ZA200505734B

ZA200505734B - Pyrazole Derivative

Info

Publication number: ZA200505734B
Application number: ZA200505734A
Authority: ZA
Inventors: Kanaya Naoaki; Ishihara Hiroaki; Kimura Youichi; Ishiyama Takashi; Ochiai Yuichi
Original assignee: Daiichi Seiyaku Co
Priority date: 2003-02-07
Filing date: 2004-02-06
Publication date: 2006-12-27
Also published as: CN1759110A; CN100436445C

Description

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Description

Pyrazole Derivative

Technical Field

The present invention relates to pyrazole derivatives endowed with platelet aggregation-inhibiting activity.

Background Art

Platelets play an important role in stopping hemorrhage caused by damage to blood vessel through coagulation to form thrombi. On the other hand, it has been known that, when vascular endothelium is injured or the blood vessel is narrowed as in the case of arteriosclerosis, platelets : aggregate and trigger thrombus or embolus formation, causing ischemic diseases such as myocardial infarction, angina pectoris, ischemic cerebrovascular disorder, and peripheral vascular disease. Therefore, platelet aggregation inhibitors are administered for prevention and treatment of such ischemic diseases. Aspirin is one such platelet aggregation inhibitor that has been used for a long time, and the effects of aspirin have been demonstrated by APT (Antiplatelet

Trialists' Collaboration) in which clinical test results obtained by administering aspirin to 100,000 patients had been subjected to metaanalysis (BMJ, vol.308, pages 81-106, 1994). Aspirin, however, is known to cause side effects such as hemorrhage in gastrointestine or like organs, namely, the

® 2005705734 so-called "aspirin-induced ulcer", and the side effect is not dose-dependent and occurs at a rate of about 1 per 100 patients (BMJ, vol.321, pages 1183-1187, 2000).

The inhibitory effect of aspirin on platelet aggregation is known to be based on the activity to inhibit the action of cyclooxygenase. Cyclooxygenases include cyclooxygenase—-1 (COX-1) and cyclooxygenase-2 (COX-2), and aspirin specifically inhibits COX-1 at a low dose, resulting in inhibition of platelet aggregation. The inhibition of

COX-1 also causes the aspirin-induced ulcer (Neurology, vol.57, Suppl.2, pages S5-S7, 2001 and Drugs Today, vol.35, pages 251-265, 1999). In addition, nonsteroidal antiinflammatory drugs are known to exhibit antiinflammatory action by selectively inhibiting COX-2.

As described above, although aspirin is useful as a platelet aggregation inhibitor, it produces a side effect of gastrointestinal dysfunction attributable to the COX-1- inhibiting action, which is an action mechanism of platelet aggregation inhibition, and there is a strong demand for new platelet aggregation inhibitors exhibiting no COX-1- inhibiting activity.

In the meanwhile, as pyrazole derivatives having antithrombotic activity, there have been known compound (A) (Japanese Patent No. 2586713 and Chem.Pharm.Bull., vol.45, pages 987-995, 1997) and compound (B) (BMJ, vol.321, pages 1183-1187, 2000).

@®

Pe MeO

TL ALA a AE or oO

Disclosure of the Invention

Compound (A), however, exhibits an ICsq value of 5.3 x 10°®* M against collagen-induced platelet aggregation, and even stronger inhibitory activity is exhibited against COX-2 (ICso, 2.4 x 1077 M). The situation is similar to the case of compound (B). The platelet aggregation inhibitory activity of compound (B) is not so potent compared with its inhibitory activity against COX-2. As described above, inhibition of

COX-2 may lead to an antiinflammatory action, and the inhibition of COX-2 is not necessarily favorable as a platelet aggregation inhibitor. In view of the situation as described above, an object of the present invention is to provide a strong inhibitor against platelet aggregation which, however, neither inhibits COX-1 nor COX-2.

The present inventors have made an extensive study in search of such a platelet aggregation inhibitor, and found that pyrazole derivatives represented by the following formulas (I) and (II) exhibit strong platelet aggregation

@ inhibitory activity without inhibiting COX-1 or COX-2, to thereby complete the invention.

Accordingly, the present snventicn provides a compound represented by formula (I), a salt of the compound, or a solvate of the compound or the salt:

R2

NA

~ (1)

RI

N—

Are” N (wherein Ar; represents a 5- or 6-membered aromatic heterocyclic group having 1 to 3 substituents; Ar; represents a 5- or 6-membered aromatic heterocyclic group which may have 1 to 3 substituents or a phenyl group which may have 1 to 3 substituents; Rl is a group represented by formula (1): : R3 (wherein ring structure A represents a 4- to 7-membered ring which may have, other than the nitrogen atom in formula (1), one hetero atom selected from among a nitrogen atom, an oxygen atom, and a sulfur atom; X represents a carbonyl group, a thiocarbonyl group, or a methylene group that may be substituted by 1 or 2 lower alkyl groups; R3 represents 1 to 4 groups on ring structure A, R3 being selected from the

® group consisting of a hydrogen atom, a halogeno group, a hydroxyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxyl group, a sulfo group, a lower alkylsulfonyl group, a lower alkyl group which may have 1 or 2 substituents, an amino group which may have 1 or 2 substituents, a carbamoyl group which may have 1 or 2 substituents, a lower acyl group, an aminosulfonyl group which may have 1 or 2 = substituents, an oxo group, a hydroxyiminocarbonyl group, a lower alkoxyiminocarbonyl group, an aralkyl group which may have 1 to 3 substituents, a 4- to 7-membered alicyclic heterocyclic group which may have 1 or 2 substituents, a phenyl group which may have 1 to 3 substituents, a 5- or 6- membered aromatic heterocyclic group which may have 1 to 3 substituents, a substituted or non-substituted 3- to 6- membered spiro alicyclic alkyl group, and a substituted or non-substituted 4- to 6-membered spiro alicyclic heterocyclic group); R2 represents a hydrogen atom, a halogeno group, a hydroxyl group, a lower alkoxy group, a lower alkyl group which may have 1 or 2 substituents, an amino group which may have 1 or 2 substituents, a carbamoyl group which may have 1 or 2 substituents, or an acyl group which may have 1 or 2 substituents).

The present invention also provides a compound represented by formula (II), a salt of the compound, or a : solvate of the compound or the salt:

R6 —— 2o—Re (11)

Ny . .

