AU5853100A

AU5853100A - Benzimidazolone derivatives and their use as phosphodiesterase inhibitors

Info

Publication number: AU5853100A
Application number: AU58531/00A
Authority: AU
Inventors: Takayuki Inoue; Tsuyoshi Mizutani; Kozo Sawada; Yuki Sawada
Original assignee: Fujisawa Pharmaceutical Co Ltd
Current assignee: Fujisawa Pharmaceutical Co Ltd
Priority date: 1999-07-21
Filing date: 2000-07-12
Publication date: 2001-02-05

Description

WO 01/05770 PCT/JPOO/04687 BENZIMIDAZOLONE DERIVATIVES AND THEIR USE AS PHOSPHODIESTERASE INHIBITORS DESCRIPTION 5 Technical Field This invention relates to heterocyclic compounds having pharmacological activities, their pharmaceutical compositions and their use as a medicament for treatment or prevention of diseases mediated by cGMP-PDE. 10 Background Art It is known that a cyclic guanosine-3',5'-monophosphate (hereinafter referred to as cGMP) derived from a guanosine-5-triphosphate possesses a relaxant activity of smooth muscle and that a cyclic 15 guanosine-3',5'-monophosphate phosphodiesterase (hereinafter refereed to as cGMP-PDE) acts to catalyze the degradation of cGMP to a guanosine-5' monophosphate. cGMP-PDE is a family of enzymes consists from PDE-I, II, V and so on. The compounds having an inhibitory activity of cGMP-PDE are disclosed in European Patent Publication Nos. 579,496; 534,443; 20 526,004; 636,626; United States Patent Nos. 3,819,631; 5,294,612; 5,488,055; International Patent Publication Nos. 93/07,124; 94/19,351; 95/18,097; 96/32,379; Japan Patent Publication Nos. 05-222,000; 07 330,777; and so on. Further, some kinds of benzimidazolone compounds having affinity 25 for receptors of vasopressin and/or oxytocin are disclosed in Japanese Patent Kokai No. Hei 8(1996)-73439. Disclosure of Invention According to one aspect of this invention, it provides novel 30 heterocyclic compounds represented by the below formula (Ia) and their pharmaceutical compositions. According to another aspect of the invention, it provides a 1 WO 01/05770 PCT/JPOO/04687 pharmaceutical composition for treatment or prevention of diseases mediated by cGMP-PDE (especially PDE-V) containing a heterocyclic compound represented by the below formula (I) as an active ingredient. 5 Specifically, the present invention provides a compound of the formula (Ia): - R 3a 1aa la (C H 2 !) 'a 10 R I \ N >( a ) Xa N

I

2 a 15 wherein Xa is CH or nitrogen atom; ya is oxygen atom or sulfur atom; Ria is a halogen atom; cyano group; nitro group; carbamoyl group; a lower alkylcarbamoyl group which may be substituted with a heterocyclic 20 group; carboxy group; a protected carboxy group; a lower alkyl group; a halo(lower)alkyl group; a lower alkoxy group; an acyl group; or a lower alkanesulfonyl group, R2a is a lower alkyl group, a cycloalkyl group or a heterocyclic group, among which the lower alkyl group may have one to three substituents 25 selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, lower alkylamino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, carboxy, lower alkanesulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl 30 carbamoyl and sulfamoyl; and the cycloalkyl group and the heterocyclic group may have one to three substituents selected from the group consisting of hydroxy, protected 2 WO 01/05770 PCT/JP00/04687 hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower 5 alkylenedioxy, carbamoyl and sulfamoyl, R3a, R4a and R5a are, the same or different, hydrogen atom, a halogen atom, a lower alkanoyl group, carboxy group, a protected carboxy group, carbamoyl group, nitro group, cyano group, a lower alkyl group optionally substituted by hydroxy, a lower alkoxy group or a lower 10 alkoxy-substituted aralkyl group; or two of R3a, R 4 a and R5a may combine together to form a lower alkylenedioxy group, m is an integer of 1 or 2, provided that when R3a is hydrogen atom, R4a is a lower alkoxy group and 15 Rsa is hydrogen atom, a halogen atom, cyano group, a lower alkyl group, a lower alkoxy group, a protected carboxy group, carboxy group or nitro group then (1) the lower alkyl group for R2a has one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy 20 substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, carboxy, lower alkanesulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl carbamoyl and sulfamoyl, (2) the cycloalkyl group for R2a has one to three substituents selected from 25 the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkylenedioxy, 30 carbamoyl and sulfamoyl, (3) the heterocyclic group for R 2 a is selected from pyrrolidinyl group, dioxanyl group and piperidyl group which groups may be substituted 3 WO 01/05770 PCT/JP00/04687 with protected carboxy, acyl, lower alkanesulfonyl, carbamoyl or sulfamoyl, (4) Ria is carbamoyl group; a lower alkylcarbamoyl group which may be substituted with a heterocyclic group; carboxy group; a protected 5 carboxy group; an acyl group; or a lower alkanesulfonyl group; (5) Xa is nitrogen atom; (6) m is an integer of 2; or (7) Ya is sulfur atom, its prodrug or a pharmaceutically acceptable salt thereof. 10 According to the present invention, it also provides a pharmaceutical composition directed to treatment or prevention of diseases mediated by cGMP-PDE which comprises a compound of the formula (I): 15 (C I) 4

(CH

2 )n R1 | R N Y (I) X N >= 20 wherein X is CH or nitrogen atom; Y is oxygen atom or sulfur atom; R1 is a halogen atom, cyano group, nitro group, carbamoyl group, a lower 25 alkylcarbamoyl group which may be substituted with a heterocyclic group, carboxy group, a protected carboxy group, a lower alkyl group, a halo(lower)alkyl group, a lower alkoxy group, an acyl group or a lower alkanesulfonyl group,

R

2 is a lower alkyl group, a cycloalkyl group or a heterocyclic group, 30 among which the lower alkyl group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, lower alkylamino, 4 WO 01/05770 PCT/JPOO/04687 acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, carboxy, lower alkanesulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl carbamoyl and sulfamoyl; and 5 the cycloalkyl group and the heterocyclic group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, lower alkanesulfonyl, 10 lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkylenedioxy, carbamoyl and sulfamoyl, R3, R4 and R5 are, the same or different, hydrogen atom, a halogen atom, a lower alkanoyl group, carboxy group, a protected carboxy group, carbamoyl group, nitro group, cyano group, a lower alkyl group 15 optionally substituted by hydroxy, a lower alkoxy group or a lower alkoxy-substituted aralkyl group, or two of R3, R4 and R5 may combine together to form a lower alkylenedioxy group, n is an integer of 1 or 2, its prodrug or a pharmaceutically acceptable salt thereof 20 in admixture with a pharmaceutically acceptable carrier or diluent. The present invention further provides an intermediate compound of the following formula (II) or its salt for preparing a compound (I). R1 H 25 N x N wherein 30 X is CH or nitrogen atom; Y is oxygen atom or sulfur atom;

R

1 is a halogen atom; cyano group; nitro group; carbamoyl group; a lower 5 WO 01/05770 PCT/JPOO/04687 alkylcarbamoyl group which may be substituted with a heterocyclic group; carboxy group; a protected carboxy group; a lower alkyl group; a halo(lower)alkyl group; a lower alkoxy group; an acyl group; or a lower alkanesulfonyl group, and 5 R2 is a lower alkyl group, a cycloalkyl group or a heterocyclic group, among which the lower alkyl group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, lower alkylamino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, 10 ureido, lower alkylureido, sulfamoylamino, protected carboxy, carboxy, lower alkanesulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl carbamoyl and sulfamoyl; and the cycloalkyl group and the heterocyclic group may have one to three substituents selected from the group consisting of hydroxy, protected 15 hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkylenedioxy, carbamoyl and sulfamoyl. 20 In the above and subsequent descriptions of the present specification, preferable examples and illustrations of the various definitions which the present invention includes within the scope are explained in detail in the following. 25 In this respect, it is to be noted that the following explanations are given by referring to R 1 to R 5 , X and Y and that Ria to R5a, Xa and ya are the same as R 1 to R5, X and Y or included therein, respectively. 30 The term "lower" is intended to mean a group having 1 to 6 carbon atoms, unless otherwise indicated. Preferably, the halogen atoms for R1, R3, R4 and R5 are fluorine, 6 WO 01/05770 PCT/JP00/04687 chlorine, bromine and iodine. Preferably, the lower alkyl groups for RI, R2, R3, R 4 and R5 are straight or branched ones having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 5 hexyl and the like. Preferably, the halo(lower)alkyl group for RI is lower alkyl groups substituted with one or more halogen atoms, in which the lower alkyl moiety and the halogen atom may be the same as exemplified in the above, respectively. Preferred examples of the halo(lower)alkyl group include 10 fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, iodomethyl, fluoroethyl, 2,2,2-trifluoroethyl, chloroethyl, 2,2,2-trichloroethyl, bromoethyl, iodoethyl, chloropropyl, bromopropyl, chlorobutyl, bromobutyl, chloropentyl, bromopentyl, chlorohexyl, bromohexyl and the like. 15 Preferably, the lower alkoxy groups for R1, R3, R 4 and R5 are straight or branched chain ones having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like. Preferably, the acyl group for R1 is lower alkanoyl (e.g., formyl, 20 acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl), aroyl (e.g., benzoyl, toluoyl, xyloyl and naphthoyl), heterocyclic carbonyl (e.g., nicotinoyl, isonicotinoyl, thenoyl and furoyl) and the like. Preferably, the lower alkanoyl groups for R 3 , R4 and R5 are the same as those illustrated as lower alkanoyl included in the acyl group for R 1 . 25 Preferably, the lower alkanesulfonyl group for R1 is straight or branched one having 1 to 6 carbon atoms such as methanesulfonyl(mesyl), ethanesulfonyl, propanesulfonyl, butanesulfonyl, pentanesulfonyl, hexanesulfonyl, 2-methylpropanesulfonyl and the like. Preferably, the protected carboxy group for R1, R 3 , R 4 and R5 is 30 carboxy groups protected by a conventional protecting group. Examples of the protected carboxy group include lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, n-butoxycarbonyl, 7 WO 01/05770 PCT/JPOO/04687 tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and isopropoxycarbonyl), ar(lower)alkyloxycarbonyl (e.g., benzyloxycarbonyl, trityloxycarobonyl, 4-methoxybenzyloxycarobnyl, 4-nitrobenzyloxycarbonyl, phenethyloxycarbonyl, bis(methoxyphenyl)methyloxycarbonyl, 3,4 5 dimethoxybenzyloxycarbonyl and benzhydryloxycarbonyl) and the like. The lower alkyl moiety of the lower alkylcarbamoyl group for R' is the same as the lower alkyl group as illustrated in the above, and said lower alkyl moiety may be substituted with a heterocyclic group as illustrated below. Examples of the lower alkylcarbamoyl group are methylcarbamoyl, 10 ethylcarbamoyl, propylcarbamoyl and the like. Examples of the lower alkylcarbamoyl group substituted with a heterocyclic group are furfurylcarbamoyl, thenylcarbamoyl, pyridylmethylcarbamoyl, pyrrolylmethylcarbamoyl, and the like. Preferably, the cycloalkyl group for R2 is cyclic saturated 15 hydrocarbon residues having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Preferably, the heterocyclic group for R2 is saturated or unsaturated, monocyclic or condensed one containing one or more hetero atoms selected from nitrogen, sulfur and oxygen atoms, such as 20 saturated or unsaturated 3 to 7-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pirazolidinyl, piperidino, piperidyl, piperazinyl, pyrrolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H- 1,2,4-triazolyl, 1H- 1,2,3-triazolyl 25 or 2H-1,2,3-triazolyl], tetrazolyl [e.g., 1H-tetrazoly or 2H-tetrazolyl] or the like; saturated or unsaturated 3 to 7-membered heteromonocyclic group containing 1 to 2 oxygen atoms, for example, pyranyl, furyl, dioxanyl, tetrahydropyranyl, tetrahydrofuryl or tetrahydrodioxanyl; 30 saturated or unsaturated 3 to 7-membered heteromonocyclic group containing 1 to 2 sulfur atoms, for example, thienyl, thiopyranyl or the like; saturated or unsaturated 3 to 7-membered heteromonocyclic group 8 WO 01/05770 PCT/JPOO/04687 containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or 1,2,5-oxadiazolyl or the like; saturated or unsaturated 3 to 7-membered heteromonocyclic group 5 containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, isothiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4 thiadiazolyl or 1,2,5-thiadiazoly] or the like; saturated or unsaturated 3 to 7-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, 10 morpholino or morpholinyl; saturated or unsaturated 3 to 7-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolidinyl, thiomorpholino or thiomorpholinyl; unsaturated condensed heterocyclic group containing 1 to 3 nitrogen atoms, 15 for example, benzopyrrolyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, quinolyl, isoquinolyl, indolyl or the like; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms, for example, benzofuryl or the like; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms 20 and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, phenoxazinyl or the like; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms, for example, benzo[b]thienyl or the like; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms 25 and 1 to 3 nitrogen atoms, for example, benzothiazolyl, benzisothiazolyl, phenothiazinyl or the like. Preferably, the aralkyl groups for R3, R 4 and R5 are lower alkyl group substituted with one or more aryl groups. Examples of the aralkyl group include benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, 30 phenylhexyl, benzhydryl, trityl, naphthylmethyl, tolylmethyl, xylylmethyl, mesitylmethyl and the like. 9 WO 01/05770 PCT/JP00/04687 Further, preferable examples of each substituents on the lower alkyl group, cycloalkyl group and heterocyclic group for R2 and the aralkyl group for R2, R3 and R 4 are explained in the following. Examples of the acyloxy group are lower alkanoyloxy (e.g., 5 formyloxy, acetyloxy, propionyloxy and butyryl), aroyloxy (e.g., benzoyloxy, toluoyloxy and naphthoyloxy), heterocyclic carbonyloxy (e.g., nicotinoyloxy, isonicotinoyloxy and furoyloxy) and the like. Examples of the acyloxy(lower)alkyl group are lower alkanoyloxy(lower)alkyl (e.g., formyloxymethyl, acetoxymethyl, 10 propionyloxymethyl and butyryloxymethyl), aroyloxy(lower)alkyl (e.g., benzoyloxymethyl, toluoyloxymethyl and naphthoyloxymethyl), heterocyclic carbonyloxy(lower)alkyl (e.g., nicotinoyloxymethyl, isonicotinoyloxymethyl and furoyloxymethyl), and the like. The acyl group and acyl moiety in the acyloxy, acylamino and 15 acyloxy(lower)alkyl groups are the same as those illustrated as the acyl group for R1. Examples of the acylamino group are lower alkanoylamino (e.g., formylamino, acetylamino, propionylamino and butyrylamino), aroylamino (e.g., benzoylamino, toluoylamino and naphthoylamino), heterocyclic 20 carbonylamino (e.g., nicotinoylamino, isonicotinoylamino and furoylamino) and the like. Suitable protective group in the protected hydroxy and protected hydroxy(lower)alkyl groups may include acyl, mono (or di or tri)phenyl(lower)alkyl which may have one or more suitable substituent(s) 25 (e.g., benzyl, 4-methoxybenzyl, trityl, etc.), tri-substituted silyl [e.g., tri(lower)alkylsilyl (e.g., trimethylsilyl, tert-butyldimethylsilyl, etc.), etc.], tetrahydropyranyl and the like. The protected carboxy group is the same as those illustrated as the protected carboxy group for R1. 30 The lower alkoxycarbonylamino group is methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, butoxycarbonylamino, isobutoxycarbonylamino, tert-butoxycarbonylamino, 10 WO 01/05770 PCT/JPOO/04687 pentyloxycarbonylamino, hexyloxycarbonylamino and the like. The lower alkanesulfonyl group and the lower alkanesulfonyl moiety in the lower alkanesulfonylamino group are the same as those illustrated as the lower alkanesulfonyl group for RI. Examples of the lower 5 alkanesulfonylamino group are methanesulfonylamino, ethanesulfonylamino and propanesulfonylamino. The lower alkylureido group is methylureido, ethylureido, propylureido, isopropylureido, butylureido, isobutylureido, tert-butylureido, pentylureido, hexylureido and the like. 10 The lower alkyl group and lower alkyl moieties in the hydroxy(lower)alkyl, acyloxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkyl ureido, lower alkyl amino, lower alkyl carbamoyl groups are the same as those illustrated as the lower alkyl group for RI to R5. Examples of hydroxy(lower)alkyl group are hydroxymethyl, hydroxyethyl, hydroxypropyl 15 and hydroxybutyl. Examples of protected hydroxy(lower)alkyl are acetoxymethyl, acetoxyethyl, acetoxypropyl, acetoxybutyl, benzyloxymethyl, benzyloxyethyl, 4-methoxybenzyloxymethyl, 4-methoxybenzyloxyethyl, trityloxymethyl, trityloxyethyl, trimethylsilyloxymethyl, trimethylsilyloxyethyl, tert-butyldimethylsilyloxymethyl, tert 20 butyldimethylsilyloxyethyl, tetrahydropyranyloxymethyl and tetrahydropyranyloxyethyl. Examples of lower alkyl ureido group are methylureido, ethylureido, propylureido and butylureido. Examples of lower alkyl amino group are mono- or di-lower alkylamino group such as methylamino, dimethylamino, ethylamino, diethylamino, propylamino, 25 butylamino. Examples of lower alkyl carbamoyl group are methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl and butylcarbamoyl. The lower alkyl group is substituted with one or more protected hydroxy groups having the acyl moiety as illustrated before. The lower alkylenedioxy group is methylenedioxy, ethylenedioxy, 30 propylenedioxy, isopropylidenedioxy and the like. The aralkyloxy group is benzyloxy, phenethyloxy, phenylpropoxy, phenylbutoxy, phenylpentyloxy, phenylhexyloxy, benzhydryloxy, trityloxy, 11 WO 01/05770 PCT/JPOO/04687 naphthylmethoxy, tolylmethoxy and the like. The lower alkoxy group in the lower-alkoxy-substituted aralkyloxy group is the same as those illustrated as the lower alkoxy group for R1, R3,

R

4 and R5. Examples of the lower-alkoxy-substituted aralkyloxy group 5 include 3,4-dimethoxybenzyloxy, 3,4-dimethoxyphenethyloxy, 3,4 dimethoxyphenylpropoxy, 3,4-dimethoxyphenylbutoxy, 3,4 dimethoxyphenylpentyloxy, 3,4-dimethoxyphenylhexyloxy, 4,4' dimethoxybenzhydryloxy, 4,4',4"-trimethoxytrityloxy and the like. The lower alkoxy groups in the lower-alkoxy-substituted aralkyl 10 group for R3, R 4 and R- are the same as those illustrated as the lower alkoxy group for R1, R3 to R5. Examples of the lower-alkoxy-substituted aralkyl group include 3,4-dimethoxybenzyl, 3,4-dimethoxyphenethyl, 3,4 dimethoxyphenylpropyl, 3,4-dimethoxyphenylbutyl, 3,4 dimethoxyphenylpentyl, 3,4-dimethoxyphenylhexyl, 4,4' 15 dimethoxybenzhydryl, 4,4',4"-trimethoxytrityl and the like. Furthermore, the lower alkylenedioxy group formed by the combination of two adjacent alkoxy groups for R 3 to RS is methylenedioxy, ethylenedioxy, propylenedioxy, isopropylidenedioxy and the like. When the lower alkyl group, cycloalkyl group or heterocyclic group 20 for R2 is substituted with two or three substitutes, those substitutes may be the same or different each other. Further, in the lower-alkoxy-substituted aralkyloxy group for R 2 or the lower-alkoxy-substituted aralkyl group for R3 to R5, the aralkyloxy or aralkyl group may be substituted with the two lower alkoxy which are the 25 same or different each other. It is to be noted that a hydrogen atom of CH for X can be also replaced with the substituent R1 to form CR1. The pharmaceutically acceptable salts may be, for example, a salt 30 with an alkali metal (e.g., sodium or potassium) and an alkaline earth metal (e.g., calcium or magnesium), an ammonium, an organic base (e.g., trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine or 12 WO 01/05770 PCT/JPOO/04687 dibenzylethylenediamine), an organic acid (e.g., acetic acid, benzoic acid, succinic acid, fumaric acid, maleic acid, lactic acid, citric acid, tartaric acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid, formic acid, p toluenesulfonic acid or trifluoroacetic acid), inorganic acid (e.g., hydrogen 5 chloride, hydrogen bromide, sulfuric acid or phosphoric acid), an amino acid (e.g., arginine, aspartic acid or glutamic acid) or the like. The compounds of the formula (I) and (Ia), their prodrugs and pharmaceutically acceptable salts thereof may contain one or more 10 asymmetric centers and thus they can exist as enantiomers or diastereoisomers. The compounds of the formula (I) and (Ia), their prodrugs and pharmaceutically acceptable salts thereof may also exist in tautomeric forms and this invention includes both mixtures and separate individual 15 tautomers. It is further to be noted that isomerization or rearrangement of the compounds (I) and (Ia), their prodrugs and pharmaceutically acceptable salts thereof may occur by the effect of light, acid, base or the like, and the compounds obtained as the result of said isomerization or rearrangement 20 are also included within the scope of the present invention. The compounds of the formula (I) and (Ia), their prodrugs and pharmaceutically acceptable salts thereof can be in the form of solvates, which are included within the scope of the present invention. The solvate preferably include a hydrate and an ethanolate. 25 Also included in the scope of the invention are radiolabelled derivatives of compounds of formula (I) and (Ia), their prodrugs and pharmaceutically acceptable salts thereof which are suitable for biological studies. 30 Preferred embodiments of the compound are represented by the formula (Ia), wherein Xa is nitrogen atom and Ria - R5a, ya and m are the same as those defined before, 13 WO 01/05770 PCT/JP00/04687 its prodrug or a pharmaceutically acceptable salt thereof. Another preferred embodiments of the compounds are represented by the formula (Ia), wherein 5 Ria is cyano group; nitro group; carbamoyl group; a lower alkylcarbamoyl group which may be substituted with a heterocyclic group; carboxy group; a lower alkoxycarbonyl group; a lower alkyl group; a halo(lower)alkyl group; a lower alkanoyl group; an aroyl group; or a lower alkanesulfonyl group, 10 R2a is a cycloalkyl group which has one to three substituents selected from the group consisting of hydroxy, acyloxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, lower alkoxycarbonyl, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, 15 acyloxy(lower)alkyl, lower alkylenedioxy, carbamoyl, and sulfamoyl; and Xa, ya, R3a, R4a, Rsa and m are the same as those defined before, its prodrug or a pharmaceutically acceptable salt thereof. Another preferred embodiments of the compounds are represented 20 by the formula (Ia), wherein Ria is cyano group; nitro group; carbamoyl group; a lower alkylcarbamoyl group which may be substituted with a heterocyclic group; carboxy group; a lower alkoxycarbonyl group; a lower alkyl group; a halo(lower)alkyl group; a lower alkanoyl group; an aroyl group; or a 25 lower alkanesulfonyl group,

