒドロキシ基、オキソ基、アミノ基、シアノ基、Ｃ１－Ｃ６アルキル基、ハロゲノ－Ｃ１－Ｃ６チオアルコキシ基が好ましい。これらの置換基の好ましい具体例としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子、オキソ基、トリフルオロメチル基、トリフルオロメトキシ基、ジフルオロメトキシ基、トリフルオロメチルチオ基、シアノ基、メチル基、エチル基、イソプロピル基、tert－ブチル基、メトキシ基等が挙げられる。なお、これらの置換基は炭化水素基上に１～５個有していてもよい。 Examples of groups that can be substituted with these divalent hydrocarbon groups include halogen atoms, halogenoalkyl groups, alkoxy groups, halogenoalkoxy groups, hydroxy groups, oxo groups, amino groups, cyano groups, alkyl groups, thioalkoxy groups, halogeno groups. A thioalkoxy group etc. are mentioned. Among these substituents, halogen atom, halogeno-C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, halogeno C 1 -C 6 alkoxy group, hydroxy group, oxo group, amino group, cyano group, C 1 -C 6 alkyl group, a halogeno -C 1 -C 6 thioalkoxy group. Preferable specific examples of these substituents include fluorine atom, chlorine atom, bromine atom, iodine atom, oxo group, trifluoromethyl group, trifluoromethoxy group, difluoromethoxy group, trifluoromethylthio group, cyano group, and methyl group. Ethyl group, isopropyl group, tert-butyl group, methoxy group and the like. These substituents may have 1 to 5 substituents on the hydrocarbon group.

エーテル結合、アルキレン基又は末端若しくは炭素－炭素結合間にエーテル結合を有するアルキレン基を有していてもよい２価の芳香族複素環式基としては、芳香族複素環式基、芳香族複素環－Ｏ－、芳香族複素環－Ｃ１－Ｃ１２アルキレン、芳香族複素環－Ｏ－Ｃ１－Ｃ１２アルキレン、芳香族複素環－Ｃ１－Ｃ１２アルキレン－Ｏ－、Ｃ１－Ｃ１２アルキレン－芳香族複素環－Ｃ１－Ｃ１２アルキレン等が挙げられる。このうち、芳香族複素環式基、芳香族複素環－Ｏ－Ｃ1－Ｃ１２アルキレン、芳香族複素環－Ｃ1－Ｃ１２アルキレンが好ましい。ここで、アルキレン基としてはＣ１－Ｃ６アルキレン基がさらに好ましい。 Examples of the divalent aromatic heterocyclic group optionally having an ether bond, an alkylene group, or an alkylene group having an ether bond between the terminal or carbon-carbon bonds include an aromatic heterocyclic group and an aromatic heterocyclic ring. -O-, aromatic heterocycle-C 1 -C 12 alkylene, aromatic heterocycle -O-C 1 -C 12 alkylene, aromatic heterocycle -C 1 -C 12 alkylene-O-, C 1 -C 12 Alkylene-aromatic heterocycle-C 1 -C 12 alkylene and the like. Of these, an aromatic heterocyclic group, an aromatic heterocycle —O—C 1 -C 12 alkylene and an aromatic heterocycle —C 1 -C 12 alkylene are preferred. Here, the alkylene group is more preferably a C 1 -C 6 alkylene group.

　芳香族複素環式基としては、Ｎ、Ｓ及びＯから選ばれるヘテロ原子を有する単環性又は二環性の芳香族複素環式基が挙げられ、Ｎ、Ｓ及びＯから選ばれるヘテロ原子を１～４個有する単環性又は二環性の芳香族複素環式基が好ましい。ここで、単環性の芳香族複素環式基としては、５～６員のものが好ましい。具体例としては、ピロリル基、フリル基、チエニル基、イミダゾリル基、ピラゾリル基、オキサゾリル基、チアゾリル基、ピリジル基、ピリミジニル基、ピラジニル基、インドリル基、ベンゾフラニル基、ベンゾチエニル基、ベンゾチアゾリル基、ベンゾオキサゾリル基、ベンゾイミダゾリル基、テトラゾリル基等が挙げられ、特にチエニル基、チアゾリル基、ピリジル基、ピリミジニル基、ベンゾチアゾリル基、ベンゾオキサゾリル基が好ましい。 Examples of the aromatic heterocyclic group include monocyclic or bicyclic aromatic heterocyclic groups having a heteroatom selected from N, S and O, and a heteroatom selected from N, S and O Monocyclic or bicyclic aromatic heterocyclic groups having 1 to 4 are preferred. Here, the monocyclic aromatic heterocyclic group is preferably a 5- to 6-membered one. Specific examples include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazol A zolyl group, a benzimidazolyl group, a tetrazolyl group and the like can be mentioned, and a thienyl group, a thiazolyl group, a pyridyl group, a pyrimidinyl group, a benzothiazolyl group, and a benzoxazolyl group are particularly preferable.

　前記２価の芳香族複素環式基の例としては、芳香族複素環、芳香族複素環－Ｏ－、芳香族複素環－Ｏ－ＣＨ２－、芳香族複素環－Ｏ－（ＣＨ２）２－、芳香族複素環－ＣＨ２－、芳香族複素環－（ＣＨ２）２－、芳香族複素環－ＣＨ２－Ｏ－、芳香族複素環－（ＣＨ２）２－Ｏ－、－ＣＨ２－芳香族複素環－ＣＨ２－等が挙げられる。 Examples of the divalent aromatic heterocyclic group include aromatic heterocycle, aromatic heterocycle-O—, aromatic heterocycle-O—CH 2 —, aromatic heterocycle-O— (CH 2 ). 2- , aromatic heterocycle —CH 2 —, aromatic heterocycle — (CH 2 ) 2 —, aromatic heterocycle —CH 2 —O—, aromatic heterocycle — (CH 2 ) 2 —O—, — CH 2 -aromatic heterocycle —CH 2 — and the like can be mentioned.

　これらの２価の芳香族複素環式基またはアルキレン基に置換し得る基としては、ハロゲン原子、ハロゲノアルキル基、アルコキシ基、ハロゲノアルコキシ基、ヒドロキシ基、アミノ基、シアノ基、アルキル基、チオアルコキシ基、ハロゲノチオアルコキシ基等が挙げられる。これらの置換基のうち、ハロゲン原子、ハロゲノ－Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、ハロゲノＣ１－Ｃ６アルコキシ基、ヒドロキシ基、アミノ基、シアノ基、Ｃ１－Ｃ６アルキル基、ハロゲノ－Ｃ１－Ｃ６チオアルコキシ基が好ましい。これらの置換基の好ましい具体例としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子、トリフルオロメチル基、トリフルオロメトキシ基、ジフルオロメトキシ基、トリフルオロメチルチオ基、シアノ基、メチル基、エチル基、イソプロピル基、メトキシ基等が挙げられる。なお、これらの置換基は、芳香族複素環式基またはアルキレン基上に１～５個有していてもよい。 Examples of groups that can be substituted with these divalent aromatic heterocyclic groups or alkylene groups include halogen atoms, halogenoalkyl groups, alkoxy groups, halogenoalkoxy groups, hydroxy groups, amino groups, cyano groups, alkyl groups, and thioalkoxy groups. Group, a halogenothioalkoxy group, and the like. Among these substituents, halogen atom, halogeno-C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, halogeno C 1 -C 6 alkoxy group, hydroxy group, amino group, cyano group, C 1 -C A 6- alkyl group and a halogeno-C 1 -C 6 thioalkoxy group are preferred. Preferable specific examples of these substituents include fluorine atom, chlorine atom, bromine atom, iodine atom, trifluoromethyl group, trifluoromethoxy group, difluoromethoxy group, trifluoromethylthio group, cyano group, methyl group, ethyl group. , Isopropyl group, methoxy group and the like. These substituents may have 1 to 5 substituents on the aromatic heterocyclic group or alkylene group.

　前記の２価のＣ２－１２脂肪族炭化水素基としては、炭素数２～１２の直鎖又は分岐鎖のアルキレン基、炭素数２～１２の直鎖又は分岐鎖のアルケニレン基、炭素数２～１２の直鎖又は分岐鎖のアルキニレン基、炭素数３～１２のシクロアルキレン基等が挙げられる。より具体的には、エチレン基、ｎ－プロピレン基、イソプロピレン基、ｎ－ブチレン基、ｎ－ペンチレン基、ｎ－ヘキシレン基等の炭素数２～６のアルキレン基；エテニレン基、プロペニレン基等の炭素数２～６のアルケニレン基；エチニレン基、プロピニレン基、ヘキシニレン等の炭素数２～６のアルキニレン基；シクロプロピレン基、シクロブチレン基、シクロペンチレン基、シクロヘキシレン基等の炭素数３～６のシクロアルキレン基が挙げられる。 Examples of the divalent C 2-12 aliphatic hydrocarbon group include a linear or branched alkylene group having 2 to 12 carbon atoms, a linear or branched alkenylene group having 2 to 12 carbon atoms, and a carbon number of 2 A -12 linear or branched alkynylene group, a cycloalkylene group having 3 to 12 carbon atoms, and the like. More specifically, an alkylene group having 2 to 6 carbon atoms such as an ethylene group, an n-propylene group, an isopropylene group, an n-butylene group, an n-pentylene group, and an n-hexylene group; an ethenylene group, a propenylene group, etc. An alkenylene group having 2 to 6 carbon atoms; an alkynylene group having 2 to 6 carbon atoms such as ethynylene group, propynylene group and hexynylene; 3 to 6 carbon atoms such as cyclopropylene group, cyclobutylene group, cyclopentylene group and cyclohexylene group Of the cycloalkylene group.

　一般式（１）中、Ａｍはアミノ基、一置換アミノ基、二置換アミノ基、又は置換基を有していてもよい窒素含有飽和複素環式基を示す。また、フタルイミド基を用いても同様の効果を得ることができる。一置換アミノ基又は二置換アミノ基の置換基としては、アルキル基、アミノアルキル基、アミノシクロアルキル基、N-アルキル-アザシクロアルキル基、アルキルアミノアルキル基、ジアルキルアミノアルキル基、アルコキシアルキル基、ヒドロキシアルキル基、チオアルコキシアルキル基等が挙げられる。より具体的には、Ｃ１－Ｃ６アルキル基、アミノ－Ｃ３－Ｃ７シクロアルキル基、N-Ｃ１－Ｃ６アルキル-Ｃ２－Ｃ６アザシクロアルキル基、アミノ－Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルキルアミノ-Ｃ１－Ｃ６アルキル基、ジＣ１－Ｃ６アルキルアミノ－Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ－Ｃ１－Ｃ６アルキル基、ヒドロキシ－Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６チオアルコキシ－Ｃ１－Ｃ６アルキル基が挙げられる。 In general formula (1), Am represents an amino group, a monosubstituted amino group, a disubstituted amino group, or a nitrogen-containing saturated heterocyclic group which may have a substituent. The same effect can be obtained by using a phthalimide group. Examples of the substituent of the monosubstituted amino group or the disubstituted amino group include an alkyl group, an aminoalkyl group, an aminocycloalkyl group, an N-alkyl-azacycloalkyl group, an alkylaminoalkyl group, a dialkylaminoalkyl group, an alkoxyalkyl group, Examples thereof include a hydroxyalkyl group and a thioalkoxyalkyl group. More specifically, a C 1 -C 6 alkyl group, an amino-C 3 -C 7 cycloalkyl group, an N—C 1 -C 6 alkyl-C 2 -C 6 azacycloalkyl group, an amino-C 1 -C 6 alkyl group, C 1 -C 6 alkylamino -C 1 -C 6 alkyl group, di C 1 -C 6 alkylamino -C 1 -C 6 alkyl group, C 1 -C 6 alkoxy -C 1 -C 6 alkyl Group, a hydroxy-C 1 -C 6 alkyl group, a C 1 -C 6 thioalkoxy-C 1 -C 6 alkyl group.

　一置換アミノ基の好ましい例としては、Ｃ１－Ｃ６アルキルアミノ基、アミノ－Ｃ１－Ｃ６アルキルアミノ基、アミノ－Ｃ３－Ｃ７シクロアルキルアミノ基、N-Ｃ１－Ｃ６アルキル-Ｃ２－Ｃ６アザシクロアルキルアミノ基等が挙げられ、具体的にはメチルアミノ基、エチルアミノ基、イソプロピルアミノ基、アミノシクロヘキシルアミノ基、アミノメチルアミノ基、アミノエチルアミノ基、アミノプロピルアミノ基、アミノブチルアミノ基、N-メチルピペリジノアミノ基が挙げられる。 Preferred examples of the monosubstituted amino group include a C 1 -C 6 alkylamino group, an amino-C 1 -C 6 alkylamino group, an amino-C 3 -C 7 cycloalkylamino group, and an N—C 1 -C 6 alkyl group. -C 2 -C 6 azacycloalkylamino group and the like, specifically, methylamino group, ethylamino group, isopropylamino group, aminocyclohexylamino group, aminomethylamino group, aminoethylamino group, aminopropylamino Group, aminobutylamino group, and N-methylpiperidinoamino group.

　二置換アミノ基の好ましい例としては、ジＣ１－Ｃ６アルキルアミノ基、ジ（アミノ－Ｃ１－Ｃ６アルキル）アミノ基、（Ｃ１－Ｃ６アルキルアミノ－Ｃ１－Ｃ６アルキル）（Ｃ１－Ｃ６アルキル）アミノ基、（ジＣ１－Ｃ６アルキルアミノ－Ｃ１－Ｃ６アルキル）（Ｃ１－Ｃ６アルキル）アミノ基、ジ（Ｃ１－Ｃ６アルコキシ－Ｃ１－Ｃ６アルキル）アミノ基等が挙げられ、具体的には、ジメチルアミノ基、ジエチルアミノ基、ジイソプロピルアミノ基、（エチル）（n-プロピル）アミノ基、ジ（アミノエチル）アミノ基、（ジメチルアミノエチル）（メチル）アミノ基、（ジエチルアミノエチル）（メチル）アミノ基、（ジエチルアミノエチル）（エチル）アミノ基、ジ（アミノプロピル）アミノ基、ジ（アミノブチル）アミノ基等が挙げられる。 Preferred examples of the disubstituted amino group include a di-C 1 -C 6 alkylamino group, a di (amino-C 1 -C 6 alkyl) amino group, and (C 1 -C 6 alkylamino-C 1 -C 6 alkyl). (C 1 -C 6 alkyl) amino group, (di-C 1 -C 6 alkylamino-C 1 -C 6 alkyl) (C 1 -C 6 alkyl) amino group, di (C 1 -C 6 alkoxy-C 1 -C 6 alkyl) amino group and the like, specifically, dimethylamino group, diethylamino group, diisopropylamino group, (ethyl) (n-propyl) amino group, di (aminoethyl) amino group, (dimethylamino Ethyl) (methyl) amino, (diethylaminoethyl) (methyl) amino, (diethylaminoethyl) (ethyl) amino, di (aminopropyl) amino, di (amino) ) Amino group, and the like.

　窒素含有飽和複素環式基としては、窒素原子を１又は２個有し、さらに酸素原子又は硫黄原子を有していてもよい５員～７員の飽和複素環式基が挙げられる。当該飽和複素環式基の好ましい例としては、ピロリジニル基、ピペリジニル基、ピペラジニル基、モルホリニル基、チオモルホリニル基、１,１-ジオキシドチオモルホリニル基、ホモピペラジニル基、ケトピペラジニル基、ジケトピペラジニル基等が挙げられる。このうち、ピペリジニル基、ピペラジニル基、モルホリニル基、チオモルホリニル基、１,１-ジオキシドチオモルホリニル基、ホモピペラジニル基等が好ましい。 Examples of the nitrogen-containing saturated heterocyclic group include 5- to 7-membered saturated heterocyclic groups which have 1 or 2 nitrogen atoms and may further have an oxygen atom or a sulfur atom. Preferred examples of the saturated heterocyclic group include pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, 1,1-dioxidethiomorpholinyl group, homopiperazinyl group, ketopiperazinyl group, diketopiperazinyl group. Groups and the like. Of these, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, 1,1-dioxidethiomorpholinyl group, homopiperazinyl group and the like are preferable.

　当該窒素含有飽和複素環式基に置換し得る基としては、アルキル基、シクロアルキル基、アミノ基、アミノアルキル基、アルコキシアルキル基、ヒドロキシアルキル基、ヒドロキシ基、オキソ基、ピペリジニル基、ピロリジニル基、モルホリニル基、シアノ基、シアノアルキル基、ハロゲン原子、ハロゲノアルキル基、ハロゲノアルコキシ基、アルキルスルホニル基、アシル基、アルキルオキシカルボニル基、アシルオキシアルキル基等が挙げられる。これらの置換基の好ましい例としては、Ｃ１－Ｃ１０アルキル基、Ｃ３－Ｃ６シクロアルキル基、アミノ基、アミノ－Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ－Ｃ１－Ｃ６アルキル基、ヒドロキシ－Ｃ１－Ｃ６アルキル基、ヒドロキシ基、オキソ基、ピペリジニル基、ピロリジニル基、モルホリニル基、シアノ基、シアノ－Ｃ１－Ｃ６アルキル基、ハロゲン原子、ハロゲノ－Ｃ１－Ｃ６アルキル基、ハロゲノ－Ｃ１－Ｃ６アルコキシ基、Ｃ１－Ｃ６アルキルスルホニル基、Ｃ１－Ｃ６アシル基、Ｃ１－Ｃ６アルキルオキシカルボニル基、Ｃ１－Ｃ６アシルオキシ－Ｃ１－Ｃ６アルキル基等が挙げられる。さらに置換基の具体例としては、メチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、イソブチル基、tert－ブチル基、n-ペンチル基、n-へキシル基、n-デシル基、シクロペンチル基、シクロヘキシル基、アミノ基、アミノエチル基、メトキシエチル基、エトキシエチル基、ヒドロキシエチル基、ヒドロキシ基、オキソ基、ピペリジニル基、ピロリジニル基、モルホリニル基、シアノ基、シアノメチル基、フッ素原子、塩素原子、臭素原子、トリフルオロメチル基、トリフルオロメトキシ基、メチルスルホニル基、エチルスルホニル基、アセチル基、t-ブトキシカルボニル基、アセチルオキシエチル基が挙げられる。なお、これらの置換基は窒素含有飽和複素環式基上に、１～５個有していてもよい。 Examples of the group that can be substituted with the nitrogen-containing saturated heterocyclic group include an alkyl group, a cycloalkyl group, an amino group, an aminoalkyl group, an alkoxyalkyl group, a hydroxyalkyl group, a hydroxy group, an oxo group, a piperidinyl group, a pyrrolidinyl group, Examples include morpholinyl group, cyano group, cyanoalkyl group, halogen atom, halogenoalkyl group, halogenoalkoxy group, alkylsulfonyl group, acyl group, alkyloxycarbonyl group, acyloxyalkyl group and the like. Preferred examples of these substituents include C 1 -C 10 alkyl group, C 3 -C 6 cycloalkyl group, amino group, amino-C 1 -C 6 alkyl group, C 1 -C 6 alkoxy-C 1- C 6 alkyl group, hydroxy-C 1 -C 6 alkyl group, hydroxy group, oxo group, piperidinyl group, pyrrolidinyl group, morpholinyl group, cyano group, cyano-C 1 -C 6 alkyl group, halogen atom, halogeno-C 1 -C 6 alkyl group, halogeno-C 1 -C 6 alkoxy group, C 1 -C 6 alkylsulfonyl group, C 1 -C 6 acyl group, C 1 -C 6 alkyloxycarbonyl group, C 1 -C 6 acyloxy- Examples thereof include C 1 -C 6 alkyl groups. Specific examples of the substituent include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, n-hexyl group, n-decyl group. Group, cyclopentyl group, cyclohexyl group, amino group, aminoethyl group, methoxyethyl group, ethoxyethyl group, hydroxyethyl group, hydroxy group, oxo group, piperidinyl group, pyrrolidinyl group, morpholinyl group, cyano group, cyanomethyl group, fluorine atom Chlorine atom, bromine atom, trifluoromethyl group, trifluoromethoxy group, methylsulfonyl group, ethylsulfonyl group, acetyl group, t-butoxycarbonyl group, and acetyloxyethyl group. These substituents may have 1 to 5 on the nitrogen-containing saturated heterocyclic group.

　Ｒ１及びＲ２は、それぞれ独立して、水素原子、ハロゲン原子、アルキル基、アルコキシ基、チオアルコキシ基、ヒドロキシ基、アミノ基、一置換アミノ基、二置換アミノ基、ハロゲノアルキル基、シアノ基、ニトロ基、チオアルキル基、チオハロゲノアルキル基、ハロゲノアルコキシ基、アシル基、カルボキシル基、アルキルアミノ基、アルコキシアルキル基、又はアルコキシカルボニル基を示す。より好ましいＲ１及びＲ２は、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、Ｃ１－Ｃ６チオアルコキシ基、ヒドロキシ基、アミノ基、Ｃ１－Ｃ６アルキルアミノ基、ジＣ１－Ｃ６アルキルアミノ基、ハロゲノ－Ｃ１－Ｃ６アルキル基、シアノ基、ニトロ基、チオＣ１－Ｃ６アルキル基、チオ－ハロゲノＣ１－Ｃ６アルキル基、ハロゲノ－Ｃ１－Ｃ６アルコキシ基、Ｃ１－Ｃ６アルカノイル基、カルボキシル基、Ｃ１－Ｃ６アルキルアミノ基、Ｃ１－Ｃ６アルコキシ－Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシカルボニル基等である。より具体的には、水素原子、メチル基が挙げられる。 R 1 and R 2 are each independently a hydrogen atom, halogen atom, alkyl group, alkoxy group, thioalkoxy group, hydroxy group, amino group, monosubstituted amino group, disubstituted amino group, halogenoalkyl group, cyano group Nitro group, thioalkyl group, thiohalogenoalkyl group, halogenoalkoxy group, acyl group, carboxyl group, alkylamino group, alkoxyalkyl group, or alkoxycarbonyl group. R 1 and R 2 are more preferably hydrogen atom, halogen atom, C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, C 1 -C 6 thioalkoxy group, hydroxy group, amino group, C 1 -C 6 alkylamino group, di-C 1 -C 6 alkylamino group, halogeno-C 1 -C 6 alkyl group, cyano group, nitro group, thio C 1 -C 6 alkyl group, thio-halogeno C 1 -C 6 alkyl group Halogeno-C 1 -C 6 alkoxy group, C 1 -C 6 alkanoyl group, carboxyl group, C 1 -C 6 alkylamino group, C 1 -C 6 alkoxy-C 1 -C 6 alkyl group, C 1 -C 6 alkoxycarbonyl group and the like. More specifically, a hydrogen atom and a methyl group are exemplified.

　一般式（１）中、Ｙが、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素基、置換基を有していてもよい２価のＣ１－１０脂肪族炭化水素－Ｃ６－１４芳香族炭化水素基、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素－Ｃ１－１０脂肪族炭化水素基、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素－Ｏ－、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素－Ｏ－Ｃ１－１０脂肪族炭化水素基、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素－Ｃ１－１０脂肪族炭化水素基－Ｏ－、置換基を有していてもよいＮ、Ｓ及びＯから選ばれるヘテロ原子を１～４個有する２価の単環性若しくは二環性の芳香族複素環式基、置換基を有していてもよいＮ、Ｓ及びＯから選ばれるヘテロ原子を１～４個有する２価の単環性若しくは二環性の芳香族複素環－Ｃ１－１２脂肪族炭化水素基、又は置換基を有していてもよいＮ、Ｓ及びＯから選ばれるヘテロ原子を１～４個有する２価の単環性若しくは二環性の芳香族複素環－Ｏ－Ｃ１－１０脂肪族炭化水素基であり；Ａｍが、置換基を有していてもよい窒素含有飽和複素環式基である化合物又はその塩がより好ましい。なお、上記Ｙは、一般式（１）中の（Ａ）で表される構造と結合した部分から構造を規定しており、ＹとＡｍの結合は、例えばＹが置換基を有していてもよい２価のＣ６－１４芳香族炭化水素－Ｏ－の場合、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素－Ｏ－Ａｍとなる。 In the general formula (1), Y is a divalent C 6-14 aromatic hydrocarbon group which may have a substituent, or a divalent C 1-10 aliphatic which may have a substituent. Hydrocarbon-C 6-14 aromatic hydrocarbon group, optionally having divalent C 6-14 aromatic hydrocarbon-C 1-10 aliphatic hydrocarbon group, having substituent Divalent C 6-14 aromatic hydrocarbon-O— which may be optionally substituted, Divalent C 6-14 aromatic hydrocarbon-O—C 1-10 aliphatic hydrocarbon group which may have a substituent A divalent C 6-14 aromatic hydrocarbon-C 1-10 aliphatic hydrocarbon group-O- which may have a substituent, N, S and O which may have a substituent A divalent monocyclic or bicyclic aromatic heterocyclic group having 1 to 4 selected heteroatoms, a substituent selected from optionally substituted N, S and O From a divalent monocyclic or bicyclic aromatic heterocyclic ring having 1 to 4 rhoatoms- C 1-12 aliphatic hydrocarbon group, or optionally substituted N, S and O A divalent monocyclic or bicyclic aromatic heterocyclic-O—C 1-10 aliphatic hydrocarbon group having 1 to 4 selected heteroatoms; and Am has a substituent More preferred are compounds that are nitrogen-containing saturated heterocyclic groups or salts thereof. In addition, said Y has prescribed | regulated the structure from the part couple | bonded with the structure represented by (A) in General formula (1), and the coupling | bonding of Y and Am is, for example, Y has a substituent. In the case of the divalent C 6-14 aromatic hydrocarbon-O—, the divalent C 6-14 aromatic hydrocarbon-O—Am which may have a substituent is obtained.

　一般式（１）中の（Ａ）で表される構造が（Ａ－１）、（Ａ－２）、（Ａ－３）、（Ａ－５）、（Ａ－６）、（Ａ－７）、（Ａ－８）、（Ａ－９）、（Ａ－１１）、（Ａ－１２）、（Ａ－１３）、（Ａ－１４）、（Ａ－１６）、（Ａ－１７）、（Ａ－１８）、（Ａ－１９）、（Ａ－２０）又は（Ａ－２１）であり；Ｙが、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素基、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素－Ｃ１－１０脂肪族炭化水素基、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素－Ｏ－、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素－Ｏ－Ｃ１－１０脂肪族炭化水素基、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素－Ｃ１－１０脂肪族炭化水素基－Ｏ－、置換基を有していてもよいＮ、Ｓ及びＯから選ばれるヘテロ原子を１～４個有する２価の単環性若しくは二環性の芳香族複素環式基、置換基を有していてもよいＮ、Ｓ及びＯから選ばれるヘテロ原子を１～４個有する２価の単環性若しくは二環性の芳香族複素環－Ｃ１－１２脂肪族炭化水素基、又は置換基を有していてもよいＮ、Ｓ及びＯから選ばれるヘテロ原子を１～４個有する２価の単環性若しくは二環性の芳香族複素環－Ｏ－Ｃ１－１０脂肪族炭化水素基であり；Ａｍが、置換基を有していてもよい窒素含有飽和複素環式基である化合物又はその塩がさらに好ましい。 The structure represented by (A) in the general formula (1) is (A-1), (A-2), (A-3), (A-5), (A-6), (A-7). ), (A-8), (A-9), (A-11), (A-12), (A-13), (A-14), (A-16), (A-17), (A-18), (A-19), (A-20) or (A-21); Y is a divalent C 6-14 aromatic hydrocarbon group optionally having substituent (s) , Divalent C 6-14 aromatic hydrocarbon-C 1-10 aliphatic hydrocarbon group which may have a substituent, divalent C 6-14 aromatic group which may have a substituent Hydrocarbon-O—, divalent C 6-14 aromatic hydrocarbon-O—C 1-10 aliphatic hydrocarbon group optionally having substituent (s), divalent optionally having substituent (s) C 6-14 aromatic hydrocarbon -C 1-10 aliphatic hydrocarbons -O-, a divalent monocyclic or bicyclic aromatic heterocyclic group having 1 to 4 heteroatoms selected from N, S and O which may have a substituent, a substituent; A divalent monocyclic or bicyclic aromatic heterocyclic-C 1-12 aliphatic hydrocarbon group having 1 to 4 heteroatoms selected from N, S and O, which may have Divalent monocyclic or bicyclic aromatic heterocyclic ring-O—C 1-10 aliphatic hydrocarbon having 1 to 4 heteroatoms selected from N, S and O which may have a group More preferred is a compound or a salt thereof, wherein Am is a nitrogen-containing saturated heterocyclic group which may have a substituent.

　また、上記化合物またはその塩のうち、一般式（１）中のＹで表される構造が、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素基、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素－Ｃ１－６脂肪族炭化水素基、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素－Ｏ－、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素－Ｏ－Ｃ１－６脂肪族炭化水素基、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素－Ｃ１－６脂肪族炭化水素基－Ｏ－、置換基を有していてもよいＮ、Ｓ及びＯから選ばれるヘテロ原子を１～４個有する２価の単環性若しくは二環性の芳香族複素環式基、置換基を有していてもよいＮ、Ｓ及びＯから選ばれるヘテロ原子を１～４個有する２価の単環性若しくは二環性の芳香族複素環－Ｃ１－６脂肪族炭化水素基、又は置換基を有していてもよいＮ、Ｓ及びＯから選ばれるヘテロ原子を１～４個有する２価の単環性若しくは二環性の芳香族複素環－Ｏ－Ｃ１－６脂肪族炭化水素基である化合物又はその塩が特に好ましく、この中でも、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素基、又は置換基を有していてもよいＮ、Ｓ及びＯから選ばれるヘテロ原子を１～４個有する２価の単環性若しくは二環性の芳香族複素環式基を有する化合物又はその塩が好ましい。 In addition, among the compounds or salts thereof, the structure represented by Y in the general formula (1) is a divalent C 6-14 aromatic hydrocarbon group which may have a substituent, or a substituent. Divalent C 6-14 aromatic hydrocarbon-C 1-6 aliphatic hydrocarbon group which may have, Divalent C 6-14 aromatic hydrocarbon-O which may have a substituent -, An optionally substituted divalent C 6-14 aromatic hydrocarbon-O—C 1-6 aliphatic hydrocarbon group, an optionally substituted divalent C 6- 14 aromatic hydrocarbon-C 1-6 aliphatic hydrocarbon group-O-, divalent monocyclic having 1 to 4 heteroatoms selected from optionally substituted N, S and O Or a bivalent aromatic heterocyclic group, a divalent monocyclic group having 1 to 4 heteroatoms selected from optionally substituted N, S and O Bicyclic aromatic heterocyclic -C 1-6 aliphatic hydrocarbon group, or it may have a substituent group N, 2 divalent monocyclic the chromatic 1 to 4 hetero atoms selected from S and O Or a bicyclic aromatic heterocyclic-O—C 1-6 aliphatic hydrocarbon group or a salt thereof is particularly preferred, and among them, a divalent C 6- which may have a substituent. 14 aromatic hydrocarbon group, or divalent monocyclic or bicyclic aromatic heterocyclic group having 1 to 4 heteroatoms selected from N, S and O which may have a substituent Or a salt thereof is preferred.

一般式（１）で表される化合物（本発明化合物（１））のうち、Ｐｉｍ阻害作用やがん細胞増殖抑制作用の強さ、代謝安定性の高さ等の理由から特に好ましい化合物は次のとおりである。
（１）５－（（１－（３－モルホリノプロピル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１）
（２）５－（（１－（４－（４－メチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物３）
（３）５－（（１－（４－（４－メチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物４）
（４）５－（（２－メチル－１－（４－（４－メチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物５）
（５）５－（（１－（３－（４－メチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物６）
（６）５－（（１－（３－（（４－メチルピペラジン－１－イル）メチル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物７） Among the compounds represented by the general formula (1) (the compound (1) of the present invention), the following are particularly preferred compounds for reasons such as Pim inhibitory action, cancer cell growth inhibitory action, high metabolic stability, and the like. It is as follows.
(1) 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 1)
(2) 5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one ( Compound 3)
(3) 5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 4)
(4) 5-((2-Methyl-1- (4- (4-methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine- 4-one (compound 5)
(5) 5-((1- (3- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one ( Compound 6)
(6) 5-((1- (3-((4-methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4 -On (compound 7)

（７）５－（（１－（４－（４－メチルピペラジニル）ベンジル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１１）
（８）５－（（１－（４－（４－メチルピペラジニル）ベンジル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１２）
（９）５－（（１－（４－（４－エチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１３）
（１０）５－（（１－（４－（４－エチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１４）
（１１）ｔｅｒｔ－ブチル　４－（４－（６－（（４－オキソ－２－チオキソチアゾリジン－５－イリデン）メチル）－１Ｈ－ベンゾ［ｄ］イミダゾール－１－イル）フェニル）ピペラジン－１－カルボキシレート（化合物１５）
（１２）５－（（１－（４－（（１－メチルピペリジン－４－イル）オキシ）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１６）
（１３）５－（（１－（４－（（１－メチルピペリジン－４－イル）オキシ）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１７）
（１４）５－（（１－（４－（（４－メチルピペラジン－１－イル）メチル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１８）
（１５）５－（（１－（４－（（４－メチルピペラジン－１－イル）メチル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１９） (7) 5-((1- (4- (4-Methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 11 )
(8) 5-((1- (4- (4-Methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 12)
(9) 5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one ( Compound 13)
(10) 5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 14)
(11) tert-butyl 4- (4- (6-((4-oxo-2-thioxothiazolidine-5-ylidene) methyl) -1H-benzo [d] imidazol-1-yl) phenyl) piperazine-1 Carboxylate (compound 15)
(12) 5-((1- (4-((1-methylpiperidin-4-yl) oxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione ( Compound 16)
(13) 5-((1- (4-((1-methylpiperidin-4-yl) oxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4 -On (compound 17)
(14) 5-((1- (4-((4-Methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione ( Compound 18)
(15) 5-((1- (4-((4-Methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4 -On (compound 19)

（１６）５－（（１－（３－（（４－メチルピペラジン－１－イル）メチル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物２０）
（１７）５－（（１－（３－（（４－エチルピペラジン－１－イル）メチル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物２１）
（１８）５－（（１－（３－（（４－エチルピペラジン－１－イル）メチル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物２２）
（１９）５－（（１－（３－（２－モルホリノエトキシ）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物２３）
（２０）５－（（１－（３－（２－モルホリノエトキシ）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物２４）
（２１）５－（（１－（４－（２－モルフォリノエトキシ）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物２５）
（２２）５－（（１－（４－（２－モルフォリノエトキシ）フェニル－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物２６） (16) 5-((1- (3-((4-Methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione ( Compound 20)
(17) 5-((1- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione ( Compound 21)
(18) 5-((1- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4 -On (compound 22)
(19) 5-((1- (3- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 23)
(20) 5-((1- (3- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 24)
(21) 5-((1- (4- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 25)
(22) 5-((1- (4- (2-morpholinoethoxy) phenyl-1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 26)

（２３）５－（（１－（４－モルフォリノフェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物２８）
（２４）５－（（１－（４－（４，４－ジフルオロピペリジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物２９）
（２５）５－（（１－（４－（４－（２－メトキシエチル）ピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物３０）
（２６）５－（（１－（４－（４－ブチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物３１）
（２７）５－（（１－（４－（４－ブチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物３２）
（２８）５－（（１－（４－（[１，４’－ビピペリジン]－１’－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物３３） (23) 5-((1- (4-morpholinophenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 28)
(24) 5-((1- (4- (4,4-difluoropiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4- ON (compound 29)
(25) 5-((1- (4- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine -4-one (compound 30)
(26) 5-((1- (4- (4-Butylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one ( Compound 31)
(27) 5-((1- (4- (4-Butylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 32)
(28) 5-((1- (4-([1,4′-bipiperidin] -1′-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine -4-one (compound 33)

（２９）５－（（１－（４－（[１，４’－ビピペリジン]－１’－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物３４）
（３０）５－（（１－（４－（４－モルフォリノピペリジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物３５）
（３１）５－（（１－（４－（４－モルフォリノピペリジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物３６）
（３２）５－（（１－（４－（４－メチル－１，４－ジアゼパン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物３７）
（３３）５－（（１－（４－（４－メチル－１，４－ジアゼパン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物３８）
（３４）５－（（１－（４－（（２－（ジメチルアミノ）エチル）（メチル）アミノ）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物３９）
（３５）５－（（１－（４－（（２－（ジメチルアミノ）エチル）（メチル）アミノ）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物４０）
（３６）５－（（１－（３－（４－（２－メトキシエチル）ピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物４１）
（３７）５－（（１－（３－（４－（２－メトキシエチル）ピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物４２）
（３８）５－（（１－（６－（４－メチルピペラジン－１－イル）ピリジン－３－イル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物４３）
（３９）５－（（１－（６－（４－メチルピペラジン－１－イル）ピリジン－３－イル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物４４） (29) 5-((1- (4-([1,4′-bipiperidin] -1′-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4- Dione (Compound 34)
(30) 5-((1- (4- (4-morpholinopiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one (Compound 35)
(31) 5-((1- (4- (4-morpholinopiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 36) )
(32) 5-((1- (4- (4-Methyl-1,4-diazepan-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine -4-one (compound 37)
(33) 5-((1- (4- (4-Methyl-1,4-diazepan-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4- Dione (Compound 38)
(34) 5-((1- (4-((2- (dimethylamino) ethyl) (methyl) amino) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine -4-one (compound 39)
(35) 5-((1- (4-((2- (dimethylamino) ethyl) (methyl) amino) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4- Dione (Compound 40)
(36) 5-((1- (3- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine -4-one (compound 41)
(37) 5-((1- (3- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4- Dione (Compound 42)
(38) 5-((1- (6- (4-Methylpiperazin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 43)
(39) 5-((1- (6- (4-Methylpiperazin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine- 4-one (compound 44)

（４０）５－（（１－（４－（４－メチルピペラジニル）フェニル）－１Ｈ－インドール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物４５）
（４１）５－（（１－（４－（４－メチルピペラジニル）ベンジル）－１Ｈ－インドール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物４６）
（４２）５－（（１－（４－（４－メチルピペラジニル）ベンジル）－１Ｈ－インドール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物４７）
（４３）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ａ］ピリジン－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物４８）
（４４）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ａ］ピリジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物４９）
（４５）５－（（３－（３－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ａ］ピリジン－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物５０）
（４６）５－（（３－（３－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ａ］ピリジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物５１）
（４７）５－（（３－（６－（４－メチルピペラジン－１－イル）ピリジン－３－イル）イミダゾ［１，２－ａ］ピリジン－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物５２）
（４８）５－（（３－（４－（（４－メチルピペラジン－１－イル）メチル）フェニル）イミダゾ［１，２－ａ］ピリジン－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物５３）
（４９）５－（（３－（４－（（４－メチルピペラジン－１－イル）メチル）フェニル）イミダゾ［１，２－ａ］ピリジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物５４）
（５０）５－（（３－（３－（（４－メチルピペラジン－１－イル）メチル）フェニル）イミダゾ［１，２－ａ］ピリジン－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物５５）
（５１）５－（（３－（３－（（４－メチルピペラジン－１－イル）メチル）フェニル）イミダゾ［１，２－ａ］ピリジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物５６） (40) 5-((1- (4- (4-Methylpiperazinyl) phenyl) -1H-indol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 45)
(41) 5-((1- (4- (4-Methylpiperazinyl) benzyl) -1H-indol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 46)
(42) 5-((1- (4- (4-Methylpiperazinyl) benzyl) -1H-indol-6-yl) methylene) thiazolidine-2,4-dione (Compound 47)
(43) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidine-4-one (Compound 48)
(44) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione (Compound 49 )
(45) 5-((3- (3- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidine-4-one (Compound 50)
(46) 5-((3- (3- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione (Compound 51 )
(47) 5-((3- (6- (4-Methylpiperazin-1-yl) pyridin-3-yl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidine -4-one (compound 52)
(48) 5-((3- (4-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidine- 4-one (compound 53)
(49) 5-((3- (4-((4-Methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione (Compound 54)
(50) 5-((3- (3-((4-Methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidine- 4-one (compound 55)
(51) 5-((3- (3-((4-Methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione (Compound 56)

（５２）５－（（３－（３－（（４－エチルピペラジン－１－イル）メチル）フェニル）イミダゾ［１，２－ａ］ピリジン－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物５７）
（５３）５－（（３－（３－（（４－エチルピペラジン－１－イル）メチル）フェニル）イミダゾ［１，２－ａ］ピリジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物５８）
（５４）５－（（３－（３－（（４－ブチルピペラジン－１－イル）メチル）フェニル）イミダゾ［１，２－ａ］ピリジン－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物５９）
（５５）５－（（３－（３－（（４－ブチルピペラジン－１－イル）メチル）フェニル）イミダゾ［１，２－ａ］ピリジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物６０）
（５６）５－（（３－（３－（（４－ヘキシルピペラジン－１－イル）メチル）フェニル）イミダゾ［１，２－ａ］ピリジン－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物６１）
（５７）５－（（３－（３－（（４－ヘキシルピペラジン－１－イル）メチル）フェニル）イミダゾ［１，２－ａ］ピリジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物６２）
（５８）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物６３）
（５９）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物６４）
（６０）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）－３Ｈ－イミダゾ［４，５－ｂ］ピリジン－５－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物６５） (52) 5-((3- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidine- 4-one (compound 57)
(53) 5-((3- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione (Compound 58)
(54) 5-((3- (3-((4-Butylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidine- 4-one (compound 59)
(55) 5-((3- (3-((4-Butylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione (Compound 60)
(56) 5-((3- (3-((4-Hexylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidine- 4-one (compound 61)
(57) 5-((3- (3-((4-Hexylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione (Compound 62)
(58) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidine-4-one (Compound 63)
(59) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 64 )
(60) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thioxothiazolidine- 4-one (compound 65)

（６１）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）－３Ｈ－イミダゾ［４，５－ｂ］ピリジン－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物６６）
（６２）５－（（１－（４－（ピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物６７）
（６３）５－（（１－（４－（４－メチルピペリジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物６８）
（６４）５－（（１－（４－（４－メチルピペリジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物６９）
（６５）５－（（１－（４－（３－（ジメチルアミノ）プロプ－１－イン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物７０）
（６６）５－（（１－（４－（３－（ジメチルアミノ）プロプ－１－イン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物７１）
（６７）５－（（１－（４－（３－（ジメチルアミノ）プロピル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物７２） (61) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 66)
(62) 5-((1- (4- (piperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 67)
(63) 5-((1- (4- (4-Methylpiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one ( Compound 68)
(64) 5-((1- (4- (4-Methylpiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 69)
(65) 5-((1- (4- (3- (Dimethylamino) prop-1-in-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thio Oxothiazolidine-4-one (Compound 70)
(66) 5-((1- (4- (3- (Dimethylamino) prop-1-in-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2, 4-dione (compound 71)
(67) 5-((1- (4- (3- (dimethylamino) propyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (compound 72)

（６８）５－（（１－（４－（６－（４－メチルピペラジン－１－イル）ヘキシ－１－イン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物７３）
（６９）５－（（１－（４－（６－（４－メチルピペラジン－１－イル）ヘキシ－１－イン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物７４）
（７０）５－（（１－（３－（２－（４－エチルピペラジン－１－イル）エトキシ）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物７５）
（７１）５－（（１－（３－（２－（４－エチルピペラジン－１－イル）エトキシ）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物７６）
（７２）５－（（１－（４－（４－エチルピペラジン－１－イル）－２－（トリフルオロメトキシ）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物７７）
（７３）５－（（１－（４－（４－エチルピペラジン－１－イル）－２－（トリフルオロメトキシ）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物７８）
（７４）５－（（１－（４－（４－エチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－イミノチアゾリジン－４－オン（化合物７９） (68) 5-((1- (4- (6- (4-Methylpiperazin-1-yl) hex-1-in-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) Methylene) -2-thioxothiazolidin-4-one (Compound 73)
(69) 5-((1- (4- (6- (4-Methylpiperazin-1-yl) hex-1-in-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) Methylene) thiazolidine-2,4-dione (compound 74)
(70) 5-((1- (3- (2- (4-Ethylpiperazin-1-yl) ethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4- Dione (Compound 75)
(71) 5-((1- (3- (2- (4-Ethylpiperazin-1-yl) ethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine -4-one (compound 76)
(72) 5-((1- (4- (4-Ethylpiperazin-1-yl) -2- (trifluoromethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2 , 4-Dione (Compound 77)
(73) 5-((1- (4- (4-Ethylpiperazin-1-yl) -2- (trifluoromethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2- Thioxothiazolidin-4-one (Compound 78)
(74) 5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-iminothiazolidine-4-one (compound 79)

（７５）５－（（３－（３－（（４－メチルピペリジン－１－イル）メチル）フェニル）イミダゾ［１，２－ａ］ピリジン－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物８０）
（７６）５－（（３－（３－（（４－アセチルピペラジン－１－イル）メチル）フェニル）イミダゾ［１，２－ａ］ピリジン－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物８１）
（７７）５－（（３－（３－（（４－アセチルピペラジン－１－イル）メチル）フェニル）イミダゾ［１，２－ａ］ピリジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物８２）
（７８）５－（（３－（３－（（４－ヒドロキシピペリジン－１－イル）メチル）フェニル）イミダゾ［１，２－ａ］ピリジン－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物８３）
（７９）５－（（３－（３－（（４－ヒドロキシピペリジン－１－イル）メチル）フェニル）イミダゾ［１，２－ａ］ピリジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物８４）
（８０）５－（（３－（２－フルオロ－４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物８５）
（８１）５－（（３－（３－フルオロ－４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物８６）
（８２）５－（（３－（３－フルオロ－４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物８７） (75) 5-((3- (3-((4-Methylpiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidine- 4-one (compound 80)
(76) 5-((3- (3-((4-acetylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidine- 4-one (compound 81)
(77) 5-((3- (3-((4-acetylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione (Compound 82)
(78) 5-((3- (3-((4-hydroxypiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidine- 4-one (compound 83)
(79) 5-((3- (3-((4-hydroxypiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione (Compound 84)
(80) 5-((3- (2-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 85)
(81) 5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidine -4-one (compound 86)
(82) 5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 87)

（８３）５－（（３－（４－（４－エチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物８８）
（８４）３－メチル－５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物８９）
（８５）５－（（３－（３－（（４－ヘキシルピペラジン－１－イル）メチル）フェニル）－３Ｈ－イミダゾ［４，５－ｂ］ピリジン－５－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物９０）
（８６）５－（（３－（３－（（４－エチルピペラジン－１－イル）メチル）フェニル）－３Ｈ－イミダゾ［４，５－ｂ］ピリジン－５－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物９１）
（８７）５－（（３－（３－（（４－エチルピペラジン－１－イル）メチル）フェニル）－３Ｈ－イミダゾ［４，５－ｂ］ピリジン－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物９２） (83) 5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 88) )
(84) 3-methyl-5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 89)
(85) 5-((3- (3-((4-Hexylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thio Oxothiazolidine-4-one (Compound 90)
(86) 5-((3- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thio Oxothiazolidine-4-one (Compound 91)
(87) 5-((3- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2, 4-dione (compound 92)

（８８）５－（（３－（３－（（４－ブチルピペラジン－１－イル）メチル）フェニル）－３Ｈ－イミダゾ［４，５－ｂ］ピリジン－５－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物９３）
（８９）５－（（３－（３－（（４－ブチルピペラジン－１－イル）メチル）フェニル）－３Ｈ－イミダゾ［４，５－ｂ］ピリジン－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物９４）
（９０）５－（（３－（３－フルオロ－４－（４－メチルピペラジン－１－イル）フェニル）－３Ｈ－イミダゾ［４，５－ｂ］ピリジン－５－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物９５）
（９１）５－（（３－（３－フルオロ－４－（４－メチルピペラジン－１－イル）フェニル）－３Ｈ－イミダゾ［４，５－ｂ］ピリジン－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物９６）
（９２）５－（（３－（３－（（１－メチルピペリジン－４－イル）メチル）フェニル）－３Ｈ－イミダゾ［４，５－ｂ］ピリジン－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物９７）
（９３）５－（（３－（３－（４－メチルピペラジン－１－カルボニル）フェニル）－３Ｈ－イミダゾ［４，５－ｂ］ピリジン－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物９８）
（９４）５－（（３－（３－（４－シクロヘキシルピペラジン－１－カルボニル）フェニル）－３Ｈ－イミダゾ［４，５－ｂ］ピリジン－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物９９）
（９５）５－（（３－（２－フルオロ－４－（４－メチルピペラジン－１－イル）フェニル）－３Ｈ－イミダゾ［４，５－ｂ］ピリジン－５－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１００）
（９６）５－（（３－（２－フルオロ－４－（４－メチルピペラジン－１－イル）フェニル）－３Ｈ－イミダゾ［４，５－ｂ］ピリジン－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１０１） (88) 5-((3- (3-((4-Butylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thio Oxothiazolidine-4-one (Compound 93)
(89) 5-((3- (3-((4-Butylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2, 4-dione (compound 94)
(90) 5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2- Thioxothiazolidin-4-one (Compound 95)
(91) 5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2 , 4-Dione (Compound 96)
(92) 5-((3- (3-((1-methylpiperidin-4-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2, 4-dione (compound 97)
(93) 5-((3- (3- (4-Methylpiperazine-1-carbonyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 98)
(94) 5-((3- (3- (4-cyclohexylpiperazine-1-carbonyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 99)
(95) 5-((3- (2-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2- Thioxothiazolidin-4-one (Compound 100)
(96) 5-((3- (2-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2 , 4-Dione (Compound 101)

（９７）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）－３Ｈ－［１，２，３］トリアゾロ［４，５－ｂ］ピリジン－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１０２）
（９８）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）－１Ｈ－インドール－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１０３）
（９９）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）フロ［２，３－ｃ］ピリジン－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１０４）
（１００）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）フロ［２，３－ｂ］ピリジン－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１０５）
（１０１）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）フロ［３，２－ｂ］ピリジン－５－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１０６）
（１０２）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）フロ［３，２－ｂ］ピリジン－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１０７）
（１０３）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）ベンゾフラン－５－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１０８）
（１０４）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）ベンゾフラン－５－イル）メチレン ）チアゾリジン－２，４－ジオン（化合物１０９）
（１０５）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）ベンゾ［ｂ］チオフェン－５－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１１０）
（１０６）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）ベンゾ［ｂ］チオフェン－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１１１） (97) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridin-5-yl) methylene) Thiazolidine-2,4-dione (Compound 102)
(98) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-indol-5-yl) methylene) thiazolidine-2,4-dione (Compound 103)
(99) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [2,3-c] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 104 )
(100) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [2,3-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 105 )
(101) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridin-5-yl) methylene) -2-thioxothiazolidine-4-one (Compound 106)
(102) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 107 )
(103) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzofuran-5-yl) methylene) -2-thioxothiazolidin-4-one (Compound 108)
(104) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzofuran-5-yl) methylene) thiazolidine-2,4-dione (Compound 109)
(105) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzo [b] thiophen-5-yl) methylene) -2-thioxothiazolidin-4-one (Compound 110)
(106) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzo [b] thiophen-5-yl) methylene) thiazolidine-2,4-dione (Compound 111)

（１０７）５－（（１－（４－（４－メチルピペラジン－１－イル）フェニル）－１Ｈ－イミダゾ［４，５－ｃ］ピリジン－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１１２）
（１０８）５－（（１－（４－（４－メチルピペラジン－１－イル）フェニル）－１Ｈ－イミダゾ［４，５－ｃ］ピリジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１１３）
（１０９）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）－［１，２，４］トリアゾロ［４，３－ａ］ピリジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１１４）
（１１０）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）ベンゾ［ｄ］イソチアゾール－５－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１１５）
（１１１）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）ベンゾ［ｄ］イソチアゾール－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１１６）
（１１２）５－（（１－（４－（４－エチルピペラジン－１－イル）フェニル）－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１１７）
（１１３）５－（（３－（４－（４－エチルピペラジン－１－イル）－３，５－ジフルオロフェニル）－３Ｈ－［１，２，３］トリアゾロ［４，５－ｂ］ピリジン－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１２２）
（１１４）５－（（３－（３－クロロ－４－（４－プロピルピペラジン－１－イル）フェニル）－３Ｈ－［１，２，３］トリアゾロ［４，５－ｂ］ピリジン－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１２３） (107) 5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-imidazo [4,5-c] pyridin-6-yl) methylene) -2-thioxothiazolidine- 4-one (compound 112)
(108) 5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-imidazo [4,5-c] pyridin-6-yl) methylene) thiazolidine-2,4-dione (Compound 113)
(109) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl)-[1,2,4] triazolo [4,3-a] pyridin-6-yl) methylene) thiazolidine- 2,4-dione (compound 114)
(110) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzo [d] isothiazol-5-yl) methylene) -2-thioxothiazolidine-4-one (Compound 115 )
(111) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzo [d] isothiazol-5-yl) methylene) thiazolidine-2,4-dione (Compound 116)
(112) 5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-pyrazolo [3,4-b] pyridin-6-yl) methylene) thiazolidine-2,4-dione (Compound 117)
(113) 5-((3- (4- (4-Ethylpiperazin-1-yl) -3,5-difluorophenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine- 5-yl) methylene) thiazolidine-2,4-dione (Compound 122)
(114) 5-((3- (3-Chloro-4- (4-propylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine-5- Yl) methylene) thiazolidine-2,4-dione (Compound 123)

（１１５）５－（（３－（４－（４－エチルピペラジン－１－イル）フェニル）－３Ｈ－［１，２，３］トリアゾロ［４，５－ｂ］ピリジン－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１２４）
（１１６）５－（（３－（４－（４－エチルピペラジン－１－イル）フェニル）－３Ｈ－［１，２，３］トリアゾロ［４，５－ｂ］ピリジン－５－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１２５）
（１１７）５－（（１－（４－（４－メチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１２６）
（１１８）５－（（１－（４－（４－メチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１２７）
（１１９）５－（（３－（４－（４－メチルピペラジン－１－イル）－フェニル）ピラゾロ［１，５－ａ］ピリミジン－５－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１２８）
（１２０）５－（（３－（４－（４－メチルピペラジン－１－イル）－フェニル）ピラゾロ［１，５－ａ］ピリミジン－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１２９）
（１２１）５－（（１－（３－クロロ－４－（４－エチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１３０）
（１２２）５－（（３－（３－メトキシ－４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１３１）
（１２３）５－（（３－（３－フルオロ－５－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１３２） (115) 5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridin-5-yl) methylene) Thiazolidine-2,4-dione (Compound 124)
(116) 5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridin-5-yl) methylene) -2-Thioxothiazolidin-4-one (Compound 125)
(117) 5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] [1,2,3] triazol-6-yl) methylene) -2-thio Oxothiazolidin-4-one (Compound 126)
(118) 5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] [1,2,3] triazol-6-yl) methylene) thiazolidine-2, 4-dione (compound 127)
(119) 5-((3- (4- (4-Methylpiperazin-1-yl) -phenyl) pyrazolo [1,5-a] pyrimidin-5-yl) methylene) -2-thioxothiazolidine-4- ON (compound 128)
(120) 5-((3- (4- (4-Methylpiperazin-1-yl) -phenyl) pyrazolo [1,5-a] pyrimidin-5-yl) methylene) thiazolidine-2,4-dione (compound 129)
(121) 5-((1- (3-Chloro-4- (4-ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 130)
(122) 5-((3- (3-Methoxy-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 131)
(123) 5-((3- (3-Fluoro-5- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 132)

（１２４）５－（（３－（３－メチル－４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１３３）
（１２５）５－（（３－（３－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１３４）
（１２６）５－（（３－（３－（２－モルホリノエチル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１３５）
（１２７）５－（（３－（３－（２－モルホリノエチル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１３６）
（１２８）５－（（３－（４－（４－メチルピペラジン－１－イル）－３－（トリフルオロメチル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１３７）
（１２９）５－（（３－（３－（（１－メチルピペリジン－４－イル）オキシ）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１３８）
（１３０）５－（（３－（３－フルオロ－４－（４－イソプロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１３９）
（１３１）５－（（３－（３－フルオロ－４－（４－プロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１４０） (124) 5-((3- (3-Methyl-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 133)
(125) 5-((3- (3- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 134 )
(126) 5-((3- (3- (2-morpholinoethyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 135)
(127) 5-((3- (3- (2-morpholinoethyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 136)
(128) 5-((3- (4- (4-Methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine- 2,4-dione (compound 137)
(129) 5-((3- (3-((1-methylpiperidin-4-yl) oxy) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 138)
(130) 5-((3- (3-Fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 139)
(131) 5-((3- (3-Fluoro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 140)

（１３２）５－（（３－（３－フルオロ－４－（４－ペンチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１４１）
（１３３）５－（（３－（４－（４－デシルピペラジン－１－イル）－３－フルオロフェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１４２）
（１３４）５－（（３－（３－（（（１－メチルピペリジン－４－イル）オキシ）メチル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１４３）
（１３５）５－（（３－（３－（４－エチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１４４）
（１３６）５－（（３－（３－（４－プロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１４５）
（１３７）５－（（３－（３－（４－イソブチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１４６）
（１３８）５－（（３－（４－（４－ブチルピペラジン－１－イル）－３－フルオロフェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１４７）
（１３９）５－（（３－（３－（（エチル（プロピル）アミノ）メチル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１４８）
（１４０）５－（（３－（３－（（１，１－ジオキシドチオモルホリノ）メチル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１４９）
（１４１）５－（（３－（３－フルオロ－４－（（３Ｒ，５Ｓ）－３，４，５－トリメチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１５０） (132) 5-((3- (3-Fluoro-4- (4-pentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 141)
(133) 5-((3- (4- (4-decylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 142)
(134) 5-((3- (3-(((1-methylpiperidin-4-yl) oxy) methyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2, 4-dione (compound 143)
(135) 5-((3- (3- (4-Ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 144 )
(136) 5-((3- (3- (4-Propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 145 )
(137) 5-((3- (3- (4-Isobutylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 146 )
(138) 5-((3- (4- (4-Butylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 147)
(139) 5-((3- (3-((Ethyl (propyl) amino) methyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 148 )
(140) 5-((3- (3-((1,1-dioxidethiomorpholino) methyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 149)
(141) 5-((3- (3-Fluoro-4-((3R, 5S) -3,4,5-trimethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6- Yl) methylene) thiazolidine-2,4-dione (compound 150)

（１４２）５－（６－（（２，４－ジオキソチアゾリジン－５－イリデン）メチル）イミダゾ［１，２－ｂ］ピリダジン－３－イル）－２－（４－メチルピペラジン－１－イル）ベンゾニトリル（化合物１５１）
（１４３）５－（（３－（３－（（１－メチルピペリジン－４－イル）メチル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１５２）
（１４４）５－（（３－（３－（ｔｅｒｔ－ブチル）－４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１５３）
（１４５）５－（（３－（２－（４－メチルピペラジン－１－イル）ピリミジン－５－イル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１５４）
（１４６）５－（（３－（４－（４－エチルピペラジン－１－イル）－３－フルオロフェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１５５）
（１４７）５－（（１－（４－（４－エチルピペラジン－１－イル）－３－フルオロフェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１５６）
（１４８）５－（（３－（４－（４－エチルピペラジン－１－イル）フェニル）－［１，２，４］トリアゾロ［４，３－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１５７）
（１４９）５－（（１－（４－（４－メチルピペラジン－１－イル）フェニル）－１Ｈ－インダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１５８） (142) 5- (6-((2,4-Dioxothiazolidine-5-ylidene) methyl) imidazo [1,2-b] pyridazin-3-yl) -2- (4-methylpiperazin-1-yl ) Benzonitrile (Compound 151)
(143) 5-((3- (3-((1-methylpiperidin-4-yl) methyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 152)
(144) 5-((3- (3- (tert-butyl) -4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine- 2,4-dione (compound 153)
(145) 5-((3- (2- (4-Methylpiperazin-1-yl) pyrimidin-5-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 154)
(146) 5-((3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 155)
(147) 5-((1- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 156)
(148) 5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl)-[1,2,4] triazolo [4,3-b] pyridazin-6-yl) methylene) thiazolidine- 2,4-dione (compound 157)
(149) 5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 158)

（１５０）５－（（１－（４－（４－メチルピペラジン－１－イル）フェニル）－１Ｈ－インダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１５９）
（１５１）５－（（３－（４－（４－プロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１６０）
（１５２）５－（（３－（４－（４－プロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１６１）
（１５３）５－（（３－（４－（４－デシルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１６２）
（１５４）５－（（３－（４－（４－デシルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１６３）
（１５５）５－（（３－（４－（４－（ｔｅｒｔ－ブチル）ピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１６４）
（１５６）５－（（３－（４－（４－（ｔｅｒｔ－ブチル）ピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１６５）
（１５７）５－（（３－（４－（４－ブチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１６６） (150) 5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 159)
(151) 5-((3- (4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidine-4-one (Compound 160)
(152) 5-((3- (4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 161 )
(153) 5-((3- (4- (4-decylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidine-4-one (Compound 162)
(154) 5-((3- (4- (4-decylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 163 )
(155) 5-((3- (4- (4- (tert-butyl) piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidine -4-one (compound 164)
(156) 5-((3- (4- (4- (tert-butyl) piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 165)
(157) 5-((3- (4- (4-Butylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidine-4-one (Compound 166)

（１５８）５－（（３－（４－（４－ブチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１６７）
（１５９）５－（（３－（４－（４－イソプロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１６８）
（１６０）５－（（３－（４－（４－ペンチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１６９）
（１６１）５－（（３－（２－（４－メチルピペラジン－１－イル）ベンゾ［ｄ］チアゾール－６－イル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン（化合物１７０）
（１６２）５－（（３－（２－（４－メチルピペラジン－１－イル）ベンゾ［ｄ］チアゾール－６－イル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１７１）
（１６３）２－（４－（４－（６－（（２，４－ジオキソチアゾリジン－５－イリデン）メチル）イミダゾ［１，２－ｂ］ピリダジン－３－イル）フェニル）ピペラジン－１－イル）アセトニトリル（化合物１７２）
（１６４）５－（（３－（４－（４－シクロペンチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１７３）
（１６５）５－（（３－（４－（４－イソブチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１７４）
（１６６）２－（４－（４－（６－（（２，４－ジオキソチアゾリジン－５－イリデン）メチル）イミダゾ［１，２－ｂ］ピリダジン－３－イル）フェニル）ピペラジン－１－イル）エチル　アセテート（化合物１７５）
（１６７）５－（（３－（４－（４－（２－ヒドロキシエチル）ピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１７６）
（１６８）５－（（３－（２－（４－メチルピペラジン－１－イル）チアゾール－５－イル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１７７） (158) 5-((3- (4- (4-Butylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 167 )
(159) 5-((3- (4- (4-Isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 168 )
(160) 5-((3- (4- (4-Pentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 169 )
(161) 5-((3- (2- (4-Methylpiperazin-1-yl) benzo [d] thiazol-6-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2 -Thioxothiazolidin-4-one (Compound 170)
(162) 5-((3- (2- (4-Methylpiperazin-1-yl) benzo [d] thiazol-6-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine- 2,4-dione (compound 171)
(163) 2- (4- (4- (6-((2,4-Dioxothiazolidine-5-ylidene) methyl) imidazo [1,2-b] pyridazin-3-yl) phenyl) piperazine-1- Yl) acetonitrile (compound 172)
(164) 5-((3- (4- (4-Cyclopentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 173 )
(165) 5-((3- (4- (4-Isobutylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 174 )
(166) 2- (4- (4- (6-((2,4-Dioxothiazolidine-5-ylidene) methyl) imidazo [1,2-b] pyridazin-3-yl) phenyl) piperazine-1- Yl) ethyl acetate (compound 175)
(167) 5-((3- (4- (4- (2-hydroxyethyl) piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4 Dione (compound 176)
(168) 5-((3- (2- (4-Methylpiperazin-1-yl) thiazol-5-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 177)

（１６９）５－（（３－（３－メチル－４－（４－プロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１８３）
（１７０）５－（（３－（４－（４－イソプロピルピペラジン－１－イル）－３－メチルフェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１８４）
（１７１）５－（（３－（４－（４－エチルピペラジン－１－イル）－３－メチルフェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１８５）
（１７２）５－（（３－（４－（１－エチルピペリジン－４－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１８６）
（１７３）５－（（３－（５－（（４－メチルピペラジン－１－イル）メチル）チオフェン－２－イル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１８７）
（１７４）５－（（３－（４－（４－エチル－２，３－ジオキソピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１８８）
（１７５）５－（（３－（４－（４－メチル－２－オキソピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１８９）
（１７６）５－（（３－（６－（４－メチルピペラジン－１－イル）ベンゾ［ｄ］オキサゾール－２－イル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１９０）
（１７７）５－（（３－（５－（２－（ジメチルアミノ）エトキシ）チオフェン－２－イル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１９１） (169) 5-((3- (3-Methyl-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 183)
(170) 5-((3- (4- (4-Isopropylpiperazin-1-yl) -3-methylphenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 184)
(171) 5-((3- (4- (4-Ethylpiperazin-1-yl) -3-methylphenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 185)
(172) 5-((3- (4- (1-Ethylpiperidin-4-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 186 )
(173) 5-((3- (5-((4-Methylpiperazin-1-yl) methyl) thiophen-2-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2 , 4-Dione (Compound 187)
(174) 5-((3- (4- (4-Ethyl-2,3-dioxopiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2 , 4-dione (Compound 188)
(175) 5-((3- (4- (4-Methyl-2-oxopiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 189)
(176) 5-((3- (6- (4-Methylpiperazin-1-yl) benzo [d] oxazol-2-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine- 2,4-dione (compound 190)
(177) 5-((3- (5- (2- (dimethylamino) ethoxy) thiophen-2-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 191)

（１７８）５－（（３－（４－（４－シクロペンチルピペラジン－１－イル）－３－フルオロフェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１９２）
（１７９）５－（（３－（３－クロロ－４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１９３）
（１８０）５－（（３－（３－クロロ－４－（４－イソプロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１９４）
（１８１）５－（（３－（３－クロロ－４－（４－エチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１９５）
（１８２）５－（（３－（３－クロロ－４－（４－プロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１９６）
（１８３）５－（（３－（３－クロロ－４－（４－シクロペンチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１９７）
（１８４）５－（（３－（４－（２－（ジメチルアミノ）エトキシ）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１９８） (178) 5-((3- (4- (4-Cyclopentylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 192)
(179) 5-((3- (3-Chloro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 193)
(180) 5-((3- (3-Chloro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 194)
(181) 5-((3- (3-Chloro-4- (4-ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 195)
(182) 5-((3- (3-Chloro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 196)
(183) 5-((3- (3-Chloro-4- (4-cyclopentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 197)
(184) 5-((3- (4- (2- (dimethylamino) ethoxy) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 198)

（１８５）５－（（３－（３－エチル－４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物２０１）
（１８６）５－（（３－（３－エチル－４－（４－エチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物２０２）
（１８７）５－（（３－（３－エチル－４－（４－プロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物２０３）
（１８８）５－（（３－（３－エチル－４－（４－イソプロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物２０４） (185) 5-((3- (3-Ethyl-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 201)
(186) 5-((3- (3-Ethyl-4- (4-ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 202)
(187) 5-((3- (3-Ethyl-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 203)
(188) 5-((3- (3-Ethyl-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 204)

　また、これらの化合物のうち、さらに好ましい化合物は次のとおりである。
（３）５－（（１－（４－（４－メチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物４）
（１０）５－（（１－（４－（４－エチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１４）
（５９）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物６４）
（６１）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）－３Ｈ－イミダゾ［４，５－ｂ］ピリジン－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物６６）
（８０）５－（（３－（２－フルオロ－４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物８５）
（８２）５－（（３－（３－フルオロ－４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物８７）
（８３）５－（（３－（４－（４－エチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物８８）
（９１）５－（（３－（３－フルオロ－４－（４－メチルピペラジン－１－イル）フェニル）－３Ｈ－イミダゾ［４，５－ｂ］ピリジン－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物９６）
（９６）５－（（３－（２－フルオロ－４－（４－メチルピペラジン－１－イル）フェニル）－３Ｈ－イミダゾ［４，５－ｂ］ピリジン－５－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１０１）
（１２１）５－（（１－（３－クロロ－４－（４－エチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１３０）
（１２３）５－（（３－（３－フルオロ－５－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１３２）
（１２５）５－（（３－（３－メチル－４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１３３）
（１２５）５－（（３－（３－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１３４）
（１２８）５－（（３－（４－（４－メチルピペラジン－１－イル）－３－（トリフルオロメチル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１３７）
（１３０）５－（（３－（３－フルオロ－４－（４－イソプロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１３９）
（１３１）５－（（３－（３－フルオロ－４－（４－プロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１４０）
（１３２）５－（（３－（３－フルオロ－４－（４－ペンチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１４１）
（１３５）５－（（３－（３－（４－エチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１４４）
（１３６）５－（（３－（３－（４－プロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１４５）
（１３８）５－（（３－（４－（４－ブチルピペラジン－１－イル）－３－フルオロフェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１４７）
（１４６）５－（（３－（４－（４－エチルピペラジン－１－イル）－３－フルオロフェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１５５）
（１４７）５－（（１－（４－（４－エチルピペラジン－１－イル）－３－フルオロフェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１５６）
（１５２）５－（（３－（４－（４－プロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１６１） Of these compounds, the more preferred compounds are as follows.
(3) 5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 4)
(10) 5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 14)
(59) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 64 )
(61) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 66)
(80) 5-((3- (2-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 85)
(82) 5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 87)
(83) 5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 88) )
(91) 5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2 , 4-Dione (Compound 96)
(96) 5-((3- (2-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2 , 4-Dione (Compound 101)
(121) 5-((1- (3-Chloro-4- (4-ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 130)
(123) 5-((3- (3-Fluoro-5- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 132)
(125) 5-((3- (3-Methyl-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 133)
(125) 5-((3- (3- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 134 )
(128) 5-((3- (4- (4-Methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine- 2,4-dione (compound 137)
(130) 5-((3- (3-Fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 139)
(131) 5-((3- (3-Fluoro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 140)
(132) 5-((3- (3-Fluoro-4- (4-pentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 141)
(135) 5-((3- (3- (4-Ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 144 )
(136) 5-((3- (3- (4-Propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 145 )
(138) 5-((3- (4- (4-Butylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 147)
(146) 5-((3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 155)
(147) 5-((1- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 156)
(152) 5-((3- (4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 161 )

（１５８）５－（（３－（４－（４－ブチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１６７）
（１５９）５－（（３－（４－（４－イソプロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１６８）
（１６０）５－（（３－（４－（４－ペンチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１６９）
（１６４）５－（（３－（４－（４－シクロペンチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１７３）
（１６８）５－（（３－（２－（４－メチルピペラジン－１－イル）チアゾール－５－イル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１７７）
（１６９）５－（（３－（３－メチル－４－（４－プロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１８３） (158) 5-((3- (4- (4-Butylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 167 )
(159) 5-((3- (4- (4-Isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 168 )
(160) 5-((3- (4- (4-Pentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 169 )
(164) 5-((3- (4- (4-Cyclopentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 173 )
(168) 5-((3- (2- (4-Methylpiperazin-1-yl) thiazol-5-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 177)
(169) 5-((3- (3-Methyl-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 183)

（１７０）５－（（３－（４－（４－イソプロピルピペラジン－１－イル）－３－メチルフェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１８４）
（１７１）５－（（３－（４－（４－エチルピペラジン－１－イル）－３－メチルフェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１８５）
（１７８）５－（（３－（４－（４－シクロペンチルピペラジン－１－イル）－３－フルオロフェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１９２）
（１７９）５－（（３－（３－クロロ－４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１９３）
（１８０）５－（（３－（３－クロロ－４－（４－イソプロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１９４）
（１８１）５－（（３－（３－クロロ－４－（４－エチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１９５）
（１８２）５－（（３－（３－クロロ－４－（４－プロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１９６）
（１８３）５－（（３－（３－クロロ－４－（４－シクロペンチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１９７） (170) 5-((3- (4- (4-Isopropylpiperazin-1-yl) -3-methylphenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 184)
(171) 5-((3- (4- (4-Ethylpiperazin-1-yl) -3-methylphenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 185)
(178) 5-((3- (4- (4-Cyclopentylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 192)
(179) 5-((3- (3-Chloro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 193)
(180) 5-((3- (3-Chloro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 194)
(181) 5-((3- (3-Chloro-4- (4-ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 195)
(182) 5-((3- (3-Chloro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 196)
(183) 5-((3- (3-Chloro-4- (4-cyclopentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 197)

　また、上記化合物のうち、特に好ましい化合物は以下のとおりである。
（３）５－（（１－（４－（４－メチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物４）
（１０）５－（（１－（４－（４－エチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１４）
（５９）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物６４）
（８２）５－（（３－（３－フルオロ－４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物８７）
（８３）５－（（３－（４－（４－エチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物８８）
（１２５）５－（（３－（３－メチル－４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１３３）
（１３０）５－（（３－（３－フルオロ－４－（４－イソプロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１３９）
（１３１）５－（（３－（３－フルオロ－４－（４－プロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１４０）
（１４６）５－（（３－（４－（４－エチルピペラジン－１－イル）－３－フルオロフェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１５５）
（１５２）５－（（３－（４－（４－プロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１６１） Of the above compounds, particularly preferred compounds are as follows.
(3) 5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 4)
(10) 5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 14)
(59) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 64 )
(82) 5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 87)
(83) 5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 88) )
(125) 5-((3- (3-Methyl-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 133)
(130) 5-((3- (3-Fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 139)
(131) 5-((3- (3-Fluoro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 140)
(146) 5-((3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 155)
(152) 5-((3- (4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 161 )

（１５９）５－（（３－（４－（４－イソプロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１６８）
（１６９）５－（（３－（３－メチル－４－（４－プロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１８３）
（１７０）５－（（３－（４－（４－イソプロピルピペラジン－１－イル）－３－メチルフェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１８４）
（１７１）５－（（３－（４－（４－エチルピペラジン－１－イル）－３－メチルフェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン（化合物１８５） (159) 5-((3- (4- (4-Isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 168 )
(169) 5-((3- (3-Methyl-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 183)
(170) 5-((3- (4- (4-Isopropylpiperazin-1-yl) -3-methylphenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 184)
(171) 5-((3- (4- (4-Ethylpiperazin-1-yl) -3-methylphenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 185)

　本発明化合物（１）の塩としては、塩酸、硫酸、硝酸等の無機酸塩、酢酸、クエン酸、フマル酸、シュウ酸、酒石酸、メタンスルホン酸、パラトルエンスルホン酸等の有機酸塩が挙げられ、塩酸、メタンスルホン酸、硫酸が好ましい。また、具体例としては、以下の化合物が挙げられる。
（１８９）５－（（１－（４－（４－メチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン　ハイドロクロライド（化合物８）
（１９０）５－（（１－（４－（４－メチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）－２－チオキソチアゾリジン－４－オン　メタンスルホナート（化合物９）
（１９１）５－（（１－（４－（４－メチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン　メタンスルホナート（化合物１０）
（１９２）５－（（１－（４－（４－エチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン　ハイドロクロライド（化合物１１８）
（１９３）５－（（１－（４－（４－エチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン　ビス（サルフェート）（化合物１１９）
（１９４）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン　メタンスルホナート（化合物１２０）
（１９５）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン　ハイドロクロライド（化合物１２１）
（１９６）５－（（３－（３－フルオロ－４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン　メタンスルホナート（化合物１７８）
（１９７）５－（（３－（４－（４－エチルピペラジン－１－イル）－３－フルオロフェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン　メタンスルホンナート（化合物１７９） Examples of the salt of the compound (1) of the present invention include inorganic acid salts such as hydrochloric acid, sulfuric acid and nitric acid, and organic acid salts such as acetic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, methanesulfonic acid and paratoluenesulfonic acid. Hydrochloric acid, methanesulfonic acid and sulfuric acid are preferred. Specific examples include the following compounds.
(189) 5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one hydro Chloride (Compound 8)
(190) 5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one methane Sulfonate (Compound 9)
(191) 5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione methanesulfonate ( Compound 10)
(192) 5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione hydrochloride (compound 118)
(193) 5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione bis (sulfate) (Compound 119)
(194) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione methanesulfonate (Compound 120)
(195) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione hydrochloride ( Compound 121)
(196) 5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione methanesulfonate (Compound 178)
(197) 5-((3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione methanesulfonate (Compound 179)

（１９８）５－（（３－（４－（４－エチルピペラジン－１－イル）－３－フルオロフェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン　ハイドロクロライド（化合物１８０）
（１９９）５－（（３－（４－（４－エチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン　メタンスルホナート（化合１８１）
（２００）５－（（１－（４－（４－エチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン　メタンスルホナート（化合物１８２）
（２０１）５－（（３－（３－フルオロ－４－（４－イソプロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン　メタンスルホンナート（化合物１９９）
（２０２）５－（（３－（３－フルオロ－４－（４－プロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン　メタンスルホンナート（化合物２００） (198) 5-((3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione hydrochloride (compound 180)
(199) 5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione methanesulfonate (Compound 181)
(200) 5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione methanesulfonate ( Compound 182)
(201) 5-((3- (3-Fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione methanesulfonate (Compound 199)
(202) 5-((3- (3-Fluoro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione methanesulfonate (compound 200)

　また、これらの化合物のうち、さらに好ましい化合物は次のとおりである。
（１９１）５－（（１－（４－（４－メチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン　メタンスルホナート（化合物１０）
（１９２）５－（（１－（４－（４－エチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン　ハイドロクロライド（化合物１１８）（１９３）５－（（１－（４－（４－エチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン　ビス（サルフェート）（化合物１１９）
（１９４）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン　メタンスルホナート（化合物１２０）
（１９５）５－（（３－（４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン　ハイドロクロライド（化合物１２１）
（１９６）５－（（３－（３－フルオロ－４－（４－メチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン　メタンスルホナート（化合物１７８）
（１９７）５－（（３－（４－（４－エチルピペラジン－１－イル）－３－フルオロフェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン　メタンスルホンナート（化合物１７９）
（１９８）５－（（３－（４－（４－エチルピペラジン－１－イル）－３－フルオロフェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン　ハイドロクロライド（化合物１８０）
（１９９）５－（（３－（４－（４－エチルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン　メタンスルホナート（化合１８１）
（２００）５－（（１－（４－（４－エチルピペラジン－１－イル）フェニル）－１Ｈ－ベンゾ［ｄ］イミダゾール－６－イル）メチレン）チアゾリジン－２，４－ジオン　メタンスルホナート（化合物１８２）
（２０１）５－（（３－（３－フルオロ－４－（４－イソプロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン　メタンスルホンナート（化合物１９９）
（２０２）５－（（３－（３－フルオロ－４－（４－プロピルピペラジン－１－イル）フェニル）イミダゾ［１，２－ｂ］ピリダジン－６－イル）メチレン）チアゾリジン－２，４－ジオン　メタンスルホンナート（化合物２００） Of these compounds, the more preferred compounds are as follows.
(191) 5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione methanesulfonate ( Compound 10)
(192) 5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione hydrochloride (compound 118) (193) 5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione bis ( Sulfate) (Compound 119)
(194) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione methanesulfonate (Compound 120)
(195) 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione hydrochloride ( Compound 121)
(196) 5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione methanesulfonate (Compound 178)
(197) 5-((3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione methanesulfonate (Compound 179)
(198) 5-((3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione hydrochloride (compound 180)
(199) 5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione methanesulfonate (Compound 181)
(200) 5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione methanesulfonate ( Compound 182)
(201) 5-((3- (3-Fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione methanesulfonate (Compound 199)
(202) 5-((3- (3-Fluoro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione methanesulfonate (compound 200)

　さらに、本発明化合物（１）又はその塩には水和物等の溶媒和物が含まれる。本発明化合物には、二重結合の存在により異性体があるが、Ｚ体、Ｅ体のいずれも含まれる。また、本発明化合物に不斉炭素原子が含まれる場合、それらの光学異性体及びラセミ体も含まれる。 Further, the compound (1) of the present invention or a salt thereof includes solvates such as hydrates. The compound of the present invention has an isomer due to the presence of a double bond, and includes both a Z-form and an E-form. Moreover, when an asymmetric carbon atom is contained in this invention compound, those optical isomers and a racemate are also contained.

　本発明化合物（１）は、例えば次の反応式に従って製造することができる。また、本発明化合物（１）の塩は、本発明化合物（１）より既知の方法により製造することができる。 The compound (1) of the present invention can be produced, for example, according to the following reaction formula. The salt of the compound (1) of the present invention can be produced from the compound (1) of the present invention by a known method.

Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009

（式中、Ｘ、Ｚ1～Ｚ8、Ｙ、Ａｍ、Ｒ1、Ｒ2及びＲ３は前記と同じ） (Wherein, X, Z 1 to Z 8 , Y, Am, R 1 , R 2 and R 3 are the same as above)

　すなわち、式（２）で表されるアルデヒドを式（３）で表される化合物とを反応させることにより、本発明化合物（１）が得られる。 That is, this invention compound (1) is obtained by making the aldehyde represented by Formula (2) react with the compound represented by Formula (3).

　アルデヒド（２）と化合物（３）との反応は、（Ａ）酢酸及び酢酸アンモニウムの存在下に反応させる方法、（Ｂ）ピペリジンやピロリジンの存在下に反応させる方法、（Ｃ）酢酸及びピペリジン存在下に反応させる方法により行うことができる。より詳細には、アルデヒド（２）と化合物（３）とを（Ａ）酢酸及び炭酸水素ナトリウムの存在下に加熱還流する方法；（Ｂ－１）ピペリジンの存在下にエタノール等のアルコール中で加熱還流する方法；（Ｂ－２）ピロリジンの存在下にエタノール等のアルコール、炭酸水素ナトリウム水溶液中で加熱還流する方法；（Ｃ）酢酸及びピペリジン存在下、アセトニトリル中で加熱還流する方法により本発明化合物（１）を製造することができる。 The reaction of aldehyde (2) with compound (3) includes (A) a reaction in the presence of acetic acid and ammonium acetate, (B) a reaction in the presence of piperidine and pyrrolidine, (C) presence of acetic acid and piperidine. It can carry out by the method of making it react below. More specifically, aldehyde (2) and compound (3) are heated and refluxed in the presence of (A) acetic acid and sodium bicarbonate; (B-1) heated in an alcohol such as ethanol in the presence of piperidine. A method of refluxing; (B-2) a method of heating and refluxing in an alcohol such as ethanol and an aqueous sodium hydrogen carbonate solution in the presence of pyrrolidine; and (C) a compound of the present invention by heating and refluxing in acetonitrile in the presence of acetic acid and piperidine. (1) can be manufactured.

　ここで（Ａ）法は、例えば酢酸中、化合物（３）に対して、０．８～１．２等量のアルデヒド（２）及び２．５等量の酢酸アンモニウムを用い、１００℃で１８時間加熱還流するのが好ましい。また（Ｂ）法は、化合物（３）に対して、０．８～１．２等量のアルデヒド（２）及び０．２～０．５等量のピペリジン又はピロリジンを用い、７０℃で２０時間加熱還流するのが好ましい。また（Ｃ）法は、化合物（３）に対して、０．８～１．２等量のアルデヒド（２）及び０．０５～０．５等量のピペリジン及び０．０５～０．５等量の酢酸を用い、還流条件で２０時間加熱還流するのが好ましい。 Here, the method (A) uses, for example, 0.8 to 1.2 equivalents of aldehyde (2) and 2.5 equivalents of ammonium acetate with respect to compound (3) in acetic acid at 100 ° C. for 18 It is preferable to heat to reflux for a period of time. In the method (B), 0.8 to 1.2 equivalents of aldehyde (2) and 0.2 to 0.5 equivalents of piperidine or pyrrolidine are used with respect to compound (3) at 70 ° C. for 20 hours. It is preferable to heat to reflux for a period of time. The method (C) is based on 0.8 to 1.2 equivalents of aldehyde (2), 0.05 to 0.5 equivalents of piperidine and 0.05 to 0.5 equivalents relative to compound (3). It is preferable to heat and reflux for 20 hours under reflux conditions using an amount of acetic acid.

　また原料であるアルデヒド（２）は、公知の手段によって製造することができる。（Ａ－１）の構造を有するアルデヒド（２ａ）は、例えば次の式に従って合成することができる。 Also, the raw material aldehyde (2) can be produced by known means. The aldehyde (2a) having the structure (A-1) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010

（式中、Ｙ、Ａｍは前記と同じ） (Wherein Y and Am are the same as above)

　化合物（４）とＮ,Ｏ-ジメチルヒドロキシルアミンとを反応させて化合物（５）を得、次いで化合物（５）とアミン化合物（Ｈ２Ｎ－Ｙ－Ａｍ）とを反応させて化合物（６）とする。化合物（６）のニトロ基を還元した後、環化反応により化合物（８）が得られる。化合物（８）のアミド部位を変換することでアルデヒド（２ａ）が得られる。 Compound (4) is reacted with N, O-dimethylhydroxylamine to obtain compound (5), and then compound (5) is reacted with amine compound (H 2 N—Y-Am) to obtain compound (6). And After reducing the nitro group of compound (6), compound (8) is obtained by cyclization reaction. Aldehyde (2a) is obtained by converting the amide moiety of compound (8).

　化合物（４）から化合物（５）への反応は、例えば、まず化合物（４）にオキサリルクロリド等を反応させて対応する酸クロリドとした後、ジメチルヒドロキシルアミンと反応させることにより行われる。 The reaction from compound (4) to compound (5) is carried out, for example, by first reacting compound (4) with oxalyl chloride or the like to give the corresponding acid chloride and then reacting with dimethylhydroxylamine.

　化合物（５）とアミン化合物（Ｈ２Ｎ－Ｙ－Ａｍ）との反応は、塩基の存在下で加熱することにより行われる。塩基としては炭酸カリウム、Ｎ，Ｎ－ジイソプロピルエチルアミン等が用いられる。反応溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチル－２－ピロリドン等を用いることが好ましい。反応は約８０℃－１００℃で１２時間程度行えばよい。 The reaction between the compound (5) and the amine compound (H 2 N—Y—Am) is carried out by heating in the presence of a base. As the base, potassium carbonate, N, N-diisopropylethylamine or the like is used. As the reaction solvent, N, N-dimethylformamide, N-methyl-2-pyrrolidone or the like is preferably used. The reaction may be performed at about 80 ° C.-100 ° C. for about 12 hours.

　化合物（６）の還元反応は、例えばパラジウム－活性炭や白金－活性炭などの触媒存在下、接触水素添加反応により行われる。また、鉄粉と塩化アンモニウムを用いて加熱してもよく、塩化すず、酢酸アンモニウム存在下、加熱してもよい。 The reduction reaction of the compound (6) is carried out by a catalytic hydrogenation reaction in the presence of a catalyst such as palladium-activated carbon or platinum-activated carbon. Moreover, you may heat using iron powder and ammonium chloride, and you may heat in the presence of tin chloride and ammonium acetate.

　化合物（７）の環化反応は、酸触媒の存在下にオルトギ酸トリエチル等を反応させることにより行われる。酸触媒としては塩酸、酢酸、パラトルエンスルホン酸、パラトルエンスルホン酸ピリジニウム等が用いられる。 The cyclization reaction of the compound (7) is performed by reacting triethyl orthoformate or the like in the presence of an acid catalyst. As the acid catalyst, hydrochloric acid, acetic acid, paratoluenesulfonic acid, pyridinium paratoluenesulfonate, or the like is used.

　化合物（８）からアルデヒド（２ａ）への反応は、化合物（８）にビスシクロペンタジエニルジルコニウム（ＩＶ）クロリドヒドリドや水素化アルミニウムリチウム等を反応させることにより行われる。 The reaction from the compound (8) to the aldehyde (2a) is carried out by reacting the compound (8) with biscyclopentadienylzirconium (IV) chloride hydride, lithium aluminum hydride or the like.

　また、アルデヒド（２ａ）は、次の反応式に従って合成することもできる。 The aldehyde (2a) can also be synthesized according to the following reaction formula.

Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011

（式中、Ｗはハロゲン原子、ヒドロキシ基、保護されたヒドロキシ基や保護されたヒドロキシアルキル基、アルコキシカルボニル基、ホルミル基、ホルミルアルキル基等の官能基を示し、Ｙ、Ａｍは前記と同じ） (W is a functional group such as a halogen atom, a hydroxy group, a protected hydroxy group, a protected hydroxyalkyl group, an alkoxycarbonyl group, a formyl group, a formylalkyl group, and Y and Am are the same as above)

　化合物（５）をアミン化合物 (Ｈ２Ｎ－Ｙ－Ｗ) と前記化合物（５）から化合物（６）への反応と同様に反応させて化合物（９）とする。化合物（９）に対し、前記化合物（６）から化合物（８）への反応と同様の反応を行うことにより化合物（１１）が得られる。また、化合物（１１）に対し、前記化合物（８）からアルデヒド（２ａ）への反応と同様の反応を行うことにより化合物（１２）が得られる。化合物（１２）にＡｍの導入を行いアルデヒド（２ａ）が得られる。また、化合物（１２）のホルミル基をアセタール保護して化合物（１３）とし、次いでＡｍを反応させて化合物（１４）を得、化合物（１４）のアセタール基を脱保護することによってもアルデヒド（２ａ)が得られる。さらに、化合物（１１)にＡｍの導入を行うことで化合物（１５）を得、次いで化合物（１５）のアミド部位を前記化合物（８）からアルデヒド（２ａ）と同様の方法で変換することでもアルデヒド（２ａ)が得られる。 Compound (5) is reacted with amine compound (H 2 N—Y—W) in the same manner as in the reaction from compound (5) to compound (6) to give compound (9). Compound (11) is obtained by performing a reaction similar to the reaction from Compound (6) to Compound (8) on Compound (9). Moreover, a compound (12) is obtained by performing reaction similar to the reaction from the said compound (8) to an aldehyde (2a) with respect to a compound (11). Am is introduced into compound (12) to obtain aldehyde (2a). Alternatively, the formyl group of compound (12) is acetal protected to give compound (13), then Am is reacted to obtain compound (14), and the acetal group of compound (14) is deprotected to remove aldehyde (2a ) Is obtained. Furthermore, compound (15) can be obtained by introducing Am into compound (11), and then the amide moiety of compound (15) can be converted from compound (8) by the same method as aldehyde (2a). (2a) is obtained.

　化合物（１２）からアルデヒド（２ａ)への反応は、例えばＷが保護されたヒドロキシアルキル基の場合、化合物（１２）のＷを脱保護してヒドロキシアルキル基とした後、メタンスルホニルクロリド等を作用させ、次いでＡｍと反応させることにより行われる。 For example, when W is a protected hydroxyalkyl group, the compound (12) is reacted with methanesulfonyl chloride after deprotecting W of the compound (12) to form a hydroxyalkyl group. Followed by reaction with Am.

　化合物（１２）のアセタール保護は、酸触媒の存在下、エチレングリコールや1,3-プロパンジオール等を反応させることにより行われる。 The acetal protection of the compound (12) is performed by reacting ethylene glycol, 1,3-propanediol or the like in the presence of an acid catalyst.

　化合物（１３)から化合物(１４)への変換は、Ｗがハロゲンの場合、例えばバックワルド-ハートウィグ クロスカップリングにより、例えばパラジウム触媒として酢酸パラジウム、塩基として炭酸セシウム、配位子として2,2'-ビス（ジフェニルホスフィノ）-1,1'-ビナフチルを用い、加熱することにより行われる。また、Ｗがホルミル基、またはホルミルアルキル基の場合、たとえば、Ａｍを、酢酸等の酸存在下、トリアセトキシボロヒドリド等の還元剤を反応させ化合物(１４)を合成することもできる。Ｗが保護されたヒドロキシアルキル基の場合は、Ｗを脱保護しヒドロキシアルキル基とした後、酸化してホルミルアルキル基とし、Ａｍを、酢酸等の酸存在下、トリアセトキシボロヒドリド等の還元剤を反応させ化合物(１４)を合成することもできる。 Conversion of compound (13) to compound (14) can be achieved when W is halogen, for example, by Backward-Hartwig-cross coupling, for example, palladium acetate as a palladium catalyst, cesium carbonate as a base, 2,2 as a ligand. It is carried out by heating using '-bis (diphenylphosphino) -1,1'-binaphthyl. When W is a formyl group or a formylalkyl group, for example, compound (14) can be synthesized by reacting Am with a reducing agent such as triacetoxyborohydride in the presence of an acid such as acetic acid. When W is a protected hydroxyalkyl group, W is deprotected to form a hydroxyalkyl group, then oxidized to formylalkyl group, and Am is a reducing agent such as triacetoxyborohydride in the presence of an acid such as acetic acid. To react to synthesize a compound (14).

　化合物（１４）のアセタール基の脱保護反応は、酸により行われる。酸としては塩酸等が用いられる。 The deprotection reaction of the acetal group of compound (14) is performed with an acid. As the acid, hydrochloric acid or the like is used.

　化合物（１１）から化合物（１５）への反応は例えば次のような例が挙げられる。Ｗが保護されたヒドロキシ基の場合は、化合物（１１）のＷを脱保護し、ヒドロキシ基とした後、塩基の存在下にアルキルハライドを反応させるアルキル化反応等により合成できる。Ｗが保護されたヒドロキシアルキル基の場合は、Ｗを脱保護しヒドロキシアルキル基とした後、メタンスルホニルクロリド等を作用させ、次いでＡｍと反応させることにより化合物（１５）を得ることができる。Ｗが保護されたヒドロキシアルキル基の場合、Ｗを脱保護しヒドロキシアルキル基とした後、酸化してホルミルアルキル基とし、Ａｍを、酢酸等の酸存在下、トリアセトキシボロヒドリド等の還元剤と反応させてもよい。また、Ｗがアルコキシカルボニル基の場合には、加水分解して、カルボン酸とした後、O-(1H-6-クロロベンゾトリアゾール-1-イル)-N,N,N',N'-テトラメチルウロニウムテトラフルオロボレート等の縮合剤を用い、Ａｍと縮合し、化合物（１５）を得ることもできる。Ｗがホルミル基、またはホルミルアルキル基の場合、例えば、Ａｍを、酢酸等の酸存在下、トリアセトキシボロヒドリド等の還元剤と反応させ化合物（１５）を合成することもできる。さらに、Ｗがハロゲンの場合は、例えばバックワルド-ハートウィグ クロスカップリングにより、パラジウム触媒として酢酸パラジウム、塩基として炭酸セシウム、配位子として2,2'-ビス（ジフェニルホスフィノ）-1,1'-ビナフチル等を用いて加熱することによりＡｍを導入し化合物（１５）を得ることができる。また、ジイソプロピルアミン等のアミン、およびヨウ化銅等の銅触媒、パラジウムジクロロビストリフェニルホスフィン等のパラジウム触媒存在下、Ａｍを有する末端アルキンを園頭カップリング反応により反応させ化合物（１５）へ変換することもでき、Ａｍを有する末端アルキンの代わりにハロゲンを有する末端アルキンを用いて園頭カップリング反応を行い、その後、炭酸カリウム等の塩基存在下、Ａｍを反応させ、（１５）を得ることもできる。さらに、園頭カップリング反応により得られた生成物の三重結合を例えばパラジウム－活性炭などの触媒存在下、接触水素化により還元することもできる。 Examples of the reaction from compound (11) to compound (15) include the following. When W is a protected hydroxy group, it can be synthesized by deprotecting W of compound (11) to form a hydroxy group and then an alkylation reaction in which an alkyl halide is reacted in the presence of a base. When W is a protected hydroxyalkyl group, W is deprotected to form a hydroxyalkyl group, then reacted with methanesulfonyl chloride or the like, and then reacted with Am to obtain compound (15). When W is a protected hydroxyalkyl group, W is deprotected to form a hydroxyalkyl group and then oxidized to formylalkyl group. Am is a reducing agent such as triacetoxyborohydride in the presence of an acid such as acetic acid. You may make it react. When W is an alkoxycarbonyl group, it is hydrolyzed to give a carboxylic acid, and then O- (1H-6-chlorobenzotriazol-1-yl) -N, N, N ′, N′-tetra Compound (15) can also be obtained by condensation with Am using a condensing agent such as methyluronium tetrafluoroborate. When W is a formyl group or a formylalkyl group, for example, Am can be reacted with a reducing agent such as triacetoxyborohydride in the presence of an acid such as acetic acid to synthesize compound (15). Further, when W is halogen, for example, by Backwald-Hartwig-cross coupling, palladium acetate as the palladium catalyst, cesium carbonate as the base, and 2,2′-bis (diphenylphosphino) -1,1 as the ligand By heating using '-binaphthyl or the like, Am can be introduced to obtain compound (15). In addition, a terminal alkyne having Am is reacted by a Sonogashira coupling reaction in the presence of an amine such as diisopropylamine, a copper catalyst such as copper iodide, and a palladium catalyst such as palladium dichlorobistriphenylphosphine to convert the compound (15). The Sonogashira coupling reaction is performed using a terminal alkyne having a halogen instead of a terminal alkyne having Am, and Am is then reacted in the presence of a base such as potassium carbonate to obtain (15). it can. Further, the triple bond of the product obtained by the Sonogashira coupling reaction can be reduced by catalytic hydrogenation in the presence of a catalyst such as palladium-activated carbon.

　化合物（１５）からアルデヒド（２ａ）への反応は、前記化合物（８）からアルデヒド（２ａ）への反応と同様の方法で行なわれる。 The reaction from compound (15) to aldehyde (2a) is carried out in the same manner as the reaction from compound (8) to aldehyde (2a).

　Ａｍの末端がアミノ基の場合は、適宜保護基を用いて合成を行い、脱保護した後に置換基を導入してもよい。 When the terminal of Am is an amino group, it may be synthesized using a protective group as appropriate, and a substituent may be introduced after deprotection.

　また、アルデヒド（２ａ）は、次の反応式に従って合成することもできる。 The aldehyde (2a) can also be synthesized according to the following reaction formula.

Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012

（式中、Ｙ、Ａｍは前記と同じ） (Wherein Y and Am are the same as above)

　化合物（４）をエステル化して化合物（１６）とし、前記化合物（５）から化合物（８）への反応と同様の方法で化合物（１９）とする。化合物（１９）のエステルをアルコールへと還元し、次いで酸化することでアルデヒド（２ａ）が得られる。また化合物（１９)は化合物（１６)にＨ２Ｎ－Ｙ－Ａｍの代わりにＨ２Ｎ－Ｙ－Ｗ（Ｗはハロゲン原子、ヒドロキシ基、保護されたヒドロキシ基や保護されたヒドロキシアルキル基、アルコキシカルボニル基、ホルミル基、ホルミルアルキル基等の官能基を示す。）を反応させ、還元、環化を行った後、化合物（１１）へのＡｍの導入方法と同様の方法で得ることもできる。また、Ａｍの末端がアミノ基の場合は、適宜保護基を用いて合成を行い、脱保護した後に置換基を導入してもよい。 Compound (4) is esterified to give compound (16), and compound (19) is obtained in the same manner as in the reaction from compound (5) to compound (8). Reduction of the ester of compound (19) to an alcohol followed by oxidation gives aldehyde (2a). The compound (19) is H 2 N-Y-W ( W instead of H 2 N-Y-Am in compound (16) is a halogen atom, hydroxy group, protected hydroxy group or protected hydroxy group, A functional group such as an alkoxycarbonyl group, a formyl group, a formylalkyl group, etc.) is reacted, reduced, and cyclized, and then obtained in the same manner as the method for introducing Am into the compound (11). . Moreover, when the terminal of Am is an amino group, it may synthesize | combine using a protective group suitably, and you may introduce | transduce a substituent after deprotecting.

　化合物（４）のエステル化反応は、メタノール等のアルコール系溶媒中、酸の存在下で加熱することにより行われる。酸としては塩酸や硫酸等が用いられる。 The esterification reaction of the compound (4) is performed by heating in the presence of an acid in an alcohol solvent such as methanol. As the acid, hydrochloric acid, sulfuric acid or the like is used.

　化合物（１９）の還元反応は、例えば水素化アルミニウムリチウムや水素化ジイソブチルアルミニウム等により行われる。 The reduction reaction of the compound (19) is performed, for example, with lithium aluminum hydride or diisobutylaluminum hydride.

　化合物（２０）の酸化反応は、デス－マーチン　ペルヨージナン、二酸化マンガン等の酸化剤を用いることにより行われる。 The oxidation reaction of the compound (20) is carried out by using an oxidizing agent such as Dess-Martin periodinane or manganese dioxide.

　またアルデヒド（２ａ）は、例えば次の反応式に従って合成することもできる。 The aldehyde (2a) can also be synthesized, for example, according to the following reaction formula.

Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013

（式中、Ｖはハロゲン原子等の官能基を示し、Ｙ、Ａｍは前記と同じ） (In the formula, V represents a functional group such as a halogen atom, and Y and Am are the same as described above.)

　化合物（２１）をベンゾイル化して化合物（２２）とし、次いで塩化チオニルと反応することにより化合物（２３）が得られる。化合物（２３）と公知の化合物（２４）とを反応させて化合物（２５）を得、次いで加熱することにより化合物（２６）が得られる。化合物（２６）のベンゾイル基を脱保護し、前記化合物（６）から化合物（８）への反応と同様の反応を行うことにより化合物（２８）が得られる。化合物（２８）に対して前記化合物（１３）からアルデヒド（２ａ）への反応と同様の反応を行うことによりアルデヒド（２ａ）が得られる。 Compound (21) is benzoylated to give compound (22), and then reacted with thionyl chloride to give compound (23). Compound (23) and known compound (24) are reacted to obtain compound (25), and then heated to obtain compound (26). Compound (28) is obtained by deprotecting the benzoyl group of compound (26) and carrying out a reaction similar to the reaction from compound (6) to compound (8). The compound (28) is subjected to a reaction similar to the reaction from the compound (13) to the aldehyde (2a) to obtain the aldehyde (2a).

　化合物（２１）のベンゾイル化反応は、塩基の存在下、ベンゾイルクロリド等を反応させることにより行われる。塩基としては水酸化ナトリウム等が用いられる。 The benzoylation reaction of compound (21) is performed by reacting benzoyl chloride or the like in the presence of a base. Sodium hydroxide or the like is used as the base.

　化合物（２２）と塩化チオニルとの反応は、加熱することにより行われる。塩化チオニルは反応溶媒として過剰量用いて行うのが好ましい。 The reaction between compound (22) and thionyl chloride is carried out by heating. Thionyl chloride is preferably used in an excess amount as a reaction solvent.

　化合物（２３）と化合物（２４）との反応は、塩基の存在下に行われる。塩基としては水素化ナトリウム等が用いられる。 The reaction between the compound (23) and the compound (24) is performed in the presence of a base. As the base, sodium hydride or the like is used.

　化合物（２５）の転位反応は、加熱することにより行われる。反応は約１８０℃で８時間行うのが好ましい。 The rearrangement reaction of compound (25) is performed by heating. The reaction is preferably carried out at about 180 ° C. for 8 hours.

　化合物（２６）の脱保護は、アルカリの存在下に行うのが好ましい。アルカリとしては水酸化カリウム等が用いられる。 The deprotection of the compound (26) is preferably performed in the presence of alkali. As the alkali, potassium hydroxide or the like is used.

　（Ａ－２）の構造を有するアルデヒド（２ｂ）は、例えば次の式に従って合成することができる。 The aldehyde (2b) having the structure (A-2) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014

（式中、Ｙ、Ａｍは前記と同じ） (Wherein Y and Am are the same as above)

　化合物（７）の環化反応により化合物（３０）を得た後、化合物（３０）のアミド部位を前記化合物（８）からアルデヒド（２ａ）への反応と同様の方法で変換することでアルデヒド（２ｂ）が得られる。 After obtaining the compound (30) by cyclization reaction of the compound (7), the amide moiety of the compound (30) is converted by the same method as the reaction from the compound (8) to the aldehyde (2a). 2b) is obtained.

　化合物（７）の環化反応は、酸触媒の存在下にオルト酢酸トリメチル等を反応させることにより行われる。酸触媒としては酢酸等が好ましい。 The cyclization reaction of the compound (7) is performed by reacting trimethyl orthoacetate or the like in the presence of an acid catalyst. As the acid catalyst, acetic acid or the like is preferable.

　（Ａ－２０）の構造を有するアルデヒド（２ｃ）は、例えば次の式に従って合成することができる。 The aldehyde (2c) having the structure (A-20) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015

（式中、Ｙ、Ａｍは前記と同じ） (Wherein Y and Am are the same as above)

　化合物（７）の環化反応により化合物（３１）を得、化合物（３１）のアミド部位を前記化合物（８）からアルデヒド（２ａ）への反応と同様の方法で変換することでアルデヒド（２ｃ）が得られる。 Compound (31) is obtained by cyclization reaction of compound (7), and the amide moiety of compound (31) is converted in the same manner as in the reaction from compound (8) to aldehyde (2a) to obtain aldehyde (2c). Is obtained.

　化合物（７）の環化反応は、酸触媒の存在下に亜硝酸ナトリウム等を反応させることにより行われる。酸触媒としては酢酸等が用いられる。 The cyclization reaction of the compound (7) is performed by reacting sodium nitrite or the like in the presence of an acid catalyst. Acetic acid or the like is used as the acid catalyst.

　（Ａ－３）の構造を有するアルデヒド（２ｄ）は、例えば次の式に従って合成することができる。 The aldehyde (2d) having the structure (A-3) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016

（式中、Ｖはハロゲン原子等の官能基を示し、Ｙ、Ａｍは前記と同じ） (In the formula, V represents a functional group such as a halogen atom, and Y and Am are the same as described above.)

　化合物（３２）とＶ－Ｙ－Ａｍとを反応させて化合物（３３）を得、化合物（３３）のシアノ基を還元してアルデヒド（２ｄ）が得られる。 Compound (32) is reacted with VY-Am to obtain compound (33), and the cyano group of compound (33) is reduced to obtain aldehyde (2d).

　化合物（３２）から化合物（３３）への反応は、例えば銅触媒としてヨウ化銅、塩基としてリン酸三カリウムを用いて加熱することにより行われる。また、塩基の存在下にアルキルハライドを反応させるアルキル化反応等によっても化合物（３３）を得ることができる。 The reaction from the compound (32) to the compound (33) is performed by heating using, for example, copper iodide as a copper catalyst and tripotassium phosphate as a base. The compound (33) can also be obtained by an alkylation reaction in which an alkyl halide is reacted in the presence of a base.

　化合物（３３）の還元反応は、例えば水素化ジイソブチルアルミニウム等により行われる。 The reduction reaction of the compound (33) is performed, for example, with diisobutylaluminum hydride or the like.

　また化合物（３３)は（３２）にＶ-Ｙ-Ａｍの代わりにＶ-Ｙ-Ｗ（Ｗはハロゲン原子、ヒドロキシ基、保護されたヒドロキシ基や保護されたヒドロキシアルキル基、アルコキシカルボニル基、ホルミル基、ホルミルアルキル基等の官能基を示す。）を反応させた後、化合物（１１）へのＡｍの導入方法と同様の方法で、Ａｍを後から導入することにより得ることもできる。 Further, compound (33) is obtained by replacing VY-Am with VYW (W is a halogen atom, a hydroxy group, a protected hydroxy group, a protected hydroxyalkyl group, an alkoxycarbonyl group, formyl instead of VY-Am. Group, a functional group such as formylalkyl group, etc.) is reacted, and then Am can be introduced by a method similar to the method for introducing Am into compound (11).

　（Ａ－５）の構造を有するアルデヒド（２ｅ）は、例えば次の式に従って合成することができる。 The aldehyde (2e) having the structure (A-5) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017

（式中、Ｑはボロン酸やボロン酸エステル等の官能基を示し、Ｙ、Ａｍは前記と同じ） (Wherein Q represents a functional group such as boronic acid or boronic acid ester, and Y and Am are the same as above)

　化合物（３４）から公知の方法（非特許文献１３）で化合物（３６）を得る。化合物（３６）とＱ－Ｙ－Ａｍを鈴木－宮浦カップリングにより反応させて化合物（３７）とし、化合物（３７）の一酸化炭素挿入反応によりアルデヒド（２ｅ）を得る。 Compound (36) is obtained from Compound (34) by a known method (Non-Patent Document 13). Compound (36) and QY-Am are reacted by Suzuki-Miyaura coupling to give compound (37), and aldehyde (2e) is obtained by carbon monoxide insertion reaction of compound (37).

　化合物（３６）とＱ－Ｙ－Ａｍとの鈴木－宮浦カップリング反応は、パラジウム触媒としてテトラキス（トリフェニルホスフィン）パラジウム（０）や１，１’－ビス（ジフェニルホスフィノ）フェロセン－パラジウム（ＩＩ）ジクロリド－ジクロロメタン錯体を用い、塩基として炭酸ナトリウムや炭酸カリウムを用いることにより行われる。 Suzuki-Miyaura coupling reaction between compound (36) and QY-Am is carried out by using tetrakis (triphenylphosphine) palladium (0) or 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) as a palladium catalyst. ) Using a dichloride-dichloromethane complex and using sodium carbonate or potassium carbonate as a base.

　化合物（３７）の一酸化炭素挿入反応は、例えば触媒としてトリス（ジベンジリデンアセトン）ジパラジウム（０）を用い、ギ酸ナトリウムと反応させることにより行われる。 The carbon monoxide insertion reaction of the compound (37) is performed, for example, by using tris (dibenzylideneacetone) dipalladium (0) as a catalyst and reacting with sodium formate.

　またアルデヒド (２ｅ) はＱ－Ｙ－Ａｍの代わりにＱ－Ｙ－Ｗ（Ｗはハロゲン原子、ヒドロキシ基、保護されたヒドロキシ基や保護されたヒドロキシアルキル基、アルコキシカルボニル基、ホルミル基、ホルミルアルキル基等の官能基を示す。）を用いて、化合物(３６)と反応させた後、化合物（１１）へのＡｍの導入方法と同様の方法で、Ａｍを後から導入することにより得ることもできる。 Aldehyde (2e) is QYW instead of QY-Am (W is halogen atom, hydroxy group, protected hydroxy group, protected hydroxyalkyl group, alkoxycarbonyl group, formyl group, formylalkyl) Or a functional group such as a group) is reacted with the compound (36), and then Am is introduced into the compound (11) by a method similar to the method for introducing Am. it can.

　またアルデヒド（２ｅ）は、次の式に従って合成することができる。 Aldehyde (2e) can be synthesized according to the following formula.

Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018

（式中、Ｑはボロン酸やボロン酸エステル等の官能基、Ｗはハロゲン原子、ヒドロキシ基、保護されたヒドロキシ基や保護されたヒドロキシアルキル基、アルコキシカルボニル基、ホルミル基、ホルミルアルキル基等の官能基を示し、Ｙ、Ａｍは前記と同じ） (Wherein Q is a functional group such as boronic acid or boronic acid ester, W is a halogen atom, hydroxy group, protected hydroxy group, protected hydroxyalkyl group, alkoxycarbonyl group, formyl group, formylalkyl group, etc. Indicates a functional group, Y and Am are the same as above)

　化合物（３８）から既知の方法（特許文献１及び非特許文献１４）で化合物（４０）を得る。化合物（４０）とＱ－Ｙ－Ｗを前記化合物（３６）から化合物（３７）への反応と同様の方法で反応させて化合物（４１）とし、化合物（１１）へのＡｍの導入方法と同様の方法により化合物（４２）が得られる。化合物（４２）に対し前記化合物（１９）から化合物（２ａ）への反応と同様の反応を行うことによりアルデヒド（２ｅ）が得られる。 Compound (40) is obtained from Compound (38) by a known method (Patent Document 1 and Non-Patent Document 14). Compound (40) and QYW are reacted in the same manner as in the reaction from Compound (36) to Compound (37) to give Compound (41), which is the same as the method for introducing Am into Compound (11). The compound (42) is obtained by the method of The compound (42) is subjected to a reaction similar to the reaction from the compound (19) to the compound (2a) to obtain the aldehyde (2e).

　（Ａ－６）の構造を有するアルデヒド（２ｆ）は、例えば次の式に従って合成することができる。 The aldehyde (2f) having the structure (A-6) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019

（式中、Ｑはボロン酸やボロン酸エステル等の官能基を示し、Ｙ、Ａｍは前記と同じ） (Wherein Q represents a functional group such as boronic acid or boronic acid ester, and Y and Am are the same as above)

　化合物（４４）とＱ－Ｙ－Ａｍを前記化合物（３６）から化合物（３７）への反応と同様の方法で反応させて化合物（４５）とする。化合物（４５）にビニル基を導入して化合物（４６）とし、化合物（４６）のビニル基を酸化的に開裂してアルデヒド（２ｆ）が得られる。 Compound (44) and QY-Am are reacted in the same manner as in the reaction from Compound (36) to Compound (37) to give Compound (45). A vinyl group is introduced into compound (45) to form compound (46), and the vinyl group of compound (46) is oxidatively cleaved to obtain aldehyde (2f).

　化合物（４５）のビニル化反応は、パラジウム触媒の存在下、トリブチルビニルスズや４，４，５，５－テトラメチル－２－ビニル－１，３，２－ジオキサボロラン等を反応させることにより行われる。 The vinylation reaction of the compound (45) is performed by reacting tributylvinyltin, 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane, etc. in the presence of a palladium catalyst. .

　化合物（４６）の二重結合開裂反応は、例えば触媒として四酸化オスミウム、再酸化剤として過ヨウ素酸ナトリウムを用いることで行われる。 The double bond cleavage reaction of the compound (46) is performed by using, for example, osmium tetroxide as a catalyst and sodium periodate as a reoxidant.

　また、Ｙに縮合二環を有するアルデヒド（２ｆ）は、例えば次の式に従って合成することができる。 Further, the aldehyde (2f) having a condensed bicyclic ring at Y can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020

（式中、Ａｍは前記と同じ） (Wherein Am is the same as above)

　化合物（４４）にビニル基を導入して化合物（４７）とし、化合物（４７）のビニル基を酸化的に開裂してアルデヒド（４８）が得られる。化合物（４４）のビニル化反応は、パラジウム触媒の存在下、トリブチルビニルスズや４，４，５，５－テトラメチル－２－ビニル－１，３，２－ジオキサボロラン等を反応させることにより行われる。化合物（４７）の二重結合開裂反応は、例えば触媒として四酸化オスミウム、再酸化剤として過ヨウ素酸ナトリウムを用いることで行われる。化合物（４８）に２－アミノフェノール類と反応させて化合物（４９）を得る。化合物（４９）に対し前記化合物（４５）からアルデヒド（２ｆ）への反応と同様の反応を行うことによりアルデヒド（２ｆ）が得られる。 A vinyl group is introduced into compound (44) to form compound (47), and the vinyl group of compound (47) is oxidatively cleaved to obtain aldehyde (48). The vinylation reaction of compound (44) is carried out by reacting tributylvinyltin, 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane, etc. in the presence of a palladium catalyst. . The double bond cleavage reaction of compound (47) is carried out, for example, by using osmium tetroxide as a catalyst and sodium periodate as a reoxidant. Compound (48) is reacted with 2-aminophenol to give compound (49). The compound (49) is subjected to a reaction similar to the reaction from the compound (45) to the aldehyde (2f) to obtain the aldehyde (2f).

　化合物（４８）と２－アミノフェノール類との反応は、酸素の存在下、活性炭を加えて加熱することにより行われる。反応溶媒としてはキシレンを用い、反応温度は１２０℃前後が好ましい。 The reaction between compound (48) and 2-aminophenols is carried out by adding activated carbon and heating in the presence of oxygen. Xylene is used as the reaction solvent, and the reaction temperature is preferably around 120 ° C.

　またアルデヒド（２ｆ）はＱ-Ｙ-Ａｍの代わりにＱ-Ｙ-Ｗ（Ｗはハロゲン原子、ヒドロキシ基、保護されたヒドロキシ基や保護されたヒドロキシアルキル基、アルコキシカルボニル基、ホルミル基、ホルミルアルキル基等の官能基を示す。）を用いて、化合物（４４)と反応させた後、化合物（１１）へのＡｍの導入方法と同様の方法で、Ａｍを後から導入することにより得ることもできる。 Aldehyde (2f) is QYW instead of QY-Am (W is halogen atom, hydroxy group, protected hydroxy group, protected hydroxyalkyl group, alkoxycarbonyl group, formyl group, formylalkyl, Or a functional group such as a group), and then reacting with the compound (44) and then introducing Am into the compound (11) in the same manner as described above. it can.

　また、化合物（４５）は公知の方法（非特許文献１５）により合成することもできる。 Compound (45) can also be synthesized by a known method (Non-patent Document 15).

　Ａｍの末端がアミノ基の場合は、適宜保護基を用いて合成を行い、脱保護した後に置換基を導入してもよい。 When the terminal of Am is an amino group, it may be synthesized using a protective group as appropriate, and a substituent may be introduced after deprotection.

　（Ａ－２１）の構造を有するアルデヒド（２ｇ）は、例えば次の式に従って合成することができる。 The aldehyde (2g) having the structure (A-21) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021

（式中、Ｑはボロン酸やボロン酸エステル等の官能基を示し、Ｙ、Ａｍは前記と同じ） (Wherein Q represents a functional group such as boronic acid or boronic acid ester, and Y and Am are the same as above)

　化合物（５１）から化合物（４４）とＱ－Ｙ－Ａｍを用いたアルデヒド（２ｆ）への反応と同様の反応を行うことによりアルデヒド（２ｇ）が得られる。 The aldehyde (2 g) is obtained by performing the same reaction as the reaction from the compound (51) to the aldehyde (2f) using the compound (44) and QY-Am.

　（Ａ－８）の構造を有するアルデヒド（２ｈ）は、例えば次の式に従って合成することができる。 The aldehyde (2h) having the structure (A-8) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022

（式中、Ｑはボロン酸やボロン酸エステル等の官能基を示し、Ｙ、Ａｍは前記と同じ） (Wherein Q represents a functional group such as boronic acid or boronic acid ester, and Y and Am are the same as above)

　化合物（５４）を、公知の方法（非特許文献１６および特許文献２）で化合物（６０）とする。化合物（６０）にＱ－Ｙ－Ａｍを前記化合物（３６）から化合物（３７）への反応と同様の方法で反応させて化合物（６１）を得る。化合物（６１）を脱保護して化合物（６２）とし、次いで前記化合物（２０）からアルデヒド（２ａ）への反応と同様に酸化してアルデヒド（２ｈ）を得る。 Compound (54) is converted to Compound (60) by a known method (Non-patent Document 16 and Patent Document 2). Compound (61) is obtained by reacting compound (60) with QY-Am in the same manner as in the reaction from compound (36) to compound (37). Compound (61) is deprotected to give compound (62), and then oxidized in the same manner as in the reaction from compound (20) to aldehyde (2a) to give aldehyde (2h).

　（Ａ－９）の構造を有するアルデヒド（２ｉ）は、例えば次の式に従って合成することができる。 The aldehyde (2i) having the structure (A-9) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023

（式中、Ｑはボロン酸やボロン酸エステル等の官能基を示し、Ｙ、Ａｍは前記と同じ） (Wherein Q represents a functional group such as boronic acid or boronic acid ester, and Y and Am are the same as above)

　化合物（６３）を、公知の方法（非特許文献１４、１６）で化合物（６７）とする。化合物（６７）にＱ－Ｙ－Ａｍを前記化合物（３６）から化合物（３７）への反応と同様の方法で反応させて化合物（６８）を得る。化合物（６８）に対し前記化合物（１９）からアルデヒド（２ａ）への反応と同様の反応を行うことによりアルデヒド（２ｉ）を得る。 Compound (63) is converted to Compound (67) by a known method (Non-Patent Documents 14 and 16). Compound (68) is obtained by reacting compound (67) with QY-Am in the same manner as in the reaction from compound (36) to compound (37). The compound (68) is subjected to a reaction similar to the reaction from the compound (19) to the aldehyde (2a) to obtain the aldehyde (2i).

　（Ａ－１４）の構造を有するアルデヒド（２ｊ）は、例えば次の式に従って合成することができる。 The aldehyde (2j) having the structure (A-14) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024

（式中、Ｑはボロン酸やボロン酸エステル等の官能基を示し、Ｙ、Ａｍは前記と同じ） (Wherein Q represents a functional group such as boronic acid or boronic acid ester, and Y and Am are the same as above)

　化合物（７０）を、公知の方法（非特許文献１７－１９）で化合物（７５）とする。化合物（７５）にＱ－Ｙ－Ａｍを前記化合物（３６）から化合物（３７）への反応と同様の方法で反応させて化合物（７６）を得る。化合物（７６）を前記化合物（３３）からアルデヒド（２ｄ）への反応と同様の方法で還元してアルデヒド（２ｊ）を得る。 Compound (70) is converted to Compound (75) by a known method (Non-patent Documents 17-19). Compound (76) is obtained by reacting compound (75) with QY-Am in the same manner as in the reaction from compound (36) to compound (37). Compound (76) is reduced by a method similar to the reaction from compound (33) to aldehyde (2d) to give aldehyde (2j).

　（Ａ－１２）の構造を有するアルデヒド（２ｋ）は、例えば次の式に従って合成することができる。 The aldehyde (2k) having the structure (A-12) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025

（式中、Ｑはボロン酸やボロン酸エステル等の官能基を示し、Ｙ、Ａｍは前記と同じ） (Wherein Q represents a functional group such as boronic acid or boronic acid ester, and Y and Am are the same as above)

　化合物（７７）にＱ－Ｙ－Ａｍを前記化合物（３６）から化合物（３７）への反応と同様の方法で反応させて化合物（７８）を得る。化合物（７８）を前記化合物（４５）からアルデヒド（２ｆ）と同様の方法で化合物（８０）とし、化合物（８０）を脱保護してアルデヒド（２ｋ）を得る。 Compound (78) is obtained by reacting compound (77) with QY-Am in the same manner as in the reaction from compound (36) to compound (37). Compound (78) is converted from compound (45) to compound (80) in the same manner as aldehyde (2f), and compound (80) is deprotected to give aldehyde (2k).

　化合物（８０）の脱保護は、トリフルオロ酢酸等の酸により行うことができる。 Compound (80) can be deprotected with an acid such as trifluoroacetic acid.

　（Ａ－１３）の構造を有するアルデヒド（２ｌ）は、例えば次の式に従って合成することができる。 The aldehyde (2l) having the structure of (A-13) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026

（式中、Ｑはボロン酸やボロン酸エステル等の官能基を示し、Ｙ、Ａｍは前記と同じ） (Wherein Q represents a functional group such as boronic acid or boronic acid ester, and Y and Am are the same as above)

　化合物（８１）を、公知の方法（非特許文献１４）で化合物（８４）とする。化合物（８４）にＱ－Ｙ－Ａｍを前記化合物（３６）から化合物（３７）への反応と同様の方法で反応させて化合物（８５）を得る。化合物（８５）に対し前記化合物（１９）からアルデヒド（２ａ）への反応と同様の反応を行うことによりアルデヒド（２ｌ）を得る。 Compound (81) is converted to Compound (84) by a known method (Non-Patent Document 14). Compound (85) is obtained by reacting compound (84) with QY-Am in the same manner as in the reaction from compound (36) to compound (37). The compound (85) is subjected to a reaction similar to the reaction from the compound (19) to the aldehyde (2a) to obtain the aldehyde (2l).

　（Ａ－１８）の構造を有するアルデヒド（２ｍ）は、例えば次の式に従って合成することができる。 The aldehyde (2m) having the structure (A-18) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027

（式中、Ｑはボロン酸やボロン酸エステル等の官能基を示し、Ｙ、Ａｍは前記と同じ） (Wherein Q represents a functional group such as boronic acid or boronic acid ester, and Y and Am are the same as above)

　化合物（８７）を臭素と反応させて化合物（８８）とし、化合物（８８）にＱ－Ｙ－Ａｍを前記化合物（３６）から化合物（３７）への反応と同様の方法で反応させてアルデヒド（２ｍ）を得る。 Compound (87) is reacted with bromine to give compound (88), and QY-Am is reacted with compound (88) in the same manner as in the reaction from compound (36) to compound (37) to give an aldehyde ( 2m).

　（Ａ－７）の構造を有するアルデヒド（２ｎ）は、例えば次の式に従って合成することができる。 The aldehyde (2n) having the structure (A-7) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028

（式中、Ｙ、Ａｍは前記と同じ） (Wherein Y and Am are the same as above)

　化合物（８９）をアミン化合物（Ｈ２Ｎ－Ｙ－Ａｍ）と反応させて化合物（９０）とする。化合物（９０）のニトロ基を還元した後、環化反応により化合物（９２）が得られる。化合物（９２）に対し前記化合物（３７）からアルデヒド（２ｅ）への反応と同様の反応を行うことによりアルデヒド（２ｎ）が得られる。また、化合物（９２）に対し前記化合物（４５）からアルデヒド（２ｆ）への反応と同様の反応を行うことによりアルデヒド（２ｎ）を得ることもできる。 Compound (89) is reacted with an amine compound (H 2 N—Y—Am) to give compound (90). After reducing the nitro group of compound (90), compound (92) is obtained by cyclization reaction. The compound (92) is subjected to a reaction similar to the reaction from the compound (37) to the aldehyde (2e) to obtain the aldehyde (2n). Alternatively, the aldehyde (2n) can be obtained by carrying out a reaction similar to the reaction from the compound (45) to the aldehyde (2f) on the compound (92).

　化合物（８９）をアミン化合物（Ｈ２Ｎ－Ｙ－Ａｍ）との反応は、エタノール等の溶媒中、塩基の存在下で行われる。塩基としてはトリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン等が好ましい。 The reaction of compound (89) with amine compound (H 2 N—Y—Am) is carried out in the presence of a base in a solvent such as ethanol. As the base, triethylamine, N, N-diisopropylethylamine and the like are preferable.

　化合物（９０）の還元反応は、例えば鉄粉と塩化アンモニウムを用いて加熱することにより行われる。 The reduction reaction of the compound (90) is performed by heating with, for example, iron powder and ammonium chloride.

　化合物（９１）の環化反応は、ホルムアミジン酢酸塩等を用いることにより行われる。 The cyclization reaction of compound (91) is performed by using formamidine acetate or the like.

　またアルデヒド(２ｎ)はＨ２Ｎ-Ｙ-Ａｍの代わりにＨ２Ｎ-Ｙ-Ｗ（Ｗはハロゲン原子、ヒドロキシ基、保護されたヒドロキシ基や保護されたヒドロキシアルキル基、アルコキシカルボニル基、ホルミル基、ホルミルアルキル基等の官能基を示す。）を用いて、化合物(４４)と反応させた後、化合物（１１）へのＡｍの導入方法と同様の方法で、Ａｍを後から導入することにより得ることもできる。 The aldehyde (2n) is H 2 N-Y-Am H 2 N-Y-W (W is a halogen atom in place of a hydroxy group, protected hydroxy group or protected hydroxy group, an alkoxycarbonyl group, formyl A functional group such as a formylalkyl group, etc.), and then reacting with the compound (44) and then introducing Am in the same manner as the method for introducing Am into the compound (11). Can also be obtained.

　Ａｍの末端がアミノ基の場合は、適宜保護基を用いて合成を行い、脱保護した後に置換基を導入してもよい。 When the terminal of Am is an amino group, it may be synthesized using a protective group as appropriate, and a substituent may be introduced after deprotection.

　（Ａ－１６）の構造を有するアルデヒド（２ｏ）は、例えば次の式に従って合成することができる。 The aldehyde (2o) having the structure (A-16) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029

（式中、Ｙ、Ａｍは前記と同じ） (Wherein Y and Am are the same as above)

　化合物（９１）を前記化合物（７）から化合物（３１）への反応と同様の方法で環化して化合物（９４）を得る。化合物（９４）に対し前記化合物（４５）からアルデヒド（２ｆ）への反応と同様の反応を行うことによりアルデヒド（２ｏ）が得られる。Ａｍの末端がアミノ基の場合は、適宜保護基を用いて合成を行い、脱保護した後に置換基を導入してもよい。 Compound (91) is cyclized in the same manner as in the reaction from compound (7) to compound (31) to give compound (94). The compound (94) is subjected to a reaction similar to the reaction from the compound (45) to the aldehyde (2f) to obtain the aldehyde (2o). When the terminal of Am is an amino group, synthesis may be performed using a protective group as appropriate, and the substituent may be introduced after deprotection.

　（Ａ－１１）の構造を有するアルデヒド（２ｐ）は、例えば次の式に従って合成することができる。 The aldehyde (2p) having the structure (A-11) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030

（式中、Ｙ、Ａｍは前記と同じ） (Wherein Y and Am are the same as above)

　化合物（９６）に対し、前記化合物（８９）からアルデヒド（２ｎ）への反応と同様の反応を行うことによりアルデヒド（２ｐ）が得られる。Ａｍの末端がアミノ基の場合は、適宜保護基を用いて合成を行い、脱保護した後に置換基を導入してもよい。 The aldehyde (2p) is obtained by performing a reaction similar to the reaction from the compound (89) to the aldehyde (2n) with respect to the compound (96). When the terminal of Am is an amino group, synthesis may be performed using a protective group as appropriate, and the substituent may be introduced after deprotection.

　（Ａ－１９）の構造を有するアルデヒド（２ｑ）は、例えば次の式に従って合成することができる。 The aldehyde (2q) having the structure (A-19) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031

（式中、Ｖはハロゲン原子等の官能基を示し、Ｙ、Ａｍは前記と同じ） (In the formula, V represents a functional group such as a halogen atom, and Y and Am are the same as described above.)

　化合物（１０１）とヒドラジン化合物（Ｈ２Ｎ－ＮＨ－Ｙ－Ｖ）とを反応させて化合物（１０２）を得、化合物（１０２）に、化合物（１１）へのＡｍの導入方法と同様の方法でＡｍを導入して化合物（１０３）が得られる。化合物（１０３）に対し前記化合物（４５）からアルデヒド（２ｆ）への反応と同様の反応を行うことによりアルデヒド（２ｑ）が得られる。 The compound (101) and the hydrazine compound (H 2 N—NH—Y—V) are reacted to obtain the compound (102), and the same method as that for introducing Am into the compound (11) is obtained in the compound (102) Introducing Am yields compound (103). The compound (103) is subjected to a reaction similar to the reaction from the compound (45) to the aldehyde (2f) to obtain the aldehyde (2q).

　化合物（１０１）とヒドラジン化合物（Ｈ２Ｎ－ＮＨ－Ｙ－Ｖ）との反応は、炭酸セシウムの存在下、加熱することにより行われる。 The reaction between the compound (101) and the hydrazine compound (H 2 N—NH—YV) is carried out by heating in the presence of cesium carbonate.

　（Ａ－１０）の構造を有するアルデヒド（２ｒ）は、例えば次の式に従って合成することができる。 The aldehyde (2r) having the structure (A-10) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032

（式中、Ｖはハロゲン原子等の官能基を示し、Ｙ、Ａｍは前記と同じ） (In the formula, V represents a functional group such as a halogen atom, and Y and Am are the same as described above.)

　化合物（１０５）とヒドラジン化合物（Ｈ２Ｎ－ＮＨ－Ｙ－Ｖ）とを反応させて化合物（１０６）を得、次いで環化反応を行い化合物（１０７）を得る。化合物（１０７）に対し前記化合物（１０２）からアルデヒド（２ｑ）への反応と同様の反応を行うことによりアルデヒド（２ｒ）が得られる。 Compound (105) is reacted with hydrazine compound (H 2 N—NH—Y—V) to obtain compound (106), and then cyclization reaction is performed to obtain compound (107). The compound (107) is subjected to a reaction similar to the reaction from the compound (102) to the aldehyde (2q) to obtain the aldehyde (2r).

　化合物（１０５）とヒドラジン化合物（Ｈ２Ｎ－ＮＨ－Ｙ－Ｖ）との反応は、塩基の存在下、加熱することにより行われる。塩基としてはＮ，Ｎ－ジイソプロピルエチルアミン等が用いられる。 The reaction between the compound (105) and the hydrazine compound (H 2 N—NH—YV) is carried out by heating in the presence of a base. As the base, N, N-diisopropylethylamine or the like is used.

　化合物（１０６）の環化反応は、炭酸セシウムの存在下、加熱することにより行われる。 The cyclization reaction of the compound (106) is performed by heating in the presence of cesium carbonate.

　（Ａ－４）の構造を有するアルデヒド（２ｓ）は、例えば次の式に従って合成することができる。 The aldehyde (2s) having the structure (A-4) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033

（式中、Ｖはハロゲン原子等の官能基を示し、Ｙ、Ａｍは前記と同じ） (In the formula, V represents a functional group such as a halogen atom, and Y and Am are the same as described above.)

　化合物（１１０）とヒドラジン化合物（Ｈ２Ｎ－ＮＨ－ＣＯ-Ｙ－Ｖ）とを反応させて化合物（１１１）を得る。化合物（１１１）に対し前記化合物（１０２）からアルデヒド（２ｑ）への反応と同様の反応を行うことによりアルデヒド（２ｓ）が得られる。 Compound (111) is obtained by reacting compound (110) with hydrazine compound (H 2 N—NH—CO—YV). The compound (111) is subjected to a reaction similar to the reaction from the compound (102) to the aldehyde (2q) to obtain the aldehyde (2s).

　化合物（１１０）とヒドラジン化合物（Ｈ２Ｎ－ＮＨ－ＣＯ-Ｙ－Ｖ）との反応は、トリエチルアミン塩酸塩等の存在下、加熱することにより行われる。反応溶媒としては、キシレン等を用いるのが好ましい。 The reaction of the compound (110) and the hydrazine compound (H 2 N—NH—CO—YV) is carried out by heating in the presence of triethylamine hydrochloride or the like. As the reaction solvent, xylene or the like is preferably used.

　（Ａ－１５）の構造を有するアルデヒド（２ｔ）は、例えば次の式に従って合成することができる。 The aldehyde (2t) having the structure (A-15) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034

（式中、Ｙ、Ａｍは前記と同じ） (Wherein Y and Am are the same as above)

　化合物（１１４）をヒドラジンへと変換し、次いでアルデヒド（ＯＨＣ－Ｙ－Ａｍ）と反応させて化合物（１１６）を得る。化合物（１１６）を酸化的に環化して化合物（１１７）を得、化合物（１１７）に対し前記化合物（４５）からアルデヒド（２ｆ）への反応と同様の反応を行うことによりアルデヒド（２ｔ）が得られる。 Compound (114) is converted to hydrazine and then reacted with aldehyde (OHC-Y-Am) to obtain compound (116). Compound (116) is oxidatively cyclized to obtain compound (117). Compound (117) is subjected to a reaction similar to the reaction from compound (45) to aldehyde (2f) to give aldehyde (2t). can get.

　化合物（１１６）の環化反応は、酸化剤を用いることで行われる。酸化剤としてはクロラミンＴ等が用いられる。 The cyclization reaction of the compound (116) is performed using an oxidizing agent. As the oxidizing agent, chloramine T or the like is used.

　（Ａ－１７）の構造を有するアルデヒド（２ｕ）は、例えば次の式に従って合成することができる。 The aldehyde (2u) having the structure (A-17) can be synthesized, for example, according to the following formula.

Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035

（式中、Ｑはボロン酸やボロン酸エステル等の官能基を示し、Ｙ、Ａｍは前記と同じ） (Wherein Q represents a functional group such as boronic acid or boronic acid ester, and Y and Am are the same as above)

　化合物（１１９）をチオールへと変換し、次いで環化反応および臭素化して化合物（１２１）を得る。化合物（１２１）をＱ－Ｙ－Ａｍを前記化合物（３６）から化合物（３７）への反応と同様の方法で反応させて化合物（１２２）を得る。化合物（１２２）に対し前記化合物（４５）からアルデヒド（２ｆ）への反応と同様の反応を行うことによりアルデヒド（２ｕ）が得られる。 Compound (119) is converted to thiol, then cyclized and brominated to give compound (121). Compound (122) is obtained by reacting compound (121) with QY-Am in the same manner as in the reaction from compound (36) to compound (37). The compound (122) is subjected to a reaction similar to the reaction from the compound (45) to the aldehyde (2f) to obtain the aldehyde (2u).

　化合物（１１９）のチオールへの変換は、硫化ナトリウム等を用いることにより行われる。 Conversion of compound (119) to thiol is performed by using sodium sulfide or the like.

　化合物（１２０）の環化反応および臭素化は、臭素を用いることで同時に行われる。 The cyclization reaction and bromination of the compound (120) are simultaneously performed using bromine.

Ｋｉｍ　Ｏ　ｅｔ　ａｌ．，Ｊ　Ｍｅｄ　Ｃｈｅｍ，５４，２４５５－２５６（２０１１）Kim O et al. , J Med Chem, 54, 2455-256 (2011) Ｓａｉｔｏｈ　Ｍ　ｅｔ　ａｌ．，Ｊ　Ｍｅｄ　Ｃｈｅｍ，５２，６２７０－８６（２００９）Saitoh M et al. , J Med Chem, 52, 6270-86 (2009) Ａｋｋａｏｕｉ　Ａ　Ｅ　ｅｔ　ａｌ．，Ｅｕｒ　Ｊ　Ｏｒｇ　Ｃｈｅｍ，８６２－７１（２０１０）Akokaui A E et al. , Eur J Org Chem, 862-71 (2010) Ｗｉｓｈｋａ　Ｄ　Ｇ　ｅｔ　ａｌ．，Ｊ　Ｍｅｄ　Ｃｈｅｍ，４９，４４２５－３６（２００６）Wishka D G et al. , J Med Chem, 49, 4425-36 (2006). Ｃｈａｒｔｏｉｒｅ　Ａ　ｅｔ　ａｌ．，Ｔｅｔｒａｈｅｄｒｏｎ，６４，１０８６７－８７３　（２００８）Chartire A et al. , Tetrahedron, 64, 10867-873 (2008) Ｓｈｉｏｔａｎｉ　Ｓ　ｅｔ　ａｌ．，Ｊ　Ｈｅｔｅｒｏｃｙｃｌｉｃ　Ｃｈｅｍ，２１，７２５－３６（１９８４）Shiotani S et al. , J Heterocyclic Chem, 21, 725-36 (1984). Ｙａｍｇｕｃｈｉ　Ｓ　ｅｔ　ａｌ．，Ｊ　Ｈｅｔｅｒｏｃｙｃｌｉｃ　Ｃｈｅｍ，３５，１２４９－５５（１９９８）Yamaguchi S et al. , J Heterocyclic Chem, 35, 1249-55 (1998).

ＷＯ２００９／５０１８３Ａ２WO2009 / 50183A2 ＷＯ２００４／０３９８１５WO2004 / 039815

　本発明化合物（１）又はその塩は、後記実施例に示すように優れたＰｉｍ阻害作用を有し、がん細胞増殖抑制作用及びアポトーシス誘導作用を有することから、抗がん剤、関節リウマチ治療薬、血管新生抑制剤、抗がん剤耐性克服剤や抗がん剤効果増強剤等の医薬として有用である。また、本発明においてＰｉｍ阻害作用はＰｉｍ－１、Ｐｉｍ－２又はＰｉｍ－３のうちいずれか１つのアイソザイムに効果があればよいが、全てのアイソザイムに効果があることがより好ましい。さらに、Ｐｉｍ阻害作用は後述の方法（試験例１）により求められるＰｉｍに対する阻害作用（ＩＣ50）（Ｐｉｍ活性を５０％阻害する化合物の濃度）が１μＭ以下であるものが好ましい。また、がん細胞増殖抑制作用は後述の方法（試験例２）により求められる増殖抑制作用（ＩＣ50）（細胞増殖を５０％抑制する化合物の濃度）が、少なくとも一種のがん細胞について１μＭ以下であるものが特に好ましい。また、代謝安定性とは例えば肝ミクロソーム中での化合物の安定性を指し、安定性が高い方が好ましい。 The compound (1) of the present invention or a salt thereof has an excellent Pim inhibitory action, as shown in Examples below, and has an inhibitory action on cancer cell proliferation and an apoptosis-inducing action. It is useful as a medicine such as a drug, an angiogenesis inhibitor, an anticancer drug resistance-resolving agent, and an anticancer drug effect enhancer. In the present invention, the Pim inhibitory action may be effective for any one of Pim-1, Pim-2, or Pim-3 isozymes, but it is more preferable that all of the isozymes are effective. Further, the Pim inhibitory action is preferably such that the inhibitory action against Pim (IC 50 ) (concentration of the compound that inhibits Pim activity by 50%) determined by the method described later (Test Example 1) is 1 μM or less. In addition, the cancer cell growth inhibitory action has a growth inhibitory action (IC 50 ) (concentration of a compound that inhibits cell growth by 50%) determined by the method described later (Test Example 2) of 1 μM or less for at least one kind of cancer cell. Are particularly preferred. Metabolic stability refers to, for example, the stability of a compound in liver microsomes, and higher stability is preferred.

　本発明化合物（１）は、そのままでも投与することができるが、効果を低減させない範囲内で、分散補助剤、賦形剤等の通常製剤化に使用されるような担体と混合し、粉剤、液剤、カプセル剤、懸濁剤、乳剤、シロップ剤、エリキシル剤、顆粒剤、丸剤、錠剤、トローチ剤、リモネーデ剤等の経口剤又は注射剤等の剤形で使用することができる。
　この様な担体としては、例えば、マンニトール、乳糖、デキストラン等の水溶性の単糖類ないしオリゴ糖類もしくは多糖類；例えばヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース等のゲル形成性又は水溶性のセルロース類；例えば結晶性セルロース、α－セルロース、架橋カルボキシメチルセルロースナトリウム、及びそれらの誘導体等の水吸収性でかつ水難溶性のセルロース類；例えばヒドロキシプロピル澱粉、カルボキシメチル澱粉、架橋澱粉、アミロース、アミロペクチン、ペクチン及びそれらの誘導体等の水吸収性でかつ水難溶性の多糖類；例えばアラビアガム、トラガントガム、グリコマンナン及びそれらの誘導体等の水吸収性でかつ水難溶性のガム類；例えばポリビニルピロリドン、架橋ポリアクリル酸及びその塩、架橋ポリビニルアルコール、ポリヒドロキシエチルメタクリレート及びそれらの誘導体等の架橋ビニル重合体類；リン脂質、コレステロール等のリポソーム等分子集合体を形成する脂質類等を挙げることができる。
　本発明化合物（１）の溶解性が低い場合には、可溶化処理を施すことができる。可溶化処理としては通常医薬に適用できる方法、例えば、ポリオキシエチレンアルコールエーテル類、ポリオキシエチレンアシルエステル類、ソルビタンアシルエステル類、ポリオキシエチレンソルビタンアシルエステル類等の界面活性剤を添加する方法、ポリエチレングリコール等の水溶性高分子を使用する方法等が挙げられる。また、必要により、可溶性の塩にする方法、シクロデキストリン等を用いて包接化合物を形成させる方法等も使用できる。 The compound (1) of the present invention can be administered as it is, but within a range not reducing the effect, it is mixed with a carrier such as a dispersion aid, excipient, etc., which is usually used for formulation, It can be used in the form of oral preparations such as liquids, capsules, suspensions, emulsions, syrups, elixirs, granules, pills, tablets, troches and limonades, or injections.
Examples of such a carrier include water-soluble monosaccharides or oligosaccharides or polysaccharides such as mannitol, lactose, and dextran; for example, gel-forming or water-soluble celluloses such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose; Water-absorbing and poorly water-soluble celluloses such as crystalline cellulose, α-cellulose, crosslinked sodium carboxymethylcellulose, and derivatives thereof; for example, hydroxypropyl starch, carboxymethyl starch, crosslinked starch, amylose, amylopectin, pectin and the like Water-absorbing and poorly water-soluble polysaccharides such as derivatives thereof; water-absorbing and poorly water-soluble gums such as gum arabic, tragacanth gum, glycomannan and derivatives thereof; Examples include crosslinked vinyl polymers such as bridged polyacrylic acid and salts thereof, crosslinked polyvinyl alcohol, polyhydroxyethyl methacrylate and derivatives thereof; and lipids that form molecular aggregates such as liposomes such as phospholipids and cholesterol. .
When the solubility of the compound (1) of the present invention is low, a solubilization treatment can be performed. As a solubilization treatment, a method that can be generally applied to a medicine, for example, a method of adding a surfactant such as polyoxyethylene alcohol ethers, polyoxyethylene acyl esters, sorbitan acyl esters, polyoxyethylene sorbitan acyl esters, Examples thereof include a method using a water-soluble polymer such as polyethylene glycol. Further, if necessary, a method of forming a soluble salt, a method of forming an inclusion compound using cyclodextrin, and the like can be used.

　本発明の医薬の投与量は、投与法や患者の症状等に合わせて適宜調整すればよいが、本発明化合物（１）又はその塩として成人１日あたり１ｍｇ～１０ｇ、さらに１００ｍｇ～１０ｇ、特に５００ｍｇ～１０ｇ投与するのが好ましい。 The dosage of the pharmaceutical agent of the present invention may be appropriately adjusted according to the administration method, patient's symptoms, etc., but the compound (1) or a salt thereof of the present invention is 1 mg to 10 g, more preferably 100 mg to 10 g, in particular, 500 mg to 10 g is preferably administered.

　また、本発明のＰｉｍ阻害剤は、上記のような医薬品製剤として用いるだけでなく、飲食品等として用いることもできる。この場合には、本発明化合物（１）又はその塩をそのまま、または各種の栄養成分を加えて、飲食品に含有せしめればよい。この飲食品は、がんの転移及び装飾、関節リウマチ等の改善、予防等に有用な保健用食品又は食品素材として利用でき、これらの飲食品又はその容器には、前記の効果を有する旨の表示を付してもよい。具体的に本発明のＰｉｍ阻害剤を飲食品に配合する場合は、飲食品して使用可能な添加剤を適宜使用し、慣用の手段を用いて食用に適した形態、例えば、顆粒状、粒状、錠剤、カプセル、ペースト等に成形してもよく、また各種の食品、例えば、ハム、ソーセージ等の食肉加工品、かまぼこ、ちくわ等の水産加工物、パン、菓子、バター、粉乳、乳酸菌飲料、発酵乳、発酵豆乳などの発酵飲食品に添加して使用してもよい。なお、飲食品には動物飼料も含まれる。 Moreover, the Pim inhibitor of the present invention can be used not only as a pharmaceutical preparation as described above but also as a food or drink. In this case, the compound (1) or a salt thereof of the present invention may be contained in food or drink as it is or with various nutritional components added. These foods and drinks can be used as health foods or food materials useful for the improvement and prevention of cancer metastasis and decoration, rheumatoid arthritis, etc., and these foods and drinks or containers thereof have the effects described above. An indication may be attached. Specifically, when the Pim inhibitor of the present invention is blended in a food or drink, an additive that can be used as a food or drink is appropriately used, and a form suitable for food using conventional means, for example, granular or granular , Tablets, capsules, pastes, etc., and various foods such as processed meat products such as ham and sausage, fishery products such as kamaboko and chikuwa, bread, confectionery, butter, milk powder, lactic acid bacteria beverages, You may add and use for fermented foods and drinks, such as fermented milk and fermented soymilk. The food and drink includes animal feed.

　次に実施例を挙げて、本発明を詳細に説明する。 Next, the present invention will be described in detail with reference to examples.

実施例１
5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１) Example 1
5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 1)

工程１
3-フルオロ-N-メトキシ-N-メチル-4-ニトロベンズアミド Process 1
3-Fluoro-N-methoxy-N-methyl-4-nitrobenzamide

Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036

　3-フルオロ-4-ニトロ安息香酸 (4.7 g, 25.4 mmol) のジクロロメタン溶液に 0 ℃ でN,N-ジメチルホルムアミド (2 drops)、塩化オキサリル (2.2 mL, 25.7 mmol) を加え、0 ℃ で 10 分撹拌した。室温に戻して 1 時間撹拌した後、0 ℃ で N,O-ジメチルヒドロキシルアミン塩酸塩を加えた。0 ℃ で 10 分撹拌した後、室温で 64 時間撹拌した。反応終了後、反応溶液に水を加え、有機層を飽和重曹水で洗浄した後、1規定 塩酸で 3 回洗浄した。水層を 酢酸エチルで抽出した後、有機層を合わせ、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、目的とする標記化合物 (4.4 g, 収率 76 %) を得た。黄色結晶: 1H-NMR (CDCl3) δ: 8.12-8.08 (1H, m), 7.65-7.61 (2H, m), 3.57 (3H, s), 3.41 (3H, s). To a dichloromethane solution of 3-fluoro-4-nitrobenzoic acid (4.7 g, 25.4 mmol), N, N-dimethylformamide (2 drops) and oxalyl chloride (2.2 mL, 25.7 mmol) were added at 0 ° C. Stir for minutes. After returning to room temperature and stirring for 1 hour, N, O-dimethylhydroxylamine hydrochloride was added at 0 ° C. The mixture was stirred at 0 ° C. for 10 minutes and then stirred at room temperature for 64 hours. After completion of the reaction, water was added to the reaction solution, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate, and then washed 3 times with 1N hydrochloric acid. The aqueous layer was extracted with ethyl acetate, and then the organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired title compound (4.4 g, yield 76%). Yellow crystals: 1 H-NMR (CDCl 3 ) δ: 8.12-8.08 (1H, m), 7.65-7.61 (2H, m), 3.57 (3H, s), 3.41 (3H, s).

工程２
N-メトキシ-N-メチル-3-((3-モルホリノプロピル)アミノ)-4-ニトロベンズアミド Process 2
N-methoxy-N-methyl-3-((3-morpholinopropyl) amino) -4-nitrobenzamide

Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037

　3-フルオロ-N-メトキシ-N-メチル-4-ニトロベンズアミド (1.0 g, 4.38 mmol) のN,N-ジメチルホルムアミド (3 mL) 溶液にN-(3-アミノプロピル)モルホリン (694 mg, 4.82 mmol)、無水炭酸カリウム (1.51 g, 10.95 mmol) を加え、70 ℃で一晩撹拌した。反応終了後、反応溶液に水を加え、ジエチルエーテル/n-ヘキサン= 1/1 溶液で抽出した。有機層を無水硫酸マグネシウムで乾燥した後、減圧下溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法で精製し、目的とする標記化合物 (744 mg, 26 %) を得た。黄色結晶: 1H-NMR (CDCl3) δ: 8.36 (1H, s), 8.19 (1H, d, J = 8.8 Hz), 7.14 (1H, d, J = 1.5 Hz), 6.83 (1H, dd, J = 8.8, 1.5 Hz), 3.76 (4H, t, J = 4.6 Hz), 3.58 (3H, s), 3.45-3.41 (2H, m), 3.36 (3H, s), 2.50-2.46 (6H, m), 1.93-1.87 (2H, m). N- (3-aminopropyl) morpholine (694 mg, 4.82) in a solution of 3-fluoro-N-methoxy-N-methyl-4-nitrobenzamide (1.0 g, 4.38 mmol) in N, N-dimethylformamide (3 mL) mmol) and anhydrous potassium carbonate (1.51 g, 10.95 mmol) were added, and the mixture was stirred at 70 ° C. overnight. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with diethyl ether / n-hexane = 1/1 solution. After drying the organic layer with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain the title compound of interest (744 mg, 26%). Yellow crystals: 1 H-NMR (CDCl 3 ) δ: 8.36 (1H, s), 8.19 (1H, d, J = 8.8 Hz), 7.14 (1H, d, J = 1.5 Hz), 6.83 (1H, dd, J = 8.8, 1.5 Hz), 3.76 (4H, t, J = 4.6 Hz), 3.58 (3H, s), 3.45-3.41 (2H, m), 3.36 (3H, s), 2.50-2.46 (6H, m ), 1.93-1.87 (2H, m).

工程３
N-メトキシ-N-メチル-1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 3
N-methoxy-N-methyl-1- (3-morpholinopropyl) -1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038

　N-メトキシ-N-メチル-3-((3-モルホリノプロピル)アミノ)-4-ニトロベンズアミド (774 mg, 2.20 mmol) の エタノール (20 mL) 溶液に 10% パラジウム－活性炭 (300 mg) を加え、水素雰囲気下、室温で 64 時間撹拌した。反応終了後、反応溶液をろ過し、減圧下溶媒を留去した。得られた粗生成物をエタノール (10 mL) に溶かし、オルトギ酸トリエチル (1.2 mL, 7.2 mmol)、1規定 塩酸 (2 mL) を加え、室温で一晩撹拌した。減圧下溶媒を留去した後、反応混合物に酢酸エチル、1規定 塩酸を加え水層を酢酸エチルで洗浄した。水層に飽和重曹水を加え、系を塩基性にした後、クロロホルムで 3 回抽出した。有機層を合わせ、無水硫酸マグネシウムで乾燥した後、溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法で精製し、目的とする標記化合物 (331 mg, 51 %) を得た。黄色液体: 1H-NMR (DMSO-D6) δ: 8.34 (1H, s), 7.90 (1H, d, J = 0.7 Hz), 7.67 (1H, d, J = 8.3 Hz), 7.44 (1H, dd, J = 8.3, 0.7 Hz), 4.32 (2H, t, J = 6.8 Hz), 3.54-3.52 (7H, m), 3.27 (3H, s), 2.26 (4H, br s), 2.18 (2H, t, J= 6.7 Hz), 1.97-1.91 (2H, m). To a solution of N-methoxy-N-methyl-3-((3-morpholinopropyl) amino) -4-nitrobenzamide (774 mg, 2.20 mmol) in ethanol (20 mL) was added 10% palladium-activated carbon (300 mg). The mixture was stirred at room temperature for 64 hours under a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered and the solvent was distilled off under reduced pressure. The obtained crude product was dissolved in ethanol (10 mL), triethyl orthoformate (1.2 mL, 7.2 mmol) and 1N hydrochloric acid (2 mL) were added, and the mixture was stirred at room temperature overnight. After evaporating the solvent under reduced pressure, ethyl acetate and 1N hydrochloric acid were added to the reaction mixture, and the aqueous layer was washed with ethyl acetate. Saturated aqueous sodium hydrogen carbonate was added to the aqueous layer to make the system basic, followed by extraction with chloroform three times. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained crude product was purified by silica gel column chromatography to obtain the target title compound (331 mg, 51%). Yellow liquid: 1 H-NMR (DMSO-D 6 ) δ: 8.34 (1H, s), 7.90 (1H, d, J = 0.7 Hz), 7.67 (1H, d, J = 8.3 Hz), 7.44 (1H, dd, J = 8.3, 0.7 Hz), 4.32 (2H, t, J = 6.8 Hz), 3.54-3.52 (7H, m), 3.27 (3H, s), 2.26 (4H, br s), 2.18 (2H, t, J = 6.7 Hz), 1.97-1.91 (2H, m).

工程４
1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒド Process 4
1- (3-morpholinopropyl) -1H-benzo [d] imidazole-6-carboxaldehyde

Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039

　アルゴン雰囲気下、N-メトキシ-N-メチル-1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド (338 mg, 1.12 mmol) のテトラヒドロフラン (THF) (10 mL) 溶液にビスシクロペンタジエニルジルコニウム(ＩＶ)クロリドヒドリド (Cp2Zr(H)Cl) (433 mg, 1.68 mmol) を加え、室温で 2 時間撹拌した。反応終了後、減圧下溶媒を留去し、得られた粗生成物をシリカゲルカラムクロマトグラフィー法で精製し、目的とする標記化合物 (83 mg, 27 %)を得た。黄色液体: 1H-NMR (CDCl3) δ: 10.10 (1H, s), 8.10 (1H, s), 8.05 (1H, dd, J = 1.5, 0.7 Hz), 7.91 (1H, dd, J = 8.3, 0.7 Hz), 7.81 (1H, dd, J = 8.3, 1.5 Hz), 4.37 (2H, t, J = 6.6 Hz), 3.72 (4H, t, J = 4.0 Hz), 2.38 (4H, t, J = 4.0 Hz), 2.25 (2H, t, J = 6.5 Hz), 2.09-2.01 (2H, m). N-methoxy-N-methyl-1- (3-morpholinopropyl) -1H-benzo [d] imidazole-6-carboxamide (338 mg, 1.12 mmol) in tetrahydrofuran (THF) (10 mL) under an argon atmosphere Biscyclopentadienylzirconium (IV) chloride hydride (Cp 2 Zr (H) Cl) (433 mg, 1.68 mmol) was added to the mixture, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to obtain the desired title compound (83 mg, 27%). Yellow liquid: 1 H-NMR (CDCl 3 ) δ: 10.10 (1H, s), 8.10 (1H, s), 8.05 (1H, dd, J = 1.5, 0.7 Hz), 7.91 (1H, dd, J = 8.3 , 0.7 Hz), 7.81 (1H, dd, J = 8.3, 1.5 Hz), 4.37 (2H, t, J = 6.6 Hz), 3.72 (4H, t, J = 4.0 Hz), 2.38 (4H, t, J = 4.0 Hz), 2.25 (2H, t, J = 6.5 Hz), 2.09-2.01 (2H, m).

工程５
5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１) Process 5
5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 1)

Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040

　1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒド (83 mg, 0.3 mmol)、ロダニン (39 mg, 0.29 mmol) のエタノール (6 mL) 溶液に ピペリジン (6 mg, 0.08 mmol) を加え 70 ℃で一晩撹拌した。反応溶液に酢酸エチルを加え、結晶を析出させた後、ろ過し、酢酸エチルで洗浄して標記化合物 (38 mg, 37 %) を得た。 黄色結晶: 1H-NMR (DMSO-D6) δ: 12.72 (1H, br s), 8.38 (1H, s), 7.85 (1H, s), 7.77 (1H, d, J= 9.0 Hz), 7.68 (1H, s), 7.42 (1H, d, J= 9.0 Hz), 4.35 (2H, t, J = 6.1 Hz), 3.60 (4H, s), 3.31 (4H, s), 2.56-2.52 (2H, m), 2.06 (2H, t, J = 6.7 Hz).
ESI-MS(m/z): 389[M+H]+. Piperidine (6 mg, 1- (3-morpholinopropyl) -1H-benzo [d] imidazole-6-carboxaldehyde (83 mg, 0.3 mmol), rhodanine (39 mg, 0.29 mmol) in ethanol (6 mL) 0.08 mmol) was added and stirred at 70 ° C. overnight. Ethyl acetate was added to the reaction solution to precipitate crystals, then filtered and washed with ethyl acetate to obtain the title compound (38 mg, 37%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 12.72 (1H, br s), 8.38 (1H, s), 7.85 (1H, s), 7.77 (1H, d, J = 9.0 Hz), 7.68 (1H, s), 7.42 (1H, d, J = 9.0 Hz), 4.35 (2H, t, J = 6.1 Hz), 3.60 (4H, s), 3.31 (4H, s), 2.56-2.52 (2H, m), 2.06 (2H, t, J = 6.7 Hz).
ESI-MS (m / z): 389 [M + H] + .

実施例２
5-((1-(1-メチルピペリジン-4-イル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物２) Example 2
5-((1- (1-Methylpiperidin-4-yl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 2)

工程１
N-メトキシ-N-メチル-3-((1-メチルピペリジン-4-イル)アミノ)-4-ニトロベンズアミド Process 1
N-methoxy-N-methyl-3-((1-methylpiperidin-4-yl) amino) -4-nitrobenzamide

Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041

　N-メトキシ-N-メチル-3-((3-モルホリノプロピル)アミノ)-4-ニトロベンズアミドの合成と同様の方法で 3-フルオロ-N-メトキシ-N-メチル-4-ニトロベンズアミド (0.31 g, 1.36 mmol)および4-アミノ-1-メチルピペリジン(171 mg, 1.5 mmol)とから標記化合物 (0.42 g, 99 %)を得た。1H-NMR (CDCl3) δ: 8.20(1H, d, J = 8.8 Hz), 8.12(1H, d, J = 6.6 Hz), 7.11(1H, d, J = 1.5 Hz), 6.85 (1H, d, J = 8.8 Hz), 3.60(1H, br s), 3.58(3H, s), 3.37(3H, s), 2.89(2H, br s), 2.40(3H, br s), 2.38(2H, br s), 2.14(2H, br s), 1.81(2H, br s). In the same way as the synthesis of N-methoxy-N-methyl-3-((3-morpholinopropyl) amino) -4-nitrobenzamide 3-fluoro-N-methoxy-N-methyl-4-nitrobenzamide (0.31 g , 1.36 mmol) and 4-amino-1-methylpiperidine (171 mg, 1.5 mmol) gave the title compound (0.42 g, 99%). 1 H-NMR (CDCl 3 ) δ: 8.20 (1H, d, J = 8.8 Hz), 8.12 (1H, d, J = 6.6 Hz), 7.11 (1H, d, J = 1.5 Hz), 6.85 (1H, d, J = 8.8 Hz), 3.60 (1H, br s), 3.58 (3H, s), 3.37 (3H, s), 2.89 (2H, br s), 2.40 (3H, br s), 2.38 (2H, br s), 2.14 (2H, br s), 1.81 (2H, br s).

工程２
N-メトキシ-N-メチル-1-(1-メチルピペリジン-4-イル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 2
N-methoxy-N-methyl-1- (1-methylpiperidin-4-yl) -1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042

　N-メトキシ-N-メチル-1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミドの合成と同様の方法で N-メトキシ-N-メチル-3-((1-メチルピペリジン-4-イル)アミノ)-4-ニトロベンズアミド (0.42 g, 1.30 mmol)を用い、標記化合物 (0.17 g, 41 %)を得た。1H-NMR (CDCl3) δ: 8.10(1H, s), 7.87(1H, s), 7.81(1H, d, J= 8.4 Hz), 7.66(1H, d, J = 8.4 Hz), 4.30(1H, br s), 3.58 (3H, s), 3.41(3H, s), 3.17(2H, br s), 2.53-2.15 (9H, m). N-methoxy-N-methyl-1- (3-morpholinopropyl) -1H-benzo [d] imidazole-6-carboxamide is synthesized in the same manner as N-methoxy-N-methyl-3-((1- Methylpiperidin-4-yl) amino) -4-nitrobenzamide (0.42 g, 1.30 mmol) was used to obtain the title compound (0.17 g, 41%). 1 H-NMR (CDCl 3 ) δ: 8.10 (1H, s), 7.87 (1H, s), 7.81 (1H, d, J = 8.4 Hz), 7.66 (1H, d, J = 8.4 Hz), 4.30 ( 1H, br s), 3.58 (3H, s), 3.41 (3H, s), 3.17 (2H, br s), 2.53-2.15 (9H, m).

工程３
1-(1-メチルピペリジン-4-イル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒド Process 3
1- (1-Methylpiperidin-4-yl) -1H-benzo [d] imidazole-6-carboxaldehyde

Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043

　1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒドの合成と同様の方法で、N-メトキシ-N-メチル-1-(1-メチルピペリジン-4-イル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド (0.17 g, 0.56 mmol)を用い、標記化合物 (0.14 g, 100 %)を得た。 In the same manner as the synthesis of 1- (3-morpholinopropyl) -1H-benzo [d] imidazole-6-carboxaldehyde, N-methoxy-N-methyl-1- (1-methylpiperidin-4-yl)- Using 1H-benzo [d] imidazole-6-carboxamide (0.17 g, 0.56 mmol), the title compound (0.14 g, 100%) was obtained.

工程４
5-((1-(1-メチルピペリジン-4-イル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物２) Process 4
5-((1- (1-Methylpiperidin-4-yl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 2)

Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044

　5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成と同様の方法で、1-(1-メチルピペリジン-4-イル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒド (0.14 g, 0.56 mmol) およびロダニン (80 mg, 0.6 mmol) とから標記化合物 (31 mg, 15 %) を得た。1H-NMR (DMSO-D6) δ: 10.30(1H, br s), 8.51(1H, s), 8.03(1H, s), 7.84(1H, d, J = 8.5 Hz), 7.76(1H, s), 7.46(1H, d, J = 8.5 Hz), 4.75(1H, br s), 3.61(2H, br s), 2.87(3H, br s), 2.50-2.30(6H, m).
ESI-MS(m/z): 359[M+H]+. In a manner similar to the synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one, The title compound (31 mg, 15%) was obtained from methylpiperidin-4-yl) -1H-benzo [d] imidazole-6-carboxaldehyde (0.14 g, 0.56 mmol) and rhodanine (80 mg, 0.6 mmol). . 1 H-NMR (DMSO-D 6 ) δ: 10.30 (1H, br s), 8.51 (1H, s), 8.03 (1H, s), 7.84 (1H, d, J = 8.5 Hz), 7.76 (1H, s), 7.46 (1H, d, J = 8.5 Hz), 4.75 (1H, br s), 3.61 (2H, br s), 2.87 (3H, br s), 2.50-2.30 (6H, m).
ESI-MS (m / z): 359 [M + H] + .

実施例３
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物３) Example 3
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 3)

工程１
N-メトキシ-N-メチル-3-(4-(4-メチルピペラジン-1-イル)フェニルアミノ)-4-ニトロベンズアミド Process 1
N-methoxy-N-methyl-3- (4- (4-methylpiperazin-1-yl) phenylamino) -4-nitrobenzamide

Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045

　N-メトキシ-N-メチル-3-((3-モルホリノプロピル)アミノ)-4-ニトロベンズアミドの合成と同様の方法で 3-フルオロ-N-メトキシ-N-メチル-4-ニトロベンズアミド (0.45 g, 2.0 mmol) と1-メチル-4-(4-アミノフェニル)ピペラジン (0.5 g, 2.5 mmol) とから標記化合物 (0.57 g, 71 %) を得た。1H-NMR (CDCl3) δ: 9.44(1H, br s), 8.22(1H, d, J = 9.0 Hz), 7.27(1H, s), 7.17(2H, d, J = 8.8 Hz), 6.97(2H, d, J = 6.8 Hz), 6.89(1H, dd, J = 7.1, 1.7 Hz), 3.52(3H, s), 3.32-3.26(4H, br s), 3.92(3H, s), 2.68(4H, br s), 2.43(3H, br s). In the same manner as the synthesis of N-methoxy-N-methyl-3-((3-morpholinopropyl) amino) -4-nitrobenzamide 3-Fluoro-N-methoxy-N-methyl-4-nitrobenzamide (0.45 g , 2.0 mmol) and 1-methyl-4- (4-aminophenyl) piperazine (0.5 g, 2.5 mmol) gave the title compound (0.57 g, 71%). 1 H-NMR (CDCl 3 ) δ: 9.44 (1H, br s), 8.22 (1H, d, J = 9.0 Hz), 7.27 (1H, s), 7.17 (2H, d, J = 8.8 Hz), 6.97 (2H, d, J = 6.8 Hz), 6.89 (1H, dd, J = 7.1, 1.7 Hz), 3.52 (3H, s), 3.32-3.26 (4H, br s), 3.92 (3H, s), 2.68 (4H, br s), 2.43 (3H, br s).

工程２
N-メトキシ-N-メチル-1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 2
N-methoxy-N-methyl-1- (4- (4-methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046

　N-メトキシ-N-メチル-1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミドの合成と同様の方法で N-メトキシ-N-メチル-3-(4-(4-メチルピペラジン-1-イル)フェニルアミノ)-4-ニトロベンズアミド (0.57 g, 1.4 mmol) を用い、標記化合物 (0.26 g, 49 %) を得た。1H-NMR (CDCl3) δ: 8.14(1H, s), 7.87(1H, s), 7.86(1H, d, J= 6.8 Hz), 7.68(1H, dd, J = 7.1, 1.5 Hz), 7.39(2H, d, J = 6.8 Hz), 7.18(2H, d, J = 6.8 Hz), 3.56(3H, s), 3.38(3H, s), 3.35(4H, br s), 2.68(2H, br s), 2.43 (3H, br s).  N-methoxy-N-methyl-1- (3-morpholinopropyl) -1H-benzo [d] imidazole-6-carboxamide is synthesized in the same manner as N-methoxy-N-methyl-3- (4- ( Using 4-methylpiperazin-1-yl) phenylamino) -4-nitrobenzamide (0.57 g, 1.4 mmol), the title compound (0.26 g, 49%) was obtained. 1 H-NMR (CDCl 3 ) δ: 8.14 (1H, s), 7.87 (1H, s), 7.86 (1H, d, J = 6.8 Hz), 7.68 (1H, dd, J = 7.1, 1.5 Hz), 7.39 (2H, d, J = 6.8 Hz), 7.18 (2H, d, J = 6.8 Hz), 3.56 (3H, s), 3.38 (3H, s), 3.35 (4H, br s), 2.68 (2H, br s), 2.43 (3H, br s).

工程３
1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒド Process 3
1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxaldehyde

Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047

　1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒドの合成と同様の方法で、N-メトキシ-N-メチル-1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミドを用い、標記化合物 (225 mg, 41 %) を得た。赤褐色結晶：1H-NMR (CDCl3) δ: 10.07 (1H, s), 8.22 (1H, s), 8.01 (1H, t, J = 0.7 Hz), 7.97 (1H, d, J = 8.3 Hz), 7.87 (1H, dd, J = 8.3, 0.7 Hz), 7.38 (2H, d, J = 9.0 Hz), 7.09 (2H, d, J = 9.0 Hz), 3.33 (4H, t, J = 5.0 Hz), 2.63 (4H, t, J = 5.0 Hz), 2.40 (3H, s).  In a manner similar to the synthesis of 1- (3-morpholinopropyl) -1H-benzo [d] imidazole-6-carboxaldehyde, N-methoxy-N-methyl-1- (4- (4-methylpiperazine-1- Yl) phenyl) -1H-benzo [d] imidazole-6-carboxamide was used to obtain the title compound (225 mg, 41%). Reddish brown crystal: 1 H-NMR (CDCl 3 ) δ: 10.07 (1H, s), 8.22 (1H, s), 8.01 (1H, t, J = 0.7 Hz), 7.97 (1H, d, J = 8.3 Hz) , 7.87 (1H, dd, J = 8.3, 0.7 Hz), 7.38 (2H, d, J = 9.0 Hz), 7.09 (2H, d, J = 9.0 Hz), 3.33 (4H, t, J = 5.0 Hz) , 2.63 (4H, t, J = 5.0 Hz), 2.40 (3H, s).

工程４
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物３) Process 4
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 3)

Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048

　5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成と同様の方法で、1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒド (0.22 g, 0.70 mmol) およびロダニン (93 g, 0.70 mmol) とから標記化合物 (212 mg, 66 %) を得た。黄色結晶：1H-NMR (DMSO-D6) δ: 11.16 (1H, br s), 8.56 (1H, s), 7.84 (1H, d, J = 8.5 Hz), 7.68 (1H, s), 7.58 (2H, d, J = 9.0 Hz), 7.50-7.48 (2H, m), 7.24 (2H, d, J = 9.0 Hz), 3.45 (4H, s), 3.09 (4H, s), 2.67 (3H, s).
ESI-MS(m/z): 436[M+H]+. In a manner similar to the synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one, (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxaldehyde (0.22 g, 0.70 mmol) and rhodanine (93 g, 0.70 mmol) and the title compound (212 mg, 66 %). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 11.16 (1H, br s), 8.56 (1H, s), 7.84 (1H, d, J = 8.5 Hz), 7.68 (1H, s), 7.58 (2H, d, J = 9.0 Hz), 7.50-7.48 (2H, m), 7.24 (2H, d, J = 9.0 Hz), 3.45 (4H, s), 3.09 (4H, s), 2.67 (3H, s).
ESI-MS (m / z): 436 [M + H] + .

実施例４
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物４) Example 4
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 4)

Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049

工程１
　5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成と同様の方法で、1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒド (300 mg, 0.94 mmol) および2,4-チアゾリジンジオン (104 mg, 0.89 mmol) とから標記化合物 (289 mg, 77%) を得た。黄色結晶：1H-NMR (DMSO-D6) δ: 11.82 (1H, br s), 8.59 (1H, s), 7.86 (1H, d, J = 8.5 Hz), 7.83 (1H, s), 7.78 (1H, s), 7.55-7.50 (3H, m), 7.20 (2H, d, J= 9.0 Hz), 3.33 (4H, t, J = 4.8 Hz), 2.72 (4H, t, J = 4.8 Hz), 2.41 (3H, s). Process 1
In a manner similar to the synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one, (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxaldehyde (300 mg, 0.94 mmol) and 2,4-thiazolidinedione (104 mg, 0.89 mmol) (289 mg, 77%) was obtained. Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 11.82 (1H, br s), 8.59 (1H, s), 7.86 (1H, d, J = 8.5 Hz), 7.83 (1H, s), 7.78 (1H, s), 7.55-7.50 (3H, m), 7.20 (2H, d, J = 9.0 Hz), 3.33 (4H, t, J = 4.8 Hz), 2.72 (4H, t, J = 4.8 Hz) , 2.41 (3H, s).

実施例５
5-((2-メチル-1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物５) Example 5
5-((2-Methyl-1- (4- (4-methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one (Compound 5)

工程１
N-メトキシ-N,2-ジメチル-1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 1
N-methoxy-N, 2-dimethyl-1- (4- (4-methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050

　4-アミノ-N-メトキシ-N-メチル-3-(4-(4-メチルピペラジン-1-イル)フェニル)アミノベンズアミド (369 mg, 1.00 mmol) をエタノール (3.00 mL) に溶かし、酢酸 (114 μL, 2.0 mmol) およびオルト酢酸トリエチル (1.80 mL, 10.0 mmol) を加え、50℃のオイルバス中で3時間撹拌した。反応混合物を室温にもどし、減圧下溶媒を留去した。残渣物にクロロホルムを加え重曹水で洗浄し、有機層を無水硫酸ナトリウムで乾燥させ、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法で精製し、標記化合物 (317 mg, 81 %) を得た。黄肌色固体: 1H-NMR (DMSO-D6) δ: 7.63 (1H, d, J = 8.3 Hz), 7.49 (1H, d, J = 8.3 Hz), 7.36 (2H, d, J = 9.0 Hz), 7.33 (1H, br s), 7.14 (2H, d, J = 9.0 Hz), 3.49 (3H, s), 3.27 (4H, t, J = 5.0 Hz), 3.23 (3H, s), 2.48 (4H, t, J = 5.0 Hz), 2.43 (3H, s), 2.25 (3H, s).
ESI-MS(m/z): 394[M+H]+. 4-Amino-N-methoxy-N-methyl-3- (4- (4-methylpiperazin-1-yl) phenyl) aminobenzamide (369 mg, 1.00 mmol) was dissolved in ethanol (3.00 mL) and acetic acid (114 μL, 2.0 mmol) and triethyl orthoacetate (1.80 mL, 10.0 mmol) were added, and the mixture was stirred in an oil bath at 50 ° C. for 3 hours. The reaction mixture was returned to room temperature and the solvent was distilled off under reduced pressure. Chloroform was added to the residue, washed with aqueous sodium hydrogen carbonate, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (317 mg, 81%). Yellowish solid: 1 H-NMR (DMSO-D 6 ) δ: 7.63 (1H, d, J = 8.3 Hz), 7.49 (1H, d, J = 8.3 Hz), 7.36 (2H, d, J = 9.0 Hz) ), 7.33 (1H, br s), 7.14 (2H, d, J = 9.0 Hz), 3.49 (3H, s), 3.27 (4H, t, J = 5.0 Hz), 3.23 (3H, s), 2.48 ( 4H, t, J = 5.0 Hz), 2.43 (3H, s), 2.25 (3H, s).
ESI-MS (m / z): 394 [M + H] + .

工程２
2-メチル-1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒド Process 2
2-Methyl-1- (4- (4-methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxaldehyde

Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051

　N-メトキシ-N,2-ジメチル-1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド (157 mg, 0.40 mmol)の THF (2.5 mL) 溶液に Cp2Zr(H)Cl (206 mg, 0.80 mmol) を0℃で滴下した。室温に昇温し3 時間撹拌した。反応終了後、クロロホルムと飽和重曹水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法で精製し、標記化合物と N-メトキシ-N,2-ジメチル-1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミドの混合物(標記化合物: N-メトキシ-N,2-ジメチル-1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド = 2:1、120 mg, 56 %)を得た。黄褐色固体:1H-NMR (DMSO-D6) δ: 9.99 (1H, s), 7.77 (2H, s), 7.65 (1H, s), 7.40 (2H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.8 Hz), 3.30-3.25 (4H, m), 2.49-2.47 (4H, m), 2.47-2.45 (3H, m), 2.25 (3H, s).
ESI-MS(m/z): 335[M+H]+. N-methoxy-N, 2-dimethyl-1- (4- (4-methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxamide (157 mg, 0.40 mmol) in THF ( 2.5 mL) Cp 2 Zr (H) Cl (206 mg, 0.80 mmol) was added dropwise to the solution at 0 ° C. The mixture was warmed to room temperature and stirred for 3 hours. After completion of the reaction, chloroform and saturated aqueous sodium hydrogen carbonate were added to extract the organic layer, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the title compound and N-methoxy-N, 2-dimethyl-1- (4- (4-methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole Of 6-carboxamide (title compound: N-methoxy-N, 2-dimethyl-1- (4- (4-methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxy Amide = 2: 1, 120 mg, 56%). Tawny solid: 1 H-NMR (DMSO-D 6 ) δ: 9.99 (1H, s), 7.77 (2H, s), 7.65 (1H, s), 7.40 (2H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.8 Hz), 3.30-3.25 (4H, m), 2.49-2.47 (4H, m), 2.47-2.45 (3H, m), 2.25 (3H, s).
ESI-MS (m / z): 335 [M + H] + .

工程３
5-((2-メチル-1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物５) Process 3
5-((2-Methyl-1- (4- (4-methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one (Compound 5)

Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052

　N-メトキシ-N,2-ジメチル-1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミドと2-メチル-1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒドの混合物 (120 mg, 0.22 mmol) の エタノール(10 mL) 溶液に、 ロダニン(29 mg, 0.22 mmol)およびピペリジン(11 μL, 0.11 mmol) を加え、還流条件下 19 時間撹拌した。反応終了後、生成した沈殿をろ過し、エタノールで洗浄して標記化合物 (3.00 mg, 3 %) を得た。黄褐色固体: 1H-NMR (DMSO-D6) δ: 7.68 (1H, d, J = 8.5 Hz), 7.46-7.39 (4H, m), 7.26-7.19 (3H, m), 3.53-3.40 (4H, m), 3.13-2.99 (4H, m), 2.64 (3H, br s), 2.42 (3H, br s).
ESI-MS(m/z): 450[M+H]+. N-methoxy-N, 2-dimethyl-1- (4- (4-methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxamide and 2-methyl-1- (4- To a solution of (4-methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxaldehyde (120 mg, 0.22 mmol) in ethanol (10 mL), rhodanine (29 mg, 0.22 mmol) ) And piperidine (11 μL, 0.11 mmol) were added, and the mixture was stirred for 19 hours under reflux conditions. After completion of the reaction, the resulting precipitate was filtered and washed with ethanol to obtain the title compound (3.00 mg, 3%). Tawny solid: 1 H-NMR (DMSO-D 6 ) δ: 7.68 (1H, d, J = 8.5 Hz), 7.46-7.39 (4H, m), 7.26-7.19 (3H, m), 3.53-3.40 ( 4H, m), 3.13-2.99 (4H, m), 2.64 (3H, br s), 2.42 (3H, br s).
ESI-MS (m / z): 450 [M + H] + .

実施例６
5-((1-(3-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物６) Example 6
5-((1- (3- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 6)

工程１
3-(3-ブロモフェニル)アミノ-N-メトキシ-N-メチル-4-ニトロベンズアミド Process 1
3- (3-Bromophenyl) amino-N-methoxy-N-methyl-4-nitrobenzamide

Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053

　N-メトキシ-N-メチル-3-((3-モルホリノプロピル)アミノ)-4-ニトロベンズアミドの合成と同様の方法で3-フルオロ-N-メトキシ-N-メチル-4-ニトロベンズアミド (3.81 g, 16.7 mmol) と3-ブロモアニリン (3.44 g, 20 mmol) とから標記化合物 (0.42 g, 7 %) を得た。1H-NMR (CDCl3) δ: 9.42 (1H, s), 8.25 (1H, d, J= 8.8 Hz), 7.49 (1H, d, J = 1.7 Hz), 7.45 (1H, m), 7.39 (1H, m), 7.37-7.22 (2H, m), 7.07 (1H, dd, J = 8.8, 1.7 Hz), 3.57 (3H, s), 3.34 (3H, s). In the same manner as the synthesis of N-methoxy-N-methyl-3-((3-morpholinopropyl) amino) -4-nitrobenzamide, 3-fluoro-N-methoxy-N-methyl-4-nitrobenzamide (3.81 g , 16.7 mmol) and 3-bromoaniline (3.44 g, 20 mmol) gave the title compound (0.42 g, 7%). 1 H-NMR (CDCl 3 ) δ: 9.42 (1H, s), 8.25 (1H, d, J = 8.8 Hz), 7.49 (1H, d, J = 1.7 Hz), 7.45 (1H, m), 7.39 ( 1H, m), 7.37-7.22 (2H, m), 7.07 (1H, dd, J = 8.8, 1.7 Hz), 3.57 (3H, s), 3.34 (3H, s).

工程２
1-(3-ブロモフェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 2
1- (3-Bromophenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054

　3-(3-ブロモフェニル)アミノ-N-メトキシ-N-メチル-4-ニトロベンズアミド (0.42 g, 1.2 mmol) をメタノール (40 mL) に溶かし、塩化すず (1.25 g, 6.6 mmol) および酢酸アンモニウム (924 mg, 12 mmol) を加え、70 ℃のオイルバス中で1.5時間撹拌した。原料の消失を確認した後、反応混合物のメタノールを留去し、クロロホルムを加え、セライトパットでろ過し、ろ液を飽和重曹水で洗浄した。有機層を無水硫酸マグネシウムで乾燥させ、減圧下、溶媒を留去した後、残留物 (0.41 g) を酢酸エチル (8 mL) に溶かし、オルトギ酸トリエチル (1.5 mL, 9 mmol) およびピリジニウムパラトルエンスルホン酸 (0.03 g, 0.12 mmol) を加え、50℃のオイルバス中で3時間撹拌した。反応混合物に酢酸エチルを加えた後、0.1 規定 塩酸、飽和重曹水で洗浄した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を留去し、標記化合物 (0.26 g, 63%) を得た。1H-NMR(CDCl3) δ: 8.32(1H, s), 7.94(1H, d, J = 1.0 Hz), 7.92(1H, d, J = 8.5 Hz), 7.76(1H, dd, J = 8.5, 1.5 Hz), 7.72(1H, m), 7.66(1H, m), 7.53-7.47(2H, m), 3.57(3H, s), 3.40(3H, s). 3- (3-Bromophenyl) amino-N-methoxy-N-methyl-4-nitrobenzamide (0.42 g, 1.2 mmol) dissolved in methanol (40 mL), tin chloride (1.25 g, 6.6 mmol) and ammonium acetate (924 mg, 12 mmol) was added, and the mixture was stirred in an oil bath at 70 ° C. for 1.5 hours. After confirming the disappearance of the raw materials, the methanol in the reaction mixture was distilled off, chloroform was added, the mixture was filtered through Celite pad, and the filtrate was washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure.The residue (0.41 g) was dissolved in ethyl acetate (8 mL), triethyl orthoformate (1.5 mL, 9 mmol) and pyridinium paratoluene. Sulfonic acid (0.03 g, 0.12 mmol) was added, and the mixture was stirred in an oil bath at 50 ° C. for 3 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain the title compound (0.26 g, 63%). 1 H-NMR (CDCl 3 ) δ: 8.32 (1H, s), 7.94 (1H, d, J = 1.0 Hz), 7.92 (1H, d, J = 8.5 Hz), 7.76 (1H, dd, J = 8.5 1.5 Hz), 7.72 (1H, m), 7.66 (1H, m), 7.53-7.47 (2H, m), 3.57 (3H, s), 3.40 (3H, s).

工程３
1-(3-ブロモフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒド Process 3
1- (3-Bromophenyl) -1H-benzo [d] imidazole-6-carboxaldehyde

Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055

　1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒドの合成と同様の方法で1-(3-ブロモフェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド (0.26 g, 0.72 mmol)を用い、標記化合物と 1-(3-ブロモフェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミドの混合物 (標記化合物: 1-(3-ブロモフェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド＝3:7, 0.3 g)を得た。1H-NMR(CDCl3) δ: 10.10(1H, s), 8.23(1H, s), 8.08(1H, s), 8.01(1H, d, J = 8.5 Hz), 7.94(1H, m), 7.75-7.65(2H, m), 7.57-7.50(2H, m). 1- (3-Bromophenyl) -1H-benzo [d] imidazole-6-carboxaldehyde was synthesized in the same manner as 1- (3-bromophenyl) -N-methoxy-N-methyl-1H-benzo [d ] Imidazole-6-carboxamide (0.26 g, 0.72 mmol) was used to combine the title compound with 1- (3-bromophenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide. A mixture (title compound: 1- (3-bromophenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide = 3: 7, 0.3 g) was obtained. 1 H-NMR (CDCl 3 ) δ: 10.10 (1H, s), 8.23 (1H, s), 8.08 (1H, s), 8.01 (1H, d, J = 8.5 Hz), 7.94 (1H, m), 7.75-7.65 (2H, m), 7.57-7.50 (2H, m).

工程４
1-(3-ブロモフェニル)-6-(1,3-ジオキサン-2-イル)-1H-ベンゾ[d]イミダゾール Process 4
1- (3-Bromophenyl) -6- (1,3-dioxan-2-yl) -1H-benzo [d] imidazole

Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056

　1-(3-ブロモフェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミドと1-(3-ブロモフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒドの混合物 (1-(3-ブロモフェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド: 1-(3-ブロモフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒド＝7: 3)をトルエン (5 mL) に溶かし、1,3-プロパンジオール (100 mg, 1.3 mmol) 、オルト酢酸トリエチル (0.5 mL, 3 mmol) およびピリジニウムパラトルエンスルホン酸 (0.05 g, 0.2 mmol) を加え、90℃のオイルバス中で2日間撹拌した。反応混合物にクロロホルムを加えた後、飽和重曹水で洗浄した。有機層を無水硫酸マグネシウムで乾燥させた後、溶媒を留去し、シリカゲルカラムクロマトグラフィー法で精製し、標記化合物 (0.11 g, 100 %) を得た。 1- (3-Bromophenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxyamide and 1- (3-bromophenyl) -1H-benzo [d] imidazole-6-carboxy Mixture of aldehydes (1- (3-bromophenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide: 1- (3-bromophenyl) -1H-benzo [d] imidazole -6-Carboxaldehyde = 7: 3) is dissolved in toluene (5 mL), 1,3-propanediol (100 mg, 1.3 mmol), triethyl orthoacetate (0.5 mL, 3 mmol) and pyridinium paratoluenesulfonate ( 0.05 g, 0.2 mmol) was added, and the mixture was stirred in an oil bath at 90 ° C for 2 days. Chloroform was added to the reaction mixture, followed by washing with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the title compound (0.11 g, 100%).

工程５
1-(3-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒド Process 5
1- (3- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxaldehyde

Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057

　1-(3-ブロモフェニル)-6-(1,3-ジオキサン-2-イル)-1H-ベンゾ[d]イミダゾール (0.11 g, 0.31 mmol)、トリスジベンジリデンアセトンジパラジウム (27 mg, 0.03 mmol) 、rac-BINAP (50 mg, 0.08 mmol) およびナトリウムt-ブトキシド (51 mg, 0.53 mmol) を減圧加熱乾燥させながらアルゴン置換した。反応容器にN-メチルピペラジン (37 mg, 0.37 mmol) のトルエン溶液 (3 mL) を加え、100℃のオイルバス中で23時間撹拌した。反応混合物を室温にもどし、1 規定 塩酸 (1.5 mL, 1.5 mmol) を加え、室温で2時間撹拌した。反応混合物を氷浴中で冷やしながら、1 規定 水酸化ナトリウム (2 mL, 2 mmol) を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥させ、減圧下、溶媒を留去した後、シリカゲルカラムクロマトグラフィー法で精製し、標記化合物 (0.02 g, 20 %) を得た。1H-NMR(CDCl3) δ: 10.09(1H, s), 8.29(1H, s), 8.09(1H, s), 7.99(1H, d, J = 8.3 Hz), 7.90(1H, d, J = 8.5 Hz), 7.48(1H, m), 7.06(1H, m), 7.00-6.96(2H, m), 3.40-3.35(4H, m), 2.74-2.69(4H, m), 2.34(3H, br s). 1- (3-Bromophenyl) -6- (1,3-dioxan-2-yl) -1H-benzo [d] imidazole (0.11 g, 0.31 mmol), trisdibenzylideneacetone dipalladium (27 mg, 0.03 mmol) ), Rac-BINAP (50 mg, 0.08 mmol) and sodium t-butoxide (51 mg, 0.53 mmol) were substituted with argon while drying under reduced pressure. A toluene solution (3 mL) of N-methylpiperazine (37 mg, 0.37 mmol) was added to the reaction vessel, and the mixture was stirred in an oil bath at 100 ° C. for 23 hours. The reaction mixture was returned to room temperature, 1N hydrochloric acid (1.5 mL, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hr. While the reaction mixture was cooled in an ice bath, 1N sodium hydroxide (2 mL, 2 mmol) was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (0.02 g, 20%). 1 H-NMR (CDCl 3 ) δ: 10.09 (1H, s), 8.29 (1H, s), 8.09 (1H, s), 7.99 (1H, d, J = 8.3 Hz), 7.90 (1H, d, J = 8.5 Hz), 7.48 (1H, m), 7.06 (1H, m), 7.00-6.96 (2H, m), 3.40-3.35 (4H, m), 2.74-2.69 (4H, m), 2.34 (3H, br s).

工程６
5-((1-(3-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物６) Step 6
5-((1- (3- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 6)

Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058

　5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成と同様の方法で、1-(3-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒド (0.02 g, 0.06 mmol) およびロダニン (12 mg, 0.09 mmol) とから標記化合物 (22 mg, 84 %) を得た。1H-NMR (DMSO-D6) δ: 8.67(1H, s), 7.85(1H, d, J= 8.3 Hz), 7.79(1H, s), 7.55-7.49(3H, m), 7.32(1H, m), 7.15(1H, m), 7.13(1H, m), 3.55-3.48(4H, s), 3.14-3.05(4H, s), 2.70(3H, s).
ESI-MS(m/z): 436[M+H]+. In a manner similar to the synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one, (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxaldehyde (0.02 g, 0.06 mmol) and rhodanine (12 mg, 0.09 mmol) and the title compound (22 mg, 84 %). 1 H-NMR (DMSO-D 6 ) δ: 8.67 (1H, s), 7.85 (1H, d, J = 8.3 Hz), 7.79 (1H, s), 7.55-7.49 (3H, m), 7.32 (1H , m), 7.15 (1H, m), 7.13 (1H, m), 3.55-3.48 (4H, s), 3.14-3.05 (4H, s), 2.70 (3H, s).
ESI-MS (m / z): 436 [M + H] + .

実施例７
5-((1-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物７) Example 7
5-((1- (3-((4-methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one ( Compound 7)

工程１
N-メトキシ-N-メチル-4-ニトロ-3-(3-((テトラヒドロ-2H-ピラン-2-イル)オキシメチル)フェニル)アミノベンズアミド Process 1
N-methoxy-N-methyl-4-nitro-3- (3-((tetrahydro-2H-pyran-2-yl) oxymethyl) phenyl) aminobenzamide

Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059

　N-メトキシ-N-メチル-3-((3-モルホリノプロピル)アミノ)-4-ニトロベンズアミドの合成と同様の方法で 3-フルオロ-N-メトキシ-N-メチル-4-ニトロベンズアミド (3.65 g, 16 mmol) と 3-((テトラヒドロ-2H-ピラン-2-イル)オキシメチル)アニリン (3.9 g, 19 mmol) とから標記化合物 (5.5 g, 82 %) を得た。1H-NMR (CDCl3) δ: 9.51(1H, s), 8.24(1H, d, J = 8.8 Hz), 7.45(1H, d, J = 1.5 Hz), 7.40(1H, t, J = 7.8 Hz), 7.29-7.20(3H, m), 6.97(1H, dd, J = 8.8, 1.5 Hz), 4.81(1H, t, J = 12.2 Hz), 4.70(1H, m), 4.51(1H, t, J = 12.2 Hz), 3.93(1H, m), 3.56(1H, m), 3.53(3H, s), 3.30(3H, s) 1.93-1.50(6H, m). In the same manner as the synthesis of N-methoxy-N-methyl-3-((3-morpholinopropyl) amino) -4-nitrobenzamide 3-Fluoro-N-methoxy-N-methyl-4-nitrobenzamide (3.65 g , 16 mmol) and 3-((tetrahydro-2H-pyran-2-yl) oxymethyl) aniline (3.9 g, 19 mmol) gave the title compound (5.5 g, 82%). 1 H-NMR (CDCl 3 ) δ: 9.51 (1H, s), 8.24 (1H, d, J = 8.8 Hz), 7.45 (1H, d, J = 1.5 Hz), 7.40 (1H, t, J = 7.8 Hz), 7.29-7.20 (3H, m), 6.97 (1H, dd, J = 8.8, 1.5 Hz), 4.81 (1H, t, J = 12.2 Hz), 4.70 (1H, m), 4.51 (1H, t , J = 12.2 Hz), 3.93 (1H, m), 3.56 (1H, m), 3.53 (3H, s), 3.30 (3H, s) 1.93-1.50 (6H, m).

工程２
N-メトキシ-N-メチル-1-(3-((テトラヒドロ-2H-ピラン-2-イル)オキシメチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 2
N-methoxy-N-methyl-1- (3-((tetrahydro-2H-pyran-2-yl) oxymethyl) phenyl) -1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060

　N-メトキシ-N-メチル-4-ニトロ-3-(3-((テトラヒドロ-2H-ピラン-2-イル)オキシメチル)フェニル)アミノベンズアミド (5.46 g, 13 mmol) のテトラヒドロフラン (80 mL) 溶液にパラジウム－活性炭エチレンジアミン複合体(600 mg) を加え、水素雰囲気下、室温で2日間撹拌した。反応終了後、反応溶液をろ過し、減圧下溶媒を留去した。残留物をテトラヒドロフラン (100 mL) に溶かし、オルトギ酸トリエチル (8 mL, 48 mmol) およびピリジニウムパラトルエンスルホン酸 (0.40 g, 1.6 mmol) を加え、60℃のオイルバス中で終夜時間撹拌した。反応混合物に酢酸エチルを加えた後、飽和重曹水で洗浄した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を留去し、シリカゲルカラムクロマトグラフィー法で精製し、標記化合物 (2.61 g, 41 % ) を得た。1H-NMR(CDCl3) δ: 8.33(1H, s), 7.95-7.91(2H, m), 7.74(1H, d, J = 8.3 Hz), 7.60-7.44(4H, m), 4.91(1H, d, J = 12.5 Hz), 4.77(1H, m), 4.62(1H, d, J = 12.7 Hz), 3.92(1H, m), 3.57(1H, m), 3.55(3H, s), 3.38(3H, s), 1.90-1.51(6H, m). N-methoxy-N-methyl-4-nitro-3- (3-((tetrahydro-2H-pyran-2-yl) oxymethyl) phenyl) aminobenzamide (5.46 g, 13 mmol) in tetrahydrofuran (80 mL) To the mixture was added palladium-activated carbon ethylenediamine complex (600 mg), and the mixture was stirred at room temperature for 2 days in a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered and the solvent was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (100 mL), triethyl orthoformate (8 mL, 48 mmol) and pyridinium p-toluenesulfonic acid (0.40 g, 1.6 mmol) were added, and the mixture was stirred in an oil bath at 60 ° C. overnight. Ethyl acetate was added to the reaction mixture, followed by washing with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the title compound (2.61 g, 41%). 1 H-NMR (CDCl 3 ) δ: 8.33 (1H, s), 7.95-7.91 (2H, m), 7.74 (1H, d, J = 8.3 Hz), 7.60-7.44 (4H, m), 4.91 (1H , d, J = 12.5 Hz), 4.77 (1H, m), 4.62 (1H, d, J = 12.7 Hz), 3.92 (1H, m), 3.57 (1H, m), 3.55 (3H, s), 3.38 (3H, s), 1.90-1.51 (6H, m).

工程３
1-(3-((テトラヒドロ-2H-ピラン-2-イル)オキシメチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒド Process 3
1- (3-((Tetrahydro-2H-pyran-2-yl) oxymethyl) phenyl) -1H-benzo [d] imidazole-6-carboxaldehyde

Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061

　1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒドの合成と同様の方法で、N-メトキシ-N-メチル-1-(3-((テトラヒドロ-2H-ピラン-2-イル)オキシメチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド (0.76 g, 1.9 mmol) を用い、標記化合物 (0.16 g, 25 %) を得た。1H-NMR(CDCl3) δ: 10.09(1H, s), 8.33(1H, s), 8.09(1H, dd, J = 1.5, 0.7 Hz), 8.01(1H, d, J = 8.3 Hz), 7.90(1H, dd, J = 8.5, 1.5 Hz), 7.62-7.46(4H, m), 4.93(1H, d, J = 12.7 Hz), 4.78(1H, m), 4.63(1H, d, J = 12.7 Hz), 3.92(1H, m), 3.59(1H, m), 1.92-1.52(6H, m). In a manner similar to the synthesis of 1- (3-morpholinopropyl) -1H-benzo [d] imidazole-6-carboxaldehyde, N-methoxy-N-methyl-1- (3-((tetrahydro-2H-pyran- Using 2-yl) oxymethyl) phenyl) -1H-benzo [d] imidazole-6-carboxamide (0.76 g, 1.9 mmol), the title compound (0.16 g, 25%) was obtained. 1 H-NMR (CDCl 3 ) δ: 10.09 (1H, s), 8.33 (1H, s), 8.09 (1H, dd, J = 1.5, 0.7 Hz), 8.01 (1H, d, J = 8.3 Hz), 7.90 (1H, dd, J = 8.5, 1.5 Hz), 7.62-7.46 (4H, m), 4.93 (1H, d, J = 12.7 Hz), 4.78 (1H, m), 4.63 (1H, d, J = 12.7 Hz), 3.92 (1H, m), 3.59 (1H, m), 1.92-1.52 (6H, m).

工程４
1-(3-ヒドロキシメチル）フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒド Process 4
1- (3-Hydroxymethyl) phenyl) -1H-benzo [d] imidazole-6-carboxaldehyde

Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062

　1-(3-((テトラヒドロ-2H-ピラン-2-イル)オキシメチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒド (0.16 g, 0.48 mmol) をエタノール (10 mL) に溶かし、1 規定 塩酸 (0.5 mL, 0.5 mmol) を加え、室温で2時間撹拌した。反応混合物を氷浴中で冷やしながら、飽和重曹水を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥させ、減圧下、溶媒を留去して、標記化合物 (0.11 g, 91 %) を得た。1H-NMR(CDCl3) δ: 10.12(1H, s), 8.71(1H, s), 8.13(1H, s), 8.09(1H, d, J = 8.3 Hz), 7.97(1H, dd, J = 8.3, 1.5 Hz), 7.67- 7.48(4H, m), 4.88(2H, s). 1- (3-((Tetrahydro-2H-pyran-2-yl) oxymethyl) phenyl) -1H-benzo [d] imidazole-6-carboxaldehyde (0.16 g, 0.48 mmol) was dissolved in ethanol (10 mL). , 1N hydrochloric acid (0.5 mL, 0.5 mmol) was added, and the mixture was stirred at room temperature for 2 hr. While cooling the reaction mixture in an ice bath, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.11 g, 91%). 1 H-NMR (CDCl 3 ) δ: 10.12 (1H, s), 8.71 (1H, s), 8.13 (1H, s), 8.09 (1H, d, J = 8.3 Hz), 7.97 (1H, dd, J = 8.3, 1.5 Hz), 7.67-7.48 (4H, m), 4.88 (2H, s).

工程５
1-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒド Process 5
1- (3-((4-Methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazole-6-carboxaldehyde

Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063

　アルゴン雰囲気下、1-(3-(ヒドロキシメチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒド (0.11 g, 0.44 mmol) を塩化メチレン (10 mL) に溶かし、氷浴中で冷やしながらジイソプロピルエチルアミン (155 mg, 1.2 mmol) およびメタンスルホニルクロリド (69 mg, 0.6 mmol) の塩化メチレン(3 mL)溶液を加え、氷浴中で6時間撹拌した。原料の消失を確認した後、反応混合物にN-メチルピペラジン (100 mg, 1 mmol) を加え、氷浴中で2時間、室温で終夜撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥させ、減圧下、溶媒を留去した後, シリカゲルカラムクロマトグラフィー法で精製し、標記化合物 (0.09 g, 61 %) を得た。1H-NMR(CDCl3) δ: 10.11(1H, s), 8.32(1H, s), 8.11(1H, s), 8.02(1H, d, J = 8.3 Hz), 7.90(1H, d, J = 8.3 Hz), 7.68-7.41(4H, m), 3.70(2H, s), 2.80-2.50(8H, m), 2.46(3H, br s). In an argon atmosphere, 1- (3- (hydroxymethyl) phenyl) -1H-benzo [d] imidazole-6-carboxaldehyde (0.11 g, 0.44 mmol) is dissolved in methylene chloride (10 mL) and cooled in an ice bath. While adding a solution of diisopropylethylamine (155 mg, 1.2 mmol) and methanesulfonyl chloride (69 mg, 0.6 mmol) in methylene chloride (3 mL), the mixture was stirred in an ice bath for 6 hours. After confirming disappearance of the starting materials, N-methylpiperazine (100 mg, 1 mmol) was added to the reaction mixture, and the mixture was stirred in an ice bath for 2 hours and at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (0.09 g, 61%). 1 H-NMR (CDCl 3 ) δ: 10.11 (1H, s), 8.32 (1H, s), 8.11 (1H, s), 8.02 (1H, d, J = 8.3 Hz), 7.90 (1H, d, J = 8.3 Hz), 7.68-7.41 (4H, m), 3.70 (2H, s), 2.80-2.50 (8H, m), 2.46 (3H, br s).

工程６
5-((1-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物７) Step 6
5-((1- (3-((4-methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one ( Compound 7)

Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064

　5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成と同様の方法で、1-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒド (0.09 g, 0.27 mmol) およびロダニン (36 mg, 0.27 mmol) とから標記化合物 (25 mg, 21 %) を得た。1H-NMR (DMSO-D6) δ: 8.67(1H, s), 7.85(1H, d, J= 8.3 Hz), 7.83(1H, s), 7.74-7.42(6H, m), 3.73(2H, s), 3.10-2.90(8H, m), 2.70(3H, s).
ESI-MS(m/z): 450[M+H]+. In a manner similar to the synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one, ((4-Methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazole-6-carboxaldehyde (0.09 g, 0.27 mmol) and rhodanine (36 mg, 0.27 mmol) from the title compound (25 mg, 21%). 1 H-NMR (DMSO-D 6 ) δ: 8.67 (1H, s), 7.85 (1H, d, J = 8.3 Hz), 7.83 (1H, s), 7.74-7.42 (6H, m), 3.73 (2H , s), 3.10-2.90 (8H, m), 2.70 (3H, s).
ESI-MS (m / z): 450 [M + H] + .

実施例８
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン ハイドロクロライド (化合物８) Example 8
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one hydrochloride (compound 8)

Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065

工程１
　5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (50 mg, 0.11 mmol) のクロロホルム (5 mL)、メタノール (5 mL) 混合溶液に6規定 塩酸 (1 mL, 6.0 mmol) を加え、2 分間撹拌した。反応終了後、減圧下溶媒を留去し、標記化合物 (49 mg, 94%) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 13.85 (1H, br s), 10.64 (1H, br s), 8.95 (1H, s), 7.95 (1H, d, J = 8.3 Hz), 7.85 (2H, s), 7.64-7.59 (3H, m), 7.27 (2H, d, J = 9.0 Hz), 3.99 (2H, d, J = 9.5 Hz), 3.53 (2H, d, J = 9.5 Hz), 3.24-3.13 (4H, m), 2.84 (3H, d, J= 4.6 Hz). Process 1
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (50 mg, To a mixed solution of 0.11 mmol) chloroform (5 mL) and methanol (5 mL) was added 6N hydrochloric acid (1 mL, 6.0 mmol), and the mixture was stirred for 2 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain the title compound (49 mg, 94%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 13.85 (1H, br s), 10.64 (1H, br s), 8.95 (1H, s), 7.95 (1H, d, J = 8.3 Hz), 7.85 (2H, s), 7.64-7.59 (3H, m), 7.27 (2H, d, J = 9.0 Hz), 3.99 (2H, d, J = 9.5 Hz), 3.53 (2H, d, J = 9.5 Hz) ), 3.24-3.13 (4H, m), 2.84 (3H, d, J = 4.6 Hz).

実施例９
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン メタンスルホナート (化合物９) Example 9
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one methanesulfonate ( Compound 9)

Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066

工程１
　5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (4.35 g, 9.98 mmol) のメタノール( 50 mL)、水 (200 mL) 混合溶液にメタンスルホン酸 (1.01 g, 10.48 mmol) を加え、2 分間撹拌した。反応終了後、減圧下溶媒を留去した。結晶を水に溶かしてろ過し、ろ液を回収後、減圧下溶媒を留去した。得られた結晶をメタノール、酢酸エチルで洗浄した後乾燥し、標記化合物 (4.20 g, 76%) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 12.62 (1H, s), 9.63 (1H, s), 8.69 (1H, s), 7.98 (1H, s), 7.91 (1H, d, J = 8.5 Hz), 7.81 (1H, s), 7.62 (2H, d, J = 9.0 Hz), 7.57 (1H, d, J = 8.5 Hz), 7.28 (2H, d, J = 9.0 Hz), 4.01 (2H, d, J = 13.7 Hz), 3.57 (2H, d, J = 13.7 Hz), 3.21 (2H, q J = 11.6 Hz), 3.06 (2H, t, J = 11.6 Hz), 2.90 (3H, s), 2.30 (3H, s). Process 1
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (4.35 g, Methanesulfonic acid (1.01 g, 10.48 mmol) was added to a mixed solution of 9.98 mmol) in methanol (50 mL) and water (200 mL), and the mixture was stirred for 2 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure. The crystals were dissolved in water and filtered. After collecting the filtrate, the solvent was distilled off under reduced pressure. The obtained crystals were washed with methanol and ethyl acetate and dried to give the title compound (4.20 g, 76%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 12.62 (1H, s), 9.63 (1H, s), 8.69 (1H, s), 7.98 (1H, s), 7.91 (1H, d, J = 8.5 Hz), 7.81 (1H, s), 7.62 (2H, d, J = 9.0 Hz), 7.57 (1H, d, J = 8.5 Hz), 7.28 (2H, d, J = 9.0 Hz), 4.01 ( 2H, d, J = 13.7 Hz), 3.57 (2H, d, J = 13.7 Hz), 3.21 (2H, q J = 11.6 Hz), 3.06 (2H, t, J = 11.6 Hz), 2.90 (3H, s ), 2.30 (3H, s).

実施例１０
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン メタンスルホナート (化合物１０) Example 10
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione methanesulfonate (Compound 10)

Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067

工程１
　5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (171 mg, 0.41 mmol) のメタノール (5 mL)、水 (5 mL) 混合溶液に メタンスルホン酸 (41 mg, 0.43 mmol) を加え、2 分間撹拌した。反応終了後、減圧下溶媒を留去した。結晶を水に溶かしてろ過し、ろ液を回収後、減圧下溶媒を留去した。得られた結晶を メタノール、酢酸エチルで洗浄した後乾燥し、標記化合物 (160 mg, 76%) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 12.62 (1H, s), 9.63 (1H, s), 8.69 (1H, s), 7.98 (1H, s), 7.91 (1H, d, J = 8.5 Hz), 7.81 (1H, s), 7.62 (2H, d, J = 9.0 Hz), 7.57 (1H, d, J = 8.5 Hz), 7.28 (2H, d, J = 9.0 Hz), 4.01 (2H, d, J = 13.7 Hz), 3.57 (2H, d, J = 13.7 Hz), 3.21 (2H, q J = 11.6 Hz), 3.06 (2H, t, J = 11.6 Hz), 2.90 (3H, s), 2.30 (3H, s). Process 1
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (171 mg, 0.41 mmol) Methanesulfonic acid (41 mg, 0.43 mmol) was added to a mixed solution of methanol (5 mL) and water (5 mL), and the mixture was stirred for 2 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure. The crystals were dissolved in water and filtered. After collecting the filtrate, the solvent was distilled off under reduced pressure. The obtained crystals were washed with methanol and ethyl acetate and dried to give the title compound (160 mg, 76%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 12.62 (1H, s), 9.63 (1H, s), 8.69 (1H, s), 7.98 (1H, s), 7.91 (1H, d, J = 8.5 Hz), 7.81 (1H, s), 7.62 (2H, d, J = 9.0 Hz), 7.57 (1H, d, J = 8.5 Hz), 7.28 (2H, d, J = 9.0 Hz), 4.01 ( 2H, d, J = 13.7 Hz), 3.57 (2H, d, J = 13.7 Hz), 3.21 (2H, q J = 11.6 Hz), 3.06 (2H, t, J = 11.6 Hz), 2.90 (3H, s ), 2.30 (3H, s).

実施例１１
5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１１)  Example 11
5-((1- (4- (4-Methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 11)

工程１
N-メトキシ-N-メチル-3-((4-(4-メチルピペラジニル)ベンジル)アミノ)-4-ニトロベンズアミド Process 1
N-methoxy-N-methyl-3-((4- (4-methylpiperazinyl) benzyl) amino) -4-nitrobenzamide

Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068

　3-フルオロ-N-メトキシ-N-メチル-4-ニトロベンズアミド (953 mg, 4.29 mmol) の N,N-ジメチルホルムアミド (5 mL) 溶液に (4-(4-メチルピペラジニル)フェニル)メチルアミン (800 mg, 3.90 mmol)、無水炭酸カリウム (1.0 g, 7.25 mmol) を加え、70 ℃で 4 時間撹拌した。反応終了後、反応溶液に水を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、減圧下溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (1.39 g, 86 %) を得た。茶色結晶: 1H-NMR (CDCl3) δ: 8.31 (1H, t, J = 5.4 Hz), 8.21 (1H, d, J = 8.8 Hz), 7.24 (2H, d, J = 8.8 Hz), 7.12 (1H, d, J = 1.5 Hz), 6.91 (2H, d, J = 8.8 Hz), 6.85 (1H, dd, J = 8.8, 1.5 Hz), 4.46 (2H, d, J = 5.4 Hz), 3.44 (3H, s), 3.30 (3H, s), 3.20 (4H, t, J = 5.0 Hz), 2.57 (4H, t, J = 5.0 Hz), 2.35 (3H, s).  (4- (4-Methylpiperazinyl) phenyl) methyl in a solution of 3-fluoro-N-methoxy-N-methyl-4-nitrobenzamide (953 mg, 4.29 mmol) in N, N-dimethylformamide (5 mL) Amine (800 mg, 3.90 mmol) and anhydrous potassium carbonate (1.0 g, 7.25 mmol) were added, and the mixture was stirred at 70 ° C. for 4 hours. After completion of the reaction, water was added to the reaction solution and extracted with chloroform. After drying the organic layer with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (1.39 g, 86%). Brown crystals: 1 H-NMR (CDCl 3 ) δ: 8.31 (1H, t, J = 5.4 Hz), 8.21 (1H, d, J = 8.8 Hz), 7.24 (2H, d, J = 8.8 Hz), 7.12 (1H, d, J = 1.5 Hz), 6.91 (2H, d, J = 8.8 Hz), 6.85 (1H, dd, J = 8.8, 1.5 Hz), 4.46 (2H, d, J = 5.4 Hz), 3.44 (3H, s), 3.30 (3H, s), 3.20 (4H, t, J = 5.0 Hz), 2.57 (4H, t, J = 5.0 Hz), 2.35 (3H, s).

工程２
N-メトキシ-N-メチル-1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 2
N-methoxy-N-methyl-1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069

　N-メトキシ-N-メチル-3-((4-(4-メチルピペラジニル)ベンジル)アミノ)-4-ニトロベンズアミド (737 mg, 1.78 mmol) の エタノール (10 mL) 溶液に 10% パラジウム－活性炭 (147 mg) を加え、水素雰囲気下、室温で 24 時間撹拌した。反応終了後、反応溶液をろ過し、減圧下溶媒を留去した。得られた粗生成物をエタノール (10 mL) に溶かし、オルトギ酸トリエチル (2.96 mL, 17.8 mmol)、酢酸 (213 mg, 3.56 mmol) を加え、室温で一晩撹拌した。減圧下溶媒を留去した後、反応混合物に酢酸エチル、飽和重層水を加え、系を塩基性にした後、クロロホルムで 3 回抽出した。有機層を合わせ、無水硫酸マグネシウムで乾燥した後、溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (340 g, 49 %) を得た。黄色結晶：1H-NMR (CDCl3) δ: 7.98 (1H, s), 7.81-7.78 (2H, m), 7.64 (1H, dd, J = 8.4, 1.6 Hz), 7.13 (2H, d, J = 8.5 Hz), 6.88 (2H, d, J = 8.5 Hz), 5.28 (2H, s), 3.49 (3H, s), 3.36 (3H, s), 3.20 (4H, t, J = 5.0 Hz), 2.56 (4H, t, J = 5.0 Hz), 2.34 (3H, s).  N-methoxy-N-methyl-3-((4- (4-methylpiperazinyl) benzyl) amino) -4-nitrobenzamide (737 mg, 1.78 mmol) in ethanol (10 mL) in 10% palladium- Activated carbon (147 mg) was added, and the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered and the solvent was distilled off under reduced pressure. The obtained crude product was dissolved in ethanol (10 mL), triethyl orthoformate (2.96 mL, 17.8 mmol) and acetic acid (213 mg, 3.56 mmol) were added, and the mixture was stirred at room temperature overnight. After evaporating the solvent under reduced pressure, ethyl acetate and saturated multistory water were added to the reaction mixture to make the system basic, followed by extraction with chloroform three times. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (340 g, 49%). Yellow crystals: 1 H-NMR (CDCl 3 ) δ: 7.98 (1H, s), 7.81-7.78 (2H, m), 7.64 (1H, dd, J = 8.4, 1.6 Hz), 7.13 (2H, d, J = 8.5 Hz), 6.88 (2H, d, J = 8.5 Hz), 5.28 (2H, s), 3.49 (3H, s), 3.36 (3H, s), 3.20 (4H, t, J = 5.0 Hz), 2.56 (4H, t, J = 5.0 Hz), 2.34 (3H, s).

工程３
1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Process 3
1- (4- (4-Methylpiperazinyl) benzyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070

　アルゴン雰囲気下、N-メトキシ-N-メチル-1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド (340 mg, 0.86 mmol) のテトラヒドロフラン (10 mL) 溶液にビスシクロペンタジエニルジルコニウム(ＩＶ)クロリドヒドリド (335 mg, 1.30 mmol) を加え、0 oC で １ 時間撹拌した。反応終了後、飽和重層水を加え、クロロホルムで 3 回抽出した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (156 mg, 47 %) を得た。黄色液体: 1H-NMR (CDCl3) δ: 10.05 (1H, s), 8.08 (1H, s), 7.92-7.90 (2H, m), 7.82 (1H, dd, J = 8.3, 1.5 Hz), 7.15 (2H, d, J = 8.8 Hz), 6.90 (2H, d, J = 8.8 Hz), 5.33 (2H, s), 3.22 (4H, t, J = 5.0 Hz), 2.57 (4H, t, J = 5.0 Hz), 2.35 (3H, s ).  Under argon atmosphere, N-methoxy-N-methyl-1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazole-6-carboxamide (340 mg, 0.86 mmol) in tetrahydrofuran ( 10 mL) To the solution was added biscyclopentadienylzirconium (IV) chloride hydride (335 mg, 1.30 mmol), and the mixture was stirred at 0 ° C. for 1 hour. Saturated multistory water was added after completion | finish of reaction, and chloroform extracted 3 times. The resulting crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (156 mg, 47%). Yellow liquid: 1 H-NMR (CDCl 3 ) δ: 10.05 (1H, s), 8.08 (1H, s), 7.92-7.90 (2H, m), 7.82 (1H, dd, J = 8.3, 1.5 Hz), 7.15 (2H, d, J = 8.8 Hz), 6.90 (2H, d, J = 8.8 Hz), 5.33 (2H, s), 3.22 (4H, t, J = 5.0 Hz), 2.57 (4H, t, J = 5.0 Hz), 2.35 (3H, s).

工程４
5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１１) Process 4
5-((1- (4- (4-Methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 11)

Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071

　1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (6.03 g, 18.8 mmol)、ロダニン (32 mg, 0.24 mmol) のエタノール (3 mL) 溶液に ピペリジン (5 mg, 0.06 mmol) を加え 80 ℃で一晩撹拌した。反応溶液に酢酸エチルを加え、結晶を析出させた後、ろ過し、酢酸エチル、エタノールで洗浄して標記化合物 (71 mg, 66 %) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 11.08 (1H, br s), 8.52 (1H, s), 7.72-7.65 (2H, m), 7.40-7.31 (4H, m), 6.95 (2H, d, J = 8.8 Hz), 5.42 (2H, s), 3.28 (4H, br s), 2.96 (4H, br s), 2.59 (3H, s).
ESI-MS(m/z): 450[M+H]+. 1- (4- (4-Methylpiperazinyl) benzyl) -1H-benzo [d] imidazole-6-carbaldehyde (6.03 g, 18.8 mmol), rhodanine (32 mg, 0.24 mmol) in ethanol (3 mL) Piperidine (5 mg, 0.06 mmol) was added to the solution and stirred at 80 ° C. overnight. Ethyl acetate was added to the reaction solution to precipitate crystals, followed by filtration and washing with ethyl acetate and ethanol to obtain the title compound (71 mg, 66%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 11.08 (1H, br s), 8.52 (1H, s), 7.72-7.65 (2H, m), 7.40-7.31 (4H, m), 6.95 ( 2H, d, J = 8.8 Hz), 5.42 (2H, s), 3.28 (4H, br s), 2.96 (4H, br s), 2.59 (3H, s).
ESI-MS (m / z): 450 [M + H] + .

実施例１２
5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１２) Example 12
5-((1- (4- (4-Methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 12)

Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072

工程１
　1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (77 mg, 0.23 mmol)、2,4-チアゾリジンジオン (26 mg, 0.22 mmol) のエタノール (2 mL) 溶液に ピペリジン (4 mg, 0.04 mmol) を加え 80 ℃で一晩撹拌した。反応溶液に酢酸エチルを加え、結晶を析出させた後、ろ過し、酢酸エチル、エタノールで洗浄して標記化合物 (21 mg, 23 %) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 11.74 (1H, br s), 8.54 (1H, s), 7.75-7.72 (3H, m), 7.40 (1H, dd, J = 8.5, 1.5 Hz), 7.29 (2H, d, J = 8.8 Hz), 6.92 (2H, d, J = 8.8 Hz), 5.41 (2H, s), 3.15 (4H, t, J = 4.8 Hz), 2.62 (4H, t, J = 4.8 Hz), 2.35 (3H, s).
ESI-MS(m/z): 434[M+H]+. Process 1
1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazole-6-carbaldehyde (77 mg, 0.23 mmol), 2,4-thiazolidinedione (26 mg, 0.22 mmol) Piperidine (4 mg, 0.04 mmol) was added to the ethanol (2 mL) solution, and the mixture was stirred at 80 ° C. overnight. Ethyl acetate was added to the reaction solution to precipitate crystals, followed by filtration and washing with ethyl acetate and ethanol to obtain the title compound (21 mg, 23%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 11.74 (1H, br s), 8.54 (1H, s), 7.75-7.72 (3H, m), 7.40 (1H, dd, J = 8.5, 1.5 Hz), 7.29 (2H, d, J = 8.8 Hz), 6.92 (2H, d, J = 8.8 Hz), 5.41 (2H, s), 3.15 (4H, t, J = 4.8 Hz), 2.62 (4H, t, J = 4.8 Hz), 2.35 (3H, s).
ESI-MS (m / z): 434 [M + H] + .

実施例１３
5-((1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物１３) Example 13
5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 13)

工程１
3-((4-(4-エチルピペラジン-1-イル)フェニル)アミノ)-N-メトキシ-N-メチル-4-ニトロベンズアミド Process 1
3-((4- (4-Ethylpiperazin-1-yl) phenyl) amino) -N-methoxy-N-methyl-4-nitrobenzamide

Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073

　N-メトキシ-N-メチル-3-((4-(4-メチルピペラジニル)ベンジル)アミノ)-4-ニトロベンズアミドの合成と同様の手法で、3-フルオロ-N-メトキシ-N-メチル-4-ニトロベンズアミド (2.3 g, 10 mmol) および 1-エチル-4-(4-アミノフェニル)ピペラジン (2.55 g, 12.42 mmol) とから標記化合物 (3.69 g, 8.92 mmol, 89 %) を得た。1H-NMR (CDCl3) δ: 9.44 (1H, br s), 8.23 (1H, d, J= 9.0 Hz), 7.27 (1H, s), 7.19 (2H, d, J= 8.8 Hz), 6.98 (2H, d, J = 6.8 Hz), 6.91 (1H, d, J = 7.8 Hz), 3.56 (3H, s), 3.60-3.30 (4H, br s), 3.92 (3H, s), 3.00-2.60 (6H, m), 1.31 (3H, br s). In a similar manner to the synthesis of N-methoxy-N-methyl-3-((4- (4-methylpiperazinyl) benzyl) amino) -4-nitrobenzamide, 3-fluoro-N-methoxy-N-methyl 4-Nitrobenzamide (2.3 g, 10 mmol) and 1-ethyl-4- (4-aminophenyl) piperazine (2.55 g, 12.42 mmol) gave the title compound (3.69 g, 8.92 mmol, 89%) . 1 H-NMR (CDCl 3 ) δ: 9.44 (1H, br s), 8.23 (1H, d, J = 9.0 Hz), 7.27 (1H, s), 7.19 (2H, d, J = 8.8 Hz), 6.98 (2H, d, J = 6.8 Hz), 6.91 (1H, d, J = 7.8 Hz), 3.56 (3H, s), 3.60-3.30 (4H, br s), 3.92 (3H, s), 3.00-2.60 (6H, m), 1.31 (3H, br s).

工程２
1-(4-(4-エチルピペラジン-1-イル)フェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 2
1- (4- (4-Ethylpiperazin-1-yl) phenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074

　N-メトキシ-N-メチル-3-((4-(4-メチルピペラジニル)ベンジル)アミノ)-4-ニトロベンズアミドの合成と同様の手法で、3-((4-(4-エチルピペラジン-1-イル)フェニル)アミノ)-N-メトキシ-N-メチル-4-ニトロベンズアミド (3.69 g, 8.92 mmol) を用い、標記化合物 (3.49 g, 8.9 mmol, quant.) を得た。1H-NMR (CDCl3) δ: 8.14 (1H, s), 7.87 (1H, s), 7.86 (1H, d, J = 6.6 Hz), 7.68 (1H, dd, J = 7.3, 1.3 Hz), 7.39 (2H, d, J = 9.0 Hz), 7.08 (2H, d, J= 8.8 Hz), 3.56 (3H, s), 3.43-3.35 (4H, br s), 3.38 (3H, br s), 2.75 (4H, br s), 2.60 (2H, br s), 1.22 (3H, br s).  In a similar manner to the synthesis of N-methoxy-N-methyl-3-((4- (4-methylpiperazinyl) benzyl) amino) -4-nitrobenzamide, 3-((4- (4-ethylpiperazine The title compound (3.49 g, 8.9 mmol, quant.) Was obtained using 1-yl) phenyl) amino) -N-methoxy-N-methyl-4-nitrobenzamide (3.69 g, 8.92 mmol). 1 H-NMR (CDCl 3 ) δ: 8.14 (1H, s), 7.87 (1H, s), 7.86 (1H, d, J = 6.6 Hz), 7.68 (1H, dd, J = 7.3, 1.3 Hz), 7.39 (2H, d, J = 9.0 Hz), 7.08 (2H, d, J = 8.8 Hz), 3.56 (3H, s), 3.43-3.35 (4H, br s), 3.38 (3H, br s), 2.75 (4H, br s), 2.60 (2H, br s), 1.22 (3H, br s).

工程３
1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Process 3
1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000075

　1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒドの合成と同様の手法で、1-(4-(4-エチルピペラジン-1-イル)フェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド (1.20 g, 3.0 mmol) およびビスシクロペンタジエニルジルコニウム(ＩＶ)クロリドヒドリド (0.93 g, 3.6 mmol) を用い、標記化合物 (0.35 g, 1.05 mmol, 50 %) を得た。1H-NMR (CDCl3) δ: 10.08 (1H, s), 8.23 (1H, s), 8.02 (1H, d, J = 1.5 Hz), 7.98 (1H, d, J= 8.3 Hz), 7.88 (1H, dd, J = 8.5, 1.5 Hz), 7.40 (2H, d, J = 8.8 Hz), 7.10 (2H, d, J = 6.8 Hz), 3.40 (4H, br s), 2.74 (4H, br s), 2.60 (2H, br s), 1.21 (3H, br s).  1- (4- (4-Methylpiperazinyl) benzyl) -1H-benzo [d] imidazole-6-carbaldehyde is prepared in a similar manner to the synthesis of 1- (4- (4-ethylpiperazin-1-yl ) Phenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide (1.20 g, 3.0 mmol) and biscyclopentadienylzirconium (IV) chloride hydride (0.93 g, 3.6 mmol) To give the title compound (0.35 g, 1.05 mmol, 50%). 1 H-NMR (CDCl 3 ) δ: 10.08 (1H, s), 8.23 (1H, s), 8.02 (1H, d, J = 1.5 Hz), 7.98 (1H, d, J = 8.3 Hz), 7.88 ( 1H, dd, J = 8.5, 1.5 Hz), 7.40 (2H, d, J = 8.8 Hz), 7.10 (2H, d, J = 6.8 Hz), 3.40 (4H, br s), 2.74 (4H, br s ), 2.60 (2H, br s), 1.21 (3H, br s).

