WO2005090328A1 - Composition hétérocyclique et son utilisation - Google Patents

Composition hétérocyclique et son utilisation Download PDF

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Publication number
WO2005090328A1
WO2005090328A1 PCT/JP2005/005995 JP2005005995W WO2005090328A1 WO 2005090328 A1 WO2005090328 A1 WO 2005090328A1 JP 2005005995 W JP2005005995 W JP 2005005995W WO 2005090328 A1 WO2005090328 A1 WO 2005090328A1
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group
ring
optionally substituted
ethyl acetate
methyl
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PCT/JP2005/005995
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English (en)
Japanese (ja)
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Tetsuji Kawamoto
Tomohiro Okawa
Yoshio Aramaki
Shoji Fukumoto
Yukio Toyoda
Shota Ikeda
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Takeda Pharmaceutical Company Limited
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Publication of WO2005090328A1 publication Critical patent/WO2005090328A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to a novel GRK inhibitor useful as an agent for preventing and treating heart failure and the like, a novel heterocyclic compound and use thereof.
  • G protein-coupled receptors such as adrenergic receptor, acetylcholine receptor, and obioid receptor, are the most important receptors for maintaining physiological functions. ⁇ Induces abnormal organ function.
  • G protein-coupled receptor kinase G protein-coupled receptor kinase, GRK
  • G protein-coupled receptor kinase is an enzyme that phosphorylates G protein-coupled receptor activated by agogosut. The body becomes less responsive to agonists (desensitization). Numerous results have been reported that suggest that this GRK acts as a pathological exacerbation factor in various diseases.
  • GRK inhibitors unlike the existing heart failure therapies, is expected as a new mechanism both capable of short-term cardiac function improved and long-term prognosis improvement.
  • an increase in GRK2 has been reported in diseased animal models, human hypertensive patients and patients with heart failure (see Sarkuration, Vol. 87, p. 454-463).
  • Recently, the gene transfer of a GRK2 inhibitory peptide into osteoblasts has been shown to increase the bone mass of genetically modified mice (see Journal 'OB' Clinical Investigation, Vol. 109, pp. 1361-1371).
  • results suggesting that a glucose-lowering effect is obtained (see US Patent Application Publication No. 2002/0028772).
  • pyrimidine derivatives having a specific structure As low molecular weight compounds having GRK inhibitory activity, pyrimidine derivatives having a specific structure (see WO 02/18350 pamphlet and Japanese Patent Application Laid-Open No. 2003-314147) are known. However, it is not a drug that can be applied clinically as a preventive or therapeutic drug for heart failure.
  • a pyrazole derivative is disclosed in WO 03/26649 pamphlet
  • a triazole derivative is disclosed in EP 0 742 229 and WO 2004/056 789 pamphlet
  • an isoxazole derivative is disclosed internationally.
  • thiazole derivatives are disclosed in WO 00Z20410 pamphlet, WO 00 203392 Pamphlet, International Oxadiazole derivatives were published in the publication No. 0 210 0 160 pamphlet and in the publication WO 2004/087699 pamphlet Journal of the Institution of
  • the present invention provides a drug which is useful as a preventive / therapeutic agent for cardiovascular diseases such as heart failure, hypertension, and arteriosclerosis based on a strong GRK inhibitory action.
  • the present inventors have conducted intensive studies on compounds having GRK inhibitory activity and found that the compound represented by the following formula (1 ′) or a salt thereof or a prodrug thereof exhibits an excellent GRK inhibitory activity. Based on the above, the present invention has been completed.
  • the compound represented by the following formula (I) or a salt thereof is a novel compound.
  • Ring ⁇ represents an optionally substituted aromatic ring
  • Ring B represents a 5-membered nitrogen-containing aromatic heterocyclic ring which may be substituted
  • Ring C represents an optionally substituted nitrogen-containing aromatic heterocyclic ring
  • X ′ represents an optionally substituted Ci-4 alkylene group
  • Y ′ is an optionally substituted imino group, one O— or one S (O) n_ (n is 0
  • Ring A represents an optionally substituted aromatic ring
  • Ring B represents an optionally substituted 5-membered nitrogen-containing aromatic heterocycle
  • ring C represents an optionally substituted nitrogen-containing aromatic heterocycle
  • X represents a Ct-4 alkylene group which may be substituted (excluding an alkylene group substituted with an oxo group);
  • Y represents an imino group which may be substituted
  • Ring B binds to a constituent carbon atom of ring C, and rings C and X bind to a constituent carbon atom of ring B. ].
  • Ring B force optionally substituted pyrrole ring, optionally substituted
  • Ring B force S optionally substituted pyrrole ring, optionally substituted pyrazole ring, optionally substituted imidazole ring, optionally substituted triazole ring, optionally substituted A compound (I) which is a good thiazole ring, an optionally substituted isoxazole ring or an oxaziazole ring;
  • R 1 represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl group
  • R 2 and R 3 each independently represent a hydrogen atom, a halogen atom
  • a carboxyl group, an optionally substituted carbamoyl group or an acyl group, and X is as defined in the above [2].
  • a compound selected from or a salt thereof is selected from or a salt thereof;
  • a method of inhibiting GRK in a mammal comprising administering an effective amount of the compound (1 ′) or a prodrug thereof to the mammal;
  • ring A represents an optionally substituted aromatic ring.
  • aromatic ring in the “optionally substituted aromatic ring” represented by ring A represents an optionally substituted aromatic ring.
  • preferably contains one to three heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms, (i) aromatic cyclic hydrocarbons, (ii) carbon atoms. And aromatic heterocycles. '
  • aromatic cyclic hydrocarbon for example, benzene, naphthalene, ⁇ anthracene, Fuenantoren, C 6 _ 14 aromatic cyclic hydrocarbon such as Asenafuchireren like.
  • aromatic heterocycle examples include furan, thiophene, pyrrole, Oxazole, isooxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole 5 to 6 of 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc.
  • aromatic monocyclic heterocycles for example, benzofuran, isobenzofuran, benzo [b] thiophene, indole, isoindolenole, 1H-indazole, benzimidazonole, benzoxazonole, 1, 2-benzoisoxazo mono, benzothiazono, 1,2-benzoisothiazole, 1 H-benzotria Zole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine, purine, pteridine, carbazole, ⁇ -canolebolin, i3-carboline, ⁇ -carboline, atarizine, phenoxazine, phenothiazine, phenazine, phenothine, phenoxine Phenanthridine, phenanthone phosphorus, indolizine, pyro mouth [1,
  • the substituent which the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have is a halogen atom, an optionally substituted hydrocarbon group, or a substituted Heterocyclic group which may be substituted, amino group which may be substituted, imidoyl group which may be substituted, amidino group which may be substituted, hydroxy group which may be substituted, which may be substituted Thiol group, A cyano group, a nitro group, a nitroso group, a sulfo group, an optionally substituted sorbamoyl group, an optionally substituted sulfamoyl group, an optionally esterified carboxyl group, an acyl group, and the like. May have 1 to 5 (preferably 1 to 3) substituents at the replaceable positions.
  • halogen atom as a substituent which the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have include, for example, fluorine, chlorine, bromine and iodine.
  • hydrocarbon group in the “optionally substituted hydrocarbon group” as a substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have include, for example, And aliphatic chain hydrocarbon groups, alicyclic hydrocarbon groups (non-aromatic cyclic hydrocarbon groups), aryl groups (aromatic hydrocarbon groups) and the like.
  • aliphatic hydrocarbon group examples include a linear or branched aliphatic hydrocarbon group such as an alkyl group, an alkenyl group, and an alkynyl group.
  • alkyl group includes, for example, methyl, ethyl, n-propynole, isopropynole, n-butyl, isobutynole, sec-butynole, tert-butynole, n-pentyl, isopentyl, neopentyl, 1-methylpropynole, n-hexyl, isohexynole, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl, 1-methylheptyl, 1— Such as ethylhexyl, n-octyl, 1-methylheptyl, and Noel. And an alkyl group (preferably C ⁇ e alkyl and the like).
  • Alkenyl group includes, for example, butyl, aryl, isopropyl,
  • 2-methinorealinole 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butul, 3-butenyl, 2-ethynole 1-buteninole, 2-methyl-1 2-buteninole, 3- Mechinore 2—Pteninole, 1-Pentinole, 2-Pentinole, 3_Pentenyl, 4-Pentinole, 4-Methinole_3—Pentinole , 1 one to Kiseninore, to 2 _ Kiseninore, Kiseenore to 3, Kiseninore to 4-, C 2 etc. cyclohexenyl 5 one - 6 alkenyl group, and the like.
  • alkynyl group examples include, for example, ethur, 1-propynyl, 2-propynyl, 1-butyninole, 2-butyninole, 3-butyninole, 1-pentynole, 2-pentynyl, 3-pentynyl, 4-pentynyl pliers - le, 1 one to hexynyl, hexynyl to 2, Kishuru to 3 _, Kishuru to 4-, C 2 _ 6 ⁇ Noreki of hexynyl, etc., to 5 - Le group.
  • the “alicyclic hydrocarbon group” as an example of the hydrocarbon group includes, for example, a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group, and a cycloalkadienyl group.
  • cycloalkyl group for example, cyclopropyl, consequent opening heptyl, cyclopentyl, cyclohexyl, cycloheptyl cyclohexane, Shikuroota chill, C 3 _ 9 cycloalkyl group such as cyclononyl and the like.
