WO2013051672A1 - Agent médicinal comprenant un dérivé de thiazolidine ou sel de celui-ci comme ingrédient actif - Google Patents

Agent médicinal comprenant un dérivé de thiazolidine ou sel de celui-ci comme ingrédient actif Download PDF

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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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methylene
phenyl
thiazolidine
dione
imidazo
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PCT/JP2012/075857
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Japanese (ja)
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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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株式会社ヤクルト本社
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Priority to JP2013537559A priority Critical patent/JP6057907B2/ja
Publication of WO2013051672A1 publication Critical patent/WO2013051672A1/fr

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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

L'invention concerne un composé ayant une excellente activité d'inhibition de Pim et utile comme agent médicinal. L'invention concerne un dérivé de thiazolidine représenté par la formule générale (1) (dans laquelle X représente O, S ou NH ; R3 représente un atome d'hydrogène ou un groupe alkyle ; au moins l'une des liaisons en pointillés est une double liaison ; Z1, Z2 et Z6 représentent indépendamment C, CH ou N ; Z3, Z4, Z5, Z7 et Z8 représentent indépendamment C, CH, N, NH, O ou S ; Y représente un groupe hydrocarboné bivalent qui a au moins un groupe hydrocarboné aromatique en C6-14 et peut avoir un substituant, un groupe hétérocyclique aromatique bivalent qui peut avoir un substituant ou un groupe hydrocarboné aliphatique en C2-12 bivalent ; Am représente un groupe amino, un groupe amino monosubstitué, un groupe amino disubstitué ou un groupe hétérocyclique saturé azoté qui peut avoir un substituant ; et R1 et R2 représentent indépendamment un atome d'hydrogène, un atome d'halogène, un groupe alcoxy, un groupe halogénoalcoxy ou similaires) ou un sel de celui-ci.
PCT/JP2012/075857 2011-10-04 2012-10-04 Agent médicinal comprenant un dérivé de thiazolidine ou sel de celui-ci comme ingrédient actif WO2013051672A1 (fr)

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JP2014201533A (ja) * 2013-04-03 2014-10-27 株式会社ヤクルト本社 チアゾロン誘導体
JP2017502936A (ja) * 2013-12-09 2017-01-26 ユーシービー バイオファルマ エスピーアールエル Ｔｎｆ活性のモジュレーターとしてのベンゾトリアゾール誘導体
US20170088530A1 (en) * 2014-05-09 2017-03-30 Shanghai Syncores Technologies Inc. Ltd. New vortioxetine intermediate and synthesis process thereof
US9828348B2 (en) 2013-11-08 2017-11-28 Purdue Pharma L.P. Benzimidazole derivatives and use thereof
US11421011B2 (en) 2017-05-18 2022-08-23 Modernatx, Inc. Polynucleotides encoding tethered interleukin-12 (IL12) polypeptides and uses thereof

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CN113717100B (zh) * 2021-10-11 2023-03-17 郑州工业应用技术学院 一种培氟沙星醛缩4-芳基氨基硫脲类衍生物的制备方法
CN114213424B (zh) * 2021-12-30 2023-05-26 杭州高光制药有限公司 一种呋喃[3，2-b]并吡啶衍生物的合成方法

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JP2014201533A (ja) * 2013-04-03 2014-10-27 株式会社ヤクルト本社 チアゾロン誘導体
US9828348B2 (en) 2013-11-08 2017-11-28 Purdue Pharma L.P. Benzimidazole derivatives and use thereof
US9975858B2 (en) 2013-11-08 2018-05-22 Purdue Pharma L.P. Benzimidazole derivatives and use thereof
JP2017502936A (ja) * 2013-12-09 2017-01-26 ユーシービー バイオファルマ エスピーアールエル Ｔｎｆ活性のモジュレーターとしてのベンゾトリアゾール誘導体
US20170088530A1 (en) * 2014-05-09 2017-03-30 Shanghai Syncores Technologies Inc. Ltd. New vortioxetine intermediate and synthesis process thereof
US9926286B2 (en) * 2014-05-09 2018-03-27 Shanghai Syncores Technologies Inc. Ltd. Vortioxetine intermediate and synthesis process thereof
US11421011B2 (en) 2017-05-18 2022-08-23 Modernatx, Inc. Polynucleotides encoding tethered interleukin-12 (IL12) polypeptides and uses thereof

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