TW200533356A - Fused pyridazine derivatives - Google Patents

Abstract

The present invention relates to medicines for the treatment and/or prevention of diseases which NAD(P)H oxidase participates in, containing fused pyridazine derivatives represented by the general formula (I), pharmacologically acceptable salts thereof, or hydrates or solvates of both: (I) wherein each symbol is as defined in the description.

Description

200533356 (1) IX. Description of the invention [Technical field to which the invention belongs] The present invention relates to novel condensation derivatives, more specifically, to condensation derivatives and their salts, and the use of these as effective ingredients. NAD (P) Η oxidase inhibitor. [Prior art] Although active oxygen molecules exist in the body, their excessive production can cause various vascular disorders. Among them, superoxide generated by NAD (P) Η and oxygen through NAD (P) Η oxidase. Anion (hereinafter also referred to as "〇2 ·") is well known as a source of generation of all reactive oxygen molecules (hereinafter also referred to as ROS). It is known to be related to diseases, such as diabetes, hyperlipidemia, Local blood pressure, myocardial infarction, angina, arteriosclerosis and other disease states cause NAD (P) Η oxidase to be increased. The relationship with myocardial infarction has been reported in the literature after the onset of myocardial infarction. NAD (P) Η oxidase is abnormally high (Non-Patent Documents 1 and 2). It has been related to asthma, and patients with asthma have already been diagnosed. There have been reports in the literature of excessive ROS production in the disease, suggesting a 'connection between NAD (P) Η oxidase and morbidity of stenosis (Non-Patent Document 3), and a relationship with arteriosclerosis' Reports on the production of superoxide anions and NAD (P) Η oxidase hypersensitivity during atherosclerosis in humans (Non-Patent Documents 4 and 5), and represent the vascular lumen factor of the heart of stenosis and myocardial infarction Diseases that cause a narrow or obstructed condition that cannot provide sufficient oxygen and nutrition to the heart for some reason are called ischemic heart disease, or acute coronary artery disease 200533356 (2) Symptoms, and they are well aware of these diseases and The relationship between NAD (P) Η oxidase hyperactivity (Non-Patent Documents 6 and 7), it is thought that inhibiting NAD (P) 亢 oxidase hyperactivity can prevent and treat the above-mentioned obstacles. NAD (P) Η oxidase inhibitors are known as DPI (Diphenylene iodonium) and Hu Huanglian (Apocynin). These compounds are non-selective inhibitors of NAD (P) regardless of whether they are in a normal state or in a disease state. Oxidases, and these drugs have high pharmacological effects, so these compounds are not considered sufficient as drugs. On the other hand, there are some reports on the pharmacological action of the derivatives. An alkoxy substituted phthalazine has a PDE4 inhibitory effect (see Patent Documents 1, 2), an imidazole-dakin compound is an adrenocortical hormone-releasing factor antagonist (see non-patent document 10), and a dagen compound is an angiogenesis inhibitor ( Reference is made to Patent Document 4), and the compound is a ligand coordinated to a copper complex (see Non-Patent Document 8). However, in these reports, there is no inhibitory effect of NAD (P) Η oxidase. Others, it is known that HYDRALAZINE, which has a blood pressure lowering effect, shows NAD (P) 使用 when it is used in an amount greater than the effective amount. Inhibitory effect of oxidase, but this effect is weak (refer to Non-Patent Document 9) A compound of S-1783783 (see Non-Patent Document 10) has been reported as a NAD (P) oxidase inhibitor However, the effective dosage in vivo test is as high as 130mg / kg, so there is no report of a strong NAD (P) oxidase inhibitory effect in the living body. [Patent Document 1] -6- 2005333.56 (3) PCT International Publication WO00 / 0 5 2 1 9 [Patent Document 2] PCT International Publication W099 / 3 245 65 [Patent Document 3] PCT International Publication WO00 / 0 1 697 [Patent Document 4] PCT International Publication W098 / 58929

[Non-Patent Document 1]

Biochemical and Biophysical Research Communicatons, 200 1, vol. 281, 1200-1206 [Non-Patent Document 2]

Journal of Clinical Pathology, 2003, 5 6, 194-199 [Non-Patent Document 3]

Arteriosclerosis Thrombosis and Vascular Biology, 2002, 22, 1 83 8-44 [Non-Patent Document 4]

Circuration, 2 0 0 2, 1 05, 1 429-3 5 [Non-Patent Document 5]

Annals New York Academy of Sciences, 2002, 902, 241-7 [Non-Patent Document 6]

Circuration, 1 999, 100, 1 494-98 [Non-Patent Document 7]

Canadian Jounral of Chemistry, 1 984, vol. 62, 2 7 5 5 200533356 (4) [Non-Patent Document 8] |

Circuration Res, 1 997, 80, 45 [Non-Patent Document 1 0]

Arteriosclerosis Thrombosis and Vascular Biology, 2001, 21: 1577 [Content of the invention]

[Problems to be Solved by the Invention] As mentioned above, at present, it is not known that NAD (P) Η oxidase inhibitors, which have sufficient inhibitory power or selectivity, are pharmaceuticals. NAD (P) Η oxidase inhibitor [Means to solve the problem] As a result of careful research to solve the problem described in the present inventors, it was found that a specific condensation D-well derivative can achieve the desired result The purpose is to achieve the invention. [Effects of the invention] The condensed daikon derivatives of the present invention have NAD (P) Η oxidase inhibitory effect and can be used as medicines for preventing or treating diseases related to the enzyme. [Best Mode for Carrying Out the Invention] The present invention relates to the following condensation derivatives or their pharmacologically acceptable -8-200533356 (5) Permissible salts, or hydrates or solvates thereof. (1) The following general formula (1)

{In the formula, a Het ring contains at least one nitrogen atom, which represents a saturated or unsaturated 5-membered heterocyclic ring bonded with carbon and dagen. [The heterocyclic ring may be selected from more than one alkyl group, hydroxyalkyl group , Alkoxyalkyl, aminoalkyl, trifluoromethyl, hydroxy, aryl, heteroaryl, halogen atom, cyano, -CC ^ R1 (wherein R1 represents a hydrogen atom, a radical, or an aromatic group Yuanji), -CONR2R3 (where R2 and R3 can be the same or different, respectively, representing a hydrogen atom, a yuan, or an aryl group that can be substituted, and feet 2 and 3 can also form a 4- to 7-membered ring together) , -C0NHS02R2a (where R2a is a hydrogen atom, an alkyl group, or an aryl group which may be substituted), -NR2R3 (where R2 and R3 have the same meanings as above), · NHCOR2a (where R2a has the same meaning as above), · NHC02R2a (where R2a is synonymous with the above), -NHS〇2R2a (where synonymous with the above), or -P (= 0) (ORh) (OR, where '' is synonymous with the above, and R3i is a hydrogen atom , Alkyl, or substituted by a substituted aryl)], 200533356

To represent any one of the rings selected from the following formula (rV0, J (:)% (where a, b, C, and d represent a carbon or nitrogen atom that can be substituted, respectively, and a, b, c, and At least two of d represent a carbon atom that may be substituted, X represents an oxygen atom or a sulfur atom, and R4 may be the same or different and represents a hydrogen atom, a halogen, an alkoxy group, a nitro group, an amine group, an alkylamine group, Dialkylamine, alkyl, or hydroxyl, k represents an integer from 0 to 4, 1 represents an integer from 0 to 2, but R4 represents a methoxy group, and Het represents a 2-thiazolyl group, and k represents 1): Hydrogen atom, halogen atom, alkyl group, trifluoromethyl group, cyano group, -C02R5 (where R5 represents a hydrogen atom, an alkyl group or an aralkyl group), -OR5 '(wherein R5' represents an alkyl group, or Substitutable phenyl group), -NR2R3 (wherein R2 and R3 have the same meanings as above), substitutable well group, substitutable vein group, substitutable fluorenyl group, substitutable phenyl group, Substituted pyridyl, substituted thienyl, substituted furanyl, substituted piperidinyl, substituted pyrrolidinyl, substituted or substituted, substituted 1,4-piperazinyl, 1-piperidinyl which may be substituted, thiazolidinyl in which ear may be substituted, azetidinyl in which may be substituted, [jy butinyl in which may be substituted, -10- 200533356 (7) However, He 1 represents 1,2,4-thiadiP bonded to Dagen at the 2-position, and represents a hydrogen atom, an alkyl group, a trifluoromethyl group, a hydroxy group, a cyano group, a carboxyl group, an oxy group, and a dialkyl group. Amine, phenyl which may be substituted, pyran which may be substituted, thienyl which may be substituted, furanyl which may be substituted, substitutable group, when formula (1) k below, B ester, alkylidene group, Morpholine

(1) [wherein '1 represents 1 or 2' R1 represents a hydrogen atom, a radical, and 'R1 in -C02 is synonymous with the above), -S02-alkyl, -S02-aryl, CONH-radical , R2 represents Yuanji, Jingji, Junji 'or -C〇2Ri, 1 ^ has the same meaning as above)], or the following formula (2) R1 (Formula, or · (where

-(2) (wherein 'R and R2b' may be the same or different and represent a hydroalkyl group, an aryl group, or a substituted sulfonyl group, respectively)} a pharmacologically acceptable salt of a condensed derivative, Or these hydrates or solvates B represent a hydrogen atom, a halogen atom, an alkyl group, a trifluoromethyl group, · C02R5 (wherein R5 represents a hydrogen atom, an alkyl group, or an aralkyl group),

In the formula, R5 'represents an alkyl group or a phenyl group which may be substituted), -NR2R, and R2 and R3 have the same meanings as above), an arylalkyl group, an aminoalkyl group, an -11- atom, a substance or a compound thereof. (2) L group, _OR5 '(; (wherein hydroxyalkane 200533356 (8) group, alkoxyalkyl group, hydrazine group that can be substituted, fluorenyl group that can be substituted, phenyl group that can be substituted 'Substitutable thienyl, substitutable furanyl, substitutable, substitutable pyrrolidinyl, substitutable morpholinyl 1,4-piperazyl, substitutable 1- (1) p-derivatives of piperidinyl {However, Hel represents a hydrogen atom, an alkyl group, a trifluoromethyl group, a hydroxy group, an ester, an alkoxy group, and a dioxane when it is bonded to a tack at the 2-position. Amines, phenylpyridyls that can be substituted, thienyls that can be substituted, morpholinyls that can be substituted with furyl groups, pulsyl groups of the following formula (1) =, pyridyl, may (substituted The piperidinyl group may be substituted and the condensed 1,2,4-thiadiazolyl cyano group, the residue may be substituted i group, may be taken

[In the formula, 1 'represents 1 or 2, R1' represents a hydrogen atom, and R1 is synonymous with the above), -S02-alkyl, _s0CONH-alkyl, and R2 'represents an alkyl group, a hydroxyl group, or a carboxyl group. , Or ·, 1 ^ has the same meaning as above)], or the following formula (2), -C02R1 (Formula 2 -aryl, or _ C02R1 (where N_R1b · R2b, (2) (where, Rlb 'and R2b 'May be the same or different, and each shows a hydrogen atom, -12-200533356 (9) alkyl, aryl, or substituted sulfonyl)] or a pharmacologically acceptable or hydrate or solvate thereof. (3) ^ ^ v; Het is an unsaturated α α 5 condensed derivative or _ _ Xu salt as described in (1) or (2). , Or hydrates or solvates of this kind. The salt of Xu, the above-mentioned academic capacity that contains at least one ring

Is the following formula: (RV ^) a, b, c, & 4 at least three of which can be substituted β is a condensed taboo derived from any one of the above (1) to (3) Permissible salts, or hydrates or solvates of these. Hydrogen atom, alkyl, trifluoromethyl, hydroxy, cyano, carboxyl OR5 (wherein, r5 represents a radical, or a substituted benzene (In the formula, R2 and R3 have the same meanings as above), or any one selected from the group consisting of lower g or its pharmacology (5) B epitope, ester,-, -nr2r3 heterocyclic ring of formula -13-200533356 ( 10)

-(R6) p

1R6) n

[In the formula, Y represents an oxygen atom or a sulfur atom, and R6 may each represent a hydrogen atom, an alkyl group, a halogen atom, an alkoxy group, a hydroxyl group, a group, -C02R1 (wherein R1 has the same meaning as the above), a nitro group, and an amine group. Amine group, dialkylamino group, trifluoromethyl group, trifluoromethoxy group, R7 group, group group, -CC ^ R1 (where R1 has the same meaning as above), ·, -s〇2-aryl group, -CONH-alkyl, or phenyl which may be substituted are the same or different, and represent a hydrogen atom, a hydroxyl group, a hydroxymethyl group CC ^ R1, where Ri is synonymous with the above), or an alkyl group, R9 represents an alkyl group , Fluorenyl, -S02 · alkyl, -S02-aryl, R1 (), hydroxy, alkyl, carboxyl, -C02R1 (wherein R1 and ", -CONR2R3 (wherein R2 and R3 and The same meaning as above), an integer of m 5, η represents an integer of 0 to 4, and P represents 0 to 3 [indicating an integer of 0 to 8] of the condensed daphne derivative of any of the above (1) to (4) or Pharmacologically acceptable salt, or solvate or solvate. (6) Or different, aryl group, end group, and academic group represent hydrogen radicals • S Ο 2 -yuan, R8 can be divided, carboxyl,- Hydrogen atom is synonymous with hydrogen atom. Integer, q item described in these water

-14- 200533356 (11) is the following formula, (r4 > 4) k represents 0, 1 or 2 and the condensed tadpole derivative described in any one of (1) to (5) above or its pharmacologically acceptable Salts, or hydrates or solvates of these. (7) A saturated or unsaturated 5-membered heterocyclic ring is any one selected from the group consisting of alkyl, hydroxyalkyl, alkoxyalkyl, trifluoromethyl, hydroxy, aryl, Heteroaryl, halogen atom, cyano, carboxyl, -C02R11 (wherein R11 represents an alkyl group or an aralkyl group), or-CONR12 R13 (wherein R12 and R13 may be the same or different, respectively, and represent a hydrogen atom , An alkyl group, or an aralkyl group which may be substituted or R12 and R13 may together form a 4 to 7-membered ring) of the following heterocyclic heterocycles: the condensations described in any one of (1) to (6) above Dazu derivatives or pharmacologically acceptable salts thereof, or hydrates or solvates thereof, imidazolyl, oxazolyl, thiazolyl, 1,2,4-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1,2,4-triazolyl, pyrazolyl, tetrazolyl, oxypyrazolyl, 2,5-dihydro-5-oxo-4H-1,2,4-thia Diazole, 2,5-dihydro-5-thio-41 ^ 1,2,4-thiadiazole, 2,5-dihydro-5-oxo-4 Η 1,2,4 -oxadiazole , 2,5-dihydro-5 -thio-4-4, 1,2,4-oxadiazole, 4,5-dihydroimidazolyl, 4,5-dihydrooxazolyl, and 4,5- Hydrogenated thiazolyl. (8) m is 0, 1 or 2, η is 0, 1 or 2, ρ is 0, 1 or 2, and q is 0 ,! Or the condensed dagen derivative according to any one of the above (1) to (7), or a pharmacologically acceptable salt thereof, or a hydrate or a solvate thereof. (9) Any one selected from the group consisting of condensed tarchin derivatives or their pharmacology -15-200533356 (12) Permissible salts, or hydrates or solvates thereof,

1- (1-methyl-1H-Wing-2-yl) -4-phenylphenyl, (4-methoxyphenyl) -4- (1-methyl-1H-imidazol-2-yl ) Phthalazine, 1β (1-methyl) H-imidazol-2-yl) -4- (4-trifluoromethoxyphenyl) phthalazine, h methyl-1Η-imidazol-2-yl) Xiao Xiao, 1- (2-furyl) -4- (1-methyl-1H-imidyl-2-yl) phthalazine, [4-O-methyl-1H · imidazol-2-yl ) Phthalazine-butyl] -piperidin-4 -alcohol, 1- (1-methyl-1H -imidino-2-yl) -4- (4-B than U yl) 2- (4-phenylphthalazin-1-yl) -3H-imidazole-4-nitrile, 3-methyl-2- (4-phenylphthalazin-1-yl) -3H-imidazole-4 -Carboxylic acid, fluorene- [5- (4,4 · dimethyl-4,5-dihydro-oxazol-2-yl) -1-methyl-1! 1-imid 1] thio-2-yl ] -4-Phenylpyrazine, 1-phenyl-4- (1H -tetra-11-s--5-yl) corazine, 1- (2-methyl-2H-tetrazol-5-yl) -4- Phenylphthalazine and 1-pyridin-4-yl-4- (2,5-dihydro-5-oxo-411-1,2,4-thiadiazol-3-yl) phthalazine. The present invention also relates to the following therapeutic or inhibitory drugs. (10) The condensed daikon derivative or the pharmacologically acceptable salt thereof described in any one of (1) to (9) above as an active ingredient. Prevention or treatment of ischemic heart disease. (Π) A prophylactic or therapeutic agent for acute coronary syndromes in which the condensed daikon derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (9) is used as an active ingredient. (1) The medicament for the prevention or treatment of myocardial infarction, the condensed daikon derivative or a pharmacologically acceptable salt thereof described in any one of (1) to (9) above as an effective ingredient. (1 3) The medicament for the prophylaxis or treatment of angina pectoris with the condensed data derivative or the pharmacologically acceptable salt thereof described in any one of (1) to (9) above as an active ingredient. (14) The shrinkage described in any one of the above (1) to (9) -16-200533356 (13) A drug for the prevention or treatment of arteriosclerosis as an effective ingredient of a hydrazine derivative or a pharmacologically acceptable salt thereof . (15) The NAD (P) (R) oxidase inhibitor as the active ingredient of the condensed daikon derivative or the pharmacologically acceptable salt thereof according to any one of (1) to (9) above. Examples of the substituent of the "substitutable phenyl group" in this specification include an alkyl group, a halogen atom, an alkoxy group, a hydroxy group, a cyano group, a carboxyl group, and -C02R1 (wherein "R1 has the same meaning as the above") nitro and amine Group, alkylamino group, dialkylamine group, trifluoromethyl group, trifluoromethoxy group, sulfide, fluorene, fluorene, -S-alkyl, -SO-alkyl, -S02-alkyl Etc., the phenyl group may be substituted by 1 to 5 of the same or different substituents mentioned above, and when 2 substituents form a ring, the "substitutable phenyl group" may also be 2,3-dihydroxy-1-benzene And furan. In addition, more preferable substituents of the "substitutable phenyl group" include an alkyl group, a halogen atom, an alkoxy group, a hydroxy group, a cyano group, a carboxyl group, -C02R1 (wherein R1 has the same meaning as the above), a nitro group, and an amine. Group, alkylamino group, dialkylamino group, trifluoromethyl group, trifluoromethoxy group, etc., the phenyl group may be substituted with 1 to 5 of the same or different substituents. The substituents of the "substitutable pyridyl group" in this specification include the same substituents as those of the "substitutable phenyl group", and the pyridyl group may be substituted with the same or different substituents from 1 to 4 Each. The substituent of the "thinyl group which may be substituted by r" in this specification includes the same substituents as those of the "substitutable phenyl group", and the thienyl group may be substituted by the same or different substituents. 1 to 3. Examples of the substituent of the "furanyl group which may be substituted" in this specification include the same substituents as the substituent of "phenyl group which may be substituted", which furanyl -17-

200533356 (14) 1-3 may be substituted with the same or different substituents. The nitrogen of the "piperidinyl group which may be substituted" in this specification may include an alkyl group, -CC ^ R1, -S02 · alkyl group, -s02-CONH-alkyl group, etc., and the substituent on the cyclic carbon may be Examples include alkyl groups and -C02R1. In the present specification, the "substituted pyrrolidinyl group" includes alkyl groups, -C02R1, -S02-alkyl groups, -302 · C 0 N N -alkyl groups, and the substituents on cyclic carbons include alkyl groups. Group, or -CC ^ R ^ in the formula, R1 is synonymous with the above), and the hydroxyl group is more preferably an alkyl group, "C02R1, -S02-alkyl group, -S02" -An aryl group, a g group, and the like. Examples of the substituent on the cyclic carbon include an alkyl group, a hydroxyl group, and 0021 ^ (wherein R1 has the same meaning as the above). In the present specification, the "substitutable 1,4-piperazinyl group" may have alkyl, fluorenyl, -S02-alkyl, and · S02-aryl substituents on the carbon of the piperazinyl ring. To replace. In the present specification, the "1-piperidinyl group which may be substituted" includes isohydroxyl, alkyl, carboxyl, -C02R1 (wherein R1 and -CONR2R3 (wherein, R2 and R3 have the same meanings as above), groups, and the like. And more preferable substituents of "1-piperidinyl which may be substituted", alkyl group, carboxyl group, -C02Ri (wherein R1 is the same as CONR2R3 (wherein R2 and R3 have the same meanings as above), etc. In the description, the substituted substituents of "morphoyl which may be substituted" are a square group, or a substituent of a hydroxyl group, a carboxyl group, a square group, or a-, a hydroxyl group, a carbapenyl group, etc. The substituents can be listed as ICONH-alkane Residues, or _ substituents, nitrogen, etc., and these substituents include the same meanings as above) alkoxy, cyano, and the like are synonymous with hydroxyl),-groups include the same -18-200533356 (15) hydroxyl, alkyl, Carboxyl group, -CC ^ R1 (wherein R1 is synonymous with the above) CONR2R3 (wherein R2 and R3 are synonymous with the above) and the like. The substituents of the "substituted thiazolidinyl group" in this specification include the same substituents as the substituents of the "substitutable phenyl group", and the alkyl group may be substituted with the same or different substituents from 1 to Three. In the present specification, the substituents of the "substitutable azetidinyl group" and the substituents of the "substitutable butyl D group" include the same substituents as the substituents of the "substitutable phenyl group". Cyclopropylalkyl and pyridyl may be substituted with the same or different substituents as described above. The "saturated or unsaturated 5-membered heterocyclic ring" in this specification may include a radical, Πoxal, thiocarbyl, 1,2,4-η-oxadioxo, 1,3,4 · Πoxadiisotope 1,2,4-triazolyl, pyrazolyl, tetrazolyl, oxypyrazolyl, 2,5-dioxo-4,1,2-4-thiadiazole, 2,5-dihydro- 5-thio-41 ^ 1,2,4-thiadi2.5-dihydro-5-oxo-4! ^-1,2,4-oxadiazole, 2,5-dihydro-5-thio 1 , 2,4-oxadiazole, 4,5-dihydroimidazolyl, 4,5-dihydrooxazolyl 4.5-dihydrodiazolyl, and the like. The substituent of the heterocyclic ring is an alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a methyl group, a hydroxy group, an aryl group, a heteroaryl group, a halogen atom, a cyano group, a carboxyl group, or -C02R11 (wherein, R11 represents a radical, Or aryl group) CONRI2R13 (wherein R12 and R13 can be the same or different from SIJ 'table atom, alkyl group, or aryl group that can be substituted, or R12 and Rl3 can be 4 to 7 member ring), etc., It is preferred that it may have one or more substituents selected from the group consisting of an alkyloxyalkyl group, a trifluoromethyl group, a hydroxyl group, an aryl group, a heteroaryl group, a halogenogen cyano group, or a carboxyl group. Seletiline ortho, substituted azetimidazolyl, i-5-orally, -4H- or trifluoro,,--Hydrogen shape, alkyl, -19-200533356 (16) In this specification " The "alkyl group" may be a linear or branched chain having 1 to 8 carbon atoms, and examples thereof include methyl, ethyl, n- (hereinafter abbreviated as η-) propyl, isopropyl, butyl, and isobutyl. Group, tertiary (hereinafter abbreviated as t-) butyl, n-pentyl, n-hexyl, or n-octyl, and the like. The "alkoxy group" in this specification is preferably a linear or branched chain having 1 to 8 carbon atoms, and examples thereof include methoxy, ethoxy, propoxy, butoxy, pentyloxy, and hexane. Oxy, octyloxy, etc. The alkylthio group is preferably a linear or branched chain having 1 to 8 carbon atoms, and examples thereof include methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, and octylthio. Base etc. The alkoxy group is preferably a linear or branched chain having 1 to 8 carbon atoms, and examples thereof include methyl methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, and hexamethylene. Ethoxy, or octyloxy. Examples of the "halogen atom" in this specification include fluorine, chlorine, bromine, and iodine. The "hydroxyalkyl group" in this specification is preferably a hydroxyalkyl group having 1 to 3 carbon atoms, and examples thereof include a hydroxymethyl group, a 2-hydroxyethyl group, and a 3-hydroxypropyl group. The aryl part of the "arylalkyl" in this specification is the same as the above, and the alkyl part thereof may preferably be a linear or branched chain having 1 to 3 carbon atoms, and examples thereof include benzyl and phenethyl , 3-phenylpropyl, 1-naphthylmethyl, 2- (1-naphthyl) ethyl, 2- (2-naphthyl) / ethyl, or 3- (2-naphthyl) propyl, etc. . The alkoxyalkyl group in this specification has the same alkoxy portion as described above, and the alkyl portion thereof may preferably be a linear or branched chain having 1 to 3 carbon atoms, and examples thereof include ethoxymethyl, Methoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 2-methoxypropyl and the like. "Aminoalkyl" in this specification may be substituted with any of -20- 200533356 (17) alkyl, square, heteroaryl, or heterocyclic groups. The nitrogen ring 'its alkyl portion may preferably be a linear or branched chain having 3 to 3 carbon atoms'. Examples include aminomethyl, aminoethyl, dimethylaminoethyl, ... Ethyl, N-phenylaminoethyl, or 3-aminopropyl. The "heterocyclic group" in this specification is a 4- to 6-membered ring group having carbon and at least one nitrogen, and may have other heteroatoms (oxygen or sulfur). Specifically, azetidine, Pyrrolyl, piperidinyl, piperazinyl, morpholin |, thiomorpholinyl, oxythiomorpholinyl, or dioxythiomorpholinyl, and the like. The "aryl group" in this specification is preferably a phenyl group, a naphthyl group, or an ortho-bicyclic cyclic bicyclic group having 8 to 10 ring atoms and at least one ring is an aromatic ring (indenyl) . The "heteroaryl group" in this specification preferably includes a 5 to 6 membered ring group having a carbon number and 1 to 4 heteroatoms (oxygen, sulfur, or nitrogen), or 8 to 10 rings derived therefrom. Bicyclic heteroaryl groups with ortho-positions of atoms, especially phenylhydrazone derivatives, or propylene, tertiary methyl, tetramethyl groups, and their combinations | Derivatives, and their stable N-oxides Etc. 'e.g. proline, furanyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, 1, 3, 5 -Oxadiazolyl, i, 2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyrimidinyl, daphnyl, 1,2,4-triazinyl, 1 , 2,3-triazinyl, 1,3,5-triazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, thienylmethyl, isothienylmethyl, benzofuranyl, Isobenzofuranyl, benzopyranyl, isoindolyl, indolyl, isoD-quinolinyl, quinolinyl, phthalazinyl, quinoxalinyl, quinolinazolyl, fluorinyl, or Benzoπoxazine and the like. -21-200533356 (18) In this specification, rR2 and R3 can form a 4- to 7-membered ring together. "R 4 to 7-membered ring" can be exemplified by, for example, Pyaddin, Shaluoyuan, Qiliyuan, Pulse, Piperidine, morpholine, azetidine, etc. The "4- to 7-membered ring" may have a substituent on the ring, and examples of the substituent include alkyl, alkoxy, hydroxyl, carboxyl, fluorenyl, sulfide, and fluorene.

