SULFONYLUREA DERIVATIVE CAPABLE OF SELECTIVELY INHIBITING MMP-13

TECHNICAL FIELD

The present invention relates to sulfonylurea derivatives which selectively inhibit MMP-13.

BACKGROUND TECHNIQUE

An extracellular matrix is composed of collagen, fibronectin, laminine, proteoglycan and the like, and has a role of tissue supporting function, proliferation, differentiation and adhesion of cells, and the like. Degradation of an extracellular matrix is associated with metalloprotease which is a protease containing a metal ion in an active center, particularly, matrix metalloprotease (MMP). As for the MMP family, many members, from MMP-1 (I type collagenase) to MMP-28, were reported and they act on growth, tissue metabolism and the like under the original physiological conditions. However, it was reported that the progress were correlated with the increase in expression (activity) of the above enzymes in various pathological states which were accompanied by the destruction of tissues and fibrosis such as osteoarthritis, articular rheumatism, corneal ulcer, periodontic disease, metastasis or infiltration of tumor, and virus infectious disease (HIV infectious disease).

The sulfonamide derivatives having MMP inhibiting activities were described in Patent Literature 1, Patent Literature 2, Patent Literature 3 and Non-Patent Literature 1.

The sulfonamide derivatives having MMP-12 inhibiting activity, and having a naphthyl group as a substituent were described in Patent Literature 4.

The thiazoles or oxazolesulfonamide derivatives having a naphthyl group as a substituent were described in Patent Literature 5.

The thiazoles or oxazolesulfonamide derivatives having a naphthyl group as a substituent were described in Patent Literature 6.

The sulfonamide derivatives having aglycanase inhibiting activity, and having a naphtyl group as a substituent were described in Patent Literature 7.

The sulfonamide derivatives having aggrecanase inhibiting activity and MMP-13 inhibiting activity were described in Patent Literature 8.

The sulfonamide derivatives having aggrecanase inhibiting activity and MMP inhibiting activities were described in Patent Literature 9.

The sulfonamide derivatives having TNF-α inhibiting activity and the MMP inhibiting activities were described in Patent Literature 10.

[Patent Literature 1] International Publication WO 97/27174

[Patent Literature 2] International Publication WO 99/04780

[Patent Literature 3] International Publication WO 00/15213

[Patent Literature 4] International Publication WO 01/83431

[Patent Literature 5 International Publication WO 02/28844

[Patent Literature 6] International Publication WO 01/83461

[Patent Literature 7] International Publication WO 03/080042

[Patent Literature 8] Japanese Patent Application Laid-Open (JP-A) No. 2000-319250

[Patent Literature 9] International Publication WO 05/061459

[Patent Literature 10] International Publication WO 98/32748

[Patent Literature 11] International Publication WO 2007/102392

[Non-Patent Literature 1] Yoshinori Tamura et al., J. Med. Chem., 1998, vol. 41, No. 4, p. 640-649

DISCLOSURE OF THE INVENTION
Problems to be Solved by the Invention

It seems that the inhibition of the activity of MMP-13 will contribute to improvement or prevention of progression of pathological states, particularly, osteoarthritis (OA), resulting from or associated with the MMP-13 activity. Therefore, the development of MMP-13 inhibitors is anticipated.

Means to Solve the Problems

In view of the aforementioned respects, the present inventors intensively continued to study. The inventors found that some novel sulfonamide derivatives exhibit the MMP-13 selective inhibiting activity and completed the invention as follows.

