WO2004054979A1

WO2004054979A1 - Jnk inhibitors

Info

Publication number: WO2004054979A1
Application number: PCT/JP2003/016159
Authority: WO
Inventors: Fumio Itoh; Shuji Kitamura; Hiroyuki Kimura; Hideki Igata
Original assignee: Takeda Pharmaceutical Company Limited
Priority date: 2002-12-18
Filing date: 2003-12-17
Publication date: 2004-07-01
Also published as: AU2003289386A1

Abstract

JNK inhibitors characterized by containing compounds represented by the following general formula, or salts or prodrugs thereof: wherein A is an optionally substituted benzene ring; R1 is an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group; R2 is hydrogen, a hydrocarbon group which may be substituted with optionally substituted hydroxyl, cyano, acyl, optionally esterified carboxyl, optionally substituted carbamoyl, or optionally substituted amino; X is an optionally substituted divalent linear hydrocarbon group; and Y is an optionally substituted nonaromatic hydrocarbon group, an optionally substituted heterocyclic group, optionally substituted hydroxyl, or optionally substituted amino.

Description

Specification

JNK inhibitor technology

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. Background art

Mammalian cells respond to extracellular stimuli by activating a signal cascade through mitogen-activated protein kinase (MA PK) 'family members. There are three types of MAPK: c-Jun N-terminal kinase (JNK) (alias: stress-activated protein kinase (SAPK)), p38 MAP kinase, and extracellular signal regulated kinase (ERK). It is activated by various signals such as factors, cytotoxicity, ultraviolet irradiation, and stress inducers. Since 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.

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. Is considered to constitute a major intracellular signaling pathway responsible for the stress response (Biochemica et Biophysica Acta, 1997, 1333, P.F85-F104). Activated JNK activates various transcription factors such as c-Jun, ATF-2, E1k1, p53 and cell death domain protein (DE 丽), 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”. ]

Regarding the relationship between JNK and various JNK-related pathologies or diseases, for example, in cardiomyocytes, it is known that 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-β, 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). Recently, it has been reported that cardiac JNK activity in patients with cardiac failure has increased after the onset of myocardial infarction, and that heart failure occurs in mice overexpressing MKK7 (JNK selective kinase) heart. The involvement of JNK in the progression process has been suggested (Journal of Molecular and Cellular Cardiology, 1999, Vol. 31, .1429-1434). In addition, it has been reported that dominant negative JNK inhibition in cardiac overload models suppresses cardiac hypertrophy without affecting blood pressure (Journal of Clinical Investigation, 1999, vol. 104, p. 39). 398). Furthermore, in an ischemia-reperfusion model, it has been reported that dominant negative ΜΚ Κ7 reduces JNK activity and suppresses cardiomyocyte death. This suggests that inhibitors of JNK may be effective in treating ischemic heart disease, heart failure, myocardial infarction prognosis, and dogs with cardiac hypertrophy.

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.

In addition, experiments using JNK1-deficient mice have reported that JNK is an important mediator related to obesity and insulin resistance (Nature, 2002, Vol. 420, p. 333-336). ).

To date, 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. However, an isoquinolinone derivative having a JNK inhibitory action has been reported only in the pamphlet of WO 03/068750 so far.

On the other hand, isoquinolinone derivatives are disclosed in JP-A-10-298164 and JP-A-20-298164.

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.

That is, the present invention (1) Equation (I)

(In the formula, ring A represents an optionally substituted benzene ring, R ¹ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, and R ² represents hydrogen. An atom, a hydrocarbon group optionally substituted by an optionally substituted hydroxy group, a cyano group, an acyl group, an optionally esterified lipoxyl group, an optionally substituted olebamoyl group or a substituted 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 heterocyclic group which may be substituted, a hydroxy group which may be substituted or an amino group which may be substituted. A JNK inhibitor comprising a compound represented by the formula: or a salt thereof or a prodrug thereof;

(2) Equation (I)

(In the formula, ring A represents an optionally substituted benzene ring, R ¹ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, and R ² represents hydrogen. An atom, a hydrocarbon group optionally substituted with an optionally substituted hydroxy group, a cyano group, an acyl group, an optionally esterified olepoxyl group, an optionally substituted olebamoyl group or a substituted X represents an optionally substituted amino group; Represents a divalent chain hydrocarbon group which may be substituted, 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. And 2-benzyl-6,7-dichloro-4-hydroxy-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid ethyl ester, 2_benzyl-4-butoxy _'6,7-Dichloro-1-oxo-1,2-dihydro-3-isoginolinecarboxylic acid ethyl ester, 2-benzyl-4-butoxy-6,7-diclo-mouth 1-oxo-1, 2-dihydro-3-isoquinoline carboxylic acid and 2-benzyl-4-butoxy-6,7-dichloro-3-hydroxymethyl-1 (2H) -isoquinolinone (except) or a salt thereof;

(3) Ring A is a formula

Wherein 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:

(4) The compound according to the above (3), wherein R ³ is a hydrogen atom, a halogen atom, an optionally substituted alkyl group or an optionally substituted amino group;

(5) The compound according to the above (3), wherein R ³ is a hydrogen atom, a halogen atom or a —4 alkyl group;

(6) The compound according to (2), wherein R ¹ is phenyl which may be substituted;

(7) The compound according to the above (2), wherein X is methylene;

(8) The compound according to the above (2), wherein Y is an optionally substituted non-aromatic hydrocarbon group; (9) The compound according to the above (2), wherein Y is an optionally substituted chain hydrocarbon group;

(10) The compound according to the above (2), wherein Υ is an optionally substituted C ₂₆ alkenyl;

(11) The compound according to the above (2), wherein Y is an optionally substituted heterocyclic group;

(12) The compound according to the above (2), wherein Y is an optionally substituted 5- or 6-membered aromatic heterocyclic group;

(13) The compound according to the above (2), wherein Y is an optionally substituted hydroxy group;

(14) The compound according to the above (2), wherein Y is a hydroxy group which may be substituted and is substituted with a carbon hydride group;

(15) The compound according to the above (2), wherein Y is an amino group which may be substituted;

(16) The compound according to the above (2), wherein Y is a cyclic amino group;

(17) The compound according to (2), wherein R ² is an optionally esterified olepoxyl group or an optionally substituted olevamoyl group;

(18) The compound according to the above (2), wherein R ² is lower alkoxycarbonyl;

(19) The compound according to the above (2), wherein R ² is an acyl group, a hydrocarbon group which may be substituted with an optionally substituted hydroxy group, or an amino group which may be substituted;

(20) Methyl 6-chloro-4- (2-hydroxymethylthiophen-3-yl) -2- (4-methoxycarbonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylate Ester, 2- (4-caproloxybenzyl) -6-chloro-4- (3-hydroxymethylthiophen-2-yl) -methyl-1,2-dioxo-1,2-dihydroisoquinoline-3-carboxylate Methyl or 2- (4-methanesulfonylbenzyl) -toxo-4- (piperidine-toyl) -1,2-dihydroisoquinoline-3-carboxylic acid methyl ester or their Ant,

(21) a prodrug of the compound according to (2);

(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;

(24) The agent according to the above (23), wherein the JNK-related condition or disease is a circulatory disease, an inflammatory disease, a neurodegenerative disease or diabetes;

(25) Chronic or acute heart failure, cardiac hypertrophy, dilated, hypertrophic or restrictive cardiomyopathy, acute coronary syndrome, chronic ischemic heart disease, acute or chronic myocarditis, left diastolic dysfunction, left systolic insufficiency, Hypertension and nephropathy associated therewith · Nephritis, vascular endothelial dysfunction, arteriosclerosis, prevention of restenosis after angioplasty · A therapeutic agent or an agent for improving the prognosis of myocardial infarction;

(26) Equation (I)

(In the formula, ring A represents an optionally substituted benzene ring, R ¹ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, and R ² represents hydrogen. An atom, a hydrocarbon group optionally substituted by an optionally substituted hydroxy group, a cyano group, an acyl group, an optionally esterified olepoxyl group, an optionally substituted olebamoyl group or a substituted 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. A method of inhibiting JNK in a mammal, which comprises administering an effective amount of the compound or a salt thereof or a prodrug thereof to the mammal;

(27) Formula for the production of a JNK inhibitor (I)

(In the formula, ring A represents an optionally substituted benzene ring, R ¹ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, and R ² represents hydrogen. An atom, a hydrocarbon group which may be substituted with an optionally substituted hydroxy group, a cyano group, an acyl group, a carboxyl group which may be esterified, a labamoyl group which may be substituted or X represents an optionally substituted divalent chain hydrocarbon group; Y represents an optionally substituted non-aromatic hydrocarbon group; an optionally substituted heterocyclic group; A ring group, an optionally substituted hydroxy group or an optionally substituted amino group; And the use of a compound or a salt thereof or a prodrug thereof. 'In the above formula, Ring A represents an optionally substituted benzene ring.

Examples of the substituent 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. Examples of the “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. Examples of the “alkyl group” 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.

Examples of the "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 _ Okuteniru, 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 .

As the “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.

, Examples of the "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. As the “aralkyl group”, a C 7 ^ ₆ aralkyl group and the like are used, and specifically, for example, benzyl, phenyl, 3-phenylpropyl, 4-phenylbutyl For example, 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.

As the "Ariru group", 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, 〇 ₆ such as naphthyl - _{1 0} Ariru group, more preferably Ru phenyl are used. Examples of the substituent that the “hydrocarbon group” in the “optionally substituted hydrocarbon group” as the substituent that the ring A may have may include, for example,

(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,

— May be substituted with a 4-alkoxy group, etc.), mono or di-C ₂ _ ₄ alkenyl-rubamoyl group (eg, N-aryl-rubamoyl); the alkenyl group is a halogen atom, a hydroxy group, a —4 alkoxy group A mono- or diphenyl-lubamoyl group, a Mono- or dibenzyl-lubamoyl group, a 4-alkoxy-l-rubonyl-l-rubamoyl group, and the like. Preparative ₄ alkyl sulfonyl Lou force Rubamoiru group, alkoxy Ichiriki Rubamoiru group, § minnow force Rubamoiru group, mono- or di C DOO ₄ alkylamino over force Rubamoiru group, mono- or Jifu enyl § amino Ichiriki Rubamoiru group, (vi) force A ropoxyl group, (vi i) a _4- alkoxy monopropyl group (for example, methoxycarbonyl, ethoxypropyl, propoxypropyl, isopropoxycarbonyl, etc.), (vi ii) a sulfo group, (ix) a halogen atom (for example, fluorine, Chlorine, bromine, iodine, etc.), (X) optionally halogenated d-4 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.), hydroxy group d _ ₄ alkoxy group, a carboxyl group optionally substituted - 4 alkoxy groups, C Bok ₄ alkoxy - Karuponiru may be substituted with group (^ 4 alkoxy group,

— ₄ alkoxy— d _ ₄ alkoxy, (: ₄ alkoxy— C ^ — ₄ alkoxy-1 _ ₄ alkoxy, (xi) phenoxy, phenoxy 1 alkyl, phenoxy ^ ₄ alkoxy, alkyl propylonoxy Groups, mono- or di-alkyl mono- or di-alkyl mono- or mono- or di-alkyl, (xi i) phenyl group which may be halogenated, phenyl C ₄ alkyl group which may be halogenated, halogen Optionally substituted phenyl C ₂ _ ₄ alkenyl group, optionally halogenated phenoxy group (for example, o-, m- or p-chlorophenoxy, o_, m- or p-bromophenoxy, etc. ), 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 may be substituted with hydroxy group, (xiv) mercapto group, thioxo group, (XV) halogen atom, carboxyl group, and _4- alkoxy A benzyloxy group or a benzylthio group, each of which may be substituted with a substituent selected from a luponyl group, (xvi) halogenation Is phenylene optionally thio group, pyridylthio group, phenylene Lucio one - 4 alkyl group, pyridylthio one (: Bok ₄ alkyl group may be (xvi i) halogenated - 4 alkylsulfinyl group (e.g., methylsulfinyl, etc. 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,

N, N- dimethylamino-sulfonyl, N, etc. N- GETS chill aminosulfonyl; the alkyl group is a halogen atom, hydroxy group, may be substituted with such C i _ ₄ alkoxy group), (χχΐί ί ^ - _{1 0} Ashiru - amino group (e.g., - ₆ Arukanoiru amino (eg, Horumiruamino, Asechiruamino, triflumizole Ruo b acetyl § amino, propionyl Rua amino, Bibaroiruamino etc.), Benzoiruamino, C DOO ₆ alkynyl Le sulfonyl § amino (for example, methanesulfonyl amino, triflumizole Ruo b methanesulfonyl Niruamino etc.), C ₆ - _{1 0} § reel sulfonyl § amino (e.g., benzenesulfonyl § Mino, toluenesulfonyl § amino, etc.); C ^ - _{1 0} Ashiru is halogen atom, hydroxy sheet group, May be substituted with a carboxyl group, etc.), benzyloxycarbonyl , Eight halogenated are unprotected alkoxycarbonyl § Mino also force Rubamoiruamino group, mono- or di - C physician ₄ alkyl force Rubamoiruamino group, (xxi) mono - or di ^ - ₄ alkylamino group (e.g., Mechiruamino, Echiru Amino The alkyl group may be substituted by a halogen atom, a hydroxy group, a alkoxy group, etc.), phenylamino, benzylamino, (xxii) a 4- to 6-membered cyclic amino group (for example, 1- Azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl, etc., 4- to 6-membered cyclic amino-carbonyl group (for example, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, piperidinyl) Nocarbonyl, morpholinocarbonyl, thio Morpholinocarbonyl, 1-piperazinylcarbonyl, etc.), 4- to 6-membered cyclic amino-carbonyldioxy group (for example, 1-pyrrolidinylcarbonyloxy, piperidinocarbonyloxy, morpholinocarbonyloxy, thiomorpholinocarbonyl 4-, 6-membered cyclic amino-carbonylamino group (for example, 1-pyrrolidinylcarbonylamino, piperidinocarponylamino, morpholinocarbonylamino, thiomorpholino) Diphenylamino, 1-piperazinylcarbonylamino, etc.), 4- to 6-membered cyclic amino-sulfonyl group (eg, 1-pyrrolidinylsulfonyl, piperidinosulfonyl, morpholinosulfonyl, thiomorpholinosulf) Honyl, 1-piperazinylsulfonyl, etc.), 4- to 6-membered cyclic amino-(^ _ ₄ alkyl group, (xx iii) halogen atom, carboxyl group, and alkoxy-substituted luponyl group. which may C i _ ₆ Ashiru group (e.g., formyl, halogenated have such good C ₂ _ ₆ Al force Noiru be such Asechiru) or 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 bets ₄ alkyl group), (xxvi) 5 Or a 10-membered heterocyclic monocarbonyl group (for example, 2- or 3 ______________________________________, 2- or 3_-furylcarbonyl, 3-, 4- or 5-birazolylcarponyl, 2-, 4-1- or 5_ Thiazolylcarbonyl, 3-, 4- or 5-isothiazolylcarbonyl, 2_, 4-mono- or 5-oxazolylcarbonyl, 1,2,3- or 1,2,4-triazolylcarbonyl, 1 H- or 2 H-tetrazolyl carbonyl, 2-, 3- or 4-pyridylcarbonyl, 2-, 4- or 5-pyrimidyl carbonyl, 3- or 4-pyridazinyl carbonyl, quinolyl carbonyl, isoki Rylcarbonyl, indolylcarbonyl, etc .; the heterocyclic group may be substituted by a C 4 alkyl group, etc.), (xxv ii) a hydroxyimino group, a C 4 alkoxyimino group, an aryl group (for example, 1- Or (xxv iii) linear or branched optionally halogenated — 4 alkylenedioxy groups (eg, methylenedioxy, ethylenedioxy, propylenedioxy, tetrafluoroethylenedioxy) Etc.) are used. 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 An aromatic heterocyclic ring containing at least one (preferably 1 to 4, more preferably 1 to 2) of 1 to 3 (preferably 1 to 2) heteroatoms selected from, a sulfur atom and a nitrogen atom And saturated or unsaturated non-aromatic heterocyclic groups (aliphatic heterocyclic groups).

Examples of the “aromatic heterocyclic group” 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, isoindolyl, 1H_ Indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoiso Sazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, 'quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, buteridinyl, carbazolyl, 0! -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 [1,2,5] thiadiazolyl, benzo [1,2,5] oxaziazolyl (Preferably 8-12 membered) aromatic condensed heterocyclic group (preferably, 1 or 2 5- or 6-membered aromatic monocyclic heterocyclic group described above (preferably More preferably, the heterocyclic ring in which 1) is condensed with 1 to 2 (preferably 1) benzene rings or the same or different heterocyclic ring 2 of the aforementioned 5- or 6-membered aromatic monocyclic heterocyclic group To 3 (preferably 2) condensed heterocyclic rings, more preferably a heterocyclic ring in which the 5- or 6-membered aromatic monocyclic heterocyclic group is condensed with a benzene ring) and the like.