Ar; (wherein ring structure B represents a 5- to 7-membered ring which may have one hetero atom or two hetero atoms which are the same or different from each other, the hetero atom(s) being selected from among a nitrogen atom, an oxygen atom, and a sulfur atom; ring structure Ar; represents a 5- or 6- membered aromatic heterocycle which may have 1 to 3 substituents or a benzene ring which may have 1 to 3 substituents; Ar, represents a 5- or 6-membered aromatic heterocyclic group which may have 1 to 3 substituents or a phenyl group which may have 1 to 3 substituents; R4 is a group represented by formula (2):

R7 —Y—N C (2) (wherein ring structure C represents a 4- to 7-membered ring which may have, other than the nitrogen atom in formula (2),

® one hetero atom selected from among a nitrogen atom, an oxygen atom, and a sulfur atom; Y represents a carbonyl group, a thiocarbonyl group, or a methylene group that may be substituted by 1 or 2 lower alkyl groups; R7 represents 1 to 4 groups on ring structure C, R7 being selected from the group consisting of a hydrogen atom, a halogeno group, a hydroxyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxyl group, a sulfo group, a lower alkylsulfonyl group, a lower alkyl group which may have 1 or 2 substituents, an amino group which may have 1 or 2 substituents, a carbamoyl group which may have 1 or 2 substituents, a lower acyl group, an aminosulfonyl group which may have 1 or 2 substituents, an oxo group, a hydroxyiminocarbonyl group, a lower alkoxyiminocarbonyl group, an aralkyl group which may have 1 to 3 substituents, a 4- to 7-membered alicyclic heterocyclic group which may have 1 or 2 substituents, a phenyl group which may have 1 to 3 substituents, a 5- or 6- membered aromatic heterocyclic group which may have 1 to 3 substituents, a substituted or non-substituted 3- to 6- membered spiro alicyclic alkyl group, and a substituted or non-substituted 4- to 6-membered spiro alicyclic heterocyclic group); each of R5 and R6 represents a group selected from the group consisting of a hydrogen atom, a halogeno group, a “hydroxyl group, a lower alkoxy group, an amino group which may have 1 or 2 substituents, a lower alkyl group which may have 1 or 2 substituents, and an oxo group).

The present invention also provides a drug containing a

® compound represented by formula (I) or (II), a salt of the compound, or a solvate of the compound or the salt.

The present invention also provides a preventive and/or therapeutic agent for an ischemic disease, containing a compound represented by formula (I) or (II), a salt of the compound, or a solvate of the compound or the salt.

The present invention also provides a drug composition containing a compound represented by formula (I) or (II), a salt of the compound, or a solvate of the compound or the salt and a pharmacologically acceptable carrier therefor.

The present invention also provides use of a compound represented by formula (I) or (II), a salt of the compound, or a solvate of the compound or the salt in production of a drug.

The present invention also provides a method for treating an ischemic disease, characterized by comprising administering an effective amount of a compound represented by formula (I) or (II), a salt of the compound, or a solvate of the compound or the salt.

The compounds (I) and (II) of the present invention, salts of the compound, and solvates of the compounds or the salts potently inhibit platelet aggregation, and accordingly, also inhibit thrombogenesis without inhibiting COX-1 or COX-2.

Therefore, they are useful as preventive and/or therapeutic agents for ischemic diseases caused by thrombus or embolus such as myocardial infarction, angina pectoris (chronic stable angina, unstable angina, etc.), ischemic

® cerebrovascular disorder (transient ischemic attack (TIA), cerebral infarction, etc.), peripheral vascular disease, embolism after replacement with an artificial vessel, thrombotic embolism after coronary artery intervention (coronary artery bypass grafting (CAGB), percutaneous transluminal coronary angioplasty (PTCA), stent placement, etc.), diabetic retinopathy and nephropathy, and embolism after replacement with an artificial heart valve, and are also useful as preventive and/or therapeutic agents for thrombus and embolus associated with vascular operation, blood extracorporeal circulation, and the like.

Best Mode for Carrying Out the Invention

Next will be described substituents and ring structures of the compounds represented by formula (I) and (II).

The aromatic heterocyclic group represented by Ar; or

Ar, is a 5- or 6-membered aromatic heterocyclic group, and specific examples include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, and pyrazolyl. . : Examples of the substituent of the aromatic heterocyclic group Ar; or Ars include a lower alkyl group, a halogeno group, a hydroxyl group, a cyano group, a lower alkoxy group, an aralkyloxy group, a lower thioalkoxy group, a lower alkoxycarbonyl group, a carboxyl group, a lower alkylsulfonyl group, an amino group which may have 1 or 2 substituents, a carbamoyl group which may be substituted by 1

® or 2 lower alkyl groups, an aminosulfonyl group which may be substituted by 1 or 2 lower alkyl groups, and a 4- to 7- membered alicyclic heterocyclic group which may have 1 or 2 substituents. These substituents will next be described.

Among the above-mentioned substituents of aromatic heterocyclic group Ar; or Ary, the lower alkyl group refers to a linear, branched, or cyclic C1-C6 alkyl group, and examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, and cyclopentylmethyl.

Examples of the halogeno group include fluoro, chloro, and bromo.

The lower alkoxy group refers to an alkoxy group which has a linear, branched, or cyclic Cl1-C6 alkyl group, and examples include methoxy, ethoxy, propoxy, 1sopropoxy, butoxy, isobutoxy, pentoxy, and cyclopentyloxy.

The aralkyl group of the aralkyloxy group refers to a group formed by the above lower alkyl group and a C6-C20 aryl group, and examples of the aralkyloxy group include benzyloxy and phenethyloxy.

The lower thioalkoxy refers to a thioalkoxy group having a linear, branched, or cyclic Cl1-Cé alkyl group, and examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, and cyclopentylthio.

The lower alkoxycarbonyl group refers to an

® alkoxycarbonyl group having a linear, branched, or cyclic Cl-

C6 alkyl group, and examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n- to tert-butoxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, and cyclopentylmethyloxycarbonyl.

The lower alkylsulfonyl group refers to an alkylsulfonyl group having a linear, branched, or cyclic Cl-

C6 alkyl group, and examples include methanesulfonyl, ethanesulfonyl, and trifluoromethanesulfonyl.

