WO2004054979A1 - Inhibiteurs de jnk - Google Patents

Inhibiteurs de jnk Download PDF

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Publication number
WO2004054979A1
WO2004054979A1 PCT/JP2003/016159 JP0316159W WO2004054979A1 WO 2004054979 A1 WO2004054979 A1 WO 2004054979A1 JP 0316159 W JP0316159 W JP 0316159W WO 2004054979 A1 WO2004054979 A1 WO 2004054979A1
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group
optionally substituted
substituted
compound
formula
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PCT/JP2003/016159
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English (en)
Japanese (ja)
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Fumio Itoh
Shuji Kitamura
Hiroyuki Kimura
Hideki Igata
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Takeda Pharmaceutical Company Limited
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Priority to AU2003289386A priority Critical patent/AU2003289386A1/en
Publication of WO2004054979A1 publication Critical patent/WO2004054979A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a c-Jun N-terminal kinase (JNK)] inhibitor having an isoquinolinone skeleton, which is useful as a medicament, a novel isoquinolinone derivative having a JNK inhibitory activity, and use thereof.
  • JNK c-Jun N-terminal kinase
  • MAPK mitogen-activated protein kinase
  • JNK c-Jun N-terminal kinase
  • SAPK stress-activated protein kinase
  • ERK extracellular signal regulated kinase
  • MAPK is a serine / threonine kinase, it is activated by phosphorylation of both threonine and tyrosine of the Thr-X-Tyr sequence in the activation loop. MAPK phosphorylates and activates various transcription factors to regulate the expression of specific genes and mediate specific responses to extracellular stimuli.
  • JNK3 Three genes, jnkl, jnk2 and jnk3, have been identified in JNK, and there are at least 10 isoforms of 'in mammals (EMBO Journal, 1996, Vol. 15, .2760-2770). Although Jnkl and jnk2 are expressed in many tissues, JNK3 may be particularly involved in neuronal function because j or 3 is specifically expressed in the brain. Stress responsiveness The MAP kinase family's JNK signaling system responds to osmotic changes, DNA damage, anisomycin, heat shock, ultraviolet irradiation, ischemia, inflammatory cytokines, and various stress stimuli related to apoptosis induction.
  • JNK activates various transcription factors such as c-Jun, ATF-2, E1k1, p53 and cell death domain protein (DE ⁇ ), and cell death (apo! ⁇ 1-cis) signals Responding to environmental changes such as various stresses by regulating the transcriptional activity of specific genes or inducing apoptosis (Proceedings of the National Academy of Sciences of the United States of America, 1998 Year, Vol. 95, .2586-2591).
  • JNK's chronic activation is seen in various conditions and diseases, such as cancer, cell death, allergy, asthma, heart disease, autoimmune disease, ischemic disease, inflammation, and neurodegenerative disease. Activation has been suggested to be closely related to the onset and exacerbation of these diseases. [In the present specification, such a disease state or disease associated with JNK activation is referred to as “JNK-related disease state or disease”. ]
  • JNK is activated by stretch stimulation and ischemia to transmit a stress signal.
  • J NK is also activated by catecholamines and angiotensin II endoselin and regulates the expression of factors involved in cardiac hypertrophy and fibrosis (BNP / ANP, TNF-, TGF- ⁇ , MMPs, etc.) (Journal of Biological Chemistry, Vol. 270, p. 29710-29717, FASEB Journal, 1996, Vol. 10, .631-636, Circulation Research, 1997, Vol. 80, p. 139-146).
  • JNK is important for T-cell activation by activating IL-12 promoter Plays a role. Recent experiments using knockout mice have reported that JNK plays an important role in the differentiation of Th1 and Th2 cells. Therefore, inhibitors of JNK may be effective in treating pathological immune diseases (Journal of I-unology, 1999, Vol. 162, p. 3176-3187, European Journal of Immunology, 1998, 28, p.3867-3877, Journal of Experimental Medicine, 1997, 186, .941-953, European Journal of Immunology, 1996, 26, p.989-994, Current Biology, 1999 , Vol. 9, .116-125).
  • JNK is activated in synovial cells of rheumatic patients, and JNK regulates MMP gene expression in IL-11-stimulated synovial cells, so JNK is greatly involved in joint destruction in rheumatic patients (Journa 1 of Clinical Investigation, 2001, '108, .73-81) 0 Based on this, JNK inhibitors may be effective in treating rheumatism .
  • JNK3 plays an important role in the development of daltamate-type neurotoxicity in JNK3 knockout mice, which resist neuronal apoptosis due to high doses of kaidonic acid (Nature, 1997 389, pp. 865-870). JNK3 is also activated in hypoxic or ischemic neurons to cause apoptosis. These suggest that JNK inhibitors may be effective in treating neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, or ischemia and hemorrhagic stroke.
  • JNK1-deficient mice have reported that JNK is an important mediator related to obesity and insulin resistance (Nature, 2002, Vol. 420, p. 333-336). ).
  • compounds having JNK inhibitory activity include, for example, indolinone derivatives in WO 99/35906, WO 99/35909 and WO 99/35921, and peracil derivatives International Publication No. 00 No. 75 118 Bread, Isoxazole derivatives in International Publication No. 01/12621, thiophene sulfonamide derivatives in International Publication No. 01 23378, International Publication No. 01Z23379, and international publication No. 01/23382 bread fried, pyrazoloant Mouth derivatives are disclosed in WO 01 Z 12609 pamphlet, and pyrimidylimidazole derivatives are disclosed in WO 01/91749 pamphlet.
  • an isoquinolinone derivative having a JNK inhibitory action has been reported only in the pamphlet of WO 03/068750 so far.
  • JP-A-00-72675 JP-A-2000-72751, JP-A-5-132463, JP-A-6-321906, JP-A-7-010844, JP-A-7-076573 and International Publication No. It is disclosed in pamphlets such as 02/062764. Purpose of the invention
  • the compounds having JNK inhibitory activity described above do not always have sufficient JNK inhibitory activity and have insufficient selectivity with other kinase inhibitory activities. The problem remains. In addition, since the physical properties (stability, solubility, etc.), oral absorption and transferability to target organs are not sufficient, practically satisfactory results have not been obtained as pharmaceuticals. There is an urgent need to develop JNK inhibitors that are excellent as effective drugs for disease states or diseases. Summary of the Invention
  • the present invention is useful and safe as a prophylactic or therapeutic agent for JNK-related conditions or diseases.
  • JNK inhibitors are provided.
  • the present inventors have conducted various studies and found that a compound having an isoquinolinone skeleton or a salt thereof has unexpectedly excellent JNK-specific inhibitory activity based on its specific chemical structure. It also has excellent properties as a pharmaceutical such as stability, and has been found to be a safe and useful drug as a preventive and therapeutic drug for JNK-related pathological conditions or diseases in mammals.
  • the present invention has been made based on the above findings.
  • ring A represents an optionally substituted benzene ring
  • R 1 represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group
  • R 2 represents hydrogen.
  • Re represents an optionally substituted amino group
  • X represents an optionally substituted divalent chain hydrocarbon group
  • Y represents an optionally substituted non-aromatic hydrocarbon group
  • a JNK inhibitor comprising a compound represented by the formula: or a salt thereof or a prodrug thereof;
  • ring A represents an optionally substituted benzene ring
  • R 1 represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group
  • R 2 represents hydrogen.
  • X represents an optionally substituted amino group
  • Y represents an optionally substituted non-aromatic hydrocarbon group, an optionally substituted heterocyclic group, and an optionally substituted It represents a droxy group or an amino group which may be substituted.
  • Ring A is a formula
  • R 3 is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, or an optionally substituted It represents a good thiol group, a substituted sulfiel group, a substituted sulfonyl group, an optionally substituted amino group, an optionally substituted sorbamoyl group or an optionally esterified carboxyl group.
  • the compound according to the above (2) which is a benzene ring represented by the following:
  • R 3 is a hydrogen atom, a halogen atom, an optionally substituted alkyl group or an optionally substituted amino group
  • (22) a medicine comprising the compound according to (2) or (21); (23) The agent according to the above (1), which is a preventive or therapeutic agent for a JNK-related disease state or disease;
  • JNK-related condition or disease is a circulatory disease, an inflammatory disease, a neurodegenerative disease or diabetes;
  • ring A represents an optionally substituted benzene ring
  • R 1 represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group
  • R 2 represents hydrogen.
  • Re represents an optionally substituted amino group
  • X represents an optionally substituted divalent chain hydrocarbon group
  • Y represents an optionally substituted non-aromatic hydrocarbon group
  • It represents a good heterocyclic group, an optionally substituted hydroxy group or an optionally substituted amino group.
  • ring A represents an optionally substituted benzene ring
  • R 1 represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group
  • R 2 represents hydrogen.
  • X represents an optionally substituted divalent chain hydrocarbon group;
  • Y represents an optionally substituted non-aromatic hydrocarbon group; an optionally substituted heterocyclic group;
  • Ring A represents an optionally substituted benzene ring.
  • substituents which ring A may have include, for example, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, an optionally substituted hydrocarbon group, a substituent An optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted thiol group, a substituted sulfinyl group, a substituted sulfonyl group, an optionally substituted amino group, an acyl group, and a substituted And a carboxyl group which may be esterified.
  • a halogen atom for example, fluorine, chlorine, bromine, iodine, etc.
  • hydrocarbon group of the “optionally substituted hydrocarbon group” as a substituent that ring A may have include, for example, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group And an aralkyl group and an aryl group.
  • alkyl group examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, noel, decyl, pendecyl, tridecyl, tetradecyl, pen evening such as "straight-chain or branched ( ⁇ _ 1 5 alkyl group” such as decyl, preferably used are C preparative 8 alkyl groups, more preferably used is an alkyl group, more preferably an alkyl group Used.
  • cycloalkyl group for example, cyclopropyl, Shikuropuchiru, shea Kuropenchiru, cyclohexyl, cycloheptyl cyclohexane, Shikurookuchiru, such Adamanchi Le "(3 _ 1 () cycloalkyl group” and the like are used, more preferably .
  • C 3 is - 8 cyclo alkyl group is used, or more preferably as a C 5 _ 7 cycloalkyl group is found using the "alkenyl group", for example pinyl, Ariru, isoproterenol base sulfonyl, 3-butenyl, 3 _ Okuparu, such as 9 one year old Kutadeseniru "C 2 - 1 8 alkenyl group” and the like are used, and more preferably used are C 2 _ 6 alkenyl, C 2 is rather more preferably - used is 4 alkenyl group .
  • alkenyl group for example pinyl, Ariru, isoproterenol base sulfonyl, 3-butenyl, 3 _ Okuparu, such as 9 one year old Kutadeseniru "C 2 - 1 8 alkenyl group” and the like are used, and more preferably used are C 2 _ 6 alkenyl, C 2 is rather
  • cycloalkenyl group for example, a “cycloalkenyl group” such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like are used, and more preferably C 3 _ 8 cycloalkenyl group are used, more preferably C 5 _ 7 cycloalkenyl group is used.
  • alkynyl group for example, Echiniru, 1 one propynyl, Puroparu Gill, 1 Buchiniru, 2-butynyl, 1 one pentynyl, 2 - pentynyl, 3-Bae "C 2 _ 8 alkynyl group” such as Nchiniru such is used, more preferably used is an alkynyl group, more preferably C 2 - 4 alkynyl group employed.
  • a C 7 ⁇ 6 aralkyl group and the like are used, and specifically, for example, benzyl, phenyl, 3-phenylpropyl, 4-phenylbutyl
  • a naphthyl-C ⁇ -6 alkyl group such as a phenyl- 6 alkyl group such as (1-naphthyl) methyl, 2- (1-naphthyl) ethyl, and 2- (2-naphthyl) ethyl is used.
  • phenyl for example phenyl, 1 one-naphthyl, 2-naphthyl, Fuenantoriru, aromatic monocyclic such as anthryl (anthryl), 2 bicyclic or tricyclic C 6 _ 1 4 Ariru group, Bifue group, tolyl group is used, preferably, full Eniru, ⁇ 6 such as naphthyl - 1 0 Ariru group, more preferably Ru phenyl are used.
  • substituent that the “hydrocarbon group” in the “optionally substituted hydrocarbon group” as the substituent that the ring A may have may include, for example,
  • a nitro group (i) a nitro group, (ii) a hydroxy group, an oxo group, (iii) a cyano group, (iv) a rubamoyl group, (V) a mono- or dialkyl monorubumoyl group (eg, N-methyl rubamoyl, N— Ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-getylcarbamoyl and the like; the alkyl group is a halogen atom, a hydroxy group,
  • alkenyl-rubamoyl group (eg, N-aryl-rubamoyl); the alkenyl group is a halogen atom, a hydroxy group, a —4 alkoxy group
  • Pirijiruokishi group C 3 - 1 0 cycloalkyl group, C 3 - 1 0 cycloalkyl -.! 4 alkoxy group, 0 3 _ 0 cycloalkyl one C 4 alkyl group, (Xi ii) an optionally halogenated C DOO 4 alkyl group (e.g., methyl, Echiru, propyl, Izopuropiru, butyl, etc.), optionally C 2 may be halogenated - 6 alkenyl group (e.g., vinyl, Ariru , 2-butenyl, 3-butenyl, etc.), optionally halogenated alkylthio groups (eg, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, etc.), and hydroxy groups Good — 4-alkyl group, 0 ⁇ _ 4 alkylthio group which
  • E chill sulfinyl Hue Nils sulfinyl group, phenylsulfinyl Lou C i _ 4 alkyl group, (xvi ii) halogenated C i _ 4 optionally alkylsulfonyl group (e.g., methylsulfonyl, Echirusu Phenylsulfonyl group, phenylsulfonyl-alkyl group, (xix) amino group, aminosulfonyl group, mono- or di-4-alkylamino Nosulfonyl groups (eg, methylaminosulfonyl, ethylaminosulfonyl,
  • C i _ 6 Ashiru group e.g., formyl, halogenated have such good C 2 _ 6 Al force Noiru be such Asechiru
  • Benzoiru group, Ouiv optionally substituted Benzoiru group with a halogen atom
  • (XXV) 5- to 10-membered heterocyclic group eg, 2- or 3-Chenyl, 2- or 3-furyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-monothiazolyl, 3- , 4 mono- or 5-isothiazolyl, 2-, 4-mono or 5-xoxazolyl, 1,2,3- or 1,2,4-triazolyl, 1 H- or 2 H-tetrazolyl, 2-, 3- or 4-mono Pyridyl 2, 4 one or 5 _ Pirimi Jill, 3- or 4 one pyridazinyl, Kinoririre, isoquinolyl, indolyl, and the like; heterocyclic group (: may be substituted with such
  • the “hydrocarbon group” may have 1 to 5 of these substituents at substitutable positions, and when having 2 or more, the substituents may be the same or different.
