# US 8,569,504 B2 · Imidazopyridine compound

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- Number: US 8,569,504 B2
- Document ID: US8569504B2
- Status: Granted
- Kind: B2
- Application number: 13/378,550
- Filed: 2010-06-16
- Published: 2012-04-19
- Granted: 2013-10-29
- Earliest claimed: 2009-06-17
- Assignees: Ono Pharmaceutical Co., Ltd.
- Applicants: Jun Takeuchi; Takayuki Inukai; Masaru Sakai
- Inventors: Jun Takeuchi; Takayuki Inukai; Masaru Sakai
- Web page: https://patentgrep.com/patent/US8569504B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 7/10: Antioedematous agents; Diuretics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/06: Antiarrhythmics
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 17/00: Drugs for dermatological disorders
- A61P 27/14: Decongestants or antiallergics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

For the prevention and/or treatment of chymase-mediated diseases such as skin diseases, circulatory diseases, digestive system diseases, respiratory diseases, liver diseases, ocular diseases or the like, a drug is provided having as an active ingredient a compound having extremely strong chymase inhibitory activity, high safety, and high metabolic stability. The compound represented by the formula (I): wherein all symbols have the same meanings as in the description, a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrug thereof, is useful as a pharmaceutical ingredient having chymase inhibitory activity for preventing and/or treating of chymase-mediated disease, such as skin diseases, circulatory diseases, digestive system diseases, respiratory diseases, liver diseases, ocular diseases or the like.

## Claims

### Claim 1

A compound represented by the formula (I)
wherein
represents a benzene ring or a naphthalene ring or a 6- to 10-membered monocyclic or bicyclic aromatic heterocycle;
R1 represents a hydrogen atom, methyl group, trifluoromethyl group, difluoromethyl group, fluorine atom or chlorine atom;
R2 represents a hydrogen atom, C1-10 alkyl group optionally substituted with 1 to 6 of R11, C2-10 alkenyl optionally substituted with 1 to 6 of R11, or C2-10 alkynyl optionally substituted with 1 to 6 of R11;
R11 represents
(i) a halogen atom,
(ii) OR8,
where R8 is (1) a hydrogen atom, (2) C1-3 alkyl group, (3) C1-3 haloalkyl group, (4) a C5-6 carbocycle, (5) a 5- to 6-membered heterocycle containing 1 to 2 nitrogen atoms, 1 oxygen atom and/or 1 optionally oxidized sulfur atom, or (6) C1-3 alkyl group substituted with a hydroxyl group, C1-3 alkoxy group or NR9R10, where R9 and R10 each independently represent a hydrogen atom, C1-3 alkyl group or phenyl group,
(iii) NR9R10, where R9 and R10 each independently represent a hydrogen atom, C1-3 alkyl group or phenyl group,
(iv) a C5-6 carbocycle optionally substituted with at least one selected from a halogen atom, oxo group and methyl group, or
(v) a 3- to 10-membered heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and/or 1 to 2 optionally oxidized sulfur atoms, optionally substituted with at least one group selected from a halogen atom, an oxo group and a methyl group;
R3 represents a hydrogen atom, methyl group, or fluorine atom;
R4 represents a hydrogen atom, C1-2 alkyl group, C1-2 haloalkyl group, or halogen atom;
R5 represents a hydrogen atom, C1-3 alkyl group, C1-3 haloalkyl group, or halogen atom;
R6 represents a hydrogen atom, C1-3 alkyl group, C1-3 haloalkyl group or halogen atom;
R7 represents a hydrogen atom, C1-4 alkyl group, allyl group, trichloroethyl group, benzyl group, phenacyl group, p-methoxybenzyl group, trityl group, or 2-chlorotrityl group;
p is an integer of 1 to 3;
q is an integer of 1 to 4; and
r is an integer of 1 to 6;
and wherein:
when p represents 2 or more, each R4 may independently be the same or different,
when q represents 2 or more, each R5 may independently be the same or different, and
when r represents 2 or more, each R6 may independently be the same or different, or a salt thereof, an N-oxide thereof, or a prodrug thereof.

