JP2002047287A - Aromatic derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an aromatic derivative having an inhibitory action on adenosine intake, useful as a myocardiac protection agent and a medicine for preventing and treating cerebral ischemia, renal disease (nephritis, diabetic nephropathy, etc.), pancreatitis, pain, convulsion, etc. SOLUTION: This aromatic derivative is represented by formula (I) [R1, R2, R3 and R4 are each hydrogen, amino, hydroxy, carboxy, a substituted or nonsubstituted mono- or lower dialkylamino, a substituted or nonsubstituted lower alkanoylamino or the like; V-W is formula (i), formula (ii) or the like; X is formula (iii) or the like; Y is O, S, N-R7 or two hydrogen atoms; and Z is a group of formula (iv) or a group of formula (v)] or its pharmacological acceptable salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a cardioprotective agent, cerebral ischemia, renal diseases (nephritis,
The present invention relates to an aromatic derivative or a pharmacologically acceptable salt thereof useful as a preventive or therapeutic agent for diabetic nephropathy, pancreatitis, pain, convulsions and the like.

[0002]

2. Description of the Related Art European Patent Publication EP 67318 (JP-A-7-26794)
9), a benzimidazolone derivative having an analgesic action and a neuroprotective action, and JP-A-7-188215, a 4-oxoquinazoline derivative useful as a circulatory drug and an antipsychotic, and WO94 / 22826 describes 4-aminopiperidine derivatives having a peripheral vasodilatory effect. Also,
International Publication WO99 / 31085 reports that 3-piperidyl-4-oxoquinazoline derivatives have a microsomal triglyceride transfer protein (MTP) inhibitory action.
In these publications, there is no description that the compound has an adenosine uptake inhibitory action, or a description that suggests the same. Furthermore, International Publication WO94 / 19342, WO
96/06841 and JP-A-8-151377 disclose quinazoline derivatives having an adenosine uptake inhibitory action,
WO98 / 33792 and WO99 / 19326 describe piperidine derivatives. On the other hand, compounds having an adenosine uptake inhibitory action are known to exhibit a cardioprotective action [Circul., 80, 1400-1411 (1.
989); American Journal of Physiology (Am. J. Physiol.), H1570-1577 (1991);
Journal of Cardiovasc. Pharmacol., 20, 173-
178 (1992)]. Furthermore, it has been reported that compounds having an adenosine uptake inhibitory activity are effective for cerebral ischemia [European Journal of Pharmacol. (Eur. J. Pharmacol.), 365, 9-25 ( 19
99)]. In addition, it has been disclosed that the quinazoline derivatives described in International Publications WO94 / 19342 and WO96 / 06841 are effective for treating nephritis and pancreatitis (International Publication WO97 / 29749, European Publication EP870502).

[0003]

SUMMARY OF THE INVENTION It is an object of the present invention to inhibit the uptake of adenosine from outside the cell and to increase the concentration of extracellular adenosine, thereby achieving anoxia such as ischemia and reperfusion injury. For cardiomyopathy from myocardial dysfunction due to hypertension or hypoxia, kidney diseases (nephritis, diabetic nephropathy, etc.)
An object of the present invention is to provide an aromatic derivative or a pharmacologically acceptable salt thereof, which is useful as an agent for preventing or treating inflammation such as foot edema, pancreatitis, convulsions, acute pain, neuropathic pain and the like.

[0004]

The present invention provides the following (1).
To (8). (1) Formula (I)

[0005]

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Wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, formamide, halogen, amino, nitro, cyano, hydroxy, carboxy, carbamoyl, substituted or unsubstituted mono or Di-lower alkylamino, substituted or unsubstituted lower alkanoylamino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkylthio, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted Represents a substituted lower alkanoyl, a substituted or unsubstituted aralkyloxy or a substituted or unsubstituted lower alkanoyloxy, and -VW- is a group represented by the formula (i)

[0007]

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Wherein R ⁵ represents a hydrogen atom, a substituted or unsubstituted lower alkyl or a substituted or unsubstituted aralkyl, or a compound of the formula (ii)

[0009]

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Wherein R ⁶ represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted aralkyl; V
W together with, -C (O) - or -CH ₂ - represents, X is -
_{(CH 2) m N (R} 5a) - ( wherein, m represents 2, 3 or 4, R ^5a has the same meaning as the R ⁵⁾ or formula (iii)

[0011]

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(Wherein, n represents 0, 1 or 2; G ¹ represents a hydrogen atom, halogen, amino, nitro, cyano, hydroxy, oxo, carboxy, carbamoyl, substituted or unsubstituted mono- or di-lower alkylamino Substituted or unsubstituted lower alkanoylamino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkoxycarbonyl,
Represents a substituted or unsubstituted aralkyloxy or a substituted or unsubstituted lower alkanoyloxy, wherein Y is O, S or NR ⁷ wherein R ⁷ is a hydrogen atom, a substituted or unsubstituted lower alkyl, Represents an unsubstituted aralkyl, substituted or unsubstituted lower alkoxycarbonyl or substituted or unsubstituted aralkyloxycarbonyl), or represents two hydrogen atoms, and Z is a group represented by the formula (iv)

[0013]

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Wherein G ² is a hydrogen atom, halogen, nitro, carboxy, cyano, hydroxy, carbamoyl,
Substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkanoyloxy, substituted or unsubstituted aralkyloxy, substituted or unsubstituted lower alkoxycarbonyl or NR ^A R ^B (where R ^A and R ^B are the same or Different from a hydrogen atom, formyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted aroyl, substituted or unsubstituted aralkyl, substituted or unsubstituted lower alkoxycarbonyl or substituted or unsubstituted And R ⁸ and R ⁹ are the same or different and represent a hydrogen atom, hydroxy, substituted or unsubstituted lower alkoxy or substituted or unsubstituted aralkyloxy] or formula (v)

[0015]

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(Wherein R ¹⁰ and R ¹¹ are the same or different and each independently represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted Lower alkanoyl, substituted or unsubstituted aryl, substituted or unsubstituted aroyl or substituted or unsubstituted aralkyl, U represents O or S, and G ² has the same meaning as defined above. Or a pharmacologically acceptable salt thereof. (2) The aromatic derivative according to the above (1), wherein Z is the formula (v), or a pharmacologically acceptable salt thereof. (3) The aromatic derivative according to the above (1) or (2), wherein -VW- is the formula (i) and R ⁵ is a hydrogen atom or a substituted or unsubstituted lower alkyl, or a pharmaceutically acceptable salt thereof. Salt. (4) X is the formula (iii), n is 1 and G ¹
Is a hydrogen atom, or the pharmacologically acceptable salt thereof according to any one of the above (1) to (3). (5) The above (1) to (1) wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and are a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, hydroxy or substituted or unsubstituted lower alkoxy. The aromatic derivative according to any of 4) or a pharmacologically acceptable salt thereof. (6) The aromatic derivative according to any one of the above (1) to (5), wherein Y is O, or a pharmacologically acceptable salt thereof. (7) A medicament comprising the aromatic derivative according to any one of the above (1) to (6) or a pharmacologically acceptable salt thereof. (8) An adenosine uptake inhibitor comprising the aromatic derivative according to any of (1) to (6) or a pharmaceutically acceptable salt thereof.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION The compound represented by the formula (I) is hereinafter referred to as compound (I). The same applies to compounds of other formula numbers. In the definition of each group of formula (I), the lower alkyl portion of lower alkyl, mono- or di-lower alkylamino, lower alkanoylamino, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, lower alkylthio and lower alkoxycarbonylamino As a linear or branched C 1-8, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl,
A chain alkyl such as octyl, and C3-8,
For example, cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned. As the lower alkenyl, straight-chain or branched C2-C6 groups such as vinyl, allyl, 1-propenyl, methacryl, crotyl, 1-butenyl, 3-butenyl, 2-pentenyl,
-Pentenyl, 2-hexenyl, 5-hexenyl and the like. Examples of lower alkynyl include straight-chain or branched-chain C 2-6 ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like. Aryl, aroyl and the aryl moiety of aroylamino include, for example, phenyl, naphthyl, biphenyl, anthryl and the like. The aralkyl moiety of aralkyl, aralkyloxy, aralkyloxycarbonyl, aralkylamino and aralkylcarbonylamino includes, for example, benzyl, phenethyl, benzhydryl, naphthylmethyl and the like having 7 to 13 carbon atoms. Halogen means each atom of fluorine, chlorine, bromine and iodine.

Substituted lower alkyl, substituted mono- or di-lower alkylamino, substituted lower alkoxy, substituted lower alkylthio, substituted lower alkanoyloxy, substituted lower alkoxycarbonyl, substituted lower alkanoyl, substituted lower alkanoylamino, substituted lower alkynyl, substituted lower alkenyl and Examples of the substituent of the substituted lower alkoxycarbonylamino include the same or different substituents having 1 to 3 halogen atoms, nitro, cyano, hydroxy, amino, carboxy, mono- or di-lower alkylamino, tri-lower alkylammonio, lower alkoxy, lower alkoxy. Examples include alkoxycarbonyl, lower alkanoyl, trifluoromethyl, lower alkanoyloxy, lower alkanoylamino, phthalimide, lower alkyl, aralkyl, aralkyloxy and the like. Where halogen, mono- or di-lower alkylamino, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy,
Lower alkanoylamino, lower alkyl, aralkyl and aralkyloxy are as defined above,
The lower alkyl moiety of the tri-lower alkylammonio has the same meaning as the lower alkyl.

The substituted aryl, substituted aralkyl, substituted aralkyloxy, substituted aralkyloxycarbonyl, substituted aroyl, substituted aroylamino, substituted aralkylamino and substituted aralkylcarbonylamino may be the same or different, and each has 1 to 3 halogen atoms, Nitro, cyano, hydroxy, amino, carboxy, lower alkyl, mono- or di-lower alkylamino, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl,
Methylenedioxy, trifluoromethyl, aralkyl and the like can be mentioned. Here, halogen, lower alkyl, mono- or di-lower alkylamino, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl and aralkyl are as defined above.

The pharmacologically acceptable salts of compound (I) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. Pharmaceutically acceptable acid addition salts of compound (I) include, for example, inorganic acid salts such as hydrochloride, sulfate, phosphate, acetate, maleate, fumarate, tartrate, and citric acid Salts, organic acid salts such as methanesulfonate, etc., and pharmacologically acceptable metal salts include, for example, alkali metal salts such as lithium salt, sodium salt and potassium salt, and alkali salts such as magnesium salt and calcium salt. Earth metal salts, aluminum salts, zinc salts and the like; pharmacologically acceptable ammonium salts include, for example, ammonium and tetramethylammonium salts; pharmacologically acceptable organic amine addition Salts include addition salts such as morpholine and piperidine, and pharmacologically acceptable amino acid addition salts include lysine, glycine and phenylalanine. Addition salts and the like.

Next, the method for producing the compound (I) and the intermediate will be described. In the manufacturing method shown below,
If the defined groups change under the conditions of the method of operation or are inappropriate for carrying out the method, methods of introducing and removing protecting groups commonly used in organic synthetic chemistry [eg, Protective Groups in Organic Synthesis No.
2nd edition (Protective Groups in Organic Synthesis 2nd Ed
ition), Green (TW Greene) Watts (PG
M. Wuts), John Wiley & Sons Inc. (1991)
Year)] can be used to obtain the target compound. In addition, the order of reaction steps such as introduction of a substituent can be changed as necessary. Production Method 1-1 Compound (I) can be produced by the following steps.

[0022]

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(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁸ , R ⁹ , R ¹⁰ , R
^{11, U, -VW-, X,} Y and G ² are the same meanings as defined above, respectively, La represents chlorine, bromine, iodine or hydroxy. (Step 1-1-1) Formula (IIIa) or Formula (III)
In b), when La is chlorine, bromine or iodine, compound (Ia) or compound (Ib) is obtained by compound (II) and compound (IIIa) or compound (III)
b), optionally in the presence of 1 to 5 equivalents of a base, a suitable solvent such as a halogenated hydrocarbon such as methylene chloride, chloroform, dichloroethane, tetrachloroethane,
Esters such as methyl acetate, ethyl acetate and butyl acetate, ethers such as ether, tetrahydrofuran (THF) and 1,4-dioxane, acetonitrile, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMS
O) in an aprotic polar solvent or a mixed solvent thereof at a temperature between 0 ° C and the boiling point of the solvent for 10 minutes to 72 hours.
It can be obtained by reacting for a time. Examples of the base that can be used include alkylamines such as triethylamine, diisopropylethylamine, and N-methylmorpholine, pyridines such as pyridine, lutidine, collidine, and 4-dimethylaminopyridine; and alkali metal carbonates such as potassium carbonate and sodium hydrogencarbonate. And alkali metal hydroxides such as salts, potassium hydroxide, sodium hydroxide, and lithium hydroxide.

In the formula (IIIa) or (IIIb), when La is hydroxy, the compound (Ia) or the compound (Ib) can be converted to a suitable condensing agent such as dicyclohexylcarbodiimide (DCC), 1- (3-dimethyl Aminopropyl) -3-ethylcarbodiimide hydrochloride (WSC HCl),
A condensing agent such as carbonyldiimidazole (CDI) is used, or La is converted to p-nitrophenoxy,
After conversion into a highly reactive group such as pentafluorophenoxy and pentafluorophenylthio, the compound can be obtained according to the above method.

Compound (IIIa) and compound (III
b) can be obtained as a commercial product or by a known method
Or according to it.
For example, among the compounds (IIIa), G^TwoIs nitro
R⁸And R⁹Is methoxy and Y is an oxygen atom
And La is hydroxy, is commercially available.
G ^TwoIs nitro and R⁸And R⁹Is ethoxy,
Compound wherein Y is an oxygen atom and La is hydroxy
Is Chemical Abstract (Chem. Abst.), 51
Volume, 17797a (1957), Volume 55, 5510b (1961)
Can be obtained according to the method shown, G^TwoIs nitro
And R⁸Or R⁹Is methoxy, and the other is
Is benzyloxy, Y is an oxygen atom, and La
Is a compound of the Journal of Med.
Original Chemistry (J. Med. Chem.), Volume 20, 1
No. 146-149 (1977).
Can be obtained. Compound (IIIb)
U is a sulfur atom and R^Ten, R¹¹And G^TwoIs a hydrogen atom
Y is an oxygen atom and La is hydroxy
Compounds are Chemical and Pharmaceutical
・ Bretan (Chem. Pharm. Bull.), Vol. 29, No. 7, 1876
-Obtained according to the method described on page 886 (1981)
be able to. In addition, International Publication WO99 / 19326 includes various
The production method of the compound (IIIa) is disclosed.

In the compound (II), X is a compound of the formula (iii)

[0027]

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Compound (IIa) represented by the formula (wherein n and G ¹ have the same meanings as described above) are described in, for example, International Publication WO96 / 06841, International Publication WO98 / 33792, or
It can be obtained according to the method disclosed in 151377. In the compound (II), X is-(CH ₂ ) _m N (R ^5a )-(wherein, R ^5a represents a group other than a hydrogen atom in the definition of R ⁵ , and m has the same meaning as described above). Compound (IIb) can be obtained according to the method shown below. Production method 1-2

[0029]

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(Where Lb represents chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy or benzenesulfonyloxy, and G ³ is lower alkanoyl such as formyl, acetyl, trifluoroacetyl and aroyl such as benzoyl) , Methoxycarbonyl,
Ethoxycarbonyl, lower alkoxycarbonyl such as tert-butoxycarbonyl, represents a group commonly used as a protecting group for an amino group such as aralkyloxycarbonyl such as benzyloxycarbonyl, and R ¹ , R ² , R ³ , R ⁴ ,
R ^5a , -VW- and m have the same meanings as described above, respectively. (Step 1-2-1) Compound (VIa) is a compound (Ia)
V) [eg, Journal of Heterocyclic Chem., 26, 150
1 to 1507 (1989), Synthetic Communication (Synth. Commun.), Vol. 14, No. 11, 1013 to 1025 (1984), Journal of Organic Chemistry (J. Org. Chem.), 51, 616-620 (1986
), Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 32, pp. 847-852 (1989), etc.] and compound (Va). 1 to 10 equivalents of a suitable base, for example, sodium hydride, alkali metal hydrides such as lithium hydride, tert-butoxide potassium, sodium methoxide, alkali metal alkoxides such as sodium ethoxide, sodium carbonate, potassium carbonate, cesium carbonate In the presence of alkali metal carbonates, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., ethers such as ether, THF, 1,4-dioxane, and non-metals such as DMF and DMSO. Protic polar solvents, alcohols such as methanol and ethanol, or a mixed solvent thereof, between -78 ° C and the boiling point of the solvent At the temperature of
It can be obtained by reacting for 1 to 72 hours.

Compound (Va) is obtained as a commercial product, or can be obtained by synthesizing it according to a known method or according thereto. (Step 1-2-2) Compound (IIb) can be prepared from compound (VI)
The a), can be prepared by treatment with an appropriate method depending on the type of G ^3. For example, when a compound (VIa) in which G ³ is lower alkanoyl or aroyl is used, water, ethers such as dioxane and THF, alcohols such as methanol and ethanol, or inorganic solvents such as hydrochloric acid and sulfuric acid in a mixed solvent thereof. Treatment with an acid at a temperature between room temperature and the boiling point of the solvent for 1 to 24 hours, or with an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. in place of the above inorganic acid By doing so, compound (IIb) is obtained.
Further, a compound (G) wherein G ³ is lower alkoxycarbonyl
When Ia) is used, water, ethers such as dioxane and THF, alcohols such as methanol, ethanol and ethylene glycol, organic acids such as acetic acid, halogenated hydrocarbons such as methylene chloride and dichloroethane, or a mixed solvent thereof By treating with an inorganic acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or an organic acid such as trifluoroacetic acid at a temperature between room temperature and the boiling point of the solvent for 1 to 24 hours, or in place of the above inorganic acid Compound (IIb) can be obtained by treatment with an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and lithium hydroxide. When the compound (VIa) in which G ³ is aralkyloxycarbonyl is used, the compound (IIb) can be obtained by catalytic reduction in addition to the above-mentioned method. Catalytic reduction is usually carried out at normal pressure with a catalyst amount of ~ 10
In the presence of an equivalent amount of a catalyst such as palladium carbon (Pd-C) or Raney nickel, an appropriate solvent such as alcohols such as methanol and ethanol, esters such as ethyl acetate, ethers such as THF and dioxane, or a mixture thereof. In a solvent, under a hydrogen atmosphere, if necessary, ammonia,
Or in the presence of an organic acid such as acetic acid, or hydrochloric acid, an inorganic acid such as sulfuric acid, at a temperature between room temperature and the boiling point of the solvent for 30 minutes to
Perform by treating for 12 hours.

In the compound (II), X is-(CH ₂ ) _m NH-
Wherein m is as defined above (II)
c) can be synthesized by the following production method. Manufacturing method 1-3

[0033]

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Wherein R ¹ , R ² , R ³ , R ⁴ , -VW-, m and
Lb is as defined above. (Step 1-3-1) Compound (VIb) is compound (Ib)
It can be obtained by reacting V) with compound (Vb) according to the method described in Step 1-2-1. (Step 1-3-2) Compound (IIc) is converted to compound (VI
b) in the presence of 1 to 10 equivalents of hydrazines such as hydrazine hydrate and phenylhydrazine, or amines such as methylamine and ethylamine in an alcohol such as methanol, ethanol and isopropanol, at room temperature to the boiling point of the solvent. At a temperature of 1 to 12 hours.

Among the compounds (Ia) in Production Method 1,
G ² is amino, substituted or unsubstituted mono- or di-lower alkylamino, substituted or unsubstituted lower alkanoylamino, substituted or unsubstituted aroylamino, substituted or unsubstituted aralkylamino, substituted or unsubstituted alkoxycarbonylamino or Compounds that are substituted or unsubstituted aralkylcarbonylamino (Ia-
b), (Ia-c), (Ia-d), (Ia-e),
(Ia-f), (Ia-g) or (Ia-h) can be synthesized by the following production method. Production method 1-4

[0036]

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Wherein R ^12a , R ^12b and R ^12c are the same or different and each represents a substituted or unsubstituted lower alkyl or a substituted or unsubstituted aralkyl, and R ^12d represents a hydrogen atom, a substituted or unsubstituted R ¹³ represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkoxy, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyloxy; Represents, R ¹ , R ² , R ³ , R ⁴ , R ⁸ , R ⁹ , -VW-, X, Y, La and L
b is as defined above. Where R ^12a and R
^12b does not simultaneously represent a substituted or unsubstituted aralkyl. Here, lower alkyl, aralkyl, lower alkoxy and aryl are as defined above, respectively.
The definition of the substituent of the substituted lower alkyl, the substituted aralkyl, the substituted lower alkoxy and the substituted aryl is as defined above.

(Step 1-4-1) Compound (Ia-b)
Can be obtained by appropriately reducing the nitro group of compound (Ia-a) by catalytic reduction, reduction using a metal, or the like. Catalytic reduction is usually carried out at room temperature and normal pressure in the presence of a catalyst such as a catalytic amount of 10 equivalents of Raney nickel, Pd-C, platinum oxide, etc., in a suitable solvent such as methanol, ethanol, ethyl acetate, dioxane, THF, acetic acid. , Water or a mixed solvent thereof under a hydrogen atmosphere. The reduction using a metal is carried out, for example, under conditions of 1 to 100 equivalents of zinc / acetic acid, iron / acetic acid, iron / hydrochloric acid, iron / ferric chloride / ethanol / water, tin / hydrochloric acid and the like, from room temperature to the boiling point of the solvent used. It is carried out at a temperature between

(Step 1-4-2) Compound (Ia-c)
Is a compound (Ia-b) and 1 to 1.5 equivalents of R ^12a -Lb (wherein R ^12a and Lb have the same meanings as defined above), respectively, and a suitable solvent such as methylene chloride, chloroform, dichloroethane, tetrachloroethane. Halogenated hydrocarbons such as methyl acetate, ethyl acetate, esters such as butyl acetate, ethers, ethers such as THF, 1,4-dioxane, aprotic polar solvents such as acetonitrile, DMF, DMSO, or these. 1 to 5 as needed in a mixed solvent
At a temperature between 0 ° C. and the boiling point of the solvent in the presence of an equivalent amount of base,
It can be obtained by reacting for 1 to 72 hours.

As the base, alkylamines such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridines such as pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium carbonate,
Alkali metal carbonates such as sodium hydrogen carbonate, alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide, alkali metal hydrides such as sodium hydride and lithium hydride, sodium methoxide, sodium ethoxide And alkali metal alkoxides such as potassium tert-butoxide.

(Step 1-4-3) Compound (Ia-d)
Is a compound (Ia-c) having 1 to 10 equivalents of R^12b−Lb (expression
Medium, R ^12bAnd Lb are as defined above, respectively)
Reacting according to the method described in Step 1-4-2
Can be manufactured.

(Step 1-4-4) Compound (Ia-b)
1 to 10 equivalents of R ^12c —CO—R ^12d (wherein R ^12c and R ^12c
12d is as defined above), a suitable solvent,
For example, methanol, ethanol, alcohols such as isopropanol, benzene, aromatic hydrocarbons such as toluene, ether, THF, ethers such as dioxane,
Or in a mixed solvent thereof, if necessary, a suitable base such as triethylamine, diisopropylethylamine,
In the presence of an alkylamine such as N-methylmorpholine, an alkali metal carbonate such as potassium carbonate or sodium hydrogen carbonate, etc., at a temperature between 0 ° C. and the boiling point of the solvent used, 1 to 48
Let react for hours. If necessary, a dehydrating agent such as molecular sieves may be appropriately added. Then under suitable reducing conditions, for example 1 to 10 equivalents of a suitable reducing agent, such as sodium borohydride, sodium cyanoborohydride,
By treating with a metal hydride complex such as sodium triacetoxyborohydride at a temperature between 0 ° C. and the boiling point of the solvent used for 30 minutes to 24 hours, or at room temperature to the boiling point of the solvent under normal conditions of catalytic reduction. The compound (Ia-e) can be obtained by performing hydrogenation at a temperature between the above.

(Step 1-4-5) Compound (Ia-b)
2 to 10 equivalents of R ^12c —CO—R ^12d (wherein R ^12c and R ^12c
12d is as defined above), a suitable solvent,
For example, methanol, ethanol, alcohols such as isopropanol, methylene chloride, halogenated hydrocarbons such as dichloroethane, in the presence of an appropriate acid such as acetic acid, hydrochloric acid, sodium cyanoborohydride, sodium triacetoxyborohydride and the like At a temperature between 0 ° C and the boiling point of the solvent for 30 minutes to 24
The compound (Ia-f) can be obtained by reacting for an hour.

(Step 1-4-6) Compound (Ia-g)
Is a compound (Ia-b) and R¹³-CO-La or (R¹³−C
O) _TwoO (where R¹³And La are as defined above.
) In the presence of a suitable base in a suitable solvent such as chloride
Methylene, dichloroethane, tetrachloroethane, etc.
Such as halogenated hydrocarbons, methyl acetate and ethyl acetate
Non-prototypes such as steles, acetonitrile, DMF, DMSO
Polar solvents, pyridines, or their mixed solvents
Medium, at a temperature between 0 ° C and the boiling point of the solvent, for 30 minutes to 72 hours.
Can be obtained. Because it uses
Triethylamine, diisopropyl
Alkylamines such as ethylamine and N-methylmorpholine
Pyridines, lutidine, collidine, 4-dimethylamido
And pyridines such as nopyridine.

(Step 1-4-7) Compound (Ia-h)
Is 1 to 10 equivalents of R with compound (Ia-g)^12a−Lb (expression
Medium, R ^12aAnd Lb are as defined above, respectively)
Suitable solvents such as ether, THF, 1,4-dioxane
Non-ethers such as ethers, acetonitrile, DMF, DMSO
In a protic polar solvent or a mixed solvent thereof, 1
~ 5 equivalents of base, e.g. sodium hydride, lithium hydride
Alkali metal hydride such as sodium, sodium methoxy
, Sodium ethoxide, potassium tert-butoxide
In the presence of any alkali metal alkoxide, 0 ° C.
Obtained by reacting at a temperature between the boiling points for 1 to 72 hours.
Can be (Step 1-4-8) Compound (Ia-c) is prepared in Step 1-4
In addition to the method described in -2, the compound (Ia-h)¹³
Depending on the type of processing,
Can be manufactured. For example, R¹³Is a hydrogen atom, substitution
Or unsubstituted lower alkyl or substituted or unsubstituted
When it is a substituted aryl, it may be water, dioxane, THF, etc.
Ethers, alcohols such as methanol and ethanol
Or a compound (Ia-h) in a mixed solvent thereof
With an inorganic acid such as hydrochloric acid or sulfuric acid between room temperature and the boiling point of the solvent.
By treating for 1 to 24 hours at the temperature of
Sodium hydroxide, potassium hydroxide instead of inorganic acids
Treated with alkali metal hydroxide such as lithium hydroxide
By doing so, compound (Ia-c) is obtained. Ma
T, R¹³Is substituted or unsubstituted lower alkoxy or
When it is a substituted or unsubstituted aralkyloxy,
Water, dioxane, ethers such as THF, methanol,
Alcohols such as ethanol and ethylene glycol,
Organic acids such as acetic acid, methylene chloride, dichloroethane
Any halogenated hydrocarbons or their mixed solvents
In the compound (Ia-h), hydrochloric acid, hydrobromic acid, sulfuric acid,
Any inorganic or organic acid such as trifluoroacetic acid
At a temperature between room temperature and the boiling point of the solvent for 1 to 24 hours
Or in place of the above inorganic acid,
Al such as thorium, potassium hydroxide and lithium hydroxide
By treating with potassium metal hydroxide, the compound (Ia)
-C) can be synthesized. Furthermore, R¹³Is also replaced
Or an unsubstituted aralkyloxy,
Compound (Ia-c) by catalytic reduction in addition to the method
It is possible. Catalytic reduction is usually carried out at normal pressure with a catalyst amount of
In the presence of 10 equivalents of a catalyst such as Pd-C, Raney nickel, etc.
Solvents such as alcohols such as methanol and ethanol
, Esters such as ethyl acetate, THF, dioxa
In ethers such as
Organic acids such as ammonia and acetic acid, or salts, if necessary
In the presence of an inorganic acid such as an acid or sulfuric acid, between room temperature and the boiling point of the solvent
Finish in 30 minutes to 12 hours at a temperature of Production method 1-5

[0046]

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(Wherein R ¹ , R ² , R ³ , R ⁴ , R ¹⁰ , R ¹¹ ,
R ^12a , R ^12b , R ^12c , R ^12d , R ¹³ , U, -VW-, X, Y, La,
And Lb each have the same meaning as defined above). In compound (Ib) in Production Method 1, G ² is amino, substituted or unsubstituted mono- or di-lower alkylamino, substituted or unsubstituted lower alkanoylamino, substituted or unsubstituted Compounds (Ib-b), (Ib-c), (Ib-c) which are unsubstituted aroylamino, substituted or unsubstituted aralkylamino, substituted or unsubstituted alkoxycarbonylamino or substituted or unsubstituted aralkylcarbonylamino
bd), (Ib-e), (Ib-f), (Ib-g)
Alternatively, (Ib-h) can be produced from compound (Ib-a) according to Steps 1-4-1 to 1-4-8 described in Production Method 1-4.

The intermediates and the target compound in the above production method are isolated by a purification method commonly used in synthetic organic chemistry, for example, neutralization, filtration, extraction, drying, concentration, recrystallization, various types of chromatography and the like. It can be purified. In addition, the intermediate can be subjected to the next reaction without purification. When it is desired to obtain a salt of compound (I), when compound (I) is obtained in the form of a salt,
It may be purified as it is, or when obtained in a free form, dissolved or suspended in an appropriate organic solvent and a salt may be formed by adding an acid or a base.

The compound (I) and its pharmacologically acceptable salts may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention. Although some of the compounds (I) may have optical isomers, the present invention also includes all possible isomers, including these, and mixtures thereof.

Compound (I) obtained by the above production method
Are shown in Tables 1 to 8.

[0051]

[Table 1]

[0052]

[Table 2]

[0053]

[Table 3]

[0054]

[Table 4]

[0055]

[Table 5]

[0056]

[Table 6]

[0057]

[Table 7]

[0058]

[Table 8]

[0059]

[Table 9]

Next, the pharmacological action of the representative compound (I) will be described with reference to test examples. Test Example 1: [3H] -Nitrobenzylthioinosine (NB
I) Binding inhibitory effect 20 times (w / v) on renal cortex of Hartley male guinea pig
Of ice-cooled 50 mmol / L Tris-HCl buffer (pH 7.4) was added and homogenized. Centrifuge the homogenate (1000x
g, 4 ° C., 10 minutes) and the supernatant was collected and centrifuged at 20,000 × g, 4 ° C., 10 minutes. The resulting precipitate is homogenized again,
Centrifugation was performed similarly. Add 4000 times 50 mmol /
L Tris-HCl buffer (pH 7.4) was added and suspended, and this was used for the test.

The test compound dimethyl sulfoxide (DMS
O) [3H] -NBI 0.5 nmol / L and tissue homogenate 25 μg (wet weight) were added to the solution, and the mixture was left at 25 ° C. for 30 minutes. Next, 4 mL of ice-cold 50 mmol / L Tris-HCl buffer (pH 7.4) was added, and the reaction was stopped by rapid suction filtration on a glass filter (GF / C Whatman) or a ready filter (Beckman). did.
The filter was transferred to a scintillation vial. After drying, scintillol EX-H was added, and the radioactivity was measured with a liquid scintillation counter. Non-specific binding amount is 5 μmol / L
The binding amount was determined in the presence of NBI. The binding inhibitory action was represented by the inhibition rate at the measured concentration or the inhibition constant (Ki value) calculated by the Cheng-Prusoff equation. The results are shown in Table 9.

[0062]

[Table 10]

[0063]

[Table 11]

[0064]

[Table 12]

Test Example 2: Inhibition of [ ³ H] -adenosine uptake Citric acid-Na blood was collected from the brachial vein of a healthy adult male (age less than 40 years old), and washed red blood cells were obtained by centrifugation. 21% DMS of test compound in 100 μL of erythrocyte suspension (2.5 × 10 ⁹ / ml)
After adding 10 μL of the O solution, the mixture was allowed to stand at room temperature for 1 hour, and 10 μL of [ ³ H] -adenosine solution was added. After 10 seconds, the reaction was stopped by adding 200 μL of a dirazep solution (1 mg / mL). Trito
After lysing red blood cells with nX-100, the incorporated tritium activity was measured with a liquid scintillation counter.
The concentration (IC ₅₀ ) of the test compound that inhibited the uptake of [ ³ H] -adenosine by 50% was calculated. The results are shown in Table 10.

[0066]

[Table 13]

[0067]

[Table 14]

Compound (I) or a pharmacologically acceptable salt thereof can be used as it is or in various pharmaceutical forms. The pharmaceutical composition of the present invention can be produced by uniformly mixing an effective amount of compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient with a pharmaceutically acceptable carrier. Desirably, these pharmaceutical compositions are in unit dosage form suitable for oral or injection administration.

In preparing the compositions in oral dosage form, any useful pharmacologically acceptable carrier can be used. Oral liquid preparations such as suspensions and syrups include water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, oils such as sesame oil, olive oil, soybean oil, p- It can be produced using preservatives such as hydroxybenzoic acid esters and flavors such as strawberry flavor and peppermint. Powders, pills, capsules and tablets contain excipients such as lactose, glucose, sucrose, mannitol, starch,
Disintegrators such as sodium alginate, lubricants such as magnesium stearate, talc, binders such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin,
It can be produced using a surfactant such as a fatty acid ester and a plasticizer such as glycerin. The injection can be prepared using a carrier comprising distilled water, a salt solution, a glucose solution or a mixture of a salt solution and a glucose solution. At this time, it is prepared as a solution, suspension or dispersion using a suitable auxiliary according to a conventional method.

The compound (I) or a pharmaceutically acceptable salt thereof can be administered orally in the above-mentioned pharmaceutical form or parenterally, for example, as an injection. Although it depends on the administration form, age, weight, and symptoms of the patient, 1 to 900 mg / 60 kg / day is appropriate. Hereinafter, embodiments of the present invention will be described with reference to examples.

[0071]

EXAMPLES Example 1: 3- [1- (3,4-diethoxybenzoyl) piperidin-4-yl]-
1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (compound 1) 1,6-dimethyl-3- (piperidin-4-yl) -1,2,3,4 -Tetrahydro-2,4-dioxoquinazoline (667 mg, 2.44 mmol)
And 3,4-diethoxybenzoic acid (513 mg, 2.44 mmol) were dissolved in methylene chloride (20 mL), and triethylamine (TE
A; 1.05 mL, 7.53 mmol), 1-hydroxybenzotriazole (HOBt; 750 mg, 4.9 mmol), WSC HCl (940 mg, 4.9 mg)
(mmol) was added and stirred at room temperature for 18 hours. The reaction solution is
It was washed with mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate and then with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were triturated with ether to give Compound 1 (947 mg, yield 83%) as white crystals. Melting point (ether): 138-138.5 ℃ Elemental analysis: C ₂₆ H ₃₁ N ₃ O Calculated (%) C; 67.08, H ; 6.71, N; 9.03 Found (%) C; 67.12, H ; 6.85, N; 8.96 FAB-MS (m / z): 466 (M ⁺ +1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.99 (1H, brs), 7.48 (1H, d
d, J = 2.0, 8.6 Hz), 7.04 (3H, m), 6.86 (1H, d, J
= 7.9 Hz), 5.22 (1H, m), 4.2-4.8 (2H, m), 4.13 (2
H, q, J = 6.9 Hz), 4.12 (2H, q, J = 6.9 Hz), 3.56
(3H, s), 2.97 (2H, m), 2.79 (2H, m), 2.41 (3H, s),
1.70 (2H, m), 1.46 (6H, t, J = 6.9 Hz).

Example 2 3- [1- (2-amino-4,5-diethoxybenzoyl) piperidin-4-yl] -1,6-dimethyl-1,2,
3,4-tetrahydro-2,4-dioxoquinazoline (compound 2) 1st step: 4,5-diethoxy-2-nitrobenzoic acid (202 mg,
0.79 mmol) in DMF (20 mL).
(Piperidin-4-yl) -1,2,3,4-tetrahydro-2,4-dioxoquinazoline (217 mg, 0.79 mmol), TEA (0.22 mL,
1.58 mmol), HOBt (243 mg, 1.59 mmol), and WSC HCl
(305 mg, 1.59 mmol) was added, followed by stirring at room temperature for 2 hours. After adding DMF (2 mL) to the reaction mixture, it was
Stirred for minutes. Water was added to the reaction solution, which was extracted with methylene chloride. The organic layer was washed with 0.5 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were triturated with acetone to give 3- [1- (4,5-diethoxy-2-nitrobenzoyl) piperidin-4-yl] -1,6. -Dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline
(233 mg, yield 58%) was obtained as pale yellow crystals. ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.98 (1H, brs), 7.70 (1H,
s), 7.48 (1H, dd, J = 1.3, 8.6 Hz), 7.07 (1H, d, J
= 8.6 Hz), 6.89 (1H, s), 5.22 (1H, m), 4.92 (1H,
m), 4.25 (2H, q, J = 6.9 Hz), 4.17 (2H, q, J = 6.9
Hz), 3.55 (3H, s), 3.46 (1H, m), 3.13 (1H, m), 2.
96 (1H, m), 2.78 (2H, m), 2.41 (3H, s), 1.82 (1H,
m), 1.58 (1H, m), 1.53 (3H, t, J = 6.9 Hz), 1.50
(3H, t, J = 6.9 Hz).

Step 2: The above compound (172 mg, 0.34 m
mol) was suspended in methanol (6 mL), and 10% Pd-C (50w
/ w% H ₂ O: catalytic amount) and aqueous ammonium formate solution (160
mg, 2.5 mmol / H ₂ O 1 mL) and then heated to reflux for 50 minutes. Celite was added to the reaction solution, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with water to give Compound 2 (152 mg, yield 94%) as white crystals. Mp (H ₂ O): 110-110.5 ℃ Elemental _{analysis: C 26 H 32 N 4 O} 5 Calculated (%) C; 64.98, H ; 6.71, N; 11.66 Found (%) C; 64.96, H ; 6.88 , N; 11.72 FAB-MS (m / z): 481 (M ⁺ +1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.99 (1H, d, J = 2.0 Hz),
7.48 (1H, dd, J = 2.0,8.3 Hz), 7.07 (1H, d, J = 8.
3 Hz), 6.77 (1H, s), 6.26 (1H, s), 5.21 (1H, m), 4.
44 (2H, m), 4.05 (2H, q, J = 6.9 Hz), 4.01 (2H, q,
J = 6.9 Hz), 3.55 (3H, s), 2.98 (2H, m), 2.80 (2
H, m), 2.41 (3H, s), 1.71 (2H, m), 1.44 (3H, t, J
= 6.9 Hz), 1.38 (3H, t, J = 6.9 Hz).

Example 3 N- [2- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -4,5-Diethoxyphenyl] formamide (Compound 3) 88% Formic acid (0.23 g, 4.4 mmol) in methylene chloride (10 mL)
, And added with WSC HCl (420 mg, 2.19 mmol) under ice-cooling, followed by stirring for 15 minutes. Compound 2 (347 m
g, 0.72 mmol) and N-methylmorpholine (NMM; 0.24 mL,
2.18 mmol) in methylene chloride (20 mL) was added and stirred at room temperature overnight. Further, 88% formic acid (0.23 g, 4.4 mmol) and WSC HCl (420 mg, 2.19 mmo) were added to the reaction mixture.
After addition of formic anhydride prepared from l), the mixture was stirred at room temperature for 45 minutes. The reaction solution was washed with 1 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure. By triturating the residue with ether and washing the crude crystals with ethanol,
Compound 3 (306 mg, yield 83%) was obtained as white crystals. Mp (ether / ethanol): 129-129.5 ℃ Elemental _{analysis: C 27 H 32 N 4 O} 6 · 0.5H 2 O Calculated (%) C; 62.66, H ; 6.43, N; 10.82 Found (%) C; 62.50, H; 6.53, N; 10.72 FAB-MS (m / z): 509 (M ⁺ +1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.00 (1H, brs), 8.40 (1H,
d, J = 2.0 Hz), 7.99 (2H, m), 7.48 (1H, dd, J = 2.
0, 8.6 Hz), 7.08 (1H, d, J = 8.6 Hz), 6.83 (1H,
s), 5.23 (1H, m), 4.41 (2H, m), 4.16 (2H, q, J =
6.9 Hz), 4.08 (2H, q, J = 6.9 Hz), 3.55 (3H, s),
3.02 (2H, m), 2.80 (2H, m), 2.41 (3H, s), 1.73 (2
H, m), 1.47 (3H, t, J = 6.9 Hz), 1.44 (3H, t, J =
6.9 Hz).