In this manual, the enzyme abbreviated as "NAD (P) Η oxidase" can also be abbreviated as NADH (Nicotinamide adenine dinucleotide / Nicotinamide adenine dinucleotide, hereinafter abbreviated as NADH) oxidase, NADH / NADPH (Nicotinamine gland Purine dinucleic acid phosphate / Nicotinamide adenine dinucleotide phosphate (hereinafter abbreviated as NADPH) oxidase, or NAD PH oxidase, as long as NADH and NADPH are used as the substrate to produce. 〇, enzymes are included in the NAD (P) Η oxidation of the present invention Enzymes, and tissues such as the vascular cell system, heart, kidney, omentum, microglial cells, and tumor cells where the NAD (P) (R) oxidase is found are not particularly limited. In the present specification, "inhibition of NAD (P) Η oxidase" includes all inhibitory effects including reducing the amount of 02_ produced by NAD (P) Η oxidase, and means, for example, inhibition of NAD (P) Η oxidase activity , Inhibit the activation process, or inhibit the performance of ingredients. The term "ischemic heart disease" in this specification refers to a condition in which the lumen of the blood vessel of the heart is narrowed or blocked for some reason, and cannot provide sufficient oxygen and nutrition to the heart. The "acute coronary syndrome" in this specification refers to a disease group in which coronary atherosclerosis-22- 200533356 (19) ruptures a coronary tumour to form a thrombus and causes a blockage in the lumen, and cannot provide sufficient oxygen and nutrition to the heart. Examples of the disease include acute myocardial infarction, unstable angina, and the like. "Myocardial infarction" in this specification refers to a state of myocardial tissue necrosis due to a high degree of ischemia caused by circulatory disturbance of the coronary arteries. This disease state can be exemplified by acute myocardial infarction, old myocardial infarction, transmural Myocardial infarction, non-transmural myocardial infarction, etc. The term "asthma" in this specification refers to temporary myocardial ischemia due to the disruption of the balance of oxygen demand and supply in the myocardium. Examples of such diseases include stable angina, unstable angina, and working angina Disease, quiet angina, heterozygous angina. "Arteriosclerosis" in this specification refers to arterial thrombosis and atheromatous arteries due to the loss of elasticity of the arteries, the narrowing of the arterial lumen, the blockage of the arteries, or the aneurysms that cause blood flow disorders in the entire tissue and organs. Wait hard. "Prevention" in this manual refers to the prevention of the disease of those who have not suffered from the disease, and the prevention of the recurrence of those who have suffered from the disease once but have been cured or whose disease has become the old disease, especially the patients with hyperlipidemia and diabetes , Hypertension patients, smokers, etc. who are considered to be at high risk of arteriosclerosis and ischemic heart disease, or patients who have suffered from arteriosclerosis and ischemic heart disease for a time will no longer cause ischemia in the future Cardiomyopathy 'is the onset of myocardial infarction and stenosis. Next, the manufacturing method of the compound of this invention is demonstrated. The compound of the present invention can be produced by combining a reaction suitable for the target compound. The method is represented by the following reaction scheme, but it is not limited to the method described below. (Manufacturing method v The following describes a manufacturing method when the part of the general formula (I) is a benzene ring 'pyridine, furan, or thiophene which can be substituted.

0 ^ 0 step (11

Step (1) is a step for producing 2-ketobenzoic acid from phthalic anhydride. (A) Addition reaction of an acid anhydride with a metal reagent, or (b) Friedel of an aryl compound and an acid anhydride. -Krafts reaction. In the case of (a), an aryl metal or an alkyl metal can be used as the organometallic reagent. Examples of the metal include lithium and magnesium. Examples of the solvent used include diethyl ether and ethers such as t-butyl methyl ether. Tetrahydrofuran (hereinafter abbreviated as THF), dioxane, hexane, cyclohexane, benzene, toluene, methylidene dichloride, -24-200533356 (21) dichloroethane, etc. These can be used alone or in combination. When the temperature is -78 ° C to 100 ° C, preferably -78 ° C to 30 ° C, and the reaction time is 5 minutes to 24 hours. (B) In the case of using aluminum chloride, titanium tetrachloride, chlorine Tin catalyst, boron trifluoride diethyl ether, etc. can be used as the catalyst. Solvents such as methylene dichloride, dichloroethane, nitrobenzene, or carbon disulfide can be used. The reaction temperature is -7 8 ° C ~ 200 ° C. It is preferably -50 ° C to 100 ° C, and the reaction time is 5 minutes to 24 hours. Step (2) is a step of producing condensed tetrahydropyridone (2). The reaction can be performed by using (1) and The reaction is carried out with hydrazine or perone hydrate. When using a solvent, water, methanol, ethanol, ethylene glycol, benzene, or toluene is used. The reaction temperature is 20 ° C ~ 200 ° C, preferably 20 ° C. C~100 ° C, the reaction time is 5 minutes ~ 4 8 hours, preferably 1 hour ~ 1 billion hours. Step (3) is a step of producing 2-ketobenzoate (3) by a Friedel-Krafts reaction of a dicarboxylic acid half ester with an aromatic compound, and B of compound (3) represents 2-thio Umyl, or 2-furyl. In this reaction, aluminum chloride, titanium tetrachloride, osmium chloride, or boron trifluoride diethyl ether is used as a catalyst, and methylene dichloride, dichloroethane, nitrobenzene, or carbon disulfide can be used. Solvent, the reaction temperature is -78 ° C ~ 200 ° C, preferably -50 ° C ~ 100 ° C, and the reaction time is 5 minutes to 24 hours. Step (4) is a step for producing the condensed tetrahydropyridone (4), and the reaction can be carried out by reacting (3) with hydrazine or a hydrazine hydrate. When using solvents, use water, methanol, ethanol, ethylene glycol, benzene, or toluene, etc. The reaction temperature is 20 ° C ~ 200 ° C, preferably 20 ° C ~ 100 ° C, -25- 200533356 (22) The reaction time is 5 minutes to 48 hours, preferably 1 hour to 10 hours. Step (5) is to react the amidine compound with a salt group such as butyllithium, etc. The ortho-metalized organometallic intermediate reacts with the amidine reagent, and in the ortho position, _ is substituted to obtain a 2-ketocarboxylic acid. In the step of amidine (5), B in compound (5) may be a substituted benzene ring, an aromatic heterocyclic ring, an alkyl group, or the like. As the fluorene compound, a fluoranilide compound, an N, N-diethylfluorene compound, a 1-phenyl-1-methylethylfluorene compound, or the like can be used. As the base, butyl lithium, B sec-butyl lithium, t-butyl lithium, or the like may be used in an amount of 1 to 3 equivalents based on the amidine compound. In this step, auxiliary tetramethylethylenediamine and the like can be added. Examples of the solvent include ethers such as diethyl ether or t-butyl methyl ether, THF, dioxane, hexane, cyclohexane, benzene, toluene, methylidene dichloride, dichloroethane, and the like. Can be used alone or in combination. Examples of the halogenating agent include N, N-dimethylamidamine derivatives, N-methyl · N-methoxyamidamine derivatives, and europium chloride. ρ The reaction temperature is -78 ° C ~ 100 ° C, preferably -78 ° C ~ 30 ° C. Step (6) is a step of obtaining 2-ketocarboxylic acid (6) from methyl 2-ketocarboxylic acid amidine (5). The reaction system can use water, sulfuric acid hydrolysis, and oxidant reaction. The reaction temperature is 20 ° C. ~ 100 ° C, reaction time is 10 minutes ~ 24 hours. Step (7) is a step for producing the condensed tetrahydrodazone (7). The reaction can be carried out by reacting (6) with hydrazine or a hydrazine hydrate, or by reacting (5) with hydrazine or a hydrazine hydrate. When using solvents, use water, methanol, ethanol, ethylene glycol, benzene, or toluene. • 26-

200533356 (23) The reaction temperature is 20 ° C ~ 200 ° C, preferably 20 ° C ~ 100t, and the time is 5 minutes ~ 48 hours, preferably 1 hour ~; [〇 小时. Step (8) is a step of reacting an organic intermetallic substance produced from 2-iodobenzoate with a tritiated reagent and introducing a fluorenyl group at the ortho position to prepare a 2-ketoester (8). The organic intermediate produced by the reaction of isopropyl Grignard reagent and the inorganic zinc compound (ZnCl2, ZnBr2, or Znl2, etc.) is converted into an organic zinc compound, and is reacted with a halogen compound in the presence of a catalyst The target compound can be produced. Divalent ethers can be used as the catalysts such as 0-valent or 2-valent Pd catalysts (Pd (PPh3) 4, ΐ (PPh3) 2 Cl2, etc.) and 0-valent or 2-valent Ni catalysts. Or t-butyl methyl ether ethers, THF, dioxane, hexane, cyclohexane, benzene, toluene, methyl chloride, dichloroethane, etc., which can be used alone or in combination. The reaction temperature is -78 ° C ~ 100 ° C, preferably -78 ° C ~ 30 ° C. Step (9) is a step of producing condensed tetrahydrocodone (11). The reaction system can be carried out by reacting (8) with hydrazine or hydrazine hydrate. When using a solvent, water, methanol, ethanol, ethylene glycol, benzene, or the like can be used. / The reaction temperature is 20 ° C to 200 ° C, preferably 20 ° C to 100 ° C, and the time is 5 minutes to 48 hours, preferably 1 hour to 10 hours. Step (10) is to react a dimethyloxaziridine compound with a group such as butyllithium and ortho-metalized organometallic intermediate to react with a tritiated reagent to introduce a fluorenyl group at the ortho position to obtain 2-ketocarboxylic acid hydrazone Step of amine (9). In the reaction, the metal carboxylic acid is used to react with lc lc Pd and so on. The toluene reaction salt, in -27-200533356 (24) Compound (5), B may be substituted benzene ring, aromatic heterocyclic ring, alkyl group, and the like. As the fluorene compound, a fluoranilide compound, an N, N-diethylfluorene compound, or a 1-phenyl-1-methylethylfluorene compound can be used. As the base, η-butyllithium, sec-butyllithium, or t-butyllithium, etc. are used in an amount of 1 to 3 equivalents based on the amidine compound. Tetramethylethylenediamine can be added as a reaction auxiliary reagent. Examples of the solvent include ethers such as diethyl ether or t-butyl methyl ether, THF, dioxane, hexane, cyclohexane, benzene, toluene, and methyl formaldehyde. Fork dichloro, dichloroethane and the like can be used alone or in combination. As the halogenating agent, N, N · dimethylamidine derivatives, N-methyl-N-methoxyamidamine derivatives, or europium chloride can be used. When rhenium chloride is used as the hydrating agent, 0- or 2-valent Pd catalysts (Pd (PPh3) 4, or Pd (PPh3) 2 Cl2, etc.) and 0- or 2-valent N i catalysts can be used as catalyst. The reaction temperature is -78 ° C ~ 100 ° C, preferably -78 ° C ~ 30 ° C. Step (11) is a step of producing 2-ketocarboxylic acid (10) from 2-ketooxazoline compound (9). The reaction can be carried out in the presence of hydrochloric acid, sulfuric acid, methanesulfonic acid, or tosylsulfonic acid. The solvent can be used alone or as a mixture of water, dioxane, THF, or methanol. In the step of ketone (1 1), the reaction can be carried out by reacting (10) with hydrazine or hydrazine hydrate. When a solvent is used, water, methanol, ethanol, ethylene glycol, benzene, or toluene is used. -28-

200533356 (25) The reaction temperature is 20 ° C ~ 200 ° C, preferably 2 (TC ~ 100 ° C, the reaction time is 5 minutes ~ 48 hours, preferably 1 hour ~ 10 hours. Step (3) It is a step of producing compound (12) by the chlorination reaction of compounds (2), (4), (7) and (11). As the chlorinating agent, thionyl chloride, phosphorus oxychloride, and trichloride can be used. Phosphorus, phosphorus pentachloride, etc. The reaction can be carried out in a solvent-free or solvent such as benzene, toluene, chloroform, or diethane, etc. Step (14) is a step of producing compound (13) from compound (12), step ( The part of G) of compound (1) in 14) represents a substituted benzene ring. It can implement by making a heterocyclic organic boron compound, a heterocyclic organic zinc compound, and a heterocyclic organic tin compound react under a catalyst. Heterocyclic organotin compounds can be prepared from organolithium or organomagnesium compounds and alkyltin chlorides, and can be used in the reaction of step (14) without isolation. Both heterocyclic organic boron compounds and heterocyclic organic zinc compounds can be prepared in the same manner as above using boron esters, zinc halides, and can be used in the reaction of step (14) without isolation. The organolithium compound can be prepared by lithiation with a salt of butyl lithium or the like, or by element-lithium exchange with a halogen compound. Pd catalysts (such as Pd (PPh3) 4, or (PPh3) 2 Cl2) with zero or two valences, and Ni catalysts with zero or two valences can be used as catalysts. The reaction temperature is -78 ° C to 200 ° C, preferably 0 ° C to 120 ° C. Examples of the solvent to be used include diethyl ether, t-butyl methyl ether, and the like, and -29-200533356 (26) ethers, THF, dioxane, hexane , Cyclohexane, benzene, toluene, xylene, methylidene chloride, dichloroethane, etc., which can be used alone or in combination. This step can be carried out by converting the compound (1 2) into a rough substance and then reacting it with an organolithium compound. The compound (13) in which the part of G) is pyridine, furan or thiophene, and the benzene ring part of the starting material in step (3), (5), (8), (10) is selected from pyridine, furan, or The compound of thiophene can be produced by the same method as above.

The compound of the present invention can be synthesized by the following method. (Manufacturing Method 2)

Step (15) Step ⑽ ——- Gv —— ^ Het (14) (15)

Step (17)-^

(16)

Step (18) B-M or B-H 〇ΓΒ (·)

B

(13) ο

co2h 〇 Impede ηη, step (19) -►

conh2 (17)

CN (18) Step (18) B-M-or B-H orB (_) Step (21) Θφ— Θφ CN Het (19)

Het (13) Step (15) is a step of making heterocyclic substituted ketone (14) from carboxylic acid. The reaction is to convert carboxylic acid to thallium chloride through thionyl chloride or chloracetin. It is carried out by treating with a heterocyclic ring such as N-methylimidazole and a salt group of triethylamine. When a solvent is used, methylene chloride, acetonitrile, benzene, or toluene is used. -30- 200533356 (27) The reaction temperature is 0 ° C ~ 100 ° C, preferably 0 ° c ~ 30 ° c, and the reaction time is 1 hour ~ 48 hours, preferably 1 hour ~ 10 hours . Step (16) is a step of producing condensed tetrahydrodrone (15). The reaction can be carried out by reacting (14) with hydrazine or a hydrazine hydrate. When a solvent is used, water, methanol, ethanol, ethylene glycol, benzene, or toluene is used. The reaction temperature is 20 ° C to 200 ° C, preferably 20 ° C to 100 ° C, and the reaction time is 5 minutes to 48 hours, preferably 1 hour to 10 hours. Step (17) is a step of producing compound (16) by a chlorination reaction of compound (15). The chlorinating agent is thionyl chloride, phosphorus oxychloride, phosphorus trichloride, or phosphorus pentachloride. The reaction can be carried out in a solvent-free or solvent such as benzene, toluene, chloroform, or dichloroethane. Step (18) is a step of producing compound (13) of the present invention from compound (16). BM represents an organometallic compound such as an organic boron compound, an organic zinc compound, or an organic tin compound. This can be performed under a catalyst. A step (18) is carried out by reacting with the compound (16). A commercially available compound may be used as the organic boron compound, the organic zinc compound, or the organic tin compound, but it may be prepared by itself. Organotin compounds can be prepared from organolithium or organomagnesium compounds and trialkyltin chloride, and can be used without 'isolation'. The organic boron compound and the organic zinc compound can be prepared in the same manner as described above using a borate ester and a zinc halide, and can be used without isolation. The organolithium compound can be prepared by lithiation of a base such as butyllithium or halogen-lithium exchange with a halogen compound. Pd catalysts with a valence of 0 or 2 (Pd (PPh3) 4 or Pd -31-200533356 (28) (PPh3) 2 Cl2, etc.) and Ni catalysts with a valence of 0 or 2 can be used as the catalyst. The reaction temperature is -78 ° C ~ 200 ° C, preferably 0 ° C ~ 120 ° C. Examples of the solvent to be used include ethers such as diethyl ether or t-butyl methyl ether, THF, dioxane, hexane, cyclohexane, benzene, toluene, xylene, methylidene dichloride, and dichloroethyl. , DMF, N-methylpyridinolone 'These can be used alone or in combination

This step can also be carried out by reacting compound (16) with B-Η, where B-Η and B (·) represent a nucleophile (amine, thiol, or metal alkoxide, etc.), The reaction temperature is -78 ° C to 200 ° C, preferably 0 ° C to 160 ° C. Examples of the solvent to be used include ethers such as diethyl ether or t-butyl methyl ether, THF, dioxane, methanol, ethanol, hexane, cyclohexane, benzene, toluene, xylene, and methylidene dichloride. , Dichloroethane, DMF, N-methylpyrrolidone, these can be used alone or in combination. Step (19) is a step of converting a carboxylic acid to amidine (17), and a conventional method can be used. Step (20) is a step for producing compound (18) by chlorination reaction of compound (17). Chlorinating agent may be used alone or in combination with thionyl chloride, phosphorus oxychloride, phosphorus trichloride, or Phosphorus pentachloride and the like can be carried out in a solvent-free or solvent such as benzene, toluene, chloroform ', or dichloroethane. Step (21) is a step for producing compound (13) of the present invention from nitrile (19), and the ring closure can be performed by a conventional method. For example, N-hydroxyamidine obtained by reacting hydroxylamine with nitrile can be treated with osmium chloride or acid anhydride to obtain oxadiazole, and various condensing agents (CDI, DCC (Dicyclohexylcarbodiimide), etc. -32 can also be used. -200533356 (29) Condensation of carboxylic acid with N-hydroxy hydrazone, and then heating it to make ring closure. It can also convert N-hydroxy hydrazone to chloroformic acid and thiocarbonyldiimidazole to convert them into oxygen. Substituted oxadiazoles and thiooxadiazoles. In addition, N · hydroxyphosphonium is added to thiocarbonyldiimidazole, and further treated with boron trifluoride ethyl ether complex to obtain thiooxadiazoles. Other examples are listed. An azide compound such as sodium azide is reacted with a nitrile to be converted into a tetrazole. An ethylenediamine derivative can also be reacted with a nitrile to obtain a dihydroimidazole.

The compound of the present invention can be further produced by the following method.

Step (22) is a step of reacting the phthalazinone compound produced by the above-mentioned method with a heterocyclic lithium compound to produce a compound of the present invention. Examples of the heterocyclic lithium compound include N-substituted-2-lithium compounds, and the amount of the heterocyclic lithium compound may be 200 to 500 mole% relative to the phthalazinone. The reaction temperature is -78 ° C ~ 65 ° C, preferably -50 ° C ~ 20 ° C. Examples of the solvent to be used include ethers such as diethyl ether or butyl methyl ether, THF, dioxane, methanol, ethanol, hexane, cyclohexane, benzene, toluene, xylene, methylidene chloride, Dichloroethane and the like can be used alone or in combination.

A -33- 200533356 (30) The compound of the present invention can also be produced by the following method (manufacturing method 4)

Step (23) Closed loop

B

When the Het step (2 3) is a conversion from a nitrile (the compound to the right of the starting material), the method can be carried out in accordance with the method of step (21), and the carboxylic acid compound (starting material) obtained by hydrolysis of the nitrile, etc The left compound) can be converted into various heterocyclic rings according to conventional methods. For example, the left compound of the starting material is converted into amidine with amine and a condensing agent, and then reacted with phosphorus pentachloride and trimethylsilazide to obtain tetrazole. In addition, by heating in the amidine compound polyphosphoric acid obtained by the reaction with acetamidine, # 1,3,4-oxadiazole can be obtained, and the compound can be converted into 1,3 by reaction with p-methoxybenzylamine. , 4-triazole derivative. Trifluoroacetic acid was added and heated to obtain a debenzylated triazole compound. Further, the 1,3,4-oxadiazole compound was treated with Lawesson's Reagent to obtain a 1,3,4-thiothia compound. The left compound of the starting material is converted with carbonyldiimidazole, ethyl malonate, magnesium chloride, and 3-oxophthalazine-1-yl-propionic acid, so that this ester can be converted into pyridine by reaction with pyrazine. Oxazoline derivatives. Substituents may be introduced into the aromatic ring of the obtained phthalazine compound (containing the heterocyclic ring 5-34-200533356 (31)). For example, chlorine, bromine, iodine, NCS, NBS, or NIS can be used for halogenation Implementation, the introduced halogen atom can be introduced into other derivatives using various metal catalysts, such as cyanation using CizCN, various organometallic compounds (organic tin compounds, organic zinc compounds, or organic boron compounds, etc.) ) Coupling can also be performed using a reaction such as a Pd compound as a catalyst. The obtained compound can also be converted into a functional group by a method of protection, deprotection, or reaction such as alkylation, hydrolysis, and the like. Each compound obtained by the above method can be isolated and purified by general chemical operations such as extraction, crystallization, recrystallization, various chromatography, and the like. The compound of the present invention is prepared into a dosage form (powder, injection, lozenge, capsule, or topical preparation, etc.) together with a suitable diluent and other additives generally used, and then the dosage form is formulated. Appropriate administration methods (such as intravenous injection, oral administration, subcutaneous administration, or local administration, etc.) can be administered to humans or animals. | The above-mentioned acid addition salt or base addition salt can be used as the salt of the compound of the formula (I), and the type of the salt is not particularly limited as long as it is physiologically tolerable. 0 Condensed daphne represented by the general formula (I) Derivative salts, or hydrates or solvates of these, can be produced from condensed derivatives by conventional methods. One or two or more compounds of the formula (I) or a salt thereof of the present invention may be directly administered to a patient, but it is preferable to add an active ingredient and a pharmacologically and pharmaceutically acceptable additive. Those skilled in the art are familiar with the formulations of 35-200533356 (32). For pharmacologically and pharmaceutically acceptable additives, excipients, disintegrating agents, binding agents, slip agents, coating agents, pigments, diluents, bases, and isotonicity agents can be used. Formulations suitable for oral administration include, for example, lozenges, capsules, powders, fine granules, granules, liquids, or syrups, and formulations suitable for non-oral administration include injections, drips, or suppositories. . Formulations suitable for oral administration can use excipients, disintegrating agents, binding agents, smoothing agents, coating agents, bases as additives, and when the compounds of the present invention are administered to patients to be treated, Other agents suitable for the treatment of a subject patient are used in combination with the compound of the present invention. The administration route of the medicine of the present invention is not particularly limited, and can be administered orally or parenterally. The dose of the medicine of the present invention can be appropriately determined according to conditions such as the purpose of disease prevention and / or treatment, the age and state of the patient, and the like. Selection, in general, about 0.001 to 100 mg / kg, preferably about 0.00 1 to 1 mg / kg for adults, administered by injection or drip, and about 0.001 to 100 mg / kg, preferably about 0.001 to 30 mg / kg is preferably administered orally. [Embodiments] The present invention will be described in more detail by the following examples, but the scope of the present invention is not limited to the following examples, and the following examples use conventional abbreviations. THF = tetrahydrofuran, DMF = N, N-dimethylformamide, DMSO = di-36- 200533356 (33) methylimine, CDI = carbonyldiimidazole, DPPA = diphenylphosphonium azide, Z = benzyloxycarbonyl, Boc = tert-butyloxycarbonyl, DMF = dimethylformamide, THF = tetrahydrofuran. NMR stands for nuclear magnetic resonance spectrum, and the number is used to indicate the general chemical shift of 5 (delta) 値, the unit is ppm. , Using TMS (tetramethylsilane) or residual protons in deuterated solvents (DMSO-D6: 2.5ppm) as internal standards, the number in parentheses after 6 値 is the number of hydrogen atoms, the next Means that system s is a unimodal line, d is a bimodal line, t is a trimodal line, q is a quadmodal line, m is a multimodal line, and br represents a wide range of absorption peaks. MS stands for mass spectrometry, the measurement method (ionization method) is in parentheses, that is, EI is the electron ionization method, FritFAB stands for the transparent glaze fast atomic impact method, and the numbers represent the observed molecular ions (M +, M + H +), Fragmented ions in m / z. (Example 1) 1- (4-ethoxyphenyl) -4- (1-methyl-1H-imidazol-2-yl)

Phtharazine hydrochloride a) Monomethyl phthalate Dissolve 30.0 g (202.5 mmol) of phthalic anhydride in methanol, heat to reflux for 2 hours, and remove the reaction solution by evaporation under reduced pressure to obtain the solid Drying under reduced pressure gave 36.9 g (100% yield) of the title compound as a colorless solid. 1H-NMR (CDC13): 3.93 (3H, s), 7.57- 7.64 (2H, m)? 7.69-7.73 (1 H, m), 7.94-7.96 (1 H, m) ° b) 2- (1- Methyl-1H-imidazol-2-yl) carbonyl benzoate methyl ester-37-

200533356 (34) 67.94 g (3 7 7.1 mmol) of the compound obtained in Example la was dissolved in thionyl chloride (160 ml), heated under reflux for 3 hours, the reaction solution was distilled off under reduced pressure, and dissolved in acetonitrile (50 ml) . In addition, 31.95 g (3 89.2 mmol) of N-methylimidazole was dissolved in acetonitrile (300 ml), 57.0 ml (410 mmol) of triethylamine was added, and the mixture was stirred under ice-cooling. The above solution was titrated in the ice-cooled stirring solution. The acetonitrile solution was stirred at room temperature for several hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the solution was washed with saturated brine, and then dried over sodium sulfate. After filtering insoluble matters, the solution was distilled off under reduced pressure. -Kihon) After purification, it was washed with Kojiri-ethyl ether to obtain 49.8 8 g (yield 54%) of the title compound as a solid. 1H-NMR (CDC13): 3.69 (3H, s), 4.15 (3H, s), 7.06 (lH, s), 7.08 (lH, s), 7.51-7.64 (3H, m), 7.96-8.00 (1H, m). c) 4- (1-methyl-1H-imidazol-2-yl) -2H-phthalazin-1-one Dissolve 40.13 g (164 mmol) of the compound obtained in Example lb in 160 ml of ethanol and add 1 1.5 ml (23 7 mmol) of hydrazine monohydrate, heated to reflux for 6 hours, cooled to room temperature, added 100 ml of diethyl ether, stirred at 0 ° C for 30 minutes, filtered to remove the precipitated solid, and Diethyl ether was washed with 3,47 g (95% yield) of the title compound. 1H-NMR (CDC13): 3.87 (3H, s), 7.07 (1H, s), 7.75- 8.00 (2H, m), 8.4 5-8.5 5 (1 H, m), 8.65-8.7 5 (1 H? m) 1 1.24 (1H, s). -38- 200533356 (35) d) 丨 -Chloro-4- (1-methyl-1H-imidazole-2-hua) phthalazine 5.40 g (23.8 7 mmol) of the compound obtained in Example 1c

Phosphorus oxychloride (8.0ml) was added to the mixture, and the mixture was heated under reflux for 3 hours. After cooling the reaction solution, the phosphorus oxychloride was distilled off under reduced pressure, and suspended in methylene chloride. 'Saturated sodium bicarbonate water and hydroxide Sodium becomes pH > 8, and the liquid layer is separated. The aqueous layer is extracted with methylidene chloride, dried with sodium sulfate with the organic layer, and the insoluble matter is filtered off, and then purified by silica gel chromatography (ethyl acetate-methylidene chloride). Then, it was washed with hexane to obtain 5.19 g (yield 89%) of the title compound as a colorless solid. The filtrate was concentrated under reduced pressure to obtain 0.21 g (4% yield) of a solid. 1H-NMR (CDC13): 4 · 0 8 (3 Η, s), 7.16 (1 Η, s), 7.3 3 (1H, s), 7.95-8.05 (2H, m), 8.30 · 8 · 40 (1H, m), 9.15-9.25 (1H, m). e) 1- (4-ethoxyphenyl) -4- (1-methyl-1H-imidazol-2-yl) phthalazine To 296 mg (1.210 mmol) of the compound obtained in Example Id was added 3 06 mg ( 1.843 mmol) of 4 · ethoxyphenylboronic acid, 524 mg (3.719 mmol) of potassium carbonate, 5 m 1 of toluene, and 2 m 1 of ethanol. Stir at room temperature while blowing nitrogen into the suspension. After 1 hour, 86 mg (0.074 mmol) of tetrakis (triphenylphosphine) palladium (0) was added, and the mixture was stirred at n ° C for 6 hours under a nitrogen gas stream. Chloroform was added to the reaction solution, and the mixture was added to the perovskite and mortar After filtering, the filtrate was concentrated under reduced pressure, and the residue was dissolved by heating in t-butyl methyl ether-ethyl acetate. The solution was cooled, and the precipitated solid was filtered to obtain 201 mg (yield 55%) of the title compound. 1H- -39- 200533356 (36) NMR (CDC13): 1.49 (3H, t), 4 · 1 0-4.2 0 (5 H, m), 7 · 09 · 7 · 13 (2H, m), 7.16 ( 1H, s), 7.34 (1H, s), 7.76-7.80 (2 H, m), 7 · 8 0-8 · 0 0 (2 H, m), 8. 16 · 8.2 0 (1 H , M), 9 · 1 5 · 9.20 (1H, m). f) 1- (4-ethoxyphenyl) -4- (1-methyl-1H-imidazol-2-yl) phthalazine hydrochloride

