AU758298B2 - Anthranilic acid derivatives as inhibitors of the cGMP-phosphodiesterase - Google Patents

Description

WO 99/54284 PCT/JP99/02028

DESCRIPTION

ANTHRANILIC ACID DERIVATIVES AS INHIBITORS OF THE CGMP-PHOSPHODIESTERASE Technical Field This invention relates to novel anthranilic acid derivatives having pharmacological activity, to a process for their production, to a pharmaceutical composition containing the same, and to their use as a medicament.

Background Art It is known that a cyclic (hereinafter referred to as cGMP) derived from a triphosphate possesses a relaxant activity of smooth muscle and that a cyclic guanosine-3',5'-monophosphate phosphodiesterase (hereinafter refereed to as cGMP-PDE) acts to catalyze the degradation of cGMP to a The compounds having an inhibitory activity of cGMP-PDE are disclosed in European Patent Publication Nos.

579,496; 534,443; 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.

Disclosure of Invention This invention relates to novel anthranilic acid derivatives, which have pharmaceutical activity such as inhibiting activity of cGMP-PDE, to a process for their production, to a pharmaceutical composition containing the same and to a use thereof.

Accordingly, one object of this invention is to provide the novel anthranilic acid derivatives, which have an inhibiting activity of cGMP-

PDE.

Another object of this invention is to provide a process for production of the anthranilic acid derivatives.

A further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, an anthranilic acid derivative.

Still further object of this invention is to provide a use of the anthranilic acid derivatives for treating or preventing various diseases.

The new anthranilic acid derivatives of this invention can be represented by the following formula 0 R H NH

R

2

R

wherein R' is hydrogen atom or a halogen atom; R2 is an electron withdrawing group;

R

3 is hydrogen atom; hydroxy group; a Ci-C6 alkoxy group; a cycloalkyl group; a substituted or unsubstituted aryl group; or an unsaturated heterocyclic group optionally substituted with CI-C6 alkyl; S A is a CI-C 6 alkylene group; 25 R 4 is a group -CR6R 7

R

8 wherein

R

6 and R 7 are each independently a CI-C6 alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy group; C 1 -C alkoxy group; acyloxy group and aryloxy group which may be substituted with cyano, or

R

6 and R7 together with the carbon atom to which R 6 and R 7 are attached may form a substituted or unsubstituted, cycloalkyl group, and is hydrogen atom; a Ci-C 6 alkoxy group; or a CI-C 6 alkcyl group optionally substituted with hydroxcy or a Cj-C 6 alkoxy; and a pro-drug thereof, and a salt thereof.

AU 3 WO 99/54284 PCT/JP99/02028 The compounds of the formula may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomers.

The compounds of the formula may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.

It is further to be noted that isomerization or rearrangement of the compounds may occur by the effect of light, acid, base or the like, and the compounds obtained as the result of said isomerization or rearrangement are also included within the scope of the present invention.

The compounds of the formula and its salts can be in the form of a solvate, which is included within the scope of the present invention.

The solvate preferably include a hydrate and an ethanolate.

Also included in the scope of invention are radiolabelled derivatives of compounds of formula which are suitable for biological studies.

According to this invention, the object compounds or its salts can be prepared by the following process.

Process 1 O 0 N A..R3

H

2 N-R(Ill)

NA'R

H

H

or its salt

NH

R

2

R

2 R4 (1) or its salt or its salt Process 2 O 0 30 OH H 2 N-A-R NA.R 3 ,HOH )N 'R R NH

NH

S N H or its reactive R2 i R R 4 derivative at amino group, R or its salt (IV)

(I)

or its reactive derivative or its salt at carboxy group, or its salt WO 99/54284 WO 9954284PCT/JP99/02028 0 R H 2 NH 2

(VI)

or its salt R A R 7

(VII)

N R 3

H

(I-1) or its salt In the above formulae, R 1

R

2 R3, R 4 R6, R7 and A are the same as those defined in the above.

Some of the starting materials are novel and can be prepared by the following processes.

0 kN

OH

R 2 0 H2N--R (V N'A, R 3

H

2

N--R

3 R H or its reactive derivative 2 F at amino group,R or its salt

(VIII

or its reactive derivative at carboxy group, or its saft

PII

or its salt ocs- 0 N. OR 2H R 6

KR

7 R

NH

R 2 R I 1 (IV-1) or its salt

(IX)

or its salt WO 99/54284 PCT/JP99/02028 Process C 0

OR

F

R

2

(X)

0

H

2

N-R

4 (II)

OR

or its reactive derivative NH at amino group, R 2 14 or its salt

R

(IV

or its salt Process D

H

2

N-A-R

3

(V)

or its reactive derivative at amino group, or its salt 0 NA'R3 R

H

NH

2

R

2

(VI)

or its salt In the above formulae, R2, R 3

R

4

R

6

R

7 and A are the same as those defined in the above, R is hydrogen atom or a lower alkyl group.

In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention includes within the scope are explained in detail in the following.

The term "lower" is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise indicated.

Suitably the lower alkyl groups and lower alkyl moieties in the terms of the halo(lower)alkyl, lower alkanesulfonyl, lower alkanesulfonyloxy, lower alkoxy, lower alkylthio, hydroxy(lower)alkyl, ar(lower)alkyl, ar(lower)alkoxy and ar(lower)alkoxycarbonyl groups may include straight or branched ones having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, WO 99/54284 PCT/JP99/02028 pentyl, isopentyl, hexyl or the like, more suitably the ones having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl or isobutyl.

Suitably the examples of the lower alkenyl groups include straight or branched ones having 2 to 6 carbon atoms, such as ethenyl, propenyl allyl or 1-propenyl), butenyl, isobutenyl, pentenyl, hexenyl or the like.

Suitable lower alkylene groups and lower alkylene moieties in the lower alkylenedioxy group may include straight or branched ones having 1 to 6 carbon atoms, such as methylene, methylmethylene, ethylene, methylethylene, trimethylene, tetramethylene, 2methyltrimethylene, pentamethylene, hexamethylene or the like, more suitably the ones having 1 to 3 carbon atoms.

Suitable examples of the acyl groups and acyl moieties in the term of the acyloxy group include aliphatic acyl groups such as lower alkanoyls formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl or pivaloyl) and acyl groups containing an aromatic or heterocyclic ring such as aroyls benzoyl, toluoyl, xyloyl or naphthoyl), ar(lower)alkanoyls phenylacetyl or phenylpropionyl), ar(lower)alkoxycarbonyls benzyloxycarbonyl or phenethyloxycarbonyl), heterocyclic carbonyls thenoyl or furoyl) and the like.

The cycloalkyl groups may include the ones having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like.

Suitably the aryl groups and aryl moieties in the terms of the ar(lower)alkyl, ar(lower)alkoxy, aryloxy, aryloxycarbonyl and aroyloxy groups may be an aromatic group having 6 to 12 carbon atoms.

Specific examples thereof are phenyl, naphthyl, indenyl, azulenyl, biphenylenyl, fluorenyl and anthracenyl.

Suitable examples of the saturated carbocyclic groups may be the cycloalkyl groups as exemplified in the above.

Suitable examples of unsaturated carbocyclic groups may include cyclopentenyl, cyclohexenyl, cycloheptenyl, 2,3-dihydro-lHindenyl, benzocyclohexyl and the like.

Suitable examples of the halogen atoms and halo moiety of the WO 99/54284 PCT/JP99/02028 halo(lower)alkyl group may be fluorine, chlorine, bromine or iodine.

Suitable examples of the unsaturated heterocyclic group may include mono- or poly-cyclic groups containing at least one hetero atom selected from nitrogen, sulfur and oxygen atoms, such as unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl or 2H- 1,2,3-triazolyl], tetrazolyl 1H-tetrazoly or 2H-tetrazolyl] or the like.; unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl or furyl; unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms, for example, thienyl or the like; unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or 1,2,5-oxadiazolyl] or the like; unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl 1,2,4thiadiazolyl, 1,3,4-thiadiazolyl or 1,2,5-thiadiazolyl] or the like; unsaturated condensed heterocyclic groups containing 1 to 2 nitrogen atoms, for example, indolyl, indazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, benzimidazolyl or the like; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms, for example, benzofuryl or the like; unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms, for example, benzo[b]thienyl or the like; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, phenoxazinyl or the like; unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, benzothiazolyl, WO 99/54284 PCT/JP99/02028 benzoisothiazolyl, phenothiazinyl or the like.

Suitable examples of the saturated heterocyclic group and heterocyclic moiety in the saturated heterocyclic sulfonyl group include monocyclic groups containing at least one hetero atom selected from nitrogen, sulfur and oxygen atoms, such as saturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms pyrrolidinyl, imidazolidinyl, piperidyl or piperazinyl]; saturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms morpholinyl]; saturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms thiazolidinyl or thiomorpholinyl]; saturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and/or 1 to 2 oxygen atoms tetrahydrothiophenyl, tetrahydrothiopyranyl, 1oxotetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, dioxacyclohexyl, tetrahydrofuranyl, tetrahydropyranyl or dioxanyl]; or the like.

Suitably carboxy protective groups in the protected carboxy group may include lower alkyl groups methyl, ethyl or tert-butyl), halo(lower)alkyl groups 2-iodomethyl or 2,2,2-trichloroethyl), ar(lower)alkyl groups benzyl, trityl, 4-methoxybenzyl, 4-nitrobenzyl, phenethyl, bis(methoxyphenyl)methyl, 3,4-dimethoxybenzyl or 4aryl groups phenyl, naphthyl, tolyl or xylyl), and the like, more suitably the lower alkyl groups such as methyl, ethyl or tert-butyl and ar(lower)alkyl groups such as benzyl.

Specific examples of the each group containing the abovementioned moiety and having substituent(s) are as follows.

As the halo(lower) alkyl group, fluoromethyl, iodomethyl, chloromethyl, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2trifluoroethyl, 2,2,2-trichloroethyl or the like may be mentioned.

WO 99/54284 WO 9954284PCT/JP99/02028 The lower alkanesulfonyl group is methanesulfonyl(mesyl), ethanesulfonyl, propanesulfonyl or the like.

The lower alkanesulfonyloxy group is methansulfonyloxy(mesyloxy), ethanesulfonyloxy, propane sulfonyloxy or the like.

The lower alkoxy group is methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy of the like.

The lower alkylthio group is methylthio, ethylthio, propylthio, butylthio, isobutylthio or the like.

The acyloxy group is formyloxy, acetyloxy, propionyloxy, benzoyloxy, toluoyloxy, naphthoyloxy, pherxylacetyloxy, theonyloxys or the like.

The hydroxy(lower)alkyl group is hydroxymethyl, hydroxyethyl or the like.

The ar(lower)alkyl group is benzyl, 4-methoxybenzyl, 4nitrobenzyl, phenethyl, trityl, bis(methoxyphenyl)methyl, 3,4dimethoxybenzyl, 4-hydroxy-3,5-di-tert-butylbenzyl) or the like.

The ar(lower)alkoxy group is benzyloxy, 4-methoxybenzyloxy, 4nitrobenzyloxy, phenethyloxy, trityloxy, bis(methoxyphenyl)methoxy, 3 ,4-dimethoxybenzyloxy, 4-hydroxy-3 ,5-di- tert-butylbenzyloxy or the like.

The lower alkylenedioxy group is methylenedioxy, ethylenedioxy and. the like.

The aryloxy group is phenoxy, naphthoxy, tolyloxy, xylyloxy or the like.

The aroyloxy group is benzoyloxy, naphthoyloxy or the like.

The saturated heterocyclic sulfonyl group is piperazinesulfonyl, piperizinesulfonyl, morpholinesulfonyl, pyrazolidinesulfonyl or the like.

Preferred embodiments of the compounds are those represented by the formula wherein R1 is hydrogen atom or a halogen atom; R2 is an electron withdrawing group; WO 99/54284 PCT/JP99/02028

R

3 is hydrogen atom; hydroxy group; a lower alkoxy group; a cycloalkyl group; a substituted or unsubstituted aryl group; or an unsaturated heterocyclic group optionally substituted with lower alkyl; A is a lower alkylene group;

R

4 is a lower alkoxy group, a substituted or unsubstituted, saturated or unsaturated heterocyclic group, an amino group optionally substituted with halo(lower)alkyl or lower alkyl, a group -CH 2

-R

wherein R 5 is a cycloalkyl group or an unsaturated heterocyclic group, or a group -CR 6

R

7

R

8 wherein

R

6 and R 7 are each independently carboxy group, a protected carboxy group, a carbamoyl group optionally substituted with lower alkyl, or a lower alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen atom; hydroxy group; cyano group; azido group; lower alkoxy group; lower alkylthio group; protected carboxy group; lower alkanesulfonyl group; acyloxy group; lower alkanesulfonyloxy group; aryl group; aryloxy group which may be substituted with cyano; unsaturated heterocyclic group which may be substituted with lower alkyl; guanidino group which may be substituted with lower alkyl, cyano and/or halogen; isothioureido group which may be substituted with lower alkyl and/or cyano; and amino group which may be substituted with acyl, protected carboxy, lower alkanesulfonyl, lower alkanesulfonyloxy or aryloxycarbonyl, or

R

6 and R 7 together with the carbon atom to which R 6 and R 7 WO 99/54284 PCT/JP99/02028 are attached may form a substituted or unsubstituted, saturated carbocyclic group, or an unsaturated carbocyclic group optionally substituted with hydroxy, and R8 is hydrogen atom; a lower alkoxy group; or a lower alkyl group optionally substituted with hydroxy or a lower alkoxy; provided that when R 4 is the group -CR6R 7 R wherein

R

6 is a lower alkyl group optionally substituted with halogen,

R

7 is a lower alkyl group optionally substituted with halogen, and Rs is hydrogen atom or a lower alkyl group, or when R 4 is the group -CH 2

-R

s wherein Rs is the same as the above,

R

3 should be hydrogen atom, hydroxy group or a cycloalkyl group, the electron withdrawing group for R 2 being selected from a group consisting of nitro group; cyano group; acyl group; halo(lower)alkyl group; sulfamoyl group; carbamoyl group optionally substituted with lower alkyl; halogen atom; lower alkenyl group optionally substituted with protected carboxy; lower alkanesulfonyl group; saturated heterocyclic sulfonyl group optionally substituted with protected carboxy; and unsaturated heterocyclic group, the substituent(s) on the aryl group for R 3 being selected from a group consisting of lower alkyl group; halo(lower)alkyl group; lower alkylthio group; halogen atom; hydroxy group; lower alkylenedioxy group; cyano group; nitro group; carboxy group; protected carboxy group; sulfamoyl group; acyl group; aryl group; ar(lower)alkoxy group; aryloxy group; lower alkoxy group which may be substituted with lower alkoxy or cycloalkyl; amino group which may be substituted with acyl, protected carboxy or lower alkyl; and carbamoyl group which may be substituted with lower alkyl, the substituent(s) on the saturated or unsaturated heterocyclic group for

R

4 being selected from a group consisting of oxo group; acyl group; protected carboxy group; lower alkanesulfonyl group; sulfamoyl group which may be substituted with protected carboxy; ar(lower)alkyl group; lower alkyl group which may be substituted with hydroxy or aryl; ureido WO 99/54284 PCT/JP99/02028 group which may be substituted with lower alkyl; guanidino group which may be substituted with protected carboxy; amidino group which may be substituted with protected carboxyl; and carbamoyl group which may be substituted with lower alkyl, and the substituent(s) on the saturated carbocyclic group formed by combination of R6 and R 7 being selected from a group consisting of lower alkyl group; halogen atom; hydroxy group; lower alkoxy group; acyloxy group; carboxy group; protected carboxy group; oxo group; amidino group which may be substituted with protected carboxy; ureido group which may be substituted with lower alkyl or aryl; guanidino group which may be substituted with protected carboxy; amino group which may be substituted with acyl, lower alkanesulfonyl or protected carboxy; and carbamoyl group which may be substituted with lower alkyl or hydroxy(lower)alkyl; and a pro-drug thereof, and a salt thereof.

Another preferred embodiments are as follows: compounds of the formula wherein RI is hydrogen atom or a halogen atom;

R

2 is an electron withdrawing group; R3.is a substituted or unsubstituted aryl group; A is a lower alkylene group; and

R

4 is a group -CR6R7R8 wherein R6 and R 7 together with the carbon atom to which R 6 and R 7 are attached may form a substituted or unsubstituted, saturated carbocyclic group, and RS is hydrogen atom; and compounds of the formula wherein RI is hydrogen atom or a halogen atom;

R

2 is an electron withdrawing group;

R

3 is a substituted or unsubstituted aryl group; A is a lower alkylene group; and

R

4 is a group -CR 6

R

7 R8 wherein R6 is a lower alkyl group substituted with hydroxy, WO 99/54284 PCT/JP99/02028

R

7 is a lower alkyl which may be substituted with hydroxy, and R8 is hydrogen atom or a lower alkyl group which may be substituted with hydroxy.

Further preferred embodiments are as follows: compounds of the formula wherein

R

1 is hydrogen atom or a halogen atom;

R

2 is nitro group, cyano group or a halo(lower)alkyl group;

R

3 is an aryl group optionally substituted with one or more substituent(s) selected from halogen and lower alkoxy; A is a lower alkylene group; and

R

4 is a group -CR6R7R8 wherein

R

6 and R 7 together with the carbon atom to which R 6 and R 7 are attached may form a saturated carbocyclic group optionally substituted with hydroxy or amino which may be substituted with acyl; and R8 is hydrogen atom; and compounds of the formula wherein

R

1 is hydrogen atom or a halogen atom;

R

2 is nitro group, cyano group or a halo(lower)alkyl group;

R

3 is an aryl group optionally substituted with one or more substituent(s) selected from halogen and lower alkoxy; A is a lower alkylene group; and

R

4 is a group -CR6R7R 8 wherein R6 is a lower alkyl group substituted with hydroxy,

R

7 is a lower alkyl group which may be substituted with hydroxy, and

R

8 is hydrogen atom or a lower alkyl group which may be substituted with hydroxy.

In accordance with the invention, it includes salts of the compounds The salts may be conventional non-toxic pharmaceutically acceptable salts, for example, a salt with an alkali metal sodium or potassium) and an alkaline earth metal calcium or magnesium), an ammonium, an organic base WO 99/54284 PCT/JP99/02028 trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine or dibenzylethylenediamine), an organic acid 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 hydrogen chloride, hydrogen bromide, sulfuric acid or phosphoric acid), an amino acid arginine, aspartic acid or glutamic acid) or the like.

The processes for preparing the starting compounds and the object compounds of the present invention are explained in detail in the following.

Process 1 A compound or its salt can be prepared by reacting a compound (II) or its salt with a compound (III) or its salt.

This reaction is usually carried out in the presence of an inorganic or an organic base.

Suitable inorganic base may include an alkali metal sodium or potassium], an alkali metal hydroxide sodium hydroxide or potassium hydroxide], an alkali metal hydrogen carbonate sodium hydrogen carbonate or potassium hydrogen carbonate], an alkali metal carbonate sodium carbonate], an alkali earth metal carbonate calcium carbonate], an alkali metal hydride sodium hydride or potassium hydride] and the like.

Suitable organic base may include tri(lower)alkylamines triethylamine or N,N-diisopropylethylamine], alkyl lithiums methyl lithium or butyl lithium], lithium diisopropylamide, lithium hexamethyldisilazido and the like.

The reaction is usually carried out in a conventional solvent such as water, alcohols methanol, ethanol or isopropyl alcohol], 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.

The reaction is preferably carried out at a temperature under cooling to warming. However, the reaction temperature is not limited.

WO 99/54284 PCT/JP99/02028 A compound or its salt can be prepared by reacting a compound (IV) or its reactive derivative at the carboxy group, or its salt, with a compound or its reactive derivative at the amino group, or its salt, according to a procedure known in the art.

Suitable reactive derivatives at the carboxy group of the compound (IV) may include the acid chloride, azide, acid anhydride, activated amide, activated ester and the like.

Suitably the acid anhydride may include anhydrides with an acid such as substituted phosphoric acid dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid or halogenated phosphoric acid), dialkylphosphorous acid, sulfuric acid, thiosulfuric acid, alkanesulfonic acid methanesulfonic acid or ethanesulfonic acid), alkanoic acid pivalic acid, pentanoic acid or isopentanoic acid), aromatic carboxylic acid benzoic acid, chlorobenzoic acid, fluorobenzoic acid or nitrobenzoic acid),or the like.

Suitably the active amide may include the imidazoylylamide, 4substituted imidazoylylamide, dimethylpyrazolylamide, triazolylamide tetrazolylamide or the like.

Suitably the active ester may include the dimethyliminomethyl [(CH3) 2 ester, vinyl ester, propargyl ester, 4-nitrophenyl ester, 2 ,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, methanesulfonylphenyl ester, phenyl thioester, p-nitrophenyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, 8 -quinolyl thioester, an ester with a N-hydroxy compound N,N-dimethylhydroxylamine, 1-hydroxy-2H-pyridone,

N-

hydroxysuccinimide, N-hydroxybenzotriazole or N-hydroxyphthalimide) or the like.

Suitably the reactive derivative at amino group of the compound may include Schiffs base type imino or its tautomeric enamine type isomer formed by the reaction of the compound with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound with a silylating reagent such as trimethylsilylchloride, N,O-bis(trimethylsilyl)acetamide,

N-

WO 99/54284 PCT/JP99/02028 trimethylsilylacetamide or the like.

Each reactive derivative of compounds (IV) and can optionally be selected from the above according to the kinds of the compounds (IV) and to be used, respectively.

When the compound (IV) is used in a free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a condensing agent.

Suitable condensing agent may include carbodiimides N,N-dicyclohexylcarbodiimide, N-cyclohexyl-N'-(4diethylaminocyclohexyl)carbodiimide or N-ethyl-N'-(3dimethylaminopropyl)carbodiimide or its hydrochloride), diphenylphosphinic azide, diphenylphosphinic chloride, diethylphosphoryl cyanide, bis( 2 -oxo- 3 -oxazolidinyl)phosphinic chloride, N,N'-carbonyldiimidazole, 2-ethoxy- -ethoxycarbonyl-1,2dihydroquinoline, cyanuric chloride or the like.

The reaction may be also carried out in the presence of an organic or inorganic base such as an alkali metal carbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine or the like.

The reaction is usually carried out in a conventional solvent such as water, acetone, alcohols methanol, ethanol or isopropyl alcohol], 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.

The reaction is preferably carried out at a temperature under cooling to warming. However, the reaction temperature is not limited.

Process 3 A compound or its salt can be prepared by reacting a compound (VI) or its salt with a ketone compound(VII) in the presence of an inorganic acid sulfuric acid or hydrogen chloride) or an organic acid acetic acid) and a reducing agent.

Suitable reducing agent may include sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, borane-pyridine complex and the like.

The reaction is usually carried out in a conventional solvent WO 99/54284 PCT/JP99/02028 such as alcohols methanol or ethanol), tetrahydrofuran, dioxane, toluene or any other organic solvent which does not adversely affect the reaction, or a mixture thereof.

The reaction is preferably carried out at a temperature under cooling to ambient temperature. However, the reaction temperature is not limited.

Instead of the ketone compound(VII), its corresponding aldehyde may be used in this reaction.

Process A The process A can be carried out in a manner similar to Process 2 by using a 2-fluorobenzoic acid derivative (VIII) and an amine compound to obtain the compound (II).

Process B The process B can be carried out in a manner similar to Process 3 by using an aminobenzoate derivative (IX) and a ketone compound (VII) to obtain the compound (IV-1).

Process C The process C can be carried out in a manner similar to Process 1 by using a 5- fluorobenzoate derivative and an amine compound (III) to obtain the compound (IV).

Process D The compound (VI) can be prepared by reacting an isatoic anhydride derivative (XI) with an amine compound This reaction is usually carried out in a conventional solvent such as acetone, 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.

The reaction is preferably carried out at a temperature under cooling to amibient temperature. However, the reaction temperature is not limited.

A pharmaceutically acceptable salt of the compound can be prepared by treating a compound with an appropriate base or acid in accordance with the conventional method.

The compounds and pharmaceutically acceptable salts thereof possess inhibitory activity of cGMP-PDE (especially PDE-V), 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.

The compounds and pharmaceutically acceptable salts thereof, therefore, are useful for the treatment and/or prevention of various diseases, such as angina, hypertension, pulmonary hypertension, congestive heart failure, glomerular diseases diabetic glomerulosclerosis), renal tubulo-intestitinal diseases nephropathy induced by tacrolimus, cyclosporin or the like), renal failure, atherosclerosis, conditions of reduced blood vessel patency post-percutaneous transluminal coronary angioplasty), peripheral vascular disease, stroke, chronic reversible obstructive lung diseases bronchitis or asthma (chronic asthma, allergic asthma)), allergic rhinitis, urticaria, glaucoma, diseases characterized by disorders of gut motility irritable bowel syndrome), erectile dysfunction organic erectile dysfunction or psychic erectile dysfunction), female sexual dysfunction, impotence, or diabetic complications diabetic gangrene, diabetic arthropathy, diabetic glomerulosclerosis, diabetic dermopathy, diabetic neuropathy, diabetic cataract or diabetic retinopathy).

Further, the compounds 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, prostatomegaly, urethra relaxation incompetence, dysuria).

It is to be noted that improvement of sexual performance is also ncluded in the treatment of erectile dysfunction or impotence.

WO 99/54284 PCT/JP99/02028 The compounds 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 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 are shown in the following.

Test Compound The test compounds are shown in Tables 1 and 2 and test methods 2 and 3.

[II] Test method 1: cGMP-Phosphodiesterase (PDE) assay 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, p127-234, 1984). In enzyme inhibition assays, the test compounds were dissolved in DMSO and then diluted with assay buffer (50 mM Tris-HC1, 0.077 mg/ml dithiothreitol and mg/ml snake venom, 1 mM EGTA, pH at final concentrations ranging from 10-10 to 10-6 M. Assays were performed at 0.1 /tM substrate 3 H]-cGMP) concentration, at 30 °C for 10 minutes using enzyme dilutions which gave 10-20% hydrolysis 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 Radioactivity of supernatant (3H-GMP) was assayed by liquid scintillation counting.

The obtained results in enzymatic inhibitory test against human platelet PDE-V are shown in Table 1.

WO 99/54284 WO 9954284PCT/JP99/02028 Table 1 Inhibitory activity Test Compounds (nM) ICso(nM) 2- (cyclopentylamino) -N-hexyl- 5-nitrobenzamide N- (2-chlorobenzyl) -2-cyclopentylamrino- 5-nitrobenzamide N- (3-chlorobenzyl) (cyclopentylamino) -5-nitrobenzamide N- (4-chlorobenzyl) (cyclopentylamino) -5-nitrobenzamide 2-(cyclopentylamino)-N-(2,4-dichlorobenzyl)-5- nitrobenzamide 2-(cyclopentylamino)-N-(3,4-dichlorobenzyl)-5- nitrobenzamide 2- (cyclopentylamino) -N-(4-fluorobenzyl) -5-nitrobenzamide 2- (cyclopentylamino) (4-methylbenzyl)-5-nitrobenzatnide 2- (cyclopentylamino) (4-methoxybenzyl)-5- nitrobenzamide 2- (cyclopentylamino)- 5-nitro-N- (4-(trifluoromethyl)benzyl]- benzainide N- (4-aniinobenzyl)-2- (cyclopentylarnino) -5-nitrobenzamide N- (4-arnino-2-chlorobenzyl) (cyclopentylamino) nitrobenzamide N- (2-chloro-4-methoxybenzyl) (cyclopentylamino)-5- nitrobenzamide 2- (cyclopentylamino) -5-nitro-N-(4-nitrobenzyl)benzamide N- (4-bromobenzyl)-2- (cyclopentylamino)-5-nitrobenzaxnide 2- (cyclopentylarnino) -5-nitro-N- (2-thienyl-methyl)- benzamide 2- (cyclopentylamino) (4-hydroxy-3-methoxybenzyl) nitrobenzamide 2 (cyclopentylamino) 5 -nitro- N-phene thylbenzamide 2- (cyclopentylamino) -5-nitro- N- (3-phenyl-propyl)benzamide N-benzyl-2- (cyclobutylamino) -5-nitrobenzamide 2-(cyclopentylamino)-N-( 3 ,4-difluorobenzyl)-5- nitrobenzatnide N-[(2-benzimidazolyl)methyll- 2 (cyclopentylamiflo)-Snitrobenzamide N-benzyl-2 -(cyclopropylamno) -nitrobeflzamlide N-bezyl2-(tans2-hdroxcycopetylaino-5-<10 nitrobenzamide -nitro ,3 benzodioxol- 5 -y1lethyl) 2- (tetrahydro- 2H thiopyran-4-ylamino)belzamide_____ 2 -(tert-butylamino) 5-nitro- N- ,3-benzodioxol- 5-ylmethyl) benzamide 2-[l -(ethoxycarb ony) piperidifl4 ylarflfoh 5- nitro- N- 3- benzodioxol- 2-(l1-benzylpiperidin-4-ylamifo) -5-nitro-N- benzodioxol- (R (1 -ethyl- 2-hydroxyethylamfiflo) 5-nitro-N-( 1,3- benzodioxol- 5-ylmethyl) benzatnide (R )-5-Nitro-2- (tetrahydro-3-f1-1ranylamino)-N-( 1,3- benzodioxol- 1,1 -dioxotetrahydro-2H-thiopyran-4-ylamino) 5-nitro-N- (1 2- [4-(methoxycarbony1)cyc1ohexylamfil]- 5-nitro-N-( 1,3- benzodioxol- 2-(4-carboxycyclohexylafllfo) 5-nitro-N-( 1,3-benzodiox Ol- 2-(4-carbamoylcyclohexyamiflo)Sfitro-N benzodioxol- (R [1-(methoxycarbonyl)ethylamino}-5-nitro-N-( 1,3- benzodioxol- 5-ylmethyl) benzamide N-benzyl-2-(3-hydroxycyclopentltamfifo) -5-nitrobenzamide 2 -13-(benzoyloxy) cyclopentylamflol-N-benzyI-")nitrobenzamide 1-(hy droxymethy)cyc1opeltYan'lioJ-5-nitro-N-(1 benzodioxol- 5-ylmethy1)belzamifde_____ 1- (hydroxymethyl)-2-methylpropylalonito-N (1 -nitro- 2- (4 -oxo cyclohexylarllro) N- ,3-benzodioxol- 5- ylmethyl) benzamide iR, 2R )-2-hydroxy- 1-(hydroxnethy1)propyl-amfiflo] 5 nitro- N- 3 -benzodioxol- 5-yl-methyl) benzatfllde 2-[l 1-(tert-butoxycarbonyl)-4-piperdlylaino]5nitro-N (1 2 -(4-pip eridinylalllno)-N- 3-benzo dioxol- 5- ylmethyl)benzamide 1-(hydroxyrnethy1) pentylamino]-5-nitro-N-(1 benzodioxol- 2-(l1-acetyl-4-piperidinylamilo) -5-nitro-N-(l1,3-benzodioxol- ethyl) benzamide 2-(l1 methyl-4-piperidinylan-io)-5-nitro-N-( 1,3- benzodioxol- 1-formyl-4-piperidinyla nino)-5-nitro-N-( 1,3-benzodioxol- N -flu oro-4-methoxybeflzyl)- 2 -hydroxy- 1- (hydroxymethyl) ethylarnino] 2-(trans-4-hydroxycyclohexyl)alhifo-N-[ 4 (methylthio)benzylj- N-(3 -ihoo4mehxbny)--tas hydroxycyclohexylamino) N- ethylene dioxyb enzyl) 2 -(traflsA- hydroxycyclohexylamino) N (3 -chloro-4 -flu orobenzy) -2 -hydroxy 1- (hydroxymnethyl) (S)--(3chlro--mehylbnzy)-2(2-ydrxy-1methylethylammno)

<IU

2- [2-hyd roxy- 1 -(hydroxymethyl)ethylaniinl-N-(3-methoxy- 4-methylbenzyl) N-cyclohexylmethyl-2-( cis-4-hydroxycyclohexylamlo) nitrobenzamide (S 1 (chloromethyl)propylamifno] 5-nitro-N-( 1,3- benzodioxol- 5-ylinethyl) benzamide (R)-N-(4-chloro-3--nitrobelzyl) [1-(hydroxy- methyl)propylamino N-(3 ,4-dimethylbenzyl)-2- (cis-4-hydroxycyclohexylaTinfo)nitrobenzamide 2 -(cis -4 -chloro cyolohexylamflo) 5 -nitro- N- 3-b enzodioxol- benzamide 2-[cis-4- (acetoxy) cyclohexylamino] dimethoxybenzyl) 2 [(trans-4-aminocycohexy) aminlo] N- 3 dimTethoxybenzyl) 2-[2-chloro- 1 -(chloromethyl)etaylafllfo]-5-nitro-N-( 1,3- benzodioxol- N-(2-chioro- 5-methoxybenzyl)- 2 -(cis-4- N- (3-chloro-4-methoxybelzyl) [2 -hydroxy- 1- (hydroxymethyl) ethylarmflol-5- (trifluoromethyl)-beflzalflde N-(3 ,4-dimTethoxylbeflzyl)- 2 R, 2S) -2-hydroxy- 1-methyl- 2-phenylethyl] N- (3,4-dimethoxybeflzyl)- 2 2 ,2-dimethyl- 1 ylamino) N- (3,4-dimethoxybenzyl) -5-nitro-2-[trans--(3propylureido) cyclohexylaxninolbenzamide N- (3 ,4dimethoxybenzyl)-flnitro- 2 2 -oxo- 1 ,3-dioxan-5ylamino)benzamide N-(4-chloro-3-ethoxybel~y)-2-(cis-4hydroxycyclohexylamilo) WO 99/54284 WO 9954284PCT/JP99/02028 N-(4-ethoxy-3-methoxybel)- 2 -(cishydroxycyclohexylam-ilo) 2-{trans-4- [2,3 -bis(tert-butoxycarboflyl) -guanidino] cyclo- hexylamino}-N- (3 ,4-dimethoxybenzyl) 2-11 -(tert-butoxycarbony1)piperidil-4-ylamilI-N- dimethoxybenzyl) (R)-2-(2-hydroxy- 1 -methylethyl) amino- 5-nitro-N-(4- phenoxybenzyl)benzamide N- (4-ethoxy-3-methoxybenzyl) -2-(trans-4- N- (3 ,4dimethoxybenzyl)-5-nitro-2-(4-piperidil- amino)benzamide N- (3,4-dimethoxybenzyl) -2-(trans-4-guanidino- cyclohexylamino) -5-nitrobenzamide hydrochloride (2-hydroxy- 1 -methylethyl) amino-5-nitro-N-( 4 phenybenzyl)benzamide N- (benzo [b]thiophen-2-ylmethyl) (cis-4- hydroxycyclohexylamino) -nitrobenzarnide 2- (cis-4-hydroxycyclohexylamliflo) -5-nitro-N- phenylbenzyl)benzamide N- (3,4-dimethoxylbenzyl)-2- -1-hydroxymethyl-3- (methylthio)propylarnino] N-(benzofuran-2-ylmethyl)-2- (cis-4-hydroxy- cyclohexylamino) 2- (cis-4-formamidocyclohexylamio) dimethoxybenzyl)- 2-[1-[1,3-bis(ter-butoxycarbonyl)amidifl-piperidifl 4 ylaminol-N-(3 ,4-dimethoxybenzyl)--nitrobeflzamfide 2- (1-arnidinopiperidin-4-ylamino) (3 ,4-dimethoxybelzyl)- hydrochloride (3-chloro-4-rnethoxybenzyl) 2- (cyclopentylamino)benzamide hydrochloride 2-[(1S,2R)-l-(carbamoyl)-2-hydroxypropyl-amino]-N-(3,4- 2-(cis-4-hydroxycyclohexylammno)-N-[3-methoxy- 4 2 methoxyethoxy)benzyl]- N-(4-cyclobutylmethoxy-3-methoxybenzyl)- 2 -[2-hydroxy- 1- (S)-N-(3,4-dimethoxybenzyl)- 2 1-(formamidomethyl)-2- As shown in the above Table 1, the compounds of the present invention have superior inhibitory activity against cGMP-PDE.

Test method 2: the effect on erection function Effect of test compound on nitroprusside or Ach-induced relaxation in isolated rat corpora cavernosa.

Male SD rats were anesthetized with sodium pentobarbital mg/kg intraperitoneally, and the corpora cavernosa was excised. The tunica albuginea was dissected according to the methods described by Italiano et al. (Pharmacological Research, 30, No.4, 1994) and used for in vitro pharmacological study. The erectile tissue strip was placed in a ml organ bath containing Krebs-Ringer solution. The bath was maintained at 37°C and bubbled with 95% 02 and 5% CO2. The strip was stretched with a resting force of 0.25 g, and isometric contraction were recorded via force development transducer on a recorder.

The strip was equilibrated in the Krebs-Ringer solution for about 60 minutes, and preconstricted by 0.1 mM norepinephrine to ascertain the responsibility of each preparation. The strip was washed several times, and then constricted by 0.1 mM norepinephrine. After getting stable constrictile response to norepinephrine, the first dose-response curve for sodium nitroprusside or Ach(acetylcholine) was obtained.

After washing a few times for 60 minutes, the strip was constricted by )s j norepinephrine again, and the second dose-response curve for sodium nitroprusside or Ach was obtained. The test compound, (3,4-dimethoxybenzyl)- 2 -(2-hydroxy- nitrobenzamide which was selected as a representative compound of this invention was added 30 minutes before adding norepinephrine.

Relaxant response elicited by 10.M nitroprusside was 20 in control preparation, but this relaxant response increased to 32 in the presence of the test compound (5 x 10-8 M).

Said compound at 5 x 10-8 M also potentiated Ach-induced relaxation of corpora cavernosa. 100 uM Ach-induced relaxant response to the contractile response induced by 10-4 M norepinephrine was only 5.0 in control preparation, but this relaxant response to Ach increased to 18.0 in the presence of said compound (5 x 10-8 M).

Effect of test compounds on the relaxation elicited by electrical field stimulation in rabbit corpora cavernosa.

The rabbit erectile tissue strip prepared according to the method described by Italiano et al. (Pharmacological Research, 30, No4, 1994) was placed 25 ml organ bath containing Krebs-Ringer solution. The bath was maintained at 37 °C and bubbled with 95% 02 and 5% CO2.

The solution also contained atropine (lgM) and guanethidine (50 LM).

The erectile tissue strip was stretched with a resting force of 0.25 g, and isometric contraction were recorded via force development transducer on a recorder. The bipolar platinum electrode connected to the electric stimulator was placed around the strip.

The strip was equilibrated in the Krebs-Ringer solution for about minutes and preconstricted by 0.1 mM norepinephrine to ascertain the responsibility of each preparation. The strip was washed several times, and then constricted by 0.1 mM norepinephrine. After getting stable contractile response to norepinephrine, the first electrical field stimulation (1 to 30 Hz, 20V, 0.5 msec duration, 90 sec interval) was delivered. 30 minutes after adding the tested compound, the second electrical field stimulation was delivered.

The compounds N-(3,4-dimethoxybenzyl)-2-(cis4- WO 99/54284 PCT/JP99/02028 and dimethoxybenzyl)-2- (2-hydroxy- 1-methyl-ethylamino) nitrobenzamide which were selected as representative compounds of this invention, at 5 x 10-8 M potentiated relaxation of corpora cavernosa elicited by electrical field stimulation in rabbit corpora cavernosa.

Relaxant response elicited by 30Hz was only 70 in control preparation, but this relaxant response increased to 100% in the presence of 5 x 10- 8 M said compounds.

Male beagle weighing 8.0 12.0 kg were anesthetized with pentobarbital sodium (35 mg/kg, After tracheotomy, the animal was artificially ventilated using a volume-cycled ventilator. The femoral artery was cannulated for continuous blood pressure and heart rate monitoring. The femoral vein was cannulated for maintenance of anesthesia and administration of tested compound.

Either the left or right cavernous nerve was exposed posterolaterally to the prostate and a cuff electrode was placed around the nerve for electrical stimulation. A 21-gauge butterfly needle was placed in the corpus cavernousum and connected to a pressure transducer for intracavernous pressure. After a period of stabilization of all parameters, erection was induced by cavernous nerve electrically stimulation (7 Hz, 10 V) and the following was measured: the duration of detumescence (time (T75) from cessation of stimulation to reduction of intracavernous pressure). The test compounds,

N-

(3,4-dimethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5nitrobenzamide and (R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1were each dissolved in PEG400. As shown in Table 2, T75 after the cessation of electrical stimulation was prolonged by the administration of the compounds (0.1 mg/kg, which were selected as representative compounds of this invention.

WO 99/54284 PCT/JP99/02028 Table 2 mean of prolongation of test compounds T75 (second) N-(3,4-dimethoxybenzyl)-2-(cis-4- 52 (R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1- 44 Test method 3: toxicities of Compound (I) Test on the toxicity by repetitive oral administration of the compounds, N-(3,4-dimethoxybenzyl)-2-(cis- 4 and dimethoxybenzyl)-2-(2-hydroxy-l-methylethylamino)-5-nitrobenzamide which were selected as representative compounds of this invention, in SD rat was conducted. The dead at dose of 32 mg/kg once a day for 14 consecutive days could not be observed.

The compound or its salt can be administered alone or in a form of a mixture, preferably, with a pharmaceutical vehicle or carrier.

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 as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, intravenous, 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, syrups, injections, troches, cataplasms, aromatic waters, lotions, buccal tablets, sublingual tablets, nasal drops and any other form suitable for use.

The carriers which can be used are water, wax, glucose, lactose, gum acacia, gelatin, mannitol, starch paster, magnesium trisilicate, talc, corn WO 99/54284 PCT/JP99/02028 starch, keratin, paraffin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid 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, 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 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 varies from and also depends upon the age and condition of each individual patient to 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 0.2mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg and 500 mg is generally administered. Daily doses for chronic 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.

(to be continued on the next page) WO 99/54284 PCT/JP99/02028 BEST MODE FOR CARRYING OUT THE INVENTION The following Examples are given only for the purpose of illustrating the present invention in more detail.

Preparation 1 A mixture of 2-fluoro-5-nitrobenzoic acid (1.00 (1,3- (980 mg), 1-[3-(dimethylamino)propyl]-3ethylcarbodiimide hydrochloride (1.55 g) and 1-hydroxybenzotriazole (1.09 g) in anhydrous dimethylformamide (10 mL) was stirred for hours at ambient temperature. The mixture was partitioned between water and ethyl acetate. The separated organic layer was washed with an aqueous saturated sodium bicarbonate solution, 1N-hydrochloric acid, water and brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 2-fluoro-5-nitro-N-(1,3-benzodioxol-5ylmethyl)benzamide as yellow powders (1.48 g).

NMR (DMSO-d6, 6) 4.38 (2H, d, J=7 Hz), 5.99 (2H, 6.80-6.98 (3H, m), 7.62 (1H, 8.39 (2H, 9.12 (1H, br) Mass m/z: 317 Example 1(1) To a solution of 2-fluoro-5-nitro-N-(1,3-benzodioxol-5ylmethyl)benzamide (150 mg) in anhydrous pyridine (3 mL) was added trans-4-aminocyclohexanol (81.4 mg), and the mixture was stirred for hours at ambient temperature, and then for 3 hours at 60 The mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and methanol (20 The eluent was concentrated and the residue was triturated with diisopropyl ether to give 2-(trans- 4 1,3-benzodioxol-5ylmethyl)benzamide as yellow powders (164 mg).

NMR (CDC1 3 1.38-1 .60 (4H, br), 2.00-2.24 (4H, br), 3.44 (1H, br), WO 99/54284 WO 9954284PCT/JP99102028 3.76 (lH, br), 4.49 (2H, d, J=7Hz), 5.97 (2H, 6.44 (1H, br), 6.67 (lH, d, J=8Hz), 6.80 (3H, in), 8.14 (lH, dd, J=4, 8Hz), 8.29 (1H, d, J=4Hz), 8.86 (lH br) Mass m/z: 412 Eample 14Z To a solution of 2-(trans-4-hydroxycyclohexylamnifo)-5-flitro-N- (1 ,3-benzodioxol-5-ylmethyl)belzamide (100 mg) in dichioromethane (3 mL) and acetonitrile (0.4 mL) were added tetrapropylammonium perruthenate (4.25 ing), 4-methylmorpholine N-oxide (42.5 mg) and molecular sieves (4A, 0.2 The resulting mixture was stirred for 2 hours at ambient temperature. The mixture was subjected to a silica gel chromatography eluting with ethyl acetate to give 5-nitro-2-(4oxocyclohexylamino) (1 ,3-benzodioxol- 5-ylmethyl)benzainide (92 mg) as a solid substance.

NMR (DMSO-16, 1.70-1.87 (2H, in), 2. 12-2.53 (4H, in), 2.49-2.60 (2H, in), 4.06 (1H, in), 4.35 (2H, d, J 6 Hz), 5.98 (2H, 6.75-6.9 1 (3H, in), 7.03 (1H, d, J 9 Hz), 8.16 (1H, dd, J 2, 9 Hz), 8.63 (1H, d, J 2 Hz), 9.22 (1H, d, J 8 Hz), 9.36 (1H, t, J 6 Hz) Mass m/z 4 10 1).

Eample2L1J (Hydroxyinethyl)propylamfiflo]-5-nitro-N-(1,3benzodioxol- 5-ylmethyl)benzamide (69mg) was obtained from 2-fluoro- 5-nitro-N- (1 ,3-benzodioxol- 5-ylmethyl)benzamide (72mg) and amino- 1 -butanol (42.4mg) in a manner similar to Example 1 inp: 128-130 *C NMR (DMSO-d 6 ,G5) :0.92 (3H, t, J=7Hz), 1.49 (1H, in), 1.67 (1H, in), 3.4- 3.65 (3H, in), 4.36 (2H, d, J=7Hz), 4.92 (1H, t, J=6Hz), 5.98 (2H, s), 6.75-6.93 (4H, in), 8.09 (1H, dd, J=2, 8Hz), 8.59 (1H, d, J=2Hz), 9.16 (1H, d, J=7Hz), 9.31 (1H, t, J=6Hz).

Examnple4= To a solution of (S WO 99/54284 WO 9954284PCT/JP99/02028 N- (1 ,3-benzodioxol-5-ylmethyl)beflzamide (127 mg) in 1,2dichioroethane (4 mL) and carbontetrachioride (2 mL) was added triphenyiphosphine (215 mg), and the mixture was stirred for an hour under reflux. The solvent was evaporated in vacuo and the residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate 1) to give (S [1 (chloromethyl)propylamino] -5-nitro-N- 3-benzodioxol- ylmnethyl)benzamide (71 mg) as a solid substance.

NMR (DMSO-d 6 0.92 (3H, t, J 7 Hz), 1.52-1.80 (2H, in), 3.82 (2H, mn), 3.99 (1H, in), 4.36 (2H, d, J 6 Hz), 5.99 (2H, 6.78-6.92 (3H, in), 6.98 (1H, d, J 9 Hz), 8.13 (1H, dd, J 9 Hz), 8.61 (1H, d, J 2 Hz), 9.19 (1H, d, J 8 Hz), 9.36 (1H, t, J 6 Hz) Mass m/z: 404 Eape31 2- [2-Hydroxy- 1- (hydroxymethyl)ethylamino] -5-nitro-N- (1,3- (108 mng) was obtained as yellow powders from 2-fluoro-5-nitro-N- (1 ,3-benzodioxol- ylmethyl)benzamide (100mg) and 2-amino-1,3-propanediol (42.9 mg) in a manner similar to Example 1(1).

NMR (DMSO-d 6 3.48-3.68 (5H, br), 4.34 (2H, d, J= 7Hz), 4.93 (2H, t, J=7Hz), 5.98 (2H, 6.78-6.96 (4H, mn), 8.12 (1H, dd, J=4Hz, 8Hz), 8.58 (1H, d, J=4Hz), 9.28 (2H, br) Mass in/z: 388 Exmpke3(2Z 2- [2-Chioro- 1- (chloromethyl)ethylamino 5-nitro-N- (1,3- (36 mg) was obtained from 2-[2hydroxy- 1- (hydroxymethyl) ethylaininoj- 5-nitro-N- (1 ,3-benzodioxol- ylmethyl)benzamide (101 mg) in a manner similar to Example 2(2).

NMR (DMSO-d 6 3.89 (4H, d, J 6 Hz), 4.36 (2H, d, J =5 Hz), 4.47 (1H, in), 5.99 (2H, 6.78-6.93 (3H, mn), 7.08 (1H, d, J 9 Hz), 8.16 (1H, dd, J 2, 9Hz), 8.64 (1 H, d, J 2 Hz), 9.39 (1 H, t, J 5 Hz), 9.44 (1 H, d, J 8 Hz) WO 99/54284 PCT/JP99/02028 Mass m/z 424, 426 Example 3(3) To a solution of N-(3,4-dimethoxybenzyl)-2-[2-hydroxy-1- (hydroxymethyl)ethylamino]-5- nitrobenzamide (134 mg) in a mixture of dichloromethane (1 mL) and pyridine (1 mL) was added triphosgene (49.1 mg) at -78°C. Then, the resulting mixture was stirred for an hour at ambient temperature. The mixture was diluted with ethyl acetate and washed successively with diluted ammonium chloride, water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate to give N-(3,4-dimethoxybenzyl)-5-nitro- 2 2 -oxo- 1,3-dioxan-5ylamino)benzamide (129 mg) as a solid substance.

NMR (CDCl 3 3.88 (3H, 3.90 (3H, 4.21 (1H, 4.49 (2H, m), 4.53 (2H, d, J 8 Hz), 4.69 (2H, 6.60-6.72 (2H, 6.84-6.96 (3H, m), 8.23 (1H, dd, J 2, 9 Hz), 8.39 (1H, d, J 2 Hz), 9.44 (1H, m) Mass m/z 430 Example 3(4) To a solution of N-(3,4-dimethoxybenzyl)-2-[2-hydroxy-1- (117 mg) in dichloromethane (5.0 mL) were added 2,2-dimethoxypropane (0.36 mL) and 4-toluenesulfonic acid (10 mg), and the mixture was stirred for minutes under reflux. The resulting mixture was diluted with ethyl acetate and washed successively with diluted sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was triturated with diethyl ether to give N-(3,4dimethoxybenzyl)-2-(2,2-dimethyl-1,3-dioxan-5-ylamino)- nitrobenzamide (105 mg) as a solid substance.