Example 4: N- [2- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -4,5-Diethoxyphenyl] acetamide (Compound 4) Compound 2 (485 mg, 1.01 mmol) was treated with methylene chloride (15 mL).
And TEA (0.4 mL, 2.9 mmol), 4-dimethylaminopyridine (DMAP; catalytic amount) and acetic anhydride (0.19 mL, 2.
(01 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with 1 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give Compound 4 (412 mg, yield 78%) as a white powder. Mp (ethanol): 164-164.5 ℃ Elemental _{analysis: C 28 H 34 N 4 O} 6 · 0.5H 2 O Calculated (%) C; 63.26, H ; 6.64, N; 10.54 Found (%) C; 63.17, H; 6.70, N; 10.55 FAB-MS (m / z): 523 (M ⁺ +1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.95 (1H, brs), 7.97 (2H,
m), 7.48 (1H, dd, J = 2.0, 8.6 Hz), 7.08 (1H, d, J
= 8.6 Hz), 6.81 (1H, s), 5.23 (1H, m), 4.40 (2H, b
rs), 4.15 (2H, q, J = 6.9 Hz), 4.07 (2H, q, J = 6.
9 Hz), 3.55 (3H, s), 3.01 (2H, m), 2.79 (2H, m), 2.
42 (3H, s), 2.22 (3H, s), 1.72 (2H, m), 1.46 (3H,
t, J = 6.9 Hz), 1.43 (3H, t, J = 6.9 Hz).

Example 5: N- [2- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -4,5-Diethoxyphenyl] propionamide (Compound 5) Compound 2 (490 mg, 1.02 mmol), TEA (0.43 mL, 3.09 mm
ol), DMAP (catalytic amount) and propionyl chloride (0.18 mL,
Compound 5 (405 mg, 74%) was obtained as white crystals in the same manner as in Example 4 except that 2.07 mmol) was used. Melting point (ethanol): 138.5-139 ° C Elemental analysis: C ₂₉ H ₃₆ N ₄ O ₆ Calculated value (%) C; 64.91, H; 6.76, N; 10.44 Actual value (%) C; 64.80, H; 6.97, N 10.35 FAB-MS (m / z): 537 (M ⁺ +1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.03 (1H, brs), 8.06 (1H,
s), 7.98 (1H, d, J = 2.3 Hz), 7.48 (1H, dd, J = 2.
3, 8.6 Hz), 7.08 (1H, d, J = 8.6 Hz), 6.82 (1H,
s), 5.23 (1H, m), 4.41 (2H, brs), 4.16 (2H, q, J =
6.9 Hz), 4.07 (2H, q, J = 6.9 Hz), 3.55 (3H, s),
3.01 (2H, m), 2.79 (2H, m), 2.47 (2H, q, J = 7.6 H
z), 2.42 (3H, s), 1.72 (2H, m), 1.46 (3H, t, J =
6.9 Hz), 1.43 (3H, t, J = 6.9 Hz), 1.27 (3H, t, J =
7.6 Hz).

Example 6: N- [2- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -4,5-Diethoxyphenyl] butyramide (Compound 6) Compound 2 (497 mg, 1.03 mmol), TEA (0.44 mL, 3.16 mm
ol), DMAP (catalytic amount) and butyric anhydride (0.68 mL, 5.16 mm
Compound 6 (469 mg, 82%) was obtained as a white crystal in the same manner as in Example 4 except that (ol) was used. The final compound was purified by recrystallization from isopropanol. Mp (isopropanol): 181.5-182 ℃ Elemental _{analysis: C 30 H 38 N 4 O} 6 Calculated (%) C; 65.44, H ; 6.96, N; 10.17 Found (%) C; 65.21, H ; 7.06, N 10.02 FAB-MS (m / z): 551 (M ⁺ +1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.01 (1H, brs), 8.04 (1H,
s), 7.98 (1H, d, J = 2.3 Hz), 7.48 (1H, dd, J =
2.3, 8.6 Hz), 7.08 (1H, d, J = 8.6 Hz), 6.82 (1H,
s), 5.23 (1H, m), 4.41 (2H, brs), 4.16 (2H, q, J =
6.9 Hz), 4.07 (2H, q, J = 6.9 Hz), 3.55 (3H, s),
3.01 (2H, m), 2.79 (2H, m), 2.41 (3H, s), 2.40 (2
H, m), 1.77 (2H, m), 1.74 (2H, m), 1.46 (3H, t, J
= 6.9 Hz), 1.42 (3H, t, J = 6.9 Hz), 1.04 (3H, t,
J = 7.6 Hz).

Example 7: 3- [1- (4,5-dimethoxy-2-nitrobenzoyl) piperidine
-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (compound 10) 4,5-dimethoxy-2-nitrobenzoic acid (2.5 g, 11 mmol )
Was dissolved in methylene chloride (90 mL) to give 1,6-dimethyl-3-
(Piperidin-4-yl) -1,2,3,4-tetrahydro-2,4-dioxoquinazoline (3.01 g, 11 mmol), TEA (4.6 mL, 33
mmol), HOBt (3.37 g, 22 mmol), and WSC HCl (4.22
g, 22 mmol), and the mixture was stirred at room temperature for 7 hours and 30 minutes.
The reaction solution was diluted with methylene chloride, chloroform and methanol, washed with 1 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude crystals were triturated with acetone / ether to give Compound 10 (4.78
g, yield 90%) as pale yellow crystals. Melting point (acetone / ether): 279-280 ° C EI-MS (m / z): 482 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.98 (1H, s), 7.72 (1H, s) ),
7.48 (1H, d, J = 8.3Hz), 7.08 (1H, d, J = 8.6H
z), 6.92 (1H, s), 5.23 (1H, m), 4.88 (1H, m), 4.05
(3H, s), 3.98 (3H, s), 3.55 (3H, s), 3.47 (1H, m),
3.14 (1H, m), 2.95 (2H, m), 2.41 (3H, s), 1.80 (1
H, m), 1.60 (1H, m).

Example 8: 3- [1- (2-amino-4,5-dimethoxybenzoyl) piperidine
-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (Compound 7) Compound 10 (4.2 g, 8.7 mmol) in methanol (210 mL)
After adding 10% Pd-C (50 w / w% H ₂ O: 0.42 g) and an aqueous solution of ammonium formate (4.12 g, 65.3 mmol / 63 mL of H ₂ O), the mixture was heated under reflux for 5 hours. Celite was added to the reaction solution, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was partitioned with chloroform / water, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1), and the obtained crude crystals were triturated with diisopropyl ether to give Compound 7 (3.36 g, yield 85%) as white crystals. As obtained. Melting point (diisopropyl ether): 235-236 ° C Elemental analysis: C ₂₄ H ₂₈ N ₄ O ₅ Calculated value (%) C; 63.70, H; 6.24, N; 12.38 Actual value (%) C; 63.64, H; 6.48, N; 12.01 EI-MS (m / z): 452 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.98 (1H, s), 7.47 (1H, dd,
J = 2.0, 8.3 Hz), 7.08 (1H, d, J = 8.6 Hz), 6.76
(1H, s), 6.36 (1H, s), 5.22 (1H, m), 4.39 (2H, m),
3.85 (3H, s), 3.82 (3H, s), 3.55 (3H, s), 3.00 (2
H, m), 2.83 (2H, m), 2.41 (3H, s), 1.72 (2H, m).

Example 9: N- [2- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -4,5-Dimethoxyphenyl] propionamide (Compound 8) Compound 7 (300 mg, 0.66 mmol) was treated with methylene chloride (20 mL).
Dissolved in TEA (0.28 mL, 2.0 mmol), DMAP (catalytic amount),
After adding propionic anhydride (0.17 mL, 1.33 mmol), the mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with chloroform, washed with 1 mol / L hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography.
(Chloroform: methanol = 40: 1), and the obtained crude crystals were triturated with diisopropyl ether to give Compound 8 (220 mg, yield 65%) as a white powder. Mp (diisopropyl ether): 169-170 ° C. Elemental _{analysis: C 27 H 32 N 4 O} 6 Calculated (%) C; 63.77, H ; 6.34, N; 11.02 Found (%) C; 63.87, H ; 6.47, N; 11.19 EI-MS (m / z): 508 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.99 (1H, s), 8.04 (1H, s),
7.98 (1H, d, J = 2.3Hz), 7.49 (1H, dd, J = 2.3,
8.6 Hz), 7.08 (1H, d, J = 8.6 Hz), 5.24 (1H, m), 4.
44 (2H, m), 3.93 (3H, s), 3.87 (3H, s), 3.55 (3H,
s), 3.02 (2H, m), 2.81 (2H, m), 2.49 (2H, q, J =
7.6 Hz), 2.41 (3H, s), 1.73 (2H, d, J = 13.2 Hz),
1.28 (3H, t, J = 7.6 Hz).

Example 10: N- [2- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -4,5-Dimethoxyphenyl] cyclopentanecarboxamide (Compound 9) Dissolve cyclopentanecarboxylic acid (0.14 mL, 1.3 mmol) in methylene chloride (6 mL), and add NMM (0.29 mL, 1.3 mmo).
l) was added to prepare cyclopentanecarboxylic anhydride. A methylene chloride solution (6 mL) of the compound 7 (300 mg, 0.66 mmol) was added thereto, and the mixture was stirred at room temperature. After 16 hours and 25 hours, cyclopentanecarboxylic anhydride and NMM prepared as described above were added, and the mixture was further stirred overnight. The reaction solution was diluted with chloroform, washed with 1 mol / L hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from ethanol to obtain Compound 9 (270 mg, yield 74%) as white crystals. Mp (ethanol): 193-194 ° C. Elemental _{analysis: C 30 H 36 N 4 O} 6 · 0.4H 2 O Calculated (%) C; 64.83, H ; 6.67, N; 10.08 Found (%) C; 64.72, H; 6.73, N; 10.21 EI-MS (m / z): 548 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.07 (1H, s), 8.10 (1H, s),
7.98 (1H, d, J = 2.6Hz), 7.49 (1H, dd, J = 7.5,
8.6 Hz), 7.08 (1H, d, J = 8.6 Hz), 6.81 (1H, s), 5.
25 (1H, m), 4.45 (2H, m), 3.99 (1H, d, J = 6.9 H
z), 3.93 (3H, s), 3.87 (3H, s), 3.54 (3H, s), 3.02
(2H, m), 2.79 (2H, m), 2.41 (3H, s), 1.75 (8H, m).

Example 11: 3- [1- (4-ethoxy-5-methoxy-2-nitrobenzoyl) piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro
-2,4-dioxoquinazoline (Compound 17) Journal of Medicinal Chemistry (J. M
ed. Chem.), 20, 146-149 (1977).
Nitrobenzoic acid (2.0 g, 8.3 mmol) was added to methylene chloride.
(72 mL) and 1,6-dimethyl-3- (piperidin-4-yl) -1,2,3,4-tetrahydro-2,4-dioxoquinazoline
(2.26 g, 8.27 mmol), TEA (3.45 mL, 24.8 mmol), HOB
t (2.53 g, 16.5 mmol), and WSC HCl (3.17 g, 16.5 mmol)
(mmol) was added and stirred at room temperature for 5 hours. The reaction solution was diluted with methylene chloride, chloroform and methanol, washed with 2 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate and then with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude crystals were triturated with acetone / ether to give Compound 17 (3.51 g, yield 86%) as white crystals. Melting point (acetone / ether): 227-229 ° C EI-MS (m / z): 496 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.98 (1H, s), 7.70 (1H, s) ),
7.49 (1H, d, J = 6.6Hz), 7.09 (1H, d, J = 8.3H
z), 6.90 (1H, s), 5.23 (1H, m), 4.93 (2H, m), 4.18
(2H, q, J = 6.9 Hz), 4.04 (3H, s), 3.56 (3H, s),
3.13 (2H, m), 2.97 (2H, m), 2.41 (3H, s), 1.81 (2
H, m), 1.52 (3H, t, J = 6.9 Hz).

Example 12: 3- [1- (2-Amino-4-ethoxy-5-methoxybenzoyl) piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro
-2,4-Dioxoquinazoline hydrochloride (Compound 11) Compound 17 (3.30 g, 6.65 mmol) in methanol (165 mL)
Suspended in, 10% Pd-C (50w / w% H 2 O: 0.33 g), aqueous solution of ammonium formate acid was added (3.14 g, 49.8 mmol / H 2 O50 mL), it was heated under reflux for 3 hours 30 minutes . Celite was added to the reaction solution, followed by filtration, and the filtrate was partitioned with water / chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1),
The crude crystals obtained were triturated with diisopropyl ether to give the free base of compound 11 (2.55
g, yield 82%). This free base (300 mg, 0.64 mmo
l) was dissolved in ethanol (8 mL), and 4 mol / L hydrochloric acid / ethyl acetate was added. The precipitated white crystals were collected by filtration to obtain Compound 11 (0.28 g, 87%). Mp (ethanol): 178-179 ° C. Elemental _{analysis: C 25 H 30 N 4 O} 5 · HCl · 1.1H 2 O Calculated (%) C; 57.43, H ; 6.40, N; 10.72 Found (%) C; 57.43, H; 6.46, N; 10.70 EI-MS (m / z): 466 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.84 (1H, s), 7.60 (1H,
d, J = 8.6 Hz), 7.34 (1H, d, J = 8.6 Hz), 6.90 (1
H, s), 6.86 (1H, s), 5.10 (1H, m), 4.15 (2H, m),
4.02 (2H, q, J = 6.9 Hz), 3.77 (3H, s), 3.48 (3H,
s), 3.04 (2H, m), 2.60 (2H, m), 2.37 (3H, s), 1.67
(2H, m), 1.35 (3H, t, J = 6.9 Hz).

Example 13: N- [2- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -5-Ethoxy-4-methoxyphenyl] acetamide (Compound 13) The free base of Compound 11 (300 mg, 0.59 mmol) was dissolved in methylene chloride (20 mL), and TEA (0.27 mL, 1.9 mmol), DM
After adding AP (catalytic amount) and acetic anhydride (0.12 mL, 1.3 mmol), the mixture was stirred at room temperature for 6 hours and 30 minutes. 1 mol of the reaction solution
After washing with / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. By recrystallizing the residue from ethanol, compound 13 (0.26
g, 80% yield) as white crystals. Mp (ethanol): 187-188 ° C. Elemental _{analysis: C 27 H 32 N 4 O} 6 · H 2 O Calculated (%) C; 61.58, H ; 6.51, N; 10.64 Found (%) C; 61.55, H 6.59, N; 10.65 EI-MS (m / z): 508 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.94 (1H, s), 7.98 (1H, s),
7.91 (1H, s), 7.49 (1H, d, J = 6.3 Hz), 7.08 (1H,
d, J = 8.6 Hz), 6.80 (1H, s), 5.24 (1H, m), 4.16
(2H, q, J = 6.9 Hz), 3.86 (3H, s), 3.55 (3H, s),
3.03 (2H, m), 2.83 (2H, m), 2.41 (3H, s), 2.24 (3
H, s), 1.85 (2H, m), 1.73 (2H, m), 1.47 (3H, t, J =
6.9 Hz).

Example 14: N- [2- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -5-Ethoxy-4-methoxyphenyl] propionamide
(Compound 15) The free base of Compound 11 (300 mg, 0.66 mmol) was dissolved in methylene chloride (20 mL), and TEA (0.27 mL, 1.9 mmol), DM
AP (catalytic amount) and propionic anhydride (0.16 mL, 1.3 mmo
After l) was added, the mixture was stirred at room temperature for 24 hours. Propionic anhydride (0.08 mL, 0.6 mmol) and TEA (0.09 mL, 0.6
mmol), and the mixture was further stirred for 6 hours and 30 minutes. Dilute the reaction solution with chloroform, 2 mol / L hydrochloric acid, saturated aqueous sodium bicarbonate,
Then, it was washed with saturated saline and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform: methanol =
50: 1), and the resulting crude crystals were triturated with ethyl acetate / ether to give Compound 15
(268 mg, 80% yield) as white crystals. Melting point (ethyl acetate / ether): 156-157 ° C Elemental analysis: C ₂₈ H ₃₄ N ₄ O ₆ Calculated (%) C; 64.35, H; 6.56, N; 10.72 Found (%) C; 64.60, H; 6.69, N; 10.39 EI-MS (m / z): 522 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.99 (1H, s), 8.01 (1H, s),
7.98 (1H, s), 7.49 (1H, d, J = 7.9 Hz), 7.08 (1H,
d, J = 8.6 Hz), 6.81 (1H, s), 5.24 (1H, m), 4.20
(2H, q, J = 6.9 Hz), 3.86 (3H, s), 3.55 (3H, s),
3.02 (2H, m), 2.77 (2H, m), 2.48 (2H, q, J = 7.6 H
z), 2.41 (3H, s), 1.90 (2H, m), 1.75 (2H, m), 1.47
(3H, t, J = 6.9 Hz), 1.26 (3H, t, J = 7.6 Hz). Compounds 18, 12, 14 and 16 were prepared in Examples 11 and 1 respectively.
Obtained according to 2, 13, and 14.

Example 15: 3- [1- (5-ethoxy-4-methoxy-2-nitrobenzoyl) piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro
-2,4-dioxoquinazoline (compound 18) Melting point (acetone / ether): 228-230 ° C EI-MS (m / z): 496 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.98 (1H, s), 7.71 (1H, s),
7.49 (1H, d, J = 6.9Hz), 7.08 (1H, d, J = 8.6H
z), 6.90 (1H, s), 5.22 (1H, m), 4.90 (2H, m), 4.27
(2H, q, J = 5.6 Hz), 3.97 (3H, s), 3.56 (3H, s),
3.14 (2H, m), 2.96 (2H, m), 2.41 (3H, s), 1.54 (3
(H, t, J = 6.9 Hz).

Example 16: 3- [1- (2-amino-5-ethoxy-4-methoxybenzoyl) piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro
-2,4-Dioxoquinazoline hydrochloride (Compound 12) Melting point (ethanol): 257-258 ° C Elemental analysis: C ₂₅ H ₃₀ N ₄ O ₅ .HCl. 1.1 H ₂ O Calculated value (%) C; 57.43, H; 6.40, N; 10.72 actual value (%) C; 57.42, H; 6.44, N; 10.66 EI-MS (m / z): 466 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm ): 7.84 (1H, s), 7.60 (1H, d
d, J = 2.0, 8.6 Hz), 7.34 (1H, d, J = 8.6 Hz), 6.8
8 (1H, s), 6.84 (1H, s), 5.09 (1H, m), 4.15 (2H,
m), 4.01 (2H, q, J = 6.9 Hz), 3.78 (3H, s), 3.48
(3H, s), 3.03 (2H, m), 2.59 (2H, m), 2.37 (3H, s),
1.66 (2H, m), 1.31 (3H, t, J = 6.9 Hz).

Example 17: N- [2- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -4-ethoxy-5-methoxyphenyl] acetamide (compound 14) mp (ethanol): 143-144 ° C. elemental _{analysis: C 27 H 32 N 4 O} 6 · H 2 O calculated (%) C; 61.58, H 6.51, N; 10.64 actual value (%) C; 61.68, H; 6.78, N; 10.52 EI-MS (m / z): 508 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.96 (1H, s), 7.98 (1H, s),
7.93 (1H, s), 7.49 (1H, d, J = 8.6 Hz), 7.08 (1H,
d, J = 8.2 Hz), 6.80 (1H, s), 5.24 (1H, m), 4.07
(2H, q, J = 6.9 Hz), 3.91 (3H, s), 3.55 (3H, s),
3.02 (2H, m), 2.81 (2H, m), 2.41 (3H, s), 2.24 (3
H, s), 1.74 (2H, m), 1.45 (3H, t, J = 6.9 Hz).

Example 18: N- [2- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -4-Ethoxy-5-methoxyphenyl] propionamide
(Compound 16) Melting point (ethyl acetate / ether): 199-200 ° C Elemental analysis: C ₂₈ H ₃₄ N ₄ O ₆ · 0.5 H ₂ O Calculated value (%) C; 63.26, H; 6.64, N; 10.54 Actual value (%) C; 63.25, H; 6.74, N; 10.45 EI-MS (m / z): 522 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.02 (1H, s), 8.04 ( 1H, s),
7.98 (1H, s), 7.48 (1H, dd, J = 2.0, 8.6 Hz), 7.0
8 (1H, d, J = 8.2 Hz), 6.81 (1H, s), 5.23 (1H, m),
4.07 (2H, q, J = 6.9 Hz), 3.92 (3H, s), 3.55 (3H,
s), 3.02 (2H, m), 2.75 (2H, m), 2.49 (2H, q, J =
7.6 Hz), 2.41 (3H, s), 1.74 (4H, m), 1.45 (3H, t,
J = 6.9 Hz), 1.27 (3H, t, J = 7.6 Hz).

Example 19: 3- [1- (5-ethoxy-2-nitro-4-phenylmethoxybenzoyl) piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro- 2,4-Dioxoquinazoline (Compound 30) Journal of Medicinal Chemistry (J.M.
Chem.), 20, 146-149 (1977), 5-ethoxy-2-nitro-4-phenylmethoxybenzoic acid synthesized from ethylvanillin (3.03 g,
9.5 mmol) in methylene chloride (110 mL) and 1,6-dimethyl-3- (piperidin-4-yl) -1,2,3,4-tetrahydro-
2,4-dioxoquinazoline (2.60 g, 9.5 mmol), TEA (3.
98 mL, 28.6 mmol), HOBt (2.92 g, 19.1 mmol) and W
After addition of SC HCl (3.65 g, 19.0 mmol), the
Stirred for hours. Dilute the reaction solution with methylene chloride, chloroform and methanol, and add 2 mol / L hydrochloric acid, saturated aqueous sodium bicarbonate,
Next, after washing with saturated saline, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were triturated with acetone / ether to give Compound 30 (3.85 g, yield 71%) as white crystals. Melting point (acetone / ether): 220-222 ° C EI-MS (m / z): 572 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.98 (1H, s), 7.76 (1H, s) ),
7.45 (6H, m), 7.08 (1H, d, J = 8.2 Hz), 6.91 (1H,
s), 5.21 (2H, s), 4.91 (1H, m), 4.27 (2H, q, J =
6.3 Hz), 3.55 (3H, s), 3.42 (2H, m), 3.12 (2H, m),
2.95 (2H, m), 2.41 (3H, s), 1.80 (2H, m), 1.53 (3
(H, t, J = 6.9 Hz).

Example 20: 3- [1- (2-amino-5-ethoxy-4-hydroxybenzoyl)
Piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (compound 20) Compound 30 (10.0 g, 17.5 mmol) in methanol (524 mL)
Dissolved in 10% Pd-C (50w / w% H ₂ O: 12.2 g) and an aqueous solution of ammonium formate (5.24 g, 83.1 mmol / H ₂ O 150 m
After L) was added, the mixture was heated under reflux for 4 hours. 10% Pd-C (3.0
g) and ammonium formate (1.29 g, 20.1 mmol) were added, and the mixture was further refluxed for 1 hour. Celite was added to the reaction solution, followed by filtration, and the filtrate was partitioned with water / chloroform. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1), and the obtained crude crystals were triturated with diisopropyl ether to give compound 20 (5.81 g,
Yield 74%). Melting point (diisopropyl ether): 126-127 ° C EI-MS (m / z): 452 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 9.08 (1H, s), 7.84 (1H,
s), 7.59 (1H, dd, J = 2.0, 8.6 Hz), 7.33 (1H, d, J
= 8.3 Hz), 6.58 (1H, s), 6.22 (1H, s), 5.07 (1H,
m), 4.90 (2H, s), 4.17 (2H, m), 3.87 (2H, q, J =
6.9 Hz), 3.47 (3H, s), 2.96 (2H, m), 2.36 (3H, s),
1.62 (2H, m), 1.26 (3H, t, J = 6.9 Hz).

Example 21: N- [2- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -4-Ethoxy-5-hydroxyphenyl] propionamide (Compound 22) Compound 20 (5.24 g, 11.6 mmol) was suspended in water (350 mL), and propionic anhydride (7.42 mL, 57.9 mmol) was added. The mixture was stirred at room temperature for 17 hours and 30 minutes. By filtering the precipitated solid and triturating with ethanol,
Compound 22 (5.15 g, yield 87%) was obtained. Melting point (ethanol): 217-218 ° C EI-MS (m / z): 508 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.88 (1H, s), 7.97 (1H, s),
7.95 (1H, s), 7.49 (1H, dd, J = 5.6, 8.6 Hz), 7.0
8 (1H, dd, J = 4.3, 8.6 Hz), 6.78 (1H, s), 5.23 (1
H, m), 4.09 (2H, q, J = 6.9 Hz), 3.57 (2H, m), 3.5
5 (3H, s), 3.00 (2H, m), 2.80 (2H, m), 2.47 (2H, q,
J = 7.6 Hz), 2.41 (3H, s), 1.73 (2H, m), 1.44 (3H,
t, J = 6.6 Hz), 1.27 (3H, t, J = 7.3 Hz).

Example 22: Ethyl [4- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,
4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -2-ethoxy-5-propionylaminophenoxy]
Acetate (Compound 24) Compound 22 (4.70 g, 9.2 mmol) was dissolved in DMF (100 mL), and ethyl bromoacetate (1.13 mL, 10.2 mmol) and cesium carbonate (3.91 g, 12.0 mmol) were added. In 3
Stirred for 0 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product as a pale yellow oil (5.33 g, apparent yield 97%).
Of these, 150 mg was crystallized from ethyl acetate / n-hexane to obtain Compound 24 (150 mg) as white crystals. Melting point (ethyl acetate / n-hexane): 158-159 ° C EI-MS (m / z): 594 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 9.30 (1H, s), 7.83 (1H,
s), 7.59 (1H, d, J = 8.6 Hz), 7.32 (1H, d, J = 8.6
Hz), 7.14 (1H, s), 6.84 (1H, s), 5.07 (1H, m), 4.
76 (2H, s), 4.17 (2H, q, J = 6.9 Hz), 4.05 (2H, q,
J = 6.9 Hz), 3.47 (3H, s), 2.96 (2H, m), 2.89 (2
H, m), 2.36 (3H, s), 1.60 (2H, m), 1.33 (3H, t, J =
6.9 Hz), 1.21 (3H, t, J = 6.9 Hz), 1.08 (3H, t, J
= 7.6 Hz).

Example 23: N- [2- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -4-Ethoxy-5- (2-hydroxyethoxy) phenyl] propionamide (Compound 28) Compound 24 (0.6 g, 1.0 mmol) was dissolved in ethanol (15 mL), and sodium borohydride (0.19 g, 5.0 mmol)
Was added and the mixture was heated under reflux for 1 hour. The reaction was concentrated under reduced pressure and the residue was partitioned with ethyl acetate / water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude crystals were triturated with ethanol to give Compound 28 (0.37 g, yield
65%) as white crystals. Mp (ethanol): 196-197 ° C. Elemental _{analysis: C 29 H 36 N 4 O} 7 · 1.2H 2 O Calculated (%) C; 60.66, H ; 6.74, N; 9.76 Found (%) C; 60.55, H; 6.52, N; 9.78 EI-MS (m / z): 552 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.94 (1H, s), 8.04 (1H, s),
7.97 (1H, s), 7.49 (1H, d, J = 8.6 Hz), 7.08 (1H,
d, J = 8.6 Hz), 6.82 (1H, s), 5.24 (1H, m), 4.19 (2
H, t, J = 4.6 Hz), 4.06 (2H, q, J = 6.9 Hz), 3.94
(2H, t, J = 4.6Hz), 3.55 (3H, s), 3.01 (2H, m), 2.
80 (2H, m), 2.48 (2H, q, J = 7.6 Hz), 2.41 (3H,
s), 2.07 (2H, m), 1.75 (2H, s), 1.43 (3H, t, J =
6.9 Hz), 1.26 (3H, t, J = 7.6 Hz).

Example 24: [4- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl]
2-ethoxy-5-propionylaminophenoxy] acetic acid
(Compound 26) Compound 24 (500 mg, 0.84 mmol) in methanol (15 mL)
Dissolved in sodium hydroxide aqueous solution (40 mg, 1 mmol /
After adding H ₂ O (5 mL), the mixture was heated under reflux for 30 minutes. The methanol was distilled off under reduced pressure, and the residue was diluted with water.
And The precipitated white crystals were collected by filtration to give Compound 26 (430 mg, yield 74%). Mp (H ₂ O): 147-149 ℃ Elemental _{analysis: C 29 H 34 N 4 O} 8 · 1.2H 2 O Calculated (%) C; 59.21, H ; 6.24, N; 9.52 Found (%) C; 59.31, H; 6.35, N; 9.57 EI-MS (m / z): 566 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 9.32 (1H, s), 7.82 (1H,
s), 7.58 (1H, dd, J = 2.0, 8.6 Hz), 7.32 (1H, d, J
= 8.6 Hz), 7.12 (1H, s), 6.82 (1H, s), 5.05 (1H,
m), 4.66 (2H, s), 4.05 (2H, q, J = 6.9 Hz), 3.46
(3H, s), 2.36 (3H, s), 1.59 (2H, m), 1.33 (3H, t, J
= 6.9 Hz), 1.07 (3H, t, J = 7.6 Hz) Compounds 29 and 1
9, 21, 23, 27 and 25 were obtained according to Examples 19 to 24, respectively, except that 4-ethoxy-2-nitro-5-phenylmethoxybenzoic acid was used as a raw material.

Example 25: 3- [1- (4-ethoxy-2-nitro-5-phenylmethoxybenzoyl) piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro- 2,4-dioxoquinazoline (Compound 29) Melting point (ethyl acetate): 179-180 ° C. EI-MS (m / z): 572 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.00 ( 1H, s), 7.72 (1H, s),
7.39 (6H, m), 7.09 (1H, d, J = 8.3 Hz), 6.98 (1H,
s), 5.30 (2H, s), 4.90 (2H, m), 4.19 (2H, q, J =
6.6 Hz), 3.56 (3H, s), 3.35 (2H, m), 3.09 (2H, m),
2.89 (2H, m), 2.41 (3H, s), 1.78 (2H, m), 1.50 (3
(H, t, J = 6.9 Hz).

Example 26: 3- [1- (2-amino-4-ethoxy-5-hydroxybenzoyl)
Piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (Compound 19) Melting point (diisopropyl ether): 230-231 ° C. EI-MS (m / m z): 452 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 8.20 (1H, s), 7.84 (1H,
s), 7.59 (1H, d, J = 8.6 Hz), 7.33 (1H, d, J = 8.6 Hz)
Hz), 6.52 (1H, s), 6.33 (1H, s), 5.07 (1H, m), 4.
74 (2H, s), 4.17 (2H, m), 3.95 (2H, q, J = 6.9 H
z), 3.47 (3H, s), 2.93 (2H, m), 2.55 (2H, m), 2.36
(3H, s), 1.65 (2H, m), 1.32 (3H, t, J = 6.9 Hz).

Example 27: N- [2- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -5-Ethoxy-4-hydroxyphenyl] propionamide (Compound 21) Melting point (ethanol): 137-138 ° C EI-MS (m / z): 508 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ ( ppm): 9.06 (1H, s), 7.99 (2H, s),
7.48 (1H, dd, J = 2.1, 8.6 Hz), 7.08 (1H, d, J =
8.6 Hz), 6.86 (1H, s), 5.22 (1H, m), 4.18 (2H, q,
J = 6.9 Hz), 3.55 (3H, s), 2.99 (2H, m), 2.75 (2H,
m), 2.47 (2H, q, J = 7.6 Hz), 2.41 (3H, s), 1.73
(2H, m), 1.44 (3H, t, J = 6.9 Hz), 1.26 (3H, t, J
= 7.6 Hz).

Example 28: Ethyl [5- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,
4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -2-ethoxy-4-propionylaminophenoxy]
Acetate (Compound 23) Melting point (ethanol): 140-141 ° C EI-MS (m / z): 594 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 9.35 (1H, s), 7.82 (1H,
s), 7.58 (1H, d, J = 6.9 Hz), 7.32 (1H, d, J = 8.6
Hz), 7.27 (1H, s), 6.73 (1H, s), 5.04 (1H, m), 4.
79 (2H, s), 4.16 (2H, q, J = 7.3 Hz), 4.03 (2H, q,
J = 7.3 Hz), 3.47 (3H, s), 2.89 (2H, m), 2.36 (3
H, s), 1.56 (2H, m), 1.34 (3H, t, J = 6.9 Hz), 1.2
0 (3H, t, J = 7.3 Hz), 1.08 (3H, t, J = 7.6 Hz).

Example 29: N- [2- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -5-ethoxy-4- (2-hydroxyethoxy) phenyl] propionamide (compound 27) melting point (ethyl acetate / n-hexane): 122-123 ° C. elemental _{analysis: C 29 H 36 N 4 O} 7 · 0.6H ₂ O Calculated (%) C; 61.82, H; 6.65, N; 9.94 Found (%) C; 61.86, H; 6.90, N; 9.80 EI-MS (m / z): 552 (M ⁺ ) ¹ H -NMR (DMSO-d ₆ ) δ (ppm): 9.32 (1H, s), 7.83 (1H,
s), 7.59 (1H, d, J = 8.6 Hz), 7.32 (1H, d, J = 8.6
Hz), 7.24 (1H, s), 6.84 (1H, s), 5.06 (1H, m), 4.
83 (2H, t, J = 5.3 Hz), 4.04 (2H, q, J = 6.9 Hz),
4.01 (2H, q, J = 7.3 Hz), 3.71 (2H, t, J = 5.3 Hz),
3.47 (3H, s), 2.36 (3H, s), 1.59 (2H, m), 1.34 (3
H, t, J = 6.9 Hz), 1.08 (3H, t, J = 7.2 Hz).

Example 30: [5- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl]
-2-ethoxy-4-propionylaminophenoxy] acetic acid
(Compound 25) Melting point (ether): 200-201 ° C Elemental analysis: C ₂₉ H ₃₄ N ₄ O ₈ · 0.3H ₂ O Calculated value (%) C; 60.89, H; 6.10, N; 9.79 Actual value (%) C; 60.91, H; 6.28, N; 9.69 EI-MS (m / z): 566 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 9.34 (1H, s), 7.83 (1H ,
s), 7.59 (1H, d, J = 7.3 Hz), 7.33 (1H, d, J = 8.6
Hz), 7.26 (1H, s), 6.73 (1H, s), 5.05 (1H, m), 4.
69 (2H, s), 4.03 (2H, q, J = 6.9 Hz), 3.47 (3H,
s), 2.36 (3H, s), 1.57 (2H, m), 1.34 (3H, t, J =
6.9 Hz), 1.08 (3H, t, J = 7.6 Hz).

Example 31: 3- [1- (4,5-diethoxy-2-nitrobenzoyl) piperidine
-4-yl] -6-methyl-4-oxo-3,4-dihydroquinazoline
(Compound 31) 4,5-diethoxy-2-nitrobenzoic acid (2.5 g, 9.8 mmol)
Was dissolved in methylene chloride (90 mL), and 6-methyl-3- (piperidin-4-yl) -4-oxo-3,4-dihydroquinazoline synthesized by a method described in JP-A-8-151377 and the like was used. Dihydrobromide (4.0 g, 9.8 mmol), TEA (4.1 mL, 29 mmo
l), HOBt (3.0 g, 19.6 mmol) and WSC HCl (3.76 g, 1
(9.6 mmol) and stirred at room temperature for 16 hours. The reaction solution was diluted with chloroform, washed with 1 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was triturated with acetone / ether to give Compound 31.
(4.46 g, yield 95%) was obtained as pale yellow crystals. Melting point (acetone / ether): 248-249 ° C Elemental analysis: C ₂₅ H ₂₈ N ₄ O ₆ .0.3 H ₂ O Calculated value (%) C; 61.79, H; 5.93, N; 11.53 Actual value (%) C; 61.76, H; 5.89, N; 11.78 EI-MS (m / z): 480 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.14 (1H, s), 8.09 (1H, s),
7.71 (1H, s), 7.62 (1H, d, J = 6.9 Hz), 6.83 (1H,
s), 6.74 (1H, s), 5.17 (1H, m), 5.04 (1H, m), 4.19
(4H, q, J = 6.9 Hz), 3.64 (1H, m), 3.28 (1H, m),
2.97 (1H, m), 2.50 (3H, s), 2.00 (4H, m), 1.51 (6
(H, t, J = 6.9 Hz).

Example 32: 3- [1- (2-amino-4,5-diethoxybenzoyl) piperidine
-4-yl] -6-methyl-4-oxo-3,4-dihydroquinazoline
(Compound 32) Compound 31 (4.0 g, 8.3 mmol) was added to methanol (200 mL) /
Dissolve in water (60 mL) and add 10% Pd-C (50 w / w% H ₂ O: 400 mg)
After adding ammonium formate (3.94 g, 62.5 mmol), the mixture was heated under reflux for 3 hours. Celite was added to the reaction solution, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with water and extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1). The resulting crude crystals were triturated with diisopropyl ether to give Compound 32 (3.13 g, yield 83%) as white crystals. Mp (diisopropyl ether): 174-175 ° C. Elemental _{analysis: C 25 H 30 N 4 O} 4 · 0.3H 2 O Calculated (%) C; 65.86, H ; 6.76, N; 12.29 Found (%) C; 65.96 , H; 6.77, N; 12.42 EI-MS (m / z): 450 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.20 (1H, s), 8.06 (1H, s),
7.58 (2H, s), 6.75 (1H, s), 6.54 (1H, s), 5.10 (1
H, m), 4.49 (2H, m), 4.07 (2H, q, J = 6.9 Hz), 4.0
1 (2H, q, J = 6.9 Hz), 3.12 (2H, m), 2.49 (3H, s),
2.03 (4H, m), 1.44 (3H, t, J = 6.9 Hz), 1.40 (3H,
t, J = 6.9 Hz).

Example 33: N- [4,5-diethoxy-2- [4- (6-methyl-4-oxo-3,4-dihydroquinazolin-3-yl) piperidin-1-ylcarbonyl]
[Phenyl] propionamide (Compound 33) Compound 32 (300 mg, 0.67 mmol) was treated with methylene chloride (20 m
L), TEA (0.28 mL, 2.0 mmol), DMAP (catalytic amount) and propionic anhydride (0.17 mL, 1.33 mmol) were added, followed by stirring at room temperature for 7 hours and 30 minutes. The reaction solution was diluted with chloroform, washed with 1 mol / L hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from ethanol to obtain Compound 33 (250 mg, yield 74%) as white crystals. Melting point (ethanol): 175-176 ° C Elemental analysis: C ₂₈ H ₃₄ N ₄ O ₅ Calculated value (%) C; 66.39, H; 6.76, N; 11.06 Actual value (%) C; 66.46, H; 6.73, N 11.13 EI-MS (m / z): 506 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.08 (1H, s), 8.19 (1H, s),
8.10 (1H, s), 7.96 (1H, s), 7.68 (1H, d, J = 8.2
Hz), 7.61 (1H, dd, J = 2.0, 8.3 Hz), 6.78 (1H, s),
5.07 (1H, m), 4.51 (2H, m), 4.16 (2H, q, J = 6.9
Hz), 4.06 (2H, q, J = 6.9 Hz), 3.12 (2H, m), 2.51
(3H, s), 2.43 (2H, q, J = 7.6 Hz), 2.05 (4H, m),
1.47 (3H, t, J = 6.9 Hz), 1.43 (3H, t, J = 6.9 H
z), 1.25 (3H, t, J = 7.6 Hz).