Examples of the “non-aromatic heterocyclic group” 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. A heterocyclic group condensed with 1 to 2 (preferably 1) benzene rings and 1 to 2 (preferably 1) non-aromatic monocyclic heterocyclic groups described above. Is a heterocyclic group condensed with 1 to 2 (preferably 1) heterocyclic groups of the aforementioned 5- or 6-membered aromatic monocyclic heterocyclic group, or 1,2,3,4-tetrahydroquinolyl, 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. And a ring group.

As the “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. As the substituent, 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. Further, as 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. As the “optionally substituted carbamoyl group”, the same groups as the “optionally substituted carbamoyl group” described below as a substituent which ring A may have, and the like are used. Further, 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. And the same number of the same groups as the substituents in the "optionally substituted hydrocarbon group" and the "optionally substituted heterocyclic group".

Among them, 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, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.), and acyl (C- ₆ alkanol (eg, formyl, alpha) Se chill, propionyl, pivaloyl, etc.), Benzoiru, C ^ - ₆ alkylsulfonyl (e.g., methanesulfonyl etc.), benzenesulfonyl, etc.), optionally halogenated C _i-6 alkoxy Cal Poni Le (e.g., methoxycarbonyl, ethoxycarbonyl Carbonyl, trifluoromethoxycarbonyl, 2,2,2,2-trifluoroethoxycarbonyl Trichloro methoxycarbonyl, 2, 2, 2-trichloro port Etokishika Ruponiru etc.), which may C i _ ₆ alkoxycarbonyl optionally (eg substituted with phenyl, benzyl O carboxymethyl cull Poni Le etc.), an optionally substituted force Rubamoiru group (For example, a group that may be substituted with one or two substituents such as lower (C ^ ₆ ) alkyl group, phenyl group, etc. such as carbamoyl, N-methylcarbamoyl, Ν, Ν-dimethylcarbamoyl, phenylcarbamoyl, etc. And 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". Further, two substituents in the Ν, Ν-disubstituted amino may be combined with a nitrogen atom to form a “cyclic amino group”. Examples of the “cyclic amino group” 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.. Ari • Le etc.) and the like 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". As the “hydrocarbon group” in the “optionally substituted hydrocarbon group”, the “hydrocarbon group” in the “optionally substituted hydrocarbon group” as a substituent which ring A may have The same groups as mentioned above are used. As the “heterocyclic group” in the “optionally substituted heterocyclic group”, the “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. Base And the "hydrocarbon group" or "heterocyclic group" in the "optionally substituted carbon hydride group" and the "optionally substituted heterocyclic group" As a preferable substituent, the "hydrocarbon group" in the "optionally substituted hydrocarbon group" and the "optionally substituted heterocyclic group" as the substituent which the ring A may have Or the same number as the substituent which the “heterocyclic group” may have, etc. The same number is used as the substituent that 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_〇 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 〇_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.

The term “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 ) In the above, the term "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. Among them, 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_〇 _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.

As 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.

In the above-mentioned `` optionally substituted rubamoyl group '', 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.). Good net A "carbamoyl group" having the "optionally substituted hydroxy group" (i.e., a "carbamoyl group" having an optionally substituted hydroxy group); An optionally substituted N-hydroxycarbamoyl group ”). In addition, two substituents in バ, Ν-disubstituted rubamoyl may be combined with a nitrogen atom to form a cyclic amino. In such a case, 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. pentyl, C ^ - e alkyl, 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. As a substituent which ring A may have, "an optionally esterified amino group" Examples of the “xyl group” include groups represented by the following formula: C〇〇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.

As the “hydrocarbon group” in the “optionally substituted carbon hydride group” and the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R ^e , A “hydrocarbon group” in the “optionally substituted hydrocarbon group” and a “heterocyclic group” in the “optionally substituted heterocyclic group” as substituents that the ring A may have The same groups as described above are 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.

The term “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. Among them, 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).

'' As the 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. The ring A substituent which may have a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), C i _ ₄ alkyl group (e.g., methyl, Echiru, propyl, isopropyl, butyl, etc. ), hydroxy-(: ₄ alkyl, C ^ - ₄ alkoxy - (- ₄ alkyl group, C ₂ - ₄ alkenyl group (e.g., vinyl, propenyl, etc. § Lil), a phenyl group which may be substituted (Preferably, an optionally halogenated ₄ alkyl group, an optionally halogenated — 4 alkoxy group, Force such Rupokishiru group and optionally phenyl substituted with a substituent selected from halogen atoms), C ₅ _ ₇ cycloalkyl over § amino group, an alkoxy group (e.g., methoxy, ethoxy, Purobokishi, isopropoxy, etc.), alkylthio group (e.g., methylthio, Echiruchio, propylthio, etc. isopropylthio), hydroxy group, carboxyl group, Shiano group, a nitro group, an amino group, mono- or di - C physician ₄ alkylamino group (e.g., Mechiruamino, Echiruamino, dimethyl amino, Dimethylamino, formyl group, mercapto group, C ₄ alkyl-carbonyl group (eg, acetyl, propionyl, butyryl). Preparative ₄ alkoxy - carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, etc. flop port Po alkoxycarbonyl), a sulfo group (- S_〇 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

(In 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 A good thiol group, a substituted sulfinyl group, a substituted sulfonyl group, an amino group which may be substituted, a rubamoyl group which may be substituted or a lipoxyl group which may be esterified. 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. ) Is preferably used.

In the above formula, 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. In the above formula, R ¹ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group.

As 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.

As the “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.

Examples of the substituent that the phenyl can have the "substituted optionally also be phenyl with" as preferred examples of R ^1, 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) or an optionally substituted phenyl group (preferably, Which may be an alkyl group, which may C Bok halogenated

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 group. (E.g., Mechiruamino, Echiruamino, dimethyl Amino, etc. Jechiruamino; - 4 alkyl halogen atom, hydroxy group, may be substituted with a carboxyl group), Ashiruamino group (for example, c ^ - ₆ Alkanoylamino (eg, formylamino, acetylamino, trifluoroacetylamino, propionylamino, pivaloylamino, etc.), benzoylamino, — 6 alkylsulfonylamino (eg, methanesulfonylamino, trifluoromethanesulfonylamino) etc.), C ₆ - _{1 0} § reel sulfonyl § amino (e.g., benzenesulfonyl § Mino, toluenesulfonyl § amino, etc.) and the like; _{1 0} Ashiru is May be substituted with a halogen atom, a hydroxy group, a carbonyl group, etc.), formyl group, mercapto group, C ₄ alkyl monocarbonyl group (eg, acetyl, propionyl, butyryl, etc .; alkyl is a halogen atom, hydroxy group, May be substituted with a carboxyl group, etc.), an alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc .; alkoxy may be substituted with a halogen atom, a 'hydroxy group, a propyloxyl group, etc.) , a sulfo group (an _{S 0 3 H), ^ -} 4 alkyl - sulfonyl group (e.g., methylsulfonyl, Echirusuruhoniru and propylsulfonyl;

(^ _ 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 group May be used), a cyclic amino-functional ruponyl group (for example, 1-pyrrolidinyl) Carbonyl, 1-piperidinocarbonyl, 4-morpholinocarbonyl, etc .; the cyclic amino may be substituted by a halogen atom, a hydroxy group, a carbonyl group, etc.), a sulfamoyl group and a mono- or di- _4- alkyl or C ₅ _ ₇ cycloalkyl - sulfamoyl group (e.g., N- methyl sulfamoyl, N- E chill sulfamoyl, N, N- dimethylsulfamoyl, N, N- such GETS chill sulfamoyl; C i _ ₄ alkyl and C ₅ _________________________________________________________7 The alkyl with _7- opening may be substituted with a halogen atom, a hydroxy group, a propyloxyl group, etc., a cyclic amino-sulfonyl group (for example, 1-pyrrolidinylsulfonyl, 1-piberidinosulfonyl, 4 1 morpholinosulfonyl, etc .; cyclic amino is a halogen atom, hydroxy group, carboxyl group Carbazolyl (N-aminocarbamoyl) group and (mono- or di- (N— (: 丄一, Arukiruamino) or (N-C ₅ one ₇ cycloalkyl § mino)) force Rubamoiru group

(E.g., (N- Mechiruamino) force Rubamoiru, (N- Echiruamino) Karubamo I le, (N, N- Jimechiruamino) force Rubamoiru, (N, etc. N- Jechiruamino) force Rubamoiru; C _ ₄ alkyl and C ₅ - ₇ 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, 2- or 3-furyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5- thiazolyl, 3-, 4-mono or 5-iso Thiazolyl, 2-, 4-mono- or 5-oxazolyl, 1,2,3- or 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, 1,2,4- or 1,3,4-mono-oxazolyl, 5 —Oxo— 4H— 1,2,4-Ioxaziazolyl, 5—Thixo 4H—1,2,4-oxadiazolyl, 1,2,4— or 1,3,4-thiadiazolyl, 5-oxo— 4H— 1,2,4-thiadiazolyl, 5-thioxo-4H—1,2,4-thiadiazolyl, 2-oxo-3H-1,2,3,5-thiadiazolyl, 2, 3, or 4 Pyridyl, 2-, 4- or 5-pyrimidyl, 3- or 4-pyridazinyl, quinolyl, isoquinolyl, indolyl, etc .; the heterocyclic group may be substituted with a halogen atom, a hydroxy group, a carboxyl group, etc.) Are preferably used, and these substituents are substituted with a phenyl group. To 1 not in the possible positions may be three substituents, if having two or more, the substituents may be the same or different. In addition, 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.

As a preferable example of R ^1, the substituent which phenyl may have in `` optionally substituted phenyl '' is i) a halogen atom, a hydroxy group or a carboxy group. 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 - a force Rubamoiru group (C ₅ _ ₇ Shikuroa alkyl is halogen atom, hydroxy group or a carboxyl group - or di C ₅ _ ₇ cycloalkyl (Optionally substituted), vi-3) Cyclic amino-propanol group (Cyclic amino is a halogen atom, hydroxy group, carboxyl group, etc.) In optionally substituted), vi i) a sulfamoyl group, vi i i-1) mono- or di-C ₄ alkyl Loose sulfamoyl group (C DOO ₄ alkyl substituted by a halogen atom, a hydroxyl group or a carboxyl group may also be), vi i i-2) mono- or di-C ₅ _ ₇ cycloalkyl § Ruki loose sulfamoyl group (C ₅ _ ₇ Sik port alkyl may be substituted with halogen atom, hydroxy group or force Rupokishiru group) Iii-1) Cyclic amino-sulfonyl group (Cyclic amino may be substituted with a halogen atom, hydroxy group, carboxyl group, etc.), ix-1) Rubazyl group, ix-2) Mono- or mono- G (N-C ^ - ₄ Arukiruamino) Ichiriki Rubamoiru group (C alkyl may be substituted with halogen atom, hydroxy group or force Rupokishiru group), IX- 3) mono - or di (N-C ₅ - ₇ cycloalkylamino) One-piece rubamoyl group (C ₅ _ ₇ cycloalkyl may be substituted with a hagen atom, hydroxy group or carboxyl group), ix-4) Cyclic amino-group Mino may be substituted with a halogen atom, a hydroxy group, a carbonyl group or the like), or X) may be substituted with an halogen atom, a hydroxy group or a carbonyl group (: ₄ alkylenedioxy group) Etc. are particularly preferred. Among them, carboxyl group, alkoxy Ichiriki Ruponiru group, forces Rubamoiru group, mono- or di one ^ - ₄ alkyl - force Rubamoiru group, cyclic amino chromatography carbonyl group, C - ₄ alkyl - sulfonyl group, or a C _i-4 alkylene An oxy group and the like are particularly preferred. A preferred example of R ¹ is “optionally substituted phenyl”.

[Wherein, 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.

Examples of the combination of X ¹ and X ^2, when both of X ¹ and X ² is an 0 _, X 1 is -0-, one S- or a N (R ') one (preferably hard 〇-) 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—).

The substituent represented by 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.

As the alkylene in the “optionally substituted alkylene” for Z, for example, (^ 4 alkylene (eg, methylene, ethylene, propylene, etc.) and the like are used.

As the substituent which the alkylene in the “optionally substituted alkylene” for Z may have, the “optionally substituted hydrocarbon” as the substituent which the ring A may have In the group, the same group as the substituent which the “hydrocarbon group” may have may be used in the same number. Examples of the 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. No.

As Z, methylene, ethylene and the like are particularly preferable. In the above formula, 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.

As the “hydrocarbon group” in the “hydrocarbon group which may be substituted with an optionally substituted hydroxy group” for R ² , 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.

As the “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

The same groups as the “carboxyl group which may be esterified” as the substituent which A may have, and the like are used.

As the `` optionally substituted rubamoyl group '' represented by R ² , the same groups as the `` optionally substituted motive rubamoyl group '' as a substituent which ring A may have, and the like are used. It is.

As the `` 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. .

As 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 of the optionally available carboxyl group 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. 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). Here, 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. As the “heterocyclic group” in the “optionally substituted heterocyclic group” for R ^D , the term “optionally substituted heterocyclic group” as a substituent which ring A may have And the same groups as those described above for "heterocyclic group". 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.

The R ^D CO as the preferred examples of Ashiru group represented by R ^2, for example formyl, Asechiru, propionyl, Puchiriru, Isopuchiriru, valeryl, Isopareri Le, pivaloyl, to Kisanoiru, cyclobutane carbonyl, cyclopentane Cal Poniru, cyclohexane carbonyl cyclohexane, crotonyl, Benzoiru, Nikochinoiru, Isonikochinoiru, triflumizole Ruo b acetyl and the like, Asechiru, propionitrile, cycloalkenyl, Puchiriru, is R ^A, such as valeryl R ^A CO which is a lower (C ₄ ) alkyl group is more preferred.

R ² is preferably an optionally esterified olepoxyl group or an optionally substituted olevamoyl group, and particularly preferably a lower alkoxycarbonyl.

• In the above formula, 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.

As the substituent in the “optionally substituted bivalent chain-like carbon-containing hydrogen group” represented by X, 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. In the above formula, 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. As the “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.

As the alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group and aralkyl group, each of the above-mentioned "optionally substituted hydrocarbon" as a substituent which the ring may have Examples of the “hydrocarbon group” in the “group” include groups similar to the alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group and aralkyl group.

As 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. .

As the “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".

In the `` heterocyclic group which may be substituted '' represented by Y, 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.

As the “optionally substituted hydroxy group” represented by Y, the same groups as the aforementioned “optionally substituted hydroxy group” as the substituent which the ring A may have, and the like are used. Can be

As the “optionally substituted amino group” represented by Y, the same groups as the aforementioned “optionally substituted amino group” as the substituent which ring A may have, and the like are used. Can be

As Y, 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. In addition, 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. The 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.

As Y, 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 Preferably feuniru

- ₆ alkyl) substituted by a hydroxy group; substituted with C ₃ _ ₈ cycloalkyl, non Dorokishi group) and the like are particularly preferred. Also, as 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. As the compound represented by the formula (I) in the present invention, 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 (hereinafter sometimes referred to as compound (I)) can be produced by reacting the compound (I) with an enzyme or gastric acid under physiological conditions in a living body. A compound which is enzymatically oxidized, reduced, hydrolyzed, etc. to be converted into compound (I), or a compound which is hydrolyzed, such as by gastric acid, to be converted into compound (I). As a prodrug of 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 Compounds in which 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.) or the compound (I) Compounds in which the xyl group is esterified or amidated (for example, the propyloxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl) Esterification, ethoxycarponyl oxethyl esterification, phthalidyl esterification, (5 _methyl-2-oxo- 1,3-dioxolane-41-yl) methyl esterification, cyclohexyloxyl force ryponylethyl esterification, methyl amidated compound, etc.). These compounds can be produced from compound (I) by a method known per se.

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).

Examples of the salt of compound (I) 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. For example, metal salts such as sodium, potassium, magnesium, and calcium, and organic salts such as trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, N-methylpyrrolidine, N-methylpiperidine, and N-methylmorpholine. Can be

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). Method A

Method D

Method E

(XI I) (Id)

Method A

When Y of the compound (I) is a substituted hydroxy group, the compound represented by the formula (II)

[The symbols in the formula are as defined above. And a salt thereof (II) or a salt thereof. Formula (III)

L-R ⁴ (III)

[L is a leaving group (eg, a halogen atom (eg, chlorine, bromine, iodine, etc.) or a formula R ^L —S〇 ₂ —〇— (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. Method A-1

When L is a hydroxyl group, compound (II) can be alkylated by a Mitsunobu reaction in a solvent that does not affect the reaction.

In this reaction, solvents such as aromatic hydrocarbons such as toluene and benzene, carbonamides such as N, N-dimethylformamide, Ν, ジメチル -dimethylacetamide and メチル -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.

In the Mitsunobu reaction, as a reagent, 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. Further, 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. Method A—2

When L is a leaving group, it is represented by RL in the above formula. Examples of 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. (^ _ ₆ alkyl group, and among them methyl, Echiru, propyl, isopropyl, butyl, C Bok ₄ alkyl group isobutyl and the like. halogen atom (e.g. fluorine represented by R ^L, chlorine , Bromine, iodine, etc.) include lower alkyl groups such as trichloromethyl, trichloromethyl, Ruoromechiru, and the like.