201 mg (0.662 mmol) of the compound obtained in Example le was dissolved in 30 ml of acetone, 4 mol hydrochloric acid-ethyl acetate solution (0.57 ml) was added, and the mixture was stirred at room temperature. After adding ether, the precipitate was filtered and This gave 252 mg of the title compound. 1H-NMR (DMSO-d6: 1.41 (3H, t), 3.96 (3H, t), 4.19 (2H, q), 7 · 2 1 · 7 · 2 5 (2 Η, m), 7.79-7.8 3 (2 H, m), 7.97 (1H, s), 8.07 (1H, s), 7.80-8.00 (2H, m), 8.16-8 · 30 (4H, m). (Implementation Example 2) 1- (1-methyl-1H-imid-2-yl) -4 · (4-trifluoromethoxyphenyl) phthalazine hydrochloride a) (1-methyl-1H-imid -2--2-yl) _4- (4-trifluoromethoxyphenyl) phthalazine The compound obtained in Example 1d and trifluoromethoxyphenylboronic acid were used to perform the same operation as in Example le This gave 506 mg (68% yield) of the title compound as a solid. 1H-NMR (CDC13) ^ 4.14 (3H9 s), 7.18 (1H, s), 7.35 (1 Η, s), 7 · 4 3-7 · 4 7 0 (2 Η, m), 7 · 8 0- 8 · 1 〇 (5 H m) 9 · 23_ -40- 200533356 (37) 9.26 (1H, m) MS (El): 3 70 (M +), 3 42, 2 8 5, 24 1, 209, 183 , 156, 129. b) (1-Methyl-1H-imidazol-2-yl) -4- (4-trifluoromethoxyphenyl) phthalein 0 hydrochloride

Using the compound obtained in Example 2a, the same operation as in Example 1f was performed to obtain 32 mg (yield 58%) of the title compound as a solid. 1H-NMR (DMSO, d6: 3.96 (3H, t), 7.67-7.75 (2H, m) 7 98-8.05 (3H, m), 8.10 (1H, s), 8.15 8.25 (4H, m). (Example 3) 1- (3,4 · dimethoxyphenyl) -4- (1-methyl-1H-imidazole-2- 2-} phthalazine hydrochloride a ) 1- (3,4-dimethoxyphenyl) -4- (1-methyl-1H-imidazol-2-yl) phthalein The compound obtained in Example 1d and 3, 4-dimethylformaldehyde were used The same operation as in Example 1 was performed on oxyphenyl_acid 'to obtain 531 mg (yield 77 ° / °) of the title compound as a solid. Ih-nmr (CDC13): 3 99 (3 H, s) , 4.01 (3H, s), 4.14 (3H, s), 7.05 -7.5 0 (5 H, pseudo), 7.85-8 · 05 (2H, m), 8.20-8.25 (1H, m), 9.10-9.20 (lH, m). B) Example of (3,4 · dimethoxyphenyl) -4- (i-methyl-1H • imidazole · 2-yl) phthalic acid_hydrochloride Use Example 3 a. The obtained compound was treated in the same manner as in Example jf «41. 200533356 (38) to obtain 404 mg (yield 58%) of the title compound as a yellow solid. 1H-NMR (DMSO-d6: 3.87 (3H, s), 3.91 (3H, s), 3.96 (1H, s), 7.24-7.2 8 (1 H, m), 7.3 9-7.4 5 (2H, m), 7.97 (1H, s), 8.07 (1H, s), 8.15-8.35 (4H, m). (Example 4) (2,4-dimethoxyphenyl) -4- (1-methyl · 1Η_imidazol-2-yl) phthalazine hydrochloride

a) 1- (2,4-dimethoxyphenyl) -4- (1-methyl-1fluoren-imidazol-2-yl) phthalazine The compound obtained in Example 1d and 2,4-dimethylformaldehyde were used. The same operation as in Example 1e was performed on oxyphenylboronic acid to obtain 326 mg (yield 78%) of the title compound as a solid. 1H-NMR (CDC13): 3.6 9 (3 Η, s), 3.92 (3 Η, s), 4.13 (3H5 s), 6.60-6.75 (2H, m), 7.15 (1H, s ), 7.33 (1H, s), 7.46_7 · 50 (1H, m), 7.75-8 · 00 (3H, m), 9.10-9 · 15 (1H, m) b) 1 -(2,4-dimethoxyphenyl) -4- (1-methyl-1H-imidazol-2-yl) phthalazine hydrochloride 'The compound obtained in Example 4a was used to carry out and implement Example 1f The same operation was performed to obtain 316 mg (yield 88%) of the title compound as a yellow solid. 1H-NMR (DMSO-d6: 3.71 (3H, s), 3.91 (3H, s), 3.98 (1H, s), 6.75-6.90 (2H, m), 7.45-7 · 48 (1H, m), 7.80-8.2 5 (6H, m) 〇-42- 200533356 (39) (Example 5) 1- (1-methyl · 1Η-imidazol-2-yl) -4- (4-pyridyl) The phthalazine used 2.80 g (11.44 mmol) of the compound obtained in Example Id and 3.25 g (26.44 mmol) of stilbidine-4-boronic acid. By performing the same operation as in Example 1e, 2.2 lg (product 67%) of the title compound as a solid. 1H-NMR (CDC13): 4.1 5 (3 Η, s), 7. 2 0 (1 Η, s), 7.37 (1H, s), 7.75 (2H, d), 7.90_8 · 10 (3H, m), 8.88 (2H, d), 9.29 (1H, d) MS (El): 28 7, 25 9, 209, 182, 156, 129,

(Example 6) 1-methoxy-4- (1-methyl-1H-imidazol-2-yl) phthalazine hydrochloride

3 42 mg (1.415 mmol) of the compound obtained in Example Id was suspended in methanol, and 65 mg (1.63 mmol) of sodium hydride (60%) was added at -70 ° C. After stirring at room temperature, 5 ( TC was stirred for 3 hours. Water was added to the reaction solution and the mixture was stirred at room temperature. The precipitated solid was filtered, and the obtained crude product was washed with hexane-ethanol to obtain 1.8 mg (yield 6 7%). Free matter. 1H-NMR (CDC13: 4.04 (3H, s), 4.58 (3H, s), 7.10 (1H, s), 7.28 (1H, s), 7.8 5 -7.9 5 (2H M), 8.20-8.3 0 (1 H, m), 8.90-9.00 (1 H, m). This compound was dissolved in 7 ml of acetone, and 4 mol of hydrochloric acid-ethyl acetate solution (0.175 ml) was added. ), Stirred at room temperature, and the precipitated solid was filtered to obtain 109 mg (yield 53%) of the title compound. 1H-NMR (DMS0-d6: 3.88 (3H, s), 4.32 (3H , S), 7.88 (1H, s), 7.99 (1H, s), 8.00-8.10 (3H, m)? 8.3 0-8.40 (1 H, m). -43 200533356 (40) (Example 7) 1- (4-cyanophenoxy) -4- (1-methyl-1H-imidazol-2-yl) phthalazine hydrochloride

220 mg (0.899 mmol) of 4-cyanophenol was dissolved in DM F, and 120 mg (1.06 mm ο 1) of sodium hydride (60%) was added and stirred at room temperature. The compound obtained in 1 d was added thereto, and the mixture was stirred at 150 ° C for 6 hours. After adding water to the reflux solution and stirring at room temperature, the precipitated solid was filtered off, heated and dissolved in ethanol, and filtered after cooling. The precipitate was separated to obtain 132 mg (yield 45%) of a solid free substance, and the filtrate was subjected to the same operation to obtain 42 mg (yield 14%) of a free substance. 1H-NMR (CDC13): 4.01 (3H, s), 7.13 (1H, s), 7.31 (1H, s), 7.48-7.52 (2Η, m), 7.75 -7.85 (2Η, m), 7 · 90-8 · 05 (2Η, m), 8.40-8.45 (1Η? M), 9.10-9.15 (1Η9 m) Dissolve 1,2 mg of this compound in acetone-diethyl ether, and add 4 mol hydrochloric acid -The ethyl acetate solution (0.27 ml) was stirred at room temperature, and the precipitated solid was filtered off to obtain 134 mg (yield 92%) of the title compound. 1114 "11 (01 ^ 50-〇16: 3.88 (3H, s), 7.6 5 -7.70 (2H, m), 7.80-7.82 (1 H, m), 7.92-7.94 (1 H, m), 8.00-8.10 (2H, m), 8.20-8.3 0 (3 H, m), 8.50-8.60 (1H, m). (Example 8) 6-methoxy-1- (1-methyl-1H- Imidazol-2-yl) -4-phenylphthalazine a) 2-Benzamidine-4-methoxy-N-phenylbenzamine. 10.83 g (63.48 mmol) of 4-methoxyphenylamidine chloride 20 ml of forked dichloride solution, titrated to 5.99 ml (64.32 mm) -44- 200533356 (41) under ice cooling

After aniline, 9.5 ml of triethylamine methyl forked dichloride solution 120 ml, stir at room temperature for 1 hour, concentrate the reaction solution, add water and extract with ethyl acetate, and use 1 M sodium hydroxide, saturated saline It was washed, dried over anhydrous magnesium sulfate, filtered, and concentrated. After adding hexane and ethyl acetate, the precipitated solid was filtered and washed with hexane to obtain 5.50 g (24.20 mmol, yield 38%) of 4-methoxy. -N-phenyl-benzidine. To 6.57 g (28.91 mmol) of 4-methoxy-N-phenylbenzidine obtained in the same manner as above, 100 ml of THF and 9.6 ml (63.6 mmol) of TMEDA (tetramethyl) were added. Ethylenediamine), cooled to -78 ° C, 42 ml (63 mmol) of η-butyl lithium hexane solution (1.5M) was titrated in this mixture under a nitrogen flow for 20 minutes. The reaction solution was stirred at 0 ° C for 15 minutes. Then, it was cooled to -78 ° C, and a 4.80 g (32.2 mmol) THF solution (40 ml) was titrated in 15 minutes. After the reaction solution was slowly returned to room temperature, methanol was added, and the solvent was concentrated under reduced pressure, and dissolved in THF-acetic acid Ethyl acetate was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Then, about 200 ml of hexane-ethyl acetate = 1: 1 was added, and then washed under heating and reflux, and cooled to The precipitate was filtered at room temperature to obtain 5.49 g (yield 57%) of the title compound, and 3.4 g of a crude product was obtained from the filtrate. b) 6-methoxy-4-phenyl-2H-phthalazin-1-one. To 8.84 g (26.68 mmol) of the compound obtained in Example 8a were added 40 ml of hydrazine monohydrate and 20 ml of ethylene glycol, and the mixture was heated. After refluxing for 2 hours, the reaction solution was cooled, 60 m 1 of water was added, and the precipitated solid -45- 200533356 (42) was filtered out. 50 ml of ethanol was added thereto, followed by rinsing under heating and reflux to obtain 5.92 g (product 88%) of the title compound. 1 H-NMR (DMSO-d6: 3.81 (3H, s), 6.95 -7.05 (1 H, m), 7.40-7.65 (6H, m), 8.2 0- 8.3 0 (1 H, m), 12.70 (1H , S). C) 6-methoxy-1- (1-methyl-1H-imidazol-2-yl) -4-phenylphthalazine

The compound obtained in Example 8b was suspended in 13 ml of THF, cooled to -30 ° C, and a THF solution of 1-methylimidazole-2-lithium (from 1.31 g (15.96 mmol) of 1) prepared by titration was titrated. -Methylimidazole, 10 ml of THF, 10 ml of n-BuLi (1.56 M)), slowly return to room temperature and stir for 10 hours, and add 50 ml of 1 to the reaction solution under ice cooling. Molar hydrochloric acid, washed with ethyl acetate, and the aqueous layer was washed with ethyl acetate-THF, and then potassium carbonate was added to make it alkaline. This was extracted with ethyl acetate, washed with saturated brine, and washed with anhydrous sulfuric acid. After drying over sodium, filtering and concentrating on silica gel, adding 50 ml of acetone and 15 ml of diethyl ether and washing at 0 ° C to obtain 771 mg (yield 60%) of the title compound as a pale yellow solid. 1H-NMR (CDC13): 3 · 8 7 (3 Η, s), 4 · 1 3 (3 Η, s), 7 · 1 4 (1H, s), 7.32 (1H, s), 7.3 5 -7.3 8 (1 H, m), 7.50-7.65 (4H, m), 7.8 0-7.8 5 (2H, m), 9.13 (1H, d). (Example 9) 6-chloro-1- (1-methyl-1H-imidazol-2-yl) -4-phenylphthalazine a) 2-phenylhydrazone-4-chloro-N-phenyl-phenylhydrazone To 15.72 g (100.4 mmol) of amine 4-chlorobenzoic acid, 100 ml of dichloromethane and 0.3 ml of DMF were titrated at room temperature over 30 minutes for 9.2 ml -46-200533356 (43) (105 mmol). Ethylene dichloride was stirred at 30 ° C for about 1 hour, and the obtained reaction solution was titrated under cooling with 1.0 ml (109.4 mmol) of aniline and 15.3 ml (10 mmol) of triethylamine. 100 ml of dichloromethane solution

After stirring at room temperature overnight, 100 ml of water was added to the reaction solution, dichloromethane was distilled off, 2 g of sodium hydroxide and 50 ml of ethanol were added, and the precipitated solid was filtered and washed with water. The solid was washed with ethyl acetate, followed by washing with a mixed solvent of hexane and ethyl acetate to obtain 21.19 g (91.46 mmol, yield 91%) of 4. · chloro-N-phenylbenzidine. Use this 19.19 g (91.46 mmol) of 4-chlorophenyl-benzimidamine was operated in the same manner as in Example 8a to obtain 16.04 g (yield 52%) of the title compound. b) 6-Chloro-4-phenyl-2H-Sodium-1-oxine Using 16.04 g (47.77 mm) of the compound obtained in Example 9a, the same operation as in Example 8b was performed to obtain 4.77 g (product 39%) of the title compound. 1H-NMR (DMS0-d6: 7.50-7 · 65 (6H, m), 7.90-7.95 (1H, m), 8.30-8.40 (1H, m), 12.96 (1H, s c) 6-Chloro-1- (1-methyl-1H-amiwa-2-yl) -4-phenylxanthene The compound obtained in Example 9b using 5 3 6 mg (2,0 8 8 mmol) The same operation as in Example 8c was performed to obtain 21 Omg (yield 31%) of the title compound. 1H-NMR (CDC13): 4.15 (3H, s), 7.18 (1H, s), 7.34 (1H, s), 7.55-7 · 65 (3H, m), 7.75-7 · 82 -47- 200533356 (44) (2H, m), 7.8 5-8.00 (1 H, m), 8.00-8.10 (1H, m), 9.29 (1H, d) ° (Example 10) 8-chlorine -1- (1-methyl-1H-imidazol-2-yl) -4-phenylphthalazine a) 6-phenylhydrazone-2-chloro-N-phenylbenzidine

Using 1.0 g (43.42 mmol) of 2-chloro-N-phenyl-phenylhydrazine synthesized in the same manner as in Example 8a, 1.0 was obtained by performing the same procedure as in Example 8a. 99 g (yield 75%) of the title compound. b) 8-Chloro-4-phenyl-2H-phthalazin-1-one 1 0.9 9 g (3 2 · 7 3 mm ο 1) of the compound obtained in Example 10 a was added with 50% sulfuric acid aqueous solution (Made from 14 m 1 of concentrated sulfuric acid and 14 m 1 of water), 10 ml of η-butanol 'heated to reflux for 2 hours', and added 200 ml of water to the reaction solution 'extracted with ethyl acetate' Rinse with saturated brine and concentrate under reduced pressure. 'Add 80 m 1 of ethanol and 5 m 1 of hydrazine 1 hydrate, and heat to reflux for 6 hours.' After cooling to room temperature ', precipitate the solid by filtration. This gave 6.48 g (77% yield) of the title compound. 1H-NMR (DMSO-d6: 7.5 0-7.60 (6H, m), 7.75-7.95 (2H, m), 12.82 (1 H, s). C) 8 · chloro-1- (1- Methyl · 1Η · imidazole · 2-yl) _4-phenylphthalazine The compound obtained in Example 1 0 b was used in the same manner as in Example 8c using 5 1 1 mg (1.99 mm mm ο 1). This gave 5 54 mg (87% yield) of the title compound. 1H_NMR (CDC13): 3.77 (3H, s), -48- 200533356 (45) 7.11 (1H, s), 7.25 (1H, s), 7.50-8.10 (8H, m) (Example 1 1) 6 -Fluoro-1-(1-methyl-1 H -imidyl-2 -yl) -4 -phenyl benzene a) 2-phenylhydrazone-4_fluoro-N-phenylbenzidine 4 · fluoro-N-phenylbenzidine, which was synthesized in the same manner as in Example 8a, was used in the same manner as in Example 9a to obtain 3 · 6 5 g ( Yield: 56%) of the title compound b) 6-fluoro-4-phenyl-2H-phthalazine- ^ one 2.55 g (7.99 mm ο 1) of Example 1 1 & obtained A 50% sulfuric acid aqueous solution (prepared from 4 m 1 of concentrated sulfuric acid and 4 m 1 of water) was added to the compound, and the mixture was heated under reflux for 2 hours, and then 40 m 1 of water was added to obtain 1.40 g (filtered 72%) of 2-phenylhydrazone-4-fluorobenzoic acid. 1H-NMR (DMSO-d6): 7.3 5 -7.45 (m, 1H), 7.4 5-7.5 5 (3H, m),

7.60-7.70 (3H, m), 8.00-8.10 (1H, m). To this 0.73 g of compound, 6 ml of ethanol and 0.16 g of hydrazine 1 hydrate were added, and the mixture was heated under reflux for 2 hours and cooled to 0 ° C. The precipitated solid was filtered to obtain 465 mg (yield 65%) of the title compound. 1 Η-NMR (DMS Ο-d 6): 7.2 5 -7.3 5 (1 H, m), 7.5 0-7.60 (5H, m), 7.70-7.80 (1 H? M), 8.3 5-8.45 (1 H, m). c) 6-fluoro-1- (1-methyl-1H-imidazol-2-yl) -4-phenylphthalazine using 139 mg (0.5 7 9 mmol) of the compound obtained in Example Ub-49- 200533356 ( 46) .The same operation was performed as in Example 8c to obtain 7 1.0 mg (yield 40%) of the title compound. 1H-NMR (CDC13): 4.15 (3H, s), 7.17 (1H, s), 7.33 (1H, s), 7.5 5-7.8 5 (7H, m), 9.30-9.40 (1 H, m) (Example 12) (1-methyl-H-imidazol-2-yl) -4 · trifluoromethylphthalazine a) 2-trifluoroacetamidobenzoic acid

8.70 g (49.65 mmol) of 4,4-dimethyl-2-phenyl-1,3-oxazole was dissolved in 35 ml of THF, and 35 ml of n-butyllithium (1 · 56M hexane solution), the mixture was stirred at 0 ° C for 40 minutes, and titrated to -50 ° C with 1 equivalent of ethyl trifluoroacetate in 50 ml at -70 ° C over 1 hour. The reaction mixture was added with ice and 4 mol hydrochloric acid The aqueous solution was extracted three times with ethyl acetate, washed with hydrochloric acid-brine, dried over anhydrous magnesium sulfate, filtered on a silica gel, and concentrated under reduced pressure to obtain 1 3 · 9 5 g of an oily substance. 40 ml of 1,4-dioxane, 50 ml of concentrated hydrochloric acid, and 30 ml of water were stirred at 100 ° C. for 6 hours. Ethyl acetate and water were added to the reaction solution, the liquid was separated and concentrated, and then 100 m 1 was added. The 6 mol aqueous hydrochloric acid solution was heated at 100 ° C for 1 hour, then ethyl acetate and water were added to the reaction solution, and the mixture was separated and concentrated, and purified by silica gel chromatography to obtain 8.34 g (yield 77 ° /.) Of the title compound as a brown oily substance. b) 4-trifluoromethyl_2H_phthalazin-1-one. Dissolve 8.34 g of the compound obtained in Example 12a in ethanol, add 4.4 ml of hydrazine monohydrate, and heat to reflux for 12 hours. Liquid-cooled-50-200533356 (47) After reaching 0 ° C, the precipitated solid was collected by filtration to obtain 5.8 g (yield 72%) of the title compound. 1H-NMR (DMSO-d6: 7.90-8.10 (3H, m), 8.30-8 · 40 (1H, m), 13.13 (1H, s). C) 1- (1-methyl-1H-imidazole -2-yl) -4-trifluoromethylpyrazine

3 6 5 mg (1.74 mm ο 1) of the compound obtained in Example 1 2 b was suspended in 6 ml of THF, cooled at -70 ° C, and 1-methylimidazole was prepared by titration. -2-lithium in THF (prepared from 561mg (6.8 3 3 mmol) of 1-methylimidazole, 60 ml of THF, 4.4 ml of n-BuLi (1.56M)), -70 It was stirred at ° C for 3 hours, and heated to -50 ° C and stirred for 1 hour. 20 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted twice with a 1 molar aqueous hydrochloric acid solution, and sodium carbonate was added to make it alkaline. Then, the mixture was extracted with ethyl acetate and saturated brine. Rinse, dry over anhydrous sodium sulfate, filter, concentrate, add hexane to the solution obtained by adding diethyl ether, and remove the solid obtained in the middle of the solvent by distillation under reduced pressure. In 5 minutes, 54.1 mg (yield 11%) of the title compound was obtained. 1H-NMR (CDC13): 4 · 1 5 (3 Η, s), 7 · 2 1 (1 Η, s), 7.37 (1 Η, s), 8.00-8.10 (2Η, m), 8.00-8.10 (2Η , M), 8.2 5 -8.3 5 (1 H, m)? 93 5 -9.45 (1H, m). (Example 13) 1- (1-methyl-iH-imidazole'2-yl) -4-phenylphthalazine was used with 5.60 g (25.20 mmol) of 4-phenyl-2H-Sk-butanone, By performing the same operation as Example 8c, the title compound was obtained in an amount of 5.87 mg (yield 81%) -51-200533356 (48). 1H-NMR (CDC13): 4.13 (3H, s), 7.17 (1H, s), 7.34 (1H, s), 7.5 5 -7.60 (3 H, m), 7.75-7.95 (4H, m ), 8.10-8.14 (1H, m), 9.19-9.25 (1H, m) MS (El): 286 (M +), 258, 209, 183, 156, 143, 129, 102, 77. (Example 14) 1- (1H-imidazol-2-yl) -4-phenylphthalazine a) 1- (1-ethoxymethyl-1H-imidazol-2-yl) -4-phenylphthalide Azine

Dissolve 6.85 g (100.6 mmol) of imidazole in 30 ml of THF, titrate a solution of 4.95 ml (51.22 mmol) in THF, stir at room temperature for 2.5 hours, add 80 ml of toluene, filter to remove the salt, and concentrate the solution to obtain 4.43 g of a crude product of 1-ethoxymethyl-1H-imidazole (yield 69%), which was dissolved in 30 ml of THF, and 35 ml (54.6 mmol) of η-butyllithium was titrated at -70 ° C ( (1.56M) was stirred for 20 minutes to obtain a yellow suspension, which was added to 15ml of 4-phenyl-211-phthalazine-1-one in THF at room temperature, and stirred for 8 minutes. After adding water, concentrated hydrochloric acid was added to adjust the pH to 8-9, and the mixture was extracted with ethyl acetate. After extraction into the aqueous layer with 2 mol hydrochloric acid, calcium carbonate was added to make it alkaline, and it was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel chromatography ( Hexane: ethyl acetate = 1: 4-ethyl acetate) was purified to obtain 0.45 g (13% yield) of the title compound. 1H-NMR (CDC13): 1.11 (3H, t), 3.52 (2H, q), 5.97 (2H, S), 7.39 (1H, d), 7.44 (1H, d), 7.5 5-7.65 (3 H, m), 7.75-8.15 (5H, m), 9.15 (1H, d). -52- 200533356 (49) b) 1- (1H-imidazol-2-yl) -4 · phenylphthalophthalate- 0.45 g (1,3 6 2 mm ο 1) of Example 1 a 6 ml of ethanol, 3 ml of water, and 3 ml of concentrated hydrochloric acid were added to the obtained compound, and the mixture was heated under reflux for 9 hours. After concentrating the reaction solution, 10 ml of acetone was added and stirred for 30 minutes. The solid was filtered to obtain 3 99 mg (95% yield) of the title compound. 1H-NMR (DMSO-d6): 7.65-7.75 (3 H, m), 7.80-7.85 (2H, m), 7.98 (2H, s), 8.15-8.25 (3H, m), 8 · 69 (1H, d) (Example 15) 1- (1-Methyl-1H-imidazol-2-yl) phthalazine

Dissolve 4.69 g (60.41 mmol) of 1-methylimidazole in 50 ml of THF

Titrate 38ml (60mmol) of n-butyllithium (1.57M) at -70 ° C under nitrogen and stir for 30 minutes. Titrate 20.53g of a solution of tri-n-butyltin chloride in THF, warm to room temperature, and add to it 2.58 g (60.86 mmol) of lithium chloride, 4 · 92 g (29.89 mmol) of 1-chlorobutane synthesized according to conventional methods, and 4.65 g (4.02 mmol) of tetrakis (diphenylphosphine) palladium ( 〇), 80ml of xylene, and then heated under nitrogen for 30 minutes, and then stirred at 130 ° C for 3.5 hours. After adding ethyl acetate to the reaction solution, after silica gel chromatography, Rinse in a mixed solvent of alkane and ethyl acetate. A total of 2.46 g (39% yield) of the title compound was obtained. 1H-NMR (CDC13): 4.10 (3H, s), 7.16 (1H, s), 7.33 (1H, s), 7.90-8.05 (3H, m), 9.05-9.15 (1H, m), 9.49 (1H, s) MS (El), 210 (Μ +), 182, 155, 129, 1 03, 82, 76, 42 • 53- (50) 200533356 Example 1 The compounds described in Examples 1 to 15 are listed below. Examples

2

Examples Examples

-54- 200533356 (51) (Example 16) 1- (1,3 -Hexan-2-yl) -4 · phenylXianxiao Dissolve 710mg (8.34mmol) of 1,3-thiazine In 6 ml of THF, titrate 5.5 ml (8.58 mmol) of n-butyllithium (1.56 M) under nitrogen at -7 (TC) and stir for 30 minutes. Add 2.87 g of tri-n-butyltin chloride and warm to room temperature. To this were added 0.41 g (9.77 mm ο 1) of lithium chloride, 1.30 g (5.40 mmol) of 1.chloro-4 · phenylphthalazine, and 0.3 g (0.26 mmol) of tetrakis ( Triphenylphosphine) Palladium (〇): After 13ml of toluene

, Heating and stirring under nitrogen for 40 hours, adding ethyl acetate and water to the reaction solution, filtering, separating, washing with saturated brine, drying over anhydrous sodium sulfate and filtering 'silica gel chromatography (hexane: ethyl acetate Ester = 2: 1), and then washed with a mixed solvent of cyclohexane and ethanol to obtain 1.128 g (yield 72%) of the title compound. 1H-NMR (CDC13): 7.5 5-7.6 5 (4 Η, m), 7.8 0 -7.8 5 (2 Η, m), 7.9 5 -8.0 5 (1 Η, m), 8.10-8.20 (lH, m) , 9.87 (lH, d). (Example 17) 1. · (4,5-dihydro-1 H-imidazol-2-yl) -4-phenylphthalazine In 0.71 g (3.07 mmol) of 4-phenylphthalazine-1-nitrile 8 mi of ethylenediamine and 55 mg of sulfur were added, and the mixture was heated under reflux for about 10 hours. After adding 100 ml of water, the precipitated solid was filtered and washed with ether to obtain 192 mg (29% yield) of the title compound. 1H-NMR (CDC13): 3.65 (2H, t), 4.29 (2H, t), 6.45 (1H, s), 7.5 5 -7.65 (3H, m), 7.70-8.00 (4H, m), 8.10 (1H, d), 9.73 (1H, d). (Example 18) 1- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -4-phenylphthalide-55- 200533356 (52) azine hydrochloride 347 mg (1.50 mmol) 0.4 ml of N-methylethylenediamine and 20 mg of sulfur were added to the 4-phenyl oxononitrile, and the reaction solution was concentrated under heating for 8 hours under reflux. After adding acetone and filtering, 0.4 ml of 4 mol was added. A solution of hydrogen chloride in acetic acid was added, and then methylidene chloride was added and the mixture was filtered and a solid was obtained to obtain 335 mg (yield 69%) of the title compound. 1H-NMR (DMS〇-d6): 3.06 (3H, s), 4.20-4.40 (4H, m), 7.70-7.90 (5H, m), 8.15-8.30 (3Η, m ), 8.30- 8.45 (1Η, m), 11.20 (1Η, s)

(Example 1 9) 1- (5-methyl- [1,2,4] -oxadiazol-2-yl) -4 phenylphthalazine 500 mg (2.162 mmol) of 4-phenylphthalide Azine: 1-Nitrile was added 5.5 ml of water, 14 ml of ethanol, 0.54 g of hydroxylamine hydrochloride, 0.67 g of potassium carbonate, and heated under reflux for 4 hours. The reaction solution was cooled to room temperature, and 40 ml of water was added, and the precipitate was filtered out. 524 mg (92% yield) of N-hydroxy-4-phenylphthalazine-1 · carboxyphosphonium. 1H-NMR (CDC13): 5.93 (2H, s), 7.21 (lH, s), 7.55-7.65 (3H, m), 7.75-7 · 80 (2H, m), 7.85 · 8 · 00 (2H , M), 8.11 (1H, d), 9.31 (1H, d), 57 mg (0.216 mmol) of this compound was added to 1 ml of acetic acid, and then cooled at 0 ° C, and 0.3 m 1 of ethyl chloride was added. After stirring at room temperature for 1 hour, 40 ml of a 1 mol sodium hydroxide aqueous solution was added, and the resulting solid was filtered and dissolved in ethyl ketone, and filtered on silica gel. The solid was precipitated by adding hexane to the filtrate to obtain 3 0 mg (yield 49%) of the title compound. 1H-NMR (CDC13): 2.82 (3H, s), 7.55-7.65 -56- 200533356 (53) (3H, m), 7.7 5-7.8 5 (2H5 m) (1H, d), 8.91 (1H D) 〇7.90- 8.05 (2H, m), 8.19 (Example 20) Phtharazine 1 · (5-Diaminomethyl- [n # oxdiazol-2 • yl) · 4-phenyl

Using the same method as in Example 19, 100 mg (0.3 7 8 mm) of N-hydroxy-4-phenylphthalazine-carboxamidine, imi's pyridine, and 0.2 ml of trifluoroacetic anhydride were obtained. 55 mg (42% yield) of the title compound. 1H_NMR (CDC13)-7.60-7.65 (3 H, m), 7.80-7.8 5 (2H, m), 7.90- 8 · 15 (2H, m), 8.26 (1H, d), 8.83 (1H, d ). (Example 21) 1- (4,5-dibromo-i-methyl-1H • imidazol-2-yl) -4 · phenylphthalazine 550 mg (1.921 mmol) of 1- (1-methyl- 1H-imidazol-2-yl) -4-phenylphthalazine was dissolved in 10 ml of chloroform, and titrated at 0.2 ml 0.2 ml of a solution of bromine in chloroform (3 ml) After heating to 0 ° C, it was stirred for 30 minutes. After adding 30 ml of a 1 mol sodium hydroxide aqueous solution, the layers were separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by silica gel chromatography. After ether washing, 308 mg (36% yield) of the title compound was obtained. 1H-NMR (CDC13): 4.1 1 (3 Η, s), 7 · 5 5-7 · 6 5 (3H, m), 7.7 5-7.8 5 (2H, m), 7.8 5-8.0 5 (2H, m), 8.16 (1H, d), 9.03 (1H, d). (Example 2 2) 1 · (5-Bromo-1 -methyl-1 H -imidazol-2-yl) -4 · phenylphthalazine-57- 200533356 (54) 2.54 g (8.87 mmol) of 1 (1-methyl-iH • imidazol-2-yl) -4-phenylphthalazine was dissolved in 40 ml of chloroform, and N-bromosuccinic acid imine (NBS) was added, followed by heating and refluxing for 1 hour. After concentration under reduced pressure After purification by silica gel chromatography, washing with hexane-ethyl acetate gave 2.02 g (yield 62%) of the title compound. 1 H-NMR (CDC13) · 4.08 (3H, s), 7.36 (1H, d), 7.5 5-7.6 5 (3 Η, m), 7.75-8.00 (4 Η, m), 8.14 (1 Η, d), 9.04 (1H, d).