NMR (CDC13,6): 1.50 (3H, 1.51 (3H, 3.68 (1H, 3.83 (2H, dd, J= 6, 12Hz), 3.88 (3H, 3.90 (3H, 4.15 (2H, dd, J 4, 12 Hz), 4.52-4.57 (2H, 6.66 (1H, d, J 9 Hz), 6.83-6.95 (3H, 6.94 (1H, 8.16 (1H, dd, J=2, 9 Hz), 8.39 (1H, d, J 2 Hz) WO 99/54284 PCT/JP99/02028 Mass m/z 446 1).

Example 4W (S )-2-[l-(tert-Butoxycarbonyl)ethylanino]-5-nitro-N-(1,3benzodioxol-5-ylmethyl)benzamide (131 mg) was obtained from 2fluoro-5-nitro-N-(1 ,3-benzodioxol-5-ylmethyl)benzamide (107 mg) and (S )-alanine tert-butyl ester hydrochloride (85.5 mg) in a manner similar to Example 1(1).

NMR (DMSO-d 6 1.41 (3H, d, J 7 Hz), 1.43 (9H, 4.30-4.38 (3H, i), 5.99 (2H, 6.71-6.93 (4H, 8.17 (1H, dd, J 2, 9 Hz), 8.62 (1H, d, J 2 Hz), 9.34-9.43 (2H, m) Mass m/z: 442 Example 41(2 To a solution of (S )-2-[1-(tert-butoxycarbonyl)ethylaino]-5nitro-N-(1 ,3-benzodioxol--5ylfethyl)benzamide (104 mg) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.6 mL), and the mixture was stirred for 2 hour at ambient temperature. The resulting mixture was evaporated in vacuo and the residue was triturated with diethyl ether to give (S )-2-(1-carboxyethylamino)-5nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (76 mg) as a solid substance.

NMR (DMSO-d 6 1.43 (3K, d, J 7 Hz), 4.31-4.42 (3H, 5.99 (2K, s), 6.73-6.93 (4H, 8.15 (1K, dd, J 2, 9 Hz), 8.61 (1K, d, J 2 Hz), 9.32-9.41 (2H, m) Mass m/z: 386 Example 2-(trans-2-Hydroxycyclopentylamino)-5-nitro-N- (1,3benzodioxol-5-ylmethyl)benzamide (107mg) was obtained as yellow powders from 2-fluoro-5-nitro-N-(1 ylmethyl)benzaiide (100mg) and trans-2-aminocyclopeftanol (47.7 mg) in a manner similar to Example 1(1).

NMR (CDC13, 6):1.55-1.75(2H, 1.76-195 (2K, 2.00-2.13 (1H, i), WO 99/54284 PCT/JP99/02028 2.26-2.38 (1H, 3.78 (1H, br), 4.16 (lH, br), 4.48 (2H, d, J=7Hz), 5.96 (2H, 6.50 (1H, br) 6.77-6.90 (4H, 8.13 (LH, dd, J=4, 8Hz), 8.30 (1H, d, J=4Hz), 8.86 (1H, br) Mass m/z: 398 Example 6 2- (2-Hydroxy- 1, 1 -dimethylethylamino) 5-nitro-N- (1,3- (80.0 mg) was obtained from 2fluoro-5-nitro-N-(1,3 -benzodioxol-5-ylmetyl)bezaide (100 ng) and 2-amino-2-methyl- 1-propanol(84.0 mg) in a manner similar to Example 1(1).

NMR (CDC 3 ,a5):1.47 (6H, 1.88 (1H, t, J=7Hz), 3.70 (2H, d, J=7Hz), 4.50 (2H, d, J=7Hz), 5.97 (2H, 6.45 (lH, br), 6.76-6.95 (4H, 8.10 (1H, dd, J=4, 8Hz), 8.28 (11, d, J=4Hz), 9.13 (lH, br) Mass m/z: 388 Example 7 (R)-2-(2-Hydroxy- 1-methylethylamino)- 5-nitro-N-(1,3- (65 ng) was obtained from 2-fluoro- 5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (93 ng) and amino- I-propanol(44 ng) in a manner similar to Example 1(1).

mp: 166-1 6 8 C NMR (DMSO-d 6 6):1.17 (3H, d, J=7Hz), 3.46 (2H, 3.76 (1H, 4.33 (2H, d, J=7Hz), 4.98 (1H, t, J=6Hz), 5.98 (2H, 6.75-6.93 (4H, 8.11 (1H, dd, J=2, 8Hz), 8.58 (11, d, J=2Hz), 9.15 (1H, d, J=7Hz), 9.29 (1H, t, J=6Hz).

Exam~le 8 5-Nitro-N-(1 ,3-benzodioxol-5-ylmethyl)- 2 2 thiazolylamino)benzamide (28 ng) was obtained from N-(1 ,3-benzodioxol-5-ylmethyl)benzamide (70 ng) and 2-aminothiazole (26.4 ng) in a manner similar to Example 1(1).

NMR (DMSO-d 6 4.43 (2H, d, J 5 Hz), 5.99 (1H, 6.81-6.91 (2H, i), 6.96 (1H, 7.27 (1H, d, J 4 Hz), 7.47 (iH, d, J 4 Hz), 8.39 (1H, dd, J WO 99/54284 PCT/JP99/02028 2, 9 Hz), 8.70-8.6 (2H, 9.70 (1H, t, J 5 Hz) Mass m/z: 397 Example 9 (R l-Ethyl-2-hydroxyethylamino)-5-nitro-N-(1,3- (55.8 mg) was obtained from 2fluoro-5-nitro-N-(1 ,3-benzodioxol-5-ylmethyl)benzamide (72 mg) and (R )-2-amino-1-butanol (0.045 mL) in a manner similar to Example 1(1).

NMR (DMSO-d6,5): 0.89 (3H, t, J 7 Hz), 1.49 (1H, 1.66 (1H, i), 3.38-3.45 (3H, 4.34 (2H, d, J 6 Hz), 4.92 (1H, t, J 5 Hz), 5.98 (2H, 6.78-6.92 (4H, 8.09 (1H, dd, J 2, 9 Hz), 8.58(lH, d, J 2 Hz), 9.16 (1H, d, J 8 Hz), 9.30 (1H, t, J 6 Hz) Mass m/z: 386 Example (R )-5-Nitro-2-(tetrahydro-3-furalamio)-N- (1 ,3-benzodioxol- (76 mg) was obtained from (1,3-benzodioxol-5-yImethyl)benzamide (80 ig) and (R aminotetrahydrofuran p-toluenesulfonate (78.2 mg) in a manner similar to Example 1(1).

NMR (DMSO-d 6 1.79 (1H, 2.31 (1H, 3.60 (1H, 3.71-3.94 (3H, 4.29 (1H, 4.37 (2H, d, J 6 Hz), 5.99 (2H, 6.81 (1H, d, J 8 Hz), 6.87-6.95 (3H, 8.17 (1H, 8.63 (1H, d, J 2 Hz), 9.26 (1H, d, J 8 Hz), 9.38 (1H, t, J 6 Hz) Mass i/z: 384 Example 11 (S )-2-[2-Hydroxy- 1-(nethoxycarbonyl) ethylanino- (1,3-benzodioxol-5-yImethyl)benzamide (73 mg) was obtained from 2fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (89 mg) and (S )-serine methyl ester hydrochloride (69.7 mg) in a manner similar to Example 1(1).

NMR (DMSO-d6,C5): 3.67 (3H, 3.74 (1H, 3.91 (1H, 4.36 (2H, d, J 6 Hz), 4.54 (1H, 5.34 (1H, t, J 5 Hz), 5.99 (2H, 6.76-6.93 (4H, WO 99/54284 PCT/JP99/02028 8.11 (1H, dd, J 2, 9 Hz), 8.62 (1H, d, J 2 Hz), 9.34 (1H, t, J 6 Hz), 9.57 (1H, d, J 8 Hz) Mass m/z: 416 Example 12 (R l-(Methoxycarbonyl)ethylaminol-5-fitr0-N- (1,3- (85 mg) was obtained from 2-fluoro- 5-nitro-N-(1,3-benzodioxo1-5-ylmethyl)bezaminde (92 mg) and (R alanine methyl ester hydrochloride (64.6 mg) in a manner similar to Example 1(1).

NMR (DMSO-d 6 1.46 (3H, d, J 7 Hz), 3.69 (3K, 4.36 (2H, d, J Hz), 4.53 (1K, 5.99 (2K, 6.75-6.93 (4H, in), 8.14 (1K, dd, J 2, 9 Hz), 8.63 (1H, d, J 2 Hz), 9.34-9.44 (2H, m) Mass m/z: 400 Example 13 2-(2,3-Dihydro- 1H-inden-2-ylamino)-5-nitro-N-( 1,3- (82.7 mg) was obtained from 2fluoro-5-nitro-N-(1 ,3-benzodioxol-5-ylmethyl)bezafide (90 mg) and 2aminoindan hydrochloride (57.6 mg) in a manner similar to Example 1(1).

NMR (DMSO-d6,8): 2.86 (2H, 3.43 (2H, 4.32 (2H, d, J 6 Hz), 4.52 (1H, 5.99 (2H, 6.75-6.79 (3K, 6.99 (1K, d, J 9 Hz), 7.15-7.20 (2H, 7.21-7.29 (2H, 8.17 (1H, dd, J 2, 9 Hz), 8.61 (1H, d, J 2 Hz), 9.26-9.35 (2K, m) Mass m/z: 430 Example 14 2-(trans-2-Aminocyclohexylamino)-5-nitro-N-(1,3-benzodioxol- 5-ylmethyl)benzamide (73.5 mg) was obtained from (1 ,3-benzodioxol-5-ylmethyl)benzaide (96 ig) and trans-i,2diaminocyclohexane (0.072iL) in a manner similar to Example 1(1).

NMR (DMSO-d6, 1.16-1.41 (4H, 1.61-1.71 (2H, 1.87-2.00 (2K, 2.84 (1H, 3.46 (1H, 4.36 (2K, 4.59 (1H, d, J 4 Hz), 5.98 WO 99/54284 WO 9954284PCT/JP99/02028 (2H, 6.78-6.92 (3H, in), 7.01 (1H, d, J =9 Hz), 8. 10 (1H, dd, J 2, 9 Hz), 8.60 (1H, d, J 2 Hz), 9. 10 (1H, d, J =8 Hz), 9.33 (1H, br) Mass m/z: 413 Eape1 2- 2R )-2-Hydroxy-1- (hydroxyinethyl)propylafilo] 1,3-benzodioxo1-5-ylmethyl)belzamilde (81.8 mg) was obtained from 2 -fluoro- 5 -nitro- N- (1 ,3 -benzodioxol- 5-ylmethy) belzaTide (93 mg) and (R )-threoninol (61.4 ing) in a manner similar to Example 1(1).

NMR (DMSO-d6,&5): 1.07 (3H, d, J 7 Hz), 3.37-3.56 (3H, in), 4.03 (1H, mn), 4.34 (2H, d, J 5 Hz), 4.83 (iH, in), 4.97 (1H, d, J 5 Hz), 5.99 (2H, 6.75-6.94 (4H, in), 8.09 (1H, dd, J 2, 9 Hz), 8.56 (1H, d, J 2 Hz), 9.23-9.30 (2H, in) Mass m/z: 402 Exampe 1 2- [2-(Tetrahydro-2-oxo-3-furanyl) amino] -5-nitro-N- (1,3- (22.8 ing) was obtained from 2fluoro- 5-nitro-N- (1 3benzodioxol-5-ylnethy)belzamide (54.8 ing) and 2-amino- y -butyrolactone hydrobromide (37.6 mng) in a manner similar to Example 1(1).

NMR (DMSO-d 6 2.15-2.3 (1H, in), 2.7-2.86 (1H, in), 4.29 (1H, in), 4.35 (2H, d, J 5 Hz), 4.42 1H, t, J=7 Hz), 4.83 (iH, in), 4.97 (1H, d, J Hz), 5.99 (2H, 6.75-6.9 1 (3H, in), 6.97 (1H, d, J 9 Hz), 8.13 (1H, dd, J 2, 9 Hz), 8.61 (1H, d, J 2 Hz), 9.24 (1H, d, J 8Hz), 9.38 (iH, t, J= 6 Hz) Mass in/z: 398 Example 1 2- (tert-Butylamino)-5-nitro-N-( 1,3-benzodioxol-5ylinethyl)benzamide (94.3 mg) was obtained from (1 ,3-benzodioxol-5-ylnethyl)beflzamfide (100 mg) and tert-butylainine (115 mg) in a manner similar to Example 1 NMR (ODC1 3 1.48 (9H, 4.48 (2H, d, J= 7 Hz), 5.96 (2H, 6.47 (1H, WO 99/54284 WO 9954284PCT/JP99/02028 br), 6.77-6.90 (4H, in), 8.11 (1H, dd, J= 4, 8 Hz), 8.29 (1H, d, J= 4 Hz), 9.08 (1H, br) Mass m/z: 370(M+).

Eape1 2- [1-(Ethoxycarbonyl)piperidin-4-ylaminol-5-nitro-N-( 1,3- (204 mg) was obtained as yellow powders from 2-fluoro-5-nitro-N-( 1,3-benzodioxol-5ylinethyl)benzamide (150 mg) and ethyl 4-amino-ipiperidinecarboxylate (122 mg) in a manner similar to Example 1(1).

NMR (CDCl 3 1.28 (3H, t, J= 7 Hz), 1.50-1.70 (2H, br), 1.97-2. 10 (2H, br), 3.06-3.23 (2H, br), 3.58-3.70 (1H, br), 3.95-4.10 (2H, br), 4.16 (2H, q, J= 7 Hz), 4.48 (2H, d, J= 7 Hz), 5.98 (2H, 6.50 (1H, br), 6.69 (1H, d, J= 8 Hz), 6.77-6.90 (3H, in), 8.16 (1H, dd, J= 4, 8Hz), 8.32 (1H, d, J= 4 Hz), 9.00 (1H, br) Mass in/z: 469(M+).

Example19 2- (1-Benzylpiperidin-4-ylamino)- 5-nitro-N- 3-benzodioxol- ylmethyl)benzamide (123 mng) was obtained as yellow powders from 2- (1 ,3-benzodioxol-5-ylmethyl)benzalnide (150 mg) and 4-amino- 1 -benzylpiperidine (122 ing) in a manner similar to Example 1 NMR (CDC1 3 1.63-1.78 (2H, br), 1.96-2.08 (2H, br), 2.17-2.33 (2H, br), 2.75-2.90 (2H, br), 3.48 (1H, br), 3.55 (2H, 4.50 (2H, d, J= 7 Hz), 5.97 (2H, 6.40 (1H, br), 6.65 (1H, d, J= 8 Hz), 6.77-6.88 (3H, mn), 7.23-7.38 in), 8.13 (1H, dd, J= 4, 8 Hz), 8.28 (LH, d, J= 4 Hz), 8.93 (1H, br) Mass in/z 489(M+).

Eape2 2- 12-Hydroxy- 1, 1-bis(hydroxymethyl)ethylaininoj (1 ,3-benzodioxol-5-ylinethyl)benzamide (14.6 mng) was obtained as brown powders from 2-fluoro-5-nitro-N-( 1,3-benzodioxol-5ylinethyl)benzainide (100 ing) and 2-amino-2-(hydroxymethyl)- 1,3- WO 99/54284 WO 9954284PCT/JP99/02028 propanediol (114 mg) in a manner similar to Example NMR (DMSO-d6, 3.65 (6H, d, 3= 7 Hz), 4.33 (2H, d, J= 7 Hz), 4.84 (3H, t, J= 7 Hz), 5.98 (2H, 6.79-6.93 (3H, in), 7.25 (1H, d, J= 8 Hz), 8.02 (1H, dd, J= 4, 8 Hz), 8.48 (1H, d, J= 4 Hz), 9.18 (1H, br), 9.29 (1H, br) Mass m/z: 418(M+).

Example 21 2- [2-Hydroxy- 1- (hydroxymethyl)- -1-methylethylamino] 1,3-benzodioxol-5-ylinethyl)benzamide (115 mng) was obtained from 2-fluoro-5-nitro-N- (1 ,3-benzodioxol-5-ylmethyl)benzaITide (150 mng) and 2-methyl-2-aminO- 1,3-propanedioI (149 mg) in a manner similar to Example 1 NMR (DMSO-d6,35): 1.26 (3H, 3.45-3.60 (4H, mn), 4.32 (2H, d, J= 7Hz), 5.00 (2H, t, J= 7 Hz), 5.98 (2H, 6.78-6.90 (3H, in), 7.08 (1H, d, J= 8 Hz), 8.03 (1H, dd, 3= 4, 8 Hz), 8.51 (1H, d, J= 4 Hz), 9.24 (1H, br), 9.33 (1H, br) Mass m/z: 402(M+).

2- (tert-Butoxyamino)-5-nitro-N-( 1,3-benzodioxol-5ylmethyl)benzamide (56.0 ing) was obtained from (1 ,3-benzodioxol-5-ylinethyl)benzamide (150 mg) and 2-tertbutoxyamine (118 mg) in a manner similar to Example 1 NMR (CDCl 3 1.35 (9K, 4.51 (2H, d, J= 7 Hz), 5.97 (2H, 6.48 (1H, br), 6.78-6.86 (3H, in), 7.28 (1K, d, J= 8 Hz), 8.19 (1H, dd, J=4, 8 Hz), 8.29 (1H, d, J= 4 Hz) Mass m/z: 386(M+).

Prparaion 23 To a solution of 4-amino- 1 -cyclohexanecarboxylic acid (500 mg) in dichioromethane (20 inL) and methanol (10 mL) was added hexane solution of trimethylsilyldiazomethane (638 mg), and the mixture was stirred for 21 hours at ambient temperature. The mixture was evaporated in vacuo to give methyl 4-amino-i1- WO 99/54284 PCT/JP99/02028 cyclohexanecarboxylate as a colorless oil (544 mg).

NMR (CDC1 3 1.27-1.73 (6H, br), 1.88-2.08 (2H, br), 2.48 (1H, m), 2.85 (1H, 3.67 and 3.68 (3H, s).

Example 231) 2-[4-(Methoxycarbonyl)cyclohexylamino]-5-nitro-N-(1,3- (381 mg) was obtained from 2fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (300 mg) and methyl 4-amino- 1-cyclohexanecarboxylate (222 mg) in a manner similar to Example 1(1).

NMR (CDC1 3 1.70-2.03 (8H, br), 2.52 (1H, br), 3.63 (1H, br), 3.71 (31H, 4.50 (2H, d, J= 7 Hz), 5.97 (2H, 6.41 (1H, br), 6.66 (1H, 6.78- 6.87 (3H, 8.14 (1H, 8.30 (1H, 8.86 and 9.08 (1H, br) Mass m/z: 456(M+).

Example 23(2 A mixture of 2-[4-(methoxycarbonyl)cyclohexylamino] N-(1,3-benzodioxol-5-ylmethyl)benzamide (269 mg), methanol (10 mL), tetrahydrofuran (10 mL) and 1N-sodium hydroxide solution (5 mL) was stirred for an hour at 60 The mixture was acidified with iNhydrochloric acid to pH 4 and the organic solvent was removed by evaporation. The aqueous layer was diluted with water and extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 2-(4-carboxycyclohexylamino)- 5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (253 mg).

NMR (DMSO-d, 1.20-2.05 (8H, br), 2.42 (1H, br), 3.77 (1H, br), 4.35 (2H, d, J= 7 Hz), 5.96 (2H, 6.78-6.95 (4H, 8.10 (1H, dd, J= 4, 8 Hz), 8.60 (1H, d, J= 4 Hz), 9.08 and 9.33 (21-1, br) Mass m/z: 440 Example 233 To a mixture of 2-(4-carboxycyclohexylamino)-5-nitro-N-(1,3- WO 99/54284 PCT/JP99/02028 (80.0 mg), 1-[3- (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (52.1 mg), 1hydroxybenzotriazole (36.7 mg) in dimethylformamide (1 mL) was added 28% ammonia solution (10 drops). After stirring for 15 hours at ambient temperature, the mixture was partitioned between water and ethyl acetate. The separated organic layer was washed with an aqueous saturated sodium bicarbonate solution, water and brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo.

The residue was purified by a silica gel column chromatography eluting with 10% methanol in chloroform. The obtained product was triturated with diisopropyl ether to give 2-(4-carbamoylcyclohexylamino)-5-nitro- N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (60.0 mg).

NMR (CDC 3 1.18-1.85 (8H, br), 2.22 (1H, br), 3.82 (1H, br), 4.37 (2H, d, J= 7 Hz), 5.99 (2H, 6.70-6.93 (5H, 7.23 (1H, br), 8.12 (1H, dd, J= 4, 8 Hz), 8.62 (1H, d, J= 4 Hz), 9.06 and 9.43 (1H, br), 9.33 (1H, br) Mass m/z 439(M+).

Example 24(1) 1-(tert-Butoxycarbonyl)-4-piperidinylamino]-5-nitro-N-(1,3benzodioxol-5-ylmethyl)benzamide (539 mg) was obtained from 2fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (480 mg) and tert-butyl 4-amino- 1-piperidinecarboxylate (604 mg) in a manner similar to Example 1(1).

NMR (CDC1 3 ,d 1.47 (9H, 1.57 (2H, br), 2.00 (2H, br), 3.08 (2H, br), 3.62 (1H, br), 4.00 (2H, br), 4.49 (2H, d, J= 7 Hz), 5.97 (2H, 6.50 (1H, br), 6.68 (1H, d, J= 8 Hz), 6.82 (3H, 8.14 (1H, dd, J= 4, 8 Hz), 8.31 (1H, d, J= 4 Hz), 9.00 (1H, d, J= 8 Hz) Mass m/z 497(M+).

Example 24(2) To a solution of 2-[1-(tert-butoxycarbonyl)-4-piperidinylamino]- 5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(469 mg) in dichloromethane (6 mL) was added trifluoroacetic acid (1.07 and the mixture was stirred for 4 hours at ambient temperature. The reaction WO 99/54284 WO 9954284PCT/JP99/02028 mixture was washed with iN-sodium hydroxide solution, water and brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with dlisopropyl ether to give 5 -nitro- 2- (4 -piperidinylamino) ,3-benzodioxol- ylmethyl)benzamide as yellow powders (335 mg).

NMR (DMSO-d 6 1.34 (2H, br), 1.89 (2H, br), 2. 10 (1H, br), 2.64 (2H, br), 2.93 (2H, br), 3.65 (1H, br), 4.34 (2H, d, J= 7 Hz), 5.98 (2H, 6.88 (4H, in), 8. 11 (1H, dd, J= 4, 8Hz), 8.61 (1H, d, 4 Hz), 9.14 (1H, d, J= 8 Hz), 9.34 (1 H, br) Mass m/z: 399(M+).

A mixture of 5-nitro-2- (4-piperidinylamino) (1 ,3-benzodioxol- (80.0 mg), acetic acid (13.3 mg), 11[3- (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (57.7 mg) and 1-hydroxybenzotriazole (40.7 mng) in anhydrous dimethylformamide (1 mL) was stirred for 3 hours at ambient temperature. The mixture was partitioned between water and ethyl acetate. The organic layer was separated and washed with an aqueous saturated sodium bicarbonate solution, water and brine. Then, the resultant was dried over magnesium sulfate and evaporated in uacuo. The residue was triturated with diisopropyl ether to give 1-acetyl-4-piperidinylamino)- 1,3-benzodioxol-5-ylmethyl)benzarnide as yellow powders (8 1.1 mg).

NMR (DMSO-d 6 1.27 (1H, br), 1.46 (1H, br), 1.95 (2H, br), 2.01 (3H, s), 2.90 (1H, br), 3.23 (1H, br), 3.75 (1H, br), 3.82 (lH, br), 4.17 (1H, br), 4.34 (2H, d, J= 7 Hz), 5.98 (2H, 6.8 1-6.90 (3H, in), 6.98 (lH, d, J= 8 Hz), 8.12 (1H, dd, J= 4, 8 Hz), 8.61 (1H, d, J= 4 Hz), 9.14 (1H, d, J= 8 Hz), 9.35 (lH, br) Mass m/z: 439(M+).

Example2(4) To a mixture of 5-nitro-2-(4-piperidinylanino)-N-(1,3- (80.0 mg) and 37% formaldehyde WO 99/54284 WO 9954284PCT/JP99/02028 solution (192 mg) in methanol (4 mL) were added sodium cyanoborohydride (37.9 mg) and acetic acid (4 drops). After stirring for 2 hours at ambient temperature, the mixture was partitioned between an aqueous saturated sodium bicarbonate solution and chloroform.

The organic layer was separated and washed with water and brine.

Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 1methyl-4-piperidinylamino) -5-nitro-N- (1 ,3-benzodioxol- ylmethyl)benzamide as yellow powders (65.0 mg).

NMR (ODC1 3 1.53-1.80 (2H, br), 2.04 (2H, br), 2.19 br), 2.32 (3H, 2.75 (2H, br), 3.48 (1H, br), 4.48 (2H, br), 5.97 (2H, 6.41 (1H, br), 6.63 (1H, br), 6.80 (3H, br), 8.13 (1H, br), 8.29 (1H, br), 8.93 (1H, br) Mass m/z: 413(M+).

Exam~ple24(5 2- (1-Formyl-4-piperidinylamino)-5-nitro-N- (1 ylmethyl)benzamide (70.0 mg) was obtained from 5-nitro-2-(4piperidinylamiino) 3-benzodioxol-5-ylmethyl)benzarnide (80.0 mg) and formic acid (10.4 mg) in a manner similar to Example 24(3).

NMR (DMSO-d 6 1.20-1.48 (2H, br), 1.90-2.08 (2H, br), 2.85-2.97 (1H, br), 3.16-3.30 (1H, br), 3.60-3.73 (1H, br), 3.80-3.95 (1H, br), 3.98-4.10 (1H, br), 4.34 (2H, d, J= 7 Hz), 5.98 (2H, 6.75-6.93 (3H, in), 7.00 (1H, d, J= 8 Hz), 7.99 (1H, 8.13 (1H, dd, J= 4, 8 Hz), 8.62 (1H, d, J= 4 Hz), 9.17 (1H, d, J= 8 Hz), 9.35 (1H, br) Mass m/z: 425(M+).

2-11- (Hydroxymethyl) cyclopentylamino]-5-nitro-N- (1,3- (130 mg) was obtained from 2fluoro-5-nitro-N- (1 ,3-benzodioxol- 5-ylmethyl)benzamide (150 mg) and 1-aminocyclopentanemethanol (81.4 mg) in a manner similar to Example 1 NMR (CDCl 3 1.66-1.86 (5H, in), 1.96 (4H, in), 3.76 (2H, d, J= 7 Hz), 4.49 (2H, d, J= 7 Hz), 5.97 (2H, 6.53 (1H, br), 6.76-6.85 (4H, in), 8.07 WO 99/54284 PCT/JP99/02028 (1H, dd, J= 4, 8 Hz), 8.29 (1H, d, J= 4 Hz), 9.06 (1H, br) Mass m/z: 412(M+).

Example 26 1-(Hydroxymethyl)-2-methylpropylamino-5-nitro-N-(1,3- (127 mg) was obtained from 2fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (150 mg) and (S)-2-amino-3-methyl-1-butanol (72.9 mg) in a manner similar to Example 1(1).

NMR (CDC13, 1.03 (6H, t, J= 7 Hz), 1.75 (1H, 2.02 (1H, 3.55 (1H, br), 3.69 (1H, 3.83 (1H, 4.50 (2H, 5.97 (2H, 6.57 (1H, br), 6.77-6.85 (4H, 8.09 (1H, dd, J= 4, 8 Hz), 8.29 (1H, d, J= 4 Hz), 8.98 (1H, br) Mass m/z: 400(M+).

Example 27 2-[1-(Hydroxymethyl)pentylaminoI-5-nitro-N-(1,3-benzodioxol- (203 mg) was prepared from (1,3-benzodioxol-5-ylmethyl)benzamide (200 mg) and 2-amino-1hexanol (221 mg) in a similar manner to that of Example 1(1) as yellow crystals.

mp 112-115 0

C

NMR (DMSO-d6,6); 0.85 (3H, t, J= 8 Hz), 1.20-1.40 (4H, 1.45 (1H, m), 1.65 (1H, 3.48 (2H, t, J= 6 Hz), 3.63 (1H, 4.27-4.44 (2H, 4.92 (1H, t, J= 6 Hz), 5.99 (2H, 6.81 (1H, d,J= 8 Hz), 6.86-6.91 (3H, 8.10 (1H, dd, J= 2, 10 Hz), 8.58 (1H, d, J= 2 Hz), 9.13 (1H, d,J= 8 Hz), 9.30 (1H, t,J= 5 Hz).

Preparation 28 2-(Cyclopropylamino)-5-nitrobenzoic acid (238 mg) was obtained from 2-fluoro-5-nitrobenzoic acid (275 mg) and cyclopropylamine (255 mg) in a manner similar to Example 1(1).

NMR (DMSO-d6,6): 0.61 (2H, 0.90 (2H, 2.69 (1H, 7.22 (1H, d, J 9 Hz), 8.26 (1H, dd, J 2, 9 Hz), 8.65 (1H, d, J 2 Hz), 8.79 (1H, br).

WO 99/54284 WO 9954284PCT/JP99/02028 Exampe28 N-Benzyl-2- (cyclopropylamfilo) -5-nitrobenzamide (151 mg) was obtained from 2-(cyclopropylamino)-5itrobelzoic acid (115 mg) and benzylamine (0.073 mL) in a manner similar to Preparation 1.

NMR (DMSO-d6,65): 0.54 (2H, in), 0.87 (2H, in), 2.62 (1H, mn), 4.46 (1H, d, J 6 Hz), 7.18 (1H, d, J 9 Hz), 7.22-7.40 (5H, mn), 8.22 (1H, in), 8.64 (1H, d, J 2 Hz), 9.06 (1H, br), 9.44 (1H, t, J 6 Hz) Mass m/ z :3 10 1).

Preparation 29 2-(2-Hydroxycyclohexylamfiflo)-flitrobeflzoic acid (291 mng) was obtained from 2-fluoro-5-nitrobenzoic acid (235 mg) and 2aminocyclohexanTol (292 mg) in a manner similar to Example 1 NMR (DMSO-d6,65): 1.15-1.45 (6H, in), 1.58-1.72 (2H, in), 1.88-2.08 (2H, in), 3.25-3.35 (3H, in), 4.95 (1H, in), 7.02 (1H, d, J 9 Hz) 8. 11 (1H, dd, J 2, 9 Hz), 8.64 (1H, d, J 2 Hz), 8.98 (1H, d, J 6 Hz).

Example29 N-Benzyl-2- (2-hydroxycyclohexylaniTino) -5-nitrobenzamide (107 mng) was obtained from 2- (2-hydroxycyclohexylaf-lfo) acid (134 mng) and benzylamine (0.068 mL) in a manner similar to Preparation 1.

NMR (DMSO-d 6 1.38-1.42 (4H, 1.55-1.7 (2H, in), 1.8-2.1 (2H, in), 3.3-3.4 (2H, in), 4.43 (2H, d, J 6 Hz), 4.92 (1H, d, J3= 6 Hz), 6.96 (1H, d, J3 9 Hz), 7.2-7.38 (5H, in), 8.09 (1H, dd, 3 2, 9 Hz), 8.62 (1H, d, 3 2 Hz), 9.28 (1H, d, J3 6 Hz), 9.39 (1H, t, J 6 Hz) Mass in/z 368 1).

Preparation 30(1) To a solution of ethyl 2 -amino- 5-nitrobenzoate (5.00 g), cyclopentanone (9.00 g) and sodium borohydride (4.05 g) in anhydrous tetrahydrofuran (100 mL) was added sulfuric acid (6 mL) under ice-water cooling. The mixture was stirred for 9 hours at 0 *C and then for WO 99/54284 PCT/JP99/02028 hours at ambient temperature. The mixture was neutralized with an aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (5 The obtained product was triturated with hexane to give ethyl 2-cyclopentylamino-5-nitrobenzoate as yellow powders (5.94 g).

NMR (CDCl 3 1.41 (3H, t, J=7Hz), 1.58-1.90 (6H, 2.10 (2H, m), 3.96 (1H, 4.36 (2H, q, J=7Hz), 6.70 (1H, d, J=8Hz), 8.18 (1H, dd, J=4, 8Hz), 8.67 (1H, br), 8.87 (1H, d, J=4Hz) Mass m/z 279 Preparation 30(2) 2-Cyclopentylamino-5-nitrobenzoic acid (5.16 g) was obtained as yellow powders from ethyl 2-cylcopentylamino-5-nitrobenzoate (5.94 g) in a manner similar to Example 23(2).

NMR (DMSO-d 6 1.47 (2H, 1.58-1.78 (4H, br), 2.10 (2H br) 4.05 (1H, m) 6.93 (1H, d, J=8Hz), 8.18 (1H, dd, J=4, 8Hz), 8.65 (1H, d, J=4Hz), 8.83 (1H, br) Mass m/z 249 Example To a mixture of 2-cyclopentylamino-5-nitrobenzoic acid (1.00 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.15 g), 1-hydroxybenzotriazole (810 mg) in anhydrous dimethylformamide mL) was added (1,3-benzodioxol-5-ylmethyl)amine (725 mg), and the mixture was stirred for 15 hours at ambient temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with an aqueous saturated sodium bicarbonate solution, water and brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of chloroform and methanol The obtained product was triturated WO 99/54284 WO 9954284PCT/JP99/02028 with diisopropyl ether and recrystallized from a mixture of hexane and ethyl acetate to give 2-cyclopentylamino- 5-nitro-N- (1,3 -benzodioxol- ylmethyl)benzamide as yellow powders (1.51 g).

NMR (CDCl 3 :1.58-1.86 (6H, in), 2.08 (2H, in), 3.90 (1H, mn), 4.50 (2H, d, J=7Hz), 5.98 (2H, 6.46 (1H, br), 6.68 (1H, d, J=8Hz), 6.83 (3H, in), 8.15 (1H, dd, J=4, 8Hz), 8.29 (1H, d, J=4Hz), 8.86(1H, br) Mass m/z: 382(M+).

Exaple 3 2- (Cyclopentylainino) (4-flu orobenzyl) -5-nitrobenzainide (138 mg) was obtained as yellow powders from nitrobenzoic acid (100 mg) and 4-fluorobenzylamine (60.0 mg) in a manner similar to Example NMR (ODC1 3 1.59-1.85 (6H, in), 2.00-2.15 (2H, in), 3.89 (1H, in), 4.58 (2H, d, J= 7 Hz), 6.54 (1H, br), 6.68 (1H, d, J= 8 Hz), 7.06 (2H, in), 7.33 (2H, in), 8.15 (1H, dd, J= 4, 8 Hz), 8.30 (1H, d, J= 4 Hz), 8.85 (1H, br) Mass m/z: 356 Example32 2- (Cyclopentylamino) -N-(4-methylbenzyl) (130 ing) was obtained as yellow powders from nitrobenzoic acid (100 mg) and 4-methylbenzylainine (58.1 mng) in a manner similar to Example NMR (CDCl 3 1.59-1.85 (6H, in), 2.03-2.15 (2H, in), 2.37 (3H, 3.90 (1H, in), 4.55 (2H, d, J= 7 Hz), 6.45 (1H, br), 6.67 (1H, d, J= 8 Hz), 7.18 (2H, d, J= 8 Hz), 7.25 (2H, d, J= 8 Hz), 8.13 (1H, dd, J= 4,8 8Hz), 8.27 (1H, d, J= 4 Hz), 8.87 (1H, br) Mass m/z: 352(M+).

Eape3 2- (Cyclopentylamino) (138 ing) was obtained as yellow powders from nitrobenzoic acid (100 ing) and 4-inethoxybenzylamine (65.8 ing) in a manner similar to Example WO 99/54284 WO 9954284PCT/JP99/02028 NMR (CDCL 3 1.59-1.85 (6H, in), 2.00-2.15 (2H, in), 3.82 (3H, 3.90 (1H, mn), 4.52 (2H, d, J= 7 Hz), 6.41 (1H, br), 6.67 (1H, d, J= 8 Hz), 6.90 (2H1, d, J= 8 Hz), 7.28 (2H, d, J= 8 Hz), 8.12 (1 H, dd, J= 4, 8Hz), 8.27 (1 H, d, J= 4 Hz), 8.88 (1H, br) Mass m/z: 368(M+).

Example 34 2- (Cyclopentylamino) -5-nitro-N- [4- (trifluoroinethyl)benzyl]benzamide (155 ing) was obtained as yellow powders from 2-(cyclopentylammlio)-5-nitrobenzoic acid (100 mng) and 4- (trifluoromethyl)benzylarnine (84.0 ing) in a manner similar to Example NMR (CDCl 3 1.59-1.85 (6H, in), 2.02-2.14 (2H, mn), 3.92 (1H, in), 4.65 (2H, d, J= 7 Hz), 6.68 (1H, d, J= 8 Hz), 6.69 (1H, br), 7.47 (2H, d, J= 8 Hz), 7.63 (2H, d, J= 8 Hz), 8.16 (1H, dd, J= 4, 8Hz), 8.37 (1H, d, J= 4 Hz), 8.85 (1H, br) Mass m/z: 406(M+).

Exam~pe 2- (Cyclopentylamino) -5-nitro-N-(4-nitrobenzyl)benzam-ide (132 mg) was obtained as yellow powders from nitrobenzoic acid (100 mg) and 4-nitrobenzylamine (90.4 mng) in a manner similar to Example NMR (CDC1 3 1.59-1.85 (6H, in), 2.03-2.15 (2H, in), 3.90 (1H, in), 4.72 (2H, d, J= 7 Hz), 6.69 (1H, d, J= 8 Hz), 6.90 (1H, br), 7.52 (2H, d, J= 8 Hz), 8.16 (1 H, dd, J= 4, 8 Hz), 8.23 (2H, d, J= 8 Hz), 8.42 (1 H, d, J= 4 Hz), 8.87 (1H, br) Mass m/z: 385 E2xmple.36 2- (Cyclopentylamino)-N- (dimethylamino) nitrobenzamide (121 ing) was obtained as yellow powders from 2acid (100 ing) and 4- (dimethylainino)benzylaxnine hydrochloride (107 ing) in a manner WO 99154284 WO 9954284PCT/JP99/02028 similar to Preparation 1.

NMR (CDCla,c5): 1.59-1.85 (6H, in), 2.03-2.15 (2H, in), 2.96 (6H, 3.91 (1H, mn), 4.47 (2H, d, J= 7 Hz), 6.32 (1H, br), 6.66 (1H, d, J= 8 Hz), 6.73 (2H, d, J= 8 Hz), 7.23 (2H, d, J= 8 Hz), 8.13 (1 H, dd, J= 4, 8 Hz), 8.27 (1 H, d, J= 4 Hz), 8.87 (1H, br) Mass m/z: 383(M+).

Sulfamoylbenzyl) (cyclopentylainino) (162 ing) was obtained as yellow powders from nitrobenzoic acid (100 mg) and 4-sulfamoylbenzylamine hydrochloride (107 mg) in a manner similar to Preparation 1.

NMR (DMSO-d 6 1.38-1.52 (2H, in), 1.56-1.74 (4H, in), 1.96-2.10 (2H, in), 3.96 (1H, in), 4.50 (2H, d, J= 7 Hz), 6.86 (1H, d, J= 8 Hz), 7.33 (2H, s), 7.50 (2H, d, J= 8 Hz), 7.78 (2H, d, J= 8 Hz), 8.15 (1H, d, J= 8 Hz), 8.67 (I1H, d, J= 4 Hz), 9. 16 (1 H, d, J= 8 Hz), 9.50 (1 H, br) Mass m/z: 417(M+).

ExampekA N- (4-Broinobenzyl) -2-(cyclopentylamino) -5-nitrobenzamnide (160 ing) was obtained as yellow powders from nitrobenzoic acid (100 mg) and 4-broinobenzylamine (107 mg) in a manner similar to Preparation 1.

NMR (CDC1 3 1.59-1.85 (6H, in), 2.03-2.15 (2H, in), 3.92 (1H, in), 4.56 (2H, d, J= 7 Hz), 6.61 (1H, br), 6.68 (1H, d, J= 8 Hz), 7.23 (2H, d, J= 8 Hz), 7.48 (2H, d, J= 8 Hz), 8.15 (1H, dd, J= 4, 8 Hz), 8.32 (1H, d, J= 4 Hz), 8.86 (1H, br) Mass m/z: 418(M+).

Example.39 2- (Cyclopentylamino) -N-furfuryl-5-nitrobenzamide (120 ing) was obtained as yellow powders from acid (100 ing) and furfurylamine (46.6 mng) in a manner similar to Preparation 1.

WO 99/54284 WO 9954284PCT/JP99/02028 NMR (CDCl 3 1.58-1.90 (6H, br), 2.03-2.18 (2H, br), 3.91 (1H, in), 4.61 (2H, d, J= 7 Hz), 6.33 (2H, in), 6.51 (1H, br), 6.69 (1H, d, J= 8 Hz), 7.40 (1 H, 8.12 (1 H, dd, J= 4, 8Hz), 8.32 (1 H, d, J= 4 Hz), 8.82 (1 H, br) Mass m/z: 328(M+).

Eample 4 2- (Cyclopentylamino) -5-nitro-N- (2-thienylmethyl)benzamide (130 mg) was obtained as yellow powders from nitrobenzoic acid (100 mg) and 2-thiophenernethylamine (54.3 nmg) in a manner similar to Preparation 1.

NMR (CDCl 3 1.59-1.85 (6H, mn), 2.01-2.17 (2H, mn), 3.90 (1H, in), 4.77 (2H, d, J= 7 Hz), 6.55 (1H, br), 6.68 (1H, d, J= 8 Hz), 6.98 (1H, in), 7.05 (1H, br), 7.28 (1H, in), 8.15 (1H, dd, J= 4, 8 Hz), 8.30 (1H, d, J= 4 Hz), 8.81 (1H, br) Mass m/z: 344(M+).

Example 41 2- (Cyclopentylamino)- 5-nitro-N-phenethylbenzaide (141 mg) was obtained as yellow powders from nitrobenzoic acid (100 mg) and phenethylamine (58.1 mg) in a manner similar to Preparation 1.

NMR (CDCl 3 1.59-1.85 (6H, in), 2.00-2.15 (2H, in), 2.94 (2H, t, J= 7 Hz), 3.68 (2H, in), 3.89 (1H, in), 6.24 (1H, br), 6.65 (1H, d, J= 8 Hz), 7.28 (3H, mn), 7.35 (2H, in), 8.13 (1H, dd, J= 4, 8 Hz), 8.19 (1H, d, J= 4 Hz), 8.75 (1H, br) Mass in/z: 352(M+).

Exn~aml42 2- (Cyclopentylainino) -5-nitro-N- (3-phenylpropyl)benzamide (120 ing) was obtained as yellow powders from nitrobenzoic acid (100 mg) and 3-phenylpropylamine (64.8 ing) in a manner similar to Preparation 1.

NMR (CDC1 3 1.59-1.85 (6H, in), 1.94-2.15 (4H, in), 2.74 (2H, t, J= 7 Hz), 3.47 (2H, in), 3.89 (1H, in), 6.13 (1H, br), 6.68 (1H, d, J= 8 Hz), WO 99/54284 PCT/JP99/02028 7.17-7.33 (5H, 8.13 (2H, 8.83 (1H, br) Mass m/z: 366(M+).

Example 43 N-f(2-Benzimidazolyl)methyl]-2-(cyclopentylamino)-5nitrobenzamide (132 mg) was obtained as yellow powders from 2acid (100 mg) and 2- (aminomethyl)benzimidazole dihydrochloride hydrate (106 mg) in a manner similar to Preparation 1.

NMR (DMSO-d 6 1.40-1.54 (2H, br), 1.54-1.75 (4H, br), 1.95-2.13 (2H, br), 3.96 (1H, br), 4.66 (2H, d, J= 7 Hz), 6.89 (1H, d, J= 8 Hz), 7.14 (2H, br), 7.45 (1H, br), 7.53 (1H, br), 8.14 (1H, dd, J= 4, 8 Hz), 8.73 (1H, d, J= 4 Hz), 9.14 (1H, br), 9.53 (1H, br), 12.32 (1H, br) Mass m/z: 378(M+).

Example 44 2-(Cyclopentylamino)-N-(4-hydroxy-3-methoxybenzyl)-5nitrobenzamide (143 mg) was obtained as yellow powders from 2acid (100 mg) and 4-hydroxy-3methoxybenzylamine hydrochloride (90.9 mg) in a manner similar to Preparation 1.

NMR (DMSO-d 6 1.39-1.53 (2H, 1.55-1.75 (4H, 1.98-2.10 (2H, 3.76 (3H, 3.96 (1H, 4.35 (2H, d, J= 7 Hz), 6.72 (2H, 6.85 (2H, 8.13 (1H, dd, J= 4,8 Hz), 8.59 (1H, d, J= 4 Hz), 8.88 (1H, 9.12 (1H, d, J= 8 Hz), 9.28 (1H, br) Mass m/z: 384(M+).

Example 2-(Cyclopentylamino)-N-(3,4-dihydroxybenzyl)-5nitrobenzamide (109 mg) was obtained as yellow powders from 2acid (100 mg) and 3,4dihydroxybenzylamine hydrobromide (106 mg) in a manner similar to Preparation 1.

NMR (DMSO-d 6 1.38-1.52 (2H, 1.54-1.75 (4H, 1.97-2.10 (2H, WO 99/54284 WO 9954284PCT/JP99/02028 in), 3.98 (1H, in), 4.28 (2H, br), 6.57 (1H, mn), 6.68 (2H, in), 6.87 (1H, d, J= 8 Hz), 8.12 (1lH, dd, J= 4, 8Hz), 8.59 (1 H, d, J= 4 Hz), 8.80 (2H, br), 9.20 (1H, d, J= 8 Hz), 9.27 (1H, br).

Example 4 2- (Cyclopentylamino) ,4-diflu orobenzyl)- (130 mg) was obtained as yellow powders from nitrobenzoic acid (100 mg) and 3,4-difluorobenzylamine (68.6 ing) in a manner similar to Preparation 1.

NMR (ODC1 3 1.58-1.87 (6H, in), 2.03-2.14 (2H, in), 3.90 (1H, in), 4.55 (2H, d, J= 7 Hz), 6.68 (1H, br), 6.69 (1H, d, J= 8 Hz), 7.04-7.22 (3H, in), 8.16 (1H, dd, J= 4, 8 Hz), 8.37 (1H, d, J= 4 Hz), 8.88 (1H, br) Mass m/z: 374 Preparation 47(1) Ethyl 5-nitro-2- (tetrahydro-2H-thiopyran-4-ylamino)benzoate (315 mg) was obtained as yellow powders from ethyl nitrobenzoate (300 mg) and tetrahydro-2H-thiopyran-4-one (746 ing) in a manner similar to Preparation 30(1).

NMR (CDCl 3 1.44 (3H, t, J= 7 Hz), 1.75-1.89 (2H, in), 2.28-2.38 (2H, mn), 2.70-2.84 (4H, mn), 3.49-3.61 (1H, in), 4.38 (2H, q, J= 7 Hz), 6.66 (1H, d, J= 8 Hz), 8.19 (1 H, dd, J= 4, 8Hz), 8.78 (1 H, br), 8.87 (1 H, d, J= 4 Hz) Mass m/z: 309(M+).

Preparation 47(2) 5-Nitro-2 -(tetrahydro-2H-thiopyran-4-ylamino)benzoic acid (280 mg) was obtained as yellow powders from ethyl 5-nitro-2-(tetrahydro- 2H-thiopyran-4-ylamino)benzoate (3 10 ing) in a manner similar to Preparation 30(2).

NMR (DMSO-d 6 1.55-1.70 (2H, in), 2. 17-2.28 (2H, br), 2.62-2.85 (4H, in), 3.66-3.82 (1H, br), 6.98 (1H, d, J= 8 Hz), 8.17 (1H, dd, J= 4, 8 Hz), 8.66 (1H, d, J= 4, Hz), 8.85 (1H, d, J= 8 Hz) Mass in/z: 281(M+).

WO 99/54284 PCT/JP99/02028 Example 47.1U 5-Nitro-N-(1,3-benzodioxol-5-ylmethyl)-2-(tetrahydro-2Hthiopyran-4-ylamino)benzamide (170 mg) was obtained as yellow powders from 5-nitro-2-(tetrahydro-2H-thiopyran-4-ylamino)benzoic acid (150 mg) and (1,3-benzodioxol-5-ylmethyl)amine (96.4 mg) in a manner similar to Preparation 1.

NMR (CDCl 3 1.75-1.90 (2H, 2.27-2.36 (2H, 2.70-2.82 (4H, m), 3.51 (1H, 4.50 (2H, d, J= 7 Hz), 5.97 (2H, 6.47 (1H, br), 6.64 (1H, d, J= 8 Hz), 6.78-6.85 (3H, 8.15 (1H, dd, J= 4, 8 Hz), 8.31 (1H, d, J= 4 Hz), 9.02 (1H, br) Mass m/z: 414(M+).

Example 47(2 To a solution of 5-nitro-N-(1,3-benzodioxol-5-ylmethyl)-2- (tetrahydro-2H-thiopyran-4-ylamino)benzamide (50.0 mg) in anhydrous dichloromethane (1 mL) was added m-chloroperbenzoic acid (41.5 mg), and the mixture was stirred for 4 hours at ambient temperature. To the mixture were added an aqueous saturated sodium thiosulfate solution and an aqueous sodium bicarbonate solution. The resulting precipitates were collected by filtration and washed with water, methanol and ethyl acetate to give 1-dioxotetrahydro-2Hthiopyran-4-ylamino)- 5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (40.0 mg).

NMR (CDC1 3 1.88-2.10 (2H, br), 2.20-2.33 (2H, br), 3.04-3.19 (2H, br), 3.29-3.43 (2H, br), 3.98 (1H, br), 4.37 (2H, d, J= 7 Hz), 5.98 (2H, s), 6.79-6.98 (4H, 8.17 (1H, 8.63 (1H, 9.18 (1H, br),9.37 (1H, br) Mass m/z: 446(M+).