Example 34: N- [4,5-diethoxy-2- [4- (6-methyl-4-oxo-3,4-dihydroquinazolin-3-yl) piperidin-1-ylcarbonyl]
[Phenyl] cyclopentanecarboxamide (Compound 34) Dissolve cyclopentanecarboxylic acid (0.14 mL, 1.3 mmol) in methylene chloride (6 mL), and add NMM (0.29 mL, 1.3 mmo).
l) Addition to prepare cyclopentanecarboxylic anhydride. A methylene chloride solution (6 mL) of the compound 32 (300 mg, 0.67 mmol) was added thereto, and the mixture was stirred at room temperature. 11 hours 30
Minutes later, cyclopentanecarboxylic anhydride prepared similarly
NMM was added and stirred for another 10 hours. The reaction solution was diluted with chloroform, washed with 1 mol / L hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1), and recrystallized from diisopropyl ether to give compound 34 (300 mg, yield 82%) as white Obtained as crystals. Melting point (diisopropyl ether): 183-184 ° C Elemental analysis: C ₃₁ H ₃₈ N ₄ O ₅ Calculated value (%) C; 68.11, H; 7.01, N; 10.25 Found value (%) C; 68.02, H; 7.18, N; 10.41 EI-MS (m / z): 546 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.11 (1H, s), 8.27 (1H, s),
8.11 (1H, s), 7.99 (1H, s), 7.72 (1H, d, J = 8.3
Hz), 7.63 (1H, d, J = 7.6 Hz), 6.79 (1H, s), 5.08
(1H, m), 4.53 (2H, m), 4.16 (2H, q, J = 6.9 Hz),
4.06 (2H, q, J = 6.9 Hz), 3.13 (2H, m), 2.73 (1H,
m), 2.52 (3H, s), 1.97 (12H, m), 1.46 (3H, t, J =
6.9 Hz), 1.43 (3H, t, J = 6.9 Hz).

Example 35: 3- [1- (1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl]-
1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (compound 35) 1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5- Ilcarboxylic acid (500 mg, 2.13 mmol) was stirred in thionyl chloride (5 mL) at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure and azeotroped with toluene, the residue was dissolved in methylene chloride (10 mL). This solution was added to 1,6-dimethyl-3
Methylene chloride of-(piperidin-4-yl) -1,2,3,4-tetrahydro-2,4-dioxoquinazoline hydrobromide (756 mg, 2.13 mmol) and TEA (1.49 mL, 10.7 mmol) Solution (10 m
L) was added dropwise under ice cooling. After stirring the reaction solution for 1 hour, it was diluted with methylene chloride (30 mL) and washed with water and then with saturated saline. The organic layer is dried over anhydrous magnesium sulfate,
Concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1), and the obtained crude crystals were triturated with ether to give Compound 35 (147 mg, 14.1%). Melting point (ether): 135-137 ° C. Elemental _{analysis: C 27 H 31 N 5 O} 4 · H 2 O Calculated (%) C; 63.89, H ; 6.55, N; 13.80 Found (%) C; 64.11, H 6.60, N; 13.30 EI-MS (m / z): 489 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.00 (1H, d, J = 1.7 Hz),
7.49 (1H, dd, J = 1.7,8.6 Hz), 7.21 (1H, dd, J =
1.7, 7.9 Hz), 7.19 (1H, d, J = 1.7 Hz), 7.08 (1H,
d, J = 8.6 Hz), 6.98 (1H, d, J = 7.9 Hz), 5.24 (1
H, m), 3.97 (2H, q, J = 7.3 Hz), 3.95 (2H, q, J =
7.3 Hz), 3.57 (3H, s), 3.49 (2H, m), 3.02 (2H, m),
2.83 (2H, m), 2.42 (3H, s), 1.69 (2H, m), 1.36 (3
H, t, J = 7.3 Hz), 1.35 (3H, t, J = 7.3 Hz).

Example 36: 3- [1- (6-benzyloxy-1,3-diethyl-2-oxo-2,3-
Dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro
-2,4-Dioxoquinazoline (Compound 39) 1st step: Dissolve 4-aminosalicylic acid (15 g, 98 mmol) in methanol (75 mL), and add concentrated sulfuric acid (7.8 mL, 147 mmo).
After l) was added, the mixture was heated under reflux at 85 ° C. for 16 hours and 30 minutes.
The reaction solution was concentrated under reduced pressure, water and then a saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Residue is n-hexane / ether
Trituration with (1: 1) gave methyl 4-aminosalicylate (10.5 g, 64%). ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 10.76 (s, 1H), 7.45 (d, 1
H, J = 8.9 Hz), 6.25-6.05 (m, 1H), 6.00 (s, 1H),
4.86 (brs, 2H), 3.78 (s, 3H).

Second step: The above compound (10.2 g, 61 mmol)
Was dissolved in methylene chloride (200 mL) and pyridine (14.8
mL, 183 mmol), followed by ethyl chloroformate (8.8 mL, 92
(mmol) was added and stirred at room temperature for 3 hours and 50 minutes. After partitioning the reaction solution with a 2 mol / L aqueous hydrochloric acid solution, the organic layer was separated and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was triturated with methanol to give 4-ethoxycarbonylaminosalicylic acid methyl ester (8.7 g, 60
%). ¹ H-NMR (CDCl ₃ ) δ (ppm): 10.86 (s, 1H), 7.76 (d, 1H,
J = 8.6 Hz), 7.76 (d, 1H, J = 2.3 Hz), 6.94 (dd, 1
H, J = 8.6, 2.3 Hz), 6.70 (brs, 1H), 4.24 (q, 2H,
J = 6.9 Hz), 3.92 (s, 3H), 1.32 (t, 3H, J = 7.3 H
z).

Third step: The above compound (8.7 g, 36 mmol)
Was dissolved in methanol (170 mL), and 28% sodium methoxide / methanol (8.2 mL, 40 mmol) was added, followed by stirring at room temperature for 30 minutes. After the reaction solution was cooled to 0 ° C, benzyl bromide (4.8 mL, 40 mmol) was added, and the mixture was added at room temperature.
Stirred for 8 hours. After partitioning the reaction mixture with water / ethyl acetate, the organic layer was separated and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3) to give methyl 2-benzyloxy-4-ethoxycarbonylaminobenzoate (6.82 g, 57%). ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.83 (d, 1H, J = 8.6 Hz),
7.55-7.20 (m, 6H), 6.81 (brs, 1H), 6.77 (dd, 1H, J
= 8.6, 2.0 Hz), 5.18 (s, 2H), 4.23 (q, 2H, J = 7.3
Hz), 3.87 (s, 3H), 1.31 (t, 3H, J = 7.3 Hz).

Step 4: The above compound (6.2 g, 19 mmol)
Was dissolved in acetic anhydride (38 mL), and fuming nitric acid (0.9
After adding 04 mL, 22.6 mmol), the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration and dried to give 2-benzyloxy-4-ethoxycarbonylamino-5-nitrobenzoic acid methyl ester (6.3 g, 90
%). ¹ H-NMR (CDCl ₃ ) δ (ppm): 10.33 (s, 1H), 8.87 (s, 1
H), 8.44 (s, 1H), 7.54 (d, 1H, J = 6.9 Hz), 7.50-
7.30 (m, 3H), 5.30 (s, 2H), 4.23 (q, 2H, J = 6.9 H
z), 3.91 (s, 3H), 1.37 (t, 3H, J = 7.3 Hz).

Step 5: The above compound (6.3 g, 17 mmol)
Was dissolved in ethanol (250 mL), stannic chloride dihydrate (19 g, 84.1 mmol) and then concentrated hydrochloric acid (1.9 mL) were added, and the mixture was stirred at room temperature for 1 hour and 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was partitioned with saturated aqueous sodium hydrogen carbonate / ethyl acetate.
The organic layer was separated and washed with saturated saline. After the organic layer was washed with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was triturated with ether to give methyl 5-amino-2-benzyloxy-4-ethoxycarbonylaminobenzoate (4.4 g, 76%). ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 8.80 (s, 1H), 7.55-7.20
(m, 6H), 7.16 (s, 1H), 4.99 (s, 2H), 4.84 (brs, 2
H), 4.14 (q, 2H, J = 6.9 Hz), 3.75 (s, 3H), 1.25
(t, 3H, J = 7.3 Hz).

Step 6: The above compound (4.3 g, 13 mmol)
Was dissolved in ethanol (130 mL), and potassium hydroxide (2.
(1 g, 37 mmol) and then heated to reflux for 2 hours and 15 minutes. The reaction solution was cooled on ice, and the precipitated crystals were collected by filtration and dried to give 6-benzyloxy-2-oxo-2,3-dihydro-1.
H-benzimidazol-5-ylcarboxylic acid (3.21 g, 90
%). ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.52 (d, 2H, J = 6.9 Hz),
7.35-7.20 (m, 3H), 6.82 (s, 1H), 6.19 (s, 1H), 4.
96 (s, 2H).

Step 7: The above compound (3.1 g, 10.9 mmo)
l) in DMSO (180 mL) and add 60% sodium hydride
(2.2 g, 55 mmol) was added. After stirring at room temperature for 30 minutes, ethyl iodide (5.2 mL, 65 mmol) was added dropwise, and the mixture was stirred at 50 ° C.
For 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water (× 4) and then with a saturated saline solution, and dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, 6-benzyloxy-1,3-diethyl-2-
Oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylic acid ethyl ester (2.2 g, 52%) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.52 (d, 1H, J = 6.3 Hz),
7.51 (s, 1H), 7.45-7.25 (m, 3H), 6.63 (s, 1H), 5.17
(s, 2H), 4.38 (q, 2H, J = 7.3 Hz), 3.93 (q, 2H, J
= 7.3 Hz), 3.90 (q, 2H, J = 7.3 Hz), 1.45-1.20 (m,
6H).

Step 8: The above compound (2.2 g, 5.7 mmol)
Was dissolved in a mixture of methanol (75 mL) and water (17 mL), sodium hydroxide (1.1 g, 29 mmol) was added, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure,
Next, a 2 mol / L hydrochloric acid aqueous solution was added to adjust the pH to acidic. The precipitated crystals are collected by filtration and dried to give 6-benzyloxy-1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylic acid (1.94 g, quantitative)
I got ¹ H-NMR (CDCl ₃ ) δ (ppm): 11.00 (brs, 1H), 7.72 (s, 1
H), 7.60-7.30 (m, 5H), 6.72 (s, 1H), 5.32 (s, 2H),
3.94 (q, 2H, J = 7.3 Hz), 3.93 (q, 2H, J = 7.3 Hz),
1.45-1.20 (m, 6H).

Ninth step: The above compound (1.7 g, 5.0 mmol)
In a methylene chloride (71 mL) solution of 1,6-dimethyl-3- (piperidin-4-yl) -1,2,3,4-tetrahydro-2,4-dioxoquinazoline (1.4 g, 5.0 mmol) , TEA (2.8 mL, 20 mmo
l), HOBt H ₂ O (1.4 g, 10 mmol) and WSC HCl (1.9 g,
10 mmol) and stirred at room temperature for 6 hours 30 minutes. After partitioning the reaction mixture with saturated aqueous sodium bicarbonate, the organic layer was separated and 2 mo
It was washed with a 1 / L aqueous hydrochloric acid solution and then with a saturated saline solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1) to give Compound 39 (2.2 g, 74%). Obtained. Melting point: 128-130 ° C EI-MS (m / z): 595 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.98 (s, 1H), 7.55-7.25 (m,
6H), 7.10-7.00 (m, 2H), 6.60 (s, 1H), 5.35-4.85
(m, 2H), 5.10 (d, 2H, J = 3.6 Hz), 4.00-3.60 (m, 5
H), 3.54 (s, 3H), 3.50-3.25 (m, 4H), 2.41 (s, 3H),
1.85-1.45 (m, 2H), 1.40-1.20 (m, 6H).

Example 37: 3- [1- (1,3-Diethyl-6-hydroxy-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl]- 1,6-dimethyl-1,2,3,4-tetrahydro-2,4
-Dioxoquinazoline (Compound 36) Compound 39 (2.0 g, 3.4 mmol) was dissolved in methanol (50 mL) and water (15 mL), and 10% Pd-C (400 mg, 50 w / w% H
After adding ₂ O) and then ammonium formate (1.1 g, 16.8 mmol), the mixture was heated under reflux for 50 minutes. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was partitioned with water / chloroform. Then, the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to obtain Compound 36 (1.35 g, 80%). Mp (ethanol): 220-222 ° C. Elemental _{analysis: C 27 H 31 N 5 O} 5 · 0.3H 2 O Calculated (%) C; 63.47, H ; 6.23, N; 13.71 Found (%) C; 63.60, H; 6.29, N; 13.43 EI-MS (m / z): 505 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.89 (s, 1H), 8.00 (d, 1H,
J = 1.3 Hz), 7.49 (dd, 1H, J = 8.3, 2.0 Hz), 7.09
(d, 1H, J = 8.6 Hz), 6.88 (s, 1H), 6.67 (s, 1H), 5.
35-5.20 (m, 1H), 4.60-4.40 (m, 2H), 3.90 (q, 2H, J
= 7.3 Hz), 3.74 (q, 2H, J = 7.3 Hz), 3.57 (s, 3
H), 3.20-2.75 (m, 4H), 2.42 (s, 3H), 1.85-1.70 (m,
2H), 1.33 (t, 3H, J = 7.3 Hz), 1.32 (t, 3H, J =
(7.3 Hz).

Example 38: 3- [1- (6-acetoxy-1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl]- 1,6-dimethyl-1,2,3,4-tetrahydro-2,4
-Dioxoquinazoline (Compound 37) Compound 36 (300 mg, 0.59 mmol) in methylene chloride (6 mL)
And TEA (0.165 mL, 1.19 mmol) was added, followed by acetyl chloride (0.063 mL, 0.89 mmol).
Stirred for 0 minutes. The reaction solution was partitioned with a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was separated. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was triturated with ethyl acetate to give compound 37 (241 mg, 74%). Mp (ethyl acetate): 254-255 ° C. Elemental _{analysis: C 29 H 33 N 5 O} 6 · 0.2H 2 O Calculated (%) C; 63.19, H ; 6.11, N; 12.71 Found (%) C; 63.12 , H; 6.21, N; 12.64 EI-MS (m / z): 547 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.98 (s, 1H), 7.48 (dd, 1H,
J = 8.3, 2.0 Hz), 7.07 (d, 1H, J = 8.3 Hz), 6.92
(s, 1H), 6.83 (s, 1H), 5.20 (brs, 1H), 5.05-4.80
(m, 1H), 3.91 (q, 4H, J = 7.3 Hz), 3.80-3.60 (m, 2
H), 3.55 (s, 3H), 3.20-2.65 (m, 4H), 2.55 (brs, 1.8
H), 2.41 (s, 3H), 2.29 (brs, 1.2H), 1.90-1.50 (m,
2H), 1.33 (t, 6H, J = 7.3 Hz).

Example 39: 3- [1- (1,3-Diethyl-6-methoxy-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl]- 1,6-dimethyl-1,2,3,4-tetrahydro-2,4-
Dioxoquinazoline (Compound 38) Compound 36 (250 mg, 0.49 mmol) was dissolved in DMF (5 mL), and 60% sodium hydride (24 mg, 0.59 mmol) was added. After stirring at room temperature for 30 minutes, methyl iodide (0.074
mL, 1.2 mmol) was added dropwise, followed by stirring at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was triturated with ethyl acetate to give Compound 38 (1941).
mg, 76%). Melting point (ethyl acetate): 268-269 ° C Elemental analysis: C ₂₈ H ₃₃ N ₅ O ₅ Calculated value (%) C; 64.72, H; 6.40, N; 13.48 Actual value (%) C; 64.52, H; 6.60, N; 13.46 EI-MS (m / z): 519 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.99 (s, 1H), 7.48 (dd, 1H,
J = 8.6, 2.3 Hz), 7.07 (d, 1H, J = 8.6 Hz), 7.03
(s, 0.6H), 6.93 (s, 0.4H), 6.59 (s, 0.4H), 6.58
(s, 0.6H), 5.30-4.85 (m, 2H), 3.93 (q, 4H, J = 7.3
Hz), 3.87 (s, 3H), 3.75-3.60 (m, 1H), 3.55 (s, 3
H), 3.30-2.50 (m, 4H), 2.41 (s, 3H), 1.85-1.50 (m,
2H), 1.34 (t, 6H, J = 7.3 Hz).

Example 40: [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl]
-1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] carboxylic acid methyl ester (Compound 4
0) First step: 5,6-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazole (10 g, 61.7 mmol) in DMF (170 mL)
And 60% sodium hydride (7.4 g, 185 mmol) was added. After stirring at room temperature for 30 minutes, ethyl iodide (1
(7.3 mL, 216 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration and dried to give 1,3-diethyl-5,6-dimethyl-2-oxo-2,3-.
Dihydro-1H-benzimidazole (9.6 g, 71%) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 6.79 (s, 2H), 3.90 (q, 4H,
J = 7.3 Hz), 2.31 (s, 6H), 1.32 (t, 6H, J = 7.3 H
z).

Step 2: The above compound (9.6 g, 44 mmol)
Was dissolved in a mixture of tert-butanol (100 mL) and water (150 mL), heated to 110 ° C, and potassium permanganate was added.
(35 g, 220 mmol) was added. After heating and refluxing at 110 ° C. for further 1 hour and 50 minutes, the reaction solution was poured into ice water, and the precipitated crystals were collected by filtration and dried to give 1,3-diethyl-2-.
Oxo-2,3-dihydro-1H-benzimidazole-5,6-dicarboxylic acid (6.0 g, 49%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.48 (s, 2H), 3.92 (q, 4
H, J = 7.3 Hz), 1.20 (t, 6H, J = 7.3 Hz).

Third step: The above compound (2.0 g, 7.2 mmol)
Was dissolved in methylene chloride (40 mL), and WSC HCl (1.65 g,
(8.6 mmol) was added, followed by stirring at room temperature for 10 minutes. After partitioning the reaction solution with water / chloroform, the organic layer was separated and dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, 1,3-diethyl-2-oxo-2,3-dihydro-1
H-benzimidazole-5,6-dicarboxylic anhydride (1.83
g, 98%). Then, the compound (1.83 g, 7.0 mmo
l) was dissolved in methanol (100 mL), a 2 mol / L aqueous hydrochloric acid solution (20 mL) was added, and the mixture was heated under reflux for 3 hours and 30 minutes.
After the reaction solution was concentrated under reduced pressure, the residue was partitioned with water / chloroform. After the organic layer was separated and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 1,3 diethyl-6-methoxycarbonyl-2-oxo-2,3-dihydro-1H.
-Benzimidazol-5-ylcarboxylic acid (1.48 g, 72
%). ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.64 (s, 1H), 7.34 (s, 1H),
3.95 (q, 4H, J = 7.3Hz), 3.91 (s, 3H), 1.37 (t, 6
(H, J = 7.3 Hz).

Fourth step: The above compound (1.0 g, 3.4 mmol)
In methylene chloride (42 mL) solution of 1,6-dimethyl-3- (piperidin-4-yl) -1,2,3,4-tetrahydro-2,4-dioxoquinazoline (935 mg, 3.4 mmol) , TEA (1.9 mL, 14 mmo
l), HOBt H ₂ O (1.05 g, 7.77 mmol), WSC HCl (1.31 g,
6.84 mmol) and stirred at room temperature overnight. Reaction solution
After partitioning with 2 mol / L aqueous hydrochloric acid / chloroform, the organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 60: 1) and recrystallized from ethyl acetate to give the compound.
40 (916 mg, 49%) was obtained. Melting point (ethyl acetate): 247-248 ° C Elemental analysis: C ₂₉ H ₃₃ N ₅ O ₆ Calculated (%) C; 63.61, H; 6.07, N; 12.79 Found (%) C; 63.47, H; 6.36, N; 12.73 EI-MS (m / z): 547 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.99 (d, 1H, J = 1.7 Hz),
7.71 (s, 0.3H), 7.66 (s, 0.7H), 7.48 (dd, 1H, J =
8.6, 2.0 Hz), 7.07 (d, 1H, J = 8.6 Hz), 7.04 (s, 0.
7H), 6.86 (s, 0.3H), 5.30-4.80 (m, 2H), 4.20-4.05
(m, 1H), 3.98 (q, 4H, J = 7.3 Hz), 3.91 (s, 3H),
3.56 (s, 3H), 3.20-2.60 (m, 4H), 2.41 (s, 3H), 1.9
0-1.70 (m, 1H), 1.60-1.45 (m, 1H), 1.36 (t, 6H, J
= 7.3 Hz).

Example 41: 3- [1- (6-Nitro-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl] -1,6-
Dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (Compound 41) 1st step: 6-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylic acid Methyl ester (1.44
g, 6.1 mmol) in methanol (48 mL) and aqueous sodium hydroxide solution (1.2 g of sodium hydroxide, 30.4 mmol).
Was dissolved in 12 mL of water) and heated at 80 ° C. for 5 hours. After methanol was distilled off under reduced pressure and water was added to the residue, the solution was adjusted to pH 2 with a 2 mol / L aqueous hydrochloric acid solution. After cooling, the precipitated solid was collected by filtration and dried to give 6-nitro-2-oxo-2,3-dihydro-1H-benzimidazole-5.
-Ylcarboxylic acid (1.16 g, 86%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 13.45 (brs, 1H), 11.40
(s, 1H), 11.37 (s, 1H), 7.49 (s, 1H), 7.22 (s, 1H).

Second step: The above compound (1.1 g, 4.8 mmol)
In methylene chloride (42 mL) solution of 1,6-dimethyl-3- (piperidin-4-yl) -1,2,3,4-tetrahydro-2,4-dioxoquinazoline (1.3 g, 4.8 mmol) , TEA (2.7 mL, 19 mmo
l), HOBt (1.5 g, 9.6 mmol) and WSC HCl (1.8 g, 9.
6 mmol) and stirred overnight at room temperature. Further, to the reaction solution, DMF (20 mL), 1,6-dimethyl-3- (piperidin-4-yl)
-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (400
mg) and WSC HCl (550 mg) were added and stirred at room temperature for 2 hours. After partitioning the reaction solution with 1 mol / L hydrochloric acid, the organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1), and then triturated with n-hexane / ether (1: 1). The compound 41 (129 mg, 6%) was obtained by the churning. ^{From 1} H-NMR, compound 41 was present as a mixture of 4: 1 rotamers. Melting point (n-hexane / ether):> 300 ° C. FAB-MS (m / z): 479 (M ⁺⁺ 1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 11.16 (s, 1H), 10.95 ( s, 1
H), 7.95 (s, 2H), 7.83 (s, 1H), 7.12 (d, 1H, J = 7.
9 Hz), 7.00, 6.87 (s, 1H respectively), 5.30-5.10 (m, 1H),
5.00-4.80 (m, 1H), 3.65-3.45 (m, 1H), 3.56 (s, 3
H), 3.25-2.60 (m, 4H), 2.41 (s, 3H), 1.90-1.75 (m,
1H), 1.67-1.45 (m, 1H).

Example 42: 3- [1- (6-Amino-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl] -1,6-
Dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline hydrochloride (Compound 42) Compound 41 (2.3 g, 4.8 mmol) in methanol (115 mL)
And added 10% Pd-C (230 mg, 50 w / w% H ₂ O) and then ammonium formate (2.3 g, 36 mmol), then 2 hours
Heated to reflux for 15 minutes. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was triturated with diisopropyl ether to give crude crystals (1.67 g, 78%).
I got The crude crystals (350 mg) were purified by silica gel column chromatography (chloroform: methanol = 10: 1) and then dissolved in ethanol. A 4 mol / L hydrochloric acid / ethyl acetate solution was added, and the precipitated crystals were washed with acetone to obtain Compound 42 (49 mg, 10%). Mp (acetone): 245-246 ° C. Elemental _{analysis: C 23 H 24 N 6 O} 5 · HCl · 0.4CH 3 COCH 3 · 2.4H 2 O Calculated (%) C; 52.71, H ; 5.89, N; 15.24 Found Value (%) C; 52.73, H; 5.96, N; 15.31 EI-MS (m / z): 448 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 8.28 (brs, 4H) , 7.84 (s,
1H), 7.59 (dd, 1H, J = 8.3, 1.3 Hz), 7.33 (d, 1H, J
= 8.6 Hz), 6.57 (s, 1H), 6.37 (s, 1H), 5.20-5.00
(m, 1H), 4.20-4.00 (m, 1H), 3.48 (s, 3H), 3.05-2.8
5 (m, 2H), 2.60-2.40 (m, 2H), 2.37 (s, 3H), 1.70-
1.55 (m, 2H).

Example 43: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -2-oxo-2,3-dihydro-1H-benzimidazole-5-
[Il] formamide (compound 43) 99% formic acid (308 mg, 6.7 mmol) in methylene chloride (15 mL)
WSC HCl (641 mg, 3.3 mmol) was added to the solution under ice cooling, and the mixture was stirred at 0 ° C for 10 minutes. Compound 42 (500 m
g, 1.1 mmol) and a solution of NMM (0.37 mL, 3.3 mmol) in methylene chloride (15 mL) were slowly added dropwise, followed by stirring at room temperature for 5 hours. The reaction mixture was further mixed with 99% formic acid (308 mg, 6.7 mmol), WSC H
A solution of Cl (641 mg, 3.3 mmol) in methylene chloride (15 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was partitioned with water, and then filtered. The organic layer of the filtrate was separated and washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline. The aqueous layer was extracted with n-butanol, and washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline. The methylene chloride layer and the n-butanol layer were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was combined with the previous residue, desalted by HP resin column chromatography (water → methanol), and triturated with acetone to give compound 43 (74 m
g, 14%). Melting point (acetone): 241-242 ° C Elemental analysis: C ₂₄ H ₂₄ N ₆ O ₅ , 0.4CH ₃ COCH ₃ , 1.1 H ₂ O Calculated value (%) C; 64.79, H; 6.66, N; 14.62 Actual value ( %) C; 64.46, H; 6.89, N; 14.70 EI-MS (m / z): 476 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 10.77 (s, 1H), 10.68 (s,
1H), 9.54 (s, 1H), 8.24 (d, 1H, J = 1.7 Hz), 7.84
(d, 1H, J = 1.7 Hz), 7.60 (d, 1H, J = 1.7 Hz), 7.5
7 (s, 1H), 7.33 (d, 1H, J = 8.6 Hz), 6.78 (s, 1H),
5.25-5.00 (m, 1H), 4.60 (brs, 2H), 3.20-2.70 (m,
4H), 2.37 (s, 3H), 1.75-1.50 (m, 2H).

Example 44: 3- [1- (1,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (compound 44) 1st step: 6-nitro-2-oxo-2,3-dihydro- 1H-benzimidazol-5-ylcarboxylic acid methyl ester (2.0
g, 8.4 mmol) was dissolved in DMF (34 mL), and 60% sodium hydride (1.01 g, 25.3 mmol) was added under ice-cooling. After stirring at room temperature for 30 minutes, methyl iodide (1.8 mL, 29 mmol)
Was added dropwise, and the mixture was further stirred at room temperature for 30 minutes. The reaction solution was poured into ice water (100 mL), stirred at room temperature for 1.5 hours, added with sodium chloride, and further stirred for 3 hours. The precipitated crystals are collected by filtration, washed with water and dried to give 1,3-dimethyl-6.
-Nitro-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylic acid methyl ester (1.74 g, 78%) was obtained.

Step 2: The above compound (1.71 g, 6.45 mmo)
l) was dissolved in methanol (50 mL), and an aqueous sodium hydroxide solution (1.29 g, 32.3 mmol of sodium hydroxide was added to distilled water 1).
(Dissolved in 3 mL), and then heated at 80 ° C. for 3 hours. After methanol was distilled off and water was added to the residue, the solution was adjusted to pH 2.5 with a 2 mol / L aqueous hydrochloric acid solution. Further water was added, and after cooling, the precipitated solid was collected by filtration and dried to give 1,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylic acid. (1.49
g, 92%).

Third step: The above carboxylic acid (1.40 g, 5.57)
mmol) in methylene chloride (58 mL).
-3- (piperidin-4-yl) -1,2,3,4-tetrahydro-2,4-dioxoquinazoline (1.53 g, 5.57 mmol), TEA (3.0 mL,
21.5 mmol), HOBt (1.67 g, 12.4 mmol) and WSC HCl
(2.01 g, 10.5 mmol) was added and stirred at room temperature overnight. After partitioning the reaction mixture with chloroform / 1 mol / L hydrochloric acid, the organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was ethyl acetate / ether (1/1).
Compound 44 (2.49
g, 88%). Mp (ethyl acetate / ether):> 300 ° C. Elemental _{analysis: C 25 H 26 N 6 O} 6 · 1.4H 2 O Calculated (%) C; 56.47, H ; 5.46, N; 15.80 Found (%) C; 56.37, H; 5.48, N; 15.83 EI-MS (m / z): 506 (M ⁺ ) 1H-NMR (CDCl3) δ (ppm): 7.98 (s, 1H), 7.85 (s, 1H),
7.49 (d, 1H, J = 6.6Hz), 7.09 (d, 1H, J = 8.6H
z), 7.04 (s, 1H), 5.30-5.15 (m, 1H), 5.05-4.85 (m,
2H), 3.56 (s, 3H), 3.52 (s, 3H), 3.50 (s, 3H), 3.
30-2.65 (m, 4H), 2.41 (s, 3H), 1.95-1.50 (m, 2H).

Example 45: 3- [1- (6-amino-1,3-dimethyl-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline hydrochloride (Compound 45) Compound 44 (2.1 g, 4.1 mmol) in methanol (105 mL)
And added 10% Pd-C (210 mg, 50 w / w% H ₂ O) and then ammonium formate (1.96 g, 31.1 mmol),
Heated to reflux for an hour. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, water was added to the residue, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. Silica gel column chromatography of the residue
(Chloroform: methanol = 30: 1)
Trituration with diisopropyl ether gave crude crystals (1.6 g, 81%). This crude crystal (30
0 mg, 0.59 mmol) was dissolved in ethyl acetate, and a 4 mol / L hydrochloric acid / ethyl acetate solution was added. After once distilling off the solvent,
Ethyl acetate was added again, and the mixture was heated under reflux at 70 ° C. for 20 minutes. The mixture was stirred at room temperature for 10 minutes and under ice cooling for 10 minutes, and the precipitated crystals were collected by filtration. The crystals were triturated with ethanol to give Compound 45 (200 mg, 62%). Mp (ethanol): 194-195 ° C. Elemental _{analysis: C 25 H 28 N 6 O} 4 · HCl · 1.9H 2 O Calculated (%) C; 54.87, H ; 6.04, N; 15.36 Found (%) C; 54.97, H; 6.19, N; 15.33 EI-MS (m / z): 476 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.84 (d, 1H, J = 1.3 Hz),
7.60 (dd, 1H, J = 1.7, 8.6 Hz), 7.34 (d, 1H, J =
8.6 Hz), 7.14 (s, 1H), 7.10 (s, 1H), 5.09 (m, 1H),
3.49 (s, 3H), 3.35 (s, 3H), 3.33 (s, 3H), 3.09
(m, 2H), 2.64 (m, 2H), 2.37 (s, 3H), 1.67 (m, 2H).

Example 46: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] formamide (compound 46) 99% formic acid (1.51 g, 32.8 mmol) in methylene chloride (33 mL)
, And added with WSC HCl (3.14 g, 16.4 mmol) under ice-cooling, followed by stirring for 30 minutes. Compound 45 (1.
30 g, 2.73 mmol) and a solution of NMM (1.50 mL, 13.6 mmol) in methylene chloride (33 mL) were added, and the mixture was stirred at room temperature overnight. Further, NMM (1.20 mL, 10.9 mmol) was added to the reaction solution, and then 99% formic acid (0.76 g, 20 mmol) and WSC HCl (1.57
g, 8.19 mmol). After this operation was performed four times, the reaction solution was partitioned with chloroform / water, and the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (× 2) and then with a saturated saline solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and trituration with diisopropyl ether gave crude crystals. As a result of analysis by HPLC (elution solvent: 30% acetonitrile / water, 0.5 mmol / L sodium octanesulfonate, pH 3), 5% of compound 45 was contained therein. 9
9% formic acid (0.012 g, 0.32 mmol) in methylene chloride (0.5 m
L), and added with WSC HCl (0.25 g, 1.3 mmol) under ice-cooling, followed by stirring for 10 minutes. Add the crude crystals to this mixture
(500 mg) and a solution of NMM (0.015 mL, 0.14 mmol) in methylene chloride (0.5 mL) were added, and the mixture was stirred at room temperature for 4 hours and 45 minutes. Further, after adding NMM (0.15 mL) to the reaction solution, 99%
Formic anhydride prepared from formic acid (0.012 g) and WSC HCl (0.025 g) was added and stirred overnight. The reaction mixture was partitioned with water / chloroform, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated saline solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and trituration with ethanol gave crude crystals. The obtained crystals were again triturated with ethanol to give Compound 46 (0.32 g, 60%). Mp (ethanol): 188-189 ° C. Elemental _{analysis: C 26 H 28 N 6 O} 5 · 0.8H 2 O Calculated (%) C; 60.18, H ; 5.75, N; 16.19 Found (%) C; 60.15, H; 6.03, N; 16.27 EI-MS (m / z): 504 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.90 (s, 1H), 8.46 (s, 1H),
8.06 (s, 1H), 7.99 (d, 1H, J = 1.7 Hz), 7.49 (dd,
1H, J = 2.0, 8.6 Hz), 7.09 (d, 1H, J = 8.6Hz), 6.
89 (s, 1H), 5.27 (m, 1H), 3.56 (s, 3H), 3.44 (s, 3
H), 3.42 (s, 3H), 3.05 (m, 2H), 2.83 (m, 2H), 2.42
(s, 3H), 1.71 (m, 2H).

Example 47: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] acetamide (Compound 47) Compound 45 (300 mg, 0.58 mmol) was treated with methylene chloride (20 m
L), acetic anhydride (0.11 mL, 1.19 mmol), TEA
(0.24 mL, 1.7 mmol) and DMAP (catalytic amount) were added, followed by stirring at room temperature overnight. After partitioning the reaction solution with water / chloroform, the organic layer was separated and washed with a 1 mol / L aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and then a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol (8 mL) to give Compound 4
7 (200 mg, 66%) was obtained. Mp (ethanol):> 300 ° C. Elemental _{analysis: C 27 H 30 N 6 O} 5 · 0.3H 2 O Calculated (%) C; 61.89, H ; 5.89, N; 16.04 Found (%) C; 61.99, H 5.93, N; 16.09 EI-MS (m / z): 518 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.83 (s, 1H), 7.98 (d, 1H,
J = 2.0 Hz), 7.94 (s, 1H), 7.49 (dd, 1H, J = 2.0,
8.6 Hz), 7.09 (d, 1H, J = 8.6 Hz), 6.87 (s, 1H), 5.
30-5.15 (m, 1H), 3.56 (s, 3H), 3.42 (s, 3H), 3.41
(s, 3H), 3.10-2.90 (m, 2H), 2.90-2.65 (m, 2H), 2.4
2 (s, 3H), 2.28 (s, 3H), 1.80-1.75 (m, 2H).

Example 48: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] cyclopentanecarboxamide (Compound 48) Compound 45 (300 mg, 0.58 mmol) was treated with methylene chloride (20 m
L) and cyclopentanecarboxylic acid (0.13 mL, 1.
2 mmol), methylene chloride in WSC HCl (0.34 g, 1.7 mmol)
(20 mL) The solution was slowly added dropwise and stirred at room temperature overnight. Furthermore, after adding NMM (0.06 mL) to the reaction solution, 99
% Formic acid (0.13 mL) and carboxylic anhydride prepared from WSC HCl (0.11 g) were added. After repeating the same operation twice, the reaction solution was partitioned with water / chloroform, the organic layer was separated, and the organic layer was washed with a 1 mol / L aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1), and recrystallized from ethanol (8 mL) to obtain Compound 48 (170 mg, 51%). Mp (ethanol): 249-250 ℃ Elemental _{analysis: C 31 H 36 N 6 O} 5 · 0.2H 2 O Calculated (%) C; 64.61, H ; 6.37, N; 14.58 Found (%) C; 64.54, H; 6.46, N; 14.58 EI-MS (m / z): 572 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.95 (s, 1H), 8.09 (s, 1)
H), 7.97 (s, 1H), 7.49 (dd, 1H, J = 2.0, 8.6 Hz),
7.08 (d, 1H, J = 8.6 Hz), 6.88 (s, 1H), 5.30-5.15
(m, 1H), 3.55 (s, 3H), 3.42 (s, 3H), 3.41 (s, 3
H), 3.15-2.95 (m, 1H), 2.95-2.65 (m, 2H), 2.41 (s,
3H), 2.15-1.65 (m, 12H).

Example 49: 3- [1- (6-amino-1,3-diethyl-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline hydrochloride (compound 49) 1st step: 6-nitro-2-oxo-2,3- Dihydro-1H-benzimidazol-5-ylcarboxylic acid methyl ester (5.0
g, 21.1 mmol) was dissolved in DMF (85 mL) and 60% sodium hydride (2.5 g, 63 mmol) was added. After stirring at room temperature for 30 minutes, ethyl iodide (5.9 mL, 74 mmol) was added dropwise, and the mixture was further stirred at room temperature for 40 minutes. The reaction solution was iced-2.4 mo
Poured into a mixture of 1 / L aqueous hydrochloric acid and extracted twice with ether. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from methanol, and the obtained yellow crystals were collected by filtration and dried to give 1,3-diethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylic acid. Methyl ester (3.8 g, yield
62%). Melting point (methanol):> 300 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.61 (s, 1H), 7.23 (s, 1)
H), 4.00 (4H, m), 3.93 (s, 3H), 1.35 (m, 6H).

Step 2: The above compound (3.8 g, 13 mmol)
Was dissolved in methanol (100 mL), an aqueous sodium hydroxide solution (2.6 g of sodium hydroxide, 65 mmol dissolved in 26 mL of water) was added, and the mixture was heated at 80 ° C. for 45 minutes. After distilling off methanol and adding ice water to the residue, the solution was added at 2 mol / L.
The pH was adjusted to 2.5 with aqueous hydrochloric acid. After cooling, the precipitated solid was collected by filtration and dried to give 1,3-diethyl-6-nitro-
2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylic acid (3.5 g, yield 97%) was obtained. Melting point: 257-258 ° C ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.98 (s, 1H), 7.63 (s, 1)
H), 3.95 (m, 4H), 1.20 (m, 6H).

Third step: The above compound (3.0 g, 11 mmol)
In methylene chloride (125 mL) solution of 3- (piperidin-4-yl) -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (2.9 g, 11 mmol) , TEA (6.0 mL, 43 mmo
l), HOBt (3.3 g, 22 mmol) and WSC HCl (4.1 g, 22
mmol) and stirred overnight at room temperature. 1 mol /
After partitioning with mL of hydrochloric acid, the organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and the residue was triturated with ethyl acetate / ether (1/1) to give 3- [1- (1,3-diethyl-6 -Nitro-2-oxo-
2,3-dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (4.6 g, (Yield 80%). Melting point (ethyl acetate / ether):> 300 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.99 (s, 1H), 7.87 (s, 1)
H), 7.49 (dd, 1H, J = 8.6, 2.0 Hz), 7.08 (d, 1H, J
= 8.2 Hz), 7.07 (s, 1H), 5.25 (m, 1H), 4.92 (brd,
2H, J = 13.2 Hz), 4.00 (m, 4H), 3.56 (s, 3H), 3.1
5 (m, 2H), 2.95 (m, 2H), 2.42 (s, 3H), 1.85 (brd,
2H, J = 13.5 Hz), 1.20 (m, 6H).