R

2 a is a cyclohexyl group which has one to three substituents selected from the group consisting of hydroxy, lower alkanoyloxy, acyl, lower-alkoxy substituted aralkyloxy, amino, lower alkanoylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower 30 alkylureido, sulfamoylamino, lower alkoxycarbonyl, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, lower alkanoyloxy(lower)alkyl, lower alkylenedioxy, carbamoyl and sulfamoyl; 14 WO 01/05770 PCT/JP00/04687 and Xa, ya, R3a, R4a, R5a and m are the same as those defined before, its prodrug or a pharmaceutically acceptable salt thereof. 5 Another preferred embodiments of the compounds are represented by the formula (la), wherein Ria is cyano group, R2a is a cyclohexyl group which has hydroxy or lower alkanoyloxy, R3a is a hydrogen atom, 10 R 4 a is a halogen atom, R5a is a lower alkoxy group, Xa, ya and m are the same as those defined before, its prodrug or a pharmaceutically acceptable salt thereof. 15 Another preferred embodiments of the compound are represented by the formula (la), wherein Xa is CH; ya is oxygen atom or sulfur atom; Ria is cyano group; nitro group; carbamoyl group; a lower alkylcarbamoyl 20 group which may be substituted with a heterocyclic group; carboxy group; a protected carboxy group; a lower alkyl group; a halo(lower)alkyl group; an acyl group; or a lower alkanesulfonyl group, R2a is a lower alkyl group, a cycloalkyl group or a heterocyclic group, each of which has one to three substituents selected from the group consisting 25 of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, carboxy, lower alkanesulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl carbamoyl and sulfamoyl; 30 R3a, R4a and R5a are, the same or different, hydrogen atom, a halogen atom, a lower alkanoyl group, carboxy group, a protected carboxy group, carbamoyl group, nitro group, cyano group, a lower alkyl group 15 WO 01/05770 PCT/JPOO/04687 optionally substituted by hydroxy, a lower alkoxy group or a lower alkoxy- substituted aralkyl group; or two of R3a, R 4 a and R5a may combine together to form a lower alkylenedioxy group, m is an integer of 1, 5 its prodrug or a pharmaceutically acceptable salt thereof. The most preferred embodiments of the compounds are 1-(3-chloro-4-methoxybenzyl)-6-cyano-3-(trans-4-hydroxycyclohexyl)- 2,3 dihydro- 1H-imidazo[4,5-b]pyridin-2-one, 10 1-(3-bromo-4-methoxybenzyl)-6-cyano-3-(trans-4-hydroxycyclohexyl)-2,3 dihydro-1H-imidazo[4,5-bjpyridin-2-one, and 1-(3-chloro-4-methoxybenzyl)-6-cyano-3-(cis-4-hydroxycyclohexyl)-2,3 dihydro- 1H-imidazo[4,5-b]pyridin-2-one. 15 According to the present invention, the above mentioned compound (I), its prodrug or pharmaceutically acceptable salt thereof is used as a pharmaceutical composition or medicament usually in admixture with a pharmaceutically acceptable carrier or diluent. 20 Preferred embodiments of the pharmaceutical composition of the present invention contain a compound of the formula (I), wherein X is nitrogen atom and R1 - Rs, Y and n are the same as those defined before, its prodrug or a pharmaceutically acceptable salt thereof as an active ingredient in admixture with a pharmaceutically acceptable carrier or 25 diluent. Another preferred embodiments of the pharmaceutical composition contain a compound of the formula (I), wherein R2 is a cycloalkyl group which may have one to three substituents selected from the group 30 consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected 16 WO 01/05770 PCT/JPOO/04687 carboxy, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkylenedioxy, carbamoyl and sulfamoyl, and X, Y, R1, R3, R4, R5 and n are the same as those defined in the above, its prodrug or a pharmaceutically acceptable salt thereof as an active 5 ingredient in admixture with a pharmaceutically acceptable carrier or diluent. The prodrug of the compound (Ia) is intended to mean a chemically modified derivative of the compound (Ia) which itself does not show a 10 pharmacological activity but may be catalytically or non-catalytically decomposed or metabolized in human or animal bodies into its pharmacologically active form. Examples of the prodrugs of the compounds (Ia) are easily hydrolyzeable esters of the compounds (Ia). 15 According to this invention, the compound (I) or its salts can be prepared by the following process. Process I 3 4 On R -- R 20 R 1 H Z(I1l) R \rN > Nn R x N Base yx N 2 2 or its salt or its salt 25 (I1) (1) In the above formula, R1, R 2 , R3, R4, R5, X, Y and n are the same as above and Zi is a halogen atom. Some of the starting materials are novel and can be prepared by the following process. 30 ProcessA 17 WO 01/05770 PCT/JPOO/04687 R2--NH 2 R NO R I Reduction R 1 NH NO2 \ NO 2 NF2 x X N NH XNH 2 R 5 or its salt or its satt or its salt (v) (VI Cyclization R 1 H 10 X 2 or its salt (1) In the above formula, R1, R 2 , X and Y are the same as above, and Z is 15 a halogen atom or hydroxy group. The processes for preparing the starting compounds and the fmal compounds (I) and (Ia) of the present invention are explained in detail in the following. 20 Process 1 A compound (I) or its salt can be prepared by reacting a compound (II) or its salt with a compound (III). This reaction is usually carried out in the presence of an inorganic 25 or organic base. Preferable inorganic bases include an alkali metal [e.g., sodium or potassium], an alkali metal hydroxide [e.g., sodium hydroxide or potassium hydroxide], an alkali metal hydrogen carbonate [e.g., sodium hydrogen carbonate or potassium hydrogen carbonate], an alkali metal carbonate 30 [e.g., sodium carbonate], an alkaline earth metal carbonate [e.g., calcium carbonate], an alkali metal hydride [e.g., sodium hydride or potassium hydride] and the like. 18 WO 01/05770 PCT/JPOO/04687 Preferable organic bases include tri(lower)alkylamines [e.g., triethylamine or N,N-diisopropylethylamine], alkyl lithiums [e.g., methyl lithium or butyl lithium], lithium diisopropylamide, lithium hexamethyldisilazido and the like. 5 The reaction is usually carried out in a conventional solvent such as tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N dimethylformamide or any other organic solvent which does not adversely affect the reaction, or a mixture thereof. In the case where the compound (I) contains a group for R1 and/or 10 R 2 which can be converted to another group belonging to R 1 and/or R2 respectively, said compound (I) can be optionally converted to another compound (I) by a conventional method. For example, a compound (I) containing a protected carboxy group can be hydrolyzed with an alkali metal hydroxide [e.g., sodium hydroxide or 15 potassium hydroxide] to give a compound (I) containing carboxy group. Further, a compound (I) containing amino group can be reacted with metal isocyanate (e.g., potassium isocyanate) to give a compound (I) containing ureido group. Concretely, such conversions can be carried out in accordance with 20 a method described in Examples or by a similar method thereto. A pharmaceutically acceptable salt of the compound (I) and (Ia) and their prodrugs can be prepared by treating a compound (I) and (Ia) and their prodrugs with an appropriate base or acid in accordance with the 25 conventional method, respectively. ProcessA A compound (II) or its salt can be prepared by 1) aminating a compound (IV) or its salt with a compound (V) to give a 30 compound (VI) or its salt, 2) reducing a nitro group of the compound (VI) or its salt to give a compound (VII) or its salt, and then 19 WO 01/05770 PCT/JPOO/04687 3) intramolecular-cyclizing two amino groups of the compound (VII) or its salt by using a coupling agent as illustrated in Preparations or by a similar method thereto. 5 Process A-1) A compound (IV) or its salt can be aminated with an amine compound (V) to give a compound (VI) or its salt. Amination condition can vary depend on the group Z of the compound (IV) or its salt. When Z is a halogen atom such as fluorine or chlorine, amination can occur between 10 the compound (IV) or its salt and the amine compound (V) under mild heating without any particular activation of the group Z of the compound (IV) or its salt. When the group Z is hydroxy, the hydroxy group for Z needs to be activated by the reaction with SOCl 2 or mesyl chloride. Then, activated compound (IV) or its salt can be animated with the amine 15 compound (V) at room temperature or under cooling. The reaction is usually carried out in a conventional solvent such as tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide or any other organic solvent which does not adversely affect the reaction, or a mixture thereof. 20 Process A-2 A compound (VI) or its salt can be reduced by a well-known method in the art such as catalytic reduction. The reduction is carried out in a conventional manner, including a chemical reduction and a catalytic 25 reduction. Suitable reducing agents to be used in the chemical reduction are a combination of metals (e.g., tin, zinc or iron) or metallic compounds (e.g., chromium chloride or chromium acetate) and organic or inorganic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p 30 toluenesulfonic acid, hydrochloric acid or hydrobromic acid). Suitable catalysts -to be used in the catalytic reduction are conventional ones such as platinum catalysts (e.g., platinum plate, spongy 20 WO 01/05770 PCT/JPOO/04687 platinum, platinum black, colloidal platinum, platinum oxide or platinum wire), palladium catalysts (e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate or palladium on barium carbonate), nickel catalysts (e.g., 5 reduced nickel, nickel oxide or Raney nickel), cobalt catalysts (e.g., reduced cobalt or Raney cobalt), iron catalysts (e.g., reduced iron or Raney iron), copper catalysts (e.g., reduced copper, Raney copper or Ullman copper) and the like. The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, 10 ethanol, propanol, N,N-dimethylformamide, tetrahydrofuran or a mixture thereof. Additionally, in the case where the above-mentioned acid to be used in the chemical reduction is in liquid, it can also be used as a solvent. The reaction is usually carried out under cooling to warming since the reaction temperature of the reduction is not critical. 15 In the case where the compound (VI) or its salt contains a group for R1 and/or R2 which can be converted to another group belonging to R1 and/or R 2 respectively, said compound (VI) or its salt can be optionally converted to another compound (VI) or its salt by a conventional method. For example, a compound (VI) or its salt containing a hydroxy group can be 20 acylated with acyl chloride [e.g., acetyl chloride] to give a compound (VI) or its salt containing an acetoxy group. Further, a compound (VI) or its salt containing an amino group can be reacted with di-tert-butyl dicarbonate to give a compound (VI) or its salt containing a tert-butoxycarbonyl group. 25 Process A-3) A compound (VII) or its salt can be intramolecular-cyclized by a coupling agent such as 1, 1'-carbonyldiimidazole, triphosgene or 1, 1' thiocarbonyldiimidazole. The reaction is usually carried out in a conventional solvent such as tetrahydrofuran, dioxane, toluene, methylene 30 chloride, chloroform, N,N-dimethylformamide or any other organic solvent which does not adversely affect the reaction, or a mixture thereof. The reaction is usually carried out under cooling to heating since the reaction 21 WO 01/05770 PCT/JPOO/04687 temperature is not critical. The compounds (I) including the compounds (Ia) and pharmaceutically acceptable salts thereof possess inhibitory activity of 5 cGMP-PDE (especially PDE-V) known to be involved in relaxant activity of smooth muscle, bronchodilator activity, vasodilative activity, relaxant activity of the penile corpus cavernosum, inhibitory activity of smooth muscle cells proliferation, inhibitory activity of allergy, and so on. Therefore, the compounds (I) including the compounds (Ia) and 10 pharmaceutically acceptable salts thereof may be useful for the treatment or prevention of various diseases, such as angina, hypertension, pulmonary hypertension, congestive heart failure, glomerular diseases (e.g., diabetic glomerulosclerosis), renal tubulo-intestitinal diseases (e.g., nephropathy induced by tacrolimus, cyclosporin or the like), renal failure, 15 atherosclerosis, conditions of reduced blood vessel patency (e.g., post percutaneous transluminal coronary angioplasty), peripheral vascular disease, stroke, chronic reversible obstructive lung diseases (e.g., bronchitis or asthma (chronic asthma, allergic asthma)), allergic rhinitis, urticaria, glaucoma, diseases characterized by disorders of gut motility (e.g., 20 irritable bowel syndrome), erectile dysfunction (e.g., organic erectile dysfunction or psychic erectile dysfunction), female sexual dysfunction, impotence, or diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic glomerulosclerosis, diabetic dermopathy, diabetic neuropathy, diabetic cataract or diabetic retinopathy). 25 Specifically, the compounds (I) and (Ia) and pharmaceutically acceptable salts thereof are also useful for the treatment and/or prevention of micturition disorder, incontinence or storage of urine disorder (such as the ones ascribed to nerve regressive affection, inflammation, injury, neoplasm, diabetes mellitus, cerebral vascular accident, surgery, 30 prostatomegaly, urethra relaxation incompetence, dysuria). It is to be noted that improvement of sexual performance is also included in the treatment of erectile dysfunction or impotence. 22 WO 01/05770 PCT/JPOO/04687 The compounds (I) and (Ia) and their salts of the present invention have much advantages, such as stronger activity, more suitable half-life, decreased adverse effect, or the like, compared to the known anthranilic 5 acid derivatives having an inhibitory activity of cGMP-PDE, which are shown in the prior arts. In order to exhibit the usefulness of the present invention, the activities of the compounds (I) are shown in the following. 10 [I] Test Compound: The test compounds were obtained in each Example shown in Table 1. [II] Test method: cGMP-Phosphodiesterase (PDE) assay 15 Human platelet cGMP-PDE was separated from other isozymes in human platelets by a modification of the method of Thompson et. al. (see Cyclic Nucleotide Phosphodiesterase (PDE), in Methods of Enzymatic analysis, Vol 4, p 127-234, 1984). Specific inhibitory activity of PDE-V was measured by following procedure. In enzyme inhibition assays, the test 20 compounds were dissolved in DMSO and then diluted with assay buffer (50 mM Tris-HCl, 0.077 mg/ml dithiothreitol and 10 mg/ml snake venom, 1 mM EGTA, pH 8.0), at final concentrations ranging from 10-10 to 10-6 M. Assays were performed at 0.1 y M substrate ([ 3 H]-cGMP) concentration, at 30 'C for 10 minutes using enzyme dilutions which gave 10-20% hydrolysis 25 of substrate. Each assay was initiated by addition of substrate and terminated by addition of anion exchange resin (Dowex @ 1-X8, 250 mg/mg) followed by centrifugation for 10 minutes (3000 rpm, at 4 *C). Radioactivity of supernatant (3H-GMP) was assayed by liquid scintillation counting. 30 The results in enzymatic inhibitory test against human platelet PDE-V are shown in Table 1. 23 WO 01/05770 PCT/JPOO/04687 Table 1 Test Compound (Example No.) Inhibitory activity ICso (nM) Example 2(21) <10 Example 2(60) <10 Example 2(81) <10 Example 2(95) <10 Example 2(109) <10 Example 4(2) <10 Example 28 <10 Example 33 <10 As shown in the above Table 1, the compounds (I) of the present invention have superior inhibitory activity against cGMP-PDE. 5 The compound (Ia), its prodrug and its salt can be administered alone and the compound (Ia) and (I), their prodrugs and their salts can be administered in a form of a composition in admixture of a pharmaceutical acceptable carrier or diluent. 10 The active ingredient of this invention can be used in a form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains a compound (Ia) or (I), its prodrug or a pharmaceutically acceptable salt thereof as an active ingredient, in admixture with an organic or inorganic carrier or diluent suitable for external, enteral, intravenous, 15 intramuscular, parenteral or intramucous applications. The active ingredient may be compounded, for example, with the conventional non toxic, pharmaceutically acceptable carriers for ointment, cream, plaster, tablets, pellets, capsules, suppositories, solution (saline, for example), emulsion, suspension (olive oil, for example), aerosols, pills, powders, 20 syrups, injections, troches, cataplasms, aromatic waters, lotions, buccal tablets, sublingual tablets, nasal drops and any other form suitable for use. 24 WO 01/05770 PCT/JPOO/04687 The carriers which can be used are water, wax, glucose, lactose, gum acacia, gelatin, mannitol, starch paster, magnesium trisilicate, talc, corn starch, keratin, paraffin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid 5 form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The active compound is included in a pharmaceutical composition in an effective amount sufficient to produce the desired effect upon the process or condition of the diseases. The active ingredient may be compounded into, for example, 10 preparations for oral application, preparations for injection, preparations for external application, preparations for inhalation, preparations for application to mucous membranes (oral mucous membrane, fascia penis, facies urethralis penis, etc.). Mammals which may be treated by the present invention include 15 livestock mammals such as cows, horses, etc., domestic animals such as dogs, cats, rats, etc. and humans, preferably humans. While the dosage of therapeutically effective amount of a compound (I) or (Ia), its salt or a pharmaceutically acceptable salt thereof varies from and also depends upon the age and condition of each individual patient to 20 be treated, in case of the systemic administration, a daily dose of about 0.01-1000 mg, preferably 0.1-500 mg and more preferably 0.5-100 mg of the active ingredient is generally given for treating the diseases, and an average single dose of about 0.2-0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg and 500 mg is generally administered. Daily doses for chronic 25 administration in humans will be in the range of about 0.3 mg/body to 1,000 mg/body. The patents, patent applications and publications cited herein above are incorporated by reference. 25 WO 01/05770 PCT/JPOO/04687 BEST MODE FOR CARRYING OUT THE INVENTION The following Examples are given only for the purpose of illustrating the present invention in more detail. 5 Preparation 1 A mixture of 2-hydroxy-3-nitro-5-(trifluoromethyl)pyridine (5.0 g), thionyl chloride(28 mL) and N,N-dimethylformamide (3 mL) was heated under reflux for 5 hours. The reaction mixture was concentrated in vacuo, and ice was added to the residue. The mixture was extracted with a 10 mixture of ethyl acetate and tetrahydrofuran. The separated organic layer was washed with brine, dried over-magnesium sulfate, and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of n-hexane and ethyl acetate (5:1) and then to an aluminum oxide ( activated, basic) column chromatography eluting with 15 ethyl acetate to give 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (4.89 g) as a yellow oil. NMR(DMSO-d 6 , 6): 9.08(1H, d, J=2.OHz), 9.21(1H, d, J=2.OHz). Preparation 2 20 Fuming nitric acid (10.4 mL) was added dropwise to a mixture of 6-hydroxynicotinic acid (15 g) and concentrated sulfuric acid(45 mL) at 0 C. The reaction mixture was slowly heated to 459C and maintained at the same temperature for 3 hours. The mixture was poured into a mixture of ice and water. The resultant precipitate was collected by suction filtration, 25 washed with water, and air-dried to give 6-hydroxy-5-nitronicotinic acid (8.63 g) as a pale yellow solid. mp. 277-278"C NMR(DMSO-d 6 , 6): 8.37(1H, d, J=2.5Hz), 8.65(1H, d, J=2.5Hz). MS m/z: 183(M+-1). 30 Preparation 3 26 WO 01/05770 PCT/JPOO/04687 A mixture of 6-hydroxy-5-nitronicotinic acid (7.58 g) and thionyl chloride (48.1 mL) were refluxed under nitrogen atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (10 mL). The 5 resultant solution was added dropwise to a mixture of ammonium hydroxide (28 % NH 3 in water, 20 mL) and dichloromethane (10mL) at 0*C with stirring. The resulting precipitate was collected by suction filtration and washed with water to give 6-hydroxy-5-nitronicotinamide (4.97 g) as a yellow solid. 10 mp. 280-281 0 C NMR(DMSO-d 6 , 6): 6.98(1H, br), 7.67(1H, br), 8.51(1H, d, J=2.5Hz), 8.58(1H, d, J=2.5Hz). MS m/z : 182(M+-1). 15 Preparation 4 Phosphorus oxychloride (2.99 mL) was added dropwise to N,N dimethylformamide (49 mL) at 00C, and the mixture was stirred at the same temperature for 15 minutes. Then 6-hydroxy-5-nitronicotinamide (4.9 g) was added portionwise to the mixture, and the reaction mixture was stirred 20 at 500C for an hour. Water was added to the reaction mixture at 00C, and the resulting precipitate was collected by filtration in vacuo. The obtained solid was washed with water to give 5-cyano-2-hydroxy-3-nitropyridine (3.17 g) as a pale brown solid. mp. 294.5-295*C 25 NMR(DMSO-d 6 , 6) 8.69(1H, d, J=2.5Hz), 8.79(lH, d, J=2.5Hz). MS m/z: 164(M+-1). Preparation 5 To a suspension of 4-chloro-3-nitrobenzoic acid (10 g) and 30 potassium carbonate (7.54 g) in N,N-dimethylformamide (100 mL) was added methyl iodide (3.24 mL) at room temperature under nitrogen 27 WO 01/05770 PCT/JPOO/04687 atmosphere. The reaction mixture was stirred at room temperature for 3.5 hours. The reaction mixture was diluted with ethyl acetate and washed successively with 1 N-hydrochloric acid, water, an aqueous saturated sodium hydrogencarbonate solution and brine. The organic layer was 5 dried over anhydrous magnesium sulfate and concentrated in vacuo. The residual solid was washed with diisopropyl ether to give methyl 4-chloro 3-nitrobenzoate (9.51 g) as a yellow solid. mp. 78-809C NMR(DMSO-d 6 , 6): 3.91(3H, s), 7.95(1H, d, J=8.5Hz), 8.20(1H, dd, J=8.5, 10 2.0Hz), 8.54(1H, d, J=2.OHz). Preparation 6 To a solution of 4-fluoro-3-nitrobenzotrifluoride (4 g) in N,N dimethylformamide (40 mL) was added trans-4-aminocyclohexanol (6.61 g), 15 and the mixture was stirred at 90'C for 4 hours under nitrogen atmosphere. After cooling to room temperature, water was added to the mixture. The resulting precipitate was collected by filtration and washed with water to give 4-(trans-4-hydroxycyclohexylamino)-3-nitrobenzotrifluoride (5.4 g) as a yellow solid. 20 mp. 136-137*C NMR(DMSO-d 6 , 6): 1.27-1.53(4H, m), 1.78-1.89(2H, m), 1.94-2.05(2H, m), 3.41-3.55(1H, m), 3.61-3.75(1H, m), 4.65(1H, d, J=4.5Hz), 7.33(1H, d, J=9.OHz), 7.78(1H, dd, J=9.0, 2.0Hz), 8.14(1H, d, J=7.5Hz), 8.31(1H, d, J=2.OHz). 25 MS m/z: 303(M+-1). Preparation 7 The following compounds described in (1) to (25) were obtained in a manner similar to Preparation 6. 30 (1) 4-(trans-4-Hydroxycyclohexylamino)-3-nitrobenzonitrile 28 WO 01/05770 PCT/JPOO/04687 mp. 181-183 0 C NMR(DMSO-d 6 , 6): 1.26-1.51(4H, m), 1.76-1.87(2H, m), 1.90-2.01(2H, m), 3.40-3.54(1H, m), 3.61-3.75(1H, m), 4.64(1H, d, J=4.OHz), 7.28(1H, d, J=9.OHz), 7.82(1H, dd, J=8.0, 2.5Hz), 8.20(1H, d, J=8.OHz), 8.5 1(1H, d, 5 J=2.5Hz). MS m/z: 260(M+-1). (2) 4-(trans-4-Hydroxycyclohexylamino)-3-nitroacetophenone mp. 182.5-183'C 10 NMR(DMSO-d 6 , 6): 1.27-1.52(4H, m), 1.78-1.88(2H, m), 1.95-2.04(2H, m), 2.52(3H, s), 3.39-3.54(1H, m), 3.63-3.76(1H, m), 4.65(1H, d, J=4.OHz), 7.23(1H, d, J=9.OHz), 8.01(1H, dd, J=9.0, 2.5Hz), 8.24(1H, d, J=7.5Hz), 8.63(1H, d, J=2.5Hz). MS m/z: 277(M+-1). 15 (3) 2-(trans-4-Hydroxycyclohexylamino)-5-(methylsulfonyl)nitrobenzene mp. 211.5-213'C NMR(DMSO-d 6 , 6): 1.28-1.53(4H, m), 1.78-1.88(2H, m), 1.93-2.04(2H, m), 3.21(3H, s), 3.42-3.55(1H, m), 3.64-3.77(1H, m), 4.65(1H, d, J=4.OHz), 20 7.36(1H, d, J=9.5Hz), 7.90(1H, dd, J=9.5, 2.5Hz), 8.24(1H, d, J=8.OHz), 8.50(1H, d, J=2.5Hz). MS m/z: 313(M+-1). (4) 4-(trans-4-Hydroxycyclohexylamino)-3-nitrobenzophenone 25 mp. 184-1859C NMR(DMSO-d 6 , 6): 1.29-1.55(4H, m), 1.80-1.90(2H, m), 1.95-2.06(2H, m), 3.42-3.55(1H, m), 3.65-3.79(1H, m), 4.65(1H, d, J=4.OHz), 7.32(1H, d, J=9.5Hz), 7.57(1H, t, J=7.5Hz), 7.58(1H, d, J=7.5Hz), 7.63-7.73(3H, m), 7.94(1H, dd, J=9.5, 2.0Hz), 8.29(1H, d, J=7.5Hz), 8.43(1H, d, J=2.OHz). 30 MS m/z: 339(M+-1). 29 WO 01/05770 PCT/JPOO/04687 (5) 4-[((R)-2-Hydroxy-1 -methylethyl) amino] -3-nitrobenzonitrile NMR(DMSO-d 6 , 6): 1.21 (3H, d, J=7.5 Hz), 3.45-3.63 (2H, m), 3.90-4.05 (1H, m), 5.14 (1H, t, J=5 Hz), 7.25 (1H, d, J=8 Hz), 7.82 (1H, dd, J=8, 2 Hz), 8.45-8.56 (2H, m). 5 (6) 4-[((S)-2-Hydroxy-1 -methylethyl) amino] -3-nitrobenzonitrile NMR(DMSO-d 6 , 6): 1.21 (3H, d, J=7.5 Hz), 3.45-3.63 (2H, m), 3.90-4.05 (1H, m), 5.14 (1H, t, J=5 Hz), 7.25 (1H, d, J=8 Hz), 7.82 (1H, dd, J=8, 2 Hz), 8.45-8.56 (2H, m). 10 (7) 4- [(trans-4-Formamidocyclohexyl) amino] -3-nitrobenzonitrile NMR(DMSO-d 6 , 6): 1.30-1.60 (4H, m), 1.76-1.92 (2H, m), 1.92-2.06 (2H, m), 3.55-3.78 (2H, m), 7.32 (1H, d, J=8 Hz), 7.82 (1H, dd, J=8, 2 Hz), 7.95 (1H, s), 8.06 (1H, d, J=8 Hz), 8.21 (1H, d, J=8 Hz), 8.52 (1H, d, J=2 Hz). 15 (8) 4-[2-Hydroxy-1-(hydroxymethyl)ethylamino]-3-nitrobenzonitrile NMR(DMSO-d 6 , 6): 3.51-3.66 (4H, m), 3.78-3.90 (1H, m), 5.06 (2H, t, J=5 Hz), 7.30 (1H, d, J=8 Hz), 7.83 (1H, dd, J=8, 2 Hz), 8.52 (1H, d, J=2 Hz), 8.67 (1H, d, J=8 Hz). 20 (9) 4-(1,1-Dimethyl-2-hydroxyethylamino)-3-nitrobenzonitrile NMR(CDC1 3 , 6):1.51 (6H, s), 1.88 (1H, br), 3.72 (2H, d, J=5 Hz), 7.17 (1H, d, J=8 Hz), 7.54 (1H, dd, J=8, 2 Hz), 8.53 (1H, d, J=2 Hz), 8.96 (1H, br). 25 (10) 4-(1,1-Dimethyl-2-hydroxyethylamino)-3-nitrobenzotrifluoride NMR(CDC1 3 , 6): 1.51 (6H, s), 1.84 (1H, t, J=5 Hz), 3.74 (2H, d, J=5 Hz), 7.20 (1H, d, J=8 Hz), 7.56 (1H, dd, J=8, 2 Hz), 8.48 (1H, d, J=2 Hz), 8.78 (1H, br s). 30 (11) 4-[(S)-1-tert-Butoxycarbonylpyrrolidin-3-ylamino]-3-nitrobenzonitrile NMR(CDC1 3 , 6 ):1.48 (9H, s), 2.05 (1H, br), 2.28-2.42 (1H, m), 3.26-3.48 (1H, 30 WO 01/05770 PCT/JPOO/04687 m), 3.48-3.64 (2H, m), 3.75-3.86 (1H, m), 4.24 (1H, br), 6.94 (1H, d, J=8 Hz), 7.64 (1H, d, J=8 Hz), 8.46 (1H, d, J=5 Hz), 8.53 (1H, s-like). (12) 4-[(R)-1-tert-Butoxycarbonylpyrrolidin-3-ylamino]-3-nitrobenzonitrile 5 NMR(CDC1 3 , 6):1.48 (9H, s), 2.05 (1H, br), 2.28-2.42 (1H, m), 3.26-3.48 (1H, m), 3.48-3.64 (2H, m), 3.75-3.86 (1H, m), 4.24 (1H, br), 6.94 (1H, d, J=8 Hz), 7.64 (1H, d, J=8 Hz), 8.46 (1H, d, J=5 Hz), 8.53 (1H, s-like). (13) 4-[1-(Hydroxymethyl)cyclopentylamino]-3-nitrobenzonitrile 10 NMR(CDC1 3 , 6): 1.66-1.93 (5H, m), 1.93-2.11 (4H, m), 3.80 (2H, d, J=4 Hz), 7.06 (1H, d, J=8 Hz), 7.53 (1H, dd, J=8, 2 Hz), 8.53 (1H, d, J=2 Hz), 8.77 (1H, br s). (14) 4-Cyclopentylamino-3-nitrobenzonitrile 15 NMR(CDC1 3 , 6): 1.59-1.91 (6H, m), 2.06-2.23 (2H, m), 3.94-4.06 (1H, m), 6.95 (1H, d, J=8 Hz), 7.57 (1H, dd, J=8, 2 Hz), 8.44 (1H, br s), 8.51 (1H, d, J=2 Hz). (15) 3-Nitro-4-(tetrahydro-4H-pyran-4-ylamino)benzonitrile 20 NMR(CDC1 3 , 6): 1.63-1.83 (2H, m), 2.01-2.14 (2H, m), 3.51-3.64 (2H, m), 3.70-3.86 (1H, m), 3.98-4.10 (2H, m), 6.94 (1H, d, J=8 Hz), 7.60 (1H, dd, J=8, 2 Hz), 8.45 (1H, br d, J=8 Hz), 8.53 (1H, d, J=2 Hz). (16) 4-Cyclohexylamino-3-nitrobenzonitrile 25 NMR(CDC1 3 , 6): 1.23-1.51 (5H, m), 1.61-1.75 (1H, m), 1.75-1.92 (2H, m), 1.96-2.14 (2H, m), 3.54 (1H, br s), 6.92 (1H, d, J=8 Hz), 7.55 (1H, d, J=8 Hz), 8.45 (1H, br), 8.50 (1H, s). MS m/z: 244.2(M+-1). 30 (17) 4-tert-Butylamino-3-nitrobenzonitrile NMR(CDC13, 6): 1.54 (9H, s), 7.15 (1H, d, J=8 Hz), 7.54 (1H, dd, J=8, 2 Hz), 31 WO 01/05770 PCT/JPOO/04687 8.53 (1H, d, J=2 Hz), 8.73 (1H, br s). MS m/z: 218.2(M+-1). (18) 4-Cycloheptylamino-3-nitrobenzonitrile 5 NMR(CDC1 3 , 6): 1.46-1.82 (10H, m), 1.94-2.11 (2H, m), 3.64-3.79 (1H, m), 6.84 (1H, d, J=8 Hz), 7.56 (1H, dd, J=8, 2 Hz), 8.41-8.56 (2H, m). (19) 4- [((S)-I -Ethyl-2-hydroxyethyl) amino] -3-nitrobenzonitrile NMR(CDCl 3 , 6): 1.03 (3H, t, J=7.5 Hz), 1.61-1.91 (3H, m), 3.65-3.90 (3H, 10 m), 7.02 (1H, d, J=8 Hz), 7.56 (1H, dd, J=8, 2 Hz), 8.52 (1H, d, J=2 Hz), 8.56 (1H, br). (20) 4- [((R) -1 -Ethyl-2-hydroxyethyl) amino] -3-nitrobenzonitrile NMR(CDC1 3 , 6): 1.03 (3H, t, J=7.5 Hz), 1.61-1.91 (3H, m), 3.65-3.89 (3H, 15 m), 7.02 (1H, d, J=8 Hz), 7.56 (1H, dd, J=8, 2 Hz), 8.52 (1H, d, J=2 Hz), 8.55 (1H, br). (21) 4-[1-(tert-Butoxycarbonyl)piperidin-4-ylamino]-3-nitrobenzonitrile NMR(CDCl3, 6): 1.48 (9H, s), 1.50-1.71 (2H, m), 1.99-2.13 (2H, m), 2.96 20 3.11 (2H, m), 3.61-3.77 (1H, m), 3.99-4.13 (2H, m), 6.94 (1H, d, J=8 Hz), 7.60 (1H, dd, J=8, 2 Hz), 8.44 (1H, d, J=8 Hz), 8.53 (1H, d, J=2 Hz). MS m/z: 345.2(M+-1). (22) 4-(t-3,t-4-Dihydroxy-r-1-cyclohexylamino)-3-nitrobenzonitrile 25 NMR(DMSO-d 6 , 6): 1.37-1.86 (4H, m), 1.86-2.06 (2H, m), 3.44-3.55 (1H, m), 3.75-3.85 (1H, m), 3.85-4.03 (1H, m), 4.50 (1H, d, J=5 Hz), 4.58 (1H, d, J=3 Hz), 7.16 (1H, d, J=8 Hz), 7.84 (1H, dd, J=8, 2 Hz), 8.20 (1H, d, J=8 Hz), 8.51 (1H, s). 