工程４
5-((1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物１３)  Process 4
5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 13)

Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076

　5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成と同様の手法で、1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (0.18 g, 0.54 mmol) およびロダニン (72 mg, 0.54 mmol) とから標記化合物 (200 mg, 82%) を得た。黄色結晶: 1H-NMR (DMSO-D6)δ: 8.56 (1H, s), 7.84 (1H, d, J= 8.3 Hz), 7.68 (1H, s), 7.58 (2H, d, J= 9.0 Hz), 7.49 (1H, dd, J = 6.9, 1.5 Hz), 7.25 (2H, d, J = 9.0 Hz), 3.46 (4H, br s), 3.13 (4H, br s), 2.97 (2H, br s), 1.21 (3H, t, J = 7.2 Hz). 
ESI-MS(m/z): 450[M+H]+.  Similar procedure to the synthesis of 5-((1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one From 1- (4- (4-ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (0.18 g, 0.54 mmol) and rhodanine (72 mg, 0.54 mmol) The title compound (200 mg, 82%) was obtained. Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 8.56 (1H, s), 7.84 (1H, d, J = 8.3 Hz), 7.68 (1H, s), 7.58 (2H, d, J = 9.0 Hz), 7.49 (1H, dd, J = 6.9, 1.5 Hz), 7.25 (2H, d, J = 9.0 Hz), 3.46 (4H, br s), 3.13 (4H, br s), 2.97 (2H, br s), 1.21 (3H, t, J = 7.2 Hz).
ESI-MS (m / z): 450 [M + H] + .

実施例１４
5-((1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４)  Example 14
5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 14)

Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077

工程１
　5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成と同様の手法で、1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (0.17 g, 0.51 mmol) および2,4-チアゾリジンジオン (60 mg, 0.51 mmol) とから標記化合物 (133 mg, 60%) を得た。黄色結晶: 1H-NMR (DMSO-D6)δ: 8.58 (1H, s), 7.86 (1H, d, J= 8.5 Hz), 7.82 (1H, s), 7.79 (1H, s), 7.54 (2H, d, J = 8.8 Hz), 7.51 (1H, m), 7.20 (2H, d, J = 8.8 Hz), 3.32 (4H, br s), 2.77 (4H, br s), 2.62 (2H, br s), 1.11 (3H, t, J = 7.2 Hz).
ESI-MS(m/z): 434[M+H]+.  Process 1
In a manner similar to the synthesis of 5-((1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione, -(4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (0.17 g, 0.51 mmol) and 2,4-thiazolidinedione (60 mg, 0.51 mmol) To give the title compound (133 mg, 60%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 8.58 (1H, s), 7.86 (1H, d, J = 8.5 Hz), 7.82 (1H, s), 7.79 (1H, s), 7.54 ( 2H, d, J = 8.8 Hz), 7.51 (1H, m), 7.20 (2H, d, J = 8.8 Hz), 3.32 (4H, br s), 2.77 (4H, br s), 2.62 (2H, br s), 1.11 (3H, t, J = 7.2 Hz).
ESI-MS (m / z): 434 [M + H] + .

実施例１５
tert-ブチル 4-(4-(6-((4-オキソ-2-チオキソチアゾリジン-5-イリデン)メチル)-1H-ベンゾ[d]イミダゾール-1-イル)フェニル)ピペラジン-1-カルボキシレート (化合物１５) Example 15
tert-butyl 4- (4- (6-((4-oxo-2-thioxothiazolidine-5-ylidene) methyl) -1H-benzo [d] imidazol-1-yl) phenyl) piperazine-1-carboxylate (Compound 15)

工程１
tert-ブチル 4-(4-((5-(メトキシ(メチル)カルバモイル)-2-ニトロフェニル)アミノ)フェニル)ピペラジン-1-カルボキシレート Process 1
tert-butyl 4- (4-((5- (methoxy (methyl) carbamoyl) -2-nitrophenyl) amino) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000078

　3-フルオロ-N-メトキシ-N-メチル-4-ニトロベンズアミド(1.04 g, 4.5 mmol) のN,N-ジメチルホルムアミド (25 mL) 溶媒中に、tert-ブチル 4-(4-アミノフェニル)ピペラジン-1-カルボキシレート (1.39 g, 5.0 mmol)、炭酸カリウム (1.05 g, 7.6 mmol) を添加し、100 ℃で一晩撹拌した。室温に放冷した後、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥、ろ過、減圧下濃縮した。標記化合物 (1.74 g, 3.6 mmol, 72 %) を得た。1H-NMR (DMSO-D6) δ: 9.41 (1H, s), 8.14 (1H, d, J = 8.8 Hz), 7.20 (2H, d, J = 9.0 Hz), 7.06 (1H, d, J = 8.8 Hz), 7.04 (2H, d, J = 9.0 Hz), 3.47 (4H, t, J = 5.0 Hz), 3.35 (3H, s), 3.13 (4H, t, J = 5.0 Hz), 2.84 (3H, s), 1.42 (9H, s). 
ESI-MS(m/z): 486[M+H]+. 3-Fluoro-N-methoxy-N-methyl-4-nitrobenzamide (1.04 g, 4.5 mmol) in N, N-dimethylformamide (25 mL) in solvent tert-butyl 4- (4-aminophenyl) piperazine -1-carboxylate (1.39 g, 5.0 mmol) and potassium carbonate (1.05 g, 7.6 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After allowing to cool to room temperature, ethyl acetate and saturated brine were added to extract the organic layer, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The title compound (1.74 g, 3.6 mmol, 72%) was obtained. 1 H-NMR (DMSO-D 6 ) δ: 9.41 (1H, s), 8.14 (1H, d, J = 8.8 Hz), 7.20 (2H, d, J = 9.0 Hz), 7.06 (1H, d, J = 8.8 Hz), 7.04 (2H, d, J = 9.0 Hz), 3.47 (4H, t, J = 5.0 Hz), 3.35 (3H, s), 3.13 (4H, t, J = 5.0 Hz), 2.84 ( 3H, s), 1.42 (9H, s).
ESI-MS (m / z): 486 [M + H] + .

工程２
tert-ブチル 4-(4-((2-アミノ-5-(メトキシ(メチル)カルバモイル)フェニル)アミノ)フェニル)ピペラジン-1-カルボキシレート Process 2
tert-butyl 4- (4-((2-amino-5- (methoxy (methyl) carbamoyl) phenyl) amino) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000079

　tert-ブチル 4-(4-((5-(メトキシ(メチル)カルバモイル)-2-ニトロフェニル)アミノ)フェニル)ピペラジン-1-カルボキシレート (1.70 g, 3.6 mmol) のメタノール溶液に、アルゴン雰囲気下パラジウム－活性炭 (300 mg) を0 ℃で添加した。水素置換した後、室温で4時間撹拌した。反応終了後、セライトろ過、減圧下濃縮し、標記化合物 (818 mg, 1.8 mmol, 50 %) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 7.33 (1H, s), 7.16 (1H, d, J = 8.2 Hz), 6.86 (2H, d, J = 9.0 Hz), 6.79 (1H, s), 6.76 (2H, d, J = 9.0 Hz), 6.67 (1H, d, J = 8.2 Hz), 5.30 (2H, br s), 3.52 (3H, s), 3.44 (4H, t, J = 4.8 Hz), 3.18 (3H, s), 2.94 (4H, t, J = 4.8 Hz), 1.42 (9H, s). 
ESI-MS(m/z): 456[M+H]+. To a methanolic solution of tert-butyl 4- (4-((5- (methoxy (methyl) carbamoyl) -2-nitrophenyl) amino) phenyl) piperazine-1-carboxylate (1.70 g, 3.6 mmol) under an argon atmosphere Palladium-activated carbon (300 mg) was added at 0 ° C. After purging with hydrogen, the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was filtered through celite and concentrated under reduced pressure to obtain the title compound (818 mg, 1.8 mmol, 50%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 7.33 (1H, s), 7.16 (1H, d, J = 8.2 Hz), 6.86 (2H, d, J = 9.0 Hz), 6.79 (1H, s), 6.76 (2H, d, J = 9.0 Hz), 6.67 (1H, d, J = 8.2 Hz), 5.30 (2H, br s), 3.52 (3H, s), 3.44 (4H, t, J = 4.8 Hz), 3.18 (3H, s), 2.94 (4H, t, J = 4.8 Hz), 1.42 (9H, s).
ESI-MS (m / z): 456 [M + H] + .

工程３
tert-ブチル 4-(4-(６-(メトキシ(メチル)カルバモイル)-1H-ベンゾ[d]イミダソール-1-イル)フェニル)ピペラジン-1-カルボキシレート Process 3
tert-butyl 4- (4- (6- (methoxy (methyl) carbamoyl) -1H-benzo [d] imidazol-1-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000080

　tert-ブチル 4-(4-((2-アミノ-5-(メトキシ(メチル)カルバモイル)フェニル)アミノ)フェニル)ピペラジン-1-カルボキシレート(818 mg, 1.8 mmol) をエタノール (10 mL) に溶かし、オルトギ酸トリエチル (2.67 g, 18 mmol)、酢酸 (216 mg, 3.6 mmol) を加え、室温で一晩撹拌した。反応混合物に酢酸エチル、飽和重層水を加え、系を塩基性にした後、クロロホルムで抽出した。有機層を合わせ、無水硫酸マグネシウムで乾燥した後、溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (0.25 g, 0.54 mmol, 30 %) を得た。1H-NMR (CDCl3) δ: 8.12 (1H, s), 7.87 (1H, s), 7.85 (1H, d, J = 7.0 Hz), 7.69 (1H, dd, J = 7.0, 1.5 Hz), 7.39 (2H, d, J = 9.0 Hz), 7.07 (2H, d, J = 9.0 Hz), 3.56 (3H, s), 3.74 (4H, br s), 3.15 (4H, br s), 1.52 (9H, s). tert-Butyl 4- (4-((2-amino-5- (methoxy (methyl) carbamoyl) phenyl) amino) phenyl) piperazine-1-carboxylate (818 mg, 1.8 mmol) was dissolved in ethanol (10 mL). , Triethyl orthoformate (2.67 g, 18 mmol) and acetic acid (216 mg, 3.6 mmol) were added and stirred overnight at room temperature. Ethyl acetate and saturated multistory water were added to the reaction mixture to make the system basic, followed by extraction with chloroform. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The resulting crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.25 g, 0.54 mmol, 30%). 1 H-NMR (CDCl 3 ) δ: 8.12 (1H, s), 7.87 (1H, s), 7.85 (1H, d, J = 7.0 Hz), 7.69 (1H, dd, J = 7.0, 1.5 Hz), 7.39 (2H, d, J = 9.0 Hz), 7.07 (2H, d, J = 9.0 Hz), 3.56 (3H, s), 3.74 (4H, br s), 3.15 (4H, br s), 1.52 (9H , s).

工程４
tert-ブチル 4-(4-(6-(ヒドロキシメチル)-1H-ベンゾ[d]イミダソール-1-イル)フェニル)ピペラジン-1-カルボキシレート Process 4
tert-Butyl 4- (4- (6- (hydroxymethyl) -1H-benzo [d] imidazol-1-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000081
Figure JPOXMLDOC01-appb-C000081

　tert-ブチル 4-(4-(6-(メトキシ(メチル)カルバモイル)-1H-ベンゾ[d]イミダゾール-1-イル)フェニル)ピペラジン-1-カルボキシレート (47 mg, 0.10 mmol) の テトラヒドロフラン (1.0 mL) 溶液にビスシクロペンタジエニルジルコニウム(ＩＶ)クロリドヒドリド (52 mg, 0.20 mmol) を0 ℃で加えた。室温に昇温し一晩撹拌した。反応終了後、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (27 mg, 66 %, 0.066 mmol) を得た。1H-NMR (CDCl3) δ: 8.05 (1H, s), 7.81 (1H, d, J = 8.1 Hz), 7.51 (1H, s), 7.37 (2H, d, J = 8.8 Hz), 7.31 (1H, d, J = 8.1 Hz), 7.06 (2H, d, J = 8.8 Hz), 4.81 (2H, s), 3.63 (4H, t, J = 5.0 Hz), 3.23 (4H, s), 1.50 (9H, s). tert-Butyl 4- (4- (6- (methoxy (methyl) carbamoyl) -1H-benzo [d] imidazol-1-yl) phenyl) piperazine-1-carboxylate (47 mg, 0.10 mmol) in tetrahydrofuran (1.0 mL) To the solution was added biscyclopentadienylzirconium (IV) chloride hydride (52 mg, 0.20 mmol) at 0 ° C. The mixture was warmed to room temperature and stirred overnight. After completion of the reaction, chloroform and saturated aqueous sodium hydrogen carbonate solution were added to extract the organic layer, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (27 mg, 66%, 0.066 mmol). 1 H-NMR (CDCl 3 ) δ: 8.05 (1H, s), 7.81 (1H, d, J = 8.1 Hz), 7.51 (1H, s), 7.37 (2H, d, J = 8.8 Hz), 7.31 ( 1H, d, J = 8.1 Hz), 7.06 (2H, d, J = 8.8 Hz), 4.81 (2H, s), 3.63 (4H, t, J = 5.0 Hz), 3.23 (4H, s), 1.50 ( 9H, s).

工程５
tert-ブチル 4-(4-(6-ホルミル-1H-ベンゾ[d]イミダゾール-1-イル)フェニル)ピペラジン-1-カルボキシレート Process 5
tert-butyl 4- (4- (6-formyl-1H-benzo [d] imidazol-1-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000082

　tert-ブチル 4-(4-(6-(ヒドロキシメチル)-1H-ベンゾ[d]イミダソール-1-イル)フェニル)ピペラジン-1-カルボキシレート (27 mg, 0.066 mmol) の塩化メチレン (2.0 mL) 溶液にデス・マーチン・ペルヨージナン (31 mg, 0.073 mmol) を0 ℃で滴下した。室温に昇温し1時間撹拌した。反応終了後、飽和チオ硫酸水素ナトリウム水溶液を添加し、酢酸エチルと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮し、標記化合物 (27 mg, quant., 0.066 mmol) を得た。白色固体: 1H-NMR (CDCl3) δ: 10.08 (1H, s), 8.24 (1H, s), 8.02 (1H, s), 7.98 (1H, dd, J = 8.3, 1.7 Hz), 7.87 (1H, dd, J = 8.3, 1.7 Hz), 7.40 (2H, t, J = 4.4 Hz), 7.09 (2H, t, J = 4.4 Hz), 3.64 (4H, t, J = 5.0 Hz), 3.26 (4H, t, J = 5.0 Hz), 1.51 (9H, s). tert-Butyl 4- (4- (6- (hydroxymethyl) -1H-benzo [d] imidazol-1-yl) phenyl) piperazine-1-carboxylate (27 mg, 0.066 mmol) in methylene chloride (2.0 mL) Dess-Martin periodinane (31 mg, 0.073 mmol) was added dropwise to the solution at 0 ° C. The mixture was warmed to room temperature and stirred for 1 hour. After completion of the reaction, a saturated aqueous sodium hydrogen thiosulfate solution was added, and the organic layer was extracted by adding ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (27 mg , quant., 0.066 mmol). White solid: 1 H-NMR (CDCl 3 ) δ: 10.08 (1H, s), 8.24 (1H, s), 8.02 (1H, s), 7.98 (1H, dd, J = 8.3, 1.7 Hz), 7.87 ( 1H, dd, J = 8.3, 1.7 Hz), 7.40 (2H, t, J = 4.4 Hz), 7.09 (2H, t, J = 4.4 Hz), 3.64 (4H, t, J = 5.0 Hz), 3.26 ( 4H, t, J = 5.0 Hz), 1.51 (9H, s).

工程６
tert-ブチル 4-(4-(6-((4-オキソ-2-チオキソチアゾリジン-5-イリデン)メチル)-1H-ベンゾ[d]イミダゾール-1-イル)フェニル)ピペラジン-1-カルボキシレート (化合物１５) Step 6
tert-butyl 4- (4- (6-((4-oxo-2-thioxothiazolidine-5-ylidene) methyl) -1H-benzo [d] imidazol-1-yl) phenyl) piperazine-1-carboxylate (Compound 15)

Figure JPOXMLDOC01-appb-C000083
Figure JPOXMLDOC01-appb-C000083

　tert-ブチル 4-(4-(6-ホルミル-1H-ベンゾ[d]イミダゾール-1-イル)フェニル)ピペラジン-1-カルボキシレート (27 mg, 0.066 mmol) をエタノール (1.00 mL) に溶かし、ロダニン (9 mg, 0.066 mmol) およびピペリジン (10 μL, 0.1 mmol) を加え、還流条件下一晩撹拌した。反応終了後、生成した沈殿をろ過し、エタノールで洗浄して標記化合物 (11 mg, 21 %, 0.021 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 13.93-13.75 (1H, m), 8.64 (1H, s), 7.91 (1H, d, J = 8.3 Hz), 7.84 (1H, s), 7.82 (1H, s), 7.56 (2H, d, J = 9.0 Hz), 7.53 (1H, d, J = 8.3 Hz), 7.20 (2H, d, J = 9.0 Hz), 3.51 (4H, t, J = 5.0 Hz), 3.24 (4H, t, J = 5.0 Hz), 1.44 (9H, s). 
ESI-MS(m/z): 522[M+H]+. Dissolve tert-butyl 4- (4- (6-formyl-1H-benzo [d] imidazol-1-yl) phenyl) piperazine-1-carboxylate (27 mg, 0.066 mmol) in ethanol (1.00 mL) (9 mg, 0.066 mmol) and piperidine (10 μL, 0.1 mmol) were added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the produced precipitate was filtered and washed with ethanol to obtain the title compound (11 mg, 21%, 0.021 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 13.93-13.75 (1H, m), 8.64 (1H, s), 7.91 (1H, d, J = 8.3 Hz), 7.84 (1H, s), 7.82 (1H, s), 7.56 (2H, d, J = 9.0 Hz), 7.53 (1H, d, J = 8.3 Hz), 7.20 (2H, d, J = 9.0 Hz), 3.51 (4H, t, J = 5.0 Hz), 3.24 (4H, t, J = 5.0 Hz), 1.44 (9H, s).
ESI-MS (m / z): 522 [M + H] + .

実施例１６
5-((1-(4-((1-メチルピペリジン-4-イル)オキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１６)  Example 16
5-((1- (4-((1-methylpiperidin-4-yl) oxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 16)

工程１
1-メチル-4-(4-ニトロフェノキシ)ピペリジン Process 1
1-methyl-4- (4-nitrophenoxy) piperidine

Figure JPOXMLDOC01-appb-C000084
Figure JPOXMLDOC01-appb-C000084

　アルゴン雰囲気下、1-メチルピペリジン-4-オール (2.53 g, 22 mmol) をN,N-ジメチルホルムアミド (15 mL) に溶解した。そこへ4-フルオロニトロベンゼン (2.82 g, 20 mmol)、炭酸カリウム (9.14 g, 66 mmol) を加え、100℃で3日間撹拌した。反応液に水を加え、酢酸エチルで抽出した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去、真空乾燥した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、目的とする標記化合物 (1.22 g, 5.2 mmol, 26 %) を得た。 1H-NMR (CDCl3) δ: 8.23 (2H, d, J = 9.3 Hz), 6.97 (2H, d, J = 9.3 Hz), 4.73 (1H, m), 3.03-2.84 (2H, m), 2.58 (3H, br s), 2.56-2.30 (2H, m), 2.15-1.99 (2H, m), 1.75-1.50 (2H, m). 1-Methylpiperidin-4-ol (2.53 g, 22 mmol) was dissolved in N, N-dimethylformamide (15 mL) under an argon atmosphere. 4-Fluoronitrobenzene (2.82 g, 20 mmol) and potassium carbonate (9.14 g, 66 mmol) were added thereto, and the mixture was stirred at 100 ° C. for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was vacuum dried. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the desired title compound (1.22 g, 5.2 mmol, 26%). 1 H-NMR (CDCl 3 ) δ: 8.23 (2H, d, J = 9.3 Hz), 6.97 (2H, d, J = 9.3 Hz), 4.73 (1H, m), 3.03-2.84 (2H, m), 2.58 (3H, br s), 2.56-2.30 (2H, m), 2.15-1.99 (2H, m), 1.75-1.50 (2H, m).

工程２
4-((1-メチルピペリジン-4-イル)オキシ)アニリン Process 2
4-((1-Methylpiperidin-4-yl) oxy) aniline

Figure JPOXMLDOC01-appb-C000085
Figure JPOXMLDOC01-appb-C000085

　1-メチル-4-(4-ニトロフェノキシ)ピペリジン (1.22 g, 5.2 mmol) をメタノール (50 mL) に溶解した。そこへ10% パラジウム－活性炭 (0.4 g) を加えた。反応容器内を水素で置換し、室温で3時間撹拌した。反応液をセライトでろ過し、濃縮次いで真空乾燥して、そのまま次の反応に使用した。 1-Methyl-4- (4-nitrophenoxy) piperidine (1.22 g, 5.2 mL) was dissolved in methanol (50 mL). Thereto was added 10% palladium-activated carbon (0.4 g). The reaction vessel was purged with hydrogen and stirred at room temperature for 3 hours. The reaction solution was filtered through celite, concentrated and then vacuum dried, and used as it was in the next reaction.

工程３
N-メトキシ-N-メチル-3-((4-((1-メチルピペリジン-4-イル)オキシ)フェニル)アミノ)-4-ニトロベンズアミド Process 3
N-methoxy-N-methyl-3-((4-((1-methylpiperidin-4-yl) oxy) phenyl) amino) -4-nitrobenzamide

Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000086

　N-メトキシ-N-メチル-3-((4-(4-メチルピペラジニル)ベンジル)アミノ)-4-ニトロベンズアミド の合成と同様の手法で、3-フルオロ-N-メトキシ-N-メチル-4-ニトロベンズアミド (1.19 g, 5.2 mmol) および 4-((1-メチルピペリジン-4-イル)オキシ)アニリン (1.07 g, 5.2 mmol) とから標記化合物 (1.91 g, 4.75 mmol, 91 %) を得た。1H-NMR (CDCl3) δ: 9.43 (1H, br s), 8.23 (1H, d, J = 8.8 Hz), 7.26 (1H, s), 7.20 (2H, d, J = 8.8 Hz), 6.96 (2H, d, J = 8.8 Hz), 6.92 (1H, dd, J = 7.1, 1.7 Hz), 4.40 (1H, br s),3.53 (3H, s), 3.30 (3H, s), 2.82 (2H, br s), 2.60-2.35 (5H, m), 2.15 (2H, br s), 1.95 (2H, br s). In a similar manner to the synthesis of N-methoxy-N-methyl-3-((4- (4-methylpiperazinyl) benzyl) amino) -4-nitrobenzamide, 3-fluoro-N-methoxy-N-methyl 4-nitrobenzamide (1.19 g, 5.2 mmol) and 4-((1-methylpiperidin-4-yl) oxy) aniline (1.07 g, 5.2 mmol) and the title compound (1.91 g, 4.75 mmol, 91%) Got. 1 H-NMR (CDCl 3 ) δ: 9.43 (1H, br s), 8.23 (1H, d, J = 8.8 Hz), 7.26 (1H, s), 7.20 (2H, d, J = 8.8 Hz), 6.96 (2H, d, J = 8.8 Hz), 6.92 (1H, dd, J = 7.1, 1.7 Hz), 4.40 (1H, br s), 3.53 (3H, s), 3.30 (3H, s), 2.82 (2H , br s), 2.60-2.35 (5H, m), 2.15 (2H, br s), 1.95 (2H, br s).

工程４
N-メトキシ-N-メチル-1-(4-((1-メチルピペリジン-4-イル)オキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 4
N-methoxy-N-methyl-1- (4-((1-methylpiperidin-4-yl) oxy) phenyl) -1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000087
Figure JPOXMLDOC01-appb-C000087

　N-メトキシ-N-メチル-1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド の合成と同様の手法で、N-メトキシ-N-メチル-3-((4-((1-メチルピペリジン-4-イル)オキシ)フェニル)アミノ)-4-ニトロベンズアミド (1.16 g, 2.80 mmol) を用い、標記化合物 (0.76 g, 1.93 mmol, 67 %) を得た。1H-NMR (CDCl3) δ: 8.13 (1H, s), 7.86 (1H, s), 7.86 (1H, d, J = 7.8 Hz), 7.68 (1H, dd, J = 7.1, 1.5 Hz), 7.40 (2H, d, J = 8.8 Hz), 7.08 (2H, d, J = 8.8 Hz), 4.45 (1H, br s),3.56 (3H, s), 3.38 (3H, s), 2.80 (2H, br s), 2.55-2.35 (5H, m), 2.16 (2H, br s), 1.97 (2H, br s). N-Methoxy-N-methyl-1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazole-6-carboxamide Using methyl-3-((4-((1-methylpiperidin-4-yl) oxy) phenyl) amino) -4-nitrobenzamide (1.16 g, 2.80 mmol), the title compound (0.76 g, 1.93 mmol, 67 %). 1 H-NMR (CDCl 3 ) δ: 8.13 (1H, s), 7.86 (1H, s), 7.86 (1H, d, J = 7.8 Hz), 7.68 (1H, dd, J = 7.1, 1.5 Hz), 7.40 (2H, d, J = 8.8 Hz), 7.08 (2H, d, J = 8.8 Hz), 4.45 (1H, br s), 3.56 (3H, s), 3.38 (3H, s), 2.80 (2H, br s), 2.55-2.35 (5H, m), 2.16 (2H, br s), 1.97 (2H, br s).

工程５
1-(4-((1-メチルピペリジン-4-イル)オキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Process 5
1- (4-((1-Methylpiperidin-4-yl) oxy) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000088
Figure JPOXMLDOC01-appb-C000088

　N-メトキシ-N-メチル-1-(4-((1-メチルピペリジン-4-イル)オキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド(0.76 g, 1.93 mmol) のテトラヒドロフラン (7 mL) 溶液中に、水素化アルミニウムリチウムのテトラヒドロフラン溶液 (1.0 M, 2.2 mL, 2.2 mmol) をアルゴン雰囲気下-78 ℃で添加した。0 ℃まで昇温し、1時間撹拌した後、塩化アンモニウム水溶液を加え、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (0.40g, 1.19 mmol, 62 %) を得た。1H-NMR (CDCl3) δ: 10.09 (1H, s), 8.23 (1H, s), 8.02 (1H, s), 7.99 (1H, d, J = 8.3 Hz), 7.88 (1H, dd, J = 6.8, 1.5 Hz), 7.44 (2H, d, J = 8.8 Hz), 7.12 (2H, d, J = 9.0 Hz), 4.55 (1H, br s), 2.91 (2H, br s), 2.60-2.40 (5H, m), 2.29 (2H, br s), 2.06 (2H, br s).  N-methoxy-N-methyl-1- (4-((1-methylpiperidin-4-yl) oxy) phenyl) -1H-benzo [d] imidazole-6-carboxamide (0.76 g, 1.93 mmol) in tetrahydrofuran (7 mL) A solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 2.2 mL, 2.2 mmol) was added to the solution at −78 ° C. under an argon atmosphere. After warming to 0 ° C. and stirring for 1 hour, an aqueous ammonium chloride solution was added, ethyl acetate and saturated brine were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.40 g, 1.19 mmol, 62%). 1 H-NMR (CDCl 3 ) δ: 10.09 (1H, s), 8.23 (1H, s), 8.02 (1H, s), 7.99 (1H, d, J = 8.3 Hz), 7.88 (1H, dd, J = 6.8, 1.5 Hz), 7.44 (2H, d, J = 8.8 Hz), 7.12 (2H, d, J = 9.0 Hz), 4.55 (1H, br s), 2.91 (2H, br s), 2.60-2.40 (5H, m), 2.29 (2H, br s), 2.06 (2H, br s).

工程６
5-((1-(4-((1-メチルピペリジン-4-イル)オキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１６) Step 6
5-((1- (4-((1-methylpiperidin-4-yl) oxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 16)

Figure JPOXMLDOC01-appb-C000089
Figure JPOXMLDOC01-appb-C000089

　5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン の合成と同様の手法で、1-(4-((1-メチルピペリジン-4-イル)オキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (0.17 g, 0.51 mmol) および 2,4-チアゾリジンジオン (60 mg, 0.51 mmol) とから標記化合物 (102 mg, 46%) を得た。黄色結晶: 1H-NMR (DMSO-D6)δ: 8.58 (1H, s), 7.85 (1H, d, J = 8.5 Hz), 7.77 (1H, s), 7.75 (1H, s), 7.63 (2H, d, J = 8.8 Hz), 7.51 (1H, d, J = 10.0 Hz), 7.26 (2H, d, J = 8.8 Hz), 4.67 (1H, br s), 3.11 (2H, br s), 2.89 (2H, br s), 2.61 (3H, br s), 2.10 (2H, br s), 1.89 (2H, br s). 
ESI-MS(m/z): 435[M+H]+.  In a manner similar to the synthesis of 5-((1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione, -(4-((1-Methylpiperidin-4-yl) oxy) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (0.17 g, 0.51 mmol) and 2,4-thiazolidinedione (60 mg, The title compound (102 mg, 46%) was obtained from 0.51 mmol). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 8.58 (1H, s), 7.85 (1H, d, J = 8.5 Hz), 7.77 (1H, s), 7.75 (1H, s), 7.63 ( 2H, d, J = 8.8 Hz), 7.51 (1H, d, J = 10.0 Hz), 7.26 (2H, d, J = 8.8 Hz), 4.67 (1H, br s), 3.11 (2H, br s), 2.89 (2H, br s), 2.61 (3H, br s), 2.10 (2H, br s), 1.89 (2H, br s).
ESI-MS (m / z): 435 [M + H] + .

実施例１７
5-((1-(4-((1-メチルピペリジン-4-イル)オキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物１７)  Example 17
5-((1- (4-((1-methylpiperidin-4-yl) oxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one ( Compound 17)

Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-C000090

工程１
　5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成と同様の手法で、1-(4-((1-メチルピペリジン-4-イル)オキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (0.22 g, 0.66 mmol) およびロダニン (87 mg, 0.66 mmol) とから標記化合物 (187 mg, 63%) を得た。黄色結晶: 1H-NMR (DMSO-D6)δ: 8.55 (1H, s), 7.82 (1H, d, J = 8.5 Hz), 7.65 (1H, s), 7.64 (2H, d, J = 8.8 Hz), 7.47 (1H, d, J = 10.0 Hz), 7.37 (1H, s), 7.28 (2H, d, J = 8.8 Hz), 4.74 (1H, br s), 3.26 (2H, br s), 3.09 (2H, br s), 2.74 (3H, br s), 2.13 (2H, br s), 1.96 (2H, br s).
ESI-MS(m/z): 451[M+H]+.  Process 1
Similar procedure to the synthesis of 5-((1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one 1- (4-((1-methylpiperidin-4-yl) oxy) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (0.22 g, 0.66 mmol) and rhodanine (87 mg, 0.66 mmol) ) To give the title compound (187 mg, 63%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 8.55 (1H, s), 7.82 (1H, d, J = 8.5 Hz), 7.65 (1H, s), 7.64 (2H, d, J = 8.8 Hz), 7.47 (1H, d, J = 10.0 Hz), 7.37 (1H, s), 7.28 (2H, d, J = 8.8 Hz), 4.74 (1H, br s), 3.26 (2H, br s), 3.09 (2H, br s), 2.74 (3H, br s), 2.13 (2H, br s), 1.96 (2H, br s).
ESI-MS (m / z): 451 [M + H] + .

実施例１８
5-((1-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１８)  Example 18
5-((1- (4-((4-methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 18)

工程１
2-((4-ニトロベンジル)オキシ)テトラヒドロ-2H-ピラン Process 1
2-((4-Nitrobenzyl) oxy) tetrahydro-2H-pyran

Figure JPOXMLDOC01-appb-C000091
Figure JPOXMLDOC01-appb-C000091

　アルゴン雰囲気下、4-ニトロベンジルアルコール (3.06 g, 20 mmol) を塩化メチレン (60 mL) に溶解した。そこへパラトルエンスルホン酸ピリジニウム (0.20 g)、ジヒドロピラン (5.0 g, 60 mmol) を加え、40℃で1時間撹拌した。反応液に炭酸水素ナトリウム水溶液を加えクロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥させ、溶媒を留去、真空乾燥して得られた残渣物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物を含む混合物 (4.98 g) を得た。1H-NMR (CDCl3) δ: 7.69 (1H, m), 7.60-7.56 (2H, m), 7.45 (1H, m), 4.83 (1H, d, J = 12.7 Hz), 4.72 (1H, m), 4.53 (1H, d, J = 12.7 Hz), 3.88 (1H, m), 3.57 (1H, m), 1.89-1.56 (6H, m). 4-nitrobenzyl alcohol (3.06 g, 20 mmol) was dissolved in methylene chloride (60 mL) under an argon atmosphere. Thereto were added pyridinium paratoluenesulfonate (0.20 g) and dihydropyran (5.0 g, 60 mmol), and the mixture was stirred at 40 ° C. for 1 hour. To the reaction solution was added an aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue obtained after vacuum drying was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a mixture (4.98 g) containing the title compound. Obtained. 1 H-NMR (CDCl 3 ) δ: 7.69 (1H, m), 7.60-7.56 (2H, m), 7.45 (1H, m), 4.83 (1H, d, J = 12.7 Hz), 4.72 (1H, m ), 4.53 (1H, d, J = 12.7 Hz), 3.88 (1H, m), 3.57 (1H, m), 1.89-1.56 (6H, m).

工程２
4-(((テトラヒドロ-2H-ピラン-2-イル)オキシ)メチル)アニリン Process 2
4-(((Tetrahydro-2H-pyran-2-yl) oxy) methyl) aniline

Figure JPOXMLDOC01-appb-C000092
Figure JPOXMLDOC01-appb-C000092

　2-((4-ニトロベンジル)オキシ)テトラヒドロ-2H-ピラン (クルード4.98 g) をテトラヒドロフラン (120 mL) に溶解した。そこへパラジウム－活性炭エチレンジアミン複合体エチレンジアミン複合体 (0.4 g) を加えた。反応容器内を水素で置換し、室温で2日間撹拌した。反応液をセライトでろ過し、濃縮、次いで真空乾燥して、得られた残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (3.80 g, 18.3 mmol, 92 % 2 steps) を得た。1H-NMR (CDCl3) δ: 7.15 (1H, m), 6.80-6.75 (2H, m), 6.66 (1H, m), 4.73 (1H, d, J = 12.0 Hz), 4.71 (1H, m), 4.44 (1H, d, J = 12.2 Hz), 3.93 (1H, m), 3.57 (1H, m), 1.90-1.54 (6H, m). 2-((4-Nitrobenzyl) oxy) tetrahydro-2H-pyran (crude 4.98 g) was dissolved in tetrahydrofuran (120 mL). Palladium-activated carbon ethylenediamine complex ethylenediamine complex (0.4 g) was added thereto. The inside of the reaction vessel was replaced with hydrogen and stirred at room temperature for 2 days. The reaction mixture was filtered through celite, concentrated, and then dried in vacuo.The resulting residue was purified by silica gel column chromatography (chloroform / methanol), and the title compound (3.80 g, 18.3 mmol, 92% 2 steps) Got. 1 H-NMR (CDCl 3 ) δ: 7.15 (1H, m), 6.80-6.75 (2H, m), 6.66 (1H, m), 4.73 (1H, d, J = 12.0 Hz), 4.71 (1H, m ), 4.44 (1H, d, J = 12.2 Hz), 3.93 (1H, m), 3.57 (1H, m), 1.90-1.54 (6H, m).

工程３
N-メトキシ-N-メチル-4-ニトロ-3-((4-(((テトラヒドロ-2H-ピラン-2-イル)オキシ)メチル)フェニル)アミノ)ベンズアミド Process 3
N-methoxy-N-methyl-4-nitro-3-((4-(((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) amino) benzamide

Figure JPOXMLDOC01-appb-C000093
Figure JPOXMLDOC01-appb-C000093

　N-メトキシ-N-メチル-3-((4-(4-メチルピペラジニル)ベンジル)アミノ)-4-ニトロベンズアミド の合成と同様の手法で、3-フルオロ-N-メトキシ-N-メチル-4-ニトロベンズアミド (4.11 g, 18 mmol) および 4-(((テトラヒドロ-2H-ピラン-2-イル)オキシ)メチル)アニリン (クルード3.37 g, 18 mmol) とから標記化合物 (クルード6.39 g) を得た。1H-NMR (CDCl3) δ: 9.52 (1H, br s), 8.24 (1H, d, J = 8.8 Hz), 7.45 (1H, s), 7.44 (2H, d, J = 8.3 Hz), 7.26 (2H, d, J = 8.3 Hz), 6.97 (1H, dd, J = 7.3, 1.5 Hz), 4.81 (1H, d, J = 12.0 Hz), 4.75 (1H, m), 4.52 (1H, d, J = 12.2 Hz),. 3.94 (1H, m), 3.59 (1H, m), 3.57 (3H, s), 3.35 (3H, s), 1.90-1.55 (6H, m). In a similar manner to the synthesis of N-methoxy-N-methyl-3-((4- (4-methylpiperazinyl) benzyl) amino) -4-nitrobenzamide, 3-fluoro-N-methoxy-N-methyl 4-nitrobenzamide (4.11 g, 18 mmol) and 4-(((tetrahydro-2H-pyran-2-yl) oxy) methyl) aniline (crude 3.37 g, 18 mmol) and the title compound (crude 6.39 g) Got. 1 H-NMR (CDCl 3 ) δ: 9.52 (1H, br s), 8.24 (1H, d, J = 8.8 Hz), 7.45 (1H, s), 7.44 (2H, d, J = 8.3 Hz), 7.26 (2H, d, J = 8.3 Hz), 6.97 (1H, dd, J = 7.3, 1.5 Hz), 4.81 (1H, d, J = 12.0 Hz), 4.75 (1H, m), 4.52 (1H, d, J = 12.2 Hz), 3.94 (1H, m), 3.59 (1H, m), 3.57 (3H, s), 3.35 (3H, s), 1.90-1.55 (6H, m).

工程４
1-(4-(ヒドロキシメチル)フェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 4
1- (4- (hydroxymethyl) phenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000094
Figure JPOXMLDOC01-appb-C000094

　N-メトキシ-N-メチル-4-ニトロ-3-((4-(((テトラヒドロ-2H-ピラン-2-イル)オキシ)メチル)フェニル)アミノ)ベンズアミドの テトラヒドロフラン (90 mL) 溶液にパラジウム－活性炭エチレンジアミン複合体 (0.8 g) を加え、水素雰囲気下、室温で 24 時間撹拌した。反応終了後、反応溶液をろ過し、減圧下溶媒を留去した。得られた粗生成物をエタノール (75 mL) に溶かし、オルトギ酸トリエチル (11.1 g, 75 mmol)、酢酸 (1.8 g、30 mmol) を加え、室温で一晩撹拌し、1規定 塩酸 (5 mL) で処理した。減圧下溶媒を留去した後、反応混合物に酢酸エチル、飽和重層水を加え、系を塩基性にした後、クロロホルムで 3 回抽出した。有機層を合わせ、無水硫酸マグネシウムで乾燥した後、溶媒を留去した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (3.57 g, 11.5 mmol, 64 %, 3 steps) を得た。1H-NMR (CDCl3) δ: 8.43 (1H, s), 7.95 (1H, s), 7.95 (1H, d, J = 8.8 Hz), 7.77 (1H, d, J = 8.6 Hz), 7.62 (2H, d, J = 8.5 Hz), 7.54 (2H, d, J = 8.6 Hz), 4.84 (3H, s), 3.56 (3H, s), 3.39 (3H, s).  To a solution of N-methoxy-N-methyl-4-nitro-3-((4-(((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) amino) benzamide in tetrahydrofuran (90 mL) was added palladium- Activated carbon ethylenediamine complex (0.8 g) was added, and the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered and the solvent was distilled off under reduced pressure. The obtained crude product was dissolved in ethanol (75 mL), triethyl orthoformate (11.1 g, 75 mmol) and acetic acid (1.8 g, 30 mmol) were added, and the mixture was stirred overnight at room temperature, 1N hydrochloric acid (5 mL ) After evaporating the solvent under reduced pressure, ethyl acetate and saturated multistory water were added to the reaction mixture to make the system basic, followed by extraction with chloroform three times. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (3.57 g, 11.5 mmol, 64%, 3 steps). 1 H-NMR (CDCl 3 ) δ: 8.43 (1H, s), 7.95 (1H, s), 7.95 (1H, d, J = 8.8 Hz), 7.77 (1H, d, J = 8.6 Hz), 7.62 ( 2H, d, J = 8.5 Hz), 7.54 (2H, d, J = 8.6 Hz), 4.84 (3H, s), 3.56 (3H, s), 3.39 (3H, s).

工程５
N-メトキシ-N-メチル-1-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 5
N-methoxy-N-methyl-1- (4-((4-methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000095
Figure JPOXMLDOC01-appb-C000095

　アルゴン雰囲気下、1-(4-(ヒドロキシメチル)フェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド (0.53 g, 1.70 mmol) を塩化メチレン (20 mL) に溶かし、氷浴中で冷やしながらジイソプロピルエチルアミン (594 mg, 4.6 mmol) およびメタンスルホニルクロリド (263 mg, 2.3 mmol) の塩化メチレン (3 mL) 溶液を加え、氷浴中で6時間撹拌した。反応終了後、反応混合物にN-メチルピペラジン (385 mg, 3.85 mmol) を加え、氷浴中で3時間、室温で終夜撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥させ、減圧下、溶媒を留去した後、 シリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) にて精製し、標記化合物 (0.41 g, 1.04 mmol , 61 %) を得た。1H-NMR (CDCl3) δ: 8.19 (1H, s), 7.93 (1H, d, J= 1.0 Hz), 7.88 (1H, d, J = 8.5 Hz), 7.70 (1H, dd, J = 7.1, 1.5 Hz), 7.54 (2H, d, J = 8.3 Hz), 7.47 (2H, d, J = 8.3 Hz), 3.63 (2H, s), 3.56 (3H, s), 3.39 (3H, s), 2.41 (3H, s). 1- (4- (hydroxymethyl) phenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide (0.53 g, 1.70 mmol) in methylene chloride (20 mL) under argon atmosphere Then, a solution of diisopropylethylamine (594 mg, 4.6 mmol) and methanesulfonyl chloride (263 mg, 2.3 mmol) in methylene chloride (3 mL) was added while cooling in an ice bath, and the mixture was stirred in an ice bath for 6 hours. After completion of the reaction, N-methylpiperazine (385 mg, 3.85 mmol) was added to the reaction mixture, and the mixture was stirred in an ice bath for 3 hours and at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.41 g, 1.04 mmol, 61%). . 1 H-NMR (CDCl 3 ) δ: 8.19 (1H, s), 7.93 (1H, d, J = 1.0 Hz), 7.88 (1H, d, J = 8.5 Hz), 7.70 (1H, dd, J = 7.1 , 1.5 Hz), 7.54 (2H, d, J = 8.3 Hz), 7.47 (2H, d, J = 8.3 Hz), 3.63 (2H, s), 3.56 (3H, s), 3.39 (3H, s), 2.41 (3H, s).

工程６
1-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Step 6
1- (4-((4-Methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000096
Figure JPOXMLDOC01-appb-C000096

　N-メトキシ-N-メチル-1-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド(0.41 g, 1.04 mmol) のテトラヒドロフラン (12 mL) 溶液中に、水素化アルミニウムリチウムのテトラヒドロフラン溶液 (1.0 M, 1.3 mL, 1.3 mmol) をアルゴン雰囲気下-78 ℃で添加した。0 ℃まで昇温し、1時間撹拌した後、塩化アンモニウム水溶液を加え、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (0.30 g, 0.90 mmol, 86 %) を得た。1H-NMR (CDCl3) δ: 10.09 (1H, s), 8.27 (1H, s), 8.08 (1H, d, J = 0.7 Hz), 7.99 (1H, d, J= 8.3 Hz), 7.88 (1H, dd, J = 6.8, 1.5 Hz), 7.58 (2H, d, J = 8.5 Hz), 7.47 (2H, d, J = 8.3 Hz), 3.63 (2H, s), 2.56 (6H, br s), 2.34 (3H, s), 2.06 (2H, br s).  N-methoxy-N-methyl-1- (4-((4-methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazole-6-carboxamide (0.41 g, 1.04 mmol) in tetrahydrofuran (12 mL) A solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 1.3 mL, 1.3 mmol) was added to the solution at −78 ° C. under an argon atmosphere. After warming to 0 ° C. and stirring for 1 hour, an aqueous ammonium chloride solution was added, ethyl acetate and saturated brine were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.30 g, 0.90 mmol, 86%). 1 H-NMR (CDCl 3 ) δ: 10.09 (1H, s), 8.27 (1H, s), 8.08 (1H, d, J = 0.7 Hz), 7.99 (1H, d, J = 8.3 Hz), 7.88 ( 1H, dd, J = 6.8, 1.5 Hz), 7.58 (2H, d, J = 8.5 Hz), 7.47 (2H, d, J = 8.3 Hz), 3.63 (2H, s), 2.56 (6H, br s) , 2.34 (3H, s), 2.06 (2H, br s).

工程７
5-((1-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１８) Step 7
5-((1- (4-((4-methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 18)

Figure JPOXMLDOC01-appb-C000097
Figure JPOXMLDOC01-appb-C000097

　5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン の合成と同様の手法で、1-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (0.17 g, 0.51 mmol) および2,4-チアゾリジンジオン (60 mg, 0.51 mmol) とから標記化合物 (209 mg, 95%) を得た。黄色結晶: 1H-NMR (DMSO-D6)δ: 8.67 (1H, s), 7.86 (1H, s), 7.85 (1H, d, J = 8.3 Hz), 7.72 (1H, s), 7.69 (2H, d, J = 8.5 Hz), 7.58 (2H, d, J = 8.5 Hz), 7.51 (1H, dd, J = 7.1, 1.2 Hz), 3.63 (2H, s), 2.80-2.40 (8H, br s), 2.45 (3H, s)
ESI-MS(m/z): 434[M+H]+.  In a manner similar to the synthesis of 5-((1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione, -(4-((4-Methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (0.17 g, 0.51 mmol) and 2,4-thiazolidinedione (60 mg, The title compound (209 mg, 95%) was obtained from 0.51 mmol). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 8.67 (1H, s), 7.86 (1H, s), 7.85 (1H, d, J = 8.3 Hz), 7.72 (1H, s), 7.69 ( 2H, d, J = 8.5 Hz), 7.58 (2H, d, J = 8.5 Hz), 7.51 (1H, dd, J = 7.1, 1.2 Hz), 3.63 (2H, s), 2.80-2.40 (8H, br s), 2.45 (3H, s)
ESI-MS (m / z): 434 [M + H] + .

実施例１９
5-((1-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物１９)  Example 19
5-((1- (4-((4-methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one ( Compound 19)

Figure JPOXMLDOC01-appb-C000098
Figure JPOXMLDOC01-appb-C000098

工程１
　5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン の合成と同様の手法で、1-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (0.13 g, 0.39 mmol) およびロダニン (52 mg, 0.39 mmol) とから標記化合物 (166 mg, 95%) を得た。黄色結晶: 1H-NMR (DMSO-D6)δ: 8.64 (1H, s), 7.83 (1H, d, J = 8.5 Hz), 7.75 (1H, s), 7.71 (2H, d, J = 8.5 Hz), 7.60 (2H, d, J = 8.5 Hz), 7.49 (1H, d, J = 8.5 Hz), 7.38 (1H, s), 3.69 (2H, s), 3.20-2.50 (8H, br s), 2.65 (3H, s). 
ESI-MS(m/z): 450[M+H]+.  Process 1
Similar procedure to the synthesis of 5-((1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one 1- (4-((4-methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (0.13 g, 0.39 mmol) and rhodanine (52 mg, 0.39 mmol ) To give the title compound (166 mg, 95%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 8.64 (1H, s), 7.83 (1H, d, J = 8.5 Hz), 7.75 (1H, s), 7.71 (2H, d, J = 8.5 Hz), 7.60 (2H, d, J = 8.5 Hz), 7.49 (1H, d, J = 8.5 Hz), 7.38 (1H, s), 3.69 (2H, s), 3.20-2.50 (8H, br s) , 2.65 (3H, s).
ESI-MS (m / z): 450 [M + H] + .

実施例２０
5-((1-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物２０)  Example 20
5-((1- (3-((4-Methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 20)

工程１
N-メトキシ-N-メチル-4-ニトロ-3-((3-(((テトラヒドロ-2H-ピラン-2-イル)オキシ)メチル)フェニル)アミノ)ベンズアミド Process 1
N-methoxy-N-methyl-4-nitro-3-((3-(((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) amino) benzamide

Figure JPOXMLDOC01-appb-C000099
Figure JPOXMLDOC01-appb-C000099

　N-メトキシ-N-メチル-3-((4-(4-メチルピペラジニル)ベンジル)アミノ)-4-ニトロベンズアミド の合成と同様の手法で、3-フルオロ-N-メトキシ-N-メチル-4-ニトロベンズアミド (3.65 g, 16 mmol) および 3-(((テトラヒドロ-2H-ピラン-2-イル)オキシ)メチル)アニリン (クルード3.17 g, 16 mmol) とから標記化合物 (クルード5.46 g, 82 %) を得た。1H-NMR (CDCl3) δ: 9.51 (1H, s), 8.24 (1H, d, J = 8.8 Hz), 7.45 (1H, d, J = 1.5 Hz), 7.40 (1H, t, J = 7.8 Hz), 7.29-7.20 (3H, m), 6.97 (1H, dd, J = 8.8, 1.5 Hz), 4.81 (1H, t, J = 12.2 Hz), 4.70 (1H, m), 4.51 (1H, t, J = 12.2 Hz), 3.93 (1H, m), 3.56 (1H, m), 3.53 (3H, s), 3.30 (3H, s) 1.93-1.50 (6H, m). In a similar manner to the synthesis of N-methoxy-N-methyl-3-((4- (4-methylpiperazinyl) benzyl) amino) -4-nitrobenzamide, 3-fluoro-N-methoxy-N-methyl -4-nitrobenzamide (3.65 g, 16 mmol) and 3-(((tetrahydro-2H-pyran-2-yl) oxy) methyl) aniline (crude 3.17 g, 16 mmol) and the title compound (crude 5.46 g, 82%). 1 H-NMR (CDCl 3 ) δ: 9.51 (1H, s), 8.24 (1H, d, J = 8.8 Hz), 7.45 (1H, d, J = 1.5 Hz), 7.40 (1H, t, J = 7.8 Hz), 7.29-7.20 (3H, m), 6.97 (1H, dd, J = 8.8, 1.5 Hz), 4.81 (1H, t, J = 12.2 Hz), 4.70 (1H, m), 4.51 (1H, t , J = 12.2 Hz), 3.93 (1H, m), 3.56 (1H, m), 3.53 (3H, s), 3.30 (3H, s) 1.93-1.50 (6H, m).

工程２
1-(3-(ヒドロキシメチル)フェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 2
1- (3- (hydroxymethyl) phenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000100
Figure JPOXMLDOC01-appb-C000100

　1-(4-(ヒドロキシメチル)フェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミドの合成と同様の手法で、N-メトキシ-N-メチル-4-ニトロ-3-((3-(((テトラヒドロ-2H-ピラン-2-イル)オキシ)メチル)フェニル)アミノ)ベンズアミド (クルード5.46 g) を用い、標記化合物 (1.15 g, 3.96 mmol) を得た。1H-NMR (CDCl3) δ: 8.35 (1H, s), 7.96 (1H, s), 7.90 (1H, d, J = 8.3 Hz), 7.74 (1H, d, J= 8.3 Hz), 7.60 (1H, s), 7.56 (1H, d, J= 7.8 Hz), 7.50-7.42 (2H, m), 4.84 (2H, s), 3.56 (3H, s), 3.39 (3H, s).  In a similar manner to the synthesis of 1- (4- (hydroxymethyl) phenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide, N-methoxy-N-methyl-4- Using nitro-3-((3-(((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) amino) benzamide (crude 5.46 g), the title compound (1.15 g, 3.96 mmol) was obtained. . 1 H-NMR (CDCl 3 ) δ: 8.35 (1H, s), 7.96 (1H, s), 7.90 (1H, d, J = 8.3 Hz), 7.74 (1H, d, J = 8.3 Hz), 7.60 ( 1H, s), 7.56 (1H, d, J = 7.8 Hz), 7.50-7.42 (2H, m), 4.84 (2H, s), 3.56 (3H, s), 3.39 (3H, s).

工程３
N-メトキシ-N-メチル-1-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 3
N-methoxy-N-methyl-1- (3-((4-methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000101
Figure JPOXMLDOC01-appb-C000101

　アルゴン雰囲気下、1-(3-(ヒドロキシメチル)フェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド (0.20 g, 0.64 mmol) を塩化メチレン (10 mL) に溶かし、氷浴中で冷やしながらジイソプロピルエチルアミン (226 mg, 1.75 mmol) およびメタンスルホニルクロリド (100 mg, 0.87 mmol) の塩化メチレン (3 mL) 溶液を加え、氷浴中で6時間撹拌した。反応終了後、反応混合物にN-メチルピペラジン (145 mg, 1.45 mmol) を加え、氷浴中で3時間、室温で3日間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥させ、減圧下、溶媒を留去した後、 シリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) にて精製し、標記化合物 (0.07 g, 0.18 mmol, 28 %) を得た。1H-NMR (CDCl3) δ: 8.21 (1H, s), 7.93 (1H, d, J = 1.5 Hz), 7.87 (1H, d, J = 8.5 Hz), 7.71 (1H, dd, J = 7.1, 1.5 Hz), 7.58 (1H, s), 7.52 (1H, t, J = 7.8 Hz), 7.44-7.38 (2H, m), 3.66 (2H, s), 3.57 (3H, s), 3.38 (3H, s), 2.80-2.60 (8H, m), 2.49 (3H, br s). 1- (3- (hydroxymethyl) phenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide (0.20 g, 0.64 mmol) was added to methylene chloride (10 mL) under an argon atmosphere. Then, a solution of diisopropylethylamine (226 mg, 1.75 mmol) and methanesulfonyl chloride (100 mg, 0.87 mmol) in methylene chloride (3 mL) was added while cooling in an ice bath, and the mixture was stirred in an ice bath for 6 hours. After completion of the reaction, N-methylpiperazine (145 mg, 1.45 mmol) was added to the reaction mixture, followed by stirring in an ice bath for 3 hours and at room temperature for 3 days. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.07 g, 0.18 mmol, 28%). . 1 H-NMR (CDCl 3 ) δ: 8.21 (1H, s), 7.93 (1H, d, J = 1.5 Hz), 7.87 (1H, d, J = 8.5 Hz), 7.71 (1H, dd, J = 7.1 , 1.5 Hz), 7.58 (1H, s), 7.52 (1H, t, J = 7.8 Hz), 7.44-7.38 (2H, m), 3.66 (2H, s), 3.57 (3H, s), 3.38 (3H , s), 2.80-2.60 (8H, m), 2.49 (3H, br s).

工程４
1-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Process 4
1- (3-((4-Methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000102
Figure JPOXMLDOC01-appb-C000102

　N-メトキシ-N-メチル-1-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド (0.07 g, 0.18 mmol) のテトラヒドロフラン (4 mL) 溶液中に、水素化アルミニウムリチウムのテトラヒドロフラン溶液 (1.0 M, 0.3 mL, 0.3 mmol) をアルゴン雰囲気下-78 ℃で添加した。0 ℃まで昇温し、1時間撹拌した後、塩化アンモニウム水溶液を加え、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (0.05 g, 0.15 mmol, 83 %) を得た。1H-NMR (CDCl3) δ: 10.11 (1H, s), 8.32 (1H, s), 8.11 (1H, s), 8.02 (1H, d, J = 8.3 Hz), 7.90 (1H, d, J = 8.3 Hz), 7.68-7.41 (4H, m), 3.70 (2H, s), 2.80-2.50 (8H, m), 2.46 (3H, br s).  N-methoxy-N-methyl-1- (3-((4-methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazole-6-carboxamide (0.07 g, 0.18 mmol) in tetrahydrofuran (4 mL) A solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 0.3 mL, 0.3 mmol) was added to the solution at −78 ° C. under an argon atmosphere. After warming to 0 ° C. and stirring for 1 hour, an aqueous ammonium chloride solution was added, ethyl acetate and saturated brine were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.05 g, 0.15 mmol, 83%). 1 H-NMR (CDCl 3 ) δ: 10.11 (1H, s), 8.32 (1H, s), 8.11 (1H, s), 8.02 (1H, d, J = 8.3 Hz), 7.90 (1H, d, J = 8.3 Hz), 7.68-7.41 (4H, m), 3.70 (2H, s), 2.80-2.50 (8H, m), 2.46 (3H, br s).

工程５
5-((1-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物２０) Process 5
5-((1- (3-((4-Methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 20)

Figure JPOXMLDOC01-appb-C000103
Figure JPOXMLDOC01-appb-C000103

　5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成と同様の手法で、1-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアルデヒド (0.05 g, 0.15 mmol) および2,4-チアゾリジンジオン (18 mg, 0.15 mmol) とから標記化合物 (58 mg, 89%) を得た。黄色結晶: 1H-NMR (DMSO-D6)δ: 8.67 (1H, s), 7.85 (1H, d, J = 8.5 Hz), 7.82 (1H, s), 7.69-7.60 (4H, m), 7.55-7.45 (2H, m), 3.70 (2H, s), 3.08-2.91 (8H, m), 2.73 (3H, s).
ESI-MS(m/z): 434[M+H]+.  In a manner similar to the synthesis of 5-((1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione, -(3-((4-Methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazole-6-carboxaldehyde (0.05 g, 0.15 mmol) and 2,4-thiazolidinedione (18 mg, 0.15 mmol) gave the title compound (58 mg, 89%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 8.67 (1H, s), 7.85 (1H, d, J = 8.5 Hz), 7.82 (1H, s), 7.69-7.60 (4H, m), 7.55-7.45 (2H, m), 3.70 (2H, s), 3.08-2.91 (8H, m), 2.73 (3H, s).
ESI-MS (m / z): 434 [M + H] + .

実施例２１
5-((1-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物２１)  Example 21
5-((1- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 21)

工程１
1-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 1
1- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000104
Figure JPOXMLDOC01-appb-C000104

　アルゴン雰囲気下、1-(3-(ヒドロキシメチル)フェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド (0.28 g, 0.9 mmol) を塩化メチレン (15 mL) に溶かし、氷浴中で冷やしながらジイソプロピルエチルアミン(315 mg, 2.44 mmol) およびメタンスルホニルクロリド (140 mg, 1.22 mmol) の塩化メチレン (3 mL) 溶液を加え、氷浴中で6時間撹拌した。反応終了後、反応混合物にN-エチルピペラジン (228 mg, 2 mmol) を加え、氷浴中で3時間、室温で3日間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥させ、減圧下、溶媒を留去した後、 シリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (0.36 g, 0.88 mmol, 98 %) を得た。1H-NMR (CDCl3) δ: 8.22 (1H, s), 7.93 (1H, d, J = 1.2 Hz), 7.88 (1H, d, J = 7.8 Hz), 7.72 (1H, dd, J = 7.1, 1.5 Hz), 7.59 (1H, s), 7.53 (1H, t, J = 7.8 Hz), 7.45-7.37 (2H, m), 3.68 (2H, s), 3.58 (3H, s), 3.39 (3H, s), 3.09 (1H, q, J = 7.4 Hz), 2.90-2.60 (8H, m), 1.56 (1H, t, J = 7.4 Hz). 1- (3- (hydroxymethyl) phenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide (0.28 g, 0.9 mmol) in methylene chloride (15 mL) under argon atmosphere Then, a solution of diisopropylethylamine (315 mg, 2.44 mmol) and methanesulfonyl chloride (140 mg, 1.22 mmol) in methylene chloride (3 mL) was added while cooling in an ice bath, and the mixture was stirred in an ice bath for 6 hours. After completion of the reaction, N-ethylpiperazine (228 mg, 2 mmol) was added to the reaction mixture, and the mixture was stirred in an ice bath for 3 hours and at room temperature for 3 days. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.36 g, 0.88 mmol, 98%). 1 H-NMR (CDCl 3 ) δ: 8.22 (1H, s), 7.93 (1H, d, J = 1.2 Hz), 7.88 (1H, d, J = 7.8 Hz), 7.72 (1H, dd, J = 7.1 , 1.5 Hz), 7.59 (1H, s), 7.53 (1H, t, J = 7.8 Hz), 7.45-7.37 (2H, m), 3.68 (2H, s), 3.58 (3H, s), 3.39 (3H , s), 3.09 (1H, q, J = 7.4 Hz), 2.90-2.60 (8H, m), 1.56 (1H, t, J = 7.4 Hz).

工程２
1-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド  Process 2
1- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000105
Figure JPOXMLDOC01-appb-C000105

　1-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド (0.36 g, 0.88 mmol) のテトラヒドロフラン (10 mL) 溶液中に、水素化アルミニウムリチウムのテトラヒドロフラン溶液 (1.0 M, 1.1 mL, 1.1 mmol) をアルゴン雰囲気下-78 ℃で添加した。0 ℃まで昇温し、1時間撹拌した後、塩化アンモニウム水溶液を加え、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (0.18 g,  0.52 mmol, 59 %) を得た。1H-NMR (CDCl3) δ: 10.01 (1H, s), 8.31 (1H, s), 8.09 (1H, s), 8.00 (1H, d, J = 8.5 Hz), 7.90 (1H, dd, J = 6.8, 1.5 Hz), 7.58 (1H, s), 7.56 (1H, t, J = 7.8 Hz), 7.48-7.40 (2H, m), 3.67 (2H, s), 2.70-2.55 (8H, m), 2.62 (1H, br s), 1.14 (1H, t, J = 6.8 Hz). 1- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide (0.36 g, 0.88 mmol) in tetrahydrofuran (10 mL) A solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 1.1 mL, 1.1 mmol) was added to the solution at −78 ° C. under an argon atmosphere. After warming to 0 ° C. and stirring for 1 hour, an aqueous ammonium chloride solution was added, ethyl acetate and saturated brine were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.18 g, 0.52 mmol, 59%). 1 H-NMR (CDCl 3 ) δ: 10.01 (1H, s), 8.31 (1H, s), 8.09 (1H, s), 8.00 (1H, d, J = 8.5 Hz), 7.90 (1H, dd, J = 6.8, 1.5 Hz), 7.58 (1H, s), 7.56 (1H, t, J = 7.8 Hz), 7.48-7.40 (2H, m), 3.67 (2H, s), 2.70-2.55 (8H, m) , 2.62 (1H, br s), 1.14 (1H, t, J = 6.8 Hz).

工程３
5-((1-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物２１) Process 3
5-((1- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 21)

Figure JPOXMLDOC01-appb-C000106
Figure JPOXMLDOC01-appb-C000106

　5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン の合成と同様の手法で、1-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (0.07 g, 0.16 mmol) および2,4-チアゾリジンジオン (19 mg, 0.16 mmol) とから標記化合物 (24 mg, 34%) を得た。黄色結晶: 1H-NMR (DMSO-D6)δ: 8.66 (1H, s), 7.85 (1H, d, J = 8.5 Hz), 7.83 (1H, s), 7.70-7.60 (4H, m), 7.56-7.45 (2H, m), 3.67 (2H, s), 2.75-2.50 (10H, m), 1.10 (1H, t, J = 7.2 Hz).
ESI-MS(m/z): 448[M+H]+.  In a manner similar to the synthesis of 5-((1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione, -(3-((4-Ethylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (0.07 g, 0.16 mmol) and 2,4-thiazolidinedione (19 mg, 0.16 mmol) gave the title compound (24 mg, 34%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 8.66 (1H, s), 7.85 (1H, d, J = 8.5 Hz), 7.83 (1H, s), 7.70-7.60 (4H, m), 7.56-7.45 (2H, m), 3.67 (2H, s), 2.75-2.50 (10H, m), 1.10 (1H, t, J = 7.2 Hz).
ESI-MS (m / z): 448 [M + H] + .

実施例２２
5-((1-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物２２)  Example 22
5-((1- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one ( Compound 22)

Figure JPOXMLDOC01-appb-C000107
Figure JPOXMLDOC01-appb-C000107

工程１
　5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン の合成と同様の手法で、1-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (0.10 g, 0.29 mmol) およびロダニン (39 mg, 0.29 mmol) とから標記化合物 (81 mg, 60%) を得た。黄色結晶: 1H-NMR (DMSO-D6)δ: 8.66 (1H, s), 7.84 (1H, d, J = 8.3 Hz), 7.72 (1H, s), 7.70 (1H, s), 7.69-7.63 (2H, m), 7.53-7.49 (2H, m), 7.40 (1H, s), 3.74 (2H, s), 2.63-2.48 (10H, m), 1.17 (1H, t, J = 7.2 Hz).
ESI-MS(m/z): 464[M+H]+.  Process 1
Similar procedure to the synthesis of 5-((1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one 1- (3-((4-ethylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (0.10 g, 0.29 mmol) and rhodanine (39 mg, 0.29 mmol ) To give the title compound (81 mg, 60%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 8.66 (1H, s), 7.84 (1H, d, J = 8.3 Hz), 7.72 (1H, s), 7.70 (1H, s), 7.69- 7.63 (2H, m), 7.53-7.49 (2H, m), 7.40 (1H, s), 3.74 (2H, s), 2.63-2.48 (10H, m), 1.17 (1H, t, J = 7.2 Hz) .
ESI-MS (m / z): 464 [M + H] + .

実施例２３
5-((1-(3-(2-モルホリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物２３) Example 23
5-((1- (3- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 23)

工程１
メチル 3-((3-(2-モルホリノエトキシ)フェニル)アミノ)-4-ニトロベンゾエート Process 1
Methyl 3-((3- (2-morpholinoethoxy) phenyl) amino) -4-nitrobenzoate

Figure JPOXMLDOC01-appb-C000108
Figure JPOXMLDOC01-appb-C000108

　N-メトキシ-N-メチル-3-((3-モルホリノプロピル)アミノ)-4-ニトロベンズアミドの合成 (実施例1、工程2) と同様の手法で、メチル 3-フルオロ-4-ニトロベンゾエート(1.16 g、 5.80 mmol) および3-(2-モルホリノエトキシ)アニリン (1.55 g、6.96 mmol) から標記化合物 (937 mg, 40%)を得た。赤色オイル: 1H-NMR (DMSO-D6) δ: 9.34 (1H, s), 8.21 (1H, d, J = 8.8 Hz), 7.95 (1H, s), 7.79 (1H, d, J = 1.7 Hz), 7.35 (1H, dd, J = 8.8, 1.7 Hz), 7.33 (1H, t, J = 8.1 Hz), 6.95-6.90 (2H, m), 4.09 (2H, t, J = 5.7 Hz), 3.82 (3H, s), 3.57 (4H, t, J = 4.5 Hz), 2.69 (2H, t, J = 5.7 Hz), 2.46 (4H, t, J = 4.6 Hz). Synthesis of N-methoxy-N-methyl-3-((3-morpholinopropyl) amino) -4-nitrobenzamide In the same manner as in Example 1, Step 2, methyl 3-fluoro-4-nitrobenzoate ( The title compound (937 mg, 40%) was obtained from 1.16 g, 5.80 mmol) and 3- (2-morpholinoethoxy) aniline (1.55 g, 6.96 mmol). Red oil: 1 H-NMR (DMSO-D 6 ) δ: 9.34 (1H, s), 8.21 (1H, d, J = 8.8 Hz), 7.95 (1H, s), 7.79 (1H, d, J = 1.7 Hz), 7.35 (1H, dd, J = 8.8, 1.7 Hz), 7.33 (1H, t, J = 8.1 Hz), 6.95-6.90 (2H, m), 4.09 (2H, t, J = 5.7 Hz), 3.82 (3H, s), 3.57 (4H, t, J = 4.5 Hz), 2.69 (2H, t, J = 5.7 Hz), 2.46 (4H, t, J = 4.6 Hz).

工程２
メチル 4-アミノ-3-((3-(2-モルホリノエトキシ)フェニル)アミノ)ベンゾエート Process 2
Methyl 4-amino-3-((3- (2-morpholinoethoxy) phenyl) amino) benzoate

Figure JPOXMLDOC01-appb-C000109
Figure JPOXMLDOC01-appb-C000109

　メチル 3-((3-(2-モルホリノエトキシ)フェニル)アミノ)-4-ニトロベンゾエート (937 mg, 2.33 mmol) をメタノール (10 mL) に溶解した。そこへ10% パラジウム－活性炭 (94 mg) を加えた。反応容器内を水素で置換し、室温で4時間撹拌した。反応液をセライトでろ過し、濃縮、真空乾燥して標記化合物 (833 mg, 92%) を得た。黒色オイル：1H-NMR (DMSO-D6) δ: 7.95 (1H, s), 7.60 (1H, d, J = 2.0 Hz), 7.48 (1H, dd, J = 8.4, 2.1 Hz), 7.19 (1H, s), 7.04 (1H, t, J = 8.1 Hz), 6.75 (1H, d, J = 8.3 Hz), 6.34-6.29 (2H, m), 5.65 (2H, s), 3.98 (2H, t, J = 5.9 Hz), 3.72 (3H, s), 3.56 (4H, t, J = 4.6 Hz), 2.64 (2H, t, J = 5.7 Hz), 2.43 (4H, t, J = 4.4 Hz). Methyl 3-((3- (2-morpholinoethoxy) phenyl) amino) -4-nitrobenzoate (937 mg, 2.33 mmol) was dissolved in methanol (10 mL). 10% palladium-activated carbon (94 mg) was added thereto. The inside of the reaction vessel was replaced with hydrogen and stirred at room temperature for 4 hours. The reaction mixture was filtered through celite, concentrated and dried under vacuum to obtain the title compound (833 mg, 92%). Black oil: 1 H-NMR (DMSO-D 6 ) δ: 7.95 (1H, s), 7.60 (1H, d, J = 2.0 Hz), 7.48 (1H, dd, J = 8.4, 2.1 Hz), 7.19 ( 1H, s), 7.04 (1H, t, J = 8.1 Hz), 6.75 (1H, d, J = 8.3 Hz), 6.34-6.29 (2H, m), 5.65 (2H, s), 3.98 (2H, t , J = 5.9 Hz), 3.72 (3H, s), 3.56 (4H, t, J = 4.6 Hz), 2.64 (2H, t, J = 5.7 Hz), 2.43 (4H, t, J = 4.4 Hz).

工程３
メチル 1-(3-(2-モルホリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 3
Methyl 1- (3- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000110
Figure JPOXMLDOC01-appb-C000110

　アルゴン雰囲気下、メチル 4-アミノ-3-((3-(2-モルホリノエトキシ)フェニル)アミノ)ベンゾエート (833 mg, 2.24 mmol) をエタノール (10 mL) に溶解した。そこへオルトぎ酸トリエチル (3.73 mL, 22.4 mmol)、酢酸 (256 μL, 4.48 mL) を加え、50℃で18時間撹拌した。反応液を濃縮し、酢酸エチルを加え、飽和重層水、水、飽和食塩水で洗浄した、酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (588 mg, 69%) を得た。紫色アモルファス状固体： 1H-NMR (DMSO-D6) δ: 8.78 (1H, s), 8.14 (1H, d, J = 1.0 Hz), 7.94 (1H, dd, J = 8.5, 1.5 Hz), 7.88 (1H, d, J = 8.3 Hz), 7.57 (1H, t, J = 8.2 Hz), 7.31 (1H, t, J = 2.1 Hz), 7.29-7.26 (1H, m), 7.14 (1H, dd, J = 8.2, 2.1 Hz), 4.21 (2H, t, J = 5.7 Hz), 3.87 (3H, s), 3.58 (4H, t, J = 4.5 Hz), 2.73 (2H, t, J = 5.7 Hz), 2.50-2.47 (4H, m). Methyl 4-amino-3-((3- (2-morpholinoethoxy) phenyl) amino) benzoate (833 mg, 2.24 mmol) was dissolved in ethanol (10 mL) under an argon atmosphere. Triethyl orthoformate (3.73 mL, 22.4 mmol) and acetic acid (256 μL, 4.48 mL) were added thereto, and the mixture was stirred at 50 ° C. for 18 hours. The reaction mixture was concentrated, ethyl acetate was added, and the mixture was washed with saturated multilayered water, water and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (588 mg, 69%). Purple amorphous solid: 1 H-NMR (DMSO-D 6 ) δ: 8.78 (1H, s), 8.14 (1H, d, J = 1.0 Hz), 7.94 (1H, dd, J = 8.5, 1.5 Hz), 7.88 (1H, d, J = 8.3 Hz), 7.57 (1H, t, J = 8.2 Hz), 7.31 (1H, t, J = 2.1 Hz), 7.29-7.26 (1H, m), 7.14 (1H, dd , J = 8.2, 2.1 Hz), 4.21 (2H, t, J = 5.7 Hz), 3.87 (3H, s), 3.58 (4H, t, J = 4.5 Hz), 2.73 (2H, t, J = 5.7 Hz ), 2.50-2.47 (4H, m).

工程４
(1-(3-(2-モルホリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール Process 4
(1- (3- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methanol

Figure JPOXMLDOC01-appb-C000111
Figure JPOXMLDOC01-appb-C000111

　アルゴン雰囲気下、メチル 1-(3-(2-モルホリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート (588 mg, 1.54 mmol) をテトラヒドロフラン (15 mL) に溶解し、-78℃に冷却した。そこへリチウムアルミニウムヒドリド テトラヒドロフラン溶液 (1.0 M, 4.62 mL, 4.62 mmol) を滴下し、-78℃で10分撹拌後、0℃に昇温させて1時間撹拌した。反応液を-78℃に冷却し、メタノールを加えクエンチした。（＋）-酒石酸ナトリウムカリウム水溶液を加え、室温に昇温させて1時間撹拌した。反応混合物を酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (NHカラム, ヘキサン/酢酸エチル) で精製し、標記化合物 (388 mg, 71%) を得た。微黄色アモルファス状個体: 1H-NMR (DMSO-D6) δ: 8.51 (1H, s), 7.70 (1H, d, J = 8.3 Hz), 7.59 (1H, d, J = 0.7 Hz), 7.53 (1H, t, J = 8.2 Hz), 7.26-7.22 (3H, m), 7.10-7.07 (1H, m), 5.22 (1H, t, J = 5.7 Hz), 4.63 (2H, d, J = 5.9 Hz), 4.20 (2H, t, J = 5.7 Hz), 3.58 (4H, t, J = 4.6 Hz), 2.73 (2H, t, J = 5.7 Hz), 2.50-2.47 (4H, m). Under an argon atmosphere, methyl 1- (3- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazole-6-carboxylate (588 mg, 1.54 mmol) was dissolved in tetrahydrofuran (15 mL), and -78 Cooled to ° C. Lithium aluminum hydride tetrahydrofuran solution (1.0 M, 4.62 mL, 4.62 mmol) was added dropwise thereto, and the mixture was stirred at -78 ° C for 10 minutes, then heated to 0 ° C and stirred for 1 hour. The reaction solution was cooled to −78 ° C. and quenched by adding methanol. (+)-Sodium potassium tartrate aqueous solution was added, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (NH column, hexane / ethyl acetate) to obtain the title compound (388 mg, 71%). Slight yellow amorphous solid: 1 H-NMR (DMSO-D 6 ) δ: 8.51 (1H, s), 7.70 (1H, d, J = 8.3 Hz), 7.59 (1H, d, J = 0.7 Hz), 7.53 (1H, t, J = 8.2 Hz), 7.26-7.22 (3H, m), 7.10-7.07 (1H, m), 5.22 (1H, t, J = 5.7 Hz), 4.63 (2H, d, J = 5.9 Hz), 4.20 (2H, t, J = 5.7 Hz), 3.58 (4H, t, J = 4.6 Hz), 2.73 (2H, t, J = 5.7 Hz), 2.50-2.47 (4H, m).

工程５
1-(3-(2-モルホリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Process 5
1- (3- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000112
Figure JPOXMLDOC01-appb-C000112

　アルゴン雰囲気下、(1-(3-(2-モルホリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール (388 mg, 1.10 mmol) を塩化メチレン (11 mL) に溶解した。そこへデス・マーチン・ペルヨージナン (560 mg, 1.21 mmol) を加え、0℃で10分撹拌した後、室温で90分撹拌した。反応液に飽和チオ硫酸ナトリウム水溶液を加えクエンチし、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (390 mg, quant) を得た。赤色オイル: 1H-NMR (DMSO-D6) δ: 10.1 (1H, s), 8.84 (1H, s), 8.21 (1H, d, J = 0.7 Hz), 7.95 (1H, d, J = 8.5 Hz), 7.87 (1H, dd, J = 8.3, 1.5 Hz), 7.57 (1H, t, J = 8.2 Hz), 7.35-7.30 (2H, m), 7.14 (1H, dd, J = 8.4, 2.3 Hz), 4.22 (2H, t, J = 5.7 Hz), 3.58 (4H, t, J = 4.6 Hz), 2.74 (2H, t, J = 5.7 Hz), 2.50-2.47 (4H, m). Under an argon atmosphere, (1- (3- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methanol (388 mg, 1.10 mmol) was dissolved in methylene chloride (11 mL). Dess-Martin periodinane (560 mg, 1.21 mmol) was added there, and it stirred at 0 degreeC for 10 minutes, Then, it stirred at room temperature for 90 minutes. The reaction solution was quenched by adding a saturated aqueous sodium thiosulfate solution, and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (390 mg, quant). Red oil: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, s), 8.84 (1H, s), 8.21 (1H, d, J = 0.7 Hz), 7.95 (1H, d, J = 8.5 Hz), 7.87 (1H, dd, J = 8.3, 1.5 Hz), 7.57 (1H, t, J = 8.2 Hz), 7.35-7.30 (2H, m), 7.14 (1H, dd, J = 8.4, 2.3 Hz) ), 4.22 (2H, t, J = 5.7 Hz), 3.58 (4H, t, J = 4.6 Hz), 2.74 (2H, t, J = 5.7 Hz), 2.50-2.47 (4H, m).

工程６
5-((1-(3-(2-モルホリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物２３) Step 6
5-((1- (3- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 23)

Figure JPOXMLDOC01-appb-C000113
Figure JPOXMLDOC01-appb-C000113

　5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、1-(3-(2-モルホリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (205 mg, 0.583 mmol) およびロダニン (78 mg, 0.583 mmol) から標記化合物 (203 mg, 75%)を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.73 (1H, s), 7.91-7.89 (2H, m), 7.89 (2H, s), 7.73 (1H, s), 7.58 (2H, t, J = 8.2 Hz), 7.54 (2H, dd, J = 8.5, 1.5 Hz), 7.36 (1H, t, J = 2.1 Hz), 7.32 (1H, dd, J = 7.8, 1.5 Hz), 7.13 (1H, dd, J = 8.2, 2.1 Hz), 4.31 (2H, t, J = 5.5 Hz), 3.65 (4H, t, J = 4.5 Hz), 2.98 (2H, t, J = 5.4 Hz), 2.74-2.70 (4H, m). 
ESI-MS(m/z): 467[M+H]+. Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) Procedure from 1- (3- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (205 mg, 0.583 mmol) and rhodanine (78 mg, 0.583 mmol). mg, 75%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.73 (1H, s), 7.91-7.89 (2H, m), 7.89 (2H, s), 7.73 (1H, s), 7.58 (2H, t , J = 8.2 Hz), 7.54 (2H, dd, J = 8.5, 1.5 Hz), 7.36 (1H, t, J = 2.1 Hz), 7.32 (1H, dd, J = 7.8, 1.5 Hz), 7.13 (1H , dd, J = 8.2, 2.1 Hz), 4.31 (2H, t, J = 5.5 Hz), 3.65 (4H, t, J = 4.5 Hz), 2.98 (2H, t, J = 5.4 Hz), 2.74-2.70 (4H, m).
ESI-MS (m / z): 467 [M + H] + .

実施例２４
5-((1-(3-(2-モルホリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物２４)  Example 24
5-((1- (3- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 24)

Figure JPOXMLDOC01-appb-C000114
Figure JPOXMLDOC01-appb-C000114

工程１
　5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、1-(3-(2-モルホリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (185 mg, 0.526 mmol) およびチアゾリジン-2,4-ジオン (62 mg, 0.526 mmol) から標記化合物 (105 mg, 44％)を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 12.41 (1H, s), 8.74 (1H, s), 7.97 (1H, s), 7.93-7.92 (1H, m), 7.91 (1H, d, J = 8.5 Hz), 7.58-7.54 (2H, m), 7.33 (1H, t, J = 2.1 Hz), 7.30 (1H, dd, J = 7.8, 1.7 Hz), 7.11 (1H, dd, J = 8.3, 2.4 Hz), 4.24 (2H, t, J = 5.6 Hz), 3.60 (4H, t, J = 4.6 Hz), 2.79 (2H, t, J = 5.6 Hz), 2.56-2.53 (4H, m). 
ESI-MS(m/z): 451[M+H]+. Process 1
Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) 1- (3- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (185 mg, 0.526 mmol) and thiazolidine-2,4-dione (62 mg, 0.526 mmol) ) Gave the title compound (105 mg, 44%). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 12.41 (1H, s), 8.74 (1H, s), 7.97 (1H, s), 7.93-7.92 (1H, m), 7.91 (1H, d, J = 8.5 Hz), 7.58-7.54 (2H, m), 7.33 (1H, t, J = 2.1 Hz), 7.30 (1H, dd, J = 7.8, 1.7 Hz), 7.11 (1H, dd, J = 8.3, 2.4 Hz), 4.24 (2H, t, J = 5.6 Hz), 3.60 (4H, t, J = 4.6 Hz), 2.79 (2H, t, J = 5.6 Hz), 2.56-2.53 (4H, m ).
ESI-MS (m / z): 451 [M + H] + .

実施例２５
5-((1-(4-(2-モルフォリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物２５) Example 25
5-((1- (4- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 25)

工程１
3-((4-(ベンジロキシ)フェニル)アミノ)-N-メトキシ-N-メチル-4-ニトロベンズアミド Process 1
3-((4- (Benzyloxy) phenyl) amino) -N-methoxy-N-methyl-4-nitrobenzamide

Figure JPOXMLDOC01-appb-C000115
Figure JPOXMLDOC01-appb-C000115

　N-メトキシ-N-メチル-3-((4-(4-メチルピペラジニル)ベンジル)アミノ)-4-ニトロベンズアミドの合成と同様の手法で、3-フルオロ-N-メトキシ-N-メチル-4-ニトロベンズアミド(1.14 g, 5.0 mmol) および 4-(ベンジロキシ)アニリン (1.30 g, 5.5 mmol) とから標記化合物 (1.32 g, 65 %, 3.2 mmol) を得た。赤褐色固体:1H-NMR (CDCl3) δ: 9.45-9.37 (1H, m), 8.25-8.19 (1H, m), 7.48-7.30 (5H, m), 7.27-7.22 (1H, m), 7.22-7.16 (2H, m), 7.05-6.99 (2H, m), 5.09 (2H, s), 3.50 (3H, s), 3.28 (3H, s). 
ESI-MS(m/z): 408[M+H]+. In a similar manner to the synthesis of N-methoxy-N-methyl-3-((4- (4-methylpiperazinyl) benzyl) amino) -4-nitrobenzamide, 3-fluoro-N-methoxy-N-methyl The title compound (1.32 g, 65%, 3.2 mmol) was obtained from -4-nitrobenzamide (1.14 g, 5.0 mmol) and 4- (benzyloxy) aniline (1.30 g, 5.5 mmol). Reddish brown solid: 1 H-NMR (CDCl 3 ) δ: 9.45-9.37 (1H, m), 8.25-8.19 (1H, m), 7.48-7.30 (5H, m), 7.27-7.22 (1H, m), 7.22 -7.16 (2H, m), 7.05-6.99 (2H, m), 5.09 (2H, s), 3.50 (3H, s), 3.28 (3H, s).
ESI-MS (m / z): 408 [M + H] + .

工程２
1-(4-(ベンジロキシ)フェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 2
1- (4- (Benzyloxy) phenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000116
Figure JPOXMLDOC01-appb-C000116

　N-メトキシ-N-メチル-1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミドの合成と同様の手法で、3-((4-(ベンジロキシ)フェニル)アミノ)-N-メトキシ-N-メチル-4-ニトロベンズアミド (1.32 g, 3.2 mmol) から標記化合物 (0.53 g, 41%) を得た。黄粘性固体: 1H-NMR (DMSO-D6) δ: 8.61 (1H, s), 7.81 (1H, d, J = 8.5 Hz), 7.75 (1H, s), 7.61 (2H, d, J = 7.6 Hz), 7.57 (1H, d, J = 8.5 Hz), 7.50 (2H, d, J = 7.6 Hz), 7.42 (2H, t, J = 7.6 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.27 (2H, d, J = 7.6 Hz), 5.22 (2H, s), 3.52 (3H, s), 3.27 (3H, s). 
ESI-MS(m/z): 388[M+H]+. In a similar manner to the synthesis of N-methoxy-N-methyl-1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazole-6-carboxamide, 3-((4- The title compound (0.53 g, 41%) was obtained from (benzyloxy) phenyl) amino) -N-methoxy-N-methyl-4-nitrobenzamide (1.32 g, 3.2 mmol). Yellow viscous solid: 1 H-NMR (DMSO-D 6 ) δ: 8.61 (1H, s), 7.81 (1H, d, J = 8.5 Hz), 7.75 (1H, s), 7.61 (2H, d, J = 7.6 Hz), 7.57 (1H, d, J = 8.5 Hz), 7.50 (2H, d, J = 7.6 Hz), 7.42 (2H, t, J = 7.6 Hz), 7.36 (1H, d, J = 7.6 Hz ), 7.27 (2H, d, J = 7.6 Hz), 5.22 (2H, s), 3.52 (3H, s), 3.27 (3H, s).
ESI-MS (m / z): 388 [M + H] + .

工程３
1-(4-ヒドロキシフェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 3
1- (4-Hydroxyphenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000117
Figure JPOXMLDOC01-appb-C000117

　1-(4-(ベンジロキシ)フェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド(0.50 g, 1.4 mmol) のエタノール溶液 (30 mL) に、アルゴン雰囲気下20％ 水酸化パラジウム－活性炭(500 mg) を0 ℃で添加した。水素置換した後、室温で一晩撹拌した。反応終了後、セライトろ過、減圧下濃縮し、標記化合物 (347 mg, 1.17 mmol, 84 %)を得た。黒色粘性体: 1H-NMR (DMSO-D6) δ: 9.48-9.30 (1H, m), 7.92 (1H, d, J = 8.5 Hz), 7.80 (1H, s), 7.72 (1H, d, J = 8.5 Hz), 7.55 (2H, d, J = 8.8 Hz), 7.05 (2H, d, J = 8.8 Hz), 3.52 (3H, s), 3.28 (3H, s). 
ESI-MS(m/z): 298[M+H]+. To an ethanol solution (30 mL) of 1- (4- (benzyloxy) phenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide (0.50 g, 1.4 mmol) under an argon atmosphere 20% Palladium hydroxide-activated carbon (500 mg) was added at 0 ° C. After purging with hydrogen, the mixture was stirred overnight at room temperature. After completion of the reaction, the mixture was filtered through celite and concentrated under reduced pressure to obtain the title compound (347 mg, 1.17 mmol, 84%). Black viscous material: 1 H-NMR (DMSO-D 6 ) δ: 9.48-9.30 (1H, m), 7.92 (1H, d, J = 8.5 Hz), 7.80 (1H, s), 7.72 (1H, d, J = 8.5 Hz), 7.55 (2H, d, J = 8.8 Hz), 7.05 (2H, d, J = 8.8 Hz), 3.52 (3H, s), 3.28 (3H, s).
ESI-MS (m / z): 298 [M + H] + .

工程２
N-メトキシ-N-メチル-1-(4-(2-モルフォリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 2
N-methoxy-N-methyl-1- (4- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000118
Figure JPOXMLDOC01-appb-C000118

　1-(4-ヒドロキシフェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド (100 mg, 0.34 mmol) のN,N-ジメチルホルムアミド (2.0 mL) 溶媒中に、炭酸セシウム (554 mg, 1.70 mmol)、ヨウ化ナトリウム (3 mg, 0.017 mmol)、4-(2-クロロエチル)モルフォリン塩酸塩 (125 mg, 0.67 mmol) を添加した。60 ℃で一晩撹拌した後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (68 mg, 49 %, 0.166 mmol) を得た。1H-NMR (CDCl3) δ: 8.13 (1H, s), 7.86 (1H, d, J = 6.0 Hz), 7.85 (1H, s), 7.69 (1H, d, J = 6.0 Hz), 7.41 (2H, d, J = 9.0 Hz), 7.09 (2H, d, J = 9.0 Hz), 4.20 (2H, t, J = 5.6 Hz), 3.77 (4H, t, J = 4.5 Hz), 3.55 (3H, s), 3.37 (3H, s), 2.87 (2H, t, J = 5.6 Hz), 2.63 (4H, t, J = 4.5 Hz). 
ESI-MS(m/z): 411[M+H]+. 1- (4-Hydroxyphenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide (100 mg, 0.34 mmol) in N, N-dimethylformamide (2.0 mL) in solvent , Cesium carbonate (554 mg, 1.70 mmol), sodium iodide (3 mg, 0.017 mmol), 4- (2-chloroethyl) morpholine hydrochloride (125 mg, 0.67 mmol) were added. After stirring at 60 ° C. overnight, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (68 mg, 49%, 0.166 mmol). 1 H-NMR (CDCl 3 ) δ: 8.13 (1H, s), 7.86 (1H, d, J = 6.0 Hz), 7.85 (1H, s), 7.69 (1H, d, J = 6.0 Hz), 7.41 ( 2H, d, J = 9.0 Hz), 7.09 (2H, d, J = 9.0 Hz), 4.20 (2H, t, J = 5.6 Hz), 3.77 (4H, t, J = 4.5 Hz), 3.55 (3H, s), 3.37 (3H, s), 2.87 (2H, t, J = 5.6 Hz), 2.63 (4H, t, J = 4.5 Hz).
ESI-MS (m / z): 411 [M + H] + .

工程３
(1-(4-(2-モルフォリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール Process 3
(1- (4- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methanol

Figure JPOXMLDOC01-appb-C000119
Figure JPOXMLDOC01-appb-C000119

　N-メトキシ-N-メチル-1-(4-(2-モルフォリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド (68 mg, 0.166 mmol) のテトラヒドロフラン (2.0 mL) 溶液にビスシクロペンタジエニルジルコニウム(ＩＶ)クロリドヒドリド (64 mg, 0.249 mmol) を0 ℃で加えた。室温に昇温し7時間撹拌した。反応終了後、酢酸エチルと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥して、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (38 mg, 65 %, 0.108 mmol) を得た。黄色粘性体: 1H-NMR (CDCl3) δ: 7.98 (1H, s), 7.77 (1H, d, J = 8.3 Hz), 7.46 (1H, s), 7.34 (2H, d, J = 8.8 Hz), 7.27 (1H, d, J = 8.3 Hz), 7.03 (2H, d, J = 8.8 Hz), 4.78 (2H, s), 4.16 (2H, t, J = 5.5 Hz), 3.74 (4H, t, J = 4.6 Hz), 2.83 (2H, t, J = 5.5 Hz), 2.60 (4H, t, J = 4.6 Hz). 
ESI-MS(m/z): 354[M+H]+. To a solution of N-methoxy-N-methyl-1- (4- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazole-6-carboxamide (68 mg, 0.166 mmol) in tetrahydrofuran (2.0 mL) Biscyclopentadienylzirconium (IV) chloride hydride (64 mg, 0.249 mmol) was added at 0 ° C. The mixture was warmed to room temperature and stirred for 7 hours. After completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to extract the organic layer, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (38 mg, 65%, 0.108 mmol). Yellow viscous material: 1 H-NMR (CDCl 3 ) δ: 7.98 (1H, s), 7.77 (1H, d, J = 8.3 Hz), 7.46 (1H, s), 7.34 (2H, d, J = 8.8 Hz ), 7.27 (1H, d, J = 8.3 Hz), 7.03 (2H, d, J = 8.8 Hz), 4.78 (2H, s), 4.16 (2H, t, J = 5.5 Hz), 3.74 (4H, t , J = 4.6 Hz), 2.83 (2H, t, J = 5.5 Hz), 2.60 (4H, t, J = 4.6 Hz).
ESI-MS (m / z): 354 [M + H] + .

工程４
1-(4-(2-モルフォリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Process 4
1- (4- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000120
Figure JPOXMLDOC01-appb-C000120

　(1-(4-(2-モルフォリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール (38 mg, 0.11 mmol) の塩化メチレン (2.0 mL) 溶液にデス・マーチン・ペルヨージナン (51 mg, 0.12 mmol) を0 ℃で滴下した。室温に昇温し2時間撹拌した。反応終了後、飽和チオ硫酸水素ナトリウム水溶液を添加し、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (33 mg, 85 %, 0.094 mmol) を得た。赤色粘性体: 1H-NMR (CDCl3) δ: 10.08 (1H, s), 8.23 (1H, s), 8.00 (1H, s), 7.98 (1H, d, J = 8.3 Hz), 7.87 (1H, d, J = 8.3 Hz), 7.43 (2H, d, J = 8.3 Hz), 7.12 (2H, d, J = 8.3 Hz), 4.22 (2H, t, J = 5.1 Hz), 3.83-3.72 (4H, m), 2.89 (2H, t, J = 5.1 Hz), 2.70-2.57 (4H, m). 
ESI-MS(m/z): 352[M+H]+. Dess Martin periodinane in a solution of (1- (4- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methanol (38 mg, 0.11 mmol) in methylene chloride (2.0 mL) (51 mg, 0.12 mmol) was added dropwise at 0 ° C. The mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, a saturated aqueous sodium hydrogensulfate solution was added, chloroform and a saturated aqueous sodium hydrogencarbonate solution were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (33 mg, 85%, 0.094 mmol). Red viscous material: 1 H-NMR (CDCl 3 ) δ: 10.08 (1H, s), 8.23 (1H, s), 8.00 (1H, s), 7.98 (1H, d, J = 8.3 Hz), 7.87 (1H , d, J = 8.3 Hz), 7.43 (2H, d, J = 8.3 Hz), 7.12 (2H, d, J = 8.3 Hz), 4.22 (2H, t, J = 5.1 Hz), 3.83-3.72 (4H , m), 2.89 (2H, t, J = 5.1 Hz), 2.70-2.57 (4H, m).
ESI-MS (m / z): 352 [M + H] + .

工程５
5-((1-(4-(2-モルフォリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物２５)  Process 5
5-((1- (4- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 25)

Figure JPOXMLDOC01-appb-C000121
Figure JPOXMLDOC01-appb-C000121

　1-(4-(2-モルフォリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (18 mg, 0.05 mmol) をエタノール (0.50 mL) に溶かし、ロダニン (6 mg, 0.045 mmol) およびピペリジン (2 μL, 0.025 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (14 mg, 86 %, 0.043 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.63 (1H, s), 7.89 (1H, d, J = 8.5 Hz), 7.76 (1H, s), 7.70 (1H, s), 7.65 (2H, d, J = 8.8 Hz), 7.52 (1H, d, J = 8.5 Hz), 7.24 (2H, d, J = 8.8 Hz), 4.28 (2H, t, J = 5.3 Hz), 3.67 (4H, t, J = 4.6 Hz), 2.98 (2H, t, J = 5.3 Hz), 2.75-2.72 (4H, m).
ESI-MS(m/z): 467[M+H]+. 1- (4- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (18 mg, 0.05 mmol) is dissolved in ethanol (0.50 mL) and rhodanine (6 mg, 0.045 mmol) is dissolved. ) And piperidine (2 μL, 0.025 mmol) were added and stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (14 mg, 86%, 0.043 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.63 (1H, s), 7.89 (1H, d, J = 8.5 Hz), 7.76 (1H, s), 7.70 (1H, s), 7.65 ( 2H, d, J = 8.8 Hz), 7.52 (1H, d, J = 8.5 Hz), 7.24 (2H, d, J = 8.8 Hz), 4.28 (2H, t, J = 5.3 Hz), 3.67 (4H, t, J = 4.6 Hz), 2.98 (2H, t, J = 5.3 Hz), 2.75-2.72 (4H, m).
ESI-MS (m / z): 467 [M + H] + .

実施例２６
5-((1-(4-(2-モルフォリノエトキシ)フェニル-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物２６)  Example 26
5-((1- (4- (2-morpholinoethoxy) phenyl-1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 26)

Figure JPOXMLDOC01-appb-C000122
Figure JPOXMLDOC01-appb-C000122

工程１
　1-(4-(2-モルフォリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (18 mg, 0.05 mmol) をエタノール (0.50 mL) に溶かし、チアゾリジン-2,4-ジオン (5 mg, 0.045 mmol) およびピペリジン (2 μL, 0.025 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (3 mg, 15 %, 0.007 mmol) を得た。灰色固体: 1H-NMR (DMSO-D6) δ: 8.64 (1H, s), 7.97 (1H, s), 7.90 (1H, d, J = 8.5 Hz), 7.80 (1H, br s), 7.64 (2H, d, J = 9.0 Hz), 7.55 (1H, d, J = 8.5 Hz), 7.24 (2H, d, J = 9.0 Hz), 5.80 (1H, br s), 4.28 (2H, t, J = 5.4 Hz), 3.68 (4H, t, J = 4.6 Hz), 2.99-2.95 (2H, m), 2.78-2.75 (4H, m).
ESI-MS(m/z): 451[M+H]+. Process 1
1- (4- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (18 mg, 0.05 mmol) is dissolved in ethanol (0.50 mL) and thiazolidine-2,4-dione (5 mg, 0.045 mmol) and piperidine (2 μL, 0.025 mmol) were added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (3 mg, 15%, 0.007 mmol). Gray solid: 1 H-NMR (DMSO-D 6 ) δ: 8.64 (1H, s), 7.97 (1H, s), 7.90 (1H, d, J = 8.5 Hz), 7.80 (1H, br s), 7.64 (2H, d, J = 9.0 Hz), 7.55 (1H, d, J = 8.5 Hz), 7.24 (2H, d, J = 9.0 Hz), 5.80 (1H, br s), 4.28 (2H, t, J = 5.4 Hz), 3.68 (4H, t, J = 4.6 Hz), 2.99-2.95 (2H, m), 2.78-2.75 (4H, m).
ESI-MS (m / z): 451 [M + H] + .

実施例２７
2-(2-(4-(6-((4-オキソ-2-チオキソチアゾリジン5-イリデン)メチル)-1H-ベンゾ[d]イミダゾール-1-イル)フェノキシ)エチル)イソインドリン-1,3-ジオン (化合物２７) Example 27
2- (2- (4- (6-((4-oxo-2-thioxothiazolidine5-ylidene) methyl) -1H-benzo [d] imidazol-1-yl) phenoxy) ethyl) isoindoline-1, 3-dione (compound 27)

工程１
1-(4-(2-(1,3-ジオキソイソインドリン-2-イル)エトキシ)フェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 1
1- (4- (2- (1,3-Dioxoisoindoline-2-yl) ethoxy) phenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000123
Figure JPOXMLDOC01-appb-C000123

　1-(4-ヒドロキシフェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド (178 mg, 0.60 mmol) のN,N-ジメチルホルムアミド (4.0 mL) 溶媒中に、炭酸セシウム (977 mg, 3.00 mmol)、ヨウ化ナトリウム (45 mg, 0.03 mmol)、2-(2-ブロモエチル)イソインドリン-1,3-ジオン (305 mg, 1.2 mmol) を添加した。60 ℃で一晩撹拌した後、酢酸エチルと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (67 mg, 24 %, 0.14 mmol) を得た。白色固体: 1H-NMR (CDCl3) δ: 8.08 (1H, s), 7.95-7.77 (4H, m), 7.77-7.59 (3H, m), 7.35 (2H, d, J = 8.8 Hz), 7.03 (2H, d, J = 8.8 Hz), 4.29 (2H, t, J = 5.6 Hz), 4.13 (2H, t, J = 5.6 Hz), 3.51 (3H, s), 3.34 (3H, s).
ESI-MS(m/z): 471[M+H]+. 1- (4-Hydroxyphenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide (178 mg, 0.60 mmol) in N, N-dimethylformamide (4.0 mL) in solvent , Cesium carbonate (977 mg, 3.00 mmol), sodium iodide (45 mg, 0.03 mmol), 2- (2-bromoethyl) isoindoline-1,3-dione (305 mg, 1.2 mmol) were added. After stirring at 60 ° C. overnight, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to extract the organic layer, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (67 mg, 24%, 0.14 mmol). White solid: 1 H-NMR (CDCl 3 ) δ: 8.08 (1H, s), 7.95-7.77 (4H, m), 7.77-7.59 (3H, m), 7.35 (2H, d, J = 8.8 Hz), 7.03 (2H, d, J = 8.8 Hz), 4.29 (2H, t, J = 5.6 Hz), 4.13 (2H, t, J = 5.6 Hz), 3.51 (3H, s), 3.34 (3H, s).
ESI-MS (m / z): 471 [M + H] + .

工程２
2-(2-(4-(6-(ヒドロキシメチル)-1H-ベンゾ[d]イミダゾール-1-イル)フェノキシ)エチル)イソインドリン-1,3-ジオン Process 2
2- (2- (4- (6- (hydroxymethyl) -1H-benzo [d] imidazol-1-yl) phenoxy) ethyl) isoindoline-1,3-dione

Figure JPOXMLDOC01-appb-C000124
Figure JPOXMLDOC01-appb-C000124

　1-(4-(2-(1,3-ジオキソイソインドリン-2-イル)エトキシ)フェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド (52 mg, 0.11 mmol) の テトラヒドロフラン (1.0 mL) 溶液に ビスシクロペンタジエニルジルコニウム(ＩＶ)クロリドヒドリド (85 mg, 0.33 mmol) を0 ℃で加えた。室温に昇温し2時間撹拌した。反応終了後、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (31 mg, 68 %, 0.075 mmol) を得た。黄色固体: 1H-NMR (CDCl3) δ: 8.02 (1H, s), 7.90-7.87 (2H, m), 7.81 (1H, d, J = 9.0 Hz), 7.77-7.71 (2H, m), 7.45 (1H, s), 7.36 (2H, d, J = 7.8 Hz), 7.31 (1H, d, J = 8.5 Hz), 7.05 (2H, d, J = 7.8 Hz), 4.80 (2H, s), 4.32 (2H, t, J = 5.7 Hz), 4.16 (2H, t, J = 5.7 Hz).
ESI-MS(m/z): 412[M+H]+. 1- (4- (2- (1,3-Dioxoisoindoline-2-yl) ethoxy) phenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide (52 mg , 0.11 mmol) in tetrahydrofuran (1.0 mL) was added biscyclopentadienylzirconium (IV) chloride hydride (85 mg, 0.33 mmol) at 0 ° C. The mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, chloroform and saturated aqueous sodium hydrogen carbonate solution were added to extract the organic layer, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (31 mg, 68%, 0.075 mmol). Yellow solid: 1 H-NMR (CDCl 3 ) δ: 8.02 (1H, s), 7.90-7.87 (2H, m), 7.81 (1H, d, J = 9.0 Hz), 7.77-7.71 (2H, m), 7.45 (1H, s), 7.36 (2H, d, J = 7.8 Hz), 7.31 (1H, d, J = 8.5 Hz), 7.05 (2H, d, J = 7.8 Hz), 4.80 (2H, s), 4.32 (2H, t, J = 5.7 Hz), 4.16 (2H, t, J = 5.7 Hz).
ESI-MS (m / z): 412 [M + H] + .

工程３
1-(4-(2-(1,3-ジオキソイソインドリン-2-イル)エトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Process 3
1- (4- (2- (1,3-Dioxoisoindoline-2-yl) ethoxy) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000125
Figure JPOXMLDOC01-appb-C000125

　2-(2-(4-(6-(ヒドロキシメチル)-1H-ベンゾ[d]イミダゾール-1-イル)フェノキシ)エチル)イソインドリン-1,3-ジオン (30 mg, 0.08 mmol) の塩化メチレン (2.0 mL) 溶液にデス・マーチン・ペルヨージナン (37 mg, 0.088 mmol) を0 ℃で滴下した。室温に昇温し2時間撹拌した。反応終了後、飽和チオ硫酸水素ナトリウム水溶液を添加し、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (6 mg, 18 %, 0.015 mmol) を得た。白色固体: 1H-NMR (CDCl3) δ: 10.06 (1H, s), 8.18 (1H, br s), 7.96 (1H, s), 7.95 (1H, d, J = 8.3 Hz), 7.87 (1H, d, J = 8.3 Hz), 7.81 (1H, d, J = 7.3 Hz), 7.66 (1H, d, J = 7.3 Hz), 7.62 (1H, t, J = 7.3 Hz), 7.53 (1H, t, J = 7.4 Hz), 7.42 (2H, d, J = 8.8 Hz), 7.12 (2H, d, J = 8.8 Hz), 4.36 (2H, t, J = 5.4 Hz), 4.06 (2H, t, J = 5.4 Hz).
ESI-MS(m/z): 414[M+H]+. 2- (2- (4- (6- (hydroxymethyl) -1H-benzo [d] imidazol-1-yl) phenoxy) ethyl) isoindoline-1,3-dione (30 mg, 0.08 mmol) in methylene chloride (2.0 mL) Dess-Martin periodinane (37 mg, 0.088 mmol) was added dropwise to the solution at 0 ° C. The mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, a saturated aqueous sodium hydrogensulfate solution was added, chloroform and a saturated aqueous sodium hydrogencarbonate solution were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (6 mg, 18%, 0.015 mmol). White solid: 1 H-NMR (CDCl 3 ) δ: 10.06 (1H, s), 8.18 (1H, br s), 7.96 (1H, s), 7.95 (1H, d, J = 8.3 Hz), 7.87 (1H , d, J = 8.3 Hz), 7.81 (1H, d, J = 7.3 Hz), 7.66 (1H, d, J = 7.3 Hz), 7.62 (1H, t, J = 7.3 Hz), 7.53 (1H, t , J = 7.4 Hz), 7.42 (2H, d, J = 8.8 Hz), 7.12 (2H, d, J = 8.8 Hz), 4.36 (2H, t, J = 5.4 Hz), 4.06 (2H, t, J = 5.4 Hz).
ESI-MS (m / z): 414 [M + H] + .

工程４
2-(2-(4-(6-((4-オキソ-2-チオキソチアゾリジン5-イリデン)メチル)-1H-ベンゾ[d]イミダゾール-1-イル)フェノキシ)エチル)イソインドリン-1,3-ジオン (化合物２７) Process 4
2- (2- (4- (6-((4-oxo-2-thioxothiazolidine5-ylidene) methyl) -1H-benzo [d] imidazol-1-yl) phenoxy) ethyl) isoindoline-1, 3-dione (compound 27)

Figure JPOXMLDOC01-appb-C000126
Figure JPOXMLDOC01-appb-C000126

　1-(4-(2-(1,3-ジオキソイソインドリン-2-イル)エトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (9 mg, 0.022 mmol) をエタノール (0.60 mL) に溶かし、ロダニン (2 mg, 0.020 mmol) およびピペリジン (0.2 μL, 0.002 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (4 mg, 35 %, 0.0076 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.63 (1H, s), 8.31 (1H, s), 7.94-7.78 (6H, m), 7.61 (2H, d, J = 8.8 Hz), 7.51 (1H, d, J = 8.3 Hz), 7.16 (2H, d, J = 8.8 Hz), 4.34 (2H, t, J = 5.2 Hz), 4.03 (2H, t, J = 5.2 Hz).
ESI-MS(m/z): 527[M+H]+. 1- (4- (2- (1,3-Dioxoisoindoline-2-yl) ethoxy) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (9 mg, 0.022 mmol) was added to ethanol (0.60 Then, rhodanine (2 mg, 0.020 mmol) and piperidine (0.2 μL, 0.002 mmol) were added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (4 mg, 35%, 0.0076 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.63 (1H, s), 8.31 (1H, s), 7.94-7.78 (6H, m), 7.61 (2H, d, J = 8.8 Hz), 7.51 (1H, d, J = 8.3 Hz), 7.16 (2H, d, J = 8.8 Hz), 4.34 (2H, t, J = 5.2 Hz), 4.03 (2H, t, J = 5.2 Hz).
ESI-MS (m / z): 527 [M + H] + .

実施例２８
5-((1-(4-モルフォリノフェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物２８) Example 28
5-((1- (4-morpholinophenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 28)

工程１
メチル 3-((4-ブロモフェニル)アミノ)-4-ニトロベンゾエート Process 1
Methyl 3-((4-bromophenyl) amino) -4-nitrobenzoate

Figure JPOXMLDOC01-appb-C000127
Figure JPOXMLDOC01-appb-C000127

　メチル 3-フルオロ-4-ニトロベンゾエート (1.9 g, 10 mmol) の N-メチル-2-ピロリドン (10 mL) 溶媒中に、4-ブロモアニリン (2.19 g, 10 mmol)、およびN-エチル-N-イソプロピルプロパン-2-アミン (3.04 mL, 18 mmol) を添加した。85 ℃で5日間撹拌し、室温に放冷した後、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) にて精製し、標記化合物 (2.06 g, 59 %, 5.86 mmol) を得た。赤褐色固体: 1H-NMR (CDCl3) δ: 9.37 (1H, s), 8.25 (1H, d, J = 8.8 Hz), 7.87 (1H, s), 7.56 (2H, d, J = 8.8 Hz), 7.40 (1H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.8 Hz), 3.90 (3H, s). Methyl 3-fluoro-4-nitrobenzoate (1.9 g, 10 mmol) in N-methyl-2-pyrrolidone (10 mL) solvent, 4-bromoaniline (2.19 g, 10 mmol), and N-ethyl-N -Isopropylpropan-2-amine (3.04 mL, 18 mmol) was added. The mixture was stirred at 85 ° C. for 5 days and allowed to cool to room temperature. Then, ethyl acetate and saturated brine were added to extract the organic layer, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (2.06 g, 59%, 5.86 mmol). Reddish brown solid: 1 H-NMR (CDCl 3 ) δ: 9.37 (1H, s), 8.25 (1H, d, J = 8.8 Hz), 7.87 (1H, s), 7.56 (2H, d, J = 8.8 Hz) , 7.40 (1H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.8 Hz), 3.90 (3H, s).

工程２
メチル 4-アミノ-3-((4-ブロモフェニル)アミノ)ベンゾエート Process 2
Methyl 4-amino-3-((4-bromophenyl) amino) benzoate

Figure JPOXMLDOC01-appb-C000128
Figure JPOXMLDOC01-appb-C000128

　メチル 3-((4-ブロモフェニル)アミノ)-4-ニトロベンゾエート (100 mg, 0.28 mmol) の酢酸エチル溶液中 (2 mL) に、臭化亜鉛 (43 mg, 0.056 mmol)、および5 % プラチナ－活性炭 (18 mg) をアルゴン雰囲気下0 ℃で添加した。水素置換した後、室温に昇温し一晩撹拌した。反応終了後、セライトろ過し減圧下濃縮した。標記化合物 (90 mg, 0.28 mmol, quant.) を得た。1H-NMR (CDCl3) δ: 7.79 (1H, br s), 7.76 (1H, d, J = 8.3 Hz), 7.29 (2H, d, J = 9.0 Hz), 6.79 (1H, d, J = 8.3 Hz), 6.58 (2H, d, J = 9.0 Hz), 5.26-5.13 (1H, m), 3.84 (3H, s). Methyl 3-((4-bromophenyl) amino) -4-nitrobenzoate (100 mg, 0.28 mmol) in ethyl acetate (2 mL), zinc bromide (43 mg, 0.056 mmol), and 5% platinum Activated carbon (18 mg) was added at 0 ° C. under an argon atmosphere. After purging with hydrogen, the mixture was warmed to room temperature and stirred overnight. After completion of the reaction, the mixture was filtered through celite and concentrated under reduced pressure. The title compound (90 mg, 0.28 mmol, quant.) Was obtained. 1 H-NMR (CDCl 3 ) δ: 7.79 (1H, br s), 7.76 (1H, d, J = 8.3 Hz), 7.29 (2H, d, J = 9.0 Hz), 6.79 (1H, d, J = 8.3 Hz), 6.58 (2H, d, J = 9.0 Hz), 5.26-5.13 (1H, m), 3.84 (3H, s).

工程３
メチル 1-(4-ブロモフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 3
Methyl 1- (4-bromophenyl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000129
Figure JPOXMLDOC01-appb-C000129

　メチル 4-アミノ-3-((4-ブロモフェニル)アミノ)ベンゾエート (1.88 g, 5.86 mmol) のテトラヒドロフラン (20 mL) 溶液中に、オルトギ酸トリエチル (1.46 mL, 8.78 mmol)、およびパラトシル酸一水和物 (65 mg, 0.38mmol) を添加した、還流条件下2時間撹拌した後、飽和炭酸水素ナトリウム水溶液を添加し、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (1.34 g, 69 %, 4.06 mmol) を得た。赤褐色固体: 1H-NMR (CDCl3) δ: 8.23 (1H, s), 8.22 (1H, s), 8.08 (1H, d, J = 8.5 Hz), 7.91 (1H, d, J = 8.5 Hz), 7.75 (2H, d, J = 8.8 Hz), 7.43 (2H, d, J = 8.8 Hz), 3.94 (3H, s). 
ESI-MS(m/z): 331[M+H]+. In a solution of methyl 4-amino-3-((4-bromophenyl) amino) benzoate (1.88 g, 5.86 mmol) in tetrahydrofuran (20 mL), triethyl orthoformate (1.46 mL, 8.78 mmol) and monohydrate paratosylate The mixture was stirred under reflux conditions for 2 hours after adding a hydrate (65 mg, 0.38 mmol), and then added with a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was extracted with ethyl acetate and saturated brine, and extracted with anhydrous sodium sulfate It was dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (1.34 g, 69%, 4.06 mmol). Reddish brown solid: 1 H-NMR (CDCl 3 ) δ: 8.23 (1H, s), 8.22 (1H, s), 8.08 (1H, d, J = 8.5 Hz), 7.91 (1H, d, J = 8.5 Hz) , 7.75 (2H, d, J = 8.8 Hz), 7.43 (2H, d, J = 8.8 Hz), 3.94 (3H, s).
ESI-MS (m / z): 331 [M + H] + .

工程４
メチル 1-(4-モルフォリノフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 4
Methyl 1- (4-morpholinophenyl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000130
Figure JPOXMLDOC01-appb-C000130

　メチル 1-(4-ブロモフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート(151 mg, 0.46 mmol) のトルエン (5 mL) 溶媒中に酢酸パラジウム (5 mg, 0.023 mmol)、rac-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル (43 mg, 0.069 mmol)、炭酸セシウム (300 mg, 0.92 mmol)、モルホリン (60 μL, 0.69 mmol) を添加した。還流条件下、一晩撹拌した後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記化合物 (92 mg, 59 %, 0.27 mmol) を得た。黒色固体: 1H-NMR (CDCl3) δ: 8.29 (1H, s), 8.20 (1H, d, J = 1.5 Hz), 8.07 (1H, dd, J = 8.5, 1.5 Hz), 7.92 (1H, d, J = 8.5 Hz), 7.41 (2H, d, J = 8.8 Hz), 7.09 (2H, d, J = 8.8 Hz), 3.94 (3H, s), 3.92 (4H, t, J = 4.8 Hz), 3.28 (4H, t, J = 4.8 Hz).
ESI-MS(m/z): 338[M+H]+. Methyl 1- (4-bromophenyl) -1H-benzo [d] imidazole-6-carboxylate (151 mg, 0.46 mmol) in toluene (5 mL) Palladium acetate (5 mg, 0.023 mmol), rac- 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (43 mg, 0.069 mmol), cesium carbonate (300 mg, 0.92 mmol), and morpholine (60 μL, 0.69 mmol) were added. After stirring overnight under reflux conditions, a saturated aqueous sodium hydrogen carbonate solution was added, ethyl acetate and saturated brine were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound (92 mg, 59%, 0.27 mmol) was obtained. Black solid: 1 H-NMR (CDCl 3 ) δ: 8.29 (1H, s), 8.20 (1H, d, J = 1.5 Hz), 8.07 (1H, dd, J = 8.5, 1.5 Hz), 7.92 (1H, d, J = 8.5 Hz), 7.41 (2H, d, J = 8.8 Hz), 7.09 (2H, d, J = 8.8 Hz), 3.94 (3H, s), 3.92 (4H, t, J = 4.8 Hz) , 3.28 (4H, t, J = 4.8 Hz).
ESI-MS (m / z): 338 [M + H] + .

工程５
(1-(4-モルフォリノフェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール Process 5
(1- (4-Morpholinophenyl) -1H-benzo [d] imidazol-6-yl) methanol

Figure JPOXMLDOC01-appb-C000131
Figure JPOXMLDOC01-appb-C000131

　メチル 1-(4-モルフォリノフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート(92 mg, 0.27 mmol) のテトラヒドロフラン (1 mL) 溶液中に、水素化アルミニウムリチウム (31 mg, 0.81 mmol) をアルゴン雰囲気下0 ℃で添加した。室温に昇温し、3時間撹拌した後、塩化アンモニウム水溶液を加え、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (28 mg, 34 %, 0.091 mmol) を得た。茶色粘性固体: 1H-NMR (CDCl3) δ: 8.07 (1H, s), 7.81 (1H, d, J = 8.3 Hz), 7.51 (1H, s), 7.38 (2H, dd, J = 8.9, 1.8 Hz), 7.31 (1H, d, J = 8.3 Hz), 7.05 (2H, dd, J = 8.9, 1.8 Hz), 4.81 (2H, s), 3.91 (4H, t, J = 4.8 Hz), 3.25 (4H, t, J = 4.8 Hz). Lithium aluminum hydride (31 mg, 0.81 mmol) in a solution of methyl 1- (4-morpholinophenyl) -1H-benzo [d] imidazole-6-carboxylate (92 mg, 0.27 mmol) in tetrahydrofuran (1 mL) ) Was added at 0 ° C. under an argon atmosphere. After warming to room temperature and stirring for 3 hours, an aqueous ammonium chloride solution was added, ethyl acetate and saturated brine were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (28 mg, 34%, 0.091 mmol). Brown sticky solid: 1 H-NMR (CDCl 3 ) δ: 8.07 (1H, s), 7.81 (1H, d, J = 8.3 Hz), 7.51 (1H, s), 7.38 (2H, dd, J = 8.9, 1.8 Hz), 7.31 (1H, d, J = 8.3 Hz), 7.05 (2H, dd, J = 8.9, 1.8 Hz), 4.81 (2H, s), 3.91 (4H, t, J = 4.8 Hz), 3.25 (4H, t, J = 4.8 Hz).

工程６
1-(4-モルフォリノフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Step 6
1- (4-morpholinophenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000132
Figure JPOXMLDOC01-appb-C000132

　(1-(4-モルフォリノフェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール (28 mg, 0.091 mmol) の塩化メチレン (2.0 mL) 溶液にデス・マーチン・ペルヨージナン (42 mg, 0.10 mmol) を0 ℃で滴下した。室温に昇温し2時間撹拌した。反応終了後、飽和チオ硫酸水素ナトリウム水溶液を添加し、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記化合物 (27 mg, quant., 0.091 mmol) を得た。黒色粘性固体: 1H-NMR (CDCl3) δ: 10.07 (1H, s), 8.24 (1H, s), 8.01 (1H, s), 7.98 (1H, d, J = 8.8 Hz), 7.87 (1H, d, J = 8.8 Hz), 7.40 (2H, d, J = 8.8 Hz), 7.08 (2H, d, J = 8.8 Hz), 3.92 (4H, t, J = 5.0 Hz), 3.27 (4H, t, J = 5.0 Hz). Dess-Martin periodinane (42 mg, 0.10) in a solution of (1- (4-morpholinophenyl) -1H-benzo [d] imidazol-6-yl) methanol (28 mg, 0.091 mmol) in methylene chloride (2.0 mL) mmol) was added dropwise at 0 ° C. The mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, a saturated aqueous sodium hydrogensulfate solution was added, chloroform and a saturated aqueous sodium hydrogencarbonate solution were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound (27 mg, quant., 0.091 mmol) was obtained. Black viscous solid: 1 H-NMR (CDCl 3 ) δ: 10.07 (1H, s), 8.24 (1H, s), 8.01 (1H, s), 7.98 (1H, d, J = 8.8 Hz), 7.87 (1H , d, J = 8.8 Hz), 7.40 (2H, d, J = 8.8 Hz), 7.08 (2H, d, J = 8.8 Hz), 3.92 (4H, t, J = 5.0 Hz), 3.27 (4H, t , J = 5.0 Hz).

工程７
5-((1-(4-モルフォリノフェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物２８) Step 7
5-((1- (4-morpholinophenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 28)

Figure JPOXMLDOC01-appb-C000133
Figure JPOXMLDOC01-appb-C000133

　1-(4-モルフォリノフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (27 mg, 0.091 mmol) をエタノール (1.00 mL) に溶かし、ロダニン (19 mg, 0.14 mmol) およびピペリジン (20 μL, 0.21 mmol) を加え、還流条件下一晩撹拌した。反応終了後、生成した沈殿をろ過し、エタノールで洗浄して標記化合物 (8 mg, 21 %, 0.019 mmol) を得た。茶褐色固体: 1H-NMR (DMSO-D6) δ: 8.58 (1H, s), 7.86 (1H, d, J = 8.5 Hz), 7.74 (1H, s), 7.61 (1H, s), 7.55 (2H, d, J = 9.0 Hz), 7.50 (1H, d, J = 8.5 Hz), 7.19 (2H, d, J = 9.0 Hz), 3.79 (4H, t, J = 4.9 Hz), 3.24 (4H, t, J = 4.9 Hz). 
ESI-MS(m/z): 423[M+H]+. 1- (4-morpholinophenyl) -1H-benzo [d] imidazole-6-carbaldehyde (27 mg, 0.091 mmol) is dissolved in ethanol (1.00 mL), and rhodanine (19 mg, 0.14 mmol) and piperidine (20 μL, 0.21 mmol) was added and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the produced precipitate was filtered and washed with ethanol to obtain the title compound (8 mg, 21%, 0.019 mmol). Brown solid: 1 H-NMR (DMSO-D 6 ) δ: 8.58 (1H, s), 7.86 (1H, d, J = 8.5 Hz), 7.74 (1H, s), 7.61 (1H, s), 7.55 ( 2H, d, J = 9.0 Hz), 7.50 (1H, d, J = 8.5 Hz), 7.19 (2H, d, J = 9.0 Hz), 3.79 (4H, t, J = 4.9 Hz), 3.24 (4H, t, J = 4.9 Hz).
ESI-MS (m / z): 423 [M + H] + .

実施例２９
5-((1-(4-(4,4-ジフルオロピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物２９)  Example 29
5-((1- (4- (4,4-Difluoropiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (compound 29)

工程１
メチル 1-(4-(4,4-ジフルオロピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 1
Methyl 1- (4- (4,4-difluoropiperidin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000134
Figure JPOXMLDOC01-appb-C000134

　メチル 1-(4-ブロモフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート(151 mg, 0.46 mmol) のトルエン (5 mL) 溶媒中に酢酸パラジウム (5 mg, 0.023 mmol)、rac-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル (43 mg, 0.069 mmol)、炭酸セシウム (300 mg, 0.92 mmol)、4,4-ジフルオロピペリジン (84 mg, 0.69 mmol) を添加した。還流条件下、一晩撹拌した後、塩化アンモニウム水溶液、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムと飽和食塩水を添加して有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (151 mg, 88 %, 0.41 mmol) を得た。黄褐色粘性体: 1H-NMR (CDCl3) δ: 8.19 (1H, s), 8.16 (1H, s), 8.03 (1H, d, J = 8.8 Hz), 7.87 (1H, d, J = 8.8 Hz), 7.39 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 3.93 (3H, s), 3.47 (4H, t, J = 5.6 Hz), 2.18-2.12 (4H, m). 
ESI-MS(m/z): 372[M+H]+. Methyl 1- (4-bromophenyl) -1H-benzo [d] imidazole-6-carboxylate (151 mg, 0.46 mmol) in toluene (5 mL) Palladium acetate (5 mg, 0.023 mmol), rac- 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (43 mg, 0.069 mmol), cesium carbonate (300 mg, 0.92 mmol), 4,4-difluoropiperidine (84 mg, 0.69 mmol) Added. After stirring overnight under reflux conditions, an aqueous ammonium chloride solution and a saturated aqueous sodium hydrogen carbonate solution were added, and the organic layer was extracted by adding chloroform and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. . The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (151 mg, 88%, 0.41 mmol). Yellowish brown viscous material: 1 H-NMR (CDCl 3 ) δ: 8.19 (1H, s), 8.16 (1H, s), 8.03 (1H, d, J = 8.8 Hz), 7.87 (1H, d, J = 8.8 Hz), 7.39 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 3.93 (3H, s), 3.47 (4H, t, J = 5.6 Hz), 2.18-2.12 ( 4H, m).
ESI-MS (m / z): 372 [M + H] + .

工程２
(1-(4-(4,4-ジフルオロピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール Process 2
(1- (4- (4,4-Difluoropiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol

Figure JPOXMLDOC01-appb-C000135
Figure JPOXMLDOC01-appb-C000135

　メチル 1-(4-(4,4-ジフルオロピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート (151 mg, 0.41 mmol) のテトラヒドロフラン (2 mL) 溶液中に、水素化アルミニウムリチウム (61 mg, 1.6 mmol) をアルゴン雰囲気下0 ℃で添加した。室温に昇温し、一晩撹拌した後、さらに水素化アルミニウムリチウム (61 mg, 1.6 mmol) を添加した。反応終了後、飽和酒石酸ナトリウムカリウム水溶液を加え、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (85 mg, 60 %, 0.025 mmol) を得た。茶色粘性固体: 1H-NMR (CDCl3) δ: 8.03 (1H, s), 7.78 (1H, d, J = 8.3 Hz), 7.51 (1H, s), 7.34 (2H, d, J = 9.0 Hz), 7.29 (1H, d, J = 8.3 Hz), 7.06 (2H, d, J = 9.0 Hz), 4.81 (3H, s), 3.45 (4H, t, J = 5.4 Hz), 2.19-2.09 (4H, m). 
ESI-MS(m/z): 344[M+H]+. In a solution of methyl 1- (4- (4,4-difluoropiperidin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate (151 mg, 0.41 mmol) in tetrahydrofuran (2 mL), Lithium aluminum hydride (61 mg, 1.6 mmol) was added at 0 ° C. under an argon atmosphere. The mixture was warmed to room temperature and stirred overnight, and further lithium aluminum hydride (61 mg, 1.6 mmol) was added. After completion of the reaction, saturated aqueous sodium potassium tartrate solution was added, ethyl acetate and saturated brine were added to extract the organic layer, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (85 mg, 60%, 0.025 mmol). Brown viscous solid: 1 H-NMR (CDCl 3 ) δ: 8.03 (1H, s), 7.78 (1H, d, J = 8.3 Hz), 7.51 (1H, s), 7.34 (2H, d, J = 9.0 Hz ), 7.29 (1H, d, J = 8.3 Hz), 7.06 (2H, d, J = 9.0 Hz), 4.81 (3H, s), 3.45 (4H, t, J = 5.4 Hz), 2.19-2.09 (4H , m).
ESI-MS (m / z): 344 [M + H] + .

工程３
1-(4-(4,4-ジフルオロピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Process 3
1- (4- (4,4-Difluoropiperidin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000136
Figure JPOXMLDOC01-appb-C000136

　(1-(4-(4,4-ジフルオロピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール (85 mg, 0.25 mmol) の塩化メチレン (4.0 mL) 溶液にデス・マーチン・ペルヨージナン (119 mg, 0.28 mmol) を0℃で滴下した。室温に昇温し2時間撹拌した。反応終了後、飽和チオ硫酸水素ナトリウム水溶液を添加し、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記化合物 (31 mg, 36 %, 0.091 mmol) を得た。1H-NMR (CDCl3) δ: 10.10 (1H, s), 8.27 (1H, s), 8.06-7.97 (2H, m), 7.90 (1H, d, J = 8.1 Hz), 7.57 (1H, s), 7.42 (1H, d, J = 8.1 Hz), 7.30-7.24 (2H, m), 3.26 (4H, t, J = 5.5 Hz), 2.28-2.19 (4H, m). To a solution of (1- (4- (4,4-difluoropiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol (85 mg, 0.25 mmol) in methylene chloride (4.0 mL) Dess-Martin periodinane (119 mg, 0.28 mmol) was added dropwise at 0 ° C. The mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, a saturated aqueous sodium hydrogensulfate solution was added, chloroform and a saturated aqueous sodium hydrogencarbonate solution were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound (31 mg, 36%, 0.091 mmol) was obtained. 1 H-NMR (CDCl 3 ) δ: 10.10 (1H, s), 8.27 (1H, s), 8.06-7.97 (2H, m), 7.90 (1H, d, J = 8.1 Hz), 7.57 (1H, s ), 7.42 (1H, d, J = 8.1 Hz), 7.30-7.24 (2H, m), 3.26 (4H, t, J = 5.5 Hz), 2.28-2.19 (4H, m).

工程４
5-((1-(4-(4,4-ジフルオロピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物２９) Process 4
5-((1- (4- (4,4-Difluoropiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one (compound 29)

Figure JPOXMLDOC01-appb-C000137
Figure JPOXMLDOC01-appb-C000137

　1-(4-(4,4-ジフルオロピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (31 mg, 0.091 mmol) をエタノール (1.00 mL) に溶かし、ロダニン (11 mg, 0.082 mmol) およびピペリジン (4 μL, 0.046 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (18 mg, 43 %, 0.039 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.72 (1H, s), 7.93-7.91 (4H, m), 7.87 (1H, s), 7.69 (1H, d, J = 8.5 Hz), 7.53 (1H, d, J = 8.5 Hz), 7.48 (1H, d, J = 8.5 Hz), 3.19 (4H, t, J = 10.9 Hz), 2.21-2.16 (4H, m). 
ESI-MS(m/z): 457[M+H]+. 1- (4- (4,4-Difluoropiperidin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (31 mg, 0.091 mmol) is dissolved in ethanol (1.00 mL) and rhodanine ( 11 mg, 0.082 mmol) and piperidine (4 μL, 0.046 mmol) were added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (18 mg, 43%, 0.039 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.72 (1H, s), 7.93-7.91 (4H, m), 7.87 (1H, s), 7.69 (1H, d, J = 8.5 Hz), 7.53 (1H, d, J = 8.5 Hz), 7.48 (1H, d, J = 8.5 Hz), 3.19 (4H, t, J = 10.9 Hz), 2.21-2.16 (4H, m).
ESI-MS (m / z): 457 [M + H] + .

実施例３０
5-((1-(4-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物３０)  Example 30
5-((1- (4- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4- ON (compound 30)

工程１
メチル 1-(4-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 1
Methyl 1- (4- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000138
Figure JPOXMLDOC01-appb-C000138

　メチル 1-(4-ブロモフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート(151 mg, 0.46 mmol) のトルエン (5 mL) 溶媒中に酢酸パラジウム (5 mg, 0.023 mmol)、rac-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル (43 mg, 0.069 mmol)、炭酸セシウム (300 mg, 0.92 mmol)、1-(2-メトキシエチル)ピペラジン (103 μL, 0.69 mmol) を添加した。還流条件下、一晩撹拌した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (163 mg, 90 %, 0.41 mmol) を得た。1H-NMR (CDCl3) δ: 8.14 (1H, s), 8.11 (1H, s), 7.99 (1H, d, J = 8.5 Hz), 7.82 (1H, d, J = 8.5 Hz), 7.32 (2H, d, J = 9.0 Hz), 7.03 (2H, d, J = 9.0 Hz), 3.88 (3H, s), 3.54 (2H, t, J = 5.1 Hz), 3.35 (3H, s), 3.30 (4H, t, J = 4.4 Hz), 2.68 (4H, t, J = 4.4 Hz), 2.64 (2H, t, J = 5.1 Hz). 
ESI-MS(m/z): 395[M+H]+. Methyl 1- (4-bromophenyl) -1H-benzo [d] imidazole-6-carboxylate (151 mg, 0.46 mmol) in toluene (5 mL) Palladium acetate (5 mg, 0.023 mmol), rac- 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (43 mg, 0.069 mmol), cesium carbonate (300 mg, 0.92 mmol), 1- (2-methoxyethyl) piperazine (103 μL, 0.69 mmol) was added. After stirring overnight under reflux conditions, a saturated aqueous sodium hydrogen carbonate solution was added, chloroform and saturated brine were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (163 mg, 90%, 0.41 mmol). 1 H-NMR (CDCl 3 ) δ: 8.14 (1H, s), 8.11 (1H, s), 7.99 (1H, d, J = 8.5 Hz), 7.82 (1H, d, J = 8.5 Hz), 7.32 ( 2H, d, J = 9.0 Hz), 7.03 (2H, d, J = 9.0 Hz), 3.88 (3H, s), 3.54 (2H, t, J = 5.1 Hz), 3.35 (3H, s), 3.30 ( 4H, t, J = 4.4 Hz), 2.68 (4H, t, J = 4.4 Hz), 2.64 (2H, t, J = 5.1 Hz).
ESI-MS (m / z): 395 [M + H] + .

工程２
(1-(4-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール Process 2
(1- (4- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol

Figure JPOXMLDOC01-appb-C000139
Figure JPOXMLDOC01-appb-C000139

　メチル 1-(4-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート(163 mg, 0.41 mmol) のテトラヒドロフラン (5 mL) 溶液中に、水素化ジイソブチルアルミニウム ヘキサン溶液 (1.0 M, 1.9 mL, 1.9 mmol) を0 ℃で添加した。室温から50℃に昇温し、一晩撹拌した。1規定塩酸を加え、酢酸エチルと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (21 mg, 14 %, 0.057 mmol) を得た。茶色粘性固体: 1H-NMR (CDCl3) δ: 8.01 (1H, s), 7.79 (1H, d, J = 8.5 Hz), 7.49 (1H, s), 7.32 (2H, d, J = 7.6 Hz), 7.29 (1H, d, J = 8.5 Hz), 7.03 (2H, d, J = 7.6 Hz), 4.79 (2H, s), 3.59 (2H, t, J = 5.4 Hz), 3.38 (3H, s), 3.31 (4H, t, J = 4.3 Hz), 2.73 (4H, t, J = 4.3 Hz), 2.69 (2H, t, J = 5.4 Hz). 
ESI-MS(m/z): 367[M+H]+. Methyl 1- (4- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate (163 mg, 0.41 mmol) in tetrahydrofuran (5 mL) Inside, diisobutylaluminum hydride hexane solution (1.0 M, 1.9 mL, 1.9 mmol) was added at 0 ° C. The temperature was raised from room temperature to 50 ° C. and stirred overnight. 1N Hydrochloric acid was added, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the organic layer was extracted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (21 mg, 14%, 0.057 mmol). Brown viscous solid: 1 H-NMR (CDCl 3 ) δ: 8.01 (1H, s), 7.79 (1H, d, J = 8.5 Hz), 7.49 (1H, s), 7.32 (2H, d, J = 7.6 Hz ), 7.29 (1H, d, J = 8.5 Hz), 7.03 (2H, d, J = 7.6 Hz), 4.79 (2H, s), 3.59 (2H, t, J = 5.4 Hz), 3.38 (3H, s ), 3.31 (4H, t, J = 4.3 Hz), 2.73 (4H, t, J = 4.3 Hz), 2.69 (2H, t, J = 5.4 Hz).
ESI-MS (m / z): 367 [M + H] + .

工程３
1-(4-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Process 3
1- (4- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000140
Figure JPOXMLDOC01-appb-C000140

　(1-(4-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール (21 mg, 0.06 mmol) の塩化メチレン (2.0 mL) 溶液に デス・マーチン・ペルヨージナン (28 mg, 0.066 mmol) を0℃で滴下した。室温に昇温し2時間撹拌した後さらにデス・マーチン・ペルヨージナン (28 mg, 0.066 mmol) を添加した。反応終了後、飽和チオ硫酸水素ナトリウム水溶液を添加し、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記化合物 (24 mg, quant., 0.066 mmol) を得た。1H-NMR (CDCl3) δ: 10.07 (1H, s), 8.22 (1H, s), 8.01 (1H, s), 7.97 (1H, d, J = 8.3 Hz), 7.87 (1H, d, J = 8.3 Hz), 7.38 (2H, d, J = 6.8 Hz), 7.08 (2H, d, J = 6.8 Hz), 3.61 (2H, t, J = 5.4 Hz), 3.40 (3H, s), 3.37 (4H, t, J = 5.1 Hz), 2.76 (4H, t, J = 5.1 Hz), 2.71 (2H, t, J = 5.4 Hz). 
ESI-MS(m/z): 365[M+H]+. (1- (4- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol (21 mg, 0.06 mmol) in methylene chloride (2.0 mL ) Dess-Martin periodinane (28 mg, 0.066 mmol) was added dropwise to the solution at 0 ° C. After warming to room temperature and stirring for 2 hours, Dess-Martin periodinane (28 mg, 0.066 mmol) was further added. After completion of the reaction, a saturated aqueous sodium hydrogensulfate solution was added, chloroform and a saturated aqueous sodium hydrogencarbonate solution were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound (24 mg, quant., 0.066 mmol) was obtained. 1 H-NMR (CDCl 3 ) δ: 10.07 (1H, s), 8.22 (1H, s), 8.01 (1H, s), 7.97 (1H, d, J = 8.3 Hz), 7.87 (1H, d, J = 8.3 Hz), 7.38 (2H, d, J = 6.8 Hz), 7.08 (2H, d, J = 6.8 Hz), 3.61 (2H, t, J = 5.4 Hz), 3.40 (3H, s), 3.37 ( 4H, t, J = 5.1 Hz), 2.76 (4H, t, J = 5.1 Hz), 2.71 (2H, t, J = 5.4 Hz).
ESI-MS (m / z): 365 [M + H] + .

工程４
5-((1-(4-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物３０)  Process 4
5-((1- (4- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4- ON (compound 30)

Figure JPOXMLDOC01-appb-C000141
Figure JPOXMLDOC01-appb-C000141

　1-(4-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (24 mg, 0.066 mmol) をエタノール (1.00 mL) に溶かし、ロダニン (8 mg, 0.059 mmol) およびピペリジン (3 μL, 0.033 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (15 mg, 47 %, 0.031 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.58 (1H, s), 7.86 (1H, d, J = 8.3 Hz), 7.72 (1H, s), 7.58 (1H, s), 7.56 (2H, d, J = 8.8 Hz), 7.50 (1H, d, J = 8.3 Hz), 7.22 (2H, d, J = 8.8 Hz), 3.60 (2H, t, J = 5.2 Hz), 3.39-3.38 (4H, m), 3.31 (3H, s), 3.05-2.93 (6H, m). 
ESI-MS(m/z): 480[M+H]+. 1- (4- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (24 mg, 0.066 mmol) was dissolved in ethanol (1.00 mL). , Rhodanine (8 mg, 0.059 mmol) and piperidine (3 μL, 0.033 mmol) were added and stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (15 mg, 47%, 0.031 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.58 (1H, s), 7.86 (1H, d, J = 8.3 Hz), 7.72 (1H, s), 7.58 (1H, s), 7.56 ( 2H, d, J = 8.8 Hz), 7.50 (1H, d, J = 8.3 Hz), 7.22 (2H, d, J = 8.8 Hz), 3.60 (2H, t, J = 5.2 Hz), 3.39-3.38 ( 4H, m), 3.31 (3H, s), 3.05-2.93 (6H, m).
ESI-MS (m / z): 480 [M + H] + .

実施例３１
5-((1-(4-(4-ブチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物３１) Example 31
5-((1- (4- (4-Butylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 31)

工程１
メチル 1-(4-(4-ブチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 1
Methyl 1- (4- (4-butylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000142
Figure JPOXMLDOC01-appb-C000142

　メチル 1-(4-ブロモフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート(300 mg, 0.91 mmol) のトルエン (7 mL) 溶液中に酢酸パラジウム (10mg, 0.046 mmol)、rac-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル (85 mg, 0.138 mmol)、炭酸セシウム (593 mg, 1.82 mmol)、1-ブチルピペラジン (194 mg, 1.37 mmol) を添加した。還流条件下、一晩撹拌した後、セライトろ過し、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (266 mg, 75 %, 0.68 mmol) を得た。1H-NMR (CDCl3) δ: 8.13 (1H, s), 8.11 (1H, s), 7.97 (1H, d, J = 8.5 Hz), 7.81 (1H, d, J = 8.5 Hz), 7.30 (2H, d, J = 5.1 Hz), 7.01 (2H, d, J = 5.1 Hz), 3.86 (3H, s), 3.26 (4H, br s), 2.59 (4H, br s), 2.38-2.36 (2H, br m), 1.50-1.47 (2H, br m), 1.34-1.32 (2H, br m), 0.94-0.86 (3H, m).
ESI-MS(m/z): 393[M+H]+. Palladium acetate (10 mg, 0.046 mmol), rac-2 in a solution of methyl 1- (4-bromophenyl) -1H-benzo [d] imidazole-6-carboxylate (300 mg, 0.91 mmol) in toluene (7 mL) , 2′-bis (diphenylphosphino) -1,1′-binaphthyl (85 mg, 0.138 mmol), cesium carbonate (593 mg, 1.82 mmol), 1-butylpiperazine (194 mg, 1.37 mmol) were added. The mixture was stirred overnight under reflux conditions, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (266 mg, 75%, 0.68 mmol). 1 H-NMR (CDCl 3 ) δ: 8.13 (1H, s), 8.11 (1H, s), 7.97 (1H, d, J = 8.5 Hz), 7.81 (1H, d, J = 8.5 Hz), 7.30 ( 2H, d, J = 5.1 Hz), 7.01 (2H, d, J = 5.1 Hz), 3.86 (3H, s), 3.26 (4H, br s), 2.59 (4H, br s), 2.38-2.36 (2H , br m), 1.50-1.47 (2H, br m), 1.34-1.32 (2H, br m), 0.94-0.86 (3H, m).
ESI-MS (m / z): 393 [M + H] + .

工程２
(1-(4-(4-ブチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール Process 2
(1- (4- (4-Butylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol

Figure JPOXMLDOC01-appb-C000143
Figure JPOXMLDOC01-appb-C000143

　メチル 1-(4-(4-ブチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート (266 mg, 0.68 mmol) のテトラヒドロフラン (7 mL) 溶液中に、水素化アルミニウムリチウムのテトラヒドロフラン溶液 (1.0 M, 2.0 mL, 2.0 mmol) をアルゴン雰囲気下-78 ℃で添加した。0 ℃に昇温しながら5時間撹拌した後、飽和酒石酸ナトリウムカリウム水溶液を加え、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記化合物 (204 mg, 82 %, 0.56 mmol) を得た。1H-NMR (CDCl3) δ: 7.93 (1H, br s), 7.73 (1H, d, J = 8.3 Hz), 7.48 (1H, s), 7.25-7.24 (3H, m), 6.98-6.94 (2H, m), 4.78 (2H, s), 3.22-3.22 (4H, m), 2.59 (4H, s), 2.39-2.36 (2H, m), 1.53-1.49 (2H, m), 1.38-1.32 (2H, m), 0.94 (3H, t, J = 7.3 Hz).
ESI-MS(m/z): 365[M+H]+. Hydrogenation of methyl 1- (4- (4-butylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate (266 mg, 0.68 mmol) in tetrahydrofuran (7 mL) A solution of lithium aluminum in tetrahydrofuran (1.0 M, 2.0 mL, 2.0 mmol) was added at −78 ° C. under an argon atmosphere. After stirring for 5 hours while raising the temperature to 0 ° C., saturated aqueous sodium potassium tartrate solution was added, ethyl acetate and saturated brine were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The title compound (204 mg, 82%, 0.56 mmol) was obtained. 1 H-NMR (CDCl 3 ) δ: 7.93 (1H, br s), 7.73 (1H, d, J = 8.3 Hz), 7.48 (1H, s), 7.25-7.24 (3H, m), 6.98-6.94 ( 2H, m), 4.78 (2H, s), 3.22-3.22 (4H, m), 2.59 (4H, s), 2.39-2.36 (2H, m), 1.53-1.49 (2H, m), 1.38-1.32 ( 2H, m), 0.94 (3H, t, J = 7.3 Hz).
ESI-MS (m / z): 365 [M + H] + .

工程３
1-(4-(4-ブチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Process 3
1- (4- (4-Butylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000144
Figure JPOXMLDOC01-appb-C000144

　(1-(4-(4-ブチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール (204 mg, 0.56 mmol) の塩化メチレン (6.0 mL) 溶液にデス・マーチン・ペルヨージナン (380 mg, 0.90 mmol) を0℃で滴下した。室温に昇温し1時間撹拌した後、飽和チオ硫酸水素ナトリウム水溶液を添加し、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (174 mg, 86 %, 0.48 mmol) を得た。1H-NMR (CDCl3) δ: 9.93 (1H, s), 8.10 (1H, s), 7.88 (1H, s), 7.83 (1H, d, J = 8.3 Hz), 7.73 (1H, d, J = 8.3 Hz), 7.25 (2H, d, J = 8.3 Hz), 6.96 (2H, d, J = 8.3 Hz), 3.20 (4H, t, J = 4.9 Hz), 2.53 (4H, t, J = 4.9 Hz), 2.31 (2H, t, J = 7.7 Hz), 1.45-1.39 (2H, m), 1.28-1.24 (2H, m), 0.84 (3H, t, J = 7.7 Hz). 
ESI-MS(m/z): 363[M+H]+. To a solution of (1- (4- (4-butylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol (204 mg, 0.56 mmol) in methylene chloride (6.0 mL) Martin periodinane (380 mg, 0.90 mmol) was added dropwise at 0 ° C. After warming to room temperature and stirring for 1 hour, saturated aqueous sodium hydrogenthiosulfate solution was added, the organic layer was extracted by adding chloroform and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure . The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (174 mg, 86%, 0.48 mmol). 1 H-NMR (CDCl 3 ) δ: 9.93 (1H, s), 8.10 (1H, s), 7.88 (1H, s), 7.83 (1H, d, J = 8.3 Hz), 7.73 (1H, d, J = 8.3 Hz), 7.25 (2H, d, J = 8.3 Hz), 6.96 (2H, d, J = 8.3 Hz), 3.20 (4H, t, J = 4.9 Hz), 2.53 (4H, t, J = 4.9 Hz), 2.31 (2H, t, J = 7.7 Hz), 1.45-1.39 (2H, m), 1.28-1.24 (2H, m), 0.84 (3H, t, J = 7.7 Hz).
ESI-MS (m / z): 363 [M + H] + .

工程４
5-((1-(4-(4-ブチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物３１)  Process 4
5-((1- (4- (4-Butylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 31)

Figure JPOXMLDOC01-appb-C000145
Figure JPOXMLDOC01-appb-C000145

　1-(4-(4-ブチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (87 mg, 0.24 mmol) をエタノール (3.0 mL) に溶かし、ロダニン (35 mg, 0.26 mmol) およびピペリジン (4.8 μL, 0.048 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (56 mg, 49 %, 0.12 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.56 (1H, s), 7.84 (1H, d, J = 8.3 Hz), 7.69 (1H, s), 7.57 (2H, d, J = 8.8 Hz), 7.50-7.49 (2H, m), 7.24 (2H, d, J = 8.8 Hz), 3.44-3.39 (4H, m), 3.09-3.07 (4H, br m), 2.88-2.85 (2H, m), 1.61-1.59 (2H, m), 1.37-1.33 (2H, m), 0.93 (3H, t, J = 7.3 Hz). 
ESI-MS(m/z): 478[M+H]+. 1- (4- (4-Butylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (87 mg, 0.24 mmol) was dissolved in ethanol (3.0 mL) and rhodanine (35 mg , 0.26 mmol) and piperidine (4.8 μL, 0.048 mmol) were added and stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (56 mg, 49%, 0.12 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.56 (1H, s), 7.84 (1H, d, J = 8.3 Hz), 7.69 (1H, s), 7.57 (2H, d, J = 8.8 Hz), 7.50-7.49 (2H, m), 7.24 (2H, d, J = 8.8 Hz), 3.44-3.39 (4H, m), 3.09-3.07 (4H, br m), 2.88-2.85 (2H, m ), 1.61-1.59 (2H, m), 1.37-1.33 (2H, m), 0.93 (3H, t, J = 7.3 Hz).
ESI-MS (m / z): 478 [M + H] + .

実施例３２
5-((1-(4-(4-ブチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物３２)  Example 32
5-((1- (4- (4-Butylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 32)

Figure JPOXMLDOC01-appb-C000146
Figure JPOXMLDOC01-appb-C000146

工程１
　1-(4-(4-ブチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (87 mg, 0.24 mmol) をエタノール (3.0 mL) に溶かし、チアゾリジン-2,4-ジオン (31 mg, 0.26 mmol) およびピペリジン (4.8 μL, 0.048 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (42 mg, 38 %, 0.091 mmol) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 8.59 (1H, s), 7.86 (2H, d, J = 8.8 Hz), 7.78 (1H, s), 7.54-7.51 (3H, m), 7.20 (2H, d, J = 8.8 Hz), 3.24-3.22 (2H, m), 2.80-2.70 (4H, m), 2.59-2.52 (4H, m), 1.56-1.46 (2H, m), 1.36-1.27 (2H, m), 0.92 (3H, t, J = 7.3 Hz). 
ESI-MS(m/z): 462[M+H]+. Process 1
1- (4- (4-Butylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (87 mg, 0.24 mmol) is dissolved in ethanol (3.0 mL) and thiazolidine-2, 4-dione (31 mg, 0.26 mmol) and piperidine (4.8 μL, 0.048 mmol) were added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (42 mg, 38%, 0.091 mmol). White solid: 1 H-NMR (DMSO-D 6 ) δ: 8.59 (1H, s), 7.86 (2H, d, J = 8.8 Hz), 7.78 (1H, s), 7.54-7.51 (3H, m), 7.20 (2H, d, J = 8.8 Hz), 3.24-3.22 (2H, m), 2.80-2.70 (4H, m), 2.59-2.52 (4H, m), 1.56-1.46 (2H, m), 1.36- 1.27 (2H, m), 0.92 (3H, t, J = 7.3 Hz).
ESI-MS (m / z): 462 [M + H] + .

実施例３３
5-((1-(4-([1,4'-ビピペリジン]-1'-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物３３) Example 33
5-((1- (4-([1,4′-bipiperidine] -1′-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4- ON (compound 33)

工程１
メチル 1-(4-([1,4'-ビピペリジン]-1'-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 1
Methyl 1- (4-([1,4'-bipiperidine] -1'-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000147
Figure JPOXMLDOC01-appb-C000147

　メチル 1-(4-ブロモフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート(300 mg, 0.46 mmol) のトルエン (10 mL) 溶媒中に酢酸パラジウム (10 mg, 0.046 mmol)、rac-2,2'-ビス(ジフェニルホスフィノ)-1,1'-ビナフチル (85 mg, 0.137 mmol)、炭酸セシウム (593 mg, 1.82 mmol)、1,4'-ビピペリジン (230 mg, 1.37 mmol) を添加した。還流条件下、一晩撹拌した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムと飽和食塩水を添加して有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (241 mg, 63 %, 0.58 mmol) を得た。1H-NMR (CDCl3) δ: 8.18 (1H, s), 8.17 (1H, s), 8.03 (1H, d, J = 8.5 Hz), 7.87 (1H, d, J = 8.5 Hz), 7.36 (2H, d, J = 9.0 Hz), 7.07 (2H, d, J = 9.0 Hz), 3.93 (3H, s), 3.92-3.83 (2H, m), 2.97-2.79 (7H, m), 2.17-2.09 (2H, m), 1.90-1.78 (6H, m), 1.61-1.51 (2H, m).
ESI-MS(m/z): 419[M+H]+. Methyl 1- (4-bromophenyl) -1H-benzo [d] imidazole-6-carboxylate (300 mg, 0.46 mmol) in toluene (10 mL) Palladium acetate (10 mg, 0.046 mmol), rac- 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (85 mg, 0.137 mmol), cesium carbonate (593 mg, 1.82 mmol), 1,4'-bipiperidine (230 mg, 1.37 mmol) Added. After stirring overnight under reflux conditions, a saturated aqueous sodium hydrogen carbonate solution was added, chloroform and saturated brine were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (241 mg, 63%, 0.58 mmol). 1 H-NMR (CDCl 3 ) δ: 8.18 (1H, s), 8.17 (1H, s), 8.03 (1H, d, J = 8.5 Hz), 7.87 (1H, d, J = 8.5 Hz), 7.36 ( 2H, d, J = 9.0 Hz), 7.07 (2H, d, J = 9.0 Hz), 3.93 (3H, s), 3.92-3.83 (2H, m), 2.97-2.79 (7H, m), 2.17-2.09 (2H, m), 1.90-1.78 (6H, m), 1.61-1.51 (2H, m).
ESI-MS (m / z): 419 [M + H] + .

工程２
(1-(4-([1,4'-ビピペリジン]-1'-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール Process 2
(1- (4-([1,4'-bipiperidin] -1'-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol

Figure JPOXMLDOC01-appb-C000148
Figure JPOXMLDOC01-appb-C000148

　メチル 1-(4-([1,4'-ビピペリジン]-1'-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート (214 mg, 0.63 mmol) のテトラヒドロフラン (6 mL) 溶液中に、水素化アルミニウムリチウムのテトラヒドロフラン溶液 (1.0 M, 1.9 mL, 1.9 mmol) をアルゴン雰囲気下-78 ℃で添加した。0 ℃に昇温し、3時間撹拌した後、飽和酒石酸ナトリウムカリウム水溶液を加え、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (122 mg, 50 %, 0.31 mmol) を得た。1H-NMR (CDCl3) δ: 7.97 (1H, s), 7.76 (1H, d, J = 8.3 Hz), 7.49 (1H, s), 7.29-7.26 (3H, m), 7.00 (2H, d, J = 8.8 Hz), 4.79 (2H, s), 3.80-3.78 (2H, m), 2.77-2.74 (2H, m), 2.57-2.55 (4H, m), 2.46-2.43 (1H, m), 1.97-1.94 (2H, m), 1.78-1.57 (6H, m), 1.52-1.42 (2H, m). 
ESI-MS(m/z): 391[M+H]+. Methyl 1- (4-([1,4'-bipiperidine] -1'-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate (214 mg, 0.63 mmol) in tetrahydrofuran (6 mL) A solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 1.9 mL, 1.9 mmol) was added at −78 ° C. under an argon atmosphere. After heating to 0 ° C. and stirring for 3 hours, a saturated aqueous sodium potassium tartrate solution was added, ethyl acetate and saturated brine were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (122 mg, 50%, 0.31 mmol). 1 H-NMR (CDCl 3 ) δ: 7.97 (1H, s), 7.76 (1H, d, J = 8.3 Hz), 7.49 (1H, s), 7.29-7.26 (3H, m), 7.00 (2H, d , J = 8.8 Hz), 4.79 (2H, s), 3.80-3.78 (2H, m), 2.77-2.74 (2H, m), 2.57-2.55 (4H, m), 2.46-2.43 (1H, m), 1.97-1.94 (2H, m), 1.78-1.57 (6H, m), 1.52-1.42 (2H, m).
ESI-MS (m / z): 391 [M + H] + .

工程３
1-(4-([1,4'-ビピペリジン]-1'-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Process 3
1- (4-([1,4'-bipiperidine] -1'-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000149
Figure JPOXMLDOC01-appb-C000149

　(1-(4-([1,4'-ビピペリジン]-1'-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール (120 mg, 0.31 mmol) の塩化メチレン (3.0 mL) 溶液にデス・マーチン・ペルヨージナン (143 mg, 0.34 mmol) を0℃で滴下した。室温に昇温し3時間撹拌した後、さらにデス・マーチン・ペルヨージナン (70 mg, 0.17 mmol) を滴下した。反応終了後、飽和チオ硫酸水素ナトリウム水溶液を添加し、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (157 mg, quant., 0.31 mmol) を得た。1H-NMR (CDCl3) δ: 10.07 (1H, s), 8.22 (1H, s), 8.01 (1H, s), 7.97 (1H, d, J = 8.5 Hz), 7.86 (1H, d, J = 8.5 Hz), 7.36 (2H, d, J = 9.0 Hz), 7.08 (2H, d, J = 9.0 Hz), 3.92-3.84 (2H, m), 2.92-2.82 (2H, m), 2.79-2.64 (5H, m), 2.11-2.02 (2H, m), 1.86-1.69 (6H, m), 1.57-1.46 (2H, m). 
ESI-MS(m/z): 389[M+H]+. (1- (4-([1,4'-bipiperidin] -1'-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol (120 mg, 0.31 mmol) in methylene chloride (3.0 mL ) Dess-Martin periodinane (143 mg, 0.34 mmol) was added dropwise to the solution at 0 ° C. After warming to room temperature and stirring for 3 hours, Dess-Martin periodinane (70 mg, 0.17 mmol) was further added dropwise. After completion of the reaction, a saturated aqueous sodium hydrogensulfate solution was added, chloroform and a saturated aqueous sodium hydrogencarbonate solution were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (157 mg, quant., 0.31 mmol). 1 H-NMR (CDCl 3 ) δ: 10.07 (1H, s), 8.22 (1H, s), 8.01 (1H, s), 7.97 (1H, d, J = 8.5 Hz), 7.86 (1H, d, J = 8.5 Hz), 7.36 (2H, d, J = 9.0 Hz), 7.08 (2H, d, J = 9.0 Hz), 3.92-3.84 (2H, m), 2.92-2.82 (2H, m), 2.79-2.64 (5H, m), 2.11-2.02 (2H, m), 1.86-1.69 (6H, m), 1.57-1.46 (2H, m).
ESI-MS (m / z): 389 [M + H] + .

工程４
5-((1-(4-([1,4'-ビピペリジン]-1'-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物３３) Process 4
5-((1- (4-([1,4′-bipiperidine] -1′-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4- ON (compound 33)

Figure JPOXMLDOC01-appb-C000150
Figure JPOXMLDOC01-appb-C000150

　1-(4-([1,4'-ビピペリジン]-1'-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (78 mg, 0.2 mmol) をエタノール (1.0 mL) に溶かし、ロダニン (27 mg, 0.20 mmol) およびピペリジン (1.98 μL, 0.02 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (24 mg, 24 %, 0.048 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.54 (1H, s), 8.32 (1H, s), 7.82 (1H, d, J = 8.5 Hz), 7.64 (1H, s), 7.54 (2H, d, J = 8.8 Hz), 7.48 (1H, d, J = 8.5 Hz), 7.39 (1H, s), 7.23 (2H, d, J = 8.8 Hz), 4.03 (2H, d, J = 12.7 Hz), 3.52-3.25 (6H, m), 3.09-2.93 (1H, m), 2.84 (2H, t, J = 12.0 Hz), 2.12 (2H, d, J = 12.0 Hz), 1.90-1.38 (6H, m). 
ESI-MS(m/z): 504[M+H]+. 1- (4-([1,4'-bipiperidin] -1'-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (78 mg, 0.2 mmol) was dissolved in ethanol (1.0 mL). , Rhodanine (27 mg, 0.20 mmol) and piperidine (1.98 μL, 0.02 mmol) were added and stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (24 mg, 24%, 0.048 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.54 (1H, s), 8.32 (1H, s), 7.82 (1H, d, J = 8.5 Hz), 7.64 (1H, s), 7.54 ( 2H, d, J = 8.8 Hz), 7.48 (1H, d, J = 8.5 Hz), 7.39 (1H, s), 7.23 (2H, d, J = 8.8 Hz), 4.03 (2H, d, J = 12.7 Hz), 3.52-3.25 (6H, m), 3.09-2.93 (1H, m), 2.84 (2H, t, J = 12.0 Hz), 2.12 (2H, d, J = 12.0 Hz), 1.90-1.38 (6H , m).
ESI-MS (m / z): 504 [M + H] + .

実施例３４
5-((1-(4-([1,4'-ビピペリジン]-1'-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物３４) Example 34
5-((1- (4-([1,4'-bipiperidine] -1'-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (compound 34)

Figure JPOXMLDOC01-appb-C000151
Figure JPOXMLDOC01-appb-C000151

工程１
　1-(4-([1,4'-ビピペリジン]-1'-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (26 mg, 0.067 mmol) をエタノール (1.5 mL) に溶かし、チアゾリジン-2,4-ジオン (8 mg, 0.067 mmol) およびピペリジン (1.3 μL, 6.69 μmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (4 mg, 12 %, 0.008 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.52 (1H, s), 8.32 (1H, s), 7.80 (1H, d, J = 8.5 Hz), 7.74 (1H, s), 7.59 (1H, s), 7.52 (2H, d, J = 9.0 Hz), 7.48 (1H, d, J = 8.5 Hz), 7.21 (2H, d, J = 9.0 Hz), 4.04-3.93 (2H, m), 3.11-2.91 (5H, m), 2.87-2.77 (2H, m), 2.08-1.97 (2H, m), 1.75-1.63 (4H, m), 1.57-1.44 (2H, m), 1.31-1.20 (2H, m). 
ESI-MS(m/z): 488[M+H]+. Process 1
1- (4-([1,4'-bipiperidin] -1'-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (26 mg, 0.067 mmol) was dissolved in ethanol (1.5 mL). , Thiazolidine-2,4-dione (8 mg, 0.067 mmol) and piperidine (1.3 μL, 6.69 μmol) were added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (4 mg, 12%, 0.008 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.52 (1H, s), 8.32 (1H, s), 7.80 (1H, d, J = 8.5 Hz), 7.74 (1H, s), 7.59 ( 1H, s), 7.52 (2H, d, J = 9.0 Hz), 7.48 (1H, d, J = 8.5 Hz), 7.21 (2H, d, J = 9.0 Hz), 4.04-3.93 (2H, m), 3.11-2.91 (5H, m), 2.87-2.77 (2H, m), 2.08-1.97 (2H, m), 1.75-1.63 (4H, m), 1.57-1.44 (2H, m), 1.31-1.20 (2H , m).
ESI-MS (m / z): 488 [M + H] + .

実施例３５
5-((1-(4-(4-モルフォリノピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物３５)  Example 35
5-((1- (4- (4-morpholinopiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 35 )

工程１
メチル 1-(4-(4-モルフォリノピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 1
Methyl 1- (4- (4-morpholinopiperidin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000152
Figure JPOXMLDOC01-appb-C000152

　メチル 1-(4-ブロモフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート(300 mg, 0.91 mmol) のトルエン (7 mL) 溶液中に酢酸パラジウム (10mg, 0.046 mmol)、rac-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル (85 mg, 0.138 mmol)、炭酸セシウム (593 mg, 1.82 mmol)、4-(ピペリジン-4-イル)モルフォリン (155 mg, 1.37 mmol) を添加した。還流条件下、一晩撹拌した後、セライトろ過し、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (196 mg, 50 %, 0.47 mmol) を得た。1H-NMR (CDCl3) δ: 8.12 (1H, s), 8.10 (1H, s), 7.96 (1H, d, J = 8.3 Hz), 7.80 (1H, d, J = 8.3 Hz), 7.28 (2H, dd, J = 8.8, 3.2 Hz), 7.00 (2H, dd, J = 8.8, 3.2 Hz), 3.85 (3H, s), 3.78 (2H, d, J = 11.4 Hz), 3.69-3.69 (4H, m), 2.79 (2H, t, J = 12.1 Hz), 2.55-2.54 (4H, m), 2.33-2.32 (1H, m), 1.93 (2H, d, J = 11.4 Hz), 1.69-1.55 (2H, m). 
ESI-MS(m/z): 421[M+H]+. Palladium acetate (10 mg, 0.046 mmol), rac-2 in a solution of methyl 1- (4-bromophenyl) -1H-benzo [d] imidazole-6-carboxylate (300 mg, 0.91 mmol) in toluene (7 mL) , 2'-bis (diphenylphosphino) -1,1'-binaphthyl (85 mg, 0.138 mmol), cesium carbonate (593 mg, 1.82 mmol), 4- (piperidin-4-yl) morpholine (155 mg, 1.37 mmol) was added. The mixture was stirred overnight under reflux conditions, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (196 mg, 50%, 0.47 mmol). 1 H-NMR (CDCl 3 ) δ: 8.12 (1H, s), 8.10 (1H, s), 7.96 (1H, d, J = 8.3 Hz), 7.80 (1H, d, J = 8.3 Hz), 7.28 ( 2H, dd, J = 8.8, 3.2 Hz), 7.00 (2H, dd, J = 8.8, 3.2 Hz), 3.85 (3H, s), 3.78 (2H, d, J = 11.4 Hz), 3.69-3.69 (4H , m), 2.79 (2H, t, J = 12.1 Hz), 2.55-2.54 (4H, m), 2.33-2.32 (1H, m), 1.93 (2H, d, J = 11.4 Hz), 1.69-1.55 ( 2H, m).
ESI-MS (m / z): 421 [M + H] + .

工程２
(1-(4-(4-モルフォリノピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール Process 2
(1- (4- (4-morpholinopiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol

Figure JPOXMLDOC01-appb-C000153
Figure JPOXMLDOC01-appb-C000153

　メチル 1-(4-(4-モルフォリノピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート (196 mg, 0.47 mmol) のテトラヒドロフラン (5 mL) 溶液中に、水素化アルミニウムリチウムのテトラヒドロフラン溶液 (1.0 M, 0.9 mL, 0.9 mmol) をアルゴン雰囲気下-78 ℃で添加した。0 ℃に昇温しながら5時間撹拌した後、飽和酒石酸ナトリウムカリウム水溶液を加え、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記化合物 (106 mg, 57 %, 0.27 mmol) を得た。白色固体: 1H-NMR (CDCl3) δ: 7.99 (1H, s), 7.79 (1H, d, J = 8.3 Hz), 7.49 (1H, s), 7.34-7.27 (3H, m), 7.03 (2H, d, J = 8.8 Hz), 4.80 (2H, s), 3.90-3.71 (6H, m), 2.82 (2H, t, J = 12.1 Hz), 2.61 (4H, br s), 2.45-2.34 (1H, m), 2.05-1.94 (2H, m), 1.76-1.62 (2H, m). 
ESI-MS(m/z): 393[M+H]+. Hydrogen in a solution of methyl 1- (4- (4-morpholinopiperidin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate (196 mg, 0.47 mmol) in tetrahydrofuran (5 mL) A solution of lithium aluminum halide in tetrahydrofuran (1.0 M, 0.9 mL, 0.9 mmol) was added at −78 ° C. under an argon atmosphere. After stirring for 5 hours while raising the temperature to 0 ° C., saturated aqueous sodium potassium tartrate solution was added, ethyl acetate and saturated brine were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The title compound (106 mg, 57%, 0.27 mmol) was obtained. White solid: 1 H-NMR (CDCl 3 ) δ: 7.99 (1H, s), 7.79 (1H, d, J = 8.3 Hz), 7.49 (1H, s), 7.34-7.27 (3H, m), 7.03 ( 2H, d, J = 8.8 Hz), 4.80 (2H, s), 3.90-3.71 (6H, m), 2.82 (2H, t, J = 12.1 Hz), 2.61 (4H, br s), 2.45-2.34 ( 1H, m), 2.05-1.94 (2H, m), 1.76-1.62 (2H, m).
ESI-MS (m / z): 393 [M + H] + .

工程３
1-(4-(4-モルフォリノピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Process 3
1- (4- (4-morpholinopiperidin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000154
Figure JPOXMLDOC01-appb-C000154

　(1-(4-(4-モルフォリノピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール (106 mg, 0.27 mmol) の塩化メチレン (3.0 mL) 溶液にデス・マーチン・ペルヨージナン (183 mg, 0.43 mmol) を0℃で滴下した。室温に昇温し3時間撹拌した後、飽和チオ硫酸水素ナトリウム水溶液を添加し、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (106 mg, quant., 0.27 mmol) を得た。1H-NMR (CDCl3) δ: 10.07 (1H, s), 8.22 (1H, br s), 8.02-8.01 (1H, m), 7.98-7.96 (1H, m), 7.88-7.85 (1H, m), 7.38-7.34 (2H, m), 7.10-7.06 (2H, m), 3.91-3.83 (2H, m), 3.83-3.75 (4H, m), 2.88 (2H, t, J = 12.3 Hz), 2.71-2.62 (4H, m), 2.52-2.42 (1H, m), 2.09-1.99 (2H, m), 1.80-1.65 (2H, m).
ESI-MS(m/z): 391[M+H]+. Add (1- (4- (4-morpholinopiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol (106 mg, 0.27 mmol) to a methylene chloride (3.0 mL) solution. -Martin periodinane (183 mg, 0.43 mmol) was dripped at 0 degreeC. After warming to room temperature and stirring for 3 hours, a saturated aqueous sodium hydrogensulfate solution was added, the organic layer was extracted by adding chloroform and a saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. . The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (106 mg, quant., 0.27 mmol). 1 H-NMR (CDCl 3 ) δ: 10.07 (1H, s), 8.22 (1H, br s), 8.02-8.01 (1H, m), 7.98-7.96 (1H, m), 7.88-7.85 (1H, m ), 7.38-7.34 (2H, m), 7.10-7.06 (2H, m), 3.91-3.83 (2H, m), 3.83-3.75 (4H, m), 2.88 (2H, t, J = 12.3 Hz), 2.71-2.62 (4H, m), 2.52-2.42 (1H, m), 2.09-1.99 (2H, m), 1.80-1.65 (2H, m).
ESI-MS (m / z): 391 [M + H] + .

工程４
5-((1-(4-(4-モルフォリノピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物３５) Process 4
5-((1- (4- (4-morpholinopiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 35 )

Figure JPOXMLDOC01-appb-C000155
Figure JPOXMLDOC01-appb-C000155

　1-(4-(4-モルフォリノピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (53 mg, 0.14 mmol) をエタノール (6.0 mL)、テトラヒドロフラン (1.5 mL) に溶かし、ロダニン (18 mg, 0.14 mmol) およびピペリジン (2.7 μL, 0.027 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (31 mg, 44 %, 0.061 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.57 (1H, s), 8.32 (1H, s), 7.85 (1H, d, J = 8.5 Hz), 7.72 (1H, s), 7.59 (1H, s), 7.53 (2H, d, J = 9.0 Hz), 7.50 (1H, d, J = 8.5 Hz), 7.20 (2H, d, J = 9.0 Hz), 4.01-3.90 (2H, m), 3.78-3.63 (4H, m), 2.95-2.72 (7H, m), 2.08-1.95 (2H, m), 1.69-1.54 (2H, m).
ESI-MS(m/z): 506[M+H]+. 1- (4- (4-morpholinopiperidin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (53 mg, 0.14 mmol) in ethanol (6.0 mL), tetrahydrofuran (1.5 mL) Then, rhodanine (18 mg, 0.14 mmol) and piperidine (2.7 μL, 0.027 mmol) were added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (31 mg, 44%, 0.061 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.57 (1H, s), 8.32 (1H, s), 7.85 (1H, d, J = 8.5 Hz), 7.72 (1H, s), 7.59 ( 1H, s), 7.53 (2H, d, J = 9.0 Hz), 7.50 (1H, d, J = 8.5 Hz), 7.20 (2H, d, J = 9.0 Hz), 4.01-3.90 (2H, m), 3.78-3.63 (4H, m), 2.95-2.72 (7H, m), 2.08-1.95 (2H, m), 1.69-1.54 (2H, m).
ESI-MS (m / z): 506 [M + H] + .

実施例３６
5-((1-(4-(4-モルフォリノピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物３６) Example 36
5-((1- (4- (4-morpholinopiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 36)

Figure JPOXMLDOC01-appb-C000156
Figure JPOXMLDOC01-appb-C000156

工程１
　1-(4-(4-モルフォリノピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (53 mg, 0.14 mmol) をエタノール (6.0 mL)、テトラヒドロフラン (1.5 mL) に溶かし、チアゾリジン-2,4-ジオン (16 mg, 0.14 mmol) およびピペリジン (2.7 μL, 0.027 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (68 mg, quant., 0.14 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.59 (1H, br s), 8.32 (1H, br s), 7.88-7.86 (2H, br m), 7.78 (1H, br s), 7.53-7.49 (2H, m), 7.18 (2H, d, J = 9.0 Hz), 3.89-3.87 (2H, m), 3.61 (4H, d, J = 4.1 Hz), 2.79 (2H, t, J = 11.5 Hz), 2.59 (4H, d, J = 4.1 Hz), 2.48-2.40 (1H, m), 1.97-1.88 (2H, m), 1.60-1.47 (2H, m).
ESI-MS(m/z): 490[M+H]+. Process 1
1- (4- (4-morpholinopiperidin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (53 mg, 0.14 mmol) in ethanol (6.0 mL), tetrahydrofuran (1.5 mL) And thiazolidine-2,4-dione (16 mg, 0.14 mmol) and piperidine (2.7 μL, 0.027 mmol) were added and stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (68 mg, quant., 0.14 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.59 (1H, br s), 8.32 (1H, br s), 7.88-7.86 (2H, br m), 7.78 (1H, br s), 7.53 -7.49 (2H, m), 7.18 (2H, d, J = 9.0 Hz), 3.89-3.87 (2H, m), 3.61 (4H, d, J = 4.1 Hz), 2.79 (2H, t, J = 11.5 Hz), 2.59 (4H, d, J = 4.1 Hz), 2.48-2.40 (1H, m), 1.97-1.88 (2H, m), 1.60-1.47 (2H, m).
ESI-MS (m / z): 490 [M + H] + .

実施例３７
5-((1-(4-(4-メチル-1,4-ジアゼパン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物３７） Example 37
5-((1- (4- (4-Methyl-1,4-diazepan-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4- ON (compound 37)

工程１
メチル 1-(4-(4-メチル-1,4-ジアゼパン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 1
Methyl 1- (4- (4-methyl-1,4-diazepan-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000157
Figure JPOXMLDOC01-appb-C000157

　メチル 1-(4-ブロモフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート(300 mg, 0.91 mmol) のトルエン (7 mL) 溶液中に酢酸パラジウム (35 mg, 0.138 mmol)、rac-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル (85 mg, 0.138 mmol)、炭酸セシウム (593 mg, 1.82 mmol)、1-メチル-1,4-ジアゼパン (169 μL, 1.37 mmol) を添加した。還流条件下、一晩撹拌した後、セライトろ過し、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (98 mg, 30 %, 0.27 mmol) を得た。1H-NMR (CDCl3) δ: 8.18 (1H, br s), 8.14 (1H, s), 8.02 (1H, d, J = 8.5 Hz), 7.86 (1H, d, J = 8.5 Hz), 7.31 (2H, d, J = 7.0 Hz), 6.82 (2H, d, J = 7.0 Hz), 3.92 (3H, s), 3.68-3.66 (2H, br m), 3.57 (2H, t, J = 6.2 Hz), 2.79 (2H, br s), 2.65 (2H, br s), 2.44 (3H, s), 2.10-2.10 (2H, m).
ESI-MS(m/z): 365[M+H]+. Palladium acetate (35 mg, 0.138 mmol), rac- in a solution of methyl 1- (4-bromophenyl) -1H-benzo [d] imidazole-6-carboxylate (300 mg, 0.91 mmol) in toluene (7 mL) 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (85 mg, 0.138 mmol), cesium carbonate (593 mg, 1.82 mmol), 1-methyl-1,4-diazepane (169 μL, 1.37 mmol) was added. The mixture was stirred overnight under reflux conditions, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (98 mg, 30%, 0.27 mmol). 1 H-NMR (CDCl 3 ) δ: 8.18 (1H, br s), 8.14 (1H, s), 8.02 (1H, d, J = 8.5 Hz), 7.86 (1H, d, J = 8.5 Hz), 7.31 (2H, d, J = 7.0 Hz), 6.82 (2H, d, J = 7.0 Hz), 3.92 (3H, s), 3.68-3.66 (2H, br m), 3.57 (2H, t, J = 6.2 Hz ), 2.79 (2H, br s), 2.65 (2H, br s), 2.44 (3H, s), 2.10-2.10 (2H, m).
ESI-MS (m / z): 365 [M + H] + .

工程２
1-(4-(4-メチル-1,4-ジアゼパン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール Process 2
1- (4- (4-Methyl-1,4-diazepan-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol

Figure JPOXMLDOC01-appb-C000158
Figure JPOXMLDOC01-appb-C000158

　メチル 1-(4-(4-メチル-1,4-ジアゼパン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート(98 mg, 0.27 mmol) のテトラヒドロフラン (3 mL) 溶液中に、水素化アルミニウムリチウムのテトラヒドロフラン溶液 (1.0 M, 0.8 mL, 0.8 mmol) をアルゴン雰囲気下-78 ℃で添加した。0 ℃に昇温しながら4時間撹拌した後、飽和酒石酸ナトリウムカリウム水溶液を加え、クロロホルムと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記化合物 (91 mg, quant., 0.27 mmol) を得た。1H-NMR (CDCl3) δ: 8.00 (1H, s), 7.94 (1H, s), 7.80 (1H, d, J = 8.3 Hz), 7.71 (1H, d, J = 8.3 Hz), 7.32-7.28 (2H, m), 6.82-6.76 (2H, m), 4.80 (2H, s), 3.68-3.62 (2H, m), 3.59-3.51 (2H, m), 2.83-2.75 (2H, m), 2.70-2.62 (2H, m), 2.43 (3H, s), 2.14-2.06 (2H, m).
ESI-MS(m/z): 337[M+H]+. Methyl 1- (4- (4-methyl-1,4-diazepan-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate (98 mg, 0.27 mmol) in tetrahydrofuran (3 mL) A solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 0.8 mL, 0.8 mmol) was added at −78 ° C. under an argon atmosphere. After stirring for 4 hours while raising the temperature to 0 ° C., saturated aqueous sodium potassium tartrate solution was added, chloroform and saturated brine were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The title compound (91 mg, quant., 0.27 mmol) was obtained. 1 H-NMR (CDCl 3 ) δ: 8.00 (1H, s), 7.94 (1H, s), 7.80 (1H, d, J = 8.3 Hz), 7.71 (1H, d, J = 8.3 Hz), 7.32- 7.28 (2H, m), 6.82-6.76 (2H, m), 4.80 (2H, s), 3.68-3.62 (2H, m), 3.59-3.51 (2H, m), 2.83-2.75 (2H, m), 2.70-2.62 (2H, m), 2.43 (3H, s), 2.14-2.06 (2H, m).
ESI-MS (m / z): 337 [M + H] + .

工程３
1-(4-(4-メチル-1,4-ジアゼパン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Process 3
1- (4- (4-Methyl-1,4-diazepan-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000159
Figure JPOXMLDOC01-appb-C000159

　(1-(4-(4-メチル-1,4-ジアゼパン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール (91 mg, 0.27 mmol) の塩化メチレン (3.0 mL) 溶液にデス・マーチン・ペルヨージナン (183 mg, 0.43 mmol) を0℃で滴下した。室温に昇温し3時間撹拌した後、飽和チオ硫酸水素ナトリウム水溶液を添加し、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (60 mg, 67 %, 0.18 mmol) を得た。1H-NMR (CDCl3) δ: 9.99 (1H, s), 8.13 (1H, s), 7.93 (1H, s), 7.91-7.87 (1H, m), 7.82-7.76 (1H, m), 7.28-7.22 (2H, m), 6.78-6.74 (2H, m), 3.71-3.62 (2H, m), 3.55-3.46 (2H, m), 2.91-2.80 (2H, m), 2.75-2.66 (2H, m), 2.46 (3H, s), 2.16-2.06 (2H, m).
ESI-MS(m/z): 335[M+H]+. (1- (4- (4-Methyl-1,4-diazepan-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol (91 mg, 0.27 mmol) in methylene chloride (3.0 mL ) Dess-Martin periodinane (183 mg, 0.43 mmol) was added dropwise to the solution at 0 ° C. After warming to room temperature and stirring for 3 hours, a saturated aqueous sodium hydrogensulfate solution was added, the organic layer was extracted by adding chloroform and a saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. . The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (60 mg, 67%, 0.18 mmol). 1 H-NMR (CDCl 3 ) δ: 9.99 (1H, s), 8.13 (1H, s), 7.93 (1H, s), 7.91-7.87 (1H, m), 7.82-7.76 (1H, m), 7.28 -7.22 (2H, m), 6.78-6.74 (2H, m), 3.71-3.62 (2H, m), 3.55-3.46 (2H, m), 2.91-2.80 (2H, m), 2.75-2.66 (2H, m), 2.46 (3H, s), 2.16-2.06 (2H, m).
ESI-MS (m / z): 335 [M + H] + .

工程４
5-((1-(4-(4-メチル-1,4-ジアゼパン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物３７)  Process 4
5-((1- (4- (4-Methyl-1,4-diazepan-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4- ON (compound 37)

Figure JPOXMLDOC01-appb-C000160
Figure JPOXMLDOC01-appb-C000160

　1-(4-(4-メチル-1,4-ジアゼパン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (30 mg, 0.09 mmol) をエタノール (2.0 mL)、テトラヒドロフラン (1.0 mL) に溶かし、ロダニン (12 mg, 0.09 mmol) およびピペリジン (0.9 μL, 0.009 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (2 mg, 5 %, 0.004 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.48 (1H, s), 7.80 (1H, d, J = 8.3 Hz), 7.60 (1H, s), 7.50 (2H, d, J = 9.0 Hz), 7.46 (1H, d, J = 8.3 Hz), 7.34 (1H, s), 7.00 (2H, d, J = 9.0 Hz), 3.81-3.70 (2H, m), 3.58-3.48 (2H, m), 2.80-2.71 (2H, m), 2.70-2.63 (2H, m), 2.42 (3H, s), 2.18-2.09 (2H, m).
ESI-MS(m/z): 450[M+H]+. 1- (4- (4-Methyl-1,4-diazepan-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (30 mg, 0.09 mmol) in ethanol (2.0 mL), tetrahydrofuran (1.0 mL) was dissolved, rhodanine (12 mg, 0.09 mmol) and piperidine (0.9 μL, 0.009 mmol) were added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (2 mg, 5%, 0.004 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.48 (1H, s), 7.80 (1H, d, J = 8.3 Hz), 7.60 (1H, s), 7.50 (2H, d, J = 9.0 Hz), 7.46 (1H, d, J = 8.3 Hz), 7.34 (1H, s), 7.00 (2H, d, J = 9.0 Hz), 3.81-3.70 (2H, m), 3.58-3.48 (2H, m ), 2.80-2.71 (2H, m), 2.70-2.63 (2H, m), 2.42 (3H, s), 2.18-2.09 (2H, m).
ESI-MS (m / z): 450 [M + H] + .

実施例３８
5-((1-(4-(4-メチル-1,4-ジアゼパン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物３８) Example 38
5-((1- (4- (4-Methyl-1,4-diazepan-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (compound 38)

Figure JPOXMLDOC01-appb-C000161
Figure JPOXMLDOC01-appb-C000161

工程１
　1-(4-(4-メチル-1,4-ジアゼパン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (30 mg, 0.09 mmol) をエタノール (2.0 mL)、テトラヒドロフラン (1.0 mL) に溶かし、チアゾリジン-2,4-ジオン (11 mg, 0.09 mmol) およびピペリジン (0.9 μL, 0.009 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (4 mg, 10 %, 0.009 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.51 (1H, s), 7.81 (1H, d, J = 8.8 Hz), 7.72 (1H, s), 7.66 (1H, s), 7.48 (3H, d, J = 8.8 Hz), 6.97 (2H, d, J = 8.8 Hz), 3.72-3.71 (2H, m), 3.53-3.52 (2H, m), 3.10-3.03 (2H, m), 3.00-2.92 (2H, m), 2.60 (3H, s), 2.09-2.08 (2H, m). 
ESI-MS(m/z): 434[M+H]+. Process 1
1- (4- (4-Methyl-1,4-diazepan-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (30 mg, 0.09 mmol) in ethanol (2.0 mL), tetrahydrofuran (1.0 mL), thiazolidine-2,4-dione (11 mg, 0.09 mmol) and piperidine (0.9 μL, 0.009 mmol) were added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (4 mg, 10%, 0.009 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.51 (1H, s), 7.81 (1H, d, J = 8.8 Hz), 7.72 (1H, s), 7.66 (1H, s), 7.48 ( 3H, d, J = 8.8 Hz), 6.97 (2H, d, J = 8.8 Hz), 3.72-3.71 (2H, m), 3.53-3.52 (2H, m), 3.10-3.03 (2H, m), 3.00 -2.92 (2H, m), 2.60 (3H, s), 2.09-2.08 (2H, m).
ESI-MS (m / z): 434 [M + H] + .

実施例３９
5-((1-(4-((2-(ジメチルアミノ)エチル)(メチル)アミノ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物３９)  Example 39
5-((1- (4-((2- (dimethylamino) ethyl) (methyl) amino) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4- ON (compound 39)

工程１
メチル 1-(4-((2-(ジメチルアミノ)エチル)(メチル)アミノ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 1
Methyl 1- (4-((2- (dimethylamino) ethyl) (methyl) amino) phenyl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000162
Figure JPOXMLDOC01-appb-C000162

　メチル 1-(4-ブロモフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート(300 mg, 0.91 mmol) のトルエン (7 mL) 溶液中に酢酸パラジウム (31 mg, 0.137 mmol)、rac-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル (85 mg, 0.137 mmol)、炭酸セシウム (889 mg, 2.73 mmol)、N1,N1,N2-トリメチルメタン-1,2-ジアミン (235 μL, 1.82 mmol) を添加した。還流条件下、一晩撹拌した後、セライトろ過し、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (64 mg, 20 %, 0.18 mmol) を得た。1H-NMR (CDCl3) δ: 8.20-8.17 (1H, m), 8.15 (1H, s), 8.02 (1H, d, J = 8.5 Hz), 7.87 (1H, d, J = 8.5 Hz), 7.32 (2H, d, J = 8.5 Hz), 6.83 (2H, d, J = 8.8 Hz), 3.92 (3H, s), 3.55 (2H, t, J = 7.4 Hz), 3.06 (3H, s), 2.55 (2H, t, J = 7.4 Hz), 2.34 (6H, s).
ESI-MS(m/z): 353[M+H]+. Palladium acetate (31 mg, 0.137 mmol), rac- in a solution of methyl 1- (4-bromophenyl) -1H-benzo [d] imidazole-6-carboxylate (300 mg, 0.91 mmol) in toluene (7 mL) 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (85 mg, 0.137 mmol), cesium carbonate (889 mg, 2.73 mmol), N 1 , N 1 , N 2 -trimethylmethane-1, 2-Diamine (235 μL, 1.82 mmol) was added. The mixture was stirred overnight under reflux conditions, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (64 mg, 20%, 0.18 mmol). 1 H-NMR (CDCl 3 ) δ: 8.20-8.17 (1H, m), 8.15 (1H, s), 8.02 (1H, d, J = 8.5 Hz), 7.87 (1H, d, J = 8.5 Hz), 7.32 (2H, d, J = 8.5 Hz), 6.83 (2H, d, J = 8.8 Hz), 3.92 (3H, s), 3.55 (2H, t, J = 7.4 Hz), 3.06 (3H, s), 2.55 (2H, t, J = 7.4 Hz), 2.34 (6H, s).
ESI-MS (m / z): 353 [M + H] + .

工程２
(1-(4-((2-(ジメチルアミノ)エチル)(メチル)アミノ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール Process 2
(1- (4-((2- (Dimethylamino) ethyl) (methyl) amino) phenyl) -1H-benzo [d] imidazol-6-yl) methanol

Figure JPOXMLDOC01-appb-C000163
Figure JPOXMLDOC01-appb-C000163

　メチル 1-(4-((2-(ジメチルアミノ)エチル)(メチル)アミノ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート (64 mg, 0.18 mmol) のテトラヒドロフラン (2 mL) 溶液中に、水素化アルミニウムリチウムのテトラヒドロフラン溶液 (1.0 M, 0.55 mL, 0.55 mmol) をアルゴン雰囲気下-78 ℃で添加した。0 ℃に昇温し、5時間撹拌した後、飽和酒石酸ナトリウムカリウム水溶液を加え、クロロホルムと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記化合物 (59 mg, quant., 0.18 mmol) を得た。1H-NMR (CDCl3) δ: 7.89 (1H, s), 7.69 (1H, d, J = 8.1 Hz), 7.41 (1H, s), 7.21 (1H, d, J = 8.1 Hz), 7.14 (2H, d, J = 9.0 Hz), 6.67 (2H, d, J = 9.0 Hz), 4.72 (2H, s), 3.42 (2H, t, J = 7.4 Hz), 2.93 (3H, s), 2.43 (2H, t, J = 7.4 Hz), 2.23 (6H, s).
ESI-MS(m/z): 325[M+H]+. Methyl 1- (4-((2- (dimethylamino) ethyl) (methyl) amino) phenyl) -1H-benzo [d] imidazole-6-carboxylate (64 mg, 0.18 mmol) in tetrahydrofuran (2 mL) A solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 0.55 mL, 0.55 mmol) was added at −78 ° C. under an argon atmosphere. After heating to 0 ° C. and stirring for 5 hours, a saturated aqueous sodium potassium tartrate solution was added, chloroform and saturated brine were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The title compound (59 mg, quant., 0.18 mmol) was obtained. 1 H-NMR (CDCl 3 ) δ: 7.89 (1H, s), 7.69 (1H, d, J = 8.1 Hz), 7.41 (1H, s), 7.21 (1H, d, J = 8.1 Hz), 7.14 ( 2H, d, J = 9.0 Hz), 6.67 (2H, d, J = 9.0 Hz), 4.72 (2H, s), 3.42 (2H, t, J = 7.4 Hz), 2.93 (3H, s), 2.43 ( 2H, t, J = 7.4 Hz), 2.23 (6H, s).
ESI-MS (m / z): 325 [M + H] + .

工程３
1-(4-((2-(ジメチルアミノ)エチル)(メチル)アミノ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Process 3
1- (4-((2- (Dimethylamino) ethyl) (methyl) amino) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000164
Figure JPOXMLDOC01-appb-C000164

　(1-(4-((2-(ジメチルアミノ)エチル)(メチル)アミノ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール (59 mg, 0.18 mmol) の塩化メチレン (1.0 mL) 溶液にデス・マーチン・ペルヨージナン (85 mg, 0.20 mmol) を0℃で滴下した。室温に昇温し2時間撹拌した後、飽和チオ硫酸水素ナトリウム水溶液を添加し、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (58 mg, quant., 0.18 mmol) を得た。白色固体: 1H-NMR (CDCl3) δ: 10.06 (1H, s), 8.22 (1H, s), 8.02-7.94 (2H, m), 7.90-7.80 (1H, m), 7.33 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz), 3.80 (2H, t, J = 7.6 Hz), 3.09 (3H, s), 2.91 (2H, t, J = 7.6 Hz), 2.63 (6H, s).
ESI-MS(m/z): 323[M+H]+. (1- (4-((2- (Dimethylamino) ethyl) (methyl) amino) phenyl) -1H-benzo [d] imidazol-6-yl) methanol (59 mg, 0.18 mmol) in methylene chloride (1.0 mL ) Dess-Martin periodinane (85 mg, 0.20 mmol) was added dropwise to the solution at 0 ° C. After warming to room temperature and stirring for 2 hours, a saturated aqueous solution of sodium hydrogenthiosulfate was added, the organic layer was extracted by adding chloroform and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. . The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (58 mg, quant., 0.18 mmol). White solid: 1 H-NMR (CDCl 3 ) δ: 10.06 (1H, s), 8.22 (1H, s), 8.02-7.94 (2H, m), 7.90-7.80 (1H, m), 7.33 (2H, d , J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz), 3.80 (2H, t, J = 7.6 Hz), 3.09 (3H, s), 2.91 (2H, t, J = 7.6 Hz), 2.63 (6H, s).
ESI-MS (m / z): 323 [M + H] + .

工程４
5-((1-(4-((2-(ジメチルアミノ)エチル)(メチル)アミノ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物３９) Process 4
5-((1- (4-((2- (dimethylamino) ethyl) (methyl) amino) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4- ON (compound 39)

Figure JPOXMLDOC01-appb-C000165
Figure JPOXMLDOC01-appb-C000165

　1-(4-((2-(ジメチルアミノ)エチル)(メチル)アミノ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (35 mg, 0.11 mmol) をエタノール (1.0 mL)、テトラヒドロフラン (2.0 mL) に溶かし、ロダニン (14 mg, 0.11 mmol) およびピペリジン (1.08 μL, 0.01 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (9 mg, 19 %, 0.021 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.50 (1H, s), 7.81 (1H, d, J = 8.5 Hz), 7.61 (1H, s), 7.51 (2H, d, J = 8.8 Hz), 7.47 (1H, d, J = 8.5 Hz), 7.37 (1H, s), 7.02 (2H, d, J = 8.8 Hz), 3.73 (2H, t, J = 7.1 Hz), 3.16 (2H, t, J = 7.1 Hz), 3.02 (3H, s), 2.77 (6H, s). 
ESI-MS(m/z): 438[M+H]+. 1- (4-((2- (dimethylamino) ethyl) (methyl) amino) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (35 mg, 0.11 mmol) was added to ethanol (1.0 mL), tetrahydrofuran Dissolved in (2.0 mL), rhodanine (14 mg, 0.11 mmol) and piperidine (1.08 μL, 0.01 mmol) were added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (9 mg, 19%, 0.021 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.50 (1H, s), 7.81 (1H, d, J = 8.5 Hz), 7.61 (1H, s), 7.51 (2H, d, J = 8.8 Hz), 7.47 (1H, d, J = 8.5 Hz), 7.37 (1H, s), 7.02 (2H, d, J = 8.8 Hz), 3.73 (2H, t, J = 7.1 Hz), 3.16 (2H, t, J = 7.1 Hz), 3.02 (3H, s), 2.77 (6H, s).
ESI-MS (m / z): 438 [M + H] + .

実施例４０
5-((1-(4-((2-(ジメチルアミノ)エチル)(メチル)アミノ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物４０)  Example 40
5-((1- (4-((2- (dimethylamino) ethyl) (methyl) amino) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (compound 40)

Figure JPOXMLDOC01-appb-C000166
Figure JPOXMLDOC01-appb-C000166

工程１
　1-(4-((2-(ジメチルアミノ)エチル)(メチル)アミノ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (35 mg, 0.11 mmol) をエタノール (1.0 mL)、テトラヒドロフラン (2.0 mL) に溶かし、チアゾリジン-2,4-ジオン (13 mg, 0.11 mmol) およびピペリジン (1.08 μL, 0.01 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (6 mg, 13 %, 0.014 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.52 (1H, s), 7.82 (1H, d, J = 8.8 Hz), 7.72 (1H, s), 7.68 (1H, s), 7.49 (3H, d, J = 8.8 Hz), 6.96 (2H, d, J = 8.8 Hz), 3.64 (2H, t, J = 7.0 Hz), 3.01 (3H, s), 2.85 (2H, t, J = 7.0 Hz), 2.53 (6H, s).
ESI-MS(m/z): 422[M+H]+. Process 1
1- (4-((2- (dimethylamino) ethyl) (methyl) amino) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (35 mg, 0.11 mmol) was added to ethanol (1.0 mL), tetrahydrofuran (2.0 mL), thiazolidine-2,4-dione (13 mg, 0.11 mmol) and piperidine (1.08 μL, 0.01 mmol) were added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (6 mg, 13%, 0.014 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.52 (1H, s), 7.82 (1H, d, J = 8.8 Hz), 7.72 (1H, s), 7.68 (1H, s), 7.49 ( 3H, d, J = 8.8 Hz), 6.96 (2H, d, J = 8.8 Hz), 3.64 (2H, t, J = 7.0 Hz), 3.01 (3H, s), 2.85 (2H, t, J = 7.0 Hz), 2.53 (6H, s).
ESI-MS (m / z): 422 [M + H] + .

実施例４１
5-((1-(3-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物４１) Example 41
5-((1- (3- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4- ON (compound 41)

工程１
メチル 3-((3-ブロモフェニル)アミノ)-4-ニトロベンゾエート Process 1
Methyl 3-((3-bromophenyl) amino) -4-nitrobenzoate

Figure JPOXMLDOC01-appb-C000167
Figure JPOXMLDOC01-appb-C000167

　メチル 3-フルオロ-4-ニトロベンゾエート(3.98 g, 20 mmol) のN,N-ジメチルホルムアミド (20 mL) 溶媒中に、3-ブロモアニリン (1.9 mL, 18 mmol)、およびN-エチル-N-イソプロピルプロパン-2-アミン(6.8 mL, 40 mmol) を添加した。100 ℃で2日間撹拌し、氷冷した後、生成する沈殿物をろ過し、ヘキサンで洗浄した。標記化合物 (2.50 g, 36 %, 7.1 mmol) を得た。赤褐色固体: 1H-NMR (CDCl3) δ: 9.39 (1H, s), 8.26 (1H, d, J = 8.8 Hz), 7.92 (1H, d, J = 1.7 Hz), 7.48-7.37 (3H, m), 7.31 (1H, t, J = 7.9 Hz), 7.26-7.22 (1H, m), 3.91 (3H, s).
ESI-MS(m/z): 351[M+H]+. Methyl 3-fluoro-4-nitrobenzoate (3.98 g, 20 mmol) in N, N-dimethylformamide (20 mL) in a solvent, 3-bromoaniline (1.9 mL, 18 mmol), and N-ethyl-N- Isopropylpropan-2-amine (6.8 mL, 40 mmol) was added. After stirring at 100 ° C. for 2 days and cooling with ice, the resulting precipitate was filtered and washed with hexane. The title compound (2.50 g, 36%, 7.1 mmol) was obtained. Reddish brown solid: 1 H-NMR (CDCl 3 ) δ: 9.39 (1H, s), 8.26 (1H, d, J = 8.8 Hz), 7.92 (1H, d, J = 1.7 Hz), 7.48-7.37 (3H, m), 7.31 (1H, t, J = 7.9 Hz), 7.26-7.22 (1H, m), 3.91 (3H, s).
ESI-MS (m / z): 351 [M + H] + .

工程２
メチル 4-アミノ-3-((3-ブロモフェニル)アミノ)ベンゾエート Process 2
Methyl 4-amino-3-((3-bromophenyl) amino) benzoate

Figure JPOXMLDOC01-appb-C000168
Figure JPOXMLDOC01-appb-C000168

　メチル 3-((3-ブロモフェニル)アミノ)-4-ニトロベンゾエート (2.5 g, 7.1 mmol) の酢酸エチル溶液中 (35 mL) に、臭化亜鉛 (321 mg, 1.4 mmol)、および5 % プラチナ－活性炭 (100 mg) をアルゴン雰囲気下0 ℃で添加した。水素置換した後、室温に昇温し5時間撹拌した。さらに臭化亜鉛 (321 mg, 1.4 mmol)、および5 % プラチナ－活性炭 (100 mg) を添加し、一晩撹拌した。反応終了後、セライトろ過し減圧下濃縮した。標記化合物 (1.47 g, 4.58 mmol, 65 %) を得た。1H-NMR (CDCl3) δ: 7.79 (1H, s), 7.04 (1H, t, J = 7.9 Hz), 7.00 (1H, t, J = 7.9 Hz), 6.96-6.92 (1H, m), 6.88-6.85 (1H, m), 6.83-6.83 (1H, br m), 6.78 (1H, br s), 6.59 (2H, br s), 5.30-5.16 (1H, m), 3.84 (3H, s).
ESI-MS(m/z): 321[M+H]+. Methyl 3-((3-bromophenyl) amino) -4-nitrobenzoate (2.5 g, 7.1 mmol) in ethyl acetate (35 mL), zinc bromide (321 mg, 1.4 mmol), and 5% platinum Activated carbon (100 mg) was added at 0 ° C. under an argon atmosphere. After purging with hydrogen, the mixture was warmed to room temperature and stirred for 5 hours. Further, zinc bromide (321 mg, 1.4 mmol) and 5% platinum-activated carbon (100 mg) were added and stirred overnight. After completion of the reaction, the mixture was filtered through celite and concentrated under reduced pressure. The title compound (1.47 g, 4.58 mmol, 65%) was obtained. 1 H-NMR (CDCl 3 ) δ: 7.79 (1H, s), 7.04 (1H, t, J = 7.9 Hz), 7.00 (1H, t, J = 7.9 Hz), 6.96-6.92 (1H, m), 6.88-6.85 (1H, m), 6.83-6.83 (1H, br m), 6.78 (1H, br s), 6.59 (2H, br s), 5.30-5.16 (1H, m), 3.84 (3H, s) .
ESI-MS (m / z): 321 [M + H] + .

工程３
メチル 1-(3-ブロモフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 3
Methyl 1- (3-bromophenyl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000169
Figure JPOXMLDOC01-appb-C000169

　メチル 4-アミノ-3-((3-ブロモフェニル)アミノ)ベンゾエート (1.47 g, 4.58 mmol) のテトラヒドロフラン (20 mL) 溶液中に、オルトギ酸トリエチル (1.14 mL, 6.87 mmol)、およびパラトシル酸一水和物 (44 mg, 0.23mmol) を添加した、還流条件下3時間撹拌した後、飽和炭酸水素ナトリウム水溶液を添加し、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (967 mg, 64 %, 2.92 mmol) を得た。黄白色固体: 1H-NMR (CDCl3) δ: 8.24-8.23 (1H, m), 8.22 (1H, s), 8.07 (1H, d, J = 8.5 Hz), 7.90 (1H, d, J = 8.5 Hz), 7.71-7.68 (1H, m), 7.68-7.64 (1H, m), 7.52-7.49 (2H, m), 3.95 (3H, s).
ESI-MS(m/z): 331[M+H]+. In a solution of methyl 4-amino-3-((3-bromophenyl) amino) benzoate (1.47 g, 4.58 mmol) in tetrahydrofuran (20 mL), triethyl orthoformate (1.14 mL, 6.87 mmol), and monosodium paratosylate The mixture was stirred under reflux conditions for 3 hours after addition of a hydrate (44 mg, 0.23 mmol), saturated aqueous sodium hydrogen carbonate solution was added, ethyl acetate and saturated brine were added, and the organic layer was extracted with anhydrous sodium sulfate. It was dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (967 mg, 64%, 2.92 mmol). Yellowish white solid: 1 H-NMR (CDCl 3 ) δ: 8.24-8.23 (1H, m), 8.22 (1H, s), 8.07 (1H, d, J = 8.5 Hz), 7.90 (1H, d, J = 8.5 Hz), 7.71-7.68 (1H, m), 7.68-7.64 (1H, m), 7.52-7.49 (2H, m), 3.95 (3H, s).
ESI-MS (m / z): 331 [M + H] + .

工程４
メチル 1-(3-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 4
Methyl 1- (3- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000170
Figure JPOXMLDOC01-appb-C000170

　メチル 1-(3-ブロモフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート(300 mg, 0.91 mmol) のトルエン (7 mL) 溶液中に酢酸パラジウム (10 mg, 0.045 mmol)、rac-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル (85 mg, 0.136 mmol)、炭酸セシウム (593 mg, 1.82 mmol)、1-(2-メトキシエチル)ピペラジン (202 μL, 1.36 mmol) を添加した。還流条件下、一晩撹拌した後、セライトろ過し、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (359 mg, quant., 0.91 mmol) を得た1H-NMR (CDCl3) δ: 8.18 (1H, s), 8.14 (1H, s), 7.96 (1H, d, J = 8.5 Hz), 7.79 (1H, d, J = 8.5 Hz), 7.38-7.34 (1H, m), 6.94 (1H, d, J = 8.3 Hz), 6.87-6.86 (2H, m), 3.85 (3H, s), 3.48 (2H, t, J = 5.4 Hz), 3.29 (3H, s), 3.26-3.24 (4H, m), 2.62-2.59 (4H, m), 2.57 (2H, t, J = 5.4 Hz).
ESI-MS(m/z): 395[M+H]+. Palladium acetate (10 mg, 0.045 mmol), rac- in a solution of methyl 1- (3-bromophenyl) -1H-benzo [d] imidazole-6-carboxylate (300 mg, 0.91 mmol) in toluene (7 mL) 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (85 mg, 0.136 mmol), cesium carbonate (593 mg, 1.82 mmol), 1- (2-methoxyethyl) piperazine (202 μL, 1.36 mmol) was added. The mixture was stirred overnight under reflux conditions, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (359 mg, quant., 0.91 mmol) 1 H-NMR (CDCl 3 ) δ: 8.18 (1H, s), 8.14 (1H, s), 7.96 (1H, d, J = 8.5 Hz), 7.79 (1H, d, J = 8.5 Hz), 7.38-7.34 (1H, m), 6.94 (1H, d, J = 8.3 Hz) , 6.87-6.86 (2H, m), 3.85 (3H, s), 3.48 (2H, t, J = 5.4 Hz), 3.29 (3H, s), 3.26-3.24 (4H, m), 2.62-2.59 (4H , m), 2.57 (2H, t, J = 5.4 Hz).
ESI-MS (m / z): 395 [M + H] + .

工程５
(1-(3-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール Process 5
(1- (3- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol

Figure JPOXMLDOC01-appb-C000171
Figure JPOXMLDOC01-appb-C000171

　メチル 1-(3-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート(410 mg, 1.04 mmol) のテトラヒドロフラン (7 mL) 溶液中に、水素化アルミニウムリチウムのテトラヒドロフラン溶液 (1.0 M, 3.1 mL, 3.1 mmol) をアルゴン雰囲気下-78 ℃で添加した。0 ℃に昇温しながら5時間撹拌した後、飽和酒石酸ナトリウムカリウム水溶液を加え、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記化合物 (52 mg, 14 %, 0.14 mmol) を得た。1H-NMR (CDCl3) δ: 7.99 (1H, s), 7.73 (1H, d, J = 8.3 Hz), 7.52 (1H, s), 7.38-7.29 (1H, m), 7.25 (1H, d, J = 8.3 Hz), 6.95-6.81 (3H, m), 4.76 (2H, s), 3.57-3.51 (2H, m), 3.33 (3H, s), 3.28-3.21 (4H, m), 2.75-2.53 (6H, m).
ESI-MS(m/z): 367[M+H]+. Methyl 1- (3- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate (410 mg, 1.04 mmol) in tetrahydrofuran (7 mL) Inside, a solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 3.1 mL, 3.1 mmol) was added at −78 ° C. under an argon atmosphere. After stirring for 5 hours while raising the temperature to 0 ° C., saturated aqueous sodium potassium tartrate solution was added, ethyl acetate and saturated brine were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The title compound (52 mg, 14%, 0.14 mmol) was obtained. 1 H-NMR (CDCl 3 ) δ: 7.99 (1H, s), 7.73 (1H, d, J = 8.3 Hz), 7.52 (1H, s), 7.38-7.29 (1H, m), 7.25 (1H, d , J = 8.3 Hz), 6.95-6.81 (3H, m), 4.76 (2H, s), 3.57-3.51 (2H, m), 3.33 (3H, s), 3.28-3.21 (4H, m), 2.75- 2.53 (6H, m).
ESI-MS (m / z): 367 [M + H] + .

工程６
1-(3-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Step 6
1- (3- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000172
Figure JPOXMLDOC01-appb-C000172

　(1-(3-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール (52 mg, 0.14 mmol) の塩化メチレン (1.0 mL) 溶液に デス・マーチン・ペルヨージナン (90 mg, 0.21 mmol) を0 ℃で滴下した。室温に昇温し1時間撹拌した後、飽和チオ硫酸水素ナトリウム水溶液を添加し、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (38 mg, 74 %, 0.10 mmol) を得た。1H-NMR (CDCl3) δ: 10.08 (1H, s), 8.28 (1H, s), 8.08 (1H, s), 7.98 (1H, d, J = 8.5 Hz), 7.88 (1H, d, J = 8.5 Hz), 7.46 (1H, t, J = 7.7 Hz), 7.04 (1H, d, J = 7.7 Hz), 6.96 (1H, s), 6.96 (1H, d, J = 7.7 Hz), 3.58 (2H, t, J = 5.4 Hz), 3.38 (3H, s), 3.37-3.32 (4H, m), 2.78-2.61 (6H, m).
ESI-MS(m/z): 365[M+H]+. (1- (3- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol (52 mg, 0.14 mmol) in methylene chloride (1.0 mL ) Dess-Martin periodinane (90 mg, 0.21 mmol) was added dropwise to the solution at 0 ° C. After warming to room temperature and stirring for 1 hour, saturated aqueous sodium hydrogenthiosulfate solution was added, the organic layer was extracted by adding chloroform and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure . The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (38 mg, 74%, 0.10 mmol). 1 H-NMR (CDCl 3 ) δ: 10.08 (1H, s), 8.28 (1H, s), 8.08 (1H, s), 7.98 (1H, d, J = 8.5 Hz), 7.88 (1H, d, J = 8.5 Hz), 7.46 (1H, t, J = 7.7 Hz), 7.04 (1H, d, J = 7.7 Hz), 6.96 (1H, s), 6.96 (1H, d, J = 7.7 Hz), 3.58 ( 2H, t, J = 5.4 Hz), 3.38 (3H, s), 3.37-3.32 (4H, m), 2.78-2.61 (6H, m).
ESI-MS (m / z): 365 [M + H] + .

工程７
5-((1-(3-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物４１)  Step 7
5-((1- (3- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4- ON (compound 41)

Figure JPOXMLDOC01-appb-C000173
Figure JPOXMLDOC01-appb-C000173

　1-(3-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (19 mg, 0.05 mmol) をエタノール (1.0 mL) に溶かし、ロダニン (7 mg, 0.05 mmol) およびピペリジン (1.0 μL, 0.01 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (17 mg, 68 %, 0.035 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.68 (1H, s), 7.86 (1H, d, J = 8.3 Hz), 7.81 (1H, s), 7.59 (1H, s), 7.56-7.47 (2H, m), 7.29 (1H, s), 7.12-7.10 (2H, m), 3.60 (2H, t, J = 5.2 Hz), 3.50-3.44 (4H, m), 3.30 (3H, s), 3.08-2.95 (6H, m). 
ESI-MS(m/z): 480[M+H]+. 1- (3- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (19 mg, 0.05 mmol) was dissolved in ethanol (1.0 mL). , Rhodanine (7 mg, 0.05 mmol) and piperidine (1.0 μL, 0.01 mmol) were added and stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (17 mg, 68%, 0.035 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.68 (1H, s), 7.86 (1H, d, J = 8.3 Hz), 7.81 (1H, s), 7.59 (1H, s), 7.56- 7.47 (2H, m), 7.29 (1H, s), 7.12-7.10 (2H, m), 3.60 (2H, t, J = 5.2 Hz), 3.50-3.44 (4H, m), 3.30 (3H, s) , 3.08-2.95 (6H, m).
ESI-MS (m / z): 480 [M + H] + .

実施例４２
5-((1-(3-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物４２)  Example 42
5-((1- (3- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (compound 42)

Figure JPOXMLDOC01-appb-C000174
Figure JPOXMLDOC01-appb-C000174

工程１
　1-(3-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (19 mg, 0.05 mmol) をエタノール (1.0 mL) に溶かし、チアゾリジン-2,4-ジオン (6 mg, 0.05 mmol) およびピペリジン (1.0 μL, 0.01 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (4 mg, 17 %, 0.008 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.26-8.20 (1H, m), 8.00-7.92 (1H, m), 7.73-7.67 (1H, m), 7.52-7.42 (2H, m), 7.19-7.09 (1H, m), 7.06-6.90 (3H, m), 3.65-3.53 (2H, m), 3.42-3.30 (7H, m), 2.84-2.61 (6H, m).
ESI-MS(m/z): 464[M+H]+. Process 1
1- (3- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (19 mg, 0.05 mmol) was dissolved in ethanol (1.0 mL). , Thiazolidine-2,4-dione (6 mg, 0.05 mmol) and piperidine (1.0 μL, 0.01 mmol) were added and stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (4 mg, 17%, 0.008 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.26-8.20 (1H, m), 8.00-7.92 (1H, m), 7.73-7.67 (1H, m), 7.52-7.42 (2H, m) , 7.19-7.09 (1H, m), 7.06-6.90 (3H, m), 3.65-3.53 (2H, m), 3.42-3.30 (7H, m), 2.84-2.61 (6H, m).
ESI-MS (m / z): 464 [M + H] + .

実施例４３
5-((1-(6-(4-メチルピペラジン-1-イル)ピリジン-3-イル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物４３)  Example 43
5-((1- (6- (4-Methylpiperazin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (compound 43 )

工程１
tert-ブチル 4-(5-((5-(メトキシカルボニル)-2-ニトロフェニル)アミノ)ピリジン-2-イル)ピペラジン-1-カルボキシレート Process 1
tert-butyl 4- (5-((5- (methoxycarbonyl) -2-nitrophenyl) amino) pyridin-2-yl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000175
Figure JPOXMLDOC01-appb-C000175

　メチル 3-((4-ブロモフェニル)アミノ)-4-ニトロベンゾエートの合成と同様の手法で、メチル 3-フルオロ-4-ニトロベンゾエート (1.18 g, 5.9 mmol) および 6-(4-tert-ブトキシカルボニルピペラジン-1-イル)ピリジン-3-アミン (1.90 g) とから標記化合物 (2.01 g, 4.39 mmol, 74 %) を得た。1H-NMR (CDCl3) δ: 8.47(1H, s), 8.37(1H, s), 8.19-8.15(2H, m), 8.00(1H, m), 7.69(1H, m), 6.87(1H, m), 3.96(3H, s), 3.74-3.69(4H, br s), 3.66-3.62(4H, br s), 1.49 (9H, s). In a manner similar to the synthesis of methyl 3-((4-bromophenyl) amino) -4-nitrobenzoate, methyl 3-fluoro-4-nitrobenzoate (1.18 g, 5.9 mmol) and 6- (4-tert-butoxy The title compound (2.01 g, 4.39 mmol, 74%) was obtained from carbonylpiperazin-1-yl) pyridin-3-amine (1.90 g). 1 H-NMR (CDCl 3 ) δ: 8.47 (1H, s), 8.37 (1H, s), 8.19-8.15 (2H, m), 8.00 (1H, m), 7.69 (1H, m), 6.87 (1H , m), 3.96 (3H, s), 3.74-3.69 (4H, br s), 3.66-3.62 (4H, br s), 1.49 (9H, s).

工程２
メチル 1-((6-(4-tert-ブトキシカルボニル)ピペラジン-1-イル)ピリジン-3-イル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 2
Methyl 1-((6- (4-tert-butoxycarbonyl) piperazin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000176
Figure JPOXMLDOC01-appb-C000176

　N-メトキシ-N-メチル-1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド の合成と同様の手法で、tert-ブチル 4-(5-((5-(メトキシカルボニル)-2-ニトロフェニル)アミノ)ピリジン-2-イル)ピペラジン-1-カルボキシレート (2.01 g, 4.4 mmol) を用い、標記化合物 (1.69 g, 3.9 mmol, 88 %) を得た。1H-NMR (CDCl3) δ: 9.25 (1H, s), 8.27 (1H, d, J= 8.8 Hz), 8.17 (1H, d, J = 2.7 Hz), 7.59 (H, d, J = 1.5 Hz), 7.47 (1H, d, J = 7.3 Hz), 7.35 (1H, d, J = 8.8 Hz), 6.77 (1H, d, J = 8.1 Hz), 3.89 (3H, s), 3.65-3.57 (8H, br s), 1.51 (9H, s).  N-methoxy-N-methyl-1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazole-6-carboxamide Using 5-((5- (methoxycarbonyl) -2-nitrophenyl) amino) pyridin-2-yl) piperazine-1-carboxylate (2.01 g, 4.4 mmol), the title compound (1.69 g, 3.9 mmol, 88 %). 1 H-NMR (CDCl 3 ) δ: 9.25 (1H, s), 8.27 (1H, d, J = 8.8 Hz), 8.17 (1H, d, J = 2.7 Hz), 7.59 (H, d, J = 1.5 Hz), 7.47 (1H, d, J = 7.3 Hz), 7.35 (1H, d, J = 8.8 Hz), 6.77 (1H, d, J = 8.1 Hz), 3.89 (3H, s), 3.65-3.57 ( 8H, br s), 1.51 (9H, s).

工程３
メチル 1-(6-(4-メチルピペラジン-1-イル)ピリジン-3-イル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 3
Methyl 1- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000177
Figure JPOXMLDOC01-appb-C000177

　アルゴン雰囲気下、メチル 1-((6-(4-tert-ブトキシカルボニル)ピペラジン-1-イル)ピリジン-3-イル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート (0.40 g, 0.91 mmol) を塩化メチレン (9 mL) に溶解し、氷浴中で冷却しながら トリフルオロ酢酸 (1.8 mL) を加え、氷浴中で1時間撹拌した。反応溶液に 1規定水酸化ナトリウム水溶液および飽和重層水を加え、クロロホルムで 3 回抽出した。有機層を無水硫酸マグネシウムで乾燥した後、減圧下溶媒を留去した。得られた粗生成物を塩化メチレン (10 mL) およびメタノール (5 mL) に溶かし、さらに 37% ホルムアルデヒド水溶液、酢酸 (66 mg) および水素化トリアセトキシホウ素 ナトリウム (290 mg, 1.37 mmol) を加え、室温で1時間撹拌した。反応混合物に飽和重層水を加え、クロロホルムで 3 回抽出した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を留去し、シリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (0.33 g, 0.91mmol, quant.) を得た。1H-NMR(CDCl3) δ: 8.32 (1H, d, J = 2.2 Hz), 8.12 (1H, s), 8.11 (1H, s), 8.05 (1H, dd, J = 7.1, 1.5 Hz), 7.89 (1H, dd, J = 7.8, 0.7 Hz), 7.59 (1H, dd, J = 6.3, 2.7 Hz), 6.82 (1H, d, J = 9.0 Hz), 3.92 (3H, s), 3.76-3.72 (4H, br s), 2.64-2.60 (4H, br s), 2.42 (3H, s). Methyl 1-((6- (4-tert-butoxycarbonyl) piperazin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-6-carboxylate (0.40 g, 0.91 mmol under argon atmosphere ) Was dissolved in methylene chloride (9 mL), trifluoroacetic acid (1.8 mL) was added while cooling in an ice bath, and the mixture was stirred in an ice bath for 1 hour. 1N Aqueous sodium hydroxide solution and saturated multistory water were added to the reaction solution, and the mixture was extracted 3 times with chloroform. After drying the organic layer with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was dissolved in methylene chloride (10 mL) and methanol (5 mL), and 37% aqueous formaldehyde solution, acetic acid (66 mg) and sodium triacetoxyborohydride (290 mg, 1.37 mmol) were added. Stir at room temperature for 1 hour. Saturated multistory water was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.33 g, 0.91 mmol, quant.). 1 H-NMR (CDCl 3 ) δ: 8.32 (1H, d, J = 2.2 Hz), 8.12 (1H, s), 8.11 (1H, s), 8.05 (1H, dd, J = 7.1, 1.5 Hz), 7.89 (1H, dd, J = 7.8, 0.7 Hz), 7.59 (1H, dd, J = 6.3, 2.7 Hz), 6.82 (1H, d, J = 9.0 Hz), 3.92 (3H, s), 3.76-3.72 (4H, br s), 2.64-2.60 (4H, br s), 2.42 (3H, s).

工程４
1-(6-(4-メチルピペラジン-1-イル)ピリジン-3-イル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Process 4
1- (6- (4-Methylpiperazin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000178
Figure JPOXMLDOC01-appb-C000178

　メチル 1-(6-(4-メチルピペラジン-1-イル)ピリジン-3-イル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート (0.33 g, 0.9 mmol) をテトラヒドロフラン (20 mL) およびエタノール (20 mL) に溶かし、塩化カルシウム (222 mg, 2 mmol) を加え、氷浴中で15分間撹拌した後、水素化ホウ素ナトリウム (151 mg, 4 mmol) を加え、氷浴中1時間さらに室温で22時間撹拌した。反応混合物に水を加え、クロロホルムで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥させ、減圧下、溶媒を留去した後、シリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、アルコール体 (0.20 g, 0.62 mmol) を得た。このものの塩化メチレン (20 mL) 溶液にデス・マーチン・ペルヨージナン (340 mg, 0.8 mmol) を加え、室温で1時間撹拌した。反応終了後、飽和チオ硫酸水素ナトリウム水溶液を添加し、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸マグネシウムにより乾燥し、ろ過、減圧下濃縮した。残留物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (0.17 g, 0.53 mmol, 85 %) を得た。1H-NMR (CDCl3) δ: 10.08 (1H, s), 8.33 (1H, d, J = 2.7 Hz), 8.19 (1H, s), 7.99 (1H, d, J = 8.3 Hz), 7.96 (1H, s), 7.89 (1H, dd, J = 6.8, 1.5 Hz), 7.62 (1H, dd, J = 6.3, 2.7 Hz), 6.84 (H, d, J = 9.0 Hz), 3.82-3.78 (4H, br s), 2.73-2.69 (4H, br s), 2.49 (3H, s). Methyl 1- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-6-carboxylate (0.33 g, 0.9 mmol) in tetrahydrofuran (20 mL) and ethanol Dissolve in (20 mL), add calcium chloride (222 mg, 2 mmol), stir in an ice bath for 15 minutes, and then add sodium borohydride.   (151 mg, 4 mmol) was added, and the mixture was stirred in an ice bath for 1 hour and further at room temperature for 22 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to give an alcohol (0.20 g, 0.62 mmol) was obtained. Dess-Martin periodinane (340 mg, 0.8 mmol) was added to a methylene chloride (20 mL) solution of this product and stirred at room temperature for 1 hour. After completion of the reaction, a saturated aqueous sodium hydrogensulfate solution was added, chloroform and a saturated aqueous sodium hydrogencarbonate solution were added, the organic layer was extracted, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.17 g, 0.53 mmol, 85%). 1 H-NMR (CDCl 3 ) δ: 10.08 (1H, s), 8.33 (1H, d, J = 2.7 Hz), 8.19 (1H, s), 7.99 (1H, d, J = 8.3 Hz), 7.96 ( 1H, s), 7.89 (1H, dd, J = 6.8, 1.5 Hz), 7.62 (1H, dd, J = 6.3, 2.7 Hz), 6.84 (H, d, J = 9.0 Hz), 3.82-3.78 (4H , br s), 2.73-2.69 (4H, br s), 2.49 (3H, s).

工程５
5-((1-(6-(4-メチルピペラジン-1-イル)ピリジン-3-イル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物４３)  Process 5
5-((1- (6- (4-Methylpiperazin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (compound 43 )

Figure JPOXMLDOC01-appb-C000179
Figure JPOXMLDOC01-appb-C000179

　5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン の合成と同様の手法で、1-(6-(4-メチルピペラジン-1-イル)ピリジン-3-イル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (0.10 g, 0.31 mmol) および2,4-チアゾリジンジオン (36 mg, 0.31 mmol) とから標記化合物(49 mg) を得た。黄色結晶: 1H-NMR (DMSO-D6)δ: 11.95 (1H, br s), 8.59 (1H, s), 8.43(1H, d, J = 2.9 Hz), 7.92 (1H, dd, J = 6.3, 2.9 Hz), 7.88 (1H, d, J = 8.5 Hz), 7.85 (1H, s), 7.77 (1H, s), 7.52 (1H, d, J= 8.3 Hz), 7.13 (1H, d, J = 9.3 Hz), 3.36-3.32 (4H, br s), 2.53-2.49 (4H, br s), 2.50 (3H, s).
ESI-MS(m/z): 421[M+H]+.  In a manner similar to the synthesis of 5-((1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione, -(6- (4-Methylpiperazin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-6-carbaldehyde (0.10 g, 0.31 mmol) and 2,4-thiazolidinedione (36 mg , 0.31 mmol) and the title compound (49 mg) was obtained. Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 11.95 (1H, br s), 8.59 (1H, s), 8.43 (1H, d, J = 2.9 Hz), 7.92 (1H, dd, J = 6.3, 2.9 Hz), 7.88 (1H, d, J = 8.5 Hz), 7.85 (1H, s), 7.77 (1H, s), 7.52 (1H, d, J = 8.3 Hz), 7.13 (1H, d, J = 9.3 Hz), 3.36-3.32 (4H, br s), 2.53-2.49 (4H, br s), 2.50 (3H, s).
ESI-MS (m / z): 421 [M + H] + .

実施例４４
5-((1-(6-(4-メチルピペラジン-1-イル)ピリジン-3-イル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物４４)  Example 44
5-((1- (6- (4-Methylpiperazin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 44)

Figure JPOXMLDOC01-appb-C000180
Figure JPOXMLDOC01-appb-C000180

工程１
　5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン の合成と同様の手法で、1-(6-(4-メチルピペラジン-1-イル)ピリジン-3-イル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (0.07 g, 0.22 mmol) およびロダニン (29 mg, 0.22 mmol) とから標記化合物 (91 mg, 95) を得た。黄色結晶: 1H-NMR (DMSO-D6)δ: 11.28 (1H, br s), 8.57 (1H, s), 8.47 (1H, d, J = 2.7 Hz), 7.97 (1H, dd, J = 6.3, 2.7 Hz), 7.85 (1H, d, J = 8.5 Hz), 7.65 (1H, s), 7.50 (1H, s), 7.50 (1H, dd, J= 8.4, 1.6 Hz), 7.19 (1H, d, J= 9.0 Hz), 3.81-3.77 (4H, br s), 3.05-3.02 (4H, br s), 2.66 (3H, s).
ESI-MS(m/z): 437[M+H]+.  Process 1
Similar procedure to the synthesis of 5-((1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one 1- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazole-6-carbaldehyde (0.07 g, 0.22 mmol) and rhodanine (29 mg, 0.22 mmol) gave the title compound (91 mg, 95). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 11.28 (1H, br s), 8.57 (1H, s), 8.47 (1H, d, J = 2.7 Hz), 7.97 (1H, dd, J = 6.3, 2.7 Hz), 7.85 (1H, d, J = 8.5 Hz), 7.65 (1H, s), 7.50 (1H, s), 7.50 (1H, dd, J = 8.4, 1.6 Hz), 7.19 (1H, d, J = 9.0 Hz), 3.81-3.77 (4H, br s), 3.05-3.02 (4H, br s), 2.66 (3H, s).
ESI-MS (m / z): 437 [M + H] + .

