MXPA98003347A

MXPA98003347A - Imidazoquinazoline derivatives

Info

Publication number: MXPA98003347A
Application number: MXPA/A/1998/003347A
Authority: MX
Inventors: Onoda Yasuo; Yamada Koji; Nomoto Yuji; Ohno Tetsuji; Ichimura Michio
Original assignee: Ichimura Michio; Kyowa Hakko Kogyo Co Ltd; Nomoto Yuji; Ohno Tetsuji; Onoda Yasuo; Yamada Koji
Priority date: 1996-08-30
Filing date: 1998-04-28
Publication date: 2000-08-01

Abstract

Imidazoquinazoline derivatives represented by general formula (I) or pharmacologically acceptable salts thereof, which have potent and selective inhibitory effects on cyclic guanosine-3', 5'-monophosphate (cGMP)-specific phosphodiesterase and are useful in, for example, treating or relieving cardiovascular diseases such as thrombosis, angina pectoris, hypertension, cardiac insufficiency and arteriosclerosis, asthma, etc. and treating sexual impotence. In said formula, R1 represents hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted tricycloalkyl, etc.;R2 represents hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted bicyclaolkyl, optionally substituted tricycloalkyl, optionally substituted lower alkenyl, optionally substituted aralkyl, etc.;R3 represents hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted tricycloalkyl, optionally substituted lower alkenyl, optionally substituted aralkyl, etc., or R2 and R3 may form together with N an optionally substituted heterocyclic group;and X represents O or S.

Description

DERIVATIVES OF IMIDAZOQUINAZOLINE Field of the invention The present invention relates to the imidazoquinazoline derivatives or pharmaceutically acceptable salts thereof, which have the specific phosphodiesterase inhibitory activity (FDE) in the 3 ', 5'-cyclic guanosine monophosphate (cGMP) and are useful for the treatment or improvement of cardiovascular diseases, such as thrombosis, angina pectoris, hypertension, heart failure, arterial sclerosis, as well as asthma, impotence and the like.

Background of the Invention The cGMP plays an important role as a second messenger in the transduction of the intracellular signal. An inhibitor of PDE specifies in cGMP, an enzyme which degrades cGMP, increases the concentration of intracellular cGMP, increases the effects of endothelial-derived relaxing factor (FRDE), nitro vasodilator or atrial natriuretic peptide, shows antiplatelet activity, the anti-contraction activity and the vasodilation activity, and are useful for the treatment of cardiovascular diseases, such Ref. 27367 T. such as thrombosis, angina pectoris, hypertension, congestive heart failure, post-PTCA restenosis. Peripheral vascular diseases, arterial sclerosis, etc., allergic inflammatory diseases such as bronchitis, chronic asthma, allergic asthma, allergic nasal catarrh, etc., alimentary canal diseases, such as irritable bowel syndrome, etc., glaucoma, impotence and the like. The inhibitory activity of PDE and the antagonistic activity of the adenosine receptor of the imidazo [4, 5-g] quinazoline derivatives are described in J. Med. Chem., 2 9, 972 (1986), J. Med. Chem., 32, 2247 (1989), J. Org. Chem., 51, 616 (1986) and the references cited here. However, these compounds are not particularly strong inhibitors of PDE nor inhibitors of PDE specified in selective cGMP.

In addition, the derivatives of 8-anilino-2,3-dihydro-lH-imidazo [4, 5-g] quinazoline-2-one are described in EP635507. However, a substituent in the 8-position in the compounds described in EP635507 are limited to an anilino group. In addition, there is no disclosure in EP635507 of the 0 inhibitory activity of the compounds.

In addition, the 2,3-dihydro-lH-imidazo [4, 5-g] quinazoline derivatives with inhibitory activity of the PDE specified in cGMP are described in WO95 / 06648. However, in the case where a substituent at the 8-position in the compounds in O95 / 06648 is aralkyl, a substituent on the aryl portion of the aralkyl is limited to dialkyl-substituted amino, such as the dimethyl amino , etc., lower alkyl, lower alkoxy, halogen and trifluoromethyl. There is no disclosure here of these compounds wherein the substituent on the aryl portion of the aralkyl is monoalkyl-substituted amino or those compounds having cyclic amino groups, such as morpholino, piperidino and thiomorpholino.

The PDE inhibitors known up to now not only inhibit the specific PDE in cGMP, but also the PDE specified in the 3 ', 51-cyclic adenosine monophosphate (cAMP), which is an enzyme similar to that, and so both cause the elevation of the concentration of cAMP, as well as that of intracellular cGMP and can cause side effects and the like. In addition, the inhibitory activities of the same are not yet sufficient, and compounds are expected and desired which are more powerful and selective.

Description of the invention The aim of the invention is to provide imidazoquinazoline derivatives or pharmaceutically acceptable salts thereof, which have potent and selective inhibitory activity of the PDE specified in cGMP, increase the concentration of intracellular cGMP, increase the effects of the endothelial-derived relaxing factor. (FRDE), nitro vasodilator or atrial natriuretic peptide, show anti-platelet activity, anti-contraction activity and vasodilation activity, and be useful for the treatment of cardiovascular diseases, such as thrombosis, angina pectoris, hypertension, congestive heart failure, post-PTCA restenosis, peripheral vascular diseases, arterial sclerosis , etc., allergic inflammatory diseases, such as bronchitis, chronic asthma, allergic asthma, allergic nasal catarrh, etc., alimentary canal diseases, such as irritable bowel syndrome, etc., glaucoma, impotence and the like.

The present invention relates to the imidazoquinazoline derivatives represented by the formula (I): wherein R1 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R2 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted benzocycloalkenyl, lower alkenyl substituted or unsubstituted, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R3 represents hydrogen, substituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl gone, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R2 and R3 combine to represent a group heterocyclic containing substituted or unsubstituted N, and X represents 0 or S, or pharmaceutically acceptable salts thereof.

Further, the compounds represented by the formula (I) are referred to as Compound (I). The same applies to the compounds of other formula numbers.

In the definitions of the groups of the formula (I), the lower alkyl includes a straight or branched chain alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. -butyl, tert-butyl, pentyl, iso-pentyl, neo-pentyl, sec-pentyl, tet-pentyl, hexyl, isohexyl, heptyl, octyl, and isooctyl. Cycloalkyl includes a cycloalkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The bicycloalkyl includes a bicycloalkyl group having 7 to 10 carbon atoms, such as the bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, and bicyclo [3.3.1] nonyl. The tricycloalkyl includes a tricycloalkyl group having 9 to 12 carbon atoms, such as the tricyclo [3.3.1.13'7] decyl, tricyclo [3.3.1.03-7] nonyl, and tricyclo [5.4.0. O2'9] undecyl. The benzocycloalkenyl includes a benzocycloalkenyl group having 8 to 12 carbon atoms, such as benzocyclobutenyl, indanyl and benzocyclooctenyl. The lower alkenyl includes a straight or branched chain alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, propenyl, methacryl, butenyl, crotyl, pentenyl and hexenyl. Aralkyl includes an aralkyl group having 7 to 15 carbon atoms, such as benzyl, phenethyl, benzhydryl and naphthylmethyl. Aryl includes phenyl and naphthyl, and heteroaryl includes pyridyl, quinolyl, isoquinolyl, thienyl, furyl, pyrrolyl, benzothienyl, benzofuryl, indolyl, tetrahydroquinolyl, tetrahydroisoquinolyl and imidazolinyl. The lower alkyl containing hydroxy includes a lower alkyl group substituted with 1 to 3 hydroxy groups, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl and 5-hydroxypentyl. The heterocyclic group containing N includes pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, homopiperazinyl, imidazolyl, 1-perhydroazepinyl, 1-perhydroazocinyl and tetrahydroisoquinolyl.

Substituted lower alkyl, substituted cycloalkyl, substituted bicycloalkyl, or substituted tricycloalkyl have the same or different 1 to 3 substituents, such as the cycloalkyl, hydroxy, lower alkoxy, hydroxyalkoxy, carboxy, lower alkoxycarbonyl, amino, monoalkyl substituted amino, dialkyl substituted amino, substituted monoaryl amino, diaryl substituted amino, nitro, halogen, heteroaryl group substituted or unsubstituted, substituted or unsubstituted alicyclic heterocyclic, etc. The alkyl portion of the lower alkoxy, lower alkoxycarbonyl, monoalkyl substituted amino and dialkyl substituted amino have the same meaning as the lower alkyl identified above. The aryl portion of the monoaryl-substituted amino and the diaryl-substituted amino have the same meaning as defined above. Halogen includes fluoro, chloro, bromo and iodo. Heteroaryl has the same meaning as defined above. Examples of the alicyclic heterocyclic groups are tetrahydrofuryl, piperidino, piperidyl, morpholino, morpholinyl, thiomorpholino, thiomorpholinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, imidazolyl and tetrahydroisoquinolyl. The substituent of the substituted alicyclic heterocyclic groups include the same lower alkyl, aryl or aralkyl as defined above. The substituted alicyclic heterocyclic group includes, for example, N-methylpiperazinyl, N-ethylpiperazinyl, N-methylhomopiperazinyl, N-Phenylpiperazinyl and N-benzylpiperazinyl.

Substituted benzocycloalkenyl, substituted lower alkenyl, substituted aralkyl, substituted aryl, substituted heteroaryl, or heterocyclic group containing substituted N have the same or different 1 to 5 substituents, such as lower alkyl, hydroxy, the same lower alkyl containing hydroxy as defined above, lower alkoxy, lower alkoxyalkyl, carboxy, lower alkoxycarbonyl, amino, monoalkyl substituted amino, dialkyl substituted amino, nitro, sulfonamide, halogen and trifluoromethyl. The alkyl portion of the lower alkyl, lower alkoxy, lower alkoxyalkyl, lower alkoxycarbonyl, monoalkyl substituted amino, and dialkyl substituted amino have the same meaning as the lower alkyl identified above. Halogen has the same meaning as the halogen identified above. Preferred examples of heterocyclic groups containing substituted N are N-methylpiperazinyl, N-ethylpiperazinyl, N-methylhomopiperazinyl, N-phenylpiperazinyl, N-benzylpiperazinyl and benzylpiperidino.

The pharmaceutically acceptable salts of the compounds (I) include the pharmaceutically acceptable acid addition salts, for example, the inorganic acid addition salts, such as the hydrochloride, hydrobromide, hydrochloride, nitrate, sulfate, phosphate, etc., and salts thereof. organic acid addition, such as the format, acetate, benzoate, tartrate, maleate, fumarate, succinate, oxalate, glyoxylate, aspartate, methanesulfonate, benzenesulfonate, etc.

Then, a process for the preparation of Compound (I) is described below.

Processes 1-1 The Start Compound (VII) for the preparation of Compound (I) can be prepared according to the following reaction steps.

(In the formula, R1, R2, and R3, have the same meanings as defined above).

The Start Compound (II) can be obtained according to known processes [J. Org. Chem., _40, 356 (1975), etc.].

Compound (III) can be obtained by reacting Compound (II) with an equivalent to an excess amount of an amine represented by the formula RXNH2 (wherein R1 has the same meaning as defined above) or an aqueous solution thereof in a solvent, such as ethanol, butanol or dimethisulfoxide, if necessary using a sealed container (in a sealed tube), from room temperature to 150 ° C for 1 to 24 hours.

The compound (IV) can be obtained by reacting Compound (III) with a chlorinating agent, such as phosphorus oxychloride, thionyl chloride or phosphorus pentachloride, if necessary in the presence of a base, such as triethylamine. , N, N-diisopropylethylamine or pyridine without a solvent or in a solvent, such as dichloromethane or 1,2-dichloroethane optionally containing N, N-dimethylformamide, from room temperature to the boiling point of the solvent used in the presence of the solvent or of room temperature to the boiling point of the chlorinating agent used in the absence of the solvent for 1 to 24 hours.

Compound (VI) can be obtained by reaction of Compound (IV) with one equivalent to an excess amount of Compound (V) (wherein R2 and R3 have the same meanings as defined above), if necessary in the presence from 3 to 10 equivalents of a base, such as triethylamine, in a solvent, such as tetrahydrofuran, from room temperature to the boiling point of the solvent employed for 30 minutes up to 24 hours. The Start Compound (V) can be obtained according to the processes described in the Reference Examples or methods similar to those. Compound (VI) can be subjected to the following reduction after its NR2R3 is protected with an appropriate protection group.

Compound (VII) can be obtained by catalytic reduction of Compound (VI) in the presence of a catalyst for catalytic reduction, such as palladium on carbon in an amount of 1/100 to 1/10 based on the weight of the substrate, in a solvent, such as water, tetrahydrofuran, methanol, ethanol or N, N-dimethylformamide, in an atmosphere of hydrogen or in a stream of hydrogen, from room temperature to the boiling point of the solvent used for 3 to 24 hours under agitation, or by reduction thereof in the presence of a reducing agent, such as ferric chloride / iron or similar (ferric chloride is added in an amount of 1/100 to 1/10 based on the weight of the substrate, all 1 to 4 equivalents of reduced iron), in a solvent, such as ethanol containing water, water or the like from room temperature to the boiling point of the solvent used for 1 to 10 hours under agitation.

Processes 1-2 Compound (a), wherein X is 0 (oxygen) can be prepared from Compound (VII) as the starting material according to the next reaction step.

(In the formula, R1, R2 and R3 have the same meanings as defined above).

Compound (Ia) can be obtained by cyclization of Compound (VII) with 1 to 10 equivalents of a carbonylation reagent, such as N, N'-carbonyldiimidazole, phosgene, urea, alkyl chlorocarbonate, aryl chlorocarbonate or the like , if necessary in the presence of 1 to 10 equivalents of a base in an inert solvent. Examples of such bases are triethylamine, pyridine, and the like. Examples of inert solvents are water, alcohols (methanol, ethanol and the like), non-polar solvents (ethyl acetate, ether and the like), polar aprotic solvents (acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide) , dimethyl sulfoxide, tetrahydrofuran, dioxane and the like) and halogenated hydrocarbons (dichloromethane, chloroform and the like). The reaction is carried out at a temperature between 0 ° C and the boiling point of the solvent used and the reaction is completed in 10 minutes up to 48 hours.

In the case of Compound (VI), where NR2R3 has been protected with an appropriate protection group, also the desired compound can be obtained by removal of the protection group after reduction in Process 1-1 and the carbonylation reaction in Process 1-2.

Process 1-3 Compound (Ib), wherein X is S (sulfur) can be prepared from Compound (VII) as the starting material according to the following reaction step: (In the formula, R1, R2 and R3 have the same meanings as defined above).

Compound (Ib) can be obtained by cyclization of Compound (VII) with a thiocarbonylation reagent, such as 1 to 10 equivalents of N, N'-thiocarbonyldiimidazole, thiophosgene, or 10 to 200 equivalents of carbon disulfide or the like, if necessary in the presence of 1 to 10 equivalents of a base in an inert solvent. Examples of such inert solvents and bases are the same as those described in Process 1-2 for the preparation of Compound (a). The reaction is carried out at a temperature between 0 ° C and the boiling point of the solvent used and is completed in 10 minutes up to 48 hours.

In the case of Compound (VI), where NRR has been protected with an appropriate protection group, the compound can also be obtained by removal of the protection group after the reduction reaction in Process 1-1 and the reaction of Thiocarbonylation in Process 1-3. The intermediates and compounds desired in the processes described above can be isolated and purified by purification methods conventionally used in organic synthesis chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization and various types of chromatography. Also the intermediates can be subjected to the subsequent reaction without purification.

Among the Compounds (I), some may have configurational isomers, geometric isomers, optical isomers or tautomers. The present invention includes all possible isomers and mixtures thereof.

In the case where a salt of Compound (I) is desired and is produced in the form of the desired salt, it can be subjected to purification as such. In the case where Compound (I) is produced in the free form and its salt is desired, Compound (I) is dissolved or suspended in an appropriate solvent, followed by the addition of an acid to form a salt, which is It can isolate and purify.

The compounds (I) and the pharmaceutically acceptable salts thereof may be in the form of adducts with water or various solvents, which are also within the scope of the present invention.

The examples of Compound (I) obtained in the present invention are shown in Table 1.

Table No. of R? Position of the Cosplaced substitution (2. 3, 4) O CH2CH3 H CH3 CH2CH3 H CH, CH2CH3 H CH.- or CH2CH3 H CH (CH3) 2 CH2CH3 H CH2CH2CH3 CH2CH3 H CH2CH3 O CH2CH3 H CH2CH2-N O \ / CH2CH3 H CHaCHaCHa- O CH2CH3 H CH2CH2OH CH, CH, H CH2CH2OCH3 No. of Position of R1 Copied substitution (2. 3. 4) 11 O CH2CH3 -C? 2CH2-0-CH2CH2- 12 CH2CH3 -CH2CH2 ^ H-CH2 H2- CH2OH 13 O CH2CH3 -CH2CH2-CH2-CH2CH2- 14 CH2CH3 -CH2CH2-N (CH3) -CH2CH2- CH, CH, -CH2Ci2"S-Ci2CH- 16 CH2CH3 -CH2CH2-0-CH2CH2- 17 CH2CH3 -Cx2CIi2"Cí2" Cri2CÍ2 18 CH2CH3 -CH2CH2-N (CH3) -CH2CH2- 19 O CH2CH3 -CH2CH2"C ^ Í2 * CÍ2Cl2 •" CH2CH3 -CH2CH2-N (CH3) -CH2CH2- Table Do not . of x j Position of R Substitution RJ Compound (2. 3. 4) 21 or CH2CH3 -CH2CH2-S-CH2CH2- 22 CH2CH3 H CH3 23 CH2CH3 H CH, 24 CH2CH3 H CH ^ O 25 CH2CH3 H CH (CH3) 2 26 CH2CH3 H C? CH2CH3 27 C? 2CH3 H CH2CH3 28 CH2CH3 H CH2CH2-N O X 29 CH2CH3 X H CH2CH2CH2-N O CH2CH3 H CH2CH2OH Position No. of Compound R1 Substitution (2. 3. 4) 31 CH H3 H CH2CH2OH 32 CÍI2CH H CH2CH2OCH3 33 CH2CH3 -CH2CH2-0-CH2CH2- 34 CHCH-i -CH2Cri2"CH-CH2 H2" CH2OH 35 s? 2C-H -CH2 H2"H2" í2CH2" 36 s CH2CH3 -CH2CUz-N (CH3yC 2 H2- 37 s CH2CH3 -CH2CH * S-Cri2CH2" 38 CH2CH -CH2CH2-0-CH2CH2- 39 CH2CH3 -CH2CH2-CH2-CH2CH2- CH2CH3 -CH2CH2-N (C? 3 > CH2CH2- Table No. of x i Position of the substitution compound R¿ RJ (2. 3. 4) 41 S CH2C? 3 -CH2CH2-O-CH2CH2- 42 S CH2CH3 -CH2CH-CH2-CH2CH2- 43 CH2CH3 -CH2CH2-N (CH3) -CH2CH2- 44 CH2CH3 4 -CH2CH2-CH2CH2- 45 CH2CH3 4 -CH2CH2-S-CH2CH2 46 CH2CH3 2 CH, CH2CH2OH 47 CH2CH3 4 -CH2-CH-CH2CH2CH2- CH2OH 48 CH2CH3 4 -CH2CH2-O-CH2CH2- 49 CH2CH3 4 H CH2CH2OH 50 CH2CH3 -CH = CH-N = CH- No. of i Position of Compound R substitution RJ (2. 3 »4) 51 CH2CH3 -CH = CH-N = CH- 52 CH2CH3 -CH2C? 2-CH2CH2CH2-CH2CH2- 53 CH2CH3 -CH2CH2"CH2 -H2CH2" Cíi2C i2 ~ 54 CH2CH3 H CH2CH2CH3 55 CH2CH3 H CH2 H2CH3 56 CH2CH3 H CH (CH3) 2 57 CH2CH3 -CH2-CH-CH2CH2CH2- CH2OH 58 CH2CH3 -CH2CH2CHCH2CH2- CH2OH 59 CH2CH3 -CH2CH2CHCH2CH2- CH2CH2OH 60 O CH2CH3 H CH (CH3) 2 Table Position No. of Compound X R1 substitution R2 R3 (2. 3. 4) 61 0 CH2CH3 2 H CH2CH3 62 s CH2CH3 ^ 2 H CH2CH3 63 s CH2CH3 2 -CH2CHCH2CH2CH2- CH2OH 64 CH2CH3 H z 65 S CH2CH3 2 H CÍ? 2CÍI2CH2C 66 0 CH2CH3 2"CH2 H2CH2CH2" 67 0 CH2CH3 2 H CH2CH2CH2C H3 70 S CH2CH3 2 -CH2 i Ci2 r? 2 ~ Table No. of x R? Position of? Substitution Compound (2. 3. 4) 71 CH2CH3 -CH2CH2-N (CH2CH3) -CH2CH2- 72 CH2CH3 H CH2CH (CH3) 2 73 CH2CH3 -C? 2C? I2CH2CH2CH2CH2" 76 CH2CH3 -Ci2"CH2" H-CH2"CH2" CH2CH2OH 77 CH2CH3 -CH2CH2-N (CH2CH3) -CH2CH2- 78 C? 2CH3 H CH2CH (CH3) 2 79 CH2CH3 H CH2CH2CH2CH2OH 80 CH2CH2CH3 -CH, -CH2-CH-CH2-CH2- I CH2OH Table Do not give. R? Position of the substitution compound (2. 3. 4) 81 CH2CH3 -CH2CH2 '^ H2"H2-Crl2CH2"' 82 CH2CH3 -CH2CH2-N (CH3) -CH2-CH2-CH2- 83 CH2CH3 H -CH2CH2OCH2CH2OH 84 CH2CH3 -CH2CH2-N (CH3) -CH2-CH2-CH2- 85 CH3 -CH2-CH2-CH-CH2-CH2- CH2OH 86 CH2CH3 H CH. -XJ 89 CH, CH, H CH, 90 CH2CH3 H CH2CH2NH -O Table 1 Position No. of Compound R > ? substitution (2. 3. 4) 91 CH2CH3 -CH2-CH2- * CH ~ CH2"CH2 '* CH2OCH3 92 CH2CH3 -CH2-CH2-CH-CH2-CH2- CH2OCH2CH3 93 CH2CH3 H H 96 CH2CH3 -CH2-CH2-N (C02CH2CH3) -CH2-CH2- Best Way to Carry Out the Invention Next, the inhibitory activity of the PDE and the pharmacological activity of the representative compounds (I) are described in more detail by the Test Examples.

Test Example 1 The inhibitory activity on PDE derived from the smooth muscle of the canine trachea. (1) Purification of an enzyme According to the method of Torphy et al. [Mol. Pharmacol., 31_, 206 (1990)], the FDE V (specific FDE in cGMP) of the smooth muscle of the canine trachea is purified. (2) Measurement of FDE activity The activity is measured based on the method of Kincaid et al.

[J.D. Corbin et al., Methos Enzymol., 159, 457 (1988), Academic Press, New York]. The measurement is carried out using, as a substrate, 1. 0 μM of [3 H] cGMP, and the reaction is carried out in a buffer having the following composition: 50 mM N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid (pH 7.2), 1 mM MgCl2 / 0.1 mg / ml soybean trypsin inhibitor.

The reaction is initiated by the addition of the enzyme and stopped by the addition of hydrochloric acid after it is reacted for 10 to 30 minutes at 30 ° C. Then, sodium hydroxide is added for neutralization and the 5'-GMP is converted to guanosine using the 5'-nucleotidase. The reaction solution is subjected to an A-25 DEAE-Sephadex column. The [3H] Guanosine is eluted with distilled water and the radioactivity is measured with a liquid scintillation counter. The inhibitor is dissolved in 1.7% DMSO.

The results on the inhibitory activity of PDE are shown in Table 2.

Table 2. Inhibitory activity of FDE V Compound No. Inhibition Ratio (%) Compound Concentration: InM 3 62 6 37 22 91 24 27 97 30 97 33 98 34 95 35 95 Test Example 2 The hypotensive effect in rats.

After urethra is anesthetized a male Spraque-Dawley rat (2 mice / group) is fixed in the supine position, a cannula is inserted into the trachea and the rat is artificially ventilated under the conditions of a tidal volume of 10 mg / kg and 60 breaths / minute. The carotid artery and the duodenum are cannulated to measure blood pressure and a drug is administered, respectively. The drug is dissolved in distilled water and administered in a duodenal fashion using the anterior cannula. The mean blood pressure (PSm) is measured up to 30 minutes after the administration of the drug and the proportion of maximum decrease (%) of the value is determined before the administration of the drug (100%). No change is observed in the PSm during 30 minutes in case of distilled water.

The results are shown in Table 3.

Table 3. Hypotensive activity Compound No. Proportion of Maximum Decrease (%) Rat, 10 mg / kg, i.d. N = 2 2 19.7 15 19.8 36 17.6 40 16.1 Test Example 3 Effect of carvenous pressure developed and the duration of tumescence in rats.