The present invention relates to; 1′) a compound represented by the general formula (I):

wherein R¹is

a) a group represented by the formula:

wherein R²⁶and R²⁸are each independently a halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkyloxy, lower alkylthio, aralkylthio, optionally substituted amino, carboxy, hydroxy, cyano, lower alkyloxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminoxaryl, acyl, lower alkylsulfonyl, lower alkylsulfinyl, aralkylsulfonyl, aralkylsulfinyl, optionally substituted aminosulfonyl, optionally substituted heteroaryl or an optionally substituted non aromatic heterocyclic group;

n¹is an integer of 0 to 3; and
R²⁸may be substituted on all substitutable atoms on the ring;
b) a group represented by the formula:

wherein E ring is benzene, pyridine, 2-pyridone, thiazole, tetrahydrothienopyrimidine or oxazole;

R²⁹is a halogen, acyl, optionally substituted lower alkyl, optionally substituted lower alkyloxy, optionally substituted lower alkenyl, optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted non-aromatic heterocyclic group, optionally substituted aminocarbonyl, optionally substituted amino or optionally substituted hydrazino;
R³⁰is each independently halogen, hydroxy, nitro, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkyloxy, optionally substituted aryloxy, optionally substituted aralkyl, optionally substituted heteroarylalkyl, lower alkylthio, aralkylthio, optionally substituted amino, carboxy, cyano, lower alkyloxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminoxaryl, acyl, lower alkylsulfonyl, lower alkylsulfinyl, aralkylsulfonyl, aralkylsulfinyl, optionally substituted aminosulfonyl, optionally substituted aryl, optionally substituted heteroaryl or an optionally substituted non-aromatic heterocyclic group;
n²is an integer of 0 to 2; and
R²⁹and R³⁰may be substituted on all substitutable atoms on the ring; or
c) a group represented by the formula:

wherein D ring is a non-aromatic carbocyclic ring, a non-aromatic heterocyclic ring or an aromatic heterocyclic ring;

R³¹is each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkyloxy, lower alkylthio, aralkylthio, optionally substituted amino, carboxy, cyano, lower alkyloxycarbonyl, lower alkyloxy lower alkylcarbonyl, optionally substituted aminocarbonyl, optionally substituted aminoxaryl, acyl, lower alkylsulfonyl, lower alkylsulfinyl, aralkylsulfonyl, aralkylsulfinyl, optionally substituted aminosulfonyl, oxo, thioxo, imino, hydroxy, hydroxyimino, optionally substituted lower alkyloxyimino, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted aralkyloxy, optionally substituted aryl or an optionally substituted non-aromatic heterocyclic group;
all substitutable atoms of the benzene ring and all substitutable atoms of D ring may be bonded to “Z”;
n³is an integer of 0 to 4;
R³¹may be substituted on all substitutable atoms of the benzene ring and all substitutable atoms of D ring;
provided that when n³is an integer of 0, D ring is not unsubstituted indole;
Z is —O—, —S—, —SO—, —SO₂—, —N(R¹⁰)—, —N(R¹⁰)—C(═O)—, —C(═O)—N(R¹⁰)—, —N(R¹⁰)—SO₂—, —SO₂—N(R¹⁰)—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —N(R¹⁰)—C(═O)—N(R¹⁰)—, —N(R¹⁰)—C(═S)—N(R¹⁰)—, —O—N═C(R⁸)—, —C(R⁸)═N—O—, —O—C(═O)—N(R¹⁰)—, N(R¹⁰)—C(═O)—O—, —C(═O)—C(═O)—, an optionally substituted non-aromatic carbocyclic group, an optionally substituted non-aromatic heterocyclic group, optionally substituted C1-C5 alkylene which may be intervened with a substituent selected from Substituent_group a, or C2-C5 optionally substituted alkenylene which may be intervened with a substituent selected from Substituent group a, or optionally substituted C2-C5 alkynylene which may be intervened with a substituent selected from Substituent group a, wherein the Substituent group a consists of —O—, —S—, —SO—, —SO₂—, —N(R¹⁰)—, —N(R¹⁰)—C(═O)—, —C(═O)—N(R¹⁰)—, —N(R¹⁰)—SO₂—, —SO₂—N(R¹⁰)—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —N(R¹⁰)—C(═O)—N(R¹⁰)—, —N(R¹⁰)—C(═S)—N(R¹⁰)—, —O—N═C(R⁸)—, —C(R⁸)═N—O—, —O—C(═O)—N(R¹⁰)—, —N(R¹⁰)—C(═O)—O—, and —C(═O)—C(═O)—;
R⁸and R¹⁰are each independently a hydrogen atom or lower alkyl;
A is a group represented by the formula;

wherein R⁶and R⁷are each independently halogen, lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, lower alkyloxy, lower alkenyloxy, lower alkylthio, halo lower alkyl, halo lower alkyloxy, halo lower alkylthio, hydroxy, hydroxy lower alkyl, mercapto, carboxy, lower alkyloxycarbonyl, lower alkylsulfonyl, acyl, acyloxy, nitro, cyano, optionally substituted amino or optionally substituted aminocarbonyl;