Preparation 48(1) Methyl 5-cyano-2-(cyclopentylamino)benzoate (2.31 g) was obtained as yellow powders from methyl 5-cyano-2-aminobenzoate (2.00 g) and cyclopentanone (3.01 mL) in a manner similar to Preparation 30(1).

NMR (CDC1 3 1.53-1.86 (6H, br), 2.00-2.14 (2H, br), 3.87 (3H, 3.90 WO 99/54284 PCT/JP99/02028 (1H, br), 6.71 (1H, d, J= 8 Hz), 7.49 (1H, dd, J= 4, 8 Hz), 8.19 (1H, d, J= 4 Hz), 8.34 (1H, br).

Preparation 48(2) A mixture of methyl 5-cyano-2-(cyclopentylamino)benzoate (2.30 methanol (100 mL) and 1N-sodium hydroxide solution (20 mL) was heated for 2 hours under reflux. The reaction mixture was acidified with 1N-hydrochloric acid to pH 4 and the organic solvent was removed by evaporation. The aqueous layer was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. Then, the resultant was evaporated in vacuo to give 5-cyano-2-(cyclopentylamino)benzoic acid (2.15 g) as pale yellow powders.

NMR (DMSO-d 6 1.43 (2H, 1.64 (4H, 2.03 (2H, 3.96 (1H, 6.89 (1H, d, J= 8 Hz), 7.68 (1H, dd, J= 4, 8 Hz), 8.09 (1H, d, J= 4 Hz), 8.51 (1H, d, J= 8 Hz) Mass m/z 229(M Preparation 48(3) To a solution of 5-cyano-2-(cyclopentylamino)benzoic acid (40.0 mg) in anhydrous tetrahydrofuran (2 mL) was added 1.5 M diisobutylaluminium hydride hexane solution (0.34 mL) under dry iceacetone cooling, and the mixture was stirred for an hour at -78 *C and then for 4 hours at ambient temperature. The reaction was quenched by addition of methanol and an aqueous saturated ammonium chloride solution. After stirring at ambient temperature for a half hour, the mixture was partitioned with 5% sulfuric acid and chloroform. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a preparative silica gel chromatography with 10% methanol in chloroform to give 2-(cyclopentylamino)-5-formylbenzoic acid (25.0 mg) as pale orange powders.

NMR (CDC1 3 1.55-1.88 (6H, 2.06-2.18 (2H, 3.97 (1H, 6.81 (1H, d, J= 8 Hz), 7.92 (1H, dd, J= 4, 8 Hz), 8.41 (1H, br), 8.48 (1H, d, J= 4 WO 99/54284 PCT/JP99/02028 Hz), 9.73 (1H, s).

Example 48 2-(Cyclopentylamino)-5-formyl-N-(1,3-benzodioxol-5ylmethyl)benzamide (489 mg) was obtained as yellow powders from 2acid (1.00 g) and (1,3-benzodioxol- (778 mg) in a manner similar to Example NMR (CDC1 3 1.55-1.87 (6H, br), 2.02-2.15 (2H, br), 3.88 (1H, br), 4.48 (2H, d, J= 7 Hz), 5.95 (2H, 6.44 (1H, br), 6.75 (1H, d, J= 8 Hz), 6.77-6.84 (3H, 7.74 (1H, d, J= 8 Hz), 7.87 (1H, 8.70 (1H, br), 9.67 (1H, s) Mass m/z: 367(M+).

Preparation 49 5-Cyano-2-fluoro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (534 mg) was obtained from 5-cyano-2-fluorobenzoic acid (300 mg) and (1,3-benzodioxol-5-ylmethyl)amine (0.26 mL) in a manner similar to Preparation 1.

NMR (DMSO-d 6 4.37 (2H, d, J 6 Hz), 6.00 (2H, 6.80-6.93 (3H, m), 7.56 (1H, t, J 9 Hz), 8.04 (1H, 8.13 (1H, dd, J 2, 6 Hz), 9.03 (1H, t, J 6 Hz) Mass m/z: 297 Example 491) (R)-5-Cyano-2-(2-hydroxy- 1-methylethylamino)-N-(1,3- (145 mg) was obtained from cyano-2-fluoro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (150 mg) and (R )-2-amino-1-propanol (0.12 mL) in a manner similar to Example 1(1).

NMR (DMSO-d 6 1.13 (3H, d, J 7 Hz), 3.42 (2H, t, J 5 Hz), 3.67 (1H, 4.32 (2H, d, J 6 Hz), 4.92 (1H, t, J 5 Hz), 5.98 (2H, 6.77-6.92 (4H, 7.60 (1H, dd, J 2, 9 Hz), 8.04 (1H, d, J 2 Hz), 8.73 (1H, d, J 8 Hz), 8.99 (1H, t, J 6 Hz) Mass m/z: 352 WO 99/54284 WO 9954284PCTIJP99/02028 Example 492 To a solution of (R )-5-cyano-2-(2-hydroxy-1rnethylethylamino) 3-benzodioxol- 5-ylmethyl)benzamide (76 mg) in ethanol (6 mL) was added IN-sodium hydroxide (0.65 mL), and the mixture was heated for 6 hours under reflux. The solvent was evaporated in vacuo. The residue was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and methanol 1) to give (R )-5-carbamoyl-2-(2-hydroxy- 1 -methylethylamrino) N- (1 ,3-benzodioxol-5-ylmethyl)benzamide (27 mg) as a solid substance.

NMR (DMSO-d 6 1.13 (3H, d, J 7 Hz), 3.3-3.5 (2H, in), 3.62 (1H, in), 4.33 (2H, d, J 5 Hz), 4.86 (1H, t, J =5 Hz), 5.98 (2H, 6.73 (1H, d, J 9 Hz), 6.77-6.90 (3H, in), 7.04 (1H, br), 7.58 (1H, br), 7.77 (1H, dd, J 2, 9 Hz), 8.14 (1H, d, J 2 Hz), 8.30 (1H, d, J 8 Hz), 8.83 (1H, t, J 5 Hz) Mass m/z: 370 5-Cyano-2- (trans-4-hydroxycyclohexylamino)-N- (1,3- (142 mng) was obtained from cyano-2-fluoro-N-( 1,3-benzodioxol-5-ylmethyl)benzaxnide (120 mg) and trans-4-aminocyclohexanol (139 mg) in a manner similar to Example 1(1).

NMR (DMSO-d 6 1.15-1.40 (4H, in), 1.75-1.86 (2H, in), 1.89-2.00 (2H, in), 3.35-3.53 (2H, mn), 4.31 (2H, d, J 6 Hz), 4.60 (1H, d, J 4 Hz), 5.98 (2H, 6.79 (1H, dd, J 2, 8 Hz), 6.83-6.92 (3H, in), 7.59 (1H, dd, J 2, 9 Hz), 8.05 (1H, d, J 2 Hz), 8.65 (1H, d, J 7 Hz), 9.01 (LH, t, J 6 Hz) Mass in/z: 392 5-Carbamoyi-2- (trans-4-hydroxycyclohexylamino)-N- (1 ,3- (51 mg) was obtained from 2- (trans-4-hydroxycyclohexyiamino)-N- (1 WO 99/54284 PCT/JP99/02028 ylmethyl)benzamide (71 mg) in a manner similar to Example 49(2).

NMR (DMSO-d 6 1.13-1.40 (4H, 1.75-1.87 (2H, m) ,1.89-2.00 (2H, 3.3-3.53 (2H, 4.33 (2H, d, J 6 Hz), 4.59 (1H, d, J 4 Hz), 5.98 (2H, 6.74 (1H, d, J 9 Hz), 6.77-6.90 (3H, 7.04 (1H, br), 7.58 (1H, br), 7.77 (1H, dd, J= 2, 9 Hz), 8.13 (1H, d, J= 2 Hz), 8.24 (1H, d, J= 8 Hz), 8.84 (1H, t, J 6 Hz) Mass m/z 410 Preparation 51 To a solution of 2-fluoro-5-nitrobenzoic acid (235 mg) in pyridine mL) was added trans-4-aminocyclohexanol (292 mg), and the mixture was stirred for 3 hours at 80 After evaporation of the solvent, the residue was dissolved in water and neutralized with 1Nhydrochloric acid (1.9 mL). The resulting precipitates were collected by filtration and washed successively with water and methanol to give 2acid (279 mg) as a solid substance.

NMR (DMSO-d 6 1.21-1.46 (4H, 1.7-1.90 (2H, 1.90-2.08 (2H, 3.3-3.65 (2H, 4.67 (1H, br), 6.98 (1H, d, J=8Hz) 8.14 (1H, dd, J=2, 8Hz), 8.66 (1H, d, J=2Hz), 8.74 (1H, d, J=7Hz).

Example 51 To a solution of 2-(trans-4-hydroxycyclohexylamino)-5nitrobenzoic acid (125 mg) in dimethylformamide (2 mL) were added 1hydroxybenzotriazole (96.4 mg), benzylamine (0.063 mL) and 1-[3- (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (137 mg).

The mixture was stirred for 3 hours at 20 The resulting mixture was diluted with ethyl acetate and washed successively with diluted hydrochloric acid, aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The resulting residue was triturated with methanol to give N-benzyl-2- (150 mg) as a solid substance.

mp 233-234 °C WO 99/54284 PCT/JP99/02028 NMR (DMSO-d 6 1.17-1.46 (4H, min), 1.72-1.87 (2H, 1.92-2.04 (2H, 3.4-3.6 (21H1, min), 4.42 (2H, d, J=7Hz), 4.62 (1H, d, J=6Hz), 6.90 (1H, d, J=8Hz), 7.22-7.39 (5H, 8.13 (1H, dd, J=2, 8Hz), 8.63(1H, d, J=2Hz), 9.10 (1H, d, J=7Hz), 9.41 (1H, t, J=6Hz).

Example 52(1 2-(trans-4-Hydroxycyclohexylamino)-5-nitro-N-(1,3- (173 mg) was obtained as a solid substance from 2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (125 mg) and (1,3-benzodioxol-5-ylmethyl)amine (0.072 mL) in a manner similar to Preparation 1.

mp 205-206 C NMR (DMSO-d 6 6) :1.20-1.45 (4H, min), 1.75-1.87 (2H, 1.92-2.02 (2H, 3.4-3.6 (2H, min), 4.34 (2H, d, J=7Hz), 4.62 (1H, d, J=6Hz), 5.99 (2H, 6.77-6.93 (4H, 8.11 (1H, dd, J=2, 8Hz), 8.60 (1H, d, J=2Hz), 9.08 (1H, d, J=7Hz), 9.33 (1H, t, J=6Hz).

Example 522 To a solution of 2-(trans-4-hydroxycyclohexylaino)-5-nitro-N- (1,3-benzodioxol-5-ylmethyl)benzamide (100 mg), benzoic acid (32.5 mg) and diethyl azodicarboxylate (46.3 mg) in anhydrous tetrahydrofuran (2 mL) was added triphenylphosphine (69.8 mg). The mixture was stirred for 4 hours at ambient temperature. The mixture was partitioned between an aqueous saturated sodium bicarbonate solution and ethyl acetate. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (5:1 to The obtained product was triturated with diisopropyl ether to give 2-[cis-4- (benzoyloxy)cyclohexylamino]-5-nitro-N-(1,3-benzodioxol-5ylmethyl)benzamide as yellow powders (68.5 mg).

NMR (CDC1 3 1.78-2.17 (8H, 3.60 (1H, br), 4 52 (2H, d, J=7Hz), 5.27 (1H, br), 5 96 (2H, 6.48 (1H, br), 6.71 (1H, d, J=8Hz), 6.78-6.87 (3H, 7.46 (2H, 7.58 (1H, 8.07 (2H, d, J=8Hz), 8.17 (1H, dd, J=4, WO 99/54284 WO 9954284PCT/JP99/02028 8Hz), 8.33 (1H, d, J=4Hz), 9.05 (1H, br) Mass m/z 5 16 Eaple A mixture of 2-(cis-4-benzoyloxycyclohexylamino) (1 ,3-benzodioxol-5-ylmethyl)benzainide (64.0 mg), methanol (5 mL), tetrahydrofuran (5 mL) and iN-sodium hydroxide solution (1 mL) was stirred for 2 hours at 60 After evaporation of the organic solvent, the aqueous layer was diluted with water and extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 2- (cis-4-hydroxycyclohexylamino) -5-nitro-N-( 1,3as yellow powders (50.5 mg).

NMR (CDCl 3 1.70-1.95 (8H, br), 3.58 (lH, br), 3.93 (1H, br), 4.51 (2H, d, J=7Hz), 5.97 (2H, 6.43 (lH, br), 6.67 (lH, d, J=8Hz), 6.78-6.87 (3H, in), 8.14 (1H, dd, J=4, 8Hz), 8.30 (1H, d, J=4Hz), 9.03 (1H, br) Mass m/z: 412 iExmle 53 2- (trans-4-Hydroxycyclohexylamino) -5-nitro-N- (2pyrazinylmethyl)benzaxnide (129 mg) was obtained as yellow powders from 2- (trans-4-hydroxycyclohexylanmino) -5-nitrobenzoic acid (150 mg) and 2-pyrazinylmethylamine (70.1 mg) in a manner similar to Example 51.

NMR (DMSO-d 6 1.13-1.40 (4H, br), 1.70-1.88 (2H, br), 1.89-2.02 (2H, br), 3.40-3.60 (2H, br), 4.53-4.68 (3H, br), 6.92 (1H, d, J= 8 Hz), 8.12 (1H, dd, J= 4, 8 Hz), 8.55 (1H, d, J= 4 Hz), 8.58-8.70 (2H, in), 8.98 d, J= 8 Hz), 9.50 (1H, br).

Exmple 4 2- (cis-4-Hydroxycyclohexylamino)- 5-nitro-N- (3,4,5trimethoxybenzyl)benzamide (106 mg) was obtained as yellow powders from 2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (80.0 mg) WO 99/54284 WO 9954284PCT/JP99/02028 and 3,4,5-trimethoxybenzylamifle (67.6 mg) in a manner similar to Example 5 1.

NMR (DMSO-d 6 1.46-1.75 (8H, br), 3.63 (3H, 3.61-3.72 (2H, br), 3.76 (6H, 4.39 (2H, d, J= 7 Hz), 4.54 (1H, d, J= 4 Hz), 6.67 (2H, 6.89 (1H, d, J=8Hz),8.12(1 H,dd, J=4, 8Hz), 8.62(1 H,d, J=4Hz), 9.22(1 H, br), 9.33 (1H, br).

Preparation To a suspension of 2-fluoro-5-nitrobenzoic acid (313 mg) in dichioromethane (4 mL) were added thionyl chloride 17 mL) and dimethylformamide (0.05 mL), and the mixture was heated for 36 hours under reflux. After evaporation of the solvent, the residue was dissolved in dichloromethane (4 mL). To this solution were added benzylamine 19 mL) and triethylamine (0.47 mL), and the mixture was stirred for 30 minutes at 0 TC. After evaporation of the solvent, the residue was dissolved in ethyl acetate and washed successively with diluted hydrochloric acid, an aqueous sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The resulting residue was triturated with diisopropyl ether to give N-benzyl- 2-flu oro- 5-nitrobenzamide (436 mg) as a solid substance.

NMR (DMSO-d 6 4.50 (2H, d, J=6Hz), 7.22-7.40 (5H, in), 7.64 (1H, t, J=8Hz), 8.38-8.47 (2H, in), 9.19(1H, t, J=6Hz).

N-Benzyl-2- [2-hydroxy-1- (hydroxymethyl) ethylamino] nitrobenzamide (54.5 mng) was obtained from nitrobenzamide (100 mng) and 2-amino- 1,3-propanediol (59.8 mng) in a manner similar to Example 1(1).

mp: 171-173 *C NMR (DMSO-d 6 3.45-3.5 (5H, in), 4.43 (2H, d, J=7Hz), 4.91 (2H, t, J=6Hz), 6.92 (1H, d, J=8Hz), 7.2-7.4 (5N, in), 8.13 dd, J=2, 8Hz), 8.62 (1H, d, J=2Hz), 9.28 (1H, d, J=7Nz), 9.36 (1H, t, J=6Hz).

Exampe WO 99/54284 PCT/JP99/02028 N-Benzyl-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide (346 mg) was obtained from N-benzyl-2-fluoro-5-nitrobenzamide (300 mg) and trans-2-aminocyclohexanol (186 mg) in a manner similar to Example 1(1).

mp: 233-234 C NMR (DMSO-d 6 1.17-1.46 (4H, 1.72-1.87 (2H, 1.92-2.04 (2H, 3.4-3.6 (2H, 4.42 (2H, d, J=7Hz), 4.62 (1H, d, J=6Hz), 6.90 (1H, d, J=8Hz), 7.22-7.39 (5H, 8.13 (1H, dd, J=2.8Hz), 8.63(1H, d, J=2Hz), 9.10 (1H, d, J=7Hz), 9.41 (1H, t, J=6Hz).

Example 57 (41 mg) was obtained from N-benzyl-2-fluoro-5-nitrobenzamide (100 mg) and 4aminomorpholine (40.9 mg) in a manner similar to Example 1(1).

NMR (DMSO-d 6 2.63-2.84 (4H, 3.22-3.78 (4H, 4.42 (2H, d, J 6 Hz), 7.2-7.4 (5H, 8.17 (1H, dd, J 2, 8 Hz), 8.63 (1H, d, J 2 Hz), 9.41 (1H, t, J 6 Hz), 9.55 (1H, s) Mass m/z: 355 Example 58 N-Benzyl-5-nitro-2-(piperidinoamino)benzamide (65 mg) was obtained from N-benzyl-2-fluoro-5-nitrobenzamide (111 mg) and 4aminopiperidine (44.6 mg) in a manner similar to Example 1(1).

NMR (DMSO-d 6 1.55-1.7 (6H, 2.4-3.0 (4H, 4.43 (2H, d, J 6 Hz), 7.2-7.4 (5H, 8.16 (1H, dd, J 2, 8 Hz), 8.63 (1H, d, J 2 Hz), 9.42 (1H, t, J 6 Hz), 9.56 (1H, s) Mass m/z: 353 Example 59 N-Benzyl-5-nitro-2-(2-thiazolylamino)benzamide (22.7 mg) was obtained from N-benzyl-2-fluoro-5-nitrobenzamide (100 mg) and 2aminothiazole (43.8 mg) in a manner similar to Example 1(1).

NMR (DMSO-d 6 ,5 4.54 (2H, d, J 6 Hz), 7.2-7.5 (6H, 7.48 (1H, m), 8.41 (1H, 8.73 (1H, d, J 9 Hz), 8.79 (1H, d, J 2 Hz), 9.79 (1H, t, J WO 99/54284 PCT/JP99/02028 6 Hz) Mass m/z 353 (M-1l).

Example N-Benzyl-2-(trans-2-hydroxycyclopentylamino)-5nitrobenzamide (215 mg) was obtained from nitrobenzamide (181 mg) and trans-2-aminocyclopentanol (100 mg) in a manner similar to Example 1(1).

NMR (CDC13, 1.54-1.96 (5H, 2.00-2.12 (1H, 2.25-2.37 (1H, m), 3.78 (1H, 4.16 (1H, 4.58 (2H, d, J= 7 Hz), 6.60 (1H, br), 6.86 (1H, d, J= 8 Hz), 7.28-7.40 (5H, 8.15 (1H, dd, J= 4, 8 Hz), 8.32 (1H, d, J= 4 Hz), 8.85 (1H, br) Mass m/z 354(M Preparation 61(1) To a solution of 1,3-cyclopentanediol (500 mg) in pyridine mL) was added benzoyl chloride (688 mg), and the mixture was stirred for 18 hours at ambient temperature. After evaporation of the solvent, the residue was partitioned between ethyl acetate and water. The separated organic layer was washed with IN-hydrochloric acid, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (3:1 to 1:1) to give 3hydroxycyclopentyl benzoate as a colorless oil (630 mg).

NMR (CDCl 3 1.63-1.78 (1H, 1.80-2.00 (1H, br), 2.04-2.20 (3H, m), 2.22-2.40 (1H, 4.40 and 4.56 (1H, 5.40 and 5.54 (1H, br), 7.42 (2H, 7.53 (1H, 8.00 (2H, d, J= 8 Hz).

Preparation 61(2) To a solution of 3-hydroxycyclopentyl benzoate (630 mg) in anhydrous tetrahydrofuran (15 mL) were added diphenylphosphoryl azide (925 mg), diethyl azodicarboxylate (585 mg) and triphenylphosphine (881 mg). After stirring for 2 hours at ambient temperature, the mixture was partitioned between ethyl acetate and WO 99/54284 WO 9954284PCT/JP99/02028 water. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel columrn chromatography eluting with a mixture of hexane and ethyl acetate (10: 1) to give 3-azidocyclopentyl benzoate as pale yellow oil (531 mg).

NMR (CDC1 3 1.74-2.46 (6H, br), 4.12-4.28 (1H, br), 5.28-5.54 (1H, br), 7.37-7.50 (2H, br), 7.5 1-7.62 (1H, br), 7.94-8.10 (2H, in).

Preparation 61(3) A mixture of 3-azidocyclopentyl. benzoate (411 mg) and palladium on activated carbon (41.1 mg) in methanol (15 mL) was stirred under hydrogen atmosphere (4 atm) for 2 hours at ambient temperature.

After removal of the catalyst, the filtrate was evaporated in vacuo to give 3-aminocyclopentyl benzoate as a pale yellow oil (354 mg).

NMR (0D01 3 1.40-2.20 (5H, br), 2.41 (1H, in), 3.43 (1H, in), 5.38 (1H, br), 7.38-7.65 (3H, br), 8.03 (2H, d, J= 8 Hz).

Exampkle 1 2- (158 mng) was obtained from N-benzyl-2-fluoro-5-nitrobenzamide (100 mg) and 3-aininocyclopentyl benzoate (112 mng) in a manner similar to Example 1 NMR (CDCl 3 1.88-2.30 (SH, br), 2.57 (1H, in), 4.08 (1H, br), 4.59 (2H, d, J= 7 Hz), 5.51 (1H, br), 6.48 (1H, br), 6.68 (1H, d, J= 8 Hz), 7.20-7.48 (7H, in), 7.52 (1H, in), 8.10 d, J= 8 Hz), 8.18 dd, J= 4, 8 Hz), 8.32 (1H, d, J= 4 Hz), 9.20 (1H, br) Mass in/z: 458(M+).

Exaple 612) N-Benzyl-2- (3-hydroxycyclopentylamino) (129 mng) was obtained from 2-(3-benzoyloxyccyclopentylamino)-N- (189 ing) in a manner similar to Example 52(3).

NMR (CDCl 3 1.62 (1H, d, J= 7 Hz), 1.74-1.98 (4H, in), 2.09-2.36 (2H, in), 3.99 (1H, mn), 4.47 (iN, br), 4.60 (2H, d, J= 7 Hz), 6.47 (iN, br), 6.65 WO 99/54284 WO 9954284PCT/JP99/02028 (1K, d, J= 8 Hz), 7.28-7.40 (5H, mn), 8.16 (1K, dd, J= 4,8 Hz), 8.31 (1H, d, J= 4 Hz), 9.05 (1H, br) Mass m/z: 356(M-1.

Preparation 62 N- Chloro-4-methoxybenzyl) -2-fluoro-5-nitrobenzamide (320 mng) was obtained as yellow oil from 2-fluoro-5-nitrobenzoic acid (300 mng) and 3-chloro-4-methoxybenzyla-mine hydrochloride (405 mg) in a manner similar to Preparation 1.

NMR (DMSO-d 6 3.90 (3H, 4.60 (2H, d, J=7Hz), 6.90 (1H, d, J=8Hz), 6.88-7.00 (1K, br), 7.20-7.40 (3H, in), 8.38 (11- in), 9.00 (1H, in).

Example 62 N- Chloro-4-methoxybenzyl) [2-hydroxy- 1- (hydroxymethyl)ethylamino]-5-nitrobenzamide (85.0 mng) was obtained from N- (3-chloro-4-methoxybenzyl)-2-fluoro-5-nitrobelzalnide (105 mg) and 2amino- 1,3-propanediol (42.4 mng) in a manner similar to Example 1 NMR (DMSO-d 6 3.54 (4H, br), 3.62 (1H, br), 3.83 (3H, 4.36 (2H, d, J=7Hz), 4.92 (2H, t, J=7Hz), 6.92 (1H, d, J=8Hz), 7.11 (1H, d, J=8Hz), 7.26 (1H, dd, J=4, 8Hz), 7.38 (1H, d, J=4Hz), 8. 10 (1H, dd, J=4, 8Hz), 8.59 (1H, d, J=4Hz), 9.30 (2H, br) Mass m/z: 408 Exampk~le 3 N- (3-Chloro-4--methoxybenzyl) -2-(trans-4-hydroxycyclo- (200 mng) was obtained from N-(3-chloro- 4-methoxybenzyl) -2-fluoro- 5-nitrobenzarnide (210 mg) and trans-4ammnocyclohexanol (107 mng) in a manner similar to Example 1(1).

NMR (DMSO-d 6 1.30 (4H, br), 1.80 (2H, br), 1.95 (2H, br), 3.50 (2H, br), 3.82 (3H, 4.35 (2H, d, J=7Hz), 4.60 (1H, d, J=4Kz), 6.90 (1H, d, J=8Kz), 7.10 (1H, d, J=8Hz), 7.25 (1H, dd, J=4, 8Hz), 7.40 (1H, d, J=4Hz), 8. 10 (1H, dd, J=4, 8Hz), 8.60 (1H, d, J=4Hz), 9.04 (1H, d, J=8Hz), 9.36 (1H, br) Mass in/z: 432 WO 99/54284 PCT/JP99/02028 Example 6=(2 2-[cis-4- (Benzoyloxy)cyclohexylamino-N-(3-chloro-4- (155 mg) was obtained from N-(3chloro-4-methoxybenzyl)-2- nitrobenzamide(197 mg) in a manner similar to Example 52(2).

NMR (CDCl 3 1.80-2.20 (8H, br), 3.60 (1H, br), 3.91 (3H, 4.54 (2H, d, J=7Hz), 5.25 (1H, br), 6.53 (1H, br), 6.72 (1H, d, J=8Hz), 6.95 (1H, d, J=8Hz), 7.25 (1H, 7.39-7.50 (3H, 7.60 (1H, 8.07 (2H, d, J=8Hz), 8.18 (LH, dd, J=4, 8Hz), 8.34 (1H, d, J=4Hz), 9.02 (1H, br).

Example 633 N-(3-Chloro-4-methoxybenzyl)-2-(cis-4-hydroxy- (85.0 mg) was obtained from 2-[cis- 4-(benzoyloxy)cyclohexylamino]-N-(3-chloro-4-methoxybenzyl)-5nitrobenzamide (155 mg) in a manner similar to Example 52(3).

.NMR (DMSO-d 6 6) 1.43-1.70 (8H, br), 3.66 (2H, br), 3.83 (3K, 4.38 (2H, d, J=7Hz), 4.54 (1H, d, J=4Hz), 6.88 (1H, d, J=8Hz), 7.12 (1H, d, J=8Hz), 7.28 (1K, dd, J=4, 8Hz), 7.39 (1H, d, J=4Hz), 8. 11(1H, dd, J=4, 8Hz), 8.61 (1H, d, J=4Hz), 9.26 (1H, d, J=8Hz), 9.36 (1H, br) Mass m/z: 432 Preparation 64 N-(3 ,4-Dimethoxybenzyl) -2-fluoro-5-nitrobenzanide (14.2 g) was obtained from 2-fluoro-5-nitrobenzoic acid (10.0 g) and 3,4dimethoxybenzylamine (9.30 g) in a manner similar to Preparation NMR (CDCl 3 3.89 (6H, 4.63 (2H, d, J=7Hz), 6.84-6.93 (4H, m), 7.30 (1H, 8.35 (1H, 9.03 (1K, m) Mass m/z: 333 Example 6411 (R)-N-(3,4-Dimethoxybenzyl)-2-(2-hydroxy- 1-methyl- (156 mg) was obtained from N-(3,4- (150 mg) and (R)-2-amino- WO 99/54284 PCT/JP99/02028 1-propanol (50.6 mg) in a manner similar to Example 1(1).

mp 125-127 °C NMR (DMSO-d 6 6) 1.17 (3H, d, J= 7 Hz), 3.46 (2H, br), 3.72 (3H, s), 3.74 (3H, 3.75 (1H, br), 4.36 (2H, d, J= 7 Hz), 4.99 (1H, t, J= 7 Hz), 6.83-6.95 (4H, 8.09 (1H, dd, J= 4, 8 Hz), 8.57 (1H, d, J= 4 Hz), 9.09 (1H, d, J= 8 Hz), 9.28 (1H, br) Mass m/z 388 Example 64(2) To a mixture of (R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1- (5.00 4-dimethylaminopyridine (1.57 g, 12.8 mmol) and triethylamine (1.79 mL) in dichloromethane (150 mL) was added acetyl chloride (1.83 mL), and the mixture was stirred for hours at ambient temperature. The mixture was washed with 1Nhydrochloric acid, water, an aqueous saturated sodium bicarbonate solution and brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether. The obtained product was recrystallized from a mixture of ethyl acetate and hexane to give (R)-2-(2-acetoxy-1methylethylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide as yellow crystals (5.10 g).

NMR (DMSO-d 6 1.22 (3H, d, J= 7 Hz), 1.99 (3H, 3.73 (3H, 3.74 (3H, 4.00-4.12 (1H, br), 4.09 (2H, br), 4.37 (2H, d, J= 7 Hz), 6.82-6.98 (4H, 8.13 (1H, dd, J= 4, 8 Hz), 8.60 (1H, d, J= 4 Hz), 9.06 (1H, d, J= 8 Hz), 9.33 (1H, br) Mass m/z 430(M Example 64(3) To a solution of (R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1methylethylamino)-5-nitrobenzamide (200 mg) in 1,2-dichloroethane mL) were added trimethyloxonium tetrafluoroborate (91.2 mg) and 2,6di-tert-butyl-4-methylpyridine (158 mg), and the mixture was heated for 3 hours under reflux. The mixture was washed with 1N-hydrochloric acid, water, an aqueous saturated sodium bicarbonate solution and WO 99/54284 WO 9954284PCT/JP99/02028 brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (3:1 to 1: The obtained product was triturated with diisopropyl ether to give (3 ,4-dimethoxybenzyl) 2- (2-methoxy-l1-methylethylamino)- nitrobenzamide as yellow powders (145 mg).

NMR (DMSO-d 6 1.17 (3H, d, J= 7 Hz), 3.29 (3H, 3.42 (2H, br), 3.73 (3H, 3.74 (3H, 3.88-4.00 (1H, br), 4.37 (2H, d, J= 7 Hz), 6.85-6.96 (4H, in), 8.12 (1H, dd, J= 4, 8Hz), 8.59 (1H, d, J= 4 Hz), 9.09 (1H, d, J= 8 Hz), 9.29 (1H, br) Mass m/z 402(M+).

(3 ,4-Dimethoxybenzyl) [1-(hydroxymethyl)propylamino]-5-nitrobenzamide (130 mg) was obtained from N-(3,4dimethoxybenzyl) -2-fluoro- 5-nitrobenzamide (150 mng) and (S)-2-amino- 1-butanol (60.0 mng) in a manner similar to Example 1(1).

mp: 168-169 TC NMR (DMSO-d 6 0.90 (3H, t, J= 7 Hz), 1.40-1.78 (2H, in), 3.48 (2H, br), 3.57 (1H, br), 3.72 (3H, 3.74 (3H, 4.38 (2H, br), 4.92 (1H, t, J= 7 Hz), 6.83-6.95 (4H, mn), 8.08 (1H, dd, J= 4, 8 Hz), 8.57 d, J= 4 Hz), 9.09 (1H, d, J= 8 Hz), 9.29 (1H, br) Mass m/z: 402 Eape6 N- (3,4-Dimethoxybenzyl) (2-hydroxy- 1,1 -dimethyl- (156 mng) was obtained from N-(3,4dimethoxybenzyl) -2-fluoro- 5-nitrobenzamide (150 mng) and 2 -amino-2methyl-i -prop anol (120 mng) in a manner similar to Example 1(1).

mp :161-162 TC NMR (DMSO-d 6 1.33 (6H, 3.43 (2H, d, J= 7 Hz), 3.73 (3H, 3.74 (3H, 4.36 (2H, d, J= 7 Hz), 5.19 (1H, t, J= 7 Hz), 6.80-6.96 (3H, in), 7.04 (1 H, d, J= 8 Hz), 8.07 (1 H, dd, J= 4, 8 Hz), 8.51 (1 H, d, J= 4 Hz), 9.27 (2H, br) WO 99/54284 WO 9954284PCT/JP99/02028 Mass m/z: 402 N- (3,4-Dimethoxybenzyl) (trans-2-hydroxycyclopentylamino)- 5-nitrobenzamide (6.18 g) was obtained from N-(3,4-dimethoxybenzyl)- (6.00 g) and trans aminocyclopentanol (3.63 g) in a manner similar to Example 1(l).

mp: 154-155 TC NMR (DMSO-d 6 1.60-1.96 (5H, in), 2.00-2.14 (1H, in), 2.27-2.40 (1H, in), 3.78 (1H, br), 3.89 (3H, 3.90 (3H, 4.16 (1H, br), 4.53 (2H, d, J= 7 Hz), 6.50 (1H, br), 6.88 (4H, br), 8.16 (1H, dd, J= 4, 8 Hz), 8.31 (1H, d, J= 4 Hz), 8.85 (1H, br) Mass m/z: 414 Example 68 (3 ,4-Dixnethoxybenzyl) (2-hydroxy- 1 -methyl- (188 mg) was obtained from N-(3,4dimethoxybenzyl) -2-fluoro- 5-nitrobenzaniide (200 mng) and -2-amino- 1 -propanol (89.9 mng) in a manner similar to Example 1 mp: 131-132 *C NMR (DMSO-d 6 1.17 (3H, d, J= 7 Hz), 3.46 (2H, br), 3.72 (3H, s), 3.74 (3H, 3.75 (1H, br), 4.36 (2H, d, J= 7 Hz), 4.99 (1H, t, J= 7 Hz), 6.83-6.95 (4H, in), 8.09 (1H, dd, J= 4, 8 Hz), 8.57 (1H, d, J= 4 Hz), 9.09 (1H, d, J= 8 Hz), 9.28 (1H, br) Mass m/z: 388 Exmple 9 N- (3,4-Dimethoxybenzyl) -5-nitro-2- ,2trifluoroethyl)hydrazinolbenzamide (27 mng) was obtained as a yellow solid substance from N-(3,4-dimethoxybenzyl)-2-fluoro-5nitrobenzamide (200 mg) and 2,2,2-trifluoroethylhydrazine (116 mg) in a manner similar to Example 1 mp 140-142 0

C

NMR (DMSO-d 6 3.47-3.65 (2H, in), 3.73 (3H, 3.74 (3H, 4.38 (2H-, WO 99/54284 WO 9954284PCT/JP99/02028 d, J 5.5 Hz), 5.81 (1H, t, J 4 Hz), 6.85 (1H, d, J 8.5 Hz), 6.91 (1H, d, J 8.5 Hz), 6.96 (1H, 7.39 (1H, d, J 8.5 Hz), 8.18 (1H, dd, J 8.5, Hz), 8.57 (1H, d, J 1.5 Hz), 9.31 (1H, t, J 5.5 Hz), 9.84 (1H, s) Mass m/z: 427(M+-1).

Example 7 N- (3,4-Dimethoxylbenzyl)-2-{[(l1R,2S) -cis-2 ,3-dihydro-2hydroxy- 1 H-inden- 1l-yl] amino)- 5-nitrobenzamide (192 mg) was obtained as yellow powders from N-(3 dimethoxylbenzyl) -2-fluoro- nitrobenzamide (153 mg) and (1R,2S)-cis-1-amino-2-indanol (137 mg) in a manner similar to Example 1 mp. 248-250 TC NMR (DMSO-d 6 2.86 (1H, d, J=16 Hz), 3. 11 (1H, dd, J=16,5 5Hz), 3.71 (3H, 3.72 (3H, 4.30-4.44 (2H, in), 4.58 (1H, in), 5.18 (1H, mn), 5.37 (1H, d, J=5 Hz), 6.80-6.97 (3H, in), 7.07-7.34 (5H, in), 8.17 (1H, dd, 2 Hz), 8.63 (1H, d, J=2 Hz), 9.30 (1H, t, J=6 Hz), 9.55 (1H, d, J=8 Hz) Mass in/z: 462(M+).

N- (3 ,4-Diinethoxylbenzyl)-2- 1(1R, 2S)-2-hydroxy-l1-inethyl-2- (167 mg) was obtained as yellow powders from 2-fluoro-N-(3 ,4-dimethoxylbenzyl)- 5-nitrobenzamide (145 mg) and (1S,2R)-(+)-Norephedrine (97 mng) in a manner similar to Example 1 m.p. 248-250 TC NMR (DMSO-d 6 2.86 (1H, d, J=16 Hz), 3. 11 (1H, dd, J=16, 5 Hz), 3.71 (3H, 3.72 (3H, 4.30-4.44 (2H, mn), 4.58 (1H, in), 5.18 (1H, in), 5.37 (1H, d, J=5 Hz), 6.80-6.97 (3H, in), 7.07-7.34 (5H, mn), 8.17 (1H, dd, 2 Hz), 8.63 (1H, d, J=2 Hz), 9.30 (1H, t, J=6 Hz), 9.55 (1H, d, J=8 Hz) Mass in/z: 462(M+).

Examnpe2 2-1(1 S, 2R)- 1-(Carbamoyl) -2-hydroxypropylamino-N-(3 ,4- (151 mg) was obtained as yellow WO 99/54284 WO 9954284PCT/JP99/02028 crystals from N- (3 ,4-dimethoxybenzyl) -2-fluoro- 5-nitrobenzamide (200 mg) and L-threoninamide hydrocloride (139 mg) in a manner similar to Example 1 NMR (DMSO-d 6 1.13 (3H, d, J 6 Hz), 3.73 (3H, 3.75 (3H, 3.91 (1H, in), 4.06 (1H, mn), 4.50 (2H, mn), 5.23 (1H, d, J 4 Hz), 6.69 (LH, d, J 9 Hz), 6.81 (1H, brd, J 8 Hz), 6.92 (1H, d, J 8 Hz), 6.98 (1H, br), 7.26 (1H, 7.44 (1H, 8.14 (1H, dd, J 3, 9Hz), 8.59 (1H, d, J 3 Hz), 9.28 (1H, t, J 5 Hz), 9.38 (1H, d, J 5 Hz) Mass 431(M-H).

Example aWj 2- [(trans-4-Aminocyclohexyl) amino] (3 ,4-diinethoxybenzyl) nitrobenzamide (12.3 g) was obtained from N-(3,4-dimethoxybenzyl)-2fluoro- 5-nitrobenzamide (10.0 g) and trans-i ,4-diaminocyclohexane (10.2 g) in a manner similar to Example 1(1).

NMR (DMSO-d 6 1.10-1.38 (4H, br), 1.72-1.82 (2H, br), 1.94-2.05 (2H, br), 2.60 (1H, br), 3.46 (1H, br), 3.73 (3H, 3.74 (3H, 4.36 (2H, d, J= 7 Hz), 6.83-6.95 (4H, in), 8. 10 (1H, dd, J= 4, 8 Hz), 8.59 (1H, d, J= 4 Hz), 9.01 (1H, d, J= 8 Hz), 9.31 (1H, br) Mass in/z 429 Examk~le Z To a solution of 2- (trans-4-aminocyclohexyl)aminol-N-(3 ,4dimethoxybenzyl)-Snitrobenzamide (10 g) in dimethylforinaiide (60 mL) was added ethyl forinate (200 mL), and the mixture was heated for 8 hours under reflux. The mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of chloroform and methanol (20: The obtained product was recrystallized from ethanol to give N-(3,4-dimethoxybenzyl)-2-[(trans-4forinamidocyclohexyl) amino] -5-nitrobenzamide as yellow crystals (7.21 g).

NMR (DMSO-d 6 1.25-1.55 (4H, br), 1.79-1.92 (2H, br), 1.95-2. 10 (2H, WO 99/54284 WO 9954284PCT/JP99/02028 br), 3.47-3.59 (1H, br), 3.60-3.72 (1H, br), 3.73 (3H, 3.74 (3H, 4.37 (2H, di, J= 7 Hz), 6.85-6.96 (4H, mn), 7.95 (1H, 8.04 (1H, br), 8.08 (1H, dd, J= 4, 8 Hz), 8.60 (1H, d, J= 4 Hz), 9.01 (1H, d, J= 8 Hz), 9.32 (1H, br) Mass m/z: 455 Example 3aQ Methanesulfonyl chloride (54 mg) and triethylamine (48 mng) were added to a solution of 2-(trans-4-aminocyclohexylamino)-N-(3,4- (134 mng) in chloroform (2 mL). The mixture was stirred for an hour at ambient temperature.

Methanesulfonyl chloride (54 mg) and triethylamine (48 mg) were added to the reaction mixture. After stirring for an hour at ambient temperature, the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and 3.6% hydrochloric acid. The separated organic layer was washed with an saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residual crystals were suspended in hot ethanol and cooled with stirring. The resultant was collected by filtration and washed with ethanol to give N-(3,4-dimethoxybenzyl)-2ltrans-4- (methanesulfonylamino) (142 mg) as yellow crystals.

NMR (DMSO-d 6 1.25-1.50 (4H, in), 1.88-2.05 (4H, in), 2.92 (3H, s), 3.18 (1H, in), 3.34-3.54 (1H, in), 3.73(3H, 3.74 (3H, 4.37 (2H, d, J 6 Hz), 6.84 (1lH, dd, J 2, 8 Hz), 6.88-6.97 (3H, mn), 7.09 (1 H, d, J =7 Hz), 8. 10 (1H, dci, J 2, 8Hz), 8.60 (1H, d, J =2 Hz), 9.00 (1H, dci, J 7 Hz), 9.32 (lH, t, J 6 Hz) Mass (ESI-) :505(M-H).

2- (trans -4-Acetamidocyclohexylamino) (3,4- (110 mng) was obtained as yellow powders from 2- (trans-4-aminocyclohexylamino) (3,4- (100 mng) and acetic acid (15.4 mng) in a manner similar to Example24(3).

WO 99/54284 PCT/JP99/02028 NMR (DMSO-d 6 1.22-1.45 (4H, br), 1.79 (3H, 1.75-1.90 (2H, br), 1.96-2.09 (2H, br), 3.44-3.63 (2H, br), 3.73 (3H, 3.74 (3H, 4.36 (2H, d, J= 7 Hz), 6.82-6.95 (4H, 7.78 (1H, d, J= 8 Hz), 8.10 (1H, dd, J= 4, 8 Hz), 8.60 (1H, d, J= 4 Hz), 9.02 (1H, d, J= 8 Hz), 9.32 (1H, br) Mass m/z: 469(M+).

Example 73(5j To a solution of 2-(trans4-aminocyclohexylamino)-N-(3,4- (100 mg) in dichloromethane (3 mL) was added propyl isocyanate (21.8 mg), and the mixture was stirred for 2 hours at ambient temperature. After evaporation of the solvent, the residue was triturated with ethyl acetate to give N-(3,4dimethoxybenzyl)-5-nitro-2-[trans-4-(3propylureido)cyclohexylamino]benzamide as yellow powders (118 mg).

NMR (DMSO-d 6 0.82 (3H, t, J= 7 Hz), 1.20-1.45 (6H, 1.79-1.90 (2H, br), 1.96-2.10 (2H, br), 2.92 (2H, q, J= 7 Hz), 3.40 (1H, br), 3.51 (1H, br), 3.73 (3H, 3.74 (3H, 4.37 (2H, d, J= 7 Hz), 5.70 (2H, br), 6.82- 6.96 (4H, 8.11 (1H, dd, J= 4, 8 Hz), 8.59 (1H, d, J= 4 Hz), 9.02 (1H, d, J= 8 Hz), 9.31 (1H, br) Mass m/z: 512(M+).

Example 73(6) N-(3,4-Dimethoxybenzyl)-5-nitro-2-[trarts-4-(3phenylureido)cyclohexylamino]benzamide (158 mg) was obtained as yellow powders from 2-(trans-4-aminocyclohexylamino)-N-(3,4- (150 mg) and phenyl isocyanate (45.9 mg) in a manner similar to Example 73(5).

NMR (DMSO-d 6 1.28-1.47 (4H, br), 1.87-1.96 (2H, br), 1.96-2.10 (2H, br), 3.45-3.63 (2H, br), 3.73 (3H, 3.75 (3H, 4.37 (2H, d, J= 7 Hz), 6.12 (1H, d, J= 8 Hz), 6.83-6.98 (5H, 7.21 (2H, 7.37 (2H, d, J= 8 Hz), 8.12 (1H, dd, J= 4, 8 Hz), 8.31 (1H, 8.61 (1H, d, J= 4 Hz), 9.05 (1H, d, J= 8 Hz), 9.33 (1H, br) Mass m/z: 546(M+).

WO 99/54284 WO 9954284PCT/JP99/02028 Exam~ple7(7 To a mixture of 2-(trans-4-aminocyclohexylamino)-N-(3,4- (300 mg) and 1 ,3-bis(tertbutoxycarbonyl)-2-methyl-2-thiopseudourea (203 mg) in ethanol mL) was added mercury(II) oxide (152 mg). The mixture was stirred for 2 hours at ambient temperature. The resultant precipitates were removed by filtration and the filtrate was evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with 2% methanol in chloroform. The obtained product was triturated with diisopropyl. ether to give 2-{trans-4-[2,3-bis(tertbutoxycarbonyl) gua-nidino] cyclohexylammno}-N- (3 ,4-dimethoxybenzyl) as yellow powders (432 mg).

NMR (CDCl 3 1.25-1.45 (4H, br), 1.50 (9H, 1.52 (9H, 1.95-2. (4H, br), 3.28-3.40 (1H, br), 3.89 (3H, 3.91 (3H, 3.85-4.00 (1H, br), 4.54 (2K, d, J= 7 Hz), 6.58 (1H, d, J= 8 Hz), 6.85-6.98 (4H, in), 8.14 (1H, dd, J= 4, 8 Hz), 8.28 (1H, d, J= 8 Hz), 8.42 (1H, d, J= 4 Hz), 8.89 (1H, d, J= 8 Hz) Mass m/z: 671(M+).

iExamnple7,3a W To a solution of 2-{trans-4-[2,3-bis(tertbutoxycarbonyl)guanidinolcyclohexylamino-N-(3 ,4-dimethoxybenzyl) (200 mg) in ethyl acetate (4 mL) was added 4Nhydrochloric acid in ethyl acetate (8 mL). The mixture was stirred for hours at ambient temperature. After evaporation of the solvent, the residue was triturated with ethyl acetate to give N-(3,4dimethoxybenzyl) -2-(trans-4-guanidinocyclohexylamino) nitrobenzaxnide hydrochloride as yellow powders (145 mg).

NMR (DMSO-d 6 1.22-1.53 (4K, br), 1.86-1.97 (2K, br), 2.00-2.11 (2H, br), 3.22-3.62 (2K, br), 3.73 (3H, 3.74 (3H, 4.37 (2K, d, J= 7 Hz), 6.84-6.96 (4H, in), 7.72 (1H, d, J= 8 Hz), 8.12 (1K, dd, J= 4, 8 Hz), 8.61 (1K, d, J= 4 Hz), 9.02 (1K, d, J= 8 Hz), 9.35 (1H, br) Mass m/z: 471(M+).

WO 99/54284 PCT/JP99/02028 Example 73(9 A mixture of 2-fluoro-N-(3,4-dimethoxybenzyl)-5nitrobenzamide (200 mg) and trans-4-formamidocyclohexylamine (170 mg) in pyridine (2 mL) was stirred for 4 hours at 50*C. The mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with 1N HC1 and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with 5 methanol in chloroform. The obtained product was recrystallized from acetone (2 mL) to give N-(3,4dimethoxybenzyl)-2- nitrobenzamide as yellow crystals (164 mg).

NMR (DMSO-d 6 ,6):1.25-1.55 (4H, br), 1.79-1.92 (2H, br), 1.95-2.10 (2H, br), 3.47-3.59 (1H, br), 3.60-3.72 (1H, br), 3.73 (3H, 3.74 (3H, 4.37 (2H, d, J= 7 Hz), 6.85-6.96 (4H, 7.95 (1H, 8.04 (1H, br), 8.08 (1H, dd, J= 4, 8 Hz), 8.60 (1H, d, J= 4 Hz), 9.01 (1H, d, J= 8 Hz), 9.32 (1H, br) Mass m/z: 455 Example 741W 2-[1-(tert-Butoxycarbonyl)piperidin-4-ylamino-N-(3,4dimethoxybenzyl)-5-nitrobenzamide (1.06 mg) was obtained as yellow powders from N-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (1.00 g) and tert-butyl 4-amino- 1-piperidinecarboxylate (899 mg) in a manner similar to Example 1(1).

NMR (CDC1 3 C5): 1.48 (9H, 1.52-1.65 (2H, br), 1.95-2.10 (2H, br), 3.03-3.17 (2H, br), 3.64 (1H, br), 3.89 (3H, 3.90 (3H, 3.94-4.06 (2H, br), 4.52 (2H, d, J= 7 Hz), 6.49 (1H, br), 6.69 (1H, d, J= 8 Hz), 6.84-6.95 (3H, 8.15 (1H, dd, J= 4, 8 Hz), 8.33 (1H, d, J= 4 Hz), 8.98 (1H, br) Mass m/z: 513(M+).

Example 74(2 N-(3,4-Dimethoxybenzyl)-5-nitro-2-(4piperidinylamino)benzamide (713 mg) was obtained as yellow powders from 2-[1-(tert-butoxycarbonyl)piperidin-4-ylamino-N-(3,4- (950 mg) in a manner similar to WO 99/54284 PCT/JP99/02028 Example 24(2).