30 (23) 4-(c-3,c-4-Dihydroxy-r-1-cyclohexylamino)-3-nitrobenzonitrile NMR(DMSO-d 6 , 6): 1.47-1.50 (1H, m), 1.50-1.91 (5H, m), 3.50-3.60 (1H, m), 32 WO 01/05770 PCT/JPOO/04687 3.72-3.80 (1H, m), 3.87-3.97 (1H, m), 4.50 (1H, d, J=5 Hz), 4.94 (1H, d, J=5 Hz), 7.20 (1H, d, J=8 Hz), 7.80 (1H, dd, J=8, 2 Hz), 8.51 (1H, d, J=2 Hz), 9.25 (1H, br). 5 (24) 4-(3-Hydroxypropylamino)-3-nitrobenzonitrile NMR (CDC1 3 , 6) : 1.95-2.07 (2H, m), 3.54 (2H, q, J=5 Hz), 3.88 (2H, q, J=5 Hz), 6.96 (1H, d, J=8 Hz), 7.60 (1H, d, J=8 Hz), 8.51 (1H, s), 8.69 (1H, br peak). MS (ES-) m/z: 220.1(M+-1). 10 (25) 4-[2-(N,N-Dimethylamino)ethylamino]-3-nitrobenzonitrile NMR (CDC1 3 , 6) : 2.65 (2H, t, J=5 Hz), 3.37 (2H, q, J=5 Hz), 6.88 (1H, d, J=8 Hz), 7.58 (1H, dd, J=8, 2 Hz), 8.51 (1H, d, J=2 Hz), 8.80 (1H, br peak). 15 Preparation 8 To a solution of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1 g) in N,N-dimethylformamide (10 mL) was added 2-amino-2-methyl-1-propanol (1.18 g) at 0 0 C. The mixture was stirred at room temperature for 3.5 hours under nitrogen atmosphere. The mixture was diluted with ethyl acetate 20 and washed successively with water and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to give 2-(1,1 -dimethyl-2-hydroxyethylamino) -3-nitro-5-(trifluoromethyl)pyridine (1.23 g) as a yellow oil. NMR(DMSO-d 6 , 6): 1.46(6H, s), 3.53(2H, d, J=5.5Hz), 5.33(1H, t, J=5.5Hz), 25 8.63(1H, d, J=2.OHz), 8.81(1H, d, J=2.OHz), 8.82(1H, s). MS m/z: 278(M+-1). Preparation 9 The following compounds described in (1) and (9) were obtained in a 30 manner similar to Preparation 8. 33 WO 01/05770 PCT/JPOO/04687 (1) 2-[((R)-2-Hydroxy- 1 -methylethyl)amino]-3-nitro-5 (trifluoromethyl)pyridine NMR(DMSO-d 6 , 6): 1.24(3H, d, J=6.5Hz), 3.56(2H, t, J=4.5Hz), 4.39 4.51(1H, m), 5.07(1H, t, J=4.5Hz), 8.60(1H, d, J=8.0Hz), 8.65(1H, d, 5 J=2.0Hz), 8.82(1H, d, J=2.OHz). MS m/z: 264(M+-1). (2) 2- [(trans-4-Formamidocyclohexyl) amino] -3 -nitro-5 (trifluoromethyl)pyridine 10 mp. 225-226"C NMR(DMSO-d 6 , S): 1.24-1.40(2H, m), 1.51-1.68(2H, m), 1.79-2.02(4H, m), 3.55-3.70(1H, m), 4.12-4.27(1H, m), 7.95(1H, d, J=1.OHz), 8.00(1H, dd, J=7.5, 1.0Hz), 8.40(1H, d, J=7.5Hz), 8.63(1H, d, J=2.5Hz), 8.82(1H, d, J=2.5Hz). 15 MS m/z: 331(M+-1). (3) 5-Cyano-2- [((R) -2-hydroxy- 1 -methylethyl) amino] -3-nitropyridine mp. 114-115cC NMR(DMSO-d 6 , 65): 1.23(3H, d, J=7.OHz), 3.54(2H, t, J=5.OHz), 4.38 20 4.51(1H, m), 5.07(1H, t, J=5.OHz), 8.69(1H, d, J=7.5Hz), 8.83(1H, d, J=2.OHz), 8.90(1H, d, J=2.OHz). MS m/z : 221(M+-1). (4) 2-(trans-4-hydroxycyclohexylamino)-3-nitro-5 25 methoxycarbonylpyridine mp. 117-118*C NMR(DMSO-d 6 , 6): 1.20-1.37(2H, m), 1.45-1.61(2H, m), 1.79-1.98(4H, m), 3.39-3.52(1H, m), 3.85(3H, s), 4.11-4.25(1H, m), 4.62(1H, d, J=4.OHz), 8.45(1H, d, J=8.OHz), 8.73(1H, d, J=2.OHz), 8.92(1H, d, J=2.OHz). 30 MS m/z: 294(M+-1) 34 WO 01/05770 PCT/JPOO/04687 (5) 5-Cyano-2-(trans-4-hydroxycyclohexylamino)-3-nitropyridine mp. 157-1589C NMR(DMSO-d 6 , 6): 1.20-1.35(2H, m), 1.45-1.61(2H, m), 1.80-1.95(4H, m), 3.39-3.50(1H, m), 4.08-4.23(1H, m), 4.63(1H, d, J=4.OHz), 8.47(1H, d, 5 J=8.OHz), 8.83(1H, d, J=2.OHz), 8.88(1H, d, J=2.OHz). MS m/z : 261(M+- 1). (6) 2- ((R) -1- tert-Butoxycarbonylpyrrolidin-3-ylamino) -3-nitro-5 (trifluoromethyl)pyridine 10 NMR(DMSO-d 6 , 6): 1.38(9H, s), 2.00-2.12(1H, m), 2.16-2.29(1H, m), 3.24 3.49(3H, m), 3.60-3.69(1H, m), 4.71-4.86(1H, m), 8.50(1H, d, J=4.5Hz), 8.64(1H, s), 8.86(1H, s). MS m/z: 375(M+-1). 15 (7) To a solution of 2-chloro-5-cyano-3-nitropyridine (3.5g)(obtained according to International Patent Application No.W09410171) in N,N dimethylformamide (35 mL) was added trans-4-aminocyclohexanol (4.39 g) at 0 *C. The mixture was stirred at room temperature under nitrogen atmosphere for 45 minutes and diluted with ethyl acetate. The mixture 20 was washed with water (3 times) and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual solid was washed with diethyl ether to give 5-cyano-2-(trans-4 hydroxycyclohexylamino)-3-nitropyridine (3.38 g) as a yellow sold. mp. 157-158*C 25 NMR(DMSO-d 6 , 6): 1.20-1.35 (2H, m), 1.45-1.61 (2H, m), 1.80-1.95 (4H, m), 3.39-3.50 (1H, m), 4.08-4.23 (1H, m), 4.63 (1H, d, J= 4.0 Hz), 8.47 (1H, d, J= 8.0 Hz), 8.83 (1H, d, J= 2.0 Hz), 8.88 (1H, d, J= 2.0 Hz). MS m/z: 261(M+-1). 30 (8) 6-(Benzimidazol-5-yl)amino-5-nitronicotinonitrile NMR(DMSO-d 6 , 6): 7.64(1H, dd, J=8, 1Hz), 8.83(1H, d, J=8Hz), 8.09(1H, d, 35 WO 01/05770 PCT/JPOO/04687 J=1Hz), 8.83(1H, d, J=lHz), 9.05(1H, d, J=lHz), 9.40(1H, s). (9) 6-(1H-Indol-5-ylamino)-5-nitronicotinonitrile mp. 198-198.59C 5 NMR(DMSO-d 6 , 6): 6.42-6.46(1H, m), 7.17(1H, d, J=8.5Hz), 7.37-7.34(1H, m), 7.40(1H, d, J=8.5Hz), 7.68-7.71(1H, m), 8.76(1H, s), 8.98(1H, s), 10.40(1H, s), 11.19(1H, brs). MS m/z: 278(M+-1). 10 Preparation 10 To a solution of 5-cyano-2-hydroxy-3-nitropyridine (600 mg) in 6mL of dichloromethane containing triethylamine(0.557 mL) was added methanesulfonyl chloride (0.295 mL) under stirring at O'C. The reaction mixture was stirred at the same temperature for 30 minutes, and then 15 trans-4-aminocyclohexanol (1.26 g) was added to the mixture at 0 0 C. After stirring at room temperature for 2 hours, the mixture was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a preparative silica gel column chromatography eluting with 5 % methanol in chloroform. The obtained 20 substance was triturated with diisopropyl ether to give 5-cyano-2-(trans-4 hydroxycyclohexylamino)-3-nitropyridine (198.9 mg) as a yellow solid. mp. 147-147.5C NMR(DMSO-d 6 , 6): 1.19-1.36(2H, m), 1.44-1.61(2H, m), 1.79-1.96(4H, m), 3.38-3.51(1H, m), 4.08-4.22(1H, m), 4.62(1H, d, J=4.OHz), 8.47(1H, d, 25 J=7.5Hz), 8.83(1H, d, J=2.5Hz), 8.88(1H, d, J=2.5Hz). MS m/z : 261(M+-1). Preparation 11 To a solution of 4-fluoro-3-nitrobenzotrifluoride (900 mg) in 30 pyridine (9 mL) was added trans-4-formamidocyclohexylamine (734 mg). The mixture was stirred at 100"C under nitrogen atmosphere for 5 hours. 36 WO 01/05770 PCT/JPOO/04687 After cooling to room temperature, water was added to the mixture. The resulting precipitate was collected by filtration and washed with water to give 4- [(trans-4-formamidocyclohexyl) amino] -3-nitrobenzotrifluoride (1.24 g) as a yellow solid. 5 mp. 174-175*C NMR(DMSO-d 6 , 6): 1.32-1.58(4H, m), 1.78-1.90(2H, m), 1.95-2.06(2H, m), 3.56-3.77(2H, m), 7.37(1H, d, J=9.5Hz), 7.77(1H, dd, J=9.5, 2.5Hz), 7.96(1H, s), 8.06(1H, d, J=7.5Hz), 8.14(1H, d, J=7.5Hz), 8.32(1H, d, J=2.5Hz). MS m/z : 330(M+-1). 10 Preparation 12 The following compounds described in (1) to (22) were obtained in a manner similar to Preparation 11. 15 (1) 3-Amino-4-cyclopentylamino-1-nitrobenzene mp. 137-1389C NMR(DMSO-d 6 , 8): 1.47-1.77(6H, m), 1.94-2.07(2H, m), -3.80-3.93(1H, m), 5.23(2H, s), 5.73(1H, d, J=6.5Hz), 6.49(1H, d, J=8.5Hz), 7.38(1H, d, J=3.OHz), 7.51(1H, dd, J=8.5, 3.0Hz). 20 MS m/z: 220(M+-1) (2) 3-Amino-4-(trans-4-hydroxycyclohexylamino)-1-nitrobenzene mp. 156-157"C NMR(DMSO-d 6 , 8): 1.19-1.40(4H, m), 1.81-2.00(4H, m), 3.29-3.48(2H, m), 25 4.60(1H, d, J=4.OHz), 5.18(2H, s), 5.59(1H, d, J=7.5Hz), 6.52(1H, d, J=9.OHz), 7.38(1H, d, J=2.5Hz), 7.50(1H, dd, J=9.0, 2.5Hz). MS m/z : 250(M+- 1). (3) 5-Chloro-2-(trans-4-hydroxycyclohexylamino)-1-nitrobenzene 30 mp. 124.5-126'C NMR(DMSO-d6, 8): 1.26-1.46(4H, m), 1.76-1.87(2H, m), 1.93-2.03(2H, m), 37 WO 01/05770 PCT/JPOO/04687 3.41-3.51(1H, m), 3.54-3.66(1H, m), 4.63(1H, d, J=4.OHz), 7.20(1H, d, J=9.5Hz), 7.55(1H, dd, J=9.5, 2.5Hz), 7.90(1H, d, J=8.OHz), 8.05(1H, d, J=2.5Hz). 5 (4) Methyl 4-(trans-4-hydroxycyclohexylamino)-3-nitrobenzoate mp. 177-179C NMR(DMSO-d 6 , 6): 1.27-1.54(4H, m), 1.78-1.90(2H, m), 1.94-2.05(2H, m), 3.41-3.55(1H, m), 3.60-3.74(1H, m), 3.83(3H, s), 4.65(1H, d, J=4.OHz), 7.24(1H, d, J=9.OHz), 7.96(1H, dd, J=9.0, 2.0Hz), 8.22(1H, d, J=7.5Hz), 10 8.62(1H, d, J=2.OHz). (5) 4-(trans-4-Hydroxycyclohexylamino)-3-nitroanisole mp. 142-142.59C NMR(DMSO-d 6 , 6): 1.26-1.45(4H, m), 1.74-2.07(4H, m), 3.39-3.64(2H, m), 15 3.74(3H, s), 4.62(1H, d, J=4.OHz), 7.14(1H, d, J=9.5Hz), 7.26(1H, dd, J=9.5, 2.5Hz), 7.47(1H, d, J=2.5Hz), 7.88(1H, d, J=7.5Hz). (6) 2- (trans-4-Hydroxycyclohexylamino) -3-nitro-5 (trifluoromethyl)pyridine 20 mp. 125-125.5 0 C NMR(DMSO-d 6 , 6): 1.20-1.36(2H, m), 1.45-1.61(2H, m), 1.80-1.98(4H, m), 3.39-3.52(1H, m), 4.08-4.24(1H, m), 4.63(1H, d, J=4.OHz), 8.37(1H, d, J=7.5Hz), 8.63(1H, d, J=1.OHz), 8.83(1H, d, J=1.OHz). MS m/z: 304(M+-1). 25 (7) 2-Cyclopentylamino-3-nitro-5-(trifluoromethyl)pyridine NMR(DMSO-d 6 , 6): 1.50-1.78(6H, m), 1.97-2.09(2H, m), 4.52-4.64(1H, m),8.46(1H, d, J=7.OHz), 8.63(1H, d, J=1.OHz), 8.83(1H, d, J=1.OHz). MS m/z: 274(M+-1) 30 (8) 4-(trans-2-Hydroxycyclopentylamino)-3-nitrobenzotrifluoride 38 WO 01/05770 PCT/JPOO/04687 mp. 92-92.59C NMR(DMSO-d 6 , 6): 1.49-1.96(5H, m), 2.16-2.30(1H, m), 3.77-3.88(1H, m), 3.95-4.06(1H, m), 5.17(1H, d, J=4.5Hz), 7.39(1H, d, J=9.5Hz), 7.82(1H, d, J=9.5Hz), 8.20(1H, d, J=7.5Hz), 8.32(1H, s). 5 MS m/z: 289(M+-1). (9) 4-[(S)-1-tert-Butoxycarbonylpyrrolidin-3-ylamino]-3 nitrobenzotrifluoride mp. 95.5-97C 10 NMR(DMSO-d 6 , 6): 1.40(9H, s), 1.93-2.07(1H, m), 2.20-2.33(1H, m), 3.23 3.47(3H, m), 3.65-3.74(1H, m), 4.36-4.48(1H, m), 7.36(1H, d, J=9.5Hz), 7.84(1H, dd, J=9.5, 2.0Hz), 8.18(1H, d, J=7.OHz), 8.33(1H, d, J=2.OHz). MS m/z: 374(M+-1). 15 (10) 4-(1H-Benzimidazol-5-ylamino)-3-nitrobenzotrifluoride mp. 229-230.5C NMR(DMSO-d 6 , 6): 7.07(1H, brs), 7.19(lH, d, J=8.0Hz), 7.55(1H, brs), 7.65(lH, brs), 7.7 1(1H, dd, J=8.0, 2.0Hz), 8.30(1H, s), 8.38(1H, d, J=2.OHz), 9.92(1H, s), 12.60(1H, s). 20 MS m/z: 323(M++1). (11) 4-(trans-4-Hydroxycyclohexylamino)-3-nitrotoluene NMR(DMSO-d 6 , 6): 1.25-1.43(4H, m), 1.76-1.89(2H, m), 1.92-2.05(2H, m), 2.22(3H, s), 3.39-3.63(2H, m), 4.63(1H, d, J=4.OHz), 7.06(1H, d, J=9.OHz), 25 7.38(1H, dd, J=9.0, 2.5Hz), 7.83(1H, d, J=7.5Hz), 7.86(1H, d, J=2.5Hz). (12) 4-[1-(Hydroxymethyl)cyclopentylamino]-3-nitrobenzotrifluoride NMR(DMSO-d 6 , 6): 1.57-2.01(8H, m), 3.56(2H, d, J=5.5Hz), 5.18(1H, t, J=5.5Hz), 7.24(1H, d, J=9.5Hz), 7.76(1H, dd, J=9.5, 2.5Hz), 8.34(1H, d, 30 J=2.5Hz), 8.61(1H, s). MS m/z: 303(M+-1). 39 WO 01/05770 PCT/JPOO/04687 (13) 4-[((R) -2-Hydroxy- 1 -methylethyl) amino] -3-nitrobenzotrifluoride mp. 96-979C NMR(DMSO-d 6 , 6): 1.23(3H, d, J=6.5Hz), 3.47-3.64(2H, m), 3.90-4.01(1H, 5 m), 5.14(1H, t, J=5.OHz), 7.31(1H, d, J=9.5Hz), 7.79(1H, dd, J=9.5, 2.0Hz), 8.32(1H, d, J=2.OHz), 8.43(1H, d, J=7.5Hz). MS m/z: 263(M+-1). (14) 4-(tert-Butylamino)-3-nitrobenzotrifluoride 10 mp. 167-1689C NMR(DMSO-d 6 , 6): 1.49(9H, s), 7.47(lH, d, J=9.5Hz), 7.74(1H, dd, J=9.5, 2.5Hz), 8.34(1H, d, J=2.5Hz), 8.45(1H, s). MS m/z : 261(M+-1). 15 (15) 4-(2-Hydroxyethylamino)-3-nitrobenzotrifluoride mp. 76-77"C NMR(DMSO-d 6 , 6): 3.49(2H, q, J=5.5Hz), 3.66(2H, q, J=5.5Hz), 5.03(1H, t, J=5.5Hz), 7.28(1H, d, J=9.5Hz), 7.80(1H, dd, J=9.5, 2.5Hz), 8.32(1H, d, J=2.5Hz), 8.56(1H, t, J=5.5Hz). 20 MS m/z: 249(M+-1). (16) 3-Nitro-4-(tetrahydro-4H-pyran-4-ylamino)benzotrifluoride mp. 113-114"C NMR(DMSO-d 6 , 6): 1.55-1.70(2H, m), 1.89-1.99(2H, m), 3.42-3.54(2H, m), 25 3.83-3.92(2H, m), 3.91-4.03(1H, m), 7.39(1H, d, J=9.OHz), 7.78(1H, dd, J=9.0, 2.5Hz), 8.17(1H, d, J=7.5Hz), 8.33(1H, d, J=2.5Hz). MS m/z: 289(M+-1). (17) 4-Isopropylamino-3-nitrobenzotrifluoride 30 mp. 107-108 0 C NMR(DMSO-d 6 , 6): 1.29(6H, d, J=6.5Hz), 4.02(1H, m), 7.28(1H, d, 40 WO 01/05770 PCT/JPOO/04687 J=9.5Hz), 7.80(1H, dd, J=9.5, 2.5Hz), 8.13(1H, d, J=6.5Hz), 8.32(1H, d, J=2.5Hz). (18) 4-Butylamino-3-nitrobenzotrifluoride 5 NMR(DMSO-d 6 , 6): 0.93(3H, t, J=7.OHz), 1.31-1.45(2H, m), 1.55-1.66(2H, m), 3.37-3.46(2H, m), 7.24(1H, d, J=9.OHz), 7.78(1H, dd, J=9.0, 2.5Hz), 8.31(1H, d, J=2.5Hz), 8.49(1H, t, J=5.5Hz). MS m/z: 261(M+-1) 10 (19) 4-Cyclohexylamino-3-nitrobenzotrifluoride mp. 82-839C NMR(DMSO-d 6 , 6): 1.17-1.50(5H, m), 1.54-1.76(3H, m), 1.89-2.00(2H, m), 3.66-3.78(1H, m), 7.32(1H, d, J=9.OHz), 7.77(1H, dd, J=9.0, 2.5Hz), 8.22(1H, d, J=7.5Hz), 8.32(1H, d, J=2.5Hz). 15 (20) 4-[(trans-4-Aminocyclohexyl)amino]-3-nitrobenzonitrile NMR(DMSO-d 6 , 6): 1.11-1.29 (2H, m), 1.35-1.51 (2H, m), 1.72-1.85 (2H, m), 1.90-2.03 (2H, m), 2.53-2.65 (1H, m), 3.56-3.72 (1H, m), 7.26 (1H, d, J=8 Hz), 7.81 (1H, dd, J=8, 2 Hz), 8.20 (1H, d, J=8 Hz), 8.51 (1H, d, J=2 Hz). 20 (21) 4- [(trans-4-Aminocyclohexyl)amino]-3-nitro-benzotrifluoride mp. 86-879C NMR(DMSO-d 6 , 6): 1.12-1.29(2H, m), 1.34-1.50(2H, m), 1.74-1.85(2H, m), 1.93-2.04(2H, m), 2.54-2.65(1H, m), 3.56-3.70(1H, m), 7.32(1H, d, J=9.OHz), 25 7.76(1H, dd, J=9.0, 2.5Hz), 8.13(1H, d, J=8.OHz), 8.30(1H, d, J=2.5Hz). MS m/z: 302(M+-1). (22) 4-(Benzimidazol-5-ylamino)-3-nitrobenzonitrile NMR(DMSO-d 6 , 6): 3.17 (1H, s),6.96 (1H, d, J=8 Hz),7.16 (1H, dd, J=8,2 30 Hz),7.57 (1H, s),7.66-7.74 (2H, m),8.30 (1H, s),8.59 (1H, d, J=2 Hz). 41 WO 01/05770 PCT/JPOO/04687 Preparation 13 To a solution of 4-(trans-4-hydroxycyclohexylamino)-3 nitrobenzonitrile (1.0 g), acetic acid (345 mg) and diethyl azodicarboxylate (2.17 g, 40% solution in toluene) in anhydrous tetrahydrofuran (25 mL) was 5 added portionwise triphenylphosphine (1.31 g) at 0"C, and the mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated in vacuo and the residue was subjected to a silica gel column chromatography eluting with a mixture of n-hexane and ethyl acetate (5:1 to 3:1) and then chloroform. The obtained substance was triturated with methanol to give 10 4-(cis-4-acetoxycyclohexylamino)-3-nitrobenzonitrile (530 mg) as yellow powders. NMR(CDC1 3 , 6): 1.66-1.86 (4H, m), 1.86-2.01 (4H, m), 2.10 (3H, s), 3.66 (1H, br), 5.00 (1H, br), 6.93 (1H, d, J=8 Hz), 7.60 (1H, dd, J=8, 2 Hz), 8.50 (1H, br), 8.53 (1H, d, J=2 Hz). 15 Preparation 14 A mixture of 4-(trans-4-hydroxycyclohexylamino)-3 nitrobenzotrifluoride (4.0 g) and 10% palladium on activated carbon (400 mg) in a mixture of methanol (20 mL) and dioxane(20 mL) was stirred under 20 hydrogen atmosphere (3 atm) at ambient temperature for 4 hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1). The obtained substance was triturated with petroleum ether to give 3 25 amino-4-(trans-4-hydroxycyclohexylamino)benzotrifluoride (3.5 g) as a pale orange solid. mp. 112-113.5*C NMR(CDCl 3 , 6): 1.19-1.55(5H, m), 1.99-2.22(4H, m), 3.21-3.39(3H, m), 3.56(1H, brs), 3.64-3.77(1H, m), 6.64(1H, d, J=8.5Hz), 6.94(1H, d, J=2.OHz), 30 7.08(1H, dd, J=8.5, 2.0Hz). MS m/z : 275(M++ 1). 42 WO 01/05770 PCT/JPOO/04687 Preparation 15 The following compounds described in (1) to (62) were obtained in a manner similar to Preparation 14. 5 (1) 3-Amino-4-(trans-4-hydroxycyclohexylamino)benzonitrile mp. 116-1179C NMR(DMSO-d 6 , 6): 1.14-1.40(4H, m), 1.78-2.03(4H, m), 3.18-3.30(1H, m), 3.38-3.49(1H, m), 4.58(1H, d, J=4.OHz), 4.98(2H, s), 5.05(1H, d, J=7.OHz), 10 6.49(1H, d, J=8.5Hz), 6.75(1H, d, J=1.5Hz), 6.90(1H, dd, J=8.5, 1.5Hz). (2) 3-Amino-4-[((R )-2-hydroxy-1-methylethyl)amino]benzotrifluoride mp. 113-114.5"C NMR(DMSO-d 6 , 6): 1.15(3H, d, J=6.5Hz), 3.25-3.56(3H, m), 4.66-4.79(2H, 15 m), 4.93(2H, s), 6.52(1H, d, J=9.OHz), 6.79(1H, d, J=9.OHz), 6.80(1H, s). MS m/z: 233(M+-1). (3) 3-Amino-4-(trans-4-hydroxycyclohexylamino)acetophenone mp. 177-178*C 20 NMR(DMSO-d 6 , 6): 1.15-1.38(4H, m), 1.80-2.00(4H, m), 2.35(3H, s), 3.21 3.34(1H, m), 3.38-3.48(1H, m), 4.58(1H, d, J=4.5Hz), 4.74(2H, s), 4.99(1H, d, J=7.5Hz), 6.45(1H, d, J=8.5Hz), 7.13(1H, d, J=2.OHz), 7.21(1H, dd, J=8.5, 2.0Hz). MS m/z: 249(M++1). 25 (4) 3-Amino-4-[(trans-4-formamidocyclohexyl)amino]benzotrifluoride NMR(DMSO-d 6 , 6): 1.17-1.47(4H, m), 1.79-1.90(2H, m), 1.96-2.07(2H, m), 3.17-3.34(1H, m), 3.54-3.68(1H, m), 4.77(1H, d, J=8.OHz), 4.94(2H, s), 6.53(1H, d, J=8.5Hz), 6.77(1H, d, J=8.5Hz), 6.78(lH, s), 7.95(1H, s), 8.03 30 (1H, d, J=7.5Hz). MS m/z: 302(M++1). 43 WO 01/05770 PCT/JPOO/04687 (5) 1 -Amino- 5-chloro-2- (trans-4-hydroxycyclohexylamino)benzene mp. 150-1519C NMR(DMSO-d 6 , 65): 1.07-1.35(4H, m), 1.76-2.03(4H, m), 3.02-3.19(1H, m), 5 3.30-3.49(1H, m), 4.19(1H, d, J=7.5Hz), 4.55(1H, d, J=4.OHz), 4.82(2H, s), 6.38(1H, d, J=8.5Hz), 6.44(1H, dd, J=8.5, 2.5Hz), 6.52(1H, d, J=2.5Hz). (6) Methyl 3-amino-4-(trans-4-hydroxycyclohexylamino)benzoate mp. 172-172.5"C 10 NMR(DMSO-d 6 , 6): 1.15-1.39(4H, m), 1.80-2.00(4H, m), 3.19-3.30(1H, m), 3.38-3.49(1H, m), 3.71(3H, s), 4.58(1H, d, J=4.OHz), 4.75(2H, s), 4.89(1H, d, J=7.5Hz), 6.46(1H, d, J=8.5Hz), 7.15(1H,.d, J=2.5Hz), 7.18(1H, dd, J=8.5, 2.5Hz). MS m/z: 265(M++1) 15 (7) 3-Amino-4-(trans-4-hydroxycyclohexylamino)anisole NMR(DMSO-d 6 , 6): 1.04-1.30(4H, m), 1.75-1.97(4H, m), 2.89-3.04(1H, m), 3.32-3.46(1H, m), 3.53-3.64(1H, m), 3.58(3H, s), 4.52(lH, d, J=4.OHz), 4.58(2H, s), 6.04(1H, dd, J=8.5, 2.5Hz), 6.19(1H, d, J=2.5Hz), 6.37(1H, d, 20 J=8.5Hz). (8) 2-(trans-4-Acetoxycyclohexylamino)-3-amino-5 (trifluoromethyl)pyridine mp. 162.5-164 0 C 25 NMR(DMSO-d 6 , 6I): 1.26-1.54(4H, m), 1.87-2.08(4H, m), 2.00(3H, s), 3.84 3.99(1H, m), 4.56-4.69(1H, m), 5.20(2H, s), 6.00(1H, d, J=7.OHz), 6.82(1H, d, J=1.5Hz), 7.67(1H, d, J=1.5Hz). MS m/z: 318(M++1). 30 (9) 3-Amino-2-cyclopentylamino-5-(trifluoromethyl)pyridine NMR(DMSO-d 6 , 6): 1.39-1.77(6H, m), 1.87-2.04(2H, m), 4.24-4.37(lH, m), 44 WO 01/05770 PCT/JPOO/04687 5.20(2H, s), 6.07(1H, d, J=7.OHz), 6.80(1H, d, J=2.OHz), 7.66(1H, d, J=2.0Hz). MS m/z : 246(M++ 1). 5 (10) 3-Amino-4- (trans-2-acetoxycyclopentylamino)benzotrifluoride NMR(DMSO-d 6 , 6): 1.50-1.85(4H, m), 1.91-2.23(2H, m), 2.03(3H, s), 3.70 3.82(1H, m), 4.87-4.95(1H, m), 4.97(1H, d, J=6.OHz), 5.01(2H, s), 6.60(1H, d, J=8.5Hz), 6.78(1H, d, J=8.5Hz), 6.80(1H, s). MS m/z: 303(M++1). 10 (11) 3-Amino-4-[(S)-1-tert-butoxycarbonylpyrrolidin-3 ylamino]benzotrifluoride NMR(DMSO-d 6 , 6): 1.40(9H, s), 1.77-1.91(1H, m), 2.08-2.21(1H, m), 3.09 3.23(1H, m), 3.30-3.45(2H, m), 3.55-3.63(1H, m), 3.97-4.10(1H, m), 15 5.03(2H, s), 5.09(1H, d, J=6.OHz), 6.53(1H, d, J=8.5Hz), 6.78(1H, d, J=8.5Hz), 6.79(1H, s). MS m/z: 346(M++1). (12) 3-Amino-4-(1H-benzimidazol-5-ylamino)benzotrifluoride 20 NMR(DMSO-d 6 , 6): 5.19(2H, s), 6.78(1H, dd, J=8.5, 2.0Hz), 6.92(1H, d, J=8.5Hz), 6.98(lH, d, J=2.OHz), 7.00-7.28(3H, m), 7.49(1H, d, J=8.5Hz), 8.07(1H, brs). MS m/z : 291(M+- 1). 25 (13) 2-(2-Acetoxy-1,1-dimethylethylamino)-3-amino-5 (trifluoromethyl)pyridine NMR(DMSO-d 6 , 6): 1.41(6H, s), 2.01(3H, s), 4.39(2H, s), 5.30(2H, s), 5.55(1H, s), 6.85(1H, d, J=2.OHz), 7.65(1H, d, J=2.OHz). MS m/z: 292(M++1). 30 (14) 4-(trans-4-Acetoxycyclohexylamino)-3-aminotoluene 45 WO 01/05770 PCT/JPOO/04687 mp. 119-1209C NMR(DMSO-d 6 , 8): 1.16-1.32(2H, m), 1.37-1.52(2H, m), 1.86-2.04(4H, m), 1.99(3H, s), 2.07(3H, s), 3.08-3.21(1H, m), 3.90(1H, d, J=8.OHz), 4.42(2H, s), 4.55-4.67(1H, m), 6.27(1H, dd, J=8.0, 2.5Hz), 6.32(1H, d, J=2.5Hz), 6.36(1H, 5 d, J=8.OHz). MS m/z: 263(M++1). (15) 4-[1-(Acetoxymethyl)cyclopentylamino]-3-aminobenzotrifluoride NMR(DMSO-d 6 , 6): 1.55-1.75(4H, m), 1.77-2.00(4H, m), 2.00(3H, s), 10 4.20(2H, s),4.60(1H, s), 5.04(2H, s), 6.61(1H, d, J=8.OHz), 6.75(1H, dd, J=8.0, 2.5Hz), 6.80(1H, d, J=2.5Hz). MS m/z: 315(M+-1). (16) 2-[((R)-2-Acetoxy- 1 -methylethyl)amino]-3-amino-5 15 (trifluoromethyl)pyridine NMR(DMSO-d 6 , 8): 1.20(3H, d, J=6.5Hz), 2.00(3H, s), 4.05(2H, d, J=5.5Hz), 4.34-4.46(1H, m), 5.22(2H, s), 6.11(1H, d, J=7.OHz), 6.85(1H, d, J=2.OHz), 7.67(1H, d, J=2.OHz). MS m/z: 278(M++1). 20 (17) 1-(trans-4-Acetoxycyclohexylamino)-2-amino-4 (methylsulfonyl)benzene mp. 230-231 0 C NMR(DMSO-d 6 , 6): 1.25-1.59(4H, m), 1.89-2.07(4H, m), 2.00(3H, s), 25 2.98(3H, s), 3.25-3.44(1H, m), 4.56-4.69(1H, m), 5.02(lH, d, J=7.5Hz), 5.04(2H, s), 6.58(1H, d, J=8.5Hz), 6.99(1H, d, J=2.5Hz), 7.00(1H, dd, J=8.5, 2.5Hz). MS m/z : 325(M+- 1). 30 (18) 4- [ ((R) -2-Acetoxy- 1 -methylethyl) amino] -3-aminobenzotrifluoride NMR(DMSO-d 6 , 6): 1.19(3H, d, J=6.5Hz), 2.02(3H, s), 3.72-3.83(1H, m), 46 WO 01/05770 PCT/JPOO/04687 3.91(1H, dd, J=10.0, 7.0Hz), 4.10(1H, dd, J=10.0, 5.5Hz), 4.85(1H, d, J=7.5Hz), 4.97(2H, s), 6.58(1H, d, J=8.OHz), 6.78(1H, d, J=8.OHz), 6.80(1H, s). MS m/z: 277(M++1). 5 (19) 2- (trans-4-Acetoxycyclohexylamino) -3-amino-5-cyanopyridine mp. 237.5-2389C NMR(DMSO-d 6 , 6): 1.27-1.54(4H, m), 1.88-2.05(4H, m), 2.00(3H, s), 3.85 3.99(1H, m), 4.56-4.68(1H, m), 5.23(2H, s), 6.27(1H, d, J=7.OHz), 6.79(1H, d, 10 J=2.OHz), 7.79(1H, d, J=2.OHz). MS m/z: 275(M++1). (20) 4-(trans-4-Acetoxycyclohexylamino)-3-aminobenzophenone mp. 215-215.59C 15 NMR(DMSO-d 6 , 6): 1.27-1.58(4H, m), 1.90-2.08(4H, m), 2.00(3H, s), 3.34 3.46(1H, m), 4.57-4.69(1H, m), 4.85(2H, s), 5.15(1H, d, J=7.5Hz), 6.53(1H, d, J=8.5Hz), 6.97(1H, dd, J=8.5, 2.0Hz), 7.09(1H, d, J=2.OHz), 7.45-7.61(5H, m). MS m/z: 353(M++1). 20 (21) 3-Amino-4-(tert-butylamino)benzotrifluoride NMR(DMSO-d 6 , 6): 1.34(9H, s), 4.31(1H, s), 4.96(2H, s), 6.77(2H, s), 6.83(1H, s). MS m/z: 233(M++1). 25 (22) 4-(2-Acetoxyethylamino)-3-aminobenzotrifluoride NMR(DMSO-d 6 , 6): 2.03(3H, s), 3.37(2H, q, J=5.5Hz), 4.18(2H, t, J=5.5Hz), 4.95(2H, s), 5.20(1H, t, J=5.5Hz), 6.55(1H, d, J=8.5Hz), 6.80(1H, d, J=8.5Hz), 6.81(1H, s). 30 MS m/z: 263(M++ 1). 47 WO 01/05770 PCT/JPOO/04687 (23) 3-Amino-4-(tetrahydro-4H-pyran-4-ylamino)benzotrifluoride NMR(DMSO-d 6 , 6): 1.35-1.50(2H, m), 1.86-1.95(2H, m), 3.37-3.46(2H, m), 3.49-3.59(1H, m), 3.84-3.93(2H, m), 4.83(1H, d, J=7.5Hz), 4.97(2H, s), 6.57(1H, d, J=9.5Hz), 6.77(1H, d, J=9.5Hz), 6.79(1H, s). 5 MS m/z : 261(M++1). (24) 3-Amino-4-(isopropylamino)benzotrifluoride NMR(DMSO-d 6 , 6): 1.17(6H, d, J=6.5Hz), 3.62(1H, m), 4.74(1H, d, J=7.5Hz), 4.94(2H, s), 6.48(1H, d, J=8.5Hz), 6.79(1H, s), 6.79(1H, d, 10 J=8.5Hz). MS m/z: 219(M++1). (25) 3-Amino-4-(butylamino)benzotrifluoride NMR(DMSO-d 6 , 6): 0.92(3H, t, J=7.5Hz), 1.33-1.46(2H, m), 1.53-1.64(2H, 15 m), 3.02-3.11(2H, m), 4.93(2H, s), 4.98(1H, t, J=5.5Hz), 6.45(1H, d, J=9.OHz), 6.77(1H, s), 6.79(1H, d, J=9.OHz). MS m/z: 233(M++1). (26) 3-Amino-4-(cyclohexylamino)benzotrifluoride 20 mp. 73.5-759C NMR(DMSO-d 6 , 6): 1.10-1.44(5H, m), 1.56-1.79(3H, m), 1.90-2.02(2H, m), 3.18-3.35(1H, m), 4.73(1H, d, J=7.5Hz), 4.94(2H, s), 6.49(1H, d, J=9.OHz), 6.77(1H, d, J=9.OHz), 6.78(1H, s). MS m/z: 259(M++1) 25 (27) 2- [(trans-4-Formamidocyclohexyl) amino] -3-amino-5 (trifluoromethyl)pyridine mp. 262.5-2639C NMR(DMSO-d 6 , 6): 1.21-1.39(4H, m), 1.75-1.88(2H, m), 1.94-2.05(2H, m), 30 3.55-3.67(1H, m), 3.79-3.94(1H, m), 5.19(2H, s), 6.00(1H, d, J=7.5Hz), 6.81(1H, d, J=2.5Hz), 7.66(1H, s), 7.95(1H, s), 7.99(1H, m). 48 WO 01/05770 PCT/JPOO/04687 MS m/z: 303(M++1). (28) 3-Amino-4-[((R)-2-hydroxy-1-methylethyl)amino]benzonitrile NMR(DMSO-d 6 , 6): 1.16 (3H, d, J=7.5 Hz), 3.23-3.40 (1H, m), 3.40-3.60 5 (2H, m), 4.76 (1H, t, J=5 Hz), 4.97 (2H, s), 5.03 (1H, d, J=7.5 Hz), 6.50 (1H, d, J=8 Hz), 6.77 (1H, d, J=2 Hz), 6.91 (1H, dd, J=8, 2 Hz). (29) 3-Amino-4-[((S)-2-hydroxy-1-methylethyl)amino]benzonitrile NMR(DMSO-d 6 , 6): 1.15 (3H, d, J=7.5 Hz), 3.25-3.40 (1H, m), 3.40-3.60 10 (2H, m), 4.76 (1H, t, J=5 Hz), 4.97 (2H, s), 5.02 (1H, d, J=7.5 Hz), 6.50 (1H, d, J=8 Hz), 6.77 (1H, d, J=2 Hz), 6.91 (1H, dd, J=8, 2 Hz). (30) 3-Amino-4-[(trans-4-formamidocyclohexyl)amino]benzonitrile NMR(DMSO-d 6 , 6): 1.18-1.44 (4H, m), 1.74-1.91 (2H, m), 1.91-2.08 (2H, m), 15 3.14-3.35 (1H, m), 3.50-3.70 (1H, m), 4.98 (2H, s), 5.10 (1H, d, J=8 Hz), 6.52 (1H, d, J=8 Hz), 6.76 (1H, d, J=2 Hz), 6.89 (1H, dd, J=8, 2 Hz), 7.94 (1H, s), 8.04 (1H, d, J=8 Hz). (31) 3-Amino-4-[(2,2-dimethyl-1,3-dioxan-5-yl)amino]benzonitrile 20 NMR(DMSO-d 6 , 6): 1.36 (3H, s), 1.40 (3H, s), 3.56-3.72 (3H, m), 3.90-4.00 (2H, m), 5.01 (2H, s), 5.18 (1H, d, J=8 Hz), 6.58 (1H, d, J=8 Hz), 6.81 (1H, d, J=2 Hz), 6.90 (1H, dd, J=8, 2 Hz). (32) 4-(2-Acetoxy-1,1-dimethylethylamino)-3-aminobenzonitrile 25 NMR(DMSO-d 6 , 6): 1.34 (6H, s), 2.03 (3H, s), 4.10 (2H, s), 4.62 (1H, s), 5.05 (2H, s), 6.78 (1H, d, J=8 Hz), 6.83 (1H, d, J=2 Hz), 6.90 (1H, dd, J=8, 2 Hz). (33) 4-[((R)-2-Acetoxy-1 -methylethyl) amino] -3-aminobenzonitrile NMR(DMSO-d 6 , 6): 1.18 (3H, d, J=7 Hz), 2.01 (3H, s), 3.76-3.97 (2H, m), 30 4.04-4.13 (1H, m), 5.01 (2H, s), 5.17 (1H, d, J=8 Hz), 6.58 (1H, d, J=8 Hz), 6.78 (1H, d, J=2 Hz), 6.91 (1H, dd, J=8, 2 Hz). 49 WO 01/05770 PCT/JPOO/04687 (34) 4- [((S) -2-Acetoxy- 1 -methylethyl) amino] -3-aminobenzonitrile NMR(DMSO-d 6 , 6): 1.19 (3H, d, J=7 Hz), 2.01 (3H, s), 3.75-3.97 (2H, m), 4.05-4.13 (1H, m), 5.01 (2H, s), 5.17 (1H, d, J=8 Hz), 6.58 (1H, d, J=8 Hz), 5 6.78 (1H, d, J=2 Hz), 6.91 (1H, dd, J=8, 2 Hz). (35) 4-(2-Acetoxy-1,1-dimethylethylamino)-3-aminobenzotrifluoride NMR(DMSO-d 6 , 6): 1.31 (6H, s), 2.03 (3H, s), 4.07 (2H, s), 4.29 (1H, s), 5.04 (2H, s), 6.73-6.89 (3H, m). 10 (36) 3-Amino-4-[(S)-i-tert-butoxycarbonylpyrrolidin-3 ylamino]benzonitrile NMR(CDCl 3 , 6): 1.47 (9H, s), 1.95 (1H, br), 2.16-2.32 (1H, m), 3.20-3.59 (6H, m), 4.00-4.11 (2H, m), 6.59 (1H, d, J=8 Hz), 6.96 (1H, s-like), 7.16 (1H, 15 d, J=8 Hz). (37) 3-Amino-4-[(R)-1-tert-butoxycarbonylpyrrolidin-3 ylamino]benzonitrile NMR(DMSO-d 6 , 6): 1.36-1.44 (9H, m), 1.78-1.91 (1H, m), 2.09-2.24 (1H, m), 20 3.08-3.22 (1H, m), 3.29-3.45 (2H, m), 3.52-3.65 (1H, m), 4.00-4.14 (1H, m), 5.08 (2H, s), 5.39 (1H, d, J=7 Hz), 6.53 (1H, d, J=8 Hz), 6.78 (1H, d, J=2 Hz), 6.93 (1H, dd, J=8, 2 Hz). (38) 3-Amino-4-[[trans-4-(N-tert 25 butoxycarbonylamino)cyclohexyl]amino]benzonitrile NMR(DMSO-d 6 , 6): 1.14-1.34 (4H, m), 1.38 (9H, s), 1.76-1.87 (2H, m), 1.94-2.03 (2H, m), 3.23 (2H, br), 4.97 (2H, s), 5.08 (1H, d, J=8 Hz), 6.49 (1H, d, J=8 Hz), 6.75 (1H, d, J=2 Hz), 6.81 (1H, d, J=8 Hz), 6.90 (1H, dd, J=8, 2 Hz). 30 (39) 3-Amino-4-(cis-4-acetoxycyclohexylamino)benzonitrile 50 WO 01/05770 PCT/JPOO/04687 NMR(DMSO-d 6 , 5): 1.48-1.89 (8H, m), 2.02 (3H, s), 3.43 (1H, br), 4.86 (1H, br), 5.03 (2H, s), 5.12 (1H, d, J=7.5 Hz), 6.52 (1H, d, J=7.5 Hz), 6.77 (1H, d, J=2 Hz), 6.90 (1H, dd, J=8, 2 Hz). 5 (40) 4-(trans-4-Acetoxycyclohexylamino)-3-aminobenzonitrile NMR(DMSO-d 6 , 6): 1.22-1.40 (2H, m), 1.40-1.60 (2H, m), 1.87-2.06 (7H, m), 3.29-3.45 (1H, m), 4.56-4.69 (1H, m), 4.90 (2H, s), 5.10 (1H, d, J=7.5 Hz), 6.52 (1H, d, J=8 Hz), 6.76 (iH, d, J=2 Hz), 6.90 (1H, dd, J=8, 2 Hz). 10 (41) 4-[1-(Acetoxymethyl)cyclopentylamino]-3-aminobenzonitrile NMR(DMSO-d 6 , 6): 1.55-1.76 (4H, m), 1.76-2.03 (7H, m), 4.19 (2H, s), 4.88 (1H, s), 5.09 (2H, s), 6.58 (1H, d, J=8 Hz), 6.79 (1H, d, J=2 Hz), 6.86 (1H, dd, J=8, 2 Hz). 15 (42) 3-Amino-4-cyclopentylaminobenzonitrile NMR(DMSO-d 6 , 6): 1.42-1.75 (6H, m), 1.90-2.04 (2H, m), 3.73-3.84 (1H, m), 5.02 (2H, s), 5.19 (1H, d, J=5 Hz), 6.46 (1H, d, J=8 Hz), 6.74 (1H, d, J=2 Hz), 6.90 (1H, dd, J=8, 2 Hz). 20 (43) 3-Amino-4-(tetrahydro-4H-pyran-4-ylamino)benzonitrile NMR(DMSO-d 6 , 5): 1.35-1.51 (2H, m), 1.84-1.94 (2H, m), 3.36-3.49 (2H, m), 3.49-3.63 (1H, m), 3.82-3.93 (2H, m), 5.01 (2H, s), 5.15 (1H, d, J=7.5 Hz), 6.56 (1H, d, J=8 Hz), 6.78 (1H, d, J=2 Hz), 6.90 (1H, dd, J=8, 2 Hz). 25 (44) 3-Amino-4-cyclohexylaminobenzonitrile NMR(DMSO-d 6 , 5): 1.08-1.26 (3H, m), 1.26-1.45 (2H, m), 1.56-1.66 (1H, m), 1.66-1.79 (2H, m), 1.89-2.00 (2H, m), 4.98 (2H, s), 5.07 (1H, d, J=8 Hz), 6.48 (1H, d, J=8 Hz), 6.76 (1H, d, J=2 Hz), 6.89 (1H, dd, J=8, 2 Hz). 30 (45) 3-Amino-4-tert-butylaminobenzonitrile NMR(CDC1 3 , 6): 1.36 (9H, s), 4.65 (1H, s), 4.99 (2H, s), 6.74 (1H, d, J=8 Hz), 51 WO 01/05770 PCT/JPOO/04687 6.81 (1H, d, J=2 Hz), 6.90 (1H, dd, J=8, 2 Hz). (46) 3-Amino-4-cycloheptylaminobenzonitrile NMR(DMSO-d 6 , 6): 1.39-1.71 (10H, m), 1.80-1.95 (2H, m), 5.00 (2H, s), 5 5.08 (1H, d, J=8 Hz), 6.37 (1H, d, J=8 Hz), 6.75 (1H, d, J=2 Hz), 6.90 (1H, dd, J=8, 2 Hz). (47) 4- [((S) -2-Acetoxy- 1 -ethylethyl) amino] -3 -amin obenzonitrile NMR(CDC1 3 , 6): 1.01 (3H, t, J=7.5 Hz), 1.53-1.79 (2H, m), 2.04 (3H, s), 2.69 10 (3H, br), 3.55-3.66 (1H, m), 4.06 (1H, dd, J= 11, 5 Hz), 4.28 (1H, dd, J= 11, 5 Hz), 6.64 (1H, d, J=8 Hz), 6.95 (1H, d, J=2 Hz), 7.15 (1H, dd, J=8, 2 Hz). (48) 4-[((R)-2-Acetoxy-1 -ethylethyl)amino] -3-aminobenzonitrile