  • Examples of the “cycloalkenyl group” include 2-cyclopentene-1-inole, 3-cyclopentene-1-inole, 2-cyclohexene-1-inole, 3-cyclohexene-1-inole, and 1-cyclobutene_ 1-inole, 1-cyclopentene 1-inole, 1-cyclohexene 1-inole, 1-cycloheptene 1 1
  • Examples of the “cycloalkadienyl group” include, for example, 2,4-cyclopentagen-1-yl, 2,4-cyclohexadiene-1-inole, and 2,5-cyclohexadiene-1-yl 6 cycloalkadienyl group and the like - C 4 and the like.
  • Examples of the "aryl group” as an example of the hydrocarbon group include a monocyclic or condensed polycyclic aromatic hydrocarbon group.Examples include C, such as phenyl, naphthyl, biphenyl, anthryl, phenanthryl, and acenaphtyryl.
  • 6 _ 14 Ariru group preferably such 6 _ 14 Ariru group, among them phenyl, 1-naphthyl, 2-naphthyl, 2-Bifue two Lil, 3 Bifue two Lil, 4 Bifue - preferably like C 6 _ 12 Ariru group Lil and the like, especially .
  • hydrocarbon groups examples include 1,2-dihydronaphthyl, 1,2,3,4_tetrahydronaphthinole, indanore, indeninole, and dihydrobenzocyclo.
  • Two or three identical or different rings constituting a group selected from the above-mentioned alicyclic hydrocarbon group and aryl group, such as butenyl and fluorenyl;
  • the ⁇ hydrocarbon group in the “optionally substituted hydrocarbon group” as a substituent which the aromatic ring in the “optionally substituted aromatic ring” may have Examples of the substituent that may be
  • (V) mono- or di-CL-4 alkyl-carbamoyl group (eg, N-methylcarbamoyl, .N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-getylcarbamoyl, etc.); May be substituted with a halogen atom, a hydroxy group, a C 1-4 alkoxy group, etc.), a mono- or di-C 2 _ 4 alkenyl-carbamoyl group (for example, N-arylcarbamoyl, etc.); The alkenyl group may be substituted with a halogen atom, a hydroxy group, a C1-4 alkoxy group, etc.), a mono- or di-fluoroalkyl group, a mono- or di-arylalkyl-dialkyl group.
  • an alkoxy monocarbonyl group for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, etc.
  • a sunolejo group (viii) a sunolejo group; (ix) halogen atoms (eg, fluorine, chlorine, bromine, iodine);
  • (X) an optionally halogenated C 1-4 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, etc.), an optionally substituted -4 alkoxy group or a carboxyl group;
  • a halogen atom optionally halogenated C 1-4 alkyl group optionally, halogen of which may C 1-4 also be alkoxy and human Dorokishi with optionally substituted C 1-4 alkyl group which may also be C 6 substituted with a substituent selected from - 12 7 aryl group (e.g., phenyl, 1 _ naphthyl, 2-naphthyl, 2-Bifue two Rinore, 3- Bifuenirinore, 4 Bifueyurinore etc.);
  • aryl group e.g., phenyl, 1 _ naphthyl, 2-naphthyl, 2-Bifue two Rinore, 3- Bifuenirinore, 4 Bifueyurinore etc.
  • Nono halogenated which may phenyl _C physician 4 alkyl group optionally halogen I spoon which may phenyl one also be C 2 4 Arukeeru group, an phenoxy group which may be halogenated (e.g., o-, m —Or p-chlorophenoxy, o_
  • a bicyclic hydrocarbon group in which a cycloalkyl group and a benzene ring are condensed for example, indanyl and the like
  • a bridged hydrocarbon group for example, adamantyl and the like
  • (XV) optionally halogenated C ⁇ 4 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, etc.), optionally halogenated C
  • alkenyl group e.g., Bulle, Ariru, 2- Buteyuru, 3-butenyl, etc.
  • optionally halogenated C t - 4 alkylthio group e.g., methylthio, Echiruchio, n- propylthio, isopropylthio, n —Butylthio, etc.
  • a C 4 alkyl group which may be substituted with a hydroxy group or a hydroxy group
  • Njiruchio group Habe were or may Benjiruokishi group optionally substituted respectively with a substituent selected from Karuboeru group - (xvii) a halogen atom, a carboxyl group and a C physician 4 alkoxy;
  • C i-alkylsulfinyl group for example, methylsulfiel, ethylsulfiel, etc.
  • a phenylsulfinyl group for example, methylsulfiel, ethylsulfiel, etc.
  • a phenylsulfinyl group for example, methylsulfiel, ethylsulfiel, etc.
  • a phenylsulfinyl group for example, methylsulfiel, ethylsulfiel, etc.
  • a phenylsulfinyl group for example, methyls
  • (XX) an optionally halogenated C 1-4 alkylsulfone group (for example, methinolesnolehoninole, ethylsulfonyl, etc.), a phenylsnolehoninole group, a phenylinolesulfonyl-alkyl group;
  • a sulfamoyl group a mono- or di-Ci-alkylsulfamoyl group (for example, methylaminosulfonyl, ethylaminosulfonyl, N, N-dimethylaminosulfonyl, N, N-methylaminosulfonyl, etc .;
  • the alkyl group may be substituted with a halogen atom, a hydroxy group, a C 1-4 alkoxy group, etc.);
  • acylamino group for example, Cie alkanoylamino (eg, formylamino, acetylamino, trifluoroacetylamino, propionylamino, bivaloylamino, etc.), benzoylamino, C ⁇ anolequinolenoleshonylamino (Eg, methanesulfonylamino, trifluoromethanesulfonylamino, etc.).
  • Cie alkanoylamino eg, formylamino, acetylamino, trifluoroacetylamino, propionylamino, bivaloylamino, etc.
  • benzoylamino C ⁇ anolequinolenoleshonylamino (Eg, methanesulfonylamino, trifluoromethanesulfonylamino, etc.).
  • reel sulfonyl ⁇ amino e.g., benzenesulfonic Ruhoniruamino, toluenesulfonyl ⁇ amino, etc.
  • C sheet 1 0 Ashiru halogen atom, arsenic Dorokishi group, may be substituted with a carboxyl group or the like], benzylidene Ruo alkoxycarbonyl ⁇ Mino, Optionally halogenated alkoxy-carbonylamino, sorbamoylamino, mono or dialkyl 4- alkyl rubamoylamino;
  • (xxiii) mono or di-C 1-4 alkylamino group for example, methylamino, Ethylamino, dimethylamino, acetylamino, etc .; the alkyl group may be substituted by a halogen atom, a hydroxy group, a C 1-4 alkoxy group, etc.), phenylamino, benzylamino;
  • (xxiv) 4- to 6-membered cyclic amino group (for example, 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl, 1,2,3,4-tetrahydroquinoline-11_, 1 , 2,3,4-tetrahydroisoquinoline-1-yl, etc., 4- to 6-membered cyclic amino-carbonyl group (for example, 1-azetidinylcarbol, 1-pyrrolidinylcarbonyl, piperidi Nocarbur, morpholinocarbonyl, thiomorpholinocarbinole, 1-piperazinylcarbonyl, 1,2,3,4-tetrahydroquinoline-1-ylcarbonyl, 1,2,3,4-tetrahydroisoquinoline-1 2- ⁇ 4 to 6-membered cyclic amino-carbonyloxy group (for example, 1-pyrrolidinylcarbonyloxy, piperidinocarbonyl
  • 4- to 6-membered cyclic amino-sulfonyl group for example, 1_pyrrolidinylsnolephonyl, piberidinosnolephonyl, morpholino snorehoninole, thiomonoreholinosnolehoninole, 1 1,2,3,4-tetrahydroquinoline, 1,1-inolesnolephoninole, 1,2,3,4-tetrahydroisoquinoline-1-ylsulfonyl, etc.), 4 to 6 Membered amino-CH alkyl group;
  • (XXV) a 6- acyl group which may be substituted with a substituent selected from a halogen atom, a carboxyl group and a Ci-4 alkoxy-carbonyl group (for example, , Formyl, optionally halogenated, such as Asechiru C 2 - 6 Arukanoiru etc.
  • a 5- to 10-membered heterocyclic monocarbonyl group for example, 2_ or 3-phenylcarbonyl, 2- or 3-furylcarbol, 3-, 4_ or 5-vinylazolinolecarbonyl, 2-, 4 _ Or 5-thiazolylcarbonyl, 3-, 4- or 5-isothiazolylcarbonyl, 2-, 4- or 5-oxazolylcarbonyl, 1, 2, 3_ or 1,2,4_ tria Zolylcarbyl, 1H- or 2H-tetrazolylcarbyl, 2-, 3- or 4-pyridylcarbonyl, 2-, 4_ or 5-pyrimidylcarboninole, 3_ or 4-pyri Dazinylcarbonyl, quinolylcarbonyl, isoquinolylcarbonyl, indolylcarbonyl, etc .; the heterocyclic group may be substituted by a C 1-4 alkyl group etc.);
  • (XXX) halogenated may be straight-chain or branched C i - 4 alkylene Okishi group (e.g., Mechirenjiokishi, Echirenjiokishi, Puropirenjio alkoxy, tetrafurfuryl O b ethylenedioxy O carboxymethyl, etc.); '
  • the “hydrocarbon group” may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) of these substituents at substitutable positions, and has 2 or more In this case, the substituents may be the same or different.