NMR (DMSO-d 6 1.20-1.40 (2H, br), 1.83-1.96 (2H, br), 2.55-2.65 (2H, br), 2.85-2.98 (2H, br), 3.56-3.68 (1H, br), 3.73 (3H, 3.74 (3H, 4.37 (2H, d, J= 7 Hz), 6.85-6.96 (4H, 8.11 (1H, dd, J= 4, 8 Hz), 8.60 (1H, d, J= 4 Hz), 9.10 (1H, d, J= 8 Hz), 9.32 (1H, br) Mass m/z: 415(M+).

Example 74(3 2-[1-[1,3-Bis(tert-butoxycarbonyl)amidino]piperidin-4-ylamino]- N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (299 mg) was obtained as yellow powders from N-(3,4-dimethoxybenzyl)-5-nitro-2-(4piperidinylamino)benzamide (200 mg) in a manner similar to Example 73(7).

NMR (CDC1 3 1.49 (9H, 1.51 (9H, 1.70-1.85 (2H, br), 2.05-2.18 (2H, br), 3.19-3.34 (2H, br), 3.67-3.78 (1H, br), 3.89 (3H, 3.90 (3H, s), 3.95-4.15 (2H, br), 4.53 (2H, d, J= 7 Hz), 6.59 (1H, br), 6.69 (1H, d, J= 8 Hz), 6.84-6.91 (3H, 8.16 (1H, dd, J= 4, 8 Hz), 8.34 (1H, d, J= 4 Hz), 9.01 (1H, d, J= 8 Hz) Mass m/z: 655(M+).

Example 7(4) 2-(1 -Amidinopiperidin-4-ylamino)-N-(3,4-dimethoxybenzyl)-5nitrobenzamide hydrochloride (150 mg) was obtained as yellow powders from 2-[i-[1,3-bis(tert-butoxycarbonyl)amidino]piperidin-4-ylamino-N- (3,4-dimethoxybenzyl)-5-nitrobenzamide (200 mg) in a manner similar to Example 73(8).

NMR (DMSO-d 6 1.40-1.58 (2H, br), 2.00-2.11 (2H, br), 3.17-3.30 (2H, br), 3.73 (3H, 3.74 (3H, 3.77-3.97 (3H, br), 4.37 (2H, d, J= 7 Hz), 6.82-7.04 (4H, 7.52 (4H, br), 8.14 (1H, dd, J= 4, 8 Hz), 8.63 (1H, d, J= 4 Hz), 9.09 (1H, d, J= 8 Hz), 9.38 (1H, br) Mass m/z: 457(M+).

Example 75(1) N-(3,4-Dimethoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)- WO 99/54284 PCT/JP99/02028 (11.8 g) was obtained from N-(3,4-dimethoxybenzyl)- (10.0 g) and trans-4-aminocyclohexanol (6.89 g) in a manner similar to Example 1(1).

NMR (DMSO-d 6 5):1.23-1.41 (4H, 1.78-1.88 (2H, br), 1.91-2.01 (2H, br), 3.50 (2H, br), 3.73 (3H, 3.74 (3H, 4.37 (2H, d, J=7Hz), 4.62 (1H, d, J=4Hz), 6.82-6.96 (4H, 8. 11 (1H, 8.60 (1H, 9.04 (1H, br), 9.32 (1K, br) Mass i/z: 428 Examle 75(2~ 2-[cis-4-(Benzoyloxy)cyclohexylaino]-N- (3,4-dimethoxybenzyl)- (9.00 g) was obtained from N-(3,4-diiethoxybenzyl)- 2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide (10.0g) in a manner similar to Example 52(2).

NMR (CDCl 3 1.78-2.15 (8H, br), 3.61 (1H, br), 3.88 (3H, 3.89 (3H, 4.56 (2H, d, J=7Hz), 5.26 (1H, br), 6.48 (1H, br), 6.71 (1H, d, J=8Hz), 6.85-6.93 (3H, 7.42-7.50 (2H, 7.58 (1H, 8.06 (2H, d, J=8Hz), 8.18 (1H, dd, J=4, 8Hz), 8.33 (1H, d, J=4Hz), 9.05 (1H, br) Mass i/z: 532 Example 750 N-(3 ,4-Diiethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5nitrobenzamide (4.56 g) was obtained from 2-[cis-4- (benzoyloxy)cyclohexylamino]-N-(3 nitrobenzamide (9.00 g) and in a manner similar to Example 52(3).

NMR (DMSO-d 6 6) 1.45-1.72 (8H, br), 3.66 (2H, br), 3.73 (3H, 3.75 (3H, 4.38 (2H, d, J=7Hz), 4.55 (1H, d, J=4Hz), 6.83-6.97 (4H, 8.12 (1H, dd, J=4, 8Hz), 8.61 (1H, d, J=4Hz), 9.26 (1H, br), 9.32 (1H, br) Mass i/z: 428 Example 75t44 To a suspension of N-(3,4-diiethoxybenzyl)-2-(cis-4hydroxycyclohexylanino)- 5-nitrobenzanide (1.0 g) in dichioromethane mL) were added triethylamine (0.49 iL) and 4- WO 99/54284 PCT/JP99/02028 dimethylaminopyridine (284 mg), and then acetyl chloride (0.20 mL) at The reaction mixture was stirred for 2 hours at 20 °C and then, acetyl chloride (0.05 mL) was added. After stirring for an hour at 20 "C, the reaction mixture was partitioned between chloroform and 1Nhydrochloric acid. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of ethyl acetate and hexane The residual solid was recrystallized from ethyl acetate to give 2-[cis-4- (acetoxy)cyclohexylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (429 mg) as yellow crystals.

mp 147-148 °C NMR (DMSO-d 6 1.55-1.90 (8H, br), 2.03 (3H, 3.73 (3H, 3.74 (1H, 3.75 (3H, 4.39 (2H, d, J= 8 Hz), 4.82 (1H, 6.85 (1H, dd, J= 2, 8 Hz), 6.92 (1H, d, J= 8 Hz), 6.93 (1H, d, J= 10 Hz), 6.97 (1H, d, J= 2 Hz), 8.12 (1H, dd, J= 3, 10 Hz), 8.63 (1H, d, J= 3 Hz), 9.26 (1H, d, J= Hz), 9.36 (1H, t, J= 6 Hz).

Example 76(1) N-(3,4-Dimethoxylbenzyl)-2-[(R)- 1 -methoxycarbonyl-3- (245 mg) was obtained from 2-fluoro-N-(3,4-dimethoxylbenzyl)- 5-nitrobenzamide (210 mg) and methionine methyl ester (205 mg) in a manner similar to Example 1(1).

NMR (DMSO-d 6 2.00-2.22 (2H, 2.03 (3H, 2.44-2.60 (2H, m), 3.70 (3H, 3.73 (3H, 3.75 (3H, 4.40 (2H, d, J=5 Hz), 4.61 (1H, dt, J=8, 6 Hz), 6.79-7.00 (4H, 8.15 (1H, dd, J=9, 3 Hz), 8.63 (1H, d, J=3 Hz), 9.32-9.43 (2H, m) Mass m/z 476(M Example 76(2) To a solution of N-(3,4-dimethoxylbenzyl)-2-[(R)-1- (175 mg) in anhydrous tetrahydrofuran (3 mL) were added lithium chloride (31mg), and then sodium borohydride (28mg) in ethanol (3mL) at WO 99/54284 WO 9954284PCT/JP99/02028 ambient temperature. The mixture was stirred for one day. After evaporation of the solvent, the residue was partitioned between ethyl acetate and 10% citric acid aqueous solution. The separated organic layer was washed with water and brine and dried over magnesium sulfate. The residual solid was recrystallized from ethyl acetate-hexane to give N- (3 ,4-dimethoxylbenzyl) -1-hydroxyrnethyl-3- (methylthio) propylamino] -5-nitrobenzaxnide (122 mg).

m.p. 150-152*C NMR (DMSO-d 6 1.73 (1H, in), 1.92 (1H, in), 2.03 (3H, 2.40-2.62 (2H, mn), 3.50 (2H, in), 3.73 (3H, 3.74 (3H, 3.78 (1H, in), 4.35 (1H, dd, J=15, 6 Hz), 4.40 (1H, dd, J=15, 6 Hz), 4.99 (1H, t, J=.5 Hz), 6.80-6.99 (4H, in), 8.12 (1H, dd, J=9, 3 Hz), 8.58 (1H, d, J=3 Hz), 8.58 (1H, d, J=3 Hz), 9. 10 (1 H, d, J=8 Hz), 9.30 (1 H, dd, J=6, 6 Hz) Mass m/z: 448(M+).

Preparation 77(l) cis tert-Butoxycarbonylamino) cyclohexylazide (266 mng) was obtained as an oil from trans-4-(N-tertbutoxycarbonylamino)cyclohexanol (200 mg) in a manner similar to Preparation 6 1(2).

NMR (CDCl 3 1.44 (9H, 1.4-1.85 (8H, in), 3.51 (1H, br), 3.71 (1H, br), 4.48 (1H, br).

Preparation 77(2) cis-4-(N-tert-Butoxycarbonylamino)cyclohexylamine (77 mng) was obtained as an oil from cis-4-(N-tertbutoxycarbonylanino)cyclohexylazide (252 ing) in a manner similar to Preparation 61(3).

NMR (CDCl 3 1.44 (9H, 1.5-1.8 (4H, in), 1.8-2.2 (4H, in), 2.91 (1H, br), 3.65 (1H, br), 4.66 (1H, br) Mass (ESI+) :215(M+H).

ExamplW 1 2-f cis-4- tert-Butoxycarbonylamino)cyclohexylaninol-N- (3,4- WO 99/54284 PCT/JP99/02028 (282 mg) was obtained as amorphous powders from N-(3,4-dimethoxybenzyl)-2-fluoro-5nitrobenzamide (200 mg) and cis-4-(N-tertbutoxycarbonylamino)cyclohexylamine (256 mg) in a manner similar to Example 1(1).

NMR (CDCl 3 1.45 (9H, 1.51-1.70 (2H, 1.75-1.94 (6H, m), 3.55-3.80 (2H, 3.89 (3H, 3.90 (3H, 4.54 (2H, d, J 5 Hz), 4.59 (1H, 6.49 (1H, 6.66 (1H, d, J 9 Hz), 6.82-6.95 (3H, 8.15 (1H, d, J 9 Hz), 8.33 (1H, d, J 2 Hz), 9.17 (1H, d, J 7 Hz) Mass (ESI-) 527(M-H).

Example 77(2) 4N-Hydrogen chloride solution in ethyl acetate (2 mL) was added to a solution of 2-[cis-4-(N-tert-butoxycarbonylamino)cyclohexylamino]- N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (270 mg) in ethyl acetate (1 mL). The mixture was stirred for 2 hours at ambient temperature. The reaction mixture was concentrated in vacuo. To the residue were added an aqueous saturated sodium bicarbonate solution and ethyl acetate.

The appeared precipitates were collected by filtration and washed with ethyl acetate and water successively to give 2-(cis-4aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (77 mg) as yellow powders. The filtrate was separated, and the aqueous layer was extracted with chloroform. The combined organic layer was dried over magnesium sulfate and concentrated in vacuo to give a second crop (137.8 mg).

NMR (DMSO-d 6 1.50-1.90 (8H, 3.16 (1H, 3.73 (3H, 3.75 (3H, 3.80 (1H, 4.40 (2H, d, J 5 Hz), 6.83-6.99 (4H, 8.14 (1H, dd, J 2, 9Hz), 8.13 (1H, dd, J 2, 9 Hz), 8.66 (1H, d, J 3 Hz), 9.35- 9.44 (2H, m) Mass (ESI+) 429(M+H), (ESI-) 427(M-H).

Example 77(3) 2-(cis-4-Formamidocyclohexylamino)-N-(3,4-dimethoxybenzyl)- 5-nitrobenzamide(129 mg) was obtained as yellow crystals from 2-(cis- WO 99/54284 PCT/JP99/02028 4-aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (180 mg) in a manner similar to Example73(2).

NMR (DMSO-d 6 1.42-1.60 (2H, 1.60-1.83 (6H, 3.65-3.78 (1H, 3.73 (3H, 3.85 (1H, 4.39 (2H, d, J 6 Hz), 6.82-6.98 (4H, m), 7.95 and 8.03 (1H, 8.12 (1H, dd, J 2, 9 Hz), 8.20 (1H, d, J 7 Hz), 8.63 (1H, d, J 2 Hz), 9.27-9.41 (2H, m) Mass (ESI+) 457(M+H), (ESI-) 455(M-H).

Preparation 78(1) lodomethane (554 mg) was added to a suspension of (benzyloxycarbonylamino)- 3-(tert-butoxycarbonylamino)propionoic acid (1.1 g) and potassium carbonate (539 mg) in N,N-dimethylformamide (7 mL). The mixture was stirred for 2 hours at ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give methyl (S)-2-(benzyloxycarbonylamino)- 3-(tertbutoxycarbonylamino)propionate (1.2 g) as an oil.

NMR (CDC1 3 1.42 (9H, 3.45-3.60 (2H, 3.76 (3H, 4.41 (1H, 4.83 (1H, 5.12 (2H, 5.79 (1H, 7.30-7.40 (5H, m).

Preparation 78(2) Sodium borohydride (251 mg) was added to a solution of methyl (S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propionate (1.17 g) in methanol (10mL) at 0 The mixture was stirred for an hour at the same temperature and then for an hour at ambient temperature. After addition of 3.6% hydrochloric acid, the mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and an aqueous saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residual crystals were suspended in hot diisopropyl ether and cooled to ambient temperature with stirring. The residual crystals were collected by filtration and washed with diisopropyl ether to give (S)-2-(benzyloxycarbonylamino)-3-(tertbutoxycarbonylamino)propanol (945 mg) as white crystals.

WO 99/54284 WO 9954284PCT/JP99/02028 NMR (CDC13,8): 1.44 (9H, 3.18-3.40 (2H4, in), 3.46-3.75 in), 4.90 (1H, in), 5.09 (2H, 5.35 (1H, d, J Hz), 7.30-7.40 (5H, m) Mass: (ESI-) 323 Preparation 78(3) Palladium on activated carbon (10 ing) was added to a solution of (benzyloxycarbonylamino)-3- (tertbutoxycarbonylamino)propanol (920 mng) in methanol (10 mL) and dioxane (1 mL). The mixture was stirred under hydrogen atmosphere (3.5 atm) for one and a half days at ambient temperature. The catalyst was removed by filtration and the filtrate was concentrated in vacuo.

The residue was dissolved in ethyl acetate, dried over magnesium sulfate, and concentrated in vacuo to give (S)-2-amino-3-(tertbutoxycarbonylamino)propanol (571lmg) as a white solid substance.

NMR (CDCl 3 1.45(9H, 2.90(1H, mn), 3.18(2H, mn), 3.49(2H, in), 4.90(1H, br) Mass: (ESI+) 191(M+H), (ESI-) 189(M-H).

1-f tert-(Butoxycarbonyl) aminomethyl]-2hydroxyethylamino}-N-(3 ,4-dimethoxybenzyl) -5-nitrobenzarnide (719 mg) was obtained as yellow crystals from N-(3,4-diinethoxybenzyl)-2- (930 mg) and (S)-2-amiino-3-(tertbutoxycarbonylamino)propanol (556 ing) in a manner similar to Example 1 NMR (DMSO-d 6 1.36 (9H, 3.08 (2H, in), 3.53 (1H, in), 3.73 (3H, s), 3.74 (3H, 4.36 (2H, d, J 6 Hz), 4.99 (1H, t, J 6 Hz), 6.84 (1H, brd, J 8 Hz), 6.90-7.06 (4H, in), 8.09(1H, dd, J 2, 9 Hz), 8.58 (1H, d, J 2 Hz), 9.20(1H, d, J 9 Hz), 9.26 (1H, t, J 6 Hz) Mass: (ESI-) 503 Examplek1%Z2 1-Itert-(Butoxycarbonyl) aminoinethyl] -2hydroxyethylamino}-N- (3 ,4-dimethoxybenzyl) WO 99/54284 PCT/JP99/02028 (618mg) was dissolved in pyridine (5 mL) and acetic anhydride (2 mL).

The mixture was stirred at ambient temperature overnight, then concentrated in vacuo. The residue was partitioned between ethyl acetate and 3.6% hydrochloric acid. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. 4N-Hydrogen chloride solution in ethyl acetate (5 mL) was added to the residue and the mixture was stirred at ambient temperature for 2 hours. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and an aqueous saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography eluting with 5% methanol in chloroform and then a mixture of 28% ammonium hydroxide, methanol and chloroform (1:10:100) to give -(acetylaminomethyl)-2-hydroxyethylamino]- N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (171 mg) as yellow crystals; NMR (DMSO-d 6 1.80 (3H, 3.09-3.30 (2H, 3.48-3.60 (2H, m), 3.66-3.78 (1H, 3.73 (3H, 3.75 (3H, 4.37 (2H, d, J 6Hz), 5.04 (1H, t, J 5 Hz), 6.85 (1H, dd, J 2, 8 Hz), 6.91 (1H, d, J 8 Hz), 6.96 (1H, d, J 2 Hz), 7.08(1H, d, J 9 Hz), 8.07-8.15 (2H, 8.58 (1H, d, J 3 Hz), 9.20 (1H, d, J 8 Hz), 9.28 (1H, t, J 6 Hz) Mass (ESI+) 447 (ESI-) 445 and (S)-2-[1-(aminomethyl)-2-hydroxyethylamino]-N-(3,4- (178mg) as amorphous powders.

NMR (DMSO-d 6 2.73(2H, 3.47-3.64(3H, 3.73(3H, 3.74(3H, 4.36(2H, 6.85(1H, dd, J=2, 8Hz), 6.90-7.00(3H, 8.09(1H, dd, J=3, 9Hz), 8.56(1H, d, J=3Hz), 9.15-9.33(2H, m) Mass (ESI+) 405(M+H).

Example 78(3) (S)-N-(3,4-Dimethoxybenzyl)-2-[ 1-(formamidomethyl)-2- (112 mg) was obtained as yellow crystals from (S)-2-[l-(aminomethyl)-2-hydroxyethylamino]-N-(3,4dimethoxybenzyl)- 5-nitrobenzamide (147 mg) in a manner similar to WO 99/54284 PCT/JP99/02028 Example 73(2).

NMR (DMSO-d 6 3.26 (2H, 3.54 (2H, 3.65-3.84 (1H, 3.73 (3H, 3.74 (3H, 4.37 (2H, d, J 6 Hz), 5.06 (1H, t, J 5 Hz), 6.85 (1H, brd, J 8 Hz), 6.91 (1H, d, J 8 Hz), 6.96 (1H, br), 7.06 (1H, d, J 9 Hz), 8.05 (1H, 8.11 (1H, dd, J 3, 9 Hz), 8.25 (1H, t, J 5 Hz), 8.60 (1H, d, J 3 Hz), 9.21 (1H, d, J 7 Hz), 9.29(1H, t, J 6 Hz) Mass (ESI+) 433 (ESI-) 431 Preparation 79(1) Diphenylphosphorylazide (2.60 g) was added dropwise to a mixture of N-(tert-butoxycarbonyl)nipecotic acid (2.06 g) and triethylamine (1.00 g) in toluene (20mL). The reaction mixture was warmed in an oil bath over 10 minutes at 100 Stirring was continued for 2 hours at 100 then the reaction vessel was taken out from the oil bath. After reflux was ceased, benzyl alcohol (1.07 g) was added to the reaction mixture. The mixture was stirred for 3 hours at 100*C, and then poured into a mixture of 3.6% hydrochloric acid, ice and ethyl acetate. The separated organic layer was washed with brine, an aqueous saturated sodium bicarbonate solution and brine, successively.

The resultant was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography eluting with 30% ethyl acetate in hexane to give 3- (benzyloxycarbonylamino)-l-tert-butoxycarbonylpiperidine (2.66g) as an oil.

NMR (CDC13, 1.44(9H, 1.40-2.00(4H, 3.09-3.45(3H, m), 3.59(1H, brd, J=13Hz), 3.70(1H, br), 4.70 and 4.88(1H, 5.10(2H, s), 7.27-7.40(5H, m) Mass: (ESI+) 335(M+H), (ESI-) 333(M-H).

Preparation 79(2) 3-Amino- 1-tert-butoxycarbonylpiperidine (1.48g) was obtained as syrup from 3-(benzyloxycarbonylamino)-1-tertbutoxycarbonylpiperidine (2.54g) in a manner similar to Preparation 78(3).

WO 99/54284 WO 9954284PCT/JP99/02028 NMR (CDCla,(d): 1.30(1H, in), 1.40-1.60(1H, mn), 1.46(9H, l.70(lH, i) 1.96(1H, mn), 2.66(1H, mn), 2.75-2.95(2H, in), 3.80(1H, in), 3.94(1H, i) Exale9,U), 2-11 -(tert-Butoxycarbonyl)piperidin-3-ylamino]-N-(3, 4 (900 mg) was obtained as amorphous powders from N- (3 ,4-dimethoxybenzyl) -2-fluoro- nitrobenzamide (700 mg) and 3-amino- 1l-tert-butoxycarbonylpiperidmne (503 mg) in a manner similar to Example 1(1).

NMR (DMSO-d 6 1.20-2.00(13K, mn), 3.10-3.65(4K, mn), 3.65-3.80(1H, mn), 3.73(3H, 3.74(3H, 4.37(2H, d, J=6Hz), 6.83(1H, d, J=8Hz), 6.84-6.96(3H, mn), 8.15(1H, dd, J=2, 9Hz), 8.65(1K, 9.15-9.45(1K, in), 9.34(1H, t, J=6Hz) Mass: (ESI+) 515(M+K), (ESI-) 513(M-H).

Exmple9.(7 A mixture of 1-(tert-butoxycarbonyl)piperidin-3-ylaminol-N- (3,4-dimethoxybenzyl)- 5-nitrobenzamide (190 ing) and 4 N hydrogenchioride solution in ethyl acetate (5 mL) was stirred for 2hours at ambient temperature. The reaction mixture was concentrated in vacuo. The residual crystals were collected by filtration and washed with ethyl acetate to give N-(3,4-diinethoxybenzyl)-5-nitro-2-(piperidin- 3-ylarnino)benzamide hydrochlor-ide (138 ing) as yellow crystals.

NMR (DMSO-d 6 1.55-1.96(3K, in), 2.04(1K, in), 2.78-2.92(2K, in), 3. 18-3.40(2K, in), 3.73(3K, 3.75(3K, 3.98(1K, in), 4.39(2K, d, J=6Kz), 6.85(1K, d, J=8Kz), 6.90-7.00(3K, in), 8. 19(1K, dd, J=3, 9Kz), 8.65(1K, d, J=3Kz), 9.08(1K, d, J=8Kz), 9.41(1K, t, J=6Kz) Mass: (ESI-) 413(M-K).

Eapl79L3)Y N-(3 ,4-Diniethoxybenzyl)-2-[ 1 -(iethanesulfonyl)piperidin-3- (100 ing) was obtained as yellow crystals from N- (3 ,4-diinethoxybenzyl) -5-nitro-2- (piperidin-3ylamino)benzamide hydrochloride (100 ing) in a manner similar to WO 99/54284 WO 9954284PCT/JP99/02028 Example 73(3).

NMR (DMSO-d 6 1.50-1.83(3H, in), 1.87(1H, mn), 2.89(3H, 2.95- 3.15(1H, in), 3.01(1H, dd, J=7, 10Hz), 3.21(1H, in), 3.41(1H, dd, J=4, 3.73(3H, 3.74(3H, 3.9 1 (1H, mn), 4.38(2H, d, J=6Hz), 6.85(1H, ad, J=2, 8Hz), 6.90-7.00(3H, mn), 8.16(1H, dd, J=3, 9Hz), 8.63(1H, d, J=3Hz), 9.25(1H, d, J=8Hz), 9.35(1H, t, J=6Hz) Mass: (ESI+) 493(M-iH), (ESI-) 491(M-H).

Exaple 24j N-(3,4-Diinethoxybenzyl)-5-nitro-2-(piperidin-3ylamino)benzamide (550 mg) was obtained as yellow crystals from 1 (tert-butoxycarbonyl)piperidin-3-ylamino] (3 ,4-dimethoxybenzyl) nitrobenzamide (802 mg) in a manner similar to Example 77(2).

NMR (DMSO-d 6 ,65):1.36-1.64(2H, mn), 1.82(1H, mn), 2.40-2.65(2H, in), 2.70(1H, mn), 2.9 6(1H, dd, J=4,lOHz), 3.63(1H, mn), 3.73(3H, 3.74(3H-, 4.38 (2H, d, J=6Hz), 6.84-6.93 (3H, mn), 6.96 (1 H, d, J=2Hz), 8. 11 (1H, dd, J=3,9Hz), 8.58(1H, d, J=3Hz), 9.20(1H, d, J=8Hz), 9.29(1H, t, J=6Hz) Mass: (ESI+) 415(M+H), (ESI-) 413(M-H).

Example N- (3,4-Diinethoxybenzyl) (1-forinylpiperidin-3-ylamino) nitrobenzamide (102 ing) was obtained as yellow crystals from N-(3,4dimethoxybenzyl) -5-nitro-2- (piperidin-3-ylamino)benzamide (126 mng) in a manner similar to Example 73(2).

NMR (DMSO-d 6 1.40-1.76(3H, mn), 1.93-2.05(1H, mn), 3.14-3.86(5H, in), 3.73(3H, 3.75(3H, 4.37(2H, d, J=5Hz), 6.84(1H, d, J=2.8Hz), 6.90-7.04(3H, in), 7.96 and 8.06(1H, 8.13 and 8.16(1H, d, J=3.9Hz), 8.63 and 8.64(1H, d, J=3Hz), 9.19 and 9.23(1H, a, J=8Hz), 9.34 and 9.35(1H, t, Mass: (ESI+) 443(M+H), (ESI-) 441(M-H).

Exampe 8 2-(l1H-Benziinidazol-5-ylainino)-N- (3 nitrobenzamide (130.9 mg) was obtained as a yellow solid substance WO 99/54284 WO 9954284PCT/JP99/02028 from N- (3 ,4-dimethoxybenzyl) -2-fluoro- 5-nitrobenzamide (200 mg) and 1 H-benziinidazole (159 mg) in a manner similar to Example 1 mp. 226.5-227 *C NMR (DMSO-d 6 3.73(3H, 3.75(3K, 4.45(2H, br), 6.90(1H, d, 3=8.0Hz), 6.94(1H, d, 7.00(1H, 7.04(lH, br), 7.11 (1H, brd, 7.51(1H, br), 7.64(1H, br), 8.10(1H, dd, J=8.5, 2.5Hz), 8.26(1H, 8.69(1K, d, 3=2.5Hz), 9.50(1H, br), 10.71(1H, br), 12.53(1H, br) Mass m/z: 448(M+ 1).

Example B14 2-1(3S, 5S)- (methoxycarbonyl)pyrrolidin-3-ylanino] N-(3 ,4-dimethoxylbenzyl) nitrobenzamide (814 mg) was obtained from N-(3,4-dimethoxylbenzyl)- 2-fluoro-5-nitrobenzamide (513 mg) and methyl (2S, 4S)-4-anuno-1- (tert-butoxycarbonyl)pyrroridine-2-carboxylate (750 mg) in a manner similar to Example 1(l).

NMR (DMSO-d 6 1.35 (9x3/5K, 1.41 (9x2/5H, 1.94 (1H, in), 2.70 (1H, in), 3.21 (1H, dd, J=11, 4 Hz), 3.56 (3x2/5H, 3.58 (3x3/5K, 3.72 (3H, 3.74 (3H, 3.85 (1H, in), 4.25-4.45 (3K, mn), 6.83-6.98 (4K, mn), 8.15 (1H, dd, J=9, 2 Hz), 8.61 (1H, d, J=2 Hz), 9.06 (1H, mn), 9.34 (1H, t, J=6 Hz) Mass in/z: 558(M+).

Exml8= A mixture of 5S)- (methoxycarbonyl)pyrrolidin- 3 -ylamino] N-(3 ,4-dimethoxylbenzyl) nitrobenzamide (143 mg) and 30% methanol solution of methylamine (4 niL) was stirred for one day at ambient temperature. After evaporation of the solvent, the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine and dried over magnesium sulfate. The residue was subjected to a silica gel column chromatography eluting with ethyl acetate to give 5S)- 1- (tert-butoxycarbonyl) (methylcarbamoyl)pyrrolidin-3-ylaminol N- (3,4- WO 99/54284 WO 9954284PCT/JP99/02028 (149 mg).

NMR (DMSO-d 6 1.48 (9H, 2.33-2.70 (2H, in), 2.79 (3H, d, J=5 Hz), 3.47 (1H, mn), 3.88 (3H, 3.90 (3H, 4.15 (1H, mn), 4.40 (1H, in), 4.50 (1H, dd, J= 16, 7 Hz), 4.57 (1H, dd, J=16, 7 Hz), 6.58 (1H, in), 6.62 (1H, d, J=9 Hz), 6.83-6.93 (3H, in), 8.16 (1H, dd, J=9,3 3Hz), 8.33 (1H, d, J=3 Hz), 8.98 (1H, m) Mass in/z: 558(M+).

ExampSle I To a solution of 5S)-1-(tert-butoxycarbonyl)-5- (inethoxycarbonyl)pyrrolidin-3-ylarnino] N-(3 ,4-dimethoxylbenzyl) nitrobenzamide (492 ing) in tetrahydrofuran (5 mL) was added lithium chloride (75 ing), and then a solution of sodium borohydride (67 mg) in ethanol (10 mL) at ambient temperature. After stirring for one day, the mixture was evaporated and the residue was partitioned between ethyl acetate and 10% citric acid aqueous solution. The organic layer was separated, washed with water and brine and dried over magnesium sulfate. The residue was subjected to a silica gel column chromatography eluting with a mixture of ethyl acetate and hexane 1 to 2:1) to give 5S)-1-(tert-butoxycarbonyl)- (hydroxyinethyl)pyrrolidin-3-ylamino] (3 nitrobenzainide (399 ing) as pale yellow foams.

NMR (DMSO-d 6 1.41 (9H, 1.93 (1H, in), 2.44 (1H, in), 3.04 (1H, in), 3.51-3.62 (2H, in), 3.70-3.95 (2H, in), 3.73 (3H, 3.74 (3H, 4.21 (1H, in), 4.38 (2H, d, J= 6 Hz), 4.84 (1H, t, J= 5 Hz), 6.8 1-6.97 (4H, in), 8.15 (1H, dd, J= 10, 3 Hz), 8.60 (1H, d, J= 3 Hz), 9.18 (1H, d, J= 8 Hz), 9.33 (I1H, t, J= 6 Hz).

Exmple8 4) A mixture of 5S)- 1-(tert-butoxycarbonyl)- (hydroxyinethyl)pyrrolidin-3-ylainino] (3 ,4-dimethoxylbenzyl) nitrobenzamide (326 ing) and 4N-hydrogen chloride solution in ethyl acetate (5 mL) was stirred for one day at ambient temperature. After evaporation of the solvent, the residue was partitioned between WO 99/54284 WO 9954284PCT/JP99102028 chloroform and an aqueous saturated sodium bicarbonate solution.

The organic layer was separated, washed with brine and dried over magnesium sulfate. The filtrate was evaporated to give N-(3,4dimethoxylbenzyl) -2-1(3S, 5S) (hydroxymethyl)pyrrolidin-3 -ylamino] 5-nitrobenzamide (242 mg) as pale yellow foams.

NMR (DMSO-d 6 1.32 (1H, in), 2.35 (1H, mn), 2.72 (1H, in), 3.13 (1H, in), 3.20-3.41 (2H, mn), 3.53 (1H, in), 3.73 (3H, 3.74 (3H, 4.05 (1H, mn), 4.38 (2H, d, J= 6 Hz), 4.61 (1H, br t, J= 5 Hz), 6.80-6.99 (4H, mn), 8.13 (1H, dd, J= 9, 3 Hz), 8.60 (1H, in), 9.13 (1H, in), 9.32 (1H, m) Mass (ES) m/z: 431(M+).

Example 81(5) N-(3,4-Dimethoxylbenzyl)-2-[(3S, (methylcarbamoyl)pyrrolidin-3 -ylamino] -5-nitrobenzamide (75 ing) was obtained as pale yellow foams from 5S)- 1-(tert-butoXycarbonyl)- (methylcarbainoyl)pyrrolidin-3-ylamino] (3 ,4-diinethoxylbenzyl) nitrobenzamide (111 ing) in a manner similar to Example 81(4).

NMR (DMSO-d 6 1.70 (1H, ddd, J=13, 5, 5 Hz), 2.43 (1H, in), 2.53 (3H, d, J=5 Hz), 2.72 (1H, dd, J= 10, 4 Hz), 3.26 (1H, dd, J=io0, 5 Hz), 3.60 (1H, in), 3.72 (3H, 3.74 (3H, 4.07 (1H, in), 4.34 (1H, dd, J=15, 6 Hz), 4.40 (1H, dd, J= 15, 6 Hz), 6.81-6.97 (4H, mn), 7.85 (1H, q, J=5 Hz), 8.14 (1H, dd, J=9, 2 Hz), 8.59 (1H, d, J=2 Hz), 9.07 (1H, d, J=8 Hz), 9.30 (1H, t, J=6 Hz) Mass in/z: 458(M+).

To a suspension of cis-4-aminocyclohexanecarboxylic acid (1.04 g) in methanol (25 mL) was added thionyl chloride (0.583 inL) under ice-water cooling. The mixture was stirred for an hour at 0 *C and for 17 hours at ambient temperature. After evaporation of the solvent, the residue was triturated with diethyl ether to give methyl cis- 4aminocyclohexanecarboxylate hydrochloride as white powders (1.37 g).

NMR (DMSO-d 6 1.40-1.68 (4H, mn), 1.73-1.85 (2H, br), 1.93-2.07 (2H, br), 2.62 (1H, mn), 3.02-3.14 (1H, br), 3.63 (3H, 8.00 (3H, br).

WO 99/54284 PCT/JP99/02028 Example 821 N-(3 ,4-Dimethoxybenzyl)-2-[cis- (1.38 g) was obtained as yellow powders from N-(3,4-dimethoxybenzyl)-2-fluoro-5nitrobenzamide (1.00 g) and methyl cis4-aminocyclohexanecarboxylate hydrochloride (985 mg) in a manner similar to Example 1(1).

NMR (DMSO-d 6 1.55-1.85 (8H, br), 2.50-2.60 (1H, br), 3.62 (3H, s), 3.73 (3H, 3.74 (3H, 3.75-3.85 (1H, br), 4.38 (2H, d, J= 7 Hz), 6.82-6.98 (4H, 8.12 (1H, dd, J= 4, 8 Hz), 8.62 (1H, d, J= 4 Hz), 9.28-9.38 (2H, br).

Examle 82(2 2-(cis-4-Carboxycyclohexylamino)-N-(3 nitrobenzamide (1.12 g) was obtained as yellow powders from N-(3,4dirnethoxybenzyl)-2-f cis-4- nitrobenzanide (1.27 g) in a manner similar to Example 23(2).

NMR (DMSO-d 6 1.55-1.85 (8H, br), 2.39-2.49 (1H, br), 3.73 (3H, s), 3.74 (3H, 3.75-3.85 (1H, br), 4.38 (2H, d, J= 7 Hz), 6.80-7.00 (4H, m), 8.12 (1H, dd, J= 4 Hz, 8 Hz), 8.61 (1H, d, J= 4 Hz), 9.33 (2H, br).

Example 8= N-(3,4-Dimethoxybenzyl)-2-[cis-4- (81.8 mg) was obtained as yellow powders from 2-(cis-4-carboxycyclohexylamino)-N- (3,4-dimethoxybenzyl)-5-nitrobenzamide (100 mg) and dimethylaiine hydrochloride (21.4 mg) in a manner similar to Example 23(3).

NMR (DMSO-d 6 1.52-1.90 (8H, br), 2.66-2.76 (1H, br), 2.80 (3H, s), 3.02 (3H, 3.73 (3H, 3.74 (3H, 3.85-3.95 (1H, br), 4.40 (2H, d, J= 7 Hz), 6.83-6.98 (4H, 8.12 (1H, dd, J= 4, 8 Hz), 8.63 (1H, d, J= 4 Hz), 9.33 (1H, br), 9.50 (1H, d, J= 8 Hz) Mass m/z: 483(M+).

Example 824 WO 99/54284 WO 9954284PCT/JP99/02028 N- (3,4-Dimethoxybenzyl)-2-[cis- 4 (2hydroxyethylcarbamoyl) cyclohexylaminol -5-nitrobenzanude (100 mg) was obtained as yellow powders from 2-(cis-4-carboxycyclohexylamino)- N-(3,4-dimethoxybenzyl)- 5-nitrobenzamide (100 mg) and 2aminoethanol (16.0 mg) in a manner similar to Example 23(3).

NMR (DMSO-d 6 1.55-1.72 br), 2.20-2.30 (1H, br), 3.06-3.16 (2H, in), 3.35-3.41 (2H, in), 3.73 (3H, 3.74 (3H, 3.78-3.88 (1H, br), 4.39 (2H, d, J= 7 Hz), 4.65 (1H, t, J= 7 Hz), 6.83-6.98 (4H, in), 7.74 (LH, br), 8.12 (1H, dd, J= 4, 8 Hz), 8.63 (1H, d, J= 4 Hz), 9.33 (1H, br), 9.43 (1H, d, J=8 Hz) Mass m/z: 499(M+).

Preparation 83(1) 4-(Benzyloxycarbonylamino)-l1-tert-butoxycarbonylpiperidine (5.44 g) was obtained as a solid substance from N-tertbutoxycarbonylisonipecotic acid (4.5 g) in a manner similar to Preparation 79(1).

NMR (CDC1 3 1.30 (2H, dq, J= 4, 10 Hz), 1.45 (9H, 1.94 (2H, br d, J= 10 Hz), 2.85 (2H, t, J= 10 Hz), 3.66 (1H, in), 4.01 (2H, br), 4.65 (1H, in), 5.09 (2H, 7.27-7.40 (5H, in).

Preparation 83(2) 4-Amino- 1-tert-butoxycarbonylpiperidine (3.83 g) was obtained as syrup from 4-(benzyloxycarbonylamino)- 1-tertbutoxycarbonylpiperidine (5.11 g) in a manner similar to Preparation 78(3).

NMR (CDC1 3 1.30(2H, in), 1 .83(2H, in), 2.56(2H, in), 2.60-2.95(3H, in), 4.06(2H, m) Mass: (ESI+) 201(M+1).

Exaple (1 2- [1-(tert-Butoxycarbonyl)piperidin-4-ylamino] -5-cyano-N- (3,4dimethoxybenzyl)benzainide (360 mng) was obtained as amorphous powders from 5-cyano-N- (3 ,4-dimethoxybenzyl) -2-fluorobenzamide (300 WO 99/54284 WO 9954284PCT/JP99/02028 mg) and 4-amino- 1-tert-butoxycarbonylpiperidine (287mg) in a manner similar to Example 1 NMR (DMSO-d 6 1.28(2H, in), 1.90(2H, mn), 3.00(2H, in), 3.6 1-3.75(1H, mn), 3.72(3H, 3.74(3H, 3.80(2H, in), 4.35(2H, d, J=6Hz), 6.83(1H, dd, J=2, 8Hz), 6.88-6.94(3H, mn), 7.63(1H, dd, J=2, 9Hz), 8.07(1H, d, J=2Hz), 8.71(1H, d, J=8Hz), 9.03(1H, t, J=6Hz) Mass: (ESI-) 493(M-H).

Exaple 32) 5-Cyano-N- (3 ,4-dimethoxybenzyl) (piperidin-4ylam-ino)benzamide hydrochloride (254 mg) was obtained as white crystals from 2- [11- (tert-butoxycarbonyl) pip eridin-4-ylamino] 5-cyano- N- (3,4-dimethoxybenzyl)benzamide (297 mg) in a manner similar to Example 79(2).

NMR (DMSO-d 6 1.60(2H, mn), 2.10(2H, mn), 3.0 1(2H, in), 3.26(2H, in), 3.64-3.87(lH, in), 3.73(3H, 3.74(3H, 4.36(2H, d, J=6Hz), 6.84(1H, dd, J=2, 8Hz), 6.89-7.00(3H, mn), 7.67(lH, dd, J=2, 8Hz), 8.12(1H, d, J=2Hz), 8.70-9.05(2H, in), 9.11I(1H, t, J=6Hz) Mass: (ESI+) 395(M+H), (ESI-) 393(M-H).

(3 ,4-diinethoxybenzyl) -2-(piperidin-4ylatnino)benzamide hydrochloride (100 mg) was partitioned between ethyl acetate and an aqueous saturated sodium bicarbonate solution.

The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in N,Ndimethylformamide (1 inL), and ethyl formate (5 mL) was added to the solution. The mixture was refluxed under heating overnight and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from ethyl acetate to give N- (3,4-diinethoxybenzyl) (1-formylpiperidin-4-ylamino)benzainide (52 ing) as white crystals.

NMR (DMSO-d 6 1.15-1.44(2H, in), 1.88-2.03(2H, mn), 2.9 1(1H, in), WO 99/54284 WO 9954284PCT/JP99/02028 3.16-3.35(2H, in), 3.60-3.85(2H, mn), 3.72(3H, 3.74(3H, 4.0l1(1H, m), 4.35(2H, d, J=5Hz), 6.83(1K, dd, J=2, 8Hz), 6.84-6.97(3H, in), 7.64(1K, dd, J=2, 9Hz), 7.99(1H, 8.07(1H, d, J=2Hz), 8.74(1K, d, J=8Hz), 9.03(1H, t, Mass: (ESI-) 421(M-H).

Exampe834 5-Cyano-N-(3,4-dimethoxybenzyl)- 2 1[ 1- (methanesulfonyl)piperidil-4-ylamfinolbenzamnide (78 mg) was obtained as white crystals from 5- cyano-N- (3 ,4-diinethoxybenzyl) -2 -(pip eridin-4ylamino)benzamide hydrochloride (100 mg) in a manner similar to Example 73(3).

NMR (DMSO-d6,65): 1.48(2H, in), 2.02(2H, mn), 2.89(3H, 2.96(2H, in), 3.50(2H, mn), 3.64(lH, in), 3.72(3K, 3.74(3H, 4.35(2H, d, 6.84(1H, dd, J=2, 8Hz), 6.88-6.96(3H, in), 7.65(lH, d, J=2, 9Hz), 8.08(1K, d, J=21-z), 8.73(1H, J=8Hz), 9.04(1H, t, Mass: (ESI-) 471(M-H).

Eample 841_ 2-11 -(tert-Butoxycarbonyl)piperidil-3-ylamifo] 5-cyano-N- (3,4dimethoxybenzyl)benzamide (368 mg) was obtained as amorphous powders from 5-cyano-N- (3 ,4-dimethoxybenzyl) -2-fluorobenzainide (300 mg) and 3-amino- 1-tert-butoxycarbonylpiPeridine (249mg) in a manner simnilar to Example 1 NMR (DMSO-d 6 1.10-1.75(12H, mn), 1.88(1K, mn), 2.95-3.65(5H, mn), 3.72(3H, 3.74(3H, 4.35(2H, d, J=6Hz), 6.80-6.96(4H, mn), 7.65(1K, d, J=9Kz), 8. 10(1H, 8.75-9. 10(1H, in), 9.03(1K, t, J=6Hz) Mass: (ESI-) 493(M-H).

Exmkle 4.2 (3 ,4-diinethoxybenzyl) (piperidin-3ylamino)benzamide (283 mng) was obtained as an oil from 2-[1-(teIbutoxycarbonyl)piperidifl- 3 -ylaxnino)- 5-cyano-N- (3,4diniethoxybenzyl)benzamfide (311 ing) in a manner similar to Example WO 99/54284 WO 9954284PCT/JP99/02028 77(2).

J=7, 10Hz), 2.56(1H, in), 2.7 1(1H, in), 2.97(1K, dd, J=4,lOHz), 3.52(1H, mn), 3.72(3H, 3.74(3H, 4.36(2H, d, J=6Hz), 6.80-6.95(4H, in), 7.60(1H, dd, J=3, 9Hz), 8.04(1H, d, J=3Hz), 8.78(1H, d, J=8Kz), 8.98(1H, t, J=6Hz) Mass: (ESI+) 395(M+K), (ESI-) 393(M-H).

Example84(3.) 5-Cyano-N-(3 ,4-dimethoxybenzyl)-2-(l1-formylpiperidin-3ylainino)benzainide (61 mg) was obtained as amorphous powders from (3 ,4-dimethoxybenzyl) (piperidin- 3-ylaniino) benzarnide (94 mg) in a manner similar to Example 73(2).

NMR (DMSO-d 6 1.40-1.75(3H, in), 3.06-3.84(5H, in), 3.72(3K, s), 3.74(3H, 4.36(2K, d, J=6Kz), 6.80-7.01(4H, in), 7.63 and 7.67(1K, d, J=9Kz), 7.95 and 8.05(1K, 8.08(1K, br), 8.80 and 8.84(1K, d, J=8Kz), 9.04(1K, t, J=6Hz) Mass: (ESI+) 423(M+H), (ESI-) 421(M-H).

Example 84(4) 5-Cyano-N-(3,4-diinethoxybenzyl)-2-[ 1- (inethanesulfonyl)piperidin-3-ylaminolbenzamide (83 mng) was obtained as white crystals from 5-cyano-N- (3 ,4-dimethoxybenzyl)-2- (piperidin-3 ylamino)benzarnide (82 mng) in a manner similar to Example 73(3).

NMR (DMSO-d 6 1.44-1.94(4H, in), 2.8-2.96(1K, mn), 2.88(3K, s), 3.04(1K, in), 3.22(1K, in), 3.42(1K, in), 3.72(3K, 3.74(3H, 3.80(1K, in), 4.36(2K, d, J=5Hz), 6.84(1K, d, J=2, 8Hz), 6.88-6.92(2K, in), 6.94(1K, d, J=2Hz), 7.66(1K, dd, J=2, 9Hz), 8.08(1K, d, J=2Kz), 8.85(1K, d, J=8Hz), 9.04(1K, t, Mass: (ESI+) 473(M+K), 495(M+Na), (ESI-) 471(M-H).

Preparation 85(1) A solution of di-tert-butyl dicarbonate (5.44 g) in dioxane (10 mL) was added dropwise to a solution of WO 99/54284 WO 9954284PCT/JP99/02028 benzyloxycarbonylaxninopyrrolidine (3.66 g) in dioxane (10 mL) under cooling on an ice bath. The reaction mixture was stirred at ambient temperature overnight, then the reaction was quenched by addition of 3-.(N,N-dimethylarnino)propylaxnine (5 mnL). The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and 3.6% hydrochloric acid. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography eluting with 30% ethyl acetate in hexane to give (S)-3-benzyloxycarbonylainino- 1-tertbutoxycarbonylpyrrolidine (1.26 g) as an oil.

NMR (CDC1 3 1.45(9H, 1.84(1H, in), 2.14(1K, in), 3.20(1K, in), 3.33-3.50(2H, in), 3.61(1H, dd, J=2, 10Hz), 4.25(1H, in), 4.85(1H, mn), 5.10(2H, 7.27-7.41(5H, in) Mass: (ESI+) 321(M+H).

Preparation 85(2) (S)-3-Ainino- l-tert-butoxycarbonylpyrrolidine (2.49 g) was obtained as syrup from (S)-3-benzyloxycarbonylamino-1-tertbutoxycarbonylpyrrolidine 10 g) in a manner similar to Preparation 78(3).

NMR (DMSO-d 6 1.39(9K, 1.57(1K, mn), 1.88(1H, mn), 2.89(1K, dd, 11lHz), 3.00-3.40(3H, in), 3.42(1K, in) Mass: (ESI+) 187(M+H).

Exmple [1-(tert-Butoxycarbonyl)pyrrolidin-3-ylanino] (3,4-diinethoxybenzyl)benzainide (368 mng) was obtained as amorphous powders from 5-cyano-N-(3,4-dimethoxybenzyl)-2-fluorobenzamide (500 ing) and (S)-3-amino- 1-tert-butoxycarbonylpyrrolidine (593 ing) in a manner similar to Example 1 NMR (DMSO-d 6 1.82(1K, in), 2.20(1K, mn), 3. 10(1K, in), 3.25-3.45(2K, mn), 3.61(1K, in), 3.72(3H, 3.74(3H, 4.18(1K, in), 4.35(2K, d, J=6Hz), 6.84(1K, dd, J=2, 8Hz), 6.80-6.94(3H, mn), 7.66(1K, dd, J=2, 8Hz), WO 99/54284 WO 9954284PCT/JP99/02028 8.09(1H, d, J=2Hz), 8.82(1W, d, J=7Hz), 9.05(1H, t, 3=6Hz).

-5-Cyano-N- (3 ,4-dimethoxybenzyl) (3pyrrolidinylamino)benzamide (201 mg) was obtained as amorphous powders from [1-(tert-butoxycarbonyl)pyrrolidin-3 -ylamino] cyano-N-(3,4-dirnethoxybenzyl)benzamide (277 mg) in a manner similar to Example 77(2).

NMR (DMSO-d 6 1.50(1IH, in), 2.1 1(1W, in), 2.57(lH, dd, J=4, 2.70-2.95(2H, in), 3.13(1W, dd, J=6, 10Hz), 3.72(3H, 3.74(3H, s), 3.96(1W, in), 4.34(2H, d, J=6Hz), 6.78-6.94(4H, in), 7.64(1H, dd, J=2, 8Hz), 8.06(1H, d, 3=2Wz), 8.72(1H, d, 3=7Hz), 9.02(1H, t, 3=6Hz) Mass: (ESI+) 381(M+H), (ESI-) 379(M-W).

115 Example ai3.

(S)-5-Cyano-N-(3 ,4-dimethoxybenzyl)-2-[ I1- (inethanesulfonyl)pyrrolidiri-3-ylamino]benzamide (81 mg) was obtained as white crystals from (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3pyrrolidinylamino)benzamide (100 mg) in a manner similar to Example 73(3).