NMR(CDC

3 , 6): 1.01 (3H, t, J=7.5 Hz), 1.51-1.80 (2H, m), 2.04 (3H, s), 2.93 15 (3H, br), 3.55-3.67 (1H, m), 4.06 (1H, dd, J=11, 5 Hz), 4.29 (1H, dd, J=11, 5 Hz), 6.62 (1H, d, J=8 Hz), 6.95 (1H, d, J=2 Hz), 7.15 (1H, dd, J=8, 2 Hz). (49) 3-Amino-4-[1-(tert-butoxycarbonyl)piperidin-4-ylamino]benzonitrile NMR(DMSO-d 6 , 6): 1.16-1.35 (2H, m), 1.40 (9H, s), 1.84-1.95 (2H, m), 20 2.79-2.98 (2H, m), 3.84-3.96 (2H, m), 4.98 (2H, s), 5.12 (1H, d, J=7.5 Hz), 6.56 (1H, d, J=8 Hz), 6.75 (1H, d, J=2 Hz), 6.90 (1H, dd, J=8, 2 Hz). (50) 3-Amino-4-(t-3,t-4-isopropylidenedioxy-r-1 cyclohexylamino)benzonitrile 25 NMR(DMSO-d 6 , 6): 1.11-1.29 (4H, m), 1.44 (3H, s), 1.53-1.70 (2H, m), 1.75-1.93 (2H, m), 2.14-2.24 (1H, m), 3.55 (1H, br), 4.05-4.15 (1H, m), 4.26-4.34 (1H, m), 5.00 (2H, s), 5.11 (1H, d, J=8 Hz), 6.45 (1H, d, J=8 Hz), 6.77 (1H, d, J=2 Hz), 6.93 (1H, dd, J=8, 2 Hz). 30 (51) 3-Amino-4-(c-3,c-4-isopropylidenedioxy-r-1 cyclohexylamino)benzonitrile 52 WO 01/05770 PCT/JPOO/04687 NMR(DMSO-d 6 , 6): 1.27 (3H, s), 1.31-1.52 (5H, m), 1.64-1.86 (2H, m), 1.95-2.07 (2H, m), 3.24-3.39 (1H, m), 4.06-4.22 (2H, m), 4.94 (2H, s), 5.16 (1H, d, J=8 Hz), 6.50 (1H, d, J=8 Hz), 6.77 (1H, d, J=2 Hz), 6.90 (1H, dd, J=8, 2 Hz). 5 (52) 2-f ((R) -2-Acetoxy- 1 -methylethyl) amino] -3-amino- 5-cyanopyridine NMR(DMSO-d 6 , 6): 1.19(3H, d, J=6.5Hz), 2.00(3H, s), 3.97-4.10(2H, m), 4.35-4.47(1H, m), 5.25(2H, s), 6.38(1H, d, J=7.OHz), 6.82(1H, d, J=2.OHz), 7.78(1H, d, J=2.OHz). 10 (53) 3-Amino-2-(trans-4-hydroxycyclohexylamino)-5 methoxycarbonylpyridine mp. 213.5-2159C NMR(DMSO-d 6 , 6): 1.16-1.35(4H, m), 1.77-2.00(4H, m), 3.36-3.47(1H, m), 15 3.73(3H, s), 3.81-3.95(1H, m), 4.55(1H, d, J=4.OHz), 4.97(2H, s), 6.01(1H, d, J=7.OHz), 7.11(1H, d, J=2.OHz), 8.01(1H, d, J=2.OHz). MS m/z: 266(M++ 1). (54) 3-Amino-4- [ [trans-4-(N- tert-butoxycarbonylamino)cyclohexyl] amino] 20 benzotrifluoride NMR(DMSO-d 6 , 6): 1.11-1.35(4H, m), 1.38(9H, s), 1.76-1.86(2H, m), 1.95 2.04(2H, m), 3.13-3.28(2H, m), 4.75(1H, d, J=7.5Hz), 4.92(2H, s), 6.50(1H, d, J=9.OHz), 6.73-6.84(3H, m). 25 (55) 3-Amino-5-cyano-2-(trans-4-hydroxycyclohexylamino)pyridine NMR(DMSO-d 6 , 6): 1.16-1.34(4H, m), 1.77-1.98(4H, m), 3.36-3.49(1H, m), 3.78-3.92(1H, m), 4.57(1H, d, J=4.5Hz), 5.20(2H, s), 6.22(1H, d, J=7.OHz), 6.77(1H, d, J=2.OHz), 7.78(1H, d, J=2.OHz). MS m/z : 231(M+-1). 30 (56) 3-Amino-2-((R)-1-tert-butoxycarbonylpyrrolidin-3-ylamino)-5 53 WO 01/05770 PCT/JPOO/04687 (trifluoromethyl)pyridine NMR(DMSO-d 6 , 6): 1.38(9H, s), 1.80-1.95(1H, m), 2.08-2.22(1H, m), 3.10 3.45(3H, m), 3.55-3.68(1H, m), 4.40-4.53(1H, m), 5.27(2H, s), 6.31(1H, d, J=4.5Hz), 6.86(1H, s), 7.69(1H, s). 5 MS m/z: 345(M+-1). (57) To a solution of 5-cyano-2-(trans-4-hydroxycyclohexylamino)-3 nitropyridine (3.35 g) in methanol (17 mL) and dioxane (17 mL) was added 10 % palladium on activated carbon (383 mg) under nitrogen atmosphere. 10 The mixture was shaken at room temperature under hydrogen atmosphere (3 atm) for 3 hours. The reaction mixture was filtered through a celite pad. The filtrate was concentrated in vacuo to give 3-amino-5-cyano-2-(trans-4 hydroxycyclohexylamino)pyridine (3.15 g) as a brown amorphous. NMR(DMSO-d 6 , 6): 1.16-1.34 (4H, m), 1.77-1.98 (4H, m), 3.36-3.49 (1H, 15 m) , 3.78-3.92 (1H, m), 4.57 (1H, d, J= 4.5 Hz), 5.20 (2H, s), 6.22 (1H, d, J= 7.0 Hz), 6.77 (1H, d, J= 2.0 Hz), 7.78 (1H, d, J = 2.0 Hz). MS m/z : 231(M+-1). (58) 5-Amino-6-(benzimidazol-5-yl)aminonicotinonitrile 20 NMR(DMSO-d 6 , 6): 7.10(lH, d, J=lHz), 7.72(1H, d, J=8Hz), 7.79(lH, dd, J=8, 1Hz), 7.93(1H, d, J=1Hz), 8.49(1H, d, J=1Hz), 8.97(1H, br s), 9.27(1H, s). (59) 5-Amino-6-(1H-indol-5-ylamino)nicotinonitrile 25 mp. 175.5-176.5*C NMR(DMSO-d 6 , 6): 5.49(2H, s), 6.38(1H, m), 6.97(1H, d, J=2.OHz), 7.22(1H, dd, J=8.5, 2.0Hz), 7.30(1H, d, J=2.OHz), 7.33(1H, d, J=8.5Hz), 7.83(1H, d, J=2.OHz), 7.85(lH, m), 8.22(1H, s), 10.98(1H, s). 30 (60) 3-Amino-4-(benzimidazol-5-ylamino)benzonitrile NMR(DMSO-d 6 , 6) : 5.22 (2H, s), 6.88 (1H, dd, J=8,2 Hz), 6.94-7.04 (3H, m), 54 WO 01/05770 PCT/JPOO/04687 7.24 (1H, s), 7.46 (1H, s), 7.55 (1H, d, J=8 Hz), 8.12 (1H, s). (61) 4-(3-Acetoxypropylamino)-3-aminobenzonitrile NMR(DMSO-d 6 , 6 ):1.89 (2H, m), 2.01 (3H, s), 3.17 (2H, q, J=5 Hz), 4.10 5 (2H, t, J=5 Hz), 4.97 (2H, s), 5.39 (1H, t, J=5 Hz), 6.47 (1H, d, J=8 Hz), 6.77 (1H, d, J=2 Hz), 6.92 (1H, dd, J=8,2 Hz). (62) 3-Amino-4-[2-(N,N-dimethylamino)ethylamino]benzonitrile NMR(DMSO-d 6 , 8): 2.18 (6H, s), 2.48 (2H, t, J=5 Hz), 3.18 (2H, q, J=5 Hz), 10 4.93 (2H, s), 5.25 (1H, t, J=5 Hz), 6.50 (1H, d, J=8 Hz), 6.81 (1H, d, J=2 Hz), 6.98 (1H, dd, J=8,2 Hz). MS (ES+) m/z: 205.4 (M++1). Preparation 16 15 To a solution of 2-(1, 1-dimethyl-2-hydroxyethylamino)-3-nitro-5 (trifluoromethyl)pyridine (1.2 g) in pyridine (12 mL) was added acetic anhydride (0.811 mL), and the mixture was stirred at room temperature under nitrogen atmosphere for 4 hours. The resulting mixture was concentrated in vacuo, and the residue was partitioned between ethyl 20 acetate and water. The separated organic layer was washed successively with 1 N-hydrochloric acid, water, an aqueous saturated sodium hydrogencarbonate solution and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give 2-(2-acetoxy- 1,1 dimethylethylamino)-3-nitro-5-(trifluoromethyl)pyridine (1.39 g) as a yellow 25 oil. NMR(DMSO-d 6 , 6): 1.53(6H, s), 2.04(3H, s), 4.37(2H, s), 8.44(1H, s), 8.66(1H, d, J=2.OHz), 8.84(1H, d, J=2.OHz). Preparation 17 30 The following compounds described in (1) to (20) were obtained in a manner similar to Preparation 16. 55 WO 01/05770 PCT/JPOO/04687 (1) 2- (trans-4-Acetoxycyclohexylamino) -3-nitro- 5- (trifluoromethyl)pyridine mp. 132.5-1359C NMR(DMSO-d 6 , 6): 1.40-1.72(4H, m), 1.91-2.04(4H, m), 2.00(3H, s), 4.16 4.31(1H, m), 4.58-4.69(1H, m), 8.40(1H, d, J=7.5Hz), 8.64(1H, d, J=1.5Hz), 5 8.84(1H, d, J=1.5Hz). MS m/z: 346(M+-1). (2) 4- (trans-2-Acetoxycyclopentylamino) -3-nitrobenzotrifluoride mp. 83-849C 10 NMR(DMSO-d 6 , 6): 1.59-1.85(4H, m), 2.02(3H, s), 2.03-2.30(2H, m), 4.11 4.22(1H, m), 5.06-5.13(1H, m), 7.38(1H, d, J=9.OHz), 7.84(1H, dd, J=9.0, 2.5Hz), 8.28(1H, d, J=7.OHz), 8.32(1H, d, J=2.5Hz). MS m/z : 331(M+-1). 15 (3) 4-(trans-4-Acetoxycyclohexylamino)-3-nitrotoluene mp. 115-1169C NMR(DMSO-d 6 , 6): 1.37-1.62(4H, m), 1.88-2.06(4H, m), 2.01(3H, s), 2.22(3H, s), 3.58-3.73(1H, m), 4.60-4.72(1H, m), 7.08(1H, d, J=8.5Hz), 7.40(1H, dd, J=8.5, 2.5Hz), 7.83(1H, d, J=8.OHz), 7.87(1H, d, J=2.5Hz). 20 MS m/z: 293(M++1). (4) 4-[1-(Acetoxymethyl)cyclopentylamino]-3-nitrobenzotrifluoride NMR(DMSO-d 6 , 6): 1.62-1.82(4H, m), 1.89-2.11(4H, m), 2.00(3H, s), 4.31(2H, s), 7.35(1H, d, J=9.OHz), 7.77(1H, dd, J=9.0, 2.5Hz), 8.34(1H, d, 25 J=2.5Hz), 8.39(1H, s). MS m/z: 345(M+-1). (5) 2-[((R)-2-Acetoxy- 1 -methylethyl) amino] -3-nitro-5 (trifluoromethyl)pyridine 30 NMR(DMSO-d 6 , 6): 1.28(3H, d, J=6.5Hz), 1.99(3H, s), 4.21(2H, dd, J=6.5, 4.0Hz), 4.70-4.85(1H, m), 8.55(1H, d, J=8.OHz), 8.66(1H, d, J=2.OHz), 56 WO 01/05770 PCT/JPOO/04687 8.84(1H, d, J=2.OHz). (6) 2-(trans-4-Acetoxycyclohexylamino)-5-(methylsulfonyl)nitrobenzene mp. 206-2079C 5 NMR(DMSO-d 6 , 6): 1.47-1.66(4H, m), 1.90-2.08(4H, m), 2.01(3H, s), 3.21(3H, s), 3.74-3.87(1H, m), 4.61-4.72(1H, m), 7.37(1H, d, J=9.5Hz), 7.92(1H, dd, J=9.5, 2.5Hz), 8.26(1H, d, J=8.OHz), 8.50(1H, d, J=2.5Hz). (7) 4- [((R) -2-Acetoxy- 1 -methylethyl) amino] -3-nitrobenzotrifluoride 10 NMR(DMSO-d 6 , 6): 1.28(3H, d, J=6.5Hz), 2.01(3H, s), 4.10-4.30(3H, m), 7.37(1H, d, J=9.0Hz), 7.82(1H, dd, J=9.0, 2.5Hz), 8.24(1H, d, J=7.5Hz), 8.32(1H, d, J=2.5Hz). (8) 2-(trans-4-Acetoxycyclohexylamino)-5-cyano-3-nitropyridine 15 mp. 168-1709C NMR(DMSO-d 6 , 6): 1.40-1.56(2H, m), 1.57-1.76(2H, m), 1.88-2.02(4H, m), 2.00(3H, s), 4.16-4.30(1H, m), 4.56-4.70(1H, m), 8.51(1H, d, J=7.5Hz), 8.84(1H, d, J=2.OHz), 8.89(1H, d, J=2.OHz). MS m/z: 303(M+-1). 20 (9) 4-(trans-4-Acetoxycyclohexylamino)-3-nitrobenzophenone mp. 205-205.5"C NMR(DMSO-d 6 , 6): 1.48-1.68(4H, m), 1.90-2.10(4H, m), 2.01(3H, s), 3.75 3.87(1H, m), 4.62-4.73(1H, m), 7.33(1H, d, J=9.5Hz), 7.57(1H, t, J=7.5Hz), 25 7.58(1H, d, J=7.5Hz), 7.65-7.73(3H, m), 7.96(1H, dd, J=9.5, 2.0Hz), 8.31(1H, d, J=7.5Hz), 8.43(1H, d, J=2.0Hz). MS m/z: 381(M+-1). (10) 4-(2-Acetoxyethylamino)-3-nitrobenzotrifluoride 30 mp. 48-48 0 C NMR(DMSO-d6, 6): 2.01(3H, s), 3.71(2H, q, J=5.5Hz), 4.25(2H, t, J=5.5Hz), 57 WO 01/05770 PCT/JPOO/04687 7.33(1H, d, J=9.OHz), 7.82(1H, dd, J=9.0, 2.0Hz), 8.32(1H, d, J=2.OHz), 8.56(1H, t, J=5.5Hz). MS m/z: 291(M+-1). 5 (11) 4-(2-Acetoxy-1,1-dimethylethylamino)-3-nitrobenzonitrile NMR(CDC1 3 , 6): 1.55 (6H, s), 2.13 (3H, s), 4.21 (2H, s), 7.16 (1H, d, J=8 Hz), 7.56 (1H, dd, J=8, 2 Hz), 8.54 (1H, d, J=2 Hz), 8.84 (1H, br). (12) 4- [((R) -2-Acetoxy- 1 -methylethyl) amino] -3-nitrobenzonitrile 10 NMR(CDC1 3 , 6): 1.40 (3H, d, J=7 Hz), 2.09 (3H, s), 3.08-4.17 (2H, m), 4.20-4.81 (1H, m), 7.06 (1H, d, J=8 Hz), 7.63 (1H, dd, J=8, 2 Hz), 8.45 (1H, br d, J=8 Hz), 8.53 (1H, d, J=2 Hz). (13) 4-[((S)-2-Acetoxy-1 -methylethyl)amino] -3-nitrobenzonitrile 15 NMR(CDC1 3 , 6): 1.40 (3H, d, J=7 Hz), 2.09 (3H, s), 3.99-4.15 (2H, m), 4.20-4.31 (1H, m), 7.05 (1H, d, J=8 Hz), 7.62 (1H, dd, J=8, 2 Hz), 8.45 (1H, br d, J=8 Hz), 8.53 (1H, d, J=2 Hz). (14) 4-[2-Acetoxy-1,1-dimethylethylamino]-3-nitrobenzotrifluoride 20 NMR(CDC1 3 , 6): 1.54 (6H, s), 2.13 (3H, s), 4.22 (2H, s), 7.18 (1H, d, J=8 Hz), 7.58 (1H, dd, J=8, 2 Hz), 8.50 (1H, d, J=2 Hz), 8.70 (1H, br s). (15) 4-(trans-4-Acetoxycyclohexylamino)-3-nitrobenzonitrile NMR(DMSO-d 6 , 6): 1.45-1.66 (4H, m), 1.87-2.06 (7H, m), 3.78 (1H, br), 25 4.59-4.72 (1H, m), 7.30 (1H, d, J=8 Hz), 7.84 (1H, dd, J=8, 2 Hz), 8.22 (1H, d, J=8 Hz), 8.52 (1H, d, J=2 Hz). (16) 4-[1-(Acetoxymethyl)cyclopentylamino]-3-nitrobenzonitrile NMR(CDC1 3 , 6): 1.70-1.94 (4H, m), 1.96-2.08 (7H, m), 4.29 (2H, s), 7.04 30 (1H, d, J=8 Hz), 7.56 (1H, dd, J=8, 2 Hz), 8.53 (1H, d, J=2 Hz), 8.70 (1H, br). 58 WO 01/05770 PCT/JPOO/04687 (17) 4- [((S) -2-Acetoxy- 1 -ethylethyl) amino] -3-nitrobenzonitrile NMR(CDCl 3 , 6): 1.05 (3H, d, J=7.5 Hz), 1.61-1.94 (2H, m), 2.07 (3H, s), 3.77-3.92 (1H, m), 4.14 (1H, dd, J=11, 5 Hz), 4.26 (1H, dd, J=11, 5 Hz), 7.05 (1H, d, J=8 Hz), 7.60 (1H, dd, J=8, 2 Hz), 8.44 (1H, d, J=8 Hz), 8.53 (1H, d, 5 J=2 Hz). (18) 4-[((R)-2-Acetoxy-1 -ethylethyl) amino] -3-nitrobenzonitrile NMR(CDC1 3 , 6): 1.05 (3H, t, J=7.5 Hz), 1.61-1.76 (2H, m), 1.76-1.94 (1H, m), 2.07 (3H, s), 3.79-3.94 (1H, m), 4.14 (1H, dd, J=11, 5 Hz), 4.26 (1H, dd, 10 J=11, 5 Hz), 7.06 (1H, d, J=8 Hz), 7.61 (1H, dd, J=8, 2 Hz), 8.44 (1H, d, J=8 Hz), 8.53 (1H, d, J=2 Hz). (19) 2-[ ((R) -2-Acetoxy- 1 -methylethyl)amino] -5-cyano-3-nitropyridine NMR(DMSO-d 6 , 6): 1.48(3H, d, J=7.OHz), 2.19(3H, s), 4.41(2H, t, J=6.OHz), 15 4.90-5.05(1H, m), 8.88(1H, d, J=7.5Hz), 9.05(lH, d, J=2.OHz), 9.11(1H, d, J=2.OHz). MS m/z: 263(M+-1). (20) 4-(3-Acetoxypropylamino)-3-nitrobenzonitrile 20 NMR (CDC1 3 , (5) : 2.04-2.18 (5H, m), 3.48 (2H, q, J=5 Hz), 4.25 (2H, t, J=5 Hz), 6.92 (1H, d, J=8 Hz), 7.63 (1H, dd, J=8,2 Hz), 8.52 (1H, d, J=2 Hz), 8.56 (1H, br peak). MS (ES-) m/z: 262.2(M+-1). 25 Preparation 18 A mixture of 4-[2-hydroxy-1-(hydroxymethyl)ethylamino]-3 nitrobenzonitrile (1.35 g), 2,2-dimethoxypropane (1.4 g) and p toluenesulfonic acid (10 mg) in anhydrous dichloromethane (30 mL) was stirred at ambient temperature for 8 hours. The mixture was poured into 30 water and extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was triturated with diethyl ether to give 4-[(2,2-dimethyl- 1,3 59 WO 01/05770 PCT/JPOO/04687 dioxan-5-yl)amino]-3-nitrobenzonitrile (1.3 g) as yellow powders. NMR(DMSO-d 6 , 6): 1.36 (3H, s), 1.45 (3H, s), 3.70-3.80 (2H, m), 3.90-3.99 (1H, m), 4.10-4.20 (2H, m), 7.29 (1H, d, J=8 Hz), 7.85 (1H, dd, J=8, 2 Hz), 8.57 (1H, d, J=2 Hz), 8.90 (1H, d, J=8 Hz). 5 Preparation 19 The following compounds described in (1) and (2) were obtained in a manner similar to Preparation 18. 10 (1) 4-(t-3,t-4-Isopropylidenedioxy-r-1-cyclohexylamino)-3-nitrobenzonitrile NMR(CDCl 3 , 6): 1.33-1.51 (4H, m), 1.56 (3H, s), 1.66-1.86 (2H, m), 1.94 2.05 (1H, m), 2.05-2.19 (1H, m), 2.41-2.51 (1H, m), 3.85-4.00 (1H, m), 4.16-4.26 (1H, m), 4.34-4.41 (1H, m), 6.96 (1H, d, J=8 Hz), 7.60 (1H, dd, J=8, 2 Hz), 8.34 (1H, br d, J=8 Hz), 8.51 (1H, d, J=2 Hz). 15 MS m/z: 316.2 (M+-1). (2) 4-(c-3,c-4-Isopropylidenedioxy-r-1-cyclohexylamino)-3 nitrobenzonitrile NMR(CDCl 3 , 6): 1.39 (3H, s), 1.59 (3H, s), 1.64-1.96 (4H, m), 2.04-2.25 (2H, 20 m), 3.76-3.88 (1H, m), 4.14-4.25 (1H, m), 4.29-4.37 (1H, m), 6.86 (1H, d, J=8 Hz), 7.56 (1H, dd, J=8, 2 Hz), 8.51 (1H, d, J=2 Hz), 9.05 (1H, br d, J=8 Hz). MS m/z: 316.1(M+-1). 25 Preparation 20 A mixture of 4-[(trans-4-aminocyclohexyl)amino]-3 nitrobenzonitrile (987 mg), di-tert-butyl dicarbonate (910 mg) and triethylamine (422 mg) in anhydrous N,N-dimethylformamide (10 mL) was stirred at ambient temperature for 5 hours. The mixture was partitioned 30 between water and ethyl acetate. The separated organic layer was washed successively with water and brine and dried over magnesium sulfate. After 60 WO 01/05770 PCT/JPOO/04687 evaporation of the solvent, the residue was triturated with diisopropyl ether to give 4- [ [ trans-4- (N- tert-butoxycarbonylamino) cyclohexyl] amino] -3 nitrobenzonitrile (1.23 g) as yellow powders. NMR(CDC1 3 , 65): 1.21-1.40 (2H, m), 1.40-1.54 (11H, m), 2.10-2.23 (4H, m), 5 3.40-3.61 (2H, m), 4.42 (1H, br), 6.90 (iH, d, J=8 Hz), 7.66 (1H, dd, J=8, 2 Hz), 8.35 (1H, d, J=8 Hz), 8.51 (1H, d, J=2 Hz). Preparation 21 4-[ trans-4- (N- tert-Butoxycarbonylamino) cyclohexy1]amino] -3 10 nitrobenzotrifluoride was obtained in a manner similar to Preparation 20. mp. 189.5-190*C NMR(DMSO-d 6 , 6): 1.48-1.75(4H, m), 1.60(9H, s), 1.97-2.08(2H, m), 2.16 2.26(2H, m), 3.43-3.52(1H, m), 3.76-3.90(1H, m), 7.06(1H, d, J=7.5Hz), 7.55(1H, d, J=9.OHz), 7.96(1H, dd, J=9.0, 2.5Hz), 8.34(1H, d, J=7.5Hz), 15 8.52(1H, d, J=2.5Hz). MS m/z: 402(M+-1). Preparation 22 To a solution of 3-amino-4-(trans-4 20 hydroxycyclohexylamino)benzotrifluoride (657 mg) in acetonitrile (7 mL) was added 1,1 '-carbonyldiimidazole (1.17 g), and the mixture was stirred at 609C under nitrogen atmosphere for 3 hours. After adding 1N-sodium hydroxide solution (5 mL), the mixture was stirred at 60'C for an hour. The mixture was neutralized with concentrated hydrochloric acid at 0"C. 25 The resulting precipitate was collected by filtration and washed successively with water and diethyl ether to give 1-(trans-4 hydroxycyclohexyl)-5-trifluoromethyl-2,3-dihydro- 1H-benzimidazol-2-one (549.5 mg) as a colorless solid. mp. 232.5-233*C 30 NMR(DMSO-d 6 , 6): 1.25-1.45(2H, m), 1.60-1.73(2H, m), 1.87-2.00(2H, m), 2.11-2.30(2H, m), 3.50-3.63(1H, m), 4.10-4.24(1H, m), 4.68(1H, d, J=4.OHz), 61 WO 01/05770 PCT/JPOO/04687 7.20(1H, s), 7.32(1H, d, J=8.5Hz), 7.49(1H, d, J=8.5Hz). MS m/z: 299(M+-1). Preparation 23 5 The following compounds described in (1) to (8) were obtained in a manner similar to Preparation 22. (1) 1-(trans-4-Hydroxycyclohexyl)-5-nitro-2,3-dihydro-1H-benzimidazol-2 one 10 mp. 300-3019C NMR(DMSO-d 6 , 65): 1.26-1.45(2H, m), 1.63-1.75(2H, m), 1.88-2.00(2H, m), 2.11-2.29(2H, m), 3.49-3.63(1H, m), 4.13-4.27(1H, m), 4.68(1H, brs), 7.53(1H, d, J=9.OHz), 7.74(1H, d, J=2.5Hz), 7.96(1H, dd, J=9.0, 2.5Hz). MS m/z: 276(M+-1). 15 (2) 5-Acetyl-1-(trans-4-hydroxycyclohexyl)-2,3-dihydro-1H-benzimidazol 2-one mp. 253.5-2559C NMR(DMSO-d 6 , 6): 1.26-1.44(2H, m), 1.61-1.72(2H, m), 1.88-1.99(2H, m), 20 2.12-2.30(2H, m), 2.54(3H, s), 3.50-3.64(1H, m), 4.10-4.24(1H, m), 4.68(1H, d, J=4.5Hz), 7.40(1H, d, J=8.5Hz), 7.49(1H, d, J=2.5Hz), 7.68(1H, dd, J=8.5, 2.5Hz). MS m/z: 273(M+-1). 25 (3) 5-Chloro-1-(trans-4-hydroxycyclohexyl)-2,3-dihydro-1H-benzimidazol 2-one mp. 248-249.5 0 C NMR(DMSO-d 6 , 6): 1.24-1.41(2H, m), 1.57-1.68(2H, m), 1.87-1.97(2H, m), 2.07-2.29(2H, m), 3.33(1H, brs), 3.49-3.62(1H, m), 4.04-4.17(1H, m), 30 4.66(1H, brs), 6.95(1H, d, J=2.5Hz), 6.98(1H, dd, J=9.0, 2.5Hz), 7.29(1H, d, J=9.OHz). 62 WO 01/05770 PCT/JPOO/04687 MS m/z: 265(M+-1). (4) 1-(trans-4-Hydroxycyclohexyl)-5-methoxycarbonyl-2,3-dihydro-1H benzimidazol-2-one 5 mp. 233-2369C NMR(DMSO-d 6 , 6): 1.25-1.43(2H, m), 1.61-1.72(2H, m), 1.87-1.99(2H, m), 2.12-2.28(2H, m), 3.34(1H, s), 3.49-3.63(1H, m), 3.82(3H, s), 4.09-4.23(1H, m), 4.67(1H, d, J=4.5Hz), 7.41(1H, d, J=8.5Hz), 7.49(1H, d, J=1.5Hz), 7.65(1H, dd, J=8.5, 1.5Hz). 10 MS m/z: 289(M+-1). (5) 1-(trans-4-Hydroxycyclohexyl)-5-methoxy-2,3-dihydro-1H benzimidazol-2-one mp. 262-2649C 15 NMR(DMSO-d 6 , 6): 1.24-1.41(2H, m), 1.56-1.67(2H, m), 1.87-1.97(2H, m), 2.05-2.23(2H, m), 3.46-3.61(1H, m), 3.57(1H, s), 3.70(3H, s), 4.00-4.14(1H, m), 4.65(1H, d, J=4.5Hz), 6.53(1H, dd, J=9.5, 2.5Hz), 6.54(1H, d, J=2.5Hz), 7.15(1H, d, J=9.5Hz). MS m/z : 261(M+- 1). 20 (6) 3-(trans-4-Hydroxycyclohexyl)-6-methoxycarbonyl-2,3-dihydro-1H imidazo[4,5-b]pyridin-2-one mp. 254.5-2559C NMR(DMSO-d 6 , 6): 1.22-1.40(2H, m), 1.62-1.74(2H, m), 1.89-2.00(2H, m), 25 2.25-2.48(2H, m), 3.40-3.55(1H, m), 3.85(3H, s), 4.17-4.30(1H, m), 4.67(1H, d, J=4.5Hz), 7.62(1H, d, J=2.OHz), 8.56(1H, d, J=2.OHz). MS m/z: 290(M+-1). (7) 6-Cyano-3-(trans-4-hydroxycyclohexyl)-2,3-dihydro-1H-imidazo[4,5 30 b]pyridin-2-one mp. 274-275C 63 WO 01/05770 PCT/JPOO/04687 NMR(DMSO-d 6 , 6): 1.22-1.39(2H, m), 1.63-1.75(2H, m), 1.88-1.99(2H, m), 2.25-2.44(2H, m), 3.42-3.55(1H, m), 4.15-4.27(1H, m), 4.68(1H, d, J=4.5Hz), 7.70(1H, d, J=2.OHz), 8.42(1H, d, J=2.OHz). MS m/z: 257(M+-1). 5 (8) 6-Cyano-3-(trans-4-hydroxycyclohexyl)- 2,3-dihydro-1H- imidazo[4,5 b]pyridin-2-one mp. 274-275C NMR(DMSO-d 6 , 6): 1.22-1.39(2H, m), 1.63-1.75(2H, m), 1.88-1.99(2H, m), 10 2.25-2.44(2H, m), 3.42-3.55(1H, m), 4.15-4.27(1H, m), 4.68(1H, d, J=4.5Hz), 7.70(1H, d, J=2.OHz), 8.42(1H, d, J=2.OHz). MS m/z: 257(M+-1). Preparation 24 15 To a solution of 2-(2-acetoxy- 1, 1-dimethylethylamino)-3-amino-5 (trifluoromethyl)pyridine (1.5 g) in acetonitrile (15 mL) was added 1,1' carbonyldiimidazole (1.25 g), and the mixture was stirred at 509C under nitrogen atmosphere for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was partitioned between 20 ethyl acetate and water. The separated organic layer was washed successively with 1 N-hydrochloric acid, water, an aqueous saturated sodium hydrogencarbonate solution and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of 25 chloroform and methanol (20:1). The obtained substance was triturated with diethyl ether to give 3-(2-acetoxy- 1, 1-dimethylethyl)-6 trifluoromethyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (736.5 mg) as a pale brown solid. mp. 132-132.59C 30 NMR(DMSO-d 6 , 6): 1.78(6H, s), 1.91(3H, s), 4.61(2H, s), 7.48(1H, d, J=1.5Hz), 8.3 1(1H, d, J=1.5Hz). 64 WO 01/05770 PCT/JPOO/04687 MS m/z: 316(M+-1). Preparation 25 The following compounds described in (1) to (48) were obtained in a 5 manner similar to Preparation 24. (1) 3-(trans-4-Acetoxycyclohexyl)-6-trifluoromethyl-2,3-dihydro-1H imidazo[4,5-b]pyridin-2-one mp. 256-2579C 10 NMR(DMSO-d 6 , 6): 1.45-1.62(2H, m), 1.72-1.85(2H, m), 1.95-2.07(2H, m), 2.02(3H, s), 2.37-2.54(2H, m), 4.25-4.40(1H, m), 4.59-4.73(1H, m), 7.53(1H, d, J=1.5Hz), 8.35(1H, d, J=1.5Hz). MS m/z : 342(M+- 1). 15 (2) 3-Cyclopentyl-6-trifluoromethyl-2,3-dihydro-1H-imidazo[4,5 b]pyridin-2-one mp. 193-194.59C NMR(DMSO-d 6 , 6): 1.55-1.72(2H, m), 1.83-1.99(4H, m), 2.11-2.29(2H, m), 4.73-4.87(1H, m), 7.53(1H, s), 8.35(1H, s). 20 MS m/z : 270(M+- 1). (3) 1-(trans-2-Acetoxycyclopentyl)-5-trifluoromethyl-2,3-dihydro-1H benzimidazol-2-one mp. 171-172*C 25 NMR(DMSO-d 6 , 6): 1.65-1.95(3H, m), 1.92(3H, s), 2.02-2.15(2H, m), 2.19 2.29(1H, m), 4.63-4.74(1H, m), 5.47-5.55(1H, m), 7.22(1H, d, J=1.OHz), 7.35(1H, dd, J=8.0, 1.0Hz), 7.40(1H, d, J=8.OHz). MS m/z : 327(M+- 1). 30 (4) 1-((S)-1-tert-Butoxycarbonylpyrrolidin-3-yl)-5-trifluoromethyl-2,3 dihydro- 1H-benzimidazol-2-one 65 WO 01/05770 PCT/JPOO/04687 mp. 189-190 0 C NMR(DMSO-d 6 , 6): 1.41(9H, s), 2.07-2.20(1H, m), 2.41-2.53(1H, m), 3.27 3.40(1H, m), 3.51-3.70(3H, m), 4.95-5.09(1H, m), 7.23(1H, s), 7.38(2H, s). MS m/z: 370(M+-1). 5 (5) 1-(1H-Benzimidazol-5-yl)-5-trifluoromethyl-2,3-dihydro-1H benzimidazol-2-one mp. 298-299 0 C NMR(DMSO-d 6 , 6): 7.07(1H, brs), 7.30(1H, brs), 7.33(1H, s), 7.35(1H, d, 10 J=8.OHz), 7.66-7.86(2H, m), 8.36(1H, s). MS m/z: 317(M+-1). (6) 1-(trans-4-Acetoxycyclohexyl)-5-methyl-2,3-dihydro-1H-benzimidazol 2-one 15 mp. 209.5-2109C NMR(DMSO-d 6 , 6): 1.44-1.61(2H, m), 1.64-1.75(2H, m), 1.96-2.06(2H, m), 2.01(3H, s), 2.18-2.35(2H, m), 2.28(3H, s), 4.11-4.25(1H, m), 4.72-4.85(1H, m), 6.73-6.79(2H, m), 7.23(1H, d, J=8.5Hz). MS m/z: 287(M+-1). 20 (7) 1-11-(Acetoxymethyl)cyclopenty]-5-trifluoromethyl-2,3-dihydro-1H benzimidazol-2-one mp. 152-1539C NMR(DMSO-d 6 , 6): 1.59-1.81(4H, m), 1.77(3H, s), 2.20-2.35(2H, m), 2.45 25 2.62(2H, m), 4.27(2H, s), 7.16(1H, d, J=1.5Hz), 7.28(lH, dd, J=8.5, 1.5Hz), 7.48(1H, d, J=8.5Hz). MS m/z: 341(M+-1). (8) 3-((R)-2-Acetoxy-1-methylethyl)-6-trifluoromethyl-2,3-dihydro-1H 30 imidazo[4,5-b]pyridin-2-one mp. 155-156"C 66 WO 01/05770 PCT/JPOO/04687 NMR(DMSO-d 6 , 6): 1.51(3H, d, J=7.OHz), 1.87(3H, s), 4.37(1H, dd, J= 11.5, 5.0Hz), 4.58(1H, dd, J=11.5, 9.5Hz), 4.68-4.82(1H, m), 7.56(1H, d, J=2.OHz), 8.35(1H, d, J=2.OHz). MS m/z: 302(M+-1). 5 (9) 1-(trans-4-Acetoxycyclohexyl)-5-methylsulfonyl-2,3-dihydro-1H benzimidazol-2-one mp. 275-275.5"C NMR(DMSO-d 6 , 6): 1.46-1.63(2H, m), 1.70-1.80(2H, m), 1.98-2.09(2H, m), 10 2.02(3H, s), 2.21-2.39(2H, m), 3.17(3H, s), 4.21-4.36(1H, m), 4.75-4.88(1H, m), 7.43(1H, d, J=2.5Hz), 7.54(1H, dd, J=8.5, 2.5Hz), 7.65(1H, d, J=8.5Hz). MS m/z : 351(M+- 1). (10) 1-((R)-2-Acetoxy-1-methylethyl)-5-trifluoromethyl-2,3-dihydro-1H 15 benzimidazol-2-one mp. 132-132.59C NMR(DMSO-d 6 , 6): 1.47(3H, d, J=7.OHz), 1.88(3H, s), 4.31(1H, dd, J=11.5, 5.0Hz), 4.49(1H, dd, J=11.5, 9.0Hz), 4.62-4.75(1H, m), 7.22(1H, s), 7.35(1H, d, J=8.5Hz), 7.46(1H, d, J=8.5Hz). 20 MS m/z: 301(M+-1). (11) 3-(trans-4-Acetoxycyclohexyl)-6-cyano-2,3-dihydro- 1H-imidazo[4,5 b]pyridin-2-one mp. 270.5-271"C 25 NMR(DMSO-d 6 , 6): 1.45-1.61(2H, m), 1.73-1.84(2H, m), 1.95-2.08(2H, m), 2.01(3H, s), 2.33-2.55(2H, m), 4.25-4.39(1H, m), 4.59-4.71(1H, m), 7.72(1H, d, J=2.OHz), 8.44(1H, d, J=2.OHz). (12) 1-(trans-4-Acetoxycyclohexyl)-5-benzoyl-2,3-dihydro-1H 30 benzimidazol-2-one mp. 275-277"C 67 WO 01/05770 PCT/JPOO/04687 NMR(DMSO-d 6 , 8): 1.48-1.65(2H, m), 1.72-1.83(2H, m), 1.95-2.10(2H, m), 2.02(3H, s), 2.22-2.40(2H, m), 4.22-4.35(1H, m), 4.74-4.87(1H, m), 7.35(1H, d, J=2.OHz), 7.45(1H, dd, J=7.5, 2.0Hz), 7.51-7.60(3H, m), 7.65(1H, d, J=7.5Hz), 7.70(2H, d, J=7.5Hz). 5 MS m/z: 377(M+-1). (13) 1- (tert-Butyl) -5-trifluoromethyl-2,3-dihydro- 1 H-benzimidazol-2-one mp. 188-190*C NMR(DMSO-d 6 , 8): 1.71(9H, s), 7.16(1H, d, J=2.5Hz), 7.26(1H, dd, J=8.5, 10 2.5Hz), 7.60(1H, d, J=8.5Hz). (14) 1-(2-Acetoxyethyl)-5-trifluoromethyl-2,3-dihydro-1H-benzimidazol-2 one mp. 124.5-125C 15 NMR(DMSO-d 6 , 8): 1.89(3H, s), 4.10(2H, t, J=5.5Hz), 4.28(2H, t, J=5.5Hz), 7.23(1H, d, J=2.OHz), 7.36(1H, d, J=8.5Hz), 7.40(1H, dd, J=8.5, 2.0Hz). MS m/z: 287(M+-1). (15) 1-(Tetrahydro-4H-pyran-4-yl)-5-trifluoromethyl-2,3-dihydro-1H 20 benzimidazol-2-one mp. 195-196C NMR(DMSO-d 6 , 6): 1.61-1.70(2H, m), 2.29-2.45(2H, m), 3.41-3.52(2H, m), 3.95-4.03(2H, m), 4.39-4.51(1H, m), 7.23(1H, d, J=1.5Hz), 7.35(1H, dd, J=8.5, 1.5Hz), 7.48(1H, d, J=8.5Hz). 25 MS m/z: 285(M+-1). (16) 1 -Isopropyl-5-trifluoromethyl-2,3-dihydro- 1 H-benzimidazol-2-one mp. 168-169TC NMR(DMSO-d 6 , 8): 1.45(6H, d, J=7.OHz), 4.61(1H, hept., J=7.OHz), 30 7.21(1H, d, J=1.OHz), 7.33(1H, dd, J=8.5, 1.0Hz), 7.45(1H, d, J=8.5Hz). MS m/z: 245(M++1). 68 WO 01/05770 PCT/JPOO/04687 (17) 1 -Butyl-5-trifluoromethyl-2,3 -dihydro- 1 H-benzimidazol-2-one mp. 140-141*C NMR(DMSO-d 6 , 6): 0.89(3H, t, J=7.OHz), 1.21-1.35(2H, m), 1.56-1.68(2H, 5 m), 3.83(2H, t, J=7.0Hz), 7.22(1H, s), 7.32(1H, d, J=8.5Hz), 7.37(1H, d, J=8.5Hz). (18) 1 -Cyclohexyl- 5-trifluoromethyl-2,3-dihydro- 1 H-benzimidazol-2-one mp. 216-2179C 10 NMR(DMSO-d 6 , 6): 1.19-1.49(3H, m), 1.61-1.75(3H, m), 1.79-1.90(2H, m), 2.02-2.18(2H, m), 4.11-4.24(1H, m), 7.21(1H, d, J=1.OHz), 7.21(1H, dd, J=8.0, 1.0Hz), 7.49(1H, d, J=8.OHz). MS m/z: 283(M+-1). 15 (19) 3-(trans-4-Formamidocyclohexyl)-6-trifluoromethyl-2,3-dihydro-1H imidazo[4,5-b]pyridin-2-one mp. 303-3049C NMR(DMSO-d 6 , 6): 1.29-1.49(2H, m), 1.70-1.81(2H, m), 1.85-1.97(2H, m), 2.35-2.52(2H, m), 3.59-3.75(1H, m), 4.20-4.35(1H, m), 7.53(1H, d, J=2.OHz), 20 7.97(1H, s), 8.05(1H, m), 8.35(1H, s). MS m/z: 327(M+-1). (20) 5-Cyano-1-(trans-4-formamidocyclohexyl)-2,3-dihydro-1H benzimidazol-2-one 25 NMR(DMSO-d 6 , 6): 1.30-1.53 (2H, m), 1.65-1.77 (2H, m), 1.82-1.99 (2H, m), 2.16-2.34 (2H, m), 3.72-3.89 (1H, m), 4.13-4.29 (1H, m), 7.36 (1H, d, J=2 Hz), 7.44 (1H, dd, J=8, 2 Hz), 7.59 (1H, d, J=8 Hz), 7.97 (1H, s), 8.04 (1H, d, J=8 Hz). 30 (21) 5-Cyano-1-(2,2-dimethyl-1,3-dioxan-5-yl)-2,3-dihydro-1H benzimidazol-2-one 69 WO 01/05770 PCT/JPOO/04687 NMR(DMSO-d 6 , 6): 1.41 (3H, s), 1.51 (3H, s), 3.99 (2H, dd, J=11, 5 Hz), 4.24 (2H, dd, J=11, 7.5 Hz), 4.46-4.58 (1H, m), 7.39 (1H, d, J=2 Hz), 7.50 (1H, dd, J=8, 2 Hz), 7.70 (1H, d, J=8 Hz). 5 (22) 1-(2-Acetoxy-1,1-dimethylethyl)-5-cyano-2,3-dihydro-1H benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.73 (6H, s), 1.89 (3H, s), 4.50 (2H, s), 7.32 (1H, d, J=2 Hz), 7.38 (1H, dd, J=8, 2 Hz), 7.58 (1H, d, J=8 Hz). 10 (23) 1-[(R)-2-Acetoxy-1-methylethyl]-5-cyano-2,3-dihydro-1H benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.46 (3H, d, J=7.5 Hz), 1.86 (3H, s), 4.29 (1H, dd, J=11, 4 Hz), 4.47 (1H, dd, J=11, 9 Hz), 4.62-4.76 (1H, m), 7.38 (1H, s), 7.41-7.51 (2H, m). 15 (24) 1-[(S)-2-Acetoxy-1-methylethyl]-5-cyano-2,3-dihydro-1H benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.46 (3H, d, J=7.5 Hz), 1.86 (3H, s), 4.29 (1H, dd, J=11, 4 Hz), 4.47 (1H, dd, J=11, 9 Hz), 4.62-4.76 (1H, m), 7.37 (1H, s), 7.41-7.51 20 (2H, m). (25) 1-(2-Acetoxy-1,1-dimethylethyl)-5-trifluoromethyl-2,3-dihydro-1H benzimidazol-2-one NMR(CDC1 3 , 6): 1.86 (6H, s), 1.98 (3H, s), 4.64 (2H, s), 7.25-7.33 (2H, m), 25 7.44 (1H, d, J=8 Hz). (26) 1-[(S)-1-tert-Butoxycarbonylpyrrolidin-3-yl]-5-cyano-2,3-dihydro-1H benzimidazol-2-one NMR(CDC1 3 , 6): 1.50 (9H, s), 2.23-2.36 (1H, m), 2.46-2.64 (1H, m), 3.41 30 3.56 (1H, m), 3.66-3.90 (3H, m), 5.04-5.20 (1H, m), 7.12 (1H, d, J=8 Hz), 7.36-7.46 (2H, m). 70 WO 01/05770 PCT/JPOO/04687 (27) 1-1(R)-1-tert-Butoxycarbonylpyrrolidin-3-yl]-5-cyano-2,3-dihydro-1H benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.41 (9H, s), 2.05-2.20 (1H, m), 2.40-2.56 (1H, m), 5 3.25-3.40 (1H, m), 3.50-3.70 (3H, m), 4.94-5.10 (1H, m), 7.31-7.41 (2H, m), 7.55 (1H, dd, J=8, 2 Hz). (28) 1-[trans-4-(N-tert-Butoxycarbonylamino)cyclohexyl]-5-cyano-2,3 dihydro- 1 H-benzimidazol-2-one 10 NMR(DMSO-d 6 , 6 ): 1.26-1.47 (11H, m), 1.63-1.74 (2H, m), 1.84-1.96 (2H, m), 2.12-2.30 (2H, m), 3.40 (1H, br), 4.07-4.21 (1H, m), 6.80 (1H, d, J=8 Hz), 7.36 (1H, d, J=2 Hz), 7.43 (1H, dd, J=8, 2 Hz), 7.55 (1H, d, J=8 Hz). (29) 1-(cis-4-Acetoxycyclohexyl)-5-cyano-2,3-dihydro-1H-benzimidazol-2 15 one