Step 4: The above compound (4.6 g, 8.6 mmol)
Was dissolved in methanol (230 mL), and 10% Pd-C (460 mg,
50w / w% H ₂ O), then ammonium formate (4.1 g, 65 mm
ol), and the mixture was refluxed for 4 hours. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. After the filtrate was concentrated under reduced pressure, distilled water was added to the residue, and insolubles were collected by filtration. The obtained solid was dissolved in chloroform, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was triturated with isopropyl ether to give compound 49.
Of the free base (3.3 g, crude yield 77%). This crystal (1.3
g, 2.6 mmol) on a silica gel column.
(Chloroform: methanol = 30: 1)
Dissolved in ethyl acetate (12 mL). To this solution was added a 4 mol / L hydrochloric acid / ethyl acetate solution (1 mL, containing 4 mmol of hydrochloric acid), and the precipitated solid was collected by filtration. Compound 49 (902 mg) was obtained by recrystallization from ethyl acetate. Mp (ethyl acetate): 178-179 ° C. Elemental _{analysis: C 27 H 32 N 6 O} 4 · HCl · 1.6H 2 O Calculated (%) C; 56.91, H ; 6.40, N; 14.75 Found (%) C 56.88, H; 6.54, N; 14.71 FAB-MS (m / z): 505 (M ⁺ +1) ¹ H-NMR (free base: CDCl ₃ ) δ (ppm): 7.95 (s, 1H), 7 .
78 (s, 1H), 7.47 (d, 1H, J = 6.3 Hz), 7.06 (d, 1H,
J = 10.2 Hz), 7.04 (s, 1H), 5.25 (m, 1H), 4.30 (b
rs, 2H), 4.00 (m, 4H), 3.53 (s, 3H), 3.23 (brs, 2
H), 2.80 (m, 2H), 2.39 (s, 3H), 1.78 (m, 2H), 1.35
(m, 6H).

Example 50: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] formamide (compound 50) 99% formic acid (913 mg, 19.8 mmol) in methylene chloride (22 mL)
, And added with WSC HCl (1.9 g, 9.9 mmol) under ice-cooling, followed by stirring for 15 minutes. Compound 49 (894
mg, 1.65 mmol) and a solution of NMM (0.9 mL, 8.3 mmol) in methylene chloride (22 mL) were added, and the mixture was stirred at room temperature overnight.
The reaction mixture was partitioned with water / chloroform, and the organic layer was
The extract was washed with a 1 / L aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution, and then with a saturated saline solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a crude crystal. By recrystallizing the obtained crude crystals from ethanol, the compound
50 (742 mg, 84% yield) was obtained. Mp (ethanol): 167-168 ° C. Elemental _{analysis: C 28 H 32 N 6 O} 5 · 0.3C 2 H 5 OH · 0.4H 2 O Calculated (%) C; 62.05, H ; 6.30, N; 15.18 Found (%) C; 62.07, H; 6.65, N; 15.28 FAB-MS (m / z): 533 (M ⁺ +1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.90 (s, 1H), 8.46 (s, 1
H), 8.09 (s, 1H), 7.99 (s, 1H), 7.49 (dd, 1H, J =
8.6, 2.0 Hz), 7.08 (d, 1H, J = 8.6 Hz), 6.92 (s, 1
H), 5.27 (m, 1H), 4.40 (brs, 2H), 3.95 (m, 4H), 3.
56 (s, 3H), 3.05 (brs, 2H), 2.83 (brs, 2H), 2.42
(s, 3H), 1.76 (m, 2H), 1.30 (m, 6H).

Example 51: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] acetamide (Compound 51) Compound 49 (300 mg, 0.59 mmol) was treated with methylene chloride (20 m
L), acetic anhydride (0.11 mL, 1.19 mmol), TEA
(0.25 mL, 1.78 mmol) and DMAP (catalytic amount) were added, followed by stirring at room temperature for 4 hours and 30 minutes. After partitioning the reaction solution with water / chloroform, the organic layer was separated and washed with a 1 mol / L aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and then a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol (10 mL) to obtain Compound 51 (168 mg, 52%). Melting point (ethanol): 272-273 ° C Elemental analysis: C ₂₉ H ₃₄ N ₆ O ₅ Calculated (%) C; 63.72, H; 6.27, N; 15.37 Found (%) C; 63.69, H; 6.53, N 15.37 EI-MS (m / z): 546 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.84 (s, 1H), 7.98 (s, 2H),
7.49 (dd, 1H, J = 8.6, 2.3 Hz), 7.08 (d, 1H, J =
8.6 Hz), 6.90 (s, 1H), 5.35-5.15 (m, 1H), 4.40 (br
s, 2H), 4.00-3.80 (m, 4H), 3.55 (s, 3H), 3.20-2.60
(m, 4H), 2.41 (s, 3H), 2.27 (s, 3H), 1.85-1.60
(m, 2H), 1.40-1.20 (m, 6H).

Example 52: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] trifluoroacetamide (compound
52) Example 51 except for using compound 49 (500 mg, 0.99 mmol) and trifluoroacetic anhydride (0.28 mL, 1.98 mmol).
Compound 52 (508 mg, 85%) was obtained in the same manner as in. Melting point (ethanol): 230-231 ° C Elemental analysis: C ₂₉ H ₃₁ F ₃ N ₆ O ₅ .0.3 H ₂ O Calculated value (%) C; 57.45, H; 5.26, N; 13.87 Actual value (%) C; 57.64, H; 5.46, N; 13.47 EI-MS (m / z): 600 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.07 (s, 1H), 7.99 (d, 1H,
J = 1.3 Hz), 7.49 (dd, 1H, J = 8.3, 2.0 Hz), 7.09
(d, 1H, J = 8.6 Hz), 7.01 (s, 1H), 5.35-5.20 (m, 1
H), 4.45 (brs, 2H), 3.96 (q, 2H, J = 7.3 Hz), 3.95
(q, 2H, J = 7.3Hz), 3.56 (s, 3H), 3.20-2.70 (m, 4
H), 2.42 (s, 3H), 1.85-1.65 (m, 2H), 1.36 (t, 3H, J
= 7.3 Hz), 1.35 (t, 3H, J = 7.3 Hz).

Example 53: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] propionamide (Compound 53) Except for using Compound 49 (300 mg, 0.59 mmol) and propionic anhydride The compound was prepared in the same manner as in Example 51.
53 (190 mg, 57%) were obtained. Mp (ethanol): 251-252 ° C. Elemental _{analysis: C 30 H 36 N 6 O} 5 Calculated (%) C; 64.27, H ; 6.47, N; 14.99 Found (%) C; 64.18, H ; 6.45, N 14.93 EI-MS (m / z): 560 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.91 (s, 1H), 8.08 (s, 1H),
7.98 (d, 1H, J = 2.0Hz), 7.49 (dd, 1H, J = 2.0,
8.6 Hz), 7.08 (d, 1H, J = 8.6 Hz), 6.90 (s, 1H), 5.
25 (m, 1H), 3.95 (q, 2H, J = 7.3 Hz), 3.93 (q, 2H,
J = 7.3 Hz), 3.55 (s, 3H), 3.04 (m, 2H), 2.76 (m,
2H), 2.53 (q, 2H, J = 7.3 Hz), 2.42 (s, 3H), 1.71
(m, 2H), 1.34 (t, 3H, J = 7.3 Hz), 1.33 (t, 3H, J
= 7.3 Hz), 1.30 (t, 3H, J = 7.3 Hz).

Example 54: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] butylamide (Compound 54) Except for using Compound 49 (300 mg, 0.59 mmol) and butyric anhydride. In the same manner as in Example 51, compound 54 (250
mg, 73%). Mp (ethanol): 258-259 ° C. Elemental _{analysis: C 31 H 38 N 6 O} 5 Calculated (%) C; 64.79, H ; 6.66, N; 14.62 Found (%) C; 64.46, H ; 6.89, N 14.70 EI-MS (m / z): 574 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.89 (s, 1H), 8.07 (s, 1H),
7.98 (s, 1H), 7.49 (dd, 1H, J = 2.0, 8.3 Hz), 7.0
9 (d, 1H, J = 8.6 Hz), 6.91 (s, 1H), 5.25 (m, 1H),
3.95 (q, 2H, J = 7.3 Hz), 3.93 (q, 2H, J = 7.3 H
z), 3.55 (s, 3H), 3.04 (m, 2H), 2.82 (m, 2H), 2.46
(q, 2H, J = 7.3 Hz), 2.42 (s, 3H), 1.80 (m, 2H),
1.34 (t, 3H, J = 7.3 Hz), 1.32 (t, 3H, J = 7.3 H
z), 1.06 (t, 3H, J = 7.3 Hz).

Example 55: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] cyclopentanecarboxamide (Compound 55) Compound 49 (300 mg, 0.59 mmol) was treated with methylene chloride (20 m
L) and cyclopentanecarboxylic acid chloride (0.11
mL, 0.89 mmol) and pyridine (0.10 mL, 1.19 mmol)
Was added, and the mixture was stirred at room temperature for 1 hour and 10 minutes. After partitioning the reaction mixture with water / chloroform, the organic layer was separated and 1 mol /
Washed with L aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and then with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1), and recrystallized from ethanol (6 mL) to give the compound. 55 (120 mg, 33%) was obtained. Mp (ethanol): 195-196 ° C. Elemental _{analysis: C 33 H 40 N 6 O} 5 Calculated (%) C; 65.98, H ; 6.71, N; 13.99 Found (%) C; 65.58, H ; 6.89, N 14.02 EI-MS (m / z): 600 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.99 (s, 1H), 8.13 (s, 1H),
7.98 (d, 1H, J = 1.3Hz), 7.49 (dd, 1H, J = 1.7,
8.9 Hz), 7.08 (d, 1H, J = 8.6 Hz), 6.91 (s, 1H), 5.
25 (m, 1H), 3.95 (q, 2H, J = 7.3 Hz), 3.93 (q, 2H,
J = 7.3 Hz), 3.55 (s, 3H), 3.05 (m, 2H), 2.82 (m,
2H), 2.42 (s, 3H), 1.69 (m, 11H), 1.34 (t, 3H, J
= 7.3 Hz), 1.32 (t, 3H, J = 7.3 Hz).

Example 56: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] cyclohexanecarboxamide (Compound 56) Compound 49 (300 mg, 0.59 mmol) was treated with methylene chloride (20 m
L) and cyclohexanecarboxylic acid (0.15 mL, 1.
2 mmol), WSC HCl (0.34 g, 1.8 mmol) and HOBt (0.1
(8 g, 1.2 mmol) in methylene chloride (20 mL) was slowly added dropwise and stirred at room temperature overnight. After partitioning the reaction solution with water / chloroform, the organic layer was separated and washed with a 1 mol / L aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and then a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was triturated with ethanol (5 mL) to obtain Compound 56 (280 mg, 77%). Melting point (ethanol): 165-166 ° C Elemental analysis: C ₃₄ H ₄₂ N ₆ O ₅ · 0.4H ₂ O Calculated value (%) C; 65.66, H; 6.94, N; 13.51 Actual value (%) C; 65.56, H; 7.11, N; 13.59 EI-MS (m / z): 614 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.97 (s, 1H), 8.10 (s, 1H),
7.98 (s, 1H), 7.49 (dd, 1H, J = 2.0, 8.6 Hz), 7.0
8 (d, 1H, J = 8.6 Hz), 6.91 (s, 1H), 5.24 (m, 1H),
3.94 (q, 2H, J = 7.3 Hz), 3.93 (q, 2H, J = 7.3 H
z), 3.55 (s, 3H), 3.04 (m, 2H), 2.82 (m, 2H), 2.41
(s, 3H), 2.36 (m, 1H), 2.03 (m, 2H), 1.84 (m, 2H),
1.74 (m, 2H), 1.59 (m, 2H), 1.40 (m, 2H), 1.34
(t, 3H, J = 7.3 Hz), 1.32 (t, 3H, J = 7.3 Hz).

Example 57: 3- [1- (1,3-Diethyl-6-methylamino-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro-
2,4-Dioxoquinazoline (Compound 57) First step: Compound 50 (2.84 g, 5.33 mmol) was added to DMF (56 m
L) and ice-cooled 60% sodium hydride (256 mg, 6.
40 mmol) was added. After stirring at room temperature for 30 minutes, methyl iodide (0.80 mL, 13 mmol) was added dropwise, and further at room temperature.
The mixture was stirred for 4 hours and 20 minutes. The reaction solution was poured into ice water and extracted three times with ethyl acetate. The organic layer was washed with water and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give N-methyl-N- [6- [4- (1,6-
Dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1,3-diethyl-2-oxo-2,3-dihydro-1H- Benzimidazole-5-
[L] formamide (2.88 g, 99%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 8.14 (d, 1H, J = 9.9 Hz),
7.84 (s, 1H), 7.58 (d, 1H, J = 7.3 Hz), 7.40-7.10
(m, 3H), 5.20-4.90 (m, 1H), 4.75-4.50 (m, 1H), 3.
89 (q, 4H, J = 7.3 Hz), 3.70-3.50 (m, 1H), 3.32
(s, 3H), 3.35-2.40 (m, 7H), 2.36 (s, 3H), 1.80-1.40
(m, 2H), 1.30-1.00 (m, 6H).

Second step: The above compound was dissolved in a 2 mol / L aqueous hydrochloric acid solution (96 mL) and heated under reflux for 1 hour and 40 minutes. A 2 mol / L aqueous sodium hydroxide solution was added to the reaction solution, and the solution was adjusted to alkaline, and then extracted twice with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol =
70: 1) and trituration with diisopropyl ether to give compound 57 (1.16 g, 43
%). Melting point (diisopropyl ether): 255-256 ° C Elemental analysis: C ₂₈ H ₃₄ N ₆ O ₄ Calculated value (%) C; 64.85, H; 6.61, N; 16.20 Actual value (%) C; 64.90, H; 6.88, N; 16.29 EI-MS (m / z): 518 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.99 (s, 1H), 7.49 (d, 1H,
J = 8.6 Hz), 7.08 (d, 1H, J = 8.3 Hz), 6.89 (s, 1
H), 6.80 (brs, 1H), 5.35-5.15 (m, 1H), 4.42 (brs, 2
H), 3.95 (q, 2H, J = 7.3 Hz), 3.92 (q, 2H, J = 7.6
Hz), 3.56 (s, 3H), 3.20-2.70 (m, 4H), 2.99 (s, 3
H), 2.42 (s, 3H), 1.85-1.65 (m, 2H), 1.45-1.20 (m,
6H).

Example 58: 3- [1- (1,3-Diethyl-6-ethylamino-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro-
2,4-dioxoquinazoline (Compound 59) Compound 50 (600 mg, 1.13 mmol) and ethyl iodide (0.22
Compound 59 (167 mg, 27%) was obtained in the same manner as in Example 57 except that mL, 2.70 mmol) was used. Melting point (ethyl acetate): 219-220 ° C Elemental analysis: C ₂₉ H ₃₆ N ₆ O ₄ Calculated value (%) C; 65.39, H; 6.81, N; 15.78 Actual value (%) C; 65.24, H; 6.99, N; 15.74 EI-MS (m / z): 532 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.84 (d, 1H, J = 2.0 Hz),
7.59 (dd, 1H, J = 8.3, 2.0 Hz), 7.32 (d, 1H, J = 8.
6 Hz), 6.90 (s, 1H), 6.54 (s, 1H), 5.15-5.00 (m, 1
H), 4.96 (t, 1H, J = 5.6 Hz), 4.15 (brs, 2H), 3.90
-3.70 (m, 4H), 3.47 (s, 3H), 3.17 (q, 2H, J = 5.3
Hz), 3.10-2.90 (m, 2H), 2.65-2.45 (m, 2H), 2.37 (s,
3H), 1.70-1.55 (m, 2H), 1.30-1.10 (m, 9H).

Example 59: 3- [1- (1,3-diethyl-2-oxo-6-propylamino-2,3-
Dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro
-2,4-Dioxoquinazoline hydrochloride (Compound 61) Compound 49 (300 mg, 0.59 mmol) was dissolved in 1% acetic acid / methylene chloride (10 mL), and propionaldehyde (0.05 m
L, 0.65 mmol) and sodium triacetoxyborohydride (0.63 g, 3.0 mmol) at room temperature for 3 hours.
Stirred for minutes. After partitioning the reaction solution with water / chloroform, the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 4
After purification by 0: 1), the residue was dissolved in ethyl acetate (6 mL). A 4 mol / L hydrochloric acid / ethyl acetate solution was added to this solution, and the precipitated solid was collected by filtration. Compound 61 (110 mg, 32%) was obtained by recrystallization from ethyl acetate. Mp (ethyl acetate): 173-174 ° C. Elemental _{analysis: C 30 H 38 N 6 O} 4 · HCl · 0.8H 2 O Calculated (%) C; 60.30, H ; 6.85, N; 14.06 Found (%) C 60.28, H; 6.86, N; 13.98 EI-MS (m / z): 546 (M ⁺ ) ¹ H-NMR (free base: CDCl ₃ ) δ (ppm): 7.97 (s, 1H), 7.9
2 (s, 1H), 7.50 (d, 1H, J = 8.6 Hz), 7.09 (d, 1H,
J = 8.6 Hz), 7.03 (s, 1H), 5.32 (m, 1H), 4.00 (q,
2H, J = 7.3 Hz), 3.98 (q, 2H, J = 7.3 Hz), 3.55
(s, 3H), 3.43 (m, 2H), 2.81 (m, 2H), 2.41 (s, 3H),
2.08 (q, 2H, J = 7.3 Hz), 1.78 (m, 2H), 1.38 (t, 3
H, J = 7.3 Hz), 1.35 (t, 3H, J = 7.3 Hz) 1.12 (t,
3H, J = 7.3Hz).

Example 60: 3- [1- (1,3-diethyl-6-isopropylamino-2-oxo-
2,3-Dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (Compound 62) Compound 62 (178) was obtained in the same manner as in Example 59, except that Compound 49 (500 mg, 0.92 mmol) and acetone were used.
mg, 35%). Mp: 207-208 ° C. Elemental _{analysis: C 30 H 38 N 6 O} 4 Calculated (%) C; 65.91, H ; 7.01, N; 15.37 Found (%) C; 65.94, H ; 7.09, N; 15.37 EI -MS (m / z): 546 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.99 (d, 1H, J = 1.3 Hz),
7.48 (dd, 1H, J = 8.9, 2.3 Hz), 7.08 (d, 1H, J =
8.6 Hz), 6.84 (s, 1H), 6.35 (brs, 1H), 5.30-5.10
(m, 1H), 4.65 (brs, 1H), 4.50-4.30 (m, 2H), 3.90
(q, 2H, J = 5.9 Hz), 3.88 (q, 2H, J = 5.9 Hz), 3.6
5 (sept, 1H, J = 6.3 Hz), 3.56 (s, 3H), 3.10-2.70
(m, 4H), 2.41 (s, 3H), 1.80-1.65 (m, 2H), 1.40-1.2
0 (m, 12H).

Example 61: 3- [1- (1,3-diethyl-6-isobutylamino-2-oxo-2,3
-Dihydro-1H-benzimidazol-5-ylcarbonyl)
Piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline hydrochloride (Compound 63) Compound 49 (300 mg, 0.59 mmol) and isobutyraldehyde
(0.06 mL, 0.65 mmol) and sodium triacetoxyborohydride (0.63 g, 2.97 mmol) except that compound 63 (140 mg, 39 mg) was obtained in the same manner as in Example 59.
%). Melting point (ethanol): 178-179 ° C Elemental analysis: C ₃₁ H ₄₀ N ₆ O ₄ HCl 0.9 H ₂ O Calculated value (%) C; 60.70, H; 7.03, N; 13.70 Actual value (%) C; 60.74, H; 7.00, N; 13.76 EI-MS (m / z): 560 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.83 (s, 1H), 7.59 (d, 1)
H, J = 9.2 Hz), 7.33 (d, 1H, J = 8.9 Hz), 7.03 (s,
1H), 6.80 (s, 1H), 5.11 (m, 1H), 4.20 (m, 2H), 3.
84 (t, 2H, J = 7.3 Hz), 3.02 (d, 2H, J = 6.9 Hz),
2.57 (m, 2H), 2.36 (s, 3H), 1.95 (m, 1H), 1.65 (m,
2H), 1.21 (t, 3H, J = 7.3 Hz), 1.18 (t, 3H, J =
7.3 Hz), 1.00 (d, 6H, J = 6.6 Hz).

Example 62: 3- [1- (6-Cyclopentylamino-1,3-diethyl-2-oxo)
-2,3-Dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline hydrochloride ( Compound 65) Compound 49 (300 mg, 0.59 mmol), cyclopentanone (0.
Compound 65 (150 mg, 41%) by the same method as in Example 59, except that 06 mL, 0.65 mmol) and sodium triacetoxyborohydride (0.63 g, 2.97 mmol) were used.
I got Mp (ethanol): 200-201 ° C. Elemental _{analysis: C 32 H 40 N 6 O} 4 · HCl · 0.5H 2 O Calculated (%) C; 62.18, H ; 6.85, N; 13.59 Found (%) C; 62.10, H; 6.92, N; 13.67 EI-MS (m / z): 572 (M ⁺ ) ¹ H-NMR (free base: CDCl ₃ ) δ (ppm): 7.99 (s, 1H), 7.4
9 (d, 1H, J = 8.6 Hz), 7.08 (d, 1H, J = 8.6 Hz), 6.
88 (s, 1H), 5.24 (m, 1H), 4.43 (m, 1H), 3.93 (q, 2
H, J = 7.3 Hz), 3.91 (q, 2H, J = 7.3 Hz), 3.55 (s,
3H), 3.05 (m, 2H), 2.84 (m, 2H), 2.41 (s, 3H), 1.9
6 (m, 10H), 1.34 (t, 3H, J = 7.3 Hz), 1.32 (t, 3H,
J = 7.3 Hz).

Example 63: 3- [1- (6-cyclohexylmethylamino-1,3-diethyl-2-
Oxo-2,3-dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl] -1,6-dimethyl-1,2,3,4-
Tetrahydro-2,4-dioxoquinazoline hydrochloride (Compound 6
6) Except for using compound 49 (300 mg, 0.59 mmol), cyclohexanecarboxaldehyde (0.09 mL, 0.65 mmol) and sodium triacetoxyborohydride (0.63 g, 2.97 mmol), a method similar to that in Example 59 was used. Compound 66
(290 mg, 77%). Melting point (ethyl acetate): 192-193 ° C Elemental analysis: C ₃₄ H ₄₄ N ₆ O ₄ HCl Calculated (%) C; 64.09, H; 7.12, N; 13.19 Found (%) C; 63.85, H; 7.32 , N; 12.95 EI-MS (m / z): 600 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.83 (s, 1H), 7.60 (d, 1)
H, J = 8.3 Hz), 7.33 (d, 1H, J = 8.6 Hz), 7.05 (s,
1H), 6.87 (s, 1H), 5.11 (m, 1H), 4.19 (m, 2H), 3.
86 (q, 2H, J = 6.6 Hz), 3.84 (q, 2H, J = 6.6 Hz),
3.06 (m, 4H), 2.58 (m, 2H), 2.36 (s, 3H), 1.84 (m,
2H), 1.67 (m, 2H), 1.21 (t, 3H, J = 6.9 Hz), 1.18
(t, 3H, J = 6.6 Hz).

Example 64: 3- [1- [1,3-Diethyl-6- (2-hydroxyethyl) amino-2-
Oxo-2,3-dihydro-1H-benzimidazol-5-ylcarbonyl] piperidin-4-yl] -1,6-dimethyl-1,2,3,4-
Tetrahydro-2,4-dioxoquinazoline (Compound 64) First step: Compound 50 (1.0 g, 1.9 mmol) was added to DMF (20 mL)
In ice-cooled 60% sodium hydride (90 mg, 2.3 m
mol) was added. After stirring at room temperature for 30 minutes, bromoacetic acid ethyl ester (0.50 mL, 4.5 mmol) was added dropwise, and the mixture was further stirred at room temperature for 2 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed three times with water and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Silica gel column chromatography of the residue (chloroform: methanol = 50: 1)
To give ethyl N-formyl-N- [6- [4-
(1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1,3-
Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] glycinate (1.08 g, 93%) was obtained.

Step 2: The above compound (550 mg, 0.89 mmo)
l) was dissolved in ethanol (28 mL) and sodium borohydride (135 mg, 3.56 mmol) was added. After stirring at room temperature for 2 hours, further sodium borohydride (100 mg)
Was added and stirred at room temperature overnight. After partitioning the reaction mixture with water / ethyl acetate, the aqueous layer was washed with ethyl acetate. The ethyl acetate washing solution and the above organic layer were combined, washed with saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, N- (2-hydroxyethyl) -N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4
-Dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] formamide (367 mg, 73%) Obtained.

Third step: The above compound (367 mg, 0.67 mmo)
l) was dissolved in a 2 mol / L aqueous hydrochloric acid solution (20 mL) and heated under reflux for 1 hour. After returning the reaction solution to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 70: 1), and the obtained crude crystals were recrystallized from ethyl acetate to give Compound 64 (134 mg, 27 mg).
%). Melting point (ethyl acetate): 185-187 ° C Elemental analysis: C ₂₉ H ₃₆ N ₆ O ₅ · 0.1 H ₂ O Calculated value (%) C; 63.28, H; 6.63, N; 15.27 Actual value (%) C; 63.39 , H; 7.03, N; 15.00 EI-MS (m / z): 548 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.98 (s, 1H), 7.48 (d, 1H,
J = 9.2 Hz), 7.08 (d, 1H, J = 8.6 Hz), 6.82 (s, 1
H), 6.43 (s, 1H), 5.30-5.20 (m, 1H), 4.40 (brs, 2
H), 4.00-3.75 (m, 6H), 3.55 (s, 3H), 3.40-3.30 (s,
3H), 3.10-2.70 (m, 4H), 2.42 (s, 3H), 1.75-1.65
(m, 2H), 1.40-4.20 (m, 6H).

Example 65: 3- [1- (6-cyanomethylamino-1,3-diethyl-2-oxo-
2,3-Dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (Compound 67) First step: Compound 50 (570 mg, 1.07 mmol) was added to DMF (56 m
L) and 60% sodium hydride (51 mg, 1.2
8 mmol) was added. After stirring at room temperature for 30 minutes, 95%
Bromoacetonitrile (0.18 mL, 2.6 mmol) was added dropwise, and the mixture was further stirred at room temperature for 2 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and N-cyanomethyl-N- [6- [4- (1,
6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1,3-diethyl-2-oxo-2,3-dihydro- 1H-benzimidazole-5
[-Yl] formamide (570 mg, 93%) was obtained.

Second step: The above compound was treated with dioxane (10 m
L) and 2 mol / L hydrochloric acid aqueous solution (0.68 mL, 1.36 mmo
l) was added and stirred at room temperature for 1 hour and 15 minutes. 2 mol / L hydrochloric acid aqueous solution (5.0 mL) was added, and the mixture was stirred at room temperature overnight.
Further, add 2 mol / L hydrochloric acid aqueous solution (3.0 mL), and add
Stirred for hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 70: 1), and then triturated with ethyl acetate.
Compound 67 (135 mg, 27%) was obtained. Melting point (ethyl acetate): 249-250 ° C EI-MS (m / z): 543 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.99 (s, 1H), 7.48 (dd, 1H,
J = 8.6, 2.3 Hz), 7.08 (d, 1H, J = 8.6 Hz), 6.89
(s, 1H), 6.47 (s, 1H), 5.35-5.15 (m, 1H), 4.40 (br
s, 2H), 4.20 (s, 2H), 3.95 (q, 2H, J = 7.3 Hz), 3.
91 (q, 2H, J = 7.3 Hz), 3.56 (s, 3H), 3.15-2.65
(m, 4H), 2.42 (s, 3H), 1.80-1.60 (m, 2H), 1.36 (t,
3H, J = 7.3 Hz), 1.32 (t, 3H, J = 7.3 Hz).

Example 66: 3- [1- (6-dimethylamino-1,3-diethyl-2-oxo-2,3-
Dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro
-2,4-Dioxoquinazoline (Compound 58) Compound 49 (500 mg, 0.99 mmol) was treated with acetonitrile (20
dissolved in 37% formalin (1.5 mL, 19.8 mmol),
Sodium cyanoborohydride (249 mg, 3.96 mmol) and bromocresol green were added and stirred at room temperature. Acetic acid was added dropwise until the reaction solution became acidic, and the mixture was stirred at room temperature overnight. After partitioning the reaction mixture with a saturated aqueous solution of sodium hydrogen carbonate / chloroform, the organic layer was separated and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 70:
After purification in 1), trituration with ethyl acetate / ether (1: 1) gave compound 58 (291 mg, 55
%). ¹ H-NMR indicated that Compound 58 was present as a 3: 2 rotamer. Melting point (ethyl acetate / ether): 255-257 ° C Elemental analysis: C ₂₉ H ₃₆ N ₆ O ₄ Calculated value (%) C; 65.39, H; 6.81, N; 15.78 Actual value (%) C; 65.21, H; 7.18, N; 15.65 EI-MS (m / z): 532 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.00 (d, 1H, J = 5.0 Hz),
7.48 (dd, 1H, J = 8.6, 2.0 Hz), 7.07 (d, 1H, J = 8.
3 Hz), 7.03, 6.95 (s, 0.4H, 0.6H respectively), 6.66, 6.62
(Each s, 0.4H, 0.6H), 5.21 (brs, 1H), 5.10-4.90
(m, 1H), 3.93 (q, 4H, J = 6.9 Hz), 3.70-3.55 (m, 1
H), 3.57 (s, 3H), 3.30-2.70 (m, 4H), 2.90 (s, 3H),
2.76 (s, 3H), 2.42 (s, 3H), 1.85-1.70 (m, 1H), 1.
65-1.50 (m, 1H), 1.35 (t, 6H, J = 7.3 Hz).

Example 67: 3- [1- (6-diethylamino-1,3-diethyl-2-oxo-2,3-
Dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro
-2,4-dioxoquinazoline hydrochloride (Compound 60) Compound 49 (500 mg, 0.99 mmol), acetaldehyde (1.
1 mL, 20 mmol) and sodium cyanoborohydride
(249 mg, 3.96 mmol) was used and the free base of compound 60 was obtained in the same manner as in Example 66. This free base was dissolved in ethyl acetate, and 4 mol / L hydrochloric acid /
An ethyl acetate solution was added, and the precipitated crystals were collected by filtration to obtain Compound 60 (232 mg, 39%). Mp (ethyl acetate): 193-195 ° C. Elemental _{analysis: C 31 H 40 N 6 O} 4 · HCl · 1.4H 2 O Calculated (%) C; 59.83, H ; 7.09, N; 13.50 Found (%) C ; 59.84, H; 7.48, N; 13.29 EI-MS (m / z): 560 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.84 (s, 2H), 7.59 (dd, 1
H, J = 8.6, 2.0 Hz), 7.35 (s, 1H), 7.31 (s, 1H),
5.20-5.05 (m, 1H), 4.80-4.65 (m, 1H), 3.93 (q, 4H,
J = 7.3 Hz), 3.90-3.50 (m, 5H), 3.47 (s, 3H), 3.4
0-3.20 (m, 2H), 3.05-2.85 (m, 1H), 2.80-2.55 (m, 1
H), 2.36 (s, 3H), 1.85-1.50 (m, 2H), 1.24 (t, 6H,
J = 6.6 Hz), 1.06 (t, 6H, J = 6.9 Hz).

Example 68: 3- [1- (1-Ethyl-3-methyl-5-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-6-ylcarbonyl) piperidin-4-yl ] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4
-Dioxoquinazoline (Compound 74) 1st step: 4-Chloro-3-nitrobenzoic acid methyl ester
(10 g, 46.4 mmol) was dissolved in DMF (200 mL), potassium carbonate (13 g, 93 mmol) and 40% aqueous methylamine solution (40
mL, 460 mmol) was added and heated at 80 ° C. for 30 minutes. After the reaction solution was cooled to room temperature, it was partitioned with water / ethyl acetate.
The organic layer was washed with water (× 3) and then with a saturated saline solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain methyl 4-methylamino-3-nitrobenzoate (7.65 g, 78%). ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.89 (d, 1H, J = 2.0 Hz),
8.36 (brs, 1H), 8.09 (dd, 1H, J = 7.9, 2.0 Hz), 6.
87 (d, 1H, J = 8.9 Hz), 3.91 (s, 3H), 3.09 (d, 3H,
J = 5.3 Hz).

Step 2: The above compound (7.5 g, 36 mmol)
Was dissolved in a mixture of methanol (188 mL) and water (56 mL), and ammonium formate (16.9 g, 268 mmol) was added.
After addition of Pd-C (750 mg, 50 w / w% H ₂ O), the mixture was heated under reflux at 85 ° C. for 1 hour and 30 minutes. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. After the filtrate was concentrated under reduced pressure, the residue was partitioned with water / chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain methyl 3-amino-4-methylaminobenzoate (5.8 g, 90%). ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.88 (d, 1H, J = 2.0 Hz),
8.35 (brs, 1H), 8.08 (dd, 1H, J = 8.9, 2.0 Hz), 6.
62 (d, 1H, J = 9.2 Hz), 3.90 (s, 3H), 3.09 (d, 3H,
J = 5.0 Hz).

Third step: The above compound (5.7 g, 32 mmol)
Was dissolved in acetonitrile (74 mL) and 1,1'-carbonyldiimidazole (6.2 g, 38 mmol) was added.
For 1 hour. After cooling the reaction solution to room temperature, the precipitated crystals were filtered and dried to give 1-methyl-2-
Oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylic acid methyl ester (5.11 g, 78%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 11.22 (brs, 1H), 7.84 (d,
1H, J = 8.3 Hz), 7.64 (s, 1H), 7.33 (d, 1H, J = 7.
9 Hz), 3.96 (s, 3H), 3.47 (s, 3H).

Step 4: The above compound (5.0 g, 24 mmol)
Was dissolved in acetic anhydride (48 mL), and fuming nitric acid (1.5 mL, 36 mmol) was slowly added dropwise while cooling with methanol / ice. After stirring for 1 hour and 25 minutes at room temperature, the reaction solution was poured into ice water,
The precipitated crystals were collected by filtration. The obtained crude crystals are washed with ethyl acetate to give 1-methyl-6-nitro-2-oxo.
-2,3-Dihydro-1H-benzimidazol-5-ylcarboxylic acid methyl ester (4.5 g, 74%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 11.72 (brs, 1H), 7.90 (s,
1H), 7.29 (s, 1H), 3.86 (s, 3H), 3.36 (s, 3H).

Step 5: The above compound (2.0 g, 8.0 mmol)
Was dissolved in DMF (34 mL) and 60% sodium hydride was added under ice-cooling.
(478 mg, 11.9 mmol) was added. After stirring at room temperature for 30 minutes, ethyl iodide (0.96 mL, 12 mmol) was added dropwise,
The mixture was further stirred at room temperature for 45 minutes. The reaction solution was poured into ice water and extracted with ether. The organic layer was washed with water (× 2) and then with a saturated saline solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 1-ethyl-3-.
Methyl-5-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-6-ylcarboxylic acid methyl ester (1.14 g,
51%). ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.60 (s, 1H), 7.23 (s, 1H),
3.99 (q, 2H, J = 7.3Hz), 3.93 (s, 3H), 3.49 (s, 3
H), 1.37 (t, 3H, J = 7.3 Hz).

Step 6: The above compound (1.0 g, 3.6 mmol)
Was dissolved in a mixture of methanol (34 mL) and water (8.5 mL), and sodium hydroxide (716 mg) was added.
Heated to reflux for 50 minutes. The methanol is distilled off and 2 mo
l / L hydrochloric acid aqueous solution was added, and after cooling, the precipitated crystals were collected by filtration,
By drying, 1-ethyl-3-methyl-5-nitro-2-
Oxo-2,3-dihydro-1H-benzimidazol-6-ylcarboxylic acid (924 mg, 97%) was obtained.

Step 7: The above compound (852 mg, 3.21 mmol)
l) in methylene chloride (36 mL)
(Piperidin-4-yl) -1,2,3,4-tetrahydro-2,4-dioxoquinazoline (878 mg, 3.21 mmol), TEA (1.79 mL,
6.42 mmol), HOBt (984 mg, 7.28 mmol), WSC HCl (1.23 mmol)
g, 6.42 mmol) and stirred overnight at room temperature. After partitioning the reaction mixture with chloroform / 2 mol / L hydrochloric acid, the organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline.
After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was triturated with ethyl acetate / ether (1: 1) to give compound 74 (1.37 g, 82%).
I got ^{From 1} H-NMR, compound 74 was present as a 4: 1 mixture of rotamers. Melting point (ethyl acetate / ether):> 300 ° C. Elemental analysis: C ₂₆ H ₂₈ N ₆ O ₆ Calculated (%) C; 58.77, H; 5.54, N; 15.82 Found (%) C; 58.90, H; 5.66 , N; 15.52 EI-MS (m / z): 520 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.02, 7.98 (s, 0.2H,
0.8H), 7.86 (d, 1H, J = 6.6 Hz), 7.09 (d, 1H, J =
6.9 Hz), 7.07, 6.90 (s, 0.8H, 0.2H respectively), 5.35-5.1
5 (m, 1H), 5.05-4.85 (m, 1H), 4.02 (q, 2H, J = 7.3
Hz), 3.56 (s, 3H), 3.50 (s, 3H), 3.30-2.60 (m, 4
H), 2.42 (s, 3H), 1.90-1.75 (m, 2H), 1.60-1.50 (m,
1H), 1.39 (t, 3H, J = 7.3 Hz).

Example 69: 3- [1- (5-amino-1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-6-ylcarbonyl) piperidin-4-yl ] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4
-Dioxoquinazoline hydrochloride (Compound 75) Compound 74 (1.1 g, 2.1 mmol) in methanol (28 mL)
Dissolve in a mixture of water (8 mL) and add 10% Pd-C (110 mg, 50w / w
% H ₂ O) and then ammonium formate (1.0 g, 15 mmol), and then heated to reflux for 4 hours. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. After the filtrate was concentrated under reduced pressure, water was added to the residue and extracted with chloroform. After the organic layer was dried over magnesium sulfate, the solvent was distilled off. After dissolving the residue in ethyl acetate, 4 mol / L hydrochloric acid / ethyl acetate was added, and the precipitated crystals were collected by filtration. Compound 75 (810 mg, 73%) was obtained by recrystallization from ethanol. Melting point (ethanol): 199-200 ° C Elemental analysis: C ₂₆ H ₃₀ N ₆ O ₄ .HCl.H ₂ O Calculated value (%) C; 57.30, H; 6.10, N; 15.42 Actual value (%) C; 57.36 , H; 6.07, N; 15.01 EI-MS (m / z): 490 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.84 (s, 1H), 7.59 (d, 1)
H, J = 8.9 Hz), 7.33 (d, 1H, J = 8.6 Hz), 7.20 (s,
1H), 7.10 (s, 1H), 5.20-5.00 (m, 1H), 4.20 (brs,
2H), 3.89 (q, 2H, J = 7.3 Hz), 3.48 (s, 3H), 3.31
(s, 3H), 3.08 (brs, 2H), 2.70-2.50 (m, 2H), 2.36
(s, 3H), 1.80-1.60 (m, 2H), 1.20 (t, 3H, J = 6.9 H
z).