  • Examples of the ⁇ complex ring group '' in the ⁇ optionally substituted heterocyclic group '' as the substituent which the aromatic ring in the ⁇ optionally substituted aromatic ring '' represented by ring A may have include: For example, as an atom (ring atom) constituting a ring system, at least one (preferably one or two) of one to three (preferably one or two) heteroatoms selected from an oxygen atom, a sulfur atom, a nitrogen atom, and the like.
  • aromatic heterocyclic group examples include, for example, furyl, cyenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolinole, pyrazolyl, 1,2,3-oxaziazolyl, 1,2,4-oxaziazolyl, 1 1,3,4-thoxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 5- or 6-membered aromatic monocyclic heterocyclic group such as tetrazolyl, pyridyl, pyridazinolene, pyrimidyl, pyragenyl and triazinyl; for example, benzofuranyl, isobenzofuranyl, benzo [b] chel, indolinole,
  • non-aromatic heterocyclic group examples include, for example, oxilanyl, azetidinyl, oxetanyl, cetanyl, pyrrolidinyl, tetrahydrofurfuryl, thiolaninole, piperidinole, tetrahydrodolinole, monoreolininole, and thiomonorenolinole.
  • a 3- to 8-membered (preferably 5- to 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group such as piperazinyl; Aromatic ring as described above such as 2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, benzopyranyl, oxazoline, oxazine diazoline, thiazoline, thiadiazoline, oxazolidine, oxadiazolidine, thiazolidine, thiadiazolidine, etc.
  • Formula heterocyclic group or Double bond of some or all of the aromatic condensed heterocyclic groups such as a non-aromatic heterocyclic groups saturation.
  • the “heterocyclic group” in the “optionally substituted heterocyclic group” has examples of the optionally substituted substituent include, for example, a ⁇ hydrocarbon group '' in the ⁇ optionally substituted hydrocarbon group '' as a substituent of the ⁇ optionally substituted aromatic ring '' represented by ring A Examples include the same number of similar groups as the substituents that may be possessed.
  • Optionally substituted amino group or “optionally substituted imidoyl group” as a substituent which the aromatic ring in the "optionally substituted aromatic ring” for ring A may have , "Optionally substituted amidino group”, “optionally substituted hydroxy group”, “optionally substituted thiol group”, amino group, imidoyl group, amidino group, hydroxy group And the substituent which the thiol group may have, for example,
  • a halogen atom eg, fluorine, chlorine, bromine, iodine
  • an optionally halogenated C ⁇ e alkoxy eg, methoxy, ethoxy, trinoleo
  • optionally halogenated C ⁇ ealkylthio optionally halogenated C ⁇ ealkylthio
  • phenyl the phenyl is halogen atoms, optionally halogenated C [physicians 6 alkyl, optionally substituted with also a C 1-6 alkoxy such as optionally halogenated
  • naphthyl which may be halogenated
  • Ji 3 - 10 Lower alkyl group which may be substituted with a substituent selected from chloroalkyl
  • Ci-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.
  • acetyl group optionally C 1-6 alkanol (eg, formyl, acetyl, propionyl, bivaloyl, trifluoroacetyl, trichloroacetyl, etc.), phenylacetyl (the phenyl is a halogen atom , Optionally substituted with C 1-6 alkyl which may be halogenated), benzoyl which may be halogenated, C 1-6 alkylsulfonyl which may be halogenated Groups (eg, methanesulfonyl, ethanesulfonyl, etc.), optionally halogenated benzenesnolephoninole, tonoleensnolephonyl, etc.];
  • C 1-6 alkanol eg, formyl, acetyl, propionyl, bivaloyl, trifluoroacetyl, trichloroacetyl,
  • (V) d- 6 alkoxymonocarbonyl group which may be nodogenated (eg, methoxycanoleboninole, ethoxycanoleboninole, trifnorolelone methoxycanoleboninole, ethoxycanoleboninole with 2,2,2-triphnoleone , Trichloromethoxycanoleponyl, 2,2,2-trichloromouth ethoxycarbonyl, etc.), C ⁇ ealkoxycarbonyl group optionally substituted by phenyl (eg, benzyloxycarbonyl, etc.);
  • nodogenated eg, methoxycanoleboninole, ethoxycanoleboninole, trifnorolelone methoxycanoleboninole, ethoxycanoleboninole with 2,2,2-triphnoleone , Trichloromethoxycanoleponyl, 2,2,2-trich
  • heterocyclic group for example, the “optionally substituted heterocyclic group” The same as the above “heterocyclic group”
  • the “amino group” in the “optionally substituted amino group” as a substituent is an optionally substituted imidoyl group (for example, C ⁇ alkylimidoyl (eg, formylimidoyl, acetylimidoyl) Etc.), C 1-6 alkoxyimidoyl, C 1-6 alkylthioimidoyl, amidino, etc.), and an amino group which may be substituted with 1 to 2 C 6 alkyls.
  • cyclic amino group examples include 1-azetidur, 1-pyrrolidinyl, piperidino, thiomorpholino, morpholino, 1-piperazinyl, and 4-position
  • a lower alkyl group eg, C ⁇ e alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc.
  • an aralkyl group eg, C?
  • ⁇ Such as benzyl, phenethyl, etc.).
  • Aralkyl group aryl group (eg, phenyl, 1-naphthyl, 2-naphthyl, etc., aryl group, etc.), 1-piperazine And a 3- to 8-membered (preferably 5- to 6-membered) cyclic amino group such as 1-pyrrolyl or 1-imidazolyl.
  • Aromatic ring in the “optionally substituted aromatic ring” represented by ring A is two substituents which lies adjacent to the above integral, linear or branched C 1 - 4 Al Kirenjiokishi group (e.g., Mechirenjiokishi, Echirenjiokishi, prop Renjiokishi) may form a like .
  • the ⁇ optionally substituted rubamoyl group '' as a substituent which the aromatic ring may have is an unsubstituted rubamoyl group
  • Other examples include an N-monosubstituent rubamoyl group and an N, N-disubstituent rubamoyl group.
  • substituent of the “N-monosubstituent rubamoyl group” examples include, for example, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, and an optionally substituted Good amino and the like.
  • Examples of the “optionally substituted hydrocarbon group” as an example of the substituent of the “N-monosubstitution rubamoyl group” include a substituent in the “optionally substituted aromatic ring” represented by ring A.
  • the same groups as the “optionally substituted hydrocarbon group” can be mentioned.
  • Examples of the “optionally substituted heterocyclic group” as an example of the substituent of the “N-monosubstituent rubamoyl group” include a substituent in the “optionally substituted aromatic ring” represented by ring A. The same groups as the “optionally substituted heterocyclic group”.
  • Examples of the “optionally substituted diamino group” as an example of the substituent of the “N-monosubstituent rubamoyl group” include the “optionally substituted aromatic ring j” represented by ring A. The same groups as the “optionally substituted amino group” and the like can be mentioned.
  • the “N, N-disubstituent rubamoyl group” means a disubstituted group having two substituents on a nitrogen atom.
  • One example of the substituent is the above-mentioned “N-monosubstituent group”.
  • the same examples as the substituents in the "rubamoyl group” include, for example, lower alkyl groups (eg, methyl, ethyl, propyl, isopropinole, butyl, tert-butyl, pentynole, hexyl, etc.) alkyl, etc.), C 3 _ 6 cycloalkyl group (e.g., cyclopropyl, cyclohexyl, etc.
  • the ⁇ optionally substituted sulfamoyl group '' as a substituent which the aromatic ring in the ⁇ optionally substituted aromatic ring '' represented by ring A may have is an unsubstituted sulfamoyl group , N-monosubstituted sulfamoyl groups and N, N-disubstituted sulfamoyl groups.
  • Examples of the substituent of the “N-monosubstituted sulfamoyl group” include the same groups as the substituent of the “N-monosubstituted sulfamoyl group”.
  • N, N-disubstituted sulfamoyl group means a sulfamoyl group having two substituents on a nitrogen atom.
  • substituents is the above-mentioned “N-monosubstituted sulfamoyl group”.
  • substituents in the "examples of other hand for example, a lower alkyl group (e.g., methyl, Echiru, propyl, isopropyl, butyl, tert- butyl, pentyl, the hexyl or the like.
  • C 3 _ 6 cycloalkyl group e.g., cyclopropyl, cyclobutyl, shea Kuropenchinore, Kishinore like cyclohexane
  • Ala ⁇ / Kinore group eg, Benjinore, Buenechiru like, preferably phenyl one C t - 4 alkyl and the like
  • two substituents may form a cyclic amino group together with a nitrogen atom.
  • examples of the cyclic aminosulfamoyl group include 1-azetijunolesulfo 2-nore, 1-pyrrolidininolesulfononole, piperidinosnolephonyl, morpholinosulfonyl, thiomorpholinosulfonyl (sulfur atom may be oxidized), 1-piperazinylsulfonyl, and lower alkyl at 4-position group (e.g., methyl, Echiru, propyl, isopropyl, heptyl, tert- Bed chill, pentyl, C 1 of cyclohexyl, etc.
  • Ararukiru group e.g., benzyl, C 7 such as phenethyl -. 1 Ararukiru
  • Aryl group eg, phenyl, 1-naphthyl, 2-naphthyl, etc., C 6 -ie 7 reel, etc.
  • 1-piperazinyl sulfe And a 3- to 8-membered (preferably 5- to 6-membered) cyclic amino-sulfonyl group such as honyl.
  • the aromatic ring in the “optionally substituted aromatic ring” represented by ring A has Examples of the “optionally esterified carboxyl group” as the optional substituent include a free carboxyl group and, for example, a lower alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group. Groups.