A male Sprague-Dawley rat is anesthetized with urethane (1.3 g / kg) subcutaneously injected into the back of the neck. The perineal incision is made and the right peduncle of the penis is exposed. For the carve pressure measurement, a needle (25G) attached to a polyethylene tube (PE50) filled with a heparin solution in the right pendulum is inserted. The polyethylene tube is connected to a pressure transducer (MPC-500, Millar Instruments) and the carvenous pressure is amplified with an amplifier (AP-621G, Nihon Kohden) and then recorded in a boom recorder (LR4220, Yokokawa Denki ). An incision is made in the abdomen and carve veins are exposed in the prostate. The nerve is placed in a bipolar tungsten electrode and is stimulated by current pulses (frequency: 20 Hz, duration: 0.2 ms, force: 3 to 5 V) for 50 seconds with an electric stimulator (SEN-3201, Nihon Koden) to induce increases in carve pressure. The test compounds are dissolved in distilled water (AD) or 0.01 N hydrochloric acid in a concentration of 1 mg / ml and injected into the carvenous body (0.02 ml / rat) with a needle (27G). Before (Pre) and 6 minutes after the administration (6 minutes) of distilled water (AD) or the test compounds, the nerve is stimulated, and the developed carvenic pressure (PCD) and the duration of the tumescence ( DT). DT is defined as the time of onset of stimulation up to 50% of the maximum carve pressure after the end of stimulation.

The results are shown in Table 4, Table 4. Effects on carve pressure developed and the duration of tumescence in rats.

DCP (mmHg) DT (sec) Compound No. Pre 6 minutes Pre 6 minutes 34 (20 μg / rat) 23.9 ± 2.0 31.1 + 4.7 3.3 ± 0.9 16.9 ± 2.4 N = 5 control (AD) 25.9 ± 3.9 26.8 ± 4.4 2.8 ± 0.3 3.0 ± 0.7 N = 5 26 (20 μg / rat) 21.5 27.7 3.8 22.9 N = 2 26 (20 μg / rat) 21.5 27.7 3.8 22.9 N = 2 (20 μg / rat) 22.6 21.2 1.6 N = 2 control (HCl 0.01N) 20.2 19.2 3.2 3.3 N = 2 The compound (I) or pharmaceutically acceptable salts thereof can be formulated in the forms normally used, for example, tablets, capsules, injections, drops, syrups, sublingual tablets, various creaming agents, suppositories, or the like, and preparations The results can be administered orally or parenterally, for example, intramuscularly, intravenously, intraarterially, by instillation or application, or rectally by suppositories. The formulation in those oral or parenteral preparations usually uses the known methods. The preparations may contain various excipients, lubricants, binders, disintegrating agents, suspending agents, isotonizing agents, emulsifiers, and the like.

Examples of carriers used for the preparations are water, distilled water for injection, physiological saline, glucose, sucrose, mannitol, lactose, starch, cellulose, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, alginate, talc, sodium citrate, calcium carbonate, calcium acid phosphate, magnesium stearate, urea, silicone resin, sorbitan fatty acid ester, glyceric acid ester, and the like.

The dose and frequency of administration varies depending on the mode of administration, the age, weight and conditions of the patients, and the like. Normally, the oral dose of 0.05 to 5 g / 60 kg / day is appropriate. In the case of instillation, the dose is preferably in the range of 0.01 to 5 mg / kg / min. And preferably does not exceed the limit of oral dose per day.

Certain embodiments of the present invention are illustrated in the following Examples and Reference Examples.

The measurement of the proton nuclear magnetic resonance (NMR) spectrum used in the Examples and Reference Examples is carried out at 270 MHz. The maximum positions are expressed as units of 1 / million (ppm) downfield of the tetramethylsilane. The maximum forms are expressed as follows: s: singlet, d: doublet, t: triplet, m: multiplet, br: broad.

Reference Example 1 2-Methylaminobenzonitrile The 2-fluorobenzonitrile (10.0 g, 82.8 mmol) is dissolved in acetonitrile (100 ml), and a solution of 40% aqueous methylamine is added thereto, followed by stirring at 60 ° C overnight. In addition, a solution of 40% aqueous methylamine (100 ml) is added thereto, followed by stirring at 60 ° C for 9 hours. The reaction mixture is concentrated under reduced pressure, then water is added to the resulting residue, the mixture is extracted with chloroform. After the organic layer is dried (over anhydrous magnesium sulfate), the drying agent is filtered, and the organic layer is concentrated under reduced pressure. The resulting oily substances are purified by silica gel column chromatography (the substances are eluted with an increasing concentration of chloroform from chloroform / hexane = 1/2 to chloroform / hexane = 1/1) to give the title compound (5.38). g, 49%).

XH-NMR (CDC13) d (ppm): 2.87 (3H, d, J = 5.0 Hz), 4.70 (1H, q, J = 5.0 Hz), 6.61-6.69 (2H, m), 7.35-7.43 (2H, ).

Reference Example 2 4-Methylaminobenzonitrile According to a manner similar to that in Reference Example 1, the title compound is synthesized from 4-fluorobenzonitrile and a 40% aqueous methylamine solution.

XH-NMR (CDC13) d (ppm): 2.87 (3H, d, J = 5.0 Hz), 4.39 (1H, br), 6.55 (2H, d, J = 8.8 Hz), 7.42 (2H, d, J = 8.8 Hz).

Reference Example 3 4-Benzylaminobenzonitrile The 4-fluorobenzonitrile (6.0 g, 49.5 mmol) is dissolved in acetonitrile (60 ml), and benzylamine is added thereto. (10.6 g, 98.9 mmol), followed by stirring at 100 ° C for 3 days. Until the reaction is completed, benzylamine (21.2 g) is added., 198 mmol), followed by stirring at 100 ° C for 1 day. The solvent is removed under reduced pressure, water is added to the resulting residue, the mixture is extracted with chloroform. After the organic layer is dried (over anhydrous magnesium sulfate), the drying agent is filtered, and the filtrate is concentrated under reduced pressure. The resulting oily substances are purified by silica gel column chromatography (the substances are eluted with an increasing concentration of chloroform from chloroform / hexane = 1/2 to chloroform / hexane = 1/1) to give the title compound (7.42). g, 72%) as oily substances.

^ -RMN (CDC13) d (ppm): 4.32 (2H, d, J = 4.7 Hz), 4.80 (1H, br), 6.55 (2H, d, J = 8.4 Hz), 7.25-7.37 (7H, m) .

Reference Example 4 4-Isopropylaminobenzonitrile According to a manner similar to that in Reference Example 3, the title compound is synthesized from 4-fluorobenzonitrile and isopropylamine.

? -NRM (CDC13) d (ppm): 1.23 (6H, d, J = 6.6 Hz), 3.61-3.69 (lH, m), 4.22 (1H, br), 6.53 (2H, d, J = 8.9 Hz) , 7.38 (2H, d, J = 8.9 Hz).

Reference Example 5 4-Propylaminobenzonitrile According to a manner similar to that in Reference Example 3, the title compound is synthesized from 4-fluorobenzonitrile and n-propylamine.

? -NRM (CDC13) d (ppm): 0.99 (3H, t, J = 7.4 Hz), 1.57-1.71 (2H, m), 3.06-3.34 (2H, m), 4.50 (1H, br), 6.55 ( 2H, d, J = 8.7 Hz), 7.38 (2H, d, J = 8.7 Hz).

Reference Example 6 4-Etylaminobenzonitrile According to a manner similar to that in Reference Example 1, the title compound is synthesized from 4-fluorobenzonitrile and a 70% aqueous ethylamine solution.

? -NRM (CDC13) d (ppm): 1.27 (3H, t, J = 7.3 Hz), 3.13-3.23 (2H, m), 4.22 (1H, br), 6.54 (2H, d, J = 8.6 Hz) , 7.40 (2H, d, J = 8.6 ~ Hz).

Reference Example 7 2- (2-Morpholinoethylamino) benzonitrile According to a manner similar to that in Reference Example 3, the title compound is synthesized from 2-fluorobenzonitrile and 4- (2-aminomethyl) morpholine.

? -NRM (CDCI3) d (ppm): 2.48-2.56 (4H, m), 2.68 (2H, t, J = 6.2 Hz), 3.20-3.27 (2H, m), 3.73-3.80 (4H, m), 5.36 (lH, br), 6.62-6.70 (2H, m), 7.35-7.41 (2H, m).

Reference Example 8 2- (3-Morpholinopropylamino) benzonitrile According to a manner similar to that in Reference Example 3, the title compound is synthesized from 2-fluorobenzonitrile and 4- (3-aminopropyl) morpholine.

? -NRM (CDC13) d (ppm): 1.79-1.92 (2H, m), 2.46-2.55 (6H, m), 3.22-3.35 (2H, m), 3.75-3.86 (4H, m), 5.67 (1H , br), 6.61-6.70 (2H, m), 7.34-7.39 (2H, m).

Reference Example 9 2- (2-Hydroxyethylamino) benzonitrile According to a manner similar to that in Reference Example 3, the title compound is synthesized from 2-fluorobenzonitrile and ethanolamine.

XH-NMR (CDCl 3) d (ppm): 3.30-3.36 (2H, m), 3.43 (lH, br), 3.80-3.85 (2H, m), 5.02 (1H, t, J = 5.0 Hz), 6.60- 6.67 (2H, m), 7.31-7.36 (2H, m).

Reference Example 10 4- (2-Hydroxyethylamino) benzonitrile According to a manner similar to that in Reference Example 3, the title compound is synthesized from 2-fluorobenzonitrile and ethanolamine.

XH-NMR (CDC13-CD30D) d (ppm): 3.26-3.32 (2H, m), 3.78-3.82 (2H, m), 6.58 (2H, d, J = 8.9 Hz), 7.39 (2H, d, J = 8.9 Hz).

Reference Example 11 2- (2-Methoxyethylamino) benzonitrile According to a manner similar to that in Reference Example 3, the title compound is synthesized from 2-fluorobenzonitrile and 2-methoxyethylamine.

XH-NMR (CDC13) d (ppm): 3.38 (2H, t, J = 5.4 Hz), 3.41 (3H, s), 3.62 (2H, t, J = 5.4 Hz), 4.86 (1H, br), 6.65 -6.70 (2H, m), 7.35-7.40 (2H, m) Reference Example 12 2-Morpholinobenzonitrile The 2-fluorobenzonitrile (1.21 g, 1.00 mmol) is dissolved in acetonitrile (50 ml), and morpholine (33 ml, 377 mmol) is added thereto, followed by stirring at 110 ° C for 2 nights. After the reaction is complete, the reaction mixture is concentrated to give oily substances, which are then purified by silica gel column chromatography (eluent: chloroform) to give the title compound (1.80 g, 95%) as oily substances ? -NMR (CDC13) d (ppm): 3.15-3.23 (4H, m), 3.83-3.97 (4H, m), 7.01-7.10 (2H, m), 7.48-7.60 (2H, m).

Reference Example 13 2- (4-Ethoxycarbonylpiperidino) benzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and ethyl isonipecotate.

? -NRM (CDCl3) d (ppm): 1.28 (3H, t, J = 7.1 Hz), 1.92-2.10 (4H, m), 2.41-2.51 (1H, m), 2.84-2.94 (2H, m), 3.51-3.58 (2H, m), 4.17 (2H, q, J = 7.1 Hz), 6.96-7.02 (2H, m), 7.44-7.56 (2H, m).

Reference Example 14 2-Piperidinobenzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and piperidine.

? -NRM (CDC13) d (ppm): 1.54-1.62 (2H, m), 1.70-1.79 (4H, m), 3.11-3.16 (4H, m), 6.90-6.99 (2H, m), 7.40-7.51 (2H, m).

Reference Example 15 2- (4-Methyl-l-piperazinyl) benzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and 1-methylpiperazine.

? -NRM (CDCl3) d (ppm): 2.36 (3H, s), 2.60-2.65 (4H, m), 3.21-3.26 (4H, m), 6.97-7.03 (2H, m), 7.45-7.56 (2H , m).

Reference Example 16 2-Tiomorfolinobenzonitrilo According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and thiomorpholine.

XH-NMR (CDC13) d (ppm): 2.84-2.88 (4H, m), 3.42-3.47 (4H, m), 7.00-7.06 (2H, m), 7.55 (1H, dd, J = 6.9 Hz, 6.9 Hz), 7.58 (1H, d, J = 6.9 Hz).

Reference Example 17 3-Morpholinobenzonitrile The 3-fluorobenzonitrile (4.35 g, 36.0 mmol) is dissolved in acetonitrile (40 ml), and morpholine (110 ml, 1.25 mmol) is added thereto, followed by stirring at 110 ° C for 3 days and nights. The reaction mixture is concentrated to give oily substances, which are then purified by silica gel column chromatography (eluent: chloroform) to give the title compound (1.80 g, 27%) as oily substances.

? -NRM (CDCl3) d (ppm): 3.15-3.19 (4H, m), 3.83-3.88 (4H, m), 7.09-7.18 (3H, m), 7.34 (lH, dd, J = 7.6 Hz, 7.6 Hz).

Reference Example 18 3-Morpholinobenzonitrile 3-cyanophenol (1.77 g, 14.9 mmol) and triethylamine (6.30 ml, 45.2 mmol) are dissolved in methylene chloride (75 ml) and stirred at -10 ° C in an argon gas atmosphere. A solution of trifluoroacetic anhydride (3.79 ml, 22.5 mmol) dissolved in methylene chloride (15 ml) is added dropwise thereto, and after the addition is complete, the mixture is stirred for 1.5 hours. After the reaction is complete, the solvent is removed under reduced pressure, and an aqueous solution of sodium hydrogen carbonate is added to the resulting concentrated residue and the mixture is extracted with methylene chloride. The organic layer is washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. The drying agent is filtered and the filtrate is concentrated. The resulting concentrated residue is purified by silica gel column chromatography (chloroform / methanol = 100) to give the oily substances. The resulting oily substances are dissolved in acetonitrile (40 ml). The morpholine (33.0 ml, 378 mmol) is added thereto and the mixture is stirred for 3 days under heating at reflux. The solvent and the unreacted reactants are distilled under reduced pressure, water is added to the concentrated residue, and the mixture is extracted with chloroform. The organic layer is dried (sodium sulfate), the drying agent is filtered, and the filtrate is concentrated. The resulting concentrated filtrate is purified by silica gel column chromatography (eluent: chloroform / hexane = 1/2) to give the title compound (0.74 g, 26%) as oily substances.

? -NRM (CDC13) d (ppm): 3.15-3.19 (4H, m), 3.83-3.88 (4H, m), 7.09-7.18 (3H, m), 7.34 (1H, dd, J = 7.6 Hz, 7.6 Hz).

Reference Example 19 3-Piperidinobenzonitrile According to a manner similar to that in Reference Example 17, the title compound is synthesized from 3-fluorobenzonitrile and piperidine.

? -NRM (CDCl3) d (ppm): 1.55-1.73 (6H, m), 3.17-3.23 (4H, m), 7.03 (1H, d, J = 7.6 Hz), 7.08-7.12 (2H, m), 7.24-7.29 (1H, m).

Reference Example 20 3- (4-Methyl-l-piperazinyl) benzonitrile According to a manner similar to that in Reference Example 17, the title compound is synthesized from 3-fluorobenzonitrile and 1-methylpiperazine.

? -NRM (CDC13) d (ppm): 2.35 (3H, s), 2.55-2.60 (4H, m), 3.21-3.25 (4H, m), 7.06-7.13 (3H, m), 7.28-7.31 (1H , m).

Reference Example 21 4-Morpholinobenzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 4-fluorobenzonitrile and morpholine.

? -NMR (CDC13) d (ppm): 3.26-3.30 (4H, m), 3.83-3.87 (4H, m), 6.86 (2H, d, J = 8.9 Hz), 7.51 (2H, d, J = 8.9 Hz).

Reference Example 22 4-Piperidinobenzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 4-fluorobenzonitrile and piperidine.

^ -RMN (CDC13) d (ppm): 1.60-1.75 (6H, m), 3.30-3.38 (4H,), 6.38 (2H, d, J = 8.9 Hz), 7.45 (2H, d, J = 8.9 Hz ).

Reference Example 23 4- (4-Methyl-l-piperazinyl) benzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 4-fluorobenzonitrile and 1-methylpiperazine.

: H-NMR (CDCl 3) d (ppm): 2.35 (3H, s), 2.52-2.59 (4H, m), 3.31-3.39 (4H, m), 6.86 (2H, d, J = 8.9 Hz), 7.49 (2H, d, J = 8.9 Hz).

Reference Example 24 4- (1-Pyrrolidinyl) benzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 4-fluorobenzonitrile and pyrrolidine.

'• H-NMR (CDC13) d (ppm): 2.01-2.09 (4H, m), 3.29-3.34 (4H, m), 6.49 (2H, d, J = 8.9 Hz), 7.43 (2H, d, J = 8.9 Hz).

Reference Example 25 4-Tiomorpholinobenzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 4-fluorobenzonitrile and thiomorpholine.

? -NRM (CDCl3) d (ppm): 2.62-2.75 (4H, m), 3.74-3.80 (4H, m), 6.81 (2H, d, J = 8.9 Hz), 7.49 (2H, d, J = 8.9 Hz).

Reference Example 26 7-Ethylamino-6-nitro-4 (3H) -quinazoline (a compound described in WO95 / 06649) The 7-chloro-6-nitro-4 (3H) -quinazolinone (20.0 g, 88.7 mmol) is suspended in n-butanol (150 ml), a 70% aqueous ethylamine solution (120 ml) is added thereto, and the mixture is stirred for 15 minutes to give a clear solution, which is then heated for 9 hours in a sealed tube in an oil bath (temperature of the oil bath set at 100 ° C). After the reaction is complete, the reaction mixture is left and cooled to precipitate small-colored solids (first crystal), which are then filtered. The first crystal is washed with methanol and ether and dried to give the desired title compound (8.27 g, 40%). The filtrate obtained at the time of acquisition of the first crystal is concentrated to precipitate a crystal, which is then filtered and subjected to the same procedures as above, to give a second crystal as the desired title compound (5.84 g, 24%) .

Reference Example 27 4-chloro-7-ethylamino-6-nitroquinazoline The 7-ethylamino-6-nitro-4 (3H) -quinazolinone (30.0 g, 128 mmol) is suspended in phosphorus oxychloride (270 ml, 2.90 mol) and the mixture is heated at 110 ° C for 2 hours under one atmosphere of argon gas (to form a clear solution). After it is confirmed that the starting material disappears, unreacted phosphorus oxychloride is removed under reduced pressure. After the residue is subjected to azeotropic distillation with toluene, the resulting oily substances are dissolved in the minimum required amount of tetrahydrofuran. The tetrahydrofuran solution obtained is poured into ice cold water by adding a sufficient amount of sodium acid carbonate, followed by extraction with ethyl acetate. The organic layer is dried (over anhydrous magnesium sulfate), and the drying agent is filtered. The filtrate is concentrated under reduced pressure to give the title compound (33.4 g).

-NRM (CDC13) d (ppm): 1.45 (3H, t, J = 7.3 Hz), 3.42-3.47 (2H, m), 7.18 (1H, s), 7.79 (1H, br), 8.84 (1H, s) ), 9.11 (1H, s).

Reference Example 28 7-Ethylamino-4- (2-methylaminobenzylamino) -6-nitroquinazoline The lithium aluminum hydride (3.28 g, 86.4 mmol) is suspended in tetrahydrofuran (100 ml), followed by stirring under ice cooling under an argon gas atmosphere. A solution of 2-methylaminobenzonitrile (3.80 g, 28.8 mmol) obtained in Reference Example 1, dissolved in tetrahydrofuran (30 ml), is added dropwise and in portions thereto. After the addition is complete, the solution is stirred for 3 hours under heating at reflux. After the reaction is complete, the reaction solution is cooled and sodium carbonate decahydrate is added thereto until the foaming ceases. Then, the insoluble compounds are filtered and the filtrate is concentrated under reduced pressure to give the oily 2-methylaminobenzylamine.

The resulting substance and triethylamine (20.0 ml, 143 mmol) are dissolved in tetrahydrofuran (100 ml), and thereto is added 4-chloro-7-ethylamino-6-nitroquinazoline (the compound obtained in Reference Example 27, 6.47 g, 25.6 mmol), followed by stirring at room temperature overnight. After the reaction is complete, the solvent is removed under reduced pressure, water is added to the resulting residue, and the resulting solids are filtered. Furthermore, they are washed with ether-methanol to give the title compound (6.88 g, 76%).

-NRM (DMS0-d6) d (ppm): 1.30 (3H, t, J = 7.2 Hz), 2.76 (3H, d, J = 4.5 Hz), 3.36-3.43 (2H, m), 4.60 (2H, d , J = 5.4 Hz), 5.73 (1H, q, J = 4.5 Hz), 6.50-6.59 (2H, m), 6.85 (1H, s), 7.08-7.16 (2H, m), 7.74 (1H, t, J = 5.4 Hz), 8.36 (1H, s), 9.05 (1H, t, J = 5.7 Hz), 9.26 (lH, s).

Reference Example 29 7-Ethylamino-4- (4-methylaminobenzylamino) -6-nitroquinazoline According to a manner similar to that in Reference Example 28, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 2 It is reduced by lithium aluminum hydride.

-NRM (DMSO-d6) d (ppm): 1.31 (3H, t, J = 7.1 Hz), 2.84 (3H, d, J = 5.3 Hz), 3.35 (2H, q, J = 7.1 Hz), 4.62 (2H, d, J = 5.3 Hz), . 45-5.60 (1H, br), 6.64 (2H, d, J = 8.6 Hz), 6.83 (lH, s), 7.19 (2H, d, J = 8.6 Hz), 7.71 (1H, t, J = 5.3 Hz), 8.32 (lH, s), 9.06 (1H, t, J = 5.3 Hz), 9.28 (1H, s).

Reference Example 30 4- (4-Benzylaminobenzylamino) -7-ethylamino-6-nitroquinazoline According to a manner similar to that in Example 28 of Reference, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 3 is reduced by lithium aluminum hydride.

-NRM (DMSO-d6) d (ppm): 1.27 (3H, t, J = 7.2 Hz), 3.33-3.41 (2H, m), 4.24 (2H, d, J = 4.5 Hz), 4.56 (2H, d) , J = 5.4 Hz), 6.20 (1H, br), 6.53 (2H, d, J = 8.4 Hz), 6.83 (1H, s), 7.06 (2H, d, J = 8.4 Hz), 7.16-7.35 (5H , m), 7.71 (1H, t, J = 5.2 Hz), 8.32 (1H, s), 9.03 (1H, t, J = 5.4 Hz), 9.25 (1H, s).

Reference Example 31 7-Ethylamino-4- (4-isopropylaminobenzylamino) -6-nitroquinazoline According to a manner similar to that in Reference Example 28, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 4 It is reduced by lithium aluminum hydride.

-NRM (CDC13) d (ppm): 1.22 (6H, d, J = 6.3 Hz), 1.40 (3H, t, J = 7.3 Hz), 3.32-3.42 (2H, m), 3.58-3.66 (1H, m), 4.68 (2H, d, J = 5.0 Hz), 6.03 (1H, br), 6.58 ( 2H, d, J = 8.6 Hz), 6.98 (1H, s), 7.20 (2H, d, J = 8.6 Hz), 7.68 (1H, t, J = 4.6 Hz), 8.54 (1H, s), 8.66 (1H, s), 9.40 (1H, br) .

Reference Example 32 7-Ethylamino-6-nitro-4- (4-propylaminobenzylamino) quinazoline According to a manner similar to that in Reference Example 28, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 5 It is reduced by lithium aluminum hydride.

? -NRM (DMS0-d6) d (ppm): 0.91 (3H, t, J = 7.4 Hz), 1.27 (3H, t, J = 7.2 Hz), 1.50-1.60 (2H, m), 2.90-2.96 ( 2H, m), 3.32-3.40 (2H, m), 4.57 (2H, d, J = 5.9 Hz), 5.48 (1H, br), 6.51 (2H, d, J = 8.4 Hz), 6.85 (1H, s ), 7.09 (2H, d, J = 8.4 Hz), 7.72 (1H, t, J = 5.9 Hz), 8.33 (1H, s), 9.07 (1H, br), 9.27 (1H, s).

Reference Example 33 7-Ethylamino-4- (4-ethylaminobenzylamino) -6-nitroquinazoline According to a manner similar to that in Reference Example 28, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 6 It is reduced by lithium aluminum hydride.

? -NRM (DMSO-d6) d (ppm): 1.14 (3H, t, J = 7.3 Hz), 1.28 (3H, t, J = 7.1 Hz), 3.00 (2H, q, J = 7.3 Hz), 3.38 (2H, q, J = 7.1 Hz), 4. 58 (2H, d, J = 5.6 Hz), 5.40 (lH, br), 6.50 (2H, d, J = 8.6 Hz), 6.83 (1H, s), 7.09 (2H, d, J = 8.6 Hz), 7.74 (1H, t, J = 5.6 Hz), 8.33 (1H, s), 9.09 (1H, t, J = 5.6 Hz), 9.28 (1H, s).