NMR(CDC

3 , 6): 1.65-1.82 (4H, m), 2.08-2.21 (5H, m), 2.35-2.52 (2H, m), 4.35-4.48 (1H, m), 5.11-5.27 (1H, m), 7.21 (1H, d, J=8 Hz), 7.37 (1H, d, J=2 Hz), 7.42 (1H, dd, J=8, 2 Hz), 9.53 (1H, s). 20 (30) 1-(trans-4-Acetoxycyclohexyl)-5-cyano-2,3-dihydro-1H-benzimidazol 2-one NMR(CDCl 3 , 6): 1.50-1.71 (2H, m), 1.89-2.03 (2H, m), 2.08 (3H, s), 2.13 2.43 (4H, mi), 4.26-4.41 (1H, m), 4.77-4.92 (1H, m), 7.20 (1H, d, J=8 Hz), 7.35-7.46 (2H, m), 9.65 (1H, s). 25 (31) 1-[1-(Acetoxymethyl)cyclopentyl]-5-cyano-2,3-dihydro-1H benzimidazol-2-one. NMR(DMSO-d 6 , 6): 1.60-1.81 (7H, m), 2.17-2.31 (2H, m), 2.40-2.64 (2H, m), 4.26 (2H, s), 7.31 (1H, s-like), 7.38 (1H, d, J=8 Hz), 7.46 (1H, d, J=8 Hz). 30 (32) 5-Cyano-1-cyclopentyl-2,3-dihydro-1H-benzimidazol-2-one 71 WO 01/05770 PCT/JPOO/04687 NMR(CDCl 3 , 6): 1.66-1.86 (2H, m), 1.91-2.15 (6H, m), 4.86 (1H, quint, J=7.5 Hz), 7.12 (1H, d, J=8 Hz), 7.34-7.42 (2H, m), 9.82 (1H, s). (33) 5-Cyano-l-(tetrahydro-4H-pyran-4-yl)-2,3-dihydro-1H-benzimidazol 5 2-one NMR(DMSO-d 6 , 6): 1.61-1.70 (2H, m), 2.26-2.45 (2H, m), 3.40-3.52 (2H, m), 3.94-4.02 (2H, m), 4.38-4.51 (1H, m), 7.38 (1H, s-like), 7.47 (2H, s-like). (34) 5-Cyano- 1 -cyclohexyl-2,3 -dihydro- 1 H-benzimidazol-2-one 10 NMR(DMSO-d 6 , 6): 1.21-1.48 (3H, m), 1.60-1.76 (3H, m), 1.76-1.90 (2H, m), 2.00-2.18 (2H, m), 4.10-4.24 (1H, m), 7.36 (1H, s), 7.44 (1H, d, J=8 Hz), 7.50 (1H, d, J=8 Hz). (35) 1- tert-Butyl-5-cyano-2,3-dihydro- 1 H-benzimidazol-2-one 15 NMR(DMSO-d 6 , 6): 1.69 (9H, s), 7.30 (1H, d, J=2 Hz), 7.36 (1H, dd, J=8, 2 Hz), 7.57 (1H, d, J=8 Hz). (36) 5-Cyano-l-cycloheptyl-2,3-dihydro-1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.65-1.91 (6H, m), 1.91-2.06 (4H, m), 2.28-2.50 (2H, m), 20 4.46-4.61 (1H, m), 7.57 (1H, s), 7.60-7.69 (2H, m). (37) 1-((S)-2-Acetoxy-1-ethylethyl)-5-cyano-2,3-dihydro-1H-benzimidazol 2-one NMR(CDC1 3 , 6): 0.93 (3H, t, J=7.5 Hz), 1.85-2.04 (4H, m), 2.10-2.28 (1H, 25 m), 4.40-4.62 (3H, m), 7.15 (1H, d, J=8 Hz), 7.37-7.45 (2H, m), 9.86 (1H, s). (38) 1-((R)-2-Acetoxy-1-ethylethyl)-5-cyano-2,3-dihydro-1H-benzimidazol 2-one NMR(CDC1 3 , 6): 0.93 (3H, t, J=7.5 Hz), 1.85-2.03 (4H, m), 2.09-2.28 (1H, 30 m), 4.41-4.63 (3H, m), 7.15 (1H, d, J=8 Hz), 7.38 (1H, d, J=2 Hz), 7.41 (1H, dd, J=8, 2 Hz), 9.61 (1H, s). 72 WO 01/05770 PCT/JPOO/04687 (39) 1-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-5-cyano-2,3-dihydro-1H benzimidazol-2-one NMR(CDC1 3 , 6): 1.51 (9H, s), 1.78-1.90 (2H, m), 2.20-2.39 (2H, m), 2.78 5 2.95 (2H, m), 4.25-4.40 (2H, m), 4.40-4.54 (1H, m), 7.19 (1H, d, J=8 Hz), 7.35 (1H, d, J=2 Hz), 7.41 (1H, dd, J=8, 2 Hz) MS m/z: 341(M+-1). (40) 5-Cyano-1-(t-3,t-4-isopropylidenedioxy-r-1-cyclohexyl)-2,3-dihydro 10 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.28 (3H, s), 1.48 (3H, s), 1.58-1.80 (2H, m), 1.86-2.12 (3H, m), 2.39-2.59 (1H, m), 4.14-4.26 (1H, m), 4.32-4.40 (1H, m), 4.40-4.58 (1H, m), 7.29-7.54 (3H, m), 11.35 (1H, s) MS m/z : 312.2 (M+-1). 15 (41) 5-Cyano-1-(c-3,c-4-isopropylidenedioxy-r-1-cyclohexyl)-2,3-dihydro 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.29 (3H, s), 1.44-1.60 (4H, m), 1.80-1.95 (2H, m), 2.10-2.36 (3H, m), 4.11-4.29 (3H, m), 7.32 (1H, d, J=8 Hz), 7.37 (1H, d, J=2 20 Hz), 7.50 (1H, dd, J=8, 2 Hz). MS m/z : 312.2 (M+-1). (42) 3-((R)-2-Acetoxy-1-methylethyl)-6-cyano-2,3-dihydro-1H imidazo[4,5-b]pyridin-2-one 25 mp. 161-161.5"C NMR(DMSO-d 6 , 6): 1.50(3H, d, J=7.OHz), 1.87(3H, s), 4.36(1H, dd, J= 11.0, 5.0Hz), 4.55(1H, dd, J=1 1.0, 9.0Hz), 4.66-4.80(1H, m), 7.74(1H, d, J=2.OHz), 8.44(1H, d, J=2.OHz). MS m/z: 259(M+-1). 30 (43) 1-[trans-4-(N-tert-Butoxycarbonylamino)cyclohexyl]-5 73 WO 01/05770 PCT/JPOO/04687 trifluoromethyl-2,3-dihydro- 1 H-benzimidazol-2-one mp. 274-275C NMR(DMSO-d 6 , 8): 1.25-1.44(2H, m), 1.40(9H, s), 1.64-1.75(2H, m), 1.84 1.95(2H, m), 2.13-2.29(2H, m), 3.29-3.49(1H, m), 4.07-4.22(1H, m), 5 6.81(1H, d, J=7.5Hz), 7.20(1H, s), 7.30(1H, d, J=8.5Hz), 7.55(1H, d, J=8.5Hz). MS m/z: 398(M+-1). (44) 3-((S)-1-tert-Butoxycarbonylpyrrolidin-3-yl)-6-trifluoromethyl-2,3 10 dihydro- 1H-imidazo[4,5-b]pyridin-2-one mp. 130-131.5*C NMR(DMSO-d 6 , 8): 1.40(6H, s), 1.43(3H, s), 2.09-2.21(1H, m), 2.53 2.73(1H, m), 3.27-3.41(1H, m), 3.51-3.66(2H, m), 3.73-3.83(1H, m), 4.99 5.13(1H, m), 7.57(1H, s), 8.34(1H, s). 15 MS m/z: 373(M++1). (45) A mixture of 3-amino-5-cyano-2-(trans-4 hydroxycyclohexylamino)pyridine (3.1 g) and 1, 1'-carbonyldiimidazole (6.49 g) in acetonitrile (31 mL) was stirred at 50*C under nitrogen atmosphere for 20 15 minutes. After adding 1N-NaOH(35mL), the mixture was stirred at 60'C for 1.5 hours. The reaction mixture was neutralized with concentrated hydrochloric acid to yield a precipitate. The resulting precipitate was collected by filtration and washed successively with water and aqueous ethanol to give 6-cyano-3-(trans-4-hydroxycyclohexyl)-2,3-dihydro-1H 25 imidazo[4,5-b]pyridin-2-one (1.93g) as a brown solid. mp. 274-275"C NMR(DMSO-d 6 , 8): 1.22-1.39 (2H, m), 1.63-1.75 (2H, m), 1.88-1.99 (2H, m), 2.25-2.44 (2H, m), 3.42-3.55 (1H, m), 4.15-4.27 (1H, m), 4.68 (1H, d, J= 4.5 Hz), 7.70 (1H, d, J= 2.0 Hz), 8.42 (1H, d, J= 2.0 Hz). 30 MS m/z: 257(M+-1). 74 WO 01/05770 PCT/JPOO/04687 (46) 3-(Benzimidazol-5-yl)-6-cyano-2,3-dihydro-1H-imidazo[4,5-bipyridin 2-one NMR(DMSO-d 6 , 6): 7.36(1H, d, J=8Hz), 7.64-7.95(3H, m), 8.34(1H, s), 8.40(1H, s), 11.85(1H, br s), 12.66(1H, br s). 5 MS (ESI) m/z: 275(M+-1). (47) 3-(1H-Indol-5-yl)-6-cyano-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2 one mp. 288-289*C 10 NMR(DMSO-d 6 , 6): 6.97(1H, d, J=3.5Hz), 7.21(1H, d, J=2.OHz), 7.62(1H, dd, J=8.5, 2.0Hz), 7.77(1H, d, J=3.5Hz), 7.80(1H, m), 7.85(1H, d, J=2.OHz), 8.16(1H, d, J=8.5Hz), 8.37(1H, d, J=2.OHz). (48) 1-(Benzimidazol-5-yl)-5-cyano-2,3-dihydro-1H-benzimidazole-2-one 15 NMR(DMSO-d 6 , 6): 7.03 (1H, d, J=8 Hz), 7.30 (1H, dd, J=8,2 Hz), 7.46 (1H, dd, J=8,2 Hz), 7.50 (1H, d), 7.69-7.81 (2H, m), 8.36 (1H, s) MS (ES-) m/z: 274.1 (M+-1). (49) 1-(3-Acetoxypropyl)-5-cyano-2,3-dihydro- 1H-benzimidazole-2-one 20 NMR(CDC1 3 , 6) : 2.05 (3H, s), 2.13 (2H, m), 4.03 (2H, t, J=5 Hz), 4.14 (2H, t, J=5 Hz), 7.06 (1H, d, J=8 Hz), 7.39 (1H, d, J=2 Hz), 7.44 (1H, dd, J=8, 2 Hz), 9.77 (1H, s). MS (ES-) m/e 258.1 (M-H). 25 (50) 1-[2-(N,N-Dimethylamino)ethyl]-5-cyano-2,3-dihydro-1H benzimidazole-2-one NMR(DMSO-d 6 , 6): 2.16 (6H, s), 2.53-2.58 (2H, m), 3.92 (2H, t, J=7 Hz), 7.33 (1H, d, J=8 Hz), 7.40 (1H, d, J=2 Hz), 7.50 (1H, dd, J=8,2 Hz) MS (ES+) m/z: 231.4 (M++1). 30 Preparation 26 75 WO 01/05770 PCT/JPOO/04687 To a solution of 3-amino-4-(trans-4 hydroxycyclohexylamino)benzotrifluoride (300 mg) in N,N dimethylformamide(3 mL) was added 1, '-thiocarbonyldiimidazole (234 mg), and the mixture was stirred at room temperature under nitrogen 5 atmosphere for 15 hours. Water was added to the mixture, and the resulting precipitate was collected by filtration. The obtained solid was washed successively with water and diethyl ether to give 1-(trans-4 hydroxycyclohexyl)-5-trifluoromethyl-2,3-dihydro- 1H-benzimidazol-2 thione (242.8 mg) as a pale brown solid. 10 mp. 280-2819C NMR(DMSO-d 6 , 6): 1.22-1.45(2H, m), 1.63-1.75(2H, m), 1.92-2.05(2H, m), 2.16-2.37(2H, m), 3.60-3.75(1H, m), 4.72(1H, d, J=4.5Hz), 4.97-5.12(1H, m), 7.41(1H, s), 7.46(1H, d, J=8.5Hz), 7.86(1H, d, J=8.5Hz). MS m/z : 315(M+-1). 15 Preparation 27 5-Cyano- 1-(trans-4-hydroxycyclohexyl)-2,3-dihydro- 1H benzimidazol-2-thione was prepared in a manner similar to Preparation 26. mp. 278.5-280'C 20 NMR(DMSO-d 6 , 6): 1.25-1.42(2H, m), 1.61-1.73(2H, m), 1.93-2.04(2H, m), 2.15-2.34(2H, m), 3.60-3.75(1H, m), 4.70(1H, d, J=5.5Hz), 4.96-5.1 1(1H, m), 7.57(1H, dd, J=8.5, 2.0Hz), 7.58(1H, d, J=2.OHz), 7.84(1H, d, J=8.5Hz). MS m/z: 272(M+-1). 25 Preparation 28 To a solution of 3-amino-4-cyclopentylamino- 1-nitrobenzene (445 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mL) in 1,2-dichloroethane (5 mL) was added triphosgene (358 mg) at 0 0 C, and the mixture was stirred at room temperature under nitrogen atmosphere for 20 minutes. The 30 resulting mixture was diluted with chloroform and washed successively with water(twice) and brine. The organic layer was dried over magnesium 76 WO 01/05770 PCT/JPOO/04687 sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of n-hexane and ethyl acetate (3:1). The obtained substance was triturated with diisopropyl ether to give 1-cyclopentyl-5-nitro-2,3-dihydro- 1 H-benzimidazol-2-one 5 (249.8 mg) as an off-white solid. mp. 252-252.59C NMR(DMSO-d 6 , 6): 1.57-1.77(2H, m), 1.81-2.11(6H, m), 4.78(1H, quint., J=8.5Hz), 7.36(1H, d, J=9.OHz), 7.75(1H, d, J=2.OHz), 7.99(1H, dd, J=9.0, 2.0Hz). 10 MS m/z: 246(M+-1). Preparation 29 The following compounds described in (1) to (5) were obtained in a manner similar to Preparation 28. 15 (1) 5-Cyano-1-(trans-4-hydroxycyclohexyl)-2,3-dihydro-1H-benzimidazol 2-one mp. 258-260'C NMR(DMSO-d 6 , 6): 1.25-1.43(2H, m), 1.59-1.77(2H, m), 1.87-1.98(2H, m), 20 2.09-2.28(2H, m), 3.46-3.63(1H, m), 4.10-4.25(1H, m), 7.35(1H, d, J= 1.0Hz), 7.43(1H, dd, J=8.0, 1.0Hz), 7.48(1H, d, J=8.OHz). MS m/z: 256(M+-1). (2) 1-((R)-2-Hydroxy-1-methylethyl)-5-trifluoromethyl-2,3-dihydro-1H 25 benzimidazol-2-one mp. 197-198"C NMR(DMSO-d 6 , 6): 1.38(3H, d, J=7.OHz), 3.56-3.67(1H, m), 3.80-3.91(1H, m), 4.36-4.50(1H, m), 4.93(1H, t, J=4.5Hz), 7.20(1H, d, J=1.5Hz), 7.31(1H, dd, J=8.5, 1.5Hz), 7.40(1H, d, J=8.5Hz), 11.19(1H, s). 30 MS m/z: 259(M+- 1). 77 WO 01/05770 PCT/JPOO/04687 (3) 1-(trans-4-Formamidocyclohexyl)-5-trifluoromethyl-2,3-dihydro-1H benzimidazol-2-one mp. 304-3069C NMR(DMSO-d 6 , 6): 1.32-1.54(2H, m), 1.66-1.78(2H, m), 1.84-2.00(2H, m), 5 2.15-2.35(2H, m), 3.69-3.89(1H, m), 4.14-4.28(1H, m), 7.21(1H, s), 7.32(1H, d, J=8.5Hz), 7.59(1H, d, J=8.5Hz), 7.97(1H, s), 8.04 (1H, d, J=7.5Hz), 11.25(1H, s). MS m/z: 326(M+-1). 10 (4) 5-Cyano-1-((R)-2-hydroxy-1-methylethyl)-2,3-dihydro-1H benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.37 (3H, d, J=7.5 Hz), 3.55-3.66 (1H, m), 3.79-3.91 (1H, m), 4.36-4.50 (1H, m), 4.94 (1H, t, J=5 Hz), 7.30-7.46 (3H, m). 15 (5) 5-Cyano-1-((S)-2-hydroxy-1-methylethyl)-2,3-dihydro-1H benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.37 (3H, d, J=7.5 Hz), 3.56-3.66 (1H, m), 3.79-3.91 (1H, m), 4.35-4.53 (1H, m), 4.94 (1H, t, J=5 Hz), 7.32-7.46 (3H, m). 20 Preparation 30 A mixture of 2-methoxyphenethyl alcohol (500 mg) and carbon tetrabromide (1.53 g) in anhydrous dichloromethane (10 mL) was stirred at 0 0 C under a nitrogen atmosphere. After adding triphenylphosphine (1.03 g) portionwise, the reaction mixture was stirred for an hour under the same 25 condition. The reaction mixture was evaporated in vacuo and the residue was subjected to a silica gel column chromatography eluting with n-hexane only and then a mixture of n-hexane and ethyl acetate (40:1 to 20:1) to give 2-methoxyphenethyl bromide (661 mg) as an oil. NMR(CDCl 3 , 6): 3.17 (2H, t, J=7.5 Hz), 3.58 (2H, t, J=7.5 Hz), 3.83 (3H, s), 30 6.80-6.99 (2H, m), 7.15 (1H, dd, J=8, 2 Hz), 7.20-7.34 (1H, m). 78 WO 01/05770 PCT/JPOO/04687 Preparation 31 To a solution of 3-bromo-4-methoxybenzaldehyde (4.98 g) in ethanol (50 mL) and tetrahydrofuran (10 mL) was added sodium borohydride (1.31 g) under ice-water cooling. The mixture was stirred at 5 0 0 C for 2 hours. After evaporation of the solvent, the residue was partitioned between ethyl acetate and water. The separated organic layer was washed successively with water and brine, and dried over magnesium sulfate. The organic layer was evaporated in vacuo to give 3-bromo-4 methoxybenzyl alcohol as a colorless oil (4.98 g). 10 NMR(CDCl 3 , 6): 1.73 (1H, t, J= 7 Hz), 3.90 (3H, s), 4.60 (2H, d, J= 7 Hz), 6.88 (1H, d, J= 8 Hz), 7.25 (1H, dd, J= 4, 8 Hz), 7.56 (1H, d, J= 4 Hz). Preparation 32 The following compounds described in (1) and (2) were obtained in a 15 manner similar to Preparation 31. (1) 3-Fluoro-4-methoxybenzyl alcohol NMR(CDCl 3 , 6): 1.73 (1H, t, J= 7 Hz), 3.88 (3H, s), 4.62 (2H, d, J= 7 Hz), 6.88-6.97 (1H, m), 7.00-7.25 (2H, m). 20 (2) 4-Methoxy-3-methylbenzyl alcohol NMR(CDCl 3 , 6): 1.59 (1H, t, J= 7 Hz), 2.22 (3H, s), 3.83 (3H, s), 4.58 (2H, d, J= 7 Hz), 6.79 (1H, d, J= 8 Hz), 7.13 (2H, m). 25 Preparation 33 A mixture of 3-cyclohexene- 1-carboxylic acid (1.8 g), triethylamine (2.2 mL) and diphenylphosphoryl azide (3.93 g) in benzene (40 mL) was refluxed for 2 hours. After adding benzyl alcohol (1.54 g), the mixture was refluxed for 10 hours. The mixture was evaporated in vacuo and the 30 obtained residue was diluted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, an aqueous saturated 79 WO 01/05770 PCT/JPOO/04687 sodium hydrogen carbonate solution and brine. The obtained organic layer was dried over sodium sulfate and evaporated in vacuo. The residues was recrystallized from hexane-diethyl ether to give benzyl N-(3 cyclohexene-1-yl)carbamate (1.72 g) as a solid. 5 NMR(CDCl 3 , 6): 1.58 (1H, m), 1.82-1.95 (2H, m), 2.05-2.36 (2H, m), 2.40 (1H, m), 3.88 (1H, m), 4.78 (1H, m), 5.55-5.72 (2H, m), 7.27-7.39 (5H, m). Preparation 34 To a solution of benzyl N-(3-cyclohexene-1-yl)carbamate (1.7 g) in a 10 mixture of tetrahydrofuran (40 mL) and water (2 mL) was added N-methyl morpholine N-oxide (1.29 g) and osmium tetroxide (5 mL of 4% solution in water). The mixture was stirred at ambient temperature for 30 minutes. The resulting mixture was evaporated in vacuo and the obtained residue was diluted with ethyl acetate. The organic layer was washed successively 15 with 1N hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution and brine. The obtained organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give (1p, 3a, 4a)-benzyl N-(3,4-dihydroxy-1 cyclohexyl)carbamate (374 mg) as a solid. 20 NMR(DMSO-d 6 , 6): 1.15 (1H, m) , 1.34 (1H, m), 1.44-1.83 (4H, m), 3.35 (1H, m), 3.64 (1H, m), 3.74 (1H, m), 4.28 (1H, d , J=3Hz), 4.34 (1H, d, J=5Hz), 4.99 (2H, s), 7.08 (1H, d, J=7Hz), 7.26-7.41 (5H, m). The residual solution after removing the crystals was evaporated. The residue was subjected to a silica gel column chromatography eluting with a 25 mixture of chloroform and methanol (9:1). The obtained product was triturated with diethyl ether to give (la, 3a, 4a)-benzyl N-(3,4-dihydroxy-1 cyclohexyl)carbamate (565 mg) as a solid. NMR(DMSO-d 6 , 6): 1.24-1.69 (6H, m), 3.23-3.46 (2H, m), 3.63 (1H, m), 4.20 (iH, d , J=2Hz), 4.50 (1H, d, J=5Hz), 4.99 (2H, s), 7.17 (1H, d, J=7H), 30 7.26-7.42 (5H, m). Preparation 35 80 WO 01/05770 PCT/JPOO/04687 A mixture of (1 , 3a, 4a)-benzyl N-(3,4-dihydroxy-1 cyclohexyl)carbamate (173 mg) and 10% palladium on activated carbon (34 mg) in ethanol (6 mL) was stirred at ambient temperature under hydrogen atmosphere (3 atm) for an hour. The catalyst was removed by filtration, 5 and the filtrate was evaporated in vacuo. The residue was recrystallized from ethanol-diethyl ether to give (1s, 3a, 4a)- 1-amino-3,4-cyclohexanediol (73 mg) as a solid. NMR(CDCl 3 , 6): 1.06-1.44 (2H, m), 1.65-1.66 (2H, m), 1.84 (1H, m), 2.04 (1H, m), 3.07 (1H, m), 3.58 (1H, m), 3.96 (1H, m). 10 Preparation 36 (la, 3a, 4a)-1-Amino-3,4-cyclohexanediol was obtained in a manner similar to Preparation 23. NMR(CDCl 3 , 6): 1.42-1.78 (7H, m), 1.91 (1H, m), 2.88 (1H, m), 3.68 (1H, m), 15 3.75 (1H, m). Preparation 37 A mixture of methyl 3-cyano-4-methoxybenzoate (5g), tetrahydrofuran (25 mL) and sodium borohydride (1.98g) was heated at 20 45 0 C. The mixture was dropwise added with methanol (6.36 mL) at 45 55*C over 15 minutes and then refluxed for 3.5 hours. After cooling to 0"C, the mixture was added with an aqueous saturated ammonium chloride solution at the same temperature. The mixture was stirred at room temperature for an hour, and extracted with ethyl acetate. The organic 25 layer was washed successively with water, an aqueous saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residual solid was triturated with diisopropyl ether to give 3-cyano-4-methoxybenzyl alcohol (3.75 g) as a pale brown solid. 30 mp. 75-76 0 C NMR(DMSO-d 6 , 6): 3.90(3H, s), 4.45(2H, d, J=5.5Hz), 5.28(1H, t, J=5.5Hz), 81 WO 01/05770 PCT/JPOO/04687 7.21(1H, d, J=9.5Hz), 7.60(1H, d, J=9.5Hz), 7.62(1H, s). Preparation 38 To a solution of 3-cyano-4-methoxybenzyl alcohol (500mg) in 5 dichloromethane (5 mL) was added phosphorus tribromide (0. 146mL) under ice-water cooling. The mixture was stirred at 09C for 3 hours and partitioned between chloroform and water. The separated organic layer was washed successively with water, an aqueous saturated sodium bicarbonate solution and brine. The organic layer was dried over 10 magnesium sulfate and evaporated in vacuo. The residual solid was triturated with diisopropyl ether to give 3-cyano-4-methoxybenzyl bromide as an off-white solid (456.3 mg). mp. 127-128*C NMR(DMSO-d 6 , 6):3.93(3H, s), 4.71(2H, s), 7.26(1H, d, J=8.5Hz), 7.76(1H, 15 dd, J=8.5, 2.5Hz), 7.84(1H, d, J=2.5Hz). Preparation 39 The following compounds described in (1) to (3) were obtained in a manner similar to Preparation 38. 20 (1) 3-Bromo-4-methoxybenzyl bromide NMR(CDCl 3 , 6): 3.90 (3H, s), 4.44 (2H, s), 6.85 (1H, d, J= 8 Hz), 7.30 (1H, dd, J= 4, 8 Hz), 7.59 (1H, d, J= 4 Hz). 25 (2) 3-Fluoro-4-methoxybenzyl bromide NMR(CDCla, 6): 3.89 (3H, s), 4.45 (2H, s), 6.91 (1H, t, J= 8 Hz), 7.07-7.15 (2H, m). (3) 4-Methyl-3-methoxybenzyl bromide 30 NMR(CDC1 3 , 6): 2.20 (3H, s), 3.83 (3H, s), 4.49 (2H, s), 6.77 (1H, d, J= 8 Hz), 7.18 (2H, m). 82 WO 01/05770 PCT/JPOO/04687 Preparation 40 A mixture of 6-hydroxy-5-nitronicotinamide (343 g), phosphorus oxychloride (40 ml) and phosphorus pentachloride (1287 g) was heated at 5 130C for 3.5 hours. After cooling to ambient temperature, the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and an aqueous saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and evaporated to afford 6-chloro-5-nitronicotinonitrile (374 g) as an oil. 10 NMR(DMSO-d 6 , 6): 9.22(1H, d, J=2.0Hz), 9.25(1H, d, J=2.OHz). Preparation 41 To a solution of 4-methoxy-3-nitrotoluene (5.02 g) and N bromosuccinimide (5.51 g) in dichloromethane (50 mL) was added 2,2' 15 azobis(4-methoxy-2,4-dimethylvaleronitrile) (463 mg). The mixture was heated under reflux for 8 hours. The solution was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with n-hexane-ethyl acetate (20:1) to give 4-methoxy-3 nitrobenzyl bromide as a pale yellow powder (5.78 g). 20 NMR(CDC1 3 , 6) : 3.98'(3H, s), 4.47 (2H, s), 7.07 (1H, d, J= 8 Hz), 7.58 (1H, dd, J= 2 Hz, 8 Hz), 7.90 (1H, d, J= 2 Hz). Preparation 42 To a solution of 4-hydroxybenzaldehyde (100 g) in chloroform (1 L) 25 was added N-chlorosuccinimide (120 g) at ambient temperature and the mixture was stirred at 50*C for 18 hours. After evaporation of the solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The crude crystals was washed with diisopropyl 30 ether and recrystallized from a mixture of ethyl acetate and n-hexane to obtain 3-chloro-4-hydroxybenzaldehyde (85.8 g) as colorless crystals. 83 WO 01/05770 PCT/JPOO/04687 NMR(CDCl 3 , 6): 6.16 (1H, br), 7.16 (1H, d, J= 8 Hz), 7.74 (1H, d, J= 8 Hz), 7.89 (1H, s), 9.83 (1H, s). Preparation 43 5 To a solution of 3-chloro-4-hydroxybenzaldehyde (153 g) in dimethylformamide (500 ml) was added potassium carbonate (203 g) under ice-cooling, followed by iodomethane (91.3 ml). After stirring at ambient temperature for 2 hours, the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The 10 combined organic layer were washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The oily residue was triturated with n-hexane to obtain 3-chloro-4-methoxybenzaldehyde (156 g) as a white powder. NMR(CDCl 3 , 6): 4.00 (3H, s), 7.05 (1H, d, J= 8 Hz), 7.78 (1H, dd, J= 2 Hz, 8 15 Hz), 7.92 (1H, d, J= 2 Hz), 9.86 (s, 1H). Preparation 44 To a solution of 3-chloro-4-methoxybenzaldehyde (156 g) in a mixture of ethanol (750 ml) and tetrahydrofuran (500 ml) was added 20 sodium borohydride (25 g) under ice-cooling. After stirring at ambient temperature for 2 hours, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, 1N-hydrochloric acid, water, aqueous sodium bicarbonate and brine, successively, and dried over magnesium sulfate. Evaporation of the solvent gave 3-chloro-4 25 methoxybenzyl alcohol (164 g) as a yellow oil. NMR(CDCl 3 , 6 ) : 1.70 (1H, t, J= 7 Hz), 3.90 (3H, s), 4.60 (2H, d, J= 7 Hz), 6.90 (1H, d, J= 8 Hz), 7.22 (1H, dd, J= 4 Hz, 8 Hz), 7.39 (1H, d, J= 4 Hz). Preparation 45 30 To a solution of 3-chloro-4-methoxybenzyl alcohol (164 g) in dichloromethane (800 ml) was added phosphorus tribromide (45.1 ml) under ice-cooling and the mixture was stirred at ambient temperature for 84 WO 01/05770 PCT/JPOO/04687 an hour followed by adding water to the mixture. The separated aqueous layer was extracted with dichloromethane. The combined organic layers were washed with an aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The oily 5 residue was triturated with n-hexane to obtain 3-chloro-4-methoxybenzyl bromide (200 g) as a white powder. NMR(CDCl 3 , 6): 3.92 (3H, s), 4.45 (2H, s), 6.89 (1H, d, J= 8 Hz), 7.27 (1H4, d, J= 8 Hz), 7.43 (1H, s). 10 Preparation 46 Fuming nitric acid(10.4ml) was added dropwise to a mixture of 6 hydroxynicotinic acid (15g) and concentrated sulfuric acid(45ml) at 0*C. The reaction mixture was slowly heated to 45*C and maintained at the same temperature for 3 hours. The mixture was poured into ice-water, 15 and the resultant precipitate was collected by suction filtration, washed with water, and air-dried to give 6-hydroxy-5-nitronicotinic acid (8.63g) as a pale yellow solid. mp. 277-278*C NMR(DMSO-d 6 , 6) : 8.37(1H, d, J=2.5Hz), 8.65(1H, d, J=2.5Hz). 20 MS m/z: 183(M+-1). Preparation 47 6-Hydroxy-5-nitronicotinic acid (7.58 g) and thionyl chloride (48.1 ml) were combined under nitrogen atmosphere, and the mixture was 25 refluxed for 2 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (10 ml), and the solution was added dropwise to the mixture of ammonium hydroxide (28% in water) (20 ml) and dichloromethane (10 ml) at 0*C with stirring. The precipitate was collected 30 by suction filtration and washed with water to give 6-Hydroxy-5 nitronicotinamide (4.97 g) as a yellow solid. 85 WO 01/05770 PCT/JPOO/04687 mp. 280-281*C NMR(DMSO-d 6 , 6): 6.98(lH, br), 7.67(lH, br), 8.51(lH, d, J=2.5Hz), 8.58(lH, d, J=2.5Hz). MS m/z: 182(M+-1). 5 Preparation 48 To a solution of 6-chloro-5-nitronicotinonitrile (3.5 g) in N,N dimethylformamide (35 ml) was added trans-4-aminocyclohexanol (4.39 g) at 0 0 C. The mixture was stirred at ambient temperature for 45 minutes 10 under nitrogen atmosphere, and diluted with ethyl acetate. The resultant organic solution was washed with water (3 times) and brine, dried over magnesium sulfate, and concentrated in vacuo. The residual solid was washed with diethyl ether to give 6-(trans-4-hydroxycyclohexylamino)-5 nitronicotinonitrile (3.38 g) as a yellow solid. 15 mp. 157-158*C NMR(DMSO-d 6 , 6) : 1.20-1.35(2H, m), 1.45-1.61(2H, m), 1.80-1.95(4H, m), 3.39-3.50(lH, m), 4.08-4.23(1H, m), 4.63(lH, d, J=4.OHz), 8.47(1H, d, J=8.OHz), 8.83(1H, d, J=2.OHz), 8.88(1H, d, J=2.OHz). MS m/z : 261(M+-1). 20 Preparation 49 6-(trans-4-Hydroxycyclohexylamino)-5-nitronicotinonitrile (3.35 g) was dissolved in a mixture of methanol (17 ml) and 1,4-dioxane (17 ml), and 10% palladium on carbon (383 mg) was added to the solution under 25 nitrogen atmosphere. The mixture was shaken at ambient temperature for 3 hours under hydrogen atmosphere (3 atm). The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo to give 5-anino-6-(trans-4-hydroxycyclohexylamino)nicotinonitrile (3.15 g) as a brown amorphous. 30 NMR(DMSO-d 6 , 6): 1.16-1.34 (4H, m), 1.77-1.98 (4H, m), 3.36-3.49 (1H, m) , 3.78-3.92 (1H, m), 4.57 (1H, d, J= 4.5 Hz), 5.20 (2H, s), 6.22 (1H, d, J= 86 WO 01/05770 PCT/JPOO/04687 7.0 Hz), 6.77 (1H, d, J= 2.0 Hz), 7.78 (1H, d, J = 2.0 Hz). MS m/z : 231(M+-1) Example 1 5 To a solution of 1-(trans-4-hydroxycyclohexyl)-5-trifluoromethyl 2,3-dihydro- 1H-benzimidazol-2-one (200 mg) in anhydrous N,N dimethylformamide (2 mL) was added portionwise sodium hydride (29.3 mg, 60 % dispersion in mineral oil) at 5 0 C under nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. After adding 10 3,4-dimethoxybenzylbromide (154 mg), the mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and water. The separated organic layer was washed successively with 1 N-hydrochloric acid, water, an aqueous saturated sodium hydrogencarbonate solution and brine. The organic layer was dried over 15 magnesium sulfate and evaporated in vacuo. The residue was subjected to a preparative silica gel column chromatography eluting with 5 % methanol in chloroform. The obtained amorphous was recrystallized from diethyl ether to give 3-(3,4-dimethoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5 trifluoromethyl-2,3-dihydro-1H-benzimidazol-2-one (217.9 mg) as a 20 colorless solid. mp. 108-110"C NMR(DMSO-d 6 , 6): 1.28-1.47(2H, m), 1.66-1.79(2H, m), 1.90-2.02(2H, m), 2.15-2.33(2H, m), 3.50-3.65(1H, m), 3.69(3H, s), 3.70(3H, s), 4.20-4.34(1H, m), 4.69(1H, d, J=4.5Hz), 5.04(2H, s), 6.82(1H, d, J=8.OHz), 6.89(1H, d, 25 J=8.OHz), 7.06(1H, s), 7.36(1H, d, J=8.OHz), 7.55(1H, d, J=8.OHz), 7.56(1H, s). Example 2 The following compounds described in (1) to (112) were obtained in 30 a manner similar to Example 1. (1) 1-Cyclopentyl-3-(3,4-dimethoxybenzyl)-5-nitro-2,3-dihydro-1H 87 WO 01/05770 PCT/JPOO/04687 benzimidazol-2-one mp. 121-123 0 C NMR(DMSO-d 6 , 6): 1.59-1.75(2H, m), 1.85-2.12(6H, m), 3.70(3H, s), 3.73(3H, s), 4.86(1H, quint., J=8.5Hz), 5.09(2H, s), 6.83(1H, dd, J=8.5, 5 2.0Hz), 6.90(1H, d, J=8.5Hz), 7.07(1H, d, J=2.0Hz), 7.44(1H, d, J=8.5Hz), 8.02(1H, dd, J=8.5, 2.0Hz), 8.07(1H, d, J=2.OHz). (2) 3-(4-Chloro-3-methoxybenzyl)-1-cyclopentyl-5-nitro-2,3-dihydro-1H benzimidazol-2-one 10 mp. 170-171.5C NMR(DMSO-d 6 , 6): 1.59-1.77(2H, m), 1.85-2.15(6H, m), 3.84(3H, s), 4.86(1H, quint., J=8.OHz), 5.17(2H, s), 6.83(1H, d, J=8.OHz), 7.28(1H, s), 7.37(1H, d, J=8.OHz), 7.46(1H, d, J=8.OHz), 8.05(1H, dd, J=8.0, 1.5Hz), 8.10(1H, d, J=1.5Hz). 15 (3) 3-(3,4-Dimethoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5-nitro-2,3 dihydro- 1H-benzinidazol-2-one mp. 175-176*C NMR(DMSO-d 6 , 6): 1.30-1.47(2H, m), 1.68-1.79(2H, m), 1.91-2.01(2H, m), 20 2.15-2.33(2H, m), 3.51-3.64(1H, m), 3.70(3H, s), 3.72(3H, s), 4.23-4.35(1H, m), 4.71(1H, d, J=4.5Hz), 5.08(2H, s), 6.83(1H, dd, J=8.5, 2.5Hz), 6.90(1H, d, J=8.5Hz), 7.05(1H, d, J=2.5Hz), 7.60(1H, d, J=9.OHz), 7.99(1H, dd, J=9.0, 2.0Hz), 8.06(1H, d, J=2.OHz). 25 (4) 3-(3,4-Dimethoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5 trifluoromethyl-2,3-dihydro- 1H-benzimidazol-2-thione NMR(DMSO-d 6 , 6): 1.28-1.45(2H, m), 1.65-1.75(2H, m), 1.90-2.00(2H, m), 2.15-2.33(2H, m), 3.55-3.74(1H, m), 3.69(3H, s), 3.71(3H, s), 4.19-4.33(1H, m), 4.56(2H, s), 4.73(1H, d, J=4.5Hz), 6.88(1H, d, J=8.OHz), 6.99(1H, dd, 30 J=8.0, 1.5Hz), 7.08(1H, d, J=1.5Hz), 7.45(lH, dd, J=8.5, 1.5Hz), 7.91(1H, d, J=8.5Hz), 7.93(1H, d, J=1.5Hz). 88 WO 01/05770 PCT/JPOO/04687 MS m/z: 467(M++1). (5) 5-Cyano-3-(3,4-dimethoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-2,3 dihydro- 1 H-benzimidazol-2-one 5 mp. 209-210'C NMR(DMSO-d 6 , 6): 1.26-1.47(2H, m), 1.65-1.77(2H, m), 1.86-2.01(2H, m), 2.13-2.32(2H, m), 3.50-3.65(1H, m), 3.70(3H, s), 3.72(3H, s), 4.20-4.34(1H, m), 4.69(1H, d, J=4.5Hz), 4.98(2H, s), 6.86(1H, d, J=8.OHz), 6.90(1H, d, J=8.OHz), 7.04(1H, s), 7.49(1H, d, J=8.OHz), 7.57(1H, d, J=8.OHz), 7.72(1H, 10 s). (6) 3-(3,4-Dimethoxybenzyl)-1-((R)-2-hydroxy-1-methylethyl)-5 trifluoromethyl-2,3-dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.42(3H, d, J=7.5Hz), 3.57-3.73(1H, m), 3.70(6H, s), 15 3.82-3.96(1H, m), 4.45-4.61(1H, m), 4.95(1H, t, J=4.5Hz), 5.05(2H, s), 6.84(1H, d, J=8.5Hz), 6.89(1H, d, J=8.5Hz), 7.05(1H, s), 7.35(1H, d, J=8.5Hz), 7.46(1H, d, J=8.5Hz), 7.52(1H, s). (7) 5-Acetyl-3-(3,4-dimethoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-2,3 20 dihydro- 1H-benzimidazol-2-one mp. 169-170*C NMR(DMSO-d 6 , 6): 1.30-1.45(2H, m), 1.65-1.77(2H, m), 1.90-2.00(2H, m), 2.15-2.33(2H, m), 2.53(3H, s), 3.52-3.64(1H, m), 3.69(3H, s), 3.71(3H, s), 4.20-4.32(1H, m), 4.69(1H, d, J=4.OHz), 5.03(2H, s), 7.78(1H, dd, J=8.0, 25 2.0Hz), 6.88(1H, d, J=8.OHz), 7.04(1H, d, J=2.OHz), 7.47(1H, d, J=8.OHz), 7.69(1H, d, J=1.5Hz), 7.71(1H, dd, J=8.0, 1.5Hz). (8) 3-(3,4-Dimethoxybenzyl)-1-(trans-4-formamidocyclohexyl)-5 trifluoromethyl-2,3-dihydro- 1H-benzimidazol-2-one 30 mp. 158-160.5"C NMR(DMSO-d 6 , 6): 1.32-1.52(2H, m), 1.70-1.83(2H, m), 1.85-2.02(2H, m), 89 WO 01/05770 PCT/JPOO/04687 2.20-2.40(2H, m), 3.69(3H, s), 3.71(3H, s), 3.75-3.89(1H, m), 4.22-4.38(1H, m), 5.05(2H, s), 6.83(1H, d, J=7.5Hz), 6.89(1H, d, J=7.5Hz), 7.07(1H, s), 7.36(1H, d, J=7.5Hz), 7.56(1H, s), 7.65(1H, d, J=7.5Hz), 7.98(1H, s), 8.05(1H, d, J=7.5Hz). 5 MS m/z: 478(M++1). (9) 5-Chloro-3--(3,4-dimethoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-2,3 dihydro- 1H-benzimidazol-2-one mp. 166-1679C 10 NMR(DMSO-d 6 , 6): 1.27-1.44(2H, m), 1.62-1.73(2H, m), 1.87-1.99(2H, m), 2.11-2.29(2H, m), 3.49-3.63(1H, m), 3.70(3H, s), 3.71(3H, s), 4.12-4.25(1H, m), 4.67(1H, d, J=4.5Hz), 4.95(2H, s), 6.81(1H, dd, J=8.5, 2.0Hz), 6.89(1H, d, J=8.5Hz), 7.02(1H, d, J=2.OHz), 7.04(1H, dd, J=8.5, 2.0Hz), 7.28(lH, d, J=2.OHz), 7.37(1H, d, J=8.5Hz). 15 (10) 3-(3,4-Dimethoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5 methoxycarbonyl-2,3-dihydro- 1 H-benzimidazol-2-one mp. 148-149.54C NMR(DMSO-d 6 , 6): 1.27-1.45(2H, m), 1.66-1.77(2H, m), 1.87-2.01(2H, m), 20 2.15-2.32(2H, m), 3.49-3.64(1H, m), 3.69(3H, s), 3.72(3H, s), 3.81(3H, s), 4.17-4.33(1H, m), 4.67(1H, d, J=4.5Hz), 5.03(2H, s), 6.73(1H, dd, J=8.5, 2.0Hz), 6.88(1H, d, J=8.5Hz), 7.01(1H, d, J=2.OHz), 7.48(1H, d, J=8.5Hz), 7.65(1H, d, J=2.OHz), 7.69(1H, dd, J=8.5, 2.0Hz). 25 (11) 3-(3,4-Dimethoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5-methoxy 2,3-dihydro- 1H-benzimidazol-2-one mp. 176-1779C NMR(DMSO-d6, 6 ): 1.27-1.43(2H, m), 1.60-1.72(2H, m), 1.87-1.99(2H, m), 2.11-2.30(2H, m), 3.50-3.62(1H, m), 3.70(9H, s), 4.09-4.22(1H, m), 4.66(1H, 30 d, J=4.5Hz), 4.91(2H, s), 6.57(1H, dd, J=8.5, 2.0Hz), 6.79(1H, d, J=2.OHz), 6.81(1H, dd, J=8.5, 2.0Hz), 6.87(1H, d, J=8.5Hz), 7.02(1H, d, J=2.OHz), 90 WO 01/05770 PCT/JPOO/04687 7.21(1H, d, J=8.5Hz). MS m/z : 413(M++ 1). (12) 3-(trans-4-Acetoxycyclohexyl)-1-(3,4-dimethoxybenzyl)-6 5 trifluoromethyl-2,3-dihydro- 1H-imidazo[4,5-b]pyridin-2-one mp. 130-133*C NMR(DMSO-d 6 , 6): 1.46-1.63(2H, m), 1.76-1.89(2H, m), 1.95-2.10(2H, m), 2.02(3H, s), 2.40-2.54(2H, m), 3.70(3H, s), 3.71(3H, s), 4.34-4.48(1H, m), 4.60-4.74(1H, m), 5.05(2H, s), 6.87(1H, d, J=8.OHz), 6.90(1H, d, J=8.OHz), 10 7.08(1H, s), 7.94(1H, s), 8.39(1H, s). MS m/z: 494(M++1). (13) 3-Cyclopentyl-1-(3,4-dimethoxybenzyl)-6-trifluoromethyl-2,3 dihydro-1H-imidazo[4,5-b]pyridin-2-one 15 mp. 115-116'C NMR(DMSO-d 6 , 6): 1.58-1.71(2H, m), 1.85-2.00(4H, m), 2.12-2.27(2H, m), 3.70(3H, s), 3.72(3H, s), 4.81-4.94(1H, m), 5.05(2H, s), 6.86(1H, dd, J=8.5, 2.5Hz), 6.89(1H, d, J=8.5Hz), 7.09(1H, d, J=2.5Hz), 7.94(1H, d, J=2.5Hz), 8.38(1H, d, J=2.5Hz). 20 (14) 1-(trans-2-Acetoxycyclopentyl)-3-(3,4-dimethoxybenzyl)-5 trifluoromethyl-2,3-dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.67-1.96(3H, m), 1.99(3H, s), 2.06-2.31(3H, m), 3.70(6H, s), 4.70-4.81(1H, m), 5.05(2H, s), 5.50-5.59(1H, m), 6.84(1H, dd, 25 J=8.5, 2.0Hz), 6.89(1H, d, J=8.5Hz), 7.03(1H, d, J=2.OHz), 7.39(1H, dd, J=8.5, 2.0Hz), 7.47(1H, d, J=8.5Hz), 7.53(1H, d, J=2.OHz). (15) 3-(trans-4-Acetoxycyclohexyl)-1-(3-chloro-4-methoxybenzyl)-6 trifluoromethyl-2,3-dihydro- 1H-imidazo[4,5-b]pyridin-2-one 30 mp. 165-1669C NMR(DMSO-d 6 , 8): 1.46-1.64(2H, m), 1.77-1.88(2H, m), 1.97-2.08(2H, m), 91 WO 01/05770 PCT/JPOO/04687 2.02(3H, s), 2.387-2.51(2H, m), 3.82(3H, s), 4.34-4.46(1H, m), 4.60-4.74(1H, m), 5.06(2H, s), 7.1 1(1H, d, J=8.OHz), 7.33(1H, dd, J=8.0, 2.5Hz), 7.52(1H, d, J=2.5Hz), 8.00(1H, d, J=1.5Hz), 8.40(1H, d, J=1.5Hz). 5 (16) 3-(3-Chloro-4-methoxybenzyl)-1- (trans-4-hydroxycyclohexyl) -5-nitro 2,3-dihydro- 1H-benzimidazol-2-one mp. 142-142.59C NMR(DMSO-d 6 , 6): 1.29-1.47(2H, m), 1.69-1.80(2H, m), 1.90-2.02(2H, m), 2.14-2.31(2H, m), 3.50-3.64(1H, m), 3.81(3H, s), 4.21-4.36(1H, m), 4.70(1H, 10 d, J=4.5Hz), 5.11(2H, s), 7.11(1H, d, J=8.5Hz), 7.30(1H, dd, J=8.5, 2.0Hz), 7.48(1H, d, J=2.OHz), 7.60(1H, d, J=9.OHz), 8.00(1H, dd, J=9.0, 2.0Hz), 8.11(1H, d, J=2.OHz). (17) 1-(3-Chloro-4-methoxybenzyl)-3-cyclopentyl-6-trifluoromethyl-2,3 15. dihydro- 1H-inidazo[4,5-b]pyridin-2-one mp. 156-15790 NMR(DMSO-d 6 , 6): 1.55-1.74(2H, m), 1.85-2.02(4H, m), 2.12-2.30(2H, m), 3.82(3H, s), 4.80-4.94(1H, m), 5.06(2H, s), 7.13(1H, d, J=8.5Hz), 7.34(1H, dd, J=8.5, 2.5Hz), 7.53(1H, d, J=2.5Hz), 8.00(1H, s), 8.40(1H, s). 20 MS m/z: 426(M++1). (18) 1-((S)-1-tert-Butoxycarbonylpyrrolidin-3-yl)-3-(3,4-dimethoxybenzyl) 5-trifluoromethyl-2,3-dihydro- 1H-benzimidazol-2-one mp. 122-122.5C 25 NMR(DMSO-d 6 , 6): 1.41(9H, s), 2.10-2.25(1H, m), 2.45-2.57(1H, m), 3.27 3.40(1H, m), 3.52-3.74(3H, m), 3.70(3H, s), 3.71(3H, s), 5.05(2H, s), 5.05 5.18(1H, m), 6.83(1H, dd, J=8.0, 2.0Hz), 6.89(1H, d, J=8.OHz), 7.09(1H, d, J=2.OHz), 7.41(1H, d, J=8.OHz), 7.44(1H, d, J=8.OHz), 7.59(1H, s). MS m/z: 522(M++1). 30 (19) 1-((S)-1-tert-Butoxycarbonylpyrrolidin-3-yl)-3-(3-chloro-4 92 WO 01/05770 PCT/JPOO/04687 methoxybenzyl)-5-trifluoromethyl-2,3-dihydro- 1H-benzimidazol-2-one mp. 157-157.5'C NMR(DMSO-d 6 , 6): 1.41(9H, s), 2.12-2.25(1H, m), 2.45-2.57(1H, m), 3.29 3.39(1H, m), 3.52-3.70(3H, m), 3.81(3H, s), 5.07(2H, s), 5.05-5.16(1H, m), 5 7.12(1H, d, J=8.5Hz), 7.30(1H, dd, J=8.5, 2.0Hz), 7.44(2H, s), 7.49(1H, d, J=2.0Hz), 7.62(1H, s). MS m/z: 526(M++1). (20) 1-(1H-Benzimidazol-5-yl)-3-(3,4-dimethoxybenzyl)-5-trifluoromethyl 10 2,3-dihydro- 1H-benzimidazol-2-one mp. 174-175*C NMR(DMSO-d 6 , 6): 3.72(3H, s), 3.74(3H, s), 5.16(2H, s), 6.93(1H, d, J=8.5Hz), 6.95(1H, s), 7.10(1H, d, J=8.5Hz), 7.16(1H, s), 7.30-7.41(2H, m), 7.68(1H, s), 7.72-7.85(2H, m), 8.38(1H, s). 15 MS m/z: 467(M+-1) (21) 1-(1H-Benzimidazol-5-yl)-3-(3-chloro-4-methoxybenzyl)-5 trifluoromethyl-2,3-dihydro- 1H-benzimidazol-2-one mp. 158-160"C 20 NMR(DMSO-d 6 , 6): 3.83(3H, s), 5.18(2H, s), 7.06-7.18(1H, br), 7.15(1H, d, J=8.5Hz), 7.30-7.45(3H, m), 7.58(1H, d, J=2.5Hz), 7.71(1H, s), 7.70-7.88(2H, br), 8.38(1H, s). MS m/z : 471(M+-1). 25 (22) 5-Acetyl-3-(3-chloro-4-methoxybenzyl)-1-(trans-4 hydroxycyclohexyl)-2,3-dihydro- 1H-benzimidazol-2-one mp. 209-210*C NMR(DMSO-d 6 , 6): 1.30-1.46(2H, m), 1.66-1.77(2H, m), 1.89-2.00(2H, m), 2.15-2.32(2H, m), 2.54(3H, s), 3.51-3.65(1H, m), 3.80(3H, s), 4.19-4.32(1H, 30 m), 4.69(1H, d, J=4.OHz), 5.06(2H, s), 7.11(1H, d, J=8.5Hz), 7.25(1H, dd, J=8.5, 2.0Hz), 7.43(1H, d, J=2.OHz), 7.48(1H, d, J=8.5Hz), 7.71(1H, d, 93 WO 01/05770 PCT/JPOO/04687 J=1.5Hz), 7.72(1H, dd, J=8.5, 1.5Hz). (23) 3-(trans-4-Acetoxycyclohexyl)-1-(3,4-dichlorobenzyl)-6 trifluoromethyl-2,3-dihydro- 1H-imidazo[4,5-b]pyridin-2-one 5 NMR(DMSO-d 6 , 6): 1.46-1.65(2H, m), 1.79-1.90(2H, m), 1.99-2.08(2H, m), 2.02(3H, s), 2.38-2.56(2H, m), 4.32-4.45(1H, m), 4.60-4.74(1H, m), 5.14(2H, s), 7.32(1H, dd, J=8.5, 2.0Hz), 7.61(1H, d, J=8.5Hz), 7.71(1H, d, J=2.OHz), 8.01(1H, d, J=2.OHz), 8.42(1H, d, J=2.OHz). 10 (24) 3-(3-Chloro-4-methoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5 trifluoromethyl-2,3-dihydro- 1 H-benzimidazol-2-one mp. 167-1681C NMR(DMSO-d 6 , 8): 1.29-1.45(2H, m), 1.65-1.76(2H, m), 1.90-2.00(2H, m), 2.14-2.30(2H, m), 3.51-3.64(1H, m), 3.81(3H, s), 4.17-4.30(1H, m), 4.69(1H, 15 d, J=4.5Hz), 5.06(2H, s), 7.11(1H, d, J=8.5Hz), 7.27(1H, dd, J=8.5, 2.0Hz), 7.37(1H, dd, J=8.5, 1.5Hz), 7.47(1H, d, J=2.OHz), 7.56(1H, d, J=8.5Hz), 7.60(1H, d, J=1.5Hz). (25) 1-(trans-4-Acetoxycyclohexyl)-3-(3,4-dimethoxybenzyl)-5-methyl-2,3 20 dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.47-1.64(2H, m), 1.67-1.80(2H, m), 1.97-2.08(2H, m), 2.02(3H, s), 2.21-2.40(2H, m), 2.28(3H, s), 3.69(3H, s), 3.71(3H, s), 4.20 4.35(1H, m), 4.73-4.86(1H, m), 4.92(2H, s), 6.77(1H, dd, J=8.0, 2.0Hz), 6.82(1H, d, J=8.0Hz), 6.87(1H, d, J=8.OHz), 6.96(1H, s), 6.99(1H, d, 25 J=2.OHz), 7.30(1H, d, J=8.OHz). MS m/z: 439(M++1). (26) 3-(3,5-Dichloro-4-methoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5 nitro-2,3-dihydro- 1H-benziinidazol-2-one 30 mp. 115-116'C NMR(DMSO-d 6 , 6): 1.30-1.46(2H, m), 1.70-1.81(2H, m), 1.90-2.00(2H, m), 94 WO 01/05770 PCT/JPOO/04687 2.13-2.31(2H, m), 3.51-3.64(1H, m), 3.79(3H, s), 4.20-4.35(1H, m), 4.69(lH, d, J=4.5Hz), 5.14(2H, s), 7.51(2H, s), 7.63(1H, d, J=9.OHz), 8.02(1H, dd, J=9.0, 2.5Hz), 8.19(1H, d, J=2.5Hz). 5 (27) 3-(3-Chloro-4-methoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5 methoxycarbonyl-2,3-dihydro- 1H-benzimidazol-2-one mp. 174-175 C NMR(DMSO-d 6 , 6): 1.29-1.45(2H, m), 1.67-1.78(2H, m), 1.89-2.00(2H, m), 2.15-2.31(2H, m), 3.50-3.64(1H, m), 3.81(3H, s), 3.82(3H, s), 4.19-4.32(1H, 10 m), 4.68(1H, d, J=4.5Hz), 5.06(2H, s), 7. 10(1H, d, J=8.5Hz), 7.22(1H, dd, J=8.5, 2.5Hz), 7.41(1H, d, J=2.5Hz), 7.50(1H, d, J=8.5Hz), 7.68(1H, s), 7.70(1H, d, J=8.5Hz). (28) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-(trans-4 15 hydroxycyclohexyl) -2,3-dihydro- 1 H-benzimidazol-2-thione NMR(DMSO-d 6 , 6): 1.29-1.47(2H, m), 1.66-1.78(2H, m), 1.89-2.01(2H, m), 2.15-2.31(2H, m), 3.55-3.70(1H, m), 3.82(3H, s), 4.18-4.31(1H, m), 4.59(2H, s), 4.73(1H, d, J=4.5Hz), 7.09(1H, d, J=8.5Hz), 7.42(1H, dd, J=8.5, 2.5Hz), 7.55(1H, dd, J=8.5, 2.5Hz), 7.57(1H, d, J=2.5Hz), 7.90(1H, d, J=8.5Hz), 20 8.10(1H, d, J=2.5Hz). MS m/z : 428(M++ 1). (29) 3-(3-Chloro-4-ethoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5 trifluoromethyl-2,3-dihydro- 1H-benzimidazol-2-one 25 mp. 147.5-149*C NMR(DMSO-d 6 , 6): 1.32(3H, t, J=7.OHz), 1.29-1.45(2H, m), 1.65-1.76(2H, m), 1.89-2.00(2H, m), 2.14-2.30(2H, m), 3.51-3.64(1H, m), 4.06(2H, q, J=7.OHz), 4.18-4.31(1H, m), 4.69(1H, d, J=4.OHz), 5.05(2H, s), 7.09(1H, d, J=8.5Hz), 7.25(1H, dd, J=8.5, 2.5Hz), 7.37(1H, dd, J=8.5, 2.5Hz), 7.46(1H, d, 30 J=2.5Hz), 7.56(1H, d, J=8.5Hz), 7.60(1H, d, J=2.5Hz). 95 WO 01/05770 PCT/JPOO/04687 (30) 3-(3-Fluoro-4-methoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5 trifluoromethyl-2,3-dihydro- 1 H-benzimidazol-2-one mp. 178-179*C NMR(DMSO-d 6 , 6): 1.29-1.46(2H, m), 1.66-1.77(2H, m), 1.90-2.00(2H, m), 5 2.15-2.31(2H, m), 3.52-3.63(1H, m), 3.79(3H, s), 4.19-4.31(1H, m), 4.69(1H, d, J=4.5Hz), 5.05(2H, s), 7.08-7.14(2H, m), 7.23(1H, d, J=13.OHz), 7.37(1H, d, J=8.5Hz), 7.56(1H, d, J=8.5Hz), 7.56(1H, s). (31) 3-(3-Bromo-4-methoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5 10 trifluoromethyl-2,3-dihydro- 1H-benzimidazol-2-one mp. 182-182.5C NMR(DMSO-d 6 , 6): 1.29-1.45(2H, m), 1.65-1.77(2H, m), 1.89-2.02(2H, m), 2.15-2.32(2H, m), 3.51-3.65(1H, m), 3.80(3H, s), 4.18-4.31(1H, m), 4.69(1H, d, J=4.5Hz), 5.06(2H, s), 7.08(1H, d, J=8.5Hz), 7.32(1H, dd, J=8.5, 2.5Hz), 15 7.37(1H, d, J=8.5Hz), 7.56(1H, d, J=8.5Hz), 7.61(1H, s), 7.63(1H, d, J=2.5Hz). (32) 1-(tert-Butyl)-3-(3-chloro-4-methoxybenzyl)-5-trifluoromethyl-2,3 dihydro- 1H-benzimidazol-2-one 20 mp. 130.5-131.5 C NMR(DMSO-d 6 , 6): 1.75(9H, s), 3.81(3H, s), 5.04(2H, s), 7.12(1H, d, J=8.5Hz), 7.26(1H, dd, J=8.5, 2.5Hz), 7.32(1H, dd, J=8.5, 2.OHz), 7.45(1H, d, J=2.5Hz), 7.54(1H, d, J=2.OHz), 7.69(1H, d, J=8.5Hz). 25 (33) 3-(3,5-Dichloro-4-methoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5 trifluoromethyl-2,3-dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.27-1.45(2H, m), 1.66-1.78(2H, m), 1.89-1.99(2H, m), 2.12-2.29(2H, m), 3.52-3.64(1H, m), 3.79(3H, s), 4.17-4.31(1H, m), 4.69(1H, d, J=4.OHz), 5.09(2H, s), 7.39(1H, dd, J=8.0, 2.OHz), 7.49(2H, s), 7.59(1H, d, 30 J=8.OHz), 7.68(1H, d, J=2.OHz). 96 WO 01/05770 PCT/JPOO/04687 (34) 3-(3-Chloro-4-methoxybenzyl)-1-(tetrahydro-4H-pyran-4-yl)-5 trifluoromethyl-2,3-dihydro- 1H-benzimidazol-2-one mp. 175-1769C NMR(DMSO-d 6 , 6): 1.66-1.76(2H, m), 2.30-2.47(2H, m), 3.43-3.55(2H, m), 5 3.81(3H, s), 3.95-4.05(2H, m), 4.46-4.60(1H, m), 5.07(2H, s), 7.11(1H, d, J=8.5Hz), 7.30(1H, dd, J=8.5, 2.5Hz), 7.41(1H, d, J=8.5Hz), 7.48(1H, d, J=2.5Hz), 7.55(1H, d, J=8.5Hz), 7.62(1H, s). (35) 3-(3-Chloro-4-methoxybenzyl)-1-isopropyl-5-trifluoromethyl-2,3 10 dihydro- 1H-benzimidazol-2-one mp. 153.5-155"C NMR(DMSO-d 6 , 6): 1.48(6H, d, J=7.OHz), 3.81(3H, s), 4.69(1H, pent., J=7.OHz), 5.06(2H, s), 7.12(1H, d, J=8.5Hz), 7.29(1H, dd, J=8.5, 2.0Hz), 7.39(1H, dd, J=8.5, 1.5Hz), 7.47(1H, d, J=2.OHz), 7.52(1H, d, J=8.5Hz), 15 7.60(1H, d, J=1.5Hz). (36) 1-Butyl-3-(3-chloro-4-methoxybenzyl)-5-trifluoromethyl-2,3-dihydro 1H-benzimidazol-2-one mp. 122-124*C 20 NMR(DMSO-d 6 , 6): 0.89(3H, t, J=7.OHz), 1.20-1.34(2H, m), 1.59-1.70(2H, m), 3.81(3H, s), 3.93(2H, t, J=7.OHz), 5.08(2H, s), 7.11(1H, d, J=8.5Hz), 7.30(1H, dd, J=8.5, 2.0Hz), 7.42(2H, s), 7.45(1H, d, J=2.OHz), 7.61(1H, s). (37) 1-Cyclohexyl-3-(3-chloro-4-methoxybenzyl)-5-trifluoromethyl-2,3 25 dihydro- 1H-benzimidazol-2-one mp. 160-16 1'C NMR(DMSO-d 6 , 6): 1.20-1.51(3H, m), 1.63-1.90(5H, m), 2.05-2.21(2H, m), 3.81(3H, s), 4.19-4.32(1H, m), 5.06(2H, s), 7.11(1H, d,.J=8.5Hz), 7.28(1H, dd, J=8.5, 2.5Hz), 7.38(1H, d, J=8.5Hz), 7.47(1H, d, J=2.5Hz), 7.57(1H, d, 30 J=8.5Hz), 7.60(1H, s). 97 WO 01/05770 PCT/JPOO/04687 (38) 1-(3-Chloro-4-methoxybenzyl)-3-(trans-4-formamidocyclohexyl)-6 trifluoromethyl-2,3-dihydro- 1H-imidazo[4,5-b]pyridin-2-one mp. 207-2089C NMR(DMSO-d 6 , 6): 1.30-1.51(2H, m), 1.75-2.00(4H, m), 2.35-2.55(2H, m), 5 3.63-3.76(1H, m), 3.82(3H, s), 4.27-4.43(1H, m), 5.06(2H, s), 7.12(1H, d, J=8.5Hz), 7.33(1H, dd, J=8.5, 2.0Hz), 7.52(1H, d, J=2.OHz), 7.97(1H, s), 8.00(1H, s), 8.06(1H, d, J=7.OHz), 8.41(1H, s). (39) 3-(4-Chloro-3-methoxybenzyl)-5-cyano-1-(trans-4 10 hydroxycyclohexyl)-2,3-dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.22-1.46 (2H, m), 1.65-1.78 (2H, m), 1.86-2.00 (2H, m), 2.12-2.30 (2H, m), 3.50-3.64 (1H, m), 3.84 (3H, s), 4.19-4.31 (1H, m), 4.69 (1H, d, J=4 Hz), 5.05 (2H, s), 6.83 (1H, dd, J= 8, 2 Hz), 7.23 (1H, d, J=2 Hz), 7.36 (1H, d, J=8 Hz), 7.50 (1H, dd, J=8, 2 Hz), 7.60 (1H, d, J=8 Hz), 7.73 (1H, 15 d, J=2 Hz). (40) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-(trans-4 hydroxycyclohexyl)-2,3-dihydro-lH-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.28-1.46 (2H, m), 1.64-1.76 (2H, m), 1.86-2.00 (2H, m), 20 2.10-2.31 (2H, m), 3.49-3.64 (1H, m), 3.81 (3H, s), 4.17-4.32 (1H, m), 4.68 (1H, d, J=4 Hz), 4.99 (3H, s), 7.10 (1H, d, J=8 Hz), 7.31 (1H, dd, J=8, 2 Hz), 7.45-7.52 (2H, m), 7.56 (1H, d, J=8 Hz), 7.78 (1H, d, J=2 Hz). (41) 5-Cyano-3-(3,4-dimethoxybenzyl)-1-((R)-2-hydroxy-1-methylethyl) 25 2,3-dihydro- 1 H-benzimidazol-2-one NMR(CDC1 3 , 6): 1.55 (3H, d, J=7.5 Hz), 3.20 (1H, dd, J=5, 7.5 Hz), 3.85 (3H, s), 3.87 (3H, s), 3.99-4.16 (2H, m), 4.44-4.56 (1H, m), 5.00 (2H, s), 6.80-6.93 (3H, m), 7.10-7.18 (2H, m), 7.40 (1H, dd, J=8, 2 Hz). 30 (42) 5-Cyano-3-(3,4-dimethoxybenzyl)-1-((S)-2-hydroxy-1-methylethyl) 2,3-dihydro- 1 H-benzimidazol-2-one 98 WO 01/05770 PCT/JPOO/04687 NMR(CDC1 3 , 6):1.55 (3H, d, J=7.5 Hz), 3.20 (1H, dd, J=5, 7.5 Hz), 3.85 (3H, s), 3.87 (3H, s), 3.99-4.16 (2H, m), 4.44-4.56 (1H, m), 5.00 (2H, s), 6.80-6.93 (3H, m), 7.11-7.19 (2H, m), 7.40 (1H, dd, J=8, 2 Hz). 5 (43) 5-Cyano-3-(3,4-dimethoxybenzyl)-1-(trans-4-formamidocyclohexyl) 2,3-dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.31-1.51 (2H, m), 1.69-1.82 (2H, m), 1.82-2.01 (2H, m), 3.70 (3H, s), 3.72 (3H, s), 3.80 (1H, br), 4.23-4.38 (1H, m), 4.99 (2H, s), 6.83-6.92 (2H, m), 7.04 (1H, s), 7.49 (1H, dd, J=8, 2 Hz), 7.66 (1H, d, J=8 Hz), 10 7.72 (1H, d, J=2 Hz), 7.97 (1H, s), 8.05 (1H, d, J=8 Hz). (44) 3-(4-Chloro-3-methoxybenzyl)-5-cyano-1-(trans-4 formamidocyclohexyl)-2,3-dihydro-1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.32-1.55 (2H, m), 1.70-1.85 (2H, m), 1.85-2.00 (2H, m), 15 2.19-2.38 (2H, m), 3.72-3.91 (4H, m), 4.22-4.37 (1H, m), 5.06 (2H, s), 6.84 (1H, d, J=8 Hz), 7.24 (1H, s), 7.36 (1H, d, J=8 Hz), 7.50 (1H, d, J=8 Hz), 7.68 (1H, d, J=8 Hz), 7.74 (1H, s), 7.94 (1H, s), 8.05 (1H, d, J=8 Hz). (45) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-(trans-4 20 formamidocyclohexyl)-2,3-dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.32-1.55 (2H, m), 1.69-1.84 (2H, m), 1.84-2.00 (2H, m), 2.17-2.86 (2H, m), 3.72-3.88 (4H, m), 4.20-4.36 (1H, m), 5.00 (2H, s), 7.11 (1H, d, J=8 Hz), 7.33 (1H, dd, J=8, 2 Hz), 7.42-7.55 (2H, m), 7.67 (2H, d, J=8 Hz), 7.78 (1H, d, J=2 Hz), 7.97 (1H, s), 8.04 (1H, d, J=8 Hz). 25 (46) 5-Cyano-3-(2-methoxyphenethyl)-1-(trans-4-hydroxycyclohexyl)-2,3 dihydro-1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.25-1.43 (2H, m), 1.56-1.69 (2H, m), 1.86-1.97 (2H, m), 2.07-2.25 (2H, m), 2.90 (2H, t, J=7.5 Hz), 3.47-3.62 (1H, m), 3.64 (3H, s), 30 4.03 (2H, t, J=7.5 Hz), 4.10-4.24 (1H, m), 4.67 (1H, d, J=5 Hz), 6.74-6.89 (2H, m), 7.05 (1H, dd, J=8, 2 Hz), 7.15 (1H, ddd, J=8, 8, 2 Hz), 7.33 (1H, s), 99 WO 01/05770 PCT/JPOO/04687 7.43 (1H, d, J=8 Hz), 7.50 (1H, d, J=8 Hz). (47) 5-Cyano-3-(3,4-dimethoxybenzyl)-1-(2,2-dimethyl-1,3-dioxan-5-yl) 2,3-dihydro- 1H-benzimidazol-2-one 5 NMR(CDC1 3 , 6):1.50 (3H, s), 1.59 (3H, s), 3.86 (3H, s), 3.89 (3H, s), 4.10 (2H, dd, J=11, 5 Hz), 4.26 (2H, dd, J=11, 7.5 Hz), 4.66-4.78 (1H, m), 4.98 (2H, s), 6.80-6.92 (3H, m), 7.17 (1H, d, J=2 Hz), 7.42 (1H, dd, J=8, 2 Hz), 7.64 (1H, d, J=8 Hz). 10 (48) 3-(4-Chloro-3-methoxybenzyl)-5-cyano-1-(2,2-dimethyl-1,3-dioxan-5 yl)-2,3-dihydro- 1H-benzimidazol-2-one NMR(CDC1 3 , 6 ):1.50 (3H, s), 1.58 (3H, s), 3.89 (3H, s), 4.10 (2H, dd, J=5, 11 Hz), 4.25 (2H, dd, J=7, 11 Hz), 4.66-4.78 (1H, m), 5.00 (2H, s), 6.80 (1H, dd, J=8, 2 Hz), 6.90 (1H, d, J=2 Hz), 7.14 (1H, d, J=2 Hz), 7.32 (1H, d, J=8 Hz), 15 7.44 (1H, dd, J=8, 2 Hz), 7.67 (1H, d, J=2 Hz). (49) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-(2,2-dimethyl-1,3-dioxan-5 yl) -2,3-dihydro- 1 H-benzimidazol-2-one NMR(DMSO-d 6 , 6 ): 1.42 (3H, s), 1.51 (3H, s), 4.04 (2H, dd, J=11, 6 Hz), 20 4.24 (2H, dd, J= 11, 7.5 Hz), 4.54-4.64 (1H, m), 5.00 (2H, s), 7.11 (1H, d, J=8 Hz), 7.33 (1H, dd, J=8, 2 Hz), 7.50 (1H, d, J=2 Hz), 7.56 (1H, dd, J=8, 2 Hz), 7.74-7.82 (2H, m). (50) 1-(2-Acetoxy-1,1-dimethylethyl)-5-cyano-3-(3,4-dimethoxybenzyl) 25 2,3-dihydro- 1H-benziiidazol-2-one NMR(CDC1 3 , 6 ):1.86 (6H, s), 1.94 (3H, s), 3.85 (3H, s), 3.87 (3H, s), 4.63 (2H, s), 4.96 (2H, s), 6.80-6.90 (3H, m), 7.12 (1H, d, J=2 Hz), 7.30 (1H, dd, J=8, 2 Hz), 7.42 (1H, d, J=8 Hz). 30 (51) 1-(2-Acetoxy-1,1-dimethylethyl)-3-(4-chloro-3-methoxybenzyl)-5 cyano-2,3-dihydro- 1H-benzimidazol-2-one 100 WO 01/05770 PCT/JPOO/04687