  • lower alkoxycarbonyl group examples include, for example, methoxycarbonyl
  • the " ⁇ reel O alkoxycarbonyl group” for example, Fuenokishikarubo two Honoré, 1-naphthoxycarbonyl, 2-naphthoquinone Shikano levo alkenyl C 6 _ 1 2 ⁇ Li Lumpur one O alkoxycarbonyl, such as and the like are preferable.
  • aralkyloxycarbonyl group examples include C 7 —i such as benzyloxycarbonyl and phenethyloxycarbonyl. Preferred are aralkyloxycarbonyl and the like (preferably, Ce—i; aryl—Ci—alkoxymonocarbonyl and the like).
  • the “lower alkoxycarboyl group”, “aryloxycarbonyl group” and “aralkyloxycarbonyl group” may have a substituent, and the substituent is represented by ring A
  • the “acyl group” as the substituent which the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have may be a carboxylic acid-derived acyl group or a sulfinic acid-derived acyl group. And sulfonic acid-derived acyl groups and phosphonic acid-derived acyl groups.
  • Examples of the “carboxylic acid-derived acyl group” include a hydrogen atom and an optionally substituted hydrocarbon group (for example, an “optionally substituted aromatic ring” represented by ring A) Groups and the like as the “optionally substituted hydrocarbon group” as a substituent in
  • an optionally substituted heterocyclic group (for example, the same as the “optionally substituted heterocyclic group” as the substituent in the “optionally substituted aromatic ring” for ring A) Group, etc.) and carbonyl (-C (O)-), such as formyl; acetyl, propionyl, butyryl, isobutyryl, norelinole, isovalerinole, vivalinore, hexanoinole, cyclobutancanolebonore, cyclobutane pentane Kano levo Nino les, Kisankanorepo two Honoré cyclohexane, black Toninore, triflumizole Ruo b acetyl C 2 _ 8 halogenated which may be linear or cyclic, such as Arukanoiru; Benzoiru, Nikochinoiru, Isonikochinoiru, and among them, Acetyl, propioninole, butyrinole
  • Examples of the “sulfinic acid-derived acyl group” include an optionally substituted hydrocarbon group (for example, an “optionally substituted aromatic ring” as a substituent in the “optionally substituted aromatic ring” for ring A) A similar hydrocarbon group as described above) or an optionally substituted heterocyclic group (for example, “optionally substituted aromatic ring” as a substituent in the “optionally substituted aromatic ring” for ring A) A group similar to "a good heterocyclic group”) and sulfinyl (-S (O)-), such as methanesulfiel, ethanesulfiel, and prono. N-sulfinyl, Proc.
  • an optionally substituted hydrocarbon group for example, an “optionally substituted aromatic ring” as a substituent in the “optionally substituted aromatic ring” for ring A
  • a similar hydrocarbon group as described above or an optionally substituted heterocyclic group (for example, “optionally substituted aromatic ring” as
  • Nsu Bruno Lev Ye Honoré cyclopentane Sno reflex Ye Honoré, good chain optionally halogenated such Kisansu Norefieru cyclohexane or cyclic C 1 - 6 alkyl Bruno less Bruno reflex Ye Honoré; benzene scan Honoré Fini Honoré, Tonoreensu Norefininore and the like.
  • an optionally substituted hydrocarbon group for example, “optionally substituted aromatic ring” represented by ring A as “substituted substituted” An optionally substituted heterocyclic group, etc.
  • an optionally substituted heterocyclic group for example, “substituted or substituted” in the “optionally substituted aromatic ring” for ring A) Or a heterocyclic group which may be the same as described above
  • a sulfol (-S (O) 2- for example, methanesnolehoninole, ethanesnolehoninole, and proha.
  • Susonorehoninore Cycloprono ,.
  • Chain / cyclic alkylsulfonyl which may be halogenated, such as benzene / sulfonyl, cyclopentansnorefonizole, cyclohexanesnoreffoninole, and the like; benzenesnorefonyl, tonolenesulfonyl, and the like.
  • acyl group derived from phosphonic acid examples include dimethylphosphono, getinolephosphono, diisopropinolephosphono, dibutynolephosphono, 2-oxo-1,3,2-dioxa Mono- or di-C 1-4 alkylphosphonos which may form a ring, such as phosphinane-2-yl.
  • I 6 alkyl group (the C 1-6 alkyl group, a halogen atom, arsenic Dorokishi force Luba Moinore, mono- or di-one benzylidene ⁇ / force ⁇ / Bamoinore, mono- one or di- one Fuene Ji carbamoyl, carboxyl, d_ 4 Alkoxy-monocarbonyl, optionally halogenated Ci-4 alkoxy, amino, mono- or di-Ci-4 alkylamino, Ci-6 alkanoylamino, optionally halogenated phenyl, halogenated Optionally substituted with benzoyl or the like);
  • C 1-6 alkenyl group (said C Medical 6 Arukeeru group may be substituted with may Yoibe Nzoiru like halogenated);
  • Hue - Le group (said phenyl is halogen atom, arsenic Dorokishi force Rubamoiru force carboxyl, sulfo group, C 1-4 alkoxy one carbonyl, optionally halogenated Rere which may be C 1-4 alkoxy,
  • Nono halogenated CL-4 may be substituted by alkyl, amino, mono, or di-CL alkylamino, Ci-e alkanoylamino, etc.);
  • a non-aromatic heterocyclic group (preferably oxazoline, the non-aromatic heterocyclic group may be substituted with an oxo group or the like);
  • the amino group may be a halogenated C ⁇ e alkyl, an optionally halogenated Ci-6 alkanol, an optionally halogenated benzoyl, a phenylacetyl (the phenyl is a halogen Atom, an optionally substituted alkyl, etc.), a mono- or di-benzylcarbamoyl group, a mono- or di-phenylethylcarbamoyl group, An alkoxy-carbonyl group which may be substituted by phenyl, an optionally halogenated ⁇ ⁇ 6 alkylsulfonyl, etc.]; a hydroxy group [the hydroxy group is phenyl (the phenyl is Or a halogen atom, which may be substituted with an optionally halogenated- 6 alkyl, etc.) and a naphthyl which may be optionally halogenated. ⁇ 6 may be substituted with alkyl,
  • a thiol group (the thiol group may be substituted with an alkyl which may be substituted with a halogen atom or a phenyl which may be halogenated, a phenyl which may be halogenated, or the like);
  • N-Ci-e alkyl (the alkyl may be substituted by a halogen atom, hydroxy, etc.)
  • N-phenyl nil (the phenyl may be substituted by a halogen atom, a halogenated Ci alkyl or the like) —a carbamoyl group;
  • N-non-aromatic heterocyclic ring preferably, tetrahydrobiranyl
  • N-bi- or tricyclic hydrocarbon preferably, tetrahydronaphthyl, indanyl, fluorenyl, or the di- or tricyclic hydrocarbon may be substituted with hydroxy or the like
  • N- C 6 - 12 7 reel (the Ariru is a halogen atom, optionally halogenated good Jii 4 alkyl, Nono halogenated which may be C 1-4 alkoxy, optionally substituted arsenide de port carboxymethyl May be substituted with Ci- 4 alkyl, etc.)
  • C ⁇ e alkyl (The C ⁇ 6 alkyl may be substituted by hydroxy, carbamoyl, etc.)
  • N—5- to 10-membered heterocyclic ring preferably, pyridyl, furyl, phenyl, indolyl, and the heterocyclic ring may be substituted with alkyl or the like
  • a 6- alkyl rubamoyl group preferably, pyridyl, furyl, phenyl, indolyl, and the heterocyclic ring may be substituted with alkyl or the like
  • Cycloalkyl (the CS.
  • the cycloalkyl may be replaced by hydroxy or the like)
  • _C 1-6 alkyl monorubumoyl group
  • N- monosubstituted sulfamoyl group e.g., N- phenyl (Said phenyl, Nono androgenic atom, may be substituted with may be C doctor 4 alkyl such as halogenated) ten I 6 alkylene loose sulfamoyl] ;
  • Nono halogenated which may also be C 2 - 8 Arukanoiru group;
  • a C 6 alkylsulfinyl group which may be nodogenized;
  • a 6- alkylsulfonyl group which may be nodogenated
  • Ring A is preferably an optionally substituted benzene ring or an optionally substituted pyridine ring, etc., and more preferably an optionally substituted benzene ring, and is preferably an optionally substituted rubamoyl group.
  • a benzene ring which may be substituted at the 3-position is particularly preferred.
  • a benzene ring which may be substituted at the 3-position with an N-monosubstituent rubamoyl group is most preferred.
  • X and X each represent an optionally substituted C 1-4 anoalkylene group.
  • ⁇ I 4 ⁇ alkylene group in the "optionally substituted C 1-4 alkylene group" represented by X, methylene, ethylene, trimethylene, tetramethylene and the like.
  • the substituent which the C 1 alkylene group may have the ⁇ substituted or substituted '' as the substituent which the aromatic ring in the ⁇ optionally substituted aromatic ring '' for ring A may have And the like, and the like may be the same as the substituents that the hydrocarbon group may have in the "hydrocarbon group which may be substituted" (however, it is preferably not an oxo group). One to three (preferably one) substitutions may be made at positions.
  • the substituent which the C 1-4 alkylene group may have,
  • X 'and X are preferably an optionally substituted methylene, and particularly preferably an unsubstituted methylene.
  • ring B represents a 5-membered nitrogen-containing aromatic heterocyclic ring which may be substituted.