Reference Example 34 7-Ethylamino-4- [2- (2-morpholinoethylamino) benzylamino] -6-nitroquinazoline According to a manner similar to that in Reference Example 28, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 7 It is reduced by lithium aluminum hydride.

XH-NMR (CDC13) d (ppm): 1.40 (3H, t, J = 7.2 Hz), 2.37-2.55 (4H, m), 2.58 (2H, t, J = 6.2 Hz), 3.20-3.25 (2H, m), 3.31-3.41 (2H, m), 3.44-3.53 (4H, m), 4.80 (2H, d, J = 5.5 Hz), 5.12 (1H, br), 6.32 (1H, t, J = 5.2 Hz ), 6.65-6.74 (2H, m), 6.98 (1H, s), 7.21-7.29 (2H), 7.68 (1H, t, J = 4.7 Hz), 8.55 (1H, s), 8.70 (1H, s) .

Reference Example 35 7-Ethylamino-4- [2- (3-morpholinopropylamino) benzylamino] -6-nitroquinazoline According to a manner similar to that in Reference Example 28, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 8 It is reduced by lithium aluminum hydride.

XH-NMR (CDC13) d (ppm): 1.40 (3H, t, J = 7.2 Hz), 1.72-1.83 (2H, m), 2.32-2.42 (6H, m), 3.17 (2H, t, J = 6.7 Hz), 3.34-3.42 (2H, m), 3.64-3.71 (4H, m), 4.82 (2H, d, J = 5.9 Hz), 5.30 (lH, br), 6.32 (1H, br), 6.67 (1H , dd, J = 7.4 Hz, 7.9 Hz), 6.71 (1H, d, J = 7.4 Hz), 6.98 (1H, s), 7.20-7.23 (2H, m), 7.70 (1H, t, J = 4.5 Hz ), 8.54 (1H, s), 8.68 (1H, s).

Reference Example 36 7-Ethylamino-4- [2- (2-hydroxyethylamino) benzylamino] -6-nitroquinazoline According to a manner similar to that in Reference Example 28, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 9 It is reduced by lithium aluminum hydride.

XH-NMR (DMSO-d6) d (ppm): 1.26 (3H, t, J = 7.1 Hz), 3.09-3.16 (2H, m), 3.58 (2H, q, J = 7.1 Hz), 3.54-3.62 ( 2H, m), 4.61 (2H, d, J = 5.3 Hz), 4.72 (1H, t, J = 5.3 Hz), 5.74 (1H, t, J = 5.3 Hz), 6.55-6.60 (2H, m), 6.86 (1H, s), 7.07-7.15 (2H, m), 7.77 (1H, t, J = 5.3 Hz), 8.38 (1H, s), 9.09 (1H, t, J = 5.6 Hz), 9.25 (lH , s).

Reference Example 37 7-Ethylamino-4- [4- (2-hydroxyethylamino) benzylamino] -6-nitroquinazoline According to a manner similar to that in Reference Example 28, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 10 It is reduced by lithium aluminum hydride.

^ -NMR (DMSO-dg) d (ppm): 1.26 (3H, t, J = 6.9 Hz), 3.03-3.09 (2H, m), 3.38 (2H, q, J = 6.9 Hz), 3.50-3.56 ( 2H, m), 4.58 (2H, d, J = 5.0 Hz), 4.65 (1H, t, J = 5.6 Hz), 5.42 (1H, t, J = 5.0 Hz), 6.54 (2H, d, J = 6.6 Hz), 6.85 (1H, s), 7.10 (2H, d, J = 6.6 Hz), 7.71 (1H, br), 8.34 (1H, s), 9.08 (1H, br), 9.27 (1H, s).

Reference Example 38 7-Ethylamino-4- [2- (2-methoxyethylamino) benzylamino] -6-nitroquinazoline According to a manner similar to that in Reference Example 28, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 11 It is reduced by lithium aluminum hydride.

-NRM (DMSO-d6) d (ppm): 1.29 (3H, t, J = 6.9 Hz), 3.18-3.23 (5H, m), 3.39 (2H, q, J = 6.9 Hz), 3.49 (2H, t , J = 5.4 Hz), 4.64 (2H, d, J = 5.9 Hz), 5.73 (1H, br), 6.58 (1H, d, J = 7.9 Hz), 6.60 (1H, d, J = 6.9 Hz), 6.86 (1H, s), 7.07-7.18 (2H, m), 7.76 (1H, t, J = 5.3 Hz), 8.37 (1H, s), 9.07 (1H, br), 9.25 (lH, s).

Reference Example 39 7-Ethylamino-4- (2-morpholinobenzylamino) -6-nitroquinazoline The lithium aluminum hydride (6.36 g, 168 mmol) is suspended in dry tetrahydrofuran (200 ml), followed by stirring under ice-cooling under an argon gas atmosphere. A solution of 2-morpholinobenzonitrile (9.56 g, 50.8 mmol) obtained in Reference Example 12, dissolved in tetrahydrofuran (150 ml), is added thereto by dripping for 30 minutes. After the reaction is complete, the solution is stirred for 2 hours under heating at reflux. After the reaction is complete, the reaction solution is cooled and sodium carbonate decahydrate is added thereto until the foaming ceases. Then, the insoluble compounds are filtered and the filtrate is concentrated to give the oily 2-morpholinobenzylamine.

The resulting substance and triethylamine (35.4 ml, 253 mmoles) is dissolved in tetrahydrofuran (200 ml), and 4-chloro-7-ethylamino-6-nitroquinazoline is added thereto. (7.34 g, 30.6 mmol), followed by stirring at room temperature overnight. After the reaction is complete, the solvent is removed under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent: chloroform / methanol = 100) to give the title compound (7.17 g, 60%).

XH-NMR (CDCl3) d (ppm): 1.41 (3H, t, J = 7.3 Hz), 3.04-3.08 (4H, m), 3.38 (2H, q, J = 7.3 Hz), 3.90-3.94 (4H, m), 4.97 (2H, d, J = .6 Hz), 7.03 (1H, s), 7.12-7.18 (1H, m), 7.25 (1H, d, J = 7.9 Hz), 7.31-7.40 (2H, m), 7.74 (lH, br), 7.87 (1H, s), 8.54 (1H, s), 8.72 (1H, s).

Reference Example 40 7-Ethylamino-4- [2- (4-hydroxyethylpiperidino) benzylamino] -6-nitroquinazoline According to a manner similar to that in Reference Example 39, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 13 It is reduced by lithium aluminum hydride.

? -NRM (DMSO-d6) d (ppm): 1.30 (3H, t, J = 7.3 Hz), 1.32-1.50 (2H, m), 1.74-1.79 (3H,), 2.62-2.70 (2H, m) , 3.07-3.12 (2H, m), 3.30-3.50 (4H, m), 4.45 (1H, t, J = 5.3 Hz), 4.84 (2H, d, J = 5.3 Hz), 6.87 (1H, s), 6.99 (1H, dd, J = 6.6 Hz, 6.9 Hz), 7.13 (1H, d, J = 7.3 Hz), 7.19-7.24 (2H, m), 7.74 (1H, t, J = 5.3 Hz), 8.31 ( 1H, s), 9.06 (1H, t, J = 5.6 Hz), 9.31 (1H, s).

Reference Example 41 7-Ethylamino-6-nitro-4- (2-piperidinobenzylamino) quinazoline According to a manner similar to that in Reference Example 39, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 14 It is reduced by lithium aluminum hydride.

XH-NMR (CDC13) d (ppm): 1.41 (3H, t, J = 7.3 Hz), 1.61-1.79 (2H, m), 1. 81-1.88 (4H, m), 2.95-3.04 (4H, m), 3.38 (2H, q, J = 7.3 Hz), 4.95 (2H, d, J = 5.0 Hz), 6.98 (1H, s), 7.10 (1H, dd, J = 7.3 Hz, 8.9 Hz), 7. 22-7.36 (3H, m), 7.71 (1H, t, J = 5.0 Hz), 8.37 (1H, br), 8.53 (1H, s), 8.72 (1H, s).

Reference Example 42 7-Ethylamino-4- [2- (4-methyl-l-piperazinyl) benzylamino] -6-nitroquinazoline According to a manner similar to that in Example 39 of Reference, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 15 is reduced by lithium aluminum hydride.

? -NRM (CDC13) d (ppm): 1.41 (3H, t, J = 7.3 Hz), 2.42 (3H, s), 2.70-2.80 (4H, m), 3.05-3.15 (4H, m), 3.40 ( 2H, q, J = 7.3 Hz), 3.70 (1H, br), 4.95 (2H, s), 6.94 (1H, s), 7.12 (1H, dd, J = 7.3 Hz, 7.3 Hz), 7.23-7.36 (3H,), 7.73 (1H, br), 8.44 (1H, br), 8.89 (1H, s).

Reference Example 43 7-Ethylamino-6-nitro-4- (2-thiomorpholinobenzylamino) quinazoline According to a manner similar to that in Reference Example 39, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 16 It is reduced by lithium aluminum hydride.

XH-NMR (DMSO-d6) d (ppm): 1.31 (3H, t, J = 7.1 Hz), 2.70-2.80 (4H, m), 3.10-3.18 (4H, m), 3.35-3.44 (2H, m ), 4.83 (2H, d, J = 5.3 Hz), 6.86 (1H, s), 7.04 (1H, dd, J = 7.3 Hz, 7.6 Hz), 7.15 (1H, d, J = 7.9 Hz), 7.21- 7.27 (2H, m), 7.73 (1H, t, J = 5.3 Hz), 8.32 (1H, s), 9.03 (1H, t, J = 5.4 Hz), 9.32 (1H, s).

Reference Example 44 7-Ethylamino-4- (3-morpholinobenzylamino) -6-nitroquinazoline According to a manner similar to that in Reference Example 39, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Example 17 or 18 Reference is reduced by lithium aluminum hydride.

-NRM (DMSO-dg) d (ppm): 1.30 (3H, t, J = 7.1 Hz), 3.06-3.15 (4H, m), 3.32-3.39 (2H, m), 3.71-3.78 (4H, m) , 4.70 (2H, d, J = 5.3 Hz), 6.79-6.85 (3H, m), 6.96 (1H, s), 7.17 (lH, dd, J = 7.9 Hz, 7.9 Hz), 7.71 (1H, t, J = 5.3 Hz), 8.32 (1H, s), 9.13 (1H, t, J = 5.6 Hz), 9.28 (1H, s).

Reference Example 45 7-Ethylamino-6-nitro-4- (3-piperidinobenzylamino) quinazoline According to a manner similar to that in Reference Example 39, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 19 It is reduced by lithium aluminum hydride.

XH-NMR (CDCl 3) d (ppm): 1.40 (3H, t, J = 7.3 Hz), 1.53-1.73 (6H, m), 3.13-3.18 (4H, m), 3.32-3.40 (2H, m), 4.77 (2H, d, J = 5.0 Hz), 6.29 (1H, br), 6.80-6.90 (2H,), 6.96 (1H, s), 6.98 (1H, s), 7.17-7.27 (1H, m), 7.67 (1H, t, J = 4.6 Hz), 8.54 (1H, s), 8.71 (1H, s).

Reference Example 46 7-Ethylamino-4- [3- (4-methyl-l-piperazinyl) benzylamino] -6-nitroquinazoline According to a manner similar to that in Reference Example 39, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 20 It is reduced by lithium aluminum hydride.

-NMR (CDCl 3) d (ppm): 1.36 (3H, t, J = 7.3 Hz), 2.31 (3H, s), 2. 49-2.58 (4H, m), 3.14-3.24 (4H, m), 3.29 (2H, q, J = 7.3 Hz), 4.77 (2H, d, J = 4.3 Hz), 6.73-6.93 (4H, m), 7.16-7.22 (2H, m), 7.61 (1H, t, J = 4.3 Hz), 8.50 (1H, s), 8.82 (1H, s).

Reference Example 47 7-Ethylamino-4- (4-morpholinobenzylamino) -6-nitroquinazoline According to a manner similar to that in Reference Example 39, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 21 It is reduced by lithium aluminum hydride.

XH-NMR (DMS0-d6) d (ppm): 1.26 (3H, t, J = 7.1 Hz), 3.30-3.07 (4H, m), 3.34 (2H, q, J = 7.1 Hz), 3.70-3.73 ( 4H, m), 4.64 (2H, d, J = 5.3 Hz), 6.85 (1H, s), 6.90 (2H, d, J = 8.6 Hz), 7.23 (2H, d, J = 8.6 Hz), 7.74 ( 1H, br), 8.33 (1H, s), 9.15 (1H, br), 9.27 (1H, s).

Reference Example 48 7-Ethylamino-6-nitro-4- (4-piperidinobenzylamino) quinazoline According to a manner similar to that in Reference Example 39, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 22 It is reduced by lithium aluminum hydride.

XH-NMR (CDCl 3) d (ppm): 1.41 (3H, t, J = 7.4 Hz), 1.50-1.80 (6H, m), 3. 02-3.19 (4H, m), 3.33-3.43 (2H, m), 4.73 (2H, s), 6.20 (1H, br), • 6. 80-7.00 (2H, m), 7.21-7.30 (3H, m), 7.69 (lH, br), 8.54 (1H, s), 8.69 (1H, s).

Reference Example 49 7-Ethylamino-4- [4- (4-methyl-l-piperazinyl) benzylamino] -6-nitroquinazoline According to a manner similar to that in Reference Example 39, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 23 It is reduced by lithium aluminum hydride.

^ -NMR (CDCl 3) d (ppm): 1.39 (3H, t, J = 7.3 Hz), 2.37 (3H, s), 2. 55-2.62 (4H, m), 3.18-3.33 (4H, m), 3.38 (2H, q, J = 7.3 Hz), 4.74 (2H, d, J = 5.0 Hz), 6.15 (1H, br), 6.93 (2H, d, J = 8.6 Hz), 6.99 (1H, s), 7.31 (2H, d, J = 8.6 Hz), 7.69 (1H, br), 8.55 (1H, s), 8.69 (1H, s).

Reference Example 50 7-Ethylamino-6-nitro-4- [4- (l-pyrrolidinyl) benzylamino) quinazoline According to a manner similar to that in Example 39 of Reference, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 24 is reduced by lithium aluminum hydride.

? -NRM (DMSO-dg) d (ppm): 1.30 (3H, t, J = 7.1 Hz), 1.91-2.00 (4H, m), 3.17-3.22 (4H, m), 3.32-3.41 (3H, m ), 4.62 (2H, d, J = 5.6 Hz), 6.48 (2H, d, J = 8.6 Hz), 6.84 (1H, s), 7.19 (2H, d, J = 8.6 Hz), 7.73 (1H, t , J = 5.6 Hz), 8.27 (1H, s), 8.32 (1H, s).

Reference Example 51 7-Ethylamino-6-nitro-4- (4-thiomorpholinobenzylamino) quinazoline According to a manner similar to that in Reference Example 39, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 25 It is reduced by lithium aluminum hydride.

-NRM (CDCI3) d (ppm): 1.41 (3H, t, J = 7.2 Hz), 2.72-2.77 (4H, m), 3.36-3.43 (2H, m), 3.55-3.61 (4H, m), 4.74 (2H, d, J = 4.9 Hz), 5.96 (1H, br), 6.90 (2H, d, J = 8.9 Hz), 7.00 (1H, s), 7.30 (2H, d, J = 8.9 Hz), 7.69 (1H, br), 8.56 (1H, s), 8.65 (1H, s).

Reference Example 52 2- [N- (2-hydroxyethyl) methylamino] benzonitrile According to a manner similar to that in Reference Example 3, the title compound is synthesized from 2-fluorobenzonitrile and N-methylethanolamine.

? -NRM (CDCI3) d (ppm): 2.60 (lH, br), 3.02 (3H, s), 3.49 (2H, t, J = 5.8 Hz), 3.87 (2H, t, J = 5.8 Hz), 6.89 (1H, dd, J = 7.3 Hz, 7.6 Hz), 7.01 (1H, d, J = 8.6 Hz), 7.39-7.52 (2H, m).

Reference Example 53 7-Ethylamino-4-. { 2- [N- (2-hydroxyethyl) ethylamino] benzylamino} -6-nitroquinazoline According to a manner similar to that in Reference Example 39, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in the Reference Example 52 is reduced by lithium aluminum hydride.

-NRM (CDC13) d (ppm): 1.37 (3H, t, J = 7.1 Hz), 1.95 (1H, br), 2.75 (3H, s), 3.19 (2H, t, J = 5.0 Hz), 3.27- 3.38 (2H, m), 3.85 (2H, t, J = 5.0 Hz), 4.95 (2H, d, J = 5.3 Hz), 6.88 (lH, s), 7.14 (1H, dd, J = 7.3 Hz, 7.3 Hz), 7.23-7.32 (2H, m), 7.46 (1H, d, J = 7.3Hz), 7.63 (1H, br), 8.20 (1H, br), 8.45 (1H, s), 8.96 (1H, s) ).

Reference Example 54 4- (3-Hydroxymethylpiperidino) benzonitrile According to a manner similar to that in Reference Example 3, the title compound is synthesized from 4-fluorobenzonitrile and 3-hydroxymethylpiperidine.

XH-NMR (CDCl 3) d (ppm): 1.20-1.32 (lH, m), 1.56-1.73 (lH, m), 1.74-1.95 (4H, m), 2.72-2.80 (1H, m), 2.87-2.98. (lH, m), 3.47-3.76 (3H, m), 3.86-3.92 (1H, m), 6.87 (2H, d, J = 8.9 Hz), 7.44 (2H, d, J = 8.9 Hz).

Reference Example 55 7-Ethylamino-4- [4- (3-hydroxymethylpiperidino) benzylamino] -6-nitroquinazoline According to a manner similar to that in Reference Example 39, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 54 It is reduced by lithium aluminum hydride.

-NRM (DMSO-dg) d (ppm): 1.00-1.15 (lH, m), 1.30 (3H, t, J = 7.2 Hz), 1.36-1.72 (4H, m), 2.34-2.39 (1H, m) , 2.57-2.66 (1H, m), 3.18-3.40 (4H, m), 3.50-3.56 (1H, m), 3.62-3.66 (lH, m), 4.45-4.49 (1H, m), 4.64 (2H, d, J = 5.4 Hz), 6.85 (1H, s), 6.86 (2H, d, J = 8.9 Hz), 7.21 (2H, d, J = 8.9 Hz), 7.71 (1H, br), 8.32 (1H, s), 9.09 (1H, t, J = 5.4 Hz), 9.27 (1H, s).

Reference Example 56 2- (1-Imidazolyl) benzonitrile The 2-fluorobenzonitrile (0.70 g, 5.78 mmol) is dissolved in acetonitrile (1 ml), and an imidazole sodium salt (1.34 g, 14.8 mmol) is added thereto, followed by stirring at 100 ° C for 1.5 hours. The reaction mixture is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (the sample is eluted with an increasing concentration of chloroform from chloroform / hexane = 1/2 to 100% chloroform) to give the title compound (0.96 g, 98%).

-NMR (CDC13) d (ppm): 7.26 (1H, s), 7.37 (1H, s), 7.41-7.57 (2H, m), 7.72-7.87 (3H, m).

Reference Example 57 7-Ethylamino-4- [2- (1-imidazolyl) benzylamino] -6-nitroquinazoline According to a manner similar to that in Reference Example 39, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 56 It is reduced by lithium aluminum hydride.

-NRM (DMSO-dg) d (ppm): 1.28 (3H, t, J = 7.1 Hz), 3.35-3.40 (2H, m), 4.56 (2H, d, J = 5.3 Hz), 6.86 (1H, s) ), 7.09 (1H, s), 7.34-7.55 (5H, m), 7.76 (1H, t, J = 5.3 Hz), 7.92 (1H, s), 8.27 (1H, s), 9.13 (1H, t, J = 5.2 Hz), 9.28 (1H, s).

Reference Example 58 2- (1-Perhydroazocinyl) benzonitrile According to a manner similar to that in Reference Example 12, the title compound is obtained from 2-fluorobenzonitrile and heptamethyleneimine.

-NRM (CDC13) d (ppm): 1.55-1.65 (6H, m), 1.76-1.82 (4H, m), 3.66-3.71 (4H, m), 6.64 (1H, dd, J = 6.9 Hz, 7.9 Hz ), 6.80 (1H, d, J = 8.6 Hz), 7.25-7.34 (1H, m), 7.43 (lH, d, J = 7.9 Hz).

Reference Example 59 4- [2- (1-Perhydroazocinyl) benzylamino] -7-ethylamino-6-nitroquinazoline According to a manner similar to that in Example 39 of Reference, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 58 is reduced by lithium aluminum hydride.

XH-NMR (CDCl3) d (ppm): 1.36 (3H, t, J = 7.1 Hz), 1.68-1.72 (10H, m), 3.14-3.15 (4H, m), 3.27-3.32 (2H, m ), 4.96 (2H, d, J = 5.3 Hz), 6.92 (1H, s), 7.00-7.06 (1H, m), 7.24-7.33 (3H, m), 7.48 (1H, br), 7.64 (1H, br), 8.48 (1H, s), 8.77 (1H, s).

Reference Example 60 2-Propylaminobenzonitrile According to a manner similar to that in Reference Example 3, the title compound is synthesized from 2-fluorobenzonitrile and n-propylamine.

XH-NMR (CDC13) d (ppm): 1.00 (3H, t, J = 7.3 Hz), 1.58-1.72 (2H, m), 3.10-3.15 (2H, m), 4.55 (1H, br), 6.58- 6.65 (2H, m), 7.32-7.38 (2H, m).

Reference Example 61 7-Ethylamino-6-nitro-4- (2-propylaminobenzylamino) quinazoline According to a manner similar to that in Reference Example 28, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 60 It is reduced by lithium aluminum hydride.

-NMR (DMSO-d6) d (ppm): 0.88 (3H, t, J = 7.3 Hz), 1.28 (3H, t, J = 7.1 Hz), 1.51-1.59 (2H, m), 2.98-3.02 (2H , m), 3.33-3.41 (2H, m), 4.64 (2H, d, J = 5.6 Hz), 5.61 (1H, br), 6.51-6.58 (2H, m), 6.86 (1H, s), 7.06- 7.15 (2H, m), 7.78 (1H, t, J = 5.3 Hz), 8.35 (1H, s), 9.10 (1H, t, J = 5.6 Hz), 9.25 (1H, s).

Reference Example 62 2-Isopropylaminobenzonitrile According to a manner similar to that in Reference Example 3, the title compound is synthesized from 2-fluorobenzonitrile and isopropylamine.

? -NRM (CDC13) d (ppm): 1.23 (6H, d, J = 6.3 Hz), 3.61-3.75 (1H, m), 4.40 (1H, br), 6.57-6.66 (2H, m), 7.30- 7.37 (2H, m).

Reference Example 63 7-Ethylamino-4- (2-isopropylaminobenzylamino) -6-nitroquinazoline According to a manner similar to that in Reference Example 28, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 62 It is reduced by lithium aluminum hydride.

? -NRM (DMS0-d6) d (ppm): 1.08 (6H, d, J = 6.3 Hz), 1.28 (3H, t, J = 7.3 Hz), 3.34-3.40 (2H, m), 3.43-3.59 ( 1H, m), 4.64 (2H, d, J = 5.6 Hz), 5.51 (1H, br), 6.51-6.58 (2H, m), 6.86 (1H, s), 7. 06-7.17 (2H, m), 7.77 (1H, t, J = 5.3 Hz), 8.37 (1H, s), 9.07 (1H, t, J = 5.6 Hz), 9.24 (1H, s).

Reference Example 64 2- (3-Hydroxymethylpiperidino) benzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and 3- (hydroxymethyl) piperidine.

? -NRM (CDC13) d (ppm): 1.23-1.33 (1H, m), 1.72-1.85 (3H, m), 1.97-2.17 (2H, m), 2.80-2.94 (2H, m), 3.35-3.52 (2H, m), 3.59-3.74 (2H, m), 6.90-7.05 (2H, m), 7.43-7.56 (2H, m).

EXAMPLE 65 Reference 7-Ethylamino-4- [2- (3-hydroxymethylpiperidino) enylamino] -6-nitroquinazoline According to a manner similar to that in Reference Example 39, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 64 It is reduced by lithium aluminum hydride.

XH-NMR (DMSO-d6) d (ppm): 1.07-1.12 (lH, m), 1.30 (3H, t, J = 7.1 Hz), 1.64-1.90 (4H, m), 2.42-2.51 (1H, m ), 2.60-2.68 (1H, m), 2.99-3.04 (1H, m), 3.06-3.20 (1H, m), 3.31-3.45 (4H,), 4.48 (1H, t, J = 5.3 Hz), 4.85 (2H, d, J = 5.3 Hz), 6.87 (1H, s), 6.99 (1H, dd, J = 7.3 Hz, 7.3 Hz), 7.11 (1H, d, J = 6.9 Hz), 7.17-7.24 (2H , m), 7.75 (1H, t, J = 5.3 Hz), 8.32 (1H, s), 9.11 (1H, t, J = 5.6 Hz), 9.32 (1H, s).