B ring is a nitrogen-containing heterocyclic ring which is optionally contained a further nitrogen atom, an oxygen atom, and/or a sulfur atom in the ring;
m and n are each independently an integer of 0 to 3;
R²is a hydrogen atom, optionally substituted lower alkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R³is a hydrogen atom, optionally substituted lower alkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R⁴is a hydrogen atom; or
R³and R⁴may be taken together with an adjacent carbon atom to form a 5- to 6-membered non-aromatic carbocyclic ring or a 5- to 6-membered non-aromatic heterocyclic ring;
R⁵is hydroxy, lower alkyloxy, or —NHOH;
an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.

More particularly, the present invention relates to the following 1) to 26).

1) a compound represented by the general formula (I):

wherein R¹is

a) a group represented by the formula:

wherein R²⁶and R²⁸are each independently a halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkyloxy, lower alkylthio, aralkylthio, optionally substituted amino, carboxy, cyano, lower alkyloxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminoxaryl, acyl, lower alkylsulfonyl, lower alkylsulfinyl, aralkylsulfonyl, aralkylsulfinyl, optionally substituted aminosulfonyl, optionally substituted heteroaryl or an optionally substituted non aromatic heterocyclic group;

n¹is an integer of 0 to 3; and
R²⁸may be substituted on all substitutable atoms on the ring;
b) a group represented by the formula:

wherein E ring is benzene, pyridine or oxazole;

R²⁹is an optionally substituted lower alkenyl, optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted non-aromatic heterocyclic group, optionally substituted aminocarbonyl or optionally substituted amino;
R³⁰is halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkyloxy, lower alkylthio, aralkylthio, optionally substituted amino, carboxy, cyano, lower alkyloxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminoxaryl, acyl, lower alkylsulfonyl, lower alkylsulfinyl, aralkylsulfonyl, aralkylsulfinyl, optionally substituted aminosulfonyl, optionally substituted heteroaryl or an optionally substituted non-aromatic heterocyclic group;
n²is an integer of 0 to 2; and
R²⁹and R³⁰may be substituted on all substitutable atoms on the ring; or
c) a group represented by the formula:

wherein D ring is a non-aromatic carbocyclic ring, a non-aromatic heterocyclic ring or an aromatic heterocyclic ring;

R³¹is halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkyloxy, lower alkylthio, aralkylthio, optionally substituted amino, carboxy, cyano, lower alkyloxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminoxaryl, acyl, lower alkylsulfonyl, lower alkylsulfinyl, aralkylsulfonyl, aralkylsulfinyl, optionally substituted aminosulfonyl, oxo, imino, hydroxyimino, optionally substituted lower alkyloxyimino, optionally substituted heteroaryl or an optionally substituted non-aromatic heterocyclic group;
n³is an integer of 0 to 2; and
all substitutable atoms of the benzene ring and all substitutable atoms of D ring may be bonded to “Z”;
R³¹may be substituted on all substitutable atoms of the benzene ring; provided that when n³is an integer of 0, D ring is not unsubstituted indole;
Z is —O—, —S—, —SO—, —SO₂—, —N(R¹⁰)—, —N(R¹⁰)—C(═O)—, —C(═O)—N(R¹⁰)—, —N(R¹⁰)—SO₂—, —SO₂—N(R¹⁰)—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —N(R¹⁰)—C(═O)—N(R¹⁰)—, —N(R¹⁰)—C(═S)—N(R¹⁰)—, —O—N═C(R⁸)—, —C(R⁸)═N—O—, —O—C(═O)—N(R¹⁰)—, —N(R¹⁰)—C(═O)—O—, —C(═O)—C(═O)—, an optionally substituted non-aromatic carbocyclic group, an optionally substituted non-aromatic heterocyclic group, optionally substituted C1-C5 alkylene which may be intervened a substituent selected from Substituent group a, or optionally substituted C2-C5 alkenylene which may be intervened with a substituent selected from Substituent group a, or optionally substituted C2-C5 alkynylene which may be intervened with a substituent selected from Substituent group a, wherein the Substituent group a consists of —O—, —S—, —SO—, —SO₂—, —N(R¹⁰)—, —N(R¹⁰)—C(═O)—, —C(═O)—N(R¹⁰)—, —N(R¹⁰)—SO₂—, —SO₂—N(R¹⁰)—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —N(R¹⁰)—C(═O)—N(R¹⁰)—, —N(R¹⁰)—C(═S)—N(R¹⁰)—, —O—N═C(R⁸)—, —C(R⁸)═N—O—, —O—C(═O)—N(R¹⁰—, —N(R¹⁰)—C(═O)—O—, and —C(═)—C(═O)—;
R⁸and R¹⁰are each independently a hydrogen atom or lower alkyl;
A is a group represented by the formula;