  • Examples of the “5-membered nitrogen-containing aromatic heterocycle” include pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, Lazole, Oxadiazole (1,2,3-Oxadiazole, 1,2,4-Oxadiazole, 1,3,4-Ioxadiazole), Frazan, Oxadiazole (1,2,3-Thiadiazole, 1,2,4— Thiadiazole, 1,3,4-thiadiazole), triazole (1,2,3-triazole, 1,2,4-triazole), tetrazole and the like.
  • Preferred are pyrrole, virazole, imidazole, triazole, thiazole, isoxazole, oxaziazole and thiaziazole.
  • the substituent which the “5-membered nitrogen-containing aromatic heterocycle” may have is the same as the substituent in the “optionally substituted aromatic ring” represented by the aforementioned ring A. These substituents may be substituted at 1 to 3 (preferably 1) at any substitutable position.
  • substituent which the ⁇ 5-membered nitrogen-containing aromatic heterocycle j may have,
  • C 1-6 alkyl group (said C ⁇ 6 alkyl group, a halogen atom, arsenic Dorokishi force Luba moil, carboxyl, optionally Hue be halogenated - Honoré, C physician 4 alkoxycarbonyl one carbonyl, Sno referencing Moi Honoré , A sulfo group, optionally halogenated Ci- 4 alkoxy, benzyloxy, amino, mono- or di-C 1-4 alkynoleamino, ⁇ ⁇ 6 alkanoinoleamino, and optionally nitrogenated ⁇ 4 Alkylthio, optionally halogenated alkylsulfiel, optionally halogenated Ci alkylsulfur, etc.) phenyl which may be halogenated;
  • Ring B may be bonded to rings C and X at any substitutable position of the “5-membered nitrogen-containing aromatic heterocyclic ring”. Rings C and X are preferably bonded to the constituent carbon atoms.
  • R 1 represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl group
  • R 2 and R 3 each independently represent a hydrogen atom, a halogen atom (Eg, fluorine, chlorine, bromine, iodine), an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted diamino group, an optionally substituted hydroxy group
  • X has the same meaning as described above.
  • the ⁇ optionally substituted hydrocarbon group '' for R 1 includes the ⁇ optionally substituted aromatic ring '' for the ⁇ optionally substituted aromatic ring '' for ring A The same groups as the “hydrocarbon group which may be substituted”.
  • the “optionally substituted heterocyclic group” for R 1 includes the “optionally substituted aromatic ring” for the “optionally substituted aromatic ring” for ring A Heterocyclic group which may be substituted '' and the like.
  • the “acyl group” represented by R 1 includes the same group as the “acyl group” as a substituent which the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have Is mentioned.
  • ⁇ I 6 alkyl group (the CI_ 6 alkyl group, a halogen atom, arsenic Dorokishi force Luba Moinore, Kanorebokishiru, Harogenihi which may phenylene also be Honoré, ⁇ I 4 alkoxycarbonyl one carbonyl, sulfamoyl, Sunoreho group, halogenated Ci-4 alkoxy, benzyloxy, amino, mono- or di-C ⁇ alkylamino, C ⁇ ealkanoylamino, optionally halogenated Ci-4alkylthio, nodogenated Optionally substituted by Ci-4 alkylsulfinyl, optionally halogenated Ci alkylsulfonyl, etc.) optionally halogenated phenole;
  • the ⁇ optionally substituted hydrocarbon group '' for R 2 and R 3 the ⁇ optionally substituted aromatic ring '' for the ⁇ optionally substituted aromatic ring '' for ring A
  • the same groups as the “optionally substituted hydrocarbon group” can be mentioned.
  • the ⁇ optionally substituted heterocyclic group '' represented by R 2 and R 3 includes the aromatic ring in the ⁇ optionally substituted aromatic ring '' represented by ring A
  • Examples of the substituent that may be mentioned include the same groups as the “optionally substituted heterocyclic group”.
  • the ⁇ amino group which may be substituted '' represented by R 2 and R 3 may be a substituent which the aromatic ring may have.
  • the same groups as the “optionally substituted amino group” and the like can be mentioned.
  • the ⁇ optionally substituted hydroxy group '' represented by R 2 and R 3 includes a substituent which the aromatic ring in the ⁇ optionally substituted aromatic ring '' represented by ring A may have And the same groups as the “optionally substituted hydroxy group”.
  • the ⁇ optionally esterified carboxyl group J '' represented by R 2 and R 3 is a substituent which the aromatic ring in the ⁇ optionally substituted aromatic ring '' represented by ring A may have And the same groups as the “carboxyl group which may be esterified”.
  • the ⁇ acyl group '' represented by R 2 and R 3 is the same as the ⁇ acyl group '' as the substituent that the aromatic ring in the ⁇ optionally substituted aromatic ring '' represented by ring A may have And the like.
  • Each of R 2 and R 3 is preferably a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, or the like.
  • C 6 alkyl group (The C ⁇ e alkyl group is a halogen atom, a hydroxy, a carboxylic acid, a caneboxyl, a feninole which may be halogenated, a C i noreco xyl caneboninole, a snorefamoinole, a sulfo group , Optionally halogenated C 1-4 alkoxy, benzyloxy, amino, mono- or di-Ct 4 alkyl Ruamino, CL- 6 ⁇ Honoré Kano I Rua Mino, Nono halogenated to 4 which may Jii have Al Kiruchio, Nono halogenated which may also be ⁇ I 4 alkylsulfinyl, halogen of which may be C 1 -L ( optionally substituted by alkylsulfonyl or the like) phenyl which may be halogenated;
  • C ⁇ e alkyl group (said ⁇ DOO 6 alkyl group, a halogen atom, arsenic Dorokishi force Luba moil, carboxyl, Nono halogenated which may be phenyl, CI- 4 Anoreko carboxymethyl one carbo - le, Surupuamoiru, a sulfo group , it may also be halogenated Ijito 4 alkoxy, Benjiruokishi, amino, mono- one or di- one CI- 4 alkyl Ruamino.
  • R 1 that is, the group substituted with N
  • tautomers may exist, but in the present invention (especially, Examples), these are collectively described.
  • the triazole ring for example,
  • R 1 is a hydrogen atom in the following two tautomers:
  • ⁇ ′ is an optionally substituted imino group, one o— or one s (
  • Y represents an imino group which may be substituted.
  • Examples of the “optionally substituted imino group” represented by Y ′ and Y include a group represented by the formula: N (R 4 ) — (wherein R 4 is a hydrogen atom, an optionally substituted hydrocarbon group)
  • the ⁇ optionally substituted aromatic ring '' for the ⁇ optionally substituted aromatic ring '' for ring A may be ⁇ The same groups as the “hydrocarbon group which may be substituted”.
  • the “optionally substituted heterocyclic group” for R 4 includes the “optionally substituted aromatic ring” for the “optionally substituted aromatic ring” for ring A. Heterocyclic group which may be substituted '' and the like.
  • the “carboxyl group which may be esterified” represented by R 4 includes the aromatic ring in the “optionally substituted aromatic ring” represented by ring A
  • Examples of the substituents that may be present include the same groups as the “optionally esterified carboxyl group”.
  • acyl group represented by R 4
  • the same group as the “acyl group” as a substituent which the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have, and the like Is mentioned.
  • an optionally substituted imino group for example, a group represented by the formula: 1 N (R 4 ) —
  • a Ci-4 alkyl group and a ⁇ ⁇ 4 anoroxy group are preferable.
  • the force Rubamoiru group, a halogenated C 2 _ 8 optionally Arukanoiru group it may also be substituted with Benzoiru group I Imino group (i.e., one N (R 4 ) —, In which R 4 hydrogen atom, Ci-4 alkyl group, phenyl group optionally substituted by Ci_ 4 alkoxy group, carbamoyl group, C 2-8 alkanoyl group optionally And a benzoyl group) are more preferable, and an R 4 hydrogen atom and a Ci-4 alkyl group are particularly preferable.
  • Y ′ or Y is a substituted imino group
  • the substituent of the imino group and the substituent of the “aromatic ring” in ring A combine to form a ring (eg, tetrahydroquinoline) Is also good.
  • ring C represents an optionally substituted nitrogen-containing aromatic complex ring.
  • nitrogen-containing aromatic heterocycle in the “optionally substituted nitrogen-containing aromatic heterocycle” for ring C include, for example, pyrrole, oxazole, isooxazole, thiazole, isothiazole, imidazole, pyrazole, and o.