NMR (DMSO-d 6 1.89(lH, mn), 2.30(1H, in), 2.90(3W, 3.09(1H, dd, J=4, 10Hz), 3.28-3.45(2H, mn), 3.62(1W, dd, 3=6, 10Hz), 3.72(3W, s), 3.74(3H, 4.25(1W, mn), 4.36(2W, d, 3=6Hz), 6.84(1W, dd, 3=2, 8Hz), 6.85-6.94(3H, mn), 7.68(1W, d, 3=2, 8Hz), 8.09(1H, d, 3=2Hz), 8.84(1W, d, 3=7Hz), 9.07(1H, t, 3=6Hz) Mass: (ESI+) 459(M+W), (ESI-) 457(M-H).

Exampkl4 -5-Cyano-N-(3 ,4-diinethoxybenzyl)-2- (1-forinylpyrrolidin-3ylainino)benzamide (89 ing) was obtained as amorphous powders from (S)-5-cyano-N-(3 ,4-dimethoxybenzyl) (3-pyrrolidinylatnino)benzamide (100 ing) in a manner similar to Example 73(2).

NMR (DMSO-d 6 1.86(1W, mn), 2.25(1H, mn), 3.15(ca.O.5H, dd, J=4, 3.25-3.75(3H, mn), 3.72(3H, 3.74(3H, 3.84(ca.0.5W, dd, 3=6, WO 99/54284 PCT/JP99/02028 4.13-4.29(1H, 4.35(lH, d, J=6Hz), 6.83(1H, d, J=8Hz), 6.88- 6.96(3H, 7.68(11H, dd, J=2, 8Hz), 8.10(1H, d, J=2Hz), 8.17 and 8.19(1H, 8.82(1H, d, J=7Hz), 9.06(1H, t, J=6Hz) Mass: (ESI+) 409(M+H), (ESI-) 407(M-H).

Example 85(51 A solution of methyl chloroformate (26 mg) in chloroform (2 mL) was added dropwise to a mixture of (S)-5-cyano-N-(3,4dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide (80 mg) and triethylamine (43 mg) in a mixture of chloroform (2 mL) and 1,3dimethyl-2-imidazolidinone (1 mL) under cooling on an ice bath. The reaction mixture was stirred for 2 hours at same temperature and the reaction was quenched by addition of 3-(N,Ndimethylamino)propylamine (0.1 mL). The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and 3.6% hydrochloric acid. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography eluting with 70% ethyl acetate in hexane.

The obtained crystals were recrystallized from a mixture of 2-propanol and diisopropyl ether to give (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-[1- (methoxycarbonyl)pyrrolidin-3-ylamino]benzamide (55 mg) as white crystals.

NMR (DMSO-d 6 ,5 1.86(1H, 2.21(1H, 3.16(1H, 3.30-3.50(2H, 3.55-3.80(1H, mi), 3.57 and 3.59(3H, 3.72(3H, 3.74(3H, s), 4.20(1H, 4.35(2H, d, J=6Hz), 6.83(1H, d, J=2, 8Hz), 6.88-6.94(3H, m), 7.66(1H, dd, J=2, 8Hz), 8.09(1H, d, J=2Hz), 8.83(1H, d, J=7Hz), 9.06(1H, t, J=6Hz) Mass: (ESI-) 437(M-H).

Example 85(6j Acetic anhydride (64 mg) was added to a solution of cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide mg) in pyridine (1 mL). The mixture was stirred for an hour at ambient WO 99/54284 WO 9954284PCT/JP99/02028 temperature. The mixture was partitioned between ethyl acetate and 1% hydrochloric acid. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine. The resultant was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by a thin layer chromatography developed with methanol in chloroform to give (1-acetylpyrrolidin-3-ylamino)- cyano-N- (3 ,4-dimethoxybenzyl)benzamide (62mg) as amorphous powders.

NMR (DMSO-d 6 1.72-1.88(1H, in), 1.92 and 1.95(3H, 2.13- 2.36(1H, in), 3.20(ca.O.5H, dd, J=3, 12Hz), 3.27(ca.0.5H, dd, J=5, 3.35-3.60(4H, in), 3.63(ca.0.5H, dd, J=6, 12Hz), 3.72(3H, 3.74(3H, s), 3.85(ca.O.5H, dd, J=4, 10Hz), 4.18 and 4.26(1H, in), 4.35(2H, d, J=6Hz), 6.83(1H, dd, J=2, 8Hz), 6.80-6.96(3H, in), 7.67(1H, dd, J=2, 8Hz), 8.09(1H, d, J=2Hz), 8.81 and 8.86(1H, d, J=6Hz), 9.06(lH, t, J=6Hz) Mass: (ESI+) 423(M+H), (ESI-) 421(M-H).

Exampe 8 -5-Cyano-N- (3 ,4-dimethoxybenzyl) (tetrahydrofuran-3ylamino)benzamide (96 mng) was obtained from 5-cyano-N-(3,4dimethoxybenzyl)-2-fluorobenzamide (126 mg) and (R aminotetrahydrofuran toluene-4-sulfonate (135 mng) in a manner similar to Example 1(1).

NMR (DMSO-d 6 1.74 (1H, in),.2.27 (1H, in), 3.54 (1H, dd, J= 3, 9Hz), 3.70-3.92 (3H, in), 3.72 (3H, 3.74 (3H, 4.20 (1H, in), 4.35 (2H, d, J= 6 Hz), 6.8 1-6.95 (4H, in), 7.66 (1H, dd, J= 2, 9 Hz), 8.08 (1H, d, J= 2 Hz) 8.8 1 (1H, d, J= 7 Hz), 9.05 (1H, t, J= 6 Hz) Mass m/z 380 1).

Exmple 87IJ (tert-Butoxycarbonyl)pyrrolidin-3-ylanino 3 ,4-dimethoxybenzyl)benzamide (918 mng) was obtained as amorphous powders from 5-cyano-N- (3 ,4-dimethoxybenzyl) -2-fluorobenzamide (700 mng) and (R)-3-amino- 1-tert-butoxycarbonylpyrrolidine (830 mng) in a manner similar to Example 1 WO 99/54284 WO 9954284PCT/JP99/02028 NMR (DMSO-d 6 1.82(1H, in), 2.20(1H, in), 3. 10(1H, in), 3.25-3.45(2H, in), 3.61(11-, in), 3.72(3K, 3.74(3H, 4.18(11-, in), 4.35(2H, d, J=6Hz), 6.84(11-, dd, J=2, 8Hz), 6.80-6.94(3H, in), 7.66(1H, dd, J=2, 8Hz), 8.09(1H, d, J=2Hz), 8.82(1H, d, J=7Hz), 9.05(1H, t, J=6Hz).

Exmple 702 Trifluoroacetic acid (5 inL) was added to a solution of (tert-butoxycarbonyl)pyrrolidin-3-ylamino] -5-cyano-N- (3,4diinethoxybenzyl)benzarnide (9 18 ing) in chloroform (5 mL). The mixture was stirred for 4 hours at ambient temperature and concentrated in vacuo. The residue was partitioned between chloroform and an aqueous saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give (R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3pyrrolidinylamino)benzainide (6 10 ing) as amorphous powders.

NMR (DMSO-d 6 1.50(1K, in), 2.11 (1H, in), 2.57(1K, dd, J=4, 2.7-2.95(2H, in), 3.13(1H, dd, J=6, 10Hz), 3.72(3H, 3.74(3H, s), 3.96(1K, mn), 4.34(2H, d, J=6Kz), 6.78-6.94(4H, in), 7.64(1H, dd, J=2, 8Hz), 8.06(1K, d, J=2Hz), 8.72(1H, d, J=7Hz), 9.02(1H, t, J=6Hz).

Exaple 7(3 (R)-5-Cyano-N-(3,4-diinethoxybenzyl)-2-[ 1- (inethanesulfonyl)pyrrolidin-3-ylamino]benzamide (93 mg) was obtained as white crystals from -5-cyano-N- (3 ,4-dimethoxybenzyl)-2-(3pyrrolidinylamino)benzamide (114 mg) in a manner similar to Example 73(3).

NMR (DMSO-d 6 1.89(1K, in), 2.30(1K, in), 2.90(3K, 3.09(1H, dd, J=4, 10Hz), 3.28-3.45(2H, in), 3.62(1K, dd, J=6, 10Hz), 3.72(3K, s), 3.74(3H, 4.25(1K, in), 4.36(2K, d, J=6Hz), 6.84(1K, dd, J=2, 8Hz), 6.85-6.94(3K, in), 7.68(1H, d, J=2, 8Hz), 8.09(1K, d, J=2Hz), 8.84(1K, d, J=7Kz), 9.07(1K, t, J=6Kz).

-5-Cyano-N- (3 ,4-diinethoxybenzyl)-2-[ 1- 100 WO 99/54284 WO 9954284PCT/JP99/02028 (methoxycarbonyl)pyrrolidin-3-ylaninolbenzarnide (94 mg) was obtained as powders from (R)-5-cyano-N- (3 ,4-dimethoxybenzyl)-2-(3pyrrolidinylamino)benzamide (116 mg) in a manner similar to Example 85(5).

NMR (DMSO-d 6 1.86(1K, in), 2.21(1K, in), 3. 16(1H, in), 3.30-3.50(2H, in), 3.55-3.80(1H, in), 3.57 and 3.59(3H, 3.72(3H, 3.74(3H, s), 4.20(1H, in), 4.35(2H, d, J=6Hz), 6.83(1H, d, J=2, 8Hz), 6.88-6.94(3K, in), 7.66(1H, dd, J=2, 8Hz), 8.09(1H, d, J=2Hz), 8.83(1K, d, J=7Kz), 9.06(1H, t, J=6Hz).

Exap~l Z 1-Acetylpyrrolidin-3-ylamino)-5-cyano-N- (3,4dimethoxybenzyl)benzamide (66 mg) was obtained as amorphous powders from -5-cyano-N-(3 ,4-dimethoxybenzyl)-2-(3pyrrolidinylamino)benzamide (100 mg) in a manner similar to Example 85(6).

NMR (DMSO-d 6 1.72-1.88(1K, in), 1.92 and 1.95(3K, 2.13- 2.36(1K, mn), 3.20(ca.0.5K, dd, J=3, 12Hz), 3.27(ca.0.5H, dd, J=5, 3.35-3.60(4K, mn), 3.63(ca.0.5K, dd, J=6, 12Hz), 3.72(3K, 3.74(3K, s), 3.85(ca.0.5H, dd, J=4, lO~z), 4.18 and 4.26(1H, in), 4.35(2K, d, J=6Kz), 6.83(1K, dd, J=2, 8Hz), 6.80-6.96(3K, in), 7.67(1K, dd, J=2, 8Kz), 8.09(1K, d, J=2Kz), 8.81 and 8.86(1K, d, J=6Kz), 9.06(1K, t, J=6Hz).

Exape 7(- (R)-5-Cyano-N-(3 ,4-dimethoxybenzyl)-2-(l1-formylpyrrolidin-3ylamino)benzamide (52 ing) was obtained as amorphous powders from -5-cyano-N- (3 ,4-dimethoxybenzyl) (3-pyrrolidinylaxnino)benzaxnide (100 ing) in a manner similar to Example 73(2).

NMR (DMSO-d 6 1.86(1K, in), 2.25(1K, mn), 3.15(ca.0.5H, dd, J=4, 10Hz), 3.25-3.75(3K, in), 3.72(3K, 3.74(3K, 3.84(ca.0.5K, dd, J=6, 4. 13-4.29(1K, in), 4.35(1K, d, J=6Hz), 6.83(1K, d, J=8Kz), 6.88- 6.96(3K, in), 7.68(1K, dd, J=2, 8Hz), 8. 10(1K, d, J=2Kz), 8.17 and 8.19(1K, 8.82(1K, d, J=7Kz), 9.06(1K, t, J=6Hz).

101 WO 99/54284 PCT/JP99/02028 Example 8717) A solution of potassium cyanate (53 mg) in water (1.5 mL) was added to a solution of (R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3pyrrolidinylamino)benzamide (100 mg) in acetic acid (1.5 mL). The mixture was stirred for 3 hours at 60 *C and then for 2 hours at 90 °C.

The reaction mixture was concentrated in vacuo and the residue was partitioned between chloroform and an aqueous saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by thin layer chromatography developed with 5% methanol in chloroform. The obtained product was triturated with diethyl ether to give carbamoylpyrrolidin-3-ylamino)-5-cyano-N-(3,4dimethoxybenzyl)benzamide (22 mg) as a powders.

NMR (DMSO-d 6 1.83(1H, 2.20(1H, 3.12(1H, dd, J=4, 3.20-3.45(2H, 3.57(1H, dd, J=6, 10Hz), 3.72(3H, 3.74(3H, s), 4.19(1H, 4.35(2H, d, J=6Hz), 5.80(2H, 6.84(1H, dd, J=2, 8Hz), 6.87-6.95(3H, 7.66(1H, dd, J=2, 8Hz), 8.09(1H, d, J=2Hz), 8.83(1H, d, J=7Hz), 9.05(1H, t, J=6Hz) Mass (ESI+) 424(M+H).

Example 87(8) A solution of benzyl alcohol (28 mg) in 1,2-dichloroethane (1 mL) was added dropwise to a solution of chlorosulfonyl isocyanate (37 mg) in 1,2-dichloroethane (2 mL) under 5 °C on an ice-salt bath. The mixture was stirred for one and a half hours at 4 To the mixture was added dropwise a mixture of (R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3pyrrolidinylamino)benzamide (100 mg) and triethylamine (40 mg) in 1,2-dichloroethane (3 mL) under 5 After addition, the reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by a thin layer chromatography developed with 5% methanol in chloroform. The obtained product was triturated with diethyl ether to give 1-(N-benzyloxycarbonylsulfamoyl)pyrrolidin-3-ylamino]-5- 102 WO 99/54284 WO 9954284PCTIJP99/02028 cyano-N-(3,4-dimethoxybenzyl)benzamide (65 mg) as a syrup.

NMR (DMSO-d 6 1.84(1H, in), 2.22(11-, in), 3.2 1(1H, dd, J=4, 3.40-3.55(2H, mn), 3.65-3.80(1H, mn), 3.71(3H, 3.72(3H, 4.20(1H, in), 4.36(2H, d, J=6Hz), 5.08(2H, 6.83(1H, dd, J=2, 8Hz), 6.89(lH, d, J=8Hz), 6.93(1H, d, J=2Hz), 7.25-7.45(6H, mn), 7.68(lH, dd, J=2, 8Hz), 8. 11(1H, d, J=2Hz), 8.85(lH, d, J=7Hz), 9.06(1H, t, J=6Hz) Mass: (ESI+) 594(M+H), (ESI-) 593(M-H).

Exmple7.{9a (R)-2-(l-Sulfamoylpyrrolidin-3-ylamino)-5-cyano- N-(3,4dimethoxybenzyl)benzamide (26 mg) was obtained as white crystals from (N-benzyloxycarbonylsulfamoyl) pyrrolidin-3-ylamino N-(3,4-diinethoxybenzyl)benzamide (60 mg) in a manner similar to Preparation 78(3).

NMR (DMSO-d 6 1.79(lH, in), 2.29(1H, in), 2.94(1H, dd, J=5, 3.15-3.30(2H, in), 3.5 1(1H, dd, J=7, 10Hz), 3.72(3H, 3.74(3H, s), 4.22(1H, in), 4.36(2H, d, J=6Hz), 6.80-6.95(6H, mn), 7.67(1H, dd, J=2, 9Hz), 8. 10(lH, d, J=2Hz), 8.85(1H, d, J=7Hz), 9.07(1H, t, J=6Hz).

Preparation 88(1) To a solution of 5-broino-2-fluorobenzaldehyde (10 g) in dimnethylformamide (60 inL) were added zinc cyanide (6.92 g) and tetrakis(triphenylphosphine)palladium(0) (2.28 and the mixture was stirred at 8000 for 6 hours. The resulting mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacua.

The residue was subjected to a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate 1) to give 5-cyano-2fluorobenzaldehyde (5.3 g) as a solid substance.

NMR (DMSO-d 6 7.35 (1H, t, J 9Hz), 7.91 (1H, in), 8.22 (1H, dd, J= 2, 7Hz), 10.36 (1H, s) Mass in/z: 150 Preparation 88(2) 103 WO 99/54284 PCT/JP99/02028 To a solution of 5-cyano-2-fluorobenzaldehyde (145 mg) in acetonitrile (2 mL) were added a sodium dihydrogenphosphate aqueous solution (23 mg in 1 mL water) and 30% hydrogen peroxide (0.09 mL).

To the resulting mixture was added dropwise a sodium chlorite aqueous solution (126mg in 1 mL water) for an hour at 0 The mixture was stirred for an hour at ambient temperature, then a small amount of sodium sulfite was added. The mixture was diluted with ethyl acetate and washed successively with 1N-hydrochloric acid and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo.

The residue was triturated with diisopropyl ether to give 5-cyano-2fluorobenzoic acid (137 mg) as a solid substance.

NMR (DMSO-d 6 7.29 (1H, t, J 9 Hz), 7.83 (1H, 8.32 (1H, dd, J 2, 7 Hz) Mass m/z 164 Preparation 88(3) 5-Cyano-N-(3,4-dimethoxybenzyl)-2-fluorobenzamide (228 mg) was obtained from 5-cyano-2-fluorobenzoic acid (130 mg) and veratrylamine 0.14 mL) in a manner similar to Preparation 1.

NMR (DMSO-d 6 3.73 (3H, 3.75 (3H, 4.40 (2H, d, J 6 Hz), 6.82-6.96 (3H, 7.56 (1H, t, J 9 Hz), 8.04 (1H, 8.11 (1H, dd, J 2, 6Hz), 9.02 (1H, t, J 6 Hz) Mass m/z: 313 Example 88(1) (S )-5-Cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1methylethylamino)benzamide (112 mg) was obtained from 3 ,4-dimethoxybenzyl)-2-fluorobenzamide (120 mg) and (S )-2-amino- 1-propanol (0.09 mL) in a manner similar to Example 1(1).

mp 142-143.5°C NMR (DMSO-d 6 1.13(3H, d, J 6 Hz), 3.42 (2H, t, J 5 Hz), 3.67 (1H, 3.72 (3H, 3.74 (3H, 4.34 (2H, d, J 5 Hz), 4.92 (1H, t, J 5 Hz), 6.81-6.95 (4H, 7.60 (1H, dd, J 2, 9 Hz), 8.03 (1H, d, J 2 Hz), 8.69 (1H, d, J 8 Hz), 8.97 (1H, t, J 5 Hz) 104 WO 99/54284 PCT/JP99/02028 Mass m/z 368 Example 88(2) To a solution of (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(2hydroxy- 1-methylethylamino)benzamide (177 mg) in dimethylformamide (4 mL) was added sodium hydride (19.2 mg) at ambient temperature.

After stirring for 20 minutes, 4-fluorobenzonitrile (63.8 mg) was added to the mixture. After stirring for an hour at 60 the mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo.

The residue was subjected to a silica gel column chromatography eluting with the mixture of chloroform and ethyl acetate to give cyano-2-[2-(4-cyanophenoxy)- 1-methylethylamino]-N-(3,4dimethoxybenzyl)benzamide (76 mg) as a solid substance.

NMR (DMSO-d 6 1.28 (3H, d, J= 7 Hz), 3.49 (2H, 3.72 (3H, 3.73 (3H, 4.13 (3H, 4.34 (2H, d, J= 6 Hz), 6.80-6.95 (4H, 7.09 (2H, d, J= 9 Hz), 7.63 (1H, dd, J= 2, 9 Hz), 7.76 (2H, d, J= 9 Hz), 8.06 (1H, d, J= 2 Hz), 8.83 (1H, d, J= 8 Hz), 9.02 (1H, t, J= 6 Hz) Mass m/z 469 Example 88(3) To a solution of (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(2hydroxy-1-methylethylamino)benzamide (4 g) in pyridine (20 mL) was added methanesulfonyl chloride (1.36 and the mixture was stirred for an hour at 0 The resulting mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give (S)-5-cyano-N-(3,4dimethoxybenzyl)-2- [2-(methanesulfonyloxy)- 1methylethylamino]benzamide (5.43 g) as an oil.

NMR (DMSO-d 6 1.22 (3H, d, J= 7 Hz), 3.17 (3H, 3.72 (3H, 3.74 (3H, 4.08 (1H, 4.23 (2H, d, J= 5 Hz), 4.36 (2H, d, J= 6 Hz), 6.81- 6.96 (4H, 7.66 (1H, dd, J= 2, 9 Hz), 8.08 (1H, d, J= 2 Hz), 8.74 (1H, d, J= 8 Hz), 9.05 (1H, t, J= 6 Hz) 105 WO 99/54284 WO 9954284PCT/JP99/02028 Mass m/z: 448 (M1+ 1).

Triphenyiphosphine (156 mg) was added to a mixture of cyano-N- (3 ,4-dimethoxybenzyl)- 2- (2-hydroxy- 1methylethylamino)benzamide (200 mg) and carbontetrabromide (215 mg) in dichioromethane (4 mL), and the mixture was stirred for an hour at ambient temperature. After evaporation of the solvent, the residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate to give 2-(2-bromo-1methylethylamino) -5-cyano-N- (3 ,4-dimethoxybenzyl)benzamide (161 mg) as a solid substance.

NMR (DMSO-d 6 ,c5):1.25 (3H, d, J= 7 Hz), 3.67 (2H, in), 3.72 (3H, 3.74 (3H, 4.04 (1H, in), 4.36 (2H, d, J= 6 Hz), 6.82-6.95 in), 7.65 (1H, dd,J= 2, 9Hz), 8.07(1H, d, J=2Hz),8.79(1H, d, J=8Hz), 9.04(1H, t,J= 6 Hz).

To a solution of (S)-2-(2-bromo- 1 N-(3,4-diinethoxybenzyl)benzamide (117 mg) in dimethylsulfoxide (2 mL) was added sodium cyanide (26.5 mng), and the mixture was stirred for an hour at 90 TC. The resulting mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate to give (S)-5-cyano-2-(2-cyano- 1methylethylamino)-N-(3,4-dimethoxybenzyl)benzamide (73 mng) as a solid substance.

NMR (DMSO-d 6 1.29 (3H, d, J= 7 Hz), 2.83 (2H, d, J= 5 Hz), 3.72 (3H, 3.74 (3H, 4.08 (1H, mn), 4.36 (2H, d, J= 6 Hz), 6.82-6.95 (4H, in), 7.66 (1H, dd, J= 2, 9 Hz), 8.09 (1H, d, J= 2 Hz), 8.78 (1H, d, J= 8 Hz), 9.07 (1H, t, J= 6 Hz) Mass m/z: 377 106 WO 99/54284 WO 9954284PCT/JP99/02028 Eamnple88(b To a solution of (S)-2-(2-bromo-1-methylethylamino)-5-cyano- N-(3,4-dimethox-ybenzyl)benzamide (61 mg) in dimethylsulfoxide (2 mL) was added imidazole (28.8 mg), and the mixture was stirred for 2 hours at 100 TC. The resulting mixture was diluted with ethyl acetate and washed successively with sodium bicarbonate solution, water and brine.

The organic layer was dried over sodium sulfate and evaporated in vacuo.

The residue was subjected to a silica gel column chromatography eluting with 10% methanol in chloroform. The obtained product was treated with hydrochloric acid to give -5-cyano-N- (3 ,4-dimethoxybenzyl) -2- (1-imidazolyl) -1-methylethylamino]benzamide hydrochloride (24 mg) as a solid substance.

NMR (DMSO-d 6 1.17 (3H, d, J= 7 Hz), 3.73 (3H, 3.75 (3H, s), 4.20-4.45 (5H, in), 6.80-6.97 (4H, mn), 7.61 (1H, dd, J= 2, 9 Hz), 7.64 (1H, 7.72 (1H, 8.08 (1H, d, J= 2 Hz), 8.63 (1H, d, J= 8 Hz), 9.09 (2H, mn) Mass in/z: 454 Examipe88M -5-Cyano-N- (3 ,4-dimethoxybenzyl) (2-methyliinidazol- 1yl)- 1-inethylethylaminolbenzamnide hydrochloride (68 mng) was obtained from (2-bromo-l1-inethylethylanino)-5-cyano-N-(3 ,4dimethoxybenzyl)benzamide (153 mg) and 2-methylimidazole (87.1 ing) in a manner similar to Example 88 NMR (DMSO-d 6 1.23 (3H, d, J= 7 Hz), 3.70 (1H, in), 3.73 (3H, 3.75 (3H, 4.29 (2H, in), 4.36 (1H, d, J= 6 Hz), 6.70-6.95 (4H, in), 7.49 (1H, d, J= 2 Hz), 7.56 (1H, dd, J= 2, 9 Hz), 7.62 (1H, d, J= 2 Hz), 8.04 (1H, d, J= 2 Hz), 8.57 (1 H, d, J= 8 Hz), 9. 11 (1 H, t, J= 6 Hz) Mass in/z: 468 Eape8W To a solution of (S)-2-(2-broino- N-(3,4-dimethoxybenzyl)benzamide (147 mg) in dimethylsulfoxide (2 inL) was added benzenesulfinic acid sodium salt (81.6 ing), and the mixture was stirred for 3 hours at 90 The resulting mixture was diluted with 107 WO 99/54284 PCT/JP99/02028 ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo.

The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate to give N-(3,4-dimethoxybenzyl)-2-(2-phenylsulfonyl- 1methylethylamino)benzamide (94 mg) as a solid substance.

NMR (DMSO-d 6 1.27 (3H, d, J= 7 Hz), 3.65 (2H, 3.72 (3H, 3.74 (3H, 4.07 (1H, 4.30 (2H, 6.62 (1H, d, J= 9 Hz), 6.83 (1H, dd, J= 2, 9 Hz), 6.91 (1H, d, J= 9 Hz), 6.92 (1H, d, J= 2 Hz), 7.48-7.69 (4H, m), 7.79 (1H, d, J= 8 Hz), 7.99 (1H, d, J= 2 Hz), 8.55 (1H, d, J= 8 Hz), 8.93 (1H, t, J= 6 Hz) Mass m/z 492 Example 88(9) To a solution of (S)-2-(2-bromo-1-methylethylamino)-5-cyano- N-(3,4-dimethoxybenzyl)benzamide (101 mg) in a mixture of dimethylformanide (1.5 mL) and water (0.2 mL) was added sodium azide (45.6 mg), and the mixture was stirred for 2 hours at 80 The resulting mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo The residue was triturated with diethyl ether to give (S)-2-(2-azido-1-methylethylamino)-5-cyano- N-(3,4-dimethoxybenzyl)benzamide (75 mg) as a solid substance.

NMR (DMSO-d 6 1.18 (3H, d, J= 7 Hz), 3.49 (2H, 3.72 (3H, 3.74 (3H, 3.96 (1H, 4.36 (2H, d, J= 6 Hz), 6.81-6.95 (4H, 7.64 (1H, dd, J= 2, 9 Hz), 8.07 (1H, d, J= 2 Hz), 8.74 (1H, d, J= 8 Hz), 9.03 (1H, t, J= 6 Hz) Mass m/z 393 Example 88(10) To a solution of (S)-2-(2-azido- (3,4-dimethoxybenzyl)benzamide (505 mg) in a mixture of ethanol (5 mL) and dichloromethane (3 mL) was added 10% palladium on activated carbon (60 mg), and the mixture was stirred under hydrogen atmosphere 108 WO 99/54284 WO 9954284PCT/JP99/02028 (1 atm) for 3 hours at ambient temperature. The resulting mixture was filtered through celite and washed with ethanol. The filtrate and the washings were combined and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with methanol in chloroform to give (S)-2-(2-amino- cyano-N.-(3,4-dimethoxybenzyl)benzamide (393 mg) as a solid substance.

NMR (DMSO-d 6 1.13 (3H, d, J= 7 Hz), 1.58 (2H, br), 2.55 (1H, in), 2.57 (1H, in), 3.54 (1H, mn), 3.72 (3H, 3.74 (3H, 4.35 (2H, d, J= 6 Hz), 6.81-6.95 (4H, mn), 7.59 (1H, dd, J= 2, 9 Hz), 8.02 (1H, d, J= 2 8.66 (1H, d, J= 8 Hz), 8.98 (1H, t, J= 6 Hz) Mass m/z 367 1).

Example88(l1) (S)-5-Cyano-N-(3 ,4-dimethoxybenzyl)-2-[2-(forinamido)- 1methylethyiaminolbenzamide (73 mng) was obtained from amino-i -methylethyiainino)-5-cyano-N- (3,4dimethoxybenzyl)benzantide (100 mng) and ethyl formate (2.0 g) in a manner similar to Example 73(2).

NMR (DMSO-d 6 1.16 (3H, d, J= 7 Hz), 3.05 (1H, in), 3.28 (1H, in), 3.70 (1H, in), 3.72 (3H, 3.74 (3H, 4.35 (2H, d, J= 6 Hz), 6.8 1-6.98 4H, in), 7.63 (1 H, dd, J= 2, 9 Hz), 8.03-8.07 (2H, in), 8.26 (1 H, in), 8.63 (1H, d, J= 8 Hz), 9.01 (1H, t, J= 6 Hz).

Mass m/z: 395 Example 8(12) To a solution of (2-amino-i 1-iethylethylamiino) 3 ,4-dimethoxybenzyl)benzamide (99 mng) in dichloroinethane (3 mL) was added acetic anhydride (38 mng), and the mixture was stirred for an hour at ambient temperature. The resulting mixture was evaporated in vacuo. The residue was triturated with diisopropyl ether to give [2-(acetan-iido)-i-inethylethylamino]-5-cyano-N-(3,4dimethoxybenzyl)benzamide (107 ing) as a solid substance.

NMR (DMSO-d 6 1.15 (3H, d, J= 7 Hz), 1.80 (3H, 3.04 (1H, mn), 3.23 109 WO 99/54284 WO 9954284PCT/JP99/02028 (1H, in), 3.68 (1H, in), 3.72 (3H, 3.74 (3H, 4.35 (2H, d, J= 6 Hz), 6.81-7.02 (4H, in), 7.63 (1H, dd, J= 2, 9 Hz) 8.05 (1H, d, 3= 8 Hz), 8.10 (1H, t, J= 6 Hz), 8.59 (1H, d, 3= 8 Hz) 9.01 (1H, t, J= 6 Hz) Mass m/ z: 409 1).

Example 88(13) To a mixture of (S)-2-(2-axino- (3,4-dimethoxybenzyl)benzamide (98 mg) and triethylarnine (0.074 mL) in dichioromethane (3 mL) was added methanesulfonyl chloride (0.029 mL), and the mixture was stirred for an hour at ambient temperature.

The resulting mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in uacuo. The residue was triturated with diisopropyl ether to give (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-[2- (methanesulfonylamino)- 1-methylethylamino~benzamide (110 mg) as a solid substance.

NMR (DMSO.-d 6 1.19 (3H, d, J=7Hz), 2.88 (3H, 2.94 (1H, in), 3.07 (1H, in), 3.68 (1H, in), 3.72 (3H, 3.74 (3H, 4.35(2H, d, J=6Hz), 6.8 1-6.94 (4H, in), 7.27 (1H, t, J=6Hz), 7.64 (1H, dd, J=2, 9Hz), 8.05 (1H, d, J=8Hz), 8.63 (1H, d, J=8Hz), 9.02 (1H, t, J=6Hz) Mass in/z: 445 Example 88(14) -5-Cyano-2- j2-(ethoxycarbonylamino)- -1 -ethylethylaniinol- N-(3,4-diinethoxybenzyl)benzaxnide (60 mg) was obtained from amino-i1 -methylethylainino) -5-cyano-N- (3 ,4-dimethoxybenzyl) benzamide (110 ing) and ethyl chloroforinate (0.04 inL) in a manner similar to Example 88(13).

NMR (DMSO-d 6 1.14 (3H, t, J=7Hz), 1. 15 (3H, d, 3=7Hz), 2.87 (1H, in), 3.15 (1H, in), 3.67 (1H, in), 3.72 (3H, 3.74 (3H, 3.98 (2H, q, 3=7Hz), 4.35 (2H, d, J=6Hz), 6.82-6.99 (4H, in), 7.37 (1H, t, 3=6Hz), 7.63 (lH, dd, J=2, 9Hz), 8.05 (1H, d, 3=8Hz), 8.59 (1H, d, J=8Hz), 9.00 (1H, t, 3=6Hz) Mass in/z 439 1).

110 WO 99/54284 PCT/JP99/02028 Example 88(15 To a solution of (S)-2-(2-amino-1-methylethylamino)-5-cyano-N- (3,4-dimethoxybenzyl)benzamide (52 mg) in ethanol (3 mL) was added dimethyl N-cyanodithioiminocarbonate (22.7 mg), and the mixture was stirred for 6 hours at ambient temperature. The solvent of the reaction mixture was evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate to give (S)-5-cyano-2-[2-(N-cyano-Smethylisothioureido)-1 -methylethylamino]-N-(3,4dimethoxybenzyl)benzamide (52 mg) as a solid substance.

NMR (DMSO-d 6 1.18 (3H, d, J=7Hz), 3.29 (1H, 3.34 (3H, 3.44 (1H, 3.72 (31-1, 3.75 (3H, 3.93 (1H, 4.36 (2H, 6.81-6.97 (4H, 7.62 (1H, dd, J=2, 9Hz), 8.06 (1H, d, J=8Hz), 8.49 (1H, br), 8.64 (1H, d, J=8Hz), 9.02 (1H, t, J=6H) Mass m/z: 465 Example 88416 To a solution of (S)-5-cyano-2-[2-(N-cyano-Smethylisothioureido) -1 -methylethylamino] dimethoxybenzyl)benzamide (48 mg) in ethanol (2 mL) was added methylamine in methanol 0.3 mL), and the mixture was stirred in a sealed tube for 6 hours at 60 The resulting mixture was evaporated in vacuo and the residue was triturated with diethyl ether to give (S)-5-cyano-2- [2-(2-cyano-3-methylguanidino)- 1methylethylamino]-N-(3,4-dimethoxybenzyl)benzamide (32 mg) as a solid substance.

NMR (DMSO-d 6 1.17 (3H, d, J= 7 Hz), 2.63 (3H, d, J= 5 Hz), 3.07 (1H, 3.27 (1H, 3.72 (3H, 3.74 (3H, 3.83 (1H, 4.35 (2H, m), 6.82-7.00 (4H, 7.07 (1H, q, J= 5Hz), 7.14 (1H, t, J= 5 Hz), 7:60 (1H, dd, J= 2, 9 Hz), 8.05 (1H, d, J= 8 Hz), 8.59 (1H, d, J= 8 Hz), 9.02 (1H, t, J 6 Hz) Mass m/z 448 Example 88(17 111 WO 99/54284 WO 9954284PCT/JP99/02028 -5-Cyano-N-(3 ,4-dimethoxybenzyl)-2- (2-hydroxy- 1 methylethylamino)benzamide (103 mg) was prepared from (3,4-dimethoxybenzyl)-2-fluorobenzamide (115 mg) arnd -2-amino- 1 propanol (0.085 mL) in a similar manner to Example 1(1).

NMR (DMSO-d 6 1.13(3H, d, J=6Hz), 3.42(2H, t, J=5Hz), 3.67(1H, in), 3.72(3H, 3.74(3H, 4.34(2H, d, J=5Hz), 4.92(1H, t, J=5Hz), 6.8 1- 6.95(4H-, in), 7.60(1H, dd, J=2, 9Hz), 8.03(1H, d, J=2Hz), 8.69(1H, d, J=8Hz), 8.97(1H, t, Mass m/z 368 1).

Preparation 89(1) (3 ,4-dimethoxybenzyl) -2-fluorobenzaxnide (4.01 g) was obtained from 5 -bromo-2 -flu orobenzoic acid (3.0 g) and veratrylamine 2.27 mL) in a in a manner similar to Preparation 1.

NMR (DMSO-d 6 3.73 (3H, 3.74 (3H, 4.38 (2H, d, J 6 Hz), 6.82-6.96 (3H, in), 7.31 (1H, t, J 9 Hz), 7.68-7.76 (2H, in), 8.94 (1H, t, J =6 Hz) Mass m/z 366, 368 1).

Preparation 89(2) To a solution of 5-broino-N-(3,4-dimethoxybenzyl)-2fluorobenzaxnide (200 mg) in dimethylformamide (2 mL) were added methyl acrylate (0.068 mL), triethylamine (0.09 mL) and dichlorobis(triphenylphosphine)palladium(II) (13.4 mg), and the mixture was stirred for 6 hours at 12000 in a sealed tube. The resulting mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate 1) to give N-(3,4-dimethoxybenzyl)-2-fluoro-5-[trans-2- (methoxycarbonyl)ethenyl)benzarmde (117 mg) as a solid substance.

NMR (DMSO-d 6 3.73 (3H, 3.74 (3H, 3.75 (3H, 4.40 (2H, d, J 6 Hz), 6.68 d, J =16 Hz), 6.82-6.96 (3H, mn), 7.36 (1H, t, J 9 Hz), 7.70 (1H, d, J 16 Hz), 7.87-7.96 (2H, in), 8.91 (1H, t, J 6 Hz).

112 WO 99/54284 PCT/JP99/02028 Mass m/z 372 Example 89(1) N-(3,4-Dimethoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)- 5-(trans-2-methoxycarbonylethenyl)benzamide (121 mg) was obtained from N-(3,4-dimethoxybenzyl)-2-fluoro-5-[trans-2- (methoxycarbonyl)ethenyl]benzamide and trans-4-aminocyclohexanol (118 mg) in a manner similar to Example 1(1).

NMR (DMSO-d 6 1.14-1.40 (4H, 1.76-1.86 (2H, 1.91-2.00 (2H, 3.35-3.53 (2H, 3.68 (3H, 3.72 (3H, 3.74 (3H, 4.37 (2H, d, J 6 Hz), 4.59 (1H, d, J 4 Hz), 6.41 (1H, d, J 16 Hz), 6.77 (1H, d, J 9 Hz), 6.83 (1H, dd, J 2, 9 Hz), 6.91 (1H, d, J 9 Hz), 6.93 (1H, d, J 2 Hz), 7.52 (1H, d, J 16 Hz), 7.61 (1H, dd, J 2, 9 Hz), 8.02 (1H, d, J 2 Hz), 8.49 (1H, d, J 8 Hz), 8.91 (1H, t, J 6 Hz).

Example 89(2) To a solution of N-(3,4-dimethoxybenzyl)-2-(trans-4hydroxycyclohexylamino)-5-(trans-2methoxycarbonylethenyl)benzamide (82 mg) in a mixture of tetrahydrofuran (2 mL) and water (0.1 mL) were added 4methylmorpholine N-oxide (53.2 mg) and 4% aqueous solution of osmium tetroxide (0.1 mL). The mixture was stirred for 2 hours under reflux. To the mixture were added 50 aqueous methanol (2 mL) and sodium periodate (161 mg). After siring for 20 minutes, the mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate to give dimethoxybenzyl)-5-formyl-2-(trans-4hydroxycyclohexylamino)benzamide (117 mg) as a solid substance.

NMR (DMSO-d 6 1.16-1.42 (4H, 1.77-1.87 (2H, 1.92-2.02 (2H, 3.38-3.54 (2H, 3.72 (3H, 3.74 (3H, 4.36 (2H, d, J 6 Hz), 4.61 (1H, d, J 4 Hz), 6.80-6.95 (4H, 7.75 (1H, dd, J 2, 9 Hz), 8.17 (1H, d, J 2 Hz), 8.79 (1H, d, J 8 Hz), 9.10 (1H, t, J 6 Hz), 9.65 (1H, s) 113 WO 99/54284 WO 9954284PCT/JP99/02028 Mass m/z: 411 Preparation N-(3 ,4-Dimethoxybenzyl)-2-fluoro-5-formylbenzamide (915.8 mg) was obtained from N- (3 ,4-dimethoxybenzyl)-2-fluoro-5vinylbenzamide 1 g) in a manner similar to Example 89(2) as a colorless solid substance.

mp. 132-133*C NMR (CDCl 3 3.86(3H, 3.89(3H, 4.64(2H, d, J=5.5Hz), 6.85(1H, d, J=8.OHz), 6.91(1H, 6.92(1H, d, J=8.QHz), 6.89-7.O1(1H, in), 7.29(1H, dd, J= 11.0, 8.5Hz), 8.06(1H, in), 8.66(1H, dd, J=7.0, 10.04(1H, s) Mass m/z: 316(M+- 1).

Preparation 90(2) N- (3,4-Dimethoxybenzyl)-2-fluoro- 5-formylbenzamide (900 mng) and glyoxal trimeric dihydrate (596 mg) were stirred in methanol (9 mL) at -10 Ammonia was bubbled through the solution for 5 minutes and the mixture was stirred for an hour at 10 The mixture was allowed to warm to ambient temperature over 16 hours, then poured into water and extracted twice with chloroform. The combined extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo.

The residue was purified by a flash column chromatography over silica gel with 5% methanol in chloroform as eluent to give N-(3,4dimethoxybenzyl)-2-fluoro-5- (1H-imidazol-2-yl)benzamide (323.1mg) as a pale brown solid substance.

mp. 164-166 0

C

NMR (DMSO-d 6 3.73(3H, 3.75(3H, 4.42(2H, d, 6.87(1H, d, J=8.OHz), 6.93(1H, d, J=8.OHz), 6.98(1H, 7.03(1H, s), 7.26(1H, 7.39(1H, t, J=8.OHz), 8.05(1H, mn), 8. 17(1H, dd, J=7.0, 8.92(1H, t, J=5.5Hz), 12.6 1(lH, s) Mass in/z: 354(M+- 1).

114 WO 99/54284 WO 9954284PCT/JP99/02028 N- (3,4-Dimethoxybenzyl) (trans-4-hydroxycyclohexylamino) 5-(1H-imidazol-2-yl)benzamide (18.5 mg) was obtained as a pale gray solid substance from N- (3 ,4-dirnethoxybenzyl)-2-fluoro-5-(l1 -imidazol- 2-yl)benzamide (70 mg) and trans-4-aminocyclohexanol (90.8 mg) in a manner similar to Example 1(1).

mp. 189-190*C NMR (DMSO-d 6 1.10-1.42(4H, in), 1.76-1.88(2H, mn), 1.93-2.05(2H, mn), 3.27-3.54(2K, in), 3.73(3H, 3.74(3H, 4.36(2H, d, 4.58(1K, d, J=4.5Hz), 6.80(1K, d, J=8.5Hz), 6.85(1H, d, J=8.O~z), 6.92(1K, d, J=8.OHz), 6.97(1H, 7.04(2H, 7.77(2H, d, J=8.O~z), 8.13(1H, 8.83(1K, t, J=5.SHz), 12.18(lH, s) Mass m/z 45 1).

Preparation 9 1(1) To a solution of 2-chloro-5-inethylphenol (5.00 g) and potassium carbonate (7.27 g) in anhydrous dimethylformamide (30 mL) was added methyl iodide (3.27 mL), and the mixture was stirred for 3 hours at ambient temperature. The mixture was partitioned between water and ethyl acetate. The separated organic layer was washed with water and brine and dried over magnesium sulfate. The resultant was evaporated in vacuo to give 4-chloro-3-methoxytoluene as a colorless oil (5.65 g).

NMR (CDCl 3 :2.34 (3K, 3.89 (3K, 6.72 (2K, mn), 7.22 (1K, d, J= 8 Hz).

Preparation- 91(2) To a solution of 4-chloro-3-methoxytoluene (5.65 g) and Nbromosuccinimide (6.74 g) in anhydrous dichioromethane (60 mL) was added 2,2 -azobis(4-methoxy-2 ,4-dimethylvaleronitrile) (674 mg). After stirring for 3 hours under reflux, the mixture was washed with water and brine, dried over magnesium sulfate and evaporated in uacuo. The residue was triturated with hexane to give 4-chloro-3-methoxybenzyl bromide as white powders (2.00 g).

NMR (ODC1 3 3.92 (3H, 4.46 (2K, 6.9 1-6.96 (2K, mn), 7.32 (1K, d, J= 8 Hz).

115 WO 99/54284 PCT/JP99/02028 Preparation 91(3) To a solution of 4-chloro-3-methoxybenzyl bromide (7.00 g) in anhydrous dimethylformamide (50 mL) was added potassium phthalimide (6.03 and the mixture was stirred for 2 hours at ambient temperature. The mixture was partitioned between ethyl acetate and water. 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 N-(4-chloro-3methoxybenzyl)phthalimide as white powders (5.88 g).

NMR (CDC1 3 6) 3.90 (3H, 4.80 (2H, 6.96 (1H, d, J= 8 Hz), 7.05 (1H, 7.25-7.31 (1H, 7.68-7.75 (2H, 7.82-7.90 (2H, m).

Preparation 91(4) To a solution of N-(4-chloro-3-methoxybenzyl)phthalimide (3.00 g) in ethanol (60 mL) was added hydrazine hydrate (2.62 mL), and the mixture was heated for an hour under reflux. The resulting precipitates were filtered off and the filtrate was evaporated in vacuo. The residue was partitioned between chloroform and an aqueous saturated sodium bicarbonate solution. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give 4-chloro-3-methoxybenzylamine as a yellow oil (1.64 g).

NMR (CDC1 3 3.86 (2H, 3.92 (3H, 6.85 (1H, d,J= 8 Hz), 6.93 (1H, 7.25-7.34 (1H, d, J= 8 Hz).

Preparation 91(5) N-(4-Chloro-3-methoxybenzyl)-2-fluoro-5-nitrobenzamide (1.97 g) was obtained from 2-fluoro5-nitrobenzoic acid (1.72 g) and 4-chloro- 3-methoxybenzylamine (1.64 g) in a manner similar to Preparation NMR (CDC13, 6) 3.85 (3H, 4.50 (2H, d, J= 7 Hz), 6.94 (1H, d, J= 8 Hz), 7.15 (1H, 7.39 (1H, d, J= 8 Hz), 7.64 (1H, 8.40-8.47 (2H, 9.21 (1H, br) Mass m/z 337 116 WO 99/54284 WO 9954284PCT/JP99/02028 Exmple 91 N- (4-Chloro-3-methoxybenzyl) [2-hydroxy- 1- (hydroxy- (165 mg) was obtained from N-(4chloro-3-methoxybenzyl)-2-fluoro-5-nitrobenzamide (150 mg) and 2amino- 1,3-propanediol (60.5 mg) in a manner similar to Example 1 mp: 176-177 TC NMR (DMSO-d 6 ,65) :3.50 (4H, br), 3.55-3.68 (1H, br), 3.82 (3H4, 4.40 (2H, d, J= 7 Hz), 4.90 (2H, t, J= 7 Hz), 6.86-6.93 (2H, in), 7.11 (1H, s), 7.3 5 (1 H, d, J= 8 Hz), 8. 10 (1 H, dd, J= 4, 8 Hz), 8.58 (1 H, d, J= 4 Hz), 9. 19 (1H, d, J= 8 Hz), 9.32 (1H, br) Mass m/z: 408 Preparation 92(1) To a mixture of 4-(methylthio)benzyl alcohol (2.00 g) and carbon tetrabromide (6.45 g) in dichioromethane (40 mL) was added triphenyiphosphine (4.08 arnd the mixture was stirred for an hour at ambient temperature. After evaporation of the solvent, the residue was purified by a silica gel columin chromatography eluting with a mixture of hexane and ethyl acetate (20: 1) to give 4- (methylthio)benzyl bromide (2.00 g) as a colorless oil.

NMR (CDCl 3 2.49 (311, 4.48 (2H, 7.20 (2H, d, J= 8 Hz), 7.32 (2H, d, J= 8 Hz).

Preparation 92(2) N-[4-(Methylthio)benzyl]phthalimide (2.40 g) was obtained as colorless powders from 4-(methylthio)benzyl bromide (1.99 g) and potassium phthalimide (1.87 g) in a manner similar to Preparation 91(3).

NMR (CDCl 3 2.45 (3H, 4.80 (2H, 7.19 (2H, d, J= 8 Hz), 7.36 (2H, d, J= 8 Hz), 7.69 (2H, mn), 7.84 (2H, in).

Preparation 92(3) 4-(Methylthio)benzylamine 17 g) was obtained as a pale yellow oil from N-[4-(inethylthio)benzyl~phthalimide (2.04 g) in a manner similar to Preparation 91(4).

117 WO 99/54284 WO 9954284PCT/JP99/02028 NMR (CDC1 3 2.48 (3H, 3.83 (2H, 7.24 (4H,s) Preparation 92(4) 2 -Flu oro-N- (methylthio) benzyl] 5 -nitrobenzamide (1.45 g) was obtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (1.35 g) and 4- (methylthio)benzylamine 15 g) in a manner similar to Preparation NMR (CDCl 3 3.89 (6H, 4.63 (2H, d, J= 7 Hz), 6.84-6.93 (4H, in), 7.30 (1H, in), 8.35 (1H, in), 9.03 (1H, mn) Mass m/z: 333(M+).

Example 92 2 (trans-4 -Hydroxycyclohexyl) amino- N- [4 (methylthio)benzyl] -5 nitrobenzamide (456 mg) was obtained as yellow powders from 2fluoro-N-[4-(methylthio)benzyl]-5-nitrobenzamide (400 mng) and trans -4aminocyclohexanol (288 mg) in a manner similar to Example 1(1).

NMR (DMSO-d 6 1.20-1.44 (4H, br), 1.75-1.88 (2H, br), 1.90-2.05 (2H, br), 2.45 (3H, 3.42-3.59 (2H, br), 4.39 (2H, d, J= 7 Hz), 4.61 (1H, d, J= 4 Hz), 6.91 (1H, d, J= 8 Hz), 7.20-7.30 (4H, in), 8.11 (1H, dd, J= 4, 8 Hz), 8.62 (1H, d, J= 4 Hz), 9.10 (1H, d, J= 8 Hz), 9.38 (1H, br) Mass m/z: 414(M+).

Preparation 93(1) 3,5-Dichloro-4-methoxytoluene (5.39 g) was obtained as yellow oil from 2,6-dichloro-4-methylphenol (5.00 g) and methyl iodide (2.64 mL) in a manner similar to preparation 9 1(1).

NMR (CDC1 3 2.27 (3H, 3.87 (3H, 7.10 (2H, s).

Preparation 93(2) 3,5-Dichloro-4-methoxybenzyl bromide 10 g) was obtained as yellow oil from 3,5-dichloro-4-methoxytoluene (5.39 g) in a manner similar to preparation 91(2).