### Claim 2 (depends on 1)

The compound described in claim 1, represented by the formula (I-a)
wherein R4-a represents a hydrogen atom, methyl group, fluorine atom or chlorine atom, R5-a represents a hydrogen atom, methyl group or fluorine atom, and
represents a benzene ring or a naphthalene ring or a 6- to 10-membered monocyclic or bicyclic aromatic heterocycle;
R2 represents a hydrogen atom, C1-10 alkyl group optionally substituted with 1 to 6 of R11, C2-10 alkenyl optionally substituted with 1 to 6 of R11, or C2-10 alkynyl optionally substituted with 1 to 6 of R11;
R11 represents
(i) a halogen atom,
(ii) OR8,
where R8 is (1) a hydrogen atom, (2) C1-3 alkyl group, (3) C1-3 haloalkyl group, (4) a C5-6 carbocycle, (5) a 5- to 6-membered heterocycle containing 1 to 2 nitrogen atoms, 1 oxygen atom and/or 1 optionally oxidized sulfur atom, or (6) C1-3 alkyl group substituted with a hydroxyl group, C1-3 alkoxy group or NR9R10, where R9 and R10 each independently represent a hydrogen atom, C1-3 alkyl group or phenyl group,
(iii) NR9R10, where R9 and R10 each independently represent a hydrogen atom, C1-3 alkyl group or phenyl group,
(iv) a C5-6 carbocycle optionally substituted with at least one selected from a halogen atom, oxo group and methyl group, or
(v) a 3- to 10-membered heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and/or 1 to 2 optionally oxidized sulfur atoms, optionally substituted with at least one group selected from a halogen atom, an oxo group and a methyl group;
R3 represents a hydrogen atom, methyl group, or fluorine atom;
R6 represents a hydrogen atom, C1-3 alkyl group, C1-3 haloalkyl group or halogen atom;
R7 represents a hydrogen atom, C1-4 alkyl group, allyl group, trichloroethyl group, benzyl group, phenacyl group, p-methoxybenzyl group, trityl group, or 2-chlorotrityl group;
q is an integer of 1 to 4; and
r is an integer of 1 to 6;
and wherein:
when q represents 2 or more, each R5-a may independently be the same or different, and
when r represents 2 or more, each R6 may independently be the same or different, or a salt thereof, an N-oxide thereof, or a prodrug thereof.

### Claim 3 (depends on 2)

The compound described in claim 2, represented by the formula (I-b) or (I-c)
wherein all symbols have the same meaning as in claim 2,
or a salt thereof, an N-oxide thereof, or a prodrug thereof.

### Claim 4 (depends on 3)

The compound described in claim 3, wherein R2 represents a hydrogen atom, C1-10 alkyl group optionally substituted with 1 to 6 of R12, C2-10 alkenyl optionally substituted with 1 to 6 of R12 or C2-10 alkynyl optionally substituted with 1 to 6 of R12; and R12 represents a halogen atom, hydroxyl group, dimethylamino group, pyrrolidinyl group, N-methylpyrrolidinyl group, piperidinyl group, phenoxy group, phenyl group optionally substituted with halogen atoms, tetrahydropyranyl group, 2,3-dihydrobenzofuranyl group, thiophenyl group, diisopropylamino group, methyl(phenyl)amino group, piperadinyl group, 2-oxo-1-pyrrolidinyl group, morpholinyl group, 1,1-dioxothiomorpholinyl group, imidazolyl group, pyridyl group, 2-methoxyethylenoxy group, dimethylaminoethylenoxy group, diethylaminoethylenoxy group, 1,2,3,4-tetrahydroisoquinolinyl group, azepanyl group, pyrazolyl group, 2-oxoimidazolidinyl group, diethylamino group, methoxy group or N-methylpyrazolyl group.