  • Examples of the “heterocyclic group” of the “optionally substituted heterocyclic group” as a substituent which ring A may have include, for example, an oxygen atom as an atom (ring atom) constituting a ring system
  • aromatic heterocyclic group examples include, for example, furyl, phenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 3,4—oxaziazolyl, furzanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl , Pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and a 5- or 6-membered aromatic monocyclic heterocyclic group, and, for example, benzofuranyl, isobenzofuranyl, benzo [b] chenyl, indolyl, is
  • -Caprolyl Ruporinyl, a-carbolinyl, acridinil, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenatridinyl, phenato-mouth linyl, indolizinyl, pyro-mouth [1,2-b] pyridazinyl, pyrazo-mouth [1,5 — A) pyridyl, imidazo [1,2—a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1, 2 , 4—Triazolo 4,1'6, such as 4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl, benzo [
  • non-aromatic heterocyclic group examples include, for example, oxilanyl, azetidinyl, oxeenyl, cesinyl, pyrrolidinyl (preferably 1-pyrrolidinyl), tetrahydrofuryl, thiolanyl, piperidinyl (preferably 1-piperidinyl) Or 4-piberidinyl), tetra ⁇ drobilanyl, morpholinyl, thiomorpholinyl, piperazinyl, etc., a 3- to 8-membered (preferably 5- to 6-membered) saturated or unsaturated (preferably saturated) non-aromatic monocyclic heterocyclic compound.
  • One or two non-aromatic monocyclic heterocyclic groups as described above such as a cyclic group (aliphatic monocyclic heterocyclic group), 2,3-dihydroindolyl, 1,3-dihydroisoindolyl, etc.
  • Non-aromatic heterocyclic compounds such as 1,2,3,4-tetrahydroisoquinolyl in which the double bonds of some or all of the above aromatic monocyclic heterocyclic groups or aromatic condensed heterocyclic groups are saturated.
  • a ring group preferably 1 heterocyclic groups of the aforementioned 5- or 6-membered aromatic monocyclic heterocyclic group, or 1,2,3,4-tetrahydroquinolyl
  • heterocyclic group in the “optionally substituted heterocyclic group”, a 5- or 6-membered aromatic monocyclic heterocyclic group is preferable, and the “heterocyclic group” has The substituent which may be present is the same as the substituent which may be possessed by the ⁇ hydrocarbon group '' in the ⁇ hydrocarbon group which may be substituted '' as the substituent which ring A may have The same number of groups are used.
  • Examples of the “optionally substituted amino group”, the “optionally substituted hydroxy group” and the “optionally substituted thiol group” as the substituents that the ring A may have are: Optionally substituted hydrocarbon, acyl, ester An optionally substituted amino group, a hydroxy group and a thiol group such as an optionally substituted olepoxyl group, an optionally substituted olebamoyl group, or an optionally substituted heterocyclic group; And the like.
  • the "hydrocarbon group” in the “optionally substituted hydrocarbon group” and the “heterocyclic group” in the “optionally substituted heterocyclic group” are each a ring A
  • the same as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” and the “heterocyclic group” in the “optionally substituted heterocyclic group” Is used.
  • the “acyl group” and the “optionally esterified alkoxyl group” as the substituent respectively, the “esterified ester group” as a substituent which ring A described below may have And the same groups as the “carboxylyl group” and “acyl group” which may be used.
  • the same groups as the “optionally substituted carbamoyl group” described below as a substituent which ring A may have, and the like are used.
  • the substituents in the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group” may each be a “substituted group that the ring A may have.
  • a halogen atom for example, fluorine, chlorine, bromine, iodine, etc.
  • an optionally halogenated 6 alkoxy for example, methoxy, ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, trichloromethoxy, 2 , 2,2-trichloromouth ethoxy, etc.
  • optionally substituted phenyl preferably, optionally halogenated.
  • ⁇ 4 alkyl group optionally halogenated- 4 alkoxy group, carboxyl group And a 5- to 10-membered heterocyclic group (eg, 2- or 3-phenyl, 2- or 3-furyl, 3-, 4- Or 5-pyrazolyl, 21,4- or 5-thiazolyl, 31-, 4- or 5-isothiazolyl, 21,4- or 5-oxazolyl, 1,2 , 3— or 1,2,4-triazolyl, 1H— or 2H—tetrazolyl, 2—, 3— or 4-monopyridyl, 2—, 4— Or 5-pyrimidyl, 3- or 4 - pyridazinyl, quinolyl, isoquinolyl, indolyl, and the like; heterocyclic group is substituted with a substituent selected from (optionally substituted like ⁇ _ 4 alkyl group) Lower alkyl (eg, d- 6 alkyl such as methyl, ethyl, propyl, iso
  • a substituent such as a heterocyclic group (such as the same group as the “heterocyclic group” in the “optionally substituted heterocyclic group” as a substituent which ring A may have).
  • Preferred examples thereof include an "amino group", a "hydroxy group”, and a "thiol group”.
  • two substituents in the ⁇ , ⁇ -disubstituted amino may be combined with a nitrogen atom to form a “cyclic amino group”.
  • cyclic amino group examples include 1-azetidinyl and 1- Pyrrolidinyl, piperidino, morpholino, thiomorpholino (sulfur atom may be oxidized), 1-piperazinyl and lower alkyl at 4-position (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl) C Bok 6 alkyl, etc.) and the like, Ararukiru (e.g., benzyl, C 7 _ 1 0 Ararukiru etc.), Ariru (eg, such as phenethyl, phenyl, 1-naphthyl, 2-naphthyl etc..
  • Ararukiru e.g., benzyl, C 7 _ 1 0 Ararukiru etc.
  • Ariru eg, such as phenethyl, phenyl
  • a 3- to 8-membered (preferably 5- to 6-membered) cyclic amino group such as 1-piperazinyl which may be possessed is used.
  • the “substituted sulfinyl group” and the “substituted sulfonyl group” as the substituents that the ring A may have are, respectively, “an optionally substituted hydroxy group”, “an optionally substituted amino group”, It represents a sulfinyl group or a sulfonyl group substituted by a substituent such as "optionally substituted hydrocarbon group” or "optionally substituted heterocyclic group”.
  • hydrocarbon group in the “optionally substituted hydrocarbon group”
  • hydrocarbon group in the “optionally substituted hydrocarbon group” as a substituent which ring A may have The same groups as mentioned above are used.
  • heterocyclic group in the “optionally substituted heterocyclic group”
  • heterocyclic group in the “optionally substituted heterocyclic group” as a substituent that ring A may have And the like.
  • the substituents that may be substituted on the hydroxy group and the amino group which are the substituents of the “substituted sulfinyl group” and “substituted sulfonyl group”, are respectively the substituents that the ring A may have The same groups as the substituents that may be possessed by the ⁇ hydroxy group '' in the ⁇ hydroxy group which may be substituted '' and the ⁇ amino group '' in the ⁇ optionally substituted amino group '' Irare, preferably, for example, (: Bok 6 alkyl group, C 3 8 cycloalkyl group, C 2 - 4 alkenyl group, C 6 1 0 Ariru group, Ashiru group, an amino group, a Hajime Tamaki (ring A Yes Examples of the substituent that may be substituted include the same groups as those described for the “cyclic ring group” in the “optionally substituted heterocyclic group”), and the like.
  • the ring A may have, for example, R A carboxylic acids such as CO OH, for example R a S 0 3 H sulphonic acids, such as, for example, R a S_ ⁇ 2 H sulfinic acids such or, for example R a OPO (oR B) phosphoric acid, such as OH (R A is a hydrogen atom, have been substituted hydrocarbon group or substituted optionally substituted indicates which may double heterocyclic group, R B represents a hydrogen atom or an optionally substituted hydrocarbon group) or the like
  • ⁇ _H used is Ashiru group obtained by removing groups, specifically showing the R a CO, R a S 0 2, R a SO, R a OPO (OR B) ⁇ ( same meaning as the symbols in the formula the ) Etc. are used.
  • hydrocarbon group in the “optionally substituted hydrocarbon group” and the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R A (and R B )
  • hydrocarbon group in “optionally substituted hydrocarbon group” and “heterocyclic group in” optionally substituted heterocyclic group " The same group as the “ring group” is used.
  • the substituents in the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group” are each as the substituents that the ring A may have The same groups and the like as the substituents in the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group” are used.
  • the R A CO such as formyl; Asechiru, propionyl, Puchiriru, I Sobuchiriru, valeryl, isovaleryl, pivaloyl, to Kisanoiru, Shikurobu evening down carbonyl, consequent opening pen evening down carbonyl, hexane force Ruponiru cyclohexane, crotonyl, Torifuruo optionally halogenated good chain have or ring-like C 2 _ 8 Arukanoiru such Roasechiru; Benzoiru, Nikochinoiru, Isonikochinoiru like.
  • Asechiru, propionyl, Puchiriru, RA such as valeryl is lower (( an alkyl group R a CO (C 2 _ 5 Arukanoiru) etc. is not preferable.
  • the R A S_ ⁇ 2 for example, methanesulfonyl, ethanesulfonyl, propane sulfonyl, cyclopropanesulfonyl, consequent opening pen evening Nsuruhoniru, chain or cyclic C i _ 6 alkylsulphonyl in such Kisansuruhoniru cyclohexane, benzene sulfonyl And toluenesulfonyl.
  • R A S A includes, for example, methanesulfinyl, ethanesulfinyl, pro Hexane sulfinyl like chain or cyclic C _ 6 alkyl sulfides two Le cyclohexane, benzene sulfinyl, toluene and the like sulfinyl.
  • R A OPO (OR 3 ), for example, a ring is formed such as dimethylphosphono, getylphosphono, diisopropylphosphono, dibutylphosphono, and 2-oxo-1,3,2-dioxaphosphinan-1-yl. (Mono- or di-alkyl) phosphono.
  • Examples of the “optionally substituted rubamoyl group” as a substituent which ring A may have include unsubstituted rubamoyl, N-monosubstituted rubamoyl and N, N-disubstituted rubamoyl. Is mentioned.
  • the optional substituent of the ⁇ optionally substituted rubamoyl group '' may be ⁇ optionally substituted '' Groups similar to the substituents that the “amino group” of the “amino group” may have (“optionally substituted carbon hydride group”, “acyl group”, “optionally substituted alkoxycarbonyl” Groups ",” optionally substituted carbamoyl groups "(preferably lower (C ⁇ e) alkyl groups such as carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, and phenylcarbamoyl) , A substituted or unsubstituted group such as a phenyl group, etc.), an "optionally substituted heterocyclic group", etc.).
  • the cyclic aminocarbonyl may be, for example, Thidinyl carbonyl, 1-pyrrolidinyl carbonyl, piperidino carbonyl, morpholino carbonyl, thiomorpholino rubonyl (sulfur atom may be oxidized), 1-piperazinyl carbonyl and lower alkyl at 4-position (eg , Methyl, ethyl, propyl, isopropyl, petit Le, tert- heptyl, a hexyl etc.
  • Ararukiru e.g., benzyl, C 7 such as phenethyl - like 1 (3 Ararukiru), ⁇ Li Ichiru (e.g., phenyl, 1 one naphthyl, C 6 2-naphthyl - 1 0 Ariru etc.), Ashiru group (e.g., formyl, Asechiru, Benzoiru, methoxy Cal Poni Le, benzyl O carboxymethyl Cal Poni Le, methylcarbamoyl Rusuruhoniru etc.) 1 may have such over A 3- to 8-membered (preferably 5- to 6-membered) cyclic aminocarbonyl such as piperazinylcarbonyl is used, etc.
  • xyl group examples include groups represented by the following formula: C ⁇ R C (where R c represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group). But In either free carboxyl, lower alkoxy force Ruponiru, Ari Ruo alkoxycarbonyl, Ararukiruokishi force Ruponiru, heterocyclic O alkoxycarbonyl, heterocyclic methyl O butoxycarbonyl and the like are preferably used.
  • the substituent which the “hydrocarbon group” and the “heterocyclic group” may be substituted each may be a “optionally substituted hydrocarbon” as a substituent which the ring A may have.
  • the same number as the substituent which the “hydrocarbon group” in “group” and the “heterocyclic group” in “optionally substituted heterocyclic group” may have are used.
  • lower alkoxyl propyl includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyl (E.g., alkoxycarbonyl, neopentyloxycarbonyl, and the like, and 6- alkoxycarbonyl and the like.
  • d—3 such as methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl Alkoxycarbonyl and the like are preferred.
  • the “lower alkoxyl propyl” may have a substituent in the “lower alkyl” part of the “lower alkoxy”, and the substituent may be “ In the “hydrocarbon group which may be substituted”, the “hydrocarbon group” may be the same as the group exemplified as the substituent which may be present.
  • the " ⁇ reel O alkoxycarbonyl" for example, phenoxy force Ruponiru, 1 one naphthoxycarbonyl, 2-naphthoxycarbonyl, etc. C 7 - 1 2 Ariruokishi force Ruponiru like.
  • the " ⁇ Lal Kill O alkoxycarbonyl" for example, base Nji Ruo propoxycarbonyl sulfonyl ,, Hue phenethyl Ruo carboxymethyl cull Poni Le etc. (: 7 - 1 5 ⁇ Lal kills O butoxycarbonyl, etc. (rather preferably is, C 6 - 10 aryl-alkoxy-alkenyl).
  • heterocyclic ring in the “heterocyclic oxycarbonyl” and the “heterocyclic methyloxycarbonyl” the heterocyclic group in the “optionally substituted heterocyclic group” as the substituent that the ring A may have The same ones as in “heterocycle” are used, and for example, pyridyl, quinolyl, indolyl, piberidinyl, tetrahydroviranyl and the like are preferably used.