NMR (CDCl 3 3.90 (3H, 4.36 (2H, 7.33 (2H, s).

118 WO 99/54284 PCT/JP99/02028 Preparation 93(3) N-(3,5-Dichloro-4-methoxybenzyl)phthalimide (6.34 g) was obtained as colorless powders from 3,5-dichloro-4-methoxybenzyl bromide (8.00 g) and potassium phthalimide (6.04 g) in a manner similar to Preparation 91(3).

NMR (CDC13, 3.86 (3H, 4.74 (2H, 7.37 (2H, 7.70-7.78 (2H, m), 7.83-7.90 (2H, m).

Preparation 93(4) 3,5-Dichloro-4-methoxybenzylamine (1.50 g) was obtained as yellow oil from N-(3,5-dichloro-4-methoxybenzyl)phthalimide (3.00 g) in a manner similar to Preparation 91(4).

NMR (CDC1 3 3.82 (2H, 3.90 (3H, 7.28 (2H, br).

Preparation 93(5) N-(3,5-Dichloro-4-methoxybenzyl)-2-fluoro-5-nitrobenzamide (2.20 g) was obtained as colorless powders from acid (1.31 g) and 3,5-dichloro-4-methoxybenzylamine (1.50 g) in a manner similar to Preparation NMR (DMSO-d 6 3.81 (3H, 4.46 (2H, d, J= 7 Hz), 7.48 (211, 7.66 (1H, t, J= 8 Hz), 8.38-8.45 (1H, 8.46-8.53 (1H, 9.20 (1H, br).

Example 93 N-(3,5-Dichloro-4-methoxybenzyl)-2-(trans-4hydroxycyclohexylamino)-5-nitrobenzamide (365 mg) was obtained as yellow powders from N-(3,5-dichloro-4-methoxybenzyl)-2-fluoro-5nitrobenzamide (400 mg) and trans-4-aminocyclohexanol (185 mg) in a manner similar to Example 1(1).

NMR (DMSO-d 6 1.20-1.43 (4H, 1.76-1.89 (2H, br), 1.91-2.01 (2H, br), 3.48 (2H, br), 3.81 (3H, 4.39 (2H, d, J= 7 Hz), 4.61 (1H, d, J= 4 Hz), 6.92 (1H, d, J= 8 Hz), 7.45 (2H, 8.12 (1H, dd, J= 4, 8 Hz), 8.63 (1H, d, J= 4 Hz), 9.03 (1H, d, J= 8 Hz), 9.37 (1H, br).

Preparation 94(1) 119 WO 99/54284 WO 9954284PCT/JP99/02028 4-Chloro-3-nitrobenzyl bromide (7.90 g) was obtained as orange oil from 4-chloro-3-nitrotoluene (5.00 g) in a manner similar to Preparation 9 1(2).

NMR (CDCl 3 4.47 (2H, 7.54 (2H, 7.92 (LH, s).

Preparation 94(2) N- Chloro-3-nitrobenzyl)phthalimide (5.49 g) was obtained as colorless powders from 4-chloro-3-nitrobenzyl bromide (7.00 g) and potassium phthalimide (5.69 g) in a manner similar to Preparation 91(3).

NMR (CDCl 3 4.88 (2H, 7.50 (1H, d, J= 8 Hz), 7.60 (1H, dd, J= 4, 8 Hz), 7.75 (2H, in), 7.88 (2H, in), 7.90 (1H, d, J= 4 Hz).

Preparation 94(3) 4-Chloro-3-nitrobenzylamine (1.27 g) was obtained as brown oil from N-(4-chloro-3-nitrobenzyl)phthalimide (3.00 g) in a manner similar to Preparation 9 1(4).

NMR (CDCl 3 3.96 (2H, 7.50 (2H, 7.89 (1H, s).

Preparation 94(4) N- Chloro-3-nitrobenzyl) -2-fluoro- 5-nitrobenzaxnide (1 .72 g) was obtained as pale yellow powders from 2-fluoro-5-nitrobenzoic acid (1 .20 g) and 4-chloro-3-nitrobenzylamine(1.25 g) in a manner similar to Preparation NMR (DMSO-d 6 4.58 (2H, d, J= 7 Hz), 7.62-7.73 (2H, in), 7.78 (1H, d, J= 8 Hz), 8.06 (1H, 8.44 (1H, in), 8.50 (1H, in), 9.29 (1H, br) Mass in/z: 352(M+).

Exampe94 (R)-N-(4-Chloro-3-nitrobenzyl)-2-[ 1- (hydroxymethyl)propylamino]-5-nitrobenzamide (150 mg) was obtained as yellow powders from N- (4-chloro-3-nitrobenzyl) -2-fluoro- nitrobenzamide (150 mg) and (R)-2-amnino-1-buta-nol (56.7 mng) in a manner similar to Example 1 NMR (DMSO-d 6 0.89 (3H, t, J= 7 Hz), 1.40-1.56 (1H, mn), 1.60-1.77 120 WO 99/54284 PCT/JP99/02028 (1H, 3.47 (2H, br), 3.60 (1H, br), 4.51 (2H, d, J= 7 Hz), 4.91 (1H, t, J= 7 Hz), 6.92 (1H, d, J= 8 Hz), 7.67 (1H, dd, J= 4, 8 Hz), 7.76 (1H, d, J= 8 Hz), 8.04 (1H, d, J= 4 Hz), 8.12 (1H, dd, J= 4, 8 Hz), 8.65 (1H, d, J= 4 Hz), 9.14 (1H, d, J= 8 Hz), 9.46 (1H, br) Mass m/z: 421(M+).

Preparation 95(1) To a mixture of 4-cyanobenzaldehyde (5.00 g) in ethanol (50 mL) and tetrahydrofuran (20 mL) was added sodium borohydride (2.16 g) under ice-water cooling, and the mixture was stirred for an hour at 0 °C.

After evaporation of the solvent, the residue was partitioned between ethyl acetate and water. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give 4-cyanobenzyl alcohol (4.76 g) as a colorless oil.

NMR (CDCl 3 1.98 (1H, t, J= 7 Hz), 4.78 (2H, d, J= 7 Hz), 7.48 (2H, d, J= 8 Hz), 7.66 (2H, d, J= 8 Hz).

Preparation 95(2) 4-Cyanobenzyl bromide (3.16 g) was obtained as colorless powders from 4-cyanobenzyl alcohol (2.35 g) in a manner similar to Preparation 92(1).

NMR (CDC 3 4.48 (2H, 7.50 (2H, d, J= 8 Hz), 7.64 (2H, d, J= 8 Hz).

Preparation 95(3) N-(4-Cyanobenzyl)phthalimide (3.75 g) was obtained as colorless powders from 4-cyanobenzyl bromide (3.00 g) and potassium phthalimide (3.12 g) in a manner similar to Preparation 91(3).

NMR (CDCl 3 6):4.89 (2H, 7.52 (2H, d, J= 8 Hz), 7.63 (2H, d, J= 8 Hz), 7.75 (2H, 7.86 (2H, m).

Preparation 95(4) 4-Cyanobenzylamine (1.61 g) was obtained as pale yellow oil from N-(4-cyanobenzyl)phthalimide (3.70 g) in a manner similar to Preparation 91(4).

121 WO 99/54284 WO 9954284PCT/JP99/02028 NMR (CDCl 3 3.96 (2H, 7.45 (2H, d, J= 8 Hz), 7.63 (2H, d. J= 8 Hz).

Preparation 95(5) N-(4-Cyanobenzyl)-2-fluoro-5-nitrobenzamide (3.07 g) was obtained as colorless powders from 2-fluoro-5-nitrobenzoic acid 19 g) and 4-cyanobenzylamine (1.61 g) in a manner similar to Preparation NMR (DMSO-d 6 4.58 (2H, d, J3=7 Hz), 7.55 (2H, d, J3=8 Hz), 7.65 (1H, t, J= 7 Hz), 7.84 (2H, d, J= 8 Hz), 8.39-8.51 (2H, in), 9.29 (1H, br) Mass m/z: 298(M+).

N- (4-Cyanobenzyl) (trans-4-hydroxycyclohexylamino)- nitrobenzamide (428 mng) was obtained as yellow powders from N-(4- (400 mg) and trans-4ammnocyclohexanol 308 mg) in a manner similar to Example 1 NMR (DMSO-d 6 1.18-1.45 (4H, br), 1.75-1.88 (2H, br), 1.90-2.00 (2H, br), 3.40-3.58 (2H, br), 4.50 (2H, d, J= 7 Hz), 4.62 (1H, d, J= 4 Hz), 6.92 (1H, d, J3= 8Hz), 7.51 (2H, d, J3=8 Hz), 7.82 (2H, d, J=8 Hz), 8.12 (1H, dd, 4, 8 Hz), 8.67 (1H, d, 4 Hz), 9.07 (1H, d, J= 8 Hz), 9.50 (1H, br) Mass m/z: 393(M+).

2-Fluoro- 5-nitro-N- (2-pyridylmethyl)benzam-ide (468 mg) was obtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (500 mg) and 2-(aminomethyl)pyridine (307 mng) in a manner similar to Preparation NMR (DMSO-d 6 4.60 (2H, d, J3= 5 Hz), 7.30 (LH, t, 5 Hz), 7.40 (1H, d, 8 Hz), 7.66 (1H, t, J= 8 Hz), 7.80 (1H, t, J= 7.5 Hz), 8.39-8.49 (1H, in), 8.49-8.57 (2H, mn), 9.24 (1H, br) Mass m/z: 276.1 Example96a 2- (trans-4-Hydroxycyclohexylamino) -5-nitro-N- (2pyridylmethyl)benzamide (580 mng) was obtained as yellow powders from 122 WO 99/54284 WO 9954284PCT/JP99/02028 2 -fluoro- 5-nitro- N-(2 -pyridylmethyl) beflzamide (450 mg) arnd trans-4aminocyclohexanol (282 mrg) in a manner similar to Example 1 NMR (DMSO-d 6 1.18-1.43 (4H, in), 1.70-1.88 (2H, in), 1.88-2.04 (2H, in), 3.38-3.59 (2H, in), 4.54 (2H, di, J= 5 Hz), 4.61 (1H, di, J= 4 Hz), 6.92 (1H, d, J= 8 Hz), 7.28 (1H, dd, J= 5, 7.5 Hz), 7.33 (1H, d, J= 8 Hz), 7.77 (I1H, td, J= 8, 2 Hz), 8.12 (1 H, dd, J= 8, 2 Hz), 8.51 (1 H, d, J= 5 Hz), 8.68 (1H, di, J= 2 Hz), 9.05 (1H, di, 3= 8 Hz), 9.48 (1H, mn) Mass m/z: 369.2 Prpaation 97 2-Fluoro- 5-nitro-N- (3-pyridylmethyl)benzamide (510 mng) was obtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (500 mg) and 3-(aminoinethyl)pyridine (307 mg) in a manner similar to Preparation NMR (DMSO-d 6 4.52 (2H, ci, J= 5 Hz), 7.40 (1H, cid, J= 5, 7.5 Hz), 7.64 (1H, t, J= 8 Hz), 7.76 (1H, di, J= 7.5 Hz), 8.36-8.51 (3H4, in), 8.59 (1H, d, J= 2 Hz), 9.25 (1H, br) Mass m/z: 274.0 Examnple 97 2- (trans-4-Hydroxycyclohexylamino)- 5-nitro-N- (3pyridylinethyl)benzamide (625 ing) was obtained as yellow powders from 2 -fluoro -5 -nitro- N- (3-pyridylinethyl) benzamide (550 mng) and trans-4aminocyclohexanol (345 mng) in a manner similar to Example 1(1).

NMR (DMSO-d 6 c5): 1.19-1.44 (4H, in), 1.7 1-1.88 (2H, in), 1.88-2.07 (2H, in), 3.40-3.6 1 (2H, in), 4.45 (2H, d, J= 5 Hz), 4.62 (1H, ci, J= 4 Hz), 6.92 (1H, di, J= 8 Hz), 7.37 (1H, dd, J= 5, 7.5 Hz), 7.43 (1H, di, J= 7.5 Hz), 8.12 (I1H, dci, J= 8, 2 Hz), 8.47 (1H, ci, J= 5 Hz), 8.56 (1H, di, J= 2 Hz), 8.63 (1H, ci, J= 2 Hz), 9.06 (1H, ci, J= 8 Hz), 9.43 (1H, in) Mass m/z: 369.3 1).

Preparation 98 2-Fluoro- 5-nitro-N- (4-pyridylmethyl) benzarnide (534 mg) was obtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (500 mg) 123 WO 99/54284 WO 9954284PCT/JP99/02028 and 4-(anainomethyl)pyridine (307 mg) in a manner similar to Preparation NMR (DMSO-d 6 4.53 (2H, d, J= 5 Hz), 7.35 (2H, d, J= 5 Hz), 7.66 (1H, t, J= 8 Hz), 8.38-8.65 (4H, in), 9.28 (1H) Mass m/z: 274.1 Exampe 9 2 (trans-4- Hydroxycyclohexylamino) 5 -nitro (4pyridylmethyl)benzamide (548 mg) was obtained as yellow powders from 2 -fluoro 5-nitro- N -(4-pyridylmethyl) benzamide (500 mng) and trans-4aminocyclohexanol (314 mg) in a manner similar to Example 1(l).

NMR (DMSO-d 6 1.14-1.43 (4H, in), 1.69-1.88 (2H, in), 1.88-2.05 (2H, in), 3.36-3.60 (2H, in), 4.45 (2H, d, J= 5 Hz), 4.61 (1H, d, J= 4 Hz), 6.93 (1H, d, J= 8 Hz), 7.31 (2H, d, J= 5 Hz), 8.13 (1H, dd, J= 8,2 Hz), 8.51 (2H, d, J= 5 Hz), 8.69 (1H, d, J= 2 Hz), 9.06 (1H, d, J= 8 Hz), 9.48 (1H, m) Mass in/z 369.2 1).

Preparation 99(l) 2-Naphthaleneinethylamine hydrochloride (1.36 g) was obtained as white powders from N-(2-naphthylmethyl)phthaliiniide (2.80 g) in a manner similar to Preparation 91(4).

NMR (DMSO-d 6 4.19 (2H, 7.51-7.60 (2H, in), 7.63 (1H, dd, J= 8, 2 Hz), 7.87-8.05 (4H, in), 8.46 (3H, br).

Preparation 99(2) 2-Fluoro-N- (2-naphthylmethyl) -5-nitrobenzamide (1.73 g) was obtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (1.00 g) and 2-naphthalenemethylamine hydrochloride 10 g) in a manner similar to Preparation NMR (DM SO-d 6 4.67 (2H, d, J= 5 Hz), 7.44-7.57 (3H, in), 7.64 (1 H, t, J= 8 Hz), 7.80-7.98 (4H, in), 8.37-8.47 (1H1, in), 8.47-8.55 (1H, in), 9.28 (1H, mn).

Exampe99 124 WO 99/54284 WO 9954284PCT/JP99/02028 2- [2-Hydroxy- 1 -(hydroxymethyl) ethylamino] (2- (156 mg) was obtained as yellow powders from 2 -flu oro- N- (2-naphthylme thyl) 5-nitrobenzamide (200 mg) and 2-amino-l1,3-propanediol (84.3 mg) in a manner similar to Example 1 NMR (DMSO-d 6 3.45-3.72 (5H, in), 4.61 (2H, d, J= 5 Hz), 4.92 (1H, t, J= 5 Hz), 6.93 (1H, d, J= 8 Hz), 7.42-7.57 (3H, in), 7.82 (1H, 7.85-7.98 (3H, in), 8.13 (lH, dd, J= 8, 2 Hz), 8.67 (1H, d, J= 2 Hz), 9.33 (1H, d, J= 8 Hz), 9.46 (1H, m) Mass in/z: 394.2 Preparation 100 2-F'luoro-N- (2-methoxyphenyl) ethyl] -5-nitrobenzamide (1.03 g) was obtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (1.00 g) and (2-methoxyphenyl)ethylamine(613 ing) in a manner similar to Preparation NMR (DMSO-d 6 2.81 (2H, t, J= 7.5 Hz), 3.44 (2H, q, J= 7.5 Hz), 3.77 (3H, 6.86 (1H, t, J= 8 Hz), 6.95 (1H, d, J= 8 Hz), 7.11-7.24 (2H, in), 7.57 (1H, t, J= 8 Hz), 8.27-8.4 1 (2H, in), 8.65 (1H, br).

2- [2-Hydroxy-1- (hydroxymethyl) ethylamino] (2inethoxyphenyl) ethyl] -5-nitrobenzainide (198 mg) was obtained as yellow powders from 2-fluoro-N- 12- (2-methoxyphenyl)ethyl] nitrobenzamide (200 ing) and 2-amino-i ,3-propanediol (85.9 mng) in a manner similar to Example l1(I).

NMR (DMSO-d 6 2.83 (2H, t, J= 7.5 Hz), 3.42 (2H, q, J= 7.5 Hz), 3.48-3.68 (5H, in), 3.79 (3H, 4.92 (2H, t, J= 5 Hz), 6.84-6.95 (2H, in), 6.97 (1H, d, J= 8 Hz), 7.12-7.27 (2H, mn), 8. 10 (1H, dd, J= 8, 2 Hz), 8.47 (1H, d, J= 2 Hz), 8.83 (1H, in), 9.17 (1H, d, J= 8 Hz) Mass m/z: 388.3 Preparation 101 N Ethoxy- 3 -methoxybenzyl) -2 -flu oro- 5-nitrobenzamide (2.51 125 WO 99/54284 WO 9954284PCT/JP99/02028 g) was obtained as pale yellow powders from 2-fluoro-5-nitrobenzoic acid (1.50 g) and 4-ethoxy-3-methoxybenzylamine(1.51 g) in a manner similar to Preparation NMR (DMSO-d 6 1.31 (3H, t, J= 7 Hz), 3.75 (3H, 3.98 (2H, q, J= 7 Hz), 4.42 (2H, d, J= 7 Hz), 6.82-6.97 (3H, in), 7.62 (1H, in), 8.39-8.44 (2H, mn), 9.11 (1H, br).

Example 101(1) 2- (trans-4-Aminocyclohexylainino) (4-ethoxy-3 inethox-ybenzyl)-5-nitrobenzamide (314 mg) was obtained as yellow powders from N- (4-ethoxy-3-methoxybenzyl) -2-fluoro- (300 mng) and trans- 1,4-cyclohexanediamine (295 mg) in a manner similar to Example 1 NMR (DMSO-d 6 1.15-1.35 (4H, br), 1.30 (3H, t, J= 7 Hz), 1.73-1.85 (2H, br), 1.94-2.05 (2H, br), 2.56-2.70 (1H, br), 3.40-3.50 (1H, br), 3.74 (3H, 3.97 (2H, q, J= 7 Hz), 4.36 (2H, d, J= 7 Hz), 6.80-6.96 (4H, in), 8. 11 (1 H, dd, J= 4, 8Hz), 8.60 (1iH, d, J= 4 Hz), 9.02 (1 H, d, J= 8 Hz), 9.3 1 (I1H, br) Mass in/z: 441(M+).

Example 10 1(2 N- (4-Ethoxy-3-methoxybenzyl) -2-(trans-4- (115 mng) was obtained as yellow powders from 2- (trans-4-aminocyclohexylamino) (4-ethoxy-3inethoxybenzyl)-5-nitrobenzamide (150 mg) in a manner similar to Example 73(2).

NMR (DMSO-d 6 1.31 (3H, t, J= 7 Hz), 1.25-1.45 (4H, br), 1.75-1.90 (2H, br), 1.94-2.10 (2H, br), 3.48-3.55 (1H, br), 3.52-3.62 (1H, br), 3.75 (3H, 3.97 (2H, q, J= 7 Hz), 4.36 (2H, d, J= 7 Hz), 6.80-6.96 (4H, in), 7.95 (1H, 8.03 (1H, br), 8. 10 (1H, dd, J= 4, 8Hz), 8.60 (1H, d, J= 4 Hz), 9.03 (1H, d, J= 8 Hz), 9.32 (1H, br) Mass in/z: 469(M+).

Preparation 102(1) 126 WO 99/54284 PCT/JP99/02028 A solution of sodium sulphite (10.6 g) in water (20 mL) was warmed to 80 °C and slowly added with stirring to a solution of chlorosulfonyl-2-fluorobenzoic acid (10 g) in acetone (10 mL), saturated aqueous sodium carbonate being added simultaneously for keeping the liquid in alkaline. The mixture was stirred at 60*C for one and a half hours, and concentrated in vacuo. The residue was suspended in a mixture of ethanol (20 mL) and water (20 mL), then iodomethane (2.61 mL) was added to the mixture. The reaction mixture was stirred for 2 hours at 60 °C and for an hour at 100 After cooling to ambient temperature, ethanol was removed in vacuo. The resultant aqueous solution was acidified with concentrated hydrochloric acid. The aqueous solution was extracted with chloroform (3 times), and the combined organic layer was dried over magnesium sulfate. After evaporation of the solvent, the residual oil was crystallized from ethanol to give 2-fluoro-5-methanesulfonylbenzoic acid (563.6 mg) as a colorless solid.

mp 194-195 °C NMR (DMSO-d 6 3.29 (3H, 7.63 (1H, dd, J 10.5, 8.5 Hz), 8.19 (1H, ddd, J 8.5, 7.0, 2.5 Hz), 8.37 (1H, dd, J 7.0, 2.5 Hz).

Mass m/z 217(M+-1) Preparation 102(2) N-(4-Chloro-3-methoxybenzyl)-2-fluoro-5methanesulfonylbenzamide (313.9 mg) was obtained as an off-white solid substance from 2-fluoro-5-methanesulfonylbenzoic acid (250 mg) and 4-chloro-3-methoxybenzylamine (203 mg) in a manner similar to Preparation mp. 121-123°C NMR (DMSO-d 6 3.28 (3H, 3.85( 3H, 4.49 (2H, d, J 6.0 Hz), 6.94 (1H, dd, J 8.0, 2.0 Hz), 7.15 (1H, d, J 2.0 Hz), 7.40 (1H, d, J Hz), 7.63 (1H, dd, J 10.0, 8.5 Hz), 8.10 (1H, 8.16 (1H, dd, J Hz), 9.17 (1H, brt, J 6.0 Hz) Mass m/z 370(M 127 WO 99/54284 WO 9954284PCT/JP99/02028 Exmple 102 N- (4-Chloro-3-methoxybenzyl)-2-(transhydroxycyclohexylamino) -methanesulfonylbenzamide (57.2 mg) was obtained as an off-white solid substance from N-(4-chloro-3methoxybenzyl) -2-fluoro- 5-methanesulfonylbenzamide (80 mg) and trans-4-aminocyclohexanol (49.6 mg) in a manner similar to Example mp. 234-235.5 'C NMR (DMSQ-d 6 61; 1. 15-1.41 (4H, in), 1.76-1.86 (2H, in), 1.90-2.02( 2H, mn), 3.10 (3H, 3.38-3.53 (2H, in), 3.84 (3H, 4.43 (2H, d, J =6 Hz), 4.60 (1H, d, J 4 Hz), 6.89 (1H, dd, J 9, 2 Hz), 6.91 (1H, d, J =9 Hz), 7.12(1H, d, J =2 Hz), 7.38 (1H, d, J 8.5Hz), 7.70 (1H, dd, J Hz), 8.11 (1H, d, J 2.5 Hz), 8.49 (1H, d, J 8 Hz), 9.20 (1H, t, J =6Hz) Mass m/z: 465(M+-1).

Preparation 103 2 -Fluoro-N- (3-fluoro-4-methoxybenzyl) -5-nitrobenzamide (1.34 g) was obtained as pale yellow powders from 2-fluoro-5-nitrobenzoic acid 16 g) and 3 -flu oro-4 -iethoxybenzylamine hydrochloride (1.00 g) in a manner similar to Preparation in.p. 112TC NMR (DMSO-d 6 3.82 (3H, 4.42 (1H, d, J=6 Hz), 7.06-7.23 (3H, in), 7.62 (1H, dd, J=9, 9 Hz), 8.37-8.47 (2H, mn), 9.15 (1H, t, J=6 Hz) Mass m/z 32 Exmple 103 N-(3-Fluoro-4-inethoxybenzyl)-2-[2-hydroxy- 1- (230 mg) was obtained as yellow powders from 2 -flu oro-N- (3 -flu oro-4-methoxybenzyl) nitrobenzamide (263 mg) and 2-amino- 1,3-propanediol (112 mg) in a manner similar to Example 1 imp. 130-132 0

C

NMR (DMSO-d 6 3.45-3.70 (5H, mn), 3.81 (3H, 4.36 (1H, d, J= 6 Hz), 4.91 (2H, t, J= 5 Hz), 6.92 (1H, d, J= 10 Hz), 7.06-7.21 (3H, mn), 8.12 (1H, 128 WO 99/54284 WO 9954284PCT/JP99/02028 dd, J= 10, 2 Hz), 8.59 (1H, d, J= 3 Hz), 9.23-9.35 (2H, m) Mass m/z: 392(M+).

Preparation 104 N (3 -Chloro-4 -flu orobenzyl) 2-flu oro- 5-nitrobenzamide (976 mg) was obtained as pale yellow powders from 2-fluoro-5-nitrobenzoic acid (1000 mng) and 3-chloro-4-fluorobenzylamine (948 mg) in a manner similar to Preparation NMR (DMSO-d 6 4.49 d, J=6 Hz), 7.32-7.46 (2H, mn), 5.57 (1H, d, J=8 Hz), 7.64 (1H, dd, J=9, 9 Hz), 8.37-8.53 (2H, in), 9.21 (1H, t, J=6 Hz) Mass m/z: 325(M+).

ExamnpeJ14 N-(3-Chloro-4-fluorobenzyl)-2-[2-hydroxy- 1- (hydroxymethyl)ethylamino]-5-nitrobenzainide (211 mg) was obtained as yellow powders from 2 -fluoro-N- (3-chloro-4-fluorobenzyl)- nitrobenzamide (207 mng) and 2-amino-i ,3-propanediol (115 mng) in a manner similar to Example 1(1).

m.p. 235-238*C NMR (DMSO-d 6 3.28-3.70 (5H, in), 4.42 (2H, d, J= 6 Hz), 4.93 (2H, t, J= 5 Hz), 6.93 (1H, d, J= 10 Hz), 7.30-7.44 (3H, mn), 7.54 (1H, dd, J=6, 2 Hz), 8.13 (1H, dd, J= 10, 3Hz), 8.62 (1H, d, J= 3 Hz), 9.28 (1H, d, J=8 Hz), 9.37 (1H, t, J=5 Hz) Mass m/z: 396(M+).

Preparation 105 N- Chloro-4-methylbenzyl) -2-fluoro- 5-nitrobenzamide (2.25 g) was obtained as pale yellow powders from 2-fluoro-5-nitrobenzoic acid (1.65 g) and 3-chloro-4-methylbenzylamine (1.46 g) in a manner similar to Preparation NMR (DMSO-d 6 2.31 (3H, 4.46 (2H, d, J=6 Hz), 7.23 (1H, dd, J=8, 1 Hz), 7.33 (1H, d, J=8 Hz), 7.39 (1H, d, J= 1 Hz), 7.64 (1H, dd, J=9, 9 Hz), 8.37-8.50 (2H, mn), 9.19 (1H, t, J=6 Hz) Mass m/z: 321(M+).

129 WO 99/54284 WO 9954284PCT/JP99/02028 Example 105 (3-Chloro-4-methylbenzyl) (2-hydroxy- 1- (131 mg) was obtained as yellow powders from N- (3 -chloro-4-methylbenzyl) -2-fluoro- (184 mg) and (S 2-amino-1-propanol (64 mg) in a manner similar to Example 1 m.p. 178-179*C NMR (DMSO-d 6 1.16 (3H, d, J=6 Hz), 2.30 (3H, 3.45 (2H, in), 3.76 (1H, in), 4.40 (2H, d, J=5 Hz), 4.99 (1H, t, J=5 Hz), 6.90 (1H, d, J=9 Hz), 7.21 (1H, dd, J=8, 1 Hz), 7.32 (1H, d, J=8 Hz), 8.12 (1H, dd, J=9, 3 Hz), 8.61 (1H, d, J=3 Hz), 9.16 (1H, d, J=8 Hz), 9.36 (1H, t, J=5 Hz) Mass m/z: 376(M+).

Preparation 106 2-Fluoro-N- (3-methoxy-4-methylbenzyl) -5-nitrobenzamide (3.31 g) was obtained as yellow powders from 2 -flu oro- 5-nitrobenzoic acid (2.60 g) and 3-methoxy-4-methylbenzylam-ine (2.30 g) in a manner similar to Preparation NMR (DMSO-d 6 2.12 (3H, 3.78 (3H, 4.46 (2H, d, J=6 Hz), 6.83 (1H, d, 3=7.5 Hz), 6.94 (1H, 7.10 (1H, d, J=7.5 Hz), 7.63 (1H, dd, 9 Hz), 8.37-8.47 (2H, in), 9.15 (1H, t, J=6 Hz) Mass m/z: 317(M+).

Example 106 2- [2-Hydroxy- 1- (hydroxymethyl) ethylaminol (3-methoxy-4- (173 mng) was obtained as yellow powders from 2-fluoro-N- (3-methoxy-4-methylbenzyl) (171 mg) 2-amino-1,3-propanediol (98 mg) in a manner similar to Example 1 m.p. 160-162TC NMR (DMSO-d 6 2.11 (3H, 3.46-3.60 (4H, in), 3.63 (1H, in), 3.77 (3H, 4.40 (2H, d, J=6 Hz), 4.92 (2H, t, J=5 Hz), 6.80 (1H, br d, J=8 Hz), 6.92 (1H, 6.92 (1H, d, J=10 Hz), 7.08 (1H, d, 3=8 Hz), 8.12 (1H, dd, 130 WO 99/54284 WO 9954284PCT/JP99/02028 3 Hz), 8.59 (1H, d, J=3 Hz), 9.21 (1H, d, J=8 Hz), 9.30 (1H, t, J=6 Hz) Mass m/z: 388(M+).

Preparation 107 (3,5-Dimethoxybenzyl) -2 -flu oro- 5-nitrobenzamide (3.08 g) was obtained as pale yellow powders from 2-fluoro-5-nitrobenzoic acid (2.12 g) and 3,5-dimethoxybenzylamine (2.01 g) in a manner similar to Preparation NMR (DMSO-d 6 3.73 (6H, 4.44 (2H, d, J=6 Hz), 6.40 (1H, dd, J=2, 2 Hz), 6.52 (2H, d, J=2 Hz), 7.64 (1H, dd, J=9, 9 Hz), 8.37-8.48 (2H, in), 9.16 (1H, t, J=6 Hz) Mass m/z: 333(M+).

Examnple107 (S)-N-(3,5-Dimethoxybenzyl)-2-(2-hydroxy- 1- (178 mg) was obtained as yellow powders from N- 5-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (169 mg) and (S )-2-amino- 1-propanol (57 mg) in a manner similar to Example 1 m.p. 98-101*C NMR (DMSO-d 6 1.16 (3H, d, J=7 Hz), 3.46 (2H, in), 3.73 (6H, 3.75 (1H, in), 4.37 (2H, d, J=6 Hz), 4.99 (1H, t, J=5 Hz), 6.39 (LH, dd, J=2, 2 Hz), 6.49 (2H, d, J=2 Hz), 6.90 (1H, d, J=10 Hz), 8.12 (1H, dd, J= 10, 2 Hz), 8.61 (1H, d, J=2 Hz), 9. 11 (iR, d, .J=8 Hz), 9.32 (1H, t, J=6 Hz) Mass in/z: 388(M+).

Preparation 108 2-Fluoro-5-nitro-N-(4-phenoxybenzyl)benzamide (1.22 g) was obtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (1.00 g) and 4-phenoxybenzylamine 13 g) in a manner similar to Preparation NMR (DMS0-cl 6 4.49 (2H, d, J=6 Hz), 6.95-7.05 (4H, mn), 7.13 (1iH, dcl, 7.5 Hz), 7.32-7.45 (4H, in), 7.63 (1H, dcl, J=9, 9 Hz), 8.37-8.50 (2H, 131 WO 99/54284 WO 9954284PCT/JP99/02028 in), 9.18 (1H, t, J=6 Hz) Mass m/z: 365(M-1).

Example -2 (2-Hydroxy- 1 -methylethyl) amino- 5-nitro-N- (4phenoxybenzyl)benzamide (197 mig) was obtained as yellow powders from 2-fluoro- 5-nitro-N- (4-phenoxybenzyl)benzamide (207 mng) and 2-amino- 1-propanol (85 mg) in a manner similar to Example 1 m.p. 127-129TC NMR (DMSO-d 6 1.16 (3H, d, J=7 Hz), 3.46 (2H, in), 3.76 (1 H, mn), 4.43 (2H, d, J=6 Hz), 4.99 (1H, t, J=5 Hz), 6.90 (1H, d, J=7 Hz), 6.99 (4H, d, J=9 Hz), 7.13 (1H, t, J=8 Hz), 7.30-7.45 (4H, in), 8.12 (1H, dd, J=10, 3 Hz), 8.62 (114, d, J=3 Hz), 9.20 (1H, d, J=8 Hz), 9.37 (1H, t, J=6 Hz) Mass m/z: 420(M+).

Preparation 109 2-Fluoro-5-nitro-N-(4-phenylbenzyl)benzainide (1.44 g) was obtained from 2-fluoro-5-nitrobenzoic acid (827 mg) and 4phenylbenzylamine (860 ing) in a manner similar to Preparation NMR (DMSO-d 6 4.55 (2H, d, J=6 Hz), 7.36 (1H, dd, J=7.5, 7.5 Hz), 7.40-7.5 1 (4H, in), 7.57-7.72 (5H, in), 8.37-8.52 (2H, in), 9.23 (1H, t, J=6 Hz) Mass in/z: 349(M+).

Examnple109 -2-(2-Hydroxy- 1 -methylethyl) amino- 5-nitro-N- (4phenybenzyl)benzamide (167 mng) was obtained as yellow powders from (4-phenybenzyl)benzamide (178 mg) and amino- I -propanol (76 ing) in a manner similar to Example 1 in.p. 168.5-170.5'C NMR (DMSO-d 6 1.17 (3H, d, J=6 Hz), 3.46 (2H, in), 3.77 (1H, in), 4.49 (2H, d, J=6 Hz), 4.99 (1H, t, J=5 Hz), 6.90 (1H, d, J=10 Hz), 7.30-7.52 in), 7.60-7.7 1 (4H, in), 8.13 (1H4, dd, J=10, 2 Hz), 8.65 (1H, d, J=2 Hz), 9.21 (1H, d, J=8 Hz), 9.42 (2H, t, J=6 Hz) 132 WO 99/54284 WO 9954284PCT/JP99/02028 Mass m/z: 404(M+).

Example I110 (1) 2- (Cyclopentylamino)-N- nitrobenzamide (760 mg) was obtained as yellow powders from 2acid (500 mg) and 4ethoxycarbonylbenzylamine (430 mg) in a manner similar to Example NMR (CDCl 3 1.38 (3H, t, J= 7 Hz), 1.59-1.85 (6H, in), 2.00-2.15 (2H, mn), 3.91 (1H, mn), 4.37 (2H, q, J= 7 Hz), 4.66 (2H, d, J= 7 Hz), 6.64 (1H, br), 6.69 (1H, d, J= 8 Hz), 7.40 (2H, d, J= 8 Hz), 8.03 (2H, d, J= 8 Hz), 8.16 (1H, dd, J= 4, 8 Hz), 8.37 (1H, d, J= 4 Hz), 8.84 (1H, br) Mass m/z: 410(M+).

Example 110(2) A mixture of 2- (cyclopentylamino) (4-ethoxycarbonylbenzyl) (645 mg), ethanol (30 inL) and iN-sodium hydroxide solution (5 mL) was heated for 2 hours under reflux. The mixture was acidified with 1 N-hydrochloric acid to pH 4 and the organic solvent was removed by evaporation. The resulting precipitates were collected by filtration and washed with water and diethyl ether to give N-(4carboxybenzyl) (cyclopentylamino)-5-nitrobenzamide as yellow powders (541 mng).

NMR (DMSO-d 6 1.38-1.50 (2H, in), 1.56-1.70 (4H, in), 2.04 (2H, mn), 3.97 (1H, in), 4.52 (2H, d, J= 7 Hz), 6.87 (1H, d, J= 8 Hz), 7.42 (2H, d, J= 8 Hz), 7.90 (2H, d, J= 8 Hz), 8.13 (1H, dd, J= 4, 8 Hz), 8.66 (1H, d, J= 4 Hz), 9.16 (1H, d, J= 8 Hz), 9.46 (1H, br) Mass nl/z: 382(M+).

Eape103 A mixture of N- (4-carboxybenzyl) -2 -(cyclopentylamino) nitrobenzamide (120 mg), 1- (dimethylamino)propyl]-3ethylcarbodiimide hydrochloride (90.0 mg) and 1 -hydroxybenzotriazole (63.4 ing) in anhydrous diinethylforinamide (2 mL) was stirred for an 133 WO 99/54284 PCT/JP99/02028 hour at ambient temperature. After addition of 28% ammonia solution drops), the mixture was stirred for 15 hours at ambient temperature and poured into water. The resulting precipitates were collected by filtration, washed with water and purified by a silica gel column chromatography eluting with 10% methanol in chloroform. The obtained product was triturated with diisopropyl ether to give N-(4- (107 mg) as yellow powders.

NMR (DMSO-d 6 1.39-1.52 (2H, 1.56-1.73 (4H, 1.98-2.10 (2H, 3.98 (1H, 4.48 (2H, d, J= 7 Hz), 6.87 (1H, d, J= 8 Hz), 7.31 (1H, br), 7.38 (2H, d, J= 8 Hz), 7.85 (2H, d, J= 8 Hz), 7.91 (1H, br), 8.13 (1H, dd, J= 4, 8 Hz), 8.67 (1H, d, J= 4 Hz), 9.15 (1H, d, J= 8 Hz), 9.44 (1H, br) Mass m/z 383(M Example 111(1) N-(4-Aminobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide (270 mg) was obtained as yellow powders from nitrobenzoic acid (300 mg) and 4-aminobenzylamine (176 mg) in a manner similar to Example NMR (DMSO-d 6 1.40-1.51 (2H, 1.55-1.75 (4H, 1.98-2.10 (2H, 3.97 (1H, 4.24 (2H, d, J= 7 Hz), 4.97 (2H, br), 6.52 (2H, d, J= 8 Hz), 6.86 (1H, d, J= 8 Hz), 6.97 (2H, d, J= 8 Hz), 8.12 (1H, dd, J= 4, 8 Hz), 8.57 (1H, d, J= 4 Hz), 9.10-9.25 (2H, m) Mass m/z 355(M Example 111(2) To a mixture of N-(4-aminobenzyl)-2-(cyclopentylamino)-5nitrobenzamide (126 mg) and triethylamine (0.119 mL) in anhydrous dichloromethane (20 mL) was added acetyl chloride (33.5 mg). After stirring for 2 hours at ambient temperature, the mixture was washed with an aqueous saturated sodium bicarbonate solution, water and brine. The resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with 10% methanol in chloroform. The 134 WO 99/54284 WO 9954284PCT/JP99/02028 obtained product was triturated with diisopropyl ether to give N-(4acetamidobenzyl) (cyclopentylamino) -5-nitrobenzamide as yellow powders (135 mg).

NMR (DMSO-d 6 1.38-1.54 (2H, in), 1.60-1.75 (4H, mn), 1.98-2.10 br), 3.96 (1H, in), 4.38 (2H, d, J= 7 Hz), 6.86 (1H, d, J= 8 Hz), 7.25 (2H, d, J= 8 Hz), 7.54 (2H, d, J= 8 Hz), 8.13 (1H, d, J= 8 Hz), 8.62 (1H, 9.17 (1H, d, J= 8 Hz), 9.35 (1H, br), 9.92 (1H, s) Mass m/z: 395(M+).

Preparation 112(1) N- [Bis(tert-butoxycarbonyl) am-ino] -2chlorobenzyllphthaliinide (2.14 g) was obtained as colorless powders from 4- [bis (tert-butoxycarbonyl) ainino]-2-chlorobenzyl bromide (2.00 g) and potassium phthaliinide (969 ing) in a manner similar to Preparation 91(3).

NMR (CDCl 3 1.42 (18H, 4.99 (2H, 7.00 (1H, dd, J= 4, 8 Hz), 7.22 (2H, in), 7.75 (2H, in), 7.87 (2H, in).

Preparation 112(2) 4- (tert-Butoxycarbonylamino)-2-chlorobenzylamine (950 mng) was obtained as colorless oil from N- [bis(tert-butoxycarbonyl) amino] 2-chlorobenzyl]phthalimide (2.00 g) in a manner similar to Preparation 9 1(4).

NMR (CDCl 3 1.50 (9H, 3.87 (2H, 7.14 (1H, mn), 7.25 (2H, in) Mass m/z: 257(M+).

Exampe 12l N- (tert-Butoxycarbonyl) antino-2-chlorobenzyl] -2- (206 mng) was obtained as yellow powders from 2-(cyclopentylamino)-5-nitrobenzoic acid (200 mng) and 4- (tert-butoxycarbonylamino)-2-chlorobenzylamine (246 ing) in a manner similar to Example 5 1.

NMR (CDCl 3 1.50 (9H, 1.59-1.85 (6H, in), 2.06 (2H, in), 3.90 (1H, in), 4.61 (2H, d, J= 7 Hz), 6.48 (1H, br), 6.54 (1H, br), 6.67 (1H, d, J= 8 135 WO 99/54284 WO 9954284PCT/JP99/02028 Hz), 7.14 (1 H, dd, J= 4, 8Hz), 7.32 (1 H, d, J= 8 Hz), 7.61 (1 H, d, J= 4 Hz), 8.13 (1H, dd, J= 4, 8 Hz), 8.28 (1H, d, J= 4 Hz), 8.77 (1H, br) Mass m/z: 487(M+).

Example I122 To a solution of N- (tert-butoxycarbonyl) amino-2 (141 mg) in anhydrous ethyl acetate (2 mL) was added 4N-hydrochloric acid ethyl acetate solution (4 mL). After stirring for 2 hours at ambient temperature, the mixture was partitioned between I-N-sodium hydroxide solution and chloroform. 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 N-(4-amino-2chlorobenzyl) (cyclopentylamino) -5-nitrobenzamide as yellow powders (102 mg).

NMR (DMSO-d 6 1.39-1.52 (2H, in), 1.55-1.74 (4H, in), 1.96-2. 10 (2H, in), 3.97 (1H, in), 4.33 (2H, d, J= 7 Hz), 5.32 (2H, 6.49 (1H, dd, J= 4, 8 Hz), 6.62 (1H, d, J= 4 Hz), 6.85 (1H, d, J= 8 Hz), 7.03 (1H, d, J= 8 Hz), 8.13 (1lH, dd, J= 4, 8Hz), 8.59 (1lH, d, J= 4 Hz), 9.07 (1lH, d, J= 8 Hz), 9.14 (1H, br) Mass m/z: 389(M+).

Preparation 113(1) N- Chloro-4-methoxybenzyl)phthalilrlide (2.40 g) was obtained as colorless powders from 2-chloro-4-methoxybenzyl bromide (2.00 g) and potassium phthalimide (1.86 g) in a manner similar to Preparation 9 1(3).

NMR (CDCl 3 3.77 (3H, 4.93 (2H, 6.74 (1H, dd, J= 4, 8 Hz), 6.92 (1H, d, J= 4 Hz), 7.22 (1H, d, J= 8 Hz), 7.73 (2H, mn), 7.86 (2H, in).

Preparation 113(2) 2-Chloro-4-methoxybenzylamine (630 mg) was obtained as pale yellow oil from N-(2-Chloro-4-inethoxybenzyl)phthalimide (1.00 g) in a manner similar to Preparation 91(4).

136 WO 99/54284 WO 9954284PCT/JP99/02028 NMR (CDCl3,c5): 3.79 (3H, 3.86 (2H, 6.78 (1H, dd, J= 4, 8 Hz), 6.92 (1H, d, J= 4 Hz), 7.27 (1H, m) Mass m/z: 154(M+).

Examnpe113 N- Chloro-4-methoxybenzyl) (cyclopentylamnino) nitrobenzamide (146 mg) was obtained as yellow powders from 2acid (100 mng) and 2-chloro-4methoxybenzylaxnine (82.3 mg) in a manner similar to Preparation 1.

NMR (CDCl 3 1.59-1.85 (6H, in), 2.00-2.13 (2H, in), 3.80 (3H, 3.90 (1H, in), 4.62 (2H, d, J= 7 Hz), 6.52 (1H, br), 6.67 (1H, d, J= 8 Hz), 6.80 (1H, dd, J= 4, 8Hz), 6.97 (1K, d, J= 4 Hz), 7.34 (1H, d, J= 8 Hz), 8.13 (1H, dd, J= 4, 8 Hz), 8.29 (1H, d, J= 4 Hz), 8.78 (1H, br) Mass m/z: 404(M+).

Preparation 114 A solution of 3-chloro-4-methoxybenzylamifle (234 mg) in N,Ndimethylformamnide (5 mL) was added dropwise to a solution of bromoisatoic anhydride (300 mg) in N,N-dimethylforinamide (3 mL).

The reaction mixture was stirred for an hour at ambient temperature.

The mixture was poured into a mixture of water and ethyl acetate. The precipitates were collected by filtration and washed with 2-propanol to give 2-amino- 5-bromo-N- (3-chloro-4-methoxybenzyl) benzamide (245 mng) as white powders.

NMR (DMSO-d 6 3.83 (3H, 4.32 (2H, d, J =6 Hz), 6.61 (2H, 6.68 (1H, d, J 9 Hz), 7.11 (1H, d, J =9 Hz), 7.25 (1H, dd, J 2, 9Hz), 7.27 (1H, dd, J 2, 9 Hz), 7.35 (1K, d, J 2 Hz), 7.69 (1H, d, J 2 Hz), 8.88 (1H, t, J =6 Hz).

Example1 4 A solution of 97% sulfuric acid (79 mg) in tetrahydrofuran mL) was added to a mixture of 2-amino-5-bromo-N-(3-chloro-4methoxybenzyl)benzamide (199 mng), cyclopentanone (68 nag) and sodium borohydride (31 mg) in tetrahydrofuran (3 mL). The mixture 137 WO 99/54284 PCT/JP99/02028 was stirred for an hour at ambient temperature. Then cyclopentanone (68 mg), sodium borohydride (31 mg) and a solution of 97% sulfuric acid mg) in tetrahydrofuran (0.5 mL) were added to the reaction mixture.

After stirring for additional 2 hours at ambient temperature, the reaction mixture was diluted with water. The resultant was made alkaline with an aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by a preparative silica gel thin layer chromatography developed by 25% ethyl acetate in hexane. The obtained substance was dissolved in diethyl ether, and 4 N-hydrogen chloride solution in ethyl acetate (0.3 mL) was added thereto. The mixture was concentrated in vacuo and the residue was triturated with diethyl ether to give 5-bromo-N-(3-chloro-4methoxybenzyl)- 2-(cyclopentylamino)benzamide hydrochloride (198 mg) as white powders.

NMR (DMSO-d 6 1.38 (2H, 1.50-1.70 (4H, 1.95 (2H, m), 3.77( 1H, 3.83 (3H, 4.32 (1H, d, J 6 Hz), 6.87 (1H, d, J 9 Hz), 7.11 (1H, d, J 9 Hz), 7.25 (1H, dd, J 2, 9 Hz), 7.35 (1H, d, J 2 Hz), 7.40 (1H, dd, J 2, 9 Hz), 7.77 (1H, d, J 2 Hz), 8.99 (1H, t, J 6 Hz) Mass (ESI+) 437,439 (ESI-) 435,437 Preparation 115 1,3-benzodioxol-5-ylmethyl)benzamide (321 mg) was obtained as white powders from 5-chloroisatoic anhydride (300 mg) and (1,3-benzodioxol-5-ylmethyl)amine (275 mg) in a manner similar to Preparation 114.

NMR (DMSO-d 6 4.30 (2H, d, J 6 Hz), 5.98 (2H, 6.58 (2H, 6.72 (1H, d, J 9 Hz), 6.78 (1H, dd, J 1, 8 Hz), 6.86 (1H, d, J 8 Hz), 6.87 (1H, d, J 1 Hz), 7.17 (1H, dd, J 2, 9 Hz),7.58 (1H, d, J 2 Hz), 8.84 (1H, t, J 6 Hz) Mass (ESI+) 305, 307 (ESI-) 303, 305 Example 115 5-Chloro-2-(cyclopentylamino)-N-(1,3-benzodioxol-5- 138 WO 99/54284 PCT/JP99/02028 ylmethyl)benzamide hydrochloride (140 mg) was obtained as white crystals from 2-amino-5-chloro-N-(1,3-benzodioxol-5ylmethyl)benzamide (135 mg) and cyclopentanone (110 mg) in a manner similar to Example 114.

NMR (DMSO-d 6 1.32-1.45 (2H, 1.50-1.73 (4H, 1.90-2.03 (2H, 4.30 (2H, d, J 6 Hz), 5.98 (2H, 6.73 (1H, d, J 9 Hz), 6.77 (1H, d, J 8 Hz), 6.86 (1H, d, J 8 Hz), 6.88 (1H, 7.29 (1H, brd, J 9 Hz), 7.67 (1H, br), 8.95 (1H, t, J 6 Hz) Mass (ESI+) 373, 375 (ESI-) 371, 373 Preparation 116 To a suspension of 5-nitroisatoic anhydride (300 mg) in dimethylformamide (4 mL) was added 2-chlorobenzylamine (245 mg), and the mixture was stirred for 15 hours at ambient temperature. The mixture was partitioned between ethyl acetate and water. 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 2-amino-N-(2-chlorobenzyl)-5nitrobenzamide as yellow powders (397 mg).