Example 70: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1-Ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] acetamide (Compound 76) Compound 75 (222 mg, 0.45 mmol) was treated with methylene chloride (15 m
L), acetic anhydride (0.085 mL, 0.91 mmol), TEA
(0.189 mL, 1.36 mmol) and DMAP (catalytic amount) were added, followed by stirring at room temperature overnight. After partitioning the reaction solution with saturated aqueous sodium hydrogen carbonate / chloroform, the organic layer was separated and washed with a 2 mol / L aqueous hydrochloric acid solution and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give Compound 76 (16
4 mg, 68%). Mp (ethyl acetate): 284-285 ℃ Elemental _{analysis: C 28 H 32 N 6 O} 5 · 0.8H 2 O Calculated (%) C; 61.48, H ; 6.19, N; 15.36 Found (%) C; 61.55 , H; 6.49, N; 15.40 EI-MS (m / z): 532 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.80 (s, 1H), 7.98 (s, 1H),
7.94 (s, 1H), 7.49 (dd, 1H, J = 8.6, 1.7 Hz), 7.0
8 (d, 1H, J = 8.6 Hz), 6.89 (s, 1H), 5.35-5.15 (m,
1H), 4.40 (brs, 2H), 3.93 (t, 2H, J = 7.3 Hz), 3.
55 (s, 3H), 3.42 (s, 3H), 3.15-2.65 (m, 4H), 2.41
(s, 3H), 2.27 (s, 3H), 1.80-1.60 (m, 2H), 1.32 (t,
3H, J = 7.3 Hz).

Example 71: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] propionamide (Compound 7
7) Compound 77 was obtained in the same manner as in Example 70 except that propionic anhydride was used instead of acetic anhydride. Melting point (ethyl acetate): 220-221 ° C Elemental analysis: C ₂₉ H ₃₄ N ₆ O ₅ Calculated value (%) C; 63.72, H; 6.27, N; 15.37 Actual value (%) C; 63.66, H; 6.52, N; 15.42 EI-MS (m / z): 546 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.89 (s, 1H), 8.03 (s, 1H),
7.98 (s, 1H), 7.49 (dd, 1H, J = 8.6, 2.0 Hz), 7.0
8 (d, 1H, J = 8.3 Hz), 6.90 (s, 1H), 5.35-5.10 (m,
1H), 4.50 (brs, 2H), 3.93 (q, 2H, J = 7.3 Hz), 3.
55 (s, 3H), 3.42 (s, 3H), 3.20-2.60 (m, 4H), 2.52
(q, 2H, J = 7.3 Hz), 2.41 (s, 3H), 1.85-1.60 (m, 2
H), 1.40-1.20 (m, 6H).

Example 72: 3- [1- (1-Ethyl-3-methyl-6-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl ] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4
-Dioxoquinazoline (Compound 70) Compound 70 was obtained in the same manner as in Example 68 except that ethylamine was used instead of methylamine in the first step and methyl iodide was used instead of ethyl iodide in the fifth step. Was done.

First step: 4-ethylamino-3-nitrobenzoic acid methyl ester ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.88 (d, 1H, J = 2.0 Hz),
8.28 (brs, 1H), 8.05 (dd, 1H, J = 9.2, 2.0 Hz), 6.
86 (s, 3H), 3.42 (q, 2H, J = 7.3 Hz), 1.40 (t, 3H,
J = 7.3 Hz).

Second step: 3-amino-4-ethylaminobenzoic acid methyl ester ¹ H-NMR (CDCL ₃ ) δ (ppm): 7.58 (d, 1H, J = 8.2 Hz),
7.43 (d, 1H, J = 2.0 Hz), 6.66 (s, 3H), 3.24 (q, 2
H, J = 7.3 Hz), 1.33 (t, 3H, J = 7.3 Hz).

Third step: 1-ethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylic acid methyl ester ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.88 (brs, 1H) ), 7.88 (d, 1
H, J = 8.3 Hz), 7.83 (s, 1H), 7.04 (d, 1H, J = 8.3
Hz), 3.99 (q, 2H, J = 7.3 Hz), 1.39 (t, 3H, J = 7.
3 Hz).

Fourth step: 1-ethyl-6-nitro-2-oxo-
2,3-dihydro-1H-benzimidazol-5-ylcarboxylic acid methyl ester ¹ H-NMR (CDCl ₃ ) δ (ppm): 10.15 (brs, 1H), 7.62 (s, 1
H), 7.39 (s, 1H), 4.01 (q, 2H, J = 7.3 Hz), 3.92
(s, 3H), 1.41 (t, 3H, J = 7.3 Hz).

Fifth step: 1-ethyl-3-methyl-6-nitro-2
-Oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylic acid methyl ester ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.61 (s, 1H), 7.23 (s, 1H),
4.21 (q, 2H, J = 7.3Hz), 3.93 (s, 3H), 3.49 (s, 3
H), 1.38 (t, 3H, J = 7.6 Hz).

Sixth step: 1-ethyl-3-methyl-6-nitro-2
-Oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylic acid ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.95 (s, 1H), 7.57 (s, 1
H), 3.96 (q, 2H, J = 7.3 Hz), 3.40 (s, 3H), 1.21
(t, 3H, J = 7.3 Hz).

Step 7: Compound 70 was present as a 7: 3 mixture of rotamers by ¹ H-NMR. Mp (ethyl acetate / ether):> 300 ° C. Elemental _{analysis: C 26 H 28 N 6 O} 6 · 0.5H 2 O Calculated (%) C; 58.97, H ; 5.52, N; 15.87 Found (%) C; 58.98, H; 5.65, N; 16.11 EI-MS (m / z): 520 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.02, 7.99 (s, 0.3H,
0.7H), 7.87 (s, 1H), 7.49 (dd, 1H, J = 8.3, 1.7 H
z), 7.09 (d, 1H, J = 8.6 Hz), 7.05, 6.89 (s,
0.7H, 0.3H), 5.35-5.15 (m, 1H), 5.05-5.85 (m, 1H),
4.01 (q, 2H, J = 7.3 Hz), 3.56 (s, 3H), 3.52 (s, 3
H), 3.35-2.60 (m, 4H), 2.42 (s, 3H), 1.95-1.80 (m,
1H), 1.65- 1.50 (m, 1H), 1.38 (t, 3H, J = 7.3 H
z).

Example 73: 3- [1- (6-Amino-1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl ] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4
-Dioxoquinazoline hydrochloride (Compound 71) Compound 71 was obtained in the same manner as in Example 69, except for using compound 70 instead of compound 74. Mp (ethyl acetate): 179-180 ° C. Elemental _{analysis: C 26 H 30 N 6 O} 4 · HCl · 0.3H 2 O Calculated (%) C; 58.65, H ; 5.98, N; 15.78 Found (%) C 58.77, H; 6.12, N; 15.51 EI-MS (m / z): 490 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.83 (s, 1H), 7.59 (d, 1
H, J = 8.6 Hz), 7.33 (d, 1H, J = 8.6 Hz), 7.19 (s,
1H), 7.15 (s, 1H), 5.20-5.00 (m, 1H), 4.20 (brs,
2H), 3.83 (q, 2H, J = 7.3 Hz), 3.48 (s, 3H), 3.34
(s, 3H), 3.08 (brs, 2H), 2.75-2.50 (m, 2H), 2.36
(s, 3H), 1.80-1.60 (m, 2H), 1.22 (t, 3H, J = 7.3 H
z).

Example 74: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1-Ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] acetamide (Compound 72) Obtained by a method similar to that in Example 70. Melting point (ethanol): 299-300 ° C Elemental analysis: C ₂₈ H ₃₂ N ₆ O ₅ Calculated value (%) C; 63.15, H; 6.06, N; 15.78 Actual value (%) C; 62.85, H; 6.18, N 15.64 EI-MS (m / z): 532 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.83 (s, 1H), 7.99 (s, 1H),
7.98 (d, 1H, J = 1.7Hz), 7.49 (dd, 1H, J = 8.6,
2.0 Hz), 7.08 (d, 1H, J = 8.6 Hz), 6.87 (s, 1H), 5.
35-5.15 (m, 1H), 4.45 (brs, 2H), 3.95 (t, 2H, J =
7.3 Hz), 3.55 (s, 3H), 3.40 (s, 3H), 3.15-2.65 (m,
4H), 2.42 (s, 3H), 2.27 (s, 3H), 1.80-1.65 (m, 2
H), 1.33 (t, 3H, J = 7.3 Hz).

Example 75: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] propionamide (Compound 7
3) Compound 73 was obtained in the same manner as in Example 70, except that compound 71 was used instead of compound 75 and propionic anhydride was used instead of acetic anhydride. Melting point (ethyl acetate): 287-288 ° C Elemental analysis: C ₂₉ H ₃₄ N ₆ O ₅ Calculated (%) C; 63.72, H; 6.27, N; 15.37 Found (%) C; 63.69, H; 6.53, N; 15.37 EI-MS (m / z): 546 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.92 (s, 1H), 8.08 (s, 1H),
7.98 (d, 1H, J = 1.7Hz), 7.49 (dd, 1H, J = 8.6,
1.6 Hz), 7.81 (d, 1H, J = 8.3 Hz), 6.88 (s, 1H), 5.
35-5.10 (m, 1H), 4.50 (brs, 2H), 3.95 (q, 2H, J =
7.3 Hz), 3.55 (s, 3H), 3.41 (s, 3H), 3.20-2.60 (m,
4H), 2.52 (q, 2H, J = 7.6 Hz), 2.42 (s, 3H), 1.85-
1.65 (m, 2H), 1.40-1.20 (m, 6H).

Example 76: 3- [1- (1-ethyl-6-nitro-2-oxo-2,3-dihydro-1H-
(Benzimidazol-5-ylcarbonyl) piperidine-4-
Yl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (compound 68) 1st step: 1-ethyl-6-nitro-2-oxo-2,3- Dihydro-
1H-benzimidazol-5-ylcarboxylic acid was prepared in Example 7
1-ethyl-6-nitro-2-oxo- obtained in the fourth step of 2
2,3-Dihydro-1H-benzimidazol-5-ylcarboxylic acid methyl ester was obtained by subjecting it to the hydrolysis reaction described in the sixth step of Example 68. ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 11.65 (s, 1H), 7.87 (s, 1
H), 7.29 (s, 1H), 3.90 (q, 2H, J = 6.3 Hz), 1.20
(t, 3H, J = 6.9 Hz)

Step 2: Compound 68 is reacted with the above carboxylic acid.
Except for using 1,6-dimethyl-3- (piperidin-4-yl) -1,2,3,4-tetrahydro-2,4-dioxoquinazoline, a method similar to that of the seventh step of Example 68 was used. Obtained. Melting point:> 300 ° C EI-MS (m / z): 506 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.72 (s, 1H), 7.99 (s, 1H),
7.88 (s, 1H), 7.49 (d, 1H, J = 8.6 Hz), 7.17 (s, 1H)
1H), 7.09 (d, 1H, J = 8.6 Hz), 5.35-5.15 (m, 1H),
5.05-4.80 (m, 1H), 4.01 (q, 2H, J = 7.3 Hz), 3.60-
3.40 (m, 1H), 3.57 (s, 3H), 2.60-2.30 (m, 4H), 2.4
1 (s, 3H), 1.90-1.50 (m, 2H), 1.41 (t, 3H, J = 7.3
Hz).

Example 77: 3- [1- (6-amino-1-ethyl-2-oxo-2,3-dihydro-1H-
(Benzimidazol-5-ylcarbonyl) piperidine-4-
Yl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline hydrochloride (Compound 69) Compound 69 was prepared in the same manner as in Example 69 except that compound 68 was used. Was obtained. Melting point (ethanol): 207-208 ° C Elemental analysis: C ₂₅ H ₂₈ N ₆ O ₄ .HCl. 1.3 H ₂ O Calculated value (%) C; 55.98, H; 5.94, N; 15.67 Actual value (%) C; 56.00, H; 6.18, N; 15.49 EI-MS (m / z): 476 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 11.06 (s, 1H), 7.84 (s, 1)
H), 7.59 (dd, 1H, J = 8.6, 2.0 Hz), 7.34 (d, 1H, J
= 8.6 Hz), 5.50-5.20 (m, 1H), 4.16 (brs, 2H), 3.81
(q, 2H, 7.3 Hz), 3.48 (s, 3H), 3.15-2.90 (m, 2H),
2.75-2.50 (m, 2H), 2.37 (s, 3H), 1.68 (d, 2H, J =
9.9 Hz), 1.21 (t, 3H, J = 6.9 Hz).

Example 78: 3- [1- [1- (2-benzyloxyethyl) -3-methyl-6-nitro
-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarbonyl] piperidin-4-yl] -1,6-dimethyl-1,2,
3,4-Tetrahydro-2,4-dioxoquinazoline (Compound 78) In the first step, 2-benzyloxyethylamine is used instead of methylamine in the first step, and methyl iodide is used instead of ethyl iodide in the fifth step. Was obtained in the same manner as in Example 68, except that The compound was found as a mixture of rotamers (7: 3) by ¹ H-NMR. Melting point (ethyl acetate / ether): 228-229 ° C Elemental analysis: C ₃₃ H ₃₄ N ₆ O ₇ Calculated (%) C; 62.71, H; 5.52, N; 13.30 Found (%) C; 62.70, H; 6.00, N; 13.29 EI-MS (m / z): 626 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.05 (s, 1H), 7.99, 7.98
(S, 0.3H, 0.7H respectively), 7.48 (d, 1H, J = 8.6 Hz), 7.
30-7.15 (m, 5H), 7.08 (d, 1H, J = 8.6 Hz), 5.30-5.
10 (m, 1H), 5.05-4.80 (m, 1H), 4.49 (s, 2H), 4.25
(t, 2H, J = 5.0 Hz), 3.79 (t, 2H, J = 5.0 Hz), 3.5
6 (s, 3H), 3.51 (s, 3H), 3.50-3.35 (m, 1H), 3.20-
2.60 (m, 4H), 2.41 (s, 3H), 1.90-1.75 (m, 1H), 1.6
0-1.40 (m, 1H).

Example 79: 3- [1- [6-amino-1- (2-hydroxyethyl) -3-methyl-2-
Oxo-2,3-dihydro-1H-benzimidazol-5-ylcarbonyl] piperidin-4-yl] -1,6-dimethyl-1,2,3,4-
Tetrahydro-2,4-dioxoquinazoline (Compound 79) Compound 79 was obtained in the same manner as in Example 69 except for using compound 78. Mp (diisopropyl ether): 198-199 ° C. Elemental _{analysis: C 26 H 30 N 6 O} 5 · 0.2 [(CH 3) 2 CH] 2 O · 1.6H 2 O Calculated (%) C; 58.78, H ; 5.53 , N; 15.12 Found (%) C; 58.78, H; 6.13, N; 14.89 EI-MS (m / z): 506 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.84 (s, 1H), 7.59 (dd, 1
H, J = 8.9, 1.7 Hz), 7.32 (d, 1H, J = 8.6 Hz), 6.8
0 (s, 1H), 6.55 (s, 1H), 5.15-5.00 (m, 1H), 4.95
(s, 1H), 4.88 (t, 2H, J = 5.3 Hz), 4.17 (brs, 2H),
3.77 (t, 2H, J = 5.6 Hz), 3.61 (q, 2H, J = 5.6 H
z), 3.47 (s, 3H), 3.25 (s, 3H), 3.10-2.90 (m, 2H),
2.85-2.45 (m, 2H), 2.36 (s, 3H), 1.70-1.50 (m, 2
H).

Example 80: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1- (2-Hydroxyethyl) -3-methyl-2-oxo-2,3-
Dihydro-1H-benzimidazol-5-yl] acetamide
(Compound 80) Compound 79 (300 mg, 0.59 mmol) was suspended in water (5 mL), acetic anhydride (0.28 mL, 3.0 mmol) was added, and the mixture was stirred overnight at room temperature. Acetic anhydride (0.11 mL) was further added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. The precipitated crystals were collected by filtration and washed with water (× 3) to give Compound 80 (287 m
g, 88%). Mp (H ₂ O): 189-190 ℃ Elemental _{analysis: C 28 H 32 N 6 O} 6 · 1.2H 2 O Calculated (%) C; 58.98, H ; 6.08, N; 14.74 Found (%) C; 59.01, H; 6.56, N; 14.47 EI-MS (m / z): 548 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 9.49 (s, 1H), 7.83 (s, 1)
H), 7.59 (d, 1H, J = 1.7 Hz), 7.32 (d, 1H, J = 8.6
Hz), 7.31 (s, 1H), 7.15 (s, 1H), 5.15-4.95 (m, 1
H), 4.86 (brs, 1H), 4.65 (brs, 1H), 3.84 (t, 2H, J
= 5.0 Hz), 3.61 (t, 2H, J = 5.0 Hz), 3.46 (s, 3
H), 3.32 (s, 3H), 3.15-2.70 (m, 4H), 2.36 (s, 3H),
2.10 (s, 3H), 1.80-1.40 (m, 2H).

Example 81: 3- [1- [1- (2-benzyloxyethyl) -3-ethyl-6-nitro
-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarbonyl] piperidin-4-yl] -1,6-dimethyl-1,2,
3,4-Tetrahydro-2,4-dioxoquinazoline (Compound 81) Compound 81 was obtained in the same manner as in Example 68 except that 2-benzyloxyethylamine was used instead of methylamine in the first step. . ^{According to 1} H-NMR, the compound was present as a 7: 3 mixture of rotamers. Mp (ethyl acetate / ether): 237-238 ° C. Elemental _{analysis: C 33 H 36 N 6 O} 7 · 1.1H 2 O Calculated (%) C; 61.83, H ; 5.83, N; 12.72 Found (%) C ; 61.89, H; 6.05, N; 12.90 EI-MS (m / z): 640 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.05 (s, 1H), 8.02, 7.99
(Each s, 0.3H, 0.7H), 7.48 (d, 1H, J = 8.3 Hz), 7.
35-7.15 (m, 5H), 7.08 (d, 1H, J = 8.3 Hz), 7.05
(s, 0.7H), 6.88 (s, 0.3H), 5.35-5.15 (m, 1H), 5.05
-4.80 (m, 1H), 4.50 (s, 2H), 4.15 (t, 2H, J = 5.0 H
z), 4.10-3.85 (m, 2H), 3.79 (t, 2H, J = 5.0 Hz),
3.56 (s, 3H), 3.45-3.40 (m, 1H), 3.25-2.60 (m, 4
H), 2.42 (s, 3H), 1.90-1.50 (m, 4H), 1.45-1.30 (m,
3H).

Example 82: 3- [1- (6-amino-3-ethyl-1- (2-hydroxyethyl) -2-
Oxo-2,3-dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl] -1,6-dimethyl-1,2,3,4-
Tetrahydro-2,4-dioxoquinazoline hydrochloride (Compound 8
2) Compound 82 was obtained in the same manner as in Example 69 except for using compound 81. Mp (diisopropyl ether): 168-169 ° C. Elemental _{analysis: C 27 H 32 N 6 O} 5 · 1.7H 2 O Calculated (%) C; 58.83, H ; 6.47, N; 15.25 Found (%) C; 59.11 , H; 6.66, N; 14.83 EI-MS (m / z): 520 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.84 (s, 1H), 7.57 (dd, 1)
H, J = 8.3, 2.0 Hz), 7.32 (d, 1H, J = 8.9 Hz), 6.8
3 (s, 1H), 6.56 (s, 1H), 5.25-5.00 (m, 1H), 4.95
(s, 1H), 4.90 (t, 2H, J = 5.8 Hz), 4.30-4.05 (brs,
2H), 3.85-3.65 (m, 4H), 3.61 (q, 2H, J = 5.6 Hz),
3.47 (s, 3H), 3.10-2.90 (m, 2H), 2.36 (s, 3H), 1.7
0-1.50 (m, 2H), 1.17 (t, 3H, J = 6.9 Hz).

Example 83: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -3-Ethyl-1- (2-hydroxyethyl) -2-oxo-2,3-
Dihydro-1H-benzimidazol-5-yl] acetamide
(Compound 83) Compound 83 was obtained in the same manner as in Example 80 except that compound 82 was used. Mp (H ₂ O): 172-173 ℃ Elemental _{analysis: C 29 H 34 N 6 O} 6 · 2.6H 2 O Calculated (%) C; 57.15, H ; 6.48, N; 13.79 Found (%) C; 57.12, H; 6.55, N; 13.81 EI-MS (m / z): 562 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 9.49 (s, 1H), 7.83 (s, 1)
H), 7.58 (d, 1H, J = 8.6 Hz), 7.32 (s, 1H), 7.31
(d, 1H, J = 8.6 Hz), 7.10 (s, 1H), 5.15-5.00 (m, 1
H), 4.88 (brs, 1H), 4.63 (brs, 1H), 4.00-3.70 (m,
4H), 3.63 (brs, 2H), 3.47 (s, 3H), 3.20-2.40 (m, 4
H), 2.36 (s, 3H), 2.11 (s, 3H), 1.80-1.30 (m, 2H),
1.21 (t, 3H, J = 6.9 Hz).

Example 84: 3- [1- [1- (2-benzyloxyethyl) -3-ethyl-5-nitro
-2-oxo-2,3-dihydro-1H-benzimidazol-6-ylcarbonyl] piperidin-4-yl] -1,6-dimethyl-1,2,
3,4-tetrahydro-2,4-dioxoquinazoline (compound 84) 1st step: 5-methyl-2-nitroaniline (13.4 g, 88 mm
ol) was dissolved in acetic acid (50 mL), and concentrated sulfuric acid (47 mL, 880 mmol) was slowly added dropwise while maintaining the temperature at 50-60 ° C. After completion of the dropwise addition, the reaction solution was cooled to 0 ° C., and an aqueous solution of sodium nitrite (8.0 g of sodium nitrite, 94 mmol was added to
) Was slowly added dropwise. After stirring at 0 ° C. for another 30 minutes, the mixture was added to potassium bromide (42.9 g, 360 mm
ol) and copper bromide (20.1 g, 140 mmol) dissolved in water (134 mL) were slowly added dropwise while maintaining the internal temperature at 10 ° C or lower. After completion of the dropwise addition, ice water (12 mL) was poured into the reaction solution, and the mixture was further stirred at 0 ° C for 15 minutes. The reaction was heated at 75 ° C. for 4 hours and then stirred at room temperature overnight. The reaction solution was partitioned with water / ether, and the organic layer was washed with water, then with a 2 mol / L aqueous sodium hydroxide solution, water, and then with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 7: 1) to give 3-bromo-4-nitrotoluene (16.2 g, 85%). ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.79 (d, 1H, J = 8.3 Hz),
7.56 (s, 1H), 7.24 (d, 1H, J = 8.3 Hz), 2.42 (s, 3
H).

Step 2: The above compound (16.1 g, 74.5 mmo)
l) in water (560 mL) and magnesium sulfate (13.5
g, 112 mmol), followed by potassium permanganate (11.8 g,
(74.7 mmol) was added and heated at 120 ° C. for 5 hours. Potassium permanganate (11.8 g, 74.7 mmol) was added to the reaction solution, and the mixture was further heated for 1 hour and 30 minutes. The reaction was cooled to 0 ° C., celite was added and stirred, then the mixture was filtered through celite. Concentrated hydrochloric acid (11 mL) was added to the filtrate, and the mixture was stirred at room temperature until the reaction solution became purple to transparent.
The reaction solution was allowed to stand at room temperature overnight, then cooled to 0 ° C., and the precipitated crystals were collected by filtration and dried to obtain 3-bromo-4-nitrobenzoic acid (4.5 g, 25%). ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 8.29 (s, 1H), 8.12 (s, 2
H).

Third step: The above compound (4.5 g, 18 mmol)
Was dissolved in methanol (17 mL) and concentrated sulfuric acid (0.8 mL, 15 mL).
(mmol) was added and the mixture was refluxed at 80 ° C. for 6 hours. After the reaction solution was concentrated under reduced pressure and partitioned with water / chloroform, the organic layer was separated. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to give 3-bromo-4-nitrobenzoic acid methyl ester.
(4.4 g, 93%). ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.39 (d, 1H, J = 1.7 Hz),
8.10 (dd, 1H, J = 8.3,1.6 Hz), 7.85 (d, 1H, J = 8.
6 Hz), 3.98 (s, 3H).

Step 4: The above compound (4.4 g, 16.9 mmo)
l) was dissolved in DMF (90 mL), 2-benzyloxyethylamine (4.3 g, 28.8 mmol), and then potassium carbonate (4.7 g).
g, 34 mmol) and heated at 80 ° C. for 30 minutes. 2-Benzyloxyethylamine (1.0 g) was added to the reaction solution, and the mixture was heated at 80 ° C for 4 hours. Under heating at 80 ° C., 2-benzyloxyethylamine (1.2 g) and then potassium carbonate (2.
4 g), and after 3 hours, 2-benzyloxyethylamine
(1.0 g), and then potassium carbonate (2.0 g).
After 30 minutes, 2-benzyloxyethylamine (1.0 g)
Was added and heated for 1 hour. After partitioning the reaction mixture with water / ethyl acetate, the organic layer was separated and washed with water (× 3) and then with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give 3- (2-benzyloxyethylamino) -4
-Nitrobenzoic acid methyl ester (1.21 g, 82%) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.89 (d, 1H, J = 2.0 Hz),
8.06 (brs, 1H), 8.03 (dd, 1H, J = 7.3, 2.0 Hz), 7.
45−7.20 (m, 5H), 6.86 (d, 1H, J = 9.2 Hz), 4.60
(s, 2H), 3.90 (s, 3H), 3.77 (t, 2H, J = 5.3 Hz),
3.56 (q, 2H, J = 5.0 Hz).

Step 5: The above compound (1.2 g, 3.6 mmol)
Was dissolved in ethanol (82 mL) and concentrated hydrochloric acid (4.1
mL) and then tin chloride dihydrate (4.1 g, 18 mmol) were added, and the mixture was heated under reflux at 100 ° C. for 4 hours and 15 minutes. Under ice cooling, water and then sodium bicarbonate were added to the reaction solution to adjust the pH to> 8. The mixture was extracted twice with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, 4-amino-3- (2-
Benzyloxyethylamino) benzoic acid methyl ester
(1.04 g, 95%). ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.50-7.10 (m, 6H), 6.48
(d, 1H, J = 8.6 Hz), 4.76 (s, 2H), 4.53 (s, 2H),
3.72 (s, 3H), 3.64 (t, 2H, J = 5.9 Hz), 3.55 (q, 2
H, J = 6.3 Hz), 3.33 (s, 3H).

Step 6: The above compound (1.0 g, 3.3 mmol)
Was dissolved in acetonitrile (13 mL) and CDI (650 mg,
(4.0 mmol) and heated at 60 ° C. for 2 hours and 20 minutes. After addition of CDI (100 mg) to the reaction mixture,
For 1 hour and 40 minutes. After concentrating the reaction solution under reduced pressure,
The residue was partitioned with chloroform / 2 mol / L aqueous hydrochloric acid.
The organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, ether was added to the residue, and the precipitated crystals were collected by filtration and dried.
1- (2-benzyloxyethyl) -2-oxo-2,3-dihydro-1
H-benzimidazol-6-ylcarboxylic acid methyl ester (512 mg, 47%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 11.29 (s, 1H), 7.80 (d, 1
H, J = 8.6 Hz), 7.66 (s, 1H), 7.50-7.20 (m, 6H),
4.60 (s, 2H), 4.18 (t, 2H, J = 5.3 Hz), 3.96 (s, 3
H), 3.83 (t, 3H, J = 5.3 Hz).

Step 7: The above compound (507 mg, 1.55 mmo
l) was dissolved in acetic anhydride (3.1 mL), and fuming nitric acid was added under ice-cooling.
(0.063 mL, 1.6 mmol) was slowly added dropwise. After stirring at room temperature for 2 hours, the reaction solution was poured into ice water. The mixture was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 1- (2-benzyloxyethyl) -5-nitro-2-oxo-2,3-dihydro-1H-benzimidazole- 6-ylcarboxylic acid methyl ester (471 mg,
82%). ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 11.95 (s, 1H), 8.39 (s, 1
H), 7.94 (s, 1H), 7.30-7.10 (m, 5H), 4.45 (s, 2H),
4.20-4.00 (m, 2H), 3.82 (s, 3H), 3.75-3.65 (m, 2
H).

Step 8: The above compound (471 mg, 1.27 mmo
l) was dissolved in DMF (8 mL), and 60% sodium hydride (76 mg, 1.9 mmol) was added under ice cooling. After stirring at room temperature for 30 minutes, ethyl iodide (0.125 mL, 1.90 mmol) was added dropwise, and the mixture was further stirred at room temperature for 2 hours. The reaction solution was poured into ice water and extracted twice with ether. The organic layer was washed with water (× 3) and then with a saturated saline solution. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 1-
Crude crystals of methyl (2-benzyloxyethyl) -3-ethyl-5-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-6-ylcarboxylate (> 507 mg, quantitative, DMF (Including a small amount). ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 8.01 (s, 1H), 7.65 (s, 1
H), 7.30-7.00 (m, 5H), 4.44 (s, 2H), 4.17 (t, 2H, J
= 5.3 Hz), 3.85 (s, 3H), 3.72 (t, 2H, J = 3.0 H
z).

Ninth step: The above compound (507 mg, 1.27 mmo
l) in methanol (4 mL) and sodium hydroxide
(254 mg, 6.35 mmol) was added, and the mixture was heated under reflux at 85 ° C. for 1 hour. The methanol was distilled off, and a 2 mol / L hydrochloric acid aqueous solution and then water were added to the residue.After cooling, the precipitated crystals were collected by filtration.
By drying, 1- (2-benzyloxyethyl) -3-
Ethyl-5-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-6-ylcarboxylic acid (345 mg, yield 74% based on the compound obtained in the seventh step) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.94 (s, 1H), 7.62 (s, 1
H), 7.35-7.00 (m, 5H), 4.45 (s, 2H), 4.20-3.80 (m,
4H), 3.72 (brs, 2H), 1.21 (t, 3H, J = 6.9 Hz).

Step 10: The above compound (340 mg, 0.92 m
mol) in methylene chloride (15 mL).
4-yl) -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (252 mg, 0.92 mmol), TEA (0.51 mL,
3.7 mmol), HOBt (249 mg, 1.84 mmol), WSC HCl (353
mg, 1.84 mmol) and stirred at room temperature overnight. After partitioning the reaction solution with chloroform / saturated aqueous sodium bicarbonate, the organic layer was separated and washed with 2 mol / L hydrochloric acid and then with saturated saline.
The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 84 (586 mg, 99%). Melting point: 129-130 ° C FAB-MS (m / z): 641 (M ⁺ +1) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.85 (s, 1H), 7.58 (d, 1)
H, J = 7.9 Hz), 7.40-7.00 (m, 8H), 5.11 (brs, 1H),
4.65 (brs, 1H), 4.46 (s, 2H), 4.25-3.80 (m, 5H),
3.72 (q, 2H, J = 5.9 Hz), 3.48 (s, 3H), 3.2-2.5
(m, 4H), 2.37 (s, 3H), 1.80-1.40 (m, 2H), 1.21 (t,
3H, J = 4.3 Hz).

Example 85: 3- [1- [5-amino-3-ethyl-1- (2-hydroxyethyl) -2-
Oxo-2,3-dihydro-1H-benzimidazol-6-ylcarbonyl] piperidin-4-yl] -1,6-dimethyl-1,2,3,4-
Tetrahydro-2,4-dioxoquinazoline (compound 85) Compound 84 (500 mg, 0.78 mmol) in methanol (25 mL)
Then, 10% Pd-C (1.5 g, 50 w / w% H ₂ O) and then ammonium formate (230 mg) were added, and the mixture was heated under reflux. Two hours later, ammonium formate (250 mg) was added to the reaction solution, and the mixture was heated under reflux for 2 hours. 10% Pd-C (0.4 g,
50 w / w% H ₂ O) was added, and the mixture was heated under reflux for 3 hours and 15 minutes. Ammonium formate (200 mg) was added again, and the mixture was heated under reflux for 40 minutes. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. After the filtrate was concentrated under reduced pressure, the residue was partitioned with water / chloroform, and the organic layer was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 4
Purified from 0: 1 to 20: 1). The resulting crude crystals were triturated with diisopropyl ether to give compound 85 (89.5 mg, 22%). Melting point (diisopropyl ether): 186-187 ° C EI-MS (m / z): 520 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.84 (s, 1H), 7.59 (dd, 1
H, J = 8.6, 2.0 Hz), 7.32 (d, 1H, J = 8.3 Hz), 6.8
4 (s, 1H), 6.57 (s, 1H), 5.20-4.80 (m, 3H), 4.15 (b
rs, 1H), 3.90-3.55 (m, 4H), 3.47 (s, 3H), 3.40-2.9
0 (m, 4H), 2.36 (s, 3H), 1.70-1.50 (m, 2H), 1.17
(t, 3H, J = 6.9 Hz).

Example 86: 3- [1- [1- (2-benzyloxyethyl) -6-nitro-2-oxo]
-2,3-Dihydro-1H-benzimidazol-5-ylcarbonyl] piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (Compound 86 Compound 86 was obtained in the same manner as in Example 68, except that 2-benzyloxyethylamine was used in place of methylamine in the first step, and the fifth step was not carried out. Melting point (ethyl acetate / ether): 208-209 ° C EI-MS (m / z): 612 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.38 (s, 1H), 8.15 (m, 2H),
7.60-7.40 (m, 1H), 7.30-7.00 (m, 7H), 5.30-5.10
(m, 1H), 5.00-4.80 (m, 1H), 4.50 (s, 2H), 4.13 (t,
2H, J = 4.6 Hz), 3.80 (t, 2H, J = 5.0 Hz), 3.56
(s, 3H), 3.50-2.60 (m, 5H), 2.41 (s, 3H), 1.90-1.45
(m, 2H).

Example 87: 3- [1- (1,3-Diethyl-6-nitro-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylmethyl) piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (Compound 87) First step: Example 49 1,3-diethyl obtained in the first step
-6-Nitro-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylic acid methyl ester (2.0 g, 6.8 mm
ol) in THF (50 mL).
(297 mg, 13.6 mmol) and then heated at 50 ° C. for 7 hours. After partitioning the reaction solution with ethyl acetate / water, the organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 1,3-diethyl-5-hydroxymethyl-6-
Nitro-2-oxo-2,3-dihydro-1H-benzimidazole
(1.61 g, 89%). ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.86 (s, 1H), 7.31 (s, 1H),
5.04 (s, 2H), 4.00 (q, 2H, J = 6.9 Hz), 3.99 (q,
2H, J = 7.3 Hz), 1.38 (t, 6H, J = 7.3 Hz).

Step 2: The above compound (1.6 g, 6.0 mmol)
Was dissolved in methylene chloride (100 mL) and manganese dioxide was added.
(15.7 g, 181 mmol) was added, followed by stirring at room temperature for 35 minutes. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. By concentrating the filtrate under reduced pressure, 1,3-diethyl-6-nitro-2-oxo-2,3-
Dihydro-1H-benzimidazole-5-carbaldehyde
(1.16 g, 73%). ¹ H-NMR (CDCl ₃ ) δ (ppm): 10.46 (s, 1H), 7.77 (s, 1
H), 7.57 (s, 1H), 4.05 (q, 4H, J = 7.3 Hz), 1.42
(t, 3H, J = 7.3 Hz), 1.39 (t, 3H, J = 7.3 Hz).

Step 3: The above compound (980 mg, 3.72 mmol)
l) was dissolved in 1% acetic acid / dimethylacetamide (32 mL) and 3- (piperidin-4-yl) -6-methyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (1.22 g, 4.47 mmo
l), then sodium triacetoxyborohydride (3.
After adding 94 g (18.6 mmol), the mixture was stirred at room temperature for 4 hours and 10 minutes. Further sodium triacetoxyborohydride
(2.0 g, 9.3 mmol) and the mixture was stirred overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted three times with chloroform.
The organic layer was washed with water (× 2) and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (chloroform: methanol = 60: 1), and then triturated with ethyl acetate / ether (1: 1) to obtain compound 87 (1.3 g, 73%). Melting point (ethyl acetate / ether): 211-212 ° C Elemental analysis: C ₂₇ H ₃₂ N ₆ O ₅ Calculated value (%) C; 62.29, H; 6.20, N; 16.14 Actual value (%) C; 62.26, H; 6.33, N; 16.18 FAB-MS (m / z): 521 (M ⁺ +1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.00 (d, 1H, J = 1.6 Hz),
7.68 (s, 1H), 7.54 (s, 1H), 7.47 (dd, 1H, J = 8.6,
1.6 Hz), 7.07 (d, 1H, J = 8.3 Hz), 5.05-4.90 (m, 1
H), 4.10-3.90 (m, 6H), 3.56 (s, 3H), 3.05-2.80 (m,
4H), 2.41 (s, 3H), 2.35-2.20 (m, 2H), 1.70-1.55
(m, 2H), 1.40 (t, 3H, J = 7.3 Hz), 1.37 (t, 3H, J =
(7.3 Hz).

Example 88: 3- [1- (6-amino-1,3-diethyl-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylmethyl) piperidin-4-yl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline dihydrochloride (Compound 88) Compound 87 (1.16 g, 2.23 mmol) in methanol (29 mL)
And 10% Pd-C (120 mg, 50 mL).
_{w / w% H 2 O)} , followed by ammonium formate (1.1 g, 17 mmol)
Was added, and the mixture was heated under reflux for 1 hour. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was partitioned with water / chloroform. Then, the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 60: 1), dissolved in ethyl acetate, and dissolved in 4 mol / L
A hydrochloric acid / ethyl acetate solution was added. After evaporating the solvent under reduced pressure, the residue is recrystallized from acetone to give the compound
88 (382 mg, 35%) was obtained. Mp (acetone): 220-222 ° C. Elemental _{analysis: C 27 H 34 N 6 O} 3 · 2HCl · 0.5H 2 O Calculated (%) C; 56.64, H ; 6.51, N; 14.68 Found (%) C; 56.58, H; 6.71, N; 14.82 EI-MS (m / z): 490 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.84 (s, 1H), 7.59 (d, 1)
H, J = 8.6 Hz), 7.36 (d, 1H, J = 6.9 Hz), 7.31 (s,
1H), 7.03 (s, 1H), 5.20-5.00 (m, 1H), 4.46 (brs, 2
H), 4.44 (s, 2H), 3.90-3.70 (m, 4H), 3.40-3.20 (m,
2H), 3.10-2.80 (m, 2H), 2.36 (s, 3H), 1.90-1.70
(m, 2H), 1.30-1.10 (m, 6H).

Example 89: 3- [1- (6-Amino-1,3-diethyl-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -6-methyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline hydrochloride (compound 89) 1,3-diethyl-6 obtained in the second step of Example 49 -Nitro-2-oxo-2,3-dihydro-1H-benzimidazole-5-
Methylene chloride of ylcarboxylic acid (821 mg, 2.94 mmol)
(42 mL) solution was added to 3- (piperidin-4-yl) -6-methyl-1,
2,3,4-tetrahydro-2,4-dioxoquinazoline hydrobromide (1.0 g, 2.94 mmol), TEA (1.6 mL, 12 mmol), HO
Bt (0.79 g, 5.9 mmol), WSC HCl (1.1 g, 5.9 mmol)
Was added and stirred at room temperature overnight. After partitioning the reaction solution with saturated aqueous sodium bicarbonate, the organic layer was washed with a 1 mol / L aqueous hydrochloric acid solution and then with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was triturated with ethyl acetate / ether (1/1) to give 3-
[1- (1,3-diethyl-6-nitro-2-oxo-2,3-dihydro-1H
-Benzimidazol-5-ylcarbonyl) piperidine-4-
Yl] -6-methyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline. Then, the compound (900 mg, 1.7 mmo
l) in methanol (45 mL), water (10 mL) and 10%
Pd-C (180 mg, 50 w / w% H ₂ O), then ammonium formate
After adding (820 mg, 13 mmol), the mixture was heated under reflux for 3 hours. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. The filtrate is concentrated under reduced pressure,
After partitioning the residue with chloroform / water, the organic layer was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Silica gel column chromatography of the residue (chloroform: methanol = 20: 1)
Then, crude crystals (470 mg) were obtained. This crude crystal (220
mg) was dissolved in ethyl acetate, and 4 mol / L hydrochloric acid /
Ethyl acetate was added, and the precipitated crystals were collected by filtration to give Compound 89 (173 mg, 35%). Melting point (ethyl acetate): 223-225 ° C EI-MS (m / z): 490 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 11.28 (s, 1H), 7.72 (s, 1
H), 7.47 (d, 1H, J = 8.3 Hz), 7.05 (d, 1H, J = 8.2
Hz), 6.85 (s, 1H), 6.55 (s, 1H), 5.02 (brs, 3H),
4.50-4.00 (m, 2H), 3.79 (q, 2H, J = 7.3 Hz), 3.73
(q, 2H, J = 6.9Hz), 3.20-2.80 (m, 2H), 2.65-2.40
(m, 2H), 2.32 (s, 3H), 1.75-1.50 (s, 3H), 1.19 (t,
3H, J = 6.6 Hz), 1.17 (t, 3H, J = 6.9 Hz).