  • the “aryloxycarbonyl”, “aralkyloxycarbonyl”, and “complex oxycarbonyl” may each have a substituent, and the substituent may be a ring A.
  • the same number and the like as the groups exemplified as the substituent which the “hydrocarbon group” may have in the “hydrocarbon group which may be substituted” in the “optionally substituted hydrocarbon group” may be used.
  • an alkoxy group e.g., methoxy, ethoxy, Purobokishi, isopropoxy, etc.
  • Preparative 4 alkoxy - carbonyl group e.g., methoxycarbonyl, ethoxycarbonyl, etc.
  • a sulfo group (- S_ ⁇ 3 H), (: Preparative 4 alkylsulfonyl group (e.g., methylsulfonyl, E chill sulfonyl propyl sulfonyl, etc.), the force Rubamoiru group and mono- or di-_ C i-4 alkyl or C 5 - 7 a cycloalkyl Ichiriki Rubamoiru group (e.g., N- methylcarbamoyl, N- Echirukarubamo I le, N, N- dimethylcarbamoyl, N , N-getylcarbamoyl) are preferably used.
  • One to three of these substituents may be substituted at substitutable positions on ring A, and when there are two or more, the substituent is In the above formula, ring A is a group represented by the formula
  • R 3 is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, or an optionally substituted
  • Benzene ring That is, in the 1-isoquinolinone skeleton, the 5-, 7-, and 8-positions are unsubstituted and have a substituent R 3 at the 6-position.
  • R 3 is a hydrogen atom, a halogen atom, an alkyl group which may be substituted (an optionally substituted hydrocarbon group as a substituent which ring A may have)
  • the “hydrocarbon group” may have the same number of the same substituents as the substituents that may be present — such as a 6-alkyl group), an optionally substituted amino group, and the like.
  • atom, a halogen atom, - such as 4 alkyl groups are more favorable preferred, a hydrogen atom, a halogen atom, such as methyl is particularly preferred.
  • R 1 represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group.
  • the ⁇ cyclic hydrocarbon group '' in the ⁇ optionally substituted cyclic hydrocarbon group '' for R 1 the ⁇ cyclic hydrocarbon group '' Among the “hydrocarbon groups” in the “good hydrocarbon groups”, the same groups as the cyclic hydrocarbon groups (eg, cycloalkyl group, cycloalkenyl group, aryl group, etc.) are used.
  • heterocyclic group in the “optionally substituted heterocyclic group” for R 1 , the above-mentioned “optionally substituted heterocyclic group” as the substituent that ring A may have The same group as the “heterocyclic group” in “Group” can be used.
  • the substituents in the ⁇ optionally substituted cyclic hydrocarbon group '' and the ⁇ optionally substituted heterocyclic group '' represented by R 1 are the same as the substituents that the ring A may have And the like.
  • the “cyclic hydrocarbon group” and the “cyclic ring group” may each have 1 to 5 (preferably 1 to 3) of these substituents at substitutable positions, When it has two or more, the substituents may be the same or different.
  • R 1 is preferably an aryl group which may be substituted, a heterocyclic group which may be substituted, and the like. Phenyl substituted at the meta and / or para position is particularly preferred.
  • a halogen atom e.g., fluorine, chlorine, a bromine, iodine, etc.
  • 4 alkyl group e.g., methyl, Echiru, propyl, I an isopropyl, butyl and the like;
  • ⁇ _ 4 alkyl may be substituted with a halogen atom, hydroxy group, Cal Pokishiru group), alkoxy one ⁇ - 4 alkyl group - 4 alkoxy halogen atom, hydroxy group, may be substituted with such force Rupokishiru group),
  • C 2 - 4 alkenyl group e.g., pinyl, Purobe alkenyl, such as ⁇ Li Le;
  • C 2 _ 4 alkenyl halogen atom A hydroxy group, a carboxyl group, or the like
  • 4 alkoxy group, etc. may phenyl optionally substituted with a substituent selected from carboxyl group and eight androgenic atoms), C 5 - 7 cycloalkyl over ⁇ amino group (C 5 - 7 Sik port alkyl eight androgenic atom, hydroxy Group, carboxyl group, etc.), alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, etc .; d-4 alkoxy is substituted with octylogen atom, hydroxy group, carboxyl group, etc.) 4 ) alkylthio group (for example, methylthio, ethylthio, propylthio, isopropylthio, etc .; 4-alkylthio may be substituted by a halogen atom, a hydroxy group, a hydroxyl group, etc.); Group, carboxyl group, cyano group, nitro group, amino group, mono- or di- 4 alkylamino
  • ( ⁇ _ 4 alkyl halogen atom, hydroxy group, may be substituted with a carboxyl group), C ⁇ 4 alkyl - sulfinyl group (e.g., Mechirusurufi two Le, E chill sulfinyl, propyl sulfinyl and the like; alkyl halogen atom, hydroxy group, may be substituted with a carboxyl group), the force Luba carbamoyl group and mono- - or di one C i-4 alkyl or C 5 - 7 cycloalkyl - power Rubamoiru group (e.g., N- methylcarbamoyl , N- E Ji carbamoyl, N, N- dimethylcarbamoyl, N, N- GETS Ji carbamoyl like; - 4 ⁇ alkyl and C 5 _ 7 cycloalkyl each halogen atom, hydroxy group, substituted with such force Rupokishiru
  • Each cycloalkyl may be substituted with an octagene atom, a hydroxy group, a carboxyl group, etc.), an N— (cyclic amino) -powered rubamoyl group (eg, N— (1-pyrrolidinyl) -powered rubamoyl, N— (1-piperidino) rubamoyl, N- (4-morpholino) rubamoyl, etc .; cyclic amino may be substituted with a halogen atom, hydroxy group, hepoxyl group, etc.), 5- to 10-membered heterocyclic group ( For example, 2- or 3-Chenyl,
  • To 1 not in the possible positions may be three substituents, if having two or more, the substituents may be the same or different.
  • linear or branched (: ⁇ 4 alkylenedioxy groups (eg, methylenedioxy, ethylenedioxy, propylenedioxy, tetrafluoroethylenedioxy, etc.) which may be halogenated, etc. Preferred as a substituent that may be possessed.
  • the substituent which phenyl may have in ⁇ optionally substituted phenyl '' is i) a halogen atom, a hydroxy group or a carboxy group.
  • a halogen atom which may be substituted with Bokishiru group ( ⁇ _ 4 alkoxy group, ii) a carboxyl group, iii) a halogen atom, a hydroxy group or force Rupokishiru group optionally substituted - 4 alkoxy one carbonyl group, iv) a halogen atom , hydroxy group or Cal Pokishiru optionally substituted alkyl chromatography alkylsulfonyl group group, V) Karubamo I le group, vi-iota) mono - or di - 4 alkyl Ichiriki Rubamoiru group (C Bok 4 alkyl Le halogen atom , a hydroxy group or a carboxyl group which may be substituted), vi-2) mono -
  • R 1 is “optionally substituted phenyl”.
  • X 1 and X 2 each independently represent —O——S—, one N (R ′) — (R ′ represents a hydrogen atom or a substituent.) Or methylene, and Z represents Represents an optionally substituted alkylene. ] Is also preferably used.
  • X 2 when X 2 is methylene, it is preferable that X 1 is methylene and X 2 is —0—, 1S— or —N (R ′) 1 (preferably 10—).
  • R ′ is the same as the substituent which the amino group may have in the ⁇ optionally substituted amino group '' as the substituent which ring A may have Groups and the like are used.
  • alkylene in the “optionally substituted alkylene” for Z for example, ( ⁇ 4 alkylene (eg, methylene, ethylene, propylene, etc.) and the like are used.
  • the “optionally substituted hydrocarbon” as the substituent which the ring A may have may have, the same group as the substituent which the “hydrocarbon group” may have may be used in the same number.
  • substituent which may be the alkylene optionally has, a halogen atom, ( ⁇ _ 4 alkyl group (e.g., methyl, Echiru, propyl, isopropyl, butyl, etc.; the C 4 alkyl halogen atom, hydroxy group, carboxyl Optionally substituted with a group, etc.), optionally substituted phenyl (preferably, optionally halogenated — 4 alkyl group, 7 optionally halogenated — 4 alkoxy group, force Phenyl which may be substituted with a substituent selected from a ropoxyl group and an octylogen atom), an oxo group and the like.
  • a halogen atom e.g., methyl, Echiru, propyl, isopropyl, butyl, etc.
  • the C 4 alkyl halogen atom hydroxy group, carboxyl Optionally substituted with a group, etc.
  • R 2 is a hydrogen atom, a hydrocarbon group optionally substituted with a hydroxy group which may be substituted, a cyano group, an acyl group, a carboxyl group which may be esterified, or a substituted group. And represents an optionally substituted amino group.
  • the term “substituent as a substituent that ring A may have” The same groups as the “hydrocarbon group” in the “hydrocarbon group that may be used” are used.
  • the substituent in the ⁇ optionally substituted hydroxy group '' which the ⁇ hydrocarbon group '' may have may be ⁇ optionally substituted '' as the substituent which the ring A may have The same groups as the substituents in the “hydroxy group” can be used.
  • acyl group represented by R 2
  • the same groups as the “acyl group” as a substituent which ring A may have, and the like are used.
  • the “optionally esterified alkoxyl group” represented by R 2 includes a ring
  • ⁇ optionally substituted amino group '' for R 2 the same groups as the ⁇ optionally substituted amino group '' as a substituent which ring A may have, and the like are used. .
  • R 2 a carboxyl group which may be esterified, a rubamoyl group which may be substituted, and the like are preferable.
  • "Esterified, represented by R 2 examples include lower alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, Alkoxycarbonyl such as isopentyloxycarbonyl, neopentyloxycarbonyl, etc.) are preferred, and C- 3 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl is more preferred.
  • lower alkoxycarbonyl eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobut
  • R 2 represents a hydrocarbon group which may be substituted with an optionally substituted hydroxy group, a cyano group, an acyl group, an optionally substituted rubazoyl group, or an optionally substituted N-- A hydroxycarbamoyl group or an optionally substituted amino group is also preferred.
  • Examples of the “hydrocarbon group which may be substituted with an optionally substituted hydroxy group” for R 2 include, for example, a 1-hydroxyalkyl group and a pyridyl-C 4 alkoxymethyl group (preferably pyridylmethoxymethyl And the like).
  • the Ashiru group represented by R 2, R D CO (R D represents a hydrogen atom, an optionally substituted carbon I inhibit hydrogen group or a substituent which may be a heterocyclic group).
  • R D represents a hydrogen atom, an optionally substituted carbon I inhibit hydrogen group or a substituent which may be a heterocyclic group.
  • the ⁇ hydrocarbon group '' in the ⁇ optionally substituted hydrocarbon group '' represented by RD may be ⁇ optionally substituted '' as a substituent which ring A may have The same group as the “hydrocarbon group” in the “hydrocarbon group” is used.
  • the substituent which each of the “hydrocarbon group” and the “complex ring group” may have may be, for example, “an optionally substituted carbon atom” as a substituent that the ring A may have.
  • the same groups and the like as the substituents in the “hydrogen group” and the “optionally substituted heterocyclic group” are used in the same numbers.
  • R 2 is preferably an optionally esterified olepoxyl group or an optionally substituted olevamoyl group, and particularly preferably a lower alkoxycarbonyl.
  • X represents a divalent chain hydrocarbon group which may be substituted.
  • the “divalent chain hydrocarbon group” in the “optionally substituted divalent chain hydrocarbon group” represented by X includes, for example, ( ⁇ -6 alkylene (eg, methylene, ethylene, trimethylene, tetramethylene, etc.), C 2 6 alkenylene (for example, Piniren, propylene, 1 - or 2 - butenylene, blanking evening Jeniren etc.) and C 2 8 alkynylene (e.g., Echiniren, 1 - or 2 - Propynylene, 1- or 2-petinylene, etc. are used.
  • ⁇ -6 alkylene eg, methylene, ethylene, trimethylene, tetramethylene, etc.
  • C 2 6 alkenylene for example, Piniren, propylene, 1 - or 2 - butenylene, blanking evening Jeniren etc.
  • C 2 8 alkynylene e.g., Echiniren, 1 - or 2 - Propyny
  • the “optionally substituted carbon” as a substituent that ring A may have The same groups as the substituents that the “hydrocarbon group” in the “hydrogen group” may have are used.
  • the “divalent chain hydrocarbon group” may have 1 to 5 (preferably 1 to 3) substituents at substitutable positions, and when it has 2 or more, The substituents may be the same or different.
  • X is preferably an optionally substituted alkylene, and particularly preferably is methylene.
  • Y represents a non-aromatic hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, a hydroxy group which may be substituted or an amino group which may be substituted.
  • non-aromatic hydrocarbon group in the “optionally substituted non-aromatic hydrocarbon group” for Y, for example, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an aralkyl And the like.
  • alkyl group cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group and aralkyl group
  • hydrocarbon group examples include groups similar to the alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group and aralkyl group.
  • the substituent which the “non-aromatic hydrocarbon group” in the “optionally substituted non-aromatic hydrocarbon group” represented by Y may have, the above-mentioned ring A may have As the substituent, the same number of the same groups as the substituents that the “hydrocarbon group” in the “optionally substituted hydrocarbon group” may have, and the like are used. .
  • heterocyclic group in the “optionally substituted heterocyclic group” represented by Y, the above-mentioned “optionally substituted heterocyclic group” as the substituent that the ring A may have And the same groups as those described above for "heterocyclic group”.
  • the substituent which may be possessed by the ⁇ heterocyclic group '' is the above-mentioned substituent which the ring A optionally has The same number of the same groups as the substituents that the “heterocyclic group” in the “optionally substituted heterocyclic group” may have, and the like are used.
  • a non-aromatic hydrocarbon group which may be substituted is preferable, and a chain hydrocarbon group which may be substituted (for example, alkyl group, alkenyl group) Group, more preferably such an alkynyl group), more preferably such substituted _ 6 which may c 2 have an alkenyl, such as ethylene is especially preferred.
  • Y is preferably an optionally substituted heterocyclic group or the like, and among them, an optionally substituted 5- or 6-membered aromatic heterocyclic group (2-phenyl, 3-phenyl, 2-furyl) , 3-furyl, 1-pyrrolyl, '3-pyridyl, 4-pyridyl, etc.) or 1-isoindolyl.