実施例４５
5-((1-(4-(4-メチルピペラジニル)フェニル)-1H-インドール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物４５)  Example 45
5-((1- (4- (4-Methylpiperazinyl) phenyl) -1H-indol-6-yl) methylene) -2-thioxothiazolidine-4-one (Compound 45)

工程１
1-(4-(4-メチルピペラジニル)フェニル)-1H-インドール-6-カルボニトリル Process 1
1- (4- (4-Methylpiperazinyl) phenyl) -1H-indole-6-carbonitrile

Figure JPOXMLDOC01-appb-C000181
Figure JPOXMLDOC01-appb-C000181

　アルゴン雰囲気下、1H-インドール-6-カルボニトリル(500 mg, 3.52 mmol)、1-(4-ブロモフェニル)-4-メチルピペラジン (748 mg, 2.93 mmol)、ヨウ化銅(I) (335 mg, 1.76 mmol)、リン酸三カリウム (1.87 g, 8.789 mmol) の N,N-ジメチルホルムアミド (10 mL) 溶液を 120 ℃で 2 日間撹拌した。反応溶液に飽和重層水を加え、クロロホルムで 3 回抽出した。有機層を無水硫酸マグネシウムで乾燥した後、減圧下溶媒を留去した。得られた粗生成物を HPLC で精製し、目的とする標記化合物 (119 mg, 13 %) を得た。黄色液体：1H-NMR (CDCl3) δ: 7.76 (1H, d, J = 1.2 Hz), 7.72 (1H, d, J = 8.1 Hz), 7.46 (1H, d, J = 3.2 Hz), 7.36 (1H, dd, J = 8.1, 1.2 Hz), 7.33 (2H, d, J = 9.0 Hz), 7.06 (2H, d, J = 9.0 Hz), 6.70 (1H, d, J = 3.2 Hz), 3.31 (4H, t, J = 5.0 Hz), 2.63 (4H, t, J = 5.0 Hz), 2.39 (3H, s). 1H-indole-6-carbonitrile (500 mg, 3.52 mmol), 1- (4-bromophenyl) -4-methylpiperazine (748 mg, 2.93 mmol), copper (I) iodide (335 mg) under argon atmosphere , 1.76 mmol), tripotassium phosphate (1.87 g, 8.789 mmol) in N, N-dimethylformamide (10 mL) was stirred at 120 ° C. for 2 days. Saturated multistory water was added to the reaction solution, and extracted three times with chloroform. After drying the organic layer with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was purified by HPLC to obtain the target title compound (119 mg, 13%). Yellow liquid: 1 H-NMR (CDCl 3 ) δ: 7.76 (1H, d, J = 1.2 Hz), 7.72 (1H, d, J = 8.1 Hz), 7.46 (1H, d, J = 3.2 Hz), 7.36 (1H, dd, J = 8.1, 1.2 Hz), 7.33 (2H, d, J = 9.0 Hz), 7.06 (2H, d, J = 9.0 Hz), 6.70 (1H, d, J = 3.2 Hz), 3.31 (4H, t, J = 5.0 Hz), 2.63 (4H, t, J = 5.0 Hz), 2.39 (3H, s).

工程２
1-(4-(4-メチルピペラジニル)フェニル)-1H-インドール-6-カルボアルデヒド Process 2
1- (4- (4-Methylpiperazinyl) phenyl) -1H-indole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000182
Figure JPOXMLDOC01-appb-C000182

　アルゴン雰囲気下、1-(4-(4-メチルピペラジニル)フェニル)-1H-インドール-6-カルボニトリル(61 mg, 0.19 mmol) のトルエン (5 mL) 溶液に -45 ℃でジイソブチルアルミニウムヒドリド ヘキサン溶液 (1.0 M, 0.39 mL, 0.39 mmol) を加えた。室温で 1 時間撹拌した後、反応溶液にメタノール (1 mL)、1.0 M 硫酸溶液(3.4 mL) を加え、一晩撹拌した。反応溶液に 1.0 M 水酸化ナトリウム水溶液を加え、系を塩基性にし、クロロホルムで 3 回抽出した。有機層を無水硫酸マグネシウムで乾燥した後、減圧下溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (27 mg, 35 %) を得た。黄色液体：1H-NMR (CDCl3) δ: 10.01 (1H, s), 7.97 (1H, s), 7.77 (1H, d, J = 8.3 Hz), 7.68 (1H, dd, J = 8.3, 1.3 Hz), 7.50 (1H, d, J = 3.0 Hz), 7.38 (2H, d, J = 9.0 Hz), 7.07 (2H, d, J = 9.0 Hz), 6.72 (1H, dd, J = 3.0, 1.3 Hz), 3.31 (4H, t, J = 5.1 Hz), 2.63 (4H, t, J = 5.1 Hz), 2.39 (3H, s). Di-isobutylaluminum hydride in toluene (5 mL) solution of 1- (4- (4-methylpiperazinyl) phenyl) -1H-indole-6-carbonitrile (61 mg, 0.19 mmol) at -45 ° C under argon atmosphere Hexane solution (1.0 M, 0.39 mL, 0.39 mmol) was added. After stirring at room temperature for 1 hour, methanol (1 mL) and 1.0 M sulfuric acid solution (3.4 mL) were added to the reaction solution, and the mixture was stirred overnight. To the reaction solution was added 1.0 M aqueous sodium hydroxide solution to basify the system, and the mixture was extracted 3 times with chloroform. After drying the organic layer with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (27 mg, 35%). Yellow liquid: 1 H-NMR (CDCl 3 ) δ: 10.01 (1H, s), 7.97 (1H, s), 7.77 (1H, d, J = 8.3 Hz), 7.68 (1H, dd, J = 8.3, 1.3 Hz), 7.50 (1H, d, J = 3.0 Hz), 7.38 (2H, d, J = 9.0 Hz), 7.07 (2H, d, J = 9.0 Hz), 6.72 (1H, dd, J = 3.0, 1.3 Hz), 3.31 (4H, t, J = 5.1 Hz), 2.63 (4H, t, J = 5.1 Hz), 2.39 (3H, s).

工程３
5-((1-(4-(4-メチルピペラジニル)フェニル)-1H-インドール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物４５)  Process 3
5-((1- (4- (4-Methylpiperazinyl) phenyl) -1H-indol-6-yl) methylene) -2-thioxothiazolidine-4-one (Compound 45)

Figure JPOXMLDOC01-appb-C000183
Figure JPOXMLDOC01-appb-C000183

　1-(4-(4-メチルピペラジニル)フェニル)-1H-インドール-6-カルボアルデヒド (101 mg, 0.30 mmol)、ロダニン (36 mg, 0.27 mmol) のエタノール (2 mL) 溶液に ピペリジン (5 mg, 0.06 mmol) を加え 80 ℃で一晩撹拌した。反応溶液に酢酸エチルを加え、結晶を析出させた後、ろ過し、酢酸エチル、エタノールで洗浄した後、シリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) により生成し、標記化合物 (2 mg, 6 %) を得た。 無色結晶: 1H-NMR (DMSO-D6) δ: 7.74 (1H, d, J = 8.5 Hz), 7.72 (1H, d, J = 3.4 Hz), 7.66 (1H, s), 7.52-7.48 (3H, m), 7.31 (1H, dd, J = 8.5, 1.3 Hz), 7.21 (2H, d, J = 8.8 Hz), 6.73 (1H, d, J = 3.4 Hz), 3.41 (4H, br s), 3.07 (4H, br s), 2.66 (3H, s).
ESI-MS(m/z): 435[M+H]+.  Piperidine (1 mL) solution of 1- (4- (4-methylpiperazinyl) phenyl) -1H-indole-6-carbaldehyde (101 mg, 0.30 mmol), rhodanine (36 mg, 0.27 mmol) in ethanol (2 mL) 5 mg, 0.06 mmol) was added and stirred at 80 ° C. overnight. Ethyl acetate was added to the reaction solution, crystals were precipitated, filtered, washed with ethyl acetate and ethanol, and then generated by silica gel column chromatography (chloroform / methanol) to give the title compound (2 mg, 6%) Got. Colorless crystals: 1 H-NMR (DMSO-D 6 ) δ: 7.74 (1H, d, J = 8.5 Hz), 7.72 (1H, d, J = 3.4 Hz), 7.66 (1H, s), 7.52-7.48 ( 3H, m), 7.31 (1H, dd, J = 8.5, 1.3 Hz), 7.21 (2H, d, J = 8.8 Hz), 6.73 (1H, d, J = 3.4 Hz), 3.41 (4H, br s) , 3.07 (4H, br s), 2.66 (3H, s).
ESI-MS (m / z): 435 [M + H] + .

実施例４６
5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-インドール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物４６)  Example 46
5-((1- (4- (4-Methylpiperazinyl) benzyl) -1H-indol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 46)

工程１
1-(4-ブロモベンジル)-1H-インドール-6-カルボニトリル Process 1
1- (4-Bromobenzyl) -1H-indole-6-carbonitrile

Figure JPOXMLDOC01-appb-C000184
Figure JPOXMLDOC01-appb-C000184

　アルゴン雰囲気下、0 ℃で、1H-インドール-6-カルボニトリル (1.5 g, 10.55 mmol) の N,N-ジメチルホルムアミド (5 mL) 溶液に水素化ナトリウム (608 mg, 12.66 mmol) を加え、30 分間撹拌した。0 ℃で 4 -ブロモベンジルブロミド (3.16 g, 12.66 mmol) の N,N-ジメチルホルムアミド (2 mL) 溶液を加え、0 ℃で 1 時間撹拌した。反応終了後、反応溶液に 1規定塩酸を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、減圧下溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (2.1 g, 69 %) を得た。黄色結晶: 1H-NMR (CDCl3) δ: 7.68 (1H, d, J = 8.1 Hz), 7.55 (1H, d, J = 0.5 Hz), 7.44 (2H, d, J = 8.5 Hz), 7.34-7.31 (2H, m), 6.95 (2H, d, J = 8.5 Hz), 6.63 (1H, dd, J = 3.2, 0.5 Hz), 5.29 (2H, s). Sodium hydride (608 mg, 12.66 mmol) was added to a solution of 1H-indole-6-carbonitrile (1.5 g, 10.55 mmol) in N, N-dimethylformamide (5 mL) at 0 ° C under an argon atmosphere. Stir for minutes. A solution of 4-bromobenzyl bromide (3.16 g, 12.66 mmol) in N, N-dimethylformamide (2 mL) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour. After completion of the reaction, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying the organic layer with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (2.1 g, 69%). Yellow crystals: 1 H-NMR (CDCl 3 ) δ: 7.68 (1H, d, J = 8.1 Hz), 7.55 (1H, d, J = 0.5 Hz), 7.44 (2H, d, J = 8.5 Hz), 7.34 -7.31 (2H, m), 6.95 (2H, d, J = 8.5 Hz), 6.63 (1H, dd, J = 3.2, 0.5 Hz), 5.29 (2H, s).

工程２
1-(4-(4-メチルピペラジニル)ベンジル)-1H-インドール-6-カルボニトリル Process 2
1- (4- (4-Methylpiperazinyl) benzyl) -1H-indole-6-carbonitrile

Figure JPOXMLDOC01-appb-C000185
Figure JPOXMLDOC01-appb-C000185

　アルゴン雰囲気下、1-(4-ブロモベンジル)-1H-インドール-6-カルボニトリル (1.0 g, 3.21 mmol) 、4-メチルピペラジン (268 mg, 2.68 mL) 、トリス（ジベンジリデン）アセトンパラジウム (247 mg, 0.27 mmol) 、rac-2,2'-ビス（ジフェニルホスフィノ）-1,1'-ビナフチル (498 mg, 0.80 mmol)、tert-ブトキシナトリウム (438 mg, 4.56 mmol) のトルエン溶液を 100 ℃で一晩撹拌した。反応終了後、反応溶液に飽和重層水を加え、クロロホルムで 3 回抽出した。有機層を無水硫酸マグネシウムで乾燥した後、減圧下溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (283 mg, 22 %) を得た。黄色液体：1H-NMR (CDCl3) δ: 7.68-7.64 (2H, m), 7.33-7.30 (2H, m), 7.04 (2H, d, J = 8.5 Hz), 6.86 (2H, d, J = 8.5 Hz), 6.58 (1H, d, J = 3.2 Hz), 5.24 (2H, s), 3.19 (4H, t, J = 5.1 Hz), 2.55 (4H, t, J = 5.1 Hz), 2.34 (3H, s). Under an argon atmosphere, 1- (4-bromobenzyl) -1H-indole-6-carbonitrile (1.0 g, 3.21 mmol), 4-methylpiperazine (268 mg, 2.68 mL), tris (dibenzylidene) acetone palladium (247 mg, 0.27 mmol), rac-2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (498 mg, 0.80 mmol), tert-butoxy sodium (438 mg, 4.56 mmol) in toluene solution. Stir overnight at ° C. After completion of the reaction, saturated multistory water was added to the reaction solution, and extracted with chloroform three times. After drying the organic layer with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (283 mg, 22%). Yellow liquid: 1 H-NMR (CDCl 3 ) δ: 7.68-7.64 (2H, m), 7.33-7.30 (2H, m), 7.04 (2H, d, J = 8.5 Hz), 6.86 (2H, d, J = 8.5 Hz), 6.58 (1H, d, J = 3.2 Hz), 5.24 (2H, s), 3.19 (4H, t, J = 5.1 Hz), 2.55 (4H, t, J = 5.1 Hz), 2.34 ( 3H, s).

工程３
1-(4-(4-メチルピペラジニル)ベンジル)-1H-インドール-6-カルボアルデヒド Process 3
1- (4- (4-Methylpiperazinyl) benzyl) -1H-indole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000186
Figure JPOXMLDOC01-appb-C000186

　アルゴン雰囲気下、1-(4-(4-メチルピペラジニル)ベンジル)-1H-インドール-6-カルボニトリル(283 mg, 0.86 mmol) のトルエン (5 mL) 溶液に -45 ℃でジイソブチルアルミニウムヒドリド ヘキサン溶液 (1.0 M, 1.2 mL, 1.2 mmol) を加えた。室温で 1 時間撹拌した後、反応溶液にメタノール (1 mL)、1.0 M 硫酸溶液(3.2 mL) を加え、一晩撹拌した。反応溶液に 0.1規定塩酸ナトリウム水溶液を加え、系を塩基性にし、クロロホルムで3回抽出した。有機層を無水硫酸マグネシウムで乾燥した後、減圧下溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法  (クロロホルム/メタノール) で精製し、目的とする標記化合物 (101 mg, 35 %) を得た。黄色結晶：1H-NMR (CDCl3) δ: 10.02 (1H, s), 7.89 (1H, s), 7.72 (1H, d, J = 8.1 Hz), 7.63 (1H, dd, J = 8.1, 0.7 Hz), 7.33 (1H, d, J = 3.2 Hz), 7.06 (2H, d, J = 8.5 Hz), 6.86 (2H, d, J = 8.5 Hz), 6.59 (1H, dd, J = 3.2, 0.7 Hz), 5.31 (2H, s), 3.18 (4H, t, J = 5.0 Hz), 2.55 (4H, t, J = 5.0 Hz), 2.34 (3H, s). Di-isobutylaluminum hydride in toluene (5 mL) solution of 1- (4- (4-methylpiperazinyl) benzyl) -1H-indole-6-carbonitrile (283 mg, 0.86 mmol) at -45 ° C under argon atmosphere Hexane solution (1.0 M, 1.2 mL, 1.2 mmol) was added. After stirring at room temperature for 1 hour, methanol (1 mL) and 1.0 M sulfuric acid solution (3.2 mL) were added to the reaction solution, and the mixture was stirred overnight. To the reaction solution was added 0.1N aqueous sodium chloride solution to basify the system, and the mixture was extracted 3 times with chloroform. After drying the organic layer with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (101 mg, 35%). Yellow crystals: 1 H-NMR (CDCl 3 ) δ: 10.02 (1H, s), 7.89 (1H, s), 7.72 (1H, d, J = 8.1 Hz), 7.63 (1H, dd, J = 8.1, 0.7 Hz), 7.33 (1H, d, J = 3.2 Hz), 7.06 (2H, d, J = 8.5 Hz), 6.86 (2H, d, J = 8.5 Hz), 6.59 (1H, dd, J = 3.2, 0.7 Hz), 5.31 (2H, s), 3.18 (4H, t, J = 5.0 Hz), 2.55 (4H, t, J = 5.0 Hz), 2.34 (3H, s).

工程４
5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-インドール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物４６)  Process 4
5-((1- (4- (4-Methylpiperazinyl) benzyl) -1H-indol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 46)

Figure JPOXMLDOC01-appb-C000187
Figure JPOXMLDOC01-appb-C000187

　1-(4-(4-メチルピペラジニル)ベンジル)-1H-インドール-6-カルボアルデヒド (101 mg, 0.30 mmol) 、ロダニン (36 mg, 0.27 mmol) のエタノール (2 mL) 溶液に ピペリジン (5 mg, 0.06 mmol) を加え 80 ℃で一晩撹拌した。反応溶液に酢酸エチルを加え、結晶を析出させた後、ろ過し、酢酸エチル、エタノールで洗浄して標記化合物 (50 mg, 41 %) を得た。 黄色結晶: 1H-NMR (DMSO-D6) δ: 11.34 (1H, br s), 7.69 (1H, d, J = 2.9 Hz), 7.65 (1H, s), 7.63 (1H, d, J = 8.5 Hz), 7.44 (1H, s), 7.22 (2H, d, J = 8.8 Hz), 7.19 (1H, dd, J = 8.5, 0.7 Hz), 6.92 (2H, d, J = 8.8 Hz), 6.51 (1H, dd, J = 2.9, 0.7 Hz), 5.35 (2H, s), 3.22 (4H, br s), 2.88 (4H, br s), 2.52 (3H, s).
ESI-MS(m/z): 449[M+H]+. Piperidine (1 mL) solution of 1- (4- (4-methylpiperazinyl) benzyl) -1H-indole-6-carbaldehyde (101 mg, 0.30 mmol) and rhodanine (36 mg, 0.27 mmol) in ethanol (2 mL) 5 mg, 0.06 mmol) was added and stirred at 80 ° C. overnight. Ethyl acetate was added to the reaction solution to precipitate crystals, followed by filtration and washing with ethyl acetate and ethanol to obtain the title compound (50 mg, 41%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 11.34 (1H, br s), 7.69 (1H, d, J = 2.9 Hz), 7.65 (1H, s), 7.63 (1H, d, J = 8.5 Hz), 7.44 (1H, s), 7.22 (2H, d, J = 8.8 Hz), 7.19 (1H, dd, J = 8.5, 0.7 Hz), 6.92 (2H, d, J = 8.8 Hz), 6.51 (1H, dd, J = 2.9, 0.7 Hz), 5.35 (2H, s), 3.22 (4H, br s), 2.88 (4H, br s), 2.52 (3H, s).
ESI-MS (m / z): 449 [M + H] + .

実施例４７
5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-インドール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物４７)  Example 47
5-((1- (4- (4-Methylpiperazinyl) benzyl) -1H-indol-6-yl) methylene) thiazolidine-2,4-dione (Compound 47)

Figure JPOXMLDOC01-appb-C000188
Figure JPOXMLDOC01-appb-C000188

工程１
　1-(4-(4-メチルピペラジニル)ベンジル)-1H-インドール-6-カルボアルデヒド (83 mg, 0.23 mmol)、2,4-チアゾリジンジオン (27 mg, 0.22 mmol) のエタノール (5 mL) 溶液に ピペリジン (4 mg, 0.04 mmol) を加え 80 ℃で一晩撹拌した。反応溶液に酢酸エチルを加え、結晶を析出させた後、ろ過し、酢酸エチル、エタノールで洗浄して標記化合物 (54 mg, 54 %) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 11.91 (1H, br s), 7.78 (1H, s), 7.73-7.71 (2H, m), 7.65 (1H, d, J = 8.1 Hz), 7.23-7.18 (3H, m), 6.88 (2H, d, J = 8.5 Hz), 6.52 (1H, d, J = 2.9 Hz), 5.34 (2H, s), 3.12 (4H, t, J = 4.8 Hz), 2.57 (4H, t, J = 4.8 Hz), 2.31 (3H, s).
ESI-MS(m/z): 433[M+H]+. Process 1
1- (4- (4-Methylpiperazinyl) benzyl) -1H-indole-6-carbaldehyde (83 mg, 0.23 mmol), 2,4-thiazolidinedione (27 mg, 0.22 mmol) in ethanol (5 mL ) Piperidine (4 mg, 0.04 mmol) was added to the solution and stirred overnight at 80 ° C. Ethyl acetate was added to the reaction solution to precipitate crystals, followed by filtration and washing with ethyl acetate and ethanol to obtain the title compound (54 mg, 54%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 11.91 (1H, br s), 7.78 (1H, s), 7.73-7.71 (2H, m), 7.65 (1H, d, J = 8.1 Hz) , 7.23-7.18 (3H, m), 6.88 (2H, d, J = 8.5 Hz), 6.52 (1H, d, J = 2.9 Hz), 5.34 (2H, s), 3.12 (4H, t, J = 4.8 Hz), 2.57 (4H, t, J = 4.8 Hz), 2.31 (3H, s).
ESI-MS (m / z): 433 [M + H] + .

実施例４８
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物４８)  Example 48
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 48 )

工程１
6-ブロモイミダゾ[1,2-a]ピリジン  Process 1
6-Bromoimidazo [1,2-a] pyridine

Figure JPOXMLDOC01-appb-C000189
Figure JPOXMLDOC01-appb-C000189

　封管に2-アミノ-5-ブロモピリジン (1.0 g, 5.78 mmol) を入れ、イソプロパノール (5 mL) に溶解した。そこへ炭酸水素ナトリウム (1.23 g, 5.78 mmol)、クロロアセトアルデヒド水溶液 (6.1 M, 1.14 mL, 6.94 mmol) を加え、100℃で24時間撹拌した。反応液をセライトでろ過し、ろ液を濃縮した。得られた残渣をクロロホルムに再溶解し、水, 飽和食塩水で洗浄した。クロロホルム層を水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (1.02 g, 89％) を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 8.92 (1H, dd, J = 2.0, 1.0 Hz), 7.93 (1H, d, J = 0.7 Hz), 7.61 (1H, d, J = 1.2 Hz), 7.56 (1H, d, J = 9.5 Hz), 7.34 (1H, dd, J = 9.5, 2.0 Hz). 2-Amino-5-bromopyridine (1.0 g, 5.78 mmol) was placed in a sealed tube and dissolved in isopropanol (5 mL). Sodium hydrogen carbonate (1.23 g, 5.78 mmol) and chloroacetaldehyde aqueous solution (6.1 M, 1.14 mL, 6.94 mmol) were added thereto, and the mixture was stirred at 100 ° C. for 24 hours. The reaction solution was filtered through celite, and the filtrate was concentrated. The obtained residue was redissolved in chloroform and washed with water and saturated brine. The chloroform layer was dried with magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (1.02 g, 89%). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 8.92 (1H, dd, J = 2.0, 1.0 Hz), 7.93 (1H, d, J = 0.7 Hz), 7.61 (1H, d, J = 1.2 Hz), 7.56 (1H, d, J = 9.5 Hz), 7.34 (1H, dd, J = 9.5, 2.0 Hz).

工程２
6-ブロモ-3-ヨードイミダゾ[1,2-a]ピリジン Process 2
6-Bromo-3-iodoimidazo [1,2-a] pyridine

Figure JPOXMLDOC01-appb-C000190
Figure JPOXMLDOC01-appb-C000190

　アルゴン雰囲気下、6-ブロモイミダゾ[1,2-a]ピリジン(1.02 g, 5.16 mmol) をアセトニトリル (15 mL) に溶解した。そこへN-ヨードコハク酸イミド (1.16 g, 5.16 mmol) を加え、室温で遮光下、17時間撹拌した。生じた析出物をろ取し、アセトニトリルで洗浄、真空乾燥して標記化合物 (1.39 g, 84％) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 8.48 (1H, dd, J = 2.0, 0.5 Hz), 7.76 (1H, s), 7.61 (1H, dd, J = 9.5, 0.5 Hz), 7.44 (1H, dd, J = 9.5, 2.0 Hz). 6-bromoimidazo [1,2-a] pyridine (1.02 g, 5.16 mmol) was dissolved in acetonitrile (15 mL) under an argon atmosphere. N-iodosuccinimide (1.16 g, 5.16 mmol) was added thereto, and the mixture was stirred at room temperature for 17 hours under light shielding. The resulting precipitate was collected by filtration, washed with acetonitrile, and dried under vacuum to obtain the title compound (1.39 g, 84%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 8.48 (1H, dd, J = 2.0, 0.5 Hz), 7.76 (1H, s), 7.61 (1H, dd, J = 9.5, 0.5 Hz), 7.44 (1H, dd, J = 9.5, 2.0 Hz).

工程３
1-メチル-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン Process 3
1-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine

Figure JPOXMLDOC01-appb-C000191
Figure JPOXMLDOC01-appb-C000191

　アルゴン雰囲気下、 1-(4-ブロモフェニル)-4-メチルピペラジン (500 mg, 1.96 mmol) をテトラヒドロフラン (30 mL) に溶解し、-78℃に冷却した。そこへtert-ブチルリチウム ヘプタン溶液 (1.58M, 2.73 mL, 4.31 mmol) を滴下し、-78℃で1時間撹拌した。さらに2-イソプロポキシ-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン (2.73 mL, 3.92 mmol) のテトラヒドロフラン (2 mL) を滴下し、室温まで徐々に昇温させながら6時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加えクエンチし、酢酸エチルで抽出した。  酢酸エチル層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (501 mg, 85%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 7.50 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz), 3.19 (4H, t, J = 5.1 Hz), 2.42 (4H, t, J = 5.0 Hz), 2.21 (3H, s), 1.26 (12H, s). Under an argon atmosphere, 1- (4-bromophenyl) -4-methylpiperazine (500 mg, 1.96 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to -78 ° C. The tert-butyllithium heptane solution (1.58M, 2.73 mL, 4.31 mmol) was dripped there, and it stirred at -78 degreeC for 1 hour. Further, add 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.73 mL, 3.92 mmol) in tetrahydrofuran (2 mL) dropwise, and gradually warm to room temperature. Stir for hours. The reaction solution was quenched by adding saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (501 mg, 85%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 7.50 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz), 3.19 (4H, t, J = 5.1 Hz) , 2.42 (4H, t, J = 5.0 Hz), 2.21 (3H, s), 1.26 (12H, s).

工程４
6-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン Process 4
6-Bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine

Figure JPOXMLDOC01-appb-C000192
Figure JPOXMLDOC01-appb-C000192

　アルゴン雰囲気下、6-ブロモ-3-ヨードイミダゾ[1,2-a]ピリジン (350 mg, 1.08 mmol) を1,4-ジオキサン (9 mL)、水 (3 mL) に懸濁した。そこへ1-メチル-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン (360 mg, 1.12 mmol)、1,1’-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド-ジクロロメタン錯体 (88 mg, 0.11 mmol)、炭酸カリウム (597 mg, 4.32 mmol) を加えた。反応容器内を脱気し、アルゴン置換した。この操作を3回繰り返した後、100℃で3時間撹拌した。反応液に水を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (NHカラム, ヘキサン/酢酸エチル) で精製し、標記化合物 (226 mg, 56%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 8.53 (1H, dd, J = 1.7, 0.7 Hz), 7.68 (1H, s), 7.63 (1H, dd, J = 9.5, 0.7 Hz), 7.50 (2H, d, J = 8.8 Hz), 7.37 (1H, dd, J = 9.5, 2.0 Hz), 7.10 (2H, d, J = 9.0 Hz), 3.23 (4H, t, J = 5.0 Hz), 2.47 (4H, t, J = 4.9 Hz), 2.24 (3H, s). Under an argon atmosphere, 6-bromo-3-iodoimidazo [1,2-a] pyridine (350 mg, 1.08 mmol) was suspended in 1,4-dioxane (9 mL) and water (3 mL). 1-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine (360 mg, 1.12 mmol), 1,1 ' -Bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (88 mg, 0.11 mmol) and potassium carbonate (597 mg, 4.32 mmol) were added. The inside of the reaction vessel was evacuated and purged with argon. This operation was repeated 3 times, followed by stirring at 100 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (NH column, hexane / ethyl acetate) to obtain the title compound (226 mg, 56%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 8.53 (1H, dd, J = 1.7, 0.7 Hz), 7.68 (1H, s), 7.63 (1H, dd, J = 9.5, 0.7 Hz), 7.50 (2H, d, J = 8.8 Hz), 7.37 (1H, dd, J = 9.5, 2.0 Hz), 7.10 (2H, d, J = 9.0 Hz), 3.23 (4H, t, J = 5.0 Hz), 2.47 (4H, t, J = 4.9 Hz), 2.24 (3H, s).

工程５
3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド Process 5
3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000193
Figure JPOXMLDOC01-appb-C000193

　6-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン (183 mg, 0.493 mmol)、ジクロロビス(トリフェニルホスフィン)パラジウム(6.9 mg, 9.86 μmol)、ぎ酸ナトリウム (50 mg, 0.740 mmol) を反応容器に入れ、反応容器内を一酸化炭素で置換した。そこへN,N-ジメチルホルムアミド (1 mL) を加えて110℃で5時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。酢酸エチル層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (73 mg, 46%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 9.99 (1H, s), 9.21 (1H, t, J= 1.1 Hz), 7.78 (1H, s), 7.71 (1H, d, J= 9.5 Hz), 7.58-7.55 (3H, m), 7.56 (3H, d, J = 8.8 Hz), 7.14 (2H, d, J= 8.8 Hz), 3.26 (4H, t, J = 5.0 Hz), 2.50-2.47 (4H, m), 2.24 (3H, s). 6-Bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine (183 mg, 0.493 mmol), dichlorobis (triphenylphosphine) palladium (6.9 mg, 9.86 μmol) and sodium formate (50 mg, 0.740 mmol) were placed in a reaction vessel, and the inside of the reaction vessel was replaced with carbon monoxide. N, N-dimethylformamide (1 mL) was added there, and it stirred at 110 degreeC for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (73 mg, 46%). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 9.99 (1H, s), 9.21 (1H, t, J = 1.1 Hz), 7.78 (1H, s), 7.71 (1H, d, J = 9.5 Hz), 7.58-7.55 (3H, m), 7.56 (3H, d, J = 8.8 Hz), 7.14 (2H, d, J = 8.8 Hz), 3.26 (4H, t, J = 5.0 Hz), 2.50 -2.47 (4H, m), 2.24 (3H, s).

工程６
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物４８) Step 6
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 48 )

Figure JPOXMLDOC01-appb-C000194
Figure JPOXMLDOC01-appb-C000194

　5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド (37 mg, 0.115 mmol) およびロダニン (15 mg, 0.115 mmol) から標記化合物 (25 mg, 50%)を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 8.73 (1H, s), 7.73 (2H, s), 7.72 (2H, d, J = 9.0 Hz), 7.59 (2H, d, J = 8.8 Hz), 7.43 (2H, dd, J = 9.5, 1.7 Hz), 7.41 (2H, s), 7.18 (2H, d, J = 8.8 Hz), 3.45 (4H, s), 3.15 (4H, s), 2.72 (3H, s).
ESI-MS(m/z): 436[M+H]+. Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (37 mg, 0.115 mmol) and rhodanine (15 mg, 0.115 mmol) Gave the title compound (25 mg, 50%). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 8.73 (1H, s), 7.73 (2H, s), 7.72 (2H, d, J = 9.0 Hz), 7.59 (2H, d, J = 8.8 Hz), 7.43 (2H, dd, J = 9.5, 1.7 Hz), 7.41 (2H, s), 7.18 (2H, d, J = 8.8 Hz), 3.45 (4H, s), 3.15 (4H, s), 2.72 (3H, s).
ESI-MS (m / z): 436 [M + H] + .

実施例４９
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物４９) Example 49
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione (Compound 49)

Figure JPOXMLDOC01-appb-C000195
Figure JPOXMLDOC01-appb-C000195

工程１
　5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド (34 mg, 0.106 mmol) およびチアゾリジン-2,4-ジオン (12 mg, 0.106 mmol) から標記化合物 (10 mg, 22%)を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.81 (1H, s), 7.73-7.71 (3H, m), 7.56 (2H, d, J = 8.8 Hz), 7.45 (1H, dd, J = 9.5, 1.7 Hz), 7.15 (2H, d, J = 8.8 Hz), 3.34 (4H, t, J = 4.8 Hz), 2.77 (4H, t, J = 4.6 Hz), 2.45 (3H, s).
ESI-MS(m/z): 420[M+H]+. Process 1
Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) Method, 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (34 mg, 0.106 mmol) and thiazolidine-2,4-dione ( The title compound (10 mg, 22%) was obtained from 12 mg, 0.106 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.81 (1H, s), 7.73-7.71 (3H, m), 7.56 (2H, d, J = 8.8 Hz), 7.45 (1H, dd, J = 9.5, 1.7 Hz), 7.15 (2H, d, J = 8.8 Hz), 3.34 (4H, t, J = 4.8 Hz), 2.77 (4H, t, J = 4.6 Hz), 2.45 (3H, s).
ESI-MS (m / z): 420 [M + H] + .

実施例５０
5-((3-(3-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物５０)  Example 50
5-((3- (3- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 50 )

工程１
1-(3-ブロモフェニル)-4-メチルピペラジン Process 1
1- (3-Bromophenyl) -4-methylpiperazine

Figure JPOXMLDOC01-appb-C000196
Figure JPOXMLDOC01-appb-C000196

　アルゴン雰囲気下、1-メチルピペラジン (549 μL, 4.99 mmol)、1,3-ジブロモベンゼン (1.80 mL, 15.0 mmol) をトルエン (15 mL) に溶解した。そこへトリス(ジベンジリデンアセトン)ジパラジウム(0) (46 mg, 0.050 mmol)、rac-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル (93 mg, 0.150 mmol) を加えた。さらにジアザビシクロウンデセン (1.87 mL, 12.5 mmol) を滴下し、 60℃に昇温した。ナトリウム tert-ブトキシド (2.21 g, 23.0 mmol) を一度に加え、60℃で1時間撹拌後、100℃で22時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。酢酸エチル層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (1.17 g, 92%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 7.13 (1H, t, J= 8.2 Hz), 7.06 (1H, t, J = 2.2 Hz), 6.94-6.89 (2H, m), 3.15 (4H, t, J= 5.0 Hz), 2.42 (4H, t, J = 5.0 Hz), 2.21 (3H, s). Under an argon atmosphere, 1-methylpiperazine (549 μL, 4.99 mmol) and 1,3-dibromobenzene (1.80 mL, 15.0 mmol) were dissolved in toluene (15 mL). Tris (dibenzylideneacetone) dipalladium (0) (46 mg, 0.050 mmol), rac-2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (93 mg, 0.150 mmol) was added thereto It was. Diazabicycloundecene (1.87 mL, 12.5 mmol) was further added dropwise, and the temperature was raised to 60 ° C. Sodium tert-butoxide (2.21 g, 23.0 mmol) was added in one portion, and the mixture was stirred at 60 ° C for 1 hour and then at 100 ° C for 22 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (1.17 g, 92%). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 7.13 (1H, t, J = 8.2 Hz), 7.06 (1H, t, J = 2.2 Hz), 6.94-6.89 (2H, m), 3.15 ( 4H, t, J = 5.0 Hz), 2.42 (4H, t, J = 5.0 Hz), 2.21 (3H, s).

工程２
1-メチル-4-(3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン Process 2
1-methyl-4- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine

Figure JPOXMLDOC01-appb-C000197
Figure JPOXMLDOC01-appb-C000197

　アルゴン雰囲気下、1-(3-ブロモフェニル)-4-メチルピペラジン (1.17 g, 4.57 mmol) を 1,4-ジオキサン (18 mL) に溶解した。そこへビスピナコレートジボロン (1.39 g, 5.48 mmol)、1,1’-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド-ジクロロメタン錯体 (75 mg, 0.091 mmol)、酢酸カリウム (897 mg, 9.14 mmol) を加えた。  反応容器内を脱気し、アルゴン置換した。この操作を3回繰り返した後、80℃で21時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。酢酸エチル層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (1.26 g, 91%) を得た。茶色オイル: 1H-NMR (DMSO-D6) δ: 7.22 (1H, t, J= 7.7 Hz), 7.17 (1H, d, J = 2.4 Hz), 7.11-7.05 (2H, m), 3.11 (4H, t, J= 4.9 Hz), 2.45 (4H, t, J = 5.0 Hz), 2.22 (3H, s), 1.07 (12H, s). 1- (3-Bromophenyl) -4-methylpiperazine (1.17 g, 4.57 mmol) was dissolved in 1,4-dioxane (18 mL) under an argon atmosphere. Bispinacolate diboron (1.39 g, 5.48 mmol), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (75 mg, 0.091 mmol), potassium acetate (897 mg, 9.14 mmol) was added. The inside of the reaction vessel was evacuated and purged with argon. This operation was repeated 3 times, followed by stirring at 80 ° C. for 21 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (1.26 g, 91%). Brown oil: 1 H-NMR (DMSO-D 6 ) δ: 7.22 (1H, t, J = 7.7 Hz), 7.17 (1H, d, J = 2.4 Hz), 7.11-7.05 (2H, m), 3.11 ( 4H, t, J = 4.9 Hz), 2.45 (4H, t, J = 5.0 Hz), 2.22 (3H, s), 1.07 (12H, s).

工程３
6-ブロモ-3-(3-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン Process 3
6-Bromo-3- (3- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine

Figure JPOXMLDOC01-appb-C000198
Figure JPOXMLDOC01-appb-C000198

　6-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジンの合成 (実施例48、工程4) と同様の手法で、6-ブロモ-3-ヨードイミダゾ[1,2-a]ピリジン (350 mg, 1.08 mmol) および1-メチル-4-(3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン (360 mg, 1.12 mmol) から標記化合物 (136 mg, 34%) を得た。淡黄色オイル: 1H-NMR (DMSO-D6) δ: 8.58 (1H, d, J = 1.0 Hz), 7.78 (1H, s), 7.65 (1H, d, J = 9.5 Hz), 7.42-7.37 (2H, m), 7.14 (1H, s), 7.07-7.03 (2H, m), 3.22 (4H, t, J = 4.9 Hz), 2.46 (4H, t, J= 4.8 Hz), 2.23 (3H, s). Synthesis of 6-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine (Example 48, Step 4) 3-Iodoimidazo [1,2-a] pyridine (350 mg, 1.08 mmol) and 1-methyl-4- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 The title compound (136 mg, 34%) was obtained from -yl) phenyl) piperazine (360 mg, 1.12 mmol). Pale yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.58 (1H, d, J = 1.0 Hz), 7.78 (1H, s), 7.65 (1H, d, J = 9.5 Hz), 7.42-7.37 (2H, m), 7.14 (1H, s), 7.07-7.03 (2H, m), 3.22 (4H, t, J = 4.9 Hz), 2.46 (4H, t, J = 4.8 Hz), 2.23 (3H, s).

工程４
3-(3-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド Process 4
3- (3- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000199
Figure JPOXMLDOC01-appb-C000199

　3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒドの合成 (実施例48、工程5) と同様の手法で、6-ブロモ-3-(3-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン (101 mg, 0.272 mmol) から標記化合物 5 mg, 40%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 10.0 (1H, s), 9.26 (1H, s), 7.88 (1H, s), 7.78-7.70 (1H, m), 7.60 (1H, dd, J = 9.4, 1.6 Hz), 7.43 (1H, t, J = 7.9 Hz), 7.20 (1H, s), 7.12 (1H, d, J = 7.6 Hz), 7.09 (1H, dd, J = 8.3, 2.2 Hz), 3.25 (4H, t, J = 4.9 Hz), 2.47 (4H, t, J = 5.0 Hz), 2.23 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (Example 48, Step 5) The title compound 5 mg, 40%) was obtained from -3- (3- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine (101 mg, 0.272 mmol). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, s), 9.26 (1H, s), 7.88 (1H, s), 7.78-7.70 (1H, m), 7.60 (1H, dd , J = 9.4, 1.6 Hz), 7.43 (1H, t, J = 7.9 Hz), 7.20 (1H, s), 7.12 (1H, d, J = 7.6 Hz), 7.09 (1H, dd, J = 8.3, 2.2 Hz), 3.25 (4H, t, J = 4.9 Hz), 2.47 (4H, t, J = 5.0 Hz), 2.23 (3H, s).

工程５
5-((3-(3-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物５０)  Process 5
5-((3- (3- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 50 )

Figure JPOXMLDOC01-appb-C000200
Figure JPOXMLDOC01-appb-C000200

　5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド (26  mg, 0.0812 mmol) およびロダニン (11 mg, 0.0812 mmol) から標記化合物 (16 mg, 46％)を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.77 (1H, s), 7.81 (1H, s), 7.73 (1H, d, J = 9.3 Hz), 7.49-7.44 (2H, m), 7.41 (1H, s), 7.32 (1H, s), 7.15 (1H, d, J = 7.6 Hz), 7.11 (1H, dd, J = 8.4, 2.1 Hz), 3.51 (4H, br.s), 3.25 (4H, br.s), 2.78 (3H, s).
ESI-MS(m/z): 436[M+H]+. Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) Methodally, 3- (3- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (26 mg, 0.0812 mmol) and rhodanine (11 mg, 0.0812 mmol) Gave the title compound (16 mg, 46%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.77 (1H, s), 7.81 (1H, s), 7.73 (1H, d, J = 9.3 Hz), 7.49-7.44 (2H, m), 7.41 (1H, s), 7.32 (1H, s), 7.15 (1H, d, J = 7.6 Hz), 7.11 (1H, dd, J = 8.4, 2.1 Hz), 3.51 (4H, br.s), 3.25 (4H, br.s), 2.78 (3H, s).
ESI-MS (m / z): 436 [M + H] + .

実施例５１
5-((3-(3-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物５１) Example 51
5-((3- (3- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione (Compound 51)

Figure JPOXMLDOC01-appb-C000201
Figure JPOXMLDOC01-appb-C000201

工程１
　5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド (35 mg, 0.109 mmol) およびチアゾリジン-2,4-ジオン (13 mg, 0.109 mmol) から標記化合物 (9 mg, 21％)を得た。淡黄色固体: 1H-NMR (DMSO-D6) δ: 8.87 (1H, s), 7.82 (1H, s), 7.76-7.71 (2H, m), 7.50-7.41 (2H, m), 7.24 (1H, s), 7.13-7.07 (2H, m), 3.36 (4H, br.s), 2.86 (4H, br.s), 2.50 (3H, s).
ESI-MS(m/z): 420[M+H]+. Process 1
Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) Method, 3- (3- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (35 mg, 0.109 mmol) and thiazolidine-2,4-dione ( The title compound (9 mg, 21%) was obtained from 13 mg, 0.109 mmol). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.87 (1H, s), 7.82 (1H, s), 7.76-7.71 (2H, m), 7.50-7.41 (2H, m), 7.24 ( 1H, s), 7.13-7.07 (2H, m), 3.36 (4H, br.s), 2.86 (4H, br.s), 2.50 (3H, s).
ESI-MS (m / z): 420 [M + H] + .

実施例５２
5-((3-(6-(4-メチルピペラジン-1-イル)ピリジン-3-イル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物５２) Example 52
5-((3- (6- (4-Methylpiperazin-1-yl) pyridin-3-yl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidine-4- ON (compound 52)

工程１
1-(5-ブロモピリジン-2-イル)-4-メチルピペラジン Process 1
1- (5-Bromopyridin-2-yl) -4-methylpiperazine

Figure JPOXMLDOC01-appb-C000202
Figure JPOXMLDOC01-appb-C000202

　アルゴン雰囲気下、1-メチルピペラジン (179 μL, 1.62 mmol)、2,5-ジブロモピリジン (500 mg, 2.11 mmol) をトルエン (16 mL) に溶解した。そこへトリス(ジベンジリデンアセトン)ジパラジウム(0) (39 mg, 0.032 mmol)、キサントホス (73 mg, 0.097 mmol)、ナトリウム tert-ブトキシド (304 mg, 2.43 mmol) を加えた。反応容器内を脱気し、アルゴン置換した。この操作を3回繰り返した後、100℃で3時間撹拌した。反応液に水を加え、 酢酸エチルで抽出した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (372 mg, 90%) を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 8.16 (1H, d, J= 2.7 Hz), 7.68-7.65 (1H, m), 6.82 (1H, d, J = 9.0 Hz), 3.45 (4H, t, J= 5.1 Hz), 2.37 (4H, t, J = 5.1 Hz), 2.20 (3H, s). Under an argon atmosphere, 1-methylpiperazine (179 μL, 1.62 mmol) and 2,5-dibromopyridine (500 mg, 2.11 mmol) were dissolved in toluene (16 mL). Tris (dibenzylideneacetone) dipalladium (0) (39 mg, 0.032 mmol), xanthophos (73 mg, 0.097 mmol), sodium tert-butoxide (304 mg, 2.43 mmol) were added thereto. The inside of the reaction vessel was evacuated and purged with argon. This operation was repeated 3 times, followed by stirring at 100 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (372 mg, 90%). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 8.16 (1H, d, J = 2.7 Hz), 7.68-7.65 (1H, m), 6.82 (1H, d, J = 9.0 Hz), 3.45 ( 4H, t, J = 5.1 Hz), 2.37 (4H, t, J = 5.1 Hz), 2.20 (3H, s).

工程２
1-メチル-4-(5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピペリジン-2-イル)ピペラジン Process 2
1-methyl-4- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) piperidin-2-yl) piperazine

Figure JPOXMLDOC01-appb-C000203
Figure JPOXMLDOC01-appb-C000203

　アルゴン雰囲気下、1-(5-ブロモピリジン-2-イル)-4-メチルピペラジン (315 mg, 1.23 mmol) をテトラヒドロフラン (8 mL) に溶解し、-78℃に冷却した。そこへn-ブチルリチウムヘキサン溶液 (1.6 M, 923 μL, 1.48 mmol) を滴下し、-78℃で30分撹拌した。さらに2-イソプロポキシ-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン (299 μL, 1.48 mmol) のテトラヒドロフラン (2 mL) を滴下し、室温まで徐々に昇温させながら22時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加えクエンチし、酢酸エチルで抽出した。酢酸エチル層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (166 mg, 45%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.32 (1H, t, J = 0.9 Hz), 7.53-7.49 (1H, m), 6.64-6.61 (1H, m), 3.54 (4H, t, J = 5.1 Hz), 2.40-2.35 (4H, m), 2.21 (3H, s), 1.26 (12H, s). Under an argon atmosphere, 1- (5-bromopyridin-2-yl) -4-methylpiperazine (315 mg, 1.23 mmol) was dissolved in tetrahydrofuran (8 mL) and cooled to -78 ° C. An n-butyllithium hexane solution (1.6 M, 923 μL, 1.48 mmol) was added dropwise thereto, and the mixture was stirred at −78 ° C. for 30 minutes. Add 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (299 μL, 1.48 mmol) in tetrahydrofuran (2 mL) dropwise, and gradually warm to room temperature. Stir for hours. The reaction solution was quenched by adding saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (166 mg, 45%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.32 (1H, t, J = 0.9 Hz), 7.53-7.49 (1H, m), 6.64-6.61 (1H, m), 3.54 (4H, t , J = 5.1 Hz), 2.40-2.35 (4H, m), 2.21 (3H, s), 1.26 (12H, s).

工程３
6-ブロモ-3-(6-(4-メチルピペラジン-1-イル)ピリジン-3-イル)イミダゾ[1,2-a]ピリジン Process 3
6-Bromo-3- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) imidazo [1,2-a] pyridine

Figure JPOXMLDOC01-appb-C000204
Figure JPOXMLDOC01-appb-C000204

　6-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジンの合成(実施例48、工程4 ) と同様の手法で、6-ブロモ-3-ヨードイミダゾ[1,2-a]ピリジン (88 mg, 0.274 mmol) および1-メチル-4-(5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピペリジン-2-イル)ピペラジン (166 mg, 0.547 mmol) から標記化合物　(54 mg, 53%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 8.52-8.51 (1H, m), 8.36 (1H, d, J = 2.4 Hz), 7.83 (1H, dd, J = 8.8, 2.4 Hz), 7.70 (1H, s), 7.63 (1H, d, J = 9.5 Hz), 7.38 (1H, dd, J = 9.5, 2.0 Hz), 7.00 (1H, d, J = 8.8 Hz), 3.58 (4H, t, J = 5.0 Hz), 2.42 (4H, t, J = 5.0 Hz), 2.23 (3H, s). Synthesis of 6-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine (Example 48, Step 4) 3-Iodoimidazo [1,2-a] pyridine (88 mg, 0.274 mmol) and 1-methyl-4- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 The title compound (54 mg, 53%) was obtained from -yl) piperidin-2-yl) piperazine (166 mg, 0.547 mmol). White solid: 1 H-NMR (DMSO-D 6 ) δ: 8.52-8.51 (1H, m), 8.36 (1H, d, J = 2.4 Hz), 7.83 (1H, dd, J = 8.8, 2.4 Hz), 7.70 (1H, s), 7.63 (1H, d, J = 9.5 Hz), 7.38 (1H, dd, J = 9.5, 2.0 Hz), 7.00 (1H, d, J = 8.8 Hz), 3.58 (4H, t , J = 5.0 Hz), 2.42 (4H, t, J = 5.0 Hz), 2.23 (3H, s).

工程４
3-(6-(4-メチルピペラジン-1-イル)ピリジン-3-イル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド Process 4
3- (6- (4-Methylpiperazin-1-yl) pyridin-3-yl) imidazo [1,2-a] pyridine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000205
Figure JPOXMLDOC01-appb-C000205

　3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒドの合成 (実施例48、工程5 ) と同様の手法で、6-ブロモ-3-(6-(4-メチルピペラジン-1-イル)ピリジン-3-イル)イミダゾ[1,2-a]ピリジン (54 mg, 0.145 mmol) から標記化合物 (20 mg, 43%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 10.0 (1H, s), 9.21 (1H, t, J = 1.2 Hz), 8.45 (1H, d, J = 2.2 Hz), 7.88 (1H, dd, J = 8.9, 2.6 Hz), 7.82 (1H, s), 7.72 (1H, d, J = 9.5 Hz), 7.58 (1H, dd, J = 9.4, 1.6 Hz), 7.04 (1H, d, J = 8.8 Hz), 3.61 (4H, t, J = 4.9 Hz), 2.43 (4H, t, J = 4.9 Hz), 2.24 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde in the same manner as in Example 48, Step 5) -3- (6- (4-Methylpiperazin-1-yl) pyridin-3-yl) imidazo [1,2-a] pyridine (54 mg, 0.145 mmol) gave the title compound (20 mg, 43%) It was. White solid: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, s), 9.21 (1H, t, J = 1.2 Hz), 8.45 (1H, d, J = 2.2 Hz), 7.88 (1H, dd, J = 8.9, 2.6 Hz), 7.82 (1H, s), 7.72 (1H, d, J = 9.5 Hz), 7.58 (1H, dd, J = 9.4, 1.6 Hz), 7.04 (1H, d, J = 8.8 Hz), 3.61 (4H, t, J = 4.9 Hz), 2.43 (4H, t, J = 4.9 Hz), 2.24 (3H, s).

工程５
5-((3-(6-(4-メチルピペラジン-1-イル)ピリジン-3-イル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物５２)  Process 5
5-((3- (6- (4-Methylpiperazin-1-yl) pyridin-3-yl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidine-4- ON (compound 52)

Figure JPOXMLDOC01-appb-C000206
Figure JPOXMLDOC01-appb-C000206

　5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(6-(4-メチルピペラジン-1-イル)ピリジン-3-イル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド (20 mg, 0.0622 mmol) およびロダニン (8 mg, 0.0622 mmol) から標記化合物 (10 mg, 38％)を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.72 (1H, s), 8.46 (1H, d, J= 2.4 Hz), 7.96 (1H, dd, J = 8.8, 2.4 Hz), 7.76 (1H, s), 7.73 (1H, d, J= 9.3 Hz), 7.45-7.42 (2H, m), 7.12 (1H, d, J = 8.8 Hz), 3.79 (4H, br.s), 3.06 (4H, br.s), 2.68 (3H, s).
ESI-MS(m/z): 437[M+H]+. Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) imidazo [1,2-a] pyridine-6-carbaldehyde (20 mg, 0.0622 mmol) and rhodanine (8 mg , 0.0622 mmol) gave the title compound (10 mg, 38%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.72 (1H, s), 8.46 (1H, d, J = 2.4 Hz), 7.96 (1H, dd, J = 8.8, 2.4 Hz), 7.76 ( 1H, s), 7.73 (1H, d, J = 9.3 Hz), 7.45-7.42 (2H, m), 7.12 (1H, d, J = 8.8 Hz), 3.79 (4H, br.s), 3.06 (4H , br.s), 2.68 (3H, s).
ESI-MS (m / z): 437 [M + H] + .

実施例５３
5-((3-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物５３)  Example 53
5-((3- (4-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 53)

工程１
4-(6-ブロモイミダゾ[1,2-a]ピリジン-3-イル)ベンズアルデヒド Process 1
4- (6-Bromoimidazo [1,2-a] pyridin-3-yl) benzaldehyde

Figure JPOXMLDOC01-appb-C000207
Figure JPOXMLDOC01-appb-C000207

　6-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジンの合成(実施例48、工程4) と同様の手法で、6-ブロモ-3-ヨードイミダゾ[1,2-a]ピリジン (350 mg, 1.08 mmol) および4-ホルミルボロン酸 (178 mg, 1.12 mmol) から標記化合物　(236 mg, 73%) を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 10.1 (1H, s), 8.83 (1H, dd, J = 1.7, 0.7 Hz), 8.09-8.05 (2H, m), 8.00 (1H, s), 7.98-7.95 (2H, m), 7.71 (1H, dd, J = 9.5, 0.7 Hz), 7.50 (1H, dd, J = 9.5, 1.7 Hz). In the same manner as in the synthesis of 6-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine (Example 48, Step 4), 6-bromo- The title compound (236 mg, 73%) was obtained from 3-iodoimidazo [1,2-a] pyridine (350 mg, 1.08 mmol) and 4-formylboronic acid (178 mg, 1.12 mmol). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, s), 8.83 (1H, dd, J = 1.7, 0.7 Hz), 8.09-8.05 (2H, m), 8.00 (1H, s ), 7.98-7.95 (2H, m), 7.71 (1H, dd, J = 9.5, 0.7 Hz), 7.50 (1H, dd, J = 9.5, 1.7 Hz).

工程２
6-ブロモ-3-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン Process 2
6-Bromo-3- (4-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine

Figure JPOXMLDOC01-appb-C000208
Figure JPOXMLDOC01-appb-C000208

　アルゴン雰囲気下、 4-(6-ブロモイミダゾ[1,2-a]ピリジン-3-イル)ベンズアルデヒド (236 mg, 0.784 mmol) を塩化メチレン (4 mL) に溶解した。そこへN-メチルピペラジン (86 μL, 0.784 mmol)、酢酸 (49 μL, 0.909 mmol) を加え、室温で5分撹拌した。さらにナトリウム トリアセトキシボロヒドリド (174 mg, 0.823 mmol) を加え、室温で23時間撹拌した。反応液に飽和重層水を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、 無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (NHカラム, ヘキサン/酢酸エチル) で精製し、標記化合物 (211 mg, 70%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.64 (1H, dd, J = 1.8, 0.9 Hz), 7.79 (1H, s), 7.67-7.62 (3H, m), 7.47 (2H, d, J= 8.3 Hz), 7.42 (1H, dd, J = 9.5, 1.7 Hz), 3.52 (2H, s), 2.48-2.28 (8H, m), 2.16 (3H, s). 4- (6-Bromoimidazo [1,2-a] pyridin-3-yl) benzaldehyde (236 mg, 0.784 mmol) was dissolved in methylene chloride (4 mL) under an argon atmosphere. Thereto were added N-methylpiperazine (86 μL, 0.784 mmol) and acetic acid (49 μL, 0.909 mmol), followed by stirring at room temperature for 5 minutes. Sodium triacetoxyborohydride (174 mg, 0.823 mmol) was further added, and the mixture was stirred at room temperature for 23 hours. Saturated multistory water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (NH column, hexane / ethyl acetate) to obtain the title compound (211 mg, 70%). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.64 (1H, dd, J = 1.8, 0.9 Hz), 7.79 (1H, s), 7.67-7.62 (3H, m), 7.47 (2H, d , J = 8.3 Hz), 7.42 (1H, dd, J = 9.5, 1.7 Hz), 3.52 (2H, s), 2.48-2.28 (8H, m), 2.16 (3H, s).

工程３
3-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド Process 3
3- (4-((4-Methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000209
Figure JPOXMLDOC01-appb-C000209

　3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒドの合成 (実施例48、工程5) と同様の手法で、6-ブロモ-3-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン (211 mg, 0.548 mmol) から標記化合物 (81 mg, 46%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 10.02 (1H, s), 9.31 (1H, s), 7.90 (1H, s), 7.76-7.70 (2H, m), 7.62-7.60 (2H, m), 7.51 (2H, d, J = 8.1 Hz), 3.55 (2H, s), 2.50-2.33 (8H, m), 2.18 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (Example 48, Step 5) The title compound (81 mg, 46%) was obtained from -3- (4-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine (211 mg, 0.548 mmol) . Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 10.02 (1H, s), 9.31 (1H, s), 7.90 (1H, s), 7.76-7.70 (2H, m), 7.62-7.60 (2H , m), 7.51 (2H, d, J = 8.1 Hz), 3.55 (2H, s), 2.50-2.33 (8H, m), 2.18 (3H, s).

工程4
5-((3-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物５３)  Process 4
5-((3- (4-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 53)

Figure JPOXMLDOC01-appb-C000210
Figure JPOXMLDOC01-appb-C000210

　5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド (38 mg, 0.114 mmol) およびロダニン (15 mg, 0.114 mmol) から標記化合物 (30 mg, 59%)を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.75 (1H, s), 7.75-7.70 (3H, m), 7.53 (2H, d, J = 8.1 Hz), 7.47 (1H, dd, J = 9.5, 1.7 Hz), 7.33 (1H, s), 3.68 (2H, s), 3.39-3.28 (4H, m), 3.18-2.99 (4H, m), 2.69 (3H, s).
ESI-MS(m/z): 450[M+H]+. Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (4-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (38 mg, 0.114 mmol) and rhodanine (15 mg, The title compound (30 mg, 59%) was obtained from 0.114 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.75 (1H, s), 7.75-7.70 (3H, m), 7.53 (2H, d, J = 8.1 Hz), 7.47 (1H, dd, J = 9.5, 1.7 Hz), 7.33 (1H, s), 3.68 (2H, s), 3.39-3.28 (4H, m), 3.18-2.99 (4H, m), 2.69 (3H, s).
ESI-MS (m / z): 450 [M + H] + .

実施例５４
5-((3-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン ((化合物５４) Example 54
5-((3- (4-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione ((compound 54)

Figure JPOXMLDOC01-appb-C000211
Figure JPOXMLDOC01-appb-C000211

工程１
　5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド (37 mg, 0.111 mmol) およびチアゾリジン-2,4-ジオン (13 mg, 0.111 mmol) から標記化合物 (9 mg, 18％)を得た。黄色固体: ESI-MS(m/z): 434[M+H]+. Process 1
Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (4-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (37 mg, 0.111 mmol) and thiazolidine-2,4 The title compound (9 mg, 18%) was obtained from -dione (13 mg, 0.111 mmol). Yellow solid: ESI-MS (m / z): 434 [M + H] + .

実施例５５
5-((3-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物５５)  Example 55
5-((3- (3-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 55)

工程１
3-(6-ブロモイミダゾ[1,2-a]ピリジン-3-イル)ベンズアルデヒド Process 1
3- (6-Bromoimidazo [1,2-a] pyridin-3-yl) benzaldehyde

Figure JPOXMLDOC01-appb-C000212
Figure JPOXMLDOC01-appb-C000212

　6-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジンの合成(実施例48、工程4) と同様の手法で、6-ブロモ-3-ヨードイミダゾ[1,2-a]ピリジン (700 mg, 2.17 mmol) および3-ホルミルフェニルホロン酸 (390 mg, 2.60 mmol) から標記化合物 (378 mg, 58%) を得た。褐色固体: 1H-NMR (DMSO-D6) δ: 10.1 (1H, s), 8.77 (1H, d, J = 1.0 Hz), 8.22 (1H, s), 8.04 (1H, dd, J = 7.6, 1.2 Hz), 7.97 (1H, dd, J = 7.6, 1.2 Hz), 7.92 (1H, s), 7.78 (1H, t, J = 7.6 Hz), 7.69 (1H, d, J = 9.5 Hz), 7.47 (1H, dd, J = 9.5, 1.7 Hz). In the same manner as in the synthesis of 6-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine (Example 48, Step 4), 6-bromo- The title compound (378 mg, 58%) was obtained from 3-iodoimidazo [1,2-a] pyridine (700 mg, 2.17 mmol) and 3-formylphenylboronic acid (390 mg, 2.60 mmol). Brown solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, s), 8.77 (1H, d, J = 1.0 Hz), 8.22 (1H, s), 8.04 (1H, dd, J = 7.6 , 1.2 Hz), 7.97 (1H, dd, J = 7.6, 1.2 Hz), 7.92 (1H, s), 7.78 (1H, t, J = 7.6 Hz), 7.69 (1H, d, J = 9.5 Hz), 7.47 (1H, dd, J = 9.5, 1.7 Hz).

工程２
6-ブロモ-3-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン Process 2
6-Bromo-3- (3-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine

Figure JPOXMLDOC01-appb-C000213
Figure JPOXMLDOC01-appb-C000213

　6-ブロモ-3-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジンの合成 (実施例53、工程2) と同様の手法で、3-(6-ブロモイミダゾ[1,2-a]ピリジン-3-イル)ベンズアルデヒド (378 mg, 1.26 mmol) および1-メチルピペラジン(180 μL, 1.64 mmol) から標記化合物 (343 mg, 71%)を得た。無色オイル: 1H-NMR (DMSO-D6) δ: 8.61 (1H, d, J = 0.7 Hz), 7.80 (1H, s), 7.66 (1H, d, J= 9.5 Hz), 7.57-7.49 (3H, m), 7.42 (1H, dd, J = 9.5, 2.0 Hz), 7.38 (1H, d, J = 7.6 Hz), 3.55 (2H, s), 2.42 (4H, br.s), 2.34 (4H, br.s), 2.15 (3H, s). Synthesis of 6-bromo-3- (4-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine (Example 53, Step 2) The title compound (343 mg, 71%) was obtained from-(6-bromoimidazo [1,2-a] pyridin-3-yl) benzaldehyde (378 mg, 1.26 mmol) and 1-methylpiperazine (180 μL, 1.64 mmol). Obtained. Colorless oil: 1 H-NMR (DMSO-D 6 ) δ: 8.61 (1H, d, J = 0.7 Hz), 7.80 (1H, s), 7.66 (1H, d, J = 9.5 Hz), 7.57-7.49 ( 3H, m), 7.42 (1H, dd, J = 9.5, 2.0 Hz), 7.38 (1H, d, J = 7.6 Hz), 3.55 (2H, s), 2.42 (4H, br.s), 2.34 (4H , br.s), 2.15 (3H, s).

工程３
3-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド Process 3
3- (3-((4-Methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000214
Figure JPOXMLDOC01-appb-C000214

　3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒドの合成 (実施例48、工程5) と同様の手法で、6-ブロモ-3-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン(343 mg, 0.890 mmol) から標記化合物 (166 mg, 56%) を得た。橙色オイル: 1H-NMR (DMSO-D6) δ: 10.00 (1H, s), 9.26 (1H, s), 7.91 (1H, s), 7.77-7.74 (1H, m), 7.67-7.61 (3H, m), 7.56-7.54 (1H, m), 7.44 (1H, d, J = 7.6 Hz), 3.58 (2H, s), 2.42 (4H, br.s), 2.33 (4H, br.s), 2.15 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (Example 48, Step 5) The title compound (166 mg, 56%) was obtained from -3- (3-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine (343 mg, 0.890 mmol) . Orange oil: 1 H-NMR (DMSO-D 6 ) δ: 10.00 (1H, s), 9.26 (1H, s), 7.91 (1H, s), 7.77-7.74 (1H, m), 7.67-7.61 (3H , m), 7.56-7.54 (1H, m), 7.44 (1H, d, J = 7.6 Hz), 3.58 (2H, s), 2.42 (4H, br.s), 2.33 (4H, br.s), 2.15 (3H, s).

工程４
5-((3-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物５５)  Process 4
5-((3- (3-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 55)

Figure JPOXMLDOC01-appb-C000215
Figure JPOXMLDOC01-appb-C000215

　5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド (71 mg,  0.212 mmol) およびロダニン (28 mg, 0.212 mmol) から標記化合物 (35 mg, 37%)を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.71 (1H, s), 7.83 (1H, s), 7.77-7.71 (2H, m), 7.63-7.54 (2H, m), 7.51-7.47 (1H, m), 7.44-7.41 (1H, m), 7.29 (1H, s), 3.73 (2H, s), 3.32 (4H, br.s), 3.10 (4H, br.s), 2.68 (3H, s).
ESI-MS(m/z): 450[M+H]+. Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (3-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (71 mg, 0.212 mmol) and rhodanine (28 mg, The title compound (35 mg, 37%) was obtained from 0.212 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.71 (1H, s), 7.83 (1H, s), 7.77-7.71 (2H, m), 7.63-7.54 (2H, m), 7.51-7.47 (1H, m), 7.44-7.41 (1H, m), 7.29 (1H, s), 3.73 (2H, s), 3.32 (4H, br.s), 3.10 (4H, br.s), 2.68 (3H , s).
ESI-MS (m / z): 450 [M + H] + .

実施例５６
5-((3-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物５６)  Example 56
5-((3- (3-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione (Compound 56 )

Figure JPOXMLDOC01-appb-C000216
Figure JPOXMLDOC01-appb-C000216

工程１
　アルゴン雰囲気下、チアゾリジン-2,4-ジオン (56 mg, 0.284 mmol)、ピロリジン (4.7 μL, 0.057 mmol) をメタノール (0.5 mL) に溶解し、70℃にした。そこへ3-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド (95 mg, 0.284 mmol) のメタノール (0.5 mL) 溶液を滴下し、7時間加熱還流した。反応液を冷却した後、濃縮した。少量のエタノールを加え、析出した固体をろ取、真空乾燥して標記化合物 (21 mg, 17％) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.78 (1H, s), 7.82 (1H, s), 7.73 (1H, d, J = 9.5 Hz), 7.68-7.65 (1H, m), 7.62-7.46 (2H, m), 7.42-7.39 (2H, m), 7.28-7.25 (1H, m), 4.14 (2H, s), 2.83 (4H, br.s), 2.57 (4H, br.s), 2.47 (3H, s).
ESI-MS(m/z): 434[M+H]+. Process 1
Under an argon atmosphere, thiazolidine-2,4-dione (56 mg, 0.284 mmol) and pyrrolidine (4.7 μL, 0.057 mmol) were dissolved in methanol (0.5 mL) and brought to 70 ° C. 3- (3-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (95 mg, 0.284 mmol) in methanol (0.5 mL) Was added dropwise and heated to reflux for 7 hours. The reaction solution was cooled and then concentrated. A small amount of ethanol was added, and the precipitated solid was collected by filtration and dried in vacuo to obtain the title compound (21 mg, 17%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.78 (1H, s), 7.82 (1H, s), 7.73 (1H, d, J = 9.5 Hz), 7.68-7.65 (1H, m), 7.62-7.46 (2H, m), 7.42-7.39 (2H, m), 7.28-7.25 (1H, m), 4.14 (2H, s), 2.83 (4H, br.s), 2.57 (4H, br.s ), 2.47 (3H, s).
ESI-MS (m / z): 434 [M + H] + .

実施例５７
5-((3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物５７) Example 57
5-((3- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 57)

工程１
6-ブロモ-3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン Process 1
6-Bromo-3- (3-((4-ethylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine

Figure JPOXMLDOC01-appb-C000217
Figure JPOXMLDOC01-appb-C000217

　アルゴン雰囲気下、3-(6-ブロモイミダゾ[1,2-a]ピリジン-3-イル)ベンズアルデヒド (209 mg, 0.694 mmol) を塩化メチレン (3 mL) に溶解した。そこへ 1-エチルピペラジン (176 μL, 1.39 mmol) を加え、室温で1時間撹拌した。さらにナトリウム トリアセトキシボロヒドリド (221 mg, 1.04 mmol) を加え、室温で15時間撹拌した。反応液に飽和重層水を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (178 mg, 64%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.61 (1H, dd, J = 2.0, 0.7 Hz), 7.81 (1H, s), 7.67 (1H, dd, J = 9.5, 0.7 Hz), 7.58-7.55 (2H, m), 7.51 (1H, t, J = 7.4 Hz), 7.43 (1H, dd, J = 9.5, 2.0 Hz), 7.38 (1H, d, J = 7.6 Hz), 3.56 (2H, s), 2.49-2.29 (8H, m), 2.30 (3H, q, J = 7.2 Hz), 0.97 (3H, t, J = 7.2 Hz). Under an argon atmosphere, 3- (6-bromoimidazo [1,2-a] pyridin-3-yl) benzaldehyde (209 mg, 0.694 mmol) was dissolved in methylene chloride (3 mL). 1-ethylpiperazine (176 μL, 1.39 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (221 mg, 1.04 mmol) was further added, and the mixture was stirred at room temperature for 15 hours. Saturated multistory water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (178 mg, 64%). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.61 (1H, dd, J = 2.0, 0.7 Hz), 7.81 (1H, s), 7.67 (1H, dd, J = 9.5, 0.7 Hz), 7.58-7.55 (2H, m), 7.51 (1H, t, J = 7.4 Hz), 7.43 (1H, dd, J = 9.5, 2.0 Hz), 7.38 (1H, d, J = 7.6 Hz), 3.56 (2H , s), 2.49-2.29 (8H, m), 2.30 (3H, q, J = 7.2 Hz), 0.97 (3H, t, J = 7.2 Hz).

工程２
3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド Process 2
3- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000218
Figure JPOXMLDOC01-appb-C000218

　3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒドの合成 (実施例48、工程5) と同様の手法で、6-ブロモ-3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン(178 mg, 0.446 mmol) から標記化合物 (166 mg, 56%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 10.0 (1H, s), 9.26 (1H, s), 7.91 (1H, s), 7.75 (1H, d, J = 6.1 Hz), 7.67-7.60 (2H, m), 7.58-7.51 (1H, m), 7.44 (1H, d, J = 7.6 Hz), 7.38-7.28 (1H, m), 3.58 (2H, s), 2.45-2.26 (11H, m), 0.97 (3H, t, J = 7.2 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (Example 48, Step 5) -3- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine (178 mg, 0.446 mmol) gave the title compound (166 mg, 56%) . Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, s), 9.26 (1H, s), 7.91 (1H, s), 7.75 (1H, d, J = 6.1 Hz), 7.67- 7.60 (2H, m), 7.58-7.51 (1H, m), 7.44 (1H, d, J = 7.6 Hz), 7.38-7.28 (1H, m), 3.58 (2H, s), 2.45-2.26 (11H, m), 0.97 (3H, t, J = 7.2 Hz).

工程３
5-((3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物５７)  Process 3
5-((3- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 57)

Figure JPOXMLDOC01-appb-C000219
Figure JPOXMLDOC01-appb-C000219

　5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド (49  mg, 0.141 mmol) およびロダニン (19 mg, 0.141 mmol) から標記化合物 (31 mg, 47%)を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.70 (1H, s), 7.83 (1H, s), 7.77-7.71 (1H, m), 7.63-7.55 (3H, m), 7.49 (1H, d, J = 9.5 Hz), 7.43 (1H, d, J= 7.6 Hz), 7.29 (1H, s), 3.74 (2H, s), 3.44 (3H, q, J = 7.0 Hz), 3.04-2.99 (8H, m), 1.06 (3H, t, J = 7.0 Hz).
ESI-MS(m/z): 464[M+H]+. Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (3-((4-ethylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (49 mg, 0.141 mmol) and rhodanine (19 mg, The title compound (31 mg, 47%) was obtained from 0.141 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.70 (1H, s), 7.83 (1H, s), 7.77-7.71 (1H, m), 7.63-7.55 (3H, m), 7.49 (1H , d, J = 9.5 Hz), 7.43 (1H, d, J = 7.6 Hz), 7.29 (1H, s), 3.74 (2H, s), 3.44 (3H, q, J = 7.0 Hz), 3.04-2.99 (8H, m), 1.06 (3H, t, J = 7.0 Hz).
ESI-MS (m / z): 464 [M + H] + .

実施例５８
5-((3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物５８) Example 58
5-((3- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione (Compound 58 )

Figure JPOXMLDOC01-appb-C000220
Figure JPOXMLDOC01-appb-C000220

工程１
　5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド (57 mg, 0.164 mmol) およびチアゾリジン-2,4-ジオン (19 mg, 0.164 mmol) から標記化合物 (5 mg, 7%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 8.51 (1H, s), 7.77 (1H, s), 7.66-7.50 (4H, m), 7.41-7.35 (2H, m), 7.30-7.23 (1H, m), 3.64-3.54 (5H, m), 2.53-2.41 (8H, m), 1.03-0.99 (3H, m).
ESI-MS(m/z): 448[M+H]+. Process 1
Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (3-((4-ethylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (57 mg, 0.164 mmol) and thiazolidine-2,4 The title compound (5 mg, 7%) was obtained from -dione (19 mg, 0.164 mmol). White solid: 1 H-NMR (DMSO-D 6 ) δ: 8.51 (1H, s), 7.77 (1H, s), 7.66-7.50 (4H, m), 7.41-7.35 (2H, m), 7.30-7.23 (1H, m), 3.64-3.54 (5H, m), 2.53-2.41 (8H, m), 1.03-0.99 (3H, m).
ESI-MS (m / z): 448 [M + H] + .

実施例５９
5-((3-(3-((4-ブチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物５９)  Example 59
5-((3- (3-((4-Butylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidine-4-one (Compound 59)

工程１
6-ブロモ-3-(3-((4-ブチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン Process 1
6-Bromo-3- (3-((4-butylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine

Figure JPOXMLDOC01-appb-C000221
Figure JPOXMLDOC01-appb-C000221

　6-ブロモ-3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジンの合成 (実施例57、工程1) と同様の手法で、3-(6-ブロモイミダゾ[1,2-a]ピリジン-3-イル)ベンズアルデヒド (246 mg, 0.817 mmol) および1-ブチルピペラジン(232 mg,  1.63 mmol) から標記化合物 (362 mg, 92%)を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.61 (1H, d, J = 1.2 Hz), 7.80 (1H, s), 7.67 (1H, d, J = 9.5 Hz), 7.58-7.55 (2H, m), 7.51 (1H, t, J = 7.6 Hz), 7.42 (1H, dd, J = 9.6, 1.8 Hz), 7.38 (1H, d, J = 7.6 Hz), 3.56 (2H, s), 2.46-2.33 (8H, m), 2.24 (2H, t, J= 7.3 Hz), 1.42-1.34 (2H, m), 1.31-1.24 (2H, m), 0.86 (3H, t, J = 7.3 Hz). Synthesis of 6-bromo-3- (3-((4-ethylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine (Example 57, Step 1) The title compound (362 mg, 92%) was obtained from-(6-bromoimidazo [1,2-a] pyridin-3-yl) benzaldehyde (246 mg, 0.817 mmol) and 1-butylpiperazine (232 mg, 1.63 mmol). Obtained. Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.61 (1H, d, J = 1.2 Hz), 7.80 (1H, s), 7.67 (1H, d, J = 9.5 Hz), 7.58-7.55 ( 2H, m), 7.51 (1H, t, J = 7.6 Hz), 7.42 (1H, dd, J = 9.6, 1.8 Hz), 7.38 (1H, d, J = 7.6 Hz), 3.56 (2H, s), 2.46-2.33 (8H, m), 2.24 (2H, t, J = 7.3 Hz), 1.42-1.34 (2H, m), 1.31-1.24 (2H, m), 0.86 (3H, t, J = 7.3 Hz) .

工程２
3-(3-((4-ブチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド  Process 2
3- (3-((4-Butylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000222
Figure JPOXMLDOC01-appb-C000222

　3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒドの合成 (実施例48、工程5) と同様の手法で、6-ブロモ-3-(3-((4-ブチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン(362 mg, 0.753 mmol) から標記化合物 (166 mg, 56%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 10.0 (1H, s), 9.27 (1H, s), 7.91 (1H, s), 7.77-7.75 (1H, m), 7.68-7.54 (4H, m), 7.43 (1H, d, J = 7.6 Hz), 3.57 (2H, s), 2.46-2.29 (8H, m), 2.24 (2H, q, J = 7.3 Hz), 1.41-1.34 (2H, m), 1.31-1.21 (2H, m), 0.86 (3H, t, J = 7.2 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (Example 48, Step 5) -3- (3-((4-Butylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine (362 mg, 0.753 mmol) gave the title compound (166 mg, 56%) . Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, s), 9.27 (1H, s), 7.91 (1H, s), 7.77-7.75 (1H, m), 7.68-7.54 (4H , m), 7.43 (1H, d, J = 7.6 Hz), 3.57 (2H, s), 2.46-2.29 (8H, m), 2.24 (2H, q, J = 7.3 Hz), 1.41-1.34 (2H, m), 1.31-1.21 (2H, m), 0.86 (3H, t, J = 7.2 Hz).

工程３
5-((3-(3-((4-ブチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物５９)  Process 3
5-((3- (3-((4-Butylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidine-4-one (Compound 59)

Figure JPOXMLDOC01-appb-C000223
Figure JPOXMLDOC01-appb-C000223

　5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-((4-ブチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド (477 mg, 0.204 mmol) およびロダニン (27 mg, 0.204 mmol) から標記化合物 (13 mg, 13%)を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.71 (1H, s), 7.84 (1H, s), 7.78-7.70 (1H, m), 7.65-7.55 (3H, m), 7.50 (1H, dd, J = 9.3, 1.7 Hz), 7.43 (1H, d, J = 7.6 Hz), 7.29 (1H, s), 3.74 (2H, s), 3.45-3.28 (4H, m), 3.04-2.99 (2H, m), 2.96-2.86 (4H, m), 1.58-1.49 (2H, m), 1.32-1.24 (2H, m), 0.89 (3H, t, J = 7.3 Hz).
ESI-MS(m/z): 492[M+H]+. Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (3-((4-butylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (477 mg, 0.204 mmol) and rhodanine (27 mg, The title compound (13 mg, 13%) was obtained from 0.204 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.71 (1H, s), 7.84 (1H, s), 7.78-7.70 (1H, m), 7.65-7.55 (3H, m), 7.50 (1H , dd, J = 9.3, 1.7 Hz), 7.43 (1H, d, J = 7.6 Hz), 7.29 (1H, s), 3.74 (2H, s), 3.45-3.28 (4H, m), 3.04-2.99 ( 2H, m), 2.96-2.86 (4H, m), 1.58-1.49 (2H, m), 1.32-1.24 (2H, m), 0.89 (3H, t, J = 7.3 Hz).
ESI-MS (m / z): 492 [M + H] + .

実施例６０
5-((3-(3-((4-ブチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物６０)  Example 60
5-((3- (3-((4-Butylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione (Compound 60 )

Figure JPOXMLDOC01-appb-C000224
Figure JPOXMLDOC01-appb-C000224

工程１
　5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-((4-ブチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド (74 mg, 0.197 mmol) およびチアゾリジン-2,4-ジオン (23 mg, 0.197 mmol) から標記化合物 (26 mg, 27%)を得た。褐色固体: 1H-NMR (DMSO-D6) δ: 8.76 (1H, s), 7.81 (1H, s), 7.77-7.71 (1H, m), 7.66-7.47 (3H, m), 7.42-7.35 (2H, m), 7.31-7.22 (1H, m), 3.65-3.55 (5H, m), 2.62-2.42 (8H, m), 1.48-1.40 (2H, m), 1.30-1.21 (6H, m), 0.85 (3H, t, J = 6.7 Hz).
ESI-MS(m/z): 504[M+H]+. Process 1
Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (3-((4-butylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (74 mg, 0.197 mmol) and thiazolidine-2,4 The title compound (26 mg, 27%) was obtained from -dione (23 mg, 0.197 mmol). Brown solid: 1 H-NMR (DMSO-D 6 ) δ: 8.76 (1H, s), 7.81 (1H, s), 7.77-7.71 (1H, m), 7.66-7.47 (3H, m), 7.42-7.35 (2H, m), 7.31-7.22 (1H, m), 3.65-3.55 (5H, m), 2.62-2.42 (8H, m), 1.48-1.40 (2H, m), 1.30-1.21 (6H, m) , 0.85 (3H, t, J = 6.7 Hz).
ESI-MS (m / z): 504 [M + H] + .

実施例６１
5-((3-(3-((4-ヘキシルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物６１)  Example 61
5-((3- (3-((4-Hexylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidine-4-one (Compound 61)

工程１
6-ブロモ-3-(3-((4-ヘキシルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン Process 1
6-Bromo-3- (3-((4-hexylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine

Figure JPOXMLDOC01-appb-C000225
Figure JPOXMLDOC01-appb-C000225

　6-ブロモ-3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジンの合成 (実施例57、工程1) と同様の手法で、3-(6-ブロモイミダゾ[1,2-a]ピリジン-3-イル)ベンズアルデヒド (207 mg, 0.687 mmol) および1-ヘキシルピペラジン(272 μL, 1.37 mmol) から標記化合物 (283 mg, 90%)を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.61 (1H, t, J = 0.9 Hz), 7.80 (1H, s), 7.67 (1H, dd, J= 9.5, 0.7 Hz), 7.58-7.55 (2H, m), 7.51 (1H, t, J = 7.6 Hz), 7.43 (1H, dd, J = 9.5, 1.7 Hz), 7.38 (1H, d, J = 7.3 Hz), 3.55 (2H, s), 2.46-2.33 (8H, m), 2.23 (2H, t, J = 7.2 Hz), 1.40-1.37 (2H, m), 1.29-1.22 (6H, m), 0.88-0.83 (3H, m). Synthesis of 6-bromo-3- (3-((4-ethylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine (Example 57, Step 1) The title compound (283 mg, 90%) was obtained from-(6-bromoimidazo [1,2-a] pyridin-3-yl) benzaldehyde (207 mg, 0.687 mmol) and 1-hexylpiperazine (272 μL, 1.37 mmol). Obtained. Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.61 (1H, t, J = 0.9 Hz), 7.80 (1H, s), 7.67 (1H, dd, J = 9.5, 0.7 Hz), 7.58- 7.55 (2H, m), 7.51 (1H, t, J = 7.6 Hz), 7.43 (1H, dd, J = 9.5, 1.7 Hz), 7.38 (1H, d, J = 7.3 Hz), 3.55 (2H, s ), 2.46-2.33 (8H, m), 2.23 (2H, t, J = 7.2 Hz), 1.40-1.37 (2H, m), 1.29-1.22 (6H, m), 0.88-0.83 (3H, m).

工程２
3-(3-((4-ヘキシルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド  Process 2
3- (3-((4-Hexylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000226
Figure JPOXMLDOC01-appb-C000226

　3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒドの合成 (実施例48、工程5) と同様の手法で、6-ブロモ-3-(3-((4-ヘキシルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン(283 mg, 0.621 mmol) から標記化合物 (166 mg, 56%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 10.0 (1H, s), 9.26 (1H, s), 7.91 (1H, s), 7.77-7.75 (1H, m), 7.67-7.61 (3H, m), 7.58-7.54 (1H, m), 7.44 (1H, d, J = 7.8 Hz), 3.58 (2H, s), 2.47-2.20 (11H, m), 1.42-1.35 (2H, m), 1.27-1.22 (6H, m), 0.87-0.83 (3H, m). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (Example 48, Step 5) -3- (3-((4-Hexylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine (283 mg, 0.621 mmol) gave the title compound (166 mg, 56%) . Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, s), 9.26 (1H, s), 7.91 (1H, s), 7.77-7.75 (1H, m), 7.67-7.61 (3H , m), 7.58-7.54 (1H, m), 7.44 (1H, d, J = 7.8 Hz), 3.58 (2H, s), 2.47-2.20 (11H, m), 1.42-1.35 (2H, m), 1.27-1.22 (6H, m), 0.87-0.83 (3H, m).

工程３
5-((3-(3-((4-ヘキシルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物６１)  Process 3
5-((3- (3-((4-Hexylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidine-4-one (Compound 61)

Figure JPOXMLDOC01-appb-C000227
Figure JPOXMLDOC01-appb-C000227

5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-((4-ヘキシルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド (66 mg, 0.163 mmol) およびロダニン (21 mg, 0.163 mmol) から標記化合物 (33 mg, 39%)を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.72 (1H, s), 7.84 (1H, s), 7.77-7.71 (1H, m), 7.65-7.55 (3H, m), 7.49 (1H, dd, J = 9.5, 1.7 Hz), 7.43 (1H, d, J = 7.6 Hz), 7.33 (1H, s), 3.75 (2H, s), 3.38-3.27 (7H, m), 3.00-2.89 (4H, m), 1.60-1.53 (2H, m), 1.29-1.23 (6H, m), 0.86 (3H, t, J= 6.8 Hz).
ESI-MS(m/z): 520[M+H]+. Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (3-((4-hexylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (66 mg, 0.163 mmol) and rhodanine (21 mg, The title compound (33 mg, 39%) was obtained from 0.163 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.72 (1H, s), 7.84 (1H, s), 7.77-7.71 (1H, m), 7.65-7.55 (3H, m), 7.49 (1H , dd, J = 9.5, 1.7 Hz), 7.43 (1H, d, J = 7.6 Hz), 7.33 (1H, s), 3.75 (2H, s), 3.38-3.27 (7H, m), 3.00-2.89 ( 4H, m), 1.60-1.53 (2H, m), 1.29-1.23 (6H, m), 0.86 (3H, t, J = 6.8 Hz).
ESI-MS (m / z): 520 [M + H] + .

実施例６２
5-((3-(3-((4-ヘキシルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物６２) Example 62
5-((3- (3-((4-Hexylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione (Compound 62 )

Figure JPOXMLDOC01-appb-C000228
Figure JPOXMLDOC01-appb-C000228

工程１
5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-((4-ヘキシルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド (77 mg, 0.190 mmol) およびチアゾリジン-2,4-ジオン (22 mg, 0.190 mmol) から標記化合物 (11 mg, 12%)を得た。褐色固体: 1H-NMR (DMSO-D6) δ: 8.76 (1H, s), 7.81 (1H, s), 7.77-7.71 (1H, m), 7.66-7.47 (3H, m), 7.42-7.35 (2H, m), 7.31-7.22 (1H, m), 3.65-3.55 (5H, m), 2.62-2.42 (8H, m), 1.48-1.40 (2H, m), 1.30-1.21 (6H, m), 0.85 (3H, t, J = 6.7 Hz).
ESI-MS(m/z): 504[M+H]+. Process 1
Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (3-((4-hexylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (77 mg, 0.190 mmol) and thiazolidine-2,4 The title compound (11 mg, 12%) was obtained from -dione (22 mg, 0.190 mmol). Brown solid: 1 H-NMR (DMSO-D 6 ) δ: 8.76 (1H, s), 7.81 (1H, s), 7.77-7.71 (1H, m), 7.66-7.47 (3H, m), 7.42-7.35 (2H, m), 7.31-7.22 (1H, m), 3.65-3.55 (5H, m), 2.62-2.42 (8H, m), 1.48-1.40 (2H, m), 1.30-1.21 (6H, m) , 0.85 (3H, t, J = 6.7 Hz).
ESI-MS (m / z): 504 [M + H] + .

実施例６３
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物６３)  Example 63
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 63 )

工程１
6-クロロ-3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Process 1
6-Chloro-3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000229
Figure JPOXMLDOC01-appb-C000229

6-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジンの合成 (実施例48、工程4) と同様の手法で、3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (674 mg, 2.90 mmol) および1-メチル-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン (1.05 g、3.48 mmol) から標記化合物 (412 mg, 43%) を得た。淡黄色固体: 1H-NMR (DMSO-D6) δ: 8.25 (1H, d, J = 9.5 Hz), 8.20 (1H, s), 7.94 (2H, d, J= 8.8 Hz), 7.35 (1H, d, J = 9.5 Hz), 7.09 (2H, d, J = 9.0 Hz), 3.24 (4H, t, J = 5.0 Hz), 2.47 (5H, t, J = 5.0 Hz), 2.23 (3H, s). Synthesis of 6-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine (Example 48, Step 4) 6-Chloroimidazo [1,2-b] pyridazine (674 mg, 2.90 mmol) and 1-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 The title compound (412 mg, 43%) was obtained from -yl) phenyl) piperazine (1.05 g, 3.48 mmol). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.25 (1H, d, J = 9.5 Hz), 8.20 (1H, s), 7.94 (2H, d, J = 8.8 Hz), 7.35 (1H , d, J = 9.5 Hz), 7.09 (2H, d, J = 9.0 Hz), 3.24 (4H, t, J = 5.0 Hz), 2.47 (5H, t, J = 5.0 Hz), 2.23 (3H, s ).

工程２
3-(4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 2
3- (4- (4-Methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000230
Figure JPOXMLDOC01-appb-C000230

アルゴン雰囲気下、6-クロロ-3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (165 mg, 0.503 mmol) をトルエン (10 mL) に溶解した。そこへトリブチリビニルスズ (154 μL, 0.528 mmol)、テトラキストリフェニルホスフィンパラジウム (87 mg, 0.075 mmol) を加えた。反応容器内を脱気し、アルゴン置換した。この操作を3回繰り返した後、120℃で18時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出した。クロロホルム層を無水硫酸マグネシウムで乾燥させ、 溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (NHカラム, ヘキサン/酢酸エチル) で精製し、標記化合物 (黄色固体, 83 mg, 52%) を得た。1H-NMR (DMSO-D6) δ: 8.14 (1H, d, J = 9.5 Hz), 8.10 (1H, s), 8.02 (2H, d, J = 8.8 Hz), 7.65-7.53 (1H, m), 7.07 (2H, d, J = 9.0 Hz), 6.89 (1H, dd, J = 17.7, 11.1 Hz), 6.35 (1H, d, J = 17.8 Hz), 5.76 (1H, d, J = 11.2 Hz), 3.23 (4H, t, J = 4.9 Hz), 2.47 (4H, t, J = 5.0 Hz), 2.23 (3H, s). 6-Chloro-3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (165 mg, 0.503 mmol) was dissolved in toluene (10 mL) under an argon atmosphere. . Tributylirivinyltin (154 μL, 0.528 mmol) and tetrakistriphenylphosphine palladium (87 mg, 0.075 mmol) were added thereto. The inside of the reaction vessel was evacuated and purged with argon. This operation was repeated 3 times, followed by stirring at 120 ° C. for 18 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (NH column, hexane / ethyl acetate) to obtain the title compound (yellow solid, 83 mg, 52%). 1 H-NMR (DMSO-D 6 ) δ: 8.14 (1H, d, J = 9.5 Hz), 8.10 (1H, s), 8.02 (2H, d, J = 8.8 Hz), 7.65-7.53 (1H, m ), 7.07 (2H, d, J = 9.0 Hz), 6.89 (1H, dd, J = 17.7, 11.1 Hz), 6.35 (1H, d, J = 17.8 Hz), 5.76 (1H, d, J = 11.2 Hz) ), 3.23 (4H, t, J = 4.9 Hz), 2.47 (4H, t, J = 5.0 Hz), 2.23 (3H, s).

工程３
3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 3
3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000231
Figure JPOXMLDOC01-appb-C000231

アルゴン雰囲気下、3-(4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (48 mg, 0.135 mmol) を1,4-ジオキサン (1 mL)、水 (330 μL) に溶解した。そこへ 2,6-ルチジン (31 μL, 0.270 mmol)、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (34 μL, 2.70 μmol)、過ヨウ素酸ナトリウム (116 mg, 0.540 mmol) を加え、室温で6時間撹拌した。反応液に飽和チオ硫酸ナトリウム水溶液を加え、クロロホルムで抽出した。クロロホルム層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (31 mg, 72%) を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.7 Hz), 8.36 (1H, s), 8.35-8.32 (1H, m), 8.08 (2H, d, J = 9.0 Hz), 7.61 (1H, d, J= 9.5 Hz), 7.11 (2H, d, J = 9.0 Hz), 3.26 (4H, t, J = 4.9 Hz), 2.50-2.46 (4H, m), 2.24 (3H, s). Under argon atmosphere, 3- (4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (48 mg, 0.135 mmol) was added to 1,4-dioxane (1 mL ) And water (330 μL). 2,6-lutidine (31 μL, 0.270 mmol), 2.5 wt% osmium tetroxide tert-butanol solution (34 μL, 2.70 μmol), sodium periodate (116 mg, 0.540 mmol) were added, and 6 at room temperature. Stir for hours. A saturated aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (31 mg, 72%). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.7 Hz), 8.36 (1H, s), 8.35-8.32 (1H, m), 8.08 (2H, d, J = 9.0 Hz), 7.61 (1H, d, J = 9.5 Hz), 7.11 (2H, d, J = 9.0 Hz), 3.26 (4H, t, J = 4.9 Hz), 2.50-2.46 (4H, m), 2.24 (3H, s).

工程４
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物６３)  Process 4
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 63 )

Figure JPOXMLDOC01-appb-C000232
Figure JPOXMLDOC01-appb-C000232

5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (43  mg, 0.134 mmol) およびロダニン (18 mg, 0.134 mmol) から標記化合物 (37 mg, 63%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.18 (1H, d, J = 9.3 Hz), 8.15 (1H, s), 8.09 (2H, d, J= 8.5 Hz), 7.56 (1H, d, J = 9.3 Hz), 7.32 (1H, s), 7.14 (2H, d, J= 8.5 Hz), 3.36-3.30 (4H, m), 3.11 (4H, br.s), 2.68 (3H, s).
ESI-MS(m/z): 437[M+H]+. Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In method, 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (43 mg, 0.134 mmol) and rhodanine (18 mg, 0.134 mmol) Gave the title compound (37 mg, 63%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.18 (1H, d, J = 9.3 Hz), 8.15 (1H, s), 8.09 (2H, d, J = 8.5 Hz), 7.56 (1H, d, J = 9.3 Hz), 7.32 (1H, s), 7.14 (2H, d, J = 8.5 Hz), 3.36-3.30 (4H, m), 3.11 (4H, br.s), 2.68 (3H, s ).
ESI-MS (m / z): 437 [M + H] + .

実施例６４
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物６４) Example 64
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 64)

Figure JPOXMLDOC01-appb-C000233
Figure JPOXMLDOC01-appb-C000233

工程１
アルゴン雰囲気下、3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (500 mg, 1.56 mmol)、チアゾリジン-2,4-ジオン (182 mg, 1.56 mmol) をアセトニトリル (50 mL) に懸濁した。そこへ酢酸 (36 μL, 0.062 mmol)、ピペリジン (31 μL, 0.031 mmol) を加え、20時間加熱還流した。反応液を冷却した後、析出した固体をろ取し、アセトニトリルで洗浄、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (452 mg, 69％) を得た。赤色固体: 1H-NMR (DMSO-D6) δ: 8.22 (1H, d, J = 9.3 Hz), 8.15 (1H, s), 8.02 (2H, d, J = 8.8 Hz), 7.72 (1H, s), 7.59 (1H, d, J = 9.3 Hz), 7.11 (2H, d, J = 8.8 Hz), 3.36 (4H, t, J = 4.8 Hz), 2.85 (4H, t, J = 4.8 Hz), 2.50 (3H, s).
ESI-MS(m/z): 421[M+H]+. Process 1
3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (500 mg, 1.56 mmol), thiazolidine-2,4-dione under argon atmosphere (182 mg, 1.56 mmol) was suspended in acetonitrile (50 mL). Acetic acid (36 μL, 0.062 mmol) and piperidine (31 μL, 0.031 mmol) were added thereto, and the mixture was heated to reflux for 20 hours. After cooling the reaction solution, the precipitated solid was collected by filtration, washed with acetonitrile, and dried in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (452 mg, 69%). Red solid: 1 H-NMR (DMSO-D 6 ) δ: 8.22 (1H, d, J = 9.3 Hz), 8.15 (1H, s), 8.02 (2H, d, J = 8.8 Hz), 7.72 (1H, s), 7.59 (1H, d, J = 9.3 Hz), 7.11 (2H, d, J = 8.8 Hz), 3.36 (4H, t, J = 4.8 Hz), 2.85 (4H, t, J = 4.8 Hz) , 2.50 (3H, s).
ESI-MS (m / z): 421 [M + H] + .

実施例６５
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物６５) Example 65
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thioxothiazolidine-4-one (Compound 65)

工程１
tert-ブチル 4-(4-ニトロフェニル)ピペラジン-1-カルボキシレート Process 1
tert-butyl 4- (4-nitrophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000234
Figure JPOXMLDOC01-appb-C000234

アルゴン雰囲気下、1-ピペラジンカルボン酸 tert-ブチル (1.2 g, 6.45 mmol) をN,N-ジメチルホルムアミド (16 mL) に溶解した。そこへ4-フルオロニトロベンゼン (1.0 g, 7.10 mmol)、炭酸カリウム (980 mg, 7.10 mmol) を加え、50℃で18時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。酢酸エチル層を1規定塩酸、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、溶媒を留去、真空乾燥して標記化合物 (1.61 g, 81%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.07 (2H, d, J= 9.5 Hz), 7.01 (2H, d, J = 9.5 Hz), 3.47 (8H, s), 1.42 (9H, s). Under an argon atmosphere, tert-butyl 1-piperazinecarboxylate (1.2 g, 6.45 mmol) was dissolved in N, N-dimethylformamide (16 mL). 4-Fluoronitrobenzene (1.0 g, 7.10 mmol) and potassium carbonate (980 mg, 7.10 mmol) were added there, and it stirred at 50 degreeC for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was dried under vacuum to obtain the title compound (1.61 g, 81%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.07 (2H, d, J = 9.5 Hz), 7.01 (2H, d, J = 9.5 Hz), 3.47 (8H, s), 1.42 (9H, s).

工程２
tert-ブチル 4-(4-アミノフェニル)ピペラジン-1-カルボキシレート Process 2
tert-Butyl 4- (4-aminophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000235
Figure JPOXMLDOC01-appb-C000235

tert-ブチル 4-(4-ニトロフェニル)ピペラジン-1-カルボキシレート (1.61 mg, 5.24 mmol) をテトラヒドロフラン (20 mL) に溶解した。そこへ10% パラジウム－活性炭 (161 mg) をエタノール (5 mL) に懸濁して加えた。反応容器内を水素で置換し、室温で2時間撹拌した。反応液をセライトでろ過し、濃縮, 真空乾燥して標記化合物 (1.40 g, 96%) を得た。褐色固体: 1H-NMR (DMSO-D6) δ: 6.70 (2H, d, J = 8.5 Hz), 6.49 (2H, d, J = 8.3 Hz), 4.61 (2H, br.s), 3.41 (4H, t, J = 4.9 Hz), 2.83 (4H, t, J = 5.0 Hz), 1.41 (9H, s). tert-Butyl 4- (4-nitrophenyl) piperazine-1-carboxylate (1.61 mg, 5.24 mmol) was dissolved in tetrahydrofuran (20 mL). Thereto was added 10% palladium-activated carbon (161 mg) suspended in ethanol (5 mL). The inside of the reaction vessel was replaced with hydrogen, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite, concentrated and dried in vacuo to give the title compound (1.40 g, 96%). Brown solid: 1 H-NMR (DMSO-D 6 ) δ: 6.70 (2H, d, J = 8.5 Hz), 6.49 (2H, d, J = 8.3 Hz), 4.61 (2H, br.s), 3.41 ( 4H, t, J = 4.9 Hz), 2.83 (4H, t, J = 5.0 Hz), 1.41 (9H, s).

工程３
tert-ブチル 4-(4-((6-ブロモ-3-ニトロピリジン-2-イル)アミノ)フェニル)ピペラジン-1-カルボキシレート Process 3
tert-butyl 4- (4-((6-bromo-3-nitropyridin-2-yl) amino) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000236
Figure JPOXMLDOC01-appb-C000236

アルゴン雰囲気下、2,6-ジブロモ-3-ニトロピリジン (1.18 g, 4.20 mmol) をエタノール (20 mL) に溶解した。そこへtert-ブチル 4-(4-アミノフェニル)ピペラジン-1-カルボキシレート (1.40 g, 5.04 mmol)、トリエチルアミン (1.14 mL, 8.40 mmol) を加え、室温で18時間撹拌した。生じた析出物をろ取し、少量の冷エタノールとヘキサンで洗浄、真空乾燥して標記化合物 (1.91 g, 95%) を得た。紫色固体: 1H-NMR (DMSO-D6) δ : 10.0 (1H, s), 8.37 (1H, d, J = 8.5 Hz), 7.44 (2H, d, J= 9.0 Hz), 7.06 (1H, d, J = 8.5 Hz), 6.99 (2H, d, J = 9.0 Hz), 3.46 (4H, t, J = 5.0 Hz), 3.11 (4H, t, J = 5.1 Hz), 1.43 (9H, s). Under an argon atmosphere, 2,6-dibromo-3-nitropyridine (1.18 g, 4.20 mmol) was dissolved in ethanol (20 mL). Thereto were added tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (1.40 g, 5.04 mmol) and triethylamine (1.14 mL, 8.40 mmol), and the mixture was stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration, washed with a small amount of cold ethanol and hexane, and dried under vacuum to obtain the title compound (1.91 g, 95%). Purple solid: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, s), 8.37 (1H, d, J = 8.5 Hz), 7.44 (2H, d, J = 9.0 Hz), 7.06 (1H, d, J = 8.5 Hz), 6.99 (2H, d, J = 9.0 Hz), 3.46 (4H, t, J = 5.0 Hz), 3.11 (4H, t, J = 5.1 Hz), 1.43 (9H, s) .

工程４
tert-ブチル 4-(4-((3-アミノ-6-ブロモピリジン-2-イル)アミノ)フェニル)ピペラジン-1-カルボキシレート Process 4
tert-butyl 4- (4-((3-amino-6-bromopyridin-2-yl) amino) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000237
Figure JPOXMLDOC01-appb-C000237

アルゴン雰囲気下、tert-ブチル 4-(4-((6-ブロモ-3-ニトロピリジン-2-イル)アミノ)フェニル)ピペラジン-1-カルボキシレート (1.91 g, 4.00 mmol) をエタノール (60 mL)、水 (24 mL) に溶解した。そこへ鉄粉 (670 mg, 12.0 mmol)、塩化アンモニウム (428 mg, 8.00 mmol) を加え、3時間加熱還流した。反応液を濃縮し、得られた残渣を酢酸エチルに再溶解して酢酸エチルで洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.46 g, 82%) を得た。茶色アモルファス状固体: 1H-NMR (DMSO-D6) δ: 7.79 (1H, s), 7.48 (2H, d, J= 9.0 Hz), 6.92 (2H, d, J = 8.8 Hz), 6.78 (1H, d, J = 7.8 Hz), 6.68 (1H, d, J = 7.8 Hz), 5.17 (2H, s), 3.46 (4H, t, J = 4.9 Hz), 3.01 (4H, t, J = 5.0 Hz), 1.42 (9H, s). Under argon atmosphere, tert-butyl 4- (4-((6-bromo-3-nitropyridin-2-yl) amino) phenyl) piperazine-1-carboxylate (1.91 g, 4.00 mmol) was added to ethanol (60 mL). , Dissolved in water (24 mL). Iron powder (670 mg, 12.0 mmol) and ammonium chloride (428 mg, 8.00 mmol) were added there, and it heated and refluxed for 3 hours. The reaction mixture was concentrated, and the resulting residue was redissolved in ethyl acetate and washed with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.46 g, 82%). Brown amorphous solid: 1 H-NMR (DMSO-D 6 ) δ: 7.79 (1H, s), 7.48 (2H, d, J = 9.0 Hz), 6.92 (2H, d, J = 8.8 Hz), 6.78 ( 1H, d, J = 7.8 Hz), 6.68 (1H, d, J = 7.8 Hz), 5.17 (2H, s), 3.46 (4H, t, J = 4.9 Hz), 3.01 (4H, t, J = 5.0 Hz), 1.42 (9H, s).

工程５
tert-ブチル 4-(4-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)ピペラジン-1-カルボキシレート Process 5
tert-Butyl 4- (4- (5-Bromo-3H-imidazo [4,5-b] pyridin-3-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000238
Figure JPOXMLDOC01-appb-C000238

アルゴン雰囲気下、tert-ブチル 4-(4-((3-アミノ-6-ブロモピリジン-2-イル)アミノ)フェニル)ピペラジン-1-カルボキシレート (1.46 g, 3.27 mmol) を2-メトキシエタノール (97 mL) に溶解した。そこへホルムアミジン酢酸塩 (1.02 g, 9.81 mmol)、を加え、6時間加熱還流した。反応液を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.27 g, 85%) を得た。褐色固体: 1H-NMR (DMSO-D6) δ: 8.78 (1H, s), 8.16 (1H, d, J= 8.3 Hz), 7.64 (2H, d, J = 8.8 Hz), 7.55 (1H, dd, J = 8.3, 0.5 Hz), 7.17 (2H, d, J = 9.0 Hz), 3.50 (4H, t, J = 4.9 Hz), 3.21 (4H, t, J = 5.1 Hz), 1.43 (9H, s). Under an argon atmosphere, tert-butyl 4- (4-((3-amino-6-bromopyridin-2-yl) amino) phenyl) piperazine-1-carboxylate (1.46 g, 3.27 mmol) was added to 2-methoxyethanol ( 97 mL). The formamidine acetate (1.02 g, 9.81 mmol) was added there, and it heated and refluxed for 6 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.27 g, 85%). Brown solid: 1 H-NMR (DMSO-D 6 ) δ: 8.78 (1H, s), 8.16 (1H, d, J = 8.3 Hz), 7.64 (2H, d, J = 8.8 Hz), 7.55 (1H, dd, J = 8.3, 0.5 Hz), 7.17 (2H, d, J = 9.0 Hz), 3.50 (4H, t, J = 4.9 Hz), 3.21 (4H, t, J = 5.1 Hz), 1.43 (9H, s).

工程６
5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン Step 6
5-Bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000239
Figure JPOXMLDOC01-appb-C000239

アルゴン雰囲気下、tert-ブチル 4-(4-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)ピペラジン-1-カルボキシレート (400 mg, 0.873 mmol) を塩化メチレン (9 mL) に溶解し、0℃に冷却した。そこへトリフルオロ酢酸 (3 mL) を加え、室温で18時間撹拌した。反応液を濃縮し、得られた残渣をクロロホルムに再溶解して飽和重層水、飽和食塩水で洗浄した。クロロホルム層を無水硫酸ナトリウムで乾燥させ、溶媒を留去、真空乾燥して標記化合物 (255 mg, 82%) を得た。褐色固体: 1H-NMR (DMSO-D6) δ: 8.78 (1H, s), 8.16 (1H, d, J= 8.5 Hz), 7.62 (2H, d, J = 9.0 Hz), 7.55 (1H, d, J = 8.3 Hz), 7.14 (2H, d, J = 9.0 Hz), 3.19 (4H, t, J = 5.0 Hz), 2.92 (4H, t, J = 5.0 Hz). Chloride tert-butyl 4- (4- (5-bromo-3H-imidazo [4,5-b] pyridin-3-yl) phenyl) piperazine-1-carboxylate (400 mg, 0.873 mmol) under argon atmosphere Methylene   Dissolved in (9 mL) and cooled to 0 ° C. Trifluoroacetic acid (3 mL) was added there, and it stirred at room temperature for 18 hours. The reaction mixture was concentrated, and the resulting residue was redissolved in chloroform and washed with saturated multilayered water and saturated brine. The chloroform layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was dried under vacuum to obtain the title compound (255 mg, 82%). Brown solid: 1 H-NMR (DMSO-D 6 ) δ: 8.78 (1H, s), 8.16 (1H, d, J = 8.5 Hz), 7.62 (2H, d, J = 9.0 Hz), 7.55 (1H, d, J = 8.3 Hz), 7.14 (2H, d, J = 9.0 Hz), 3.19 (4H, t, J = 5.0 Hz), 2.92 (4H, t, J = 5.0 Hz).

工程７
5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン Step 7
5-Bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000240
Figure JPOXMLDOC01-appb-C000240

アルゴン雰囲気下、5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン (255 mg, 0.712 mmol) を塩化メチレン (14 mL) に溶解した。そこへ 37% ホルムアルデヒド水溶液 (318 μL, 4.27 mmol) を加え、室温で1時間撹拌した。さらにナトリウム トリアセトキシボロヒドリド (453 mg, 2.14 mmol) を加え、室温で15時間撹拌した。反応液に飽和重層水を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (199 mg, 75%) を得た。淡ピンク色固体: 1H-NMR (DMSO-D6) δ: 8.77 (1H, s), 8.16 (1H, d, J= 8.5 Hz), 7.61 (2H, d, J = 9.0 Hz), 7.55 (1H, dd, J = 8.3, 1.0 Hz), 7.15 (2H, d, J = 9.0 Hz), 3.24 (4H, t, J = 4.9 Hz), 2.48 (4H, t, J = 5.1 Hz), 2.24 (3H, s). Dissolve 5-bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (255 mg, 0.712 mmol) in methylene chloride (14 mL) under argon atmosphere did. A 37% aqueous formaldehyde solution (318 μL, 4.27 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (453 mg, 2.14 mmol) was further added, and the mixture was stirred at room temperature for 15 hours. Saturated multistory water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (199 mg, 75%). Light pink solid: 1 H-NMR (DMSO-D 6 ) δ: 8.77 (1H, s), 8.16 (1H, d, J = 8.5 Hz), 7.61 (2H, d, J = 9.0 Hz), 7.55 ( 1H, dd, J = 8.3, 1.0 Hz), 7.15 (2H, d, J = 9.0 Hz), 3.24 (4H, t, J = 4.9 Hz), 2.48 (4H, t, J = 5.1 Hz), 2.24 ( 3H, s).

工程８
3-(4-(4-メチルピペラジン-1-イル)フェニル)-5-ビニル-3H-イミダゾ[4,5-b]ピリジン Process 8
3- (4- (4-Methylpiperazin-1-yl) phenyl) -5-vinyl-3H-imidazo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000241
Figure JPOXMLDOC01-appb-C000241

3-(4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例63、工程2) と同様の手法で、5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン (199 mg, 0.535 mmol) およびトリブチリビニルスズ (234 μL, 0.803 mmol) から標記化合物 (83 mg, 49%)を得た。淡黄色固体: 1H-NMR (DMSO-D6) δ: 8.75 (1H, s), 7.72 (2H, d, J = 9.0 Hz), 7.65-7.54 (1H, m), 7.52 (1H, d, J = 8.3 Hz), 7.15 (2H, d, J = 9.0 Hz), 6.90 (1H, dd, J = 17.6, 10.7 Hz), 6.21 (1H, dd, J = 17.6, 1.5 Hz), 5.45 (1H, d, J = 12.2 Hz), 3.23 (4H, t, J = 4.9 Hz), 2.48 (4H, t, J = 5.9 Hz), 2.24 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 63, Step 2) Titled from 3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (199 mg, 0.535 mmol) and tributyvinyltin (234 μL, 0.803 mmol) The compound (83 mg, 49%) was obtained. Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.75 (1H, s), 7.72 (2H, d, J = 9.0 Hz), 7.65-7.54 (1H, m), 7.52 (1H, d, J = 8.3 Hz), 7.15 (2H, d, J = 9.0 Hz), 6.90 (1H, dd, J = 17.6, 10.7 Hz), 6.21 (1H, dd, J = 17.6, 1.5 Hz), 5.45 (1H, d, J = 12.2 Hz), 3.23 (4H, t, J = 4.9 Hz), 2.48 (4H, t, J = 5.9 Hz), 2.24 (3H, s).

工程９
3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド  Step 9
3- (4- (4-Methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000242
Figure JPOXMLDOC01-appb-C000242

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド(実施例63、工程3) と同様の手法で、3-(4-(4-メチルピペラジン-1-イル)フェニル)-5-ビニル-3H-イミダゾ[4,5-b]ピリジン(83 mg, 0.260 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (65 μL、5.20 μmol) から標記化合物 (16 mg, 19%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 10.0 (1H, s), 9.03 (1H, s), 8.39 (1H, d, J = 8.3 Hz), 7.97 (1H, dd, J = 8.3, 0.7 Hz), 7.72 (2H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.8 Hz), 3.26 (4H, t, J = 4.9 Hz), 2.52-2.48 (4H, m), 2.25 (3H, s). In a similar manner to 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3), 3- (4- (4-Methylpiperazin-1-yl) phenyl) -5-vinyl-3H-imidazo [4,5-b] pyridine (83 mg, 0.260 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol (65 μL, The title compound (16 mg, 19%) was obtained from 5.20 μmol). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, s), 9.03 (1H, s), 8.39 (1H, d, J = 8.3 Hz), 7.97 (1H, dd, J = 8.3 , 0.7 Hz), 7.72 (2H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.8 Hz), 3.26 (4H, t, J = 4.9 Hz), 2.52-2.48 (4H, m), 2.25 (3H, s).

工程１０
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物６５) Step 10
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thioxothiazolidine-4-one (Compound 65)

Figure JPOXMLDOC01-appb-C000243
Figure JPOXMLDOC01-appb-C000243

5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド (16  mg, 0.050 mmol) およびロダニン (7 mg, 0.050 mmol) から標記化合物 (11 mg, 50%)を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.91 (1H, s), 8.27 (1H, d, J= 8.3 Hz), 7.83 (3H, d, J = 8.5 Hz), 7.63 (1H, s), 7.20 (2H, d, J= 8.3 Hz), 3.40-3.32 (4H, m), 2.91 (4H, br.s), 2.53 (3H, s).
ESI-MS(m/z): 437[M+H]+. Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde (16 mg, 0.050 mmol) and rhodanine (7 mg, The title compound (11 mg, 50%) was obtained from 0.050 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.91 (1H, s), 8.27 (1H, d, J = 8.3 Hz), 7.83 (3H, d, J = 8.5 Hz), 7.63 (1H, s), 7.20 (2H, d, J = 8.3 Hz), 3.40-3.32 (4H, m), 2.91 (4H, br.s), 2.53 (3H, s).
ESI-MS (m / z): 437 [M + H] + .

実施例６６
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物６６) Example 66
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 66 )

Figure JPOXMLDOC01-appb-C000244
Figure JPOXMLDOC01-appb-C000244

工程１
5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド (17 mg, 0.053 mmol) およびチアゾリジン-2,4-ジオン (6 mg, 0.053 mmol) から標記化合物 (1.8 mg, 8%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 12.0 (1H, br.s), 8.89 (1H, s), 8.29 (1H, d, J = 8.1 Hz), 7.91 (1H, s), 7.84 (1H, d, J = 8.3 Hz), 7.77 (2H, d, J = 8.8 Hz), 7.17 (2H, d, J = 9.0 Hz), 4.14 (2H, s), 3.28 (4H, t, J = 4.9 Hz), 2.61 (4H, t, J = 4.8 Hz), 2.32 (3H, s).
ESI-MS(m/z): 421[M+H]+. Process 1
Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde (17 mg, 0.053 mmol) and thiazolidine-2,4 The title compound (1.8 mg, 8%) was obtained from -dione (6 mg, 0.053 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 12.0 (1H, br.s), 8.89 (1H, s), 8.29 (1H, d, J = 8.1 Hz), 7.91 (1H, s), 7.84 (1H, d, J = 8.3 Hz), 7.77 (2H, d, J = 8.8 Hz), 7.17 (2H, d, J = 9.0 Hz), 4.14 (2H, s), 3.28 (4H, t, J = 4.9 Hz), 2.61 (4H, t, J = 4.8 Hz), 2.32 (3H, s).
ESI-MS (m / z): 421 [M + H] + .

実施例６７
5-((1-(4-(ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物６７) Example 67
5-((1- (4- (piperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 67)

工程１
メチル 1-(4-(4-(tert-ブトキシカルボニル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 1
Methyl 1- (4- (4- (tert-butoxycarbonyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000245
Figure JPOXMLDOC01-appb-C000245

メチル 1-(4-ブロモフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート(300 mg, 0.91 mmol) のトルエン (7 mL) 溶液中に酢酸パラジウム (10 mg, 0.046 mmol)、rac-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル (85 mg, 0.137 mmol)、炭酸セシウム (593 mg, 1.82 mmol)、tert-ブチル ピペラジン-1-カルボキシレート (254mg, 1.37 mmol) を添加した。還流条件下、一晩撹拌した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記化合物 (306 mg, 77 %, 0.70 mmol) を得た。1H-NMR (CDCl3) δ: 8.18 (1H, br s), 8.16 (1H, s), 8.03 (1H, d, J = 8.5 Hz), 7.87 (1H, d, J = 8.5 Hz), 7.39 (2H, d, J = 9.0 Hz), 7.08 (2H, d, J = 9.0 Hz), 3.93 (3H, s), 3.64 (4H, t, J = 5.1 Hz), 3.26 (4H, t, J = 5.1 Hz), 1.51 (9H, s). 
ESI-MS(m/z): 437[M+H]+. Palladium acetate (10 mg, 0.046 mmol), rac- in a solution of methyl 1- (4-bromophenyl) -1H-benzo [d] imidazole-6-carboxylate (300 mg, 0.91 mmol) in toluene (7 mL) 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (85 mg, 0.137 mmol), cesium carbonate (593 mg, 1.82 mmol), tert-butyl piperazine-1-carboxylate (254 mg, 1.37 mmol) ) Was added. After stirring overnight under reflux conditions, a saturated aqueous sodium hydrogen carbonate solution was added, chloroform and saturated brine were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound (306 mg, 77%, 0.70 mmol) was obtained. 1 H-NMR (CDCl 3 ) δ: 8.18 (1H, br s), 8.16 (1H, s), 8.03 (1H, d, J = 8.5 Hz), 7.87 (1H, d, J = 8.5 Hz), 7.39 (2H, d, J = 9.0 Hz), 7.08 (2H, d, J = 9.0 Hz), 3.93 (3H, s), 3.64 (4H, t, J = 5.1 Hz), 3.26 (4H, t, J = 5.1 Hz), 1.51 (9H, s).
ESI-MS (m / z): 437 [M + H] + .

工程２
tert-ブチル 4-(4-(6-(ヒドロキシメチル)-1H-ベンゾ[d]イミダゾール-1-イル)フェニル)ピペラジン-1-カルボキシレート Process 2
tert-butyl 4- (4- (6- (hydroxymethyl) -1H-benzo [d] imidazol-1-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000246
Figure JPOXMLDOC01-appb-C000246

メチル 1-(4-(4-(tert-ブトキシカルボニル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート(306 mg, 0.70 mmol) のテトラヒドロフラン (7 mL) 溶液中に、水素化ジイソブチルアルミニウムのヘキサン溶液 (1.0 M, 2.8 mL, 2.8 mmol) を-78 ℃で添加した。5時間撹拌した後、飽和酒石酸ナトリウムカリウム水溶液を加え、酢酸エチルと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (86 mg, 30 %, 0.21 mmol) を得た。1H-NMR (CDCl3) δ: 7.99 (1H, s), 7.77 (1H, d, J = 8.3 Hz), 7.50 (1H, s), 7.33 (2H, d, J = 8.8 Hz), 7.28 (1H, d, J = 8.3 Hz), 7.03 (2H, d, J = 8.8 Hz), 4.80 (2H, s), 3.61 (4H, t, J = 5.0 Hz), 3.20 (4H, t, J = 5.0 Hz), 1.50 (9H, s). 
ESI-MS(m/z): 409[M+H]+. Methyl 1- (4- (4- (tert-butoxycarbonyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate (306 mg, 0.70 mmol) in tetrahydrofuran (7 mL) Inside, a hexane solution of diisobutylaluminum hydride (1.0 M, 2.8 mL, 2.8 mmol) was added at −78 ° C. After stirring for 5 hours, saturated aqueous sodium potassium tartrate solution was added, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (86 mg, 30%, 0.21 mmol). 1 H-NMR (CDCl 3 ) δ: 7.99 (1H, s), 7.77 (1H, d, J = 8.3 Hz), 7.50 (1H, s), 7.33 (2H, d, J = 8.8 Hz), 7.28 ( 1H, d, J = 8.3 Hz), 7.03 (2H, d, J = 8.8 Hz), 4.80 (2H, s), 3.61 (4H, t, J = 5.0 Hz), 3.20 (4H, t, J = 5.0 Hz), 1.50 (9H, s).
ESI-MS (m / z): 409 [M + H] + .

工程３
tert-ブチル 4-(4-(6-ホルミル-1H-ベンゾ[d]イミダゾール-1-イル)フェニル)ピペラジン-1-カルボキシレート Process 3
tert-butyl 4- (4- (6-formyl-1H-benzo [d] imidazol-1-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000247
Figure JPOXMLDOC01-appb-C000247

tert-ブチル 4-(4-(6-(ヒドロキシメチル)-1H-ベンゾ[d]イミダゾール-1-イル)フェニル)ピペラジン-1-カルボキシレート (86 mg, 0.21 mmol) の塩化メチレン (3.0 mL) 溶液に デス・マーチン・ペルヨージナン (143 mg, 0.337 mmol) を0℃で滴下した。室温に昇温し2時間撹拌した後、飽和チオ硫酸水素ナトリウム水溶液を添加し、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記化合物 (61 mg, 71 %, 0.150 mmol) を得た。1H-NMR (CDCl3) δ: 10.07 (1H, s), 8.23 (1H, s), 8.01 (1H, s), 7.97 (1H, d, J = 8.3 Hz), 7.87 (1H, d, J = 8.3 Hz), 7.40 (2H, d, J = 8.8 Hz), 7.09 (2H, d, J = 8.8 Hz), 3.64 (4H, t, J = 5.0 Hz), 3.26 (4H, t, J = 5.0 Hz), 1.51 (9H, s).
ESI-MS(m/z): 407[M+H]+. tert-Butyl 4- (4- (6- (hydroxymethyl) -1H-benzo [d] imidazol-1-yl) phenyl) piperazine-1-carboxylate (86 mg, 0.21 mmol) in methylene chloride (3.0 mL) Dess-Martin periodinane (143 mg, 0.337 mmol) was added dropwise to the solution at 0 ° C. After warming to room temperature and stirring for 2 hours, a saturated aqueous solution of sodium hydrogenthiosulfate was added, the organic layer was extracted by adding chloroform and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. . The title compound (61 mg, 71%, 0.150 mmol) was obtained. 1 H-NMR (CDCl 3 ) δ: 10.07 (1H, s), 8.23 (1H, s), 8.01 (1H, s), 7.97 (1H, d, J = 8.3 Hz), 7.87 (1H, d, J = 8.3 Hz), 7.40 (2H, d, J = 8.8 Hz), 7.09 (2H, d, J = 8.8 Hz), 3.64 (4H, t, J = 5.0 Hz), 3.26 (4H, t, J = 5.0 Hz), 1.51 (9H, s).
ESI-MS (m / z): 407 [M + H] + .

工程４
1-(4-(ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド  Process 4
1- (4- (Piperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000248
Figure JPOXMLDOC01-appb-C000248

tert-ブチル 4-(4-(6-ホルミル-1H-ベンゾ[d]イミダゾール-1-イル)フェニル)ピペラジン-1-カルボキシレート (61 mg, 0.15 mmol) の塩化メチレン (1.0 mL) 溶液に トリフルオロ酢酸 (11.6 μL, 0.15 mmol) を0℃で滴下した。室温に昇温し2時間撹拌した。さらにトリフルオロ酢酸(116 μL, 1.5 mmol)を追加し反応終了後、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記化合物 (41 mg, 89 %, 0.134 mmol) を得た。1H-NMR (CDCl3) δ: 10.06 (s, 1H), 8.22-8.20 (m, 1H), 8.00-7.97 (m, 2H), 7.87-7.85 (m, 1H), 7.41-7.36 (m, 2H), 7.10-7.07 (m, 2H), 3.29 (t, J = 4.9 Hz, 4H), 3.11 (t, J = 4.9 Hz, 4H). 
ESI-MS(m/z): 307[M+H]+. Tritate a solution of tert-butyl 4- (4- (6-formyl-1H-benzo [d] imidazol-1-yl) phenyl) piperazine-1-carboxylate (61 mg, 0.15 mmol) in methylene chloride (1.0 mL). Fluoroacetic acid (11.6 μL, 0.15 mmol) was added dropwise at 0 ° C. The mixture was warmed to room temperature and stirred for 2 hours. Further, trifluoroacetic acid (116 μL, 1.5 mmol) was added, and after completion of the reaction, chloroform and saturated aqueous sodium hydrogen carbonate solution were added to extract the organic layer, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The title compound (41 mg, 89%, 0.134 mmol) was obtained. 1 H-NMR (CDCl 3 ) δ: 10.06 (s, 1H), 8.22-8.20 (m, 1H), 8.00-7.97 (m, 2H), 7.87-7.85 (m, 1H), 7.41-7.36 (m, 2H), 7.10-7.07 (m, 2H), 3.29 (t, J = 4.9 Hz, 4H), 3.11 (t, J = 4.9 Hz, 4H).
ESI-MS (m / z): 307 [M + H] + .

工程５
5-((1-(4-(ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物６７) Process 5
5-((1- (4- (piperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 67)

Figure JPOXMLDOC01-appb-C000249
Figure JPOXMLDOC01-appb-C000249

1-(4-(ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (18 mg, 0.06 mmol) をエタノール (1.0 mL) に溶かし、チアゾリジン-2,4-ジオン (8 mg, 0.065 mmol) およびピペリジン (1.2 μL, 0.012 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (6 mg, 25 %, 0.015 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.52 (1H, s), 7.79 (1H, d, J = 8.5 Hz), 7.74 (1H, s), 7.57 (2H, d, J = 8.8 Hz), 7.51 (1H, s), 7.47 (1H, d, J = 8.5 Hz), 7.25 (2H, d, J = 8.8 Hz), 3.43 (4H, t, J = 5.0 Hz), 3.22 (4H, t, J = 5.0 Hz). 
ESI-MS(m/z): 406[M+H]+. 1- (4- (Piperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (18 mg, 0.06 mmol) is dissolved in ethanol (1.0 mL) and thiazolidine-2,4-dione (8 mg, 0.065 mmol) and piperidine (1.2 μL, 0.012 mmol) were added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (6 mg, 25%, 0.015 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.52 (1H, s), 7.79 (1H, d, J = 8.5 Hz), 7.74 (1H, s), 7.57 (2H, d, J = 8.8 Hz), 7.51 (1H, s), 7.47 (1H, d, J = 8.5 Hz), 7.25 (2H, d, J = 8.8 Hz), 3.43 (4H, t, J = 5.0 Hz), 3.22 (4H, t, J = 5.0 Hz).
ESI-MS (m / z): 406 [M + H] + .

実施例６８
5-((1-(4-(4-メチルピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物６８)  Example 68
5-((1- (4- (4-Methylpiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 68)

工程１
メチル 1-(4-(4-メチルピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 1
Methyl 1- (4- (4-methylpiperidin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000250
Figure JPOXMLDOC01-appb-C000250

メチル 1-(4-ブロモフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート(300 mg, 0.91 mmol) のトルエン (7 mL) 溶液中に酢酸パラジウム (10mg, 0.046 mmol)、rac-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル (85 mg, 0.138 mmol)、炭酸セシウム (593 mg, 1.82 mmol)、4-メチルピペリジン (160 μL, 1.37 mmol) を添加した。還流条件下、一晩撹拌した後、セライトろ過し、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (195 mg, 62 %, 0.56 mmol) を得た。1H-NMR (CDCl3) δ: 8.10 (1H, s), 8.08 (1H, s), 7.94 (1H, d, J = 8.5 Hz), 7.78 (1H, d, J = 8.5 Hz), 7.25 (2H, d, J = 9.0 Hz), 6.98 (2H, d, J = 9.0 Hz), 3.84 (3H, s), 3.69-3.66 (2H, m), 2.74-2.71 (2H, m), 1.71-1.68 (2H, m), 1.51-1.48 (1H, m), 1.31-1.28 (2H, m), 0.92 (3H, s).
ESI-MS(m/z): 350[M+H]+. Palladium acetate (10 mg, 0.046 mmol), rac-2 in a solution of methyl 1- (4-bromophenyl) -1H-benzo [d] imidazole-6-carboxylate (300 mg, 0.91 mmol) in toluene (7 mL) , 2′-bis (diphenylphosphino) -1,1′-binaphthyl (85 mg, 0.138 mmol), cesium carbonate (593 mg, 1.82 mmol), 4-methylpiperidine (160 μL, 1.37 mmol) were added. The mixture was stirred overnight under reflux conditions, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (195 mg, 62%, 0.56 mmol). 1 H-NMR (CDCl 3 ) δ: 8.10 (1H, s), 8.08 (1H, s), 7.94 (1H, d, J = 8.5 Hz), 7.78 (1H, d, J = 8.5 Hz), 7.25 ( 2H, d, J = 9.0 Hz), 6.98 (2H, d, J = 9.0 Hz), 3.84 (3H, s), 3.69-3.66 (2H, m), 2.74-2.71 (2H, m), 1.71-1.68 (2H, m), 1.51-1.48 (1H, m), 1.31-1.28 (2H, m), 0.92 (3H, s).
ESI-MS (m / z): 350 [M + H] + .

工程２
(1-(4-(4-メチルピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール Process 2
(1- (4- (4-Methylpiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol

Figure JPOXMLDOC01-appb-C000251
Figure JPOXMLDOC01-appb-C000251

メチル 1-(4-(4-メチルピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート (195 mg, 0.558 mmol) のテトラヒドロフラン (6 mL) 溶液中に、水素化アルミニウムリチウムのテトラヒドロフラン溶液 (1.0 M, 1.7 mL, 1.7 mmol) をアルゴン雰囲気下-78 ℃で添加した。0 ℃に昇温しながら4時間撹拌した後、飽和酒石酸ナトリウムカリウム水溶液を加え、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (129 mg, 0.40 mmol, 72 %) を得た。1H-NMR (CDCl3) δ: 7.97 (1H, s), 7.75 (1H, d, J = 8.1 Hz), 7.48 (1H, s), 7.28-7.23 (3H, m), 7.02 (2H, d, J = 9.0 Hz), 4.80 (2H, s), 3.75-3.67 (2H, m), 2.83-2.71 (2H, m), 1.83-1.72 (2H, m), 1.64-1.49 (1H, m), 1.43-1.33 (2H, m), 1.00 (3H, d, J = 6.6 Hz). 
ESI-MS(m/z): 322[M+H]+. Hydrogenation of methyl 1- (4- (4-methylpiperidin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate (195 mg, 0.558 mmol) in tetrahydrofuran (6 mL) A solution of lithium aluminum in tetrahydrofuran (1.0 M, 1.7 mL, 1.7 mmol) was added at −78 ° C. under an argon atmosphere. After stirring for 4 hours while raising the temperature to 0 ° C., saturated aqueous sodium potassium tartrate solution was added, ethyl acetate and saturated brine were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (129 mg, 0.40 mmol, 72%). 1 H-NMR (CDCl 3 ) δ: 7.97 (1H, s), 7.75 (1H, d, J = 8.1 Hz), 7.48 (1H, s), 7.28-7.23 (3H, m), 7.02 (2H, d , J = 9.0 Hz), 4.80 (2H, s), 3.75-3.67 (2H, m), 2.83-2.71 (2H, m), 1.83-1.72 (2H, m), 1.64-1.49 (1H, m), 1.43-1.33 (2H, m), 1.00 (3H, d, J = 6.6 Hz).
ESI-MS (m / z): 322 [M + H] + .

工程３
1-(4-(4-メチルピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Process 3
1- (4- (4-Methylpiperidin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000252
Figure JPOXMLDOC01-appb-C000252

(1-(4-(4-メチルピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール(129 mg, 0.40 mmol) の塩化メチレン (4.0 mL) 溶液にデス・マーチン・ペルヨージナン (272 mg, 0.64 mmol) を0℃で滴下した。室温に昇温し3時間撹拌した後、飽和チオ硫酸水素ナトリウム水溶液を添加し、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (105 mg, 82 %, 0.33 mmol) を得た。1H-NMR (CDCl3) δ: 10.05 (1H, s), 8.22 (1H, br s), 8.01 (1H, br s), 7.96 (1H, d, J = 8.5 Hz), 7.86 (1H, d, J = 8.5 Hz), 7.35 (2H, d, J = 8.8 Hz), 7.07 (2H, d, J = 8.8 Hz), 3.78-3.76 (2H, m), 2.84-2.81 (2H, m), 1.80-1.77 (2H, m), 1.67-1.53 (1H, m), 1.39-1.36(2H, m), 1.01 (3H, br s). 
ESI-MS(m/z): 320[M+H]+. To a solution of (1- (4- (4-methylpiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol (129 mg, 0.40 mmol) in methylene chloride (4.0 mL) Martin periodinane (272 mg, 0.64 mmol) was added dropwise at 0 ° C. After warming to room temperature and stirring for 3 hours, a saturated aqueous sodium hydrogensulfate solution was added, the organic layer was extracted by adding chloroform and a saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. . The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (105 mg, 82%, 0.33 mmol). 1 H-NMR (CDCl 3 ) δ: 10.05 (1H, s), 8.22 (1H, br s), 8.01 (1H, br s), 7.96 (1H, d, J = 8.5 Hz), 7.86 (1H, d , J = 8.5 Hz), 7.35 (2H, d, J = 8.8 Hz), 7.07 (2H, d, J = 8.8 Hz), 3.78-3.76 (2H, m), 2.84-2.81 (2H, m), 1.80 -1.77 (2H, m), 1.67-1.53 (1H, m), 1.39-1.36 (2H, m), 1.01 (3H, br s).
ESI-MS (m / z): 320 [M + H] + .

工程４
5-((1-(4-(4-メチルピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物６８)  Process 4
5-((1- (4- (4-Methylpiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 68)

Figure JPOXMLDOC01-appb-C000253
Figure JPOXMLDOC01-appb-C000253

1-(4-(4-メチルピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (52 mg, 0.16 mmol) をエタノール (4.0 mL) に溶かし、ロダニン (24 mg, 0.18 mmol) およびピペリジン (3.2 μL, 0.033 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (17 mg, 24 %, 0.039 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.63 (1H, s), 7.90 (1H, d, J = 8.5 Hz), 7.84 (1H, s), 7.81 (1H, s), 7.55-7.47 (3H, m), 7.16 (2H, d, J = 9.0 Hz), 3.83-3.79 (2H, m), 2.79-2.76 (2H, m), 1.74-1.71 (2H, m), 1.63-1.51 (1H, m), 1.31-1.20 (2H, m), 0.96 (3H, d, J = 6.6 Hz).
ESI-MS(m/z): 435[M+H]+. 1- (4- (4-Methylpiperidin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (52 mg, 0.16 mmol) was dissolved in ethanol (4.0 mL) and rhodanine (24 mg , 0.18 mmol) and piperidine (3.2 μL, 0.033 mmol) were added and stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (17 mg, 24%, 0.039 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.63 (1H, s), 7.90 (1H, d, J = 8.5 Hz), 7.84 (1H, s), 7.81 (1H, s), 7.55- 7.47 (3H, m), 7.16 (2H, d, J = 9.0 Hz), 3.83-3.79 (2H, m), 2.79-2.76 (2H, m), 1.74-1.71 (2H, m), 1.63-1.51 ( 1H, m), 1.31-1.20 (2H, m), 0.96 (3H, d, J = 6.6 Hz).
ESI-MS (m / z): 435 [M + H] + .

実施例６９
5-((1-(4-(4-メチルピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物６９)  Example 69
5-((1- (4- (4-Methylpiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 69)

Figure JPOXMLDOC01-appb-C000254
Figure JPOXMLDOC01-appb-C000254

工程１
1-(4-(4-メチルピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (52 mg, 0.16 mmol) をエタノール (4.0 mL) に溶かし、チアゾリジン-2,4-ジオン (21 mg, 0.18 mmol) およびピペリジン (3.2 μL, 0.033 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (26 mg, 38 %, 0.06 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 12.62-12.53 (1H, m), 8.61 (1H, s), 7.97 (1H, s), 7.89 (1H, d, J = 8.5 Hz), 7.80 (1H, s), 7.53 (1H, d, J = 8.5 Hz), 7.50 (2H, d, J = 8.8 Hz), 7.16 (2H, d, J = 8.8 Hz), 3.83-3.80 (2H, m), 2.78-2.75 (2H, m), 1.74-1.71 (2H, m), 1.62-1.50 (1H, m), 1.29-1.23 (2H, m), 0.96 (3H, d, J = 6.6 Hz). 
ESI-MS(m/z): 419[M+H]+. Process 1
1- (4- (4-Methylpiperidin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (52 mg, 0.16 mmol) is dissolved in ethanol (4.0 mL) and thiazolidine-2, 4-dione (21 mg, 0.18 mmol) and piperidine (3.2 μL, 0.033 mmol) were added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (26 mg, 38%, 0.06 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 12.62-12.53 (1H, m), 8.61 (1H, s), 7.97 (1H, s), 7.89 (1H, d, J = 8.5 Hz), 7.80 (1H, s), 7.53 (1H, d, J = 8.5 Hz), 7.50 (2H, d, J = 8.8 Hz), 7.16 (2H, d, J = 8.8 Hz), 3.83-3.80 (2H, m ), 2.78-2.75 (2H, m), 1.74-1.71 (2H, m), 1.62-1.50 (1H, m), 1.29-1.23 (2H, m), 0.96 (3H, d, J = 6.6 Hz).
ESI-MS (m / z): 419 [M + H] + .

実施例７０
5-((1-(4-(3-(ジメチルアミノ)プロプ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物７０)  Example 70
5-((1- (4- (3- (dimethylamino) prop-1-in-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine- 4-one (compound 70)

工程１
メチル 3-((4-ヨードフェニル)アミノ)-4-ニトロベンゾエート Process 1
Methyl 3-((4-iodophenyl) amino) -4-nitrobenzoate

Figure JPOXMLDOC01-appb-C000255
Figure JPOXMLDOC01-appb-C000255

メチル 3-フルオロ-4-ニトロベンゾエート(3.98 g, 20 mmol) のN,N-ジメチルホルムアミド (20 mL) 溶媒中に、4-ヨードアニリン (4.38 g, 20 mmol)、およびN-エチル-N-イソプロピルプロパン-2-アミン(7.0 mL, 40 mmol) を添加した。125 ℃で2日間撹拌し、室温に放冷した後、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) にて精製し、標記化合物 (6.98g, 17.6 mmol, 88 %) を得た。赤褐色固体: 1H-NMR (CDCl3) δ: 9.36 (1H, s), 8.25 (1H, d, J = 8.8 Hz), 7.90 (1H, s), 7.75 (2H, d, J = 8.5 Hz), 7.40 (1H, d, J = 8.8 Hz), 7.05 (2H, d, J = 8.5 Hz), 3.90 (3H, s). 
ESI-MS(m/z): 399[M+H]+. Methyl 3-fluoro-4-nitrobenzoate (3.98 g, 20 mmol) in N, N-dimethylformamide (20 mL) in a solvent, 4-iodoaniline (4.38 g, 20 mmol), and N-ethyl-N- Isopropylpropan-2-amine (7.0 mL, 40 mmol) was added. After stirring at 125 ° C. for 2 days and allowing to cool to room temperature, ethyl acetate and saturated brine were added to extract the organic layer, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (6.98 g, 17.6 mmol, 88%). Reddish brown solid: 1 H-NMR (CDCl 3 ) δ: 9.36 (1H, s), 8.25 (1H, d, J = 8.8 Hz), 7.90 (1H, s), 7.75 (2H, d, J = 8.5 Hz) , 7.40 (1H, d, J = 8.8 Hz), 7.05 (2H, d, J = 8.5 Hz), 3.90 (3H, s).
ESI-MS (m / z): 399 [M + H] + .

工程２
メチル 4-アミノ-3-((4-ヨードフェニル)アミノ)ベンゾエート Process 2
Methyl 4-amino-3-((4-iodophenyl) amino) benzoate

Figure JPOXMLDOC01-appb-C000256
Figure JPOXMLDOC01-appb-C000256

メチル 3-((4-ヨードフェニル)アミノ)-4-ニトロベンゾエート (6.08 g, 17.5 mmol) の酢酸エチル溶液中 (200 mL) に、臭化亜鉛 (1.58 mg, 7.01 mmol)、および5 % プラチナ－活性炭 (1 g) をアルゴン雰囲気下0 ℃で添加した。水素置換した後、室温に昇温し一晩撹拌した。さらに5 % プラチナ－活性炭 (1 g) を添加し反応終了後、セライトろ過し減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) にて精製し、標記化合物 (2.68 g, 7.29 mmol, 42 %) を得た。1H-NMR (CDCl3) δ: 7.79-7.68 (2H, m), 7.42 (2H, d, J = 8.8 Hz), 6.72 (1H, d, J = 8.3 Hz), 6.43 (2H, d, J = 8.8 Hz), 5.37-5.18 (1H, m), 4.34-4.18 (2H, m), 3.81 (3H, s).
ESI-MS(m/z): 369[M+H]+. Methyl 3-((4-iodophenyl) amino) -4-nitrobenzoate (6.08 g, 17.5 mmol) in ethyl acetate (200 mL), zinc bromide (1.58 mg, 7.01 mmol), and 5% platinum Activated carbon (1 g) was added at 0 ° C. under an argon atmosphere. After purging with hydrogen, the mixture was warmed to room temperature and stirred overnight. Further, 5% platinum-activated carbon (1 g) was added, and after the reaction was completed, the mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (2.68 g, 7.29 mmol, 42%). 1 H-NMR (CDCl 3 ) δ: 7.79-7.68 (2H, m), 7.42 (2H, d, J = 8.8 Hz), 6.72 (1H, d, J = 8.3 Hz), 6.43 (2H, d, J = 8.8 Hz), 5.37-5.18 (1H, m), 4.34-4.18 (2H, m), 3.81 (3H, s).
ESI-MS (m / z): 369 [M + H] + .

工程３
メチル 1-(4-ヨードフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 3
Methyl 1- (4-iodophenyl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000257
Figure JPOXMLDOC01-appb-C000257

メチル 4-アミノ-3-((4-ヨードフェニル)アミノ)ベンゾエート (3.00 g, 8.26 mmol) のテトラヒドロフラン (35 mL) 溶液中に、オルトギ酸トリエチル (2.06 mL, 12.4 mmol)、およびパラトシル酸一水和物 (79 mg, 0.41 mmol) を添加した。還流条件下2時間撹拌した後、飽和炭酸水素ナトリウム水溶液を添加し、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (3.03 g, 97 %, 8.01 mmol) を得た。茶色固体: 1H-NMR (CDCl3) δ: 8.29 (s, 1H), 8.22 (s, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 8.3 Hz, 2H), 3.94 (s, 3H).
ESI-MS(m/z): 379[M+H]+. In a solution of methyl 4-amino-3-((4-iodophenyl) amino) benzoate (3.00 g, 8.26 mmol) in tetrahydrofuran (35 mL), triethyl orthoformate (2.06 mL, 12.4 mmol) and monohydrate paratosylate The Japanese product (79 mg, 0.41 mmol) was added. After stirring under reflux conditions for 2 hours, a saturated aqueous sodium hydrogen carbonate solution was added, ethyl acetate and saturated brine were added to extract the organic layer, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (3.03 g, 97%, 8.01 mmol). Brown solid: 1 H-NMR (CDCl 3 ) δ: 8.29 (s, 1H), 8.22 (s, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 8.3 Hz, 2H) , 7.93 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 8.3 Hz, 2H), 3.94 (s, 3H).
ESI-MS (m / z): 379 [M + H] + .

工程４
メチル 1-(4-(3-(ジメチルアミノ)プロプ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 4
Methyl 1- (4- (3- (dimethylamino) prop-1-in-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000258
Figure JPOXMLDOC01-appb-C000258

メチル 1-(4-ヨードフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート(50 mg, 0.132 mmol)、パラジウムジクロロビストリフェニルホスフィン (9 mg, 0.013 mmol)、ヨウ化銅 (3 mg, 0.013 mmol) のテトラヒドロフラン溶液中に、N,N-ジメチルプロプ-2-イン-1-アミン(27.8 μL, 0.264 mmol)、ジイソプロピルアミン(94 μL, 0.661 mmol)を添加した。室温で3時間撹拌した後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物(44 mg, 99 %, 0.132 mmol) を得た。茶色固体: 1H-NMR (CDCl3) δ: 8.25 (1H, s), 8.23 (1H, s), 8.06 (1H, d, J = 8.5 Hz), 7.89 (1H, d, J = 8.5 Hz), 7.67 (2H, d, J = 6.6 Hz), 7.48 (2H, d, J = 6.6 Hz), 3.94 (3H, s), 3.52 (2H, s), 2.41 (6H, s).
ESI-MS(m/z): 334[M+H]+. Methyl 1- (4-iodophenyl) -1H-benzo [d] imidazole-6-carboxylate (50 mg, 0.132 mmol), palladium dichlorobistriphenylphosphine (9 mg, 0.013 mmol), copper iodide (3 mg, 0.013 mmol) in a tetrahydrofuran solution were added N, N-dimethylprop-2-in-1-amine (27.8 μL, 0.264 mmol) and diisopropylamine (94 μL, 0.661 mmol). After stirring at room temperature for 3 hours, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (44 mg, 99%, 0.132 mmol). Brown solid: 1 H-NMR (CDCl 3 ) δ: 8.25 (1H, s), 8.23 (1H, s), 8.06 (1H, d, J = 8.5 Hz), 7.89 (1H, d, J = 8.5 Hz) , 7.67 (2H, d, J = 6.6 Hz), 7.48 (2H, d, J = 6.6 Hz), 3.94 (3H, s), 3.52 (2H, s), 2.41 (6H, s).
ESI-MS (m / z): 334 [M + H] + .

工程５
(1-(4-(3-(ジメチルアミノ)プロプ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール Process 5
(1- (4- (3- (Dimethylamino) prop-1-in-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol

Figure JPOXMLDOC01-appb-C000259
Figure JPOXMLDOC01-appb-C000259

メチル 1-(4-(3-(ジメチルアミノ)プロプ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート(200 mg, 0.6 mmol) のテトラヒドロフラン (6 mL) 溶液中に、水素化アルミニウムリチウムのテトラヒドロフラン溶液 (1.0 M, 1.8 mL, 1.8 mmol) をアルゴン雰囲気下-78 ℃で添加した。0 ℃に昇温しながら4時間撹拌した後、飽和酒石酸ナトリウムカリウム水溶液を加え、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記化合物 (75 mg, 41 %, 0.25 mmol) を得た。1H-NMR (CDCl3) δ: 8.04 (1H, br s), 7.77 (1H, br s), 7.59-7.56 (3H, br m), 7.41-7.40 (2H, br m), 7.31 (1H, d, J = 10.0 Hz), 4.83 (2H, s), 3.47 (2H, s), 2.39 (6H, s). 
ESI-MS(m/z): 306[M+H]+. Methyl 1- (4- (3- (dimethylamino) prop-1-in-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate (200 mg, 0.6 mmol) in tetrahydrofuran (6 mL ) A solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 1.8 mL, 1.8 mmol) was added to the solution at −78 ° C. under an argon atmosphere. After stirring for 4 hours while raising the temperature to 0 ° C., saturated aqueous sodium potassium tartrate solution was added, ethyl acetate and saturated brine were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The title compound (75 mg, 41%, 0.25 mmol) was obtained. 1 H-NMR (CDCl 3 ) δ: 8.04 (1H, br s), 7.77 (1H, br s), 7.59-7.56 (3H, br m), 7.41-7.40 (2H, br m), 7.31 (1H, d, J = 10.0 Hz), 4.83 (2H, s), 3.47 (2H, s), 2.39 (6H, s).
ESI-MS (m / z): 306 [M + H] + .

工程６
1-(4-(3-(ジメチルアミノ)プロプ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Step 6
1- (4- (3- (Dimethylamino) prop-1-in-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000260
Figure JPOXMLDOC01-appb-C000260

(1-(4-(3-(ジメチルアミノ)プロプ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール (75 mg, 0.25 mmol) の塩化メチレン (3.0 mL) 溶液に デス・マーチン・ペルヨージナン (167 mg, 0.39 mmol) を0℃で滴下した。室温に昇温し3時間撹拌した。反応終了後、飽和チオ硫酸水素ナトリウム水溶液を添加し、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (61 mg, 82 %, 0.201 mmol) を得た。1H-NMR (CDCl3) δ: 10.09 (1H, s), 8.30 (1H, s), 8.08 (1H, s), 7.99 (1H, d, J = 8.3 Hz), 7.89 (1H, d, J = 8.3 Hz), 7.68 (2H, d, J = 8.5 Hz), 7.50 (2H, d, J = 8.5 Hz), 3.56 (2H, s), 2.44 (6H, s). 
ESI-MS(m/z): 304[M+H]+. (1- (4- (3- (Dimethylamino) prop-1-in-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol (75 mg, 0.25 mmol) in methylene chloride ( 3.0 mL) Dess-Martin periodinane (167 mg, 0.39 mmol) was added dropwise to the solution at 0 ° C. The mixture was warmed to room temperature and stirred for 3 hours. After completion of the reaction, a saturated aqueous sodium hydrogensulfate solution was added, chloroform and a saturated aqueous sodium hydrogencarbonate solution were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (61 mg, 82%, 0.201 mmol). 1 H-NMR (CDCl 3 ) δ: 10.09 (1H, s), 8.30 (1H, s), 8.08 (1H, s), 7.99 (1H, d, J = 8.3 Hz), 7.89 (1H, d, J = 8.3 Hz), 7.68 (2H, d, J = 8.5 Hz), 7.50 (2H, d, J = 8.5 Hz), 3.56 (2H, s), 2.44 (6H, s).
ESI-MS (m / z): 304 [M + H] + .

工程７
5-((1-(4-(3-(ジメチルアミノ)プロプ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物７０) Step 7
5-((1- (4- (3- (dimethylamino) prop-1-in-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine- 4-one (compound 70)

Figure JPOXMLDOC01-appb-C000261
Figure JPOXMLDOC01-appb-C000261

1-(4-(3-(ジメチルアミノ)プロプ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (30 mg, 0.099 mmol) をエタノール (2.0 mL) に溶かし、ロダニン (15 mg, 0.109 mmol) およびピペリジン (1.96 μL, 0.020 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (16 mg, 39 %, 0.039 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.74 (1H, s), 7.89 (1H, d, J = 8.5 Hz), 7.87 (1H, s), 7.82-7.75 (4H, m), 7.61 (1H, s), 7.53 (1H, d, J = 8.5 Hz), 3.92 (2H, s), 2.58 (6H, s). 
ESI-MS(m/z): 419[M+H]+. 1- (4- (3- (dimethylamino) prop-1-in-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (30 mg, 0.099 mmol) in ethanol (2.0 mL) Then, rhodanine (15 mg, 0.109 mmol) and piperidine (1.96 μL, 0.020 mmol) were added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (16 mg, 39%, 0.039 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.74 (1H, s), 7.89 (1H, d, J = 8.5 Hz), 7.87 (1H, s), 7.82-7.75 (4H, m), 7.61 (1H, s), 7.53 (1H, d, J = 8.5 Hz), 3.92 (2H, s), 2.58 (6H, s).
ESI-MS (m / z): 419 [M + H] + .

実施例７１
5-((1-(4-(3-(ジメチルアミノ)プロプ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物７１)  Example 71
5-((1- (4- (3- (Dimethylamino) prop-1-in-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 71)

Figure JPOXMLDOC01-appb-C000262
Figure JPOXMLDOC01-appb-C000262

工程１
1-(4-(3-(ジメチルアミノ)プロプ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (30 mg, 0.099 mmol) をエタノール (2.0 mL) に溶かし、チアゾリジン-2,4-ジオン (13 mg, 0.109 mmol) およびピペリジン (1.96 μL, 0.020 mmol) を加え、還流条件下一晩撹拌した。さらにチアゾリジン-2,4-ジオン (13 mg, 0.109 mmol) およびピペリジン (6.00 μL, 0.060 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (10 mg, 25 %, 0.025 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.76 (1H, s), 7.98-7.90 (3H, m), 7.81-7.71 (4H, m), 7.56 (1H, d, J = 8.5 Hz), 3.64 (2H, s), 2.37 (6H, s). 
ESI-MS(m/z): 403[M+H]+. Process 1
1- (4- (3- (dimethylamino) prop-1-in-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (30 mg, 0.099 mmol) in ethanol (2.0 mL) And thiazolidine-2,4-dione (13 mg, 0.109 mmol) and piperidine (1.96 μL, 0.020 mmol) were added and stirred overnight under reflux conditions. Further, thiazolidine-2,4-dione (13 mg, 0.109 mmol) and piperidine (6.00 μL, 0.060 mmol) were added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (10 mg, 25%, 0.025 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.76 (1H, s), 7.98-7.90 (3H, m), 7.81-7.71 (4H, m), 7.56 (1H, d, J = 8.5 Hz ), 3.64 (2H, s), 2.37 (6H, s).
ESI-MS (m / z): 403 [M + H] + .

実施例７２
5-((1-(4-(3-(ジメチルアミノ)プロピル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物７２)  Example 72
5-((1- (4- (3- (dimethylamino) propyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 72)

工程１
メチル 1-(4-(3-(ジメチルアミノ)プロピル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 1
Methyl 1- (4- (3- (dimethylamino) propyl) phenyl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000263
Figure JPOXMLDOC01-appb-C000263

メチル 1-(4-(3-(ジメチルアミノ)プロプ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート(200 mg, 0.60 mmol) のメタノール (15 mL) 溶液に、アルゴン雰囲気下プラチナ－活性炭 (100 mg) を0 ℃で添加した。水素置換した後、室温に昇温し一晩撹拌した。反応終了後、セライトろ過し減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (144 mg, 0.43 mmol, 71 %) を得た。1H-NMR (CDCl3) δ: 8.15 (2H, s), 7.96-7.94 (1H, br m), 7.81-7.78 (1H, br m), 7.37-7.35 (4H, m), 3.85 (3H, s), 2.72 (2H, t, J = 6.5 Hz), 2.57 (2H, t, J = 6.5 Hz), 2.42 (6H, s), 1.97-1.94 (2H, br m). 
ESI-MS(m/z): 338[M+H]+. Methyl 1- (4- (3- (dimethylamino) prop-1-in-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate (200 mg, 0.60 mmol) in methanol (15 mL ) Platinum-activated carbon (100 mg) was added to the solution at 0 ° C. under an argon atmosphere. After purging with hydrogen, the mixture was warmed to room temperature and stirred overnight. After completion of the reaction, the mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (144 mg, 0.43 mmol, 71%). 1 H-NMR (CDCl 3 ) δ: 8.15 (2H, s), 7.96-7.94 (1H, br m), 7.81-7.78 (1H, br m), 7.37-7.35 (4H, m), 3.85 (3H, s), 2.72 (2H, t, J = 6.5 Hz), 2.57 (2H, t, J = 6.5 Hz), 2.42 (6H, s), 1.97-1.94 (2H, br m).
ESI-MS (m / z): 338 [M + H] + .

工程２
(1-(4-(3-(ジメチルアミノ)プロピル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール Process 2
(1- (4- (3- (Dimethylamino) propyl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol

Figure JPOXMLDOC01-appb-C000264
Figure JPOXMLDOC01-appb-C000264

メチル 1-(4-(3-(ジメチルアミノ)プロピル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート (144 mg, 0.43 mmol) のテトラヒドロフラン (4 mL) 溶液中に、水素化アルミニウムリチウムのテトラヒドロフラン溶液 (1.0 M, 0.86 mL, 0.86 mmol) をアルゴン雰囲気下-78 ℃で添加した。0 ℃に昇温しながら4時間撹拌した後、飽和酒石酸ナトリウムカリウム水溶液を加え、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (59 mg, 0.19 mmol, 44 %) を得た。1H-NMR (CDCl3) δ: 8.03 (1H, s), 7.78 (1H, d, J = 8.3 Hz), 7.57 (1H, br s), 7.37-7.28 (5H, m), 4.81 (2H, s), 2.69 (2H, t, J = 7.8 Hz), 2.33 (2H, t, J = 7.8 Hz), 2.24 (6H, s), 1.88-1.78 (2H, m). 
ESI-MS(m/z): 310[M+H]+. In a solution of methyl 1- (4- (3- (dimethylamino) propyl) phenyl) -1H-benzo [d] imidazole-6-carboxylate (144 mg, 0.43 mmol) in tetrahydrofuran (4 mL), aluminum hydride A solution of lithium in tetrahydrofuran (1.0 M, 0.86 mL, 0.86 mmol) was added at −78 ° C. under an argon atmosphere. After stirring for 4 hours while raising the temperature to 0 ° C., saturated aqueous sodium potassium tartrate solution was added, ethyl acetate and saturated brine were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (59 mg, 0.19 mmol, 44%). 1 H-NMR (CDCl 3 ) δ: 8.03 (1H, s), 7.78 (1H, d, J = 8.3 Hz), 7.57 (1H, br s), 7.37-7.28 (5H, m), 4.81 (2H, s), 2.69 (2H, t, J = 7.8 Hz), 2.33 (2H, t, J = 7.8 Hz), 2.24 (6H, s), 1.88-1.78 (2H, m).
ESI-MS (m / z): 310 [M + H] + .

工程３
1-(4-(3-(ジメチルアミノ)プロピル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Process 3
1- (4- (3- (Dimethylamino) propyl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000265
Figure JPOXMLDOC01-appb-C000265

(1-(4-(3-(ジメチルアミノ)プロピル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール (60 mg, 0.19 mmol) の塩化メチレン (2.0 mL) 溶液にデス・マーチン・ペルヨージナン (132 mg, 0.31 mmol) を0 ℃で滴下した。室温に昇温し3時間撹拌した後、飽和チオ硫酸水素ナトリウム水溶液を添加し、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (50 mg, 86 %, 0.16 mmol) を得た。1H-NMR (CDCl3) δ: 10.12 (1H, s), 8.32 (1H, s), 8.12 (1H, s), 8.03 (1H, d, J = 8.3 Hz), 7.92 (1H, d, J = 8.3 Hz), 7.49 (4H, d, J = 3.9 Hz), 2.88-2.81 (2H, m), 2.62-2.55 (2H, m), 2.45 (6H, s), 2.05-1.97 (2H, m). 
ESI-MS(m/z): 308[M+H]+. Dess Martin in (1- (4- (3- (dimethylamino) propyl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol (60 mg, 0.19 mmol) in methylene chloride (2.0 mL) -Periodinane (132 mg, 0.31 mmol) was added dropwise at 0 ° C. After warming to room temperature and stirring for 3 hours, a saturated aqueous sodium hydrogensulfate solution was added, the organic layer was extracted by adding chloroform and a saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. . The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (50 mg, 86%, 0.16 mmol). 1 H-NMR (CDCl 3 ) δ: 10.12 (1H, s), 8.32 (1H, s), 8.12 (1H, s), 8.03 (1H, d, J = 8.3 Hz), 7.92 (1H, d, J = 8.3 Hz), 7.49 (4H, d, J = 3.9 Hz), 2.88-2.81 (2H, m), 2.62-2.55 (2H, m), 2.45 (6H, s), 2.05-1.97 (2H, m) .
ESI-MS (m / z): 308 [M + H] + .

工程４
5-((1-(4-(3-(ジメチルアミノ)プロピル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物７２)  Process 4
5-((1- (4- (3- (dimethylamino) propyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 72)

Figure JPOXMLDOC01-appb-C000266
Figure JPOXMLDOC01-appb-C000266

1-(4-(3-(ジメチルアミノ)プロピル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (50 mg, 0.16 mmol) をエタノール (4.0 mL) に溶かし、ロダニン (24 mg, 0.18 mmol) およびピペリジン (3.2 μL, 0.033 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (34 mg, 50 %, 0.08 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.61 (1H, s), 7.83 (1H, d, J = 8.5 Hz), 7.72 (1H, s), 7.67 (2H, d, J = 8.3 Hz), 7.55 (2H, d, J = 8.3 Hz), 7.49 (1H, d, J = 8.5 Hz), 7.35 (1H, s), 2.98 (2H, t, J = 7.8 Hz), 2.77 (2H, t, J = 7.8 Hz), 2.70 (6H, s), 2.06-1.96 (2H, m). 
ESI-MS(m/z): 423[M+H]+. 1- (4- (3- (dimethylamino) propyl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (50 mg, 0.16 mmol) was dissolved in ethanol (4.0 mL) and rhodanine (24 mg, 0.18 mmol) and piperidine (3.2 μL, 0.033 mmol) were added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (34 mg, 50%, 0.08 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.61 (1H, s), 7.83 (1H, d, J = 8.5 Hz), 7.72 (1H, s), 7.67 (2H, d, J = 8.3 Hz), 7.55 (2H, d, J = 8.3 Hz), 7.49 (1H, d, J = 8.5 Hz), 7.35 (1H, s), 2.98 (2H, t, J = 7.8 Hz), 2.77 (2H, t, J = 7.8 Hz), 2.70 (6H, s), 2.06-1.96 (2H, m).
ESI-MS (m / z): 423 [M + H] + .

実施例７３
5-((1-(4-(6-(4-メチルピペラジン-1-イル)ヘキシ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物７３)  Example 73
5-((1- (4- (6- (4-methylpiperazin-1-yl) hex-1-in-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene)- 2-Thioxothiazolidine-4-one (Compound 73)

工程１
メチル 1-(4-(6-クロロヘキシ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 1
Methyl 1- (4- (6-chlorohex-1-in-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000267
Figure JPOXMLDOC01-appb-C000267

メチル 1-(4-ヨードフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート(600 mg, 1.59 mmol)、パラジウムジクロロビストリフェニルホスフィン (111 mg, 0.16 mmol)、ヨウ化銅 (30 mg, 0.16 mmol) のテトラヒドロフラン (10 mL) 溶液中に、6-クロロヘキシ-1-イン (385 μL, 3.17 mmol)、ジイソプロピルアミン (1.13 mL, 7.93 mmol) を添加した。室温で3時間撹拌した後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物(583 mg, 99 %, 0.159 mmol) を得た。茶色粘性体: 1H-NMR (CDCl3) δ: 8.19 (2H, s), 8.01 (1H, d, J = 8.5 Hz), 7.84 (1H, d, J = 8.5 Hz), 7.57 (2H, dd, J = 8.5, 3.0 Hz), 7.42 (2H, dd, J = 8.5, 3.0 Hz), 3.89 (3H, s), 3.59 (2H, td, J = 6.8, 3.2 Hz), 2.47 (2H, td, J = 6.8, 3.2 Hz), 1.99-1.90 (2H, m), 1.81-1.72 (2H, m).
ESI-MS(m/z): 367[M+H]+. Methyl 1- (4-iodophenyl) -1H-benzo [d] imidazole-6-carboxylate (600 mg, 1.59 mmol), palladium dichlorobistriphenylphosphine (111 mg, 0.16 mmol), copper iodide (30 mg, To a solution of 0.16 mmol) in tetrahydrofuran (10 mL), 6-chlorohex-1-yne (385 μL, 3.17 mmol) and diisopropylamine (1.13 mL, 7.93 mmol) were added. After stirring at room temperature for 3 hours, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (583 mg, 99%, 0.159 mmol). Brown viscous material: 1 H-NMR (CDCl 3 ) δ: 8.19 (2H, s), 8.01 (1H, d, J = 8.5 Hz), 7.84 (1H, d, J = 8.5 Hz), 7.57 (2H, dd , J = 8.5, 3.0 Hz), 7.42 (2H, dd, J = 8.5, 3.0 Hz), 3.89 (3H, s), 3.59 (2H, td, J = 6.8, 3.2 Hz), 2.47 (2H, td, J = 6.8, 3.2 Hz), 1.99-1.90 (2H, m), 1.81-1.72 (2H, m).
ESI-MS (m / z): 367 [M + H] + .

工程２
メチル 1-(4-(6-(4-メチルピペラジン-1-イル)ヘキシ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート Process 2
Methyl 1- (4- (6- (4-methylpiperazin-1-yl) hex-1-in-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate

Figure JPOXMLDOC01-appb-C000268
Figure JPOXMLDOC01-appb-C000268

メチル 1-(4-(6-クロロヘキシ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート (563 mg, 1.5 mmol)、炭酸カリウム(1.17 g, 8.4 mmol)、ヨウ化ナトリウム (345 mg, 2.3 mmol) のアセトン (15 mL) 溶液中に1-メチルピペラジン (0.85 mL, 7.7 mmol) を室温下滴下した。還流条件下一晩加熱し、反応終了後減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (604 mg, 91 %, 0.14 mmol) を得た。 1H-NMR (CDCl3) δ: 8.24 (1H, s), 8.22 (1H, s), 8.06 (1H, d, J = 8.5 Hz), 7.89 (1H, d, J = 8.5 Hz), 7.61 (2H, d, J = 8.3 Hz), 7.45 (2H, d, J = 8.3 Hz), 7.27 (1H, s), 3.93 (3H, s), 2.63-2.35 (12H, m), 2.31 (3H, s), 1.75-1.58 (4H, m). 
ESI-MS(m/z): 431[M+H]+. Methyl 1- (4- (6-chlorohex-1-in-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate (563 mg, 1.5 mmol), potassium carbonate (1.17 g, 8.4 mmol) ), Sodium iodide (345 mg, 2.3 mmol) in acetone (15 mL) was added dropwise 1-methylpiperazine (0.85 mL, 7.7 mmol) at room temperature. After heating overnight under reflux conditions, the reaction was completed and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (604 mg, 91%, 0.14 mmol). . 1 H-NMR (CDCl 3 ) δ: 8.24 (1H, s), 8.22 (1H, s), 8.06 (1H, d, J = 8.5 Hz), 7.89 (1H, d, J = 8.5 Hz), 7.61 ( 2H, d, J = 8.3 Hz), 7.45 (2H, d, J = 8.3 Hz), 7.27 (1H, s), 3.93 (3H, s), 2.63-2.35 (12H, m), 2.31 (3H, s ), 1.75-1.58 (4H, m).
ESI-MS (m / z): 431 [M + H] + .

工程３
(1-(4-(6-(4-メチルピペラジン-1-イル)ヘキシ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール Process 3
(1- (4- (6- (4-Methylpiperazin-1-yl) hex-1-in-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol

Figure JPOXMLDOC01-appb-C000269
Figure JPOXMLDOC01-appb-C000269

メチル 1-(4-(6-(4-メチルピペラジン-1-イル)ヘキシ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレート (250 mg, 0.58 mmol) のテトラヒドロフラン (6 mL) 溶液中に、水素化アルミニウムリチウムのテトラヒドロフラン溶液 (1.0 M, 1.7 mL, 1.7 mmol) をアルゴン雰囲気下-78 ℃で添加した。0 ℃に昇温しながら5時間撹拌した後、飽和酒石酸ナトリウムカリウム水溶液を加え、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (233 mg, 0.58 mmol, 99 %) を得た。1H-NMR (CDCl3) δ: 8.03 (1H, d, J = 4.6 Hz), 7.79 (1H, d, J = 8.3 Hz), 7.58-7.52 (3H, m), 7.42-7.35 (2H, m), 7.31 (1H, d, J = 8.3 Hz), 4.81 (2H, s), 2.76-2.37 (12H, m), 2.29 (3H, s), 1.75-1.58 (4H, m). 
ESI-MS(m/z): 403[M+H]+. Methyl 1- (4- (6- (4-methylpiperazin-1-yl) hex-1-in-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate (250 mg, 0.58 mmol ) In tetrahydrofuran (6 mL) was added a solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 1.7 mL, 1.7 mmol) at −78 ° C. under an argon atmosphere. After stirring for 5 hours while raising the temperature to 0 ° C., saturated aqueous sodium potassium tartrate solution was added, ethyl acetate and saturated brine were added, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (233 mg, 0.58 mmol, 99%). 1 H-NMR (CDCl 3 ) δ: 8.03 (1H, d, J = 4.6 Hz), 7.79 (1H, d, J = 8.3 Hz), 7.58-7.52 (3H, m), 7.42-7.35 (2H, m ), 7.31 (1H, d, J = 8.3 Hz), 4.81 (2H, s), 2.76-2.37 (12H, m), 2.29 (3H, s), 1.75-1.58 (4H, m).
ESI-MS (m / z): 403 [M + H] + .

工程４
1-(4-(6-(4-メチルピペラジン-1-イル)ヘキシ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド  Process 4
1- (4- (6- (4-Methylpiperazin-1-yl) hex-1-in-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000270
Figure JPOXMLDOC01-appb-C000270

(1-(4-(6-(4-メチルピペラジン-1-イル)ヘキシ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノール (233 mg, 0.58 mmol) の塩化メチレン (6.0 mL) 溶液にデス・マーチン・ペルヨージナン (393 mg, 0.93 mmol) を0℃で滴下した。室温に昇温し3時間撹拌した後、飽和チオ硫酸水素ナトリウム水溶液を添加し、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (209 mg, 90 %, 0.52 mmol) を得た。1H-NMR (CDCl3) δ: 10.09 (1H, s), 8.28 (1H, s), 8.07 (1H, s), 7.99 (1H, d, J = 8.3 Hz), 7.89 (1H, d, J = 8.3 Hz), 7.61 (2H, d, J = 7.1 Hz), 7.46 (2H, d, J = 7.1 Hz), 2.89-2.55 (8H, m), 2.54-2.46 (4H, m), 2.40 (3H, s), 1.78-1.63 (4H, m). 
ESI-MS(m/z): 401[M+H]+. (1- (4- (6- (4-Methylpiperazin-1-yl) hex-1-yn-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methanol (233 mg, 0.58 mmol) in methylene chloride (6.0 mL) was added dropwise Dess-Martin periodinane (393 mg, 0.93 mmol) at 0 ° C. After warming to room temperature and stirring for 3 hours, a saturated aqueous sodium hydrogensulfate solution was added, the organic layer was extracted by adding chloroform and a saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. . The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (209 mg, 90%, 0.52 mmol). 1 H-NMR (CDCl 3 ) δ: 10.09 (1H, s), 8.28 (1H, s), 8.07 (1H, s), 7.99 (1H, d, J = 8.3 Hz), 7.89 (1H, d, J = 8.3 Hz), 7.61 (2H, d, J = 7.1 Hz), 7.46 (2H, d, J = 7.1 Hz), 2.89-2.55 (8H, m), 2.54-2.46 (4H, m), 2.40 (3H , s), 1.78-1.63 (4H, m).
ESI-MS (m / z): 401 [M + H] + .

工程５
5-((1-(4-(6-(4-メチルピペラジン-1-イル)ヘキシ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物７３)  Process 5
5-((1- (4- (6- (4-methylpiperazin-1-yl) hex-1-in-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene)- 2-Thioxothiazolidine-4-one (Compound 73)

Figure JPOXMLDOC01-appb-C000271
Figure JPOXMLDOC01-appb-C000271

1-(4-(6-(4-メチルピペラジン-1-イル)ヘキシ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (100 mg, 0.25 mmol) をエタノール (5.0 mL) に溶かし、ロダニン (37 mg, 0.28 mmol) およびピペリジン (2.5 μL, 0.025 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (50 mg, 39 %, 0.097 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.66 (1H, s), 8.32 (1H, s), 7.84 (1H, d, J = 8.5 Hz), 7.75 (1H, d, J = 1.5 Hz), 7.72 (2H, d, J = 8.8 Hz), 7.65 (2H, d, J = 8.8 Hz), 7.50 (1H, dd, J = 8.5, 1.5 Hz), 7.38 (1H, s), 3.39-3.23 (2H, m), 2.99-2.56 (10H, m), 2.52 (3H, s), 1.71-1.57 (4H, m). 
ESI-MS(m/z): 516[M+H]+. 1- (4- (6- (4-Methylpiperazin-1-yl) hex-1-yn-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (100 mg, 0.25 mmol) Was dissolved in ethanol (5.0 mL), rhodanine (37 mg, 0.28 mmol) and piperidine (2.5 μL, 0.025 mmol) were added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (50 mg, 39%, 0.097 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.66 (1H, s), 8.32 (1H, s), 7.84 (1H, d, J = 8.5 Hz), 7.75 (1H, d, J = 1.5 Hz), 7.72 (2H, d, J = 8.8 Hz), 7.65 (2H, d, J = 8.8 Hz), 7.50 (1H, dd, J = 8.5, 1.5 Hz), 7.38 (1H, s), 3.39- 3.23 (2H, m), 2.99-2.56 (10H, m), 2.52 (3H, s), 1.71-1.57 (4H, m).
ESI-MS (m / z): 516 [M + H] + .

実施例７４
5-((1-(4-(6-(4-メチルピペラジン-1-イル)ヘキシ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物７４)  Example 74
5-((1- (4- (6- (4-Methylpiperazin-1-yl) hex-1-in-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine -2,4-dione (Compound 74)

Figure JPOXMLDOC01-appb-C000272
Figure JPOXMLDOC01-appb-C000272

工程１
1-(4-(6-(4-メチルピペラジン-1-イル)ヘキシ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (100 mg, 0.25 mmol) をエタノール (5.0 mL) に溶かし、チアゾリジン-2,4-ジオン (32 mg, 0.28 mmol) およびピペリジン (2.5 μL, 0.025 mmol) を加え、還流条件下一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (3 mg, 2 %, 0.006 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.68 (1H, s), 7.85 (2H, d, J = 8.0 Hz), 7.72 (2H, d, J = 8.0 Hz), 7.67-7.65 (3H, m), 7.52 (1H, d, J = 8.5 Hz), 3.48-3.23 (2H, m), 2.76-2.54 (10H, m), 2.39 (3H, s), 1.70-1.54 (4H, m). 
ESI-MS(m/z): 500[M+H]+. Process 1
1- (4- (6- (4-Methylpiperazin-1-yl) hex-1-yn-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (100 mg, 0.25 mmol) Was dissolved in ethanol (5.0 mL), thiazolidine-2,4-dione (32 mg, 0.28 mmol) and piperidine (2.5 μL, 0.025 mmol) were added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (3 mg, 2%, 0.006 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.68 (1H, s), 7.85 (2H, d, J = 8.0 Hz), 7.72 (2H, d, J = 8.0 Hz), 7.67-7.65 ( 3H, m), 7.52 (1H, d, J = 8.5 Hz), 3.48-3.23 (2H, m), 2.76-2.54 (10H, m), 2.39 (3H, s), 1.70-1.54 (4H, m) .
ESI-MS (m / z): 500 [M + H] + .

実施例７５
5-((1-(3-(2-(4-エチルピペラジン-1-イル)エトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物７５)  Example 75
5-((1- (3- (2- (4-Ethylpiperazin-1-yl) ethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (compound 75)

工程１
エチル 2-(3-ニトロフェノキシ)アセテート Process 1
Ethyl 2- (3-nitrophenoxy) acetate

Figure JPOXMLDOC01-appb-C000273
Figure JPOXMLDOC01-appb-C000273

3-ニトロフェノール (2.78 g, 20 mmol) をN,N-ジメチルホルムアミド (20 mL) に溶かし、炭酸カリウム (6.91 g, 50 mmol) およびブロモ酢酸エチル (3.35 g, 20 mmol) を加え、90 ℃のオイルバス中で2時間撹拌した。反応終了後、反応混合物に酢酸エチルを加え、水で洗浄した。有機層を無水硫酸マグネシウムで乾燥させた後、溶媒を留去し、シリカゲルカラムクロマトグラフィー法で精製し、標記化合物 (4.30 g, 19 mmol, 96 %) を得た。1H-NMR (CDCl3) δ: 7.89 (1H, m), 7.73 (1H, m), 7.47 (1H, m), 7.29 (1H, m), 4.72 (2H, s), 4.31 (2H, q, J = 7.1 Hz), 1.33 (3H, t, J = 7.1 Hz). Dissolve 3-nitrophenol (2.78 g, 20 mmol) in N, N-dimethylformamide (20 mL), add potassium carbonate (6.91 g, 50 mmol) and ethyl bromoacetate (3.35 g, 20 mmol), and add 90 ° C. In an oil bath for 2 hours. After completion of the reaction, ethyl acetate was added to the reaction mixture and washed with water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the title compound (4.30 g, 19 mmol, 96%). 1 H-NMR (CDCl 3 ) δ: 7.89 (1H, m), 7.73 (1H, m), 7.47 (1H, m), 7.29 (1H, m), 4.72 (2H, s), 4.31 (2H, q , J = 7.1 Hz), 1.33 (3H, t, J = 7.1 Hz).

工程２
エチル 2-(3-((5-(メトキシ(メチル)カルボニル)-2-ニトロフェニル)アミノ)フェノキシ)アセテート Process 2
Ethyl 2- (3-((5- (methoxy (methyl) carbonyl) -2-nitrophenyl) amino) phenoxy) acetate

Figure JPOXMLDOC01-appb-C000274
Figure JPOXMLDOC01-appb-C000274

エチル 2-(3-ニトロフェノキシ)アセテート (4.30 g, 19 mmol) のメタノール (45 mL) 溶液に 10% パラジウム－活性炭 (0.8 g) を加え、水素雰囲気下、室温で 終夜撹拌した。反応終了後、反応溶液をろ過し、減圧下溶媒を留去した後、3-フルオロ-N-メトキシ-N-メチル-4-ニトロベンズアミド (953 mg, 4.29 mmol) の N,N-ジメチルホルムアミド の合成と同様の方法で標記化合物の混合物 (5.44 g) を得た。 To a solution of ethyl 2- (3-nitrophenoxy) acetate (4.30 g, 19 mmol) in methanol (45 mL) was added 10% palladium-activated carbon (0.8 g) and stirred overnight at room temperature in a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered and the solvent was distilled off under reduced pressure. Then, 3-fluoro-N-methoxy-N-methyl-4-nitrobenzamide (953 mg, 4.29 mmol) N, N-dimethylformamide A mixture 標記 (5.44 g) 標記 of the title compound was obtained in the same manner as in the synthesis.

工程３
エチル 2-(3-(6-(メトキシ(メチル)カルボニル)-1H-ベンゾ[d]イミダゾール-1-イル)フェノキシ)アセテート Process 3
Ethyl 2- (3- (6- (methoxy (methyl) carbonyl) -1H-benzo [d] imidazol-1-yl) phenoxy) acetate

Figure JPOXMLDOC01-appb-C000275
Figure JPOXMLDOC01-appb-C000275

エチル 2-(3-((5-(メトキシ(メチル)カルボニル)-2-ニトロフェニル)アミノ)フェノキシ)アセテート の混合物 (5.44 g) を用い、N-メトキシ-N-メチル-3-((4-(4-メチルピペラジニル)ベンジル)アミノ)-4-ニトロベンズアミド の合成と同様の方法で標記化合物 (2.50 g, 6.5 mmol) を得た。1H-NMR (CDCl3) δ: 8.25 (1H, s), 7.95 (1H, s), 7.89 (1H, d, J = 8.5 Hz), 7.72 (1H, d, J = 8.5 Hz), 7.51 (1H, m), 7.17 (1H, m), 7.08 (1H, m), 7.01 (1H, m), 4.70 (2H, s ), 4.30 (2H, q, J = 7.2 Hz), 1.31 (3H, t, J = 7.2 Hz). Using a mixture of ethyl 2- (3-((5- (methoxy (methyl) carbonyl) -2-nitrophenyl) amino) phenoxy) acetate (5.44 g), N-methoxy-N-methyl-3-((4 The title compound (2.50 g, 6.5 mmol) was obtained in the same manner as in the synthesis of-(4-methylpiperazinyl) benzyl) amino) -4-nitrobenzamide. 1 H-NMR (CDCl 3 ) δ: 8.25 (1H, s), 7.95 (1H, s), 7.89 (1H, d, J = 8.5 Hz), 7.72 (1H, d, J = 8.5 Hz), 7.51 ( 1H, m), 7.17 (1H, m), 7.08 (1H, m), 7.01 (1H, m), 4.70 (2H, s), 4.30 (2H, q, J = 7.2 Hz), 1.31 (3H, t , J = 7.2 Hz).

工程４
2-(3-(6-(ヒドロキシメチル)-1H-ベンゾ[d]イミダゾール-1-イル)フェノキシ)エタノール Process 4
2- (3- (6- (hydroxymethyl) -1H-benzo [d] imidazol-1-yl) phenoxy) ethanol

Figure JPOXMLDOC01-appb-C000276
Figure JPOXMLDOC01-appb-C000276

エチル 2-(3-(6-(メトキシ(メチル)カルボニル)-1H-ベンゾ[d]イミダゾール-1-イル)フェノキシ)アセテート (2.50 g, 6.5 mmol) をテトラヒドロフラン (100 mL) およびエタノール (100 mL) に溶かし、塩化カルシウム (2.5 g, 22.5 mmol) を加え、氷浴中で15分間撹拌した後、水素化ホウ素ナトリウム (1.0 g, 26 mmol) を加え、氷浴中で3時間撹拌した。反応混合物を氷浴中で冷やしながら1M 硫酸水素カリウム水溶液を加え15分間撹拌した後、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥させ、減圧下、溶媒を留去し、シリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物の混合物 (1.36 g) を得た。 Ethyl 2- (3- (6- (methoxy (methyl) carbonyl) -1H-benzo [d] imidazol-1-yl) phenoxy) acetate (2.50 g, 6.5 mmol) in tetrahydrofuran (100 mL) and ethanol (100 mL ), Calcium chloride (2.5 g, 22.5 mmol) was added, and the mixture was stirred in an ice bath for 15 minutes, and then sodium borohydride.   (1.0 g, 26 mmol) was added, and the mixture was stirred in an ice bath for 3 hours. The reaction mixture was cooled in an ice bath, 1M aqueous potassium hydrogen sulfate solution was added, and the mixture was stirred for 15 minutes, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to give a mixture of the title compounds (1.36 g )

工程５
1-(3-(2-ヒドロキシエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Process 5
1- (3- (2-hydroxyethoxy) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000277
Figure JPOXMLDOC01-appb-C000277

2-(3-(6-(ヒドロキシメチル)-1H-ベンゾ[d]イミダゾール-1-イル)フェノキシ)エタノール (0.31 g, 1.1 mmol) を用い、1-(4-(3-(ジメチルアミノ)プロプ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒドの合成と同様の方法で標記化合物 (0.26 g, 0.9 mmol, 84 %) を得た。1H-NMR (CDCl3) δ: 10.14 (1H, s), 9.36 (1H, s), 8.24 (1H, d, J = 8.3 Hz), 8.21 (1H, s), 8.10 (1H, m), 7.58 (1H, d, J = 8.3 Hz), 7.35-7.15 (3H, m), 4.24 (2H, m), 4.03 (2H, m). 2- (3- (6- (hydroxymethyl) -1H-benzo [d] imidazol-1-yl) phenoxy) ethanol (0.31 g, 1.1 mmol) was used to give 1- (4- (3- (dimethylamino) The title compound (0.26 g, 0.9 mmol, 84%) was obtained in the same manner as the synthesis of prop-1-in-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde. 1 H-NMR (CDCl 3 ) δ: 10.14 (1H, s), 9.36 (1H, s), 8.24 (1H, d, J = 8.3 Hz), 8.21 (1H, s), 8.10 (1H, m), 7.58 (1H, d, J = 8.3 Hz), 7.35-7.15 (3H, m), 4.24 (2H, m), 4.03 (2H, m).

工程６
1-(3-(2-(4-エチルピペラジン-1-イル)エトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Step 6
1- (3- (2- (4-Ethylpiperazin-1-yl) ethoxy) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000278
Figure JPOXMLDOC01-appb-C000278

アルゴン雰囲気下、1-(3-(2-ヒドロキシエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (0.26 g, 0.92 mmol) を塩化メチレン (10 mL) に溶かし、氷浴中で冷やしながらジイソプロピルエチルアミン (284 mg, 2.2 mmol) およびメタンスルホニルクロリド (126 mg, 1.1 mmol) の塩化メチレン (3 mL) 溶液を加え、氷浴中で4時間撹拌した後、反応混合物に N-エチルピペラジン (342 mg, 3 mmol) を加え、氷浴中で3時間、室温で終夜撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥させ、減圧下、溶媒を留去した後、 シリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (0.14 g, 0.37 mmol , 40 %) を得た。1H-NMR (CDCl3) δ: 10.10 (1H, s), 8.29 (1H, s), 8.11 (1H, s), 8.00 (1H, d, J = 8.3 Hz), 7.90 (1H, d, J = 8.3 Hz), 7.52 (1H, m), 7.13 (1H, m), 7.08-7.05 (2H, m), 4.20 (2H, t, J = 5.7 Hz), 2.90 (2H, t, J = 5.7 Hz), 2.81-2.40 (10H, m), 1.26 (3H, br s). In an argon atmosphere, 1- (3- (2-hydroxyethoxy) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (0.26 g, 0.92 mmol) was dissolved in methylene chloride (10 mL) and placed in an ice bath. Then, a solution of diisopropylethylamine (284 mg, 2.2 mmol) and methanesulfonyl chloride (126 mg, 1.1 mmol) in methylene chloride (3 mL) was added while stirring in an ice bath, and the mixture was stirred in an ice bath for 4 hours. Piperazine (342 mg, 3 mmol) was added, and the mixture was stirred in an ice bath for 3 hours and at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.14 g, 0.37 mmol, 40%). 1 H-NMR (CDCl 3 ) δ: 10.10 (1H, s), 8.29 (1H, s), 8.11 (1H, s), 8.00 (1H, d, J = 8.3 Hz), 7.90 (1H, d, J = 8.3 Hz), 7.52 (1H, m), 7.13 (1H, m), 7.08-7.05 (2H, m), 4.20 (2H, t, J = 5.7 Hz), 2.90 (2H, t, J = 5.7 Hz ), 2.81-2.40 (10H, m), 1.26 (3H, br s).

工程７
5-((1-(3-(2-(4-エチルピペラジン-1-イル)エトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物７５)  Step 7
5-((1- (3- (2- (4-Ethylpiperazin-1-yl) ethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (compound 75)

Figure JPOXMLDOC01-appb-C000279
Figure JPOXMLDOC01-appb-C000279

5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン と同様の方法で、1-(3-(2-(4-エチルピペラジン-1-イル)エトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (0.09 g, 0.24 mmol) およびチアゾリジン-2,4-ジオン (28 mg, 0.24 mmol) とから標記化合物 (46 mg, 40 %) を得た。1H-NMR (DMSO-D6) δ: 8.26 (1H, s), 7.85 (1H, m), 7.80-7.73 (2H, m), 7.48 (1H, m), 7.38 (1H, m), 7.13 (1H, d, J = 2.0 Hz), 7.08- 7.03 (2H, m), 4.23 (2H, t, J = 5.1 Hz), 2.96 (2H, t, J = 5.1 Hz), 2.93-2.70 (10H, m), 1.26 (3H, br s).
ESI-MS(m/z): 478[M+H]+. In the same manner as 5-((1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione, 3- (2- (4-Ethylpiperazin-1-yl) ethoxy) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (0.09 g, 0.24 mmol) and thiazolidine-2,4-dione (28 mg , 0.24 mmol) and the title compound (46 mg, 40%) was obtained. 1 H-NMR (DMSO-D 6 ) δ: 8.26 (1H, s), 7.85 (1H, m), 7.80-7.73 (2H, m), 7.48 (1H, m), 7.38 (1H, m), 7.13 (1H, d, J = 2.0 Hz), 7.08- 7.03 (2H, m), 4.23 (2H, t, J = 5.1 Hz), 2.96 (2H, t, J = 5.1 Hz), 2.93-2.70 (10H, m), 1.26 (3H, br s).
ESI-MS (m / z): 478 [M + H] + .

実施例７６
5-((1-(3-(2-(4-エチルピペラジン-1-イル)エトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物７６)  Example 76
5-((1- (3- (2- (4-Ethylpiperazin-1-yl) ethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4- ON (compound 76)

Figure JPOXMLDOC01-appb-C000280
Figure JPOXMLDOC01-appb-C000280

工程１
5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン と同様の方法で、1-(3-(2-(4-エチルピペラジン-1-イル)エトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (0.05 g, 0.13 mmol) およびロダニン (18 mg, 0.13 mmol) とから標記化合物 (38 mg, 59 %) を得た。1H-NMR (DMSO-D6)δ: 8.66(1H, s), 7.84 (1 H, d, J = 8.5 Hz H), 7.78 (1H, s), 7.58 (1H, m), 7.51 (1H, m), 7.40 (1H, s), 7.34-7.29 (2H, m), 7.11 (1H, m), 4.27 (2H, t, J = 5.4 Hz), 3.10-2.60 (12H, m), 1.16 (3H, t, J = 7.3 Hz). 
ESI-MS(m/z): 494[M+H]+. Process 1
In the same manner as 5-((1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one, 1- (3- (2- (4-Ethylpiperazin-1-yl) ethoxy) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (0.05 g, 0.13 mmol) and rhodanine (18 mg, 0.13 mmol ) To give the title compound (38 mg, 59%). 1 H-NMR (DMSO-D 6 ) δ: 8.66 (1H, s), 7.84 (1 H, d, J = 8.5 Hz H), 7.78 (1H, s), 7.58 (1H, m), 7.51 (1H , m), 7.40 (1H, s), 7.34-7.29 (2H, m), 7.11 (1H, m), 4.27 (2H, t, J = 5.4 Hz), 3.10-2.60 (12H, m), 1.16 ( (3H, t, J = 7.3 Hz).
ESI-MS (m / z): 494 [M + H] + .

実施例７７
5-((1-(4-(4-エチルピペラジン-1-イル)-2-(トリフルオロメトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物７７)  Example 77
5-((1- (4- (4-Ethylpiperazin-1-yl) -2- (trifluoromethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4- Dione (Compound 77)

工程１
N-(4-ブロモ-2-(トリフルオロメトキシ)フェニル)ベンズアミド Process 1
N- (4-Bromo-2- (trifluoromethoxy) phenyl) benzamide

Figure JPOXMLDOC01-appb-C000281
Figure JPOXMLDOC01-appb-C000281

4-ブロモ-2-(トリフルオロメトキシ)アニリン (5.12 g, 20 mmol) を酢酸エチル (40 mL) に溶かし、氷浴中で冷やしながら1規定水酸化ナトリウム水溶液 (22 mL, 22 mmol) を加えた後、ベンゾイルクロリド (2.81 g, 20 mmol) の酢酸エチル (10 mL) 溶液をゆっくり加え、氷浴中で6時間撹拌した。反応混合物中の析出物をろ過し、精製水、酢酸エチル、ヘキサンで洗浄し、標記化合物 (6.70 g, 19 mmol , 93 %) を得た。1H-NMR (CDCl3) δ: 8.55 (1H, d, J = 8.8 Hz), 8.10 (1H, d, J = 7.6 Hz), 7.90- 7.84 (2H, m), 7.61 (1H, d, J = 7.6 Hz), 7.58-7.45 (4H, m). 4-Bromo-2- (trifluoromethoxy) aniline (5.12 g, 20 mmol) is dissolved in ethyl acetate (40 mL), and 1N aqueous sodium hydroxide solution (22 mL, 22 mmol) is added while cooling in an ice bath. After that, a solution of benzoyl chloride (2.81 g, 20 mmol) in ethyl acetate (10 mL) was slowly added, and the mixture was stirred in an ice bath for 6 hours. The precipitate in the reaction mixture was filtered and washed with purified water, ethyl acetate and hexane to obtain the title compound (6.70 g, 19 mmol, 93%). 1 H-NMR (CDCl 3 ) δ: 8.55 (1H, d, J = 8.8 Hz), 8.10 (1H, d, J = 7.6 Hz), 7.90-7.84 (2H, m), 7.61 (1H, d, J = 7.6 Hz), 7.58-7.45 (4H, m).

工程２
N-(5-(1,3-ジオキサン-2-イル)-2-ニトロフェニル)-4-ブロモ-2-(トリフルオロメトキシ)アニリン Process 2
N- (5- (1,3-Dioxane-2-yl) -2-nitrophenyl) -4-bromo-2- (trifluoromethoxy) aniline

Figure JPOXMLDOC01-appb-C000282
Figure JPOXMLDOC01-appb-C000282

N-(4-ブロモ-3-(トリフルオロメトキシ)フェニル)ベンズアミド (6.70 g, 19 mmol) を塩化チオニル (10 mL) に溶かし、80℃のオイルバス中で終夜撹拌した。反応混合物を減圧加熱条件で乾固した。次に別途、N,N-ジメチルホルムアミド (50 mL) に水素ナトリウム (880 mg, 22 mmol) を加え氷浴中で15分間撹拌した後、5-(1,3-ジオキサン-2-イル)-2-ニトロフェノール (4.05 g, 18 mmol) を加え、氷浴中で20分間撹拌した。この反応液に先の乾固物の N,N-ジメチルホルムアミド (10 mL) 溶液を加え、室温で20分間、80℃のオイルバス中で終夜撹拌した。反応混合物に酢酸エチルを加え、水で洗浄し、有機層を無水硫酸マグネシウムで乾燥させ、減圧下、溶媒を留去した。シリカゲルカラムクロマトグラフィー法で精製した後、180℃のオイルバス中で8時間撹拌した後、クロロホルムに溶かし、シリカゲルカラムクロマトグラフィー法で精製した。精製物を、メタノール (90 mL) に溶かし、水 (10 mL) および水酸化カリウム (3.50 g, 62 mmol) を加え、75℃のオイルバス中で終夜撹拌した。反応混合物中のメタノールを留去した後、水を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥させ、減圧下、溶媒を留去した後、シリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (2.65 g, 5.7 mmol , 31%) を得た。1H-NMR (CDCl3) δ: 9.40 (1H, s), 8.22 (1H, d, J = 8.8 Hz), 7.52 (1H, s), 7.47 (1H, dd, J = 8.8, 2.0 Hz), 7.41 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 1.5 Hz), 7.02 (1H, dd, J = 7.1, 1.7 Hz), 5.41 (1H, s), 4.28-4.20 (2H, m), 4.00-3.90 (2H, m), 2.19 (1H, m), 1.46 (1H, m). N- (4-Bromo-3- (trifluoromethoxy) phenyl) benzamide (6.70 g, 19 mmol) was dissolved in thionyl chloride (10 mL) and stirred in an oil bath at 80 ° C. overnight. The reaction mixture was dried under reduced pressure heating conditions. Next, separately, sodium hydride (880 mg, 22 mmol) was added to N, N-dimethylformamide (50 mL) and stirred in an ice bath for 15 minutes, and then 5- (1,3-dioxan-2-yl)- 2-Nitrophenol (4.05 g, 18 mmol) was added and stirred in an ice bath for 20 minutes. To this reaction solution was added a solution of the previously dried product in N, N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 20 minutes in an oil bath at 80 ° C. overnight. Ethyl acetate was added to the reaction mixture, washed with water, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. After purification by silica gel column chromatography, the mixture was stirred in an oil bath at 180 ° C. for 8 hours, dissolved in chloroform, and purified by silica gel column chromatography. The purified product was dissolved in methanol (90 mL), water (10 mL) and potassium hydroxide (3.50 g, 62 mmol) were added, and the mixture was stirred overnight in a 75 ° C. oil bath. Methanol in the reaction mixture was distilled off, water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (2.65 g, 5.7 mmol, 31%). . 1 H-NMR (CDCl 3 ) δ: 9.40 (1H, s), 8.22 (1H, d, J = 8.8 Hz), 7.52 (1H, s), 7.47 (1H, dd, J = 8.8, 2.0 Hz), 7.41 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 1.5 Hz), 7.02 (1H, dd, J = 7.1, 1.7 Hz), 5.41 (1H, s), 4.28-4.20 (2H , m), 4.00-3.90 (2H, m), 2.19 (1H, m), 1.46 (1H, m).

工程３
1-(4-ブロモ-2-(トリフルオロメトキシ)フェニル)-6-(1,3-ジオキサン-2-イル)-1H-ベンゾ[d]イミダゾール Process 3
1- (4-Bromo-2- (trifluoromethoxy) phenyl) -6- (1,3-dioxan-2-yl) -1H-benzo [d] imidazole

Figure JPOXMLDOC01-appb-C000283
Figure JPOXMLDOC01-appb-C000283

N-メトキシ-N-メチル-1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-カルボキシアミドの合成と同様の手法で、N-(5-(1,3-ジオキサン-2-イル)-2-ニトロフェニル)-4-ブロモ-2-(トリフルオロメトキシ)アニリン (2.65 g, 5.7 mmol) から標記化合物 (0.19 g , 0.43 mmol, 8 % 2 steps) を得た。1H-NMR (CDCl3) δ: 8.40 (1H, s), 7.87 (1H, d, J = 8.3 Hz), 7.70 (1H, m), 7.67 (1H, dd, J = 6.3, 2.1 Hz), 7.50-7.41 (3H, m), 5.62 (1H, s), 4.30-4.25 (2H, m), 4.08-3.96 (2H, m), 2.23 (1H, m), 1.48 (1H, m). In a similar manner to the synthesis of N-methoxy-N-methyl-1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazole-6-carboxamide, N- (5- ( 1,3-Dioxane-2-yl) -2-nitrophenyl) -4-bromo-2- (trifluoromethoxy) aniline (2.65 g, 5.7 mmol) to the title compound (0.19 g, 0.43 mmol, 8% 2 steps ) 1 H-NMR (CDCl 3 ) δ: 8.40 (1H, s), 7.87 (1H, d, J = 8.3 Hz), 7.70 (1H, m), 7.67 (1H, dd, J = 6.3, 2.1 Hz), 7.50-7.41 (3H, m), 5.62 (1H, s), 4.30-4.25 (2H, m), 4.08-3.96 (2H, m), 2.23 (1H, m), 1.48 (1H, m).

工程４
1-(4-(4-エチルピペラジン-1-イル)-2-(トリフルオロメトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド  Process 4
1- (4- (4-Ethylpiperazin-1-yl) -2- (trifluoromethoxy) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000284
Figure JPOXMLDOC01-appb-C000284

メチル 1-(3-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレートの合成と同様の手法で、化合物 1-(4-ブロモ-2-(トリフルオロメトキシ)フェニル)-6-(1,3-ジオキサン-2-イル)-1H-ベンゾ[d]イミダゾール (0.19 g, 0.43 mmol) をアミノ化した後、1規定塩酸で処理して、飽和重層水を加え、系を塩基性にした後、クロロホルムで 3 回抽出した。有機層を合わせ、無水硫酸マグネシウムで乾燥した後、溶媒を留去した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (0.09 g , 0.22 mmol, 50 % 2 steps) を得た。1H-NMR (CDCl3) δ: 10.06 (1H, s), 8.14 (1H, s), 7.99 (1H, d, J = 8.8 Hz), 7.88 (1H, dd, J = 8.3, 1.5 Hz), 7.81 (1H, S), 7.01-6.96 (2H, m), 3.70-3.39 (4H, br s), 3.03-2.48 (6H, br s), 1.25 (3H, br s). Methyl 1- (3- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carboxylate is prepared in a manner similar to the synthesis of compound 1- (4- Bromo-2- (trifluoromethoxy) phenyl) -6- (1,3-dioxan-2-yl) -1H-benzo [d] imidazole (0.19 g, 0.43 mmol) was aminated, then 1N hydrochloric acid was used. After treatment, saturated multistory water was added to make the system basic, and the mixture was extracted three times with chloroform. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.09 g, 0.22 mmol, 50% 2 steps). 1 H-NMR (CDCl 3 ) δ: 10.06 (1H, s), 8.14 (1H, s), 7.99 (1H, d, J = 8.8 Hz), 7.88 (1H, dd, J = 8.3, 1.5 Hz), 7.81 (1H, S), 7.01-6.96 (2H, m), 3.70-3.39 (4H, br s), 3.03-2.48 (6H, br s), 1.25 (3H, br s).

工程５
5-((1-(4-(4-エチルピペラジン-1-イル)-2-(トリフルオロメトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物７７) Process 5
5-((1- (4- (4-Ethylpiperazin-1-yl) -2- (trifluoromethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4- Dione (Compound 77)

Figure JPOXMLDOC01-appb-C000285
Figure JPOXMLDOC01-appb-C000285

5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオンと同様の方法で、1-(4-(4-エチルピペラジン-1-イル)-2-(トリフルオロメトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (0.05 g, 0.12 mmol) およびチアゾリジン-2,4-ジオン (14 mg, 0.12 mmol) とから標記化合物 (35 mg, 56 %) を得た。1H-NMR (DMSO-D6) δ: 13.25 (1H, br s), 8.09 (1H, s), 7.94 (1H, s), 7.94 (1H, d, J = 8.5 Hz), 7.48 (1H, dd, J = 8.5, 1.7 Hz), 7.45 (1H, d, J = 8.8 Hz), 7.38 (1H, d, J = 1.5 Hz), 7.05-6.98 (2H, m), 3.95-3.60 (4H, m), 3.21-2.88 (6H, m), 1.50 (3H, br s). 
ESI-MS(m/z): 518[M+H]+. In the same manner as 5-((1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione, 1- ( 4- (4-Ethylpiperazin-1-yl) -2- (trifluoromethoxy) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (0.05 g, 0.12 mmol) and thiazolidine-2,4-dione (14 mg, 0.12 mmol) gave the title compound (35 mg, 56%). 1 H-NMR (DMSO-D 6 ) δ: 13.25 (1H, br s), 8.09 (1H, s), 7.94 (1H, s), 7.94 (1H, d, J = 8.5 Hz), 7.48 (1H, dd, J = 8.5, 1.7 Hz), 7.45 (1H, d, J = 8.8 Hz), 7.38 (1H, d, J = 1.5 Hz), 7.05-6.98 (2H, m), 3.95-3.60 (4H, m ), 3.21-2.88 (6H, m), 1.50 (3H, br s).
ESI-MS (m / z): 518 [M + H] + .

実施例７８
5-((1-(4-(4-エチルピペラジン-1-イル)-2-(トリフルオロメトキシ)フェニル) -1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物７８)  Example 78
5-((1- (4- (4-Ethylpiperazin-1-yl) -2- (trifluoromethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine -4-one (Compound 78)

Figure JPOXMLDOC01-appb-C000286
Figure JPOXMLDOC01-appb-C000286

工程１
5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンと同様の方法で、1-(4-(4-エチルピペラジン-1-イル)-2-(トリフルオロメトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (0.05 g, 0.12 mmol) およびロダニン (16 mg, 0.12 mmol) とから標記化合物 (3 mg, 5 %) を得た。1H-NMR (DMSO-D6) δ: 8.39 (1H, s), 7.98-7.94 (2H, m), 7.50-7.40 (3H, m), 7.08-7.00 (2H, m), 4.00-3.65 (4H, m), 3.15-2.80 (6H, m), 1.50 (3H, br s). 
ESI-MS(m/z): 534[M+H]+. Process 1
In a manner similar to 5-((1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one, 1- (4- (4-Ethylpiperazin-1-yl) -2- (trifluoromethoxy) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (0.05 g, 0.12 mmol) and rhodanine (16 mg , 0.12 mmol) gave the title compound (3 mg, 5%). 1 H-NMR (DMSO-D 6 ) δ: 8.39 (1H, s), 7.98-7.94 (2H, m), 7.50-7.40 (3H, m), 7.08-7.00 (2H, m), 4.00-3.65 ( 4H, m), 3.15-2.80 (6H, m), 1.50 (3H, br s).
ESI-MS (m / z): 534 [M + H] + .

実施例７９
5-((1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-イミノチアゾリジン-4-オン (化合物７９) Example 79
5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-iminothiazolidin-4-one (Compound 79)

Figure JPOXMLDOC01-appb-C000287
Figure JPOXMLDOC01-appb-C000287

工程１
1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド (392 mg, 1.17 mmol)、2-イミノチアゾリジン-4-オン(143 mg, 1.23 mmol) のエタノール (5 mL) 懸濁液にピペリジン (25 mg, 0.29 mmol) を加え80 ℃で 20 時間撹拌した。反応溶液に酢酸エチルを加え、ろ過し、エタノールで洗浄した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (140 mg, 28 %) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 9.39 (1H, s), 9.10 (1H, s), 8.56 (1H, s), 7.87 (1H, d, J = 8.5 Hz), 7.76 (2H, s), 7.54-7.51 (3H, m), 7.17 (2H, d, J = 9.0 Hz), 3.26 (4H, t, J = 5.1 Hz), 2.54 (4H, t, J = 5.1 Hz), 2.40 (2H, q, J = 7.1 Hz), 1.06 (3H, t, J = 7.1 Hz). Process 1
1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (392 mg, 1.17 mmol), 2-iminothiazolidine-4-one (143 mg, Piperidine (25 mg, 0.29 mmol) was added to a suspension of 1.23 mmol) in ethanol (5 mL), and the mixture was stirred at 80 ° C. for 20 hours. Ethyl acetate was added to the reaction solution, filtered, and washed with ethanol. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (140 mg, 28%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 9.39 (1H, s), 9.10 (1H, s), 8.56 (1H, s), 7.87 (1H, d, J = 8.5 Hz), 7.76 ( 2H, s), 7.54-7.51 (3H, m), 7.17 (2H, d, J = 9.0 Hz), 3.26 (4H, t, J = 5.1 Hz), 2.54 (4H, t, J = 5.1 Hz), 2.40 (2H, q, J = 7.1 Hz), 1.06 (3H, t, J = 7.1 Hz).

実施例８０
5-((3-(3-((4-メチルピペリジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物８０)  Example 80
5-((3- (3-((4-methylpiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 80)

工程１
6-ブロモ-3-(3-((4-メチルピペリジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン  Process 1
6-Bromo-3- (3-((4-methylpiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine

Figure JPOXMLDOC01-appb-C000288
Figure JPOXMLDOC01-appb-C000288

6-ブロモ-3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジンの合成 (実施例57、工程1) と同様の手法で、3-(6-ブロモイミダゾ[1,2-a]ピリジン-3-イル)ベンズアルデヒド (143 mg, 0.475 mmol) および1-メチルピペリジン (112 μL, 0.950 mmol) から標記化合物 (175 mg, 96%)を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.61 (1H, s), 7.80 (1H, s), 7.66 (1H, dd, J = 9.5, 0.7 Hz), 7.57-7.49 (3H, m), 7.42 (1H, dd, J = 9.5, 1.7 Hz), 7.38 (1H, d, J = 7.6 Hz), 3.54 (2H, s), 2.84-2.80 (2H, m), 1.99-1.91 (2H, m), 1.58 (2H, d, J= 11.7 Hz), 1.37-1.30 (1H, m), 1.21-1.12 (2H, m), 0.89 (3H, d, J = 6.3 Hz). Synthesis of 6-bromo-3- (3-((4-ethylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine (Example 57, Step 1) The title compound (175 mg, 96%) was obtained from-(6-bromoimidazo [1,2-a] pyridin-3-yl) benzaldehyde (143 mg, 0.475 mmol) and 1-methylpiperidine (112 μL, 0.950 mmol). Obtained. Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.61 (1H, s), 7.80 (1H, s), 7.66 (1H, dd, J = 9.5, 0.7 Hz), 7.57-7.49 (3H, m ), 7.42 (1H, dd, J = 9.5, 1.7 Hz), 7.38 (1H, d, J = 7.6 Hz), 3.54 (2H, s), 2.84-2.80 (2H, m), 1.99-1.91 (2H, m), 1.58 (2H, d, J = 11.7 Hz), 1.37-1.30 (1H, m), 1.21-1.12 (2H, m), 0.89 (3H, d, J = 6.3 Hz).

工程２
3-(3-((4-メチルピペリジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド Process 2
3- (3-((4-Methylpiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000289
Figure JPOXMLDOC01-appb-C000289

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒドの合成 (実施例48、工程5) と同様の手法で、6-ブロモ-3-(3-((4-メチルピペリジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン (175 mg, 0.455 mmol) から標記化合物 (166 mg, 56%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 10.0 (1H, s), 9.26 (1H, s), 7.91 (1H, s), 7.77-7.74 (1H, m), 7.65-7.61 (3H, m), 7.57-7.54 (1H, m), 7.43 (1H, d, J = 7.6 Hz), 3.55 (2H, s), 2.82 (2H, d, J = 11.5 Hz), 1.99-1.92 (2H, m), 1.57 (2H, d, J= 12.4 Hz), 1.37-1.28 (1H, m), 1.19-1.09 (2H, m), 0.88 (3H, d, J = 6.6 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (Example 48, Step 5) The title compound (166 mg, 56%) was obtained from -3- (3-((4-methylpiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine (175 mg, 0.455 mmol) . Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, s), 9.26 (1H, s), 7.91 (1H, s), 7.77-7.74 (1H, m), 7.65-7.61 (3H , m), 7.57-7.54 (1H, m), 7.43 (1H, d, J = 7.6 Hz), 3.55 (2H, s), 2.82 (2H, d, J = 11.5 Hz), 1.99-1.92 (2H, m), 1.57 (2H, d, J = 12.4 Hz), 1.37-1.28 (1H, m), 1.19-1.09 (2H, m), 0.88 (3H, d, J = 6.6 Hz).

工程３
5-((3-(3-((4-メチルピペリジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物８０)  Process 3
5-((3- (3-((4-methylpiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 80)

Figure JPOXMLDOC01-appb-C000290
Figure JPOXMLDOC01-appb-C000290

5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-((4-メチルピペリジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド (17 mg, 0.0510 mmol) およびロダニン (7 mg, 0.0510 mmol) から標記化合物 (14 mg, 60％)を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.79 (1H, s), 7.87 (1H, s), 7.83-7.74 (3H, m), 7.66 (1H, t, J = 7.6 Hz), 7.56 (1H, d, J = 7.8 Hz), 7.47 (1H, d, J = 9.5 Hz), 7.34 (1H, s), 4.28 (2H, s), 3.40-3.27 (2H, m), 2.90-2.80 (2H, m), 1.78 (2H, d, J = 12.9 Hz), 1.64-1.54 (1H, m), 1.38-1.26 (2H, m), 0.91 (3H, d, J = 6.3 Hz). 
ESI-MS(m/z): 449[M+H]+. Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (3-((4-methylpiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (17 mg, 0.0510 mmol) and rhodanine (7 mg, The title compound (14 mg, 60%) was obtained from 0.0510 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.79 (1H, s), 7.87 (1H, s), 7.83-7.74 (3H, m), 7.66 (1H, t, J = 7.6 Hz), 7.56 (1H, d, J = 7.8 Hz), 7.47 (1H, d, J = 9.5 Hz), 7.34 (1H, s), 4.28 (2H, s), 3.40-3.27 (2H, m), 2.90-2.80 (2H, m), 1.78 (2H, d, J = 12.9 Hz), 1.64-1.54 (1H, m), 1.38-1.26 (2H, m), 0.91 (3H, d, J = 6.3 Hz).
ESI-MS (m / z): 449 [M + H] + .

実施例８１
5-((3-(3-((4-アセチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物８１)  Example 81
5-((3- (3-((4-acetylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 81)

工程１
1-(4-(3-(6-ブロモイミダゾ[1,2-a]ピリジン-3-イル)ベンジル)ピペラジン-1-イル)エタノン Process 1
1- (4- (3- (6-Bromoimidazo [1,2-a] pyridin-3-yl) benzyl) piperazin-1-yl) ethanone

Figure JPOXMLDOC01-appb-C000291
Figure JPOXMLDOC01-appb-C000291

6-ブロモ-3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジンの合成 (実施例57、工程1) と同様の手法で、3-(6-ブロモイミダゾ[1,2-a]ピリジン-3-イル)ベンズアルデヒド (131 mg, 0.435 mmol) および1-アセチルピペラジン(112 mg, 0.870 mmol) から標記化合物 (174 mg, 97%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.63-8.62 (1H, m), 7.81 (1H, s), 7.67 (1H, dd, J = 9.5, 0.7 Hz), 7.60-7.58 (2H, m), 7.53 (1H, t, J = 7.6 Hz), 7.43 (1H, dd, J = 9.6, 1.8 Hz), 7.42-7.39 (1H, m), 3.61 (2H, s), 3.46-3.43 (4H, m), 2.45-2.41 (2H, m), 2.37-2.34 (2H, m), 1.98 (3H, s). Synthesis of 6-bromo-3- (3-((4-ethylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine (Example 57, Step 1) The title compound (174 mg, 97%) was obtained from-(6-bromoimidazo [1,2-a] pyridin-3-yl) benzaldehyde (131 mg, 0.435 mmol) and 1-acetylpiperazine (112 mg, 0.870 mmol). Obtained. Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.63-8.62 (1H, m), 7.81 (1H, s), 7.67 (1H, dd, J = 9.5, 0.7 Hz), 7.60-7.58 (2H , m), 7.53 (1H, t, J = 7.6 Hz), 7.43 (1H, dd, J = 9.6, 1.8 Hz), 7.42-7.39 (1H, m), 3.61 (2H, s), 3.46-3.43 ( 4H, m), 2.45-2.41 (2H, m), 2.37-2.34 (2H, m), 1.98 (3H, s).

工程２
3-(3-((4-アセチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド Process 2
3- (3-((4-Acetylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000292
Figure JPOXMLDOC01-appb-C000292

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒドの合成 (実施例48、工程5 ) と同様の手法で、1-(4-(3-(6-ブロモイミダゾ[1,2-a]ピリジン-3-イル)ベンジル)ピペラジン-1-イル)エタノン (174 mg, 0.421 mmol) から標記化合物 (47 mg, 31%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.5 Hz), 9.27-9.26 (1H, m), 7.92 (1H, s), 7.76 (1H, d, J = 9.3 Hz), 7.67 (1H, dd, J = 7.7, 1.3 Hz), 7.65 (1H, s), 7.62 (1H, dd, J= 9.4, 1.6 Hz), 7.60-7.56 (1H, m), 7.47-7.45 (1H, m), 3.62 (2H, s), 3.46-3.42 (4H, m), 2.43 (2H, t, J = 4.8 Hz), 2.36 (2H, t, J = 4.9 Hz), 1.98 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (Example 48, Step 5) 4- (3- (6-Bromoimidazo [1,2-a] pyridin-3-yl) benzyl) piperazin-1-yl) ethanone (174 mg, 0.421 mmol) was transformed into the title compound (47 mg, 31%). Obtained. Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.5 Hz), 9.27-9.26 (1H, m), 7.92 (1H, s), 7.76 (1H, d, J = 9.3 Hz), 7.67 (1H, dd, J = 7.7, 1.3 Hz), 7.65 (1H, s), 7.62 (1H, dd, J = 9.4, 1.6 Hz), 7.60-7.56 (1H, m), 7.47 -7.45 (1H, m), 3.62 (2H, s), 3.46-3.42 (4H, m), 2.43 (2H, t, J = 4.8 Hz), 2.36 (2H, t, J = 4.9 Hz), 1.98 ( 3H, s).

工程３
5-((3-(3-((4-アセチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物８１) Process 3
5-((3- (3-((4-acetylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 81)

Figure JPOXMLDOC01-appb-C000293
 
Figure JPOXMLDOC01-appb-C000293
  

5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-((4-アセチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド (25 mg, 0.0778 mmol) およびロダニン (10 mg, 0.0778 mmol) から標記化合物 (5 mg, 13％) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.98 (1H, s), 7.89 (1H, s), 7.80 (1H, d, J = 9.3 Hz), 7.72-7.67 (3H, m), 7.59 (1H, t, J = 7.6 Hz), 7.49-7.46 (2H, m), 3.82 (2H, s), 3.49 (4H, s), 2.63 (2H, s), 2.56 (2H, s), 1.99 (3H, s).
ESI-MS(m/z): 478[M+H]+. Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (3-((4-acetylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (25 mg, 0.0778 mmol) and rhodanine (10 mg, The title compound (5 mg, 13%) was obtained from 0.0778 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.98 (1H, s), 7.89 (1H, s), 7.80 (1H, d, J = 9.3 Hz), 7.72-7.67 (3H, m), 7.59 (1H, t, J = 7.6 Hz), 7.49-7.46 (2H, m), 3.82 (2H, s), 3.49 (4H, s), 2.63 (2H, s), 2.56 (2H, s), 1.99 (3H, s).
ESI-MS (m / z): 478 [M + H] + .

実施例８２
5-((3-(3-((4-アセチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物８２)  Example 82
5-((3- (3-((4-acetylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione (Compound 82 )

Figure JPOXMLDOC01-appb-C000294
Figure JPOXMLDOC01-appb-C000294

工程１
5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-((4-アセチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒド (22 mg, 0.0685 mmol) およびチアゾリジン-2,4-ジオン (8 mg, 0.0685 mmol) から標記化合物 (8 mg, 25%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 8.53 (1H, s), 7.78 (1H, s), 7.67-7.52 (4H, m), 7.41-7.25 (2H, m), 6.50-6.40 (1H, m), 3.61 (2H, s), 3.47-3.42 (4H, m), 2.47-2.33 (4H, m), 1.96 (3H, s).
ESI-MS(m/z): 462[M+H]+. Process 1
Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (3-((4-acetylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (22 mg, 0.0685 mmol) and thiazolidine-2,4 The title compound (8 mg, 25%) was obtained from -dione (8 mg, 0.0685 mmol). White solid: 1 H-NMR (DMSO-D 6 ) δ: 8.53 (1H, s), 7.78 (1H, s), 7.67-7.52 (4H, m), 7.41-7.25 (2H, m), 6.50-6.40 (1H, m), 3.61 (2H, s), 3.47-3.42 (4H, m), 2.47-2.33 (4H, m), 1.96 (3H, s).
ESI-MS (m / z): 462 [M + H] + .

実施例８３
5-((3-(3-((4-ヒドロキシピペリジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物８３)  Example 83
5-((3- (3-((4-hydroxypiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 83)

工程１
メチル イミダゾ[1,2-a]ピリジン-6-カルボキシレート Process 1
Methyl imidazo [1,2-a] pyridine-6-carboxylate

Figure JPOXMLDOC01-appb-C000295
Figure JPOXMLDOC01-appb-C000295

アルゴン雰囲気下、クロロアセトアルデヒド 水溶液 (6.1 M, 1.78 mL, 10.8 mmol) をエタノール(40 mL) と混合した。そこへメチル 6-アミノニコチネート (1.50 g, 9.86 mmol) を加え、17時間加熱還流した。反応液を濃縮し、得られた残渣を水 (100 mL) に再溶解した。炭酸水素ナトリウムを用いてpHを8に調整し、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去、真空乾燥して標記化合物 (1.70 g, 98%) を得た。褐色固体: 1H-NMR (DMSO-D6) δ: 9.35 (1H, t, J = 1.3 Hz), 8.12 (1H, s), 7.69 (1H, d, J= 1.5 Hz), 7.63 (2H, d, J = 1.5 Hz), 3.89 (3H, s). Under an argon atmosphere, an aqueous chloroacetaldehyde solution (6.1 M, 1.78 mL, 10.8 mmol) was mixed with ethanol (40 mL). Methyl 6-aminonicotinate (1.50 g, 9.86 mmol) was added there, and it heated and refluxed for 17 hours. The reaction mixture was concentrated, and the resulting residue was redissolved in water (100 mL). The pH was adjusted to 8 with sodium hydrogen carbonate and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was dried under vacuum to obtain the title compound (1.70 g, 98%). Brown solid: 1 H-NMR (DMSO-D 6 ) δ: 9.35 (1H, t, J = 1.3 Hz), 8.12 (1H, s), 7.69 (1H, d, J = 1.5 Hz), 7.63 (2H, d, J = 1.5 Hz), 3.89 (3H, s).

工程２
メチル 3-ヨードイミダゾ[1,2-a]ピリジン-6-カルボキシレート  Process 2
Methyl 3-iodoimidazo [1,2-a] pyridine-6-carboxylate

Figure JPOXMLDOC01-appb-C000296
Figure JPOXMLDOC01-appb-C000296

アルゴン雰囲気下、メチル イミダゾ[1,2-a]ピリジン-6-カルボキシレート (1.70 g, 9.65 mmol) をアセトニトリル (100 mL) に溶解し、0℃に冷却した。そこへN-ヨードコハク酸イミド (2.39 g, 10.6 mmol) を加え、80℃で4時間撹拌した。反応液を0℃に冷却し、生じた析出物をろ取、真空乾燥して標記化合物 (2.74 g, 94%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 8.80-8.79 (1H, m), 7.87 (1H, s), 7.71-7.70 (2H, m), 3.93 (3H, s). Under an argon atmosphere, methylimidazo [1,2-a] pyridine-6-carboxylate (1.70 g, 9.65 mmol) was dissolved in acetonitrile (100 mL) and cooled to 0 ° C. N-iodosuccinimide (2.39 g, 10.6 mmol) was added there, and it stirred at 80 degreeC for 4 hours. The reaction mixture was cooled to 0 ° C., and the resulting precipitate was collected by filtration and dried in vacuo to obtain the title compound (2.74 g, 94%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 8.80-8.79 (1H, m), 7.87 (1H, s), 7.71-7.70 (2H, m), 3.93 (3H, s).

工程３
メチル 3-(3-ホルミルフェニル)イミダゾ[1,2-a]ピリジン-6-カルボキシレート  Process 3
Methyl 3- (3-formylphenyl) imidazo [1,2-a] pyridine-6-carboxylate

Figure JPOXMLDOC01-appb-C000297
Figure JPOXMLDOC01-appb-C000297

6-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジンの合成 (実施例48、工程4) と同様の手法で、メチル 3-ヨードイミダゾ[1,2-a]ピリジン-6-カルボキシレート (350 mg, 1.16 mmol) および3-ホルミルボロン酸 (208 mg, 1.39 mmol) から標記化合物 (289 mg, 89%) を得た。薄橙色固体: 1H-NMR (DMSO-D6) δ: 10.1 (1H, s), 9.00 (1H, d, J= 0.7 Hz), 8.22 (1H, t, J = 1.7 Hz), 8.09-8.01 (2H, m), 8.00 (1H, s), 7.85 (1H, t, J = 7.7 Hz), 7.79 (1H, d, J= 9.5 Hz), 7.73 (1H, dd, J = 9.5, 1.7 Hz), 3.88 (3H, s). Synthesis of 6-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine (Example 48, Step 4) The title compound (289 mg, 89%) was obtained from imidazo [1,2-a] pyridine-6-carboxylate (350 mg, 1.16 mmol) and 3-formylboronic acid (208 mg, 1.39 mmol). Pale orange solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, s), 9.00 (1H, d, J = 0.7 Hz), 8.22 (1H, t, J = 1.7 Hz), 8.09-8.01 (2H, m), 8.00 (1H, s), 7.85 (1H, t, J = 7.7 Hz), 7.79 (1H, d, J = 9.5 Hz), 7.73 (1H, dd, J = 9.5, 1.7 Hz) , 3.88 (3H, s).

工程４
メチル 3-(3-(4-ヒドロキシピペリジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボキシレート Process 4
Methyl 3- (3- (4-hydroxypiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carboxylate

Figure JPOXMLDOC01-appb-C000298
Figure JPOXMLDOC01-appb-C000298

6-ブロモ-3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジンの合成 (実施例57、工程1) と同様の手法で、メチル 3-(3-ホルミルフェニル)イミダゾ[1,2-a]ピリジン-6-カルボキシレート (210 mg, 0.749 mmol) および4-ヒドロキシピペリジン (152 mg, 1.50 mmol) から標記化合物 (227 mg, 53%) を得た。白色アモルファス状物: 1H-NMR (DMSO-D6) δ: 8.99 (1H, d, J = 1.0 Hz), 7.89 (1H, s), 7.75 (1H, dd, J = 9.5, 0.7 Hz), 7.70 (1H, dd, J = 9.4, 1.6 Hz), 7.59-7.53 (3H, m), 7.42-7.40 (1H, m), 4.56 (1H, d, J = 4.1 Hz), 3.87 (3H, s), 3.54 (2H, s), 3.50-3.43 (1H, m), 2.75-2.69 (2H, m), 2.09 (2H, t, J= 10.0 Hz), 1.76-1.69 (2H, m), 1.46-1.37 (2H, m). Synthesis of 6-bromo-3- (3-(((4-ethylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine (Example 57, Step 1) The title compound (227 mg, 53%) from 3- (3-formylphenyl) imidazo [1,2-a] pyridine-6-carboxylate (210 mg, 0.749 mmol) and 4-hydroxypiperidine (152 mg, 1.50 mmol) ) White amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.99 (1H, d, J = 1.0 Hz), 7.89 (1H, s), 7.75 (1H, dd, J = 9.5, 0.7 Hz), 7.70 (1H, dd, J = 9.4, 1.6 Hz), 7.59-7.53 (3H, m), 7.42-7.40 (1H, m), 4.56 (1H, d, J = 4.1 Hz), 3.87 (3H, s) , 3.54 (2H, s), 3.50-3.43 (1H, m), 2.75-2.69 (2H, m), 2.09 (2H, t, J = 10.0 Hz), 1.76-1.69 (2H, m), 1.46-1.37 (2H, m).