Example 90: N- [6- [4- (6-methyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl]-
1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] acetamide (Compound 90) Compound 89 (250 mg, 0.51 mmol) was treated with methylene chloride (20 m
Acetic anhydride (0.096 mL, 1.0 mmol), TEA (0.
After adding 213 mL (1.53 mmol) and DMAP (catalytic amount), the mixture was stirred at room temperature overnight. After partitioning the reaction solution with saturated aqueous sodium hydrogen carbonate / chloroform, the organic layer was separated and washed with a 2 mol / L aqueous hydrochloric acid solution and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol (5 mL) to give the compound.
90 (178 mg, 65%) was obtained. Mp (ethanol): 279-281 ° C. Elemental _{analysis: C 28 H 32 N 6 O} 5 · 0.4H 2 O Calculated (%) C; 62.30, H ; 6.12, N; 15.57 Found (%) C; 62.37, H; 6.16, N; 15.61 EI-MS (m / z): 532 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.83 (brs, 1H), 7.96 (s, 1)
H), 7.86 (dd, 1H, J = 7.9, 2.3 Hz), 7.50-7.35 (m,
1H), 7.25-7.10 (m, 1H), 6.90 (s, 1H), 5.35-5.10
(m, 1H), 4.80-4.15 (m, 3H), 4.05-3.80 (m, 5H), 3.5
8 (s, 3H), 3.25-2.60 (m, 2H), 2.28 (s, 3H), 2.00-
1.55 (m, 2H), 1.45-1.20 (m, 6H).

Example 91: 3- [1- (1,3-diethyl-6-nitro-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -1-methoxycarbonylmethyl-6-methyl-1,2,3,
4-Tetrahydro-2,4-dioxoquinazoline (Compound 91) First step: 3- (1-ethoxycarbonylpiperidin-4-yl) -6-methyl-1,2,3,4-tetrahydro-2,4 -Dioxoquinazoline (1.0 g, 3.0 mmol) was dissolved in DMF (20 mL),
Under ice cooling, 60% sodium hydride (145 mg, 3.62 mmol) was added. After stirring at room temperature for 30 minutes, ethyl bromoacetate
(0.5 mL, 4.53 mmol) was added dropwise, and the mixture was further stirred at room temperature for 2 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with water (× 3) and then with saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 1-ethoxycarbonylmethyl-3- (1-ethoxycarbonylpiperidin-4-yl) -6-methyl-1,2,3,
4-tetrahydro-2,4-dioxoquinazoline (1.2 g, 94
%). ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.00 (s, 1H), 7.43 (dd, 1H,
J = 8.6, 2.3 Hz), 6.83 (d, 1H, J = 8.6 Hz), 5.20-
5.00 (m, 1H), 4.30 (brs, 2H), 4.24 (q, 2H, J = 7.3
Hz), 4.14 (q, 2H, J = 7.3 Hz), 3.00-2.60 (m, 4H),
2.40 (s, 1H), 1.75-1.50 (m, 2H), 1.28 (t, 3H, J =
7.9 Hz), 1.27 (t, 3H, J = 7.3 Hz).

Step 2: The above compound (1.2 g, 2.9 mmol)
Was dissolved in a 47% aqueous solution of hydrobromic acid (10 mL).
Heated to reflux for minutes. The reaction solution was concentrated under reduced pressure to about one third, and the residue was triturated with methanol to give 1-carboxymethyl-3- (piperidin-4-yl) -6-methyl-1,2,3,4. -Tetrahydro-2,4-dioxoquinazoline hydrobromide (847 mg, 74%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 8.68 (brs, 1H), 8.36 (br
s, 1H), 7.87 (d, 1H, J = 2.0 Hz), 7.57 (dd, 1H, J =
8.6, 2.0 Hz), 7.27 (d, 1H, J = 8.6 Hz), 5.20-5.00
(m, 1H), 4.83 (s, 2H), 3.60-3.40 (m, 2H), 3.20-2.
60 (m, 4H), 2.36 (s, 1H), 1.85-1.65 (m, 2H).

Step 3: The above compound (840 mg, 2.1 mmo)
l) in methanol (20 mL) and concentrated sulfuric acid (0.34 mL,
6.3 mmol) and heated to reflux at 90 ° C. overnight. The reaction solution was concentrated under reduced pressure to obtain 1-methoxycarbonylmethyl-3- (piperidin-4-yl) -6-methyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline. . Then, 1,3 mmol was added to a solution of this compound (2.1 mmol) in methylene chloride (35 mL).
-Diethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylic acid (707 mg, 2.5 mmol), T
EA (2.9 mL, 21 mmol), HOBt (0.57 g, 4.2 mmol) and WSC HCl (809 mg, 4.2 mmol) were added and stirred at room temperature overnight. After partitioning the reaction solution with saturated aqueous sodium hydrogen carbonate, the organic layer was separated and washed with a 2 mol / L aqueous hydrochloric acid solution and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was triturated with ethyl acetate / ether (1/1) to give compound 91 (1.1 g,
88%). Melting point (ethyl acetate / ether): 296-296.5 ° C EI-MS (m / z): 592 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.01 (d, 1H, J = 1.7 Hz) ,
7.87 (s, 1H), 7.45 (dd, 1H, J = 8.6, 2.0 Hz), 7.05
(s, 1H), 6.84 (d, 1H, J = 8.6 Hz), 5.30-4.80 (m, 4
H), 4.00 (q, 4H, J = 7.3 Hz), 3.60-3.40 (m, 1H),
3.35-2.60 (m, 4H), 2.41 (s, 3H), 2.00-1.50 (m, 2
H), 1.39 (t, 3H, J = 7.3 Hz).

Example 92: 3- [1- (6-amino-1,3-diethyl-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -1-methoxycarbonylmethyl-6-methyl-1,2,3,
4-Tetrahydro-2,4-dioxoquinazoline (Compound 92) Compound 91 (947 mg, 1.6 mmol) in methanol (24 mL)
And 10% Pd-C (100 mg, 50w / w% H
After adding ₂ O) and then ammonium formate (756 mg, 12 mmol), the mixture was heated under reflux for 45 minutes. Additional 10% Pd in reaction
-C (100 mg, 50 w / w% H ₂ O) was added, and the mixture was heated under reflux for 1 hour and 30 minutes. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 60: 1) to give compound 92 (602 mg, 67%). Melting point: 145-147 ° C EI-MS (m / z): 562 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.02 (d, 1H, J = 1.7 Hz),
7.44 (dd, 1H, J = 8.3, 2.0 Hz), 6.83 (d, 1H, J = 8.
6 Hz), 6.81 (s, 1H), 6.38 (s, 1H), 5.30-5.10 (m, 1
H), 4.86 (s, 2H), 4.40 (brs, 2H), 3.88 (q, 2H, J =
6.9 Hz), 3.87 (q, 2H, J = 7.3 Hz), 3.80 (s, 3H),
3.15-2.85 (m, 4H), 2.40 (s, 3H), 1.85-1.65 (m, 2
H), 1.31 (t, 3H, J = 7.3 Hz).

Example 93: 3- [1- (6-Amino-1,3-diethyl-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -1-carboxymethyl-6-methyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline hydrochloride (Compound 93) Compound 92 (194 mg, 0.33 mmol) was added to methanol (3 mL)
And a 2 mol / L aqueous sodium hydroxide solution was added. After refluxing the reaction solution at 85 ° C. for 1 hour, the reaction solution was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was washed with ethyl acetate. The precipitated crystals were collected by filtration to give Compound 93.
(96 mg, 50%) was obtained. Mp (H ₂ O): 192-193 ℃ Elemental _{analysis: C 28 H 32 N 6 O} 6 · HCl · 0.6H 2 O Calculated (%) C; 56.44, H ; 5.78, N; 14.10 Found (%) C; 56.90, H; 6.30, N; 14.08 EI-MS (m / z): 548 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.87 (d, 1H, J = 1.7 Hz) ),
7.56 (dd, 1H, J = 8.6, 2.3 Hz), 7.26 (d, 1H, J =
8.6 Hz), 6.92 (s, 1H), 6.64 (s, 1H), 5.15-5.00 (m,
1H), 4.82 (s, 2H), 4.20 (brs, 2H), 3.80 (q, 2H, J
= 7.3 Hz), 3.78 (q, 2H, J = 7.3 Hz), 3.15-2.95 (m,
2H), 2.65-2.40 (m, 2H), 2.36 (s, 3H), 1.70-1.50
(m, 2H), 1.20 (t, 3H, J = 6.9 Hz), 1.17 (t, 3H, J
= 7.3 Hz).

Example 94: 3- [1- (6-amino-1,3-diethyl-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -1- (2-hydroxyethyl) -6-methyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (Compound 94) Compound 92 (300 mg, 0.53 mmol) was added to ethanol (15 mL)
Sodium borohydride (81 mg, 2.1 mmol)
Was added and stirred at room temperature for 2 hours and 50 minutes. Further, sodium borohydride (40 mg) was added to the reaction mixture, and the
Stirred for minutes. Then lithium borohydride (50 mg)
Was added and stirred for 2 hours. The reaction solution was poured into water and extracted twice with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 94 (160 mg, 56%). Melting point: 184-186 ° C EI-MS (m / z): 534 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.00 (d, 1H, J = 1.7 Hz),
7.46 (dd, 1H, J = 8.6, 2.3 Hz), 7.17 (d, 1H, J = 8.
6 Hz), 6.81 (s, 1H), 6.38 (s, 1H), 5.30-5.10 (m, 1
H), 4.40 (brs, 2H), 4.31 (t, 2H, J = 5.6 Hz), 3.99
(t, 2H, J = 5.6Hz), 3.88 (q, 2H, J = 7.3Hz), 3.8
6 (q, 2H, J = 7.3 Hz), 3.10-2.70 (m, 4H), 2.40 (s,
3H), 1.80-1.60 (m, 2H), 1.31 (t, 6H, J = 7.3 Hz).

Example 95: 3- [1- (1,3-Diethyl-6-nitro-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -6-methoxy-1-methyl-1,2,3,4-tetrahydro-
2,4-dioxoquinazoline (Compound 98) 1st step: 5-methoxy-2-nitrobenzoic acid (25.0 g, 127
mmol) in methylene chloride (400 mL), thionyl chloride (18.5 mL, 254 mmol), and then pyridine (13.3 mL, 2
After adding 54 mmol), the mixture was heated under reflux for 1 hour and 25 minutes. After further adding thionyl chloride (18.5 mL, 254 mmol) and then pyridine (13.3 mL, 254 mmol) to the reaction solution, the mixture was heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was dissolved in methylene chloride (200 mL), and then TEA (35 mL, 254 mmol),
Then 1-benzyl-4-aminopiperidine (30 mL, 254 m
mol) was added and stirred overnight at room temperature. After partitioning the reaction solution with water, the organic layer was separated and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was triturated with ethanol to give N-
(1-Benzylpiperidin-4-yl) -5-methoxy-2-nitrobenzamide (17.3 g, 47 mmol) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.10 (d, 1H, J = 8.9 Hz),
7.40-7.20 (m, 2H), 6.96 (dd, 1H, J = 8.9, 2.6 Hz),
6.90 (d, 1H, J = 2.6 Hz), 5.77 (d, 1H, J = 8.3 H
z), 4.15-3.95 (m, 1H), 3.90 (s, 3H), 3.57 (s, 2H),
3.00-2.80 (m, 2H), 2.35-2.00 (m, 4H), 1.75-1.50
(m, 2H).

Step 2: The above compound (17.3 g, 46.9 mmo)
l) in ethanol (500 mL) and 10% Pd-C (1.73
g, after addition of _{50w / w% H 2 O)} , under a hydrogen atmosphere and stirred overnight at room temperature. Further 10% Pd-C (3.46 g, 50w / w% H ₂ O)
Was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours.
After adding Celite to the reaction solution and stirring, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give 2-amino-N- (1-benzylpiperidin-4-yl) -5-methoxybenzamide ( 14.9 g, 94%). ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.40-7.20 (m, 5H), 6.86 (s,
1H), 6.84 (dd, 1H, J = 8.3, 3.0 Hz), 6.63 (d, 1H,
J = 7.6 Hz), 6.27 (d, 1H, J = 7.6 Hz), 4.05-3.85
(m, 1H), 3.73 (s, 3H), 3.50 (s, 2H), 2.98-2.70 (m, 1H)
2H), 2.25-1.85 (m, 4H), 1.65-1.45 (m, 2H).

Step 3: The above compound (14.9 g, 43.9 mmo)
To l), ethyl chloroformate (62 mL, 648 mmol) was added, and the mixture was heated at 80 ° C for 2 hours and 40 minutes. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethanol (500 mL). After potassium hydroxide (9.13 g, 163 mmol) was added to the ethanol solution, the mixture was heated under reflux for 1 hour and 25 minutes. Water and then a 3 mmol / L aqueous hydrochloric acid solution were added to the residue to adjust the pH to 4. After partitioning this solution with water / chloroform, the organic layer was separated and washed with water and then with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 3- (1-benzylpiperidin-4-yl) -6-methoxy-1 ,.
2,3,4-tetrahydro-2,4-dioxoquinazoline (15.8 g,
83%).

Step 4: 60% sodium hydride (2.08 g,
(52 mmol) was suspended in DMF (250 mL), and the above compound (15.
A solution of 8 g, 43.3 mmol) in DMF (250 mL) was slowly added. After stirring at room temperature for 50 minutes, methyl iodide (4.04 m
L, 64.9 mmol) was added dropwise, and the mixture was further stirred at room temperature for 3 hours. The reaction was poured into water and then an aqueous ammonium chloride solution was added. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals (9.8 g). The crude crystals are subjected to silica gel column chromatography (hexane: ethyl acetate =
1: 4) to give 3- (1-benzylpiperidine-
4-yl) -6-methoxy-1-methyl-1,2,3,4-tetrahydro-
2,4-Dioxoquinazoline (5.63 g, 34%) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.65 (d, 1H, J = 3.0 Hz),
7.45-7.15 (m, 5H), 7.23 (d, 1H, J = 3.0 Hz), 5.05-
4.90 (m, 1H), 3.87 (s, 3H), 3.59 (s, 2H), 3.55 (s,
3H), 3.10-2.60 (m, 4H), 2.30-2.10 (m, 1H), 1.70-
1.50 (m, 1H).

Step 5: The above compound (4.85 g, 12.8 mm)
ol) in ethanol (480 mL) and dissolve in a hydrogen atmosphere.
The mixture was stirred at room temperature for 4 hours and 40 minutes. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. By concentrating the filtrate under reduced pressure, 6-methoxy-1-
Methyl-3- (piperidin-4-yl) -1,2,3,4-tetrahydro-
2,4-Dioxoquinazoline (3.25 g, 93%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 10.48 (brs, 1H), 7.62 (d,
1H, J = 3.6 Hz), 7.47 (s, 1H), 7.39 (s, 1H), 5.15-
5.00 (s, 1H), 4.40-4.20 (m, 1H), 3.82 (s, 3H), 3.4
8 (s, 3H), 3.45-3.35 (m, 1H), 3.30-2.85 (m, 4H),
1.90-1.75 (m, 2H).

Step 6: The above compound (3.0 g, 11 mmol)
In a methylene chloride (126 mL) solution of 1,3-diethyl-6-nitro-2-oxo-2,3-dihydro- obtained in the second step of Example 49.
1H-benzimidazol-5-ylcarboxylic acid (3.07 g, 1
1.0 mmol), TEA (7.67 mL, 55.0 mmol), HOBt H ₂ O (2.9
7 g, 22.0 mmol) and WSC HCl (4.21 g, 22.0 mmol) were added and stirred at room temperature overnight. The reaction solution was treated with methylene chloride /
After partitioning with saturated aqueous sodium bicarbonate, the organic layer was separated and washed with 2 mol / L hydrochloric acid and then with saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was triturated with ethyl acetate / ether (1: 1) to obtain Compound 98 (4.16 g, 69%). . Melting point (ethyl acetate / ether):> 300 ° C. EI-MS (m / z): 550 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.88 (s, 1H), 7.70-7.60 (m ,
1H), 7.35-7.10 (m, 2H), 7.06 (s, 1H), 5.35-4.85
(m, 2H), 4.01 (q, 4H, J = 7.3 Hz), 3.88 (s, 3H),
3.65-3.40 (m, 1H), 3.57 (s, 3H), 3.30-2.60 (m, 4
H), 1.95-1.50 (m, 2H), 1.45-1.25 (m, 6H).

Example 96: 3- [1- (6-amino-1,3-diethyl-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -6-methoxy-1-methyl-1,2,3,4-tetrahydro-
2,4-Dioxoquinazoline hydrochloride (Compound 99) Compound 98 (2.0 g, 3.6 mmol) in methanol (100 mL)
And added 10% Pd-C (400 mg, 50 w / w% H ₂ O) and then ammonium formate (1.71 g, 27.2 mmol), then added 40%
Heated to reflux for minutes. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was partitioned with water / chloroform.
The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate.
An L hydrochloric acid / ethyl acetate solution was added, and the precipitated crystals were collected by filtration. The crystals were again reslurried with ethyl acetate to obtain Compound 99 (1.56 g, 77%). Mp (ethyl acetate): 192-193 ° C. Elemental _{analysis: C 27 H 32 N 6 O} 5 · HCl · 0.8H 2 O Calculated (%) C; 56.75, H ; 6.10, N; 14.71 Found (%) C ; 56.85, H; 6.37, N; 14.30 EI-MS (m / z): 520 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.49 (s, 1H), 7.39 (s, 1
H), 7.25 (s, 1H), 7.23 (s, 1H), 5.20-5.00 (m, 1H),
4.20 (brs, 2H), 4.00-3.80 (m, 4H), 3.83 (s, 3H), 3.
50 (s, 3H), 3.18 (brs, 2H), 2.75-2.55 (m, 2H), 1.8
0-1.60 (m, 2H), 1.30-1.15 (m, 6H).

Example 97: N- [6- [4- (6-methoxy-1-methyl-1,2,3,4-tetrahydro-
2,4-Dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] acetamide (Compound 100) Compound 99 (300 mg, 0.58 mmol) was treated with methylene chloride (20 m
L), and acetic anhydride (0.108 mL, 1.15 mmol), TEA
(0.141 mL, 1.72 mmol) and DMAP (catalytic amount) were added, followed by stirring at room temperature for 4 hours and 45 minutes. After partitioning the reaction mixture with saturated aqueous sodium bicarbonate / chloroform, the organic layer was separated and 2 mo
It was washed with a 1 / L aqueous hydrochloric acid solution and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was triturated with ethyl acetate / ether (1/1) to give Compound 100 (226 mg, 69%).
I got Mp (ethyl acetate / ether): 204-205 ° C. Elemental _{analysis: C 29 H 34 N 6 O} 6 · 0.8H 2 O Calculated (%) C; 60.36, H ; 6.22, N; 14.56 Found (%) C 60.27, H; 6.24, N; 14.56 EI-MS (m / z): 562 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.88 (brs, 1H), 7.96 (s, 1)
H), 7.63 (d, 1H, J = 3.0 Hz), 7.28 (dd, 1H, J = 8.
9, 3.0 Hz), 7.13 (d, 1H, J = 9.2 Hz), 6.91 (s, 1
H), 5.35-5.15 (m, 1H), 4.40 (brs, 2H), 3.94 (q, 2
H, J = 7.3 Hz), 3.93 (q, 2H, J = 7.3 Hz), 3.88 (s,
3H), 3.56 (s, 3H), 3.20-2.65 (m, 4H), 2.27 (s, 3
H), 1.80-1.70 (m, 2H), 1.34 (t, 3H, J = 6.9 Hz),
1.33 (t, 3H, J = 6.9 Hz).

Example 98: 3- [1- (1,3-Diethyl-6-nitro-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -6-hydroxy-1-methyl-1,2,3,4-tetrahydro
-2,4-Dioxoquinazoline (Compound 95) A 48% aqueous solution of hydrobromic acid was added to Compound 98 (1.86 g, 3.38 mmol), and the mixture was refluxed for 8 hours and 10 minutes. Saturated aqueous sodium bicarbonate was slowly added to the reaction solution, and the solution was adjusted to alkaline.
Extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give Compound 95.
(1.31 g, 72%). Melting point:> 300 ° C. EI-MS (m / z): 536 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.87 (s, 1H), 7.70-7.60 (m,
1H), 7.30-6.85 (m, 2H), 5.35-4.80 (m, 2H), 4.15-3.
90 (m, 4H), 3.65-3.40 (m, 1H), 3.56 (s, 3H), 3.30-
2.60 (m, 4H), 1.90-1.50 (m, 2H), 1.45-1.25 (m, 6
H).

Example 99: 3- [1- (6-amino-1,3-diethyl-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -6-hydroxy-1-methyl-1,2,3,4-tetrahydro
-2,4-Dioxoquinazoline (Compound 96) Compound 95 (1.18 g, 2.20 mmol) in methanol (120 mL)
And 10% Pd-C (230 mg, 50 w / w% H ₂ O) was added, followed by ammonium formate (1.04 g, 16.5 mmol).
Heated to reflux for 0 minutes. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was partitioned with water / chloroform. Then, the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain Compound 96 (0.8 g, 72%). Mp (ethyl acetate): 273-274 ℃ Elemental _{analysis: C 26 H 30 N 6 O} 5 · 0.2H 2 O Calculated (%) C; 61.21, H ; 6.01, N; 16.47 Found (%) C; 61.25 , H; 6.20, N; 16.52 EI-MS (m / z): 506 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.68 (d, 1H, J = 2.6 Hz),
7.22 (dd, 1H, J = 9.2,3.0 Hz), 7.04 (d, 1H, J = 2.
9 Hz), 6.85 (s, 1H), 6.39 (s, 1H), 5.30-5.10 (m, 1
H), 4.40 (brs, 2H), 3.95-3.80 (m, 4H), 3.53 (s, 3
H), 3.15-2.70 (m, 4H), 1.80-1.65 (m, 2H), 1.29 (t,
6H, J = 7.3 Hz).

Example 100: N- [6- [4- (6-hydroxy-1-methyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1- Ylcarbonyl] -1,3-diethyl-2-oxo-2,3-dihydro-1H-
[Benzimidazol-5-yl] acetamide (Compound 97) Compound 96 (250 mg, 0.49 mmol) was dissolved in water (4 mL), acetic anhydride (0.232 mL, 2.42 mmol) was added, and the mixture was stirred at room temperature overnight. . Further acetic anhydride (0.138 mL, 1.47mmol)
Was added and stirred at room temperature overnight. Further, water (4 mL) and then acetic anhydride (0.138 mL, 1.47 mmol) were added, and the mixture was stirred at room temperature for 7 hours. Acetic anhydride (0.138mL, 1.47mmo
l) and stirred overnight at room temperature, followed by acetic anhydride (0.138
mL, 1.47 mmol) and stirred at room temperature for 2 hours. The reaction solution was filtered, and the obtained crystals were washed with water and dried to obtain Compound 97 (188 mg, 70%). Mp (H ₂ O): 192-194 ℃ Elemental _{analysis: C 28 H 32 N 6 O} 6 · 1.2H 2 O Calculated (%) C; 58.98, H ; 6.08, N; 14.74 Found (%) C; 59.02, H; 6.58, N; 14.78 EI-MS (m / z): 548 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.80 (s, 1H), 7.86 (s, 1H),
7.63 (d, 1H, J = 2.6Hz), 7.20 (dd, 1H, J = 8.9,
3.0 Hz), 7.01 (d, 1H, J = 8.9 Hz), 6.94 (s, 1H), 5.
30-5.10 (m, 1H), 4.80-4.20 (m, 4H), 3.94 (q, 4H, J
= 7.3 Hz), 3.49 (s, 3H), 3.20-2.60 (m, 2H), 2.30
(s, 3H), 1.90-1.60 (m, 2H), 1.45-1.20 (m, 6H).

Example 101: 3- [1- (1,3-diethyl-6-nitro-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -6-fluoro-1-methyl-1,2,3,4-tetrahydro-
2,4-Dioxoquinazoline (Compound 101) 1st step: 2-amino-5-fluorobenzoic acid (5.01 g, 32.
3 mmol) was dissolved in methanol (100 mL), 4 mol / L hydrochloric acid / 1,4-dioxane (25 mL) was added, and the mixture was heated under reflux for 4 hours. Add 4 mol / L hydrochloric acid / 1,4-dioxane (20
mL), and the mixture was further heated under reflux overnight. Next, methanol (50 mL) and 4 mol / L hydrochloric acid / 1,4-dioxane (20 mL) were added to the reaction solution, and the mixture was heated under reflux for 4 days. Further, 4 mol / L hydrochloric acid / 1,4-dioxane (20 mL) was added to the reaction solution,
Heated to reflux for 3 days. The reaction solution was concentrated under reduced pressure, and ice and saturated aqueous sodium hydrogen carbonate were added to the residue. The mixture was extracted twice with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1).
Purification in 6) gave 2-amino-5-fluorobenzoic acid methyl ester hydrochloride (2.83 g, 52%). ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.53 (dd, 1H, J = 9.6, 3.0
Hz), 7.03 (ddd, 1H, J = 9.2, 7.9, 3.0 Hz), 6.61 (d
d, 1H, J = 8.9, 4.6 Hz), 5.58 (brs, 2H), 3.87 (s,
3H).

Step 2: The above compound (2.79 g, 16.5 mmo)
l) in methylene chloride (50 mL) and TEA (1.3 mL,
9.33 mmol) was added. Under ice-cooling, phenyl chloroformate (2.3 mL, 18.3 mmol) was added to this mixture with methylene chloride.
(2.0 mL) was added dropwise over 15 minutes. After stirring at room temperature for 4 hours, TEA (1.3 mL, 9.3 mmol) was added, and the mixture was further stirred overnight. 4-Amino-1-ethoxycarbonylpiperidine (3.8 mL, 19 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 4 hours and 20 minutes. Methylene chloride was added to the reaction solution, washed twice with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was triturated with diisopropyl ether / ether / n-hexane to give N- (4-fluoro-2-methoxycarbonylphenyl) -N ′-(1-ethoxycarbonylpiperidin-4-yl) urea (5.12 g) , 81%). ¹ H-NMR (CDCl ₃ ) δ (ppm): 10.12 (s, 1H), 8.51 (dd, 1
H, J = 9.2, 5.0 Hz), 7.64 (dd, 1H, J = 9.2, 3.3 H
z), 7.40-7.15 (m, 6H), 4.61 (d, 1H, J = 7.6 Hz),
3.91 (s, 3H), 3.80-3.60 (m, 1H), 3.53 (s, 2H), 3.0
0-2.80 (m, 2H), 2.30-1.90 (m, 4H) 1.70-1.40 (m, 2
H).

Step 3: The above compound (2.0 g, 5.4 mmol)
Was dissolved in DMF (25 mL) and lithium hydroxide monohydrate (4
60 mg, 11 mmol) was added. After stirring at 50 ° C for 1 hour and 15 minutes, the reaction solution was returned to room temperature, and methyl iodide (0.8 mL,
13 mmol) was added. After stirring at room temperature for 3 hours, the reaction solution was partitioned with saturated aqueous sodium hydrogen carbonate / toluene. The organic layer was separated, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was triturated with diisopropyl ether to give 3- (1-ethoxycarbonylpiperidin-4-yl) -6-fluoro-1-methyl-1,2,3,4.
-Tetrahydro-2,4-dioxoquinazoline (1.2 g, 63%)
I got ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.75 to 7.60 (m, 1H), 7.50-
7.40 (m, 1H), 7.30-7.05 (m, 1H), 5.10-4.90 (m, 1H),
4.10 (brs, 2H), 4.04 (q, 2H, J = 6.9 Hz), 3.47
(s, 3H), 2.85 (brs, 2H), 2.50-2.30 (m, 2H), 1.75-
1.50 (m, 2H), 1.18 (t, 3H, J = 6.9 Hz).

Step 4: The above compound (1.2 g, 3.4 mmol)
Was dissolved in a 47% aqueous solution of hydrobromic acid (20 mL).
Heated to reflux for 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was azeotroped twice with a mixed solution of toluene / methanol. 6-Fluoro-1-methyl-3- (piperidin-4-yl) -1,2,3,4-tetrahydro-2,4-dioxoquinazoline hydrobromide by triturating the residue with ethanol (1.1
g, 89%). ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 8.80 (brs, 1H), 8.45 (br
s, 1H), 7.90-7.45 (m, 3H), 5.20-5.00 (m, 1H), 3.51
(s, 3H), 3.50-3.25 (m, 2H), 3.20-2.65 (m, 4H), 1.
95-1.65 (m, 2H).

Fifth step: Example 49 Obtained in the second step
1,3-diethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylic acid (500 mg, 1.79 mm
ol) in methylene chloride (21 mL) solution, the compound obtained in the fourth step (641 mg, 1.79 mmol) and TEA (1.0 mL, 7.16
mmol), HOBt H ₂ O (548 mg, 4.06 mmol) and WSC HCl
(687 mg, 3.58 mmol) was added and the mixture was stirred at room temperature overnight.
After partitioning the reaction solution with chloroform / saturated aqueous sodium bicarbonate, the organic layer was separated and washed with 2 mol / L hydrochloric acid and then with saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was triturated with ethyl acetate / ether (1: 1) to give Compound 101 (665 mg,
69%). Melting point (ethyl acetate / ether):> 300 ° C. Elemental analysis: C ₂₆ H ₂₇ FN ₆ O ₆ Calculated (%) C; 57.99, H; 5.05, N; 15.61 Found (%) C; 57.82, H; 5.16 , N; 15.73 EI-MS (m / z): 538 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.95-7.80 (m, 2H), 7.45-7.3
5 (m, 1H), 7.20-7.10 (m, 1H), 7.06 (s, 0.7H), 6.90
(s, 0.3H), 5.30-5.25 (m, 1H), 5.05-4.85 (m, 1H),
4.10-3.90 (m, 4H), 3.58 (s, 3H), 3.55-3.45 (m, 1
H), 3.25-2.60 (m, 4H), 1.95-1.75 (m, 1H), 1.70-1.50
(m, 1H), 1.45-1.30 (m, 6H).

Example 102: 3- [1- (6-amino-1,3-diethyl-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -6-fluoro-1-methyl-1,2,3,4-tetrahydro-
2,4-Dioxoquinazoline hydrochloride (Compound 102) Compound 101 (1.68 g, 3.12 mmol) in methanol (42 mL)
Dissolved in a mixture of water and water (12.6 mL) and 10% Pd-C (170 m
g, 50 w / w% H ₂ O), followed by ammonium formate (1.48 g, 2
(3.4 mmol), and the mixture was heated under reflux for 2 hours and 40 minutes.
After adding celite to the reaction solution and stirring, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was partitioned with water / chloroform. Then, the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure,
The residue was purified by silica gel column chromatography (chloroform: methanol = 60: 1). The free base of the obtained compound 102 was dissolved in ethyl acetate, and 4 mol / L hydrochloric acid /
An ethyl acetate solution was added, and the precipitated crystals were collected by filtration to obtain Compound 102 (960 mg, 56%). Mp (ethyl acetate): 214-216 ° C. Elemental _{analysis: C 26 H 29 FN 6 O} 4 · HCl · 0.5H 2 O Calculated (%) C; 56.37, H ; 5.64, N; 15.17 Found (%) C ; 56.46, H; 5.59, N; 14.85 EI-MS (m / z): 508 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.80-7.60 (m, 2H), 7.49
(dd, 1H, J = 9.2, 4.0 Hz), 7.21 (s, 1H), 7.19 (s,
1H), 5.20-5.00 (m, 1H), 4.00-3.80 (m, 6H), 3.50
(s, 3H), 3.08 (brs, 2H), 2.70-2.50 (m, 2H), 1.80-
1.60 (m, 2H), 1.35-1.10 (m, 6H).

Example 103: N- [6- [4- (6-fluoro-1-methyl-1,2,3,4-tetrahydro-
2,4-Dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] acetamide (Compound 103) Compound 102 (300 mg, 0.55 mmol) was treated with methylene chloride (20 m
L), acetic anhydride (0.104 mL, 1.10 mmol), TEA
(0.23 mL, 1.7 mmol) and DMAP (catalytic amount) were added, followed by stirring at room temperature overnight. After partitioning the reaction mixture with saturated aqueous sodium bicarbonate / chloroform, the organic layer was separated and washed with a 2 mol / L aqueous hydrochloric acid solution and then with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol (10 mL) to give Compound 103.
(216 mg, 71%). Melting point (ethanol): 267-270 ° C Elemental analysis: C ₂₈ H ₃₁ FN ₆ O ₅ · H ₂ O Calculated value (%) C; 59.15, H; 5.85, N; 14.78 Actual value (%) C; 59.24, H 5.82, N; 14.71 EI-MS (m / z): 550 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.83 (brs, 1H), 7.96 (s, 1)
H), 7.86 (dd, 1H, J = 7.3, 2.3 Hz), 7.50-7.35 (m,
1H), 7.25-7.10 (m, 1H), 6.90 (s, 1H), 5.35-5.10
(m, 1H), 4.80-4.15 (m, 3H), 4.05-3.80 (m, 5H), 3.5
8 (s, 3H), 3.25-2.60 (m, 2H), 2.28 (s, 3H), 2.00-
1.55 (m, 2H), 1.45-1.20 (m, 6H). Example 104: N- [6- [4- (6-fluoro-1-methyl-1,2,3,4-tetrahydro-
2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] propionamide (Compound 10
4) Compound 102 (300 mg, 0.55 mmol) was converted to methylene chloride (20 m
L), and propionic anhydride (0.141 mL, 1.10 mmo)
l), TEA (0.23 mL, 1.7 mmol) and DMAP (catalytic amount) were added, followed by stirring at room temperature overnight. After partitioning the reaction solution with 2 mol / L aqueous hydrochloric acid / chloroform, the organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate (10 mL) to obtain Compound 104 (242 mg, 78%). Melting point (ethyl acetate): 234-235 ° C Elemental analysis: C ₂₉ H ₃₃ FN ₆ O ₅ Calculated (%) C; 61.69, H; 5.89, N; 14.88 Found (%) C; 61.38, H; 6.17, N; 14.78 EI-MS (m / z): 564 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.98 (s, 1H), 8.06 (s, 1H),
7.86 (dd, 1H, J = 8.3, 3.3 Hz), 7.45-7.35 (m, 1
H), 7.17 (dd, 1H, J = 9.2, 4.0 Hz), 6.90 (s, 1H),
5.30-5.15 (m, 1H), 4.40 (brs, 2H), 4.05-3.85 (m, 4
H), 3.57 (s, 3H), 3.04 (brs, 2H), 2.75 (brs, 2H),
2.52 (q, 2H, J = 7.3 Hz), 1.85-1.60 (m, 2H), 1.45-
1.20 (m, 9H).

Example 105: 3- [1- (1,3-Diethyl-6-nitro-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -6-chloro-1-methyl-1,2,3,4-tetrahydro-2,4
-Dioxoquinazoline (Compound 105) First step: 3- (1-ethoxycarbonylpiperidin-4-yl) -6- obtained according to the first to third steps of Example 101
Chloro-1-methyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (1.9 g, 5.2 mmol) in 48% aqueous hydrobromic acid
(28 mL) and heated under reflux at 110 ° C. for 3 hours and 45 minutes. The reaction solution was concentrated under reduced pressure, and the residue was azeotroped once with methanol. The residue was triturated with methanol to give 6-chloro-1-methyl-3- (piperidin-4-yl)-
There was obtained 1,2,3,4-tetrahydro-2,4-dioxoquinazoline hydrobromide (1.76 g, 90%). ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 8.74 (brs, 1H), 8.42 (br
s, 1H), 7.95 (d, 1H, J = 2.6 Hz), 7.81 (dd, 1H, J =
8.9, 2.6 Hz), 7.48 (d, 1H, J = 8.9 Hz), 5.15-5.00
(m, 1H), 3.49 (s, 3H), 3.45-3.25 (m, 2H), 3.20-2.
95 (m, 2H), 2.90-2.65 (m, 2H), 1.90-1.70 (m, 2H).

Step 2: The above compound (1.0 g, 2.7 mmol)
In a methylene chloride (42 mL) solution of 1,3-diethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylic acid obtained in the second step of Example 49 ( 745 mg,
2.7 mmol), TEA (1.9 mL, 13 mmol), HOBt H ₂ O (721 m
g, 5.34 mmol) and WSC HCl (1.0 g, 5.3 mmol) were added and stirred at room temperature overnight. After partitioning the reaction solution with chloroform / saturated aqueous sodium bicarbonate, the organic layer was separated and washed with 2 mol / L hydrochloric acid and then with saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was triturated with ethyl acetate / ether (1: 1) to obtain Compound 105 (821 mg, 55%). Melting point (ethyl acetate / ether):> 300 ° C EI-MS (m / z): 554 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 8.12 (s, 1H), 7.97 (d , 1
H, J = 2.3 Hz), 7.81 (dd, 1H, J = 8.9, 2.6 Hz), 7.
47 (d, 1H, J = 8.9 Hz), 7.36 (s, 1H), 5.25-5.00
(m, 1H), 4.66 (brs, 1H), 4.10-3.85 (m, 5H), 3.49
(s, 3H), 3.00-2.50 (m, 4H), 1.75 (brs, 1H), 1.65-
1.40 (m, 1H), 1.23 (t, 3H, J = 6.9 Hz).

Example 106: 3- [1- (6-amino-1,3-diethyl-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -6-chloro-1-methyl-1,2,3,4-tetrahydro-2,4
-Dioxoquinazoline hydrochloride (Compound 106) Compound 105 (737 mg, 1.33 mmol) in ethanol (50 mL)
Stannic chloride dihydrate (1.5 g, 6.6 mmo
l) Then, concentrated hydrochloric acid (1.5 mL) was added, and the mixture was heated under reflux at 100 ° C for 3 hours. The reaction solution was concentrated under reduced pressure to about 1/3, and a saturated aqueous sodium hydrogen carbonate solution was slowly added to the residue. The mixture was extracted twice with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, a 4 mol / L hydrochloric acid / ethyl acetate solution was added, and the precipitated crystals were collected by filtration to give Compound 106 (586).
mg, 74%). Mp (ethyl acetate): 177-178 ° C. Elemental _{analysis: C 26 H 29 ClN 6 O} 4 · HCl Calculated (%) C; 55.62, H ; 5.39, N; 14.97 Found (%) C; 55.54, H ; 5.45, N; 14.88 EI-MS (m / z): 524 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.97 (d, 1H, J = 2.3 Hz),
7.81 (dd, 1H, J = 8.9, 2.6 Hz), 7.48 (d, 1H, J =
9.2 Hz), 7.17 (s, 1H), 7.09 (s, 1H), 5.15-4.95 (m,
1H), 4.15 (brs, 2H), 3.95-3.75 (m, 4H), 3.49 (s,
3H), 3.10 (brs, 2H), 2.70-2.50 (m, 2H), 1.80-1.60
(m, 2H), 1.30-1.10 (m, 6H).