  • heterocyclic group substituents which may be possessed by a carboxyl group, an alkoxy one carbonyl group, a halo gen atom, may optionally be halogenated ( ⁇ _ 4 alkoxy group ,, halogenated may have an alkyl group And an alkyl group which may be substituted with a hydroxy group, mono, a di-C- 4 alkylamino group and the like.
  • an optionally substituted hydroxy group and the like are also preferable, and among them, a hydroxy group substituted with an optionally substituted hydrocarbon group (for example, a halogen atom, an optionally halogenated C i _ 4 alkoxy, C 3 - 1 0 cycloalkyl group, a 5- to 1 0-membered heterocyclic group, or a mono- or di - 4 hydroxy groups are substituted with alkyl which may be substituted with such Arukiruamino; halogen atom, a halogenated Optionally substituted alkoxy, optionally halogenated phenyl, 5- to 10-membered heterocyclic group or C 7 _ 16 aralkyl which may be substituted by mono- or di- 4-alkylamino
  • an optionally substituted hydrocarbon group for example, a halogen atom, an optionally halogenated C i _ 4 alkoxy, C 3 - 1 0 cycloalkyl group, a
  • Y an optionally substituted amino group or the like is preferable, and among them, alkyl which may be octogenated, phenyl which may be halogenated, C 2 which may be halogenated — 6 alkanols or halogenated Amino group, cyclic amino group (eg, pyrrolidinyl, 1-piberidinyl, 1-morpholinyl, etc.) Preferred.
  • 6-chloro-4- (2-hydroxymethylthiophen-3-yl) -2- (4-methoxycarbodilpendyl) -toxo- 1,2-dihydroisoquinoline-3-carboxylic acid methyl ester, 2- (4-hydroxypropyl) -6-chloro-4- (3-hydroxymethylthiophen-2-yl) -toxo-1, 2-dihydroisoquinoline-3-carboxylic acid methyl ester or 2- (4-methanesulfonylbenzyl) -toxo-4- (piperidin-1-yl) -1,2, -dihydroisoquinoline-3-butyric acid Methyl esters and the like are particularly preferably used.
  • the prodrug of the compound represented by the above formula (I) or a salt thereof can be produced by reacting the compound (I) with an enzyme or gastric acid under physiological conditions in a living body.
  • an enzyme or gastric acid under physiological conditions in a living body.
  • a compound which is hydrolyzed, such as by gastric acid to be converted into compound (I).
  • a compound in which the amino group of compound (I) is acylated, alkylated, or phosphorylated for example, the amino group of compound (I) is eicosanoylated, alanylated, Pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolan-141-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, bivaloyloxymethylation, tert-butylidyl compound
  • the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinyl, etc.) , Fumarylation, alanylation, dimethylaminomethylcarbonylation, etc.
  • the prodrug of compound (I) can be prepared under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. 7, Molecular Design, pp. 163-198. It may change to the object (I).
  • salt of compound (I) examples include pharmacologically acceptable salts and the like, for example, trifluoroacetic acid, acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, cunic acid, dalconic acid, ascorbic acid, benzoic acid Acid addition salts with acids such as acid, methanesulfonic acid, p-toluenesulfonic acid, caffeic acid, fumaric acid, phosphonic acid, hydrochloric acid, nitric acid, hydrobromic acid, hydroiodic acid, sulfamic acid, sulfuric acid, etc.
  • acids such as acid, methanesulfonic acid, p-toluenesulfonic acid, caffeic acid, fumaric acid, phosphonic acid, hydrochloric acid, nitric acid, hydrobromic acid, hydroiodic acid, sulfamic acid, sulfuric acid, etc.
  • metal salts such as sodium, potassium, magnesium, and calcium
  • organic salts such as trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, N-methylpyrrolidine, N-methylpiperidine, and N-methylmorpholine.
  • an optically active form of the compound (I) When an optically active form of the compound (I) is required, it can be obtained, for example, by using an optically active starting material or by resolving the racemic form of the compound using a method known per se. be able to.
  • Compound (I) or a salt thereof can be produced, for example, by the methods A to F shown below.
  • Each of the compounds described in the following reaction formulas may form a salt as long as the compound does not inhibit the reaction, and examples of such a salt include those similar to the salt of compound (I).
  • [L is a leaving group (eg, a halogen atom (eg, chlorine, bromine, iodine, etc.) or a formula R L —S ⁇ 2 — ⁇ — (where R L is a lower alkyl optionally substituted with a halogen atom) Or a phenyl group which may be substituted)), or a hydroxyl group, and R 4 represents the “optionally substituted hydroxy group” for the aforementioned Y A group corresponding to the substituent of the hydroxy group is shown.
  • the compound (I) can be produced by reacting the compound represented by the formula or a salt thereof.
  • compound (II) can be alkylated by a Mitsunobu reaction in a solvent that does not affect the reaction.
  • solvents such as aromatic hydrocarbons such as toluene and benzene, carbonamides such as N, N-dimethylformamide, ⁇ , ⁇ ⁇ ⁇ ⁇ -dimethylacetamide and ⁇ ⁇ ⁇ -methylpyrrolidone, and dimethyl sulfoxide Sulfoxides, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, and other commonly used aprotic solvents such as acetonitrile, ethylene glycol dimethyl ether, tetrahydrofuran and dioxane can be used. Of these, tetrahydrofuran is preferred.
  • a combination of azodicarboxylic acids such as acetyl diazocarboxylate, diisopropyl azodicarboxylate and bisdimethylamide azodicarboxylate and phosphines such as triphenylphosphine, tributylphosphine and trimethylphosphine is preferably used.
  • phosphines such as triphenylphosphine, tributylphosphine and trimethylphosphine is preferably used.
  • phosphoranes such as cyanomethylene tributyl phosphorane can be used alone.
  • This reaction is carried out using about 1 to 3 mol of alcohols and about 1 to 3 mol of Mitsunobu reaction reagent per 1 mol of compound (II), usually in tetrahydrofuran at 0 to about the boiling point of the solvent for 5 to 40 hours, preferably Is carried out at 0 to room temperature for about 1 to 20 hours.
  • L is a leaving group
  • L is represented by RL in the above formula.
  • the lower alkyl group in the ⁇ lower alkyl group optionally substituted by a halogen atom '' include, for example, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl , 2-Echirubuchiru etc.
  • halogen atom e.g. fluorine represented by R L, chlorine , Bromine, iodine, etc.
  • R L chlorine
  • Bromine iodine
  • Ruoromechiru and the like.
  • a phenyl group which may be substituted represented by R L
  • R L for example, lower alkyl groups (e.g. methyl, Echiru, propyl, isopropyl, Petit Le etc.), lower alkoxy (e.g. methoxy, ethoxy, Purobokishi , Isopropoxy, butoxy and the like-6 alkoxy groups), a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group and the like.
  • lower alkyl groups e.g. methyl, Echiru, propyl, isopropyl, Petit Le etc.
  • lower alkoxy e.g. methoxy, ethoxy, Purobokishi , Isopropoxy, butoxy and the like-6 alkoxy groups
  • a halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
  • This reaction is an alkylation reaction and can be generally performed in a solvent that does not affect the reaction in the presence of a base.
  • alkali metal hydrides such as potassium hydride and sodium hydride
  • carbons such as lithium ethoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like
  • Inorganic bases such as metal alkoxides of the numbers 1 to 6, such as lithium hydroxide, lithium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, etc., such as triethylamine, tri (n-propyl) ) Amine, tri (n-butyl) amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, arcolidine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine , 1, 5— Azabishikuro [4.3.
  • an iodide such as lithium iodide or sodium iodide may be added as a reaction accelerator.
  • a solvent that does not inhibit the reaction is appropriately selected.
  • solvents include alcohols such as methanol, edanol, propanol, isopropanol, butanol, tert-butanol, etc., for example, dioxane, tetrahydrofuran, getyl ether, tert-butyl methyl ether, diisopropyl pill Ethers, ethers such as ethylene glycol-dimethyl ether, for example, esters such as ethyl formate, ethyl acetate, and n-butyl acetate, for example, dichloromethane, chloroform, carbon tetrachloride, trichlene, 1,2-dichloroethane, etc.
  • Halogenated hydrocarbons such as n-hexane, benzene, and toluene, for example, formamide, ⁇ , ⁇ -dimethylformamide, amides such as ⁇ , ⁇ -dimethylacetamide, for example, acetonitrile, propionitrile Etc. nitrile Besides etc., dimethyl sulfoxide, sulfolane, to hexa methyl phosphoramide, water and the like are used alone or as a mixed solvent.
  • This reaction is performed using about 1 to 3 mol of the alkylating agent (III) and about 1 to 3 mol of the base per 1 mol of the compound (II), usually at 0 ° C to about the boiling point of the solvent for 5 to 40 hours. It is preferable to perform the reaction at room temperature to about 100 ° C. for about 10 to 20 hours.
  • L 1 represents a leaving group
  • 5 and 1 ′ ′ each represent a group corresponding to the substituent of the amino group in the “optionally substituted amino group”.
  • L 2 and L 3 each represent a leaving group
  • R 6 represents a divalent group capable of forming a cyclic amino group represented by Y.
  • the compound (I) can be produced by reacting with an alkylating agent, an acylating agent or a salt thereof represented by the following formula:
  • the same groups as the leaving groups represented by L are used.
  • This reaction is an acylation reaction or an alkylation reaction, and can be generally performed in a solvent that does not affect the reaction in the presence of a base.
  • a base for example, an alkali metal hydride such as potassium hydride or sodium hydride, for example, a carbon atom 1 such as lithium methoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
  • lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate and other inorganic bases for example, triethylamine, tri (n-propyl) amine , Tri (n-butyl) amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, arcolidine, N, N-dimethylaniline, N-methylbiperidine, N-methylpyrrolidine, N-methyl Morpholine, 1,5—dzabisik B [4.3.0] Non-5-ene, 1,4-diazapicyclo [2.2.2] octane, 1,8 diazabicyclo [5.4.0]-Organic amines such as 7- pentacene, 2-tert- Butylimino-2-ethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphoric acid
  • a solvent that does not inhibit the reaction is appropriately selected.
  • a solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol, for example, dioxane, tetrahydrofuran, getyl ether, tert-butyl methyl ether, diisopropyl ether, and the like.
  • Ethers such as ethylene glycol-dimethyl ether, for example, esters such as ethyl formate, ethyl acetate, and n-butyl acetate; for example, dichloromethane, chloroform, carbon tetrachloride, trichlene, 1,2-dichlorobenzene, etc.
  • Halogenated hydrocarbons such as n-hexane, benzene, toluene and the like, such as formamide, ⁇ , ⁇ ⁇ ⁇ ⁇ -dimethylformamide, ⁇ ⁇ ⁇ , ⁇ ⁇ ⁇ ⁇ -dimethylacetamide and the like, amides such as acetonitrile and propioni Nitriles such as tolyl
  • dimethyl sulfoxide, sulfolane, to hexa methyl phosphoramide, water and the like are used alone or as a mixed solvent.
  • the reaction is performed in one or two steps.
  • the compound (V) used in the first and second steps and (V ′) the base and the solvent may be the same or different.
  • This reaction uses about 1 to 3 mol of the compound (V) or the conjugated compound (V ′) and about 1 to 3 mol of the base per 1 mol of the compound (IV) or the compound (Ia), and is usually 0 ° It is preferable to carry out the reaction for about 5 to 40 hours at about the boiling point of C to the solvent, preferably for about 10 to 20 hours at room temperature to about 100.
  • the reaction may be carried out in one step or two steps in the substitution of L 2 and L 3.
  • the base and the solvent used may be the same or different.
  • reaction In this reaction, compound (VI) :! Using about 3 to 3 moles and about 2 to 4 moles of a base, the reaction is usually performed at 0 ° C to about the boiling point of the solvent for 5 to 40 hours, preferably at room temperature to about 100 ° C for about 10 to 20 hours.
  • the reaction in the second step uses about 2 to 4 mol of a base per 1 mol of the compound (Ia '), and is usually performed at 0 ° C to about the boiling point of the solvent for 5 to 40 hours. It is preferable to carry out the reaction at room temperature to about 100 ° C. for about 10 to 20 hours.
  • a compound which is pyrrolyl optionally substituted for Y in compound (I) can be prepared by a method known per se (for example, SYNTHETIC COMMUNICATION, 1991, 21 (15-16), p. 1567-1576) or a method analogous thereto, by reacting compound (IV) with a 2,5-dimethoxytetrahydrofuran derivative in the presence of an acid or a base.
  • the compound (I) which is a triazolyl in which Y may be substituted may be a hydrazine such as 1,2-bis [(dimethylamino) methylene ”hydrazine or the like according to a method known per se. (Journal of American Chemical Society, 1995, 117 (22), p.5951-5957, etc.) and [1, 3, 4] oxaziazol derivatives (Journal of Heterocyclic Chemistry, 1989, 6 (1), p. 225-230).
  • OTf represents a trifluoromethanesulfonyloxy group, and other symbols have the same meanings as described above.
  • Q represents an atomic group capable of performing a cross-coupling reaction (eg, an atomic group bonded with boron, tin, magnesium, or the like, etc.), and Y 1 represents an optionally substituted heterocyclic group or Shows an aromatic hydrocarbon group.
  • VIII or a salt thereof, or a compound of the formula (VIII ′)
  • shaku 5 and shaku 5 ′ are the amino in the “optionally substituted amino group”.
  • a group corresponding to a substituent which the group may have; R 5 and R 5 ′ may form a cyclic amino group together with the nitrogen atom;
  • a compound (VI I) or a salt thereof and a compound (VI II) or a salt thereof, or an amino compound (VI I I) or a salt thereof are cross-coupled in the presence of a metal catalyst (Suzuki coupling reaction, The compound (I) is produced by performing a Heck reaction, a Stille coupling reaction, an amination reaction of Buchba 1d, and the like.
  • This reaction is usually carried out in the presence of a base.
  • the base include alkali metal hydrides such as sodium hydride and potassium hydride, and water such as lithium hydroxide, sodium hydroxide and potassium hydroxide.
  • Inorganic bases such as metalloids, for example, metal alkoxides having 1 to 6 carbon atoms such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, etc., for example, trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine
  • Organic bases such as 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4 diazabicyclo [
  • This reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected.