Examples of the substituent in "a phenyl group which may be substituted" represented by 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.

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.

In this reaction, as a base, for example, alkali metal hydrides such as potassium hydride and sodium hydride, for example, 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. 0] non-one 5-E down, 1, 4- Jiazabishikuro [2. 2.2] Octane, 1,8-diazabicyclo [5.4.0] — Organic amines such as 7-pentadecene, 2-tert-butylimino-2-ethylpyramino-1,3,3-dimethyl-perhydro-1,3,2 -Diazaphosphorin and its resin are used.

In this reaction, an iodide such as lithium iodide or sodium iodide may be added as a reaction accelerator.

As the solvent used in this reaction, a solvent that does not inhibit the reaction is appropriately selected. Examples of such 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, Ν, Ν-dimethylformamide, amides such as Ν, Ν-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. Method B

When Y of the compound (I) is a substituted amino group (including a cyclic amiso group), the compound represented by the formula (IV)

(IV)

[The symbols in the formula are as defined above. Or a salt thereof with a compound of the formula (V) (and (V '))

There one R ⁵ (V) (L ¹ one R ⁵ '(V))

[In the formula, L ¹ represents a leaving group, and ^{5 and} 1 ′ ′ each represent a group corresponding to the substituent of the amino group in the “optionally substituted amino group”. ] Or the formula (VI)

L ² -R ⁶ -L ³ (VI)

[In the formula, L ² and L ³ each represent a leaving group, and 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:

As the leaving groups represented by LL ² and L ³ , 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. In this reaction, as 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. To 6 metal alkoxides, for example, 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-diazaphosphorin and its resin are used.

As the solvent used in this reaction, a solvent that does not inhibit the reaction is appropriately selected. this Examples of such 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, Ν, ジメチル -dimethylformamide, アミド, ジメチル -dimethylacetamide and the like, amides such as acetonitrile and propioni Nitriles such as tolyl In addition, dimethyl sulfoxide, sulfolane, to hexa methyl phosphoramide, water and the like are used alone or as a mixed solvent. '

When the compound (V) is reacted with the compound (V) to obtain the compound (I), the reaction is performed in one or two steps. When the reaction is performed in 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.

When the compound (IV) is reacted with the compound (VI) to obtain the compound (I), the reaction may be carried out in one step or two steps in the substitution of L ² and L ^3. When the reaction proceeds in two steps, the base and the solvent used may be the same or different.

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. When the reaction is carried out in two steps, 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. Further, as a method similar to Method B, 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.

Further, 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). Method C

When Y of the compound (I) is a non-aromatic hydrocarbon group which may be substituted, a heterocyclic group which may be substituted or an amino group which may be substituted, the compound represented by the formula (VII)

[In the formula, OTf represents a trifluoromethanesulfonyloxy group, and other symbols have the same meanings as described above. Or a salt thereof and a compound of the formula (VI II) QY ¹ (VI II)

[In the formula, 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 ′)

NHR ⁵ R ⁵ '(VII Γ)

[In the formula, 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; And the salt thereof to produce the compound (I). In this method, 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. Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride, and water such as lithium hydroxide, sodium hydroxide and potassium hydroxide. Alkali metal oxides, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, for example, hydrogen bicarbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate 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 [2.2.2] octane, 1,8-diazabicyclo [5.4.0] 17-indene For example, organic lithiums such as methyllithium, n-butyllithium, sec-butyllithium and tert-butyllithium, and lithium amides such as lithium diisopropylamide are used.

This reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such 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, Ν, ジメチル -dimethylformamide Amides such as, Ν, Ν-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. Can be

In general, the cross-coupling reaction can be accelerated by using a metal catalyst. In this reaction, a metal complex having various ligands is used as a metal catalyst. For example, 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, etc.] , A rhodium compound [e.g., Indium rhodium, etc.], cobalt compounds, platinum compounds and the like are used, and among them, palladium nickel compounds are preferred. The amount of the catalyst to be used is about 1-0.000001 mol, preferably about 0.1-0.0001 mol, per 1 mol of compound (VI1).

In this reaction, about 0.8 to 10 moles, preferably about 0.9 to 2 moles, and about 1 to about 20 bases of compound (VIII) or compound (VII （) per mole of compound (VII) Moles, preferably about 1 to about 5 moles are used.

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. Method D

When Y of the compound (I) is an optionally substituted aromatic heterocyclic group, the compound represented by the formula (IX)

[Wherein, ² represents an aromatic heterocyclic group which may be substituted, and other symbols have the same meanings as described above. In the compound (IX) or a salt thereof represented by the following formula, the compound (lb) or a salt thereof in which Υ of the compound (I) is an aromatic heterocyclic group which may be substituted is obtained by intramolecular cyclization. Can be manufactured.

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. 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, 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, Ν, Ν-dimethylformamide, N, N-dimethylacetamide, for example, nitrites such as acetonitrile, propionitrile, etc. In addition to such class, dimethyl sulfoxide, sulfolane, to hexa methyl phosphoramide, water and the like are used alone or as a mixed solvent.

In this reaction, as a base, for example, an alkali metal hydride such as potassium hydride or sodium hydride, for example, lithium ethoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc. 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-butyrolithium, and lithium Lithium amides such as beam diisopropylamide is used.

In this reaction, 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. Method E

When Y of compound (I) is an aromatic heterocyclic group which may be substituted, and R ² is a propyloxyl group or an acyl group which may be substituted, formula (X)

[Wherein, R ² ′ represents an optionally substituted carboxyl group or an acyl group, and other symbols have the same meanings as described above. And a compound (X) or a salt thereof represented by the formula: (XI)

H ² N— X— R ¹ (XI)

[The symbols in the formula are as defined above. After reacting with the amino compound (XI) or a salt thereof represented by the formula (I), Y of the compound (I) is an aromatic heterocyclic group which may be substituted, and R ² is Compound (I c) which is a carboxyl group or an acyl group which may be substituted, or a salt thereof can be produced. This reaction is performed without a solvent or in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such solvents 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 η-hexane, benzene, toluene, and the like, amides such as formamide, Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, For example, acetone, methyl ethyl ketone,

Ketones, for example, nitriles such as acetonitrile and propionitrile, and dimethylsulfoxide, sulfolane, hexamethylphosphoramide, water and the like are used alone or as a mixed solvent.

This reaction is preferably carried out in the presence of a base. Such bases include, for example, inorganic bases such as sodium carbonate, potassium carbonate, and sodium hydrogen carbonate, such as triethylamine, tri (η-propyl) amine, and tri ( η-butyl) amine, disopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, arcolidine, Ν, Ν-dimethylaniline, Ν-methylbiperidine, Ν-methylpiperidine, Ν-methylmorpholine, etc. Amines are used.

• In this reaction, about 1 to about 20 mol, preferably about 1 to about 5 mol, of compound (XI) is used per 1 mol of compound (X).

The reaction temperature ranges from about 120 to about 150 ° C, preferably from about 10 to about 80 ° C. It is.

The 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

C

Although the 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. Examples of such 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.

As the solvent used in the dehydration step, a solvent that does not inhibit the reaction is appropriately selected. As such a solvent, 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. '

The 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. Method F

When Y of compound (I) is an aromatic heterocyclic group which may be substituted, and R ² is a carboxyl group or an acyl group which may be substituted, formula (XI I)

[The symbols in the formula are as defined above. (XII I) and the formula (XIII)

L ^4- one X—R ¹ (XIII)

[In the formula, L ⁴ represents a leaving group (having the same meaning as L above). A compound represented by the formula (X III) to give a compound (I) wherein Y in compound (I) is an optionally substituted aromatic heterocyclic group and R ² is an optionally substituted carboxyl or acyl group. I d) can be manufactured.

This method is carried out by subjecting compound (XII) or a salt thereof to an alkylation reaction using compound (XIII) or a salt thereof.

This reaction is generally performed in a solvent in the presence of a base. 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 τ-oxide, sodium hydroxide, sodium carbonate, carbonated lime, cesium carbonate, sodium hydrogencarbonate For example, triethylamine, tri (η-propyl) amine, tri (η-butyl) amine, disopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, arcolidine, Ν, Ν-dimethylaniline, Ν-methylpiperidine, Ν-methylpyrrolidine, Ν-methylmorpholine, 1,5-diaza Organic amines such as cyclo [4.3.0] non-1-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] _7-undecene, 2-tert- Butylimino-2-ethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorin and its resins.

As such a solvent, 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, Ν, ァ -dimethylacetamide, etc. 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.

In this reaction, about 1 to about 5 mol, preferably about 1 to about 2 mol, of the compound (XIII) is used per 1 mol of the compound (XII).

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. Method G

A compound of the formula (Ie), wherein R ² of the compound (I) is

[The symbols in the formula are as defined above. The compound (Ie) represented by the formula (If) obtained by the above-mentioned method E or by the above-mentioned methods A to D

[In the formula, 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 τΚ 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, ρ-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 Ν, Ν-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.

It is also possible to produce various derivatives by using the compound (Ie) thus obtained and modifying the carboxyl group of the compound (Ie) by a method known per se or a method analogous thereto. it can. For example: 1) By esterifying compound (Ie), the compound of formula (Ig)

[In the formula, 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. For example, 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. 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.

2) By reducing the compound (Ie), the compound of the formula (Ih)

[The symbols in the formula are as defined above. The compound (Ih) represented by the formula: can be produced.

This reduction reaction can be performed by a method known per se or a method analogous thereto. For example, 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.

3) Amidating the compound (Ie), the compound of the formula (Ii)

Wherein corresponding to 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. For example, 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.

4) By converting the lipoxyl group of the compound (Ie) to an amino group, the compound of the formula (Ij)

[The symbols in the formula are as defined above. ] (I j) can be produced.

This inversion can be performed by a method known per se such as Curtius rearrangement, H ofmann anti-j¾ ヽ, or Schmidt reaction, or a method analogous thereto. For example, the compound (I e) or its reaction can be used. Azide derivatives (eg, acid halides, acid anhydrides, active esters, esters, imidazolides, etc.) are converted to acid azides, and the isocyanates are directly formed by thermal rearrangement of the acid azides. A method of deprotecting a carbamate-type protecting group of amine produced by hydrolysis or reaction with an alcohol can be used. Method H

In the substituent represented by RR ² , R ³ , Y and ring A of compound (I), 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.

For example, 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. In the case of an amino group, it can be converted by, for example, amidation, sulfonylation, nitrosation, alkylation, arylation, imidation and the like. In the case of a hydroxy group, it can be converted by a reaction such as esterification, sulfamoylation, sulfonylation, alkylation, arylation, oxidation, halogenation and the like. In the case of a carbonyl group, it can be converted by a reaction such as reduction, oxidation, imination (including oximation and hydrazone), (thio) ketalization, alkylidation, and thiocaronylation. In the case of thiol group, It can be converted by reactions such as alkylation and oxidation. In the case of an ester group, it can be converted by a reaction such as reduction or hydrolysis. In the case of a sulfo group, it can be converted by a reaction such as sulfonamidation or reduction. In the case of 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.

Wherein the symbols are as defined above. The compound (II) or a salt thereof can be produced, for example, by the following method. Formula (X IV)

[Wherein, R ¹¹ represents an optionally substituted hydrocarbon group or an optionally substituted complex ring, and other symbols have the same meanings as described above. Or a salt thereof or a reactive derivative thereof (eg, acid halide, acid anhydride, active ester, ester, imidazolide acid, azide acid, etc.) with the formula (XV)

1

X—R

HN (XV)

[Wherein the symbols have the same meanings as described above. Or a salt thereof (XV) By reacting with formula (XVI)

[The symbols in the formula are as defined above. The amide compound (XVI) represented by the formula: or a salt thereof can be produced.

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. By subjecting the obtained compound txVI) or a salt thereof to an intramolecular cyclization reaction in the same manner as in the above method D, the compound of the formula (II)

[The symbols in the formula are as defined above. Or a salt thereof.

Compound (XVI) used in the above-mentioned Method I can also be produced according to the following Method J.

Wherein the symbols in the formula are as defined above, or a salt thereof, and a compound of the formula (XV)

[Wherein the symbols have the same meanings as described above. By reacting with the compound (XV) or a salt thereof represented by the formula (XV I I I)

(XVIII)

[Wherein the symbols have the same meanings as described above. (XVI I I) or a salt thereof.

This reaction is carried out according to a conventional method, in a solvent that does not adversely influence the reaction.

Examples of 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 (XVIII) thus obtained is led to the compound (XVI) according to the method shown in the above Reaction G-1. Method K Formula (IV)

Wherein the symbols are as defined above. The compound (IV) or a salt thereof can be produced, for example, by the following method. Expression (XIX)

(XIV) or a salt thereof or a reactive derivative thereof (eg, acid halide, acid anhydride, active ester, ester, imidazolide acid, azide acid, etc.) by the formula (XV)

[Wherein the symbols have the same meanings as described above. By reacting with compound (XV) or a salt thereof represented by the formula (XX)

[The symbols in the formula are as defined above. The amide compound (XX) or a salt thereof represented by the formula:

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. By subjecting the obtained compound (XX) or a salt thereof to an intramolecular cyclization reaction in the same manner as in the above method D, the compound of the formula (IV)

[The symbols in the formula are as defined above. ] The compound (IV) represented by these, or its salt can be manufactured. Method

Expression (X)

[The symbols in the formula are as defined above. The isocoumarin compound (X) or a salt thereof represented by the formula (XXII)

(The symbols in the formula are as defined above.) A compound represented by the formula (XXI I) or a salt thereof and a compound represented by the formula (XXIII)

[In the formula, Z represents a leaving group (having the same meaning as L in the above.), And R ¹² represents a lower (C ^ ₆ ) alkyl group (eg, methyl, ethyl, propyl, butyl, tert-butyl group, etc.). Shown. With the compound (XXIII) or a salt thereof in the presence of a base, followed by dehydration and decarboxylation under acidic conditions to give the isocoumarin compound (X). A compound having a carboxyl group at the 3-position can be produced. If desired, the carboxylic acid can be esterified to produce a 3-position ester. Method M

Equation (X I I)

[The symbols in the formula are as defined above. The compound (XII) or a salt thereof represented by the formula (X)

[Wherein the symbols have the same meanings as described above. The compound (X) or a salt thereof is reacted with ammonia and then dehydrated under acidic conditions to produce the compound (X). Method N

Formula (XX I V)

Wherein the symbols are as defined above. The compound (IX) or a salt thereof represented by the formula (XXII)

[The symbols in the formula are as defined above. (XXI I) or a salt thereof or a reactive derivative thereof (for example, acid octylide, acid anhydride, active ester, ester, acid imidazolide, acid azide, etc.) by the formula (XV)

[Wherein the symbols have the same meanings as described above. Or a salt thereof (XV) or a salt thereof.

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

Equation (V I I)

[Wherein the symbols have the same meanings as described above. The compound (VII) or a salt thereof represented by the formula:

[The symbols in the formula are as defined above. The compound (II) or a salt thereof represented by the formula (I) or a salt thereof in the presence of a base is converted to a triflating reagent (for example, trifluoromethanesulfonic anhydride). Product, bis (trifluoromethanesulfonyl) aniline, etc.).

As the base used in this reaction, for example, alkali metal hydrides such as sodium hydride, potassium hydride, etc., for example, 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; eg 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 [2.2.2] octane, and 1,8-diazabicyclo [5.4.0] -7_indene Organic lithiums such as methyllithium, n-butyllithium, sec-butyllithium and tert-butyllithium, and lithium amides such as lithium diisopropylamide are preferably used.

This reaction is generally performed in a solvent, and 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, 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, N-dimethylacetamide; and nitriles, for example, acetonitrile and propionitrile Kind In addition, dimethyl sulfoxide, sulfolane, hexamethylphosphoramide, water and the like are used alone or as a mixed solvent. 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.

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.

In 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,

(For example, _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. as these substituents, 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.

The protecting group of the carboxyl group, for example, 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. As these substituents, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), formyl, (: ₆ alkyl-carbonyl (for example, acetyl, ethylcarbonyl, butylcarbonyl, etc.), a nitro group and the like are used. And the number of substituents is about 1 to 3.

As the protective group for hydroxy group, for example, 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. Examples of these substituents 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.