工程５
1-(3-(6-(ヒドロキシメチル)イミダゾ[1,2-a]ピリジン-3-イル)ベンジル)ピペリジン-4-オール  Process 5
1- (3- (6- (hydroxymethyl) imidazo [1,2-a] pyridin-3-yl) benzyl) piperidin-4-ol

Figure JPOXMLDOC01-appb-C000299
Figure JPOXMLDOC01-appb-C000299

(1-(3-(2-モルホリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノールの合成(実施例23、工程4) と同様の手法で、メチル 3-(3-(4-ヒドロキシピペリジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボキシレート (259 mg, 0.709 mmol) およびリチウムアルミニウムヒドリド テトラヒドロフラン溶液 (1M、2.13 mL, 2.13 mmol) から標記化合物 (134 mg, 56%) を得た。白色アモルファス状固体: 1H-NMR (DMSO-D6) δ: 8.41 (1H, s), 7.72 (1H, s), 7.62 (1H, d, J = 9.3 Hz), 7.54-7.51 (3H, m), 7.39-7.35 (1H, m), 7.26 (1H, dd, J = 9.3, 1.5 Hz), 5.31 (1H, t, J = 5.6 Hz), 4.53 (3H, d, J= 5.4 Hz), 3.54 (2H, s), 3.49-3.41 (1H, m), 2.75-2.67 (2H, m), 2.12-2.04 (2H, m), 1.75-1.68 (2H, m), 1.45-1.35 (2H, m). Synthesis of (1- (3- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methanol (Example 23, Step 4) (4-Hydroxypiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carboxylate (259 mg, 0.709 mmol) and lithium aluminum hydride in tetrahydrofuran (1M, 2.13 mL, 2.13 mmol) Gave the title compound (134 mg, 56%). White amorphous solid: 1 H-NMR (DMSO-D 6 ) δ: 8.41 (1H, s), 7.72 (1H, s), 7.62 (1H, d, J = 9.3 Hz), 7.54-7.51 (3H, m ), 7.39-7.35 (1H, m), 7.26 (1H, dd, J = 9.3, 1.5 Hz), 5.31 (1H, t, J = 5.6 Hz), 4.53 (3H, d, J = 5.4 Hz), 3.54 (2H, s), 3.49-3.41 (1H, m), 2.75-2.67 (2H, m), 2.12-2.04 (2H, m), 1.75-1.68 (2H, m), 1.45-1.35 (2H, m) .

工程６
3-(3-((4-ヒドロキシピペリジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボキシカルボアルデヒド  Step 6
3- (3-((4-Hydroxypiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carboxycarbaldehyde

Figure JPOXMLDOC01-appb-C000300
Figure JPOXMLDOC01-appb-C000300

アルゴン雰囲気下、1-(3-(6-(ヒドロキシメチル)イミダゾ[1,2-a]ピリジン-3-イル)ベンジル)ピペリジン-4-オール (134 mg, 0.397 mmol) を塩化メチレン (4 mL) に溶解した。そこへ二酸化マンガン (500 mg) を加え、室温で16時間撹拌した。反応液をセライトでろ過し、濃縮、真空乾燥して標記化合物 (103 mg, 77%) を得た。薄黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 10.0 (1H, s), 9.27 (1H, s), 7.92 (1H, s), 7.76 (1H, d, J = 9.3 Hz), 7.66-7.61 (3H, m), 7.56 (1H, t, J = 7.6 Hz), 7.43 (1H, d, J = 7.8 Hz), 4.58 (1H, d, J = 4.1 Hz), 3.55 (2H, s), 3.49-3.42 (1H, m), 2.75-2.69 (2H, m), 2.08 (2H, t, J= 9.8 Hz), 1.71 (2H, d, J = 9.8 Hz), 1.43-1.36 (2H, m). 1- (3- (6- (hydroxymethyl) imidazo [1,2-a] pyridin-3-yl) benzyl) piperidin-4-ol (134 mg, 0.397 mmol) in methylene chloride (4 mL) ). Manganese dioxide (500 mg) was added thereto, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through celite, concentrated and dried under vacuum to obtain the title compound (103 mg, 77%). Pale yellow amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, s), 9.27 (1H, s), 7.92 (1H, s), 7.76 (1H, d, J = 9.3 Hz) , 7.66-7.61 (3H, m), 7.56 (1H, t, J = 7.6 Hz), 7.43 (1H, d, J = 7.8 Hz), 4.58 (1H, d, J = 4.1 Hz), 3.55 (2H, s), 3.49-3.42 (1H, m), 2.75-2.69 (2H, m), 2.08 (2H, t, J = 9.8 Hz), 1.71 (2H, d, J = 9.8 Hz), 1.43-1.36 (2H , m).

工程７
5-((3-(3-((4-ヒドロキシピペリジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物８３)  Step 7
5-((3- (3-((4-hydroxypiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 83)

Figure JPOXMLDOC01-appb-C000301
Figure JPOXMLDOC01-appb-C000301

5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-((4-ヒドロキシピペリジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボキシカルボアルデヒド (47 mg, 0.140 mmol) およびロダニン (19 mg, 0.140 mmol) から標記化合物 (40 mg, 63％) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.82 (1H, s), 7.88 (1H, s), 7.84-7.76 (3H, m), 7.66 (1H, t, J= 7.7 Hz), 7.58-7.55 (1H, m), 7.49 (1H, d, J = 10.2 Hz), 7.38 (1H, s), 4.36 (1H, t, J = 5.0 Hz), 3.47-3.40 (2H, m), 3.37-3.30 (1H, m), 3.26-3.15 (2H, m), 2.53-2.46 (2H, m), 1.91-1.82 (2H, m), 1.68-1.55 (2H, m).
ESI-MS(m/z): 451[M+H]+. Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (3-((4-hydroxypiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carboxycarbaldehyde (47 mg, 0.140 mmol) and rhodanine (19 mg , 0.140 mmol) gave the title compound (40 mg, 63%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.82 (1H, s), 7.88 (1H, s), 7.84-7.76 (3H, m), 7.66 (1H, t, J = 7.7 Hz), 7.58-7.55 (1H, m), 7.49 (1H, d, J = 10.2 Hz), 7.38 (1H, s), 4.36 (1H, t, J = 5.0 Hz), 3.47-3.40 (2H, m), 3.37 -3.30 (1H, m), 3.26-3.15 (2H, m), 2.53-2.46 (2H, m), 1.91-1.82 (2H, m), 1.68-1.55 (2H, m).
ESI-MS (m / z): 451 [M + H] + .

実施例８４
5-((3-(3-((4-ヒドロキシピペリジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物８４)  Example 84
5-((3- (3-((4-hydroxypiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione (compound 84 )

Figure JPOXMLDOC01-appb-C000302
Figure JPOXMLDOC01-appb-C000302

工程１
5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-((4-ヒドロキシピペリジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボキシカルボアルデヒド (53 mg, 0.158 mmol) およびチアゾリジン-2,4-ジオン (19 mg, 0.158mmol) から標記化合物 (13 mg, 20%) を得た。薄黄色固体: ESI-MS(m/z): 435 [M+H]+. Process 1
Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (3-((4-hydroxypiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carboxycarbaldehyde (53 mg, 0.158 mmol) and thiazolidine-2, The title compound (13 mg, 20%) was obtained from 4-dione (19 mg, 0.158 mmol). Pale yellow solid: ESI-MS (m / z): 435 [M + H] + .

実施例８５
5-((3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物８５)  Example 85
5-((3- (2-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 85)

工程１
1-(3-フルオロフェニル)ピペラジン Process 1
1- (3-Fluorophenyl) piperazine

Figure JPOXMLDOC01-appb-C000303
Figure JPOXMLDOC01-appb-C000303

アルゴン雰囲気下、 3-ブロモフルオロベンゼン (1.50 g, 8.57 mmol) をトルエン (40 mL) に溶解した。そこへピペラジン (4.43 g, 51.4 mmol)、tert-ブトキシナトリウム (1.15 g, 12.0 mmol) を加えた。さらにrac-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル (160 mg, 0.257 mmol)、トリス(ジベンジリデンアセトン)ジパラジウム(0) (78 mg, 0.0857 mmol) を加え、反応容器内を脱気、アルゴン置換した後、16時間加熱還流した。反応液を酢酸エチルで希釈し、水で洗浄した。ついで酢酸エチル層を1規定塩酸で抽出し、酢酸エチルで洗浄した。水層のpHを8に調整した後、クロロホルムで抽出した。クロロホルム層を無水硫酸マグネシウムで乾燥させ、溶媒を留去、真空乾燥して標記化合物 (776 mg, 50%) を得た。薄黄色オイル: 1H-NMR (DMSO-D6) δ: 7.22-7.16 (1H, m), 6.75-6.67 (2H, m), 6.54-6.49 (1H, m), 3.08-3.04 (4H, m), 2.82-2.79 (4H, m). Under an argon atmosphere, 3-bromofluorobenzene (1.50 g, 8.57 mmol) was dissolved in toluene (40 mL). Piperazine (4.43 g, 51.4 mmol) and tert-butoxy sodium (1.15 g, 12.0 mmol) were added thereto. Add rac-2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (160 mg, 0.257 mmol), tris (dibenzylideneacetone) dipalladium (0) (78 mg, 0.0857 mmol), The reaction vessel was deaerated and purged with argon, and then heated to reflux for 16 hours. The reaction solution was diluted with ethyl acetate and washed with water. Then, the ethyl acetate layer was extracted with 1N hydrochloric acid and washed with ethyl acetate. The pH of the aqueous layer was adjusted to 8, and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was dried under vacuum to obtain the title compound (776 mg, 50%). Pale yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 7.22-7.16 (1H, m), 6.75-6.67 (2H, m), 6.54-6.49 (1H, m), 3.08-3.04 (4H, m ), 2.82-2.79 (4H, m).

工程２
tert-ブチル 4-(3-フルオロフェニル)ピペラジン-1-カルボキシレート Process 2
tert-butyl 4- (3-fluorophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000304
Figure JPOXMLDOC01-appb-C000304

アルゴン雰囲気下、1-(3-フルオロフェニル)ピペラジン(776 mg, 4.31 mmol) を塩化メチレン (40 mL) に溶解した。そこへトリエチルアミン (1.17 mL, 8.62 mmol) を加えた。さらに二炭酸ジ-tert-ブチル (1.03 g, 4.74 mmol) の塩化メチレン溶液 (5 mL) を滴下し、室温で1時間撹拌した。反応液を酢酸エチルで希釈し、水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (992 mg, 82%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 7.25-7.19 (1H, m), 6.78-6.73 (2H, m), 6.59-6.54 (1H, m), 3.44 (4H, t, J = 5.1 Hz), 3.14 (4H, t, J = 5.2 Hz), 1.42 (9H, s). 1- (3-Fluorophenyl) piperazine (776 mg, 4.31 mmol) was dissolved in methylene chloride (40 mL) under an argon atmosphere. Triethylamine (1.17 mL, 8.62 mmol) was added there. Further, a methylene chloride solution (5 mL) of di-tert-butyl dicarbonate (1.03 g, 4.74 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (992 mg, 82%). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 7.25-7.19 (1H, m), 6.78-6.73 (2H, m), 6.59-6.54 (1H, m), 3.44 (4H, t, J = 5.1 Hz), 3.14 (4H, t, J = 5.2 Hz), 1.42 (9H, s).

工程３
tert-ブチル 4-(4-ブロモ-3-フルオロフェニル)ピペラジン-1-カルボキシレート Process 3
tert-butyl 4- (4-bromo-3-fluorophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000305
Figure JPOXMLDOC01-appb-C000305

アルゴン雰囲気下、tert-ブチル 4-(3-フルオロフェニル)ピペラジン-1-カルボキシレート(1.75 g, 6.25 mmol) を酢酸 (13 mL) に溶解した。そこへ臭素 (354 μL, 6.88 mmol) を滴下し、室温で1時間撹拌した。反応液を濃縮し、酢酸エチルに再溶解して飽和重層水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.74 g, 78%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 7.45 (1H, t, J = 8.8 Hz), 6.95 (1H, dd, J = 12.7, 2.7 Hz), 6.74 (1H, dd, J = 8.9, 2.8 Hz), 3.43 (4H, t, J = 5.2 Hz), 3.16 (4H, t, J = 5.2 Hz), 1.42 (9H, s). Under an argon atmosphere, tert-butyl 4- (3-fluorophenyl) piperazine-1-carboxylate (1.75 g, 6.25 mmol) was dissolved in acetic acid (13 mL). Bromine (354 μL, 6.88 mmol) was added dropwise thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, redissolved in ethyl acetate, and washed with saturated multistory water. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.74 g, 78%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 7.45 (1H, t, J = 8.8 Hz), 6.95 (1H, dd, J = 12.7, 2.7 Hz), 6.74 (1H, dd, J = 8.9 , 2.8 Hz), 3.43 (4H, t, J = 5.2 Hz), 3.16 (4H, t, J = 5.2 Hz), 1.42 (9H, s).

工程４
tert-ブチル 4-(3-フルオロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレート Process 4
tert-butyl 4- (3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000306
Figure JPOXMLDOC01-appb-C000306

アルゴン雰囲気下、tert-ブチル 4-(4-ブロモ-3-フルオロフェニル)ピペラジン-1-カルボキシレート(700 mg, 1.95 mmol) をジメチルスルホキシド (10 mL) に溶解した。そこへビス(ピナコラ-ト)ジボロン (590 mg, 2.34 mmol)、酢酸カリウム (670 mg, 6.83 mmol) を加えた。さらに1,1’-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド-ジクロロメタン錯体 (140 mg, 0.176 mmol)、を加え、反応容器内を脱気、アルゴン置換した後、120℃で3時間撹拌した。反応液を酢酸エチルで希釈し、水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (752 mg, 67%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 7.44 (1H, t, J = 7.9 Hz), 6.73 (1H, dd, J = 8.5, 2.2 Hz), 6.64 (1H, dd, J = 13.3, 2.1 Hz), 3.42 (4H, t, J = 5.0 Hz), 3.25 (4H, t, J = 5.2 Hz), 1.42 (9H, s), 1.26 (12H, s). Under an argon atmosphere, tert-butyl 4- (4-bromo-3-fluorophenyl) piperazine-1-carboxylate (700 mg, 1.95 mmol) was dissolved in dimethyl sulfoxide (10 mL). Bis (pinacolato) diboron (590 mg, 2.34 mmol) and potassium acetate (670 mg, 6.83 mmol) were added thereto. Further, 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (140 mg, 0.176 mmol) was added, and the reaction vessel was degassed and purged with argon, then at 120 ° C. for 3 hours. Stir. The reaction solution was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (752 mg, 67%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 7.44 (1H, t, J = 7.9 Hz), 6.73 (1H, dd, J = 8.5, 2.2 Hz), 6.64 (1H, dd, J = 13.3 , 2.1 Hz), 3.42 (4H, t, J = 5.0 Hz), 3.25 (4H, t, J = 5.2 Hz), 1.42 (9H, s), 1.26 (12H, s).

工程５
tert-ブチル 4-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-3-フルオロフェニル)ピペラジン-1-カルボキシレート  Process 5
tert-butyl 4- (4- (6-chloroimidazo [1,2-b] pyridazin-3-yl) -3-fluorophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000307
Figure JPOXMLDOC01-appb-C000307

6-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジンの合成 (実施例48、工程4) と同様の手法で、3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (359 mg, 1.54 mmol) およびtert-ブチル 4-(3-フルオロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレート (752 mg, 1.85 mmol) から標記化合物 (452 mg, 68%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.28 (1H, d, J = 9.5 Hz), 8.01 (1H, d, J = 2.2 Hz), 7.86-7.82 (1H, m), 7.40 (1H, d, J = 9.5 Hz), 6.99-6.91 (2H, m), 3.47 (4H, t, J = 4.9 Hz), 3.29 (4H, t, J = 5.1 Hz), 1.43 (9H, s). Synthesis of 6-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine (Example 48, Step 4) 6-Chloroimidazo [1,2-b] pyridazine (359 mg, 1.54 mmol) and tert-butyl 4- (3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2- The title compound (452 mg, 68%) was obtained from dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (752 mg, 1.85 mmol). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.28 (1H, d, J = 9.5 Hz), 8.01 (1H, d, J = 2.2 Hz), 7.86-7.82 (1H, m), 7.40 (1H, d, J = 9.5 Hz), 6.99-6.91 (2H, m), 3.47 (4H, t, J = 4.9 Hz), 3.29 (4H, t, J = 5.1 Hz), 1.43 (9H, s) .

工程６
6-クロロ-3-(2-フルオロ-4-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Step 6
6-Chloro-3- (2-fluoro-4- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000308
Figure JPOXMLDOC01-appb-C000308

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程6) と同様の手法で、tert-ブチル 4-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-3-フルオロフェニル)ピペラジン-1-カルボキシレート (452 mg, 1.05 mmol) およびトリフルオロ酢酸 (2 mL) から標記化合物 (180 mg, 52%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.28 (1H, d, J = 9.5 Hz), 8.00 (1H, d, J = 2.4 Hz), 7.82 (1H, t, J = 8.8 Hz), 7.39 (1H, d, J = 9.5 Hz), 6.94 (1H, s), 6.92-6.90 (1H, m), 3.20 (4H, t, J= 5.1 Hz), 2.85 (4H, t, J = 5.0 Hz). Synthesis of 5-bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 6) From-(4- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) -3-fluorophenyl) piperazine-1-carboxylate (452 mg, 1.05 mmol) and trifluoroacetic acid (2 mL) The title compound (180 mg, 52%) was obtained. Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.28 (1H, d, J = 9.5 Hz), 8.00 (1H, d, J = 2.4 Hz), 7.82 (1H, t, J = 8.8 Hz ), 7.39 (1H, d, J = 9.5 Hz), 6.94 (1H, s), 6.92-6.90 (1H, m), 3.20 (4H, t, J = 5.1 Hz), 2.85 (4H, t, J = 5.0 Hz).

工程７
6-クロロ-3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Step 7
6-Chloro-3- (2-fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000309
Figure JPOXMLDOC01-appb-C000309

5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程7) と同様の手法で、6-クロロ-3-(2-フルオロ-4-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (180 mg, 0.543 mmol) および37% ホルムアルデヒド水溶液 (243 μL、3.26 mmol) から標記化合物 (148 mg, 79%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.28 (1H, d, J = 9.3 Hz), 8.00 (1H, d, J = 2.4 Hz), 7.82 (1H, t, J = 8.7 Hz), 7.39 (1H, d, J = 9.5 Hz), 6.97-6.95 (1H, m), 6.93 (1H, s), 3.29 (4H, t, J = 5.0 Hz), 2.45 (4H, t, J = 5.0 Hz), 2.23 (3H, s). Synthesis of 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 7) From -chloro-3- (2-fluoro-4- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (180 mg, 0.543 mmol) and 37% aqueous formaldehyde (243 μL, 3.26 mmol) The title compound (148 mg, 79%) was obtained. Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.28 (1H, d, J = 9.3 Hz), 8.00 (1H, d, J = 2.4 Hz), 7.82 (1H, t, J = 8.7 Hz) ), 7.39 (1H, d, J = 9.5 Hz), 6.97-6.95 (1H, m), 6.93 (1H, s), 3.29 (4H, t, J = 5.0 Hz), 2.45 (4H, t, J = 5.0 Hz), 2.23 (3H, s).

工程８
3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン  Process 8
3- (2-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000310
Figure JPOXMLDOC01-appb-C000310

3-(4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例63、工程2) と同様の手法で、6-クロロ-3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (180 mg, 0.543 mmol) およびトリブチリビニルスズ (174 μL, 0.597 mmol) から標記化合物 (78 mg, 43%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.17 (1H, d, J = 9.5 Hz), 7.95 (2H, t, J = 8.9 Hz), 7.91 (2H, d, J = 2.4 Hz), 7.64 (1H, d, J = 9.5 Hz), 6.96-6.91 (2H, m), 6.83 (1H, dd, J = 17.7, 11.1 Hz), 6.33 (1H, d, J = 17.8 Hz), 5.74 (1H, d, J = 11.2 Hz), 3.28 (4H, t, J = 5.0 Hz), 2.45 (4H, t, J = 5.0 Hz), 2.23 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 63, Step 2) From 3- (2-fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (180 mg, 0.543 mmol) and tributyvinyltin (174 μL, 0.597 mmol) The title compound (78 mg, 43%) was obtained. Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.17 (1H, d, J = 9.5 Hz), 7.95 (2H, t, J = 8.9 Hz), 7.91 (2H, d, J = 2.4 Hz) , 7.64 (1H, d, J = 9.5 Hz), 6.96-6.91 (2H, m), 6.83 (1H, dd, J = 17.7, 11.1 Hz), 6.33 (1H, d, J = 17.8 Hz), 5.74 ( 1H, d, J = 11.2 Hz), 3.28 (4H, t, J = 5.0 Hz), 2.45 (4H, t, J = 5.0 Hz), 2.23 (3H, s).

工程９
3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド  Step 9
3- (2-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000311
Figure JPOXMLDOC01-appb-C000311

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (78 mg, 0.231 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (58 μL、4.62 μmol) から標記化合物 (29 mg, 37%) を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 9.96 (1H, s), 8.36 (1H, d, J = 9.5 Hz), 8.16 (1H, d, J = 2.4 Hz), 7.98 (1H, t, J = 9.0 Hz), 7.65 (1H, d, J = 9.5 Hz), 7.00-6.94 (2H, m), 3.30 (4H, t, J = 5.1 Hz), 2.46 (4H, t, J = 5.0 Hz), 2.24 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 2-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (78 mg, 0.231 mmol) and 2.5 wt% osmium tetroxide tert-butanol solution ( The title compound (29 mg, 37%) was obtained from 58 μL, 4.62 μmol). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 9.96 (1H, s), 8.36 (1H, d, J = 9.5 Hz), 8.16 (1H, d, J = 2.4 Hz), 7.98 (1H, t, J = 9.0 Hz), 7.65 (1H, d, J = 9.5 Hz), 7.00-6.94 (2H, m), 3.30 (4H, t, J = 5.1 Hz), 2.46 (4H, t, J = 5.0 Hz), 2.24 (3H, s).

工程１０
5-((3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物８５) Step 10
5-((3- (2-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 85)

Figure JPOXMLDOC01-appb-C000312
Figure JPOXMLDOC01-appb-C000312

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (29 mg, 0.086 mmol) およびチアゾリジン-2,4-ジオン (10 mg, 0.086 mmol) から標記化合物 (18 mg, 49%) を得た。赤色固体: 1H-NMR (DMSO-D6) δ: 8.25 (1H, d, J = 9.3 Hz), 8.00 (1H, d, J = 2.0 Hz), 7.89 (1H, t, J = 8.8 Hz), 7.73 (1H, s), 7.64 (1H, d, J = 9.3 Hz), 7.02-6.93 (2H, m), 3.38 (4H, t, J = 4.9 Hz), 2.74 (4H, t, J = 4.9 Hz), 2.43 (3H, s). 
ESI-MS(m/z): 439[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (2-fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (29 mg, 0.086 mmol) and thiazolidine-2,4-dione (10 mg, 0.086 mmol) gave the title compound (18 mg, 49%). Red solid: 1 H-NMR (DMSO-D 6 ) δ: 8.25 (1H, d, J = 9.3 Hz), 8.00 (1H, d, J = 2.0 Hz), 7.89 (1H, t, J = 8.8 Hz) , 7.73 (1H, s), 7.64 (1H, d, J = 9.3 Hz), 7.02-6.93 (2H, m), 3.38 (4H, t, J = 4.9 Hz), 2.74 (4H, t, J = 4.9 Hz), 2.43 (3H, s).
ESI-MS (m / z): 439 [M + H] + .

実施例８６
5-((3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物８６) Example 86
5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidine-4- ON (compound 86)

工程１
1-(4-(4-ブロモ-2-フルオロフェニル)ピペラジン-1-イル)-2,2,2-トリフルオロエタノン Process 1
1- (4- (4-Bromo-2-fluorophenyl) piperazin-1-yl) -2,2,2-trifluoroethanone

Figure JPOXMLDOC01-appb-C000313
Figure JPOXMLDOC01-appb-C000313

アルゴン雰囲気下、1-(2-フルオロフェニル)ピペラジン(800 mg, 4.44 mmol) を塩化メチレン (10 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (968 μL, 7.10 mmol) を加えた。さらに無水トリフルオロ酢酸 (668 μL, 4.88 mmol) を滴下し、0℃で4時間撹拌した。反応液に水を加え、1規定塩酸を用いて酸性にした。反応混合物をクロロホルムで抽出し、クロロホルム層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣 (1.37 g) を酢酸 (15 mL) に溶解し、0℃に冷却した。そこへ臭素 (240 μL, 4.66 mL) を滴下し、0℃で10分撹拌後、室温で1時間撹拌した。反応液に水を加え、さらに1Mメタ重亜硫酸ナトリウム水溶液を加え、クロロホルムで抽出した。クロロホルム層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.50 g, 95%) を得た。透明オイル: 1H-NMR (DMSO-D6) δ: 7.49 (1H, dd, J = 12.2, 2.2 Hz), 7.34-7.32 (1H, m), 7.03 (1H, t, J = 9.0 Hz), 3.73 (4H, t, J= 8.9 Hz), 3.11-3.07 (4H, m). Under an argon atmosphere, 1- (2-fluorophenyl) piperazine (800 mg, 4.44 mmol) was dissolved in methylene chloride (10 mL) and cooled to 0 ° C. Triethylamine (968 μL, 7.10 mmol) was added thereto. Further, trifluoroacetic anhydride (668 μL, 4.88 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was acidified with 1N hydrochloric acid. The reaction mixture was extracted with chloroform, the chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue (1.37 g) was dissolved in acetic acid (15 mL) and cooled to 0 ° C. Bromine (240 μL, 4.66 mL) was added dropwise thereto, followed by stirring at 0 ° C. for 10 minutes and then at room temperature for 1 hour. Water was added to the reaction solution, and a 1M sodium metabisulfite aqueous solution was further added, followed by extraction with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.50 g, 95%). Clear oil: 1 H-NMR (DMSO-D 6 ) δ: 7.49 (1H, dd, J = 12.2, 2.2 Hz), 7.34-7.32 (1H, m), 7.03 (1H, t, J = 9.0 Hz), 3.73 (4H, t, J = 8.9 Hz), 3.11-3.07 (4H, m).

工程２
2,2,2-トリフルオロ-1-(4-(2-フルオロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-イル)エタノン Process 2
2,2,2-trifluoro-1- (4- (2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1 -Ill) Ethanon

Figure JPOXMLDOC01-appb-C000314
Figure JPOXMLDOC01-appb-C000314

tert-ブチル 4-(3-フルオロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレート(実施例85、工程4) と同様の手法で、1-(4-(4-ブロモ-2-フルオロフェニル)ピペラジン-1-イル)-2,2,2-トリフルオロエタノン (1.50 g, 4.22 mmol) およびビス(ピナコラ-ト)ジボロン (1.23 g, 5.06 mmol) から標記化合物 (1.50 g、88%)を得た。白色固体: 1H-NMR (DMSO-D6) δ: 7.42 (1H, dd, J = 7.9, 1.3 Hz), 7.29 (1H, dd, J = 13.4, 1.2 Hz), 7.05 (1H, t, J = 8.4 Hz), 3.76-3.72 (4H, m), 3.18-3.15 (4H, m), 1.28 (12H, s). tert-Butyl 4- (3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (Example 85, process 4) In the same manner as in 1), 1- (4- (4-bromo-2-fluorophenyl) piperazin-1-yl) -2,2,2-trifluoroethanone (1.50 g, 4.22 mmol) and bis (pinacola -To) The title compound (1.50 g, 88%) was obtained from diboron (1.23 g, 5.06 mmol). White solid: 1 H-NMR (DMSO-D 6 ) δ: 7.42 (1H, dd, J = 7.9, 1.3 Hz), 7.29 (1H, dd, J = 13.4, 1.2 Hz), 7.05 (1H, t, J = 8.4 Hz), 3.76-3.72 (4H, m), 3.18-3.15 (4H, m), 1.28 (12H, s).

工程３
6-クロロ-3-(3-フルオロ-4-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Process 3
6-Chloro-3- (3-fluoro-4- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000315
Figure JPOXMLDOC01-appb-C000315

アルゴン雰囲気下、 3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (721 mg, 3.10 mmol) を1,4-ジオキサン (25 mL)、水 (5 mL) に懸濁した。そこへ2,2,2-トリフルオロ-1-(4-(2-フルオロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-イル)エタノン (1.50 g, 3.72 mmol)、炭酸ナトリウム (1.15 g, 10.9 mmol)、テトラキストリフェニルホスフィンパラジウム (143 mg, 0.124 mmol) を加えた。反応容器内を脱気し、アルゴン置換した。この操作を3回繰り返した後、100℃で17時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。酢酸エチル層を1規定塩酸で抽出した。水層に1規定水酸化ナトリウム溶液を加えて塩基性にし、クロロホルムで抽出した。クロロホルム層を無水硫酸マグネシウムで乾燥させ、溶媒を留去、真空乾燥して標記化合物 (788 mg, 77%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.31 (1H, s), 8.29 (1H, d, J= 9.5 Hz), 7.92-7.87 (2H, m), 7.41 (1H, d, J = 9.5 Hz), 7.17 (1H, t, J= 9.1 Hz), 3.01 (4H, t, J = 4.8 Hz), 2.86 (4H, t, J = 4.8 Hz), 2.37-2.32 (1H, m). Under an argon atmosphere, 3-bromo-6-chloroimidazo [1,2-b] pyridazine (721 mg, 3.10 mmol) was suspended in 1,4-dioxane (25 mL) and water (5 mL). There 2,2,2-trifluoro-1- (4- (2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine -1-yl) ethanone (1.50 g, 3.72 mmol), sodium carbonate (1.15 g, 10.9 mmol), tetrakistriphenylphosphine palladium (143 mg, 0.124 mmol) were added. The inside of the reaction vessel was evacuated and purged with argon. This operation was repeated 3 times, followed by stirring at 100 ° C. for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was extracted with 1N hydrochloric acid. The aqueous layer was made basic by adding 1N sodium hydroxide solution and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was dried under vacuum to obtain the title compound (788 mg, 77%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.31 (1H, s), 8.29 (1H, d, J = 9.5 Hz), 7.92-7.87 (2H, m), 7.41 (1H, d, J = 9.5 Hz), 7.17 (1H, t, J = 9.1 Hz), 3.01 (4H, t, J = 4.8 Hz), 2.86 (4H, t, J = 4.8 Hz), 2.37-2.32 (1H, m).

工程４
6-クロロ-3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Process 4
6-Chloro-3- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000316
Figure JPOXMLDOC01-appb-C000316

5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程7) と同様の手法で、6-クロロ-3-(3-フルオロ-4-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (788 mg, 2.38 mmol) および37% ホルムアルデヒド水溶液 (1.06 mL, 14.3 mmol) から標記化合物 (586 mg, 71%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.32 (1H, s), 8.29 (1H, d, J= 9.5 Hz), 7.93-7.87 (2H, m), 7.41 (1H, d, J = 9.0 Hz), 7.19 (1H, t, J= 9.1 Hz), 3.11 (4H, t, J = 4.6 Hz), 2.51-2.49 (4H, m), 2.24 (3H, s). Synthesis of 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 7) From -chloro-3- (3-fluoro-4- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (788 mg, 2.38 mmol) and 37% aqueous formaldehyde solution (1.06 mL, 14.3 mmol) The title compound (586 mg, 71%) was obtained. Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.32 (1H, s), 8.29 (1H, d, J = 9.5 Hz), 7.93-7.87 (2H, m), 7.41 (1H, d, J = 9.0 Hz), 7.19 (1H, t, J = 9.1 Hz), 3.11 (4H, t, J = 4.6 Hz), 2.51-2.49 (4H, m), 2.24 (3H, s).

工程５
3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 5
3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000317
Figure JPOXMLDOC01-appb-C000317

3-(4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例63、工程2) と同様の手法で、6-クロロ-3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (586 mg, 1.69 mmol) およびトリブチリビニルスズ (541 μL、1.86 mmol) から標記化合物 (320 mg, 56%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.24 (1H, s), 8.18 (1H, d, J = 9.3 Hz), 8.02-7.96 (2H, m), 7.66 (1H, d, J = 9.5 Hz), 7.16 (1H, t, J = 9.1 Hz), 6.92 (1H, dd, J = 17.7, 11.1 Hz), 6.38 (1H, d, J = 17.8 Hz), 5.79 (1H, d, J = 11.2 Hz), 3.10 (4H, t, J = 4.6 Hz), 2.51-2.49 (4H, m), 2.25 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 63, Step 2) From 3- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (586 mg, 1.69 mmol) and tributyvinyltin (541 μL, 1.86 mmol) The title compound (320 mg, 56%) was obtained. Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.24 (1H, s), 8.18 (1H, d, J = 9.3 Hz), 8.02-7.96 (2H, m), 7.66 (1H, d, J = 9.5 Hz), 7.16 (1H, t, J = 9.1 Hz), 6.92 (1H, dd, J = 17.7, 11.1 Hz), 6.38 (1H, d, J = 17.8 Hz), 5.79 (1H, d, J = 11.2 Hz), 3.10 (4H, t, J = 4.6 Hz), 2.51-2.49 (4H, m), 2.25 (3H, s).

工程６
3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Step 6
3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000318
Figure JPOXMLDOC01-appb-C000318

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ [1,2-b]ピリダジン (320 mg, 0.948 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (238 μL、19.0 μmol) から標記化合物 (211 mg, 66%) を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 10.1 (1H, d, J = 0.7 Hz), 8.48 (1H, d, J = 1.2 Hz), 8.37 (1H, d, J = 9.3 Hz), 8.08-8.02 (2H, m), 7.65 (1H, dd, J = 9.3, 1.0 Hz), 7.19 (1H, t, J = 8.9 Hz), 3.12 (4H, t, J = 4.6 Hz), 2.52-2.49 (4H, m), 2.24 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (320 mg, 0.948 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol ( The title compound (211 mg, 66%) was obtained from 238 μL, 19.0 μmol). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, d, J = 0.7 Hz), 8.48 (1H, d, J = 1.2 Hz), 8.37 (1H, d, J = 9.3 Hz) , 8.08-8.02 (2H, m), 7.65 (1H, dd, J = 9.3, 1.0 Hz), 7.19 (1H, t, J = 8.9 Hz), 3.12 (4H, t, J = 4.6 Hz), 2.52- 2.49 (4H, m), 2.24 (3H, s).

工程７
5-((3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物８６) Step 7
5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidine-4- ON (compound 86)

Figure JPOXMLDOC01-appb-C000319
Figure JPOXMLDOC01-appb-C000319

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (102 mg, 0.301 mmol) およびロダニン (40 mg, 0.301 mmol) から標記化合物 (99 mg, 73%) を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 8.26 (1H, s), 8.21 (1H, d, J = 9.3 Hz), 8.11 (1H, d, J = 14.1 Hz), 7.96 (1H, d, J = 8.8 Hz), 7.61 (1H, d, J = 9.5 Hz), 7.34 (1H, s), 7.22 (1H, t, J = 8.8 Hz), 3.19-3.09 (4H, m), 2.70-2.66 (4H, m), 2.50 (3H, s). 
ESI-MS(m/z): 455[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (102 mg, 0.301 mmol) and rhodanine (40 mg, 0.301 mmol) gave the title compound (99 mg, 73%). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 8.26 (1H, s), 8.21 (1H, d, J = 9.3 Hz), 8.11 (1H, d, J = 14.1 Hz), 7.96 (1H, d, J = 8.8 Hz), 7.61 (1H, d, J = 9.5 Hz), 7.34 (1H, s), 7.22 (1H, t, J = 8.8 Hz), 3.19-3.09 (4H, m), 2.70- 2.66 (4H, m), 2.50 (3H, s).
ESI-MS (m / z): 455 [M + H] + .

実施例８７
5-((3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物８７)  Example 87
5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 87)

Figure JPOXMLDOC01-appb-C000320
Figure JPOXMLDOC01-appb-C000320

工程１
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (109 mg, 0.321 mmol) およびチアゾリジン-2,4-ジオン (38 mg, 0.321 mmol) から標記化合物 (78 mg, 56%) を得た。茶色固体: 1H-NMR (DMSO-D6) δ: 8.27 (1H, s), 8.25 (1H, d, J = 9.5 Hz), 8.11 (1H, dd, J = 14.4, 2.0 Hz), 7.88 (1H, dd, J = 8.4, 2.1 Hz), 7.70 (1H, s), 7.63 (1H, d, J = 9.3 Hz), 7.19 (1H, t, J = 9.0 Hz), 3.22 (4H, s), 2.86 (4H, s), 2.50 (3H, s).
ESI-MS(m/z): 439[M+H]+. Process 1
Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (109 mg, 0.321 mmol) and thiazolidine-2,4-dione (38 mg, 0.321 mmol) gave the title compound (78 mg, 56%). Brown solid: 1 H-NMR (DMSO-D 6 ) δ: 8.27 (1H, s), 8.25 (1H, d, J = 9.5 Hz), 8.11 (1H, dd, J = 14.4, 2.0 Hz), 7.88 ( 1H, dd, J = 8.4, 2.1 Hz), 7.70 (1H, s), 7.63 (1H, d, J = 9.3 Hz), 7.19 (1H, t, J = 9.0 Hz), 3.22 (4H, s), 2.86 (4H, s), 2.50 (3H, s).
ESI-MS (m / z): 439 [M + H] + .

実施例８８
5-((3-(4-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物８８) Example 88
5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 88)

工程１
1-(4-ブロモフェニル)-4-エチルピペラジン Process 1
1- (4-Bromophenyl) -4-ethylpiperazine

Figure JPOXMLDOC01-appb-C000321
Figure JPOXMLDOC01-appb-C000321

ブロモ-4-ヨードベンゼン(2 g, 7.07 mmol)、1-エチルピペラジン(1.79 mL, 14.14 mmol)、リン酸カリウム(4.56 g, 26.2 mmol)、ヨウ化銅 (269 mg, 1.41 mmol) の2-プロパノール (20 mL) 溶液中に、エチレングリコール (1.18 mL, 21.2 mmol) を室温下添加した。アルゴン置換した後、還流条件下2日間撹拌した。セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 ( 808 mg, 34%, 3.00 mmol) を得た。1H-NMR (CDCl3) δ: 7.34 (2H, d, J = 9.0 Hz), 6.79 (2H, d, J = 9.0 Hz), 3.30-3.17 (4H, m), 2.74-2.62 (4H, m), 2.61-2.47 (2H, m), 1.18 (3H, t, J = 7.1 Hz). 
ESI-MS(m/z): 269[M+H]+. Bromo-4-iodobenzene (2 g, 7.07 mmol), 1-ethylpiperazine (1.79 mL, 14.14 mmol), potassium phosphate (4.56 g, 26.2 mmol), copper iodide (269 mg, 1.41 mmol) 2- Ethylene glycol (1.18 mL, 21.2 mmol) was added to a propanol (20 mL) solution at room temperature. After replacing with argon, the mixture was stirred under reflux conditions for 2 days. After filtration through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (808 mg, 34%, 3.00 mmol). 1 H-NMR (CDCl 3 ) δ: 7.34 (2H, d, J = 9.0 Hz), 6.79 (2H, d, J = 9.0 Hz), 3.30-3.17 (4H, m), 2.74-2.62 (4H, m ), 2.61-2.47 (2H, m), 1.18 (3H, t, J = 7.1 Hz).
ESI-MS (m / z): 269 [M + H] + .

工程２
1-エチル-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン Process 2
1-ethyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine

Figure JPOXMLDOC01-appb-C000322
Figure JPOXMLDOC01-appb-C000322

1-(4-ブロモフェニル)-4-エチルピペラジン (300 mg, 1.11 mmol) のテトラヒドロフラン (10 mL) 溶液中に、n-ブチルリチウムヘキサン溶液 (1.60 M, 1.05 mL, 1.67 mmol)を-78 ℃で滴下した。一時間撹拌した後、2-イソプロポキシ-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン (270 μL, 1.34 mmol) のテトラヒドロフラン (5 mL) 溶液をゆっくり滴下した。室温に昇温し一晩撹拌した。反応終了後、飽和塩化アンモニウム水溶液をゆっくり滴下し、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 ( 283 mg, 80%, 9.6 mmol) を得た。 1H-NMR (CDCl3) δ: 7.71 (2H, d, J = 8.8 Hz), 6.90 (2H, d, J = 8.8 Hz), 3.36-3.31 (4H, m), 2.67-2.61 (4H, m), 2.57-2.47 (2H, m), 1.32 (12H, s), 1.16 (3H, t, J = 6.3 Hz).
ESI-MS(m/z): 317[M+H]+. In a solution of 1- (4-bromophenyl) -4-ethylpiperazine (300 mg, 1.11 mmol) in tetrahydrofuran (10 mL), add n-butyllithium hexane solution (1.60 M, 1.05 mL, 1.67 mmol) to -78 ° C. It was dripped at. After stirring for 1 hour, a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (270 μL, 1.34 mmol) in tetrahydrofuran (5 mL) was slowly added dropwise. The mixture was warmed to room temperature and stirred overnight. After completion of the reaction, a saturated aqueous ammonium chloride solution was slowly added dropwise and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (283 mg, 80%, 9.6 mmol). 1 H-NMR (CDCl 3 ) δ: 7.71 (2H, d, J = 8.8 Hz), 6.90 (2H, d, J = 8.8 Hz), 3.36-3.31 (4H, m), 2.67-2.61 (4H, m ), 2.57-2.47 (2H, m), 1.32 (12H, s), 1.16 (3H, t, J = 6.3 Hz).
ESI-MS (m / z): 317 [M + H] + .

工程３
6-クロロ-3-(4-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Process 3
6-Chloro-3- (4- (4-ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000323
Figure JPOXMLDOC01-appb-C000323

3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (173 mg, 0.90 mmol) の1,4-ジオキサン (6 mL)、水(1 mL) の混合溶液中に、1-エチル-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン (283 mg, 0.75 mmol)、テトラキストリフェニルホスフィンパラジウム (35 mg, 0.03 mmol)、炭酸ナトリウム (277 mg, 2.61 mmol) を添加した。アルゴン置換した後、還流条件下一晩撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (152 mg, 60 %, 0.45 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.25 (1H, d, J = 9.5 Hz), 8.20 (1H, s), 7.94 (2H, d, J = 9.0 Hz), 7.35 (1H, d, J = 9.5 Hz), 7.09 (2H, d, J = 9.0 Hz), 3.24 (4H, t, J = 4.9 Hz), 2.51 (4H, t, J = 4.9 Hz), 2.38 (2H, q, J = 7.2 Hz), 1.04 (3H, t, J = 7.2 Hz).
ESI-MS(m/z): 342[M+H]+. In a mixed solution of 3-bromo-6-chloroimidazo [1,2-b] pyridazine (173 mg, 0.90 mmol) in 1,4-dioxane (6 mL) and water (1 mL), 1-ethyl-4 -(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine (283 mg, 0.75 mmol), tetrakistriphenylphosphine palladium (35 mg, 0.03 mmol ), Sodium carbonate (277 mg, 2.61 mmol) was added. After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (152 mg, 60%, 0.45 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.25 (1H, d, J = 9.5 Hz), 8.20 (1H, s), 7.94 (2H, d, J = 9.0 Hz), 7.35 (1H, d, J = 9.5 Hz), 7.09 (2H, d, J = 9.0 Hz), 3.24 (4H, t, J = 4.9 Hz), 2.51 (4H, t, J = 4.9 Hz), 2.38 (2H, q, J = 7.2 Hz), 1.04 (3H, t, J = 7.2 Hz).
ESI-MS (m / z): 342 [M + H] + .

工程４
3-(4-(4-エチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 4
3- (4- (4-Ethylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000324
Figure JPOXMLDOC01-appb-C000324

6-クロロ-3-(4-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (571 mg, 1.74 mmol) の1,4-ジオキサン (20 mL)、水(4 mL) の混合溶液中に 4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (447 μL, 2.61 mmol)、酢酸パラジウム (39 mg, 0.17 mmol)、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル (143 mg, 0.35 mmol)、リン酸カリウム (2.77 g, 13.06 mmol) を添加した。アルゴン置換した後、還流条件下一晩撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) にて精製し、標記化合物 (354 mg, 64 %, 1.11 mmol) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.14 (1H, d, J = 9.5 Hz), 8.10 (1H, s), 8.02 (2H, d, J = 9.0 Hz), 7.60 (1H, d, J = 9.5 Hz), 7.07 (2H, d, J = 9.0 Hz), 6.89 (1H, dd, J = 17.8, 11.0 Hz), 6.35 (1H, d, J = 17.8 Hz), 5.76 (1H, d, J = 11.0 Hz), 3.22 (4H, t, J = 4.9 Hz), 2.51 (4H, t, J = 4.9 Hz), 2.38 (2H, q, J = 7.2 Hz), 1.04 (3H, t, J = 7.2 Hz).
ESI-MS(m/z): 334[M+H]+. 6-chloro-3- (4- (4-ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (571 mg, 1.74 mmol) of 1,4-dioxane (20 mL), water ( 4 mL) in a mixed solution of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (447 μL, 2.61 mmol), palladium acetate (39 mg, 0.17 mmol), 2- Dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (143 mg, 0.35 mmol) and potassium phosphate (2.77 g, 13.06 mmol) were added. After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (354 mg, 64%, 1.11 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.14 (1H, d, J = 9.5 Hz), 8.10 (1H, s), 8.02 (2H, d, J = 9.0 Hz), 7.60 (1H, d, J = 9.5 Hz), 7.07 (2H, d, J = 9.0 Hz), 6.89 (1H, dd, J = 17.8, 11.0 Hz), 6.35 (1H, d, J = 17.8 Hz), 5.76 (1H, d, J = 11.0 Hz), 3.22 (4H, t, J = 4.9 Hz), 2.51 (4H, t, J = 4.9 Hz), 2.38 (2H, q, J = 7.2 Hz), 1.04 (3H, t, J = 7.2 Hz).
ESI-MS (m / z): 334 [M + H] + .

工程５
3-(4-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 5
3- (4- (4-Ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000325
Figure JPOXMLDOC01-appb-C000325

3-(4-(4-エチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (354 mg, 1.06 mmol) の1,4-ジオキサン (10 mL)、水 (3 mL) の混合溶液中に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (267 μL, 0.021 mmol)、2,6-ルチジン (247 μL, 2.12 mmol)、過ヨウ素酸ナトリウム (908 mg, 4.25 mmol) を添加した。アルゴン置換した後、室温で4時間撹拌した。セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (95 mg, 27 %, 0.28 mmol) を得た。 1H-NMR (DMSO-D6) δ: 10.02 (1H, s), 8.36 (1H, s), 8.33 (1H, d, J = 9.3 Hz), 8.08 (2H, d, J = 9.0 Hz), 7.61 (1H, d, J = 9.3 Hz), 7.11 (2H, d, J = 9.0 Hz), 3.29-3.21 (4H, m), 2.55-2.50 (4H, m), 2.38 (2H, q, J = 7.1 Hz), 1.05 (3H, t, J = 7.1 Hz). 
ESI-MS(m/z): 336[M+H]+. 3- (4- (4-Ethylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (354 mg, 1.06 mmol) of 1,4-dioxane (10 mL), water ( 3 mL) in a 2.5 wt% osmium tetroxide tert-butanol solution (267 μL, 0.021 mmol), 2,6-lutidine (247 μL, 2.12 mmol), sodium periodate (908 mg, 4.25 mmol) ) Was added. After purging with argon, the mixture was stirred at room temperature for 4 hours. After filtration through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (95 mg, 27%, 0.28 mmol). 1 H-NMR (DMSO-D 6 ) δ: 10.02 (1H, s), 8.36 (1H, s), 8.33 (1H, d, J = 9.3 Hz), 8.08 (2H, d, J = 9.0 Hz), 7.61 (1H, d, J = 9.3 Hz), 7.11 (2H, d, J = 9.0 Hz), 3.29-3.21 (4H, m), 2.55-2.50 (4H, m), 2.38 (2H, q, J = 7.1 Hz), 1.05 (3H, t, J = 7.1 Hz).
ESI-MS (m / z): 336 [M + H] + .

工程６
5-((3-(4-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物８８)  Step 6
5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 88)

Figure JPOXMLDOC01-appb-C000326
Figure JPOXMLDOC01-appb-C000326

3-(4-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (45 mg, 0.13 mmol) をアセトニトリル (5.0 mL) に溶かし、チアゾリジン-2,4-ジオン (16 mg, 0.13 mmol)、ピペリジン (2.7 μL, 0.027 mmol)、および酢酸 (3.1 μL, 0.054 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (7.5 μL, 0.05 mmol) を添加した後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (33 mg, 57 %, 0.076 mmol) を得た。赤褐色固体: 1H-NMR (DMSO-D6) δ: 8.21 (1H, d, J = 9.3 Hz), 8.15 (1H, s), 8.03 (2H, d, J = 8.8 Hz), 7.69 (1H, s), 7.58 (1H, d, J = 9.3 Hz), 7.12 (2H, d, J = 8.8 Hz), 3.40-3.22 (4H, m), 2.92-2.82 (4H, m), 2.77-2.66 (2H, m), 1.14 (3H, t, J = 7.1 Hz). 
ESI-MS(m/z): 435[M+H]+. 3- (4- (4-Ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (45 mg, 0.13 mmol) was dissolved in acetonitrile (5.0 mL) and thiazolidine-2 , 4-dione (16 mg, 0.13 mmol), piperidine (2.7 μL, 0.027 mmol), and acetic acid (3.1 μL, 0.054 mmol) were added and stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (7.5 μL, 0.05 mmol) was added, and the mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol), and the title compound (33 mg, 57%, 0.076 mmol) was obtained. Reddish brown solid: 1 H-NMR (DMSO-D 6 ) δ: 8.21 (1H, d, J = 9.3 Hz), 8.15 (1H, s), 8.03 (2H, d, J = 8.8 Hz), 7.69 (1H, s), 7.58 (1H, d, J = 9.3 Hz), 7.12 (2H, d, J = 8.8 Hz), 3.40-3.22 (4H, m), 2.92-2.82 (4H, m), 2.77-2.66 (2H , m), 1.14 (3H, t, J = 7.1 Hz).
ESI-MS (m / z): 435 [M + H] + .

実施例８９
3-メチル-5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物８９)  Example 89
3-methyl-5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 89)

Figure JPOXMLDOC01-appb-C000327
Figure JPOXMLDOC01-appb-C000327

工程１
3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (250 mg, 0.78 mmol)、3-メチルチアゾリジン-2,4-ジオン(106 mg, 0.81 mmol) のアセトニトリル (10 mL) 懸濁液に酢酸 (19 mg, 0.31 mmol)、ピペリジン (13 mg, 0.16 mmol) を加え、20 時間加熱還流した。反応終了後、個体をろ過し、アセトニトリルで洗浄した後、乾燥した、目的とする標記化合物 (223 mg, 66 %) を得た。茶褐色結晶: 1H-NMR (DMSO-D6) δ: 8.29 (1H, d, J = 9.5 Hz), 8.16 (1H, s), 8.05 (1H, s), 7.91 (2H, d, J = 9.0 Hz), 7.69 (1H, d, J = 9.5 Hz), 7.09 (2H, d, J = 9.0 Hz), 3.26 (4H, t, J = 4.9 Hz), 3.11 (3H, s), 2.51-2.48 (4H, m), 2.25 (3H, s). Process 1
3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (250 mg, 0.78 mmol), 3-methylthiazolidine-2,4-dione ( Acetic acid (19 mg, 0.31 mmol) and piperidine (13 mg, 0.16 mmol) were added to a suspension of 106 mg, 0.81 mmol) in acetonitrile (10 mL), and the mixture was heated to reflux for 20 hours. After completion of the reaction, the solid was filtered, washed with acetonitrile, and then dried to obtain the target title compound (223 mg, 66%). Brownish crystals: 1 H-NMR (DMSO-D 6 ) δ: 8.29 (1H, d, J = 9.5 Hz), 8.16 (1H, s), 8.05 (1H, s), 7.91 (2H, d, J = 9.0 Hz), 7.69 (1H, d, J = 9.5 Hz), 7.09 (2H, d, J = 9.0 Hz), 3.26 (4H, t, J = 4.9 Hz), 3.11 (3H, s), 2.51-2.48 ( 4H, m), 2.25 (3H, s).

実施例９０
5-((3-(3-((4-ヘキシルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物９０) Example 90
5-((3- (3-((4-Hexylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thioxothiazolidine- 4-one (compound 90)

工程１
3-ニトロベンジル アセテート Process 1
3-Nitrobenzyl acetate

Figure JPOXMLDOC01-appb-C000328
Figure JPOXMLDOC01-appb-C000328

アルゴン雰囲気下、3-ニトロベンジルアルコール (1.00 g, 6.53 mmol) をクロロホルム (12 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (934 mL, 6.86 mmol) を加え、さらにアセチルクロリド (928 μL, 13.1 mmol) を滴下し、0℃で10分撹拌後、室温で1時間撹拌した。反応液を1規定塩酸、水、飽和食塩水で洗浄した。クロロホルム層を無水硫酸マグネシウムで乾燥させ、溶媒を留去、真空乾燥して標記化合物 (1.30 g, quant) を得た。薄黄色オイル: 1H-NMR (DMSO-D6) δ: 8.25-8.24 (1H, m), 8.22-8.19 (1H, m), 7.86-7.83 (1H, m), 7.69 (1H, t, J= 7.9 Hz), 5.22 (2H, s), 2.11 (3H, s) Under an argon atmosphere, 3-nitrobenzyl alcohol (1.00 g, 6.53 mmol) was dissolved in chloroform (12 mL) and cooled to 0 ° C. Triethylamine (934 mL, 6.86 mmol) was added thereto, acetyl chloride (928 μL, 13.1 mmol) was further added dropwise, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 1 hour. The reaction mixture was washed with 1N hydrochloric acid, water, and saturated brine. The chloroform layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was dried under vacuum to obtain the title compound (1.30 g, quant). Pale yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.25-8.24 (1H, m), 8.22-8.19 (1H, m), 7.86-7.83 (1H, m), 7.69 (1H, t, J = 7.9 Hz), 5.22 (2H, s), 2.11 (3H, s)

工程２
3-アミノベンジル アセテート Process 2
3-Aminobenzyl acetate

Figure JPOXMLDOC01-appb-C000329
Figure JPOXMLDOC01-appb-C000329

アルゴン雰囲気下、3-ニトロベンジル アセテート (1.30 g, 6.53 mmol) を酢酸 (50 mL) に溶解した。そこへ亜鉛 (2.90 g, 44.4 mmol) を少量ずつ加え、室温で4時間撹拌した。反応液をセライトでろ過し、ろ液を濃縮した。得られた残渣を酢酸エチルに再溶解し、飽和重層水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、 溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (956 mg, 90%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 6.98 (1H, t, J = 7.7 Hz), 6.53-6.45 (3H, m), 5.11 (2H, s), 4.91 (2H, s), 2.05 (3H, s). 3-nitrobenzyl acetate (1.30 g, 6.53 mmol) was dissolved in acetic acid (50 mL) under an argon atmosphere. Zinc (2.90 g, 44.4 mmol) was added little by little thereto, and the mixture was stirred at room temperature for 4 hours. The reaction solution was filtered through celite, and the filtrate was concentrated. The obtained residue was redissolved in ethyl acetate and washed with saturated multistory water. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (956 mg, 90%). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 6.98 (1H, t, J = 7.7 Hz), 6.53-6.45 (3H, m), 5.11 (2H, s), 4.91 (2H, s), 2.05 (3H, s).

工程３
3-((6-ブロモ-3-ニトロピリジン-2-イル)アミノ)ベンジル アセテート Process 3
3-((6-Bromo-3-nitropyridin-2-yl) amino) benzyl acetate

Figure JPOXMLDOC01-appb-C000330
Figure JPOXMLDOC01-appb-C000330

tert-ブチル 4-(4-((6-ブロモ-3-ニトロピリジン-2-イル)アミノ)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例65、工程3) と同様の手法で、2,6-ジブロモ-3-ニトロピリジン (1.37g、4.87 mmol) および3-アミノベンジル アセテート (956 mg, 5.84 mmol) から標記化合物 (1.35g, 76%) を得た。橙色固体:  1H-NMR (DMSO-D6) δ: 10.1 (1H, s), 8.41 (1H, d, J = 8.5 Hz), 7.62 (1H, s), 7.58 (1H, d, J = 8.1 Hz), 7.40 (1H, t, J= 7.8 Hz), 7.19-7.15 (2H, m), 5.10 (2H, s), 2.10 (3H, s). Synthesis of tert-butyl 4- (4-((6-bromo-3-nitropyridin-2-yl) amino) phenyl) piperazine-1-carboxylate in the same manner as in Example 65, Step 3 The title compound (1.35 g, 76%) was obtained from 1,6-dibromo-3-nitropyridine (1.37 g, 4.87 mmol) and 3-aminobenzyl acetate (956 mg, 5.84 mmol). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, s), 8.41 (1H, d, J = 8.5 Hz), 7.62 (1H, s), 7.58 (1H, d, J = 8.1 Hz), 7.40 (1H, t, J = 7.8 Hz), 7.19-7.15 (2H, m), 5.10 (2H, s), 2.10 (3H, s).

工程４
3-((3-アミノ-6-ブロモピリジン-2-イル)アミノ)ベンジル アセテート Process 4
3-((3-Amino-6-bromopyridin-2-yl) amino) benzyl acetate

Figure JPOXMLDOC01-appb-C000331
Figure JPOXMLDOC01-appb-C000331

tert-ブチル 4-(4-((3-アミノ-6-ブロモピリジン-2-イル)アミノ)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例65、工程4) と同様の手法で、3-((6-ブロモ-3-ニトロピリジン-2-イル)アミノ)ベンジル アセテート (1.35g、3.69 mmol) から標記化合物 (1.13g, 91%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.04 (1H, s), 7.60 (2H, d, J = 9.3 Hz), 7.26 (1H, t, J = 7.7 Hz), 6.94-6.77 (3H, m), 5.27 (2H, s), 5.05 (2H, s), 2.09 (3H, s). Synthesis of tert-butyl 4- (4-((3-amino-6-bromopyridin-2-yl) amino) phenyl) piperazine-1-carboxylate in the same manner as in Example 65, Step 4 The title compound (1.13 g, 91%) was obtained from-((6-bromo-3-nitropyridin-2-yl) amino) benzyl acetate (1.35 g, 3.69 mmol). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.04 (1H, s), 7.60 (2H, d, J = 9.3 Hz), 7.26 (1H, t, J = 7.7 Hz), 6.94-6.77 ( 3H, m), 5.27 (2H, s), 5.05 (2H, s), 2.09 (3H, s).

工程５
3-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンジル アセテート Process 5
3- (5-Bromo-3H-imidazo [4,5-b] pyridin-3-yl) benzyl acetate

Figure JPOXMLDOC01-appb-C000332
Figure JPOXMLDOC01-appb-C000332

tert-ブチル 4-(4-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例65、工程5) と同様の手法で、3-((3-アミノ-6-ブロモピリジン-2-イル)アミノ)ベンジル アセテート (1.13 g、3.36 mmol) およびホルムアミジン酢酸塩 (1.05 g, 10.1 mmol) から標記化合物 (1.13g, 91%) を得た。茶色固体: 1H-NMR (DMSO-D6) δ: 8.91 (1H, s), 8.19 (1H, d, J= 8.3 Hz), 7.89-7.88 (1H, m), 7.84 (1H, d, J = 7.3 Hz), 7.64 (1H, t, J= 7.8 Hz), 7.59 (1H, d, J = 8.3 Hz), 7.51-7.48 (1H, m), 5.20 (2H, s), 2.12 (3H, s). Synthesis of tert-butyl 4- (4- (5-bromo-3H-imidazo [4,5-b] pyridin-3-yl) phenyl) piperazine-1-carboxylate (Example 65, Step 5) Procedure from 3-((3-amino-6-bromopyridin-2-yl) amino) benzyl acetate (1.13 g, 3.36 mmol) and formamidine acetate (1.05 g, 10.1 mmol) to the title compound (1.13 g, 91%). Brown solid: 1 H-NMR (DMSO-D 6 ) δ: 8.91 (1H, s), 8.19 (1H, d, J = 8.3 Hz), 7.89-7.88 (1H, m), 7.84 (1H, d, J = 7.3 Hz), 7.64 (1H, t, J = 7.8 Hz), 7.59 (1H, d, J = 8.3 Hz), 7.51-7.48 (1H, m), 5.20 (2H, s), 2.12 (3H, s ).

工程６
(3-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)メタノール Step 6
(3- (5-Bromo-3H-imidazo [4,5-b] pyridin-3-yl) phenyl) methanol

Figure JPOXMLDOC01-appb-C000333
Figure JPOXMLDOC01-appb-C000333

アルゴン雰囲気下、3-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンジル アセテート (497 mg, 1.44 mmol) をメタノール (14 mL) に懸濁し、0℃に冷却した。そこへナトリウムメトキシド メタノール溶液 (5 M, 346 μL, 1.73 mmol) を加え、0℃で10分撹拌後、室温で1時間撹拌した。反応液に飽和食塩水を加え、クロロホルムで抽出した。クロロホルム層を無水硫酸マグネシウムで乾燥させ、溶媒を留去、真空乾燥して標記化合物 (464 mg, quant) を得た。褐色固体: 1H-NMR (DMSO-D6) δ: 8.87 (1H, s), 8.19 (1H, d, J= 8.3 Hz), 7.77 (1H, s), 7.72-7.69 (1H, m), 7.59 (2H, t, J = 7.7 Hz), 7.58 (2H, d, J = 8.3 Hz), 7.48-7.44 (1H, m), 4.62 (2H, s), 3.36 (3H, s). Under argon atmosphere, 3- (5-bromo-3H-imidazo [4,5-b] pyridin-3-yl) benzyl acetate (497 mg, 1.44 mmol) was suspended in methanol (14 mL) and cooled to 0 ° C. did. Sodium methoxide methanol solution (5 M, 346 μL, 1.73 mmol) was added thereto, followed by stirring at 0 ° C. for 10 minutes and then at room temperature for 1 hour. Saturated saline was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was dried under vacuum to obtain the title compound (464 mg, quant). Brown solid: 1 H-NMR (DMSO-D 6 ) δ: 8.87 (1H, s), 8.19 (1H, d, J = 8.3 Hz), 7.77 (1H, s), 7.72-7.69 (1H, m), 7.59 (2H, t, J = 7.7 Hz), 7.58 (2H, d, J = 8.3 Hz), 7.48-7.44 (1H, m), 4.62 (2H, s), 3.36 (3H, s).

工程７
3-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンズアルデヒド Step 7
3- (5-Bromo-3H-imidazo [4,5-b] pyridin-3-yl) benzaldehyde

Figure JPOXMLDOC01-appb-C000334
Figure JPOXMLDOC01-appb-C000334

アルゴン雰囲気下、(3-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)メタノール (464 mg, 1.44 mmol) を塩化メチレン (28 mL) に溶解し、0℃に冷却した。そこへデス・マーチン・ペルヨージナン (733 mg, 1.73 mmol) を加え、0℃で10分撹拌後、室温で3時間撹拌した。反応液に飽和チオ硫酸ナトリウム水溶液を加えクエンチし、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (433 mg, 99％) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 10.1 (1H, s), 9.01 (1H, s), 8.42 (1H, t, J = 1.6 Hz), 8.26-8.23 (1H, m), 8.22 (1H, d, J= 8.3 Hz), 8.07-8.04 (1H, m), 7.89 (1H, t, J = 7.9 Hz), 7.62 (1H, d, J= 8.3 Hz). Under an argon atmosphere, (3- (5-bromo-3H-imidazo [4,5-b] pyridin-3-yl) phenyl) methanol (464 mg, 1.44 mmol) was dissolved in methylene chloride (28 mL). Cooled to ° C. Dess-Martin periodinane (733 mg, 1.73 mmol) was added thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 3 hours. The reaction solution was quenched by adding a saturated aqueous sodium thiosulfate solution, and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (433 mg, 99%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, s), 9.01 (1H, s), 8.42 (1H, t, J = 1.6 Hz), 8.26-8.23 (1H, m), 8.22 (1H, d, J = 8.3 Hz), 8.07-8.04 (1H, m), 7.89 (1H, t, J = 7.9 Hz), 7.62 (1H, d, J = 8.3 Hz).

工程８
5-ブロモ-3-(3-((4-ヘキシルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン Process 8
5-Bromo-3- (3-((4-hexylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000335
Figure JPOXMLDOC01-appb-C000335

6-ブロモ-3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジンの合成 (実施例57、工程1) と同様の手法で、3-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンズアルデヒド (130 mg, 0.430 mmol) および1-ヘキシルピペラジン(170 μL, 0.860 mmol) から標記化合物 (182 mg, 93%) を得た。黄色オイル:  1H-NMR (DMSO-D6) δ: 8.90 (1H, s), 8.19 (1H, d, J= 8.3 Hz), 7.79 (1H, s), 7.74-7.71 (1H, m), 7.58 (1H, d, J = 8.1 Hz), 7.56 (1H, d, J = 6.3 Hz), 7.42 (1H, d, J = 7.6 Hz), 3.58 (2H, s), 2.50-2.29 (8H, m), 2.25-2.20 (2H, m), 1.40-1.35 (2H, m), 1.29-1.22 (6H, m), 0.85 (3H, t, J = 6.7 Hz). Synthesis of 6-bromo-3- (3-((4-ethylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine (Example 57, Step 1) The title compound (182 mg, 93) from-(5-bromo-3H-imidazo [4,5-b] pyridin-3-yl) benzaldehyde (130 mg, 0.430 mmol) and 1-hexylpiperazine (170 μL, 0.860 mmol) %). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.90 (1H, s), 8.19 (1H, d, J = 8.3 Hz), 7.79 (1H, s), 7.74-7.71 (1H, m), 7.58 (1H, d, J = 8.1 Hz), 7.56 (1H, d, J = 6.3 Hz), 7.42 (1H, d, J = 7.6 Hz), 3.58 (2H, s), 2.50-2.29 (8H, m ), 2.25-2.20 (2H, m), 1.40-1.35 (2H, m), 1.29-1.22 (6H, m), 0.85 (3H, t, J = 6.7 Hz).

工程９
3-(3-((4-ヘキシルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド Step 9
3- (3-((4-Hexylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000336
Figure JPOXMLDOC01-appb-C000336

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒドの合成 (実施例48、工程5) と同様の手法で、5-ブロモ-3-(3-((4-ヘキシルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン (174 mg, 0.399 mmol) から標記化合物 (73 mg, 45%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.7 Hz), 9.16 (1H, s), 8.40 (1H, d, J = 0.5 Hz), 8.01-7.79 (4H, m), 7.62-7.53 (1H, m), 7.47-7.38 (1H, m), 3.60 (2H, s), 2.48-2.29 (8H, m), 2.23 (2H, t, J = 7.2 Hz), 1.41-1.35 (2H, m), 1.29-1.20 (6H, m), 0.88-0.82 (3H, m). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (Example 48, Step 5) -3- (3-((4-Hexylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridine (174 mg, 0.399 mmol) to the title compound (73 mg, 45%) Got. Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.7 Hz), 9.16 (1H, s), 8.40 (1H, d, J = 0.5 Hz), 8.01-7.79 ( 4H, m), 7.62-7.53 (1H, m), 7.47-7.38 (1H, m), 3.60 (2H, s), 2.48-2.29 (8H, m), 2.23 (2H, t, J = 7.2 Hz) , 1.41-1.35 (2H, m), 1.29-1.20 (6H, m), 0.88-0.82 (3H, m).

工程１０
5-((3-(3-((4-ヘキシルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物９０) Step 10
5-((3- (3-((4-Hexylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thioxothiazolidine- 4-one (compound 90)

Figure JPOXMLDOC01-appb-C000337
Figure JPOXMLDOC01-appb-C000337

5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-((4-ヘキシルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド (73 mg, 0.180 mmol) およびロダニン (24 mg, 0.180 mmol) から標記化合物 (28 mg, 30％) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 9.02 (1H, s), 7.83 (1H, dd, J = 8.1, 1.5 Hz), 7.80 (1H, d, J = 8.5 Hz), 7.60 (1H, t, J = 7.8 Hz), 7.53 (1H, s), 7.48 (1H, d, J = 7.8 Hz), 3.89 (2H, s), 3.03-2.91 (4H, m), 2.82-2.78 (2H, m), 2.74-2.60 (4H, m), 1.55-1.49 (2H, m), 1.25 (6H, s), 0.85 (3H, t, J = 6.7 Hz).
ESI-MS(m/z): 521[M+H]+. Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (3-((4-hexylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde (73 mg, 0.180 mmol) and rhodanine ( The title compound (28 mg, 30%) was obtained from 24 mg, 0.180 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 9.02 (1H, s), 7.83 (1H, dd, J = 8.1, 1.5 Hz), 7.80 (1H, d, J = 8.5 Hz), 7.60 ( 1H, t, J = 7.8 Hz), 7.53 (1H, s), 7.48 (1H, d, J = 7.8 Hz), 3.89 (2H, s), 3.03-2.91 (4H, m), 2.82-2.78 (2H , m), 2.74-2.60 (4H, m), 1.55-1.49 (2H, m), 1.25 (6H, s), 0.85 (3H, t, J = 6.7 Hz).
ESI-MS (m / z): 521 [M + H] + .

実施例９１
5-((3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物９１)  Example 91
5-((3- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thioxothiazolidine- 4-one (compound 91)

工程１
3-(5-ビニル-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンジル アセテート Process 1
3- (5-Vinyl-3H-imidazo [4,5-b] pyridin-3-yl) benzyl acetate

Figure JPOXMLDOC01-appb-C000338
Figure JPOXMLDOC01-appb-C000338

3-(4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例63、工程2) と同様の手法で、3-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンジル アセテート (843 mg, 2.44 mmol) およびトリブチリビニルスズ (1.06 mL, 3.66 mmol) から標記化合物 (716 mg, quant) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.90 (1H, s), 8.17 (1H, d, J = 8.3 Hz), 8.06 (1H, s), 7.94 (1H, dd, J = 7.9, 1.8 Hz), 7.63 (1H, t, J = 7.8 Hz), 7.53 (1H, d, J = 8.3 Hz), 7.46 (1H, d, J = 7.8 Hz), 6.93 (1H, dd, J = 17.6, 10.7 Hz), 6.27 (1H, dd, J = 17.4, 1.3 Hz), 5.48 (1H, dd, J = 10.6, 1.3 Hz), 5.21 (2H, s), 2.11 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 63, Step 2) -Bromo-3H-imidazo [4,5-b] pyridin-3-yl) benzyl acetate (843 mg, 2.44 mmol) and tributylivinyltin (1.06 mL, 3.66 mmol) to give the title compound (716 mg, quant) Obtained. Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.90 (1H, s), 8.17 (1H, d, J = 8.3 Hz), 8.06 (1H, s), 7.94 (1H, dd, J = 7.9 , 1.8 Hz), 7.63 (1H, t, J = 7.8 Hz), 7.53 (1H, d, J = 8.3 Hz), 7.46 (1H, d, J = 7.8 Hz), 6.93 (1H, dd, J = 17.6 , 10.7 Hz), 6.27 (1H, dd, J = 17.4, 1.3 Hz), 5.48 (1H, dd, J = 10.6, 1.3 Hz), 5.21 (2H, s), 2.11 (3H, s).

工程２
3-(5-ホルミル-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンジル アセテート  Process 2
3- (5-Formyl-3H-imidazo [4,5-b] pyridin-3-yl) benzyl acetate

Figure JPOXMLDOC01-appb-C000339
Figure JPOXMLDOC01-appb-C000339

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(5-ビニル-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンジル アセテート (716 mg, 2.44 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (612 μL, 0.049 mmol) から標記化合物 (573 mg, 80%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.7 Hz), 9.17 (1H, s), 8.42 (1H, dd, J = 8.3, 0.7 Hz), 8.01-7.99 (2H, m), 7.97-7.94 (1H, m), 7.67 (1H, t, J= 7.8 Hz), 7.52 (1H, d, J = 7.8 Hz), 5.22 (2H, s), 2.12 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) Title compound from 5-vinyl-3H-imidazo [4,5-b] pyridin-3-yl) benzyl acetate (716 mg, 2.44 mmol) and 2.5 wt% osmium tetroxide tert-butanol solution (612 μL, 0.049 mmol) (573 mg, 80%) was obtained. White solid: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.7 Hz), 9.17 (1H, s), 8.42 (1H, dd, J = 8.3, 0.7 Hz), 8.01- 7.99 (2H, m), 7.97-7.94 (1H, m), 7.67 (1H, t, J = 7.8 Hz), 7.52 (1H, d, J = 7.8 Hz), 5.22 (2H, s), 2.12 (3H , s).

工程３
3-(5-(1,3-ジオキソラン-2-イル)-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンジル アセテート  Process 3
3- (5- (1,3-Dioxolan-2-yl) -3H-imidazo [4,5-b] pyridin-3-yl) benzyl acetate

Figure JPOXMLDOC01-appb-C000340
Figure JPOXMLDOC01-appb-C000340

アルゴン雰囲気下、3-(5-ホルミル-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンジル アセテート (573 mg, 1.94 mmol) をトルエン (20 mL) に溶解した。そこへポリエチレングリコール (541 μL, 9.70 mmol)、パラトルエンスルホン酸一水和物 (11 mg, 0.058 mmol) を加え、ディーン・スターク装置を用いて3時間加熱還流した。反応液を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (577 mg, 88%) を得た。透明オイル: 1H-NMR (DMSO-D6) δ: 8.95 (1H, s), 8.26 (1H, d, J= 8.3 Hz), 7.98 (1H, s), 7.93-7.90 (1H, m), 7.63 (1H, t, J = 7.8 Hz), 7.55 (1H, d, J = 8.3 Hz), 7.47 (1H, d, J = 7.6 Hz), 5.84 (1H, s), 5.20 (2H, s), 4.17-4.14 (2H, m), 4.02-3.99 (2H, m), 2.11 (3H, s). Under an argon atmosphere, 3- (5-formyl-3H-imidazo [4,5-b] pyridin-3-yl) benzyl acetate (573 mg, 1.94 mmol) was dissolved in toluene (20 mL). Polyethylene glycol (541 μL, 9.70 mmol) and paratoluenesulfonic acid monohydrate (11 mg, 0.058 mmol) were added thereto, and the mixture was heated to reflux for 3 hours using a Dean-Stark apparatus. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (577 mg, 88%). Clear oil: 1 H-NMR (DMSO-D 6 ) δ: 8.95 (1H, s), 8.26 (1H, d, J = 8.3 Hz), 7.98 (1H, s), 7.93-7.90 (1H, m), 7.63 (1H, t, J = 7.8 Hz), 7.55 (1H, d, J = 8.3 Hz), 7.47 (1H, d, J = 7.6 Hz), 5.84 (1H, s), 5.20 (2H, s), 4.17-4.14 (2H, m), 4.02-3.99 (2H, m), 2.11 (3H, s).

工程４
(3-(5-(1,3-ジオキソラン-2-イル)-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)メタノール  Process 4
(3- (5- (1,3-Dioxolan-2-yl) -3H-imidazo [4,5-b] pyridin-3-yl) phenyl) methanol

Figure JPOXMLDOC01-appb-C000341
Figure JPOXMLDOC01-appb-C000341

アルゴン雰囲気下、3-(5-(1,3-ジオキソラン-2-イル)-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンジル アセテート (577 mg, 1.70 mmol) をメタノール (9 mL) に溶解し、0℃に冷却した。そこへナトリウムメトキシド メタノール溶液 (340 mL, 1.70 mmol) を加え、 0℃で10分撹拌後、 室温で1時間撹拌した。反応液に飽和食塩水を加え、クロロホルムで抽出した。クロロホルム層を無水硫酸マグネシウムで乾燥させ、溶媒を留去、真空乾燥して標記化合物 (486 mg, 96%) を得た。透明オイル: 1H-NMR (DMSO-D6) δ: 8.91 (1H, s), 8.25 (1H, d, J= 8.3 Hz), 7.88 (1H, s), 7.80-7.78 (1H, m), 7.58 (2H, t, J = 7.8 Hz), 7.54 (2H, d, J = 8.3 Hz), 7.43 (1H, d, J = 7.6 Hz), 5.83 (1H, s), 5.37 (1H, t, J = 5.7 Hz), 4.62 (2H, d, J = 5.6 Hz), 4.18-4.15 (2H, m), 4.02-3.99 (2H, m). 3- (5- (1,3-Dioxolan-2-yl) -3H-imidazo [4,5-b] pyridin-3-yl) benzyl acetate (577 mg, 1.70 mmol) was added to methanol (9 (mL) and cooled to 0 ° C. Sodium methoxide methanol solution (340 mL, 1.70 mmol) was added thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 1 hour. Saturated saline was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was dried under vacuum to obtain the title compound (486 mg, 96%). Clear oil: 1 H-NMR (DMSO-D 6 ) δ: 8.91 (1H, s), 8.25 (1H, d, J = 8.3 Hz), 7.88 (1H, s), 7.80-7.78 (1H, m), 7.58 (2H, t, J = 7.8 Hz), 7.54 (2H, d, J = 8.3 Hz), 7.43 (1H, d, J = 7.6 Hz), 5.83 (1H, s), 5.37 (1H, t, J = 5.7 Hz), 4.62 (2H, d, J = 5.6 Hz), 4.18-4.15 (2H, m), 4.02-3.99 (2H, m).

工程５
3-(5-(1,3-ジオキソラン-2-イル)-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンズアルデヒド Process 5
3- (5- (1,3-Dioxolan-2-yl) -3H-imidazo [4,5-b] pyridin-3-yl) benzaldehyde

Figure JPOXMLDOC01-appb-C000342
Figure JPOXMLDOC01-appb-C000342

アルゴン雰囲気下、(3-(5-(1,3-ジオキソラン-2-イル)-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)メタノール (486 mg, 1.63 mmol) を塩化メチレン (16 mL) に溶解した。そこへ二酸化マンガン (2.0 g) を加え、室温で22時間撹拌した。反応液をセライトでろ過し、ろ液を濃縮, 真空乾燥して標記化合物 (426 mg, 89%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 10.1 (1H, s), 9.07 (1H, s), 8.55 (1H, t, J = 2.0 Hz), 8.35-8.32 (1H, m), 8.28 (1H, d, J= 8.3 Hz), 8.02 (1H, d, J = 7.6 Hz), 7.88 (1H, t, J = 7.8 Hz), 7.57 (1H, d, J = 8.3 Hz), 5.86 (1H, s), 4.19-4.16 (2H, m), 4.04-4.00 (2H, m). (3- (5- (1,3-Dioxolan-2-yl) -3H-imidazo [4,5-b] pyridin-3-yl) phenyl) methanol (486 mg, 1.63 mmol) was chlorinated under an argon atmosphere. Methylene   Dissolved in (16 mL). Manganese dioxide (2.0 g) was added thereto, and the mixture was stirred at room temperature for 22 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated and dried under vacuum to obtain the title compound (426 mg, 89%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, s), 9.07 (1H, s), 8.55 (1H, t, J = 2.0 Hz), 8.35-8.32 (1H, m), 8.28 (1H, d, J = 8.3 Hz), 8.02 (1H, d, J = 7.6 Hz), 7.88 (1H, t, J = 7.8 Hz), 7.57 (1H, d, J = 8.3 Hz), 5.86 ( 1H, s), 4.19-4.16 (2H, m), 4.04-4.00 (2H, m).

工程６
5-(1,3-ジオキソラン-2-イル)-3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン  Step 6
5- (1,3-Dioxolan-2-yl) -3- (3-((4-ethylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000343
Figure JPOXMLDOC01-appb-C000343

6-ブロモ-3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジンの合成 (実施例57、工程1) と同様の手法で、3-(5-(1,3-ジオキソラン-2-イル)-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンズアルデヒド (186 mg, 0.630 mmol) および1-エチルピペラジン (128 μL, 1.26 mmol) から標記化合物 (192 mg, 78%) を得た。透明オイル: 1H-NMR (DMSO-D6) δ: 8.93 (1H, s), 8.25 (1H, d, J = 8.3 Hz), 7.90 (1H, s), 7.81-7.78 (1H, m), 7.56 (1H, t, J = 7.8 Hz), 7.54 (1H, d, J= 8.3 Hz), 7.39 (1H, d, J = 7.8 Hz), 5.83 (1H, s), 4.18-4.15 (2H, m), 4.02-3.99 (2H, m), 3.58 (2H, s), 2.50-2.33 (8H, m), 2.30 (2H, q, J= 7.2 Hz), 0.97 (3H, t, J = 7.1 Hz). Synthesis of 6-bromo-3- (3-((4-ethylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine (Example 57, Step 1) -(5- (1,3-Dioxolan-2-yl) -3H-imidazo [4,5-b] pyridin-3-yl) benzaldehyde (186 mg, 0.630 mmol) and 1-ethylpiperazine (128 μL, 1.26 mmol) gave the title compound (192 mg, 78%). Clear oil: 1 H-NMR (DMSO-D 6 ) δ: 8.93 (1H, s), 8.25 (1H, d, J = 8.3 Hz), 7.90 (1H, s), 7.81-7.78 (1H, m), 7.56 (1H, t, J = 7.8 Hz), 7.54 (1H, d, J = 8.3 Hz), 7.39 (1H, d, J = 7.8 Hz), 5.83 (1H, s), 4.18-4.15 (2H, m ), 4.02-3.99 (2H, m), 3.58 (2H, s), 2.50-2.33 (8H, m), 2.30 (2H, q, J = 7.2 Hz), 0.97 (3H, t, J = 7.1 Hz) .

工程７
3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド  Step 7
3- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000344
Figure JPOXMLDOC01-appb-C000344

アルゴン雰囲気下、5-(1,3-ジオキソラン-2-イル)-3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン(192 mg, 0.488 mmol) をテトラヒドロフラン (1.6 mL)、水 (813 μL) に溶解した。そこへ6規定塩酸 (813 μL, 4.88 mmol) を加え、50℃で3時間撹拌した。反応液を冷却し、酢酸エチルを加え、1規定水酸化ナトリウム溶液、飽和食塩水で洗浄した。酢酸エチル層無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (133 mg, 78%) を得た。薄黄色オイル: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.7 Hz), 9.16 (1H, s), 8.42 (1H, dd, J = 8.2, 0.6 Hz), 8.00 (1H, d, J = 8.1 Hz), 7.91 (1H, s), 7.86-7.83 (1H, m), 7.60 (1H, t, J= 7.8 Hz), 7.45 (1H, d, J = 7.8 Hz), 3.60 (2H, s), 2.50-2.30 (8H, m), 2.30 (2H, q, J = 7.1 Hz), 0.97 (3H, t, J= 7.1 Hz). 5- (1,3-Dioxolan-2-yl) -3- (3-((4-ethylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridine under argon atmosphere (192 mg, 0.488 mmol) was dissolved in tetrahydrofuran (1.6 mL) and water (813 μL). 6N hydrochloric acid (813 μL, 4.88 mmol) was added thereto, and the mixture was stirred at 50 ° C. for 3 hours. The reaction mixture was cooled, ethyl acetate was added, and the mixture was washed with 1N sodium hydroxide solution and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (133 mg, 78%). Light yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.7 Hz), 9.16 (1H, s), 8.42 (1H, dd, J = 8.2, 0.6 Hz), 8.00 (1H, d, J = 8.1 Hz), 7.91 (1H, s), 7.86-7.83 (1H, m), 7.60 (1H, t, J = 7.8 Hz), 7.45 (1H, d, J = 7.8 Hz) , 3.60 (2H, s), 2.50-2.30 (8H, m), 2.30 (2H, q, J = 7.1 Hz), 0.97 (3H, t, J = 7.1 Hz).

工程８
5-((3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物９１)  Process 8
5-((3- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thioxothiazolidine- 4-one (compound 91)

Figure JPOXMLDOC01-appb-C000345
Figure JPOXMLDOC01-appb-C000345

5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド (47 mg, 0.135 mmol) およびロダニン (18 mg, 0.135 mmol) から標記化合物 (21 mg, 33%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 9.03 (1H, s), 8.31-8.29 (1H, m), 8.26 (1H, d, J = 8.3 Hz), 7.85-7.82 (1H, m), 7.80 (1H, d, J = 8.3 Hz), 7.60 (1H, t, J = 7.8 Hz), 7.52-7.46 (2H, m), 3.91 (2H, s), 3.09-2.98 (4H, m), 2.96-2.89 (2H, m), 2.79-2.58 (4H, m), 1.13 (3H, t, J = 7.2 Hz). 
ESI-MS(m/z): 465[M+H]+. Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (3-((4-ethylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde (47 mg, 0.135 mmol) and rhodanine ( The title compound (21 mg, 33%) was obtained from 18 mg, 0.135 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 9.03 (1H, s), 8.31-8.29 (1H, m), 8.26 (1H, d, J = 8.3 Hz), 7.85-7.82 (1H, m ), 7.80 (1H, d, J = 8.3 Hz), 7.60 (1H, t, J = 7.8 Hz), 7.52-7.46 (2H, m), 3.91 (2H, s), 3.09-2.98 (4H, m) , 2.96-2.89 (2H, m), 2.79-2.58 (4H, m), 1.13 (3H, t, J = 7.2 Hz).
ESI-MS (m / z): 465 [M + H] + .

実施例９２
5-((3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物９２)  Example 92
5-((3- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 92)

Figure JPOXMLDOC01-appb-C000346
Figure JPOXMLDOC01-appb-C000346

工程１
5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド (133 mg, 0.381 mmol) およびチアゾリジン-2,4-ジオン (45 mg, 0.381 mmol) から標記化合物 (106 mg, 62%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 9.01 (1H, s), 8.29 (1H, d, J = 8.3 Hz), 8.09 (1H, s), 7.84-7.81 (3H, m), 7.59 (1H, t, J = 7.8 Hz), 7.46 (1H, d, J = 7.6 Hz), 3.67 (2H, s), 2.64-2.46 (11H, m), 1.02 (3H, t, J = 7.2 Hz). 
ESI-MS(m/z): 449[M+H]+. Process 1
Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (3-((4-ethylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde (133 mg, 0.381 mmol) and thiazolidine- The title compound (106 mg, 62%) was obtained from 2,4-dione (45 mg, 0.381 mmol). White solid: 1 H-NMR (DMSO-D 6 ) δ: 9.01 (1H, s), 8.29 (1H, d, J = 8.3 Hz), 8.09 (1H, s), 7.84-7.81 (3H, m), 7.59 (1H, t, J = 7.8 Hz), 7.46 (1H, d, J = 7.6 Hz), 3.67 (2H, s), 2.64-2.46 (11H, m), 1.02 (3H, t, J = 7.2 Hz ).
ESI-MS (m / z): 449 [M + H] + .

実施例９３
5-((3-(3-((4-ブチルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物９３)  Example 93
5-((3- (3-((4-Butylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thioxothiazolidine- 4-one (compound 93)

工程１
3-(3-((4-ブチルピペラジン-1-イル)メチル)フェニル)-5-(1,3-ジオキソラン-2-イル)-3H-イミダゾ[4,5-b]ピリジン Process 1
3- (3-((4-Butylpiperazin-1-yl) methyl) phenyl) -5- (1,3-dioxolan-2-yl) -3H-imidazo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000347
Figure JPOXMLDOC01-appb-C000347

6-ブロモ-3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジンの合成 (実施例57、工程1) と同様の手法で、3-(5-(1,3-ジオキソラン-2-イル)-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンズアルデヒド (167 mg, 0.566 mmol) および1-ブチルピペラジン (161 mg, 1.13 mmol) から標記化合物 (210 mg, 88%) を得た。透明オイル: 1H-NMR (DMSO-D6) δ: 8.93 (1H, s), 8.25 (1H, d, J = 8.3 Hz), 7.90 (1H, s), 7.81-7.78 (1H, m), 7.56 (1H, t, J = 7.8 Hz), 7.54 (1H, d, J= 8.3 Hz), 7.39 (1H, d, J = 7.6 Hz), 5.83 (1H, s), 4.19-4.15 (2H, m), 4.02-3.99 (2H, m), 3.58 (2H, s), 2.50-2.33 (8H, m), 2.24 (3H, t, J= 7.3 Hz), 1.42-1.35 (2H, m), 1.31-1.22 (2H, m), 0.87 (3H, t, J = 7.2 Hz). Synthesis of 6-bromo-3- (3-((4-ethylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine (Example 57, Step 1) -(5- (1,3-Dioxolan-2-yl) -3H-imidazo [4,5-b] pyridin-3-yl) benzaldehyde (167 mg, 0.566 mmol) and 1-butylpiperazine (161 mg, 1.13 mmol) gave the title compound (210 mg, 88%). Clear oil: 1 H-NMR (DMSO-D 6 ) δ: 8.93 (1H, s), 8.25 (1H, d, J = 8.3 Hz), 7.90 (1H, s), 7.81-7.78 (1H, m), 7.56 (1H, t, J = 7.8 Hz), 7.54 (1H, d, J = 8.3 Hz), 7.39 (1H, d, J = 7.6 Hz), 5.83 (1H, s), 4.19-4.15 (2H, m ), 4.02-3.99 (2H, m), 3.58 (2H, s), 2.50-2.33 (8H, m), 2.24 (3H, t, J = 7.3 Hz), 1.42-1.35 (2H, m), 1.31- 1.22 (2H, m), 0.87 (3H, t, J = 7.2 Hz).

工程２
3-(3-((4-ブチルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド Process 2
3- (3-((4-Butylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000348
Figure JPOXMLDOC01-appb-C000348

3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒドの合成 (実施例91、工程7) と同様の手法で、3-(3-((4-ブチルピペラジン-1-イル)メチル)フェニル)-5-(1,3-ジオキソラン-2-イル)-3H-イミダゾ[4,5-b]ピリジン (210 mg, 0.498 mmol)から標記化合物 (177 mg, 94%)を得た。白色固体: 1H-NMR (DMSO-D6) δ: 10.0 (1H, s), 9.16 (1H, s), 8.42 (1H, d, J= 8.3 Hz), 8.00 (1H, d, J = 8.1 Hz), 7.91 (1H, s), 7.86-7.83 (1H, m), 7.60 (1H, t, J = 7.8 Hz), 7.44 (1H, d, J= 7.6 Hz), 3.60 (2H, s), 2.50-2.33 (8H, m), 2.24 (2H, t, J = 7.3 Hz), 1.42-1.34 (2H, m), 1.31-1.22 (2H, m), 0.86 (3H, t, J= 7.3 Hz). Synthesis of 3- (3-((4-ethylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde (similar to Example 91, Step 7) 3- (3-((4-Butylpiperazin-1-yl) methyl) phenyl) -5- (1,3-dioxolan-2-yl) -3H-imidazo [4,5-b] pyridine ( The title compound (177 mg, 94%) was obtained from 210 mg, 0.498 mmol). White solid: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, s), 9.16 (1H, s), 8.42 (1H, d, J = 8.3 Hz), 8.00 (1H, d, J = 8.1 Hz), 7.91 (1H, s), 7.86-7.83 (1H, m), 7.60 (1H, t, J = 7.8 Hz), 7.44 (1H, d, J = 7.6 Hz), 3.60 (2H, s), 2.50-2.33 (8H, m), 2.24 (2H, t, J = 7.3 Hz), 1.42-1.34 (2H, m), 1.31-1.22 (2H, m), 0.86 (3H, t, J = 7.3 Hz) .

工程３
5-((3-(3-((4-ブチルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物９３) Process 3
5-((3- (3-((4-Butylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thioxothiazolidine- 4-one (compound 93)

Figure JPOXMLDOC01-appb-C000349
Figure JPOXMLDOC01-appb-C000349

5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-((4-ブチルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド (73 mg, 0.193 mmol) およびロダニン (26 mg, 0.193 mmol) から標記化合物 (15 mg, 16％) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 9.03 (1H, s), 8.28-8.26 (2H, m), 7.84-7.81 (2H, m), 7.62-7.56 (2H, m), 7.48 (1H, d, J = 7.6 Hz), 3.89 (2H, s), 2.99-2.67 (11H, m), 1.55-1.49 (2H, m), 1.32-1.23 (2H, m), 0.88 (3H, t, J= 7.3 Hz).
ESI-MS(m/z): 493[M+H]+. Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (3-((4-butylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde (73 mg, 0.193 mmol) and rhodanine ( The title compound (15 mg, 16%) was obtained from 26 mg, 0.193 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 9.03 (1H, s), 8.28-8.26 (2H, m), 7.84-7.81 (2H, m), 7.62-7.56 (2H, m), 7.48 (1H, d, J = 7.6 Hz), 3.89 (2H, s), 2.99-2.67 (11H, m), 1.55-1.49 (2H, m), 1.32-1.23 (2H, m), 0.88 (3H, t , J = 7.3 Hz).
ESI-MS (m / z): 493 [M + H] + .

実施例９４
5-((3-(3-((4-ブチルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物９４)  Example 94
5-((3- (3-((4-Butylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 94)

Figure JPOXMLDOC01-appb-C000350
Figure JPOXMLDOC01-appb-C000350

工程１
5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-((4-ブチルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド (177 mg, 0.469 mmol) およびチアゾリジン-2,4-ジオン (55 mg, 0.469 mmol) から標記化合物 (143 mg, 64%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 9.01 (1H, s), 8.30 (1H, d, J = 8.1 Hz), 8.07 (1H, s), 7.86-7.81 (4H, m), 7.59 (1H, t, J = 7.8 Hz), 7.46 (1H, d, J = 7.3 Hz), 3.66 (2H, s), 2.55-2.33 (11H, m), 1.45-1.38 (2H, m), 1.31-1.22 (2H, m), 0.86 (3H, t, J = 7.3 Hz). 
ESI-MS(m/z): 477[M+H]+. Process 1
Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (3-((4-butylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde (177 mg, 0.469 mmol) and thiazolidine- The title compound (143 mg, 64%) was obtained from 2,4-dione (55 mg, 0.469 mmol). White solid: 1 H-NMR (DMSO-D 6 ) δ: 9.01 (1H, s), 8.30 (1H, d, J = 8.1 Hz), 8.07 (1H, s), 7.86-7.81 (4H, m), 7.59 (1H, t, J = 7.8 Hz), 7.46 (1H, d, J = 7.3 Hz), 3.66 (2H, s), 2.55-2.33 (11H, m), 1.45-1.38 (2H, m), 1.31 -1.22 (2H, m), 0.86 (3H, t, J = 7.3 Hz).
ESI-MS (m / z): 477 [M + H] + .

実施例９５
5-((3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物９５)  Example 95
5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thioxothiazolidine -4-one (compound 95)

工程１
tert-ブチル 4-(2-フルオロ-4-ニトロフェニル)ピペラジン-1-カルボキシレート Process 1
tert-butyl 4- (2-fluoro-4-nitrophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000351
Figure JPOXMLDOC01-appb-C000351

アルゴン雰囲気下、3,4-ジフルオロニトロベンゼン (476 mg, 4.34 mmol) をN,N-ジメチルホルムアミド (8 mL) に溶解した。そこへ 1-(tert-ブトキシカルボニル)ピペラジン (800 mg, 4.30 mmol)、炭酸カリウム (1.78 g, 13.0 mmol) を加え、50℃で14時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。酢酸エチル層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた固体を真空乾燥して標記化合物 (1.27 g, 91%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.05-8.00 (2H, m), 7.18 (1H, t, J = 9.1 Hz), 3.49 (4H, t, J= 4.9 Hz), 3.26 (4H, t, J = 5.1 Hz), 1.42 (9H, s). Under an argon atmosphere, 3,4-difluoronitrobenzene (476 mg, 4.34 mmol) was dissolved in N, N-dimethylformamide (8 mL). 1- (tert-butoxycarbonyl) piperazine (800 mg, 4.30 mmol) and potassium carbonate (1.78 g, 13.0 mmol) were added thereto, and the mixture was stirred at 50 ° C. for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained solid was vacuum-dried to obtain the title compound (1.27 g, 91%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.05-8.00 (2H, m), 7.18 (1H, t, J = 9.1 Hz), 3.49 (4H, t, J = 4.9 Hz), 3.26 ( 4H, t, J = 5.1 Hz), 1.42 (9H, s).

工程２
tert-ブチル 4-(4-アミノ-2-フルオロフェニル)ピペラジン-1-カルボキシレート Process 2
tert-butyl 4- (4-amino-2-fluorophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000352
Figure JPOXMLDOC01-appb-C000352

tert-ブチル 4-(2-フルオロ-4-ニトロフェニル)ピペラジン-1-カルボキシレート (1.27 g, 3.92 mmol) をメタノール (16 mL)、テトラヒドロフラン (4 mL) に溶解した。そこへ10% パラジウム－活性炭 (208 mg) を加え、反応容器内を水素で置換し、室温で8時間撹拌した。反応液をセライトでろ過し、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.02 g, 92%) を得た。赤色オイル: 1H-NMR (DMSO-D6) δ: 6.77 (1H, t, J = 9.1 Hz), 6.35-6.27 (2H, m), 5.03 (2H, br.s), 3.41 (4H, br.s), 2.75 (4H, t, J = 4.9 Hz), 1.41 (9H, s). Tert-butyl 4- (2-fluoro-4-nitrophenyl) piperazine-1-carboxylate (1.27 g, 3.92 mmol) was dissolved in methanol (16 mL) and tetrahydrofuran (4 mL). Thereto was added 10% palladium-activated carbon (208 mg), the inside of the reaction vessel was replaced with hydrogen, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was filtered through celite and concentrated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.02 g, 92%). Red oil: 1 H-NMR (DMSO-D 6 ) δ: 6.77 (1H, t, J = 9.1 Hz), 6.35-6.27 (2H, m), 5.03 (2H, br.s), 3.41 (4H, br .s), 2.75 (4H, t, J = 4.9 Hz), 1.41 (9H, s).

工程３
tert-ブチル 4-(4-((6-ブロモ-3-ニトロピリジン-2-イル)アミノ)-2-フルオロフェニル)ピペラジン-1-カルボキシレート Process 3
tert-butyl 4- (4-((6-bromo-3-nitropyridin-2-yl) amino) -2-fluorophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000353
Figure JPOXMLDOC01-appb-C000353

tert-ブチル 4-(4-((6-ブロモ-3-ニトロピリジン-2-イル)アミノ)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例65、工程3) と同様の手法で、2,6-ジブロモ-3-ニトロピリジン (843 mg, 2.99 mmol) およびtert-ブチル 4-(4-アミノ-2-フルオロフェニル)ピペラジン-1-カルボキシレート (1.06 g、3.59 mmol) から標記化合物 (881 mg, 59%) を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 10.0 (1H, s), 8.40 (1H, d, J= 8.8 Hz), 7.54 (1H, dd, J = 14.3, 2.3 Hz), 7.35 (1H, dd, J= 8.7, 2.3 Hz), 7.15 (1H, d, J= 8.5 Hz), 7.07 (1H, t, J = 9.3 Hz), 3.48 (4H, s), 2.96 (4H, t, J= 5.0 Hz), 1.43 (9H, s). Synthesis of tert-butyl 4- (4-((6-bromo-3-nitropyridin-2-yl) amino) phenyl) piperazine-1-carboxylate in the same manner as in Example 65, Step 3 , 6-Dibromo-3-nitropyridine (843 mg, 2.99 mmol) and tert-butyl 4- (4-amino-2-fluorophenyl) piperazine-1-carboxylate (1.06 g, 3.59 mmol) to give the title compound (881 mg, 59%). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, s), 8.40 (1H, d, J = 8.8 Hz), 7.54 (1H, dd, J = 14.3, 2.3 Hz), 7.35 ( 1H, dd, J = 8.7, 2.3 Hz), 7.15 (1H, d, J = 8.5 Hz), 7.07 (1H, t, J = 9.3 Hz), 3.48 (4H, s), 2.96 (4H, t, J = 5.0 Hz), 1.43 (9H, s).

工程４
tert-ブチル 4-(4-((3-アミノ-6-ブロモピリジン-2-イル)アミノ)-2-フルオロフェニル)ピペラジン-1-カルボキシレート  Process 4
tert-butyl 4- (4-((3-amino-6-bromopyridin-2-yl) amino) -2-fluorophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000354
Figure JPOXMLDOC01-appb-C000354

tert-ブチル 4-(4-((3-アミノ-6-ブロモピリジン-2-イル)アミノ)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例65、工程4) と同様の手法で、tert-ブチル 4-(4-((6-ブロモ-3-ニトロピリジン-2-イル)アミノ)-2-フルオロフェニル)ピペラジン-1-カルボキシレート (881 mg, 1.78 mmol) から標記化合物 (606 mg, 73%) を得た。黒色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.04 (1H, s), 7.60 (1H, dd, J = 15.2, 2.3 Hz), 7.26 (1H, dd, J = 8.7, 2.3 Hz), 7.00 (1H, t, J = 9.4 Hz), 6.83 (1H, d, J = 7.8 Hz), 6.76 (1H, d, J = 8.1 Hz), 5.23 (2H, br.s), 3.47 (4H, s), 2.89 (4H, t, J = 4.9 Hz), 1.42 (9H, s). Synthesis of tert-butyl 4- (4-((3-amino-6-bromopyridin-2-yl) amino) phenyl) piperazine-1-carboxylate (Example 65, Step 4) -Butyl 4- (4-((6-bromo-3-nitropyridin-2-yl) amino) -2-fluorophenyl) piperazine-1-carboxylate (881 mg, 1.78 mmol) to the title compound (606 mg, 73%). Black amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.04 (1H, s), 7.60 (1H, dd, J = 15.2, 2.3 Hz), 7.26 (1H, dd, J = 8.7, 2.3 Hz ), 7.00 (1H, t, J = 9.4 Hz), 6.83 (1H, d, J = 7.8 Hz), 6.76 (1H, d, J = 8.1 Hz), 5.23 (2H, br.s), 3.47 (4H , s), 2.89 (4H, t, J = 4.9 Hz), 1.42 (9H, s).

工程５
tert-ブチル 4-(4-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)-2-フルオロフェニル)ピペラジン-1-カルボキシレート Process 5
tert-butyl 4- (4- (5-bromo-3H-imidazo [4,5-b] pyridin-3-yl) -2-fluorophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000355
Figure JPOXMLDOC01-appb-C000355

tert-ブチル 4-(4-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例65、工程5) と同様の手法で、tert-ブチル 4-(4-((3-アミノ-6-ブロモピリジン-2-イル)アミノ)-2-フルオロフェニル)ピペラジン-1-カルボキシレート (406 mg, 1.30 mmol) およびホルムアミジン酢酸塩 (1.05 g, 3.90 mmol) から標記化合物 (555 mg, 90%)を得た。紫色固体: 1H-NMR (DMSO-D6) δ: 8.86 (1H, s), 8.17 (1H, d, J= 8.3 Hz), 7.77 (1H, dd, J = 13.4, 2.4 Hz), 7.65 (1H, dd, J= 8.7, 2.6 Hz), 7.58 (1H, d, J= 8.3 Hz), 7.29 (1H, t, J = 9.1 Hz), 3.52 (4H, s), 3.05 (4H, t, J= 5.0 Hz), 1.44 (9H, s). Synthesis of tert-butyl 4- (4- (5-bromo-3H-imidazo [4,5-b] pyridin-3-yl) phenyl) piperazine-1-carboxylate (Example 65, Step 5) Procedure, tert-butyl 4- (4-((3-amino-6-bromopyridin-2-yl) amino) -2-fluorophenyl) piperazine-1-carboxylate (406 mg, 1.30 mmol) and formamidine The title compound (555 mg, 90%) was obtained from the acetate (1.05 g, 3.90 mmol). Purple solid: 1 H-NMR (DMSO-D 6 ) δ: 8.86 (1H, s), 8.17 (1H, d, J = 8.3 Hz), 7.77 (1H, dd, J = 13.4, 2.4 Hz), 7.65 ( 1H, dd, J = 8.7, 2.6 Hz), 7.58 (1H, d, J = 8.3 Hz), 7.29 (1H, t, J = 9.1 Hz), 3.52 (4H, s), 3.05 (4H, t, J = 5.0 Hz), 1.44 (9H, s).

工程６
5-ブロモ-3-(3-フルオロ-4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン  Step 6
5-Bromo-3- (3-fluoro-4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000356
Figure JPOXMLDOC01-appb-C000356

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程6) と同様の手法で、tert-ブチル 4-(4-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)-2-フルオロフェニル)ピペラジン-1-カルボキシレート (555 mg, 1.17 mmol) およびトリフルオロ酢酸 (3 mL) から標記化合物 (203 mg, 46%) を得た。褐色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.84 (1H, s), 8.17 (1H, d, J= 8.3 Hz), 7.73 (1H, dd, J = 13.5, 2.6 Hz), 7.65-7.62 (1H, m), 7.57 (1H, d, J = 8.5 Hz), 7.25 (1H, t, J= 9.1 Hz), 3.05 (4H, t, J = 4.9 Hz), 2.93 (4H, t, J = 4.9 Hz). Synthesis of 5-bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 6) -(4- (5-Bromo-3H-imidazo [4,5-b] pyridin-3-yl) -2-fluorophenyl) piperazine-1-carboxylate (555 mg, 1.17 mmol) and trifluoroacetic acid (3 The title compound (203 mg, 46%) was obtained from mL). Brown amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.84 (1H, s), 8.17 (1H, d, J = 8.3 Hz), 7.73 (1H, dd, J = 13.5, 2.6 Hz), 7.65-7.62 (1H, m), 7.57 (1H, d, J = 8.5 Hz), 7.25 (1H, t, J = 9.1 Hz), 3.05 (4H, t, J = 4.9 Hz), 2.93 (4H, t , J = 4.9 Hz).

工程７
5-ブロモ-3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン  Step 7
5-Bromo-3- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000357
Figure JPOXMLDOC01-appb-C000357

5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程7) と同様の手法で、5-ブロモ-3-(3-フルオロ-4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン (203 mg, 0.540 mmol) および37% ホルムアルデヒド水溶液 (241 μL、3.24 mmol) から標記化合物 (171 mg, 81%) を得た。白色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.85 (1H, s), 8.18 (1H, d, J = 8.5 Hz), 7.74 (1H, dd, J = 13.7, 2.4 Hz), 7.65-7.62 (1H, m), 7.58 (1H, d, J= 8.3 Hz), 7.26 (1H, t, J = 9.1 Hz), 3.10 (4H, t, J = 4.8 Hz), 2.52-2.49 (4H, m), 2.25 (3H, s). Synthesis of 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 7) -Bromo-3- (3-fluoro-4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (203 mg, 0.540 mmol) and 37% aqueous formaldehyde (241 μL, 3.24 mmol) gave the title compound (171 mg, 81%). White amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.85 (1H, s), 8.18 (1H, d, J = 8.5 Hz), 7.74 (1H, dd, J = 13.7, 2.4 Hz), 7.65-7.62 (1H, m), 7.58 (1H, d, J = 8.3 Hz), 7.26 (1H, t, J = 9.1 Hz), 3.10 (4H, t, J = 4.8 Hz), 2.52-2.49 (4H m), 2.25 (3H, s).

工程８
3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド Process 8
3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000358
Figure JPOXMLDOC01-appb-C000358

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボアルデヒドの合成 (実施例48、工程5 ) と同様の手法で、5-ブロモ-3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン (171 mg, 0.440 mmol) から標記化合物 (87 mg, 58%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 10.0 (1H, s), 8.87 (1H, s), 8.44-8.40 (1H, m), 8.21 (1H, dd, J = 8.1, 1.5 Hz), 7.89-7.84 (1H, m), 7.77-7.72 (1H, m), 7.30-7.22 (1H, m), 3.13-3.08 (4H, m), 2.53-2.48 (4H, m), 2.25 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine-6-carbaldehyde (Example 48, Step 5) -3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (171 mg, 0.440 mmol) to the title compound (87 mg, 58% ) Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, s), 8.87 (1H, s), 8.44-8.40 (1H, m), 8.21 (1H, dd, J = 8.1, 1.5 Hz ), 7.89-7.84 (1H, m), 7.77-7.72 (1H, m), 7.30-7.22 (1H, m), 3.13-3.08 (4H, m), 2.53-2.48 (4H, m), 2.25 (3H , s).

工程９
5-((3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物９５)  Step 9
5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thioxothiazolidine -4-one (compound 95)

Figure JPOXMLDOC01-appb-C000359
Figure JPOXMLDOC01-appb-C000359

5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド (40 mg, 0.118 mmol) およびロダニン (16 mg, 0.1118 mmol) から標記化合物 (20 mg, 38％) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.99 (1H, s), 8.29 (1H, d, J = 8.3 Hz), 7.99 (1H, dd, J = 13.7, 2.4 Hz), 7.86 (1H, d, J = 8.3 Hz), 7.78-7.74 (1H, m), 7.66 (1H, s), 7.32-7.26 (1H, m), 3.25 (4H, s), 2.96 (4H, s), 2.56 (3H, s).
ESI-MS(m/z): 455[M+H]+. Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde (40 mg, 0.118 mmol) and rhodanine The title compound (20 mg, 38%) was obtained from (16 mg, 0.1118 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.99 (1H, s), 8.29 (1H, d, J = 8.3 Hz), 7.99 (1H, dd, J = 13.7, 2.4 Hz), 7.86 ( 1H, d, J = 8.3 Hz), 7.78-7.74 (1H, m), 7.66 (1H, s), 7.32-7.26 (1H, m), 3.25 (4H, s), 2.96 (4H, s), 2.56 (3H, s).
ESI-MS (m / z): 455 [M + H] + .

実施例９６
5-((3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物９６)  Example 96
5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4- Dione (Compound 96)

Figure JPOXMLDOC01-appb-C000360
Figure JPOXMLDOC01-appb-C000360

工程１
5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド (39 mg, 0.115 mmol) およびチアゾリジン-2,4-ジオン (13 mg, 0.115 mmol) から標記化合物 (12 mg, 22％) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 8.98 (1H, s), 8.30 (1H, d, J = 8.3 Hz), 7.97 (1H, dd, J = 13.7, 2.4 Hz), 7.91 (1H, s), 7.85 (1H, d, J = 8.1 Hz), 7.71 (1H, dd, J = 8.8, 2.4 Hz), 7.26 (1H, t, J = 9.3 Hz), 3.15 (4H, t, J = 4.4 Hz), 2.64 (4H, s), 2.33 (3H, s). 
ESI-MS(m/z): 439[M+H]+. Process 1
Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) In the procedure, 3- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde (39 mg, 0.115 mmol) and thiazolidine The title compound (12 mg, 22%) was obtained from -2,4-dione (13 mg, 0.115 mmol). White solid: 1 H-NMR (DMSO-D 6 ) δ: 8.98 (1H, s), 8.30 (1H, d, J = 8.3 Hz), 7.97 (1H, dd, J = 13.7, 2.4 Hz), 7.91 ( 1H, s), 7.85 (1H, d, J = 8.1 Hz), 7.71 (1H, dd, J = 8.8, 2.4 Hz), 7.26 (1H, t, J = 9.3 Hz), 3.15 (4H, t, J = 4.4 Hz), 2.64 (4H, s), 2.33 (3H, s).
ESI-MS (m / z): 439 [M + H] + .

実施例９７
5-((3-(3-((1-メチルピペリジン-4-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物９７)  Example 97
5-((3- (3-((1-methylpiperidin-4-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 97)

工程１
ジエチル 3-ニトロベンジルホスホネート Process 1
Diethyl 3-nitrobenzylphosphonate

Figure JPOXMLDOC01-appb-C000361
Figure JPOXMLDOC01-appb-C000361

アルゴン雰囲気下、3-ニトロベンジル ブロミド (2.0 g, 9.26 mmol) をトルエン (20 mL) に溶解した。そこへ亜りん酸トリエチル (1.60 mL, 9.26 mmol) を加え、24時間加熱還流した。反応液を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (2.05 g, 81%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.19-8.17 (1H, m), 8.14-8.10 (1H, m), 7.76-7.73 (1H, m), 7.63 (1H, t, J = 7.9 Hz), 4.04-3.94 (4H, m), 3.50 (1H, s), 3.44 (1H, s), 1.17 (6H, t, J = 7.1 Hz). 3-nitrobenzyl bromide (2.0 g, 9.26 mmol) was dissolved in toluene (20 mL) under an argon atmosphere. The triethyl phosphite (1.60 mL, 9.26 mmol) was added there, and it heated and refluxed for 24 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (2.05 g, 81%). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.19-8.17 (1H, m), 8.14-8.10 (1H, m), 7.76-7.73 (1H, m), 7.63 (1H, t, J = 7.9 Hz), 4.04-3.94 (4H, m), 3.50 (1H, s), 3.44 (1H, s), 1.17 (6H, t, J = 7.1 Hz).

工程２
tert-ブチル 4-(3-ニトロベンジリデン)ピペリジン-1-カルボキシレート  Process 2
tert-butyl 4- (3-nitrobenzylidene) piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000362
Figure JPOXMLDOC01-appb-C000362

アルゴン雰囲気下、ジエチル 3-ニトロベンジルホスホネート (2.05 g, 7.51 mmol) をテトラヒドロフラン (30 mL) に溶解し、0℃に冷却した。そこへ1-(tert-ブトキシカルボニル)-4-ピペリドン (1.50 g, 7.51 mmol) を加えた。さらに水素化ナトリウム (60%, 330 mg, 8.26 mmol) を加え、0℃で10分撹拌後、室温で4時間撹拌した。反応液に飽和塩化ナトリウム水溶液を加え、酢酸エチルで抽出した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.85 g, 78%) を得た。薄黄色オイル: 1H-NMR (DMSO-D6) δ: 8.10-8.07 (1H, m), 8.02-8.01 (1H, m), 7.69 (1H, d, J = 7.8 Hz), 7.64 (1H, t, J = 7.9 Hz), 6.50 (1H, s), 3.44 (2H, t, J = 5.7 Hz), 3.36 (2H, t, J = 5.9 Hz), 2.41 (2H, t, J = 5.5 Hz), 2.33 (2H, t, J = 5.5 Hz), 1.42 (9H, s). Under an argon atmosphere, diethyl 3-nitrobenzylphosphonate (2.05 g, 7.51 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to 0 ° C. 1- (tert-butoxycarbonyl) -4-piperidone (1.50 g, 7.51 mmol) was added thereto. Further, sodium hydride (60%, 330 mg, 8.26 mmol) was added, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 4 hours. A saturated aqueous sodium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.85 g, 78%). Pale yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.10-8.07 (1H, m), 8.02-8.01 (1H, m), 7.69 (1H, d, J = 7.8 Hz), 7.64 (1H, t, J = 7.9 Hz), 6.50 (1H, s), 3.44 (2H, t, J = 5.7 Hz), 3.36 (2H, t, J = 5.9 Hz), 2.41 (2H, t, J = 5.5 Hz) , 2.33 (2H, t, J = 5.5 Hz), 1.42 (9H, s).

工程３
tert-ブチル 4-(3-アミノベンジル)ピペリジン-1-カルボキシレート Process 3
tert-Butyl 4- (3-aminobenzyl) piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000363
Figure JPOXMLDOC01-appb-C000363

tert-ブチル 4-(3-ニトロベンジリデン)ピペリジン-1-カルボキシレート (1.85 g, 5.82 mmol) をエタノール (20 mL) に溶解した。そこへ10% パラジウム－活性炭 (185 mg) をエタノール (5 mL) に懸濁して加えた。反応容器内を水素で置換し、室温で15時間撹拌した。反応液をセライトでろ過,、濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.44 g, 85%) を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 6.89 (1H, t, J = 7.6 Hz), 6.38-6.34 (2H, m), 6.29 (1H, d, J = 7.3 Hz), 4.91 (2H, s), 3.89 (2H, d, J = 12.0 Hz), 2.67-2.58 (2H, m), 2.32 (2H, d, J = 6.8 Hz), 1.62-1.52 (1H, m), 1.54 (2H, d, J = 12.9 Hz), 1.38 (9H, s), 1.03-0.93 (2H, m). tert-Butyl 4- (3-nitrobenzylidene) piperidine-1-carboxylate (1.85 g, 5.82 mmol) was dissolved in ethanol (20 mL). 10% palladium-activated carbon (185 mg) was suspended in ethanol (5 mL) and added thereto. The inside of the reaction vessel was replaced with hydrogen, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was filtered through celite and concentrated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.44 g, 85%). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 6.89 (1H, t, J = 7.6 Hz), 6.38-6.34 (2H, m), 6.29 (1H, d, J = 7.3 Hz), 4.91 ( 2H, s), 3.89 (2H, d, J = 12.0 Hz), 2.67-2.58 (2H, m), 2.32 (2H, d, J = 6.8 Hz), 1.62-1.52 (1H, m), 1.54 (2H , d, J = 12.9 Hz), 1.38 (9H, s), 1.03-0.93 (2H, m).

工程４
tert-ブチル 4-(3-((6-ブロモ-3-ニトロピリジン-2-イル)アミノ)ベンジル)ピペリジン-1-カルボキシレート Process 4
tert-butyl 4- (3-((6-bromo-3-nitropyridin-2-yl) amino) benzyl) piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000364
Figure JPOXMLDOC01-appb-C000364

アルゴン雰囲気下、 2,6-ジブロモ-3-ニトロピリジン(1.17 g, 4.14 mmol) をエタノール (20 mL) に溶解した。そこへtert-ブチル 4-(3-アミノベンジル)ピペリジン-1-カルボキシレート (1.44 g, 4.97 mmol)、トリエチルアミン (1.13 mL, 8.28 mmol) を加え、室温で20時間撹拌した。反応液を濃縮し、酢酸エチルに再溶解して1規定塩酸、水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.42 g, 70%) を得た。橙色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 10.1 (1H, s), 8.40 (1H, d, J = 8.5 Hz), 7.42-7.40 (2H, m), 7.32-7.28 (1H, m), 7.14 (1H, d, J = 8.5 Hz), 7.00 (1H, d, J = 7.6 Hz), 3.93 (2H, d, J = 11.7 Hz), 2.70-2.60 (2H, m), 2.52 (2H, d, J = 6.3 Hz), 1.73-1.66 (1H, m), 1.61 (2H, d, J = 12.4 Hz), 1.38 (9H, s), 1.11-1.00 (2H, m). Under an argon atmosphere, 2,6-dibromo-3-nitropyridine (1.17 g, 4.14 mmol) was dissolved in ethanol (20 mL). Thereto were added tert-butyl 4- (3-aminobenzyl) piperidine-1-carboxylate (1.44 g, 4.97 mmol) and triethylamine (1.13 mL, 8.28 mmol), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated, redissolved in ethyl acetate, and washed with 1N hydrochloric acid, water, and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.42 g, 70%). Orange amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, s), 8.40 (1H, d, J = 8.5 Hz), 7.42-7.40 (2H, m), 7.32-7.28 (1H , m), 7.14 (1H, d, J = 8.5 Hz), 7.00 (1H, d, J = 7.6 Hz), 3.93 (2H, d, J = 11.7 Hz), 2.70-2.60 (2H, m), 2.52 (2H, d, J = 6.3 Hz), 1.73-1.66 (1H, m), 1.61 (2H, d, J = 12.4 Hz), 1.38 (9H, s), 1.11-1.00 (2H, m).

工程５
tert-ブチル 4-(3-((3-アミノ-6-ブロモピリジン-2-イル)アミノ)ベンジル)ピペリジン-1-カルボキシレート Process 5
tert-butyl 4- (3-((3-amino-6-bromopyridin-2-yl) amino) benzyl) piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000365
Figure JPOXMLDOC01-appb-C000365

tert-ブチル 4-(4-((3-アミノ-6-ブロモピリジン-2-イル)アミノ)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例65、工程4) と同様の手法で、tert-ブチル 4-(3-((6-ブロモ-3-ニトロピリジン-2-イル)アミノ)ベンジル)ピペリジン-1-カルボキシレート (1.42 g, 2.90 mmol) から標記化合物 (1.17 g, 88%) を得た。褐色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 7.91 (1H, s), 7.40-7.38 (2H, m), 7.17 (1H, dd, J = 8.8, 7.6 Hz), 6.83 (1H, d, J = 7.8 Hz), 6.75 (2H, d, J = 7.8 Hz), 6.72 (2H, d, J = 7.6 Hz), 5.22 (2H, s), 3.93 (2H, d, J = 13.2 Hz), 2.70-2.60 (2H, m), 2.46 (2H, d, J= 6.8 Hz), 1.70-1.63 (1H, m), 1.62 (2H, d, J = 13.2 Hz), 1.38 (9H, s), 1.10-1.01 (2H, m). Synthesis of tert-butyl 4- (4-((3-amino-6-bromopyridin-2-yl) amino) phenyl) piperazine-1-carboxylate (Example 65, Step 4) The title compound (1.17 g, 88%) was obtained from 4-butyl 4- (3-((6-bromo-3-nitropyridin-2-yl) amino) benzyl) piperidine-1-carboxylate (1.42 g, 2.90 mmol). Obtained. Brown amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 7.91 (1H, s), 7.40-7.38 (2H, m), 7.17 (1H, dd, J = 8.8, 7.6 Hz), 6.83 (1H , d, J = 7.8 Hz), 6.75 (2H, d, J = 7.8 Hz), 6.72 (2H, d, J = 7.6 Hz), 5.22 (2H, s), 3.93 (2H, d, J = 13.2 Hz ), 2.70-2.60 (2H, m), 2.46 (2H, d, J = 6.8 Hz), 1.70-1.63 (1H, m), 1.62 (2H, d, J = 13.2 Hz), 1.38 (9H, s) , 1.10-1.01 (2H, m).

工程６
tert-ブチル 4-(3-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンジル)ピペリジン-1-カルボキシレート Step 6
tert-butyl 4- (3- (5-bromo-3H-imidazo [4,5-b] pyridin-3-yl) benzyl) piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000366
Figure JPOXMLDOC01-appb-C000366

tert-ブチル 4-(4-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例65、工程5) と同様の手法で、tert-ブチル 4-(3-((3-アミノ-6-ブロモピリジン-2-イル)アミノ)ベンジル)ピペリジン-1-カルボキシレート (1.17 g、2.54 mmol) およびホルムアミジン酢酸塩 (793 mg, 7.62 mmol) から標記化合物 (1.21 g、quant) を得た。ピンク色固体:1H-NMR (DMSO-D6) δ: 8.89 (1H, s), 8.18 (1H, d, J = 8.3 Hz), 7.70-7.66 (2H, m), 7.58 (1H, d, J = 8.3 Hz), 7.54 (1H, t, J = 7.7 Hz), 7.31 (1H, d, J = 7.6 Hz), 3.93 (2H, d, J = 12.7 Hz), 2.70-2.63 (2H, m), 2.63 (2H, d, J = 7.1 Hz), 1.80-1.71 (1H, m), 1.63 (2H, d, J = 11.5 Hz), 1.38 (9H, s), 1.14-1.04 (2H, m). Synthesis of tert-butyl 4- (4- (5-bromo-3H-imidazo [4,5-b] pyridin-3-yl) phenyl) piperazine-1-carboxylate (Example 65, Step 5) In the procedure, tert-butyl 4- (3-((3-amino-6-bromopyridin-2-yl) amino) benzyl) piperidine-1-carboxylate (1.17 g, 2.54 mmol) and formamidine acetate (793 mg, 7.62 mmol) gave the title compound (1.21 g, quant). Pink solid: 1 H-NMR (DMSO-D 6 ) δ: 8.89 (1H, s), 8.18 (1H, d, J = 8.3 Hz), 7.70-7.66 (2H, m), 7.58 (1H, d, J = 8.3 Hz), 7.54 (1H, t, J = 7.7 Hz), 7.31 (1H, d, J = 7.6 Hz), 3.93 (2H, d, J = 12.7 Hz), 2.70-2.63 (2H, m) , 2.63 (2H, d, J = 7.1 Hz), 1.80-1.71 (1H, m), 1.63 (2H, d, J = 11.5 Hz), 1.38 (9H, s), 1.14-1.04 (2H, m).

工程７
tert-ブチル 4-(3-(5-ビニル-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンジル)ピペリジン-1-カルボキシレート Step 7
tert-butyl 4- (3- (5-vinyl-3H-imidazo [4,5-b] pyridin-3-yl) benzyl) piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000367
Figure JPOXMLDOC01-appb-C000367

3-(4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例63、工程2) と同様の手法で、tert-ブチル 4-(3-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンジル)ピペリジン-1-カルボキシレート (1.21 g、2.54 mmol) およびトリブチリビニルスズ (813 μL、2.79 mmol) から標記化合物 (894 mg, 84%) を得た。褐色固体: 1H-NMR (DMSO-D6) δ: 8.88 (1H, s), 8.17 (1H, d, J = 8.3 Hz), 7.82 (1H, s), 7.80-7.76 (1H, m), 7.54-7.51 (2H, m), 7.28 (1H, d, J= 7.6 Hz), 6.93 (1H, dd, J = 17.3, 10.7 Hz), 6.25 (1H, dd, J= 17.3, 1.5 Hz), 5.47 (1H, dd, J= 10.7, 1.5 Hz), 3.94 (2H, d, J= 11.5 Hz), 2.72-2.61 (2H, m), 2.64 (2H, d, J = 7.1 Hz), 1.81-1.72 (1H, m), 1.64 (2H, d, J = 13.4 Hz), 1.38 (9H, s), 1.16-1.05 (2H, m). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 63, Step 2) -(3- (5-Bromo-3H-imidazo [4,5-b] pyridin-3-yl) benzyl) piperidine-1-carboxylate (1.21 g, 2.54 mmol) and tributyvinyltin (813 μL, 2.79 mmol) gave the title compound (894 mg, 84%). Brown solid: 1 H-NMR (DMSO-D 6 ) δ: 8.88 (1H, s), 8.17 (1H, d, J = 8.3 Hz), 7.82 (1H, s), 7.80-7.76 (1H, m), 7.54-7.51 (2H, m), 7.28 (1H, d, J = 7.6 Hz), 6.93 (1H, dd, J = 17.3, 10.7 Hz), 6.25 (1H, dd, J = 17.3, 1.5 Hz), 5.47 (1H, dd, J = 10.7, 1.5 Hz), 3.94 (2H, d, J = 11.5 Hz), 2.72-2.61 (2H, m), 2.64 (2H, d, J = 7.1 Hz), 1.81-1.72 ( 1H, m), 1.64 (2H, d, J = 13.4 Hz), 1.38 (9H, s), 1.16-1.05 (2H, m).

工程８
tert-ブチル 4-(3-(5-ホルミル-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンジル)ピペリジン-1-カルボキシレート Process 8
tert-Butyl 4- (3- (5-formyl-3H-imidazo [4,5-b] pyridin-3-yl) benzyl) piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000368
Figure JPOXMLDOC01-appb-C000368

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、tert-ブチル 4-(3-(5-ビニル-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンジル)ピペリジン-1-カルボキシレート (894 mg, 2.14 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (536 μL、42.8 μmol) から標記化合物 (671 mg, 75%) を得た。白色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 10.0 (1H, s), 9.16 (1H, s), 8.42 (1H, d, J = 8.3 Hz), 8.00 (1H, d, J= 8.3 Hz), 7.83-7.79 (2H, m), 7.56 (1H, t, J = 7.7 Hz), 7.33 (1H, d, J= 7.6 Hz), 3.93 (2H, d, J = 12.4 Hz), 2.73-2.60 (2H, m), 2.65 (2H, d, J = 7.1 Hz), 1.82-1.73 (1H, m), 1.63 (2H, d, J = 11.7 Hz), 1.38 (9H, s), 1.15-1.05 (2H, m). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 4- (3- (5-Vinyl-3H-imidazo [4,5-b] pyridin-3-yl) benzyl) piperidine-1-carboxylate (894 mg, 2.14 mmol) and 2.5 wt% osmium tetroxide tert- The title compound (671 mg, 75%) was obtained from a butanol solution (536 μL, 42.8 μmol). White amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, s), 9.16 (1H, s), 8.42 (1H, d, J = 8.3 Hz), 8.00 (1H, d, J = 8.3 Hz), 7.83-7.79 (2H, m), 7.56 (1H, t, J = 7.7 Hz), 7.33 (1H, d, J = 7.6 Hz), 3.93 (2H, d, J = 12.4 Hz), 2.73-2.60 (2H, m), 2.65 (2H, d, J = 7.1 Hz), 1.82-1.73 (1H, m), 1.63 (2H, d, J = 11.7 Hz), 1.38 (9H, s), 1.15 -1.05 (2H, m).

工程９
tert-ブチル 4-(3-(5-(1,3-ジオキサン-2-イル)-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンジル)ピペリジン-1-カルボキシレート Step 9
tert-butyl 4- (3- (5- (1,3-dioxan-2-yl) -3H-imidazo [4,5-b] pyridin-3-yl) benzyl) piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000369
Figure JPOXMLDOC01-appb-C000369

アルゴン雰囲気下、 tert-ブチル 4-(3-(5-ホルミル-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンジル)ピペリジン-1-カルボキシレート (693 mg, 1.65 mmol) をトルエン (40 mL) に溶解した。そこへ1,3-プロパンジオール (119 μL, 1.65 mmol)、10-カンファースルホン酸 (38 mg, 0.165 mmol) を加え、ディーン・スターク装置を用いて3時間加熱還流した。反応液に飽和重層水を加え、酢酸エチルで抽出した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (242 mg, 31%) を得た。白色アモルファス状物質:1H-NMR (DMSO-D6) δ: 8.89 (1H, s), 8.22 (1H, d, J= 8.3 Hz), 7.75-7.71 (2H, m), 7.54 (2H, d, J = 8.1 Hz), 7.29 (1H, d, J= 7.8 Hz), 5.57 (1H, s), 4.16 (2H, dd, J= 11.2, 4.6 Hz), 4.01-3.94 (2H, m), 3.98-3.91 (2H, m), 2.72-2.62 (2H, m), 2.64 (2H, d, J = 7.1 Hz), 2.12-1.99 (1H, m), 1.80-1.72 (1H, m), 1.64 (2H, d, J= 12.2 Hz), 1.47 (1H, d, J = 13.7 Hz), 1.38 (9H, s), 1.15-1.05 (2H, m). Under argon atmosphere, tert-butyl 4- (3- (5-formyl-3H-imidazo [4,5-b] pyridin-3-yl) benzyl) piperidine-1-carboxylate (693 mg, 1.65 mmol) in toluene (40 mL). 1,3-propanediol (119 μL, 1.65 mmol) and 10-camphorsulfonic acid (38 mg, 0.165 mmol) were added thereto, and the mixture was heated to reflux for 3 hours using a Dean-Stark apparatus. Saturated multistory water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (242 mg, 31%). White amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.89 (1H, s), 8.22 (1H, d, J = 8.3 Hz), 7.75-7.71 (2H, m), 7.54 (2H, d , J = 8.1 Hz), 7.29 (1H, d, J = 7.8 Hz), 5.57 (1H, s), 4.16 (2H, dd, J = 11.2, 4.6 Hz), 4.01-3.94 (2H, m), 3.98 -3.91 (2H, m), 2.72-2.62 (2H, m), 2.64 (2H, d, J = 7.1 Hz), 2.12-1.99 (1H, m), 1.80-1.72 (1H, m), 1.64 (2H , d, J = 12.2 Hz), 1.47 (1H, d, J = 13.7 Hz), 1.38 (9H, s), 1.15-1.05 (2H, m).

工程１０
5-(1,3-ジオキサン-2-イル)-3-(3-(ピペリジン-4-イルメチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン Step 10
5- (1,3-Dioxane-2-yl) -3- (3- (piperidin-4-ylmethyl) phenyl) -3H-imidazo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000370
Figure JPOXMLDOC01-appb-C000370

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程6) と同様の手法で、tert-ブチル 4-(3-(5-(1,3-ジオキサン-2-イル)-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンジル)ピペリジン-1-カルボキシレート (242 mg, 0.506 mmol) およびトリフルオロ酢酸 (1 mL) から標記化合物 (169 mg, 88%) を得た。橙色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.88 (1H, s), 8.22 (1H, d, J = 8.3 Hz), 7.75-7.69 (2H, m), 7.55-7.51 (2H, m), 7.28 (1H, d, J= 7.6 Hz), 5.57 (1H, s), 4.16 (2H, dd, J= 10.7, 4.9 Hz), 3.97 (2H, t, J= 11.0 Hz), 2.98 (2H, d, J = 12.2 Hz), 2.62 (2H, d, J = 6.8 Hz), 2.53-2.45 (2H, m), 2.12-2.01 (1H, m), 1.74-1.68 (1H, m), 1.62 (2H, d, J = 12.9 Hz), 1.48 (1H, d, J = 13.7 Hz), 1.20-1.10 (2H, m). Synthesis of 5-bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 6) -(3- (5- (1,3-Dioxane-2-yl) -3H-imidazo [4,5-b] pyridin-3-yl) benzyl) piperidine-1-carboxylate (242 mg, 0.506 mmol) The title compound (169 mg, 88%) was obtained from trifluoroacetic acid (1 mL). Orange amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.88 (1H, s), 8.22 (1H, d, J = 8.3 Hz), 7.75-7.69 (2H, m), 7.55-7.51 (2H , m), 7.28 (1H, d, J = 7.6 Hz), 5.57 (1H, s), 4.16 (2H, dd, J = 10.7, 4.9 Hz), 3.97 (2H, t, J = 11.0 Hz), 2.98 (2H, d, J = 12.2 Hz), 2.62 (2H, d, J = 6.8 Hz), 2.53-2.45 (2H, m), 2.12-2.01 (1H, m), 1.74-1.68 (1H, m), 1.62 (2H, d, J = 12.9 Hz), 1.48 (1H, d, J = 13.7 Hz), 1.20-1.10 (2H, m).

工程１１
5-(1,3-ジオキサン-2-イル)-3-(3-((1-メチルピペリジン-4-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン Step 11
5- (1,3-Dioxane-2-yl) -3- (3-((1-methylpiperidin-4-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000371
Figure JPOXMLDOC01-appb-C000371

5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程7) と同様の手法で、5-(1,3-ジオキサン-2-イル)-3-(3-(ピペリジン-4-イルメチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン (169 mg, 0.447 mmol) および37% ホルムアルデヒド水溶液 (200 μL、2.68 mmol) から標記化合物 (125 mg, 71%) を得た。黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.88 (1H, s), 8.22 (1H, d, J = 8.3 Hz), 7.75-7.70 (2H, m), 7.54 (2H, d, J= 8.3 Hz), 7.53 (2H, t, J = 7.8 Hz), 7.28 (1H, d, J = 7.8 Hz), 5.57 (1H, s), 4.16 (2H, dd, J = 10.7, 5.1 Hz), 4.01-3.94 (2H, m), 2.81 (2H, d, J = 10.2 Hz), 2.63 (2H, d, J = 6.6 Hz), 2.19 (3H, s), 2.12-2.00 (1H, m), 1.96-1.86 (2H, m), 1.64-1.55 (1H, m), 1.62 (2H, d, J= 12.2 Hz), 1.48 (1H, d, J = 13.7 Hz), 1.31-1.22 (2H, m). Synthesis of 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 7) -(1,3-Dioxane-2-yl) -3- (3- (piperidin-4-ylmethyl) phenyl) -3H-imidazo [4,5-b] pyridine (169 mg, 0.447 mmol) and 37% formaldehyde The title compound (125 mg, 71%) was obtained from an aqueous solution (200 μL, 2.68 mmol). Yellow amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.88 (1H, s), 8.22 (1H, d, J = 8.3 Hz), 7.75-7.70 (2H, m), 7.54 (2H, d , J = 8.3 Hz), 7.53 (2H, t, J = 7.8 Hz), 7.28 (1H, d, J = 7.8 Hz), 5.57 (1H, s), 4.16 (2H, dd, J = 10.7, 5.1 Hz ), 4.01-3.94 (2H, m), 2.81 (2H, d, J = 10.2 Hz), 2.63 (2H, d, J = 6.6 Hz), 2.19 (3H, s), 2.12-2.00 (1H, m) , 1.96-1.86 (2H, m), 1.64-1.55 (1H, m), 1.62 (2H, d, J = 12.2 Hz), 1.48 (1H, d, J = 13.7 Hz), 1.31-1.22 (2H, m ).

工程１２
3-(3-((1-メチルピペリジン-4-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド Step 12
3- (3-((1-Methylpiperidin-4-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000372
Figure JPOXMLDOC01-appb-C000372

3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒドの合成 (実施例91、工程7) と同様の手法で、5-(1,3-ジオキサン-2-イル)-3-(3-((1-メチルピペリジン-4-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン(125 mg, 0.318 mmol) から標記化合物 (72 mg, 68%)を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 10.0 (1H, s), 9.16 (1H, s), 8.41 (1H, d, J= 8.3 Hz), 8.00 (1H, dd, J = 8.3, 0.5 Hz), 7.82-7.79 (2H, m), 7.57-7.54 (1H, m), 7.32 (1H, d, J = 7.6 Hz), 2.77 (2H, d, J = 11.0 Hz), 2.64 (2H, d, J = 6.6 Hz), 2.16 (3H, s), 1.91-1.82 (2H, m), 1.62 (2H, d, J = 13.2 Hz), 1.60-1.53 (1H, m), 1.31-1.21 (2H, m). Synthesis of 3- (3-((4-ethylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde (similar to Example 91, Step 7) In the procedure, 5- (1,3-dioxan-2-yl) -3- (3-((1-methylpiperidin-4-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridine ( The title compound (72 mg, 68%) was obtained from 125 mg, 0.318 mmol). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, s), 9.16 (1H, s), 8.41 (1H, d, J = 8.3 Hz), 8.00 (1H, dd, J = 8.3 , 0.5 Hz), 7.82-7.79 (2H, m), 7.57-7.54 (1H, m), 7.32 (1H, d, J = 7.6 Hz), 2.77 (2H, d, J = 11.0 Hz), 2.64 (2H , d, J = 6.6 Hz), 2.16 (3H, s), 1.91-1.82 (2H, m), 1.62 (2H, d, J = 13.2 Hz), 1.60-1.53 (1H, m), 1.31-1.21 ( 2H, m).

工程１３
5-((3-(3-((1-メチルピペリジン-4-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物９７) Step 13
5-((3- (3-((1-methylpiperidin-4-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 97)

Figure JPOXMLDOC01-appb-C000373
Figure JPOXMLDOC01-appb-C000373

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-((1-メチルピペリジン-4-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド (72 mg, 0.215 mmol) およびチアゾリジン-2,4-ジオン (25 mg, 0.215 mmol) から標記化合物 (37 mg, 40%) を得た。褐色固体: 1H-NMR (DMSO-D6) δ: 8.99 (1H, s), 8.23 (1H, d, J = 8.3 Hz), 8.14 (1H, s), 7.81 (1H, dd, J = 7.9, 1.3 Hz), 7.72 (1H, d, J = 8.3 Hz), 7.66 (1H, s), 7.54 (1H, t, J = 7.9 Hz), 7.30 (1H, d, J = 7.6 Hz), 3.38-3.27 (2H, m), 3.12 (2H, d, J = 12.0 Hz), 2.73 (2H, d, J = 7.1 Hz), 2.50 (3H, s), 1.88-1.80 (1H, m), 1.77 (2H, d, J= 14.4 Hz), 1.43-1.33 (2H, m).
ESI-MS(m/z): 434[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3-((1-methylpiperidin-4-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde (72 mg , 0.215 mmol) and thiazolidine-2,4-dione (25 mg, 0.215 mmol) gave the title compound (37 mg, 40%). Brown solid: 1 H-NMR (DMSO-D 6 ) δ: 8.99 (1H, s), 8.23 (1H, d, J = 8.3 Hz), 8.14 (1H, s), 7.81 (1H, dd, J = 7.9 , 1.3 Hz), 7.72 (1H, d, J = 8.3 Hz), 7.66 (1H, s), 7.54 (1H, t, J = 7.9 Hz), 7.30 (1H, d, J = 7.6 Hz), 3.38- 3.27 (2H, m), 3.12 (2H, d, J = 12.0 Hz), 2.73 (2H, d, J = 7.1 Hz), 2.50 (3H, s), 1.88-1.80 (1H, m), 1.77 (2H , d, J = 14.4 Hz), 1.43-1.33 (2H, m).
ESI-MS (m / z): 434 [M + H] + .

実施例９８
5-((3-(3-(4-メチルピペラジン-1-カルボニル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物９８)  Example 98
5-((3- (3- (4-Methylpiperazine-1-carbonyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 98 )

工程１
メチル 3-((6-ブロモ-3-ニトロピリジン-2-イル)アミノ)ベンゾエート Process 1
Methyl 3-((6-bromo-3-nitropyridin-2-yl) amino) benzoate

Figure JPOXMLDOC01-appb-C000374
Figure JPOXMLDOC01-appb-C000374

tert-ブチル 4-(4-((6-ブロモ-3-ニトロピリジン-2-イル)アミノ)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例65、工程3) と同様の手法で、2,6-ジブロモ-3-ニトロピリジン (800 mg, 2.84 mmol) およびメチル 3-アミノベンゾエート (515 mg, 3.41 mmol) から標記化合物 (581 mg, 58%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.2 (1H, s), 8.42 (1H, dd, J = 8.5, 0.5 Hz), 8.26 (1H, t, J = 1.8 Hz), 7.88-7.86 (1H, m), 7.78-7.75 (1H, m), 7.55 (1H, t, J = 7.9 Hz), 7.20 (1H, d, J = 8.5 Hz), 3.88 (3H, s). Synthesis of tert-butyl 4- (4-((6-bromo-3-nitropyridin-2-yl) amino) phenyl) piperazine-1-carboxylate in the same manner as in Example 65, Step 3 The title compound (581 mg, 58%) was obtained from 1,6-dibromo-3-nitropyridine (800 mg, 2.84 mmol) and methyl 3-aminobenzoate (515 mg, 3.41 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.2 (1H, s), 8.42 (1H, dd, J = 8.5, 0.5 Hz), 8.26 (1H, t, J = 1.8 Hz), 7.88- 7.86 (1H, m), 7.78-7.75 (1H, m), 7.55 (1H, t, J = 7.9 Hz), 7.20 (1H, d, J = 8.5 Hz), 3.88 (3H, s).

工程２
メチル 3-((3-アミノ-6-ブロモピリジン-2-イル)アミノ)ベンゾエート Process 2
Methyl 3-((3-amino-6-bromopyridin-2-yl) amino) benzoate

Figure JPOXMLDOC01-appb-C000375
Figure JPOXMLDOC01-appb-C000375

tert-ブチル 4-(4-((3-アミノ-6-ブロモピリジン-2-イル)アミノ)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例65、工程4) と同様の手法で、メチル 3-((6-ブロモ-3-ニトロピリジン-2-イル)アミノ)ベンゾエート (581 mg, 1.65 mmol) から標記化合物 (477 mg, 90%) を得た。黒色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.26 (1H, s), 8.19 (1H, t, J= 2.0 Hz), 8.00-7.97 (1H, m), 7.50-7.48 (1H, m), 7.42 (1H, t, J = 7.8 Hz), 6.88 (1H, d, J = 7.8 Hz), 6.82 (1H, d, J = 7.8 Hz), 5.30 (2H, s), 3.86 (3H, s). Synthesis of tert-butyl 4- (4-((3-amino-6-bromopyridin-2-yl) amino) phenyl) piperazine-1-carboxylate in the same manner as in Example 65, Step 4) The title compound (477 mg, 90%) was obtained from 3-((6-bromo-3-nitropyridin-2-yl) amino) benzoate (581 mg, 1.65 mmol). Black amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.26 (1H, s), 8.19 (1H, t, J = 2.0 Hz), 8.00-7.97 (1H, m), 7.50-7.48 (1H , m), 7.42 (1H, t, J = 7.8 Hz), 6.88 (1H, d, J = 7.8 Hz), 6.82 (1H, d, J = 7.8 Hz), 5.30 (2H, s), 3.86 (3H , s).

工程３
メチル 3-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンゾエート Process 3
Methyl 3- (5-bromo-3H-imidazo [4,5-b] pyridin-3-yl) benzoate

Figure JPOXMLDOC01-appb-C000376
Figure JPOXMLDOC01-appb-C000376

tert-ブチル 4-(4-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例65、工程5) と同様の手法で、メチル 3-((3-アミノ-6-ブロモピリジン-2-イル)アミノ)ベンゾエート (477 mg, 1.48 mmol) およびホルムアミジン酢酸塩 (462 mg, 4.44 mmol) から標記化合物 (518 mg, quant) を得た。褐色固体: 1H-NMR (DMSO-D6) δ: 8.99 (1H, s), 8.46 (1H, t, J = 2.0 Hz), 8.21 (1H, d, J = 8.3 Hz), 8.18-8.15 (1H, m), 8.09-8.06 (1H, m), 7.80 (1H, t, J= 7.9 Hz), 7.74 (1H, s), 7.61 (1H, d, J= 8.3 Hz), 3.92 (3H, s). Synthesis of tert-butyl 4- (4- (5-bromo-3H-imidazo [4,5-b] pyridin-3-yl) phenyl) piperazine-1-carboxylate (Example 65, Step 5) Procedure from methyl 3-((3-amino-6-bromopyridin-2-yl) amino) benzoate (477 mg, 1.48 mmol) and formamidine acetate (462 mg, 4.44 mmol) to the title compound (518 mg, quant). Brown solid: 1 H-NMR (DMSO-D 6 ) δ: 8.99 (1H, s), 8.46 (1H, t, J = 2.0 Hz), 8.21 (1H, d, J = 8.3 Hz), 8.18-8.15 ( 1H, m), 8.09-8.06 (1H, m), 7.80 (1H, t, J = 7.9 Hz), 7.74 (1H, s), 7.61 (1H, d, J = 8.3 Hz), 3.92 (3H, s ).

工程４
3-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)安息香酸 Process 4
3- (5-Bromo-3H-imidazo [4,5-b] pyridin-3-yl) benzoic acid

Figure JPOXMLDOC01-appb-C000377
Figure JPOXMLDOC01-appb-C000377

アルゴン雰囲気下、メチル 3-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)ベンゾエート (502 mg, 1.48 mmol) をメタノール (15 mL)、テトラヒドロフラン (10 mL) に懸濁した。そこへ1規定水酸化ナトリウム (5 mL) を加え、50℃で1時間撹拌した。反応液を濃縮し、酢酸エチルに再溶解して1規定水酸化ナトリウム溶液で抽出した。水層を1規定塩酸で酸性にし、飽和食塩水を加え、テトラヒドロフランで抽出した。テトラヒドロフラン層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた固体を水で洗浄して標記化合物 (324 mg, 69%) を得た。褐色固体: 1H-NMR (DMSO-D6) δ: 13.4 (1H, s), 8.99 (1H, s), 8.43 (1H, t, J = 2.0 Hz), 8.20 (1H, d, J= 8.3 Hz), 8.14-8.11 (1H, m), 8.07-8.04 (1H, m), 7.78 (1H, t, J = 7.9 Hz), 7.61 (1H, dd, J = 8.4, 0.6 Hz). Methyl 3- (5-bromo-3H-imidazo [4,5-b] pyridin-3-yl) benzoate (502 mg, 1.48 mmol) was suspended in methanol (15 mL) and tetrahydrofuran (10 mL) under an argon atmosphere. It became cloudy. 1N sodium hydroxide (5 mL) was added thereto, and the mixture was stirred at 50 ° C. for 1 hour. The reaction mixture was concentrated, redissolved in ethyl acetate, and extracted with 1N sodium hydroxide solution. The aqueous layer was acidified with 1N hydrochloric acid, saturated brine was added, and the mixture was extracted with tetrahydrofuran. The tetrahydrofuran layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained solid was washed with water to give the title compound (324 mg, 69%). Brown solid: 1 H-NMR (DMSO-D 6 ) δ: 13.4 (1H, s), 8.99 (1H, s), 8.43 (1H, t, J = 2.0 Hz), 8.20 (1H, d, J = 8.3 Hz), 8.14-8.11 (1H, m), 8.07-8.04 (1H, m), 7.78 (1H, t, J = 7.9 Hz), 7.61 (1H, dd, J = 8.4, 0.6 Hz).

工程５
(3-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)(4-メチルピペラジン-1-イル)メタノン Process 5
(3- (5-Bromo-3H-imidazo [4,5-b] pyridin-3-yl) phenyl) (4-methylpiperazin-1-yl) methanone

Figure JPOXMLDOC01-appb-C000378
Figure JPOXMLDOC01-appb-C000378

アルゴン雰囲気下3-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)安息香酸 (180 mg, 0.566 mmol) をN,N-ジメチルホルムアミド (3 mL) に溶解し、0℃に冷却した。そこへO-(1H-6-クロロベンゾトリアゾール-1-イル)-N,N,N',N'-テトラメチルウロニウムテトラフルオロボレート (241 mg, 0.679 mmol)、N,N-ジイソプロピルエチルアミン (355 μL, 2.04 mmol)、1-メチルピペラジン (75 μL, 0.679 mL) を加え、0℃で10分撹拌後、室温で1時間撹拌した。反応液に飽和重層水を加え、酢酸エチルで抽出した。酢酸エチル層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、シリカゲルパッドを通してろ過した。ろ液を濃縮, 真空乾燥して標記化合物 (106 mg, 47%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 8.97 (1H, s), 8.20 (1H, d, J = 8.3 Hz), 7.98-7.94 (2H, m), 7.71 (1H, t, J = 7.8 Hz), 7.60 (1H, d, J = 8.3 Hz), 7.52-7.50 (1H, m), 3.65 (2H, s), 3.44 (2H, s), 2.38 (4H, s), 2.22 (3H, s). 3- (5-Bromo-3H-imidazo [4,5-b] pyridin-3-yl) benzoic acid (180 mg, 0.566 mmol) was dissolved in N, N-dimethylformamide (3 mL) under an argon atmosphere. Cooled to 0 ° C. O- (1H-6-chlorobenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate (241 mg, 0.679 mmol), N, N-diisopropylethylamine ( 355 μL, 2.04 mmol) and 1-methylpiperazine (75 μL, 0.679 mL) were added, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 1 hour. Saturated multistory water was added to the reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered through a silica gel pad. The filtrate was concentrated and dried under vacuum to obtain the title compound (106 mg, 47%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 8.97 (1H, s), 8.20 (1H, d, J = 8.3 Hz), 7.98-7.94 (2H, m), 7.71 (1H, t, J = 7.8 Hz), 7.60 (1H, d, J = 8.3 Hz), 7.52-7.50 (1H, m), 3.65 (2H, s), 3.44 (2H, s), 2.38 (4H, s), 2.22 (3H , s).

工程６
(4-メチルピペラジン-1-イル)(3-(5-ビニル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)メタノン Step 6
(4-Methylpiperazin-1-yl) (3- (5-vinyl-3H-imidazo [4,5-b] pyridin-3-yl) phenyl) methanone

Figure JPOXMLDOC01-appb-C000379
Figure JPOXMLDOC01-appb-C000379

3-(4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例63、工程2) と同様の手法で、(3-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)(4-メチルピペラジン-1-イル)メタノン (106 mg, 0.265 mmol) およびトリブチリビニルスズ (85 μL, 0.286 mmol) から標記化合物 (61 mg, 66%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.95 (1H, s), 8.18 (1H, d, J = 8.3 Hz), 8.11-8.08 (2H, m), 7.72-7.68 (1H, m), 7.55 (1H, d, J= 8.3 Hz), 7.47 (1H, d, J = 7.8 Hz), 6.94 (1H, dd, J = 17.3, 10.7 Hz), 6.25 (1H, dd, J = 17.4, 1.6 Hz), 5.49 (1H, dd, J = 10.6, 1.6 Hz), 3.66 (2H, s), 3.47-3.40 (2H, m), 2.39-2.29 (4H, m), 2.20 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 63, Step 2) 5-Bromo-3H-imidazo [4,5-b] pyridin-3-yl) phenyl) (4-methylpiperazin-1-yl) methanone (106 mg, 0.265 mmol) and tributyvinyltin (85 μL, 0.286 mmol) gave the title compound (61 mg, 66%). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.95 (1H, s), 8.18 (1H, d, J = 8.3 Hz), 8.11-8.08 (2H, m), 7.72-7.68 (1H, m ), 7.55 (1H, d, J = 8.3 Hz), 7.47 (1H, d, J = 7.8 Hz), 6.94 (1H, dd, J = 17.3, 10.7 Hz), 6.25 (1H, dd, J = 17.4, 1.6 Hz), 5.49 (1H, dd, J = 10.6, 1.6 Hz), 3.66 (2H, s), 3.47-3.40 (2H, m), 2.39-2.29 (4H, m), 2.20 (3H, s).

工程７
3-(3-(4-メチルピペラジン-1-カルボニル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド Step 7
3- (3- (4-Methylpiperazine-1-carbonyl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000380
Figure JPOXMLDOC01-appb-C000380

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、(4-メチルピペラジン-1-イル)(3-(5-ビニル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)メタノン (61 mg, 0.176 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (44 μL, 3.52 μmol) から標記化合物 (34 mg, 55%) を得た。微黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.7 Hz), 9.22 (1H, s), 8.43 (1H, d, J = 8.3 Hz), 8.11-8.09 (1H, m), 8.04 (1H, t, J = 1.7 Hz), 8.02 (1H, d, J = 8.3 Hz), 7.74 (1H, t, J = 7.9 Hz), 7.55-7.52 (1H, m), 3.66 (2H, s), 3.45 (2H, s), 2.41-2.31 (4H, m), 2.21 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) Methylpiperazin-1-yl) (3- (5-vinyl-3H-imidazo [4,5-b] pyridin-3-yl) phenyl) methanone (61 mg, 0.176 mmol) and 2.5 wt% osmium tetroxide tert- The title compound (34 mg, 55%) was obtained from a butanol solution (44 μL, 3.52 μmol). Slight yellow amorphous substance: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.7 Hz), 9.22 (1H, s), 8.43 (1H, d, J = 8.3 Hz), 8.11 -8.09 (1H, m), 8.04 (1H, t, J = 1.7 Hz), 8.02 (1H, d, J = 8.3 Hz), 7.74 (1H, t, J = 7.9 Hz), 7.55-7.52 (1H, m), 3.66 (2H, s), 3.45 (2H, s), 2.41-2.31 (4H, m), 2.21 (3H, s).

工程８
5-((3-(3-(4-メチルピペラジン-1-カルボニル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物９８) Process 8
5-((3- (3- (4-Methylpiperazine-1-carbonyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 98 )

Figure JPOXMLDOC01-appb-C000381
Figure JPOXMLDOC01-appb-C000381

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-(4-メチルピペラジン-1-カルボニル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド (34 mg, 0.0973 mmol) およびチアゾリジン-2,4-ジオン (11 mg, 0.0973 mmol) から標記化合物 (25 mg, 56%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 9.08 (1H, s), 8.33 (1H, d, J = 8.1 Hz), 8.12 (1H, t, J = 1.7 Hz), 8.09-8.06 (1H, m), 7.95 (1H, s), 7.89 (1H, d, J = 8.3 Hz), 7.72 (1H, t, J = 7.9 Hz), 7.52 (1H, d, J = 7.8 Hz), 3.69 (2H, s), 3.45 (2H, s), 2.51-2.38 (4H, m), 2.25 (3H, s).
ESI-MS(m/z): 449[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3- (4-methylpiperazine-1-carbonyl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde (34 mg, 0.0973 mmol ) And thiazolidine-2,4-dione (11 mg, 0.0973 mmol) to give the title compound (25 mg, 56%). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 9.08 (1H, s), 8.33 (1H, d, J = 8.1 Hz), 8.12 (1H, t, J = 1.7 Hz), 8.09-8.06 (1H, m), 7.95 (1H, s), 7.89 (1H, d, J = 8.3 Hz), 7.72 (1H, t, J = 7.9 Hz), 7.52 (1H, d, J = 7.8 Hz), 3.69 (2H, s), 3.45 (2H, s), 2.51-2.38 (4H, m), 2.25 (3H, s).
ESI-MS (m / z): 449 [M + H] + .

実施例９９
5-((3-(3-(4-シクロヘキシルピペラジン-1-カルボニル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物９９)  Example 99
5-((3- (3- (4-cyclohexylpiperazine-1-carbonyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 99 )

工程１
(3-(5-ブロモイ-3H-ミダゾ[4,5-b]ピリジン-3-イル)フェニル)-(4-シクロヘキシルピペラジン-1-イル)メタノン  Process 1
(3- (5-Bromo-3H-midazo [4,5-b] pyridin-3-yl) phenyl)-(4-cyclohexylpiperazin-1-yl) methanone

Figure JPOXMLDOC01-appb-C000382
Figure JPOXMLDOC01-appb-C000382

(3-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)(4-メチルピペラジン-1-イル)メタノンの合成 (実施例98、工程5) と同様の手法で、3-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)安息香酸 (124 mg, 0.390 mmol) および1-シクロヘキシルピペラジン (79 mg, 0.468 mmol) から標記化合物 (148 mg, 81%) を得た。褐色固体: 1H-NMR (DMSO-D6) δ: 8.96 (1H, d, J = 0.5 Hz), 8.20 (1H, dd, J = 8.3, 0.5 Hz), 7.97-7.93 (2H, m), 7.71 (1H, t, J= 7.9 Hz), 7.61 (1H, dd, J = 8.3, 0.5 Hz), 7.51 (1H, d, J = 7.8 Hz), 3.63 (2H, s), 3.41 (2H, s), 2.59-2.50 (4H, m), 2.31-2.24 (1H, m), 1.77-1.70 (4H, m), 1.57 (1H, d, J= 12.0 Hz), 1.19 (4H, t, J = 9.5 Hz), 1.10-1.01 (1H, m). Synthesis of (3- (5-bromo-3H-imidazo [4,5-b] pyridin-3-yl) phenyl) (4-methylpiperazin-1-yl) methanone (Example 98, Step 5) Procedure from 3- (5-bromo-3H-imidazo [4,5-b] pyridin-3-yl) benzoic acid (124 mg, 0.390 mmol) and 1-cyclohexylpiperazine (79 mg, 0.468 mmol) (148 mg, 81%) was obtained. Brown solid: 1 H-NMR (DMSO-D 6 ) δ: 8.96 (1H, d, J = 0.5 Hz), 8.20 (1H, dd, J = 8.3, 0.5 Hz), 7.97-7.93 (2H, m), 7.71 (1H, t, J = 7.9 Hz), 7.61 (1H, dd, J = 8.3, 0.5 Hz), 7.51 (1H, d, J = 7.8 Hz), 3.63 (2H, s), 3.41 (2H, s ), 2.59-2.50 (4H, m), 2.31-2.24 (1H, m), 1.77-1.70 (4H, m), 1.57 (1H, d, J = 12.0 Hz), 1.19 (4H, t, J = 9.5 Hz), 1.10-1.01 (1H, m).

工程２
(4-シクロヘキシルピペラジン-1-イル)-(3-(5-ビニル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)メタノン Process 2
(4-Cyclohexylpiperazin-1-yl)-(3- (5-vinyl-3H-imidazo [4,5-b] pyridin-3-yl) phenyl) methanone

Figure JPOXMLDOC01-appb-C000383
Figure JPOXMLDOC01-appb-C000383

3-(4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例63、工程2) と同様の手法で、(3-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-(4-シクロヘキシルピペラジン-1-イル)メタノン (148 mg, 0.316 mmol) およびトリブチリビニルスズ (101 μL, 0.348 mmol) から標記化合物 (136 mg, quant) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 8.95 (1H, s), 8.18 (1H, d, J = 8.5 Hz), 8.09-8.07 (2H, m), 7.65-7.60 (1H, m), 7.58-7.53 (1H, m), 7.46 (1H, d, J = 7.6 Hz), 6.94 (1H, dd, J = 17.3, 10.7 Hz), 6.25 (1H, dd, J = 17.6, 1.2 Hz), 5.48 (1H, dd, J = 10.7, 1.2 Hz), 3.63 (2H, s), 3.41 (2H, s), 2.58-2.50 (4H, m), 2.30-2.24 (1H, m), 1.77-1.69 (4H, m), 1.57 (1H, d, J = 11.0 Hz), 1.23-1.13 (4H, m), 1.10-1.03 (1H, m). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 63, Step 2) 5-Bromo-3H-imidazo [4,5-b] pyridin-3-yl) phenyl)-(4-cyclohexylpiperazin-1-yl) methanone (148 mg, 0.316 mmol) and tributyvinyltin (101 μL, The title compound (136 mg, quant) was obtained from 0.348 mmol). White solid: 1 H-NMR (DMSO-D 6 ) δ: 8.95 (1H, s), 8.18 (1H, d, J = 8.5 Hz), 8.09-8.07 (2H, m), 7.65-7.60 (1H, m ), 7.58-7.53 (1H, m), 7.46 (1H, d, J = 7.6 Hz), 6.94 (1H, dd, J = 17.3, 10.7 Hz), 6.25 (1H, dd, J = 17.6, 1.2 Hz) , 5.48 (1H, dd, J = 10.7, 1.2 Hz), 3.63 (2H, s), 3.41 (2H, s), 2.58-2.50 (4H, m), 2.30-2.24 (1H, m), 1.77-1.69 (4H, m), 1.57 (1H, d, J = 11.0 Hz), 1.23-1.13 (4H, m), 1.10-1.03 (1H, m).

工程３
3-(3-(4-シクロヘキシルピペラジン-1-カルボニル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド Process 3
3- (3- (4-Cyclohexylpiperazine-1-carbonyl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000384
Figure JPOXMLDOC01-appb-C000384

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、(4-シクロヘキシルピペラジン-1-イル)-(3-(5-ビニル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)メタノン (136 mg, 0.316 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (79 μL, 6.32 μmol) から標記化合物 (62 mg, 47%) を得た。微黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 10.0 (1H, s), 9.22 (1H, s), 8.43 (1H, d, J = 8.3 Hz), 8.11-8.07 (1H, m), 8.04-7.99 (2H, m), 7.73 (1H, t, J = 7.8 Hz), 7.53 (1H, d, J= 6.6 Hz), 3.62 (2H, s), 3.41 (2H, s), 2.59-2.49 (4H, m), 2.29-2.22 (1H, m), 1.77-1.68 (4H, m), 1.58-1.53 (1H, m), 1.24-1.13 (4H, m), 1.10-1.00 (1H, m). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) Cyclohexylpiperazin-1-yl)-(3- (5-vinyl-3H-imidazo [4,5-b] pyridin-3-yl) phenyl) methanone (136 mg, 0.316 mmol) and 2.5 wt% osmium tetroxide tert -The title compound (62 mg, 47%) was obtained from a butanol solution (79 μL, 6.32 μmol). Slight yellow amorphous substance: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, s), 9.22 (1H, s), 8.43 (1H, d, J = 8.3 Hz), 8.11-8.07 (1H, m), 8.04-7.99 (2H, m), 7.73 (1H, t, J = 7.8 Hz), 7.53 (1H, d, J = 6.6 Hz), 3.62 (2H, s), 3.41 (2H, s), 2.59-2.49 (4H, m), 2.29-2.22 (1H, m), 1.77-1.68 (4H, m), 1.58-1.53 (1H, m), 1.24-1.13 (4H, m), 1.10-1.00 (1H , m).

工程４
5-((3-(3-(4-シクロヘキシルピペラジン-1-カルボニル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物９９) Process 4
5-((3- (3- (4-cyclohexylpiperazine-1-carbonyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 99 )

Figure JPOXMLDOC01-appb-C000385
Figure JPOXMLDOC01-appb-C000385

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-(4-シクロヘキシルピペラジン-1-カルボニル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド (62 mg, 0.149 mmol) およびチアゾリジン-2,4-ジオン (17 mg, 0.149 mmol) から標記化合物 (25 mg, 56%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 9.08 (1H, s), 8.33 (1H, d, J = 8.3 Hz), 8.12 (1H, s), 8.08-8.06 (1H, m), 7.95 (1H, s), 7.89 (1H, d, J= 8.1 Hz), 7.71 (1H, t, J = 7.9 Hz), 7.52 (1H, d, J = 7.6 Hz), 3.67 (2H, s), 3.42 (2H, s), 2.68-2.52 (4H, m), 2.36-2.30 (1H, m), 1.78-1.70 (4H, m), 1.56 (1H, d, J = 12.4 Hz), 1.24-1.13 (4H, m), 1.10-1.01 (1H, m).
ESI-MS(m/z): 517[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3- (4-cyclohexylpiperazine-1-carbonyl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde (62 mg, 0.149 mmol ) And thiazolidine-2,4-dione (17 mg, 0.149 mmol) gave the title compound (25 mg, 56%). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 9.08 (1H, s), 8.33 (1H, d, J = 8.3 Hz), 8.12 (1H, s), 8.08-8.06 (1H, m) , 7.95 (1H, s), 7.89 (1H, d, J = 8.1 Hz), 7.71 (1H, t, J = 7.9 Hz), 7.52 (1H, d, J = 7.6 Hz), 3.67 (2H, s) , 3.42 (2H, s), 2.68-2.52 (4H, m), 2.36-2.30 (1H, m), 1.78-1.70 (4H, m), 1.56 (1H, d, J = 12.4 Hz), 1.24-1.13 (4H, m), 1.10-1.01 (1H, m).
ESI-MS (m / z): 517 [M + H] + .

実施例１００
5-((3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物１００)  Example 100
5-((3- (2-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thioxothiazolidine -4-one (compound 100)

工程１
tert-ブチル 4-(3-フルオロ-4-ニトロフェニル)ピペラジン-1-カルボキシレート Process 1
tert-butyl 4- (3-fluoro-4-nitrophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000386
Figure JPOXMLDOC01-appb-C000386

アルゴン雰囲気下、2,4-ジフルオロニトロベンゼン (1.0 g, 6.29 mmol) をN,N-ジメチルホルムアミド (10 mL) に溶解した。そこへ1-エチル-3-メチルイミダゾリウム ジメチル ホスファート (11.6 g) を加え均一な溶液とした。さらに1-(tert-ブトキシカルボニル)ピペラジン (1.41 g, 7.55 mmol)、炭酸カリウム (2.60 g, 18.8 mmol) を加え、 室温で3時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.80 g, 88%) を得た。黄色固体: 1H-NMR (CDCl3) δ: 8.05 (1H, t, J = 9.1 Hz), 6.60 (1H, dd, J = 9.4, 2.8 Hz), 6.54 (1H, dd, J = 14.9, 2.7 Hz), 3.61 (4H, t, J = 5.2 Hz), 3.42 (4H, t, J = 5.4 Hz), 1.49 (9H, s). Under an argon atmosphere, 2,4-difluoronitrobenzene (1.0 g, 6.29 mmol) was dissolved in N, N-dimethylformamide (10 mL). 1-Ethyl-3-methylimidazolium dimethyl phosphate (11.6 g) was added thereto to make a homogeneous solution. Furthermore, 1- (tert-butoxycarbonyl) piperazine (1.41 g, 7.55 mmol) and potassium carbonate (2.60 g, 18.8 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.80 g, 88%). Yellow solid: 1 H-NMR (CDCl 3 ) δ: 8.05 (1H, t, J = 9.1 Hz), 6.60 (1H, dd, J = 9.4, 2.8 Hz), 6.54 (1H, dd, J = 14.9, 2.7 Hz), 3.61 (4H, t, J = 5.2 Hz), 3.42 (4H, t, J = 5.4 Hz), 1.49 (9H, s).

工程２
tert-ブチル 4-(4-アミノ-3-フルオロフェニル)ピペラジン-1-カルボキシレート Process 2
tert-butyl 4- (4-amino-3-fluorophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000387
Figure JPOXMLDOC01-appb-C000387

tert-ブチル 4-(3-フルオロ-4-ニトロフェニル)ピペラジン-1-カルボキシレート (1.80 g, 5.53 mmol) をテトラヒドロフラン (20 mL) に溶解した。そこへ10% パラジウム－活性炭 (180 mg) をエタノール (5 mL) に懸濁して加え、反応容器内を水素で置換し、室温で2時間撹拌した。反応液をセライトでろ過し、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.61 g, 98%) を得た。赤色オイル: 1H-NMR (DMSO-D6) δ: 6.70-6.65 (2H, m), 6.55 (1H, dd, J = 8.7, 2.6 Hz), 4.61 (2H, s), 3.41 (4H, t, J = 4.9 Hz), 2.87 (4H, t, J = 5.1 Hz), 1.41 (9H, s). tert-Butyl 4- (3-fluoro-4-nitrophenyl) piperazine-1-carboxylate (1.80 g, 5.53 mmol) was dissolved in tetrahydrofuran (20 mL). Thereto was added 10% palladium-activated carbon (180 mg) suspended in ethanol (5 mL), the inside of the reaction vessel was replaced with hydrogen, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite and concentrated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.61 g, 98%). Red oil: 1 H-NMR (DMSO-D 6 ) δ: 6.70-6.65 (2H, m), 6.55 (1H, dd, J = 8.7, 2.6 Hz), 4.61 (2H, s), 3.41 (4H, t , J = 4.9 Hz), 2.87 (4H, t, J = 5.1 Hz), 1.41 (9H, s).

工程３
tert-ブチル 4-(4-((6-ブロモ-3-ニトロピリジン-2-イル)アミノ)-3-フルオロフェニル)ピペラジン-1-カルボキシレート Process 3
tert-butyl 4- (4-((6-bromo-3-nitropyridin-2-yl) amino) -3-fluorophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000388
Figure JPOXMLDOC01-appb-C000388

tert-ブチル 4-(4-((6-ブロモ-3-ニトロピリジン-2-イル)アミノ)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例65、工程3) と同様の手法で、2,6-ジブロモ-3-ニトロピリジン (1.28 g、4.53 mmol) およびtert-ブチル 4-(4-アミノ-3-フルオロフェニル)ピペラジン-1-カルボキシレート (1.61 g, 5.43 mmol) から標記化合物 (1.95 g, 87%) を得た。紫色固体: 1H-NMR (DMSO-D6) δ: 9.94 (1H, s), 8.39 (1H, d, J = 8.5 Hz), 7.53 (1H, t, J = 9.1 Hz), 7.10 (1H, d, J = 8.5 Hz), 6.93 (1H, dd, J = 14.0, 2.6 Hz), 6.82 (1H, dd, J = 8.9, 2.3 Hz), 3.46 (4H, t, J = 5.0 Hz), 3.18 (4H, t, J = 5.1 Hz), 1.43 (9H, s). Synthesis of tert-butyl 4- (4-((6-bromo-3-nitropyridin-2-yl) amino) phenyl) piperazine-1-carboxylate in the same manner as in Example 65, Step 3 , 6-Dibromo-3-nitropyridine (1.28 g, 4.53 mmol) and tert-butyl 4- (4-amino-3-fluorophenyl) piperazine-1-carboxylate (1.61 g, 5.43 mmol) to give the title compound (1.95 g, 87%). Purple solid: 1 H-NMR (DMSO-D 6 ) δ: 9.94 (1H, s), 8.39 (1H, d, J = 8.5 Hz), 7.53 (1H, t, J = 9.1 Hz), 7.10 (1H, d, J = 8.5 Hz), 6.93 (1H, dd, J = 14.0, 2.6 Hz), 6.82 (1H, dd, J = 8.9, 2.3 Hz), 3.46 (4H, t, J = 5.0 Hz), 3.18 ( 4H, t, J = 5.1 Hz), 1.43 (9H, s).

工程４
tert-ブチル 4-(4-((3-アミノ-6-ブロモピリジン-2-イル)アミノ)-3-フルオロフェニル)ピペラジン-1-カルボキシレート Process 4
tert-butyl 4- (4-((3-amino-6-bromopyridin-2-yl) amino) -3-fluorophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000389
Figure JPOXMLDOC01-appb-C000389

tert-ブチル 4-(4-((3-アミノ-6-ブロモピリジン-2-イル)アミノ)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例65、工程4) と同様の手法で、tert-ブチル 4-(4-((6-ブロモ-3-ニトロピリジン-2-イル)アミノ)-3-フルオロフェニル)ピペラジン-1-カルボキシレート (1.95 g, 3.92 mmol) から標記化合物 (1.66 g, 91%) を得た。紫色固体: 1H-NMR (DMSO-D6) δ: 7.44-7.39 (2H, m), 6.86 (1H, dd, J = 14.1, 2.7 Hz), 6.78 (1H, d, J = 7.8 Hz), 6.75 (1H, dd, J = 9.0, 2.7 Hz), 6.67 (1H, d, J = 7.8 Hz), 5.14 (2H, s), 3.45 (4H, t, J = 4.9 Hz), 3.10 (4H, t, J = 5.1 Hz), 1.42 (9H, s). Synthesis of tert-butyl 4- (4-((3-amino-6-bromopyridin-2-yl) amino) phenyl) piperazine-1-carboxylate (Example 65, Step 4) -Butyl 4- (4-((6-bromo-3-nitropyridin-2-yl) amino) -3-fluorophenyl) piperazine-1-carboxylate (1.95 g, 3.92 mmol) to the title compound (1.66 g, 91%). Purple solid: 1 H-NMR (DMSO-D 6 ) δ: 7.44-7.39 (2H, m), 6.86 (1H, dd, J = 14.1, 2.7 Hz), 6.78 (1H, d, J = 7.8 Hz), 6.75 (1H, dd, J = 9.0, 2.7 Hz), 6.67 (1H, d, J = 7.8 Hz), 5.14 (2H, s), 3.45 (4H, t, J = 4.9 Hz), 3.10 (4H, t , J = 5.1 Hz), 1.42 (9H, s).

工程５
tert-ブチル 4-(4-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)-3-フルオロフェニル)ピペラジン-1-カルボキシレート Process 5
tert-Butyl 4- (4- (5-Bromo-3H-imidazo [4,5-b] pyridin-3-yl) -3-fluorophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000390
Figure JPOXMLDOC01-appb-C000390

tert-ブチル 4-(4-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例65、工程5) と同様の手法で、tert-ブチル 4-(4-((3-アミノ-6-ブロモピリジン-2-イル)アミノ)-3-フルオロフェニル)ピペラジン-1-カルボキシレート (1.66 g, 3.56 mmol) およびホルムアミジン酢酸塩 (1.11 g, 10.7 mmol) から標記化合物 (1.63 g, 96%) を得た。ピンク色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.66 (1H, s), 8.18 (1H, d, J= 8.3 Hz), 7.56 (1H, d, J = 8.1 Hz), 7.54 (1H, t, J = 8.9 Hz), 7.10 (1H, dd, J = 14.0, 2.6 Hz), 6.97 (1H, dd, J = 9.0, 2.4 Hz), 3.48 (4H, t, J = 4.9 Hz), 3.30 (4H, t, J = 5.2 Hz), 1.43 (9H, s). Synthesis of tert-butyl 4- (4- (5-bromo-3H-imidazo [4,5-b] pyridin-3-yl) phenyl) piperazine-1-carboxylate (Example 65, Step 5) Tert-butyl 4- (4-((3-amino-6-bromopyridin-2-yl) amino) -3-fluorophenyl) piperazine-1-carboxylate (1.66 g, 3.56 mmol) and formamidine The title compound (1.63 g, 96%) was obtained from the acetate (1.11 g, 10.7 mmol). Pink amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.66 (1H, s), 8.18 (1H, d, J = 8.3 Hz), 7.56 (1H, d, J = 8.1 Hz), 7.54 (1H, t, J = 8.9 Hz), 7.10 (1H, dd, J = 14.0, 2.6 Hz), 6.97 (1H, dd, J = 9.0, 2.4 Hz), 3.48 (4H, t, J = 4.9 Hz) , 3.30 (4H, t, J = 5.2 Hz), 1.43 (9H, s).

工程６
5-ブロモ-3-(2-フルオロ-4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン Step 6
5-Bromo-3- (2-fluoro-4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000391
Figure JPOXMLDOC01-appb-C000391

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程6) と同様の手法で、tert-ブチル 4-(4-(5-ブロモ-3H-イミダゾ[4,5-b]ピリジン-3-イル)-3-フルオロフェニル)ピペラジン-1-カルボキシレート (1.63 g, 3.42 mmol) およびトリフルオロ酢酸 (9 mL) から標記化合物 (1.04 g, 81%) を得た。ベージュ色固体: 1H-NMR (DMSO-D6) δ: 8.64 (1H, s), 8.17 (1H, d, J= 8.3 Hz), 7.55 (1H, d, J = 8.3 Hz), 7.50 (1H, t, J = 8.9 Hz), 7.04 (1H, dd, J = 14.1, 2.7 Hz), 6.93 (1H, dd, J = 9.0, 2.7 Hz), 3.21 (4H, t, J = 5.0 Hz), 2.85 (4H, t, J = 5.0 Hz), 2.67 (1H, s). Synthesis of 5-bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 6) -(4- (5-Bromo-3H-imidazo [4,5-b] pyridin-3-yl) -3-fluorophenyl) piperazine-1-carboxylate (1.63 g, 3.42 mmol) and trifluoroacetic acid (9 mL) gave the title compound (1.04 g, 81%). Beige solid: 1 H-NMR (DMSO-D 6 ) δ: 8.64 (1H, s), 8.17 (1H, d, J = 8.3 Hz), 7.55 (1H, d, J = 8.3 Hz), 7.50 (1H , t, J = 8.9 Hz), 7.04 (1H, dd, J = 14.1, 2.7 Hz), 6.93 (1H, dd, J = 9.0, 2.7 Hz), 3.21 (4H, t, J = 5.0 Hz), 2.85 (4H, t, J = 5.0 Hz), 2.67 (1H, s).

工程７
5-ブロモ-3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン Step 7
5-Bromo-3- (2-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000392
Figure JPOXMLDOC01-appb-C000392

5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程7) と同様の手法で、5-ブロモ-3-(2-フルオロ-4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン (500 mg, 1.33 mmol) および37% ホルムアルデヒド水溶液 (594 μL, 7.98 mmol) から標記化合物 (499 mg, 96%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 8.65 (1H, s), 8.17 (1H, dd, J= 8.3, 0.5 Hz), 7.55 (1H, dd, J= 8.3, 0.5 Hz), 7.51 (1H, t, J= 8.9 Hz), 7.07 (1H, dd, J = 14.1, 2.7 Hz), 6.95 (1H, dd, J= 9.0, 2.7 Hz), 3.30 (4H, t, J= 5.0 Hz), 2.46 (4H, t, J = 5.0 Hz), 2.24 (3H, s). Synthesis of 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 7) -Bromo-3- (2-fluoro-4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (500 mg, 1.33 mmol) and 37% aqueous formaldehyde (594 μL, 7.98 mmol) gave the title compound (499 mg, 96%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 8.65 (1H, s), 8.17 (1H, dd, J = 8.3, 0.5 Hz), 7.55 (1H, dd, J = 8.3, 0.5 Hz), 7.51 (1H, t, J = 8.9 Hz), 7.07 (1H, dd, J = 14.1, 2.7 Hz), 6.95 (1H, dd, J = 9.0, 2.7 Hz), 3.30 (4H, t, J = 5.0 Hz ), 2.46 (4H, t, J = 5.0 Hz), 2.24 (3H, s).

工程８
3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-5-ビニル-3H-イミダゾ[4,5-b]ピリジン Process 8
3- (2-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -5-vinyl-3H-imidazo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000393
Figure JPOXMLDOC01-appb-C000393

3-(4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例63、工程2) と同様の手法で、5-ブロモ-3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン (499 mg, 1.28 mmol) およびトリブチリビニルスズ (410 μL, 1.41 mmol) から標記化合物 (363 mg, 84%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.57 (1H, s), 8.15 (1H, d, J = 8.3 Hz), 7.55-7.51 (2H, m), 7.06 (1H, dd, J = 14.1, 2.7 Hz), 6.95 (1H, dd, J = 8.9, 2.6 Hz), 6.86 (1H, dd, J = 17.4, 10.9 Hz), 6.14 (1H, dd, J = 17.6, 1.5 Hz), 5.43 (1H, d, J = 12.2 Hz), 3.29 (4H, t, J = 5.0 Hz), 2.46 (4H, t, J = 5.0 Hz), 2.24 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 63, Step 2) 3- (2-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (499 mg, 1.28 mmol) and tributyvinyltin (410 μL, 1.41 mmol) gave the title compound (363 mg, 84%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.57 (1H, s), 8.15 (1H, d, J = 8.3 Hz), 7.55-7.51 (2H, m), 7.06 (1H, dd, J = 14.1, 2.7 Hz), 6.95 (1H, dd, J = 8.9, 2.6 Hz), 6.86 (1H, dd, J = 17.4, 10.9 Hz), 6.14 (1H, dd, J = 17.6, 1.5 Hz), 5.43 (1H, d, J = 12.2 Hz), 3.29 (4H, t, J = 5.0 Hz), 2.46 (4H, t, J = 5.0 Hz), 2.24 (3H, s).

工程９
3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド Step 9
3- (2-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000394
Figure JPOXMLDOC01-appb-C000394

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-5-ビニル-3H-イミダゾ[4,5-b]ピリジン (363 mg, 1.08 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (271 μL, 21.6 μmol) から標記化合物 (62 mg, 47%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 9.96 (1H, s), 8.89 (1H, d, J= 16.3 Hz), 8.41 (1H, d, J = 8.3 Hz), 7.98 (1H, d, J = 8.3 Hz), 7.58 (1H, t, J = 8.9 Hz), 7.09 (1H, dd, J = 14.3, 2.6 Hz), 6.98 (1H, dd, J = 8.9, 2.6 Hz), 3.33-3.30 (4H, m), 2.47 (4H, t, J= 5.0 Hz), 2.24 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 2-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -5-vinyl-3H-imidazo [4,5-b] pyridine (363 mg, 1.08 mmol) and 2.5 wt% osmium tetroxide tert- The title compound (62 mg, 47%) was obtained from a butanol solution (271 μL, 21.6 μmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 9.96 (1H, s), 8.89 (1H, d, J = 16.3 Hz), 8.41 (1H, d, J = 8.3 Hz), 7.98 (1H, d, J = 8.3 Hz), 7.58 (1H, t, J = 8.9 Hz), 7.09 (1H, dd, J = 14.3, 2.6 Hz), 6.98 (1H, dd, J = 8.9, 2.6 Hz), 3.33- 3.30 (4H, m), 2.47 (4H, t, J = 5.0 Hz), 2.24 (3H, s).

工程１０
5-((3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物１００)  Step 10
5-((3- (2-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thioxothiazolidine -4-one (compound 100)

Figure JPOXMLDOC01-appb-C000395
Figure JPOXMLDOC01-appb-C000395

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド (99 mg, 0.292 mmol) およびロダニン (39 mg, 0.292 mmol) から標記化合物 (99 mg, 74%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.78 (1H, d, J = 1.2 Hz), 8.29 (1H, d, J = 8.3 Hz), 7.84 (1H, d, J = 8.3 Hz), 7.65 (1H, s), 7.65 (1H, t, J = 8.9 Hz), 7.15 (1H, dd, J = 13.9, 2.7 Hz), 7.01 (1H, dd, J = 9.0, 2.4 Hz), 3.42 (4H, t, J = 4.9 Hz), 2.79 (4H, t, J = 5.0 Hz), 2.46 (3H, s). 
ESI-MS(m/z): 455[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (2-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde (99 The title compound (99 mg, 74%) was obtained from mg, 0.292 mmol) and rhodanine (39 mg, 0.292 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.78 (1H, d, J = 1.2 Hz), 8.29 (1H, d, J = 8.3 Hz), 7.84 (1H, d, J = 8.3 Hz) , 7.65 (1H, s), 7.65 (1H, t, J = 8.9 Hz), 7.15 (1H, dd, J = 13.9, 2.7 Hz), 7.01 (1H, dd, J = 9.0, 2.4 Hz), 3.42 ( 4H, t, J = 4.9 Hz), 2.79 (4H, t, J = 5.0 Hz), 2.46 (3H, s).
ESI-MS (m / z): 455 [M + H] + .

実施例１０１
5-((3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１０１)  Example 101
5-((3- (2-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4- Dione (Compound 101)

Figure JPOXMLDOC01-appb-C000396
Figure JPOXMLDOC01-appb-C000396

工程１
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-カルボアルデヒド (106 mg, 0.312 mmol) およびチアゾリジン-2,4-ジオン (37 mg, 0.312 mmol) から標記化合物 (90 mg, 66%) を得た。黄土色固体: 1H-NMR (DMSO-D6) δ: 8.75 (1H, d, J = 1.0 Hz), 8.30 (1H, d, J = 8.3 Hz), 7.90 (1H, s), 7.83 (1H, d, J = 8.3 Hz), 7.60 (1H, t, J = 8.9 Hz), 7.12 (1H, dd, J = 14.1, 2.4 Hz), 6.99 (1H, dd, J = 9.0, 2.4 Hz), 3.33 (4H, t, J = 5.0 Hz), 2.55 (4H, t, J = 5.0 Hz), 2.30 (3H, s).
ESI-MS(m/z): 439[M+H]+. Process 1
Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (2-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde (106 mg, 0.312 mmol) and thiazolidine-2,4-dione (37 mg, 0.312 mmol) gave the title compound (90 mg, 66%). Ocher solid: 1 H-NMR (DMSO-D 6 ) δ: 8.75 (1H, d, J = 1.0 Hz), 8.30 (1H, d, J = 8.3 Hz), 7.90 (1H, s), 7.83 (1H , d, J = 8.3 Hz), 7.60 (1H, t, J = 8.9 Hz), 7.12 (1H, dd, J = 14.1, 2.4 Hz), 6.99 (1H, dd, J = 9.0, 2.4 Hz), 3.33 (4H, t, J = 5.0 Hz), 2.55 (4H, t, J = 5.0 Hz), 2.30 (3H, s).
ESI-MS (m / z): 439 [M + H] + .

実施例１０２
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１０２)  Example 102
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2 , 4-Dione (Compound 102)

工程１
tert-ブチル 4-(4-(5-ブロモ-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イル)フェニル)ピペラジン-1-カルボキシレート Process 1
tert-butyl 4- (4- (5-bromo-3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000397
Figure JPOXMLDOC01-appb-C000397

0 ℃ で tert-ブチル 4-(4-((3-アミノ-6-ブロモピリジン-2-イル)アミノ)フェニル)ピペラジン-1-カルボキシレート(1.5 g, 3.35 mmol) の塩化メチレン (5 mL)、水（5 mL）、酢酸（8 mL） 溶液に亜硝酸ナトリウム (608 mg, 12.66 mmol) を加え、室温で2 時間撹拌した。反応終了後、反応溶液に 飽和重層水を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、ろ過し、減圧下溶媒を留去し目的とする標記化合物 (1.56 g, quant.) を得た。
黄色オイル: 1H-NMR (DMSO-D6) δ: 8.63 (1H, d, J = 8.8 Hz), 7.86 (2H, d, J = 9.0 Hz), 7.77 (1H, d, J = 8.8 Hz), 7.23 (2H, d, J = 9.0 Hz), 3.50 (4H, t, J = 5.5 Hz), 3.26 (4H, t, J = 5.5 Hz), 1.44 (9H, s). Methylene chloride (5 mL) of tert-butyl 4- (4-((3-amino-6-bromopyridin-2-yl) amino) phenyl) piperazine-1-carboxylate (1.5 g, 3.35 mmol) at 0 ° C Sodium nitrite (608 mg, 12.66 mmol) was added to a solution of water (5 mL) and acetic acid (8 mL), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, saturated multistory water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain the title compound (1.56 g, quant.).
Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.63 (1H, d, J = 8.8 Hz), 7.86 (2H, d, J = 9.0 Hz), 7.77 (1H, d, J = 8.8 Hz) , 7.23 (2H, d, J = 9.0 Hz), 3.50 (4H, t, J = 5.5 Hz), 3.26 (4H, t, J = 5.5 Hz), 1.44 (9H, s).

工程２
5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン Process 2
5-Bromo-3- (4- (piperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000398
Figure JPOXMLDOC01-appb-C000398

tert-ブチル 4-(4-(5-ブロモ-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イル)フェニル)ピペラジン-1-カルボキシレート (1.56 g, 3.40 mmol) のクロロホルム (3 mL） 溶液に 0 ℃で トリフルオロ酢酸 (15 mL) を加え、室温で一晩撹拌した。反応終了後、減圧下、溶媒およびトリフルオロ酢酸を留去し、残渣にクロロホルムを加え、飽和重層水で洗浄した。水層をクロロホルムで抽出した後、有機層をあわせ、無水硫酸マグネシウムで乾燥した。ろ過した後、減圧下、溶媒を留去し、目的とする標記化合物 (358 mg, 30%) を得た。黄色オイル: 1H-NMR (CDCl3) δ: 8.28 (1H, d, J = 8.5 Hz), 8.06 (2H, d, J = 9.0 Hz), 7.55 (1H, d, J = 8.5 Hz), 7.11 (2H, d, J = 9.0 Hz), 3.35 (4H, t, J = 5.0 Hz), 3.17 (4H, t, J = 5.0 Hz), 1.78 (1H, br s). tert-Butyl 4- (4- (5-Bromo-3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl) phenyl) piperazine-1-carboxylate (1.56 g, 3.40 mmol ) In chloroform (3 mL) was added trifluoroacetic acid (15 mL) at 0 ° C., and the mixture was stirred overnight at room temperature. After completion of the reaction, the solvent and trifluoroacetic acid were distilled off under reduced pressure, and chloroform was added to the residue, followed by washing with saturated multistory water. The aqueous layer was extracted with chloroform, and then the organic layers were combined and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the desired title compound (358 mg, 30%). Yellow oil: 1 H-NMR (CDCl 3 ) δ: 8.28 (1H, d, J = 8.5 Hz), 8.06 (2H, d, J = 9.0 Hz), 7.55 (1H, d, J = 8.5 Hz), 7.11 (2H, d, J = 9.0 Hz), 3.35 (4H, t, J = 5.0 Hz), 3.17 (4H, t, J = 5.0 Hz), 1.78 (1H, br s).

工程３
5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン Process 3
5-Bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000399
Figure JPOXMLDOC01-appb-C000399

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン (358 mg, 1.0 mmol) のアセトニトリル (10 mL) 溶液に 37% ホルムアルデヒド水溶液 (508 mg, 7.0 mmol) を加え室温で 1 時間撹拌した。水素化トリアセトキシホウ素ナトリウム (625 mg, 3.0 mmol) を加え、一晩室温で撹拌した。反応終了後、反応溶液に飽和重層水を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、ろ過し、減圧下溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (164 mg, 45 %) を得た。黄色オイル: 1H-NMR (CDCl3) δ: 8.27 (1H, d, J = 8.5 Hz), 8.04 (2H, d, J = 9.0 Hz), 7.54 (1H, d, J = 8.5 Hz), 7.10 (2H, d, J = 9.0 Hz), 3.35 (4H, t, J = 5.1 Hz), 2.70 (4H, t, J = 5.1 Hz), 2.41 (3H, s). 5-Bromo-3- (4- (piperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine (358 mg, 1.0 mmol) in acetonitrile (10 mL) To the solution was added 37% aqueous formaldehyde solution (508 mg, 7.0 mmol), and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (625 mg, 3.0 mmol) was added, and the mixture was stirred overnight at room temperature. Saturated multistory water was added to the reaction solution after completion | finish of reaction, and chloroform extracted. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (164 mg, 45%). Yellow oil: 1 H-NMR (CDCl 3 ) δ: 8.27 (1H, d, J = 8.5 Hz), 8.04 (2H, d, J = 9.0 Hz), 7.54 (1H, d, J = 8.5 Hz), 7.10 (2H, d, J = 9.0 Hz), 3.35 (4H, t, J = 5.1 Hz), 2.70 (4H, t, J = 5.1 Hz), 2.41 (3H, s).

工程４
3-(4-(4-メチルピペラジン-1-イル)フェニル)-5-ビニル-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン Process 4
3- (4- (4-Methylpiperazin-1-yl) phenyl) -5-vinyl-3H- [1,2,3] triazolo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000400
Figure JPOXMLDOC01-appb-C000400

アルゴン気流下、5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン (164 mg, 0.44mmol)、トリブチルビニルスズ (152 mg, 0.48 mmol)、テトラキストリフェニルホスフィンパラジウム(46 mg, 0.04 mmol) のトルエン (50 mL) 溶液を一晩還流した。反応終了後反応溶液に飽和重層水を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、ろ過し、減圧下溶媒を留去した。得られた残渣をアセトニトリルに溶かし、アセトニトリル層をヘキサンで洗浄した。アセトニトリル層を回収し、溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (60 mg, 44 %) を得た。黄色オイル: 1H-NMR (CDCl3) δ: 8.35 (1H, d, J = 8.5 Hz), 8.15 (2H, d, J = 9.0 Hz), 7.49 (1H, d, J = 8.5 Hz), 7.11 (2H, d, J = 9.0 Hz), 6.98 (1H, dd, J = 17.6, 10.9 Hz), 6.40 (1H, d, J = 17.6 Hz), 5.67 (1H, d, J = 10.9 Hz), 3.33 (4H, t, J = 5.0 Hz), 2.62 (4H, t, J = 5.0 Hz), 2.39 (3H, s). Under a stream of argon, 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine (164 mg, 0.44 mmol ), A solution of tributylvinyltin (152 mg, 0.48 mmol), tetrakistriphenylphosphine palladium (46 mg, 0.04 mmol) in toluene (50 mL) was refluxed overnight. Saturated multistory water was added to the reaction solution after completion | finish of reaction, and chloroform extracted. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in acetonitrile, and the acetonitrile layer was washed with hexane. The acetonitrile layer was collected and the solvent was distilled off. The obtained crude product was purified by a silica gel column chromatography method (chloroform / methanol) to obtain the target title compound (60 mg, 44%). Yellow oil: 1 H-NMR (CDCl 3 ) δ: 8.35 (1H, d, J = 8.5 Hz), 8.15 (2H, d, J = 9.0 Hz), 7.49 (1H, d, J = 8.5 Hz), 7.11 (2H, d, J = 9.0 Hz), 6.98 (1H, dd, J = 17.6, 10.9 Hz), 6.40 (1H, d, J = 17.6 Hz), 5.67 (1H, d, J = 10.9 Hz), 3.33 (4H, t, J = 5.0 Hz), 2.62 (4H, t, J = 5.0 Hz), 2.39 (3H, s).

工程５
3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-カルボアルデヒド Process 5
3- (4- (4-Methylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000401
Figure JPOXMLDOC01-appb-C000401

3-(4-(4-メチルピペラジン-1-イル)フェニル)-5-ビニル-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン (60 mg, 0.19 mmol) の 水 (1 mL), 1,4-ジオキサン (3 mL) 混合溶液に、2,6-ルチジン (41 mg, 0.38 mmol)、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (23 m, 0.01 mmol)、過ヨウ素酸ナトリウム (163 mg, 0.76 mmol) を加え室温で 4 時間撹拌した。反応終了後、反応溶液に飽和チオ硫酸ナトリウム水溶液を加え、ろ過した。ろ液に、飽和重層水を加え、水層をクロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、ろ過し、減圧下溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (19 mg, 32 %) を得た。黄色オイル: 1H-NMR (CDCl3) δ: 10.19 (1H, s), 8.59 (1H, d, J = 8.5 Hz), 8.15 (2H, d, J = 9.0 Hz), 8.10 (1H, d, J = 8.5 Hz), 7.14 (2H, d, J = 9.0 Hz), 3.36 (4H, t, J = 5.0 Hz), 2.63 (4H, t, J = 5.0 Hz), 2.40 (3H, s). 3- (4- (4-Methylpiperazin-1-yl) phenyl) -5-vinyl-3H- [1,2,3] triazolo [4,5-b] pyridine (60 mg, 0.19 mmol) in water ( 1 mL), 1,4-dioxane (3 mL), 2,6-lutidine (41 mg, 0.38 mmol), 2.5 wt% osmium tetroxide tert-butanol solution (23 m, 0.01 mmol), periodate Sodium acid (163 mg, 0.76 mmol) was added and stirred at room temperature for 4 hours. After completion of the reaction, a saturated aqueous sodium thiosulfate solution was added to the reaction solution and filtered. Saturated multistory water was added to the filtrate, and the aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by a silica gel column chromatography method (chloroform / methanol) to obtain the target title compound (19 mg, 32%). Yellow oil: 1 H-NMR (CDCl 3 ) δ: 10.19 (1H, s), 8.59 (1H, d, J = 8.5 Hz), 8.15 (2H, d, J = 9.0 Hz), 8.10 (1H, d, J = 8.5 Hz), 7.14 (2H, d, J = 9.0 Hz), 3.36 (4H, t, J = 5.0 Hz), 2.63 (4H, t, J = 5.0 Hz), 2.40 (3H, s).

工程６
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１０２)  Step 6
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2 , 4-Dione (Compound 102)

Figure JPOXMLDOC01-appb-C000402
Figure JPOXMLDOC01-appb-C000402

3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-カルボアルデヒド (19 mg, 0.06 mmol)、チアゾリジン-2,4-ジオン (7 mg, 0.06 mmol) のエタノール (5 mL) 懸濁液にピペリジン (13 mg, 0.015 mmol) を加え 80 ℃で 20 時間撹拌した。反応溶液に酢酸エチルを加え、ろ過し、エタノールで洗浄した。結晶を回収し乾燥させ、目的とする標記化合物 (4 mg, 16 %) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 11.82 (1H, br s), 8.72 (1H, d, J = 8.5 Hz), 8.06 (2H, d, J = 9.0 Hz), 7.97 (1H, d, J = 8.5 Hz), 7.95 (1H, s), 7.25 (2H, d, J = 9.0 Hz), 3.38 (4H, t, J = 4.6 Hz), 2.74 (4H, t, J = 4.6 Hz), 2.42 (3H, s).  3- (4- (4-Methylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine-5-carbaldehyde (19 mg, 0.06 mmol), thiazolidine Piperidine (13 mg, 0.015 mmol) was added to a suspension of -2,4-dione (7 mg, 0.06 mmol) in ethanol (5 mL), and the mixture was stirred at 80 ° C. for 20 hours. Ethyl acetate was added to the reaction solution, filtered, and washed with ethanol. The crystals were collected and dried to obtain the desired title compound (4 mg, 16%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 11.82 (1H, br s), 8.72 (1H, d, J = 8.5 Hz), 8.06 (2H, d, J = 9.0 Hz), 7.97 (1H , d, J = 8.5 Hz), 7.95 (1H, s), 7.25 (2H, d, J = 9.0 Hz), 3.38 (4H, t, J = 4.6 Hz), 2.74 (4H, t, J = 4.6 Hz ), 2.42 (3H, s).

実施例１０３
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-インドール-5-イル)メチレン)チアゾリジン-2,4-ジオン （化合物１０３)  Example 103
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-indol-5-yl) methylene) thiazolidine-2,4-dione (Compound 103)

工程１
tert-ブチル 5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-インドール-1-カルボキシレート  Process 1
tert-butyl 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indole-1-carboxylate

Figure JPOXMLDOC01-appb-C000403
Figure JPOXMLDOC01-appb-C000403

アルゴン雰囲気下、tert-ブチル 5-ブロモ-3-ヨード-1H-インドール-1-カルボキシレート (1.00 g, 2.08 mmol)、1-メチル-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン (599 mg, 1.98 mmol)、テトラキストリフェニルホスフィンパラジウム(228 mg, 0.20 mmol)、炭酸カリウム (734 mg, 6.93 mmol) の 水 (4 mL), N, N-ジメチルホルムアミド (16 mL) 溶液を 90 ℃で 2 時間撹拌した。反応終了後、反応溶液に飽和重層水を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、ろ過し、減圧下溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (645 mg, 69 %) を得た。黄色オイル: 1H-NMR (CDCl3) δ: 8.08 (1H, d, J = 8.8 Hz), 7.90 (1H, d, J = 2.0 Hz), 7.61 (1H, s), 7.49 (2H, d, J = 9.0 Hz), 7.43 (1H, dd, J = 8.8, 2.0 Hz), 7.03 (2H, d, J = 9.0 Hz), 3.28 (4H, t, J = 5.0 Hz), 2.61 (4H, t, J = 5.0 Hz), 2.38 (3H, s), 1.68 (9H, s). Under an argon atmosphere, tert-butyl 5-bromo-3-iodo-1H-indole-1-carboxylate (1.00 g, 2.08 mmol), 1-methyl-4- (4- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine (599 mg, 1.98 mmol), tetrakistriphenylphosphine palladium (228 mg, 0.20 mmol), potassium carbonate (734 mg, 6.93 mmol) in water ( 4 mL), N, N-dimethylformamide (16 mL) solution was stirred at 90 ° C. for 2 hours. Saturated multistory water was added to the reaction solution after completion | finish of reaction, and chloroform extracted. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (645 mg, 69%). Yellow oil: 1 H-NMR (CDCl 3 ) δ: 8.08 (1H, d, J = 8.8 Hz), 7.90 (1H, d, J = 2.0 Hz), 7.61 (1H, s), 7.49 (2H, d, J = 9.0 Hz), 7.43 (1H, dd, J = 8.8, 2.0 Hz), 7.03 (2H, d, J = 9.0 Hz), 3.28 (4H, t, J = 5.0 Hz), 2.61 (4H, t, J = 5.0 Hz), 2.38 (3H, s), 1.68 (9H, s).

工程２
tert-ブチル 3-(4-(4-メチルピペラジン-1-イル)フェニル)-5-ビニル-1H-インドール-1-カルボキシレート  Process 2
tert-butyl 3- (4- (4-methylpiperazin-1-yl) phenyl) -5-vinyl-1H-indole-1-carboxylate

Figure JPOXMLDOC01-appb-C000404
Figure JPOXMLDOC01-appb-C000404

アルゴン雰囲気下、tert-ブチル 5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-インドール-1-カルボキシレート (645 mg, 1.37 mmol)、4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (422 mg, 2.74 mmol)、テトラキストリフェニルホスフィンパラジウム(158 mg, 0.14 mmol)、炭酸カリウム (508 mg, 4.80 mmol) の 水 (5.5 mL)、ジメトキシエタン (22 mL) 溶液を 90 ℃で一晩撹拌した。反応終了後、反応溶液に飽和重層水を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、ろ過し、減圧下溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (130 mg, 23 %) を得た。黄色オイル: 1H-NMR (CDCl3) δ: 8.13 (1H, d, J = 8.7 Hz), 7.78 (1H, d, J = 1.6 Hz), 7.61 (1H, s), 7.54 (2H, d, J = 8.8 Hz), 7.46 (1H, dd, J = 8.7, 1.6 Hz), 7.04 (2H, d, J = 8.8 Hz), 6.82 (1H, dd, J = 17.6, 10.7 Hz), 5.75 (1H, d, J = 17.6 Hz), 5.21 (1H, d, J = 10.7 Hz), 3.29 (4H, t, J = 5.0 Hz), 2.62 (4H, t, J = 5.0 Hz), 2.38 (3H, s), 1.68 (9H, s). Tert-butyl 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indole-1-carboxylate (645 mg, 1.37 mmol), 4,4,5 under argon atmosphere , 5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (422 mg, 2.74 mmol), tetrakistriphenylphosphine palladium (158 mg, 0.14 mmol), potassium carbonate (508 mg, 4.80 mmol) in water ( 5.5 mL) and dimethoxyethane (22 mL) were stirred at 90 ° C. overnight. Saturated multistory water was added to the reaction solution after completion | finish of reaction, and chloroform extracted. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (130 mg, 23%). Yellow oil: 1 H-NMR (CDCl 3 ) δ: 8.13 (1H, d, J = 8.7 Hz), 7.78 (1H, d, J = 1.6 Hz), 7.61 (1H, s), 7.54 (2H, d, J = 8.8 Hz), 7.46 (1H, dd, J = 8.7, 1.6 Hz), 7.04 (2H, d, J = 8.8 Hz), 6.82 (1H, dd, J = 17.6, 10.7 Hz), 5.75 (1H, d, J = 17.6 Hz), 5.21 (1H, d, J = 10.7 Hz), 3.29 (4H, t, J = 5.0 Hz), 2.62 (4H, t, J = 5.0 Hz), 2.38 (3H, s) , 1.68 (9H, s).

工程３
tert-ブチル 5-ホルミル-3-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-インドール-1-カルボキシレート  Process 3
tert-butyl 5-formyl-3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indole-1-carboxylate

Figure JPOXMLDOC01-appb-C000405
Figure JPOXMLDOC01-appb-C000405

tert-ブチル 3-(4-(4-メチルピペラジン-1-イル)フェニル)-5-ビニル-1H-インドール-1-カルボキシレート (130 mg, 0.31 mmol) の 水 (1 mL)、1,4-ジオキサン (3 mL) 混合溶液に、2,6-ルチジン (66 mg, 0.62 mmol)、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (39 mg, 0.05 mmol)、過ヨウ素酸ナトリウム (266 mg, 1.25 mmol) を加え室温で 4 時間撹拌した。反応終了後、反応溶液に飽和チオ硫酸ナトリウム水溶液を加え、ろ過した。ろ液に、飽和重層水を加え、水層をクロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、ろ過し、減圧下溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (81 mg, 62 %) を得た。黄色オイル: 1H-NMR (CDCl3) δ: 10.07 (1H, s), 8.35 (1H, d, J = 8.5 Hz), 8.32 (1H, d, J = 1.2 Hz), 7.90 (1H, dd, J = 8.5, 1.2 Hz), 7.71 (1H, s), 7.55 (2H, d, J = 8.8 Hz), 7.06 (2H, d, J = 8.8 Hz), 3.30 (4H, t, J = 5.0 Hz), 2.62 (4H, t, J = 5.0 Hz), 2.38 (3H, s), 1.70 (9H, s). tert-Butyl 3- (4- (4-methylpiperazin-1-yl) phenyl) -5-vinyl-1H-indole-1-carboxylate (130 mg, 0.31 mmol) in water (1 mL), 1,4 -Dioxane (3 mL) mixed solution, 2,6-lutidine (66 mg, 0.62 mmol), 2.5 wt% osmium tetroxide tert-butanol solution (39 mg, 0.05 mmol), sodium periodate (266 mg, 1.25 mmol) was added and stirred at room temperature for 4 hours. After completion of the reaction, a saturated aqueous sodium thiosulfate solution was added to the reaction solution and filtered. Saturated multistory water was added to the filtrate, and the aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound of interest (81 mg, 62%). Yellow oil: 1 H-NMR (CDCl 3 ) δ: 10.07 (1H, s), 8.35 (1H, d, J = 8.5 Hz), 8.32 (1H, d, J = 1.2 Hz), 7.90 (1H, dd, J = 8.5, 1.2 Hz), 7.71 (1H, s), 7.55 (2H, d, J = 8.8 Hz), 7.06 (2H, d, J = 8.8 Hz), 3.30 (4H, t, J = 5.0 Hz) , 2.62 (4H, t, J = 5.0 Hz), 2.38 (3H, s), 1.70 (9H, s).

工程４
3-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-インドール-5-カルボアルデヒド Process 4
3- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-indole-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000406
Figure JPOXMLDOC01-appb-C000406

tert-ブチル 5-ホルミル-3-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-インドール-1-カルボキシレート (130 mg, 0.31 mmol) のクロロホルム (5 mL) 溶液に 0 ℃で トリフルオロ酢酸 (4 mL) を加え、室温で一晩撹拌した。反応終了後、減圧下溶媒およびトリフルオロ酢酸を留去し、残渣にクロロホルムを加え、飽和重層水で洗浄した。水層をクロロホルムで抽出した後、有機層をあわせ、無水硫酸マグネシウムで乾燥した。ろ過した後、溶媒を減圧下留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (12 mg, 12 %) を得た。黄色結晶: 1H-NMR (CDCl3) δ: 10.04 (1H, s), 8.69 (1H, s), 8.41 (1H, d, J = 1.5 Hz), 7.81 (1H, dd, J = 8.5, 1.5 Hz), 7.57 (2H, d, J = 8.8 Hz), 7.49 (1H, dd, J = 8.5, 0.5 Hz), 7.38 (1H, dd, J = 2.4, 0.5 Hz), 7.05 (2H, d, J = 8.8 Hz), 3.29 (4H, t, J = 5.0 Hz), 2.64 (4H, t, J = 5.0 Hz), 2.39 (3H, s). tert-Butyl 5-formyl-3- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indole-1-carboxylate (130 mg, 0.31 mmol) in chloroform (5 mL) at 0 ° C Add trifluoroacetic acid (4 mL) and stir at room temperature overnight. After completion of the reaction, the solvent and trifluoroacetic acid were distilled off under reduced pressure, chloroform was added to the residue, and the mixture was washed with saturated multilayer water. The aqueous layer was extracted with chloroform, and then the organic layers were combined and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (12 mg, 12%). Yellow crystals: 1 H-NMR (CDCl 3 ) δ: 10.04 (1H, s), 8.69 (1H, s), 8.41 (1H, d, J = 1.5 Hz), 7.81 (1H, dd, J = 8.5, 1.5 Hz), 7.57 (2H, d, J = 8.8 Hz), 7.49 (1H, dd, J = 8.5, 0.5 Hz), 7.38 (1H, dd, J = 2.4, 0.5 Hz), 7.05 (2H, d, J = 8.8 Hz), 3.29 (4H, t, J = 5.0 Hz), 2.64 (4H, t, J = 5.0 Hz), 2.39 (3H, s).

工程５
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-インドール-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１０３) Process 5
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-indol-5-yl) methylene) thiazolidine-2,4-dione (Compound 103)

Figure JPOXMLDOC01-appb-C000407
Figure JPOXMLDOC01-appb-C000407

3-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-インドール-5-カルボアルデヒド (12 mg, 0.04 mmol)、チアゾリジン-2,4-ジオン (5 mg, 0.04 mmol) のエタノール (5 mL) 懸濁液にピペリジン (一滴) を加え80 ℃で 20 時間撹拌した。反応溶液に酢酸エチルを加え、ろ過し、エタノールで洗浄した。結晶を回収し乾燥させ、目的とする標記化合物 (2 mg, 12 %) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 11.97 (1H, br s), 11.57 (1H, d, J = 2.4 Hz), 8.11 (1H, d, J = 1.5 Hz), 7.87 (1H, s), 7.67 (1H, d, J = 2.4 Hz), 7.58 (2H, d, J = 8.5 Hz), 7.55 (1H, d, J = 9.0 Hz), 7.38 (1H, dd, J = 8.5, 1.5 Hz), 7.06 (2H, d, J = 9.0 Hz), 3.23 (4H, t, J = 4.4 Hz), 2.63 (4H, t, J = 4.4 Hz), 2.35 (3H, s). 3- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-indole-5-carbaldehyde (12 mg, 0.04 mmol), thiazolidine-2,4-dione (5 mg, 0.04 mmol) in ethanol (5 mL) Piperidine (one drop) was added to the suspension and stirred at 80 ° C. for 20 hours. Ethyl acetate was added to the reaction solution, filtered, and washed with ethanol. The crystals were collected and dried to obtain the desired title compound (2 mg, 12%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 11.97 (1H, br s), 11.57 (1H, d, J = 2.4 Hz), 8.11 (1H, d, J = 1.5 Hz), 7.87 (1H , s), 7.67 (1H, d, J = 2.4 Hz), 7.58 (2H, d, J = 8.5 Hz), 7.55 (1H, d, J = 9.0 Hz), 7.38 (1H, dd, J = 8.5, 1.5 Hz), 7.06 (2H, d, J = 9.0 Hz), 3.23 (4H, t, J = 4.4 Hz), 2.63 (4H, t, J = 4.4 Hz), 2.35 (3H, s).

実施例１０４
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[2,3-c]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１０４) Example 104
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [2,3-c] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 104)

工程１
2-クロロ-6-(ヒドロキシメチル)ピリジン-3-オール Process 1
2-Chloro-6- (hydroxymethyl) pyridin-3-ol

Figure JPOXMLDOC01-appb-C000408
Figure JPOXMLDOC01-appb-C000408

アルゴン雰囲気下、 2-クロロピリジン-3-オール (5.0 g, 38.6 mmol) を水 (35 mL) に懸濁した。そこへ炭酸水素ナトリウム (4.86 g, 57.9 mmol) を加え、90℃で溶解するまで撹拌した。37% ホルムアルデヒド水溶液 (10.55 mL, 135 mmol) を6回に分けて加えた (反応液を90℃にし、最初に3 mLを加え、90分毎に2 mLを3回、0.55 mLを1回加えた。さらに0.50 mLを15時間後に加えた)。90℃で4時間撹拌後、0℃に冷却し、氷 (20 mL) を加え、6規定塩酸 (10 mL) でpHを1に調整した後、0℃で90分撹拌した。反応液をろ過し、ろ液を酢酸エチルで抽出した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (4.38 g, 71%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 10.5 (1H, s), 7.33 (1H, d, J= 8.3 Hz), 7.27 (1H, dd, J = 8.3, 0.5 Hz), 5.36 (1H, s), 4.40 (2H, d, J= 4.4 Hz). Under an argon atmosphere, 2-chloropyridin-3-ol (5.0 g, 38.6 mmol) was suspended in water (35 mL). Sodium hydrogen carbonate (4.86 g, 57.9 mmol) was added thereto and stirred at 90 ° C. until dissolved. 37% aqueous formaldehyde solution (10.55 mL, 135 mmol) was added in 6 portions (the reaction solution was brought to 90 ° C, 3 mL was first added, 2 mL was added 3 times and 0.55 mL was added once every 90 minutes) An additional 0.50 mL was added after 15 hours). After stirring at 90 ° C for 4 hours, the mixture was cooled to 0 ° C, ice (20 mL) was added, pH was adjusted to 1 with 6N hydrochloric acid (10 mL), and the mixture was stirred at 0 ° C for 90 minutes. The reaction solution was filtered, and the filtrate was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (4.38 g, 71%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 10.5 (1H, s), 7.33 (1H, d, J = 8.3 Hz), 7.27 (1H, dd, J = 8.3, 0.5 Hz), 5.36 ( 1H, s), 4.40 (2H, d, J = 4.4 Hz).

工程２
2-クロロ-6-(ヒドロキシメチル)-4-ヨードピリジン-3-オール Process 2
2-Chloro-6- (hydroxymethyl) -4-iodopyridin-3-ol

Figure JPOXMLDOC01-appb-C000409
Figure JPOXMLDOC01-appb-C000409

アルゴン雰囲気下、2-クロロ-6-(ヒドロキシメチル)ピリジン-3-オール (4.38 g, 27.4 mmol) を水 (80 mL) に懸濁した。そこへ炭酸水素ナトリウム (6.90 g, 82.2 mmol) を加え、反応液が澄明になるまで撹拌した。ヨウ素 (7.30 g, 28.8 mmol) を加え、室温で40時間撹拌した。反応液に2規定硫酸水素ナトリウム水溶液を加えてpHを3に調整した後、酢酸エチルで抽出した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。生じた固体をろ取し、酢酸エチルで洗浄、真空乾燥して標記化合物 (4.31 g, 55%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 10.4 (1H, s), 7.75 (1H, s), 4.40 (2H, s). Under an argon atmosphere, 2-chloro-6- (hydroxymethyl) pyridin-3-ol (4.38 g, 27.4 mmol) was suspended in water (80 mL). Sodium hydrogen carbonate (6.90 g, 82.2 mmol) was added thereto, and the mixture was stirred until the reaction solution became clear. Iodine (7.30 g, 28.8 mmol) was added, and the mixture was stirred at room temperature for 40 hours. A 2N aqueous sodium hydrogen sulfate solution was added to the reaction solution to adjust the pH to 3, followed by extraction with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The resulting solid was collected by filtration, washed with ethyl acetate, and dried under vacuum to obtain the title compound (4.31 g, 55%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 10.4 (1H, s), 7.75 (1H, s), 4.40 (2H, s).

工程３
2-クロロ-6-(ヒドロキシメチル)-4-((トリメチルシリル)エチニル)ピリジン-3-オール Process 3
2-Chloro-6- (hydroxymethyl) -4-((trimethylsilyl) ethynyl) pyridin-3-ol

Figure JPOXMLDOC01-appb-C000410
Figure JPOXMLDOC01-appb-C000410

アルゴン雰囲気下、2-クロロ-6-(ヒドロキシメチル)-4-ヨードピリジン-3-オール (4.31 g, 15.1 mmol) をクロロホルム (30 mL)、テトラヒドロフラン (15 mL) に溶解した。そこへトリメチルシリルacetylene (3.25 mL, 21.1 mmol)、ジクロロビス(トリフェニルホスフィン)パラジウム (354 mg, 0.453 mmol)、ヨウ化銅(Ｉ) (48 mg, 0.227 mmol) を加え、反応容器内を脱気し、アルゴン置換した。そこへTEA (7.10 mL, 46.8 mmol) を加え、室温で90分撹拌した。反応液をクロロホルムで希釈し、1規定塩酸で洗浄した。水層をクロロホルムで抽出し、有機層をまとめて飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (3.13 g, 81%) を得た。黄色固体: H-NMR (DMSO-D6) δ: 10.3 (1H, s), 7.30 (1H, s), 5.40 (1H, t, J= 5.9 Hz), 4.39 (2H, d, J = 5.4 Hz), 0.25 (9H, s). Under an argon atmosphere, 2-chloro-6- (hydroxymethyl) -4-iodopyridin-3-ol (4.31 g, 15.1 mmol) was dissolved in chloroform (30 mL) and tetrahydrofuran (15 mL). Trimethylsilylacetylene (3.25 mL, 21.1 mmol), dichlorobis (triphenylphosphine) palladium (354 mg, 0.453 mmol) and copper (I) iodide (48 mg, 0.227 mmol) were added thereto, and the reaction vessel was degassed. And replaced with argon. TEA (7.10 mL, 46.8 mmol) was added there, and it stirred at room temperature for 90 minutes. The reaction mixture was diluted with chloroform and washed with 1N hydrochloric acid. The aqueous layer was extracted with chloroform, and the organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (3.13 g, 81%). Yellow solid: H-NMR (DMSO-D 6 ) δ: 10.3 (1H, s), 7.30 (1H, s), 5.40 (1H, t, J = 5.9 Hz), 4.39 (2H, d, J = 5.4 Hz ), 0.25 (9H, s).

工程４
(7-クロロフロ[2,3-c]ピリジン-5-イル)メタノール Process 4
(7-Chlorofuro [2,3-c] pyridin-5-yl) methanol

Figure JPOXMLDOC01-appb-C000411
Figure JPOXMLDOC01-appb-C000411

アルゴン雰囲気下、2-クロロ-6-(ヒドロキシメチル)-4-((トリメチルシリル)エチニルピリジン-3-オール(3.54 g, 13.8 mmol) をメタノール (25 mL) に溶解した。そこへヨウ化銅(Ｉ) (131 mg, 0.690 mmol)、ジイソプロピルアミン (3.30 mL, 23.5 mmol) を加え、50℃で6時間撹拌した。反応液を室温に冷却し、飽和重層水 (8 mL) を加え、次いで1規定水酸化ナトリウム水溶液 (16 mL) を加えて室温で終夜撹拌した。反応混合物をセライトを用いてろ過し、ろ液を濃縮した。得られた残渣に水を加え、クロロホルムで抽出した。クロロホルム層を無水硫酸マグネシウムで乾燥させ、溶媒を留去、真空乾燥して標記化合物 (1.79 g, 71%) を得た。 黄色固体: 1H-NMR (DMSO-D6) δ: 8.32 (1H, d, J = 2.0 Hz), 7.76 (1H, d, J = 0.5 Hz), 7.20 (1H, d, J = 2.2 Hz), 5.58 (1H, t, J = 5.9 Hz), 4.61 (2H, d, J = 5.9 Hz). Under an argon atmosphere, 2-chloro-6- (hydroxymethyl) -4-((trimethylsilyl) ethynylpyridin-3-ol (3.54 g, 13.8 mmol) was dissolved in methanol (25 mL), and copper iodide ( I) (131 mg, 0.690 mmol) and diisopropylamine (3.30 mL, 23.5 mmol) were added and stirred for 6 hours at 50 ° C. The reaction was cooled to room temperature, saturated multistory water (8 mL) was added, then 1 Normal aqueous sodium hydroxide solution (16 mL) was added, and the mixture was stirred overnight at room temperature, the reaction mixture was filtered through celite, the filtrate was concentrated, water was added to the resulting residue, and the mixture was extracted with chloroform. Was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was dried under vacuum to obtain the title compound (1.79 g, 71%) Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.32 (1H, d , J = 2.0 Hz), 7.76 (1H, d, J = 0.5 Hz), 7.20 (1H, d, J = 2.2 Hz), 5.58 (1H, t, J = 5.9 Hz), 4.61 (2H, d, J = 5.9 Hz).

工程５
フロ[2,3-c]ピリジン-5-イルメタノール  Process 5
Furo [2,3-c] pyridin-5-ylmethanol

Figure JPOXMLDOC01-appb-C000412
Figure JPOXMLDOC01-appb-C000412

アルゴン雰囲気下、(7-クロロフロ[2,3-c]ピリジン-5-イル)メタノール (1.79 g, 9.74 mmol) をエタノール (50 mL) に溶解した。そこへ亜鉛 (1.91 g, 29.2 mmol) を加え、 70℃に加熱した。さらに濃塩酸 (4.87 mL, 0.0195 mmol) を加え、1時間加熱還流した。反応液をセライトを用いてろ過し、ろ液を濃縮した。得られた残渣を酢酸エチル (53 mL) と水 (8 mL) に溶解し、20%炭酸水素ナトリウム水溶液 (17 mL) を滴下して1時間加熱還流した。酢酸エチル層を分け、水層をセライトを用いてろ過した。ろ液を酢酸エチルで抽出し、有機層を合わせて無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (316 mg, 22%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 8.84 (1H, s), 8.20 (1H, d, J= 2.2 Hz), 7.74 (1H, d, J = 0.7 Hz), 7.07 (1H, dd, J = 2.2, 1.0 Hz), 5.42 (1H, t, J = 5.9 Hz), 4.65 (2H, d, J = 5.6 Hz). Under an argon atmosphere, (7-chlorofuro [2,3-c] pyridin-5-yl) methanol (1.79 g, 9.74 mmol) was dissolved in ethanol (50 mL). Zinc (1.91 g, 29.2 mmol) was added there, and it heated at 70 degreeC. Further, concentrated hydrochloric acid (4.87 mL, 0.0195 mmol) was added, and the mixture was heated to reflux for 1 hour. The reaction solution was filtered using celite, and the filtrate was concentrated. The obtained residue was dissolved in ethyl acetate (53 mL) and water (8 mL), 20% aqueous sodium hydrogen carbonate solution (17 mL) was added dropwise, and the mixture was heated to reflux for 1 hr. The ethyl acetate layer was separated and the aqueous layer was filtered using celite. The filtrate was extracted with ethyl acetate, the organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (316 mg, 22%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 8.84 (1H, s), 8.20 (1H, d, J = 2.2 Hz), 7.74 (1H, d, J = 0.7 Hz), 7.07 (1H, dd, J = 2.2, 1.0 Hz), 5.42 (1H, t, J = 5.9 Hz), 4.65 (2H, d, J = 5.6 Hz).

工程６
フロ[2,3-c]ピリジン-5-イルメチル アセテート  Step 6
Furo [2,3-c] pyridin-5-ylmethyl acetate

Figure JPOXMLDOC01-appb-C000413
Figure JPOXMLDOC01-appb-C000413

アルゴン雰囲気下、フロ[2,3-c]ピリジン-5-イルメタノール (316 mg, 2.12 mmol) をピリジン (2 mL) に溶解した。そこへ無水酢酸 (601 μL, 6.36 mmol) を加え、室温で90分撹拌した。反応液を濃縮し、得られた残渣を酢酸エチルに再溶解して飽和重層水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去、真空乾燥して標記化合物 (381 mg, 94%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.92 (1H, d, J = 0.7 Hz), 8.26 (1H, dd, J = 2.2, 0.5 Hz), 7.75 (1H, s), 7.09-7.08 (1H, m), 5.21 (2H, s), 2.11 (3H, s). Under an argon atmosphere, furo [2,3-c] pyridin-5-ylmethanol (316 mg, 2.12 mmol) was dissolved in pyridine (2 mL). Acetic anhydride (601 μL, 6.36 mmol) was added thereto, and the mixture was stirred at room temperature for 90 minutes. The reaction solution was concentrated, and the resulting residue was redissolved in ethyl acetate and washed with saturated multistory water. The ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was dried under vacuum to obtain the title compound (381 mg, 94%). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.92 (1H, d, J = 0.7 Hz), 8.26 (1H, dd, J = 2.2, 0.5 Hz), 7.75 (1H, s), 7.09- 7.08 (1H, m), 5.21 (2H, s), 2.11 (3H, s).

工程７
(3-ブロモフロ[2,3-c]ピリジン-5-イル)メチル アセテート Step 7
(3-Bromofuro [2,3-c] pyridin-5-yl) methyl acetate

Figure JPOXMLDOC01-appb-C000414
Figure JPOXMLDOC01-appb-C000414

アルゴン雰囲気下、フロ[2,3-c]ピリジン-5-イルメチル アセテート (381 mg, 1.99 mmol) を塩化メチレン (10 mL) に溶解し、0℃に冷却した。そこへ臭素 (717 μL, 13.9 mmol) を加え、0℃で10分撹拌後、室温で48時間撹拌した。反応液に飽和チオ硫酸ナトリウム水溶液を加えてクエンチし、クロロホルムで抽出した。クロロホルム層を飽和重層水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (145 mg, 27%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 9.00 (1H, s), 8.58 (1H, s), 7.65 (1H, s), 5.25 (2H, s), 2.12 (3H, s). Under an argon atmosphere, furo [2,3-c] pyridin-5-ylmethyl acetate (381 mg, 1.99 mmol) was dissolved in methylene chloride (10 mL) and cooled to 0 ° C. Bromine (717 μL, 13.9 mmol) was added thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 48 hours. The reaction solution was quenched by adding a saturated aqueous sodium thiosulfate solution, and extracted with chloroform. The chloroform layer was washed with saturated multilayer water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (145 mg, 27%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 9.00 (1H, s), 8.58 (1H, s), 7.65 (1H, s), 5.25 (2H, s), 2.12 (3H, s).

工程８
(3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[2,3-c]ピリジン-5-イル)メチル アセテート  Process 8
(3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [2,3-c] pyridin-5-yl) methyl acetate

Figure JPOXMLDOC01-appb-C000415
Figure JPOXMLDOC01-appb-C000415

6-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジンの合成(実施例48、工程4 ) と同様の手法で、(3-ブロモフロ[2,3-c]ピリジン-5-イル)メチル アセテート (145 mg, 0.537 mmol) および1-メチル-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン (195 mg, 0.644 mmol) から標記化合物 (86 mg, 44%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.96 (1H, d, J = 0.7 Hz), 8.54 (1H, s), 7.98 (1H, s), 7.61 (2H, d, J = 8.8 Hz), 7.08 (2H, d, J= 8.8 Hz), 5.25 (2H, s), 3.21 (4H, t, J= 5.0 Hz), 2.47 (4H, t, J = 5.2 Hz), 2.24 (3H, s), 2.10 (3H, s). Synthesis of 6-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine (Example 48, Step 4) [2,3-c] pyridin-5-yl) methyl acetate (145 mg, 0.537 mmol) and 1-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2- The title compound (86 mg, 44%) was obtained from dioxaborolan-2-yl) phenyl) piperazine (195 mg, 0.644 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.96 (1H, d, J = 0.7 Hz), 8.54 (1H, s), 7.98 (1H, s), 7.61 (2H, d, J = 8.8 Hz), 7.08 (2H, d, J = 8.8 Hz), 5.25 (2H, s), 3.21 (4H, t, J = 5.0 Hz), 2.47 (4H, t, J = 5.2 Hz), 2.24 (3H, s), 2.10 (3H, s).