wherein R⁶and R⁷are each independently halogen, lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, lower alkyloxy, lower alkenyloxy, lower alkylthio, halo lower alkyl, halo lower alkyloxy, halo lower alkylthio,hydroxy, hydroxy lower alkyl, mercapto, carboxy, lower alkyloxycarbonyl, lower alkylsulfonyl, acyl, acyloxy, nitro, cyano, optionally substituted amino, or optionally substituted aminocarbonyl;

B ring is a nitrogen-containing heterocyclic ring which is optionally contained a further nitrogen atom, an oxygen atom, and/or a sulfur atom in the ring;
m and n are each independently an integer of 0 to 3;
R²is a hydrogen atom, optionally substituted lower alkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R³is a hydrogen atom, optionally substituted lower alkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R⁴is a hydrogen atom; or
R³and R⁴may be taken together with an adjacent carbon atom to form a 5- to 6-membered non-aromatic carbocyclic group or a 5- to 6-membered non-aromatic heterocyclic group;
R⁵is hydroxy, lower alkyloxy, or —NHOH;
an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.
2) The compound according to 1′) or 1), wherein R¹is a group represented by the formula:

wherein R²⁶, R²⁸, and n¹are as defined in above 1),

an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.
3) The compound according to any one of 1′), 1) or 2), wherein R¹is a group represented by the formula:

wherein R²⁶, R²⁸, and n¹are as defined in above 1);

an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.
4) The compound according to any one of above 1′), or 1) to 3), wherein R¹is a group represented by the formula:

wherein R²⁶, R²⁸, and n¹are as defined in above 1),

an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.
5) The compound according to any one of 1′) or 1) to 3), wherein R¹is a group represented by the formula:

wherein R²⁶, R²⁸, and n¹are as defined in above 1),

an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.
6) The compound according to 1′) or 1), wherein R¹is a group represented by the formula:

wherein E ring, R²⁹, R³⁰, and n²are as defined in above 1),

an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.
7) The compound according to 1′) or 1), wherein R¹is a group represented by the formula:

wherein D ring, R³¹and n²are as defined in above 1),

an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.
8) The compound according to any one of 1′) or 1) to 7), which is represented by the general formula (II):

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, Z, m, n and B ring are as defined in above 1),

an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.