Reference Example 66 3- (4-Ethoxycarbonylpiperidino) benzonitrile According to a manner similar to that in Reference Example 17, the title compound is synthesized from 3-fluorobenzonitrile and ethyl isonipecotate ? -NRM (CDC13) d (ppm): 1.28 (3H, t, J = 7.3 Hz), 1.77-1.92 (2H, m), 1.95-2.07 (2H, m), 2.42-2.54 (1H, m), 2.81-2.91 (2H, m), 3.62-3.70 (2H, m), 4.15 (2H, q, J = 7.3 Hz), 7.05-7.14 (3H, m), 7.27-7.34 (1H, m).

Reference Example 67 7-Ethylamino-4- [3- (4-hydroxymethylpiperidino) benzylamino] -6-nitroquinazoline According to a manner similar to that in Reference Example 39, the title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 66 It is reduced by lithium aluminum hydride.

? -NRM (DMSO-d6) d (ppm): 1.20-1.50 (5H, m), 1.71-1.77 (2H, m), 2.58-2.66 (2H, m), 3.26-3.43 (5H, m), 3.64 -3.69 (2H, m), 4.45 (1H, t, J = 5.3 Hz), 4.69 (2H, d, J = 5.6 Hz), 6.72-6.86 (3H, m), 6.95 (1H, s), 7.13 ( 1H, dd, J = 7.9 Hz, 7.9 Hz), 7.75 (1H, t, J = 5.6 Hz), 8.32 (1H, s), 9.17 (1H, t, J = 5.8 Hz), 9.30 (lH, s) .

Reference Example 68 2- [4- (2-Hydroxyethyl) piperidino] benzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and 4- (2-hydroxyethyl) piperidine.

^ -RMN (CDC13) d (ppm): 1.49-1.62 (6H, m), 1.82-1.87 (2H, m), 2.75-2.83 (2H, m), 3.56-3.61 (2H, m), 3.72-3.77 (2H, m), 6.93-7.01 (2H, m), 7.42-7.56 (2H, m).

Reference Example 69 7-Ethylamino-4-. { 2- [4- (2-hydroxyethyl) piperidino] benzylamino} -6-nitroquinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 68 is reduced by lithium aluminum hydride.

XH-NMR (DMS0-d6) d (ppm): 1.26-1.60 (7H, m), 1.74-1.79 (2H, m), 2. 62-2.70 (2H, m), 3.05-3.13 (2H, m), 3.32-3.52 (5H, m), 4.33 (1H, t, J = 5.2 Hz), 4.84 (2H, d, J = 5.4 Hz), 6.87 (1H, s), 6.93-7.02 (1H, m), 7.12 (1H, d, J = 7.4 Hz), 7.19-7.28 (2H, m), 7.74 (1H, t, J = 5.2 Hz), 8.32 (1H, s), 9.07 (lH, t, J = 5.4 Hz), 9.31 (1H, s).

Reference Example 70 2- (4-Ethoxycarbonyl-l-piperazinyl) benzaldehyde 2-Fluorobenzaldehyde (3.0 g, 24.2 mmol), 1- (ethoxycarbonyl) piperazine (4.2 ml, 28.7 ml), and calcium carbonate (2.46 g, 24.6 mmol) are reacted at 120 ° C for 7.5 hours in dimethyl sulfoxide ( 12 ml). After the reaction is complete, the insoluble compounds are filtered and the resulting filtrate is extracted by adding water and ethyl acetate thereto. The organic layer is dried over anhydrous magnesium sulfate and concentrated to give oily substances. The resulting oil substances are purified by column chromatography on silica gel (eluent: from hexane / ethyl acetate = 4/1 to hexane / ethyl acetate = 1/1) to give the title compound (4.29 g, 68% ).

? -NRM (CDC13) d (ppm): 1.29 (3H, t, J = 7.3 Hz), 3.03-3.07 (4H, m), 3.67-3.71 (4H, m), 4.14 (2H, q, J = 7.3 Hz), 7.10-7.19 (2H, m), 7.52 (1H, dd, J = 7.6 Hz, 7.9 Hz), 7.83 (lH, d, J = 7.6 Hz), 10.35 (1H, s).

Reference Example 71 4- [2- (4-Ethoxycarbonyl-l-piperazinyl) benzylamino] -7-ethylamino-6-nitroquinazoline The title compound (2.5 g, 9.54 mmol) obtained in Reference Example 70 is dissolved in ethanol (25 ml), and hydroxylamine hydrochloride (0.862 g, 12.4 mmol) and sodium carbonate (1.32 g, 12.5 mmoles), followed by stirring at room temperature overnight. After the reaction is complete, the insoluble compounds are filtered and the filtrate is concentrated, thereby obtaining the oily substances. 10% palladium carbon catalyst (2.30 g) is added to the resulting oily substances in methanol (100 ml) and the mixture is stirred at room temperature overnight under a hydrogen atmosphere. After the reaction is complete, the catalyst is filtered with a filtration aid. The compound obtained (2.1 g) by concentration of the resulting filtrate, 4-chloro-7-ethylamino-6-nitroquinazoline (2.00 g, 7.92 mmol) and triethylamine (5.50 ml, 40.3 mmol) are stirred overnight in tetrahydrofuran ( 50 ml). After the reaction is complete, the reaction solution is concentrated and the resulting oily substances are purified by column chromatography on silica gel (eluent: chloroform / methanol = 30/1) to give the title compound (1.53 g, 40%).

^ -RMN (DMSO-d6) d (ppm): 1.21 (3H, t, J = 7.1 Hz), 1.29 (3H, t, J = 7.1 Hz), 2.85-2.89 (4H, m), 3.38 (2H, q, J = 7.1 Hz), 3. 43-3.57 (4H, m), 4.07 (2H, q, J = 7.1 Hz), 4.87 (2H, d, J = 5.3 Hz), 6. 87 (1H, s), 7.05 (1H, dd, J = 6.9 Hz, 7.9 Hz), 7.16 (1H, d, J = 7.9 Hz), 7.22-7.28 (2H, m), 7.77 (lH, t, J = 5.3 Hz), 8.33 (1H, s), 9.14 (1H, t, J = 5.3 Hz) , 9.32 (1H, s).

Reference Example 72 2-Etylaminobenzonitrile According to a manner similar to that in Reference Example 12, the title compound is obtained from 2-fluorobenzonitrile and a 70% aqueous ethylamine solution.

-NRM (CDCl 3) d (ppm): 1.25 (3H, t, J = 7.3 Hz), 3.13-3.21 (2H, m), 4.55 (1H, br), 6.58-6.64 (2H, m), 7.28-7.37 (2H, m).

Reference Example 73 7-Ethylamino-4- (2-ethylaminobenzylamino) -6-nitroquinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 72 is reduced by lithium aluminum hydride.

XH-NMR (DMSO-d6) d (ppm):, 1.17 (3H, t, J = 7.1 Hz), 1.28 (3H, t, J = 7.3 Hz), 3.04-3.17 (2H, m), 3.33-3.43 (2H, m), 4.64 (2H, d, J = 5.9 Hz), 5.62 (1H, br), 6.52-6.59 (2H, m), 6.87 (1H, s), 7.07-7.15 (2H, m), 7.78 (lH, t, J = 5.3 Hz), 8.36 (1H, s), 9.11 (1H, t, J = 5.9 Hz), 9.25 (1H, s).

Reference Example 74 2-Cyclopentylaminobenzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and cyclopentylamine.

XH-NMR (CDC13) d (ppm): 1.45-1.81 (6H, m), 1.98-2.15 (2H, m), 3.78-3.87 (1H, m), 4.52 (1H, br), 6.59-6.69 (2H , m), 7.27-7.38 (2H, m).

Reference Example 75 4- (2-Cyclopentylaminobenzylamino) -7-ethylamino-6-nitroquinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 74 is reduced by lithium aluminum hydride.

XH-NMR (DMSO-d6) d (ppm): 1.28 (3H, t, J = 7.1 Hz), 1.39-1.65 (6H, m), 1.85-1.90 (2H, m), 3.33-3.43 (2H, m ), 3.72-3.80 (1H, m), 4.65 (2H, d, J = 5.9 Hz), 5.60 (1H, d, J = 5.9 Hz), 6.52-6.58 (2H, m), 6.86 (1H, s) , 7.07-7.17 (2H, m), 7.76 (1H, t, J = 5.3 Hz), 8.35 (1H, s), 9.06 (1H, t, J = 5.9 Hz), 9.24 (1H, s).

Reference Example 76 2- Butylaminobenzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and butylamine.

^ -RMN (CDC13) d (ppm): 0.95 (3H, t, J = 7.3 Hz), 1.35-1.48 (2H, m), 1.56-1.67 (2H, m), 3.13-3.18 (2H, m), 4.52 (1H, br), 6.59-6.64 (2H, m), 7.31-7.38 (2H, m).

Reference Example 77 4- (2-Butylaminobenzylamino) -7-ethylamino-6-nitroquinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 76 is reduced by lithium aluminum hydride. 2 H-NMR (DMSO-dg) d (ppm): 0.85 (3H, t, J = 7.3 Hz), 1.25-1.37 (5H, m), 1. 46-1.57 (2H, m), 2.95-3.05 (2H, m), 3.38 (2H, q, J = 6.9Hz), 4.64 (2H, d, J = 5.9 Hz), 5.53 (1H, br), 6.51 -6.59 (2H, m), 6.87 (1H, s), 7.06-7.15 (2H, m), 7.77 (lH, t, J = 5.3Hz), 35 (1H, s) 9. OI (1H, t, J = 5.9Hz), 9.25 (1H, s).

Reference Example 78 2- (l-pyrrolidinyl) benzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and pyrrolidine.

? -NRM (CDC13) d (ppm): 1.95-2.02 (4H, m), 3.35-3.61 (4H, m), 6.56-6.66 (2H, m), 7.28-7.34 (1H, m), 7.40-7.44 (1H, m).

Reference Example 79 7-Ethylamino-6-nitro-4- [2- (l-pyrrolidinyl) benzylamino] quinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 78 is reduced by lithium aluminum hydride.

-NRM (DMSO-d6) d (ppm): 1.29 (3H, t, J = 7.1 Hz), 1.87-1.92 (4H, m), 3.13-3.18 (4H, m), 3.34-3.44 (2H, m) , 4.76 (2H, d, J = 5.3Hz), 6.82-6.87 (2H, m), 6.98 (1H, d, J = 7.6Hz), 7.12-7.18 (2H, m), 7.75 (1H, t, J = 5.4Hz), 8.32 (lH, s), 9.11 (1H, t, J = 5.3Hz), 9.33 (1H, s).

Reference Example 80 2-Cyclohexylaminobenzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and cyclohexylamine.

-NRM (CDC13) d (ppm): 1.16-1.45 (5H, m), 1.62-1.67 (1H, m), 1.75-1.82 (2H, m), 1.99-2.04 (2H, m), 3.30-3.37 ( 1H, m), 4.45 (1H, m), 6.57-6.67 (2H, m), 7.30-7.39 (2H, m).

Reference Example 81 4- (2-Cyclohexylaminobenzylamino) -7-ethylamino-6-nitroquinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 80 It is reduced by lithium aluminum hydride.

^ -NMR (DMSO-dg) d (ppm): 1.05-1.18 (3H, m), 1.20-1.37 (5H, m), 1.55-1.69 (3H, m), 1.85-1.89 (2H, m), 3.15 -3.24 (1H, m), 3.33-3.43 (2H, m), 4.64 (2H, d, J = 5.6 Hz), 5.50 (1H, d, J = 7.3 Hz), 6.50-6.58 (2H, m), 6.87 (1H, s), 7.05-7.18 (2H, m), 7.77 (1H, t, J = 5.1 Hz), 8.37 (1H, s), 9.06 (1H, t, J = 5.6 Hz), 9.24 (1H , s).

Reference Example 82 2- (4-Ethyl-l-piperazinyl) benzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and 4-ethylpiperazine.

-NRM (CDC13) d (ppm): 1.13 (3H, t, J = 7.3 Hz), 2.50 (2H, q, J = 7.3 Hz), 2.66-2.70 (4H, m), 3.24-3.28 (4H, m ), 6.96-7.03 (2H, m), 7.45-7.60 (2H, m).

Reference Example 83 7-Ethylamino-4- [2- (4-ethyl-l-piperazinyl) benzylamino] -6-nitroquinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 82 is reduced by lithium aluminum hydride.

-NRM (DMSO-dg) d (ppm): 1.03 (3H, t, J = 7.3 Hz), 1.28 (3H, t, J = 7.1 Hz), 2.39 (2H, q, J = 7.3 Hz), 2.50- 2.60 (4H, m), 2.85-2.93 (4H, m), 3.36-3.44 (2H, m), 4.84 (2H, d, J = 5.3 Hz), 6.87 (1H, s), 7.02 (1H, dd, J = 6.6 Hz, 6.9 Hz), 7.15 (1H, d, J = 6.9 Hz), 7.16-7.24 (2H, m), 7.75 (1H, t, J = 5.3 Hz), 8.32 (1H, s), 9.08 (1H, br), 9.31 (1H, s).

Reference Example 84 2- (2-Methylpropylamino) benzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and isobutylamine.

? -NRM (CDCl3) d (ppm): 0.99 (6H, d, J = 7.6 Hz), 1.80-1.97 (1H, m), 2.97-3.00 (2H, m), 4.61 (1H, br), 6.58- 6.64 (2H, m), 7.31-7.37 (2H, m).

Reference Example 85 7-Ethylamino-4- [2- (2-methylpropylamino) benzylamino] -6-nitroquinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 84 is reduced by lithium aluminum hydride.

: H-NMR (DMS0-d6) d (ppm): 0.86 (6H, d, J = 6.6 Hz), 1.28 (3H, t, J = 7.1 Hz), 1.75-1.86 (1H, m), 2.86-2.88 (2H, m), 3.34-3.43 (2H, m), 4.66 (2H, d, J = 5.9 Hz), 5.63 (1H, t, J = 5.1 Hz), 6.49-6.55 (2H, m), 6.85 ( 1H, s), 7.05-7.17 (2H, m), 7.76 (1H, t, J = 5.3 Hz), 8.35 (1H, s), 9.07 (1H, t, J = 5.9 Hz), 9.24 (1H, s ).

Reference Example 86 2- (1-Perbenzoazepinyl) benzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and hexamethyleneimine.

XH-NMR (CDC13) d (ppm): 1.59-1.64 (4H, m), 1.86-1.87 (4H, m), 3.52-3.65 (4H, m), 6.61-6.72 (1H, m), 6.84 (1H , d, J = 8.6 Hz), 7.29-7.36 (1H, m), 7.45 (1H, d, J = 7.9 Hz).

Reference Example 87 4- [2- (1-Perhydroazepinyl) benzylamino] -7-ethylamino-6-nitroquinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 86 is reduced by lithium aluminum hydride.

-NRM (DMSO-dg) d (ppm): 1.29 (3H, t, J = 7.2 Hz), 1.61-1.90 (8H, m), 3.06-3.14 (4H, m), 3.33-3.44 (2H, m) , 4.85 (2H, d, J = 5.4 Hz), 6.87 (1H, s), 6.93-6.99 (1H, m), 7.09-7.22 (3H, m), 7.74 (1H, t, J = 5.4 Hz), 8.32 (1H, s), 9.06 (1H, t, J = 5.4 Hz), 9.32 (1H, s).

Reference Example 88 2- (I-Tricyclo [3.3.1.13'7] decyl) aminobenzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and 1-adamantanamine.

? -NRM (CDC13) d (ppm): 1.67-1.76 (7H, m), 1.99-2.01 (6H, m), 2.15-2.22 (2H, m), 4.38 (1H, br), 6.64 (lH, dd) , J = 7.6 Hz, 7.6 Hz), 7.01 (1H, d, J = 8.6 Hz), 7.26-7.38 (2H, m).

Example 89 Reference 7-Ethylamino-6-nitro-4- [2- (1-tricyclo [3.3.1.13-7] decyl) aminobenzylamino] quinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 88 is reduced by lithium aluminum hydride.

XH-NMR (DMS0-d6) d (ppm): 1.27 (3H, t, J = 7.3 Hz), 1.56-1.70 (6H, m), 1.80-1.90 (6H, m), 2.00-2.09 (3H, m ), 3.32-3.43 (2H, m), 4.68 (2H, d, J = 5.9 Hz), 4.95 (1H, br), 6.62 (1H, dd, J = 7.3 Hz, J = 7.6 Hz), 6.87 (1H, s), 6.92 (1H, d, J = 7.6 Hz), 7.07 (1H, dd, J = 7.3 Hz, 7.6 Hz), 7.19 (1H, d, J = 7.6 Hz), 7.77 (1H, t, J = 5.3 Hz), 8.36 (1H, s), 9.04 (1H, t, J = 5.9 Hz), 9.26 (1H, s).

Reference Example 90 2- (4-Hydroxybutylamino) benzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and 4-hydroxybutylamine.

-NRM (CDC13-CD30D) d (ppm): 1.62-1.79 (4H, m), 3.20-3.25 (2H, m), 3.67-3.72 (2H, m), 6.61-6.67 (2H, m), 7.33- 7.40 (2H, m).

Reference Example 91 7-Ethylamino-4- [2- (4-hydroxybutylamino) benzylamino] -6-nitroquinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 90 is reduced by lithium aluminum hydride.

XH-NMR (DMS0-d6) d (ppm): 1.27 (3H, t, J = 6.9 Hz), 1.45-1.64 (4H, m), 3.00-3.08 (2H, m), 3.33-3.47 (4H, m ), 4.40 (1H, t, J = 5.0 Hz), 4.63 (2H, d, J = 5.6 Hz), 5.62 (lH, br), 6.52-6.55 (2H, m), 6.85 (1H, s), 7.06 -7.15 (2H, m), 7.76 (1H, t, J = 5.3 Hz), 8.36 (1H, s), 9.08 (1H, t, J = 5.6 Hz), 9.24 (1H, s).

Reference Example 92 6-nitro-7-propi1-4 3H) -quinazoline The 7-chloro-6-nitro-4- (3H) -quinazoline (5g, 22.2 mmol) is heated at 140 ° C in dimethyl sulfoxide (15 ml). The n-propylamine (5 ml, 60.8 mmol) is added thereto at the same temperature and the mixture is stirred for 30 minutes. After the reaction is complete, the reaction mixture is cooled, and therefore the precipitated crystal is collected, washed with methanol and dried to give the title compound.

-NRM (DMSO-dg) d (ppm): 0.98 (3H, t, J = 7.4 Hz), 1.63-1.74 (2H, m), 3.31-3.39 (2H, m), 6.91 (1H, s), 8.08 (1H, s), 8.15 (1H, t, J = 5.3 Hz), 8.73 (1H, s), 12.00 (1H, br).

Reference Example 93 4- [2- (4-Hydroxymethylpiperidino) benzylamino] -6-nitro-7-propylaminoquinazoline The compound (1.2 g, 4.84 mmol) obtained in Reference Example 92 is suspended in phosphorus oxychloride (11 ml, 118 mmol) and the mixture is heated at 110 ° C for 2 hours under an atmosphere of argon gas to form a clear solution. After it is confirmed that the starting material disappears, unreacted phosphorus oxychloride is removed under reduced pressure. After the residue is subjected to azeotropic distillation with toluene, the resulting oily substances are dissolved in the minimum required amount of tetrahydrofuran. The tetrahydrofuran solution obtained is poured into ice cold water with a sufficient amount of sodium hydrogen carbonate, followed by extraction with ethyl acetate. The organic layer is dried (over anhydrous magnesium sulfate), and the drying agent is filtered. The filtrate is concentrated under reduced pressure to give orange solids (1.39 g).

The title compound is obtained from the above orange solids (1.39 g) and a compound obtained after the compound in Reference Example 13 is reduced by lithium aluminum hydride.

-NRM (DMSO-d6) d (ppm): 1.00 (3H, t, J = 7.3 Hz), 1.26-1.63 (3H, m), 1.66-1.79 (4H, m), 2.62-2.70 (2H, m) , 3.06-3.15 (2H, m), 3.29-3.36 (4H,), 4.47 (1H, t, J = 5.1 Hz), 4.84 (2H, d, J = 5.3 Hz), 6.87 (1H, s), 6.96 -7.09 (1H, m), 7.11-7.25 (3H, m), 7.83 (1H, t, J = 5.4 Hz), 8.33 (1H, s), 9.11 (1H, t, J = 5.3 Hz), 9.32 ( 1H, s).

Reference Example 94 2- (4-Methyl-l-homopiperazinyl) benzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and 4-methylhomopiperazine.

-NRM (CDC13) d (ppm): 2.01-2.10 (2H, m), 2.41 (3H, s), 2.63-2.67 (2H, m), 2.80-2.84 (2H, m), 3.59-3.68 (2H, m), 3.69-3.71 (2H, m), 6.71-6.78 (1H, m), 6.85 (1H, d, J = 8.6 Hz), 7.33-7.45 (1H, m), 7.47 (1H, d, J = 7.9 Hz).

Reference Example 95 7-Ethylamino-4- [2- (4-methyl-l-homopiperazinyl) benzylamino] -6-nitroquinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 94 is reduced by lithium aluminum hydride.

XH-NMR (DMSO-d6) d (ppm): 1.31 (3H, t, J = 7.1 Hz), 2.10-2.27 (2H, m), 2.81 (3H, s), 3.09-3.18 (2H, m), 3.20-3.42 (8H, m), 4.87 (2H, d, J = 4.3 Hz), 6.87 (1H, s), 7.04-7.10 (1H, m), 7.21-7.30 (3H, m), 7.76 (lH, t, J = 5.1 Hz), 8.33 (1H, s), 9.17 (1H, t, J = 4.3 Hz), 9.36 (1H, s).

Reference Example 96 2- [2- (2-Hydroxyethoxy) ethylamino] benzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and 2- (2-aminoethoxy) ethanol.

-NRM (CDC13) d (ppm): 2.50 (1H, br), 3.34-3.47 (3H, m), 3.60-3.69 (2H, m), 3.70-3.80 (4H, m), 6.67-6.70 (2H, m), 7.35-7.42 (2H, m).

Reference Example 97 7-Ethylamino-4-. { 2- [2- (2-hydroxyethoxy) ethylamino] enylamino} -6-nitroquinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 96 is reduced by lithium aluminum hydride.

XH-NMR (DMSO-d6) d (ppm): 1.27 (3H, t, J = 7.1 Hz), 3.21-3.30 (2H, m), 3. 36-3.45 (6H, m), 3.58 (2H, t, J = 5.8 Hz), 4.56 (1H, br), 4.63 (2H, d, J = 5.9 Hz), 5.67 (1H, br), 6.55-6.61 (2H, m), 6.87 (1H, s), 7. 08-7.16 (2H, m), 7.77 (1H, t, J = 5.3 Hz), 8.38 (1H, s), 9.10 (1H, t, J = 5.9 Hz), 9.26 (lH, s).

Reference Example 98 7-Methylamino-6-nitro-4 (3H) -quinazoline The 7-chloro-6-nitro-4 (3H) -quinazoline (6.06 g, 26.9 mmol) is heated at 110 ° C in dimethyl sulfoxide (20 ml). A solution of 40% aqueous methylamine (80 ml) is added intermittently at the same temperature and the mixture is stirred for 30 minutes. After the reaction is complete, the reaction mixture is cooled, and therefore the crystal thus precipitated is collected, washed with methanol and dried (5.38 g).

-NRM (DMS0-d6) d (ppm): 3.04 (3H, d, J = 4.0 Hz), 6.90 (lH, s), 8.24 (1H, s), 8.28 (1H, br), 8.81 (1H, s) ), 12.00 (1H, br).

Reference Example 99 4- [2- (4-Hydroxymethylpiperidino) benzylamino] -7-methylamino-6-nitroquinazoline The compound (7.0 g, 31.8 mmol) obtained in Reference Example 98 and N, N-diisopropylethylamine (10 ml, 57.4 mmol) is suspended in phosphorus oxychloride (80 ml, 858 mmol) and the mixture is heated to 110 ° C for 2 hours under an argon atmosphere to form a clear solution. After it is confirmed that the starting material disappears, unreacted phosphorus oxychloride is removed under reduced pressure. After the residue is subjected to azeotropic distillation with toluene, the resulting oily substances are dissolved in the minimum required amount of tetrahydrofuran. The tetrahydrofuran solution obtained is poured into ice cold water with a sufficient amount of sodium hydrogen carbonate, followed by extraction with ethyl acetate. The organic layer is dried (over anhydrous magnesium sulfate), and the drying agent is filtered. The filtrate is concentrated under reduced pressure to give orange solids.

The title compound is obtained from the above orange solids and a compound obtained after the compound in Reference Example 13 is reduced by lithium aluminum hydride.