### Claim 5 (depends on 3)

The compound described in claim 3, wherein R2 represents C1-6 alkyl group substituted with 1 to 6 of R12, C2-6 alkenyl group optionally substituted with 1 to 6 of R12, or C2-6 alkynyl group optionally substituted with 1 to 6 of R12, and R12 represents a halogen atom, hydroxyl group, dimethylamino group, pyrrolidinyl group, N-methylpyrrolidinyl group, piperidinyl group, phenoxy group, phenyl group optionally substituted with halogen atoms, tetrahydropyranyl group, 2,3-dihydrobenzofuranyl group, thiophenyl group, diisopropylamino group, methyl(phenyl)amino group, piperadinyl group, 2-oxo-1-pyrrolidinyl group, morpholinyl group, 1,1-dioxothiomorpholinyl group, imidazolyl group, pyridyl group, 2-methoxyethylenoxy group, dimethylaminoethylenoxy group, diethylaminoethylenoxy group, 1,2,3,4-tetrahydroisoquinolinyl group, azepanyl group, pyrazolyl group, 2-oxoimidazolidinyl group, diethylamino group, methoxy group or N-methylpyrazolyl group.

### Claim 6 (depends on 4)

The compound described in claim 4, wherein R7 is a hydrogen atom.

### Claim 7 (depends on 6)

The compound described in claim 6, wherein the compound represented by the formula (I) is selected from the group consisting of
(1) 2-{3-[(4-methyl-1H-indol-3-yl)methyl]imidazo[1,2-a]pyridin-2-yl}-1-naphthoic acid,
(2) 2-{3-[(1,4-dimethyl-1H-indol-3-yl)methyl]-6-methylimidazo[1,2-a]pyridin-2-yl}benzoic acid,
(3) 2-{3-[(1,4-dimethyl-1H-indol-3-yl)methyl]imidazo[1,2-a]pyridin-2-yl}benzoic acid,
(4) 2-{3-[(1-ethyl-4-methyl-1H-indol-3-yl)methyl]imidazo[1,2-a]pyridin-2-yl}benzoic acid,
(5) 2-{6-fluoro-3-[(4-methyl-1H-indol-3-yl)methyl]imidazo[1,2-a]pyridin-2-yl}-1-naphthoic acid,
(6) 2-{3-[(5-fluoro-4-methyl-1H-indol-3-yl)methyl]imidazo[1,2-a]pyridin-2-yl}benzoic acid,
(7) 2-[3-({4-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(8) 2-(3-{[4-methyl-1-(2-propanyl)-1H-indol-3-yl]methyl}imidazo[1,2-a]pyridin-2-yl)-1-naphthoic acid,
(9) 2-{3-[(4-methyl-1-propyl-1H-indol-3-yl)methyl]imidazo[1,2-a]pyridin-2-yl}-1-naphthoic acid,
(10) 2-{3-[(1-ethyl-4-methyl-1H-indol-3-yl)methyl]imidazo[1,2-a]pyridin-2-yl}-1-naphthoic acid,
(11) 2-{3-[(5-fluoro-4-methyl-1H-indol-3-yl)methyl]imidazo[1,2-a]pyridin-2-yl}-1-naphthoic acid,
(12) 2-(3-{[1-(2-hydroxyethyl)-4-methyl-1H-indol-3-yl]methyl}imidazo[1,2-a]pyridin-2-yl)-1-naphthoic acid,
(13) 2-[3-({1-[3-(dimethylamino)-2-hydroxypropyl]-4-methyl-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(14) 2-(3-{[1-(2,3-dihydroxypropyl)-4-methyl-1H-indol-3-yl]methyl}imidazo[1,2-a]pyridin-2-yl)-1-naphthoic acid,
(15) 2-[3-({1-[2-(dimethylamino)ethyl]-4-methyl-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(16) 2-[3-({1-[3-(dimethylamino)propyl]-4-methyl-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(17) 2-[3-({4-methyl-1-[2-(pyrrolidin-1-yl)ethyl]-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(18) 2-[3-({4-methyl-1-[2-(1-methylpyrrolidin-2-yl)ethyl]-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(19) 2-[3-({4-methyl-1-[2-(piperidin-1-yl)ethyl]-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(20) 2-(3-{[4-methyl-1-(2-phenoxyethyl)-1H-indol-3-yl]methyl}imidazo[1,2-a]pyridin-2-yl)-1-naphthoic acid,
(21) 2-[3-({1-[(3R)-3-hydroxy-3-phenylpropyl]-4-methyl-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(22) 2-[3-({1-[(3S)-3-hydroxy-3-phenylpropyl]-4-methyl-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(23) 2-[3-({1-[2-(4-fluorophenyl)ethyl]-4-methyl-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(24) 2-[3-({4-methyl-1-[2-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(25) 2-[3-({1-[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]-4-methyl-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(26) 2-(3-{[4-methyl-1-(3-phenylpropyl)-1H-indol-3-yl]methyl}imidazo[1,2-a]pyridin-2-yl)-1-naphthoic acid,
(27) 2-(3-{[4-methyl-1-(piperidin-4-ylmethyl)-1H-indol-3-yl]methyl}imidazo[1,2-a]pyridin-2-yl)-1-naphthoic acid,
(28) 2-(3-{[1-(3-hydroxypropyl)-4-methyl-1H-indol-3-yl]methyl}imidazo[1,2-a]pyridin-2-yl)-1-naphthoic acid,