9) The compound according to any one of 1′) or 1) to 7), which is represented by the general formula (III):

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, Z, m, n and B ring are as defined in above 1),

an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.
10) The compound according to any one of 1′) or 1) to 9), wherein Z is —C(R⁸)(R⁹)—, —O—, —S—, —SO—, —SO₂—, —N(R¹⁰)—, —C(R⁸)(R⁹)—C(R⁸)(R⁹)—, —C(R⁸)═C(R⁹)—, —C≡C—, —O—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—O—, —S—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—S—, —SO—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—SO—, —SO₂—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—SO₂—, —N(R¹⁰)—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—N(R¹⁰)—, —N(R¹⁰)—C(═O)—, —C(═O)—N(R¹⁰)—, —N(R¹⁰)—SO₂—, —SO₂—N(R¹⁰)—, —C(R⁸)(R⁹)—C(═O)—, —C(═O)—C(R⁸)(R⁹)—, —C(═O)C(═O)—, —C(R⁸)(R⁹)—C(R⁸)(R⁹)—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—C(R⁸)═C(R⁹)—, —C(R⁸)═C(R⁹)—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—C≡C—, —C≡C—C(R⁸)(R⁹)—, —O—C(R⁸)(R⁹)—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—O—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—C(R⁸)(R⁹)—O—, —S—C(R⁸)(R⁹)—C(R⁸)(R⁹)—, C(R⁸)(R⁹)—S—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—C(R⁸)(R⁹)—S—, —SO—C(R⁸)(R⁹)—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—SO—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—C(R⁸)(R⁹)—SO—, —SO₂—C(R⁸)(R⁹)—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—SO₂—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—C(R⁸)(R⁹)—SO₂—, —N(R¹⁰)—C(R⁸)(R⁹)—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—N(R¹⁰)—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—C(R⁸)(R⁹)—N(R¹⁰)—, —C(═O)—C(R⁸)(R⁹)—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—C(═O)—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—C(R⁸)(R⁹)—C(═O)—, —C(R⁸)(R⁹)—N(R¹⁰)—C(═O)—, —N(R¹⁰)—C(═O)—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—C(═O)—N(R¹⁰)—, —C(═O)—N(R¹⁰)—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—N(R¹⁰)—SO₂—, —N(R¹⁰)—SO₂—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—SO₂—N(R¹⁰)—, —SO₂—N(R¹⁰)—C(R⁸)(R⁹)—, —N(R¹⁰)—C(═O)—N(R¹⁰)—, —N(R¹⁰)—C(—S)—N(R¹⁰)—, —O—N═C(R⁸)—, —C(R⁸)═N—O—, —O—C(═O)—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—C(═O)—O—, —O—C(═O)—N(R¹⁰)—, or —N(R¹⁰)—C(═O)—O—, wherein R⁸, R⁹and R¹⁰are each independently a hydrogen atom or lower alkyl, an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.
11) The compound according to any one of 1′) or 1) to 10), wherein Z is —C(R⁸)(R⁹)—C(R⁸)(R⁹)—, —C(R⁸)═C(R⁹)—, —C≡C—, —O—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—O—, —S—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—S—, —SO—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—SO—, —SO₂—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—SO₂—, —N(R¹⁰)—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—N(R¹⁰)—, —N(R¹⁰)—C(═O)—, —C(═O)—N(R¹⁰)—, —N(R¹⁰)—SO₂—, —SO₂—N(R¹⁰)—, —C(R⁸)(R⁹)—C(═O)—, —C(═O)—C(R⁸)(R⁹)—, or —C(═O)C(═O)—, wherein R⁸, R⁹and R¹⁰are each independently a hydrogen atom or lower alkyl,
an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.
12) The compound according to any one of 1′) or 1) to 11), wherein Z is —CH₂—CH₂—, —CH═CH—, —C≡C—, —O—CH₂—, or —CH₂—O—,
an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.
13) The compound according to any one of 1′) or 1) to 12), wherein Z is —C≡C— or —CH═CH—,
an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.
14) The compound according to any one of 1′) or 1) to 13), wherein a group represented by the formula:

is a group represented by the formula:

wherein X is a carbon atom or a nitrogen atom, a C ring is a 5- to 8-membered nitrogen-containing heterocyclic ring, and R⁷and m are as defined in above 1),

an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.
15) The compound according to any one of 1′) or 1) to 14), wherein a group represented by the formula:

is a group represented by the formula:

wherein R⁷and m are as defined in above 1),

an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.
16) The compound according to any one of 1′) or 1) to 15), wherein R²is a hydrogen atom,
an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.
17) The compound according to any one of 1′) or 1) to 16), wherein R³is a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, tert-butyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxymethyl, carboxyethyl, methyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenyl, 4-hydroxyphenyl, 4-fluorophenyl, 4-methyloxyphenyl, benzyl, 4-hydroxybenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-methoxybenzyl, indol-3-ylmethyl, 1-carboxymethylindol-3-ylmethyl, thiazol-4-ylmethyl, carboxymethyloxybenzyl, or cyclopropylmethyl;
R⁴is a hydrogen atom; or
R³and R⁴may be taken together with an adjacent carbon to form a ring represented by the formula:

an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.