工程９
(3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[2,3-c]ピリジン-5-イル)メタノール Step 9
(3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [2,3-c] pyridin-5-yl) methanol

Figure JPOXMLDOC01-appb-C000416
Figure JPOXMLDOC01-appb-C000416

アルゴン雰囲気下、(3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[2,3-c]ピリジン-5-イル)メチル アセテート (86 mg, 0.235 mmol) をメタノール (2 mL) に溶解し、0℃に冷却した。そこへナトリウムメトキシド メタノール溶液 (47 μL, 0.235 mmol) を加え、0℃で10分撹拌後、室温で30分撹拌した。反応液に飽和食塩水を加え、クロロホルムで抽出した。クロロホルム層を無水硫酸マグネシウムで乾燥させ、溶媒を留去、真空乾燥して標記化合物 (42 mg, 55%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.7 Hz), 8.36 (1H, s), 8.08 (2H, d, J = 9.0 Hz), 7.61 (1H, d, J = 9.3 Hz), 7.11 (2H, d, J = 9.0 Hz), 3.25 (4H, t, J = 5.0 Hz), 2.50-2.46 (4H, m), 2.24 (3H, s). (3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [2,3-c] pyridin-5-yl) methyl acetate (86 mg, 0.235 mmol) in methanol (2 mL) ) And cooled to 0 ° C. Sodium methoxide methanol solution (47 μL, 0.235 mmol) was added thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 30 minutes. Saturated saline was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was dried under vacuum to obtain the title compound (42 mg, 55%). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.7 Hz), 8.36 (1H, s), 8.08 (2H , d, J = 9.0 Hz), 7.61 (1H, d, J = 9.3 Hz), 7.11 (2H, d, J = 9.0 Hz), 3.25 (4H, t, J = 5.0 Hz), 2.50-2.46 (4H m), 2.24 (3H, s).

工程１０
3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[2,3-c]ピリジン-5-カルボアルデヒド  Step 10
3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [2,3-c] pyridine-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000417
Figure JPOXMLDOC01-appb-C000417

3-(3-((4-ヒドロキシピペリジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボキシカルボアルデヒドの合成 (実施例48、工程4 ) と同様の手法で、(3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[2,3-c]ピリジン-5-イル)メタノール (42 mg, 0.130 mmol) および二酸化マンガン (200 mg) から標記化合物 (31 mg, 74%) を得た。薄黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 10.1 (1H, s), 9.23 (1H, d, J= 0.7 Hz), 8.69 (1H, s), 8.46 (1H, d, J= 0.7 Hz), 7.65 (2H, d, J = 8.8 Hz), 7.11 (2H, d, J = 8.8 Hz), 3.23 (4H, t, J = 5.0 Hz), 2.50-2.46 (4H, m), 2.24 (3H, s). Synthesis of 3- (3-((4-hydroxypiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carboxycarbaldehyde (Example 48, Step 4) , (3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [2,3-c] pyridin-5-yl) methanol (42 mg, 0.130 mmol) and manganese dioxide (200 mg) The compound (31 mg, 74%) was obtained. Pale yellow amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, s), 9.23 (1H, d, J = 0.7 Hz), 8.69 (1H, s), 8.46 (1H, d, J = 0.7 Hz), 7.65 (2H, d, J = 8.8 Hz), 7.11 (2H, d, J = 8.8 Hz), 3.23 (4H, t, J = 5.0 Hz), 2.50-2.46 (4H, m) , 2.24 (3H, s).

工程１１
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[2,3-c]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１０４) Step 11
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [2,3-c] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 104)

Figure JPOXMLDOC01-appb-C000418
Figure JPOXMLDOC01-appb-C000418

5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[2,3-c]ピリジン-5-カルボアルデヒド (31 mg, 0.097 mmol) およびチアゾリジン-2,4-ジオン (11 mg, 0.097 mmol) から標記化合物 (17 mg, 42%)を得た。白色固体: 1H-NMR (DMSO-D6) δ: 9.16 (1H, s), 8.63 (1H, s), 8.55 (1H, s), 7.99 (1H, s), 7.68 (2H, d, J= 8.8 Hz), 7.08 (2H, d, J = 8.8 Hz), 3.24 (4H, t, J = 4.9 Hz), 2.54 (4H, t, J = 5.0 Hz), 2.28 (3H, s). 
ESI-MS(m/z): 421[M+H]+. Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) Method, 3- (4- (4-methylpiperazin-1-yl) phenyl) furo [2,3-c] pyridine-5-carbaldehyde (31 mg, 0.097 mmol) and thiazolidine-2,4-dione ( The title compound (17 mg, 42%) was obtained from 11 mg, 0.097 mmol). White solid: 1 H-NMR (DMSO-D 6 ) δ: 9.16 (1H, s), 8.63 (1H, s), 8.55 (1H, s), 7.99 (1H, s), 7.68 (2H, d, J = 8.8 Hz), 7.08 (2H, d, J = 8.8 Hz), 3.24 (4H, t, J = 4.9 Hz), 2.54 (4H, t, J = 5.0 Hz), 2.28 (3H, s).
ESI-MS (m / z): 421 [M + H] + .

実施例１０５
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[2,3-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１０５)  Example 105
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [2,3-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 105)

工程１
メチル 6-ヒドロキシニコチネート  Process 1
Methyl 6-hydroxynicotinate

Figure JPOXMLDOC01-appb-C000419
Figure JPOXMLDOC01-appb-C000419

アルゴン雰囲気下、6-ヒドロキシニコチン酸 (5.0 g, 35.9 mmol) をメタノール (50 mL) に懸濁した。そこへ濃硫酸 (2 mL) を加え、15時間加熱還流した。反応液を濃縮し、得られた残渣を水に再溶解して飽和重層水でpHを8に調整した後、酢酸エチルで抽出した。酢酸エチル層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた固体をエーテルで洗浄して標記化合物 (白色固体, 2.94 g, 54%) を得た。 1H-NMR (DMSO-D6) δ: 12.1 (1H, br.s), 8.04 (1H, dd, J = 2.7, 0.5 Hz), 7.79 (1H, dd, J = 9.6, 2.6 Hz), 6.37 (1H, dd, J = 9.6, 0.6 Hz), 3.77 (3H, s). 6-Hydroxynicotinic acid (5.0 g, 35.9 mmol) was suspended in methanol (50 mL) under an argon atmosphere. Concentrated sulfuric acid (2 mL) was added there, and it heated and refluxed for 15 hours. The reaction mixture was concentrated, and the resulting residue was redissolved in water, adjusted to pH 8 with saturated multistory water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained solid was washed with ether to obtain the title compound (white solid, 2.94 g, 54%). 1 H-NMR (DMSO-D 6 ) δ: 12.1 (1H, br.s), 8.04 (1H, dd, J = 2.7, 0.5 Hz), 7.79 (1H, dd, J = 9.6, 2.6 Hz), 6.37 (1H, dd, J = 9.6, 0.6 Hz), 3.77 (3H, s).

工程２
メチル 6-ヒドロキシ-5-ヨードニコチネート  Process 2
Methyl 6-hydroxy-5-iodonicotinate

Figure JPOXMLDOC01-appb-C000420
Figure JPOXMLDOC01-appb-C000420

アルゴン雰囲気下、メチル 6-ヒドロキシニコチネート (2.94 g, 19.2 mmol) をメタノール (30 mL) に懸濁した。そこへN-ヨードコハク酸イミド (4.32 g, 19.2 mmol) を加え、50℃で1時間撹拌した。さらに濃塩酸 (0.15 mL) を加え、 50℃で20時間撹拌した。反応液を0℃に冷却し、水 (120 mL) を加え、析出物をろ取し、水で洗浄、真空乾燥して標記化合物 (3.88 g, 72.5%) を得た。 1H-NMR (DMSO-D6) δ: 12.5 (1H, br.s), 8.37 (1H, d, J= 2.4 Hz), 8.10 (1H, d, J = 2.2 Hz), 3.33 (3H, s). Methyl 6-hydroxynicotinate (2.94 g, 19.2 mmol) was suspended in methanol (30 mL) under an argon atmosphere. N-iodosuccinimide (4.32 g, 19.2 mmol) was added there, and it stirred at 50 degreeC for 1 hour. Concentrated hydrochloric acid (0.15 mL) was further added, and the mixture was stirred at 50 ° C. for 20 hours. The reaction mixture was cooled to 0 ° C., water (120 mL) was added, the precipitate was collected by filtration, washed with water, and dried in vacuo to give the title compound (3.88 g, 72.5%). 1 H-NMR (DMSO-D 6 ) δ: 12.5 (1H, br.s), 8.37 (1H, d, J = 2.4 Hz), 8.10 (1H, d, J = 2.2 Hz), 3.33 (3H, s ).

工程３
メチル 6-ヒドロキシ-5-((トリメチルシリル)エチニル)ニコチネート Process 3
Methyl 6-hydroxy-5-((trimethylsilyl) ethynyl) nicotinate

Figure JPOXMLDOC01-appb-C000421
Figure JPOXMLDOC01-appb-C000421

アルゴン雰囲気下、メチル 6-ヒドロキシ-5-ヨードニコチネート(5.19 g, 18.6 mmol) をテトラヒドロフラン (36 mL) に溶解した。そこへ酢酸パラジウム (42 mg, 0.186 mmol)、トリフェニルホスフィン (98 mg, 0.372 mmol)、n-ブチルアミン (3.91 mL, 37.2 mmol)、ヨウ化銅(Ｉ) (71 mg, 0.372 mmol) を加え、反応容器内を脱気し、アルゴン置換した。そこへトリメチルシリルアセイレン(3.34 mL, 24.2 mmol) を加え、室温で16時間撹拌した。反応液をクロロホルムで希釈し、1規定塩酸で洗浄した。水層をクロロホルムで抽出し、有機層をまとめて飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (4.12 g, 89%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 12.6 (1H, s), 8.08 (1H, d, J= 2.2 Hz), 7.92 (1H, d, J = 2.7 Hz), 3.77 (3H, s), 0.22 (9H, s). Methyl 6-hydroxy-5-iodonicotinate (5.19 g, 18.6 mmol) was dissolved in tetrahydrofuran (36 mL) under an argon atmosphere. Palladium acetate (42 mg, 0.186 mmol), triphenylphosphine (98 mg, 0.372 mmol), n-butylamine (3.91 mL, 37.2 mmol), copper (I) iodide (71 mg, 0.372 mmol) were added thereto, The inside of the reaction vessel was evacuated and purged with argon. Trimethylsilylaceylene (3.34 mL, 24.2 mmol) was added there, and it stirred at room temperature for 16 hours. The reaction mixture was diluted with chloroform and washed with 1N hydrochloric acid. The aqueous layer was extracted with chloroform, and the organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (4.12 g, 89%). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 12.6 (1H, s), 8.08 (1H, d, J = 2.2 Hz), 7.92 (1H, d, J = 2.7 Hz), 3.77 (3H , s), 0.22 (9H, s).

工程４
メチル フロ[2,3-b]ピリジン-5-カルボキシレート Process 4
Methyl furo [2,3-b] pyridine-5-carboxylate

Figure JPOXMLDOC01-appb-C000422
Figure JPOXMLDOC01-appb-C000422

アルゴン雰囲気下、メチル 6-ヒドロキシ-5-((トリメチルシリル)エチニル)ニコチネート (4.11 g, 16.5 mmol) をエタノール (25 mL) に溶解した。そこへヨウ化銅(Ｉ) (157 mg, 0.825 mmol) を加え、トリエチルアミン (25 mL) で希釈し、70℃で5時間撹拌した。さらに炭酸カリウム (2.28 g, 16.5 mmol) を加え、70℃で7時間撹拌した。反応液を室温に冷却し、メタノール (25 mL) で希釈した後、活性炭 (1.3 g) を加え、 30分加熱還流した。反応混合物をセライトを用いてろ過し、ろ液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (425 mg, 15%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 8.88 (1H, d, J = 2.2 Hz), 8.69 (1H, d, J = 2.2 Hz), 8.26 (1H, d, J = 2.4 Hz), 7.16 (1H, d, J = 2.4 Hz), 3.92 (3H, s). Methyl 6-hydroxy-5-((trimethylsilyl) ethynyl) nicotinate (4.11 g, 16.5 mmol) was dissolved in ethanol (25 mL) under an argon atmosphere. Copper (I) iodide (157 mg, 0.825 mmol) was added thereto, diluted with triethylamine (25 mL), and stirred at 70 ° C. for 5 hours. Furthermore, potassium carbonate (2.28 g, 16.5 mmol) was added, and the mixture was stirred at 70 ° C. for 7 hours. The reaction mixture was cooled to room temperature, diluted with methanol (25 mL), activated carbon (1.3 g) was added, and the mixture was heated to reflux for 30 min. The reaction mixture was filtered using celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (425 mg, 15%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 8.88 (1H, d, J = 2.2 Hz), 8.69 (1H, d, J = 2.2 Hz), 8.26 (1H, d, J = 2.4 Hz) , 7.16 (1H, d, J = 2.4 Hz), 3.92 (3H, s).

工程５
エチル 3-ブロモフロ[2,3-b]ピリジン-5-カルボキシレート  Process 5
Ethyl 3-bromofuro [2,3-b] pyridine-5-carboxylate

Figure JPOXMLDOC01-appb-C000423
Figure JPOXMLDOC01-appb-C000423

アルゴン雰囲気下、メチル フロ[2,3-b]ピリジン-5-カルボキシレート (675 mg, 3.81 mmol) を塩化メチレン (12 mL) に溶解し、0℃に冷却した。そこへ臭素 (9.8 mL, 190 mmol) を加え、0℃で10分撹拌後、室温で3時間撹拌した。反応液に飽和チオ硫酸ナトリウム水溶液を加えてクエンチし、クロロホルムで抽出した。クロロホルム層を飽和重層水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、白色固体 (710 mg) を得た。この白色固体をテトラヒドロフラン (10 mL) に溶解し、0℃に冷却した。そこへ 1M 水酸化カリウム エタノール溶液 (3 mL) を加え、0℃で10分撹拌後、室温で5分撹拌した。反応液に水を加え、酢酸エチルで抽出した。酢酸エチル層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去、真空乾燥して標記化合物 (521 mg, 51%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 8.95 (1H, d, J = 2.2 Hz), 8.61 (1H, d, J = 4.4 Hz), 8.47 (1H, dd, J = 3.7, 2.4 Hz), 4.40 (2H, q, J = 7.2 Hz), 1.38 (3H, t, J = 7.2 Hz).  Under an argon atmosphere, methyl furo [2,3-b] pyridine-5-carboxylate (675 mg, 3.81 mmol) was dissolved in methylene chloride (12 mL) and cooled to 0 ° C. Bromine (9.8 mL, 190 mmol) was added thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 3 hours. The reaction solution was quenched by adding a saturated aqueous sodium thiosulfate solution, and extracted with chloroform. The chloroform layer was washed with saturated multilayer water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give a white solid (710 mg). This white solid was dissolved in tetrahydrofuran (10 mL) and cooled to 0 ° C. 1M potassium hydroxide ethanol solution (3 mL) was added thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 5 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was dried under vacuum to obtain the title compound (521 mg, 51%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 8.95 (1H, d, J = 2.2 Hz), 8.61 (1H, d, J = 4.4 Hz), 8.47 (1H, dd, J = 3.7, 2.4 Hz), 4.40 (2H, q, J = 7.2 Hz), 1.38 (3H, t, J = 7.2 Hz).

工程６
エチル 3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[2,3-b]ピリジン-5-カルボキシレート Step 6
Ethyl 3- (4- (4-methylpiperazin-1-yl) phenyl) furo [2,3-b] pyridine-5-carboxylate

Figure JPOXMLDOC01-appb-C000424
Figure JPOXMLDOC01-appb-C000424

6-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジンの合成(実施例48、工程4) と同様の手法で、エチル 3-ブロモフロ[2,3-b]ピリジン-5-カルボキシレート (354 mg, 1.31 mmol) および1-メチル-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン (473 mg, 1.57 mmol) から標記化合物　(227 mg, 47%) を得た。標記化合物 (227 mg, 47%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 10.1 (1H, s), 9.23 (1H, d, J= 0.7 Hz), 8.69 (1H, s), 8.46 (1H, d, J= 0.7 Hz), 7.65 (2H, d, J = 8.8 Hz), 7.11 (2H, d, J = 8.8 Hz), 3.23 (4H, t, J = 5.0 Hz), 2.50-2.46 (4H, m), 2.24 (3H, s). Synthesis of 6-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine (Example 48, Step 4) [2,3-b] pyridine-5-carboxylate (354 mg, 1.31 mmol) and 1-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- The title compound (227 mg, 47%) was obtained from 2-yl) phenyl) piperazine (473 mg, 1.57 mmol). The title compound (227 mg, 47%) was obtained. Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, s), 9.23 (1H, d, J = 0.7 Hz), 8.69 (1H, s), 8.46 (1H, d, J = 0.7 Hz), 7.65 (2H, d, J = 8.8 Hz), 7.11 (2H, d, J = 8.8 Hz), 3.23 (4H, t, J = 5.0 Hz), 2.50-2.46 (4H, m), 2.24 (3H, s).

工程７
(3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[2,3-b]ピリジン-5-イル)メタノール  Step 7
(3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [2,3-b] pyridin-5-yl) methanol

Figure JPOXMLDOC01-appb-C000425
Figure JPOXMLDOC01-appb-C000425

(1-(3-(2-モルホリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノールの合成(実施例23、工程4) と同様の手法で、エチル 3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[2,3-b]ピリジン-5-カルボキシレート (227 mg, 0.621 mmol) およびリチウムアルミニウムヒドリド テトラヒドロフラン溶液 (1.0 M, 1.86 mL, 1.86 mmol) から標記化合物 (64 mg, 32%)を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.38 (1H, s), 8.30 (2H, d, J = 1.7 Hz), 7.61 (2H, d, J = 8.8 Hz), 7.08 (2H, d, J = 8.8 Hz), 5.38 (1H, t, J = 5.7 Hz), 4.67 (2H, d, J = 5.9 Hz), 3.21 (4H, t, J = 5.0 Hz), 2.50-2.47 (4H, m), 2.24 (3H, s). Synthesis of (1- (3- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methanol (Example 23, Step 4) From (4-methylpiperazin-1-yl) phenyl) furo [2,3-b] pyridine-5-carboxylate (227 mg, 0.621 mmol) and lithium aluminum hydride in tetrahydrofuran (1.0 M, 1.86 mL, 1.86 mmol) The title compound (64 mg, 32%) was obtained. Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.38 (1H, s), 8.30 (2H, d, J = 1.7 Hz), 7.61 (2H, d, J = 8.8 Hz), 7.08 (2H , d, J = 8.8 Hz), 5.38 (1H, t, J = 5.7 Hz), 4.67 (2H, d, J = 5.9 Hz), 3.21 (4H, t, J = 5.0 Hz), 2.50-2.47 (4H m), 2.24 (3H, s).

工程８
3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[2,3-b]ピリジン-5-カルボアルデヒド Process 8
3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [2,3-b] pyridine-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000426
Figure JPOXMLDOC01-appb-C000426

3-(3-((4-ヒドロキシピペリジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボキシカルボアルデヒドの合成 (実施例48、工程4 ) と同様の手法で、(3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[2,3-b]ピリジン-5-イル)メタノール (64 mg, 0.198 mmol) および二酸化マンガン (300 mg) から標記化合物 (31 mg, 49%) を得た。黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 10.2 (1H, s), 8.92 (1H, d, J= 2.0 Hz), 8.85 (1H, d, J = 2.0 Hz), 8.58 (1H, s), 7.67 (2H, d, J= 8.8 Hz), 7.10 (2H, d, J = 8.8 Hz), 3.22 (4H, t, J = 5.0 Hz), 2.50-2.46 (4H, m), 2.24 (3H, s). Synthesis of 3- (3-((4-hydroxypiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carboxycarbaldehyde (Example 48, Step 4) , (3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [2,3-b] pyridin-5-yl) methanol (64 mg, 0.198 mmol) and manganese dioxide (300 mg) The compound (31 mg, 49%) was obtained. Yellow amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 10.2 (1H, s), 8.92 (1H, d, J = 2.0 Hz), 8.85 (1H, d, J = 2.0 Hz), 8.58 ( 1H, s), 7.67 (2H, d, J = 8.8 Hz), 7.10 (2H, d, J = 8.8 Hz), 3.22 (4H, t, J = 5.0 Hz), 2.50-2.46 (4H, m), 2.24 (3H, s).

工程９
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[2,3-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１０５)  Step 9
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [2,3-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 105)

Figure JPOXMLDOC01-appb-C000427
Figure JPOXMLDOC01-appb-C000427

5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成 (実施例1、工程5) と同様の手法で、3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[2,3-b]ピリジン-5- カルボアルデヒド (31 mg, 0.097 mmol) およびチアゾリジン-2,4-ジオン (11 mg, 0.097 mmol) から標記化合物 (6 mg, 15%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.59 (1H, d, J = 2.2 Hz), 8.51 (1H, d, J = 2.2 Hz), 8.50 (1H, s), 7.80 (1H, s), 7.66 (2H, d, J = 8.8 Hz), 7.15 (2H, d, J = 9.0 Hz), 3.35 (4H, s), 2.84 (4H, s), 2.50 (3H, s).
ESI-MS(m/z): 421[M+H]+. Synthesis of 5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Example 1, Step 5) Method, 3- (4- (4-methylpiperazin-1-yl) phenyl) furo [2,3-b] pyridine-5-carbaldehyde (31 mg, 0.097 mmol) and thiazolidine-2,4-dione ( The title compound (6 mg, 15%) was obtained from 11 mg, 0.097 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.59 (1H, d, J = 2.2 Hz), 8.51 (1H, d, J = 2.2 Hz), 8.50 (1H, s), 7.80 (1H, s), 7.66 (2H, d, J = 8.8 Hz), 7.15 (2H, d, J = 9.0 Hz), 3.35 (4H, s), 2.84 (4H, s), 2.50 (3H, s).
ESI-MS (m / z): 421 [M + H] + .

実施例１０６
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１０６)  Example 106
5-((3- (4- (4-methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridin-5-yl) methylene) -2-thioxothiazolidin-4-one (Compound 106 )

工程１
2-ブロモピリジン-3-イル アセテート Process 1
2-Bromopyridin-3-yl acetate

Figure JPOXMLDOC01-appb-C000428
Figure JPOXMLDOC01-appb-C000428

アルゴン雰囲気下、2-ブロモ-3-ヒドロキシピリジン (5.0 g, 28.7 mmol) を塩化メチレン (75 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (15.7 mL, 114.8 mmol) を加えた。さらにアセチルクロリド (4.08 mL, 57.4 mmol) の塩化メチレン溶液 (25 mL) を滴下し、室温まで徐々に昇温させながら16時間撹拌した。反応液をろ過し、ろ液を水で洗浄した。水層を酢酸エチルで抽出し、有機層を合わせて無水硫酸マグネシウムで乾燥させ、溶媒を留去、真空乾燥して標記化合物 (5.61 g, 90%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.33 (1H, dd, J = 4.4, 1.7 Hz), 7.80 (1H, dd, J = 8.3, 1.7 Hz), 7.57-7.54 (1H, m), 2.37 (3H, s). Under an argon atmosphere, 2-bromo-3-hydroxypyridine (5.0 g, 28.7 mmol) was dissolved in methylene chloride (75 mL) and cooled to 0 ° C. Triethylamine (15.7 mL, 114.8 mmol) was added there. Further, a methylene chloride solution (25 mL) of acetyl chloride (4.08 mL, 57.4 mmol) was added dropwise, and the mixture was stirred for 16 hours while gradually warming to room temperature. The reaction solution was filtered, and the filtrate was washed with water. The aqueous layer was extracted with ethyl acetate, the organic layers were combined and dried over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was dried under vacuum to obtain the title compound (5.61 g, 90%). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.33 (1H, dd, J = 4.4, 1.7 Hz), 7.80 (1H, dd, J = 8.3, 1.7 Hz), 7.57-7.54 (1H, m ), 2.37 (3H, s).

工程２
フロ[3,2-b]ピリジン  Process 2
Furo [3,2-b] pyridine

Figure JPOXMLDOC01-appb-C000429
Figure JPOXMLDOC01-appb-C000429

アルゴン雰囲気下、ジクロロビス(トリフェニルホスフィン)パラジウム(594 mg, 0.779 mmol)、ヨウ化銅(Ｉ) (297 mg, 1.56 mmol) をテトラヒドロフラン (130 mL) に懸濁した。そこへトリエチルアミン (53 mL, 389.7 mmol) を加えた。さらに2-ブロモピリジン-3-イル アセテート (5.61 g, 26.0 mmol) とトリメチルシリルアセチレン (4.67 mL, 33.8 mmol) のテトラヒドロフラン溶液 (20 mL) を加え、室温で90分撹拌した。反応液をセライトでろ過し、ろ液を濃縮した。得られた残渣をメタノール(60 mL) に溶解し、フッ化カリウム (5.43 g, 93.5 mmol) を少量ずつ加え、室温で20時間撹拌した。反応液をセライトでろ過し、ろ液を濃縮した。得られた残渣を酢酸エチルに溶解し、水、飽和チオ硫酸ナトリウム水溶液で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (2.20 g, 71%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.54-8.52 (1H, m), 8.32 (1H, dd, J = 2.3, 0.6 Hz), 8.06-8.03 (1H, m), 7.36-7.33 (1H, m), 7.15-7.14 (1H, m). Under an argon atmosphere, dichlorobis (triphenylphosphine) palladium (594 mg, 0.779 mmol) and copper (I) iodide (297 mg, 1.56 mmol) were suspended in tetrahydrofuran (130 mL). Triethylamine (53 mL, 389.7 mmol) was added there. Furthermore, a tetrahydrofuran solution (20 mL) of 2-bromopyridin-3-yl acetate (5.61 g, 26.0 mmol) and trimethylsilylacetylene (4.67 mL, 33.8 mmol) was added, and the mixture was stirred at room temperature for 90 minutes. The reaction solution was filtered through celite, and the filtrate was concentrated. The obtained residue was dissolved in methanol (60 mL), potassium fluoride (5.43 g, 93.5 mmol) was added little by little, and the mixture was stirred at room temperature for 20 hr. The reaction solution was filtered through celite, and the filtrate was concentrated. The obtained residue was dissolved in ethyl acetate and washed with water and a saturated aqueous sodium thiosulfate solution. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.20 g, 71%). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.54-8.52 (1H, m), 8.32 (1H, dd, J = 2.3, 0.6 Hz), 8.06-8.03 (1H, m), 7.36-7.33 (1H, m), 7.15-7.14 (1H, m).

工程３
3-ブロモフロ[3,2-b]ピリジン Process 3
3-Bromofuro [3,2-b] pyridine

Figure JPOXMLDOC01-appb-C000430
Figure JPOXMLDOC01-appb-C000430

アルゴン雰囲気下、フロ[3,2-b]ピリジン (835 mg, 7.01 mmol) を四塩化炭素 (70 mL) に溶解し、-10℃に冷却した。そこへ臭素 (361 μL, 7.01 mmol) の四塩化炭素溶液 (30 mL) を滴下し、室温まで徐々に昇温させながら18時間撹拌した。反応液を濃縮し、得られた残渣を酢酸エチルに溶解してシリカゲルパッドでろ過した。ろ液を濃縮し、得られた固体 (958 mg) をメタノール (12 mL) に溶解した。そこへ 10% 水酸化ナトリウム水溶液 (3 mL) を加え、室温で5分撹拌した。反応液を濃縮し、得られた残渣を酢酸エチルに溶解して水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去、真空乾燥して標記化合物 (644 mg, 46%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 8.66 (1H, dd, J = 4.9, 1.2 Hz), 7.91 (1H, s), 7.80 (1H, dd, J = 8.4, 1.3 Hz), 7.33 (1H, dd, J = 8.4, 4.8 Hz). Under an argon atmosphere, furo [3,2-b] pyridine (835 mg, 7.01 mmol) was dissolved in carbon tetrachloride (70 mL) and cooled to −10 ° C. The carbon tetrachloride solution (30 mL) of bromine (361 microliters, 7.01 mmol) was dripped there, and it stirred for 18 hours, heating up gradually to room temperature. The reaction mixture was concentrated, and the resulting residue was dissolved in ethyl acetate and filtered through a silica gel pad. The filtrate was concentrated and the obtained solid (958 mg) was dissolved in methanol (12 mL). A 10% aqueous sodium hydroxide solution (3 mL) was added thereto, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated, and the resulting residue was dissolved in ethyl acetate and washed with water. The ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was dried under vacuum to obtain the title compound (644 mg, 46%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 8.66 (1H, dd, J = 4.9, 1.2 Hz), 7.91 (1H, s), 7.80 (1H, dd, J = 8.4, 1.3 Hz), 7.33 (1H, dd, J = 8.4, 4.8 Hz).

工程４
3-ブロモフロ[3,2-b]ピリジン 4-オキシド Process 4
3-Bromofuro [3,2-b] pyridine 4-oxide

Figure JPOXMLDOC01-appb-C000431
Figure JPOXMLDOC01-appb-C000431

アルゴン雰囲気下、3-ブロモフロ[3,2-b]ピリジン(1.20 g, 6.03 mmol) を塩化メチレン (40 mL) に溶解した。そこへm-クロロ過安息香酸 (2.23 g, 9.05 mmol) を加え、室温で49時間撹拌した。反応液をアルミナ (80 g) を用いてろ過し、ろ液を濃縮、真空乾燥して標記化合物 (932 mg, 72%) を得た。白色固体: 1H-NMR (CDCl3) δ: 8.26-8.23 (1H, m), 7.75 (1H, d, J = 1.0 Hz), 7.48 (1H, dd, J = 8.5, 3.2 Hz), 7.24-7.20 (1H, m). Under an argon atmosphere, 3-bromofuro [3,2-b] pyridine (1.20 g, 6.03 mmol) was dissolved in methylene chloride (40 mL). M-Chloroperbenzoic acid (2.23 g, 9.05 mmol) was added there, and it stirred at room temperature for 49 hours. The reaction mixture was filtered using alumina (80 g), and the filtrate was concentrated and dried under vacuum to obtain the title compound (932 mg, 72%). White solid: 1 H-NMR (CDCl 3 ) δ: 8.26-8.23 (1H, m), 7.75 (1H, d, J = 1.0 Hz), 7.48 (1H, dd, J = 8.5, 3.2 Hz), 7.24- 7.20 (1H, m).

工程５
3-ブロモフロ[3,2-b]ピリジン-5-カルボニトリル  Process 5
3-Bromofuro [3,2-b] pyridine-5-carbonitrile

Figure JPOXMLDOC01-appb-C000432
Figure JPOXMLDOC01-appb-C000432

アルゴン雰囲気下、 3-ブロモフロ[3,2-b]ピリジン-4-オキシド (932 mg, 4.35 mmol) をアセトニトリル (70 mL) に溶解した。そこへトリエチルアミン (889 mL, 6.53 mmol)、トリメチルシリルシアニド (1.35 mL, 10.9 mmol) を加え、84時間加熱還流した。反応液を濃縮し、水を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (534 mg, 55%) を得た。薄黄色固体: 1H-NMR (CDCl3) δ: 8.07 (1H, s), 7.93 (1H, d, J= 8.5 Hz), 7.75 (1H, d, J = 8.5 Hz). Under an argon atmosphere, 3-bromofuro [3,2-b] pyridine-4-oxide (932 mg, 4.35 mmol) was dissolved in acetonitrile (70 mL). Triethylamine (889 mL, 6.53 mmol) and trimethylsilylcyanide (1.35 mL, 10.9 mmol) were added there, and it heated and refluxed for 84 hours. The reaction mixture was concentrated, water was added, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (534 mg, 55%). Pale yellow solid: 1 H-NMR (CDCl 3 ) δ: 8.07 (1H, s), 7.93 (1H, d, J = 8.5 Hz), 7.75 (1H, d, J = 8.5 Hz).

工程６
3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-カルボニトリル Step 6
3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridine-5-carbonitrile

Figure JPOXMLDOC01-appb-C000433
Figure JPOXMLDOC01-appb-C000433

アルゴン雰囲気下、 3-ブロモフロ[3,2-b]ピリジン-5-カルボニトリル (534 mg, 2.39 mmol) を1,4-ジオキサン (20 mL), 水 (4 mL) に溶解した。そこへ1-メチル-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン (867 mg, 2.87 mmol)、炭酸ナトリウム (887 mg, 8.37 mmol)、テトラキストリフェニルホスフィンパラジウム(110 mg, 0.0956 mmol) を加え、反応容器内を脱気し、アルゴン置換した。この操作を3回繰り返した後、100℃で12時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。酢酸エチル層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、得られた固体をヘキサン/酢酸エチル (1/1, 10 mL) で洗浄して標記化合物 (570 mg, 75%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.95 (1H, s), 8.35 (1H, d, J= 8.5 Hz), 8.07 (1H, d, J = 8.3 Hz), 8.01 (2H, d, J = 8.8 Hz), 7.08 (2H, d, J = 8.8 Hz), 3.22 (4H, t, J = 5.0 Hz), 2.47 (4H, t, J = 5.0 Hz), 2.23 (3H, s) Under an argon atmosphere, 3-bromofuro [3,2-b] pyridine-5-carbonitrile (534 mg, 2.39 mmol) was dissolved in 1,4-dioxane (20 mL) and water (4 mL). 1-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine (867 mg, 2.87 mmol), sodium carbonate (887) mg, 8.37 mmol) and tetrakistriphenylphosphine palladium (110 mg, 0.0956 mmol) were added, and the inside of the reaction vessel was deaerated and purged with argon. This operation was repeated 3 times, followed by stirring at 100 ° C. for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform / methanol), and the resulting solid was washed with hexane / ethyl acetate (1/1, 10 mL) to give the title compound (570 mg, 75%). Obtained. Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.95 (1H, s), 8.35 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.3 Hz), 8.01 (2H , d, J = 8.8 Hz), 7.08 (2H, d, J = 8.8 Hz), 3.22 (4H, t, J = 5.0 Hz), 2.47 (4H, t, J = 5.0 Hz), 2.23 (3H, s )

工程７
3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-カルボアルデヒド  Step 7
3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridine-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000434
Figure JPOXMLDOC01-appb-C000434

アルゴン雰囲気下、3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-カルボニトリル (570 mg, 1.79 mmol) を塩化メチレン(18 mL)に溶解し、0℃に冷却した。  そこへジイソブチルアルミニウムヒドリド トルエン溶液 (1.0 M, 2.15 mL, 2.15 mmol) を滴下し、-78℃で3時間撹拌した。ジイソブチルアルミニウムヒドリド トルエン溶液 (1.0 M, 2.15 mL, 2.15 mmol) を追加し、-78℃で1時間撹拌した。反応液に1規定塩酸 (8 mL) を加え、0℃に昇温して4時間撹拌した。1規定水酸化ナトリウム溶液を用いて塩基性にし、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (112 mg, 20%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 10.1 (1H, s), 8.90 (1H, s), 8.29 (1H, d, J = 8.5 Hz), 8.13 (2H, d, J= 8.8 Hz), 8.01 (1H, d, J = 8.5 Hz), 7.08 (2H, d, J = 8.8 Hz), 3.23 (4H, t, J = 4.9 Hz), 2.48 (4H, t, J = 5.1 Hz), 2.24 (3H, s). 3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridine-5-carbonitrile (570 mg, 1.79 mmol) in methylene chloride (18 mL) under argon atmosphere Dissolved and cooled to 0 ° C. The diisobutylaluminum hydride toluene solution (1.0 M, 2.15 mL, 2.15 mmol) was dripped there, and it stirred at -78 degreeC for 3 hours. Diisobutylaluminum hydride in toluene (1.0 M, 2.15 mL, 2.15 mmol) was added, and the mixture was stirred at -78 ° C for 1 hr. 1N Hydrochloric acid (8 mL) was added to the reaction mixture, the temperature was raised to 0 ° C., and the mixture was stirred for 4 hr. The mixture was made basic with 1N sodium hydroxide solution and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (112 mg, 20%). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, s), 8.90 (1H, s), 8.29 (1H, d, J = 8.5 Hz), 8.13 (2H, d, J = 8.8 Hz), 8.01 (1H, d, J = 8.5 Hz), 7.08 (2H, d, J = 8.8 Hz), 3.23 (4H, t, J = 4.9 Hz), 2.48 (4H, t, J = 5.1 Hz) ), 2.24 (3H, s).

工程８
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１０６) Process 8
5-((3- (4- (4-methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridin-5-yl) methylene) -2-thioxothiazolidin-4-one (Compound 106 )

Figure JPOXMLDOC01-appb-C000435
Figure JPOXMLDOC01-appb-C000435

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-カルボアルデヒド (35 mg, 0.109 mmol) およびロダニン (15 mg, 0.109 mmol) から標記化合物 (31 mg, 64%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.81 (1H, s), 8.21-8.17 (3H, m), 7.86 (1H, d, J = 8.5 Hz), 7.63 (1H, s), 3.34 (4H, s), 2.88 (4H, s), 2.52 (3H, s).
ESI-MS(m/z): 437[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (4- (4-methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridine-5-carbaldehyde (35 mg, 0.109 mmol) and rhodanine The title compound (31 mg, 64%) was obtained from (15 mg, 0.109 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.81 (1H, s), 8.21-8.17 (3H, m), 7.86 (1H, d, J = 8.5 Hz), 7.63 (1H, s), 3.34 (4H, s), 2.88 (4H, s), 2.52 (3H, s).
ESI-MS (m / z): 437 [M + H] + .

実施例１０７
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１０７)  Example 107
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione (Compound 107)

Figure JPOXMLDOC01-appb-C000436
Figure JPOXMLDOC01-appb-C000436

工程１
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-カルボアルデヒド (81 mg, 0.252 mmol) およびチアゾリジン-2,4-ジオン (30 mg, 0.252 mmol) から標記化合物 (69 mg, 65%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.81 (1H, s), 8.20 (1H, d, J = 8.5 Hz), 8.13 (2H, d, J = 8.8 Hz), 7.94 (1H, s), 7.89 (1H, d, J = 8.5 Hz), 7.07 (2H, d, J = 8.8 Hz), 3.26 (4H, t, J = 4.8 Hz), 2.59 (4H, t, J = 4.6 Hz), 2.32 (3H, s). 
ESI-MS(m/z): 421[M+H]+. Process 1
Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (4- (4-methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridine-5-carbaldehyde (81 mg, 0.252 mmol) and thiazolidine The title compound (69 mg, 65%) was obtained from -2,4-dione (30 mg, 0.252 mmol). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.81 (1H, s), 8.20 (1H, d, J = 8.5 Hz), 8.13 (2H, d, J = 8.8 Hz), 7.94 (1H , s), 7.89 (1H, d, J = 8.5 Hz), 7.07 (2H, d, J = 8.8 Hz), 3.26 (4H, t, J = 4.8 Hz), 2.59 (4H, t, J = 4.6 Hz ), 2.32 (3H, s).
ESI-MS (m / z): 421 [M + H] + .

実施例１０８
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾフラン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１０８)  Example 108
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzofuran-5-yl) methylene) -2-thioxothiazolidin-4-one (Compound 108)

工程１
メチル 2,3-ジヒドロベンゾフラン-5-カルボキシレート Process 1
Methyl 2,3-dihydrobenzofuran-5-carboxylate

Figure JPOXMLDOC01-appb-C000437
Figure JPOXMLDOC01-appb-C000437

アルゴン雰囲気下、2,3-ジヒドロベンゾフラン-5-カルボアルデヒド (2.0 g, 13.5 mmol) をメタノール (15 mL) に溶解し、0℃に冷却した。そこへ水酸化カリウム (2.32 g, 35.1 mmol) を加えた。さらにヨウ素 (4.45 g, 17.6 mmol) のメタノール溶液 (45 mL) を滴下し、0℃で10分撹拌後、室温で4時間撹拌した。反応液を酢酸エチルで希釈し、1M 亜硫酸ナトリウム水溶液、水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (2.08 g, 86%) を得た。白色固体: 1H-NMR (CDCl3) δ: 7.89-7.85 (2H, m), 6.79 (1H, d, J = 8.3 Hz), 4.65 (2H, t, J = 8.8 Hz), 3.87 (3H, s), 3.24 (2H, t, J = 8.8 Hz). Under an argon atmosphere, 2,3-dihydrobenzofuran-5-carbaldehyde (2.0 g, 13.5 mmol) was dissolved in methanol (15 mL) and cooled to 0 ° C. Potassium hydroxide (2.32 g, 35.1 mmol) was added there. Further, a methanol solution (45 mL) of iodine (4.45 g, 17.6 mmol) was added dropwise, followed by stirring at 0 ° C. for 10 minutes and then at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, and washed with 1M aqueous sodium sulfite solution, water, and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.08 g, 86%). White solid: 1 H-NMR (CDCl 3 ) δ: 7.89-7.85 (2H, m), 6.79 (1H, d, J = 8.3 Hz), 4.65 (2H, t, J = 8.8 Hz), 3.87 (3H, s), 3.24 (2H, t, J = 8.8 Hz).

工程２
メチル ベンゾフラン-5-カルボキシレート  Process 2
Methyl benzofuran-5-carboxylate

Figure JPOXMLDOC01-appb-C000438
Figure JPOXMLDOC01-appb-C000438

アルゴン雰囲気下、メチル 2,3-ジヒドロベンゾフラン-5-カルボキシレート (2.08 g, 11.7 mmol) をクロロベンゼン (20 mL) に溶解した。そこへN-ブロモコハク酸イミド (2.28 g, 12.8 mmol)、2,2'-アゾビス(イソブチロニトリル) (38 mg, 0.233 mmol) を加え、85℃で4時間撹拌した。反応液に酢酸エチルを加え、水、飽和重層水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (2.20 g, quant) を得た。白色固体: 1H-NMR (CDCl3) δ: 8.35 (1H, d, J = 1.7 Hz), 8.03 (1H, dd, J = 8.8, 1.7 Hz), 7.69 (1H, d, J = 2.2 Hz), 7.55-7.52 (1H, m), 6.85-6.84 (1H, m), 3.95 (3H, s). Methyl 2,3-dihydrobenzofuran-5-carboxylate (2.08 g, 11.7 mmol) was dissolved in chlorobenzene (20 mL) under an argon atmosphere. N-bromosuccinimide (2.28 g, 12.8 mmol) and 2,2′-azobis (isobutyronitrile) (38 mg, 0.233 mmol) were added thereto, and the mixture was stirred at 85 ° C. for 4 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated multilayer water. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (2.20 g, quant). White solid: 1 H-NMR (CDCl 3 ) δ: 8.35 (1H, d, J = 1.7 Hz), 8.03 (1H, dd, J = 8.8, 1.7 Hz), 7.69 (1H, d, J = 2.2 Hz) , 7.55-7.52 (1H, m), 6.85-6.84 (1H, m), 3.95 (3H, s).

工程３
メチル 3-ブロモベンゾフラン-5-カルボキシレート  Process 3
Methyl 3-bromobenzofuran-5-carboxylate

Figure JPOXMLDOC01-appb-C000439
Figure JPOXMLDOC01-appb-C000439

アルゴン雰囲気下、メチル ベンゾフラン-5-カルボキシレート (2.20 g, 11.7 mmol) を塩化メチレン (20 mL) に溶解し、 0℃に冷却した。そこへ臭素 (600 μL, 11.7 mmol) を滴下し、0℃で10分撹拌後、室温で90分撹拌した。反応液を1M 亜硫酸ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた固体 (3.55 g) をテトラヒドロフラン (15 mL) に溶解し、0℃に冷却した。水酸化カリウム (698 mg, 10.6 mmol) のメタノール溶液 (5 mL) を滴下し、0℃で20分撹拌した。反応液を酢酸エチルで希釈し、水、飽和重層水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.93 g, 71%) を得た。白色固体: 1H-NMR (CDCl3) δ: 8.30 (1H, d, J = 1.7 Hz), 8.09 (1H, dd, J = 8.8, 1.7 Hz), 7.72 (1H, s), 7.53 (1H, d, J = 8.8 Hz), 3.97 (3H, s). Under an argon atmosphere, methyl benzofuran-5-carboxylate (2.20 g, 11.7 mmol) was dissolved in methylene chloride (20 mL) and cooled to 0 ° C. Bromine there   (600 μL, 11.7 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 90 minutes. The reaction mixture was washed with 1M aqueous sodium sulfite solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained solid (3.55 g) was dissolved in tetrahydrofuran (15 mL) and cooled to 0 ° C. A methanol solution (5 mL) of potassium hydroxide (698 mg, 10.6 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 20 minutes. The reaction solution was diluted with ethyl acetate and washed with water and saturated multistory water. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.93 g, 71%). White solid: 1 H-NMR (CDCl 3 ) δ: 8.30 (1H, d, J = 1.7 Hz), 8.09 (1H, dd, J = 8.8, 1.7 Hz), 7.72 (1H, s), 7.53 (1H, d, J = 8.8 Hz), 3.97 (3H, s).

工程４
メチル 3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾフラン-5-カルボキシレート Process 4
Methyl 3- (4- (4-methylpiperazin-1-yl) phenyl) benzofuran-5-carboxylate

Figure JPOXMLDOC01-appb-C000440
Figure JPOXMLDOC01-appb-C000440

3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-カルボニトリルの合成 (実施例106、工程6) と同様の手法で、メチル 3-ブロモベンゾフラン-5-カルボキシレート (400 mg, 1.57 mmol) および1-メチル-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン (569 mg, 1.88 mmol) から標記化合物 (368 mg, 67%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 8.43 (1H, d, J = 1.5 Hz), 8.37 (1H, s), 8.00 (1H, dd, J= 8.5, 1.7 Hz), 7.77 (1H, d, J= 8.5 Hz), 7.57 (2H, d, J = 8.8 Hz), 7.10 (2H, d, J = 8.8 Hz), 3.89 (3H, s), 3.22 (4H, t, J = 5.0 Hz), 2.47 (4H, t, J = 5.0 Hz), 2.24 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridine-5-carbonitrile in the same manner as in Example 106, Step 6) Bromobenzofuran-5-carboxylate (400 mg, 1.57 mmol) and 1-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) The title compound (368 mg, 67%) was obtained from piperazine (569 mg, 1.88 mmol). White solid: 1 H-NMR (DMSO-D 6 ) δ: 8.43 (1H, d, J = 1.5 Hz), 8.37 (1H, s), 8.00 (1H, dd, J = 8.5, 1.7 Hz), 7.77 ( 1H, d, J = 8.5 Hz), 7.57 (2H, d, J = 8.8 Hz), 7.10 (2H, d, J = 8.8 Hz), 3.89 (3H, s), 3.22 (4H, t, J = 5.0 Hz), 2.47 (4H, t, J = 5.0 Hz), 2.24 (3H, s).

工程５
(3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾフラン-5-イル)メタノール  Process 5
(3- (4- (4-Methylpiperazin-1-yl) phenyl) benzofuran-5-yl) methanol

Figure JPOXMLDOC01-appb-C000441
Figure JPOXMLDOC01-appb-C000441

(1-(3-(2-モルホリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メタノールの合成(実施例23、工程4) と同様の手法で、メチル 3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾフラン-5-カルボキシレート (368 mg, 1.05 mmol) およびリチウムアルミニウムヒドリド テトラヒドロフラン溶液 (1.0 M, 3.15 mL, 3.15 mmol) から標記化合物 (195 mg, 58%)を得た。白色固体: 1H-NMR (DMSO-D6) δ: 8.20 (1H, s), 7.82 (1H, s), 7.58-7.55 (3H, m), 7.31 (1H, dd, J= 8.4, 1.3 Hz), 7.07 (2H, d, J= 8.8 Hz), 5.22 (1H, t, J = 5.9 Hz), 4.62 (2H, d, J = 5.9 Hz), 3.20 (4H, t, J = 4.9 Hz), 2.47 (4H, t, J = 5.0 Hz), 2.24 (3H, s). Synthesis of (1- (3- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methanol (Example 23, Step 4) From (4-methylpiperazin-1-yl) phenyl) benzofuran-5-carboxylate (368 mg, 1.05 mmol) and lithium aluminum hydride tetrahydrofuran solution (1.0 M, 3.15 mL, 3.15 mmol) to the title compound (195 mg, 58% ) White solid: 1 H-NMR (DMSO-D 6 ) δ: 8.20 (1H, s), 7.82 (1H, s), 7.58-7.55 (3H, m), 7.31 (1H, dd, J = 8.4, 1.3 Hz ), 7.07 (2H, d, J = 8.8 Hz), 5.22 (1H, t, J = 5.9 Hz), 4.62 (2H, d, J = 5.9 Hz), 3.20 (4H, t, J = 4.9 Hz), 2.47 (4H, t, J = 5.0 Hz), 2.24 (3H, s).

工程６
3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾフラン-5-カルボアルデヒド  Step 6
3- (4- (4-Methylpiperazin-1-yl) phenyl) benzofuran-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000442
Figure JPOXMLDOC01-appb-C000442

3-(3-((4-ヒドロキシピペリジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-カルボキシカルボアルデヒドの合成 (実施例48、工程4 ) と同様の手法で、(3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾフラン-5-イル)メタノール (195 mg, 0.605 mmol) および二酸化マンガン (1.0 g) から標記化合物 (98 mg, 51%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 10.1 (1H, s), 8.49 (1H, d, J = 1.7 Hz), 8.42 (1H, s), 7.94 (1H, dd, J = 8.5, 1.5 Hz), 7.85 (1H, d, J = 8.8 Hz), 7.64 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 3.22 (4H, t, J = 4.9 Hz), 2.50-2.47 (4H, m), 2.24 (3H, s). Synthesis of 3- (3-((4-hydroxypiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine-6-carboxycarbaldehyde (Example 48, Step 4) , (3- (4- (4-Methylpiperazin-1-yl) phenyl) benzofuran-5-yl) methanol (195 mg, 0.605 mmol) and manganese dioxide (1.0 g) to give the title compound (98 mg, 51%) Got. Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, s), 8.49 (1H, d, J = 1.7 Hz), 8.42 (1H, s), 7.94 (1H, dd, J = 8.5, 1.5 Hz), 7.85 (1H, d, J = 8.8 Hz), 7.64 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 3.22 (4H, t, J = 4.9 Hz), 2.50-2.47 (4H, m), 2.24 (3H, s).

工程７
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾフラン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１０８) Step 7
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzofuran-5-yl) methylene) -2-thioxothiazolidin-4-one (Compound 108)

Figure JPOXMLDOC01-appb-C000443
Figure JPOXMLDOC01-appb-C000443

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾフラン-5-カルボアルデヒド (34 mg, 0.106 mmol) およびロダニン (14 mg, 0.106 mmol) から標記化合物 (30 mg, 65%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.34 (1H, d, J = 2.0 Hz), 8.04 (1H, s), 7.75 (1H, d, J = 8.5 Hz), 7.66 (2H, d, J = 8.5 Hz), 7.57 (1H, d, J = 8.5 Hz), 7.51 (1H, s), 7.16 (2H, d, J = 8.8 Hz), 3.42 (4H, s), 3.10 (4H, s), 2.69 (3H, s).
ESI-MS(m/z): 436[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) , Step 1) from 3- (4- (4-methylpiperazin-1-yl) phenyl) benzofuran-5-carbaldehyde (34 mg, 0.106 mmol) and rhodanine (14 mg, 0.106 mmol) The title compound (30 mg, 65%) was obtained. Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.34 (1H, d, J = 2.0 Hz), 8.04 (1H, s), 7.75 (1H, d, J = 8.5 Hz), 7.66 (2H, d, J = 8.5 Hz), 7.57 (1H, d, J = 8.5 Hz), 7.51 (1H, s), 7.16 (2H, d, J = 8.8 Hz), 3.42 (4H, s), 3.10 (4H, s), 2.69 (3H, s).
ESI-MS (m / z): 436 [M + H] + .

実施例１０９
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾフラン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１０９)  Example 109
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzofuran-5-yl) methylene) thiazolidine-2,4-dione (Compound 109)

Figure JPOXMLDOC01-appb-C000444
Figure JPOXMLDOC01-appb-C000444

工程１
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾフラン-5-カルボアルデヒド (58 mg, 0.181 mmol) およびチアゾリジン-2,4-ジオン (21 mg, 0.181 mmol) から標記化合物 (13 mg, 17%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 8.35 (1H, s), 8.14 (1H, s), 7.85 (1H, s), 7.77 (1H, d, J = 8.8 Hz), 7.64-7.59 (3H, m), 7.12 (2H, d, J = 6.8 Hz), 3.30 (4H, s), 2.72 (4H, s), 2.42 (3H, s). 
ESI-MS(m/z): 420[M+H]+. Process 1
Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (4- (4-methylpiperazin-1-yl) phenyl) benzofuran-5-carbaldehyde (58 mg, 0.181 mmol) and thiazolidine-2,4-dione (21 mg, 0.181 mmol) gave the title compound (13 mg, 17%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 8.35 (1H, s), 8.14 (1H, s), 7.85 (1H, s), 7.77 (1H, d, J = 8.8 Hz), 7.64- 7.59 (3H, m), 7.12 (2H, d, J = 6.8 Hz), 3.30 (4H, s), 2.72 (4H, s), 2.42 (3H, s).
ESI-MS (m / z): 420 [M + H] + .

実施例１１０
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾ[b]チオフェン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１１０)  Example 110
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzo [b] thiophen-5-yl) methylene) -2-thioxothiazolidin-4-one (Compound 110)

工程１
3-ブロモベンゾ[b]チオフェン-5-カルボアルデヒド Process 1
3-Bromobenzo [b] thiophene-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000445
Figure JPOXMLDOC01-appb-C000445

アルゴン雰囲気下、1-ベンゾチオフェン-5-カルボアルデヒド (500 mg, 3.08 mmol) を酢酸 (5 mL) に溶解し、0℃に冷却した。そこへ臭素 (238 μL, 4.62 mmol) を滴下し、0℃で10分撹拌後、室温で3時間撹拌した。反応液に水を加え、 酢酸エチルで抽出した。酢酸エチル層を飽和重層水、飽和チオ硫酸ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (596 mg, 80%) を得た。白色固体: 1H-NMR (CDCl3) δ: 10.2 (1H, s), 8.32 (1H, t, J = 0.7 Hz), 8.00-7.86 (2H, m), 7.57 (1H, s). In an argon atmosphere, 1-benzothiophene-5-carbaldehyde (500 mg, 3.08 mmol) was dissolved in acetic acid (5 mL) and cooled to 0 ° C. Bromine (238 μL, 4.62 mmol) was added dropwise thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated multistory water, saturated aqueous sodium thiosulfate, and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (596 mg, 80%). White solid: 1 H-NMR (CDCl 3 ) δ: 10.2 (1H, s), 8.32 (1H, t, J = 0.7 Hz), 8.00-7.86 (2H, m), 7.57 (1H, s).

工程２
3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾ[b]チオフェン-5-カルボアルデヒド Process 2
3- (4- (4-Methylpiperazin-1-yl) phenyl) benzo [b] thiophene-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000446
Figure JPOXMLDOC01-appb-C000446

3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-カルボニトリルの合成 (実施例106、工程6) と同様の手法で、3-ブロモベンゾ[b]チオフェン-5-カルボアルデヒド(596 mg, 2.47 mmol) および1-メチル-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン (897 mg, 2.96 mmol) から標記化合物 (771 mg, 93%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.1 (1H, s), 8.42 (1H, d, J= 1.0 Hz), 8.27 (1H, d, J = 8.3 Hz), 7.89 (1H, dd, J = 8.5, 1.5 Hz), 7.85 (1H, s), 7.51 (2H, d, J= 8.8 Hz), 7.11 (2H, d, J = 8.8 Hz), 3.24 (4H, t, J = 5.0 Hz), 2.50-2.45 (4H, m), 2.24 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridine-5-carbonitrile in the same manner as in Example 106, Step 6) [b] thiophene-5-carbaldehyde (596 mg, 2.47 mmol) and 1-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) The title compound (771 mg, 93%) was obtained from (phenyl) piperazine (897 mg, 2.96 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, s), 8.42 (1H, d, J = 1.0 Hz), 8.27 (1H, d, J = 8.3 Hz), 7.89 (1H, dd, J = 8.5, 1.5 Hz), 7.85 (1H, s), 7.51 (2H, d, J = 8.8 Hz), 7.11 (2H, d, J = 8.8 Hz), 3.24 (4H, t, J = 5.0 Hz), 2.50-2.45 (4H, m), 2.24 (3H, s).

工程３
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾ[b]チオフェン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１１０) Process 3
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzo [b] thiophen-5-yl) methylene) -2-thioxothiazolidin-4-one (Compound 110)

Figure JPOXMLDOC01-appb-C000447
Figure JPOXMLDOC01-appb-C000447

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾ[b]チオフェン-5-カルボアルデヒド(349 mg, 1.04 mmol) およびロダニン (138 mg, 1.04 mmol) から標記化合物 (322 mg, 69%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.15 (1H, d, J = 8.3 Hz), 8.02 (1H, d, J = 1.2 Hz), 7.78 (1H, s), 7.58 (1H, dd, J = 9.1, 2.1 Hz), 7.56 (2H, d, J = 8.8 Hz), 7.45 (1H, s), 7.17 (2H, d, J= 8.8 Hz), 3.44 (4H, s), 3.15 (4H, s), 2.71 (3H, s). 
ESI-MS(m/z): 452[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (4- (4-methylpiperazin-1-yl) phenyl) benzo [b] thiophene-5-carbaldehyde (349 mg, 1.04 mmol) and rhodanine (138 mg, The title compound (322 mg, 69%) was obtained from 1.04 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.15 (1H, d, J = 8.3 Hz), 8.02 (1H, d, J = 1.2 Hz), 7.78 (1H, s), 7.58 (1H, dd, J = 9.1, 2.1 Hz), 7.56 (2H, d, J = 8.8 Hz), 7.45 (1H, s), 7.17 (2H, d, J = 8.8 Hz), 3.44 (4H, s), 3.15 ( 4H, s), 2.71 (3H, s).
ESI-MS (m / z): 452 [M + H] + .

実施例１１１
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾ[b]チオフェン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１１１) Example 111
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzo [b] thiophen-5-yl) methylene) thiazolidine-2,4-dione (Compound 111)

Figure JPOXMLDOC01-appb-C000448
Figure JPOXMLDOC01-appb-C000448

工程１
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾ[b]チオフェン-5-カルボアルデヒド(365 mg, 1.08 mmol) およびチアゾリジン-2,4-ジオン (127 mg, 1.08 mmol) から標記化合物 (250 mg, 53%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.17 (1H, d, J = 8.3 Hz), 8.10 (1H, s), 7.79 (2H, s), 7.61 (1H, dd, J = 8.3, 1.2 Hz), 7.53 (2H, d, J = 8.5 Hz), 7.14 (2H, d, J = 8.5 Hz), 3.33 (4H, t, J = 4.8 Hz), 2.79 (4H, t, J = 4.8 Hz), 2.46 (3H, s). 
ESI-MS(m/z): 436[M+H]+. Process 1
Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (4- (4-methylpiperazin-1-yl) phenyl) benzo [b] thiophene-5-carbaldehyde (365 mg, 1.08 mmol) and thiazolidine-2,4 -The title compound (250 mg, 53%) was obtained from -dione (127 mg, 1.08 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.17 (1H, d, J = 8.3 Hz), 8.10 (1H, s), 7.79 (2H, s), 7.61 (1H, dd, J = 8.3 , 1.2 Hz), 7.53 (2H, d, J = 8.5 Hz), 7.14 (2H, d, J = 8.5 Hz), 3.33 (4H, t, J = 4.8 Hz), 2.79 (4H, t, J = 4.8 Hz), 2.46 (3H, s).
ESI-MS (m / z): 436 [M + H] + .

実施例１１２
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-イミダゾ[4,5-c]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物１１２)  Example 112
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-imidazo [4,5-c] pyridin-6-yl) methylene) -2-thioxothiazolidine-4-one (Compound 112)

工程１
tert-ブチル 4-(4-((2-ブロモ-5-ニトロピリジン-4-イル)アミノ)フェニル)ピペラジン-1-カルボキシレート Process 1
tert-butyl 4- (4-((2-bromo-5-nitropyridin-4-yl) amino) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000449
Figure JPOXMLDOC01-appb-C000449

tert-ブチル 4-(4-アミノフェニル)ピペラジン-1-カルボキシレート(50 mg, 0.177 mmol)、2,4-ジブロモ-5-ニトロピリジン (59 mg, 0.213 mmol) のエタノール (1 mL) 溶液中に、トリエチルアミン (49 μL) を室温で滴下した。一晩撹拌し、反応終了後、減圧下濃縮乾固し、標記化合物 (85 mg, quant., 0.18 mmol) を得た。赤褐色固: 1H-NMR (CDCl3) δ: 9.59 (1H, s), 9.05 (1H, s), 7.63-7.50 (2H, m), 7.33 (2H, d, J = 8.5 Hz), 7.07 (1H, s), 3.98-3.88 (4H, m), 3.43-3.34 (4H, m), 1.50 (9H, s). 
ESI-MS(m/z): 478[M+H]+. tert-Butyl 4- (4-aminophenyl) piperazine-1-carboxylate (50 mg, 0.177 mmol), 2,4-dibromo-5-nitropyridine (59 mg, 0.213 mmol) in ethanol (1 mL) Triethylamine (49 μL) was added dropwise at room temperature. The mixture was stirred overnight, and after completion of the reaction, the mixture was concentrated to dryness under reduced pressure to obtain the title compound (85 mg, quant., 0.18 mmol). Reddish brown solid: 1 H-NMR (CDCl 3 ) δ: 9.59 (1H, s), 9.05 (1H, s), 7.63-7.50 (2H, m), 7.33 (2H, d, J = 8.5 Hz), 7.07 ( 1H, s), 3.98-3.88 (4H, m), 3.43-3.34 (4H, m), 1.50 (9H, s).
ESI-MS (m / z): 478 [M + H] + .

工程２
tert-ブチル 4-(4-((5-アミノ-2-ブロモピリジン-4-イル)アミノ)フェニル)ピペラジン-1-カルボキシレート Process 2
tert-butyl 4- (4-((5-amino-2-bromopyridin-4-yl) amino) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000450
Figure JPOXMLDOC01-appb-C000450

tert-ブチル 4-(4-((2-ブロモ-5-ニトロピリジン-4-イル)アミノ)フェニル)ピペラジン-1-カルボキシレート (85 mg, 0.177 mmol) のエタノール (4 mL)、水 (2 mL) の混合溶液中に、鉄粉 (30 mg, 0.53 mmol)、塩化アンモニウム (19 mg, 0.35 mmol) を室温で添加した。還流条件下、3時間撹拌し、反応終了後セライトろ過、減圧下濃縮乾固した。酢酸エチル、飽和炭酸水素ナトリウム水溶液を添加し有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記化合物 (79 mg, 99 %, 0.17 mmol) を得た。赤茶色固体: 1H-NMR (CDCl3) δ: 7.64 (1H, s), 6.99 (2H, d, J = 7.1 Hz), 6.85 (2H, d, J = 7.1 Hz), 6.77 (1H, s), 6.07 (1H, br s), 3.51 (4H, t, J = 4.1 Hz), 3.38-3.35 (2H, m), 3.03 (4H, t, J = 4.1 Hz), 1.42 (9H, s). 
ESI-MS(m/z): 448[M+H]+. tert-Butyl 4- (4-((2-bromo-5-nitropyridin-4-yl) amino) phenyl) piperazine-1-carboxylate (85 mg, 0.177 mmol) in ethanol (4 mL), water (2 mL) was mixed with iron powder (30 mg, 0.53 mmol) and ammonium chloride (19 mg, 0.35 mmol) at room temperature. The mixture was stirred for 3 hours under reflux conditions. After completion of the reaction, the mixture was filtered through Celite and concentrated to dryness under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to extract the organic layer, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The title compound (79 mg, 99%, 0.17 mmol) was obtained. Red-brown solid: 1 H-NMR (CDCl 3 ) δ: 7.64 (1H, s), 6.99 (2H, d, J = 7.1 Hz), 6.85 (2H, d, J = 7.1 Hz), 6.77 (1H, s ), 6.07 (1H, br s), 3.51 (4H, t, J = 4.1 Hz), 3.38-3.35 (2H, m), 3.03 (4H, t, J = 4.1 Hz), 1.42 (9H, s).
ESI-MS (m / z): 448 [M + H] + .

工程３
tert-ブチル 4-(4-(6-ブロモ-1H-イミダゾ[4,5-c]ピリジン-1-イル)フェニル)ピペラジン-1-カルボキシレート Process 3
tert-Butyl 4- (4- (6-Bromo-1H-imidazo [4,5-c] pyridin-1-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000451
Figure JPOXMLDOC01-appb-C000451

tert-ブチル 4-(4-((5-アミノ-2-ブロモピリジン-4-イル)アミノ)フェニル)ピペラジン-1-カルボキシレート (79 mg, 0.177 mmol) の2-メトキシエタノール (5 mL) 溶液中にホルムアミジン酢酸塩 (55 mg, 0.531 mmol) を添加した。還流条件下、4時間撹拌した後、減圧下濃縮乾固した。標記化合物 (81 mg, 99 %, 0.17 mmol) を得た。褐色固体: 1H-NMR (CDCl3) δ: 8.92 (1H, s), 8.08 (1H, s), 7.57 (1H, s), 7.34 (2H, d, J = 8.8 Hz), 7.07 (2H, d, J = 8.8 Hz), 3.63 (4H, t, J = 5.0 Hz), 3.26 (4H, t, J = 5.0 Hz), 1.50 (9H, s). 
ESI-MS(m/z): 458[M+H]+. A solution of tert-butyl 4- (4-((5-amino-2-bromopyridin-4-yl) amino) phenyl) piperazine-1-carboxylate (79 mg, 0.177 mmol) in 2-methoxyethanol (5 mL) Inside, formamidine acetate (55 mg, 0.531 mmol) was added. After stirring for 4 hours under reflux conditions, the mixture was concentrated to dryness under reduced pressure. The title compound (81 mg, 99%, 0.17 mmol) was obtained. Brown solid: 1 H-NMR (CDCl 3 ) δ: 8.92 (1H, s), 8.08 (1H, s), 7.57 (1H, s), 7.34 (2H, d, J = 8.8 Hz), 7.07 (2H, d, J = 8.8 Hz), 3.63 (4H, t, J = 5.0 Hz), 3.26 (4H, t, J = 5.0 Hz), 1.50 (9H, s).
ESI-MS (m / z): 458 [M + H] + .

工程４
6-ブロモ-1-(4-(ピペラジン-1-イル)フェニル)-1H-イミダゾ[4,5-c]ピリジン Process 4
6-Bromo-1- (4- (piperazin-1-yl) phenyl) -1H-imidazo [4,5-c] pyridine

Figure JPOXMLDOC01-appb-C000452
Figure JPOXMLDOC01-appb-C000452

tert-ブチル 4-(4-(6-ブロモ-1H-イミダゾ[4,5-c]ピリジン-1-イル)フェニル)ピペラジン-1-カルボキシレート (81 mg, 0.177 mmol) の塩化メチレン (2.0 mL) 溶液にトリフルオロ酢酸 (0.6 mL, 7.79 mmol) を0℃で滴下した。室温に昇温し2時間撹拌した。反応終了後、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記化合物 (63 mg, quant., 0.177 mmol) を得た。 1H-NMR (CDCl3) δ: 8.91 (1H, s), 8.07 (1H, s), 7.58 (1H, s), 7.32 (2H, d, J = 8.8 Hz), 7.07 (2H, d, J = 8.8 Hz), 3.35-3.23 (4H, m), 3.16-3.05 (4H, m), 2.76-2.41 (1H, m). 
ESI-MS(m/z): 358[M+H]+. tert-Butyl 4- (4- (6-bromo-1H-imidazo [4,5-c] pyridin-1-yl) phenyl) piperazine-1-carboxylate (81 mg, 0.177 mmol) in methylene chloride (2.0 mL ) Trifluoroacetic acid (0.6 mL, 7.79 mmol) was added dropwise to the solution at 0 ° C. The mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, chloroform and saturated aqueous sodium hydrogen carbonate solution were added to extract the organic layer, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The title compound (63 mg, quant., 0.177 mmol) was obtained. 1 H-NMR (CDCl 3 ) δ: 8.91 (1H, s), 8.07 (1H, s), 7.58 (1H, s), 7.32 (2H, d, J = 8.8 Hz), 7.07 (2H, d, J = 8.8 Hz), 3.35-3.23 (4H, m), 3.16-3.05 (4H, m), 2.76-2.41 (1H, m).
ESI-MS (m / z): 358 [M + H] + .

工程５
6-ブロモ-1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-イミダゾ[4,5-c]ピリジン Process 5
6-Bromo-1- (4- (4-methylpiperazin-1-yl) phenyl) -1H-imidazo [4,5-c] pyridine

Figure JPOXMLDOC01-appb-C000453
Figure JPOXMLDOC01-appb-C000453

6-ブロモ-1-(4-(ピペラジン-1-イル)フェニル)-1H-イミダゾ[4,5-c]ピリジン (63 mg, 0.177 mmol) のクロロホルム (2 mL) 溶液中に、37% ホルムアルデヒド水溶液 (79 μL, 1.062 mmol) を滴下し、室温下一時間撹拌した。さらにナトリウムトリアセトキシボロヒドリド (113 mg, 0.531 mmol) を添加し、室温で15分間撹拌した。反応終了後、クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記化合物 (66 mg, quant., 0.177 mmol) を得た。 1H-NMR (CDCl3) δ: 8.83 (1H, s), 7.99 (1H, s), 7.49 (1H, s), 7.24 (2H, d, J = 9.0 Hz), 6.99 (2H, d, J = 9.0 Hz), 3.26 (4H, t, J = 4.6 Hz), 2.57 (4H, t, J = 4.6 Hz), 2.33 (3H, s). 
ESI-MS(m/z): 372[M+H]+. 37% formaldehyde in a solution of 6-bromo-1- (4- (piperazin-1-yl) phenyl) -1H-imidazo [4,5-c] pyridine (63 mg, 0.177 mmol) in chloroform (2 mL) Aqueous solution (79 μL, 1.062 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Furthermore, sodium triacetoxyborohydride (113 mg, 0.531 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. After completion of the reaction, chloroform and saturated aqueous sodium hydrogen carbonate solution were added to extract the organic layer, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The title compound (66 mg, quant., 0.177 mmol) was obtained. 1 H-NMR (CDCl 3 ) δ: 8.83 (1H, s), 7.99 (1H, s), 7.49 (1H, s), 7.24 (2H, d, J = 9.0 Hz), 6.99 (2H, d, J = 9.0 Hz), 3.26 (4H, t, J = 4.6 Hz), 2.57 (4H, t, J = 4.6 Hz), 2.33 (3H, s).
ESI-MS (m / z): 372 [M + H] + .

工程６
1-(4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニル-1H-イミダゾ[4,5-c]ピリジン Step 6
1- (4- (4-Methylpiperazin-1-yl) phenyl) -6-vinyl-1H-imidazo [4,5-c] pyridine

Figure JPOXMLDOC01-appb-C000454
Figure JPOXMLDOC01-appb-C000454

6-ブロモ-1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-イミダゾ[4,5-c]ピリジン (50 mg, 0.14 mmol)、テトラキストリフェニルホスフィンパラジウム (15 mg, 0.01 mmol) のトルエン (1 mL) 溶媒中に、ビニルトリブチルスズ (59 μL, 0.20 mmol) を滴下した。アルゴン置換した後、還流条件下一晩撹拌し、反応終了後クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (17 mg, 40 %, 0.053 mmol) を得た。白色固体: 1H-NMR (CDCl3) δ: 9.13 (1H, s), 8.06 (1H, s), 7.37 (1H, s), 7.36 (2H, d, J = 9.0 Hz), 7.09 (2H, d, J = 9.0 Hz), 6.88 (1H, dd, J = 17.3, 10.7 Hz), 6.22 (1H, d, J = 17.3 Hz), 5.43 (1H, d, J = 10.7 Hz), 3.40-3.33 (4H, m), 2.75-2.65 (4H, m), 2.43 (3H, s). 
ESI-MS(m/z): 319[M+H]+. 6-bromo-1- (4- (4-methylpiperazin-1-yl) phenyl) -1H-imidazo [4,5-c] pyridine (50 mg, 0.14 mmol), tetrakistriphenylphosphine palladium (15 mg, Into a toluene (1 mL) solvent of 0.01 mmol), vinyltributyltin (59 μL, 0.20 mmol) was added dropwise. After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, the organic layer was extracted by adding chloroform and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (17 mg, 40%, 0.053 mmol). White solid: 1 H-NMR (CDCl 3 ) δ: 9.13 (1H, s), 8.06 (1H, s), 7.37 (1H, s), 7.36 (2H, d, J = 9.0 Hz), 7.09 (2H, d, J = 9.0 Hz), 6.88 (1H, dd, J = 17.3, 10.7 Hz), 6.22 (1H, d, J = 17.3 Hz), 5.43 (1H, d, J = 10.7 Hz), 3.40-3.33 ( 4H, m), 2.75-2.65 (4H, m), 2.43 (3H, s).
ESI-MS (m / z): 319 [M + H] + .

工程７
1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-イミダゾ[4,5-c]ピリジン-6-カルボアルデヒド Step 7
1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-imidazo [4,5-c] pyridine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000455
Figure JPOXMLDOC01-appb-C000455

1-(4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニル-1H-イミダゾ[4,5-c]ピリジン (198 mg, 0.620 mmol)、過ヨウ素酸ナトリウム (530 mg, 2.48 mmol) を1,4-ジオキサン (6 mL)、水 (2 mL) の混合溶液に溶解し、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (156 μL, 0.012 mL)、2,6-ルチジン (144 μL, 1.24 mmol) を滴下した。アルゴン雰囲気下、室温で4時間撹拌した。反応終了後、飽和チオ硫酸ナトリウム水溶液を加え、セライトろ過した。ろ液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (113 mg, 57 %, 0.352 mmol) を得た。白色固体: 1H-NMR (CDCl3) δ: 10.21 (1H, s), 9.30 (1H, s), 8.28 (1H, s), 8.15 (1H, s), 7.37 (2H, d, J = 9.0 Hz), 7.09 (2H, d, J = 9.0 Hz), 3.41-3.40 (4H, br m), 2.74-2.72 (4H, br m), 2.46 (3H, s).
ESI-MS(m/z): 322[M+H]+. 1- (4- (4-Methylpiperazin-1-yl) phenyl) -6-vinyl-1H-imidazo [4,5-c] pyridine (198 mg, 0.620 mmol), sodium periodate (530 mg, 2.48 mmol) is dissolved in a mixed solution of 1,4-dioxane (6 mL) and water (2 mL), 2.5 wt% osmium tetroxide tert-butanol solution (156 μL, 0.012 mL), 2,6-lutidine (144 μL, 1.24 mmol) was added dropwise. The mixture was stirred at room temperature for 4 hours under an argon atmosphere. After completion of the reaction, a saturated aqueous sodium thiosulfate solution was added, and the mixture was filtered through celite. A saturated aqueous sodium hydrogen carbonate solution was added to the filtrate, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was refine | purified by the silica gel column chromatography method (chloroform / methanol), and the title compound (113 mg, 57%, 0.352 mmol) was obtained. White solid: 1 H-NMR (CDCl 3 ) δ: 10.21 (1H, s), 9.30 (1H, s), 8.28 (1H, s), 8.15 (1H, s), 7.37 (2H, d, J = 9.0 Hz), 7.09 (2H, d, J = 9.0 Hz), 3.41-3.40 (4H, br m), 2.74-2.72 (4H, br m), 2.46 (3H, s).
ESI-MS (m / z): 322 [M + H] + .

工程８
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-イミダゾ[4,5-c]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１１２) Process 8
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-imidazo [4,5-c] pyridin-6-yl) methylene) -2-thioxothiazolidine-4-one (Compound 112)

Figure JPOXMLDOC01-appb-C000456
Figure JPOXMLDOC01-appb-C000456

1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-イミダゾ[4,5-c]ピリジン-6-カルボアルデヒド (50 mg, 0.16 mmol) をアセトニトリル (5.0 mL) に溶かし、ロダニン (21 mg, 0.16 mmol)、ピペリジン (3.08 μL, 0.031 mmol)、および酢酸 (3.58 μL, 0.062 mmol) を加え、100℃で一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (36 mg, 53 %, 0.082 mmol) を得た。黄褐色固体: 1H-NMR (DMSO-D6) δ: 9.21 (1H, s), 8.75 (1H, s), 8.16 (1H, s), 7.71 (1H, s), 7.56 (2H, d, J = 9.0 Hz), 7.18 (2H, d, J = 9.0 Hz), 3.32 (4H, t, J = 4.8 Hz), 2.68 (4H, t, J = 4.8 Hz), 2.39 (3H, s).
ESI-MS(m/z): 437[M+H]+. 1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-imidazo [4,5-c] pyridine-6-carbaldehyde (50 mg, 0.16 mmol) was dissolved in acetonitrile (5.0 mL). Rhodanine (21 mg, 0.16 mmol), piperidine (3.08 μL, 0.031 mmol), and acetic acid (3.58 μL, 0.062 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (36 mg, 53%, 0.082 mmol). Tawny solid: 1 H-NMR (DMSO-D 6 ) δ: 9.21 (1H, s), 8.75 (1H, s), 8.16 (1H, s), 7.71 (1H, s), 7.56 (2H, d, J = 9.0 Hz), 7.18 (2H, d, J = 9.0 Hz), 3.32 (4H, t, J = 4.8 Hz), 2.68 (4H, t, J = 4.8 Hz), 2.39 (3H, s).
ESI-MS (m / z): 437 [M + H] + .

実施例１１３
5- ((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-イミダゾ[4,5-c]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１１３)  Example 113
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-imidazo [4,5-c] pyridin-6-yl) methylene) thiazolidine-2,4-dione (compound 113 )

Figure JPOXMLDOC01-appb-C000457
Figure JPOXMLDOC01-appb-C000457

工程１
1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-イミダゾ[4,5-c]ピリジン-6-カルボアルデヒド (50 mg, 0.16 mmol) をアセトニトリル (5.0 mL) に溶かし、チアゾリジン-2,4-ジオン (18 mg, 0.16 mmol)、ピペリジン (3.08 μL, 0.031 mmol)、および酢酸 (3.58 μL, 0.062 mmol) を加え、100℃で一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (38 mg, 58 %, 0.090 mmol) を得た。灰色固体: 1H-NMR (DMSO-D6) δ: 9.19 (1H, s), 8.75 (1H, s), 8.17 (1H, s), 7.93 (1H, s), 7.54 (2H, d, J = 9.0 Hz), 7.17 (2H, d, J = 9.0 Hz), 3.27 (4H, t, J = 5.0 Hz), 2.53 (4H, t, J = 5.0 Hz), 2.28 (3H, s).
ESI-MS(m/z): 421[M+H]+. Process 1
1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-imidazo [4,5-c] pyridine-6-carbaldehyde (50 mg, 0.16 mmol) was dissolved in acetonitrile (5.0 mL). Thiazolidine-2,4-dione (18 mg, 0.16 mmol), piperidine (3.08 μL, 0.031 mmol), and acetic acid (3.58 μL, 0.062 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (38 mg, 58%, 0.090 mmol). Gray solid: 1 H-NMR (DMSO-D 6 ) δ: 9.19 (1H, s), 8.75 (1H, s), 8.17 (1H, s), 7.93 (1H, s), 7.54 (2H, d, J = 9.0 Hz), 7.17 (2H, d, J = 9.0 Hz), 3.27 (4H, t, J = 5.0 Hz), 2.53 (4H, t, J = 5.0 Hz), 2.28 (3H, s).
ESI-MS (m / z): 421 [M + H] + .

実施例１１４
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)-[1,2,4]トリアゾロ[4,3-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１１４)  Example 114
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl)-[1,2,4] triazolo [4,3-a] pyridin-6-yl) methylene) thiazolidine-2,4 -Dione (compound 114)

工程１
5-ブロモ-2-ヒドラジニルピリジン Process 1
5-Bromo-2-hydrazinylpyridine

Figure JPOXMLDOC01-appb-C000458
Figure JPOXMLDOC01-appb-C000458

2,5-ジブロモピリジン (1 g, 4.22 mmol) のピリジン (10 mL) 溶液中に、ヒドラジン一水和物 (1.54 mL, 31.65 mmol) を滴下した。アルゴン置換した後、還流条件下一晩撹拌した。反応終了後、減圧下濃縮した。標記化合物 (745 mg, 94 %, 3.96 mmol) を得た。1H-NMR (CDCl3) δ: 8.13 (1H, s), 7.57 (1H, d, J = 8.8 Hz), 6.72 (1H, d, J = 8.8 Hz), 6.34-5.87 (1H, m), 3.71-3.07 (2H, m). 
ESI-MS(m/z): 188[M+H]+. Hydrazine monohydrate (1.54 mL, 31.65 mmol) was added dropwise to a solution of 2,5-dibromopyridine (1 g, 4.22 mmol) in pyridine (10 mL). After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated under reduced pressure. The title compound (745 mg, 94%, 3.96 mmol) was obtained. 1 H-NMR (CDCl 3 ) δ: 8.13 (1H, s), 7.57 (1H, d, J = 8.8 Hz), 6.72 (1H, d, J = 8.8 Hz), 6.34-5.87 (1H, m), 3.71-3.07 (2H, m).
ESI-MS (m / z): 188 [M + H] + .

工程２
1-(4-((E)-((Z)-(5-ブロモピリジン-2(1H)-イリデン)ヒドラゾノ)メチル)フェニル)-4-メチルピペラジン  Process 2
1- (4-((E)-((Z)-(5-Bromopyridine-2 (1H) -ylidene) hydrazono) methyl) phenyl) -4-methylpiperazine

Figure JPOXMLDOC01-appb-C000459
Figure JPOXMLDOC01-appb-C000459

4-(4-メチルピペラジン-1-イル)ベンズアルデヒド (109 mg, 0.53 mmol) のエタノール (2 mL) 溶液中に、5-ブロモ-2-ヒドラジニルピリジン (100 mg, 0.53 mmol) を室温で添加した。還流条件下、3時間撹拌し、反応終了後、減圧下濃縮乾固した。標記化合物 (196 mg, 99 %, 0.52 mmol) を得た。 1H-NMR (DMSO-D6) δ: 10.81 (1H, s), 8.15 (1H, s), 7.93 (1H, s), 7.76 (1H, d, J = 8.8 Hz), 7.50 (2H, d, J = 8.8 Hz), 7.15 (1H, d, J = 8.8 Hz), 6.95 (2H, d, J = 8.8 Hz), 3.20 (4H, t, J = 4.6 Hz), 2.45 (4H, t, J = 4.6 Hz), 2.23 (3H, s). 
ESI-MS(m/z): 374[M+H]+. In a solution of 4- (4-methylpiperazin-1-yl) benzaldehyde (109 mg, 0.53 mmol) in ethanol (2 mL), 5-bromo-2-hydrazinylpyridine (100 mg, 0.53 mmol) was added at room temperature. Added. The mixture was stirred for 3 hours under reflux conditions, and after completion of the reaction, the mixture was concentrated to dryness under reduced pressure. The title compound (196 mg, 99%, 0.52 mmol) was obtained. 1 H-NMR (DMSO-D 6 ) δ: 10.81 (1H, s), 8.15 (1H, s), 7.93 (1H, s), 7.76 (1H, d, J = 8.8 Hz), 7.50 (2H, d , J = 8.8 Hz), 7.15 (1H, d, J = 8.8 Hz), 6.95 (2H, d, J = 8.8 Hz), 3.20 (4H, t, J = 4.6 Hz), 2.45 (4H, t, J = 4.6 Hz), 2.23 (3H, s).
ESI-MS (m / z): 374 [M + H] + .

工程３
6-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-[1,2,4]トリアゾロ[4,3-a]ピリジン Process 3
6-Bromo-3- (4- (4-methylpiperazin-1-yl) phenyl)-[1,2,4] triazolo [4,3-a] pyridine

Figure JPOXMLDOC01-appb-C000460
Figure JPOXMLDOC01-appb-C000460

1-(4-((E)-((Z)-(5-ブロモピリジン-2(1H)-イリデン)ヒドラゾノ)メチル)フェニル)-4-メチルピペラジン (339 mg, 0.91 mmol) のテトラヒドロフラン (9 mL) 溶液中に、クロラミン-T三水和物 (281 mg, 0.99 mmol) を室温下添加した。60℃で2時間撹拌した後、さらにクロラミン-T三水和物 (154 mg, 0.54 mmol) を添加し、1時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (202 mg, 60 %, 0.54 mmol) を得た。 1H-NMR (CDCl3) δ: 8.38 (1H, s), 7.71-7.69 (3H, m), 7.29 (1H, d, J = 9.5 Hz), 7.09 (2H, d, J = 8.5 Hz), 3.43-3.42 (4H, m), 2.72-2.70 (4H, m), 2.45 (3H, s). 
ESI-MS(m/z): 372[M+H]+. 1- (4-((E)-((Z)-(5-Bromopyridine-2 (1H) -ylidene) hydrazono) methyl) phenyl) -4-methylpiperazine (339 mg, 0.91 mmol) in tetrahydrofuran (9 mL) Chloramine-T trihydrate (281 mg, 0.99 mmol) was added to the solution at room temperature. After stirring at 60 ° C. for 2 hours, chloramine-T trihydrate (154 mg, 0.54 mmol) was further added and stirred for 1 hour. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (202 mg, 60%, 0.54 mmol). 1 H-NMR (CDCl 3 ) δ: 8.38 (1H, s), 7.71-7.69 (3H, m), 7.29 (1H, d, J = 9.5 Hz), 7.09 (2H, d, J = 8.5 Hz), 3.43-3.42 (4H, m), 2.72-2.70 (4H, m), 2.45 (3H, s).
ESI-MS (m / z): 372 [M + H] + .

工程４
3-(4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニル-[1,2,4]トリアゾロ[4,3-a]ピリジン Process 4
3- (4- (4-Methylpiperazin-1-yl) phenyl) -6-vinyl- [1,2,4] triazolo [4,3-a] pyridine

Figure JPOXMLDOC01-appb-C000461
Figure JPOXMLDOC01-appb-C000461

6-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-[1,2,4]トリアゾロ[4,3-a]ピリジン (229 mg, 0.62 mmol)、テトラキストリフェニルホスフィンパラジウム (71 mg, 0.062 mmol) のトルエン (5 mL) 溶媒中に、ビニルトリブチルスズ (271 μL, 0.92 mmol) を滴下した。アルゴン置換した後、還流条件下一晩撹拌し、反応終了後クロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (80 mg, 41 %, 0.25 mmol) を得た。黄色固体: 1H-NMR (CDCl3) δ: 8.10 (1H, s), 7.76 (1H, d, J = 9.8 Hz), 7.73 (2H, d, J = 8.8 Hz), 7.47 (1H, d, J = 9.8 Hz), 7.09 (2H, d, J = 8.8 Hz), 6.62 (1H, dd, J = 17.6, 11.0 Hz), 5.79 (1H, d, J = 17.6 Hz), 5.42 (1H, d, J = 11.0 Hz), 3.54-3.47 (4H, m), 2.91-2.78 (4H, m), 2.55 (3H, s). 
ESI-MS(m/z): 320[M+H]+. 6-Bromo-3- (4- (4-methylpiperazin-1-yl) phenyl)-[1,2,4] triazolo [4,3-a] pyridine (229 mg, 0.62 mmol), tetrakistriphenylphosphine Vinyltributyltin (271 μL, 0.92 mmol) was added dropwise to a toluene (5 mL) solvent of palladium (71 mg, 0.062 mmol). After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, the organic layer was extracted by adding chloroform and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (80 mg, 41%, 0.25 mmol). Yellow solid: 1 H-NMR (CDCl 3 ) δ: 8.10 (1H, s), 7.76 (1H, d, J = 9.8 Hz), 7.73 (2H, d, J = 8.8 Hz), 7.47 (1H, d, J = 9.8 Hz), 7.09 (2H, d, J = 8.8 Hz), 6.62 (1H, dd, J = 17.6, 11.0 Hz), 5.79 (1H, d, J = 17.6 Hz), 5.42 (1H, d, J = 11.0 Hz), 3.54-3.47 (4H, m), 2.91-2.78 (4H, m), 2.55 (3H, s).
ESI-MS (m / z): 320 [M + H] + .

工程５
3-(4-(4-メチルピペラジン-1-イル)フェニル)-[1,2,4]トリアゾロ[4,3-a]ピリジン-6-カルボアルデヒド Process 5
3- (4- (4-Methylpiperazin-1-yl) phenyl)-[1,2,4] triazolo [4,3-a] pyridine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000462
Figure JPOXMLDOC01-appb-C000462

3-(4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニル-[1,2,4]トリアゾロ[4,3-a]ピリジン (44 mg, 0.14 mmol)、過ヨウ素酸ナトリウム (118 mg, 0.55 mmol) を 1,4-ジオキサン (3 mL)、水 (1 mL) の混合溶液に溶解し、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 ( 35 μL, 0.0028 mmol)、2,6-ルチジン (32μL, 0.28 mmol) を滴下した。アルゴン雰囲気下、室温で4時間撹拌した。反応終了後、飽和チオ硫酸ナトリウム水溶液を加え、セライトろ過した。ろ液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (24 mg, 54 %, 0.075 mmol) を得た。1H-NMR (CDCl3) δ: 9.93 (1H, s), 8.74 (1H, s), 7.85 (1H, d, J = 9.5 Hz), 7.77-7.69 (3H, m), 7.11 (2H, d, J = 8.8 Hz), 3.41-3.39 (4H, m), 2.66-2.63 (4H, m), 2.41 (3H, s). 3- (4- (4-Methylpiperazin-1-yl) phenyl) -6-vinyl- [1,2,4] triazolo [4,3-a] pyridine (44 mg, 0.14 mmol), sodium periodate (118 mg, 0.55 mmol) was dissolved in a mixed solution of 1,4-dioxane (3 mL) and water (1 mL), 2.5 wt% osmium tetroxide tert-butanol solution (35 μL, 0.0028 mmol), 2, 6-Lutidine (32 μL, 0.28 mmol) was added dropwise. The mixture was stirred at room temperature for 4 hours under an argon atmosphere. After completion of the reaction, a saturated aqueous sodium thiosulfate solution was added, and the mixture was filtered through celite. A saturated aqueous sodium hydrogen carbonate solution was added to the filtrate, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (24 mg, 54%, 0.075 mmol). 1 H-NMR (CDCl 3 ) δ: 9.93 (1H, s), 8.74 (1H, s), 7.85 (1H, d, J = 9.5 Hz), 7.77-7.69 (3H, m), 7.11 (2H, d , J = 8.8 Hz), 3.41-3.39 (4H, m), 2.66-2.63 (4H, m), 2.41 (3H, s).

工程６
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)-[1,2,4]トリアゾロ[4,3-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１１４) Step 6
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl)-[1,2,4] triazolo [4,3-a] pyridin-6-yl) methylene) thiazolidine-2,4 -Dione (compound 114)

Figure JPOXMLDOC01-appb-C000463
Figure JPOXMLDOC01-appb-C000463

3-(4-(4-メチルピペラジン-1-イル)フェニル)-[1,2,4]トリアゾロ[4,3-a]ピリジン-6-カルボアルデヒド (21 mg, 0.07 mmol) をアセトニトリル (3.0 mL) に溶かし、チアゾリジン-2,4-ジオン (8 mg, 0.07 mmol)、ピペリジン (1.3 μL, 0.013 mmol)、および酢酸 (1.5 μL, 0.026 mmol) を加え、100℃で6時間撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (20 mg, 73 %, 0.048 mmol) を得た。 1H-NMR (DMSO-D6) δ: 9.22 (1H, s), 8.07 (2H, d, J = 8.8 Hz), 7.89 (1H, d, J = 9.5 Hz), 7.81 (1H, d, J = 9.5 Hz), 7.71 (1H, s), 7.11 (2H, d, J = 8.8 Hz), 3.42-3.27 (4H, m), 2.83-2.80 (4H, m), 2.50 (3H, s). 
ESI-MS(m/z): 421[M+H]+. 3- (4- (4-Methylpiperazin-1-yl) phenyl)-[1,2,4] triazolo [4,3-a] pyridine-6-carbaldehyde (21 mg, 0.07 mmol) in acetonitrile (3.0 To the residue, thiazolidine-2,4-dione (8 mg, 0.07 mmol), piperidine (1.3 μL, 0.013 mmol), and acetic acid (1.5 μL, 0.026 mmol) were added and stirred at 100 ° C. for 6 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (20 mg, 73%, 0.048 mmol). 1 H-NMR (DMSO-D 6 ) δ: 9.22 (1H, s), 8.07 (2H, d, J = 8.8 Hz), 7.89 (1H, d, J = 9.5 Hz), 7.81 (1H, d, J = 9.5 Hz), 7.71 (1H, s), 7.11 (2H, d, J = 8.8 Hz), 3.42-3.27 (4H, m), 2.83-2.80 (4H, m), 2.50 (3H, s).
ESI-MS (m / z): 421 [M + H] + .

実施例１１５
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾ[d]イソチアゾール-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１１５)  Example 115
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzo [d] isothiazol-5-yl) methylene) -2-thioxothiazolidin-4-one (Compound 115)

工程１
5-クロロ-2-メルカプトベンゾニトリル Process 1
5-chloro-2-mercaptobenzonitrile

Figure JPOXMLDOC01-appb-C000464
Figure JPOXMLDOC01-appb-C000464

5-クロロ-2-フルオロベンゾニトリル (100 mg, 0.64 mmol) のN,N-ジメチルホルムアミド (2 mL) 溶媒中に、硫化ナトリウム9水和物 (168 mg, 0.70 mmol) を室温下添加した。一晩撹拌した後、反応終了後、1規定塩酸水溶液を添加し、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (46 mg, 42 %, 0.27 mmol) を得た。1H-NMR (CDCl3) δ: 7.71 (1H, d, J = 8.5 Hz), 7.63 (1H, d, J = 2.2 Hz), 7.56 (1H, dd, J = 8.5, 2.2 Hz). Sodium sulfide nonahydrate (168 mg, 0.70 mmol) was added to a N, N-dimethylformamide (2 mL) solvent of 5-chloro-2-fluorobenzonitrile (100 mg, 0.64 mmol) at room temperature. After stirring overnight, after completion of the reaction, a 1N aqueous hydrochloric acid solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (46 mg, 42%, 0.27 mmol). 1 H-NMR (CDCl 3 ) δ: 7.71 (1H, d, J = 8.5 Hz), 7.63 (1H, d, J = 2.2 Hz), 7.56 (1H, dd, J = 8.5, 2.2 Hz).

工程２
3-ブロモ-5-クロロベンゾ[d]イソチアゾール Process 2
3-Bromo-5-chlorobenzo [d] isothiazole

Figure JPOXMLDOC01-appb-C000465
Figure JPOXMLDOC01-appb-C000465

5-クロロ-2-メルカプトベンゾニトリル (40 mg, 0.24 mmol) の酢酸エチル (400 μL)溶液中に、臭素 (12 μL, 0.23 mmol) を0℃で滴下した。室温に昇温した後、60℃で3時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (46 mg, 78 %, 0.185 mmol) を得た。1H-NMR (CDCl3) δ: 8.00 (1H, d, J = 2.0 Hz), 7.86 (1H, d, J = 8.8 Hz), 7.58 (1H, dd, J = 8.8, 2.0 Hz). 
ESI-MS(m/z): 247[M+H]+. Bromine (12 μL, 0.23 mmol) was added dropwise at 0 ° C. to a solution of 5-chloro-2-mercaptobenzonitrile (40 mg, 0.24 mmol) in ethyl acetate (400 μL). After warming to room temperature, it stirred at 60 degreeC for 3 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (46 mg, 78%, 0.185 mmol). 1 H-NMR (CDCl 3 ) δ: 8.00 (1H, d, J = 2.0 Hz), 7.86 (1H, d, J = 8.8 Hz), 7.58 (1H, dd, J = 8.8, 2.0 Hz).
ESI-MS (m / z): 247 [M + H] + .

工程３
5-クロロ-3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾ[d]イソチアゾール Process 3
5-Chloro-3- (4- (4-methylpiperazin-1-yl) phenyl) benzo [d] isothiazole

Figure JPOXMLDOC01-appb-C000466
Figure JPOXMLDOC01-appb-C000466

3-ブロモ-5-クロロベンゾ[d]イソチアゾール (346 mg, 1.39 mmol) の1,4-ジオキサン (30 mL)、水(10 mL) の混合溶液中に、1-メチル-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン (505 mg, 1.67 mmol)、テトラキストリフェニルホスフィンパラジウム (322 mg, 0.28 mmol)、水酸化カリウム (273 mg, 4.87 mmol) を添加した。アルゴン置換した後、還流条件下一晩撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (214 mg, 45 %, 0.622 mmol) を得た。1H-NMR (CDCl3) δ: 8.16 (1H, s), 7.88 (1H, d, J = 8.7 Hz), 7.77 (2H, d, J = 9.0 Hz), 7.50 (1H, d, J = 8.7 Hz), 7.07 (2H, d, J = 9.0 Hz), 3.44-3.33 (4H, m), 2.80-2.59 (4H, m), 2.44 (3H, s). 
ESI-MS(m/z): 344[M+H]+. In a mixed solution of 3-bromo-5-chlorobenzo [d] isothiazole (346 mg, 1.39 mmol) in 1,4-dioxane (30 mL) and water (10 mL), 1-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine (505 mg, 1.67 mmol), tetrakistriphenylphosphine palladium (322 mg, 0.28 mmol), hydroxylated Potassium (273 mg, 4.87 mmol) was added. After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (214 mg, 45%, 0.622 mmol). 1 H-NMR (CDCl 3 ) δ: 8.16 (1H, s), 7.88 (1H, d, J = 8.7 Hz), 7.77 (2H, d, J = 9.0 Hz), 7.50 (1H, d, J = 8.7 Hz), 7.07 (2H, d, J = 9.0 Hz), 3.44-3.33 (4H, m), 2.80-2.59 (4H, m), 2.44 (3H, s).
ESI-MS (m / z): 344 [M + H] + .

工程４
3-(4-(4-メチルピペラジン-1-イル)フェニル)-5-ビニルベンゾ[d]イソチアゾール Process 4
3- (4- (4-Methylpiperazin-1-yl) phenyl) -5-vinylbenzo [d] isothiazole

Figure JPOXMLDOC01-appb-C000467
Figure JPOXMLDOC01-appb-C000467

5-クロロ-3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾ[d]イソチアゾール (548 mg, 1.59 mmol) の1,4-ジオキサン (20 mL)、水(4 mL) の混合溶液中に 4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (409 μL, 2.39 mmol)、酢酸パラジウム (36 mg, 0.16 mmol)、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル (131 mg, 0.32 mmol)、リン酸カリウム (2.53 g, 11.93 mmol) を添加した。アルゴン置換した後、還流条件下一晩撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) にて精製し、標記化合物 ( 525 mg, 98 %, 1.57 mmol) を得た。1H-NMR (CDCl3) δ: 8.11 (1H, s), 7.91 (1H, d, J = 8.3 Hz), 7.80 (2H, d, J = 8.8 Hz), 7.67 (1H, d, J = 8.3 Hz), 7.08 (2H, d, J = 8.8 Hz), 6.85 (1H, dd, J = 17.7, 10.9 Hz), 5.84 (1H, d, J = 17.7 Hz), 5.34 (1H, d, J = 10.9 Hz), 3.42 (4H, t, J = 4.8 Hz), 2.74-2.72 (4H, br m), 2.46 (3H, s). 
ESI-MS(m/z): 336[M+H]+. 5-chloro-3- (4- (4-methylpiperazin-1-yl) phenyl) benzo [d] isothiazole (548 mg, 1.59 mmol) in 1,4-dioxane (20 mL), water (4 mL) 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (409 μL, 2.39 mmol), palladium acetate (36 mg, 0.16 mmol), 2-dicyclohexylphosphino -2 ', 6'-dimethoxybiphenyl (131 mg, 0.32 mmol) and potassium phosphate (2.53 g, 11.93 mmol) were added. After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (525 mg, 98%, 1.57 mmol). 1 H-NMR (CDCl 3 ) δ: 8.11 (1H, s), 7.91 (1H, d, J = 8.3 Hz), 7.80 (2H, d, J = 8.8 Hz), 7.67 (1H, d, J = 8.3 Hz), 7.08 (2H, d, J = 8.8 Hz), 6.85 (1H, dd, J = 17.7, 10.9 Hz), 5.84 (1H, d, J = 17.7 Hz), 5.34 (1H, d, J = 10.9 Hz), 3.42 (4H, t, J = 4.8 Hz), 2.74-2.72 (4H, br m), 2.46 (3H, s).
ESI-MS (m / z): 336 [M + H] + .

工程５
3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾ[d]イソチアゾール-5-カルボアルデヒド  Process 5
3- (4- (4-Methylpiperazin-1-yl) phenyl) benzo [d] isothiazole-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000468
Figure JPOXMLDOC01-appb-C000468

3-(4-(4-メチルピペラジン-1-イル)フェニル)-5-ビニルベンゾ[d]イソチアゾール (520 mg, 1.55 mmol) の1,4-ジオキサン (10 mL)、水 (3 mL) の混合溶液中に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (389 μL, 0.031 mmol)、2,6-ルチジン (361 μL, 3.10 mmol)、過ヨウ素酸ナトリウム (1.33 g, 6.20 mmol) を添加した。アルゴン置換した後、室温で4時間撹拌した。反応終了後、セライトろ過し、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 ( 171 mg, 33%, 0.51 mmol) を得た。1H-NMR (CDCl3) δ: 10.13 (1H, s), 8.65 (1H, s), 8.12-8.05 (2H, m), 7.83 (2H, d, J = 8.8 Hz), 7.09 (2H, d, J = 8.8 Hz), 3.46-3.45 (4H, m), 2.77-2.74 (4H, m), 2.47 (3H, s). 
ESI-MS(m/z): 338[M+H]+. 3- (4- (4-Methylpiperazin-1-yl) phenyl) -5-vinylbenzo [d] isothiazole (520 mg, 1.55 mmol) in 1,4-dioxane (10 mL), water (3 mL) 2.5 wt% osmium tetroxide tert-butanol solution (389 μL, 0.031 mmol), 2,6-lutidine (361 μL, 3.10 mmol), sodium periodate (1.33 g, 6.20 mmol) were added to the mixed solution. . After purging with argon, the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was filtered through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was refine | purified by the silica gel column chromatography method (chloroform / methanol), and the title compound (171 mg, 33%, 0.51 mmol) was obtained. 1 H-NMR (CDCl 3 ) δ: 10.13 (1H, s), 8.65 (1H, s), 8.12-8.05 (2H, m), 7.83 (2H, d, J = 8.8 Hz), 7.09 (2H, d , J = 8.8 Hz), 3.46-3.45 (4H, m), 2.77-2.74 (4H, m), 2.47 (3H, s).
ESI-MS (m / z): 338 [M + H] + .

工程６
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾ[d]イソチアゾール-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１１５) Step 6
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzo [d] isothiazol-5-yl) methylene) -2-thioxothiazolidin-4-one (Compound 115)

Figure JPOXMLDOC01-appb-C000469
Figure JPOXMLDOC01-appb-C000469

3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾ[d]イソチアゾール-5-カルボアルデヒド (80 mg, 0.24 mmol) をアセトニトリル (8.0 mL) に溶かし、ロダニン (32 mg, 0.24 mmol)、ピペリジン (4.7 μL, 0.047 mmol)、および酢酸 (5.4 μL, 0.095 mmol) を加え、100℃で一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (8 mg, 7 %, 0.018 mmol) を得た。黄褐色固体: 1H-NMR (DMSO-D6) δ: 8.35-8.29 (2H, m), 7.85 (2H, d, J = 8.8 Hz), 7.79 (1H, d, J = 8.3 Hz), 7.49 (1H, s), 7.21 (2H, d, J = 8.8 Hz), 3.56-3.42 (4H, m), 3.19-3.08 (4H, m), 2.72 (3H, s). 
ESI-MS(m/z): 453[M+H]+. 3- (4- (4-Methylpiperazin-1-yl) phenyl) benzo [d] isothiazole-5-carbaldehyde (80 mg, 0.24 mmol) was dissolved in acetonitrile (8.0 mL) and rhodanine (32 mg, 0.24 mmol), piperidine (4.7 μL, 0.047 mmol), and acetic acid (5.4 μL, 0.095 mmol) were added and stirred at 100 ° C. overnight. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (8 mg, 7%, 0.018 mmol). Tawny solid: 1 H-NMR (DMSO-D 6 ) δ: 8.35-8.29 (2H, m), 7.85 (2H, d, J = 8.8 Hz), 7.79 (1H, d, J = 8.3 Hz), 7.49 (1H, s), 7.21 (2H, d, J = 8.8 Hz), 3.56-3.42 (4H, m), 3.19-3.08 (4H, m), 2.72 (3H, s).
ESI-MS (m / z): 453 [M + H] + .

実施例１１６
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾ[d]イソチアゾール-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１１６) Example 116
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzo [d] isothiazol-5-yl) methylene) thiazolidine-2,4-dione (Compound 116)

Figure JPOXMLDOC01-appb-C000470
Figure JPOXMLDOC01-appb-C000470

工程１
3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾ[d]イソチアゾール-5-カルボアルデヒド (80 mg, 0.24 mmol) をアセトニトリル (8.0 mL) に溶かし、チアゾリジン-2,4-ジオン (28 mg, 0.24 mmol)、ピペリジン (4.7 μL, 0.047 mmol)、および酢酸 (5.4 μL, 0.095 mmol) を加え、100℃で一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (30 mg, 29 %, 0.069 mmol) を得た。 1H-NMR (DMSO-D6) δ: 8.42 (1H, s), 8.35 (1H, d, J = 8.5 Hz), 7.87-7.78 (4H, m), 7.19 (2H, d, J = 8.8 Hz), 3.41 (4H, t, J = 5.1 Hz), 2.84 (4H, t, J = 5.1 Hz), 2.50 (3H, s). 
ESI-MS(m/z): 437[M+H]+. Process 1
3- (4- (4-Methylpiperazin-1-yl) phenyl) benzo [d] isothiazole-5-carbaldehyde (80 mg, 0.24 mmol) was dissolved in acetonitrile (8.0 mL) and thiazolidine-2,4- Dione (28 mg, 0.24 mmol), piperidine (4.7 μL, 0.047 mmol), and acetic acid (5.4 μL, 0.095 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (30 mg, 29%, 0.069 mmol). 1 H-NMR (DMSO-D 6 ) δ: 8.42 (1H, s), 8.35 (1H, d, J = 8.5 Hz), 7.87-7.78 (4H, m), 7.19 (2H, d, J = 8.8 Hz ), 3.41 (4H, t, J = 5.1 Hz), 2.84 (4H, t, J = 5.1 Hz), 2.50 (3H, s).
ESI-MS (m / z): 437 [M + H] + .

実施例１１７
5-((1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ピラゾロ[3,4-b]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１１７) Example 117
5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-pyrazolo [3,4-b] pyridin-6-yl) methylene) thiazolidine-2,4-dione (Compound 117 )

工程１
3-((2-(4-ブロモフェニル)ヒドラゾノ)メチル)-2,6-ジクロロピリジン Process 1
3-((2- (4-Bromophenyl) hydrazono) methyl) -2,6-dichloropyridine

Figure JPOXMLDOC01-appb-C000471
Figure JPOXMLDOC01-appb-C000471

2,6-ジクロロニコチンアルデヒド (1.76 g, 10 mmol) および (4-ブロモフェニル)ヒドラジン 塩酸塩 (2.24 g, 10 mmol) をアセトニトリル (100 mL) に溶かし、ジイソプロピルエチルアミン (3.10 g, 24 mmol) を滴下した後、還流条件下一晩撹拌した。反応終了後、減圧下濃縮し、残留物をヘキサン/クロロホルム=1/1溶液で洗浄して標記化合物 (2.27 g, 6.6 mmol, 66 %) を得た。1H-NMR (CDCl3) δ: 11.12 (1H, s), 8.42 (1H, d, J = 8.3 Hz), 8.06 (1H, s), 7.58 (1H, d, J = 8.3 Hz), 7.41 (2H, d, J = 8.8 Hz), 7.08 (2H, d, J = 8.8 Hz).  2,6-dichloronicotinaldehyde (1.76 g, 10 mmol) and (4-bromophenyl) hydrazine hydrochloride (2.24 g, 10 mmol) were dissolved in acetonitrile (100 mL), and diisopropylethylamine (3.10 g, 24 mmol) was dissolved. After dropwise addition, the mixture was stirred overnight under reflux conditions. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was washed with a hexane / chloroform = 1/1 solution to obtain the title compound (2.27 g, 6.6 mmol, 66%). 1 H-NMR (CDCl 3 ) δ: 11.12 (1H, s), 8.42 (1H, d, J = 8.3 Hz), 8.06 (1H, s), 7.58 (1H, d, J = 8.3 Hz), 7.41 ( 2H, d, J = 8.8 Hz), 7.08 (2H, d, J = 8.8 Hz).

工程２
1-(4-ブロモフェニル)-6-クロロ-1H-ピラゾロ[3,4-b]ピリジン  Process 2
1- (4-Bromophenyl) -6-chloro-1H-pyrazolo [3,4-b] pyridine

Figure JPOXMLDOC01-appb-C000472
Figure JPOXMLDOC01-appb-C000472

3-((2-(4-ブロモフェニル)ヒドラゾノ)メチル)-2,6-ジクロロピリジン(2.27 g, 6.6 mmol) をジメチルスルホキシド (20 mL) に溶かし、炭酸セシウム (4.30 g, 13.2 mmol) を加えた後、120℃のオイルバス中で一晩撹拌した。反応混合物にヘキサン／クロロホルム=1/1 溶液を加え、固体をろ取して標記化合物 (0.66 g, 2.1 mmol, 32 %) を得た。1H-NMR (CDCl3) δ: 8.19 (2H, d, J = 9.0 Hz), 8.18 (1H, s), 8.07 (1H, d, J = 8.3 Hz), 7.65 (2H, d, J = 9.0 Hz), 7.25 (1H, d, J = 8.3 Hz).  3-((2- (4-Bromophenyl) hydrazono) methyl) -2,6-dichloropyridine (2.27 g, 6.6 mmol) was dissolved in dimethyl sulfoxide (20 mL), and cesium carbonate (4.30 g, 13.2 mmol) was dissolved. After the addition, the mixture was stirred overnight in an oil bath at 120 ° C. A hexane / chloroform = 1/1 solution was added to the reaction mixture, and the solid was collected by filtration to obtain the title compound (0.66 g, 2.1 mmol, 32%). 1 H-NMR (CDCl 3 ) δ: 8.19 (2H, d, J = 9.0 Hz), 8.18 (1H, s), 8.07 (1H, d, J = 8.3 Hz), 7.65 (2H, d, J = 9.0 Hz), 7.25 (1H, d, J = 8.3 Hz).

工程３
6-クロロ-1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ピラゾロ[3,4-b]ピリジン Process 3
6-Chloro-1- (4- (4-ethylpiperazin-1-yl) phenyl) -1H-pyrazolo [3,4-b] pyridine

Figure JPOXMLDOC01-appb-C000473
Figure JPOXMLDOC01-appb-C000473

メチル 1-(4-モルフォリノフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボキシレートの合成と同様の手法で、1-(4-ブロモフェニル)-6-クロロ-1H-ピラゾロ [3,4-b]ピリジン (0.43 g, 1.4 mmol) およびN-エチルピペラジン (0.24 g, 2.4 mmol) とから標記化合物 (0.23 g , 0.67 mmol, 59 %) を得た。1H-NMR (CDCl3) δ: 8.23 (2H, d, J = 8.8 Hz), 7.93 (1H, s), 7.83 (1H, d, J = 8.8 Hz), 7.60 (2H, d, J = 9.0 Hz), 6.66 (1H, d, J = 9.0 Hz), 3.90-3.70 (4H, m), 2.70-2.50 (6H, m), 1.20 (3H, br s). Similar to the synthesis of methyl 1- (4-morpholinophenyl) -1H-benzo [d] imidazole-6-carboxylate, 1- (4-bromophenyl) -6-chloro-1H-pyrazolo [3, 4-b] pyridine (0.43 g, 1.4 mmol) and N-ethylpiperazine (0.24 g, 2.4 mmol) gave the title compound (0.23 g, 0.67 mmol, 59%). 1 H-NMR (CDCl 3 ) δ: 8.23 (2H, d, J = 8.8 Hz), 7.93 (1H, s), 7.83 (1H, d, J = 8.8 Hz), 7.60 (2H, d, J = 9.0 Hz), 6.66 (1H, d, J = 9.0 Hz), 3.90-3.70 (4H, m), 2.70-2.50 (6H, m), 1.20 (3H, br s).

工程４
1-(4-(4-エチルピペラジン-1-イル)フェニル)-6-ビニル-1H-ピラゾロ[3,4-b]ピリジン Process 4
1- (4- (4-Ethylpiperazin-1-yl) phenyl) -6-vinyl-1H-pyrazolo [3,4-b] pyridine

Figure JPOXMLDOC01-appb-C000474
Figure JPOXMLDOC01-appb-C000474

3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成と同様の手法で、6-クロロ-1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ピラゾロ[3,4-b]ピリジン (0.23 g, 0.67 mmol) から標記化合物 (0.10 g , 0.30 mmol, 45 %) を得た。1H-NMR (CDCl3) δ: 8.27 (2H, d, J = 8.3 Hz), 7.95 (1H, s), 7.85 (1H, d, J = 9.0 Hz), 7.54 (2H, d, J = 8.8 Hz), 6.76 (1H, m), 6.67 (1H, d, J = 9.0 Hz), 5.78 (1H, dd, J = 16.8, 0.7 Hz), 5.26 (1H, d, J = 11.7 Hz), 3.94-3.75 (4H, m), 2.81-2.55 (6H, m), 1.23 (3H, br s). In a similar manner to the synthesis of 3- (2-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine, 6-chloro-1- (4 The title compound (0.10 g, 0.30 mmol, 45%) was obtained from-(4-ethylpiperazin-1-yl) phenyl) -1H-pyrazolo [3,4-b] pyridine (0.23 g, 0.67 mmol). 1 H-NMR (CDCl 3 ) δ: 8.27 (2H, d, J = 8.3 Hz), 7.95 (1H, s), 7.85 (1H, d, J = 9.0 Hz), 7.54 (2H, d, J = 8.8 Hz), 6.76 (1H, m), 6.67 (1H, d, J = 9.0 Hz), 5.78 (1H, dd, J = 16.8, 0.7 Hz), 5.26 (1H, d, J = 11.7 Hz), 3.94- 3.75 (4H, m), 2.81-2.55 (6H, m), 1.23 (3H, br s).

工程５
1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ピラゾロ[3,4-b]ピリジン-6-カルボアルデヒド Process 5
1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-pyrazolo [3,4-b] pyridine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000475
Figure JPOXMLDOC01-appb-C000475

3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成と同様の手法で、1-(4-(4-エチルピペラジン-1-イル)フェニル)-6-ビニル-1H-ピラゾロ[3,4-b]ピリジン (0.10 g, 0.30 mmol) から標記化合物 (0.07 g , 0.21 mmol, 70 %) を得た。1H-NMR (CDCl3) δ: 10.03 (1H, s), 8.57 (2H, d, J = 8.1 Hz), 8.10-8.01 (3H, m), 7.89 (1H, d, J = 8.5 Hz), 6.72 (1H, d, J = 9.0 Hz), 4.10-3.85 (4H, m), 3.15-2.56(6H, m), 1.34 (3H, br s). In a similar manner to the synthesis of 3- (2-fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde, 1- (4- (4 The title compound (0.07 g, 0.21 mmol, 70%) was obtained from -ethylpiperazin-1-yl) phenyl) -6-vinyl-1H-pyrazolo [3,4-b] pyridine (0.10 g, 0.30 mmol). 1 H-NMR (CDCl 3 ) δ: 10.03 (1H, s), 8.57 (2H, d, J = 8.1 Hz), 8.10-8.01 (3H, m), 7.89 (1H, d, J = 8.5 Hz), 6.72 (1H, d, J = 9.0 Hz), 4.10-3.85 (4H, m), 3.15-2.56 (6H, m), 1.34 (3H, br s).

工程６
5-((1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ピラゾロ[3,4-b]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１１７) Step 6
5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-pyrazolo [3,4-b] pyridin-6-yl) methylene) thiazolidine-2,4-dione (Compound 117 )

Figure JPOXMLDOC01-appb-C000476
Figure JPOXMLDOC01-appb-C000476

5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオンと同様の方法で、1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ピラゾロ[3,4-b]ピリジン-6-カルボアルデヒド (0.07 g, 0.21 mmol) およびチアゾリジン-2,4-ジオン (25 mg, 0.21 mmol) とから標記化合物 (33 mg, 36 %) を得た。1H-NMR (DMSO-D6) δ: 8.47 (2H, d, J = 8.8 Hz), 8.18 (1H, s), 8.05 (1H, d, J = 9.0 Hz), 7.76 (2H, d, J = 8.8 Hz), 7.72 (1H, s), 6.99 (1H, d, J = 9.0 Hz), 3.90-3.69 (4H, m), 2.75-2.61 (6H, m), 1.12 (3H, t, J = 7.2 Hz). 
ESI-MS(m/z): 435[M+H]+. In the same manner as 5-((1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione, 1- ( 4- (4-Ethylpiperazin-1-yl) phenyl) -1H-pyrazolo [3,4-b] pyridine-6-carbaldehyde (0.07 g, 0.21 mmol) and thiazolidine-2,4-dione (25 mg, 0.21 mmol) gave the title compound (33 mg, 36%). 1 H-NMR (DMSO-D 6 ) δ: 8.47 (2H, d, J = 8.8 Hz), 8.18 (1H, s), 8.05 (1H, d, J = 9.0 Hz), 7.76 (2H, d, J = 8.8 Hz), 7.72 (1H, s), 6.99 (1H, d, J = 9.0 Hz), 3.90-3.69 (4H, m), 2.75-2.61 (6H, m), 1.12 (3H, t, J = 7.2 Hz).
ESI-MS (m / z): 435 [M + H] + .

実施例１１８
5-((1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン ハイドロクロライド (化合物１１８)  Example 118
5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione hydrochloride (Compound 118)

Figure JPOXMLDOC01-appb-C000477
Figure JPOXMLDOC01-appb-C000477

工程１
5-((1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (50 mg, 0.12 mmol) のメタノール (1 mL) 懸濁液に 0.1規定塩酸水溶液 (1.18 mL, 0.12 mmol) を加え 5 分間撹拌した。減圧下、溶媒を留去した後、残渣を水に溶かし、ろ過した。ろ液にメタノールを加え、減圧下、溶媒を留去した。得られた結晶をメタノールで洗浄した後、乾燥し、目的とする目的とする標記化合物 (34 mg, 63 %) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 12.61 (1H, s), 9.82 (1H, br s), 8.66 (1H, s), 7.98 (1H, s), 7.91 (1H, d, J = 8.3 Hz), 7.81 (1H, d, J = 1.6 Hz), 7.62 (2H, d, J = 9.0 Hz), 7.56 (1H, dd, J = 8.3, 1.6 Hz), 7.28 (2H, d, J = 9.0 Hz), 4.04-3.99 (2H, m), 3.63-3.60 (2H, m), 3.24-3.21 (2H, m), 3.17-3.11 (4H, m), 1.29 (3H, t, J = 7.3 Hz). Process 1
5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (50 mg, 0.12 mmol) 0.1M aqueous hydrochloric acid (1.18 mL, 0.12 mmol) was added to a methanol (1 mL) suspension, and the mixture was stirred for 5 minutes. After evaporating the solvent under reduced pressure, the residue was dissolved in water and filtered. Methanol was added to the filtrate, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with methanol and dried to give the desired title compound (34 mg, 63%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 12.61 (1H, s), 9.82 (1H, br s), 8.66 (1H, s), 7.98 (1H, s), 7.91 (1H, d, J = 8.3 Hz), 7.81 (1H, d, J = 1.6 Hz), 7.62 (2H, d, J = 9.0 Hz), 7.56 (1H, dd, J = 8.3, 1.6 Hz), 7.28 (2H, d, J = 9.0 Hz), 4.04-3.99 (2H, m), 3.63-3.60 (2H, m), 3.24-3.21 (2H, m), 3.17-3.11 (4H, m), 1.29 (3H, t, J = (7.3 Hz).

実施例１１９
5-((1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン ビス(サルフェート) (化合物１１９) Example 119
5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione bis (sulfate) (Compound 119 )

Figure JPOXMLDOC01-appb-C000478
Figure JPOXMLDOC01-appb-C000478

工程１
5-((1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (40 mg, 0.09 mmol) のメタノール (1mL) 懸濁液に 0.1規定硫酸水溶液 (3.68 mL, 0.18 mmol) を加え、5 分間撹拌した。減圧下溶媒を留去した後、残渣を水に溶かし、ろ過した。ろ液にメタノールを加え、減圧下、溶媒を留去した。得られた結晶をメタノールで洗浄した後、乾燥し、目的とする目的とする標記化合物 (37 mg, 63 %) を得た。茶褐色結晶: 1H-NMR (DMSO-D6) δ: 12.61 (1H, s), 9.29 (1H, s), 8.70 (1H, s), 7.98 (1H, s), 7.92 (1H, d, J = 8.8 Hz), 7.80 (1H, d, J = 1.7 Hz), 7.62 (2H, d, J = 9.0 Hz), 7.57 (1H, dd, J = 8.8, 1.7 Hz), 7.29 (2H, d, J = 9.0 Hz), 4.04 (2H, s), 4.01 (3H, s), 3.64-3.61 (2H, m), 3.26-3.22 (2H, m), 3.19-3.16 (2H, m), 3.09-3.03 (2H, m), 1.28 (3H, t, J = 7.3 Hz). Process 1
5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (40 mg, 0.09 mmol) 0.1M aqueous sulfuric acid solution (3.68 mL, 0.18 mmol) was added to a methanol (1 mL) suspension, and the mixture was stirred for 5 minutes. After evaporating the solvent under reduced pressure, the residue was dissolved in water and filtered. Methanol was added to the filtrate, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with methanol and dried to give the desired title compound (37 mg, 63%). Brownish crystals: 1 H-NMR (DMSO-D 6 ) δ: 12.61 (1H, s), 9.29 (1H, s), 8.70 (1H, s), 7.98 (1H, s), 7.92 (1H, d, J = 8.8 Hz), 7.80 (1H, d, J = 1.7 Hz), 7.62 (2H, d, J = 9.0 Hz), 7.57 (1H, dd, J = 8.8, 1.7 Hz), 7.29 (2H, d, J = 9.0 Hz), 4.04 (2H, s), 4.01 (3H, s), 3.64-3.61 (2H, m), 3.26-3.22 (2H, m), 3.19-3.16 (2H, m), 3.09-3.03 ( 2H, m), 1.28 (3H, t, J = 7.3 Hz).

実施例１２０
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン メタンスルホナート (化合物１２０) Example 120
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione methanesulfonate (compound 120 )

Figure JPOXMLDOC01-appb-C000479
Figure JPOXMLDOC01-appb-C000479

工程１
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (1.50 g, 3.57 mmol) をメタノール (150 mL)、水 (100 mL) に懸濁した。そこへ2 M メタンスルホン酸水溶液 (1.78 mL, 3.57 mmol) を加え、室温で10分撹拌し溶解させた。反応液を濃縮乾固し、得られた固体にメタノール (100 mL) を加え30分加熱還流した。反応液を冷却して吸引ろ過し、得られた結晶をメタノールとエーテルで洗浄して標記化合物 (1.49 g, 81%) を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 8.30 (1H, d, J = 9.3 Hz), 8.19 (1H, s), 7.98 (2H, d, J= 8.8 Hz), 7.94 (1H, s), 7.69 (1H, d, J= 9.3 Hz), 7.19 (2H, d, J = 9.0 Hz), 3.33 (8H, s), 2.89 (3H, s), 2.30 (3H, s). Process 1
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (1.50 g, 3.57 mmol ) Was suspended in methanol (150 mL) and water (100 mL). 2 M methanesulfonic acid aqueous solution (1.78 mL, 3.57 mmol) was added there, and it stirred for 10 minutes and made it melt | dissolve at room temperature. The reaction mixture was concentrated to dryness, methanol (100 mL) was added to the obtained solid, and the mixture was heated to reflux for 30 min. The reaction mixture was cooled and suction filtered, and the resulting crystals were washed with methanol and ether to give the title compound (1.49 g, 81%). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 8.30 (1H, d, J = 9.3 Hz), 8.19 (1H, s), 7.98 (2H, d, J = 8.8 Hz), 7.94 (1H, s), 7.69 (1H, d, J = 9.3 Hz), 7.19 (2H, d, J = 9.0 Hz), 3.33 (8H, s), 2.89 (3H, s), 2.30 (3H, s).

実施例１２１
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン ハイドロクロライド (化合物１２１)  Example 121
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione hydrochloride (Compound 121)

Figure JPOXMLDOC01-appb-C000480
Figure JPOXMLDOC01-appb-C000480

工程１
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (50 mg, 0.12 mmol) のメタノール (1 mL) 懸濁液に 0.1規定塩酸水溶液 (1.2 mL, 0.12 mmol) を加え、5 分間撹拌した。減圧下溶媒を留去した後、残渣を水に溶かし、ろ過した。ろ液にメタノールを加え、減圧下、溶媒を留去した。得られた結晶をメタノールで洗浄した後、乾燥し、目的とする目的とする標記化合物 (22 mg, 40 %) を得た。茶褐色結晶: 1H-NMR (DMSO-D6) δ: 12.70 (1H, s), 10.17 (1H, s), 8.30 (1H, d, J = 9.5 Hz), 8.19 (1H, s), 7.98 (2H, d, J = 8.5 Hz), 7.94 (1H, s), 7.69 (1H, d, J = 9.5 Hz), 7.18 (2H, d, J = 8.5 Hz), 3.98 (2H, br s), 3.52 (2H, br s), 3.19 (4H, br s), 2.86 (3H, s). Process 1
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (50 mg, 0.12 mmol ) Was added to a suspension of methanol (1 mL) in 0.1N aqueous hydrochloric acid (1.2 mL, 0.12 mmol) and stirred for 5 minutes. After evaporating the solvent under reduced pressure, the residue was dissolved in water and filtered. Methanol was added to the filtrate, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with methanol and dried to give the desired title compound (22 mg, 40%). Brown crystal: 1 H-NMR (DMSO-D 6 ) δ: 12.70 (1H, s), 10.17 (1H, s), 8.30 (1H, d, J = 9.5 Hz), 8.19 (1H, s), 7.98 ( 2H, d, J = 8.5 Hz), 7.94 (1H, s), 7.69 (1H, d, J = 9.5 Hz), 7.18 (2H, d, J = 8.5 Hz), 3.98 (2H, br s), 3.52 (2H, br s), 3.19 (4H, br s), 2.86 (3H, s).

実施例１２２
5-((3-(4-(4-エチルピペラジン-1-イル)-3,5-ジフルオロフェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１２２) Example 122
5-((3- (4- (4-Ethylpiperazin-1-yl) -3,5-difluorophenyl) -3H- [1,2,3] triazolo [4,5-b] pyridin-5-yl ) Methylene) thiazolidine-2,4-dione (Compound 122)

工程１
1-(2,6-ジフルオロ-4-ニトロフェニル)-4-エチルピペラジン Process 1
1- (2,6-difluoro-4-nitrophenyl) -4-ethylpiperazine

Figure JPOXMLDOC01-appb-C000481
Figure JPOXMLDOC01-appb-C000481

1,2,3-トリフルオロ-5-ニトロベンゼン (4.19 g, 23.64 mmol) の N,N-ジメチルホルムアミド (5 mL) 溶液に 1-エチルピペラジン (800 mg, 3.90 mmol)、無水炭酸カリウム (5.45 g, 39.4 mmol) を加え、80 ℃で 終夜撹拌した。反応終了後、反応溶液に水を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、減圧下溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、目的とする標記化合物 (2.0 g, 37%) を得た。茶色個体: 1H-NMR (CDCl3) δ: 7.76 (2H, d, J = 10.0 Hz), 3.42 (4H, t, J = 4.9 Hz), 2.58 (4H, t, J = 4.9 Hz), 2.48 (2H, q, J = 7.2 Hz), 1.12 (3H, t, J = 7.2 Hz). 1-Ethylpiperazine (800 mg, 3.90 mmol), anhydrous potassium carbonate (5.45 g) in a solution of 1,2,3-trifluoro-5-nitrobenzene (4.19 g, 23.64 mmol) in N, N-dimethylformamide (5 mL) , 39.4 mmol) was added and stirred at 80 ° C. overnight. After completion of the reaction, water was added to the reaction solution and extracted with chloroform. After drying the organic layer with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (2.0 g, 37%). Brown solid: 1 H-NMR (CDCl 3 ) δ: 7.76 (2H, d, J = 10.0 Hz), 3.42 (4H, t, J = 4.9 Hz), 2.58 (4H, t, J = 4.9 Hz), 2.48 (2H, q, J = 7.2 Hz), 1.12 (3H, t, J = 7.2 Hz).

工程２
4-(4-エチルピペラジン-1-イル)-3,5-ジフルオロアニリン Process 2
4- (4-Ethylpiperazin-1-yl) -3,5-difluoroaniline

Figure JPOXMLDOC01-appb-C000482
Figure JPOXMLDOC01-appb-C000482

1-(2,6-ジフルオロ-4-ニトロフェニル)-4-エチルピペラジン (5.34 g, 19.7 mmol) の エタノール (50 mL) 溶液に 10% パラジウム－活性炭 (600 mg) を加え、水素雰囲気下、室温で 一晩間撹拌した。反応終了後、反応溶液をろ過し、減圧下溶媒を留去した。目的とする標記化合物(3.27 g, 69%) を得た。茶色結晶：1H-NMR (CDCl3) δ: 6.16 (2H, d, J = 11.0 Hz), 3.66 (2H, br s), 3.13 (4H, t, J = 4.6 Hz), 2.56 (4H, t, J = 4.6 Hz), 2.47 (2H, q, J = 7.2 Hz), 1.11 (3H, t, J = 7.2 Hz). To a solution of 1- (2,6-difluoro-4-nitrophenyl) -4-ethylpiperazine (5.34 g, 19.7 mmol) in ethanol (50 mL) was added 10% palladium-activated carbon (600 mg). Stir at room temperature overnight. After completion of the reaction, the reaction solution was filtered and the solvent was distilled off under reduced pressure. The target title compound (3.27 g, 69%) was obtained. Brown crystals: 1 H-NMR (CDCl 3 ) δ: 6.16 (2H, d, J = 11.0 Hz), 3.66 (2H, br s), 3.13 (4H, t, J = 4.6 Hz), 2.56 (4H, t , J = 4.6 Hz), 2.47 (2H, q, J = 7.2 Hz), 1.11 (3H, t, J = 7.2 Hz).

工程３
6-ブロモ-N-(4-(4-エチルピペラジン-1-イル)-3,5-ジフルオロフェニル)-3-ニトロピリジン-2-アミン Process 3
6-Bromo-N- (4- (4-ethylpiperazin-1-yl) -3,5-difluorophenyl) -3-nitropyridin-2-amine

Figure JPOXMLDOC01-appb-C000483
Figure JPOXMLDOC01-appb-C000483

4-(4-エチルピペラジン-1-イル)-3,5-ジフルオロアニリン(1.5 g, 6.22 mmol) 及び2,6-ジブロモ-3-ニトロピリジン (1.81 g, 6.53 mmol) の エタノール (20 mL) 溶液に ジイソプロピルエチルアミン (2.2 mL, 12.44 mmol) を加え、室温で 2日間撹拌した。反応終了後、減圧下溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、目的とする標記化合物 (1.22 g, 44%) を得た。茶色固体: 1H-NMR (CDCl3) δ: 10.16 (1H, br s), 8.34 (1H, d, J =8.5 Hz), 7.25 (2H, d, J = 12.4 Hz), 7.02 (1H, d, J = 8.5 Hz), 3.26 (4H, t, J = 4.8 Hz), 2.59 (4H, t, J = 4.8 Hz), 2.49 (2H, q, J = 7.2 Hz), 1.13 (3H, t, J = 7.2 Hz). 4- (4-Ethylpiperazin-1-yl) -3,5-difluoroaniline (1.5 g, 6.22 mmol) and 2,6-dibromo-3-nitropyridine (1.81 g, 6.53 mmol) in ethanol (20 mL) Diisopropylethylamine (2.2 mL, 12.44 mmol) was added to the solution, and the mixture was stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the desired title compound (1.22 g, 44%). Brown solid: 1 H-NMR (CDCl 3 ) δ: 10.16 (1H, br s), 8.34 (1H, d, J = 8.5 Hz), 7.25 (2H, d, J = 12.4 Hz), 7.02 (1H, d , J = 8.5 Hz), 3.26 (4H, t, J = 4.8 Hz), 2.59 (4H, t, J = 4.8 Hz), 2.49 (2H, q, J = 7.2 Hz), 1.13 (3H, t, J = 7.2 Hz).

工程４
6-ブロモ-N2-(4-(4-エチルピペラジン-1-イル)-3,5-ジフルオロフェニル)ピリジン-2,3-ジアミン Process 4
6-Bromo-N 2- (4- (4-ethylpiperazin-1-yl) -3,5-difluorophenyl) pyridine-2,3-diamine

Figure JPOXMLDOC01-appb-C000484
Figure JPOXMLDOC01-appb-C000484

tert-ブチル 4-(4-((3-アミノ-6-ブロモピリジン-2-イル)アミノ)フェニル)ピペラジン-1-カルボキシレートの合成と同様の手法で、6-ブロモ-N-(4-(4-エチルピペラジン-1-イル)-3,5-ジフルオロフェニル)-3-ニトロピリジン-2-アミン (1.22 g、2.76 mmol) から標記化合物 (277 mg, 24%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.24 (1H, s), 7.31 (2H, d, J = 12.4 Hz), 6.88 (1H, d, J = 8.1 Hz), 6.83 (1H, d, J = 7.8 Hz), 5.26 (2H, s), 3.04 (4H, t, J = 4.4 Hz), 2.45 (4H, t, J = 4.4 Hz), 2.36 (2H, q, J =7.3 Hz), 1.00 (3H, t, J = 7.3 Hz). In a similar manner to the synthesis of tert-butyl 4- (4-((3-amino-6-bromopyridin-2-yl) amino) phenyl) piperazine-1-carboxylate, 6-bromo-N- (4- The title compound (277 mg, 24%) was obtained from (4-ethylpiperazin-1-yl) -3,5-difluorophenyl) -3-nitropyridin-2-amine (1.22 g, 2.76 mmol). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.24 (1H, s), 7.31 (2H, d, J = 12.4 Hz), 6.88 (1H, d, J = 8.1 Hz), 6.83 (1H, d, J = 7.8 Hz), 5.26 (2H, s), 3.04 (4H, t, J = 4.4 Hz), 2.45 (4H, t, J = 4.4 Hz), 2.36 (2H, q, J = 7.3 Hz) , 1.00 (3H, t, J = 7.3 Hz).

工程５
5-ブロモ-3-(4-(4-エチルピペラジン-1-イル)-3,5-ジフルオロフェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン Process 5
5-Bromo-3- (4- (4-ethylpiperazin-1-yl) -3,5-difluorophenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000485
Figure JPOXMLDOC01-appb-C000485

tert-ブチル 4-(4-(5-ブロモ-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イル)フェニル)ピペラジン-1-カルボキシレートの合成と同様の手法で、6-ブロモ-N2-(4-(4-エチルピペラジン-1-イル)-3,5-ジフルオロフェニル)ピリジン-2,3-ジアミン (630 mg、1.50 mmol) から標記化合物 (415 mg, 65%) を得た。黄色オイル: 1H-NMR (CDCl3) δ: 8.29 (1H, d, J = 8.5 Hz), 7.88 (2H, d, J = 10.0 Hz), 7.59 (1H, d, J = 8.5 Hz), 3.35 (4H, t, J = 4.8 Hz), 2.63 (4H, t, J = 4.8 Hz), 2.52 (2H, q, J = 7.2 Hz), 1.15 (3H, t, J = 7.2 Hz). A similar approach to the synthesis of tert-butyl 4- (4- (5-bromo-3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl) phenyl) piperazine-1-carboxylate From 6-bromo-N 2- (4- (4-ethylpiperazin-1-yl) -3,5-difluorophenyl) pyridine-2,3-diamine (630 mg, 1.50 mmol) to the title compound (415 mg , 65%). Yellow oil: 1 H-NMR (CDCl 3 ) δ: 8.29 (1H, d, J = 8.5 Hz), 7.88 (2H, d, J = 10.0 Hz), 7.59 (1H, d, J = 8.5 Hz), 3.35 (4H, t, J = 4.8 Hz), 2.63 (4H, t, J = 4.8 Hz), 2.52 (2H, q, J = 7.2 Hz), 1.15 (3H, t, J = 7.2 Hz).

工程６
3-(4-(4-エチルピペラジン-1-イル)-3,5-ジフルオロフェニル)-5-ビニル-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン Step 6
3- (4- (4-Ethylpiperazin-1-yl) -3,5-difluorophenyl) -5-vinyl-3H- [1,2,3] triazolo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000486
Figure JPOXMLDOC01-appb-C000486

アルゴン気流下、5-ブロモ-3-(4-(4-エチルピペラジン-1-イル)-3,5-ジフルオロフェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン (415 mg, 0.98 mmol)、4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (226 mg, 1.47 mmol)、酢酸パラジウム (22 mg, 0.1 mmol) リン酸三カリウム (728 mg, 3.34 mmol) および 2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル (82 mg, 0.2 mmol) のトルエン (20 mL)、溶液を4時間加熱還流した。反応終了後、反応溶液に飽和重層水を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、ろ過し、減圧下溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (75 mg, 20%) を得た。黄色オイル: 1H-NMR (CDCl3) δ: 8.37 (1H, d, J = 8.5 Hz), 8.03 (2H, d, J = 10.0 Hz), 7.52 (1H, d, J = 8.5 Hz), 7.00 (1H, dd, J = 17.3, 11.0 Hz), 6.45 (1H, d, J = 17.3 Hz), 5.73 (1H, d, J = 11.0 Hz), 3.34 (4H, t, J = 4.8 Hz), 2.62 (4H, t, J = 4.8 Hz), 2.51 (2H, q, J = 7.3 Hz), 1.15 (3H, t, J = 7.3 Hz). 5-Bromo-3- (4- (4-ethylpiperazin-1-yl) -3,5-difluorophenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine under argon flow (415 mg, 0.98 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (226 mg, 1.47 mmol), palladium acetate (22 mg, 0.1 mmol) triphosphate A solution of potassium (728 mg, 3.34 mmol) and 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (82 mg, 0.2 mmol) in toluene (20 mL) was heated to reflux for 4 hours. Saturated multistory water was added to the reaction solution after completion | finish of reaction, and chloroform extracted. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (75 mg, 20%). Yellow oil: 1 H-NMR (CDCl 3 ) δ: 8.37 (1H, d, J = 8.5 Hz), 8.03 (2H, d, J = 10.0 Hz), 7.52 (1H, d, J = 8.5 Hz), 7.00 (1H, dd, J = 17.3, 11.0 Hz), 6.45 (1H, d, J = 17.3 Hz), 5.73 (1H, d, J = 11.0 Hz), 3.34 (4H, t, J = 4.8 Hz), 2.62 (4H, t, J = 4.8 Hz), 2.51 (2H, q, J = 7.3 Hz), 1.15 (3H, t, J = 7.3 Hz).

工程７
3-(4-(4-エチルピペラジン-1-イル)-3,5-ジフルオロフェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-カルボアルデヒド Step 7
3- (4- (4-Ethylpiperazin-1-yl) -3,5-difluorophenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000487
Figure JPOXMLDOC01-appb-C000487

3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-カルボアルデヒドの合成と同様の手法で、3-(4-(4-エチルピペラジン-1-イル)-3,5-ジフルオロフェニル)-5-ビニル-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン (75 mg、0.2 mmol) から標記化合物 (27 mg, 36%) を得た。黄色オイル: 1H-NMR (CDCl3) δ: 10.23 (1H, d, J = 0.7 Hz), 8.62 (1H, dd, J = 8.5, 0.7 Hz), 8.14 (1H, d, J = 8.5 Hz), 8.03 (2H, d, J = 10.2 Hz), 3.38 (4H, t, J = 5.0 Hz), 2.64 (4H, t, J = 5.0 Hz), 2.53 (2H, q, J = 7.2 Hz), 1.16 (3H, t, J = 7.2 Hz). In a similar manner to the synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine-5-carbaldehyde, 3 -(4- (4-Ethylpiperazin-1-yl) -3,5-difluorophenyl) -5-vinyl-3H- [1,2,3] triazolo [4,5-b] pyridine (75 mg, 0.2 mmol) gave the title compound (27 mg, 36%). Yellow oil: 1 H-NMR (CDCl 3 ) δ: 10.23 (1H, d, J = 0.7 Hz), 8.62 (1H, dd, J = 8.5, 0.7 Hz), 8.14 (1H, d, J = 8.5 Hz) , 8.03 (2H, d, J = 10.2 Hz), 3.38 (4H, t, J = 5.0 Hz), 2.64 (4H, t, J = 5.0 Hz), 2.53 (2H, q, J = 7.2 Hz), 1.16 (3H, t, J = 7.2 Hz).

工程８
5-((3-(4-(4-エチルピペラジン-1-イル)-3,5-ジフルオロフェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１２２) Process 8
5-((3- (4- (4-Ethylpiperazin-1-yl) -3,5-difluorophenyl) -3H- [1,2,3] triazolo [4,5-b] pyridin-5-yl ) Methylene) thiazolidine-2,4-dione (Compound 122)

Figure JPOXMLDOC01-appb-C000488
Figure JPOXMLDOC01-appb-C000488

3-(4-(4-エチルピペラジン-1-イル)-3,5-ジフルオロフェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-カルボアルデヒド (5 mg, 0.01 mmol)、2,4-チアゾリジンジオン (2 mg, 0.01 mmol) のアセトニトリル (2 mL) 溶液に ピペリジン(1 mg, 0.01 mmol)、酢酸 (1 mg, 0.02 mmol) を加え 80 ℃で一晩撹拌した。反応溶液に酢酸エチルを加え、結晶を析出させた後、ろ過し、酢酸エチル、エタノールで洗浄して標記化合物 (1 mg, 17%) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 12.21 (1H, br s), 8.74 (1H, d, J = 8.5 Hz), 8.16 (2H, d, J = 10.2 Hz), 7.98 (1H, d, J = 8.5 Hz), 7.88 (1H, s), 3.33 (4H, br s), 2.82 (4H, br s), 2.72-2.68 (2H, m), 1.12 (4H, t, J = 7.2 Hz).
ESI-MS(m/z): 472[M+H]+. 3- (4- (4-Ethylpiperazin-1-yl) -3,5-difluorophenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine-5-carbaldehyde (5 mg , 0.01 mmol) and 2,4-thiazolidinedione (2 mg, 0.01 mmol) in acetonitrile (2 mL), add piperidine (1 mg, 0.01 mmol) and acetic acid (1 mg, 0.02 mmol) at 80 ° C overnight. Stir. Ethyl acetate was added to the reaction solution to precipitate crystals, followed by filtration and washing with ethyl acetate and ethanol to obtain the title compound (1 mg, 17%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 12.21 (1H, br s), 8.74 (1H, d, J = 8.5 Hz), 8.16 (2H, d, J = 10.2 Hz), 7.98 (1H , d, J = 8.5 Hz), 7.88 (1H, s), 3.33 (4H, br s), 2.82 (4H, br s), 2.72-2.68 (2H, m), 1.12 (4H, t, J = 7.2 Hz).
ESI-MS (m / z): 472 [M + H] + .

実施例１２３
5-((3-(3-クロロ-4-(4-プロピルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１２３) Example 123
5-((3- (3-Chloro-4- (4-propylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridin-5-yl) methylene ) Thiazolidine-2,4-dione (Compound 123)

工程１
tert-ブチル 4-(2-クロロ-4-ニトロフェニル)ピペラジン-1-カルボキシレート Process 1
tert-butyl 4- (2-chloro-4-nitrophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000489
Figure JPOXMLDOC01-appb-C000489

1-(2,6-ジフルオロ-4-ニトロフェニル)-4-エチルピペラジンの合成と同様の手法で、2-クロロ-1-フルオロ-4-ニトロベンゼン (2.26 g、10.74 mmol) とtert-ブチル ピペラジン-1-カルボキシレート (2.0 g、10.74 mmol) から標記化合物 (4.43 g, quant.) を得た。茶色オイル: 1H-NMR (CDCl3) δ: 8.27 (1H, d, J = 2.6 Hz), 8.11 (1H, dd, J = 9.2, 2.6 Hz), 7.04 (1H, d, J = 9.2 Hz), 3.63 (4H, t, J = 4.9 Hz), 3.15 (4H, t, J = 4.9 Hz), 1.49 (9H, s). In a similar manner to the synthesis of 1- (2,6-difluoro-4-nitrophenyl) -4-ethylpiperazine, 2-chloro-1-fluoro-4-nitrobenzene (2.26 g, 10.74 mmol) and tert-butyl piperazine The title compound (4.43 g, quant.) Was obtained from -1-carboxylate (2.0 g, 10.74 mmol). Brown oil: 1 H-NMR (CDCl 3 ) δ: 8.27 (1H, d, J = 2.6 Hz), 8.11 (1H, dd, J = 9.2, 2.6 Hz), 7.04 (1H, d, J = 9.2 Hz) , 3.63 (4H, t, J = 4.9 Hz), 3.15 (4H, t, J = 4.9 Hz), 1.49 (9H, s).

工程２
tert-ブチル 4-(4-((6-ブロモ-3-ニトロピリジン-2-イル)アミノ)-2-クロロフェニル)ピペリジン-1-カルボキシレート Process 2
tert-butyl 4- (4-((6-bromo-3-nitropyridin-2-yl) amino) -2-chlorophenyl) piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000490
Figure JPOXMLDOC01-appb-C000490

アルゴン雰囲気下、tert-ブチル 4-(2-クロロ-4-ニトロフェニル)ピペラジン-1-カルボキシレート(1.71 g, 5.0 mmol) 、鉄粉 (838 mg, 15.0 mmol)、塩化アンモニウム (535 mg, 10.0 mmol) のエタノール (60 mL)、水 (20 mL) 混合溶液を3時間加熱還流した。反応終了後、減圧下溶媒を留去し、得られた残渣を酢酸エチルに溶かして水で洗浄し、水層を酢酸エチルで抽出した。有機層を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下、溶媒を留去した。得られた残渣をエタノールに溶かし、2,6-ジブロモ-3-ニトロピリジン(1.24 g, 4.40 mmol)、トリエチルアミン (1.2 mL, 8.8 mmol) を加え、室温で18時間撹拌した。反応終了後、析出物をろ取し、少量の冷エタノールとヘキサンで洗浄後、乾燥し、標記化合物 (1.61 g, 65%) を得た。茶色固体: 1H-NMR (CDCl3) δ: 10.14 (1H, s), 8.33 (1H, d, J =8.3 Hz), 7.73 (1H, d, J = 2.6 Hz), 7.52 (1H, dd, J = 8.6, 2.6 Hz), 7.05 (1H, d, J = 8.9 Hz), 6.98 (1H, d, J = 8.6 Hz), 3.62 (4H, t, J = 5.0 Hz), 3.01 (4H, t, J = 5.0 Hz), 1.49 (9H, s). Under argon atmosphere, tert-butyl 4- (2-chloro-4-nitrophenyl) piperazine-1-carboxylate (1.71 g, 5.0 mmol), iron powder (838 mg, 15.0 mmol), ammonium chloride (535 mg, 10.0 mmol) in ethanol (60 mL) and water (20 mL) were heated to reflux for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the resulting residue was dissolved in ethyl acetate and washed with water, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in ethanol, 2,6-dibromo-3-nitropyridine (1.24 g, 4.40 mmol) and triethylamine (1.2 mL, 8.8 mmol) were added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the precipitate was collected by filtration, washed with a small amount of cold ethanol and hexane, and dried to obtain the title compound (1.61 g, 65%). Brown solid: 1 H-NMR (CDCl 3 ) δ: 10.14 (1H, s), 8.33 (1H, d, J = 8.3 Hz), 7.73 (1H, d, J = 2.6 Hz), 7.52 (1H, dd, J = 8.6, 2.6 Hz), 7.05 (1H, d, J = 8.9 Hz), 6.98 (1H, d, J = 8.6 Hz), 3.62 (4H, t, J = 5.0 Hz), 3.01 (4H, t, J = 5.0 Hz), 1.49 (9H, s).

工程３
tert-ブチル 4-(4-(5-ブロモ-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イル)-2-クロロフェニル)ピペラジン-1-カルボキシレート Process 3
tert-butyl 4- (4- (5-bromo-3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl) -2-chlorophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000491
Figure JPOXMLDOC01-appb-C000491

アルゴン雰囲気下、tert-ブチル 4-(4-((6-ブロモ-3-ニトロピリジン-2-イル)アミノ)-2-クロロフェニル)ピペリジン-1-カルボキシレート (706 mg, 1.37 mmol) 、鉄粉 (229 mg, 4.10 mmol)、塩化アンモニウム (147 mg, 2.74 mmol) のエタノール (20 mL)、水 (5 mL) 混合溶液を3時間加熱還流した。反応終了後、減圧下溶媒を留去し、得られた残渣を酢酸エチルに溶かして水で洗浄し、水層を酢酸エチルで抽出した。有機層を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下、溶媒を留去した。得られた残渣を塩化メチレン (5 mL)、水（5 mL）、酢酸（8 mL） 溶液に溶かし、０ ℃で亜硝酸ナトリウム (91 mg, 1.32 mmol) を加え、室温で2 時間撹拌した。反応終了後、反応溶液に 飽和重層水を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、ろ過し、減圧下溶媒を留去し目的とする標記化合物 (868 mg, quant.) を得た。褐色個体: 1H-NMR (CDCl3) δ: 8.30-8.28 (2H, m), 8.13 (1H, dd, J = 8.6, 2.3 Hz), 7.58 (1H, d, J = 8.6 Hz), 7.23 (1H, d, J = 9.2 Hz), 3.65 (4H, t, J =4.9 Hz), 3.09 (4H, t, J = 4.9 Hz), 1.50 (9H, s). Under argon atmosphere, tert-butyl 4- (4-((6-bromo-3-nitropyridin-2-yl) amino) -2-chlorophenyl) piperidine-1-carboxylate (706 mg, 1.37 mmol), iron powder A mixed solution of (229 mg, 4.10 mmol), ammonium chloride (147 mg, 2.74 mmol) in ethanol (20 mL) and water (5 mL) was heated to reflux for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the resulting residue was dissolved in ethyl acetate and washed with water, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in a solution of methylene chloride (5 mL), water (5 mL) and acetic acid (8 mL), sodium nitrite (91 mg, 1.32 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hr. After completion of the reaction, saturated multistory water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain the title compound (868 mg, quant.). Brown solid: 1 H-NMR (CDCl 3 ) δ: 8.30-8.28 (2H, m), 8.13 (1H, dd, J = 8.6, 2.3 Hz), 7.58 (1H, d, J = 8.6 Hz), 7.23 ( 1H, d, J = 9.2 Hz), 3.65 (4H, t, J = 4.9 Hz), 3.09 (4H, t, J = 4.9 Hz), 1.50 (9H, s).

工程４
5-ブロモ-3-(3-クロロ-4-(4-プロピルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン Process 4
5-Bromo-3- (3-chloro-4- (4-propylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000492
Figure JPOXMLDOC01-appb-C000492

tert-ブチル 4-(4-(5-ブロモ-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イル)-2-クロロフェニル)ピペラジン-1-カルボキシレート (400 mg, 0.81 mmol) をクロロホルム(9 mL) に溶解し、0℃でトリフルオロ酢酸 (15 mL) を加え、室温で18時間撹拌した。反応液を濃縮し、得られた残渣をクロロホルムに溶かして飽和重層水、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥させ、溶媒を留去した。得られた残渣をテトラヒドロフラン (20 mL) に溶かし、酢酸 (32 mg, 0.53 mmol)、プロピオンアルデヒド (46 mg, 0.80 mmol) を加え、室温で1時間撹拌した後、ナトリウム トリアセトキシボロヒドリド (224 mg, 1.06 mmol) を加え、室温で15時間撹拌した。反応液に飽和重層水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (106mg, 30%) を得た。褐色固体: 1H-NMR (CDCl3) δ: 8.29 (1H, d, J = 8.7 Hz), 8.25 (1H, d, J = 2.3 Hz), 8.12 (1H, dd, J = 8.7, 2.3 Hz), 7.57 (1H, d, J = 8.7 Hz), 7.28 (1H, d, J = 8.7 Hz), 3.20 (4H, br s), 2.70 (4H, br s), 2.46-2.39 (2H, m), 1.57-1.56 (2H, m), 0.96 (3H, t, J = 7.3 Hz). tert-Butyl 4- (4- (5-bromo-3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl) -2-chlorophenyl) piperazine-1-carboxylate (400 mg , 0.81 mmol) was dissolved in chloroform (9 mL), trifluoroacetic acid (15 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated, and the resulting residue was dissolved in chloroform and washed with saturated multilayered water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was dissolved in tetrahydrofuran (20 mL), acetic acid (32 mg, 0.53 mmol) and propionaldehyde (46 mg, 0.80 mmol) were added, and the mixture was stirred at room temperature for 1 hr, followed by sodium triacetoxyborohydride (224 mg). , 1.06 mmol) was added, and the mixture was stirred at room temperature for 15 hours. Saturated multistory water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (106 mg, 30%). Brown solid: 1 H-NMR (CDCl 3 ) δ: 8.29 (1H, d, J = 8.7 Hz), 8.25 (1H, d, J = 2.3 Hz), 8.12 (1H, dd, J = 8.7, 2.3 Hz) , 7.57 (1H, d, J = 8.7 Hz), 7.28 (1H, d, J = 8.7 Hz), 3.20 (4H, br s), 2.70 (4H, br s), 2.46-2.39 (2H, m), 1.57-1.56 (2H, m), 0.96 (3H, t, J = 7.3 Hz).

工程５
3-(3-クロロ-4-(4-プロルピペラジン-1-イル)フェニル)-5-ビニル-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン Process 5
3- (3-Chloro-4- (4-prolpiperazin-1-yl) phenyl) -5-vinyl-3H- [1,2,3] triazolo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000493
Figure JPOXMLDOC01-appb-C000493

3-(4-(4-メチルピペラジン-1-イル)フェニル)-5-ビニル-3H-[1,2,3]トリアゾロ[4,5-b]ピリジンの合成と同様の手法で、5-ブロモ-3-(3-クロロ-4-(4-プロピルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン (106 mg、0.24 mmol) から標記化合物 (25 mg, 27%) を得た。黄色オイル: 1H-NMR (CDCl3) δ: 8.42 (1H, d, J = 2.7 Hz), 8.37 (1H, d, J = 8.7 Hz), 8.23 (1H, dd, J = 8.7, 2.7 Hz), 7.51 (1H, d, J = 8.7 Hz), 7.26 (1H, d, J = 8.7 Hz), 7.00 (1H, dd, J = 17.4, 11.0 Hz), 6.43 (1H, dd, J = 17.4, 0.9 Hz), 5.70 (1H, dd, J = 11.0, 0.9 Hz), 3.19 (4H, s), 2.70 (4H, s), 2.42 (2H, t, J = 7.8 Hz), 1.62-1.54 (2H, m), 0.95 (3H, t, J = 7.3 Hz). In a similar manner to the synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) -5-vinyl-3H- [1,2,3] triazolo [4,5-b] pyridine, From bromo-3- (3-chloro-4- (4-propylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine (106 mg, 0.24 mmol) The title compound (25 mg, 27%) was obtained. Yellow oil: 1 H-NMR (CDCl 3 ) δ: 8.42 (1H, d, J = 2.7 Hz), 8.37 (1H, d, J = 8.7 Hz), 8.23 (1H, dd, J = 8.7, 2.7 Hz) , 7.51 (1H, d, J = 8.7 Hz), 7.26 (1H, d, J = 8.7 Hz), 7.00 (1H, dd, J = 17.4, 11.0 Hz), 6.43 (1H, dd, J = 17.4, 0.9 Hz), 5.70 (1H, dd, J = 11.0, 0.9 Hz), 3.19 (4H, s), 2.70 (4H, s), 2.42 (2H, t, J = 7.8 Hz), 1.62-1.54 (2H, m ), 0.95 (3H, t, J = 7.3 Hz).

工程６
3-(3-クロロ-4-(4-プロピルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-カルボアルデヒド Step 6
3- (3-Chloro-4- (4-propylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000494
Figure JPOXMLDOC01-appb-C000494

3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-カルボアルデヒドの合成と同様の手法で、3-(3-クロロ-4-(4-プロルピペラジン-1-イル)フェニル)-5-ビニル-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン (25 mg、0.07 mmol) から標記化合物 (12 mg, 40%) を得た。黄色個体: 1H-NMR (CDCl3) δ: 10.22 (1H, s), 8.61 (1H, d, J =8.6 Hz), 8.40 (1H, d, J = 2.7 Hz), 8.24 (1H, dd, J = 8.6, 2.7 Hz), 8.13 (1H, d, J = 8.6 Hz), 7.30 (1H, d, J = 8.6 Hz), 3.22 (4H, br s), 2.71 (4H, br s), 2.43 (2H, t, J = 7.7 Hz), 1.63-1.55 (2H, m), 0.96 (3H, t, J = 7.2 Hz). In a similar manner to the synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine-5-carbaldehyde, 3 -(3-Chloro-4- (4-prolpiperazin-1-yl) phenyl) -5-vinyl-3H- [1,2,3] triazolo [4,5-b] pyridine (25 mg, 0.07 mmol ) Gave the title compound (12 mg, 40%). Yellow solid: 1 H-NMR (CDCl 3 ) δ: 10.22 (1H, s), 8.61 (1H, d, J = 8.6 Hz), 8.40 (1H, d, J = 2.7 Hz), 8.24 (1H, dd, J = 8.6, 2.7 Hz), 8.13 (1H, d, J = 8.6 Hz), 7.30 (1H, d, J = 8.6 Hz), 3.22 (4H, br s), 2.71 (4H, br s), 2.43 ( 2H, t, J = 7.7 Hz), 1.63-1.55 (2H, m), 0.96 (3H, t, J = 7.2 Hz).

工程７
5-((3-(3-クロロ-4-(4-プロピルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１２３) Step 7
5-((3- (3-Chloro-4- (4-propylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridin-5-yl) methylene ) Thiazolidine-2,4-dione (Compound 123)

Figure JPOXMLDOC01-appb-C000495
Figure JPOXMLDOC01-appb-C000495

3-(3-クロロ-4-(4-プロピルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-カルボアルデヒド (5 mg, 0.01 mmol)、2,4-チアゾリジンジオン (2 mg, 0.01 mmol) のアセトニトリル (2 mL) 溶液に ピペリジン(1 mg, 0.006 mmol)、酢酸 (1mg, 0.01 mmol) を加え 80 ℃で一晩撹拌した。反応溶液に酢酸エチルを加え、結晶を析出させた後、ろ過し、酢酸エチル、エタノールで洗浄して標記化合物 (2 mg, 13%) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 11.95 (1H, br s), 8.77 (1H, d, J = 8.2 Hz), 8.54 (1H, d, J = 2.3 Hz), 8.14 (1H, dd, J = 8.7, 2.3 Hz), 8.02 (1H, d, J = 8.7 Hz), 7.97 (1H, s), 7.48 (1H, d, J = 8.7 Hz), 3.17 (4H, br s), 2.77 (4H, br s), 2.68-2.64 (2H, m), 1.59-1.49 (2H, m), 0.91 (3H, t, J = 7.3 Hz).
ESI-MS(m/z): 484[M+H]+. 3- (3-Chloro-4- (4-propylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine-5-carbaldehyde (5 mg, 0.01 mmol) and 2,4-thiazolidinedione (2 mg, 0.01 mmol) in acetonitrile (2 mL) were added piperidine (1 mg, 0.006 mmol) and acetic acid (1 mg, 0.01 mmol), and the mixture was stirred at 80 ° C. overnight. Ethyl acetate was added to the reaction solution to precipitate crystals, followed by filtration and washing with ethyl acetate and ethanol to obtain the title compound (2 mg, 13%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 11.95 (1H, br s), 8.77 (1H, d, J = 8.2 Hz), 8.54 (1H, d, J = 2.3 Hz), 8.14 (1H , dd, J = 8.7, 2.3 Hz), 8.02 (1H, d, J = 8.7 Hz), 7.97 (1H, s), 7.48 (1H, d, J = 8.7 Hz), 3.17 (4H, br s), 2.77 (4H, br s), 2.68-2.64 (2H, m), 1.59-1.49 (2H, m), 0.91 (3H, t, J = 7.3 Hz).
ESI-MS (m / z): 484 [M + H] + .

実施例１２４
5-((3-(4-(4-エチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１２４)  Example 124
5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2 , 4-Dione (Compound 124)

工程１
5-ブロモ-3-(4-(4-エチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン Process 1
5-Bromo-3- (4- (4-ethylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000496
Figure JPOXMLDOC01-appb-C000496

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン (451 mg, 1.25 mmol)、ヨードエタン (293 mg, 1.88 mmol)、炭酸カリウム (345 mg, 2.5 mmol) のアセトン (20 mL) 溶液を加熱還流下、終夜撹拌した。反応溶液に水を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、ろ過し、減圧下溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (171 mg, 35%) を得た。黄色オイル: 1H-NMR (CDCl3) δ: 8.27 (1H, d, J = 8.5 Hz), 8.02 (2H, d, J = 9.0 Hz), 7.54 (1H, d, J = 8.5 Hz), 7.10 (2H, d, J = 9.0 Hz), 3.34 (4H, t, J = 5.1 Hz), 2.65 (4H, t, J = 5.1 Hz), 2.51 (2H, q, J = 7.3 Hz), 1.16 (3H, t, J = 7.3 Hz). 5-Bromo-3- (4- (piperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine (451 mg, 1.25 mmol), iodoethane (293 mg, 1.88 mmol), a solution of potassium carbonate (345 mg, 2.5 mmol) in acetone (20 mL) was stirred with heating under reflux overnight. Water was added to the reaction solution and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (171 mg, 35%). Yellow oil: 1 H-NMR (CDCl 3 ) δ: 8.27 (1H, d, J = 8.5 Hz), 8.02 (2H, d, J = 9.0 Hz), 7.54 (1H, d, J = 8.5 Hz), 7.10 (2H, d, J = 9.0 Hz), 3.34 (4H, t, J = 5.1 Hz), 2.65 (4H, t, J = 5.1 Hz), 2.51 (2H, q, J = 7.3 Hz), 1.16 (3H , t, J = 7.3 Hz).

工程２
3-(4-(4-エチルピペラジン-1-イル)フェニル)-5-ビニル-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン Process 2
3- (4- (4-Ethylpiperazin-1-yl) phenyl) -5-vinyl-3H- [1,2,3] triazolo [4,5-b] pyridine

Figure JPOXMLDOC01-appb-C000497
Figure JPOXMLDOC01-appb-C000497

3-(4-(4-メチルピペラジン-1-イル)フェニル)-5-ビニル-3H-[1,2,3]トリアゾロ[4,5-b]ピリジンの合成と同様の手法で、5-ブロモ-3-(4-(4-エチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン (221 mg、0.57 mmol) から標記化合物 (143 mg, 74%) を得た。黄色個体: 1H-NMR (CDCl3) δ: 7.55-7.51 (1H, m), 7.48-7.44 (3H, m), 7.10 (2H, d, J = 8.6 Hz), 6.97 (1H, dd, J = 16.8, 10.2 Hz), 6.38 (1H, d, J = 16.8 Hz), 5.65 (1H, d, J = 10.2 Hz), 3.32 (4H, s), 2.64 (4H, s), 2.50 (2H, q, J = 7.4 Hz), 1.15 (3H, t, J =7.4 Hz). In a similar manner to the synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) -5-vinyl-3H- [1,2,3] triazolo [4,5-b] pyridine, Bromo-3- (4- (4-ethylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine (221 mg, 0.57 mmol) to the title compound (143 mg, 74%). Yellow solid: 1 H-NMR (CDCl 3 ) δ: 7.55-7.51 (1H, m), 7.48-7.44 (3H, m), 7.10 (2H, d, J = 8.6 Hz), 6.97 (1H, dd, J = 16.8, 10.2 Hz), 6.38 (1H, d, J = 16.8 Hz), 5.65 (1H, d, J = 10.2 Hz), 3.32 (4H, s), 2.64 (4H, s), 2.50 (2H, q , J = 7.4 Hz), 1.15 (3H, t, J = 7.4 Hz).

工程３
3-(4-(4-エチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-カルボアルデヒド Process 3
3- (4- (4-Ethylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000498
Figure JPOXMLDOC01-appb-C000498

3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-カルボアルデヒドの合成と同様の手法で、3-(4-(4-エチルピペラジン-1-イル)フェニル)-5-ビニル-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン (143 mg、0.42 mmol) から標記化合物 (57 mg, 40%) を得た。黄色個体: 1H-NMR (CDCl3) δ: 10.17 (1H, s), 8.55 (1H, d, J = 8.6 Hz), 8.15-8.04 (3H, m), 7.11 (2H, d, J = 8.7 Hz), 3.33 (4H, br s), 2.63 (4H, br s), 2.48 (2H, q, J = 7.3 Hz), 1.12 (3H, t, J =7.3 Hz). In a similar manner to the synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine-5-carbaldehyde, 3 -(4- (4-Ethylpiperazin-1-yl) phenyl) -5-vinyl-3H- [1,2,3] triazolo [4,5-b] pyridine (143 mg, 0.42 mmol) to the title compound ( 57 mg, 40%). Yellow solid: 1 H-NMR (CDCl 3 ) δ: 10.17 (1H, s), 8.55 (1H, d, J = 8.6 Hz), 8.15-8.04 (3H, m), 7.11 (2H, d, J = 8.7 Hz), 3.33 (4H, br s), 2.63 (4H, br s), 2.48 (2H, q, J = 7.3 Hz), 1.12 (3H, t, J = 7.3 Hz).

工程４
5-((3-(4-(4-エチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１２４)  Process 4
5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2 , 4-Dione (Compound 124)

Figure JPOXMLDOC01-appb-C000499
Figure JPOXMLDOC01-appb-C000499

5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成と同様の手法で、3-(4-(4-エチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-カルボアルデヒド (30 mg、0.09 mmol) から標記化合物 (2 mg, 5%) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 11.69 (1H, br s), 8.67 (1H, d, J = 6.0 Hz), 8.03 (2H, d, J = 8.3 Hz), 7.93-7.88 (2H, m), 7.21 (2H, d, J =8.3 Hz), 3.33 (4H, br s), 2.73 (4H, br s), 2.58 (2H, q, J = 7.2 Hz), 1.08 (3H, t, J = 7.2 Hz).
ESI-MS(m/z): 436[M+H]+. In a manner similar to the synthesis of 5-((1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione, 3 Title compound from-(4- (4-Ethylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine-5-carbaldehyde (30 mg, 0.09 mmol) (2 mg, 5%) was obtained. Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 11.69 (1H, br s), 8.67 (1H, d, J = 6.0 Hz), 8.03 (2H, d, J = 8.3 Hz), 7.93-7.88 (2H, m), 7.21 (2H, d, J = 8.3 Hz), 3.33 (4H, br s), 2.73 (4H, br s), 2.58 (2H, q, J = 7.2 Hz), 1.08 (3H, t, J = 7.2 Hz).
ESI-MS (m / z): 436 [M + H] + .

実施例１２５
5-((3-(4-(4-エチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物１２５)  Example 125
5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridin-5-yl) methylene) -2- Thioxothiazolidine-4-one (Compound 125)

Figure JPOXMLDOC01-appb-C000500
Figure JPOXMLDOC01-appb-C000500

工程１
5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成と同様の手法で、3-(4-(4-エチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-カルボアルデヒド (27 mg、0.08 mmol) から標記化合物 (16 mg, 44%) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 10.88 (1H, br s), 8.67 (1H, d, J = 8.6 Hz), 8.14 (2H, d, J = 9.2 Hz), 7.93 (1H, d, J = 8.6 Hz), 7.57 (1H, s), 7.27 (2H, d, J = 9.2 Hz), 3.43 (4H, br s), 3.11 (4H, br s), 2.94-2.92 (2H, m), 1.20 (3H, t, J = 7.2 Hz).
ESI-MS(m/z): 452[M+H]+. Process 1
Similar procedure to the synthesis of 5-((1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one 3- (4- (4-Ethylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine-5-carbaldehyde (27 mg, 0.08 mmol) Gave the title compound (16 mg, 44%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 10.88 (1H, br s), 8.67 (1H, d, J = 8.6 Hz), 8.14 (2H, d, J = 9.2 Hz), 7.93 (1H , d, J = 8.6 Hz), 7.57 (1H, s), 7.27 (2H, d, J = 9.2 Hz), 3.43 (4H, br s), 3.11 (4H, br s), 2.94-2.92 (2H, m), 1.20 (3H, t, J = 7.2 Hz).
ESI-MS (m / z): 452 [M + H] + .

実施例１２６
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d][1,2,3]トリアゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１２６)  Example 126
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] [1,2,3] triazol-6-yl) methylene) -2-thioxothiazolidine- 4-one (compound 126)

工程１
N-メトキシ-N-メチル-1-(4-(4-メチルピペラジン-1-イル)-フェニル)-3H-ベンゾ[d][1,2,3]トリアゾール-6-カルボキシアミド Process 1
N-methoxy-N-methyl-1- (4- (4-methylpiperazin-1-yl) -phenyl) -3H-benzo [d] [1,2,3] triazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000501
Figure JPOXMLDOC01-appb-C000501

N-メトキシ-N-メチル-3-(4-(4-メチルピペラジン-1-イル)フェニルアミノ)-4-ニトロベンズアミド (3.48 g, 8.71 mmol) の エタノール (10 mL) 溶液に 10% パラジウム－活性炭 (350 mg) を加え、水素雰囲気下、室温で 24 時間撹拌した。反応終了後、反応溶液をろ過し、減圧下溶媒を留去した。残渣を塩化メチレン (5 mL)、水（5 mL）、酢酸（8 mL） 溶液に溶かし、0℃で亜硝酸ナトリウム (608 mg, 12.66 mmol) を加え、室温で2 時間撹拌した。反応終了後、反応溶液に 飽和重層水を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、ろ過し、減圧下溶媒を留去し目的とする標記化合物 (1.02 g, 31%) を得た。黄色結晶: 1H-NMR (CDCl3) δ: 8.13 (1H, dd, J = 8.5, 1.0 Hz), 8.04 (1H, s), 7.71 (1H, dd, J =8.5, 1.0 Hz), 7.62 (2H, d, J =9.0 Hz), 7.10 (2H, d, J = 9.0 Hz), 3.53 (3H, s), 3.40 (3H, s), 3.34 (4H, t, J = 5.0 Hz), 2.62 (4H, t, J = 5.0 Hz), 2.39 (3H, s). To a solution of N-methoxy-N-methyl-3- (4- (4-methylpiperazin-1-yl) phenylamino) -4-nitrobenzamide (3.48 g, 8.71 mmol) in ethanol (10 mL) was added 10% palladium- Activated carbon (350 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 24 hours. After completion of the reaction, the reaction solution was filtered and the solvent was distilled off under reduced pressure. The residue was dissolved in a solution of methylene chloride (5 mL), water (5 mL) and acetic acid (8 mL), sodium nitrite (608 mg, 12.66 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hr. After completion of the reaction, saturated multistory water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain the desired title compound (1.02 g, 31%). Yellow crystal: 1 H-NMR (CDCl 3 ) δ: 8.13 (1H, dd, J = 8.5, 1.0 Hz), 8.04 (1H, s), 7.71 (1H, dd, J = 8.5, 1.0 Hz), 7.62 ( 2H, d, J = 9.0 Hz), 7.10 (2H, d, J = 9.0 Hz), 3.53 (3H, s), 3.40 (3H, s), 3.34 (4H, t, J = 5.0 Hz), 2.62 ( 4H, t, J = 5.0 Hz), 2.39 (3H, s).

工程２
1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d][1,2,3]トリアゾール-6-カルボアルデヒド Process 2
1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] [1,2,3] triazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000502
Figure JPOXMLDOC01-appb-C000502

1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒドの合成と同様の手法で、N-メトキシ-N-メチル-1-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-ベンゾ[d][1,2,3]トリアゾール-6-カルボキシアミド (1.02 g, 2.68 mmol) から標記化合物 (980 mg, quant.) を得た。黄色結晶: 1H-NMR (CDCl3) δ: 10.17 (1H, s), 8.25 (1H, d, J =8.5 Hz), 8.21 (1H, t, J = 1.1 Hz), 7.96 (1H, dd, J = 8.5, 1.5 Hz), 7.63 (2H, d, J = 9.3 Hz), 7.12 (2H, d, J = 9.0 Hz), 3.36 (4H, t, J = 5.0 Hz), 2.63 (4H, t, J = 5.1 Hz), 2.39 (3H, s). In a similar manner to the synthesis of 1- (4- (4-methylpiperazinyl) benzyl) -1H-benzo [d] imidazole-6-carbaldehyde, N-methoxy-N-methyl-1- (4- ( 4-Methylpiperazin-1-yl) phenyl) -3H-benzo [d] [1,2,3] triazole-6-carboxamide (1.02 g, 2.68 mmol) gave the title compound (980 mg, quant.) It was. Yellow crystals: 1 H-NMR (CDCl 3 ) δ: 10.17 (1H, s), 8.25 (1H, d, J = 8.5 Hz), 8.21 (1H, t, J = 1.1 Hz), 7.96 (1H, dd, J = 8.5, 1.5 Hz), 7.63 (2H, d, J = 9.3 Hz), 7.12 (2H, d, J = 9.0 Hz), 3.36 (4H, t, J = 5.0 Hz), 2.63 (4H, t, J = 5.1 Hz), 2.39 (3H, s).

工程３
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d][1,2,3]トリアゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１２６) Process 3
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] [1,2,3] triazol-6-yl) methylene) -2-thioxothiazolidine- 4-one (compound 126)

Figure JPOXMLDOC01-appb-C000503
Figure JPOXMLDOC01-appb-C000503

1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d][1,2,3]トリアゾール-6-カルボアルデヒド (105 mg, 0.33 mmol)、ロダニン (47 mg, 0.35 mmol) のアセトニトリル (10 mL) 溶液に酢酸 (16 mg, 0.26 mmol)、ピペリジン(11 mg, 0.13 mmol)を加え 80 ℃で20時間撹拌した。反応溶液に酢酸エチルを加え、結晶を析出させた後、ろ過し、酢酸エチル、エタノールで洗浄して標記化合物 (110 mg, 76%) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 12.65 (1H, s), 8.21 (1H, d, J = 8.5 Hz), 7.88 (1H, s), 7.75 (2H, d, J = 8.8 Hz), 7.66 (1H, dd, J = 8.5, 1.5 Hz), 7.46 (1H, s), 7.30 (2H, d, J = 8.8 Hz), 3.52 (4H, br s), 3.18 (4H, br s), 2.74 (3H, s).
ESI-MS(m/z): 437[M+H]+. 1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] [1,2,3] triazole-6-carbaldehyde (105 mg, 0.33 mmol), rhodanine (47 mg, Acetic acid (16 mg, 0.26 mmol) and piperidine (11 mg, 0.13 mmol) were added to a solution of 0.35 mmol) in acetonitrile (10 mL), and the mixture was stirred at 80 ° C. for 20 hours. Ethyl acetate was added to the reaction solution to precipitate crystals, followed by filtration and washing with ethyl acetate and ethanol to obtain the title compound (110 mg, 76%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 12.65 (1H, s), 8.21 (1H, d, J = 8.5 Hz), 7.88 (1H, s), 7.75 (2H, d, J = 8.8 Hz), 7.66 (1H, dd, J = 8.5, 1.5 Hz), 7.46 (1H, s), 7.30 (2H, d, J = 8.8 Hz), 3.52 (4H, br s), 3.18 (4H, br s ), 2.74 (3H, s).
ESI-MS (m / z): 437 [M + H] + .

実施例１２７
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d][1,2,3]トリアゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１２７)  Example 127
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] [1,2,3] triazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 127)

Figure JPOXMLDOC01-appb-C000504
Figure JPOXMLDOC01-appb-C000504

工程１
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成と同様の手法で、1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d][1,2,3]トリアゾール-6-カルボアルデヒド (166 mg, 0.55 mmol) から標記化合物 (161 mg, 77%) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 11.40 (1H, s), 8.22 (1H, d, J = 8.8 Hz), 8.01 (1H, s), 7.79 (1H, s), 7.71 (2H, d, J = 9.0 Hz), 7.67 (1H, dd, J = 8.8, 1.3 Hz), 7.25 (2H, d, J = 9.0 Hz), 3.41 (4H, t, J = 4.5 Hz), 2.86 (4H, t, J = 4.5 Hz), 2.86 (3H, s).
ESI-MS(m/z): 421[M+H]+. Process 1
A similar approach to the synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione 1- (4- (4-methylpiperazin-1-yl) phenyl) -1H-benzo [d] [1,2,3] triazole-6-carbaldehyde (166 mg, 0.55 mmol) to the title compound ( 161 mg, 77%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 11.40 (1H, s), 8.22 (1H, d, J = 8.8 Hz), 8.01 (1H, s), 7.79 (1H, s), 7.71 ( 2H, d, J = 9.0 Hz), 7.67 (1H, dd, J = 8.8, 1.3 Hz), 7.25 (2H, d, J = 9.0 Hz), 3.41 (4H, t, J = 4.5 Hz), 2.86 ( 4H, t, J = 4.5 Hz), 2.86 (3H, s).
ESI-MS (m / z): 421 [M + H] + .

実施例１２８
5-((3-(4-(4-メチルピペラジン-1-イル)-フェニル)ピラゾロ[1,5-a]ピリミジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１２８)  Example 128
5-((3- (4- (4-Methylpiperazin-1-yl) -phenyl) pyrazolo [1,5-a] pyrimidin-5-yl) methylene) -2-thioxothiazolidine-4-one (compound 128)

工程１
5-クロロ-3-(4-(4-メチルピペラジン-1-イル)-フェニル)ピラゾロ[1,5-a]ピリミジン Process 1
5-Chloro-3- (4- (4-methylpiperazin-1-yl) -phenyl) pyrazolo [1,5-a] pyrimidine

Figure JPOXMLDOC01-appb-C000505
Figure JPOXMLDOC01-appb-C000505

3-ブロモ-5-クロロピラゾロ[1,5-a]ピリミジン (500 mg, 2.10 mmol) の1,4-ジオキサン (20 mL)、水(4 mL) の混合溶液中に、1-メチル-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン (530 mg, 1.75 mmol)、酢酸パラジウム (38 mg, 0.17 mmol)、テトラキストリフェニルホスフィン (183 mg, 0.7 mmol)、炭酸ナトリウム (649 mg, 6.12 mmol) を加えた。アルゴン置換した後、還流条件下一晩撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (581 mg, quant.) を得た。黄色固体: 1H-NMR (CDCl3) δ: 8.55 (1H, d, J = 7.4 Hz), 8.10 (2H, d, J = 8.6 Hz), 8.05 (1H, s), 7.25 (1H, d, J = 7.4 Hz), 7.00 (2H, d, J = 8.6 Hz), 3.37 (4H, t, J = 5.2 Hz), 2.59 (4H, t, J = 5.2 Hz), 2.37 (3H, s). In a mixed solution of 3-bromo-5-chloropyrazolo [1,5-a] pyrimidine (500 mg, 2.10 mmol) in 1,4-dioxane (20 mL) and water (4 mL), 1-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine (530 mg, 1.75 mmol), palladium acetate (38 mg, 0.17 mmol), tetrakistri Phenylphosphine (183 mg, 0.7 mmol) and sodium carbonate (649 mg, 6.12 mmol) were added. After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (581 mg, quant.). Yellow solid: 1 H-NMR (CDCl 3 ) δ: 8.55 (1H, d, J = 7.4 Hz), 8.10 (2H, d, J = 8.6 Hz), 8.05 (1H, s), 7.25 (1H, d, J = 7.4 Hz), 7.00 (2H, d, J = 8.6 Hz), 3.37 (4H, t, J = 5.2 Hz), 2.59 (4H, t, J = 5.2 Hz), 2.37 (3H, s).

工程２
3-(4-(4-メチルピペラジン-1-イル)-フェニル)-5-ビニルピラゾロ[1,5-a]ピリミジン Process 2
3- (4- (4-Methylpiperazin-1-yl) -phenyl) -5-vinylpyrazolo [1,5-a] pyrimidine

Figure JPOXMLDOC01-appb-C000506
Figure JPOXMLDOC01-appb-C000506

3-(4-(4-エチルピペラジン-1-イル)-3,5-ジフルオロフェニル)-5-ビニル-3H-[1,2,3]トリアゾロ[4,5-b]ピリジンの合成と同様の手法で、5-クロロ-3-(4-(4-メチルピペラジン-1-イル)-フェニル)ピラゾロ[1,5-a]ピリミジン (581 mg, 1.77 mmol) から標記化合物 (331 mg, 59%) を得た。黄色結晶: 1H-NMR (CDCl3) δ: 8.55 (1H, d, J = 7.4 Hz), 8.13 (1H, s), 8.09 (2H, d, J =9.2 Hz), 7.21 (1H, d, J = 7.4 Hz), 7.01 (2H, d, J = 9.2 Hz), 6.96 (1H, dd, J = 17.8, 10.9 Hz), 6.09 (1H, dd, J = 17.8, 1.7 Hz), 5.29 (1H, dd, J =10.9, 1.7 Hz), 3.38 (4H, t, J =4.6 Hz), 2.62 (4H, t, J = 4.6 Hz), 2.39 (3H, s). Similar to the synthesis of 3- (4- (4-ethylpiperazin-1-yl) -3,5-difluorophenyl) -5-vinyl-3H- [1,2,3] triazolo [4,5-b] pyridine From the 5-chloro-3- (4- (4-methylpiperazin-1-yl) -phenyl) pyrazolo [1,5-a] pyrimidine (581 mg, 1.77 mmol) to the title compound (331 mg, 59 %). Yellow crystals: 1 H-NMR (CDCl 3 ) δ: 8.55 (1H, d, J = 7.4 Hz), 8.13 (1H, s), 8.09 (2H, d, J = 9.2 Hz), 7.21 (1H, d, J = 7.4 Hz), 7.01 (2H, d, J = 9.2 Hz), 6.96 (1H, dd, J = 17.8, 10.9 Hz), 6.09 (1H, dd, J = 17.8, 1.7 Hz), 5.29 (1H, dd, J = 10.9, 1.7 Hz), 3.38 (4H, t, J = 4.6 Hz), 2.62 (4H, t, J = 4.6 Hz), 2.39 (3H, s).

工程３
3-(4-(4-メチルピペラジン-1-イル)-フェニル)ピラゾロ[1,5-a]ピリミジン-5-カルボアルデヒド Process 3
3- (4- (4-Methylpiperazin-1-yl) -phenyl) pyrazolo [1,5-a] pyrimidine-5-carbaldehyde

Figure JPOXMLDOC01-appb-C000507
Figure JPOXMLDOC01-appb-C000507

3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-カルボアルデヒドの合成と同様の手法で、3-(4-(4-メチルピペラジン-1-イル)-フェニル)-5-ビニルピラゾロ[1,5-a]ピリミジン (331 mg, 1.04 mmol) から標記化合物 (223 mg, 67%) を得た。黄色結晶: 1H-NMR (CDCl3) δ: 10.36 (1H, s), 8.65 (1H, d, J = 7.3 Hz), 8.53 (1H, s), 8.14 (2H, d, J = 9.2 Hz), 7.43 (1H, d, J = 7.3 Hz), 7.01 (2H, d, J = 9.2 Hz), 3.41 (4H, t, J = 5.0 Hz), 2.60 (4H, t, J = 5.0 Hz), 2.38 (3H, s). In a similar manner to the synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine-5-carbaldehyde, 3 The title compound (223 mg, 67%) was obtained from-(4- (4-methylpiperazin-1-yl) -phenyl) -5-vinylpyrazolo [1,5-a] pyrimidine (331 mg, 1.04 mmol). Yellow crystals: 1 H-NMR (CDCl 3 ) δ: 10.36 (1H, s), 8.65 (1H, d, J = 7.3 Hz), 8.53 (1H, s), 8.14 (2H, d, J = 9.2 Hz) , 7.43 (1H, d, J = 7.3 Hz), 7.01 (2H, d, J = 9.2 Hz), 3.41 (4H, t, J = 5.0 Hz), 2.60 (4H, t, J = 5.0 Hz), 2.38 (3H, s).

工程４
5-((3-(4-(4-メチルピペラジン-1-イル)-フェニル)ピラゾロ[1,5-a]ピリミジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１２８)  Process 4
5-((3- (4- (4-Methylpiperazin-1-yl) -phenyl) pyrazolo [1,5-a] pyrimidin-5-yl) methylene) -2-thioxothiazolidine-4-one (compound 128)

Figure JPOXMLDOC01-appb-C000508
Figure JPOXMLDOC01-appb-C000508

5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d][1,2,3]トリアゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オンの合成と同様の手法で、3-(4-(4-メチルピペラジン-1-イル)-フェニル)ピラゾロ[1,5-a]ピリミジン-5-カルボアルデヒド (581 mg、1.77 mmol) から標記化合物 (25 mg, 48%) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 12.34 (1H, br s), 9.16 (1H, d, J = 7.8 Hz), 8.40 (1H, s), 8.26 (2H, d, J = 9.2 Hz), 7.78 (1H, d, J = 7.3 Hz), 7.73 (1H, s), 7.13 (2H, d, J = 9.2 Hz), 3.44 (4H, t, J = 5.0 Hz), 2.75 (4H, t, J = 5.0 Hz), 2.44 (3H, s).
ESI-MS(m/z): 437[M+H]+. 5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] [1,2,3] triazol-6-yl) methylene) -2-thioxothiazolidine- In a manner similar to the synthesis of 4-one, 3- (4- (4-methylpiperazin-1-yl) -phenyl) pyrazolo [1,5-a] pyrimidine-5-carbaldehyde (581 mg, 1.77 mmol) Gave the title compound (25 mg, 48%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 12.34 (1H, br s), 9.16 (1H, d, J = 7.8 Hz), 8.40 (1H, s), 8.26 (2H, d, J = 9.2 Hz), 7.78 (1H, d, J = 7.3 Hz), 7.73 (1H, s), 7.13 (2H, d, J = 9.2 Hz), 3.44 (4H, t, J = 5.0 Hz), 2.75 (4H , t, J = 5.0 Hz), 2.44 (3H, s).
ESI-MS (m / z): 437 [M + H] + .

実施例１２９
5-((3-(4-(4-メチルピペラジン-1-イル)-フェニル)ピラゾロ[1,5-a]ピリミジン-5-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１２９)  Example 129
5-((3- (4- (4-Methylpiperazin-1-yl) -phenyl) pyrazolo [1,5-a] pyrimidin-5-yl) methylene) thiazolidine-2,4-dione (Compound 129)

Figure JPOXMLDOC01-appb-C000509
Figure JPOXMLDOC01-appb-C000509

工程１
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成と同様の手法で、3-(4-(4-メチルピペラジン-1-イル)-フェニル)ピラゾロ[1,5-a]ピリミジン-5-カルボアルデヒド (181 mg、0.56 mmol) から標記化合物 (146 mg, 62%) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 12.08 (1H, s), 9.15 (1H, d, J = 7.8 Hz), 8.41 (1H, s), 8.23 (2H, d, J = 8.7 Hz), 7.96 (1H, s), 7.77 (1H, d, J =7.8 Hz), 7.11 (2H, d, J = 8.7 Hz), 3.38 (4H, t, J = 5.3 Hz), 2.55 (4H, t, J = 5.3 Hz), 2.30 (3H, s).
ESI-MS(m/z): 421[M+H]+. Process 1
A similar approach to the synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione From 3- (4- (4-methylpiperazin-1-yl) -phenyl) pyrazolo [1,5-a] pyrimidine-5-carbaldehyde (181 mg, 0.56 mmol) to the title compound (146 mg, 62% ) Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 12.08 (1H, s), 9.15 (1H, d, J = 7.8 Hz), 8.41 (1H, s), 8.23 (2H, d, J = 8.7 Hz), 7.96 (1H, s), 7.77 (1H, d, J = 7.8 Hz), 7.11 (2H, d, J = 8.7 Hz), 3.38 (4H, t, J = 5.3 Hz), 2.55 (4H, t, J = 5.3 Hz), 2.30 (3H, s).
ESI-MS (m / z): 421 [M + H] + .

実施例１３０
5-((1-(3-クロロ-4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１３０)  Example 130
5-((1- (3-Chloro-4- (4-ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 130 )

工程１
tert-ブチル 4-(4-アミノ-2-クロロフェニル)-ピペラジン-1-カルボキシレート Process 1
tert-butyl 4- (4-amino-2-chlorophenyl) -piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000510
Figure JPOXMLDOC01-appb-C000510

tert-ブチル 4-(2-クロロ-4-ニトロフェニル)ピペラジン-1-カルボキシレート (4.43 g, 12.96  mmol) のエタノール (50 mL) 溶液に 10% パラジウム－活性炭 (400 mg) を加えた。反応容器内を水素で置換し、室温で一晩撹拌した。反応液をろ過し、減圧下溶媒を留去した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (1.23 g, 30%) を得た。褐色固体: 1H-NMR (CDCl3) δ: 6.85 (1H, d, J = 8.0 Hz), 6.75 (1H, d, J = 2.3 Hz), 6.55 (1H, dd, J = 8.0, 2.3 Hz), 3.57 (4H, t, J = 5.2 Hz), 2.87 (4H, t, J = 5.2 Hz), 1.56 (2H, br s), 1.48 (9H, s). To a solution of tert-butyl 4- (2-chloro-4-nitrophenyl) piperazine-1-carboxylate (4.43 g, 12.96 mmol) in ethanol (50 mL) was added 10% palladium-activated carbon (400 mg). The inside of the reaction vessel was replaced with hydrogen and stirred overnight at room temperature. The reaction solution was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (1.23 g, 30%). Brown solid: 1 H-NMR (CDCl 3 ) δ: 6.85 (1H, d, J = 8.0 Hz), 6.75 (1H, d, J = 2.3 Hz), 6.55 (1H, dd, J = 8.0, 2.3 Hz) , 3.57 (4H, t, J = 5.2 Hz), 2.87 (4H, t, J = 5.2 Hz), 1.56 (2H, br s), 1.48 (9H, s).

工程２
tert-ブチル 4-(2-クロロ-4-((5-(メトキシ(メチル)カルバモイル)-2-ニトロフェニル)アミノ)フェニル)ピペラジン-1-カルボキシレート Process 2
tert-butyl 4- (2-chloro-4-((5- (methoxy (methyl) carbamoyl) -2-nitrophenyl) amino) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000511
Figure JPOXMLDOC01-appb-C000511

N-メトキシ-N-メチル-3-((4-(4-メチルピペラジニル)ベンジル)アミノ)-4-ニトロベンズアミドの合成と同様の手法で、3-フルオロ-N-メトキシ-N-メチル-4-ニトロベンズアミド (1.16 g, 5.08 mmol) および tert-ブチル 4-(4-アミノ-2-クロロフェニル)-ピペリジン-1-カルボキシレート (1.25 g, 4.23 mmol) から標記化合物 (226 mg, 9%) を得た。黄色結晶: 1H-NMR (CDCl3) δ: 9.37 (1H, s), 8.23 (1H, d, J =8.6 Hz), 7.36 (1H, d, J = 1.7 Hz), 7.31 (1H, d, J = 2.3 Hz), 7.15 (1H, dd, J = 8.6, 2.3 Hz), 7.05 (1H, d, J = 8.6 Hz), 6.99 (1H, dd, J = 8.6, 1.7 Hz), 3.62 (4H, t, J = 4.9 Hz), 3.55 (3H, s), 3.31 (3H, s), 3.01 (4H, t, J =4.9 Hz), 1.50 (9H, s). In a similar manner to the synthesis of N-methoxy-N-methyl-3-((4- (4-methylpiperazinyl) benzyl) amino) -4-nitrobenzamide, 3-fluoro-N-methoxy-N-methyl From 4-nitrobenzamide (1.16 g, 5.08 mmol) and tert-butyl 4- (4-amino-2-chlorophenyl) -piperidine-1-carboxylate (1.25 g, 4.23 mmol) to the title compound (226 mg, 9% ) Yellow crystals: 1 H-NMR (CDCl 3 ) δ: 9.37 (1H, s), 8.23 (1H, d, J = 8.6 Hz), 7.36 (1H, d, J = 1.7 Hz), 7.31 (1H, d, J = 2.3 Hz), 7.15 (1H, dd, J = 8.6, 2.3 Hz), 7.05 (1H, d, J = 8.6 Hz), 6.99 (1H, dd, J = 8.6, 1.7 Hz), 3.62 (4H, t, J = 4.9 Hz), 3.55 (3H, s), 3.31 (3H, s), 3.01 (4H, t, J = 4.9 Hz), 1.50 (9H, s).

工程３
tert-ブチル 4-(2-クロロ-4-(6-(メトキシ(メチル)カルバモイル)-1H-ベンゾ[d]イミダゾール-1-イル)フェニル)ピペラジン-1-カルボキシレート Process 3
tert-butyl 4- (2-chloro-4- (6- (methoxy (methyl) carbamoyl) -1H-benzo [d] imidazol-1-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000512
Figure JPOXMLDOC01-appb-C000512

アルゴン雰囲気下、tert-ブチル 4-(2-クロロ-4-((5-(メトキシ(メチル)カルバモイル)-2-ニトロフェニル)アミノ)フェニル)ピペラジン-1-カルボキシレート (226 mg, 0.43 mmol) 、鉄粉 (73 mg, 1.30 mmol)、塩化アンモニウム (46 mg, 0.86 mmol) のエタノール (20 mL)、水 (5 mL) 混合溶液を3時間加熱還流した。反応終了後、減圧下溶媒を留去し、得られた残渣を酢酸エチルに再溶解して水で洗浄し、水層を酢酸エチルで抽出した。有機層を合わせ、無水硫酸マグネシウムで乾燥し、減圧下、溶媒を留去した。得られた粗生成物をエタノール (5 mL) に溶かし、オルトギ酸トリエチル (0.3 mL, 1.6 mmol)、酢酸 (38 mg, 0.64 mmol) を加え、室温で一晩撹拌した。減圧下溶媒を留去した後、反応混合物に酢酸エチル、飽和重層水を加え、系を塩基性にした後、クロロホルムで 3 回抽出した。有機層を合わせ、無水硫酸マグネシウムで乾燥した後、溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (100 mg, 49%) を得た。黄色結晶：1H-NMR (CDCl3) δ: 8.14 (1H, s), 7.89 (1H, d, J =1.2 Hz), 7.86 (1H, d, J = 8.2 Hz), 7.71 (1H, dd, J = 8.5, 1.2 Hz), 7.56 (1H, d, J = 2.5 Hz), 7.40 (1H, dd, J = 8.5, 2.5 Hz), 7.19 (1H, d, J = 8.2 Hz), 3.66 (4H, t, J = 5.0 Hz), 3.56 (3H, s), 3.39 (3H, s), 3.08 (4H, t, J =5.0 Hz), 1.51 (9H, s). Under argon atmosphere, tert-butyl 4- (2-chloro-4-((5- (methoxy (methyl) carbamoyl) -2-nitrophenyl) amino) phenyl) piperazine-1-carboxylate (226 mg, 0.43 mmol) , A mixture of iron powder (73 mg, 1.30 mmol), ammonium chloride (46 mg, 0.86 mmol) in ethanol (20 mL) and water (5 mL) was heated to reflux for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the resulting residue was redissolved in ethyl acetate, washed with water, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was dissolved in ethanol (5 mL), triethyl orthoformate (0.3 mL, 1.6 mmol) and acetic acid (38 mg, 0.64 mmol) were added, and the mixture was stirred overnight at room temperature. After evaporating the solvent under reduced pressure, ethyl acetate and saturated multistory water were added to the reaction mixture to make the system basic, followed by extraction with chloroform three times. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The resulting crude product was purified by a silica gel column chromatography method (chloroform / methanol) to obtain the target title compound (100 mg, 49%). Yellow crystals: 1 H-NMR (CDCl 3 ) δ: 8.14 (1H, s), 7.89 (1H, d, J = 1.2 Hz), 7.86 (1H, d, J = 8.2 Hz), 7.71 (1H, dd, J = 8.5, 1.2 Hz), 7.56 (1H, d, J = 2.5 Hz), 7.40 (1H, dd, J = 8.5, 2.5 Hz), 7.19 (1H, d, J = 8.2 Hz), 3.66 (4H, t, J = 5.0 Hz), 3.56 (3H, s), 3.39 (3H, s), 3.08 (4H, t, J = 5.0 Hz), 1.51 (9H, s).

工程４
1-(3-クロロ-4-(ピペラジン-1-イル)フェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 4
1- (3-Chloro-4- (piperazin-1-yl) phenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000513
Figure JPOXMLDOC01-appb-C000513

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成と同様の手法で、tert-ブチル 4-(2-クロロ-4-(6-(メトキシ(メチル)カルバモイル)-1H-ベンゾ[d]イミダゾール-1-イル)フェニル)ピペラジン-1-カルボキシレート(100 mg, 0.2 mmol) から標記化合物 (31 mg, 39%) を得た。褐色個体: 1H-NMR (CDCl3) δ: 8.13 (1H, s), 7.88-7.85 (2H, m), 7.70 (1H, dd, J = 8.5, 1.6 Hz), 7.54 (1H, d, J = 2.3 Hz), 7.39 (1H, dd, J = 8.7, 2.3 Hz), 7.22 (1H, d, J = 8.7 Hz), 3.56 (3H, s), 3.39 (3H, s), 3.15 (8H, s), 1.60 (1H, br s). In a similar manner to the synthesis of 5-bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine, tert-butyl 4- (2-chloro-4- The title compound (31 mg, 39%) was obtained from (6- (methoxy (methyl) carbamoyl) -1H-benzo [d] imidazol-1-yl) phenyl) piperazine-1-carboxylate (100 mg, 0.2 mmol). It was. Brown solid: 1 H-NMR (CDCl 3 ) δ: 8.13 (1H, s), 7.88-7.85 (2H, m), 7.70 (1H, dd, J = 8.5, 1.6 Hz), 7.54 (1H, d, J = 2.3 Hz), 7.39 (1H, dd, J = 8.7, 2.3 Hz), 7.22 (1H, d, J = 8.7 Hz), 3.56 (3H, s), 3.39 (3H, s), 3.15 (8H, s ), 1.60 (1H, br s).

工程５
1-(3-クロロ-4-(4-エチルピペラジン-1-イル)フェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 5
1- (3-Chloro-4- (4-ethylpiperazin-1-yl) phenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000514
Figure JPOXMLDOC01-appb-C000514

5-ブロモ-3-(4-(4-エチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジンの合成と同様の手法で、1-(3-クロロ-4-(ピペラジン-1-イル)フェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド (30 mg, 0.08 mmol) から標記化合物 (21 mg, 63%) を得た。褐色個体: 1H-NMR (CDCl3) δ: 8.14 (1H, s), 7.88-7.85 (2H, m), 7.70 (1H, dd, J = 8.2, 1.2 Hz), 7.54 (1H, d, J = 2.5 Hz), 7.39 (1H, dd, J = 8.5, 2.5 Hz), 7.24 (1H, d, J = 8.2 Hz), 3.56 (3H, s), 3.38 (3H, s), 3.25 (4H, t, J = 4.4 Hz), 2.80 (4H, t, J =4.4 Hz), 2.63 (2H, q, J = 7.3 Hz), 1.21 (3H, t, J = 7.3 Hz). In a similar manner to the synthesis of 5-bromo-3- (4- (4-ethylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridine, From (3-chloro-4- (piperazin-1-yl) phenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide (30 mg, 0.08 mmol) to the title compound (21 mg , 63%). Brown solid: 1 H-NMR (CDCl 3 ) δ: 8.14 (1H, s), 7.88-7.85 (2H, m), 7.70 (1H, dd, J = 8.2, 1.2 Hz), 7.54 (1H, d, J = 2.5 Hz), 7.39 (1H, dd, J = 8.5, 2.5 Hz), 7.24 (1H, d, J = 8.2 Hz), 3.56 (3H, s), 3.38 (3H, s), 3.25 (4H, t , J = 4.4 Hz), 2.80 (4H, t, J = 4.4 Hz), 2.63 (2H, q, J = 7.3 Hz), 1.21 (3H, t, J = 7.3 Hz).

工程６
1-(3-クロロ-4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Step 6
1- (3-Chloro-4- (4-ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000515
Figure JPOXMLDOC01-appb-C000515

1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒドの合成と同様の手法で、1-(3-クロロ-4-(4-エチルピペラジン-1-イル)フェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド(21 mg, 0.05 mmol) から標記化合物 (5 mg, 28%) を得た。褐色個体: 1H-NMR (CDCl3) δ: 10.09 (1H, s), 8.22 (1H, s), 8.03 (1H, t, J = 1.1 Hz), 7.99 (1H, d, J = 8.7 Hz), 7.89 (1H, dd, J = 8.5, 1.1 Hz), 7.54 (1H, d, J = 2.7 Hz), 7.40 (1H, dd, J = 8.7, 2.7 Hz), 7.25 (1H, d, J = 8.5 Hz), 3.22 (4H, br s), 2.72 (4H, br s), 2.56 (2H, q, J =7.3 Hz), 1.17 (3H, t, J = 7.3 Hz). 1- (4- (4-Methylpiperazinyl) benzyl) -1H-benzo [d] imidazole-6-carbaldehyde was prepared in a similar manner to the synthesis of 1- (3-chloro-4- (4-ethylpiperazine The title compound (5 mg, 28%) was obtained from 1-yl) phenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide (21 mg, 0.05 mmol). Brown solid: 1 H-NMR (CDCl 3 ) δ: 10.09 (1H, s), 8.22 (1H, s), 8.03 (1H, t, J = 1.1 Hz), 7.99 (1H, d, J = 8.7 Hz) , 7.89 (1H, dd, J = 8.5, 1.1 Hz), 7.54 (1H, d, J = 2.7 Hz), 7.40 (1H, dd, J = 8.7, 2.7 Hz), 7.25 (1H, d, J = 8.5 Hz), 3.22 (4H, br s), 2.72 (4H, br s), 2.56 (2H, q, J = 7.3 Hz), 1.17 (3H, t, J = 7.3 Hz).

工程７
5-((1-(3-クロロ-4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１３０) Step 7
5-((1- (3-Chloro-4- (4-ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 130 )

Figure JPOXMLDOC01-appb-C000516
Figure JPOXMLDOC01-appb-C000516

1-(3-クロロ-4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド(5 mg, 0.01 mmol)、2,4-チアゾリジンジオン(2 mg, 0.014 mmol) のアセトニトリル (2 mL) 溶液に ピペリジン(1 mg, 0.01 mmol)、酢酸 (1 mg, 0.02 mmol) を加え 80 ℃で一晩撹拌した。反応溶液に酢酸エチルを加え、結晶を析出させた後、ろ過し、酢酸エチル、エタノールで洗浄して標記化合物 (1 mg, 14%) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 11.88 (1H, s), 8.61 (1H, s), 7.84-7.75 (4H, m), 7.64 (1H, dd, J = 8.7, 2.7 Hz), 7.48 (1H, dd, J = 8.5, 1.6 Hz), 7.39 (1H, d, J = 8.7 Hz), 3.10 (4H, br s), 2.71 (4H, br s), 2.62-2.60 (2H, m), 1.06 (3H, t, J = 7.1 Hz).
ESI-MS(m/z): 468[M+H]+. 1- (3-Chloro-4- (4-ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazole-6-carbaldehyde (5 mg, 0.01 mmol), 2,4-thiazolidinedione (2 Piperidine (1 mg, 0.01 mmol) and acetic acid (1 mg, 0.02 mmol) were added to a solution of mg, 0.014 mmol) in acetonitrile (2 mL), and the mixture was stirred at 80 ° C. overnight. Ethyl acetate was added to the reaction solution to precipitate crystals, followed by filtration and washing with ethyl acetate and ethanol to obtain the title compound (1 mg, 14%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 11.88 (1H, s), 8.61 (1H, s), 7.84-7.75 (4H, m), 7.64 (1H, dd, J = 8.7, 2.7 Hz ), 7.48 (1H, dd, J = 8.5, 1.6 Hz), 7.39 (1H, d, J = 8.7 Hz), 3.10 (4H, br s), 2.71 (4H, br s), 2.62-2.60 (2H, m), 1.06 (3H, t, J = 7.1 Hz).
ESI-MS (m / z): 468 [M + H] + .

実施例１３１
5-((3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１３１) Example 131
5-((3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 131)

工程１
tert-ブチル 4-(2-メトキシフェニル)ピペラジン-1-カルボキシレート Process 1
tert-Butyl 4- (2-methoxyphenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000517
Figure JPOXMLDOC01-appb-C000517

アルゴン雰囲気下、1-(2-メトキシフェニル)ピペラジン(800 mg, 4.16 mmol) をジクロロメタン (40 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (1.13 mL, 8.32 mmol) を加えた。さらに二炭酸ジ-tert-ブチル (999 mg, 4.58 mmol) を滴下し、0℃で10分撹拌後、室温で17時間撹拌した。反応液を0.1規定塩酸、水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.19 g, 98%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 6.99-6.92 (2H, m), 6.90-6.85 (2H, m), 3.78 (3H, s), 3.44 (4H, t, J = 4.8 Hz), 2.89 (4H, t, J = 5.0 Hz), 1.42 (9H, s). Under an argon atmosphere, 1- (2-methoxyphenyl) piperazine (800 mg, 4.16 mmol) was dissolved in dichloromethane (40 mL) and cooled to 0 ° C. Triethylamine (1.13 mL, 8.32 mmol) was added there. Di-tert-butyl dicarbonate (999 mg, 4.58 mmol) was further added dropwise, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 17 hours. The reaction mixture was washed with 0.1N hydrochloric acid, water, and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.19 g, 98%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 6.99-6.92 (2H, m), 6.90-6.85 (2H, m), 3.78 (3H, s), 3.44 (4H, t, J = 4.8 Hz ), 2.89 (4H, t, J = 5.0 Hz), 1.42 (9H, s).

工程２
tert-ブチル 4-(4-ブロモ-2-メトキシフェニル)ピペラジン-1-カルボキシレート Process 2
tert-butyl 4- (4-bromo-2-methoxyphenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000518
Figure JPOXMLDOC01-appb-C000518

アルゴン雰囲気下、tert-ブチル 4-(2-メトキシフェニル)ピペラジン-1-カルボキシレート(1.19 g, 4.06 mmol) を酢酸 (8 mL) に溶解し、0℃に冷却した。そこへ臭素 (230 μL, 4.47 mmol) を滴下し、0℃で10分撹拌後、室温で1時間撹拌した。反応液を酢酸エチルで希釈し、飽和重層水、飽和チオ硫酸ナトリウム水溶液、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (325 mg, 22%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 7.09 (1H, d, J = 2.2 Hz), 7.04 (1H, dd, J = 8.1, 2.0 Hz), 6.82 (1H, d, J = 8.3 Hz), 3.80 (3H, s), 3.43 (4H, s), 2.87 (4H, t, J = 4.9 Hz), 1.41 (9H, s). Under an argon atmosphere, tert-butyl 4- (2-methoxyphenyl) piperazine-1-carboxylate (1.19 g, 4.06 mmol) was dissolved in acetic acid (8 mL) and cooled to 0 ° C. Bromine (230 μL, 4.47 mmol) was added dropwise thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, and washed with saturated multistory water, saturated aqueous sodium thiosulfate solution, and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (325 mg, 22%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 7.09 (1H, d, J = 2.2 Hz), 7.04 (1H, dd, J = 8.1, 2.0 Hz), 6.82 (1H, d, J = 8.3 Hz), 3.80 (3H, s), 3.43 (4H, s), 2.87 (4H, t, J = 4.9 Hz), 1.41 (9H, s).

工程３
tert-ブチル 4-(2-メトキシ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレート Process 3
tert-Butyl 4- (2-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000519
Figure JPOXMLDOC01-appb-C000519

tert-ブチル 4-(3-フルオロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例85、工程4) と同様の手法で、tert-ブチル 4-(4-ブロモ-2-メトキシフェニル)ピペラジン-1-カルボキシレート(325 mg, 0.875 mmol) およびビス(ピナコラート)ジボロン (267 mg, 1.05 mmol) から標記化合物 (257 mg, 70%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 7.23 (1H, d, J = 7.8 Hz), 7.12 (1H, d, J = 1.2 Hz), 6.88 (1H, d, J = 7.8 Hz), 3.79 (3H, s), 3.44 (4H, s), 2.94 (4H, t, J = 4.9 Hz), 1.42 (9H, s), 1.28 (12H, s). Synthesis of tert-butyl 4- (3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (Example 85) In the same manner as in step 4), tert-butyl 4- (4-bromo-2-methoxyphenyl) piperazine-1-carboxylate (325 mg, 0.875 mmol) and bis (pinacolato) diboron (267 mg, 1.05 mmol ) Gave the title compound (257 mg, 70%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 7.23 (1H, d, J = 7.8 Hz), 7.12 (1H, d, J = 1.2 Hz), 6.88 (1H, d, J = 7.8 Hz) , 3.79 (3H, s), 3.44 (4H, s), 2.94 (4H, t, J = 4.9 Hz), 1.42 (9H, s), 1.28 (12H, s).

工程４
tert-ブチル 4-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-2-メトキシフェニル)ピペラジン-1-カルボキシレート Process 4
tert-butyl 4- (4- (6-chloroimidazo [1,2-b] pyridazin-3-yl) -2-methoxyphenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000520
Figure JPOXMLDOC01-appb-C000520

3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-カルボニトリルの合成 (実施例106、工程6) と同様の手法で、3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (130 mg, 0.558 mmol) およびtert-ブチル 4-(2-メトキシ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレート(257 mg, 0.614 mmol) から標記化合物 (125 mg, 51%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.31 (1H, s), 8.28 (1H, d, J = 9.5 Hz), 7.68 (1H, dd, J = 8.3, 2.0 Hz), 7.65-7.53 (1H, m), 7.39 (1H, d, J = 9.5 Hz), 7.06 (1H, d, J = 8.3 Hz), 3.89 (3H, s), 3.48 (4H, s), 2.99 (4H, t, J =4.8 Hz), 1.43 (9H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridine-5-carbonitrile (Example 106, Step 6) -6-Chloroimidazo [1,2-b] pyridazine (130 mg, 0.558 mmol) and tert-butyl 4- (2-methoxy-4- (4,4,5,5-tetramethyl-1,3,2) The title compound (125 mg, 51%) was obtained from -dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (257 mg, 0.614 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.31 (1H, s), 8.28 (1H, d, J = 9.5 Hz), 7.68 (1H, dd, J = 8.3, 2.0 Hz), 7.65- 7.53 (1H, m), 7.39 (1H, d, J = 9.5 Hz), 7.06 (1H, d, J = 8.3 Hz), 3.89 (3H, s), 3.48 (4H, s), 2.99 (4H, t , J = 4.8 Hz), 1.43 (9H, s).

工程５
6-クロロ-3-(3-メトキシ-4-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Process 5
6-Chloro-3- (3-methoxy-4- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000521
Figure JPOXMLDOC01-appb-C000521

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程6) と同様の手法で、tert-ブチル 4-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-2-メトキシフェニル)ピペラジン-1-カルボキシレート(125 mg、0.282 mmol) およびトリフルオロ酢酸(0.5 mL) から標記化合物 (52 mg, 54%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.30 (1H, s), 8.28 (1H, d, J = 9.5 Hz), 7.68 (1H, dd, J = 8.3, 2.0 Hz), 7.65-7.53 (1H, m), 7.39 (1H, d, J = 9.5 Hz), 7.03 (1H, d, J = 8.3 Hz), 3.88 (3H, s), 3.34 (1H, s), 2.99 (4H, t, J =4.5 Hz), 2.89 (4H, t, J = 4.6 Hz). Synthesis of 5-bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 6) From-(4- (6-chloroimidazo [1,2-b] pyridazin-3-yl) -2-methoxyphenyl) piperazine-1-carboxylate (125 mg, 0.282 mmol) and trifluoroacetic acid (0.5 mL) The title compound (52 mg, 54%) was obtained. Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.30 (1H, s), 8.28 (1H, d, J = 9.5 Hz), 7.68 (1H, dd, J = 8.3, 2.0 Hz), 7.65- 7.53 (1H, m), 7.39 (1H, d, J = 9.5 Hz), 7.03 (1H, d, J = 8.3 Hz), 3.88 (3H, s), 3.34 (1H, s), 2.99 (4H, t , J = 4.5 Hz), 2.89 (4H, t, J = 4.6 Hz).

工程６
6-クロロ-3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Step 6
6-Chloro-3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000522
Figure JPOXMLDOC01-appb-C000522

5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程7) と同様の手法で、6-クロロ-3-(3-メトキシ-4-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (52 mg, 0.151 mmol) および 37% ホルムアルデヒド水溶液 (67 μL, 0.906 mmol) から標記化合物 (25 mg, 46%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.30 (1H, s), 8.28 (1H, d, J = 9.5 Hz), 7.68 (1H, dd, J =8.2, 1.8 Hz), 7.63 (1H, d, J =1.7 Hz), 7.39 (1H, d, J = 9.5 Hz), 7.04 (1H, d, J = 8.3 Hz), 3.88 (3H, s), 3.05 (4H, s), 2.48 (4H, s), 2.23 (3H, s). Synthesis of 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 7) From 2-chloro-3- (3-methoxy-4- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (52 mg, 0.151 mmol) and 37% aqueous formaldehyde solution (67 μL, 0.906 mmol) The title compound (25 mg, 46%) was obtained. Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.30 (1H, s), 8.28 (1H, d, J = 9.5 Hz), 7.68 (1H, dd, J = 8.2, 1.8 Hz), 7.63 ( 1H, d, J = 1.7 Hz), 7.39 (1H, d, J = 9.5 Hz), 7.04 (1H, d, J = 8.3 Hz), 3.88 (3H, s), 3.05 (4H, s), 2.48 ( 4H, s), 2.23 (3H, s).

工程７
3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Step 7
3- (3-Methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000523
Figure JPOXMLDOC01-appb-C000523

アルゴン雰囲気下、6-クロロ-3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (25 mg, 0.0699 mmol) を1,4-ジオキサン (875 μL) に溶解した。そこへ酢酸パラジウム (1.6 mg, 0.00699 mmol)、2-ジシクロヘキシルフォスフィノ-2',6'-ジメトキシビフェニル (5.7 mg, 0.0140 mmol)、4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (14 μL, 0.0839 mmol) を加え、反応容器内を脱気した後、室温で10分撹拌した。そこへリン酸三カリウム (111 mg, 0.524 mmol) の水溶液 (175 μL) を加え、60℃で14時間撹拌した。反応液に1規定水酸化ナトリウム溶液を加え、酢酸エチルで抽出した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (24 mg, 98%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.16 (1H, d, J = 9.5 Hz), 7.79 (1H, d, J = 2.0 Hz), 7.71 (1H, dd, J = 8.3, 2.0 Hz), 7.62 (1H, d, J = 9.5 Hz), 7.01 (1H, d, J = 8.3 Hz), 6.91 (1H, dd, J = 17.9, 11.1 Hz), 6.37 (1H, d, J = 17.8 Hz), 5.77 (1H, d, J = 11.5 Hz), 3.89 (3H, s), 3.04 (4H, s), 2.51-2.49 (4H, m), 2.23 (3H, s). Under an argon atmosphere, 6-chloro-3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (25 mg, 0.0699 mmol) was added to 1,4- Dissolved in dioxane (875 μL). Palladium acetate (1.6 mg, 0.00699 mmol), 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (5.7 mg, 0.0140 mmol), 4,4,5,5-tetramethyl-2-vinyl-1 , 3,2-Dioxaborolane (14 μL, 0.0839 mmol) was added and the reaction vessel was degassed, followed by stirring at room temperature for 10 minutes. The aqueous solution (175 microliters) of tripotassium phosphate (111 mg, 0.524 mmol) was added there, and it stirred at 60 degreeC for 14 hours. 1N sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (24 mg, 98%). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.16 (1H, d, J = 9.5 Hz), 7.79 (1H, d, J = 2.0 Hz), 7.71 (1H, dd, J = 8.3, 2.0 Hz), 7.62 (1H, d, J = 9.5 Hz), 7.01 (1H, d, J = 8.3 Hz), 6.91 (1H, dd, J = 17.9, 11.1 Hz), 6.37 (1H, d, J = 17.8 Hz), 5.77 (1H, d, J = 11.5 Hz), 3.89 (3H, s), 3.04 (4H, s), 2.51-2.49 (4H, m), 2.23 (3H, s).

工程８
3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 8
3- (3-Methoxy-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000524
Figure JPOXMLDOC01-appb-C000524

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (24 mg, 0.0687 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (17 μL, 1.37 μmol) から標記化合物 (3 mg, 12%) を得た。橙色固体: 1H-NMR (CDCl3) δ: 10.1 (1H, d, J = 0.5 Hz), 8.19 (1H, s), 8.14 (1H, d, J =9.5 Hz), 7.69-7.66 (3H, m), 7.10 (1H, d, J = 8.5 Hz), 3.99 (3H, s), 3.50 (4H, s), 3.17 (4H, s), 2.74 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (24 mg, 0.0687 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol ( The title compound (3 mg, 12%) was obtained from 17 μL, 1.37 μmol). Orange solid: 1 H-NMR (CDCl 3 ) δ: 10.1 (1H, d, J = 0.5 Hz), 8.19 (1H, s), 8.14 (1H, d, J = 9.5 Hz), 7.69-7.66 (3H, m), 7.10 (1H, d, J = 8.5 Hz), 3.99 (3H, s), 3.50 (4H, s), 3.17 (4H, s), 2.74 (3H, s).

工程９
5-((3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１３１) Step 9
5-((3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 131)

Figure JPOXMLDOC01-appb-C000525
Figure JPOXMLDOC01-appb-C000525

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (3 mg, 0.00854 mmol) およびチアゾリジン-2,4-ジオン (1 mg, 0.00854 mmol) から標記化合物 (2 mg, 57%) を得た。赤色固体: 1H-NMR (DMSO-D6) δ: 8.26 (1H, d, J = 9.3 Hz), 8.20 (1H, s), 7.75 (1H, s), 7.67 (1H, d, J = 8.5 Hz), 7.63 (1H, d, J = 9.5 Hz), 7.58 (1H, d, J = 2.0 Hz), 7.07 (1H, d, J = 8.3 Hz), 3.92 (3H, s), 3.33 (4H, s), 3.11 (4H, s), 2.67 (3H, s).
ESI-MS(m/z): 451[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (3 mg, 0.00854 mmol) and thiazolidine-2,4-dione (1 mg, 0.00854 mmol) gave the title compound (2 mg, 57%). Red solid: 1 H-NMR (DMSO-D 6 ) δ: 8.26 (1H, d, J = 9.3 Hz), 8.20 (1H, s), 7.75 (1H, s), 7.67 (1H, d, J = 8.5 Hz), 7.63 (1H, d, J = 9.5 Hz), 7.58 (1H, d, J = 2.0 Hz), 7.07 (1H, d, J = 8.3 Hz), 3.92 (3H, s), 3.33 (4H, s), 3.11 (4H, s), 2.67 (3H, s).
ESI-MS (m / z): 451 [M + H] + .

実施例１３２
5-((3-(3-フルオロ-5-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１３２)  Example 132
5-((3- (3-Fluoro-5- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 132)

工程１
tert-ブチル 4-(3-ブロモ-5-フルオロフェニル)ピペラジン-1-カルボキシレート Process 1
tert-Butyl 4- (3-bromo-5-fluorophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000526
Figure JPOXMLDOC01-appb-C000526

アルゴン雰囲気下、1-(tert-ブトキシカルボニル)ピペラジン (1.0 g, 5.37 mmol)、1,3-ジブロモ-5-フルオロベンゼン (2.01 g, 16.1 mmol) を1,4-ジオキサン (30 mL) に溶解した。そこへ炭酸セシウム (4.38 g, 13.4 mmol)、4,5-ビス(ジフェニルホスフィノ)-9,9-ジメチルキサンテン (311 mg, 0.537 mmol)、トリス(ジベンジリデンアセトン)ジパラジウム (0) (492 mg, 0.537 mmol) を加え, 100℃で18時間撹拌した。反応混合物をセライトでろ過し、ろ液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (NHカラム, ヘキサン/酢酸エチル) で精製し、標記化合物 (314 mg, 16%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 6.94 (1H, s), 6.84-6.78 (2H, m), 3.42 (4H, t, J = 5.1 Hz), 3.20 (4H, t, J = 5.2 Hz), 1.42 (9H, s). 1- (tert-Butoxycarbonyl) piperazine (1.0 g, 5.37 mmol), 1,3-dibromo-5-fluorobenzene (2.01 g, 16.1 mmol) dissolved in 1,4-dioxane (30 mL) under argon atmosphere did. Cesium carbonate (4.38 g, 13.4 mmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (311 mg, 0.537 mmol), tris (dibenzylideneacetone) dipalladium (0) (492 mg, 0.537 mmol) was added, and the mixture was stirred at 100 ° C. for 18 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (NH column, hexane / ethyl acetate) to obtain the title compound (314 mg, 16%). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 6.94 (1H, s), 6.84-6.78 (2H, m), 3.42 (4H, t, J = 5.1 Hz), 3.20 (4H, t, J = 5.2 Hz), 1.42 (9H, s).

工程２
tert-ブチル 4-(3-フルオロ-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレート Process 2
tert-butyl 4- (3-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000527
Figure JPOXMLDOC01-appb-C000527

tert-ブチル 4-(3-フルオロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例85、工程4) と同様の手法で、tert-ブチル 4-(3-ブロモ-5-フルオロフェニル)ピペラジン-1-カルボキシレート (314 mg, 0.874 mmol) およびビス(ピナコラート)ジボロン (266 mg, 1.05 mmol) から標記化合物 (252 mg, 71%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 7.00 (1H, d, J = 2.4 Hz), 6.90 (1H, dt, J = 12.7, 2.3 Hz), 6.76 (1H, dd, J = 8.2, 2.3 Hz), 3.44 (4H, t, J = 4.9 Hz), 3.14 (4H, t, J = 5.1 Hz), 1.42 (9H, s), 1.29 (12H, s). Synthesis of tert-butyl 4- (3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (Example 85) In the same manner as in step 4), tert-butyl 4- (3-bromo-5-fluorophenyl) piperazine-1-carboxylate (314 mg, 0.874 mmol) and bis (pinacolato) diboron (266 mg, 1.05 mmol) ) Gave the title compound (252 mg, 71%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 7.00 (1H, d, J = 2.4 Hz), 6.90 (1H, dt, J = 12.7, 2.3 Hz), 6.76 (1H, dd, J = 8.2 , 2.3 Hz), 3.44 (4H, t, J = 4.9 Hz), 3.14 (4H, t, J = 5.1 Hz), 1.42 (9H, s), 1.29 (12H, s).

工程３
tert-ブチル 4-(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-5-フルオロフェニル)ピペラジン-1-カルボキシレート Process 3
tert-butyl 4- (3- (6-chloroimidazo [1,2-b] pyridazin-3-yl) -5-fluorophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000528
Figure JPOXMLDOC01-appb-C000528

3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-カルボニトリルの合成 (実施例106、工程6) と同様の手法で、3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (131 mg, 0.564 mmol) およびtert-ブチル 4-(3-フルオロ-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレート(252 mg, 0.620 mmol) から標記化合物 (145 mg, 60%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.42 (1H, s), 8.32 (1H, d, J = 9.5 Hz), 7.65-7.53 (1H, m), 7.48 (1H, s), 7.46 (1H, d, J = 9.5 Hz), 7.41 (1H, d, J = 9.5 Hz), 6.86 (1H, dt, J = 12.4, 2.2 Hz), 3.48 (4H, t, J = 4.9 Hz), 3.26 (4H, t, J = 5.0 Hz), 1.43 (9H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridine-5-carbonitrile (Example 106, Step 6) -6-Chloroimidazo [1,2-b] pyridazine (131 mg, 0.564 mmol) and tert-butyl 4- (3-fluoro-5- (4,4,5,5-tetramethyl-1,3,2) The title compound (145 mg, 60%) was obtained from -dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (252 mg, 0.620 mmol). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.42 (1H, s), 8.32 (1H, d, J = 9.5 Hz), 7.65-7.53 (1H, m), 7.48 (1H, s) , 7.46 (1H, d, J = 9.5 Hz), 7.41 (1H, d, J = 9.5 Hz), 6.86 (1H, dt, J = 12.4, 2.2 Hz), 3.48 (4H, t, J = 4.9 Hz) , 3.26 (4H, t, J = 5.0 Hz), 1.43 (9H, s).