XH-NMR (DMSO-d6) d (ppm): 1.28-1.56 (3H, m), 1.71-1.80 (2H, m), 2.52-2.73 (2H, m), 2.99 (3H, d, J = 4.6 Hz ), 3.01-3.12 (2H, m), 3. 23-3.42 (2H, m), 4.47 (1H, br), 4.84 (2H, d, J = 5.3 Hz), 6.82 (1H, s), 6.96-7.02 (1H, m), 7.11-7.25 (3H, m), 7.93 (1H, br), 8.28 (1H, s), 9.08 (1H, t, J = 5.3 Hz), 9.31 (1H, s).

Reference Example 100 2- (2-Furylmethylamino) benzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and 2- (aminomethyl) furan.

? -NRM (CDC13) d (ppm): 4.41 (2H, s), 4.60 (1H, br), 6.25-6.27 (1H, m), 6.32-6.34 (lH, m), 6.68-6.77 (2H, m ), 7.35-7.41 (3H, m).

Reference Example 101 7-Ethylamino-4- [2- (2-furylmethylamino) benzylamino] -6-nitroquinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 100 is reduced by lithium aluminum hydride.

-NMR (CDCl 3) d (ppm): 1.39 (3H, t, J = 7.1 Hz), 3.31-3.41 (2H, m), 4. 28 (2H, s), 4.84 (2H, s), 6.18-6.20 (1H, m), 6.29-6.32 (1H, m), 6. 68-6.74 (2H, m), 7.03 (1H, s), 7.19-7.31 (4H, m), 7.73 (1H, br), 8.24 (1H, s), 8.78 (1H, s), 9.26 (1H, s).

Reference Example 102 2- (1, 2, 3, 4-Tetrahydroisoquinolin-2-yl) benzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and 1, 2, 3, 4-tetrahydroisoquinoline.

-NRM (CDC13) d (ppm): 3.07-3.11 (2H, m), 3.65-3.69 (2H, m), 4.41 (2H, s), 6.93-6.99 (1H, m), 7.05-7.21 (5H, m), 7.43-7.50 (1H, m), 7.58 (1H, dd, J = 1.7 Hz, 7.6 Hz).

Reference Example 103 7-Ethylamino-6-nitro-4- [2- (1,2,3, -tetrahydroisoquinolin-2-yl) benzylamino] quinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 102 is reduced by lithium aluminum hydride.

-NRM (CDCl 3) d (ppm): 1.38 (3H, t, J = 7.3 Hz), 3.10-3.15 (2H, m), 3.31-3.42 (4H, m), 4.21 (2H, s), 5.01 (2H , d, J = 4.0 Hz), 6.98 (1H, s), 7.00-7.20 (5H, m), 7.25-7.39 (3H, m), 7.65 (1H, br), 8.11 (1H, t, J = 4.0 Hz), 8.41 (1H, s), 8.47 (lH, s).

Reference Example 104 2- (2-Tetrahydrofurylmethylamino) benzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and 2- (tetrahydrofuryl) methylamine.

? -NRM (CDC13) d (ppm): 1.60-1.73 (lH, m), 1.86-2.11 (3H, m), 3.17-3.24 (1H, m), 3.31-3.47 (1H, m), 3.75-3.81 (1H, m), 3.83-3.96 (1H, m), 4.09-4.19 (1H, m), 4.39 (1H, br), 6.63-6.72 (2H, m), 7.27-7.40 (2H, m).

Reference Example 105 7-Ethylamino-6-nitro-4- [2- (2-tetrahydrofurylmethylamino) benzylamino] quinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 104 is reduced by lithium aluminum hydride.

XH-NMR (CDC13) d (ppm): 1.40 (3H, t, J = 7.3 Hz), 1.53-1.63 (1H, m), 1.80-2.01 (3H, m), 3.03-3.11 (1H, m), 3.20-3.26 (lH, m), 3.32-3.43 (2H, m), 3.64-3.78 (2H, m), 4.02-4.09 (lH, m), 4.83 (2H, br), 5.20 (1H, s), 6.66-6.73 (2H, m), 6.80 (1H, s), 7.02 (1H, s), 7.19-7.26 (2H, m), 7.72 (1H, br), 8.53 (1H, s), 8.79 (1H, s).

Reference Example 106 2- (2-thienylmethylamino) benzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and 2-aminomethylthiophene.

? -NRM (CDC13) d (ppm): 4.61 (2H, s), 5.60 (1H, br), 6.69-6.75 (2H, m), 6.95-7.03 (2H, m), 7.24 (1H, d, J = 7.6 Hz), 7.34-7.43 (2H, m).

Reference Example 107 7-Ethylamino-6-nitro-4- [2- (2-thienylmethylamino) benzylamino] quinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 106 it is reduced by lithium aluminum hydride.

? -NRM (CDCl3) d (ppm): 1.39 (3H, t, J = 7.3 Hz), 3.29-3.39 (2H, m), 4.47 (2H, d, J = 4.3 Hz), 4.83 (2H, d, J = 5.9 Hz), 6.08 (lH, br), 6.40 (1H, t, J = 4.3 Hz), 6.69-6.75 (2H, m), 6.91-6.95 (3H, m), 7.17-7.26 (3H, m ), 7.68 (1H, t, J = 5.9 Hz), 8.11 (1H, s), 8.79 (1H, s).

Reference Example 108 2- (2-Phenylaminoethylamino) benzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and N-phenylethylenediamine.

-NMR (CDCl 3) d (ppm): 3.41-3.65 (4H, m), 3.80 (1H, br), 4.79 (1H, br), 6.67-6.80 (5H, m), 7.16-7.24 (2H, m) , 7.34-7.41 (2H, m).

Reference Example 109 7-Ethylamino-6-nitro-4- [2- (2-phenylaminoethylamino) benzylamino] quinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 108 is reduced by lithium aluminum hydride.

? -NRM (CDC13) d (ppm): 1.36 (3H, t, J = 7.3 Hz), 3.23-3.43 (7H, m), 4.80 (2H, d, J = 4.6 Hz), 5.60 (1H, br) , 6.45-6.49 (2H, m), 6.59-6.69 (3H, m), 6.80-6.92 (2H, m), 7.02-7.09 (2H, m), 7.17-7.25 (2H,), 7.65 (1H, t , J = 4.6 Hz), 8.35 (1H, s), 8.70 (1H, s).

Reference Example 110 2- (4-Hydroxymethylpiperidino) benzonitrile The lithium aluminum hydride (0.90 g, 23.7 mmol) is suspended in tetrahydrofuran (20 ml), followed by stirring under cooling with ice in an argon gas atmosphere. A solution of 2- (4-ethoxycarbonylpiperidino) benzonitrile (6.00 g, 23.3 mmol) obtained in Reference Example 13, dissolved in tetrahydrofuran (50 ml), is added thereto either dropwise or by portions. After the reaction is complete, the solution is stirred for 1 hour at the same temperature. After the reaction is complete, the reaction mixture is cooled and sodium carbonate decahydrate is added thereto until the foaming ceases. Then, the insoluble compounds are filtered and the filtrate is concentrated to give the title compound (5.0 g).

XH-NMR (CDC13) d (ppm): 1.43-1.74 (4H, m), 1.83-1.92 (2H, m), 2.77-2.93 (2H, m), 3.53-3.69 (4H, m), 6.94-7.04 (2H, m), 7.43-7.53 (1H, m), 7.55 (1H, d, J = 7.9 Hz).

Reference Example 111 2- (4-Methoxymethylpiperidino) benzonitrile The compound (2.94 g, 13.6 mmol) obtained in Reference Example 110 is dissolved in N, N-dimethylformamide (14 ml) under cooling with ice and sodium hydride (40% in oil, 0.83 g, 21%) is added thereto. mmoles), the mixture is stirred for 2 hours at the same temperature, and methyl iodide is added thereto (1.3 ml, 20.9 mmol). Then, the mixture is stirred at 60 ° C for 20 minutes. After the reaction is complete, the reaction mixture is poured into cold water with ice and extracted with ether, and the organic layer is dried (over anhydrous magnesium sulfate) and the organic layer is concentrated and purified by chromatography on silica gel column (chloroform / ethyl acetate = 10/1) to give the title compound (3.01 g, 96%).

-NRM (CDC13) d (ppm): 1.43-1.58 (2H, m), 1.68-1.79 (1H, m), 1.80-1.90 (2H, m), 2.75-2.84 (2H, m), 3.29 (2H, d, J = 6.3 Hz), 3.36 (3H, s), 3.53-3.62 (2H, m), 6.93-7.12 (2H, m), 7.41-7.50 (1H, m), 7.53 (1H, d, J = 7.6 Hz).

Reference Example 112 7-Ethylamino-4- [2- (4-methoxymethylpiperidino) benzylamino] -6-nitroquinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 111 is reduced by lithium aluminum hydride.

XH-NMR (DMSO-d6) d (ppm): 1.29 (3H, t, J = 7.1 Hz), 1.31-1.42 (2H, m), 1.67-1.77 (3H, m), 2.62-2.72 (2H, m ), 3.05-3.10 (2H, m), 3.18 (2H, d, J = 4.3 Hz), 3.25 (3H, s), 3.34-3.44 (2H, m), 4.83 (2H, d, J = 5.3 Hz) , 6.87 (1H, s), 7.00 (1H, dd, J = 7.3 Hz, 7.3 Hz), 7.13 (1H, d, J = 7.9 Hz), 7.19-7.25 (2H, m), 7.76 (1H, t, J = 5.4 Hz), 8.33 (1H, s), 9.10 (lH, t, J = 5.3 Hz), 9.31 (1H, s).

Reference Example 113 2- (4-Ethoxymethylpiperidino) benzonitrile According to a manner similar to that in Reference Example 111, the title compound is obtained from the compound obtained in Reference Example 110 and ethyl iodide.

-NRM (CDC13) d (ppm): 1.18 (3H, t, J = 7.1 Hz), 1.43-1.57 (2H, m), 1.70-1.81 (1H, m), 1.86-1.92 (2H, m), 2.74 -2.84 (2H, m), 3.33 (2H, d, J = 6.6 Hz), 3.49 (2H, q, J = 7.1 Hz), 3.57-3.76 (2H, m), 6.92-7.02 (2H, m), 7.44 (1H, dd, J = 7.3 Hz, 8.6 Hz), 7.53 (1H, d, J = 7.6 Hz).

Reference Example 114 4- [2- (4-? Oxymethylpiperidino) benzylamino] -7-ethylamino-nitroquinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 113 is reduced by lithium aluminum hydride.

-NRM (DMSO-d6) d (ppm): 1.12 (3H, t, J = 6.9 Hz), 1.26-1.42 (5H, m), 1.60-1.79 (3H, m), 2.62-2.72 (2H, m) , 3.06-3.15 (2H, m), 3.27 (2H, d, J = 5.9 Hz), 3.34-3.46 (4H, m), 4.84 (2H, d, J = 5.0 Hz), 6.87 (1H, s), 7.00 (1H, dd, J = 7.3 Hz, 7.6 Hz), 7.13 (1H, d, J = 7.9 Hz), 7.19-7.25 (2H, m), 7.75 (1H, t, J = 5.3 Hz), 8.33 ( 1H, s), 9.09 (1H, t, J = 5.0 Hz), 9.31 (1H, s).

Reference Example 115 4- (2-Aminobenzylamino) -7-ethylamino-6-nitroquinazoline 4-Chloro-7-ethylamino-6-nitroquinazoline (5.00 g, 19.8 mmol), triethylamine (8.3 ml, 60.9 mmol), and 2-aminobenzylamine (2.9 g, 23.8 mmol) are stirred at room temperature overnight in tetrahydrofuran. After the reaction is complete, the solution is concentrated under reduced pressure, and the resulting solids are washed with methanol to give the title compound (5.23 g, 78%).

-NMR (DMSO-dg) d (ppm): 1.28 (3H, t, J = 7.1 Hz), 3.33-3.45 (4H, m), 4.59 (2H, br), 5.27 (lH, br), 6.52 (1H , dd, J = 7.3 Hz, 7.6 Hz), 6.64 (1H, d, J = 7.9 Hz), 6.85 (1H, s), 6.96 (1H, dd, J = 7.3 Hz, 7.9 Hz), 7.08 (1H, d, J = 7.6 Hz), 7.77 (1H, t, J = 5.3 Hz), 8.34 (1H, s), 9.27 (1H, s).

Reference Example 116 4- [2- (tert-Butoxycarbonylamino) benzylamino] -7-ethylamino-6-nitroquinazoline The compound (2.50 g, 7.40 mmol) obtained in Reference Example 115 is suspended in tetrahydrofuran (150 ml), and di-tert-butyldicarbonate (7.2 ml, 31.3 mmol) and triethylamine are added thereto, followed by stirring all the night at room temperature. After the reaction is complete, the resulting solution is concentrated under reduced pressure and the resulting solids are purified by silica gel column chromatography (chloroform / ethyl acetate = 5/1) to give the title compound (2.80 g. , 87%).

? -NRM (CDC13) d (ppm): 1.37 (3H, t, J = 7.3 Hz), 1.56 (9H, s), 3. 31-3.39 (2H, m), 4.81 (2H, d, J = 5.6 Hz), 5.62 (1H, br), 6.95-7.10 (2H, m), 7.15-7.30 (2H, m), 7.38 (1H, d, J = 7.3 Hz), 7.73-7.88 (2H, m), 8.57 (1H, s), 8.93 (1H, s).

Reference Example 117 8- [2- (tert-Butoxycarbonylamino) benzylamino] -3-ethyl-2,3-dihydro-1-H-imidazo [4, 5-g] quinazolin-2-thione.

The compound (1.50 g, 3.42 mmol) obtained in Reference Example 116 is suspended in a mixed solvent of methanol (50 ml) and tetrahydrofuran (75 ml), thereto added 10% palladium carbon catalyst (0.2 g). ), and the mixture is stirred overnight in an atmosphere of hydrogen gas. After the reaction is completed, the catalyst is filtered with a filtration aid, then carbon disulfide is added to the filtrate (10 mL, 166 mmol) and triethylamine (10.0 mL, 71.8 mmol), and the mixture is stirred at room temperature overnight. After the reaction is complete, the reaction mixture is concentrated under reduced pressure and the resulting solids are washed with methanol and purified by recrystallization (N, N-dimethylformamide / water) to give the title compound (1.04 g, %).

XH-NMR (DMSO-dg) d (ppm): 1.30 (3H, t, J = 6.9 Hz), 1.50 (9H, s), 4.35 (2H, d, J = 6.9 Hz), 4.69 (2H, d, J = 5.9 Hz), 7.03 (1H, dd, J = 7.3 Hz, 7.6 Hz), 7.23 (1H, dd, J = 7.3 Hz, 8.2 Hz), 7.37 (1H, d, J = 7.6 Hz), 7.62 ( 1H, s), 7.73 (1H, d, J = 8.2 Hz), 8.01 (1H, s), 8.44 (1H, s), 8.98 (1H, t, J = 5.9 Hz), 10.28 (1H, br), 13.30 (1H, s).

Reference Example 118 2-Cyclobutylaminobenzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and cyclobutylamine.

XH-NMR (CDC13) d (ppm): 1.75-1.99 (4H, m), 2.40-2.50 (2H, m), 3.91-4.01 (1H, m), 4.50 (1H, br), 6.57 (1H, d) , J = 8.6 Hz), 6.65 (1H, dd, J = 7.3 Hz, 7.9 Hz), 7.32-7.40 (2H, m).

Reference Example 119 4- (2-Cyclobutylaminobenzylamino) -7-ethylamino-6-nitroquinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 118 is reduced by lithium aluminum hydride.

XH-NMR (CDCl 3) d (ppm): 1.38 (3H, t, J = 7.3 Hz), 1.71-1.89 (4H, m), 2.30-2.41 (2H, m), 3.33-3.38 (2H, m), 3.81-3.89 (1H, m), 4.84 (2H, br), 5.65 (1H, br), 6.51 (1H, d, J = 7.9 Hz), 6.65 (1H, dd, J = 7.3 Hz, 7.6 Hz), 6.80 (1H, br), 7.01 (1H, s), 7.15-7.24 (2H, m), 7.73 (1H, t, J = 4.8 Hz), 8.53 (1H, s), 8.80 (1H, s).

Reference Example 120 2- (Exo-2-Bicyclo [2.2.1] etylamino) benzonitrile According to a manner similar to that in Reference Example 12, the title compound is synthesized from 2-fluorobenzonitrile and exo-2-aminonorbornane.

'-H-NMR (CDC13) d (ppm): 1.13-1.32 (4H,), 1.46-1.61 (3H, m), 1.81-1.90 (1H, m), 2.26-2.38 (2H, m), 3.26- 3.30 (1H,), 4.39 (1H, br), 6.60-6.67 (2H, m), 7.28-7.39 (2H, m).

Reference Example 121 4- [2- (Exo-2-Bicyclo [2.2.1] hetylamino) benzylamino] -7-ethylamino-6-nitroquinazoline The title compound is obtained from 4-chloro-7-ethylamino-6-nitroquinazoline and a compound obtained after the compound in Reference Example 120 is reduced by lithium aluminum hydride.

? -NRM (CDC13) d (ppm): 1.04-1.27 (5H, m), 1.34-1.55 (5H, m), 1.71-1.78 (1H, m), 2.17-2.23 (2H, m), 2.40 (1H , br), 3.19-3.21 (1H, m), 3.28-3.35 (2H, m), 4.73-4.91 (2H, m), 6.55-6.64 (2H, m), 6.85 (1H, br), 6.96 (1H , s), 7.16-7.21 (2H, m), 7.70 (1H, t, J = 4.6 Hz), 8.49 (1H, s), 8.78 (1H, s).

Example 1 2 3-Ethyl-8- (2-methylaminobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 1) The 7-ethylamino-4- (2-methylaminobenzylamino) -6-nitroquinazoline (4.00 g, 11.4 mmol) obtained in Reference Example 28 is suspended in a mixed solvent of methanol (100 ml) and tetrahydrofuran (150 ml). 10% palladium on carbon catalyst (0.40 g) is added to this suspension, and the mixture is stirred overnight under an atmosphere of hydrogen gas. After the reaction is complete, the catalyst is filtered with a filtration aid and the resulting filtrate is divided equally. One of the equal parts is concentrated under reduced pressure, then the resulting concentrated residue is dissolved in acetonitrile (100 ml), and N, N'-carbonyldiimidazole (2.80 g, 17.3 mmol) is added thereto, followed by stirring for 5 hours. under heating at reflux. After the reaction is complete, the solvent is removed under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent: chloroform / methanol = 100) to give a free base (1.31 g) of the title compound. The resulting free base is suspended in methanol (50 ml), and an excess amount of 4N-hydrochloric acid-ethyl acetate is added thereto under cooling with ice. The solution is concentrated to a medium and the precipitated crystal thus washed with ether-ethanol to give the title compound (1.48 g, 62%).

'H-NMR (DMSO-d6) d (ppm): 1.28 (3H, t, J = 7.2 Hz), 2.92 (3H, s), 3.95 (2H, q, J = 7.2 Hz), 4.60 (1H, br ), 4.90 (2H, d, J = 4.0 Hz), 6.94-7.05 (2H, m), 7.26-7.35 (2H, m), 7.49 (1H, s), 8.22 (1H, s), 8.84 (1H, s), 10.61 (1H, t, J = 4.0 Hz), 11.98 (1H, s).

Example 2 2 3-Ethyl-8- (4-methylaminobenzylamino) -2,3-dihydro-1H-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 2) According to a manner similar to that in Example 1, the title compound is obtained from the compound as the starting material obtained in Reference Example 29.

-NRM (DMSO-dg) d (ppm): 1.24 (3H, t, J = 7.3 Hz), 2.80 (3H, s), 3.60 (1H, br), 3.91 (2H, q, J = 7.3 Hz), 4.88 (2H, d, J = 5.6 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.45 (2H, d, J = 8.3 Hz), 7.50 (1H, s), 8.19 (1H, s), 8.78 (1H, s), 10.62 (lH, t, J = 5.6 Hz), 12.02 (1H, s).

Example 3 2 8- (4-Benzylaminobenzylamino) -3-ethyl-2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 3) According to a manner similar to that in Example 1, the title compound is obtained from the compound as the starting material obtained in Reference Example 30.

XH-NMR (DMSO-d6) d (ppm): 1.27 (3H, t, J = 7.2 Hz), 3.94 (2H, q, J = 7.2 Hz), 4.37 (2H, s), 4.83 (2H, d, J = 5.4 Hz), 6.90-7.00 (2H, m), 7.20-7.45 (8H, m), 7.48 (1H, s), 8.15 (1H, s), 8.78 (1H, s), 10.46 (1H, t , J = 5.4 Hz), 11.98 (1H, s).

Example 4 2 3-Ethyl-8- (4-isopropylaminobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 4) According to a manner similar to that in Example 1, the title compound is obtained from the compound as the starting material obtained in Reference Example 31.

? -NRM (DMSO-d6) d (ppm): 1.23-1.31 (9H, m), 3.61-3.66 (2H, m), 3.95 (2H, q, J = 7.3 Hz), 4.94 (2H, d, J = 5.6 Hz), 7.41-7.53 (5H, m), 8.17 (1H, s), 8.81 (1H, s), 10.53 (1H, t, J = 5.6 Hz), 11.99 (lH, s).

Example 5 2 3-Ethyl-8- (4-propylaminobenzylamino) -2,3-dihydro-1H-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 5) According to a manner similar to that in Example 1, the title compound is obtained from the compound as the starting material obtained in Reference Example 32.

? -NRM (DMSO-dg) d (ppm): 0.93 (3H, t, J = 7.4 Hz), 1.27 (3H, t, J = 7.1 Hz), 1.58-1.71 (2H, m), 3.10-3.16 ( 2H, m), 3.60 (1H, br), 3.94 (2H, q, J = 7.1 Hz), 4.90 (2H, d, J = 5.6 Hz), 7.29-7.35 (2H,), 7.43-7.48 (3H, ), 8.17 (lH, s), 8.81 (1H, s), 10.54 (1H, t, J = 5.6 Hz), 12.01 (1H, s).

Example 6 2 3-Ethyl-8- (4-ethylaminobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 6) According to a manner similar to that in Example 1, the title compound is obtained from the compound as the starting material obtained in Reference Example 33.

? -NRM (DMSO-dg) d (ppm): 1.20-1.30 (6H, m), 3.23 (2H, q, J = 6.9 Hz), 3.61 (1H, br), 3.95 (2H, q, J = 7.3) Hz), 4.91 (2H, d, J = 5.6 Hz), 7.29-7.40 (2H, m), 7.44-7.50 (3H, m), 8.15 (1H, s), 8.81 (1H, s), 10.49 (1H , t, J = 5.6 Hz), 11.99 (1H, s).

Example 7 3 3-Ethyl-8- [2- (2-morpholinoethylamino) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 7) According to a manner similar to that in Example 1, the title compound is obtained from the compound obtained in Reference Example 34.

-NRM (DMSO-d6) d (ppm): 1.27 (3H, t, J = 6.9 Hz), 3.10-3.30 (2H, m), 3.35-3.60 (6H, m), 3.80-4.00 (6H, m) , 4.81 (2H, d, J = 5.4 Hz), 5.70 (1H, br), 6.63 (1H, dd, J = 7.4 Hz, 7.4 Hz), 6.74 (1H, d, J = 7.9 Hz), 7.14 (1H , dd, J = 7.4 Hz, 7.9 Hz), 7.22 (lH, d, J = 7.4 Hz), 7.51 (1H, s), 8.31 (1H, s), 8.83 (1H, s), 10.65 (1H, t , J = 5.4 Hz), 12.00 (1H, s).

Example 8 3 3-Ethyl-8- [2- (3-morpholinopropylamino) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 8) According to a manner similar to that in Example 1, the title compound is obtained from the compound obtained in Reference Example 35.

XH-NMR (DMSO-dg) d (ppm): 1.29 (3H, t, J = 7.2 Hz), 2.20-2.28 (2H, m), 3.05-3.20 (2H, m), 3.27-3.51 (6H, m ), 3.85-4.00 (6H, m), 4.89 (2H, d, J = 5.4 Hz), 5.70 (lH, br), 6.82 (lH, dd, J = 6.9 Hz, 6.9 Hz), 6.94 (1H, d , J = 7.9 Hz), 7.21 (1H, dd, J = 6.9 Hz, 7.9 Hz), 7.35 (1H, d, J = 6.9 Hz), 7.51 (lH, s), 8.30 (lH, s), 8.90 ( 1H, s), 10.74 (1H, t, J = 5.4 Hz), 11.79 (1H, s).