The amino group which may have 1 or 2 substituents refers to a non-substituted amino group, an amino group substituted by 1 or 2 lower alkyl groups described above, a lower alkanoylamino group, a lower alkoxycarbonylamino group, or a ureido group which may be substituted by 1 or 2 lower alkyl groups described above. Examples of the amino group substituted by 1 or 2 lower alkyl groups described above include methylamino, ethylamino, propylamino, isopropylamino, cyclopropylamino, butylamino, isobutylamino, cyclopentylmethylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-methyl-N-ethylamino, N-ethyl-

N-propylamino, and N-methyl-N-cyclopentylmethylamino. The lower alkanoylamino group refers to an amino group substituted by a linear or branched C2-C6 alkanoyl group, and examples include acetylamino and propionylamino. The lower alkoxycarbonylamino group refers to an amino group substituted by a linear or branched C2-C6 lower

® alkoxycarbonyl group, and examples include methoxycarbonylamino and ethoxycarbonylamino. Examples of the ureido group which may be substituted by 1 or 2 lower alkyl groups described above include aminocarbonylamino, N1- methylaminocarbonylamino, Nl-ethylaminocarbonylamino, N3- methylaminocarbonylamino, N1,Nl-dimethylaminocarbonylamino,

N1,N3-dimethylaminocarbonylamino, and Nl-methyl-N3- ethylaminocarbonylamino.

The carbamoyl group which may be substituted by 1 or 2 lower alkyl groups refers to a non-substituted carbamoyl group or a carbamoyl group substituted by 1 or 2 lower alkyl group described above, and examples include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, and methylethylcarbamoyl.

The aminosulfonyl group which may be substituted by 1 or 2 lower alkyl groups refers to a non-substituted aminosulfonyl group or an aminosulfonyl group substituted by 1 or 2 lower alkyl group described above, and examples include methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, n- to tert- butylaminosul fonyl, cyclopropylaminosulfonyl, cyclobutylaminosulfonyl, cyclopentylaminosulfonyl, cyclohexylaminosulfonyl, cyclopentylmethylaminosulfonyl, dimethylaminosulfonyl, and diethylaminosulfonyl.

Examples of the 4- to 7-membered alicyclic heterocyclic group of the 4- to 7-membered alicyclic heterocyclic group which may have 1 or 2 substituents include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, hexahydropyridazinyl,

® hexahydropyrimidinyl, pyrazolidinyl, imidazolidinyl, homopiperazinyl, morpholinyl, and thiomorpholinyl. Examples of the alicyclic heterocyclic group substituted by 1 or 2 groups include 3-aminocazetidin-1l-yl, 3-methylaminoazetidin-1- yl, 3-dimethylaminoazetidin-1-yl, 2-carbamoylazetidin-l-yl, 2-methylcarbamoylazetidin-1-y1, 2-dimethylcarbamoylazetidin- 1-yl, 3-carbamoylazetidin-1-yl, 3-methylcarbamoylazetidin-1- yl, 3-dimethylcarbamoylazetidin-1-yl, 3-hydroxypyrrolidino, 3-methoxymethylpyrrolidino, 2-carbamoylpyrrolidino, 2- methylcarbamoylpyrrolidino, 2-dimethylcarbamoylpyrrolidino, 3-carbamoylpyrrolidino, 3-methylcarbamoylpyrrolidino, 3- dimethylcarbamoylpyrrolidino, 3-aminopiperidino, 4- aminopiperidino, 3-methylaminopiperidino, 4- methylaminopiperidino, 3-dimethylaminopiperidino, 4- dimethylaminopiperidino, 2-methylpiperidino, 3- methylpiperidino, 4-methylpiperidino, 2,2-dimethylpiperidino, 3,3-dimethylpiperidino, 4,4-dimethylpiperidino, 2- carbamoylpiperidino, 3-carbamoylpiperidino, 4- carbamoylpiperidino, 2-methylcarbamoylpiperidino, 3- methylcarbamoylpiperidino, 4-methylcarbamoylpiperidino, 2- dimethylcarbamoylpiperidino, 3-dimethylcarbamoylpiperidino, 4-dimethylcarbamoylpiperidino, 4-methylpiperazino, 4- cyclopropylpiperazino, 4-carbamoylpiperazino, 2,2- dimethylmorpholino, and 3, 3-dimethylmorpholino.

A substituent on the aromatic heterocyclic group Ar; is preferably present at the para position with respect to the pyrazole ring.

®

Examples of the substituents of the phenyl group which is represented by Ar, and which may have 1 to 3 substituents include those listed above in relation to the aromatic heterocyclic group Ar,. The 5- or 6-membered aromatic heterocyclic group represented by Ar, also includes non- substituted compounds.

The aromatic heterocyclic group Ar, represents a 5- or ; 6-membered aromatic heterocyclic group or a phenyl group, which groups may have 1 to 3 substituents. Examples of the aromatic heterocyclic group include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, and pyrazolyl.

The aromatic heterocyclic ring Ars represents a 5- or 6- membered aromatic heterocyclic ring or a benzene ring which rings have 1 to 3 substituents. Examples of the aromatic heterocyclic ring include pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, furan ring, thiophene ring, pyrrole ring, imidazole ring, triazole ring, oxazole ring, isoxazole ring, thiazole ring, and pyrazole ring.

Examples of the substituent of the aromatic heterocyclic group Ar, or the aromatic heterocyclic ring Ars include those listed above in relation to Ar; and Ary.

When the aromatic heterocyclic group Ar; has a substituent at the para position with respect to the pyrazole ring, preferably, Ar;, which is an aromatic heterocyclic group or a phenyl group is not substituted or has a substituent at the meta position with respect to the pyrazole ring.

Each of the ring structures A and C is a 4- to 7- membered ring which may have, as a structural atom thereof and in addition to the nitrogen atom shown in formulas (1) and (2), a single "hetero" atom selected from among nitrogen atom, oxygen atom, and sulfur atom, and the "hetero" atom may be the same or different from the nitrogen atom. Examples of the 4- to 7-membered ring include saturated heterocyclic rings such as azetidine ring, pyrrolidine ring, imidazolidine ring, pyrazoline ring, piperidine ring, piperazine ring, morpholine ring, thiomorpholine ring, hexahydropyridazine ring, hexahydropyrimidine ring, homopiperazine ring, and azepane ring; and unsaturated heterocclic rings pyrrole ring, dihydropyrrole ring, imidazole ring, dihydroimidazole ring, pyrazole ring, dihydropyridine ring, dihydropyrimidine ring, and dihydropyrazine ring.