(Example 23) 3-methyl-2- (4-phenylphthalazin-1-yl) -3H-imidazole-4-carbonitrile 212 mg (0.580 mmol) of the compound obtained in Example 22 was dissolved in 3 ml of NMP, add 64 mg (0.715 mmol) of cuprous chloride, heat at 200 ° C (oil bath temperature) for about 2 hours, cool to room temperature, add 40 ml of water and 0.42 g of ethylenediamine tetra Acetic acid dihydrate, potassium carbonate, and chloroform, filtered with kyanite, separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated, and subjected to silica gel chromatography (hexane ·· ethyl acetate = 2 : 1) Purification and washing with hexane · ethyl acetate gave 55.7 mg (yield 31%) of the title compound. 1H-NMR (CDC13): 4.23 (3H, s), 7.5 5-7.6 5 (3 H, m), 7.8 0- 7.8 5 (2H, m), 7.85-8 · 00 (3H, m), 8.20 ( 1H, d), 8.98 (1H, d) MS (El): 311 (M +), 3 1 0, 2 8 3, 267, 234, 208, 205, 129, 77. (Example 24) l- [5- (4,4-dimethyl-4,5-dihydrooxazol-2-yl) -1-methyl-iH-imidazol-2-yl] -4-benzene Phthalozine dissolves 505 mg (5.09 mm ο 1) of 4,4-dimethyl-2-D-oxine in -58- 200533356 (55) 10 ml of diethyl ether in nitrogen Titrate 3.6 ml (5.62 mmol) of n-butyllithium (1.56 M) at -70 ° C under a dream and stir for 30 minutes, then add 1.85 g (5.68 mmol) and 3 ml of diethyl ether. The solution was slowly warmed to room temperature, and 0.30 g (0.26 mmol) of tetrakis (triphenylphosphine) palladium (0) and 0.88 g (2. 4 1 mm ο 1) obtained in Example 25 were added. compound of,

1 2 ml of toluene, blowing in nitrogen for 20 minutes, heating under reflux for 14 hours, and purifying by silica gel chromatography (ethyl acetate), washing with hexane-ethyl acetate to obtain 689 mg (yield 75%) Title compound. 1 Η-NMR (CDC13): 1.41 (6Η, s), 4.07 (2Η, s), 4.34 (3Η, s), 7.5 5 -7.65 (3 H, m), 7.75-8.00 (5H, m), 8.14 (1H, d), 8.85 (1H, d). (Example 25) 4.5 ml of 3-methyl-2- (4-phenylphthalazin-1-yl) -3H-imidazole-4-carboxylic acid was added to the compound obtained in Example 24 at 689 mg (1.796 mmol) 1,4 · dioxane, 3 ml of water, 3 ml of concentrated hydrochloric acid, heating and refluxing for 9 hours, concentrating the reaction solution under reduced pressure, adding toluene and concentrating under reduced pressure, and repeating the operation twice. Ethanol was added to the solution under reduced pressure, and the precipitated solid was filtered after adding acetone. Water and ethanol were added thereto, and the mixture was heated to reflux to dissolve. The solution was cooled to room temperature, and the precipitated solid was filtered to obtain 3 70 mg (yield 62%). ) Of the title compound. 1H_NMR (CDC13): 4.07 (3H, s), 7.60-7.70 (3H, m), 7.75-7.85 (2H, m), 7.94 (1H, s), 8.00-8.10 (3H, m), 8.50-8.60 (1H, m), 13.2 (1H, broads) MS (FritFAB): 331 (M +), -59- 200533356 (56) 2 8 7, 23 2, 207, 149, 77 ° (implementation Example 2 6) 8-(1 -Methyl_1 fluorene-imidazol-2-yl) -5 -phenylpyrido [2,3-d] a coa) 5-phenyl-7H-pyrido [2 , 3-d] daco-8-one

To 2.26 g of 3-phenylhydrazone-pyridine-2-carboxylic acid synthesized according to a conventional method (Monatsh. Chem. 1 990, 121 (11), 909) was added i.6 ml of hydrazine monohydrate, 20 ml of Ethanol was heated to reflux, cooled to room temperature, and the precipitated solid was filtered off to obtain 1.48 g (yield 72%) of the title compound. b) 8-Chloro-5-phenyl-pyrido [2,3-d]. Add 1.48 g of the compound obtained in Example 26a to about 6 ml of phosphorus oxychloride and heat to reflux for about 30 minutes. The reaction solution was poured into a mixture of ice and an aqueous sodium hydroxide solution, extracted with methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated, and then purified by silica gel chromatography and washing with sodium hydroxide. This gave 1.05 g (65% yield) of the title compound. c) 8- (1-Methyl-1H-imidazol-2-yl) -5-phenylpyrido [2,3-d] Da dissolves 183 mg (2.23 mmol) of 1-methylimidazole in 2.5 ml THF, titrate 1.5 ml (2.81 mmol) of n-butyllithium (1.8M) at -70 ° C under nitrogen and stir for 15 minutes, add 915 mg (2.81 mmol) of tri-n-butyltin chloride in THF 2.5 ml of solution, warming -60-200533356 (57) to room temperature, and 112 mg (2.64 mmol) of lithium chloride '2 5 4 mg (1.1 3 8 mm ο 1) of Example 2 6 b The obtained compound, 200 mg (0.173 mmol) of tetrakis (triphenylphosphine) palladium (〇) and toluene were heated and stirred at 90 ° C. for 6 · 5 hours under nitrogen, and chloroform was added to the reaction solution, followed by silica gel chromatography. Method (chloroform: ethyl acetate: triethylamine), ethyl acetate, ethyl acetate, washing, heating and dissolving in ethanol-hexane, and cooling, and then filtering out the precipitated solid to obtain 130 mg (yield 40%) of Title compound. 1H-NMR (CDC13): 4.0 6 (3 Η, s), 7.20 (1 Η, s), 7.4 3 (1H, s), 7.60-7.70 (3H, m), 7.75 -7.85 (3 H , M), 8.49 (1H, dd), 9.44 (1H, dd). (Example 27) 1- (1-methyl-1H-imidazol-2-yl) -4-phenylphthalazine Dissolve 126 mg (1.53 mmol) of N-methylimidazole in THF (10 ml). Cool at 78 ° C, titrate 1.0 ml of η-butyllithium-hexane solution (1.56M) under a nitrogen gas atmosphere, stir at -78 ° C for 1 hour, add 0.5g (1.39mmol) to the reaction solution 1-Phenyl-4- (P-toluenesulfonaminium) phthalazine synthesized by a conventional method (Heterocycles 1994, 39 (1), 345), stirred at the same temperature for 1 hour, then warmed to room temperature and stirred 2 5 hours, add water to the reaction solution, extract with ethyl acetate, dry with sodium sulfate, filter, and concentrate under reduced pressure. The balance obtained is purified by silica gel chromatography (dichloromethane-ethyl acetate) to obtain 20 5 mg (52% yield) of the title compound. ih-NMR (CDC13): 4. 14 (3H? s), 7.18 (lH, d), 7.26 (iH, d), 7.58-7.61 (3H, m), 7.80-7 · 87 (3H, m), 7.96 (iH, t), 8 14 (1H, d), 9.20 (1H, d) -61-200533356 (58) (Example 28) 1- (1-methyl-1H-imidazol-2-yl ) -4- (p-toluene) phthalazine a) 4- (p-toluene) ugazin-1-one

A mixture of 5.0 g (20.8 mmol) of p-toluene · benzoic acid, 1.61 ml (31.2 mmol) of hydrazine monohydrate, and ethanol (15 ml) was heated under reflux for 6 hours. After cooling to room temperature, the pressure was reduced. The solid obtained by concentrating the solvent was washed with water-ethanol to obtain 4.86 g (yield 99%) of the title compound. 1H-NMR (CDC13): 2 · 4 6 (3 Η, s), 7 · 3 3 (2 Η, d), 7 · 4 8 (2H, d), 7.7 8-7.8 3 (3 H, m) , 8.51-8.55 (1H, m), 10.37 (1H, brs). b) To a solution of l-chloro · 4- (ρ-toluisa) phthalazine in 2.85 g (12.1 mmol) of 1,2-dichloroethane (12 ml) obtained in Example 28a was added 1.4 ml (14.5 mmol After heating to reflux for 3 hours, the reaction solution after cooling to room temperature was poured into ice water, and extracted with dichloromethane. The organic layer was dried and filtered over anhydrous sodium sulfate, and the resulting concentrate was used under reduced pressure. Purified by silica gel chromatography (dichloromethane-ethyl acetate) and washed with hexane to obtain 2.7 g (yield 90%) of the title compound. 1H-NMR (CDC13): 2 · 4 8 (3 Η, s), 7 · 3 8 (2 Η, d), 7.63 (2H, d), 7.8 8 -7.94 (1 H, m), 7.97-8.02 (1 H, m), 8.10 (1H, d), 8.38 (1H, d). -62- 200533356 (59) c) Implementation of 1 · (p -methylbensyl) -4- (ρ · toluenesulfonyl) phenylpyrazine in 1. 7 6 g (6 · 8 9 mm ο 1) Example 2 To a solution of the compound obtained in 8 b in DMF (20 ml) was added 2.46 g (1 3 · 8 mm ο 1) of sodium p-toluenesulfinylsulfinate ', which was heated at 90 ° C for 3 hours and cooled. After reaching room temperature, water was added to the reaction solution, and the precipitated solid was filtered and washed with water. The obtained solid was purified by silica gel chromatography (dichloromethane-ethyl acetate) to obtain 2.26 g (88% yield). Title compound. 111 to 1 ^ 11 (0〇 (: 13): 2,48

(3H, d), 7.42 (2H, d), 7.5 5 -7.5 7 (3 H, m), 7.69-7.72 (2H, m), 7.97-8.09 (4H, m), 8.18 (1H , D), 9 · 21 (1H, d). d) Compound obtained in Example 2 8 c of 1.0 g (2.6 7 mm ο 1) of (1-methyl-1H-imidazol-2-yl) -4- (p-toluene) phthalide The same operation as in Example 27 was performed to obtain 404 mg (yield 50%) of the title compound. 1H-NMR (CDC13): 7 · 16 (1 Η, s), 7 · 3 4 (1 Η, s), 7. 40 (2 Η, d), 7.71 (2 Η, d), 7.83 · 7 · 96 (2Η, m), 8.15

(Example 29) 1- (4-methoxyphenyl) -4- (1-methyl · 1Η-imidazol-2-yl) phthalazine hydrochloride 'a) 4-methoxyphenyl-〇 · Benzoic acid dissolved 3.0 g (20.3 mmol) of succinic anhydride in THF (50 ml), cooled at -78 ° C, and titrated 44.6 ml of 4-methoxyphenyl magnesium bromide in THF (0.5 M), warming to room temperature and stirring for 2.5 hours, adding water to the reaction solution, extracting with ethyl acetate, drying with sulfur-63-200533356 (60) sodium sulfate, filtering and condensing the solvent under reduced pressure with heptane -Ethyl acetate-ethanol decantation to obtain 3.08 g (73% yield) of the title compound ° 1H-NMR (DMSO-d6): 3.18 (3H, s), 7.01 (2H, d), 7.36 (1H, d), 7.5 6-7.72 (4H, d), 7.96 (1H, d). b) 4- (4-methoxyphenyl) -2H-phthalazine-i-one was obtained in the same manner as in Example 2 8 a using 3.81 g (14.9 mmol) of the compound obtained in Example 29a to obtain 3.87 g (yield 0%) of the title compound. 1H-NMR (CDC13): 3.90 (3H, s) 5 7.05 (2H, d), 7.53 (2H, d), 7.79-7.82 (3 H, m), 8.5 0-8.54 (1 H, m) 10.13 (1 H, brs). c) 1-Chloro-4- (4-methoxyphenyl) phthalazine

Using 3.87 g (15.3 mmol) of the compound obtained in Example 29b, the same operation as in Example 2 8 b was performed to obtain 4.0 8 g (yield 98%) of the title compound. 1H-NMR (CDC13): 3 · 9 2 (3 Η, s), 7 · 10 (2H, d), 7.70 (2H, d), 7.92-8.00 (2H, m), 8.12 (1H, d), 8.38 (1H, d). d) l- (4-methoxyphenyl) -4- (P-toluenesulfonylsulfonium) phenylphthalazine The compound obtained in Example 29c was treated with 1.0 g (3.69 mmol) of Example 31c. In the same manner, 1.05 g (yield 79%) of the title compound was obtained. 1H-NMR (CDC13): 2 · 4 7 (3 Η, s), 3 · 9 0 (3 Η, s), 7.07 (2H, d), 7.41 (2 H, d), 7 · 6 9 (2 H, d), 7 · 9 6-8 · 0 7 -64- 200533356 (61) (4H, m), 8.23 (1H, d), 9.19 (1H, d) e) 1- (4 -Methoxyphenyl) -4- (bumethyl-1H-imidazo-2-yl) phthalein The compound obtained in Example 29d using 1.05 g (2.69 mm) was carried out in the same manner as in Example 2 7 The title compound was obtained in an amount of 3 52 mg (41% yield). 1H-NMR (CDC13): 3.93 (3H, s), 4.13

(3H, s), 7.11-7.16 (3H, m), 7.34 (1H, d), 7.7 8-7.8 0 (2H, m), 7 · 8 6-7.9 4 (2 Η, m), 8 · 1 7 (1 Η, d), 9 · 1 8 (1 Η, d) MS (El): 3 1 6 (M +), 3 00, 2 8 8, 272, 244, 209. 1 8 3, 156, 1 29 f) (4-Methoxyphenyl) -4- (1-methyl-1H-imidazol-2-yl) phthalazine hydrochloride at 100 mg (0 · 3 2 mm ο 1) Example 2 To a methanol solution of the compound obtained in Example 9e was added 0.09 ml of 4 mol hydrochloric acid-ethyl acetate, and the mixture was stirred at room temperature for 4 hours. The precipitated solid was filtered to obtain 1 12 mg (yield 100%). Title compound. 1H-NMR (DMSO-d6): 3.91 (3H, s), 3.96 (3H, s), 7.26 (2H, d), 7.84 (2H-d), 7.99 (1Η, s), 8. · 10 (lH, s), 8.18-8.29 (4A, m). (Example 30) 4 · (3-methoxyphenyl) -bu (bumethyl-1H-imidazol-2-yl) phthalazine hydrochloride a) 3.0 g of 3-methoxyphenylbenzoic acid (20.3 mmol) of succinic anhydride and 22.3ml (22.3mmol) -65-

200533356 (62) of 3-methoxyphenyl magnesium bromide in THF (1.0M). The same operation as in Example 29a was performed to obtain 4 95 g (yield 96%) of the titled OH-NMR (CDC13). : 3 · 8 4 (3 Η, s), 7 · 1 0-7 · 1 6 (2 Η, 7 · 28 (1Η, t), 7.3 7- 7.3 9 (2Η, m), 7.5 6- 7.5 9 (1 Η, 7.63 -7.66 (1 H, m), 8.08 (1H, d). B) 4.95 g (19.3 mm) of 4- (3-methoxyphenyl) -2H-pyrazin-1-one l) The compound obtained in Example 30a was subjected to the same operation as in Example 28a to obtain 4.64 g (yield of the title compound. 1H-NMR (CDC13) · 3.87 (3H, s), 7.08 (1H , M), 7.08: 7.17 (2H, m), 7.44 (1H, t), 7.78 (3Η, m), 8.51-8.54 (1Η, m), 10,37 (1Η, brs). C) l -Chloro-4- (3-methoxyphenyl) phthalazine was obtained in the same manner as in Example 31b using 4.64 g (18.4 mmol) of Example 30b to obtain 4.71 g (yield of the title compound 1H-NMR (CDC13): 3.89 (3H, s), 7.14 (1H, m), 7.27-7.29 (2H, m), 7.46-7.51 (1H, 7.93-7.96 (1H, m), 7.99-8.04 (1H, m), 8.12 (1 Η, 8.40 (1H, d) 〇d) 1- (3-form Phenyl) -4- (p-toluenesulfonylsulfonium) phenylphthalazine The same operation as in Example 28c was carried out using 1.0 g (3.69 mmol) of the compound obtained in Example 30c to obtain 725 mg (yield implementation Compound m), m), compound 9 5%) 7.05--7.8 1 compound 95%) 7.11-m), d), compound -66- 54%) 200533356 (63). 1H-NMR (CDC13): 2 · 4 8 (3 Η, s), 3 · 8 6 (3H, s), 7.10-7.12 (1H, m) 9 7.2 3-7.2 5 (2 H, m), 7.41 -7.48 (3H, m), 7.97-7.99 (1 H, m), 8.03 · 8 · 11 (3H, m), 8.2 1 (1H, d), 9.21 (1H, d). e) 1- (3-Methoxyphenyl) -4- (1-methyl-1H-imid-2-yl)

Using 7 2 5 mg (1.86 mm ο 1) of the compound obtained in Example 30 d, the same operation as in Example 27 was performed to obtain 3 8 2 mg (65.5% yield) of the title compound. . 1H-NMR (CDC13): 3 · 9 1 (3 Η, s), 4 · 1 4 (3H, s), 7.13-7.14 (1H, m), 7.18 (1H, s), 7.3 5 -7.3 8 (3 H, m), 7.47-7.50 (1 H, m), 7.87-7.90 (1 H, m), 7.93-7.96 (1H, m), 8.16 (1H, d), 9.20 (1H, d) 〇f) For 1- (3-methoxyphenyl) -4- (1-methyl-1H-amidino-2-yl) hydrazine hydrochloride 3 8 2 g (1 · 2 1 mm ο 1) The compound obtained in Example 30e was treated in the same manner as in Example 2 9f to obtain 4 17 mg (yield 64%) of the title compound. 1H-NMR (DMSO-d6): 3.87 (3H, s), 3.96 (3H, d), 7.2 2-7.26 (ΙΗ-m), 7.34-7.37 (2H, m), 7.59 (1H, t) , 7.85 (1H, s), 7.98 (1H, s), 8.14-8.18 (3H, m), 8.3 3 -8.3 6 (1 H, m). The compounds described in Examples 16 to 30 are listed below. -67- 200533356 (64) Examples

Examples Example 16 eg 21 Ο

-68- 200533356 (65) (Example 31) 1- (4-chlorophenyl) -4- (1-methyl-1H-imidazol-2-yl) phthalazine a) 4- (4-chlorophenyl ) -2H-phthalazin-1-one

Using 3.0 g (20.3 mmol) of acetic anhydride and 22.3 ml (22.3 mmol) of 4-chlorophenyl magnesium bromide diethyl ether solution (1.0M), the same operation as in Example 29a was performed to obtain 4-chlorobenzene. -O-benzoic acid, and the same operation as in Example 102a was performed with 4-chlorophenyl-O-benzoic acid to obtain 3.28 g (yield 63%) of the title compound. : I H-NMR (CDC13): 7.52-7.56 (4H, m), 7.70-7.73 (lH, m), 7.80-7.8 3 (2H, m), 8.52-8.55 (1H, m), 10.19 (1H, brs). b) 1-chloro-4- (4-chlorophenyl) phthalazine Using 3.28 g (12.8 mmol) of the compound obtained in Example 31a, the same operation as in Example 28b was performed to obtain 3.3 Og (yield 94%). ) Of the title compound. 1H-NMR (CDC13): 7.55-7.58 (2H? M) 5 7.67-7.70 (2H, m), 7.94-7.97 (1 H, m), 8.00-8.06 (2H, m), 8.3 9-8.42 (1 H, m). c) 1- (4-Anophenyl) -4- (p-toluene fluorene) was added to the compound obtained in Example 3 1 b of 1.0 g (3.6 4 mm ο 1), and The same operation as in Example 28c was performed to obtain 928 mg (yield 65%) of the title compound. 1H-NMR (CDC13): 2.49 (3H9 s), 7.42- 7.44 (2H, m), 7.55 (2H, d), 7.67 (2H, d), 8.00-8.16 (5H, m) , 9 · 22 (1H, d). -69- 200533356 (66) d) Example of 1- (4-chlorophenyl) -4- (1-methyl- 丨 ^ ami!) Zine · 2-yl) phthalein 92 7mg (2.35mmol) The compound obtained in 31c was treated in the same manner as in Example 2 7c to obtain 369 mg (yield 49%) of the title compound. 1 H-NMR (CDC13): 4.14 (3H, s), 7.17 (1Η, d), 7.35 (1Η, d), 7.5 7- 7.59 (2Η, m), 7.75-7.78 (2Η, m ), 7.88-7.91 (1H, m), 7.96-7.97 (1 H, m), 8.08 (1H, d), 9.24 (1H, d).