Example 9 2 3-Ethyl-8- [2- (2-hydroxyethylamino) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 9) The compound (0.91 g, 2.38 mmol) obtained in Example 36 of Reference is suspended in a mixed solvent of methanol (90 ml) and tetrahydrofuran (72 ml), palladium in 10% carbon is added thereto. (50% water content, 0.50 g), and the mixture is stirred overnight in an atmosphere of hydrogen gas. After the reaction is complete, the catalyst is filtered with a filtration aid and the resulting filtrate is concentrated under reduced pressure. The resulting concentrated residue is dissolved in N, N-dimethylacetamide (37 ml), and urea is added thereto (1.21 g, 20.1 mmol), followed by stirring at 120 ° C for 4 and then at 160 ° C for 6 hours. After the reaction is complete, the solvent is removed under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent: chloroform / methanol = 20) to give a free base (0.45 g) of the Title. The resulting free base is suspended in methanol (10 ml), and an excess amount of 4N-hydrochloric acid-ethyl acetate is added thereto under cooling with ice. The solution is concentrated to a medium and the precipitated crystal is washed with ether-ethanol to give the title compound (0.28 g, 26%).

'-H-NMR (DMSO-d6) d (ppm): 1.27 (3H, t, J = 7.2 Hz), 3.37-3.42 (2H, m), 3.74-3.78 (2H, m), 3.93 (2H, q , J = 7.2 Hz), 4.91 (2H, d, J = 5.0 Hz), 4.98 (1H, br), 6.30-6.70 (1H, br), 7.05 (1H, dd, J = 6.9 Hz, 7.3 Hz), 7.18 (1H, d, J = 7.6 Hz), 7.31 (1H, dd, J = 7.3 Hz, J = 7.6 Hz), 7.44 (1H, d, J = 6.9 Hz), 7.53 (1H, s), 8.25 ( 1H, s), 8.85 (1H, s), 10.83 (1H, br), 12.04 (1H, s).

Example 10 2 3-Ethyl-8- [2- (2-methoxyethylamino) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 10) According to a manner similar to that in Example 1, the title compound is obtained from the compound as the starting material obtained in Reference Example 38.

XH-NMR (DMSO-dg) d (ppm): 1.28 (3H, t, J = 7.2 Hz), 3.27 (3H, s), 3. 42-3.49 (2H, m), 3.63 (2H, t, J = 5.4 Hz), 3.94 (2H, q, J = 7.2 Hz), 4.88 (2H, d, J = 5.4 Hz), 6.00-6.40 (1H , m), 6.93 (1H, dd, J = 7.4 Hz, 7.4 Hz), 7.03 (1H, d, J = 7.9 Hz), 7.26 (lH, dd, J = 7.4 Hz, 7.9 Hz), 7.38 (1H, d, J = 7.4 Hz), 7.54 (1H, s), 8.23 (1H, s), 8.82 (1H, s)., 10.68 (1H, br), 12.00 (1H, s).

Example 11 1 3-Ethyl-8- (2-morpholinobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 11) The 7-ethylamino-4- (2-morpholinobenzylamino) -6-nitroquinazoline (3.10 g, 7.60 mmol) obtained in Reference Example 39 is suspended in a mixed solvent of methanol (100 ml) and tetrahydrofuran (150 ml). 10% palladium on carbon catalyst (0.31 g) is added to this suspension, and the mixture is stirred for 8 hours at room temperature in a hydrogen gas atmosphere. After the reaction is complete, the catalyst is filtered with a filtration aid and the resulting filtrate is divided equally. One of the equal parts is concentrated under reduced pressure, then the resulting concentrated residue is dissolved in acetonitrile (100 ml), and N.N1-carbonyldiimidazole (1.80 g, 11.1 mmol) is added thereto, followed by stirring for 6 hours under refluxing. After the reaction is complete, the solvent is removed under reduced pressure and the resulting solids are collected and washed with water and methanol. Further the solids are dried to give a free base (1.27 g) of the title compound. The resulting free base is suspended in methanol (50 ml), and an excess amount of 4N-hydrochloric acid-ethyl acetate is added thereto under cooling with ice. The solution is concentrated to a medium and the precipitated crystal is washed with ether-ethanol to give the title compound (1.50 g, 89%). 1 H-NMR (DMSO-dg) d (ppm): 1.28 (3H, t, J = 7.1 Hz), 2.89-2.92 (4H, m), 3.73-3.77 (4H, m), 3.96 (2H, q, J = 7.1 Hz), 5.05 (2H, d, J = 5.3 Hz), 7.15 (1H, dd, J = 7.3 Hz, 7.9 Hz), 7.31-7.43 (3H, m), 7.58 (lH, s), 8.26 (1H, s), 8.91 (1H, s), 10.37 (lH, br), 12. 06 (1H, s).

Example 12 2 3-Ethyl-8- [2- (4-hydroxymethylpiperidino) benzylamino] -2,3-dihydro-lH-imidazo [4,5-g] quinazolin-2-one hydrochloride (Compound 12) According to a manner similar to that in Example 9, the title compound is obtained from the compound obtained in Reference Example 40.

? -NMR (DMSO-d6) d (ppm): 1.30 (3H, t, J = 7.2 Hz), 1.70-2.05 (5H, m), 3.20-3.60 (6H, m), 3.94 (2H, q, J = 7.2 Hz), 4.90 (1H, br), 5.12 (2H, s), 7.27-7.60 (4H, m), 7.56 (1H, s), 8.21 (1H, s), 8.81 (1H, s), 11.70 (1H, br), 11.98 (1H, s).

Example 13 2 3-Ethyl-8- (2-piperidinobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 13) According to a manner similar to that in Example 11, the title compound is obtained from the compound obtained in Reference Example 41.

XH-NMR (DMSO-d6) d (ppm): 1.28 (3H, t, J = 7.1 Hz), 1.62-1.75 (2H, m), 1.80-1.98 (4H, m), 4.00 (2H, q, J = 7.1 Hz), 4.20-4.43 (4H, m), 5.08 (2H, d, J = 5.3 Hz), 7.23-7.34 (1H, m), 7.36-7.58 (3H, m), 7.62 (1H, s) , 8.28 (1H, s), 8.92 (1H, s), 10.60 (1H, br), 12.08 (1H, s).

Example 14 3 3-Ethyl-8- [2- (4-methyl-1-piperazinyl) benzylamino] -2,3-dihydro-1H-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 14) According to a manner similar to that in Example 11, the title compound is obtained from the compound obtained in Reference Example 42.

XH-NMR (DMSO-d6) d (ppm): 1.28 (3H, t, J = 7.1 Hz), 2.85 (3H, s), 3.23-3.44 (6H, m), 3.50-3.54 (2H, m), 3.95 (2H, q, J = 7.1 Hz), 5.03 (2H, d, J = 5.3 Hz), 7.10 (1H, dd, J = 6.6 Hz, 6.9 Hz), 7.22 (1H, d, J = 7.6 Hz) , 7.27-7.33 (2H, m), 7.57 (1H, s), 8.27 (1H, s), 8.97 (1H, s), 10.51 (1H, t, J = 5.3 Hz), 12.04 (1H, s).

Example 15 1 3-Ethyl-8- (2-thiomorpholinobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 15) According to a manner similar to that in Example 11, the title compound is obtained from the compound obtained in Reference Example 43.

? -NMR (DMSO-d6) d (ppm): 1.30 (3H, t, J = 7.2 Hz), 2.80-2.95 (4H, m), 3.15-3.28 (4H, m), 3.93 (2H, q, J = 7.2 Hz), 5.02 (2H, d, J = 5.4 Hz), 7.07 (1H, dd, J = 6.9 Hz, 7.4 Hz), 7.21-7.32 (3H, m), 7.56 (1H, s), 8.21 ( 1H, s), 8.77 (lH, s), 10.36 (1H, t, J = 5.4 Hz), 11.97 (1H, s).

Example 16 2 3-Ethyl-8- (3-morpholinobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 16) According to a manner similar to that in Example 11, the title compound is obtained from the compound obtained in Reference Example 44.

XH-NMR (DMSO-dg) d (ppm): 1.29 (3H, t, J = 7.2 Hz), 3.23-3.31 (4H, m), 3.85-4.00 (6H, m), 4.93 (2H, d, J = 5.4 Hz), 7.11 (1H, d, J = 7.4 Hz), 7.23 (1H, d, J = 7.4 Hz), 7.32 (1H, dd, J = 7.4 Hz, 7.4 Hz), 7.42 (1H, s), 7.53 (1H, s), 8.21 (1H, s), 8.79 (1H, s), 10.57 (1H, t, J = 5.4 Hz), 11.98 (1H, s).

Example 17 2 3-Ethyl-8- (3-piperidinobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 17) According to a manner similar to that in Example 11, the title compound is obtained from the compound obtained in Reference Example 45.

XH-NMR (DMSO-d6) d (ppm): 1.29 (3H, t, J = 7.1 Hz), 1.66-1.70 (2H, m), 1.80-2.11 (4H, m), 3.35-3.49 (4H, m ), 3.96 (2H, q, J = 7.1 Hz), 4.96 (2H, d, J = 5.3 Hz), 7.45-7.55 (3H, m), 7.66-7.75 (1H, m), 7.87-7.90 (1H, m), 8.18 (1H, s), 8.82 (1H, s), 10.57 (1H, br), 12.00 (1H, s).

Example 18 3 3-Ethyl-8- [3- (4-methyl-1-piperazinyl) benzylamino) -2,3-dihydro-1H-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 18) According to a manner similar to that in Example 11, the title compound is obtained from the compound obtained in Reference Example 46.

? -NRM (DMSO-dg) d (ppm): 1.30 (3H, t, J = 7.1 Hz), 2.82 (3H, s), 3.15-3.23 (4H, m), 3.43-3.51 (2H, m), 3.74-3.82 (2H, m), 3.93 (2H, q, J = 7.1 Hz), 4.90 (2H, d, J = 5.6 Hz), 6.88-6.95 (2H, m), 7.10 (1H, s), 7.23 (1H, dd, J = 7.9 Hz, 7.9 Hz), 7.54 (1H, s), 8.24 (1H, s), 8.82 (1H, s), 10.57 (1H, t, J = 5.6 Hz), 12.00 (1H , s).

Example 19 2-Ethyl-8- (4-piperidinobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 19) According to a manner similar to that in Example 11, the title compound is obtained from the compound obtained in Reference Example 48.

XH-NMR (DMSO-dg) d (ppm): 1.29 (3H, t, J = 6.9 Hz), 1.60-1.79 (2H, m), 1.81-2.11 (4H, m), 3.35-3.49 (4H, m ), 3.96 (2H, q, J = 6.9 Hz), 4.95 (2H, d, J = 5.6 Hz), 7.49 (lH, s), 7.50-7.55 (2H, m), 7.72-7.77 (2H, m) , 8.18 (1H, s), 8.81 (lH, s), 10.58 (1H, br), 12.00 (1H, s).

Example 20 3 3-Ethyl-8- [4- (4-methyl-1-piperazinyl) benzylamino] -2,3-dihydro-1H-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 20) According to a manner similar to that in Example 11, the title compound is obtained from the compound obtained in Reference Example 49.

XH-NMR (DMSO-dg) d (ppm): 1.28 (3H, t, J = 7.1 Hz), 2.80 (3H, s), 3. 06-3.21 (4H, m), 3.41-3.50 (2H, m), 3.75-3.85 (2H, m), 3.94 (2H, q, J = 7.1 Hz), 4.84 (2H, d, J = 5.6 Hz) , 6.97 (2H, d, J = 8.9 Hz), 7.31 (2H, d, J = 8.9 Hz), 7.53 (1H, s), 8.20 (lH, s),, 80 (1H, s) 10.57 (1H, t, J = 5.6 Hz), 12.00 (1H, s).

Example 21 2 3-Ethyl-8- (4-thiomorpholinobenzylamino) -2,3-dihydro-lH-imidazo [4,5-g] quinazolin-2-one hydrochloride (Compound 21) According to a manner similar to that in Example 11, the title compound is obtained from the compound obtained in Reference Example 51.

-NRM (DMSO-dg) d (ppm): 1.29 (3H, t, J = 7.2 Hz), 2.90-3.10 (4H, m), 3.55-3.70 (4H, m), 3.95 (2H, q, J = 7.2 Hz), 4.90 (2H, d, J = 5.5 Hz), 7. 35-7.47 (4H, m), 7.50 (1H, s), 8.19 (1H, s), 8.79 (lH, s), 10.55 (1H, t, J = 5.5 Hz), 11.98 (1H, s).

Example 22 2 3-Ethyl-8- (2-methylaminobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 22) 7-Etylamino-4- (2- methylaminobenzylamino) -6-nitroquinazoline (4.00 g, 11.4 mmol) obtained in Reference Example 28 is suspended in a mixed solvent of methanol (100 ml) and tetrahydrofuran (150 ml). 10% carbon palladium catalyst (0.40 g) is added to this suspension, and the mixture is stirred at room temperature overnight under a hydrogen gas atmosphere. After the reaction is complete, the catalyst is filtered with a filtration aid and the resulting filtrate is divided equally. Triethylamine (1.60 ml, 11.5 mmol) and carbon disulfide (5.10 ml, 84.7 mmol) are added to one of the equal parts (not concentrated) and the mixture is stirred at room temperature. After the reaction is complete, the solvent is removed under reduced pressure, ether is added to the resulting residue, and the precipitated crystal is collected and dried to give a free base (2.40 g) of the title compound. The resulting free base is suspended in methanol (80 ml), and an excess amount of 4N-hydrochloric acid-ethyl acetate is added thereto under cooling with ice. The solution is concentrated to a medium and the precipitated crystal is washed with ether-ethanol to give the title compound (2.15 g, 86%).

-NMR (DMSO-d6) d (ppm): 1.32 (3H, t, J = 7.2 Hz), 2.91 (3H, s), 4.10 (1H, br), 4.36 (2H, q, J = 7.2 Hz), 4.92 (2H, br), 6.91-7.02 (2H, m), 7.25-7.33 (2H, m), 7.72 (1H, s), 8.43 (1H, s), 8.89 (1H, s), 10.77 (1H, br), 13.73 (1H, s).

Example 23 2 3-Ethyl-8- (4-methylaminobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 23) The compound (5.40 g, 15.3 mmol) obtained in Reference Example 29 is suspended in a mixed solvent of methanol (700 ml) and tetrahydrofuran (900 ml). 10% carbon palladium catalyst (0.81 g) is added to this suspension, and the mixture is stirred at room temperature for 3.5 hours in a hydrogen gas atmosphere. After the reaction is complete, the catalyst is filtered with a filtration aid, and triethylamine (13.6 ml, 97.7 mmol) and carbon disulfide (51.0 ml, 847 mmol) are added to 3/4 of the resulting filtrate, and The mixture is stirred at room temperature overnight. To complete the reaction, carbon disulfide (50.0 ml, 830 mmol) is added thereto, followed by further stirring at room temperature overnight. After the reaction is complete, the solvent is removed under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent [chloroform / methanol = 80) to give the title compound. The free base is suspended in methanol (100 ml), and an excess amount of hydrochloric acid '4N-ethyl acetate is added thereto under cooling with ice. The solution is concentrated to a medium and the precipitated crystal is washed with ether-ethanol to give the title compound (0.780 g, 16%).

^ -RMN (DMS0-d6) d (ppm): 1.30 (3H, t, J = 6.9 Hz), 2.82 (3H, s), 3.60 (1H, br), 4.35 (2H, q, J = 6.9 Hz), 4.93 (2H, d, J = 5.6 Hz), 7.32 (2H, d, J = 8.3 Hz), 7.49 (2H, d, J = 8.3 Hz), 7.75 (1H, s), 8.41 (1H, s), 8.86 (1H, s), 10.83 (1H, t, J = 5.6 Hz), 13.79 (1H, s).

Example 24 2 8- (4-Benzylaminobenzylamino) -3-ethyl-2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 24) According to a manner similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 30.

-NRM (DMSO-dg) d (ppm): 1.32 (3H, t, J = 7.2 Hz), 4.31-4.37 (4H, m), 4.60 (1H, br), 4.86 (2H, d, J = 5.4 Hz ), 6.90-7.02 (2H, m), 7.20-7.43 (7H, m), 7.70 (1H, s), 8.36 (1H, s), 8.83 (1H, s), 10.83 (1H, t, J = 5.4 Hz), 13.70 (1H, s).

Example 25 2 3-Ethyl-8- (4-isopropylaminobenzylamino) -2,3-dihydro-lH-imidazo [4,5-g] quinazolin-2-thione hydrochloride (Compound 25) According to a manner similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 31.

-NRM (DMSO-dg) d (ppm): 1.24-1.34 (9H, m), 3.52-3.68 (2H, m), 4.36 (2H, q, J = 7.3 Hz), 4.97 (2H, d, J = 5.3 Hz), 7.43-7.54 (4H, m), 7.73 (1H, s), 8.39 (1H, s), 8.86 (lH, s), 10.78 (1H, t, J = 5.3 Hz), 13.75 (1H, s).

Example 26 2 3-Ethyl-8- (4-propylaminobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 26) According to a manner similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 32.

? -NRM (DMSO-dg) d (ppm): 0.93 (3H, t, J = 7.3 Hz), 1.32 (3H, t, J = 6.9 Hz), 1.60-1.70 (2H, m), 3.12 (2H, t, J = 7.4 Hz), 3.80 (1H, br), 4.36 (2H, q, J = 6.9 Hz) , 4.92 (2H, d, J = 5.3 Hz), 7.21-7.24 (2H, m), 7.40-7.44 (2H, m), 7.68 (1H, s), 8.36 (1H, s), 8.87 (lH, s ), 10.68 (1H, br), 13.76 (1H, s). FAB-MASS: m / z calculated for C2iH24N6S 392, observed 393 (M + l).

Example 27 2 3-Ethyl-8- (4-ethylaminobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 27) According to a manner similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 33.

'-H-NMR (DMSO-d6) d (ppm): 1.22-1.35 (6H, m), 3.25 (2H, q, J = 7.3 Hz), 3.60 (1H, br), 4.36 (2H, q, J = 7.3 Hz), 4.95 (2H, d, J = 5.3 Hz), 7.37-7.40 (2H,), 7.47-7.51 (2H, m), 7.70 (1H, s), 8.38 (1H, s), 8.86 ( 1H, s), 10.74 (1H, t, J = 5.3 Hz), 13.74 (1H, s).

Example 28 3 3-Ethyl-8- [2- (2-morpholinoethylamino) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 28) According to a manner similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 34.

XH-NMR (DMSO-dg) d (ppm): 1.32 (3H, t, J = 7.2 Hz), 3.10-3.30 (2H, m), 3.35-3.60 (6H, m), 3.85-4.00 (4H, m ), 4.35 (2H, q, J = 7.2 Hz), 4.60 (1H, br), 4.86 (2H, d, J = 4.9 Hz), 6.64 (1H, dd, J = 7.4 Hz, 7.9 Hz), 6.76 (1H, d, J = 7.9 Hz), 7.15 (1H, dd , J = 7.4 Hz, 8.4 Hz), 7.24 (1H, d, J = 8.4 Hz), 7.77 (1H, s), 8.53 (1H, s), 8.89 (1H, s), 10.85 (1H, t, J = 4.9 Hz), 13.75 (lH, s).

Example 29 3 3-Ethyl-8- [2- (3-morpholinopropylamino) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 29) According to a manner similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 35.

XH-NMR (DMSO-dg) d (ppm): 1.33 (3H, t, J = 7.1 Hz), 2.20-2.24 (2H, m), 3. 00-3.15 (2H, m), 3.25-3.48 (6H, m), 3.90-3.97 (4H, m), 4.35 (2H, q, J = 7.1 Hz), 4.88 (2H, d, J = 4.6 Hz) , 5.00 (1H, br), 6.73 (1H, dd, J = 7.3 Hz, 7.6 Hz), 6.82 (1H, d, J = 7.9 Hz), 7.18 (1H, dd, J = 7.6 Hz, 7.9 Hz), 7.30 (1H, d, J = 7.3 Hz), 7.74 (1H, s), 8.51 (1H, s), 8.96 (lH, s), 10.89 (1H, t, J = 4.6 Hz), 13.72 (1H, s) ).

Example 30 2 3-Ethyl-8- [2- (2-hydroxyethylamino) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 30) According to a manner similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 36.

-NRM (DMSO-dg) d (ppm): 1.32 (3H, t, J = 6.9 Hz), 3.30-3.42 (2H, m), 3.71-3.77 (2H, m), 4.35 (2H, q, J = 6.9 Hz), 4.91 (2H, br), 6.50 (1H, br), 6.70 (1H, br), 6.85-7.02 (2H, m), 7.23-7.38 (2H, m), 7.71 (1H, s), 8.39 (1H, s), 8.90 (1H, s), 10.75 (1H, br), 13.73 (1H, s).

Example 31 2 3-Ethyl-8- [4- (2-hydroxyethylamino) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 31) According to a manner similar to that in Example 22, the title compound is obtained from the compound obtained in the. Reference Example 37 XH-NMR (DMSO-d6) d (ppm): 1.32 (3H, t, J = 6.9 Hz), 3.25-3.28 (2H, m), 3.66 (2H, t, J = 5.9 Hz), 4.36 (2H, q, J = 6.9 Hz), 4.94 (2H, d, J = 5.4 Hz), 5.10 (1H, br), 6.70 (1H, br), 7.34 (2H, d, J = 8.4 Hz), 7.47 (2H, d, J = 8.4 Hz), 7.73 (1H, s), 8.40 (1H, s), 8.84 (1H, s), 10.77 (1H, t, J = 5.4 Hz), 13.72 (1H, s).

Example 32 2 3-Ethyl-8- [2- (2-methoxyethylamino) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 32) According to a manner similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 38.

XH-NMR (DMSO-dg) d (ppm): 1.32 (3H, t, J = 7.2 Hz), 3.25 (3H, s), 3.38-3.47 (2H, m), 3.60 (2H, t, J = 5.3 Hz), 4.35 (2H, q, J = 7.1 Hz), 4.90 (2H, d, J = 4.6 Hz), 5.80 (1H, br), 6.84-6.97 (2H, m), 7.22-7.24 (2H, m), 7.75 (1H, s), 8.41 (1H, s), 8.88 (1H, s), 10.82 (1H, br), 13.20 (1H, s).

Example 33 1 3-Ethyl-8- (2-morpholinobenzylamino) -2,3-dihydro-lH-imidazo [4,5-g] quinazolin-2-thione hydrochloride (Compound 33) The 7-ethylamino-4- (2-morpholinobenzylamino) -6-nitroquinazoline (2.00 g, 4.90 mmol) obtained in Reference Example 39 is suspended in a mixed solvent of methanol (100 ml) and tetrahydrofuran (150 ml). 10% carbon palladium catalyst (0.20 g) is added to this suspension, and the mixture is stirred at room temperature overnight under an atmosphere of hydrogen gas. After the reaction is complete, the catalyst is filtered with a filtration aid and triethylamine (1.40 ml, 10.1 mmol) and carbon disulfide (3.00 ml, 49.9 mmol) are added to the resulting filtrate, and the mixture is stirred at Room temperature all night. To complete the reaction, stir at 50 ° C for 2 hours. After the reaction is complete, the solvent is removed under reduced pressure, and the resulting solids are collected. The solids are recrystallized (2 times) with N, N-dimethylformamide / water and further purified by column chromatography on silica gel (eluent: chloroform / methanol = 100) to give a free base of the title compound. The resulting free base is suspended in methanol (50 ml), and an excess amount of 4N-hydrochloric acid-ethyl acetate is added thereto under cooling with ice. The solution is concentrated to a medium and the precipitated crystal is collected to give the title compound (1.66 g, 74%).

XH-NMR (DMSO-dg) d (ppm): 1.32 (3H, t, J = 6.9 Hz), 2.91-2.94 (4H, m), 3.75-3.78 (4H, m), 4.36 (2H, q, J = 6.9 Hz), 5.08 (2H, d, J = 5.3 Hz), 7.08 (1H, dd, J = 7.3 Hz, 8.9 Hz), 7.22-7.34 (3H, m), 7.77 (1H, s), 8.42 ( 1H, s), 8.85 (1H, s), 10.58 (1H, t, J = 5.3 Hz), 13.72 (1H, s).

FAB-MASS: m / z calculated for C22H24N6OS 420, observed 421 (M + l).

Example 34 2 3-Ethyl-8- [2- (4-hydroxymethylpiperidino) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 34) According to a manner similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 40.

? -NRM (DMSO-dg) d (ppm): 1.33 (3H, t, J = 6.9 Hz), 1.50-1.94 (5H, m), 3.20-3.50 (6H, m), 4.33 (2H, q, J = 6.9 Hz), 4.80 (lH, br), 5.16 (2H, d, J = 4.6 Hz), 7.15-7.60 (4H, m), 7.80 (1H, s), 8.43 (1H, s), 8.87 (1H , s), 10.89 (1H, br), 13.71 (1H, s).

FAB-MASS: m / z calculated for 448, observed 449 (M + l) Example 35 2 3-Ethyl-8- (2-piperidinobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 35) According to a manner similar to that in Example 33, the title compound is obtained from the compound obtained in Reference Example 41.