As 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. When 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; ■ For example, 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 · Nephritis, diabetic nephropathy, diabetic retinopathy, vascular endothelial dysfunction, cardiovascular diseases such as arteriosclerosis or restenosis after coronary angioplasty; rheumatoid arthritis, osteoarthritis, gout , Bronchitis, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, mucinous colitis, ulcerative colitis, Crohn's disease, gastritis, esophagitis, multiple sclerosis, eczema, dermatitis, hepatitis, thread Inflammatory diseases such as spherical nephritis; asthma, chronic obstructive pulmonary disease, allergic disease, obstructive pulmonary disease (C0PD), obesity, diabetes, diabetic retinopathy, diabetic neuropathy, psoriasis, cancer; Prion diseases such as Huntington's chorea, Parkinson's disease, epilepsy, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, diabetic neuropathy, peripheral neuropathy, Spine or spinal cord injury or cerebral cerebrovascular accident ((stroke, during, stroke, subarachnoid hemorrhage, cerebral hemorrhage, cerebral cerebral occlusion) Any neurodegenerative degenerative disease, such as embolism, etc., caused by nervous system neuropathy; vertebral spinal cord injury, cerebral blood vessels Disorders ((Stroke, stroke, subarachnoid hemorrhage, cerebral brain hemorrhage, cerebral cerebral embolism, etc.)), heart, heart, kidney Ischemic injury damage to organs of organs selected from kidney, liver, liver and brain and brain, ischemia ischemia re-reperfusion injury, Self-immune immuno-epidemic disease, flfl storage failure, rejection at the time of transplantation or transplantation What kind of preventive preventive treatment Zaima also Taha is Ruru Ki can be in for for with city and breaks improvement good agent agent of after cardiac myocardial infarction muscle infarction 塞予 prognosis good Ruruko it and Gaga. . In favor of, or chronic chronic or acute acute cardiac insufficiency, hypertrophic cardiomegaly, chronic chronic or acute ischemic ischemia Cardiomyopathy, cardiomyositis, chronic chronic joint arthritis, osteoarthritis of the joint arthritis, inflammatory inflammatory bowel disease, , Asthma, asthma, ischemia / reperfusion injury, visceral organ failure, cerebral apoplexy, cerebrovascular injury, visceral organ transplantation It is an agent for the prophylaxis and prevention of rejection and rejection after planting. .

When the compound of the present invention is appropriately applied to each of the above-mentioned diseases, it is necessary to use the compound which is commonly used for those diseases. It is possible that a drug or drug is used in combination with a curative therapy and, where appropriate, combined. . For example, in the case of heart failure, all of the following 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 ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, T, etc., Tetellurmisasarultattan, irrubebesasarutattan, epprolosasarutattan, Oorulmeme sasarultattan, huororarasarsarutattan, etc.)),]] 33 Receptor antagonist / antagonist (eg, for example, Proplobloburaranorololol, Nana dodrolol, Chitimololol, 22ppraradilolol, Bubninitorolol Lulu, イン, イン, カ, カ, カ, カ, ピ, ピ, ピ, ピ, カ, カ, カ, カ, カ, カ, カ, カ, ピ,,,,,,,,. Labebe Evening Lorolleul, Amomosulala Lorolleul, Arolotichtinolololurle, etc.)), CCaa antagonists (eg, Mamanini digipin,ル, ルルルな二, 二ソ二な二二ななななななななななななななななななななな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 ,, Toto

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, argatroban, gabexate, ozacrel sodium, ethyl icosapentate, beraprost sodium, alprosidil, pentoxifylline, thiso Nitrate, streptokinase, etc.), antiarrhythmic drugs (eg, quinidine, procarinamide, disopyramide, ajmaline, cibenzoline, lidocaine, diphenylhydantoin, mexiletine, propafenone, flecainide, pirgicinide, phenytoin, etc.チ Muchannel blocker; Power channel blocker such as Amiodapan; calcium channel blocker such as verapamil and diltiazem; PDE inhibitors (eg, amrinone, milrinone, olprinone hydrochloride); antidiabetic drugs (eg, Tolupumidamide, chlorpropamide, glicloviramide, acetohexamide, tolazamide, dalibenclamide, dalibuzole, etc .; sulfonylurea agents; metformin hydrochloride, buformin hydrochloride, etc .; It can be used in combination with anti-obesity drugs, such as α-darcosidase inhibitors such as ribose and acalcose, insulin-improving drugs such as pioglitazone and troglitazone; drugs for treating diabetic complications such as insulin, glucagon, and epalrestat) It can also be applied to patients who have undergone type heart prosthesis, implantable cardioverter-defibrillator, ventricular pacing, pachiseven surgery, heart transplantation or cell transplantation. For example, in the case of acute myocardial infarction or the prognosis of myocardial infarction, antithrombotic drugs (eg, heparin sodium, heparin calcium, フ -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, fluvastatin, cerivastatin, atorvastatin; fibrates such as synfibrate, clofibrate aluminum, clinofibrate, fenofibrate, etc.), It can be used in combination with cell transplantation and stem cell augmentation drugs (eg, G-CSF), stents, coronary revascularization such as PTCA and CABG. For example, in rheumatoid arthritis, 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, morphine hydrochloride, salicylic acid, atotopine, scopolamine, morphine, pethidine, reporuinol, ketoprofen, naproxen, oxymorphone or salts thereof), immunomodulators or immunosuppressants (Eg, methotrexate, cyclosporine, evening crolimus, dasperimus, azathioprine, anti-lymphocyte serum, dried sulfonated immunoglobulin, erythropoietin, colony stimulating factor, inulin leukin, interferon, etc.), steroids (eg, dexamethasone) , Hexestrol, Metimazol, Methazone, Beamethasone, Triamcinolone, Triamcinolone acetonide, Fluocinonide, Fluocinolone acetonide, Prednisolone, Methylprednisolone, Co acetate Lutisone, hydrocortisone, fluorometron, beclomethasone propionate, estriol, etc., p38 MAP kinase inhibitor, anti-TNF-α drug (eg, etanercebut, infliximab, D2E7, CDP-57 PASSTNF-, soluble TNF- α receptor, TNF-α binding protein, Anti-TNF-α antibody, etc., cyclooxygenase inhibitors (eg, salicylic acid derivatives such as celecoxib, oral fuecoxib, aspirin, ΜΚ-663, valdecoxib, SC-57666, thylakoxib, S-2474, diclofenac, indomethacin, Loxoprofen, etc.).

Further, when the compound of the present invention is 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. 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 κ 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. In addition, various organ regeneration methods such as heart regeneration, kidney regeneration, 塍 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. Examples of dosage forms for parenteral administration include injections, injections, drops, suppositories, etc. Is mentioned. In addition, 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. In addition, in the case of producing the above-mentioned dosage form, if necessary, 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.

For example, 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. In the case of powders and capsules, excipients, etc., in the case of syrups, sweeteners, etc., in the case of emulsions or suspensions, suspending agents, surfactants , An emulsifier and the like.

Examples of excipients include lactose, sucrose, dextrose, starch, sucrose, microcrystalline cell mouth And mannitol, sodium hydrogen carbonate, calcium phosphate, calcium sulfate, and the like.

Examples of 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. Examples of disintegrants include starch, calcium carbonate and the like.

Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, purified talc and the like.

Examples of sweetening agents include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like.

Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, polyoxyl stearate 40, and the like. Examples of suspending agents include gum arabic, sodium alginate, sodium propyloxymethyl cellulose, methyl cellulose, bentonite and the like. Examples of emulsifiers include gum arabic, tragacanth, gelatin, polysorbate

80 and the like.

When the compound (I) or a salt thereof is produced in the above-mentioned dosage form, if necessary, 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. An adult (body weight: about 60 kg), 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.

When 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). 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. Examples of the oily liquid include sesame oil and soybean oil, which may be used in combination with a solubilizing agent such as benzyl benzoate or benzyl alcohol. In addition, 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.) And preservatives (eg, benzyl alcohol, phenol, etc.). The prepared injection is usually filled into an ampoule. When the compound of the present invention and another drug are used in combination, 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. Simultaneous administration of the two preparations obtained by the formulation via the same administration route, (3) The time difference between the same administration route of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug, (4) Compound of the present invention and concomitant drug (5) Simultaneous administration by different administration routes of two preparations obtained by separately formulating the compound and (5) Different administration routes of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug (Eg, administration of the compound of the present invention—concomitant drug in the order of administration or administration in the reverse order). 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. For example, when the administration subject is a human, 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.

Elution in the column chromatography of the examples was performed under observation by TLC (Thin Layer Chromatography, thin layer chromatography). In the TLC observation, a 6 0 F _{2 5 4} or Fuji Shirishia Chemical Co. NH of 'Merck (Merck) manufactured as a TLC plate, the solvent used as an elution solvent in column chromatography as a developing solvent, A UV detector was adopted as the detection method. The column gel used was Kieselgel 60 (70 to 230 mesh) or Kieselgel 60 (230 to 400 mesh), also manufactured by Merck. NMR spectra were measured with a Varian Gemini 200 or Mercury 300 spectrometer using tetramethylsilane as an internal or external standard, and the chemical shifts were coupled as d values. Constants are given in Hz. The IR spectrum was measured with a Shimadzu FTIR-8200 spectrometer. In the examples, HPLC was measured under the following conditions to determine purity and the like.

Measuring equipment: Shimadzu LC-ΙΟΑνρ system (unless otherwise specified) or Agilent 1100 system ''

Column: CAPSEL PAK C18UG120 S-3 μτη, 2.0 X 50mm

Solvent: Solution A; water containing 0.1% trifluoroacetic acid,

Solution B; acetonitrile containing 0.1% trifluoroacetic acid

Gradient cycle: (Method A): 0.00 min (Solution A / B = 90/10), 2.00 min (Solution A / B = 5/95), 2.75 min (Solution A / B = 5/95) , 2.76 min (Solution A / B = 90/10), 3.45 min (Solution A / B = 90/10), or (Method B): 0.00 min (Solution A / B = 90/10),. 4.00 min (Solution A / B = 5/95), 5.50 min (Solution A / B = 5/95), 5.51 min (Solution A / B = 90/10), 8.00 min (Solution A / B) = 90/10)

Injection volume: 101, Flow rate: 0.5 ml / min Detection method: UV 220nm

In the examples, the mass spectrum (MS) was measured under the following conditions.

Measuring equipment: Micromass Platform II, Waters, War Yuichizu ZMD, or JEOL Ltd.〗 MS-AX505W

Ionization: Atmospheric Pressure Chemical Ionization (APCI), Electron Impact Ionization (Electron Spray Ionization: ESI), or Fast Atom Bombardment (FAB)

For purification of the compounds in Reference Examples and Examples, in addition to column chromatography, the following preparative HPLC device or medium pressure preparative LC device was used.

1) Preparative HP LC equipment: Gilson high-throughput purification system

Column: YMC Combiprep 0DS-A S-5 ^ m, 50 X 20

Solvent: Solution A; water containing 0.1% trifluoroacetic acid,

Solution B; acetonitrile containing 0.1% trifluoroacetic acid

Gradient cycle: 0.00 minutes (Solution A / B = 90/10), 1.20 minutes (Solution A / B = 90/10), 4.75 minutes (Solution A / B = 0/100), 7.30 minutes (A Solution / B solution = 0/100), 7.40 minutes (A / B solution = 90/10), 7.50 minutes (A / B solution = 90/10)

Flow rate: 25 ml / min, detection method: UV 220nm 2) Medium pressure preparative LC instrument: Moritex high-throughput purification system (purif 8) Column: Yamazen HI-FLASH ™ COLUMN (silica gel: 4 (^ 11, 60 people), 26 x 100 mm or 20 65 mm

Flow rate: 20 ml / min

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.

S singlelett singlet)

d doublet

t triplet

q quartet

dd double doublet

m multiplet

br broad

brs broad singlet

J Katsuf ¹ Jongbiki 'number (.coupling constant)

CDC1 ₃ double black hole Holm

DMSO-d _6- fold dimethyl sulfoxide

Ή-NMR proton nuclear magnetic resonance

WS C water-soluble carbodiimide

THF DMF dimethylformamide

DMSO dimethyl sulfoxide

T f trifluoromethanesulfo

Me methyl The sequence numbers in the sequence listing in the present specification indicate the following sequences.

[SEQ ID NO: 1] ' Primer: Shows the nucleotide sequence of TNK1-U.

[SEQ ID NO: 2]

2 shows the nucleotide sequence of primer 1-NK1-L.

[SEQ ID NO: 3]

The nucleotide sequence of primer MKK7-U is shown.

[SEQ ID NO: 4]

The nucleotide sequence of primer MKK7-L is shown.

[SEQ ID NO: 5]

The nucleotide sequence of primer CAM7-U is shown.

[SEQ ID NO: 6]

The nucleotide sequence of primer CAM7-L is shown.

[SEQ ID NO: 7]

The nucleotide sequence of primer cJUN-U is shown.

[SEQ ID NO: 8]

Shows the nucleotide sequence of primer c JI -L. Example 1

2-benzyl-6-cloth-4-hydroxy-1-oxo-1, 2-dihydroisoquinoline-3-force rubonic acid methyl ester

To a methanol solution (50 ml) of 4-chlorophthalic anhydride (12.1 g) was added sodium methoxide (3.6 g), and the mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, and the residue was separated with ethyl acetate and 1 N hydrochloric acid. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a mixture of 4-chlorophthalic acid and 2-methyl ester. A mixture of methyl bromoacetate (10.1 g), triethylamine (9.7 ml) and THF (70 ml) A ^ solution (351111) of benzylamine (7.1 _§ ) was added dropwise to the solution with stirring with stirring, and the mixture was stirred for 1 hour. After stirring at room temperature for another hour, the solvent was removed under reduced pressure. The residue was separated with ethyl acetate and water, and the organic layer was dried over magnesium sulfate and concentrated to dryness under reduced pressure. Then, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (16.5) was added to a mixture of this product, a mixture of 4-chlorophthalic acid 1- and 2-methyl esters (described above) and acetonitrile (70 ml). g) and 4-hydroxybenzotriazole-hydrate (11.2 g) were added, and the mixture was stirred at room temperature for 12 hours. After the solvent was removed under reduced pressure, the residue was diluted with ethyl acetate, liquid-separated with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried and concentrated to dryness. Next, this product was dissolved in methanol (100 ml), a 28% sodium methoxide / methanol solution (26 g) was added under stirring at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, the residue was separated with ethyl acetate and 1N hydrochloric acid, and the organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1), and recrystallized from hexane / ethyl acetate to give the title compound as yellow crystals (4.5 g).

_{Ή-NMR (CDC1 3) δ} : 3.81 (3H, s), 5.61 (2H, s), 7.00-7.10 (2H, m), 7.16-7.32 (3H, m), 7.66 (1H, dd, J = 1.8 , 8.4 Hz), 8.14 (1H, d, J = 1.8 Hz), 8.44 (1H, dd, J = 0.3, 8.4 Hz), 11.02 (1H, s). Example 1 (2)

2- (Benzo [1,3] dioxo-1-ylmethyl) -6-bromo-4-hydroxy-1-oxo-1, 2-dihydroisoquinoline-3-methylpyrunoic acid methyl ester

This compound was synthesized according to the method described in Example 1 using 4-bromofluoric anhydride and piperonylamine. Pale yellow crystals (29% yield).

_{Ή NMR (CDC1 3) δ 3.89} (3Η, s), 5.27 (2H, s), 5.91 (2H, s), 6.50-6.57 (2H, m), 6.71 (1H, dd, J = 1.8, 7.8 Hz), 7.82 (1H, dd, J = 1.8, 8.4 Hz), 8.32 (1H, d, J = 1.8 Hz), 8.35 (1H, d, J = 8.4 Hz), 10.96 (1H, s). MS (ESI +): 432.0 (M + H), 434.0. Example 1 (3)

6-methyl-2- (2,3-dihydrobenzofuran-5-ylmethyl) -4-hydroxy-1-oxo-1, 2-dihydroisoquinoline-3-carboxylic acid methyl ester

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%).

_{'Η NMR (CDC1 3) δ} : 3.11 (2Η, t, J = 8.4 Hz), 3.89 (3H, s), 4.52 (2H, t, J = 8.4 Hz), 5.55 (2H, s), 6.67 (1H , d, J = 7.8 Hz), 6.79-6.89 (2H, m), 7.66 (1H, dd, J = 2.1, 8.1 Hz), 8.13 (1H, dd, J = 0.6, 2.1 Hz), 8.44 (1H, d, J = 8.1 Hz), 10.90 (1H, s). Example 1 (4)

6-chloro- 4-hydroxy-2- (4-methoxycarbonylbenzyl) -1-methyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

This compound was synthesized according to the method shown in Example 1 using 4-chlorophthalic anhydride and 4- (methoxypropanol) benzylamine. Pale yellow crystals. Ή NMR (CDCI3) δ: 3.75 (3Η, s), 3.89 (3H, s), 5.59 (2H, s), 7.15 (2H, d, J = 8.7 Hz), 7.68 (1H, dd, J = 2.1, 8.7 Hz), 7.96 (2H, d, J-8.7 Hz), 8.17 (1H, d, J = 2.1 Hz), 8.43 (1H, d, J = 8.7 Hz), 11.9 (1H, s). (Five)

6-co mouth mouth 4-Hyd mouth xy-2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroxy mouth isoquinoline-3-carboxylic acid methyl ester

This compound was synthesized according to the method shown in Example 1 using 4-mouth phthalic anhydride and 4_ (mesulfonyl) benzylamine. Yellow crystals.