(Example 32) 1- (4-fluorophenyl) -4- (1 · methyl-1H-imidazole-2 · yl) phthalazine a) 4- (4-fluorophenyl) -2H-pyrazine- 1-one was treated with 3.0 g (20.3 mmol) of succinic anhydride and 22.3 ml (22.3 mmol) of 4-fluorophenylmagnesium bromide in THF (1.0M) in the same manner as in Example 29a to obtain 4-fluoro Phenylbenzoic acid was treated in the same manner as in Example 28a with 4-fluorophenylbenzoic acid to obtain 3.37 g (yield 69%) of the title compound. 1H-NMR (CDC13): 7 · 2 3-7.2 4 (1 Η, m), 7.59-7.61 (2Η, m), 7.74 (1Η, m), 7.81-7.84 (3Η, m), 8.58 (1H, m), 10.35 (1H, brs). b) 1-chloro-4- (4-fluorophenyl) phthalphthalazine 3.37 g (14.0 mmol) of the compound obtained in Example 32a was subjected to the same operation as in Example 28b to obtain 2.78 g (yield 77 %) Of the title compound. 1H-NMR (DMSO-d6) · 7.42 (2H, t), 7.78-7 · 83 (2H, m), 8.03 (1H, d), 8.14-8 · 22 (2H, m) , -70-

200533356 (67) 8.14 (1H, d). c) (4-fluorophenyl) -4- (p-toluenesulfonaminium) phenylphthalazine was obtained in 1.0 g (3.87 mmol) from Example 32b, and the same procedure as in Example 2 8 c was performed. Operation to give 009 mg (yield of the title compound. 1H-NMR (CDC13): 2.49 (3H, s), 7.29 (2H, m), 7.43 (2H, d), 7.70-7.74 (2H, m), 8.18 (5H, m), 9.22 (1H, d). D) 1- (4-fluorophenyl) -4- (1-methyl-1H-imidazol-2-yl) phthalazine Using 900 mg (2.38 mmol) of the medium obtained in Example 32c, the same operation as in Example 27 was performed to obtain 501 mg (yield of the title compound. 1 H-NMR (CDC13): 4 · 14 (3H, s), (1H, d), 7.29-7.35 (3H, m), 7.80-7.84 (2H, m), 7.92 (1H, m), 7.95 -7.97 (1 H, m), 8.10 (1H, d), Compound, 62%) 7.23-8.00- compound 69%) 7.18 7.89-9.22

(Example 33) 342 mg (4.r7 mmol) of N-methylpyrazole was used for 1- (2-methyl-2H-pyrazol-3-yl) -4-phenylphthalazine. The operation gave 254 mg (yield 32%) of the title 11H-NMR (CDC13): 4.13 (3H, s), 6.72 (1H, d), 7.62 (3H, m), 7.71 ( 1H, d), 7.81-7.84 (2H, m), 7.94 (2H, m), 8. 1 8-8.26 (2H, m). Examples. 7.59- 7.90- -71-200533356 (68) (Example 34) (2-furyl) -4- (1-methyl-1H-imidazol-2-yl) phthalazine a) 1- (2-furan ) -4- (butosamidinesulfonyl) phenylphthalazine 816 mg (3.54 mm) of 1-chloro-4- synthesized by a conventional method (Japanese Unexamined Patent Application Publication No. 6-1 3 5 93 8) (20furyl) phthalazine was treated in the same manner as in Example 28c to obtain 1.06 g (yield 86%) of the title compound. 1 H-NMR (CDC13): 2.4 8 (3 Η, s), 6 · 6 7 (1 Η, d d),

7.4 1 (2H, d), 7.55 (lH, d), 7.79 (1H, d), 8.00-8 · 08 (4H, m), 9.01-9.02 (1H, m), 9.18-9.19 ( 1H, m). b) 1- (2-furyl) · (1-methyl-1H-imidazol-2-yl) phthalazine Using 1.06 g (3.03 mmol) of the compound obtained in Example 34a, the same procedure as in Example 27 was carried out. This operation yielded 420 mg (yield 50%) of the title compound. 1 H-NMR (CDC13) ·· 4 · 1 1 (3 Η, s), 6.7 1 (1H, dd), 7.16 (1H, d), 7.33 (1H, d), 7.51 (1H, d) , 7.79-7.80 (1 H, m), 7.94-7.98 (2H, m), 8.86-8.90 (1 H, m), 9.15-9.19 (1H, m) MS (El): 276, 248, 220, 193 (183, 167, 156, 149, 129) (Example 35) 7- (Bumethyl-1H-imidazol-2-yl) -4-phenylthien [2,3-d] Da coax a) 4- Phenyl-6H · thiono [2,3-d] daco-7-one was treated with 6.5 g (35.9 mmol) of 2- (2-thienyl) -4,4-dimethyloxazole. In the same manner as in Example 34a, the title compound was obtained in an amount of 4.91 g (yield: -72-200533356 (69) 59%). 1 H-NMR (DMSO-d6): 7.51-7.55 (4H, m), 7.69-7 · 72 (2H, m), 8.27 (1H, d), 13.13 (1H, brs) ob) 7-chlorine -4-phenylthien [2,3-d]

The same procedure as in Example 28b was carried out using 4.91 g (21.3 mm m ο 1) of the compound obtained in Example 3 5a to obtain 5.17 g (yield 97%) of the title compound. 1H-NMR (CDC13): 7.5 7-7.62 (3H, m) 7.73 (1H, d) 9 7.89-7.92 (2H5 m), 7.96 (1H, d). c) 7- (1-Methyl-1H-Wei-2-Zi-2-yl) -4-phenylpyrene [2,3-d] Tower mouth well for 50 mg (2 · 0 3 mm ο 1) The compound obtained in Example 3 5 b was treated in the same manner as in Example 15 to obtain 527 mg (yield 89%) of the title compound. 1H-NMR (CDC13): 4 · 3 9 (3 Η, s), 7 · 1 4 (1H, s), 7. 37 (1H, s), 7.55-7.62 (3H, m), 7.71 ( 1H, d), 7.95 -7.99 (3 H, m). (Constant Example 36) 4- (1-methyl-1H-Misozan-2-yl) -4 · phenylpyrano [2,3-d] dagen'a) 2- (carboxyphenyl Methyl) -3_furancarboxylic acid methyl ester

5.0 g (44.6 mmol) of 3-furancarboxylic acid in THF

(100ml), cooled at -78 ° C, titrated a separately prepared LDA solution (98.1mm) under a nitrogen gas atmosphere, and stirred at -7 ° C for 30 minutes, and 5.22g (49.1mmol) was added to the reaction solution. ) Benzaldehyde THF -73- 200533356 (70)

(10ml) solution, stirred at the same temperature for 1 hour, and then warmed to room temperature. To the reaction solution was added a dilute hydrochloric acid aqueous solution 'extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure' to obtain 2- ( To a solution of 1.5 g (6.87 mmol) of 2 (hydroxyphenylmethyl) -3-furancarboxylic acid in DMF (13 ml) was added i.i4 g (8.25 mmol) of Potassium carbonate and 1.46 g (10. 3 mmol) of methyl iodide were stirred at room temperature for 7 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sulfuric acid. After drying and filtering with sodium, it was concentrated under reduced pressure, and the remainder was purified by silica gel chromatography (hexane-ethyl acetate) to obtain 1.33 g (yield 84 ° /) of the title compound. 1 H-NMR (CDC13): 3.86 (3H, s), 5.20 (1H, d), 6.13 (1H, d), 6.88 (1H, d), 7.29-7 · 43 (6H, m). b) 7-Phenyl-5H-furo [2,3-d] dakin-4-one 1.51 g (6.50 mmol) of the compound obtained in Example 36a in dichloromethane (12 ml) was added to 3.0 g (7.15mm〇l)

Martinperiodinane's dichloromethane solution (20ml), stir at room temperature for 1 hour, pour the reaction solution into a sodium thiosulfate solution, extract with dichloromethane, and extract the organic layer with saturated sodium bicarbonate and saturated brine. Rinse, dry, filter over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the balance by silica gel chromatography ($ alkane-ethyl acetate) to obtain 2-phenylhydrazone-3_furancarboxylic acid methyl ester, using 1. 0.08 g (4.69 mmol) of 2-phenylhydrazone-3-furancarboxylic acid methyl ester was treated in the same manner as in Example 28a to obtain 787 mg (yield 57%) of the title compound. 1H-NMR (CDC13): 7 · 1 8 (1 Η, d), 7 · 4 9- -74- 200533356 (71) 7.57 (3H, m), 7.82 (1H, d), 8.10-8.13 ( 2H, m), 10.57 (1 H, brs). c) 4-Chloro-7-phenylfuro [2,3-d] daphthine The compound obtained in Example 36b was treated with 7 8 7 mg (3.71 mmol). The same operation as in Example 28b was performed to obtain 74 Omg. (82% yield) of the title compound. 1 H-NMR (CDC13): 7.04 (1H, d), 7.58-

7.60 (3H, m), 7.98 (1H, d), 8.42-8.44 (2H, m). d) 4- (1-methyl-1H-amiwa-2-yl) -4-phenylpyrano [2,3-d] tower was obtained using 300 mg (1.30 mmol) of Example 36c The compound was treated in the same manner as in Example 15 to obtain 292 mg (yield 69%) of the title compound. 1 H-NMR (CDC13): 4.3 4 (3 Η, s), 7.12 (1H, d), 7.31 (1H, d), 7.5 5-7.63 (3 H, m), 7.84 (1H, d) ), 7.96 (1H, m), 8.51-8.54 (2H, m) (Example 37) 4- (4methoxyphenyl) -7- (1-methyl-1H · imidazol-2-yl) Thieno [2,3-d] Dagen hydrochloride a) 7- (1-methyl-1H-imidazol-2-yl) -5H-Thino [2,3-d] Dagen-4 -Ketone Dissolve 3.0 g (23.4 mmol) of 3-thiophenecarboxylic acid in THF (40 ml), cool at 0 ° C, and titrate a separately prepared lda heptane-THF-ethylbenzene solution (2.0 in a nitrogen atmosphere). (M) Stir at 25.8m with Ot for 30 minutes, add 2.89g (25.8mmol) of N-methylimido-2-carboxaldehyde in THF (10ml) to the reaction solution, and heat to room temperature and stir for 1 hour. To the -75-200533356 (72) reaction solution was added ice water, and the aqueous layer was washed with ethyl acetate. 7.40 g (46.8 mmol) of potassium permanganate was added to the reaction solution, and the reaction solution was stirred at room temperature for 4 hours. After filtering through forsterite, the filtrate was neutralized with concentrated hydrochloric acid and concentrated under reduced pressure to obtain 2- (1-methyl-1H-imidazole-2-carbonyl) -3-thiophenecarboxylic acid. 1H -imidazole-2-carbonyl) -3 -thiophenecarboxylic acid The same operation as in Example 28a, to give 3.50 g of (64% yield) of the title compound. 1 H-NMR (CDC13): 4.06 (3H, s), 7.40 (1H, d), 7.24 (1H, d),

7.81 (2H, s), 10.72 (1H, brs). D) 4-chloro-7- (1-methyl-11 ^ imidazol-2-yl) thien and [2,3- (1) Da Teng will be 3 1 0 mg (1 · 3 4 mm ο 1) Example 3 1 ml of phosphorus oxychloride was added to the compound obtained in 7a, and the mixture was stirred at 100 ° C for 2 hours. Ice water was added to the reaction solution, and the mixture was neutralized with an aqueous sodium hydroxide solution. The organic layer was extracted with dichloromethane. After drying filtration over anhydrous sodium sulfate and concentration under reduced pressure, the obtained solid was purified by silica gel chromatography (dichloromethane-ethyl acetate) to obtain 275 mg (yield 82%) of the title compound. 1H-NMR (CDC13) : 4.31 (3H, s), 7.13 (1H, d), 7.34 (1H, d), 7.63 (1H, d), 8.01 (1H, d). C) 4- (4methoxy Phenyl) -7 · (1-methyl-1H-imidazol-2-yl) thiono [2,3-d] Daqin hydrochloride with 275 mg (1.10 mmol) of Example 3 7 b The obtained compound and 4-methoxyphenylboronic acid were treated in the same manner as in Example 1 to obtain 4- (4methoxyphenyl) -7- (1-methyl-1H-imidazole · 2-yl). Thieno-76- 200533356 (73) [2,3-d] Dagen, 4- (4-methoxychenyl) -7- (1-methyl-1H-imidazol-2-yl) thien [2,3-d] Tilling and Example 30f Was repeated to give 3 4 8mg (88% yield) of the title compound. 1H-NMR (DMSO-d6): 3.09 (3H, s), 4.25 (3H, s), 7.24 (2H, d), 7.39 (1H, s), 7.65 (1H, s), 7.85 (2H, d), 7.96 (2H, d), 8.25 (2H, d)

(Example 38) 7- (4methoxyphenyl) -4- (1-methyl_1H-imidazol-2-yl) thiono [2,3-d] daquinone hydrochloride a) 4 -(1-methyl-1H_imidazol-2-yl) -5H-thien [2,3-d] da-coated · 7-one 0.5 g (3.90 mm) of 2-thiophenecarboxylic acid The same operation was performed as in Example 37a to obtain 168 mg (yield 19%) of the title compound. 1H-NMR (CDC13): 3.98 (3H, s), 7.40 (1H, s), 7.21 (1H, s), 7.87 (1H, d), 8.42 (1H, d), 10.1 1 (1H, brs ). b) 7-chloro · 4- (1-methyl-1H-imidazol-2 · yl) thiono [2,3-d] DAD Well 125 mg (0.54 mm) of the compound obtained in Example 38a The same operation was performed as in Example 37b to obtain 75 mg (yield 56%) of the title compound. 1 H-NMR (CDC13): 4 · 2 2 (3 Η, s), 7 · 1 3 (1 Η, s), 7.30 (1 Η, s), 7.93 (1 Η, d), 8.65 (1 Η, d) 〇e) 7_ (4methoxyphenyl) -4- (1-methyl-1H-imidazol-2-yl) thien t2,3-d] Dagen hydrochloride 74mg (0.3 0mmol The compound obtained in Example 3 8b was subjected to the same operation as in Example 77c in 2005-35633356 (74) to obtain 58 mg (yield 54%) of the title compound. 1H-NMR (DMSO-d6): 3.91 (3H? S), 4.10 (3H, s), 7.26 (2H, d), 7.64 (lH, s), 7.81 (lH, s), 8.15-8 · 21 ( 3H, m), 8.5 2 to 8.54 (1 H, m). (Example 39) 1- (1-methyl-1H-imidazol-2-yl) -4- (3-thienyl) phthalein

Using 5 40 mg (2.21 mmol) of the compound obtained in Example Id and 5 66 mg (4.42 mmmol) of 3-thiophene boronic acid, the same operation as in Example 1e was performed to obtain 500 mg (yield 77%) of the title Compounds. 1H-NMR (CDC13): 4.13 (3H, s), 7.16 (1H, d), 7.34 (1H, d), 7.5 5 -7.5 7 (1 H, m), 7.66-7.68 (1 H, m), 7.90-7.96 (3 H, m), 8.30 (1H, m), 9.22 (1H, m). (Example 40) 1- (1-methyl-1H-imidazol-2-yl) -4- (2-thienyl) phthalazine Compound obtained by using 540 mg (2.2 1 mm) of Example Id and 5 66 mg (4.42 mmmol) of 2-thiophene boronic acid was obtained in the same manner as in Example 1 e. 90 mg (60% yield) of the title compound. 1H-NMR (CDC13): 4.13 (3H, s), 7.17 (1H, s), 7.28 · 7.13 (lH, m), 7.35 (lH, s), 7.64 (lH, d), 7.76 ( lH, d), 7.94-7.98 (2H, m), 8.5 3-8.5 6 (1 H, m), 9.20-9.23 (1 H, m). (Example 41) 1 · (1-methyl-1H-imidazol-2-yl) · 4- (4-morpholinyl) phthalide -78- 200533356 (75) hydrazine hydrochloride

3 00 mg (1 .2 3ηΐΓηο1) of the compound obtained in Example 1 d and 3 2 1 mg (3 .68 mm ο 1) of morpholine in N-methylpyrrolidone solution (0.4 5 m 1) were added to 1 After stirring at 40 ° C for 8 hours, after cooling to room temperature, water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried and filtered with anhydrous sodium sulfate, and concentrated under reduced pressure. Ethyl) was purified to give 1- (bumethyl_1H_imidazole · 2-yl) -4- (4-morpholinyl) phthalazine 'with ii -methyl-1 hydrazone-imidazole-2 -yl) -4- The same operation as in Example 29f was performed on morpholine 4-yl-phthalazine to obtain 340 mg (yield 84%) of the title compound. 1 H-NMR (DMSO-d6): 3 · 6 4-3.6 7 (4 Η, m), 3. 8 8 (3H, s), 3.90-3.92 (4H, m), 7. · 89 (1H, s), 7.99-8.08 (4H, m), 8.28-8.3 1 (1H, m) 〇 (Example 4 2) 1-[4-(1 -methyl-1 H -Mizu-2 · Yl) pyrazine-1-yl] piperidin-4-one. 250 mg (1.02 mmol) of the compound obtained in Example 1 d and 155 mg (1.53 mmol) of 4-hydroxypiperidine, 155 mg (1.53 mmol) of N-methylmorpholine, the same operation as in Example 41 was performed to obtain 279 mg (yield 88%) of the title compound. 1H-NMR (CDC13): 1.76 (1H, brs)? 1.8 5-1.94 (2H, m), 2.13-2.18 (2H, m), 3.28-3.36 (2H, m), 3.8 7 -3.9 3 (2H, m), 4.00-4.01 (1H, m), 4.04 (3H, s), 7.10 (1H, s), 7.28 (1H, d), 7.82 -7.8 5 (2H, m), 8.04-8 07 (1H, m), 8.90- 8.94 (1 H, m) MS (El): 309 (M +), 292.2 2 8 0, 264, 252, 23 8, 209, 1 8 2, 1 0 0 (8,2,5 6 ° -79- 200533356 (76) (Example 43) Bu (1-methyl-1H-imidazole > yl) (4-methyl-piperazine d.yl) phthalazine hydrochloride salt

Using 25 Omg (1.02 mmol) of the compound obtained in Example 1d and 307 mg (3.06 mmol) of N-methylpiperazine ', the same operation as in Example 41 was performed to obtain 3 3 0 mg (yield 9 4%) of the title compound. 1 H _ NMR (DMS0-d6): 2 · 8 9 (3 Η, s), 3 · 3 4 · 3 · 5 6 (6 H, m), 3.90 (3H, s), 3.97-4.12 ( 2H, m), 7.26 (1H, s), 7.52 (1H, s), 7.9 8-8.05 (2H, m), 8.20-8.22 (1 H, m), 8.74-8.77 (1H, m) 〇 (implementation Example 44) 1 · (bumethyl-1H · imidazol-2-yl) -4- (2-pyridyl) phthalazine a) 1-chloro-4-pyridin-2-yl-phthalazine was used in accordance with the conventional method (Synth Commun. 1999, 29 (3), 45 7) 5.0 g (22.4 mmol) of 4- (2-pyridinyl) -2 fluorene-phthalazin-1-one synthesized in the same manner as in Example 37b. This operation yielded 4.74 g (88% yield) of the title compound. 1H-NMR (CDC13): 7.48-7.51 (1H, m), 7.96-8.02 (3 H, m), 8.22 (1H, d), 8.38-8.41 (1H, m), 8.81-8 · 85 (2H, m). b) 1- (1-methyl-1H-imidazol-2-yl) · 4 · (2-pyridyl) phthalazine 300 mg (1.24 mmol) of the compound obtained in Example 4 4 a was used and implemented By the same procedure as in Example 38d, 169 mg (yield 47%) of -80- 200533356 (77) was obtained as the title compound. 1H-NMR (CDC13): 4 · 1 2 (3 Η, s), 7 · 19 (1H9 s), 7.36 (1H, s), 7.50 (1H, m), 7.92-7.99 (3 H, m) , 8.25 (1H, m), 8.74-8.75 (1 H, m), 8.78-8.84 (1 H, m), 9.17-9.20 (1H, m). (Example 45) 1- (2-Pyridinyl) -4- (1H-tetramethyl-5-yl) pyrazine sodium salt

a) A solution of 4- (2-pyridyl) pyrazine · 1-nitrile in 600 mg (2.48 mmol) of the compound obtained in Example 44a in DMF (8 ml) was added with 221 mg (1.24 mmol) of p- Toluene sodium sulfite, 243 mg (3.73 mmol) of potassium cyanide, heated at 90 degrees for 5.5 hours, cooled to room temperature, water was added to the reaction solution, and the precipitated solid was filtered and washed with water. The obtained solid was used for After silica gel chromatography (dichloromethane-ethyl acetate) purification, 306 mg (54% yield) of the title compound was obtained. 1H-NMR (CDC13): 7.5 2-7.54 (1 H, m), 8.10-8.12 (3H, m), 8.3 4- 8.3 9 (2H, m), 8.85 (1H, m), 9.04-9.08 (1 Η, m) 0 b) 1- (2-pyridyl) -4- (1H-tetrazol-5-yl) phthalazine 3 0 8 mg (1.33 mmol) of the compound obtained in Example 4 5 a in toluene (5 ml) To the solution, trimethylsilazide '33 mg (13 mm) of di-η-butyltin oxide was added, and the mixture was heated under reflux for 60 hours. After the reaction solution was concentrated under reduced pressure, the solid was washed with methanol to obtain 267 mg (product 73%) of the title compound. 1 H-NMR (DMSO-d6): 7 · 6 8-7 · 7 2 (1 H, m), -81-200533356 (78) 8.14-8.29 (4H, m), 8.74 (1H, d), 8 · 89 (1H, d), 9.42 (1H, d) ° c) 1- (2-pyridyl) -4 · (1H-tetrazol-5-yl) phthalazine sodium salt

To 135 mg (0.49 mmol) of the methanol (5 ml) solution of Example 45b was added 1.1 ml of a sodium methyl alcohol methanol solution (28%), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. Rinse with acetone-methanol to give 124 mg (85% yield) of the title compound. 1H-NMR (DMSO-d6): 7 · 6 3-7 · 6 5 (1 Η, m), 7 · 9 8-8 · 0 3 (2 Η, m), 8.1 8 8 · 15 (2H, m ), 8.59-8.60 (1H, m), 8.85 (1H, d), 9.04-9.08 (1 H, m). The compounds described in Examples 3 1 to 4 5 are listed below.

• 82 · 200533356 (79) Example

Examples Examples

35

40

-83 · 200533356 (80) (Example 4 6) 1-(3 -fluorene ratio D amidyl) -4-(1 fluorene -tetrawas 5-yl) oloxazone sodium a) 4- (3-pyridyl) -Phthalazine-1-nitrile is used according to a conventional method (Synth. Commun. 1999, 29 (3),

457) Synthesized 2.33§ (10.411111101) of 4- (3 -radosyl) -2H-phthalazin-1-one, the same operation as in Example 37b was performed to obtain 2.30 g (91% yield) 1-Chloro- 4-D is more than 0-D-3-yl-brewed. 1H-NMR (CDC13): 7.54-7.5 8 (1 H, m), 8.01-8.13 (4H, m), 8.45 (1H, d), 8.82-8.84 (1H, m), 8.99 (1H, d ) Using 700 mg (2.90 mmol) of this compound, the same operation as in Example 45a was performed to obtain 522 mg (yield 78%) of the title compound. 1H-NMR (CDC13): 7.58-7.62 (1H, m), 8.10 * 8.22 (4H, m), 8.43 (1H, m), 8.87-8.89 (1H, m), 9.04 (1H, d). b) 1- (3-pyridyl) -4- (1H-tetrazol-5-yl) phthalazine was subjected to the same operation as in Example 45b using 5 20 mg (2.24 mm) of the compound obtained in Example 46a, This gave 5 3 3 mg (yield 86%) of the title compound. 1 H-NMR (DMSO-d6) ·· 7.7 0-7 · 7 4 (1 Η, m), 8.13-8.22 (2H? M), 8.26-8.31 (1H? M)? 8.8 6- 8.8 8 (1 H, m), 9.02 (1H, d), 9.43 (1H, d). O 1- (3-pyridyl) _4- (1H-tetrazol 5-yl) phthalazine sodium salt was subjected to the same operation as in Example 4 5 c using 164 mg (0.59 mmol) of the compound obtained in Example 46b to obtain 175 mg (99% yield) -84-200533356 (81) of the title compound. 1H-NMR (DMSO-d6) • 7.66-7.71 (1H m), 7.97-8.91 (3H, d), 8.25 (1H, d), 8.82 (1H, ..., 8.98 (1H, s) ), 9.10 (1H, d). (Example 4 7) 1 _ (4-pyridyl) -4-(1H · tetrazol-5-yl) phthalazine sodium salt a) chloro-4- (4- Pyridyl) -phthalazine

4.1.3 g (18.5 mmol) of 4- (4-fluorene ratio D-Amino) obtained by the same method as described in Example 44 was exposed to 1- 嗣, and the same operation as in Example 3 7 b was performed. This gave 4.43 g (99% yield) of the title compound. 1H-NMR (CDC13): 7.66-7.68 (2H? M)? 7.99-8.01 (2H, m), 8.03-8.09 (1H, m), 8.45 (1H, d), 8.86-8 · 89 ( 2Η, m). b) 4- (4-pyridyl) -phthalazine-1-carbonitrile was treated in the same manner as in Example 45a with 1.2 g (4.97 mmol) of the compound obtained in Example 47a to obtain 98.7 mg (86% yield) Title compound. 1H-NMR (CDC13): 7.70-7.72 (2H, m), 8.10- 8.19 (3H, m), 8.44-8.4 8 (1 H, m), 8.9 b 8.93 (2H, m). c) (4-pyridyl) · 4- (1H-tetrazol-5-yl) phthalazine was used in Example 4 7 5 5 0 mg (2 · 20 mm ο 1) as in the Example The same operation as 45b 'gave 487 mg (81% yield) of 84-7.8 6 (2H, m), the title compound. 1H-NMR (DMSO-d6) • 85- 200533356 (82) 8.11-8.19 (2H, m), 8.27-8 · 31 (1H, m), 8.89-8.91 (2H, m), 9.45 (1H, d) . d) 1- (4-pyridyl) -4- (1H-tetrazol-5-yl) phthalazine sodium salt

Using 487 mg (k77 mm) of the compound obtained in Example 47c, the same operation as in Example 45c was performed to obtain 489 mg (yield 93%) of the title compound. 1 H-NMR (DMSO-d6): 7.80-7.82 (2H, m), 7.98-8.0 7 (3H, m), 8.84-8 · 86 (2H, m), 9.14 (1H, d) . (Example 48) 1- (4-pyridyl) -4- (2,5-hydroxy-5-oxo-4'-1,2,4 · oxadiazol-3-yl) phthalazine hydrochloride a) To 53 mg (1.94 mmol) of the compound obtained in Example 4 7 b of N-hydroxy-4- (4-pyridyl) phthalazine-1-carboxylate was added ethanol (15 ml) of I53 mg (2.13 mm). Hydroxylamine hydrochloride, 120 mg (2.13 mmol) of potassium hydroxide, heated to reflux for 4 hours, cooled to room temperature, and concentrated the solvent under reduced pressure. The precipitated solid was washed with aqueous ethanol to obtain 42.8 mg (yield 83). %) Of the title compound. 1H-NMR (CDC13): 5.93 (2H, brs), 6.91 (1H, s), 7.69-7.71 (2H, m), 7.8 8-8.04 (3 H, m), 8.8 7- 8.8 9 (2H , M), 9.40 (1H, d). b) 1- (4-pyridyl) -4- (2,5-dihydro-5-oxo-411-1,2,4-oxadiazol-3-yl) phthalazine hydrochloride 200 mg (0.75 mmol) -86-200533356 (83)

The THF (3 ml) solution was cooled to Ot: 0.15 ml (1.06 mmol) of triethylamine and 1 17 mg (1.0 mmol) of ethyl chloroformate were added, stirred at room temperature overnight, and water was added to the reaction solution. The precipitated solid was filtered, washed with water, dried, dissolved in pyridine (5 ml), heated to reflux for 12 hours, cooled to room temperature, and the solvent was concentrated under reduced pressure. The obtained solid was washed with acetone-methanol. 'To obtain 1- (4-L-fluorenyl) -4- (2,5-monochloro-5-oxo-4H-1,2,4-oxadiazol-3-yl) phthalazine, use 1- ( 4-pyridyl) -4- (2,5-dihydro-5_oxy-4H-1,2,4-oxadiazol-3-yl) phthalazine The same method as in Example 29f was performed to obtain 193 mg ( Yield: 78%) of the title compound. 111-NMR (DMSO-d): 8.04 (2H, m) 5 8 · 11-8 · 22 (2H, m), 8.26-8.31 (1H, m), 9.01 (1H, d), 9.07 (1H , D). (Example 49) 1- (4-pyridyl) -4- (2,5-dihydro-5-oxo-411-1,2,4-oxadiazol-3-yl) phthalazine sodium salt 2 5 5 mg (0.96 mmol) of the compound obtained in Example 48a in THF (10 ml) was added with 286 mg (1.44 mmol) of thiocarbonyldiimide, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution. The precipitated solid was spilled, washed with water, dried, and then 'dissolved in THF (20 ml), and 660 mg (4.6 9 mmol) of boron trifluoride ethyl ether complex was added. The mixture was refluxed for 3 hours and cooled to room temperature. After the solvent was concentrated under reduced pressure, water was added and the obtained solid was washed with acetone-methanol to obtain 1_ (4-pyridyl) -4- (2,5-dihydro-5-oxo-411-1, 2,4-oxamonozol-3-yl) phthalazine is obtained from 1- (4-pyridyl) · 4 · (2,5_dihydrooxy-4H_1,2,4-dioxine Methoxy-87-200533356 (84) sodium methoxide solution (05 M) was added to the methanol-thin solution of fermented methanol, and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The obtained solid was washed with acetone-methanol to obtain 94 mg (yield 30%) of the title compound. 1 H-NMR (DMSO-d): 7.7 9-7 · 8 3 (2 Η, m), 7.9 7-8 · 1 4 (3 Η, m), 8 · 5 9-8 · 7 0 (1 Η , M), 8.84_8 · 85 (2H, m). (Example 50) 1- (2-pyridyl) -4- (2,5-dihydro-5-oxo-4H-1,2,4-oxazine

Diazol-3-yl) phthalazine sodium salt a) N-Hydroxy-4- (2-pyridyl) -phthalazine · 1-carboxyfluorene was compounded with 500 mg (2.15 mmol) of the compound obtained in Example 47a Example 4 8a The same procedure was performed to obtain 4 17 mg (yield 73%) of the title compound. 1H-NMR (CDC13): 5 · 9 1 (2 Η, brs), 6.8 3 (1H, s), 7.48-7.51 (1H, m), 7.90-7 · 99 (3H, m), 8 · 22 (1H, d), 8.71-8.75 (1H, m), 8.84 (1H, d), 9.29-9.32 (1 H, m).

b) 1- (2-pyridyl). 4- (2,5-dihydro-5-oxo-411-1,2,4-oxadiazol-3-yl) phthalazine sodium salt will be 170 mg (0.64 mm ο 1) The compound obtained in Example 50a was treated in the same manner as in Example 84b to obtain 1- (2-pyridyl) -4- (2,5-dihydro-5 -oxo -4 Η · 1,2,4 · oxadiazol-3 -yl) phthalazine, based on the obtained 1 _ (2 _ pyridyl) -4-(2,5 -dihydro · 5 -oxy-4 Η -1,2,4-oxadiazol · 3-yl) phthalazine (3ml) was added with sodium methoxide methanol solution (0.5M) 1.2ml, stirred at room temperature overnight, and the reaction solution was concentrated under reduced pressure Then, the obtained solid -88- (85) 200533356 was washed with acetone-methanol to obtain 140 mg (yield 82%) of the title compound. 1H-NMR (DMSO-d): 7.63 to 7.67 (1 H? M), 8.02 to 8.16 (4H, m), 8.58 to 8.61 (1H, m), 8.78 to 8.86 (2H, m). (Example 51) 1- (2-pyridyl) -4- (2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl) phthalazine