NMR(CDC

3 , 6): 1.87 (6H, s), 1.93 (3H, s), 3.88 (3H, s), 4.63 (2H, s), 4.99 (2H, s), 6.79 (1H, dd, J=8, 2 Hz), 6.91 (1H, d, J=2 Hz), 7.07 (iH, d, J=2 Hz), 7.29-7.36 (2H, m), 7.44 (1H, d, J=8 Hz). 5 (52) 1-(2-Acetoxy-1,1-dimethylethyl)-3-(3-chloro-4-methoxybenzyl)-5 cyano-2,3-dihydro- 1H-benzimidazol-2-one

NMR(CDC

3 , 6): 1.86 (6H, s), 1.97 (3H, s), 3.89 (3H, s), 4.62 (3H, s), 4.95 (3H, s), 6.90 (1H, d, J=8 Hz), 7.06 (1H, d, J=2 Hz), 7.17 (1H, dd, J=8, 2 Hz), 7.25-7.35 (2H, m), 7.44 (1H, d, J=8 Hz). 10 (53) 1-[(R)-2-Acetoxy-1-methylethyl]-3-(4-chloro-3-methoxybenzyl)-5 cyano-2,3-dihydro- 1H-benzimidazol-2-one NMR(CDC1 3 , 6): 1.63 (3H, d, J=7.5 Hz), 1.91 (3H, s), 3.88 (3H, s), 4.41 (1H, dd, J=11, 4 Hz), 4.56 (1H, dd, J=11, 9 Hz), 4.70-4.85 (1H, m), 5.02 (2H, s), 15 6.80 (1H, dd, J=8, 2 Hz), 6.91 (1H, d, J=2 Hz), 7.11 (1H, d, J=2 Hz), 7.14 (1H, d, J=8 Hz), 7.33 (1H, d, J=8 Hz), 7.39 (1H, dd, J=8, 2 Hz). (54) 1-[(R)-2-Acetoxy-1-methylethyl]-3-(3-chloro-4-methoxybenzyl)-5 cyano-2,3-dihydro- 1H-benzimidazol-2-one 20 NMR(CDC 3 , 6): 1.63 (3H, d, J=7.5 Hz), 1.94 (3H, s), 3.89 (3H, s), 4.41 (1H, dd, J=11, 4 Hz), 4.54 (1H, dd, J=11, 9 Hz), 4.73-4.87 (1H, m), 4.94 (1H, d, J=15 Hz), 5.02 (1H, d, J=15 Hz), 6.90 (1H, d, J=8 Hz), 7.09 (1H, d, J=2 Hz), 7.14 (1H, d, J=8 Hz), 7.19 (1H, dd, J=8, 2 Hz), 7.30 (1H, d, J=2 Hz), 7.39 (1H, dd, J=8, 2 Hz). 25 (55) 1-[(S)-2-Acetoxy-1-methylethyl]-3-(4-chloro-3-methoxybenzyl)-5 cyano-2,3-dihydro- 1 H-benzimidazol-2-one NMR(CDC1 3 , 6): 1.63 (3H, d, J=7.5 Hz), 1.91 (3H, s), 3.88 (3H, s), 4.41 (1H, dd, J=11, 4 Hz), 4.56 (1H, dd, J=11, 9 Hz), 4.70-4.85 (1H, m), 5.02 (2H, s), 30 6.80 (1H, dd, J=8, 2Hz), 6.91 (1H, d, J=2 Hz), 7.11 (1H, d, J=2 Hz), 7.14 (1H, d, J=8 Hz), 7.33 (1H, d, J=8 Hz), 7.40 (1H, dd, J=8, 2 Hz). 101 WO 01/05770 PCT/JPOO/04687 (56) 1-[(S)-2-Acetoxy-1-methylethyl]-3-(3-chloro-4-methoxybenzyl)-5 cyano-2,3-dihydro- 1H-benzimidazol-2-one NMR(CDC1 3 , 6): 1.63 (3H, d, J=7.5 Hz), 1.94 (3H, s), 3.89 (3H, s), 4.41 (1H, 5 dd, J=11, 4 Hz), 4.54 (1H, dd, J=11, 9 Hz), 4.73-4.87 (1H, m), 4.94 (1H, d, J=15 Hz), 5.02 (1H, d, J=15 Hz), 6.90 (1H, d, J=8 Hz), 7.09 (1H, d, J=2 Hz), 7.14 (1H, d, J=8 Hz), 7.19 (1H, dd, J=8, 2 Hz), 7.30 (1H, d, J=2 Hz), 7.39 (1H, dd, J=8, 2 Hz). 10 (57) 1-(2-Acetoxy-1,1-dimethylethyl)-3-(3,4-dimethoxybenzyl)-5 trifluoromethyl-2,3-dihydro-1H-benzimidazol-2-one NMR(CDC1 3 , 6): 1.86 (6H, s), 1.98 (3H, s), 3.84 (3H, s), 3.85 (3H, s), 4.65 (2H, s), 4.99 (2H, s), 6.78-6.92 (3H, m), 7.14 (1H, d, J=2 Hz), 7.22-7.31 (1H, m), 7.43 (1H, d, J=8 Hz). 15 (58) 1-(2-Acetoxy-1,1-dimethylethyl)-3-(4-chloro-3-methoxybenzyl)-5 trifluoromethyl-2,3-dihydro- 1H-benzimidazol-2-one NMR(CDC1 3 , 6): 1.86 (6H, s), 1.94 (3H, s), 3.87 (3H, s), 4.64 (2H, s), 5.01 (2H, s), 6.81 (1H, dd, J=8, 2 Hz), 6.93 (1H, d, J=2 Hz), 7.09 (1H, s-like), 20 7.25-7.34 (2H, m), 7.46 (1H, d, J=8 Hz). (59) 1-(2-Acetoxy-1,1-dimethylethyl)-3-(3-chloro-4-methoxybenzyl)-5 trifluoromethyl-2,3-dihydro- 1 H-benzimidazol-2-one NMR(CDC1 3 , 6): 1.86 (6H, s), 1.97 (3H, s), 3.88 (3H, s), 4.64 (2H, s), 4.97 25 (2H, s), 6.89 (1H, d, J=8 Hz), 7.07 (1H, d, J=2 Hz), 7.19 (1H, dd, J=8, 2 Hz), 7.23-7.35 (2H, m), 7.44 (1H, d, J=8 Hz). (60) 1-{(S)-1-tert-Butoxycarbonylpyrrolidin-3-yl]-3-(3-chloro-4 methoxybenzyl)-5-cyano-2,3-dihydro-1H-benzimidazol-2-one 30 NMR(CDC1 3 , 6): 1.49 (9H, s), 2.24-2.36 (1H, m), 2.45-2.63 (1H, m), 3.41 3.55 (1H, m), 3.66-3.85 (3H, m), 3.90 (3H, s), 4.90 (2H, s), 5.09-5.21 (1H, m), 102 WO 01/05770 PCT/JPOO/04687 6.90 (1H, d, J=8 Hz), 7.08-7.15 (2H, m), 7.21 (1H, dd, J=8, 2 Hz), 7.33 (1H, d, J=2 Hz), 7.40 (1H, d, J=8 Hz). (61) 1-[(R)-1-tert-Butoxycarbonylpyrrolidin-3-yl]-3-(3-chloro-4 5 methoxybenzyl)-5-cyano-2,3-dihydro-1H-benzimidazol-2-one NMR(CDCl 3 , 6): 1.49 (9H, s), 2.21-2.36 (1H, m), 2.45-2.63 (1H, m), 3.40 3.55 (1H, m), 3.66-3.85 (3H, m), 3.90 (3H, s), 4.97 (2H, s), 5.08-5.24 (1H, m), 6.90 (1H, d, J=8 Hz), 7.06-7.14 (2H, m), 7.21 (1H, dd, J=8, 2 Hz), 7.33 (1H, d, J=2 Hz), 7.40 (1H, d, J=8 Hz). 10 (62) 1-[trans-4-(N-tert-Butoxycarbonylamino)cyclohexyl]-3-(3-chloro-4 methoxybenzyl)-5-cyano-2,3-dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.28-1.46 (11H, m), 1.68-1.78 (2H, m), 1.85-1.96 (2H, m), 2.14-2.32 (2H, m), 3.40 (1H, br), 3.81 (3H, s), 4.15-4.30 (1H, m), 4.99 15 (2H, s), 6.83 (1H, d, J=8 Hz), 7.11 (1H, d, J=8 Hz), 7.31 (1H, dd, J=8, 2 Hz), 7.46-7.53 (2H, m), 7.64 (1H, d, J=8 Hz), 7.77 (1H, s-like). (63) 1-(cis-4-Acetoxycyclohexyl)-3-(3-chloro-4-methoxybenzyl)-5-cyano 2,3-dihydro-1H-benzimidazol-2-one 20 NMR(CDCl 3 , 6): 1.64-1.83 (4H, m), 2.06-2.20 (5H, m), 2.36-2.54 (2H, m), 3.90 (3H, s), 4.36-4.50 (1H, m), 4.98 (2H, s), 5.10-5.16 (1H, m), 6.90 (1H, d, J=8 Hz), 7.11 (1H, d, J=2 Hz), 7.16-7.23 (2H, m), 7.33 (1H, d, J=2 Hz), 7.39 (1H, dd, J=8, 2 Hz). 25 (64) 1-(trans-4-Acetoxycyclohexyl)-5-cyano-3-piperonyl-2,3-dihydro-1H benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.47-1.65 (2H, m), 1.72-1.84 (2H, m), 1.97-2.10 (5H, m), 2.20-2.40 (2H, m), 4.27-4.41 (1H, m), 4.75-4.88 (1H, m), 4.96 (2H, s), 5.98 (2H, s), 6.84-6.94 (2H, m), 6.97 (1H, s), 7.50 (1H, d, J=2 Hz), 7.66 (1H, d, 30 J=8 Hz), 7.73 (1H, s). 103 WO 01/05770 PCT/JPOO/04687 (65) 1-(trans-4-Acetoxycyclohexyl)-3-(2-chlorobenzyl)-5-cyano-2,3 dihydro- 1H-benzimidazol-2-one NMR(CDCl 3 , 6): 1.52-1.70 (2H, m), 1.91-2.03 (2H, m), 2.08 (3H, s), 2.14 2.41 (4H, m), 4.33-4.48 (1H, m), 4.76-4.90 (1H, m), 5.19 (2H, s), 7.05-7.15 5 (2H, m), 7.15-7.30 (3H, m), 7.36-7.46 (2H, m). (66) 1-(trans-4-Acetoxycyclohexyl)-3-(3-chlorobenzyl)-5-cyano-2,3 dihydro- 1 H-benzimidazol-2-one NMR(CDC1 3 , 6): 1.50-1.69 (2H, m), 1.90-2.03 (2H, m), 2.10-2.40 (4H, m), 10 4.33-4.46 (1H, m), 4.76-4.90 (1H, m), 5.03 (2H, s), 7.07 (1H, d, J=2 Hz), 7.14-7.24 (2H, m), 7.24-7.34 (4H, m), 7.40 (1H, dd, J=8, 2 Hz). (67) 1-(trans-4-Acetoxycyclohexyl)-3-(4-chlorobenzyl)-5-cyano-2,3 dihydro- 1 H-benzimidazol-2-one 15 NMR(CDC1 3 , 6): 1.50-1.69 (2H, m), 1.90-2.01 (2H, m), 2.07 (3H, s), 2.13 2.40 (4H, m), 4.30-4.45 (1H, m), 4.76-4.89 (1H, m), 5.02 (2H, s), 7.08 (1H, d, J=2 Hz), 7.14-7.29 (3H, m), 7.31 (2H, d, J=8 Hz), 7.39 (1H, dd, J=8, 2 Hz). (68) 3-(2-Chloro-4-methoxybenzyl)-5-cyano-1-(trans-4 20 hydroxycyclohexyl) -2,3-dihydro- 1 H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.28-1.45 (2H, m), 1.66-1.78 (2H, m), 1.88-2.00 (2H, m), 2.14-2.31 (2H, m), 3.50-3.64 (1H, m), 3.75 (3H, s), 4.17-4.32 (1H, m), 4.68 (1H, d, J=5 Hz), 5.08 (2H, s), 6.88 (1H, dd, J=8, 2 Hz), 7.01 (1H, d, J=8 Hz), 7.09 (1H, d, J=2 Hz), 7.49-7.55 (2H, m), 7.61 (1H, d, J=8 Hz). 25 (69) 5-Cyano-3-(3,4-dichlorobenzyl)-1-(trans-4-hydroxycyclohexyl)-2,3 dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.28-1.46 (2H, m), 1.66-1.78 (2H, m), 1.88-2.00 (2H, m), 2.12-2.30 (2H, m), 3.50-3.65 (1H, m), 4.17-4.32 (1H, m), 4.68 (1H, d, J=5 30 Hz), 5.07 (2H, s), 7.30 (1H, dd, J=8, 2 Hz), 7.52 (1H, dd, J=8, 2 Hz), 7.56 7.65 (2H, m), 7.68 (1H, d, J=2 Hz), 7.79 (1H, d, J=2 Hz). 104 WO 01/05770 PCT/JPOO/04687 (70) 5-Cyano-3-(3,5-dichloro-4-methoxybenzyl)-1-(trans-4 hydroxycyclohexyl)-2,3-dihydro- 1H-benzimidazol-2-one NMR(CDC1 3 , 5 ):1.45-1.63 (2H, m), 1.89-2.00 (2H, m), 2.10-2.39 (4H, m), 5 3.70-3.86 (1H, m), 3.89 (3H, s), 4.24-4.38 (1H, m), 4.95 (2H, s), 7.09 (1H, d, J=2 Hz), 7.18 (1H, d, J=8 Hz), 7.26 (2H, s), 7.41 (1H, dd, J=8, 2 Hz). (71) 3-(3-Chloro-4-ethoxybenzyl)-5-cyano-1-(trans-4-hydroxycyclohexyl) 2,3-dihydro- 1H-benzimidazol-2-one 10 NMR(CDC1 3 , 6): 1.41-1.62 (5H, m), 1.87-1.99 (2H, m), 2.11-2.39 (4H, m), 3.73-3.86 (1H, m), 4.10 (2H, q, J=7.5 Hz), 4.25-4.37 (1H, m), 4.95 (2H, s), 6.88 (1H, d, J=8 Hz), 7.10 (1H, d, J=2 Hz), 7.12-7.20 (2H, m), 7.30 (1H, d, J=2 Hz), 7.39 (1H, dd, J=8, 2 Hz). 15 (72) 3-(3-Bromo-4-methoxybenzyl)-5-cyano-1-(trans-4 hydroxycyclohexyl)-2,3-dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 8): 1.27-1.45 (2H, m), 1.65-1.76 (2H, m), 1.88-1.99 (2H, m), 2.12-2.30 (2H, m), 3.50-3.64 (1H, m), 3.80 (3H, s), 4.17-4.31 (1H, m), 4.68 (1H, d, J=5 Hz), 4.99 (2H, s), 7.06 (1H, d, J=8 Hz), 7.36 (1H, dd, J=8, 2 Hz), 20 7.50 (1H, d, J=8 Hz), 7.56 (1H, d, J=8 Hz), 7.64 (1H, d, J=2 Hz), 7.79 (1H, d, J=2 Hz). (73) 5-Cyano-3-(3-fluoro-4-methoxybenzyl)-1-(trans-4 hydroxycyclohexyl)-2,3-dihydro- 1H-benzimidazol-2-one 25 NMR(DMSO-d 6 , 6): 1.27-1.45 (2H, m), 1.65-1.76 (2H, m), 1.88-1.99 (2H, m), 2.12-2.29 (2H, m), 3.50-3.64 (1H, m), 3.79 (3H, s), 4.16-4.31 (1H, m), 4.67 (1H, d, J=5 Hz), 4.99 (2H, s), 7.07-7.19 (2H, m), 7.25 (1H, d, J=11 Hz), 7.50 (1H, d, J=8 Hz), 7.56 (1H, d, J=8 Hz), 7.74 (1H, d, J=2 Hz). 30 (74) 5-Cyano-3-(4-methoxy-3-methylbenzyl)-1-(trans-4 hydroxycyclohexyl)-2,3-dihydro- 1H-benzimidazol-2-one 105 WO 01/05770 PCT/JPOO/04687 NMR(DMSO-d 6 , 6): 1.28-1.45 (2H, m), 1.64-1.75 (2H, m), 1.87-1.99 (2H, m), 2.09 (3H, s), 2.12-2.30 (2H, m), 3.50-3.64 (1H, m), 3.74 (3H, s), 4.19-4.30 (1H, m), 4.68 (1H, d, J=5 Hz), 4.95 (2H, s), 6.88 (1H, d, J=8 Hz), 7.14-7.21 (2H, m), 7.49 (1H, d, J=8 Hz), 7.56 (1H, d, J=8 Hz), 7.68 (1H, s). 5 (75) 3-(3-Chloro-4-ethoxybenzyl)-5-cyano-1-(trans-4 formamidocyclohexyl)-2,3-dihydro- 1H-benzimidazol-2-one NMR(CDC1 3 , 6 ):1.36-1.55 (5H, m), 1.91-2.05 (2H, m), 2.11-2.43 (4H, m), 3.95-4.15 (3H, m), 4.34-4.48 (1H, m), 4.96 (2H, s), 5.44 (1H, d, J=7.5 Hz), 10 6.88 (1H, d, J=8 Hz), 7.10 (1H, d, J=2 Hz), 7.11-7.21 (2H, m), 7.30 (1H, d, J=2 Hz), 7.38 (1H, dd, J=8, 2 Hz), 8.16 (1H, s). (76) 5-Cyano-3-(3,4-dichlorobenzyl)-1-(trans-4-formamidocyclohexyl)-2,3 dihydro- 1H-benzimidazol-2-one 15 NMR(CDC1 3 , 6): 1.37-1.59 (2H, m), 1.92-2.04 (2H, m), 2.13-2.44 (4H, m), 3.96-4.11 (1H, m), 4.33-4.46 (1H, m), 5.00 (2H, s), 5.42 (1H, d, J=8 Hz), 7.08 (1H, d, J=2 Hz), 7.14 (1H, dd, J=8, 2 Hz), 7.21 (1H, d, J=8 Hz), 7.36-7.46 (3H, m), 8.17 (1H, s). 20 (77) 1-[1-(Acetoxymethyl)cyclopentyl]-3-(3-chloro-4-methoxybenzyl)-5 cyano-2,3-dihydro- 1H-benzimidazol-2-one NMR(CDC1 3 , 6): 1.70-1.96 (7H, m), 2.34-2.47 (2H, m), 2.64-2.73 (2H, m), 3.89 (3H, s), 4.35 (2H, s), 4.95 (2H, s), 6.90 (1H, d, J=8 Hz), 7.04 (1H, s), 7.20 (1H, dd, J=8, 2 Hz), 7.28-7.36 (3H, m). 25 (78) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-cyclopentyl-2,3-dihydro 1H-benzimidazol-2-one NMR(CDC1 3 , 6): 1.69-1.84 (2H, m), 1.90-2.15 (6H, m), 3.89 (3H, s), 4.90 (1H, quint, J=7.5 Hz), 4.97 (2H, s), 6.90 (1H, d, J=8 Hz), 7.07-7.14 (2H, m), 30 7.20 (1H, dd, J=8, 2 Hz), 7.31-7.41 (2H, m). 106 WO 01/05770 PCT/JPOO/04687 (79) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-(tetrahydro-4H-pyran-4-yl) 2,3-dihydro- 1H-benzimidazol-2-one NMR(CDCl 3 , 6): 1.76-1.86 (2H, m), 2.38-2.55 (2H, m), 3.51-3.64 (2H, m), 3.89 (3H, s), 4.11-4.20 (2H, m), 4.57-4.71 (1H, m), 4.98 (2H, s), 6.90 (1H, d, 5 J=8 Hz), 7.11 (1H, d, J=2 Hz), 7.20 (1H, dd, J=8, 2 Hz), 7.26-7.34 (2H, m), 7.40 (1H, dd, J=8, 2 Hz). (80) 1-(cis-4-Acetoxycyclohexyl)-3-(3,4-dimethoxybenzyl)-5-cyano-2,3 dihydro- 1 H-benzimidazol-2-one 10 NMR(DMSO-d 6 , 6): 1.57-1.85 (4H, m), 1.85-2.01 (2H, m), 2.11 (3H, s), 2.26-2.49 (2H, m), 3.70 (3H, s), 3.72 (3H, s), 4.30-4.45 (1H, m), 4.90-5.04 (3H, m), 6.89 (2H, s-like), 7.05 (1H, s-like), 7.40 (1H, d, J=8 Hz), 7.55 (1H, dd, J=8, 2 Hz), 7.73 (1H, d, J=2 Hz). 15 (81) 5-Cyano-3-(3-cyano-4-methoxybenzyl)-1-(trans-4 hydroxycyclohexyl)-2,3-dihydro- 1H-benzimidazol-2-one mp. 191-1939C NMR(DMSO-d 6 , 6): 1.26-1.44 (2H, m), 1.64-1.77 (2H, m), 1.87-2.00 (2H, m), 2.10-2.30 (2H, m), 3.49-3.64 (1H, m), 3.87 (3H, s), 4.16-4.32 (1H, m), 4.72 20 (1H, d, J=5 Hz), 5.01 (2H, s), 7.21 (1H, d, J=8 Hz), 7.49 (1H, d, J=8 Hz), 7.55 (1H, d, J=8 Hz), 7.64 (1H, dd, J=8, 2 Hz), 7.74-7.80 (2H, m). (82) 3-(3-Bromo-4-methoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5-nitro 2,3-dihydro- 1H-benzimidazol-2-one 25 NMR(DMSO-d 6 , 6): 1.29-1.46 (2H, m), 1.66-1.79 (2H, m), 1.87-2.01 (2H, m), 2.14-2.31 (2H, m), 3.50-3.65 (1H, m), 3.80 (3H, s), 4.20-4.36 (1H, m), 4.69 (1H, d, J=5 Hz), 5.11 (2H, s), 7.06 (1H, d, J=8 Hz), 7.34 (1H, dd, J=8, 2 Hz), 7.56-7.66 (2H, m), 8.00 (1H, dd, J=8, 2 Hz), 8.11 (1H, d, J=2 Hz). 30 (83) 3-(3-Fluoro-4-methoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5-nitro 2,3-dihydro- 1 H-benzimidazol-2-one 107 WO 01/05770 PCT/JPOO/04687 NMR(DMSO-d 6 , 6): 1.28-1.46 (2H, m), 1.70-1.80 (2H, m), 1.90-2.01 (2H, m), 2.14-2.31 (2H, m), 3.50-3.64 (1H, m), 3.79 (3H, s), 4.22-4.36 (1H, m), 4.70 (1H, d, J=5 Hz), 5.10 (2H, s), 7.09-7.19 (2H, m), 7.24 (1H, d, J=8 Hz), 7.61 (1H, d, J=8 Hz), 8.00 (1H, dd, J=8, 2 Hz), 8.08 (iH, d, J=2 Hz). 5 (84) 1-(trans-4-Hydroxycyclohexyl)-3-(4-methoxy-3-methylbenzyl)-5-nitro 2,3-dihydro- 1H-benzimidazol-2-one NMR(CDC1 3 , 6): 1.45-1.65 (2H, m), 1.86-1.99 (2H, m), 2.12-2.23 (5H, m), 2.23-2.40 (2H, m), 3.74-3.87 (4H, m), 4.26-4.41 (1H, m), 5.00 (2H, s), 6.77 10 (1H, d, J=8 Hz), 7.10-7.21 (3H, m), 7.82 (1H, d, J=2 Hz), 8.02 (1H, dd, J=8, 2 Hz). (85) 3-(4-Methoxy-3-methylbenzyl)-1-(trans-4-hydroxycyclohexyl)-5 trifluoromethyl-2,3-dihydro- 1 H-benzimidazol-2-one 15 NMR(CDC1 3 , 6): 1.46-1.64 (2H, m), 1.86-1.97 (2H, m), 2.11-2.23 (5H, m), 2.23-2.40 (2H, m), 3.74-3.88 (4H, m), 4.26-4.40 (1H, m), 4.97 (2H, s), 6.76 (1H, d, J=8 Hz), 7.10-7.18 (4H, m), 7.31 (1H, d, J=8 Hz). (86) 3-(3-Cyano-4-methoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5 20 trifluoromethyl-2,3-dihydro- 1H-benzimidazol-2-one NMR(CDC1s, 6): 1.44-1.63 (2H, m), 1.88-1.99 (2H, m), 2.11-2.23 (2H, m), 2.33-2.40 (2H, m), 3.73-3.88 (2H, m), 3.92 (3H, s), 4.26-4.40 (1H, m), 5.01 (2H, s), 6.95 (1H, d, J=8 Hz), 7.07 (1H, s-like), 7.19 (1H, d, J=8 Hz), 7.37 (1H, d, J=8 Hz), 7.49-7.56 (2H, m). 25 (87) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-cyclohexyl-2,3-dihydro-1H benzimidazol-2-one NMR(CDC1 3 , 6): 1.19-1.37 (1H, m), 1.37-1.55 (2H, m), 1.73-1.85 (1H, m), 1.85-2.02 (4H, m), 2.02-2.21 (2H, m), 3.89 (3H, s), 4.25-4.40 (1H, m), 4.97 30 (2H, s), 6.89 (1H, d, J=8 Hz), 7.08 (1H, d, J=2 Hz), 7.15-7.28 (2H, m), 7.30 7.42 (2H, m). 108 WO 01/05770 PCT/JPOO/04687 (88) 1-tert-Butyl-3-(3-chloro-4-methoxybenzyl)-5-cyano-2,3-dihydro-1H benzimidazol-2-one NMR(CDC1 3 , 6): 1.82 (9H, s), 3.89 (3H, s), 4.93 (2H, s), 6.89 (1H, d, J=8 Hz), 5 7.05 (1H, d, J=2 Hz), 7.17 (1H, dd, J=8, 2 Hz), 7.27-7.34 (2H, m), 7.45 (1H, d, J=8 Hz). (89) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-cycloheptyl-2,3-dihydro 1H-benzimidazol-2-one 10 NMR(CDC1 3 , 6): 1.54-2.04 (10H, m), 2.11-2.27 (2H, m), 3.89 (3H, s), 4.44 4.57 (1H, m), 4.96 (2H, s), 6.89 (1H, d, J=8 Hz), 7.07 (1H, s), 7.13-7.23 (2H, m), 7.32 (1H, d, J=2 Hz), 7.36 (1H, dd, J=8, 2 Hz). (90) 3-(3-Bromo-4-methoxybenzyl)-5-cyano-1-(trans-4 15 formamidocyclohexyl)-2,3-dihydro-1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.31-1.54 (2H, m), 1.70-1.81 (2H, m), 1.88-1.99 (2H, m), 2.18-2.35 (2H, m), 3.72-3.89 (4H, m), 4.21-4.36 (1H, m), 5.00 (2H, s), 7.07 (1H, d, J=8 Hz), 7.36 (1H, dd, J=8, 2 Hz), 7.50 (1H, dd, J=8, 2 Hz), 7.61-7.70 (2H, m), 7.79 (1H, s), 7.97 (1H, s), 8.04 (1H, d, J=8 Hz). 20 (91) 3-(3-Bromo-4-methoxybenzyl)-5-cyano-1-(tetrahydro-2H-pyran-4-yl) 2,3-dihydro- 1 H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.64-1.75 (2H, m), 2.30-2.46 (2H, m), 3.41-3.54 (2H, m), 3.94-4.04 (2H, m), 4.45-4.60 (1H, m), 5.00 (2H, s), 7.08 (1H, d, J=8 Hz), 7.37 25 (1H, dd, J=8, 2 Hz), 7.49-7.59 (2H, m), 7.65 (1H, d, J=2 Hz), 7.80 (1H, s). (92) 1-[(S)-2-Acetoxy-1-ethylethyl]-3-(3-chloro-4-methoxybenzyl)-5-cyano 2,3-dihydro- 1H-benzimidazol-2-one NMR(CDC1 3 , 6): 0.93 (3H, t, J=7.5 Hz), 1.86-2.03 (4H, m), 2.07-2.26 (1H, 30 m), 3.89 (3H, s), 4.38-4.64 (3H, m), 4.95 (1H, d, J=15 Hz), 5.03 (1H, d, J=15 Hz), 6.89 (1H, d, J=8 Hz), 7.09 (1H, d, J=2 Hz), 7.11 (1H, d, J=8 Hz), 7.17 (1H, 109 WO 01/05770 PCT/JPOO/04687 dd, J=8, 2 Hz), 7.28 (1H, d, J=2 Hz), 7.38 (1H, dd, J=8, 2 Hz). (93) 1-[(R)-2-Acetoxy-1-ethylethyl]-3-(3-chloro-4-methoxybenzyl)-5-cyano 2,3-dihydro- 1H-benzimidazol-2-one 5 NMR(CDCl 3 , 6): 0.93 (3H, t, J=7.5 Hz), 1.85-2.04 (4H, m), 2.07-2.27 (1H, m), 3.89 (3H, s), 4.39-4.64 (3H, m), 4.95 (1H, d, J=15 Hz), 5.04 (1H, d, J=15 Hz), 6.90 (iH, d, J=8 Hz), 7.08 (1H, d, J=2 Hz), 7.12 (1H, d, J=8 Hz), 7.17 (1H, dd, J=8, 2 Hz), 7.28 (1H, d, J=2 Hz), 7.38 (1H, dd, J=8, 2 Hz). 10 (94) 1-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-3-(3-chloro-4 methoxybenzyl)-5-cyano-2,3-dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.42 (9H, s), 1.68-1.79 (2H, m), 2.09-2.29 (2H, m), 2.75-3.00 (2H, m), 3.80 (3H, s), 4.02-4.15 (2H, m), 4.36-4.53 (1H, m), 4.98 (2H, s), 7.10 (1H, d, J=8 Hz), 7.30 (1H, dd, J=8, 2 Hz), 7.45-7.56 (3H, m), 15 7.76 (1H, s). (95) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-(t-3,t-4 isopropylidenedioxy-r- 1-cyclohexyl)-2,3-dihydro- 1H-benzimidazol-2-one NMR(CDC1 3 , 6): 1.39 (3H, s), 1.58 (3H, s), 1.75-1.91 (1H, m), 1.91-2.27 (4H, 20 m), 2.55-2.68 (1H, m), 3.90 (3H, s), 4.24-4.34 (1H, m), 4.44-4.50 (1H, m), 4.50-4.64 (1H, m), 4.96 (2H, s), 6.90 (1H, d, J=8 Hz), 7.06-7.15 (2H, m), 7.20 (1H, d, J=8 Hz), 7.32 (1H, s), 7.40 (1H, d, J=8 Hz). (96) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-(c-3,c-4 25 isopropylidenedioxy-r- 1-cyclohexyl)-2,3-dihydro- 1 H-benzimidazol-2-one NMR(CDC1 3 , 6): 1.41 (3H, s), 1.62 (3H, s), 1.68-1.79 (1H, m), 1.83-2.00 (1H, m), 2.05-2.20 (1H, m), 2.20-2.51 (3H, m), 3.90 (3H, s), 4.25-4.43 (3H, m), 4.98 (2H, s), 6.90 (1H, d, J=8 Hz), 7.11 (1H, s), 7.15-7.29 (2H, m), 7.32 (1H, s), 7.39 (1H, d, J=8 Hz). 30 (97) 3- (3-Cyano-4-methoxybenzyl)- 1 -(trans-4-hydroxycyclohexyl) -5-nitro 110 WO 01/05770 PCT/JPOO/04687 2,3-dihydro- 1H-benzimidazol-2-one mp. 122-1249C NMR(DMSO-d 6 , 6): 1.28-1.46(2H, m), 1.68-1.81(2H, m), 1.89-2.00(2H, m), 2.13-2.30(2H, m), 3.51-3.65(1H, m), 3.88(3H, s), 4.20-4.35(1H, m), 4.70(1H, 5 d, J=4.OHz), 5.13(2H, s), 7.24(1H, d, J=9.OHz), 7.61(1H, d, J=9.OHz), 7.64(1H, dd, J=9.0, 2.0Hz), 7.77(1H, d, J=2.OHz), 8.01(1H, dd, J=9.0, 2.0Hz), 8.13(1H, d, J=2.OHz). (98) 1-(3-Chloro-4-methoxybenzyl)-3-(trans-4-hydroxycyclohexyl)-6 10 methoxycarbonyl-2,3-dihydro- 1H-imidazo[4,5-bjpyridin-2-one mp. 146-1480C NMR(DMSO-d 6 , 6): 1.25-1.42(2H, m), 1.68-1.79(2H, m), 1.92-2.00(2H, m), 2.25-2.48(2H, m), 3.44-3.58(1H, m), 3.81(3H, s), 3.85(3H, s), 4.25-4.40(1H, m), 4.70(1H, d, J=4.5Hz), 5.08(2H, s), 7.11(1H, d, J=8.5Hz), 7.27(1H, dd, 15 J=8.5, 2.0Hz), 7.47(lH, d, J=2.OHz), 7.94(1H, d, J=2.OHz), 8.60(1H, d, J=2.OHz). (99) 1-[trans-4-(N-tert-Butoxycarbonylamino)cyclohexyll-3-(3-chloro-4 methoxybenzyl)-5-trifluoromethyl-2,3-dihydro- 1H-benzimidazol-2-one 20 mp. 185.5-187*C NMR(DMSO-d 6 , 6): 1.30-1.46(2H, m), 1.40(9H, s), 1.68-1.77(2H, m), 1.86 1.96(2H, m), 2.15-2.32(2H, m), 3.35-3.48(1H, m), 3.81(3H, s), 4.16-4.31(1H, m), 5.06(2H, s), 6.83(1H, d, J=7.5Hz), 7.10(1H, d, J=8.5Hz), 7.28(1H, dd, J=8.5, 2.5Hz), 7.36(1H, dd, J=8.5, 2.0Hz), 7.46(1H, d, J=2.5Hz), 7.60(1H, d, 25 J=2.OHz), 7.63(1H, d, J=8.5Hz). (100) 1-(3-Bromo-4-methoxybenzyl)-6-cyano-3-(trans-4 hydroxycyclohexyl)-2,3-dihydro- 1H-imidazo[4,5-b]pyridin-2-one mp. 114-116 0 C 30 NMR(DMSO-d 6 , 6): 1.21-1.40(2H, m), 1.67-1.77(2H, m), 1.89-2.00(2H, m), 2.26-2.43(2H, m), 3.41-3.55(1H, m), 3.81(3H, s), 4.21-4.35(1H, m), 4.70(1H, 111 WO 01/05770 PCT/JPOO/04687 d, J=4.5Hz), 4.98(2H, s), 7.08(1H, d, J=8.5Hz), 7.38(1H, dd, J=8.5, 2.5Hz), 7.66(1H, d, J=2.5Hz), 8.11(lH, d, J=2.OHz), 8.48(1H, d, J=2.OHz). (101) 6-Cyano-3-(trans-4-hydroxycyclohexyl)-1-(4-methoxy-3 5 methylbenzyl)-2,3-dihydro- 1 H-imidazo[4,5-b]pyridin-2-one mp. 168-1699C NMR(DMSO-d 6 , 6): 1.22-1.40(2H, m), 1.67-1.77(2H, m), 1.89-1.99(2H, m), 2.10(3H, s), 2.27-2.44(2H, m), 3.42-3.55(1H, m), 3.74(3H, s), 4.22-4.36(1H, m), 4.70(1H, d, J=4.5Hz), 4.94(2H, s), 6.88(1H, d, J=8.OHz), 7.18(1H, d, 10 J=2.OHz), 7.21(1H, dd, J=8.0, 2.0Hz), 8.02(1H, d, J=2.OHz), 8.47(1H, d, J=2.OHz). (102) 6-Cyano-l-(3-cyano-4-methoxybenzyl)-3-(trans-4 hydroxycyclohexyl)-2,3-dihydro- 1H-imidazo[4,5-b]pyridin-2-one 15 mp. 133-1349C NMR(DMSO-d 6 , 6): 1.21-1.42(2H, m), 1.68-1.80(2H, m), 1.90-1.99(2H, m), 2.26-2.43(2H, m), 3.39-3.51(1H, m), 3.89(3H, s), 4.21-4.33(1H, m), 4.70(1H, d, J=4.5Hz), 5.01(2H, s), 7.23(1H, d, J=8.5Hz), 7.69(1H, dd, J=8.5, 2.5Hz), 7.81(1H, d, J=2.5Hz), 8.09(1H, d, J=2.OHz), 8.48(1H, d, J=2.OHz). 20 (103) 3-((S)-1-tert-Butoxycarbonylpyrrolidin-3-yl)-1-(3-chloro-4 methoxybenzyl)-6-trifluoromethyl-2,3-dihydro- 1H-imidazo[4,5-b]pyridin-2 one mp. 87-89C 25 NMR(DMSO-d 6 , 6): 1.40(6H, s), 1.43(3H, s), 2.12-2.27(1H, m), 2.53 2.73(1H, m), 3.29-3.40(1H, m), 3.52-3.69(2H, m), 3.75-3.83(1H, m), 3.83(3H, s), 5.07(2H, s), 5.07-5.19(1H, m), 7.12(1H, d, J=8.5Hz), 7.35(1H, dd, J=8.5, 2.5Hz), 7.53(1H, d, J=2.5Hz), 7.57(1H, s), 8.34(1H, s). MS m/z: 527(M++1). 30 (104) 3-(Benzimidazol-5-yl)-1-(3-chloro-4-methoxybenzyl)-6-cyano-2,3 112 WO 01/05770 PCT/JPOO/04687 dihydro- 1H-imidazo[4,5-b]pyridin-2-one mp 163-166*C NMR(DMSO-d 6 , 6): 3.84(3H, s), 5.10(2H, s), 7.14(1H, d, J=8Hz), 7.36 7.49(2H, m), 7.61(1H, d, J=lHz), 7.67(1H, br d, J=8Hz), 7.79(1H, br d, 5 J=8Hz), 7.87(1H, br s), 8.19(1H, br s), 8.35(1H, s), 8.45(1H, br s). MS (ESI) m/z: 429(M+-1). (105) 1-(3-Chloro-4-methoxybenzyl)-3-(1H-indol-5-yl)-6-cyano-2,3 dihydro- 1H-imidazo[4,5-b]pyridin-2-one 10 mp. 281-282C NMR(DMSO-d 6 , 6) :3.85(3H, s), 5.12(2H, s), 6.99(1H, d, J=2.5Hz), 7.16(1H, d, J=8.5Hz), 7.47(1H, dd, J=8.5, 2.0Hz), 7.58-7.65(2H, m), 7.85(1H, d, J=2.5Hz), 7.98(1H, d, J=2.OHz), 8.09(1H, d, J=8.5Hz), 8.21(1H, d, J=2.OHz), 8.48(1H, d, J=2.OHz). 15 (106) 5-Cyano-3-(3-formyl-4-methoxybenzyl)-1-(trans-4 hydroxycyclohexyl)-1,3-dihydro-2H-benzimidazol-2-one NMR(CDC1 3 , 6): 1.46-1.66 (2H, br), 1.88-2.05 (2H, br), 2.14-2.40 (4H, br), 3.77-3.92 (1H, m), 3.93 (3H, s), 4.26-4.40 (1H, m), 5.02 (2H, s), 6.97-7.06 20 (2H, m), 7.15 (1H, d, J= 8 Hz), 7.38 (1H, d, J= 8 Hz), 7.48 (1H, dd, J= 2 Hz, 8 Hz), 7.71 (1H, d, J= 2 Hz), 10.44 (1H, s). (107) 5-Cyano-1-(trans-4-hydroxycyclohexyl)-3-(4-methoxy-3 methoxycarbonylbenzyl)-1,3-dihydro-2H-benzimidazol-2-one 25 NMR(DMSO-d 6 , 6) : 1.28-1.48 (2H, br), 1.65-1.80 (2H, br), 1.88-2.02 (2H, br), 2.14-2.33 (2H, br), 3.52-3.66 (1H, br), 3.77 (3H, s), 3.78 (3H, s), 4.18 4.33 (1H, br), 4.68 (1H, d, J= 4 Hz), 5.03 (2H, s), 7.11 (1H, d, J= 8 Hz), 7.46-7.60 (3H, m), 7.67 (1H, d, J= 2 Hz), 7.77 (1H, d, J= 2 Hz), 30 (108) 3-(3-Acetyl-4-methoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5 nitro- 1,3-dihydro-2H-benzimidazol-2-one 113 WO 01/05770 PCT/JPOO/04687 NMR(DMSO-d 6 , 6) : 1.32-1.48 (2H, br), 1.67-1.82 (2H, br), 1.88-2.04 (2H, br), 2.16-2.33 (2H, br), 2.49 (3H, s), 3.50-3.66 (1H, br), 3.86 (3H, s), 4.23 4.38 (1H, br), 4.70 (1H, d, J= 7 Hz), 5.14 (2H, s), 7.16 (1H, d, J= 8 Hz), 7.51 (1H, dd, J= 2 Hz, 8 Hz), 7.61 (2H, m), 8.00 (1H, dd, J= 2 Hz, 8 Hz), 8.09 (1H, 5 d, J= 2 Hz). (109) 1- (trans-4-Hydroxycyclohexyl) -3- (4-methoxy-3-nitrobenzyl) -5-nitro 1,3-dihydro-2H-benzimidazol-2-one NMR(DMSO-d 6 , 8) : 1.30-1.48 (2H, br), 1.68-1.83 (2H, br), 1.92-2.03 (2H, 10 br), 2.16-2.33 (2H, br), 3.52-3.67 (1H, br), 3.89 (3H, s), 4.23-4.37 (1H, br), 4.70 (1H, d, J= 4 Hz), 5.19 (2H, s), 7.35 (1H, d, J= 8 Hz), 7.61 (1H, d, J= 8 Hz), 7.62 (1H, dd, J= 2 Hz, 8 Hz), 7.94 (1H, d, J= 2 Hz), 8.01 (1H, dd, J= 2 Hz, 8 Hz), 8.17 (1H, d, J= 2 Hz). 15 (110) 1-(Benzimidazol-5-yl)-3-(3-chloro-4-methoxybenzyl)-5-cyano-2,3 dihydro- 1H-benzimidazole-2-one NMR(DMSO-d 6 , 8): 3.84 (3H, s), 5.11 (2H, s), 7.09 (1H, d, J=8 Hz), 7.16 (1H, d, J=8 Hz), 7.35 (1H, dd, J=8,2 Hz), 7.45 (1H, dd, J=8,2 Hz), 7.51 (1H, dd, J=8,2 Hz), 7.59 (1H, d, J=2 Hz), 7.75-7.82 (2H, m), 7.86 (1H, d, J=2 Hz), 8.38 20 (1H, s). (111) 1-(3-Acetoxypropyl)-3-(3-chloro-4-methoxybenzyl)-5-cyano-2,3 dihydro- 1H-benzimidazole-2-one