  • solvents include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol, such as dioxane, tetrahydrofuran, getyl ether, tert-butyl methyl ether, and diisopropyl ether.
  • Ethers such as ethylene glycol-dimethyl ether; for example, esters such as ethyl formate, ethyl acetate, and n-butyl acetate; Halogenated hydrocarbons such as methane, carbon form, carbon tetrachloride, trichlene, 1,2-dichloroethane, etc., hydrocarbons such as n-hexane, benzene, toluene, etc., for example, formamide, ⁇ , ⁇ ⁇ ⁇ ⁇ -dimethylformamide Amides such as, ⁇ , ⁇ -dimethyla and cetamide, for example nitriles such as acetonitrile and propionitrile, and dimethylsulfoxide, sulfolane, hexamethylphosphoramide, water and the like are used alone or as a mixed solvent.
  • Halogenated hydrocarbons such as methane, carbon form, carbon tetrachloride, trichlene, 1,
  • the cross-coupling reaction can be accelerated by using a metal catalyst.
  • a metal complex having various ligands is used as a metal catalyst.
  • palladium compounds eg, palladium acetate, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) chloride, dichlorobis (Triethylphosphine) palladium, Tris (dibenzylideneaceton) dipalladium-2,2'-bis (diphenylphosphino) -1,1, 1, -binaphthyl, palladium acetate I) and 1,1'-bis (diph Complexes of enylphosphino) phenic acid etc.), nickel compounds [eg, tetrakis (triphenylphosphine) nickel, bis (triethylphosphine) nickel chloride, shiridanibis (triphenylphosphine) nickel
  • the reaction temperature is about -10 ° C to about 250 ° C, preferably about 0 ° C to about 150 ° C.
  • the reaction time varies depending on the compound (VI 1), compound (VIII) or compound (VII (), metal catalyst, type of base or solvent, reaction temperature, etc., but is usually about 1 minute to about 200 hours, preferably about 5 minutes. ⁇ 100 hours.
  • This cyclization reaction is carried out by reacting compound (IX) with a base.
  • This reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected.
  • a solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol and the like, for example, dioxane, tetrahydrofuran, getyl ether, tert-butyl methyl ether, disopropyl ether Ethers such as ethylene glycol and dimethyl ether; esters such as ethyl formate, ethyl acetate and n-butyl acetate; halogenated carbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene and 1,2-dichloroethane, etc.
  • Hydrogens for example, hydrocarbons such as n-hexane, benzene, toluene, etc., for example, amides such as formamide, ⁇ , ⁇ -dimethylformamide, N, N-dimethylacetamide, for example, nitrites such as acetonitrile, propionitrile, etc.
  • dimethyl sulfoxide, sulfolane, to hexa methyl phosphoramide, water and the like are used alone or as a mixed solvent.
  • an alkali metal hydride such as potassium hydride or sodium hydride
  • Inorganic bases such as metal alkoxides having 1 to 6 carbon atoms, such as lithium hydroxide, hydroxide hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc., such as triethylamine, tri (n-propyl) amine, Tri (n-butyl) amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, arcolidine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methyl Organic amines such as morpholine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-indene Organic lithiums such as methyllithium, n-butyrolithium, sec-butyrolithium, tert-buty
  • a base is used in an amount of about 0.01 to about 100 mol, preferably about 0.1 to about 3 mol, per 1 mol of compound (IX).
  • the reaction temperature is from about 180 ° C to about 200 ° C (:, preferably, from about 120 ° C to about 100 ° C).
  • the reaction time varies depending on the compound (IX), the type of the base catalyst, the type of the solvent, the reaction temperature and the like, but is usually about 1 minute to about 72 hours, preferably about 15 minutes to about 24 hours.
  • R 2 ′ represents an optionally substituted carboxyl group or an acyl group, and other symbols have the same meanings as described above.
  • solvents examples include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, and the like, for example, dioxane, tetrahydrofuran, dimethyl ether, tert-butyl methyl ether, diisopropyl Ethers such as ether and ethylene glycol-dimethyl ether, for example, esters such as ethyl formate, ethyl acetate, and n-butyl acetate, for example, dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, 1,2-dichloromethane Halogenated hydrocarbons such as benzene, hydrocarbons such as ⁇ -hexane, benzene, toluene, and the like, amides such as formamide, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, For example,
  • Such bases include, for example, inorganic bases such as sodium carbonate, potassium carbonate, and sodium hydrogen carbonate, such as triethylamine, tri ( ⁇ -propyl) amine, and tri ( ⁇ -butyl) amine, disopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, arcolidine, ⁇ , ⁇ -dimethylaniline, ⁇ -methylbiperidine, ⁇ -methylpiperidine, ⁇ -methylmorpholine, etc. Amines are used.
  • the reaction temperature ranges from about 120 to about 150 ° C, preferably from about 10 to about 80 ° C. It is.
  • reaction time varies depending on the type of compound (X) or (XI), the type of solvent, the reaction temperature, etc., but is usually about 1 minute to about 72 hours, preferably about 15 minutes to about 24 hours
  • dehydration step of this reaction may be completed only by the reaction of compound (X) and compound (XI) depending on the conditions, dehydration is usually performed using an acid.
  • acids include organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid; mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and perchloric acid; Lewis acids such as aluminum, zinc chloride, boron trifluoride etherate and titanium tetrachloride are used.
  • a solvent that does not inhibit the reaction is appropriately selected.
  • a solvent used in the reaction between compound (X) and compound (XI) is used.
  • the reaction temperature is from about 120 ° C to about 200 ° C, preferably from about 0 to about 120 ° C. '
  • reaction time varies depending on the reaction conditions, but is usually about 1 minute to about 72 hours, preferably about 15 minutes to about 15 hours.
  • L 4 represents a leaving group (having the same meaning as L above).
  • This method is carried out by subjecting compound (XII) or a salt thereof to an alkylation reaction using compound (XIII) or a salt thereof.
  • Bases used in this reaction include, for example, alkali metal hydrides such as potassium hydride and sodium hydride, for example, lithium ethoxide, lithium tert-butoxide, sodium methoxide, sodium methoxide, Metal alkoxides having 1 to 6 carbon atoms such as potassium tert-butoxide, for example, inorganic bases such as lithium hydroxide, potassium ⁇ -oxide, sodium hydroxide, sodium carbonate, carbonated lime, cesium carbonate, sodium hydrogencarbonate
  • a solvent that does not inhibit the reaction is appropriately selected.
  • examples of such a solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, and the like, for example, dioxane, tetrahydrofuran, getyl ether, tert-butyl methyl ether, diisopropyl ether, Ethers such as ethylene glycol-dimethyl ether, for example, esters such as ethyl formate, ethyl acetate, and n-butyl acetate; halogens such as dichloromethane, chloroform, carbon tetrachloride, trichlorene, and 1,2-dichlorobenzene Hydrocarbons, for example, n-hexane, benzene, toluene, etc., for example, formamide, N, N-dimethylformamide, ⁇ , ⁇
  • Amides for example, nitriles such as acetonitrile, propionitrile and the like, dimethyl sulfoxide, sulfolane, hexamethylphosphoramide, water and the like are used alone or as a mixed solvent.
  • the reaction temperature is from about -50 to about 150 ° C, preferably from about 120 to about 100 ° C.
  • the reaction time varies depending on the type of the compound (XII) or (XIII), the type of the solvent and the base, the reaction temperature and the like, but is usually about 1 minute to about 100 hours, preferably about 15 minutes to about 48 hours.
  • R 7 represents an optionally substituted lower (trialkyl group (eg, methyl, ethyl, propyl, butyl, tert-butyl group, etc.), and other symbols have the same meanings as described above.)]
  • This hydrolysis reaction can be performed by a method known per se or a method analogous thereto, for example, a method using an acid, a method using a base, and a method using reduction.
  • the method by ultraviolet light, te A method using traptyl ammonium fluoride, a method using palladium acetate, and the like are used.
  • the acid method is mainly used in the case of t-butyl ester.
  • Preferred examples of the acid used include organic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid and P-toluenesulfonic acid; And organic acids such as hydrobromic acid and sulfuric acid.
  • the method using a base is usually used in the case of a lower alkyl ester.
  • Preferred examples of the base used include, for example, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium ⁇ potassium oxide, magnesium hydroxide, and water.
  • Alkali earth metal hydroxides such as calcium oxide, alkali metal carbonates such as sodium carbonate and carbonated lime, alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate, alkali hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate Metals, alkali metal acetates such as sodium acetate, potassium acetate, etc., alkaline earth metals such as calcium phosphate, magnesium phosphate, etc., disodium hydrogen phosphate, hydrogen phosphate Examples include inorganic bases such as aqueous ammonia. The reduction method is applied to, for example, deprotection of a carboxyl group protected by benzyloxymethyl, benzyl, ⁇ -nitrobenzyl, benzhydryl and the like.
  • Preferred examples of the reduction method used include reduction with zinc / acetic acid, catalytic reduction and the like.
  • the method using ultraviolet light is used, for example, for deprotection of a hepoxyl group protected with 0-nitrobenzyl.
  • the method using tetrabutylammonium fluoride is used as a method for obtaining a carboxyl group by removing a protecting group from silyl ether type esters such as 2-trimethylsilylethyl and silyl esters.
  • the method using palladium acetate is used, for example, as a method for removing a protecting group from an aryl ester to obtain a carboxyl group.
  • the reaction is generally advantageously carried out in a solvent.
  • the solvent used is usually water, for example, alcohols such as methanol, ethanol, and propanol; for example, ethers such as tetrahydrofuran, dimethoxyethane, and dioxane; for example, amides of ⁇ , ⁇ -dimethylformamide, for example, dimethyl sulfoxide Aprotic polar solvents such as sulfoxides, etc .; mixed solvents thereof; and solvents which do not adversely affect the reaction.
  • Liquid acids or bases can also be used as solvents.
  • the reaction is usually carried out at a temperature in the range of 20 to 120 ° C (preferably 0 to 100 ° C).
  • the reaction time is generally 10 minutes to 48 hours, preferably 0.5 hours to 24 hours.
  • R 8 represents a hydrocarbon which may have a substituent or a heterocyclic group which may have a substituent, and other symbols have the same meanings as described above.
  • the compound (Ig) represented by this can be manufactured.
  • This esterification reaction can be carried out by a method known per se or a method analogous thereto.
  • the compound (Ie) is converted to R 8 _L 5 [wherein L 5 is a leaving group (having the same meaning as L above).
  • the other symbols are as defined above.
  • a method of reacting compound (Ie) with an alcohol represented by R 8 —OH in the presence of an acid catalyst a method of reacting compound (Ie) with an alcohol represented by R 8 —OH, a condensing agent [for example, carbodiimides (DC Using WSC, DIC, etc.), phosphoric acid derivatives (eg, ethyl cyanophosphate, diphenyl azide phosphate, BOP-C1 etc.), or reagents such as triphenylphosphine and getyl azodicarbonate.
  • a condensing agent for example, carbodiimides (DC Using WSC, DIC, etc.), phosphoric acid derivatives (eg, ethyl cyanophosphate, diphenyl azide phosphate, BOP-C1 etc.), or reagents such as triphenylphosphine and getyl azodicarbonate.
  • the Mitsunobu reaction to be used or a method in which a reactive derivative of compound (Ie) (eg, acid halide, active ester, acid azide, etc.) is reacted with an alcohol represented by R 8 —OH in the presence of a base, etc. be able to.
  • a reactive derivative of compound (Ie) eg, acid halide, active ester, acid azide, etc.
  • This reduction reaction can be performed by a method known per se or a method analogous thereto.
  • compound (Ie) or a reactive derivative thereof eg, acid octylide, acid anhydride, active ester, ester, acid imidazolide
  • Acid azide, etc. using a reducing agent (eg, sodium borohydride, lithium aluminum hydride, diisobutyl aluminum hydride, dipolane, etc.) can be used.
  • a reducing agent eg, sodium borohydride, lithium aluminum hydride, diisobutyl aluminum hydride, dipolane, etc.
  • R 9 and R 1 Q each represent a hydrogen atom or the R 2 at the indicated as have force Rubamoiru group of the "unsubstituted or optionally force Rubamoiru group optionally” may location even substituent, A group to be used.
  • the compound (Ii) represented by the formula (Ii) can be produced. This amidation reaction can be carried out by a method known per se or a method analogous thereto.
  • a compound (I e) and an amine can be condensed with a condensing agent [for example, carbodiimides (DC WSC, DIC, etc.), a phosphoric acid derivative (eg, cyano) Or reactive derivatives of compound (Ie) (eg, acid halides, acid anhydrides, active esters, esters, imidazolide acids, acid azides, etc.) May be reacted with amine.
  • a condensing agent for example, carbodiimides (DC WSC, DIC, etc.
  • a phosphoric acid derivative eg, cyano
  • reactive derivatives of compound (Ie) eg, acid halides, acid anhydrides, active esters, esters, imidazolide acids, acid azides, etc.
  • This inversion can be performed by a method known per se such as Curtius rearrangement, H ofmann anti-j3 ⁇ 4 ⁇ , or Schmidt reaction, or a method analogous thereto.
  • the compound (I e) or its reaction can be used.
  • Azide derivatives eg, acid halides, acid anhydrides, active esters, esters, imidazolides, etc.
  • a method of deprotecting a carbamate-type protecting group of amine produced by hydrolysis or reaction with an alcohol can be used.
  • a functional group convertible to the substituent for example, a carboxyl group, an amino group, a hydroxy group, a carbonyl group, a thiol group) Group, ester group, sulfo group, halogen atom, etc.
  • various compounds can be produced by converting the functional group by a method known per se or a method analogous thereto.
  • a hepoxyl group in the case of a hepoxyl group, it can be converted by a reaction such as esterification, reduction, amidation, or conversion to an amino group which may be protected as described in the above method G.
  • an amino group it can be converted by, for example, amidation, sulfonylation, nitrosation, alkylation, arylation, imidation and the like.
  • a hydroxy group it can be converted by a reaction such as esterification, sulfamoylation, sulfonylation, alkylation, arylation, oxidation, halogenation and the like.
  • a carbonyl group it can be converted by a reaction such as reduction, oxidation, imination (including oximation and hydrazone), (thio) ketalization, alkylidation, and thiocaronylation.
  • thiol group It can be converted by reactions such as alkylation and oxidation.