The ring structure B is a 5- to 7-membered ring which may have one hetero atom or two hetero atoms which are the same or different from each other, the hetero atom(s) being selected from among nitrogen atom, oxygen atom, and sulfur atom. For example, when the ring structure B is fused with

Ars and the pyrazole ring, there may be formed 1,4- dihydroindeno|[l,2-c]pyrazole ring, 1,4-dihydro-4- oxoindeno (1, 2-clpyrazole ring, 4,5-dihydro-1H- benzo[glindazole ring, 1,4-dihydrochromeno({4,3-c]lpyrazole ring, or similar rings.

Next will be described the substituents R2, R3, R5, R6,

® and R7.

Examples of the halogeno group include fluoro, chloro, and bromo.

The lower alkoxy group refers to an alkoxy group having a linear, branched, or cyclic C1-C6 alkyl group, and examples include methoxy, ethoxy, propoxy, isopropoxy, n- to tert- butoxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and cyclopentylmethyloxy.

The lower alkoxycarbonyl group refers to an alkoxycarbonyl group having a linear, branched, or cyclic Cl-

The lower alkylsulfonyl refers to a sulfonyl group having a linear, branched, or cyclic Cl-C6 alkyl group, and examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, n- to tert-butylsulfonyl, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, and cyclopentylmethylsulfonyl.

The lower alkyl group which may have 1 or 2 substituents refers to a linear, branched, or cyclic Cl-Cé6 alkyl group which may have one substituent or two substituents which are the same or different from each other, the substituent (s) being selected from the group consisting of a hydroxyl group; a halogeno group; a carboxyl group; a

® sulfo group; a Cl1-C3 linear, branched, or cyclic alkoxy group; an alkoxycarbonyl group having a C1-C3 linear, branched, or cyclic alkyl group; an amino which may be substituted by one or two C1-C3 linear, branched, or cyclic alkyl groups; a carbamoyl group which may be substituted by one or two Cl-C3 linear, branched, or cyclic alkyl groups; and a ureido group which may be substituted by one or two Cl-

C3 linear, branched, or cyclic alkyl groups.

Specific examples include methyl, ethyl, propyl, isopropyl, n- to tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, hydroxymethyl, 2-hydroxyethyl, 3- hydroxypropyl, 2-hydroxypropyl, 2-fluoroethyl, 3~fluoropropyl, 2-fluoropropyl, 2-fluorocyclopropyl, 2-chloroethyl, 3- chloropropyl, 2-chloropropyl, trifluoromethyl, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 2-carboxypropyl, sulfomethyl, 2-sulfoethyl, 1l-sulfoethyl, 3-sulfopropyl, 2-sulfopropyl, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, 2-methoxyethyl, 3-methoxypropyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, 2- methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2- propoxycarbonylethyl, aminomethyl, 2-aminoethyl, l-aminoethyl, 3-aminopropyl, 2-aminopropyl, methylaminomethyl, 2- (methylamino) ethyl, 1-(methylamino)ethyl, 3- (methylamino) propyl, 2-(methylamino)propyl, . dimethylaminomethyl, 2-(dimethylamino)ethyl, 1- (dimethylamino) ethyl, 3- (dimethylamino) propyl, 2-

® (dimethylamino) propyl, 2-(methylethylamino)ethyl, 1- (methylethylamino)ethyl, carbamoylmethyl, methylcarbamoylmethyl, ethylcarbamoylmethyl, dimethylcarbamoylmethyl, methylethylcarbamoylmethyl, carbamoylethyl, methylcarbamoylethyl, ethylcarbamoylethyl, dimethylcarbamoylethyl, methylethylcarbamoylethyl, carbamoylpropyl, 2-carbamoylcyclopropyl, ureidomethyl, N3- methylureidomethyl, N3-ethylureidomethyl, N3,N3- dimethylureidomethyl, N3-methyl-N3-ethylureidomethyl, 2- (ureido) ethyl, 2-(N3-methylureido)ethyl, 2-(N3- ethylureido)ethyl, 2-(N3,N3-dimethylureido)ethyl, 2-(N3- methyl-N3-ethylureido) ethyl, 3-(ureido)propyl, 2- (ureido) cyclopropyl, Nl-methylureidomethyl, NI1- ‘ethylureidomethyl, N1,Nl-dimethylureidomethyl, Nl-methyl-N1- ethylureidomethyl, 2-(ureido)ethyl, 2-(Nl-methylureido)ethyl, 2- (Nl-ethylureido)ethyl, 2-(N1,Nl-dimethylureido)ethyl, 2- (Nl-methyl-Nl-ethylureido) ethyl, N1,N3-dimethylureidomethyl,

Nl-methyl-N3-ethylureidomethyl, 2-(N3-methyl-N1- ethyl)ureidoethyl, 2-(N1,N3-diethylureido)ethyl, l-carbamoyl- 2-hydroxyethyl, and 1,2-dicarbamoylethyl.

The amino group which may have 1 or 2 substituents refers to an amino group which may be substituted by one or two Cl1l-C6 linear, branched, or cyclic alkyl groups, and examples include non-substituted amino, methylamino, ethylamino, propylamino, isopropylamino, n- to tert- butylamino, pentylamino, hexylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino,

® cyclopropylmethylamino, cyclopentylmethylamino, dimethylamino, methylethylamino, diethylamino, methylpropylamino, methylisopropylamino, methylcyclopropylamino, methylcyclopropylmethylamino, and methyl-tert- butoxycarbonylamino.

The carbamoyl group which may have 1 or 2 substituents refers to a carbamoyl group which may be substituted by one or two Cl1-C6 linear, branched, or cyclic alkyl groups, and examples include non-substituted carbamoyl, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, n- to tert-butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl, cyclopropylmethylcarbamoyl, cyclopentylmethylcarbamoyl, dimethylcarbamoyl, methylethylcarbamoyl, diethylcarbamoyl, methylpropylcarbamoyl, methylisopropylcarbamoyl, methylcyclopropylcarbamoyl, and methylcyclopropylmethylcarbamoyl.

The lower acyl refers to an acyl group having a linear, branched, or cyclic C1-Cé6 alkyl group, and examples include formyl, acetyl, propionyl, n- and iso-butyryl, pivaloyl, cyclopropylcarbonyl, cyclobutyrylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cyclopropylmethylcarbonyl, cyclobutylmethylcarbonyl, and cyclopentylmethylcarbonyl.