NMR(CDC

3 , 6) : 2.02 (3H, s), 2.14 (2H, m), 3.89 (3H, s), 4.05 (2H, t, J=5 Hz), 25 4.13 (2H, t, J=5 Hz), 4.98 (2H, s), 6.90 (1H, d, J=8 Hz), 7.04 (1H, d, J=8 Hz), 7.09 (1H, d, J=2 Hz), 7.20 (1H, dd, J=8, 2 Hz), 7.32 (1H, d, J=2 Hz), 7.41 (1H, dd, J=8, 2 Hz). (112) 3-(3-Chloro-4-methoxybenzyl)- 1-[2-(N,N-dimethylamino)ethyl]-5 30 cyano-2,3-dihydro- 1H- benzimidazole-2-one NMR(CDC1 3 , 8): 2.31 (6H, s), 2.66 (2H, t, J=7 Hz), 3.89 (3H, s), 4.04 (2H, t, 114 WO 01/05770 PCT/JPOO/04687 J=7 Hz), 4.98 (2H, s), 6.88 (1H, d, J=8 Hz), 7.05-7.11 (2H, m), 7.18 (1H, dd, J=8,2 Hz), 7.30 (1H, d, J=2 Hz), 7.40 (1H, d, J=8 Hz). Example 3 5 To a solution of 3-(2-acetoxy- 1, 1-dimethylethyl)-6-trifluoromethyl 2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (150 mg) in anhydrous N,N dimethylformamide (1.5 mL) was added portionwise sodium hydride (20.8 mg , 60% dispersion in mineral oil) at 5oC under nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. After adding 10 3-chloro-4-methoxybenzylbromide (117 mg), the mixture was stirred at room temperature for 4 hours. After adding tetrahydrofuran (2 mL), methanol (1 mL) and 1N-sodium hydroxide solution (1 mL), the mixture was refluxed for an hour. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate 15 and water. The separated organic layer was washed successively with water, 1N-hydrochloric acid, an aqueous saturated sodium hydrogencarbonate solution and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residual solid was washed with diethyl ether to give 1-(3-chloro-4-methoxybenzyl)-3-(1, 1 20 dimethyl-2-hydroxyethyl)-6-trifluoromethyl-2,3-dihydro- 1H-imidazo[4,5 b]pyridin-2-one (161.6 mg) as an orange solid. mp. 195-1979C NMR(DMSO-d 6 , 6): 1.73(6H, s), 3.82(3H, s), 3.88(2H, d, J=6.5Hz), 4.89(1H, t, J=6.5Hz), 5.03(2H, s), 7.12(1H, d, J=8.5Hz), 7.31(1H, dd, J=8.5, 2.5Hz), 25 7.49(1H, d, J=2.5Hz), 7.91(1H, d, J=1.5Hz), 8.35(1H, d, J=1.5Hz). MS m/z : 430(M++ 1). Example 4 The following compounds described in (1) to (8) were obtained in a 30 manner similar to Example 3. (1) 1-[1-(Acetoxymethyl)cyclopentyl]-3-(3-chloro-4-methoxybenzyl)-5 115 WO 01/05770 PCT/JPOO/04687 trifluoromethyl-2,3-dihydro- 1 H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.56-1.77(4H, m), 2.19-2.33(2H, m), 2.45-2.55(2H, m), 3.55(2H, d, J=5.5Hz), 3.81(3H, s), 4.99(1H, t, J=6.OHz), 5.03(2H, s), 7.10(1H, d, J=8.5Hz), 7.25-7.33(2H, m), 7.46(1H, d, J=2.OHz), 7.48(1H, d, J=8.5Hz), 5 7.49(1H, s). MS m/z: 453(M+-1). (2) 1-(3-Chloro-4-methoxybenzyl)-3-((R)-2-hydroxy-1-methylethyl)-6 trifluoromethyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one 10 mp. 154.5-155C NMR(DMSO-d 6 , 6): 1.44(3H, d, J=7.OHz), 3.59-3.69(1H, m), 3.82(3H, s), 3.98-4.09(1H, m), 4.52-4.66(1H, m), 4.91(1H, t, J=6.OHz), 5.07(2H, s), 7.12(1H, d, J=8.5Hz), 7.33(1H, dd, J=8.5, 2.0Hz), 7.50(1H, d, J=2.OHz), 7.95(1H, d, J=2.OHz), 8.38(1H, d, J=2.OHz). 15 MS m/z: 416(M++1). (3) 3-(3-Chloro-4-methoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5 methylsulfonyl-2,3-dihydro- 1H-benzimidazol-2-one mp. 265-265.5*C 20 NMR(DMSO-d 6 , 6): 1.28-1.45(2H, m), 1.65-1.77(2H, m), 1.90-2.01(2H, m), 2.14-2.32(2H, m), 3.17(3H, s), 3.51-3.65(1H, m), 3.81(3H, s), 4.20-4.34(1H, m), 4.70(1H, d, J=4.5Hz), 5.07(2H, s), 7.11(1H, d, J=8.5Hz), 7.25(1H, dd, J=8.5, 2.5Hz), 7.46(1H, d, J=2.5Hz), 7.58(1H, d, J=8.5Hz), 7.63(1H, d, J=8.5Hz), 7.74(1H, s). 25 (4) 3-(3-Chloro-4-methoxybenzyl)-1-((R)-2-hydroxy-1-methylethyl)-5 trifluoromethyl-2,3-dihydro- 1 H-benzimidazol-2-one mp. 108-1099C NMR(DMSO-d 6 , 6): 1.42(3H, d, J=7.OHz), 3.60-3.70(1H, m), 3.81(3H, s), 30 3.84-3.95(1H, m), 4.46-4.60(1H, m), 4.97(1H, t, J=5.5Hz), 5.07(2H, s), 7.11(1H, d, J=8.5Hz), 7.29(1H, d, J=8.5Hz), 7.37(1H, d, J=8.5Hz), 7.47(1H, 116 WO 01/05770 PCT/JPOO/04687 s), 7.48(1H, d, J=8.5Hz), 7.57(1H, s). MS m/z: 413(M+-1). (5) 1-(3-Chloro-4-methoxybenzyl)-6-cyano-3-(trans-4-hydroxycyclohexyl) 5 2,3-dihydro- 1 H-imidazo[4,5-b]pyridin-2-one mp. 176-176.5*C NMR(DMSO-d 6 , 6): 1.22-1.40(2H, m), 1.67-1.77(2H, m), 1.89-2.00(2H, m), 2.25-2.45(2H, m), 3.42-3.55(1H, m), 3.82(3H, s), 4.21-4.35(1H, m), 4.68(1H, d, J=5.5Hz), 4.98(2H, s), 7.12(1H, d, J=8.5Hz), 7.35(1H, dd, J=8.5, 2.5Hz), 10 7.52(1H, d, J=2.5Hz), 8.10(1H, d, J=2.OHz), 8.48(1H, d, J=2.OHz). (6) 5-Benzoyl-3-(3-chloro-4-methoxybenzyl)-1-(trans-4 hydroxycyclohexyl)-2,3-dihydro- 1H-benzimidazol-2-one mp. 160.5-1629C 15 NMR(DMSO-d 6 , 6): 1.29-1.46(2H, m), 1.69-1.80(2H, m), 1.90-2.01(2H, m), 2.16-2.33(2H, m), 3.50-3.64(1H, m), 3.83(3H, s), 4.20-4.34(1H, m), 4.70(1H, d, J=4.OHz), 5.05(2H, s), 7.11(1H, d, J=8.5Hz), 7.24(1H, dd, J=8.5, 2.5Hz), 7.41(1H, d, J=2.5Hz), 7.46(1H, t, J=8.5Hz), 7.50-7.55(3H, m), 7.63(2H, d, J=8.5Hz), 7.66(2H, d, J=7.5Hz). 20 (7) 3-(3-Chloro-4-methoxybenzyl)-1-(2-hydroxyethyl)-5-trifluoromethyl 2,3-dihydro- 1H-benzinidazol-2-one mp. 106-107'C NMR(DMSO-d 6 , 6): 3.67(2H, q, J=5.5Hz), 3.81(3H, s), 3.97(2H, t, J=5.5Hz), 25 4.90(1H, t, J=5.5Hz), 5.08(2H, s), 7.11(1H, d, J=8.5Hz), 7.31(1H, dd, J=8.5, 2.5Hz), 7.41(2H, s), 7.48(1H, d, J=2.5Hz), 7.58(1H, s). (8) 1-(3-Chloro-4-methoxybenzyl)-6-cyano-3-((R)-2-hydroxy-1 methylethyl)-2,3-dihydro- 1H-imidazo[4,5-b]pyridin-2-one 30 mp. 164-1659C NMR(DMSO-d 6 , 6): 1.43(3H, d, J=7.OHz), 3.56-3.69(1H, m), 3.82(3H, s), 117 WO 01/05770 PCT/JPOO/04687 3.95-4.07(1H, m), 4.53-4.65(1H, m), 4.91(1H, t, J=6.OHz), 5.00(2H, s), 7.12(1H, d, J=8.5Hz), 7.35(1H, dd, J=8.5, 2.0Hz), 7.51(1H, d, J=2.OHz), 8.08(1H, d, J=2.OHz), 8.47(1H, d, J=2.OHz). 5 Example 5 To a solution of 5-cyano-3-(3,4-dimethoxybenzyl)-1-(2,2-dimethyl 1,3-dioxan-5-yl)-2,3-dihydro-1H-benzimidazol-2-one (140 mg) in tetrahydrofuran (2 mL) was added 1 N-hydrochloric acid (1.5 mL), and the mixture was stirred at ambient temperature for 8 hours. After evaporation 10 of the solvent, the residue was partitioned between water and a mixture of chloroform and methanol (10:1). The separated organic layer was washed with brine and dried over magnesium sulfate. After evaporation of solvent, the residue was subjected to a preparative thin-layer chromatography eluting with a mixture of chloroform and methanol (10:1). The obtained 15 substance was triturated with diethyl ether to give 5-cyano-3-(3,4 dimethoxybenzyl)-1-[2-hydroxy-1-(hydroxymethyl)ethyl]-2,3-dihydro-1H benzimidazol-2-one (92 mg) as powders. NMR(DMSO-d 6 , 6): 3.64-3.83 (8H, m), 3.83-3.99 (2H, m), 4.38-4.50 (1H, m), 4.93 (2H, t, J=5 Hz), 5.00 (1H, s, J=2 Hz), 6.89 (2H, s-like), 7.02 (1H, s-like), 20 7.40-7.53 (2H, m), 7.66 (1H, s-like). Example 6 The following compounds described in (1) and (4) were obtained in a manner similar to Example 5. 25 (1) 3-(4-Chloro-3-methoxybenzyl)-5-cyano-1-[2-hydroxy-1 (hydroxymethyl) ethyl] -2,3-dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 3.70-3.85 (5H, m), 3.85-3.98 (2H, m), 4.38-4.50 (1H, m), 4.94 (2H, t, J=5 Hz), 5.08 (2H, s), 6.88 (1H, dd, J=8, 2 Hz), 7.20 (1H, d, J=2 30 Hz), 7.36 (1H, d, J=8 Hz), 7.42-7.53 (2H, m), 7.68 (1H, s-like). (2) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-[2-hydroxy-1 118 WO 01/05770 PCT/JPOO/04687 (hydroxymethyl) ethyl] -2,3-dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6 ): 3.70-3.84 (5H, m), 3.84-3.98 (2H, m), 4.36-4.50 (1H, m), 4.93 (2H, t, J=5 Hz), 5.01 (2H, s), 7.12 (1H, d, J=8 Hz), 7.35 (1H, dd, J=8, 2 Hz), 7.40-7.52 (3H, m), 7.73 (1H, s-like). 5 (3) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-(t-3,t-4-dihydroxy-r-1 cyclohexyl)-2,3-dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.55-1.89 (4H, m), 2.07-2.44 (2H, m), 3.62 (1H, br), 3.81 (3H, s), 3.90 (1H, br), 4.53 (1H, d, J=6 Hz), 4.56-4.70 (2H, m), 4.99 (2H, 10 s), 7.11 (1H, d, J=8 Hz), 7.31 (1H, dd, J=8, 2 Hz), 7.46-7.66 (3H, m), 7.78 (1H, d, J=2 Hz). (4) 3-(3-Chloro-4-methoxybenzyl)-5-cyano--1-(c-3,c-4-dihydroxy-r-1 cyclohexyl)-2,3-dihydro- 1H-benzimidazol-2-one 15 NMR(DMSO-d 6 , 6): 1.35-1.65 (3H, m), 1.74-1.85 (1H, m), 2.21-2.49 (2H, m), 3.51-3.62 (1H, m), 3.78 (1H, br), 3.81 (3H, s), 4.27-4.42 (1H, m), 4.53 (1H, d, J=3 Hz), 4.67 (1H, d, J=6 Hz), 5.00 (2H, s), 7.11 (1H, d, J=8 Hz), 7.34 (1H, dd, J=8, 2 Hz), 7.39 (1H, d, J=8 Hz), 7.49 (1H, d, J=2 Hz), 7.56 (1H, dd, J=8, 2 Hz), 7.79 (1H, d, J=2 Hz). 20 Example 7 4N-Hydrogen chloride solution in ethyl acetate (5 mL) was added to a suspension of 1-[(S)-1-tert-butoxycarbonylpyrrolidin-3-yl-3-(3-chloro-4 methoxybenzyl)-5-cyano-2,3-dihydro-1H-benzimidazol-2-one (520 mg) in 25 ethyl acetate (5 mL) at 0*C. The mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated in vacuo. To the residue was added an aqueous saturated sodium bicarbonate solution and ethyl acetate. The separated organic layer was washed successively with water and brine and dried over magnesium sulfate. After 30 evaporation of the solvent, the residue was triturated with diethyl ether to give 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-[(S)-pyrrolidin-3-yl]-2,3 119 WO 01/05770 PCT/JPOO/04687 dihydro- 1H-benzimidazol-2-one (287 mg) as amorphous powders. NMR(CDCl 3 , 6): 2.02-2.17 (1H, m), 2.25-2.45 (1H, m), 2.94-3.06 (1H, m), 3.22-3.46 (3H, m), 3.89 (3H, s), 4.97 (2H, s), 4.99-5.11 (1H, m), 6.91 (1H, d, J=8 Hz), 7.10 (1H, s), 7.20 (1H, dd, J=8, 2 Hz), 7.33 (1H, d, J=2 Hz), 7.40 (1H, 5 dd, J=8, 2 Hz), 7.51 (iH, d, J=8 Hz). Example 8 The following compounds described in (1) to (4) were obtained in a manner similar to Example 7. 10 (1) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-[(R)-pyrrolidin-3-yl]-2,3 dihydro- 1H-benzimidazol-2-one NMR(CDC1 3 , 6): 2.01-2.16 (1H, m), 2.22-2.37 (1H, m), 2.92-3.04 (1H, m), 3.21-3.46 (3H, m), 3.90 (3H, s), 4.97 (2H, s), 4.99-5.11 (1H, m), 6.90 (1H, d, 15 J=8 Hz), 7.10 (1H, d, J=2 Hz), 7.20 (1H, dd, J=8, 2 Hz), 7.33 (2H, d, J=2 Hz), 7.40 (1H, dd, J=8, 2 Hz), 7.51 (1H, d, J=8 Hz). (2) 1-(trans-4-Aminocyclohexyl)-3-(3-chloro-4-methoxybenzyl)-5-cyano 2,3-dihydro- 1H-benzimidazol-2-one 20 NMR(DMSO-d 6 , 6): 1.14-1.31 (2H, m), 1.57-1.69 (4H, m), 1.69-1.94 (2H, m), 2.10-2.30 (2H, m), 2.61-2.77 (1H, m), 3.81 (3H, s), 4.15-4.30 (1H, m), 4.99 (2H, s), 7.11 (1H, d, J=8 Hz), 7.32 (1H, dd, J=8, 2 Hz), 7.46-7.59 (3H, m), 7.78 (1H, s-like). 25 (3) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-(piperidin-4-yl)-2,3-dihydro 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.57-1.70 (2H, m), 2.09-2.30 (2H, m), 2.52-2.65 (2H, m), 3.00-3.11 (2H, m), 3.81 (3H, s), 4.26-4.41 (1H, m), 5.00 (2H, s), 7.11 (1H, d, J=8 Hz), 7.33 (1H, dd, J=8, 2 Hz), 7.48-7.60 (3H, m), 7.79 (1H, s). 30 (4) 1-(trans-4-Aminocyclohexyl)-3-(3-chloro-4-methoxybenzyl)-5 120 WO 01/05770 PCT/JPOO/04687 trifluoromethyl-2,3-dihydro- 1H-benzimidazol-2-one mp. 167-168.5*C NMR(DMSO-d 6 , 6): 1.22-1.40(2H, m), 1.67-1.79(2H, m), 1.87-1.98(2H, m), 2.15-2.31(2H, m), 2.76-2.90(1H, m), 3.81(3H, s), 4.17-4.33(1H, m), 5.06(2H, 5 s), 7.11(1H, d, J=8.5Hz), 7.28(1H, dd, J=8.5, 2.5Hz), 7.38(1H, d, J=8.5Hz), 7.46(1H, d, J=2.5Hz), 7.57(1H, d, J=8.5Hz), 7.61(1H, s). MS m/z: 454(M++1). Example 9 10 A solution of 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-[(S) pyrrolidin-3-yl]-2,3-dihydro-1H-benzimidazol-2-one (80 mg) in ethyl formate (2 mL) was heated under reflux for 10 hours. After evaporation of the solvent, the residue was subjected to a preparative thin-layer chromatography eluting with a mixture of chloroform and methanol (15:1) 15 to give 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-[(S)-1-formylpyrrolidin-3 yl]-2,3-dihydro-1H-benzimidazol-2-one (52 mg) as amorphous powders. NMR(CDC1 3 , 6): 2.32-2.46 (1H, m), 2.50-2.71 (1H, m), 3.55-3.72 (1H, m), 3.84-4.16 (6H, m), 4.97 (2H, s), 5.03-5.24 (1H, m), 6.90 (1H, d, J=8 Hz), 7.00-7. 10 (1H, m), 7.10-7.16 (1H, m), 7.16-7.24 (1H,m), 7.30-7.36 (1H, m), 20 7.38-7.45 (1H, m), 8.30-8.35 (1H, m). Example 10 The following compounds described in (1) and (2) were obtained in a manner similar to Example 9. 25 (1) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-[(R)-1-formylpyrrolidin-3 yl]-2,3-dihydro- 1H-benzimidazol-2-one NMR(CDCl 3 , 6): 2.32-2.46 (1H, m), 2.51-2.71 (1H, m), 3.55-3.73 (1H, m), 3.84-4.17 (6H, m), 4.97 (2H, s), 5.04-5.24 (1H, m), 6.90 (1H, d, J=8 Hz), 30 6.99-7. 10 (1H, m), 7.10-7.15 (1H, m), 7.15-7.25 (1H, m), 7.30-7.35 (1H, m), 7.37-7.45 (1H, m), 8.30-8.35 (1H, m). 121 WO 01/05770 PCT/JPOO/04687 (2) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-(1-formylpiperidin-4-yl) 2,3-dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , ): 1.75-1.89 (2H, m), 2.04-2.35 (2H, m), 2.67-2.81 (1H, m), 3.14-3.25 (1H, m), 3.74-3.89 (4H, m), 4.30-4.40 (1H, m), 4.51-4.65 (1H, m), 5 5.00 (2H, s), 7.11 (1H, d, J=8 Hz), 7.34 (1H, dd, J=8, 2 Hz), 7.49 (1H, d, J=2 Hz), 7.50-7.60 (2H, m), 7.79 (1H, s), 8.04 (1H, s). Example 11 Methanesulfonyl chloride (27 mg) and triethylamine (24 mg) were 10 added to a solution of 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-[(S) pyrrolidin-3-yl]-2,3-dihydro-1H-benzimidazol-2-one (75 mg) in dichloromethane (2 mL). The reaction mixture was stirred at 0"C for 3 hours. The reaction mixture was poured into water and extracted with a mixture of chloroform and methanol (5:1). The organic layer was washed 15 with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The obtained crystals were suspended in hot ethyl acetate and then cooled with stirring. The resulting precipitate was collected by filtration and washed with ethyl acetate to give 3-(3 chloro-4-methoxybenzyl)-5-cyano- 1- [(S)-1-methanesulfonylpyrrolidin-3 20 yl-2,3-dihydro-1H-benzimidazol-2-one (76 mg) as colorless crystals. NMR(DMSO-d 6 , 6): 2.23-2.36 (1H, m), 2.36-2.54 (1H, m), 3.01 (3H, s), 3.29-3.41 (1H, m), 3.55-3.72 (3H, m), 3.82 (3H, s), 5.01 (2H, s), 5.13-5.26 (1H, m), 7.11 (1H, d, J=8 Hz), 7.35 (1H, dd, J=8, 2 Hz), 7.47-7.53 (2H, m), 7.60 (1H, d, J=8 Hz), 7.80 (1H, s). 25 Example 12 The following compounds described in (1) to (3) were obtained in a manner similar to Example 11. 30 (1) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-[(R)-1 methanesulfonylpyrrolidin-3-yl]-2,3-dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 2.23-2.37 (1H, m), 2.37-2.54 (1H, m), 3.01 (3H, s), 122 WO 01/05770 PCT/JPOO/04687 3.26-3.40 (1H, m), 3.56-3.73 (1H, m), 3.82 (3H, s), 5.01 (2H, s), 5. 13-5.17 (1H, m), 7.12 (1H, d, J=8 Hz), 7.35 (1H, dd, J=8, 2 Hz), 7.47-7.54 (2H, m), 7.60 (1H, d, J=8 Hz), 7.80 (1H, s). 5 (2) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-(trans-4 methanesulfonylaminocyclohexyl)-2,3-dihydro- 1 H-benzimidazol-2-one NMR(CDC1 3 , 6): 1.36-1.55 (2H, m), 1.69-1.81 (2H, m), 1.96-2.09 (2H, m), 2.95 (3H, s), 3.35 (1H, br), 3.81 (3H, s), 4.19-4.32 (1H, m), 5.00 (2H, s), 7.06-7.15 (2H, m), 7.33 (1H, dd, J=8, 2 Hz), 7.47-7.55 (2H, m), 7.65 (1H, d, 10 J=8 Hz), 7.79 (1H, s). (3) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-(1 methanesulfonylpiperidin-4-yl)-2,3-dihydro-1H-benzimidazol-2-one NMR(CDC1 3 , 6): 1.94-2.04 (2H, m), 2.41-2.60 (2H, m), 2.82-2.96 (5H, m), 15 3.90 (3H, s), 4.00-4.10 (2H, m), 4.48-4.64 (1H, m), 4.98 (2H, s), 6.90 (1H, d, J=8 Hz), 7.13 (1H, d, J=2 Hz), 7.20 (1H, dd, J=8, 2 Hz), 7.25 (1H, d, J=8 Hz), 7.32 (1H, d, J=2 Hz), 7.41 (1H, dd, J=8, 2 Hz). Example 13 20 A solution of potassium cyanate (40 mg) in water (1 mL) was added to a mixture of 1-(trans-4-aminocyclohexyl)-3-(3-chloro-4-methoxybenzyl) 5-cyano-2,3-dihydro-1H-benzimidazol-2-one (100 mg) and 1 N hydrochloric acid (0.25 mL) in 1,4-dioxane (1.4 mL). The reaction mixture was stirred at ambient temperature for 20 hours. The mixture was 25 partitioned between ethyl acetate and water. The separated organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was triturated with diethyl ether and washed with isopropyl alcohol to give 1-(trans-4-ureidocyclohexyl)-3-(3-chloro-4 methoxybenzyl)-5-cyano-2,3-dihydro-1H-benzimidazol-2-one (71 mg) as 30 powders. NMR(DMSO-d 6 , 6): 1.21-1.40 (2H, m), 1.67-1.79 (2H, m), 1.89-2.01 (2H, m), 123 WO 01/05770 PCT/JPOO/04687 2.14-2.33 (2H, m), 3.50 (1H, br), 3.81 (3H, s), 4.20-4.35 (1H, m), 5.00 (2H, s), 5.36 (2H, s), 5.89 (1H, d, J=8 Hz), 7.11 (1H, d, J=8 Hz), 7.32 (1H, dd, J=8, 2 Hz), 7.46-7.53 (2H, m), 7.64 (1H, d, J=8 Hz), 7.78 (1H, s). 5 Example 14 The following compounds described in (1) and (2) were obtained in a manner similar to Example 13. (1) 1-(1-carbamoylpiperidin-4-yl)-3-(3-chloro-4-methoxybenzyl)-5-cyano 10 2,3-dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 3): 1.66-1.76 (2H, m), 2.09-2.30 (2H, m), 2.75-2.37 (2H, m), 3.81 (3H, s), 4.05-4.15 (2H, m), 4.39-4.52 (1H, m), 4.99 (2H, s), 6.02 (2H, s), 7.11 (1H, d, J=8 Hz), 7.34 (1H, dd, J=8, 2 Hz), 7.44-7.56 (3H, m), 7.79 (1H, d, J=2 Hz). 15 (2) 1-(trans-4-Ureidocyclohexyl)-3-(3-chloro-4-methoxybenzyl)-5 trifluoromethyl-2,3-dihydro- 1 H-benzimidazol-2-one mp. 164-165.5"C NMR(DMSO-d 6 , 6): 1.23-1.41(2H, m), 1.69-1.79(2H, m), 1.90-2.00(2H, m), 20 2.16-2.34(2H, m), 3.42-3.56(1H, m), 3.81(3H, s), 4.21-4.35(1H, m), 5.07(2H, s), 5.37(2H, s), 5.90(1H, d, J=7.5Hz), 7.11(1H, d, J=8.5Hz), 7.28(1H, dd, J=8.5, 2.0Hz), 7.37(1H, dd, J=8.5, 2.0Hz), 7.47(1H, d, J=2.OHz), 7.60(1H, d, J=2.OHz), 7.61(1H, d, J=8.5Hz). 25 Example 15 A mixture of 1-(trans-4-aminocyclohexyl)-3-(3-chloro-4 methoxybenzyl)-5-cyano-2,3-dihydro-1H-benzimidazol-2-one (90 mg) and sulfamide (42 mg) in ethylene glycol dimethyl ether (3 mL) was refluxed overnight. The mixture was concentrated in vacuo, and the residue was 30 partitioned between chloroform and water. The separated organic layer was washed with an aqueous saturated sodium chloride solution, dried 124 WO 01/05770 PCT/JPOO/04687 over magnesium sulfate, and concentrated in vacuo. The residue was subjected to a preparative thin-layer chromatography eluting with a mixture of chloroform and methanol (10:1). The obtained crystals were collected by filtration and washed with diethyl ether to give 1-(trans-4 5 aminosulfonamidocyclohexyl)-3-(3-chloro-4-methoxybenzyl)-5-cyano-2,3 dihydro-1H-benzimidazol-2-one (41 mg) as powders. NMR(DMSO-d 6 , 6): 1.32-1.50 (2H, m), 1.70-1.81 (2H, m), 2.04-2.16 (2H, m), 2.16-2.34 (2H, m), 3.25 (1H, br), 3.81 (3H, s), 4.15-4.30 (1H, m), 4.99 (2H, s), 6.50 (2H, s), 6.61 (1H, d, J=8 Hz), 7.11 (1H, d, J=8 Hz), 7.31 (1H, dd, J=8, 2 10 Hz), 7.46-7.54 (2H, m), 7.61 (1H, d, J=8 Hz), 7.78 (1H, s). Example 16 1-(1-Sulfamoylpiperidin-4-yl)-3-(3-chloro-4-methoxybenzyl)-5 cyano-2,3-dihydro- 1H-benzimidazol-2-one was obtained in a manner 15 similar to Example 15. NMR(DMSO-d 6 , 6): 1.80-1.91 (2H, m), 2.31-2.49 (2H, m), 2.66-2.81 (2H, m), 3.59-3.74 (2H, m), 3.82 (3H, s), 4.31-4.47 (1H, m), 5.01 (2H, s), 6.90 (2H, br s), 7.11 (1H, d, J=8 Hz), 7.32 (1H, dd, J=8, 2 Hz), 7.54 (2H, s-like), 7.77 (1H, s). 20 Example 17 A mixture of 1-(trans-4-aminocyclohexyl)-3-(3-chloro-4 methoxybenzyl)-5-cyano-2,3-dihydro-1H-benzimidazol-2-one (100 mg) and methyl isocyanate (17 mg) in dichloromethane (3 mL) was stirred at 0 0 C for 25 2 hours under nitrogen atmosphere. The mixture was partitioned between water and a mixture of chloroform and methanol (5:1). The separated organic layer was washed with water and dried over magnesium sulfate. After evaporation of the solvent, the residue was subjected to a preparative thin-layer chromatography eluting with a mixture of chloroform and 30 methanol (10:1). The obtained substance was triturated with diethyl ether to give 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-[trans-4-(3 125 WO 01/05770 PCT/JPOO/04687 methylureido)cyclohexyl]-2,3-dihydro-1H-benzimidazol-2-one (69 mg) as colorless powders. NMR(DMSO-d 6 , 6): 1.21-1.40 (2H, m), 1.67-1.77 (2H, m), 1.88-1.98 (2H, m), 2.16-2.34 (2H, m), 2.54 (3H, d, J=5 Hz), 3.45-3.60 (1H, m), 3.81 (3H, s), 5 4.20-4.34 (1H, m), 4.99 (2H, s), 5.56-5.64 (1H, m), 5.79 (1H, d, J=7.5 Hz), 7.11 (1H, d, J=8 Hz), 7.32 (1H, dd, J=8, 2 Hz), 7.46-7.82 (2H, m), 7.63 (1H, d, J=8 Hz), 7.77 (1H, d, J=2 Hz). Example 18 10 A mixture of 3-(trans-4-acetoxycyclohexyl)-1-(3,4 dimethoxybenzyl)-6-trifluoromethyl-2,3-dihydro- 1H-imidazo[4,5-bjpyridin 2-one (125 mg) in a mixture of tetrahydrofuran (1 mL), methanol (0.5 mL) and 1N-sodium hydroxide (0.507 mL) was refluxed for an hour. After cooling to room temperature, the mixture was concentrated in vacuo. 15 Water was added to the residue, and the resulting precipitate was collected by filtration. The obtained solid was washed with water and subjected to a preparative silica gel column chromatography eluting with 5% methanol in chloroform. The obtained solid was washed with a mixture of diethyl ether and diisopropyl ether to give 1-(3,4-dimethoxybenzyl)-3-(trans-4 20 hydroxycyclohexyl)-6-trifluoromethyl-2,3-dihydro- 1H-imidazo[4,5 b]pyridin-2-one (62.9 mg) as a colorless solid. mp. 128-130"C NMR(DMSO-d 6 , 6): 1.22-1.41(2H, m), 1.67-1.77(2H, m), 1.90-2.00(2H, m), 2.25-2.47(2H, m), 3.43-3.56(1H, m), 3.70(3H, s), 3.71(3H, s), 4.25-4.39(1H, 25 m), 4.69(1H, d, J=4.5Hz), 5.04(2H, s), 6.86(1H, dd, J=8.5, 2.5Hz), 6.89(1H, d, J=8.5Hz), 7.07(1H, d, J=2.5Hz), 7.93(1H, d, J=2.5Hz), 8.38(1H, d, J=2.5Hz). Example 19 The following compounds described in (1) to (26) were obtained in a 30 manner similar to Example 18. 126 WO 01/05770 PCT/JPOO/04687 (1) 3- (3,4-Dimethoxybenzyl) -1- (trans-2-hydroxycyclopentyl) -5 trifluoromethyl-2,3-dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 65): 1.51-1.64(1H, m), 1.73-1.87(2H, m), 1.91-2.17(3H, m), 3.70(3H, s), 3.71(3H, s), 4.38-4.59(2H, m), 5.05(1H, d, J=4.5Hz), 5.05(2H, s), 5 6.84(1H, dd, J=8.0, 2.5Hz), 6.90(1H, d, J=8.OHz), 7.08(1H, d, J=2.5Hz), 7.37(1H, d, J=8.OHz), 7.40(1H, d, J=8.OHz), 7.57(1H, s). (2) 1-(3-Chloro-4-methoxybenzyl)-3-(trans-4-hydroxycyclohexyl)-6 trifluoromethyl-2,3-dihydro- 1H-imidazo[4,5-b]pyridin-2-one 10 mp. 121-1239C NMR(DMSO-d 6 , 6): 1.23-1.41(2H, m), 1.67-1.80(2H, m), 1.90-2.02(2H, m), 2.25-2.47(2H, m), 3.43-3.56(1H, m), 3.81(3H, s), 4.24-4.37(1H, m), 4.70(1H, brs), 5.05(2H, s), 7.12(1H, d, J=8.5Hz), 7.32(1H, dd, J=8.5, 2.5Hz), 7.51(1H, d, J=2.5Hz), 7.99(1H, d, J=2.5Hz), 8.39(1H, d, J=2.5Hz). 15 (3) 1-(3,4-Dichlorobenzyl)-3-(trans-4-hydroxycyclohexyl)-6 trifluoromethyl-2,3-dihydro- 1H-imidazo[4,5-b]pyridin-2-one mp. 170-171.5C NMR(DMSO-d 6 , 65): 1.25-1.40(2H, m), 1.70-1.80(2H, m), 1.90-1.99(2H, m), 20 2.26-2.47(2H, m), 3.43-3.56(1H, m), 4.22-4.36(1H, m), 4.69(1H, d, J=4.5Hz), 5.13(2H, s), 7.3 1(1H, dd, J=8.0, 2.OHz), 7.61(1H, d, J=8.OHz), 7.70(1H, d, J=2.OHz), 8.00(1H, d, J=2.OHz), 8.41(1H, d, J=2.OHz). (4) 3-(3,4-Dimethoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5-methyl-2,3 25 dihydro- 1H-benzimidazol-2-one mp. 174-175C NMR(DMSO-d 6 , 6): 1.26-1.44(2H, m), 1.60-1.72(2H, m), 1.88-2.00(2H, m), 2.12-2.29(2H, m), 2.27(3H, s), 3.50-3.64(1H, m), 3.69(3H, s), 3.70(3H, s), 4.12-4.25(1H, m), 4.66(1H, d, J=4.5Hz), 4.91(2H, s), 6.77(1H, dd, J=8.0, 30 2.0Hz), 6.81(1H, d, J=8.OHz), 6.87(1H, d, J=8.OHz), 6.95(1H, s), 6.99(1H, d, J=2.OHz), 7.21(1H, d, J=8.OHz). 127 WO 01/05770 PCT/JPOO/04687 MS m/z: 397(M++1). (5) 5-Carboxy-3-(3-chloro-4-methoxybenzyl)-1-(trans-4 hydroxycyclohexyl)-2,3-dihydro- 1H-benzimidazol-2-one 5 mp. 275-2769C NMR(DMSO-d 6 , 6): 1.28-1.46(2H, m), 1.66-1.78(2H, m), 1.89-2.01(2H, m), 2.15-2.32(2H, m), 3.50-3.64(1H, m), 3.81(3H, s), 4.17-4.31(1H, m), 4.68(1H, d, J=4.5Hz), 5.05(2H, s), 7.10(1H, d, J=8.5Hz), 7.22(1H, dd, J=8.5, 2.5Hz), 7.40(1H, d, J=2.5Hz), 7.46(1H, d, J=8.5Hz), 7.64(1H, s), 7.68(1H, d, 10 J=8.5Hz). MS m/z : 429(M+-1). (6) 5-Cyano-3-(3,4-dimethoxybenzyl)-1-(1,1-dimethyl-2-hydroxyethy) 2,3-dihydro- 1H-benzimidazol-2-one 15 NMR(DMSO-d 6 , 6): 1.68 (6H, s), 3.70 (3H, s), 3.71 (3H, s), 3.82 (2H, d, J=5 Hz), 4.97 (2H, s), 5.06 (1H, t, J=5 Hz), 6.82-6.93 (2H, m), 7.03 (1H, d, J=2 Hz), 7.41 (1H, dd, J=8, 2 Hz), 7.60-7.70 (2H, m). (7) 3-(4-Chloro-3-methoxybenzyl)-5-cyano-1-(1,1-dimethyl-2 20 hydroxyethyl)-2,3-dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.69 (6H, s), 3.78-3.87 (5H, m), 5.01-5.09 (3H, m), 6.83 (11H, dd, J=8, 2 Hz), 7.22 (1H, d, J=2 Hz), 7.36 (11H, d, J=8 Hz), 7.44 (11H, dd, J=8, 2 Hz), 7.63-7.77 (2H, m). 25 (8) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-(1,1-dimethyl-2 hydroxyethyl)-2,3-dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.68 (6H, s), 3.78-3.85 (5H, m), 4.98 (2H, s), 5.05 (1H, t, J=5 Hz), 7.11 (1H, d, J=8 Hz), 7.30 (1H, dd, J=8, 2 Hz), 7.42 (1H, dd, J=8, 2 Hz), 7.47 (1H, d, J=2 Hz), 7.65 (1H, d, J=8 Hz), 7.70 (1H, d, J=2 Hz). 30 (9) 3-(4-Chloro-3-methoxybenzyl)-5-cyano-1-[(R)-2-hydroxy-1 128 WO 01/05770 PCT/JPOO/04687 methylethyl]-2,3-dihydro- 1H-benzimidazol-2-one NMR(CDCl 3 , 6 ): 1.55 (3H, d, J=7.5 Hz), 3.05 (1H, dd, J=7, 4 Hz), 3.88 (3H, s), 3.99-4.16 (2H, m), 4.46-4.59 (1H, m), 5.03 (2H, s), 6.80 (1H, dd, J=8, 2 Hz), 6.90 (1H, d, J=2 Hz), 7.14 (1H, d, J=2 Hz), 7.16 (1H, d, J=8 Hz), 7.33 (1H, 5 d, J=8 Hz), 7.42 (1H, dd, J=8, 2 Hz). (10) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-[(R)-2-hydroxy-1 methylethyl]-2,3-dihydro- 1H-benzimidazol-2-one NMR(CDC1 3 , 6 ): 1.55 (3H, d, J=7.5 Hz), 3.10 (1H, dd, J=7, 4 Hz), 3.90 (3H, 10 s), 4.00-4.16 (2H, m), 4.45-4.58 (1H, m), 4.98 (2H, s), 6.90 (1H, d, J=8 Hz), 7.11 (1H, d, J=2 Hz), 7.14-7.24 (2H, m), 7.32 (1H, d, J=2 Hz), 7.41 (1H, dd, J=8, 2 Hz). (11) 3-(4-Chloro-3-methoxybenzyl)-5-cyano-1-[(S)-2-hydroxy-1 15 methylethyl]-2,3-dihydro- 1H-benzimidazol-2-one NMR(CDC1 3 , 6): 1.55 (3H, d, J=7.5 Hz), 3.05 (1H, dd, J=7, 4 Hz), 3.88 (3H, s), 3.99-4.16 (2H, m), 4.46-4.59 (1H, m), 5.03 (2H, s), 6.81 (1H, dd, J=8, 2 Hz), 6.90 (1H, d, J=2 Hz), 7.13 (1H, d, J=2 Hz), 7.16 (1H, d, J=8 Hz), 7.33 (1H, d, J=8 Hz), 7.42 (1H, dd, J=8, 2 Hz). 20 (12) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-[(S)-2-hydroxy-1 methylethyl]-2,3-dihydro- 1H-benzimidazol-2-one NMR(CDC1 3 , 6): 1.55 (3H, d, J=7.5 Hz), 3.10 (1H, dd, J=7, 4 Hz), 3.90 (3H, s), 4.00-4.16 (2H, m), 4.45-4.58 (1H, m), 4.98 (2H, s), 6.90 (1H, d, J=8 Hz), 25 7.11 (1H, d, J=2 Hz), 7.14-7.23 (2H, m), 7.32 (1H, d, J=2 Hz), 7.41 (1H, dd, J=8, 2 Hz). (13) 1-(1,1-Dimethyl-2-hydroxyethyl)-3-(3,4-dimethoxybenzyl)-5 trifluoromethyl-2,3-dihydro- 1 H-benzimidazol-2-one 30 NMR(CDC1 3 , 6): 1.65 (6H, s), 3.86 (6H, s), 4.04 (2H, d, J=7.5 Hz), 7.74 (1H, t, J=7.5 Hz), 5.01 (2H, s), 6.79-6.93 (3H, m), 7.21 (1H, s), 7.35 (1H, d, J=8 129 WO 01/05770 PCT/JPOO/04687 Hz), 7.43 (1H, d, J=8 Hz). (14) 3-(4-Chloro-3-methoxybenzyl)-1-(1,1-dimethyl-2-hydroxyethyl)-5 trifluoromethyl-2,3-dihydro- 1H-benzimidazol-2-one 5 NMR(CDC1 3 , 6): 1.65 (6H, s), 3.88 (3H, s), 4.05 (2H, d, J=7.5 Hz), 4.64 (1H, t, J=7.5 Hz), 5.04 (2H, s), 6.80 (1H, dd, J=8, 2 Hz), 6.92 (1H, d, J=2 Hz), 7.17 (1H, s), 7.30 (1H, d, J=8 Hz), 7.36 (1H, d, J=8 Hz), 7.44 (1H, d, J=8 Hz). (15) 3-(3-Chloro-4-methoxybenzyl)-1-(1,1-dimethyl-2-hydroxyethyl)-5 10 trifluoromethyl-2,3-dihydro- 1H-benzimidazol-2-one NMR(CDC1 3 , 6): 1.65 (8H, s), 3.89 (3H, s), 4.05 (2H, d, J=7.5 Hz), 4.67 (1H, t, J=7.5 Hz), 4.99 (2H, s), 6.89 (1H, d, J=8 Hz), 7.15 (1H, s), 7.18 (1H, dd, J=8, 2 Hz), 7.33-7.40 (2H, m), 7.45 (1H, d, J=8 Hz). 15 (16) 3-(3-Chloro-4-methoxybenzyl)-1-(cis-4-hydroxycyclohexyl)-5-cyano 2,3-dihydro- 1H-benzimidazol-2-one NMR(CDC1 3 , 6): 1.64-1.80 (4H, m), 1.94-2.05 (2H, m), 2.46-2.64 (2H, m), 3.89 (3H, s), 4.20 (1H, br s), 4.40-4.54 (1H, m), 4.98 (2H, s), 6.90 (1H, d, J=8 Hz), 7.09 (1H, s), 7.20 (1H, dd, J=8, 2 Hz), 7.30-7.40 (3H, m). 20 (17) 5-Cyano-1-(trans-4-hydroxycyclohexyl)-3-piperonyl-2,3-dihydro-1H benzimidazol-2-one NMR(CDC13, 6): 1.45-1.61 (2H, m), 1.86-1.98 (2H, m), 2.10-2.39 (4H, m), 3.72-3.86 (1H, m), 4.24-4.38 (1H, i), 4.95 (2H, s), 5.95 (2H, s), 6.75-6.84 25 (3H, m), 7.11 (1H, d, J=2 Hz), 7.14 (1H, d, J=8 Hz), 7.36 (1H, dd, J=8, 2 Hz). (18) 3-(2-Chlorobenzyl)-1-(trans-4-hydroxycyclohexyl)-5-cyano-2,3 dihydro- 1 H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.29-1.45 (2H, m), 1.67-1.79 (2H, m), 1.89-2.01 (2H, m), 30 2.14-2.32 (2H, m), 3.51-3.64 (1H, m), 4.19-4.34 (1H, m), 4.68 (1H, d, J=4 Hz), 5.15 (2H, s), 6.94 (1H, d, J=8 Hz), 7.25-7.38 (2H, m), 7.49-7.60 (3H, m), 130 WO 01/05770 PCT/JPOO/04687 7.64 (d, J=8 Hz, 1H). (19) 3-(3-Chlorobenzyl)-1-(trans-4-hydroxycyclohexyl)-5-cyano-2,3 dihydro- 1 H-benzimidazol-2-one 5 NMR(DMSO-d 6 , 6): 1.27-1.45 (2H, m), 1.66-1.76 (2H, m), 1.89-1.99 (2H, m), 2.12-2.30 (2H, m), 3.50-3.64 (1H, m), 4.17-4.32 (1H, m), 4.67 (1H, d, J=4 Hz), 5.07 (2H, s), 7.25-7.32 (1H, m), 7.32-7.41 (2H, m), 7.45 (1H, s), 7.51 (1H, dd, J=8, 2 Hz), 7.59 (1H, d, J=8 Hz), 7.76 (1H, d, J=2 Hz). 10 (20) 3-(4-Chlorobenzyl)-1-(trans-4-hydroxycyclohexyl)-5-cyano-2,3 dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.45-1.61 (2H, m), 1.86-1.98 (2H, m), 2.11-2.39 (4H, m), 3.73-3.87 (1H, m), 4.24-4.38 (1H, m), 5.01 (2H, s), 7.08 (1H, d, J=2 Hz), 7.15 (1H, d, J=8 Hz), 7.24 (2H, d, J=8 Hz), 7.32 (2H, d, J=8 Hz), 7.38 (1H, dd, J=8, 15 2 Hz). (21) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-[1 (hydroxymethyl)cyclopentyl]-2,3-dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.71-1.88 (2H, m), 1.88-2.04 (2H, m), 2.21-2.36 (2H, m), 20 2.36-2.49 (2H, m), 3.28 (1H, t, J=7.5 Hz), 3.84-3.94 (5H, m), 4.95 (2H, s), 6.90 (1H, d, J=8 Hz), 7.10 (1H, d, J=2 Hz), 7.19 (1H, dd, J=8, 2 Hz), 7.26 7.37 (3H, m). (22) 3-(3,4-Dimethoxybenzyl)-1-(cis-4-hydroxycyclohexyl)-5-cyano-2,3 25 dihydro- 1H-benzimidazol-2-one NMR(DMSO-d 6 , 6): 1.43-1.66 (4H, m), 1.75-1.86 (2H, m), 3.70 (3H, s), 3.72 (3H, s), 3.90 (1H, br), 4.24-4.38 (1H, m), 4.58 (1H, d, J=4 Hz), 4.99 (2H, s), 6.84-6.93 (2H, m), 7.05 (1H, s-like), 7.41 (1H, d, J=8 Hz), 7.55 (1H, dd, J=8, 2 Hz), 7.73 (1H, d, J=2 Hz). 30 (23) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-[(S)-1-ethyl-2 131 WO 01/05770 PCT/JPOO/04687 hydroxyethyl]-2,3-dihydro- 1H-benzimidazol-2-one NMR(CDCla, 6): 0.944 (3H, t, J=7.5 Hz), 1.93-2.14 (2H, m), 2.96-3.08 (1H, m), 3.89 (3H, s), 3.94-4.06 (1H, m), 4.06-4.21 (1H, m), 4.21-4.34 (1H, m), 4.99 (2H, s), 6.90 (1H, d, J=8 Hz), 7.10 (1H, d, J=2 Hz), 7.13-7.20 (2H, m), 5 7.30 (1H, d, J=2 Hz), 7.40 (1H, dd, J=8, 2 Hz). (24) 3-(3-Chloro-4-methoxybenzyl)-5-cyano-1-[(R)-1-ethyl-2 hydroxyethyl]-2,3-dihydro- 1H-benzimidazol-2-one