¾ image _{R (CDC1 3) δ 3.03 (} 3Η, s), 3.76 (3H, s), 5.55 (2H, s), 7.32 (2H, d, J = 8.7 Hz), 7.69 (1H, dd, J = 2.1 , 8.7 Hz), 7.88 (2H, d, J = 8.7 Hz), 8.19 (1H, d, 2.1 Hz), 8.40 (1H, d, J-8.7 Hz), 11.29 (1H, s). 6)

2-Benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

To a DMF solution (45 ml) of 2-benzyl-6-cloth-4-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (4.5 g) was added hydrogen under stirring at 0 ° C. Sodium bromide (630 mg) was added, and the mixture was stirred for 30 minutes. Next, N-phenyltrifluoromethanesulfonimide (5.6 g) was added, and the mixture was further stirred at room temperature for 3 hours. did. The residue was separated with ethyl acetate and water, the organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 4/1 to 1/1) to give the title compound (3.0 g) as colorless crystals.

Ή one _{NMR (CDC1 3) δ: 3.69} (3Η, s), 5.51 (2H, s), 7.14-7.19 (2H, m), 7.23-7.35 (3H, m), 7.64 (1H, dd, J = 2.1 , 8.4 Hz), 7.76 (1H, d, J = 2.1 Hz), 8.46 (1H, d, J = 8.4 Hz). Example 1 (7)

6-Hokuguchi- 2- (2,3-Dihydrobenzofuran-5-ylmethyl) -Toxo-4-trifluoromethyl sulfonyloxy-1,2-dihydroisoquinoline-3-Methylester

According to the method shown in Example 1 (6), 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). _{¾ NMR (CDC1 3) δ:} 3.14 (2H, t, / = 9.0 Hz), 3.78 (3H, s), 4.54 (2H, t, / = 9.0 Hz), 5.42 (2H, s), 6.69 (1H, d, / = 8.4 Hz), 6.92 (1H, dd, / = 2.1, 8.4 Hz), 7.02 (1H, s), 7.63 (1H, dd, / = 2.1, 8.7 Hz), 7.75 (1H, d, / = 2.1 Hz), 8.45 (1H, d, / = 8.7 Hz). Example 1 (8)

6-chloro-2- (4-methoxycarbonylbenzyl) -toxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

This compound was prepared according to the method described in Example 1 (6), methyl 6-chloro-4-hydroxy-2- (4-methoxycarbonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylate, methyl ester Was synthesized using Colorless crystals.

_{Ή NMR (CDC1 3) δ:} 3.71 (3H, s), 3.90 (3H, s), 5.54 (2H, s), 7.23 (2H, d, J = 8.4 Hz), 7.65 (1H, d, J = 8.4 Hz), 7.78 (1H, s), 7.98 (2H, d, J-8. Hz), 8.45 (1H, d, J = 8.4 Hz). Example 1 (9)

6-Chloro-2- (4-methansulfonylbenzyl) -toxo _4_trifluoromethylsulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

This compound was prepared according to the method shown in Example 1 (6), 6-chloro-4-hydroxy-2- (4-methanesulfonylpentyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester Was synthesized using Colorless crystals.

Marauder R (CDC1 ₃ ) δ: 3.02 (3Η, s), 3.79 (3H, s), 5.49 (2H, s), 7.40 (2H, d, 8.4 Hz), 7.65 (1H, dd, J = 1.8, 8.4) Hz), 7.79 (1H, d, J = 1.8 Hz), 7.89 (2H, d, J = 8.4 Hz), 8.42 (1H, d, J = 8.4 Hz). Example 1 (10)

4-Amino-2- (4-methanesulfonylbenzyl) -toxo-1,2-dihydroisoquinolin-3-carboxylic acid methyl ester

To a mixture of methyl bromoacetate (2.47 ml), triethylamine (8.65 ml) and THF (46 ml) was added dropwise a THF solution (46 ml) of 4- (methanesulfonyl) benzylamine (4.6 g) while stirring at 0 ° C. Stirred for 1 hour. After stirring at room temperature for another 3 hours, the solvent was removed under reduced pressure. The residue was separated with ethyl acetate and water, and the organic layer was dried over magnesium sulfate and concentrated to dryness under reduced pressure. Then, a mixture of this product, 2-cyanobenzoic acid (2.63 g) and acetonitrile (46 ml) was added to the mixture of tetraethyl-3- (3-dimethylaminopropyl) rubodiimide hydrochloride (5.14 g) and 4-hydroxybenzoic acid. Triazole-hydrate (3.56 g) was added, and the mixture was stirred at room temperature for 12 hours. After the solvent was removed under reduced pressure, the residue was diluted with ethyl acetate, liquid-separated with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried and concentrated to dryness. Next, 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.

¾ image _{R (CDC1 3) δ 3.03 (} 3H, s), 3.66 (3H, s), 5.43 (2H, s), 5.67 (2H, s), 7.36 (2H, d, 8.1 Hz), 7.68-7.88 ( 3H, m), 7.86 (2H, d, 8.1 Hz), 8.54 (1H, d, J-8.4 Hz). MS (ESI +): 387 (M + H). Example 1 (1 1)

2- (Benzo [1,3] dioxole-5-ylmethyl) -6-bromo-4-butoxy-1-oxo-1,2-dihydroisoquinoline-3-hydroxyluponic acid methyl ester

2- (Benzo [1,3] dioxol-5-ylmethyl) -6-bromo-4-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (200 mg), triphenyl To a THF solution (4 ml) of phosphine (160 rag) and n-butanol (55) was added a getyl azodicarboxylate / toluene solution (40%, 2701) under stirring at room temperature, and the mixture was stirred at room temperature for 1 hour. . After completion of the reaction, the reaction solution was concentrated, and the residue was purified by preparative HPLC to give the title compound (72 mg) as colorless crystals. ¾ noodles _{R (CDC1 3) δ: 0.99} (3Η, ί, J = 7.5 Hz), 1.43-1.58 (2H, m), 1.69-1.81 (2H, in), 3.80 (3H, s), 3.92 (2H, d, J = 6.3 Hz), 5.23 (2H, s), 5.92 (2H, s), 6.66-6.75 (3H, m), 7.68 (1H, m), 7.89 (1H, d, J = 1.8 Hz), 8.33 (1H, d, J = 8.7 Hz). MS (ESI +): 488.0 (M + H),

490.0. The compound of 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

Example 2

2- (benzo [1,3] dioxo-1-ylmethyl) -4-benzyloxy-6-bromo-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Colorless powder (67% yield). ¾ negation _{R (CDC1 3) δ: 3.69} (3H, s), 4.98 (2H, s), 5.25 (2H, s), 5.92 (2H, s), 6.66-6.75 (3H, m), 7.33-7.46 ( 5H, m), 7.69 (1H, dd, J = 2.1, 8.4 Hz), 7.91 (1H, d, J = 2.1 Hz), 8.34 (1H, d, 8.4 Hz). MS (ESH): 522.1 (M + H), 524.1. Example 3

2- (benzo [1,3] dioxol-5-ylmethyl) -6-promo-1-oxo-4- (pyridine-4-ylmethoxy) -1,2, -dihydroisoquinoline-3-carboxylic acid methyl ester trifluoroacetic acid salt

Beige powder (42% yield). _{¾ NMR (CDC1 3) δ:} 3.67 (3Η, s), 5.20 (2H, s), 5.25 (2H, s), 5.92 (2H, s), 6.64-6.76 (3H, m), 7.70-7.80 (4H , M), 8.37 (1H, d, J = 8.7 Hz), 8.84 (1H, d, J = 6.6 Hz). MS (ESI +): 523.1 (M + H), 525.1.

2- (Benzo [1,3] dioxol-5-ylmethyl) -4- (biphenyl-4-ylmethoxy) -6-bromo-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Yellow crystals (41% yield). _{Ή NMR (CDC1 3) <5} : 3.73 (3H, s), 5.02 (2H, s), 5.26 (2H; s), 5.92 (2H, s), 6.67-6.77 (3H, m), 7.33-7.52 ( 5H, m), 7.58-7.67 (4H, m) _: 7.69 (1H, dd, J = 1.8, 8.4 Hz), 7.93 (1H, d, J = 1.8 Hz), 8.35 (1H, d, J-8.4 Hz). MS (ESI +): 598.1 (M + H), 600.1. Example 5

2- (benzo [1,3] dioxol-5-ylmethyl) -6-bromo-4-cyclohexylmethoxy-1-methyl-1,1-oxo-1,2-dihydroisoquinoline-3-carboxylate

Pale yellow oil (44% yield). ¾ 丽 R (CDC1 ₃ ) δ 1.02-1.42 (5Η, m), 1.66-2.18 (6H, m), 3.71 (2H, d, J = 6.0 Hz), 3.79 (3H, s), 5.23 (2H, s ), 5.92 (2H, s), 6.65-6.75 (3H, m), 7.68 (1H, dd, J = 1.8, 8.7 Hz), 7.89 (1H, d, 1.8 Hz), 8.33 (1H, d, J = 8.7 Hz). MS (ESI +): 528.1 (MIH), 530.1. Example 6

2- (Benzo [1,3] dioxo-5-ylmethyl) -6-butamo-4- (furan-2-ylmethoxy) -toxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester Ester

Pale yellow crystals (42% yield). Ή NMR (CDC1 ₃ ) δ 3.81 (3Η, m), 4.91 (2H, s), 5.25 (2H, s), 5.92 (2H, s), 6.35-6.39 (2H, m), 6.66-6.75 (3H, m), 7.47 (1H, m), 7.68 (1H, dd, J = 2.1, 8.7 Hz), 7.93 (1H, d, J = 2.1 Hz), 8.32 (1H, d, J = 8.7 Hz) .MS ( ESI +): 512.0, (M + H), 514.0. Methyl 2- (benzo [1,3] dioxo-5-ylmethyl) -6-butamo-4- (4-methoxybenzyloxy) -1-oxo-1,2-dihydroisoquinoline-3-carboxylate ester

Colorless crystals (53% yield). 'Η NMR (CDC1 ₃ ) δ 3.73 (3Η, s), 3.83 (3H, s), 4.90 (2H, s), 5.25 (2H, s), 5.92 (2H, s), 6.66-6.75 (3H, m ), 6.93 (2H, d, J = 8.7 Hz), 7.32 (2H, d, J = 8.7 Hz), 7.68 (1H, dd, J = 1.8, 8.4 Hz), 7.89 (1H, d, J = 1.8 Hz) ), 8.33 (1H, d, J = 8.4 Hz). MS (ESI +): 552.0 (M + H), 554.0. Example 8

2- (Benzo [1,3] dioxol-5-ylmethyl) -6-bromo-4- (2,2-diphenylethoxy) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Pale yellow crystals (12% yield). _{Ή NMR (CDC1 3) δ 3.58} (3Η, s), 4.40-4.50 (3H, m), 5.20 (2H, s), 5.91 (2H, s), 6.63-6.74 (3H, m), 7.22-7.42 ( 11H, m), 7.63 (1H, dd, J = 2.1, 8.7 Hz), 8.28 (1H, d, J = 8.7 Hz). MS (ESI +): 612.1 (M + H), 614.1.

2- (Benzo [1,3] dioxole-5-ylmethyl) -6-butamo-4- (2-methoxyethoxy) -toxo-1,2,2-dihydroisoquinoline-3-methylruponic acid methyl ester Br ~

MeC ^

Pale yellow crystals (44% yield). _{¾ NMR (CDC1 3) δ:} 3.47 (3Η, s), 3.64-3.70 (2H, m), 3,81 (3H, s), 3.99-4.05 (2H, m), 5.24 (2H, s), 5.92 (2H, s), 6.66-6.75 (3H, ni), 7.68 (1H, dd, J = 1.8, 8.7 Hz), 8.15 (1H, d, J = 1.8 Hz), 8.32 (1H, d, J = 8.7 Hz). MS (ESI: 490.0 (M + H), 492.0. Example 10

2_ (Benzo [1,3] dioxol-5-ylmethyl) -6-bromo-1-oxo-4-phenethyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Colorless crystals (53% yield). _{¾ NMR (CDC1 3) δ:} 3.06 (2Η, t, J = 6.3 Hz), 3.59 (3H, s), 4.12 (2H, t, J = 6.3 Hz), 5.20 (2H, s), 5.91 (2H, s), 6.63-6.73 (3H, m), 7.23-7.39 (5H, m), 7.57 (1H, d, J = 2.1 Hz), 7.64 (1H, dd, J = 2.1, 8.4 Hz), 8.29 (1H , d, J = 8.4 Hz). MS (ESI +): 536.1 (M + H), 538.1.

2- (benzo [1,3] dioxo-l-5-ylmethyl) -6-bromo-4- [2- (4-dimethylaminophenyl) ethoxy] -1-oxo-1,2-dihydroisoquinoline-3- Carboxylic acid methyl ester trifluoroacetate

Brown oil (59%). _{'Η NMR (CDC1 3) δ} 3.10 (2Η, t, J = 6.0 Hz), 3.23 (6H, s), 3.68 (3H, s), 4.13 (2H, t, J = 6.0 Hz), 5.20 (2H, s), 5.92 (2H, s), 6.63-6.75 (3H, m), 7.39 (1H, d, J = 1.8 Hz), 7.48 (2H, d, J = 8.4 Hz), 7.57 (2H, d, J = 8.4 Hz), 7.65 (1H, dd, J = 1.8, 8.4 Hz), 8.30 (1H, d, J = 8. Hz). MS (ESI +): 579.1 (M + H), 581.1.

2- (Benzo [1,3] dioxole-5-ylmethyl) -6-bromo-4-cyclohexyloxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Pale yellow crystals (45% yield). _{Ή NMR (CDC1 3) δ 1.12-1.62} (6Η, m), 1.70-1.85 (2H, m), 1.90-2.03 (2H, m), 3.77 (3H, s), 3.84 (1H, m), 5.27 ( 2H, s), 5.91 (2H, s), 6.62-6.74 (3H, m), 7.68 (1H, dd, J = 1.8, 8.7 Hz), 7.95 (1H, d, J-1.8 Hz), 8.33 (1H , d, J = 8.7 Hz). MS (ESI +): 514.1 (M + H), 516.1. The compound of Examples 13-15 was prepared according to the method described in Example 1 (11), using 2-benzyl-6. -Cross mouth- Synthesized using methyl 4-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylate and the corresponding alcohol. Example 13 2-Benzyl-6-co-mouth-toxo-4--4-phenethyloxy-1,--3 -Rubonic acid methyl ester

Yellow oil (30% yield). MS (ESI +): 448.1 (M + H), 450.1.