The aminosulfonyl group which may have 1 or 2 substituents refers to an aminosulfonyl group which may be

® substituted by one or two C1-C3 alkyl groups, and examples include non-substituted aminosulfonyl, aminosulfonyl, methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, cyclopropylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl, methylethylaminosulfonyl, methylpropylaminosulfonyl, dimethylaminosulfonyl, and diethylaminosulfonyl.

The lower alkoxyiminocarbonyl group refers to an iminocarbonyl group substituted by an alkoxy group having a "linear, branched, or cyclic C1-C6 alkyl group, and examples include methoxyiminocarbonyl, ethoxyiminocarbonyl, propoxyiminocarbonyl, isopropoxyiminocarbonyl, n- to tert- butoxyiminocarbonyl, cyclobutyloxyiminocarbonyl, : cyclopentyloxyiminocarbonyl, cyclohexyloxyiminocarbonyl, and cyclopentylmethyloxyiminocarbonyl.

The aralkyl group which may have 1 to 3 substituents refers to an aralkyl group which is formed of a linear, . branched, or cyclic Cl1-C6 alkyl group and a C6-C20 aryl group and which may have 1 to 3 substituents. Examples include benzyl and phenethyl.

Examples of the substituents of the aralkyl group include hydroxyl, carboxyl, sulfo, cyano, and nitro.

Examples of the substituents referred to in connection with the "phenyl group which may have 1 to 3 substituents" also include these groups.

Examples of the 5- or 6-membered aromatic heterocyclic group which may have 1 to 3 substituents include pyridyl,

® pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, and ~ pyrazolyl.

Examples of the substituents include those listed above in relation to Ar; and Ary.

Examples of the 4- to 7-membered alicyclic heterocyclic group which may have 1 or 2 substituents include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, hexahydropyridazinyl, hexahydropyrimidinyl, pyrazolidinyl, imidazolidinyl, ’ homopiperazinyl, morpholinyl, and thiomorpholinyl.

The alicyclic heterocyclic group may be substituted, and examples of the substituents include a hydroxyl group, an oxo group, a carboxyl group, a sulfo group, a cyano group, a nitro group, the above-described halogeno group, the above- described lower alkoxy group, alkylsulfonyl group, the above- described lower alkyl group which may have 1 or 2 substituents, the above-described amino group which may have 1 or 2 substituents, the above-described carbamoyl group which may have 1 or 2 substituents, the above-described lower acyl group, and the above-described aminosulfonyl group which may have 1 or 2 substituents.

Examples of the substituted or non-substituted 3- to 6- membered spiro alicyclic alkyl group include cyclopropanespiro, cyclobutanespiro, cyclopentanespiro, and cyclohexanespiro.

The spiro alicyclic alkyl group may be substituted, and examples of the substituent include a hydroxyl group, an oxo

® group, the above-described lower alkoxy group, the above- described lower alkyl group which may have 1 or 2 substituents, the above-described amino group which may have 1 or 2 substituents, the above-described carbamoyl group which may have 1 or 2 substituents, the above-described lower acyl group, and the above-described aminosulfonyl group which may have 1 or 2 substituents.

The substituted or non-substituted 4- to 6-membered spiro alicyclic heterocyclic group refers to a spiro - heterocyclic group which may have a single double bond, and examples include azetidinespiro, pyrrolidinespiro, piperidinespiro, piperazinespiro, pyrazolidinespiro, imidazolinespiro, morpholinespiro, and thiomorpholinespiro.

Examples of the substituent of the spiro alicyclic heterocyclic group include a hydroxyl group, an oxo dgroup, a carboxyl group, the above-described lower alkoxy group, the above-described lower alkyl group which may have 1 or 2 substituents, the above-described amino group which may have 1 or 2 substituents, the above-described carbamoyl group which may have 1 or 2 substituents, the above-described acyl group which may have 1 or 2 substituents, and the above- described aminosulfonyl group which may have 1 or 2 substituents.

The compounds (I) and (II) of the present invention will next be described in more detail.

Ar; in formula (I) is preferably a 6-membered aromatic heterocyclic group which has 1 to 3 substituents, more

® preferably a pyridyl group having 1 to 3 substituents, a pyridazinyl group having 1 to 3 substituents, or a pyrazinyl group having 1 to 3 substituents, still more preferably a pyridyl group having 1 to 3 substituents or a pyridazinyl group having 1 to 3 substituents.

Ar, in formula (I) is preferably a 6-membered aromatic heterocyclic group which may have 1 to 3 substituents or a phenyl group which may have 1 to 3 substituents, more preferably a pyridyl group which may have 1 to 3 substituents, a pyridazinyl group which may have 1 to 3 substituents, a pyrazinyl group which may have 1 to 3 substituents, or a phenyl group which may have 1 to 3 substituents.

As mentioned above, the aromatic heterocyclic group represented by Ar; or Ar, has one to three substituents.

Examples of preferred ones of the substituents include a Ci-e alkyl group, a halogeno group, a Ci-s alkoxy group, a Ci-s alkylamino group, and a di(Ci-¢ alkyl)amino group.

Ar, in formula (I) is preferably a pyridyl group which may have 1 to 3 substituents, a pyridazinyl group which may have 1 to 3 substituents, a pyrazinyl group which may have 1 to 3 substituents, a pyrrolyl group which may have 1 to 3 substituents, or a phenyl group which may have 1 to 3 substituents.

Ar; in formula (II) is preferably a 6-membered aromatic heterocyclic ring which may have 1 to 3 substituents or a benzene ring which may have 1 to 3 substituents. Moreover,

Ar; is preferably a pyridine ring which may have 1 to 3

® substituents or a benzene ring which may have 1 to 3 substituents.

Each of Ar; in formula (I) and Ar, in formula (II) is preferably 3-pyridyl, 6-methoxy-3-pyridyl, 6-methyl-3-pyridyl, 6-ethyl-3-pyridyl, 6-chloro-3-pyridyl, 6-ethoxy-3-pyridyl, 6- isopropyloxy-3-pyridyl, 6-methylamino-3-pyridyl, 6- cyclopropylamino-3-pyridyl, 5-methoxy-2-pyridyl, 6-methoxy-3- pyridazinyl, 6-methyl-3-pyridazinyl, S5-methoxy-2-pyrimidinyl, 5-methyl-2-pyrimidinyl, 2-methoxy-5-pyrimidinyl, 2-methyl-5- pyrimidinyl, 5-methoxy-2-pyrazinyl, or 5-methoxy-2-pyrazinyl.