Example 107: N- [6- [4- (6-chloro-1-methyl-1,2,3,4-tetrahydro-2,
4-Dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] formamide (Compound 107) 88% Formic acid (589 mg, 12.8 mmol) in methylene chloride (20 mL)
, And added with WSC HCl (1.2 g, 6.4 mmol) under ice-cooling, followed by stirring for 30 minutes. To this mixture was added compound 106 (1.1
2 g, 2.1 mmol) and a solution of NMM (1.17 mL, 10.7 mmol) in methylene chloride (20 mL) were added, and the mixture was stirred at room temperature for 4 hours and 30 minutes. Further, 88% formic acid (0.60 mg, 11 mmol) was added to the reaction solution.
And formic anhydride prepared from WSC HCl (1.2 g, 6.4 mmol) was added. After stirring at room temperature overnight, this operation was performed once more, followed by stirring overnight. The reaction solution was partitioned with chloroform / aqueous saturated sodium bicarbonate solution, and the organic layer was washed with a 2 mol / L aqueous hydrochloric acid solution and then with a saturated saline solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the compound 107 (0.789 g,
67%). Mp (ethyl acetate): 192-193 ° C. Elemental _{analysis: C 27 H 29 ClN 6 O} 5 · 0.5H 2 O Calculated (%) C; 57.70, H ; 5.38, N; 14.95 Found (%) C; 57.71 , H; 5.39, N; 14.92 EI-MS (m / z): 553 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.87 (s, 1H), 8.46 (s, 1H),
8.16 (d, 1H, J = 2.6Hz), 8.09 (s, 3H), 7.63 (dd,
1H, J = 8.6, 2.3 Hz), 7.14 (d, 1H, J = 8.9Hz), 6.9
1 (s, 1H), 5.35-5.15 (m, 1H), 4.45 (brs, 2H), 3.96
(q, 2H, J = 6.9 Hz), 3.93 (q, 2H, J = 6.3 Hz), 3.
57 (s, 3H), 3.20-2.65 (m, 4H), 1.85-1.65 (m, 2H),
1.35 (t, 3H, J = 7.3 Hz), 1.33 (t, 3H, J = 7.3 H
z).

Example 108: N- [6- [4- (6-chloro-1-methyl-1,2,3,4-tetrahydro-2,
4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] acetamide (Compound 108) Compound 106 (200 mg, 0.36 mmol) in methylene chloride (13 m
L), acetic anhydride (0.067 mL, 0.71 mmol), TEA
(0.15 mL, 1.1 mmol) and DMAP (catalytic amount) were added, followed by stirring at room temperature for 1 hour and 30 minutes. Acetic anhydride (0.050 mL, 0.53 mmol) was further added to the reaction solution, and the mixture was stirred overnight.
After partitioning the reaction solution with saturated aqueous sodium hydrogen carbonate / chloroform, the organic layer was separated and washed with a 2 mol / L aqueous hydrochloric acid solution and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to obtain Compound 108 (130 mg, 66%). Mp (ethanol): 264-265 ° C. Elemental _{analysis: C 28 H 31 ClN 6 O} 5 · 1.2H 2 O Calculated (%) C; 57.13, H ; 5.72, N; 14.28 Found (%) C; 57.12, H; 5.55, N; 14.28 EI-MS (m / z): 567 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 9.50 (s, 1H), 7.95 (d, 1)
H, J = 2.6 Hz), 7.80 (dd, 1H, J = 8.9, 2.6 Hz), 7.
46 (d, 1H, J = 9.2 Hz), 7.31 (s, 1H), 7.11 (s, 1
H), 5.15-4.95 (m, 1H), 4.65 (brs, 1H), 3.95-3.75
(m, 4H), 3.55 (brs, 1H), 3.48 (s, 3H), 3.20-2.70
(m, 4H), 1.85-1.35 (m, 2H), 1.20 (t, 6H, J = 7.3 H
z).

Example 109: 3- [1- (1,3-Diethyl-6-methylamino-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl] -6-Chloro-1-methyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (Compound 109) Compound 107 (633 mg, 1.14 mmol) is dissolved in DMF (12 mL), and ice Under cooling, 60% sodium hydride (55 mg, 1.4 mmol) was added. After stirring at room temperature for 30 minutes, methyl iodide (0.
(171 mL, 2.75 mmol) was added dropwise, and the mixture was further stirred at room temperature for 3 hours. The reaction solution was poured into ice water and extracted three times with ethyl acetate. The organic layer was washed with water (× 3) and then with a saturated saline solution.
The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give N-methyl-N- [6- [4- (6-chloro-1-
Methyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline
-3-yl) piperidin-1-ylcarbonyl] -1,3-diethyl-
2-Oxo-2,3-dihydro-1H-benzimidazol-5-yl] formamide (657 mg, quantitative) was obtained. Next, this compound was dissolved in a 2 mol / L aqueous hydrochloric acid solution (15 mL) and heated under reflux for 1 hour and 20 minutes. After the temperature of the reaction solution was returned to room temperature, a saturated sodium bicarbonate solution was added to adjust the solution to be alkaline, and then extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1), and triturated with ethyl acetate to give compound 109 (221 mg,
36%). Mp (ethyl acetate): 235-236 ° C. Elemental _{analysis: C 27 H 31 ClN 6 O} 4 Calculated (%) C; 60.16, H ; 5.80, N; 15.59 Found (%) C; 60.16, H ; 5.96, N; 15.71 EI-MS (m / z): 538 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.17 (d, 1H, J = 2.3 Hz),
7.62 (dd, 1H, J = 8.9,2.6 Hz), 7.13 (d, 1H, J = 8.
9 Hz), 6.83 (s, 1H), 6.31 (s, 1H), 5.30-5.00 (m, 2
H), 4.55-4.30 (m, 2H), 3.92 (q, 2H, J = 7.3 Hz),
3.89 (q, 2H, J = 7.3 Hz), 3.56 (s, 3H), 3.10-2.70
(m, 4H), 2.88 (s, 3H), 1.80-1.60 (m, 2H), 1.34 (t,
3H, J = 7.3 Hz), 1.31 (t, 3H, J = 7.3 Hz). Example 110: 6-amino-3- [1- (6-amino-1,3-diethyl-2-oxo-2, 3-
Dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl] -1-methyl-1,2,3,4-tetrahydro-2,4
-Dioxoquinazoline dihydrochloride (Compound 110) 1st step: 3- (1-ethoxycarbonylpiperidin-4-yl) -1- obtained according to the 1st to 3rd steps of Example 101
Methyl-6-nitro-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (1.0 g, 2.7 mmol) in 48% aqueous hydrobromic acid
(10 mL) and heated under reflux at 110 ° C. for 1 hour and 30 minutes. The reaction solution was cooled on ice, and the precipitated crystals were collected by filtration. The crystals are washed with water and dried to give 1-methyl-6-nitro-3-
(Piperidin-4-yl) -1,2,3,4-tetrahydro-2,4-dioxoquinazoline hydrobromide (850 mg, 83%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 8.71 (d, 1H, J = 2.6 Hz),
8.70 (brs, 1H), 8.55 (dd, 1H, J = 9.2, 2.6 Hz), 8.
35 (brs, 1H), 7.66 (d, 1H, J = 9.2 Hz), 5.20-5.00
(m, 1H), 3.57 (s, 3H), 3.50-3.30 (m, 2H), 3.20-2.9
5 (m, 2H), 2.85-2.65 (m, 2H), 1.90-1.70 (m, 2H).

Step 2: The above compound (820 mg, 2.1 mmo
l) in methylene chloride (35 mL) solution, 1,3-diethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylate obtained in the second step of Example 49 Acid (594
mg, 2.1 mmol), TEA (1.2 mL, 8.5 mmol), HOBt H ₂ O (5
75 mg, 4.3 mmol) and WSC HCl (816 mg, 4.3 mmol) were added and stirred at room temperature overnight. The reaction solution is chloroform /
After partitioning with saturated aqueous sodium hydrogen carbonate, the organic layer was separated and washed with 2 mol / L hydrochloric acid and then with saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was triturated with ethyl acetate / ether (1: 1) to give 3- [1- (1,3-diethyl-6 -Nitro-2-oxo-2,3
-Dihydro-1H-benzimidazol-5-ylcarbonyl)
Piperidin-4-yl] -1-methyl-6-nitro-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (672 mg, 56%) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.20 (m, 1H), 8.51 (dd, 1H,
J = 8.9, 2.3 Hz), 7.88 (s, 1H), 7.32 (d, 1H, J =
9.2 Hz), 7.06 (s, 1H), 5.30-4.80 (m, 2H), 4.20-3.8
0 (m, 4H), 3.66 (s, 3H), 3.60-3.40 (m, 2H), 3.30-
2.50 (m, 4H), 1.95-1.75 (m, 2H), 1.65-1.50 (m, 2
H), 1.45-1.25 (m, 6H).

Third step: The above compound (600 mg, 1.06 mmo)
l) in methanol (30 mL) and 10% Pd-C (120 m
g, 50 w / w% H ₂ O), followed by ammonium formate (501 mg, 7.
(95 mmol), and the mixture was heated under reflux for 1 hour and 40 minutes. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was partitioned with water / chloroform. Then, the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain a crude crystal (439 mg).
I got The crude crystals (189 mg) were dissolved in ethyl acetate (5 mL), a 4 mol / L hydrochloric acid / ethyl acetate solution was added, and the precipitated crystals were collected by filtration to give Compound 110 (151 mg, 6 mg).
1%). Melting point (ethyl acetate): 202-204 ° C EI-MS (m / z): 505 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.95 (d, 1H, J = 1.3 Hz),
7.66 (dd, 1H, J = 8.6,1.7 Hz), 7.49 (d, 1H, J = 9.
2 Hz), 7.19 (s, 1H), 5.15-5.00 (m, 1H), 4.15 (brs,
2H), 3.95-3.75 (m, 4H), 5.51 (s, 3H), 3.20-2.90
(m, 2H), 2.75-2.50 (m, 2H), 1.80-1.55 (m, 2H), 1.3
0-1.10 (m, 6H).

Example 111 N- [6- [4- (6-acetylamino-1-methyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidine-1 -
Ylcarbonyl] -1,3-diethyl-2-oxo-2,3-dihydro
-1H-benzimidazol-5-yl] acetamide (compound
111) Compound 110 (250 mg, 0.49 mmol) was treated with methylene chloride (20 m
L), acetic anhydride (0.184 mL, 1.96 mmol), TEA
(0.410 mL, 2.94 mmol) and DMAP (catalytic amount) were added, followed by stirring at room temperature overnight. After partitioning the reaction mixture with saturated aqueous sodium bicarbonate / chloroform, the organic layer was separated and washed with a 2 mol / L aqueous hydrochloric acid solution and then with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1), and then triturated with ethyl acetate / ether (1: 1) to obtain compound 111 (124 mg, 43%). Melting point (ethyl acetate / ether): 206-208 ° C EI-MS (m / z): 589 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 10.16 (s, 1H), 9.51 ( s, 1
H), 8.29 (d, 1H, J = 2.3 Hz), 7.94 (d, 1H, J = 8.9
Hz), 7.37 (d, 1H, J = 9.2 Hz), 7.32 (s, 1H), 7.12
(s, 1H), 5.15-4.90 (m, 1H), 4.65 (brs, 1H), 3.95-
3.75 (m, 4H), 3.48 (s, 3H), 3.45-3.30 (m, 1H), 3.1
5-2.70 (m, 2H), 2.13 (s, 3H), 2.06 (s, 3H), 1.80-1.
35 (m, 2H), 1.21 (t, 6H, J = 6.9 Hz).

Example 112: 3- [2- (1,3-Diethyl-6-nitro-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonylamino) ethyl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (compound 112) First step: 5-methyl-2 -Nitrobenzoic acid methyl ester
(20.8 g, 107 mmol) in methanol (400 mL) and water (100
mL) and 10% Pd-C (2.1 g, 50w / w% H
After adding ₂ O) and then ammonium formate (34 g, 533 mmol), the mixture was heated under reflux for 30 minutes. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was partitioned with water / chloroform. Then, the organic layer was separated and dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, 2-amino-5
-Methylbenzoic acid methyl ester (15.9 g, 90%) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.65 (s, 1H), 7.09 (dd, 1H,
J = 8.3, 1.9 Hz), 6.59 (d, 1H, J = 8.6 Hz), 5.54
(brs, 2H), 3.86 (s, 3H), 2.22 (s, 3H).

Step 2: The above compound (15.9 g, 96.1 mmo)
l) was dissolved in pyridine (50 mL), p-toluenesulfonyl chloride (19.2 g, 101 mmol) was added, and the mixture was stirred at room temperature for 3 hours and 50 minutes. Water (1.5 L) was added to the reaction solution, and the precipitated crystals were filtered. The crystals were washed with water and dried to obtain N- (2-methoxycarbonyl-4-methylphenyl) -p-toluenesulfonamide (27.7 g, 90%). ¹ H-NMR (CDCl ₃ ) δ (ppm): 10.38 (s, 1H), 7.75-7.65
(m, 3H), 7.59 (d, 1H, J = 8.6 Hz), 3.84 (s, 3H), 2.
35 (s, 3H), 2.26 (s, 3H).

Step 3: The above compound (27.5 g, 86.2 mmo)
l) in DMF (110 mL) and 60% sodium hydride
(3.45 g, 86.2 mmol) was added. After stirring at room temperature for 30 minutes, methyl iodide (10.7 mL, 172 mmol) was added dropwise,
The mixture was stirred at room temperature for 1 hour and 10 minutes. After partitioning the reaction mixture with water / ethyl acetate, the organic layer was separated and washed with water (× 3) and then with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was triturated with n-hexane to obtain N- (2-methoxycarbonyl-4-methylphenyl) -N-methyl-p-toluenesulfonamide (27.7 g, 96%). ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.64 (d, 1H, J = 2.3 Hz),
7.53 (d, 2H, J = 8.3 Hz), 7.26 (d, 2H, J = 8.3 H
z), 7.20 (dd, 1H, J = 8.3, 1.6 Hz), 6.80 (d, 1H, J
= 8.3 Hz), 3.82 (s, 3H), 3.24 (s, 3H), 2.42 (s, 3
H), 2.37 (s, 3H).

Step 4: The above compound (26.5 g, 79.5 mmo)
l) in acetic acid (165 mL), and add 48% aqueous hydrobromic acid solution.
(165 mL) and phenol (16.5 g, 175 mmol) were added, followed by stirring at room temperature overnight. The reaction solution was poured into a 5 mol / L aqueous hydrochloric acid solution (250 mL) and washed twice with ether. Sodium hydrogen carbonate (360 g) was added to the aqueous layer, and the solution was adjusted to slightly alkaline, and then extracted twice with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, 5-methyl
2-methylaminobenzoic acid methyl ester (10.1 g, 71
%). ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.70 (s, 1H), 7.43 (brs, 1
H), 7.21 (dd, 1H, J = 8.6, 2.3 Hz), 6.60 (d, 1H, J
= 8.6 Hz), 3.84 (s, 3H), 2.89 (s, 3H), 2.23 (s, 3
H).

Step 5: The above compound (9.83 g, 54.9 mmo)
l) in acetic acid (196 mL) and potassium cyanate (5.5 mL).
6 g, 68.6 mmol), and the mixture was stirred at room temperature for 1 hour and 50 minutes. The reaction solution was concentrated under reduced pressure, and water (100 mL) was added to the residue.
Next, a 2 mol / L aqueous sodium hydroxide solution (100 mL) was added, and the mixture was heated at 80 ° C. for 2 hours and 10 minutes. The reaction solution was ice-cooled, adjusted to pH 1 with a 2 mol / L hydrochloric acid aqueous solution, and the precipitated crystals were collected by filtration to give 1,6-dimethyl-1,2,3,4-tetrahydro-2,4-. Dioxoquinazoline (7.66 g, 73%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 11.45 (brs, 1H), 7.77 (s,
1H), 7.54 (d, 1H, J = 8.6 Hz), 7.29 (d, 1H, J = 8.
6 Hz), 3.40 (s, 3H), 2.34 (s, 3H).

Step 6: The above compound (1.5 g, 7.9 mmoL)
Was dissolved in DMF (45 mL), and 60% sodium hydride (379
mg, 9.5 mmol). After stirring at room temperature for 30 minutes,
N- (2-Bromoethyl) phthalimide (4.0 g, 16 mmol) was added, and the mixture was stirred at room temperature overnight. The precipitated crystals are collected by filtration, washed with water, and dried to give N- [2- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline-3-
Yl) ethyl] phthalimide (1.67 g, 58%) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.87 (s, 1H), 7.80-7.60 (m,
4H), 7.46 (dd, 1H, J = 8.3, 2.0 Hz), 7.07 (d, 1H,
J = 8.6 Hz), 4.43 (t, 2H, J = 5.3 Hz), 4.10 (t, 2H,
J = 5.0 Hz), 3.49 (s, 3H), 2.36 (s, 3H).

Step 7: The above compound (1.56 g, 4.3 mmo)
l) was dissolved in ethanol (31 mL), hydrazine monohydrate (0.42 mL, 8.6 mmol) was added, and the mixture was heated under reflux for 1 hour and 10 minutes. Add hydrazine monohydrate (0.2 mL, 4
mmol), and the mixture was further heated under reflux for 2 hours and 20 minutes. The precipitated white crystals were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was triturated with ether to give 3- (2
-Aminoethyl) -1,6-dimethyl-1,2,3,4-tetrahydro-
2,4-Dioxoquinazoline (1.1 g, quantitative) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.02 (s, 1H), 7.49 (d, 1H,
J = 8.3 Hz), 7.10 (d, 1H, J = 8.6 Hz), 4.19 (t, 2H,
J = 6.6 Hz), 3.58 (s, 3H), 3.03 (t, 2H, J = 6.6 H
z), 2.41 (s, 3H).

Step 8: The above compound (312 mg, 1.34 mmo)
l) in methylene chloride (13 mL) was added to the 1,3-diethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylate obtained in the second step of Example 49. Acid (374
mg, 1.34 mmol), TEA (0.75 mL, 5.4 mmol), HOBt H ₂ O
(361 mg, 2.68 mmol) and WSC HCl (514 mg, 2.68 mm
ol) and stirred at room temperature overnight. After partitioning the reaction solution with chloroform / 2 mol / L aqueous hydrochloric acid, the organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was triturated with ethyl acetate / ether (1: 1) to obtain compound 112 (458 mg, 69%). . Melting point (ethyl acetate / ether): 262-264 ° C EI-MS (m / z): 494 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.98 (d, 1H, J = 1.0 Hz) ,
7.70 (s, 1H), 7.52 (dd, 1H, J = 8.6, 1.6 Hz), 7.14
(d, 1H, J = 8.6 Hz), 7.07 (s, 1H), 6.68 (brs, 1H),
4.45-4.35 (m, 2H), 4.05-3.80 (m, 6H), 3.59 (s, 3
H), 2.41 (s, 3H), 1.37 (t, 3H, J = 7.3 Hz), 1.36
(t, 3H, J = 7.3 Hz).

Example 113: 3- [2- (6-amino-1,3-diethyl-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonylamino) ethyl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (Compound 113) Compound 112 (350 mg, 0.71 mmol) To methanol (15 mL)
And 10% Pd-C (70 mg, 50 w / w% H ₂ O) and then ammonium formate (335 mg, 5.31 mmol) were added, and the mixture was heated under reflux for 3 hours and 45 minutes. Add 10% Pd-C (35 mg, 50w)
/ w% H ₂ O), and the mixture was further heated under reflux for 1 hour. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was partitioned with water / ethyl acetate. Then, the organic layer was separated and washed with saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The compound is obtained by triturating the residue with diisopropyl ether.
113 (213 mg, 65%) was obtained. Melting point (diisopropyl ether): 256-258 ° C EI-MS (m / z): 464 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.01 (s, 1H), 7.51 (d, 1H,
J = 6.3 Hz), 7.21 (brs, 1H), 7.12 (d, 1H, J = 8.6
Hz), 7.01 (s, 1H), 6.26 (s, 1H), 4.55-4.35 (m, 2
H), 3.93 (q, 2H, J = 7.3 Hz), 3.84 (q, 2H, J = 7.3
Hz), 3.60 (s, 3H), 2.41 (s, 3H), 1.41 (t, 3H, J =
7.3 Hz), 1.29 (t, 3H, J = 7.3 Hz).

Example 114: N- [6- [2- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) ethylaminocarbonyl] -1 ,
3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] acetamide (Compound 114) Compound 113 (300 mg, 0.65 mmol) was treated with methylene chloride (30 m
L), acetic anhydride (0.122 mL, 1.29 mmol), TEA
(0.27 mL, 1.9 mmol) and DMAP (catalytic amount) were added, followed by stirring at room temperature overnight. After partitioning the reaction solution with saturated aqueous sodium hydrogen carbonate / chloroform, the organic layer was separated and washed with a 2 mol / L aqueous hydrochloric acid solution and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was triturated with ethyl acetate to give the compound.
114 (290 mg, 89%) was obtained. Melting point (ethyl acetate): 291-293 ° C EI-MS (m / z): 506 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 11.55 (s, 1H), 8.41 (s, 1)
H), 8.02 (s, 1H), 7.70-7.50 (m, 2H), 7.20-7.10 (m,
2H), 4.60-4.40 (m, 2H), 4.00 (t, 2H, J = 7.3Hz),
3.93 (q, 2H, J = 7.3 Hz), 3.85-3.75 (m, 2H), 3.60
(s, 3H), 2.42 (s, 3H), 2.16 (s, 3H), 1.44 (t, 3H, J
= 7.3 Hz), 1.33 (t, 3H, J = 7.3 Hz).
15, 116 and 117 were obtained according to Examples 112 to 114, respectively.

Example 115: 3- [3- (1,3-diethyl-6-nitro-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonylamino) propyl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (Compound 115) Melting point (ethyl acetate / ether): 258 -259 ° C EI-MS (m / z): 508 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.95 (d, 1H, J = 1.7 Hz), 7.
80 (s, 1H), 7.51 (dd, 1H, J = 8.6, 2.3 Hz), 7.15
(s, 1H), 7.12 (d, 1H, J = 8.3 Hz), 7.05 (t, 1H, J
= 6.6 Hz), 4.25 (t, 2H, J = 5.9 Hz), 4.01 (q, 2H,
J = 7.3 Hz), 4.00 (q, 2H, J = 7.3 Hz), 3.58 (s, 3
H), 3.44 (q, 2H, J = 6.3 Hz), 2.40 (s, 3H), 1.39
(t, 6H, J = 7.3 Hz).

Example 116: 3- [3- (6-amino-1,3-diethyl-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonylamino) propyl] -1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (Compound 116) Melting point (ethyl acetate): 217-219 ℃ elemental _{analysis: C 25 H 30 N 6 O} 4 · H 2 O calculated (%) C; 60.47, H ; 6.50, N; 16.92 Found (%) C; 60.44, H ; 6.44, N; 16.75 EI- MS (m / z): 478 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.00 (s, 1H), 7.60-7.40 (m,
2H), 7.32 (s, 1H), 7.13 (d, 1H, J = 8.6 Hz), 6.31
(s, 1H), 5.58 (brs, 2H), 4.26 (t, 2H, J = 6.3 H
z), 3.98 (q, 2H, J = 7.3 Hz), 3.87 (q, 2H, J = 7.3
Hz), 3.61 (s, 3H), 3.39 (q, 2H, J = 5.3 Hz), 2.43
(s, 3H), 2.10-1.95 (m, 2H), 1.44 (t, 3H, J = 7.3
Hz), 1.32 (t, 3H, J = 7.3 Hz).

Example 117: N- [6- [3- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) propylaminocarbonyl]-
1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] acetamide (Compound 117) Melting point (ethyl acetate): 294-295 ° C Elemental analysis: C ₂₇ H ₃₂ N ₆ O ₅ · 0.2 H ₂ O calculated (%) C; 61.87, H ; 6.23, N; 16.03 Found (%) C; 61.76, H ; 6.49, N; 16.24 EI-MS (m / z): 520 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 11.74 (s, 1H), 8.47 (s, 1)
H), 8.00 (s, 1H), 7.85 (brs, 1H), 7.54 (q, 1H, J =
8.6 Hz), 7.50 (s, 1H), 7.16 (d, 1H, J = 8.6 Hz),
4.27 (t, 2H, J = 6.3 Hz), 4.05 (q, 2H, J = 6.9 H
z), 3.97 (q, 2H, J = 7.3 Hz), 3.62 (s, 3H), 3.41
(q, 2H, J = 5.9 Hz), 2.43 (s, 3H), 2.22 (s, 3H), 2.
20-2.00 (m, 2H), 1.47 (t, 3H, J = 6.9 Hz), 1.36
(t, 3H, J = 6.9Hz).

Example 118: 3- [1- (1,3-diethyl-6-nitro-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -6-methyl-4-oxo-3,4-dihydroquinazoline
(Compound 119) Example 49 1,3-Diethyl-6-nitro- obtained in the second step
2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylic acid (1.14 g, 4.08 mmol) in methylene chloride (48
mL) solution, 3- (piperidin-4-yl) -6-methyl-4-oxo-3,4-dihydroquinazoline dihydrobromide (1.70 g,
4.08 mmol), TEA (2.28 mL, 16.3 mmol), HOBt H ₂ O (1.
25 g, 9.25 mmol) and WSC HCl (1.57 g, 8.16 mmol)
Was added and stirred at room temperature overnight. After partitioning the reaction solution with 1 mol / L hydrochloric acid, the organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was triturated with ethyl acetate / ether (1: 1) to obtain compound 119 (1.85 g, 90%). ^{From 1} H-NMR, compound 119
Was found to exist as a mixture of rotamers (7: 3). Melting point (ethyl acetate / ether):> 300 ° C Elemental analysis: C ₂₆ H ₂₈ N ₆ O ₅ .HCl.0.2 H ₂ O Calculated value (%) C; 57.34, H; 5.44, N; 15.43 Actual value (%) C; 57.46, H; 5.71, N; 15.38 EI-MS (m / z): 504 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.33, 8.18 (s, 0.3H,
0.7H), 8.08 (s, 1H), 7.87 (s, 1H), 7.75-7.50 (m, 2
H), 7.07, 6.91 (respectively, s, 0.3H, 0.7H), 5.30-4.90 (m,
2H), 4.20-3.80 (m, 4H), 3.70-3.50 (m, 1H), 3.40-
2.80 (m, 1H), 2.50 (s, 3H), 2.35-1.80 (m, 4H), 1.38
(q, 6H, J = 5.9 Hz).

Example 119: 3- [1- (6-amino-1,3-diethyl-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -6-methyl-4-oxo-3,4-dihydroquinazoline dihydrochloride (Compound 120) Compound 119 (1.63 g, 3.23 mmol) in methanol (82 mL)
And water (24 mL) and 10% Pd-C (163 mg, 50w / w% H
_{After addition of 2} O) and then ammonium formate (1.50 g, 24.2 mmol), the mixture was refluxed for 4 hours and 30 minutes. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1) to obtain crude crystals (1.1 g). The crystals (250 mg) were dissolved in ethanol (5 mL), and a 4 mol / L hydrochloric acid / ethyl acetate solution was added. After the solvent was distilled off once, ethanol was added again, and the mixture was heated under reflux at 70 ° C for 20 minutes. The mixture was stirred from room temperature to under ice-cooling, and the precipitated crystals were collected by filtration to obtain Compound 120 (242 mg, 55%). Mp (ethanol): 182-184 ° C. Elemental _{analysis: C 26 H 30 N 6 O} 3 · 2HCl · 3.2H 2 O Calculated (%) C; 51.61, H ; 6.40, N; 13.89 Found (%) C; 51.69, H; 6.78, N; 13.87 EI-MS (m / z): 474 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.16 (s, 1H), 8.07 (s, 1H),
7.59 (d, 2H, J = 1.0Hz), 6.79 (s, 1H), 6.60 (s, 1
H), 5.20-5.00 (m, 1H), 4.52 (brs, 2H), 3.89 (q, 2H,
J = 7.3 Hz), 3.88 (q, 2H, J = 7.3 Hz), 3.30-3.80
(m, 4H), 2.49 (s, 3H), 2.10-1.90 (2H, m), 1.31 (t,
3H, J = 7.3 Hz), 1.31 (t, 3H, J = 7.3 Hz).

Example 120: N- [6- [4- (6-methyl-4-oxo-3,4-dihydroquinazoline-
3-yl) piperidin-1-ylcarbonyl] -1,3-diethyl-2
-Oxo-2,3-dihydro-1H-benzimidazol-5-yl]
Formamide (Compound 121) 99% formic acid (478 mg, 10.4 mmol) in methylene chloride (12 mL)
, And added with WSC HCl (996 mg, 5.20 mmol) under ice-cooling, followed by stirring for 30 minutes. Compound 120 (4
74 mg, 0.87 mmol) and a solution of NMM (0.50 mL, 4.3 mmol) in methylene chloride (12 mL) were added, and the mixture was stirred at room temperature for 8 hours and 30 minutes. Furthermore, 99% formic acid (239 mg, 5.2 mmol) was added to the reaction solution.
And formic anhydride prepared from WSC HCl (498 mg, 2.6 mmol) were added and stirred overnight. Again add 99% formic acid (120 mg,
After adding formic anhydride prepared from 2.6 mmol) and WSC HCl (250 mg, 1.3 mmol) and stirring for 3 hours, the reaction solution was partitioned between chloroform / saturated aqueous sodium hydrogen carbonate and the organic layer was washed with saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was triturated with diisopropyl ether to obtain Compound 121 (398 mg, 91%). Melting point (diisopropyl ether): 275-276 ° C EI-MS (m / z): 502 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.00 (s, 1H), 8.43 (s, 1H) ,
8.09 (s, 1H), 8.04 (d, 2H, J = 4.6 Hz), 7.61 (s,
1H), 6.87 (s, 1H), 5.10-4.95 (m, 1H), 4.50 (brs, 2
H), 3.96 (q, 2H, J = 6.9 Hz), 3.93 (q, 2H, J = 5.9
Hz), 3.80-3.60 (m, 1H), 3.40-3.00 (m, 3H), 2.51
(s, 3H), 2.20-1.80 (m, 2H), 1.40-1.25 (m, 6H).

Example 121: N- [6- [4- (6-methyl-4-oxo-3,4-dihydroquinazoline-
3-yl) piperidin-1-ylcarbonyl] -1,3-diethyl-2
-Oxo-2,3-dihydro-1H-benzimidazol-5-yl]
Propionamide (Compound 122) Compound 120 (200 mg, 0.42 mmol) was treated with methylene chloride (13 m
L), and propionic anhydride (0.11 mL, 0.84 mmo
l), TEA (0.18 mL, 1.3 mmol) and DMAP (catalytic amount) were added, and the mixture was stirred at room temperature for 5 hours and 30 minutes. After partitioning the reaction solution with 1 mol / L aqueous hydrochloric acid / chloroform, the organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate (5 mL) to obtain Compound 122 (190 mg, 85%). Melting point (ethyl acetate): 291-292 ° C Elemental analysis: C ₂₉ H ₃₄ N ₆ O ₄ 0.7 H ₂ O 0.4 CH ₃ CO ₂ C ₂ H ₅ Calculated value (%) C; 63.54, H; 6.73, N 14.53 actual value (%) C; 63.50, H; 6.82, N; 14.61 EI-MS (m / z): 530 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.99 (s, 1H) ), 8.47 (s, 1H),
8.11 (s, 1H), 8.00 (s, 1H), 7.76 (d, 1H, J = 8.3
Hz), 7.64 (dd, 1H, J = 2.0, 8.3 Hz), 6.92 (s, 1H),
5.20-5.00 (m, 1H), 4.75-4.40 (m, 2H), 4.13 (q, 2H,
J = 7.3 Hz), 3.95 (q, 2H, J = 6.9 Hz), 3.92 (q, 2
H, J = 6.9 Hz), 3.30-3.05 (m, 2H), 2.52 (s, 3H),
2.48-2.38 (m, 2H), 2.20-2.05 (m, 2H), 2.05 (s, 3
H), 1.34 (t, 3H, J = 6.9 Hz), 1.32 (t, 3H, J = 7.3
Hz), 1.28 (t, 3H, J = 7.3 Hz).

Example 122: N- [6- [4- (6-methyl-4-oxo-3,4-dihydroquinazoline-
3-yl) piperidin-1-ylcarbonyl] -1,3-diethyl-2
-Oxo-2,3-dihydro-1H-benzimidazol-5-yl]
Cyclopentanecarboxamide (Compound 123) Cyclopentanecarboxylic acid (0.046 mL, 0.42 mmol) was dissolved in methylene chloride (2 mL), and the mixture was cooled under ice-cooling with WSC HCl (120
mg, 0.63 mmol) and stirred for 30 minutes. Compound 120 (100 mg, 0.21 mmol) and NMM (0.093 m
L, 0.84 mmol) in methylene chloride (2 mL).
Stirred overnight at room temperature. Furthermore, cyclopentanecarboxylic acid (0.046 mL, 0.42 mmol) and WSC HCl (40 mg,
(2.1 mmol) was added, followed by NMM
(0.023 mL, 0.21 mmol) was added and stirred for 10 hours. The reaction solution was partitioned with chloroform / 1 mol / L aqueous hydrochloric acid, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol (4 mL) to give Compound 123 (60 mg, 50%). Mp (ethanol): 210-211 ° C. Elemental _{analysis: C 32 H 38 N 6 O} 4 · 0.8H 2 O Calculated (%) C; 65.69, H ; 6.82, N; 14.36 Found (%) C; 65.64, H; 6.95, N; 14.38 EI-MS (m / z): 570 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.00 (s, 1H), 8.10 (s, 2H),
8.01 (s, 1H), 7.66 (d, 1H, J = 8.3 Hz), 7.60 (dd,
1H, J = 1.7, 8.3 Hz), 6.86 (s, 1H), 5.15-5.00 (m,
1H), 4.80-4.30 (m, 2H), 3.94 (q, 2H, J = 7.3 Hz),
3.94 (q, 2H, J = 7.3 Hz), 3.30-3.00 (m, 2H), 2.85-
2.70 (m, 1H), 2.51 (s, 3H), 2.15-1.60 (m, 12H), 1.3
4 (t, 3H, J = 7.3 Hz), 1.32 (t, 3H, J = 7.3 Hz) The following compounds 124, 125 and 126 were prepared in Example 11 respectively.
It was obtained according to 8-120.

Example 123: 3- [1- (1,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -6-methyl-4-oxo-3,4-dihydroquinazoline
(Compound 124) Melting point (ethyl acetate):> 300 ° C. Elemental analysis: C ₂₄ H ₂₄ N ₆ O ₅ Calculated (%) C; 60.50, H; 5.08, N; 17.64 Found (%) C; 60.24, H ; 5.12, N; 17.54 EI-MS (m / z): 476 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.18 (s, 1H), 8.09 (s, 1H),
7.88 (d, 1H, J = 2.3 Hz), 7.71-7.58 (m, 2H), 6.90
(s, 1H), 5.20-4.90 (m, 1H), 3.70-3.55 (m, 2H), 3.5
1 (s, 3H), 3.48 (s, 3H), 3.40-3.15 (m, 2H), 3.15-
2.90 (m, 2H), 2.50 (s, 3H), 2.30-2.05 (m, 2H).

Example 124: 3- [1- (6-amino-1,3-dimethyl-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -6-methyl-4-oxo-3,4-dihydroquinazoline
(Compound 125) Melting point (ethyl acetate): 289-290 ° C Elemental analysis: C ₂₄ H ₂₆ N ₆ O ₃ Calculated value (%) C; 64.56, H; 5.87, N; 18.82 Actual value (%) C; 64.63, H; 6.02, N; 18.89 EI-MS (m / z): 446 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.17 (s, 1H), 8.07 (s, 1H),
7.59 (d, 2H, J = 2.3 Hz), 6.77 (s, 1H), 6.57 (s, 1
H), 5.20-5.05 (m, 1H), 4.65-4.40 (m, 2H), 3.37 (s,
3H), 3.36 (s, 3H), 3.25-3.05 (m, 2H), 3.05-2.65
(m, 2H), 2.49 (s, 3H), 2.15-1.95 (m, 2H).

Example 125: N- [6- [4- (6-methyl-4-oxo-3,4-dihydroquinazoline-
3-yl) piperidin-1-ylcarbonyl] -1,3-dimethyl-2
-Oxo-2,3-dihydro-1H-benzimidazol-5-yl]
Formamide (Compound 126) Melting point (ethanol): 271-272 ° C Elemental analysis: C ₂₅ H ₂₆ N ₆ O ₄ .0.4H ₂ O Calculated value (%) C; 62.33, H; 5.61, N; 17.45 Actual value (%) ) C; 62.38, H; 5.68, N; 17.47 EI-MS (m / z): 474 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.06 (s, 1H), 8.56 (s, 1H),
8.46 (s, 1H), 8.11 (s, 1H), 8.02 (s, 1H), 7.75
(d, 1H, J = 8.3 Hz), 7.64 (d, 1H, J = 6.3 Hz), 6.91
(s, 1H), 5.15-5.00 (m, 1H), 4.65-4.35 (m, 2H), 3.
44 (s, 3H), 3.43 (s, 3H), 3.30-3.10 (m, 2H), 2.52
(s, 3H), 2.45-2.05 (m, 4H).

Example 126: 6-chloro-3- [1- (1,3-diethyl-6-nitro-2-oxo-2,3-
Dihydro-1H-benzimidazol-5-ylcarbonyl) piperidin-4-yl] -4-oxo-3,4-dihydroquinazoline
(Compound 127) Example 49 1,3-Diethyl-6-nitro- obtained in the second step
2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylic acid (300 mg, 1.07 mmol) in methylene chloride (12.
6 mL) solution was added to 6-chloro-3- (piperidin-4-yl) -4-oxo-3,4-dihydroquinazoline dihydrobromide (460 mg,
1.1 mmol), TEA (0.60 mL, 4.3 mmol), HOBt H ₂ O (0.3
3 g, 2.1 mmol) and WSC HCl (0.41 g, 2.1 mmol) were added and stirred at room temperature overnight. After partitioning the reaction solution with 1 mol / L hydrochloric acid, the organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was triturated with ethyl acetate to give Compound 127 (360 mg, 62%).
I got Melting point (ethyl acetate): 162-164 ° C EI-MS (m / z): 524 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.40 (s, 1H), 8.29 (dd, 1H,
J = 2.3, 6.9 Hz), 7.88 (d, 1H, J = 2.3 Hz) 7.82
(d, 1H, J = 7.6 Hz), 7.77 (dd, 1H, J = 1.7, 6.9 H
z), 6.91 (s, 1H), 5.25-5.00 (m, 1H), 4.04 (q, 2H,
J = 6.9 Hz), 4.02 (q, 2H, J = 7.3 Hz), 3.75-2.90
(m, 4H), 2.70-1.80 (m, 4H), 1.39 (t, 3H, J = 7.3 H
z), 1.37 (t, 3H, J = 6.9 Hz).

Example 127: 3- [1- (6-Amino-1,3-diethyl-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -4-oxo-3,4-dihydroquinazoline (Compound 11
8) Compound 127 (0.36 g, 0.69 mmol) in methanol (18 mL)
 And water (5.4 mL), and dissolved in 10% Pd-C (40 mg, 50w / w% H
_TwoO) and then ammonium formate (0.32 g, 5.1 mmol).
After the addition, the mixture was heated under reflux for 3 hours. Add 10% Pd-C (40
mg, 50w / w% H _TwoO) and heated to reflux for another 35 minutes
After that, 10% Pd-C (10 mg, 50w / w% H_TwoO), then ammonium formate
(0.32 g, 5.1 mmol) was added. 2 hours more
After 10% Pd-C (10 mg, 50w / w% H_TwoO), then ammonium formate
(0.32 g, 5.1 mmol) and heat to reflux for 40 minutes.
Was. After adding celite to the reaction solution and stirring,
The material was filtered through celite. The filtrate is concentrated under reduced pressure,
The residue was purified by silica gel column chromatography (chloropho
Purification was carried out with the use of lume: methanol = 60: 1) to obtain crude crystals. This
Trituration of crude crystals with diisopropyl ether
By this, compound 118 (130 mg, 41%) was obtained. Melting point (diisopropyl ether): 156-156.5 ° C EI-MS (m / z): 460 (M⁺)¹ H-NMR (DMSO-d₆) δ (ppm): 8.54 (s, 1H), 8.18 (d, 1
H, J = 7.6 Hz), 7.83 (d, 1H, J = 7.3 Hz), 7.69 (d,
 1H, J = 7.9 Hz), 7.55 (t, 1H, J = 7.3 Hz), 6.95
(s, 1H), 6.55 (s, 1H), 5.20-5.05 (m, 1H), 5.05-4.9
0 (m, 2H), 4.40-4.00 (m, 2H), 3.79 (q, 2H, J = 7.6
 Hz), 3.77 (q, 2H, J = 7.6 Hz), 3.20-2.95 (m, 2H),
 2.20-1.95 (m, 2H), 1.95-1.80 (m, 2H), 1.19 (t, 3
H, J = 6.6 Hz), 1.18 (t, 3H, J = 6.6 Hz).