2-Benzyl-6-cyclohexyl-toxo-4- (pyridine-4-ylmethoxy) -1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Yellow crystals (17% yield). 'H MR (CDC1 ₃ ) 6: 3.57 (3H, s), 5.01 (2H, s), 5.37 (2H, s), 7.16-7.37 (7H, ra), 7.56 (1H, dd, J-2.2, 8.8 Hz), 7.68 (1H, d, J = 2.2 Hz), 8.46 (1H, d, J = 8.8 Hz), 8.65 (2H, d, J = 6.0 Hz). MS (ESI +): 435.1 (M + H) , 437.1. Example 15

2-benzyl-6-chloro-4- (2-methoxyethoxy) -toxo-1, 2-dihydroisoquinoline-3-carboxylic acid methyl ester

Yellow crystals (10% yield). _{'HNMR (CDC1 3) δ:} 3.46 (3Η, s), 3.63-3.70 (2H, m), 3.72 (3H, s), 4.04-4.10 (2H, m), 5.35 (2H, m), 7.17-7.33 (5H, m), 7.53 (1H, dd J = 2.1, 8.7 Hz), 7.97 (1H, dd, J = 0.6, 2.1 Hz), 8.41 (1H, dd, J = 0.6

MS (ESI +): 402.1 (M + H), 404.1. Example 16

6-Cupro-2- (2,3-dihydrobenzofuran-5-ylmethyl) -toxo-4- (Thiphen-3-yl) -1, 2-dihydroisoquinoline-3-methylpropanoic acid methyl ester

6-Port mouth 2- (2,3-dihydrobenzofuran-5-ylmethyl) -1-oxo-4- 4-trifluoromethanesulfonyloxy-1,2- in an eggplant flask with Jim port Dihydridoisoquinoline-3-carboxylic acid methyl ester (175 nig), sodium carbonate (96 mg), 3-thiophenboronic acid (52 mg), tetrakis (triphenylphosphine) palladium (0) (12 mg), toluene (2.0 ml) A mixture of water (0.4 ml) and ethanol (0.4 ml) was degassed by a vacuum line, replaced by argon, and stirred at 80 ° C. for 12 hours. After cooling the reaction solution, the reaction solution was separated with water and ethyl ethyl sulfate, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give the title compound (120 mg) as a colorless powder. _{'Η NMR (CDC1 3) 6} : 3.14 (2H, t, J = 8.7 Hz), 3.71 (3H, s), 4.53 (2H, t, J = 8.7 Hz), 6.67 (1H, d, J = 8.1 Hz ), 7.00 (1H, dd, J = 1.8, 8.1 Hz), 7.07 (1H, dd, J = 1.5, 4.8 Hz), 7.26-7.33 (4H, m), 7.28 (1H, m), 7.44 (1H, dd, J = 3.0, 4.8 Hz), 7.50 (1H, dd, J-2.1, 8.4 Hz), 8.47 (1H, dd, J = 0.3, 8.4 Hz). MS (ESI I): 452.1 (M + H) , 454.1. Example 17

6-chloro-2- (2,3-dihydrobenzofuran-5-ylmethyl) -1-oxo-4- (pyridine -4- -yl)-1,2-dihydroisoquinoline-3-methylpropanoic acid methyl ester

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). _{^ NMR (CDC1 3) δ:} 3.15 (2H, t, J = 8.7 Hz), 3.30 (3H, s), 4.54 (2H, t, J = 8.7 Hz), 5.35 (2H, s), 6.68 (1H, d, J = 8.1 Hz), 6.98 (1H, dd, J = 1.8, 8.1 Hz), 7.12 (1H, d, J = 1.8 Hz), 7.14 (1H, m), 7.24 (2H, d, J = 6.0 Hz), 7.54 (1H, dd, J = 2.1, 9.0 Hz), 8.51 (1H, d, J = 9.0 Hz), 8.72 (2H, d, J = 6.0 Hz). MS (ESH): 447.1 r, 49.0 Example 1 8

2-benzyl-2-methyl-4-oxo-4- (pyridine-3-yl) -1,2-dihydroisoquinolin-3-carboxylic acid methyl ester

According to the method shown in Example 16, 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). 'Thigh R (CDC1 ₃ ) (5: 3.24 (3H, s), 5.44 (2H, s), 7.09 (1H, m), 7.21-7.34 (5H, m), 7.41 (1H, m), 7.54 (1H , Dd, J = 2.1, 8.4 Hz), 7.64 (1H, dt, J = 2.1, 7.8 Hz), 8.51 (1H, dd, J = 0.3, 8.4 Hz), 8.55 (1H, d, J-1.5 Hz) , 8.69 (1H, dd, J = 1.5, 4.8 Hz). MS (ESI +): 405.0 (M + H), 407.0. Example 19

2-benzyl-6-chloro-toxo-4- (pyridine-4-yl) -1,2-dihydroisoquinolin-3-carboxylic acid methyl ester

This compound was prepared according to the method described in Example 16 to give methyl 2-benzyl-6-oct-1-ol-4-oxo-4-trifluorosulfonyloxy-1,2-dihydroisoquinoline-3-carboxylate and 4-carboxylic acid. It was synthesized using pyridylporonic acid. Yellow powder (23% yield). _{Ή NMR (CDC1 3) 6 3.22} (3H, s), 5.44 (2H, s), 7.12 (1H, d, J = 1.8 Hz), 7.20-7.34 (7H, m), 7.54 (1H, m), 8.51 (1H, d, J = 8.4 Hz), 8.72 (2H, d, J = 6.0 Hz). MS (ESI +): 405.0 (M + H), 407.0 Example 20

6-Chloro-4- (5-hydroxymethylthiophen-2-yl) -2- (4-methoxycarbonylbenzyl)-1-oxo-1,2, -dihydroisoquinoline-3 -Hydronic acid methyl ester

6-cout mouth-2- (4-methoxycarbonyl benzyl) -1 -oxo-4-trifluoromethyl sulfonyloxy-1,2,2-dihydroisoquinoline-3- in a eggplant flask with a Dimroth Carboxylic acid methyl ester (180 mg), sodium carbonate (71 mg), 5-formyl-2-thiophenboronic acid (63 mg), tetrakis (triphenylphosphine) palladium (0) (19 mg), toluene (2.0 ml ), Water (0.4 ml) and ethanol (0.4 ml) were degassed by a vacuum line, replaced by argon, and stirred at 80 ° C for 12 hours. After cooling the reaction solution, the reaction solution was separated with water and ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 4/1 to 1/1) to give a yellow oily 6-oct-4- (5-formylthiophen-2-ene). ) -2- (4-Methoxycarbenylpentyl) -toxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (90 mg) was obtained.

Next, sodium borohydride (3.4 mg) was added to a methanol (1.0 ml) solution of the product under stirring (TC), and the mixture was stirred for 1 hour. The reaction solution was concentrated, and the residue was diluted with 1N hydrochloric acid and acetic acid. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 4/1 to 1/1) to give a colorless powder. The title compound (50 mg) was obtained.

'H Keio _{R (CDC1 3) δ 2.08 (} 1H, t, J = 6.0 Hz), 3.73 (3H, s), 3.89 (3H, s), 4.87 (2H, d, J = 6.0 Hz), 5.41 (2H , s), 6.90 (1H, d, J = 3.3 Hz), 6.99 (1H, d, J = 3.3 Hz), 7.31 (2H, d, J = 8.1 Hz), 7.47 (1H, d, J = 2.1 Hz) ), 7.52 (1H, dd, J = 2.1, 8.7 Hz), 7.98 (2H, d, J = 8.1 Hz), 8.44 (1H, d, J = 8.7 Hz) .MS (ESI +): 498 (M + H ), 500. Example 21

6-Mouth D-4- (2-Hydroxymethylthiophene-3-yl) -2- (4-methoxycarbonylbenzyl) -Toxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

According to the method shown in Example 20, 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). ¾丽_{R (CDC1 3) δ 2.35 (} 1H, t, J = 6.3 Hz), 3.34 (3H, s), 3.90 (3H, s), 4.53 (2H, d, J = 6.3 Hz), 5.26 (1H, d, J = 15.6 Hz), 5.53 (1H, d, J = 15.6 Hz), 6.88 (1H, d, J = 5.1 Hz), 7.10 (1H, d, J = 1.8 Hz), 7.30 (2H , d, J = 8.7 Hz), 7.40 (1H, d, J = 5.1 Hz), 7.53 (1H, dd, J = 1.8, 8.4 Hz), 7.98 (2H, d, J = 8.7 Hz), 8.46 (1H , d, J = 8.4 Hz). MS (ESI +): 498 (M + H), 500. Example 22

2- (4-Hydroxybenzyl) -6-chloro-4- (5-hydroxymethylthiophen-2-yl) -toxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

6-Chloro-4- (5-hydroxymethylthiophen-2-yl) -2- (4-methoxycarbodirubenzyl)-1-oxo-1,2-dihydroisoquinoline-3-methyl methyl sulfonate To a solution of the ester (50 mg) in methanol (4.0 ml) was added 1N sodium hydroxide (250-1), and the mixture was stirred at room temperature for 1 hour. The reaction solution was adjusted to pH 3 with 1N hydrochloric acid, and then concentrated under reduced pressure. After separating the residue with water and ethyl acetate, the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 10/1) to give the title compound (44 mg) as yellow crystals. _{¾ NMR (CDC1 3) δ:} 3.40 (3Η, s), 4.88 (2H, s), 5.41 (2H, s), 6.92 (1H, d, J = 3.3 Hz), 7.00 (1H, dt, J - 0.6 , 3.3 Hz), 7.35 (2H, d, J = 8.7 Hz), 7.47-7.56 (2H, m), 8.04 (2H, d, J = 8.7 Hz), 8.45 (1H, dd, J = 0.6, 8.4 Hz MS (ESI +): 484 (M + H), 486. 'Example 23

2-(4-Hydroxybenzyl) -6-cook mouth -4- (2-Hydroxymethylthiophen-3-yl) -toxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

According to the method shown in Example 22, the present compound was prepared as follows: 6-cloth-4- (2-hydroxymethylthiophen-3-yl) -2- (4-methoxycarbonyldipentyl) -1-oxo-1,2 -Dihydrido Synthesis was performed using isoquinoline-3-carboxylic acid methyl ester. Light yellow powder (100% yield). ^{_{l H NMR (CDC1 3) δ}} 3.36 (3Η, s), 4.55 (2H, s), 5.26 (1H, d, J = 15.6 Hz), 5.53 (1H, d, J = 15.6 Hz), 6.89 (1H, d, J = 5.1 Hz), 7.10 (1H, d, J = 1.8 Hz), 7.34 (2H, d, J = 8.4 Hz), 7.41 (1H, d, J = 5.1 Hz), 7.54 (1H, dd, J = 1.8, 8.4 Hz), 8.04 (2H, d, J = 8.4 Hz), 8.47 (1H, d, J-8.4 Hz). MS (ESI +): 484 (M + H), 486. Example 24

2- (4-hydroxypropyl) -6-chloro- 4- (3-hydroxymethylthiophen-2-yl) -toxo-1, 2-dihydroisoquinoline-3-hydroxypropyl methyl ester

6-Chloro-2- (4-methoxycarbonylbenzyl) -1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid in an eggplant flask with a Dimroth Methyl ester (180 mg), sodium carbonate (71 mg), 3-formyl-2-thiophenboronic acid (63 mg), tetrakis (triphenylphosphine) palladium (0) (19 mg), toluene (2.0 ml), A mixture of water (0.4 ml) and ethanol (0.4 ml) was degassed by a vacuum line, replaced with argon, and stirred at 80 ° C for 12 hours. After cooling the reaction mixture, the reaction mixture was separated with water and ethyl acetate. After drying with a shim, the mixture was concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 4/1 to 1/1) to give a yellow oil of 6-oct-4--4- (3-formylthiophen-2-yl). )-2- (4-Methoxycarbonylpyndyl) -toxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (40 mg) was obtained.

Sodium borohydride (3 mg) was added to a methanol (1.0 ml) solution of this product under stirring at 0 ° C, and the mixture was stirred for 1 hour. The reaction solution was concentrated, the residue was partitioned between 1N hydrochloric acid and ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 4/1 to 1/1) to give a colorless powder of 6-hydroxy-4- (3-hydroxymethylthiophene-2-y). ) -Ϊ- (4-Methoxycarbonyl pendyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (22 mg) was obtained. Next, 1N sodium hydroxide (1101) was added to a methanol (2.0 ml) solution of this product, and the mixture was stirred at room temperature for 1 hour. The reaction solution was adjusted to pH 3 with 1N hydrochloric acid, and then concentrated under reduced pressure. After partitioning the residue with water and ethyl acetate, the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 10/1) to give the title compound (17 mg) as pale yellow crystals. '

_{¾ NMR (CDC1 3) δ:} 3.42 (3Η, s), 4.35 (1H, d, J = 12.6 Hz), 4.43 (1H, d, J = 12.6 Hz), 5.30 (1H, d, J = 16.2 Hz) , 5.46 (1H, d, J = 16.2 Hz), 7.18 (1H, m), 7.24 (1H, d 'J = 5.1 Hz), 7.34 (2H, d, J = 8.4 Hz), 7.47 (1H, d, J = 5.1 Hz), 7.53 (1H, dd, J = 1.8, 8.4 Hz), 8.05 (2H, d, J = 8.4 Hz), 8.45 (1H, d, J = 8.4 Hz). MS (ESI +): 484 (M + H), 486. Example 25

6-Couguchi-4-[3- (1-Hydroxyethyl) thiophene-2-yl] -2- (4-methylsulfonyl pentyl) -toxo-1,2-dihydroisoquinoline-3-carboxyl Acid methyl ester

6-chloro-2- (4-methanesulfonylbenzyl)-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline- in an eggplant flask with a gym port 3-Carboxylic acid methyl ester (2.0 g), sodium carbonate (765 mg), 3-formyl-2-thiophenepoic acid (675 nig), tetrakis (triphenylphosphine) palladium (0) (208 mg), toluene A mixture of (20 ml), water (4 ml) and ethanol (4 ml) was degassed by a vacuum line, replaced with argon, and stirred at 80 for 12 hours. After cooling the reaction solution, the reaction solution was separated with water and ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 4/1 to 1/1) to give 6-chloro-4- (3-formylthiophen-2-yl) as a pale yellow powder. 2- (4-Methanesulfonylpentyl) -toxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (140 nig) was obtained. _{¾ NMR (CDC1 3) δ:} 3.03 (3Η, s), 3.42 (3H, s), 5.35 (1H, d, J = 15.6 Hz), 5.42 (1H, d, J = 15.6 Hz), 7.18 (1H, d, J = 2.1 Hz), 7.47 (2H, d, J = 8.1 Hz), 7.50-7.62 (3H, m), 7.90 (2H, d, J = 8.1 Hz), 8.44 (1H, dd, J = 0.6 , 8.7 Hz), 9.62 (1H, s).

To a THF solution (2 ml) of this product (62 mg) was added a THF solution of methylmagnesium bromide (lmol / 1: 240) at room temperature, and the mixture was stirred for 1 hour. After completion of the reaction, 1N hydrochloric acid was added to the reaction solution, and the mixture was separated and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 1/1 to 1/4) to give the title compound (22 mg) as a pale yellow powder.

_{Ή NMR (CDC1 3) (5} : 1.40 (3H, d, J = 6.6 Hz), 2.52 (1H, s), 3.03 (3H, s), 3.49 (3H, s), 4.59 (1H, m), 5.20 (1H, d, J = 16.2 Hz), 5.44 (1H, d, J = 16.2 Hz), 7.15 (1H, d, J-2.1 Hz), 7.27 (1H, d, J = 5.4 Hz), 7.40-7.50 (3H, m), 7.53 (1H, dd, J = 2.1, 8.7 Hz), 7.91 (2H, d, J = 8.4 Hz), 8.41 (1H, d, J = 8.7 Hz). MS (ESI +): 514 (MH ₂ 0), 516. Example 26

6-Couguchi-4- 4- [3- [Hydroxy (phenyl) methyl] thiophen-2-yl]-2- (4-methylsulfonylpentyl) -toxo-1,2-dihydroisoquinoline-3 -Carboxylic acid methyl ester

According to the method shown in 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%).

_{¾ NMR (CDC1 3) δ:} 2.91 (1H, d, J = 2.6 Hz), 3.04 (3H, s), 3.55 (3H, s), 5.25 (1H, d, had 16.0 Hz), 5.48 (1H, d , J = 16.0 Hz), 5.56 (1H, d, J-2.6 Hz), 7.05-7.11 (2H, m), 7.12-7.27 (5H, m), 7.42 (1H, d, J = 5.8 Hz), 7.46 -7.56 (3H, m), 7.93 (2H, d, J = 8.8 Hz), 8.40 (1H, d, J = 8.8 Hz). MS (ESI +): 576 mm, 578. Example 27

6-chloro-4- (5-formylthiophen-2-yl) -2- (4-methanesulfonylbenzyl) -toxo_1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

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).