18) The compound according to any one of 1′) or 1) to 17), wherein R³is a hydrogen atom,methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, tert-butyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxymethyl, carboxyethyl, methyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenyl, 4-hydroxyphenyl, 4-fluorophenyl, 4-methyloxyphenyl, benzyl, 4-hydroxybenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-methoxybenzyl, indol-3-ylmethyl, 1-carboxymethylindol-3-ylmethyl, thiazol-4-ylmethyl, carboxymethyloxybenzyl, or cyclopropylmethyl, and

R⁴is a hydrogen atom, an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.

19) The compound according to any one of 1′) or 1) to 18), wherein R⁵is hydroxy,

an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.

20) A pharmaceutical composition containing the compound as defined in any one of 1) to 19) as an active ingredient.

21) A pharmaceutical composition for inhibiting MMP-13 which contains the compound as defined in any one of 1) to 19) as an active ingredient.

22) A pharmaceutical composition for treating or preventing osteoarthritis containing the compound as defined in any one of 1) to 19) as an active ingredient.

23) A method of treating a disease resulting from, or associated with MMP-13 of a mammal, comprising administering to a mammal including a human therapeutically effective amount of the compound as defined in any one of 1) to 19).

24) A method of treating osteoarthritis of a mammal, comprising administering to a mammal including a human therapeutically effective amount of the compound as defined in any one of 1) to 19).

25) Use of the compound as defined in any one of 1) to 19), for preparing a medicament for treating a disease resulting from associated with MMP-13.

26) Use of the compound as defined in any one of 1) to 19), for preparing a medicament for treating osteoarthritis.

In the present specification, the term “lower alkyl” which is used alone or in combination with other terms includes straight chained or branched monovalent hydrocarbon groups comprised of 1 to 8 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl and the like are exemplified. Preferable is C1-C6 alkyl. Further, C1-C3 alkyl is preferable.

In the present specification, the term “cycloalkyl” includes C3-C8 cycloalkyl. For example they are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Preferable is C3-C6 cycloalkyl.

In the present specification, the “lower alkenyl” which is used alone or in combination with other terms includes straight chained or branched monovalent hydrocarbon group comprised of 2 to 8 carbon atoms, having one or more double bonds. For example, vinyl, allyl, propenyl, crotonyl, isopentenyl, various butenyl isomers and the like are exemplified. Preferable is C2-C6 alkenyl. Further, C2-C4 alkenyl is preferable.

In the present specification, the “cycloalkenyl” includes cycloalkenyls comprised of 3 to 8 carbon atoms, having one or more double bonds in the ring. For example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl are exemplified. Preferable is C3-C6 cycloalkenyl.

In the present specification, the “lower alkynyl” includes straight chained or branched monovalent hydrocarbon groups comprised of 2 to 8 carbon atoms, having one or more triple bonds, which may have a double bond. For example, ethynyl, 2-propynyl, 3-butynyl, 4-pentynyl, 5-hexynyl, 6-heptynyl, 7-octynyl and the like are exemplified. Preferable is C2-C6 alkynyl. Further, C2-C4 alkynyl is preferable.

In the present specification, the “cycloalkynyl” includes cycloalkynyl comprised of 4 to 8 carbon atoms, having one or more triple bonds in the ring, which may have a double bond. For example, cyclobutynyl, cyclopentynyl, cyclohexynyl, cycloheptynyl, and cyclooctynyl are exemplified. Preferable is C4-C6 cycloalkynyl.