Example 128: N- [1- (1,3-diethyl-6-nitro-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -4-methylphthalimide (Compound 128) First step:
4-methylphthalic anhydride (4.0 g, 25 mmol) and 4-amino
A mixture of 1-benzylpiperidine (5.0 mL, 25 mmol) was heated at 170 ° C. for 1 hour. After returning the reaction solution to room temperature, it was partitioned with chloroform / saturated aqueous sodium hydrogen carbonate, and the organic layer was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was triturated with methanol to obtain N- (1-benzylpiperidin-4-yl) -4-methylphthalimide (5.2 g, 63%). ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.69 (d, 1H, J = 7.6 Hz),
7.62 (s, 1H), 7.48 (d, 1H, J = 7.6 Hz), 4.20-4.00
(m, 1H), 3.64 (s, 2H), 3.15-2.95 (m, 2H), 2.70-2.5
0 (m, 2H), 2.50 (s, 3H), 2.30-2.10 (m, 2H), 1.75-
1.60 (m, 2H). Second step: The above compound (4.58 g, 13.7 mm)
ol) in methanol (92 mL), 10% Pd-C (2.29 g,
50 w / w% H ₂ O) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. 10% Pd-C (2.0 g, 50 w / w% H ₂ O) was added to the reaction solution, and the mixture was heated and refluxed at 80 ° C. for 4 hours under a hydrogen atmosphere. Further, a 2 mol / L aqueous hydrochloric acid solution (9 mL) was added to the reaction solution, and the mixture was refluxed for 6 hours and 30 minutes under a hydrogen atmosphere. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was partitioned with chloroform / saturated aqueous sodium bicarbonate, and then the organic layer was separated and washed with saturated saline. The organic layer is dried over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure to obtain 4-methyl-N- (piperidin-4-yl) phthalimide (2.6 g, 78%). ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.72 (d, 1H, J = 7.3 Hz),
7.66 (s, 1H), 7.62 (d, 1H, J = 7.3 Hz), 4.10-3.90
(m, 1H), 3.10-2.90 (m, 2H), 2.60-2.40 (m, 2H), 2.
47 (s, 3H), 2.25-2.05 (m, 2H), 1.70-1.50 (m, 2H).
Third step: Example 49 1,3-diethyl obtained in the second step
To a solution of -6-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylic acid (1.7 g, 6.1 mmol) in methylene chloride (63 mL) was added the above compound (1.5 g, 6.1 mmo).
l), TEA (3.4 mL, 25 mmol), HOBt H ₂ O (1.7 g, 12 mmo
l) and WSC HCl (2.4 g, 12 mmol) were added and stirred at room temperature overnight. After partitioning the reaction solution with chloroform / saturated aqueous sodium hydrogen carbonate, the organic layer was separated and washed with a 1 mol / L aqueous hydrochloric acid solution and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
8 (2.1 g, 68%) was obtained. Mp: 298-299 ℃ Elemental _{analysis: C 26 H 27 N 5 O} 6 · 0.3H 2 O Calculated (%) C; 61.12, H ; 5.44, N; 13.71 Found (%) C; 61.19, H ; 5.54 , N; 13.71 EI-MS (m / z): 505 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 8.13 (s, 1H), 7.75 (d, 1)
H, J = 7.3 Hz), 7.69 (s, 1H), 7.64 (d, 1H, J = 7.6
Hz), 7.39 (s, 1H), 4.65 (brs, 1H), 4.35-4.20 (m, 1
H), 4.00 (q, 4H, J = 6.9 Hz), 3.60-3.40 (m, 1H),
3.32 (s, 3H), 3.15-2.80 (m, 2H), 2.48 (s, 3H), 2.2
5-2.10 (m, 2H), 1.95-1.50 (m, 2H), 1.24 (t, 6H, J =
(7.3 Hz).

Example 129: N- [1- (6-amino-1,3-diethyl-2-oxo-2,3-dihydro-
1H-benzimidazol-5-ylcarbonyl) piperidine-
4-yl] -4-methylphthalimide hydrochloride (Compound 129) Compound 128 (2.0 g, 4.0 mmol) in methanol (100 mL)
Then, 10% Pd-C (200 mg, 50 w / w% H ₂ O) and then ammonium formate (1.9 g, 30 mmol) were added, and the mixture was heated under reflux for 2 hours. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was partitioned with chloroform / water. Then, the organic layer was separated and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 60: 1) and dissolved in ethyl acetate. To this solution was added 4 mol / L hydrochloric acid / ethyl acetate, and the precipitated crystals were collected by filtration to give Compound 129 (8
10 mg, 40%). Melting point (ethyl acetate): 198-200 ° C Elemental analysis: C ₂₆ H ₂₉ N ₅ O ₄ .HCl Calculated value (%) C; 60.99, H; 5.91, N; 13.68 Actual value (%) C; 61.05, H; 6.17, N; 13.69 EI-MS (m / z): 475 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.72 (d, 1H, J = 7.6 Hz),
7.70 (s, 1H), 7.64 (d, 1H, J = 7.6 Hz), 7.14 (s,
1H), 7.01 (s, 1H), 4.35-4.15 (m, 1H), 3.95-3.75
(m, 4H), 3.60-3.40 (m, 2H), 3.25-2.95 (m, 2H), 2.4
9 (s, 3H), 2.45-2.20 (m, 2H), 1.90-1.70 (m, 2H),
1.30-1.10 (m, 6H).

Example 130: N- [6- [4- (4-methylphthalimido) piperidin-1-ylcarbonyl] -1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazole- 5-yl] acetamide (Compound 130) Compound 129 (300 mg, 0.59 mmol) was treated with methylene chloride (20 m
L), acetic anhydride (0.11 mL, 0.1.2 mmol), TEA
(0.254 mL, 1.76 mmol) and DMAP (catalytic amount) were added, followed by stirring at room temperature overnight. After partitioning the reaction mixture with saturated aqueous sodium bicarbonate / chloroform, the organic layer was separated and washed with a 2 mol / L aqueous hydrochloric acid solution and then with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. By recrystallizing the residue from ethanol, compound 130 (260 m
g, 86%). Melting point (ethanol): 288-290 ° C Elemental analysis: C ₂₈ H ₃₁ N ₅ O ₅ Calculated (%) C; 64.98, H; 6.04, N; 13.53 Found (%) C; 64.90, H; 5.99, N 13.34 EI-MS (m / z): 517 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 9.55 (s, 1H), 7.74 (d, 1)
H, J = 7.6 Hz), 7.69 (s, 1H), 7.63 (d, 1H, J = 7.6
Hz), 7.30 (s, 1H), 7.12 (s, 1H), 4.65 (brs, 1H),
4.35-4.15 (m, 1H), 3.95-3.75 (m, 4H), 3.45 (brs, 1
H), 3.15-2.65 (m, 2H), 2.47 (s, 3H), 2.35-2.00 (m,
2H), 2.11 (s, 3H), 1.90-1.55 (m, 2H), 1.20 (t, 6H,
J = 6.9 Hz).

Example 131: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] hydroxyacetamide (Compound 13
1) First step: N- [6- [4-] was obtained in the same manner as in Example 51 except that Compound 49 (500 mg, 0.99 mmol) and benzyloxyacetyl chloride (0.235 mL, 1.5 mmol) were used.
(1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1,3-
Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] benzyloxyacetamide (666 mg,> 99
%).

Step 2: The above compound was treated with methanol (63 m
L) and water (6.3 mL) and dissolved in 10% Pd-C (0.13
g, 50 w / w% H ₂ O), followed by ammonium formate (0.45 g, 7.
After 2 mmol), the mixture was heated under reflux for 5.5 hours. After adding celite to the reaction solution and stirring, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, water was added to the residue, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. By triturating the residue with ethyl acetate, compound 131 (0.3
3 g, 61%). Melting point (ethyl acetate): 240-241 ° C Elemental analysis: C ₂₉ H ₃₄ N ₆ O ₆ · 0.3 H ₂ O Calculated value (%) C; 61.32, H; 6.14, N; 14.80 Actual value (%) C; 61.40 , H; 6.15, N; 14.77 EI-MS (m / z): 563 (M ⁺ +1) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 9.41 (s, 1H), 8.10 (s, 1
H), 7.95 (s, 1H), 7.52 (d, 1H, J = 8.6 Hz), 7.11
(d, 1H, J = 8.6 Hz), 6.91 (s, 1H), 5.40-5.20 (m, 1
H), 5.15-4.65 (m, 1H), 4.33 (s, 2H), 3.96 (d, 4H,
J = 7.3 Hz), 3.95-3.70 (m, 1H), 3.56 (s, 3H), 3.30
-2.65 (m, 4H), 2.43 (s, 3H), 1.90-1.50 (m, 2H), 1.
35 (t, 3H, J = 6.9 Hz), 1.33 (t, 3H, J = 6.9 Hz).

Example 132: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] dimethylaminoacetamide (Compound 132) Compound 49 (562 mg, 1.1 mmol) and N, N-dimethylglycine
Compound 132 (894 mg,> 99%) was obtained in the same manner as in Example 48 except that (0.17 g, 1.7 mmol) was used. Melting point (ether): 225-226 ° C. Elemental _{analysis: C 31 H 39 N 7 O} 5 · 0.8H 2 O Calculated (%) C; 61.64, H ; 6.77, N; 16.23 Found (%) C; 61.49, H; 6.68, N; 16.42 EI-MS (m / z): 589 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 9.95 (brs, 1H), 7.99 (s,
1H), 7.97 (s, 1H), 7.48 (dd, 1H, J = 8.6, 2.0 Hz),
7.07 (d, 1H, J = 8.3 Hz), 6.91 (s, 1H), 5.30-5.10
(m, 1H), 5.10-4.70 (m, 2H), 4.10-3.80 (m, 6H), 3.
54 (s, 3H), 3.30-2.60 (m, 4H), 2.44 (s, 6H), 2.41
(s, 3H), 2.00-1.50 (m, 2H), 1.34 (t, 3H, J = 7.3 H
z), 1.33 (t, 3H, J = 7.3 Hz).

Example 133: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-iodide) iodide
2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] carbamoylmethyltrimethylammonium ( Compound 133) Compound 132 (500 mg, 0.85 mmol) in methanol (5 mL)
And ethyl acetate (5 mL).
(0.53 mL, 8.5 mmol) and then stirred at room temperature overnight. After addition of iodomethane (0.26 mL, 4.3 mmol), the mixture was stirred at room temperature for 1.5 hours, and the reaction solution was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (chloroform: methanol = 25: 1 to 8: 1), and then triturated with diethyl ether to obtain compound 133 (0.45 g, 88%). Melting point (ether): 212-213 ° C ESI-MS (m / z): 604 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 10.09 (s, 1H), 7.94 (s, 1)
H), 7.49 (dd, 1H, J = 8.6, 2.0 Hz), 7.28 (s, 1H),
7.09 (d, 1H, J = 8.6 Hz), 6.99 (s, 1H), 5.35-4.50
(m, 5H), 3.93 (q, 2H, J = 7.3 Hz), 3.92 (q, 2H, J
= 6.9 Hz), 3.63 (s, 9H), 3.55 (s, 3H), 3.30-2.50
(m, 4H), 2.42 (s, 3H), 1.95-1.60 (m, 2H), 1.33 (t,
3H, J = 7.3 Hz), 1.32 (t, 3H, J = 7.3 Hz).

Example 134: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1-Ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] hydroxyacetamide (Compound 134) Compound 134 was prepared except that compound 75 was used as a starting material. Obtained by a method similar to Example 131. Melting point (ethyl acetate): 206-207 ° C Elemental analysis: C ₂₈ H ₃₂ N ₆ O ₆ Calculated (%) C; 61.30, H; 5.88, N; 15.32 Found (%) C; 61.08, H; 6.17, N; 15.06 ESI-MS (m / z): 549 (M ⁺ +1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.39 (s, 1H), 8.07 (s, 1H),
7.95 (d, 1H, J = 1.7Hz), 7.52 (dd, 1H, J = 8.6,
1.7 Hz), 7.11 (d, 1H, J = 8.6 Hz), 6.90 (s, 1H), 5.
35-5.20 (m, 1H), 5.10-4.70 (m, 2H), 4.33 (s, 2H),
3.92 (q, 2H, J = 7.3 Hz), 3.75 (brs, 1H), 3.56 (s,
3H), 3.43 (s, 3H), 3.20-2.70 (m, 4H), 2.43 (s, 3
H), 1.90-1.50 (m, 2H), 1.32 (t, 3H, J = 7.3 Hz).

Example 135: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1-Ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] dimethylaminoacetamide
(Compound 135) Compound 135 was obtained in the same manner as in Example 132, except that compound 75 was used as a starting material. Melting point (ether): 254-255 ° C. Elemental _{analysis: C 30 H 37 N 7 O} 5 Calculated (%) C; 62.59, H ; 6.48, N; 17.03 Found (%) C; 62.52, H ; 6.68, N 16.64 ESI-MS (m / z): 576 (M ⁺ +1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.94 (brs, 1H), 7.97 (s, 1)
H), 7.95 (s, 1H), 7.48 (d, 1H, J = 8.6 Hz), 7.07
(d, 1H, J = 8.6 Hz), 6.92 (s, 1H), 5.30-5.15 (m, 1
H), 5.10-4.70 (m, 2H), 3.94 (q, 2H, J = 7.3 Hz),
3.54 (s, 3H), 3.42 (s, 3H), 3.30-2.75 (m, 6H), 2.44
(s, 3H), 2.41 (s, 3H), 1.90-1.50 (m, 2H), 1.33
(t, 3H, J = 7.3 Hz).

Example 136: N- [6- [4- (6-fluoro-1-methyl-1,2,3,4-tetrahydro-
2,4-Dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] hydroxyacetamide (Compound 136 Compound 136 was obtained in the same manner as in Example 131, except that compound 102 was used as a starting material. Mp (ethanol): 176-177 ° C. Elemental _{analysis: C 28 H 31 N 6 O} 6 F · 1.2H 2 O Calculated (%) C; 57.18, H ; 5.72, N; 14.29 Found (%) C; 57.23 , H; 5.87, N; 14.26 ESI-MS (m / z): 567 (M ⁺ +1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.38 (brs, 1H), 8.08 (s, 1)
H), 7.90-7.80 (m, 1H), 7.50-7.40 (m, 1H), 7.25-7.15
(m, 1H), 6.90 (s, 1H), 5.35-5.15 (m, 1H), 5.00-4.6
0 (m, 2H), 4.33 (s, 2H), 3.96 (q, 4H, J = 7.3 Hz),
3.58 (s, 3H), 3.30-2.60 (m, 4H), 1.90-1.50 (m, 2
H), 1.35 (t, 3H, J = 7.3 Hz), 1.33 (t, 3H, J = 7.3
Hz).

Example 137: 3- [1- (5-Amino-1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-6-ylcarbonyl) piperidin-4-yl ] -6-Fluoro-1-methyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline hydrochloride (Compound 137) Compound 137 is 1,6-dimethyl-3- (piperidine-4- Il) -1,
Instead of 2,3,4-tetrahydro-2,4-dioxoquinazoline, 6-fluoro-1- obtained in the fourth step of Example 101
Methyl-3- (piperidin-4-yl) -1,2,3,4-tetrahydro-
Other than using 2,4-dioxoquinazoline hydrobromide,
This was obtained by performing the same operations as in the seventh step of Example 68, and then performing the same operations as in Example 69. Melting point (ethyl acetate): 167-168 ° C ESI-MS (m / z): 495 (M ⁺ +1) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.80-7.60 (m, 2H), 7.55-
7.40 (m, 1H), 7.31 (s, 1H), 7.14 (s, 1H), 5.15-5.00
(m, 1H), 4.25-3.90 (m, 2H), 3.90 (q, 2H, J = 6.9 H
z), 3.52 (s, 3H), 3.33 (s, 3H), 3.20-2.80 (m, 2H),
2.75-2.50 (m, 2H), 1.80-1.60 (m, 2H), 1.20 (t, 3H,
J = 6.9 Hz).

Example 138: N- [6- [4- (6-Fluoro-1-methyl-1,2,3,4-tetrahydro-
2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1-ethyl-3-methyl-2-oxo-2,3-dihydro-
[1H-benzimidazol-5-yl] hydroxyacetamide (Compound 138) Compound 138 was obtained in the same manner as in Example 131 except that compound 137 was used as a starting material. Melting point (ethyl acetate): 214-215 ° C ESI-MS (m / z): 553 (M ⁺ +1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.37 (brs, 1H), 8.05 (s, 1
H), 7.90-7.80 (m, 1H), 7.50-7.40 (m, 1H), 7.25-7.15
(m, 1H), 6.90 (s, 1H), 5.35-5.15 (m, 1H), 5.00-4.6
0 (m, 2H), 4.32 (s, 2H), 3.92 (q, 2H, J = 6.9 Hz),
3.58 (s, 3H), 3.43 (s, 3H), 3.25-2.35 (m, 4H), 1.9
0-1.50 (m, 2H), 1.32 (t, 3H, J = 6.9 Hz).

Example 139: N- [6- [4- (6-chloro-1-methyl-1,2,3,4-tetrahydro-2,
4-Dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] acetoxyacetamide (Compound 139) Compound 139 was obtained in the same manner as in Example 108 except that acetoxyacetyl chloride was used instead of acetic anhydride. Mp (ethyl acetate): 231 - 232 ° C. Elemental _{analysis: C 30 H 33 N 6 O} 7 Cl · 0.3H 2 O Calculated (%) C; 57.15, H ; 5.37, N; 13.33 Found (%) C; 57.31, H; 5.51, N; 13.04 ESI-MS (m / z): 625 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.61 (brs, 1H), 8.15 (d, 1)
H, J = 2.3 Hz), 8.03 (s, 1H), 7.62 (dd, 1H, J = 2.
3, 8.9 Hz), 7.13 (d, 1H, J = 8.9 Hz), 6.92 (s, 1
H), 5.35-5.15 (m, 1H), 4.80 (s, 2H), 4.70-4.20 (m,
2H), 3.96 (q, 2H, J = 6.9 Hz), 3.93 (q, 2H, J = 6.
9 Hz), 3.55 (s, 3H), 3.20-2.60 (m, 4H), 2.29 (s, 3
H), 1.80-1.60 (m, 2H), 1.34 (t, 3H, J = 6.9 Hz),
1.33 (t, 3H, J = 6.9 Hz).

Example 140: N- [6- [4- (6-chloro-1-methyl-1,2,3,4-tetrahydro-2,
4-Dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] hydroxyacetamide (Compound 140) Compound 140 was obtained in the same manner as in Example 131 except that compound 106 was used as a starting material. Mp (water): 261-262 ° C. Elemental _{analysis: C 28 H 31 N 6 O} 6 Cl · 0.2H 2 O Calculated (%) C; 57.33, H ; 5.39, N; 14.33 Found (%) C; 57.37 , H; 5.48, N; 14.33 ESI-MS (m / z): 583 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.38 (brs, 1H), 8.12 (d, 1)
H, J = 2.3 Hz), 8.08 (s, 1H), 7.65 (dd, 1H, J = 2.
3, 8.9 Hz), 7.16 (d, 1H, J = 8.9 Hz), 6.90 (s, 1
H), 5.35-5.15 (m, 1H), 5.00-4.60 (m, 2H), 4.32 (s,
2H), 3.95 (q, 4H, J = 6.9 Hz), 3.57 (s, 3H), 3.30-
2.30 (m, 4H), 1.90-1.50 (m, 2H), 1.33 (t, 6H, J =
6.9 Hz).

Example 141: N- [6- [4- (6-chloro-1-methyl-1,2,3,4-tetrahydro-2,
4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] dimethylaminoacetamide
(Compound 141) Compound 141 was obtained in the same manner as in Example 132 except that compound 106 was used as a starting material. Melting point (ethyl acetate): 230-231 ° C ESI-MS (m / z): 610 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.90 (brs, 1H), 8.13 (s, 1)
H), 7.98 (s, 1H), 7.61 (d, 1H, J = 8.9 Hz), 7.11
(d, 1H, J = 8.9 Hz), 6.88 (s, 1H), 5.35-5.15 (m, 1
H), 5.00-4.60 (m, 2H), 3.91 (q, 4H, J = 6.9 Hz),
3.55 (s, 3H), 3.30-2.60 (m, 4H), 2.44 (s, 6H), 1.8
0-1.60 (m, 2H), 1.34 (t, 6H, J = 6.9 Hz).

Example 142: N- [6- [4- (6-chloro-1-methyl-1,2,3,4-tetrahydro-2,
4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] malonamic acid methyl ester
(Compound 142) Compound 142 was prepared in the same manner as in Example 1 except that 3-chloro-3-oxopropionic acid methyl ester was used instead of acetic anhydride.
08 obtained in a similar manner. Mp (ethanol): 210-211 ° C. Elemental _{analysis: C 30 H 33 N 6 O} 7 Cl Calculated (%) C; 57.64, H ; 5.32, N; 13.44 Found (%) C; 57.71, H ; 5.41, N; 13.25 ESI-MS (m / z): 625 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.75 (brs, 1H), 8.13 (s, 1)
H), 7.93 (s, 1H), 7.62 (d, 1H, J = 8.9 Hz), 7.13
(d, 1H, J = 8.9 Hz), 6.91 (s, 1H), 5.30-5.15 (m, 1
H), 5.00-4.50 (m, 2H), 3.94 (q, 4H, J = 6.9 Hz),
3.83 (s, 3H), 3.65 (s, 2H), 3.55 (s, 3H), 3.25-2.50
(m, 4H), 1.80-1.55 (m, 2H), 1.33 (t, 6H, J = 6.9
Hz).

Example 143: 6-chloro-3- [1- (1-ethyl-3-methyl-5-nitro-2-oxo)
-2,3-Dihydro-1H-benzimidazol-6-ylcarbonyl) piperidin-4-yl] -1-methyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline hydrochloride (Compound 143 Compound 143 was obtained in the sixth step of Example 68 in place of 1,3-diethyl-6-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-5-ylcarboxylic acid. -Ethyl-3-
Obtained by a method similar to the second step of Example 105 except that methyl-5-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-6-ylcarboxylic acid was used. Melting point (ethyl acetate / ether):> 300 ° C. ESI-MS (m / z): 541 (M ⁺ +1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.15 (s, 1H), 7.86 (s) , 1H),
7.62 (d, 1H, J = 8.9Hz), 7.14 (d, 1H, J = 8.9H
z), 7.06 (s, 1H), 5.30-5.15 (m, 1H), 5.05-4.80 (m,
1H), 4.20-4.00 (m, 1H), 4.02 (q, 2H, J = 7.6 Hz),
3.98 (s, 3H), 3.57 (s, 3H), 3.30-2.60 (m, 4H), 1.
90-1.50 (m, 2H), 1.40 (t, 3H, J = 6.9 Hz).

Example 144: 3- [1- (5-Amino-1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-6-ylcarbonyl) piperidin-4-yl ] -6-Chloro-1-methyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline hydrochloride (Compound 144) Compound 144 was prepared according to Example 106 except that compound 143 was used as a starting material. Was obtained in the same manner as described above. Mp (ethyl acetate): 184-185 ° C. Elemental _{analysis: C 25 H 27 N 6 O} 4 Cl Calculated (%) C; 51.31, H ; 5.55, N; 14.36 Found (%) C; 51.37, H ; 5.49 , N; 14.30 ESI-MS (m / z): 511 (M ⁺ +1) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.97 (d, 1H, J = 2.6 Hz),
7.79 (dd, 1H, J = 2.6, 8.9 Hz), 7.47 (d, 1H, J =
8.9 Hz), 7.17 (s, 1H), 7.05 (s, 1H), 5.15-5.00 (m,
1H), 4.50-3.90 (m, 2H), 3.90 (q, 2H, J = 7.3 Hz),
3.51 (s, 3H), 3.33 (s, 3H), 3.25-2.90 (m, 2H), 2.
70-2.45 (m, 2H), 1.80-1.55 (m, 2H), 1.22 (t, 3H, J
= 7.3 Hz).

Example 145: N- [6- [4- (6-chloro-1-methyl-1,2,3,4-tetrahydro-2,
4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H
-Benzimidazol-5-yl] acetamide (Compound 14
5) Compound 145 was obtained in the same manner as in Example 51 except that compound 144 was used as a starting material. Mp (ethyl acetate): 252-253 ° C. Elemental _{analysis: C 27 H 29 N 6 O} 5 Cl · 0.8H 2 O Calculated (%) C; 57.15, H ; 5.44, N; 14.81 Found (%) C; 57.18, H; 5.25, N; 14.47 ESI-MS (m / z): 553 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.78 (brs, 1H), 8.14 (d, 1)
H, J = 2.6 Hz), 7.92 (s, 1H), 7.62 (dd, 1H, J = 2.
6, 8.9 Hz), 7.13 (d, 1H, J = 8.6 Hz), 6.88 (s, 1
H), 5.35-5.15 (m, 1H), 5.00-4.40 (m, 2H), 3.93 (q,
2H, J = 7.3 Hz), 3.56 (s, 3H), 3.42 (s, 3H), 3.20
-2.60 (m, 4H), 2.27 (s, 3H), 1.85-1.55 (m, 2H), 1.
32 (t, 3H, J = 7.3 Hz).

Example 146: N- [6- [4- (6-chloro-1-methyl-1,2,3,4-tetrahydro-2,
4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H
-Benzimidazol-5-yl] propionamide (Compound 146) Compound 146 was obtained in the same manner as in Example 53 except that compound 144 was used as a starting material. Mp (ethyl acetate): 257-258 ° C. Elemental _{analysis: C 28 H 31 N 6 O} 5 Cl · 0.3H 2 O Calculated (%) C; 58.75, H ; 5.56, N; 14.68 Found (%) C; 58.84, H; 5.71, N; 14.43 ESI-MS (m / z): 567 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 8.86 (brs, 1H), 8.14 (d, 1)
H, J = 2.6 Hz), 8.01 (s, 1H), 7.62 (dd, 1H, J = 2.
6, 8.9 Hz), 7.13 (d, 1H, J = 8.6 Hz), 6.88 (s, 1
H), 5.35-5.15 (m, 1H), 5.00-4.40 (m, 2H), 3.93 (q,
2H, J = 7.3 Hz), 3.56 (s, 3H), 3.42 (s, 3H), 3.20
-2.60 (m, 4H), 2.52 (d, 2H, J = 6.9 Hz), 1.85-1.60
(m, 2H), 1.32 (t, 3H, J = 7.3 Hz), 1.30 (t, 3H, J
= 6.9 Hz).

Example 147: N- [6- [4- (6-chloro-1-methyl-1,2,3,4-tetrahydro-2,
4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H
-Benzimidazol-5-yl] acetoxyacetamide
(Compound 147) Compound 147 was obtained in the same manner as in Example 139 except that compound 144 was used as a starting material. Melting point (ethyl acetate): 237-238 ° C ESI-MS (m / z): 611 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.59 (brs, 1H), 8.15 (d, 1)
H, J = 2.3 Hz), 7.99 (s, 1H), 7.61 (dd, 1H, J = 2.
3, 8.9 Hz), 7.12 (d, 1H, J = 8.9 Hz), 6.91 (s, 1
H), 5.35-5.15 (m, 1H), 5.00-4.50 (m, 2H), 4.80 (s,
2H), 3.93 (q, 2H, J = 6.9 Hz), 3.55 (s, 3H), 3.43
(s, 3H), 3.20-2.60 (m, 4H), 2.28 (s, 3H), 1.80-1.6
0 (m, 2H), 1.33 (t, 3H, J = 6.9 Hz).

Example 148: N- [6- [4- (6-chloro-1-methyl-1,2,3,4-tetrahydro-2,
4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H
-Benzimidazol-5-yl] hydroxyacetamide
(Compound 148) Compound 148 was obtained in the same manner as in Example 131, except that compound 144 was used as a starting material. Mp (ethyl acetate): 223-224 ° C. Elemental _{analysis: C 27 H 29 N 6 O} 6 Cl · 0.5H 2 O Calculated (%) C; 56.10, H ; 5.23, N; 14.54 Found (%) C; 56.05, H; 5.12, N; 14.52 ESI-MS (m / z): 569 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.36 (brs, 1H), 8.13 (d, 1)
H, J = 2.3 Hz), 8.05 (s, 1H), 7.65 (dd, 1H, J = 2.
3, 8.9 Hz), 7.16 (d, 1H, J = 8.9 Hz), 6.90 (s, 1
H), 5.35-5.15 (m, 1H), 5.00-4.50 (m, 2H), 4.33 (s,
2H), 3.92 (q, 2H, J = 7.3 Hz), 3.57 (s, 3H), 3.43
(s, 3H), 3.20-2.30 (m, 4H), 1.80-1.60 (m, 2H), 1.3
2 (t, 3H, J = 7.3 Hz).

Example 149: N- [6- [4- (6-chloro-1-methyl-1,2,3,4-tetrahydro-2,
4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H
[Benzimidazol-5-yl] malonamic acid methyl ester (Compound 149) Compound 149 was obtained in the same manner as in Example 142, except that compound 144 was used as a starting material. Mp (ethyl acetate): 217-218 ° C. Elemental _{analysis: C 29 H 31 N 6 O} 7 Cl · 0.2H 2 O Calculated (%) C; 56.67, H ; 5.15, N; 13.67 Found (%) C; 56.72, H; 5.17, N; 13.59 ESI-MS (m / z): 611 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.76 (brs, 1H), 8.12 (d, 1)
H, J = 2.3 Hz), 7.87 (s, 1H), 7.61 (dd, 1H, J = 2.
3, 8.9 Hz), 7.12 (d, 1H, J = 8.9 Hz), 6.90 (s, 1
H), 5.35-5.10 (m, 1H), 5.00-4.50 (m, 2H), 3.93 (q,
2H, J = 7.3 Hz), 3.83 (s, 3H), 3.65 (s, 2H), 3.55
(s, 3H), 3.41 (s, 3H), 3.20-2.50 (m, 4H), 1.90-1.
55 (m, 2H), 1.32 (t, 3H, J = 7.3 Hz).

Example 150: N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1-Ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] malonamic acid methyl ester (Compound 150) Compound 150 is a compound other than using Compound 75 as a starting material. Was obtained in the same manner as in Example 142. Mp: 225-226 ° C. Elemental _{analysis: C 30 H 34 N 6 O} 7 · 0.3H 2 O Calculated (%) C; 60.45, H ; 5.85, N; 14.10 Found (%) C; 60.62, H ; 5.98 , N; 13.83 ESI-MS (m / z): 591 (M ⁺ +1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.76 (brs, 1H), 7.97 (s, 1)
H), 7.90 (s, 1H), 7.48 (d, 1H, J = 8.6 Hz), 7.07
(d, 1H, J = 8.6 Hz), 6.92 (s, 1H), 5.35-5.15 (m, 1
H), 5.05-4.50 (m, 2H), 3.93 (q, 2H, J = 7.3 Hz),
3.83 (s, 3H), 3.66 (brs, 2H), 3.54 (s, 3H), 3.41
(s, 3H), 3.20-2.60 (m, 4H), 2.42 (s, 3H), 1.80-1.50
(m, 2H), 1.32 (t, 3H, J = 7.3 Hz).

Example 151 N- [6- [4- (1,6-dimethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl ] -1-Ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] malonamic acid (Compound 151) Compound 150 (0.35 g, 0.58 mmol) in methanol (12 mL)
Dissolved in a mixture of water and water (3 mL).
(0.046 g, 1.2 mmol) and then stirred at room temperature for 3.5 hours. After washing the reaction solution with chloroform, a 1 mol / L hydrochloric acid aqueous solution was added to make the solution acidic. After extraction with chloroform, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was triturated with ethyl acetate to give compound 151 (0.29 g, 86%). Mp (ethyl acetate): 207-208 ° C. Elemental _{analysis: C 29 H 32 N 6 O} 7 · 0.7H 2 O Calculated (%) C; 59.11, H ; 5.71, N; 14.26 Found (%) C; 59.17 , H; 5.78, N; 13.97 ESI-MS (m / z): 577 (M ⁺ +1) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.36 (brs, 1H), 7.97 (s, 1)
H), 7.71 (s, 1H), 7.48 (d, 1H, J = 8.6 Hz), 7.08
(d, 1H, J = 8.6 Hz), 6.87 (s, 1H), 5.35-5.20 (m, 1
H), 5.00-4.60 (m, 2H), 3.93 (q, 2H, J = 6.9 Hz),
3.71 (brs, 2H), 3.54 (s, 3H), 3.42 (s, 3H), 3.30-
2.60 (m, 4H), 2.41 (s, 3H), 1.80-1.50 (m, 2H), 1.32
(t, 3H, J = 6.9 Hz).

Example 152: N- [6- [4- (6-chloro-1-methyl-1,2,3,4-tetrahydro-2,
4-Dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] malonamic acid (Compound 152) Compound 152 was obtained in the same manner as in Example 151 except that compound 142 was used as a starting material. Mp (ethanol): 184-185 ° C. Elemental _{analysis: C 29 H 31 N 6 O} 7 Cl · 1.4H 2 O Calculated (%) C; 54.74, H ; 5.35, N; 13.21 Found (%) C; 55.08 , H; 5.41, N; 12.81 ESI-MS (m / z): 611 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.35 (brs, 1H), 8.14 (d, 1)
H, J = 2.0 Hz), 7.73 (s, 1H), 7.62 (dd, 1H, J = 2.
0, 8.9 Hz), 7.13 (d, 1H, J = 8.9 Hz), 6.88 (s, 1
H), 5.35-5.15 (m, 1H), 5.00-4.60 (m, 2H), 3.94 (q,
4H, J = 7.3 Hz), 3.68 (brs, 2H), 3.55 (s, 3H), 3.
30-2.30 (m, 4H), 1.80-1.50 (m, 2H), 1.34 (t, 6H, J
= 7.3 Hz).

Example 153: N- [6- [4- (6-chloro-1-methyl-1,2,3,4-tetrahydro-2,
4-dioxoquinazolin-3-yl) piperidin-1-ylcarbonyl] -1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H
-Benzimidazol-5-yl] malonamic acid (Compound 15
3) Compound 153 was obtained in the same manner as in Example 151 except that compound 149 was used as a starting material. Mp (ethanol): 189-190 ° C. Elemental _{analysis: C 28 H 29 N 6 O} 7 Cl · 0.8H 2 O Calculated (%) C; 55.00, H ; 5.04, N; 13.74 Found (%) C; 55.07 , H; 4.94, N; 13.53 ESI-MS (m / z): 597 (M ⁺ ) ¹ H-NMR (CDCl ₃ ) δ (ppm): 9.43 (brs, 1H), 8.12 (s, 1)
H), 7.62 (s, 1H), 7.61 (d, 1H, J = 8.9 Hz), 7.13
(d, 1H, J = 8.9 Hz), 6.88 (s, 1H), 5.35-5.15 (m, 1
H), 5.00-4.60 (m, 2H), 3.93 (q, 2H, J = 6.9 Hz),
3.68 (brs, 2H), 3.54 (s, 3H), 3.41 (s, 3H), 3.30-
2.30 (m, 4H), 1.80-1.50 (m, 2H), 1.32 (t, 3H, J =
6.9 Hz).

[0291]

According to the present invention, it has an adenosine uptake inhibitory effect and is useful as a cardioprotective agent, a cerebral ischemia, a preventive or therapeutic agent for renal diseases (nephritis, diabetic nephropathy, etc.), pancreatitis, pain, convulsions, etc. Or a pharmacologically acceptable salt thereof.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 13/12 A61P 13/12 25/04 25/04 25/28 25/28 29/00 29/00 43 / 00 111 43/00 111 C07D 401/14 C07D 401/14 403/12 403/12 (72) Inventor Hiromi Nonaka 1188 Shimotsukari, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture F-term in Kyowa Hakko Kogyo Co., Ltd. 4C063 AA01 AA03 CC26 CC31 DD10 DD26 EE01 4C086 AA01 AA02 AA03 BC46 GA07 MA01 MA04 NA14 ZA06 ZA08 ZA36 ZA66 ZA81 ZB11 ZC02

Claims (8)

[Claims] 1. A compound of the formula (I) Wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, formamide, halogen, amino, nitro, cyano, hydroxy, carboxy, carbamoyl, substituted or unsubstituted mono- or di-lower alkyl Amino, substituted or unsubstituted lower alkanoylamino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkylthio, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted lower Represents alkanoyl, substituted or unsubstituted aralkyloxy or substituted or unsubstituted lower alkanoyloxy, and -VW- is a group represented by the formula (i): (Wherein, R ⁵ represents a hydrogen atom, a substituted or unsubstituted lower alkyl or a substituted or unsubstituted aralkyl)
Or the formula (ii): Wherein R ⁶ represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl, or V and W There together, -C (O) - or -CH ₂ - represents, X is _{- (CH 2) m N (} R 5a) -
(Wherein, m represents 2, 3 or 4, R ^5a has the same meaning as the R ⁵⁾ or formula (iii) embedded image (Wherein n represents 0, 1 or 2; G ¹ represents a hydrogen atom, halogen, amino, nitro, cyano, hydroxy, oxo,
Carboxy, carbamoyl, substituted or unsubstituted mono- or di-lower alkylamino, substituted or unsubstituted lower alkanoylamino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkoxycarbonyl, Represents a substituted or unsubstituted aralkyloxy or a substituted or unsubstituted lower alkanoyloxy), wherein Y is O, S
Or NR ⁷ (wherein R ⁷ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted lower alkoxycarbonyl or substituted or unsubstituted aralkyloxycarbonyl) Or two hydrogen atoms, and Z is represented by the formula (i
v) embedded image Wherein G ² is a hydrogen atom, halogen, nitro, carboxy, cyano, hydroxy, carbamoyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkanoyloxy, substituted or unsubstituted aralkyloxy, substituted or unsubstituted Substituted lower alkoxycarbonyl or NR ^A R ^B (where R ^A and R ^B are the same or different and each represents a hydrogen atom, formyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted Aroyl, substituted or unsubstituted aralkyl, substituted or unsubstituted lower alkoxycarbonyl or substituted or unsubstituted aralkylcarbonyl), and R ⁸ and R ⁹ are the same or different,
Represents a hydrogen atom, hydroxy, substituted or unsubstituted lower alkoxy or substituted or unsubstituted aralkyloxy] or a compound of formula (v) (Wherein R ¹⁰ and R ¹¹ are the same or different, and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkanoyl, A substituted or unsubstituted aryl, a substituted or unsubstituted aroyl or a substituted or unsubstituted aralkyl, U represents O or S, and G ² has the same meaning as defined above); Its pharmacologically acceptable salts. 2. The aromatic derivative according to claim 1, wherein Z is the formula (v), or a pharmacologically acceptable salt thereof. 3. The aromatic derivative according to claim 1, wherein -VW- is the formula (i), and R ⁵ is a hydrogen atom or a substituted or unsubstituted lower alkyl, or a pharmacologically acceptable derivative thereof. Salt. 4. X is of formula (iii), n is 1;
4. The aromatic derivative according to claim ¹ , wherein G ¹ is a hydrogen atom, or a pharmacologically acceptable salt thereof. 5. The method according to claim ¹ , wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, hydroxy or substituted or unsubstituted lower alkoxy. 4. The aromatic derivative according to any one of 4) or a pharmacologically acceptable salt thereof. 6. The aromatic derivative according to claim 1, wherein Y is O, or a pharmacologically acceptable salt thereof. 7. A medicament comprising the aromatic derivative according to claim 1 or a pharmacologically acceptable salt thereof. 8. An adenosine uptake inhibitor comprising the aromatic derivative according to claim 1 or a pharmaceutically acceptable salt thereof.