Among them, 6-methoxy-3-pyridyl, 6-methyl-3-pyridyl, 5- methoxy-2-pyridyl, 6-methoxy-3-pyridazinyl, 6-methyl-3- pyridazinyl, 5-methoxy-2-pyrimidinyl, S5-methyl-2-pyrimidinyl, 5-methoxy-2-pyrazinyl, 5-methyl-2-pyrazinyl are more preferred. Of these, 6-methoxy-3-pyridyl, 6-methyl-3-pyridyl, 5-methoxy-2-pyridyl, 6-methoxy-3-pyridazinyl are still more preferred.

Ar, is preferably phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-hydroxyphenyl, 3- fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 6-methoxy-2-pyridyl, 6-methyl-2-pyridyl, 6-methoxy-3-pyridyl, 6-methyl-2-pyridyl, 6-methoxy-2-pyridyl, 6-methyl-2-pyridyl, 3-methoxy-2-pyridyl, 3-methyl-2-pyridyl, 3-fluoro-2-pyridyl, 4-fluoro-2-pyridyl, 5-fluoro-2-pyridyl,

® 6-fluoro-2-pyridyl, 4-methyl-2-pyridyl, 4-ethyl-2-pyridyl, 4- methoxy-2-pyridyl, 4-ethoxy-2-pyridyl, 4-cyano-2-pyridyl, 4- carbamoyl-2-pyridyl, 4-pyrrolidinyl-2-pyridyl, 4-methylthio- 2-pyridyl, 4-methanesulfonyl-2-pyridyl, 4-carboxy-2-pyridyl, 6-methoxy-3-pyridazinyl, 6-methyl-3-pyridazinyl, 5-methoxy-2- pyrimidinyl, S5-methyl-2-pyrimidinyl, 5-methoxy-2-pyrazinyl, 5-methyl-2-pyrazinyl, pyrrol-l-yl, pyrrol-2-yl, pyrrol-3-yl, l1-methylpyrrol-2-yl, l-methylpyrrol-3-yl, l-ethylpyrrol-2-yl, or l-ethylpyrrol-3-yl. Among them, phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 2-methoxyphenyl, 2- hydroxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 4-fluorophenyl, 4- chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4- hydroxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 6-methoxy-3- pyridyl, 6-methyl-3-pyridyl, 6-methoxy-2-pyridyl, 6-methyl-2- pyridyl, 3-fluoro-2-pyridyl, 4-fluoro-2-pyridyl, 5-fluoro-2- pyridyl, 6-fluoro-2-pyridyl, 4-methyl-2-pyridyl, 4-ethyl-2- pyridyl, 4-methoxy-2-pyridyl, 4-cyano-2-pyridyl, 4-carbamoyl- 2-pyridyl, 4-pyrrolidinyl-2-pyridyl, 3-methoxy-2-pyridyl, 3- methyl-2-pyridyl, 6-methoxy-3-pyridazinyl, 6-methyl-3- pyridazinyl, 5-methoxy-2-pyrimidinyl, 5-methyl-2-pyrimidinyl, 5-methoxy-2-pyrazinyl, 5-methyl-2-pyrazinyl, pyrrol-l-yl, pyrrol-2-yl, pyrrol-3-yl, l-methylpyrrol-2-yl, 1- methylpyrrol-3-yl, l-ethylpyrrol-2-yl, and l-ethylpyrrol-3-yl are more preferred.

Ars is preferably a benzene ring or a pyridine ring, more preferably a benzene ring.

®

As already mentioned above, Rl represents a group represented by the following formula (1):

R3 —x{x (1) and X represents a carbonyl group, a thiocarbonyl group, or a methylene group which may be substituted by 1 or 2 lower alkyl groups. The group represented by X is preferably a carbonyl group or methylene group which may be substituted by 1 or 2 lower alkyl groups, more preferably a carbonyl group.

Also already described above, R4 represents a group represented by the following formula (2):

R7 and Y represents a carbonyl group, a thiocarbonyl group, Or a methylene group which may be substituted by 1 or 2 lower alkyl groups. The group represented by Y is preferably a carbonyl group or a methylene group which may be substituted by 1 or 2 lower alkyl groups, more preferably a carbonyl group.

Examples of the ring structures A and C in the above formulas (1) and (2) include saturated heterocyclic rings such as azetidine ring, pyrrolidine ring, imidazolidine ring, pyrazoline ring, piperidine ring, piperazine ring, morpholine

® ring, thiomorpholine ring, hexahydropyridazine ring, hexahydropyrimidine ring, homopiperazine ring, and azepane ring, and unsaturated heterocyclic rings such as pyrrole ring, dihydropyrrole ring, imidazole ring, dihydroimidazole ring, pyrazole ring, dihydropyridine ring, dihydropyrimidine ring, and dihydropyrazine ring. Of these, preferred are saturated rings such as azetidine ring, pyrrolidine ring, imidazolidine ring, pyrazoline ring, piperidine ring, piperazine ring, morpholine ring, thiomorpholine ring, hexahydropyridazine ring, hexahydropyrimidine ring, homopiperazine ring, and azepane ring.

Typical substituents represented by the following formulas:

R3 R7 / / —N A and —N C \ \ in formulas (1) or (2) include the following: :

Azetidin-1-yl, 3-oxoazetidin-1-yl, 2-oxoazetidin-1-yl, 3-aminoazetidin-1-yl, 3-methylaminoazetidin-1-yl, 3- dimethylaminoazetidin-1-yl, 2-methylazetidin-1-yl, 3- methylazetidin-1-yl, 2,2-dimethylazetidin-1-yl, 3,3- dimethylazetidin-1-yl, 2, 2-dimethyl-3-dimethylaminoazetidin- 1-y1, 3-dimethylaminomethylazetidin-1-yl, 3-methoxyazetidin- 1-yl, 2-hydroxymethylazetidin-1-vl, 3-hydroxymethylazetidin- 1-yl, 3-hydroxyazetidin-1l-yl, 2-carboxyazetidin-1-yl, 3-