  • Oxadiazole (1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), furazane, thiadiazole (1,2,3-thiadiazole, 1,2,4-thiadiazole, 1 , 3, 4—thiadiazole ), Triazole (1,2,3-triazole, 1,2,4-triazole), tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine (1,2,4-triazine, 1,3,5- Triazine) 5- or 6-membered nitrogen-containing aromatic monocyclic heterocycle such as a ring; for example, indole, isoindole, 1H-indazole, benzimidazole, benzoxazonole, 1,2-benzoisoxazonole, benzo Thiazole, 1,2-benzoisothiazole, 1H-benzotriazole, quinoline, isoquinoline
  • Examples of the substituent that the “nitrogen-containing aromatic heterocycle” may have include the same groups as the substituents in the “optionally substituted aromatic ring” represented by the aforementioned ring A, and the like. These substituents may be substituted at 1 to 4 (preferably 1 to 2) at any substitutable position. Examples of the substituent which the “nitrogen-containing aromatic heterocycle” may have include:
  • a sulfo group An alkoxy group which may be halogenated;
  • a C 1-6 alkyl group (the C 1-6 alkyl group may be substituted with a halogen atom, a hydroxy group, a carbamoyloxy group, or the like);
  • a phenyl group which may be halogenated is a phenyl group which may be halogenated
  • the alkyl group may be a halogen atom, an optionally peroxylated alkoxy, an optionally non-perogenated C 1-6 alkylthio, phenyl (the phenyl is A halogen atom, optionally halogenated Ci-6 alkyl, optionally halogenated Ci 6 alkoxy, etc.), C ⁇ . May be substituted with a substituent selected from cycloalkyl.];
  • Ci-e alkanoylamino group An optionally halogenated Ci-e alkanoylamino group
  • a benzoylamino group which may be halogenated A benzoylamino group which may be halogenated
  • Phenyl optionally substituted rubamoylamino group which may be nodogenated;
  • An aromatic heterocycle (preferably thiophene);
  • the “nitrogen-containing aromatic heterocycle” in the “optionally substituted nitrogen-containing aromatic heterocycle” represented by ring C has two or more substituents adjacent to each other, the substituents are bonded to each other a ring (e.g., cyclopentane, cyclohexane, C 4 _ 8 cycloalkane ring such as shea Kuroheputan, benzene ring) to form a A little.
  • a ring e.g., cyclopentane, cyclohexane, C 4 _ 8 cycloalkane ring such as shea Kuroheputan, benzene ring
  • Ring C may be bonded to ring B at any of the substitutable positions of the “nitrogen-containing aromatic heterocycle”. It is preferable to combine with
  • Ring C is preferably a pyridine ring which may be substituted or a pyrimidine ring which may be substituted.
  • Ring C is preferably a pyridine ring which may be substituted or a pyrimidine ring which may be substituted.
  • each of ring C ′ and ring C ′′ may be substituted.
  • each of ring C ′ and ring C ′′ may have include the same groups as the substituents that the ring may have.
  • the nitrogen atom constituting the pyridine ring may be oxidized.
  • Examples of the compound represented by the formula (I) in the present invention include:
  • Ring A is a benzene ring substituted at the 3-position with an optionally substituted sorbamoyl group or the like (preferably, an N-monosubstituted carbamoyl group);
  • Ring B is a 1,2,4_triazole ring (preferably represented by the formula:
  • R 1 represents C 6 alkyl or the like.
  • Ring C is an optionally substituted pyridine ring or an optionally substituted Midine ring (more preferably, the formula:
  • the rings C ′ and C ′′ may be substituted with a Ci-alkyl group which may be substituted with a hydroxy group, an esterified propyloxyl group, or the like.]
  • X is methylene
  • Y is _NH—
  • salts of the compounds () and (I) include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Is mentioned.
  • metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • salt with an organic base examples include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) ) Methylamine], t-butylamine, cyclohexylamine, dicyclohexamine, ⁇ , N′-dibenzinoleethylenediamine and the like.
  • salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Preferred examples of the salt with an organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfone Acid and salts with ⁇ -toluenesulfonic acid and the like.
  • Preferable examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, and ornithine.
  • Preferred examples of the salt with the acidic amino acid include, for example, aspartic acid, glutamic acid, and the like. And salts thereof.
  • an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt, etc.) , Ammonium salt, etc.
  • a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
  • examples thereof include salts with organic acids such as acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and ⁇ -toluenesulfonic acid.
  • the compound (I) of the present invention can be obtained, for example, by a method represented by the following reaction formula or a method analogous thereto.
  • Compounds (II) to (IX) in the formula include those in the form of a salt.
  • Examples of such a salt include the same as the salt of the compound represented by the formula (I). Are used.
  • the compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be used for recrystallization, distillation, chromatography, etc. It can be easily purified by separation means.
  • L 1 is a leaving group (eg, a halogen atom (eg, fluorine, chlorine, bromine, iodine)) or a reactive derivative of sulfonic acid (eg, sulfonic acid ester, active sulfonic acid amide (eg, 1,2,4-triazolide, imidazolide, etc., quaternary aminesulfonyl compound (eg, N-methylpyrrolidinium salt, etc.), bissulfonyl imide (eg, N-phenylbissulfonylimide, etc.)
  • M 1 is a hydrogen atom, an alkali metal (eg, lithium, potassium, sodium, cesium, etc.), an alkaline earth metal (eg, calcium, magnesium, etc.) or a leaving group (eg, trimethylsilyl group, etc.) And other symbols are as defined above.
  • the compound (I) can be produced by reacting the compound (III) or a salt thereof represented by the following formula: This reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected.
  • solvents include alcohols (eg, methanol, ethanol
  • ethers eg, dioxane, tetrahydrofuran, getyl ether, tert-butyl methyl ether, diisopropyl ether, ethylene glycol-dimethyl ether, etc.
  • esters eg, formic acid
  • carboxylic acids eg, formic acid, acetic acid, propionic acid, etc.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, carbon tetrachloride, trichloroethylene
  • 1,2-dichloroethane, benzene, etc. hydrocarbons (eg, n-hexane, benzene, toluene, etc.), amides (eg, formamide, N, N
  • This reaction may be performed in the presence of a base, if necessary.
  • a base for example, lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, Inorganic bases such as sodium hydrogencarbonate and hydrogencarbonate; alkali metal salts of fatty acids such as sodium formate, sodium acetate and potassium acetate; for example, triethylamine, tri (n-propyl) amine, tri (n-butyl) Organic amines such as pyridine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, norethidine, ⁇ -collidine, ⁇ , ⁇ -dimethylaniline, ⁇ -methylbiperidine, ⁇ -methinolepi-open lysine, ⁇ -methylmorpholine, etc. Is used.
  • the compound (II) is 0.5 to 5 equivalents, preferably 0.8 to 2 equivalents, and the base is 0.5 to 10 equivalents, preferably 0.8, based on 1 equivalent of the compound (II). ⁇ 5 equivalents are used respectively.
  • the reaction temperature is from 120 to 200 ° C, preferably from 0 to 170 ° C.
  • the reaction time depends on the type of compound (II) or (III), type of solvent, reaction temperature, etc. Usually, it is about 1 minute to about 72 hours, preferably about 15 minutes to about 24 hours.
  • M 2 is a hydrogen atom, an alkali metal (eg, lithium, potassium, sodium, cesium, etc.), an alkaline earth metal (eg, calcium, magnesium, etc.) or a leaving group (eg, trimethylsilyl group, etc.) And other symbols are as defined above.
  • an alkali metal eg, lithium, potassium, sodium, cesium, etc.
  • an alkaline earth metal eg, calcium, magnesium, etc.
  • a leaving group eg, trimethylsilyl group, etc.
  • L 2 represents a leaving group, and other symbols have the same meanings as described above.
  • the compound (I) can be produced by reacting the compound (V) or a salt thereof represented by the following formula: As the leaving group for L 2, such groups similar leaving group represented by L 1 is used.
  • This reaction is generally performed in a solvent, and if necessary, in the presence of a base.
  • a solvent and base used in this reaction the same solvents and bases as described in the above-mentioned Method A can be used.
  • the compound (V) is 0.5 to 10 equivalents, preferably 0.8 to 5 equivalents, and the base is 0.5 to 20 equivalents, preferably 0.8 to 10 equivalents to 1 equivalent of the compound (IV). Used 10 equivalents each.
  • the reaction temperature is between ⁇ 50 and 150 ° C., preferably between 20 and 120 ° C.
  • the reaction time varies depending on the type of compound (IV) or (V), the type of solvent and base, the reaction temperature, etc., but is usually about 1 minute to about 100 hours, preferably about 15 minutes to about 24 hours. .
  • the compound (I) can be produced by reacting the compound (VII) or a salt thereof represented by the following formula: This reaction is generally performed in a solvent, and if necessary, in the presence of a base. As the solvent and base used in this reaction, the same solvents and bases as described in the above-mentioned Method A can be used.
  • compound (VI) is used in an amount of 0.5 to 10 equivalents, preferably 0.8 to 5 equivalents, and a base is used in an amount of 0.5 to 20 equivalents, preferably 0.8 to 1 equivalent based on 1 equivalent of compound (VII). Used 10 equivalents each.
  • the reaction temperature is from 150 to 150 ° C, preferably from 120 to 120 ° C.
  • the reaction time varies depending on the type of compound (VI) or (VII), the type of solvent and base, the reaction temperature, etc., but is usually about 1 minute to about 100 hours, preferably about 15 minutes to about 24 hours. .
  • R 5 is "optionally substituted C 1 - 4 alkylene group" represented by hydrogen or X indicates C 1 alkylene group having optionally be substituent at, X a is It represents a C i _ 3 alkylene group which may be substituted, and other symbols have the same meanings as described above.
  • the compound (I) can be produced by reducing the compound (VIII) or a salt thereof represented by the formula:
  • a reducing agent for example, hydrogen; for example, a metal such as an alkali metal such as lithium, sodium, and potassium and an alkaline earth metal such as calcium; for example, an amalgam such as zinc-amalgam, aluminum-amalgam, and zinc-copper alloy;
  • metal salts such as chromium chloride (11), chromium sulfate ( ⁇ ), chromium acetate ( ⁇ ), chromium perchlorate ( ⁇ ), titanium chloride ( ⁇ ), and samarium iodide;
  • Metal hydrides such as hydrogenated tri-n-triptyltin and triethylsilane; for example, sodium borohydride, sodium trimethoxyborohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, trihydrogen hydride —Sec—lithium butylboron, lithium trisiamylborohydride, hydrogen Potassium tri-sec-buty
  • This reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected.