工程４
6-クロロ-3-(3-フルオロ-5-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Process 4
6-Chloro-3- (3-fluoro-5- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000529
Figure JPOXMLDOC01-appb-C000529

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程6) と同様の手法で、tert-ブチル 4-(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-5-フルオロフェニル)ピペラジン-1-カルボキシレート(145 mg, 0.336 mmol) およびトリフルオロ酢酸 (0.5 mL) から標記化合物 (72 mg, 65%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.41 (1H, s), 8.31 (1H, d, J = 8.5 Hz), 7.65-7.53 (1H, m), 7.47 (1H, s), 7.45 (1H, d, J = 9.5 Hz), 7.37-7.34 (1H, m), 6.80 (1H, dt, J = 12.8, 2.3 Hz), 3.19 (4H, t, J = 5.0 Hz), 2.86 (4H, t, J = 4.9 Hz). Synthesis of 5-bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 6) From-(3- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) -5-fluorophenyl) piperazine-1-carboxylate (145 mg, 0.336 mmol) and trifluoroacetic acid (0.5 mL) The title compound (72 mg, 65%) was obtained. Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.41 (1H, s), 8.31 (1H, d, J = 8.5 Hz), 7.65-7.53 (1H, m), 7.47 (1H, s), 7.45 (1H, d, J = 9.5 Hz), 7.37-7.34 (1H, m), 6.80 (1H, dt, J = 12.8, 2.3 Hz), 3.19 (4H, t, J = 5.0 Hz), 2.86 (4H , t, J = 4.9 Hz).

工程５
6-クロロ-3-(3-フルオロ-5-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Process 5
6-Chloro-3- (3-fluoro-5- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000530
Figure JPOXMLDOC01-appb-C000530

5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程7) と同様の手法で、6-クロロ-3-(3-フルオロ-5-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (72 mg, 0.217 mmol) および 37% ホルムアルデヒド水溶液 (97 μL、1.30 mmol) から標記化合物 (33 mg, 44%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.42 (1H, s), 8.31 (1H, d, J = 9.5 Hz), 7.48 (1H, s), 7.45 (1H, d, J = 9.5 Hz), 7.37 (1H, d, J = 10.0 Hz), 6.83 (1H, dt, J = 12.7, 2.2 Hz), 3.27 (4H, t, J = 5.0 Hz), 2.47 (4H, t, J = 5.0 Hz), 2.23 (3H, s). Synthesis of 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 7) From -chloro-3- (3-fluoro-5- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (72 mg, 0.217 mmol) and 37% aqueous formaldehyde solution (97 μL, 1.30 mmol) The title compound (33 mg, 44%) was obtained. Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.42 (1H, s), 8.31 (1H, d, J = 9.5 Hz), 7.48 (1H, s), 7.45 (1H, d, J = 9.5 Hz), 7.37 (1H, d, J = 10.0 Hz), 6.83 (1H, dt, J = 12.7, 2.2 Hz), 3.27 (4H, t, J = 5.0 Hz), 2.47 (4H, t, J = 5.0 Hz), 2.23 (3H, s).

工程６
3-(3-フルオロ-5-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Step 6
3- (3-Fluoro-5- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000531
Figure JPOXMLDOC01-appb-C000531

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、6-クロロ-3-(3-フルオロ-5-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (33 mg, 0.0954 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (18 μL, 0.105 mmol) から標記化合物 (19 mg, 59%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.35 (1H, s), 8.20 (1H, d, J = 9.5 Hz), 7.68 (1H, d, J = 9.5 Hz), 7.63 (1H, s), 7.44 (1H, d, J = 10.0 Hz), 6.92 (1H, dd, J = 17.8, 11.0 Hz), 6.79 (1H, dt, J = 12.8, 2.1 Hz), 6.38 (1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.0 Hz), 3.27 (4H, t, J = 5.0 Hz), 2.50-2.47 (4H, m), 2.24 (3H, s). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) 6-chloro-3- (3-fluoro-5- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (33 mg, 0.0954 mmol) and 4,4,5,5- The title compound (19 mg, 59%) was obtained from tetramethyl-2-vinyl-1,3,2-dioxaborolane (18 μL, 0.105 mmol). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.35 (1H, s), 8.20 (1H, d, J = 9.5 Hz), 7.68 (1H, d, J = 9.5 Hz), 7.63 (1H, s), 7.44 (1H, d, J = 10.0 Hz), 6.92 (1H, dd, J = 17.8, 11.0 Hz), 6.79 (1H, dt, J = 12.8, 2.1 Hz), 6.38 (1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.0 Hz), 3.27 (4H, t, J = 5.0 Hz), 2.50-2.47 (4H, m), 2.24 (3H, s).

工程７
3-(3-フルオロ-5-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Step 7
3- (3-Fluoro-5- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000532
Figure JPOXMLDOC01-appb-C000532

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-フルオロ-5-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (19 mg, 0.0563 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (14 μL, 1.12 μmol) から標記化合物 (4 mg, 21%) を得た。黄色オイル: 1H-NMR (CDCl3) δ: 10.1 (1H, s), 8.21 (1H, s), 8.15 (1H, d, J = 9.5 Hz), 7.71 (1H, d, J = 9.3 Hz), 7.42-7.38 (2H, m), 6.69 (1H, dt, J = 11.5, 2.2 Hz), 3.53 (4H, s), 2.93 (4H, s), 2.62 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3-Fluoro-5- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (19 mg, 0.0563 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol ( The title compound (4 mg, 21%) was obtained from 14 μL, 1.12 μmol). Yellow oil: 1 H-NMR (CDCl 3 ) δ: 10.1 (1H, s), 8.21 (1H, s), 8.15 (1H, d, J = 9.5 Hz), 7.71 (1H, d, J = 9.3 Hz) , 7.42-7.38 (2H, m), 6.69 (1H, dt, J = 11.5, 2.2 Hz), 3.53 (4H, s), 2.93 (4H, s), 2.62 (3H, s).

工程８
5-((3-(3-フルオロ-5-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１３２) Process 8
5-((3- (3-Fluoro-5- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 132)

Figure JPOXMLDOC01-appb-C000533
Figure JPOXMLDOC01-appb-C000533

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-フルオロ-5-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (4 mg, 0.0118 mmol) およびチアゾリジン-2,4-ジオン (1 mg, 0.0118 mmol) から標記化合物 (4 mg, 72%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.30 (1H, s), 8.27 (1H, d, J = 9.5 Hz), 7.73 (1H, s), 7.67 (1H, d, J = 9.5 Hz), 7.49 (1H, s), 7.40 (1H, d, J = 9.0 Hz), 6.86 (1H, d, J = 12.4 Hz), 3.38 (4H, s), 2.82 (4H, s), 2.48 (3H, s).
ESI-MS(m/z): 439[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3-fluoro-5- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (4 mg, 0.0118 mmol) and thiazolidine-2,4-dione (1 mg, 0.0118 mmol) gave the title compound (4 mg, 72%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.30 (1H, s), 8.27 (1H, d, J = 9.5 Hz), 7.73 (1H, s), 7.67 (1H, d, J = 9.5 Hz), 7.49 (1H, s), 7.40 (1H, d, J = 9.0 Hz), 6.86 (1H, d, J = 12.4 Hz), 3.38 (4H, s), 2.82 (4H, s), 2.48 ( 3H, s).
ESI-MS (m / z): 439 [M + H] + .

実施例１３３
5-((3-(3-メチル-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１３３) Example 133
5-((3- (3-Methyl-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 133)

工程１
tert-ブチル 4-(2-メチル-4-ニトロフェニル)ピペラジン-1-カルボキシレート Process 1
tert-butyl 4- (2-methyl-4-nitrophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000534
Figure JPOXMLDOC01-appb-C000534

アルゴン雰囲気下、2-フルオロ-5-ニトロトルエン(1.0 g, 6.45 mmol)、1-(tert-ブトキシカルボニル)ピペラジン (4.46 g, 32.3 mmol) をアセトニトリル (5 mL) に溶解した。そこへ1-ブチル-3-メチルイミダゾリウム ヘキサフルオロホスフェート (133 μL, 0.645 mmol) を加え、95℃で24時間撹拌した。反応液に酢酸エチルを加え、水、1規定塩酸、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (905 mg, 44%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.07-8.02 (2H, m), 7.14 (1H, d, J = 8.8 Hz), 3.49 (4H, s), 2.96 (4H, t, J = 5.0 Hz), 2.35 (3H, s), 1.43 (9H, s). Under an argon atmosphere, 2-fluoro-5-nitrotoluene (1.0 g, 6.45 mmol) and 1- (tert-butoxycarbonyl) piperazine (4.46 g, 32.3 mmol) were dissolved in acetonitrile (5 mL). 1-butyl-3-methylimidazolium hexafluorophosphate (133 μL, 0.645 mmol) was added thereto, and the mixture was stirred at 95 ° C. for 24 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, 1N hydrochloric acid and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (905 mg, 44%). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.07-8.02 (2H, m), 7.14 (1H, d, J = 8.8 Hz), 3.49 (4H, s), 2.96 (4H, t, J = 5.0 Hz), 2.35 (3H, s), 1.43 (9H, s).

工程２
tert-ブチル 4-(4-アミノ-2-メチルフェニル)ピペラジン-1-カルボキシレート Process 2
tert-butyl 4- (4-amino-2-methylphenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000535
Figure JPOXMLDOC01-appb-C000535

tert-ブチル 4-(2-メチル-4-ニトロフェニル)ピペラジン-1-カルボキシレート (905 mg, 2.82 mmol) をエタノール (10 mL)、テトラヒドロフラン (10 mL) に溶解した。そこへ10% パラジウム-活性炭 (91 mg) をエタノール(5 mL) に懸濁して加えた。反応容器内を水素で置換し、室温で2時間撹拌した。反応液をセライトでろ過し、濃縮、真空乾燥して標記化合物 (847 mg, quant.) を得た。褐色固体: 1H-NMR (DMSO-D6) δ: 6.74 (1H, d, J = 8.5 Hz), 6.39 (1H, d, J = 2.7 Hz), 6.34 (1H, dd, J = 8.3, 2.7 Hz), 4.69 (2H, s), 3.40 (4H, s), 2.63 (4H, t, J = 4.9 Hz), 2.12 (3H, s), 1.41 (9H, s). Tert-butyl 4- (2-methyl-4-nitrophenyl) piperazine-1-carboxylate (905 mg, 2.82 mmol) was dissolved in ethanol (10 mL) and tetrahydrofuran (10 mL). Thereto was added 10% palladium-activated carbon (91 mg) suspended in ethanol (5 mL). The inside of the reaction vessel was replaced with hydrogen, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite, concentrated and dried under vacuum to obtain the title compound (847 mg, quant.). Brown solid: 1 H-NMR (DMSO-D 6 ) δ: 6.74 (1H, d, J = 8.5 Hz), 6.39 (1H, d, J = 2.7 Hz), 6.34 (1H, dd, J = 8.3, 2.7 Hz), 4.69 (2H, s), 3.40 (4H, s), 2.63 (4H, t, J = 4.9 Hz), 2.12 (3H, s), 1.41 (9H, s).

工程３
tert-ブチル 4-(4-ヨード-2-メチルフェニル)ピペラジン-1-カルボキシレート Process 3
tert-butyl 4- (4-iodo-2-methylphenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000536
Figure JPOXMLDOC01-appb-C000536

アルゴン雰囲気下、tert-ブチル 4-(4-アミノ-2-メチルフェニル)ピペラジン-1-カルボキシレート(847 mg, 2.82 mmol) をアセトニトリル (15 mL) に溶解した。そこへジヨードメタン (907 μL, 11.3 mmol) を加えた。さらに亜硝酸tert-ブチル (735 μL, 6.20 mmol) のアセトニトリル溶液 (5 mL) を滴下し、室温で1時間後、60℃で6時間撹拌した。反応液を酢酸エチルで希釈し、水、飽和チオ硫酸ナトリウム水溶液で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (571 mg, 50%) を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 7.52 (1H, d, J = 2.2 Hz), 7.47 (1H, dd, J = 8.3, 2.2 Hz), 6.82 (1H, d, J = 8.3 Hz), 3.44 (4H, s), 2.75 (4H, t, J =5.0 Hz), 2.21 (3H, s), 1.42 (9H, s). Under an argon atmosphere, tert-butyl 4- (4-amino-2-methylphenyl) piperazine-1-carboxylate (847 mg, 2.82 mmol) was dissolved in acetonitrile (15 mL). Diiodomethane (907 μL, 11.3 mmol) was added thereto. Furthermore, an acetonitrile solution (5 mL) of tert-butyl nitrite (735 μL, 6.20 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour and then at 60 ° C. for 6 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated aqueous sodium thiosulfate solution. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (571 mg, 50%). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 7.52 (1H, d, J = 2.2 Hz), 7.47 (1H, dd, J = 8.3, 2.2 Hz), 6.82 (1H, d, J = 8.3 Hz), 3.44 (4H, s), 2.75 (4H, t, J = 5.0 Hz), 2.21 (3H, s), 1.42 (9H, s).

工程４
tert-ブチル 4-(2-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレート Process 4
tert-butyl 4- (2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000537
Figure JPOXMLDOC01-appb-C000537

tert-ブチル 4-(3-フルオロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例85、工程4) と同様の手法で、tert-ブチル 4-(4-ヨード-2-メチルフェニル)ピペラジン-1-カルボキシレート(571 mg, 1.42 mmol) およびビス(ピナコラート)ジボロン (397 mg, 1.56 mmol) から標記化合物 (511 mg, 89%) を得た。黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 7.47-7.44 (2H, m), 6.98 (1H, d, J = 7.8 Hz), 3.46 (4H, s), 2.80 (4H, t, J = 4.9 Hz), 2.24 (3H, s), 1.42 (9H, s), 1.27 (12H, s). Synthesis of tert-butyl 4- (3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (Example 85) In the same manner as in step 4), tert-butyl 4- (4-iodo-2-methylphenyl) piperazine-1-carboxylate (571 mg, 1.42 mmol) and bis (pinacolato) diboron (397 mg, 1.56 mmol ) Gave the title compound (511 mg, 89%). Yellow amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 7.47-7.44 (2H, m), 6.98 (1H, d, J = 7.8 Hz), 3.46 (4H, s), 2.80 (4H, t , J = 4.9 Hz), 2.24 (3H, s), 1.42 (9H, s), 1.27 (12H, s).

工程５
tert-ブチル 4-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-2-メチルフェニル)ピペラジン-1-カルボキシレート Process 5
tert-butyl 4- (4- (6-chloroimidazo [1,2-b] pyridazin-3-yl) -2-methylphenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000538
Figure JPOXMLDOC01-appb-C000538

3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-カルボニトリルの合成 (実施例106、工程6) と同様の手法で、3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (268 mg, 1.15 mmol) およびtert-ブチル 4-(2-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレート(511 mg, 1.27 mmol) から標記化合物 (308 mg, 63%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.28 (1H, d, J = 9.5 Hz), 8.23 (1H, s), 7.91 (1H, dd, J = 8.3, 2.2 Hz), 7.86 (1H, d, J = 2.2 Hz), 7.39 (1H, d, J = 9.3 Hz), 7.18 (1H, d, J = 8.3 Hz), 3.50 (4H, s), 2.86 (4H, t, J = 4.9 Hz), 2.35 (3H, s), 1.44 (9H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridine-5-carbonitrile (Example 106, Step 6) -6-Chloroimidazo [1,2-b] pyridazine (268 mg, 1.15 mmol) and tert-butyl 4- (2-methyl-4- (4,4,5,5-tetramethyl-1,3,2) The title compound (308 mg, 63%) was obtained from -dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (511 mg, 1.27 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.28 (1H, d, J = 9.5 Hz), 8.23 (1H, s), 7.91 (1H, dd, J = 8.3, 2.2 Hz), 7.86 ( 1H, d, J = 2.2 Hz), 7.39 (1H, d, J = 9.3 Hz), 7.18 (1H, d, J = 8.3 Hz), 3.50 (4H, s), 2.86 (4H, t, J = 4.9 Hz), 2.35 (3H, s), 1.44 (9H, s).

工程６
6-クロロ-3-(3-メチル-4-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Step 6
6-Chloro-3- (3-methyl-4- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000539
Figure JPOXMLDOC01-appb-C000539

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程6) と同様の手法で、tert-ブチル 4-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-2-メチルフェニル)ピペラジン-1-カルボキシレート(308 mg, 0.720 mmol) およびトリフルオロ酢酸 (1 mL) から標記化合物 (247 mg, quant.) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.28 (1H, d, J = 9.5 Hz), 8.23 (1H, s), 7.93 (1H, dd, J =8.4, 2.1 Hz), 7.87 (1H, d, J =2.2 Hz), 7.39 (1H, d, J = 9.5 Hz), 7.20 (1H, d, J = 8.5 Hz), 3.17 (4H, t, J = 4.8 Hz), 3.04 (4H, t, J = 4.8 Hz), 2.35 (3H, s). Synthesis of 5-bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 6) From-(4- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) -2-methylphenyl) piperazine-1-carboxylate (308 mg, 0.720 mmol) and trifluoroacetic acid (1 mL) The title compound (247 mg, quant.) Was obtained. Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.28 (1H, d, J = 9.5 Hz), 8.23 (1H, s), 7.93 (1H, dd, J = 8.4, 2.1 Hz), 7.87 (1H, d, J = 2.2 Hz), 7.39 (1H, d, J = 9.5 Hz), 7.20 (1H, d, J = 8.5 Hz), 3.17 (4H, t, J = 4.8 Hz), 3.04 (4H , t, J = 4.8 Hz), 2.35 (3H, s).

工程７
6-クロロ-3-(3-メチル-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Step 7
6-Chloro-3- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000540
Figure JPOXMLDOC01-appb-C000540

5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程7) と同様の手法で、6-クロロ-3-(3-メチル-4-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (247 mg, 0.720 mmol) および 37% ホルムアルデヒド水溶液 (322 μL、4.32 mmol) から標記化合物 (171 mg, 69%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.27 (1H, d, J = 9.5 Hz), 8.22 (1H, s), 7.90 (1H, dd, J = 8.3, 2.0 Hz), 7.84 (1H, d, J = 1.7 Hz), 7.38 (1H, d, J = 9.5 Hz), 7.17 (1H, d, J = 8.5 Hz), 2.91 (4H, t, J = 4.5 Hz), 2.51-2.49 (4H, m), 2.33 (3H, s), 2.25 (3H, s). Synthesis of 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 7) From -chloro-3- (3-methyl-4- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (247 mg, 0.720 mmol) and 37% aqueous formaldehyde solution (322 μL, 4.32 mmol) The title compound (171 mg, 69%) was obtained. Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.27 (1H, d, J = 9.5 Hz), 8.22 (1H, s), 7.90 (1H, dd, J = 8.3, 2.0 Hz), 7.84 (1H, d, J = 1.7 Hz), 7.38 (1H, d, J = 9.5 Hz), 7.17 (1H, d, J = 8.5 Hz), 2.91 (4H, t, J = 4.5 Hz), 2.51-2.49 (4H, m), 2.33 (3H, s), 2.25 (3H, s).

工程８
3-(3-メチル-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 8
3- (3-Methyl-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000541
Figure JPOXMLDOC01-appb-C000541

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、6-クロロ-3-(3-メチル-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (171 mg, 0.500 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (94 μL, 0.550 mmol) から標記化合物 (158 mg, 95%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.16 (1H, d, J = 9.5 Hz), 8.13 (1H, s), 7.99 (1H, dd, J = 8.3, 2.2 Hz), 7.93 (1H, d, J = 2.0 Hz), 7.62 (1H, d, J = 9.5 Hz), 7.15 (1H, d, J = 8.3 Hz), 6.90 (1H, dd, J = 17.8, 11.0 Hz), 6.36 (1H, d, J = 17.8 Hz), 5.77 (1H, d, J = 11.2 Hz), 2.91 (4H, t, J = 4.9 Hz), 2.51-2.49 (4H, m), 2.33 (3H, s), 2.25 (3H, s). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) 6-chloro-3- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (171 mg, 0.500 mmol) and 4,4,5,5- The title compound (158 mg, 95%) was obtained from tetramethyl-2-vinyl-1,3,2-dioxaborolane (94 μL, 0.550 mmol). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.16 (1H, d, J = 9.5 Hz), 8.13 (1H, s), 7.99 (1H, dd, J = 8.3, 2.2 Hz), 7.93 ( 1H, d, J = 2.0 Hz), 7.62 (1H, d, J = 9.5 Hz), 7.15 (1H, d, J = 8.3 Hz), 6.90 (1H, dd, J = 17.8, 11.0 Hz), 6.36 ( 1H, d, J = 17.8 Hz), 5.77 (1H, d, J = 11.2 Hz), 2.91 (4H, t, J = 4.9 Hz), 2.51-2.49 (4H, m), 2.33 (3H, s), 2.25 (3H, s).

工程９
3-(3-メチル-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Step 9
3- (3-Methyl-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000542
Figure JPOXMLDOC01-appb-C000542

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-メチル-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (158 mg, 0.474 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (119 μL, 9.48 μmol) から標記化合物 (73 mg, 46%) を得た。橙色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.7 Hz), 8.39 (1H, s), 8.35 (1H, dd, J =9.3, 0.7 Hz), 8.06 (1H, dd, J =8.2, 2.1 Hz), 7.99 (1H, d, J =2.0 Hz), 7.63 (1H, d, J = 9.3 Hz), 7.18 (1H, d, J = 8.5 Hz), 2.92 (4H, t, J = 4.3 Hz), 2.52-2.49 (4H, m), 2.35 (3H, s), 2.26 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (158 mg, 0.474 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol ( The title compound (73 mg, 46%) was obtained from 119 μL, 9.48 μmol). Orange amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.7 Hz), 8.39 (1H, s), 8.35 (1H, dd, J = 9.3, 0.7 Hz), 8.06 (1H, dd, J = 8.2, 2.1 Hz), 7.99 (1H, d, J = 2.0 Hz), 7.63 (1H, d, J = 9.3 Hz), 7.18 (1H, d, J = 8.5 Hz), 2.92 (4H, t, J = 4.3 Hz), 2.52-2.49 (4H, m), 2.35 (3H, s), 2.26 (3H, s).

工程１０
5-((3-(3-メチル-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１３３)  Step 10
5-((3- (3-Methyl-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 133)

Figure JPOXMLDOC01-appb-C000543
Figure JPOXMLDOC01-appb-C000543

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-メチル-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (73 mg, 0.218 mmol) およびチアゾリジン-2,4-ジオン (25 mg, 0.218 mmol) から標記化合物 (51 mg, 54%) を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 8.23 (1H, d, J = 9.3 Hz), 8.18 (1H, s), 8.12 (1H, d, J = 2.0 Hz), 7.84 (1H, dd, J = 8.3, 2.0 Hz), 7.67 (1H, s), 7.60 (1H, d, J = 9.3 Hz), 7.17 (1H, d, J = 8.3 Hz), 3.03 (4H, s), 2.90 (4H, s), 2.54 (3H, s), 2.39 (3H, s).
ESI-MS(m/z): 435[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (73 mg, 0.218 mmol) and thiazolidine-2,4-dione (25 mg, 0.218 mmol) gave the title compound (51 mg, 54%). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 8.23 (1H, d, J = 9.3 Hz), 8.18 (1H, s), 8.12 (1H, d, J = 2.0 Hz), 7.84 (1H, dd, J = 8.3, 2.0 Hz), 7.67 (1H, s), 7.60 (1H, d, J = 9.3 Hz), 7.17 (1H, d, J = 8.3 Hz), 3.03 (4H, s), 2.90 ( 4H, s), 2.54 (3H, s), 2.39 (3H, s).
ESI-MS (m / z): 435 [M + H] + .

実施例１３４
5-((3-(3-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１３４) Example 134
5-((3- (3- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 134)

工程１
1-(3-ブロモフェニル)ピペラジン塩酸塩 Process 1
1- (3-Bromophenyl) piperazine hydrochloride

Figure JPOXMLDOC01-appb-C000544
Figure JPOXMLDOC01-appb-C000544

アルゴン雰囲気下、3-ブロモアニリン (2.0 g, 11.63 mmol) をn-ブタノール (25 mL) に溶解した。そこへビス(2-クロロエチル)アミン塩酸塩(2.08 g, 11.63 mmol)、炭酸ナトリウム (1.23 g, 11.63 mmol) を加え、24時間加熱還流した。反応液を室温まで冷却し、生じた析出物をろ取した。得られた固体に水を加え、クロロホルムで抽出した。クロロホルム層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をジエチルエーテル (10 mL) に懸濁し、4 M 塩酸 酢酸エチル溶液 (2.9 mL) を加え、生じた析出物をろ取、真空乾燥して標記化合物 (1.63 g, 50%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 9.27 (2H, s), 7.20 (1H, t, J = 8.2 Hz), 7.17-7.15 (1H, m), 7.01-6.97 (2H, m), 3.41 (4H, t, J =5.3 Hz), 3.18 (4H, s). Under an argon atmosphere, 3-bromoaniline (2.0 g, 11.63 mmol) was dissolved in n-butanol (25 mL). Bis (2-chloroethyl) amine hydrochloride (2.08 g, 11.63 mmol) and sodium carbonate (1.23 g, 11.63 mmol) were added thereto, and the mixture was heated to reflux for 24 hours. The reaction solution was cooled to room temperature, and the resulting precipitate was collected by filtration. Water was added to the obtained solid and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was suspended in diethyl ether (10 mL), 4 M hydrochloric acid ethyl acetate solution (2.9 mL) was added, and the resulting precipitate was collected by filtration and dried in vacuo to give the title compound (1.63 g, 50%). Obtained. White solid: 1 H-NMR (DMSO-D 6 ) δ: 9.27 (2H, s), 7.20 (1H, t, J = 8.2 Hz), 7.17-7.15 (1H, m), 7.01-6.97 (2H, m ), 3.41 (4H, t, J = 5.3 Hz), 3.18 (4H, s).

工程２
tert-ブチル 4-(3-ブロモフェニル)ピペラジン-1-カルボキシレート Process 2
tert-butyl 4- (3-bromophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000545
Figure JPOXMLDOC01-appb-C000545

アルゴン雰囲気下, 1-(3-ブロモフェニル)ピペラジン塩酸塩 (1.63 g, 5.85 mmol) をジクロロメタン (40 mL) に懸濁し、0℃に冷却した。そこへトリエチルアミン (2.39 mL, 17.6 mmol) を加えた。さらに二炭酸ジ-tert-ブチル (1.40 g, 6.44 mmol) のジクロロメタン溶液 (20 mL) を滴下し、0℃で10分撹拌後、室温で20時間撹拌した。反応液を1規定塩酸、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.72 g, 86%) を得た。透明オイル: 1H-NMR (DMSO-D6) δ: 7.17-7.14 (1H, m), 7.09 (1H, s), 6.94 (2H, d, J = 7.7 Hz), 3.43 (4H, t, J = 4.7 Hz), 3.13 (4H, t, J = 5.0 Hz), 1.42 (9H, s). Under an argon atmosphere, 1- (3-bromophenyl) piperazine hydrochloride (1.63 g, 5.85 mmol) was suspended in dichloromethane (40 mL) and cooled to 0 ° C. Triethylamine (2.39 mL, 17.6 mmol) was added there. Further, a dichloromethane solution (20 mL) of di-tert-butyl dicarbonate (1.40 g, 6.44 mmol) was added dropwise thereto, followed by stirring at 0 ° C. for 10 minutes and then at room temperature for 20 hours. The reaction mixture was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.72 g, 86%). Clear oil: 1 H-NMR (DMSO-D 6 ) δ: 7.17-7.14 (1H, m), 7.09 (1H, s), 6.94 (2H, d, J = 7.7 Hz), 3.43 (4H, t, J = 4.7 Hz), 3.13 (4H, t, J = 5.0 Hz), 1.42 (9H, s).

工程３
tert-ブチル 4-(3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレート Process 3
tert-Butyl 4- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000546
Figure JPOXMLDOC01-appb-C000546

tert-ブチル 4-(3-フルオロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例85、工程4) と同様の手法で、tert-ブチル 4-(3-ブロモフェニル)ピペラジン-1-カルボキシレート(480 mg, 1.41 mmol) およびビス(ピナコラート)ジボロン (430 mg, 1.55 mmol) から標記化合物 (439 mg, 80%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 7.25 (1H, t, J = 7.7 Hz), 7.19 (1H, d, J = 2.4 Hz), 7.14 (1H, d, J = 7.1 Hz), 7.09 (1H, dd, J = 7.6, 2.4 Hz), 3.45 (4H, t, J = 4.9 Hz), 3.07 (4H, t, J = 5.2 Hz), 1.42 (9H, s), 1.28 (12H, s). Synthesis of tert-butyl 4- (3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (Example 85) In the same manner as in Step 4), the title compound was obtained from tert-butyl 4- (3-bromophenyl) piperazine-1-carboxylate (480 mg, 1.41 mmol) and bis (pinacolato) diboron (430 mg, 1.55 mmol). (439 mg, 80%) was obtained. White solid: 1 H-NMR (DMSO-D 6 ) δ: 7.25 (1H, t, J = 7.7 Hz), 7.19 (1H, d, J = 2.4 Hz), 7.14 (1H, d, J = 7.1 Hz) , 7.09 (1H, dd, J = 7.6, 2.4 Hz), 3.45 (4H, t, J = 4.9 Hz), 3.07 (4H, t, J = 5.2 Hz), 1.42 (9H, s), 1.28 (12H, s).

工程４
tert-ブチル 4-(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-カルボキシレート Process 4
tert-butyl 4- (3- (6-chloroimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000547
Figure JPOXMLDOC01-appb-C000547

3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-カルボニトリルの合成 (実施例106、工程6) と同様の手法で、3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (239 mg, 1.03 mmol) およびtert-ブチル 4-(3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレート (439 mg, 1.13 mmol) から標記化合物 (259 mg, 61%) を得た。黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.32 (1H, s), 8.29 (1H, d, J = 9.5 Hz), 7.61 (1H, s), 7.56 (1H, d, J = 7.6 Hz), 7.41 (1H, d, J = 9.5 Hz), 7.40 (1H, t, J =7.9 Hz), 7.03 (1H, dd, J = 8.4, 2.3 Hz), 3.50 (4H, t, J = 4.9 Hz), 3.20 (4H, t, J = 5.2 Hz), 1.43 (9H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridine-5-carbonitrile (Example 106, Step 6) -6-Chloroimidazo [1,2-b] pyridazine (239 mg, 1.03 mmol) and tert-butyl 4- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 The title compound (259 mg, 61%) was obtained from -yl) phenyl) piperazine-1-carboxylate (439 mg, 1.13 mmol). Yellow amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.32 (1H, s), 8.29 (1H, d, J = 9.5 Hz), 7.61 (1H, s), 7.56 (1H, d, J = 7.6 Hz), 7.41 (1H, d, J = 9.5 Hz), 7.40 (1H, t, J = 7.9 Hz), 7.03 (1H, dd, J = 8.4, 2.3 Hz), 3.50 (4H, t, J = 4.9 Hz), 3.20 (4H, t, J = 5.2 Hz), 1.43 (9H, s).

工程５
6-クロロ-3-(3-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Process 5
6-Chloro-3- (3- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000548
Figure JPOXMLDOC01-appb-C000548

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程6) と同様の手法で、tert-ブチル 4-(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-カルボキシレート(259 mg, 0.626 mmol) およびトリフルオロ酢酸 (1 mL) から標記化合物 (115 mg, 59%) を得た。黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.31 (1H, s), 8.29 (1H, d, J = 9.5 Hz), 7.60 (1H, s), 7.51 (1H, d, J = 7.8 Hz), 7.41 (1H, d, J = 9.5 Hz), 7.37 (1H, t, J =7.9 Hz), 7.00 (1H, dd, J = 8.4, 2.3 Hz), 3.15 (4H, t, J = 5.0 Hz), 2.88 (4H, t, J = 4.9 Hz). Synthesis of 5-bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 6) The title compound (115) was prepared from-(3- (6-chloroimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazine-1-carboxylate (259 mg, 0.626 mmol) and trifluoroacetic acid (1 mL). mg, 59%). Yellow amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.31 (1H, s), 8.29 (1H, d, J = 9.5 Hz), 7.60 (1H, s), 7.51 (1H, d, J = 7.8 Hz), 7.41 (1H, d, J = 9.5 Hz), 7.37 (1H, t, J = 7.9 Hz), 7.00 (1H, dd, J = 8.4, 2.3 Hz), 3.15 (4H, t, J = 5.0 Hz), 2.88 (4H, t, J = 4.9 Hz).

工程６
6-クロロ-3-(3-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Step 6
6-Chloro-3- (3- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000549
Figure JPOXMLDOC01-appb-C000549

5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程7) と同様の手法で、6-クロロ-3-(3-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (115 mg, 0.360 mmol) および 37% ホルムアルデヒド水溶液 (164 μL、2.16 mmol) から標記化合物 (90 mg, 76%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.32 (1H, s), 8.29 (1H, d, J = 9.5 Hz), 7.61 (1H, s), 7.52 (1H, d, J = 7.6 Hz), 7.41 (1H, d, J = 9.5 Hz), 7.37 (1H, t, J =8.1 Hz), 7.01 (1H, dd, J = 8.3, 2.4 Hz), 3.23 (4H, t, J = 5.0 Hz), 2.50-2.47 (4H, m), 2.24 (3H, s). Synthesis of 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 7) The title compound from 90-chloro-3- (3- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (115 mg, 0.360 mmol) and 37% aqueous formaldehyde (164 μL, 2.16 mmol) (90 mg, 76%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.32 (1H, s), 8.29 (1H, d, J = 9.5 Hz), 7.61 (1H, s), 7.52 (1H, d, J = 7.6 Hz), 7.41 (1H, d, J = 9.5 Hz), 7.37 (1H, t, J = 8.1 Hz), 7.01 (1H, dd, J = 8.3, 2.4 Hz), 3.23 (4H, t, J = 5.0 Hz), 2.50-2.47 (4H, m), 2.24 (3H, s).

工程７
3-(3-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Step 7
3- (3- (4-Methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000550
Figure JPOXMLDOC01-appb-C000550

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、6-クロロ-3-(3-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (90 mg, 0.275 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (52 μL, 0.303 mmol) から標記化合物 (68 mg, 77%) を得た。黄色油状物質: 1H-NMR (DMSO-D6) δ: 8.24 (1H, s), 8.18 (1H, d, J = 9.3 Hz), 7.77 (1H, t, J = 2.0 Hz), 7.64 (1H, d, J = 9.5 Hz), 7.57 (1H, d, J = 7.8 Hz), 7.35 (1H, t, J = 7.9 Hz), 6.98 (1H, dd, J = 8.2, 2.3 Hz), 6.90 (1H, dd, J = 17.8, 11.2 Hz), 6.37 (1H, d, J = 17.8 Hz), 5.77 (1H, d, J = 11.2 Hz), 3.23 (4H, t, J = 4.9 Hz), 2.52-2.48 (4H, m), 2.24 (3H, s). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) 6-chloro-3- (3- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (90 mg, 0.275 mmol) and 4,4,5,5-tetramethyl-2 The title compound (68 mg, 77%) was obtained from -vinyl-1,3,2-dioxaborolane (52 μL, 0.303 mmol). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.24 (1H, s), 8.18 (1H, d, J = 9.3 Hz), 7.77 (1H, t, J = 2.0 Hz), 7.64 (1H , d, J = 9.5 Hz), 7.57 (1H, d, J = 7.8 Hz), 7.35 (1H, t, J = 7.9 Hz), 6.98 (1H, dd, J = 8.2, 2.3 Hz), 6.90 (1H , dd, J = 17.8, 11.2 Hz), 6.37 (1H, d, J = 17.8 Hz), 5.77 (1H, d, J = 11.2 Hz), 3.23 (4H, t, J = 4.9 Hz), 2.52-2.48 (4H, m), 2.24 (3H, s).

工程８
3-(3-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 8
3- (3- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000551
Figure JPOXMLDOC01-appb-C000551

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (68 mg, 0.213 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (53 μL, 4.26 μmol) から標記化合物 (15 mg, 22%) を得た。黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.7 Hz), 8.48 (1H, s), 8.37 (1H, d, J = 9.3 Hz), 7.79 (1H, s), 7.66 (1H, d, J = 9.3 Hz), 7.63 (1H, d, J = 7.8 Hz), 7.39 (1H, t, J = 8.1 Hz), 7.03 (1H, dd, J = 8.2, 2.3 Hz), 3.25 (4H, t, J = 5.0 Hz), 2.51-2.48 (4H, m), 2.24 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3- (4-Methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (68 mg, 0.213 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol (53 μL, 4.26 μmol) gave the title compound (15 mg, 22%). Yellow amorphous substance: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.7 Hz), 8.48 (1H, s), 8.37 (1H, d, J = 9.3 Hz), 7.79 ( 1H, s), 7.66 (1H, d, J = 9.3 Hz), 7.63 (1H, d, J = 7.8 Hz), 7.39 (1H, t, J = 8.1 Hz), 7.03 (1H, dd, J = 8.2 , 2.3 Hz), 3.25 (4H, t, J = 5.0 Hz), 2.51-2.48 (4H, m), 2.24 (3H, s).

工程９
5-((3-(3-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１３４) Step 9
5-((3- (3- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 134)

Figure JPOXMLDOC01-appb-C000552
Figure JPOXMLDOC01-appb-C000552

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (15 mg, 0.0467 mmol) およびチアゾリジン-2,4-ジオン (5 mg, 0.0467 mmol) から標記化合物 (11 mg, 58%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.24 (1H, d, J = 9.3 Hz), 8.21 (1H, s), 7.71 (1H, s), 7.68 (1H, s), 7.62 (1H, d, J =9.5 Hz), 7.51 (1H, d, J = 7.8 Hz), 7.39 (1H, t, J = 8.1 Hz), 7.03 (1H, dd, J = 8.2, 1.8 Hz), 3.33 (4H, s), 2.86 (4H, s), 2.50 (3H, s).
ESI-MS(m/z): 421[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (15 mg, 0.0467 mmol) and thiazolidine The title compound (11 mg, 58%) was obtained from -2,4-dione (5 mg, 0.0467 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.24 (1H, d, J = 9.3 Hz), 8.21 (1H, s), 7.71 (1H, s), 7.68 (1H, s), 7.62 ( 1H, d, J = 9.5 Hz), 7.51 (1H, d, J = 7.8 Hz), 7.39 (1H, t, J = 8.1 Hz), 7.03 (1H, dd, J = 8.2, 1.8 Hz), 3.33 ( 4H, s), 2.86 (4H, s), 2.50 (3H, s).
ESI-MS (m / z): 421 [M + H] + .

実施例１３５
5-((3-(3-(2-モルホリノエチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１３５) Example 135
5-((3- (3- (2-morpholinoethyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 135)

工程１
3-ブロモフェネチルアセテート Process 1
3-Bromophenethyl acetate

Figure JPOXMLDOC01-appb-C000553
Figure JPOXMLDOC01-appb-C000553

アルゴン雰囲気下、1-(3-ブロモフェニル)エチルアルコール (1.0 g, 4.97 mmol) をジクロロメタン (25 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (711 μL, 5.22 mmol) を加えた。さらにアセチルクロリド (707 μL, 9.94 mmol) を滴下し、0℃で10分撹拌後、室温で1時間撹拌した。反応混合物を1規定塩酸、水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去、真空乾燥して表題化合物 (1.20 g, 99%) を得た。透明オイル: 1H-NMR (CDCl3) δ: 7.38-7.36 (2H, m), 7.20-7.13 (2H, m), 4.27 (2H, t, J = 7.0 Hz), 2.91 (2H, t, J = 7.0 Hz), 2.04 (3H, s). Under an argon atmosphere, 1- (3-bromophenyl) ethyl alcohol (1.0 g, 4.97 mmol) was dissolved in dichloromethane (25 mL) and cooled to 0 ° C. Triethylamine (711 μL, 5.22 mmol) was added thereto. Further, acetyl chloride (707 μL, 9.94 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 1 hour. The reaction mixture was washed with 1N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, evaporated and evaporated in vacuo to give the title compound (1.20 g, 99%). Clear oil: 1 H-NMR (CDCl 3 ) δ: 7.38-7.36 (2H, m), 7.20-7.13 (2H, m), 4.27 (2H, t, J = 7.0 Hz), 2.91 (2H, t, J = 7.0 Hz), 2.04 (3H, s).

工程２
3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェネチルアセテート Process 2
3- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) phenethyl acetate

Figure JPOXMLDOC01-appb-C000554
Figure JPOXMLDOC01-appb-C000554

アルゴン雰囲気下、6-クロロイミダゾ[1,2-b]ピリダジン (581 mg, 3.78 mmol)、3-ブロモフェネチルアセテート (1.20 g, 4.92 mmol) をトルエン (20 mL) に溶解した。そこへ酢酸パラジウム (85 mg, 0.378 mmol)、トリフェニルホスフィン (198 mg, 0.756 mmol)、炭酸カリウム (1.04 g, 7.56 mmol) を加え、反応容器内を脱気し、アルゴン置換した。この操作を3回繰り返した後、110 ℃で19時間撹拌した。反応液に水を加え、クロロホルムで抽出した。クロロホルム層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (521 mg, 44%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.31 (1H, s), 8.30 (1H, d, J = 9.5 Hz), 8.00-7.95 (2H, m), 7.49 (1H, t, J = 7.7 Hz), 7.43 (1H, d, J = 9.5 Hz), 7.33 (1H, d, J =7.6 Hz), 4.29 (2H, t, J = 6.7 Hz), 2.98 (2H, t, J = 6.8 Hz), 2.00 (3H, s). Under an argon atmosphere, 6-chloroimidazo [1,2-b] pyridazine (581 mg, 3.78 mmol) and 3-bromophenethyl acetate (1.20 g, 4.92 mmol) were dissolved in toluene (20 mL). Palladium acetate (85 mg, 0.378 mmol), triphenylphosphine (198 mg, 0.756 mmol) and potassium carbonate (1.04 g, 7.56 mmol) were added thereto, and the inside of the reaction vessel was deaerated and purged with argon. This operation was repeated 3 times, followed by stirring at 110 ° C. for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (521 mg, 44%). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.31 (1H, s), 8.30 (1H, d, J = 9.5 Hz), 8.00-7.95 (2H, m), 7.49 (1H, t, J = 7.7 Hz), 7.43 (1H, d, J = 9.5 Hz), 7.33 (1H, d, J = 7.6 Hz), 4.29 (2H, t, J = 6.7 Hz), 2.98 (2H, t, J = 6.8 Hz), 2.00 (3H, s).

工程３
2-(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)エタノール Process 3
2- (3- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) phenyl) ethanol

Figure JPOXMLDOC01-appb-C000555
Figure JPOXMLDOC01-appb-C000555

アルゴン雰囲気下、3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェネチルアセテート(521 mg, 1.65 mmol) をメタノール (8 mL) に懸濁し、0℃に冷却した。そこへ 5 M ナトリウムメトキシド メタノール溶液 (330 μL, 1.65 mmol) を加え、0℃で1時間撹拌した。反応液に飽和食塩水を加え、クロロホルムで抽出した。クロロホルム層を無水硫酸マグネシウムで乾燥させ、溶媒を留去、真空乾燥して標記化合物 (461 mg, quant.) を得た。薄黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.31 (1H, d, J = 9.5 Hz), 8.30 (1H, s), 7.94 (1H, d, J =8.1 Hz), 7.91 (1H, s), 7.46 (1H, t, J = 7.6 Hz), 7.43 (1H, d, J =9.5 Hz), 7.29 (1H, d, J = 7.6 Hz), 3.67 (2H, t, J = 7.1 Hz), 2.82 (2H, t, J = 7.1 Hz). Under an argon atmosphere, 3- (6-chloroimidazo [1,2-b] pyridazin-3-yl) phenethyl acetate (521 mg, 1.65 mmol) was suspended in methanol (8 mL) and cooled to 0 ° C. 5 M sodium methoxide methanol solution (330 μL, 1.65 mmol) was added thereto, and the mixture was stirred at 0 ° C. for 1 hour. Saturated saline was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was dried under vacuum to obtain the title compound (461 mg, quant.). Pale yellow amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.31 (1H, d, J = 9.5 Hz), 8.30 (1H, s), 7.94 (1H, d, J = 8.1 Hz), 7.91 (1H, s), 7.46 (1H, t, J = 7.6 Hz), 7.43 (1H, d, J = 9.5 Hz), 7.29 (1H, d, J = 7.6 Hz), 3.67 (2H, t, J = 7.1 Hz), 2.82 (2H, t, J = 7.1 Hz).

工程４
2-(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)アセトアルデヒド Process 4
2- (3- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) phenyl) acetaldehyde

Figure JPOXMLDOC01-appb-C000556
Figure JPOXMLDOC01-appb-C000556

アルゴン雰囲気下、2-(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)エタノール (461 mg, 1.65 mmol) をジクロロメタン (8 mL) に懸濁し、0℃に冷却した。そこへデス・マーチン・ペルヨージナン (840 mg, 1.98 mmol) を加え、0℃で10分撹拌後、室温で30分撹拌した。反応液に飽和重層水、飽和チオ硫酸ナトリウム水溶液を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (301 mg, 67%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 9.76 (1H, t, J = 1.8 Hz), 8.31 (1H, d, J = 9.5 Hz), 8.30 (1H, s), 8.04 (1H, d, J =7.8 Hz), 7.93 (1H, s), 7.54 (1H, t, J = 7.7 Hz), 7.44 (1H, d, J =9.5 Hz), 7.31 (1H, d, J = 7.8 Hz), 3.89 (2H, d, J = 1.7 Hz). Under an argon atmosphere, 2- (3- (6-chloroimidazo [1,2-b] pyridazin-3-yl) phenyl) ethanol (461 mg, 1.65 mmol) was suspended in dichloromethane (8 mL) and brought to 0 ° C. Cooled down. Dess-Martin periodinane (840 mg, 1.98 mmol) was added thereto, followed by stirring at 0 ° C. for 10 minutes and then at room temperature for 30 minutes. Saturated multistory water and saturated sodium thiosulfate aqueous solution were added to the reaction liquid, and chloroform extracted. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (301 mg, 67%). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 9.76 (1H, t, J = 1.8 Hz), 8.31 (1H, d, J = 9.5 Hz), 8.30 (1H, s), 8.04 (1H, d, J = 7.8 Hz), 7.93 (1H, s), 7.54 (1H, t, J = 7.7 Hz), 7.44 (1H, d, J = 9.5 Hz), 7.31 (1H, d, J = 7.8 Hz) , 3.89 (2H, d, J = 1.7 Hz).

工程５
4-(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェネチル)モルホリン Process 5
4- (3- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) phenethyl) morpholine

Figure JPOXMLDOC01-appb-C000557
Figure JPOXMLDOC01-appb-C000557

6-ブロモ-3-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジンの合成 (実施例53、工程2) と同様の手法で、2-(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)アセトアルデヒド (301 mg, 1.11 mmol) およびモルホリン (194 μL, 2.22 mmol) から標記化合物 (350 mg, 92%)を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.32-8.29 (2H, m), 7.96-7.93 (2H, m), 7.48-7.41 (2H, m), 7.30 (1H, d, J = 7.8 Hz), 3.58 (4H, t, J = 4.6 Hz), 2.83 (2H, t, J = 7.8 Hz), 2.58 (2H, t, J = 7.7 Hz), 2.45 (4H, s). Synthesis of 6-bromo-3- (4-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine (Example 53, Step 2) -(3- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) phenyl) acetaldehyde (301 mg, 1.11 mmol) and morpholine (194 μL, 2.22 mmol) to the title compound (350 mg, 92% ) Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.32-8.29 (2H, m), 7.96-7.93 (2H, m), 7.48-7.41 (2H, m), 7.30 (1H, d, J = 7.8 Hz), 3.58 (4H, t, J = 4.6 Hz), 2.83 (2H, t, J = 7.8 Hz), 2.58 (2H, t, J = 7.7 Hz), 2.45 (4H, s).

工程６
4-(3-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)フェネチル)モルホリン Step 6
4- (3- (6-vinylimidazo [1,2-b] pyridazin-3-yl) phenethyl) morpholine

Figure JPOXMLDOC01-appb-C000558
Figure JPOXMLDOC01-appb-C000558

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、4-(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェネチル)モルホリン (350 mg, 1.02 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (192 μL, 1.12 mmol) から標記化合物 (269 mg, 79%) を得た。黄色油状物質: 1H-NMR (DMSO-D6) δ: 8.22 (1H, s), 8.19 (1H, d, J = 9.5 Hz), 8.04 (1H, s), 8.01 (1H, d, J = 7.8 Hz), 7.66 (1H, d, J = 9.5 Hz), 7.43 (1H, t, J =7.7 Hz), 7.26 (1H, d, J = 7.6 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.38 (1H, d, J = 17.6 Hz), 5.78 (1H, d, J = 11.0 Hz), 3.58 (4H, t, J = 4.6 Hz), 2.83 (2H, t, J = 7.8 Hz), 2.59 (2H, t, J = 7.8 Hz), 2.45 (4H, s). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) 4- (3- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) phenethyl) morpholine (350 mg, 1.02 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1 The title compound (269 mg, 79%) was obtained from 1,3,2-dioxaborolane (192 μL, 1.12 mmol). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.22 (1H, s), 8.19 (1H, d, J = 9.5 Hz), 8.04 (1H, s), 8.01 (1H, d, J = 7.8 Hz), 7.66 (1H, d, J = 9.5 Hz), 7.43 (1H, t, J = 7.7 Hz), 7.26 (1H, d, J = 7.6 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.38 (1H, d, J = 17.6 Hz), 5.78 (1H, d, J = 11.0 Hz), 3.58 (4H, t, J = 4.6 Hz), 2.83 (2H, t, J = 7.8 Hz ), 2.59 (2H, t, J = 7.8 Hz), 2.45 (4H, s).

工程７
3-(3-(2-モルホリノエチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Step 7
3- (3- (2-morpholinoethyl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000559
Figure JPOXMLDOC01-appb-C000559

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、4-(3-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)フェネチル)モルホリン (269 mg, 0.804 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (202 μL, 16.1 μmol) から標記化合物 (177 mg, 65%) を得た。黄色油状物質: 1H-NMR (DMSO-D6) δ: 10.1 (1H, d, J = 0.7 Hz), 8.47 (1H, s), 8.38 (1H, dd, J = 9.5, 0.7 Hz), 8.10-8.07 (2H, m), 7.67 (1H, d, J = 9.3 Hz), 7.48 (1H, t, J = 8.1 Hz), 7.32 (1H, d, J = 7.8 Hz), 3.59 (4H, t, J = 4.6 Hz), 2.86 (2H, t, J = 7.8 Hz), 2.60 (2H, t, J = 7.8 Hz), 2.46 (4H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) Title from 3- (6-vinylimidazo [1,2-b] pyridazin-3-yl) phenethyl) morpholine (269 mg, 0.804 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol (202 μL, 16.1 μmol) The compound (177 mg, 65%) was obtained. Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, d, J = 0.7 Hz), 8.47 (1H, s), 8.38 (1H, dd, J = 9.5, 0.7 Hz), 8.10 -8.07 (2H, m), 7.67 (1H, d, J = 9.3 Hz), 7.48 (1H, t, J = 8.1 Hz), 7.32 (1H, d, J = 7.8 Hz), 3.59 (4H, t, J = 4.6 Hz), 2.86 (2H, t, J = 7.8 Hz), 2.60 (2H, t, J = 7.8 Hz), 2.46 (4H, s).

工程８
5-((3-(3-(2-モルホリノエチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１３５)  Process 8
5-((3- (3- (2-morpholinoethyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 135)

Figure JPOXMLDOC01-appb-C000560
Figure JPOXMLDOC01-appb-C000560

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-(2-モルホリノエチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (88 mg, 0.262 mmol) およびロダニン (35 mg, 0.262 mmol) から標記化合物 (95 mg, 80%) を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 8.27 (1H, d, J = 9.3 Hz), 8.25 (1H, s), 8.19 (1H, s), 7.89 (1H, d, J = 7.8 Hz), 7.68 (1H, d, J = 9.5 Hz), 7.53-7.49 (2H, m), 7.39 (1H, d, J =7.8 Hz), 3.73 (4H, s), 3.19-3.09 (4H, m), 3.00 (4H, s).
ESI-MS(m/z): 452[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3- (2-morpholinoethyl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (88 mg, 0.262 mmol) and rhodanine (35 mg, The title compound (95 mg, 80%) was obtained from 0.262 mmol). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 8.27 (1H, d, J = 9.3 Hz), 8.25 (1H, s), 8.19 (1H, s), 7.89 (1H, d, J = 7.8 Hz), 7.68 (1H, d, J = 9.5 Hz), 7.53-7.49 (2H, m), 7.39 (1H, d, J = 7.8 Hz), 3.73 (4H, s), 3.19-3.09 (4H, m ), 3.00 (4H, s).
ESI-MS (m / z): 452 [M + H] + .

実施例１３６
5-((3-(3-(2-モルホリノエチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１３６) Example 136
5-((3- (3- (2-morpholinoethyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 136)

Figure JPOXMLDOC01-appb-C000561
Figure JPOXMLDOC01-appb-C000561

工程１
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-(2-モルホリノエチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (89 mg, 0.265 mmol) およびチアゾリジン-2,4-ジオン (31 mg, 0.265 mmol) から標記化合物 (55 mg, 48%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.30 (1H, d, J = 9.3 Hz), 8.24 (1H, s), 8.05 (1H, s), 7.86 (1H, d, J = 7.8 Hz), 7.83 (1H, s), 7.69 (1H, d, J = 9.5 Hz), 7.48 (1H, t, J = 7.7 Hz), 7.35 (1H, d, J =7.8 Hz), 3.63 (4H, t, J = 4.5 Hz), 2.93 (2H, t, J = 7.9 Hz), 2.79 (2H, t, J = 7.8 Hz), 2.63 (4H, s).
ESI-MS(m/z): 436[M+H]+. Process 1
Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3- (2-morpholinoethyl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (89 mg, 0.265 mmol) and thiazolidine-2,4 -The title compound (55 mg, 48%) was obtained from -dione (31 mg, 0.265 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.30 (1H, d, J = 9.3 Hz), 8.24 (1H, s), 8.05 (1H, s), 7.86 (1H, d, J = 7.8 Hz), 7.83 (1H, s), 7.69 (1H, d, J = 9.5 Hz), 7.48 (1H, t, J = 7.7 Hz), 7.35 (1H, d, J = 7.8 Hz), 3.63 (4H, t, J = 4.5 Hz), 2.93 (2H, t, J = 7.9 Hz), 2.79 (2H, t, J = 7.8 Hz), 2.63 (4H, s).
ESI-MS (m / z): 436 [M + H] + .

実施例１３７
5-((3-(4-(4-メチルピペラジン-1-イル)-3-(トリフルオロメチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１３７) Example 137
5-((3- (4- (4-Methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4 -Dione (Compound 137)

工程１
tert-ブチル 4-(4-ニトロ-2-(トリフルオロメチル)フェニル)ピペラジン-1-カルボキシレート Process 1
tert-butyl 4- (4-nitro-2- (trifluoromethyl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000562
Figure JPOXMLDOC01-appb-C000562

アルゴン雰囲気下、2-フルオロ-5-ニトロベンゾトリフルオリド (1.0 g, 4.78 mmol) をN,N-ジメチルホルムアミド (20 mL) に溶解した。そこへ1-(tert-ブトキシカルボニル)ピペラジン (1.78 g, 9.56 mmol)、炭酸カリウム (2.64 g, 19.1 mmol) を加え、70℃で3時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。酢酸エチル層を1規定塩酸、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、表題化合物 (1.27 g, 71%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.45-8.40 (2H, m), 7.62 (1H, d, J = 9.0 Hz), 3.47 (4H, s), 3.06 (4H, t, J = 4.9 Hz), 1.43 (9H, s). Under an argon atmosphere, 2-fluoro-5-nitrobenzotrifluoride (1.0 g, 4.78 mmol) was dissolved in N, N-dimethylformamide (20 mL). 1- (tert-butoxycarbonyl) piperazine (1.78 g, 9.56 mmol) and potassium carbonate (2.64 g, 19.1 mmol) were added thereto, and the mixture was stirred at 70 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.27 g, 71%). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.45-8.40 (2H, m), 7.62 (1H, d, J = 9.0 Hz), 3.47 (4H, s), 3.06 (4H, t, J = 4.9 Hz), 1.43 (9H, s).

工程２
tert-ブチル 4-(4-アミノ-2-(トリフルオロメチル)フェニル)ピペラジン-1-カルボキシレート Process 2
tert-butyl 4- (4-amino-2- (trifluoromethyl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000563
Figure JPOXMLDOC01-appb-C000563

tert-ブチル 4-(4-アミノ-2-メチルフェニル)ピペラジン-1-カルボキシレートの合成 (実施例133、工程2) と同様の手法で、tert-ブチル 4-(4-ニトロ-2-(トリフルオロメチル)フェニル)ピペラジン-1-カルボキシレート (1.27 g, 3.39 mmol) から標記化合物 (1.14 g, 97%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 7.23 (1H, d, J = 8.5 Hz), 6.81 (1H, d, J = 2.7 Hz), 6.75 (1H, dd, J = 8.5, 2.7 Hz), 5.38 (2H, s), 3.37 (4H, s), 2.66 (4H, t, J = 4.9 Hz), 1.41 (9H, s). Synthesis of tert-butyl 4- (4-amino-2-methylphenyl) piperazine-1-carboxylate (Example 133, Step 2) The title compound (1.14 g, 97%) was obtained from (trifluoromethyl) phenyl) piperazine-1-carboxylate (1.27 g, 3.39 mmol). White solid: 1 H-NMR (DMSO-D 6 ) δ: 7.23 (1H, d, J = 8.5 Hz), 6.81 (1H, d, J = 2.7 Hz), 6.75 (1H, dd, J = 8.5, 2.7 Hz), 5.38 (2H, s), 3.37 (4H, s), 2.66 (4H, t, J = 4.9 Hz), 1.41 (9H, s).

工程３
tert-ブチル 4-(4-ブロモ-2-(トリフルオロメチル)フェニル)ピペラジン-1-カルボキシレート Process 3
tert-butyl 4- (4-bromo-2- (trifluoromethyl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000564
Figure JPOXMLDOC01-appb-C000564

アルゴン雰囲気下、tert-ブチル 4-(4-アミノ-2-(トリフルオロメチル)フェニル)ピペラジン-1-カルボキシレート (1.14 g, 3.29 mmol) をアセトニトリル (20 mL) に溶解し、0℃に冷却した。そこへ亜硝酸tert-ブチル (507 μL, 4.94 mmol) を滴下し、0℃で30分撹拌した。さらに臭化銅 (II) (808 mg, 3.62 mmol) を加え、0℃で10分撹拌後、室温で3時間撹拌した。反応液に飽和食塩水を加え、酢酸エチルで抽出した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (813 mg, 60%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 7.88-7.83 (2H, m), 7.54 (1H, d, J = 8.5 Hz), 3.42 (4H, s), 2.80 (4H, t, J = 4.9 Hz), 1.42 (9H, s). Under argon atmosphere, tert-butyl 4- (4-amino-2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (1.14 g, 3.29 mmol) was dissolved in acetonitrile (20 mL) and cooled to 0 ° C. did. Thereto was added dropwise tert-butyl nitrite (507 μL, 4.94 mmol), and the mixture was stirred at 0 ° C. for 30 minutes. Further, copper (II) bromide (808 mg, 3.62 mmol) was added, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 3 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (813 mg, 60%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 7.88-7.83 (2H, m), 7.54 (1H, d, J = 8.5 Hz), 3.42 (4H, s), 2.80 (4H, t, J = 4.9 Hz), 1.42 (9H, s).

工程４
tert-ブチル 4-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-2-(トリフルオロメチル)フェニル)ピペラジン-1-カルボキシレート Process 4
tert-butyl 4- (4- (6-chloroimidazo [1,2-b] pyridazin-3-yl) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000565
Figure JPOXMLDOC01-appb-C000565

3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェネチルアセテートの合成(実施例135、工程2) と同様の手法で、6-クロロイミダゾ[1,2-b]ピリダジン (235 mg, 1.53 mmol) およびtert-ブチル 4-(4-ブロモ-2-(トリフルオロメチル)フェニル)ピペラジン-1-カルボキシレート (813 mg, 1.99 mmol) から標記化合物 (340 mg, 46%) を得た。薄黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.44-8.43 (1H, m), 8.43 (1H, s), 8.36-8.32 (2H, m), 7.75 (1H, d, J = 8.5 Hz), 7.47 (1H, d, J =9.5 Hz), 3.47 (4H, s), 2.89 (4H, t, J = 4.9 Hz), 1.44 (9H, s). In the same manner as in the synthesis of 3- (6-chloroimidazo [1,2-b] pyridazin-3-yl) phenethyl acetate (Example 135, step 2), 6-chloroimidazo [1,2-b] pyridazine (235 mg, 1.53 mmol) and tert-butyl 4- (4-bromo-2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (813 mg, 1.99 mmol) to the title compound (340 mg, 46%) Got. Pale yellow amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.44-8.43 (1H, m), 8.43 (1H, s), 8.36-8.32 (2H, m), 7.75 (1H, d, J = 8.5 Hz), 7.47 (1H, d, J = 9.5 Hz), 3.47 (4H, s), 2.89 (4H, t, J = 4.9 Hz), 1.44 (9H, s).

工程５
6-クロロ-3-(4-(ピペラジン-1-イル)-3-(トリフルオロメチル)フェニル)イミダゾ[1,2-b]ピリダジン Process 5
6-Chloro-3- (4- (piperazin-1-yl) -3- (trifluoromethyl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000566
Figure JPOXMLDOC01-appb-C000566

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程6) と同様の手法で、tert-ブチル 4-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-2-(トリフルオロメチル)フェニル)ピペラジン-1-カルボキシレート (340 mg, 0.706 mmol) およびトリフルオロ酢酸 (1 mL) から標記化合物 (244 mg, 91%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.40 (2H, s), 8.33 (2H, d, J = 9.5 Hz), 7.67 (1H, d, J =8.5 Hz), 7.46 (1H, d, J = 9.5 Hz), 2.88 (8H, s). Synthesis of 5-bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 6) -(4- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (340 mg, 0.706 mmol) and trifluoroacetic acid ( The title compound (244 mg, 91%) was obtained from 1 mL). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.40 (2H, s), 8.33 (2H, d, J = 9.5 Hz), 7.67 (1H, d, J = 8.5 Hz), 7.46 (1H , d, J = 9.5 Hz), 2.88 (8H, s).

工程６
6-クロロ-3-(4-(4-メチルピペラジン-1-イル)-3-(トリフルオロメチル)フェニル)イミダゾ[1,2-b]ピリダジン Step 6
6-Chloro-3- (4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000567
Figure JPOXMLDOC01-appb-C000567

5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程7) と同様の手法で、6-クロロ-3-(4-(ピペラジン-1-イル)-3-(トリフルオロメチル)フェニル)イミダゾ[1,2-b]ピリダジン (244 mg, 0.639 mmol) および 37% ホルムアルデヒド水溶液 (285 μL、3.83 mmol) から標記化合物 (191 mg, 76%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.41-8.40 (1H, m), 8.41 (1H, d, J = 0.7 Hz), 8.34-8.31 (1H, m), 8.32 (1H, dd, J = 9.5, 0.7 Hz), 7.71 (1H, d, J = 8.8 Hz), 7.46 (1H, dd, J = 9.5, 0.7 Hz), 2.94 (4H, t, J = 4.6 Hz), 2.50-2.46 (4H, m), 2.24 (3H, s). Synthesis of 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 7) -Chloro-3- (4- (piperazin-1-yl) -3- (trifluoromethyl) phenyl) imidazo [1,2-b] pyridazine (244 mg, 0.639 mmol) and 37% aqueous formaldehyde (285 μL, The title compound (191 mg, 76%) was obtained from 3.83 mmol). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.41-8.40 (1H, m), 8.41 (1H, d, J = 0.7 Hz), 8.34-8.31 (1H, m), 8.32 (1H, dd, J = 9.5, 0.7 Hz), 7.71 (1H, d, J = 8.8 Hz), 7.46 (1H, dd, J = 9.5, 0.7 Hz), 2.94 (4H, t, J = 4.6 Hz), 2.50- 2.46 (4H, m), 2.24 (3H, s).

工程７
3-(4-(4-メチルピペラジン-1-イル)-3-(トリフルオロメチル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Step 7
3- (4- (4-Methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000568
Figure JPOXMLDOC01-appb-C000568

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、6-クロロ-3-(4-(4-メチルピペラジン-1-イル)-3-(トリフルオロメチル)フェニル)イミダゾ[1,2-b]ピリダジン(191 mg, 0.483 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (91 μL, 0.531 mmol) から標記化合物 (154 mg, 82%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.58 (1H, d, J = 2.0 Hz), 8.39 (1H, dd, J = 8.5, 2.0 Hz), 8.35 (1H, d, J = 0.7 Hz), 8.22 (1H, d, J = 9.5 Hz), 7.68 (2H, d, J = 9.5 Hz), 6.89 (1H, dd, J = 17.8, 11.0 Hz), 6.39 (1H, d, J = 17.8 Hz), 5.79 (1H, d, J = 11.0 Hz), 2.94 (4H, t, J = 4.6 Hz), 2.51-2.46 (4H, m), 2.24 (3H, s). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) 6-chloro-3- (4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) imidazo [1,2-b] pyridazine (191 mg, 0.483 mmol) and 4,4, The title compound (154 mg, 82%) was obtained from 5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (91 μL, 0.531 mmol). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.58 (1H, d, J = 2.0 Hz), 8.39 (1H, dd, J = 8.5, 2.0 Hz), 8.35 (1H, d, J = 0.7 Hz), 8.22 (1H, d, J = 9.5 Hz), 7.68 (2H, d, J = 9.5 Hz), 6.89 (1H, dd, J = 17.8, 11.0 Hz), 6.39 (1H, d, J = 17.8 Hz), 5.79 (1H, d, J = 11.0 Hz), 2.94 (4H, t, J = 4.6 Hz), 2.51-2.46 (4H, m), 2.24 (3H, s).

工程８
3-(4-(4-メチルピペラジン-1-イル)-3-(トリフルオロメチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 8
3- (4- (4-Methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000569
Figure JPOXMLDOC01-appb-C000569

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(4-(4-メチルピペラジン-1-イル)-3-(トリフルオロメチル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (154 mg, 0.398 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (100 μL, 7.96 μmol) から標記化合物 (29 mg, 19%) を得た。黄色固体: 1H-NMR (CDCl3) δ: 10.0 (1H, d, J = 0.7 Hz), 8.54-8.52 (1H, m), 8.42-8.38 (1H, m), 8.37 (1H, d, J = 1.0 Hz), 8.24 (1H, dd, J = 9.5, 2.0 Hz), 7.74-7.67 (2H, m), 2.94 (4H, t, J = 4.5 Hz), 2.51-2.49 (4H, m), 2.24 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 4- (4-Methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (154 mg, 0.398 mmol) and 2.5 wt% osmium tetroxide tert -The title compound (29 mg, 19%) was obtained from a butanol solution (100 μL, 7.96 μmol). Yellow solid: 1 H-NMR (CDCl 3 ) δ: 10.0 (1H, d, J = 0.7 Hz), 8.54-8.52 (1H, m), 8.42-8.38 (1H, m), 8.37 (1H, d, J = 1.0 Hz), 8.24 (1H, dd, J = 9.5, 2.0 Hz), 7.74-7.67 (2H, m), 2.94 (4H, t, J = 4.5 Hz), 2.51-2.49 (4H, m), 2.24 (3H, s).

工程９
5-((3-(4-(4-メチルピペラジン-1-イル)-3-(トリフルオロメチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１３７) Step 9
5-((3- (4- (4-Methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4 -Dione (Compound 137)

Figure JPOXMLDOC01-appb-C000570
Figure JPOXMLDOC01-appb-C000570

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(4-(4-メチルピペラジン-1-イル)-3-(トリフルオロメチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (29 mg, 0.0745 mmol) およびチアゾリジン-2,4-ジオン (9 mg, 0.0745 mmol) から標記化合物 (16 mg, 45%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.37 (1H, d, J = 2.2 Hz), 8.35-8.32 (1H, m), 8.31 (1H, s), 8.28 (1H, d, J = 9.3 Hz), 7.71-7.66 (3H, m), 3.05 (4H, t, J = 4.6 Hz), 2.80 (4H, s), 2.49 (3H, s).
ESI-MS(m/z): 489[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde ( The title compound (16 mg, 45%) was obtained from 29 mg, 0.0745 mmol) and thiazolidine-2,4-dione (9 mg, 0.0745 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.37 (1H, d, J = 2.2 Hz), 8.35-8.32 (1H, m), 8.31 (1H, s), 8.28 (1H, d, J = 9.3 Hz), 7.71-7.66 (3H, m), 3.05 (4H, t, J = 4.6 Hz), 2.80 (4H, s), 2.49 (3H, s).
ESI-MS (m / z): 489 [M + H] + .

実施例１３８
5-((3-(3-((1-メチルピペリジン-4-イル)オキシ)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１３８) Example 138
5-((3- (3-((1-methylpiperidin-4-yl) oxy) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 138 )

工程１
3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノール Process 1
3- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenol

Figure JPOXMLDOC01-appb-C000571
Figure JPOXMLDOC01-appb-C000571

アルゴン雰囲気下、3-ヒドロキシフェニルボロン酸 (600 mg, 4.35 mmol) をジクロロメタン (8 mL) に溶解した。そこへピナコール (565 mg, 4.79 mmol) を加え、室温で4時間撹拌した。反応液を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製して標記化合物(992 mg, quant.) を得た。無色オイル: 1H-NMR (DMSO-D6) δ: 9.33 (1H, s), 7.18 (1H, t, J = 7.6 Hz), 7.10-7.07 (2H, m), 6.88-6.85 (1H, m), 1.28 (12H, s). Under an argon atmosphere, 3-hydroxyphenylboronic acid (600 mg, 4.35 mmol) was dissolved in dichloromethane (8 mL). Pinacol (565 mg, 4.79 mmol) was added there, and it stirred at room temperature for 4 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (992 mg, quant.). Colorless oil: 1 H-NMR (DMSO-D 6 ) δ: 9.33 (1H, s), 7.18 (1H, t, J = 7.6 Hz), 7.10-7.07 (2H, m), 6.88-6.85 (1H, m ), 1.28 (12H, s).

工程２
tert-ブチル 4-ヒドロキシピペリジン-1-カルボキシレート Process 2
tert-Butyl 4-hydroxypiperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000572
Figure JPOXMLDOC01-appb-C000572

アルゴン雰囲気下、1-(tert-ブトキシカルボニル)-4-ピペリドン (800 mg, 4.02 mmol) をエタノール (4 mL) に溶解し、0℃に冷却した。そこへ水素化ホウ素ナトリウム (228 mg, 6.03 mmol) を少量ずつ加え、0℃で10分撹拌後、室温で3時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加えてクエンチし、エタノールを留去した後、酢酸エチルで抽出した。酢酸エチル層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去、真空乾燥して標記化合物 (827 mg, quant.) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 4.70 (1H, d, J = 4.1 Hz), 3.68-3.57 (3H, m), 2.98-2.89 (2H, m), 1.70-1.63 (2H, m), 1.38 (9H, s), 1.27-1.17 (2H, m). Under an argon atmosphere, 1- (tert-butoxycarbonyl) -4-piperidone (800 mg, 4.02 mmol) was dissolved in ethanol (4 mL) and cooled to 0 ° C. Thereto was added sodium borohydride (228 mg, 6.03 mmol) little by little, followed by stirring at 0 ° C. for 10 minutes and then at room temperature for 3 hours. The reaction solution was quenched by adding a saturated aqueous ammonium chloride solution, and ethanol was distilled off, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was dried under vacuum to obtain the title compound (827 mg, quant.). White solid: 1 H-NMR (DMSO-D 6 ) δ: 4.70 (1H, d, J = 4.1 Hz), 3.68-3.57 (3H, m), 2.98-2.89 (2H, m), 1.70-1.63 (2H , m), 1.38 (9H, s), 1.27-1.17 (2H, m).

工程３
tert-ブチル 4-(3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノキシ)ピペリジン-1-カルボキシレート Process 3
tert-butyl 4- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000573
Figure JPOXMLDOC01-appb-C000573

アルゴン雰囲気下、3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノール (992 mg, 4.35 mmol)、tert-ブチル 4-ヒドロキシピペリジン-1-カルボキシレート (1.29 g, 6.41 mmol) をテトラヒドロフラン (10 mL) に溶解し、0℃に冷却した。そこへトリフェニルホスフィン(1.71 g, 6.53 mmol) を加え、さらに40% アゾジカルボン酸ジエチル トルエン溶液 (2.97 mL, 6.53 mmol) を滴下し、0℃で10分撹拌後、室温で29時間撹拌した。反応液を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製して標記化合物(357 mg, 20%) を得た。無色オイル: 1H-NMR (DMSO-D6) δ: 7.32-7.23 (2H, m), 7.17 (1H, s), 7.12-7.09 (1H, m), 4.59-4.54 (1H, m), 3.62-3.55 (2H, m), 3.33-3.19 (11H, m), 1.89-1.79 (2H, m), 1.55-1.44 (2H, m), 1.40 (9H, s), 1.29 (12H, s). Under argon atmosphere, 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (992 mg, 4.35 mmol), tert-butyl 4-hydroxypiperidine-1-carboxy The rate (1.29 g, 6.41 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to 0 ° C. Triphenylphosphine (1.71 g, 6.53 mmol) was added thereto, 40% diethyl azodicarboxylate in toluene (2.97 mL, 6.53 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 29 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (357 mg, 20%). Colorless oil: 1 H-NMR (DMSO-D 6 ) δ: 7.32-7.23 (2H, m), 7.17 (1H, s), 7.12-7.09 (1H, m), 4.59-4.54 (1H, m), 3.62 -3.55 (2H, m), 3.33-3.19 (11H, m), 1.89-1.79 (2H, m), 1.55-1.44 (2H, m), 1.40 (9H, s), 1.29 (12H, s).

工程４
tert-ブチル 4-(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェノキシ)ピペリジン-1-カルボキシレート Process 4
tert-butyl 4- (3- (6-chloroimidazo [1,2-b] pyridazin-3-yl) phenoxy) piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000574
Figure JPOXMLDOC01-appb-C000574

3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-カルボニトリルの合成 (実施例106、工程6) と同様の手法で、3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (187 mg, 0.805 mmol) およびtert-ブチル 4-(3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノキシ)ピペリジン-1-カルボキシレート (357 mg, 0.885 mmol) から標記化合物 (225 mg, 65%) を得た。薄黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.35 (1H, s), 8.31 (1H, d, J = 9.3 Hz), 7.73 (1H, t, J =2.0 Hz), 7.66 (1H, d, J = 8.3 Hz), 7.45 (1H, t, J = 8.1 Hz), 7.43 (1H, d, J = 9.5 Hz), 7.04 (1H, dd, J = 7.9, 2.1 Hz), 4.68-4.62 (1H, m), 3.76-3.71 (2H, m), 3.21-3.15 (2H, m), 2.02-1.97 (2H, m), 1.61-1.52 (2H, m), 1.41 (9H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridine-5-carbonitrile (Example 106, Step 6) -6-Chloroimidazo [1,2-b] pyridazine (187 mg, 0.805 mmol) and tert-butyl 4- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 The title compound (225 mg, 65%) was obtained from -yl) phenoxy) piperidine-1-carboxylate (357 mg, 0.885 mmol). Pale yellow amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.35 (1H, s), 8.31 (1H, d, J = 9.3 Hz), 7.73 (1H, t, J = 2.0 Hz), 7.66 (1H, d, J = 8.3 Hz), 7.45 (1H, t, J = 8.1 Hz), 7.43 (1H, d, J = 9.5 Hz), 7.04 (1H, dd, J = 7.9, 2.1 Hz), 4.68 -4.62 (1H, m), 3.76-3.71 (2H, m), 3.21-3.15 (2H, m), 2.02-1.97 (2H, m), 1.61-1.52 (2H, m), 1.41 (9H, s) .

工程５
6-クロロ-3-(3-(ピペリジン-4-イルオキシ)フェニル)イミダゾ[1,2-b]ピリダジン Process 5
6-Chloro-3- (3- (piperidin-4-yloxy) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000575
Figure JPOXMLDOC01-appb-C000575

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程6) と同様の手法で、tert-ブチル 4-(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェノキシ)ピペリジン-1-カルボキシレート(225 mg, 0.525 mmol) およびトリフルオロ酢酸 (1 mL) から標記化合物 (155 mg, 90%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.35 (1H, s), 8.31 (1H, d, J = 9.5 Hz), 7.74 (1H, t, J =2.0 Hz), 7.65-7.60 (1H, m), 7.43 (1H, d, J = 9.5 Hz), 7.43 (1H, t, J =7.9 Hz), 7.01 (1H, dd, J = 8.2, 2.6 Hz), 4.54-4.47 (1H, m), 3.04-2.99 (2H, m), 2.69-2.63 (2H, m), 2.05-1.99 (2H, m), 1.57-1.48 (2H, m). Synthesis of 5-bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 6) -(3- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) phenoxy) piperidine-1-carboxylate (225 mg, 0.525 mmol) and trifluoroacetic acid (1 mL) to give the title compound (155 mg, 90%). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.35 (1H, s), 8.31 (1H, d, J = 9.5 Hz), 7.74 (1H, t, J = 2.0 Hz), 7.65-7.60 (1H, m), 7.43 (1H, d, J = 9.5 Hz), 7.43 (1H, t, J = 7.9 Hz), 7.01 (1H, dd, J = 8.2, 2.6 Hz), 4.54-4.47 (1H, m), 3.04-2.99 (2H, m), 2.69-2.63 (2H, m), 2.05-1.99 (2H, m), 1.57-1.48 (2H, m).

工程６
6-クロロ-3-(3-((1-メチルピペリジン-4-イル)オキシ)フェニル)イミダゾ[1,2-b]ピリダジン Step 6
6-Chloro-3- (3-((1-methylpiperidin-4-yl) oxy) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000576
Figure JPOXMLDOC01-appb-C000576

5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程7) と同様の手法で、6-クロロ-3-(3-(ピペリジン-4-イルオキシ)フェニル)イミダゾ[1,2-b]ピリダジン (155 mg, 0.471 mmol) および 37% ホルムアルデヒド水溶液 (210 μL、2.83 mmol) から標記化合物 (101 mg, 63%) を得た。黄色油状物質: 1H-NMR (DMSO-D6) δ: 8.35 (1H, s), 8.31 (1H, d, J = 9.5 Hz), 7.73 (1H, t, J =2.0 Hz), 7.63 (1H, d, J = 7.8 Hz), 7.43 (1H, t, J = 8.1 Hz), 7.43 (1H, d, J = 9.5 Hz), 7.01 (1H, dd, J = 8.3, 2.4 Hz), 4.48-4.42 (1H, m), 2.70-2.64 (2H, m), 2.21-2.15 (2H, m), 2.19 (3H, s), 2.05-1.99 (2H, m), 1.72-1.64 (2H, m). Synthesis of 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 7) The title compound from 101-chloro-3- (3- (piperidin-4-yloxy) phenyl) imidazo [1,2-b] pyridazine (155 mg, 0.471 mmol) and 37% aqueous formaldehyde (210 μL, 2.83 mmol) mg, 63%). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.35 (1H, s), 8.31 (1H, d, J = 9.5 Hz), 7.73 (1H, t, J = 2.0 Hz), 7.63 (1H , d, J = 7.8 Hz), 7.43 (1H, t, J = 8.1 Hz), 7.43 (1H, d, J = 9.5 Hz), 7.01 (1H, dd, J = 8.3, 2.4 Hz), 4.48-4.42 (1H, m), 2.70-2.64 (2H, m), 2.21-2.15 (2H, m), 2.19 (3H, s), 2.05-1.99 (2H, m), 1.72-1.64 (2H, m).

工程７
3-(3-((1-メチルピペリジン-4-イル)オキシ)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Step 7
3- (3-((1-Methylpiperidin-4-yl) oxy) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000577
Figure JPOXMLDOC01-appb-C000577

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、6-クロロ-3-(3-((1-メチルピペリジン-4-イル)オキシ)フェニル)イミダゾ[1,2-b]ピリダジン(101 mg, 0.295 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (56 μL, 0.325 mmol) から標記化合物 (61 mg, 60%) を得た。薄黄色オイル: 1H-NMR (DMSO-D6) δ: 8.26 (1H, s), 8.20 (1H, d, J = 9.5 Hz), 7.82 (1H, t, J =2.1 Hz), 7.70 (1H, d, J = 7.8 Hz), 7.67 (1H, d, J = 9.5 Hz), 7.41 (1H, t, J = 8.1 Hz), 6.97 (1H, dd, J = 8.1, 2.4 Hz), 6.88 (1H, dd, J = 17.8, 11.0 Hz), 6.38 (1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.0 Hz), 4.49-4.43 (1H, m), 2.67-2.62 (2H, m), 2.20-2.15 (2H, m), 2.19 (3H, s), 2.03-1.97 (2H, m), 1.73-1.64 (2H, m). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) 6-chloro-3- (3-((1-methylpiperidin-4-yl) oxy) phenyl) imidazo [1,2-b] pyridazine (101 mg, 0.295 mmol) and 4,4,5,5-tetra The title compound (61 mg, 60%) was obtained from methyl-2-vinyl-1,3,2-dioxaborolane (56 μL, 0.325 mmol). Light yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.26 (1H, s), 8.20 (1H, d, J = 9.5 Hz), 7.82 (1H, t, J = 2.1 Hz), 7.70 (1H , d, J = 7.8 Hz), 7.67 (1H, d, J = 9.5 Hz), 7.41 (1H, t, J = 8.1 Hz), 6.97 (1H, dd, J = 8.1, 2.4 Hz), 6.88 (1H , dd, J = 17.8, 11.0 Hz), 6.38 (1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.0 Hz), 4.49-4.43 (1H, m), 2.67-2.62 (2H, m), 2.20-2.15 (2H, m), 2.19 (3H, s), 2.03-1.97 (2H, m), 1.73-1.64 (2H, m).

工程８
3-(3-((1-メチルピペリジン-4-イル)オキシ)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 8
3- (3-((1-Methylpiperidin-4-yl) oxy) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000578
Figure JPOXMLDOC01-appb-C000578

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-((1-メチルピペリジン-4-イル)オキシ)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (61 mg, 0.178 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (45 μL, 3.56 μmol) から標記化合物 (23 mg, 38%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 10.0 (1H, s), 8.52 (1H, s), 8.39 (1H, d, J = 9.5 Hz), 7.84 (1H, t, J = 2.1 Hz), 7.78 (1H, d, J =7.8 Hz), 7.68 (1H, d, J = 9.3 Hz), 7.46 (1H, t, J = 8.1 Hz), 7.03 (1H, dd, J = 7.8, 2.4 Hz), 4.52-4.45 (1H, m), 2.68-2.63 (2H, m), 2.22-2.16 (2H, m), 2.19 (3H, s), 2.04-1.99 (2H, m), 1.74-1.65 (2H, m). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3-((1-Methylpiperidin-4-yl) oxy) phenyl) -6-vinylimidazo [1,2-b] pyridazine (61 mg, 0.178 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol (45 μL, 3.56 μmol) gave the title compound (23 mg, 38%). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, s), 8.52 (1H, s), 8.39 (1H, d, J = 9.5 Hz), 7.84 (1H, t, J = 2.1 Hz), 7.78 (1H, d, J = 7.8 Hz), 7.68 (1H, d, J = 9.3 Hz), 7.46 (1H, t, J = 8.1 Hz), 7.03 (1H, dd, J = 7.8, 2.4 Hz), 4.52-4.45 (1H, m), 2.68-2.63 (2H, m), 2.22-2.16 (2H, m), 2.19 (3H, s), 2.04-1.99 (2H, m), 1.74-1.65 ( 2H, m).

工程９
5-((3-(3-((1-メチルピペリジン-4-イル)オキシ)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１３８) Step 9
5-((3- (3-((1-methylpiperidin-4-yl) oxy) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 138 )

Figure JPOXMLDOC01-appb-C000579
Figure JPOXMLDOC01-appb-C000579

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-((1-メチルピペリジン-4-イル)オキシ)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (23 mg, 0.0684 mmol) およびチアゾリジン-2,4-ジオン (8 mg, 0.0684 mmol) から標記化合物 (14 mg, 47%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.27 (1H, s), 8.21 (1H, d, J = 9.3 Hz), 8.03 (1H, s), 7.69 (1H, d, J = 7.8 Hz), 7.58 (1H, d, J = 9.3 Hz), 7.52 (1H, s), 7.45 (1H, t, J = 7.9 Hz), 7.07 (1H, dd, J = 8.3, 2.4 Hz), 4.74-4.69 (1H, m), 3.20-3.14 (2H, m), 3.01-2.93 (2H, m), 2.67 (3H, s), 2.13-2.06 (2H, m), 2.00-1.91 (2H, m).
ESI-MS(m/z): 436[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3-((1-methylpiperidin-4-yl) oxy) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (23 mg, 0.0684 mmol ) And thiazolidine-2,4-dione (8 mg, 0.0684 mmol) gave the title compound (14 mg, 47%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.27 (1H, s), 8.21 (1H, d, J = 9.3 Hz), 8.03 (1H, s), 7.69 (1H, d, J = 7.8 Hz), 7.58 (1H, d, J = 9.3 Hz), 7.52 (1H, s), 7.45 (1H, t, J = 7.9 Hz), 7.07 (1H, dd, J = 8.3, 2.4 Hz), 4.74- 4.69 (1H, m), 3.20-3.14 (2H, m), 3.01-2.93 (2H, m), 2.67 (3H, s), 2.13-2.06 (2H, m), 2.00-1.91 (2H, m).
ESI-MS (m / z): 436 [M + H] + .

実施例１３９
5-((3-(3-フルオロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１３９) Example 139
5-((3- (3-Fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 139)

工程１
6-クロロ-3-(3-フルオロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Process 1
6-Chloro-3- (3-fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000580
Figure JPOXMLDOC01-appb-C000580

アルゴン雰囲気下、6-クロロ-3-(3-フルオロ-4-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (150 mg, 0.452 mmol) をジクロロメタン (4.5 mL) に溶解した。そこへアセトン (67 μL, 0.904 mmol)、酢酸 (2.6 μL, 0.0452 mmol) を加え、室温で30分撹拌した。さらにナトリウムトリアセトキシボロヒドリド (144 mg, 0.678 mmol) を加え、室温で17時間撹拌した。反応液に飽和重層水を加えクエンチし、1規定水酸化ナトリウム溶液を加え、クロロホルムで抽出した。クロロホルム層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (97 mg, 57%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.32 (1H, s), 8.29 (1H, d, J = 9.3 Hz), 7.92-7.87 (2H, m), 7.41 (1H, d, J = 9.5 Hz), 7.18 (1H, t, J = 9.1 Hz), 3.09 (4H, t, J =4.6 Hz), 2.72-2.66 (1H, m), 2.62 (4H, t, J = 4.5 Hz), 1.02 (6H, d, J =6.3 Hz). 6-Chloro-3- (3-fluoro-4- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (150 mg, 0.452 mmol) dissolved in dichloromethane (4.5 mL) under argon atmosphere did. Acetone (67 μL, 0.904 mmol) and acetic acid (2.6 μL, 0.0452 mmol) were added thereto, and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (144 mg, 0.678 mmol) was further added, and the mixture was stirred at room temperature for 17 hours. The reaction solution was quenched by adding saturated multistory water, 1N sodium hydroxide solution was added, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (97 mg, 57%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.32 (1H, s), 8.29 (1H, d, J = 9.3 Hz), 7.92-7.87 (2H, m), 7.41 (1H, d, J = 9.5 Hz), 7.18 (1H, t, J = 9.1 Hz), 3.09 (4H, t, J = 4.6 Hz), 2.72-2.66 (1H, m), 2.62 (4H, t, J = 4.5 Hz), 1.02 (6H, d, J = 6.3 Hz).

工程２
3-(3-フルオロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 2
3- (3-Fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000581
Figure JPOXMLDOC01-appb-C000581

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、6-クロロ-3-(3-フルオロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (97 mg, 0.259 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (49 μL, 0.285 mmol) から標記化合物 (77 mg, 81%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.23 (1H, s), 8.18 (1H, d, J = 9.5 Hz), 8.02-7.96 (2H, m), 7.65 (1H, d, J = 9.3 Hz), 7.15 (1H, t, J = 9.1 Hz), 6.92 (1H, dd, J = 17.9, 11.1 Hz), 6.37 (1H, d, J = 17.8 Hz), 5.78 (1H, d, J = 11.0 Hz), 3.09 (4H, t, J = 4.6 Hz), 2.73-2.66 (1H, m), 2.62 (4H, t, J = 4.6 Hz), 1.02 (6H, d, J = 6.6 Hz). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) 6-chloro-3- (3-fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (97 mg, 0.259 mmol) and 4,4,5,5- The title compound (77 mg, 81%) was obtained from tetramethyl-2-vinyl-1,3,2-dioxaborolane (49 μL, 0.285 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.23 (1H, s), 8.18 (1H, d, J = 9.5 Hz), 8.02-7.96 (2H, m), 7.65 (1H, d, J = 9.3 Hz), 7.15 (1H, t, J = 9.1 Hz), 6.92 (1H, dd, J = 17.9, 11.1 Hz), 6.37 (1H, d, J = 17.8 Hz), 5.78 (1H, d, J = 11.0 Hz), 3.09 (4H, t, J = 4.6 Hz), 2.73-2.66 (1H, m), 2.62 (4H, t, J = 4.6 Hz), 1.02 (6H, d, J = 6.6 Hz).

工程３
3-(3-フルオロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 3
3- (3-Fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000582
Figure JPOXMLDOC01-appb-C000582

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-フルオロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (77 mg, 0.211 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (53 μL, 4.22 μmol) から標記化合物 (34 mg, 44%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.1 (1H, s), 8.48 (1H, s), 8.37 (1H, t, J = 5.1 Hz), 8.08-8.01 (2H, m), 7.65 (1H, d, J = 9.3 Hz), 7.18 (1H, t, J = 8.9 Hz), 3.11 (4H, t, J = 4.6 Hz), 2.73-2.65 (1H, m), 2.63 (4H, s), 1.02 (6H, d, J = 6.6 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3-Fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (77 mg, 0.211 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol ( The title compound (34 mg, 44%) was obtained from 53 μL, 4.22 μmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, s), 8.48 (1H, s), 8.37 (1H, t, J = 5.1 Hz), 8.08-8.01 (2H, m), 7.65 (1H, d, J = 9.3 Hz), 7.18 (1H, t, J = 8.9 Hz), 3.11 (4H, t, J = 4.6 Hz), 2.73-2.65 (1H, m), 2.63 (4H, s ), 1.02 (6H, d, J = 6.6 Hz).

工程４
5-((3-(3-フルオロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１３９) Process 4
5-((3- (3-Fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 139)

Figure JPOXMLDOC01-appb-C000583
Figure JPOXMLDOC01-appb-C000583

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-フルオロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (34 mg, 0.0925 mmol) およびチアゾリジン-2,4-ジオン (11 mg, 0.0925 mmol) から標記化合物 (19 mg, 45%) を得た。赤褐色固体: 1H-NMR (DMSO-D6) δ: 8.26 (1H, s), 8.24 (1H, d, J = 9.2 Hz), 8.11 (1H, dd, J =14.3, 1.7 Hz), 7.88 (1H, dd, J =8.4, 1.6 Hz), 7.68 (1H, s), 7.62 (1H, d, J = 9.2 Hz), 7.19 (1H, t, J =8.9 Hz), 3.24 (4H, s), 3.12-3.06 (1H, m), 2.98 (4H, s), 1.15 (6H, d, J = 6.6 Hz).
ESI-MS(m/z): 467[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3-fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (34 mg, 0.0925 mmol) and thiazolidine-2,4-dione (11 mg, 0.0925 mmol) gave the title compound (19 mg, 45%). Reddish brown solid: 1 H-NMR (DMSO-D 6 ) δ: 8.26 (1H, s), 8.24 (1H, d, J = 9.2 Hz), 8.11 (1H, dd, J = 14.3, 1.7 Hz), 7.88 ( 1H, dd, J = 8.4, 1.6 Hz), 7.68 (1H, s), 7.62 (1H, d, J = 9.2 Hz), 7.19 (1H, t, J = 8.9 Hz), 3.24 (4H, s), 3.12-3.06 (1H, m), 2.98 (4H, s), 1.15 (6H, d, J = 6.6 Hz).
ESI-MS (m / z): 467 [M + H] + .

実施例１４０
5-((3-(3-フルオロ-4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４０)  Example 140
5-((3- (3-Fluoro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 140)

工程１
6-クロロ-3-(3-フルオロ-4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Process 1
6-Chloro-3- (3-fluoro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000584
Figure JPOXMLDOC01-appb-C000584

6-クロロ-3-(3-フルオロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジンの合成 (実施例139、工程1) と同様の手法で、6-クロロ-3-(3-フルオロ-4-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン(150 mg, 0.452 mmol) およびプロピオンアルデヒド (65 μL, 0.904 mmol) から標記化合物 (121 mg, 72%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.32 (1H, s), 8.29 (1H, d, J = 9.5 Hz), 7.93-7.88 (2H, m), 7.41 (1H, d, J = 9.5 Hz), 7.19 (1H, t, J = 9.1 Hz), 3.11 (4H, t, J =4.6 Hz), 2.54 (4H, t, J = 4.1 Hz), 2.30 (2H, t, J = 7.4 Hz), 1.52-1.43 (2H, m), 0.88 (3H, t, J =7.3 Hz). Synthesis of 6-chloro-3- (3-fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (Example 139, Step 1) Titled from 6-chloro-3- (3-fluoro-4- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (150 mg, 0.452 mmol) and propionaldehyde (65 μL, 0.904 mmol) The compound (121 mg, 72%) was obtained. Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.32 (1H, s), 8.29 (1H, d, J = 9.5 Hz), 7.93-7.88 (2H, m), 7.41 (1H, d, J = 9.5 Hz), 7.19 (1H, t, J = 9.1 Hz), 3.11 (4H, t, J = 4.6 Hz), 2.54 (4H, t, J = 4.1 Hz), 2.30 (2H, t, J = 7.4 Hz), 1.52-1.43 (2H, m), 0.88 (3H, t, J = 7.3 Hz).

工程２
3-(3-フルオロ-4-(4-プロピルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 2
3- (3-Fluoro-4- (4-propylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000585
Figure JPOXMLDOC01-appb-C000585

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、6-クロロ-3-(3-フルオロ-4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (121 mg, 0.324 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (61 μL, 0.356 mmol) から標記化合物 (76 mg, 64%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.23 (1H, s), 8.18 (1H, d, J = 9.2 Hz), 8.01-7.96 (2H, m), 7.65 (1H, d, J = 9.5 Hz), 7.16 (1H, t, J = 9.0 Hz), 6.92 (1H, dd, J = 17.8, 11.2 Hz), 6.37 (1H, d, J = 17.8 Hz), 5.78 (1H, d, J = 11.2 Hz), 3.10 (4H, t, J = 4.7 Hz), 2.53 (4H, t, J = 4.6 Hz), 2.30 (2H, t, J = 7.3 Hz), 1.52-1.44 (2H, m), 0.88 (3H, t, J = 7.4 Hz). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) 6-chloro-3- (3-fluoro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (121 mg, 0.324 mmol) and 4,4,5,5- The title compound (76 mg, 64%) was obtained from tetramethyl-2-vinyl-1,3,2-dioxaborolane (61 μL, 0.356 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.23 (1H, s), 8.18 (1H, d, J = 9.2 Hz), 8.01-7.96 (2H, m), 7.65 (1H, d, J = 9.5 Hz), 7.16 (1H, t, J = 9.0 Hz), 6.92 (1H, dd, J = 17.8, 11.2 Hz), 6.37 (1H, d, J = 17.8 Hz), 5.78 (1H, d, J = 11.2 Hz), 3.10 (4H, t, J = 4.7 Hz), 2.53 (4H, t, J = 4.6 Hz), 2.30 (2H, t, J = 7.3 Hz), 1.52-1.44 (2H, m), 0.88 (3H, t, J = 7.4 Hz).

工程３
3-(3-フルオロ-4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 3
3- (3-Fluoro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000586
Figure JPOXMLDOC01-appb-C000586

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-フルオロ-4-(4-プロピルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (76 mg, 0.208 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (52 μL, 4.16 μmol) から標記化合物 (29 mg, 38%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.1 (1H, s), 8.48 (1H, s), 8.37 (1H, d, J = 9.3 Hz), 8.08-8.02 (2H, m), 7.65 (1H, d, J = 9.5 Hz), 7.19 (1H, t, J = 8.9 Hz), 3.12 (4H, t, J = 4.8 Hz), 2.54 (4H, t, J = 4.4 Hz), 2.30 (2H, t, J = 7.4 Hz), 1.53-1.44 (2H, m), 0.89 (3H, t, J = 7.3 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3-fluoro-4- (4-propylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (76 mg, 0.208 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol ( The title compound (29 mg, 38%) was obtained from 52 μL, 4.16 μmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, s), 8.48 (1H, s), 8.37 (1H, d, J = 9.3 Hz), 8.08-8.02 (2H, m), 7.65 (1H, d, J = 9.5 Hz), 7.19 (1H, t, J = 8.9 Hz), 3.12 (4H, t, J = 4.8 Hz), 2.54 (4H, t, J = 4.4 Hz), 2.30 ( 2H, t, J = 7.4 Hz), 1.53-1.44 (2H, m), 0.89 (3H, t, J = 7.3 Hz).

工程４
5-((3-(3-フルオロ-4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４０) Process 4
5-((3- (3-Fluoro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 140)

Figure JPOXMLDOC01-appb-C000587
Figure JPOXMLDOC01-appb-C000587

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-フルオロ-4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (29 mg, 0.0789 mmol) およびチアゾリジン-2,4-ジオン (9 mg, 0.0789 mmol) から標記化合物 (19 mg, 52%) を得た。赤褐色固体: 1H-NMR (DMSO-D6) δ: 8.26 (1H, s), 8.26 (1H, d, J = 8.6 Hz), 8.09 (1H, dd, J = 14.3, 2.0 Hz), 7.86 (1H, dd, J = 8.4, 1.9 Hz), 7.74 (1H, s), 7.64 (1H, d, J = 9.5 Hz), 7.18 (1H, t, J = 8.9 Hz), 3.21 (4H, s), 2.85 (4H, s), 2.59 (2H, t, J =7.4 Hz), 1.60-1.52 (2H, m), 0.91 (3H, t, J = 7.4 Hz).
ESI-MS(m/z): 467[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3-fluoro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (29 mg, 0.0789 mmol) and thiazolidine-2,4-dione (9 mg, 0.0789 mmol) gave the title compound (19 mg, 52%). Reddish brown solid: 1 H-NMR (DMSO-D 6 ) δ: 8.26 (1H, s), 8.26 (1H, d, J = 8.6 Hz), 8.09 (1H, dd, J = 14.3, 2.0 Hz), 7.86 ( 1H, dd, J = 8.4, 1.9 Hz), 7.74 (1H, s), 7.64 (1H, d, J = 9.5 Hz), 7.18 (1H, t, J = 8.9 Hz), 3.21 (4H, s), 2.85 (4H, s), 2.59 (2H, t, J = 7.4 Hz), 1.60-1.52 (2H, m), 0.91 (3H, t, J = 7.4 Hz).
ESI-MS (m / z): 467 [M + H] + .

実勢例１４１
5-((3-(3-フルオロ-4-(4-ペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４１) Example 141
5-((3- (3-Fluoro-4- (4-pentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 141)

工程１
6-クロロ-3-(3-フルオロ-4-(4-ペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Process 1
6-Chloro-3- (3-fluoro-4- (4-pentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

6-クロロ-3-(3-フルオロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジンの合成 (実施例139、工程1) と同様の手法で、6-クロロ-3-(3-フルオロ-4-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン(120 mg, 0.362 mmol) およびバレルアルデヒド (76 μL, 0.724 mmol) から標記化合物 (91 mg, 63%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.32 (1H, s), 8.29 (1H, d, J = 9.5 Hz), 7.93-7.87 (2H, m), 7.41 (1H, d, J = 9.5 Hz), 7.18 (1H, t, J = 9.1 Hz), 3.10 (4H, t, J =4.6 Hz), 2.54-2.50 (4H, m), 2.32 (2H, t, J = 7.4 Hz), 1.50-1.43 (2H, m), 1.34-1.25 (4H, m), 0.88 (3H, t, J = 7.0 Hz). Synthesis of 6-chloro-3- (3-fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (Example 139, Step 1) Titled from 6-chloro-3- (3-fluoro-4- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (120 mg, 0.362 mmol) and valeraldehyde (76 μL, 0.724 mmol) The compound (91 mg, 63%) was obtained. Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.32 (1H, s), 8.29 (1H, d, J = 9.5 Hz), 7.93-7.87 (2H, m), 7.41 (1H, d, J = 9.5 Hz), 7.18 (1H, t, J = 9.1 Hz), 3.10 (4H, t, J = 4.6 Hz), 2.54-2.50 (4H, m), 2.32 (2H, t, J = 7.4 Hz), 1.50-1.43 (2H, m), 1.34-1.25 (4H, m), 0.88 (3H, t, J = 7.0 Hz).

工程２
3-(3-フルオロ-4-(4-ペンチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 2
3- (3-Fluoro-4- (4-pentylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000589
Figure JPOXMLDOC01-appb-C000589

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、6-クロロ-3-(3-フルオロ-4-(4-ペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (91 mg, 0.226 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (43 μL, 0.249 mmol) から標記化合物 (46 mg, 52%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.23 (1H, s), 8.18 (1H, d, J = 9.2 Hz), 8.01-7.96 (2H, m), 7.65 (1H, d, J = 9.7 Hz), 7.16 (1H, t, J = 8.9 Hz), 6.92 (1H, dd, J = 17.8, 11.5 Hz), 6.37 (1H, d, J = 17.8 Hz), 5.78 (1H, d, J = 11.5 Hz), 3.09 (4H, s), 2.55-2.52 (4H, m), 2.34-2.31 (2H, m), 1.47 (2H, t, J = 7.2 Hz), 1.34-1.26 (4H, m), 0.88 (3H, t, J = 7.2 Hz). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) 6-chloro-3- (3-fluoro-4- (4-pentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (91 mg, 0.226 mmol) and 4,4,5,5- The title compound (46 mg, 52%) was obtained from tetramethyl-2-vinyl-1,3,2-dioxaborolane (43 μL, 0.249 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.23 (1H, s), 8.18 (1H, d, J = 9.2 Hz), 8.01-7.96 (2H, m), 7.65 (1H, d, J = 9.7 Hz), 7.16 (1H, t, J = 8.9 Hz), 6.92 (1H, dd, J = 17.8, 11.5 Hz), 6.37 (1H, d, J = 17.8 Hz), 5.78 (1H, d, J = 11.5 Hz), 3.09 (4H, s), 2.55-2.52 (4H, m), 2.34-2.31 (2H, m), 1.47 (2H, t, J = 7.2 Hz), 1.34-1.26 (4H, m) , 0.88 (3H, t, J = 7.2 Hz).

工程３
3-(3-フルオロ-4-(4-ペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 3
3- (3-Fluoro-4- (4-pentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000590
Figure JPOXMLDOC01-appb-C000590

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-フルオロ-4-(4-ペンチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (46 mg, 0.117 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (29 μL, 2.34 μmol) から標記化合物 (27 mg, 58%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.1 (1H, s), 8.48 (1H, s), 8.37 (1H, d, J = 9.3 Hz), 8.08-8.02 (2H, m), 7.65 (1H, d, J = 9.5 Hz), 7.19 (1H, t, J = 8.9 Hz), 3.12 (4H, t, J = 4.8 Hz), 2.54 (4H, t, J = 4.8 Hz), 2.33 (2H, t, J = 7.4 Hz), 1.50-1.43 (2H, m), 1.34-1.24 (4H, m), 0.89 (3H, t, J =7.0 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3-fluoro-4- (4-pentylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (46 mg, 0.117 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol ( The title compound (27 mg, 58%) was obtained from 29 μL, 2.34 μmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, s), 8.48 (1H, s), 8.37 (1H, d, J = 9.3 Hz), 8.08-8.02 (2H, m), 7.65 (1H, d, J = 9.5 Hz), 7.19 (1H, t, J = 8.9 Hz), 3.12 (4H, t, J = 4.8 Hz), 2.54 (4H, t, J = 4.8 Hz), 2.33 ( 2H, t, J = 7.4 Hz), 1.50-1.43 (2H, m), 1.34-1.24 (4H, m), 0.89 (3H, t, J = 7.0 Hz).

工程４
5-((3-(3-フルオロ-4-(4-ペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４１) Process 4
5-((3- (3-Fluoro-4- (4-pentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 141)

Figure JPOXMLDOC01-appb-C000591
Figure JPOXMLDOC01-appb-C000591

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-フルオロ-4-(4-ペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (27 mg, 0.0683 mmol) およびチアゾリジン-2,4-ジオン (8 mg, 0.0683 mmol) から標記化合物 (17 mg, 51%) を得た。赤褐色固体: 1H-NMR (DMSO-D6) δ: 8.26 (1H, s), 8.25 (1H, d, J = 9.5 Hz), 8.09 (1H, dd, J = 14.5, 2.1 Hz), 7.86 (1H, dd, J = 8.4, 1.9 Hz), 7.72 (1H, s), 7.64 (1H, d, J = 9.5 Hz), 7.18 (1H, t, J = 9.0 Hz), 3.21 (4H, s), 2.86 (4H, s), 2.62 (2H, t, J =7.7 Hz), 1.57-1.51 (2H, m), 1.35-1.26 (4H, m), 0.90 (3H, t, J = 7.0 Hz).
ESI-MS(m/z): 495[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3-fluoro-4- (4-pentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (27 mg, 0.0683 mmol) and thiazolidine-2,4-dione (8 mg, 0.0683 mmol) gave the title compound (17 mg, 51%). Reddish brown solid: 1 H-NMR (DMSO-D 6 ) δ: 8.26 (1H, s), 8.25 (1H, d, J = 9.5 Hz), 8.09 (1H, dd, J = 14.5, 2.1 Hz), 7.86 ( 1H, dd, J = 8.4, 1.9 Hz), 7.72 (1H, s), 7.64 (1H, d, J = 9.5 Hz), 7.18 (1H, t, J = 9.0 Hz), 3.21 (4H, s), 2.86 (4H, s), 2.62 (2H, t, J = 7.7 Hz), 1.57-1.51 (2H, m), 1.35-1.26 (4H, m), 0.90 (3H, t, J = 7.0 Hz).
ESI-MS (m / z): 495 [M + H] + .

実施例１４２
5-((3-(4-(4-デシルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４２)  Example 142
5-((3- (4- (4-decylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 142)

工程１
6-クロロ-3-(4-(4-デシルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン Process 1
6-Chloro-3- (4- (4-decylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000592
Figure JPOXMLDOC01-appb-C000592

6-クロロ-3-(3-フルオロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジンの合成 (実施例139、工程1) と同様の手法で、6-クロロ-3-(3-フルオロ-4-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン(120 mg, 0.362 mmol) およびデカナール (136 μL, 0.724 mmol) から標記化合物 (99 mg, 58%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.32 (1H, s), 8.29 (1H, d, J = 9.3 Hz), 7.93-7.87 (2H, m), 7.41 (1H, d, J = 9.3 Hz), 7.18 (1H, t, J = 9.0 Hz), 3.10 (4H, t, J =4.6 Hz), 2.54-2.51 (4H, m), 2.32 (2H, t, J = 7.3 Hz), 1.47-1.42 (2H, m), 1.30-1.23 (14H, m), 0.86 (3H, t, J = 6.8 Hz). Synthesis of 6-chloro-3- (3-fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (Example 139, Step 1) Title compound from 6-chloro-3- (3-fluoro-4- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (120 mg, 0.362 mmol) and decanal (136 μL, 0.724 mmol) (99 mg, 58%) was obtained. Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.32 (1H, s), 8.29 (1H, d, J = 9.3 Hz), 7.93-7.87 (2H, m), 7.41 (1H, d, J = 9.3 Hz), 7.18 (1H, t, J = 9.0 Hz), 3.10 (4H, t, J = 4.6 Hz), 2.54-2.51 (4H, m), 2.32 (2H, t, J = 7.3 Hz), 1.47-1.42 (2H, m), 1.30-1.23 (14H, m), 0.86 (3H, t, J = 6.8 Hz).

工程２
3-(4-(4-デシルピペラジン-1-イル)-3-フルオロフェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 2
3- (4- (4-decylpiperazin-1-yl) -3-fluorophenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000593
Figure JPOXMLDOC01-appb-C000593

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、6-クロロ-3-(4-(4-デシルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン (99 mg, 0.210 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (40 μL, 0.231 mmol) から標記化合物 (68 mg, 70%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.23 (1H, s), 8.18 (1H, d, J = 9.2 Hz), 8.01-7.96 (2H, m), 7.65 (1H, d, J = 9.5 Hz), 7.15 (1H, t, J = 9.0 Hz), 6.92 (1H, dd, J = 17.8, 11.2 Hz), 6.37 (1H, d, J = 17.8 Hz), 5.78 (1H, d, J = 11.5 Hz), 3.09 (4H, t, J = 4.6 Hz), 2.54-2.50 (4H, m), 2.32 (2H, t, J = 7.3 Hz), 1.45 (2H, t, J = 6.9 Hz), 1.30-1.24 (14H, m), 0.86 (3H, t, J = 6.9 Hz). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) 6-chloro-3- (4- (4-decylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazine (99 mg, 0.210 mmol) and 4,4,5,5- The title compound (68 mg, 70%) was obtained from tetramethyl-2-vinyl-1,3,2-dioxaborolane (40 μL, 0.231 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.23 (1H, s), 8.18 (1H, d, J = 9.2 Hz), 8.01-7.96 (2H, m), 7.65 (1H, d, J = 9.5 Hz), 7.15 (1H, t, J = 9.0 Hz), 6.92 (1H, dd, J = 17.8, 11.2 Hz), 6.37 (1H, d, J = 17.8 Hz), 5.78 (1H, d, J = 11.5 Hz), 3.09 (4H, t, J = 4.6 Hz), 2.54-2.50 (4H, m), 2.32 (2H, t, J = 7.3 Hz), 1.45 (2H, t, J = 6.9 Hz), 1.30-1.24 (14H, m), 0.86 (3H, t, J = 6.9 Hz).

工程３
3-(4-(4-デシルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 3
3- (4- (4-decylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000594
Figure JPOXMLDOC01-appb-C000594

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(4-(4-デシルピペラジン-1-イル)-3-フルオロフェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (68 mg, 0.147 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (29 μL, 2.34 μmol) から標記化合物 (44 mg, 64%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.1 (1H, s), 8.48 (1H, s), 8.37 (1H, d, J = 9.5 Hz), 8.07-8.02 (2H, m), 7.65 (1H, d, J =9.5 Hz), 7.19 (1H, t, J = 8.9 Hz), 3.11 (4H, s), 2.54 (4H, s), 2.34-2.31 (2H, m), 1.47-1.44 (2H, m), 1.30-1.24 (14H, m), 1.09 (3H, t, J =7.0 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 4- (4-decylpiperazin-1-yl) -3-fluorophenyl) -6-vinylimidazo [1,2-b] pyridazine (68 mg, 0.147 mmol) and 2.5 wt% osmium tetroxide tert-butanol solution ( The title compound (44 mg, 64%) was obtained from 29 μL, 2.34 μmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, s), 8.48 (1H, s), 8.37 (1H, d, J = 9.5 Hz), 8.07-8.02 (2H, m), 7.65 (1H, d, J = 9.5 Hz), 7.19 (1H, t, J = 8.9 Hz), 3.11 (4H, s), 2.54 (4H, s), 2.34-2.31 (2H, m), 1.47-1.44 (2H, m), 1.30-1.24 (14H, m), 1.09 (3H, t, J = 7.0 Hz).

工程４
5-((3-(4-(4-デシルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４２) Process 4
5-((3- (4- (4-decylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 142)

Figure JPOXMLDOC01-appb-C000595
Figure JPOXMLDOC01-appb-C000595

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(4-(4-デシルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (44 mg, 0.0945 mmol) およびチアゾリジン-2,4-ジオン (11 mg, 0.0945 mmol) から標記化合物 (31 mg, 59%) を得た。赤褐色固体: 1H-NMR (DMSO-D6) δ: 8.26-8.24 (2H, m), 8.09 (1H, d, J = 14.3 Hz), 7.86 (1H, d, J = 8.6 Hz), 7.71 (1H, s), 7.63 (1H, d, J = 9.5 Hz), 7.18 (1H, t, J = 8.9 Hz), 3.20 (4H, s), 2.84 (4H, s), 2.64-2.58 (2H, m), 1.55-1.50 (2H, m), 1.31-1.24 (14H, m), 0.86 (3H, t, J = 6.6 Hz).
ESI-MS(m/z): 565[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (4- (4-decylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (44 mg, 0.0945 mmol) and thiazolidine-2,4-dione (11 mg, 0.0945 mmol) gave the title compound (31 mg, 59%). Reddish brown solid: 1 H-NMR (DMSO-D 6 ) δ: 8.26-8.24 (2H, m), 8.09 (1H, d, J = 14.3 Hz), 7.86 (1H, d, J = 8.6 Hz), 7.71 ( 1H, s), 7.63 (1H, d, J = 9.5 Hz), 7.18 (1H, t, J = 8.9 Hz), 3.20 (4H, s), 2.84 (4H, s), 2.64-2.58 (2H, m ), 1.55-1.50 (2H, m), 1.31-1.24 (14H, m), 0.86 (3H, t, J = 6.6 Hz).
ESI-MS (m / z): 565 [M + H] + .

実施例１４３
5-((3-(3-(((1-メチルピペリジン-4-イル)オキシ)メチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４３)  Example 143
5-((3- (3-(((1-methylpiperidin-4-yl) oxy) methyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 143)

工程１
tert-ブチル 4-((3-ブロモベンジル)オキシ)ピペリジン-1-カルボキシレート Process 1
tert-butyl 4-((3-bromobenzyl) oxy) piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000596
Figure JPOXMLDOC01-appb-C000596

アルゴン雰囲気下、tert-ブチル 4-ヒドロキシピペリジン-1-カルボキシレート (836 mg, 4.02 mmol) をテトラヒドロフラン (10 mL) に溶解し、0℃に冷却した。そこへ水素化ナトリウム (60% in oil, 161 mg, 4.02 mmol) を加え、0℃で30分撹拌した。さらに3-ブロモベンジルブロミド (1.0 g, 4.02 mmol) を加え、0℃で10分撹拌後、室温で20時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、 表題化合物 (379 mg, 26%) を得た。薄黄色オイル: 1H-NMR (DMSO-D6) δ: 7.52 (1H, s), 7.49-7.46 (1H, m), 7.36-7.29 (2H, m), 4.52 (2H, s), 3.66-3.60 (2H, m), 3.58-3.53 (1H, m), 3.07-3.00 (2H, m), 1.85-1.80 (2H, m), 1.44-1.36 (2H, m), 1.39 (9H, s). Under an argon atmosphere, tert-butyl 4-hydroxypiperidine-1-carboxylate (836 mg, 4.02 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to 0 ° C. Sodium hydride (60% in oil, 161 mg, 4.02 mmol) was added there, and it stirred at 0 degreeC for 30 minutes. 3-Bromobenzyl bromide (1.0 g, 4.02 mmol) was further added, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 20 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (379 mg, 26%). Pale yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 7.52 (1H, s), 7.49-7.46 (1H, m), 7.36-7.29 (2H, m), 4.52 (2H, s), 3.66- 3.60 (2H, m), 3.58-3.53 (1H, m), 3.07-3.00 (2H, m), 1.85-1.80 (2H, m), 1.44-1.36 (2H, m), 1.39 (9H, s).

工程２
tert-ブチル 4-((3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)ベンジル)オキシ)ピペリジン-1-カルボキシレート Process 2
tert-butyl 4-((3- (6-chloroimidazo [1,2-b] pyridazin-3-yl) benzyl) oxy) piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000597
Figure JPOXMLDOC01-appb-C000597

3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェネチルアセテートの合成(実施例135、工程2) と同様の手法で、6-クロロイミダゾ[1,2-b]ピリダジン (120 mg, 0.785 mmol) およびtert-ブチル 4-((3-ブロモベンジル)オキシ)ピペリジン-1-カルボキシレート (379 mg, 1.02 mmol) から標記化合物 (161 mg, 46%) を得た。薄黄色オイル: 1H-NMR (DMSO-D6) δ: 8.33 (1H, s), 8.31 (1H, d, J = 9.5 Hz), 8.14 (1H, s), 7.98 (1H, d, J = 7.7 Hz), 7.52 (1H, t, J = 7.7 Hz), 7.44 (1H, d, J = 9.5 Hz), 7.38 (1H, d, J = 7.4 Hz), 4.63 (2H, s), 3.67-3.62 (3H, m), 3.13-3.06 (2H, m), 1.88-1.84 (2H, m), 1.51-1.44 (2H, m), 1.40 (9H, s) In the same manner as in the synthesis of 3- (6-chloroimidazo [1,2-b] pyridazin-3-yl) phenethyl acetate (Example 135, step 2), 6-chloroimidazo [1,2-b] pyridazine The title compound (161 mg, 46%) was obtained from (120 mg, 0.785 mmol) and tert-butyl 4-((3-bromobenzyl) oxy) piperidine-1-carboxylate (379 mg, 1.02 mmol). Pale yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.33 (1H, s), 8.31 (1H, d, J = 9.5 Hz), 8.14 (1H, s), 7.98 (1H, d, J = 7.7 Hz), 7.52 (1H, t, J = 7.7 Hz), 7.44 (1H, d, J = 9.5 Hz), 7.38 (1H, d, J = 7.4 Hz), 4.63 (2H, s), 3.67-3.62 (3H, m), 3.13-3.06 (2H, m), 1.88-1.84 (2H, m), 1.51-1.44 (2H, m), 1.40 (9H, s)

工程３
6-クロロ-3-(3-((ピペリジン-4-イルオキシ)メチル)フェニル)イミダゾ[1,2-b]ピリダジン Process 3
6-Chloro-3- (3-((piperidin-4-yloxy) methyl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000598
Figure JPOXMLDOC01-appb-C000598

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程6) と同様の手法で、tert-ブチル 4-((3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)ベンジル)オキシ)ピペリジン-1-カルボキシレート (161 mg, 0.363 mmol) およびトリフルオロ酢酸 (1 mL) から標記化合物 (111 mg, 89%) を得た。薄黄色オイル: 1H-NMR (DMSO-D6) δ: 8.31 (1H, s), 8.31-8.29 (1H, m), 8.10 (1H, s), 7.98 (1H, d, J = 7.7 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.43 (1H, d, J = 9.5 Hz), 7.37 (1H, d, J = 7.7 Hz), 4.60 (2H, s), 3.48-3.43 (1H, m), 2.96-2.92 (2H, m), 2.50-2.44 (2H, m), 1.92-1.88 (2H, m), 1.43-1.34 (2H, m). Synthesis of 5-bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 6) Titled from-((3- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) benzyl) oxy) piperidine-1-carboxylate (161 mg, 0.363 mmol) and trifluoroacetic acid (1 mL) The compound (111 mg, 89%) was obtained. Pale yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.31 (1H, s), 8.31-8.29 (1H, m), 8.10 (1H, s), 7.98 (1H, d, J = 7.7 Hz) , 7.52 (1H, t, J = 7.6 Hz), 7.43 (1H, d, J = 9.5 Hz), 7.37 (1H, d, J = 7.7 Hz), 4.60 (2H, s), 3.48-3.43 (1H, m), 2.96-2.92 (2H, m), 2.50-2.44 (2H, m), 1.92-1.88 (2H, m), 1.43-1.34 (2H, m).

工程４
6-クロロ-3-(3-(((1-メチルピペリジン-4-イル)オキシ)メチル)フェニル)イミダゾ[1,2-b]ピリダジン Process 4
6-Chloro-3- (3-(((1-methylpiperidin-4-yl) oxy) methyl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000599
Figure JPOXMLDOC01-appb-C000599

5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程7) と同様の手法で、6-クロロ-3-(3-((ピペリジン-4-イルオキシ)メチル)フェニル)イミダゾ[1,2-b]ピリダジン (111 mg, 0.324 mmol) および 37% ホルムアルデヒド水溶液 (145 μL, 1.94 mmol) から標記化合物 (81 mg, 70%) を得た。薄黄色オイル: 1H-NMR (DMSO-D6) δ: 8.31 (1H, s), 8.31 (1H, d, J = 8.0 Hz), 8.10 (1H, s), 7.98 (1H, d, J = 7.7 Hz), 7.52 (1H, t, J = 7.7 Hz), 7.43 (1H, d, J =9.5 Hz), 7.37 (1H, d, J = 7.7 Hz), 4.59 (2H, s), 3.45-3.39 (1H, m), 2.64-2.59 (2H, m), 2.14 (3H, s), 2.06-2.00 (2H, m), 1.91-1.87 (2H, m), 1.59-1.52 (2H, m). Synthesis of 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 7) Title from 3-chloro-3- (3-((piperidin-4-yloxy) methyl) phenyl) imidazo [1,2-b] pyridazine (111 mg, 0.324 mmol) and 37% aqueous formaldehyde solution (145 μL, 1.94 mmol) The compound (81 mg, 70%) was obtained. Pale yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.31 (1H, s), 8.31 (1H, d, J = 8.0 Hz), 8.10 (1H, s), 7.98 (1H, d, J = 7.7 Hz), 7.52 (1H, t, J = 7.7 Hz), 7.43 (1H, d, J = 9.5 Hz), 7.37 (1H, d, J = 7.7 Hz), 4.59 (2H, s), 3.45-3.39 (1H, m), 2.64-2.59 (2H, m), 2.14 (3H, s), 2.06-2.00 (2H, m), 1.91-1.87 (2H, m), 1.59-1.52 (2H, m).

工程５
3-(3-(((1-メチルピペリジン-4-イル)オキシ)メチル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 5
3- (3-(((1-Methylpiperidin-4-yl) oxy) methyl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000600
Figure JPOXMLDOC01-appb-C000600

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、6-クロロ-3-(3-(((1-メチルピペリジン-4-イル)オキシ)メチル)フェニル)イミダゾ[1,2-b]ピリダジン (81 mg, 0.250 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (43 μL, 0.231 mmol) から標記化合物 (47 mg, 59%) を得た。薄黄色オイル: 1H-NMR (DMSO-D6) δ: 8.24-8.19 (3H, m), 8.05 (1H, d, J = 7.7 Hz), 7.66 (1H, d, J = 9.5 Hz), 7.49 (1H, t, J =7.7 Hz), 7.34 (1H, d, J = 7.2 Hz), 6.90 (1H, dd, J = 17.8, 11.2 Hz), 6.39 (1H, d, J = 17.8 Hz), 5.78 (1H, d, J = 11.2 Hz), 4.59 (2H, s), 3.44-3.41 (1H, m), 2.64-2.58 (2H, m), 2.13 (3H, d, J = 1.1 Hz), 2.05-1.99 (2H, m), 1.90-1.86 (2H, m), 1.58-1.51 (2H, m). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) 6-chloro-3- (3-((((1-methylpiperidin-4-yl) oxy) methyl) phenyl) imidazo [1,2-b] pyridazine (81 mg, 0.250 mmol) and 4,4,5, The title compound (47 mg, 59%) was obtained from 5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (43 μL, 0.231 mmol). Light yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.24-8.19 (3H, m), 8.05 (1H, d, J = 7.7 Hz), 7.66 (1H, d, J = 9.5 Hz), 7.49 (1H, t, J = 7.7 Hz), 7.34 (1H, d, J = 7.2 Hz), 6.90 (1H, dd, J = 17.8, 11.2 Hz), 6.39 (1H, d, J = 17.8 Hz), 5.78 (1H, d, J = 11.2 Hz), 4.59 (2H, s), 3.44-3.41 (1H, m), 2.64-2.58 (2H, m), 2.13 (3H, d, J = 1.1 Hz), 2.05- 1.99 (2H, m), 1.90-1.86 (2H, m), 1.58-1.51 (2H, m).

工程６
3-(3-(((1-メチルピペリジン-4-イル)オキシ)メチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Step 6
3- (3-(((1-Methylpiperidin-4-yl) oxy) methyl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000601
Figure JPOXMLDOC01-appb-C000601

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-(((1-メチルピペリジン-4-イル)オキシ)メチル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (47 mg, 0.135 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (34 μL, 2.70 μmol) から標記化合物 (11 mg, 23%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 10.0 (1H, s), 8.48 (1H, s), 8.39 (1H, d, J = 9.5 Hz), 8.21 (1H, s), 8.14 (1H, d, J = 7.7 Hz), 7.68 (1H, d, J = 9.2 Hz), 7.54 (1H, t, J =7.7 Hz), 7.41 (1H, d, J = 7.4 Hz), 4.61 (2H, s), 3.46-3.40 (1H, m), 2.64-2.59 (2H, m), 2.13 (3H, s), 2.04-1.99 (2H, m), 1.91-1.86 (2H, m), 1.58-1.51 (2H, m). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3-(((1-Methylpiperidin-4-yl) oxy) methyl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (47 mg, 0.135 mmol) and 2.5 wt% osmium tetroxide tert-butanol The title compound (11 mg, 23%) was obtained from the solution (34 μL, 2.70 μmol). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, s), 8.48 (1H, s), 8.39 (1H, d, J = 9.5 Hz), 8.21 (1H, s), 8.14 ( 1H, d, J = 7.7 Hz), 7.68 (1H, d, J = 9.2 Hz), 7.54 (1H, t, J = 7.7 Hz), 7.41 (1H, d, J = 7.4 Hz), 4.61 (2H, s), 3.46-3.40 (1H, m), 2.64-2.59 (2H, m), 2.13 (3H, s), 2.04-1.99 (2H, m), 1.91-1.86 (2H, m), 1.58-1.51 ( 2H, m).

工程７
5-((3-(3-(((1-メチルピペリジン-4-イル)オキシ)メチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４３) Step 7
5-((3- (3-(((1-methylpiperidin-4-yl) oxy) methyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 143)

Figure JPOXMLDOC01-appb-C000602
Figure JPOXMLDOC01-appb-C000602

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-(((1-メチルピペリジン-4-イル)オキシ)メチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (11 mg, 0.0314 mmol) およびチアゾリジン-2,4-ジオン (4 mg, 0.0314 mmol) から標記化合物 (4 mg, 30%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.38 (1H, s), 8.25 (1H, s), 8.19 (1H, d, J = 9.2 Hz), 8.01 (1H, d, J = 7.7 Hz), 7.56 (1H, d, J = 9.5 Hz), 7.52 (1H, t, J = 7.7 Hz), 7.45 (1H, s), 7.43 (1H, d, J =7.4 Hz), 4.68 (2H, s), 3.70-3.66 (1H, m), 3.12-3.04 (2H, m), 2.89-2.75 (2H, m), 2.59 (3H, s), 2.02-1.94 (2H, m), 1.83-1.73(2H, m).
ESI-MS(m/z): 450[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3-(((1-methylpiperidin-4-yl) oxy) methyl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (11 mg , 0.0314 mmol) and thiazolidine-2,4-dione (4 mg, 0.0314 mmol) gave the title compound (4 mg, 30%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.38 (1H, s), 8.25 (1H, s), 8.19 (1H, d, J = 9.2 Hz), 8.01 (1H, d, J = 7.7 Hz), 7.56 (1H, d, J = 9.5 Hz), 7.52 (1H, t, J = 7.7 Hz), 7.45 (1H, s), 7.43 (1H, d, J = 7.4 Hz), 4.68 (2H, s), 3.70-3.66 (1H, m), 3.12-3.04 (2H, m), 2.89-2.75 (2H, m), 2.59 (3H, s), 2.02-1.94 (2H, m), 1.83-1.73 ( 2H, m).
ESI-MS (m / z): 450 [M + H] + .

実施例１４４
5-((3-(3-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４４)  Example 144
5-((3- (3- (4-Ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 144)

工程１
6-クロロ-3-(3-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Process 1
6-Chloro-3- (3- (4-ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000603
Figure JPOXMLDOC01-appb-C000603

アルゴン雰囲気下、6-クロロ-3-(3-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (187 mg, 0.596 mmol) をN,N-ジメチルホルムアミド (3 mL) に溶解した。そこへ炭酸セシウム (388 mg, 1.19 mmol) を加え、室温で10分撹拌した。さらにヨードエタン (143 μL, 1.79 mmol) を加え、80℃で1時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。酢酸エチル層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (62 mg, 30%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.31 (1H, s), 8.29 (1H, d, J = 9.5 Hz), 7.61 (1H, s), 7.51 (1H, d, J = 7.2 Hz), 7.41 (1H, d, J = 9.5 Hz), 7.37 (1H, t, J =8.0 Hz), 7.01 (1H, d, J = 8.6 Hz), 3.23 (4H, t, J = 4.4 Hz), 2.53 (4H, t, J = 4.7 Hz), 2.38 (2H, q, J = 7.2 Hz), 1.05 (3H, t, J = 7.2 Hz). 6-Chloro-3- (3- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (187 mg, 0.596 mmol) in N, N-dimethylformamide (3 mL) under argon atmosphere Dissolved. Cesium carbonate (388 mg, 1.19 mmol) was added there, and it stirred at room temperature for 10 minutes. Further, iodoethane (143 μL, 1.79 mmol) was added, and the mixture was stirred at 80 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (62 mg, 30%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.31 (1H, s), 8.29 (1H, d, J = 9.5 Hz), 7.61 (1H, s), 7.51 (1H, d, J = 7.2 Hz), 7.41 (1H, d, J = 9.5 Hz), 7.37 (1H, t, J = 8.0 Hz), 7.01 (1H, d, J = 8.6 Hz), 3.23 (4H, t, J = 4.4 Hz) , 2.53 (4H, t, J = 4.7 Hz), 2.38 (2H, q, J = 7.2 Hz), 1.05 (3H, t, J = 7.2 Hz).

工程２
3-(3-(4-エチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 2
3- (3- (4-Ethylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000604
Figure JPOXMLDOC01-appb-C000604

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、6-クロロ-3-(3-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (62 mg, 0.181 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (34 μL, 0.199 mmol) から標記化合物 (54 mg, 90%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.23 (1H, s), 8.18 (1H, d, J = 9.7 Hz), 7.77 (1H, s), 7.64 (1H, d, J = 9.5 Hz), 7.56 (1H, d, J = 7.7 Hz), 7.35 (1H, t, J = 8.0 Hz), 6.98 (1H, d, J = 8.0 Hz), 6.90 (1H, dd, J = 17.8, 11.2 Hz), 6.37 (1H, d, J = 17.8 Hz), 5.77 (1H, d, J = 11.2 Hz), 3.23 (4H, t, J = 4.6 Hz), 2.54 (4H, t, J = 4.6 Hz), 2.39 (2H, q, J = 7.3 Hz), 1.05 (3H, t, J = 7.3 Hz). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) 6-chloro-3- (3- (4-ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (62 mg, 0.181 mmol) and 4,4,5,5-tetramethyl-2 The title compound (54 mg, 90%) was obtained from -vinyl-1,3,2-dioxaborolane (34 μL, 0.199 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.23 (1H, s), 8.18 (1H, d, J = 9.7 Hz), 7.77 (1H, s), 7.64 (1H, d, J = 9.5 Hz), 7.56 (1H, d, J = 7.7 Hz), 7.35 (1H, t, J = 8.0 Hz), 6.98 (1H, d, J = 8.0 Hz), 6.90 (1H, dd, J = 17.8, 11.2 Hz), 6.37 (1H, d, J = 17.8 Hz), 5.77 (1H, d, J = 11.2 Hz), 3.23 (4H, t, J = 4.6 Hz), 2.54 (4H, t, J = 4.6 Hz) , 2.39 (2H, q, J = 7.3 Hz), 1.05 (3H, t, J = 7.3 Hz).

工程３
3-(3-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 3
3- (3- (4-Ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000605
Figure JPOXMLDOC01-appb-C000605

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-(4-エチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (47 mg, 0.135 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (41 μL, 3.24 μmol) から標記化合物 (11 mg, 20%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.0 (1H, s), 8.48 (1H, s), 8.37 (1H, d, J = 9.2 Hz), 7.80 (1H, s), 7.66 (1H, d, J = 9.2 Hz), 7.62 (1H, d, J = 7.7 Hz), 7.39 (1H, t, J = 8.0 Hz), 7.03 (1H, dd, J = 8.3, 2.3 Hz), 3.26 (4H, s), 2.55 (4H, s), 2.42-2.37 (2H, m), 1.05 (3H, t, J = 7.2 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3- (4-Ethylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (47 mg, 0.135 mmol) and 2.5 wt% osmium tetroxide in tert-butanol (41 μL, 3.24 μmol) gave the title compound (11 mg, 20%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, s), 8.48 (1H, s), 8.37 (1H, d, J = 9.2 Hz), 7.80 (1H, s), 7.66 ( 1H, d, J = 9.2 Hz), 7.62 (1H, d, J = 7.7 Hz), 7.39 (1H, t, J = 8.0 Hz), 7.03 (1H, dd, J = 8.3, 2.3 Hz), 3.26 ( 4H, s), 2.55 (4H, s), 2.42-2.37 (2H, m), 1.05 (3H, t, J = 7.2 Hz).

工程４
5-((3-(3-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４４) Process 4
5-((3- (3- (4-Ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 144)

Figure JPOXMLDOC01-appb-C000606
Figure JPOXMLDOC01-appb-C000606

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (11 mg, 0.0328 mmol) およびチアゾリジン-2,4-ジオン (4 mg, 0.0328 mmol) から標記化合物 (10 mg, 68%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.24 (1H, d, J = 9.5 Hz), 8.21 (1H, s), 7.74 (1H, s), 7.66 (1H, s), 7.62 (1H, d, J =9.5 Hz), 7.51 (1H, d, J = 7.7 Hz), 7.39 (1H, t, J = 7.9 Hz), 7.03 (1H, dd, J = 8.0, 1.7 Hz), 3.35 (4H, s), 2.93 (4H, s), 2.78-2.73 (2H, m), 1.14 (3H, t, J = 7.3 Hz)
ESI-MS(m/z): 435[M+H]+ Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3- (4-ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (11 mg, 0.0328 mmol) and thiazolidine The title compound (10 mg, 68%) was obtained from -2,4-dione (4 mg, 0.0328 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.24 (1H, d, J = 9.5 Hz), 8.21 (1H, s), 7.74 (1H, s), 7.66 (1H, s), 7.62 ( 1H, d, J = 9.5 Hz), 7.51 (1H, d, J = 7.7 Hz), 7.39 (1H, t, J = 7.9 Hz), 7.03 (1H, dd, J = 8.0, 1.7 Hz), 3.35 ( 4H, s), 2.93 (4H, s), 2.78-2.73 (2H, m), 1.14 (3H, t, J = 7.3 Hz)
ESI-MS (m / z): 435 [M + H] +

実施例１４５
5-((3-(3-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４５)  Example 145
5-((3- (3- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 145)

工程１
6-クロロ-3-(3-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Process 1
6-Chloro-3- (3- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000607
Figure JPOXMLDOC01-appb-C000607

6-クロロ-3-(3-フルオロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジンの合成 (実施例139、工程1) と同様の手法で、6-クロロ-3-(3-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (171 mg, 0.545 mmol) およびプロピオンアルデヒド (79 μL, 1.09 mmol) から標記化合物 (104 mg, 54%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.31 (1H, s), 8.29 (1H, d, J = 9.5 Hz), 7.60 (1H, s), 7.51 (1H, d, J = 7.4 Hz), 7.41 (1H, d, J = 9.5 Hz), 7.37 (1H, t, J = 7.9 Hz), 7.00 (1H, d, J = 8.3 Hz), 3.22 (4H, t, J = 4.3 Hz), 2.52 (4H, t, J = 5.2 Hz), 2.29 (2H, t, J = 7.4 Hz), 1.52-1.45 (2H, m), 0.88 (3H, t, J = 7.3 Hz). Synthesis of 6-chloro-3- (3-fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (Example 139, Step 1) From 6-chloro-3- (3- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (171 mg, 0.545 mmol) and propionaldehyde (79 μL, 1.09 mmol), the title compound (104 mg , 54%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.31 (1H, s), 8.29 (1H, d, J = 9.5 Hz), 7.60 (1H, s), 7.51 (1H, d, J = 7.4 Hz), 7.41 (1H, d, J = 9.5 Hz), 7.37 (1H, t, J = 7.9 Hz), 7.00 (1H, d, J = 8.3 Hz), 3.22 (4H, t, J = 4.3 Hz) , 2.52 (4H, t, J = 5.2 Hz), 2.29 (2H, t, J = 7.4 Hz), 1.52-1.45 (2H, m), 0.88 (3H, t, J = 7.3 Hz).

工程２
3-(3-(4-プロピルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 2
3- (3- (4-propylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000608
Figure JPOXMLDOC01-appb-C000608

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、6-クロロ-3-(3-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (104 mg, 0.292 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (55 μL, 0.321 mmol) から標記化合物 (95 mg, 94%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.23 (1H, s), 8.18 (1H, d, J = 9.5 Hz), 7.77 (1H, s), 7.64 (1H, d, J = 9.5 Hz), 7.56 (1H, d, J = 6.9 Hz), 7.35 (1H, t, J = 8.0 Hz), 6.97 (1H, d, J = 7.7 Hz), 6.90 (1H, dd, J = 17.8, 11.2 Hz), 6.36 (1H, d, J = 17.8 Hz), 5.77 (1H, d, J = 11.2 Hz), 3.23 (4H, s), 2.52 (4H, s), 2.30 (2H, t, J = 7.4 Hz), 1.51-1.46 (2H, m), 0.89 (3H, t, J =7.3 Hz). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) 6-chloro-3- (3- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (104 mg, 0.292 mmol) and 4,4,5,5-tetramethyl-2 The title compound (95 mg, 94%) was obtained from -vinyl-1,3,2-dioxaborolane (55 μL, 0.321 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.23 (1H, s), 8.18 (1H, d, J = 9.5 Hz), 7.77 (1H, s), 7.64 (1H, d, J = 9.5 Hz), 7.56 (1H, d, J = 6.9 Hz), 7.35 (1H, t, J = 8.0 Hz), 6.97 (1H, d, J = 7.7 Hz), 6.90 (1H, dd, J = 17.8, 11.2 Hz), 6.36 (1H, d, J = 17.8 Hz), 5.77 (1H, d, J = 11.2 Hz), 3.23 (4H, s), 2.52 (4H, s), 2.30 (2H, t, J = 7.4 Hz), 1.51-1.46 (2H, m), 0.89 (3H, t, J = 7.3 Hz).

工程３
3-(3-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 3
3- (3- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000609
Figure JPOXMLDOC01-appb-C000609

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-(4-プロピルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (95 mg, 0.273 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (68 μL, 5.46 μmol) から標記化合物 (43 mg, 45%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.0 (1H, s), 8.48 (1H, s), 8.37 (1H, d, J = 9.2 Hz), 7.79 (1H, s), 7.66 (1H, d, J = 9.5 Hz), 7.62 (1H, d, J = 7.4 Hz), 7.39 (1H, t, J = 8.0 Hz), 7.02 (1H, dd, J = 8.2, 2.1 Hz), 3.25 (4H, t, J = 5.0 Hz), 2.53 (4H, t, J = 4.9 Hz), 2.30 (2H, t, J = 7.4 Hz), 1.53-1.45 (2H, m), 0.89 (3H, t, J = 7.4 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3- (4-propylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (95 mg, 0.273 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol (68 μL, 5.46 μmol) gave the title compound (43 mg, 45%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, s), 8.48 (1H, s), 8.37 (1H, d, J = 9.2 Hz), 7.79 (1H, s), 7.66 ( 1H, d, J = 9.5 Hz), 7.62 (1H, d, J = 7.4 Hz), 7.39 (1H, t, J = 8.0 Hz), 7.02 (1H, dd, J = 8.2, 2.1 Hz), 3.25 ( 4H, t, J = 5.0 Hz), 2.53 (4H, t, J = 4.9 Hz), 2.30 (2H, t, J = 7.4 Hz), 1.53-1.45 (2H, m), 0.89 (3H, t, J = 7.4 Hz).

工程４
5-((3-(3-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４５) Process 4
5-((3- (3- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 145)

Figure JPOXMLDOC01-appb-C000610
Figure JPOXMLDOC01-appb-C000610

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (43 mg, 0.123 mmol) およびチアゾリジン-2,4-ジオン (14 mg, 0.123 mmol) から標記化合物 (27 mg, 48%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.25 (1H, d, J = 9.5 Hz), 8.21 (1H, s), 7.71-7.70 (2H, m), 7.64 (1H, d, J = 9.5 Hz), 7.50 (1H, d, J = 7.7 Hz), 7.39 (1H, t, J = 7.9 Hz), 7.03 (1H, dd, J = 8.0, 2.3 Hz), 3.33 (4H, s), 2.87 (4H, s), 2.63-2.58 (2H, m), 1.60-1.53 (2H, m), 0.90 (3H, t, J = 7.4 Hz).
ESI-MS(m/z): 449[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (43 mg, 0.123 mmol) and thiazolidine The title compound (27 mg, 48%) was obtained from -2,4-dione (14 mg, 0.123 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.25 (1H, d, J = 9.5 Hz), 8.21 (1H, s), 7.71-7.70 (2H, m), 7.64 (1H, d, J = 9.5 Hz), 7.50 (1H, d, J = 7.7 Hz), 7.39 (1H, t, J = 7.9 Hz), 7.03 (1H, dd, J = 8.0, 2.3 Hz), 3.33 (4H, s), 2.87 (4H, s), 2.63-2.58 (2H, m), 1.60-1.53 (2H, m), 0.90 (3H, t, J = 7.4 Hz).
ESI-MS (m / z): 449 [M + H] + .

実施例１４６
5-((3-(3-(4-イソブチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４６) Example 146
5-((3- (3- (4-Isobutylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 146)

工程１
6-クロロ-3-(3-(4-イソブチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Process 1
6-Chloro-3- (3- (4-isobutylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000611
Figure JPOXMLDOC01-appb-C000611

6-クロロ-3-(3-フルオロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジンの合成 (実施例139、工程1) と同様の手法で、6-クロロ-3-(3-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (136 mg, 0.433 mmol) およびイソブチルアルデヒド (79 μL, 0.866 mmol) から標記化合物 (125 mg, 78%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.31 (1H, s), 8.29 (1H, d, J = 9.5 Hz), 7.61 (1H, s), 7.51 (1H, d, J = 8.0 Hz), 7.41 (1H, d, J = 9.5 Hz), 7.37 (1H, t, J = 8.0 Hz), 7.01 (1H, d, J = 8.3 Hz), 3.22 (4H, s), 2.50-2.47 (4H, m), 2.10 (2H, d, J = 7.2 Hz), 1.85-1.79 (1H, m), 0.89 (6H, d, J = 6.3 Hz). Synthesis of 6-chloro-3- (3-fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (Example 139, Step 1) From 6-chloro-3- (3- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (136 mg, 0.433 mmol) and isobutyraldehyde (79 μL, 0.866 mmol), the title compound (125 mg , 78%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.31 (1H, s), 8.29 (1H, d, J = 9.5 Hz), 7.61 (1H, s), 7.51 (1H, d, J = 8.0 Hz), 7.41 (1H, d, J = 9.5 Hz), 7.37 (1H, t, J = 8.0 Hz), 7.01 (1H, d, J = 8.3 Hz), 3.22 (4H, s), 2.50-2.47 ( 4H, m), 2.10 (2H, d, J = 7.2 Hz), 1.85-1.79 (1H, m), 0.89 (6H, d, J = 6.3 Hz).

工程２
3-(3-(4-イソブチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 2
3- (3- (4-Isobutylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000612
Figure JPOXMLDOC01-appb-C000612

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、6-クロロ-3-(3-(4-イソブチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (125 mg, 0.338 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (64 μL, 0.372 mmol) から標記化合物 (145 mg, quant.) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.23 (1H, s), 8.18 (1H, d, J = 9.5 Hz), 7.76 (1H, s), 7.64 (1H, d, J = 9.5 Hz), 7.56 (1H, d, J = 7.7 Hz), 7.35 (1H, t, J = 7.9 Hz), 6.97 (1H, d, J = 8.3 Hz), 6.90 (1H, dd, J = 17.9, 11.0 Hz), 6.37 (1H, d, J = 17.8 Hz), 5.77 (1H, d, J = 11.2 Hz), 3.23 (4H, t, J = 4.9 Hz), 2.52-2.46 (4H, m), 2.10 (2H, d, J = 7.2 Hz), 1.85-1.79 (1H, m), 0.89 (6H, d, J = 6.3 Hz). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) 6-chloro-3- (3- (4-isobutylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (125 mg, 0.338 mmol) and 4,4,5,5-tetramethyl-2 The title compound (145 mg, quant.) Was obtained from -vinyl-1,3,2-dioxaborolane (64 μL, 0.372 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.23 (1H, s), 8.18 (1H, d, J = 9.5 Hz), 7.76 (1H, s), 7.64 (1H, d, J = 9.5 Hz), 7.56 (1H, d, J = 7.7 Hz), 7.35 (1H, t, J = 7.9 Hz), 6.97 (1H, d, J = 8.3 Hz), 6.90 (1H, dd, J = 17.9, 11.0 Hz), 6.37 (1H, d, J = 17.8 Hz), 5.77 (1H, d, J = 11.2 Hz), 3.23 (4H, t, J = 4.9 Hz), 2.52-2.46 (4H, m), 2.10 ( 2H, d, J = 7.2 Hz), 1.85-1.79 (1H, m), 0.89 (6H, d, J = 6.3 Hz).

工程３
3-(3-(4-イソブチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 3
3- (3- (4-Isobutylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000613
Figure JPOXMLDOC01-appb-C000613

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-(4-イソブチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (145 mg, 0.338 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (85 μL, 6.76 μmol) から標記化合物 (56 mg, 46%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.9 Hz), 8.48 (1H, s), 8.37 (1H, d, J = 9.2 Hz), 7.79 (1H, s), 7.66 (1H, d, J = 9.5 Hz), 7.62 (1H, d, J = 7.7 Hz), 7.39 (1H, t, J = 8.0 Hz), 7.02 (1H, dd, J = 8.3, 2.6 Hz), 3.25 (4H, t, J = 4.9 Hz), 2.52 (4H, t, J = 4.9 Hz), 2.11 (2H, d, J = 7.4 Hz), 1.86-1.78 (1H, m), 0.89 (6H, d, J = 6.6 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3- (4-Isobutylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (145 mg, 0.338 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol (85 μL, 6.76 μmol) gave the title compound (56 mg, 46%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.9 Hz), 8.48 (1H, s), 8.37 (1H, d, J = 9.2 Hz), 7.79 (1H, s), 7.66 (1H, d, J = 9.5 Hz), 7.62 (1H, d, J = 7.7 Hz), 7.39 (1H, t, J = 8.0 Hz), 7.02 (1H, dd, J = 8.3, 2.6 Hz), 3.25 (4H, t, J = 4.9 Hz), 2.52 (4H, t, J = 4.9 Hz), 2.11 (2H, d, J = 7.4 Hz), 1.86-1.78 (1H, m), 0.89 ( (6H, d, J = 6.6 Hz).

工程４
5-((3-(3-(4-イソブチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４６) Process 4
5-((3- (3- (4-Isobutylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 146)

Figure JPOXMLDOC01-appb-C000614
Figure JPOXMLDOC01-appb-C000614

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-(4-イソブチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (56 mg, 0.154 mmol) およびチアゾリジン-2,4-ジオン (18 mg, 0.154 mmol) から標記化合物 (40 mg, 56%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.28 (1H, d, J = 9.5 Hz), 8.21 (1H, s), 7.80 (1H, s), 7.67 (1H, d, J = 9.2 Hz), 7.62 (1H, s), 7.46 (1H, d, J =8.0 Hz), 7.38 (1H, t, J = 7.9 Hz), 7.02 (1H, dd, J = 8.0, 2.0 Hz), 3.36-3.27 (4H, m), 2.68 (4H, s), 2.27 (2H, d, J = 6.6 Hz), 1.91-1.84 (1H, m), 0.90 (6H, d, J = 6.6 Hz).
ESI-MS(m/z): 463[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3- (4-isobutylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (56 mg, 0.154 mmol) and thiazolidine The title compound (40 mg, 56%) was obtained from -2,4-dione (18 mg, 0.154 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.28 (1H, d, J = 9.5 Hz), 8.21 (1H, s), 7.80 (1H, s), 7.67 (1H, d, J = 9.2 Hz), 7.62 (1H, s), 7.46 (1H, d, J = 8.0 Hz), 7.38 (1H, t, J = 7.9 Hz), 7.02 (1H, dd, J = 8.0, 2.0 Hz), 3.36- 3.27 (4H, m), 2.68 (4H, s), 2.27 (2H, d, J = 6.6 Hz), 1.91-1.84 (1H, m), 0.90 (6H, d, J = 6.6 Hz).
ESI-MS (m / z): 463 [M + H] + .

実施例１４７
5-((3-(4-(4-ブチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４７)  Example 147
5-((3- (4- (4-Butylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 147)

工程１
3-(4-(4-ブチルピペラジン-1-イル)-3-フルオロフェニル)-6-クロロイミダゾ[1,2-b]ピリダジン Process 1
3- (4- (4-Butylpiperazin-1-yl) -3-fluorophenyl) -6-chloroimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000615
Figure JPOXMLDOC01-appb-C000615

アルゴン雰囲気下、6-クロロ-3-(3-フルオロ-4-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (150 mg, 0.452 mmol) をジクロロメタン (4.5 mL) に溶解した。そこへブチルアルデヒド (80 μL, 0.904 mmol) を加え、室温で1時間撹拌した。さらにナトリウムトリアセトキシボロヒドリド (144 mg, 0.678 mmol) を加え、室温で3時間撹拌した。反応液に飽和重層水を加え、クロロホルムで抽出した。クロロホルム層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (128 mg, 73%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.32 (1H, s), 8.29 (1H, d, J = 9.5 Hz), 7.93-7.88 (2H, m), 7.41 (1H, d, J = 9.5 Hz), 7.18 (1H, t, J = 9.2 Hz), 3.10 (4H, t, J =4.7 Hz), 2.53 (4H, t, J = 4.4 Hz), 2.33 (2H, t, J = 7.3 Hz), 1.48-1.40 (2H, m), 1.36-1.28 (2H, m), 0.90 (3H, t, J = 7.3 Hz). 6-Chloro-3- (3-fluoro-4- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (150 mg, 0.452 mmol) dissolved in dichloromethane (4.5 mL) under argon atmosphere did. Butyraldehyde (80 μL, 0.904 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (144 mg, 0.678 mmol) was further added, and the mixture was stirred at room temperature for 3 hours. Saturated multistory water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (128 mg, 73%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.32 (1H, s), 8.29 (1H, d, J = 9.5 Hz), 7.93-7.88 (2H, m), 7.41 (1H, d, J = 9.5 Hz), 7.18 (1H, t, J = 9.2 Hz), 3.10 (4H, t, J = 4.7 Hz), 2.53 (4H, t, J = 4.4 Hz), 2.33 (2H, t, J = 7.3 Hz), 1.48-1.40 (2H, m), 1.36-1.28 (2H, m), 0.90 (3H, t, J = 7.3 Hz).

工程２
3-(4-(4-ブチルピペラジン-1-イル)-3-フルオロフェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 2
3- (4- (4-Butylpiperazin-1-yl) -3-fluorophenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000616
Figure JPOXMLDOC01-appb-C000616

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、3-(4-(4-ブチルピペラジン-1-イル)-3-フルオロフェニル)-6-クロロイミダゾ[1,2-b]ピリダジン (125 mg, 0.338 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (62 μL, 0.363 mmol) から標記化合物 (103 mg, 82%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.23 (1H, s), 8.18 (1H, d, J = 9.5 Hz), 8.01-7.96 (2H, m), 7.16 (1H, t, J = 9.2 Hz), 6.92 (1H, dd, J = 17.8, 11.2 Hz), 6.37 (1H, d, J = 17.8 Hz), 5.78 (1H, d, J = 11.5 Hz), 3.10 (4H, t, J = 4.6 Hz), 2.54-2.52 (4H, m), 2.33 (2H, t, J = 7.3 Hz), 1.48-1.42 (2H, m), 1.36-1.28 (2H, m), 0.90 (3H, t, J = 7.4 Hz). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) 3- (4- (4-Butylpiperazin-1-yl) -3-fluorophenyl) -6-chloroimidazo [1,2-b] pyridazine (125 mg, 0.338 mmol) and 4,4,5,5- The title compound (103 mg, 82%) was obtained from tetramethyl-2-vinyl-1,3,2-dioxaborolane (62 μL, 0.363 mmol). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.23 (1H, s), 8.18 (1H, d, J = 9.5 Hz), 8.01-7.96 (2H, m), 7.16 (1H, t, J = 9.2 Hz), 6.92 (1H, dd, J = 17.8, 11.2 Hz), 6.37 (1H, d, J = 17.8 Hz), 5.78 (1H, d, J = 11.5 Hz), 3.10 (4H, t, J = 4.6 Hz), 2.54-2.52 (4H, m), 2.33 (2H, t, J = 7.3 Hz), 1.48-1.42 (2H, m), 1.36-1.28 (2H, m), 0.90 (3H, t, J = 7.4 Hz).

工程３
3-(4-(4-ブチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 3
3- (4- (4-Butylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000617
Figure JPOXMLDOC01-appb-C000617

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(4-(4-ブチルピペラジン-1-イル)-3-フルオロフェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (103 mg, 0.271 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (68 μL, 5.42 μmol) から標記化合物 (48 mg, 46%) を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 10.1 (1H, s), 8.47 (1H, s), 8.37 (1H, d, J = 9.5 Hz), 8.08-8.01 (2H, m), 7.65 (1H, d, J =9.2 Hz), 7.18 (1H, t, J = 8.9 Hz), 3.12 (4H, t, J = 4.6 Hz), 2.55-2.52 (4H, m), 2.34 (2H, t, J =7.3 Hz), 1.48-1.42 (2H, m), 1.36-1.28 (2H, m), 0.90 (3H, t, J = 7.3 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 4- (4-Butylpiperazin-1-yl) -3-fluorophenyl) -6-vinylimidazo [1,2-b] pyridazine (103 mg, 0.271 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol ( The title compound (48 mg, 46%) was obtained from 68 μL, 5.42 μmol). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, s), 8.47 (1H, s), 8.37 (1H, d, J = 9.5 Hz), 8.08-8.01 (2H, m), 7.65 (1H, d, J = 9.2 Hz), 7.18 (1H, t, J = 8.9 Hz), 3.12 (4H, t, J = 4.6 Hz), 2.55-2.52 (4H, m), 2.34 (2H, t , J = 7.3 Hz), 1.48-1.42 (2H, m), 1.36-1.28 (2H, m), 0.90 (3H, t, J = 7.3 Hz).

工程４
5-((3-(4-(4-ブチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４７) Process 4
5-((3- (4- (4-Butylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 147)

Figure JPOXMLDOC01-appb-C000618
Figure JPOXMLDOC01-appb-C000618

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(4-(4-ブチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (48 mg, 0.126 mmol) およびチアゾリジン-2,4-ジオン (15 mg, 0.126 mmol) から標記化合物 (16 mg, 26%) を得た。赤色固体: 1H-NMR (DMSO-D6) δ: 8.26 (1H, s), 8.25 (1H, d, J = 9.5 Hz), 8.09 (1H, dd, J = 14.3, 2.0 Hz), 7.86 (1H, dd, J = 8.4, 1.9 Hz), 7.73 (1H, s), 7.64 (1H, d, J = 9.5 Hz), 7.18 (1H, t, J = 8.9 Hz), 3.21 (4H, s), 2.85 (4H, s), 2.64-2.61 (2H, m), 1.56-1.50 (2H, m), 1.37-1.30 (2H, m), 0.92 (3H, t, J = 7.3 Hz).
ESI-MS(m/z): 481[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (4- (4-butylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (48 mg, 0.126 mmol) and thiazolidine-2,4-dione (15 mg, 0.126 mmol) gave the title compound (16 mg, 26%). Red solid: 1 H-NMR (DMSO-D 6 ) δ: 8.26 (1H, s), 8.25 (1H, d, J = 9.5 Hz), 8.09 (1H, dd, J = 14.3, 2.0 Hz), 7.86 ( 1H, dd, J = 8.4, 1.9 Hz), 7.73 (1H, s), 7.64 (1H, d, J = 9.5 Hz), 7.18 (1H, t, J = 8.9 Hz), 3.21 (4H, s), 2.85 (4H, s), 2.64-2.61 (2H, m), 1.56-1.50 (2H, m), 1.37-1.30 (2H, m), 0.92 (3H, t, J = 7.3 Hz).
ESI-MS (m / z): 481 [M + H] + .

実施例１４８
5-((3-(3-((エチル(プロピル)アミノ)メチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４８) Example 148
5-((3- (3-((Ethyl (propyl) amino) methyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 148)

工程１
(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)メタノール Process 1
(3- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) phenyl) methanol

Figure JPOXMLDOC01-appb-C000619
Figure JPOXMLDOC01-appb-C000619

3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-カルボニトリルの合成 (実施例106、工程6) と同様の手法で、3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (1.02 g, 4.39 mmol) および3-(ヒドロキシメチル)フェニルボロン酸 (800 mg, 5.27 mmol) から標記化合物 (866 mg, 76%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.30 (1H, d, J = 9.5 Hz), 8.29 (1H, s), 8.01 (1H, s), 7.98 (1H, d, J = 7.7 Hz), 7.51 (1H, t, J = 7.7 Hz), 7.43 (1H, d, J =9.5 Hz), 7.39 (1H, d, J = 7.4 Hz), 5.30 (1H, t, J = 5.7 Hz), 4.59 (2H, d, J = 5.7 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridine-5-carbonitrile (Example 106, Step 6) The title compound (866 mg, 76%) was obtained from -6-chloroimidazo [1,2-b] pyridazine (1.02 g, 4.39 mmol) and 3- (hydroxymethyl) phenylboronic acid (800 mg, 5.27 mmol). . Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.30 (1H, d, J = 9.5 Hz), 8.29 (1H, s), 8.01 (1H, s), 7.98 (1H, d, J = 7.7 Hz), 7.51 (1H, t, J = 7.7 Hz), 7.43 (1H, d, J = 9.5 Hz), 7.39 (1H, d, J = 7.4 Hz), 5.30 (1H, t, J = 5.7 Hz) ), 4.59 (2H, d, J = 5.7 Hz).

工程２
3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)ベンズアルデヒド Process 2
3- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) benzaldehyde

Figure JPOXMLDOC01-appb-C000620
Figure JPOXMLDOC01-appb-C000620

2-(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)アセトアルデヒドの合成 (実施例135、工程４) と同様の手法で、(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)メタノール (1.02 g, 4.39 mmol) およびデス・マーチン・ペルヨージナン (1.69 g, 4.00 mmol) から標記化合物 (874 mg, quant.) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 10.1 (1H, s), 8.65 (1H, t, J = 1.6 Hz), 8.45 (1H, s), 8.43 (1H, dq, J =7.8, 1.0 Hz), 8.35 (1H, d, J =9.5 Hz), 7.97 (1H, dt, J = 7.6, 1.4 Hz), 7.80 (1H, t, J = 7.7 Hz), 7.49 (1H, d, J = 9.5 Hz). Synthesis of 2- (3- (6-chloroimidazo [1,2-b] pyridazin-3-yl) phenyl) acetaldehyde (3- (6-Chloroimidazo) in the same manner as in Example 135, Step 4 The title compound (874 mg, quant.) Was obtained from [1,2-b] pyridazin-3-yl) phenyl) methanol (1.02 g, 4.39 mmol) and Dess-Martin periodinane (1.69 g, 4.00 mmol). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, s), 8.65 (1H, t, J = 1.6 Hz), 8.45 (1H, s), 8.43 (1H, dq, J = 7.8, 1.0 Hz), 8.35 (1H, d, J = 9.5 Hz), 7.97 (1H, dt, J = 7.6, 1.4 Hz), 7.80 (1H, t, J = 7.7 Hz), 7.49 (1H, d, J = 9.5 Hz).

工程３
N-(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)ベンジル)-N-エチルプロパン-1-アミン Process 3
N- (3- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) benzyl) -N-ethylpropan-1-amine

Figure JPOXMLDOC01-appb-C000621
Figure JPOXMLDOC01-appb-C000621

6-ブロモ-3-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジンの合成 (実施例53、工程2) と同様の手法で、3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)ベンズアルデヒド (150 mg, 0.582 mmol) およびN-エチル-N-プロピルアミン (141 μL, 1.16 mmol) から標記化合物 (184 mg, 96%)を得た。薄黄色オイル: 1H-NMR (DMSO-D6) δ: 8.30 (1H, d, J = 9.5 Hz), 8.28 (1H, s), 8.08 (1H, s), 7.93 (1H, d, J = 7.7 Hz), 7.48 (1H, t, J = 7.6 Hz), 7.42 (1H, d, J = 9.5 Hz), 7.36 (1H, d, J = 7.4 Hz), 3.62 (2H, s), 2.52-2.47 (2H, m), 2.40 (2H, t, J =7.2 Hz), 1.51-1.43 (2H, m), 1.01 (3H, t, J = 7.2 Hz), 0.86 (3H, t, J =7.3 Hz). Synthesis of 6-bromo-3- (4-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine (Example 53, Step 2) -(6-Chloroimidazo [1,2-b] pyridazin-3-yl) benzaldehyde (150 mg, 0.582 mmol) and N-ethyl-N-propylamine (141 μL, 1.16 mmol) to the title compound (184 mg, 96%). Pale yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.30 (1H, d, J = 9.5 Hz), 8.28 (1H, s), 8.08 (1H, s), 7.93 (1H, d, J = 7.7 Hz), 7.48 (1H, t, J = 7.6 Hz), 7.42 (1H, d, J = 9.5 Hz), 7.36 (1H, d, J = 7.4 Hz), 3.62 (2H, s), 2.52-2.47 (2H, m), 2.40 (2H, t, J = 7.2 Hz), 1.51-1.43 (2H, m), 1.01 (3H, t, J = 7.2 Hz), 0.86 (3H, t, J = 7.3 Hz) .

工程４
N-エチル-N-(3-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)ベンジル)プロパン-1-アミン Process 4
N-ethyl-N- (3- (6-vinylimidazo [1,2-b] pyridazin-3-yl) benzyl) propan-1-amine

Figure JPOXMLDOC01-appb-C000622
Figure JPOXMLDOC01-appb-C000622

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、N-(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)ベンジル)-N-エチルプロパン-1-アミン (184 mg, 0.560 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (105 μL, 0.616 mmol) から標記化合物 (136 mg, 76%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.21-8.20 (1H, m), 8.21 (1H, s), 8.19 (1H, d, J = 9.2 Hz), 7.99-7.97 (1H, m), 7.65 (1H, d, J =9.5 Hz), 7.45 (1H, t, J = 7.6 Hz), 7.32 (1H, d, J = 7.7 Hz), 6.89 (1H, dd, J = 17.8, 11.2 Hz), 6.40 (1H, d, J = 17.8 Hz), 5.78 (1H, d, J = 11.5 Hz), 3.61 (2H, s), 2.52-2.47 (2H, m), 2.40 (2H, t, J = 7.3 Hz), 1.50-1.43 (2H, m), 1.01 (3H, t, J = 7.0 Hz), 0.85 (3H, t, J = 7.4 Hz). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) N- (3- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) benzyl) -N-ethylpropan-1-amine (184 mg, 0.560 mmol) and 4,4,5,5- The title compound (136 mg, 76%) was obtained from tetramethyl-2-vinyl-1,3,2-dioxaborolane (105 μL, 0.616 mmol). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.21-8.20 (1H, m), 8.21 (1H, s), 8.19 (1H, d, J = 9.2 Hz), 7.99-7.97 (1H, m ), 7.65 (1H, d, J = 9.5 Hz), 7.45 (1H, t, J = 7.6 Hz), 7.32 (1H, d, J = 7.7 Hz), 6.89 (1H, dd, J = 17.8, 11.2 Hz) ), 6.40 (1H, d, J = 17.8 Hz), 5.78 (1H, d, J = 11.5 Hz), 3.61 (2H, s), 2.52-2.47 (2H, m), 2.40 (2H, t, J = 7.3 Hz), 1.50-1.43 (2H, m), 1.01 (3H, t, J = 7.0 Hz), 0.85 (3H, t, J = 7.4 Hz).

工程５
3-(3-((エチル(プロピル)アミノ)メチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 5
3- (3-((Ethyl (propyl) amino) methyl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000623
Figure JPOXMLDOC01-appb-C000623

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、N-エチル-N-(3-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)ベンジル)プロパン-1-アミン (136 mg, 0.424 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (106 μL, 8.48 μmol) から標記化合物 (68 mg, 50%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.9 Hz), 8.45 (1H, s), 8.38 (1H, dd, J = 9.5, 0.9 Hz), 8.18 (1H, s), 8.08 (1H, d, J = 7.7 Hz), 7.67 (1H, d, J = 9.5 Hz), 7.51 (1H, t, J = 7.7 Hz), 7.40 (1H, d, J = 7.7 Hz), 3.64 (2H, s), 2.54-2.49 (2H, m), 2.41 (2H, t, J =7.3 Hz), 1.51-1.43 (2H, m), 1.01 (3H, t, J = 7.0 Hz), 0.85 (3H, t, J =7.3 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) -N- (3- (6-vinylimidazo [1,2-b] pyridazin-3-yl) benzyl) propan-1-amine (136 mg, 0.424 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol ( The title compound (68 mg, 50%) was obtained from 106 μL, 8.48 μmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.9 Hz), 8.45 (1H, s), 8.38 (1H, dd, J = 9.5, 0.9 Hz), 8.18 ( 1H, s), 8.08 (1H, d, J = 7.7 Hz), 7.67 (1H, d, J = 9.5 Hz), 7.51 (1H, t, J = 7.7 Hz), 7.40 (1H, d, J = 7.7 Hz), 3.64 (2H, s), 2.54-2.49 (2H, m), 2.41 (2H, t, J = 7.3 Hz), 1.51-1.43 (2H, m), 1.01 (3H, t, J = 7.0 Hz ), 0.85 (3H, t, J = 7.3 Hz).

工程６
5-((3-(3-((エチル(プロピル)アミノ)メチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４８) Step 6
5-((3- (3-((Ethyl (propyl) amino) methyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 148)

Figure JPOXMLDOC01-appb-C000624
Figure JPOXMLDOC01-appb-C000624

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-((エチル(プロピル)アミノ)メチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (68 mg, 0.211 mmol) およびチアゾリジン-2,4-ジオン (25 mg, 0.211 mmol) から標記化合物 (35 mg, 39%) を得た。橙色固体, 35 mg, 39%: 1H-NMR (DMSO-D6) δ: 8.27 (1H, d, J = 9.4 Hz), 8.25 (1H, s), 8.23 (1H, s), 8.05 (1H, d, J = 7.6 Hz), 7.70 (1H, s), 7.66 (1H, d, J = 9.4 Hz), 7.57 (1H, t, J = 7.7 Hz), 7.51 (1H, d, J =7.6 Hz), 3.99 (2H, s), 2.81-2.75 (2H, m), 2.69-2.65 (2H, m), 1.60-1.51 (2H, m), 1.10 (3H, t, J = 7.2 Hz), 0.85 (3H, t, J = 7.4 Hz).
ESI-MS(m/z): 422[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3-((ethyl (propyl) amino) methyl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (68 mg, 0.211 mmol) and thiazolidine The title compound (35 mg, 39%) was obtained from -2,4-dione (25 mg, 0.211 mmol). Orange solid, 35 mg, 39%: 1 H-NMR (DMSO-D 6 ) δ: 8.27 (1H, d, J = 9.4 Hz), 8.25 (1H, s), 8.23 (1H, s), 8.05 (1H , d, J = 7.6 Hz), 7.70 (1H, s), 7.66 (1H, d, J = 9.4 Hz), 7.57 (1H, t, J = 7.7 Hz), 7.51 (1H, d, J = 7.6 Hz) ), 3.99 (2H, s), 2.81-2.75 (2H, m), 2.69-2.65 (2H, m), 1.60-1.51 (2H, m), 1.10 (3H, t, J = 7.2 Hz), 0.85 ( (3H, t, J = 7.4 Hz).
ESI-MS (m / z): 422 [M + H] + .

実施例１４９
5-((3-(3-((1,1-ジオキシドチオモルホリノ)メチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４９) Example 149
5-((3- (3-((1,1-dioxidethiomorpholino) methyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 149 )

工程１
4-(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)ベンジル)チオモルホリン 1,1-ジオキシド Process 1
4- (3- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) benzyl) thiomorpholine 1,1-dioxide

Figure JPOXMLDOC01-appb-C000625
Figure JPOXMLDOC01-appb-C000625

6-ブロモ-3-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジンの合成 (実施例53、工程2) と同様の手法で、3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)ベンズアルデヒド (120 mg, 0.466 mmol) およびチオモルホリン-1,1-ジオキシド (126 mg, 0.932 mmol) から標記化合物 (143 mg, 81%) を得た。薄黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.33 (1H, s), 8.31 (1H, d, J = 9.4 Hz), 8.08 (1H, s), 8.01-7.99 (1H, m), 7.52 (1H, t, J = 7.8 Hz), 7.44 (1H, d, J = 9.6 Hz), 7.38 (1H, d, J = 7.8 Hz), 3.78 (2H, s), 3.15 (4H, t, J = 5.0 Hz), 2.95-2.92 (4H, m). Synthesis of 6-bromo-3- (4-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridine (Example 53, Step 2) -(6-Chloroimidazo [1,2-b] pyridazin-3-yl) benzaldehyde (120 mg, 0.466 mmol) and thiomorpholine-1,1-dioxide (126 mg, 0.932 mmol) to give the title compound (143 mg, 81%). Pale yellow amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.33 (1H, s), 8.31 (1H, d, J = 9.4 Hz), 8.08 (1H, s), 8.01-7.99 (1H, m), 7.52 (1H, t, J = 7.8 Hz), 7.44 (1H, d, J = 9.6 Hz), 7.38 (1H, d, J = 7.8 Hz), 3.78 (2H, s), 3.15 (4H, t, J = 5.0 Hz), 2.95-2.92 (4H, m).

工程２
4-(3-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)ベンジル)チオモルホリン 1,1-ジオキシド Process 2
4- (3- (6-vinylimidazo [1,2-b] pyridazin-3-yl) benzyl) thiomorpholine 1,1-dioxide

Figure JPOXMLDOC01-appb-C000626
Figure JPOXMLDOC01-appb-C000626

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、4-(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)ベンジル)チオモルホリン 1,1-ジオキシド (143 mg, 0.379 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (71 μL, 0.417 mmol) から標記化合物 (114 mg, 82%) を得た。黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.24 (1H, s), 8.20 (1H, d, J = 9.4 Hz), 8.15 (1H, s), 8.10-8.07 (1H, m), 7.66 (1H, d, J = 9.4 Hz), 7.50 (1H, t, J = 7.7 Hz), 7.36 (1H, d, J = 7.6 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.39 (1H, d, J = 17.6 Hz), 5.78 (1H, d, J = 11.4 Hz), 3.78 (2H, s), 3.14 (4H, t, J = 5.0 Hz), 2.95-2.93 (4H, m). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) 4- (3- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) benzyl) thiomorpholine 1,1-dioxide (143 mg, 0.379 mmol) and 4,4,5,5-tetramethyl The title compound (114 mg, 82%) was obtained from -2-vinyl-1,3,2-dioxaborolane (71 μL, 0.417 mmol). Yellow amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.24 (1H, s), 8.20 (1H, d, J = 9.4 Hz), 8.15 (1H, s), 8.10-8.07 (1H, m ), 7.66 (1H, d, J = 9.4 Hz), 7.50 (1H, t, J = 7.7 Hz), 7.36 (1H, d, J = 7.6 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz) ), 6.39 (1H, d, J = 17.6 Hz), 5.78 (1H, d, J = 11.4 Hz), 3.78 (2H, s), 3.14 (4H, t, J = 5.0 Hz), 2.95-2.93 (4H , m).

工程３
3-(3-((1,1-ジオキシドチオモルホリノ)メチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 3
3- (3-((1,1-dioxidethiomorpholino) methyl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000627
Figure JPOXMLDOC01-appb-C000627

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、4-(3-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)ベンジル)チオモルホリン 1,1-ジオキシド(114 mg, 0.309 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (77 μL, 6.18 μmol) から標記化合物 (81 mg, 71%) を得た。黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.7 Hz), 8.49 (1H, s), 8.39 (1H, dd, J =9.4, 0.9 Hz), 8.18 (1H, s), 8.16-8.14 (1H, m), 7.68 (1H, d, J = 9.6 Hz), 7.55 (1H, t, J = 7.8 Hz), 7.43-7.40 (1H, m), 3.80 (2H, s), 3.15 (4H, t, J = 5.3 Hz), 2.96-2.93 (4H, m). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3- (6-vinylimidazo [1,2-b] pyridazin-3-yl) benzyl) thiomorpholine 1,1-dioxide (114 mg, 0.309 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol (77 μL , 6.18 μmol) gave the title compound (81 mg, 71%). Yellow amorphous substance: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.7 Hz), 8.49 (1H, s), 8.39 (1H, dd, J = 9.4, 0.9 Hz), 8.18 (1H, s), 8.16-8.14 (1H, m), 7.68 (1H, d, J = 9.6 Hz), 7.55 (1H, t, J = 7.8 Hz), 7.43-7.40 (1H, m), 3.80 (2H, s), 3.15 (4H, t, J = 5.3 Hz), 2.96-2.93 (4H, m).

工程４
5-((3-(3-((1,1-ジオキシドチオモルホリノ)メチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１４９) Process 4
5-((3- (3-((1,1-dioxidethiomorpholino) methyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 149 )

Figure JPOXMLDOC01-appb-C000628
Figure JPOXMLDOC01-appb-C000628

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-((1,1-ジオキシドチオモルホリノ)メチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (81 mg, 0.219 mmol) およびチアゾリジン-2,4-ジオン (26 mg, 0.219 mmol) から標記化合物 (35 mg, 34%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.33 (1H, d, J = 9.4 Hz), 8.28 (1H, s), 8.11 (1H, s), 7.93 (1H, s), 7.93-7.91 (1H, m), 7.74 (1H, d, J = 9.4 Hz), 7.53 (1H, t, J = 7.7 Hz), 7.47 (1H, d, J =7.6 Hz), 3.80 (2H, s), 3.12 (4H, t, J = 4.9 Hz), 2.94-2.92 (4H, m).
ESI-MS(m/z): 470[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3-((1,1-dioxidethiomorpholino) methyl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (81 mg, 0.219 mmol ) And thiazolidine-2,4-dione (26 mg, 0.219 mmol) gave the title compound (35 mg, 34%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.33 (1H, d, J = 9.4 Hz), 8.28 (1H, s), 8.11 (1H, s), 7.93 (1H, s), 7.93- 7.91 (1H, m), 7.74 (1H, d, J = 9.4 Hz), 7.53 (1H, t, J = 7.7 Hz), 7.47 (1H, d, J = 7.6 Hz), 3.80 (2H, s), 3.12 (4H, t, J = 4.9 Hz), 2.94-2.92 (4H, m).
ESI-MS (m / z): 470 [M + H] + .

実施例１５０
5-((3-(3-フルオロ-4-((3R,5S)-3,4,5-トリメチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１５０) Example 150
5-((3- (3-Fluoro-4-((3R, 5S) -3,4,5-trimethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene ) Thiazolidine-2,4-dione (Compound 150)

工程１
(3R,5S)-1-(2-フルオロ-4-ニトロフェニル)-3,5-ジメチルピペラジン Process 1
(3R, 5S) -1- (2-Fluoro-4-nitrophenyl) -3,5-dimethylpiperazine

Figure JPOXMLDOC01-appb-C000629
Figure JPOXMLDOC01-appb-C000629

アルゴン雰囲気下、3,4-ジフルオロニトロベンゼン (1.0 g, 6.29 mmol) をアセトニトリル (15 mL) に溶解した。そこへcis-3,5-ジメチルピペラジン (861 mg, 7.55 mmol)、N,N-ジイソプロピルエチルアミン (2.19 mL, 12.6 mmol) を加え、80℃で2時間撹拌した。反応液に水を加え、クロロホルムで抽出した。クロロホルム層を飽和重層水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (NHカラム、クロロホルム/メタノール) で精製し、標記化合物 (1.42 g, 89%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.00-7.96 (2H, m), 7.14 (1H, t, J = 8.9 Hz), 3.53 (2H, d, J = 10.6 Hz), 2.89-2.83 (2H, m), 2.43 (2H, t, J = 11.2 Hz), 2.28 (1H, s), 1.00 (6H, d, J = 6.3 Hz). Under an argon atmosphere, 3,4-difluoronitrobenzene (1.0 g, 6.29 mmol) was dissolved in acetonitrile (15 mL). Cis-3,5-dimethylpiperazine (861 mg, 7.55 mmol) and N, N-diisopropylethylamine (2.19 mL, 12.6 mmol) were added thereto, and the mixture was stirred at 80 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated multilayered water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (NH column, chloroform / methanol) to obtain the title compound (1.42 g, 89%). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.00-7.96 (2H, m), 7.14 (1H, t, J = 8.9 Hz), 3.53 (2H, d, J = 10.6 Hz), 2.89- 2.83 (2H, m), 2.43 (2H, t, J = 11.2 Hz), 2.28 (1H, s), 1.00 (6H, d, J = 6.3 Hz).

工程２
(2R,6S)-tert-ブチル 4-(2-フルオロ-4-ニトロフェニル)-2,6-ジメチルピペラジン-1-カルボキシレート Process 2
(2R, 6S) -tert-butyl 4- (2-fluoro-4-nitrophenyl) -2,6-dimethylpiperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000630
Figure JPOXMLDOC01-appb-C000630

アルゴン雰囲気下、(3R,5S)-1-(2-フルオロ-4-ニトロフェニル)-3,5-ジメチルピペラジン (1.17 g, 4.63 mmol) をテトラヒドロフラン (7 mL) に溶解し、0℃に冷却した。そこへ二炭酸ジ-tert-ブチル (2.18 g, 9.26 mmol) を加えた。さらに炭酸カリウム (1.03 g, 6.95 mmol) の水溶液 (7.5 mL) を加え、0℃で10分撹拌後、室温で22時間撹拌した。反応液に飽和食塩水を加え、クロロホルムで抽出した。クロロホルム層を1規定塩酸、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製し, 表題化合物 (1.54 g, 94%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.07-8.02 (2H, m), 7.19 (1H, t, J = 9.3 Hz), 4.16-4.12 (2H, m), 3.52 (2H, d, J = 12.3 Hz), 3.04 (2H, dd, J = 12.2, 4.2 Hz), 1.43 (9H, s), 1.26 (6H, d, J =6.9 Hz). (3R, 5S) -1- (2-Fluoro-4-nitrophenyl) -3,5-dimethylpiperazine (1.17 g, 4.63 mmol) was dissolved in tetrahydrofuran (7 mL) under an argon atmosphere and cooled to 0 ° C. did. Di-tert-butyl dicarbonate (2.18 g, 9.26 mmol) was added thereto. Further, an aqueous solution (7.5 mL) of potassium carbonate (1.03 g, 6.95 mmol) was added, stirred at 0 ° C. for 10 minutes, and then stirred at room temperature for 22 hours. Saturated saline was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.54 g, 94%). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.07-8.02 (2H, m), 7.19 (1H, t, J = 9.3 Hz), 4.16-4.12 (2H, m), 3.52 (2H, d, J = 12.3 Hz), 3.04 (2H, dd, J = 12.2, 4.2 Hz), 1.43 (9H, s), 1.26 (6H, d, J = 6.9 Hz).

工程３
(2R,6S)-tert-ブチル 4-(4-アミノ-2-フルオロフェニル)-2,6-ジメチルピペラジン-1-カルボキシレート Process 3
(2R, 6S) -tert-butyl 4- (4-amino-2-fluorophenyl) -2,6-dimethylpiperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000631
Figure JPOXMLDOC01-appb-C000631

tert-ブチル 4-(4-アミノ-2-メチルフェニル)ピペラジン-1-カルボキシレートの合成 (実施例133、工程2) と同様の手法で、(2R,6S)-tert-ブチル 4-(2-フルオロ-4-ニトロフェニル)-2,6-ジメチルピペラジン-1-カルボキシレート (1.54 g, 4.37 mmol) から標記化合物 (1.29 g, 92%) を得た。薄ピンク色固体: 1H-NMR (DMSO-D6) δ: 6.74 (1H, t, J = 9.3 Hz), 6.37-6.29 (2H, m), 5.00 (2H, s), 4.06-4.01 (2H, m), 2.90 (2H, d, J = 11.2 Hz), 2.67 (2H, dd, J = 11.3, 4.2 Hz), 1.28 (6H, d, J = 6.9 Hz). Synthesis of tert-butyl 4- (4-amino-2-methylphenyl) piperazine-1-carboxylate In the same manner as in Example 133, Step 2, (2R, 6S) -tert-butyl 4- (2 The title compound (1.29 g, 92%) was obtained from -fluoro-4-nitrophenyl) -2,6-dimethylpiperazine-1-carboxylate (1.54 g, 4.37 mmol). Light pink solid: 1 H-NMR (DMSO-D 6 ) δ: 6.74 (1H, t, J = 9.3 Hz), 6.37-6.29 (2H, m), 5.00 (2H, s), 4.06-4.01 (2H , m), 2.90 (2H, d, J = 11.2 Hz), 2.67 (2H, dd, J = 11.3, 4.2 Hz), 1.28 (6H, d, J = 6.9 Hz).

工程４
(2R,6S)-tert-ブチル 4-(4-ブロモ-2-フルオロフェニル)-2,6-ジメチルピペラジン-1-カルボキシレート Process 4
(2R, 6S) -tert-butyl 4- (4-bromo-2-fluorophenyl) -2,6-dimethylpiperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000632
Figure JPOXMLDOC01-appb-C000632

tert-ブチル 4-(4-ブロモ-2-(トリフルオロメチル)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例137、工程3) と同様の手法で、(2R,6S)-tert-ブチル 4-(4-アミノ-2-フルオロフェニル)-2,6-ジメチルピペラジン-1-カルボキシレート (1.29 g, 4.00 mmol) および臭化銅 (II) (983 mg, 4.40 mmol) から標記化合物 (768 mg, 50%) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 7.46 (1H, dd, J = 12.0, 2.3 Hz), 7.33-7.31 (1H, m), 6.99 (1H, t, J = 9.0 Hz), 4.12-4.07 (2H, m), 3.15 (2H, d, J =11.7 Hz), 2.78 (2H, dd, J =11.7, 4.0 Hz), 1.43 (9H, s), 1.28 (6H, d, J = 6.9 Hz). Synthesis of tert-butyl 4- (4-bromo-2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (2R, 6S) -tert-butyl in the same manner as in Example 137, Step 3 4- (4-Amino-2-fluorophenyl) -2,6-dimethylpiperazine-1-carboxylate (1.29 g, 4.00 mmol) and copper (II) bromide (983 mg, 4.40 mmol) gave the title compound (768 mg, 50%). White solid: 1 H-NMR (DMSO-D 6 ) δ: 7.46 (1H, dd, J = 12.0, 2.3 Hz), 7.33-7.31 (1H, m), 6.99 (1H, t, J = 9.0 Hz), 4.12-4.07 (2H, m), 3.15 (2H, d, J = 11.7 Hz), 2.78 (2H, dd, J = 11.7, 4.0 Hz), 1.43 (9H, s), 1.28 (6H, d, J = 6.9 Hz).

工程５
(2R,6S)-tert-ブチル 4-(2-フルオロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)-2,6-ジメチルピペラジン-1-カルボキシレート Process 5
(2R, 6S) -tert-butyl 4- (2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -2,6-dimethyl Piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000633
Figure JPOXMLDOC01-appb-C000633

tert-ブチル 4-(3-フルオロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例85、工程4) と同様の手法で、(2R,6S)-tert-ブチル 4-(4-ブロモ-2-フルオロフェニル)-2,6-ジメチルピペラジン-1-カルボキシレート (768 mg, 1.98 mmol) およびビス(ピナコラート)ジボロン (553 mg, 2.18 mmol) から標記化合物 (704 mg, 82%) を得た。白色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 7.41 (1H, dd, J =7.9, 1.3 Hz), 7.29 (1H, dd, J =13.0, 1.3 Hz), 7.02 (1H, t, J =8.4 Hz), 4.13-4.08 (2H, m), 3.26 (2H, d, J = 12.6 Hz), 2.81 (2H, dd, J =11.9, 4.2 Hz), 1.43 (9H, s), 1.28 (6H, d, J = 6.6 Hz), 1.28 (12H, s). Synthesis of tert-butyl 4- (3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (Example 85) In the same manner as in step 4), (2R, 6S) -tert-butyl 4- (4-bromo-2-fluorophenyl) -2,6-dimethylpiperazine-1-carboxylate (768 mg, 1.98 mmol) The title compound (704 mg, 82%) was obtained from bis (pinacolato) diboron (553 mg, 2.18 mmol). White amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 7.41 (1H, dd, J = 7.9, 1.3 Hz), 7.29 (1H, dd, J = 13.0, 1.3 Hz), 7.02 (1H, t , J = 8.4 Hz), 4.13-4.08 (2H, m), 3.26 (2H, d, J = 12.6 Hz), 2.81 (2H, dd, J = 11.9, 4.2 Hz), 1.43 (9H, s), 1.28 (6H, d, J = 6.6 Hz), 1.28 (12H, s).

工程６
(2R,6S)-tert-ブチル 4-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-2-フルオロフェニル)-2,6-ジメチルピペラジン-1-カルボキシレート Step 6
(2R, 6S) -tert-butyl 4- (4- (6-chloroimidazo [1,2-b] pyridazin-3-yl) -2-fluorophenyl) -2,6-dimethylpiperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000634
Figure JPOXMLDOC01-appb-C000634

3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-カルボニトリルの合成 (実施例106、工程6) と同様の手法で、3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (704 mg, 1.62 mmol) および (2R,6S)-tert-ブチル 4-(2-フルオロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)-2,6-ジメチルピペラジン-1-カルボキシレート (704 mg, 1.62 mmol) から標記化合物 (477 mg, 77%) を得た。黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.32 (1H, s), 8.30 (1H, d, J = 9.5 Hz), 7.94-7.88 (2H, m), 7.42 (1H, d, J = 9.5 Hz), 7.20 (1H, t, J = 8.9 Hz), 4.16-4.11 (2H, m), 3.30 (2H, d, J = 11.7 Hz), 2.86 (2H, dd, J = 11.7, 4.3 Hz), 1.44 (9H, s), 1.32 (6H, d, J =6.9 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridine-5-carbonitrile (Example 106, Step 6) -6-Chloroimidazo [1,2-b] pyridazine (704 mg, 1.62 mmol) and (2R, 6S) -tert-butyl 4- (2-fluoro-4- (4,4,5,5-tetramethyl) -1,3,2-Dioxaborolan-2-yl) phenyl) -2,6-dimethylpiperazine-1-carboxylate (704 mg, 1.62 mmol) gave the title compound (477 mg, 77%). Yellow amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.32 (1H, s), 8.30 (1H, d, J = 9.5 Hz), 7.94-7.88 (2H, m), 7.42 (1H, d , J = 9.5 Hz), 7.20 (1H, t, J = 8.9 Hz), 4.16-4.11 (2H, m), 3.30 (2H, d, J = 11.7 Hz), 2.86 (2H, dd, J = 11.7, 4.3 Hz), 1.44 (9H, s), 1.32 (6H, d, J = 6.9 Hz).

工程７
6-クロロ-3-(4-((3R,5S)-3,5-ジメチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン Step 7
6-Chloro-3- (4-((3R, 5S) -3,5-dimethylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000635
Figure JPOXMLDOC01-appb-C000635

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程6) と同様の手法で、(2R,6S)-tert-ブチル 4-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-2-フルオロフェニル)-2,6-ジメチルピペラジン-1-カルボキシレート (477 mg, 1.04 mmol) およびトリフルオロ酢酸 (2 mL) から標記化合物 (337 mg, 90%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.31 (1H, s), 8.28 (1H, d, J = 9.5 Hz), 7.88 (1H, dd, J =23.9, 1.9 Hz), 7.88 (1H, s), 7.40 (1H, d, J = 9.5 Hz), 7.16 (1H, t, J = 8.9 Hz), 3.32-3.30 (2H, m), 2.96-2.91 (2H, m), 2.28 (2H, t, J = 10.7 Hz), 1.01 (6H, d, J = 6.3 Hz). Synthesis of 5-bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine In the same manner as in Example 65, Step 6, (2R, 6S ) -tert-butyl 4- (4- (6-chloroimidazo [1,2-b] pyridazin-3-yl) -2-fluorophenyl) -2,6-dimethylpiperazine-1-carboxylate (477 mg, The title compound (337 mg, 90%) was obtained from 1.04 mmol) and trifluoroacetic acid (2 mL). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.31 (1H, s), 8.28 (1H, d, J = 9.5 Hz), 7.88 (1H, dd, J = 23.9, 1.9 Hz), 7.88 (1H, s), 7.40 (1H, d, J = 9.5 Hz), 7.16 (1H, t, J = 8.9 Hz), 3.32-3.30 (2H, m), 2.96-2.91 (2H, m), 2.28 ( 2H, t, J = 10.7 Hz), 1.01 (6H, d, J = 6.3 Hz).

工程８
6-クロロ-3-(3-フルオロ-4-((3R,5S)-3,4,5-トリメチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Process 8
6-Chloro-3- (3-fluoro-4-((3R, 5S) -3,4,5-trimethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000636
Figure JPOXMLDOC01-appb-C000636

5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程7) と同様の手法で、6-クロロ-3-(4-((3R,5S)-3,5-ジメチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン (150 mg, 0.417 mmol) および 37% ホルムアルデヒド水溶液 (186 μL, 2.50 mmol) から標記化合物 (115 mg, 74%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.31 (1H, s), 8.29 (1H, d, J = 9.6 Hz), 7.92-7.85 (2H, m), 7.41 (1H, d, J = 9.4 Hz), 7.16 (1H, t, J = 9.2 Hz), 3.36-3.32 (2H, m), 2.56-2.50 (2H, m), 2.37-2.30 (2H, m), 2.21 (3H, s), 1.06 (6H, d, J = 6.0 Hz). Synthesis of 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 7) -Chloro-3- (4-((3R, 5S) -3,5-dimethylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazine (150 mg, 0.417 mmol) and 37 The title compound (115 mg, 74%) was obtained from an aqueous formaldehyde solution (186 μL, 2.50 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.31 (1H, s), 8.29 (1H, d, J = 9.6 Hz), 7.92-7.85 (2H, m), 7.41 (1H, d, J = 9.4 Hz), 7.16 (1H, t, J = 9.2 Hz), 3.36-3.32 (2H, m), 2.56-2.50 (2H, m), 2.37-2.30 (2H, m), 2.21 (3H, s) , 1.06 (6H, d, J = 6.0 Hz).

工程９
3-(3-フルオロ-4-((3R,5S)-3,4,5-トリメチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Step 9
3- (3-Fluoro-4-((3R, 5S) -3,4,5-trimethylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000637
Figure JPOXMLDOC01-appb-C000637

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、6-クロロ-3-(3-フルオロ-4-((3R,5S)-3,4,5-トリメチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (115 mg, 0.308 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (58 μL, 0.339 mmol) から標記化合物 (127 mg, quant.) を得た。黄色油状物質: 1H-NMR (DMSO-D6) δ: 8.25 (1H, s), 8.18 (1H, d, J = 9.6 Hz), 8.02-7.96 (2H, m), 7.65 (1H, d, J = 9.2 Hz), 7.14 (1H, t, J = 9.0 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.37 (1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.2 Hz), 3.36-3.29 (2H, m), 2.56-2.46 (2H, m), 2.36-2.30 (2H, m), 2.21 (3H, s), 1.06 (6H, d, J = 6.0 Hz). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) 6-Chloro-3- (3-fluoro-4-((3R, 5S) -3,4,5-trimethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (115 mg, 0.308 mmol ) And 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (58 μL, 0.339 mmol) to give the title compound (127 mg, quant.). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.25 (1H, s), 8.18 (1H, d, J = 9.6 Hz), 8.02-7.96 (2H, m), 7.65 (1H, d, J = 9.2 Hz), 7.14 (1H, t, J = 9.0 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.37 (1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.2 Hz), 3.36-3.29 (2H, m), 2.56-2.46 (2H, m), 2.36-2.30 (2H, m), 2.21 (3H, s), 1.06 (6H, d, J = 6.0 Hz ).

工程１０
3-(3-フルオロ-4-((3R,5S)-3,4,5-トリメチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Step 10
3- (3-Fluoro-4-((3R, 5S) -3,4,5-trimethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000638
Figure JPOXMLDOC01-appb-C000638

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-フルオロ-4-((3R,5S)-3,4,5-トリメチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (127 mg, 0.308 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (77 μL, 6.16 μmol) から標記化合物 (56 mg, 50%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.1 (1H, d, J = 0.7 Hz), 8.48 (1H, s), 8.37 (1H, dd, J =9.4, 0.7 Hz), 8.08-8.00 (2H, m), 7.65 (1H, d, J = 9.4 Hz), 7.17 (1H, t, J = 8.9 Hz), 3.37-3.31 (2H, m), 2.55 (2H, t, J = 10.9 Hz), 2.37-2.30 (2H, m), 2.22 (3H, s), 1.07 (6H, d, J = 6.2 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3-Fluoro-4-((3R, 5S) -3,4,5-trimethylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (127 mg, 0.308 mmol) and 2.5 The title compound (56 mg, 50%) was obtained from wt% osmium tetroxide tert-butanol solution (77 μL, 6.16 μmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, d, J = 0.7 Hz), 8.48 (1H, s), 8.37 (1H, dd, J = 9.4, 0.7 Hz), 8.08- 8.00 (2H, m), 7.65 (1H, d, J = 9.4 Hz), 7.17 (1H, t, J = 8.9 Hz), 3.37-3.31 (2H, m), 2.55 (2H, t, J = 10.9 Hz) ), 2.37-2.30 (2H, m), 2.22 (3H, s), 1.07 (6H, d, J = 6.2 Hz).

工程１１
5-((3-(3-フルオロ-4-((3R,5S)-3,4,5-トリメチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１５０) Step 11
5-((3- (3-Fluoro-4-((3R, 5S) -3,4,5-trimethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene ) Thiazolidine-2,4-dione (Compound 150)

Figure JPOXMLDOC01-appb-C000639
Figure JPOXMLDOC01-appb-C000639

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-フルオロ-4-((3R,5S)-3,4,5-トリメチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (56 mg, 0.152 mmol) およびチアゾリジン-2,4-ジオン (18 mg, 0.152 mmol) から標記化合物 (34 mg, 49%) を得た。赤色固体: 1H-NMR (DMSO-D6) δ: 8.27 (1H, s), 8.24 (1H, d, J = 9.4 Hz), 8.12 (1H, dd, J =14.5, 1.9 Hz), 7.89 (1H, dd, J =8.5, 1.8 Hz), 7.68 (1H, s), 7.62 (1H, d, J = 9.4 Hz), 7.18 (1H, t, J =8.9 Hz), 3.48 (2H, d, J = 11.7 Hz), 2.95-2.84 (2H, m), 2.73 (2H, t, J = 11.6 Hz), 2.49 (3H, s), 1.20 (6H, d, J = 6.4 Hz).
ESI-MS(m/z): 468[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3-fluoro-4-((3R, 5S) -3,4,5-trimethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine The title compound (34 mg, 49%) was obtained from -6-carbaldehyde (56 mg, 0.152 mmol) and thiazolidine-2,4-dione (18 mg, 0.152 mmol). Red solid: 1 H-NMR (DMSO-D 6 ) δ: 8.27 (1H, s), 8.24 (1H, d, J = 9.4 Hz), 8.12 (1H, dd, J = 14.5, 1.9 Hz), 7.89 ( 1H, dd, J = 8.5, 1.8 Hz), 7.68 (1H, s), 7.62 (1H, d, J = 9.4 Hz), 7.18 (1H, t, J = 8.9 Hz), 3.48 (2H, d, J = 11.7 Hz), 2.95-2.84 (2H, m), 2.73 (2H, t, J = 11.6 Hz), 2.49 (3H, s), 1.20 (6H, d, J = 6.4 Hz).
ESI-MS (m / z): 468 [M + H] + .

実施例１５１
5-(6-((2,4-ジオキソチアゾリジン-5-イリデン)メチル)イミダゾ[1,2-b]ピリダジン-3-イル)-2-(4-メチルピペラジン-1-イル)ベンゾニトリル (化合物１５１)  Example 151
5- (6-((2,4-Dioxothiazolidine-5-ylidene) methyl) imidazo [1,2-b] pyridazin-3-yl) -2- (4-methylpiperazin-1-yl) benzonitrile (Compound 151)

工程１
tert-ブチル 4-(4-ブロモ-2-シアノフェニル)ピペラジン-1-カルボキシレート Process 1
tert-butyl 4- (4-bromo-2-cyanophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000640
Figure JPOXMLDOC01-appb-C000640

アルゴン雰囲気下、5-ブロモ-2-フルオロベンゾニトリル(1.0 g, 5.00 mmol)、1-(tert-ブトキシカルボニル)ピペラジン (1.02 g, 5.05 mmol) をN,N-ジメチルホルムアミド (10 mL) に溶解した。そこへ炭酸ナトリウム (1.06 g, 10.0 mmol) を加え、100℃で7時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (553 mg, 30%) を得た。透明オイル: 1H-NMR (CDCl3) δ: 7.68 (1H, d, J = 2.5 Hz), 7.59 (1H, dd, J = 8.8, 2.4 Hz), 6.88 (1H, d, J = 8.9 Hz), 3.63 (4H, t, J = 5.0 Hz), 3.13 (4H, t, J = 5.0 Hz), 1.48 (9H, s). Dissolve 5-bromo-2-fluorobenzonitrile (1.0 g, 5.00 mmol) and 1- (tert-butoxycarbonyl) piperazine (1.02 g, 5.05 mmol) in N, N-dimethylformamide (10 mL) under an argon atmosphere. did. Sodium carbonate (1.06 g, 10.0 mmol) was added there, and it stirred at 100 degreeC for 7 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (553 mg, 30%). Clear oil: 1 H-NMR (CDCl 3 ) δ: 7.68 (1H, d, J = 2.5 Hz), 7.59 (1H, dd, J = 8.8, 2.4 Hz), 6.88 (1H, d, J = 8.9 Hz) , 3.63 (4H, t, J = 5.0 Hz), 3.13 (4H, t, J = 5.0 Hz), 1.48 (9H, s).

工程２
tert-ブチル 4-(2-シアノ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレート Process 2
tert-butyl 4- (2-cyano-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000641
Figure JPOXMLDOC01-appb-C000641

tert-ブチル 4-(3-フルオロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例85、工程4) と同様の手法で、tert-ブチル 4-(4-ブロモ-2-シアノフェニル)ピペラジン-1-カルボキシレート(553 mg, 1.51 mmol) およびビス(ピナコラート)ジボロン (422 mg, 1.66 mmol) から標記化合物 (421 mg, 68%) を得た。白色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 7.83-7.80 (2H, m), 7.15 (1H, d, J = 8.2 Hz), 3.50 (4H, t, J = 4.7 Hz), 3.20 (4H, t, J = 5.0 Hz), 1.42 (9H, s), 1.28 (12H, s). Synthesis of tert-butyl 4- (3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (Example 85) In the same manner as in step 4), tert-butyl 4- (4-bromo-2-cyanophenyl) piperazine-1-carboxylate (553 mg, 1.51 mmol) and bis (pinacolato) diboron (422 mg, 1.66 mmol ) Gave the title compound (421 mg, 68%). White amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 7.83-7.80 (2H, m), 7.15 (1H, d, J = 8.2 Hz), 3.50 (4H, t, J = 4.7 Hz), 3.20 (4H, t, J = 5.0 Hz), 1.42 (9H, s), 1.28 (12H, s).

工程３
tert-ブチル 4-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-2-シアノフェニル)ピペラジン-1-カルボキシレート Process 3
tert-butyl 4- (4- (6-chloroimidazo [1,2-b] pyridazin-3-yl) -2-cyanophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000642
Figure JPOXMLDOC01-appb-C000642

3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-カルボニトリルの合成 (実施例106、工程6) と同様の手法で、3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (197 mg, 0.849 mmol) およびtert-ブチル 4-(2-シアノ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレート(421 mg, 1.02 mmol) から標記化合物 (272 mg, 73%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.44 (1H, d, J = 2.3 Hz), 8.38 (1H, s), 8.33 (1H, dd, J = 8.8, 2.2 Hz), 8.31 (1H, d, J = 9.4 Hz), 7.44 (1H, d, J = 9.4 Hz), 7.36 (1H, d, J = 8.9 Hz), 3.53 (4H, s), 3.22 (4H, t, J = 5.0 Hz), 1.44 (9H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridine-5-carbonitrile (Example 106, Step 6) -6-Chloroimidazo [1,2-b] pyridazine (197 mg, 0.849 mmol) and tert-butyl 4- (2-cyano-4- (4,4,5,5-tetramethyl-1,3,2) The title compound (272 mg, 73%) was obtained from -dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (421 mg, 1.02 mmol). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.44 (1H, d, J = 2.3 Hz), 8.38 (1H, s), 8.33 (1H, dd, J = 8.8, 2.2 Hz), 8.31 (1H, d, J = 9.4 Hz), 7.44 (1H, d, J = 9.4 Hz), 7.36 (1H, d, J = 8.9 Hz), 3.53 (4H, s), 3.22 (4H, t, J = 5.0 Hz), 1.44 (9H, s).

工程４
5-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-2-(ピペラジン-1-イル)ベンゾニトリル Process 4
5- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) -2- (piperazin-1-yl) benzonitrile

Figure JPOXMLDOC01-appb-C000643
Figure JPOXMLDOC01-appb-C000643

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程6) と同様の手法で、tert-ブチル4-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-2-シアノフェニル)ピペラジン-1-カルボキシレート (272 mg, 0.620 mmol) およびトリフルオロ酢酸 (1 mL) から標記化合物 (190 mg, 91%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.40 (1H, d, J = 2.3 Hz), 8.36 (1H, s), 8.31 (1H, d, J =9.4 Hz), 8.31 (1H, dd, J = 8.6, 1.7 Hz), 7.44 (1H, d, J = 9.6 Hz), 7.32 (1H, d, J = 8.7 Hz), 3.18 (4H, t, J = 4.8 Hz), 2.90 (4H, t, J = 4.8 Hz). Synthesis of 5-bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 6) From-(4- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) -2-cyanophenyl) piperazine-1-carboxylate (272 mg, 0.620 mmol) and trifluoroacetic acid (1 mL) The title compound (190 mg, 91%) was obtained. Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.40 (1H, d, J = 2.3 Hz), 8.36 (1H, s), 8.31 (1H, d, J = 9.4 Hz), 8.31 (1H , dd, J = 8.6, 1.7 Hz), 7.44 (1H, d, J = 9.6 Hz), 7.32 (1H, d, J = 8.7 Hz), 3.18 (4H, t, J = 4.8 Hz), 2.90 (4H , t, J = 4.8 Hz).

工程５
5-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-2-(4-メチルピペラジン-1-イル)ベンゾニトリル Process 5
5- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) -2- (4-methylpiperazin-1-yl) benzonitrile

Figure JPOXMLDOC01-appb-C000644
Figure JPOXMLDOC01-appb-C000644

5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程7) と同様の手法で、5-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-2-(ピペラジン-1-イル)ベンゾニトリル (190 mg, 0.561 mmol) および 37% ホルムアルデヒド水溶液 (251 μL, 3.34 mmol) から標記化合物 (124 mg, 63%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.41 (1H, d, J = 2.1 Hz), 8.37 (1H, s), 8.32-8.30 (2H, m), 7.44 (1H, d, J = 9.4 Hz), 7.34 (1H, d, J = 8.9 Hz), 3.26 (4H, t, J =4.8 Hz), 2.52 (4H, t, J = 4.9 Hz), 2.26 (3H, s). Synthesis of 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 7) -(6-Chloroimidazo [1,2-b] pyridazin-3-yl) -2- (piperazin-1-yl) benzonitrile (190 mg, 0.561 mmol) and 37% aqueous formaldehyde solution (251 μL, 3.34 mmol) Gave the title compound (124 mg, 63%). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.41 (1H, d, J = 2.1 Hz), 8.37 (1H, s), 8.32-8.30 (2H, m), 7.44 (1H, d, J = 9.4 Hz), 7.34 (1H, d, J = 8.9 Hz), 3.26 (4H, t, J = 4.8 Hz), 2.52 (4H, t, J = 4.9 Hz), 2.26 (3H, s).

工程６
2-(4-メチルピペラジン-1-イル)-5-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)ベンゾニトリル Step 6
2- (4-Methylpiperazin-1-yl) -5- (6-vinylimidazo [1,2-b] pyridazin-3-yl) benzonitrile

Figure JPOXMLDOC01-appb-C000645
Figure JPOXMLDOC01-appb-C000645

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、5-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-2-(4-メチルピペラジン-1-イル)ベンゾニトリル (124 mg, 0.351 mmol) および 4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (66 μL, 0.386 mmol) から標記化合物 (74 mg, 62%) を得た。黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.50 (1H, d, J = 2.1 Hz), 8.42-8.39 (1H, m), 8.29 (1H, s), 8.20 (1H, d, J = 9.6 Hz), 7.67 (1H, d, J = 9.4 Hz), 7.31 (1H, d, J = 8.9 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.38 (1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.0 Hz), 3.25 (4H, t, J = 4.7 Hz), 2.53 (4H, t, J = 4.9 Hz), 2.26 (3H, s). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) 5- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) -2- (4-methylpiperazin-1-yl) benzonitrile (124 mg, 0.351 mmol) and 4,4,5,5 The title compound (74 mg, 62%) was obtained from -tetramethyl-2-vinyl-1,3,2-dioxaborolane (66 μL, 0.386 mmol). Yellow amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.50 (1H, d, J = 2.1 Hz), 8.42-8.39 (1H, m), 8.29 (1H, s), 8.20 (1H, d , J = 9.6 Hz), 7.67 (1H, d, J = 9.4 Hz), 7.31 (1H, d, J = 8.9 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.38 (1H, d , J = 17.6 Hz), 5.79 (1H, d, J = 11.0 Hz), 3.25 (4H, t, J = 4.7 Hz), 2.53 (4H, t, J = 4.9 Hz), 2.26 (3H, s).

工程７
5-(6-ホルミルイミダゾ[1,2-b]ピリダジン-3-イル)-2-(4-メチルピペラジン-1-イル)ベンゾニトリル Step 7
5- (6-Formylimidazo [1,2-b] pyridazin-3-yl) -2- (4-methylpiperazin-1-yl) benzonitrile

Figure JPOXMLDOC01-appb-C000646
Figure JPOXMLDOC01-appb-C000646

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、2-(4-メチルピペラジン-1-イル)-5-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)ベンゾニトリル (74 mg, 0.218 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (55 μL, 4.36 μmol) から標記化合物 (30 mg, 40%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.1 (1H, s), 8.54 (1H, d, J = 1.1 Hz), 8.53 (1H, d, J =0.7 Hz), 8.46 (1H, dd, J = 8.8, 1.3 Hz), 8.39 (1H, d, J = 9.4 Hz), 7.67 (1H, dd, J = 9.4, 0.7 Hz), 7.34 (1H, d, J = 8.7 Hz), 3.27 (4H, t, J = 4.7 Hz), 2.53 (4H, t, J = 4.7 Hz), 2.26 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 4-Methylpiperazin-1-yl) -5- (6-vinylimidazo [1,2-b] pyridazin-3-yl) benzonitrile (74 mg, 0.218 mmol) and 2.5 wt% osmium tetroxide tert-butanol solution (55 μL, 4.36 μmol) gave the title compound (30 mg, 40%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, s), 8.54 (1H, d, J = 1.1 Hz), 8.53 (1H, d, J = 0.7 Hz), 8.46 (1H, dd, J = 8.8, 1.3 Hz), 8.39 (1H, d, J = 9.4 Hz), 7.67 (1H, dd, J = 9.4, 0.7 Hz), 7.34 (1H, d, J = 8.7 Hz), 3.27 ( 4H, t, J = 4.7 Hz), 2.53 (4H, t, J = 4.7 Hz), 2.26 (3H, s).

工程８
5-(6-((2,4-ジオキソチアゾリジン-5-イリデン)メチル)イミダゾ[1,2-b]ピリダジン-3-イル)-2-(4-メチルピペラジン-1-イル)ベンゾニトリル (化合物１５１) Process 8
5- (6-((2,4-Dioxothiazolidine-5-ylidene) methyl) imidazo [1,2-b] pyridazin-3-yl) -2- (4-methylpiperazin-1-yl) benzonitrile (Compound 151)

Figure JPOXMLDOC01-appb-C000647
Figure JPOXMLDOC01-appb-C000647

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、5-(6-ホルミルイミダゾ[1,2-b]ピリダジン-3-イル)-2-(4-メチルピペラジン-1-イル)ベンゾニトリル (30 mg, 0.0866 mmol) およびチアゾリジン-2,4-ジオン(10 mg, 0.0866 mmol) から標記化合物 (17 mg, 33%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.53 (1H, d, J = 2.1 Hz), 8.31 (1H, s), 8.29 (1H, dd, J = 8.8, 2.2 Hz), 8.28 (1H, d, J = 9.4 Hz), 7.76 (1H, s), 7.67 (1H, d, J = 9.4 Hz), 7.33 (1H, d, J = 8.7 Hz), 3.34 (4H, t, J = 4.7 Hz), 2.80 (4H, s), 2.46 (3H, s).
ESI-MS(m/z): 446[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 5- (6-formylimidazo [1,2-b] pyridazin-3-yl) -2- (4-methylpiperazin-1-yl) benzonitrile (30 mg, 0.0866 mmol) and thiazolidine-2,4-dione (10 mg, 0.0866 mmol) gave the title compound (17 mg, 33%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.53 (1H, d, J = 2.1 Hz), 8.31 (1H, s), 8.29 (1H, dd, J = 8.8, 2.2 Hz), 8.28 ( 1H, d, J = 9.4 Hz), 7.76 (1H, s), 7.67 (1H, d, J = 9.4 Hz), 7.33 (1H, d, J = 8.7 Hz), 3.34 (4H, t, J = 4.7 Hz), 2.80 (4H, s), 2.46 (3H, s).
ESI-MS (m / z): 446 [M + H] + .

実施例１５２
5-((3-(3-((1-メチルピペリジン-4-イル)メチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１５２) Example 152
5-((3- (3-((1-methylpiperidin-4-yl) methyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 152 )

工程１
3-ブロモベンジルホスホン酸ジエチル Process 1
3-bromobenzylphosphonic acid diethyl ester

Figure JPOXMLDOC01-appb-C000648
Figure JPOXMLDOC01-appb-C000648

アルゴン雰囲気下、3-ブロモベンジルブロミド (2.5 g, 10.0 mmol) をトルエン (10 mL) に溶解した。そこへ亜リン酸トリエチル (1.73 mL, 10.0 mmol) を加え、24時間加熱還流した。反応液を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製して標記化合物 (2.92 g, 95%) を得た。透明オイル: 1H-NMR (DMSO-D6) δ: 7.50-7.48 (1H, m), 7.46-7.41 (1H, m), 7.29-7.27 (2H, m), 3.96 (4H, q, J = 7.0 Hz), 3.27 (2H, d, J = 21.8 Hz), 1.17 (6H, t, J = 7.0 Hz). Under an argon atmosphere, 3-bromobenzyl bromide (2.5 g, 10.0 mmol) was dissolved in toluene (10 mL). The triethyl phosphite (1.73 mL, 10.0 mmol) was added there, and it heated and refluxed for 24 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (2.92 g, 95%). Clear oil: 1 H-NMR (DMSO-D 6 ) δ: 7.50-7.48 (1H, m), 7.46-7.41 (1H, m), 7.29-7.27 (2H, m), 3.96 (4H, q, J = 7.0 Hz), 3.27 (2H, d, J = 21.8 Hz), 1.17 (6H, t, J = 7.0 Hz).

工程２
tert-ブチル 4-(3-ブロモベンジリデン)ピペリジン-1-カルボキシレート Process 2
tert-Butyl 4- (3-bromobenzylidene) piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000649
Figure JPOXMLDOC01-appb-C000649

アルゴン雰囲気下、水素化ナトリウム (60% in oil, 570 mg, 14.3 mmol) をテトラヒドロフラン(10 mL) に懸濁し、0℃に冷却した。そこへ3-ブロモベンジルホスホン酸ジエチル(2.92 g, 9.50 mmol) のテトラヒドロフラン溶液 (10 mL) を滴下し、0℃で30分撹拌した。さらに1-(tert-ブトキシカルボニル)-4-ピペリドン (2.08 g, 10.5 mmol) のテトラヒドロフラン溶液 (10 mL) を滴下し、0℃で10分撹拌後、室温で5時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.24 g, 37%) を得た。透明オイル: 1H-NMR (DMSO-D6) δ: 7.43-7.39 (2H, m), 7.30 (1H, t, J = 7.8 Hz), 7.23 (1H, d, J = 7.8 Hz), 6.35 (1H, s), 3.41 (2H, t, J = 5.7 Hz), 3.34 (2H, t, J = 5.7 Hz), 2.37 (2H, t, J =5.4 Hz), 2.28 (2H, t, J = 5.4 Hz), 1.41 (9H, s). Under an argon atmosphere, sodium hydride (60% in oil, 570 mg, 14.3 mmol) was suspended in tetrahydrofuran (10 mL) and cooled to 0 ° C. The tetrahydrofuran solution (10 mL) of diethyl 3-bromobenzylphosphonate (2.92 g, 9.50 mmol) was dripped there, and it stirred at 0 degreeC for 30 minutes. Further, a tetrahydrofuran solution (10 mL) of 1- (tert-butoxycarbonyl) -4-piperidone (2.08 g, 10.5 mmol) was added dropwise, followed by stirring at 0 ° C. for 10 minutes and then at room temperature for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.24 g, 37%). Clear oil: 1 H-NMR (DMSO-D 6 ) δ: 7.43-7.39 (2H, m), 7.30 (1H, t, J = 7.8 Hz), 7.23 (1H, d, J = 7.8 Hz), 6.35 ( 1H, s), 3.41 (2H, t, J = 5.7 Hz), 3.34 (2H, t, J = 5.7 Hz), 2.37 (2H, t, J = 5.4 Hz), 2.28 (2H, t, J = 5.4 Hz), 1.41 (9H, s).

工程３
tert-ブチル 4-(3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン)ピペリジン-1-カルボキシレート Process 3
tert-butyl 4- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene) piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000650
Figure JPOXMLDOC01-appb-C000650

tert-ブチル 4-(3-フルオロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例85、工程4) と同様の手法で、tert-ブチル 4-(3-ブロモベンジリデン)ピペリジン-1-カルボキシレート(1.24 g, 3.51 mmol) およびビス(ピナコラート)ジボロン (980 mg, 3.86 mmol) から標記化合物 (1.30 g, 93%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 7.53-7.49 (2H, m), 7.36-7.34 (2H, m), 6.39 (1H, s), 3.41 (2H, t, J = 5.6 Hz), 3.34-3.30 (2H, m), 2.36 (2H, t, J = 5.5 Hz), 2.28 (2H, t, J = 5.5 Hz), 1.41 (9H, s), 1.29 (12H, s). Synthesis of tert-butyl 4- (3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (Example 85) In the same manner as in step 4), the title compound was obtained from tert-butyl 4- (3-bromobenzylidene) piperidine-1-carboxylate (1.24 g, 3.51 mmol) and bis (pinacolato) diboron (980 mg, 3.86 mmol). (1.30 g, 93%) was obtained. Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 7.53-7.49 (2H, m), 7.36-7.34 (2H, m), 6.39 (1H, s), 3.41 (2H, t, J = 5.6 Hz), 3.34-3.30 (2H, m), 2.36 (2H, t, J = 5.5 Hz), 2.28 (2H, t, J = 5.5 Hz), 1.41 (9H, s), 1.29 (12H, s).

工程４
tert-ブチル 4-(3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジル)ピペリジン-1-カルボキシレート Process 4
tert-butyl 4- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl) piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000651
Figure JPOXMLDOC01-appb-C000651

tert-ブチル 4-(3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジリデン)ピペリジン-1-カルボキシレート(1.30 g, 3.27 mmol) をエタノール (10 mL) に溶解した。そこへ10% パラジウム-活性炭 (130 mg) をエタノール (5 mL) に懸濁して加えた。反応容器内を水素で置換し、室温で16時間撹拌した。反応液をセライトでろ過し、濃縮、真空乾燥して標記化合物 (1.29 g, 97%) を得た。薄黄色油状物質: 1H-NMR (DMSO-D6) δ: 7.50-7.47 (2H, m), 7.30-7.28 (2H, m), 3.90 (2H, d, J = 12.4 Hz), 2.68-2.57 (2H, m), 2.52-2.47 (2H, m), 1.68-1.59 (1H, m), 1.53-1.49 (2H, m), 1.38 (9H, s), 1.29 (12H, s), 1.08-0.96 (2H, m). tert-Butyl 4- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene) piperidine-1-carboxylate (1.30 g, 3.27 mmol) in ethanol ( 10 mL). 10% palladium-activated carbon (130 mg) was suspended in ethanol (5 mL) and added thereto. The inside of the reaction vessel was replaced with hydrogen, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through celite, concentrated and dried under vacuum to obtain the title compound (1.29 g, 97%). Pale yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 7.50-7.47 (2H, m), 7.30-7.28 (2H, m), 3.90 (2H, d, J = 12.4 Hz), 2.68-2.57 (2H, m), 2.52-2.47 (2H, m), 1.68-1.59 (1H, m), 1.53-1.49 (2H, m), 1.38 (9H, s), 1.29 (12H, s), 1.08-0.96 (2H, m).

工程５
tert-ブチル 4-(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)ベンジル)ピペリジン-1-カルボキシレート Process 5
tert-butyl 4- (3- (6-chloroimidazo [1,2-b] pyridazin-3-yl) benzyl) piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000652
Figure JPOXMLDOC01-appb-C000652

3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-カルボニトリルの合成 (実施例106、工程6) と同様の手法で、3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (617 mg, 2.65 mmol) およびtert-ブチル 4-(3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジル)ピペリジン-1-カルボキシレート (1.28 g, 3.18 mmol) から標記化合物 (862 mg, 76%) を得た。薄黄色油状物質: 1H-NMR (DMSO-D6) δ: 8.30 (1H, d, J = 9.4 Hz), 8.29 (1H, s), 7.91 (1H, d, J =7.8 Hz), 7.86 (1H, s), 7.46 (1H, t, J = 7.7 Hz), 7.42 (1H, d, J =9.4 Hz), 7.24 (1H, d, J = 7.6 Hz), 3.93 (2H, d, J = 11.9 Hz), 2.71-2.60 (2H, m), 2.61 (2H, d, J =7.1 Hz), 1.79-1.69 (1H, m), 1.62 (2H, d, J = 12.6 Hz), 1.38 (9H, s), 1.13-1.03 (2H, m). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridine-5-carbonitrile (Example 106, Step 6) -6-Chloroimidazo [1,2-b] pyridazine (617 mg, 2.65 mmol) and tert-butyl 4- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 The title compound (862 mg, 76%) was obtained from -yl) benzyl) piperidine-1-carboxylate (1.28 g, 3.18 mmol). Pale yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.30 (1H, d, J = 9.4 Hz), 8.29 (1H, s), 7.91 (1H, d, J = 7.8 Hz), 7.86 ( 1H, s), 7.46 (1H, t, J = 7.7 Hz), 7.42 (1H, d, J = 9.4 Hz), 7.24 (1H, d, J = 7.6 Hz), 3.93 (2H, d, J = 11.9 Hz), 2.71-2.60 (2H, m), 2.61 (2H, d, J = 7.1 Hz), 1.79-1.69 (1H, m), 1.62 (2H, d, J = 12.6 Hz), 1.38 (9H, s ), 1.13-1.03 (2H, m).

工程６
tert-ブチル 4-(3-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)ベンジル)ピペリジン-1-カルボキシレート Step 6
tert-butyl 4- (3- (6-vinylimidazo [1,2-b] pyridazin-3-yl) benzyl) piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000653
Figure JPOXMLDOC01-appb-C000653

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、tert-ブチル 4-(3-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)ベンジル)ピペリジン-1-カルボキシレート(862 mg, 2.02 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (380 μL, 2.42 mmol) から標記化合物 (676 mg, 80%) を得た。薄黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.21 (1H, s), 8.19 (1H, d, J = 9.6 Hz), 7.99-7.97 (2H, m), 7.66 (1H, d, J = 9.4 Hz), 7.43 (1H, t, J = 8.0 Hz), 7.20 (1H, d, J =7.6 Hz), 6.89 (1H, dd, J =17.7, 11.1 Hz), 6.37 (1H, d, J =17.6 Hz), 5.77 (1H, d, J = 11.2 Hz), 3.93 (2H, d, J = 11.9 Hz), 2.71-2.60 (2H, m), 2.61 (1H, d, J =7.1 Hz), 1.79-1.70 (1H, m), 1.62 (2H, d, J = 13.1 Hz), 1.38 (9H, s), 1.14-1.03 (2H, m). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) tert-Butyl 4- (3- (6-chloroimidazo [1,2-b] pyridazin-3-yl) benzyl) piperidine-1-carboxylate (862 mg, 2.02 mmol) and 4,4,5,5- The title compound (676 mg, 80%) was obtained from tetramethyl-2-vinyl-1,3,2-dioxaborolane (380 μL, 2.42 mmol). Pale yellow amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.21 (1H, s), 8.19 (1H, d, J = 9.6 Hz), 7.99-7.97 (2H, m), 7.66 (1H, d, J = 9.4 Hz), 7.43 (1H, t, J = 8.0 Hz), 7.20 (1H, d, J = 7.6 Hz), 6.89 (1H, dd, J = 17.7, 11.1 Hz), 6.37 (1H, d, J = 17.6 Hz), 5.77 (1H, d, J = 11.2 Hz), 3.93 (2H, d, J = 11.9 Hz), 2.71-2.60 (2H, m), 2.61 (1H, d, J = 7.1 Hz), 1.79-1.70 (1H, m), 1.62 (2H, d, J = 13.1 Hz), 1.38 (9H, s), 1.14-1.03 (2H, m).

工程７
3-(3-(ピペリジン-4-イルメチル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Step 7
3- (3- (Piperidin-4-ylmethyl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000654
Figure JPOXMLDOC01-appb-C000654

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程6) と同様の手法で、tert-ブチル 4-(3-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)ベンジル)ピペリジン-1-カルボキシレート(676 mg, 1.62 mmol) およびトリフルオロ酢酸 (3 mL) から標記化合物 (515 mg, quant.) を得た。薄黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.21 (1H, s), 8.19 (1H, d, J = 9.4 Hz), 7.97-7.95 (2H, m), 7.65 (1H, d, J = 9.4 Hz), 7.43 (1H, t, J = 8.0 Hz), 7.19 (1H, d, J =7.6 Hz), 6.89 (1H, dd, J =17.9, 11.0 Hz), 6.38 (1H, d, J =17.4 Hz), 5.78 (1H, d, J = 11.7 Hz), 2.91 (2H, d, J = 11.7 Hz), 2.58 (2H, d, J = 6.9 Hz), 2.44-2.37 (2H, m), 1.68-1.61 (1H, m), 1.57 (2H, d, J = 13.3 Hz), 1.15-1.05 (2H, m). Synthesis of 5-bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 6) -(3- (6-vinylimidazo [1,2-b] pyridazin-3-yl) benzyl) piperidine-1-carboxylate (676 mg, 1.62 mmol) and trifluoroacetic acid (3 mL) gave the title compound (515 mg, quant.) was obtained. Pale yellow amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.21 (1H, s), 8.19 (1H, d, J = 9.4 Hz), 7.97-7.95 (2H, m), 7.65 (1H, d, J = 9.4 Hz), 7.43 (1H, t, J = 8.0 Hz), 7.19 (1H, d, J = 7.6 Hz), 6.89 (1H, dd, J = 17.9, 11.0 Hz), 6.38 (1H, d, J = 17.4 Hz), 5.78 (1H, d, J = 11.7 Hz), 2.91 (2H, d, J = 11.7 Hz), 2.58 (2H, d, J = 6.9 Hz), 2.44-2.37 (2H, m), 1.68-1.61 (1H, m), 1.57 (2H, d, J = 13.3 Hz), 1.15-1.05 (2H, m).

工程８
3-(3-((1-メチルピペリジン-4-イル)メチル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 8
3- (3-((1-Methylpiperidin-4-yl) methyl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000655
Figure JPOXMLDOC01-appb-C000655

5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程7) と同様の手法で、3-(3-(ピペリジン-4-イルメチル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (515 mg, 1.62 mmol) および 37% ホルムアルデヒド水溶液 (724 μL, 9.72 mmol) から標記化合物 (403 mg, 75%) を得た。薄黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.21 (1H, s), 8.19 (1H, d, J = 9.2 Hz), 7.98-7.95 (2H, m), 7.65 (1H, d, J = 9.4 Hz), 7.43 (1H, t, J = 8.0 Hz), 7.19 (1H, d, J = 7.6 Hz), 6.89 (1H, dd, J = 17.6, 11.0 Hz), 6.38 (1H, d, J = 17.9 Hz), 5.78 (1H, d, J = 11.4 Hz), 2.73 (2H, d, J = 11.2 Hz), 2.59 (2H, d, J = 7.1 Hz), 2.12 (3H, s), 1.78 (2H, t, J = 10.8 Hz), 1.59 (2H, d, J = 13.5 Hz), 1.54-1.46 (1H, m), 1.29-1.19 (2H, m). Synthesis of 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 7) From (3- (piperidin-4-ylmethyl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (515 mg, 1.62 mmol) and 37% aqueous formaldehyde (724 μL, 9.72 mmol), the title compound (403 mg, 75%). Pale yellow amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.21 (1H, s), 8.19 (1H, d, J = 9.2 Hz), 7.98-7.95 (2H, m), 7.65 (1H, d, J = 9.4 Hz), 7.43 (1H, t, J = 8.0 Hz), 7.19 (1H, d, J = 7.6 Hz), 6.89 (1H, dd, J = 17.6, 11.0 Hz), 6.38 (1H, d, J = 17.9 Hz), 5.78 (1H, d, J = 11.4 Hz), 2.73 (2H, d, J = 11.2 Hz), 2.59 (2H, d, J = 7.1 Hz), 2.12 (3H, s) , 1.78 (2H, t, J = 10.8 Hz), 1.59 (2H, d, J = 13.5 Hz), 1.54-1.46 (1H, m), 1.29-1.19 (2H, m).