  • an ester group it can be converted by a reaction such as reduction or hydrolysis.
  • a sulfo group it can be converted by a reaction such as sulfonamidation or reduction.
  • a halogen atom it can be converted by various nucleophilic substitution reactions, various force coupling reactions, and the like.
  • the raw material compounds (I 1), (IV), (VI I), (IX), (X) and (XI I) used in the above-mentioned production methods A to F are, for example, as shown below. It can be produced by a method known per se or a method analogous thereto.
  • R 11 represents an optionally substituted hydrocarbon group or an optionally substituted complex ring, and other symbols have the same meanings as described above.
  • a salt thereof or a reactive derivative thereof eg, acid halide, acid anhydride, active ester, ester, imidazolide acid, azide acid, etc.
  • This reaction is an amidation reaction, and the reactive derivative of compound (XIV), reaction conditions, reaction solvent, reaction time and the like are performed according to the method described in the above-mentioned method G-3.
  • the obtained compound txVI) or a salt thereof is subjected to an intramolecular cyclization reaction in the same manner as in the above method D, the compound of the formula (II)
  • This reaction is carried out according to a conventional method, in a solvent that does not adversely influence the reaction.
  • solvents that do not affect the reaction include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran, dioxane, and getyl ether. And ethyl acetate. These solvents may be used in a mixture at an appropriate ratio.
  • the amount of compound (XV) to be used is about 1 to about 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (XVI I).
  • the reaction temperature is usually in the range of ⁇ 30 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is usually from 10 minutes to 48 hours, preferably from 0.5 to 20 hours.
  • the compound (XVI II) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. .
  • the compound (IV) or a salt thereof can be produced, for example, by the following method.
  • This reaction is an amidation reaction, and the reactive derivative of compound (XIX), reaction conditions, reaction solvent, reaction time and the like are performed according to the method described in the above-mentioned method G-3.
  • the compound (XX) or a salt thereof is subjected to an intramolecular cyclization reaction in the same manner as in the above method D, the compound of the formula (IV)
  • Z represents a leaving group (having the same meaning as L in the above.)
  • R 12 represents a lower (C ⁇ 6 ) alkyl group (eg, methyl, ethyl, propyl, butyl, tert-butyl group, etc.).
  • This reaction is an amidation reaction, and the reactive derivative of the compound (XXII), the reaction conditions, the reaction solvent, the reaction time and the like are performed according to the method described in the above method G-3.
  • Method O is an amidation reaction, and the reactive derivative of the compound (XXII), the reaction conditions, the reaction solvent, the reaction time and the like are performed according to the method described in the above method G-3.
  • alkali metal hydrides such as sodium hydride, potassium hydride, etc.
  • alkali metal hydrides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc., and magnesium hydroxide
  • Alkaline earth metal hydroxides such as calcium hydroxide and the like
  • alkali metal carbonates such as sodium carbonate and potassium carbonate
  • inorganic bases such as the alkali metal bicarbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate
  • sodium C1-C6 metal alkoxides such as methoxide, sodium ethoxide, sodium tert-butoxide, and the like, for example, trimethylamine, triethylamine, disopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N— Methylmorpholine, 1,5 gyr Organic bases such as zabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.
  • This reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected.
  • a solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol, for example, dioxane, tetrahydrofuran, getyl ether, tert-butyl methyl ether, diisopropyl ether, ethylene glycol Ethers such as methyl dimethyl ether; esters such as ethyl formate, ethyl acetate and n-butyl acetate; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene and 1,2-dichloroethane , For example, hydrocarbons such as n-hexane, benzene, and toluene; amides, for example, formamide, N, N-dimethylformamide, N,
  • the raw material conjugates (XIV), (XV), (XV II), (XIX) and (XXI I) used in the above-mentioned production methods A to O may be purchased from commercial products or may be obtained by a method known per se or It can be manufactured by a method according to it.
  • a compound When a compound is obtained in a free state by each reaction of the present invention, it may be converted to a salt according to a conventional method. It can also be converted to salt.
  • each reaction of the method for producing the compound (I) and each reaction of the synthesis of the starting compound when the starting compound has an amino group, a carboxyl group, or a hydroxy group as a substituent, these groups are generally used in peptide chemistry and the like.
  • the target compound may be obtained by removing the protecting group as necessary after the reaction, if necessary.
  • Examples of the protecting group for an amino group include formyl, which may have a substituent,
  • s- alkylcarbonyl eg, acetyl, ethylcarbonyl, etc.
  • phenylcarbonyl alkyl-oxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl (Boc), etc.)
  • aryloxy carbonyl A loe
  • phenylalanine O alkoxycarbonyl Furuorenirumechi Ruo alkoxycarbonyl (Fmo c), C? ⁇ .
  • Ararukiru Ichiriki Ruponiru e.g., base down Jill carbonyl
  • C 7 _ 1Q 7 aralkyl one O butoxycarbonyl for example, benzyl O carboxymethyl Cal Poni Le (Z), etc.
  • C 7 _ 10 Ararukiru e.g., benzyl
  • trityl phthaloyl or N, such as N- dimethylaminomethylene is used.
  • phenyl group a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), d-6 A Kill one carbonyl (e.g., Mechirukaruponiru, Echirukaruponiru, etc. Puchirukaruponiru) and nitro groups, the number of substituents is about 1 to 3.
  • halogen atom e.g., fluorine, chlorine, bromine, iodine, etc.
  • d-6 A Kill one carbonyl e.g., Mechirukaruponiru, Echirukaruponiru, etc. Puchirukaruponiru
  • the number of substituents is about 1 to 3.
  • the protecting group of the carboxyl group may have a substituent group, (Bok 6 alkyl (e.g., methyl, Echiru, n- propyl, i one propyl, n- butyl Le, tert _ butyl, etc.), Aryl, benzyl, phenyl, trityl or tria Ruquilsilyl and the like are used.
  • a substituent group e.g., methyl, Echiru, n- propyl, i one propyl, n- butyl Le, tert _ butyl, etc.
  • Aryl, benzyl, phenyl, trityl or tria Ruquilsilyl and the like are used.
  • halogen atom for example, fluorine, chlorine, bromine, iodine, etc.
  • formyl for example, acetyl, ethylcarbonyl, butylcarbonyl, etc.
  • alkyl-carbonyl for example, acetyl, ethylcarbonyl, butylcarbonyl, etc.
  • a nitro group and the like are used.
  • the number of substituents is about 1 to 3.
  • the protective group for hydroxy group may have a substituent, C ⁇ - 6 alkyl (e.g., methyl, Echiru, n- propyl, i one propyl, n- butyl, tert- butyl, etc.), C 7 _ 1 Q aralkyl (eg, benzyl, etc.), formyl, alkyl monocarbonyl (eg, acetyl, ethyl carbonyl, etc.), benzoyl,.
  • Aralkyl-carbonyl eg, benzylcarbonyl, etc.
  • tetrahydropyranyl furanyl, silyl and the like are used.
  • substituents examples include halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), C 6 alkyl (e.g., methyl, Echiru, etc. n- propyl) phenyl, C 7 _ 1 0 Ararukiru (e.g., benzyl, etc. ), ( ⁇ _ 6 alkoxy (eg, methoxy, ethoxy, n-propoxy, etc.), nitro group, etc. are used, and the number of substituents is 1 to 4 or so.
  • halogen atom e.g., fluorine, chlorine, bromine, iodine, etc.
  • C 6 alkyl e.g., methyl, Echiru, etc. n- propyl
  • Ararukiru e.g., benzyl, etc.
  • ⁇ _ 6 alkoxy eg, methoxy, ethoxy
  • a method for removing the protecting group a method known per se or a method analogous thereto is used. Examples thereof include an acid, a base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate. A method of treating with tetrabutylammonium fluoride, palladium acetate or the like is used.
  • the compound (I) thus obtained can be obtained from the reaction mixture by a means known per se, for example, extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, thin-layer chromatography, high-performance liquid for preparative separation. Isolation and purification can be performed by using means such as chromatography (HPLC) and medium pressure preparative liquid chromatography (medium pressure preparative LC).
  • the salt of the compound (I) can be prepared by a known method, for example, by adding an inorganic acid or an organic acid when the compound (I) is a basic compound, or by adding the compound (I) to an acidic compound. When it is a product, it can be produced by adding an organic base or an inorganic base.
  • optical isomers can exist in compound (I), both of these individual optical isomers and mixtures thereof are, of course, included in the scope of the present invention. It can be optically divided according to a means known per se or can be manufactured individually. .
  • Compound (I) may be a hydrate, and both hydrate and non-hydrate are included in the scope of the present invention.
  • the compound (I) may be labeled with an isotope (eg, ⁇ , 14 C, 35 S, 125 I, etc.).
  • the JNK inhibitor having an isoquinolinone skeleton of the present invention selectively inhibits JNK, has low toxicity, and has few side effects (for example, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, It is better as a drug in terms of drug interaction, carcinogenicity, etc.) and is useful as a safe drug.
  • the JNK inhibitor having an isoquinolinone skeleton of the present invention is excellent in mammals (for example, mice, rats, hamsters, rabbits, cats, dogs, dogs, higgs, monkeys, humans, etc.). It exhibits a selective inhibitory effect on J NK, and has excellent (oral) absorbability and (metabolism) stability, etc., so that J NK-related conditions or diseases; ⁇
  • chronic or acute heart failure cardiac hypertrophy, dilated, hypertrophic, Restrictive cardiomyopathy, acute coronary syndrome (including acute myocardial infarction, unstable angina), chronic ischemic heart disease (including exertional angina, old myocardial infarction and associated angina)
  • Acute or chronic myocarditis left diastolic dysfunction, left systolic dysfunction, ventricular, nodular or atrial arrhythmias, pulmonary hypertension, aneurysms or varices, peripheral circulatory insufficiency Hypertension and its ⁇ Nephriti
  • drugs are used: (A, A, C, C, EE) , Aralarseceptpriril, capaptoptopril, cisilarazazazapriril, dederarapupriril, fenaralapril, liridino noppril, tetemocacapril, Totralando dolaraprilil, kikinanappuryluryl, imimidaburiburiruru, bevenanazezepriluriru, beberinrindodopripriruru, etc.)), anandigiototetenshinshin II II receptor antagonist antagonist (e.g., orally orally sasarultatan, kacande de sasarurutan tanshisirelexexetiryl, babaruru sasarurutata ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
  • CCaa antagonists eg, Mamanini digipin, ⁇ , ⁇ ⁇ ⁇ ⁇ ⁇ , ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ Etc.
  • diuretic drugs e.g., benventilyl luhidide oral mouth chlorochlorolothithia azide, sissy chloropepenticia azide, etheticia azide, baboon Dodroloc chloro-oral mouth thithia azide, hydridrolofurfurmethetia azide, methetic chlorotiti azidide, Jijidodo ,, Popo Lili Chichi A Azizi Dodo ,
  • Zide diuretics zide diuretics; chlorthalidone, clofenamide, indapamide, mefluside, methicran, sotrazone, trinomide, kinesenozone, metolazone, furosemide, Loop diuretics such as mefluside; potassium-sparing diuretics such as spironolactone, evrelenone, and triamterene, etc., digital squirrel preparations (eg, digitoxin, digoxin, methyldigoxin, lanatoside, prossilalidine, etc.), endocerin antagonist Drugs (bosentan, tezosentan, etc.), vasopressin antagonists (YM-087, etc.), ANP or BNP preparations, Ca sensitivity enhancers (eg, reposimendan, pimobendan, etc.), anticoagulants (eg, perfurin, sodium citrate, activity Tissue factor pathway inhibitor, antithrombin III, dalteparin sodium
  • antithrombotic drugs eg, heparin sodium, heparin calcium, ⁇ -farin, fondaparin (arixtra), ximelagatran (egzan evening), factor Xa inhibition
  • Anticoagulant drugs such as drugs; thrombolytic drugs such as perokinase; aspirin, sulfinpyrazone (anturane), dipyridamole (persantin), aclovidin (panaldine), syrosuzole (pletar), clopidogrel,
  • Antiplatelet agents such as aviciximab (leopro) and tirofiban (aglastat), angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist, / 3 receptor antagonist, antidiabetic agent, hyperlipidemia treatment
  • Drugs eg, HMG-CoA reductase inhibitors such as pravastatin, flu
  • non-steroidal anti-inflammatory drugs eg, acetaminophen, phenacetin, ethenzamide, sulpyrine, antipyrine, migrenin, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, Nilbudin, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, flokkufenin, epirizole, tiaramid hydrochloride, zaltoprofen, gabexyl mesylate, mosquito mesylate , Perinas quintin, colchicine, probenedide, sulfinpyrazone, benzobromalone, aloprinol, sodium gold sodium thiomalate, here Sodium salonate, sodium salicylate
  • the compound of the present invention when applied to each of the above-mentioned diseases, it can be used in combination with a biological agent (eg, antibody, vaccine preparation, etc.), or in combination with gene therapy, etc. It can also be applied as a therapy.
  • a biological agent eg, antibody, vaccine preparation, etc.
  • gene therapy etc.
  • Antibodies and vaccines include, for example, vaccines against angiotensin II, vaccines against CETP, CETP antibodies, TNF o; antibodies against antibodies and other cytokines, amyloid vaccines, type 1 diabetes vaccines (Pept or DIAPEP-277), anti-HIV antibodies and HIV vaccine preparations, as well as antibodies against cytokinin, renin-angiotensin enzymes and their products or pectin preparations, enzymes involved in blood lipid metabolism Examples include antibodies or vaccine preparations against protein, antibodies or vaccines relating to enzymes and proteins involved in blood coagulation and fibrinolysis, and antibodies or vaccine preparations against proteins involved in glucose metabolism and insulin resistance. In addition, it can be used in combination with biologics related to growth factors such as GH and IGF.
  • Examples of gene therapy include, for example, a therapy using cytokines, genes related to renin-angiotensin enzymes and their products, G proteins, G protein-coupled receptors and their kinases, and NF ⁇ Treatment methods using DNA decoys such as B decoys, treatment methods using antisense, genes related to enzymes and proteins involved in blood lipid metabolism (for example, metabolism and excretion of cholesterol or toridariseride or HDL-cholesterol or blood phospholipids) Related to enzymes and proteins involved in angiogenesis therapy for peripheral vascular obstruction (eg, growth factors such as HGF, VEGF, etc.) Therapy using genes, Therapy using genes related to proteins involved in glucose metabolism and insulin resistance, Cytokines such as TNF Antisense to the health care industry.