The same procedure as in Example 49 was performed on the compound obtained in Example 50a with 500 mg (2.15 m m ο 1) to obtain 98 mg (yield 34%) of the title compound. 1 H-NMR (DMSO-d6): 7.68-7.71 (1H, m), 8.13-8.22 (4H, m), 8.71-8.74 (1H, m), 8.8 8-8.89 (2H, m) (Example 52 ) 5-Phenyl-8- (1H-tetrazol-5-yl) pyrido [2,3-d] pyridine hydrochloride a) 5-phenyl-7H-pyrido [2,3-d] 6,7-dihydro-5-obtained by conventional methods (Monatsh. Chem. 1 990, 1 2 1 (1 1), 9 0 9) obtained from dagen-8-one at 8.14 g (26.9 mmol) Add hydroxy · 5,6-diphenyl-5H-pyridino [3,4-b] pyridin-7-one to 12 ml of hydrazine monohydrate, heat to reflux for 5 hours, and add water after cooling at 0 ° C. After neutralizing with acetic acid, the precipitated solid was filtered off, and then washed with water to obtain 3.85 g (yield 64%) of the title compound. 1H-NMR (CDC13): 7.57 (5H, m), 7.74 (1H, dd), 8.14 · 8 · 17 (1H, m), 9.15-9.17 (1H, m), 10.26 (1H, brs ). -89- 200533356 (86) b) 8-chloro-5-phenylpyrido [2,3-d] was used to perform the same procedure as in Example 37b using 3.84 g (17.2 mmol) of the compound obtained in Example 52a. Operation 'yielded 2.49 g (60% yield) of the title compound. 1H-NMR (CDC13): 7 · 6 0-7 · 6 2 (3 Η, m), 7.72 -7.7 5 (2H, m), 7.8 6- 7.89 (1 H, m), 8.44 (1H, dd), 9.3 6-9.3 7 (1 H, m).

c) 8- (2-benzyloxymethyl-2H-tetrazol-5-yl) -5-phenylpyrido [2,3-d] dalphine 300 mg (1.24 mm) 1) The compound obtained in Example 5 2 b and 714 mg (1.49 mmol) of 2-benzyloxymethyl-5- () obtained according to a conventional method (Tetrahedron Lett. 2000, 41 (16), 2805) Tributyltin) tetrazole was treated in the same manner as in Example 15 to obtain 1,65 mg (yield 34%) of the title compound. 1H-NMR (CDC13): 4.84 (2H, s), 6.16 (2H, s), 7.3 6-7.42 (5H, m), 7.64: 7 · 66 (3H, m), 7.83 -7.89 ( 3 H, m), 8.5 5-8.5 7 (1 H, m), 9.40-9.41 (1H, m) d) 5-phenyl-8- (1H-tetrazol-5-yl) pyrido [2, 3-d] Dagen hydrochloride in a solution of 160 mg (405 mmol) of the compound obtained in Example 52c in methanol (4 ml), 0.61 ml of a 4 mol hydrochloric acid-ethyl acetate solution was added, and the mixture was heated under reflux for 3 hours. After cooling at room temperature and concentrating the solvent under reduced pressure, the precipitated solid was washed with acetone-methanol to obtain U3 mg (yield 90%) of the title compound. 1H-NMR (DMSO-d6): 7.69-7.71 -90- 200533356 (87) (3H, m), 7.8 6- 7.8 9 (2H, m), 8.11-8.16 (lH, m), 8.56-8 · 59 (1H, m), 9.44-9.46 (1H, m) (Example 5 3) 400 mg (1.73 mmol) of 1-phenyl-4-(1 H -tetrazol-5-yl) phthalocyanine The 4-phenylphthalazine-1 -nitrile obtained by the conventional method (Heterocyc 1 es 1 994, 3 9 (1), 1 4 5) was used for

-Example 4 5b The same procedure was performed to give 225 mg (yield 48%) of the title compound. 1H-NMR (CDC13): 7.67 -7.69 (3 H, m)? 7.84- 7.87 (2H, m), 8.04_8 · 06 (1H, m), 8.14-8.17 (1H, m), 8.2 5 (1 Η, d), 9 · 7 8 (1 d, d) MS (F rit FAB): 2 7 5 (M + H +), 247, 23 2, 205, 1 89, 77 (Example 54 ) a) 1- (Bumethyl-1H-tetrazol-5-yl) -4-phenylphthalazine b) 1- (2-methyl-2H-tetrazol-5-yl) -4 · phenylphthalazine 280 mg (1.02 mmol) of the compound obtained in Example 5 3 was dissolved in DMF (3.5 ml), cooled to 0 ° C, and 65 mg (1.63 mmol) of sodium hydride (60%) was added under a nitrogen gas atmosphere at 0 ° C. Stir for 30 minutes, add '274mg (1.63mmol) of methyl iodide to the reaction solution, stir at room temperature overnight, add water to the reaction solution, filter out the precipitated solid, and use silica gel chromatography (dichloromethane- After ethyl acetate) purification, the title compound was obtained. a) 1- (1-methyl-1H-tetrazol-5-yl) -4-phenylphthalazine: 97 mg (yield -91-200533356 (88) 3 3%)

Rf = 0.5 25 (methylene chloride / ethyl acetate = 5/1) ih-NMR (CDC13): 4.59 (3H, s), 7.62-7.64 (3H, m), 7.81-7.85 (2H, m), 7.99 -8.02 (1 H, m), 8.05-8.0 8 (1 H, m), 8.24 (1H, d), 9.24 (1H, d).

b) 1- (2-methyl-2H-tetra-sat-5 · yl) -4-phenyl vocal: l23mg (yield 4 2%)

Rf = 0175 (dichloromethane / ethyl acetate = 5/1) IH-NMR (CDC13) ··· 59 · (3H, s), 7.59-7.61 (3H, m), 7.80-7.8 3 (2H, m ), 7.9 3 -7.96 (1 H, m), 7.98-8.01 (1H, m), 8.17-8.21 (1H, m), 9.06 (1H, d) MS (El): 2 8 8 (M +), 232, 217, 203, 1 89, 176, 163, 77 (Example 55) 5- (4-phenylphthalazin-1-yl) -2,4-dihydropyrazole-3 · one a) 4 -Phenylphthalazine-1-carboxylic acid To 2.2 g (9.51 mmol) of 4-phenylphthalazine-1-carbonitrile was added 50% sulfuric acid (30 ml), and the mixture was heated under reflux for 7 hours, and the reaction solution was cooled to 0 ° After C, the solution was neutralized with an aqueous sodium oxide solution, and the precipitated solid was filtered and washed with ice water to obtain 1.77 g (yield 75%) of the title compound. 1H-NMR (DMSO-d6): 7.63-7.74 (5H, m), 8.01-8.08 (3H, m), 8.48 (1H, m) ο b) 5- (4-phenylhydrazone- l-based) · 2,4 · dihydrola ^ 3-3--3-one-92- 200533356 (89)

695 mg (4.29 mmol) of carbonylimidazole was added to a solution of 9 7 5 mg (3.90 mm ο 1) of the compound obtained in Example 5 5 a in THF (10 ml), and the mixture was stirred at 50 ° C for 2 hours. After the reaction solution was cooled to 0 ° C, 72 9 mg (4.29 mmol) of potassium ethyl malonate and 408 mg (4.9 mm) were added and heated under reflux for 5 hours. After the reaction solution was cooled, A dilute aqueous hydrochloric acid solution was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The remaining amount was purified by silica gel chromatography (hexane-ethyl acetate) to obtain 571 mg (yield 46 %) Of 3-oxo-3- (4-phenylphthalazin-1-yl) propanoic acid methyl ester, based on the obtained 236 mg (0.74 mmol) of 3-oxo-3- (4-phenylphthalein 0.7 ml of hydrazine monohydrate was added to a solution of methylazine-1-yl) propionic acid methyl ester in ethanol (3 ml), and heated under reflux for 6 hours. After cooling to room temperature, the solvent was concentrated under reduced pressure, and the obtained solid was Washing with ethyl ether-ethanol gave 189 mg (89% yield) of the title compound. 1H-NMR (CD30D): 7.63 -7.65 (3 H, m), 7.72-7.76 (2H, m)? 7.98- 8.12 (4H, m), 8.85 (1H, brs). (Example 56) 1- (5-methyl [1,3,4] oxadiazol-2-yl) -4-phenylphthalazine a) 2-ethylfluorenyl-1- (4-phenylphthalide Add 505 mg (3.12 mmol) of fluorenyldiimidazole to a solution of the compound obtained in Example 5 5 a of 6,000 mg (2. 40 mm ο 1) in THF (12 ml). After stirring at 5 (TC for 2 hours, the reaction solution was cooled to 0 ° C., then 195 mg (2.64 mmol) of acetamidine hydrazine was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and extracted with dichloromethane , Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained body was washed with hexane-ethyl acetate-93-

200533356 (90) to give 597 mg (yield 70%) of the title compound. (CDC13): 2.20 (3H, s), 7.60-7.62 (3 H, m), (2H, m), 7.94 (1H, t), 7.98-8.02 (1 H, m), 8 ·] , 8.21 (1H, brs), 9.43 (1H, d). b) 1- (5-methyl [1,3,4] oxadiazol-2-yl) -4-phenylphthalazine will be 2 50 mg (0. 8 2 mm ο 1) Example 5 6 a The mixture of 5.0 g of polyphosphoric acid obtained was stirred at 120 ° C for 2 hours, cooled to room temperature and added with ice water, neutralized with sodium carbonate, taken with two, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was washed with hexane-ethyl acetate to obtain 203 mg (yield 86%) of the compound. 1 H-NMR (CDC13): 2.78 (3H, s), 7.61-m), 7.81-7.84 (2H, m), 7.97 (1H, t), 8.08 (1H, (1H, d), 9.54 ( 1H, d). (Example 57) 1- (5-methyl [1,3,4] oxadiazol-2-yl) -4-benzene; 3 3 6 mg (1.10 mmol) of Example 56a To the obtained toluene (1 ml) solution was added 577 mg (1.4 3 mm ο 1), and the mixture was heated under reflux for 1 hour. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was dried with anhydrous sodium sulfate and filtered. The remaining amount was purified by silica gel chromatography (dichloro E ethyl) to obtain a standard of 208 mg (62% yield). 1H-NMR (CDC13): 2 · 9 2 (3 H, s), 7 · 6 0-7 · 6 3 7 · 80 · 7 · 84 (2H, m), 7.95 -7.98 (1 H, m), 8.05-8.1 1 H-NMR 7.75-7.78 5 (1H, d) compounds and The title of the solid extracted from the reaction solution with methyl chloride was 7.63 (3H,, t), 8.22 Lawson's reagent sodium bicarbonate of the phthalazine compound, concentrated acetane-acetic acid compound (3H, m), 0 (1H, m) -94- 200533356 (91), 8.20 (1H, d), 9.84 (1H, d)

(Example 58) (5-methyl-4H- [1,2,4] triazol-3-yl) -4-phenylphthalazine A compound obtained in Example 56b was obtained with 95 mg (0.3 3 mmol) And a mixture of 0.7 ml of benzylamine, stirred at 150 ° C for 2 days, cooled the reaction solution to room temperature and added water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Add trifluoroacetic acid (1.3ml) to the amount, heat and reflux for 10 hours, concentrate the reaction solution under reduced pressure, dilute with dichloromethane, rinse with dilute hydrochloric acid aqueous solution, cool the aqueous layer to ° C, and neutralize with sodium hydroxide aqueous solution. The obtained solid was filtered off to obtain 67 mg (yield 71%) of the title compound. 1H-NMR (CDC13): 2.63 (3H, s), 7.5 9: 7.62 (3 H, m), 7.78_7 · 82 (2H, m), 7.94 (1H, t), 8.06 (1H, t), 8.16 (1H, d), 9.81 (1H, brs). (Example 5 9) 1-(1-Methyl-1H-imidazol-2-yl) -4-phenylpyrido [3,4-d] hydrochloride &) 4-phenyl- 211-pyrido [3,4- (1) dacrobone was synthesized according to a conventional method (Monatsh · Chem · 1 990, 121 (11), 909) 8.63 g (28.6 mmol) of 5,6 -Dihydro-7-hydroxy-6,7-diphenyl-711-pyridino [4,3-(:] pyridin-5-one) was carried out in the same manner as in Example 54a to obtain 6.13 g (yield 96%) of the title compound. 1H-NMR (CDC13): 7.5 8-7 · 6 2 (5 Η, m), 8. 2 9 (1 Η, d), 9.03 (1H, d), 9.21 ( 1H, s), 10.15 (1H, brs). -95- 200533356 (92) b) 1-chloro-4-phenylpyrido [3,4-d] 5 mm ο 1) The compound obtained in Example 5 9 a was subjected to the same operation as in Example 3 7 b to obtain 3.28 g (yield 49%) of the title compound. 1H-NMR (CDC13): 7.63 -7.65 (3 H, m), 7.79-7.82 (2H, m), 8.13 (1H, d), 9.16 (1H, d), 9.56 (1H, s) °

c) 1- (1-methyl-1H-imidazol-2-yl) -4-phenylpyrido [3,4-d] hydrochloride hydrochloride was obtained by treating 300 mg (1.24 mmol) of Example 59b The compound was treated in the same manner as in Example 15 to obtain 291 mg (yield 82%) of 1- (1-methyl_1H-imidazol-2-yl) 4-phenylpyrido [3,4-d] The same operation as in Example 30f was carried out using 1- (bumethyl-1H_imidazol-2-yl) 4-phenylpyrido [3,4-d] dagen to obtain 3 5 1 mg (yield 9 6%) of the title compound. 1H-NMR (DMSO-d6): 4.04 (3H, s), 7.71-7 · 73 (3Η, m), 7.78 (1Η, m), 7.94-7.96 (3Η, m), 8.47 (1Η , M), 9.20 (1H, d), 9.55 (1H, s). The compounds described in Examples 46 to 39 are listed below. • 96- 200533356 (93)

-97 200533356 (94) (Example 60) 4- (1-methyl-1H-imidazol-2-yl) -7_ (2-pyridyl) thien [2,3-d] Dagen 2 hydrochloric acid Salt a) 7- (2-pyridyl) -5H-thien [2,3-d] daco-4-one with 8.90 mg (69.4 mmol) of 3-thiophene residual acid and 8.18 g (76.3 mmol) of 2-A ratio (1%), the same operation as in Example 37a was performed to obtain 7.62 g (48% yield) of the title compound .: ih-NMR (DMSO-d6) · 7.72-7.79 (1), m), 7.88 (1H, d), 8.02

8.09 (1H, m), 8.71 (1H, d), 9 · 0 4-9 · 0 6 (2 H, m). b) 4-chloro-7- (2-pyridyl) -thiono [2,3-d] daqin 7.62 g (33.2 mmol) of the compound obtained in Example 60a was subjected to the same operation as in Example 37b This gave 7.92 g (97% yield) of the title compound. 1H-NMR (CDC13): 7 · 4 3-7 · 4 8 (1 Η, m), 7.75 (1H, d), 7.9, 7.98 (1H, m), 8.04 (1H, d), 8.80-8.88 ( 2H, m).

c) 4- (1-Methyl-1H-imidazol-2-yl) -7- (2-pyridyl) thiono [2,3-d] Dagen 2 hydrochloride will be 300 mg (1.21 mmol) The compound obtained in Example 60b was subjected to the same operation as in Example 15 to obtain 4- (1-methyl-1H-imidazol-2-yl) -7- (2-pyridyl) thien [2,3- d] Tack, using 4- (1-methyl-1H-imidazol-2-yl) -7- (2-pyridyl) thiono [2,3_d] Tack to perform the same procedure as in Example 2 9 f This gave 166 mg (37% yield) of the title compound. 1H-NMR (DMSO-d6): 4 · 1 2 (3 Η, s), 7 · 6 5-7 · 7 1 (2 Η, -98- 200533356 (95) m), 7.82 (1H, s ), 8.14-8.20 (2H, m), 8.55 (1H, d), 8.89 (1H, d), 8.95 (1H, d). (Example 61) 4- (1-methyl-1H-imidino-2-yl) -7- (4-pyridyl) thino [2,3-d] Dagen a) 7-pyridine- (4-pyridyl) -5H-thiono [2,3-d] diketan-4-one

Using 11.7 g (90.9 mmol) of 3-thiophenecarboxylic acid and 10.7 g (100 mmol) of 4-pyridinecarboxaldehyde, the same operation as in Example 37a was performed to obtain 5.90 g (yield 82%) of the title. Compounds. ih-NMR (DMS0-d6): 7.90 (1H, d), 8.40-8.44 (2H, m), 8.66 (1 H, d), 9.06-9.1 1 (2Η, m). 1b) 4-Chloro-7- (4-pyridyl) thiono [2,3-d] Dagen 5.90 g (25.7 mmol) of the compound obtained in Example 61a was treated in the same manner as in Example 3 7 b This was obtained in an amount of 1.98 g (31% yield) of the title compound. 1H-NMR (CDC13): 7.75 (1H? D), 8.02-8.04 (3H, m), 8.8 8-8.90 (2H, m). c) 4- (1-Methyl-1H-imidazol-2-yl) -7- (4-pyridyl) thiono [2,3-d] Titanoin will be 3 00 mg (1.21 mmol) of Example 61b The obtained compound was treated in the same manner as in Example 15 to obtain 43 mg (yield 12%) of the title compound. 1 H-NMR (CDC13): 4 · 3 0 (3 Η, s), 7 · 1 7 (1 Η, s), 7.34 (1 Η, s), 7.96 (1 Η, d), 8.11-8.13 (2 Η, m), 8.77 -99- 200533356 (96) (1H, d), 8.88-8.90 (2H, m) (Example 62) 7. (i-methyl_1H-imidazol-2-yl) -4- ( 2-pyridyl) thiono [2,3-d] taffine hydrochloride

The same operation as in Example 15 was performed using 300 mg (1.20 mmol) of the compound obtained in Example 3 7 b and 529 mg (1.44 mm) of tri-η-butyl (2-pyridyl) tin. , To obtain 7- (1-methylimidazol-2-yl) -4- (2-pyridyl) thien [2,3-d] da-peng, using 7- (1-methyl-1fluorene-imidazole- 2-yl) -4- (2-pyridyl) thien [2,3-d] dachin was carried out in the same manner as in Example 29f to obtain 103 mg (yield 26%) of the title compound. 1H-NMR (DMSO-d6): 4 · 3 0 (3 Η, s), 7 · 3 5 (1 Η, s), 7.61-7 · 64 (2H, m), 8.08-8.13 (1H, m), 8.43 (1H, d), 8.5 7-8.60 (2H, m), 8.87 (1H, d). (Example 63) 7- (1-methyl-1H-imidazol-2-yl) -4- (4-pyridyl) thien [2,3-d] 20 mm ο 1) of the compound obtained in Example 3 7 b and 5 5 6 mg (1.44 mmol) of tri-η-butyl (4-fluorene ratio D adenyl) tin were subjected to the same operation as in Example 15, This gave 121 mg (34% yield) of the title compound. 1H-NMR (CDC13): 7 · 1 7 (1 Η, s), 7 · 3 9 (1 Η, d), 7.71 (1H, d), 7.89-7.91 (2H, m), 8.05 (1H , D), 8.86-8.88 (2H? M). (Example 64) (5-oxo-4,5-dihydro- [1,2,4] oxadiazol-3-yl) -4-benzene-100- 200533356 (97) phthalazine a) N -Hydroxy-4-phenylphthalazine-1-carboxyfluorene

1.05 7 g (4.569 mmol) of 4-cyanophthalazine-benzonitrile, 442 mg (6.3 6 mm ο 1) of hydrochloric acid via amine and 447 mg (5.45 mmol) of sodium acetate were added to ethanol: water = 5: 1 mixed The solution was heated to reflux for 80 minutes, the reaction solution was cooled to room temperature, ethanol was distilled off under reduced pressure, the reaction solution was diluted with water, the precipitated solid was filtered, washed with water, and dried under reduced pressure to obtain 1.066 gmg (yield 88%) of the title compound as a pale yellow solid. 1H-NMR (DMSO-d6): 6 · 2 4 (2 Η, s, N Η 2), 7 · 6 2 7 · 6 6 (3 Η, m), 7.73 -7.77 (2 Η, m), 7.99- 8.10 (3Η, m), 9.03 · 9 · 07 (1Η, m), 10 · 36 (1Η, s, OH). b) Example of 1- (5-oxo-4,5-dihydro_ [1,2,4] phosphonium dioxo-3-yl) -4-phenylfluorene exposed 3 02 mg (1.143 mmol) The compound obtained in 64a was dissolved in pyridine (5 ml), and 0.1 17 ml (1.23 mmol) of ethyl chloroformate was added while stirring at room temperature, and the mixture was heated and refluxed for 4 hours. After cooling the reaction solution, an aqueous citric acid solution was added to adjust the pH to < 4, the precipitated solid was filtered, washed with water, and dried under reduced pressure to obtain 298 mg (yield 90%) of the title compound as a pale yellow solid. ih-NMR (DMSO-d6): 7.36-7.42 (1 H, m), 7.66-7.69 (2H, m), 7.76-7.82 (2H, m), 8.13-8.15 (1H, m), 8.19-8.24 ( 1H, m), 8.57-8.59 (1H, m), 9.02 (2H, d, J = 8.4), 13.67 (1H, brs). (Example 65) 1-phenyl-4- (5-thio-4,5-dihydro 41,2,41.:-3- -101-200533356 (98) yl) phthalazine

249 mg (0.942 mm) of the compound obtained in Example 64a was dissolved in acetonitrile (7 ml), and 3 68 mg (1.86 mmol) of thiocarbonyldiimidazole (90%) was added while stirring at room temperature, followed by 0.56 ml (3. 7 5 mmol) of DBU, stirred at the same temperature for 6 and a half hours, an aqueous citric acid solution was added to the reaction solution to pH &lt; 4, the precipitated solid was filtered, washed with water, and dried under reduced pressure. This gave 293 mg (100% yield) of the title compound as a pale yellow solid. 1 H-NMR (DMSO-d6): 7.67-7.70 (3H, m), 7.79-7 · 82 (2H, m), 8.15-8.27 (3H, m), 8.93 (1H, d, J = 8.2). (Example 66) l- {4- (1H-tetrazol-5-yl) phthalazine-butyl} piperidin-4-onea) 4-oxo-3,4-dihydro-3H-phthalazine- 1-carboxylic acid Refer to the method of Ishikawa et al. (Document Chem · Pharm · Bull · 28 (9) 2 770-2 778 (1 98 0)) to synthesize the title compound, potassium hydroxide (85% grade) 8.85 g (134. lmmol) was dissolved in water (250ml), 8.28g (50.44mmol) of 2 · acetamidobenzoic acid was added here, and the mixture was stirred at room temperature. At this time, the amount of dissolved in water (350ml) was titrated over 20 minutes. 15.94 g (100.9 mmol) of potassium permanganate ', stirred at the same temperature for another 90 minutes, filtered the insoluble matter with fluorite, washed with water (500 ml), slowly added dry ice to the mother liquor, saturated carbon dioxide, and added The hydrazine hydrate (40 ml) was then heated and stirred at 80 ° C. for 4 hours. The reaction solution was ice-cooled. A 6 mol aqueous hydrochloric acid solution was added to pH ˜1. The precipitated solid was filtered and dried under reduced pressure to obtain 7.3 Og (product 76%) of the title compound as a colorless solid. 1H- • 102- 200533356 (99) NMR (DMSO-d6): 7.90 (1H, t, J = 7.5), 7.96- 8.02 (1 H, m), 8.29 (1H, d, J = 7.5), 8.58 (1H, d, J = 8.1), 13.11 (1H, S), 13.2-14.0 (1H, broad). b) 4-oxo-3,4-dihydro-3H-phthalazine-1-carboxylic acid sulfonamide

4.19 g (22.03 mmol) of the compound obtained in Example 66a was added to dichloromethane (150 ml), and the mixture was stirred under ice cooling. At this time, A 3.40 ml (24.4 mmol) of triethylamine and 3.10 ml were sequentially added. (23.6 mmol) of isobutyl chloroformate. After stirring at the same temperature for 30 minutes, 28% ammonia solution was added all at once, and stirred at room temperature for 4 5 minutes. Diethyl ether was added to the reaction solution, and the precipitate was filtered out. The solid was washed sequentially with water, dilute hydrochloric acid, and water, and dried under reduced pressure to obtain 3.49 g (yield 84%) of the title compound as a colorless solid. 1H-NMR (DMS0-d6): 7.70 (1H, s), 7.85-7.98 (3H, m), 8.28 (1H, d, J = 7.6), 8.59 (1H, d5 J = 8.0), 12.8- 13.2 (1H, broad). c) 4-Chlorophthalazine-1-carbonitrile Add 3.48 g (18.40 mmol) of the compound obtained in Example 66b to a mixed solution of thionyl chloride / (30 ml) -phosphine chloride (30 ml) The mixture was stirred at 11 (TC for 3 and a half hours, and the reaction solution was distilled off under reduced pressure. The obtained oil was dissolved in dichloromethane and washed with saturated sodium bicarbonate water and thenardite water (sodium sulfate water). After drying over magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the obtained oil was purified by silica gel chromatography (ethyl acetate · dichloromethane) to obtain 1.99 g (yield 5 7 ° / 〇) of the title compound as a pale yellow-103-200533356 (100) solid. 1H-NMR (CDC13): 8.17-8.23 (2H, m), 8.3 4- 8.3 8 (1 H, m), 8.43-8.47 (1 H, m) 〇d) 4- {4- (hydroxypiperidine-butyl) phthalazine-benzonitrile

48 8 mg (2.574 mmol) of the compound obtained in Example 66c and 830 mg (8.2 l mmol) of 4-hydroxypiperidine were dissolved in N · methylpiperidone, and the mixture was stirred with superheating at 110 ° C for 90 minutes. The reaction solution was cooled to room temperature, and a solid was precipitated by adding water. After filtering, washing with water, and drying under reduced pressure, 5 19 mg (yield 79%) of the title compound was obtained as a pale yellow solid. 1H-NMR (DMSO-d6): 1 · 5 -1 · 7 (2 Η, m), 1 · 8-2 · 0 (2 Η, m), 3.41-3.50 (2H, m), 3.80-3.8 7 (1 H, m), 3.97-4.05 (2H, m), 4.86 (1H, d, J = 4.2, OH), 8.0 0-8 · 1 6 (4 H, m). e) 4- {4- (1H-tetrazol-5-yl) phthalazin-1-yl} piperidin-4-one. 2 94 mg (1.156 mmol) of the compound obtained in Example 66d, trimethyl formamide Shixiyuan base azide (7ml) and 34.5mg (0.139mmol) of dibutyltin oxide were dissolved in toluene (10ml), stirred at U0 ° C for 30 hours, and the solvent was distilled off under reduced pressure. The obtained oil The material was purified by silica gel chromatography (methanol-dichloromethane) to obtain 114 mg (33% yield) of the title compound as a pale yellow solid. 1H-NMR (DMSO-d6): 1.64-1.76 (2H, m)? 1.96-2.02 (2H? M), 3.2-3.5 (2H, m), 3.81-3 · 95 (3H, m), 4.85 (1H , Brs, OH), 8.02-8.13 (2H, m), 8.18 (1H, d, J = 8.5), 9.23 (1H, d, J = 8.0). -104- 200533356 (101) (Example 67) l- {4- (5-oxo-4,5-dihydro- [1,2,4] oxadiazol-3-yl) phthalofluorene-l-yl E Bing-4- 嗣

a) 4- [4- (t-Butyldimethylsilyloxy) piperidin-1-yl] phthalazine-1-carbonitrile The compound obtained in Example 6 6 d from 522 mg (2.05 3 mmol) and 310 mg (4.5 5 3 mmol) of imidazole was dissolved in DMF (5 ml) and stirred under ice cooling. At this time, 371 mg (2.462 mmol) of chloro-t-butyldimethylsilane was added, and the mixture was stirred at the same temperature for 3 hours. Ethyl acetate The reaction solution was diluted, washed with saturated brine, dried over magnesium sulfate, filtered, and the oil obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (dichloromethane) to obtain 63 5 mg (yield 84). %) Of the title compound as a pale yellow solid. 1H-NMR (CDC13): 0.11 (6H, s), 0.93 (9H? S) 9 1.77- 1 · 8 4 (2 Η, m), 1 · 9 9-2 · 0 6 (2 Η, m), 3 · 6 2-3.7 1 (2 Η, m), 3.92-4.0 0 (2H, m), 4.07-4 · 10 (1H, m), 7.84-7.97 (2H, m), 8.02 (1H, d5 J = 8.4), 8 · 15 (1H, d, J = 7.8). b) 4_ [4- (t-Butyldimethylsilyloxy) piperidine- 丨 _yl] phthalazine- 丨 _carboxyl The compound obtained in Example 6 7 a was used to perform the same procedure as in Example 6 4 a The same operation was performed to obtain the title compound (649 ftig (67% yield)) as a pale yellow solid. 1 H-NMR (CDC13): 0.1 1 (6 μm, s), 0.9 2 (9 μm, s), 1.8 0- 1.87 (2H, m), 1.99-2.08 (2H, m), 3.3 7 -3.5 7 (2H, m), 3.78-3.83 (2H, m), 3.97-4.05 (1 H, m), 5.79 (2H, s, NH2), 7.7 6-7.84 (2H, m), 8.00 -8.04 (1 H, m), 9.08-9.12 (1 H, m) 0 -105- 200533356 (102) c) 1-{4-(5 -oxy-4,5 -dihydro- [1,2, 4] oxadiazole-3 -yl) phthalazine-1 -yl} piperidine-4 -one