工程９
3-(3-((1-メチルピペリジン-4-イル)メチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Step 9
3- (3-((1-Methylpiperidin-4-yl) methyl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000656
Figure JPOXMLDOC01-appb-C000656

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-((1-メチルピペラジン-4-イル)メチル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (403 mg, 1.21 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (303 μL, 24.2 μmol) から標記化合物 (182 mg, 45%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.9 Hz), 8.46 (1H, s), 8.38 (1H, dd, J =9.4, 0.9 Hz), 8.06-8.03 (1H, m), 8.01-8.00 (1H, m), 7.67 (1H, d, J = 9.4 Hz), 7.47 (1H, t, J = 7.7 Hz), 7.25 (1H, d, J = 7.6 Hz), 2.73 (2H, d, J = 11.4 Hz), 2.61 (2H, d, J = 6.9 Hz), 2.12 (3H, s), 1.78 (2H, t, J = 10.8 Hz), 1.59 (2H, d, J = 12.6 Hz), 1.55-1.48 (1H, m), 1.30-1.19 (2H, m). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3-((1-Methylpiperazin-4-yl) methyl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (403 mg, 1.21 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol (303 μL, 24.2 μmol) gave the title compound (182 mg, 45%). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.9 Hz), 8.46 (1H, s), 8.38 (1H, dd, J = 9.4, 0.9 Hz), 8.06- 8.03 (1H, m), 8.01-8.00 (1H, m), 7.67 (1H, d, J = 9.4 Hz), 7.47 (1H, t, J = 7.7 Hz), 7.25 (1H, d, J = 7.6 Hz) ), 2.73 (2H, d, J = 11.4 Hz), 2.61 (2H, d, J = 6.9 Hz), 2.12 (3H, s), 1.78 (2H, t, J = 10.8 Hz), 1.59 (2H, d , J = 12.6 Hz), 1.55-1.48 (1H, m), 1.30-1.19 (2H, m).

工程１０
5-((3-(3-((1-メチルピペリジン-4-イル)メチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１５２) Step 10
5-((3- (3-((1-methylpiperidin-4-yl) methyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 152 )

Figure JPOXMLDOC01-appb-C000657
Figure JPOXMLDOC01-appb-C000657

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-((1-メチルピペリジン-4-イル)メチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (182 mg, 0.544 mmol) およびチアゾリジン-2,4-ジオン (64 mg, 0.544 mmol) から標記化合物 (165 mg, 70%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.38 (1H, s), 8.26 (1H, s), 8.18 (1H, d, J = 9.4 Hz), 7.94-7.92 (1H, m), 7.54 (1H, d, J =9.4 Hz), 7.44 (1H, t, J = 7.7 Hz), 7.43 (1H, s), 7.23 (1H, d, J =7.8 Hz), 3.30 (2H, t, J = 16.1 Hz), 2.81-2.71 (2H, m), 2.72 (2H, d, J = 6.9 Hz), 2.64 (3H, s), 1.93-1.84 (1H, m), 1.82 (2H, d, J = 14.0 Hz), 1.47-1.37 (2H, m).
ESI-MS(m/z): 434[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3-((1-methylpiperidin-4-yl) methyl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (182 mg, 0.544 mmol ) And thiazolidine-2,4-dione (64 mg, 0.544 mmol) gave the title compound (165 mg, 70%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.38 (1H, s), 8.26 (1H, s), 8.18 (1H, d, J = 9.4 Hz), 7.94-7.92 (1H, m), 7.54 (1H, d, J = 9.4 Hz), 7.44 (1H, t, J = 7.7 Hz), 7.43 (1H, s), 7.23 (1H, d, J = 7.8 Hz), 3.30 (2H, t, J = 16.1 Hz), 2.81-2.71 (2H, m), 2.72 (2H, d, J = 6.9 Hz), 2.64 (3H, s), 1.93-1.84 (1H, m), 1.82 (2H, d, J = 14.0 Hz), 1.47-1.37 (2H, m).
ESI-MS (m / z): 434 [M + H] + .

実施例１５３
5-((3-(3-(tert-ブチル)-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１５３)  Example 153
5-((3- (3- (tert-butyl) -4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4 -Dione (Compound 153)

工程１
4-ブロモ-2-(tert-ブチル)アニリン Process 1
4-Bromo-2- (tert-butyl) aniline

Figure JPOXMLDOC01-appb-C000658
Figure JPOXMLDOC01-appb-C000658

アルゴン雰囲気下、2-(tert-ブチル)アニリン(1.2 g, 8.04 mmol) をテトラヒドロフラン (10 mL) に溶解した。そこへテトラブチルアンモニウム トリブロミド (3.88 g, 8.04 mmol) を少量ずつ加え、0℃で30分撹拌した。反応液に水を加え、酢酸エチルで抽出した。酢酸エチル層を飽和チオ硫酸ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.71 g, 93%) を得た。ピンク色オイル: 1H-NMR (DMSO-D6) δ: 7.09 (1H, d, J = 2.5 Hz), 7.02 (1H, dd, J = 8.5, 2.3 Hz), 6.60 (1H, d, J = 8.5 Hz), 4.97 (2H, s), 1.30 (9H, s). 2- (tert-butyl) aniline (1.2 g, 8.04 mmol) was dissolved in tetrahydrofuran (10 mL) under an argon atmosphere. Tetrabutylammonium tribromide (3.88 g, 8.04 mmol) was added little by little, and it stirred at 0 degreeC for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.71 g, 93%). Pink oil: 1 H-NMR (DMSO-D 6 ) δ: 7.09 (1H, d, J = 2.5 Hz), 7.02 (1H, dd, J = 8.5, 2.3 Hz), 6.60 (1H, d, J = 8.5 Hz), 4.97 (2H, s), 1.30 (9H, s).

工程２
1-(4-ブロモ-2-(tert-ブチル)フェニル)ピペラジン塩酸塩 Process 2
1- (4-Bromo-2- (tert-butyl) phenyl) piperazine hydrochloride

Figure JPOXMLDOC01-appb-C000659
Figure JPOXMLDOC01-appb-C000659

アルゴン雰囲気下、4-ブロモ-2-(tert-ブチル)アニリン (1.71 g, 7.49 mmol) をジグリム (10 mL) に溶解した。そこへビス(2-クロロエチル)アミン塩酸塩(1.47 g, 8.24 mmol) を加え、69時間加熱還流した。反応液に1規定水酸化ナトリウム溶液を加え、酢酸エチルで抽出した。酢酸エチル層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣を酢酸エチル/ジエチルエーテル (1:1, 20 mL) で希釈し、4 M塩酸 酢酸エチル溶液 (1.87 mL) を加え、生じた析出物をろ取、真空乾燥して標記化合物 (紫色固体, 1.63 g, 50%) を得た。紫色固体: 1H-NMR (DMSO-D6) δ: 9.14 (2H, d, J = 26.3 Hz), 7.50 (1H, dd, J = 8.5, 2.3 Hz), 7.42 (1H, d, J = 2.5 Hz), 7.27 (1H, d, J = 8.5 Hz), 3.34 (2H, d, J = 9.8 Hz), 3.13-3.00 (4H, m), 2.83 (2H, d, J = 10.1 Hz), 1.37 (9H, s). 4-Bromo-2- (tert-butyl) aniline (1.71 g, 7.49 mmol) was dissolved in diglyme (10 mL) under an argon atmosphere. Bis (2-chloroethyl) amine hydrochloride (1.47 g, 8.24 mmol) was added thereto, and the mixture was heated to reflux for 69 hours. 1N sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was diluted with ethyl acetate / diethyl ether (1: 1, 20 mL), 4 M hydrochloric acid ethyl acetate solution (1.87 mL) was added, and the resulting precipitate was collected by filtration, dried in vacuo and dried with the title compound ( A purple solid, 1.63 g, 50%) was obtained. Purple solid: 1 H-NMR (DMSO-D 6 ) δ: 9.14 (2H, d, J = 26.3 Hz), 7.50 (1H, dd, J = 8.5, 2.3 Hz), 7.42 (1H, d, J = 2.5 Hz), 7.27 (1H, d, J = 8.5 Hz), 3.34 (2H, d, J = 9.8 Hz), 3.13-3.00 (4H, m), 2.83 (2H, d, J = 10.1 Hz), 1.37 ( 9H, s).

工程３
tert-ブチル 4-(4-ブロモ-2-(tert-ブチル)フェニル)ピペラジン-1-カルボキシレート Process 3
tert-butyl 4- (4-bromo-2- (tert-butyl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000660
Figure JPOXMLDOC01-appb-C000660

アルゴン雰囲気下、1-(4-ブロモ-2-(tert-ブチル)フェニル)ピペラジン塩酸塩 (1.53 g, 4.59 mmol) をジクロロメタン (10 mL) に懸濁し、0℃に冷却した。そこへトリエチルアミン (1.56 mL, 11.5 mmol)、二炭酸ジ-tert-ブチル(1.10 g, 5.05 mmol) を加え、0℃で10分撹拌後、室温で14時間撹拌した。反応液に飽和重層水を加え、酢酸エチルで抽出した。酢酸エチル層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.20 g, 66%) を得た。白色固体: 1H-NMR (CDCl3) δ: 7.47 (1H, d, J = 2.5 Hz), 7.33 (1H, dd, J = 8.5, 2.3 Hz), 7.14 (1H, d, J = 8.5 Hz), 4.06 (2H, d, J = 12.6 Hz), 3.08-3.01 (2H, m), 2.81-2.75 (4H, m), 1.49 (9H, s), 1.41 (9H, s). Under an argon atmosphere, 1- (4-bromo-2- (tert-butyl) phenyl) piperazine hydrochloride (1.53 g, 4.59 mmol) was suspended in dichloromethane (10 mL) and cooled to 0 ° C. Triethylamine (1.56 mL, 11.5 mmol) and di-tert-butyl dicarbonate (1.10 g, 5.05 mmol) were added thereto, followed by stirring at 0 ° C. for 10 minutes and then at room temperature for 14 hours. Saturated multistory water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.20 g, 66%). White solid: 1 H-NMR (CDCl 3 ) δ: 7.47 (1H, d, J = 2.5 Hz), 7.33 (1H, dd, J = 8.5, 2.3 Hz), 7.14 (1H, d, J = 8.5 Hz) , 4.06 (2H, d, J = 12.6 Hz), 3.08-3.01 (2H, m), 2.81-2.75 (4H, m), 1.49 (9H, s), 1.41 (9H, s).

工程４
tert-ブチル 4-(2-(tert-ブチル)-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イルフェニル)ピペラジン-1-カルボキシレート Process 4
tert-butyl 4- (2- (tert-butyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylphenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000661
Figure JPOXMLDOC01-appb-C000661

tert-ブチル 4-(3-フルオロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレートの合成 (実施例85、工程4) と同様の手法で、tert-ブチル 4-(4-ブロモ-2-(tert-ブチル)フェニル)ピペラジン-1-カルボキシレート (1.20 g, 3.02 mmol) およびビス(ピナコラート)ジボロン (844 mg, 3.32 mmol) から標記化合物 (932 mg, 69%) を得た。白色固体: 1H-NMR (CDCl3) δ: 7.83 (1H, d, J = 1.4 Hz), 7.68 (1H, dd, J = 7.8, 1.6 Hz), 7.29 (1H, d, J = 7.8 Hz), 4.06 (2H, d, J = 13.1 Hz), 3.10-3.03 (2H, m), 2.87-2.76 (4H, m), 1.49 (9H, s), 1.46 (9H, s), 1.33 (12H, s). Synthesis of tert-butyl 4- (3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (Example 85) In the same manner as in step 4), tert-butyl 4- (4-bromo-2- (tert-butyl) phenyl) piperazine-1-carboxylate (1.20 g, 3.02 mmol) and bis (pinacolato) diboron (844 mg, 3.32 mmol) gave the title compound (932 mg, 69%). White solid: 1 H-NMR (CDCl 3 ) δ: 7.83 (1H, d, J = 1.4 Hz), 7.68 (1H, dd, J = 7.8, 1.6 Hz), 7.29 (1H, d, J = 7.8 Hz) , 4.06 (2H, d, J = 13.1 Hz), 3.10-3.03 (2H, m), 2.87-2.76 (4H, m), 1.49 (9H, s), 1.46 (9H, s), 1.33 (12H, s ).

工程５
tert-ブチル 4-(2-(tert-ブチル)-4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-カルボキシレート Process 5
tert-butyl 4- (2- (tert-butyl) -4- (6-chloroimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000662
Figure JPOXMLDOC01-appb-C000662

3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-カルボニトリルの合成 (実施例106、工程6) と同様の手法で、3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (233 mg, 1.00 mmol) およびtert-ブチル 4-(2-(tert-ブチル)-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イルフェニル)ピペラジン-1-カルボキシレート(534 mg, 1.20 mmol) から標記化合物 (326 mg, 69%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.29 (1H, d, J = 9.6 Hz), 8.28 (1H, s), 8.10 (1H, d, J = 2.3 Hz), 7.88 (1H, dd, J = 8.2, 2.1 Hz), 7.57 (1H, d, J = 8.2 Hz), 7.41 (1H, d, J = 9.4 Hz), 3.98 (2H, d, J = 11.9 Hz), 3.05-2.91 (2H, m), 2.86-2.75 (4H, m), 1.48 (9H, s), 1.44 (9H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridine-5-carbonitrile (Example 106, Step 6) -6-Chloroimidazo [1,2-b] pyridazine (233 mg, 1.00 mmol) and tert-butyl 4- (2- (tert-butyl) -4- (4,4,5,5-tetramethyl-1) , 3,2-Dioxaborolan-2-ylphenyl) piperazine-1-carboxylate (534 mg, 1.20 mmol) gave the title compound (326 mg, 69%) Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.29 (1H, d, J = 9.6 Hz), 8.28 (1H, s), 8.10 (1H, d, J = 2.3 Hz), 7.88 (1H, dd, J = 8.2, 2.1 Hz), 7.57 (1H, d, J = 8.2 Hz), 7.41 (1H, d, J = 9.4 Hz), 3.98 (2H, d, J = 11.9 Hz), 3.05-2.91 (2H, m), 2.86-2.75 (4H, m), 1.48 (9H, s), 1.44 (9H, s).

工程６
tert-ブチル 4-(2-(tert-ブチル)-4-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-カルボキシレート Step 6
tert-butyl 4- (2- (tert-butyl) -4- (6-vinylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000663
Figure JPOXMLDOC01-appb-C000663

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、tert-ブチル 4-(2-(tert-ブチル)-4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-カルボキシレート (326 mg, 0.694 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (131 μL, 0.763 mmol) から標記化合物 (267 mg, 83%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.25 (1H, d, J = 2.1 Hz), 8.19 (1H, s), 8.18 (1H, d, J = 9.2 Hz), 7.91 (1H, dd, J = 8.2, 2.1 Hz), 7.65 (1H, d, J = 9.6 Hz), 7.53 (1H, d, J = 8.5 Hz), 6.87 (1H, dd, J = 17.7, 11.1 Hz), 6.38 (1H, d, J = 17.6 Hz), 5.78 (1H, d, J = 11.7 Hz), 3.98 (2H, d, J = 11.4 Hz), 3.05-2.92 (2H, m), 2.86-2.74 (4H, m), 1.48 (9H, s), 1.44 (9H, s). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) tert-butyl 4- (2- (tert-butyl) -4- (6-chloroimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazine-1-carboxylate (326 mg, 0.694 mmol) and The title compound (267 mg, 83%) was obtained from 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (131 μL, 0.763 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.25 (1H, d, J = 2.1 Hz), 8.19 (1H, s), 8.18 (1H, d, J = 9.2 Hz), 7.91 (1H, dd, J = 8.2, 2.1 Hz), 7.65 (1H, d, J = 9.6 Hz), 7.53 (1H, d, J = 8.5 Hz), 6.87 (1H, dd, J = 17.7, 11.1 Hz), 6.38 ( 1H, d, J = 17.6 Hz), 5.78 (1H, d, J = 11.7 Hz), 3.98 (2H, d, J = 11.4 Hz), 3.05-2.92 (2H, m), 2.86-2.74 (4H, m ), 1.48 (9H, s), 1.44 (9H, s).

工程７
3-(3-(tert-ブチル)-4-(ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Step 7
3- (3- (tert-Butyl) -4- (piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000664
Figure JPOXMLDOC01-appb-C000664

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程6) と同様の手法で、tert-ブチル 4-(2-(tert-ブチル)-4-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-カルボキシレート (267 mg, 0.578 mmol) およびトリフルオロ酢酸 (1 mL) から標記化合物 (184 mg, 88%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.23 (1H, d, J = 2.3 Hz), 8.18 (1H, d, J = 9.4 Hz), 8.18 (1H, s), 7.92 (1H, dd, J = 8.2, 2.3 Hz), 7.65 (1H, d, J = 9.6 Hz), 7.50 (1H, d, J = 8.2 Hz), 6.87 (1H, dd, J = 17.9, 11.0 Hz), 6.38 (1H, d, J = 17.6 Hz), 5.78 (1H, d, J = 11.4 Hz), 2.92 (2H, d, J = 8.7 Hz), 2.85-2.82 (4H, m), 2.69-2.66 (2H, m), 1.48 (9H, s). Synthesis of 5-bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 6) -(2- (tert-butyl) -4- (6-vinylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazine-1-carboxylate (267 mg, 0.578 mmol) and trifluoroacetic acid ( The title compound (184 mg, 88%) was obtained from 1 mL). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.23 (1H, d, J = 2.3 Hz), 8.18 (1H, d, J = 9.4 Hz), 8.18 (1H, s), 7.92 (1H, dd, J = 8.2, 2.3 Hz), 7.65 (1H, d, J = 9.6 Hz), 7.50 (1H, d, J = 8.2 Hz), 6.87 (1H, dd, J = 17.9, 11.0 Hz), 6.38 ( 1H, d, J = 17.6 Hz), 5.78 (1H, d, J = 11.4 Hz), 2.92 (2H, d, J = 8.7 Hz), 2.85-2.82 (4H, m), 2.69-2.66 (2H, m ), 1.48 (9H, s).

工程８
3-(3-(tert-ブチル)-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 8
3- (3- (tert-butyl) -4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000665
Figure JPOXMLDOC01-appb-C000665

5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程7) と同様の手法で、3-(3-(tert-ブチル)-4-(ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (184 mg, 0.509 mmol) および 37% ホルムアルデヒド水溶液 (227 μL, 3.05 mmol) から標記化合物 (151 mg, 79%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.23 (1H, d, J = 2.1 Hz), 8.18 (1H, d, J = 9.6 Hz), 8.18 (1H, s), 7.92 (1H, dd, J =8.2, 2.3 Hz), 7.64 (1H, d, J =9.4 Hz), 7.54 (1H, d, J = 8.5 Hz), 6.87 (1H, dd, J = 17.7, 11.1 Hz), 6.38 (1H, d, J = 17.6 Hz), 5.78 (1H, d, J = 11.4 Hz), 3.01-2.95 (2H, m), 2.79 (2H, d, J =10.8 Hz), 2.70 (2H, d, J = 11.4 Hz), 2.25 (3H, s), 2.21-2.14 (2H, m), 1.48 (9H, s). Synthesis of 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 7) -(3- (tert-butyl) -4- (piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (184 mg, 0.509 mmol) and 37% aqueous formaldehyde (227 μL, The title compound (151 mg, 79%) was obtained from 3.05 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.23 (1H, d, J = 2.1 Hz), 8.18 (1H, d, J = 9.6 Hz), 8.18 (1H, s), 7.92 (1H, dd, J = 8.2, 2.3 Hz), 7.64 (1H, d, J = 9.4 Hz), 7.54 (1H, d, J = 8.5 Hz), 6.87 (1H, dd, J = 17.7, 11.1 Hz), 6.38 ( 1H, d, J = 17.6 Hz), 5.78 (1H, d, J = 11.4 Hz), 3.01-2.95 (2H, m), 2.79 (2H, d, J = 10.8 Hz), 2.70 (2H, d, J = 11.4 Hz), 2.25 (3H, s), 2.21-2.14 (2H, m), 1.48 (9H, s).

工程９
3-(3-(tert-ブチル)-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ1,2-b]ピリダジン-6-カルボアルデヒド Step 9
3- (3- (tert-Butyl) -4- (4-methylpiperazin-1-yl) phenyl) imidazo1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000666
Figure JPOXMLDOC01-appb-C000666

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-(tert-ブチル)-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (151 mg, 0.402 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (101 μL, 8.04 μmol) から標記化合物 (44 mg, 29%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.9 Hz), 8.43 (1H, s), 8.37 (1H, dd, J =9.4, 0.9 Hz), 8.21 (1H, d, J =2.3 Hz), 8.00 (1H, dd, J = 8.2, 2.1 Hz), 7.66 (1H, d, J = 9.4 Hz), 7.59 (1H, d, J = 8.2 Hz), 2.99 (2H, t, J = 10.1 Hz), 2.80 (2H, d, J = 11.0 Hz), 2.71 (2H, d, J = 11.2 Hz), 2.26 (3H, s), 2.19 (2H, t, J = 10.2 Hz), 1.49 (9H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3- (tert-butyl) -4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (151 mg, 0.402 mmol) and 2.5 wt% osmium tetroxide tert -The title compound (44 mg, 29%) was obtained from a butanol solution (101 μL, 8.04 μmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.9 Hz), 8.43 (1H, s), 8.37 (1H, dd, J = 9.4, 0.9 Hz), 8.21 ( 1H, d, J = 2.3 Hz), 8.00 (1H, dd, J = 8.2, 2.1 Hz), 7.66 (1H, d, J = 9.4 Hz), 7.59 (1H, d, J = 8.2 Hz), 2.99 ( 2H, t, J = 10.1 Hz), 2.80 (2H, d, J = 11.0 Hz), 2.71 (2H, d, J = 11.2 Hz), 2.26 (3H, s), 2.19 (2H, t, J = 10.2 Hz), 1.49 (9H, s).

工程１０
5-((3-(3-(tert-ブチル)-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１５３) Step 10
5-((3- (3- (tert-butyl) -4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4 -Dione (Compound 153)

Figure JPOXMLDOC01-appb-C000667
Figure JPOXMLDOC01-appb-C000667

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-(tert-ブチル)-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ1,2-b]ピリダジン-6-カルボアルデヒド (44 mg, 0.117 mmol) およびチアゾリジン-2,4-ジオン (14 mg, 0.117 mmol) から標記化合物 (30 mg, 54%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.24 (1H, d, J = 9.4 Hz), 8.14 (1H, s), 7.97 (1H, dd, J = 8.1, 1.9 Hz), 7.83 (1H, d, J = 2.1 Hz), 7.65 (1H, s), 7.61 (1H, d, J = 9.4 Hz), 7.54 (1H, d, J = 8.2 Hz), 3.07 (4H, t, J = 12.0 Hz), 2.83 (2H, d, J = 11.4 Hz), 2.66-2.56 (2H, m), 2.52 (3H, s), 1.48 (9H, s).
ESI-MS(m/z): 477[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3- (tert-butyl) -4- (4-methylpiperazin-1-yl) phenyl) imidazo-1,2-b] pyridazine-6-carbaldehyde (44 mg, 0.117 mmol) and thiazolidine-2,4-dione (14 mg, 0.117 mmol) gave the title compound (30 mg, 54%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.24 (1H, d, J = 9.4 Hz), 8.14 (1H, s), 7.97 (1H, dd, J = 8.1, 1.9 Hz), 7.83 ( 1H, d, J = 2.1 Hz), 7.65 (1H, s), 7.61 (1H, d, J = 9.4 Hz), 7.54 (1H, d, J = 8.2 Hz), 3.07 (4H, t, J = 12.0 Hz), 2.83 (2H, d, J = 11.4 Hz), 2.66-2.56 (2H, m), 2.52 (3H, s), 1.48 (9H, s).
ESI-MS (m / z): 477 [M + H] + .

実施例１５４
5-((3-(2-(4-メチルピペラジン-1-イル)ピリミジン-5-イル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１５４) Example 154
5-((3- (2- (4-Methylpiperazin-1-yl) pyrimidin-5-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 154)

工程１
tert-ブチル 4-(5-ブロモピリミジン-2-イル)ピペラジン-1-カルボキシレート Process 1
tert-butyl 4- (5-bromopyrimidin-2-yl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000668
Figure JPOXMLDOC01-appb-C000668

アルゴン雰囲気下、5-ブロモ-2-クロロピリミジン(750 mg, 3.88 mmol)を1,4-ジオキサン (19 mL) に溶解した。そこへ1-(tert-ブトキシカルボニル)ピペラジン (1.08 g, 5.82 mmol)、炭酸カリウム (965 mg, 6.98 mmol) を加え、2時間加熱還流した。反応液に水を加え、ジエチルエーテルで抽出した。ジエチルエーテル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.04 g, 78%) を得た。白色固体: 1H-NMR (CDCl3) δ: 8.31 (2H, s), 3.77 (4H, dd, J = 6.2, 4.4 Hz), 3.49 (4H, dd, J = 6.3, 4.2 Hz), 1.49 (9H, s). Under an argon atmosphere, 5-bromo-2-chloropyrimidine (750 mg, 3.88 mmol) was dissolved in 1,4-dioxane (19 mL). 1- (tert-butoxycarbonyl) piperazine (1.08 g, 5.82 mmol) and potassium carbonate (965 mg, 6.98 mmol) were added thereto, and the mixture was heated to reflux for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The diethyl ether layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.04 g, 78%). White solid: 1 H-NMR (CDCl 3 ) δ: 8.31 (2H, s), 3.77 (4H, dd, J = 6.2, 4.4 Hz), 3.49 (4H, dd, J = 6.3, 4.2 Hz), 1.49 ( 9H, s).

工程２
tert-ブチル 4-(5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピリミジン-2-イル)ピペラジン-1-カルボキシレート Process 2
tert-butyl 4- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidin-2-yl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000669
Figure JPOXMLDOC01-appb-C000669

アルゴン雰囲気下、tert-ブチル 4-(5-ブロモピリミジン-2-イル)ピペラジン-1-カルボキシレート (1.03 g, 3.00 mmol) を1,4-ジオキサン (30 mL) に溶解した。そこへビス(ピナコラート)ジボロン (1.52 g, 6.00 mmol)、炭酸カリウム (1.47 g, 15.0 mmol) を加えた。さらに(1,1'-ビス(ジフェニルホスフィノ)フェロセン)パラジウム(II)ジクロリド ジクロロメタン錯体 (245 mg, 0.300 mmol) を加え、反応容器内を脱気、アルゴン置換した後、120℃で17時間撹拌した。反応液に酢酸エチル、水を加え、セライトでろ過した。酢酸エチル層を取り、水層を酢酸エチルで抽出した。酢酸エチル層を合わせて飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (733 mg, 63%) を得た。白色固体: 1H-NMR (CDCl3) δ: 8.63 (2H, s), 3.90 (4H, s), 3.51 (4H, s), 1.49 (9H, s), 1.32 (12H, s). Under an argon atmosphere, tert-butyl 4- (5-bromopyrimidin-2-yl) piperazine-1-carboxylate (1.03 g, 3.00 mmol) was dissolved in 1,4-dioxane (30 mL). Bis (pinacolato) diboron (1.52 g, 6.00 mmol) and potassium carbonate (1.47 g, 15.0 mmol) were added thereto. Further, (1,1'-bis (diphenylphosphino) ferrocene) palladium (II) dichloride dichloromethane complex (245 mg, 0.300 mmol) was added, the reaction vessel was degassed, purged with argon, and then stirred at 120 ° C for 17 hours. did. Ethyl acetate and water were added to the reaction mixture, and the mixture was filtered through celite. The ethyl acetate layer was taken and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (733 mg, 63%). White solid: 1 H-NMR (CDCl 3 ) δ: 8.63 (2H, s), 3.90 (4H, s), 3.51 (4H, s), 1.49 (9H, s), 1.32 (12H, s).

工程３
tert-ブチル 4-(5-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)ピリミジン-2-イル)ピペラジン-1-カルボキシレート Process 3
tert-Butyl 4- (5- (6-chloroimidazo [1,2-b] pyridazin-3-yl) pyrimidin-2-yl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000670
Figure JPOXMLDOC01-appb-C000670

3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-カルボニトリルの合成 (実施例106、工程6) と同様の手法で、3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (364 mg, 1.57 mmol) および tert-ブチル 4-(5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピリミジン-2-イル)ピペラジン-1-カルボキシレート(733 mg, 1.88 mmol) から標記化合物 (509 mg, 78%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 9.01 (2H, s), 8.29 (1H, d, J = 9.4 Hz), 8.25 (1H, s), 7.40 (1H, d, J = 9.4 Hz), 3.83-3.81 (4H, m), 3.44 (4H, t, J = 5.3 Hz), 1.44 (9H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridine-5-carbonitrile (Example 106, Step 6) -6-Chloroimidazo [1,2-b] pyridazine (364 mg, 1.57 mmol) and tert-butyl 4- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 The title compound (509 mg, 78%) was obtained from -yl) pyrimidin-2-yl) piperazine-1-carboxylate (733 mg, 1.88 mmol). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 9.01 (2H, s), 8.29 (1H, d, J = 9.4 Hz), 8.25 (1H, s), 7.40 (1H, d, J = 9.4 Hz), 3.83-3.81 (4H, m), 3.44 (4H, t, J = 5.3 Hz), 1.44 (9H, s).

工程４
tert-ブチル 4-(5-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)ピリミジン-2-イル)ピペラジン-1-カルボキシレート Process 4
tert-Butyl 4- (5- (6-Vinylimidazo [1,2-b] pyridazin-3-yl) pyrimidin-2-yl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000671
Figure JPOXMLDOC01-appb-C000671

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、tert-ブチル 4-(5-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)ピリミジン-2-イル)ピペラジン-1-カルボキシレート (509 mg, 1.22 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (230 μL, 1.34 mmol) から標記化合物 (355 mg, 71%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 9.11 (2H, s), 8.18 (1H, d, J = 9.6 Hz), 8.18 (1H, s), 7.65 (1H, d, J = 9.6 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.36 (1H, d, J = 17.6 Hz), 5.77 (1H, d, J = 11.4 Hz), 3.83-3.80 (4H, m), 3.44 (4H, t, J = 5.2 Hz), 1.44 (9H, s). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) tert-butyl 4- (5- (6-chloroimidazo [1,2-b] pyridazin-3-yl) pyrimidin-2-yl) piperazine-1-carboxylate (509 mg, 1.22 mmol) and 4,4, The title compound (355 mg, 71%) was obtained from 5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (230 μL, 1.34 mmol). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 9.11 (2H, s), 8.18 (1H, d, J = 9.6 Hz), 8.18 (1H, s), 7.65 (1H, d, J = 9.6 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.36 (1H, d, J = 17.6 Hz), 5.77 (1H, d, J = 11.4 Hz), 3.83-3.80 (4H, m) , 3.44 (4H, t, J = 5.2 Hz), 1.44 (9H, s).

工程５
3-(2-(ピペラジン-1-イル)ピリミジン-5-イル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 5
3- (2- (Piperazin-1-yl) pyrimidin-5-yl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000672
Figure JPOXMLDOC01-appb-C000672

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程6) と同様の手法で、tert-ブチル 4-(5-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)ピリミジン-2-イル)ピペラジン-1-カルボキシレート (355 mg, 0.871 mmol) およびトリフルオロ酢酸 (1.5 mL) から標記化合物 (216 mg, 81%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 9.07 (2H, s), 8.18 (1H, d, J = 9.6 Hz), 8.16 (1H, s), 7.64 (1H, d, J = 9.6 Hz), 6.90 (1H, dd, J = 17.9, 11.0 Hz), 6.35 (1H, d, J = 17.9 Hz), 5.77 (1H, d, J = 11.4 Hz), 3.76 (4H, t, J = 5.0 Hz), 2.80 (4H, t, J = 5.0 Hz). Synthesis of 5-bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 6) From-(5- (6-vinylimidazo [1,2-b] pyridazin-3-yl) pyrimidin-2-yl) piperazine-1-carboxylate (355 mg, 0.871 mmol) and trifluoroacetic acid (1.5 mL) The title compound (216 mg, 81%) was obtained. Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 9.07 (2H, s), 8.18 (1H, d, J = 9.6 Hz), 8.16 (1H, s), 7.64 (1H, d, J = 9.6 Hz), 6.90 (1H, dd, J = 17.9, 11.0 Hz), 6.35 (1H, d, J = 17.9 Hz), 5.77 (1H, d, J = 11.4 Hz), 3.76 (4H, t, J = 5.0 Hz), 2.80 (4H, t, J = 5.0 Hz).

工程６
3-(2-(4-メチルピペラジン-1-イル)ピリミジン-5-イル)-6-ビニルイミダゾ[1,2-b]ピリダジン Step 6
3- (2- (4-Methylpiperazin-1-yl) pyrimidin-5-yl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000673
Figure JPOXMLDOC01-appb-C000673

5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程7) と同様の手法で、3-(2-(ピペラジン-1-イル)ピリミジン-5-イル)-6-ビニルイミダゾ[1,2-b]ピリダジン (216 mg, 0.703 mmol) および 37% ホルムアルデヒド水溶液 (314 μL, 4.22 mmol) から標記化合物 (150 mg, 66%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 9.08 (2H, s), 8.18 (1H, d, J = 9.4 Hz), 8.16 (1H, s), 7.64 (1H, d, J = 9.4 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.35 (1H, d, J = 17.6 Hz), 5.77 (1H, d, J = 11.2 Hz), 3.81 (4H, t, J = 5.0 Hz), 2.39 (4H, t, J = 5.2 Hz), 2.23 (3H, s). Synthesis of 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 7) From-(2- (piperazin-1-yl) pyrimidin-5-yl) -6-vinylimidazo [1,2-b] pyridazine (216 mg, 0.703 mmol) and 37% aqueous formaldehyde (314 μL, 4.22 mmol) The title compound (150 mg, 66%) was obtained. Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 9.08 (2H, s), 8.18 (1H, d, J = 9.4 Hz), 8.16 (1H, s), 7.64 (1H, d, J = 9.4 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.35 (1H, d, J = 17.6 Hz), 5.77 (1H, d, J = 11.2 Hz), 3.81 (4H, t, J = 5.0 Hz), 2.39 (4H, t, J = 5.2 Hz), 2.23 (3H, s).

工程７
3-(2-(4-メチルピペラジン-1-イル)ピリミジン-5-イル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Step 7
3- (2- (4-Methylpiperazin-1-yl) pyrimidin-5-yl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000674
Figure JPOXMLDOC01-appb-C000674

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(2-(4-メチルピペラジン-1-イル)ピリミジン-5-イル)-6-ビニルイミダゾ[1,2-b]ピリダジン (150 mg, 0.467 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (117 μL, 9.34 μmol) から標記化合物 (46 mg, 31%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.1 (1H, d, J = 0.7 Hz), 9.15 (2H, s), 8.42 (1H, s), 8.37 (1H, dd, J = 9.4, 0.7 Hz), 7.64 (1H, d, J = 9.4 Hz), 3.84 (4H, t, J = 5.0 Hz), 2.40 (4H, t, J =4.9 Hz), 2.24 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 2- (4-Methylpiperazin-1-yl) pyrimidin-5-yl) -6-vinylimidazo [1,2-b] pyridazine (150 mg, 0.467 mmol) and 2.5 wt% osmium tetroxide tert-butanol solution ( The title compound (46 mg, 31%) was obtained from 117 μL, 9.34 μmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, d, J = 0.7 Hz), 9.15 (2H, s), 8.42 (1H, s), 8.37 (1H, dd, J = 9.4 , 0.7 Hz), 7.64 (1H, d, J = 9.4 Hz), 3.84 (4H, t, J = 5.0 Hz), 2.40 (4H, t, J = 4.9 Hz), 2.24 (3H, s).

工程８
5-((3-(2-(4-メチルピペラジン-1-イル)ピリミジン-5-イル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１５４) Process 8
5-((3- (2- (4-Methylpiperazin-1-yl) pyrimidin-5-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 154)

Figure JPOXMLDOC01-appb-C000675
Figure JPOXMLDOC01-appb-C000675

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(2-(4-メチルピペラジン-1-イル)ピリミジン-5-イル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (46 mg, 0.142 mmol) およびチアゾリジン-2,4-ジオン (17 mg, 0.142 mmol) から標記化合物 (42 mg, 70%) を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 9.08 (2H, s), 8.26 (1H, d, J = 9.4 Hz), 8.22 (1H, s), 7.72 (1H, s), 7.63 (1H, d, J = 9.4 Hz), 3.92 (4H, s), 2.71 (4H, s), 2.44 (3H, s).
ESI-MS(m/z): 423[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (2- (4-methylpiperazin-1-yl) pyrimidin-5-yl) imidazo [1,2-b] pyridazine-6-carbaldehyde (46 mg, 0.142 mmol) and thiazolidine-2,4-dione (17 mg, 0.142 mmol) gave the title compound (42 mg, 70%). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 9.08 (2H, s), 8.26 (1H, d, J = 9.4 Hz), 8.22 (1H, s), 7.72 (1H, s), 7.63 ( 1H, d, J = 9.4 Hz), 3.92 (4H, s), 2.71 (4H, s), 2.44 (3H, s).
ESI-MS (m / z): 423 [M + H] + .

実施例１５５
5-((3-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１５５)  Example 155
5-((3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 155)

工程１
1-(4-ブロモ-2-フルオロフェニル)ピペラジン Process 1
1- (4-Bromo-2-fluorophenyl) piperazine

Figure JPOXMLDOC01-appb-C000676
Figure JPOXMLDOC01-appb-C000676

5Lコルベンに 1-(4-(4-ブロモ-2-フルオロフェニル)ピペラジン-1-イル)-2,2,2-トリフルオロエタノン (238 g, 0.669 mol)、メタノール (2.3 L) を加え、室温で炭酸カリウム (241 g, 1.75 mol) を加えて1時間攪拌した。不溶物をろ別し、メタノールで洗浄した。ろ液を濃縮し、残渣にジクロロメタン、水を加えて分液した。水層をジクロロメタンで2回抽出し、硫酸マグネシウムで乾燥して濃縮し、標記化合物 (154 g, 89%) を得た。白色固体: 1H-NMR (CDCl3) δ: 7.22-7.13 (2H, m), 6.81 (1H, m), 3.09-3.00 (8H, m). Add 1- (4- (4-bromo-2-fluorophenyl) piperazin-1-yl) -2,2,2-trifluoroethanone (238 g, 0.669 mol), methanol (2.3 L) to 5 L Kolben, Potassium carbonate (241 g, 1.75 mol) was added at room temperature and stirred for 1 hour. Insoluble material was filtered off and washed with methanol. The filtrate was concentrated and dichloromethane and water were added to the residue for liquid separation. The aqueous layer was extracted twice with dichloromethane, dried over magnesium sulfate and concentrated to obtain the title compound (154 g, 89%). White solid: 1 H-NMR (CDCl 3 ) δ: 7.22-7.13 (2H, m), 6.81 (1H, m), 3.09-3.00 (8H, m).

工程２
1-(4-ブロモ-2-フルオロフェニル)-4-エチルピペラジン Process 2
1- (4-Bromo-2-fluorophenyl) -4-ethylpiperazine

Figure JPOXMLDOC01-appb-C000677
Figure JPOXMLDOC01-appb-C000677

3Lコルベンに 1-(4-ブロモ-2-フルオロフェニル)ピペラジン (145 g, 0.558 mol)、アセトン (1.4 L)、炭酸カリウム (77.1 g, 0.558 mol) を加え、室温でヨードエタン (87.0 g, 0.558 mol) を加えて終夜加熱還流させた。放冷後、不溶物をろ別し、酢酸エチルで洗浄した。ろ液に酢酸エチル、水を加えて分液し、有機層を飽和食塩水で洗浄、硫酸マグネシウムで乾燥した。溶媒を減圧留去したあと、ヘプタンに懸濁させ、不溶物をろ別した。ろ液を濃縮し、標記化合物 (170 g, quant.) を得た。 薄黄色オイル: 1H-NMR (CDCl3) δ: 7.22-7.13 (2H, m), 6.81 (1H, m), 3.14-3.01 (4H, m), 2.66-2.59 (4H, m), 2.54-2.43 (2H, m), 1.12 (3H, t, J = 7.5 Hz ). 1- (4-Bromo-2-fluorophenyl) piperazine (145 g, 0.558 mol), acetone (1.4 L), potassium carbonate (77.1 g, 0.558 mol) were added to 3 L Kolben, and iodoethane (87.0 g, 0.558 mol) was added at room temperature. mol) was added and heated to reflux overnight. After allowing to cool, the insoluble material was filtered off and washed with ethyl acetate. Ethyl acetate and water were added to the filtrate for liquid separation, and the organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the solvent was suspended in heptane, and the insoluble material was filtered off. The filtrate was concentrated to obtain the title compound (170 g, quant.). Pale yellow oil: 1 H-NMR (CDCl 3 ) δ: 7.22-7.13 (2H, m), 6.81 (1H, m), 3.14-3.01 (4H, m), 2.66-2.59 (4H, m), 2.54- 2.43 (2H, m), 1.12 (3H, t, J = 7.5 Hz).

工程３
1-エチル-4-(2-フルオロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン Process 3
1-ethyl-4- (2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine

Figure JPOXMLDOC01-appb-C000678
Figure JPOXMLDOC01-appb-C000678

2Lコルベンに 1-(4-ブロモ-2-フルオロフェニル)-4-エチルピペラジン (50.0 g, 0.174 mol)、酢酸カリウム (59.8 g, 0.609 mol)、ビスピナコラトジボロン (53.1 g, 0.209 mol)、ジメチルスルホキシド (700 mL) を加え、減圧脱気を5回行った。ここに 1,1’-ビスジフェニルホスフィノフェロセンパラジウムジクロリドジクロロメタン錯体 (12.8 g, 15.7 mmol) を加え、120℃で3時間攪拌した。放冷後、水、酢酸エチルを加えて分液した。有機層を飽和食塩水で洗浄、硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー法 (ヘプタン/酢酸エチル) で精製して標記化合物 (37.8 g, 65%) を得た。茶色オイル: 1H-NMR (CDCl3) δ: 7.52-7.40 (2H, m), 6.92 (1H, m), 3.22-3.15 (4H, m), 2.67-2.59 (4H, m), 2.54-2.43 (2H, m), 1.28 (12H, s), 1.12 (3H, t, J = 7.5 Hz ). 1- (4-Bromo-2-fluorophenyl) -4-ethylpiperazine (50.0 g, 0.174 mol), potassium acetate (59.8 g, 0.609 mol), bispinacolatodiboron (53.1 g, 0.209 mol) in 2 L Kolben Dimethyl sulfoxide (700 mL) was added, and vacuum degassing was performed 5 times. 1,1′-bisdiphenylphosphinoferrocene palladium dichloride dichloromethane complex (12.8 g, 15.7 mmol) was added thereto, and the mixture was stirred at 120 ° C. for 3 hours. After allowing to cool, water and ethyl acetate were added to separate the layers. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (37.8 g, 65%). Brown oil: 1 H-NMR (CDCl 3 ) δ: 7.52-7.40 (2H, m), 6.92 (1H, m), 3.22-3.15 (4H, m), 2.67-2.59 (4H, m), 2.54-2.43 (2H, m), 1.28 (12H, s), 1.12 (3H, t, J = 7.5 Hz).

工程４
6-クロロ-3-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン Process 4
6-Chloro-3- (4- (4-ethylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000679
Figure JPOXMLDOC01-appb-C000679

1Lコルベンに3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (15.0 g, 64.5 mol)、1-エチル-4-(2-フルオロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン (25.9 g, 77.4 mmol)、炭酸ナトリウム ( 23.9 g, 226 mmol)、1,4-ジオキサン (300 mL)、水 (60.0 mL) を加え、減圧脱気を5回行った。テトラキストリフェニルホスフィンパラジウム (2.98 g, 2.58 mmol) を加え、加熱還流下20時間攪拌した。反応液を放冷後、水を加えて酢酸エチルで2回抽出し、有機層を集めて飽和食塩水で洗浄、硫酸マグネシウムで乾燥した。溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー法 (ジクロロメタン/メタノール) で精製して標記化合物 (14.4 g, 62%) を得た。黄色固体: 1H-NMR (CDCl3) δ: 8.01 (1H, s), 7.95 (1H, d, J = 10.0 Hz), 7.82-7.73 (2H, m), 7.12-7.02 (2H, m), 3.26-3.19 (4H, m), 2.71-2.63 (4H, m), 2.57-2.45 (2H, m), 1.15(3H, t, J = 7.5 Hz ). To 1 L Kolben 3-bromo-6-chloroimidazo [1,2-b] pyridazine (15.0 g, 64.5 mol), 1-ethyl-4- (2-fluoro-4- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine (25.9 g, 77.4 mmol), sodium carbonate (23.9 g, 226 mmol), 1,4-dioxane (300 mL), water (60.0 mL) And vacuum degassing was performed 5 times. Tetrakistriphenylphosphine palladium (2.98 g, 2.58 mmol) was added, and the mixture was stirred for 20 hours with heating under reflux. The reaction mixture was allowed to cool, water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was collected, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the title compound (14.4 g, 62%). Yellow solid: 1 H-NMR (CDCl 3 ) δ: 8.01 (1H, s), 7.95 (1H, d, J = 10.0 Hz), 7.82-7.73 (2H, m), 7.12-7.02 (2H, m), 3.26-3.19 (4H, m), 2.71-2.63 (4H, m), 2.57-2.45 (2H, m), 1.15 (3H, t, J = 7.5 Hz).

工程５
3-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 5
3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000680
Figure JPOXMLDOC01-appb-C000680

1Lコルベンに 6-クロロ-3-(4-(4-エチル-4-ピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン (14.3 g, 39.7 mmol)、トルエン (286 mL) を加え、減圧脱気を5回行った。ここにトリブチルビニルスズ (13.9 g, 43.7 mmol)、テトラキストリフェニルホスフィンパラジウム (4.60 g, 3.97 mmol) を加え、加熱還流下17時間攪拌した。反応液を放冷後、溶媒を減圧留去した。酢酸エチル、水、フッ化カリウムを加えて室温で終夜攪拌した。セライトろ過で不溶物を取り除き、酢酸エチルで洗浄した。ろ液を分離し、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥して溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製した。残渣に酢酸エチルを加えて結晶化させ、ろ過し、酢酸エチルで洗浄して標記化合物 (6.40 g, 46%) を得た。黄色結晶: 1H-NMR (CDCl3) δ: 7.96 (1H, s), 7.95-7.76 (3H, m), 7.30 (1H, m), 7.06 (1H, m), 6.92 (1H, m), 6.16 (1H, m), 5.70 (1H, m), 3.27-3.19 (4H, m), 2.72-2.66 (4H, m), 2.52 (2H, q, J = 7.5 Hz ), 1.15 (3H, t, J =7.5 Hz ). To 1 L Kolben, 6-chloro-3- (4- (4-ethyl-4-piperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazine (14.3 g, 39.7 mmol), toluene ( 286 mL) and vacuum degassing was performed 5 times. Tributylvinyltin (13.9 g, 43.7 mmol) and tetrakistriphenylphosphine palladium (4.60 g, 3.97 mmol) were added thereto, and the mixture was stirred for 17 hours with heating under reflux. After allowing the reaction solution to cool, the solvent was distilled off under reduced pressure. Ethyl acetate, water and potassium fluoride were added and stirred overnight at room temperature. The insoluble material was removed by Celite filtration and washed with ethyl acetate. The filtrate was separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol). The residue was crystallized by adding ethyl acetate, filtered and washed with ethyl acetate to obtain the title compound (6.40 g, 46%). Yellow crystals: 1 H-NMR (CDCl 3 ) δ: 7.96 (1H, s), 7.95-7.76 (3H, m), 7.30 (1H, m), 7.06 (1H, m), 6.92 (1H, m), 6.16 (1H, m), 5.70 (1H, m), 3.27-3.19 (4H, m), 2.72-2.66 (4H, m), 2.52 (2H, q, J = 7.5 Hz), 1.15 (3H, t, J = 7.5 Hz).

工程６
3-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Step 6
3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000681
Figure JPOXMLDOC01-appb-C000681

500mLコルベンに 3-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (6.20 g, 17.6 mol)、1,4-ジオキサン (124 mL)、水 (44 mL)、2,6-ルチジン (3.77 g, 35.2 mol)、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (4.4 mL, 0.352 mmol)、過ヨウ素酸ナトリウム (15.1 g, 70.4 mol) を加え、室温で終夜攪拌した。反応液をセライトろ過し、酢酸エチルで洗浄した。ろ液に飽和チオ硫酸ナトリウム水を加えて洗浄し、水層を酢酸エチルで抽出した。有機層を合わせ、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製した。得られた個体を酢酸エチルに懸濁させてろ過し、標記化合物 (2.76 g, 45%) を得た。黄色固体: 1H-NMR (CDCl3) δ: 10.13 (1H, s), 8.16 (1H, s), 8.13 (1H, d, J = 9.3 Hz), 7.91-7.78 (2H, m), 7.67 (1H, d, J = 9.3 Hz), 7.13 (1H, m), 3.30-3.22(4H, m), 2.73-2.67 (4H, m), 2.53 (2H, q, J = 7.5 Hz), 1.16 (3H, t, J = 7.5 Hz ). 3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) -6-vinylimidazo [1,2-b] pyridazine (6.20 g, 17.6 mol), 1,4-dioxane in 500 mL Kolben (124 mL), water (44 mL), 2,6-lutidine (3.77 g, 35.2 mol), 2.5 wt% osmium tetroxide tert-butanol solution (4.4 mL, 0.352 mmol), sodium periodate (15.1 g, 70.4 mol) was added and stirred at room temperature overnight. The reaction solution was filtered through celite and washed with ethyl acetate. The filtrate was washed with a saturated aqueous sodium thiosulfate solution, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol). The obtained solid was suspended in ethyl acetate and filtered to obtain the title compound (2.76 g, 45%). Yellow solid: 1 H-NMR (CDCl 3 ) δ: 10.13 (1H, s), 8.16 (1H, s), 8.13 (1H, d, J = 9.3 Hz), 7.91-7.78 (2H, m), 7.67 ( 1H, d, J = 9.3 Hz), 7.13 (1H, m), 3.30-3.22 (4H, m), 2.73-2.67 (4H, m), 2.53 (2H, q, J = 7.5 Hz), 1.16 (3H , t, J = 7.5 Hz).

工程７
5-((3-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１５５) Step 7
5-((3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 155)

Figure JPOXMLDOC01-appb-C000682
Figure JPOXMLDOC01-appb-C000682

1Lコルベンに3-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (2.56 g, 7.24 mmol)、2,4-チアゾリジンジオン (848 mg, 7.24 mmol)、ピペリジン ( 144 μL, 1.45 mmol)、酢酸 (166 μL, 2.90 mmol)、アセトニトリル (256 mL) を加え、加熱還流下18時間攪拌した。反応液を放冷し、氷冷下30分攪拌後、得られた固体をろ過、アセトニトリルで洗浄して粗結晶を2.50 g 得た。粗結晶をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製して標記化合物 (1.80 g, 55%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.28 (1H, s), 8.25 (1H, d, J = 9.4 Hz), 8.11 (1H, dd, J = 14.4, 2.1 Hz), 7.88 (1H, dd, J = 8.4, 2.1 Hz), 7.70 (1H, s), 7.63 (1H, d, J = 9.4 Hz), 7.19 (1H, t, J = 9.0 Hz), 3.26-3.15 (4H, m), 2.94-2.73 (4H, m), 2.77-2.72 (2H, m), 1.14 (3H, t, J = 7.5 Hz). To 1 L Kolben 3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (2.56 g, 7.24 mmol), 2,4- Thiazolidinedione (848 mg, 7.24 mmol), piperidine (144 μL, 1.45 mmol), acetic acid (166 μL, 2.90 mmol), and acetonitrile (256 mL) were added, and the mixture was stirred with heating under reflux for 18 hours. The reaction solution was allowed to cool and stirred for 30 minutes under ice-cooling. The resulting solid was filtered and washed with acetonitrile to obtain 2.50 g of crude crystals. The crude crystals were purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (1.80 g, 55%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.28 (1H, s), 8.25 (1H, d, J = 9.4 Hz), 8.11 (1H, dd, J = 14.4, 2.1 Hz), 7.88 ( 1H, dd, J = 8.4, 2.1 Hz), 7.70 (1H, s), 7.63 (1H, d, J = 9.4 Hz), 7.19 (1H, t, J = 9.0 Hz), 3.26-3.15 (4H, m ), 2.94-2.73 (4H, m), 2.77-2.72 (2H, m), 1.14 (3H, t, J = 7.5 Hz).

実施例１５６
5-((1-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン(化合物１５６)  Example 156
5-((1- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (compound 156 )

工程１
3-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)アミノ)-N-メトキシ-N-メチル-4-ニトロベンズアミド Process 1
3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) amino) -N-methoxy-N-methyl-4-nitrobenzamide

Figure JPOXMLDOC01-appb-C000683
Figure JPOXMLDOC01-appb-C000683

アルゴン雰囲気下、N-エチルピペラジン (1.29 g, 11.3 mmol) を N,N-ジメチルホルムアミド (5 mL) に溶解した。そこへ3,4-ジフルオロニトロベンゼン (1.59 g, 10 mmol)、炭酸カリウム (3.46 g, 25 mmol) を加え、 90℃で2時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。 酢酸エチル層を無水硫酸ナトリウムで乾燥させ、溶媒を留去した。残留物を、エタノール (150 mL)、水 (60 mL) に溶解した。そこへ鉄粉 (1.68 g, 30 mmol)、塩化アンモニウム (1.07 g, 20 mmol) を加え、5時間加熱還流した。反応液をセライトでろ過し、ろ液を濃縮した。得られた残渣を酢酸エチルに再溶解して飽和重層水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた粗生成物と 3-フルオロ-N-メトキシ-N-メチル-4-ニトロベンズアミド (2.05 g, 9 mmol) とから、N-メトキシ-N-メチル-3-((4-(4-メチルピペラジニル)ベンジル)アミノ)-4-ニトロベンズアミドの合成と同様の手法で、標記化合物 (2.64 g, 3工程57 %) を得た。1H-NMR (CDCl3) δ: 9.44(1H, br s), 8.23 (1H, d, J = 9.0 Hz), 7.30-7.20 (2H, m), 7.02-6.95 (3H, m), 3.54 (3H, s), 3.50-3.30 (4H, br s), 3.32 (3H, s), 3.08-2.60 (6H, m), 1.30 (3H, br s). Under an argon atmosphere, N-ethylpiperazine (1.29 g, 11.3 mmol) was dissolved in N, N-dimethylformamide (5 mL). 3,4-Difluoronitrobenzene (1.59 g, 10 mmol) and potassium carbonate (3.46 g, 25 mmol) were added thereto, and the mixture was stirred at 90 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was dissolved in ethanol (150 mL) and water (60 mL). Iron powder (1.68 g, 30 mmol) and ammonium chloride (1.07 g, 20 mmol) were added there, and it heated and refluxed for 5 hours. The reaction solution was filtered through celite, and the filtrate was concentrated. The obtained residue was redissolved in ethyl acetate and washed with saturated multistory water. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. From the obtained crude product and 3-fluoro-N-methoxy-N-methyl-4-nitrobenzamide (2.05 g, 9 mmol), N-methoxy-N-methyl-3-((4- (4- (4- In the same manner as in the synthesis of methylpiperazinyl) benzyl) amino) -4-nitrobenzamide, the title compound (2.64 g, 57% for 3 steps) was obtained. 1 H-NMR (CDCl 3 ) δ: 9.44 (1H, br s), 8.23 (1H, d, J = 9.0 Hz), 7.30-7.20 (2H, m), 7.02-6.95 (3H, m), 3.54 ( 3H, s), 3.50-3.30 (4H, br s), 3.32 (3H, s), 3.08-2.60 (6H, m), 1.30 (3H, br s).

工程２
1-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド Process 2
1- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide

Figure JPOXMLDOC01-appb-C000684
Figure JPOXMLDOC01-appb-C000684

3-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)アミノ)-N-メトキシ-N-メチル-4-ニトロベンズアミド(2.64 g, 5.70 mmol) をエタノール (85 mL)、水(34 mL) に溶解した。そこへ鉄粉 (955 mg, 17.1 mmol)、塩化アンモニウム (609 mg, 11.4 mmol) を加え、5時間加熱還流した。反応液をセライトでろ過し、ろ液を濃縮した。得られた残渣を酢酸エチルに再溶解して飽和重層水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。残留物にエタノール(30 mL) を加え、オルトギ酸トリエチル (4.45 g, 30 mmol)、および酢酸 (720 mg, 12 mmol) を添加した。50℃で終夜撹拌した後、飽和炭酸水素ナトリウム水溶液を添加し、酢酸エチルと飽和食塩水を加えて有機層を抽出し、無水硫酸ナトリウムにより乾燥、ろ過、減圧下濃縮した。残留物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (1.70 g, 2工程72%) を得た。1H-NMR (CDCl3) δ: 8.11 (1H, s), 7.87 (1H, s), 7.85 (1H, d, J = 8.2 Hz), 7.69 (1H, dd, J = 7.3, 1.4 Hz), 7.23-7.21 (2H, m), 7.12 (1H, t, J = 9.2 Hz), 3.54 (3H, s), 3.50-3.35(4H, br s), 3.37 (3H, s), 3.18-2.78 (6H, br s), 1.35 (3H, br s).  3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) amino) -N-methoxy-N-methyl-4-nitrobenzamide (2.64 g, 5.70 mmol) in ethanol (85 mL), Dissolved in water (34 mL). Iron powder (955 mg, 17.1 mmol) and ammonium chloride (609 mg, 11.4 mmol) were added there, and it heated and refluxed for 5 hours. The reaction solution was filtered through celite, and the filtrate was concentrated. The obtained residue was redissolved in ethyl acetate and washed with saturated multistory water. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. Ethanol (30 mL) was added to the residue, and triethyl orthoformate (4.45 g, 30 mmol) and acetic acid (720 mg, 12 mmol) were added. After stirring at 50 ° C. overnight, saturated aqueous sodium hydrogen carbonate solution was added, ethyl acetate and saturated brine were added, and the organic layer was extracted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (1.70 g, 2 steps 72%). 1 H-NMR (CDCl 3 ) δ: 8.11 (1H, s), 7.87 (1H, s), 7.85 (1H, d, J = 8.2 Hz), 7.69 (1H, dd, J = 7.3, 1.4 Hz), 7.23-7.21 (2H, m), 7.12 (1H, t, J = 9.2 Hz), 3.54 (3H, s), 3.50-3.35 (4H, br s), 3.37 (3H, s), 3.18-2.78 (6H , br s), 1.35 (3H, br s).

工程３
1-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド Process 3
1- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) -1H-benzo [d] imidazole-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000685
Figure JPOXMLDOC01-appb-C000685

1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒドの合成と同様の手法で、1-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)-N-メトキシ-N-メチル-1H-ベンゾ[d]イミダゾール-6-カルボキシアミド(1.70 g, 4.13 mmol) およびビスシクロペンタジエニルジルコニウム(ＩＶ)クロリドヒドリド (1.30 g, 4.8 mmol) を用い、標記化合物 (0.41 g, 28%) を得た。1H-NMR (CDCl3) δ: 10.09 (1H, s), 8.22 (1H, s), 8.04 (1H, d, J = 0.9 Hz), 7.99 (1H, d, J = 8.2 Hz), 7.90 (1H, dd, J =7.3, 1.4 Hz), 7.27-7.22 (2H, m), 7.16 (1H, t, J = 8.7 Hz), 3.48-3.28 (4H, br s), 2.98-2.78 (4H, br s), 2.71 (2H, br s), 1.29 (3H, br s). 1- (4- (4-Methylpiperazinyl) benzyl) -1H-benzo [d] imidazole-6-carbaldehyde is prepared in a similar manner to the synthesis of 1- (4- (4-ethylpiperazin-1-yl ) -3-Fluorophenyl) -N-methoxy-N-methyl-1H-benzo [d] imidazole-6-carboxamide (1.70 g, 4.13 mmol) and biscyclopentadienylzirconium (IV) chloride hydride (1.30 g , 4.8 mmol) to give the title compound (0.41 g, 28%). 1 H-NMR (CDCl 3 ) δ: 10.09 (1H, s), 8.22 (1H, s), 8.04 (1H, d, J = 0.9 Hz), 7.99 (1H, d, J = 8.2 Hz), 7.90 ( 1H, dd, J = 7.3, 1.4 Hz), 7.27-7.22 (2H, m), 7.16 (1H, t, J = 8.7 Hz), 3.48-3.28 (4H, br s), 2.98-2.78 (4H, br s), 2.71 (2H, br s), 1.29 (3H, br s).

工程４
5-((1-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１５６) Process 4
5-((1- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 156 )

Figure JPOXMLDOC01-appb-C000686
Figure JPOXMLDOC01-appb-C000686

1-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)-1H-ベンゾ[d]イミダゾール-6-カルボアルデヒド(0.41 g, 1.16 mmol) をエタノール (6 mL) に溶かし、チアゾリジン-2,4-ジオン (136 mg, 1.16 mmol) およびピペリジン (35 mg, 0.4 mmol) を加え、70℃で一晩撹拌した。析出物をろ過し、エタノールで洗浄した後、減圧下加熱乾燥して標記化合物 (349 mg, 67%) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 8.65 (1H, s), 7.89-7.85 (3H, m), 7.66 (1H, dd, J = 10.5, 2.7 Hz), 7.54-7.49(2H, m), 7.30 (1H, t, J = 9.2 Hz), 3.30-3.10 (4H, br s), 2.91-2.71 (4H, br s), 2.67 (2H, br s), 1.11 (3H, t, J = 7.1 Hz).
ESI-MS(m/z): 452[M+H]+.  1- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) -1H-benzo [d] imidazole-6-carbaldehyde (0.41 g, 1.16 mmol) was dissolved in ethanol (6 mL), Thiazolidine-2,4-dione (136 mg, 1.16 mmol) and piperidine (35 mg, 0.4 mmol) were added, and the mixture was stirred at 70 ° C. overnight. The precipitate was filtered, washed with ethanol, and then dried by heating under reduced pressure to obtain the title compound (349 mg, 67%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 8.65 (1H, s), 7.89-7.85 (3H, m), 7.66 (1H, dd, J = 10.5, 2.7 Hz), 7.54-7.49 (2H , m), 7.30 (1H, t, J = 9.2 Hz), 3.30-3.10 (4H, br s), 2.91-2.71 (4H, br s), 2.67 (2H, br s), 1.11 (3H, t, J = 7.1 Hz).
ESI-MS (m / z): 452 [M + H] + .

実施例１５７
5-((3-(4-(4-エチルピペラジン-1-イル)フェニル)-[1,2,4]トリアゾロ[4,3-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１５７)  Example 157
5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl)-[1,2,4] triazolo [4,3-b] pyridazin-6-yl) methylene) thiazolidine-2,4 -Dione (Compound 157)

工程１
3-(4-ブロモフェニル)-6-クロロ-[1,2,4]トリアゾロ[4,3-b]ピリダジン Process 1
3- (4-Bromophenyl) -6-chloro- [1,2,4] triazolo [4,3-b] pyridazine

Figure JPOXMLDOC01-appb-C000687
Figure JPOXMLDOC01-appb-C000687

3,6-ジクロロピリダジン (2.98 g, 20 mmol) にトリエチルアミン塩酸塩 (3.03 g, 22 mmol) およびキシレン (30 mL) を加えた後、4-ブロモベンゾヒドラジド (4.73 g, 22 mmol) を加えアルゴン置換した後、140℃で4時間撹拌した。反応混合物をろ過し、固体を酢酸エチルおよびヘキサンで洗浄した後、減圧加熱乾燥して標記化合物 (5.96 g, 19.3 mmol, 96%) を得た。1H-NMR (CDCl3) δ: 8.39 (2H, d, J = 8.3 Hz), 8.18 (1H, d, J = 9.5 Hz), 7.73 (2H, d, J = 8.3 Hz), 7.19 (1H, d, J = 9.5 Hz). Triethylamine hydrochloride (3.03 g, 22 mmol) and xylene (30 mL) were added to 3,6-dichloropyridazine (2.98 g, 20 mmol), followed by 4-bromobenzohydrazide (4.73 g, 22 mmol) and argon. After the replacement, the mixture was stirred at 140 ° C. for 4 hours. The reaction mixture was filtered, and the solid was washed with ethyl acetate and hexane, and then dried by heating under reduced pressure to obtain the title compound (5.96 g, 19.3 mmol, 96%). 1 H-NMR (CDCl 3 ) δ: 8.39 (2H, d, J = 8.3 Hz), 8.18 (1H, d, J = 9.5 Hz), 7.73 (2H, d, J = 8.3 Hz), 7.19 (1H, d, J = 9.5 Hz).

工程２
6-クロロ-3-(4-(4-エチルピペラジン-1-イル)フェニル)-[1,2,4]トリアゾロ[4,3-b]ピリダジン Process 2
6-Chloro-3- (4- (4-ethylpiperazin-1-yl) phenyl)-[1,2,4] triazolo [4,3-b] pyridazine

Figure JPOXMLDOC01-appb-C000688
Figure JPOXMLDOC01-appb-C000688

アルゴン雰囲気下、1-エチルピペラジン (299 mg, 2.6 mmol)、3-(4-ブロモフェニル)-6-クロロ-[1,2,4]トリアゾロ[4,3-b]ピリダジン(619 mg, 2 mmol)、トリス(ジベンジリデンアセトン)ジパラジウム(0) (92 mg, 0.1 mmol)、2-ジシクロヘキシルホスフィノ-2',6'-ジメトキシビフェニル (164 mg, 0.4 mmol) のトルエン (5 mL) 溶液にナトリウム tert-ブトキシド (288 mg, 3 mmol) を加え、100℃で終夜撹拌した。反応液に水を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (0.06 g, 9%) を得た。1H-NMR (CDCl3) δ: 8.33 (2H, d, J = 8.1 Hz), 7.98 (1H, d, J = 10.0 Hz), 7.68 (2H, d, J = 8.5 Hz), 6.97 (1H, d, J = 10.0 Hz), 3.97-3.80 (4H, m), 3.10-2.65 (6H, m), 1.36 (3H, br s). 1-ethylpiperazine (299 mg, 2.6 mmol), 3- (4-bromophenyl) -6-chloro- [1,2,4] triazolo [4,3-b] pyridazine (619 mg, 2) under argon atmosphere mmol), tris (dibenzylideneacetone) dipalladium (0) (92 mg, 0.1 mmol), 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (164 mg, 0.4 mmol) in toluene (5 mL) To the mixture was added sodium tert-butoxide (288 mg, 3 mmol), and the mixture was stirred at 100 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.06 g, 9%). 1 H-NMR (CDCl 3 ) δ: 8.33 (2H, d, J = 8.1 Hz), 7.98 (1H, d, J = 10.0 Hz), 7.68 (2H, d, J = 8.5 Hz), 6.97 (1H, d, J = 10.0 Hz), 3.97-3.80 (4H, m), 3.10-2.65 (6H, m), 1.36 (3H, br s).

工程３
3-(4-(4-エチルピペラジン-1-イル)フェニル)-6-ビニル-[1,2,4]トリアゾロ[4,3-b]ピリダジン Process 3
3- (4- (4-Ethylpiperazin-1-yl) phenyl) -6-vinyl- [1,2,4] triazolo [4,3-b] pyridazine

Figure JPOXMLDOC01-appb-C000689
Figure JPOXMLDOC01-appb-C000689

6-クロロ-3-(4-(4-エチルピペラジン-1-イル)フェニル)-[1,2,4]トリアゾロ[4,3-b]ピリダジン (0.38 g, 1.1 mmol)、テトラキストリフェニルホスフィンパラジウム (230 mg, 0.2 mmol) のトルエン (20 mL) 溶液中に、トリブチルビニルスズ (0.5 mL, 1.6 mmol) を滴下した。アルゴン置換した後、還流条件下一晩撹拌し、反応終了後クロロホルムおよび炭酸水素ナトリウム水溶液を加えて有機層を抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残留物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (0.20 g, 54%) を得た。1H-NMR (CDCl3) δ: 8.46 (2H, d, J = 8.5 Hz), 7.95 (1H, d, J = 9.5 Hz), 7.57 (2H, d, J = 8.5 Hz), 6.96 (1H, d, J = 10.2 Hz), 6.79 (1H, m), 5.87 (1H, d, J = 17.6 Hz), 5.35 (1H, d, J = 11.0 Hz), 3.78-3.58 (4H, m), 2.75-2.48 (6H, m), 1.40 (3H, br s). 6-chloro-3- (4- (4-ethylpiperazin-1-yl) phenyl)-[1,2,4] triazolo [4,3-b] pyridazine (0.38 g, 1.1 mmol), tetrakistriphenylphosphine Tributylvinyltin (0.5 mL, 1.6 mmol) was added dropwise to a toluene (20 mL) solution of palladium (230 mg, 0.2 mmol). After purging with argon, the mixture was stirred overnight under reflux conditions. After the reaction was completed, chloroform and an aqueous sodium hydrogen carbonate solution were added to extract the organic layer. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.20 g, 54%). 1 H-NMR (CDCl 3 ) δ: 8.46 (2H, d, J = 8.5 Hz), 7.95 (1H, d, J = 9.5 Hz), 7.57 (2H, d, J = 8.5 Hz), 6.96 (1H, d, J = 10.2 Hz), 6.79 (1H, m), 5.87 (1H, d, J = 17.6 Hz), 5.35 (1H, d, J = 11.0 Hz), 3.78-3.58 (4H, m), 2.75- 2.48 (6H, m), 1.40 (3H, br s).

工程４
3-(4-(4-エチルピペラジン-1-イル)フェニル)-[1,2,4]トリアゾロ[4,3-b]ピリダジン-6-カルボアルデヒド Process 4
3- (4- (4-Ethylpiperazin-1-yl) phenyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000690
Figure JPOXMLDOC01-appb-C000690

アルゴン雰囲気下、3-(4-(4-エチルピペラジン-1-イル)フェニル)-6-ビニル-[1,2,4]トリアゾロ[4,3-b]ピリダジン (0.20 g, 0.6 mmol)、過ヨウ素酸ナトリウム (513 mg, 2.4 mmol) を 1,4-ジオキサン (4.5 mL)、水 (1.5 mL) の混合溶媒に溶解し、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (150 μL, 0.012 mmol)、2,6-ルチジン (128 mg, 1.2 mmol) を加え、室温で6時間撹拌した。反応終了後、飽和チオ硫酸ナトリウム水溶液を加え、セライトろ過した。ろ液に炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (0.08 g, 40%) を得た。1H-NMR (CDCl3) δ: 10.09 (1H, s), 8.66 (2H, d, J = 8.3 Hz), 8.06 (2H, d, J = 8.8Hz), 7.99 (1H, d, J = 10.2 Hz), 7.12 (1H, d, J = 10.2 Hz), 3.80-3.62 (4H, m), 2.80-2.63 (4H, m), 2.58 (2H, m), 1.19 (3H, t, J = 7.2 Hz). Under an argon atmosphere, 3- (4- (4-ethylpiperazin-1-yl) phenyl) -6-vinyl- [1,2,4] triazolo [4,3-b] pyridazine (0.20 g, 0.6 mmol), Dissolve sodium periodate (513 mg, 2.4 mmol) in a mixed solvent of 1,4-dioxane (4.5 mL) and water (1.5 mL) and add 2.5 wt% osmium tetroxide tert-butanol solution (150 μL, 0.012 mmol) ) And 2,6-lutidine (128 mg, 1.2 mmol) were added, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, a saturated aqueous sodium thiosulfate solution was added, and the mixture was filtered through celite. A sodium bicarbonate aqueous solution was added to the filtrate, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.08 g, 40%). 1 H-NMR (CDCl 3 ) δ: 10.09 (1H, s), 8.66 (2H, d, J = 8.3 Hz), 8.06 (2H, d, J = 8.8 Hz), 7.99 (1H, d, J = 10.2 Hz), 7.12 (1H, d, J = 10.2 Hz), 3.80-3.62 (4H, m), 2.80-2.63 (4H, m), 2.58 (2H, m), 1.19 (3H, t, J = 7.2 Hz ).

工程５
5-((3-(4-(4-エチルピペラジン-1-イル)フェニル)-[1,2,4]トリアゾロ[4,3-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１５７) Process 5
5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl)-[1,2,4] triazolo [4,3-b] pyridazin-6-yl) methylene) thiazolidine-2,4 -Dione (Compound 157)

Figure JPOXMLDOC01-appb-C000691
Figure JPOXMLDOC01-appb-C000691

3-(4-(4-エチルピペラジン-1-イル)フェニル)-[1,2,4]トリアゾロ[4,3-b]ピリダジン-6-カルボアルデヒド (0.08 g, 0.24 mmol) をアセトニトリル (8 mL) に溶かし、チアゾリジン-2,4-ジオン (28 mg, 0.24 mmol)、ピペリジン (4.2 mg, 0.05 mmol)、および酢酸 (6.0 mg, 0.1 mmol) を加え、80℃で24時間撹拌した。反応終了後、減圧下濃縮乾固し、残留物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (41 mg, 39%) を得た。 1H-NMR (DMSO-D6) δ: 8.56 (2H, d, J = 8.5 Hz), 8.22 (1H, d, J = 10.2 Hz), 7.89 (2H, d, J = 8.5 Hz), 7.74 (1H, s), 7.59 (1H, d, J = 10.0 Hz), 3.89-3.61 (4H, m), 2.85-2.63 (4H, m), 2.59 (2H, m), 1.10 (3H, t, J = 7.2 Hz). 
ESI-MS(m/z): 436[M+H]+. 3- (4- (4-Ethylpiperazin-1-yl) phenyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-carbaldehyde (0.08 g, 0.24 mmol) in acetonitrile (8 To the mixture, thiazolidine-2,4-dione (28 mg, 0.24 mmol), piperidine (4.2 mg, 0.05 mmol), and acetic acid (6.0 mg, 0.1 mmol) were added and stirred at 80 ° C. for 24 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (41 mg, 39%). 1 H-NMR (DMSO-D 6 ) δ: 8.56 (2H, d, J = 8.5 Hz), 8.22 (1H, d, J = 10.2 Hz), 7.89 (2H, d, J = 8.5 Hz), 7.74 ( 1H, s), 7.59 (1H, d, J = 10.0 Hz), 3.89-3.61 (4H, m), 2.85-2.63 (4H, m), 2.59 (2H, m), 1.10 (3H, t, J = 7.2 Hz).
ESI-MS (m / z): 436 [M + H] + .

実施例１５８
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-インダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１５８)  Example 158
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 158)

工程１
1-(4-ブロモフェニル)-6-クロロ-1H-インダゾール Process 1
1- (4-Bromophenyl) -6-chloro-1H-indazole

Figure JPOXMLDOC01-appb-C000692
Figure JPOXMLDOC01-appb-C000692

2,4-ジクロロベンズアルデヒド (1.56 g, 8.95 mmol)、(4-ブロモフェニル)ヒドラジン塩酸塩 (20 g, 8.95 mmol)、炭酸セシウム (8.75 g, 26.8 mmol) のN-メチルピロリドン (50 mL)溶液中に、トリエチルアミン (0.91 mL. 8.95 mmol) を室温下滴下した。130℃で一晩撹拌し、反応終了後、飽和食塩水を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (2.18 g, 79%) を得た。 1H-NMR (CDCl3) δ: 8.17 (1H, d, J = 1.0 Hz), 7.83-7.64 (4H, m), 7.64-7.54 (2H, m), 7.32-7.19 (1H, m).
ESI-MS(m/z): 307[M+H]+. 2,4-dichlorobenzaldehyde (1.56 g, 8.95 mmol), (4-bromophenyl) hydrazine hydrochloride (20 g, 8.95 mmol), cesium carbonate (8.75 g, 26.8 mmol) in N-methylpyrrolidone (50 mL) Triethylamine (0.91 mL. 8.95 mmol) was added dropwise at room temperature. The mixture was stirred at 130 ° C. overnight. After completion of the reaction, saturated brine was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (2.18 g, 79%). 1 H-NMR (CDCl 3 ) δ: 8.17 (1H, d, J = 1.0 Hz), 7.83-7.64 (4H, m), 7.64-7.54 (2H, m), 7.32-7.19 (1H, m).
ESI-MS (m / z): 307 [M + H] + .

工程２
6-クロロ-1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-インダゾール Process 2
6-Chloro-1- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazole

Figure JPOXMLDOC01-appb-C000693
Figure JPOXMLDOC01-appb-C000693

1-(4-ブロモフェニル)-6-クロロ-1H-インダゾール (1.0 g,3.25 mmol )、酢酸パラジウム (36 mg, 0.16 mmol)、2,2'-ビス（ジフェニルホスフィノ）-1,1'-ビナフチル (304 mg, 0.49 mmol)、tert-ブトキシナトリウム (937 mg, 9.75 mmol) のトルエン (20 mL) 溶液中に、1-メチルピペラジン (537 μL, 4.88 mmol) を室温下滴下した。アルゴン置換した後、還流条件下一晩撹拌した。反応終了後、室温まで放冷した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (559 mg, 53%) を得た。 1H-NMR (CDCl3) δ: 8.13 (1H, s), 7.70 (1H, d, J = 8.5 Hz), 7.64 (1H, s), 7.53 (2H, d, J = 9.0 Hz), 7.17 (1H, d, J = 8.5 Hz), 7.07 (2H, d, J = 9.0 Hz), 3.34 (4H, t, J = 5.0 Hz), 2.69 (4H, t, J = 5.0 Hz), 2.43 (3H, s).
ESI-MS(m/z): 327[M+H]+. 1- (4-Bromophenyl) -6-chloro-1H-indazole (1.0 g, 3.25 mmol), palladium acetate (36 mg, 0.16 mmol), 2,2'-bis (diphenylphosphino) -1,1 ' 1-Methylpiperazine (537 μL, 4.88 mmol) was added dropwise at room temperature to a solution of -binaphthyl (304 mg, 0.49 mmol) and tert-butoxy sodium (937 mg, 9.75 mmol) in toluene (20 mL). After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (559 mg, 53%). 1 H-NMR (CDCl 3 ) δ: 8.13 (1H, s), 7.70 (1H, d, J = 8.5 Hz), 7.64 (1H, s), 7.53 (2H, d, J = 9.0 Hz), 7.17 ( 1H, d, J = 8.5 Hz), 7.07 (2H, d, J = 9.0 Hz), 3.34 (4H, t, J = 5.0 Hz), 2.69 (4H, t, J = 5.0 Hz), 2.43 (3H, s).
ESI-MS (m / z): 327 [M + H] + .

工程３
1-(4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニル-1H-インダゾール Process 3
1- (4- (4-Methylpiperazin-1-yl) phenyl) -6-vinyl-1H-indazole

Figure JPOXMLDOC01-appb-C000694
Figure JPOXMLDOC01-appb-C000694

6-クロロ-1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-インダゾール (559 mg, 1.71 mmol) の1,4-ジオキサン (24 mL)、水 (4 mL) の混合溶液中に4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (439 μL, 2.57 mmol)、酢酸パラジウム (38 mg, 0.17 mmol)、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル (140 mg, 0.34 mmol)、リン酸三カリウム (2.72 g, 12.8 mmol) を添加した。アルゴン置換した後、還流条件下5時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (544 mg, 99%) を得た。 1H-NMR (CDCl3) δ: 8.12 (1H, s), 7.72 (1H, d, J = 8.3 Hz), 7.58-7.56 (3 H, m), 7.35 (1H, d, J = 8.3 Hz), 7.08 (2H, d, J = 9.0 Hz), 6.82 (1H, dd, J = 17.4, 10.9 Hz), 5.83 (1H, d, J = 17.4 Hz), 5.32 (1H, d, J = 10.9 Hz), 3.34 (4H, t, J = 4.9 Hz), 2.69 (4H, t, J = 4.9 Hz), 2.43 (3H, s).
ESI-MS(m/z): 319[M+H]+. 6-Chloro-1- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazole (559 mg, 1.71 mmol) in 1,4-dioxane (24 mL) and water (4 mL) 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (439 μL, 2.57 mmol), palladium acetate (38 mg, 0.17 mmol), 2-dicyclohexylphosphino-2 in solution ', 6'-Dimethoxybiphenyl (140 mg, 0.34 mmol) and tripotassium phosphate (2.72 g, 12.8 mmol) were added. After replacing with argon, the mixture was stirred for 5 hours under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (544 mg, 99%). 1 H-NMR (CDCl 3 ) δ: 8.12 (1H, s), 7.72 (1H, d, J = 8.3 Hz), 7.58-7.56 (3 H, m), 7.35 (1H, d, J = 8.3 Hz) , 7.08 (2H, d, J = 9.0 Hz), 6.82 (1H, dd, J = 17.4, 10.9 Hz), 5.83 (1H, d, J = 17.4 Hz), 5.32 (1H, d, J = 10.9 Hz) , 3.34 (4H, t, J = 4.9 Hz), 2.69 (4H, t, J = 4.9 Hz), 2.43 (3H, s).
ESI-MS (m / z): 319 [M + H] + .

工程４
1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-インダゾール-6-カルボアルデヒド Process 4
1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-indazole-6-carbaldehyde

1-(4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニル-1H-インダゾール (606 mg, 1.90 mmol) の1,4-ジオキサン (15 mL)、水 (3 mL) の混合溶液中に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (478 μL, 0.038 mmol)、2,6-ルチジン (443 μL, 3.81 mmol)、過ヨウ素酸ナトリウム (1.63 mg, 3.81 mmol) を添加した。アルゴン置換した後、室温で5時間撹拌した。セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (307 mg, 50%) を得た。 1H-NMR (CDCl3) δ: 10.11 (1H, s), 8.25 (1H, s), 8.15 (1H, s), 7.91 (1H, d, J = 8.3 Hz), 7.74 (1H, d, J = 8.3 Hz), 7.59 (2H, d, J = 7.0 Hz), 7.10 (2H, d, J = 7.0 Hz), 3.38 (4H, t, J = 5.0 Hz), 2.74-2.71 (4H, m), 2.46 (3H, s).
ESI-MS(m/z): 321[M+H]+. 1- (4- (4-Methylpiperazin-1-yl) phenyl) -6-vinyl-1H-indazole (606 mg, 1.90 mmol) in 1,4-dioxane (15 mL) and water (3 mL) To the solution, 2.5 wt% osmium tetroxide tert-butanol solution (478 μL, 0.038 mmol), 2,6-lutidine (443 μL, 3.81 mmol), and sodium periodate (1.63 mg, 3.81 mmol) were added. After purging with argon, the mixture was stirred at room temperature for 5 hours. After filtration through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (307 mg, 50%). 1 H-NMR (CDCl 3 ) δ: 10.11 (1H, s), 8.25 (1H, s), 8.15 (1H, s), 7.91 (1H, d, J = 8.3 Hz), 7.74 (1H, d, J = 8.3 Hz), 7.59 (2H, d, J = 7.0 Hz), 7.10 (2H, d, J = 7.0 Hz), 3.38 (4H, t, J = 5.0 Hz), 2.74-2.71 (4H, m), 2.46 (3H, s).
ESI-MS (m / z): 321 [M + H] + .

工程５
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-インダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１５８) Process 5
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 158)

Figure JPOXMLDOC01-appb-C000696
Figure JPOXMLDOC01-appb-C000696

1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-インダゾール-6-カルボアルデヒド (150 mg, 0.45 mmol) をアセトニトリル (15 mL) に溶かし、ロダニン (60 mg, 0.45 mmol)、ピペリジン (8.8 μL, 0.090 mmol)、および酢酸 (10.3 μL, 0.18 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (25 μL, 0.18 mmol) を添加した後、ろ過し、アセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (131 mg, 65%) を得た。黄褐色固体: 1H-NMR (DMSO-D6) δ: 8.34 (1H, s), 8.32 (1H, s), 7.93 (1H, d, J = 8.5 Hz), 7.84 (1H, s), 7.65 (2H, d, J = 9.0 Hz), 7.45 (1H, s), 7.41 (1H, d, J = 8.5 Hz), 7.23 (2H, d, J = 9.0 Hz), 3.49-3.42 (4H, m), 3.18-3.11 (4H, m), 2.72 (3H, s).
ESI-MS(m/z): 436[M+H]+. 1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-indazole-6-carbaldehyde (150 mg, 0.45 mmol) is dissolved in acetonitrile (15 mL) and rhodanine (60 mg, 0.45 mmol) , Piperidine (8.8 μL, 0.090 mmol), and acetic acid (10.3 μL, 0.18 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (25 μL, 0.18 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (131 mg, 65%). Tawny solid: 1 H-NMR (DMSO-D 6 ) δ: 8.34 (1H, s), 8.32 (1H, s), 7.93 (1H, d, J = 8.5 Hz), 7.84 (1H, s), 7.65 (2H, d, J = 9.0 Hz), 7.45 (1H, s), 7.41 (1H, d, J = 8.5 Hz), 7.23 (2H, d, J = 9.0 Hz), 3.49-3.42 (4H, m) , 3.18-3.11 (4H, m), 2.72 (3H, s).
ESI-MS (m / z): 436 [M + H] + .

実施例１５９
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-インダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１５９) Example 159
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) methylene) thiazolidine-2,4-dione (Compound 159)

Figure JPOXMLDOC01-appb-C000697
Figure JPOXMLDOC01-appb-C000697

工程１
1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-インダゾール-6-カルボアルデヒド (150 mg, 0.45 mmol) をアセトニトリル (15 mL) に溶かし、チアゾリジン-2,4-ジオン (53 mg, 0.45 mmol)、ピペリジン (8.8 μL, 0.090 mmol)、および酢酸 (10.3 μL, 0.18 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (25 μL, 0.18 mmol) を添加した後、ろ過し、アセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (35 mg, 18%) を得た。黄褐色固体: 1H-NMR (DMSO-D6) δ: 8.36 (1H, s), 8.32 (1H, s), 7.96 (1H, d, J = 8.8 Hz), 7.95 (1H, s), 7.80 (1H, s), 7.62 (2H, d, J = 9.0 Hz), 7.43 (1H, d, J = 8.8 Hz), 7.19 (2H, d, J = 9.0 Hz), 3.37-3.32 (4H, m), 2.85-2.80 (4H, m), 2.49 (3H, s).
ESI-MS(m/z): 420[M+H]+. Process 1
1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-indazole-6-carbaldehyde (150 mg, 0.45 mmol) is dissolved in acetonitrile (15 mL) and thiazolidine-2,4-dione ( 53 mg, 0.45 mmol), piperidine (8.8 μL, 0.090 mmol), and acetic acid (10.3 μL, 0.18 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (25 μL, 0.18 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (35 mg, 18%). Tawny solid: 1 H-NMR (DMSO-D 6 ) δ: 8.36 (1H, s), 8.32 (1H, s), 7.96 (1H, d, J = 8.8 Hz), 7.95 (1H, s), 7.80 (1H, s), 7.62 (2H, d, J = 9.0 Hz), 7.43 (1H, d, J = 8.8 Hz), 7.19 (2H, d, J = 9.0 Hz), 3.37-3.32 (4H, m) , 2.85-2.80 (4H, m), 2.49 (3H, s).
ESI-MS (m / z): 420 [M + H] + .

実施例１６０
5-((3-(4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１６０)  Example 160
5-((3- (4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 160 )

工程１
1-(4-ブロモフェニル)-4-プロピルピペラジン Process 1
1- (4-Bromophenyl) -4-propylpiperazine

Figure JPOXMLDOC01-appb-C000698
Figure JPOXMLDOC01-appb-C000698

1-(4-ブロモフェニル)ピペラジン (1 g, 4.15 mmol) のテトラヒドロフラン (10 mL) 溶液中に、プロピオンアルデヒド (357 μL, 4.98 mmol)、酢酸 (237 μL, 4.15 mmol) を室温下添加した。水素化トリアセトキシホウ素ナトリウム (1.32 g, 6.22 mmol) を添加した後、室温で2時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (740 mg, 63%) を得た。 1H-NMR (CDCl3) δ: 7.25 (2H, d, J = 9.0 Hz), 6.71 (2H, d, J = 9.0 Hz), 3.11 (4H, t, J = 4.9 Hz), 2.53 (4H, t, J = 4.9 Hz), 2.29 (2H, t, J = 7.8 Hz), 1.57-1.42 (2H, m), 0.85 (3H, t, J = 7.3 Hz).
ESI-MS(m/z): 283[M+H]+. Propionaldehyde (357 μL, 4.98 mmol) and acetic acid (237 μL, 4.15 mmol) were added at room temperature to a solution of 1- (4-bromophenyl) piperazine (1 g, 4.15 mmol) in tetrahydrofuran (10 mL). After adding sodium triacetoxyborohydride (1.32 g, 6.22 mmol), the mixture was stirred at room temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (740 mg, 63%). 1 H-NMR (CDCl 3 ) δ: 7.25 (2H, d, J = 9.0 Hz), 6.71 (2H, d, J = 9.0 Hz), 3.11 (4H, t, J = 4.9 Hz), 2.53 (4H, t, J = 4.9 Hz), 2.29 (2H, t, J = 7.8 Hz), 1.57-1.42 (2H, m), 0.85 (3H, t, J = 7.3 Hz).
ESI-MS (m / z): 283 [M + H] + .

工程２
1-プロピル-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン Process 2
1-propyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine

Figure JPOXMLDOC01-appb-C000699
Figure JPOXMLDOC01-appb-C000699

1-(4-ブロモフェニル)-4-プロピルピペラジン (898 mg, 3.17 mmol) のテトラヒドロフラン (45 mL) 溶液中に、n-ブチルリチウム ヘキサン溶液 (1.6 M, 2.97 mL, 4.76 mmol) をアルゴン雰囲気下、-78℃で滴下した。1時間撹拌した後、4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン (770 μL, 3.80 mmol) のテトラヒドロフラン (10 mL) 溶液をゆっくり滴下した。室温下一晩撹拌した後、塩化アンモニウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (867 mg, 83%) を得た。 1H-NMR (CDCl3) δ: 7.70 (2H, d, J = 8.5 Hz), 6.89 (2H, d, J = 8.5 Hz), 3.38-3.26 (4H, m), 2.69-2.55 (4H, m), 2.46-2.34 (2H, m), 1.64-1.52 (2H, m), 1.32 (12H, s), 0.99-0.90 (3H, m).
ESI-MS(m/z): 331[M+H]+. In a solution of 1- (4-bromophenyl) -4-propylpiperazine (898 mg, 3.17 mmol) in tetrahydrofuran (45 mL), add n-butyllithium hexane solution (1.6 M, 2.97 mL, 4.76 mmol) under an argon atmosphere. The solution was added dropwise at -78 ° C. After stirring for 1 hour, a solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (770 μL, 3.80 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise. After stirring overnight at room temperature, an aqueous ammonium chloride solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (867 mg, 83%). 1 H-NMR (CDCl 3 ) δ: 7.70 (2H, d, J = 8.5 Hz), 6.89 (2H, d, J = 8.5 Hz), 3.38-3.26 (4H, m), 2.69-2.55 (4H, m ), 2.46-2.34 (2H, m), 1.64-1.52 (2H, m), 1.32 (12H, s), 0.99-0.90 (3H, m).
ESI-MS (m / z): 331 [M + H] + .

工程３
6-クロロ-3-(4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Process 3
6-Chloro-3- (4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000700
Figure JPOXMLDOC01-appb-C000700

3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (609 mg, 2.63 mmol) の1,4-ジオキサン (20 mL)、水(3 mL) の混合溶液中に、1-プロピル-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン (867 mg, 2.63 mmol)、テトラキストリフェニルホスフィンパラジウム (101 mg, 0.088 mmol)、炭酸ナトリウム (812 mg, 7.66 mmol) を添加した。アルゴン置換した後、還流条件下一晩撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (677 mg, 87%) を得た。黄色固体: 1H-NMR (CDCl3) δ: 7.98 (1H, s), 7.94 (2H, d, J = 6.3 Hz), 7.92 (1H, d, J = 6.6 Hz), 7.04 (2H, d, J = 6.3 Hz), 7.02 (1H, d, J = 6.6 Hz), 3.33 (4H, t, J = 4.5 Hz), 2.66 (4H, t, J = 4.5 Hz), 2.41 (2H, t, J = 7.8 Hz), 1.61-1.57 (2H, m), 0.95 (3H, t, J = 7.4 Hz). In a mixed solution of 3-bromo-6-chloroimidazo [1,2-b] pyridazine (609 mg, 2.63 mmol) in 1,4-dioxane (20 mL) and water (3 mL), 1-propyl-4 -(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine (867 mg, 2.63 mmol), tetrakistriphenylphosphine palladium (101 mg, 0.088 mmol ), Sodium carbonate (812 mg, 7.66 mmol) was added. After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (677 mg, 87%). Yellow solid: 1 H-NMR (CDCl 3 ) δ: 7.98 (1H, s), 7.94 (2H, d, J = 6.3 Hz), 7.92 (1H, d, J = 6.6 Hz), 7.04 (2H, d, J = 6.3 Hz), 7.02 (1H, d, J = 6.6 Hz), 3.33 (4H, t, J = 4.5 Hz), 2.66 (4H, t, J = 4.5 Hz), 2.41 (2H, t, J = 7.8 Hz), 1.61-1.57 (2H, m), 0.95 (3H, t, J = 7.4 Hz).

工程４
3-(4-(4-プロピルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 4
3- (4- (4-propylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000701
Figure JPOXMLDOC01-appb-C000701

6-クロロ-3-(4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (568 mg, 1.59 mmol) の1,4-ジオキサン (24 mL)、水(4 mL) の混合溶液中に4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (328 μL, 1.92 mmol)、酢酸パラジウム (36 mg, 0.16 mmol)、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル (131 mg, 0.32 mmol)、リン酸三カリウム (2.541 g, 11.97 mmol) を添加した。アルゴン置換した後、還流条件下5時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (261 mg, 47%) を得た。 1H-NMR (CDCl3) δ: 8.00 (1H, d, J = 9.0 Hz), 7.94 (1H, s), 7.93 (1H, d, J = 9.0 Hz), 7.27 (2H, d, J = 9.0 Hz), 7.04 (2H, d, J = 9.0 Hz), 6.90 (1H, dd, J = 17.8, 11.0 Hz), 6.13 (1H, d, J = 17.8 Hz), 5.68 (1H, d, J = 11.0 Hz), 3.51-3.29 (4H, m), 2.93-2.64 (4H, m), 2.61-2.39 (2H, m), 1.77-1.53 (2H, m), 0.97 (3H, t, J = 7.3 Hz).
ESI-MS(m/z): 348[M+H]+. 6-chloro-3- (4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (568 mg, 1.59 mmol) of 1,4-dioxane (24 mL), water ( 4 mL) in a mixed solution of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (328 μL, 1.92 mmol), palladium acetate (36 mg, 0.16 mmol), 2- Dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (131 mg, 0.32 mmol) and tripotassium phosphate (2.541 g, 11.97 mmol) were added. After replacing with argon, the mixture was stirred for 5 hours under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (261 mg, 47%). 1 H-NMR (CDCl 3 ) δ: 8.00 (1H, d, J = 9.0 Hz), 7.94 (1H, s), 7.93 (1H, d, J = 9.0 Hz), 7.27 (2H, d, J = 9.0 Hz), 7.04 (2H, d, J = 9.0 Hz), 6.90 (1H, dd, J = 17.8, 11.0 Hz), 6.13 (1H, d, J = 17.8 Hz), 5.68 (1H, d, J = 11.0 Hz), 3.51-3.29 (4H, m), 2.93-2.64 (4H, m), 2.61-2.39 (2H, m), 1.77-1.53 (2H, m), 0.97 (3H, t, J = 7.3 Hz) .
ESI-MS (m / z): 348 [M + H] + .

工程５
3-(4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 5
3- (4- (4-Propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000702
Figure JPOXMLDOC01-appb-C000702

3-(4-(4-プロピルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (261 mg, 0.75 mmol) の1,4-ジオキサン (10 mL)、水 (2 mL) の混合溶液中に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (189 μL, 0.015 mmol)、2,6-ルチジン (175 μL, 1.50 mmol)、過ヨウ素酸ナトリウム (643 mg, 3.00 mmol) を添加した。アルゴン置換した後、室温で6時間撹拌した。セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (201 mg, 77%) を得た。 1H-NMR (CDCl3) δ: 10.11 (1H, s), 8.14 (1H, s), 8.11 (1H, d, J = 9.4 Hz), 8.01 (2H, d, J = 8.8 Hz), 7.64 (1H, d, J = 9.4 Hz), 7.08 (2H, d, J = 7.0 Hz), 3.65-3.39 (4H, m), 3.00-2.72 (4H, m), 2.72-2.49 (2H, m), 1.85-1.62 (2H, m), 0.99 (3H, t, J = 7.4 Hz).
ESI-MS(m/z): 350[M+H]+. 3- (4- (4-propylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (261 mg, 0.75 mmol) of 1,4-dioxane (10 mL), water ( 2 mL), 2.5 wt% osmium tetroxide tert-butanol solution (189 μL, 0.015 mmol), 2,6-lutidine (175 μL, 1.50 mmol), sodium periodate (643 mg, 3.00 mmol) ) Was added. After replacing with argon, the mixture was stirred at room temperature for 6 hours. After filtration through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (201 mg, 77%). 1 H-NMR (CDCl 3 ) δ: 10.11 (1H, s), 8.14 (1H, s), 8.11 (1H, d, J = 9.4 Hz), 8.01 (2H, d, J = 8.8 Hz), 7.64 ( 1H, d, J = 9.4 Hz), 7.08 (2H, d, J = 7.0 Hz), 3.65-3.39 (4H, m), 3.00-2.72 (4H, m), 2.72-2.49 (2H, m), 1.85 -1.62 (2H, m), 0.99 (3H, t, J = 7.4 Hz).
ESI-MS (m / z): 350 [M + H] + .

工程６
5-((3-(4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１６０) Step 6
5-((3- (4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 160 )

Figure JPOXMLDOC01-appb-C000703
Figure JPOXMLDOC01-appb-C000703

3-(4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (100 mg, 0.29 mmol) をアセトニトリル (10 mL) に溶かし、ロダニン (38 mg, 0.29 mmol)、ピペリジン (5.7 μL, 0.057 mmol)、および酢酸 (6.6 μL, 0.12 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (16 μL, 0.12 mmol) を添加した後、ろ過し、アセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (85 mg, 64%) を得た。 1H-NMR (DMSO-D6) δ: 8.19 (1H, d, J = 9.5 Hz), 8.15 (1H, s), 8.07 (2H, d, J = 8.8 Hz), 7.58 (1H, d, J = 9.5 Hz), 7.39 (1H, s), 7.14 (2H, d, J = 8.8 Hz), 3.52-3.39 (4H, m), 3.25-3.12 (4H, m), 2.94-2.85 (2H, m), 1.70-1.60 (2H, m), 0.93 (3H, t, J = 7.3 Hz).
ESI-MS(m/z): 465[M+H]+. 3- (4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (100 mg, 0.29 mmol) was dissolved in acetonitrile (10 mL) and rhodanine (38 mg, 0.29 mmol), piperidine (5.7 μL, 0.057 mmol), and acetic acid (6.6 μL, 0.12 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (16 μL, 0.12 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (85 mg, 64%). 1 H-NMR (DMSO-D 6 ) δ: 8.19 (1H, d, J = 9.5 Hz), 8.15 (1H, s), 8.07 (2H, d, J = 8.8 Hz), 7.58 (1H, d, J = 9.5 Hz), 7.39 (1H, s), 7.14 (2H, d, J = 8.8 Hz), 3.52-3.39 (4H, m), 3.25-3.12 (4H, m), 2.94-2.85 (2H, m) , 1.70-1.60 (2H, m), 0.93 (3H, t, J = 7.3 Hz).
ESI-MS (m / z): 465 [M + H] + .

実施例１６１
5-((3-(4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１６１)  Example 161
5-((3- (4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 161)

Figure JPOXMLDOC01-appb-C000704
Figure JPOXMLDOC01-appb-C000704

工程１
3-(4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (100 mg, 0.29 mmol) をアセトニトリル (10 mL) に溶かし、チアゾリジン-2,4-ジオン (34 mg, 0.29 mmol)、ピペリジン (5.7 μL, 0.057 mmol)、および酢酸 (6.6 μL, 0.12 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (16 μL, 0.12 mmol) を添加した後、ろ過し、アセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (65 mg, 51%) を得た。 1H-NMR (DMSO-D6) δ: 8.22 (1H, d, J = 9.3 Hz), 8.15 (1H, s), 8.01 (2H, d, J = 8.8 Hz), 7.73 (1H, s), 7.59 (1H, d, J = 9.3 Hz), 7.11 (2H, d, J = 8.8 Hz), 3.40-3.26 (4H, m), 2.89-2.77 (4H, m), 2.62-2.54 (2H, m), 1.62-1.49 (2H, m), 0.91 (3H, t, J = 7.2 Hz).
ESI-MS(m/z): 449[M+H]+. Process 1
3- (4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (100 mg, 0.29 mmol) was dissolved in acetonitrile (10 mL) and thiazolidine-2 , 4-dione (34 mg, 0.29 mmol), piperidine (5.7 μL, 0.057 mmol), and acetic acid (6.6 μL, 0.12 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (16 μL, 0.12 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (65 mg, 51%). 1 H-NMR (DMSO-D 6 ) δ: 8.22 (1H, d, J = 9.3 Hz), 8.15 (1H, s), 8.01 (2H, d, J = 8.8 Hz), 7.73 (1H, s), 7.59 (1H, d, J = 9.3 Hz), 7.11 (2H, d, J = 8.8 Hz), 3.40-3.26 (4H, m), 2.89-2.77 (4H, m), 2.62-2.54 (2H, m) , 1.62-1.49 (2H, m), 0.91 (3H, t, J = 7.2 Hz).
ESI-MS (m / z): 449 [M + H] + .

実施例１６２
5-((3-(4-(4-デシルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１６２)  Example 162
5-((3- (4- (4-decylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 162 )

工程１
1-(4-ブロモフェニル)-4-デシルピペラジン Process 1
1- (4-Bromophenyl) -4-decylpiperazine

Figure JPOXMLDOC01-appb-C000705
Figure JPOXMLDOC01-appb-C000705

1-(4-ブロモフェニル)ピペラジン (1 g, 4.15 mmol) のテトラヒドロフラン (10 mL) 溶液中に、デカナール (937 μL, 4.98 mmol)、酢酸 (237 μL, 4.15 mmol) を室温下添加した。水素化トリアセトキシホウ素ナトリウム (1.32 g, 6.22 mmol) を添加した後、室温で2時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.34 g, 85%) を得た。 1H-NMR (CDCl3) δ: 7.33 (2H, d, J = 9.0 Hz), 6.79 (2H, d, J = 9.0 Hz), 3.21-3.20 (4H, m), 2.66-2.63 (4H, m), 2.49-2.37 (2H, m), 1.63-1.51 (2H, m), 1.39-1.18 (14H, m), 0.88 (3H, t, J = 6.7 Hz).
ESI-MS(m/z): 381[M+H]+. Decanal (937 μL, 4.98 mmol) and acetic acid (237 μL, 4.15 mmol) were added to a solution of 1- (4-bromophenyl) piperazine (1 g, 4.15 mmol) in tetrahydrofuran (10 mL) at room temperature. After adding sodium triacetoxyborohydride (1.32 g, 6.22 mmol), the mixture was stirred at room temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.34 g, 85%). 1 H-NMR (CDCl 3 ) δ: 7.33 (2H, d, J = 9.0 Hz), 6.79 (2H, d, J = 9.0 Hz), 3.21-3.20 (4H, m), 2.66-2.63 (4H, m ), 2.49-2.37 (2H, m), 1.63-1.51 (2H, m), 1.39-1.18 (14H, m), 0.88 (3H, t, J = 6.7 Hz).
ESI-MS (m / z): 381 [M + H] + .

工程２
1-デシル-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン Process 2
1-decyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine

Figure JPOXMLDOC01-appb-C000706
Figure JPOXMLDOC01-appb-C000706

1-(4-ブロモフェニル)-4-デシルピペラジン(1.34 g, 3.52 mmol) のテトラヒドロフラン(80 mL) 溶液中に、n-ブチルリチウム ヘキサン溶液 (1.6 M, 3.3 mL, 5.28 mmol) をアルゴン雰囲気下、-78℃で滴下した。1時間撹拌した後、4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン (854 μL, 4.22 mmol) のテトラヒドロフラン (20 mL) 溶液をゆっくり滴下した。室温下一晩撹拌した後、塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (1.48 mg, 98%) を得た。 1H-NMR (CDCl3) δ: 7.68 (2H, d, J = 8.8 Hz), 6.87 (2H, d, J = 8.8 Hz), 3.27 (4H, t, J = 4.8 Hz), 2.58 (4H, t, J = 4.8 Hz), 2.40-2.34 (2H, m), 1.56-1.48 (2H, m), 1.37-1.17 (14H, m), 0.86 (3H, t, J = 6.8 Hz).
ESI-MS(m/z): 429[M+H]+. In a solution of 1- (4-bromophenyl) -4-decylpiperazine (1.34 g, 3.52 mmol) in tetrahydrofuran (80 mL), add n-butyllithium hexane solution (1.6 M, 3.3 mL, 5.28 mmol) under an argon atmosphere. The solution was added dropwise at -78 ° C. After stirring for 1 hour, a solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (854 μL, 4.22 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise. After stirring overnight at room temperature, an aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (1.48 mg, 98%). 1 H-NMR (CDCl 3 ) δ: 7.68 (2H, d, J = 8.8 Hz), 6.87 (2H, d, J = 8.8 Hz), 3.27 (4H, t, J = 4.8 Hz), 2.58 (4H, t, J = 4.8 Hz), 2.40-2.34 (2H, m), 1.56-1.48 (2H, m), 1.37-1.17 (14H, m), 0.86 (3H, t, J = 6.8 Hz).
ESI-MS (m / z): 429 [M + H] + .

工程３
6-クロロ-3-(4-(4-デシルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン Process 3
6-Chloro-3- (4- (4-decylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000707
Figure JPOXMLDOC01-appb-C000707

3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (805 mg, 3.46 mmol) の1,4-ジオキサン(30 mL)、水(5 mL) の混合溶液中に、1-デシル-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン (1.48 g, 3.46 mmol)、テトラキストリフェニルホスフィンパラジウム (160 mg, 0.14 mmol)、炭酸ナトリウム (1.29 g, 12.12 mmol) を添加した。アルゴン置換した後、還流条件下一晩撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (1.30 g, 83%) を得た。1H-NMR (CDCl3) δ: 8.04-7.88 (4H, m), 7.10-6.99 (3H, m), 3.43-3.30 (4H, m), 2.75-2.62 (4H, m), 2.50-2.38 (2H, m), 1.65-1.52 (2H, m), 1.42-1.18 (14H, m), 0.89 (3H, t, J = 6.7 Hz).
ESI-MS(m/z): 454[M+H]+. In a mixed solution of 3-bromo-6-chloroimidazo [1,2-b] pyridazine (805 mg, 3.46 mmol) in 1,4-dioxane (30 mL) and water (5 mL), 1-decyl-4 -(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine (1.48 g, 3.46 mmol), tetrakistriphenylphosphine palladium (160 mg, 0.14 mmol ), Sodium carbonate (1.29 g, 12.12 mmol) was added. After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (1.30 g, 83%). 1 H-NMR (CDCl 3 ) δ: 8.04-7.88 (4H, m), 7.10-6.99 (3H, m), 3.43-3.30 (4H, m), 2.75-2.62 (4H, m), 2.50-2.38 ( 2H, m), 1.65-1.52 (2H, m), 1.42-1.18 (14H, m), 0.89 (3H, t, J = 6.7 Hz).
ESI-MS (m / z): 454 [M + H] + .

工程４
3-(4-(4-デシルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 4
3- (4- (4-decylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000708
Figure JPOXMLDOC01-appb-C000708

6-クロロ-3-(4-(4-デシルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (1.30 g, 2.86 mmol) の 1,4-ジオキサン (30 mL)、水(5 mL) の混合溶液中に 4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (588 μL, 3.44 mmol)、酢酸パラジウム (64 mg, 0.28 mmol)、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル (235 mg, 0.57 mmol)、リン酸三カリウム (4.56 g, 21.5 mmol) を添加した。アルゴン置換した後、還流条件下6時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (869 mg, 68%) を得た。1H-NMR (CDCl3) δ: 7.99 (2H, d, J = 9.0 Hz), 7.93-7.91 (2H, m), 7.27 (1H, s), 7.04 (2H, d, J = 9.0 Hz), 6.89 (1H, dd, J = 17.8, 11.2 Hz), 6.13 (1H, d, J = 17.8 Hz), 5.67 (1H, d, J = 11.2 Hz), 3.33 (4H, t, J = 4.9 Hz), 2.67 (4H, t, J = 4.9 Hz), 2.47-2.40 (2H, m), 1.62-1.52 (2H, m), 1.37-1.25 (14H, m), 0.88 (3H, t, J = 7.1 Hz).
ESI-MS(m/z): 446[M+H]+. 6-chloro-3- (4- (4-decylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (1.30 g, 2.86 mmol) of 1,4-dioxane (30 mL), water ( 5 mL) in a mixed solution of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (588 μL, 3.44 mmol), palladium acetate (64 mg, 0.28 mmol), 2- Dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (235 mg, 0.57 mmol) and tripotassium phosphate (4.56 g, 21.5 mmol) were added. After replacing with argon, the mixture was stirred for 6 hours under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (869 mg, 68%). 1 H-NMR (CDCl 3 ) δ: 7.99 (2H, d, J = 9.0 Hz), 7.93-7.91 (2H, m), 7.27 (1H, s), 7.04 (2H, d, J = 9.0 Hz), 6.89 (1H, dd, J = 17.8, 11.2 Hz), 6.13 (1H, d, J = 17.8 Hz), 5.67 (1H, d, J = 11.2 Hz), 3.33 (4H, t, J = 4.9 Hz), 2.67 (4H, t, J = 4.9 Hz), 2.47-2.40 (2H, m), 1.62-1.52 (2H, m), 1.37-1.25 (14H, m), 0.88 (3H, t, J = 7.1 Hz) .
ESI-MS (m / z): 446 [M + H] + .

工程５
3-(4-(4-デシルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 5
3- (4- (4-decylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000709
Figure JPOXMLDOC01-appb-C000709

3-(4-(4-デシルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (869 mg, 1.95 mmol) の1,4-ジオキサン (30 mL)、水 (9 mL) の混合溶液中に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (490 μL, 0.039 mmol)、2,6-ルチジン (454 μL, 3.9 mmol)、過ヨウ素酸ナトリウム (1.67 mg, 7.8 mmol) を添加した。アルゴン置換した後、室温で4時間撹拌した。セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (480 mg, 55%) を得た。 1H-NMR (CDCl3) δ: 10.10 (1H, s), 8.13 (1H, s), 8.09 (1H, d, J = 9.5 Hz), 7.99 (2H, d, J = 9.0 Hz), 7.62 (1H, d, J = 9.5 Hz), 7.07 (2H, d, J = 9.0 Hz), 3.44-3.30 (4H, m), 2.77-2.63 (4H, m), 2.45 (2H, t, J = 7.6 Hz), 1.63-1.53 (2H, m), 1.43-1.17 (14H, m), 0.89 (3H, t, J = 6.8 Hz).
ESI-MS(m/z): 448[M+H]+. 3- (4- (4-decylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (869 mg, 1.95 mmol) of 1,4-dioxane (30 mL), water ( 9 mL), 2.5 wt% osmium tetroxide tert-butanol solution (490 μL, 0.039 mmol), 2,6-lutidine (454 μL, 3.9 mmol), sodium periodate (1.67 mg, 7.8 mmol) ) Was added. After purging with argon, the mixture was stirred at room temperature for 4 hours. After filtration through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (480 mg, 55%). 1 H-NMR (CDCl 3 ) δ: 10.10 (1H, s), 8.13 (1H, s), 8.09 (1H, d, J = 9.5 Hz), 7.99 (2H, d, J = 9.0 Hz), 7.62 ( 1H, d, J = 9.5 Hz), 7.07 (2H, d, J = 9.0 Hz), 3.44-3.30 (4H, m), 2.77-2.63 (4H, m), 2.45 (2H, t, J = 7.6 Hz ), 1.63-1.53 (2H, m), 1.43-1.17 (14H, m), 0.89 (3H, t, J = 6.8 Hz).
ESI-MS (m / z): 448 [M + H] + .

工程６
5-((3-(4-(4-デシルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１６２) Step 6
5-((3- (4- (4-decylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 162 )

Figure JPOXMLDOC01-appb-C000710
Figure JPOXMLDOC01-appb-C000710

3-(4-(4-デシルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (240 mg, 0.54 mmol) をアセトニトリル (15 mL) に溶かし、ロダニン (71 mg, 0.54 mmol)、ピペリジン (10.6 μL, 0.11 mmol)、および酢酸 (12 μL, 0.21 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (30 μL, 0.21 mmol) を添加した後、ろ過し、アセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (176 mg, 5%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.18 (1H, d, J = 9.5 Hz), 8.15 (1H, s), 8.08 (2H, d, J = 8.5 Hz), 7.57 (1H, d, J = 9.5 Hz), 7.33 (1H, s), 7.14 (2H, d, J = 8.5 Hz), 3.44-3.24 (4H, m), 3.19-3.03 (4H, m), 2.95-2.80 (2H, m), 1.67-1.54 (2H, m), 1.36-1.18 (14H, m), 0.86 (3H, t, J = 6.3 Hz).
ESI-MS(m/z): 563[M+H]+. 3- (4- (4-decylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (240 mg, 0.54 mmol) was dissolved in acetonitrile (15 mL) and rhodanine (71 mg, 0.54 mmol), piperidine (10.6 μL, 0.11 mmol), and acetic acid (12 μL, 0.21 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (30 μL, 0.21 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (176 mg, 5%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.18 (1H, d, J = 9.5 Hz), 8.15 (1H, s), 8.08 (2H, d, J = 8.5 Hz), 7.57 (1H, d, J = 9.5 Hz), 7.33 (1H, s), 7.14 (2H, d, J = 8.5 Hz), 3.44-3.24 (4H, m), 3.19-3.03 (4H, m), 2.95-2.80 (2H , m), 1.67-1.54 (2H, m), 1.36-1.18 (14H, m), 0.86 (3H, t, J = 6.3 Hz).
ESI-MS (m / z): 563 [M + H] + .

実施例１６３
5-((3-(4-(4-デシルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１６３)  Example 163
5-((3- (4- (4-decylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 163)

Figure JPOXMLDOC01-appb-C000711
Figure JPOXMLDOC01-appb-C000711

工程１
3-(4-(4-デシルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (240 mg, 0.54 mmol) をアセトニトリル (15 mL) に溶かし、チアゾリジン-2,4-ジオン (63 mg, 0.54 mmol)、ピペリジン (10.6 μL, 0.11 mmol)、および酢酸 (12 μL, 0.21 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (30 μL, 0.21 mmol) を添加した後、ろ過し、アセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (179 mg, 61%) を得た。赤褐色固体: 1H-NMR (DMSO-D6) δ: 8.22 (1H, d, J = 9.3 Hz), 8.15 (1H, s), 8.02 (2H, d, J = 8.5 Hz), 7.71 (1H, s), 7.59 (1H, d, J = 9.3 Hz), 7.11 (2H, d, J = 8.5 Hz), 3.45-3.22 (4H, m), 2.88-2.77 (4H, m), 2.65-2.56 (2H, m), 1.61-1.49 (2H, m), 1.34-1.18 (14H, m), 0.86 (3H, t, J = 6.1 Hz).
ESI-MS(m/z): 547[M+H]+. Process 1
3- (4- (4-decylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (240 mg, 0.54 mmol) was dissolved in acetonitrile (15 mL) and thiazolidine-2 , 4-dione (63 mg, 0.54 mmol), piperidine (10.6 μL, 0.11 mmol), and acetic acid (12 μL, 0.21 mmol) were added and stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (30 μL, 0.21 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (179 mg, 61%). Reddish brown solid: 1 H-NMR (DMSO-D 6 ) δ: 8.22 (1H, d, J = 9.3 Hz), 8.15 (1H, s), 8.02 (2H, d, J = 8.5 Hz), 7.71 (1H, s), 7.59 (1H, d, J = 9.3 Hz), 7.11 (2H, d, J = 8.5 Hz), 3.45-3.22 (4H, m), 2.88-2.77 (4H, m), 2.65-2.56 (2H , m), 1.61-1.49 (2H, m), 1.34-1.18 (14H, m), 0.86 (3H, t, J = 6.1 Hz).
ESI-MS (m / z): 547 [M + H] + .

実施例１６４
5-((3-(4-(4-(tert-ブチル)ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物１６４)  Example 164
5-((3- (4- (4- (tert-butyl) piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidine-4- ON (compound 164)

工程１
1-(4-ブロモフェニル)-4-(tert-ブチル)ピペラジン Process 1
1- (4-Bromophenyl) -4- (tert-butyl) piperazine

Figure JPOXMLDOC01-appb-C000712
Figure JPOXMLDOC01-appb-C000712

ブロモ-4-ヨードベンゼン (2.00 g, 7.07 mmol)、1-tert-ブチルピペラジン (1.11 g, 7.77 mmol)、リン酸三カリウム (5.55 g, 26.1 mmol)、ヨウ化銅 (269 mg, 1.41 mmol) の2-プロパノール (20 mL) 溶液中に、エチレングリコール (1.32 mL, 21.2 mmol) を室温下添加した。アルゴン置換した後、還流条件下一晩撹拌した。セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.19 g, 57%) を得た。 1H-NMR (CDCl3) δ: 7.70 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz), 3.38-3.25 (4H, m), 2.85-2.70 (4H, m), 1.14 (9H, s).
ESI-MS(m/z): 297[M+H]+. Bromo-4-iodobenzene (2.00 g, 7.07 mmol), 1-tert-butylpiperazine (1.11 g, 7.77 mmol), tripotassium phosphate (5.55 g, 26.1 mmol), copper iodide (269 mg, 1.41 mmol) Ethylene glycol (1.32 mL, 21.2 mmol) was added to a solution of 2-propanol (20 mL) at room temperature. After purging with argon, the mixture was stirred overnight under reflux conditions. After filtration through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.19 g, 57%). 1 H-NMR (CDCl 3 ) δ: 7.70 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz), 3.38-3.25 (4H, m), 2.85-2.70 (4H, m ), 1.14 (9H, s).
ESI-MS (m / z): 297 [M + H] + .

工程２
1-(tert-ブチル)-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン Process 2
1- (tert-butyl) -4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine

Figure JPOXMLDOC01-appb-C000713
Figure JPOXMLDOC01-appb-C000713

1-(4-ブロモフェニル)-4-tert-ブチルピペラジン (1.19 g, 4.00 mmol) のテトラヒドロフラン (60 mL) 溶液中に、n-ブチルリチウム ヘキサン溶液(1.6 M, 3.8 mL, 6.00 mmol)をアルゴン雰囲気下、-78℃で滴下した。1時間撹拌した後、4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン (975 μL, 4.82 mmol) のテトラヒドロフラン (20 mL) 溶液をゆっくり滴下した。室温下4時間撹拌した後、塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (500 mg, 36%) を得た。1H-NMR (CDCl3) δ: 7.70 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz), 3.32-3.25 (4H, m), 2.77-2.69 (4H, m), 1.32 (12H, s), 1.24 (9H, s).
ESI-MS(m/z): 345[M+H]+. In a solution of 1- (4-bromophenyl) -4-tert-butylpiperazine (1.19 g, 4.00 mmol) in tetrahydrofuran (60 mL), add n-butyllithium hexane solution (1.6 M, 3.8 mL, 6.00 mmol) to argon. It was added dropwise at −78 ° C. in an atmosphere. After stirring for 1 hour, a solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (975 μL, 4.82 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise. After stirring at room temperature for 4 hours, an aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (500 mg, 36%). 1 H-NMR (CDCl 3 ) δ: 7.70 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz), 3.32-3.25 (4H, m), 2.77-2.69 (4H, m ), 1.32 (12H, s), 1.24 (9H, s).
ESI-MS (m / z): 345 [M + H] + .

工程３
3-(4-(4-(tert-ブチル)ピペラジン-1-イル)フェニル)-6-クロロイミダゾ[1,2-b]ピリダジン Process 3
3- (4- (4- (tert-butyl) piperazin-1-yl) phenyl) -6-chloroimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000714
Figure JPOXMLDOC01-appb-C000714

3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (337 mg, 1.45 mmol) の 1,4-ジオキサン(20 mL)、水(3 mL) の混合溶液中に、1-tert-ブチル-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン (500 mg, 1.45 mmol)、テトラキストリフェニルホスフィンパラジウム (67 mg, 0.058 mmol)、炭酸ナトリウム (538 mg, 5.08 mmol) を添加した。アルゴン置換した後、還流条件下一晩撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (389 mg, 73%) を得た。 1H-NMR (DMSO-D6) δ: 8.25 (1H, d, J = 9.5 Hz), 8.19 (1H, s), 7.93 (2H, d, J = 8.5 Hz), 7.35 (1H, d, J = 9.5 Hz), 7.08 (2H, d, J = 8.5 Hz), 3.24-3.19 (4H, m), 2.69-2.61 (4H, m), 1.06 (9H, s).
ESI-MS(m/z): 370[M+H]+. 3-Bromo-6-chloroimidazo [1,2-b] pyridazine (337 mg, 1.45 mmol) in 1,4-dioxane (20 mL) and water (3 mL) in a mixed solution of 1-tert-butyl -4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine (500 mg, 1.45 mmol), tetrakistriphenylphosphine palladium (67 mg, 0.058 mmol) and sodium carbonate (538 mg, 5.08 mmol) were added. After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (389 mg, 73%). 1 H-NMR (DMSO-D 6 ) δ: 8.25 (1H, d, J = 9.5 Hz), 8.19 (1H, s), 7.93 (2H, d, J = 8.5 Hz), 7.35 (1H, d, J = 9.5 Hz), 7.08 (2H, d, J = 8.5 Hz), 3.24-3.19 (4H, m), 2.69-2.61 (4H, m), 1.06 (9H, s).
ESI-MS (m / z): 370 [M + H] + .

工程４
3-(4-(4-(tert-ブチル)ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 4
3- (4- (4- (tert-butyl) piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000715
Figure JPOXMLDOC01-appb-C000715

3-(4-(4-(tert-ブチル)ピペラジン-1-イル)フェニル)-6-クロロイミダゾ[1,2-b]ピリダジン (389 mg, 1.05 mmol) の1,4-ジオキサン (12 mL)、水(2 mL) の混合溶液中に 4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (216 μL, 1.26 mmol)、酢酸パラジウム (24 mg, 0.11 mmol)、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル (86 mg, 0.21 mmol)、リン酸三カリウム (1.67 g, 7.89 mmol) を添加した。アルゴン置換した後、還流条件下4時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (336 mg, 88%) を得た。1H-NMR (DMSO-D6) δ:8.14 (1H, d, J = 9.5 Hz), 8.09 (1H, s), 8.01 (2H, d, J = 8.8 Hz), 7.59 (1H, d, J = 9.5 Hz), 7.05 (2H, d, J = 8.8 Hz), 6.94-6.85 (1H, m), 6.35 (1H, d, J = 17.8 Hz), 5.76 (1H, d, J = 11.2 Hz), 3.21-3.19 (4H, br m), 2.66-2.63 (4H, br m), 1.07 (9H, s).
ESI-MS(m/z): 362[M+H]+. 3- (4- (4- (tert-butyl) piperazin-1-yl) phenyl) -6-chloroimidazo [1,2-b] pyridazine (389 mg, 1.05 mmol) of 1,4-dioxane (12 mL ) And water (2 mL) in a mixed solution of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (216 μL, 1.26 mmol), palladium acetate (24 mg, 0.11 mmol ), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (86 mg, 0.21 mmol), and tripotassium phosphate (1.67 g, 7.89 mmol) were added. After replacing with argon, the mixture was stirred under reflux conditions for 4 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (336 mg, 88%). 1 H-NMR (DMSO-D 6 ) δ: 8.14 (1H, d, J = 9.5 Hz), 8.09 (1H, s), 8.01 (2H, d, J = 8.8 Hz), 7.59 (1H, d, J = 9.5 Hz), 7.05 (2H, d, J = 8.8 Hz), 6.94-6.85 (1H, m), 6.35 (1H, d, J = 17.8 Hz), 5.76 (1H, d, J = 11.2 Hz), 3.21-3.19 (4H, br m), 2.66-2.63 (4H, br m), 1.07 (9H, s).
ESI-MS (m / z): 362 [M + H] + .

工程５
3-(4-(4-(tert-ブチル)ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 5
3- (4- (4- (tert-Butyl) piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000716
Figure JPOXMLDOC01-appb-C000716

3-(4-(4-tert-ブチル)ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン(336 mg, 0.93 mmol) の1,4-ジオキサン (16 mL)、水(6 mL) の混合溶液中に、2.5 wt% 四酸化オスミウムtert-ブタノール溶液 (233 μL, 0.019 mmol)、2,6-ルチジン (217 μL, 1.86 mmol)、過ヨウ素酸ナトリウム (795 mg, 3.72 mmol) を添加した。アルゴン置換した後、室温で3時間撹拌した。セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (142 mg, 42%) を得た。 1H-NMR (DMSO-D6) δ: 10.02 (1H, s), 8.36-8.30 (2H, m), 8.07 (2H, d, J = 6.1 Hz), 7.61-7.59 (1 H, m), 7.09 (2H, d, J = 6.1 Hz), 3.24-3.19 (4H, m), 2.69-2.62 (4H, m), 1.06 (9H, s).
ESI-MS(m/z): 364[M+H]+. 3- (4- (4-tert-Butyl) piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (336 mg, 0.93 mmol) of 1,4-dioxane (16 mL) , Water (6 mL) in a mixed solution of 2.5 wt% osmium tetroxide tert-butanol (233 μL, 0.019 mmol), 2,6-lutidine (217 μL, 1.86 mmol), sodium periodate (795 mg , 3.72 mmol) was added. After replacing with argon, the mixture was stirred at room temperature for 3 hours. After filtration through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (142 mg, 42%). 1 H-NMR (DMSO-D 6 ) δ: 10.02 (1H, s), 8.36-8.30 (2H, m), 8.07 (2H, d, J = 6.1 Hz), 7.61-7.59 (1 H, m), 7.09 (2H, d, J = 6.1 Hz), 3.24-3.19 (4H, m), 2.69-2.62 (4H, m), 1.06 (9H, s).
ESI-MS (m / z): 364 [M + H] + .

工程６
5-((3-(4-(4-(tert-ブチル)ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン(化合物１６４) Step 6
5-((3- (4- (4- (tert-butyl) piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidine-4- ON (compound 164)

Figure JPOXMLDOC01-appb-C000717
Figure JPOXMLDOC01-appb-C000717

3-(4-(4-tert-ブチル)ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (71 mg, 0.20 mmol) をアセトニトリル (7 mL) に溶かし、ロダニン (26 mg, 0.20 mmol)、ピペリジン (3.9 μL, 0.04 mmol)、および酢酸 (4.5 μL, 0.08 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (10.9 μL, 0.08 mmol) を添加した後、ろ過し、アセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (62 mg, 66%) を得た。1H-NMR (DMSO-D6) δ: 8.18 (1H, d, J = 9.5 Hz), 8.15 (1H, br s), 8.11 (2H, d, J = 7.1 Hz), 7.56 (1H, d, J = 9.5 Hz), 7.32 (1H, s), 7.16 (2H, d, J = 7.1 Hz), 3.39-3.27 (4H, m), 2.53-2.45 (4H, m), 1.33 (9H, s).
ESI-MS(m/z): 479[M+H]+. 3- (4- (4-tert-butyl) piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (71 mg, 0.20 mmol) was dissolved in acetonitrile (7 mL). Rhodanine (26 mg, 0.20 mmol), piperidine (3.9 μL, 0.04 mmol), and acetic acid (4.5 μL, 0.08 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (10.9 μL, 0.08 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (62 mg, 66%). 1 H-NMR (DMSO-D 6 ) δ: 8.18 (1H, d, J = 9.5 Hz), 8.15 (1H, br s), 8.11 (2H, d, J = 7.1 Hz), 7.56 (1H, d, J = 9.5 Hz), 7.32 (1H, s), 7.16 (2H, d, J = 7.1 Hz), 3.39-3.27 (4H, m), 2.53-2.45 (4H, m), 1.33 (9H, s).
ESI-MS (m / z): 479 [M + H] + .

実施例１６５
5-((3-(4-(4-(tert-ブチル)ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン(化合物１６５)  Example 165
5-((3- (4- (4- (tert-butyl) piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 165)

Figure JPOXMLDOC01-appb-C000718
Figure JPOXMLDOC01-appb-C000718

工程１
3-(4-(4-tert-ブチル)ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (71 mg, 0.20 mmol) をアセトニトリル (7 mL) に溶かし、チアゾリジン-2,4-ジオン (23 mg, 0.20 mmol)、ピペリジン (3.9 μL, 0.04 mmol)、および酢酸 (4.5 μL, 0.08 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (10.9 μL, 0.08 mmol) を添加した後、ろ過し、アセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (39 mg, 43%) を得た。1H-NMR (DMSO-D6) δ: 8.21 (1H, d, J = 9.5 Hz), 8.15 (1H, s), 8.04 (2H, d, J = 8.8 Hz), 7.67 (1H, s), 7.58 (1H, d, J = 9.5 Hz), 7.13 (2H, d, J = 8.8 Hz), 3.46-3.36 (4H, m), 3.13-3.02 (4H, m), 1.24 (9H, s).
ESI-MS(m/z): 463[M+H]+. Process 1
3- (4- (4-tert-butyl) piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (71 mg, 0.20 mmol) was dissolved in acetonitrile (7 mL). Thiazolidine-2,4-dione (23 mg, 0.20 mmol), piperidine (3.9 μL, 0.04 mmol), and acetic acid (4.5 μL, 0.08 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (10.9 μL, 0.08 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (39 mg, 43%). 1 H-NMR (DMSO-D 6 ) δ: 8.21 (1H, d, J = 9.5 Hz), 8.15 (1H, s), 8.04 (2H, d, J = 8.8 Hz), 7.67 (1H, s), 7.58 (1H, d, J = 9.5 Hz), 7.13 (2H, d, J = 8.8 Hz), 3.46-3.36 (4H, m), 3.13-3.02 (4H, m), 1.24 (9H, s).
ESI-MS (m / z): 463 [M + H] + .

実施例１６６
5-((3-(4-(4-ブチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１６６)  Example 166
5-((3- (4- (4-Butylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 166 )

工程１
tert-ブチル 4-(4-ブロモフェニル)ピペラジン-1-カルボキシレート Process 1
tert-butyl 4- (4-bromophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000719
Figure JPOXMLDOC01-appb-C000719

1-(4-ブロモフェニル)ピペラジン (3.0 g, 12.8 mmol) のジクロロメタン (83 mL) 溶液中に、二炭酸ジ-tert-ブチル (2.97 mL, 12.8 mmol)、トリエチルアミン (3.0 mL, 21.5 mmol) を室温下滴下した。2時間撹拌した後、さらに二炭酸ジ-tert-ブチル (0.30 mL, 1.28 mmol) を添加した。室温で2時間撹拌し、反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮し、標記化合物 (4.59 g, 99%) を得た。 1H-NMR (CDCl3) δ: 7.36 (2H, d, J = 8.8 Hz), 6.80 (2H, d, J = 8.8 Hz), 3.58 (4H, t, J = 5.0 Hz), 3.10 (4H, t, J = 5.0 Hz), 1.48 (9H, s).
ESI-MS(m/z): 341[M+H]+. Di-tert-butyl dicarbonate (2.97 mL, 12.8 mmol) and triethylamine (3.0 mL, 21.5 mmol) were added to a solution of 1- (4-bromophenyl) piperazine (3.0 g, 12.8 mmol) in dichloromethane (83 mL). The solution was added dropwise at room temperature. After stirring for 2 hours, more di-tert-butyl dicarbonate (0.30 mL, 1.28 mmol) was added. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (4.59 g, 99%). 1 H-NMR (CDCl 3 ) δ: 7.36 (2H, d, J = 8.8 Hz), 6.80 (2H, d, J = 8.8 Hz), 3.58 (4H, t, J = 5.0 Hz), 3.10 (4H, t, J = 5.0 Hz), 1.48 (9H, s).
ESI-MS (m / z): 341 [M + H] + .

工程２
tert-ブチル 4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレート Process 2
tert-butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000720
Figure JPOXMLDOC01-appb-C000720

tert-ブチル 4-(4-ブロモフェニル)ピペラジン-1-カルボキシレート(4.59 g, 13.4 mmol)、酢酸カリウム (3.96 g, 40.4 mmol) の 1,4-ジオキサン (100 mL) 溶液に ビス(ピナコラート)ジボロン (3.86 g, 15.2 mmol)、1,1′-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド-ジクロロメタン錯体 (1.098 g, 1.35 mmol) を添加した。アルゴン置換した後、90℃で一晩撹拌した。反応終了後、セライトろ過し、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (3.98 g, 76%) を得た。 1H-NMR (CDCl3) δ: 7.72 (2H, d, J = 8.8 Hz), 6.90 (2H, d, J = 8.8 Hz), 3.58 (4H, t, J = 4.8 Hz), 3.22 (4H, t, J = 4.8 Hz), 1.48 (9H, s), 1.33 (12H, s).
ESI-MS(m/z): 389[M+H]+. tert-Butyl 4- (4-bromophenyl) piperazine-1-carboxylate (4.59 g, 13.4 mmol), potassium acetate (3.96 g, 40.4 mmol) in 1,4-dioxane (100 mL) solution in bis (pinacolato) Diboron (3.86 g, 15.2 mmol), 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (1.098 g, 1.35 mmol) were added. After purging with argon, the mixture was stirred at 90 ° C. overnight. After completion of the reaction, the mixture was filtered through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (3.98 g, 76%). 1 H-NMR (CDCl 3 ) δ: 7.72 (2H, d, J = 8.8 Hz), 6.90 (2H, d, J = 8.8 Hz), 3.58 (4H, t, J = 4.8 Hz), 3.22 (4H, t, J = 4.8 Hz), 1.48 (9H, s), 1.33 (12H, s).
ESI-MS (m / z): 389 [M + H] + .

工程３
tert-ブチル 4-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-カルボキシレート Process 3
tert-butyl 4- (4- (6-chloroimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000721
Figure JPOXMLDOC01-appb-C000721

3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (2.38 g, 10.2 mmol) の 1,4-ジオキサン(100 mL)、水(16 mL) の混合溶液中に、tert-ブチル 4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレート(3.976 g, 10.2 mmol)、テトラキストリフェニルホスフィンパラジウム (473 mg, 0.41 mmol)、炭酸ナトリウム(3.80 g, 35.8 mmol) を添加した。アルゴン置換した後、還流条件下一晩撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (3.998 g, 94%) を得た。 1H-NMR (DMSO-D6) δ: 8.25 (1H, d, J = 9.5 Hz), 8.21 (1H, s), 7.96 (2H, d, J = 9.0 Hz), 7.35 (1H, d, J = 9.5 Hz), 7.11 (2H, d, J = 9.0 Hz), 3.49 (4H, t, J = 5.0 Hz), 3.22 (4H, t, J = 5.0 Hz), 1.43 (9H, s).
ESI-MS(m/z): 414[M+H]+. In a mixed solution of 3-bromo-6-chloroimidazo [1,2-b] pyridazine (2.38 g, 10.2 mmol) in 1,4-dioxane (100 mL) and water (16 mL), tert-butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (3.976 g, 10.2 mmol), tetrakistriphenylphosphine palladium (473 mg, 0.41 mmol) and sodium carbonate (3.80 g, 35.8 mmol) were added. After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (3.998 g, 94%). 1 H-NMR (DMSO-D 6 ) δ: 8.25 (1H, d, J = 9.5 Hz), 8.21 (1H, s), 7.96 (2H, d, J = 9.0 Hz), 7.35 (1H, d, J = 9.5 Hz), 7.11 (2H, d, J = 9.0 Hz), 3.49 (4H, t, J = 5.0 Hz), 3.22 (4H, t, J = 5.0 Hz), 1.43 (9H, s).
ESI-MS (m / z): 414 [M + H] + .

工程４
tert-ブチル 4-(4-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-カルボキシレート Process 4
tert-butyl 4- (4- (6-vinylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000722
Figure JPOXMLDOC01-appb-C000722

tert-ブチル 4-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-カルボキシレート ( 3.998 g, 9.66 mmol) の 1,4-ジオキサン(100 mL)、水 (16 mL) の混合溶液中に4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (1.98 mL, 11.59 mmol)、酢酸パラジウム (217 mg, 0.96 mmol)、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル (793 mg, 1.93 mmol)、リン酸三カリウム (15.4 g, 72.4 mmol) を添加した。アルゴン置換した後、還流条件下4時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.98 g, 51%) を得た。 1H-NMR (DMSO-D6) δ: 8.15 (1H, d, J = 9.5 Hz), 8.12 (1H, s), 8.04 (2H, d, J = 9.0 Hz), 7.60 (1H, d, J = 9.5 Hz), 7.10 (2H, d, J = 9.0 Hz), 6.89 (1H, dd, J = 17.7, 11.2 Hz), 6.35 (1H, d, J = 17.7 Hz), 5.76 (1H, d, J = 11.2 Hz), 3.49 (4H, t, J = 5.1 Hz), 3.21 (4H, t, J = 5.1 Hz), 1.43 (9H, s).
ESI-MS(m/z): 406[M+H]+. tert-Butyl 4- (4- (6-chloroimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazine-1-carboxylate (3.998 g, 9.66 mmol) of 1,4-dioxane (100 mL ), Water (16 mL) in a mixed solution of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.98 mL, 11.59 mmol), palladium acetate (217 mg, 0.96 mmol) ), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (793 mg, 1.93 mmol), and tripotassium phosphate (15.4 g, 72.4 mmol) were added. After replacing with argon, the mixture was stirred under reflux conditions for 4 hours. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.98 g, 51%). 1 H-NMR (DMSO-D 6 ) δ: 8.15 (1H, d, J = 9.5 Hz), 8.12 (1H, s), 8.04 (2H, d, J = 9.0 Hz), 7.60 (1H, d, J = 9.5 Hz), 7.10 (2H, d, J = 9.0 Hz), 6.89 (1H, dd, J = 17.7, 11.2 Hz), 6.35 (1H, d, J = 17.7 Hz), 5.76 (1H, d, J = 11.2 Hz), 3.49 (4H, t, J = 5.1 Hz), 3.21 (4H, t, J = 5.1 Hz), 1.43 (9H, s).
ESI-MS (m / z): 406 [M + H] + .

工程５
3-(4-(ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 5
3- (4- (Piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000723
Figure JPOXMLDOC01-appb-C000723

tert-ブチル 4-(4-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-カルボキシレート(1.3 g, 3.2 mmol) のジクロロメタン (42 mL) 溶液中に、トリフルオロ酢酸 (5.2 mL, 67.3 mmol) を0℃で滴下した。室温に昇温して2時間撹拌し、反応終了後、飽和炭酸水素ナトリウム水溶液でpH7に中和した。クロロホルムで抽出した後、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (863 mg, 88%) を得た。 1H-NMR (DMSO-D6) δ: 8.15 (1H, d, J = 9.5 Hz), 8.11 (1H, s), 8.03 (2H, d, J = 8.8 Hz), 7.60 (1H, d, J = 9.5 Hz), 7.08 (2H, d, J = 8.8 Hz), 6.89 (1H, dd, J = 17.8, 11.0 Hz), 6.36 (1H, d, J = 17.8 Hz), 5.76 (1H, d, J = 11.0 Hz), 3.23 (4H, t, J = 5.0 Hz), 3.17 (1H, s), 2.98 (4H, t, J = 5.0 Hz).
ESI-MS(m/z): 306[M+H]+. tert-Butyl 4- (4- (6-vinylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazine-1-carboxylate (1.3 g, 3.2 mmol) in dichloromethane (42 mL) , Trifluoroacetic acid (5.2 mL, 67.3 mmol) was added dropwise at 0 ° C. The mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, the mixture was neutralized to pH 7 with a saturated aqueous sodium hydrogen carbonate solution. After extraction with chloroform, it was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (863 mg, 88%). 1 H-NMR (DMSO-D 6 ) δ: 8.15 (1H, d, J = 9.5 Hz), 8.11 (1H, s), 8.03 (2H, d, J = 8.8 Hz), 7.60 (1H, d, J = 9.5 Hz), 7.08 (2H, d, J = 8.8 Hz), 6.89 (1H, dd, J = 17.8, 11.0 Hz), 6.36 (1H, d, J = 17.8 Hz), 5.76 (1H, d, J = 11.0 Hz), 3.23 (4H, t, J = 5.0 Hz), 3.17 (1H, s), 2.98 (4H, t, J = 5.0 Hz).
ESI-MS (m / z): 306 [M + H] + .

工程６
3-(4-(4-ブチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Step 6
3- (4- (4-Butylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000724
Figure JPOXMLDOC01-appb-C000724

3-(4-(ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (100 mg, 0.33 mmol) のテトラヒドロフラン (5 mL) 溶液中に、ブタナール (35 μL, 0.39 mmol)、酢酸 (19 μL, 0.33 mmol) を室温下添加した。水素化トリアセトキシホウ素ナトリウム (104 mg, 0.49 mmol) を添加した後、室温で2時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (82 mg, 69%) を得た。 1H-NMR (CDCl3) δ: 7.99 (2H, d, J = 9.0 Hz), 7.93 (1H, s), 7.92 (1H, d, J = 9.5 Hz), 7.25 (1H, d, J = 9.5 Hz), 7.04 (2H, d, J = 9.0 Hz), 6.89 (1H, dd, J = 17.9, 11.2 Hz), 6.13 (1H, d, J = 17.9 Hz), 5.67 (1H, d, J = 11.2 Hz), 3.34 (4H, t, J = 4.9 Hz), 2.68 (4H, t, J = 4.9 Hz), 2.49-2.41 (2H, m), 1.61-1.52 (2H, m), 1.42-1.33 (2H, m), 0.95 (3H, t, J = 7.3 Hz).
ESI-MS(m/z): 362[M+H]+. In a solution of 3- (4- (piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (100 mg, 0.33 mmol) in tetrahydrofuran (5 mL), butanal (35 μL, 0.39 mmol) and acetic acid (19 μL, 0.33 mmol) were added at room temperature. After adding sodium triacetoxyborohydride (104 mg, 0.49 mmol), the mixture was stirred at room temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (82 mg, 69%). 1 H-NMR (CDCl 3 ) δ: 7.99 (2H, d, J = 9.0 Hz), 7.93 (1H, s), 7.92 (1H, d, J = 9.5 Hz), 7.25 (1H, d, J = 9.5 Hz), 7.04 (2H, d, J = 9.0 Hz), 6.89 (1H, dd, J = 17.9, 11.2 Hz), 6.13 (1H, d, J = 17.9 Hz), 5.67 (1H, d, J = 11.2 Hz), 3.34 (4H, t, J = 4.9 Hz), 2.68 (4H, t, J = 4.9 Hz), 2.49-2.41 (2H, m), 1.61-1.52 (2H, m), 1.42-1.33 (2H , m), 0.95 (3H, t, J = 7.3 Hz).
ESI-MS (m / z): 362 [M + H] + .

工程７
3-(4-(4-ブチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Step 7
3- (4- (4-Butylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000725
Figure JPOXMLDOC01-appb-C000725

3-(4-(4-ブチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (105 mg, 0.29 mmol) の 1,4-ジオキサン (5 mL)、水 (1.8 mL) の混合溶液中に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (73 μL, 5.81 μmol)、2,6-ルチジン (68 μL, 0.58 mmol)、過ヨウ素酸ナトリウム (249 mg, 1.16 mmol) を添加した。アルゴン置換した後、室温で4時間撹拌した。セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (84 mg, 80%) を得た。 1H-NMR (DMSO-D6) δ: 10.03 (1H, s), 8.35 (1H, s), 8.33 (1H, d, J = 9.2 Hz), 8.08 (2H, d, J = 9.2 Hz), 7.61 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 9.2 Hz), 3.28-3.22 (4H, m), 2.55-2.49 (4H, m), 2.36-2.30 (2H, m), 1.50-1.42 (2H, m), 1.37-1.28 (2H, m), 0.91 (3H, t, J = 7.4 Hz).
ESI-MS(m/z): 364[M+H]+. 3- (4- (4-Butylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (105 mg, 0.29 mmol) of 1,4-dioxane (5 mL), water ( 1.8 mL) in a 2.5 wt% osmium tetroxide tert-butanol solution (73 μL, 5.81 μmol), 2,6-lutidine (68 μL, 0.58 mmol), sodium periodate (249 mg, 1.16 mmol) ) Was added. After purging with argon, the mixture was stirred at room temperature for 4 hours. After filtration through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (84 mg, 80%). 1 H-NMR (DMSO-D 6 ) δ: 10.03 (1H, s), 8.35 (1H, s), 8.33 (1H, d, J = 9.2 Hz), 8.08 (2H, d, J = 9.2 Hz), 7.61 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 9.2 Hz), 3.28-3.22 (4H, m), 2.55-2.49 (4H, m), 2.36-2.30 (2H, m) , 1.50-1.42 (2H, m), 1.37-1.28 (2H, m), 0.91 (3H, t, J = 7.4 Hz).
ESI-MS (m / z): 364 [M + H] + .

工程８
5-((3-(4-(4-ブチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１６６) Process 8
5-((3- (4- (4-Butylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidin-4-one (Compound 166 )

Figure JPOXMLDOC01-appb-C000726
Figure JPOXMLDOC01-appb-C000726

3-(4-(4-ブチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (42 mg, 0.12 mmol) をアセトニトリル (5 mL) に溶かし、ロダニン (16 mg, 0.12 mmol)、ピペリジン (2.3 μL, 0.02 mmol)、および酢酸 (2.7 μL, 0.05 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (6.4 μL, 0.05 mmol) を添加した後、ろ過し、アセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (25 mg, 45%) を得た。 1H-NMR (DMSO-D6) δ: 8.19 (1H, d, J = 9.7 Hz), 8.15 (1H, s), 8.07 (2H, d, J = 8.6 Hz), 7.58 (1H, d, J = 9.7 Hz), 7.38 (1H, s), 7.15 (2H, d, J = 8.6 Hz), 3.25-3.10 (4H, m), 3.00-2.88 (2H, m), 2.56-2.49 (4H, m), 1.67-1.57 (2H, m), 1.40-1.31 (2H, m), 0.94 (3H, t, J = 8.6 Hz).
ESI-MS(m/z): 479[M+H]+. 3- (4- (4-Butylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (42 mg, 0.12 mmol) was dissolved in acetonitrile (5 mL) and rhodanine (16 mg, 0.12 mmol), piperidine (2.3 μL, 0.02 mmol), and acetic acid (2.7 μL, 0.05 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (6.4 μL, 0.05 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (25 mg, 45%). 1 H-NMR (DMSO-D 6 ) δ: 8.19 (1H, d, J = 9.7 Hz), 8.15 (1H, s), 8.07 (2H, d, J = 8.6 Hz), 7.58 (1H, d, J = 9.7 Hz), 7.38 (1H, s), 7.15 (2H, d, J = 8.6 Hz), 3.25-3.10 (4H, m), 3.00-2.88 (2H, m), 2.56-2.49 (4H, m) , 1.67-1.57 (2H, m), 1.40-1.31 (2H, m), 0.94 (3H, t, J = 8.6 Hz).
ESI-MS (m / z): 479 [M + H] + .

実施例１６７
5-((3-(4-(4-ブチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１６７) Example 167
5-((3- (4- (4-Butylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 167)

Figure JPOXMLDOC01-appb-C000727
Figure JPOXMLDOC01-appb-C000727

工程１
3-(4-(4-ブチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (42 mg, 0.12 mmol) をアセトニトリル (5 mL) に溶かし、チアゾリジン-2,4-ジオン (14 mg, 0.12 mmol)、ピペリジン (2.3 μL, 0.02 mmol)、および酢酸 (2.7 μL, 0.05 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (6.4 μL, 0.05 mmol) を添加した後、ろ過し、アセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (17 mg, 32%) を得た。 1H-NMR (DMSO-D6) δ: 8.22 (1H, d, J = 9.2 Hz), 8.15 (1H, s), 8.01 (2H, d, J = 8.6 Hz), 7.73 (1H, s), 7.59 (1H, d, J = 9.2 Hz), 7.11 (2H, d, J = 8.6 Hz), 2.91-2.80 (4H, m), 2.67-2.58 (2H, m), 2.57-2.47 (4H, m), 1.60-1.49 (2H, m), 1.40-1.29 (2H, m), 0.92 (3H, t, J = 7.4 Hz).
ESI-MS(m/z): 463[M+H]+. Process 1
3- (4- (4-Butylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (42 mg, 0.12 mmol) was dissolved in acetonitrile (5 mL) and thiazolidine-2 , 4-dione (14 mg, 0.12 mmol), piperidine (2.3 μL, 0.02 mmol), and acetic acid (2.7 μL, 0.05 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (6.4 μL, 0.05 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (17 mg, 32%). 1 H-NMR (DMSO-D 6 ) δ: 8.22 (1H, d, J = 9.2 Hz), 8.15 (1H, s), 8.01 (2H, d, J = 8.6 Hz), 7.73 (1H, s), 7.59 (1H, d, J = 9.2 Hz), 7.11 (2H, d, J = 8.6 Hz), 2.91-2.80 (4H, m), 2.67-2.58 (2H, m), 2.57-2.47 (4H, m) , 1.60-1.49 (2H, m), 1.40-1.29 (2H, m), 0.92 (3H, t, J = 7.4 Hz).
ESI-MS (m / z): 463 [M + H] + .

実施例１６８
5-((3-(4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１６８)  Example 168
5-((3- (4- (4-Isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 168)

工程１
3-(4-(4-イソプロピルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 1
3- (4- (4-Isopropylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000728
Figure JPOXMLDOC01-appb-C000728

3-(4-(ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (150 mg, 0.49 mmol) のテトラヒドロフラン (8 mL) 溶液中に、アセトン (87 μL, 1.18 mmol)、酢酸 (28 μL, 0.49 mmol) を室温下添加した。水素化トリアセトキシホウ素ナトリウム (157 mg, 0.74 mmol) を添加した後、室温で2時間撹拌した。さらにアセトン (87 μL, 1.18 mmol) を添加し70℃に昇温し3時間撹拌した。飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (119 mg, 70%) を得た。 1H-NMR (DMSO-D6) δ: 8.14 (1H, d, J = 9.7 Hz), 8.09 (1H, s), 8.01 (2H, d, J = 9.2 Hz), 7.59 (1H, d, J = 9.7 Hz), 7.06 (2H, d, J = 9.2 Hz), 6.89 (1H, dd, J = 17.8, 11.3 Hz), 6.35 (1H, d, J = 17.8 Hz), 5.76 (1H, d, J = 11.3 Hz), 3.25-3.19 (4H, m), 2.74-2.66 (1H, m), 2.64-2.57 (4H, m), 1.02 (6H, d, J = 6.3 Hz).
ESI-MS(m/z): 348[M+H]+. In a solution of 3- (4- (piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (150 mg, 0.49 mmol) in tetrahydrofuran (8 mL), acetone (87 μL, 1.18 mmol) and acetic acid (28 μL, 0.49 mmol) were added at room temperature. After adding sodium triacetoxyborohydride (157 mg, 0.74 mmol), the mixture was stirred at room temperature for 2 hours. Acetone (87 μL, 1.18 mmol) was further added, the temperature was raised to 70 ° C., and the mixture was stirred for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (119 mg, 70%). 1 H-NMR (DMSO-D 6 ) δ: 8.14 (1H, d, J = 9.7 Hz), 8.09 (1H, s), 8.01 (2H, d, J = 9.2 Hz), 7.59 (1H, d, J = 9.7 Hz), 7.06 (2H, d, J = 9.2 Hz), 6.89 (1H, dd, J = 17.8, 11.3 Hz), 6.35 (1H, d, J = 17.8 Hz), 5.76 (1H, d, J = 11.3 Hz), 3.25-3.19 (4H, m), 2.74-2.66 (1H, m), 2.64-2.57 (4H, m), 1.02 (6H, d, J = 6.3 Hz).
ESI-MS (m / z): 348 [M + H] + .

工程２
3-(4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 2
3- (4- (4-Isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000729
Figure JPOXMLDOC01-appb-C000729

3-(4-(4-イソプロピルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (119 mg, 0.34 mmol) の 1,4-ジオキサン (5 mL)、水(1.8 mL) の混合溶液中に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (86 μL, 6.85 μmol)、2,6-ルチジン (80 μL, 0.69 mmol)、過ヨウ素酸ナトリウム (293 mg, 1.37 mmol) を添加した。アルゴン置換した後、室温で6時間撹拌した。セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (96 mg, 80 %) を得た。 1H-NMR (DMSO-D6) δ: 10.03 (1H, s), 8.35 (1H, s), 8.33 (1H, d, J = 9.2 Hz), 8.08 (2H, d, J = 8.6 Hz), 7.61 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 8.6 Hz), 3.27-3.19 (4H, m), 2.74-2.65 (1H, m), 2.64-2.56 (4H, m), 1.02 (6H, d, J = 6.3 Hz).
ESI-MS(m/z): 350[M+H]+. 3- (4- (4-Isopropylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (119 mg, 0.34 mmol) of 1,4-dioxane (5 mL), water ( 1.8 mL), 2.5 wt% osmium tetroxide tert-butanol solution (86 μL, 6.85 μmol), 2,6-lutidine (80 μL, 0.69 mmol), sodium periodate (293 mg, 1.37 mmol) ) Was added. After replacing with argon, the mixture was stirred at room temperature for 6 hours. After filtration through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (96 mg, 80%). 1 H-NMR (DMSO-D 6 ) δ: 10.03 (1H, s), 8.35 (1H, s), 8.33 (1H, d, J = 9.2 Hz), 8.08 (2H, d, J = 8.6 Hz), 7.61 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 8.6 Hz), 3.27-3.19 (4H, m), 2.74-2.65 (1H, m), 2.64-2.56 (4H, m) , 1.02 (6H, d, J = 6.3 Hz).
ESI-MS (m / z): 350 [M + H] + .

工程３
5-((3-(4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１６８) Process 3
5-((3- (4- (4-Isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 168)

Figure JPOXMLDOC01-appb-C000730
Figure JPOXMLDOC01-appb-C000730

3-(4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (96 mg, 0.28 mmol) をアセトニトリル (10 mL) に溶かし、チアゾリジン-2,4-ジオン (32 mg, 0.28 mmol)、ピペリジン (5.4 μL, 0.06 mmol)、および酢酸 (6.3 μL, 0.11 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (15 μL, 0.11 mmol) を添加した後、ろ過し、アセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (48 mg, 39 %) を得た。 1H-NMR (DMSO-D6) δ: 8.21 (1H, d, J = 9.2 Hz), 8.15 (1H, s), 8.03 (2H, d, J = 9.2 Hz), 7.68 (1H, s), 7.58 (1H, d, J = 9.2 Hz), 7.12 (2H, d, J = 9.2 Hz), 3.37-3.29 (4H, m), 3.00-2.90 (4H, m), 2.55-2.52 (1H, m), 1.15 (6H, br s).
ESI-MS(m/z): 449[M+H]+. 3- (4- (4-Isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (96 mg, 0.28 mmol) was dissolved in acetonitrile (10 mL) and thiazolidine-2 , 4-dione (32 mg, 0.28 mmol), piperidine (5.4 μL, 0.06 mmol), and acetic acid (6.3 μL, 0.11 mmol) were added and stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (15 μL, 0.11 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (48 mg, 39%). 1 H-NMR (DMSO-D 6 ) δ: 8.21 (1H, d, J = 9.2 Hz), 8.15 (1H, s), 8.03 (2H, d, J = 9.2 Hz), 7.68 (1H, s), 7.58 (1H, d, J = 9.2 Hz), 7.12 (2H, d, J = 9.2 Hz), 3.37-3.29 (4H, m), 3.00-2.90 (4H, m), 2.55-2.52 (1H, m) , 1.15 (6H, br s).
ESI-MS (m / z): 449 [M + H] + .

実施例１６９
5-((3-(4-(4-ペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１６９) Example 169
5-((3- (4- (4-Pentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 169)

工程１
3-(4-(4-ペンチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 1
3- (4- (4-Pentylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000731
Figure JPOXMLDOC01-appb-C000731

3-(4-(ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (150 mg, 0.49 mmol) のテトラヒドロフラン (8 mL) 溶液中に、ペンタナール (63 μL, 0.59 mmol)、酢酸 (28 μL, 0.49 mmol) を室温下添加した。水素化トリアセトキシホウ素ナトリウム (157 mg, 0.74 mmol) を添加した後、室温で1時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (141 mg, 76%) を得た。 1H-NMR (DMSO-D6) δ: 8.14 (1H, d, J = 9.7 Hz), 8.10 (1H, s), 8.01 (2H, d, J = 8.6 Hz), 7.59 (1H, d, J = 9.7 Hz), 7.06 (2H, d, J = 8.6 Hz), 6.89 (1H, dd, J = 17.8, 10.9 Hz), 6.35 (1H, d, J = 17.8 Hz), 5.76 (1H, d, J = 10.9 Hz), 3.28-3.16 (4H, m), 2.55-2.48 (4H, m), 2.34-2.27 (2H, m), 1.52-1.41 (2H, m), 1.37-1.22 (4H, m), 0.88 (3H, t, J = 7.2 Hz).
ESI-MS(m/z): 376[M+H]+. In a solution of 3- (4- (piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (150 mg, 0.49 mmol) in tetrahydrofuran (8 mL), pentanal (63 μL, 0.59 mmol) and acetic acid (28 μL, 0.49 mmol) were added at room temperature. After adding sodium triacetoxyborohydride (157 mg, 0.74 mmol), the mixture was stirred at room temperature for 1 hour. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (141 mg, 76%). 1 H-NMR (DMSO-D 6 ) δ: 8.14 (1H, d, J = 9.7 Hz), 8.10 (1H, s), 8.01 (2H, d, J = 8.6 Hz), 7.59 (1H, d, J = 9.7 Hz), 7.06 (2H, d, J = 8.6 Hz), 6.89 (1H, dd, J = 17.8, 10.9 Hz), 6.35 (1H, d, J = 17.8 Hz), 5.76 (1H, d, J = 10.9 Hz), 3.28-3.16 (4H, m), 2.55-2.48 (4H, m), 2.34-2.27 (2H, m), 1.52-1.41 (2H, m), 1.37-1.22 (4H, m), 0.88 (3H, t, J = 7.2 Hz).
ESI-MS (m / z): 376 [M + H] + .

工程２
3-(4-(4-ペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 2
3- (4- (4-Pentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000732
Figure JPOXMLDOC01-appb-C000732

3-(4-(4-ペンチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (141 mg, 0.38 mmol) の 1,4-ジオキサン (5 mL)、水 (1.8 mL) の混合溶液中に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (94 μL, 7.51 μmol)、2,6-ルチジン (87 μL, 0.75 mmol)、過ヨウ素酸ナトリウム (321 mg, 1.50 mmol) を添加した。アルゴン置換した後、室温で5時間撹拌した。セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (77 mg, 54%) を得た。 1H-NMR (DMSO-D6) δ: 10.02 (1H, s), 8.37-8.30 (2H, m), 8.07 (2H, d, J = 9.2 Hz), 7.60 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 9.2 Hz), 3.27-3.19 (4H, m), 2.55-2.46 (4H, m), 2.36-2.26 (2H, m), 1.51-1.42 (2H, m), 1.35-1.22 (4H, m), 0.88 (3H, t, J = 7.0 Hz).
ESI-MS(m/z): 378[M+H]+. 3- (4- (4-Pentylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (141 mg, 0.38 mmol) of 1,4-dioxane (5 mL), water ( 1.8 mL) in a 2.5 wt% osmium tetroxide tert-butanol solution (94 μL, 7.51 μmol), 2,6-lutidine (87 μL, 0.75 mmol), sodium periodate (321 mg, 1.50 mmol) ) Was added. After purging with argon, the mixture was stirred at room temperature for 5 hours. After filtration through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (77 mg, 54%). 1 H-NMR (DMSO-D 6 ) δ: 10.02 (1H, s), 8.37-8.30 (2H, m), 8.07 (2H, d, J = 9.2 Hz), 7.60 (1H, d, J = 9.2 Hz ), 7.10 (2H, d, J = 9.2 Hz), 3.27-3.19 (4H, m), 2.55-2.46 (4H, m), 2.36-2.26 (2H, m), 1.51-1.42 (2H, m), 1.35-1.22 (4H, m), 0.88 (3H, t, J = 7.0 Hz).
ESI-MS (m / z): 378 [M + H] + .

工程３
5-((3-(4-(4-ペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１６９) Process 3
5-((3- (4- (4-Pentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 169)

Figure JPOXMLDOC01-appb-C000733
Figure JPOXMLDOC01-appb-C000733

3-(4-(4-ペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (76 mg, 0.20 mmol) をアセトニトリル (7 mL) に溶かし、チアゾリジン-2,4-ジオン (24 mg, 0.20 mmol)、ピペリジン (4.0 μL, 0.04 mmol)、および酢酸 (4.6 μL, 0.08 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (11 μL, 0.08 mmol) を添加した後、ろ過し、アセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (42 mg, 44%) を得た。 1H-NMR (DMSO-D6) δ: 8.22 (1H, d, J = 9.2 Hz), 8.15 (1H, s), 8.01 (2H, d, J = 9.2 Hz), 7.72 (1H, s), 7.59 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 9.2 Hz), 3.37-3.30 (4H, m), 2.87-2.80 (4H, m), 2.65-2.58 (2H, m), 1.60-1.51 (2H, m), 1.36-1.23 (4H, m), 0.89 (3H, t, J = 7.2 Hz).
ESI-MS(m/z): 477[M+H]+. 3- (4- (4-pentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (76 mg, 0.20 mmol) was dissolved in acetonitrile (7 mL) and thiazolidine-2 , 4-dione (24 mg, 0.20 mmol), piperidine (4.0 μL, 0.04 mmol), and acetic acid (4.6 μL, 0.08 mmol) were added and stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (11 μL, 0.08 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (42 mg, 44%). 1 H-NMR (DMSO-D 6 ) δ: 8.22 (1H, d, J = 9.2 Hz), 8.15 (1H, s), 8.01 (2H, d, J = 9.2 Hz), 7.72 (1H, s), 7.59 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 9.2 Hz), 3.37-3.30 (4H, m), 2.87-2.80 (4H, m), 2.65-2.58 (2H, m) , 1.60-1.51 (2H, m), 1.36-1.23 (4H, m), 0.89 (3H, t, J = 7.2 Hz).
ESI-MS (m / z): 477 [M + H] + .

実施例１７０
5-((3-(2-(4-メチルピペラジン-1-イル)ベンゾ[d]チアゾール-6-イル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１７０) Example 170
5-((3- (2- (4-Methylpiperazin-1-yl) benzo [d] thiazol-6-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxo Thiazolidin-4-one (Compound 170)

工程１
6-ブロモ-2-(4-メチルピペラジン-1-イル)ベンゾ[d]チアゾール Process 1
6-Bromo-2- (4-methylpiperazin-1-yl) benzo [d] thiazole

Figure JPOXMLDOC01-appb-C000734
Figure JPOXMLDOC01-appb-C000734

6-ブロモ-2-クロロベンゾ[d]チアゾール (2.50 g, 10 mmol) のエタノール溶液に、1-メチルピペラジン (1.10 mL, 10 mmol)、トリエチルアミン (4.20 mL, 30 mmol) を室温下滴下した。アルゴン置換した後、還流条件下一晩撹拌した。反応終了後、濃縮乾固し、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (3.018 mg, 96%) を得た。白色固体; 1H-NMR (CDCl3) δ: 7.71 (1H, s), 7.37 (2H, br s), 3.94-3.66 (4H, m), 2.97-2.65 (4H, m), 2.53 (3H, s).
ESI-MS(m/z): 312[M+H]+. To an ethanol solution of 6-bromo-2-chlorobenzo [d] thiazole (2.50 g, 10 mmol), 1-methylpiperazine (1.10 mL, 10 mmol) and triethylamine (4.20 mL, 30 mmol) were added dropwise at room temperature. After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was concentrated to dryness, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (3.018 mg, 96%). White solid; 1 H-NMR (CDCl 3 ) δ: 7.71 (1H, s), 7.37 (2H, br s), 3.94-3.66 (4H, m), 2.97-2.65 (4H, m), 2.53 (3H, s).
ESI-MS (m / z): 312 [M + H] + .

工程２
2-(4-メチルピペラジン-1-イル)-6-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾ[d]チアゾール Process 2
2- (4-Methylpiperazin-1-yl) -6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzo [d] thiazole

Figure JPOXMLDOC01-appb-C000735
Figure JPOXMLDOC01-appb-C000735

6-ブロモ-2-(4-メチルピペラジン-1-イル)ベンゾ[d]チアゾール (3.018 g, 9.67 mmol)、酢酸カリウム (2.85 g, 29.0 mmol) の1,4-ジオキサン (100 mL) 溶液にビス(ピナコラート)ジボロン (2.70 g, 10.6 mmol)、1,1′-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド-ジクロロメタン錯体 (789 mg, 0.97 mmol) を添加した。アルゴン置換した後、90℃で一晩撹拌した。反応終了後、セライトろ過し、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 ( 3.47 g, quant.) を得た。 1H-NMR (CDCl3) δ: 8.07 (1H, s), 7.75 (1H, d, J = 8.6 Hz), 7.53 (1H, d, J = 8.0 Hz), 3.83-3.73 (4H, m), 2.75-2.63 (4H, m), 2.45 (3H, s), 1.35 (12H, s).
ESI-MS(m/z): 360[M+H]+. To a solution of 6-bromo-2- (4-methylpiperazin-1-yl) benzo [d] thiazole (3.018 g, 9.67 mmol) and potassium acetate (2.85 g, 29.0 mmol) in 1,4-dioxane (100 mL) Bis (pinacolato) diboron (2.70 g, 10.6 mmol), 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (789 mg, 0.97 mmol) was added. After purging with argon, the mixture was stirred at 90 ° C. overnight. After completion of the reaction, the mixture was filtered through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (3.47 g, quant.). 1 H-NMR (CDCl 3 ) δ: 8.07 (1H, s), 7.75 (1H, d, J = 8.6 Hz), 7.53 (1H, d, J = 8.0 Hz), 3.83-3.73 (4H, m), 2.75-2.63 (4H, m), 2.45 (3H, s), 1.35 (12H, s).
ESI-MS (m / z): 360 [M + H] + .

工程３
6-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-2-(4-メチルピペラジン-1-イル)ベンゾ[d]チアゾール Process 3
6- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) -2- (4-methylpiperazin-1-yl) benzo [d] thiazole

Figure JPOXMLDOC01-appb-C000736
Figure JPOXMLDOC01-appb-C000736

3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (2.27 g, 9.77 mmol) の 1,4-ジオキサン (100 mL)、水 (16 mL) の混合溶液中に、2-(4-メチルピペラジン-1-イル)-6-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾ[d]チアゾール (3.51 g, 9.77 mmol)、テトラキストリフェニルホスフィンパラジウム (451 mg, 0.39 mmol)、炭酸ナトリウム(3.62 g, 34.2 mmol)を添加した。アルゴン置換した後、還流条件下一晩撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (2.53 g, 67%) を得た。
1H-NMR (DMSO-D6) δ: 8.48 (1H, s), 8.29 (1H, s), 8.29 (1H, d, J = 8.0 Hz), 8.03 (1H, d, J = 8.0 Hz), 7.59 (1H, d, J = 9.0 Hz), 7.40 (1H, d, J = 9.0 Hz), 3.61 (4H, t, J = 5.2 Hz), 2.46 (4H, t, J = 5.2 Hz), 2.25 (3H, s).
ESI-MS(m/z): 385[M+H]+. In a mixed solution of 3-bromo-6-chloroimidazo [1,2-b] pyridazine (2.27 g, 9.77 mmol) in 1,4-dioxane (100 mL) and water (16 mL), 2- (4- Methylpiperazin-1-yl) -6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzo [d] thiazole (3.51 g, 9.77 mmol), tetrakistriphenyl Phosphine palladium (451 mg, 0.39 mmol) and sodium carbonate (3.62 g, 34.2 mmol) were added. After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (2.53 g, 67%).
1 H-NMR (DMSO-D 6 ) δ: 8.48 (1H, s), 8.29 (1H, s), 8.29 (1H, d, J = 8.0 Hz), 8.03 (1H, d, J = 8.0 Hz), 7.59 (1H, d, J = 9.0 Hz), 7.40 (1H, d, J = 9.0 Hz), 3.61 (4H, t, J = 5.2 Hz), 2.46 (4H, t, J = 5.2 Hz), 2.25 ( 3H, s).
ESI-MS (m / z): 385 [M + H] + .

工程４
2-(4-メチルピペラジン-1-イル)-6-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)ベンゾ[d]チアゾール Process 4
2- (4-Methylpiperazin-1-yl) -6- (6-vinylimidazo [1,2-b] pyridazin-3-yl) benzo [d] thiazole

Figure JPOXMLDOC01-appb-C000737
Figure JPOXMLDOC01-appb-C000737

6-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-2-(4-メチルピペラジン-1-イル)ベンゾ[d]チアゾール (2.53 g, 6.57 mmol) の 1,4-ジオキサン (100 mL)、水 (16 mL) の混合溶液中に4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (1.35 mL, 7.89 mmol)、酢酸パラジウム (148 mg, 0.66 mmol)、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル  (540 mg, 1.32 mmol)、リン酸三カリウム (10.46 g, 49.3 mmol) を添加した。アルゴン置換した後、還流条件下4時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (2.058 g, 81%) を得た。 1H-NMR (DMSO-D6) δ: 8.62 (1H, s), 8.22 (1H, s), 8.18 (1H, d, J = 9.2 Hz), 8.10 (1H, d, J = 8.6 Hz), 7.65 (1H, d, J = 9.2 Hz), 7.57 (1H, d, J = 8.6 Hz), 6.95 (1H, dd, J = 17.8, 10.9 Hz), 6.37 (1H, d, J = 17.8 Hz), 5.78 (1H, d, J = 10.9 Hz), 3.63-3.58 (4H, m), 2.48-2.44 (4H, m), 2.25 (3H, s).
ESI-MS(m/z): 377[M+H]+. 6- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) -2- (4-methylpiperazin-1-yl) benzo [d] thiazole (2.53 g, 6.57 mmol) of 1,4- In a mixed solution of dioxane (100 mL) and water (16 mL), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.35 mL, 7.89 mmol), palladium acetate (148 mg, 0.66 mmol), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (540 mg, 1.32 mmol), tripotassium phosphate (10.46 g, 49.3 mmol) were added. After replacing with argon, the mixture was stirred under reflux conditions for 4 hours. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (2.058 g, 81%). 1 H-NMR (DMSO-D 6 ) δ: 8.62 (1H, s), 8.22 (1H, s), 8.18 (1H, d, J = 9.2 Hz), 8.10 (1H, d, J = 8.6 Hz), 7.65 (1H, d, J = 9.2 Hz), 7.57 (1H, d, J = 8.6 Hz), 6.95 (1H, dd, J = 17.8, 10.9 Hz), 6.37 (1H, d, J = 17.8 Hz), 5.78 (1H, d, J = 10.9 Hz), 3.63-3.58 (4H, m), 2.48-2.44 (4H, m), 2.25 (3H, s).
ESI-MS (m / z): 377 [M + H] + .

工程５
3-(2-(4-メチルピペラジン-1-イル)ベンゾ[d]チアゾール-6-イル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 5
3- (2- (4-Methylpiperazin-1-yl) benzo [d] thiazol-6-yl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000738
Figure JPOXMLDOC01-appb-C000738

2-(4-メチルピペラジン-1-イル)-6-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)ベンゾ[d]チアゾール (2.00 g, 5.31 mmol) の 1,4-ジオキサン (70 mL)、水 (20 mL) の混合溶液中に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (1.3 mL, 0.11 mmol)、2,6-ルチジン (1.2 mL, 10.6 mmol)、過ヨウ素酸ナトリウム (4.55 g, 21.2 mmol) を添加した。アルゴン置換した後、室温で4時間撹拌した。セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (217 mg, 11%) を得た。 1H-NMR (DMSO-D6) δ: 10.09 (1H, s), 8.71 (1H, s), 8.47 (1H, s), 8.37 (1H, d, J = 9.2 Hz), 8.16 (1H, d, J = 8.6 Hz), 7.65 (1H, d, J = 9.2 Hz), 7.61 (1H, d, J = 8.6 Hz), 3.61 (4H, t, J = 4.9 Hz), 2.47 (4H, t, J = 4.9 Hz), 2.25 (3H, s).
ESI-MS(m/z): 379[M+H]+. 2- (4-Methylpiperazin-1-yl) -6- (6-vinylimidazo [1,2-b] pyridazin-3-yl) benzo [d] thiazole (2.00 g, 5.31 mmol) of 1,4- In a mixed solution of dioxane (70 mL) and water (20 mL), 2.5 wt% osmium tetroxide tert-butanol solution (1.3 mL, 0.11 mmol), 2,6-lutidine (1.2 mL, 10.6 mmol), periodate Sodium acid (4.55 g, 21.2 mmol) was added. After purging with argon, the mixture was stirred at room temperature for 4 hours. After filtration through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (217 mg, 11%). 1 H-NMR (DMSO-D 6 ) δ: 10.09 (1H, s), 8.71 (1H, s), 8.47 (1H, s), 8.37 (1H, d, J = 9.2 Hz), 8.16 (1H, d , J = 8.6 Hz), 7.65 (1H, d, J = 9.2 Hz), 7.61 (1H, d, J = 8.6 Hz), 3.61 (4H, t, J = 4.9 Hz), 2.47 (4H, t, J = 4.9 Hz), 2.25 (3H, s).
ESI-MS (m / z): 379 [M + H] + .

工程６
5-((3-(2-(4-メチルピペラジン-1-イル)ベンゾ[d]チアゾール-6-イル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン (化合物１７０) Step 6
5-((3- (2- (4-Methylpiperazin-1-yl) benzo [d] thiazol-6-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxo Thiazolidin-4-one (Compound 170)

Figure JPOXMLDOC01-appb-C000739
Figure JPOXMLDOC01-appb-C000739

3-(2-(4-メチルピペラジン-1-イル)ベンゾ[d]チアゾール-6-イル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (100 mg, 0.26 mmol) をアセトニトリル (10 mL) に溶かし、ロダニン (35 mg, 0.26 mmol)、ピペリジン (5.2 μL, 0.05 mmol)、および酢酸 (6.1 μL, 0.11 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (15 μL, 0.11 mmol)を添加した後、ろ過し、アセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (88 mg, 68%) を得た。 1H-NMR (DMSO-D6) δ: 8.71 (1H, s), 8.27 (1H, s), 8.25 (1H, d, J = 9.5 Hz), 8.02 (1H, d, J = 8.6 Hz), 7.66 (1H, d, J = 9.5 Hz), 7.61 (1H, d, J = 8.6 Hz), 7.52 (1H, s), 3.77-3.71 (4H, m), 2.92-2.85 (4H, m), 2.53 (3H, s).
ESI-MS(m/z): 478[M+H]+. 3- (2- (4-Methylpiperazin-1-yl) benzo [d] thiazol-6-yl) imidazo [1,2-b] pyridazine-6-carbaldehyde (100 mg, 0.26 mmol) in acetonitrile (10 Then, rhodanine (35 mg, 0.26 mmol), piperidine (5.2 μL, 0.05 mmol), and acetic acid (6.1 μL, 0.11 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (15 μL, 0.11 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (88 mg, 68%). 1 H-NMR (DMSO-D 6 ) δ: 8.71 (1H, s), 8.27 (1H, s), 8.25 (1H, d, J = 9.5 Hz), 8.02 (1H, d, J = 8.6 Hz), 7.66 (1H, d, J = 9.5 Hz), 7.61 (1H, d, J = 8.6 Hz), 7.52 (1H, s), 3.77-3.71 (4H, m), 2.92-2.85 (4H, m), 2.53 (3H, s).
ESI-MS (m / z): 478 [M + H] + .

実施例１７１
5-((3-(2-(4-メチルピペラジン-1-イル)ベンゾ[d]チアゾール-6-イル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン(化合物１７１)  Example 171
5-((3- (2- (4-Methylpiperazin-1-yl) benzo [d] thiazol-6-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4 -Dione (Compound 171)

Figure JPOXMLDOC01-appb-C000740
Figure JPOXMLDOC01-appb-C000740

工程１
3-(2-(4-メチルピペラジン-1-イル)ベンゾ[d]チアゾール-6-イル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (100 mg, 0.26 mmol) をアセトニトリル (10 mL) に溶かし、チアゾリジン-2,4-ジオン (31 mg, 0.26 mmol)、ピペリジン (5.2 μL, 0.05 mmol)、および酢酸(6.1 μL, 0.11 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (15 μL, 0.11 mmol) を添加した後、ろ過し、アセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (23 mg, 18%) を得た。1H-NMR (DMSO-D6) δ: 8.60 (1H, s), 8.28 (1H, d, J = 9.7 Hz), 8.25 (1H, s), 7.93 (1H, d, J = 8.3 Hz), 7.84 (1H, s), 7.67 (1H, d, J = 9.7 Hz), 7.60 (1H, d, J = 8.3 Hz), 3.66 (4H, t, J = 5.2 Hz), 2.62 (4H, t, J = 5.2 Hz), 2.35 (3H, s).
ESI-MS(m/z): 494[M+H]+. Process 1
3- (2- (4-Methylpiperazin-1-yl) benzo [d] thiazol-6-yl) imidazo [1,2-b] pyridazine-6-carbaldehyde (100 mg, 0.26 mmol) in acetonitrile (10 To the mixture, thiazolidine-2,4-dione (31 mg, 0.26 mmol), piperidine (5.2 μL, 0.05 mmol), and acetic acid (6.1 μL, 0.11 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (15 μL, 0.11 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (23 mg, 18%). 1 H-NMR (DMSO-D 6 ) δ: 8.60 (1H, s), 8.28 (1H, d, J = 9.7 Hz), 8.25 (1H, s), 7.93 (1H, d, J = 8.3 Hz), 7.84 (1H, s), 7.67 (1H, d, J = 9.7 Hz), 7.60 (1H, d, J = 8.3 Hz), 3.66 (4H, t, J = 5.2 Hz), 2.62 (4H, t, J = 5.2 Hz), 2.35 (3H, s).
ESI-MS (m / z): 494 [M + H] + .

実施例１７２
2-(4-(4-(6-((2,4-ジオキソチアゾリジン-5-イリデン)メチル)イミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-イル)アセトニトリル (化合物１７２)  Example 172
2- (4- (4- (6-((2,4-Dioxothiazolidine-5-ylidene) methyl) imidazo [1,2-b] pyridazin-3-yl) phenyl) piperazin-1-yl) acetonitrile (Compound 172)

工程１
2-(4-(4-(6-ビニリイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-イル)アセトニトリル Process 1
2- (4- (4- (6-Vinylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazin-1-yl) acetonitrile

Figure JPOXMLDOC01-appb-C000741
Figure JPOXMLDOC01-appb-C000741

3-(4-(ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (70 mg, 0.23 mmol)、炭酸カリウム (32 mg, 0.23 mmol) のN,N-ジメチルホルムアミド (1 mL) 溶液中に、2-ブロモアセトニトリル (18 μL, 0.25 mmol) を室温下滴下した。アルゴン置換し、4時間撹拌した。反応終了後、減圧下濃縮乾固し、粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (54 mg, 68%) を得た。 1H-NMR (DMSO-D6) δ: 8.14 (1H, d, J = 9.2 Hz), 8.11 (1H, s), 8.03 (2H, d, J = 9.2 Hz), 7.60 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 9.2 Hz), 6.89 (1H, dd, J = 17.8, 11.5 Hz), 6.35 (1H, d, J = 17.8 Hz), 5.76 (1H, d, J = 11.5 Hz), 3.82 (2H, s), 3.29 (4H, t, J = 5.2 Hz), 2.65 (4H, t, J = 5.2 Hz).
ESI-MS(m/z): 345[M+H]+. 3- (4- (Piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (70 mg, 0.23 mmol), potassium carbonate (32 mg, 0.23 mmol) in N, N-dimethyl 2-bromoacetonitrile (18 μL, 0.25 mmol) was added dropwise to a formamide (1 mL) solution at room temperature. The atmosphere was replaced with argon, and the mixture was stirred for 4 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (54 mg, 68%). 1 H-NMR (DMSO-D 6 ) δ: 8.14 (1H, d, J = 9.2 Hz), 8.11 (1H, s), 8.03 (2H, d, J = 9.2 Hz), 7.60 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 9.2 Hz), 6.89 (1H, dd, J = 17.8, 11.5 Hz), 6.35 (1H, d, J = 17.8 Hz), 5.76 (1H, d, J = 11.5 Hz), 3.82 (2H, s), 3.29 (4H, t, J = 5.2 Hz), 2.65 (4H, t, J = 5.2 Hz).
ESI-MS (m / z): 345 [M + H] + .

工程２
2-(4-(4-(6-ホルミルイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-イル)アセトニトリル Process 2
2- (4- (4- (6-Formylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazin-1-yl) acetonitrile

Figure JPOXMLDOC01-appb-C000742
Figure JPOXMLDOC01-appb-C000742

2-(4-(4-(6-ビニリイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-イル)アセトニトリル (93 mg, 0.27 mmol) の1,4-ジオキサン (4 mL)、水 (1 mL ) の混合溶液に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (68 μL, 5.4 μmol)、2,6-ルチジン (63 μL, 0.54 mmol)、過ヨウ素酸ナトリウム (231 mg, 1.08 mmol) を添加した。アルゴン置換した後、室温で5時間撹拌した。セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (51 mg, 55%) を得た。 1H-NMR (DMSO-D6) δ: 10.03 (1H, s), 8.36 (1H, s), 8.33 (1H, d, J = 9.2 Hz), 8.09 (2H, d, J = 9.2 Hz), 7.61 (1H, d, J = 9.2 Hz), 7.13 (2H, d, J = 9.2 Hz), 3.82 (2H, s), 3.32 (4H, t, J = 5.2 Hz), 2.65 (4H, t, J = 5.2 Hz).
ESI-MS(m/z): 347[M+H]+. 2- (4- (4- (6-Vinylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazin-1-yl) acetonitrile (93 mg, 0.27 mmol) of 1,4-dioxane (4 mL ), Water (1 mL), 2.5 wt% osmium tetroxide tert-butanol solution (68 μL, 5.4 μmol), 2,6-lutidine (63 μL, 0.54 mmol), sodium periodate (231 mg) , 1.08 mmol) was added. After purging with argon, the mixture was stirred at room temperature for 5 hours. After filtration through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (51 mg, 55%). 1 H-NMR (DMSO-D 6 ) δ: 10.03 (1H, s), 8.36 (1H, s), 8.33 (1H, d, J = 9.2 Hz), 8.09 (2H, d, J = 9.2 Hz), 7.61 (1H, d, J = 9.2 Hz), 7.13 (2H, d, J = 9.2 Hz), 3.82 (2H, s), 3.32 (4H, t, J = 5.2 Hz), 2.65 (4H, t, J = 5.2 Hz).
ESI-MS (m / z): 347 [M + H] + .

工程３
2-(4-(4-(6-((2,4-ジオキソチアゾリジン-5-イリデン)メチル)イミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-イル)アセトニトリル (化合物１７２) Process 3
2- (4- (4- (6-((2,4-Dioxothiazolidine-5-ylidene) methyl) imidazo [1,2-b] pyridazin-3-yl) phenyl) piperazin-1-yl) acetonitrile (Compound 172)

Figure JPOXMLDOC01-appb-C000743
Figure JPOXMLDOC01-appb-C000743

2-(4-(4-(6-ホルミルイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-イル)アセトニトリル (51 mg, 0.15 mmol) をアセトニトリル (5 mL) に溶かし、チアゾリジン-2,4-ジオン (17 mg, 0.15 mmol)、ピペリジン (2.9 μL, 0.03 mmol)、および酢酸 (3.4 μL, 0.06 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (8.2 μL, 0.06 mmol) を添加した後、ろ過し、アセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (28 mg, 43%) を得た。 1H-NMR (DMSO-D6) δ: 8.27 (1H, d, J = 9.2 Hz), 8.16 (1H, s), 7.94 (2H, d, J = 8.6 Hz), 7.91 (1H, s), 7.66 (1H, d, J = 9.2 Hz), 7.12 (2H, d, J = 8.6 Hz), 3.82 (2H, s), 3.31-3.28 (4H, m), 2.67 (4H, t, J = 4.9 Hz).
ESI-MS(m/z): 446[M+H]+. 2- (4- (4- (6-formylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazin-1-yl) acetonitrile (51 mg, 0.15 mmol) was dissolved in acetonitrile (5 mL). , Thiazolidine-2,4-dione (17 mg, 0.15 mmol), piperidine (2.9 μL, 0.03 mmol), and acetic acid (3.4 μL, 0.06 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (8.2 μL, 0.06 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (28 mg, 43%). 1 H-NMR (DMSO-D 6 ) δ: 8.27 (1H, d, J = 9.2 Hz), 8.16 (1H, s), 7.94 (2H, d, J = 8.6 Hz), 7.91 (1H, s), 7.66 (1H, d, J = 9.2 Hz), 7.12 (2H, d, J = 8.6 Hz), 3.82 (2H, s), 3.31-3.28 (4H, m), 2.67 (4H, t, J = 4.9 Hz ).
ESI-MS (m / z): 446 [M + H] + .

実施例１７３
5-((3-(4-(4-シクロペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１７３)  Example 173
5-((3- (4- (4-Cyclopentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 173)

工程１
3-(4-(4-シクロペンチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 1
3- (4- (4-Cyclopentylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000744
Figure JPOXMLDOC01-appb-C000744

3-(4-(ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (100 mg, 0.33 mmol)、炭酸カリウム (45 mg, 0.33 mmol) のN,N-ジメチルホルムアミド (1 mL) 溶液中に、ヨードシクロペンタン (42 μL, 0.36 mmol) を室温下滴下した。アルゴン置換し、4時間撹拌した。さらに、炭酸カリウム (45 mg, 0.33 mmol)、ヨードシクロペンタン (42 μL, 0.36 mmol) を加えた。反応終了後、減圧下濃縮乾固し、粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (76 mg, 62%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.14 (1H, d, J = 9.7 Hz), 8.09 (1H, s), 8.02 (2H, d, J = 9.2 Hz), 7.59 (1H, d, J = 9.7 Hz), 7.06 (2H, d, J = 9.2 Hz), 6.89 (1H, dd, J = 17.8, 11.5 Hz), 6.35 (1H, d, J = 17.8 Hz), 5.76 (1H, d, J = 11.5 Hz), 3.57-3.52 (1H, m), 3.22 (4H, t, J = 4.9 Hz), 2.56 (4H, t, J = 4.9 Hz), 1.86-1.79 (2H, m), 1.67-1.59 (2H, m), 1.57-1.48 (2H, m), 1.43-1.31 (2H, m).
ESI-MS(m/z): 374[M+H]+. 3- (4- (Piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (100 mg, 0.33 mmol), potassium carbonate (45 mg, 0.33 mmol) in N, N-dimethyl In a formamide (1 mL) solution, iodocyclopentane (42 μL, 0.36 mmol) was added dropwise at room temperature. The atmosphere was replaced with argon, followed by stirring for 4 hours. Furthermore, potassium carbonate (45 mg, 0.33 mmol) and iodocyclopentane (42 μL, 0.36 mmol) were added. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (76 mg, 62%). Yellow solid: 1H-NMR (DMSO-D 6 ) δ: 8.14 (1H, d, J = 9.7 Hz), 8.09 (1H, s), 8.02 (2H, d, J = 9.2 Hz), 7.59 (1H, d , J = 9.7 Hz), 7.06 (2H, d, J = 9.2 Hz), 6.89 (1H, dd, J = 17.8, 11.5 Hz), 6.35 (1H, d, J = 17.8 Hz), 5.76 (1H, d , J = 11.5 Hz), 3.57-3.52 (1H, m), 3.22 (4H, t, J = 4.9 Hz), 2.56 (4H, t, J = 4.9 Hz), 1.86-1.79 (2H, m), 1.67 -1.59 (2H, m), 1.57-1.48 (2H, m), 1.43-1.31 (2H, m).
ESI-MS (m / z): 374 [M + H] + .

工程２
3-(4-(4-シクロペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 2
3- (4- (4-Cyclopentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000745
Figure JPOXMLDOC01-appb-C000745

3-(4-(4-シクロペンチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (76 mg, 0.20 mmol) の 1,4-ジオキサン (5 mL)、水 (1 mL) の混合溶液中に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (51 μL, 4.1 μmol)、2,6-ルチジン (47 μL, 0.41 mmol)、過ヨウ素酸ナトリウム (174 mg, 0.82 mmol) を添加した。アルゴン置換した後、室温で5時間撹拌した。セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (69 mg, 90%) を得た。 1H-NMR (DMSO-D6) δ: 10.03 (1H, s), 8.35 (1H, s), 8.33 (1H, d, J = 9.2 Hz), 8.08 (2H, d, J = 9.2 Hz), 7.60 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 9.2 Hz), 3.58-3.52 (1H, m), 3.28-3.20 (4H, m), 2.61-2.53 (4H, m), 1.87-1.79 (2H, m), 1.68-1.59 (2H, m), 1.57-1.47 (2H, m), 1.42-1.32 (2H, m).
ESI-MS(m/z): 376[M+H]+. 3- (4- (4-Cyclopentylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (76 mg, 0.20 mmol) of 1,4-dioxane (5 mL), water ( 1 wt.), 2.5 wt% osmium tetroxide tert-butanol solution (51 μL, 4.1 μmol), 2,6-lutidine (47 μL, 0.41 mmol), sodium periodate (174 mg, 0.82 mmol) ) Was added. After purging with argon, the mixture was stirred at room temperature for 5 hours. After filtration through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (69 mg, 90%). 1 H-NMR (DMSO-D 6 ) δ: 10.03 (1H, s), 8.35 (1H, s), 8.33 (1H, d, J = 9.2 Hz), 8.08 (2H, d, J = 9.2 Hz), 7.60 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 9.2 Hz), 3.58-3.52 (1H, m), 3.28-3.20 (4H, m), 2.61-2.53 (4H, m) , 1.87-1.79 (2H, m), 1.68-1.59 (2H, m), 1.57-1.47 (2H, m), 1.42-1.32 (2H, m).
ESI-MS (m / z): 376 [M + H] + .

工程３
5-((3-(4-(4-シクロペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１７３) Process 3
5-((3- (4- (4-Cyclopentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 173)

Figure JPOXMLDOC01-appb-C000746
Figure JPOXMLDOC01-appb-C000746

3-(4-(4-シクロペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (69 mg, 0.18 mmol) をアセトニトリル (5 mL) に溶かし、チアゾリジン-2,4-ジオン (22 mg, 0.18 mmol)、ピペリジン (3.9 μL, 0.04 mmol)、および酢酸 (4.6 μL, 0.08 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (11 μL, 0.08 mmol) を添加した後、ろ過し、アセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (16 mg, 18%) を得た。 1H-NMR (DMSO-D6) δ: 8.22 (1H, d, J = 9.2 Hz), 8.15 (1H, s), 8.01 (2H, d, J = 9.2 Hz), 7.73 (1H, s), 7.59 (1H, d, J = 9.2 Hz), 7.11 (2H, d, J = 9.2 Hz), 3.59-3.53 (1H, m), 3.38-3.33 (4H, m), 2.96-2.88 (4H, m), 1.95-1.88 (2H, m), 1.71-1.63 (2H, m), 1.59-1.46 (4H, m).
ESI-MS(m/z): 475[M+H]+. 3- (4- (4-Cyclopentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (69 mg, 0.18 mmol) was dissolved in acetonitrile (5 mL) and thiazolidine-2 , 4-dione (22 mg, 0.18 mmol), piperidine (3.9 μL, 0.04 mmol), and acetic acid (4.6 μL, 0.08 mmol) were added and stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (11 μL, 0.08 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (16 mg, 18%). 1 H-NMR (DMSO-D 6 ) δ: 8.22 (1H, d, J = 9.2 Hz), 8.15 (1H, s), 8.01 (2H, d, J = 9.2 Hz), 7.73 (1H, s), 7.59 (1H, d, J = 9.2 Hz), 7.11 (2H, d, J = 9.2 Hz), 3.59-3.53 (1H, m), 3.38-3.33 (4H, m), 2.96-2.88 (4H, m) , 1.95-1.88 (2H, m), 1.71-1.63 (2H, m), 1.59-1.46 (4H, m).
ESI-MS (m / z): 475 [M + H] + .

実施例１７４
5-((3-(4-(4-イソブチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１７４) Example 174
5-((3- (4- (4-Isobutylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 174)

工程１
3-(4-(4-イソブチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 1
3- (4- (4-Isobutylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000747
Figure JPOXMLDOC01-appb-C000747

3-(4-(ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (100 mg, 0.33 mmol) のテトラヒドロフラン (3 mL) 溶液中に、イソブチルアルデヒド (36 μL, 0.39 mmol)、酢酸 (19 μL, 0.33 mmol) を室温下添加した。水素化トリアセトキシホウ素ナトリウム (104 mg, 0.49 mmol) を添加した後、室温で2時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (104 mg, 88%) を得た。 1H-NMR (DMSO-D6) δ: 8.14 (1H, d, J = 9.2 Hz), 8.10 (1H, s), 8.02 (2H, d, J = 9.2 Hz), 7.59 (1H, d, J = 9.2 Hz), 7.07 (2H, d, J = 9.2 Hz), 6.89 (1H, dd, J = 17.9, 11.4 Hz), 6.35 (1H, d, J = 17.9 Hz), 5.76 (1H, d, J = 11.4 Hz), 3.23 (4H, t, J = 5.0 Hz), 2.53-2.46 (4H, m), 2.10 (2H, d, J = 7.3 Hz), 1.87-1.74 (1H, m), 0.89 (6H, d, J = 6.9 Hz).
ESI-MS(m/z): 362[M+H]+. In a solution of 3- (4- (piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (100 mg, 0.33 mmol) in tetrahydrofuran (3 mL), isobutyraldehyde (36 μL, 0.39 mmol) and acetic acid (19 μL, 0.33 mmol) were added at room temperature. After adding sodium triacetoxyborohydride (104 mg, 0.49 mmol), the mixture was stirred at room temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (104 mg, 88%). 1 H-NMR (DMSO-D 6 ) δ: 8.14 (1H, d, J = 9.2 Hz), 8.10 (1H, s), 8.02 (2H, d, J = 9.2 Hz), 7.59 (1H, d, J = 9.2 Hz), 7.07 (2H, d, J = 9.2 Hz), 6.89 (1H, dd, J = 17.9, 11.4 Hz), 6.35 (1H, d, J = 17.9 Hz), 5.76 (1H, d, J = 11.4 Hz), 3.23 (4H, t, J = 5.0 Hz), 2.53-2.46 (4H, m), 2.10 (2H, d, J = 7.3 Hz), 1.87-1.74 (1H, m), 0.89 (6H , d, J = 6.9 Hz).
ESI-MS (m / z): 362 [M + H] + .

工程２
3-(4-(4-イソブチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 2
3- (4- (4-Isobutylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000748
Figure JPOXMLDOC01-appb-C000748

3-(4-(4-イソブチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (104 mg, 0.29 mmol) の 1,4-ジオキサン (5 mL)、水 (1 mL) の混合溶液中に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (72 μL, 5.8 μmol)、2,6-ルチジン (67 μL, 0.58 mmol)、過ヨウ素酸ナトリウム (246 mg, 1.15 mmol) を添加した。アルゴン置換した後、室温で5時間撹拌した。セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (51 mg, 49%) を得た。 1H-NMR (DMSO-D6) δ: 10.03 (1H, s), 8.36 (1H, s), 8.33 (1H, d, J = 8.7 Hz), 8.08 (2H, d, J = 9.2 Hz), 7.61 (1H, d, J = 8.7 Hz), 7.10 (2H, d, J = 9.2 Hz), 3.25 (4H, t, J = 5.0 Hz), 2.55-2.47 (4H, m), 2.10 (2H, d, J = 7.3 Hz), 1.87-1.77 (1H, m), 0.89 (6H, d, J = 6.4 Hz).
ESI-MS(m/z): 364[M+H]+. 3- (4- (4-Isobutylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (104 mg, 0.29 mmol) of 1,4-dioxane (5 mL), water ( 1 wt.), 2.5 wt% osmium tetroxide tert-butanol solution (72 μL, 5.8 μmol), 2,6-lutidine (67 μL, 0.58 mmol), sodium periodate (246 mg, 1.15 mmol) ) Was added. After purging with argon, the mixture was stirred at room temperature for 5 hours. After filtration through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (51 mg, 49%). 1 H-NMR (DMSO-D 6 ) δ: 10.03 (1H, s), 8.36 (1H, s), 8.33 (1H, d, J = 8.7 Hz), 8.08 (2H, d, J = 9.2 Hz), 7.61 (1H, d, J = 8.7 Hz), 7.10 (2H, d, J = 9.2 Hz), 3.25 (4H, t, J = 5.0 Hz), 2.55-2.47 (4H, m), 2.10 (2H, d , J = 7.3 Hz), 1.87-1.77 (1H, m), 0.89 (6H, d, J = 6.4 Hz).
ESI-MS (m / z): 364 [M + H] + .

工程３
5-((3-(4-(4-イソブチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１７４) Process 3
5-((3- (4- (4-Isobutylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 174)

Figure JPOXMLDOC01-appb-C000749
Figure JPOXMLDOC01-appb-C000749

3-(4-(4-イソブチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (51 mg, 0.14 mmol) をアセトニトリル (5 mL) に溶かし、チアゾリジン-2,4-ジオン(16 mg, 0.14 mmol)、ピペリジン (2.8 μL, 0.03 mmol)、および酢酸 (3.2 μL, 0.06 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (7.8 μL, 0.06 mmol) を添加した後、ろ過し、アセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (33 mg, 51%) を得た。 1H-NMR (DMSO-D6) δ: 8.25 (1H, d, J = 9.2 Hz), 8.16 (1H, s), 7.97 (2H, d, J = 9.2 Hz), 7.83 (1H, s), 7.63 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 9.2 Hz), 3.37-3.30 (4H, m), 2.75-2.67 (4H, m), 2.35-2.27 (2H, m), 1.94-1.80 (1H, m), 0.92 (6H, d, J = 6.4 Hz).
ESI-MS(m/z): 463[M+H]+. 3- (4- (4-Isobutylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (51 mg, 0.14 mmol) was dissolved in acetonitrile (5 mL) and thiazolidine-2 , 4-dione (16 mg, 0.14 mmol), piperidine (2.8 μL, 0.03 mmol), and acetic acid (3.2 μL, 0.06 mmol) were added and stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (7.8 μL, 0.06 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (33 mg, 51%). 1 H-NMR (DMSO-D 6 ) δ: 8.25 (1H, d, J = 9.2 Hz), 8.16 (1H, s), 7.97 (2H, d, J = 9.2 Hz), 7.83 (1H, s), 7.63 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 9.2 Hz), 3.37-3.30 (4H, m), 2.75-2.67 (4H, m), 2.35-2.27 (2H, m) , 1.94-1.80 (1H, m), 0.92 (6H, d, J = 6.4 Hz).
ESI-MS (m / z): 463 [M + H] + .

実施例１７５
２-(4-(4-(6-((2,4-ジオキソチアゾリジン-5-イリデン)メチル)イミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-イル)エチル　アセテート (化合物１７５)  Example 175
2- (4- (4- (6-((2,4-Dioxothiazolidine-5-ylidene) methyl) imidazo [1,2-b] pyridazin-3-yl) phenyl) piperazin-1-yl) ethyl Acetate (Compound 175)

工程１
2-(4-(4-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-イル)エチル　アセテート Process 1
2- (4- (4- (6-Vinylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazin-1-yl) ethyl acetate

Figure JPOXMLDOC01-appb-C000750
Figure JPOXMLDOC01-appb-C000750

3-(4-(ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (150 mg, 0.49 mmol)、炭酸カリウム (68 mg, 0.49 mmol) のN,N-ジメチルホルムアミド (1.5 mL) 溶液中に、2-ブロモエチルアセテート (60 μL, 0.54 mmol) を室温下滴下した。室温で3時間撹拌後、さらに炭酸カリウム (68 mg, 0.49 mmol) を加え90度で3時間撹拌した。反応終了後、減圧下濃縮乾固し、粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (125 mg, 65%) を得た。 黄色固体: 1H-NMR (DMSO-D6) δ: 8.14 (1H, d, J = 9.7 Hz), 8.10 (1H, s), 8.02 (2H, d, J = 9.2 Hz), 7.59 (1H, d, J = 9.7 Hz), 7.07 (2H, d, J = 9.2 Hz), 6.89 (1H, dd, J = 17.8, 11.5 Hz), 6.35 (1H, d, J = 17.8 Hz), 5.76 (1H, d, J = 11.5 Hz), 4.16 (2H, t, J = 5.7 Hz), 3.22 (4H, t, J = 4.9 Hz), 2.65-2.57 (6H, m), 2.03 (3H, s).
ESI-MS(m/z): 392[M+H]+. 3- (4- (Piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (150 mg, 0.49 mmol), potassium carbonate (68 mg, 0.49 mmol) in N, N-dimethyl To the formamide (1.5 mL) solution, 2-bromoethyl acetate (60 μL, 0.54 mmol) was added dropwise at room temperature. After stirring at room temperature for 3 hours, potassium carbonate (68 mg, 0.49 mmol) was further added, and the mixture was stirred at 90 degrees for 3 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (125 mg, 65%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.14 (1H, d, J = 9.7 Hz), 8.10 (1H, s), 8.02 (2H, d, J = 9.2 Hz), 7.59 (1H, d, J = 9.7 Hz), 7.07 (2H, d, J = 9.2 Hz), 6.89 (1H, dd, J = 17.8, 11.5 Hz), 6.35 (1H, d, J = 17.8 Hz), 5.76 (1H, d, J = 11.5 Hz), 4.16 (2H, t, J = 5.7 Hz), 3.22 (4H, t, J = 4.9 Hz), 2.65-2.57 (6H, m), 2.03 (3H, s).
ESI-MS (m / z): 392 [M + H] + .

工程２
2-(4-(4-(6-ホルミルイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-イル)エチル アセテート Process 2
2- (4- (4- (6-Formylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazin-1-yl) ethyl acetate

Figure JPOXMLDOC01-appb-C000751
Figure JPOXMLDOC01-appb-C000751

2-(4-(4-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-イル)エチル　アセテート (125 mg, 0.34 mmol) の 1,4-ジオキサン (5 mL)、水 (1 mL) の混合溶液中に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (80 μL, 6.4 μmol)、2,6-ルチジン (74 μL, 0.64 mmol)、過ヨウ素酸ナトリウム (273 mg, 1.28 mmol) を添加した。アルゴン置換した後、室温で6時間撹拌した。セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (93 mg, 74%) を得た。1H-NMR (DMSO-D6) δ: 10.02 (1H, s), 8.35 (1H, s), 8.33 (1H, d, J = 9.2 Hz), 8.08 (2H, d, J = 9.2 Hz), 7.60 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 9.2 Hz), 4.16 (2H, t, J = 5.7 Hz), 3.25 (4H, t, J = 4.9 Hz), 2.64-2.58 (6H, m), 2.03 (3H, s).
ESI-MS(m/z): 394[M+H]+. 2- (4- (4- (6-vinylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazin-1-yl) ethyl acetate (125 mg, 0.34 mmol) of 1,4-dioxane ( 5 wt.), Water (1 mL), 2.5 wt% osmium tetroxide tert-butanol solution (80 μL, 6.4 μmol), 2,6-lutidine (74 μL, 0.64 mmol), sodium periodate (273 mg, 1.28 mmol) was added. After replacing with argon, the mixture was stirred at room temperature for 6 hours. After filtration through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (93 mg, 74%). 1 H-NMR (DMSO-D 6 ) δ: 10.02 (1H, s), 8.35 (1H, s), 8.33 (1H, d, J = 9.2 Hz), 8.08 (2H, d, J = 9.2 Hz), 7.60 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 9.2 Hz), 4.16 (2H, t, J = 5.7 Hz), 3.25 (4H, t, J = 4.9 Hz), 2.64- 2.58 (6H, m), 2.03 (3H, s).
ESI-MS (m / z): 394 [M + H] + .

工程３
２-(4-(4-(6-((2,4-ジオキソチアゾリジン-5-イリデン)メチル)イミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-イル)エチル　アセテート (化合物１７５) Process 3
2- (4- (4- (6-((2,4-Dioxothiazolidine-5-ylidene) methyl) imidazo [1,2-b] pyridazin-3-yl) phenyl) piperazin-1-yl) ethyl Acetate (Compound 175)

Figure JPOXMLDOC01-appb-C000752
Figure JPOXMLDOC01-appb-C000752

2-(4-(4-(6-ホルミルイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-イル)エチル アセテート (25 mg, 0.06 mmol) をアセトニトリル (2 mL) に溶かし、チアゾリジン-2,4-ジオン (8 mg, 0.06 mmol)、ピペリジン (1.3 μL, 0.01 mmol)、および酢酸 (1.5 μL, 0.03 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (3.5 μL, 0.03 mmol)を添加した後、ろ過し、アセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (9 mg, 29%) を得た。 1H-NMR (DMSO-D6) δ: 8.26 (1H, d, J = 9.6 Hz), 8.15 (1H, s), 7.94 (2H, d, J = 9.2 Hz), 7.87 (1H, s), 7.64 (1H, d, J = 9.6 Hz), 7.09 (2H, d, J = 9.2 Hz), 4.18 (2H, t, J = 6.0 Hz), 3.27 (4H, t, J = 4.8 Hz), 2.74-2.65 (6H, m), 2.04 (3H, s).
ESI-MS(m/z): 493[M+H]+. 2- (4- (4- (6-formylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazin-1-yl) ethyl acetate (25 mg, 0.06 mmol) in acetonitrile (2 mL) After dissolving, thiazolidine-2,4-dione (8 mg, 0.06 mmol), piperidine (1.3 μL, 0.01 mmol), and acetic acid (1.5 μL, 0.03 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (3.5 μL, 0.03 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (9 mg, 29%). 1 H-NMR (DMSO-D 6 ) δ: 8.26 (1H, d, J = 9.6 Hz), 8.15 (1H, s), 7.94 (2H, d, J = 9.2 Hz), 7.87 (1H, s), 7.64 (1H, d, J = 9.6 Hz), 7.09 (2H, d, J = 9.2 Hz), 4.18 (2H, t, J = 6.0 Hz), 3.27 (4H, t, J = 4.8 Hz), 2.74- 2.65 (6H, m), 2.04 (3H, s).
ESI-MS (m / z): 493 [M + H] + .

実施例１７６
5-((3-(4-(4-(2-ヒドロキシエチル)ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１７６)  Example 176
5-((3- (4- (4- (2-hydroxyethyl) piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione ( Compound 176)

工程１
3-(4-(4-(2-ヒドロキシエチル)ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 1
3- (4- (4- (2-hydroxyethyl) piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000753
Figure JPOXMLDOC01-appb-C000753

2-(4-(4-(6-ホルミルイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-イル)エチル アセテート (65 mg, 0.16 mmol) のメタノール (7 mL) 溶液中に、炭酸水素ナトリウム (16 mg, 0.16 mmol) を0℃で添加した。アルゴン雰囲気下、30分撹拌した後、さらに炭酸水素ナトリウム (32 mg, 0.32 mmol) を加え、室温下30分撹拌した。濃縮乾固し、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (24 mg, 41%) を得た。 1H-NMR (CDCl3) δ: 10.10 (1H, s), 8.14 (1H, s), 8.10 (1H, d, J = 9.2 Hz), 8.01 (2H, d, J = 9.2 Hz), 7.63 (1H, d, J = 9.2 Hz), 7.08 (2H, d, J = 9.2 Hz), 3.74 (2H, t, J = 5.0 Hz), 3.39 (4H, t, J = 5.0 Hz), 2.81 (4H, t, J = 5.0 Hz), 2.71 (2H, t, J = 5.0 Hz).
ESI-MS(m/z): 352[M+H]+. 2- (4- (4- (6-formylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazin-1-yl) ethyl acetate (65 mg, 0.16 mmol) in methanol (7 mL) Inside, sodium bicarbonate (16 mg, 0.16 mmol) was added at 0 ° C. After stirring for 30 minutes under an argon atmosphere, sodium hydrogen carbonate (32 mg, 0.32 mmol) was further added, and the mixture was stirred for 30 minutes at room temperature. The mixture was concentrated to dryness, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (24 mg, 41%). 1 H-NMR (CDCl 3 ) δ: 10.10 (1H, s), 8.14 (1H, s), 8.10 (1H, d, J = 9.2 Hz), 8.01 (2H, d, J = 9.2 Hz), 7.63 ( 1H, d, J = 9.2 Hz), 7.08 (2H, d, J = 9.2 Hz), 3.74 (2H, t, J = 5.0 Hz), 3.39 (4H, t, J = 5.0 Hz), 2.81 (4H, t, J = 5.0 Hz), 2.71 (2H, t, J = 5.0 Hz).
ESI-MS (m / z): 352 [M + H] + .

工程２
5-((3-(4-(4-(2-ヒドロキシエチル)ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１７６) Process 2
5-((3- (4- (4- (2-hydroxyethyl) piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione ( Compound 176)

Figure JPOXMLDOC01-appb-C000754
Figure JPOXMLDOC01-appb-C000754

3-(4-(4-(2-ヒドロキシエチル)ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (24 mg, 0.07 mmol) をアセトニトリル (2 mL) に溶かし、チアゾリジン-2,4-ジオン (8 mg, 0.06 mmol)、ピペリジン (1.3 μL, 0.01 mmol)、および酢酸 (1.5 μL, 0.03 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (3.5 μL, 0.03 mmol) を添加した後、ろ過し、アセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (10 mg, 33%) を得た。 1H-NMR (DMSO-D6) δ: 8.23 (1H, d, J = 9.6 Hz), 8.15 (1H, s), 8.00 (2H, d, J = 9.2 Hz), 7.76 (1H, s), 7.60 (1H, d, J = 9.6 Hz), 7.11 (2H, d, J = 9.2 Hz), 3.69-3.61 (2H, m), 3.40-3.35 (4H, m), 2.97-2.88 (4H, m), 2.84-2.73 (2H, m).
ESI-MS(m/z): 451[M+H]+. 3- (4- (4- (2-hydroxyethyl) piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (24 mg, 0.07 mmol) in acetonitrile (2 mL) After dissolving, thiazolidine-2,4-dione (8 mg, 0.06 mmol), piperidine (1.3 μL, 0.01 mmol), and acetic acid (1.5 μL, 0.03 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (3.5 μL, 0.03 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (10 mg, 33%). 1 H-NMR (DMSO-D 6 ) δ: 8.23 (1H, d, J = 9.6 Hz), 8.15 (1H, s), 8.00 (2H, d, J = 9.2 Hz), 7.76 (1H, s), 7.60 (1H, d, J = 9.6 Hz), 7.11 (2H, d, J = 9.2 Hz), 3.69-3.61 (2H, m), 3.40-3.35 (4H, m), 2.97-2.88 (4H, m) , 2.84-2.73 (2H, m).
ESI-MS (m / z): 451 [M + H] + .

実施例１７７
5-((3-(2-(4-メチルピペラジン-1-イル)チアゾール-5-イル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１７７)  Example 177
5-((3- (2- (4-Methylpiperazin-1-yl) thiazol-5-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 177)

工程１
5-ブロモ-2-(4-メチルピペラジン-1-イル)チアゾール Process 1
5-Bromo-2- (4-methylpiperazin-1-yl) thiazole

Figure JPOXMLDOC01-appb-C000755
Figure JPOXMLDOC01-appb-C000755

2,5-ジブロモチアゾール (1.20 g, 4.94 mmol)、ピペラジン (1.27 g, 14.82 mmol) のテトラヒドロフラン (15 mL) 溶液中に、トリエチルアミン (2.07 mL, 14.82 mmol) を滴下した。封管中、マイクロウェーブ条件下、130℃で1時間加熱した。反応終了後、減圧下、濃縮乾固した。残渣物の塩化メチレン (40 mL) 溶液中に、37% ホルムアルデヒド水溶液 (1.47 mL, 19.76 mmol) を室温下添加し、30分撹拌した。水素化トリアセトキシホウ素ナトリウム (2.09 g, 9.88 mmol) を添加した後、室温で1時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (1.29 g, 99%) を得た。 1H-NMR (CDCl3) δ: 7.07 (1H, s), 3.47 (4H, t, J = 5.3 Hz), 2.53 (4H, t, J = 5.3 Hz), 2.35 (3H, s).
ESI-MS(m/z): 262[M+H]+. Triethylamine (2.07 mL, 14.82 mmol) was added dropwise to a solution of 2,5-dibromothiazole (1.20 g, 4.94 mmol) and piperazine (1.27 g, 14.82 mmol) in tetrahydrofuran (15 mL). The tube was heated at 130 ° C. for 1 hour under microwave conditions. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure. To a solution of the residue in methylene chloride (40 mL), 37% aqueous formaldehyde solution (1.47 mL, 19.76 mmol) was added at room temperature and stirred for 30 minutes. After adding sodium triacetoxyborohydride (2.09 g, 9.88 mmol), the mixture was stirred at room temperature for 1 hour. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (1.29 g, 99%). 1 H-NMR (CDCl 3 ) δ: 7.07 (1H, s), 3.47 (4H, t, J = 5.3 Hz), 2.53 (4H, t, J = 5.3 Hz), 2.35 (3H, s).
ESI-MS (m / z): 262 [M + H] + .

工程２
5-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-2-(4-メチルピペラジン-1-イル)チアゾール Process 2
5- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) -2- (4-methylpiperazin-1-yl) thiazole

Figure JPOXMLDOC01-appb-C000756
Figure JPOXMLDOC01-appb-C000756

5-ブロモ-2-(4-メチルピペラジン-1-イル)チアゾール (1.344 g, 5.13 mmol) のテトラヒドロフラン (50 mL) 溶液中に、n-ブチルリチウム ヘキサン溶液 (1.6 M, 3.5 mL, 5.64 mmol) をアルゴン雰囲気下、-78℃で滴下した。30分撹拌した後、4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン (2.07 mL, 10.25 mmol) をゆっくり滴下した。室温下3時間撹拌した後、減圧下濃縮した。残渣物のトルエン (50 mL)、エタノール (50 mL) 混合溶液中に3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (1.19 g, 5.13 mmol)、テトラキストリフェニルホスフィンパラジウム (296 mg, 0.25 mmol)、炭酸カリウム (1.42 g, 10.26 mmol) を添加した。アルゴン置換した後、還流条件下、一晩撹拌した。反応終了後、セライトろ過し、酢酸エチルで洗浄した。減圧下、濃縮乾固し、粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (300 mg, 17%) を得た。 1H-NMR (DMSO-D6) δ: 8.26 (1H, d, J = 9.2 Hz), 8.15 (1H, s), 7.92 (1H, s), 7.37 (1H, d, J = 9.2 Hz), 3.50 (4H, t, J = 5.0 Hz), 2.46 (4H, t, J = 5.0 Hz), 2.24 (3H, s).
ESI-MS(m/z): 335[M+H]+. N-Butyllithium in hexane (1.6 M, 3.5 mL, 5.64 mmol) in a solution of 5-bromo-2- (4-methylpiperazin-1-yl) thiazole (1.344 g, 5.13 mmol) in tetrahydrofuran (50 mL) Was added dropwise at −78 ° C. under an argon atmosphere. After stirring for 30 minutes, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.07 mL, 10.25 mmol) was slowly added dropwise. After stirring at room temperature for 3 hours, the mixture was concentrated under reduced pressure. 3-Bromo-6-chloroimidazo [1,2-b] pyridazine (1.19 g, 5.13 mmol), tetrakistriphenylphosphine palladium (296 mg) in a mixed solution of the residue toluene (50 mL) and ethanol (50 mL) , 0.25 mmol), potassium carbonate (1.42 g, 10.26 mmol) was added. After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, the mixture was filtered through celite and washed with ethyl acetate. The mixture was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (300 mg, 17%). 1 H-NMR (DMSO-D 6 ) δ: 8.26 (1H, d, J = 9.2 Hz), 8.15 (1H, s), 7.92 (1H, s), 7.37 (1H, d, J = 9.2 Hz), 3.50 (4H, t, J = 5.0 Hz), 2.46 (4H, t, J = 5.0 Hz), 2.24 (3H, s).
ESI-MS (m / z): 335 [M + H] + .

工程３
2-(4-メチルピペラジン-1-イル)-5-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)チアゾール Process 3
2- (4-Methylpiperazin-1-yl) -5- (6-vinylimidazo [1,2-b] pyridazin-3-yl) thiazole

Figure JPOXMLDOC01-appb-C000757
Figure JPOXMLDOC01-appb-C000757

5-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-2-(4-メチルピペラジン-1-イル)チアゾール (320 mg, 0.96 mmol) の1,4-ジオキサン (20 mL)、水(3 mL) の混合溶液中に 4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (196 μL, 1.15 mmol)、酢酸パラジウム (22 mg)、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル (78 mg, 0.196 mmol)、リン酸三カリウム (1.521 g, 7.17 mmol) を添加した。アルゴン置換した後、還流条件下4時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (100 mg, 32%) を得た。 1H-NMR (DMSO-D6) δ: 8.16 (1H, d, J = 9.2 Hz), 8.05 (1H, s), 7.97 (1H, s), 7.34 (1H, d, J = 9.2 Hz), 6.92 (1H, dd, J = 17.6, 11.2 Hz), 6.40 (1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.2 Hz), 3.49 (4H, t, J = 5.0 Hz), 2.46 (4H, t, J = 5.0 Hz), 2.24 (3H, s).
ESI-MS(m/z): 327[M+H]+. 5- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) -2- (4-methylpiperazin-1-yl) thiazole (320 mg, 0.96 mmol) of 1,4-dioxane (20 mL ), Water (3 mL) in a mixed solution of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (196 μL, 1.15 mmol), palladium acetate (22 mg), 2 -Dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (78 mg, 0.196 mmol) and tripotassium phosphate (1.521 g, 7.17 mmol) were added. After replacing with argon, the mixture was stirred under reflux conditions for 4 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (100 mg, 32%). 1 H-NMR (DMSO-D 6 ) δ: 8.16 (1H, d, J = 9.2 Hz), 8.05 (1H, s), 7.97 (1H, s), 7.34 (1H, d, J = 9.2 Hz), 6.92 (1H, dd, J = 17.6, 11.2 Hz), 6.40 (1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.2 Hz), 3.49 (4H, t, J = 5.0 Hz), 2.46 (4H, t, J = 5.0 Hz), 2.24 (3H, s).
ESI-MS (m / z): 327 [M + H] + .

工程４
3-(2-(4-メチルピペラジン-1-イル)チアゾール-5-イル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 4
3- (2- (4-Methylpiperazin-1-yl) thiazol-5-yl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000758
Figure JPOXMLDOC01-appb-C000758

2-(4-メチルピペラジン-1-イル)-5-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)チアゾール (100 mg, 0.31 mmol) の 1,4-ジオキサン (5 mL)、水 (1 mL) の混合溶液中に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (77 μL, 6.1 μmol)、2,6-ルチジン (71 μL, 0.61 mmol)、過ヨウ素酸ナトリウム (262 mg, 1.23 mmol) を添加した。アルゴン置換した後、室温で3時間撹拌した。反応終了後、セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (8 mg, 8%) を得た。1H-NMR (CDCl3) δ: 10.12 (1H, s), 8.11 (1H, d, J = 9.2 Hz), 8.04 (1H, s), 8.03 (1H, s), 7.65 (1H, d, J = 9.2 Hz), 3.96-3.75 (4H, m), 3.01-2.79 (3H, m), 2.68-2.51 (4H, m). 2- (4-Methylpiperazin-1-yl) -5- (6-vinylimidazo [1,2-b] pyridazin-3-yl) thiazole (100 mg, 0.31 mmol) of 1,4-dioxane (5 mL ), Water (1 mL), 2.5 wt% osmium tetroxide tert-butanol solution (77 μL, 6.1 μmol), 2,6-lutidine (71 μL, 0.61 mmol), sodium periodate (262 mg, 1.23 mmol) was added. After replacing with argon, the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was filtered through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (8 mg, 8%). 1 H-NMR (CDCl 3 ) δ: 10.12 (1H, s), 8.11 (1H, d, J = 9.2 Hz), 8.04 (1H, s), 8.03 (1H, s), 7.65 (1H, d, J = 9.2 Hz), 3.96-3.75 (4H, m), 3.01-2.79 (3H, m), 2.68-2.51 (4H, m).

工程５
5-((3-(2-(4-メチルピペラジン-1-イル)チアゾール-5-イル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１７７) Process 5
5-((3- (2- (4-Methylpiperazin-1-yl) thiazol-5-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 177)

Figure JPOXMLDOC01-appb-C000759
Figure JPOXMLDOC01-appb-C000759

3-(2-(4-メチルピペラジン-1-イル)チアゾール-5-イル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (8 mg, 0.02 mmol) をアセトニトリル (2 mL) に溶かし、チアゾリジン-2,4-ジオン (3 mg, 0.06 mmol)、ピペリジン (0.5 μL, 4.87 μmol)、および酢酸 (0.6 μL, 9.74 μmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン(1.4 μL, 9.74 μmol) を添加した後、ろ過し、アセトニトリルで洗浄し、標記化合物 (2.3 mg, 22%) を得た。 1H-NMR (DMSO-D6) δ: 8.26 (1H, d, J = 9.6 Hz), 8.06 (2H, br s), 7.78 (1H, s), 7.64 (1H, d, J = 9.6 Hz), 3.57 (4H, t, J = 5.0 Hz), 2.65 (4H, t, J = 5.0 Hz), 2.38 (3H, s). 
ESI-MS(m/z): 428[M+H]+. 3- (2- (4-Methylpiperazin-1-yl) thiazol-5-yl) imidazo [1,2-b] pyridazine-6-carbaldehyde (8 mg, 0.02 mmol) was dissolved in acetonitrile (2 mL). , Thiazolidine-2,4-dione (3 mg, 0.06 mmol), piperidine (0.5 μL, 4.87 μmol), and acetic acid (0.6 μL, 9.74 μmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (1.4 μL, 9.74 μmol) was added, followed by filtration and washing with acetonitrile to obtain the title compound (2.3 mg, 22%). 1 H-NMR (DMSO-D 6 ) δ: 8.26 (1H, d, J = 9.6 Hz), 8.06 (2H, br s), 7.78 (1H, s), 7.64 (1H, d, J = 9.6 Hz) , 3.57 (4H, t, J = 5.0 Hz), 2.65 (4H, t, J = 5.0 Hz), 2.38 (3H, s).
ESI-MS (m / z): 428 [M + H] + .

実施例１７８
5-((3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン メタンスルホナート (化合物１７８) Example 178
5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione methanesulfo Nart (Compound 178)

Figure JPOXMLDOC01-appb-C000760
Figure JPOXMLDOC01-appb-C000760

工程１
5-((3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (50 mg, 0.114 mmol) を水 (5 mL) に懸濁した。そこへ2 M メタンスルホン酸 (57 μL, 0.114 mmol) を加え、室温で5分撹拌した。反応液をフィルターでろ過し、ろ液を濃縮した。得られた残渣にエタノール (5 mL) を加えて懸濁させ、30分加熱還流した。反応液を室温まで冷却し、生じた固体をろ取、真空乾燥して標記化合物 (53 mg, 87%) を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 8.33 (1H, d, J = 9.5 Hz), 8.30 (1H, s), 8.06 (1H, dd, J =14.0, 1.7 Hz), 7.94 (1H, s), 7.82 (1H, dd, J = 8.6, 1.7 Hz), 7.73 (1H, d, J = 9.2 Hz), 7.27 (1H, t, J = 8.9 Hz), 3.46-3.34 (8H, m), 2.88 (3H, s), 2.30 (3H, s). Process 1
5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (50 mg, 0.114 mmol) was suspended in water (5 mL). 2 M methanesulfonic acid (57 microliters, 0.114 mmol) was added there, and it stirred at room temperature for 5 minutes. The reaction solution was filtered through a filter, and the filtrate was concentrated. Ethanol (5 mL) was added to the resulting residue for suspension, and the mixture was heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature, and the resulting solid was collected by filtration and dried in vacuo to give the title compound (53 mg, 87%). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 8.33 (1H, d, J = 9.5 Hz), 8.30 (1H, s), 8.06 (1H, dd, J = 14.0, 1.7 Hz), 7.94 ( 1H, s), 7.82 (1H, dd, J = 8.6, 1.7 Hz), 7.73 (1H, d, J = 9.2 Hz), 7.27 (1H, t, J = 8.9 Hz), 3.46-3.34 (8H, m ), 2.88 (3H, s), 2.30 (3H, s).