  • cytokines genes related to renin-angiotensin enzymes and their products
  • G proteins G protein-coupled receptors and their kinases
  • NF ⁇ Treatment methods using DNA decoys such as B deco
  • various organ regeneration methods such as heart regeneration, kidney regeneration, ⁇ regeneration, and blood vessel regeneration, cell transplantation therapy using bone marrow cells (bone marrow mononuclear cells, bone marrow stem cells, etc.), and artificial organs using tissue engineering (artificial blood vessels and myocardium) Cell sheet) Noh.
  • the compound (I) or a salt thereof of the present invention can be administered orally or parenterally as it is or by mixing a pharmacologically acceptable carrier.
  • the preparation of the present invention containing the compound (I) or a salt thereof may be administered orally in the form of tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (soft capsules) Preparations, microcapsules), syrups, emulsions, suspensions and the like.
  • dosage forms for parenteral administration include injections, injections, drops, suppositories, etc. Is mentioned.
  • a suitable base material eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, a mixture of a polymer of butyric acid and a polymer of dalicholic acid, polyglycerol fatty acid ester, etc. It is also effective to make a combination sustained release preparation.
  • the content of the compound (I) or a salt thereof in the preparation of the present invention varies depending on the form of the preparation, but is usually 2 to 85% by weight, preferably 5 to 70% by weight based on the whole preparation. is there.
  • 'As a method for producing the compound (I) or a salt thereof in the above-mentioned dosage form a known production method generally used in the art can be applied.
  • excipients, binders, disintegrants, lubricants, sweeteners, and the like usually used in the field of formulation when producing the dosage form. It can be produced by appropriately adding an appropriate amount of a surfactant, a suspending agent, an emulsifier and the like.
  • the compound (I) or a salt thereof when the compound (I) or a salt thereof is prepared into a tablet, the compound (I) or a salt thereof can be prepared by adding an excipient, a binder, a disintegrant, a lubricant, etc., and is prepared into pills and granules. In this case, it can be produced by adding an excipient, a binder, a disintegrant and the like.
  • excipients, etc. in the case of syrups, sweeteners, etc., in the case of emulsions or suspensions, suspending agents, surfactants , An emulsifier and the like.
  • excipients examples include lactose, sucrose, dextrose, starch, sucrose, microcrystalline cell mouth And mannitol, sodium hydrogen carbonate, calcium phosphate, calcium sulfate, and the like.
  • binders include 5 to 10% by weight starch paste, 10 to 20% by weight gum arabic solution or gelatin solution, 1 to 5% by weight tragacanth solution, carboxymethylcellulose solution, sodium alginate solution, glycerin And the like.
  • disintegrants include starch, calcium carbonate and the like.
  • lubricant examples include magnesium stearate, stearic acid, calcium stearate, purified talc and the like.
  • sweetening agents examples include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like.
  • surfactant examples include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, polyoxyl stearate 40, and the like.
  • suspending agents include gum arabic, sodium alginate, sodium propyloxymethyl cellulose, methyl cellulose, bentonite and the like.
  • emulsifiers include gum arabic, tragacanth, gelatin, polysorbate
  • a coloring agent, a preservative, an aromatic, a flavoring agent, a stabilizer, a thickener, etc. which are usually used in the field of purification, may be used.
  • An appropriate amount can be added.
  • the preparation of the present invention containing compound (I) or a salt thereof is stable, has low toxicity, and can be used safely.
  • the daily dose varies depending on the condition and weight of the patient, the type of compound, the route of administration, etc. For example, in the case of oral administration to patients with heart failure (cardiomyopathy), myocardial infarction prognosis, myocarditis, rheumatism, etc.
  • the daily dose is about 1 to 100 mg, preferably about 3 to 30 mg, more preferably, as an active ingredient (compound (I) or a salt thereof). Is about 10 to 20 mg, and these can be administered once or in two to three divided doses.
  • the compound (I) of the present invention or a salt thereof is administered parenterally, it is usually administered in liquid form (eg, For example, injections).
  • liquid form eg, For example, injections
  • the single dose varies depending on the subject of administration, target organ, symptoms, administration method, etc., for example, in the form of an injection, usually about 0.01 11 ⁇ to about 1001 per kg of body weight. It is convenient to administer by intravenous injection of 1, preferably about 0.01 to about 501 131, more preferably about 0.01 to about 20 mg.
  • Injections include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, intravenous injections, etc., and sustained-release preparations include iontophoresis transdermals It is.
  • Such injections are prepared by a method known per se, that is, by dissolving, suspending or emulsifying the compound (I) of the present invention or a salt thereof in a sterile aqueous or oily liquid.
  • Aqueous solutions for injection include physiological saline, isotonic solutions containing dextrose and other adjuvants (eg, D-sorbitol, D-mannitol, sodium chloride, etc.). It may be used in combination with an alcohol (eg, ethanol), a polyalcohol (eg, propylene glycol, polyethylene glycol), a nonionic surfactant (eg, polysorbate 80, HCO-50), and the like.
  • oily liquid examples include sesame oil and soybean oil, which may be used in combination with a solubilizing agent such as benzyl benzoate or benzyl alcohol.
  • a solubilizing agent such as benzyl benzoate or benzyl alcohol.
  • buffers for example, phosphate buffer, sodium acetate buffer
  • soothing agents for example, Shirazider Benzalkonium, Proforce hydrochloride, etc.
  • stabilizers for example, human serum albumin, polyethylene glycol, etc.
  • preservatives eg, benzyl alcohol, phenol, etc.
  • the administration form of the compound of the present invention and the concomitant drug is not particularly limited, as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
  • Such administration forms include, for example, (1) administration of a single preparation obtained by simultaneously preparing a compound of the present invention and a concomitant drug, and (2) separate administration of the compound of the present invention and the concomitant drug.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding 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 compound (I) of the present invention or a salt thereof has an excellent JNK-specific inhibitory activity and an excellent oral absorption, so that it is a safe and effective medicament for preventing JNK-related pathologies or diseases. ⁇ Used advantageously for treatment.
  • the present invention is further described in the following Examples, Preparation Examples and Experimental Examples, which are merely illustrative and do not limit the present invention, and do not depart from the scope of the present invention. It may be changed.
  • Solvent Solution A; water containing 0.1% trifluoroacetic acid,
  • MS mass spectrum
  • Measuring equipment Micromass Platform II, Waters, War Yuichizu ZMD, or JEOL Ltd. ⁇ MS-AX505W
  • APCI Atmospheric Pressure Chemical Ionization
  • ESI Electron Impact Ionization
  • FAB Fast Atom Bombardment
  • Solvent Solution A; water containing 0.1% trifluoroacetic acid,
  • Detection method The values in parentheses in the UV 254 nm mixed solvent are the volume mixing ratio of each solvent. % In the solution represents the number of g in 10 Oml of the solution.
  • the symbols in Reference Examples and Examples have the following meanings.
  • primer CAM7-U The nucleotide sequence of primer CAM7-U is shown.
  • primer CAM7-L The nucleotide sequence of primer CAM7-L is shown.
  • primer cJUN-U The nucleotide sequence of primer cJUN-U is shown.
  • This compound was synthesized according to the method described in Example 1 using 4-chlorophthalic anhydride and (2,3-dihydro-1-benzofuran-5-ylmethyl) amine. Colorless crystals (yield 12%).
  • This compound was synthesized according to the method shown in Example 1 using 4-mouth phthalic anhydride and 4_ (mesulfonyl) benzylamine. Yellow crystals.
  • this compound was prepared using 6-chloro-2- (2-, 2,3-dihydrobenzofuran-5-ylmethylyl) -4-hydroxy-toxo-1,2-dihydroisoquinoline-3-. It was synthesized using carboxylic acid methyl ester. Colorless crystals (66% yield).
  • this product was dissolved in methanol (41 ml), and a 28% sodium methoxide / methanol solution (4.1 g) was added under stirring at room temperature, followed by stirring at room temperature for 1 hour.
  • the reaction solution was concentrated, the residue was separated with ethyl acetate and 1 N hydrochloric acid, and the organic layer was dried and concentrated.
  • the residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from ethyl ether / ethyl acetate to give the title compound (2.2 g) as yellow crystals.
  • Example 2-12 was prepared according to the method described in Example 1 (11) according to 2- (benzo [1,3] dioxo-l-5-ylmethyl) -6-bromo-4-hydroxy-1-. Synthesized using oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester and the corresponding alcohol
  • reaction solution was separated with water and ethyl ethyl sulfate, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure.
  • This compound was prepared according to the method described in Example 16 to give 6-chloro-2- (2-, 2,3-dihydrobenzofuran-5-ylmethyl) -toxo-4-tritrifluoromethanesulfonyloxy-1,2- It was synthesized using dihydroisoquinoline-3-carboxylic acid methyl ester and 4-pyridylboronic acid. Colorless crystals (20% yield).
  • the present compound was prepared as follows: 2-benzyl-6-chloro-1-oxo-4--4-trifluoromethanesulfonyloxy-1,2-i-3-methylpyruvonic acid methyl ester and getyl 3- It was synthesized using pyridylborane. Colorless powder (9% yield).
  • the present compound was prepared by treating 6-chloro-2- (4-methoxycarbodirubenzyl) -1-cyclohexyl-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline -Synthesized with methyl 3-ester-sulfonic acid and 2-formyl-3-thiophenbolonic acid. Colorless powder (24% yield).
  • Example 25 the present compound was obtained by treating 6-chloro-2- (4-methanesulfonylbenzyl) -toxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid It was synthesized using methyl ester and phenylmagnesium bromide. Pale yellow powder (yield 45%).
  • This compound was prepared according to the method described in Example 16 to give 6-chloro-2--2- (4-methanesulfonylbenzyl) -toxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3- It was synthesized using carboxylic acid methyl ester and 5-formyl-2-thiophenboronic acid. Brown powder (68% yield).
  • a solution of (90 mg) in THF (3.6 ml) was added with a solution of methylmagnesium bromide in THF (lmol / I, 348 ⁇ 1) at room temperature, and the mixture was stirred for 1 hour.
  • 1N hydrochloric acid was added to the reaction solution, liquid separation and extraction were performed with ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure.
  • 6-Chloro-2- (4-methanesulfonylbenzyl) -toxo-4- (thiophen-2-yl) -1,2, -dihydroisoquinoline-3-methylpyruvonic acid methyl ester This compound was prepared according to the method shown in Example 16 to give 6-chloro-2- (4-methanesulfonylbenzyl) -1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3- It was synthesized using carboxylic acid methyl ester and 2-thiophenboronic acid. Beige powder (32% yield).
  • This compound was prepared according to the method described in Example 16 to give 6-chloro-2- (4-methanesulfonylbenzyl) -1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3- It was synthesized using carboxylic acid methyl ester and 3-thiophenboronic acid. Colorless crystals (78% yield).
  • This compound was prepared according to the method shown in Example 32 by treating 6-chloro-2- (4-methanesulfonylbenzyl) -toxo-4-trifluoromethanesulfonyloxy-1,2,2-dihydroisoquinoline-3-carboxylic acid It was synthesized using methyl ester and 2-tributyltin thiophene. Colorless powder (yield 31%).
  • Example 11 4-Amino-2- (4-methylsulfonylbenzyl) -toxo-1,2-dihydroisoquinoline-3-hydroxypyruvonic acid methyl ester (0.12 g) obtained in one (10), A mixture of 2,5-dimethoxytetrahydrofuran (40) and acetic acid (1.2 ml) was heated under reflux for 1.5 hours. After cooling the reaction solution, the solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure.
  • Example 11 4-Amino-2- (4-methanesulfonylpentyl) -toxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (0.10 g) obtained in one (10), 1, Sodium hydride (33 mg) was added to a mixture of 5-dibromopentane (44) and DMF (2.0 ml), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was diluted with ethyl acetate and washed with a 5% aqueous hydrogen sulfate aqueous solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure.
  • Example 1 4-amino-2- (4-methanesulfonylpentyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (0.25 g) obtained in (10), triphenyl diacetate A mixture of bismuth (0.43 g), bis (2,2-dimethylpropanoic acid) copper (II) (0.25 g) and dichloromethane (12 ml) was stirred under a nitrogen atmosphere for 24 hours. After completion of the reaction, the reaction solution is washed with 1N hydrochloric acid and saturated saline, and dried over magnesium sulfate. Then, the mixture was concentrated under reduced pressure.
  • This compound was prepared according to the method described in Example 37, using 4-amino-2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carbonitrile and 1,5-dibutene mopentane. Was synthesized using Pale yellow crystals (35% yield).
  • JNK inhibitors containing the compound represented by the formula (I) or a salt thereof according to the present invention as an active ingredient eg, chronic or acute heart failure, cardiac hypertrophy, prognosis of myocardial infarction, myocarditis, rheumatoid arthritis, osteoarthritis
  • Inflammatory bowel disease, asthma, ischemia / reperfusion injury, organ failure, stroke, cerebrovascular disorder, etc. Can be manufactured.
  • ingredients (additives) other than the active ingredient may be those listed in the Japanese Pharmacopoeia, the Pharmaceutical Standards outside the Pharmacopoeia or the Pharmaceutical Excipient Standards.
  • the genetic manipulation method described in the following experimental examples is based on the method described in a companion book (Maniatis et al., Molecular-Cloning, Cold Spring Harbor Laboratory 1989) or the protocol described in the reagent attached protocol. I followed.
  • the PCR reaction was performed by the Hot Stai method using AmpliWax PCR Gem 100 (Takara Shuzo).
  • AmpliWax PCR Gem 100 (Takara Shuzo).
  • 10 X LA PCR Buffer 2 K 2.5 mM dNTP solution 3 K 12.5 HU Primer solution 2.5 25 mM MgCl 2 solution 2 / zl and sterilized distilled water 8 ⁇ il were mixed.
  • human kidney cDNA (l ng / ml) as ⁇ type 11; 10 x LA PCR Buffer 3 2.5 mM dNTP solution 5 K 25 mM MgCl 2 solution 31 1; TaKaRa LA Taq DNA polymerase (Takara Shuzo) 0.5 ⁇ , 17.5 xl of sterile distilled water were mixed.