Using the compound obtained in Example 6 7 b, the same operation as in Example 6 4 b was performed to obtain a pale yellow amorphous solid, which was dissolved in THF, and 1 mol of tetrabutylammonium fluoride (2.7 ml) was added and left to stand. After 1 night, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (methanol-dichloromethane), and washed with a mixed solvent of ethyl acid and hexane to obtain 146 mg (yield 53%). The title compound is a pale yellow solid. 1 H-NMR (DMSO-d6): 1.64-1 · 75 (2H, m), 1.96-2.01 (2H, m), 3.34-3.42 (2H, m), 3.8, 3.96 (3H, m), 4.85 (1H, s), 7.99-8.08 (2H, m), 8.14-8.18 (1H, m), 8.79-8.83 (1 H, m), 13.30 (1H, s, NH) (Example 68) l- {4- (5-thio-4,5-dihydro- [1,2,4] oxadiazol-3-yl) phthalazine-butyl} piperidin-4-one was used in Example 67a The title compound was obtained in the same manner as in Example 65 to obtain 269 mg (yield 67%) of a pale yellow solid. 1H-NMR (DMSO-d6): 1.64- 1.7 5 (2H, m), 1.95-2.02 (2H, m), 3.3 6-3.43 (2H, m), 3.82-3.96 (3 H, m), 4.6- 5.0 (1H, broad), 8.00- 8.09 (2H, m), 8.15-8 · 19 (1H, m), 8.6 8-8.72 (1 H, m). (Example 69) 4-{(Bumethyl-1H-imidazol-2-yl) -phthalazine-1-ylbuphenazinea) 1- (bumethyl-1H-imidazol-2-yl) -4- (4- Tert-Butyldimethylsilane-106-200533356 (103) oxyoxyphenyl) Presented with 41 lmg of the compound obtained in Example Id and 0.66g of 4-4-t-butyldimethylsilyl Oxyphenylboronic acid was treated in the same manner as in Example 1 to obtain 478 mg (yield 68%) of the title compound as a solid. 1H-NMR (CDC13): 0 · 28 (6H, s), 1.04 (9H, s), 4.12 (3H, s), 7.05 (2H, d), 7.16 (1H, s), 7.34 (1H, s), 7.72 (2H, d), 7.8 0-8.00 (2H, m), 8.17 (1H, d), 9.18 (1H, d).

b) 4-{(1-methyl-1H-imidazol-2-yl) -phthalazine-l-yl} -phenol

307 mg of the compound obtained in Example 69a was dissolved in 6 ml of THF, 0.8 ml of tetrabutylammonium fluoride (1M THF solution) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, and acetone was added to the residue. 0.2 ml of a 4 mol ethyl acetate solution of hydrochloric acid was added thereto, and isopropanol was added thereto, followed by heating to reflux, cooling to room temperature, and filtering out the precipitated solid to obtain 150 mg (yield 67%) of the title compound as a solid. 1H-NMR (DMSO-d6): 3.97 (3H, t), 7.01 (2H, d), 7.26 (1H, s), 7.53 (1H, s), 7.56 (2H, d), 8.00-8.15 ( 3H, m), 8.92 (1H, d), 9.98 (1H, brs) MS (El): 3 02 (M +), 274, 209, 183, 156, 151, 1 29, 65 (Examples 7 〇) 1-(4-methoxy-piperidine-1 -yl) -4-(bumethyl-1 H -imidazol-2-yl) phthalazine hydrochloride

A solution of 200 mg (.65 nimol) of the compound obtained in Example 42 and 28 mg (0.71 mm) of sodium hydride in DMF (1.5 ml) was used at 0 ° C -107- 200533356 (104).

Stir for 30 minutes, add 0.05 ml (.78 mmol) of methyl iodide to the reaction solution, stir at room temperature overnight, add water to the reaction solution, extract with ethyl acetate, dry with anhydrous sodium sulfate and filter , Concentrated under reduced pressure, and the balance was purified by silica gel chromatography (dichloromethane-methanol) to obtain 1- (4-methoxy-piperidin-1-yl) -4- (1-methyl-1H-imidazole- 2-yl) phthalazine was added to an ethyl acetate solution of 1- (4-methoxy-piperidin-1-yl) -4- (1-methyl_1H-imidazol-2-yl) phthalazine 0.14 ml of a 4 mol hydrochloric acid-ethyl acetate solution was stirred at room temperature overnight, and the precipitated solid was filtered to obtain 183 mg (yield 79%) of the title compound. 1H-NMR (CD30D): 1.94 (2H, m), 2.20-2.23 (2H, m), 3.45 (3H, s), 3.63-3.70 (3H, m), 4.05 (2H, m), 7.74 ( 1H, d), 7.80 (1H, d), 8.05-8.12 (3H, m), 8.34-8.3 7 (1 H, m). (Example 71) 400 mg (1.64 mmol) of ethyl l- [4- (1-methyl-1H-imidazole · 2-yl) -phthalazin-1-yl] -piperidine-4-carboxylate The compound obtained in Example Id and 307 mg (3.06 mmol) of ethyl acetonium diacetate residue, 0.27 ml (2.45 mmol) of N-methylmorpholine in tert-butanol (0.65 ml), and heated It was refluxed for 4.5 hours, and after cooling to room temperature, the solvent was concentrated under reduced pressure. The obtained solid was suspended and washed with hexane-ethyl acetate to obtain 500 mg (yield 84%) of the title compound. 1H-NMR (CD30D): 1.31 (3H9 t), 2.07-2.1 5 (4H, m) 5 2.5 9-2.62 (1 H, m), 3.17-3.25 (2H, m), 3.96-4 · 00 (2H , M), 4.05 (3H, s), 4.17-4.24 (2H, d), 7.10 (1H, d), 7.28 (1H5 d) 9 7.8 2-7.8 5 (2 H? M)? 8.05-8.0 8 ( 1 H? M)? -108- 200533356 (105) 8.93-8.97 (1 H, m). (Example 72) {(2R) · 1- [4- (1-methyl · 1H-imidazol-2 · yl) phthalazine-; ι] yl] pyrrolidin-2-yl} methanol (200 mg (1.23 mmol) of the compound obtained in Example η, 0.15 ml (1.47 mmol) of D-prolinol, and 016 ml (147 mmol) of N-methylmorpholine were subjected to the same operation as in Example 71 to obtain ( 27%) of the title compound. 1H-NMR (CDC13): 1.83-1.90 (2H, m), 2.08-2.09 (lH, m), 2.28-2.30 (lH, m), 3.80-3 · 86 (1H, m), 3.90 -4.03 (5H , M), 4.15 · 4 · 18 (1H, m), 4.89-4.91 (lH, m), 7.08 (1H, d), 7.26 (1H, d), 7.76-7.84 (2H, m) , 8.18-8.21 (1H, m), 8.74-8.77 (1 H, m). (Example 73) 1- [4- (1-methyl-1H-imidazol-2-yl) phthalazin-1-yl] azetidin-3-ol was obtained using 200 mg (0.82 mmol) of Example Id The compound and 171 mg (0.98 mmol) of 3-galatidinol and 0.22 ml (0.98 mmol) of N.methylmorpholine were treated in the same manner as in Example 71 to obtain 1.67 mg (yield 73%). Title compound. 1 H_NMR (CDC13): 3.71-3.75 (1H, m), 3.93 (3H, s), 4.00_4.05 (1H, m), 4.51 (2H, m), 4.67-4.69 (1 H, m ), 7.17 (1H, d), 7.29 (1H, d), 8.05-8.11 (2H, m), 8.45 -8.8 8 (1 H, m), 9.05 -9.08 (1 H, m) -109- 200533356 ( (106) (Example 74) {(2S) -l- [4- (1-methyl-1H-imidazol-2-yl) phthalazin-1-yl] D ratio slightly higher than 2 -yl} for methanol 3 〇OOmg (1.23mmol) of the compound obtained in Example Id and 0.15ml (i 47mmol) of L-prolinol, 0.16ml (1.47mmol) of N-methylmorpholine were carried out in the same manner as in Example 71. This operation yielded 186 mg (yield 49%) of the title compound. 1H-NMR (CDC13): 1.7 (2H, m), 2.09 (1H, m), 2.28 (1H, m), 3.80-3 · 86 (1H, m),

3.93-4.03 (5H, m), 4.16-4.18 (1H, m), 4.89 (1H, m), 7 0 8 UH, d), 7.25 (1H, d), 7.73-7 · 84 (2H, m), 8.18-8.21 (1H, m), 8.73-8.76 (1 H, m). The compounds described in Examples 60 to 74 are listed below.

-110- 200533356 (107)

-111 200533356 (108) (Example 75) {3methyl-2- (4-pyridylphthalazin-1-yl) -3H-imidazol-4-yl} methanol

To 3 03 mg (0.916 mmol) of the carboxylic acid obtained by the method of Example 25 was added 12 ml of THF and 0.15 ml (0.997 mmol) of triethylamine, and the mixture was stirred at room temperature for 5 minutes and cooled to -25. ° C, 0.16 ml (1.22 mmol) of isobutyl chloroformate was added, and stirred for 20 minutes. The precipitated solid was filtered off, washed with 6 ml of THF, and the filtrate was cooled to -45 ° C, and 34 mg (0.899 mm) was added. 〇1) of sodium tetrahydroborate, the temperature was raised to -25 ° C while stirring for 40 minutes, the reaction solution was cooled to -45 ° C and saturated saline was added, and then extracted with THF, washed with saturated saline and used After drying over anhydrous sodium sulfate, the solution was filtered and concentrated under reduced pressure. 10 ml of water and 3 ml of concentrated hydrochloric acid were added thereto, stirred at 50 ° C for 3 hours, washed with ethyl acetate, and calcium carbonate was added at 0 ° C. After making it alkaline, it was extracted with ethyl acetate, and then sequentially washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography of ethyl acetate as the eluent was added to the obtained material. Alkane: ethyl acetate = 20: 1 and stirred, the precipitated solid was filtered to obtain 47.6 mg (yield 16.6%) of the standard Title compounds. 1 H-NMR (CDC13): 4.09 (3H, s), 4.78 (2H, s), 7.26 (lH, s), 7.50-7.70 (3 H, m), 7.70-8.00 (4H, m), 8 · 14 (2H, d), 9.00 (2H, d). (Example 76) 4- (1-methyl-1H-imidazol-2-yl) phthalazine-1-carbonitrile 496 mg (6.04 mmol) of 1-methylimidyl chloride was dissolved in 8 ml of THF, and- At 70 ° C, 4.1 ml of η-butyllithium (1.58M hexane solution, 6.47 mmol) was added, and after stirring for 20 minutes, 2.13 g (6.54 -112- 200533356 (109) mmol) of trichloride was added. Butyltin, the temperature was raised to room temperature in about 1.5 hours, and 0.15 g (3.5 mmol) of lithium chloride and 567 mg (2.990 mmol) of 4-chlorophthalazine-1 obtained in Example 66c were introduced. -Nitrile, 0.35 g (0.30 mmol) of tetrakis (triphenylphosphine) palladium (〇), 20 ml of toluene, 60-

After heating at 70 ° C for 10-20 minutes, the mixture was heated under reflux for about 3 hours. The reaction solution was purified by column chromatography (hexane · ethyl acetate: dichloromethane) to obtain a brown solid. The dimethyl ether was recrystallized to obtain 188.7 mg (0.802 mmol, 27%) of the intended product, and 25.6 mg (0.109 mmol, 3.6%) of the intended product was obtained from the filtrate. 1H-NMR (CDC13): 4.17 (3H, s), 7.23 (1H, s), 7.39 (1H, s), 8.00-8'20 (2H, m), 8.3 0-8.40 (1 H, m), 9.40-9.50 (1 H, m). (Example 77) Example Id of 200 mg (0.82 mmol) of (1-methyl "fluoren-imidazol-2-yl) -4- (1,3-thiazolidin-3-yl) phthalazine hydrochloride The obtained compound, 0.08 ml (0.98 mmol) of thiazine, and 0.11 ml (0.98 mmol) of N-methylmorpholine were subjected to the same operation as in Example 71 to obtain 1 · (1-methyl-1H -Imidazol-2-yl) -4- (1,3-thiazolidine-3-yl) phthalazine, at 1- (1-methyl-1H_imidazol-2-yl) -4- (1,3- To an ethyl acetate solution of thiazolidine-3-yl) phthalazine was added 0.1 1 ml of a 4 mol hydrochloric acid-ethyl acetate solution, and the mixture was stirred at room temperature overnight, and the precipitated solid was filtered to obtain 1 12 mg (product 81%) of the title compound. 1H-NMR (DMSO-d6): 3.22 (2H, t), 3.87 (3H, s), 4.23 (2H, t), 5.07 (2H, s), 7.92 -8 · 08 (5H, m), 8.46-8.49 (1Η, m) o -113- 200533356 (110) (Example 7 8) 1-[4-(1-methyl-1 Η-imidazole-2- A) phthalazine-1 -yl] piperidine-4-nitrile a) 4-cyanopiperidine hydrochloride

To a solution of N-tert-butoxycarbonyl-4 -cyanopiperidine in THF (9.0 ml) was added 3.6 ml of a 4 mol hydrochloric acid-ethyl acetate solution, and the mixture was stirred at room temperature overnight, and the precipitated solid Suspension with ether-ethyl acetate gave 677 mg (96% yield) of the title compound. 1H-NMR (DMSO-d6): 1.87-1 · 94 (2H, m), 2.06-2.09 (2H, m), 2.95-3.03 (2H, m), 3.12-3.20 (3H, m), 9.05 (1H , Brs) 〇b) 1_ [4- (Bumethyl-1H-imidazol-2-yl) phthalazin-1-yl] piperidine-4-carbonitrile obtained with 200 mg (0.82 mmol) of Example Id A compound, 144 mg (0.98 mm ο 1) of the compound obtained in Example 7 8a, and 0.22 ml (0.98 mmol) of N-methylmorpholine were subjected to the same operation as in Example 71. This gave 192 mg (yield 74%) of the title compound. 1H-NMR (CDC13): 2.16-2_26 (4H, m), 2.93-2.94 (lH, m), 3.43- 3.50 (2H ,, 3.82 · 3 · 88 (2H, m), 4. · 5 (3H, s), 7.12 UH, d), 7.29 (lH, d), 7.83-7 · 89 (2H, m), 8.00 · 8 · 04 (1H, m), 8.97- 9.00 (1 H, m) 〇 (Example 79) 4- [4_ (1-methyl-1H_imidyl 11-yl) benzo-1 -yl] benzonitrile 2000 mg (0 · 8 2 mm 0 1) The compound obtained in Example 1 d and 180 mg (1.23 mm) of 4-cyanophenylboronic acid 'were subjected to the same operation as in Examples 1e -114- 200533356 (111) to obtain 1 94 mg (76% yield) of the title compound. 1H-NMR (CDC13): 4.15 (3H, s), 7.20 (1H, d), 7.36 (1H, d), 7.8 9- 8.03 (7H, m), 9.27-9.3 0 ( 1 H, m). (Example 80) 4- [4- (1-Methyl-1H-imidazol-2-yl) phthalazin-1-yl] phenylarsinic acid

Using 200 mg (0.8 2 mmol) of the compound obtained in Example 1 d and 136 mg (0.82 mmol) of 4-endylphenylboronic acid, the same operation was performed as in Example le to obtain 137 mg (yield 76%) of the title. Compounds. 1H-NMR (DMSO-d6): 4.00 (3H, s), 7.29 (1H, d), 7.57 (1H, d), 7.92 (2Η, d), 8.04-8.13 (3Η, m), 8.19 (2Η, d), 9.00 · 9.03 (1H, m). (Example 81) 4- (1-Methyl-1H_imidazol-2-yl) -1-phenylpyrido [3,4-d] Daqina) 4- (1-methyl-1H-imidazole 2-yl) pyrido [3,4-d] dagen-1 (2H) -one at 5.0 g (4 0.6 mmo 1) in 4-D to B-determined acid, 3.9 ml (42.6 mmol) of aniline 7.5 ml (44.7 mmol) of diethyl cyanophosphonate and 6.2 ml (44.7 mmol) of triethylamine under ice cooling, and stir for 1 hour, then After overnight, the solid precipitated after adding water was washed with hexane-ethyl acetate to obtain 5.6 g of N-phenylisoxanthine. 3.0 g (15.1mmol) of N-phenylisoxanthine Amine, 5.0 ml (33.3 mmol) of tetramethylethylenediamine dissolved in THF (40 m 1) -115- 200533356 (112)

, Cooled to -78 ° C, titrated 21.1ml of η-butyllithium-hexane solution (1.58M) under a nitrogen gas atmosphere, and stirred at -78t for 1 hour, and added the reaction solution by a conventional method (J · Chem. Soc. Perkin Transl 1994, 3, 23 9) 2.8 g (18.2 mmol) of 1-methyl-1 1-fluorene-imidazole · 2-carboxylic acid ethyl ester synthesized, stirred at the same temperature for 2 hours, and then heated up After stirring at room temperature for 2.5 hours, methanol was added to the reaction solution, and the solvent was concentrated under reduced pressure. Water was added to the remaining amount. The precipitated solid was neutralized with hydrochloric acid and washed with hexane-ethyl acetate to obtain 3.1. g of 3-hydroxy-3- (1-methyl-1fluoren-imidazol-2-yl) -2-phenyl-2,3-dihydro-1H-pyrrole [3,4-c] pyridin-1-one With 3-hydroxy-3- (1-methyl-1H-imidazol-2-yl) -2-phenyl-2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-1- Ketone and 15 m 1 of hydrazine 1 hydrate were treated in the same manner as in Example 2 a to obtain 1.67 g (yield 49%) of the title compound. 1 Η-NMR (DMS0-d6): 3 · 8 5 (3 Η, s), 7 · 19 (1 Η, s), 7.4 5 (1 Η, s), 8.14 (1 Η, d), 9.01 ( 1Η, d), 9.96 (1Η, d), 13.25 (1Η, brs) 0) l-chloro-4- (1-methyl-1H-imidazol-2-yl) pyrido [3,4-d] Using 1.56 g of the compound obtained in Example 81a and about 5 mi of phosphorus oxychloride in the D-d well, the same operation as in Example 26b was performed to obtain 607 mg (yield 36%) of the title compound. 1H-NMR (CDC13): 4.15 (3H, s), 7.21 (1H, d), 7.38 (1H, d), 8.06- 8.0 8 (1 H, m), 9.15 (1H, d), 10.70 (1H, s). c) 4- (1-methyl-1H-imidazol-2-yl) -1-phenylpyrido [3,4-d] tower co-116- 200533356 (113) with 3 0 0 mg (1 · 2 2 mm ο 1) The compound obtained in Example 8 1 b and 184 mg (1.46 mmol) of phenylboronic acid were subjected to the same operation as in Example 1 to obtain 298 mg (yield 85%) of the title compound. 1H-NMR (CDC13): 4.21 (3H, s), 7.22 (1H, s), 7.40 (1H, s), 7.61-7.64 (3H, m), 7.82-7.8 5 (2H, m) 5 7.9 0- 7.92 (1 H, m), 9.20 (1H, d), 10.70 (1H, d).

(Example 82) 1- (5-methyl-2-furan) -4- (1-methyl-1H-imidazol-2-yl) Stazine hydrochloride a) 4- (5-methyl-2 -Furan) -2H-phthalazin-1-one With 2.0 g (11. 1 mmol) of methyl phthalate and 1.5 ml (16.7 mmol) of 2-methylfuran, according to a conventional method ( S. Benkaikaihei 6-1 3 5 93 8) was synthesized to obtain 3 48 mg (yield 14%) of the title compound. 1 H-NMR (CDC13): 2.4 7 (3 Η, s), 6 · 2 1 (1 Η, m), 6. 83 (1 Η, d), 7.8 3 -7.92 (2 Η, m), 8 · 3 7 (1Η, d), 8.49- 8.5 2 (1 H, m), 10 · 02 (1H, brs). b) 1-chloro-4- (5-methyl-2-furan) -2H-phthalazine was carried out with 3 43 mg (1.52 mmol) of the compound obtained in Example 8 2 a and 0.17 ml of phosphorus oxychloride The title compound was obtained in the same manner as in Example 28b (yield: 72%). 1 H-NMR (CDC13): 2.53 (3H, s), 6.28-6.29 (lH, m), 7.35 (lH, d), 7.98-8.03 (2H, m), 8.3 3 -8.3 6 (1 H, m ), 8.86-8.8 9 (1 H, m). -117 · 200533356 (114) c) 1- (5-methyl-2_furan) _4- (1-methyl-1H-imidazol-2-yl) phthalazine

The same operation as in Example 26c was performed using 2 6 mg (1.08 mm ο 1) of the compound obtained in Example 8 2 b and 0.13 ml (1.61 mmol) of N · methylimide. 1- (5-methyl-2_furan) · 4- (1-methyl-1H-imidazole · 2-yl) phthalazine is obtained at 1- (5-methyl-2-furan) -4- (1 -Methyl-1hydrazine-imidazol-2-yl) phthalazine in ethyl acetate solution was added 0.18 mi of 4 mol hydrochloric acid-acetate solution, stirred overnight, and the precipitated solid was filtered to obtain 189 mg (yield 54%) of the title compound. 1 Η-NMR (DMSO-d6): 2.55 (3H, s), 3.94 (3H, s), 6.54 (1H, d), 7.55 (1H, d), 7.77 (1H, m), 7.91 (1H, m), 8.12-8.24 (2H, m), 8.34 (1H, m), 8.96 (1H, d). (Example 83) 3-Methyl-2- (phenylphthalazine-butyl) -3H-imidazole-4-carboxylic acid In the same manner as in Example 25, 75 mg of the title compound was obtained. 1H-NMR (DMSO-d6): 4.04 (3H, s), 7.92 (lH, m), 8.00-8.15 (2H, m), 8.2 5 -8.3 5 (1 H, m), 8.48 ( 1H, d), 9 · 80 (1H, s). (Example 84) 1. · (4 · trifluoromethylphenyl) · 4- (bumethylimidazol-2-yl) phthalazine 0.63 g of the compound obtained in Example 1d, and Λ trifluoro in 0.53 § Methylphenylboronic acid was obtained in the same manner as in Example 1e.

518 mg (57% yield) of the title compound as a solid. 1H_NMR, 7 36 (1H, s) (CDC13): 4 · 15 (3H, s), 7.19 (1H, s), //; -118- (115) 200533356 7.8 0-8 · 1 0 (7 Η, m), 9 · 2 5 (1 Η, d) (Example 85) dimethyl-4- {4- (1-methyl-1Η_imidazole-2_yl) 駄 _ 1 -yl} phenyl The amine was subjected to the same operation as in Example 1e with 0.58 g of the compound obtained in Example Id and 0.47 dimethylamine phenylboronic acid 'to obtain 161 mg (yield 21%) of the title compound as a solid. . ih_nmr (CDC13): 3.09 (6H, s), 4.12 (3H, s), 6.90 (2H, d), 7.15 (1H, d), 7.33 (1H, d), 7.78 (2H, d) ), 7 800 (2h, m), 8.27 (1H, d), 9.12 (1H, d). (Example 86) Bu (2-methoxyphenyl) -4- (1-methyl-1H-imidazolyl) phthalazine hydrochloride

Using 0.50 g of the compound obtained in Example 1 d and 0.35 g of 2-methoxyphenylboronic acid ', the same operation as in Example 1 e was performed to obtain an oily product (2 -Methoxyphenyl) (1-methyl "fluorene · imidazole · 2-yl) 敝, dissolve it in a mixed solvent of ethyl acetate 'heptane, add 4 mol hydrochloric acid_ethyl acetate solution' and filter The precipitated solid gave 277 mg (yield 39%) of the title compound. 1H-NMR (DMSO-d6): 3.71 (3Η, s), (1H, dd) 9 8.05-8. 3 99 (3 H, m), 7.23 (1H, t), 7.33 (1H, d), 7.51 7 70-7.85 (1H, m), 7.92 (1H, d), 8.04 (1H, d) 20 (2 ^) , 8.20-8.3 0 (1 1 ^) 0, M-methylphenyl) -4- (1-methyl-1H-imidazol-2-yl) (Example 87) I · (4-Stem-119- 200533356 (116) For phthalazine, 1.45 g of the compound obtained in Example 1 d and 1.02 g of 4-methylphenylboronic acid were subjected to the same operation as in Example 1 to obtain 8 86 mg (yield 45%) of the title compound as a solid. 1H-NMR (CDC13): 2.59 (3H, s), 4.13 (3H, s), 7.17 (1H, s), 7.34 (1Η, s) , 7.46 (2Η, d), 7.76 (2 Hf, d), 7.80-8.10 (2H, m), 8.15 (1H, d), 9.19 (1H, d). (Example 88) 1- (2,3-dihydro-1-benzofuran-5 -Yl) -4- (1-methyl · 1H-imidazol-2-yl) phthalazine

620 mg (3.11 mmol) of 5-bromo-2,3-dihydro-1-benzofuran in 10 ml of THF was added to η-butyllithium at a temperature of -70 ° C and stirred for 30 minutes. 4- (1-methyl-1Η-Miso-2-yl) -2Η-pyran-1-one (refer to Example 1 c) was added, and the temperature was gradually raised to room temperature and left overnight. The reaction solution was added with water After extraction with ethyl acetate, this was extracted with 1 mole of hydrochloric acid, followed by addition of 1 mole of sodium oxide aqueous solution to make it alkaline, and extracted with ethyl acetate. It was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained solid was washed with stirring while adding diethyl ether, and filtered off to obtain 130.9 mg (yield 37%) of the title compound. 1H-NMR (CDC13): 3.35 (3H, t), 4.12 (3H, s), 4.70 (2H, t), 6.98 (1H, d), 7.16 (1H, s ), 7.33 (1H, s), 7.57 (1H, d), 7.71 (1H, s), 7.80-8 · 00 (2H, m), 8.19 (1H, d), 9.17 (1H, d ) 〇-120- 200533356 (117) (Example 8 9) 1-{4-(pyridin-2-yl) -3 -methyl-1 hydrazone-imidazole-2 -yl} phthalazine will be used in Example 22 268 mg (.927 mmol) of 1- {4-bromo-3-methyl-1H-imidazol-2-yl} synthesized from (丨 _methyl-1 丨 -imidazol-2-yl) phthalazine in the same method Phthalazine, 378 mg (1.027 mmol) of 2-pyridyltributyltin, 0.06 g (1.4 mmol) of lithium chloride, 160 mg (0.1 38 mmol) of tetrakis (triphenylphosphine) palladium (0), 7.5 ml of Toluene

The mixture was heated under reflux for about 6 hours, and the resulting solid was purified by column chromatography (ethyl acetate: chloroform to ethyl acetate) and washed with ethyl acetate to obtain 157 mg (yield 59%) of the title compound. 1H-NMR (CDC13): 4.27 (3H, s), 4.70 (2H, t), 7 "0-7.13 (lH, M), 7.60-7.70 (lH, M), 7.33 (lH, s), 7.70- 7.90 (lH, m), 7.90-8.10 (3H, m), 8.71 (1H, d), 8.86 (1H, d), 9.54 (1H, s) Example 7 5 to Example 8 9 The compounds listed are listed below.