NMR (DMSO-d 6 4.50 (2H, d, J= 7 Hz), 6.82 (1H, d, J= 8 Hz), 7.27- 7.41 (3H, 7.47 (1H, d, J= 8 Hz), 7.80 (2H, br), 8.05 (1H, dd, J= 4, 8 Hz), 8.65 (1H, d, J= 4 Hz), 9.28 (1H, br) Mass m/z 304 Example 116 N-(2-Chlorobenzyl)-2-cyclopentylamino-5-nitrobenzamide (152 mg) was obtained as yellow powders from 2-amino-N-(2-chlorobenzyl)- (150 mg) and cyclopentanone (61.9 mg) in a manner similar to Preparation 30(1).

NMR (CDCl 3 1.58-1.84 (6H, 2.00-2.15 (2H, 3.88 (1H, 4.68 (2H, d, J= 7 Hz), 6.60 (1H, br), 6.68 (1H, d, J= 8 Hz), 7.27 (2H, 7.42 (2H, 8.15 (1H, dd, J= 4, 8 Hz), 8.32 (1H, d, J= 4 Hz), 8.78 (1H, br).

Mass m/z 372 139 WO 99/54284 WO 9954284PCT/JP99/02028 Preparation 117 2 -Amino-N- (3-chlorobenzyl) -5-nitrobenzamide (400 mg) was obtained as yellow powders from 5-nitroisatoic anhydride (300 mg) and 3-chlorobenzylamine (245 mg) in a manner similar to Preparation 114.

NMR (DMSO-d6,65): 4.42 (2H, d, J= 7 Hz), 6.80 (1H, d, J= 8 Hz), 7.28- 7.40 (4H, in), 7.82 (2H, br), 8.03 (1H, dd, J= 4, 8 Hz), 8.59 (1H, d, J= 4 Hz), 9.28 (1H, br) Mass m/z: 304(M+).

Example 117 N- (3-Chlorobenzyl) -2-(cyclopentylamino) -5-nitrobenzamide (136 mg) was obtained as yellow powders from 2-amino-N-(3-chlorobenzyl)- (150 mg) and cyclopentanone (61.9 mg) in a manner similar to Preparation 30(1).

NMR (ODC1 3 1.58-1.84 (6H, in), 2.00-2.15 (2H, mn), 3.88 (1H, in), 4.58 (2H, d, J= 7 Hz), 6.60 (1H, br), 6.68 (1H, d, J= 8 Hz), 7.20-7.35 (4H, in), 8. 15 (1H, dd, J= 4, 8 Hz), 8.32 (1H, d, J= 4 Hz), 8.85 (1H, br) Mass m/z: 372(M+).

Preparation 118 2-Amino-N- (4-chlorobenzyl) -5-nitrobenzamide (407 mng) was obtained as yellow powders from 5-nitroisatoic anhydride (300 mg) and 4-chlorobenzylamine (245 ing) in a manner similar to Preparation 114.

NMR (DMSO-d6,65): 4.42 (2H, d, J= 7 Hz), 6.80 (1H, d, J= 8 Hz), 7.32- 7.44 (4H, mn), 7.82 (2H, br), 8.03 (1H, dd, J= 4, 8 Hz), 8.58 (1H, d, J= 4 Hz), 9.30 (1H, br) Mass m/z: 304(M+).

Exmple 1 8 N- (4-Chlorobenzyl) (cyclopentylamino) (97.7 mng) was obtained as yellow powders from 2-amino-N-(4- (150 mg) and cyclopentanone (61.9 ing) in a manner similar to Preparation 30(1).

NMR (CDCl3, 1.58-1.84 (6H, in), 2.00-2.15 (2H, in), 3.88 (1H, in), 4.57 140 WO 99/54284 WO 9954284PCT/JP99/02028 (2H, d, J= 7 Hz), 6.54 (1H, br), 6.68 (1H, d, J= 8 Hz), 7.27 -7.36 (4H, in), 8.15 (1H, dd, J= 4, 8 Hz), 8.32 (1H, d, J= 4 Hz), 8.78 (1H, br) Mass m/z: 372(M+).

Preparation 119 2 -Amino- N-hexyl- 5-nitrobenzamide (1.09 g) was obtained as yellow powders from 5-nitroisatoic anhydride (1.00 g) and hexylamine (583 mg) in a manner similar to Preparation 114.

NMR (DMSO-d 6 0.85 (3H, br), 1.30 (6H, br), 1.52 (2H, br), 3.20 (2H, in), 6.78 (1H, d, J= 8 Hz), 7.75 (2H, br), 8.02 (1H, dd, J= 4, 8 Hz), 8.48 (1H, d, J= 4 Hz), 8.67 (1H, br) Mass m/z: 264(M+).

Exampe 19 2-(Cyclopentylamino)-N-hexyl-5-litrobelzamide (98.0 mg) was obtained as yellow powders from (100 mg) and cyclopentanone (47.6 mg) in a manner similar to Preparation 30(1).

NMR (CDCl 3 0.90 (3H, br), 1.28-1.48 (6H, br), 1.58-1.83 (8H, br), 2.07 (2H, br), 3.38 (2H, in), 3.89 (1H, br), 6.20 (1H, br), 6.63 (1H, d, J= 8 Hz), 8.12 (1H, dd, J= 4, 8 Hz), 8.29 (1H, d, J= 4 Hz), 8.82 (1H, br) Mass m/z: 332(M+).

Example 120 N-Hexyl- 5-nitro-2-( (2-thienylmethyl)aminolbenzatnide (124 mg) was obtained as yellow powders from nitrobenzainide (200 mng) and 2-thiophenecarboxaldehyde (93.0 mng) in a manner similar to Preparation 30(1).

NMR (CDCl 3 0.90 (3H, br), 1.28-1.48 (6H, br), 1.60-1.70 (2H, br), 3.41 (2H, in), 4.66 (2H, d, J= 7 Hz), 6.28 (1H, br), 6.72 (1H, d, J= 8 Hz), 6.98 (1H, in), 7.03 (1H, in), 7.24 (1H, in), 8.15 (1H, dd, J= 4, 8 Hz), 8.33 (1Hi, d, J= 4 Hz), 9.17 (1H, br) Mass in/z: 360(M+).

141 WO 99/54284 WO 9954284PCT/JP99/02028 Exampe 1I 2- (Cycloheptylamino)-N-hexyl-5-nitrobenzamide (225 mg) was obtained as yellow powders from 2 -amnino- N-h exyl- (200 mg) and cycloheptanone (211 mg) in a manner similar to Preparation 30(1).

NMR (CDC1 3 0.89 (3H, br), 1.28-1.45 (6H, br), 1.48-1.78 (12H, br), 1.93-2.06 (2H, br), 3.40 (2H, in), 3.60 (1H, in), 6.20 (1H, br), 6.57 (1H, d, J= 8 Hz), 8.13 (1H, dd, J= 4, 8 Hz), 8.30 (1H, d, J= 4 Hz), 8.88 (1H, br) Mass m/z: 360(M+).

Preparation 122 2-Amino-N-(5-hydroxypentyl)-5-nitrobenzamide (167 mg) was obtained as yellow powders from 5-nitroisatoic anhydride (200 mg) and 1-pentanol (119 mng) in a manner similar to Preparation 114.

NMR (DMSO-d 6 1.25-1.60 (6H, mn), 3.22 (2H, in), 3.40 (2H, mn), 4.37 (1H, t, J= 7 Hz), 6.78 (1H, d, J= 8 Hz), 7.75 (2H, br), 8.02 (1H, dd, J= 4, 8 Hz), 8.49 (1H, d, J= 4 Hz), 8.68 (1H, br) Mass m/z: 266(M+).

Examnpe 122 2- (Cyclopentylamino)-N- (5-hydroxypentyl) (83.5 ing) was obtained as yellow powders from (150 mg) and cyclopentanone (142 ing) in a manner similar to Preparation 30(1).

NMR (CDCl3,65): 1.43-1.88 (12H, br), 2.00-2.15 (2H, br), 3.43 (2H, mn), 3.69 (2H, t, J= 7 Hz), 3.83-3.96 (1H, in), 6.55 (1H, br), 6.65 (1H, mn), 8.13 (1H, dd, J= 4, 8 Hz), 8.36 (1H, d, J= 4 Hz), 8.86 (1H, br) Mass in/z: 334(M+).

Preparation 123 2-Amino-N- (3-ethoxypropyl) -5-nitrobenzamide (332 mg) was obtained as yellow powders from 5-nitroisatoic anhydride (300 mng) and 3-ethoxypropylaxnine (178 ing) in a manner similar to Preparation 114.

NMR (DMSO-d 6 1.10 (3H, t, J= 7 Hz), 1.25 (2H, in), 3.29 (2H, in), 3.42 142 WO 99/54284 WO 9954284PCT/JP99/02028 (4H, mn), 6.78 (1H, d, J= 8 Hz), 7.76 (2H, br), 8.01 (1H, dd, J= 4, 8 Hz), 8.48 (1H, d, J= 4 Hz), 8.68 (1H, br) Mass m/z: 266(M+).

Examiple 123 2- (Cyclopentylamino) (3-ethoxypropyl) -5-nitrobenzainide (150 ing) was obtained as yellow powders from 2-amino-N- (3-ethoxypropyl)- (150 mg) and cyclopentanone (165 mg) in a manner similar to Preparation 30(1).

NMR (CDCl 3 1.28 (3H, t, J= 7 Hz), 1.6 1-1.84 (6H, br), 1.93 (2H, in), 2.03-2.12 (2H, mn), 3.57 (4H, in), 3.68 (2H, t, J= 7 Hz), 3.91 (1H, mn), 6.67 (1H, d, J= 8 Hz), 7.45 (1H, br), 8.15 (1H, dd, J= 4, 8 Hz), 8.32 (1H, d, J= 4 Hz), 9.01 (1H, br) Mass m/z: 334(M+).

Preparation 124 (1.66 g) was obtained as yellow powders from 5-nitroisatoic anhydride (1.50 g) and benzylamine (850 ing) in a manner similar to Preparation 114.

NMR (DMSO-d 6 4.45 (2H, d, J= 7 Hz), 6.80 (1H, d, J= 8 Hz), 7.26 (1H, mn), 7.33 (4H, in), 7.80 (2H, br), 8.01 (1H, dd, J= 4, 8 Hz), 8.58 (1H, d, J= 4 Hz), 9.28 (1H, br) Mass in/z: 270(M+).

ExampeJ24 (210 mng) was obtained as yellow powders from (200 ing) and cyclobutanone (77.5 ing) in a manner similar to preparation 30(1).

NMR (ODC1 3 c5): 1.80-2.10 (4H, in), 2.44-2.55 (2H, in), 4.00 (1H, mn), 4.6 1- (2H, d, J= 7 Hz), 6.52 (1H, br), 6.53 (1H, d, J= 8 Hz), 7.28-7.42 (5H, mn), 8.12 (1H, dd, J= 4, 8 Hz), 8.31 (1H, d, J= 4 Hz), 8.89 (1H, br) Mass in/z: 324(M+).

143 WO 99154284 WO 9954284PCT/JP99/02028 Example 19 N-Benzyl-2 -cycloheptylamnino-5-nitrobelzaIide (165 mg) was obtained as yellow powders from (200 mg) and cycloheptanone (372 mg) in a manner similar to Preparation 30(1).

NMR (CDCl 3 1.44-1.80 (10H, br), 1.95-2.07 (2H, br), 3.63 (1H, in), 4.61 (2H, d, J= 7 Hz), 6.47 (1H, br), 6.58 (1H, d, J= 8 Hz), 7.29-7.42 in), 8.15 (1H, dd, J= 4, 8 Hz), 8.30 d, J= 4 Hz), 8.90 (1H, br) Mass m/z: 366(M+).

Example 26 N-Benzyl-2- (cyclohexylamino) -5-nitrobenzamide (135 mng) was obtained as yellow powders from 2-amino-N-benzy1-5-nitrobenzainide (200 mg) and cyclohexanone (217 mng) in a manner similar to Preparation 30(1).

NMR (CDC1 3 1.27-1.70 (6H, br), 1.80 (2H, br), 2.03 (2H, br), 3.46 (1H, br), 4.59 (2H, d, J= 7 Hz), 6.46 (1H, 6.66 (1K, d, J= 8 Hz), 7.28-7.40 in), 8.13 (1H, dd, J= 4, 8 Hz), 8.32 (1H, d, J= 4 Kz),8.88 (1K, br) Mass m/z: 352(M+).

Preparation 127 2-Amino-N- (2 ,4-dichlorobenzyl) -5-nitrobenzainide (437 mng) was obtained as yellow powders from 5-nitroisatoic anhydride (300 ing) and 2,4-dichlorobenzylamine (305 mng) in a manner similar to Preparation 116.

NMR (DMSO-d 6 4.48 (2H, d, J= 7 Hz), 6.83 (1H, d, J= 8 Hz), 7.42 (2H, in), 7.63 (1K, 7.81 (2H, br), 8.05 (1H, dd, J= 4, 8 Hz), 8.64 (1H, d, J= 4 Hz), 9.29 (1K, br).

ExampleI27 2- (Cyclopentylamino) (2,4 -dichlorobenzyl) (151 ing) was obtained as yellow powders from 2-.amino-N-(2,4- (150 mng) and cyclopentanone (111 mng) in a manner similar to Preparation 30(1).

144 WO 99/54284 WO 9954284PCT/JP99/02028 NMR (CDCl 3 1.58-1.88 (6H, in), 2.08 (2H, mn), 3.89 (1 H, mn), 4.65 (2H, d, J= 7 Hz), 6.67 (1H, d, J= 8 Hz), 6.65-6.75 (1H, br), 7.25 (1H, mn), 7.36 (1 H, d, J= 8 Hz), 7.43 (1 H, d, J= 4 Hz), 8.13 (1 H, dd, J= 4, 8 Hz), 8.33 (1 H, d, J= 4 Hz), 8.75 (1H, br).

Preparation 128 2 -Amino-N- (3 ,4-dichlorobenzyl) -5-nitrobenzamide (444 mng) was obtained as yellow powders from 5-nitroisatoic anhydride (300 mg) and 3,4-dichlorobenzylainine (305 mg) in a manner similar to Preparation 116.

NMR (DM SO-d 6 4.43 (2H, d, J= 7 Hz), 6.83 (1 H, d, J= 8 Hz), 7.33 (1 H, d, J= 8 Hz), 7.59 (2H, in), 7.83 (2H, br), 8.04 (1H, dd, J= 4, 8 Hz), 8.58 (1H, d, J= 4 Hz), 9.32 (1H, br).

Exampe 28a 2- (Cyclopentylamino) (3 ,4-dichlorobenzyl) (81.8 mg) was obtained as yellow powders from 2-amiino-N-(3,4dichlorobenzyl) -5-nitrobenzamide (150 mg) and cyclopentanone (111 ing) in a manner similar to Preparation 30(1).

NMR (CDCl 3 1.58-1.86 (6H, in), 2.07 (2H, in), 3.90 (1H, in), 4.56 (2H, d, J= 7 Hz), 6.63 (1H, br), 6.69 (1H, d, J= 8 Hz), 7.18 (1H, d, J= 8 Hz), 7.43 (2H, in), 8.17 (1H, dd, J= 4, 8 Hz), 8.35 (1H, d, J= 4 Hz), 8.85 (1H, br).

Preparation 129(1) Methyl 2-(trans-4-hydroxycyclohexylamino) nitrobenzoate(20.4 g) was obtained as yellow powders from methyl 2fluoro- 5-nitrobenzoate (15.0 g) and trans-4-aminocyclohexanol (13.0 g) in a manner similar to Example 1 NMR (CDCl 3 1.36-1.57 (4H, in), 1.97-2.25 (4H, in), 3.43-3.56 (1H, in), 3.70-3.84 (1H, in), 3.90 (3H, 6.69 (1H, d, J= 8 Hz), 8.19 (1H, dd, J= 2, 8 Hz), 8.60 (1H, br d, J= 8 Hz), 8.87 (1H, d, J= 2 Hz) Mass m/z: 294.(EI+).

Preparation 129 (2) 145 WO 99/54284 PCT/JP99/02028 Methyl 2-(cis-4-acetoxycyclohexylamino)-5-nitrobenzoate (14.6 g) was obtained as yellow powders from methyl 2-(trans-4- (20.0 g) in a manner similar to Example 52(2).

NMR (DMSO-d 6 1.56-1.92 (8H, 2.04 (3H, 3.74-3.86 (1H, m), 3.89 (3H, 4.85 (1H, br), 7.05 (1H, d, J= 8 Hz), 8.20 (1H, dd, J= 2, 8 Hz), 8.64-8.73 (2H, m).

Preparation 129(3) 2-(cis-4-Hydroxycyclohexylamino)-5-nitrobenzoic acid (11.7 g) was obtained as yellow powders from methyl 2-(cis-4- (14.4 g) in a manner similar to Example 52(3).

NMR (DMSO-d 6 1.45-1.84 (8H, 3.62-3.81 (2H, 4.57 (1H, br), 6.95 (1H, d, J= 8 Hz), 8.15 (1H, dd, J= 2, 8 Hz), 8.66 (1H, d, J= 2 Hz), 8.99 (1H, d, J= 8 Hz) Mass m/z 279.1 (M+ 1 Preparation 129(4) To a mixture of 3-methoxy-4-nitrobenzyl alcohol (3.00 g) and carbon tetrabromide (8.15 g) in dichloromethane (60 mL) was added triphenylphosphine (5.16 g) under ice-water cooling, and the mixture was stirred for an hour at ambient temperature. After evaporation of the solvent, the residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (5:1) to give 3-methoxy-4-nitrobenzyl bromide as pale yellow powders (4.87 g).

NMR (CDCl 3 3.99 (3H, 4.47 (2H, 7.04 (1H, d, J= 8 Hz), 7.10 (1H, 7.83 (1H, d, J= 8 Hz).

Preparation 129(5) N-(3-Methoxy-4-nitrobenzyl)phthalimide (4.49 g) was obtained as colorless powders from 3-methoxy-4-nitrobenzylbromide (4.00 g) and potassium phthalimide (3.31 g) in a manner similar to Preparation 91(3).

NMR (CDC1 3 3.97 (3H, 4.87 (2H, 7.07 (1H, d, J= 8 Hz), 7.18 (1H, 146 WO 99/54284 WO 9954284PCT/JP99/02028 7.72-7.80 (2H, in), 7.81 (1H, d, J= 8 Hz), 7.83-7.91 (2H, in).

Preparation 129 (6) 3-Methoxy-4-nitrobenzylam~ifle (1.28 g) was obtained as yellow oil from N-(3-methoxy-4-nitrobenzyl)phthalimilde (3.00 g) in a manner similar to Preparation 91(4).

NMR (CDCl3,65): 3.97 (2H, 3.98 (3H, 6.95 (1H, d, J= 8 Hz), 7. 10 (1H, 7.84 (1H, d, J= 8 Hz).

Exampe129 2- (cis-4-Hydroxycyclohexylanfo) (3-methoxy-4-nitrobenzyl) (110 mng) was obtained as yellow powders from 2-(cisacid (100 mg) and 3methoxy-4-nitrobenzylamine (78.0 mng) in a manner similar to Preparation 1.

NMR (DMSO-d 6 1.44-1.75 (8H, br), 3.66 (2H, br), 3.93 (3H, 4.54 (3H, bin), 6.90 (1H, d, J= 8 Hz), 7.06 (1H, d, J= 8 Hz), 7.34 (1H, 7.88 (1H, d, J= 8 Hz), 8.13 (1H, dd, J= 4, 8 Hz), 8.69 (1H, d, J= 4 Hz), 9.27 (1H, br), 9.49 (1H, br) Mass m/z: 443(M+).

Preparation 130(1) N- Chloro- 5-inethoxybenzyl)phthalimide (7.69 g) was obtained as colorless powders from 2-chloro-5-methoxybenzyl bromide (8.30 g) and potassium phthalirnide (6.85 g) in a manner similar to Preparation 91(3).

NMR (CDCl 3 3.73 (3H, 4.95 (2H, 6.75 (2H, in), 7.27 (1K, in), 7.75 (2H, in), 7.88 (2H, in).

Preparation 130(2) (1.67 g) was obtained as yellow oil from N-(2-chloro-5-inethoxybenzyl)phthalirnide (3.00 g) in a manner similar to Preparation 91(4).

NMR (CDC1 3 3.80 (3H, 3.89 (2H, 6.73 (1K, dd, J= 4, 8 Hz), 6.94 147 WO 99/54284 PCT/JP99/02028 (1H, d, J= 4 Hz), 7.25 (1H, d, J= 8 Hz).

Example 130 N-(2-Chloro-5-methoxybenzyl)-2-(cis-4hydroxycyclohexylamino)-5-nitrobenzamide (125 mg) was obtained as yellow powders from 2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (100 mg) and 2-chloro-5-methoxybenzylamine (73.5 mg) in a manner similar to Preparation 1.

NMR (DMSO-d 6 1.45-1.75 (8H, br), 3.61-3.72 (2H, br), 3.74 (3H, s), 4.48 (2H, d, J= 7 Hz), 4.53 (1H, d, J= 4 Hz), 6.88-6.93 (3H, 7.39 (1H, d, J= 8 Hz), 8.13 (1H, dd, J= 4, 8 Hz), 8.67 (1H, d, J= 4 Hz), 9.17 (1H, d, J= 8 Hz), 9.36 (1H, br) Mass m/z 432(M+).

Preparation 131(1) To a solution of 3-hydroxy-4-methoxybenzoic acid (10.0 g) in methanol (100 mL) was added cone. sulfuric acid (10 mL) under icewater cooling, and the mixture was heated for 15 hours under reflux.

After evaporation of the solvent, the residue was partitioned between ethyl acetate and water. The separated organic layer was washed with an aqueous saturated sodium bicarbonate solution, water and brine.

The resultant was dried over magnesium sulfate and evaporated in vacuo to give methyl 3-hydroxy-4-methoxybenzoate as a brown oil (9.43 g).

NMR (CDCl 3 3.88 (3H, 3.95 (3H, 5.69 (1H, 6.87 (1H, d, J= 8 Hz), 7.57-7.64 (2H, m).

Preparation 131(2) To a mixture of methyl 3-hydroxy-4-methoxybenzoate (4.00 g) and potassium carbonate (4.55 g) in dimethylformamide (20 mL) was added ethyl iodide (2.63 mL) under water-cooling and the mixture was stirred for 2 hours at ambient temperature. The mixture was partitioned between water and ethyl acetate. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give methyl 3-ethoxy-4-methoxybenzoate as 148 WO 99/54284 PCT/JP99/02028 pale brown powders (4.55 g).

NMR (CDC13,6): 1.49 (3H, t, J= 7 Hz), 3.89 (3H, 3.93 (3H, 4.16 (2H, q, J= 7 Hz), 6.89 (1H, d, J= 8 Hz), 7.54 (1H, d, J= 4 Hz), 7.66 (1H, dd, J= 4, 8 Hz).

Preparation 131(3) A mixture of methyl 3-ethoxy-4-methoxybenzoate (4.42 g), methanol (160 mL) and 1N-sodium hydroxide solution (40 mL) was heated for 2 hours under reflux. The reaction mixture was acidified with 1N-hydrochloric acid to pH 4, and the organic solvent was removed by evaporation. The aqueous layer was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with hexane to give 3-ethoxy-4-methoxybenzoic acid as colorless powders (3.76 g).

NMR (CDCl 3 1.50 (3H, t, J= 7 Hz), 3.95 (3H, 4.17 (2H, q, J= 7 Hz), 6.92 (1H, d, J= 8 Hz), 7.60 (1H, d, J= 4 Hz), 7.76 (1H, dd, J= 4, 8 Hz) Mass m/z 195(M+).

Preparation 131(4) To a mixture of 3-ethoxy-4-methoxybenzoic acid (3.66 g) and oxalyl chloride (2.12 mL) in dichloromethane (40 mL) was added dimethylformamide (5 drops), and the mixture was stirred for 2 hours at ambient temperature. After evaporation of the solvent, the residue was redissolved in dichloromethane (40 mL). The solution was added to a mixture of 28% ammonia solution (40 mL) and dichloromethane (40 mL) under ice-water cooling. The mixture was stirred for an hour at ambient temperature. The resulting precipitates were collected by filtration and washed with water and diethyl ether to give 3-ethoxy-4methoxybenzamide as colorless powders (3.40 g).

NMR (DMSO-d 6 1.34 (3H, t, J= 7 Hz), 3.80 (3H, 4.04 (2H, q, J= 7 Hz), 7.00 (1H, d, J= 8 Hz), 7.18 (1H, br), 7.39-7.51 (2H, 7.83 (1H, br).

Preparation 131(5) 149 WO 99/54284 PCT/JP99/02028 To a solution of 3-ethoxy-4-methoxybenzamide (3.30 g) in pyridine (33 mL) was added phosphorus oxychloride (1.73 mL) under ice-water cooling, and the mixture was stirred for 2 hours at ambient temperature. After evaporation of the solvent, the residue was partitioned between ethyl acetate and water under ice-water cooling.

The separated organic layer was washed with 1N-hydrochloric acid, water and brine, dried over magnesium sulfate and evaporated in vacuo.

The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (5:1 to 4:1) to give 3-ethoxy- 4-methoxybenzonitrile as colorless powders (2.83 g).

NMR (CDC1 3 1.49 (3H, t, J= 7 Hz), 3.93 (3H, 4.10 (2H, q, J= 7 Hz), 6.90 (1H, d, J= 8 Hz), 7.08 (1H, d, J= 4 Hz), 7.27 (1H, dd, J= 4, 8 Hz).

Preparation 131(6) To a suspension of lithium aluminum hydride (1.17 g) in anhydrous tetrahydrofuran (15 mL) was added a solution of 3-ethoxy- 4-methoxybenzonitrile (2.73 g) in tetrahydrofuran (15 mL). The mixture was stirred for an hour under water cooling and then for an hour at ambient temperature. Potassium sodium (+)-tartrate aqueous solution was added to the mixture under ice-water cooling. The mixture was diluted with ethyl acetate and the insolubles were filtered off. After evaporation of the filtrate, ethyl acetate was added. The solution was dried over magnesium sulfate and evaporated in vacuo to give 3-ethoxy- 4-methoxybenzylamine as yellow oil (2.81 g).

NMR (CDC1 3 1.47 (3H, t, J= 7 Hz), 3.80 (2H, 3.87 (3H, 4.12 (2H, q, J= 7 Hz), 6.80-6.90 (3H, m).

Example 131 N-(3-Ethoxy-4-methoxybenzyl)-2-(cis-4hydroxycyclohexylamino)-5-nitrobenzamide (130 mg) was obtained as yellow powders from 2-(cis4-hydroxycyclohexylamino)-5-nitrobenzoic acid (100 mg) and 3-ethoxy-4-methoxybenzylamine (77.6 mg) in a manner similar to Preparation 1.

NMR (DMSO-d 6 1.32 (3H, t, J= 7 Hz), 1.45-1.80 (8H, br), 3.60-3.75 150 WO 99/54284 WO 9954284PCT/JP99/02028 (2H, br), 3.73 (3H, 3.99 (2H, q, J= 7 Hz), 4.37 (2H, d, J= 7 Hz), 4.55 (1H, d, J= 4 Hz), 6.82-6.96 (4H, in), 8. 10 (1K, dd, J= 4, 8 Hz), 8.60 (1H, d, J= 4 Hz), 9.24 (1H, d, J= 8 Hz), 9.32 (1H, br) Mass m/z: 442(M+).

Preparation 132(1) 4-Chloro-3-ethoxytoluefle (6.08 g) was obtained as pale yellow oil from 2-chloro-5-methylphenol (5.00 g) and ethyl iodide (4.21 mL) in a manner similar to Preparation 9 1(1).

NMR (CDC1 3 1.46 (3H, t, J= 7 Hz), 2.32 (3H, 4.09 (2H, q, J= 7 Hz), 6.66-6.73 (2H, in), 7.22 (1H, d, J= 8 Hz).

Preparation 132(2) 4-Chloro-3-ethoxybenzyl bromide (8.75 g) was obtained as yellow oil from 4-chloro-3-ethoxytoluene (6.00 g) in a manner similar to Preparation 91(2).

NMR (CDCl 3 1.48 (3H, t, J= 7 Hz), 4.11 (2H, q, J= 7 Hz), 4.44 (2H, s), 6.84-6.95 (2H, in), 7.30 (1H, d, J= 8 Hz).

Preparation 132(3) N- (4-Chloro-3-ethoxybenzyl)phthalmide (7.88 g) was obtained as colorless powders from 4-chloro-3-ethoxybenzyl bromide (8.75 g) and potassium phthalimide (6.82 g) in a manner similar to Preparation 91(3).

NMR (CDCl 3 1.46 (3H, t, J= 7 Hz), 4.11 (2H, q, J= 7 Hz), 4.78 (2H, s), 6.95 (1H, d, J= 8 Hz), 7.04 (1H, 7.27 (1H, d, J= 8 Hz), 7.72 (2H, mn), 7.85 (2H, in).

Preparation 132(4 4-Chloro-3-ethoxybenzylamlfle (2.25 g) was obtained as yellow oil from N-(4-chloro-3-ethoxybenzyl)phthalimide (4.00 g) in a manner similar to Preparation 91(4).

NMR (CDCl 3 1.48 (3H, t, J= 7 Hz), 3.82 (2H, 4.12 (2H, q, J= 7 Hz), 6.79 (1H, d, J= 8 Hz), 6.90 (1H, 7.25 (1H, d, J= 8 Hz).

151 WO 99/54284 WO 9954284PCT/JP99/02028 Exampe 32 N- (4-Chloro-3-ethoxybenzyl) (cis-4-hydroxycyclohexylamino)- (130 mg) was obtained as yellow powders from 2-(cisacid (100 mg) and 4-chioro- 3-ethoxybenzylamine (79.5 mg) in a manner similar to Preparation 1.

NMR (DMSO-d 6 1.36 (3H, t, J= 7 Hz), 1.45-1.80 (8H, br), 3.58-3.65 (2H, br), 4.11 (2H, q, J= 7 Hz), 4.44 (2H, d, J= 7 Hz), 4.56 (1H, d, J= 4 Hz), 6.86-6.92 (2H, in), 7.12 (1H, 7.38 (1H, d, J= 8 Hz), 8.12 (1H, dd, J= 4, 8 Hz), 8.64 (1H, d, J= 4 Hz), 9.25 (1H, d, J= 8 Hz), 9.40 (1H, br) Mass m/z: 446(M+).

Preparation 133(l) Methyl 4-hydroxy-3-methoxybenzoate (25.2 g) was obtained as colorless powders from 4-hydroxy-3-methoxybenzoic acid (25.9 g) in a manner similar to Preparation 13 1(1).

NMR (CDCl 3 3.89 (3H, 3.94 (3H, 6.07 (1H, 6.94 (1H, d, J= 8 Hz), 7.55 (1H, 7.64 (1H, d, J= 8 Hz).

Preparation 133(2) Methyl 4-ethoxy- 3-methoxybenzo ate 10 g) was obtained as colorless powders from methyl 4-hydroxy-3-methoxybenzoate (4.00 g) and ethyl iodide (2.63 mL) in a manner similar to Preparation 13 1(2).

NMR (CDC1 3 1.50 (3H, t, J= 7 Hz), 3.89 (3H, 3.93 (3H, 4.14 (2H, q, J= 7 Hz), 6.88 (1H, d, J= 8 Hz), 7.54 (1H, d, J= 4 Hz), 7.65 (1H, dd, J= 4, 8Hz).

Preparation 133(3) 4-Ethoxy-3-inethoxybenzoic acid (3.46 g) was obtained as colorless powders from methyl 4-ethoxy- 3-meth oxybenzo ate (3.97 g) in a manner similar to Preparation 13 1(3).

NMR (CDC1 3 1.52 (3H, t, J= 7 Hz), 3.92 (3H, 4.18 (2H, q, J= 7 Hz), 6.89 (1H, d, J= 8 Hz), 7.58 (1H, 7.73 (1H, d, J= 8 Hz) Mass m/z: 195(M+).

152 WO 99/54284 WO 9954284PCT/JP99/02028 Preparation 133(4) 4-Ethoxy--3-methoxybenzamide (1.74 g) was obtained as colorless powders from 4-ethoxy-3-methoxybenzoic acid (3.36 g) in a manner similar to Preparation 131(4).

NMR (DMSO-d 6 1.34 (3H, t, J=7 Hz), 3.79 (3H, 4.05 (2H, q, J= 7 Hz), 6.97 (1H, d, J= 8Hz), 7.19 (1H, br), 7.44-7.49 (2H, in), 7.85 (1H, br).

Preparation 133(5) 4-Ethoxy-3-methoxybenzonitrile (1.88 g) was obtained as colorless powders from 4-ethoxy-3-methoxybenzamide (2.21 g) in a manner similar to Preparation 131(5).

NMR (CDCl 3 1.52 (3H, t, J= 7 Hz), 3.89 (3H, 4.17 (2K, q, 3= 7 Hz), 6.88 (1H, d, J= 8 Hz), 7.07 (1K, d, J= 4 Hz), 7.25 (1H, dd, J= 4, 8 Hz) Mass m/z 178(M+).

Preparation 133(6) 4-Ethoxy-3-methoxybenzylamine (1.77 g) was obtained as colorless oil from 4-ethoxy-3-methoxybenzonitrile (1.78 g) in a manner similar to Preparation 13 1(6).

NMR (CDCl 3 1.46 (3H, t, J= 7Hz), 3.81 (2H, 3.89 (3K, 4.09 (2H, q, J= 7 Hz), 6.80-6.90 (3H, in).

Exapk-3 N- (4-Ethoxy-3-methoxybenzyl) -2-(cis-4hydroxycyclohexylamino)-5-nitrobenzamide (120 mg) was obtained as yellow powders from 2-(cis-4-hydroxycyclohexylamino)-5-nitrobelzoic acid (100 mg) and 4-ethoxy-3-methoxybenzylarnine (77.6 mg) in a manner similar to Preparation 1.

NMR (DMSO-d 6 1.31 (3H, t, J= 7 Hz), 1.43-1.75 (8H, br), 3.62-3.72 (2K, br), 3.75 (3H, 3.97 (2H, q, J= 7Hz), 4.38 (2H, d, J=7 Hz), 4.55 (1K, d, 3= 4Hz), 6.81-6.97 (4K, in), 8. 11 (1H, dd, J= 4, 8Hz), 8.61 (1H, d, 3=4 Hz), 9.27 (1H, d, J= 8 Hz), 9.32 (1H, br) Mass m/z 442(M+).

153 WO 99/54284 WO 9954284PCT/JP99/02028 Preparation 134(1) Ethyl 3-methoxy-4-(2-methoxyethoxy)benzoate (5.69 g) was obtained as colorless powders from ethyl 4-hydroxy-3-methoxybenzoate (5.00 g) and 2-methoxyethyl bromide (3.59 mL) in a manner similar to Preparation 131(2).

NMR (CDCl 3 1.39 (3H, t, J= 7 Hz), 3.46 (3H, 3.81 (2H, t, J= 4 Hz), 3.91 (3H, 4.23 (2H, t, J= 4 Hz), 4.35 (2H, q, J= 7 Hz), 6.91 (1H, d, J= 8 Hz), 7.55 (1H, d, J= 4 Hz), 7.65 (1H, dd, J= 4, 8 Hz).

Preparation 134(2) 3-Methoxy-4-(2-methoxyethoxy)benzoic acid (4.57 g) was obtained as colorless powders from ethyl 3-methoxy-4-(2methoxyethoxy)benzoate (5.68 g) in a manner similar to Preparation 13 1(3).

NMR (DMSO-d 6 3.31 3.68 (2H, t, J= 4 Hz), 3.80 (3M, 4.15 (2H1, t, J= 4 Hz), 7.05 (1H, d, J= 8 Hz), 7.44 (1H, d, J= 4 Hz), 7.53 (1H, dd, J= 4, 8 Hz) Mass m/z: 225(M+).

Preparation 134(3) 3.-Methoxy-4- (2-methoxyethoxy)benzainide (3.86 g) was obtained as colorless powders from 3-methoxy-4-(2methoxyethoxy)benzoic acid (4.56 g) in a manner similar to Preparation 13 1(4).

NMR (DMSO-d 6 3.31 (3H, 3.67 (2H, t, J= 4 Hz), 3.80 (3H, 4.12 (2H, t, J= 4 Hz), 7.00 (1H, d, J= 8 Hz), 7.21 (1H, br), 7.46 (2H, in), 7.86 (1H, br).

Preparation 134(4) 3-Methoxy-4-(2-methoxyethoxy)benzonitrile (3.21 g) was obtained as colorless powders from 3-methoxy-4-(2methox-yethoxy)benzamide (3.66 g) in a manner similar to Preparation 13 NMR (CDCl3,(5): 3.45 (3H, 3.81 (2H, t, J= 4 Hz), 3.88 (3H, 4.20 (2H, 154 WO 99/54284 PCT/JP99/02028 t, J= 4 Hz), 6.93 (1H, d, J= 8 Hz), 7.08 (1H, d, J= 4 Hz), 7.25 (1H, dd, J= 4, 8 Hz).

Preparation 134(5) 3-Methoxy-4-(2-methoxyethoxy)benzylamine (3.26 g) was obtained as pale yellow oil from 3-methoxy-4-(2methoxyethoxy)benzonitrile (3.11 g) in a manner similar to Preparation 131(6).

NMR (CDC13, 3.45 (3H, 3.77 (2H, t, J= 4 Hz), 3.79 (2H, 3.87 (3H, 4.16 (2H, t, J= 4 Hz), 6.78-6.92 (3H, m).

Example 134 2-(cis-4-Hydroxycyclohexylamino)-N-[3-methoxy-4-(2- (150 mg) was obtained as yellow powders from 2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (120 mg) and 3-methoxy-4-(2-methoxyethoxy)benzylamine (109 mg) in a manner similar to Preparation 1.

NMR (DMSO-d 6 1.45-1.75 (8H, br), 3.30 (3H, 3.62 (2H, 3.60- 3.70 (2H, br), 3.75 (3H, 4.03 (2H, 4.38 (2H, d, J= 7 Hz), 4.56 (1H, d, J= 4 Hz), 6.83-6.98 (4H, 8.11 (1H, dd, J= 4, 8 Hz), 8.61 (1H, d, J= 4 Hz), 9.26 (1H, br), 9.32 (1H, br).

Preparation 135(1) Ethyl 4-cyclobutylmethoxy-3-methoxybenzoate (6.32 g) was obtained as colorless oil from ethyl 4-hydroxy-3-methoxybenzoate (5.00 g) and cyclobutylmethyl bromide (4.30 mL) in a manner similar to Preparation 131(2).

NMR (CDC1 3 1.41 (3H, t, J= 7 Hz), 1.80-2.05 (4H, 2.13-2.28 (2H, 2.78-2.96 (1H, 3.91 (3H, 4.04 (2H, d, J= 7 Hz), 4.35 (2H, q, J= 7 Hz), 6.87 (1H, d, J= 8 Hz), 7.54 (1H, d, J= 4 Hz), 7.65 (1H, dd, J= 4, 8 Hz).

Preparation 135(2) 4-Cyclobutylmethoxy-3-methoxybenzoic acid (5.10 g) was 155 WO 99/54284 WO 9954284PCT/.JP99/02028 obtained as colorless powders from ethyl 4-cyclobutylmethoxy-3methoxybenzoate (6.20 g) in a manner similar to Preparation 13 1(3).

NMR (DMSO-d 6 1.76-1.98 (4H, in), 2.00-2.17 (2H, in), 2.65-2.83 (1H, in), 3.80 (3H, 4.00 (2H, d, J= 7 Hz), 7.04 (1H, d, J= 8 Hz), 7.43 (1H1, d, J= 4 Hz), 7.54 (1H, dd, J= 4, 8 Hz) Mass m/z: 235(M+).

Preparation 135(3) 4-Cyclobutylmethoxy-3-methoxybenzamide (4.50 g) was obtained as colorless powders from 4-cyclobutylinethoxy-3methoxybenzoic acid (4.90 g) in a manner similar to Preparation 131(4).

NMR (DMSO-d 6 1.75-2.00 (4H, in), 2.03-2.17 (2H1, in), 2.67-2.80 (1H, in), 3.79 (3H, 3.98 (2H, d, J= 7 Hz), 6.99 (1H, d, J= 8 Hz), 7.19 (111, br), 7.43-7.50 (211, in), 7.85 (1H1, br).

Preparation 135(4) 4-Cyclobutylmethoxy-3-nethoxybenzonitrile (3.21 g) was obtained as colorless powders from 4-cyclobutylmethoxy-3inethoxybenzamide (4.35 g) in a manner similar to Preparation 13 NMR (DMSO-d 6 1.80-2.06 (4H, in), 2. 12-2.27 (2H, in), 2.78-2.94 (111, in), 3.87 (311, 4.03 (2H1, d, J= 7 Hz), 6.88 (1H1, d, J= 8 Hz), 7.07 (111, d, J= 4 Hz), 7.25 (1H, dd, J= 4, 8 Hz).

Preparation 135(5) 4-Cyclobutylinethoxy-3-methoxybenzylamline (3.61 g) was obtained as pale yellow oil from 4-cyclobutylmethoxy-3methoxybenzonitrile (3.54 g) in a manner similar to Preparation 131(6).

NMR (CDC 3 ,6):1.80-2.00 (411, in), 2.10-2.25 (2H, in), 2.76-2.92 (111, in), 3.81 (2H, 3.87 (311, 3.98 (2H, d, J= 7 Hz), 6.78-6.86 (311, in).

Preparation 135(6) N- (4-Cyclobutylmethoxy-3 -iethoxybenzyl) -2-fluoro- nitrobenzainide (3.17 g) was obtained as yellow powders from 2-fluoroacid (2.33 g) and 4-cyclobutylrnethoxy-3- 156 WO 99/54284 WO 9954284PCT/JP99/02028 methoxybenzylamine(2.87 g) in a manner similar to Preparation NMR (DMSO-d 6 1.75-1.98 (4H, in), 2.02-2.14 (2H, in), 2.63-2.78 (1H, in), 3.75 (3H, 3.90 (2H, d, J= 7 Hz), 4.42 (2H, d, J= 7 Hz), 6.83-6.98 (3H, in), 7.63 (1H, t, J= 7 Hz), 8.37-8.44 in), 9.12 (1H, br) Mass m/z: 387(M-1.

Example 135 N- Cyclobutylmethoxy-3-methoxybelzyl) -hydroxy- 1- (123 mg) was obtained as yellow powders from N- (4-cyclobutylmethoxy-3-nethoxybenzyl) -2- (150 mng) and 2-arnino- 1,3-propanediol (52.8 mg) in a manner similar to Example 1 NMR (DMSO-d 6 1.75-1.98 (4H, in), 2.00-2.15 (2H, in), 2.65-2.79 (1H, mn), 3.50-3.60 (4H, br), 3.60-3.70 (1H, br), 3.74 (3H, 3.89 (2H, d, J= 7 Hz), 4.36 (2H, d, J= 7 Hz), 4.93 (2H, t, J= 7 Hz), 6.83 (1H, dd, J= 4, 8 Hz), 6.89-7.00 (3H, in), 8.12 (1H, dd, J= 4, 8 Hz), 8.57 (1H, d, J= 4 Hz), 9.21 (111, d, J= 8 Hz), 9.27 (1H, br).

Example 36 A mixture of 2- (cis-4-hydroxycyclohexylamino) acid (120 mng), cyclohexanemethylamine (53.3 mng), 1-[3- (diinethylamino)propyl]-3-ethylcarbodiimide hydrochloride (107 mg) and 1-hydroxybenzotriazole (81.0 mng) in anhydrous dimethylformamide (3 mL) was stirred for 18 hours at ambient temperature. The mixture was partitioned between water and ethyl acetate. The separated organic layer was washed with iN-hydrochloric acid, water, an aqueous saturated sodium bicarbonate solution and brine, successively, and dried over magnesium sulfate. After evaporation of the solvent, the residue was triturated with diisopropyl ether to give Ncyclohexylinethyl-2- (cis-4-hydroxycyclohexylamino) (157 mg) as yellow powders.

NMR (DMSO-d 6 0.83-1.04 (2H, in), 1.04-1.3 1 (3H, in), 1.40-1.82 (14H, in), 3.09 (2H, t, J= 7 Hz), 3.65 (2H, br), 4.55 (1H, d, J= 4 Hz), 6.86 (1H, d, J= 8 Hz), 8. 10 (1H, dd, J= 2, 8 Hz), 8.55 (1H, d, J= 2 Hz), 8.83 (1H, 157 WO 99/54284 WO 9954284PCT/JP99/02028 in), 9.25 (1H, d, J= 8 Hz) Mass m/z: 374.3 Example 137 2- (cis-4-Hydroxycyclohexylamino) (1-naphthylmethyl) nitrobenzamide (165 mg) was obtained as yellow powders from 2-(cis-4hydroxycyclohexylanino) -5-nitrobenzoic acid (120 mng) and 1naphthalenemethylamine (74.0 mg) in a manner similar to Example 136.

NMR (DMSO-d 6 1.45-1.80 (8H, in), 3.67 (2H, br), 4.58 (1H, d, J= 4 Hz), 4.94 (2H, d, J= 5 Hz), 6.89 (1H, d, J= 8 Hz), 7.45-7.66 (4H, in), 7.84-7.93 (1H, in), 7.97 (1H, dd, J= 2, 8 Hz), 8.11 (1H, dd, J= 2, 9Hz), 8.17 (1H, d, J= 8 Hz), 8.61 (1H, d, J= 2 Hz), 9.26 (1H, d, J= 8 Hz), 9.43 (1H, mn) Mass m/z: 418.2 Example 138 2- (cis-4-Hydroxycyclohexylamino) -5-nitro-N- (2quinolinylmethyl)benzamide (53.0 mg) was obtained as yellow powders from 2- (cis-4-hydroxycyclohexylainino) -5-nitrobenzoic acid (100 mng) and 2-aininomethyiqunoline (62.1 ing) in a manner similar to Example 136.

NMR (DMSO-d 6 1.39-1.76 (8H, in), 3.65 (2H, br), 4.51 (1H, d, J= 4 Hz), 4.74 (2H, d, J= 5 Hz), 6.93 (1H, d, J= 8 Hz), 7.52-7.64 (2H, in), 7.76 (1H, t, J= 8 Hz), 7.95-8.04 (2H, in), 8.14 (1H, dd, J= 2, 8 Hz), 8.37 (1H, d, J= 8 Hz), 8.78 (1H, d, J= 2 Hz), 9.25 (1H, d, J= 8 Hz), 9.63 (114, in) Mass m/z 419.2 1).

Example139 2- (cis-4-Hydroxycyclohexylamino) -5-nitro-N- 1phenylethyllbenzamide (123 ing) was obtained as yellow powders from 2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (120 mng) and 1-phenylethylarnine (62.3 ing) in a manner similar to Example 136.

NMR (DMSO-d 6 1.41-1.72 (1 1H, in), 3.65 (2H, br), 4.53 (1H, d, J= 4 Hz), 5. 10-5.24 (1H, in), 6.87 (1H, d, J= 8 Hz), 7. 19-7.30 (1H, in), 7.30- 7.45 (4H, in), 8.12 (1H, dd, J= 2, 8 Hz), 8.71 (1H, d, J= 2 Hz), 9.10-9.23 158 WO 99/54284 PCT/JP99/02028 (2H, m) Mass m/z 382.2 Preparation 140(1) To a solution of 2-(trifluoromethyl)benzyl bromide (1.50 g) in ethanol (15 mL) was added a solution of sodium cyanide (461 mg) in water (15 mL) at ambient temperature, and the mixture was heated for 3 hours under reflux After evaporation of the organic solvent, the aqueous layer was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give [2-(trifluoromethyl)phenyl]acetonitrile (1.08 g) as an oil.

NMR (CDC1 3 3.97 (2H, 7.48 (1H, t, J= 8 Hz), 7.62 (1H, t, J= 8 Hz), 7.66-7.75 (2H, m).

Preparation 140(2) 2-[2-(Trifluoromethyl)phenyl]ethylamine hydrochloride (187 mg) was obtained as pale yellow powders from [2- (trifluoromethyl)phenyl]acetonitrile (1.08 g) in a manner similar to Preparation 131(6).

NMR (DMSO-d 6 2.94-3.15 (4H, 7.44-7.59 (2H, 7.62-7.79 (2H, 8.16 (2H, br).

Example 140 A mixture of 2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (120 mg), [2-(trifluoromethyl)phenyl]ethylamine hydrochloride (111 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (86.4 mg) and 1hydroxybenzotriazole (81.0 mg) in anhydrous dimethylformamide (3 mL) was stirred for 18 hours at ambient temperature. The mixture was partitioned between water and ethyl acetate. The separated organic layer was washed with 1N-hydrochloric acid, water, an aqueous saturated sodium bicarbonate solution and brine, successively, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by a preparative silica gel thin layer 159 WO 99/54284 WO 9954284PCT/JP99/02028 chromatography with a mixture of hexane and ethyl acetate The obtained product was recrystallized from a mixture of petroleum ether and diethyl ether to give 2 -(cis -4 -hydroxycyclohexylamino) 5-nitro-N (trifluoromethyl)phenyllethyl~benzarnide (157 mg) as yellow powders.

NMR (DMSO-d 6 1.44-1.75(8H, in), 3.03(2H, t, J=7.5Hz), 3.51(2H, q, 3.66(2H, br), 4.56(1H, d, J=4Hz), 6.87(1H, d, J=8Hz), 7.41- 7.55(2H, in), 7.64(1H, t, J=8Hz), 7.71(1.H, d, J=8Hz), 8.11I(1H, d, J=2Hz), 8.53(1H, d, J=2Hz), 9.00(1H, in), 9.14(1H, d, J=8Hz) Mass m/z: 450.2 Preparation 14 1(1) .4-Bromomethylthiazole (1.80 g) was obtained as an oil from 4methylthiazole (1.00 g) and N-bromosuccinimide (1.97 g) in a manner similar to Preparation 91(2).

NMR (DMSO-d 6 4.65 (2H, 7.37 (1H, d, J=2 Hz), 8.82 (1H, d, J= 2 Hz).

Preparation 141(2) N-(Thiazol-4-ylmethyl)phthalimide (1.20 g) was obtained as white powders from 4-bromomethylthiazole (1.80 g) and potassium phthalimide (1.87 g) in a manner similar to Preparation 9 1(3).