(29) 2-[3-({1-[2-(dipropan-2-ylamino)ethyl]-4-methyl-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(30) 2-[3-({4-methyl-1-[2-(piperazin-1-yl)ethyl]-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(31) 2-[3-({4-methyl-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(32) 2-[3-({1-[2-(1,1-dioxidethiomorpholin-4-yl)ethyl]-4-methyl-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(33) 2-[3-({1-[2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl]-4-methyl-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(34) 2-{3-[(1-{2-[2-(diethylamino)ethoxy]ethyl}-4-methyl-1H-indol-3-yl)methyl]imidazo[1,2-a]pyridin-2-yl}-1-naphthoic acid,
(35) 2-[3-({4-methyl-1-[2-(1-methyl-1H-pyrazol-4-yl)ethyl]-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(36) 2-{3-[(1-{2-[2-(dimethylamino)ethoxy]ethyl}-4-methyl-1H-indol-3-yl)methyl]imidazo[1,2-a]pyridin-2-yl}-1-naphthoic acid,
(37) 2-(3-{[4-methyl-1-(4-methylpent-3-en-1-yl)-1H-indol-3-yl]methyl}imidazo[1,2-a]pyridin-2-yl)-1-naphthoic acid,
(38) 2-[3-({1-[2-(3-fluorophenyl)ethyl]-4-methyl-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(39) 2-[3-({4-methyl-1-[2-(1H-pyrazol-1-yl)ethyl]-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(40) 2-[3-({1-[2-(azepan-1-yl)ethyl]-4-methyl-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(41) 2-{3-[(4-methyl-1-{2-[methyl(phenyl)amino]ethyl}-1H-indol-3-yl)methyl]imidazo[1,2-a]pyridin-2-yl}-1-naphthoic acid,
(42) 2-[3-({1-[2-(1H-imidazol-1-yl)ethyl]-4-methyl-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(43) 2-[3-({4-methyl-1-[2-(pyridin-4-yl)ethyl]-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(44) 2-[3-({1-[2-(2-methoxyethoxy)ethyl]-4-methyl-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(45) 2-[3-({4-methyl-1-[2-(thiophen-3-yl)ethyl]-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(46) 2-[3-({4-methyl-1-[2-(thiophen-2-yl)ethyl]-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(47) 2-(3-{[4-methyl-1-(3-methylbut-3-en-1-yl)-1H-indol-3-yl]methyl}imidazo[1,2-a]pyridin-2-yl)-1-naphthoic acid,
(48) 2-[3-({4-methyl-1-[2-(2-oxoimidazolidin-1-yl)ethyl]-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(49) 2-(3-{[1-(but-3-en-1-yl)-4-methyl-1H-indol-3-yl]methyl}imidazo[1,2-a]pyridin-2-yl)-1-naphthoic acid,
(50) 2-[3-({4-methyl-1-[(3Z)-pent-3-en-1-yl]-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(51) 2-[3-({4-methyl-1-[3-(pyridin-2-yl)propyl]-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(52) 2-(3-{[1-(3,4-dihydroxybutyl)-4-methyl-1H-indol-3-yl]methyl}imidazo[1,2-a]pyridin-2-yl)-1-naphthoic acid,
(53) 2-[3-({1-[2-(diethylamino)ethyl]-4-methyl-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(54) 2-(3-{[1-(4-fluorobutyl)-4-methyl-1H-indol-3-yl]methyl}imidazo[1,2-a]pyridin-2-yl)-1-naphthoic acid,
(55) 2-(3-{[4-methyl-1-(4,4,4-trifluorobutyl)-1H-indol-3-yl]methyl}imidazo[1,2-a]pyridin-2-yl)-1-naphthoic acid,
(56) 2-(3-{[1-(4-hydroxybutyl)-4-methyl-1H-indol-3-yl]methyl}imidazo[1,2-a]pyridin-2-yl)-1-naphthoic acid,
(57) 2-(3-{[1-(3-fluoropropyl)-4-methyl-1H-indol-3-yl]methyl}imidazo[1,2-a]pyridin-2-yl)-1-naphthoic acid,
(58) 2-(3-{[4-methyl-1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-indol-3-yl]methyl}imidazo[1,2-a]pyridin-2-yl)-1-naphthoic acid,
(59) 2-[3-({4-methyl-1-[3-(pyridin-3-yl)propyl]-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(60) 2-[3-({4-methyl-1-[3-(pyridin-4-yl)propyl]-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(61) 2-[3-({1-[3-(1H-imidazol-1-yl)propyl]-4-methyl-1H-indol-3-yl}methyl)imidazo[1,2-a]pyridin-2-yl]-1-naphthoic acid,
(62) 2-(3-{[1-(2-hydroxypropyl)-4-methyl-1H-indol-3-yl]methyl}imidazo[1,2-a]pyridin-2-yl)-1-naphthoic acid,
(63) 2-(3-{[1-(2-hydroxy-3-methoxypropyl)-4-methyl-1H-indol-3-yl]methyl}imidazo[1,2-a]pyridin-2-yl)-1-naphthoic acid,
(64) 2-(3-{[1-(2-hydroxy-2-methylpropyl)-4-methyl-1H-indol-3-yl]methyl}imidazo[1,2-a]pyridin-2-yl)-1-naphthoic acid, and
(65) 2-(3-{[1-(2-hydroxy-3-phenoxypropyl)-4-methyl-1H-indol-3-yl]methyl}imidazo[1,2-a]pyridin-2-yl)-1-naphthoic acid.