In the present specification, the “alkylene” includes divalent hydrocarbon group corresponding to the above “lower alkyl”.

In the present specification, the “alkenylene” includes divalent hydrocarbon group corresponding to the above “lower alkenyl”.

In the present specification, the “alkynylene” includes divalent hydrocarbon group corresponding to the above “lower alkynyl”.

In the present specification, the “C1-C5 alkylene which may be intervened with a substituent selected from Substituent group a” includes (substituent selected from Substituent group a)-(C1-C5 alkylene), (C1-C5 alkylene)-(substituent selected from Substituent group a), and (alkylene)-(substituent selected from Substituent group a)-(alkylene), provided that the sum of lengths of both alkylene chains is an integer of 1 to 5.

In the present specification, the term “aryl” which is used alone or in combination with other terms includes monocyclic aromatic hydrocarbon group or fused aromatic hydrocarbon group in which 2 or 3 aromatic rings are fused. For example, phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like are exemplified.

As the “aryl” in R², phenyl is preferable.

As the “aryl” in R³, phenyl is preferable.

In the present specification, the term “naphthyl” includes 1-naphthyl and 2-naphthyl.

In the present specification, the term “aralkyl” which is used alone or in combination with other terms is the abovementioned “lower alkyl” which is substituted with one or more of the abovementioned “aryl”, which may be substituted at all possible positions. For example, benzyl, phenylethyl (e.g. 2-phenylethyl, etc.), phenylpropyl (e.g. 3-phenylpropyl, etc.), naphthylmethyl (e.g. 1-naphthylmethyl, 2-naphthylmethyl, etc.), anthrylmethyl (e.g. 9-anthrylmethyl, etc.), biphenylmethyl (e.g. 4-biphenylmethyl, etc.) and the like are exemplified. Preferably, benzyl, and phenylethyl are exemplified.

As the “aralkyl” in R², phenyl C1-C3 alkyl is preferable, and benzyl is particularly preferable.

As the “aralkyl” in R³, phenyl C1-C6 alkyl and naphthyl C1-C6 alkyl are preferable. Further preferable are phenyl C1-C3 alkyl and naphthyl C1-C3 alkyl, for example, benzyl, phenylethyl, 1-naphthylmethyl, and 2-naphthylmethyl.

In the present specification, the term “heteroaryl” which is used alone or in combination with other terms includes 5- to 6-membered aromatic ring containing, in the ring, one or more atoms arbitrarily selected from oxygen atoms, sulfur atoms and nitrogen atoms, and these may be fused with cycloalkyl, aryl, non-aromatic heterocyclic group, or other heteroaryl, and may be fused at all possible positions. For example, pyrrolyl (e.g. 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (e.g. 2-furyl, 3-furyl), thienyl (e.g. 2-thienyl, 3-thienyl), imidazolyl (e.g. 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g. 1-pyrazolyl, 3-pyrazolyl), isothiazolyl (e.g. 3-isothiazolyl), isoxazolyl (e.g. 3-isoxazolyl), oxazolyl (e.g. 2-oxazolyl), thiazolyl (e.g. 2-thiazolyl), pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrazinyl (e.g. 2-pyrazinyl), pyrimidinyl (e.g. 2-pyrimidinyl, 4-pyrimidinyl), pyridazinyl (e.g. 3-pyridazinyl), tetrazolyl (e.g. 1H-tetrazolyl), oxadiazolyl (e.g. 1,3,4-oxadiazolyl), thiadiazolyl (e.g. 1,3,4-thiadiazolyl), indolizinyl (e.g. 2-indolizinyl, 6-indolizinyl), isoindolyl (e.g. 2-isoindolyl), indolyl (e.g. 1-indolyl, 2-indolyl, 3-indolyl, 5-indolyl, 6-indolyl), indazolyl (e.g. 3-indazolyl), purinyl (e.g. 8-purinyl), quinolizinyl (e.g. 2-quinolizinyl), isoquinolyl (e.g. 3-isoquinolyl), quinolyl (e.g. 2-quinolyl, 5-quinolyl), phthalazinyl (e.g. 1-phthalazinyl), naphthyridinyl (e.g. 2-naphthyridinyl), quinoxanyl (e.g. 2-quinoxanyl), quinazolinyl (e.g. 2-quinazolinyl), cinnolinyl (e.g. 3-cinnolinyl), pteridinyl (e.g. 2-pteridinyl), carbazolyl (e.g. 2-carbazolyl, 3-carbazolyl), phenanthridinyl (e.g. 2-phenanthridinyl, 3-phenanthridinyl), acridinyl (e.g. 1-acridinyl, 2-acridinyl), dibenzofuranyl (e.g. 1-dibenzofuranyl, 2-dibenzofuranyl, 3-dibenzofuranyl), benzimidazolyl (e.g. 2-benzimidazolyl, benzisoxazolyl (e.g. 3-benzisoxazolyl), benzoxazolyl (e.g. 2-benzoxazolyl), benzoxadiazolyl (e.g. 4-benzoxadiazolyl), benzisothiazolyl (e.g. 3-benzisothiazolyl), benzothiazolyl (e.g. 2-benzothiazolyl, 5-benzothiazolyl), benzofuryl (e.g. 2-benzofuryl, 3-benzofuryl, 5-benzofuryl), benzothienyl (e.g. 2-benzothienyl), thienopyrimidinyl and the like are exemplified.