NMR(CDC

3 , 6): 0.94 (3H, t, J=7.5 Hz), 1.94-2.14 (2H, m), 2.98-3.06 (1H, 10 m), 3.89 (1H, s), 3.97-4.07 (1H, m), 4.10-4.21 (1H, m), 4.22-4.34 (1H, m), 4.99 (2H, s), 6.90 (1H, d, J=8 Hz), 7.11 (1H, d, J=2 Hz), 7.14-7.20 (2H, m), 7.30 (1H, d, J=2 Hz), 7.40 (1H, dd, J=8, 2 Hz). (25) 6-Carboxy-1-(3-chloro-4-methoxybenzyl)-3-(trans-4 15 hydroxycyclohexyl)-2,3-dihydro- 1H-imidazo[4,5-b]pyridin-2-one mp. 262-262.5*C NMR(DMSO-d 6 , 6): 1.23-1.41(2H, m), 1.68-1.80(2H, m), 1.90-2.01(2H, m), 2.32-2.48(2H, m), 3.44-3.58(1H, m), 3.81(3H, s), 4.25-4.39(1H, m), 4.69(1H, d, J=4.5Hz), 5.07(2H, s), 7.12(1H, d, J=8.5Hz), 7.27(1H, dd, J=8.5, 2.0Hz), 20 7.47(1H, d, J=2.OHz), 7.90(1H, d, J=2.OHz), 8.58(1H, d, J=2.OHz). MS m/z: 430(M+-1). (26) 3-(3-Chloro-4-methoxybenzyl)-1-(3-hyoxypropyl)-5-cyano-2,3 dihydro- 1 H-benzimidazole-2-one 25 NMR(DMSO-d 6 , 6): 1.80 (2H, m), 3.36-3.55 (2H, m), 3.82 (3H, s), 3.96 (2H, t, J=7 Hz), 4.66 (1H, t, J=4 Hz), 5.02 (2H, s), 7.10 (1H, d, J=8 Hz), 7.32 (1H, dd, J=8,2 Hz), 7.40 (1H, d, J=8 Hz), 7.48 (1H, d, J=2 Hz), 7.56 (1H, dd, J=8,2 Hz), 7.75 (1H, d, J=2 Hz). 30 Example 20 A mixture of 5-carboxy-3-(3-chloro-4-methoxybenzyl)-1-(trans-4 132 WO 01/05770 PCT/JPOO/04687 hydroxycyclohexyl)-2,3-dihydro-1H-benzimidazol-2-one (72 mg), ammonium hydroxide (0.1 mL, 28% NH 3 in water), 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35.2mg) and 1 hydroxybenzotriazole (27.1 mg) in anhydrous dimethylformamide (1 mL) 5 was stirred at ambient temperature for 4 hours. The mixture was partitioned between water and ethyl acetate. The separated organic layer was washed successively with an aqueous saturated sodium bicarbonate solution, water, 1N-hydrochloric acid and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was 10 subjected to a preparative silica gel column chromatography eluting with 5 % methanol in chloroform. The obtained solid was washed with acetonitrile to give 5-carbamoyl-3-(3-chloro-4-methoxybenzyl)-1-(trans-4 hydroxycyclohexyl)-2,3-dihydro-1H-benzimidazol-2-one (217.9 mg) as a colorless solid. 15 mp. 291.5-292C NMR(DMSO-d 6 , 6): 1.26-1.46(2H, m), 1.67-1.78(2H, m), 1.90-2.02(2H, m), 2.15-2.35(2H, m), 3.52-3.65(1H, m), 3.81(3H, s), 4.19-4.31(1H, m), 4.69(1H, brs), 5.05(2H, s), 7.11(1H, d, J=8.5Hz), 7.23(1H, dd, J=8.5, 2.0Hz), 7.40(1H, d, J=2.OHz), 7.47(1H, d, J=8.5Hz), 7.65(1H, s), 7.68(1H, d, J=8.5Hz). 20 MS m/z: 429(M+-1). Example 21 The following compounds described in (1) and (2) were obtained in a manner similar to Example 20. 25 (1) 1-(3-Chloro-4-methoxybenzyl)-6-furfurylcarbamoyl-3-(trans-4 hydroxycyclohexyl)-2,3-dihydro- 1H-imidazo[4,5-b]pyridin-2-one mp. 193-194.5'C NMR(DMSO-d 6 , 6): 1.24-1.42(2H, m), 1.67-1.79(2H, m), 1.90-2.01(2H, m), 30 2.32-2.48(2H, m), 3.44-3.58(1H, m), 3.82(3H, s), 4.23-4.37(1H, m), 4.49(2H, d, J=5.5Hz), 4.70(1H,br s), 5.02(2H, s), 6.28(1H, m), 6.40(1H, m), 7.1 1(1H, d, 133 WO 01/05770 PCT/JPOO/04687 J=8.5Hz), 7.27(1H, dd, J=8.5, 2.0Hz), 7.46(1H, s), 7.59(1H, m), 7.91(1H, d, J=2.OHz), 8.53(1H, s), 8.99(1H, t, J=5.5Hz). (2) 1-(3-Chloro-4-methoxybenzyl)-6-(3-picolylcarbamoyl)-3-(trans-4 5 hydroxycyclohexyl)-2,3-dihydro- 1H-imidazo[4,5-b]pyridin-2-one mp. 134-1359C NMR(DMSO-d6, 6 ): 1.26-1.42(2H, m), 1.68-1.79(2H, m), 1.90-2.01(2H, m), 2.32-2.52(2H, m), 3.45-3.58(1H, m), 3.82(3H, s), 4.24-4.37(1H, m), 4.51(2H, d, J=5.5Hz), 4.70(1H,brs), 5.03(2H, s), 7.11(1H, d, J=8.5Hz), 7.27(1H, dd, 10 J=8.5, 2.0Hz), 7.37(1H, dd, J=7.5, 5.5Hz), 7.46(1H, s), 7.72(1H, m), 7.93(1H, d, J=2.OHz), 8.47(1H, d, J=5.5Hz), 8.56(2H, s), 9.13(1H, t, J=5.5Hz). MS m/z: 522(M++1). Example 22 15 The following compounds described in (1) to (3) were obtained in a manner similar to Preparation 16. (1) 1-(trans-4-Acetoxycyclohexyl)-3-(3,4-dimethoxybenzyl)-5-nitro-2,3 dihydro- 1H-benzimidazol-2-one 20 mp. 207-207.59C NMR(DMSO-d 6 , 6): 1.49-1.66(2H, m), 1.75-1.87(2H, m), 1.98-2.10(2H, m), 2.02(3H, s), 2.23-2.42(2H, m), 3.70(3H, s), 3.72(3H, s), 4.33-4.46(1H, m), 4.75-4.88(1H, m), 5.09(2H, s), 6.83(1H, dd, J=8.5, 2.5Hz), 6.90(1H, d, J=8.5Hz), 7.05(1H, d, J=2.5Hz), 7.70(1H, d, J=9.OHz), 7.99(1H, dd, J=9.0, 25 2.0Hz), 8.06(1H, d, J=2.OHz). (2) 1-(trans-4-Acetamidocyclohexyl)-3-(3-chloro-4-methoxybenzyl)-5 cyano-2,3--dihydro- 1H-benzimidazol-2-one NMR(CDCl 3 , 6): 1.32-1.49 (2H, m), 1.89-2.03 (5H, m), 2.15-2.38 (4H, m), 30 3.84-4.01 (4H, m), 4.35-4.49 (1H, m), 4.97 (2H, s), 5.36 (1H, d, J=8 Hz), 6.89 (1H, d, J=8 Hz), 7.10 (1H, d, J=2 Hz), 7.16-7.24 (2H, m), 7.31 (1H, d, J=2 Hz), 134 WO 01/05770 PCT/JPOO/04687 7.38 (1H, dd, J=8, 2 Hz). (3) 1-(1-Acetylpiperidin-4-yl)-3-(3-chloro-4-methoxybenzyl)-5-cyano-2,3 dihydro- 1H-benzimidazol-2-one 5 NMR(CDC1 3 , 6): 1.86-2.01 (2H, m), 2.18 (3H, s), 2.20-2.41 (2H, m), 2.60 2.75 (1H, m), 3.17-3.31 (1H, m), 3.90 (3H, s), 3.96-4.09 (1H, m), 4.50-4.65 (1H, m), 4.84-5.03 (3H, m), 6.90 (1H, d, J=8 Hz), 7.07 (1H, s), 7.15 (1H, d, J=8 Hz), 7.20 (1H, dd, J=8, 2 Hz), 7.32 (1H, d, J=2 Hz), 7.37 (1H, dd, J=8, 2 Hz). 10 Example 23 To a mixture of 1-(3-chloro-4-methoxybenzyl)-6-cyano-3-(trans-4 hydroxycyclohexyl)- 2,3-dihydro-1H- imidazo[4,5-blpyridin-2-one (500 mg), acetic acid (76.9 mg) and diethyl azodicarboxylate (221 mg) in anhydrous 15 tetrahydrofuran (5 mL) was added triphenylphosphine (334 mg). The mixture was stirred at ambient temperature for overnight. The mixture was evaporated in vacuo, and the residue was purified by a silica gel column chromatography eluting with a mixture of n-hexane and ethyl acetate (3:1) to give 3-(cis-4-acetoxycyclohexyl)- 1-(3-chloro-4 20 methoxybenzyl)- 6-cyano-2,3-dihydro-1H- imidazo[4,5-b]pyridin-2-one (150 mg) as a pale yellow gum. NMR(CDC13, 6 ): 1.62-1.78(4H, m), 2.06-2.19(5H, m), 2.68-2.84(2H, m), 3.89(3H, s), 4.50(1H, m), 4.95(2H, s), 5.08(1H, br s), 6.40(1H, br s), 6.90(1H, d, J=7Hz), 7.14(1H, d, J=1Hz), 7.19(1H, dd, J=8, 1Hz), 7.31(1H, d, J=1Hz), 25 8.31(1H, s). Example 24 To a suspension of 3-(cis-4-acetoxycyclohexyl)-1-(3-chloro-4 methoxybenzyl)- 6-cyano-2,3-dihydro-1H- imidazo[4,5-b]pyridin-2-one 30 (150 mg) in methanol (3 ml) was added potassium carbonate (180 mg). The mixture was stirred at ambient temperature for 2 hours, then potassium carbonate (180 mg) was added thereto. After stirring for 2 hours, the 135 WO 01/05770 PCT/JPOO/04687 mixture was added with potassium carbonate (180 mg). After stirring overnight, the mixture was added with water and extracted with chloroform. The extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a preparative thin-layer chromatography on 5 silica gel developing with a mixture of ethyl acetate and n-hexane (2:1) to give 1-(3-chloro-4-methoxybenzyl)-6-cyano-3-(cis-4-hydroxycyclohexyl) 2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (50 mg) as an oil. mp 197-198C NMR(CDCl 3 , 6) : 1.61-1.78(4H, m), 1.94-2.06(2H, m), 2.75-2.94(2H, m), 10 3.90(3H, s), 4.15(1H, br s), 4.46(1H, m), 4.97(2H, s), 6.91(1H, d, J=8Hz), 7.15(1H, d, J=1Hz), 7.19(lH, dd, J=8, 1Hz), 7.33(1H, d, J=1Hz), 8.32(1H, d, J=lHz). Example 25 15 To a solution of 5-cyano-3-(3-formyl-4-methoxybenzyl)-1-(trans-4 hydroxycyclohexyl)-1,3-dihydro-2H-benzimidazol-2-one (35.0 mg) in a mixture of ethanol (2 mL) and tetrahydrofuran (1 mL) was added sodium borohydride (3.27 mg) under ice cooling, and the mixture was stirred at 0*C for 2 hours. The mixture was partitioned between ethyl acetate and water. 20 The separated organic layer was washed with 1N-hydrochloric acid, water, saturated sodium bicarbonate solution and brine, successively, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by a preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (10:1). The crude product was triturated with 25 diisopropyl ether to give 5-cyano-1-(trans-4-hydroxycyclohexyl)-3-(3 hydroxymethyl-4-methoxybenzyl)-1,3-dihydro-2H-benzimidazol-2-one as a colorless powder (20.0 mg). NMR(DMSO-d 6 , 6) : 1.28-1.48 (2H, br), 1.65-1.78 (2H, br), 1.88-2.03 (2H, br), 2.14-2.35 (2H, br), 3.53-3.66 (1H, br), 3.73 (3H, s), 4.18-4.35 (1H, br), 30 4.42 (2H, d, J= 7 Hz), 4.68 (1H, d, J= 4 Hz), 5.00 (2H, s), 5.01 (1H, br), 6.90 (1H, d, J= 8 Hz), 7.24 (1H, d, J= 8 Hz), 7.37 (1H, s), 7.49 (1H, d, J= 8 Hz), 136 WO 01/05770 PCT/JPOO/04687 7.55 (1H, d, J= 8 Hz), 7.65 (1H, s). MS (m/z) 406. Example 26 5 To a solution of 1-(trans-4-hydroxycyclohexyl)-3-(4-methoxy-3 methoxycarbonylbenzyl)-5-cyano-2,3-dihydro- 1H-benzimidazole-2-one (120 mg) in methanol (10 mL) and tetrahydrofuran (2 mL) was added iN aqueous sodium hydroxide solution (3 mL) and the mixture was stirred at 60'C for an hour. After the solution was acidified with IN-hydrochloric 10 acid, the organic solvent of the solution was removed by evaporation. The aqueous layer was diluted with water and extracted with a mixture of chloroform and methanol (4:1). The separated organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 3-(3 15 carboxy-4-methoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5-cyano-2,3 dihydro- 1H-benzimidazole-2-one as a colorless powder (88.8 mg). NMR(DMSO-d 6 , 6): 1.28-1.47 (2H, br), 1.66-1.78 (2H, br), 1.88-2.03 (2H, br), 2.14-2.33 (2H, br), 3.52-3.66 (1H, br), 3.78 (3H, s), 4.18-4.33 (1H,. br), 4.68 (1H, br), 5.02 (2H, s), 7.08 (1H, d, J= 8 Hz), 7.46-7.58 (3H, m), 7.66 (1H, 20 s), 7.77 (1H, s). MS (m/z) 420. Example 27 A solution of 3-(3-carboxy-4-methoxybenzyl)-1-(trans-4 25 hydroxycyclohexyl)-5-cyano-2,3-dihydro-1H-benzimidazole-2-one (51.0 mg), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (34.8 mg), 1-hydroxybenotriazole (24.5 mg) in anhydrous dimethylformamide (2 mL) was stirred at ambient temperature for 2 hours. After adding 28% ammonium solution (7 drops), the mixture was stirred at ambient 30 temperature for 2 hours. The mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with iN hydrochloric acid, water, saturated sodium bicarbonate solution and brine, 137 WO 01/05770 PCT/JPOO/04687 successively, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 3-(3-carbamoyl-4 methoxybenzyl)- 1-(trans-4-hydroxycyclohexyl)-5-cyano-2,3-dihydro-1H benzimidazole-2-oneas a colorless powder (28.6 mg). 5 NMR(CDCl 3 , 6) : 1.29-1.47 (2H, br), 1.65-1.78 (2H, br), 1.88-2.03 (2H, br), 2.13-2.32 (2H, br), 3.50-3.66 (1H, br), 3.85 (3H, s), 4.17-4.35 (1H, br), 4.68 (1H, d, J= 7 Hz), 5.03 (2H, s), 7.09 (1H, d, J= 8 Hz), 7.44-7.58 (4H, br), 7.62 (1H, br), 7.73 (1H, s), 7.79 (1H, s). 10 Example 28 To a suspension of 3-(3-chloro-4-methoxybenzyl)-1-(piperidin-4 yl)-5-cyano-2,3-dihydro-1H-benzimidazole-2-one (91 mg) in methanol (5 mL) were added 37% formaldehyde aqueous solution (220 mg), sodium cyanotrihydroborate (43.2 mg) and acetic acid (5 drops) under nitrogen at 15 ambient temperature. After stirring for 2 hours at same temperature, the reaction mixture was poured into saturated sodium bicarbonate solution and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diethyl ether to give 3-(3-chloro-4-methoxybenzyl)-5-cyano 20 1-(1-methylpiperidin-4-yl)-2,3-dihydro- 1H-benzimidazole-2-one (75 mg) as an amorphous powder. NMR(CDCl 3 , 6 ) : 1.78-1.90 (2H, m), 2.10-2.24 (2H, m), 2.32-2.52 (5H, m), 2.98-3.09 (2H, m), 3.89 (3H, s), 4.37-4.51 (1H, m), 4.99 (2H, s), 6.90 (1H, d, J=8 Hz), 7.10 (1H, d, J=2 Hz), 7.20 (1H, dd, J=8,2 Hz),7.30-7.39 (3H, m). 25 Example 29 A solution of methyl chloroformate (25.7 mg) in chloroform (1 ml) was added dropwise to a mixture of 3-(3-chloro-4-methoxybenzyl)-5 cyano-1-[(S)-pyrrolidin-3-yl]-2,3-dihydro-1H-benzimidazole- 2-one (80 mg) 30 and triethylamine (31.7 mg) in a mixture of chloroform (1.6 ml) and 1,3 dimethyl-2-imidazolidinone (0.8 ml) under cooling on an ice bath. The reaction mixture was stirred at same temperature for 2 hours and 138 WO 01/05770 PCT/JPOO/04687 quenched by addition of 3-(N,N-dimethylamino)propylamine (0.1 ml). The mixture was poured into water and extracted with chloroform. The organic layer was washed with 1N-hydrochloric acid, water, an aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and 5 concentrated in vacuo. The residue was purified by a preparative thin layer chromatography (10 % methanol in chloroform) to give 3-(3-chloro-4 methoxybenzyl)-5-cyano- 1-[(S)-1-methoxycarbonylpyrrolidin-3-yl]-2,3 dihydro-1H-benzimidazole-2-one (55 mg). NMR(CDCl 3 , 6): 2.26-2.40 (1H, in), 2.49-2.65 (1H, m), 3.45-3.60 (1H, m), 10 3.75 (3H, s), 3.79-3.92 (6H, m), 4.97 (2H, s), 5.09-5.24 (1H, m), 6.90 (1H, d, J=8 Hz), 7.05-7.14 (2H, m), 7.21 (1H, dd, J=8, 2 Hz), 7.32 (1H, d, J=2 Hz), 7.40 (1H, d, J=8 Hz). Example 30 15 To a mixture of 3-(3-chloro-4-methoxybenzyl)-1-(3-hyoxypropyl)-5 cyano-2,3-dihydro-1H-benzimidazole-2-one (320 mg) and triethylamine (435 mg) in a mixture of dimethyl sulfoxide (3 mL) and dichloromethane (3 mL) was added portionwise sulfur trioxide pyridine complex (342 mg) at ambient temperature. After stirring at the same temperature for 3 hours, 20 the reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel chromatography eluting with chloroform to give 3-(3-chloro-4 methoxybenzyl)-5-cyano- 1-(2-formylethyl)-2,3-dihydro- 1H-benzimidazole 25 2-one (258 mg) as a powder. NMR(CDCl 3 , 6): 3.06 (2H, t, J=8 Hz), 3.89 (3H, s), 4.24 (2H, t, J=8 Hz), 4.97 (2H, s), 6.90 (1H, d, J=8 Hz), 7.10 (1H, d, J=8 Hz), 7.15-7.24 (2H, m), 7.31 (1H, d, J=2 Hz), 7.44 (1H, d, J=8 Hz), 9.85 (1H, s). 30 Example 31 To a suspension of 3-(3-chloro-4-methoxybenzyl)-5-cyano- 1-(2 formylethyl)-2,3-dihydro-1H- benzimidazole-2-one (220 mg, 0.56 mmol) in 139 WO 01/05770 PCT/JPOO/04687 a mixture of water (1 mL) and tert-butyl alcohol (4 mL) were added 2 methyl-2-butene (185 mg, 2.64 mmol) and sodium dihydrogenphosphate (78.5 mg, 0.654 mmol) at ambient temperature. To the mixture was added portionwise sodium chlorite (238 mg, 2.63 mmol), and the resulting mixture 5 was stirred for 2 hours at ambient temperature. The reaction mixture was cooled in an ice bath, adjusted to pH 3 with 1N-hydrochloric acid. The resulting precipitate was collected by vacuum filtration and washed with ethyl acetate to give 3-[3-(3-chloro-4-methoxybenzyl)-5-cyano-2-one- 2,3 dihydro- 1H-benzimidazole- 1-yl]propionic acid (167 mg) as a solid. 10 NMR(DMSO-d 6 , 6): 2.68 (2H, t, J=7 Hz), 3.81 (3H, s), 4.12 (2H, t, J=7 Hz), 5.01 (2H, s), 7.10 (1H, d, J=8 Hz), 7.31 (lH, dd, J=8,2 Hz), 7.41-7.50 (2H, m), 7.54 (1H, dd, J=8,2 Hz), 7.74 (1H, d, J=2 Hz). Example 32 15 A mixture of 3-[3-(3-chloro-4-methoxybenzyl)-5-cyano-2-one-2,3 dihydro- 1H-benzimidazole- 1-yl]propionic acid (45 mg), N-methylamine hydrochloride (9.5 mg), 1-hydroxybenzotriazole (22 mg), and 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide (24 mg) in anhydrous N,N dimethylformamide (3 mL) was stirred at ambient temperature for 18 hours. 20 The mixture was partitioned between water and ethyl acetate. The separated organic layer was washed with 1N-hydrochloric acid, water, saturated sodium bicarbonate solution and brine, successively, and dried over magnesium sulfate. After evaporation of the solvent, the residue was triturated with diethyl ether to give 3-[3-(3-chloro-4-methoxybenzyl)-5 25 cyano-2-one-2,3-dihydro- 1H-benzimidazole- 1-yl]-N-methylpropionamide (33 mg) as a pale yellow powder. NMR(CDCl 3 , 6): 2.70 (2H, t, J=6 Hz), 2.74 (3H, d, J=5 Hz), 3.89 (3H, s), 4.26 (2H, t, J=6 Hz), 4.97 (2H, s), 5.74 (1H, br peak), 6.90 (1H, d, J=8 Hz), 7.08 (1H, d, J=2 Hz), 7.19 (1H, dd, J=8, 2 Hz), 7.26-7.32 (2H, m), 7.43 (1H, 30 dd, J=8, 2 Hz). Example 33 140 WO 01/05770 PCT/JPOO/04687 Sodium hydride (60% dispersion in mineral oil, 3.58g) was added portionwise to a solution 6-cyano-3-(trans-4-hydroxycyclohexyl)-2,3 dihydro-1H-imidazo[4,5-b]pyridin-2-one(21 g) in N,N-dimethylformamide (210 ml) at 0*C, and the mixture was stirred at ambient temperature for an 5 hour. After adding 3-chloro-4-methoxybenzyl bromide (20.1 g) at ambient temperature, the reaction mixture was stirred at same temperature for 3 hours and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (twice). The combined organic layer was washed with water (twice) and brine, and dried over magnesium sulfate. 10 After evaporation of the solvent, the residue was purified by a silica gel column chromatography eluting with 5% methanol in chloroform and crystallization from ethanol. The crude crystals were suspended in water (400 ml) and stirred at 65*C for 14 hours to give 1-(3-chloro-4 methoxybenzyl)-6-cyano- 3-(trans-4-hydroxycyclohexyl)- 2,3-dihydro-1H 15 imidazo[4,5-b]pyridin-2-one (19.9 g) as a colorless solid. NMR(DMSO-d 6 , 5): 1.25-1.40 (2H, m), 1.68-1.77 (2H, m), 1.90-2.00 (2H, m), 2.26-2.44 (2H, m), 3.42-3.55 (1H, m), 3.82 (3H, s), 4.22-4.35 (1H, m), 4.68 (1H, d, J= 5.5 Hz), 4.98 (2H, s), 7.12 (1H, d, J= 8.5 Hz), 7.35 (1H, dd, J= 8.5, 2.0 Hz), 7.52 (lH, d, J= 2.0 Hz), 8.10 (1H, d, J= 2.0 Hz), 8.48 (1H,. d, J= 20 2.0 Hz). 141

Claims

1. A compound of the formula (Ia): 5 ( a (|H)m R \ N>==ya (Ia) Xa N '2a 10 wherein Xa is CH or nitrogen atom; Ya is oxygen atom or sulfur atom; Ria is a halogen atom; cyano group; nitro group; carbamoyl group; a lower 15 alkylcarbamoyl group which may be substituted with a heterocyclic group; carboxy group; a protected carboxy group; a lower alkyl group; a halo(lower)alkyl group; a lower alkoxy group; an acyl group; or a lower alkanesulfonyl group, R2a is a lower alkyl group, a cycloalkyl group or a heterocyclic group, 20 among which the lower alkyl group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, lower alkylamino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, carboxy, 25 lower alkanesulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl carbamoyl and sulfamoyl; and the cycloalkyl group and the heterocyclic group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower 30 alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkylenedioxy, 142 WO 01/05770 PCT/JPOO/04687 carbamoyl and sulfamoyl, R3a, R4a and Rsa are, the same or different, hydrogen atom, a halogen atom, a lower alkanoyl group, carboxy group, a protected carboxy group, carbamoyl group, nitro group, cyano group, a lower alkyl group 5 optionally substituted by hydroxy, a lower alkoxy group or a lower alkoxy-substituted aralkyl group; or two of R3a, R 4 a and R5a may combine together to form a lower alkylenedioxy group, m is an integer of 1 or 2, 10 provided that when R3a is hydrogen atom, R4a is a lower alkoxy group and R5a is hydrogen atom, a halogen atom, cyano group, a lower alkyl group, a lower alkoxy group, a protected carboxy group, carboxy group or nitro group, then (1) the lower alkyl group for R2a has one to three substituents selected 15 from the group consisting of hydroxy, protected hydroxy, acyl, lower alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, carboxy, lower alkanesulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl carbamoyl 20 and sulfamoyl, (2) the cycloalkyl group for R2a has one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower 25 alkylureido, sulfamoylamino, protected carboxy, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkylenedioxy, carbamoyl and sulfamoyl, (3) the heterocyclic group for R2a is selected from pyrrolidinyl group, dioxanyl group and piperidyl group which groups may be substituted 30 with protected carboxy, acyl, lower alkanesulfonyl, carbamoyl or sulfamoyl, (4) Ria is carbamoyl group; a lower alkylcarbamoyl group which may be 143 WO 01/05770 PCT/JPOO/04687 substituted with a heterocyclic group; carboxy group; a protected carboxy group; an acyl group; or a lower alkanesulfonyl group; (5) Xa is nitrogen atom; (6) m is an integer of 2; or 5 (7) ya is sulfur atom, its prodrug or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1, wherein Xa is nitrogen atom, its prodrug or a pharmaceutically acceptable salt thereof. 10

3. A compound of the formula (Ia): W R 3 a la (CH 2 ) 5a 15 y N (a Xa N R2a wherein 20 Xa is CH; ya is oxygen atom or sulfur atom; Ria is cyano group; nitro group; carbamoyl group; a lower alkylcarbamoyl group which may be substituted with a heterocyclic group; carboxy group; a protected carboxy group; a lower alkyl group; a 25 halo(lower)alkyl group; an acyl group; or a lower alkanesulfonyl group, R2a is a lower alkyl group, a cycloalkyl group or a heterocyclic group, each of which has one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower 30 alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, carboxy, lower alkanesulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl carbamoyl and sulfamoyl; 144 WO 01/05770 PCT/JP00/04687 R3a, R4a and R5a are, the same or different, hydrogen atom, a halogen atom, a lower alkanoyl group, carboxy group, a protected carboxy group, carbamoyl group, nitro group, cyano group, a lower alkyl group optionally substituted by hydroxy, a lower alkoxy group or a lower 5 alkoxy-substituted aralkyl group; or two of R3a, R4a and R5a may combine together to form a lower alkylenedioxy group, m is an integer of 1, its prodrug or a pharmaceutically acceptable salt thereof. 10

4. A compound of claim 1 or 2, wherein Ria is cyano group; nitro group; carbamoyl group; a lower alkylcarbamoyl group which may be substituted with a heterocyclic group; carboxy group; a lower alkoxycarbonyl group; a lower alkyl group; a halo(lower)alkyl group; a lower alkanoyl group; an aroyl group; 15 or a lower alkanesulfonyl group, R2a is a cycloalkyl group which has one to three substituents selected from the group consisting of hydroxy, acyloxy, acyl, lower-alkoxy substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, 20 lower alkoxycarbonyl, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, acyloxy(lower)alkyl, lower alkylenedioxy, carbamoyl, and sulfamoyl; its prodrug or a pharmaceutically acceptable salt thereof. 25

5. A compound of claim 4, wherein R2a is a cyclohexyl group which has one to three substituents selected from the group consisting of hydroxy, lower alkanoyloxy, acyl, lower alkoxy-substituted aralkyloxy, amino, lower alkanoylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower 30 alkylureido, sulfamoylamino, lower alkoxycarbonyl, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, lower alkanoyloxy(lower)alkyl, lower alkylenedioxy, carbamoyl and sulfamoyl; 145 WO 01/05770 PCT/JP00/04687 its prodrug or a pharmaceutically acceptable salt thereof.

6. A compound of claim 5, wherein Ria is cyano group, 5 R2a is a cyclohexyl group which has hydroxy or lower alkanoyloxy, R3a is a hydrogen atom, R4a is a halogen atom, Rsa is a lower alkoxy group, its prodrug or a pharmaceutically acceptable salt thereof. 10

7. A compound of claim 6 which is selected from the group consisting of 1-(3-chloro-4-methoxybenzyl)-6-cyano- 3-(trans-4-hydroxycyclohexyl) 2,3-dihydro- 1 H-imidazo [4,5-b]pyridin-2-one, 1-(3-bromo-4-methoxybenzyl)-6-cyano-3-(trans-4-hydroxycyclohexyl) 15 2,3-dihydro-lH-imidazo[4,5-bjpyridin-2-one and 1-(3-chloro-4-methoxybenzyl)-6-cyano-3-(cis-4-hydroxycyclohexyl)-2,3 dihydro- 1H-imidazo[4,5-bjpyridin-2-one.

8. A process for preparing a compound of the formula (Ia): 20 \N N (Ia) >Ya 25 Xa N R2a wherein Xa is CH or nitrogen atom; Ya is oxygen atom or sulfur atom; 30 Ria is a halogen atom; cyano group; nitro group; carbamoyl group; a lower alkylcarbamoyl group which may be substituted with a heterocyclic group; carboxy group; a protected carboxy group; a lower alkyl group; a 146 WO 01/05770 PCT/JP00/04687 halo(lower)alkyl group; a lower alkoxy group; an acyl group; or a lower alkanesulfonyl group, R2a is a lower alkyl group, a cycloalkyl group or a heterocyclic group, among which the lower alkyl group may have one to three substituents 5 selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, lower alkylamino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, carboxy, lower alkanesulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl 10 carbamoyl and sulfamoyl; and the cycloalkyl group and the heterocyclic group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, 15 protected carboxy, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkylenedioxy, carbamoyl and sulfamoyl, R3a, R4a and R5a are, the same or different, hydrogen atom, a halogen atom, a lower alkanoyl group, carboxy group, a protected carboxy group, 20 carbamoyl group, nitro group, cyano group, a lower alkyl group optionally substituted by hydroxy, a lower alkoxy group or a lower alkoxy-substituted aralkyl group; or two of R3a, R4a and R5a may combine together to form a lower alkylenedioxy group, m is an integer of 1 or 2, 25 provided that when R3a is hydrogen atom, R4a is a lower alkoxy group and RSa is hydrogen atom, a halogen atom, cyano group, a lower alkyl group, a lower alkoxy group, a protected carboxy group, carboxy group or nitro group, then 30 (1) the lower alkyl group for R 2 a has one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower alkoxy-substituted aralkyloxy, amino, acylamino, lower 147 WO 01/05770 PCT/JPOO/04687 alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, carboxy, lower alkanesulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl carbamoyl and sulfamoyl, 5 (2) the cycloalkyl group for R 2 a has one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower alkoxy- substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, lower alkanesulfonyl, 10 lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkylenedioxy, carbamoyl and sulfamoyl, (3) the heterocyclic group for R 2 a is selected from pyrrolidinyl group, dioxanyl group and piperidyl group which groups may be substituted with protected carboxy, acyl, lower alkanesulfonyl, carbamoyl or 15 sulfamoyl, (4) Ria is carbamoyl group; a lower alkylcarbamoyl group which may be substituted with a heterocyclic group; carboxy group; a protected carboxy group; an acyl group; or a lower alkanesulfonyl group; (5) Xa is nitrogen atom; 20 (6) m is an integer of 2; or (7) ya is sulfur atom, its prodrug or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of the formula (Ila): 25 Rla H SN ~'la > ya (Ila) R2a 30 wherein Ria, R2a, Xa and ya are as defined above, or its salt with a compound of the formula (IlIa): 148 WO 01/05770 PCT/JPOO/04687 R3a 4a (|||a) m R 5 a zi 5 wherein R3a, R4a, R5a and m are as defined above, and ZI is a halogen atom, in the presence of a base.

9. A compound of the formula (II): R1 H 10 \IN N Y (II) X N wherein 15 X is CH or nitrogen atom; Y is oxygen atom or sulfur atom; R 1 is a halogen atom; cyano group; nitro group; carbamoyl group; a lower alkylcarbamoyl group which may be substituted with a heterocyclic group; carboxy group; a protected carboxy group; a lower alkyl group; a 20 halo(lower)alkyl group; a lower alkoxy group; an acyl group; or a lower alkanesulfonyl group, and R 2 is a lower alkyl group, a cycloalkyl group or a heterocyclic group, among which the lower alkyl group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, 25 lower-alkoxy-substituted aralkyloxy, amino, lower alkylamino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, carboxy, lower alkanesulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl carbamoyl and sulfamoyl; and the cycloalkyl group and the heterocyclic 30 group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower 149 WO 01/05770 PCT/JPOO/04687 alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkylenedioxy, carbamoyl and sulfamoyl, 5 or its salt.

10. A compound of claim 9, wherein X is nitrogen atom; 10 Y is oxygen atom or sulfur atom; R 1 is cyano group and R2 is a cycloalkyl group which may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower alkoxy-substituted aralkyloxy, amino, acylamino, lower 15 alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkylenedioxy, carbamoyl and sulfamoyl. 20

11. A process for preparing a compound of the formula (II): R1 H X~ N 25 wherein R1, R2, X and Y are as defined in claim 9, or its salt, which comprises intramolecular-cyclizing a compound of the formula (VII): R1 30 NH 2 (VII) X NH 150 WO 01/05770 PCT/JPOO/04687 wherein R1, R 2 and X are defined as in claim 9, or its salt.

12. A pharmaceutical composition for treatment or prevention of 5 diseases mediated by cGMP-PDE containing as an active ingredient a compound of the formula (I): -M3 (CH)'\ 10 N N (I) wherein 15 X is CH or nitrogen atom; Y is oxygen atom or sulfur atom; R1 is a halogen atom, cyano group, nitro group, carbamoyl group, a lower alkylcarbamoyl group which may be substituted with a heterocyclic group, carboxy group, a protected carboxy group, a lower alkyl group, a 20 halo(lower)alky1 group, a lower alkoxy group, an acyl group or a lower alkanesulfonyl group, R 2 is a lower alkyl group, a cycloalkyl group or a heterocyclic group, among which the lower alkyl group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, 25 lower-alkoxy-substituted aralkyloxy, amino, lower alkylamono, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, carboxy, lower alkanesulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl carbamoyl and sulfamoyl; and the cycloalkyl group and the heterocyclic 30 group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower 151 WO 01/05770 PCT/JPOO/04687 alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkylenedioxy, carbamoyl and sulfamoyl, 5 R3, R 4 and R5 are, the same or different, hydrogen atom, a halogen atom, a lower alkanoyl group, carboxy group, a protected carboxy group, carbamoyl group, nitro group, cyano group, a lower alkyl group optionally substituted by hydroxy, a lower alkoxy group or a lower alkoxy-substituted aralkyl group, or two of R3, R 4 and R5 may combine 10 together to form a lower alkylenedioxy group, n is an integer of 1 or 2, its prodrug or a pharmaceutically acceptable salt thereof. in admixture with a pharmaceutically acceptable carrier or diluent. 15

13. A pharmaceutical composition of claim 12, wherein X in the formula (I) is nitrogen atom.

14. A pharmaceutical composition of claim 12 or 13, wherein R 2 in the formula (I) is a cycloalkyl group which may have one to three substituents 20 selected from the group consisting of hydroxy, protected hydroxy acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower 25 alkylenedioxy, carbamoyl and sulfamoyl.

15. A pharmaceutical composition of claim 12, wherein the diseases mediated by cGMP-PDE are angina, hypertension, pulmonary hypertension, congestive heart failure, glomerular diseases, renal tubulo-intestitinal 30 diseases, renal failure, atherosclerosis, conditions of reduced blood vessel patency, peripheral vascular disease, stroke, bronchitis, asthma, allergic rhinitis, urticaria, glaucoma, diseases characterized by disorders of gut 152 WO 01/05770 PCT/JPOO/04687 motility, erectile dysfunction, female sexual dysfunction, impotence, diabetic complications, micturition disorder, or incontinence and storage of urine disorder. 5

16. A pharmaceutical composition of claim 12, 13 or 14, wherein the disease mediated by cGMP-PDE is erectile dysfunction and impotence.

17. A use of a compound of the formula (I) for the manufacture of a medicament for treatment or prevention of diseases mediated by cGMP 10 PDE.

18. A method for treatment and/or prevention of angina, hypertension, pulmonary hypertension, congestive heart failure, glomerular diseases, renal tubulo-intestitinal diseases, renal failure, atherosclerosis, conditions 15 of reduced blood vessel patency, peripheral vascular disease, stroke, bronchitis, asthma, allergic rhinitis, urticaria, glaucoma, diseases characterized by disorders of gut motility, erectile dysfunction, female sexual dysfunction, impotence, diabetic complications, micturition disorder, or incontinence or storage of urine disorder, by administering a 20 pharmaceutical composition of claim 12. 153