® carboxyazetidin-1-yl, 2-carbamoylazetidin-1-yl, 2- methylcarbamoylazetidin-1-yl, 2-dimethylcarbamoylazetidin-1- yl, 3-carbamoylazetidin-1-yl, 3-methylcarbamoylazetidin-1l-yl, 3-dimethylcarbamoylazetidin-1-yl, pyrrolidino, 2- oxopyrrolidino, 3-oxopyrrolidino, 2,5-dioxopyrrolidino, 3-

aminopyrrolidino, 3-methylaminopyrrolidino, 2- dimethylaminomethylpyrrolidino, 3-dimethylaminopyrrolidino, 2-methylpyrrolidino, 3-methylpyrrolidino, 2,2- dimethylpyrrolidino, 3,3-dimethylpyrrolidino, 2,2-dimethyl-3- dimethylaminopyrrolidino, 2-hydroxymethylpyrrolidino, 3- hydroxymethylpyrrolidino, 3-methoxypyrrolidino, 2- methoxymethylpyrrolidino, 3-methoxymethylpyrrolidino, 2- carboxypyrrolidino, 3-carboxypyrrolidino, 2- carbamoylpyrrolidino, 2-methylcarbamoylpyrrolidino, 2- dimethylcarbamoylpyrrolidino, 3-carbamoylpyrrolidino, 3- methylcarbamoylpyrrolidino, 3-dimethylcarbamoylpyrrolidino, imidazolidin-1-yl, 3-methylimidazolidin-1-yl, 2- oxoimidazolidin-1-yl, 4-oxoimidazolidin-1-yl, 3-methyl-2- oxoimidazolidin-1-yl, 3-methyl-4-oxoimidazolidin-1-yl, 2,2- dimethylimidazolin-1-yl, pyrazolidin-1l-yl, 2-

methylpyrazolidin-1-yl, 3-oxopyrazolidin-1-yl, 3,5- dioxopyrazolidin-1l-yl, piperidino, 2-oxopiperidino, 3- oxopiperidino, 4-oxopiperidino, 3-hydroxypiperidino, 4- hydroxypiperidino, 2-hydroxyiminopiperidino, 3- hydroxyiminopiperidino, 4-hydroxyiminopiperidino, 2- methoxypiperidino, 3-methoxypiperidino, 4-methoxypiperidino, 2-methoxyiminopiperidino, 3-methoxyiminopiperidino, 4-

® methoxyiminopiperidino, 3-aminopiperidino, 4-aminopiperidino, 3-methylaminopiperidino, 4-methylaminopiperidino, 3- dimethylaminopiperidino, 4-dimethylaminopiperidino, 2- methylpiperidino, 3-methylpiperidino, 4-methylpiperidino, 2,2-dimethylpiperidino, 3,3-dimethylpiperidino, 4,4- dimethylpiperidino, 4-fluoropiperidino, 4-chloropiperidino, 3,3-difluoropiperidino, 4,4-difluoropiperidino, 3,3- dichloropiperidino, 4,4-dichloropiperidino, 2- : hydroxymethylpiperidino, 3-hydroxymethylpiperidino, 4- hydroxymethylpiperidino, 2-carboxypiperidino, 3- carboxypiperidino, 4-carboxypiperidino, 2-carbamoylpiperidino, 3-carbamoylpiperidino, 4-carbamoylpiperidino, 2- : methylcarbamoylpiperidino, 3-methylcarbamoylpiperidino, 4- methylcarbamoylpiperidino, 2-dimethylcarbamoylpiperidino, 3- dimethylcarbamoylpiperidino, 4-dimethylcarbamoylpiperidino, 2-carboxymethylpiperidino, 3-carboxymethylpiperidino, 4- carboxymethylpiperidino, 2-methoxymethylpiperidino, 3- methoxymethylpiperidino, 4-methoxymethylpiperidino, 2- aminomethylpiperidino, 3-aminomethylpiperidino, 4- aminomethylpiperidino, 2-methylaminomethylpiperidino, 3- methylaminomethylpiperidino, 4-methylaminomethylpiperidino, 2-dimethylaminomethylpiperidino, 3- dimethylaminomethylpiperidino, 4- dimethylaminomethylpiperidino, 2-aminoethylpiperidino, 3- aminocethylpiperidino, 4-aminoethylpiperidino, 2- methylaminoethylpiperidino, 3-methylaminoethylpiperidino, 4- methylaminoethylpiperidino, 2-dimethylaminoethylpiperidino,

® 3-dimethylaminoethylpiperidino, 4- dimethylaminoethylpiperidino, piperazino, 2-oxopiperazino, 3- oxopiperazino, 2-oxo-4-methylpiperazino, 3-0x0-4- nethylpiperazino, 4-formylpiperazino, 2,3-dioxopiperazino, 3, 5~dioxopiperazino, 2, 6-dioxopiperazino, 2,3-dioxo-4- methylpiperazino, 3,5-dioxo-4-methylpiperazino, 2,6-dioxo-4- methylpiperazino, 2-methylpiperazino, 3-methylpiperazino, 4- methylpiperazino, 2-ethylpiperazino, 3-ethylpiperazino, 4- ethylpiperazino, 2-isopropylpiperazino, 3-isopropylpiperazino, 4-isopropylpiperazino, 2-cyclopropylpiperazino, 3- cyclopropylpiperazino, 4-cyclopropylpiperazino, 4- cyclobutylpiperazino, 2-cyclopropanespiropiperazino, 3- cyclopropanespiropiperazino, 2,2-dimethylpiperazino, 3,3- dimethylpiperazino, 2,3-dimethylpiperazino, 2,4- dimethylpiperazino, 3,4-dimethylpiperazino, 3,5- dimethylpiperazino, 2,6-dimethylpiperazino, 2-ethyl-4- methylpiperazino, 3-ethyl-4-methylpiperazino, 2-isopropyl-4- methylpiperazino, 3-isopropyl-4-methylpiperazino, 2- cyclopropyl-4-methylpiperazino, 3-cyclopropyl-4- methylpiperazino, 3-methyl-4-benzylpiperazino, 4- phenylpiperazino, 4- (2-pyridyl)piperazino, 1,2,6- trimethylpiperazino, 3,4, 5-trimethylpiperazino, 2,2,4- trimethylpiperazino, 3,3,4-trimethylpiperazino, 3,3,4- trimethyl-5-oxopiperazino, 2,2,4-trimethyl-3-oxopiperazino, 2-cyclopropanespiro-4-methylpiperazino, 3-cyclopropanespiro- 4-methylpiperazino, 2-cyclopropanespiro-4-methyl-3- oxopiperazino, 3-cyclopropanespiro-4-methyl-5-oxopiperazino,