  • a solvent include liquid ammonia, alcohols (eg, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc.), ethers (eg, dioxane, tetrahydrofuran, jetinole).
  • the reducing agent is used in 0.1 to 20 equivalents, preferably about 0.4 to 10 equivalents, per 1 equivalent of compound (VIII).
  • This reaction may be carried out in the presence of a metal salt, an acid or a base, if necessary.
  • a metal salt examples include cerium (III) chloride, covanolate (II) chloride and nickel chloride (111). ), Zinc chloride, titanium chloride, tin chloride (11), rhodium chloride, cadmium chloride, bisacetylacetonato copper (II), copper iodide (I), etc., and sulfuric acid, acetic acid as an acid. Acetic acid, methanesulfonic acid and the like are used, and getylamine and the like are used as a base.
  • these metal salts, acids or bases are used in 0.1 to 20 equivalents, preferably 0.5 to 10 equivalents, per 1 equivalent of compound (VIII). Can be
  • the reaction temperature is from about 10 ° C to about 250 ° C, preferably from about 15 ° C to about 150 ° C.
  • reaction time varies depending on the type of compound (VIII), metal salt, acid or base or solvent, reaction temperature, etc., but is usually about 1 minute to about 50 hours, preferably about 5 minutes to about 24 hours. is there.
  • This reaction is performed in the presence of a reducing agent.
  • a reducing agent those similar to the reducing agent described in Method D and the like are used.
  • This reaction is generally performed in a solvent, and if necessary, in the presence of a metal salt, acid or base.
  • a metal salt, acid or base those similar to the solvent, metal salt, acid and base described in Method D above can be used.
  • the reducing agent is used in 0.1 to 20 equivalents, preferably about 0.4 to 10 equivalents, relative to 1 equivalent of compound (IX), and the metal salt, acid or base is used in 0.1 equivalent.
  • the target compound can be obtained by removing the protecting group.
  • the introduction or removal of these protecting groups can be performed by a method known per se, for example, Wiley-Interscience, 1999, “Protective Groups in Organic Synthesis,
  • Compound (I) can be isolated and purified by known means, for example, phase transfer, concentration, solvent extraction, fractionation, liquid conversion, crystallization, recrystallization, chromatography and the like.
  • compound (I) When compound (I) is obtained as a free compound, it can be converted to a target salt by a method known per se or a method analogous thereto, and conversely, when compound (I) is obtained as a salt, It can be converted to a free form or another desired salt by a known method or a method analogous thereto.
  • a prodrug of compound (I) is a compound that is converted into compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) is enzymatically oxidized, reduced, hydrolyzed, or the like. Or a compound that undergoes hydrolysis or the like by gastric acid or the like to change to compound (I).
  • Examples of the prodrug of the compound (I) include compounds in which the amino group of the compound (I) is acylated, alkylated, and phosphorylated (for example, the amino group of the compound (I) is eicosanoylated, oxidized, pentyl).
  • Aminocarboylation (5-Methylinole-2-oxo-1,3-dioxolene-4-inolene) Methoxyca ⁇ / boninolelation, Tetrahydrofuraellation, Pyrrolidylmethylation, Vivaloyloxymethylation, compounds in which the hydroxyl group of compound (I) has been acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group of compound (I) has been acetylated, palmitoy).
  • prodrug of compound (I) changes to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals”, Vol. 7, Molecular Design, pp. 163 to 198. It may be something.
  • Compound (I) 1 When the compound has isomers such as an optical isomer, a stereoisomer, a positional isomer, and a rotatable isomer, any one of the isomers and a mixture are included in the compound (I).
  • the compound (I) ′ when the compound (I) has an optical isomer, the compound (I) ′ includes the optical isomer separated from the racemate.
  • Each of these isomers can be obtained as a single product by known synthesis techniques and separation techniques (concentration, solvent extraction, column chromatography, recrystallization, etc.).
  • the compound (I) may be in the form of a crystal, and the compound (I) includes a single crystal form or a mixture of crystal forms. Crystals can be produced by crystallization by applying a crystallization method known per se.
  • the compound (I) may be a solvate (for example, a hydrate or the like) or a non-solvate, and both are included in the compound (I).
  • the agent of the present invention has low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.), is safe, and has GRK inhibitory activity, particularly strong GRK2 inhibitory activity.
  • low toxicity eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.
  • GRK inhibitory activity particularly strong GRK2 inhibitory activity.
  • heart disease for example, humans, monkeys, cats, pigs, pomas, mice, mice, rats, guinea pigs, dogs, and egrets
  • heart disease cardiovascular hypertrophy
  • Acute heart failure and chronic heart failure including congestive heart disease, cardiomyopathy, angina pectoris, myocarditis, atrial and ventricular arrhythmias, tachycardia, myocardial infarction, etc.), myocardial ischemia, venous insufficiency, after myocardial infarction Heart failure Transition, hypertension, pulmonary heart, atherosclerosis including atherosclerosis (aneurysm, coronary sclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, etc.), vascular hyperplasia, intervention (percutaneous coronary angioplasty) , Stent placement, coronary artery endoscopy, intravascular ultrasound, coronary infusion thrombolysis, etc.), vascular hypertrophy or occlusion and organ
  • the concept of prevention of heart failure includes myocardial infarction, angina pectoris, cardiac bypass, thrombolytic therapy, and treatment of prognosis after coronary revascularization, etc.
  • Control of progression or worsening of heart failure, or maintenance of cardiac function during non-drug therapy for severe heart failure Is also included.
  • the agent of the present invention When the agent of the present invention is applied to the prevention or treatment of heart failure and the like, regardless of the difference in causative diseases such as ischemic heart disease, cardiomyopathy and hypertension, and the difference in symptoms such as systolic insufficiency and diastolic insufficiency, Short-term medication is expected to improve cardiac contractility and diastolic properties without side effects such as hypotension, tachycardia, and decreased renal blood flow. It is expected that the prognosis will be improved over time (improved survival rate, reduced cardiac accident rate, etc.).
  • the compound of the present invention may be used alone or in accordance with a conventional method (for example, a method described in the Japanese Pharmacopoeia) to mix a pharmacologically acceptable carrier, such as tablets (sugar-coated tablets, film-coated tablets) ), Powders, granules, capsules, solutions, emulsions, suspensions, injections, suppositories, sustained-release preparations, patches, etc., orally or parenterally (eg, topical, rectal, Intravenous administration) can be safely administered.
  • a pharmacologically acceptable carrier such as tablets (sugar-coated tablets, film-coated tablets) ), Powders, granules, capsules, solutions, emulsions, suspensions, injections, suppositories, sustained-release preparations, patches, etc., orally or parenterally (eg, topical, rectal, Intravenous administration) can be safely administered.
  • the content of the compound of the present invention in the pharmaceutical composition is about 0.01 to 11% by weight, preferably about 2 to 85% by weight of the whole composition.
  • the dose of the compound of the present invention varies depending on the administration subject, administration route, disease and the like.
  • it when administered as an oral agent to an adult (body weight of about 6 O kg) as a therapeutic agent for heart failure, it may be an active ingredient About 1 to 100 mg, preferably about 3 to 300 mg, more preferably about 10 to 200 mg as the compound (I), which is administered in 1 to 1 or several divided doses Can be.
  • the compound of the present invention may be appropriately used as drugs usually used for treatment of heart failure, for example, digitalis, catecholamine (eg, dobutamine, donomin, denopamine, zamoterol, etc.),] 3 blocker (bisoprolol, carvedilol, etc.), Nitric acid (Nitroglycerin, etc.), hydralazine, Ca antagonist (amlodipine, etc.), ACE inhibitor (enalapril, etc.), ⁇ antagonist (candesartan, etc.), diuretic (furosemide, etc.), PDE inhibitor (milrinone, etc.), Ca-sensitized drugs (such as pimobendan), thrombolytics (such as t-PA), anticoagulants (such as heparin and perfurin), antiplatelet drugs (such as aspirin), antiarrhythmic drugs (such as amiodarone), and HMG-CoA Reductase inhibitors (atropastatin, si, tri
  • the compound of the present invention when it is applied to each of the above-mentioned diseases, it can be used in combination with a biological agent (eg, antibody, vaccine preparation, etc.). It is also possible to apply as.
  • a biological agent eg, antibody, vaccine preparation, etc.
  • antibodies and vaccines include vaccines against angiotensin II, vaccines against CETP, CETP antibodies, antibodies against TNFa antibody and other cytokines, amyloid] 3 vaccine, type 1 diabetes vaccine (Peptor Etc., as well as antibodies or vaccine preparations against cytokinin, renin-angiotensin enzymes and their products, antibodies or vaccine preparations against enzymes and proteins involved in blood lipid metabolism, blood Antibodies or vaccines for enzymes involved in the coagulation / fibrinolytic system in the cells, vaccines, and antibodies to proteins involved in glucose metabolism or insulin resistance.
  • gene therapy methods include, for example, therapeutic methods using genes related to cytokinin, renin-angiotensin enzyme and its products, and signal transduction systems such as i3 receptor and adenylate cycling. Therapy using related genes, ARKct or] 3 arrestin, etc.
  • organ regeneration methods such as heart regeneration, kidney regeneration, ⁇ regeneration, and blood vessel regeneration, and other cells capable of differentiating into bone marrow cells (bone marrow mononuclear cells, bone marrow stem cells, etc.) and muscle (embryonic stem cells, myoblasts) It can also be used in combination with vascular and cardiomyogenic therapies utilizing cell and other transplants.