_{Ή NMR (CDC1 3) δ 3.02} (3Η, s), 3.44 (3H, s), 5.39 (2H, s), 7.17 (1H, d, J = 3.6 Hz), 7.36 (1H, d, J = 1.5 Hz ), 7.47 (2H, d, J = 8.4 Hz), 7.56 (1H, dd, J = 2.1, 8.7 Hz), 7.80 (1H, d, J = 2.1 Hz), 7.89 (2H, d, J = 8.4 Hz) ), 8.44 (1H, d, J = 8.7 Hz), 9.95 (1H, s). MS (ESI +): 516 (M + H), 518. Example 28

6-Cupro-4- [5- (1-Hydroxyquishethyl) thiophen-2-yl] -2- (4-methylsulfonylbenzyl) -toxo-1,2-dihydroisoquinoline-3-carboxyl Acid methyl ester

6-cout mouth-4- (5-formylthiophene-2-yl) -2- (4-methylsulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester 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. After completion of the reaction, 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. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 1/1 to 1/4) to give the title compound (59 mg) as colorless crystals. _{Ή NMR (CDC1 3) δ 1.65} (3Η, d, J = 6.3 Hz), 2.05 (1H, d, J = 4.5 Hz), 3.02 (3H, s), 3.44 (3H, s), 5.16 (1H, m ), 5.37 (2H, s), 6.93 (1H, d, J = 3.6 Hz), 6.96 (1H, d, J = 3.6 Hz), 7.4-7.56 (4H, m), 7.88 (2H, d, J = 8.7 Hz), 8.41 (1H, d, J = 8.4 Hz). MS (ESH): 532 (M + H), Example 29

4- (5-carboxythiophen-2-yl) -6-chloro-2- (4-methanesulfonylbenzyl) -toxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

6-chloro- 4- (5-formylthiophen-2-yl) -2- (4-methanesulfonylbenzyl)-1-oxo-1,2-dihydroisoquinoline-3- 3-fluorocarboxylic acid methyl ester (90 mg), sodium dihydrogen phosphate (21 mg), 2-methyl-2-butene (83), THF (2.0 ml), butanol (1.0 ml) and water (2.0 ml) at 0 ° C. Under stirring, sodium chlorite (59 mg) was added, and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure, and the residue was separated with 1N hydrochloric acid and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was washed with ethyl acetate and dried to give the title compound (53 mg) as a pale yellow powder. Thigh R (CDC1 ₃ ) δ 3.03 ( ₃ (, s), 3.46 (3H, s), 5.39 (2H, s), 7.09, (1H, d, J = 3.6 Hz), 7.39 (1H, d, J = 2.1 Hz), 7.47 (2H, d, 9.0 Hz), 7.56 (1H, dd, J = 2.1, 8.7 Hz), 7.86-7.94 (3H, m), 8.44 (1H, d, J = 8.1 Hz). MS (ESI +): 532 (M + H), 534. Example 30

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). 'Η NMR (CDC1 ₃ ) δ 3.02 (3Η, s), 3.41 (3H, s), 5.38 (2H, s), 7.03-7.15 (2H, m), 7.42-7.55 (5H, m), 7.89 (2H , d, J = 8.1 Hz), 8.41 (1H, d, J = 8.4 Hz). MS (ESI +): 488 (M + H), 490. Example 31

6-coguchi-2- (4-methanesulfonylpentyl) -toxo-4- (thiophen-3-yl) -1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

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). _{'HNMR (CDC1 3) δ:} 3.07 (3Η, s), 3.70 (3H, s), 5.39 (2H, br), 7.09 (1H, dd, J = 1.2, 4.8 Hz), 7.29 (1H, dd, J = 1.2, 3.0 Hz), 7.33 (1H, d, J = 2.1 Hz), 7.44-7.50 (3H, m), 7.52 (1H, dd, J = 2.1, 8.7 Hz), 7.88 (2H, d, J = 8.4 Hz), 8.43 (1H, d, J = 8.7 Hz). MS (ESI I): 488 (M + H), 490. Example 32

6-chloro-2- (4-methanesulfonylbenzyl) -toxo-4-vinyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

6-chloro-2- (4-methanesulfonylpentyl) -toxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) ゝ lithium chloride (23 nig ), Bis (triphenylphosphine) palladium (II) chloride (3 mg), 2,6-di-tert-butyl-4-methylphenol '(4 mg), and vinyltributyltin (55) in DMF (4.9 ml). It was dissolved and stirred at 90 ° C for 2 hours under a nitrogen atmosphere. After cooling the reaction solution, water was added to the system, extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 1/1) to give the title compound (5 mg) as a pale yellow powder. _{NMR (CDC1 3) δ 3.02 (} 3Η, s), 3.66 (3Η, s), 5.36 (2H, s), 5.48 (1H, dd, J = 1.5, 17.4 Hz), 5.60 (1H, dd, J = 1.5 , 11.1 Hz), 6.69 (1H, dd, J = 11.1, 17.4 Hz), 7.44 (2H, d, J-8.7 Hz), 7.53 (1H, dd, J = 2.1, 8.4 Hz), 7.68 (1H, d , J = 2.1 Hz), 7.88 (2H, d, J-8.7 Hz), 8.40 (1H, d, J = 8.4 Hz). MS (ESI +): 432 (M + H), 434.

6-chloro-2- (4-methanesulfonylbenzyl) -4-vinyl-2H-isoquinoline-toone

This compound was obtained as a by-product in the reaction of Example 32. Colorless powder (33% yield). Thigh R (CDC1 ₃ ) δ 3.02 (3Η, s), 5.29 (2H, s), 5.37 (1H, dd, J = 1.2, 10.8 Hz), 5.53 (1H, dd, J = 0.6, 17.1 Hz), 6.84 (1H, dd, J = 10.8, 17.1 Hz), 7.21 (1H, s), 7.46-7.54 (3H, m), 7.69 (1H, d, J = 2.1 Hz), 7.91 (2H, d, J- 8.1 Hz), 8.39 (1H, d, J = 8.7 Hz). MS (ESI +): 374 (M + H), 376. Example 34

6-chloro-4- (furan-2-yl) -2- (4-methanesulfonylbenzyl) -2H-isoquinolin-1-one

This compound was prepared according to the method described in Example 32 to give 6-chloro-2- (4-methanesulfonylbenzyl) -toxo-4-4-1, trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3 -Synthesized using carboxylic acid methyl ester and 2-tributyltin furan. Yellow powder (47% yield). _{Ή NMR (CDC1 3) δ ··} 3.02 (3Η, s), 5.31 (2H, s), 6.54 (2H, s), 7.38 (1H, s), 7.48-7.58 (4H, m), 7.88-7.96 ( 3H, m), 8.43 (1H, d, J = 8.4 Hz). MS (ESI +): 414 (M + H), 416. Example 35

6-chloro-1- (4-methanesulfonylbenzyl) -4- (thiophen-2-yl) -2H-isoquinolin-1-one

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%). 'Η NMR (CDC1 ₃ ) δ 3.03 (3Η, s), 5.29 (2H, s), 7.11-7.18 (2H, m), 7.24 (1H, s), 7.41 (1H, dd, J = 1.5, 5.1 Hz ), 7.50 (1H, m), 7.53 (2H, d, J-8.4 Hz), 7.74 (1H, d, J = 1.8 Hz), 7.92 (2H, d, J = 8.4 Hz), 8.43 (1H, d , J = 8.7 Hz) .MS (ESI +): 430 (M + H), 432.

2- (4-methylsulfonylbenzyl) -1-oxo-4- (pyrrole-tolyl) -1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

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. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 2 / 1-1 / 2) to give the title compound (0.11 g) as colorless crystals. Ή 丽 R (CDC1 ₃ ) (5: 3.02 (3H, s), 3.45 (3H, s), 5.42 (2H, s), 6.31 (2H, t, J = 2.1 Hz), 6.75 (2H, ί, J = 2.1 Hz), 7.13 (1H, dd, J = 1.2, 8.1 Hz), 7.49 (2H, d, J = 8.1 Hz), 7.58-7.72 (2H, m), 7.89 (2H, d, J = 8.1 Hz) ), 8.48 (1H, m). MS (ESI +): 437 (M + H). 2- (4-methanesulfonylbenzyl) -1-oxo-4- (piperidine-tolyl) -1,2-dihydrido Mouth isoquinoline-3-carboxylic acid methyl ester

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. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 2/1 to 1/1) to give the title compound (37 mg) as a yellow powder. ΉΝΜΙ (CDC1 ₃ ) δ 1.44-1.80 (6Η, m), 2.88-2.99 (2H, m), 3.01 (3H, s), 3.22-3.34 (2H, m), 3.77 (3H, s), 5.25 (2H , s), 7.46 (2H, d, 8.1 Hz), 7.55 (1H, m), 7.72 (1H, m), 7.83-7.93 (3H, m), 8.46 (1H, dd, J = 0.6, 8.1 Hz Examples 38-41 were synthesized according to a method similar to the method shown in Example 37. Example 38

2- (4-Methanesulfonyl-pentyl) -1-oxo-4- (pyrrolidine-tolyl) -1,2-dihydrogen Mouth isoquinoline-3-carboxylic acid methyl ester

Yellow powder (15% yield). ¾ Awakening R (CDC1 ₃ ) δ: 1.94-2.12 (4Η, m), 3.02 (3H, s),

3.18-3.28 (4H, m), 3.73 (3H, s), 5.24 (2H, s), 7.49 (2H, d, J = 8.7 Hz),

7.50-7.63 (2H, m), 7.70 (1H, m), 7.87 (2H, d, J = 8.7 Hz), 8.49 (1H, dd, J = 0.9, 8.1 Hz).

2- (4-methylsulfonylbenzyl) -4- (morpholine-4-yl) -1 -oxo-1, 2-dihydrido isoquinoline-3-carboxylic acid methyl ester

Yellow crystals (15% yield). _{'Η NMR (CDC1 3) δ} : 2.84-2.94 (2Η, m), 3.02 (3H, s), 3.44-3.68 (4H, m), 3.79 (3H, s), 3.89 (2H, dt, J = 3.6 , 10.8 Hz), 5.25 (2H, s), 7.46 (2H, d, 9.0 Hz), 7.57 (1H, m), 7.74 (1H, m), 7.84-7.96 (3H,

■ m), 8.48 (1H, dd, J: 1,5, 8.1 Hz).

4-dimethylamino-2- (4-methylsulfonylbenzyl) -toxo-1, 2-dihydroisoquinoline-3-carboxylic acid methyl ester

Colorless crystals (23% yield). _{'Η NMR (CDC1 3) δ} : 2.88 (6Η, s), 3.01 (3H, s), 3.75 (3H; s), 5.26 (2H, s), 7.46 (2H, d, J = 8.4 Hz), 7.55 (1H, m), 7.72 (1H, m) _: 7.78-7.90 (3H, m), 8.47 (1H, m).

4- (1,3-dihydroisoindole-2-yl) -2- (4-methylsulfonylbenzylyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

Pale yellow powder (21% yield). 'Η NMR (CDC1 ₃ ) δ 3.03 (3Η, s), 3.68 (3H, s), 4.64 (4H, s), 5.28 (2H, s), 7.23-7.36 (5H, m), 7.52 (2H, d , J = 8.4 Hz), 7.48-7.65 (2H, in), 7.89 (2H, d, J: = 8.4 Hz), 8.51 (1H, m) .Example 42

2- (4-Mesulfonylbenzyl) -4-([1,2,4] triazol-4-yl) -2H-isoquinolin-1-one

Example 1 4-Amino-2- (4-methanesulfonylpentyl) -1-oxo-1,2-dihydroisoquinoline-3-caprolubonic acid methyl ester (0.15 g) obtained in (10), 1,2- A mixture of bis [(dimethylamino) methylene] hydrazine dihydrochloride (0.1 lg) and pyridine (3 ml) was heated to reflux for 48 hours. After cooling the reaction solution, the solvent was distilled off under reduced pressure. The residue was purified by medium pressure preparative LC (ethyl acetate-ethyl acetate / methanol = 4/1) to give the title compound (23 mg) as a brown powder. Ή noodles _{R (CDC1 3) δ: 3.04} (3H, s), 5.33 (2H, s), 7.04 (1H, d, J-7.8 Hz), 7.36 (1H, s), 7.56 (2H, d, J = 8.4 Hz), 7.67 (1H, m), 7.75 (1H, dt, J = 1.5 , 14.4 Hz), 7.94 (2H, d, J = 8.4 Hz), 8.33 (2H, s), 8.54 (1H, d, J = 0.9, 7.8 Hz).

4-benzyloxycarbonylamino-2- (4-methanesulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

4-amino-2- (4-methanesulfonyl-pentyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (0.47 g) obtained in Example 1 (10), benzyloxycarponyl chloride A mixture of (260), potassium carbonate (252 mg) and THF (5.0 ml) was heated under reflux for 10 hours. After the completion of the reaction, the reaction solution was diluted with dichloromethane and washed with 1N hydrochloric acid. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 1/1 to 1/10) to give the title compound (600 mg) as a colorless powder. _{'H NMR (CDC1 3) δ} : 3.02 (3Η, s), 3.61 (3H, s), 5.18 (2H, br), 5.39 (2H, s), 7.26-7.48 (5H, m), 7.43 (2H, d, J = 8.4 Hz), 7.59-7.70 (2H, m), 7.76 (1H, m), 7.87 (2H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 0.6, 8.7 Hz). Example 44

4-Benzyloxycarbonylamino-2- (4-methansulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid

4-benzyloxycarbonylamino-2- (4-methylsulfonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carponic acid methyl ester (0.59 g) obtained in Example 43, water A mixture of lithium oxide monohydrate (238 mg), 1,4-dioxane (6 ml) and water (2.0 ml) was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction solution was diluted with dichloromethane and washed with 1N hydrochloric acid. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (480 mg) as a pale yellow powder. Marauder R (DMS0-d ₆ ) δ: 3.18 (3Η, s), 5.13 (2Η, s), 5.34 (2H, s), 7.06-7.50 (7H, m), 7.56-7.70 (2H, m), 7.78-7.92 (3H, m), 8.27 (1H, d, J = 8.1 Hz), 9.18 (1H, s).

2- (4-methanesulfoerbenzyl) -1-oxo-4-phenylamino-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester

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. The residue was purified by medium pressure preparative LC (hexane / ethyl acetate = 1/1 to 1/4) to give the title compound (260 mg) as colorless crystals. Awakening R (CDC13) δ: 3.03 ( ₃ (, s), 3.62 (3H, s), 5.40 (2H, s), 5.64 (1H, s), 6.60 (2H, d, J-8.1 Hz), 6.82 (1H, t, J = 7.2 Hz), 7.15 (2H, t, J-7.8 Hz), 7.45 (2H, d, J = 8.4 Hz), 7.54-7.72 (3H, m), 7.89 (2H, d, J = 8.4 Hz), 8.48 (1H, dd, J = 2.1, 7.5 Hz).

4-Amino-2- (4-methylsulfonylbenzyl) -l-oxo-l, 2-dihydroisoquinolin--3-hexanolitrile

To a mixture of 4- (methanesulfonyl) benzylamine hydrochloride (10.3 g), potassium carbonate (16.1 g) and DMF (100 ml) was added dropwise bromoacetonitrile (3.4 ml) with stirring at 0 ° C. Stirred for hours. The insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel gel chromatography (ethyl acetate-ethyl acetate / methyl alcohol = 10/1) to obtain colorless crystals ( 4-Methanesulfonyl pentylamino) acetonitrile (5.6 g) was obtained.

To a mixture of this product, 2-cyanobenzoic acid (3.86 g) and acetonitrile (56 ml), add 1-ethyl-3- (3-dimethylaminopropyl) carposimide hydrochloride (7.2 g) and 4-hydroxybenzotria Zole-hydrate (5.0 g) was added, and the mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, and the residue was diluted with ethyl acetate, washed successively with a 5% aqueous solution of potassium hydrogen sulfate, saturated aqueous sodium hydrogen carbonate and saturated brine, dried and concentrated under reduced pressure. Silica residue

-Ethyl acetate) to give colorless oily 2-cyanocyanomethyl-N- (4-methanesulfonylpentyl) benzamide (3.9 g). Next, this product was dissolved in methanol (78 ml), a 28% sodium methoxide / methanol solution (4.3 g) was added under stirring at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was separated with ethyl acetate and 1 N hydrochloric acid. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/4) to give the title compound (3.0 g) as pale yellow crystals. _{¾NMR (CDC1 3) δ: 3.03} (3Η, s), 4.46 (2H, s), '5.45 (2H, s), 7.62 (2H, d, J = 8.7 Hz), 7.65-7.88 (3H, m), 7.90 (2H, d, J = 8.7 Hz), 8.58 (1H, dd, J = 1.5, 8.1 Hz).

2- (4-methylsulfonylbenzyl) -1-oxo- (4-piperidin-toyl) -1,2-dihydrol mouth isoquinoline-3- 3-caprolitolitrile

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). _{NMR (CDC1 3) 6: 1.70-1.86} (6H, m), 3.03 (3H, s), 3.10-3.34 (4H, m), 5.50 (2H, s), 7.60 (2H, d, J = 8.1 Hz) , 7.69 (1H, m), 7.79 (1H, m), 7.90 (2H, d, J = 8.1 Hz), 8.01 (1H, d, J = 8.1 Hz), 8.49 (1H, dd, J = 0.6, 8.1 Hz). Formulation Example 1

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.

In addition, in the following formulations, the 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.

1. Capsules

(1) 40 mg of the compound obtained in Example 21

(2) Lactose 7 Omg

(3) Microcrystalline cellulose 9mg

(4) Magnesium stearate lmg

1 capsule 12 Omg

After mixing (1), (2) and 1/2 of (3) and (4), granulate. Add the remaining (4) to this and encapsulate the whole in a gelatin capsule.

2. Capsules

(1) 40 mg of the compound obtained in Example 24

(2) Lactose 7 Omg

(3) Microcrystalline cellulose 9mg

(4) Magnesium stearate 1 mg

1 capsule 12 Omg

After mixing (1), (2) with 1Z2 of (3) and (4), granulate. Add the remaining (4) to this and encapsulate the whole into a gelatin capsule.

3. Capsules

(1) 40 mg of the compound obtained in Example 37

(2) Easy 7 Omg

(3) Microcrystalline cellulose 9mg

(4) Magnesium stearate lmg

One force pusher 120 mg

After mixing (1), (2) with 1Z2 of (3) and (4), granulate. Add the remaining (4) to this and encapsulate the whole into a gelatin capsule. 4. Tablet

(1) Compound 4 Omg obtained in Example 21

(2) Easy 1 ^ 58mg

(3) Corn starch 18mg

(4) Microcrystalline cellulose 3.5 mg

(5) 0.5mg

1 tablet 120mg

After mixing 2/3 of (1), (2), (3) and (4) and 1/2 of (5), granulate. The remaining (4) and (5) are added in two to the granules and pressed into tablets.

5. Tablet

(1) 40 mg of the compound obtained in Example 24

(2) Easy] ^ 58mg

(3) Corn starch 18mg

(4) Microcrystalline cellulose 3.5mg

(5) 0.5 mg of magnesium stearate

1 tablet 12 Omg

After mixing 2/3 of (1), (2), (3), and (4) and 1-2 of (5), granulate. The remaining (4) and (5) are added in two to the granules and pressed into tablets.