  • One AmpliWaxPCRGemlOO (Takara Shuzo) was added to the prepared lower layer mixture, treated at 70 ° C for 5 minutes and on ice for 5 minutes, and the upper layer mixture was added to prepare a PCR reaction solution.
  • the tube containing the reaction solution was set on a thermal cycler (PerkinElmer) and treated with 95 for 2 minutes. Further, a cycle of 95 ° C for 15 seconds and 68 ° C for 2 minutes was repeated 35 times, followed by treatment at 72 ° C for 8 minutes.
  • the resulting PCR product was subjected to agarose gel (1%) electrophoresis, and a 1.2 kb DNA fragment containing the JNK1 gene was recovered from the gel, digested with the restriction enzymes Kpnl and Xhol, and 4.8 kb Xhol-Kpnl of the plasmid pFASTBACl (GIBC0BRL)
  • a plasmid pFBJNKl inserted into the fragment was prepared.
  • a virus stock BAC-HJNK1 of a recombinant baculovirus was prepared. '
  • PCR was performed using The PCR reaction was performed by the Hot Sta method using AmpliWax PCR Gem 100 (Takara Shuzo).
  • As the lower layer mixture 10 X LA PCR Buffer 2 i 2.5 mM dNTP solution 3 ⁇ 1, 12.5 primer solution 2.5251 ⁇ 12 solution 21 each, and sterile distilled water 81 were mixed.
  • the top layer solution mixture human ⁇ cDNA of (l ng / ml) 1 ⁇ 10 x LAPCR Buffer 3 II K 2.5 mM dNTP solution as ⁇ 5 / zl, 251 ⁇ 3 ⁇ 43 ⁇ 4 ( : 1 2 solution 3 1, TaKaRa LA Taq DNA polymerase (Takara Shuzo) 0.5 ⁇ 1 and sterile distilled water 17.5 / ⁇ I were mixed in.
  • One Amplifax PCR Gem 100 (Takara Shuzo) was added to the prepared lower layer mixture, and the mixture was treated at 70 ° C for 5 minutes and on ice for 5 minutes.
  • the mixed solution in the upper layer was added to prepare a PCR reaction solution.
  • the tube containing the reaction solution was set on a Thermal Cycler (Perkin Elmer), and treated at 95 ° C for 2 minutes. The cycle was repeated 35 times at 15 ° C. for 2 minutes at 68 ° C. and then for 8 minutes at 72 ° C.
  • the PCR product was subjected to agarose gel (1) electrophoresis, and the PCR product containing the MKK7 gene was After recovering the DNA fragment of No. 3 from the gel, it was introduced into T7Blue-T vector (Novagen) to obtain plasmid PHMKK7.
  • plasmid pFBcaMKK7 The 4.8 kb EcoRI-Xbal fragment of plasmid pFASTBACl (GIBC0 BRL) and the 1.3 kb EcoRI-Xbal fragment of plasmid pcaMKK7 were ligated to prepare plasmid pFBcaMKK7. Using the plasmid pFBcaMKK7 and the BAC-T0-BAC Baculovirus Expression System (GIBC0 BRL), a virus stock BAC-caMKK7 of a recombinant baculovirus was prepared. (3) Growing cJUN gene
  • the gene encoding the N-terminal 79 amino acids of cJUN was amplified by PCR using PCR.
  • the PCR reaction was performed by the Hot Start method using AmpliWax PCR Gem 100 (Takara Shuzo).
  • As the lower layer mixture 10 X Pyrobest PCR Buffer 2 n 2.5 mM dNTP solution 3 12.5 ⁇ each of the primer solution 2.5 l ⁇ ⁇ and sterile distilled water 101 were mixed.
  • For the upper layer mixture use human skeletal muscle cDNA (l ng / ml) as type III, 11 x 10 x Pyrobest PCR Buffer 3 II K 2.5 mM dNTP solution 1 n Ta aRa Pyrobest DNA polymerase (Takara Shuzo) 0.5 i sterile distilled water 24.5 il mixed.
  • One AmpliWax PCR Gem .100 was added to the prepared lower layer mixture, and the mixture was treated at 70 ° C for 5 minutes and on ice for 5 minutes.
  • the upper layer mixture was added to prepare a PCR reaction solution.
  • the tube containing the reaction solution was set on a thermocycler (PerkinElmer) and treated at 95 ° C for 2 minutes. Further, a cycle of 95 ° C. for 15 seconds and 68 ° C. for 30 seconds was repeated 35 times, followed by treatment at 72 ° C. for 8 minutes.
  • the resulting PCR product was subjected to agarose gel (1%) electrophoresis, and a 240 bp DNA fragment containing the cJUN gene was recovered from the gel, digested with the restriction enzymes EcoRI and Notl, and 4.9 of plasmid pGEX6P-1 (Amersham Pharmacia) was obtained.
  • a plasmid pGEJUN inserted into the kb EcoRI-Notl fragment was prepared.
  • the ampicillin-resistant strain PGEJI / JM109 obtained by transforming the plasmid PGEJ ring into Escherichia coli JM109 (Toyobo) was prepared.
  • the 0681 ring / 109 strain was cultured in 150 ml of LB medium (10 g / l tryptone, 5 g / l yeast extract, 10 g / l sodium chloride) containing 50 111 ampicillin at ⁇ 200 ° C. and 37 ° C. 15 ml of the culture solution was added to 150 ml of fresh LB medium, cultured at 200 ° C. for 2 hours at 37 ° C., and further cultured for 6 hours by adding ImM IPTG (Wako Pure Chemical Industries).
  • the culture was centrifuged at 8000 ⁇ ⁇ ⁇ for 10 minutes to collect the cells, washed with PBS, and frozen at -80. After suspending in 20 ml of Lysis buffer (B-PER bacterial protein extraction reagent (Pierce), Protease inhibitor Ccmplete (Boehringer)), it was shaken at room temperature for 10 minutes. After centrifugation (14000 rpm, 15 minutes, 4 ° C), the GST-cJII fusion protein was purified using the Redipack GST Purification Module (Amersham Pharmacia).
  • Lysis buffer B-PER bacterial protein extraction reagent (Pierce), Protease inhibitor Ccmplete (Boehringer)
  • the acid-insoluble fraction was transferred and washed with 250 mM phosphoric acid. After drying at 45: for 60 minutes, 401 of Microscint 0 (Packard Japan) was added, and the radioactivity was measured with TopCount (Packard Japan). The concentration (IC 5 value) of the test compound required to inhibit the incorporation of 32 P into the acid-insoluble fraction by 50% was calculated using PRISM 2.01 (GraphPad Software). Experimental example 2
  • LPS SIGMA, Derived from E. coli
  • the compound was suspended in 0.5% methylcellulose and was administered 60 minutes before LPS administration.
  • the control group similarly received only 0.5% methylcellose.
  • LPS administration 90 minutes after Pentobarubi evening Ichiru (50 mg / kg, given intraperitoneally throw) Blood was collected in syringe containing Apurochinin ⁇ EDTA from the abdominal aorta under anesthesia and centrifuged 10 minutes at 3000 ⁇ m, 4 D C Thus, plasma was obtained. TNF 0 in plasma was measured using ELISA Kit (GENZYME).
  • LPS SIGMA, Derived from E. coli
  • the compound was orally or intravenously administered by the method described in (1-1) or (1-2).
  • the heart was excised, the heartbeat was stopped in ice-cold TBS buffer (50 raM Tris-HCl pH 7.4, 150 mM NaCl), and the left heart was collected.
  • the sa1 le of 101 was loaded on a 10% separation gel (BI0RAD) and electrophoresed at 150 V for 60 minutes.
  • the protein on the gel was transferred to a methanol-treated PVDF membrane (B10RAD) at 100 V for 1 hour using a wet blotting method.
  • TBS-T 0.05% Tween20
  • the membrane was blocked with 5 skimmilk / TBS-T (blocking buffer) for 1 hour at room temperature. Thereafter, the mixture was reacted with an anti-phosphorylated c-Jun (ser63) mouse monoclonal antibody (KM-1: SANTA CRUZ; diluted 250-fold with a blocking buffer) at room temperature for 1.5 hours.
  • Table 1 shows the inhibitory effects of human JNK1, p38 and ERK1.
  • the compound (I) of the present invention or a salt thereof has an excellent JNK-specific inhibitory activity and an excellent oral absorption, so that it can be used as a safe and effective medicament for JNK-related disease states. Or for the prevention and treatment of diseases.

Abstract

L'invention concerne des inhibiteurs de JNK caractérisés en ce qu'ils contiennent des composés représentés par la formule générale suivante, ou des sels ou des promédicaments de ceux-ci. Dans la formule, A représente un noyau benzène éventuellement substitué ; R1 représente un groupe hydrocarbure cyclique éventuellement substitué ou un groupe hétérocyclique éventuellement substitué ; R2 représente hydrogène, un groupe hydrocarbure pouvant être substitué par hydroxyle éventuellement substitué, cyano, acyle, carboxyle éventuellement estérifié, carbamoyle éventuellement substitué ou amino éventuellement substitué ; X représente un groupe hydrocarbure linéaire divalent éventuellement substitué ; et Y représente un groupe hydrocarbure non aromatique éventuellement substitué, un groupe hétérocyclique éventuellement substitué, hydroxyle éventuellement substitué ou amino éventuellement substitué.
PCT/JP2003/016159 2002-12-18 2003-12-17 Inhibiteurs de jnk WO2004054979A1 (fr)

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Cited By (22)

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WO2005074921A1 (fr) * 2004-02-09 2005-08-18 University Of Zurich Traitement de l'atherosclerose
EP1676574A2 (fr) 2004-12-30 2006-07-05 Johnson & Johnson Vision Care, Inc. Procédé favorisant la survie des tissus ou cellules griffées
US8691813B2 (en) 2008-11-28 2014-04-08 Janssen Pharmaceuticals, Inc. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
US8691849B2 (en) 2008-09-02 2014-04-08 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
US8697689B2 (en) 2008-10-16 2014-04-15 Janssen Pharmaceuticals, Inc. Indole and benzomorpholine derivatives as modulators of metabotropic glutamate receptors
US8722894B2 (en) 2007-09-14 2014-05-13 Janssen Pharmaceuticals, Inc. 1,3-disubstituted-4-phenyl-1H-pyridin-2-ones
US8748621B2 (en) 2007-09-14 2014-06-10 Janssen Pharmaceuticals, Inc. 1,3-disubstituted 4-(aryl-X-phenyl)-1H-pyridin-2-ones
US8785486B2 (en) 2007-11-14 2014-07-22 Janssen Pharmaceuticals, Inc. Imidazo[1,2-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US8841323B2 (en) 2006-03-15 2014-09-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US8906939B2 (en) 2007-03-07 2014-12-09 Janssen Pharmaceuticals, Inc. 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
US8937060B2 (en) 2009-05-12 2015-01-20 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US8946205B2 (en) 2009-05-12 2015-02-03 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US8993591B2 (en) 2010-11-08 2015-03-31 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9012448B2 (en) 2010-11-08 2015-04-21 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9067891B2 (en) 2007-03-07 2015-06-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US9085577B2 (en) 2009-05-12 2015-07-21 Janssen Pharmaceuticals, Inc. 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9114138B2 (en) 2007-09-14 2015-08-25 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′] bipyridinyl-2′-ones
US9271967B2 (en) 2010-11-08 2016-03-01 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
US10106542B2 (en) 2013-06-04 2018-10-23 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US10537573B2 (en) 2014-01-21 2020-01-21 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use

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WO2005074921A1 (fr) * 2004-02-09 2005-08-18 University Of Zurich Traitement de l'atherosclerose
EP1676574A2 (fr) 2004-12-30 2006-07-05 Johnson & Johnson Vision Care, Inc. Procédé favorisant la survie des tissus ou cellules griffées
US9266834B2 (en) 2006-03-15 2016-02-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US8841323B2 (en) 2006-03-15 2014-09-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US9067891B2 (en) 2007-03-07 2015-06-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US8906939B2 (en) 2007-03-07 2014-12-09 Janssen Pharmaceuticals, Inc. 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
US11071729B2 (en) 2007-09-14 2021-07-27 Addex Pharmaceuticals S.A. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
US9132122B2 (en) 2007-09-14 2015-09-15 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
US8722894B2 (en) 2007-09-14 2014-05-13 Janssen Pharmaceuticals, Inc. 1,3-disubstituted-4-phenyl-1H-pyridin-2-ones
US8748621B2 (en) 2007-09-14 2014-06-10 Janssen Pharmaceuticals, Inc. 1,3-disubstituted 4-(aryl-X-phenyl)-1H-pyridin-2-ones
US9114138B2 (en) 2007-09-14 2015-08-25 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′] bipyridinyl-2′-ones
US8785486B2 (en) 2007-11-14 2014-07-22 Janssen Pharmaceuticals, Inc. Imidazo[1,2-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US8691849B2 (en) 2008-09-02 2014-04-08 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
US8697689B2 (en) 2008-10-16 2014-04-15 Janssen Pharmaceuticals, Inc. Indole and benzomorpholine derivatives as modulators of metabotropic glutamate receptors
US8691813B2 (en) 2008-11-28 2014-04-08 Janssen Pharmaceuticals, Inc. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
US9737533B2 (en) 2009-05-12 2017-08-22 Janssen Pharmaceuticals. Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US8946205B2 (en) 2009-05-12 2015-02-03 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9085577B2 (en) 2009-05-12 2015-07-21 Janssen Pharmaceuticals, Inc. 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US8937060B2 (en) 2009-05-12 2015-01-20 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US9226930B2 (en) 2009-05-12 2016-01-05 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-a] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US10071095B2 (en) 2009-05-12 2018-09-11 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of neurological and psychiatric disorders
US9271967B2 (en) 2010-11-08 2016-03-01 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US8993591B2 (en) 2010-11-08 2015-03-31 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9012448B2 (en) 2010-11-08 2015-04-21 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US10106542B2 (en) 2013-06-04 2018-10-23 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US10584129B2 (en) 2013-06-04 2020-03-10 Janssen Pharmaceuticals Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
US10537573B2 (en) 2014-01-21 2020-01-21 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11103506B2 (en) 2014-01-21 2021-08-31 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use

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