### Claim 8 (depends on 1)

A pharmaceutical composition containing the compound represented by the formula (I) described in claim 1, a salt thereof, an N-oxide thereof, or a prodrug thereof as an active ingredient.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising the compound represented by the formula (I) described in claim 1, a salt thereof, an N-oxide thereof, or a prodrug thereof in combination with at least one kind selected from non-steroidal anti-inflammatory drugs, steroid drugs, immune suppressors, prostaglandins, anti-allergic drugs, mediator release inhibitors, leukotriene receptor antagonists, antihistamines, opioid agonists, phosphodiesterase inhibitors, forskolin preparations, nitric oxide synthase inhibitors, cannabinoid-2 receptor stimulants, decoy preparations, aminosalicylic acid preparations, diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, anti-arrhythmic drugs, digitalis preparations, chymase inhibitors, renin inhibitors, calcium antagonists, beta blockers, nitrate drugs, anti-aldosterone drugs, cardiac stimulants, antiplatelet drugs, anticoagulants, antifibrotic drugs, antihyperglycemic drugs, antihypertensive drugs, lipid improvers, anti-obesity drugs, liver supporting drugs and antioxidants.

### Claim 10 (depends on 1)

A method for the treatment of a chymase-mediated disease, comprising administering to a patient an effective amount of the compound represented by the formula (I) described in claim 1, a salt thereof, an N-oxide thereof, or a prodrug thereof, wherein the chymase-mediated disease is at least one member selected from the group consisting of atopic dermatitis, ulcerative colitis, heart failure, pulmonary fibrosis, aneurysm, non-alcoholic steatohepatitis, peptic ulcer, and allergic conjunctivitis.