6. Tablet

(1) 40 mg of the compound obtained in Example 37

(2) Lactose 58mg

(3) Corn starch 18mg

(4) Microcrystalline cellulose 3.5mg

(5) 0.5 mg of magnesium stearate

1 tablet 12 Omg

After mixing (1), (2), (3) and 2Z3 of (4) and 1Z2 of (5), granulate. Add the remaining (4) and (5) to the granules and press-mold into tablets. Formulation Example 2

1. After dissolving 5 Omg of the compound obtained in Example 21 in 50 ml of distilled water for injection in Japan, add distilled water for injection to 10 Oml. The solution is filtered under sterile conditions, and then 1 ml of this solution is taken, filled into an injection vial under sterile conditions, freeze-dried and sealed.

2. Dissolve 50 mg of the compound obtained in Example 24 in 50 ml of distilled water for injection in Japan, and add distilled water for injection to 10 Oml. Filter this solution under sterile conditions, take 1 ml each of this solution, fill in vials for injection under sterile conditions, freeze-dry and seal.

3. After dissolving 50 mg of the compound obtained in Example 37 in 50 ml of distilled water for injection in Japan, add 10 ml of distilled water for injection in Japan. Filter this solution under sterile conditions, take 1 ml each of this solution, fill in vials for injection under sterile conditions, freeze-dry and seal. Experimental example 1

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.

(1) Cloning of human JNK1 gene and preparation of recombinant baculovirus Cloning of the human JNK1 gene was performed using kidney cDNA (Toyobo, QUICK-Clone cDNA) as type III and reported by Derijard, B. et al. (Cell, 76). , 1025-1037 (1994)), a primer set prepared with reference to the nucleotide sequence of the JNK1 gene.

J K1-U:

5'-ACAACTCGAGATAACATATGGCTCATCATCATCATCATCATAGCAGAAGCAAGCGTGACAAC-3 '(SEQ ID NO: 1)

JNK1-L:

5 '-TCCCGGGTACCTCACTGCTGCACCTGTGCTAA -3'

(SEQ ID NO: 2) PCR was carried out using

The PCR reaction was performed by the Hot Stai method using AmpliWax PCR Gem 100 (Takara Shuzo). As a lower layer mixed solution, 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. As the upper layer mixed solution, human kidney cDNA (l ng / ml) as 铸 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. Using the plasmid pFBJNKl and the BAC-TO-BAC Baculovirus Expression System (GIBC0 BRL), a virus stock BAC-HJNK1 of a recombinant baculovirus was prepared. '

(2) Cloning of Human MKK7 Gene and Preparation of Recombinant Baculovirus Cloning of the human MKK7 gene was performed using mouse cDNA (Toyobo, QUICK-Clone cDNA) as a type II report by Foltz, IN et al. (J. Biol. Chem., 273 (15), 9344-9351 (1998))

MKK7-U:

5'-ACCAGAATTCATAACATATGGCTCATCATCATCATCATCATGCGGCGTCCTCCCTGGAACAG-3 '(SEQ ID NO: 3)

MKK7-L:

5'- ACCCTCTAGACAAGCAGCTACCTGAAGAAGG -3 '' (SEQ ID NO: 4)

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滕臓cDNA of (l ng / ml) 1 μΛ 10 x LAPCR Buffer 3 II K 2.5 mM dNTP solution as铸型5 / zl, 251 ^ ¾¾ ( : 1 2 solution 3 1, TaKaRa LA Taq DNA polymerase (Takara Shuzo) 0.5μ1 and sterile distilled water 17.5 / χI 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. After processing, 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.

A constitutively active form of MK7 reported by Wang, Y. et al. (J. Biol. Chem., 273 (10), 5423-5426, 1998) (271st Ser is Asp, 275th Thr is Asp) Primer set to prepare

CAM7-U:

5 '-GGCCGCCTGGTGGACGACAAAGCCAAGGACCGGAGCGCCGGCTG-3'

(SEQ ID NO: 5)

CAM7-L:

5 '-CAGCCGGCGCTCCGGTCCTTGGCTTTGTCGTCCACCAGGCGGCC-3'

(SEQ ID NO: 6)

Mutations were introduced using the QuikChange Site-Directed Mutagenesis Kit (Stratagene) to obtain pcaMKK7.

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

Cloning of the human cJUN gene was performed using skeletal muscle cDNA (Toyobo, QUICK-Clone cDNA) as type III, reported by Hattori, K. et al. (Pro Natl. Acad. Sci. USA, 85 (23), 9148-9152). (1988)) Primer set prepared with reference to the base sequence of cJUN gene

cJUN-U:

5 '-AAAAGAATTCATGACTGCAAAGATGGAAACGACC-3'

(SEQ ID NO: 7)

cJUN-L:

5 '-AAAAGCGGCCGCTCACAGGCGCTCCAGCTCGGGCGACGC -3'

(SEQ ID NO: 8)

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 μ each of the primer solution 2.5 lι \ 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 (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 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.

(4) Preparation of activated INK1

100 ml Sf-900 containing 10% fetal bovine serum so that Sf_21 cells become lxlO ⁶ eel Is / ml After inoculation and seeding on an IIII SSFFMM culture medium ((GGIIBBCCOOBBRRLL)), the cells were cultured and cultured at 2277 for 2244 hours. . Recombination Babakyuuro

After adding BBAACC-ccaaMMKKKK77, respectively, and adding 00..22 mmll, the cells were further cultured for 60 hours. After the cells were separated from the culture solution by centrifugation (3000 rpm, 10 min), the cells were washed twice with PBS. After suspending the cells in 10 ml Lysis buffer (25 mM HEPES (pH 7.5), l¾TritonX, 130 mM aCl, ImMEDTA, ImM DTT, 25 mM jS-glycerophosphate 20 ^ M leupeptin, ImM APMSF, ImM Sodium orthovanadate), homogenizer (P0LYTR0N) The cells were disrupted by performing the treatment 4 times at 20000 rpm for 30 seconds. Activated JNK1 was purified from the supernatant obtained by centrifugation (40000 rpm, 45 minutes) using Anti-FLAG M2 Affinity Gel (Sydama).

(5) Preparation of recombinant c

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 8000ι · ριη 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).

(6) Measurement of JNK inhibitory activity

2.51 of the test compound dissolved in DMS0 was added to a 37.5 l reaction solution (25 mM HEPES (pH 7.5), 10 mM magnesium acetate) containing 50 ng of activated JNK1 and lgc J, and then incubated at 30 ° C for 5 minutes. ATP solution (2.5 ^ M ATP, OO tCi [ § - ³² P] ATP) and the reaction was started by Rukoto be added 10 / l. After reacting at 30 ° C for 60 minutes, the reaction was stopped by adding 501 of a 20% TCA solution. After leaving the reaction solution at 0 ° C for 20 minutes, use Cell Harvester (Packard Japan) to filter on the GF / C filter (Packard Japan). 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

Measurement of TNF production inhibition activity

After seeded with THP-1 cells cultured in RPMI1640 medium (GIBCO BRL) containing 1% inactivated fetal bovine serum and 10 mM HEPES (pH 7.5) so as to lxl0 ⁵ cel Is / well into 96 © El plate, DMS0 The test compound dissolved in was added to 1/21.

After culturing at 37 ° C for 1 hour in a carbon dioxide gas incubator, LPS (Wako Pure Chemical Industries) was added to a final concentration of 5 g / ml. After culturing in a carbon dioxide incubator at 37 ° C for 4 hours, a supernatant was obtained by centrifugation. The TNFa concentration in the supernatant was measured with an ELISA kit (Diacron). The concentration (IC5 ( ₎ value) of the test compound required to inhibit TNFa production by 50% was calculated using PRISM2.01 (GraphPad Software). Experiment 3

TNF measurement after LPS administration (rat)

(1) Oral administration:

9-10-week-old male Jcl: Wistar rats were used. LPS (SIGMA, Derived from E. coli) (dissolved in physiological saline) was intraperitoneally administered at 5 ing / kg. 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卬m, 4 ^D C Thus, plasma was obtained. TNF 0 in plasma was measured using ELISA Kit (GENZYME).

(2) Intravenous administration: A 9-10 week old male kl: Wistar rat was used. LPS (SIGMA, Derived from E. coli) (dissolved in physiological saline) was intraperitoneally administered at 5 mg / kg. Compounds were dissolved in DMAA / PEG400 (1: 1) and performed 10 minutes before LPS administration. In the control group, similarly, only DMAA / PEG400 (1: 1) was administered. 90 minutes after LPS administration Pentobarbital (50 mg / kg, intraperitoneal administration) Blood is collected from the abdominal aorta using an aprotinin / EDTA-containing syringe under anesthesia, and plasma is obtained by centrifugation at 3000 rpm, 4 ° C for 10 minutes. Was. TNFa in plasma was measured using ELISA Kit (GENZYME). Experimental example 4

Measurement of cardiac phosphorylation C-Jun after LPS administration (rat)

9-10-week-old male Jcl: Wistar rats were used. LPS (SIGMA, Derived from E. coli) (dissolved in physiological saline) was intraperitoneally administered at 5 mg / kg. The compound was orally or intravenously administered by the method described in (1-1) or (1-2). Ninety minutes after LPS administration, 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. Left ventricle in 5.0 ml of ice-cold Lysis buffer (20 mM Tris-HCl pH 7.4, 1% NP40, 0.1% SDS, 150 mM NaCK ImM EDTA 0.Img / ml PMSF, 0.3 TIU aprotinin ImM sodium orthovanadate) After homogenizing and centrifuging at 12000 rpm (15800 g) at 4 ° C for 30 minutes, the supernatant was collected and used as a tissue extract. The protein amount was measured using the Bradford method (BI0RAD: Protein assay). 8 g of anti-c-Jun rabbit polyclonal antibody (H79: SANTA CRUZ) and 201 Protein A-Agarose (SANTA CRUZ) were added to the tissue extract containing 10 mg of protein, and the mixture was stirred at 4 ° C. . Centrifuge at 2500rpm, 4 ° C for 5 minutes, remove the supernatant, and wash 3 times with TBS buf fer (50mM Tris-HCl pH7.4, M NaCK 0.Img / ml PMSF, 0.3TIU aprotinin ImM sodium orthovanadate) Then, the resultant was dissolved in 60 zl of Lae Sample li sample buffer (BI0RAD). 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. After washing the membrane with 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. After washing the membrane with TBS-T (5 min, twice), the membrane was reacted with HRP-labeled anti-mouse IgG secondary antibody (Amersham) diluted 2000-fold with blocking buffer for 1 hour at room temperature. Washed with T (5 min, 3 times) and TBS. The membrane was reacted with 2 ml of ECL reaction solution (ECL Plus: Amersham) for 5 minutes, exposed to X-ray film for 1 minute, immersed in developer for 90 seconds, washed with water, and immersed in fixer to remove the film. Developed. The developed X-ray film was captured by Deskscanl and automatically corrected, and then automatically corrected by Photoshop to reverse the color tone. The band density observed at the target molecular weight was quantified using a Photoshop histogram. Experimental result

Table 1 shows the inhibitory effects of human JNK1, p38 and ERK1.

table 1

This indicates that the compound (I) of the present invention or a salt thereof has excellent JNK-specific inhibitory activity. Industrial potential

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.

Claims

The scope of the claims

1. Formula (I)

[In the formula, ring A represents an optionally substituted benzene ring, R ¹ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, and R ² represents hydrogen. An 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, a labamoyl group which may be substituted or substituted 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 heterocyclic group which may be substituted, a hydroxy group which may be substituted or an amino group which may be substituted. ] A JNK inhibitor comprising a compound represented by the formula: or a salt thereof or a prodrug thereof.

2. Formula (I)

(Wherein, ring A is substituted; 'represents a ring; R ¹ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group; R ² represents a hydrogen atom; A hydrocarbon group which may be substituted with an optionally substituted hydroxy group, X represents a cyano group, an acyl group, an optionally esterified olepoxyl group, an optionally substituted olebamoyl group or an optionally substituted amino group, and X represents an optionally substituted divalent A chain hydrocarbon group, Y is an optionally substituted non-aromatic hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group or an optionally substituted Shows an amino group. And a compound represented by the formula: (Ethyl 2-benzyl-6,7-dichloro-4-hydroxy-1-oxo-1, 2-dihydro-3-isoquinolinecarboxylic acid ethyl ester, 2-benzyl-4-butoxy -6,7-Dimethyl-1-oxo-1,2,2-dihydro-3-isoquinolinecarboxylic acid ethyl ester, 2-benzyl-4-butoxy-6,7-dichloro-1-oxo-1,2 -Dihydro-3-isoquinolinecarboxylic acid and 2-benzyl-4-butoxy-6,7-dichloro-3-hydroxymethyl-K2H) -isoquinolinone) or salts thereof.

3. Ring A is a formula

Wherein 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 A good thiol group, a substituted sulfinyl group, a substituted sulfonyl group, an amino group which may be substituted, a rubamoyl group which may be substituted or a carboxyl group which may be esterified. The compound according to claim 2, which is a benzene ring represented by the formula:

4. The compound according to claim ³ , wherein R ³ is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, or an optionally substituted amino group. '

5. The compound according to claim ³ , wherein R ³ is a hydrogen atom, a halogen atom or a C ₄ alkyl group.

6. The compound of claim 2, wherein substituted R ¹ power is also good phenyl.

7. The compound according to claim 2, wherein X is methylene.

8. The compound according to claim 2, wherein Y is a non-aromatic hydrocarbon group which may be substituted.

9. The compound according to claim 2, wherein Υ is an optionally substituted chain hydrocarbon group.

10. The compound according to claim 2, wherein Υ is an optionally substituted C ₂₆ alkenyl.

11. The compound according to claim 2, wherein Y is a heterocyclic group which may be substituted.

12. The compound according to claim 2, wherein Y is a 5- or 6-membered aromatic heterocyclic group which may be substituted.

13. The compound according to claim 2, wherein Y is an optionally substituted hydroxy group.

14. The compound according to claim 2, wherein Y is a hydroxy group substituted with an optionally substituted hydrocarbon group.

15. The compound according to claim 2, wherein Y is an optionally substituted amino group.

16. The compound according to claim 2, wherein Y is a cyclic amino group.

17. The compound according to claim 2, wherein R ² is an optionally esterified olepoxyl group or an optionally substituted olevamoyl group.

18. The compound according to claim 2, wherein R ² is lower alkoxycarbonyl.

19. The compound according to claim ² , wherein R ² is an acyl group, a hydrocarbon group optionally substituted with a hydroxy group optionally substituted, or an amino group optionally substituted.

20.6-Methyl -4- (2-hydroxymethylthiophen-3-yl) -2- (4-methoxycarbonylbenzyl) -1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester, 2 -(4-potoxybenzyl) -6-chloro- 4- (3-hydroxymethylthiophen-2-yl) -toxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester or 2- ( 4-Methanesulfonylpentyl) -toxo-4- (piperidine-tolyl) -1,2-dihydroisoquinoline-3-carboxylic acid methyl ester or a salt thereof.

21. A prodrug of the compound of claim 2.

22. A medicament comprising the compound according to claim 2 or 21.

23. The agent according to claim 1, which is a prophylactic or therapeutic agent for a JNK-related condition or disease.

24. JNK-related conditions or diseases are cardiovascular diseases, inflammatory diseases, neurodegenerative diseases Or the agent according to claim 23, which is diabetes.

2 5 Chronic or acute heart failure, cardiac hypertrophy, dilated, hypertrophic or restricted cardiomyopathy, acute coronary syndrome, chronic ischemic heart disease, acute or chronic myocarditis, left diastolic dysfunction, left heart contractile dysfunction, hypertension The agent according to claim 1, which is a prophylactic or therapeutic agent for nephritis, vascular endothelial dysfunction, arteriosclerosis, restenosis after angioplasty, or an agent for improving prognosis of myocardial infarction.

26. Formula (I)

[In the formula, ring A represents an optionally substituted benzene ring, R ¹ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, and R ² represents hydrogen. An atom, a hydrocarbon group optionally substituted with a hydroxy group which may be substituted, a cyano group, an acyl group, an optionally esterified olepoxyl group, an optionally substituted olebamoyl group or X 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 heterocyclic group which may be substituted, a hydroxy group which may be substituted or an amino group which may be substituted. ] A method for inhibiting JNK in a mammal, which comprises administering to the mammal an effective amount of the compound or a salt thereof or a prodrug thereof represented by the formula:

27. Formula for the production of JNK inhibitors (I)

[In the formula, ring A represents an optionally substituted benzene ring, R ¹ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, and R ² represents hydrogen. An atom, a hydrocarbon group which may be substituted with an optionally substituted hydroxy group, a cyano group, an acyl group, a carboxyl group which may be esterified, a labamoyl group which may be substituted or Represents an optionally substituted amino group; X represents an optionally substituted divalent chain hydrocarbon group; Y represents an optionally substituted non-aromatic hydrocarbon group, which may be substituted It represents a heterocyclic group, an optionally substituted hydroxy group or an optionally substituted amino group. ] The use of a compound represented by the formula or a salt thereof or a prodrug thereof.