-NMR (DMSO-d6) d (ppm): 1.32 (3H, t, J = 7.1 Hz), 1.64-1.91 (6H, m), 4.32-4.50 (6H, m), 5.12 (2H, d, J = 4.3 Hz), 7.10-7.35 (1H, m), 7.40- 7.60 (3H, m), 7.77 (1H, s), 8.41 (1H, s), 8.88 (1H, s), 10.76 (1H, br), 13.73 (1H, s).

FAB-MASS: m / z calculated for C23H2gN6S 418, observed 419 (M + l).

Example 36 3 3-Ethyl-8- [2- (4-methyl-1-piperazinyl) benzylamino] -2,3-dihydro-1H-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 36) According to a manner similar to that in Example 33, the title compound is obtained from the compound obtained in Reference Example 42.

? -NMR (DMSO-d6) d (ppm): 1.32 (3H, t, J = 7.1 Hz), 2.85 (3H, s), 3.23-3.30 (6H, m), 3.46-3.52 (2H, m), 4.36 (2H, q, J = 7.1 Hz), 5.06 (2H, d, J = 5.3 Hz), 7.11 (1H, dd, J = 6.9 Hz, 7.9 Hz), 7.23 (1H, d, J = 7.6 Hz) , 7.29-7.35 (2H, m), 7.80 (1H, s), 8.47 (1H, s), 8.85 (1H, s), 10.69 (1H, t, J = 5.3 Hz), 13.75 (1H, s).

Example 37 1 3-Ethyl-8- (2-thiomorpholinobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 37) According to a manner similar to that in Example 33, the title compound is obtained from the compound obtained in Reference Example 43.

XH-NMR (DMSO-dg) d (ppm): 1.33 (3H, t, J = 6.9 Hz), 2.72-2.91 (4H, m), 3.15-3.20 (4H, m), 4.36 (2H, q, J = 6.9 Hz), 5.04 (2H, d, J = 5.4 Hz), 7.07 (1H, dd, J = 7.4 Hz, 7.4 Hz), 7.21-7.33 (3H, m), 7.76 (1H, s), 8.42 ( 1H, s), 8.84 (lH, s), 10.55 (1H, t, J = 5.4 Hz), 13.70 (1H, s).

Example 38 2 3-Ethyl-8- (3-morpholinobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 38) According to a manner similar to that in Example 33, the title compound is obtained from the compound obtained in Reference Example 44. 1H-R (DMSO-de) d (ppm): 1.33 (3H, t, J = 7.2 Hz), 3.20-3.25 (4H, m), 3. 80-3.90 (4H,), 4.36 (2H, q, J = 7.2 Hz), 4.94 (2H, d, J = 5.4 Hz), 7. 01 (1H, d, J = 7.4 Hz), 7.10 (1H, d, J = 7.9 Hz), 7.22-7.31 (2H, m), 7. 73 (1H, s), 8.40 (1H, s), 8.85 (1H, s), 10.70 (1H, t, J = 5.4 Hz), 13.70 (1H, s).

FAB-MASS: m / z calculated for C22H24N6OS 420, observed 421 (M + l).

Example 39 2 3-Ethyl-8- (3-piperidinobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 39) According to a manner similar to that in Example 33, the title compound is obtained from the compound obtained in Reference Example 45. 1 H-NMR (DMSO-d 6) d (ppm): 1.33 (3H, t, J = 7.1 Hz), 1.66-2.13 (6H, m), 3. 44-3.62 (4H, m), 4.36 (2H, q, J = 7.1 Hz), 4.98 (2H, d, J = 5.3 Hz), 7. 36-7.50 (2H, m), 7.55-7.73 (2H, m), 7.78-7.90 (1H, m), 8.40 (1H, s), 8.88 (1H, s), 10.80 (1H, br), 13.75 ( 1H, s).

FAB-MASS: m / z calculated for C23H2gN6S 418, observed 419 (M + l).

Example 40 3 3-Ethyl-8- [3- (4-methyl-1-piperazinyl) benzylamino] -2,3-dihydro-1H-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 40) According to a manner similar to that in Example 333, the title compound is obtained from the compound obtained in Reference Example 46.

^ -RM (DMSO-d5) d (ppm): 1.23 (3H, t, J = 7.1 Hz), 2.72 (3H, s), 3.06- 3.13 (4H, m), 3.39-3.42 (2H, m), 3.68-3.71 (2H, m), 4.27 (2H, q, J = 7.1 Hz), 4.83 (2H, d, J = 5.3 Hz), 6.79-6.86 (2H, m), 7.00 (1H, s), 7.14 (1H, dd, J = 7.9 Hz, 7.9 Hz), 7.65 (1H, s), 8.33 (1H, s), 8.77 (1H, s), 10.65 (1H, t, J = 5.3 Hz), 13.65 (1H , s).

Example 41 2 3-Ethyl-8- (4-morpholinobenzylamino) -2,3-dihydro-lH-imidazo [4,5-g] quinazolin-2-thione hydrochloride (Compound 41) According to a manner similar to that in Example 33, the title compound is obtained from the compound obtained in Reference Example 47. 1 H-NMR (DMSO-dg) d (ppm): 1.30 (3H, t, J = 7.1 Hz), 3.14-3.16 (4H, m), 3.76-3.80 (4H, m), 4.34 (2H, q, J = 7.1 Hz), 4.87 (2H, d, J = 5.6 Hz), 7.07 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.4 Hz), 7.72 (1H, s), 8.38 ( 1H, s), 8.86 (1H, s), 10.70 (1H, br), 13.76 (1H, s).

Example 42 2 3-Ethyl-8- (4-piperidinobenzylamino) -2,3-dihydro-1H-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 42) According to a manner similar to that in Example 33, the title compound is obtained from the compound obtained in Reference Example 48.

XH-NMR (DMSO-d6) d (ppm): 1.31 (3H, t, J = 7.1 Hz), 1.50-1.79 (2H, m), 1. 80-2.10 (4H, m), 3.50-3.90 (4H, m), 4.36 (2H, q, J = 7.1 Hz), 4.97 (2H, d, J = 5.3 Hz), 7.56 (2H, d, J = 7.9 Hz), 7.70-7.87 (3H, m), 8.41 (1H, s), 8.86 (1H, s), 10.83 (1H, br), 13.76 (1H, s).

Example 43 3 3-Ethyl-8- [4- (4-methyl-1-piperazinyl) benzylamino] -2,3-dihydro-1H-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 43) According to a manner similar to that in Example 33, the title compound is obtained from the compound obtained in Reference Example 49.

? -NMR (DMSO-d6) d (ppm): 1.31 (3H, t, J = 7.1 Hz), 2.80 (3H, s), 3.06-3.21 (4H, m), 3.41-3.49 (2H, m), 3.75-3.80 (2H, m), 4.33 (2H, q, J = 7.1 Hz), 4.87 (2H, d, J = 5.6 Hz), 6.97 (2H, d, J = 8.6 Hz), 7.32 (2H, d , J = 8.6 Hz), 7.74 (1H, s), 8.39 (1H, s), 8.86 (1H, s), 10.72 (1H, t, J = 5.6 Hz), 13.75 (1H, s).

Example 44 2 3-Ethyl-8- [4- (1-pyrrolidinyl) benzylamino] -2,3-dihydro-1H-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 44) According to a manner similar to that in Example 33, the title compound is obtained from the compound obtained in Reference Example 50.

XH-NMR (DMSO-dg) d (ppm): 1.31 (3H, t, J = 7.1 Hz), 1.99-2.05 (4H, m), 3.20-3.30 (4H, m), 4.34 (2H, q, J = 7.1 Hz), 4.85 (2H, d, J = 5.6 Hz), 6.70-6.78 (2H, m), 7.29-7.39 (2H, m), 7.73 (1H, s), 8.38 (1H, s), 8.85 (1H, s), 10.68 (1H, t, J = 5.6 Hz), 13.71 (1H, s).

Example 45 2 3-Ethyl-8- (4-thiomorpholinobenzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 45) According to a manner similar to that in Example 33, the title compound is obtained from the compound obtained in Reference Example 51. 1 H-NMR (DMSO-dg) d (ppm): 1.31 (3H, t, J = 7.2 Hz), 2.85-3.05 (4H, m), 3.55-3.70 (4H, m), 4.35 (2H, q, J = 7.2 Hz), 4.91 (2H, d, J = 5.4 Hz), 7.30-7.52 (4H, m), 7.74 (1H, s), .8.39 (1H, s), 8.86 (lH, s), 10.75 ( 1H, t, J = 5.4 Hz), 13.74 (1H, s).

Example 46 2 3-ethyl-8- Hydrochloride. { 2- [N- (2-hydroxyethyl) methylamino] benzylamino} -2, 3-dihydro-lH-imidazo [4,5-g] quinazolin-2-thione (Compound 46) According to a manner similar to that in Example 33, the title compound is obtained from the compound obtained in Reference Example 53.

? -NRM (DMSO-dg) d (ppm): 1.31 (3H, t, J = 7.1 Hz), 3.25 (3H, s), 3.80- 3.90 (4H, m), 4.20 (1H, br), 4.35 ( 2H, q, J = 7.1 Hz), 5.13 (2H, br), 7. 35-7.60 (3H, m), 7.75-7.80 (2H, m), 8.45 (1H, s), 8.99 (1H, s), 11.07 (1H, s), 13.70 (1H, s).

Example 47 2 3-Ethyl-8- [4- (3-hydroxymethylpiperidino) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 47) According to a manner similar to that in Example 33, the title compound is obtained from the compound obtained in Reference Example 55.

XH-NMR (DMSO-dg) d (ppm): 1.31 (3H, t, J = 7.1 Hz), 1.80-2.15 (3H, m), 2.20-2.60 (3H, m), 3.40-4.00 (6H, m ), 4.34 (2H, q, J = 7.1 Hz), 4.96 (2H, d, J = 5.6 Hz), 7.53-7.79 (5H, m), 8.29 (lH, s), 8.87 (lH, s), 10.75 (1H, br), 13.70 (1H, s).

Example 48 2 3-Ethyl-8- (4-morpholinobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 48) According to a manner similar to that in Example 1, the title compound is obtained from the compound as the starting material obtained in Reference Example 47.

-NRM (DMSO-dg) d (ppm): 1.26 (3H, t, J = 6.9 Hz), 3.17-3.20 (4H, m), 3.84-3.97 (6H, m), 4.87 (2H, d, J = 5.3 Hz), 7.24-7.27 (2H, m), 7.39-7.43 (2H, m), 7.53 (1H, s), 8.22 (1H, s), 8.79 (lH, s), 10.02 (1H, br), 12.03 (1H, s).

Example 49 2 3-Ethyl-8- [4- (2-hydroxyethylamino) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 49) According to a manner similar to that in Example 9, the title compound is obtained from the compound as the starting material obtained in Reference Example 37.

XH-NMR (DMSO-dg) d (ppm): 1.26 (3H, t, J = 7.1 Hz), 3.26-3.30 (2H, m), 3.64-3.68 (2H, m), 3.93 (2H, q, J = 7.1 Hz), 4.07 (1H, br), 4.91 (2H, d, J = 5.6 Hz), 6.50 (1H, br), 7.38 (2H, d, J = 8.2 Hz), 7.49 (2H, d, J = 8.2 Hz), 7.52 (1H, s), 8.23 (1H, s), 8.80 (1H, s), 10.70 (1H, br), 12.04 (1H, s).

Example 50 3 3-Ethyl-8- [2- (1-imidazolyl) benzylamino] -2,3-dihydro-IH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 50) According to a manner similar to that in Example 1, the title compound is obtained from the compound as the starting material obtained in Reference Example 57.

XH-NMR (DMSO-dg) d (ppm): 1.26 (3H, t, J = 7.3 Hz), 3.93 (2H, q, J = 7.3 Hz), 4.74 (2H, d, J = 5.3 Hz), 7.54-7.65 (4H, m), 7.80 (1H, d, J = 7.6 Hz), 7.90 (1H, s), 8.12 (lH, s), 8.25 (lH, s), 8.71 (1H, s), 9.61 (1H, s), 10.86 (1H, t, J = 5.3 Hz), 12.05 (1H, s).

Example 51 3 3-Ethyl-8- [2- (1-imidazolyl) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 51) According to a manner similar to that in Example 22, the title compound is obtained from the compound as the starting material obtained in Reference Example 57. ^ -NMR (DMSO-d6) d (ppm): 1.30 (3H, t, J = 7.1 Hz), 4.34 (2H, q, J = 7.1 Hz), 4.78 (2H, d, J = 5.0 Hz), 7.53 -7.67 (3H, m), 7.77-7.82 (2H, m), 7.90 (1H, s), 8.10 (1H, s), 8.41 (1H, s), 8.77 (1H, s), 9.60 (1H, s) ), 10.94 (1H, br), 13.78 (1H, s).

Example 52 2 8- [2- (1-Perhydroazocinyl) benzylamino] -3-ethyl-2,3-dihydro-lH-imidazo [4,5-g] quinazolin-2-one hydrochloride (Compound 52) According to a manner similar to that in Example 1, the title compound is obtained from the compound as the starting material obtained in Reference Example 59.

? -NRM (DMSO-d6) d (ppm): 1.28 (3H, t, J = 7.1 Hz), 1.60-1.90 (10H, m), 3.10-3.30 (4H, m), 3.96 (2H, q, J) = 7.1 Hz), 5.09 (2H, d, J = 5.3 Hz), 7. 00-7.40 (4H, m), 7.56 (1H, s), 8.25 (1H, s), 8.79 (1H, s), 10.54 (1H, br), 12.03 (1H, s).

Example 53 2 8- [2- (1-Perhydroazocinyl) benzylamino] -3-ethyl-2, 3-dihydro-lH-imidazo [4,5-g] quinazolin-2-thione hydrochloride (Compound 53) According to a manner similar to that in Example 22, the title compound is obtained from the compound as the starting material obtained in Reference Example 59.

-NMR (DMSO-d6) d (ppm): 1.31 (3H, t, J = 7.1 Hz), 1.60-1.90 (10H, m), 3.15-3.30 (4H, m), 4.35 (2H, q, J = 7.1 Hz), 5.13 (2H, d, J = 5.3 Hz), 7.05-7.42 (4H, m), 7.82 (1H, s), 8.48 (1H, s), .85 (1H, s) 10.81 (1H, br), 13.80 (lH, s).

Example 54 2 3-Ethyl-8- (2-propylaminobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 54) According to a manner similar to that in Example 1, the title compound is obtained from the compound obtained in Reference Example 61. 1 H-NMR (DMSO-dg) d (ppm): 0.94 (3H, t, J = 7.4 Hz), 1.25 (3H, t, J = 7.1 Hz), 1.70-1.78 (2H, m), 3.20-3.26 ( 2H, m), 3.91 (2H, q, J = 7.1 Hz), 4. 80 (1H, br), 4.93 (2H, d, J = 4.3 Hz), 6.95-7.05 (1H, m), 7.10-7.20 (1H, m), 7.29 (1H, dd, J = 5.9 Hz, 7.3.Hz), 7.39 (1H, d, J = 7.3 Hz), 7.53 (1H, s), 8.23 (1H, s), 8.82 ( 1H, s), 10.74 (1H, br), 12.01 (1H, s).

Example 55 2 3-Ethyl-8- (2-propylaminobenzylamino) -2,3-dihydro-1H-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 55) According to a manner similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 61.

-NRM (DMSO-dg) d (ppm): 0.96 (3H, t, J = 7.4 Hz), 1.30 (3H, t, J = 7.1 Hz), 1.69-1.78 (2H, m), 3.20-3.26 (2H , m), 4.34 (2H, q, J = 7.1 Hz), 4.50 (1H, br), 4.96 (2H, br), 6.90-7.00 (1H, m), 7.01-7.15 (1H, m), 7.26- 7.38 (2H, m), 7.78 (1H, s), 8.45 (1H, s), 8.90 (1H, s), 10.88 (1H, br), 13.78 (1H, s).

Example 56 2 3-Ethyl-8- (2-isopropylaminobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 56) According to a manner similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 63.

-NRM (DMSO-dg) d (ppm): 1.27-1.35 (9H, m), 3.60-4.00 (2H, m), 4.35 (2H, q, J = 7.1 Hz), 5.01 (2H, br), 7.10 -7.22 (1H, m), 7.23-7.48 (3H, m) 7.77 (1H, s), 8.44 (1H, s), 8.91 (1H, s), 10.90 (1H, br), 13.81 (1H, s) .

Example 57 2 3-Ethyl-8- [2- (3-hydroxymethylpiperidino) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 57) According to a manner similar to that in Example 9, the title compound is obtained from the compound as the starting material obtained in Reference Example 65.

? -NMR (DMSO-d6) d (ppm): 1.27 (3H, t, J = 6.9 Hz), 1.75-2.20 (3H, m), 2. 80-3.20 (3H, m), 3.30-3.55 (4H, m), 3.85-4.20 (4H, m), 5.08 (2H, br) 7.17-7.50 (4H,), 7.56 (1H, s), 8.22 ( 1H, s), 8.81 (1H, s), 10.60 (1H, br), 12.03 (1H, s).

Example 58 2 3-Ethyl-8- [3- (4-hydroxymethylpiperidino) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 58) According to a manner similar to that in Example 33, the title compound is obtained from the compound as the starting material obtained in Reference Example 67.

? -NRM (DMSO-dg) d (ppm): 1.30 (3H, t, J = 6.9 Hz), 1.70-2.00 (4H, m), 3. 40-3.80 (8H, m), 4.35 (2H, q, J = 6.9Hz), 4.98 (2H, d, J = 5.6 Hz), 7. 46-7.49 (2H, m) 7.60-7.95 (3H, m), 8.43 (1H, s), 8.88 (1H, s), 10.87 (1H, br), 13.79 (1H, s).

Example 59 2 3-ethyl-8- Hydrochloride. { 2- [4- (2-hydroxyethyl) piperidino] benzylamino} -2, 3-dihydro-lH-imidazo [4,5-g] quinazolin-2-thione (Compound 59) According to a manner similar to that in Example 22, the title compound is obtained from the compound as the starting material obtained in Reference Example 69.

-NRM (DMSO-dg) d (ppm): 1.31 (3H, t, J = 6.9 Hz), 1.46-1.56 (2H, m), 1.60-2.00 (4H, m), 3.10-3.43 (5H,), 3.45-3.52 (2H, m), 4.35 (2H, q, J = 6.9 Hz) 4.50 (1H, br), 5.10 (2H, br), 7.20-7.52 (4H, m), 7.79 (1H, s), 8.42 (1H, s), 8.88 (1H, s), 10.70 (1H, br), 13.76 (1H, s).

Example 60 2 3-Ethyl-8- (2-isopropylaminobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 60) According to a manner similar to that in Example 1, the title compound is obtained from the compound as the starting material obtained in Reference Example 63. 1 H-NMR (DMS0-d 6) d (ppm): 1.25-1.33 (9H,), 3.75-3.90 (1H, m), 3.95 (2H, q, J = 7.2Hz), 4.27 (1H, br), 4.97 (2H, br), 7.00-7.48 (4H, m) 7.49 (1H, s), 8.18 (1H, s), 8.86 (1H, s), 10.60 (1H, br), 12.00 (1H, Example 61 2 3-Ethyl-8- (2-ethylaminobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 61) According to a manner similar to that in Example 1, the title compound is obtained from the compound as the starting material obtained in Reference Example 73.

XH-NMR (DMSO-dg) d (ppm): 1.25-1.37 (6H, m), 3.35-3.46 (2H, m), 3.95 (2H, q, J = 7.3 Hz), 4.60 (1H, br), 4.98 (2H, br), 7.05-7.15 (1H, m), 7.15-7.37 (2H, m), 7.44 (1H, d, J = 7.6 Hz), 7.52 (1H, s), 8.23 (1H, s) , 8.85 (1H, s), 10.71 (1H, s), 12.01 (1H, s).

Example 62 2 3-Ethyl-8- (2-ethylaminobenzylamino) -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 62) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound as the starting material obtained in Reference Example 73. 1 H-NMR (DMSO-dg) d (ppm): 1.28-1.34 (6H, m), 3.18-3.31 (2H, m), 4.20 (1H, br), 4.36 (2H, q, J = 7.0 Hz), 4.95 (2H, br), 6.85-7.20 (2H, m), 7.25-7.40 (2H, m), 7.72 (1H, s), 8.41 (1H, s), 8.90 (1H, s), 10.70 (1H, br), 13.76 (1H, s).

Example 63 2 3-Ethyl-8- [2- (3-hydroxymethylpiperidino) benzylamino] 2,3-dihydro-lH-imidazo [4,5-g] quinazolin-2-thione hydrochloride (Compound 63) According to an almost similar to that in Example 22, the title compound is obtained from the compound as the starting material obtained in Reference Example 65.

? -NRM (DMSO-dg) d (ppm): 1.32 (3H, t, J = 7.1 Hz), 1.72-2.15 (3H, m), 2.70-3.00 (2H, m), 3.15-3.46 (4H, m ), 4.10-4.50 (5H, m), 5.11 (2H, d, J = 5.0 Hz), 7.10-7.50 (4H, m), 7.79 (1H, s), 8.43 (1H, s), 8.87 (1H, s), 10.84 (1H, br), 13.75 (1H, s).

Example 64 2 8- (2-Cyclopentylaminobenzylamino) -3-ethyl-2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 64) According to a manner similar to that in Example 22, the title compound is obtained from the compound as the starting material obtained in Reference Example 75.

-NRM (DMSO-d6) d (ppm): 1.31 (3H, t, J = 7.1 Hz), 1.51-1.80 (6H, m), 1.90-2.05 (2H, m), 3.90-4.00 (1H, m) , 4.36 (2H, q, J = 7.1 Hz), 4.50 (1H, br), 4.98 (2H, br), 6.95-7.15 (2H, m), 7.28-7.35 (2H, m), 7.74 (1H, s ), 8.41 (1H, s), 8.91 (1H, s), 10.77 (1H, s), 13.77 (1H, s).

Example 65 2 8- (2-Butylaminobenzylamino) -3-ethyl-2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 65) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound as the starting material obtained in Reference Example 77.

- MN (DMSO-dg) d (ppm): 0.91 (3H, t, J = 7.3 Hz), 1.28-1.42 (5H, m), 1.64-1.72 (2H, m), 3.21-3.27 (2H, m) , 4.35 (2H, q, J = 7.1 Hz), 4.50 (1H, br), 4.94 (2H, br), 6.90-7.05 (2H, m), 7.25-7.35 (2H, m), 7.74 (1H, s ), 8.42 (1H, s), 8.90 (1H, s), 10.79 (1H, br), 13.78 (1H, s).

Example 67 2 8- (2-Butylaminobenzylamino) -3-ethyl-2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 67) According to a manner almost similar to that in Example 1, the title compound is obtained from the compound as the starting material obtained in Reference Example 77.

? -NRM (DMSO-d6) d (ppm): 0.92 (3H, t, J = 7.4 Hz), 1.28 (3H, t, J = 7.1 Hz), 1.33-1.47 (2H, m), 1.68-1.80 (2H, m), 3.26-3.33 (2H, m), 3.95 (2H, q, J = 7.1 Hz), 4.60 (1H, br), 4.97 (2H, d, J = 4.3 Hz), 7.00-7.10 (1H, m), 7.12-7.20 (1H, m), 7.25-7.35 (1H, m), 7.42 (1H, d, J = 7.3 Hz), 7.52 (1H, s), 8.22 (1H, s), 8.84 (1H, s), 10.68 (1H, t, J = 4.3 Hz), 12.00 (1H, s).

Example 68 2 8- (2-Cyclohexylaminobenzylamino) -3-ethyl-2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 68) According to a manner similar to that in Example 22, the title compound is obtained from the compound as the starting material obtained in Reference Example 81. 1 H-NMR (DMSO-dg) d (ppm): 1.24-1.46 (7H, m), 1.48-1.67 (2H, m), 1.70-1.82 (2H, m), 2.03-2.08 (2H, m), 3.44 -3.52 (1H, m), 4.20 (1H, br), 4.36 (2H, q, J = 7.3 Hz), 5.02 (2H, s), 7.11-7.33 (3H, m), 7.44-7.48 (1H, m ), 7.74 (1H, s), 8.41 (1H, s), 8.91 (1H, s), 10.80 (lH, s), 13.75 (1H, s).

Example 69 2 8- (2-Cyclohexylaminobenzylamino) -3-ethyl-2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 69) According to a manner similar to that in Example 1, the title compound is obtained from the compound as the starting material obtained in Reference Example 81.

XH-NMR (DMSO-d6) d (ppm): 1.24-1.31 (6H, m), 1.54-1.63 (3H, m), 1.77-1.82 (2H, m), 2.05-2.09 (2H, m), 3.45. -3.60 (1H, m), 3.95 (2H, q, J = 6.9 Hz), 4.45 (1H, br), 5.02 (2H, d, J = 4.6 Hz), 7.21-7.45 (3H, m), 7.51- 7.54 (2H, m), 8.22 (1H, s), 8.85 (1H, s), 10.72 (1H, t, J = 4.6 Hz), 12.01 (1H, s).