実施例１７９
5-((3-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン メタンスルホンナート (化合物１７９) Example 179
5-((3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione methanesulfone Nart (Compound 179)

Figure JPOXMLDOC01-appb-C000761
Figure JPOXMLDOC01-appb-C000761

工程１
5-((3-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (90 mg, 0.2 mmol) をメタノール (2 mL)、水 (2 mL) に懸濁した。そこへメタンスルホン酸 (19 mg, 0.2 mmol) を加え、室温で10分撹拌し溶解させた。反応液を濃縮乾固し、得られた固体にメタノールを加え30分加熱還流した。反応液を冷却して吸引ろ過し、得られた結晶をメタノールとエーテルで洗浄して標記化合物 (108 mg, 98%) を得た。橙黄色固体: 1H-NMR (DMSO-D6) δ: 12.69 (1H, br s), 9.35 (1H, br s), 8.30 (1H, d, J = 9.2 Hz), 8.27 (1H, s), 8.01 (1H, dd, J = 11.9, 2.1 Hz), 7.91 (1H, s), 7.78 (1H, dd, J = 6.7, 1.6 Hz), 7.71 (1H, d, J = 9.6 Hz), 7.24 (1H, t, J = 8.9 Hz), 3.66-3.55 (4H, m), 3.27-3.17 (4H, m), 3.15-3.05 (2H, m), 2.26 (3H, s), 1.23 (3H, t, J = 7.3 Hz). Process 1
5-((3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (90 mg, 0.2 mmol) was suspended in methanol (2 mL) and water (2 mL). Methanesulfonic acid (19 mg, 0.2 mmol) was added thereto, and the mixture was stirred for 10 minutes at room temperature to dissolve. The reaction solution was concentrated to dryness, methanol was added to the obtained solid, and the mixture was heated to reflux for 30 minutes. The reaction mixture was cooled and suction filtered, and the obtained crystals were washed with methanol and ether to give the title compound (108 mg, 98%). Orange-yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 12.69 (1H, br s), 9.35 (1H, br s), 8.30 (1H, d, J = 9.2 Hz), 8.27 (1H, s) , 8.01 (1H, dd, J = 11.9, 2.1 Hz), 7.91 (1H, s), 7.78 (1H, dd, J = 6.7, 1.6 Hz), 7.71 (1H, d, J = 9.6 Hz), 7.24 ( 1H, t, J = 8.9 Hz), 3.66-3.55 (4H, m), 3.27-3.17 (4H, m), 3.15-3.05 (2H, m), 2.26 (3H, s), 1.23 (3H, t, J = 7.3 Hz).

実施例１８０
5-((3-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン ハイドロクロライド (化合物１８０)  Example 180
5-((3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione hydrochloride (Compound 180)

Figure JPOXMLDOC01-appb-C000762
Figure JPOXMLDOC01-appb-C000762

工程１
5-((3-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン(45 mg, 0.1 mmol) のメタノール (1 mL) 懸濁液に 0.1規定塩酸水溶液 (1.0 mL, 0.1 mmol) を加え、5 分間撹拌した。減圧下溶媒を留去した後、残渣を水に溶かし、ろ過した。ろ液にメタノールを加え、減圧下、溶媒を留去した。得られた結晶をメタノールで洗浄した後、乾燥し、目的とする目的とする標記化合物 (42 mg, 86%) を得た。橙黄色固体: 1H-NMR (DMSO-D6) δ: 12.76 (1H, br s), 9.89 (1H, br s), 8.34 (1H, d, J = 9.2 Hz), 8.30 (1H, s), 8.06 (1H, dd, J = 12.4, 1.8 Hz), 7.95 (1H, s), 7.82 (1H, dd, J = 6.4, 1.8 Hz), 7.74 (1H, d, J = 9.2 Hz), 7.28 (1H, t, J = 8.9 Hz), 3.68-3.60 (4H, m), 3.40-3.19 (6H, m), 1.28 (3H, t, J = 7.1 Hz). Process 1
5-((3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (45 To a suspension of mg, 0.1 mmol) in methanol (1 mL) was added 0.1N hydrochloric acid aqueous solution (1.0 mL, 0.1 mmol), and the mixture was stirred for 5 minutes. After evaporating the solvent under reduced pressure, the residue was dissolved in water and filtered. Methanol was added to the filtrate, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with methanol and dried to give the desired title compound (42 mg, 86%). Orange-yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 12.76 (1H, br s), 9.89 (1H, br s), 8.34 (1H, d, J = 9.2 Hz), 8.30 (1H, s) , 8.06 (1H, dd, J = 12.4, 1.8 Hz), 7.95 (1H, s), 7.82 (1H, dd, J = 6.4, 1.8 Hz), 7.74 (1H, d, J = 9.2 Hz), 7.28 ( 1H, t, J = 8.9 Hz), 3.68-3.60 (4H, m), 3.40-3.19 (6H, m), 1.28 (3H, t, J = 7.1 Hz).

実施例１８１
5-((3-(4-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン メタンスルホナート (化合１８１)  Example 181
5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione methanesulfonate (compound 181 )

Figure JPOXMLDOC01-appb-C000763
Figure JPOXMLDOC01-appb-C000763

工程１
5-((3-(4-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (12 mg, 0.03 mmol) の水 (1.0 mL) 溶液中に、2 Mメタンスルホン酸水溶液 (13.8 μL, 0.03 mmol) を室温下滴下した。10分間撹拌した後、反応液を濃縮乾固し、得られた固体にメタノール (1.0 mL) を加え、30分間加熱還流した。反応液を冷却して吸引ろ過し、得られた結晶をメタノールで洗浄して、標記化合物 (10 mg, 68%,) を得た。 1H-NMR (DMSO-D6) δ: 8.29 (1H, d, J = 9.7 Hz), 8.18 (1H, s), 7.98 (2H, d, J = 8.6 Hz), 7.92 (1H, s), 7.68 (1H, d, J = 9.7 Hz), 7.19 (2H, d, J = 8.6 Hz), 3.38-3.32 (4H, m), 3.23-3.16 (2H, m), 2.53-2.48 (4H, m), 2.31 (3H, s), 1.27 (3H, t, J = 7.4 Hz). Process 1
5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (12 mg, 0.03 mmol ) In water (1.0 mL) was added dropwise 2 M aqueous methanesulfonic acid solution (13.8 μL, 0.03 mmol) at room temperature. After stirring for 10 minutes, the reaction solution was concentrated to dryness, methanol (1.0 mL) was added to the obtained solid, and the mixture was heated to reflux for 30 minutes. The reaction mixture was cooled and suction filtered, and the resulting crystals were washed with methanol to give the title compound (10 mg, 68%). 1 H-NMR (DMSO-D 6 ) δ: 8.29 (1H, d, J = 9.7 Hz), 8.18 (1H, s), 7.98 (2H, d, J = 8.6 Hz), 7.92 (1H, s), 7.68 (1H, d, J = 9.7 Hz), 7.19 (2H, d, J = 8.6 Hz), 3.38-3.32 (4H, m), 3.23-3.16 (2H, m), 2.53-2.48 (4H, m) , 2.31 (3H, s), 1.27 (3H, t, J = 7.4 Hz).

実施例１８２
5-((1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン メタンスルホナート (化合物１８２)  Example 182
5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione methanesulfonate (Compound 182)

Figure JPOXMLDOC01-appb-C000764
Figure JPOXMLDOC01-appb-C000764

工程１
5-((1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン (1.19 g, 2.74 mmol) のメタノール (10 mL)、水 (40 mL) 混合溶液にメタンスルホン酸 (276 mg, 2.88 mmol) を加え、2 分間撹拌した。反応終了後、減圧下溶媒を留去した。結晶を水に溶かしてろ過し、ろ液を回収後、減圧下溶媒を留去した。得られた結晶を メタノール、酢酸エチルで洗浄した後乾燥し、標記化合物 (1.24 g, 86%) を得た。黄色結晶: 1H-NMR (DMSO-D6) δ: 12.60 (1H, br s), 9.38 (1H, br s), 8.65 (1H, s), 7.98 (1H, s), 7.91 (1H, d, J = 8.5 Hz), 7.80 (1H, d, J = 1.7 Hz), 7.62 (2H, d, J = 8.8 Hz), 7.56 (1H, dd, J = 8.5, 1.7 Hz), 7.28 (2H, d, J = 8.8 Hz), 4.00 (2H, s), 3.61 (2H, s), 3.27-3.07 (6H, m), 2.30 (3H, s), 1.28 (3H, t, J = 7.3 Hz). Process 1
5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione (1.19 g, 2.74 mmol) Methanesulfonic acid (276 mg, 2.88 mmol) was added to a mixed solution of methanol (10 mL) and water (40 mL), and the mixture was stirred for 2 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure. The crystals were dissolved in water and filtered. After collecting the filtrate, the solvent was distilled off under reduced pressure. The obtained crystals were washed with methanol and ethyl acetate and dried to give the title compound (1.24 g, 86%). Yellow crystals: 1 H-NMR (DMSO-D 6 ) δ: 12.60 (1H, br s), 9.38 (1H, br s), 8.65 (1H, s), 7.98 (1H, s), 7.91 (1H, d , J = 8.5 Hz), 7.80 (1H, d, J = 1.7 Hz), 7.62 (2H, d, J = 8.8 Hz), 7.56 (1H, dd, J = 8.5, 1.7 Hz), 7.28 (2H, d , J = 8.8 Hz), 4.00 (2H, s), 3.61 (2H, s), 3.27-3.07 (6H, m), 2.30 (3H, s), 1.28 (3H, t, J = 7.3 Hz).

実施例１８３
5-((3-(3-メチル-4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１８３) Example 183
5-((3- (3-Methyl-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 183)

工程１
tert-ブチル 4-(2-メチル-4-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-カルボキシレート Process 1
tert-butyl 4- (2-methyl-4- (6-vinylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000765
Figure JPOXMLDOC01-appb-C000765

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、tert-ブチル 4-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-2-メチルフェニル)ピペラジン-1-カルボキシレート(870 mg, 2.03 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (382 μL, 2.23 mmol) から標記化合物 (735 mg, 86%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.16 (1H, d, J = 9.6 Hz), 8.14 (1H, s), 8.01-7.96 (2H, m), 7.63 (1H, d, J = 9.6 Hz), 7.15 (1H, d, J = 8.2 Hz), 6.90 (1H, dd, J = 17.7, 11.1 Hz), 6.36 (1H, d, J = 17.6 Hz), 5.77 (1H, d, J = 11.4 Hz), 3.50 (4H, s), 2.86 (4H, t, J = 4.9 Hz), 2.36 (3H, s), 1.44 (9H, s). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) tert-butyl 4- (4- (6-chloroimidazo [1,2-b] pyridazin-3-yl) -2-methylphenyl) piperazine-1-carboxylate (870 mg, 2.03 mmol) and 4,4, The title compound (735 mg, 86%) was obtained from 5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (382 μL, 2.23 mmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.16 (1H, d, J = 9.6 Hz), 8.14 (1H, s), 8.01-7.96 (2H, m), 7.63 (1H, d, J = 9.6 Hz), 7.15 (1H, d, J = 8.2 Hz), 6.90 (1H, dd, J = 17.7, 11.1 Hz), 6.36 (1H, d, J = 17.6 Hz), 5.77 (1H, d, J = 11.4 Hz), 3.50 (4H, s), 2.86 (4H, t, J = 4.9 Hz), 2.36 (3H, s), 1.44 (9H, s).

工程２
3-(3-メチル-4-(ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 2
3- (3-Methyl-4- (piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000766
Figure JPOXMLDOC01-appb-C000766

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程6) と同様の手法で、tert-ブチル 4-(2-メチル-4-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-カルボキシレート(735 mg, 1.75 mmol) およびトリフルオロ酢酸 (3 mL) から標記化合物 (546 mg, 98%) を得た。黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.16 (1H, d, J = 9.6 Hz), 8.13 (1H, s), 7.99 (1H, dd, J =8.2, 2.3 Hz), 7.94 (1H, d, J =1.8 Hz), 7.62 (1H, d, J = 9.2 Hz), 7.13 (1H, d, J = 8.2 Hz), 6.90 (1H, dd, J = 17.9, 11.0 Hz), 6.36 (1H, d, J = 17.4 Hz), 5.77 (1H, d, J = 11.4 Hz), 2.93-2.90 (4H, m), 2.86-2.84 (4H, m), 2.34 (3H, s). Synthesis of 5-bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 6) From-(2-methyl-4- (6-vinylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazine-1-carboxylate (735 mg, 1.75 mmol) and trifluoroacetic acid (3 mL) The title compound (546 mg, 98%) was obtained. Yellow amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.16 (1H, d, J = 9.6 Hz), 8.13 (1H, s), 7.99 (1H, dd, J = 8.2, 2.3 Hz), 7.94 (1H, d, J = 1.8 Hz), 7.62 (1H, d, J = 9.2 Hz), 7.13 (1H, d, J = 8.2 Hz), 6.90 (1H, dd, J = 17.9, 11.0 Hz), 6.36 (1H, d, J = 17.4 Hz), 5.77 (1H, d, J = 11.4 Hz), 2.93-2.90 (4H, m), 2.86-2.84 (4H, m), 2.34 (3H, s).

工程３
3-(3-メチル-4-(4-プロピルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 3
3- (3-Methyl-4- (4-propylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000767
Figure JPOXMLDOC01-appb-C000767

3-(4-(4-ブチルピペラジン-1-イル)-3-フルオロフェニル)-6-クロロイミダゾ[1,2-b]ピリダジンの合成 (実施例147、工程1) と同様の手法で、3-(3-メチル-4-(ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (270 mg, 0.845 mmol) およびプロピオンアルデヒド (122 μL, 1.69 mmol) から標記化合物 (127 mg, 42%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.16 (1H, dd, J = 9.4, 0.5 Hz), 8.13 (1H, s), 7.99 (1H, dd, J = 8.2, 1.8 Hz), 7.93 (1H, d, J = 1.6 Hz), 7.62 (1H, d, J = 9.4 Hz), 7.15 (1H, d, J = 8.5 Hz), 6.90 (1H, dd, J = 17.7, 11.1 Hz), 6.36 (1H, d, J = 17.6 Hz), 5.77 (1H, d, J = 11.7 Hz), 2.91 (4H, t, J = 4.4 Hz), 2.56-2.52 (4H, m), 2.33 (3H, s), 2.31 (2H, t, J = 7.2 Hz), 1.53-1.44 (2H, m), 0.89 (3H, t, J = 7.3 Hz). Synthesis of 3- (4- (4-butylpiperazin-1-yl) -3-fluorophenyl) -6-chloroimidazo [1,2-b] pyridazine (Example 147, Step 1) Titled from 3- (3-methyl-4- (piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (270 mg, 0.845 mmol) and propionaldehyde (122 μL, 1.69 mmol) The compound (127 mg, 42%) was obtained. Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.16 (1H, dd, J = 9.4, 0.5 Hz), 8.13 (1H, s), 7.99 (1H, dd, J = 8.2, 1.8 Hz), 7.93 (1H, d, J = 1.6 Hz), 7.62 (1H, d, J = 9.4 Hz), 7.15 (1H, d, J = 8.5 Hz), 6.90 (1H, dd, J = 17.7, 11.1 Hz), 6.36 (1H, d, J = 17.6 Hz), 5.77 (1H, d, J = 11.7 Hz), 2.91 (4H, t, J = 4.4 Hz), 2.56-2.52 (4H, m), 2.33 (3H, s ), 2.31 (2H, t, J = 7.2 Hz), 1.53-1.44 (2H, m), 0.89 (3H, t, J = 7.3 Hz).

工程４
3-(3-メチル-4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 4
3- (3-Methyl-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000768
Figure JPOXMLDOC01-appb-C000768

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-メチル-4-(4-プロピルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (127 mg, 0.351 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (88 μl, 7.02 μmol) から標記化合物 (70 mg, 55%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.7 Hz), 8.38 (1H, s), 8.35 (1H, dd, J = 9.4, 0.7 Hz), 8.05 (1H, dd, J = 8.4, 2.2 Hz), 7.98 (1H, d, J = 1.6 Hz), 7.63 (1H, d, J = 9.4 Hz), 7.18 (1H, d, J = 8.5 Hz), 2.93 (4H, t, J = 4.4 Hz), 2.56-2.52 (4H, m), 2.35 (3H, s), 2.35-2.30 (2H, m), 1.53-1.44 (2H, m), 0.89 (3H, t, J = 7.4 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3-methyl-4- (4-propylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (127 mg, 0.351 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol ( The title compound (70 mg, 55%) was obtained from 88 μl, 7.02 μmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.7 Hz), 8.38 (1H, s), 8.35 (1H, dd, J = 9.4, 0.7 Hz), 8.05 ( 1H, dd, J = 8.4, 2.2 Hz), 7.98 (1H, d, J = 1.6 Hz), 7.63 (1H, d, J = 9.4 Hz), 7.18 (1H, d, J = 8.5 Hz), 2.93 ( 4H, t, J = 4.4 Hz), 2.56-2.52 (4H, m), 2.35 (3H, s), 2.35-2.30 (2H, m), 1.53-1.44 (2H, m), 0.89 (3H, t, J = 7.4 Hz).

工程５
5-((3-(3-メチル-4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１８３) Process 5
5-((3- (3-Methyl-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 183)

Figure JPOXMLDOC01-appb-C000769
Figure JPOXMLDOC01-appb-C000769

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-メチル-4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (63 mg, 0.173 mmol) およびチアゾリジン-2,4-ジオン (20 mg, 0.173 mmol) から標記化合物 (45 mg, 56%) を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 8.23 (1H, d, J = 9.2 Hz), 8.18 (1H, s), 8.10 (1H, d, J = 1.6 Hz), 7.83 (1H, dd, J = 8.4, 1.9 Hz), 7.70 (1H, s), 7.61 (1H, d, J = 9.4 Hz), 7.17 (1H, d, J = 8.5 Hz), 3.03 (4H, s), 2.89 (4H, s), 2.68-2.61 (2H, m), 2.39 (3H, s), 1.62-1.53 (2H, m), 0.92 (3H, t, J = 7.3 Hz).
ESI-MS(m/z): 463[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3-methyl-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (63 mg, 0.173 mmol) and thiazolidine-2,4-dione (20 mg, 0.173 mmol) gave the title compound (45 mg, 56%). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 8.23 (1H, d, J = 9.2 Hz), 8.18 (1H, s), 8.10 (1H, d, J = 1.6 Hz), 7.83 (1H, dd, J = 8.4, 1.9 Hz), 7.70 (1H, s), 7.61 (1H, d, J = 9.4 Hz), 7.17 (1H, d, J = 8.5 Hz), 3.03 (4H, s), 2.89 ( 4H, s), 2.68-2.61 (2H, m), 2.39 (3H, s), 1.62-1.53 (2H, m), 0.92 (3H, t, J = 7.3 Hz).
ESI-MS (m / z): 463 [M + H] + .

実施例１８４
5-((3-(4-(4-イソプロピルピペラジン-1-イル)-3-メチルフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１８４) Example 184
5-((3- (4- (4-Isopropylpiperazin-1-yl) -3-methylphenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 184)

工程１
3-(4-(4-イソプロピルピペラジン-1-イル)-3-メチルフェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 1
3- (4- (4-Isopropylpiperazin-1-yl) -3-methylphenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000770
Figure JPOXMLDOC01-appb-C000770

アルゴン雰囲気下、3-(3-メチル-4-(ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (270 mg, 0.845 mmol) をジクロロメタン (8 mL) に溶解した。そこへアセトン (125 μL, 1.69 mmol)、酢酸 (48 μL, 0.845 mmol) を加え、室温で1時間撹拌した。さらにナトリウムトリアセトキシボロヒドリド (269 mg, 1.27 mmol) を加え、室温で15時間撹拌した。反応液に飽和重層水を加え、クロロホルムで抽出した。クロロホルム層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (211 mg, 69%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.16 (1H, d, J = 9.6 Hz), 8.13 (1H, s), 7.98 (1H, dd, J =8.4, 1.9 Hz), 7.93 (1H, d, J =1.6 Hz), 7.62 (1H, d, J = 9.4 Hz), 7.14 (1H, d, J = 8.5 Hz), 6.90 (1H, dd, J = 17.7, 11.1 Hz), 6.36 (1H, d, J = 17.6 Hz), 5.77 (1H, d, J = 11.4 Hz), 2.90 (4H, s), 2.73-2.65 (1H, m), 2.62 (4H, s), 2.33 (3H, s), 1.03 (6H, d, J = 6.6 Hz). 3- (3-Methyl-4- (piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (270 mg, 0.845 mmol) dissolved in dichloromethane (8 mL) under argon atmosphere did. Acetone (125 μL, 1.69 mmol) and acetic acid (48 μL, 0.845 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (269 mg, 1.27 mmol) was further added, and the mixture was stirred at room temperature for 15 hours. Saturated multistory water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (211 mg, 69%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.16 (1H, d, J = 9.6 Hz), 8.13 (1H, s), 7.98 (1H, dd, J = 8.4, 1.9 Hz), 7.93 ( 1H, d, J = 1.6 Hz), 7.62 (1H, d, J = 9.4 Hz), 7.14 (1H, d, J = 8.5 Hz), 6.90 (1H, dd, J = 17.7, 11.1 Hz), 6.36 ( 1H, d, J = 17.6 Hz), 5.77 (1H, d, J = 11.4 Hz), 2.90 (4H, s), 2.73-2.65 (1H, m), 2.62 (4H, s), 2.33 (3H, s ), 1.03 (6H, d, J = 6.6 Hz).

工程２
3-(4-(4-イソプロピルピペラジン-1-イル)-3-メチルフェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 2
3- (4- (4-Isopropylpiperazin-1-yl) -3-methylphenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000771
Figure JPOXMLDOC01-appb-C000771

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(4-(4-イソプロピルピペラジン-1-イル)-3-メチルフェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (211 mg, 0.584 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (146 μl, 11.7 μmol) から標記化合物 (41 mg, 19%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.9 Hz), 8.38 (1H, s), 8.35 (1H, dd, J =9.4, 0.7 Hz), 8.05 (1H, dd, J =8.2, 2.1 Hz), 7.98 (1H, d, J =1.8 Hz), 7.63 (1H, d, J = 9.4 Hz), 7.17 (1H, d, J = 8.5 Hz), 2.92 (4H, s), 2.74-2.63 (1H, m), 2.63 (4H, s), 2.36 (3H, s), 1.03 (6H, d, J = 6.4 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 4- (4-Isopropylpiperazin-1-yl) -3-methylphenyl) -6-vinylimidazo [1,2-b] pyridazine (211 mg, 0.584 mmol) and 2.5 wt% osmium tetroxide tert-butanol solution ( The title compound (41 mg, 19%) was obtained from 146 μl, 11.7 μmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.9 Hz), 8.38 (1H, s), 8.35 (1H, dd, J = 9.4, 0.7 Hz), 8.05 ( 1H, dd, J = 8.2, 2.1 Hz), 7.98 (1H, d, J = 1.8 Hz), 7.63 (1H, d, J = 9.4 Hz), 7.17 (1H, d, J = 8.5 Hz), 2.92 ( 4H, s), 2.74-2.63 (1H, m), 2.63 (4H, s), 2.36 (3H, s), 1.03 (6H, d, J = 6.4 Hz).

工程３
5-((3-(4-(4-イソプロピルピペラジン-1-イル)-3-メチルフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１８４) Process 3
5-((3- (4- (4-Isopropylpiperazin-1-yl) -3-methylphenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 184)

Figure JPOXMLDOC01-appb-C000772
Figure JPOXMLDOC01-appb-C000772

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(4-(4-イソプロピルピペラジン-1-イル)-3-メチルフェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (35 mg, 0.0963 mmol) およびチアゾリジン-2,4-ジオン (11 mg, 0.0963 mmol) から標記化合物 (16 mg, 35%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.22 (1H, d, J = 9.2 Hz), 8.17 (1H, s), 8.12 (1H, d, J = 1.8 Hz), 7.85 (1H, dd, J = 8.5, 2.1 Hz), 7.64 (1H, s), 7.59 (1H, d, J = 9.4 Hz), 7.17 (1H, d, J = 8.5 Hz), 3.06 (4H, s), 3.02 (4H, s), 2.55-2.46 (1H, m), 2.40 (3H, s), 1.18 (6H, d, J = 6.6 Hz).
ESI-MS(m/z): 463[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (4- (4-isopropylpiperazin-1-yl) -3-methylphenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (35 mg, 0.0963 mmol) and thiazolidine-2,4-dione (11 mg, 0.0963 mmol) gave the title compound (16 mg, 35%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.22 (1H, d, J = 9.2 Hz), 8.17 (1H, s), 8.12 (1H, d, J = 1.8 Hz), 7.85 (1H, dd, J = 8.5, 2.1 Hz), 7.64 (1H, s), 7.59 (1H, d, J = 9.4 Hz), 7.17 (1H, d, J = 8.5 Hz), 3.06 (4H, s), 3.02 ( 4H, s), 2.55-2.46 (1H, m), 2.40 (3H, s), 1.18 (6H, d, J = 6.6 Hz).
ESI-MS (m / z): 463 [M + H] + .

実施例１８５
5-((3-(4-(4-エチルピペラジン-1-イル)-3-メチルフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１８５) Example 185
5-((3- (4- (4-Ethylpiperazin-1-yl) -3-methylphenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 185)

工程１
3-(4-(4-エチルピペラジン-1-イル)-3-メチルフェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 1
3- (4- (4-Ethylpiperazin-1-yl) -3-methylphenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000773
Figure JPOXMLDOC01-appb-C000773

アルゴン雰囲気下、3-(3-メチル-4-(ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (262 mg, 0.820 mmol) をN,N-ジメチルホルムアミド (4 mL) に溶解した。そこへヨードエタン (79 μL, 0.984 mmol)、炭酸カリウム (170 mg, 1.23 mmol) を加え、室温で1時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。酢酸エチル層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (198 mg, 70%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.16 (1H, dd, J =9.4, 0.5 Hz), 8.13 (1H, s), 7.99 (1H, dd, J = 8.2, 1.8 Hz), 7.94-7.93 (1H, m), 7.62 (1H, d, J = 9.6 Hz), 7.15 (1H, d, J = 8.5 Hz), 6.90 (1H, dd, J = 17.7, 11.1 Hz), 6.36 (1H, d, J = 17.6 Hz), 5.77 (1H, d, J = 11.4 Hz), 2.91 (4H, t, J = 4.1 Hz), 2.56-2.52 (4H, m), 2.40 (2H, q, J = 7.3 Hz), 2.33 (3H, s), 1.05 (3H, t, J = 7.2 Hz). Under argon atmosphere, 3- (3-methyl-4- (piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (262 mg, 0.820 mmol) was replaced with N, N-dimethylformamide ( 4 mL). The iodoethane (79 microliters, 0.984 mmol) and potassium carbonate (170 mg, 1.23 mmol) were added there, and it stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (198 mg, 70%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.16 (1H, dd, J = 9.4, 0.5 Hz), 8.13 (1H, s), 7.99 (1H, dd, J = 8.2, 1.8 Hz), 7.94-7.93 (1H, m), 7.62 (1H, d, J = 9.6 Hz), 7.15 (1H, d, J = 8.5 Hz), 6.90 (1H, dd, J = 17.7, 11.1 Hz), 6.36 (1H , d, J = 17.6 Hz), 5.77 (1H, d, J = 11.4 Hz), 2.91 (4H, t, J = 4.1 Hz), 2.56-2.52 (4H, m), 2.40 (2H, q, J = 7.3 Hz), 2.33 (3H, s), 1.05 (3H, t, J = 7.2 Hz).

工程２
3-(4-(4-エチルピペラジン-1-イル)-3-メチルフェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 2
3- (4- (4-Ethylpiperazin-1-yl) -3-methylphenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000774
Figure JPOXMLDOC01-appb-C000774

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(4-(4-エチルピペラジン-1-イル)-3-メチルフェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (198 mg, 0.570 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (143 μl, 11.4 μmol) から標記化合物 (141 mg, 71%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.7 Hz), 8.38 (1H, s), 8.35 (1H, dd, J =9.4, 0.9 Hz), 8.06 (1H, dd, J =8.4, 2.2 Hz), 7.98 (1H, d, J =1.6 Hz), 7.63 (1H, d, J = 9.4 Hz), 7.18 (1H, d, J = 8.2 Hz), 2.93 (4H, t, J = 4.4 Hz), 2.58-2.53 (4H, m), 2.41 (2H, q, J =7.2 Hz), 2.35 (3H, s), 1.05 (3H, t, J = 7.2 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 4- (4-Ethylpiperazin-1-yl) -3-methylphenyl) -6-vinylimidazo [1,2-b] pyridazine (198 mg, 0.570 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol ( The title compound (141 mg, 71%) was obtained from 143 μl, 11.4 μmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.7 Hz), 8.38 (1H, s), 8.35 (1H, dd, J = 9.4, 0.9 Hz), 8.06 ( 1H, dd, J = 8.4, 2.2 Hz), 7.98 (1H, d, J = 1.6 Hz), 7.63 (1H, d, J = 9.4 Hz), 7.18 (1H, d, J = 8.2 Hz), 2.93 ( 4H, t, J = 4.4 Hz), 2.58-2.53 (4H, m), 2.41 (2H, q, J = 7.2 Hz), 2.35 (3H, s), 1.05 (3H, t, J = 7.2 Hz).

工程３
5-((3-(4-(4-エチルピペラジン-1-イル)-3-メチルフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１８５) Process 3
5-((3- (4- (4-Ethylpiperazin-1-yl) -3-methylphenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 185)

Figure JPOXMLDOC01-appb-C000775
Figure JPOXMLDOC01-appb-C000775

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(4-(4-エチルピペラジン-1-イル)-3-メチルフェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (123 mg, 0.352 mmol) およびチアゾリジン-2,4-ジオン (41 mg, 0.352 mmol) から標記化合物 (114 mg, 72%) を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 8.22 (1H, d, J = 9.4 Hz), 8.18 (1H, s), 8.12 (1H, d, J = 1.8 Hz), 7.85 (1H, dd, J = 8.4, 1.9 Hz), 7.66 (1H, s), 7.60 (1H, d, J = 9.4 Hz), 7.18 (1H, d, J = 8.5 Hz), 3.05 (4H, s), 2.96 (4H, s), 2.80 (2H, q, J = 7.2 Hz), 2.39 (3H, s), 1.16 (3H, t, J =7.2 Hz).
ESI-MS(m/z): 449[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (4- (4-ethylpiperazin-1-yl) -3-methylphenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (123 mg, 0.352 mmol) and thiazolidine-2,4-dione (41 mg, 0.352 mmol) gave the title compound (114 mg, 72%). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 8.22 (1H, d, J = 9.4 Hz), 8.18 (1H, s), 8.12 (1H, d, J = 1.8 Hz), 7.85 (1H, dd, J = 8.4, 1.9 Hz), 7.66 (1H, s), 7.60 (1H, d, J = 9.4 Hz), 7.18 (1H, d, J = 8.5 Hz), 3.05 (4H, s), 2.96 ( 4H, s), 2.80 (2H, q, J = 7.2 Hz), 2.39 (3H, s), 1.16 (3H, t, J = 7.2 Hz).
ESI-MS (m / z): 449 [M + H] + .

実施例１８６
5-((3-(4-(1-エチルピペリジン-4-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１８６) Example 186
5-((3- (4- (1-Ethylpiperidin-4-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 186)

工程１
tert-ブチル 4-(4-ブロモフェニル)-5,6-ジヒドロピリジン-1(2H)-カルボキシレート Process 1
tert-butyl 4- (4-bromophenyl) -5,6-dihydropyridine-1 (2H) -carboxylate

Figure JPOXMLDOC01-appb-C000776
Figure JPOXMLDOC01-appb-C000776

アルゴン雰囲気下、4-ブロモヨードベンゼン (1.13 g, 4 mmol)、tert-ブチル 4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-5,6-ジヒドロピリジン-1(2H)-カルボキシレート (1.23 g, 4 mmol)、テトラキストリフェニルホスフィンパラジウム (180 mg, 0.16 mmol)、炭酸ナトリウム (1.48 g, 14 mmol) の 水 (3.6 mL)、1,4-ジオキサン(18 mL) 溶液を 110 ℃で一晩撹拌した。反応終了後、反応溶液に飽和重層水を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、ろ過し、減圧下溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (0.73 g, 54%) を得た。1H-NMR (CDCl3) δ: 7.46-7.44 (2H, m), 7.25-7.22 (2H, m), 6.03 (1H, m), 4.07-4.05 (2H, m), 3.64-3.62 (2H, m), 2.50-2.46 (2H, m), 1.49 (9H, s). 4-bromoiodobenzene (1.13 g, 4 mmol), tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5,6 under argon atmosphere -Dihydropyridine-1 (2H) -carboxylate (1.23 g, 4 mmol), tetrakistriphenylphosphine palladium (180 mg, 0.16 mmol), sodium carbonate (1.48 g, 14 mmol) in water (3.6 mL), 1,4 The dioxane (18 mL) solution was stirred at 110 ° C. overnight. Saturated multistory water was added to the reaction solution after completion | finish of reaction, and chloroform extracted. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (0.73 g, 54%). 1 H-NMR (CDCl 3 ) δ: 7.46-7.44 (2H, m), 7.25-7.22 (2H, m), 6.03 (1H, m), 4.07-4.05 (2H, m), 3.64-3.62 (2H, m), 2.50-2.46 (2H, m), 1.49 (9H, s).

工程２
tert-ブチル 4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)-5,6-ジヒドロピリジン-1(2H)-カルボキシレート Process 2
tert-butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -5,6-dihydropyridine-1 (2H) -carboxylate

Figure JPOXMLDOC01-appb-C000777
Figure JPOXMLDOC01-appb-C000777

tert-ブチル 4-(4-ブロモフェニル)-5,6-ジヒドロピリジン-1(2H)-カルボキシレート (0.73 g, 2.17 mmol)、酢酸カリウム (746 mg, 7.6 mmol)、ビス(ピナコラート)ジボロン (661 mg, 2.6 mmol) をジメチルスルホキシド (10 mL) に溶かし、減圧脱気を5回行った。さらに、1,1’-ビスジフェニルホスフィノフェロセンパラジウムジクロリドジクロロメタン錯体 (117 mg, 0.22 mmol) を加え、100℃で終夜攪拌した。冷却後、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物(0.15 g, 18 %) を得た。1H-NMR (CDCl3) δ: 7.77 (1H, d, J = 8.7 Hz), 7.38 (1H, d, J = 8.2 Hz), 6.09 (1H, m), 4.09-4.06 (2H, m), 3.65-3.61 (2H, m), 2.55-2.51 (2H, m), 1.49 (9H, s), 1.34 (12H, s). tert-butyl 4- (4-bromophenyl) -5,6-dihydropyridine-1 (2H) -carboxylate (0.73 g, 2.17 mmol), potassium acetate (746 mg, 7.6 mmol), bis (pinacolato) diboron (661 mg, 2.6 mmol) was dissolved in dimethyl sulfoxide (10 mL), and vacuum degassing was performed 5 times. Furthermore, 1,1′-bisdiphenylphosphinoferrocene palladium dichloride dichloromethane complex (117 mg, 0.22 mmol) was added, and the mixture was stirred at 100 ° C. overnight. After cooling, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.15 g, 18%). 1 H-NMR (CDCl 3 ) δ: 7.77 (1H, d, J = 8.7 Hz), 7.38 (1H, d, J = 8.2 Hz), 6.09 (1H, m), 4.09-4.06 (2H, m), 3.65-3.61 (2H, m), 2.55-2.51 (2H, m), 1.49 (9H, s), 1.34 (12H, s).

工程３
tert-ブチル 4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペリジン-1-カルボキシレート Process 3
tert-butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000778
Figure JPOXMLDOC01-appb-C000778

tert-ブチル 4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)-5,6-ジヒドロピリジン-1(2H)-カルボキシレート (0.15 g, 0.39 mmol)、のテトラヒドロフラン (8 mL) 溶液にパラジウム－活性炭エチレンジアミン複合体 (0.04 g) を加え、水素雰囲気下、室温で24時間撹拌した。反応終了後、反応溶液をろ過し、減圧下溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (0.11 g, 73 %) を得た。1H-NMR (CDCl3) δ: 7.75 (1H, d, J = 8.2 Hz), 7.20 (1H, d, J = 7.9 Hz), 4.26-4.20 (2H, m), 2.82-2.67 (2H, m), 2.65-2.61 (1H, m), 1.83-1.76 (2H, m), 1.67-1.59 (2H, m), 1.47 (9H, s), 1.32 (12H, s). tert-Butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -5,6-dihydropyridine-1 (2H) -carboxylate (0.15 g, 0.39 mmol) in a tetrahydrofuran (8 mL) solution was added palladium-activated carbon ethylenediamine complex (0.04 g), and the mixture was stirred at room temperature for 24 hours in a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.11 g, 73%). 1 H-NMR (CDCl 3 ) δ: 7.75 (1H, d, J = 8.2 Hz), 7.20 (1H, d, J = 7.9 Hz), 4.26-4.20 (2H, m), 2.82-2.67 (2H, m ), 2.65-2.61 (1H, m), 1.83-1.76 (2H, m), 1.67-1.59 (2H, m), 1.47 (9H, s), 1.32 (12H, s).

工程４
tert-ブチル 4-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペリジン-1-カルボキシレート Process 4
tert-butyl 4- (4- (6-chloroimidazo [1,2-b] pyridazin-3-yl) phenyl) piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000779
Figure JPOXMLDOC01-appb-C000779

3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (72 mg, 0.31 mmol)、tert-ブチル 4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペリジン-1-カルボキシレート (0.11 g, 0.28 mmol)、炭酸ナトリウム (106 mg, 1 mmol) を 1,4-ジオキサン (5 mL)、水 (1 mL) の混合溶液に溶かし、減圧脱気を5回行った。さらに、テトラキストリフェニルホスフィンパラジウム (35 mg, 0.03 mmol) を加え、加熱還流下16時間攪拌した。反応液を冷却した後、水を加えて酢酸エチルで2回抽出した。有機層を合わせ飽和食塩水で洗浄した後、硫酸マグネシウムで乾燥した。溶媒を減圧留去した後、得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (0.12 g, 93 %) を得た。1H-NMR (CDCl3) δ: 8.03 (1H, s), 7.97 (2H, d, J = 7.8 Hz), 7.91 (1H, d, J = 9.6 Hz), 7.36 (2H, d, J = 8.2 Hz), 7.12 (1H, d, J = 9.2 Hz), 4.31-4.22 (2H, m), 1.91-1.80 (2H, m), 1.75-1.60 (2H, m), 1.50 (9H, s). 3-Bromo-6-chloroimidazo [1,2-b] pyridazine (72 mg, 0.31 mmol), tert-butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl) phenyl) piperidine-1-carboxylate (0.11 g, 0.28 mmol), sodium carbonate (106 mg, 1 mmol) in 1,4-dioxane (5 mL) and water (1 mL) And was degassed under reduced pressure 5 times. Furthermore, tetrakistriphenylphosphine palladium (35 mg, 0.03 mmol) was added, and the mixture was stirred for 16 hours with heating under reflux. The reaction mixture was cooled, water was added, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.12 g, 93%). 1 H-NMR (CDCl 3 ) δ: 8.03 (1H, s), 7.97 (2H, d, J = 7.8 Hz), 7.91 (1H, d, J = 9.6 Hz), 7.36 (2H, d, J = 8.2 Hz), 7.12 (1H, d, J = 9.2 Hz), 4.31-4.22 (2H, m), 1.91-1.80 (2H, m), 1.75-1.60 (2H, m), 1.50 (9H, s).

工程５
6-クロロ-3-(4-(1-エチルピペリジン-4-イル)フェニル)イミダゾ[1,2-b]ピリダジン Process 5
6-Chloro-3- (4- (1-ethylpiperidin-4-yl) phenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000780
Figure JPOXMLDOC01-appb-C000780

tert-ブチル 4-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペリジン-1-カルボキシレート (0.12 g, 0.29 mmol) を塩化メチレン (2.6 mL) に溶解し、0℃でトリフルオロ酢酸 (0.4 mL) を加え、室温で2時間撹拌した。減圧下溶媒を留去し、得られた残渣をクロロホルムに溶かして飽和重層水、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥させ、溶媒を留去した。得られた残渣をN,N-ジメチルホルムアミド (1 mL) に溶かし、ヨードエタン (47 mg, 0.3 mmol)、炭酸カリウム (55 mg, 0.4 mmol) を加え、室温で3時間撹拌した。反応溶液に水を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、ろ過し、減圧下溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (0.05 g, 51%) を得た。1H-NMR (CDCl3) δ: 8.03 (1H, s), 7.97 (2H, d, J = 8.7 Hz), 7.95 (1H, d, J = 9.2 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.08 (1H, d, J = 9.2 Hz), 3.31-3.27 (2H, m), 2.69-2.62 (3H, m), 2.35-2.24 (2H, m), 2.19-2.04 (2H, m), 1.99-1.93 (2H, m), 1.27 (3H, m). tert-Butyl 4- (4- (6-chloroimidazo [1,2-b] pyridazin-3-yl) phenyl) piperidine-1-carboxylate (0.12 g, 0.29 mmol) in methylene chloride   Dissolved in (2.6 mL), trifluoroacetic acid (0.4 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hr. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in chloroform and washed with saturated multistory water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was dissolved in N, N-dimethylformamide (1 mL), iodoethane (47 mg, 0.3 mmol) and potassium carbonate (55 mg, 0.4 mmol) were added, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction solution and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the target title compound (0.05 g, 51%). 1 H-NMR (CDCl 3 ) δ: 8.03 (1H, s), 7.97 (2H, d, J = 8.7 Hz), 7.95 (1H, d, J = 9.2 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.08 (1H, d, J = 9.2 Hz), 3.31-3.27 (2H, m), 2.69-2.62 (3H, m), 2.35-2.24 (2H, m), 2.19-2.04 (2H, m) , 1.99-1.93 (2H, m), 1.27 (3H, m).

工程６
3-(4-(1-エチルピペリジン-4-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Step 6
3- (4- (1-Ethylpiperidin-4-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000781
Figure JPOXMLDOC01-appb-C000781

アルゴン雰囲気下、6-クロロ-3-(4-(1-エチルピペリジン-4-イル)フェニル)イミダゾ[1,2-b]ピリダジン (0.05 g, 0.15 mmol) の 1,4-ジオキサン (2 mL) 溶液に、酢酸パラジウム (3.4 mg, 0.015 mmol)、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル (12.3 mg, 0.03 mmol)、4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (37 mg, 0.24 mmol) を加え、反応容器内を脱気した後、室温で10分撹拌した。そこへリン酸三カリウム (238 mg, 1.1 mmol) の水溶液 (0.4 mL) を加え、110℃で終夜撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (0.01 g, 20 %) を得た。1H-NMR (CDCl3) δ: 8.04 (2H, d, J = 8.2 Hz), 7.99 (1H, s), 7.96 (1H, d, J = 9.6 Hz), 7.40 (2H, d, J = 8.2 Hz), 7.31 (1H, d, J = 9.6 Hz), 6.91 (1H, dd, J = 17.9, 11.0 Hz), 6.15 (1H, d, J = 17.9 Hz), 5.70 (1H, d, J = 11.0 Hz), 3.48-3.37 (2H, m), 2.88-2.65 (3H, m), 2.57-2.38 (2H, m), 2.36-2.20 (2H, m), 2.05-1.99 (2H, m), 1.37 (3H, m). 6-Chloro-3- (4- (1-ethylpiperidin-4-yl) phenyl) imidazo [1,2-b] pyridazine (0.05 g, 0.15 mmol) in 1,4-dioxane (2 mL under argon atmosphere ) Solution with palladium acetate (3.4 mg, 0.015 mmol), 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (12.3 mg, 0.03 mmol), 4,4,5,5-tetramethyl-2-vinyl -1,3,2-Dioxaborolane (37 mg, 0.24 mmol) was added and the reaction vessel was degassed, followed by stirring at room temperature for 10 minutes. The aqueous solution (0.4 mL) of tripotassium phosphate (238 mg, 1.1 mmol) was added there, and it stirred at 110 degreeC overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.01 g, 20%). 1 H-NMR (CDCl 3 ) δ: 8.04 (2H, d, J = 8.2 Hz), 7.99 (1H, s), 7.96 (1H, d, J = 9.6 Hz), 7.40 (2H, d, J = 8.2 Hz), 7.31 (1H, d, J = 9.6 Hz), 6.91 (1H, dd, J = 17.9, 11.0 Hz), 6.15 (1H, d, J = 17.9 Hz), 5.70 (1H, d, J = 11.0 Hz), 3.48-3.37 (2H, m), 2.88-2.65 (3H, m), 2.57-2.38 (2H, m), 2.36-2.20 (2H, m), 2.05-1.99 (2H, m), 1.37 ( 3H, m).

工程７
3-(4-(1-エチルピペリジン-4-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Step 7
3- (4- (1-Ethylpiperidin-4-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000782
Figure JPOXMLDOC01-appb-C000782

3-(4-(1-エチルピペリジン-4-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (0.01 g, 0.03 mmol) の 1,4-ジオキサン (2.25 mL)、水(0.75 mL) 溶液に、2,6-ルチジン (6.4 mg, 0.06 mmol)、2.5 wt% 四酸化オスミウムtert-ブタノール溶液 (6.2 mg, 0.0006 mmol)、過ヨウ素酸ナトリウム (25.7 mg, 0.12 mmol) を加え、室温で終夜攪拌した。反応液をセライトろ過し、酢酸エチルで洗浄した。ろ液に飽和チオ硫酸ナトリウム水を加えて洗浄し、水層を酢酸エチルで抽出した。有機層を合わせ飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (3 mg, 30%)を得た。1H-NMR (CDCl3) δ: 10.11 (1H, d, J = 0.9 Hz), 8.20 (1H, s), 8.14 (1H, d, J = 9.2 Hz), 8.06 (2H, d, J = 8.2 Hz), 7.69 (1H, d, J = 9.2 Hz), 7.49 (2H, d, J = 8.2 Hz), 3.73-3.69 (2H, m), 3.15-3.10 (2H, m), 2.89-2.69 (5H, m), 2.12-2.08 (2H, m), 1.56 (3H, t, J = 7.3 Hz). 3- (4- (1-ethylpiperidin-4-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (0.01 g, 0.03 mmol) of 1,4-dioxane (2.25 mL), water ( 0.75 mL) 2,6-lutidine (6.4 mg, 0.06 mmol), 2.5 wt% osmium tetroxide tert-butanol solution (6.2 mg, 0.0006 mmol), sodium periodate (25.7 mg, 0.12 mmol) And stirred at room temperature overnight. The reaction solution was filtered through celite and washed with ethyl acetate. The filtrate was washed with a saturated aqueous sodium thiosulfate solution, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (3 mg, 30%). 1 H-NMR (CDCl 3 ) δ: 10.11 (1H, d, J = 0.9 Hz), 8.20 (1H, s), 8.14 (1H, d, J = 9.2 Hz), 8.06 (2H, d, J = 8.2 Hz), 7.69 (1H, d, J = 9.2 Hz), 7.49 (2H, d, J = 8.2 Hz), 3.73-3.69 (2H, m), 3.15-3.10 (2H, m), 2.89-2.69 (5H , m), 2.12-2.08 (2H, m), 1.56 (3H, t, J = 7.3 Hz).

工程８
5-((3-(4-(1-エチルピペリジン-4-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１８６) Process 8
5-((3- (4- (1-Ethylpiperidin-4-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 186)

Figure JPOXMLDOC01-appb-C000783
Figure JPOXMLDOC01-appb-C000783

3-(4-(1-エチルピペリジン-4-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (3 mg, 0.01 mmol)、2,4-チアゾリジンジオン (6 mg, 0.05 mmol)、ピペリジン (2 mg, 0.02 mmol)、酢酸 (2.4 mg, 0.04 mmol) のアセトニトリル (3 mL) 溶液を加熱還流下24時間攪拌した。反応液を冷却した後、溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製して標記化合物 (6 mg, quant.) を得た。1H-NMR (DMSO-D6) δ: 12.51 (1H, br s), 8.25 (1H, d, J = 9.6 Hz), 8.22 (1H, s), 8.10 (2H, d, J = 7.8 Hz), 7.74 (1H, s), 7.63 (1H, d, J = 9.6 Hz), 7.39 (2H, d, J = 7.8 Hz), 3.60-3.50 (2H, m), 3.32-3.20 (2H, m), 3.13-2.88 (5H, m), 2.10-2.05 (2H, m), 1.23 (3H, t, J = 7.3 Hz).
ESI-MS(m/z): 434[M+H]+. 3- (4- (1-Ethylpiperidin-4-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (3 mg, 0.01 mmol), 2,4-thiazolidinedione (6 mg, 0.05 mmol), piperidine (2 mg, 0.02 mmol), and acetic acid (2.4 mg, 0.04 mmol) in acetonitrile (3 mL) were stirred with heating under reflux for 24 hours. After cooling the reaction solution, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (6 mg, quant.). 1 H-NMR (DMSO-D 6 ) δ: 12.51 (1H, br s), 8.25 (1H, d, J = 9.6 Hz), 8.22 (1H, s), 8.10 (2H, d, J = 7.8 Hz) , 7.74 (1H, s), 7.63 (1H, d, J = 9.6 Hz), 7.39 (2H, d, J = 7.8 Hz), 3.60-3.50 (2H, m), 3.32-3.20 (2H, m), 3.13-2.88 (5H, m), 2.10-2.05 (2H, m), 1.23 (3H, t, J = 7.3 Hz).
ESI-MS (m / z): 434 [M + H] + .

実施例１８７
5-((3-(5-((4-メチルピペラジン-1-イル)メチル)チオフェン-2-イル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン(化合物１８７) Example 187
5-((3- (5-((4-methylpiperazin-1-yl) methyl) thiophen-2-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 187)

工程１
1-((5-ブロモチオフェン-2-イル)メチル)-4-メチルピペラジン Process 1
1-((5-Bromothiophen-2-yl) methyl) -4-methylpiperazine

Figure JPOXMLDOC01-appb-C000784
Figure JPOXMLDOC01-appb-C000784

5-ブロモチオフェン-2-カルボアルデヒド (1.14 mL, 10.5 mmol) のジクロロメタン (100 mL) 溶液中に、1-メチルピペラジン (1.15 mL, 10.5 mmol)、酢酸 (599 μL, 10.5 mmol) を室温下添加した。水素化トリアセトキシホウ素ナトリウム (2.88 g, 13.6 mmol) を添加した後、室温で2時間撹拌した。飽和食塩水を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.32 g, 46%) を得た。 1H-NMR (CDCl3) δ: 6.84 (1H, d, J = 3.7 Hz), 6.63 (1H, d, J = 3.7 Hz), 3.61 (2H, s), 2.70-2.38 (8H, m), 2.28 (3H, s). Add 1-methylpiperazine (1.15 mL, 10.5 mmol) and acetic acid (599 μL, 10.5 mmol) to a solution of 5-bromothiophene-2-carbaldehyde (1.14 mL, 10.5 mmol) in dichloromethane (100 mL) at room temperature did. After adding sodium triacetoxyborohydride (2.88 g, 13.6 mmol), the mixture was stirred at room temperature for 2 hours. Saturated brine was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.32 g, 46%). 1 H-NMR (CDCl 3 ) δ: 6.84 (1H, d, J = 3.7 Hz), 6.63 (1H, d, J = 3.7 Hz), 3.61 (2H, s), 2.70-2.38 (8H, m), 2.28 (3H, s).

工程２
6-クロロ-3-(5-((4-メチルピペラジン-1-イル)メチル)チオフェン-2-イル)イミダゾ[1,2-b]ピリダジン Process 2
6-Chloro-3- (5-((4-methylpiperazin-1-yl) methyl) thiophen-2-yl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000785
Figure JPOXMLDOC01-appb-C000785

1-((5-ブロモチオフェン-2-イル)メチル)-4-メチルピペラジン(1.00 g, 3.63 mmol) のテトラヒドロフラン (30 mL) 溶液中に、n-ブチルリチウム ヘキサン溶液 (1.6 N, 2.5 mL, 4.00 mmol) をアルゴン雰囲気下、-78℃で滴下した。30分撹拌した後、4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン (0.88 mL, 4.36 mmol) をゆっくり滴下した。室温下3時間撹拌した後、減圧下濃縮した。残渣物の 1,4-ジオキサン (40 mL)、水 (6 mL) 混合溶液中に3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (837 mg, 3.6 mmol)、テトラキストリフェニルホスフィンパラジウム (166 mg, 0.14 mmol)、炭酸ナトリウム (1.34 g, 12.6 mmol) を添加した。アルゴン置換した後、還流条件下、一晩撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。減圧下、濃縮乾固し、粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (796 mg, 64%) を得た。 1H-NMR (CDCl3) δ: 7.99 (1H, s), 7.91 (1H, d, J = 9.6 Hz), 7.67 (1H, d, J = 3.7 Hz), 7.04 (1H, d, J = 9.6 Hz), 6.96 (1H, d, J = 3.7 Hz), 3.76 (2H, s), 2.69-2.46 (8H, m), 2.33 (3H, s).
ESI-MS(m/z): 348[M+H]+. In a solution of 1-((5-bromothiophen-2-yl) methyl) -4-methylpiperazine (1.00 g, 3.63 mmol) in tetrahydrofuran (30 mL), n-butyllithium hexane solution (1.6 N, 2.5 mL, 4.00 mmol) was added dropwise at -78 ° C under an argon atmosphere. After stirring for 30 minutes, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.88 mL, 4.36 mmol) was slowly added dropwise. After stirring at room temperature for 3 hours, the mixture was concentrated under reduced pressure. 3-Bromo-6-chloroimidazo [1,2-b] pyridazine (837 mg, 3.6 mmol), tetrakistriphenylphosphine in a mixed solution of the residue 1,4-dioxane (40 mL) and water (6 mL) Palladium (166 mg, 0.14 mmol) and sodium carbonate (1.34 g, 12.6 mmol) were added. After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The mixture was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (796 mg, 64%). 1 H-NMR (CDCl 3 ) δ: 7.99 (1H, s), 7.91 (1H, d, J = 9.6 Hz), 7.67 (1H, d, J = 3.7 Hz), 7.04 (1H, d, J = 9.6 Hz), 6.96 (1H, d, J = 3.7 Hz), 3.76 (2H, s), 2.69-2.46 (8H, m), 2.33 (3H, s).
ESI-MS (m / z): 348 [M + H] + .

工程３
3-(5-((4-メチルピペラジン-1-イル)メチル)チオフェン-2-イル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 3
3- (5-((4-Methylpiperazin-1-yl) methyl) thiophen-2-yl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000786
Figure JPOXMLDOC01-appb-C000786

6-クロロ-3-(5-((4-メチルピペラジン-1-イル)メチル)チオフェン-2-イル)イミダゾ[1,2-b]ピリダジン(796 mg, 2.29 mmol) の 1,4-ジオキサン(40 mL)、水 (6 mL) の混合溶液中に4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (470 μL, 2.75 mmol)、酢酸パラジウム (51 mg, 0.23 mmol)、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル (188 mg, 0.46 mmol)、リン酸三カリウム (3.64 g, 17.2 mmol) を添加した。アルゴン置換した後、還流条件下6時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (674 mg, 87%) を得た。 1H-NMR (DMSO-D6) δ: 8.21 (1H, s), 8.19 (1H, d, J = 9.2 Hz), 7.73 (1H, d, J = 3.7 Hz), 7.63 (1H, d, J = 9.2 Hz), 7.04 (1H, d, J = 3.7 Hz), 6.94 (1H, dd, J = 17.4, 11.0 Hz), 6.43 (1H, d, J = 17.4 Hz), 5.80 (1H, d, J = 11.0 Hz), 3.72 (2H, s), 2.50-2.24 (8H, m), 2.15 (3H, s).
ESI-MS(m/z): 340[M+H]+. 6-Chloro-3- (5-((4-methylpiperazin-1-yl) methyl) thiophen-2-yl) imidazo [1,2-b] pyridazine (796 mg, 2.29 mmol) of 1,4-dioxane (40 mL), water (6 mL) in a mixed solution 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (470 μL, 2.75 mmol), palladium acetate (51 mg , 0.23 mmol), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (188 mg, 0.46 mmol), tripotassium phosphate (3.64 g, 17.2 mmol) were added. After replacing with argon, the mixture was stirred for 6 hours under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (674 mg, 87%). 1 H-NMR (DMSO-D 6 ) δ: 8.21 (1H, s), 8.19 (1H, d, J = 9.2 Hz), 7.73 (1H, d, J = 3.7 Hz), 7.63 (1H, d, J = 9.2 Hz), 7.04 (1H, d, J = 3.7 Hz), 6.94 (1H, dd, J = 17.4, 11.0 Hz), 6.43 (1H, d, J = 17.4 Hz), 5.80 (1H, d, J = 11.0 Hz), 3.72 (2H, s), 2.50-2.24 (8H, m), 2.15 (3H, s).
ESI-MS (m / z): 340 [M + H] + .

工程４
3-(5-((4-メチルピペラジン-1-イル)メチル)チオフェン-2-イル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 4
3- (5-((4-Methylpiperazin-1-yl) methyl) thiophen-2-yl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000787
Figure JPOXMLDOC01-appb-C000787

3-(5-((4-メチルピペラジン-1-イル)メチル)チオフェン-2-イル)-6-ビニルイミダゾ[1,2-b]ピリダジン (674 mg, 1.99 mmol) の 1,4-ジオキサン (20 mL)、水 (4 mL) の混合溶液中に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (499 μL, 0.04 mmol)、2,6-ルチジン (463 μL, 3.97 mmol)、過ヨウ素酸ナトリウム (1.70 g, 7.94 mmol) を添加した。アルゴン置換した後、室温で5時間撹拌した。反応終了後、セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (88 mg, 13%) を得た。 1H-NMR (DMSO-D6) δ: 10.08 (1H, s), 8.45 (1H, s), 8.38 (1H, d, J = 9.2 Hz), 7.86 (1H, d, J = 3.7 Hz), 7.66 (1H, d, J = 9.2 Hz), 7.11 (1H, d, J = 3.7 Hz), 3.74 (2H, s), 2.49-2.26 (8H, m), 2.16 (3H, s).
ESI-MS(m/z): 342[M+H]+. 3- (5-((4-Methylpiperazin-1-yl) methyl) thiophen-2-yl) -6-vinylimidazo [1,2-b] pyridazine (674 mg, 1.99 mmol) of 1,4-dioxane (20 mL) and water (4 mL) in a mixed solution of 2.5 wt% osmium tetroxide tert-butanol (499 μL, 0.04 mmol), 2,6-lutidine (463 μL, 3.97 mmol), periodic acid Sodium (1.70 g, 7.94 mmol) was added. After purging with argon, the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the mixture was filtered through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (88 mg, 13%). 1 H-NMR (DMSO-D 6 ) δ: 10.08 (1H, s), 8.45 (1H, s), 8.38 (1H, d, J = 9.2 Hz), 7.86 (1H, d, J = 3.7 Hz), 7.66 (1H, d, J = 9.2 Hz), 7.11 (1H, d, J = 3.7 Hz), 3.74 (2H, s), 2.49-2.26 (8H, m), 2.16 (3H, s).
ESI-MS (m / z): 342 [M + H] + .

工程５
5-((3-(5-((4-メチルピペラジン-1-イル)メチル)チオフェン-2-イル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン(化合物１８７) Process 5
5-((3- (5-((4-methylpiperazin-1-yl) methyl) thiophen-2-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 187)

Figure JPOXMLDOC01-appb-C000788
Figure JPOXMLDOC01-appb-C000788

3-(5-((4-メチルピペラジン-1-イル)メチル)チオフェン-2-イル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (88 mg, 0.26 mmol) をアセトニトリル (3 mL) に溶かし、チアゾリジン-2,4-ジオン (30 mg, 0.26 mmol)、ピペリジン (5.1 μL, 0.05 mmol)、および酢酸 (5.9 μL, 0.10 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (14.4 μl, 0.10 mmol) を添加した後、ろ過しアセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (50 mg, 44%) を得た。 1H-NMR (DMSO-D6) δ: 8.22 (1H, s), 8.20 (1H, d, J = 9.6 Hz), 7.79 (1H, d, J = 3.7 Hz), 7.56 (1H, d, J = 9.6 Hz), 7.53 (1H, s), 7.11 (1H, d, J = 3.7 Hz), 3.85 (2H, s), 3.40-3.25 (4H, m), 3.09-2.92 (4H, m), 2.62 (3H, s).
ESI-MS(m/z): 441[M+H]+. 3- (5-((4-Methylpiperazin-1-yl) methyl) thiophen-2-yl) imidazo [1,2-b] pyridazine-6-carbaldehyde (88 mg, 0.26 mmol) in acetonitrile (3 mL ), Thiazolidine-2,4-dione (30 mg, 0.26 mmol), piperidine (5.1 μL, 0.05 mmol), and acetic acid (5.9 μL, 0.10 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (14.4 μl, 0.10 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (50 mg, 44%). 1 H-NMR (DMSO-D 6 ) δ: 8.22 (1H, s), 8.20 (1H, d, J = 9.6 Hz), 7.79 (1H, d, J = 3.7 Hz), 7.56 (1H, d, J = 9.6 Hz), 7.53 (1H, s), 7.11 (1H, d, J = 3.7 Hz), 3.85 (2H, s), 3.40-3.25 (4H, m), 3.09-2.92 (4H, m), 2.62 (3H, s).
ESI-MS (m / z): 441 [M + H] + .

実施例１８８
5-((3-(4-(4-エチル-2,3-ジオキソピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１８８) Example 188
5-((3- (4- (4-Ethyl-2,3-dioxopiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 188)

工程１
1-(4-ブロモフェニル)-4-エチルピペラジン-2,3-ジオン Process 1
1- (4-Bromophenyl) -4-ethylpiperazine-2,3-dione

Figure JPOXMLDOC01-appb-C000789
Figure JPOXMLDOC01-appb-C000789

1-ブロモ-4-ヨードベンゼン (2 g, 7.07 mmol)、1-エチルピペラジン-2,3-ジオン (0.91 g, 6.43 mmol)、ヨウ化銅（I） (61 mg, 0.32 mmol)、リン酸三カリウム (2.73 g, 12.85 mmol) のN,N-ジメチルホルムアミド (30 mL) 溶液中に、N,N'-ジメチルエチレンジアミン (69 μL, 0.64 mmol) を室温で滴下した。アルゴン置換した後、90℃で一晩撹拌した。室温に放冷した後、セライトろ過し、減圧下濃縮した。飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (357 mg, 19%) を得た。 1H-NMR (CDCl3) δ: 7.54 (2H, d, J = 8.7 Hz), 7.25 (2H, d, J = 8.7 Hz), 3.97-3.94 (2H, m), 3.70-3.67 (2H, m), 3.61 (2H, q, J = 7.3 Hz), 1.25 (3H, t, J = 7.3 Hz).
ESI-MS(m/z): 297[M+H]+. 1-bromo-4-iodobenzene (2 g, 7.07 mmol), 1-ethylpiperazine-2,3-dione (0.91 g, 6.43 mmol), copper (I) iodide (61 mg, 0.32 mmol), phosphoric acid N, N′-dimethylethylenediamine (69 μL, 0.64 mmol) was added dropwise at room temperature to a solution of tripotassium (2.73 g, 12.85 mmol) in N, N-dimethylformamide (30 mL). After purging with argon, the mixture was stirred at 90 ° C. overnight. The mixture was allowed to cool to room temperature, filtered through celite, and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (357 mg, 19%). 1 H-NMR (CDCl 3 ) δ: 7.54 (2H, d, J = 8.7 Hz), 7.25 (2H, d, J = 8.7 Hz), 3.97-3.94 (2H, m), 3.70-3.67 (2H, m ), 3.61 (2H, q, J = 7.3 Hz), 1.25 (3H, t, J = 7.3 Hz).
ESI-MS (m / z): 297 [M + H] + .

工程２
1-エチル-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-2,3-ジオン Process 2
1-ethyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-2,3-dione

Figure JPOXMLDOC01-appb-C000790
Figure JPOXMLDOC01-appb-C000790

1-(4-ブロモフェニル)-4-エチルピペラジン-2,3-ジオン (357 mg, 1.20 mmol)、酢酸カリウム (354 mg, 3.60 mmol) の 1,4-ジオキサン (30 mL) 溶液にビス(ピナコラート)ジボロン (336 mg, 1.30 mmol)、1,1′-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド-ジクロロメタン錯体 (98 mg, 0.12 mmol) を添加した。アルゴン置換した後、90℃で一晩撹拌した。反応終了後、セライトろ過し、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (360 mg, 87%) を得た。 1H-NMR (DMSO-D6) δ: 7.71 (2H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz), 3.97-3.94 (2H, m), 3.70-3.64 (2H, m), 3.44 (2H, q, J = 7.2 Hz), 1.30 (12H, s), 1.12 (3H, t, J = 7.1 Hz).
ESI-MS(m/z): 345[M+H]+. 1- (4-Bromophenyl) -4-ethylpiperazine-2,3-dione (357 mg, 1.20 mmol), potassium acetate (354 mg, 3.60 mmol) in 1,4-dioxane (30 mL) solution in bis ( Pinacolato) diboron (336 mg, 1.30 mmol), 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (98 mg, 0.12 mmol) were added. After purging with argon, the mixture was stirred at 90 ° C. overnight. After completion of the reaction, the mixture was filtered through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (360 mg, 87%). 1 H-NMR (DMSO-D 6 ) δ: 7.71 (2H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz), 3.97-3.94 (2H, m), 3.70-3.64 (2H , m), 3.44 (2H, q, J = 7.2 Hz), 1.30 (12H, s), 1.12 (3H, t, J = 7.1 Hz).
ESI-MS (m / z): 345 [M + H] + .

工程３
1-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)-4-エチルピペラジン-2,3-ジオン Process 3
1- (4- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) phenyl) -4-ethylpiperazine-2,3-dione

Figure JPOXMLDOC01-appb-C000791
Figure JPOXMLDOC01-appb-C000791

3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (243 mg, 1.05 mmol) の 1,4-ジオキサン (20 mL)、水(3 mL) の混合溶液中に、1-エチル-4-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-2,3-ジオン (360 mg, 1.05 mmol)、テトラキストリフェニルホスフィンパラジウム (48 mg, 0.04 mmol)、炭酸ナトリウム (388 mg, 3.66 mmol) を添加した。アルゴン置換した後、還流条件下一晩撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (263 mg, 68%) を得た。
1H-NMR (DMSO-D6) δ: 8.36-8.30 (2H, m), 8.13 (2H, d, J = 8.7 Hz), 7.59 (2H, d, J = 8.7 Hz), 7.44 (1H, d, J = 9.4 Hz), 4.04-4.01 (2H, m), 3.73-3.71 (2H, m), 3.47 (2H, q, J = 7.3 Hz), 1.15 (3H, t, J = 7.3 Hz). 3-Bromo-6-chloroimidazo [1,2-b] pyridazine (243 mg, 1.05 mmol) in 1,4-dioxane (20 mL) and water (3 mL) in a mixed solution of 1-ethyl-4 -(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-2,3-dione (360 mg, 1.05 mmol), tetrakistriphenylphosphine palladium (48 mg, 0.04 mmol) and sodium carbonate (388 mg, 3.66 mmol) were added. After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (263 mg, 68%).
1 H-NMR (DMSO-D 6 ) δ: 8.36-8.30 (2H, m), 8.13 (2H, d, J = 8.7 Hz), 7.59 (2H, d, J = 8.7 Hz), 7.44 (1H, d , J = 9.4 Hz), 4.04-4.01 (2H, m), 3.73-3.71 (2H, m), 3.47 (2H, q, J = 7.3 Hz), 1.15 (3H, t, J = 7.3 Hz).

工程４
1-エチル-4-(4-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-2,3-ジオン Process 4
1-ethyl-4- (4- (6-vinylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazine-2,3-dione

Figure JPOXMLDOC01-appb-C000792
Figure JPOXMLDOC01-appb-C000792

1-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)-4-エチルピペラジン-2,3-ジオン (263 mg, 0.71 mmol) の 1,4-ジオキサン (20 mL)、水(3 mL) の混合溶液中に 4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (146 μL, 0.85 mmol)、酢酸パラジウム (16 mg, 0.07 mmol)、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル (58 mg, 0.46 mmol)、リン酸三カリウム (1.13 g, 5.33 mmol) を添加した。アルゴン置換した後、還流条件下6時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (162 mg, 63%) を得た。 1H-NMR (DMSO-D6) δ: 8.33-8.18 (5H, m), 7.57 (2H, d, J = 6.9 Hz), 6.93 (1H, dd, J = 17.9, 11.0 Hz), 6.39 (1H, d, J = 17.9 Hz), 5.79 (1H, d, J = 11.0 Hz), 4.02 (2H, t, J = 6.6 Hz), 3.72 (2H, t, J = 6.6 Hz), 3.47 (2H, q, J = 7.0 Hz), 1.15 (3H, t, J = 7.0 Hz).
ESI-MS(m/z): 362[M+H]+. 1- (4- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) phenyl) -4-ethylpiperazine-2,3-dione (263 mg, 0.71 mmol) of 1,4-dioxane ( 20 mL) and water (3 mL) in a mixed solution of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (146 μL, 0.85 mmol), palladium acetate (16 mg, 0.07 mmol), 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (58 mg, 0.46 mmol), tripotassium phosphate (1.13 g, 5.33 mmol) were added. After replacing with argon, the mixture was stirred for 6 hours under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (162 mg, 63%). 1 H-NMR (DMSO-D 6 ) δ: 8.33-8.18 (5H, m), 7.57 (2H, d, J = 6.9 Hz), 6.93 (1H, dd, J = 17.9, 11.0 Hz), 6.39 (1H , d, J = 17.9 Hz), 5.79 (1H, d, J = 11.0 Hz), 4.02 (2H, t, J = 6.6 Hz), 3.72 (2H, t, J = 6.6 Hz), 3.47 (2H, q , J = 7.0 Hz), 1.15 (3H, t, J = 7.0 Hz).
ESI-MS (m / z): 362 [M + H] + .

工程５
3-(4-(4-エチル-2,3-ジオキソピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 5
3- (4- (4-Ethyl-2,3-dioxopiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000793
Figure JPOXMLDOC01-appb-C000793

1-エチル-4-(4-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-2,3-ジオン (162 mg, 0.45 mmol) の 1,4-ジオキサン (5 mL)、水 (1 mL) の混合溶液中に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (113 μL, 8.97 μmol)、2,6-ルチジン (104 μL, 0.89 mmol)、過ヨウ素酸ナトリウム (384 mg, 1.79 mmol) を添加した。アルゴン置換した後、室温で5時間撹拌した。反応終了後、セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (55 mg, 34%) を得た。 1H-NMR (DMSO-D6) δ: 10.07 (1H, s), 8.51 (1H, s), 8.40 (1H, d, J = 9.6 Hz), 8.29 (2H, d, J = 9.2 Hz), 7.69 (1H, d, J = 9.6 Hz), 7.61 (2H, d, J = 9.2 Hz), 4.05-4.02 (2H, m), 3.74-3.71 (2H, m), 3.47 (2H, q, J = 7.2 Hz), 1.15 (3H, t, J = 7.2 Hz).
ESI-MS(m/z): 364[M+H]+. 1-ethyl-4- (4- (6-vinylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazine-2,3-dione (162 mg, 0.45 mmol) of 1,4-dioxane ( 5 wt.), Water (1 mL), 2.5 wt% osmium tetroxide tert-butanol solution (113 μL, 8.97 μmol), 2,6-lutidine (104 μL, 0.89 mmol), sodium periodate (384 mg, 1.79 mmol) was added. After purging with argon, the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the mixture was filtered through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (55 mg, 34%). 1 H-NMR (DMSO-D 6 ) δ: 10.07 (1H, s), 8.51 (1H, s), 8.40 (1H, d, J = 9.6 Hz), 8.29 (2H, d, J = 9.2 Hz), 7.69 (1H, d, J = 9.6 Hz), 7.61 (2H, d, J = 9.2 Hz), 4.05-4.02 (2H, m), 3.74-3.71 (2H, m), 3.47 (2H, q, J = 7.2 Hz), 1.15 (3H, t, J = 7.2 Hz).
ESI-MS (m / z): 364 [M + H] + .

工程６
5-((3-(4-(4-エチル-2,3-ジオキソピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１８８) Step 6
5-((3- (4- (4-Ethyl-2,3-dioxopiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione (Compound 188)

Figure JPOXMLDOC01-appb-C000794
Figure JPOXMLDOC01-appb-C000794

3-(4-(4-エチル-2,3-ジオキソピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (55 mg, 0.15 mmol) をアセトニトリル (2 mL) に溶かし、チアゾリジン-2,4-ジオン (18 mg, 0.15 mmol)、ピペリジン (3.0 μL, 0.03 mmol)、および酢酸 (3.5 μL, 0.06 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (8.4 μL, 0.06 mmol) を添加した後、ろ過しアセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (24 mg, 34%) を得た。1H-NMR (DMSO-D6) δ: 8.34 (1H, d, J = 9.6 Hz), 8.33 (1H, s), 8.17 (2H, d, J = 9.2 Hz), 7.93 (1H, s), 7.73 (1H, d, J = 9.6 Hz), 7.61 (2H, d, J = 9.2 Hz), 4.08-4.01 (2H, m), 3.76-3.70 (2H, m), 3.47 (2H, q, J = 7.3 Hz), 1.15 (3H, t, J = 7.3 Hz).
ESI-MS(m/z): 463[M+H]+. 3- (4- (4-Ethyl-2,3-dioxopiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (55 mg, 0.15 mmol) in acetonitrile (2 mL ), Thiazolidine-2,4-dione (18 mg, 0.15 mmol), piperidine (3.0 μL, 0.03 mmol), and acetic acid (3.5 μL, 0.06 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (8.4 μL, 0.06 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (24 mg, 34%). 1 H-NMR (DMSO-D 6 ) δ: 8.34 (1H, d, J = 9.6 Hz), 8.33 (1H, s), 8.17 (2H, d, J = 9.2 Hz), 7.93 (1H, s), 7.73 (1H, d, J = 9.6 Hz), 7.61 (2H, d, J = 9.2 Hz), 4.08-4.01 (2H, m), 3.76-3.70 (2H, m), 3.47 (2H, q, J = 7.3 Hz), 1.15 (3H, t, J = 7.3 Hz).
ESI-MS (m / z): 463 [M + H] + .

実施例１８９
5-((3-(4-(4-メチル-2-オキソピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１８９) Example 189
5-((3- (4- (4-Methyl-2-oxopiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 189)

工程１
1-(4-ブロモフェニル)-4-メチルピペラジン-2-オン Process 1
1- (4-Bromophenyl) -4-methylpiperazin-2-one

Figure JPOXMLDOC01-appb-C000795
Figure JPOXMLDOC01-appb-C000795

1-ブロモ-4-ヨードベンゼン (2.73 g, 9.64 mmol)、4-メチルピペラジン-2-オン (1.00 g, 8.76 mmol)、ヨウ化銅（I） (83 mg, 0.44 mmol)、リン酸三カリウム (3.72 g, 17.5 mmol) の N,N-ジメチルホルムアミド (40 mL) 溶液中に、N,N'-ジメチルエチレンジアミン (94 μL, 0.64 mmol) を室温で滴下した。アルゴン置換した後、90℃で2日撹拌した。室温に放冷した後、セライトろ過し、減圧下濃縮した。飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.38 g, 59%) を得た。 1H-NMR (CDCl3) δ: 7.52 (2H, d, J = 9.0 Hz), 7.19 (2H, d, J = 9.0 Hz), 3.74-3.68 (2H, m), 3.31-3.27 (2H, m), 2.85-2.78 (2H, m), 2.42 (3H, br s).
ESI-MS(m/z): 269[M+H]+. 1-bromo-4-iodobenzene (2.73 g, 9.64 mmol), 4-methylpiperazin-2-one (1.00 g, 8.76 mmol), copper (I) iodide (83 mg, 0.44 mmol), tripotassium phosphate N, N′-dimethylethylenediamine (94 μL, 0.64 mmol) was added dropwise at room temperature to a solution of (3.72 g, 17.5 mmol) in N, N-dimethylformamide (40 mL). After replacing with argon, the mixture was stirred at 90 ° C. for 2 days. The mixture was allowed to cool to room temperature, filtered through celite, and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.38 g, 59%). 1 H-NMR (CDCl 3 ) δ: 7.52 (2H, d, J = 9.0 Hz), 7.19 (2H, d, J = 9.0 Hz), 3.74-3.68 (2H, m), 3.31-3.27 (2H, m ), 2.85-2.78 (2H, m), 2.42 (3H, br s).
ESI-MS (m / z): 269 [M + H] + .

工程２
4-メチル-1-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-2-オン Process 2
4-Methyl-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazin-2-one

Figure JPOXMLDOC01-appb-C000796
Figure JPOXMLDOC01-appb-C000796

1-(4-ブロモフェニル)-4-メチルピペラジン-2-オン (1.38 g, 5.10 mmol)、酢酸カリウム (1.51 g, 15.4 mmol) の 1,4-ジオキサン (50 mL) 溶液にビス(ピナコラート)ジボロン (1.43 g, 5.70 mmol)、1,1′-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド-ジクロロメタン錯体 (419 mg, 0.50 mmol) を添加した。アルゴン置換した後、90℃で一晩撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、目的とする標記化合物 (1.62 g, quant.) を得た。 1H-NMR (DMSO-D6) δ: 7.68 (2H, d, J = 8.2 Hz), 7.36 (2H, d, J = 8.2 Hz), 3.93 (2H, s), 3.66 (2H, t, J = 5.3 Hz), 2.72 (2H, t, J = 5.3 Hz), 2.28 (3H, s), 1.07 (12H, s).
ESI-MS(m/z): 317[M+H]+. 1- (4-Bromophenyl) -4-methylpiperazin-2-one (1.38 g, 5.10 mmol), potassium acetate (1.51 g, 15.4 mmol) in 1,4-dioxane (50 mL) solution in bis (pinacolato) Diboron (1.43 g, 5.70 mmol), 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (419 mg, 0.50 mmol) was added. After purging with argon, the mixture was stirred at 90 ° C. overnight. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the desired title compound (1.62 g, quant.). 1 H-NMR (DMSO-D 6 ) δ: 7.68 (2H, d, J = 8.2 Hz), 7.36 (2H, d, J = 8.2 Hz), 3.93 (2H, s), 3.66 (2H, t, J = 5.3 Hz), 2.72 (2H, t, J = 5.3 Hz), 2.28 (3H, s), 1.07 (12H, s).
ESI-MS (m / z): 317 [M + H] + .

工程３
1-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)-4-メチルピペラジン-2-オン Process 3
1- (4- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) phenyl) -4-methylpiperazin-2-one

Figure JPOXMLDOC01-appb-C000797
Figure JPOXMLDOC01-appb-C000797

3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (1.32 g, 5.66 mmol) の 1,4-ジオキサン (60 mL)、水(10 mL) の混合溶液中に、4-メチル-1-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-2-オン (1.79 mg, 5.66 mmol)、テトラキストリフェニルホスフィンパラジウム (262 mg, 0.23 mmol)、炭酸ナトリウム (2.10 g, 19.8 mmol) を添加した。アルゴン置換した後、還流条件下一晩撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (1.84 g, 95%) を得た。 1H-NMR (DMSO-D6) δ: 8.33 (1H, s), 8.31 (1H, d, J = 9.6 Hz), 8.10 (2H, d, J = 8.7 Hz), 7.53 (2H, d, J = 8.7 Hz), 7.43 (1H, d, J = 9.6 Hz), 3.94 (2H, s), 3.73 (2H, t, J = 5.5 Hz), 2.76 (2H, t, J = 5.5 Hz), 2.30 (3H, s).
ESI-MS(m/z): 342[M+H]+. In a mixed solution of 3-bromo-6-chloroimidazo [1,2-b] pyridazine (1.32 g, 5.66 mmol) in 1,4-dioxane (60 mL) and water (10 mL), 4-methyl-1 -(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazin-2-one (1.79 mg, 5.66 mmol), tetrakistriphenylphosphine palladium (262 mg, 0.23 mmol) and sodium carbonate (2.10 g, 19.8 mmol) were added. After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (1.84 g, 95%). 1 H-NMR (DMSO-D 6 ) δ: 8.33 (1H, s), 8.31 (1H, d, J = 9.6 Hz), 8.10 (2H, d, J = 8.7 Hz), 7.53 (2H, d, J = 8.7 Hz), 7.43 (1H, d, J = 9.6 Hz), 3.94 (2H, s), 3.73 (2H, t, J = 5.5 Hz), 2.76 (2H, t, J = 5.5 Hz), 2.30 ( 3H, s).
ESI-MS (m / z): 342 [M + H] + .

工程４
4-メチル-1-(4-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-2-オン Process 4
4-Methyl-1- (4- (6-vinylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazin-2-one

Figure JPOXMLDOC01-appb-C000798
Figure JPOXMLDOC01-appb-C000798

1-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)-4-メチルピペラジン-2-オン(1.84 g, 5.37 mmol) の 1,4-ジオキサン(100 mL)、水 (16 mL) の混合溶液中に4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (1.10 mL, 5.91 mmol)、酢酸パラジウム (121 mg, 0.54 mmol)、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル (441 mg, 1.07 mmol)、リン酸三カリウム (8.55 g, 40.3 mmol) を添加した。アルゴン置換した後、還流条件下6時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (457 mg, 26%) を得た。 1H-NMR (DMSO-D6) δ: 8.24 (1H, s), 8.23-8.16 (3H, m), 7.68 (1H, d, J = 9.6 Hz), 7.50 (2H, d, J = 8.7 Hz), 6.92 (1H, dd, J = 17.9, 11.0 Hz), 6.38 (1H, d, J = 17.9 Hz), 5.78 (1H, d, J = 11.0 Hz), 3.73 (2H, t, J = 5.5 Hz), 3.15 (2H, s), 2.75 (2H, t, J = 5.5 Hz), 2.30 (3H, s).
ESI-MS(m/z): 334[M+H]+. 1- (4- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) phenyl) -4-methylpiperazin-2-one (1.84 g, 5.37 mmol) of 1,4-dioxane (100 mL ), Water (16 mL) in a mixed solution of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.10 mL, 5.91 mmol), palladium acetate (121 mg, 0.54 mmol) ), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (441 mg, 1.07 mmol), and tripotassium phosphate (8.55 g, 40.3 mmol) were added. After replacing with argon, the mixture was stirred for 6 hours under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (457 mg, 26%). 1 H-NMR (DMSO-D 6 ) δ: 8.24 (1H, s), 8.23-8.16 (3H, m), 7.68 (1H, d, J = 9.6 Hz), 7.50 (2H, d, J = 8.7 Hz ), 6.92 (1H, dd, J = 17.9, 11.0 Hz), 6.38 (1H, d, J = 17.9 Hz), 5.78 (1H, d, J = 11.0 Hz), 3.73 (2H, t, J = 5.5 Hz ), 3.15 (2H, s), 2.75 (2H, t, J = 5.5 Hz), 2.30 (3H, s).
ESI-MS (m / z): 334 [M + H] + .

工程５
3-(4-(4-メチル-2-オキソピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 5
3- (4- (4-Methyl-2-oxopiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000799
Figure JPOXMLDOC01-appb-C000799

4-メチル-1-(4-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-2-オン (457 mg, 1.37 mmol) の 1,4-ジオキサン (15 mL)、水 (3 mL) の混合溶液中に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (344 μL, 0.03 mmol)、2,6-ルチジン (319 μL, 2.74 mmol)、過ヨウ素酸ナトリウム (1.17 g, 5.48 mmol) を添加した。アルゴン置換した後、室温で6時間撹拌した。反応終了後、セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (122 mg, 27%) を得た。 1H-NMR (DMSO-D6) δ: 10.06 (1H, d, J = 0.9 Hz), 8.49 (1H, s), 8.39 (1H, dd, J = 9.6, 0.9 Hz), 8.24 (2H, d, J = 8.7 Hz), 7.68 (1H, d, J = 9.6 Hz), 7.55 (2H, d, J = 8.7 Hz), 3.75 (2H, t, J = 5.3 Hz), 3.15 (2H, s), 2.76 (2H, t, J = 5.3 Hz), 2.31 (3H, s).
ESI-MS(m/z): 336[M+H]+. 4-methyl-1- (4- (6-vinylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazin-2-one (457 mg, 1.37 mmol) of 1,4-dioxane (15 mL ), Water (3 mL), 2.5 wt% osmium tetroxide tert-butanol solution (344 μL, 0.03 mmol), 2,6-lutidine (319 μL, 2.74 mmol), sodium periodate (1.17 g, 5.48 mmol) was added. After replacing with argon, the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the mixture was filtered through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (122 mg, 27%). 1 H-NMR (DMSO-D 6 ) δ: 10.06 (1H, d, J = 0.9 Hz), 8.49 (1H, s), 8.39 (1H, dd, J = 9.6, 0.9 Hz), 8.24 (2H, d , J = 8.7 Hz), 7.68 (1H, d, J = 9.6 Hz), 7.55 (2H, d, J = 8.7 Hz), 3.75 (2H, t, J = 5.3 Hz), 3.15 (2H, s), 2.76 (2H, t, J = 5.3 Hz), 2.31 (3H, s).
ESI-MS (m / z): 336 [M + H] + .

工程６
5-((3-(4-(4-メチル-2-オキソピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１８９)  Step 6
5-((3- (4- (4-Methyl-2-oxopiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 189)

Figure JPOXMLDOC01-appb-C000800
Figure JPOXMLDOC01-appb-C000800

3-(4-(4-メチル-2-オキソピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (122 mg, 0.36 mmol) をアセトニトリル (4 mL) に溶かし、チアゾリジン-2,4-ジオン (43 mg, 0.36mmol)、ピペリジン (7.2 μL, 0.07 mmol)、および酢酸 (8.3 μL, 0.15 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (20.0 μL, 0.15 mmol) を添加した後、ろ過しアセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (24 mg, 34%) を得た。 1H-NMR (DMSO-D6) δ: 8.33 (1H, d, J = 9.2 Hz), 8.31 (1H, s), 8.14 (2H, d, J = 8.7 Hz), 7.91 (1H, s), 7.73 (1H, d, J = 9.2 Hz), 7.54 (2H, d, J = 8.7 Hz), 3.77 (2H, t, J = 5.3 Hz), 3.21 (2H, s), 2.82 (2H, t, J = 5.3 Hz), 2.34 (3H, s).
ESI-MS(m/z): 435[M+H]+. 3- (4- (4-Methyl-2-oxopiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (122 mg, 0.36 mmol) was dissolved in acetonitrile (4 mL). , Thiazolidine-2,4-dione (43 mg, 0.36 mmol), piperidine (7.2 μL, 0.07 mmol), and acetic acid (8.3 μL, 0.15 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (20.0 μL, 0.15 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (24 mg, 34%). 1 H-NMR (DMSO-D 6 ) δ: 8.33 (1H, d, J = 9.2 Hz), 8.31 (1H, s), 8.14 (2H, d, J = 8.7 Hz), 7.91 (1H, s), 7.73 (1H, d, J = 9.2 Hz), 7.54 (2H, d, J = 8.7 Hz), 3.77 (2H, t, J = 5.3 Hz), 3.21 (2H, s), 2.82 (2H, t, J = 5.3 Hz), 2.34 (3H, s).
ESI-MS (m / z): 435 [M + H] + .

実施例１９０
5-((3-(6-(4-メチルピペラジン-1-イル)ベンゾ[d]オキサゾール-2-イル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン(化合物１９０) Example 190
5-((3- (6- (4-Methylpiperazin-1-yl) benzo [d] oxazol-2-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4 -Dione (Compound 190)

工程１
5-(4-メチルピペラジン-1-イル)-2-ニトロフェノール Process 1
5- (4-Methylpiperazin-1-yl) -2-nitrophenol

Figure JPOXMLDOC01-appb-C000801
Figure JPOXMLDOC01-appb-C000801

5-フルオロ-2-ニトロフェノール (2.50 g, 15.9 mmol)、1-メチルピペラジン(1.75 mL, 15.9 mmol) の N,N-ジメチルホルムアミド (80 mL) 溶液中に、炭酸カリウム (4.40 g, 31.8 mmol) を添加した。アルゴン置換した後、90℃で一晩撹拌した。減圧下、濃縮乾固した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (488 mg, 13%) を得た。 1H-NMR (CDCl3) δ: 11.22 (1H, s), 7.95 (1H, d, J = 9.6 Hz), 6.44 (1H, dd, J = 9.6, 2.7 Hz), 6.32 (1H, d, J = 2.7 Hz), 3.56-3.46 (4H, m), 2.65-2.53 (4H, m), 2.39 (3H, s).
ESI-MS(m/z): 238[M+H]+. In a solution of 5-fluoro-2-nitrophenol (2.50 g, 15.9 mmol) and 1-methylpiperazine (1.75 mL, 15.9 mmol) in N, N-dimethylformamide (80 mL), potassium carbonate (4.40 g, 31.8 mmol) ) Was added. After purging with argon, the mixture was stirred at 90 ° C. overnight. After concentration to dryness under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (488 mg, 13%). 1 H-NMR (CDCl 3 ) δ: 11.22 (1H, s), 7.95 (1H, d, J = 9.6 Hz), 6.44 (1H, dd, J = 9.6, 2.7 Hz), 6.32 (1H, d, J = 2.7 Hz), 3.56-3.46 (4H, m), 2.65-2.53 (4H, m), 2.39 (3H, s).
ESI-MS (m / z): 238 [M + H] + .

工程２
2-アミノ-5-(4-メチルピペラジン-1-イル)フェノール Process 2
2-Amino-5- (4-methylpiperazin-1-yl) phenol

Figure JPOXMLDOC01-appb-C000802
Figure JPOXMLDOC01-appb-C000802

5-(4-メチルピペラジン-1-イル)-2-ニトロフェノール (488 mg, 2.06 mmol)のメタノール (10 mL) 溶液中に、10% パラジウム－活性炭 (93 mg) をアルゴン雰囲気下、0℃で添加した。水素置換した後、室温で5時間撹拌した。反応終了後、セライトろ過し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (354 mg, 83%) を得た。 1H-NMR (CDCl3) δ: 6.71 (1H, d, J = 7.8 Hz), 6.42-6.34 (2H, m), 3.01 (4H, t, J = 5.0 Hz), 2.58 (4H, t, J = 5.0 Hz), 2.36 (3H, s). In a solution of 5- (4-methylpiperazin-1-yl) -2-nitrophenol (488 mg, 2.06 mmol) in methanol (10 mL), 10% palladium-activated carbon (93 mg) was added at 0 ° C under an argon atmosphere. Added at. After purging with hydrogen, the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the mixture was filtered through celite, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (354 mg, 83%). 1 H-NMR (CDCl 3 ) δ: 6.71 (1H, d, J = 7.8 Hz), 6.42-6.34 (2H, m), 3.01 (4H, t, J = 5.0 Hz), 2.58 (4H, t, J = 5.0 Hz), 2.36 (3H, s).

工程３
6-クロロ-3-ビニルイミダゾ[1,2-b]ピリダジン Process 3
6-Chloro-3-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000803
Figure JPOXMLDOC01-appb-C000803

3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (2.00 g, 8.60 mmol) の 1,4-ジオキサン (100 mL)、水 (16 mL) の混合溶液中に 4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (1.47 mL, 8.60 mmol)、テトラキストリフェニルホスフィンパラジウム(398 mg, 0.34 mmol)、炭酸ナトリウム (3.19 g, 30.1 mmol) を添加した。アルゴン置換した後、還流条件下6時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (1.34 g, 87%) を得た。 1H-NMR (CDCl3) δ: 7.96-7.84 (2H, m), 7.02 (1H, d, J = 9.2 Hz), 6.96 (1H, dd, J = 18.1, 11.7 Hz), 6.17 (1H, d, J = 18.1 Hz), 5.47 (1H, d, J = 11.7 Hz).
ESI-MS(m/z): 180[M+H]+. 3-Bromo-6-chloroimidazo [1,2-b] pyridazine (2.00 g, 8.60 mmol) in a mixed solution of 1,4-dioxane (100 mL) and water (16 mL) 4,4,5, 5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.47 mL, 8.60 mmol), tetrakistriphenylphosphine palladium (398 mg, 0.34 mmol), sodium carbonate (3.19 g, 30.1 mmol) were added. After replacing with argon, the mixture was stirred for 6 hours under reflux conditions. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.34 g, 87%). 1 H-NMR (CDCl 3 ) δ: 7.96-7.84 (2H, m), 7.02 (1H, d, J = 9.2 Hz), 6.96 (1H, dd, J = 18.1, 11.7 Hz), 6.17 (1H, d , J = 18.1 Hz), 5.47 (1H, d, J = 11.7 Hz).
ESI-MS (m / z): 180 [M + H] + .

工程４
6-クロロイミダゾ[1,2-b]ピリダジン-3-カルボアルデヒド Process 4
6-Chloroimidazo [1,2-b] pyridazine-3-carbaldehyde

Figure JPOXMLDOC01-appb-C000804
Figure JPOXMLDOC01-appb-C000804

6-クロロ-3-ビニルイミダゾ[1,2-b]ピリダジン (1.34 g, 7.46 mmol) の 1,4-ジオキサン (70 mL)、水 (14 mL) の混合溶液中に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (1.87 mL, 0.15 mmol)、2,6-ルチジン (1.74 mL, 14.9 mmol)、過ヨウ素酸ナトリウム (6.38 g, 29.8 mmol) を添加した。アルゴン置換した後、室温で6時間撹拌した。反応終了後、セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (657 mg, 49%) を得た。 1H-NMR (DMSO-D6) δ: 10.17 (1H, s), 8.55 (1H, s), 8.45 (1H, d, J = 9.6 Hz), 7.74 (1H, d, J = 9.6 Hz).
ESI-MS(m/z): 182[M+H]+. In a mixed solution of 6-chloro-3-vinylimidazo [1,2-b] pyridazine (1.34 g, 7.46 mmol) in 1,4-dioxane (70 mL) and water (14 mL), 2.5 wt% tetraoxide. Osmium tert-butanol solution (1.87 mL, 0.15 mmol), 2,6-lutidine (1.74 mL, 14.9 mmol), and sodium periodate (6.38 g, 29.8 mmol) were added. After replacing with argon, the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the mixture was filtered through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (657 mg, 49%). 1 H-NMR (DMSO-D 6 ) δ: 10.17 (1H, s), 8.55 (1H, s), 8.45 (1H, d, J = 9.6 Hz), 7.74 (1H, d, J = 9.6 Hz).
ESI-MS (m / z): 182 [M + H] + .

工程５
2-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-6-(4-メチルピペラジン-1-イル)ベンゾ[d]オキサゾール Process 5
2- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) -6- (4-methylpiperazin-1-yl) benzo [d] oxazole

Figure JPOXMLDOC01-appb-C000805
Figure JPOXMLDOC01-appb-C000805

6-クロロイミダゾ[1,2-b]ピリダジン-3-カルボアルデヒド (227 mg, 1.25 mmol)、2-アミノ-5-(4-メチルピペラジン-1-イル)フェノール (260 mg, 1.25 mmol) の m-キシレン (5 mL) 溶液中に、活性炭 (300 mg) を添加した。空気中、120℃で一晩加熱撹拌した。反応終了後、セライトろ過し、減圧下濃縮乾固した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (203 mg, 44%) を得た。 1H-NMR (CDCl3) δ: 8.52 (1H, s), 8.05 (1H, d, J = 9.6 Hz), 7.74 (1H, d, J = 9.0 Hz), 7.26 (1H, d, J = 9.6 Hz), 7.16 (1H, d, J = 2.0 Hz), 7.04 (1H, dd, J = 9.0, 2.0 Hz), 3.49-3.35 (4H, m), 2.94-2.77 (4H, m), 2.54 (3H, s). Of 6-chloroimidazo [1,2-b] pyridazine-3-carbaldehyde (227 mg, 1.25 mmol), 2-amino-5- (4-methylpiperazin-1-yl) phenol (260 mg, 1.25 mmol) Activated carbon (300 mg) was added to a solution of m-xylene (5 mL). The mixture was heated and stirred overnight at 120 ° C. in air. After completion of the reaction, the mixture was filtered through Celite and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (203 mg, 44%). 1 H-NMR (CDCl 3 ) δ: 8.52 (1H, s), 8.05 (1H, d, J = 9.6 Hz), 7.74 (1H, d, J = 9.0 Hz), 7.26 (1H, d, J = 9.6 Hz), 7.16 (1H, d, J = 2.0 Hz), 7.04 (1H, dd, J = 9.0, 2.0 Hz), 3.49-3.35 (4H, m), 2.94-2.77 (4H, m), 2.54 (3H , s).

工程６
6-(4-メチルピペラジン-1-イル)-2-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)ベンゾ[d]オキサゾール Step 6
6- (4-Methylpiperazin-1-yl) -2- (6-vinylimidazo [1,2-b] pyridazin-3-yl) benzo [d] oxazole

Figure JPOXMLDOC01-appb-C000806
Figure JPOXMLDOC01-appb-C000806

2-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)-6-(4-メチルピペラジン-1-イル)ベンゾ[d]オキサゾール (203 mg, 0.55 mmol) の 1,4-ジオキサン (10 mL)、水 (1.6 mL) の混合溶液中に 4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (104 μL, 0.61 mmol)、酢酸パラジウム (12 mg, 0.06 mmol)、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル (45 mg, 0.11 mmol)、リン酸三カリウム (876 mg, 4.13 mmol) を添加した。アルゴン置換した後、還流条件下6時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (163 mg, 82%) を得た。 1H-NMR (DMSO-D6) δ: 8.49 (1H, s), 8.32 (1H, d, J = 9.6 Hz), 7.86 (1H, d, J = 9.6 Hz), 7.66 (1H, d, J = 8.7 Hz), 7.32 (1H, d, J = 2.3 Hz), 7.10 (1H, dd, J = 8.7, 2.3 Hz), 6.97 (1H, dd, J = 17.4, 11.4 Hz), 6.47 (1H, d, J = 17.4 Hz), 5.86 (1H, d, J = 11.4 Hz), 3.24 (4H, t, J = 5.0 Hz), 2.48 (4H, t, J = 5.0 Hz), 2.24 (3H, s).
ESI-MS(m/z): 362[M+H]+. 2- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) -6- (4-methylpiperazin-1-yl) benzo [d] oxazole (203 mg, 0.55 mmol) of 1,4- In a mixed solution of dioxane (10 mL) and water (1.6 mL), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (104 μL, 0.61 mmol), palladium acetate (12 mg, 0.06 mmol), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (45 mg, 0.11 mmol), and tripotassium phosphate (876 mg, 4.13 mmol) were added. After replacing with argon, the mixture was stirred for 6 hours under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (163 mg, 82%). 1 H-NMR (DMSO-D 6 ) δ: 8.49 (1H, s), 8.32 (1H, d, J = 9.6 Hz), 7.86 (1H, d, J = 9.6 Hz), 7.66 (1H, d, J = 8.7 Hz), 7.32 (1H, d, J = 2.3 Hz), 7.10 (1H, dd, J = 8.7, 2.3 Hz), 6.97 (1H, dd, J = 17.4, 11.4 Hz), 6.47 (1H, d , J = 17.4 Hz), 5.86 (1H, d, J = 11.4 Hz), 3.24 (4H, t, J = 5.0 Hz), 2.48 (4H, t, J = 5.0 Hz), 2.24 (3H, s).
ESI-MS (m / z): 362 [M + H] + .

工程７
3-(6-(4-メチルピペラジン-1-イル)ベンゾ[d]オキサゾール-2-イル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Step 7
3- (6- (4-Methylpiperazin-1-yl) benzo [d] oxazol-2-yl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000807
Figure JPOXMLDOC01-appb-C000807

6-(4-メチルピペラジン-1-イル)-2-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)ベンゾ[d]オキサゾール (163 mg, 0.45 mmol) の 1,4-ジオキサン (7mL)、水 (1.4 mL) の混合溶液中に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (114 μL, 9.05 μmol)、2,6-ルチジン (105 μL, 0.91 mmol)、過ヨウ素酸ナトリウム (387 mg, 1.81 mmol) を添加した。アルゴン置換した後、室温で6時間撹拌した。反応終了後、セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (44 mg, 27%) を得た。 1H-NMR (DMSO-D6) δ: 10.12 (1H, s), 8.74 (1H, s), 8.51 (1H, d, J = 8.7 Hz), 7.82 (1H, d, J = 9.6 Hz), 7.69 (1H, d, J = 9.6 Hz), 7.33 (1H, br s), 7.13 (1H, d, J = 8.7 Hz), 3.28-3.22 (4H, m), 2.50-2.47 (4H, m), 2.25 (3H, s).
ESI-MS(m/z): 363[M+H]+. 6- (4-Methylpiperazin-1-yl) -2- (6-vinylimidazo [1,2-b] pyridazin-3-yl) benzo [d] oxazole (163 mg, 0.45 mmol) of 1,4- 2.5 wt% osmium tetroxide tert-butanol solution (114 μL, 9.05 μmol), 2,6-lutidine (105 μL, 0.91 mmol), periodic acid in a mixed solution of dioxane (7 mL) and water (1.4 mL) Sodium (387 mg, 1.81 mmol) was added. After replacing with argon, the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the mixture was filtered through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (44 mg, 27%). 1 H-NMR (DMSO-D 6 ) δ: 10.12 (1H, s), 8.74 (1H, s), 8.51 (1H, d, J = 8.7 Hz), 7.82 (1H, d, J = 9.6 Hz), 7.69 (1H, d, J = 9.6 Hz), 7.33 (1H, br s), 7.13 (1H, d, J = 8.7 Hz), 3.28-3.22 (4H, m), 2.50-2.47 (4H, m), 2.25 (3H, s).
ESI-MS (m / z): 363 [M + H] + .

工程８
5-((3-(6-(4-メチルピペラジン-1-イル)ベンゾ[d]オキサゾール-2-イル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン(化合物１９０) Process 8
5-((3- (6- (4-Methylpiperazin-1-yl) benzo [d] oxazol-2-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4 -Dione (Compound 190)

Figure JPOXMLDOC01-appb-C000808
Figure JPOXMLDOC01-appb-C000808

3-(6-(4-メチルピペラジン-1-イル)ベンゾ[d]オキサゾール-2-イル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (44 mg, 0.12 mmol) をアセトニトリル (3 mL) に溶かし、チアゾリジン-2,4-ジオン (14 mg, 0.12mmol)、ピペリジン (2.4 μL, 0.02 mmol)、および酢酸 (2.8 μL, 0.04 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (6.8 μL, 0.04 mmol) を添加した後、ろ過しアセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (27 mg, 48%) を得た。 1H-NMR (DMSO-D6) δ: 8.57 (1H, s), 8.39 (1H, d, J = 9.6 Hz), 7.82 (1H, d, J = 9.6 Hz), 7.80 (1H, s), 7.63 (1H, d, J = 8.7 Hz), 7.28 (1H, d, J = 2.3 Hz), 7.17 (1H, dd, J = 8.7, 2.3 Hz), 3.34 (4H, t, J = 4.8 Hz), 2.77 (4H, t, J = 4.8 Hz), 2.44 (3H, s).
ESI-MS(m/z): 462[M+H]+. 3- (6- (4-Methylpiperazin-1-yl) benzo [d] oxazol-2-yl) imidazo [1,2-b] pyridazine-6-carbaldehyde (44 mg, 0.12 mmol) in acetonitrile (3 To the mixture, thiazolidine-2,4-dione (14 mg, 0.12 mmol), piperidine (2.4 μL, 0.02 mmol), and acetic acid (2.8 μL, 0.04 mmol) were added and stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (6.8 μL, 0.04 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (27 mg, 48%). 1 H-NMR (DMSO-D 6 ) δ: 8.57 (1H, s), 8.39 (1H, d, J = 9.6 Hz), 7.82 (1H, d, J = 9.6 Hz), 7.80 (1H, s), 7.63 (1H, d, J = 8.7 Hz), 7.28 (1H, d, J = 2.3 Hz), 7.17 (1H, dd, J = 8.7, 2.3 Hz), 3.34 (4H, t, J = 4.8 Hz), 2.77 (4H, t, J = 4.8 Hz), 2.44 (3H, s).
ESI-MS (m / z): 462 [M + H] + .

実施例１９１
5-((3-(5-(2-(ジメチルアミノ)エトキシ)チオフェン-2-イル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン(化合物１９１) Example 191
5-((3- (5- (2- (dimethylamino) ethoxy) thiophen-2-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 191 )

工程１
N,N-ジメチル-2-(チオフェン-2-イルオキシ)エタンアミン Process 1
N, N-dimethyl-2- (thiophen-2-yloxy) ethanamine

Figure JPOXMLDOC01-appb-C000809
Figure JPOXMLDOC01-appb-C000809

銅 (64 mg, 0.05 mmol)、リン酸三カリウム (4.25 g, 20.0 mmol) の 2-(ジメチルアミノ)エタノール (10 mL) 溶液中に、2-ヨードチオフェン (1.02 mL, 10.0 mmol)、4-メチルピペラジン (2.20 mL, 20.0 mmol) を室温で滴下した。アルゴン置換した後、75℃で一晩撹拌した。室温に放冷した後、セライトろ過し、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (1.09 g, 60%) を得た。 1H-NMR (DMSO-D6) δ: 6.72 (2H, d, J = 2.7 Hz), 6.31 (1H, t, J = 2.7 Hz), 4.09 (2H, t, J = 5.7 Hz), 2.60 (2H, t, J = 5.7 Hz), 2.19 (6H, s). In a solution of copper (64 mg, 0.05 mmol), tripotassium phosphate (4.25 g, 20.0 mmol) in 2- (dimethylamino) ethanol (10 mL), 2-iodothiophene (1.02 mL, 10.0 mmol), 4- Methyl piperazine (2.20 mL, 20.0 mmol) was added dropwise at room temperature. After purging with argon, the mixture was stirred at 75 ° C. overnight. The mixture was allowed to cool to room temperature, filtered through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (1.09 g, 60%). 1 H-NMR (DMSO-D 6 ) δ: 6.72 (2H, d, J = 2.7 Hz), 6.31 (1H, t, J = 2.7 Hz), 4.09 (2H, t, J = 5.7 Hz), 2.60 ( 2H, t, J = 5.7 Hz), 2.19 (6H, s).

工程１
2-((5-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)チオフェン-2-イル)オキシ)-N,N-ジメチルエタンアミン Process 1
2-((5- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) thiophen-2-yl) oxy) -N, N-dimethylethanamine

Figure JPOXMLDOC01-appb-C000810
Figure JPOXMLDOC01-appb-C000810

N,N-ジメチル-2-(チオフェン-2-イルオキシ)エタンアミン(1.09 g, 5.99 mmol)のテトラヒドロフラン (30 mL) 溶液中に、n-ブチルリチウム ヘキサン溶液 (1.6 N, 4.49 mL, 7.19 mmol) をアルゴン雰囲気下、-78℃で滴下した。1時間撹拌した後、4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン (1.45mL, 7.19 mmol) をゆっくり滴下した。室温下一晩撹拌した後、減圧下濃縮した。残渣物の 1,4-ジオキサン (60 mL)、水(10 mL) 混合溶液中に 3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (1.39 g, 5.99 mmol)、テトラキストリフェニルホスフィンパラジウム (277 mg, 0.24 mmol)、炭酸ナトリウム (2.22 g, 21.0 mmol) を添加した。アルゴン置換した後、還流条件下、一晩撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。減圧下、濃縮乾固し、粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (797 mg, 40%) を得た。 1H-NMR (DMSO-D6) δ: 8.26 (1H, d, J = 9.6 Hz), 8.21 (1H, s), 7.52 (1H, d, J = 4.1 Hz), 7.37 (1H, d, J = 9.6 Hz), 6.49 (1H, d, J = 4.1 Hz), 4.21 (2H, t, J = 5.5 Hz), 2.65 (2H, t, J = 5.5 Hz), 2.22 (6H, s).
ESI-MS(m/z): 323[M+H]+. In a solution of N, N-dimethyl-2- (thiophen-2-yloxy) ethanamine (1.09 g, 5.99 mmol) in tetrahydrofuran (30 mL), add n-butyllithium hexane solution (1.6 N, 4.49 mL, 7.19 mmol). The solution was added dropwise at -78 ° C under an argon atmosphere. After stirring for 1 hour, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.45 mL, 7.19 mmol) was slowly added dropwise. After stirring overnight at room temperature, the mixture was concentrated under reduced pressure. 3-Bromo-6-chloroimidazo [1,2-b] pyridazine (1.39 g, 5.99 mmol), tetrakistriphenylphosphine in a mixed solution of the residue 1,4-dioxane (60 mL) and water (10 mL) Palladium (277 mg, 0.24 mmol) and sodium carbonate (2.22 g, 21.0 mmol) were added. After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The mixture was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (797 mg, 40%). 1 H-NMR (DMSO-D 6 ) δ: 8.26 (1H, d, J = 9.6 Hz), 8.21 (1H, s), 7.52 (1H, d, J = 4.1 Hz), 7.37 (1H, d, J = 9.6 Hz), 6.49 (1H, d, J = 4.1 Hz), 4.21 (2H, t, J = 5.5 Hz), 2.65 (2H, t, J = 5.5 Hz), 2.22 (6H, s).
ESI-MS (m / z): 323 [M + H] + .

工程２
N,N-ジメチル-2-((5-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)チオフェン-2-イル)オキシ)エタンアミン Process 2
N, N-dimethyl-2-((5- (6-vinylimidazo [1,2-b] pyridazin-3-yl) thiophen-2-yl) oxy) ethanamine

Figure JPOXMLDOC01-appb-C000811
Figure JPOXMLDOC01-appb-C000811

2-((5-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)チオフェン-2-イル)オキシ)-N,N-ジメチルエタンアミン (797 mg, 2.47 mmol) の 1,4-ジオキサン (50 mL)、水 (8 mL) の混合溶液中に 4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (465 μL, 2.72 mmol)、酢酸パラジウム (55 mg, 0.25 mmol)、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル (203 mg, 0.49 mmol)、リン酸三カリウム (3.93 g, 18.5 mmol) を添加した。アルゴン置換した後、還流条件下3時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (273 mg, 35%) を得た。 1H-NMR (DMSO-D6) δ: 8.16 (1H, d, J = 9.6 Hz), 8.14 (1H, s), 7.58 (1H, d, J = 9.6 Hz), 7.52 (1H, d, J = 4.1 Hz), 6.92 (1H, dd, J = 17.9, 11.0 Hz), 6.47 (1H, d, J = 4.1 Hz), 6.41 (1H, d, J = 17.9 Hz), 5.79 (1H, d, J = 11.0 Hz), 4.20 (2H, t, J = 5.7 Hz), 2.65 (2H, t, J = 5.7 Hz), 2.22 (6H, s).
ESI-MS(m/z): 315[M+H]+. 2-((5- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) thiophen-2-yl) oxy) -N, N-dimethylethanamine (797 mg, 2.47 mmol) of 1, 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (465 μL, 2.72 mmol), palladium acetate in a mixed solution of 4-dioxane (50 mL) and water (8 mL) (55 mg, 0.25 mmol), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (203 mg, 0.49 mmol), and tripotassium phosphate (3.93 g, 18.5 mmol) were added. After replacing with argon, the mixture was stirred under reflux conditions for 3 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (273 mg, 35%). 1 H-NMR (DMSO-D 6 ) δ: 8.16 (1H, d, J = 9.6 Hz), 8.14 (1H, s), 7.58 (1H, d, J = 9.6 Hz), 7.52 (1H, d, J = 4.1 Hz), 6.92 (1H, dd, J = 17.9, 11.0 Hz), 6.47 (1H, d, J = 4.1 Hz), 6.41 (1H, d, J = 17.9 Hz), 5.79 (1H, d, J = 11.0 Hz), 4.20 (2H, t, J = 5.7 Hz), 2.65 (2H, t, J = 5.7 Hz), 2.22 (6H, s).
ESI-MS (m / z): 315 [M + H] + .

工程３
3-(5-(2-(ジメチルアミノ)エトキシ)チオフェン-2-イル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 3
3- (5- (2- (Dimethylamino) ethoxy) thiophen-2-yl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000812
Figure JPOXMLDOC01-appb-C000812

N,N-ジメチル-2-((5-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)チオフェン-2-イル)オキシ)エタンアミン (273 mg, 0.87 mmol) の 1,4-ジオキサン (10 mL)、水 (2 mL) の混合溶液中に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (218 μL, 0.02 mmol)、2,6-ルチジン (202 μL, 1.74 mmol)、過ヨウ素酸ナトリウム (743 mg, 3.47 mmol) を添加した。アルゴン置換した後、室温で6時間撹拌した。反応終了後、セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (124 mg, 45%) を得た。 1H-NMR (DMSO-D6) δ: 10.07 (1H, s), 8.36 (1H, s), 8.35 (1H, d, J = 9.6 Hz), 7.65 (1H, d, J = 4.1 Hz), 7.61 (1H, d, J = 9.6 Hz), 6.52 (1H, d, J = 4.1 Hz), 4.23 (2H, t, J = 5.5 Hz), 2.67 (2H, t, J = 5.5 Hz), 2.23 (6H, s).
ESI-MS(m/z): 317[M+H]+. N, N-dimethyl-2-((5- (6-vinylimidazo [1,2-b] pyridazin-3-yl) thiophen-2-yl) oxy) ethanamine (273 mg, 0.87 mmol) of 1,4 -In a mixed solution of dioxane (10 mL) and water (2 mL), 2.5 wt% osmium tetroxide tert-butanol solution (218 μL, 0.02 mmol), 2,6-lutidine (202 μL, 1.74 mmol), excess Sodium iodate (743 mg, 3.47 mmol) was added. After replacing with argon, the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the mixture was filtered through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (124 mg, 45%). 1 H-NMR (DMSO-D 6 ) δ: 10.07 (1H, s), 8.36 (1H, s), 8.35 (1H, d, J = 9.6 Hz), 7.65 (1H, d, J = 4.1 Hz), 7.61 (1H, d, J = 9.6 Hz), 6.52 (1H, d, J = 4.1 Hz), 4.23 (2H, t, J = 5.5 Hz), 2.67 (2H, t, J = 5.5 Hz), 2.23 ( 6H, s).
ESI-MS (m / z): 317 [M + H] + .

工程４
5-((3-(5-(2-(ジメチルアミノ)エトキシ)チオフェン-2-イル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン(化合物１９１) Process 4
5-((3- (5- (2- (dimethylamino) ethoxy) thiophen-2-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 191 )

Figure JPOXMLDOC01-appb-C000813
Figure JPOXMLDOC01-appb-C000813

3-(5-(2-(ジメチルアミノ)エトキシ)チオフェン-2-イル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (124 mg, 0.39 mmol) をアセトニトリル (4 mL) に溶かし、チアゾリジン-2,4-ジオン (46 mg, 0.39mmol)、ピペリジン (7.8 μL, 0.08 mmol)、および酢酸 (9.0 μL, 0.16 mmol) を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (21.9 μL, 0.16 mmol) を添加した後、ろ過しアセトニトリルで洗浄した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (72 mg, 44%) を得た。 1H-NMR (DMSO-D6) δ: 8.20 (1H, d, J = 9.6 Hz), 8.12 (1H, s), 7.65 (1H, d, J = 4.1 Hz), 7.60 (1H, s), 7.56 (1H, d, J = 9.6 Hz), 6.59 (1H, d, J = 4.1 Hz), 4.39 (2H, t, J = 5.3 Hz), 3.18 (2H, t, J = 5.3 Hz), 2.59 (6H, s).
ESI-MS(m/z): 416[M+H]+. 3- (5- (2- (dimethylamino) ethoxy) thiophen-2-yl) imidazo [1,2-b] pyridazine-6-carbaldehyde (124 mg, 0.39 mmol) was dissolved in acetonitrile (4 mL), Thiazolidine-2,4-dione (46 mg, 0.39 mmol), piperidine (7.8 μL, 0.08 mmol), and acetic acid (9.0 μL, 0.16 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (21.9 μL, 0.16 mmol) was added, followed by filtration and washing with acetonitrile. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (72 mg, 44%). 1 H-NMR (DMSO-D 6 ) δ: 8.20 (1H, d, J = 9.6 Hz), 8.12 (1H, s), 7.65 (1H, d, J = 4.1 Hz), 7.60 (1H, s), 7.56 (1H, d, J = 9.6 Hz), 6.59 (1H, d, J = 4.1 Hz), 4.39 (2H, t, J = 5.3 Hz), 3.18 (2H, t, J = 5.3 Hz), 2.59 ( 6H, s).
ESI-MS (m / z): 416 [M + H] + .

実施例１９２
5-((3-(4-(4-シクロペンチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１９２) Example 192
5-((3- (4- (4-Cyclopentylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 192)

工程１
6-クロロ-3-(4-(4-シクロペンチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン Process 1
6-Chloro-3- (4- (4-cyclopentylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000814
Figure JPOXMLDOC01-appb-C000814

6-クロロ-3-(3-フルオロ-4-(ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン (400 mg, 1.21 mmol) を N,N-ジメチルホルムアミド(4.5 mL) に溶解した。そこへシクロペンチルヨージド (167 μL, 1.45 mmol)、炭酸カリウム (251 mg, 1.82 mmol) を加え、室温で1時間撹拌した。シクロペンチルヨージド (167 μL, 1.45 mmol) を追加し、さらに室温で5時間撹拌した後、80℃で1時間撹拌した。反応液に水を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (184 mg, 38%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.32 (1H, s), 8.29 (1H, d, J = 9.6 Hz), 7.93-7.88 (2H, m), 7.41 (1H, d, J = 9.4 Hz), 7.18 (1H, t, J = 9.2 Hz), 3.10 (4H, t, J = 4.7 Hz), 2.59 (4H, s), 2.55-2.50 (1H, m), 1.86-1.78 (2H, m), 1.67-1.59 (2H, m), 1.57-1.48 (2H, m), 1.40-1.31 (2H, m). 6-Chloro-3- (3-fluoro-4- (piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine (400 mg, 1.21 mmol) in N, N-dimethylformamide (4.5 mL) Dissolved. Cyclopentyl iodide (167 μL, 1.45 mmol) and potassium carbonate (251 mg, 1.82 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. Cyclopentyl iodide (167 μL, 1.45 mmol) was added, and the mixture was further stirred at room temperature for 5 hours, and then stirred at 80 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (184 mg, 38%). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.32 (1H, s), 8.29 (1H, d, J = 9.6 Hz), 7.93-7.88 (2H, m), 7.41 (1H, d, J = 9.4 Hz), 7.18 (1H, t, J = 9.2 Hz), 3.10 (4H, t, J = 4.7 Hz), 2.59 (4H, s), 2.55-2.50 (1H, m), 1.86-1.78 ( 2H, m), 1.67-1.59 (2H, m), 1.57-1.48 (2H, m), 1.40-1.31 (2H, m).

工程２
3-(4-(4-シクロペンチルピペラジン-1-イル)-3-フルオロフェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 2
3- (4- (4-Cyclopentylpiperazin-1-yl) -3-fluorophenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000815
Figure JPOXMLDOC01-appb-C000815

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、6-クロロ-3-(4-(4-シクロペンチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン (184 mg, 0.460 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (87 μL, 0.506 mmol) から標記化合物 (146 mg, 81%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.23 (1H, s), 8.18 (1H, d, J =9.4 Hz), 8.02-7.96 (2H, m), 7.65 (1H, d, J = 9.6 Hz), 7.15 (1H, t, J =9.2 Hz), 6.92 (1H, dd, J =17.6, 11.0 Hz), 6.37 (1H, d, J =17.6 Hz), 5.78 (1H, d, J = 11.2 Hz), 3.09 (4H, t, J = 4.5 Hz), 2.59 (4H, s), 2.55-2.50 (1H, m), 1.85-1.78 (2H, m), 1.67-1.58 (2H, m), 1.57-1.48 (2H, m), 1.40-1.31 (2H, m). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) 6-chloro-3- (4- (4-cyclopentylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazine (184 mg, 0.460 mmol) and 4,4,5,5- The title compound (146 mg, 81%) was obtained from tetramethyl-2-vinyl-1,3,2-dioxaborolane (87 μL, 0.506 mmol). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.23 (1H, s), 8.18 (1H, d, J = 9.4 Hz), 8.02-7.96 (2H, m), 7.65 (1H, d, J = 9.6 Hz), 7.15 (1H, t, J = 9.2 Hz), 6.92 (1H, dd, J = 17.6, 11.0 Hz), 6.37 (1H, d, J = 17.6 Hz), 5.78 (1H, d, J = 11.2 Hz), 3.09 (4H, t, J = 4.5 Hz), 2.59 (4H, s), 2.55-2.50 (1H, m), 1.85-1.78 (2H, m), 1.67-1.58 (2H, m ), 1.57-1.48 (2H, m), 1.40-1.31 (2H, m).

工程３
3-(4-(4-シクロペンチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 3
3- (4- (4-Cyclopentylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000816
Figure JPOXMLDOC01-appb-C000816

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(4-(4-シクロペンチルピペラジン-1-イル)-3-フルオロフェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (146 mg, 0.373 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (93 μl, 7.46 μmol) から標記化合物 (80 mg, 55%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.1 (1H, d, J = 0.9 Hz), 8.48 (1H, s), 8.37 (1H, dd, J = 9.4, 0.9 Hz), 8.10-8.02 (2H, m), 7.66 (1H, d, J = 9.4 Hz), 7.18 (1H, t, J = 9.0 Hz), 3.11 (4H, s), 2.60 (4H, s), 2.55-2.49 (1H, m), 1.86-1.79 (2H, m), 1.67-1.59 (2H, m), 1.56-1.48 (2H, m), 1.40-1.33 (2H, m). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 4- (4-Cyclopentylpiperazin-1-yl) -3-fluorophenyl) -6-vinylimidazo [1,2-b] pyridazine (146 mg, 0.373 mmol) and 2.5 wt% osmium tetroxide tert-butanol solution ( The title compound (80 mg, 55%) was obtained from 93 μl, 7.46 μmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.1 (1H, d, J = 0.9 Hz), 8.48 (1H, s), 8.37 (1H, dd, J = 9.4, 0.9 Hz), 8.10- 8.02 (2H, m), 7.66 (1H, d, J = 9.4 Hz), 7.18 (1H, t, J = 9.0 Hz), 3.11 (4H, s), 2.60 (4H, s), 2.55-2.49 (1H , m), 1.86-1.79 (2H, m), 1.67-1.59 (2H, m), 1.56-1.48 (2H, m), 1.40-1.33 (2H, m).

工程４
5-((3-(4-(4-シクロペンチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１９２) Process 4
5-((3- (4- (4-Cyclopentylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 192)

Figure JPOXMLDOC01-appb-C000817
Figure JPOXMLDOC01-appb-C000817

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(4-(4-シクロペンチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (80 mg, 0.203 mmol) およびチアゾリジン-2,4-ジオン (24 mg, 0.203 mmol) から標記化合物 (31 mg, 31%) を得た。赤褐色固体: 1H-NMR (DMSO-D6) δ: 8.27 (1H, s), 8.25 (1H, d, J = 9.4 Hz), 8.10 (1H, dd, J = 14.5, 1.9 Hz), 7.87 (1H, dd, J = 8.4, 1.9 Hz), 7.71 (1H, s), 7.64 (1H, d, J = 9.4 Hz), 7.18 (1H, t, J = 8.9 Hz), 3.22 (4H, s), 2.94 (4H, s), 1.94-1.88 (2H, m), 1.71-1.63 (2H, m), 1.59-1.47 (4H, m).
ESI-MS(m/z): 493[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (4- (4-cyclopentylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (80 mg, 0.203 mmol) and thiazolidine-2,4-dione (24 mg, 0.203 mmol) gave the title compound (31 mg, 31%). Reddish brown solid: 1 H-NMR (DMSO-D 6 ) δ: 8.27 (1H, s), 8.25 (1H, d, J = 9.4 Hz), 8.10 (1H, dd, J = 14.5, 1.9 Hz), 7.87 ( 1H, dd, J = 8.4, 1.9 Hz), 7.71 (1H, s), 7.64 (1H, d, J = 9.4 Hz), 7.18 (1H, t, J = 8.9 Hz), 3.22 (4H, s), 2.94 (4H, s), 1.94-1.88 (2H, m), 1.71-1.63 (2H, m), 1.59-1.47 (4H, m).
ESI-MS (m / z): 493 [M + H] + .

実施例１９３
5-((3-(3-クロロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１９３) Example 193
5-((3- (3-Chloro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 193)

工程１
tert-ブチル 4-(2-クロロフェニル)ピペラジン-1-カルボキシレート Process 1
tert-butyl 4- (2-chlorophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000818
Figure JPOXMLDOC01-appb-C000818

1-(2-クロロフェニル)ピペラジン (2.0 g, 10.2 mmol) をジクロロメタン (40 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (2.75 mL, 20.4 mmol) を加えた。さらに二炭酸ジ-tert-ブチル (3.33 g, 15.3 mmol) のジクロロメタン溶液 (20 mL) を滴下し、0℃で10分撹拌後、室温で3時間撹拌した。反応液を1規定塩酸、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (3.05 g, quant) を得た。白色固体: 1H-NMR (DMSO-D6) δ: 7.42 (1H, dd, J = 7.9, 1.5 Hz), 7.30 (1H, ddd, J = 8.5, 6.9, 1.1 Hz), 7.16 (1H, dd, J = 8.0, 1.6 Hz), 7.06 (1H, ddd, J = 8.4, 6.8, 1.0 Hz), 3.47 (4H, t, J = 4.7 Hz), 2.91 (4H, t, J = 5.0 Hz), 1.42 (9H, s). 1- (2-Chlorophenyl) piperazine (2.0 g, 10.2 mmol) was dissolved in dichloromethane (40 mL) and cooled to 0 ° C. Triethylamine (2.75 mL, 20.4 mmol) was added there. Further, a dichloromethane solution (20 mL) of di-tert-butyl dicarbonate (3.33 g, 15.3 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 3 hours. The reaction mixture was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (3.05 g, quant). White solid: 1 H-NMR (DMSO-D 6 ) δ: 7.42 (1H, dd, J = 7.9, 1.5 Hz), 7.30 (1H, ddd, J = 8.5, 6.9, 1.1 Hz), 7.16 (1H, dd , J = 8.0, 1.6 Hz), 7.06 (1H, ddd, J = 8.4, 6.8, 1.0 Hz), 3.47 (4H, t, J = 4.7 Hz), 2.91 (4H, t, J = 5.0 Hz), 1.42 (9H, s).

工程２
tert-ブチル 4-(4-ブロモ-2-クロロフェニル)ピペラジン-1-カルボキシレート Process 2
tert-butyl 4- (4-bromo-2-chlorophenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000819
Figure JPOXMLDOC01-appb-C000819

アルゴン雰囲気下、tert-ブチル 4-(2-クロロフェニル)ピペラジン-1-カルボキシレート (2.38 g, 7.63 mmol) をジクロロメタン (40 mL) に溶解し、0℃に冷却した。そこへN-ブロモスクシンイミド (1.36 g, 7.63 mmol) を加え、0℃で10分撹拌後、室温で3時間撹拌した。N-ブロモスクシンイミド (680 mg, 3.82 mmol) を追加し、室温で2時間撹拌した。反応液を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製して標記化合物 (1.19 g, 41%) を得た。無色オイル: 1H-NMR (DMSO-D6) δ: 7.67 (1H, d, J = 2.3 Hz), 7.49 (1H, dd, J = 8.5, 2.3 Hz), 7.11 (1H, d, J = 8.7 Hz), 3.46 (4H, t, J = 4.6 Hz), 2.90 (4H, t, J = 4.9 Hz), 1.42 (9H, s). Under an argon atmosphere, tert-butyl 4- (2-chlorophenyl) piperazine-1-carboxylate (2.38 g, 7.63 mmol) was dissolved in dichloromethane (40 mL) and cooled to 0 ° C. N-bromosuccinimide (1.36 g, 7.63 mmol) was added thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 3 hours. N-bromosuccinimide (680 mg, 3.82 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.19 g, 41%). Colorless oil: 1 H-NMR (DMSO-D 6 ) δ: 7.67 (1H, d, J = 2.3 Hz), 7.49 (1H, dd, J = 8.5, 2.3 Hz), 7.11 (1H, d, J = 8.7 Hz), 3.46 (4H, t, J = 4.6 Hz), 2.90 (4H, t, J = 4.9 Hz), 1.42 (9H, s).

工程３
tert-ブチル 4-(2-クロロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレート Process 3
tert-butyl 4- (2-chloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000820
Figure JPOXMLDOC01-appb-C000820

1-メチル-4-(3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジンの合成 (実施例50、工程2) と同様の手法で、tert-ブチル 4-(4-ブロモ-2-クロロフェニル)ピペラジン-1-カルボキシレート (1.19 g, 3.16 mmol) およびビス(ピナコラート)ジボロン (883 mg, 3.48 mmol) から標記化合物 (1.04 g, 78%) を得た。白色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 7.59 (1H, d, J = 1.4 Hz), 7.56 (1H, dd, J = 8.0, 1.4 Hz), 7.14 (1H, d, J = 8.0 Hz), 3.47 (4H, t, J = 4.2 Hz), 2.96 (4H, t, J = 4.9 Hz), 1.42 (9H, s), 1.28 (12H, s). Synthesis of 1-methyl-4- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine (Example 50, step 2) From tert-butyl 4- (4-bromo-2-chlorophenyl) piperazine-1-carboxylate (1.19 g, 3.16 mmol) and bis (pinacolato) diboron (883 mg, 3.48 mmol), the title compound (1.04 g, 78 %). White amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 7.59 (1H, d, J = 1.4 Hz), 7.56 (1H, dd, J = 8.0, 1.4 Hz), 7.14 (1H, d, J = 8.0 Hz), 3.47 (4H, t, J = 4.2 Hz), 2.96 (4H, t, J = 4.9 Hz), 1.42 (9H, s), 1.28 (12H, s).

工程４
tert-ブチル 4-(2-クロロ-4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-カルボキシレート Process 4
tert-butyl 4- (2-chloro-4- (6-chloroimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000821
Figure JPOXMLDOC01-appb-C000821

3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-カルボニトリルの合成 (実施例106、工程6) と同様の手法で、3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (477 mg, 2.05 mmol) およびtert-ブチル 4-(2-クロロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)ピペラジン-1-カルボキシレート (1.04 mg, 2.46 mmol) から標記化合物 (685 mg, 75%) を得た。薄黄色固体: 1H-NMR (DMSO-D6) δ: 8.35 (1H, s), 8.31 (1H, d, J = 9.6 Hz), 8.19 (1H, d, J = 2.1 Hz), 8.05 (1H, dd, J = 8.5, 2.3 Hz), 7.43 (1H, d, J = 9.6 Hz), 7.33 (1H, d, J = 8.5 Hz), 3.51 (4H, s), 3.01 (4H, t, J = 4.9 Hz), 1.44 (9H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridine-5-carbonitrile (Example 106, Step 6) -6-Chloroimidazo [1,2-b] pyridazine (477 mg, 2.05 mmol) and tert-butyl 4- (2-chloro-4- (4,4,5,5-tetramethyl-1,3,2) The title compound (685 mg, 75%) was obtained from -dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (1.04 mg, 2.46 mmol). Pale yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.35 (1H, s), 8.31 (1H, d, J = 9.6 Hz), 8.19 (1H, d, J = 2.1 Hz), 8.05 (1H , dd, J = 8.5, 2.3 Hz), 7.43 (1H, d, J = 9.6 Hz), 7.33 (1H, d, J = 8.5 Hz), 3.51 (4H, s), 3.01 (4H, t, J = 4.9 Hz), 1.44 (9H, s).

工程５
tert-ブチル 4-(2-クロロ-4-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-カルボキシレート Process 5
tert-butyl 4- (2-chloro-4- (6-vinylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000822
Figure JPOXMLDOC01-appb-C000822

3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例131、工程7) と同様の手法で、tert-ブチル 4-(2-クロロ-4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-カルボキシレート (685 mg, 1.53 mmol) および4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン (288 μL, 1.68 mmol) から標記化合物 (555 mg, 83%) を得た。黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.29 (1H, d, J = 2.1 Hz), 8.27 (1H, s), 8.20 (1H, d, J = 9.2 Hz), 8.14 (1H, dd, J = 8.5, 2.1 Hz), 7.67 (1H, d, J = 9.4 Hz), 7.31 (1H, d, J = 8.7 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.38 (1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.7 Hz), 3.51 (4H, s), 3.00 (4H, t, J = 4.9 Hz), 1.44 (9H, s). Synthesis of 3- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 131, Step 7) tert-butyl 4- (2-chloro-4- (6-chloroimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazine-1-carboxylate (685 mg, 1.53 mmol) and 4,4, The title compound (555 mg, 83%) was obtained from 5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (288 μL, 1.68 mmol). Yellow amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.29 (1H, d, J = 2.1 Hz), 8.27 (1H, s), 8.20 (1H, d, J = 9.2 Hz), 8.14 ( 1H, dd, J = 8.5, 2.1 Hz), 7.67 (1H, d, J = 9.4 Hz), 7.31 (1H, d, J = 8.7 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.38 (1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.7 Hz), 3.51 (4H, s), 3.00 (4H, t, J = 4.9 Hz), 1.44 (9H, s).

工程６
3-(3-クロロ-4-(ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Step 6
3- (3-Chloro-4- (piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000823
Figure JPOXMLDOC01-appb-C000823

5-ブロモ-3-(4-(ピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程6) と同様の手法で、tert-ブチル 4-(2-クロロ-4-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-カルボキシレート (555 mg, 1.26 mmol) およびトリフルオロ酢酸 (2 mL) から標記化合物 (546 mg, 83%) を得た。黄色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 8.26 (1H, d, J = 2.1 Hz), 8.26 (1H, s), 8.19 (1H, d, J =9.4 Hz), 8.13 (1H, dd, J = 8.5, 2.1 Hz), 7.66 (1H, d, J = 9.6 Hz), 7.27 (1H, d, J = 8.5 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.38 (1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.4 Hz), 2.98 (4H, t, J = 4.4 Hz), 2.90 (4H, t, J = 4.6 Hz). Synthesis of 5-bromo-3- (4- (piperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 6) From-(2-chloro-4- (6-vinylimidazo [1,2-b] pyridazin-3-yl) phenyl) piperazine-1-carboxylate (555 mg, 1.26 mmol) and trifluoroacetic acid (2 mL) The title compound (546 mg, 83%) was obtained. Yellow amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 8.26 (1H, d, J = 2.1 Hz), 8.26 (1H, s), 8.19 (1H, d, J = 9.4 Hz), 8.13 ( 1H, dd, J = 8.5, 2.1 Hz), 7.66 (1H, d, J = 9.6 Hz), 7.27 (1H, d, J = 8.5 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.38 (1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.4 Hz), 2.98 (4H, t, J = 4.4 Hz), 2.90 (4H, t, J = 4.6 Hz).

工程７
3-(3-クロロ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Step 7
3- (3-Chloro-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000824
Figure JPOXMLDOC01-appb-C000824

5-ブロモ-3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジンの合成 (実施例65、工程7) と同様の手法で、3-(3-クロロ-4-(ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (120 mg, 0.353 mmol) および37% ホルムアルデヒド水溶液 (158 μL, 2.12 mmol) から標記化合物 (92 mg, 74%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.27 (1H, d, J = 2.1 Hz), 8.26 (1H, s), 8.19 (1H, d, J = 9.6 Hz), 8.13 (1H, dd, J = 8.5, 2.1 Hz), 7.66 (1H, d, J = 9.4 Hz), 7.29 (1H, d, J = 8.5 Hz), 6.90 (1H, dd, J = 17.7, 11.1 Hz), 6.38 (1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.2 Hz), 3.05 (4H, s), 2.54-2.48 (4H, m), 2.25 (3H, s). Synthesis of 5-bromo-3- (4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridine (Example 65, Step 7) From-(3-chloro-4- (piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (120 mg, 0.353 mmol) and 37% aqueous formaldehyde (158 μL, 2.12 mmol) The title compound (92 mg, 74%) was obtained. Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.27 (1H, d, J = 2.1 Hz), 8.26 (1H, s), 8.19 (1H, d, J = 9.6 Hz), 8.13 (1H, dd, J = 8.5, 2.1 Hz), 7.66 (1H, d, J = 9.4 Hz), 7.29 (1H, d, J = 8.5 Hz), 6.90 (1H, dd, J = 17.7, 11.1 Hz), 6.38 ( 1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.2 Hz), 3.05 (4H, s), 2.54-2.48 (4H, m), 2.25 (3H, s).

工程８
3-(3-クロロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 8
3- (3-Chloro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000825
Figure JPOXMLDOC01-appb-C000825

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-クロロ-4-(4-メチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (92 mg, 0.260 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (65 μl, 5.20 μmol) から標記化合物 (43 mg, 47%) を得た。橙色アモルファス状物質: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.9 Hz), 8.50 (1H, s), 8.38 (1H, dd, J =9.4, 0.7 Hz), 8.29 (1H, d, J =2.1 Hz), 8.19 (1H, dd, J = 8.4, 2.2 Hz), 7.67 (1H, d, J = 9.4 Hz), 7.33 (1H, d, J = 8.7 Hz), 3.07 (4H, s), 2.55-2.50 (4H, m), 2.26 (3H, s). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3-chloro-4- (4-methylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (92 mg, 0.260 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol ( The title compound (43 mg, 47%) was obtained from 65 μl, 5.20 μmol). Orange amorphous material: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.9 Hz), 8.50 (1H, s), 8.38 (1H, dd, J = 9.4, 0.7 Hz), 8.29 (1H, d, J = 2.1 Hz), 8.19 (1H, dd, J = 8.4, 2.2 Hz), 7.67 (1H, d, J = 9.4 Hz), 7.33 (1H, d, J = 8.7 Hz), 3.07 (4H, s), 2.55-2.50 (4H, m), 2.26 (3H, s).

工程９
5-((3-(3-クロロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１９３) Step 9
5-((3- (3-Chloro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 193)

Figure JPOXMLDOC01-appb-C000826
Figure JPOXMLDOC01-appb-C000826

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-クロロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (43 mg, 0.121 mmol) およびチアゾリジン-2,4-ジオン (14 mg, 0.121 mmol) から標記化合物 (21 mg, 38%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.41 (1H, d, J = 2.3 Hz), 8.29 (1H, s), 8.26 (1H, d, J = 9.4 Hz), 7.98 (1H, dd, J = 8.5, 2.1 Hz), 7.71 (1H, s), 7.65 (1H, d, J = 9.4 Hz), 7.31 (1H, d, J = 8.5 Hz), 3.17 (4H, s), 2.86 (4H, s), 2.50 (3H, s).
ESI-MS(m/z): 455[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3-chloro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (43 mg, 0.121 mmol) and thiazolidine-2,4-dione (14 mg, 0.121 mmol) gave the title compound (21 mg, 38%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.41 (1H, d, J = 2.3 Hz), 8.29 (1H, s), 8.26 (1H, d, J = 9.4 Hz), 7.98 (1H, dd, J = 8.5, 2.1 Hz), 7.71 (1H, s), 7.65 (1H, d, J = 9.4 Hz), 7.31 (1H, d, J = 8.5 Hz), 3.17 (4H, s), 2.86 ( 4H, s), 2.50 (3H, s).
ESI-MS (m / z): 455 [M + H] + .

実施例１９４
5-((3-(3-クロロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１９４) Example 194
5-((3- (3-Chloro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 194)

工程１
3-(3-クロロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 1
3- (3-Chloro-4- (4-isopropylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000827
Figure JPOXMLDOC01-appb-C000827

3-(4-(4-イソプロピルピペラジン-1-イル)-3-メチルフェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例184、工程1)と同様の手法で、3-(3-クロロ-4-(ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (110 mg, 0.324 mmol) およびアセトン (48 μL, 0.648 mmol) から標記化合物 (82 mg, 66%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.26 (1H, d, J = 2.1 Hz), 8.26 (1H, s), 8.19 (1H, d, J = 9.4 Hz), 8.12 (1H, dd, J = 8.5, 2.1 Hz), 7.67 (1H, s), 7.28 (1H, d, J = 8.5 Hz), 6.91 (1H, dd, J = 17.6, 11.0 Hz), 6.38 (1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.2 Hz), 3.05 (4H, s), 2.74-2.66 (1H, m), 2.63 (4H, s), 1.02 (6H, d, J = 6.4 Hz). Synthesis of 3- (4- (4-isopropylpiperazin-1-yl) -3-methylphenyl) -6-vinylimidazo [1,2-b] pyridazine in the same manner as in Example 184, Step 1) Title compound from 3- (3-chloro-4- (piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (110 mg, 0.324 mmol) and acetone (48 μL, 0.648 mmol) (82 mg, 66%) was obtained. Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.26 (1H, d, J = 2.1 Hz), 8.26 (1H, s), 8.19 (1H, d, J = 9.4 Hz), 8.12 (1H, dd, J = 8.5, 2.1 Hz), 7.67 (1H, s), 7.28 (1H, d, J = 8.5 Hz), 6.91 (1H, dd, J = 17.6, 11.0 Hz), 6.38 (1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.2 Hz), 3.05 (4H, s), 2.74-2.66 (1H, m), 2.63 (4H, s), 1.02 (6H, d, J = 6.4 Hz ).

工程２
3-(3-クロロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 2
3- (3-Chloro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000828
Figure JPOXMLDOC01-appb-C000828

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-クロロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (82 mg, 0.215 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (54 μl, 4.30 μmol) から標記化合物 (48 mg, 58%) を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.9 Hz), 8.50 (1H, s), 8.38 (1H, dd, J =9.4, 0.9 Hz), 8.29 (1H, d, J =2.1 Hz), 8.19 (1H, dd, J = 8.2, 1.8 Hz), 7.67 (1H, d, J = 9.4 Hz), 7.32 (1H, d, J = 8.7 Hz), 3.07 (4H, s), 2.74-2.64 (1H, m), 2.64 (4H, s), 1.03 (6H, d, J = 5.7 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3-chloro-4- (4-isopropylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (82 mg, 0.215 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol ( The title compound (48 mg, 58%) was obtained from 54 μl, 4.30 μmol). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.9 Hz), 8.50 (1H, s), 8.38 (1H, dd, J = 9.4, 0.9 Hz), 8.29 ( 1H, d, J = 2.1 Hz), 8.19 (1H, dd, J = 8.2, 1.8 Hz), 7.67 (1H, d, J = 9.4 Hz), 7.32 (1H, d, J = 8.7 Hz), 3.07 ( 4H, s), 2.74-2.64 (1H, m), 2.64 (4H, s), 1.03 (6H, d, J = 5.7 Hz).

工程３
5-((3-(3-クロロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１９４) Process 3
5-((3- (3-Chloro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 194)

Figure JPOXMLDOC01-appb-C000829
Figure JPOXMLDOC01-appb-C000829

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-クロロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (48 mg, 0.125 mmol) およびチアゾリジン-2,4-ジオン (15 mg, 0.125 mmol) から標記化合物 (21 mg, 35%) を得た。橙色固体: 1H-NMR ( DMSO-D6) δ: 8.40 (1H, d, J = 2.1 Hz), 8.28 (1H, s), 8.26 (1H, d, J =9.4 Hz), 7.98 (1H, dd, J = 8.5, 2.1 Hz), 7.70 (1H, s), 7.65 (1H, d, J = 9.4 Hz), 7.32 (1H, d, J =8.5 Hz), 3.20 (4H, s), 3.15-3.04 (1H, m), 2.98 (4H, s), 1.16 (6H, d, J = 6.4 Hz).
ESI-MS(m/z): 483[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3-chloro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (48 mg, 0.125 mmol) and thiazolidine-2,4-dione (15 mg, 0.125 mmol) gave the title compound (21 mg, 35%). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 8.40 (1H, d, J = 2.1 Hz), 8.28 (1H, s), 8.26 (1H, d, J = 9.4 Hz), 7.98 (1H, dd, J = 8.5, 2.1 Hz), 7.70 (1H, s), 7.65 (1H, d, J = 9.4 Hz), 7.32 (1H, d, J = 8.5 Hz), 3.20 (4H, s), 3.15- 3.04 (1H, m), 2.98 (4H, s), 1.16 (6H, d, J = 6.4 Hz).
ESI-MS (m / z): 483 [M + H] + .

実施例１９５
5-((3-(3-クロロ-4-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１９５) Example 195
5-((3- (3-Chloro-4- (4-ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound (195)

工程１
3-(3-クロロ-4-(4-エチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 1
3- (3-Chloro-4- (4-ethylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000830
Figure JPOXMLDOC01-appb-C000830

3-(3-クロロ-4-(ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (120 mg, 0.353 mmol) をN,N-ジメチルホルムアミド (2 mL) に溶解した。そこへヨードエタン (34 μL, 0.424 mmol)、炭酸カリウム (73 mg, 0.530 mmol) を加え、室温で2時間撹拌した。ヨードエタン (23 μL, 0.282 mmol) を追加し、さらに室温で1時間撹拌した。反応液に水を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (84 mg, 65%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.27 (1H, d, J = 2.1 Hz), 8.26 (1H, s), 8.19 (1H, d, J =9.6 Hz), 8.13 (1H, dd, J = 8.5, 2.3 Hz), 7.66 (1H, d, J = 9.4 Hz), 7.29 (1H, d, J = 8.5 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.38 (1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.4 Hz), 3.06 (4H, s), 2.57-2.53 (4H, m), 2.40 (2H, q, J = 7.3 Hz), 1.04 (3H, t, J =7.2 Hz). 3- (3-Chloro-4- (piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (120 mg, 0.353 mmol) in N, N-dimethylformamide (2 mL) Dissolved. The iodoethane (34 microliters, 0.424 mmol) and potassium carbonate (73 mg, 0.530 mmol) were added there, and it stirred at room temperature for 2 hours. Iodoethane (23 μL, 0.282 mmol) was added, and the mixture was further stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (84 mg, 65%). Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.27 (1H, d, J = 2.1 Hz), 8.26 (1H, s), 8.19 (1H, d, J = 9.6 Hz), 8.13 (1H, dd, J = 8.5, 2.3 Hz), 7.66 (1H, d, J = 9.4 Hz), 7.29 (1H, d, J = 8.5 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.38 ( 1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.4 Hz), 3.06 (4H, s), 2.57-2.53 (4H, m), 2.40 (2H, q, J = 7.3 Hz), 1.04 (3H, t, J = 7.2 Hz).

工程２
3-(3-クロロ-4-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 2
3- (3-Chloro-4- (4-ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000831
Figure JPOXMLDOC01-appb-C000831

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-クロロ-4-(4-エチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (84 mg, 0.228 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (57 μl, 4.56 μmol) から標記化合物 (43 mg, 51%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.0 (1H, s), 8.50 (1H, s), 8.38 (1H, d, J = 9.4 Hz), 8.29 (1H, d, J = 2.1 Hz), 8.20 (1H, dd, J =8.5, 1.8 Hz), 7.67 (1H, d, J =9.4 Hz), 7.32 (1H, d, J = 8.7 Hz), 3.08 (4H, s), 2.56 (4H, s), 2.41 (2H, q, J = 7.1 Hz), 1.05 (3H, t, J = 7.1 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3-chloro-4- (4-ethylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (84 mg, 0.228 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol ( The title compound (43 mg, 51%) was obtained from 57 μl, 4.56 μmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, s), 8.50 (1H, s), 8.38 (1H, d, J = 9.4 Hz), 8.29 (1H, d, J = 2.1 Hz), 8.20 (1H, dd, J = 8.5, 1.8 Hz), 7.67 (1H, d, J = 9.4 Hz), 7.32 (1H, d, J = 8.7 Hz), 3.08 (4H, s), 2.56 ( 4H, s), 2.41 (2H, q, J = 7.1 Hz), 1.05 (3H, t, J = 7.1 Hz).

工程３
5-((3-(3-クロロ-4-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１９５)  Process 3
5-((3- (3-Chloro-4- (4-ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound (195)

Figure JPOXMLDOC01-appb-C000832
Figure JPOXMLDOC01-appb-C000832

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-クロロ-4-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (43 mg, 0.116 mmol) およびチアゾリジン-2,4-ジオン (14 mg, 0.116 mmol) から標記化合物 (19 mg, 35%) を得た。茶色固体: 1H-NMR (DMSO-D6) δ: 8.41 (1H, d, J = 2.1 Hz), 8.28 (1H, s), 8.26 (1H, d, J = 9.4 Hz), 7.99 (1H, dd, J = 8.4, 2.2 Hz), 7.70 (1H, s), 7.65 (1H, d, J = 9.4 Hz), 7.32 (1H, d, J = 8.5 Hz), 3.18 (4H, s), 2.91 (4H, s), 2.74 (2H, q, J =7.2 Hz), 1.14 (3H, t, J = 7.2 Hz).
ESI-MS(m/z): 469[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3-chloro-4- (4-ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (43 mg, 0.116 mmol) and thiazolidine-2,4-dione (14 mg, 0.116 mmol) gave the title compound (19 mg, 35%). Brown solid: 1 H-NMR (DMSO-D 6 ) δ: 8.41 (1H, d, J = 2.1 Hz), 8.28 (1H, s), 8.26 (1H, d, J = 9.4 Hz), 7.99 (1H, dd, J = 8.4, 2.2 Hz), 7.70 (1H, s), 7.65 (1H, d, J = 9.4 Hz), 7.32 (1H, d, J = 8.5 Hz), 3.18 (4H, s), 2.91 ( 4H, s), 2.74 (2H, q, J = 7.2 Hz), 1.14 (3H, t, J = 7.2 Hz).
ESI-MS (m / z): 469 [M + H] + .

実施例１９６
5-((3-(3-クロロ-4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１９６) Example 196
5-((3- (3-Chloro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 196)

工程１
3-(3-クロロ-4-(4-プロピルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 1
3- (3-Chloro-4- (4-propylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000833
Figure JPOXMLDOC01-appb-C000833

3-(4-(4-ブチルピペラジン-1-イル)-3-フルオロフェニル)-6-クロロイミダゾ[1,2-b]ピリダジンの合成 (実施例147、工程1) と同様の手法で、3-(3-クロロ-4-(ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (120 mg, 0.353 mmol) およびプロピオンアルデヒド (51 μL, 0.706 mmol) から標記化合物 (51 mg, 38%) を得た。黄色オイル: 1H-NMR (DMSO-D6) δ: 8.27 (1H, d, J = 2.1 Hz), 8.26 (1H, s), 8.19 (1H, d, J = 9.6 Hz), 8.13 (1H, dd, J = 8.5, 2.3 Hz), 7.66 (1H, d, J = 9.6 Hz), 7.29 (1H, d, J = 8.7 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.38 (1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.4 Hz), 3.06 (4H, s), 2.56-2.53 (4H, m), 2.31 (2H, t, J = 7.3 Hz), 1.53-1.44 (2H, m), 0.89 (3H, t, J = 7.4 Hz). Synthesis of 3- (4- (4-butylpiperazin-1-yl) -3-fluorophenyl) -6-chloroimidazo [1,2-b] pyridazine (Example 147, Step 1) Titled from 3- (3-chloro-4- (piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (120 mg, 0.353 mmol) and propionaldehyde (51 μL, 0.706 mmol) The compound (51 mg, 38%) was obtained. Yellow oil: 1 H-NMR (DMSO-D 6 ) δ: 8.27 (1H, d, J = 2.1 Hz), 8.26 (1H, s), 8.19 (1H, d, J = 9.6 Hz), 8.13 (1H, dd, J = 8.5, 2.3 Hz), 7.66 (1H, d, J = 9.6 Hz), 7.29 (1H, d, J = 8.7 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.38 ( 1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.4 Hz), 3.06 (4H, s), 2.56-2.53 (4H, m), 2.31 (2H, t, J = 7.3 Hz), 1.53-1.44 (2H, m), 0.89 (3H, t, J = 7.4 Hz).

工程２
3-(3-クロロ-4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 2
3- (3-Chloro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000834
Figure JPOXMLDOC01-appb-C000834

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-クロロ-4-(4-プロピルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (51 mg, 0.134 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (34 μl, 2.68 μmol) から標記化合物 (25 mg, 49%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.9 Hz), 8.50 (1H, s), 8.38 (1H, dd, J =9.4, 0.9 Hz), 8.29 (1H, d, J =2.1 Hz), 8.20 (1H, dd, J = 8.5, 2.1 Hz), 7.67 (1H, d, J = 9.4 Hz), 7.33 (1H, d, J = 8.5 Hz), 3.08 (4H, s), 2.56 (4H, s), 2.32 (2H, t, J = 7.4 Hz), 1.53-1.44 (2H, m), 0.89 (3H, t, J = 7.3 Hz). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3-chloro-4- (4-propylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (51 mg, 0.134 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol ( The title compound (25 mg, 49%) was obtained from 34 μl, 2.68 μmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.9 Hz), 8.50 (1H, s), 8.38 (1H, dd, J = 9.4, 0.9 Hz), 8.29 ( 1H, d, J = 2.1 Hz), 8.20 (1H, dd, J = 8.5, 2.1 Hz), 7.67 (1H, d, J = 9.4 Hz), 7.33 (1H, d, J = 8.5 Hz), 3.08 ( 4H, s), 2.56 (4H, s), 2.32 (2H, t, J = 7.4 Hz), 1.53-1.44 (2H, m), 0.89 (3H, t, J = 7.3 Hz).

工程３
5-((3-(3-クロロ-4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１９６) Process 3
5-((3- (3-Chloro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 196)

Figure JPOXMLDOC01-appb-C000835
Figure JPOXMLDOC01-appb-C000835

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオンの合成 (実施例64、工程1) と同様の手法で、3-(3-クロロ-4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (25 mg, 0.0651 mmol) およびチアゾリジン-2,4-ジオン (8 mg, 0.0651 mmol) から標記化合物 (9 mg, 29%) を得た。橙色固体: 1H-NMR (DMSO-D6) δ: 8.39 (1H, d, J = 2.1 Hz), 8.28 (1H, s), 8.27 (1H, d, J = 9.4 Hz), 7.97 (1H, dd, J = 8.5, 2.1 Hz), 7.73 (1H, s), 7.66 (1H, d, J = 9.4 Hz), 7.31 (1H, d, J = 8.5 Hz), 3.16 (4H, s), 2.83 (4H, s), 2.59-2.54 (2H, m), 1.61-1.51 (2H, m), 0.91 (3H, t, J = 7.4 Hz).
ESI-MS(m/z): 483[M+H]+. Synthesis of 5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64) In the same manner as in step 1), 3- (3-chloro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (25 mg, 0.0651 mmol) and thiazolidine-2,4-dione (8 mg, 0.0651 mmol) gave the title compound (9 mg, 29%). Orange solid: 1 H-NMR (DMSO-D 6 ) δ: 8.39 (1H, d, J = 2.1 Hz), 8.28 (1H, s), 8.27 (1H, d, J = 9.4 Hz), 7.97 (1H, dd, J = 8.5, 2.1 Hz), 7.73 (1H, s), 7.66 (1H, d, J = 9.4 Hz), 7.31 (1H, d, J = 8.5 Hz), 3.16 (4H, s), 2.83 ( 4H, s), 2.59-2.54 (2H, m), 1.61-1.51 (2H, m), 0.91 (3H, t, J = 7.4 Hz).
ESI-MS (m / z): 483 [M + H] + .

実施例１９７
5-((3-(3-クロロ-4-(4-シクロペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１９７) Example 197
5-((3- (3-Chloro-4- (4-cyclopentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 197)

工程１
3-(3-クロロ-4-(4-シクロペンチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン Process 1
3- (3-Chloro-4- (4-cyclopentylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine

Figure JPOXMLDOC01-appb-C000836
Figure JPOXMLDOC01-appb-C000836

3-(4-(4-イソプロピルピペラジン-1-イル)-3-メチルフェニル)-6-ビニルイミダゾ[1,2-b]ピリダジンの合成 (実施例184、工程1) と同様の手法で、3-(3-クロロ-4-(ピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (124 mg, 0.365 mmol) およびシクロペンタノン (65 μL, 0.730 mmol) から標記化合物 (94 mg, 63%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.27 (1H, d, J = 2.1 Hz), 8.26 (1H, s), 8.19 (1H, d, J = 9.2 Hz), 8.13 (1H, dd, J = 8.5, 2.1 Hz), 7.66 (1H, d, J = 9.6 Hz), 7.28 (1H, d, J = 8.5 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.38 (1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.4 Hz), 3.05 (4H, s), 2.60 (4H, s), 2.55-2.50 (1H, m), 1.87-1.79 (2H, m), 1.69-1.59 (2H, m), 1.57-1.48 (2H, m), 1.41-1.32 (2H, m). Synthesis of 3- (4- (4-isopropylpiperazin-1-yl) -3-methylphenyl) -6-vinylimidazo [1,2-b] pyridazine (Example 184, Step 1) From 3- (3-chloro-4- (piperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (124 mg, 0.365 mmol) and cyclopentanone (65 μL, 0.730 mmol) The title compound (94 mg, 63%) was obtained. Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.27 (1H, d, J = 2.1 Hz), 8.26 (1H, s), 8.19 (1H, d, J = 9.2 Hz), 8.13 (1H, dd, J = 8.5, 2.1 Hz), 7.66 (1H, d, J = 9.6 Hz), 7.28 (1H, d, J = 8.5 Hz), 6.91 (1H, dd, J = 17.7, 11.1 Hz), 6.38 ( 1H, d, J = 17.6 Hz), 5.79 (1H, d, J = 11.4 Hz), 3.05 (4H, s), 2.60 (4H, s), 2.55-2.50 (1H, m), 1.87-1.79 (2H , m), 1.69-1.59 (2H, m), 1.57-1.48 (2H, m), 1.41-1.32 (2H, m).

工程２
3-(3-クロロ-4-(4-シクロペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 2
3- (3-Chloro-4- (4-cyclopentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000837
Figure JPOXMLDOC01-appb-C000837

3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒドの合成 (実施例63、工程3) と同様の手法で、3-(3-クロロ-4-(4-シクロペンチルピペラジン-1-イル)フェニル)-6-ビニルイミダゾ[1,2-b]ピリダジン (94 mg, 0.230 mmol) および2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (58 μl, 4.60 μmol) から標記化合物 (68 mg, 72%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 10.0 (1H, d, J = 0.9 Hz), 8.50 (1H, s), 8.38 (1H, dd, J =9.4, 0.9 Hz), 8.29 (1H, d, J =2.1 Hz), 8.20 (1H, dd, J = 8.5, 2.3 Hz), 7.67 (1H, d, J = 9.4 Hz), 7.31 (1H, d, J = 8.5 Hz), 3.07 (4H, s), 2.61 (4H, s), 2.55-2.48 (1H, m), 1.85-1.79 (2H, m), 1.66-1.59 (2H, m), 1.57-1.50 (2H, m), 1.41-1.32 (2H, m). Synthesis of 3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (Example 63, Step 3) 3-chloro-4- (4-cyclopentylpiperazin-1-yl) phenyl) -6-vinylimidazo [1,2-b] pyridazine (94 mg, 0.230 mmol) and 2.5 wt% osmium tetroxide solution in tert-butanol ( The title compound (68 mg, 72%) was obtained from 58 μl, 4.60 μmol). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 10.0 (1H, d, J = 0.9 Hz), 8.50 (1H, s), 8.38 (1H, dd, J = 9.4, 0.9 Hz), 8.29 ( 1H, d, J = 2.1 Hz), 8.20 (1H, dd, J = 8.5, 2.3 Hz), 7.67 (1H, d, J = 9.4 Hz), 7.31 (1H, d, J = 8.5 Hz), 3.07 ( 4H, s), 2.61 (4H, s), 2.55-2.48 (1H, m), 1.85-1.79 (2H, m), 1.66-1.59 (2H, m), 1.57-1.50 (2H, m), 1.41- 1.32 (2H, m).

工程３
5-((3-(3-クロロ-4-(4-シクロペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１９７) Process 3
5-((3- (3-Chloro-4- (4-cyclopentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (compound 197)

Figure JPOXMLDOC01-appb-C000838
Figure JPOXMLDOC01-appb-C000838

5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (実施例64、工程1) の合成と同様の手法で、3-(3-クロロ-4-(4-シクロペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (68 mg, 0.166 mmol) およびチアゾリジン-2,4-ジオン (19 mg, 0.166 mmol) から標記化合物 (25 mg, 30%) を得た。黄色固体: 1H-NMR (DMSO-D6) δ: 8.40 (1H, d, J = 2.3 Hz), 8.28 (1H, s), 8.26 (1H, d, J = 9.2 Hz), 7.98 (1H, dd, J = 8.4, 2.2 Hz), 7.71 (1H, s), 7.65 (1H, d, J = 9.4 Hz), 7.30 (1H, d, J = 8.5 Hz), 3.17 (4H, s), 2.91 (4H, s), 2.69-2.63 (1H, m), 1.95-1.86 (2H, m), 1.72-1.62 (2H, m), 1.60-1.44 (4H, m).
ESI-MS(m/z): 509[M+H]+. 5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Example 64, process 1) 3- (3-Chloro-4- (4-cyclopentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (68 mg, 0.166 mmol) and thiazolidine-2,4-dione (19 mg, 0.166 mmol) gave the title compound (25 mg, 30%). Yellow solid: 1 H-NMR (DMSO-D 6 ) δ: 8.40 (1H, d, J = 2.3 Hz), 8.28 (1H, s), 8.26 (1H, d, J = 9.2 Hz), 7.98 (1H, dd, J = 8.4, 2.2 Hz), 7.71 (1H, s), 7.65 (1H, d, J = 9.4 Hz), 7.30 (1H, d, J = 8.5 Hz), 3.17 (4H, s), 2.91 ( 4H, s), 2.69-2.63 (1H, m), 1.95-1.86 (2H, m), 1.72-1.62 (2H, m), 1.60-1.44 (4H, m).
ESI-MS (m / z): 509 [M + H] + .

実施例１９８
5-((3-(4-(2-(ジメチルアミノ)エトキシ)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１９８) Example 198
5-((3- (4- (2- (dimethylamino) ethoxy) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 198)

工程１
4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェノール Process 1
4- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) phenol

Figure JPOXMLDOC01-appb-C000839
Figure JPOXMLDOC01-appb-C000839

3-ブロモ-6-クロロイミダゾ[1,2-b]ピリダジン (2.11 g, 9.09 mmol) の 1,4-ジオキサン (100 mL)、水 (16 mL) の混合溶液中に、4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノール (2.00 g, 9.09 mmol)、テトラキストリフェニルホスフィンパラジウム(420 mg, 0.36 mmol)、炭酸ナトリウム (3.37 g, 31.8 mmol) を添加した。アルゴン置換した後、還流条件下一晩撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (1.29 g, 58%) を得た。 1H-NMR (DMSO-D6) δ: 9.80 (1H, s), 8.26 (1H, d, J = 9.2 Hz), 8.17 (1H, s), 7.90 (2H, d, J = 9.2 Hz), 7.36 (1H, d, J = 9.2 Hz), 6.93 (2H, d, J = 9.2 Hz).
ESI-MS(m/z): 246[M+H]+. In a mixed solution of 3-bromo-6-chloroimidazo [1,2-b] pyridazine (2.11 g, 9.09 mmol) in 1,4-dioxane (100 mL) and water (16 mL), 4- (4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (2.00 g, 9.09 mmol), tetrakistriphenylphosphine palladium (420 mg, 0.36 mmol), sodium carbonate (3.37 g, 31.8 mmol) was added. After purging with argon, the mixture was stirred overnight under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (1.29 g, 58%). 1 H-NMR (DMSO-D 6 ) δ: 9.80 (1H, s), 8.26 (1H, d, J = 9.2 Hz), 8.17 (1H, s), 7.90 (2H, d, J = 9.2 Hz), 7.36 (1H, d, J = 9.2 Hz), 6.93 (2H, d, J = 9.2 Hz).
ESI-MS (m / z): 246 [M + H] + .

工程２
2-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェノキシ)-N,N-ジメチルエタンアミン Process 2
2- (4- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) phenoxy) -N, N-dimethylethanamine

Figure JPOXMLDOC01-appb-C000840
Figure JPOXMLDOC01-appb-C000840

4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェノール (500 mg, 2.04 mmol)、2-クロロ-N,N-ジメチルエタンアミン塩酸塩 (586 mg, 4.07 mmol)、炭酸セシウム (3.32 g, 10.18 mmol)、ヨウ化ナトリウム (16 mg, 0.10 mmol) のN,N-ジメチルホルムアミド (20 mL) 溶液をアルゴン雰囲気下、120℃で一晩撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (265 mg, 41%) を得た。 1H-NMR (DMSO-D6) δ: 8.28 (1H, d, J = 10.0 Hz), 8.24 (1H, s), 8.01 (2H, d, J = 9.2 Hz), 7.38 (1H, d, J = 10.0 Hz), 7.13 (2H, d, J = 9.2 Hz), 4.13 (2H, t, J = 5.7 Hz), 2.66 (2H, t, J = 5.7 Hz), 2.24 (6H, s).
ESI-MS(m/z): 317[M+H]+. 4- (6-chloroimidazo [1,2-b] pyridazin-3-yl) phenol (500 mg, 2.04 mmol), 2-chloro-N, N-dimethylethanamine hydrochloride (586 mg, 4.07 mmol), A solution of cesium carbonate (3.32 g, 10.18 mmol) and sodium iodide (16 mg, 0.10 mmol) in N, N-dimethylformamide (20 mL) was stirred overnight at 120 ° C. under an argon atmosphere. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (265 mg, 41%). 1 H-NMR (DMSO-D 6 ) δ: 8.28 (1H, d, J = 10.0 Hz), 8.24 (1H, s), 8.01 (2H, d, J = 9.2 Hz), 7.38 (1H, d, J = 10.0 Hz), 7.13 (2H, d, J = 9.2 Hz), 4.13 (2H, t, J = 5.7 Hz), 2.66 (2H, t, J = 5.7 Hz), 2.24 (6H, s).
ESI-MS (m / z): 317 [M + H] + .

工程３
N,N-ジメチル-2-(4-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)フェノキシ)エタンアミン Process 3
N, N-dimethyl-2- (4- (6-vinylimidazo [1,2-b] pyridazin-3-yl) phenoxy) ethanamine

Figure JPOXMLDOC01-appb-C000841
Figure JPOXMLDOC01-appb-C000841

2-(4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェノキシ)-N,N-ジメチルエタンアミン (265 mg, 0.84 mmol) の 1,4-ジオキサン (10 mL)、水(2 mL) の混合溶液中に 4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン(157 μL, 0.92 mmol)、酢酸パラジウム (19 mg, 0.08 mmol)、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル (69 mg, 0.17 mmol)、リン酸三カリウム (1.33 g, 6.27 mmol) を添加した。アルゴン置換した後、還流条件下5時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (ヘキサン/酢酸エチル) で精製し、標記化合物 (104 mg, 40%) を得た。 1H-NMR (DMSO-D6) δ: 8.17 (1H, d, J = 9.2 Hz), 8.14 (1H, s), 8.09 (2H, d, J = 8.7 Hz), 7.63 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 8.7 Hz), 6.90 (1H, dd, J = 17.9, 11.0 Hz), 6.36 (1H, d, J = 17.9 Hz), 5.77 (1H, d, J = 11.0 Hz), 4.12 (2H, t, J = 6.0 Hz), 2.65 (2H, t, J = 6.0 Hz), 2.23 (6H, s).
ESI-MS(m/z): 309[M+H]+. 2- (4- (6-Chloroimidazo [1,2-b] pyridazin-3-yl) phenoxy) -N, N-dimethylethanamine (265 mg, 0.84 mmol) of 1,4-dioxane (10 mL) , 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (157 μL, 0.92 mmol), palladium acetate (19 mg, 0.08 mmol) in a mixed solution of water (2 mL) 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (69 mg, 0.17 mmol) and tripotassium phosphate (1.33 g, 6.27 mmol) were added. After replacing with argon, the mixture was stirred for 5 hours under reflux conditions. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (104 mg, 40%). 1 H-NMR (DMSO-D 6 ) δ: 8.17 (1H, d, J = 9.2 Hz), 8.14 (1H, s), 8.09 (2H, d, J = 8.7 Hz), 7.63 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 8.7 Hz), 6.90 (1H, dd, J = 17.9, 11.0 Hz), 6.36 (1H, d, J = 17.9 Hz), 5.77 (1H, d, J = 11.0 Hz), 4.12 (2H, t, J = 6.0 Hz), 2.65 (2H, t, J = 6.0 Hz), 2.23 (6H, s).
ESI-MS (m / z): 309 [M + H] + .

工程４
3-(4-(2-(ジメチルアミノ)エトキシ)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド Process 4
3- (4- (2- (Dimethylamino) ethoxy) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde

Figure JPOXMLDOC01-appb-C000842
Figure JPOXMLDOC01-appb-C000842

N,N-ジメチル-2-(4-(6-ビニルイミダゾ[1,2-b]ピリダジン-3-イル)フェノキシ)エタンアミン (104 mg, 0.34 mmol) の 1,4-ジオキサン (5 mL)、水 (1 mL) の混合溶液中に、2.5 wt% 四酸化オスミウム tert-ブタノール溶液 (85 μL, 6.74 μmol)、2,6-ルチジン (79 μL, 0.67 mmol)、過ヨウ素酸ナトリウム (289 mg, 1.35 mmol) を添加した。アルゴン置換した後、室温で4時間撹拌した。反応終了後、セライトろ過した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー法 (クロロホルム/メタノール) で精製し、標記化合物 (45 mg, 43 %, 0.15 mmol) を得た。 1H-NMR (DMSO-D6) δ: 10.03 (1H, s), 8.40 (1H, s), 8.36 (1H, d, J = 9.2 Hz), 8.16 (2H, d, J = 9.2 Hz), 7.64 (1H, d, J = 9.2 Hz), 7.14 (2H, d, J = 9.2 Hz), 4.17-4.12 (4H, m), 2.69-2.65 (4H, m), 2.24 (6H, s). 
ESI-MS(m/z): 311[M+H]+. N, N-dimethyl-2- (4- (6-vinylimidazo [1,2-b] pyridazin-3-yl) phenoxy) ethanamine (104 mg, 0.34 mmol) of 1,4-dioxane (5 mL), In a mixed solution of water (1 mL), 2.5 wt% osmium tetroxide tert-butanol solution (85 μL, 6.74 μmol), 2,6-lutidine (79 μL, 0.67 mmol), sodium periodate (289 mg, 1.35 mmol) was added. After purging with argon, the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was filtered through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (45 mg, 43%, 0.15 mmol). 1 H-NMR (DMSO-D 6 ) δ: 10.03 (1H, s), 8.40 (1H, s), 8.36 (1H, d, J = 9.2 Hz), 8.16 (2H, d, J = 9.2 Hz), 7.64 (1H, d, J = 9.2 Hz), 7.14 (2H, d, J = 9.2 Hz), 4.17-4.12 (4H, m), 2.69-2.65 (4H, m), 2.24 (6H, s).
ESI-MS (m / z): 311 [M + H] + .

工程５
5-((3-(4-(2-(ジメチルアミノ)エトキシ)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (化合物１９８) Process 5
5-((3- (4- (2- (dimethylamino) ethoxy) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (Compound 198)

Figure JPOXMLDOC01-appb-C000843
Figure JPOXMLDOC01-appb-C000843

3-(4-(2-(ジメチルアミノ)エトキシ)フェニル)イミダゾ[1,2-b]ピリダジン-6-カルボアルデヒド (45 mg, 0.15 mmol) をアセトニトリル (3 mL) に溶かし、チアゾリジン-2,4-ジオン (17 mg, 0.15mmol)、ピペリジン (2.9 μL, 0.03 mmol)、および酢酸 (3.3 μL, 0.06 mmol)を加え、100℃で一晩撹拌した。反応終了後、トリエチルアミン (8.1 μL, 0.06 mmol) を添加した後、ろ過しアセトニトリルで洗浄した。標記化合物(15 mg, 25%) を得た。 1H-NMR (DMSO-D6) δ: 8.28-8.09 (4H, m), 7.56 (2H, d, J = 9.6 Hz), 7.15 (2H, d, J = 9.6 Hz), 4.32 (2H, t, J = 5.3 Hz), 3.23 (2H, t, J = 5.3 Hz), 2.65 (6H, s).
ESI-MS(m/z): 410[M+H]+. 3- (4- (2- (dimethylamino) ethoxy) phenyl) imidazo [1,2-b] pyridazine-6-carbaldehyde (45 mg, 0.15 mmol) was dissolved in acetonitrile (3 mL) and thiazolidine-2, 4-dione (17 mg, 0.15 mmol), piperidine (2.9 μL, 0.03 mmol), and acetic acid (3.3 μL, 0.06 mmol) were added, and the mixture was stirred at 100 ° C. overnight. After completion of the reaction, triethylamine (8.1 μL, 0.06 mmol) was added, followed by filtration and washing with acetonitrile. The title compound (15 mg, 25%) was obtained. 1 H-NMR (DMSO-D 6 ) δ: 8.28-8.09 (4H, m), 7.56 (2H, d, J = 9.6 Hz), 7.15 (2H, d, J = 9.6 Hz), 4.32 (2H, t , J = 5.3 Hz), 3.23 (2H, t, J = 5.3 Hz), 2.65 (6H, s).
ESI-MS (m / z): 410 [M + H] + .

実施例１９９
5-((3-(3-フルオロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン メタンスルホンナート (化合物１９９) Example 199
5-((3- (3-Fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione methanesulfone Nart (Compound 199)

Figure JPOXMLDOC01-appb-C000844
Figure JPOXMLDOC01-appb-C000844

工程１
5-((3-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン メタンスルホンナートの合成と同様の手法で、5-((3-(3-フルオロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (952 mg, 2.04 mmol) から標記化合物 (926 mg, 81%) を得た。褐色結晶: 1H-NMR (DMSO-D6) δ: 12.73 (1H, br s), 9.31 (1H, br s), 8.34 (1H, d, J = 9.2 Hz), 8.30 (1H, s), 8.06 (1H, dd, J= 14.2, 1.8 Hz), 7.95 (1H, s), 7.82 (1H, dd, J = 8.9, 1.8 Hz), 7.74 (1H, d, J = 9.2 Hz), 7.29 (1H, t, J= 8.9 Hz), 3.70-3.67 (2H, m), 3.60-3.55 (3H, m), 3.34-3.26 (2H, m), 3.19-3.12 (2H, m), 2.30 (3H, s), 1.32 (6H, d, J= 6.4 Hz). Process 1
5-((3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione methanesulfone In a manner similar to the synthesis of narate, 5-((3- (3-fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) The title compound (926 mg, 81%) was obtained from thiazolidine-2,4-dione (952 mg, 2.04 mmol). Brown crystals: 1 H-NMR (DMSO-D 6 ) δ: 12.73 (1H, br s), 9.31 (1H, br s), 8.34 (1H, d, J = 9.2 Hz), 8.30 (1H, s), 8.06 (1H, dd, J = 14.2, 1.8 Hz), 7.95 (1H, s), 7.82 (1H, dd, J = 8.9, 1.8 Hz), 7.74 (1H, d, J = 9.2 Hz), 7.29 (1H , t, J = 8.9 Hz), 3.70-3.67 (2H, m), 3.60-3.55 (3H, m), 3.34-3.26 (2H, m), 3.19-3.12 (2H, m), 2.30 (3H, s ), 1.32 (6H, d, J = 6.4 Hz).

実施例２００
5-((3-(3-フルオロ-4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン メタンスルホンナート (化合物２００) Example 200
5-((3- (3-Fluoro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione methanesulfone Nart (compound 200)

Figure JPOXMLDOC01-appb-C000845
Figure JPOXMLDOC01-appb-C000845

工程１
5-((3-(3-フルオロ-4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン (513 mg, 1.1 mmol) をメタノール (11 mL)、水 (6 mL) に懸濁した。そこへメタンスルホン酸 (106 mg, 1.1 mmol) を加え、室温で10分撹拌し溶解させた。反応液を濃縮乾固し、得られた固体にメタノールを加え30分加熱還流した。反応液を冷却して吸引ろ過し、得られた結晶をメタノールとエーテルで洗浄し、標記化合物 (0.58 g, 94%) を得た。赤橙色固体: 1H-NMR (DMSO-D6) δ: 9.37 (1H, br s), 8.30 (1H, d, J = 9.2 Hz), 8.27 (1H, s), 8.02 (1H, dd, J = 12.4, 1.8 Hz), 7.91 (1H, s), 7.78 (1H, dd, J = 6.4, 1.8 Hz), 7.71 (1H, d, J = 9.6 Hz), 7.24 (1H, t, J = 8.9 Hz), 3.63-3.55 (4H, m), 3.27-3.17 (4H, m), 3.29-3.18 (2H, m), 3.15-3.05 (4H, m), 2.25 (3H, s), 1.72-1.61 (2H, m), 0.91 (3H, t, J = 7.3 Hz). Process 1
5-((3- (3-Fluoro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione (513 mg, 1.1 mmol) was suspended in methanol (11 mL) and water (6 mL). Methanesulfonic acid (106 mg, 1.1 mmol) was added thereto, and the mixture was stirred for 10 minutes at room temperature to dissolve. The reaction solution was concentrated to dryness, methanol was added to the obtained solid, and the mixture was heated to reflux for 30 minutes. The reaction mixture was cooled and suction filtered, and the resulting crystals were washed with methanol and ether to give the title compound (0.58 g, 94%). Red-orange solid: 1 H-NMR (DMSO-D 6 ) δ: 9.37 (1H, br s), 8.30 (1H, d, J = 9.2 Hz), 8.27 (1H, s), 8.02 (1H, dd, J = 12.4, 1.8 Hz), 7.91 (1H, s), 7.78 (1H, dd, J = 6.4, 1.8 Hz), 7.71 (1H, d, J = 9.6 Hz), 7.24 (1H, t, J = 8.9 Hz ), 3.63-3.55 (4H, m), 3.27-3.17 (4H, m), 3.29-3.18 (2H, m), 3.15-3.05 (4H, m), 2.25 (3H, s), 1.72-1.61 (2H , m), 0.91 (3H, t, J = 7.3 Hz).

試験例１
Ｐｉｍ－１，Ｐｉｍ－２およびＰｉｍ－３活性に対する阻害作用の評価法
　蛍光共鳴エネルギー転移（ＦＲＥＴ）法を利用したＰｉｍ活性測定法により、表１～表５に示す本発明化合物のｉｎ ｖｉｔｒｏにおけるＰｉｍ－１，Ｐｉｍ－２およびＰｉｍ－３阻害作用を評価した。なお、本実験では、Ｐｉｍ阻害作用を有することが知られているＳＧＩ－１７７６（非特許文献９）を陽性対照薬として用いた。ＤＭＳＯに溶解した被験化合物をＡＴＰ含有Ｍｉｌｌｉ－Ｑ水で希釈後、３８４ウェル黒色プレートに５μＬ／ｗｅｌｌ加えた。さらに２ｘ ｋｉｎａｓｅ ｂｕｆｆｅｒ（１００ｍＭ ＨＥＰＥＳ，ｐＨ７．５，２０ｍＭ ＭｇＣｌ２，２ｍＭ ＥＧＴＡ，０．０２％Ｂｒｉｊ－３５）で調製したＰｉｍおよびＳｅｒ／Ｔｈｒ７ ｐｅｐｔｉｄｅ（ｉｎｖｉｔｒｏｇｅｎ）を５μＬ／ｗｅｌｌ加え、２５℃にて１時間インキュベートした。インキュベート後、Dｅｖｅｌｏｐｍｅｎｔ Ｓｏｌｕｔｉｏｎ（ｉｎｖｉｔｒｏｇｅｎ）を５μＬ／ｗｅｌｌ加えて、さらに２５℃にて１時間インキュベート後、蛍光強度（ｅｘｃｉｔａｔｉｏｎ：４００ｎｍ／ｅｍｉｓｓｉｏｎ：４４５ｎｍおよびｅｘｃｉｔａｔｉｏｎ：４００ｎｍ／ｅｍｉｓｓｉｏｎ：５２０ｎｍ）を測定し、ペプチド基質のリン酸化率（％）を算出した。なお、コントロールは被験化合物を含まない条件で測定した。表１～表５に、本発明化合物のＰｉｍ－１、Ｐｉｍ－２およびＰｉｍ－３活性に及ぼす作用をＩＣ５０値（Ｐｉｍ活性を５０％阻害する化合物の濃度）で表した。また、図１は化合物３とＳＧＩ－１７７６のＰｉｍ－１、Ｐｉｍ－２およびＰｉｍ－３活性に及ぼす用量依存的な阻害作用を表す。本発明化合物はＰｉｍ－１、Ｐｉｍ－２およびＰｉｍ－３に対して阻害作用を有していることでより高いがん細胞増殖抑制効果が期待できるため、全てのアイソザイムに対してＩＣ５０値が1μＭ以下であるものについて評価した。本発明の化合物は、Ｐｉｍ－１、Ｐｉｍ－２およびＰｉｍ－３に対して強力な阻害作用を示した。 Test example 1
Evaluation Method of Inhibitory Action on Pim-1, Pim-2 and Pim-3 Activity Pim activity measurement method using fluorescence resonance energy transfer (FRET) method was used for in vitro Pim of the compounds of the present invention shown in Tables 1 to 5. -1, Pim-2 and Pim-3 inhibitory effects were evaluated. In this experiment, SGI-1776 (Non-patent Document 9), which is known to have a Pim inhibitory action, was used as a positive control drug. The test compound dissolved in DMSO was diluted with ATP-containing Milli-Q water, and added to a 384 well black plate at 5 μL / well. Further, Pim and Ser / Thr7 peptide (invitrogen) prepared with 2 × kinase buffer (100 mM HEPES, pH 7.5, 20 mM MgCl 2 , 2 mM EGTA, 0.02% Brij-35) were added at 5 μL / well, and 1 at 25 ° C. Incubated for hours. After incubation, 5 μL / well of Development Solution (invitrogen) was added, and further incubated at 25 ° C. for 1 hour, and then the fluorescence intensity (excitation: 400 nm / emission: 445 nm and excitation: 400 nm / emission: 520 nm) was measured. The phosphorylation rate (%) of was calculated. In addition, control was measured on the conditions which do not contain a test compound. Tables 1 to 5 show the effects of the compounds of the present invention on Pim-1, Pim-2 and Pim-3 activities as IC 50 values (concentrations of compounds that inhibit Pim activity by 50%). FIG. 1 also shows the dose-dependent inhibitory effect of Compound 3 and SGI-1776 on Pim-1, Pim-2 and Pim-3 activities. Since the compound of the present invention has an inhibitory action on Pim-1, Pim-2 and Pim-3, it can be expected to have a higher cancer cell proliferation inhibitory effect. Therefore, an IC 50 value is obtained for all isozymes. Evaluation was made for those of 1 μM or less. The compounds of the present invention showed a potent inhibitory action against Pim-1, Pim-2 and Pim-3.

Figure JPOXMLDOC01-appb-T000846
Figure JPOXMLDOC01-appb-T000846

Figure JPOXMLDOC01-appb-T000847
Figure JPOXMLDOC01-appb-T000847

Figure JPOXMLDOC01-appb-T000848
Figure JPOXMLDOC01-appb-T000848

Figure JPOXMLDOC01-appb-T000849
Figure JPOXMLDOC01-appb-T000849

Figure JPOXMLDOC01-appb-T000850
Figure JPOXMLDOC01-appb-T000850

試験例２
がん細胞の増殖に対する抑制作用
　表６～表８に示す本発明化合物について、ヒト肺がんＡ５４９細胞、ヒト大腸がんＨＴ－２９細胞およびヒト大腸がんＨＣＴ１１６細胞の増殖に及ぼす作用をｉｎ ｖｉｔｒｏにて評価した。なお、本実験では、Ｐｉｍ阻害作用を有することが知られているＳＧＩ－１７７６を陽性対照薬として用いた。各細胞を１０％ＦＢＳ／ＲＰＭＩ１６４０に浮遊させ、９６ウェルプレートに播種して５％ＣＯ２、３７℃にて３時間培養後、ＤＭＳＯに溶解した被験化合物を１０％ＦＢＳ／ＲＰＭＩ１６４０で希釈して加え、さらに９６時間培養した。培養後、ＴｅｔｒａＣｏｌｏｒ ＯＮＥ（生化学工業）を使用して、添付の操作手順に従って生細胞数を測定した。なお、コントロールは被験化合物を含まない条件で測定した。表６～表８に、本発明化合物のＡ５４９、ＨＴ－２９およびＨＣＴ１１６細胞の増殖に及ぼす作用をＩＣ５０値（細胞増殖を５０％抑制する化合物の濃度）で表した。また、図２は化合物３とＳＧＩ－１７７６のＡ５４９、ＨＴ－２９およびＨＣＴ１１６細胞の増殖に及ぼす用量依存的な抑制作用を表す。本発明の化合物は、Ａ５４９、ＨＴ－２９およびＨＣＴ１１６細胞の増殖に対して強力な抑制作用を示した。 Test example 2
Inhibitory action on proliferation of cancer cells The compounds of the present invention shown in Tables 6 to 8 have an in vitro effect on the proliferation of human lung cancer A549 cells, human colon cancer HT-29 cells and human colon cancer HCT116 cells. evaluated. In this experiment, SGI-1776, which is known to have a Pim inhibitory action, was used as a positive control drug. Each cell was suspended in 10% FBS / RPMI1640, seeded in a 96-well plate, cultured at 5% CO 2 and 37 ° C. for 3 hours, and a test compound dissolved in DMSO was diluted with 10% FBS / RPMI1640 and added. The cells were further cultured for 96 hours. After culturing, the number of viable cells was measured using TetraColor ONE (Seikagaku Corporation) according to the attached operation procedure. In addition, control was measured on the conditions which do not contain a test compound. Tables 6 to 8 show the effects of the compounds of the present invention on the proliferation of A549, HT-29 and HCT116 cells as IC 50 values (concentrations of compounds that inhibit cell proliferation by 50%). FIG. 2 also shows the dose-dependent inhibitory effect of Compound 3 and SGI-1776 on the proliferation of A549, HT-29 and HCT116 cells. The compounds of the present invention showed a strong inhibitory effect on the proliferation of A549, HT-29 and HCT116 cells.

Figure JPOXMLDOC01-appb-T000851
Figure JPOXMLDOC01-appb-T000851

Figure JPOXMLDOC01-appb-T000852
Figure JPOXMLDOC01-appb-T000852

Figure JPOXMLDOC01-appb-T000853
Figure JPOXMLDOC01-appb-T000853

試験例３
４Ｅ－ＢＰ１およびＢＡＤのリン酸化に対する抑制作用
　がん細胞の増殖に対して抑制作用を示した本発明の化合物が、細胞内のＰｉｍを標的としていることを確認する目的で、ヒト前立腺がんＰＣ－３細胞における４Ｅ－ＢＰ１およびＢＡＤのリン酸化に及ぼす作用をウェスタンブロッティング法により検討した。ＰＣ－３細胞に被験化合物を含む０％ＦＢＳ／ＲＰＭＩ１６４０を加えて、５％ＣＯ２、３７℃にて３時間培養した。なお、コントロールには被験化合物を含まない０％ＦＢＳ／ＲＰＭＩ１６４０を使用した。その後、細胞を氷冷ＰＢＳで２回洗浄し、可溶化溶液（１０ｍＭ Ｔｒｉｓ－ＨＣｌ，ｐＨ７．４，０．１％ＮＰ－４０，０．１％デオキシコール酸ナトリウム，０．１％ＳＤＳ，０．１５Ｍ ＮａＣｌ，１ｍＭ ＥＤＴＡ，１０μｇ／ｍｌ アプロチニン）を加えて細胞を溶解した。この溶解液について電気泳動を実施し、アクリルアミドゲル内の蛋白質を、セミドライ型転写装置を用いてイモビロンＰＶＤＦメンブランに転写した。転写後、メンブランをブロッキングし、一次抗体（抗Ｐｈｏｓｐｈｏ－４Ｅ－ＢＰ１ Ｔｈｒ３７／４６抗体：Ｃｅｌｌ Ｓｉｇｎａｌｉｎｇ Ｔｅｃｈｎｏｌｏｇｙ、抗４Ｅ－ＢＰ１抗体：Ｃｅｌｌ Ｓｉｇｎａｌｉｎｇ Ｔｅｃｈｎｏｌｏｇｙ、抗Ｐｈｏｓｐｈｏ－ＢＡＤ（ｐＳｅｒ１１２）抗体：Ｓｉｇｍａ Ａｌｄｒｉｃｈ、抗ＢＡＤ抗体：Ｓｉｇｍａ Ａｌｄｒｉｃｈ、抗α－Ｔｕｂｕｌｉｎ抗体：Ｓｉｇｍａ Ａｌｄｒｉｃｈ）溶液に４℃で一晩浸した。さらに二次抗体溶液に室温で２時間浸した後、ＥＣＬ ｐｒｉｍｅ（ＧＥ ｈｅａｌｔｈｃａｒｅ）を用いてメンブラン上の目的蛋白質を検出した。その結果、図３に示すように、本発明の化合物は、細胞増殖抑制作用を示す濃度において、４Ｅ－ＢＰ１およびＢＡＤのリン酸化を抑制した。この結果から、本発明の化合物が細胞内のＰｉｍを阻害して細胞増殖抑制作用を発揮することが示唆された。 Test example 3
Inhibitory effect on phosphorylation of 4E-BP1 and BAD For the purpose of confirming that the compound of the present invention showing an inhibitory action on proliferation of cancer cells targets intracellular Pim, human prostate cancer PC The effect on 4E-BP1 and BAD phosphorylation in -3 cells was examined by Western blotting. 0% FBS / RPMI1640 containing a test compound was added to PC-3 cells, and the cells were cultured at 37 ° C for 3 hours with 5% CO 2 . As a control, 0% FBS / RPMI1640 containing no test compound was used. Thereafter, the cells were washed twice with ice-cold PBS, solubilized solution (10 mM Tris-HCl, pH 7.4, 0.1% NP-40, 0.1% sodium deoxycholate, 0.1% SDS, 0 .15M NaCl, 1 mM EDTA, 10 μg / ml aprotinin) was added to lyse the cells. The lysate was subjected to electrophoresis, and the protein in the acrylamide gel was transferred to the Immobilon PVDF membrane using a semi-dry type transfer apparatus. After transcription, the membrane was blocked, and the primary antibody (anti-Phospho-4E-BP1 Thr37 / 46 antibody: Cell Signaling Technology, anti-4E-BP1 antibody: Cell Signaling Technology, anti-Phospho-BAD (Ser112) anti-Phos-BAD (Ser112) antibody) Antibody: Sigma Aldrich, anti-α-Tubulin antibody: Sigma Aldrich) solution at 4 ° C. overnight. Furthermore, after immersing in a secondary antibody solution at room temperature for 2 hours, the target protein on the membrane was detected using ECL prime (GE healthcare). As a result, as shown in FIG. 3, the compound of the present invention inhibited phosphorylation of 4E-BP1 and BAD at a concentration showing a cell growth inhibitory action. From these results, it was suggested that the compound of the present invention inhibits intracellular Pim and exerts cell growth inhibitory action.

試験例４
アポトーシス誘導作用
　細胞内のＤＮＡ断片化を指標に、本発明化合物のがん細胞に対するアポトーシス誘導作用をｉｎ ｖｉｔｒｏにて評価した。なお、本実験では、Ｐｉｍ阻害作用を有することが知られているＳＧＩ－１７７６と、アポトーシスを誘導することが知られているトポイソメラーゼ１阻害剤のＳＮ－３８を陽性対照薬として用いた。ヒト大腸がんＨＣＴ１１６細胞を１％ＦＢＳ／ＲＰＭＩ１６４０に浮遊させ、９６ウェルプレートに播種して５％ＣＯ２、３７℃にて３時間培養後、ＤＭＳＯに溶解した被験化合物を１％ＦＢＳ／ＲＰＭＩ１６４０で希釈して加え、さらに４８時間培養した。培養後、Ｃｅｌｌ Ｄｅａｔｈ Ｄｅｔｅｃｔｉｏｎ ＥＬＩＳＡ ＰＬＵＳ（Ｒｏｃｈｅ）を使用して、添付の操作手順に従って細胞内のＤＮＡ断片量を測定した。なお、コントロールは被験化合物を含まない条件で測定した。結果は、コントロールにおけるＤＮＡ断片量を１とした相対量（Ｆｏｌｄ）で表した。その結果、図４に示すように、本発明の化合物は、細胞増殖抑制作用を示す濃度において、ＤＮＡの断片化を誘導した。この結果から、本発明の化合物がアポトーシス誘導作用を発揮することが示唆された。 Test example 4
Apoptosis-inducing action Using the DNA fragmentation in cells as an index, the apoptosis-inducing action of the compounds of the present invention on cancer cells was evaluated in vitro. In this experiment, SGI-1776, known to have Pim inhibitory action, and SN-38, a topoisomerase 1 inhibitor known to induce apoptosis, were used as positive control drugs. Human colon cancer HCT116 cells were suspended in 1% FBS / RPMI1640, seeded in a 96-well plate, cultured at 5% CO 2 and 37 ° C. for 3 hours, and then the test compound dissolved in DMSO was dissolved in 1% FBS / RPMI1640. Diluted and added and incubated for an additional 48 hours. After culturing, the amount of DNA fragment in the cells was measured using Cell Death Detection ELISA PLUS (Roche) according to the attached operation procedure. In addition, control was measured on the conditions which do not contain a test compound. The result was expressed as a relative amount (Fold) with the amount of DNA fragment in the control as 1. As a result, as shown in FIG. 4, the compound of the present invention induced DNA fragmentation at a concentration exhibiting a cell growth inhibitory action. From these results, it was suggested that the compound of the present invention exerts apoptosis-inducing action.

試験例５
ヒト急性骨髄性白血病ＭＶ－４－１１細胞移植マウスにおける抗腫瘍効果
　本発明化合物のｉｎ ｖｉｖｏにおける抗腫瘍効果についてヒト急性骨髄性白血病ＭＶ－４－１１細胞移植マウスを用いて検討した。雄性、６週齡のＢＡＬＢ／ｃ系マウスの鼠径部皮下にＭＶ－４－１１細胞を移植後（５ｘ１０６ｃｅｌｌｓ／ｍｏｕｓｅ）、１／２ａｂ２（ａは腫瘍の長径、ｂは短径）より求めた推定腫瘍体積が約１００ｍｍ３に達した時点（１日目）より２日に１回３週間、５％グルコースに溶解した本発明の化合物を静脈内（ｉ．ｖ．）または経口（ｐ．ｏ．）投与した。また、コントロールは本発明の化合物の非投与群とした。２２日目に腫瘍を摘出して重量を測定した後、次式により腫瘍増殖阻止率ＩＲ（％）を求めた。
腫瘍増殖阻止率ＩＲ（％） 
＝（１－投与群の腫瘍重量／非投与対照群の腫瘍重量）×１００
　その結果、表９に示すように、本発明の化合物はｉｎ ｖｉｖｏにおいて抗腫瘍効果を発揮することが示された。 Test Example 5
Antitumor effect in mice transplanted with human acute myeloid leukemia MV-4-11 cells The in vivo antitumor effect of the compound of the present invention was examined using mice transplanted with human acute myeloid leukemia MV-4-11 cells. Male, after implantation the MV-4-11 cells groin subcutaneously BALB / c mice of 6 weeks old (5x10 6 cells / mouse), 1 / 2ab 2 (a major axis of the tumor, b is the minor axis) than The compound of the present invention dissolved in 5% glucose is administered intravenously (iv) or orally (p) once every two days for 3 weeks once the estimated tumor volume obtained reaches about 100 mm 3 (Day 1). O.) Administration. The control was a non-administration group of the compound of the present invention. On the 22nd day, the tumor was excised and weighed, and then the tumor growth inhibition rate IR (%) was determined by the following formula.
Tumor growth inhibition rate IR (%)
= (1-tumor weight of administration group / tumor weight of non-administration control group) × 100
As a result, as shown in Table 9, it was shown that the compound of the present invention exerts an antitumor effect in vivo.

Figure JPOXMLDOC01-appb-T000854
Figure JPOXMLDOC01-appb-T000854

Claims (19)

　一般式（１）
Figure JPOXMLDOC01-appb-C000001
 （式中、Ｘは、Ｏ、Ｓ又はＮＨを示し；
Ｒ３は水素原子またはアルキル基を示し；
破線は、少なくとも一つが二重結合であることを示し；
Ｚ1、Ｚ2及びＺ6は、それぞれ独立してＣ、ＣＨ又はＮを示し、Ｚ3、Ｚ4、Ｚ5、Ｚ7及び
Ｚ8は、それぞれ独立してＣ、ＣＨ、Ｎ、ＮＨ、Ｏ又はＳを示し；
Ｙは、Ｃ６－１４芳香族炭化水素基を少なくとも一つ有し、かつ末端若しくは炭素－炭素結合間にエーテル結合を有していてもよく置換基を有していてもよい２価の炭化水素基、置換基を有していてもよくエーテル結合、アルキレン基又は末端若しくは炭素－炭素結合間にエーテル結合を有するアルキレン基を有していてもよい２価の芳香族複素環式基、又は２価のＣ２－１２脂肪族炭化水素基を示し；
Ａｍは、アミノ基、一置換アミノ基、二置換アミノ基、又は置換基を有していてもよい窒素含有飽和複素環式基を示し；
Ｒ1及びＲ2は、それぞれ独立して、水素原子、ハロゲン原子、アルキル基、アルコキシ基、チオアルコキシ基、ヒドロキシ基、アミノ基、一置換アミノ基、二置換アミノ基、ハロゲノアルキル基、シアノ基、ニトロ基、チオアルキル基、チオハロゲノアルキル基、ハロゲノアルコキシ基、アシル基、カルボキシル基、アルキルアミノ基、アルコキシアルキル基、又はアルコキシカルボニル基を示す。）
で表されるチアゾリジン誘導体又はその塩。 General formula (1)
Figure JPOXMLDOC01-appb-C000001
 Wherein X represents O, S or NH;
R 3 represents a hydrogen atom or an alkyl group;
The dashed line indicates that at least one is a double bond;
Z 1 , Z 2 and Z 6 each independently represent C, CH or N, and Z 3 , Z 4 , Z 5 , Z 7 and Z 8 each independently represent C, CH, N, NH, Indicates O or S;
Y has at least one C 6-14 aromatic hydrocarbon group, and may have an ether bond between a terminal or a carbon-carbon bond or may have a substituent. A hydrogen group, an optionally substituted ether group, an alkylene group, or a divalent aromatic heterocyclic group optionally having an alkylene group having an ether bond between the terminal or carbon-carbon bonds, or Represents a divalent C 2-12 aliphatic hydrocarbon group;
Am represents an amino group, a monosubstituted amino group, a disubstituted amino group, or a nitrogen-containing saturated heterocyclic group which may have a substituent;
R 1 and R 2 are each independently a hydrogen atom, halogen atom, alkyl group, alkoxy group, thioalkoxy group, hydroxy group, amino group, monosubstituted amino group, disubstituted amino group, halogenoalkyl group, cyano group Nitro group, thioalkyl group, thiohalogenoalkyl group, halogenoalkoxy group, acyl group, carboxyl group, alkylamino group, alkoxyalkyl group, or alkoxycarbonyl group. )
Or a salt thereof. 　一般式（１）中、Ｒ３が水素原子である請求項１記載のチアゾリジン誘導体又はその塩。 The thiazolidine derivative or a salt thereof according to claim 1, wherein R 3 in formula (1) is a hydrogen atom. 一般式（１）中、Ｙが、Ｃ６－１４芳香族炭化水素基を少なくとも一つ有し、かつ末端若しくは炭素－炭素結合間にエーテル結合を有していてもよく置換基を有していてもよい２価の炭化水素基、又は置換基を有していてもよくエーテル結合、アルキレン基又は末端若しくは炭素－炭素結合間にエーテル結合を有するアルキレン基を有していてもよい２価の芳香族複素環式基である請求項１又は２記載のチアゾリジン誘導体又はその塩。 In the general formula (1), Y has at least one C 6-14 aromatic hydrocarbon group, and may have an ether bond between a terminal or a carbon-carbon bond, and has a substituent. May be a divalent hydrocarbon group, or may have a substituent, an ether bond, an alkylene group, or a divalent hydrocarbon group that has an ether group between the terminal or carbon-carbon bonds. The thiazolidine derivative or a salt thereof according to claim 1 or 2, which is an aromatic heterocyclic group. 　一般式（１）中、ＸがＯ又はＳである請求項１～３のいずれか１項記載のチアゾリジン誘導体又はその塩。 The thiazolidine derivative or a salt thereof according to any one of claims 1 to 3, wherein in the general formula (1), X is O or S. 　一般式（１）中、ＸがＯである請求項１～４のいずれか１項記載のチアゾリジン誘導体又はその塩。 The thiazolidine derivative or a salt thereof according to any one of claims 1 to 4, wherein in the general formula (1), X is O. 　一般式（１）中、
Figure JPOXMLDOC01-appb-C000002
 で表わされる構造が、芳香族環である請求項１～５のいずれか１項記載のチアゾリジン誘導体又はその塩。 In general formula (1),
Figure JPOXMLDOC01-appb-C000002
 The thiazolidine derivative or a salt thereof according to any one of claims 1 to 5, wherein the structure represented by is an aromatic ring. 　一般式（１）中、Ｚ4、Ｚ5及びＺ6がＣ又はＣＨである請求項１～６のいずれか１項記載のチアゾリジン誘導体又はその塩。 The thiazolidine derivative or a salt thereof according to any one of claims 1 to 6, wherein, in the general formula (1), Z 4 , Z 5 and Z 6 are C or CH. 　一般式（１）中、
Figure JPOXMLDOC01-appb-C000003
 で表される構造が、次の（Ａ－１）～（Ａ－２１）から選ばれる構造である請求項１～６のいずれか１項記載のチアゾリジン誘導体又はその塩。
Figure JPOXMLDOC01-appb-C000004
 In general formula (1),
Figure JPOXMLDOC01-appb-C000003
 The thiazolidine derivative or a salt thereof according to any one of claims 1 to 6, wherein the structure represented by the formula (A-1) to (A-21) is a structure selected from the following:
Figure JPOXMLDOC01-appb-C000004
 　一般式（１）中、Ｙが、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素基、置換基を有していてもよい２価のＣ１－１０脂肪族炭化水素－Ｃ６－１４芳香族炭化水素基、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素－Ｃ１－１０脂肪族炭化水素基、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素－Ｏ－、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素－Ｏ－Ｃ１－１０脂肪族炭化水素基、置換基を有していてもよい２価のＣ６－１４芳香族炭化水素－Ｃ１－１０脂肪族炭化水素基－Ｏ－、置換基を有していてもよいＮ、Ｓ及びＯから選ばれるヘテロ原子を１～４個有する２価の単環性若しくは二環性の芳香族複素環式基、置換基を有していてもよいＮ、Ｓ及びＯから選ばれるヘテロ原子を１～４個有する２価の単環性若しくは二環性の芳香族複素環－Ｃ１－１２脂肪族炭化水素基、又は置換基を有していてもよいＮ、Ｓ及びＯから選ばれるヘテロ原子を１～４個有する２価の単環性若しくは二環性の芳香族複素環－Ｏ－Ｃ１－１０脂肪族炭化水素基である請求項１～８のいずれか１項記載のチアゾリジン誘導体又はその塩。 In the general formula (1), Y is a divalent C 6-14 aromatic hydrocarbon group which may have a substituent, or a divalent C 1-10 aliphatic which may have a substituent. Hydrocarbon-C 6-14 aromatic hydrocarbon group, optionally having divalent C 6-14 aromatic hydrocarbon-C 1-10 aliphatic hydrocarbon group, having substituent Divalent C 6-14 aromatic hydrocarbon-O— which may be optionally substituted, Divalent C 6-14 aromatic hydrocarbon-O—C 1-10 aliphatic hydrocarbon group which may have a substituent A divalent C 6-14 aromatic hydrocarbon-C 1-10 aliphatic hydrocarbon group-O- which may have a substituent, N, S and O which may have a substituent A divalent monocyclic or bicyclic aromatic heterocyclic group having 1 to 4 selected heteroatoms, a substituent selected from optionally substituted N, S and O From a divalent monocyclic or bicyclic aromatic heterocyclic ring having 1 to 4 rhoatoms- C 1-12 aliphatic hydrocarbon group, or optionally substituted N, S and O 9. The divalent monocyclic or bicyclic aromatic heterocyclic-O—C 1-10 aliphatic hydrocarbon group having 1 to 4 selected heteroatoms. Thiazolidine derivatives or salts thereof. 　Ａｍが、置換基を有していてもよい窒素含有飽和複素環式基である請求項１～９のいずれか１項記載のチアゾリジン誘導体又はその塩。 The thiazolidine derivative or a salt thereof according to any one of claims 1 to 9, wherein Am is a nitrogen-containing saturated heterocyclic group which may have a substituent. 　下記から選ばれるチアゾリジン誘導体又はその塩。
5-((1-(3-モルホリノプロピル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((2-メチル-1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(3-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン
tert-ブチル 4-(4-(6-((4-オキソ-2-チオキソチアゾリジン-5-イリデン)メチル)-1H-ベンゾ[d]イミダゾール-1-イル)フェニル)ピペラジン-1-カルボキシレート
5-((1-(4-((1-メチルピペリジン-4-イル)オキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((1-(4-((1-メチルピペリジン-4-イル)オキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((1-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((1-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((1-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(3-(2-モルホリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン 
5-((1-(3-(2-モルホリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((1-(4-(2-モルフォリノエトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン 
5-((1-(4-(2-モルフォリノエトキシ)フェニル-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((1-(4-モルフォリノフェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン 
5-((1-(4-(4,4-ジフルオロピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン 
5-((1-(4-(4-ブチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-(4-ブチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((1-(4-([1,4'-ビピペリジン]-1'-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-([1,4'-ビピペリジン]-1'-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((1-(4-(4-モルフォリノピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-(4-モルフォリノピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((1-(4-(4-メチル-1,4-ジアゼパン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン 
5-((1-(4-(4-メチル-1,4-ジアゼパン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((1-(4-((2-(ジメチルアミノ)エチル)(メチル)アミノ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-((2-(ジメチルアミノ)エチル)(メチル)アミノ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((1-(3-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン 
5-((1-(3-(4-(2-メトキシエチル)ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((1-(6-(4-メチルピペラジン-1-イル)ピリジン-3-イル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((1-(6-(4-メチルピペラジン-1-イル)ピリジン-3-イル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-(4-メチルピペラジニル)フェニル)-1H-インドール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-インドール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-(4-メチルピペラジニル)ベンジル)-1H-インドール-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(3-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(3-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(6-(4-メチルピペラジン-1-イル)ピリジン-3-イル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(3-((4-メチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン 
5-((3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-((4-ブチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン 
5-((3-(3-((4-ブチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-((4-ヘキシルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(3-((4-ヘキシルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((1-(4-(ピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((1-(4-(4-メチルピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-(4-メチルピペリジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((1-(4-(3-(ジメチルアミノ)プロプ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-(3-(ジメチルアミノ)プロプ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((1-(4-(3-(ジメチルアミノ)プロピル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-(6-(4-メチルピペラジン-1-イル)ヘキシ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-(6-(4-メチルピペラジン-1-イル)ヘキシ-1-イン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((1-(3-(2-(4-エチルピペラジン-1-イル)エトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((1-(3-(2-(4-エチルピペラジン-1-イル)エトキシ)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-(4-エチルピペラジン-1-イル)-2-(トリフルオロメトキシ)フェニル) -1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((1-(4-(4-エチルピペラジン-1-イル)-2-(トリフルオロメトキシ)フェニル) -1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン 
5-((1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)-2-イミノチアゾリジン-4-オン
5-((3-(3-((4-メチルピペリジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(3-((4-アセチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(3-((4-アセチルピペラジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(3-((4-ヒドロキシピペリジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(3-((4-ヒドロキシピペリジン-1-イル)メチル)フェニル)イミダゾ[1,2-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(4-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
3-メチル-5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-((4-ヘキシルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(3-((4-エチルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(3-((4-ブチルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン 
5-((3-(3-((4-ブチルピペラジン-1-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(3-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-((1-メチルピペリジン-4-イル)メチル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-(4-メチルピペラジン-1-カルボニル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-(4-シクロヘキシルピペラジン-1-カルボニル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(2-フルオロ-4-(4-メチルピペラジン-1-イル)フェニル)-3H-イミダゾ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-インドール-5-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[2,3-c]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[2,3-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン 
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)フロ[3,2-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾフラン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン 
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾフラン-5-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾ[b]チオフェン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン 
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾ[b]チオフェン-5-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-イミダゾ[4,5-c]ピリジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-イミダゾ[4,5-c]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)-[1,2,4]トリアゾロ[4,3-a]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾ[d]イソチアゾール-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン 
5-((3-(4-(4-メチルピペラジン-1-イル)フェニル)ベンゾ[d]イソチアゾール-5-イル)メチレン)チアゾリジン-2,4-ジオン
5-((1-(4-(4-エチルピペラジン-1-イル)フェニル)-1H-ピラゾロ [3,4-b]ピリジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-エチルピペラジン-1-イル)-3,5-ジフルオロフェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-クロロ-4-(4-プロピルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-エチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-エチルピペラジン-1-イル)フェニル)-3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d][1,2,3]トリアゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d][1,2,3]トリアゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-メチルピペラジン-1-イル)-フェニル)ピラゾロ[1,5-a]ピリミジン-5-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(4-(4-メチルピペラジン-1-イル)-フェニル)ピラゾロ[1,5-a]ピリミジン-5-イル)メチレン)チアゾリジン-2,4-ジオン
5-((1-(3-クロロ-4-(4-エチルピペラジン-1-イル)フェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン) チアゾリジン-2,4-ジオン
5-((3-(3-メトキシ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-フルオロ-5-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(3-メチル-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(3-(2-モルホリノエチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン 
5-((3-(3-(2-モルホリノエチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(4-(4-メチルピペラジン-1-イル)-3-(トリフルオロメチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-((1-メチルピペリジン-4-イル)オキシ)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-フルオロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-フルオロ-4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-フルオロ-4-(4-ペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(4-(4-デシルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-(((1-メチルピペリジン-4-イル)オキシ)メチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(3-(4-イソブチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-ブチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-((エチル(プロピル)アミノ)メチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-((1,1-ジオキシドチオモルホリノ)メチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(3-フルオロ-4-((3R,5S)-3,4,5-トリメチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-(6-((2,4-ジオキソチアゾリジン-5-イリデン)メチル)イミダゾ[1,2-b]ピリダジン-3-イル)-2-(4-メチルピペラジン-1-イル)ベンゾニトリル 
5-((3-(3-((1-メチルピペリジン-4-イル)メチル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-(tert-ブチル)-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(2-(4-メチルピペラジン-1-イル)ピリミジン-5-イル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((1-(4-(4-エチルピペラジン-1-イル)-3-フルオロフェニル)-1H-ベンゾ[d]イミダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-エチルピペラジン-1-イル)フェニル)-[1,2,4]トリアゾロ[4,3-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-インダゾール-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン 
5-((1-(4-(4-メチルピペラジン-1-イル)フェニル)-1H-インダゾール-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-デシルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(4-(4-デシルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(4-(4-(tert-ブチル)ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(4-(4-(tert-ブチル)ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-ブチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン 
5-((3-(4-(4-ブチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(4-(4-ペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(2-(4-メチルピペラジン-1-イル)ベンゾ[d]チアゾール-6-イル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)-2-チオキソチアゾリジン-4-オン
5-((3-(2-(4-メチルピペラジン-1-イル)ベンゾ[d]チアゾール-6-イル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
2-(4-(4-(6-((2,4-ジオキソチアゾリジン-5-イリデン)メチル)イミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-イル)アセトニトリル
5-((3-(4-(4-シクロペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-イソブチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
2-(4-(4-(6-((2,4-ジオキソチアゾリジン-5-イリデン)メチル)イミダゾ[1,2-b]ピリダジン-3-イル)フェニル)ピペラジン-1-イル)エチル　アセテート 
5-((3-(4-(4-(2-ヒドロキシエチル)ピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(2-(4-メチルピペラジン-1-イル)チアゾール-5-イル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-メチル-4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-イソプロピルピペラジン-1-イル)-3-メチルフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-エチルピペラジン-1-イル)-3-メチルフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(4-(1-エチルピペリジン-4-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(5-((4-メチルピペラジン-1-イル)メチル)チオフェン-2-イル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-エチル-2,3-ジオキソピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(4-(4-メチル-2-オキソピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(6-(4-メチルピペラジン-1-イル)ベンゾ[d]オキサゾール-2-イル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(5-(2-(ジメチルアミノ)エトキシ)チオフェン-2-イル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(4-(4-シクロペンチルピペラジン-1-イル)-3-フルオロフェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-クロロ-4-(4-メチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-クロロ-4-(4-イソプロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-クロロ-4-(4-エチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
5-((3-(3-クロロ-4-(4-プロピルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン
5-((3-(3-クロロ-4-(4-シクロペンチルピペラジン-1-イル)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン 
および
5-((3-(4-(2-(ジメチルアミノ)エトキシ)フェニル)イミダゾ[1,2-b]ピリダジン-6-イル)メチレン)チアゾリジン-2,4-ジオン  A thiazolidine derivative selected from the following or a salt thereof.
5-((1- (3-morpholinopropyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((2-Methyl-1- (4- (4-methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one
5-((1- (3- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one
5-((1- (3-((4-methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one
5-((1- (4- (4-Methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one
5-((1- (4- (4-Methylpiperazinyl) benzyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one
5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
tert-butyl 4- (4- (6-((4-oxo-2-thioxothiazolidine-5-ylidene) methyl) -1H-benzo [d] imidazol-1-yl) phenyl) piperazine-1-carboxylate
5-((1- (4-((1-Methylpiperidin-4-yl) oxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((1- (4-((1-Methylpiperidin-4-yl) oxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one
5-((1- (4-((4-Methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((1- (4-((4-methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one
5-((1- (3-((4-Methylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((1- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((1- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one
5-((1- (3- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one
5-((1- (3- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((1- (4- (2-morpholinoethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one
5-((1- (4- (2-morpholinoethoxy) phenyl-1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((1- (4-morpholinophenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one
5-((1- (4- (4,4-Difluoropiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one
5-((1- (4- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4- on
5-((1- (4- (4-Butylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one
5-((1- (4- (4-Butylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((1- (4-([1,4′-bipiperidine] -1′-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4- on
5-((1- (4-([1,4'-bipiperidine] -1'-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((1- (4- (4-morpholinopiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one
5-((1- (4- (4-morpholinopiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((1- (4- (4-Methyl-1,4-diazepan-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4- on
5-((1- (4- (4-Methyl-1,4-diazepan-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((1- (4-((2- (dimethylamino) ethyl) (methyl) amino) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4- on
5-((1- (4-((2- (dimethylamino) ethyl) (methyl) amino) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((1- (3- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4- on
5-((1- (3- (4- (2-methoxyethyl) piperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((1- (6- (4-Methylpiperazin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((1- (6- (4-Methylpiperazin-1-yl) pyridin-3-yl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidin-4-one
5-((1- (4- (4-Methylpiperazinyl) phenyl) -1H-indol-6-yl) methylene) -2-thioxothiazolidine-4-one
5-((1- (4- (4-Methylpiperazinyl) benzyl) -1H-indol-6-yl) methylene) -2-thioxothiazolidin-4-one
5-((1- (4- (4-Methylpiperazinyl) benzyl) -1H-indol-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one
5-((3- (3- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (6- (4-Methylpiperazin-1-yl) pyridin-3-yl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidine-4- on
5-((3- (4-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one
5-((3- (4-((4-Methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-((4-methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one
5-((3- (3-((4-Methylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one
5-((3- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-((4-Butylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidine-4-one
5-((3- (3-((4-Butylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-((4-Hexylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidine-4-one
5-((3- (3-((4-Hexylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidine-4-one
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thioxothiazolidine-4-one
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione
5-((1- (4- (piperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((1- (4- (4-Methylpiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one
5-((1- (4- (4-Methylpiperidin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((1- (4- (3- (dimethylamino) prop-1-in-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine- 4-on
5-((1- (4- (3- (Dimethylamino) prop-1-in-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((1- (4- (3- (dimethylamino) propyl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4-one
5-((1- (4- (6- (4-methylpiperazin-1-yl) hex-1-in-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene)- 2-Thioxothiazolidine-4-one
5-((1- (4- (6- (4-Methylpiperazin-1-yl) hex-1-in-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine -2,4-dione
5-((1- (3- (2- (4-Ethylpiperazin-1-yl) ethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((1- (3- (2- (4-Ethylpiperazin-1-yl) ethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine-4- on
5-((1- (4- (4-Ethylpiperazin-1-yl) -2- (trifluoromethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4- Dione
5-((1- (4- (4-Ethylpiperazin-1-yl) -2- (trifluoromethoxy) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-thioxothiazolidine -4-on
5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) -2-iminothiazolidin-4-one
5-((3- (3-((4-methylpiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one
5-((3- (3-((4-acetylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one
5-((3- (3-((4-acetylpiperazin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-((4-hydroxypiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) -2-thioxothiazolidin-4-one
5-((3- (3-((4-hydroxypiperidin-1-yl) methyl) phenyl) imidazo [1,2-a] pyridin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (2-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidine-4- on
5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
3-Methyl-5-((3- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-((4-Hexylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thioxothiazolidine- 4-on
5-((3- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thioxothiazolidine- 4-on
5-((3- (3-((4-Ethylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-((4-Butylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thioxothiazolidine- 4-on
5-((3- (3-((4-Butylpiperazin-1-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thioxothiazolidine -4-on
5-((3- (3-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4- Dione
5-((3- (3-((1-methylpiperidin-4-yl) methyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione
5-((3- (3- (4-Methylpiperazine-1-carbonyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione
5-((3- (3- (4-Cyclohexylpiperazine-1-carbonyl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione
5-((3- (2-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) -2-thioxothiazolidine -4-on
5-((3- (2-Fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3H-imidazo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2,4- Dione
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2 , 4-dione
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-indol-5-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [2,3-c] pyridin-5-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [2,3-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridin-5-yl) methylene) -2-thioxothiazolidine-4-one
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) furo [3,2-b] pyridin-5-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzofuran-5-yl) methylene) -2-thioxothiazolidin-4-one
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzofuran-5-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzo [b] thiophen-5-yl) methylene) -2-thioxothiazolidine-4-one
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzo [b] thiophen-5-yl) methylene) thiazolidine-2,4-dione
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-imidazo [4,5-c] pyridin-6-yl) methylene) -2-thioxothiazolidine-4-one
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-imidazo [4,5-c] pyridin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl)-[1,2,4] triazolo [4,3-a] pyridin-6-yl) methylene) thiazolidine-2,4 -Zeon
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzo [d] isothiazol-5-yl) methylene) -2-thioxothiazolidine-4-one
5-((3- (4- (4-Methylpiperazin-1-yl) phenyl) benzo [d] isothiazol-5-yl) methylene) thiazolidine-2,4-dione
5-((1- (4- (4-Ethylpiperazin-1-yl) phenyl) -1H-pyrazolo [3,4-b] pyridin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Ethylpiperazin-1-yl) -3,5-difluorophenyl) -3H- [1,2,3] triazolo [4,5-b] pyridin-5-yl ) Methylene) thiazolidine-2,4-dione
5-((3- (3-Chloro-4- (4-propylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridin-5-yl) methylene ) Thiazolidine-2,4-dione
5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridin-5-yl) methylene) thiazolidine-2 , 4-dione
5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl) -3H- [1,2,3] triazolo [4,5-b] pyridin-5-yl) methylene) -2- Thioxothiazolidine-4-one
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] [1,2,3] triazol-6-yl) methylene) -2-thioxothiazolidine- 4-on
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-benzo [d] [1,2,3] triazol-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Methylpiperazin-1-yl) -phenyl) pyrazolo [1,5-a] pyrimidin-5-yl) methylene) -2-thioxothiazolidin-4-one
5-((3- (4- (4-Methylpiperazin-1-yl) -phenyl) pyrazolo [1,5-a] pyrimidin-5-yl) methylene) thiazolidine-2,4-dione
5-((1- (3-Chloro-4- (4-ethylpiperazin-1-yl) phenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-Methoxy-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-Fluoro-5- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-Methyl-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3- (4-Methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3- (2-morpholinoethyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidin-4-one
5-((3- (3- (2-morpholinoethyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4 -Zeon
5-((3- (3-((1-methylpiperidin-4-yl) oxy) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-Fluoro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-Fluoro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-Fluoro-4- (4-pentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-decylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-(((1-methylpiperidin-4-yl) oxy) methyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3- (4-Ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3- (4-Isobutylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Butylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-((Ethyl (propyl) amino) methyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-((1,1-dioxidethiomorpholino) methyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-Fluoro-4-((3R, 5S) -3,4,5-trimethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene ) Thiazolidine-2,4-dione
5- (6-((2,4-Dioxothiazolidine-5-ylidene) methyl) imidazo [1,2-b] pyridazin-3-yl) -2- (4-methylpiperazin-1-yl) benzonitrile
5-((3- (3-((1-methylpiperidin-4-yl) methyl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3- (tert-butyl) -4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4 -Zeon
5-((3- (2- (4-Methylpiperazin-1-yl) pyrimidin-5-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((1- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenyl) -1H-benzo [d] imidazol-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Ethylpiperazin-1-yl) phenyl)-[1,2,4] triazolo [4,3-b] pyridazin-6-yl) methylene) thiazolidine-2,4 -Zeon
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) methylene) -2-thioxothiazolidine-4-one
5-((1- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-indazol-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidine-4-one
5-((3- (4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-decylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidin-4-one
5-((3- (4- (4-decylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4- (tert-butyl) piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidine-4- on
5-((3- (4- (4- (tert-butyl) piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Butylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxothiazolidine-4-one
5-((3- (4- (4-Butylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Pentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (2- (4-Methylpiperazin-1-yl) benzo [d] thiazol-6-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) -2-thioxo Thiazolidin-4-one
5-((3- (2- (4-Methylpiperazin-1-yl) benzo [d] thiazol-6-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4 -Zeon
2- (4- (4- (6-((2,4-Dioxothiazolidine-5-ylidene) methyl) imidazo [1,2-b] pyridazin-3-yl) phenyl) piperazin-1-yl) acetonitrile
5-((3- (4- (4-Cyclopentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Isobutylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
2- (4- (4- (6-((2,4-Dioxothiazolidine-5-ylidene) methyl) imidazo [1,2-b] pyridazin-3-yl) phenyl) piperazin-1-yl) ethyl acetate
5-((3- (4- (4- (2-hydroxyethyl) piperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (2- (4-Methylpiperazin-1-yl) thiazol-5-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-Methyl-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Isopropylpiperazin-1-yl) -3-methylphenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Ethylpiperazin-1-yl) -3-methylphenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (1-Ethylpiperidin-4-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (5-((4-methylpiperazin-1-yl) methyl) thiophen-2-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione
5-((3- (4- (4-Ethyl-2,3-dioxopiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4- Dione
5-((3- (4- (4-Methyl-2-oxopiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (6- (4-Methylpiperazin-1-yl) benzo [d] oxazol-2-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4 -Zeon
5-((3- (5- (2- (dimethylamino) ethoxy) thiophen-2-yl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (4- (4-Cyclopentylpiperazin-1-yl) -3-fluorophenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-Chloro-4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-Chloro-4- (4-isopropylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-Chloro-4- (4-ethylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-Chloro-4- (4-propylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
5-((3- (3-Chloro-4- (4-cyclopentylpiperazin-1-yl) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione
and
5-((3- (4- (2- (dimethylamino) ethoxy) phenyl) imidazo [1,2-b] pyridazin-6-yl) methylene) thiazolidine-2,4-dione 　請求項１～１１のいずれか１項記載のチアゾリジン誘導体又はその塩を含有するＰｉｍ阻害剤。 A Pim inhibitor comprising the thiazolidine derivative or a salt thereof according to any one of claims 1 to 11. 　請求項１～１１のいずれか１項記載のチアゾリジン誘導体又はその塩を含有する医薬。 A pharmaceutical comprising the thiazolidine derivative or a salt thereof according to any one of claims 1 to 11. 　抗がん剤である請求項１３記載の医薬。 The medicament according to claim 13, which is an anticancer agent. 　がん治療のための、請求項１～１１のいずれか１項記載のチアゾリジン誘導体又はその塩。 The thiazolidine derivative or a salt thereof according to any one of claims 1 to 11, for cancer treatment. 　Ｐｉｍ阻害のための、請求項１～１１のいずれか１項記載のチアゾリジン誘導体又はその塩。 The thiazolidine derivative or a salt thereof according to any one of claims 1 to 11, for inhibiting Pim. 　抗がん剤製造のための、請求項１～１１のいずれか１項記載のチアゾリジン誘導体又はその塩。 The thiazolidine derivative or a salt thereof according to any one of claims 1 to 11, for producing an anticancer agent. 　Ｐｉｍ阻害剤製造のための、請求項１～１１のいずれか１項記載のチアゾリジン誘導体又はその塩。 The thiazolidine derivative or a salt thereof according to any one of claims 1 to 11, for producing a Pim inhibitor. 　請求項１～１１のいずれか１項記載のチアゾリジン誘導体又はその塩の有効量を投与することを特徴とするがんの治療方法。 A method for treating cancer, comprising administering an effective amount of a thiazolidine derivative or a salt thereof according to any one of claims 1 to 11.
PCT/JP2012/075857 2011-10-04 2012-10-04 Medicinal agent comprising thiazolidine derivative or salt thereof as active ingredient Ceased WO2013051672A1 (en)

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