121 200533356 (118)

Example 〆 85

-122- 200533356 (119) (Example 90) 1-Isobutyl-4- (1-methyl-1H-imidyl-2-yl) was obtained using the method described in Example Id. 481mg (1.97mmol) of 1-chloro-4- (1-methyl-1H-imidazol-2-yl) phthalazine, 408mg

(4.00 mmol) of isobutylboronic acid, 112 mg (0.137 mmol) of dichloro (1,1'-bisdiphenylphosphinoferrocene) palladium methylene dichloride complex, 562 mg (4.0 7 mmol) of Potassium carbonate, 8 ml of a mixture of 1,4-dioxan, heated and stirred at 100 ° C for about 20 hours, added water to the reaction solution, and extracted with methylene chloride, and extracted with 1 mole of hydrochloric acid After removing insoluble solids by filtration, add sodium hydroxide to make it alkaline, extract with methylene chloride, rinse with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure, and then use column chromatography ( After ethyl acetate: methanol gradient) purification, the obtained solid was washed with hexane to obtain 1 17 mg (yield 22%) of the title compound. 1H-NMR (CDC13): 1.06 (6H, d), 2.37 (1H, hep), 3.28 (2H, d), 4.09 (3H, s), 7.14 (lH, s), 7.30 (lH, s), 7.80 -8.00 (2H, m), 8.1-8.25 (1H, m), 9.00-9.15 (1H, m). (Example 91) 1-methyl-4- (1-methyl-1H-imidazol-2-yl) phthalazine 506 mg (2.07 mmol) of 1-chloro-4- (1-methyl-1H-imidazole) · 2-yl) Corazine, 408nig (4.83mmol) of methylboronic acid, 1700nig (0.2208mmol) of dichloro (1,1′-bisdiphenylphosphinoferrocene iron) palladium methylidene Mixture, 852 mg (6.16 mmol) of carbonate, 15 ml of 1,4-dioxane, heated to reflux for about 1 day, added water to the reaction solution, and extracted with methylidene dichloride. Extraction with hydrochloric acid, filtering insoluble solids, adding sodium hydroxide to make it alkaline, extracting with methylidene chloride-123- (120) 200533356, washing with saturated brine, drying over sodium sulfate-free and filtering After concentration under reduced pressure, the residue was purified by a short silica gel column (ethyl acetate: methanol gradient), and the obtained solid was separated and purified by HPLC to obtain 1 73 mg (yield 37%) of the title compound. 1H-NMR (CDC13): 3.07 (3H? S), 4.07 (3H, s), 7.14 (1H, s), 7.31 (1H, s), 7.08-8.00 (2H, m), 8.05- 8.15 (1H, m) 9 9.00-9.15 (1H, m).

(Example 92) Methyl-4- {4- (1-methyl-1H-imidazol-2-yl) phthalazin-1-yl} phenyl maple was obtained from 618 mg (1.85 9 mmol) of Example 8 7 The compound was dissolved in 16 ml of methylene dichloride, 0.74 g of mCPBA (m-chloroperbenzoic acid, purity &gt; 65%) was added under ice-cooling, and the mixture was stirred for about 1 hour. To the reaction solution were added an aqueous sodium sulfate solution and sodium hydroxide. The aqueous solution was separated, and the organic layer was washed with an aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and then subjected to silica gel chromatography (ethyl acetate- &gt; ethyl acetate: methanol = 4). : 1) The fractional fraction that flowed out first was concentrated and washed with 1-butyl methyl ether to obtain 316.7 mg (yield 47%) of the title compound as a solid. 1H-NMR (CDC13): 3 · 1 7 (3 Η, s), 4.15 (3 Η, s), 7 · 2 0 (1H, s), 7.37 (1H; s), 7.08-8.10 ( 5H, m), 8.15-8.25 (2H, m), 9.20-9.3 0 (1 H, m). MS (LC-MS) · 3 6 5 (M + 1) (Example 93) Methyl-4- {4- (1-methyl-1H-imidazol-2-yl) phthalazine-phenyl} benzene -124- 200533356 (121)

The fraction was fractionated and washed with acetone and butyl methyl ether to obtain 174.7 mg (yield: 27%) of the title compound as a solid. 1H-NMR (CDC13): 2.84 (3H, s), 4.14 (3H, s), 7.19 (1H, s), 7.36 (1H, s), 7.08-8 · 05 (6H, m ), 8.07 (1H, d), 9.26 (1H, d). MS (LC-MS): 3 49 (M + 1) (Example 94) [4- (2-methyl-2H-pyrazol-3-yl) phthalazin-1-yl] piperazine

Pyridin-4-one 2 hydrochloride a) methyl 2- (2-methyl-2H-pyrazol-3-yl) carbonylbenzoate 27.51 g (153 mmol) of monomethyl phthalate, 50 ml of methylene dichloride, 12.5 ml (171 mmol) of thionyl chloride, 0.5 ml of DMF, stirred at room temperature for about 4.5 hours, concentrated under reduced pressure, and then added 100 ml of THF to obtain a thallium chloride solution. In another container, a mixture of 12.52 g (152 mmol) of 1-methylpyrazole and 200 m 1 of t-butyl methyl ether was cooled at -70 ° C, and a 1.54M η-butyllithium hexane solution was titrated and stirred for about For 1 hour, zinc bromide was added thereto and stirred for about 30 minutes. 8.2 g (7.1 mmol) of tetrakis (triphenylphosphine) palladium (〇) was added at -60 ×: adding a previously prepared rhenium chloride solution, The temperature was gradually raised to room temperature and left overnight. Water and ethyl acetate were added to the reaction solution for liquid separation. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with saturated brine, and then After drying and filtering over anhydrous sodium sulfate, the solution was concentrated under reduced pressure, and purified by column chromatography (hexane: ethyl acetate = 1 00: 1-3: 1). The obtained product was suspended in 5 ml of ethyl acetate. , I00mi mixed solvent of hexane and stirred, cooled to 0 ° C and filtered off to obtain 12.46 g ((yield 33%) of 2- (2- -125- 200533356 (122) methyl-2H -Pyrazol-3-yl) carbonyl benzoate. 1H-NMR (CDC13): 3.17 (3H, s), 4.32 (3H, s), 6.19 (1H, d), 7.38 (1H, d ), 7.48 (1H, dd), 7.5 0-7.70 (2H, m), 8.00 (1H, dd). B) 4- (2-methyl-2H-pyrazol-3-yl) -2H- Phthalazin-1-one

To the ketocarboxylic acid obtained in Example 94a, 2.7 ml of hydrazine monohydrate and 100 ml of ethanol were added, and the mixture was heated under reflux for 7.5 hours. The precipitated solid was cooled and filtered to obtain 9.89 g (yield 86%) of a solid. 4- (2-methyl-2H-pyrazol-3-yl) -2H · phthalazin-1-one. 1H-NMR (DMSO-d6): 3.81 (3H, s), 6.64 (1H, d), 7.60- 7.70 (2H, m), 7.80-8.00 (2Η, m), 8.34 (1H, dd), 13.06 Implementation of (1H, s) 〇c) l-chloro-4- (2-methyl-2H-pyrazol-3-yl) phthalazine for 5.05 g (2 2 · 3 2 mm ο 1) The compound obtained in Example 1b and 5.2 ml of phosphorus oxychloride were treated in the same manner as in Example Id to obtain 4.95 g (yield 91%) of the title compound. 1H-NMR (CDC13): 4.07 (3H, s) 9 6.6 8 (1 H, d) 9 7.6 9 (1 H? D), 7.95 -8.20 (2H, m), 8.19 (1H? D), 8.42 ( 1H? D). d) l- [4- (2-methyl-2H-pyrazol-3-yl) phthalazin-1-yl] piperidin-4-one 2 hydrochloride 3 3 9 mg (1 · 3 8 5 mm ο 1) of the compound obtained in Example 9 4 c '3 2 0 mg (3.1 64 mmol) of 4-based vein, 2 ml of ^ ^ ^ heating and stirring at 15-126- 200533356 (123) ° C After about 8 hours, the solvent was completely distilled off, and the residue was dissolved in acetone and a 4M hydrochloric acid-ethyl acetate solution was added to filter out the precipitated solid to obtain 3 95 mg (yield 75%) of the title compound. 1 Η-NMR (DMS 〇-d6): 1.70- 1.8 5 (2H, m), 1.95-2.15 (2H, m), 3.60-3.75 (2H, m), 3.88 (3H, s), 3.90-4.00 ( 1 H, m), 4.00-4.15 (2H, m), 6.78 (1H, d), 7.72 (1H, d), 7.9 0-8 · 0 5 (1 H, m), 8.0 5-8.2 5 (2H , m), 8.3 5-8.4 5 (1 H, m).

(Example 95) 1- (2-methyl-2H-pyrazol-3-yl) phthalazine

69.8 mg (2.8 16 mm) of the compound obtained in Example 94c, 0.6 ml (4.3 mmol) of triethylamine, 12 ml of isopropanol, 6 ml of THF, and about 60 mg of 50% aqueous palladium carbon (10 %), And stirred at 40-50 ° C for about 8 hours under a hydrogen gas environment. Chloroform was added to the reaction solution, and the mixture was filtered on fluorite, concentrated under reduced pressure, and dissolved in chloroform with 1 M hydroxide. Rinse with an aqueous sodium solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 820 mg of the crude product 1- (2-methyl-2Η-pyrazol-3-yl) _3,4_dihydro-3H-phthalein Azine. 1H-NMR (CDC13): 3.94 (3H, s), 4.30 (2H, s), 6.22 (1H, s), 6.40 (1H, d), 7.10-7.20 (2H, m)? 7.20-7.50 ( 2H, m), 7.54 (1H, d) 393 mg of which was added with 5ml of toluene and (K35g of activated manganese dioxide, heated to reflux for about 2 hours, chloroform was added to the reaction solution and filtered on the fluorite and reduced After concentration under pressure, 2 ml of t-butyl methyl ether, 10 ml of hexane were added and stirred, and the precipitated solid was filtered off to obtain 279.2 mg (yield 72%) of the title compound. 1H-NMR (CDC13): 4.08 (3H, s), -127- 200533356 (124) 6 · 6 9 (1 Η, d), 7 · 6 9 (1 Η, d), 7 · 9 0-8 · 3 0 (4 Η, m), 9 · 5 6 (1 Η, s) ° (Example 96) 1-hydrazino-4- (1-methyl-1 Η-imidazol-2-yl)

A mixture of 420 mg (1.717 mmol) of the compound obtained in Example Id, 8 m 1 of isopropanol, and 1 m 1 of hydrazine 1 hydrate was stirred at room temperature for about 4 hours. After concentration under reduced pressure, 4 ml was added. The isopropyl alcohol was stirred at 0 ° C. for 1 hour, and the solid was filtered to obtain 297 mg (yield 72%) of the title compound. 1H-NMR (CDC13): 3 · 9 1 (3 Η, s), 7.0 7 (1 Η, s), 7.27 (1 Η, s), 7.60-7.75 (2 Η, m), 7.90 (1H , d), 8.06 (1H, d). (Example 97) N-methyl-N '-{3-methyl-2- (4-phenylphthalazin-1-yl) -3H-imidazole-4-carbonylamino} piperazine at 2 5 3 mg (0.766 mmol) of the carboxylic acid obtained in Example 25 was added with 15 ml of methylidene chloride and 0.2 ml (1.43 ηΐΓηο1) of triethylamine, followed by ice-cooling. At this time, 0.13 ml (1. OOmmol) isobutyl chloroformate for about 1 hour 'Add 0.1ml (0.90mmol) of N-methyl Emei' and stir at room temperature, 'Add sodium hydroxide aqueous solution to the reaction solution for liquid separation' The organic layer was sequentially washed with an aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The yellow solid obtained was washed with ether to obtain 153 mg (yield 49%). ) Of the title compound. 1 Η-NMR (CDC13): 2.38 (3Η, s), 2.40-2.60 (m, 4H), 3.70- 3.90 (4H, m), 4.11 (3H, s), 7.44 (1H, s) , 7.50-7.7 (3H, -128- .90 200533356 (125) m), 7.70- 8.00 (4H? M)? 8.10-8.20 (1H, m), 8.70-8 (1H, m). The compounds described in Examples 90 to 97 are listed below. Examples

Examples Examples

The results of the pharmacological tests of the compounds of the examples are as follows. (Fang Baizhou Lian ve η (Experimental Example 1) NAD (P) Η oxidase inhibitory effect (in vitro) method) Human umbilical vein endothelial cells (abbreviated as HUVEC, purchased from BioWhittaker Company) were added with glucose under high glucose About 1 culture, the cells were dissolved in Lysisbuffer containing a surfactant, measured by the immunosorbent assay (ELISA = enzyme-linked immuno sol • 129- (126) (126) 200533356 assay) due to excess glucose table. The present or activated n AD (P) 氧化 oxidase produces increased leukocyte hormone 8 (Interleukin-8, hereinafter abbreviated as IL-8), and the compounds are evaluated using the increased amount of IL-8 as an indicator. IL-8 production in cells cultured with high sugar added to the test compound was A, IL-8 production in cells cultured with high sugar was added to B, and IL-8 production in cells cultured at normal sugar concentration was C Calculate the inhibition rate as follows. Inhibition rate (%) = 100- ((A-C) / (B-C)) χίοο The results are shown in the table below.

-130- 200533356 (127) [Table 1]

Example inhibition rate (%) 1 μΜ Example inhibition rate (° / 〇) 1 μΜ 5 59 34 _ 9 1 6 91 35 _ 5 2 9 100 36 _ 8 1 12 48 41 53 13, 2 7 71 42 78 15 66 43 69 18 54 50 __ 72 19 87 5 1 100 23 97 53 100 25 98 54b _ 83 _ 26 5 5 58 87 —29 78 65 68 32 57 69 _ 5 1 (Experiment Example 2) NAD (P) Η Oxidase inhibitory effect (in vivo) (method) 40 mg / kg dissolved in 0.05 mg citric acid was intravenously administered from the tail f # vein of Wistarar rats (male, purchased from Japan SLC). Gray streptozotocin (hereinafter abbreviated as STZ) in buffer solution (P4.5) was used to create diabetic mice. One week after STZ injection, blood was collected from the tail vein using a heparin-treated capillary tube and immediately frozen. Blood centipede was obtained after centrifugation at 3000 rpm, 15 min, and 4 ° C. Blood glucose 値 -131-200533356 (128) Measured by the enzyme method "GLU neo SHINO TEST" (Shino TEST) with glucose , Measured with an enzyme immunoassay analyzer (SPCTRAMAX250, Molecular Devices). The compound was administered orally once a day to diabetic mice for 3 days, and the measurement day of the aorta's 0 2 _ was the day when the compound was not administered. NAD (P) Η oxidase activity is based on aorta · 0, production as an indicator, changing the method of David. G. Harrison et al. (J · C 1 i η · I n v e s t · 9 1,

2546-2551, 1993). The detailed method is as follows. After bleeding from the abdominal aorta of normal mice and diabetic mice, the thoracic aorta was removed, and the removed aorta was placed in Krebs-Hepesbuffer, and peripheral tissues were removed to prepare a circular specimen of about 5 mm. Move the circular specimen to Krebs-Hepesbuffer containing 0.25mM lucigenin, add NADH of 5 00 // Μ, and use a photometer (MULTI-BIOLUMATLB9505 C or AutoLumatPlus, Valac Belludo Company) Measured at 37 ° C for 10 minutes, and evaluated by plotting the area under the curve (AUC) of the chemiluminescence / radical and antioxidant (vertical axis) curve with respect to the measurement time (horizontal axis). After chemiluminescence), the wet weight of the loop-shaped specimen was measured to normalize the amount of Ό 2 Ό. The normalized free radicals and antioxidants of diabetic rats after administration are A, and the normalized free radicals and antioxidants of non-administered diabetic rats are B '. The inhibition rate (%) was calculated by the formula. Inhibition rate (%) = 100- ((A-C) / (B-C)) x 100 The results are listed in the table below -132- 200533356 (129).

In vivo experimental inhibition rate (%) Example 0.1 mg / kg 5 48 13, 27 1 04 15 109 19 5 2 23 96 29 66 34 96 42 * 74 53 115 54b 33 58 94 [Industrial availability] This The condensed daikon derivative of the invention has NAD (P) η oxidase inhibitory effect and can be an effective drug for preventing and treating diseases related to the enzyme. Furthermore, this application is based on a Japanese patent application filed on February 24, 2004 (Japanese Patent Application No. 2004-047 1 29, the entirety of which is cited. -133-

Claims (1)

200533356 (1) 10. Scope of patent application 1. A condensed dagen derivative or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof, characterized in that the condensed dagen derivative is as follows: (I), {In the formula, the Het ring contains at least one nitrogen atom, which represents a saturated or unsaturated 5-membered heterocyclic ring bonded with carbon and dagen. [The heterocyclic ring can be selected from more than one alkyl group, hydroxyalkyl group , Alkoxyalkyl, aminoalkyl, trifluoromethyl, hydroxy, aryl, heteroaryl, halogen atom, cyano, -CO2R1 (wherein R1 represents a hydrogen atom, an alkyl group, or an aralkyl group ), -Conr2r3 (where R2 and R3 may be the same or different, respectively, representing a hydrogen atom, an alkyl group, or an aryl group that may be substituted, and R2 and R3 may form a 4- to 7-membered ring together), -C0NHS02R2a ( In the formula, R2a is a hydrogen atom, an alkyl group, or an aryl group which may be substituted), -NR2R3 (where R2 and r3 have the same meanings as above), -NHCOR2a (where R2a has the same meaning as above), -NHC02R2a (formula In the formula, R2a has the same meaning as above), -NHS〇2R2a (where R2a has the same meaning as above), or -P (= 0) (OR2a) (OR3a) (where R2a has the same meaning as above, and 11321 is a hydrogen atom or an alkane Group, or a substituent which may be substituted by an aryl group], -134- 200533356 (2) To represent any one of the rings selected from (In the formula, a, b, c, and d each represent a substitutable atom, and at least two of a, b, c, and d each represent an atom; X represents an oxygen atom or a sulfur atom; R4 may be the same hydrogen atom, Halogen, alkoxy, nitro, amine, alkylamine, alkyl, or hydroxyl, k represents an integer from 0 to 4, and R is an integer of 1, but R4 represents a methoxy group and Het represents 2-thiol 1 ), 8 represents a hydrogen atom, a halogen atom, a radical, tri-, -C02R5 (where R5 represents a hydrogen atom, an alkyl group, or 5 OR5 '(wherein, R5' represents an alkyl group, or a phenyl group which may be substituted) (Wherein R2 and R3 have the same meanings as above), arylalkyl group, alkyl group, alkoxyalkyl group, hydrazino group which can be substituted, supplementary fluorenyl group which can be substituted, can be substituted Phenyl, may be taken, substituted thienyl, substituted furanyl, pyridyl, substituted pyrrolidinyl, may be substituted in place of 1,4-piperazinyl, may Substituted 丨 _ piperidinyl, alkyl, aziridinyl which may be substituted, but helium may be substituted, but Hel represents a 2,4-thiadicarbon atom or nitrogen bonded to daphne at the 2-position Replaced carbon Are different, and represents a radical, a dialkyl radical represents 0 to 2 oxazolyl, k represents methyl, cyano or triphenyl),-) '-nr2r3 alkyl, hydroxy-substituted pyridyl substituted pyridyl, Substituted thiazoleazetidinyl, where B represents -135- 200533356 Hydrogen atom, alkyl group, dialkylamine, substitutable thienyl group, the following formula (1) monomethyl, methane, cyanide, residue, ester, phenyl group substituted with oxy group, may be Substituted pyridyl, furanyl which may be substituted, morpholinyl which may be substituted, [In the formula, 1 represents 1 or ^ 1?. -T 1 times 2, R represents a hydrogen atom, an alkyl group, _co2R1 (in the formula, R1 has the same meaning as above), and s0 is strictly c. " -3〇2- / Carbonyl, _3〇2_aryl, or _CONH_fluorenyl, R2, represents an alkyl group, a hydroxyl group, a carboxyl group, or -C〇2Ri (wherein 'R is synonymous with the above)] Or the following formula (2) N-R1b. R2b · (2) (In the formula, j Rlb and R2b may be the same or different and each represents a hydrogen atom, an alkyl group, an aryl group, or a substituted sulfonyl group.)}. 2 · If the condensed dagen derivative or the pharmacologically acceptable salt thereof, or a hydrate or solvate thereof, as described in item 1 of the patent application scope, wherein the condensed dacon derivative is B represents a hydrogen atom, a halogen Atom, courtyard, trichloromethyl, cyano, -C02R5 (where R5 represents a hydrogen atom, an alkyl group or an aralkyl group), -〇r5 (where, r5 represents an alkyl group, or may be substituted Phenyl), -NR2R3 (wherein R2 and R3 have the same meanings as above), arylalkyl, and amine-136-200533356 Radical, alkyl, alkoxyalkyl, hydrazine which can be substituted, vein group which can be substituted, fluorenyl group which can be substituted, phenyl group which can be substituted, and quatyl which can be substituted , Substituted Thienyl, Substituted Furanyl, Substituted Piperidinyl, Substituted pyrrolidinyl, Substituted Morpholine, Substituted 1,4-piperazine And 1-piperidinyl which can be substituted {However, He 1 represents a bond at the 2-position with a da, 1,2,4_thiadiazole, b represents a hydrogen atom, an alkyl group, and trifluoro Methyl, hydroxy, cyano, carboxy, ester, alkoxy, dialkylamine, phenyl which may be substituted, pyridyl which may be substituted, thienyl which may be substituted, furanyl which is substituted, Substituted morpholinyl, the following formula (1) [In the formula, Γ represents 1 or 2, and r represents a hydrogen atom, and the radical -C02R1 (wherein R1 has the same meaning as above), -S02-superior, CONH-superior, and R1 2 represents a radical, hydroxyl, and carboxyl. , R1 has the same meaning as above)], or the following formula (2) S 〇2 -aryl, or-or -COj1 (wherein a hydrogen atom, -137-1 2 (wherein, Rlb 'and R2b' may be Are the same or different 200533356 (5) Alkyl, aryl, or substituted sulfonyl group)}. 3 · If the condensed tadpole derivative or the pharmacologically tolerable derivative of the scope of the patent application item No. 2 or No. 2 A salt, or a hydrate or a solvate thereof, in which Het is an unsaturated 5-membered heterocyclic ring containing at least one nitrogen atom in the ring and bonded with carbon and dagen. 4 · As for the first item in the scope of patent application The condensed daikon derivative or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof according to any one of items 3 to 3, wherein Q is the following formula, And at least 3 of d indicate a carbon atom that may be substituted 5 · such as a condensed data derivative of any one of the scope of claims 1 to 4 of the patent application or a pharmacologically acceptable _, or this And other hydrates or solvates' in which B is a hydrogen atom, a radical, a trifluoromethyl group, a hydroxyl group, a cyano group, a carboxyl group, an ester, -OR5 (wherein R5 represents an alkyl group, or a benzene which may be substituted Group), -NR2R3 (wherein R2 and R3 have the same meanings as above), or any one selected from heterocyclic ring -138-200533356 [In the formula, Y represents an oxygen atom or a sulfur atom, and R6 may be the same or different, respectively, and represents a hydrogen atom, an alkyl group, a halogen atom, an alkoxy group, a hydroxyl group, a cyano group, a carboxyl group, and -C02R1 (wherein Ri and the above Synonymous), nitro, amine, alkylamino, dialkylamino, trifluoromethyl, trifluoromethoxy, R7 represents a hydrogen atom, a radical, -CO2R1 (wherein R1 has the same meaning as above) , -S〇2_ 院 基, -S〇2-aryl, -CONH-alkyl, or phenyl which can be substituted, R8 may be the same or different, respectively, and represents a hydrogen atom, a hydroxyl group, a hydroxymethyl group, and a carboxyl group , -CC ^ R1. (Wherein R] has the same meaning as above), or an alkyl group, R9 represents a hydrogen atom, an alkyl group, a fluorenyl group, -S02-alkyl group, · S02-aryl group, and R1G represents a hydrogen atom, a hydroxyl group , Alkyl, carboxyl, -CO2R1 (where R1 is synonymous with the above), -CONR2R3 (where R2 and r3 are synonymous with the above), 111 represents an integer from 0 to 5, η represents an integer from 0 to 4, and p represents An integer of 0 to 3, q represents an integer of 0 to 8; 6 · If the condensation of any one of items 1 to 5 of the scope of the patent application, the dagen derivative or its pharmacologically acceptable salt, or these hydrates or solvates, wherein -139- 200533356 (7) is the following formula, k represents 0, 1, or 2. 7. Condensation tower derivatives or pharmacologically acceptable salts thereof, or hydrates or solvates of any one of items 1 to 6 of the patent application, which are saturated or unsaturated The 5-membered heterocyclic ring is any one selected from the group consisting of an alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a trifluoromethyl group, a hydroxyl group, an aryl group, a heteroaryl group, a halogen atom, Cyano, carboxyl, -COiR11 (wherein Rl1 represents an alkyl group or an aralkyl group), or -CONR12 R13 (wherein R12 and R13 may be the same as or different from gij, representing a hydrogen atom, an alkyl group, or Substituted aralkyl, or R12 and R13 may together form a 4- to 7-membered ring) Heterocyclic rings of the following heterocycles, imidazolyl, oxazolyl, thiazolyl, 1,2,4-oxadiazolyl, 1 , 3,4-oxadiazolyl, 1,2,4-triazolyl, pyrazolyl, tetrazolyl, oxypyrazolyl, 2,5-dihydro-5 -oxo-4H-1, 2, 4-thiazine, 2,5-dihydro-5-thio-41 ^ -1, 2,4-dithiazine, 2,5-dihydro-5-oxo-4H-1, 2, 4-oxadiazole, 2,5-dihydro-5-thio_4H-1,2,4-oxadiazole, 4,5 · dihydroimidazolyl, 4,5-dihydrooxazolyl and 4 , 5 _ thiazolyl. 8 · If the condensed dagen derivatives or pharmacologically acceptable salts thereof, or hydrates or solvates thereof according to any one of claims 1 to 7 of the scope of the patent application, wherein m is 0, 1 Or 2, n is 0, ι or 2, p is 0, 1 or 2, and q is 0, 1 or 2. -140- 200533356 9. A condensed dagen derivative or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof, characterized in that the condensed dagen derivative is any one selected from the following compounds, Azol-2-yl) -4- (4-triP-imidazolyl) phthalazine, 1- (1-methyl-1H-imid (4-trifluoromethoxyphenyl) phthalazine, ^ (1 _Methyl_1H_ imidazol-2 -yl) hydrazine, 1-(2-furyl) -4-(1 · methyl- 丨 H _imidazolyl · • 2-yl) phthalazine, 1- [4- (Bumethyl-1H · imidazol-2-yl) phthalazin-1-yl] -piper-4- (4-pyridyl) phthalazin-4-ol, Bu (1-methyl-1H-imidazole) · 2-yl), 3-methyl-2- (4-phenylphthalazin-1-yl) -3H-imidazole-4-carbonitrile, 3-methyl-2- (4-phenyluglyn-1 -Yl) -3H-imidazole-4-residual acid, i- [5- (4,4-dimethyl-4,5-dihydro-oxazol-2-yl) -1-methyl-1H -Imidazol-2-yl] -4-phenylphthalazine, 1 · phenyl-4- (1H-tetrazol-5-yl) phthalazine, 1- (2-methyl-2H-tetrazol-5- ) -4-phenylphthalazine, and 1-pyridin-4-yl-4- (2,5-dihydro-5-oxo-4H-1,2,4 · thiadiazol-3-yl) phthalein Azine. Φ 1 〇—A preventive or therapeutic drug for ischemic heart disease, characterized in that it is a condensed hydrazone derivative or a pharmacologically acceptable derivative thereof according to any one of claims 1 to 9 of the scope of patent application. Permissible salts are used as active ingredients. 1 1 · Prediction of an acute coronary syndrome Or a therapeutic drug, which is characterized by using a condensed daco derivative or a pharmacologically acceptable salt thereof as an active ingredient in any one of claims 1 to 9. 12. A prevention or treatment of myocardial infarction The medicament is characterized by using the condensed daquad derivative or the pharmacologically acceptable salt thereof as an active ingredient in any one of claims 1 to 9. -141-200533356 〇) 13. A narrow mind The medicine for preventing or treating the disease is characterized in that the condensed daikon derivative or the pharmacologically acceptable salt thereof according to any one of claims 1 to 9 of the scope of patent application is used as an active ingredient. 14 · A prophylactic or therapeutic drug for arteriosclerosis, which is characterized by using a condensed daikon derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 9 of the patent application as an active ingredient. 15 · — An NAD (P) Η oxidase inhibitor, characterized in that it is a condensed daikon derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 9 of the patent application 4 ^ Active ingredients. 142 200533356 VII. (1) The designated representative of this case is as follows: None. (2) Brief description of the representative symbols of the components of this representative: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: [化 1] —N ^ n-r1 ^ ⑵ \ _y, R2b · [Chemical formula 5] -4 ·