Example 70 2 3-Ethyl-8- [2- (l-pyrrolidinyl) benzylamino] -2,3-dihydro-lH-imidazo [4,5-g] quinazolin-2-thione hydrochloride (Compound 70) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound as the starting material obtained in Reference Example 79. 1 H-NMR (DMSO-dg) d (ppm): 1.31 (3H, t, J = 7.1 Hz), 2.05-2.25 (4H, m), 3.60-3.85 (4H, m), 4.36 (2H, q, J = 7.1 Hz), 5.17 (2H, br), 7.27-7.45 (1H, m), 7.48-7.65 (3H, m), 7.76 (1H, s), 8.43 (1H, s), 8.90 (lH, s) , 10.92 (1H, br), 13.86 (1H, s).

Example 71 3 3-Ethyl-8- [2- (4-ethyl-l-piperazinyl) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 71) According to a manner almost similar to that in Example 1, the title compound is obtained from the compound obtained in Reference Example 83.

XH-NMR (DMS0-d6) d (ppm): 1.25-1.36 (6H, m), 3.18-3.46 '(8H, m), 3.54-3.58 (2H, m), 3.95 (2H, q, J = 7.2 Hz), 5.03 (2H, d, J = 5.6 Hz), 7.10 (1H, dd, J = 7.6 Hz, 8.2 Hz), 7.22 (1H, d, J = 6.9 Hz), 7.28-7.34 (2H, m) , 7.57 (1H, s), 8.26 (1H, s), 8.80 (1H, s), 10.51 (1H, t, J = 5.6 Hz), 12.05 (1H, s).

Example 72 2 3-Ethyl-8- [2- (2-methylpropylamino) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 72) According to a manner almost similar to that in Example 1, the title compound is obtained from the compound obtained in Reference Example 85.

XH-NMR (DMSO-dg) d (ppm): 0.90 (6H, d, J = 6.9 Hz), 1.28 (3H, t, J = 7.1) Hz), 2.04-2.10 (1H, m), 3.06-3.09 (2H, m), 3.94 (2H, q, J = 7.1 Hz), 4.90 (2H, d, J = 5.3 Hz), 6.40 (lH, br ), 6.88-6.92 (1H, m), 6.95-7.02 (1H, m), 7.24 (1H, dd, J = 7.6 Hz, 7.6 Hz), 7.35 (1H, d, J = 7.3 Hz), 7. 54 (1H, s), 8.24 (1H, s), 8.84 (1H, s), 10.70 (1H, t, J = 5.3 Hz), 12.02 (1H, s).

Example 73 2 8- [2- (1-Perhydroazepinyl) benzylamino] -3-ethyl-2,3-dihydro-lH-imidazo [4,5-g] quinazolin-2-thione hydrochloride (Compound 73) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 87.

XH-NMR (DMSO-d6) d (ppm): 1.32 (3H, t, J = 7.1 Hz), 1.75-1.86 (4H, m), 1.90-2.15 (4H, m), 3.50-3.70 (2H, m ), 4.35 (2H, q, J = 7.1 Hz), 4.60-4.85 (2H, m), 5.16 (2H, br), 7.27-7.50 (4H, m), 7.80 (1H, s), 8.46 (1H, s), 8.87 (1H, s), 11.00 (1H, s), 13.76 (1H, s).

Example 74 2 8- (2-Cyclopentylaminobenzylamino) -3-ethyl-2, 3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 74) According to a manner almost similar to that in Example 1, the title compound is obtained from the compound obtained in Reference Example 75.

XH-NMR (DMSO-dg) d (ppm): 1.27 (3H, t, J = 7.1 Hz), 1.55-1.72 (2H, m), 1.75-1.90 (4H, m), 1.93-2.00 (2H, m ), 3.94 (2H, q, J = 7.1 Hz), 3.95-4.00 (1H, m), 5.00 (2H, d, J = 4.6 Hz), 5.20 (1H, br), 7.09-7.20 (1H, m) , 7.27-7.40 (2H, m), 7.42-7.50 (1H, m), 7.54 (1H, s), 8.23 (1H, s), 8.85 (1H, s), 10.72 (1H, t, J = 4.6 Hz ), 12.01 (1H, s).

Example 75 2 3-Ethyl-8- [2- (1-tricyclo [3.3.1.13'7] decyl) aminobenzylamino] -2,3-dihydro-lH-imidazo [4,5-g] quinazolin-2-hydrochloride tiona (Compound 75) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 89.

? -NRM (DMSO-dg) d (ppm): 1.33 (3H, t, J = 7.1 Hz), 1.66-1.74 (6H, m), 2.12-2.52 (9H, m), 3.06 (lH, br), 4.37 (2H, q, J = 7.1 Hz), 5.20 (2H, d, J = 5.0 Hz), 7.46-7.54 (3H, m), 7.65-7.68 (1H, m), 7.78 (1H, s), 8.41 (1H, s), 8.95 (1H, s), 10.94 (1H, t, J = 5.0 Hz), 13.76 (1H, s).

Example 76 2 3-ethyl-8- Hydrochloride. { 2- [4- (2-hydroxyethyl) piperidino] benzylamino} -2, 3-dihydro-lH-imidazo [4,5-g] quinazolin-2-one (Compound 76) According to a manner almost similar to that in Example 9, the title compound is obtained from the compound obtained in Reference Example 69.

? -NRM (DMSO-dg) d (ppm): 1.30 (3H, t, J = 7.1 Hz), 1.46-1.72 (4H, m), 1.75-1.90 (2H, m), 2.70-3.40 (7H, m ), 3.97 (2H, q, J = 7.1 Hz), 5.08 (2H, br), 6.40 (1H, br), 7.10-7.40 (4H, m), 7.48 (1H, s), 8.24 (lH, s) , 8.81 (1H, s), 10.30 (lH, br), 11.95 (1H, s).

Example 77 3 3-Ethyl-8- [2- (4-ethyl-1-piperazinyl) benzylamino] -2,3-dihydro-1H-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 77) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 83.

-NRM (DMSO-d6) d (ppm): 1.31-1.39 (6H, m), 3.18-3.32 (8H, m), 3.50-3.61 (2H, m), 4.37 (2H, q, J = 7.3 Hz) , 5.07 (2H, d, J = 5.6 Hz), 7.12 (1H, dd, J = 6.9 Hz, 7.9 Hz), 7.23-7.35 (3H, m), 7.71 (1H, s), 8.42 (1H, s) , 8.85 (1H, s), 10.57 (1H, t, J = 5.6 Hz), 13.71 (1H, s).

Example 78 2 3-Ethyl-8- [2- (2-methylpropylamino) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 78) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 85.

XH-NMR (DMSO-d6) d (ppm): 0.96 (6H, d, J = 6.6 Hz), 1.32 (3H, t, J = 7.1 Hz), 1.97-2.02 (1H, m), 2.99-3.03 ( 2H, m), 4.36 (2H, q, J = 7.1 Hz), 4.90 (2H, d, J = 4.6 Hz), 5.00 (1H, br), 6.75-6.84 (2H, m), 7.16-7.28 (2H , m), 7.72 (1H, s), 8.40 (1H, s), 8.89 (1H, s), 10.69 (1H, t, J = 4.6 Hz), 13.73 (1H, s).

Example 79 2 3-Ethyl-8- [2- (4-hydroxybutylamino) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 79) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 91.

XH-NMR (DMSO-dg) d (ppm): 1.32 (3H, t, J = 6.9 Hz), 1.50-1.60 (2H, m), 1.75-1.86 (2H, m), 3.29-3.32 (2H, m ), 3.41-3.50 (2H, m), 4.36 (2H, q, J = 6.9 Hz), 4.99 (2H, br), 5.00 (1H, br), 5.30 (1H, br), 7.05-7.29 (2H, m), 7.32 (1H, dd, J = 6.9 Hz, 8.6 Hz), 7.41 (1H, d, J = 7.3 Hz), 7.73 (1H, s) 41 (1H, s), 8.90 (1H, s), 10.82 (lH, s), 13.74 (1H, s) Example 80 2 8- [2- (4-Hydroxymethylpiperidino) benzylamino] -3-propyl-2,3-dihydro-lH-imidazo [4,5-g] quinazolin-2-thione hydrochloride (Compound 80) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 93.

? -NRM (DMSO-dg) d (ppm): 0.95 (3H, t, J = 7.4 Hz), 1.50-2.00 (7H, m), 3.20-3.70 (6H, m), 4.28 (2H, t, J) = 7.1 Hz), 5.15 (2H, br), 5.70 (lH, br), 7.20-7.55 (4H,), 7.82 (lH, s), 8.43 (1H, s), (1H, s) 10.45 (1H, br), 13.76 (1H, s).

Example 81 2 3- [2- (1-Perhydroazepinyl) benzylamino] -3-ethyl-2,3-dihydro-lH-imidazo [4,5-g] quinazolin-2-one hydrochloride (Compound 81) According to a manner almost similar to that in Example 1, the title compound is obtained from the compound obtained in Reference Example 87.

-NMR (DMSO-d6) d (ppm): 1.30 (3H, t, J = 7.3 Hz), 1.70-1.90 (4H, m), 1.95-2.10 (4H, m), 3.50-3.70 (4H, m) , 3.96 (2H, q, J = 7.3 Hz), 5.14 (2H, br), 7.26-7.80 (5H, m), 8.22 (1H, s), 1 (1H, s), 10.60 (1H, s), 11.99 (1H, s).

Example 82 3 3-Ethyl-8- [2- (4-methyl-l-homopiperazinyl) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 82) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 95.

-NRM (DMS0-d6) d (ppm): 1.34 (3H, t, J = 7.1 Hz), 2.09-2.15 (1H, m), 2.27-2.33 (1H, m), 2.88 (3H, s), 3.14 -3.20 (2H, m), 3.29-3.46 (2H, m), 3.47-3.59 (4H, m), 4.37 (2H, q, J = 7.1 Hz), 5.09 (2H, d, J = 5.6 Hz), 7.02-7.09 (1H, m), 7.28-7.31 (3H, m), 7.74 (1H, s), 8.47 (lH, s), 8.85 (1H, s), 10.65 (1H, t, J = 5.6 Hz) , 13.73 (1H, s).

Example 83 2 3-ethyl-8- Hydrochloride. { 2- [2- (2-hydroxyethoxy) ethylamino] benzylamino} -2, 3-dihydro-lH-imidazo [4,5-g] quinazolin-2-thione (Compound 83) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 97.

-NRM (DMSO-d6) d (ppm): 1.33 (3H, t, J = 7.3 Hz), 3.41-3.52 (6H, m), 3.72 (2H, t, J = 5.3 Hz), 4.36 (2H, q , J = 7.3 Hz), 4.91 (2H, d, J = 5.3 Hz), 5.55 (2H, br), 6.86-7.00 (2H, m), 7.25 (1H, dd, J = 7.3 Hz, 7.9 Hz), 7.35 (1H, d, J = 7.9 Hz), 7.70 (1H, s), 8.39 (1H, s), 8.92 (1H, s), 10.72 (1H, t, J = 5.3 Hz), 13.72 (1H, s) ).

Example 84 3 3-Ethyl-8- [2- (4-methyl-l-homopiperazinyl) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-one hydrochloride (Compound 84) According to a manner almost similar to that in Example 1, the title compound is obtained from the compound obtained in Reference Example 95.

? -NMR (DMSO-d6) d (ppm): 1.28 (3H, t, J = 7.3 Hz), 2.12-2.17 (1H, m), 2.25-2.32 (1H, m), 2.84 (3H, s), 3.12-3.18 (2H, m), 3.31-3.61 (6H, m), 3.94 (2H, q, J = 7.3 Hz), 5.05 (2H, d, J = 5.6 Hz), 7.04-7.10 (1H, m) , 7.27-7.33 (3H, m), 7.56 (1H, s), 8.28 (1H, s), 8.79 (1H, s), 10.51 (1H, t, J = 5.6 Hz), 12.02 (1H, s).

Example 85 2 8- [2- (4-Hydroxymethylpiperidino) benzylamino] -3-methyl-2,3-dihydro-lH-imidazo [4,5-g] quinazolin-2-thione hydrochloride (Compound 85) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 99.

-NMR (DMSO-dg) d (ppm): 1.56-1.87 (5H, m), 3.00-3.50 (7H, m), 3.74 (3H, s), 5.10 (2H, br), 7.13-7.37 (4H, m), 7.69 (1H, s), 8.39 (1H, s), 8.87 (1H, s), 10.60 (1H, br), 13.72 (1H, s).

Example 86 2 3-Ethyl-8- [2- (2-furylmethylamino) benzylamino] -2,3-dihydro-1H-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 86) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 101.

XH-NMR (DMSO-dg) d (ppm): 1.30 (3H, t, J = 7.1 Hz), 4.30-4.46 (4H, m), 4. 83 (2H, d, J = 5.3 Hz), 6.03 (1H, br), 6.30-6.37 (2H, m), 6.66 (1H, dd, J = 7.3 Hz, 8.6 Hz), 6.77 (1H, d, J = 8.2 Hz), 7.12 (1H, d, J = 8.2 Hz, 8. 6 Hz), 7.20 (1H, d, J = 7.3 Hz), 7.50 (1H, s), 7.78 (1H, s), 8.44 (1H, s), 8.81 (1H, s), 10.79 (1H, t, J = 5.3 Hz), 13.81 (1H, s).

Example 87 1 3-Ethyl-8- [2- (1,2,3,4-tetrahydroisoquinolin-2-yl) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-hydrochloride tiona (Compound 87) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 103.

-NRM (DMSO-d6) d (ppm): 1.31 (3H, t, J = 7.1 Hz), 2.95-3.03 (2H, m), 3.25-3.37 (2H, m), 4.18 (2H, br), 4.34 (2H, q, J = 7.1 Hz), 5.10 (2H, d, J = 5.0 Hz), 7.10-7.15 (5H, m), 7.32-7.40 (3H, m), 7.76 (1H, s), 8.42 ( 1H, s), 8.76 (1H, s), 10.68 (1H, t, J = 5.0 Hz), 13.77 (1H, s).

Example 88 2 3-Ethyl-8- [2- (2-tetrahydrofurylmethylamino) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 88) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 105.

XH-NMR (DMSO-dg) d (ppm): 1.37 (3H, t, J = 7.1 Hz), 1.51-1.70 (1H,), 1.75-2.00 (3H, m), 3.05-3.35 (2H,), 3.60-3.80 (2H, m), 4.02-4.15 (1H, m), 4.35 (2H, q, J = 7.1 Hz), 4.90 (2H, br), 5.10 (1H, br), 6.70-6.83 (2H, m), 7.15-7.25 (2H, m), 7.75 (lH, s), 8.42 (1H, s), 8.82 (1H, s), 10.50 (1H, s), 13.77 (1H, s).

Example 89 2 3-Ethyl-8- [2- (2-thienyl) methylamino) benzylamino] -2,3-dihydro-lH-imidazo [4,5-g] quinazolin-2-thione hydrochloride (Compound 89) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 107.

XH-NMR (DMSO-dg) d (ppm): 1.32 (3H, t, J = 7.3 Hz), 4.36 (2H, q, J = 7.3 Hz), 4.57 (2H, br), 4.85 (2H, d, J = 4.6 Hz), 5.60 (1H, br), 6.60-6.78 (2H, m), 6.91-6.95 (1H, m), 7.04-7.50 (4H, m), 7.69 (1H, s), 8.39 (1H , s), 8.74 (1H, s), 10.60 (1H, t, J = 4.6 Hz), 13.73 (1H, s).

Example 90 3 3-Ethyl-8- [2- (2-phenylaminoethylamino) benzylamino] -2,3-dihydro-lH-imidazo [4,5-g] quinazolin-2-thione hydrochloride (Compound 90) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 109.

-NRM (DMSO-dg) d (ppm): 1.33 (3H, t, J = 7.0 Hz), 3.45-3.55 (4H, m), 4.36 (2H, q, J = 7.0 Hz), 4.89 (2H, d) , J = 5.3 Hz), 5.20 (2H, br), 6.63-6.75 (2H, m), 7.12-7.36 (7H, m), 7.66 (1H, s), 8.46 (1H, s), 8.86 (1H, s), 10.70 (1H, br), 13.71 (1H, s).

Example 91 2 3-Ethyl-8- [2- (4-methoxymethylpiperidino) benzylamino] -2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 91) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 112.

XH-NMR (DMSO-d6) d (ppm): 1.32 (3H, t, J = 7.1 Hz), 1.50-2.00 (5H, m), 2.60-3.20 (2H, m), 3.25-3.50 (7H, m ), 4.35 (2H, q, J = 7.1 Hz), 5.10 (2H, br), 7.05-7.50 (4H, m), 7.77 (1H, s), 8.41 (1H, s), 8.87 (1H, s), 10.60 (1H, br), 13.76 (1H, s).

Example 92 2 8- [2- (4-Ethoxymethylpiperidino) benzylamino] -3-ethyl-2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 92) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 114.

LH-NMR (DMSO-d6) d (ppm): 1.15 (3H, t, J = 6.9 Hz), 1.33 (3H, t, J = 7.1 Hz), 1.50-2.00 (5H, m), 3.10-3.50 (8H, m), 4.36 (2H, q, J = 7.1 Hz), . 13 (2H, br), 7.19-7.39 (4H, m), 7.77 (1H, s), 8.42 (1H, s), 8.87 (1H, s), 10.77 (1H, br), 13.73 (1H, s) .

Example 93 2 8- (2-Aminobenzylamino) -3-ethyl-2,3-dihydro-lH-imidazo [4,5-g] quinazolin-2-thione hydrochloride (Compound 93) The compound (0.58 g, 1.29 mmol) obtained in Reference Example 117 is suspended in methanol (40 ml), and 4N-ethyl acetate hydrochloric acid (10 ml) is added dropwise to the mixture under ice cooling. After the addition is complete, the temperature of the mixture is gradually increased, and stirred at room temperature for 1 hour. After the reaction is complete, the solution is concentrated, and the precipitated solids are filtered and washed with methanol-ether and dried to give the title compound.

? -NRM (DMSO-d6) d (ppm): 1.32 (3H, t, J = 7.1 Hz), 3.93 (2H, br), 4.36 (2H, q, J = 7.1 Hz), 5.03 (2H, s) , 7.14-7.19 (1H, m), 7.29-7.41 (3H, m), 7.71 (1H, s), 8.42 (1H, s), 8.91 (1H, s), 10.75 (1H, br), 13.76 (1H , s).

Example 94 2 8- (2-Cyclobutylaminobenzylamino) -3-ethyl-2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 94) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 119.

? -NRM (DMSO-dg) d (ppm): 1.31 (3H, t, J = 7.1 Hz), 1.74-1.85 (2H, m), 2.16-2.33 (4H, m), 4.01-4.08 (1H, m ), 4.35 (2H, q, J = 7.1 Hz), 4.95 (2H, d, J = 4.6 Hz), 5.20 (1H, br), 6.90-7.00 (2H, m), 7.24 (1H, dd, J = 7.6 Hz, 7.9 Hz), 7.32 (1H, d, J = 7.6 Hz), 7.77 (lH, s), 8.45 (1H, s), 8.91 (1H, s), 10.85 (1H, t, J = 4.6 Hz ), 13.76 (1H, s).

EXAMPLE 95 2 8- [2-Exo- (2-bicyclo [2.2.1] heptylamino) benzylamino] -3-ethyl-2,3-dihydro-lH-imidazo [4, 5-g] quinazolin-2- hydrochloride thione (Compound 95) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 121.

XH-NMR (DMSO-d6) d (ppm): 1.08-1.21 (4H, m), 1.32 (3H, t, J = 7.1 Hz), 1.49-1.60 (4H,), 1.70-1.78 (1H, m) , 2.25-2.32 (2H, m), 3.34-3.38 (1H, m), 4.36 (2H, q, J = 7.1 Hz), 4.92 (2H, d, J = 4.6 Hz), 6.79-6.85 (2H, m ), 7.21 (1H, dd, J = 7.6 Hz, 7.6 Hz), 7.28 (1H, d, J = 7.3 Hz), 7.72 (1H, s), 8.38 (1H, s), 8.90 (1H, s), 10.68 (1H, t, J = 4.6 Hz), 13.73 (1H, s).

Example 96 2 8- [2- (4-Ethoxycarbonyl-1-piperazinyl) benzylamino] -3-ethyl-2, 3-dihydro-1H-imidazo [4, 5-g] quinazolin-2-thione hydrochloride (Compound 96) According to a manner almost similar to that in Example 22, the title compound is obtained from the compound obtained in Reference Example 71.

XH-NMR (as free base, DMSO-d6) d (ppm): 1.24 (3H, t, J = 7.1 Hz), 1.34 (3H, t, J = 7.1 Hz), 2.88-2.93 (4H, m), 3.50-3.60 (4H, m), 4.09 (2H, q, J = 7.1 Hz), 4.36 (2H, q, J = 7.1 Hz), 4.93 (2H, d, J = 5.3 Hz), 7.02 (1H, dd , J = 7.3 Hz, 7.3 Hz), 7.13 (1H, d, J = 7.3 Hz), 7.20-7.27 (2H, m), 7.56 (1H, s), 8.14 (1H, s), 8.42 (1H, s ), 8.85 (1H, t, J = 5.3 Hz), 13.22 (1H, s).

Pharmaceutical preparation 1 (Tablets) Tablets with the following composition are prepared in a usual manner.

Compound 100 mg Lactose 60 mg Potato starch 30 mg Polyvinyl alcohol 2 mg Magnesium stearate 1 mg Trace tar pigment Pharmaceutical preparation 2 (Powder) A powder with the following composition is prepared in a usual manner.

Compound 34 150 mg Lactose 280 mg Pharmaceutical preparation 3 (Syrup) A syrup with the following composition is prepared in a usual manner: Compound 33 100 mg Refined white sugar 40 g Ethyl P-hydroxybenzoate 40 mg Propyl P-hydroxybenzoate 10 mg Strawberry flavor 0.1 cc The total amount is adjusted to 100 cc by adding water.

Industrial Applicability According to the present invention, there are provided imidazoquinazoline derivatives or pharmaceutically acceptable salts thereof, which have potent and selective inhibitory activity of the phosphodiesterase (FDE) specific in the 3 ', 5'-cyclic guanosine monophosphate (cGMP) , increases the concentration of intracellular cGMP, increases the effects of endothelial-derived relaxant factor (FRDE), nitro vasodilator or atrial natriuretic peptide, shows antiplatelet activity, anti-vasoconstriction activity and vasodilation activity, and is useful for the treatment or improvement of cardiovascular diseases, such as thrombosis, angina pectoris, hypertension, congestive heart failure, post-PTCA restenosis, peripheral vascular diseases, arterial sclerosis, etc., allergic inflammatory diseases, such as bronchitis, chronic asthma, allergic asthma, nasal catarrh allergic, etc., alimentary canal diseases, such such as irritable bowel syndrome, etc., glucome, impotence and the like.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims

1. An imidazoquinazoline derivative represented by the formula (I): characterized in that R1 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R2 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted benzocycloalkenyl, lower alkenyl substituted or unsubstituted, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R3 represents hydrogen, substituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted bicycloalkyl or unsubstituted, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R2 and R3 combine to represent a heterocyclic group containing substituted or unsubstituted N, and X represents 0 or S, or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, characterized in that R3 is hydrogen.

3. A compound according to claim 1, characterized in that R 2 is a substituted or unsubstituted lower alkyl, and R 3 is a lower alkyl containing hydroxy.

4. A compound according to claim 1, characterized in that R2 and R3 combine to represent a heterocyclic group containing substituted or unsubstituted N.

5. A compound according to claim 1, characterized in that R1 is a substituted or unsubstituted alkyl.

6. A compound according to claim 1, characterized in that X is S.

7. A compound according to claim 1, characterized in that R1 is a substituted or unsubstituted lower alkyl.

8. A compound according to claim 7, characterized in that R 2 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted lower alkenyl, or substituted aralkyl or unsubstituted, R3 represents hydrogen, substituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted aralkyl.

9. A compound according to claim 7, characterized in that R2 and R3 combine to represent a heterocyclic group containing substituted or unsubstituted N. SUMMARY OF THE INVENTION The present invention provides imidazoquinazoline derivatives represented by the formula (I): wherein R1 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricycloalkyl or the like, R2 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl , substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aralkyl or the like, R3 represents hydrogen, substituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aralkyl or the like, and R2 and R combine to represent a heterocyclic group containing substituted or unsubstituted N, X represents 0 or S, or salts pharmaceutically acceptable thereof, which have potent and selective inhibitory activity of the specific phosphodiesterase (FDE) in 3 A 5 '-cyclic guanosine monophosphate (cGMP) and are useful for the treatment or amelioration of cardiovascular diseases, such as thrombosis, angina pectoris, hypertension, heart failure, arterial sclerosis, as well as asthma, impotence and the like.