Claims

1. A compound represented by formula (I), a salt of the compound, or a solvate of the compound or the salt: R2 AT Aa —R1 (1) N— Are” N (wherein Ar; represents a pyridyl group having 1 to 3 substituents, a pyridazinyl group having 1 to 3 substituents, or a pyrazinyl group having 1 to 3 substituents; Ar; represents a pyridyl group which may have 1 to 3 substituents, a pyridazinyl group which may have 1 to 3 substituents, a pyrazinyl group which may have 1 to 3 substituents, a pyrrolyl group which may have 1 to 3 substituents or a phenyl group which may have 1 to 3 substituents; Rl is a group represented by formula (1): : R3 (wherein ring structure A represents azetidine ring, pyrrolidine ring, imidazolidine ring, pyrazoline ring, piperidine ring, piperazine ring, morpholine ring, thiomorpholine ring, hexahydropyridazine ring, 407 Amended sheet: 20 September 2006 hexahydropyrimidine ring, homopiperazine ring, or azepane ring; X represents a carbonyl group; R3 represents 1 to 4 groups on ring structure A, R3 being selected from the group consisting of a hydrogen atom, a halogeno group, a hydroxyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxyl group, a sulfo group, a lower alkylsulfonyl group, a lower alkyl group which may have 1 or 2 substituents, an amino group which may have 1 or 2 substituents, a carbamoyl group which may have 1 or 2 substituents, a lower acyl group, an aminosulfonyl group which may have 1 or 2 substituents, an oxo group, a hydroxyiminocarbonyl group, a lower alkoxyiminocarbonyl group, and a substituted or non- substituted 3- to 6-membered spiro alicyclic alkyl group); R2 represents a hydrogen atom, a halogeno group, or a lower alkyl group which may have 1 or 2 substituents.

2. The compound as described in claim 1, a salt of the compound, or a solvate of the compound or the salt, wherein Ar; is a pyridyl group having 1 to 3 substituents or a pyridazinyl group having 1 to 3 substituents.

3. The compound as described in any one of claims 1 to 2, a salt of the compound, or a solvate of the compound or the salt, wherein Ar; is a pyridyl group which may have 1 to 3 substituents, a pyrrolyl group which may have 1 to 3 substituents, or a phenyl group which may have 1 to 3 substituents.

4. The compound as described in any one of claims 1 to 3, a salt of the compound, or a solvate of the compound or 408 Amended sheet: 20 September 2006 the salt, wherein the moiety represented by the following formula: R3 —N A \ is a group selected from among, a 3-dimethylaminoazetidin-1- yl group, a 2,2-dimethyl-3-dimethylaminoazetidin-1-yl group, a 2-hydroxymethylazetidin-1-yl group, a 2-carbamoylazetidin- 1-yl group, a 2-oxopyrrolidino group, a 2- hydroxymethylpyrrolidino group, a 2-carbamoylpyrrolidino group, a 2-hydroxymethylpiperidino group, a 2- carbamoylpiperidino group, a 2-methylcarbamoylpiperidino group, a 2-dimethylcarbamoylpiperidino group, a 3-oxo-4- methylpiperazino group, a 4-methylpiperazino group, a 4- ethylpiperazino group, a 4-isopropylpiperazino group, a 4- cyclopropylpiperazino group, a 2,4-dimethylpiperazino group, a 3,4-dimethylpiperazino group, a 3-cyclopropyl-4- methylpiperazino group, a 3,4,5-trimethylpiperazino group, a 2,2,4-trimethylpiperazino group, a 3,3,4-trimethylpiperazino group, a 2-cyclopropanespiro-4-methylpiperazino group, a morpholino group, a 3-carbamoylmorpholino group, a 1,1- dioxothiomorpholino group, a 2-methylhexahydropyridazin-1-yl group, a 3-methylhexahydropyridazin-1-yl group, a 3-oxo-4- methylhomopiperazino group, a 5-oxo-4-methylhomopiperazino group, a 4-methylhomopiperazino group, a 4- ethylhomopiperazino group, a 4-cyclopropylhomopiperazino 409 Amended sheet: 20 September 2006 group, a piperidino group, a 4-methoxypiperidino group, a thiomorpholino group, a 4,4-difluoropiperidino group, a 3,3- difluoropiperidino group, a 4-fluoropiperidino group, a 2- dimethylaminomethylpyrrolidino group, a 3- dimethylaminopyrrolidino group, a 3-methyl-4-oxoimidazolidin- 1-yl group, a 3-methoxypyrrolidino group, a 2- acetylhexahydropyridazin-1-yl group, and a 2- carbamoylhexahydropyridazin-1-yl group.

5. A compound, a salt of the compound, or a solvate of the compound or the salt, the compound being selected from the group consisting of the following compounds (1) to (16): : oo OM (1) = © e . . 0 ’ z= x Re ~~ | < SN /\ N - N— = New, N \——/ 4 N N pz | : MeQ™. N pr } Ke0 N (3) a y a . (4) “ x : 0 ; or Lr peo” SNE Meo” SN N ®) ® : oo : _ ¢ , = /\ y n> Ne % N N— xi \ ARCA oo NeQ N Ke HN 410 Amended sheet: 20 September 2006

Mm FZ ® Lo Sn on 0 ’ Sy — 0 — y/ N ) RY N N— or oo LF vo neo” w=" we” A oo © = 10) 7 ) Po SN YX SN 8 ol y/ N : - 4 N SN : No Co Lh _ Li ted” SN” Co © Hed” NF SE SAD x a2 a x, | 0 oo x 0 N — /\ N = WARY or or ~ 20” SN Med” N (13) = (1 ~~

DN . N= 7 SN Ney? Noo Ne? ON LZ i» 0 MeO” TN Neo” “N° =~ as Sw 38) om i? NM ph 0 EN ——/ ~~ M N ( 07 MeO HN Hed N

6. A medicament containing a compound as described in any one of claims 1 to 5, a salt of the compound, or a solvate of the compound or the salt. 411 Amended sheet: 20 September 2006

7. A preventive and/or therapeutic agent for an ischemic disease, wherein the agent contains a compound as described in any one of claims 1 to 5, a salt of the compound, or a solvate of the compound or the salt.

8. A pharmaceutical composition containing a compound as described in any one of claims 1 to 5, a salt of the compound, or a solvate of the compound or the salt, and a pharmacologically acceptable carrier therefor.

9. Use, in the manufacture of a medicament, of a compound as described in any one of claims 1 to 5, a salt of the compound, or a solvate of the compound or the salt.

10. Use as described in claim 9, wherein the medicament is used for treating an ischemic disease. 412 Amended sheet: 20 September 2006