  • Examples of the administration form include (1) administration of a single preparation obtained by simultaneously preparing a compound of the present invention and a concomitant drug, and (2) preparation of a single preparation obtained by separately preparing the compound of the present invention and a concomitant drug. (3) simultaneous administration of the same formulation by the same route of administration, (3) administration of the two formulations obtained by separately formulating the compound of the present invention and the concomitant drug with the same route of administration differing in time, (4) Simultaneous administration of two formulations obtained by separately formulating the compound of the present invention and a concomitant drug by different administration routes; (5) Obtained by separately formulating the compound of the present invention and a concomitant drug Administration of the two preparations at different times by different administration routes (for example, administration of the compound of the present invention ⁇ concomitant drug, or administration in the reverse order) and the like.
  • the dose of the concomitant drug can be appropriately determined based on the dose clinically used.
  • the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination, and the like.
  • the concomitant drug may be used in an amount of 0.01 to 100 parts by weight based on 1 part by weight of the compound of the present invention.
  • the GRK inhibitor of the present invention exhibits excellent preventive and therapeutic effects on various diseases such as heart failure. ⁇
  • the silica gel for the column is also Kieselgel 60 (70 to 230 mesh) or Kieselgel 60 (230 to 400 mesh) manufactured by Merck, or Kogel C—300 (4) manufactured by Wako Pure Chemical Industries, Ltd. 5 to 75 ⁇ ) was used.
  • As the basic silica gel for the column basic silica NH-DM1020 (100 to 200 mesh) manufactured by Fuji Silicon Chemicals, Inc. was used.
  • the NMR spectrum is measured with a Varian Gemini 200 or Mercury 300 spectrometer using tetramethylsilane as an internal or external reference, and the chemical shift is coupled as a ⁇ value. Constants are given in Hz.
  • IR spectra were measured with a Shimadzu FTIR-8200 PC-type spectrometer.
  • the figures in parentheses indicate the volume mixing ratio of each solvent.
  • The% in the solution represents the number of grams in 100 ml of the solution.
  • the symbols in Reference Examples and Examples have the following meanings.
  • the aqueous layer was dissolved with sodium chloride until saturated and extracted with THF (2X 50 mL).
  • the combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was dissolved in ethanol (100 mL), acetic acid (1.0 mL) was added, and the mixture was stirred at 90 ° C for 5 hours.
  • the reaction mixture was concentrated under reduced pressure, ethyl acetate (200 mL) was added, and the mixture was washed with brine (75 mL). After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
  • N-Benzyl-N-methyl-3-nitrobenzamide (2.70 g), chloridium chloride (0.55 g) and reduced iron (3.35 g) are mixed in 85% ethanol (50 mL) and mixed at 85 ° C. The mixture was stirred at C for 70 minutes. The reaction mixture was filtered using celite and washed with methanol. The combined filtrate and washings were concentrated under reduced pressure, the residue was diluted with ethyl acetate (200 mL), and the mixture was washed with water (2 ⁇ 100 mL) and brine (50 mL).
  • the separated organic layer was washed with saturated saline (100 mL), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the residue was dissolved in ethyl sulphate (100 mL), washed three times with water (100 mL), further washed with saturated saline (100 mL), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. 8.91 g (yield: 85%) of the compound was obtained as an orange liquid.
  • 3_Methyl-4-pyridinecarboxyimidhydrazide (3.3 g) was suspended in THF (40 mL) and dichloromethane (40 mL), and DBU (5.6 mL) was added. Chloroacetyl chloride (3.5 mL) was added dropwise at 0 ° C over 10 minutes, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added ethyl acetate (500 mL), the mixture was washed with saturated saline (150 mL), the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was dissolved in ethanol (150 mL) and acetic acid (1.5 mL), and the mixture was stirred at 90 ° C for 5 hours.
  • the reaction mixture was concentrated under reduced pressure, and a saturated saline solution (75 mL) and a small amount of water were added.
  • the mixture was extracted with ethyl acetate (300 mL, 2 ⁇ 100 mL), the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Ethyl 2,4-dioxo-4_ (4-pyridyl) butyrate (32 g) and hydroxyamine hydrochloride (22.9 g) were mixed in ethanol (250 mL). And concentrated hydrochloric acid (40 mL) was added. The mixture was stirred at 100 ° C for 6 days, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol-ethyl acetate.
  • 3-Ditrophenyl isocyanate (8.10 g) was dissolved in THF (150 mL), benzylamine (5.9 mL) was added dropwise, and the mixture was stirred at room temperature for 6.5 hours. Hexane was added to the reaction mixture, and the precipitated crystals were collected by filtration and dried to give the title compound (13.0 g, yield 97%) as colorless crystals.
  • the reaction mixture was concentrated under reduced pressure, and 1N sodium hydroxide (140 mL) was added to the residue at 0 ° C to adjust the pH of the mixture to about 4.
  • the precipitated solid is collected by filtration, water and And dried at 80 for 2 hours to obtain 64 g of a solid.
  • 5- (4-pyridyl) pyrazole_3_carboxylate hydrochloride (2.32 g), N-methoxy-1-N-methylamine hydrochloride (1.20 g), triethylamine (3.6 mL), WSC (2.37 g) and 1-hydroxyl 1 H-benzotriazole monohydrate (0.16 g) were mixed with DMF (50 mL) and stirred at room temperature for 60 hours. Water (300 mL) was added to the reaction mixture, and the mixture was extracted with ethynole acetate (500 mL ⁇ 3 X 150 mL), followed by honolem (3 X 150 mL), and the organic layer was dried over anhydrous sodium sulfate.
  • N-Methoxy N-methyl-5- (4-pyridyl) pyrazole-3 Dissolve boxamide (535 mg) in THF (35 mL), add lithium aluminum hydride (87 mg) at 130 ° C, and raise the mixture to 0 ° C for 1 hour. Stirred. Water (10 mL) was added at ⁇ 30 ° C., and saturated saline (30 mL) was added, and the reaction mixture was extracted with THF (1 50 mL) and then with chloroform (5 ⁇ 50 mL). . Each organic layer was dried over anhydrous sodium sulfate and filtered through celite. The filtrate was concentrated under reduced pressure to give the title compound (398 mg, quantitative) as a pale yellow solid. This compound was used for the next reaction without further purification.
  • 3,3-Dibromo-1,1,1-trifluoroacetone (36.1 g) and sodium acetate (21.9 g) were mixed with water (50 mlj) and stirred at 110 ° C for 30 minutes. After returning the reaction mixture to room temperature, isonicotine aldehyde (11.5 g), 25% aqueous ammonia (13 mL) and methanol (50 mL) were added, and the mixture was stirred at room temperature for 36 hours. The mixture was concentrated under reduced pressure, ethanol was added to the residue, and the mixture was concentrated again under reduced pressure, and ethyl acetate (400 mL) was added to the residue.
  • the layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the crystals were crystallized to give 5.88 g of the title compound as pale yellow crystals.
  • Triethylamine (5.6 mL) was added to the mixture at -78 ° C, and the mixture was stirred at room temperature for 10 minutes, and the solvent was distilled off under reduced pressure.
  • Water 50 mL was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated saline (50 mL), dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure.
  • the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 2.01 g (quantitative) of the title compound as a pale yellow liquid. .
  • the reaction mixture was concentrated under reduced pressure, added with water (50 mL), neutralized with 1N hydrochloric acid, and then added with a saturated aqueous solution of sodium hydrogen carbonate (20 mL).
  • the mixture was extracted with ethyl acetate (300 mL, 100 mL), and the organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 706 mg of the title compound as colorless crystals.

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Abstract

Un composé représenté par la formule suivante (I') : (I') [où le cycle A représente un cycle aromatique facultativement substitué ; le cycle B représente un hétérocycle aromatique azoté à 5 éléments facultativement substitué ; le cycle C représente un hétérocycle aromatique azoté facultativement substitué ; X' représente un alkylène en C1 à C4 facultativement substitué ; et Y' représente un imino-, -O-, ou -S(O)n facultativement substitué (où n vaut 0, 1 ou 2)] ; et un inhibiteur de la protéine kinase GR contenant le composé, un de ses sels ou un promédicament de l’un d’entre eux. Le composé est utile pour la prévention ou le traitement de l’insuffisance cardiaque, etc.
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US8211929B2 (en) 2004-12-30 2012-07-03 Exelixis, Inc. Pyrimidine derivatives as kinase modulators and method of use
WO2007034846A1 (fr) * 2005-09-22 2007-03-29 Takeda Pharmaceutical Company Limited Agent tonicardiaque comprenant un inhibiteur de la grk
US8222256B2 (en) 2006-07-05 2012-07-17 Exelixis, Inc. Methods of using IGFIR and ABL kinase modulators
US7674801B2 (en) * 2006-12-04 2010-03-09 Astrazeneca Ab Alkyl urea substituted pyridines
US10426760B2 (en) 2007-07-17 2019-10-01 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
JP2015007100A (ja) * 2007-07-17 2015-01-15 プレキシコン，インコーポレーテッド キナーゼ調節のための化合物と方法、及びそのための適応
US9469640B2 (en) 2007-07-17 2016-10-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9844539B2 (en) 2007-07-17 2017-12-19 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
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US8268872B2 (en) 2008-02-22 2012-09-18 Radius Health, Inc. Selective androgen receptor modulators
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