NMR (DMSO-d 6 5.06 (2H, 7.30 (1H, d, J=2 Hz), 7.68-7.80 (2H, in), 7.84-7.92 (2H, in), 8.76 (1H, d, J=2 Hz).

Preparation 141(3) 4-Aminomethyithiazole hydrochloride (305 mg) was obtained as white powders from N-(thiazol-4-ylmethyl)phthalimide 15 g) in a manner similar to Preparation 91(4).

NMR (DMSO-d 6 4.18 (2H, q, J= 5 Hz), 7.83 (1H, d, J= 2 Hz), 8.52 (3H, br), 9.20 (1H, d, J= 2 Hz).

Examipe 41 2- (cis-4-Hydroxycyclohexylamino) -5-nitro-N- (4thiazolylmethyl)benzamide (92 mng) was obtained as yellow powders from 160 WO 99/54284 WO 9954284PCT/JP99/02028 2 cis-4 -hydroxycycloh exylamin o) 5 -nitrobenzoic acid (120 mg) and 4aminomethyithiazole hydrochloride (70.9 mg) in a manner similar to Preparation 1.

NMR (DMSO-d 6 1.42-1.76 (8H, in), 3.65 (211, br), 4.54 (1H, d, J= 4 Hz), 4.59 (1H, d, J= 5 Hz), 6.89 (111, d, J= 8 Hz), 7.52 (1H, d, J= 2 Hz), 8.12 (1H, dd, J= 2, 8Hz), 8.66 (111, d, J= 2 Hz), 9.07 (11, d, J= 2 Hz), 9.28 (1H, d, J= 8 Hz), 9.45 (1H1, m) Mass m/z: 375.2 (Mt-H).

Preparation 142(1) 2-Cyanobenzo[b]thiophene (250 mg) was obtained as an oil from benzo[bjthiophene-2-carboxamide (500 mg) in a manner similar to Preparation 131(5).

NMR (CDC1 3 7.48 (111, t, 8 Hz), 7.54 (111, t, 8 Hz), 7.84-7.94 (311, in).

Preparation 142(2) 2-(Aminomethyl)benzo[b]thiophene hydrochloride (281 mng) was obtained as pale yellow powders from 2-cyanobenzo[b]thiophene (250 mng) in a manner similar to Preparation 13 1(6).

NMR (DMSO-d 6 4.35 (2H, 7.34-7.45 (211, in), 7.57 (1H, 7.83- 7.90 (1H1, in), 7.96-8.04 (1H1, in), 8.67 (3H, br).

Eample142 N-(Benzolbthiophen-2-ylmethyl)-2-(cis-4- (104 ing) was obtained as yellow powders from 2-(cis-4-hydroxycyclohexylamino) acid (100 mg) and 2- (aniinoinethyl) benzo [bithiophene hydrochloride (78.4 mg) in a manner similar to Example 140.

NMR (DMSO-d 6 1.44-1.80 (811, in), 3.66 (211, br), 4.57 (111, d, J= 4 Hz), 4.72 (2H, d, J= 5 Hz), 6.91 (111, d, J= 8 Hz), 7.24-7.28 (3H, in), 7.79 (1LH,d, J=8Hz),7. 9 1(1 H,d,J=8 Hz), 8.13 (1 H,dd, J=2, 8Hz),8.64(1 H, d, J= 2 Hz), 9.26 (1H1, d, J= 8 Hz), 9.62 (111, in).

161 WO 99/54284 WO 9954284PCT/JP99/02028 Preparation 143(l) 2-Cyanobenzofuran (402 mg) was obtained as an oil from benzofuran-2-carboxamide (500 mg) in a manner similar to Preparation 13 NMR (CDC1 3 7.37 (1H, t, J= 8 Hz), 7.43-7.60 (3H, in), 7.69 (1H, d, J= 8 Hz).

Preparation 143(2) 2- (Aminomethyl)benzofuran hydrochloride (333 mg) was obtained as pale yellow powders from 2-cyanobenzofuran (400 mg) in a manner similar to Preparation 13 1(6).

NMR (DMSO-d 6 4.23 7.03 (1H, 7.28 (1H, t, J= 8 Hz), 7.35 (1H, t J= 8 Hz), 7.60 (1H, d, J=8 Hz), 7.69 (1H, d, J= 8 Hz), 8.62 (3H, br).

Exml14 N- (Benzofuran-2-ylmethyl) (cis-4-hydroxycyclohexylamino) nitrobenzamide (154 mg) was obtained as yellow powders from 2.-(cis-4acid (120 mg) and 2- (aminomethyl)benzofuran hydrochloride (86.5 mg) in a manner similar to Example 140.

NMR (DMSO-d 6 1.43-1.77 (8H, in), 3.67 (2H, br), 4.55 (1H, d, J= 4 Hz), 4.63 (2H, d, J= 5 Hz), 6.81 (1H, 6.90 (1H, d, J= 8 Hz), 7.22 (1H, t, J= 8 Hz), 7.27 (1H, t, J= 8 Hz), 7.56 (1H, d, J= 8 Hz), 7.60 (1H, d, J= 8 Hz), 8.11 (1H, dd, J= 2, 8Hz), 8.67 (1H, d, J= 2 Hz), 9.30 (1H, d, J= 8 Hz), 9.49 (1H, m).

Example 144 N- (3,4-Dimethylbenzyl) (cis-4-hydroxycyclohexylamino)- nitrobenzamide (185 mng) was obtained as yellow powders from 2-(cis-4hydroxycyclohexyl) amino- 5-nitrobenzoic acid (200 mng) and 3,4dimethylbenzylamine (116 mg) in a manner similar to Preparation 1.

m.p. 157-158TC NMR (DMSO-d6,c5): 1.34-1.74 (8H, in), 2.19 (3H, 2.21 (3H, 3.60- 3.72 (2H, in), 4.38 (2H, d, J=5 Hz), 4.55 (1H, d, J=4 Hz), 6.88 (1H, d, 162 WO 99/54284 WO 9954284PCT/1P99/02028 Hz), 7.04 (1 H, br d, J=8 Hz), 7.07-7.14 (2H, in), 8. 11 (1 H, dd, J=10, 3 Hz), 8.62 (1H, d, J=3 Hz), 9.30 (1H, d, J=8 Hz), 9.34 (1H, t, J=5 Hz) Mass m/z: 396(M,).

Exa~mpe 14 2 (cis-4- Hydroxycyclohexylamino) 5-nitro- N-(4 phenylbenzyl)benzamide (113 mg) was obtained as yellow powders from 2- (cis-4-hydroxycyclohexyl) amino- 5-nitrobenzoic acid (78 mg) -and 4phenylbenzylamine (61 mng) in a manner similar to Preparation 1.

m.p. 168-170TC NMR (DMSO-d 6 1.43-1.80 (8H, in), 3.59-3.75 (2H, in), 4.50 (2H, d, J=6 Hz), 4.55 (1H, d, J=5 Hz), 6.90 (1H, d, J=10 Hz), 7.35 (1H, dd, Hz), 7.39-7.52 (4H, mn), 7.65 (4H, mn), 8.12 (1H, dd, J=10, 2 Hz), 8.67 (1H, d, J=2 Hz), 9.33 (1H, d, J=8 Hz), 9.45 (1H, t, J=6 Hz).

Preparation 146(1) Methyl 3-benzyloxy-4-methoxybenzoate (5.70 g) was obtained as colorless powders from methyl 3-hydroxy-4-methoxybenzoate (4.00 g) and benzyl bromide (3.13 mL) in a manner similar to Preparation 131(2).

NMR (CDCl 3 3.87 (3H, 3.93 (3H, 5.18 (2H, 6.90 (1H, d, J= 8 Hz), 7.28-7.40 (3H, in), 7.46 (2H, in), 7.61 (1H, d, J= 4 Hz), 7.68 (1H, dd, J= 4, 8 Hz).

Preparation 146(2) 3-Benzyloxy-4-methoxybenzoic acid (5.06 g) was obtained as colorless powders from methyl 3-benzyloxy-4-rnethoxybenzoate (5.60 g) in a manner similar to Preparation 13 1(3).

NMR (DMSO-d 6 3.84 (3H, 5.13 (2H, 7.07 (114, d, J= 8 Hz), 7.30-7.50 in), 7.53 (1H, d, J= 4 Hz), 7.58 (1H, dd, J= 4, 8 Hz).

Preparation 146(3) 3-Benzyloxy-4-inethoxybenzainide (4.03 g) was obtained as colorless powders from 3-benzyloxy-4-inethoxybenzoic acid (4.96 g) in a manner similar to Preparation 131(4).

163 WO 99/54284 WO 9954284PCT/JP99/02028 NMR (DMSO-d 6 3.81 (3H, 5.11 (2H, 7.02 (1H, d, J= 8 Hz), 7.21 (1H, br), 7.32-7.47 (5H, in), 7.51 (1H, dd, J= 4, 8 Hz), 7.58 (1H, d, J= 4 Hz), 7.85 (1H, br).

Preparation 146(4) 3-Benzyloxy-4-methoxybenzonitrile (3.35 g) was obtained as colorless powders from 3-benzyloxy-4-methoxybenzamide (3.93 g) in a manner similar to Preparation 13 NMR (CDCl 3 3.94 (3H, 5. 15 (2H, 6.91 (1H, d, J= 8 Hz), 7. 10 (1H, d, J= 4 Hz), 7.25-7.45 (6H, in).

Preparation 146(5) 3-Benzyloxy-4-methoxybeflzylatne (3.51 g) was obtained as pale yellow oil from 3-benzyloxy-4-methoxybenzonitrile (3.30 g) in a manner similar to Preparation 13 1(6).

NMR (CDCl 3 3.76 (2H, 3.88 (3H, 5.16 (2H, 6.83-6.90 (3H, in), 7.24-7.45 (5H, in).

Exmpe14 N-(3-Benzyloxy-4-inethoxybenzyl)- 2 -(cis- 4 (152 ing) was obtained as yellow powders from 2- (cis-4-hydroxycyclohexylamino) acid (100 mng) and 3-benzyloxy-4-inethoxybenzylamfifle (104 mng) in a manner similar to Preparation 1.

NMR (DMSG-d6,6): 1.45-1.77 (8H, br), 3.62-3.72 (2H, br), 3.75 (3H, s), 4.37 (2K, d, J= 7 Hz), 4.56 (1H, d, J= 4 Hz), 5.06 (2H, 6.85-6.97 (3H, in), 7.05 (1K, d, J= 2 Hz), 7.24-7.37 (3H, in), 7.40-7.47 (2H, in), 8.12 (1H, dd, J= 4, 8 Hz), 8.61 (1H, d, J= 4 Hz), 9.30 (2H, br) Mass in/z 504(M+).

Preparation 147(1) 3,4-Ethylenedioxybenzyl bromide (2.31 g) was obtained as colorless oil from 3,4-ethylenedioxybenzyl alcohol (2.00 g) and carbon tetrabroinide (5.99 g) in a manner similar to Preparation 129(4).

164 WO 99/54284 WO 9954284PCT/JP99/02028 NMR (CDCl 3 4.25 (4H, 4.44 (2H, 6.78-6.94 (3H, in).

Preparation 147(2) N- (3,4-Ethylenedioxybenzyl)phthalimide (2.65 g) was obtained as white powders from 3,4-ethylenedioxybenzyl bromide (2.31 g) and potassium phthalimide (1.92 g) in a manner similar to preparation 91(3).

NMR (CDCl 3 4.20 (4H, 4.64 (2H, 6.72-6.8 1 (3H1, in), 7.80-7.93 (4H1, m) Mass m/z :296.1 1).

Preparation 147(3) 3,4-Ethylenedioxybenzylamine hydrochloride (1.70 g) was obtained as white powders from N-(3,4ethylenedioxybenzyl)phthalimide(2.60 g) in a manner similar to Preparation 9 1(4).

NMR (DMSO-d 6 3.88 (2H1, q-like), 4.24 (4H, 6.84-6.97 (211, in), 7.03 (1H1, d, J= 2 Hz), 8.29 (3H, br).

Preparation 147(4) N- (3 ,4-Ethylenedioxybenzyl) -2-fluoro- 5-nitrobenzamide (1.39 g) was obtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (1.00 g) and 3,4-ethylenedioxybenzylamine hydrochloride 14 g) in a manner similar to Preparation NMR (DMSO-d 6 4.19 (4H1, 4.34 (1H, d, J= 5 Hz), 6.73-6.84 (3H, in), 7.59 (1H, t, J= 8 Hz), 8.34-8.44 (2H, in), 9.07 (111, m) Mass m/z 331.4 1).

Example 147 N- (3,4-Ethylenedioxybenzyl)-2-(trans-4hydroxycyclohexylainino)-5-nitrobenzamide (496 ing) was obtained as yellow powders from N- (3 ,4 -ethylenedioxybenzyl) -2 -flu oro 5 nitrobenzamide (400 ing) and travs-4-aminocyclohexanol (208 ing) in a manner similar to Example 1 NMR (DMSO-d 6 1.20-1.43 (4H1, in), 1.73-1.88 (2H, in), 1.88-2.05 (2H, 165 WO 99/54284 WO 9954284PCT/JP99/02028 in), 3.40-3.59 (2H, in), 4.21 (4H, 4.30 (2H, d, J= 5 Hz), 4.62 (1H, d, J= 4 Hz), 6.74-6.84 (3H, in), 6.90 (1 H, d, J= 8 Hz), 8. 11 (1 H, dd, J= 8, 2 Hz), 8.59 (1H, d, J= 2 Hz), 9.08 (1H, d, J= 8 Hz), 9.30 (1H, mn) Mass m/ z 426.2 Preparation 148 N- (3-Chloro-4-methoxybenzyl)-2-fluoro-5- (trifluoromethyl)benzamide (2.92 g) was obtained from (trifluoromethyl)benzoic acid (1.76 g) and 3-chloro-4methoxybenzylamine 1.45 g) in a in a manner similar to Preparation 1.

NMR (DMSO-d 6 3.83 (3H, 4.41 (2H, d, J= 6 Hz), 7.13 (1H, d, J= 9 Hz), 7.29 (1H, dd, J= 2, 8 Hz), 7.41 (1H, d, J= 2 Hz), 7.58 (1H, t, J= 9 Hz), 7.93 (1H, in), 7.97 (1H, d, J= 8 Hz), 9.08 (1H, t, J= 6 Hz).

Example 148 N- (3-Chloro-4-methoxybenzyl)-2- [2-hydroxy- 1- (hydroxymethyl) ethylamino] -5-(trifluoromethyl) benzam-ide (91 mg) was obtained from N- (3-chloro-4-inethoxybenzyl) -2-fluoro- (trifluoromethyl) benzamide (194 mg) and 2-amino-i ,3-propanediol (147 mg) in a manner similar to Example 1 NMR (DMSO-d 6 3.4-3.6 (5H, in), 3.83 (3H, 4.35 (2H, d, J= 6 Hz), 4.83 (2H, mn), 6.91 (1H, d, J= 9 Hz), 7.11 (1H, d, J= 9 Hz), 7.26 (1H, dd, J= 2, 9 Hz), 7.37 (1H, d, J= 2 Hz), 7.53 (1H, dd, J= 2, 9 Hz), 7.93 (1H, d, J= 2 Hz), 8.63 (1H, in), 9.07 (1H, t, J= 6 Hz) Mass m/z 431 Example 149(1)1 -2-11- (tert-Butoxycarbonyl)pyrrolidin- 3-ylaminol (3 -chioro- 4-methoxybenzyl) (trifluoroinethyl)benzamide (696 mng) was obtained as amorphous powders from N (3 -chloro-4-methoxybenzyl) 2-flu oro- trifluoromethylbenzamide (700 ing) and (R)-3-amino- 1-tertbutoxycarbonylpyrrolidine (721 ing) in a manner similar to Example 1 NMR (DMSO-d 6 1.39(9H, 1.83(1H, mn), 2.20(1H, in), 3.09(1H, in), 3.25-3.45(2H, in), 3.6 1(1H, in), 3.83(3H, 4.15(1H, in), 4.36(2H, d, 166 WO 99/54284 WO 9954284PCTI.JP99/02028 J=6Hz), 6.93(1H, d, J=8Hz), 7.10(1H, d, J=8Hz), 7.25(1K, dd, J=2, 8Hz), 7.36(1K, d, J=2Hz), 7.59(1H, brd, J=8Hz), 7.98(1K, br), 8.61(1K, d, J=7Hz), 9.17(lH, t, J=6Hz) Mass (ESI+) 528(M+H), (ESI-) 526(M-H).

Example 149(2) (3-Chloro-4-methoxybenzyl) (3-pyrrolidinylamino) (trifluoromethyl)benzamide (448 mg) was obtained as amorphous powders from (tert-butoxycarbonyl)pyrrolidin- 3-.ylaminol-N- (3chloro-4-methoxybenzyl)-5-(trifluoromethyl)benzamide (596 mg) in a manner similar to Example 87(2).

NMR (DMSO-d 6 1.49(1H, in), 2. 10(1K, mn), 2.55(1H, dd, J=4, 2.7-2.95(2H, in), 3.13(1H, dd, J=6, 10Hz), 3.83(3H, 3.93(1H, mn), 4.35(2H, d, J=6Hz), 6.83(1K, d, J=SHz), 7.11 (1H, d, J=8Hz), 7.26(1H, dd, J=2 8Hz), 7.37(1H, d, J=2Hz), 7.56(1H, dd, J=2, 8Hz), 7.95(1K, d, J=2Hz), 8.52(1H, d, J=7Kz), 9.13(1K, t, J=6Hz) Mass: (ESI+) 428(M+K), (ESI-) 426(M-H).

Example 149(3) (R)-N-(3-Chloro-4-methoxybenzyl)-2-[ 1- (methoxycarbonyl)pyrrolidin-3-ylamino 5-triflu oromethylbenzamide (119 mg) was obtained as amorphous powders from (R)-N-(3-chloro-4methoxybenzyl)-2- (3-pyrrolidinylamino) (trifluoromethyl)benzamide (109 mng) in a manner similar to Example 85(5).

NMR (DMSO-d 6 1.86(1H,mi), 2.2 1(1K,mi), 3. 16(1H,mi), 3.30-3.50(2H, in), 3.58 and 3.59(3K, 3.66(1K, in), 3.83(3H, 4.18(1H, in), 4.36(2H, d, J=6Hz), 6.93(1K, d, J=9Hz), 7.11l(1K, d, J=9Hz), 7.25(1H, dd, J=2, 9Hz), 7.36(1K, d, J=2Kz), 7.59(1H, brd, J=9Hz), 7.99(1H, br), 8.62(1H, d, J=7Hz), 9.18(1H, t, J=6Hz).

Example 150 (1) (tert-Butoxycarbonyl)pyrrolidin-3-ylaminol (3-chioro- 4-inethoxybenzyl) (trifluoroinethyl)benzainide (516 mng) was obtained as amorphous powders from N- (3-chloro-4-methoxyb enzyl) 2-flu oro- 167 WO 99/54284 WO 9954284PCT/JP99/02028 trifluoroinethylbenzamide (700 mg) and (S)-3-amino-1-tertbutoxycarbonylpyrrolidine (72 1 mg) in a manner similar to Example 1 NMR (DMSO-d 6 1.39(9H, 1.83(1H, in), 2.20(1H, in), 3.09(1H, in), 3.25-3.45(2H, in), 3.61(1H, in), 3.83(3H, 4.15(1H, in), 4.36(2H, d, J=6Hz), 6.93(1H, d, J=8Hz), 7.10(1H, d, J=8Hz), 7.25(1H, dd, J=2, 8Hz), 7.36(1H, d, J=2Hz), 7.59(1H, brd, J=8Hz), 7.98(1H, brs), 8.6 1(1H, d, J=7Hz), 9.17(1H, t, J=6Hz).

Example 150(2) (3-.Chloro-4-methoxybenzyl)-2- (trifluoromethyl)benzamide (262 mng) was obtained as amorphous powders from [1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino-N-(3chloro-4-inethoxybenzyl) (trifluoroinethyl)benzamide (430 mng) in a manner similar to Example 87(2).

NMR (DMSO-d 6 1.49(1H, in), 2.1O(1H, mn), 2.55(1H, dd, J=4, 2.7-2.95(2H, in), 3.13(1H, dd, J=6, 10Hz), 3.83(3H, 3.93(1H, in), 4.35(2H, d, J=6Hz), 6.83(1H, d, J=8Hz), 7.11 (1H, d, J=8Hz), 7.26(1H, dd, J=2, 8Hz), 7.37(1H, d, J=2Hz), 7.56(1H, dd, J=2, 8Hz), 7.95(1H, d, J=2Hz), 8.52(1H, d, J=7Hz), 9.13(1H, t, J=6Hz) Mass (ESI+) 428(M+H), (ESI-) 426(M-H).

-N-(3-Chloro-4-methoxybenzyl)-2-[ 1- (inethoxycarbonyl)pyrrolidin-3-ylamino] (trifluoroinethyl)benzainide (105 ing) was obtained as amorphous powders from (S)-N-(3-chloro-4methoxybenzyl) (3-pyrrolidinylamino) (trifluoroinethyl)benzamide (115 mg) in a manner similar to Example 85(5).

NMR (DMSO-d 6 1.86(1H, in), 2.2 1 (1H, mn), 3.16(1H, in), 3.30-3.50(2H, in), 3.58 and 3.59(3H, 3.66(1H, in), 3.83(3H, 4.18(1H, mn), 4.36(2H, d, J=6Hz), 6.93(1H, d, J=9Hz), 7.11 (1H, d, J=9Hz), 7.25(1H, dd, J=2, 9Hz), 7.36(1H, d, J=2Hz), 7.59(1H, brd, J=9Hz), 7.99(1H, br), 8.62(1H, d, J=7Hz), 9.18(1H, t, J=6Hz).

Preparation 151 168 WO 99/54284 WO 9954284PCT/JP99/02028 4-Chloro-2 ,5-difluoro-N- (3 ,4-diinethoxybenzyl)benzamiide (1.66 g) was obtained from 4-chloro-2,5-difluorobenzoic acid (1.05 g) and veratrylamine (0.91 inL) in a in a manner similar to preparation 1.

NMR (DMSO-d6,6 3.73 (3H, 3.74 (3H, 4.39 (2H, d, J= 6 Hz), 6.81-6.97 (3H, in), 7.67 (1H, dd, J= 6, 9 Hz), 7.79 (1H, dd, J= 6, 9 Hz), 8.96 (1H, t, J= 6 Hz).

Exmple 51 4 Chloro- N- (3 ,4-dimethoxybenzyl) 5-flu oro- 2- (trans-4hydroxycyclohexylamino)benzaxnide (27 mg) was obtained from 4chloro-2 ,5-difluoro-N- (3 ,4-dliiethoxybenzyl)benzamide (102 ing) and trans-4-aminocyclohexanol (103 ing) in a manner similar to Example 1 NMR (DMSO-d 6 1.06-1.39 (4H, in), 1.74-1.84 (2H, mn), 1.88-1.97 (2H, in), 3.38-3.53 (2H, mn), 3.72 (3H, 3.73 (3H, 4.33 (2H, d, J= 6 Hz), 4.57 (1H, d, J= 4 Hz), 6.80-6.93 (4H, in), 7.66 (1H, d, J= 11 Hz), 7.83 (1H, d, J= 8 Hz), 8.89 (LH, t, J= 6 Hz).

Preparation 152(1) 5-Broino-N- (4-chloro-3-inethoxybenzyl) -2-fluorobenzainide (3.07 g) was obtained as colorless powders from 5-bromo-2fluorobenzoic acid (2.00 g) and 4-chloro-3-methoxybenzylaline (1.72 g) in a manner similar to Preparation 1.

NMR (DMSO-d 6 3.85 (3H, 4.45 (2H, d, J= 7 Hz), 6.91 (1H, dd, J= 4, 8 Hz), 7.13 (1H, d, J= 4 Hz), 7.32 (1H, t, J= 8 Hz), 7.38 (1H, d, J= 8 Hz), 7.69-7.80 (2H, in), 9.05 (1H, br).

Preparation 152(2) To a solution of 5-bromo-N-(4-chloro-3-methoxybenzyl)- 2 fluorobenzamide (2.00 g) in toluene (40 inL) were added tetrakis (triphenylphosphine) plladiumf (217 mng) and tributylvinyltin (1.87 and the mixture was heated for 4 hours under reflux. After evaporation of the solvent, the residue was partitioned between ethyl acetate and saturated potassium fluoride solution. The remaining 169 WO 99/54284 PCT/JP99/02028 precipitates were removed by filtration. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (3:1) to give N-(4-chloro-3-methoxybenzyl)-2-fluoro-5-vinylbenzamide as pale yellow powders (1.51 g).

NMR (CDC1 3 3.90 (3H, 4.65 (2H, br), 5.31 (1H, d, J= 10 Hz), 5.77 (1H, d, J= 15 Hz), 6.65-6.78 (1H, dd, J= 10, 15 Hz), 6.84-6.94 (2H, br), 6.96-7.10 (2H, 7.33 (1H, d, J= 8 Hz), 7.50 (1H, 8.12 (1H, dd, J= 4, 8 Hz) Mass m/z 318(M+).

Preparation 152(3) A mixture of copper(I) chloride (464 mg) and palladium(II) chloride (83.2 mg) in a mixture of dimethylformamide (42 mL) and water (6 mL) was stirred for an hour under oxygen atmosphere (1 atm) at ambient temperature. To the mixture was added N-(4-chloro-3- (1.50 After stirring for 6 hours at 60 the mixture was partitioned between ethyl acetate and 1N-hydrochoric acid. The separated organic layer was washed with water, an aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (2:1 to 1:1) to give 5-acetyl-2fluoro-N-(4-chloro-3-methoxybenzyl)benzamide as colorless powders (719 mg).

NMR (DMSO-d 6 2.61 (3H, 3.85 (3H, 4.48 (2H, d, J= 7 Hz), 6.94 (1H, dd, J= 4, 8 Hz), 7.15 (1H, d, J= 4 Hz), 7.39 (1H, d, J= 8 Hz), 7.47 (1H, t, J= 8 Hz), 8.12 (1H, 8.19 (1H, dd, J= 4, 8 Hz), 9.09 (1H, br) Mass m/z :334(M Example 152 (R)-5-Acetyl-N-(4-chloro-3-methoxybenzyl)-2-(2-hydroxy-1methylethylamino)benzamide (68.1 mg) was obtained as colorless 170 WO 99/54284 WO 9954284PCT/JP99/02028 powders from 5-acetyl-N-(4-chloro-3-methoxybenzyl)-2fluorobenzamide (100 mg) and -2 -amino- 1-propanol (44.7 mg) in a manner similar to Example 1(1).

NMR (DMSO-d 6 1.14 (3H, d, J= 7 Hz), 2.47 (3H, 3.38-3.50 (2H, in), 3.62-3.72 (1H, br), 3.85 (3H, 4.43 (2H, d, J= 7 Hz), 4.91 (1H, t, J= 7 Hz), 6.80 (1H, d, J= 8 Hz), 6.91 (1H, dd, J= 4, 8Hz), 7.13 (l1H, d, J= 4Hz), 7.38 (1H, d, J= 8 Hz), 7.86 (1H, dd, J= 4, 8 Hz), 8.25 (1H, d, J= 4 Hz), 8.63 (1H, d, J= 8 Hz), 9.17 (1H, br).

Preparation 153(1) 5-Chlorosulfonyl-2-fluorobenzoic acid (2 g) was dissolved in dichloromethane (20 mL) under nitrogen atmosphere and cooled to 0 TC.

tert-Butyl 1-piperazinecarboxylate (3.12 g) was added portionwise to the solution at 0 TC and stirred for 3 hours at ambient temperature. The organic solvent was evaporated in vacuo, and the residue was dissolved in IN-sodium hydroxide solution. The aqueous solution was washed with diethyl ether and acidified with iN-hydrochloric acid. The precipitates were collected by filtration and washed with water to give (tert-butoxycarbonyl)piperazin- 1-ylsulfonyll -2-fluorobenzoic acid (2.26 g) as a colorless solid substance.

mp. 203-204.5'C NMR (DMSO-d 6 1.35 (9H, 2.84-3.01 (4H, in), 3.35-3.54 (4H, in), 7.62 dd, J= 9.0, 8.5 Hz), 7.95-8.04 (1H, in), 8.14 (1H, dd, J= 7.0, Hz) Mass m/z: 387(M+-1) Preparation 153(2) (tert-Butoxycarbonyl)piperazin- 1 -ylsulfonyl] (3,4dimethoxybenzyl) -2 -flu orobenzamide (1.34 g) was obtained as off-white amorphous substance from 5-[4-(tert-butoxycarbonyl)piperazin- 1ylsulfonyl]-2-fluorobenzoic acid (1.0 g) and 3,4-diinethoxybenzylamine (452 mg) in a manner similar to Preparation 1.

NMR (DMSO-d 6 1.34(9H, 2.85-2.94(4H, mn), 3.36-3.44(4H, in), 3.73(3H, 3.74(3H, 4.42(2H, d, J=6.OHz), 6.86(1H, dd, J=8.0, 171 WO 99/54284 WO 9954284PCT/JP99/02028 6.92(1K, d, J=8.OHz), 6.96(1H, d, J=1.5Hz), 7.60(1K, t, J=9.0Hz), 7.85- 7.92(2H, in), 9.04(1K, t, J=6.OHz).

Example 153(l) 5 (tert-Butoxycarbonyl) pip erazin 1 -ylsulfonyl] N- (3,4 dimethoxybenzyl) (trans-4-hydroxycyclohexylamino)benzamide (191.8 mg) was obtained as off-white solid substance from 5-[4-(tertbutoxycarbonyl) piperazin- 1-ylsulfonyl] (3 ,4-dimethoxybenzyl) -2fluorobenzamide (200 mg) and trans-4-amninocyclohexanol (129mg) in a manner similar to Example 1(1).

mp. 221-222*C NMR (DMSO-d 6 1.13-1.41(4H, in), 1.34(9K, 1.76-1.86(2K, in), 1.90-2.01(2H, in), 2.77-2.88(4H, in), 3.30-3.54(6H, in), 3.72(3H, s), 3.73(3K, 4.36(2K, d, 4.60(1K, d, J=4.5Hz), 6.83(1H, d, J=7.5Hz), 6.89(1H, 6.93(2H, d, J=7.5Hz), 7.52(1H, d, 7.91(1K, 8.50(1H, d, J=7.5Hz), 9.15(1H, t, J=6.OHz) Mass m/z: 631(M+-1).

Exampe32) N- (3 ,4-Dimethoxybenzyl) (trans-4-hydroxycyclohexylamino) (88.3mg) was obtained as a pale yellow solid substance from 5- (tert-butoxycarbonyl)piperazin- 1-ylsulfonyll- N- (3,4-dimiethoxybenzyl)-2-( trans-4-hydroxycyclohexylamino)benzamilde (125mg) in a manner similar to Examnple 77(2).

M.P. 108-1 NMR (DMSO-d 6 1.15-1.41(4K, in), 1.75-1.86(2K, in), 1.90-2.01(2K, in), 2.65-2.79(8K, in), 3.29-3.51(3K, in), 3.72(3K, 3.73(3K, 4.35(2H, d, J=6.OHz), 4.60(1K, d, J=4.SHz), 6.81(1K, dd, J=8.0, 1.0Hz), 6.90(2K, d, 6.94(1K, d, 7.5 1(1K, dd, J=8.0, 1.0Hz), 7.9 1(1H, d, 8.53(1K, d, J=7.OHz), 9. 18(1K, t, J=.O~z) Mass in/z 533(M++ 1).

Example 53(3) To a mixture of N- (3 -flu oro-4-inethoxybenzyl) 2- (trans-4 172 WO 99/54284 WO 9954284PCT/JP99/02028 hydroxycyclohexylamino)- 5-nitrobenzamide (262 mg), benzoic acid (115 mg) and diethyl azodicarboxylate (164 mg) in anhydrous tetrahydrofuran (6 mL) was added triphenyiphosphine (247 mg). After stirring for one day at ambient temperature, the mixture was evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (4:1 to 2: Collection of an upper fraction gave 2 -cyclohexenylamino) -N (3 -flu oro-4 as yellow powders (40 mg).

m.p. 140TC NMR (DMSO-d 6 1.61 (1H, in), 1.82-2.26 (4H, mn), 2.45 (1H, mn), 3.81 (3H, 3.85 (1H, in), 4.37 (2H, d, J3=5 Hz), 5.64 (1H, br d, J=9 Hz), 5.73 (1H, br d, J=9 Hz), 6.94 (1H, d, J3=9 Hz), 7.06-7.22 (3H, in), 8.12 (1H, dd, J=9, 3 Hz), 8.62 (1H, d, J3=3 Hz), 9.19 (1H, d, J=8 Hz), 9.35 (1H, t, J=5 Hz) Mass in/z (ES) 398.

Collection of a lower fraction gave 2-(cis-4-benzoyloxycyclohexylainino)- N- (3-fluoro-4-methoxybenzyl)- 5-nitrobenzamide as yellow powders (249 mng).

NMR (DMSO-d 6 1.60-1.78 (2H, in), 1.80-1.97 (6H, in), 3.75 (1H, in), 3.81 (3H, 4.40 (2H, d, J=6 Hz), 5.14 (1H, br), 6.97 (1H, d, J=10 Hz), 7.07-7.22 (2H, in), 7.45-7.60 (2H, in), 7.67 (1H, dd, J=7, 7 Hz), 8.01 (2xlH, d, J=7 Hz), 8.44 (1H, dd, J=10, 2 Hz), 8.64 (1H, d, J=2 Hz), 9.26 (1H, d, J=8 Hz), 9.39 (1H, t, J=6 Hz) Mass m/z (ES) :520.

Preparation 154 N-(4-Chloro-3-inethoxybenzoyl) -5-cyano-2-fluorobenzamide (4.00 g) was obtained as colorless powders from 5- cyano-2 -flu orobenzoic acid (4.57 g) and 4-chloro-3-methoxybenzylamine (150 mng) in a manner similar to Preparation 1.

NMR (DMSO-d 6 3.85(3H, 4.46(2H, d, J=7Hz), 6.93(1H, dd, J=4, 8Hz), 7.13(1H, d, .3=4Hz), 7.39(1H, d, J=8Hz), 7.58(1H, t, J=8Hz), 8.06(1H, in), 8.13(1H, dd, J=4, 8Hz), 9.12(1H, br).

173 Example 154 (R)-N-(4-Chloro-3-methoxybenzyl)-5-cyano-2-(2-hydroxy-1methylethylamino)benzamide (153 mg) was obtained as colorless powders from N-(4-chloro-3-methoxybenzyl)-5-cyano-2fluorobenzamide (150 mg) and (R)-2-amino-l-propanol (70.7 mg) in a manner similar to Example 1(1).

NMR (DMSO-d 6 1.12(3H, d, J=7Hz), 3.42(2H, t, J=7Hz), 3.60-3.74(1H, br), 3.85(3H, 4.41(2H, d, J=7Hz), 4.93(1H, t, J=7Hz), 6.84(1H, d, J=8Hz), 6.92(1H, dd, J=4, 8Hz), 7.12(1H, d, J=4Hz), 7.37(1H, d, J=8Hz), 7.61(1H, dd, J=4, 8Hz), 8.06(1H, d, J=4Hz), 8.69(1H, d, J=8Hz), 9.07(1H, br) Mass m/z: 372.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

o* 174

Claims (16)

1. A compound of the formula jI): 0 A 3 R 1 ~LN' R NH R 2 R wherein R, is hydrogen atom or a halogen atom; R2 is an electron withdrawing group; R 3 is hydrogen atom; hydroxy group; a Ci-C 6 alkoxy group; a cycloalkyl. group; a substituted or unsubstituted aryl group; or an unsaturated heterocyclic group optionally substituted with Ci-C6' alkyl; A is a CI-C 6 alkylene group; R4 is a group -CR6R7RB wherein and R7 are each independently a Cl-Ce alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy group; Cj-C 6 ailcoxy group; acyloxy group and aryloxy group which may be substituted with cyano, or R6 and R7 together with the carbon atom to which R 6 and R7 are attached may form a substituted or unsubstituted, cycloalkyl group, and R8 is hydrogen atom; a Ci-C, 6 alkoxy group; or a Ci-C6 alkyl group optionally substituted wvith hydroxy or a Ci-C 6 alkoxy; and a pro-drug thereof, and a salt thereof. 175

2. A compound of claim 1, wherein the electron withdrawing group for R2 is selected from a group consisting of nitro group; cyario group; acyl group; halo(Cl-Co,)alkyl group; sulfamoyl group; carbanioyl. group optionally substituted with C 1 -C 6 alkyl; halogen atom; C2 -C6 alkenyl group optionally substituted with protected carboxy; C 1 -C 6 alkanesulfonyl group; saturated heterocyclic sulfonyl group optiona.11y substituted with protected 0 carboxy; and unsaturated heterocyclic group,. 15 the substituent(s) on the aryl group for R 3 iS/are. selected from a group consisting Of Cl-C 6 alkyl group; halo(Cl-CG)alkyl group; Ci-Cr, aflkyithio group; halogen atom; hydroxy group; Ci-C6 aflcylenedioxy group; cyano group; nitro group; carboxy group; protected carboxy group; sulfainoyl group; acyl group; aryl group; ax(Ci-C6)gakoxy group; aryloxy group; CI-C6 alkoxy group which may be substituted with C 3 -C6 alkoxy or cycloalkyl; amino group which may be substituted with acyl, protected carboxy or C 1 -C6 aflkyl; and carbamoyl group which may be substituted with CI-C 6 alkYl, the substituent(s) on the cycloalkyl group formed by combination of R6 and R 7 is/are selected from a group consisting of Ci-C6 alkyl group; halogen atom; hydroxy group; Ci-C6 alkoxy group; acyloxy group; :25 carboxy group; protected carboxy group; oxo group; almdlfo group which may be substituted with protected carboxy; ureido group which may be substituted with C1-C6 alkyl. or aryl; guanidina group which may be substituted with protected carboxy; amino group which may be substituted with acyl, CI-C 6 alkanesulfonyl or protected carboxy; and carbamoyl group which may be substituted with C 1 -C6 alkyl or hydroxy(CI-Cs)alkyl.

3. A compound of Claim 1, wherein 176 R3 is a substituted or unsubstituted aryl group; R 4 is a group -CR6R 7 R8 wherein R 6 and R7 together with the carbon atom to which R6 and R 7 are attached form a substituted or unsubstituted, cycloalkyl group, and R8 is hydrogen atom.

4. A compound of Claim 3, wherein R2 is nitro group, cyano group or a halo(Ci-C6)alkyl group; R3 is an aryl group optionally substituted with one or more substituent(s) selected from halogen and C 1 -C 6 alkoxy; R 4 is a group -CR6R7R8 wherein R6 and R7 together with the carbon atom to which R 6 and R 7 are 15 attached form a cycloalkyl group optionally substituted with hydroxy or amino which may be substituted with acyl; and R 8 is hydrogen atom, A compound of Claim 4 which is N- (2-chlorobenzyl)-2 N-(3-chlorobenzyl) N- (4-chlorobenzyl)-2-(cyclopentylaniino)-5-nitrobenzaznide, 2* 2- (cyclopentylamino)-N-(2 2 -cyclopentylarnino-5-nitro-N-( 1,3-benzodioxol-5-ylmethyl)benzamide, 2-(cyclopentylamino) (4-flu 2- N- (2-chloro-4-methoxybenzyl) N- (4-bromobenzyl) -2-(cyclopentylaqmino) 2 2- (cyclopentylamino)-5-nitro-N-(3-phenylpropyl)benzam~ide, N-benzyl-2- N-benzyl-2-(cyclohexylamino) N-benzyl-2-(trans-4-hydroxycyclohexylamino)- 177 2- (trans-4-hydroxycyclohexylamnino) -nitro-N-( 1 3 hyl) benzamide, 2-(cyclopentylamino) ,4-di fl uoroberizyl)- 5 -nitro benzamide, N-benzyl-2- (cyclopropylamino) N-benzyl-2-(2 -hydroxycyclohexylaxnino) N-benzyl-2-(trans-2 -hydroxycycopentyamino)-S-nitrobenamide, 2- (cyclopentylamino) -5-formyl-N- (1 ,3-benzodioxo1-5-yhxnethyl)benzamnjd e, 2- (trans-2-hyctroxycyclopentyrlanino) -5-nitro-N-( 1,3-benzodioxol-5-ylxne thyl)benizarnide, 2- [cis- 4 -(benzoyloxy)cyclohexylaznino]-N-(3 bcnzamide, 2 -[cis- 4 -(benzoyloxy)cyclohexylamino]-5-nitro-N.(1,3 thyl)benzamide, N- (3 .4-diniethoxybenzyl) (trans-4-hydroxycyclohexylaniino) nizamzide, 2 -(cis-4-hydroxycyclohexylamino)-5-nitro-N-( 1,3-benzodioxol-5-ylznethy I)benzamide, N-benzyl-2-(3-.hydroxycyclopentylamino) 2-f 3- N-(3 ,4-dimethoxybenzyl) amnide, 2- (trans-2-aminocyclohexylamino)-5-nitro-N- (1 ***yl)benizamide, N- (3-chloro-4-metho,,Kybenzyl) -2-(cis-4-hydroxycyclohexylamiino)-5-nitro benzamide, 2 -[cis-4-(benzoyloxy)cyclohexylaminol -N-(3-chloro-4-znethoxybenzyl) nitrobenzamide, N-(3-chloro-4-rnethoxybenzyl) (trans-4-hydroxycyclohexylamino) trobenzaxnide, N-(3,4-dimethoxybenzyl) -2-(trans-2-.hydroxycyclopentylamino)-5-nitrob enzamide, N- 5-dichloro-4-methoxybenzyl) -2-(trans-4-hydroxycyclohexylamino) N-(3 ,4-ethylenedioxybenzy1)-.2-(trans-4-hydroxycyclohexyamino) STp, r178 obenzamide, 2- (cis-4-hydroxycyclohexylamino) -nitro-N-(3 5-trimethoxybenzl) be nzainide, 2- [cis-4- (acetoxy)cyclohexylarninol zamnide, 2- [(trans-4-axninocyclohexyl)amino-N- (3 nzaniide, 2- (cis-4-hydroxycyclohexylamino) ide, 2- (trans-4-acetamidocyclohexylanmino) (3,4-dimethoxybenzyl)-5-nitro benzaznide, N-(3 ,4-dimethoxybenzyl) [(trans-4-formaridocyclohexyl)axnino] obenzamide, N- (2-chioro- 5-methoxybenzyl)-2-(cis-4-hydroxycyclohexylamino) -n~itro benzaxnide, 2- (cis-4-benzoyloxycyclohexylaxnino)- N- (3-fluoro-4-methoxybenzyl)-5-nitrobenzaxnide, N- (3-ethoxy-4-znethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino) obenzamide, 2 .'N-(4-chloro-3 -ethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5 -nitro- benzamide, N-(4-ethoxy-3-methoxybenzyl) -2-(cis-4-hydroxycyclohexylamino) obenzamide, 2-(traris-4-aminocyclohexylamino)-N-(4-ethoxy-3-methoxybenzyl)-5-nitr 25obenzamide, N-(4-ethoxy-3-methoxybenzyl) -2-.(trans-4-fornaxidocyclohexylaxnino)-5 -nitrobenzamide, 5 -cyano-2-(trans-4-hydroxycycohexylarnino)-N-( 1,3-benzodioxol-5-ylm ethyl) benzaxnide, 2-(cis-4-formanidocyclohexylaxnino) ,4-dimethoxybenzyl) nzamide, 2- (ci s-4-hydroxycyclohexylamnmo)-5-nitro-N- S)-1 -phenylethyllbenza mide,

5-bromno-N-(3-chloro-4-methoxybenzyl)-2-(cyclopentylaxnino)benzamide 179 S -chloro-2 -(cyclopentylarnino) (1 4-chloro-N- (3 ,4-diinethoxyberizyl) -5-fluoro-2-(trans-4-hydroxycyclohexy lamino)benzamide, or 2-(cis-4-amninocyclohexylamino) mide, or a salt thereof.

6. A compound of Claim 1, wherein R3 is a substituted or unsubstituted aryl group; R4 is a group -CR6R7R8 wherein R 6 is a CI-C 6 alkyl group substituted with hydroxy, R 7 is a C 1 -C 6 alkyl which may be substituted with hydroxy, and 15 Ra is hydrogen atom or a C 1 -C 6 alkyl group which may be substituted with hydroxy. 25

7. A compound of Claim 6, wherein R2 is nitro group, cyano group or a halo (CI-C6)alkyl group; and R3 is an aryl group optionally substituted with one or more substituent(s) selected from halogen and Ci-C6 sflkoxy.

8. A compound of Claim 7 which is N-benzyl-2- [2-hydroxy- 1 -(hydroxymethyl)ethylaniino] t (R )-2-(l1-ethyl-2-hydroxyethylarmno)- 5-nitro-N- (1 ,3-benzodioxol- thyl)benzamide, 1 -(hydroxymethyl)propylaminol -5-nitro-N-( 1,3-benzodioxol-S-ylm ethyl)benzamide, (R)-2-(2-hydroxy- 1-inethylethylaraino) -nitro-N-( 1,3-benzodioxol-5-ylm ethyl)benzatnide, 2- [2-hydroxy- 1, 1-bis(hydroxymethyl)ethylamino]-5-nitro-N-( 1,3-benzodi 2- (2-hydroxy- 1, 1-dimethylethylamino)-5-nitro-N-( 1,3-benzodioxol-5-yI 180 xnethyl)benzarmide, 2- [2-hydroxy- 1- (hydroxymethiyl)ethylaxninoj -5-nitro-N- (1 ,3-benzodioxol- benzamide, 2- [2-hydroxy- 1 -(hydroxymethyl)-l1-methylethylamino]- 5-nitro-N-( 1,3-be -(hydroxymethyl) -2-methylpropylamino]-5-nitro-N- (1 ,3-benzodio xol- 2-[(1R, 2R )-2-hydroxy- 1 -(hydroxymethyl)propylamino] -5-nitro-N-( 1,3-benzo N- (3-chloro-4-rnethioxybenzyl) -2-f 2-hydroxy- 1- (hydroxy-ruethyl) ethylam 2-[1 -(hydroxymethyl)pentylamino] -5-nitro-N-( 1,3 0 .0 is (R)-N-(3,4-dixnethoxybenzyl)-2-(2-hydroxy- bcnzamide, (3 ,4-dimethoxybenzyl)-2- [1-(hydroxym:ethyl)propylanmino] enzamide, N- (3,4-dimethoxybenzyl) -2-(2-hydroxy- 1, 1-dimethylethylamino) benzainide, N-(3-fluoro-4-inethoxybenzyl) -2-[2-hydroxy-l1-(hydroxymethyl) ethylami no] nitrobenzamide, *0 0 0 0 0 .0 N- (4-chloro-3-methoxybenzyl)-2-[2-hydroxy-l1-(hydroxymethyl)ethylami no] 2- [2-hydroxy-l1-(hydroxymethyl)ethylaninoJl-N-(2-naphthylmethy1)-5-niit robenzaxnide, 02- [2-hydroxy- 1- (hydroxymethyl)ethylamnino]-N- [2-(2-methoxyphenyl)eth yl] N-(3-chloro-4-fluorobenzyl)-2-[2-hydroxy- 1 -(hydroxymethyl)ethylanhinol ,4-dinaethoxybenzyl)-2-(2-hydroxy- 1 -methyletbylamino) benzarnide, 5-dimethoxybenzyl) -2-(2-hydroxy- 1 -methylethylJ benzam-ide, N-(3 -chloro-4-methoxybenzyl) -2-[2-hydroxy-l1-(hydroxymethyl)ethylami Vff-ls181 a CI-Cs alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy group; CI-C 6 alkoxy group; acyloxy group and aryloxy group which may be substituted with cyano, or R6 and R 7 together with the carbon atom to which R 6 and R 7 are attached may form a substituted or unsubstituted, cycloalkyl group, and RS is hydrogen atom; a Ci-C6 alkoxy group; or a Ci-C6 alkyl group optionally substituted with hydroxy or Ci-C6 alkoxy; and a salt thereof, which comprises 15 reacting a compound of the formula (II) F or its salt, with a compound of (HI) H 2 N-R (III) 25 or its salt, wherein RI, R 2 R 3 R 4 and A are as defined above, or reacting a compound of the formula (IV): 0 ._^OH R1 L (IV) NH 2 R or its salt, with a compound of the formula H 2 N-A-R 3 (V) 183 or its salt, wherein R 2 R3, R 4 and A are as defined above, or subjecting a compound of the formula (VI): 0 N (VI H 2 or its salt, to reductive alkylation with a compound of formula (VII): 0 R 6 A R 7 or its salt, wherein RI, R 2 R3, R6, R 7 and A are as defined above.

11. A pharmaceutical composition which comprises, as an active ingredient, a compound of Claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier.

12. A pharmaceutical composition comprising a compound of Claim 1, as an active ingredient, in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient. S0*

13. A composition of Claim 11 for the use of the treatment and/or prevention of angina, hypertension, pulmonary hypertension, congestive heart failure, glomerular diseases, renal tubulo-intestitinal 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 motility, erectile dysfunction, female sexual dysfunction, impotence, diabetic complications, micturition disorder, or incontinence or storage of urine disorder. 184

14. A composition of Claim 11 for the use of the treatment of erectile dysfunction or impotence. A use of the compound of Claim 1 for the manufacture of a medicament for inhibiting cGMP-PDE.

16. A use of the compound of Claim 1 for the manufacture of a medicament for treatment and/or prevention of angina, hypertension, pulmonary hypertension, congestive heart failure, glomerular diseases, renal tubulo-intestitinal 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 motility, erectile dysfunction, female sexual dysfunction, impotence, diabetic complications, micturition disorder, or incontinence or storage of urine disorder. r r r r a o a a

17. A compound of formula according to claim 1, substantially as hereinbefore described with reference to the Examples.

18. A process according to claim 10, substantially as hereinbefore described with reference to the Examples.

19. A compound of formula as defined in any one of claims 1 to 9 or claim 17 prepared by the process of claim DATED this 9 t h day of December, 2002 Fujisawa Pharmaceutical Co., Ltd By DAVIES COLLISON CAVE Patent Attorneys for the Applicants 185