As the “heteroaryl” in R²⁹, thiazolyl, oxazolyl, benzoxazolyl benzothienyl, benzothiazolyl and the like are preferable.

As the “heteroaryl” in R²⁶, R²⁸, R³⁰and R³¹, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl and the like are preferable.

As the “heteroaryl” in R², pyridyl, thienyl, furyl, imidazolyl and the like are preferable.

As the “heteroaryl” in R³, indolyl, imidazolyl, furyl, thienyl and the like are preferable.

In the present specification, the term “heteroarylalkyl” is the abovementioned “lower alkyl” substituted with one or more of the abovementioned “heteroaryl” at the arbitrary positions, and these can be substituted at all possible positions. For example, oxazolylmethyl (e.g. 2-oxazolylmethyl, 4-oxazolylmethyl), thiazolylmethyl (e.g. 2-thiazolylmethyl, 4-thiazolylmethyl), oxazolylethyl (e.g. 5-oxazolyl-2-ethyl), thiazolylethyl (e.g. 5-thiazolyl-2-ethyl), benzoxazolylmethyl (e.g. benzoxazol-2-ylmethyl), benzothiazolylmethyl (e.g. benzothiazol-2-ylmethyl), indolylmethyl (e.g. indol-3-ylmethyl), imidazolylmethyl (e.g. 4-imidazolylmethyl), indazolylmethyl (e.g. 1-indazolylmethyl), benzotriazolylmethyl (e.g. 1-benzotriazolylmethyl), benzoquinolylmethyl (e.g. 2-benzoquinolylmethyl), benzimidazolylmethyl (e.g. benzimidazol-2-methyl), pyridylmethyl (e.g. 4-pyridylmethyl), furylmethyl (e.g. furan-2-ylmethyl), thienylmethyl (e.g. thiophen-2-ylmethyl) and the like are exemplified.

Examples of the “heteroarylalkyl” in R²are indolylmethyl (e.g. indol-3-ylmethyl), imidazolylmethyl (e.g. imidazol-5-ylmethyl), thienylmethyl (e.g. thiophen-2-ylmethyl), thiazolylmethyl (e.g. 2-thiazolylmethyl, 4-thiazolylmethyl, pyridylmethyl and the like.

Examples of the “heteroarylalkyl” in R³, R³⁰and R³¹are indolylmethyl (e.g. indol-3-ylmethyl), imidazolylmethyl (e.g. imidazol-5-ylmethyl), benzoxazolylmethyl (e.g. benzoxazol-2-ylmethyl), benzothiazolylmethyl (e.g. benzothiazol-2-ylmethyl), benzimidazolylmethyl (e.g. benzimidazol-2-ylmethyl), thienylmethyl (e.g. thiophen-2-ylmethyl), thiazolylmethyl (e.g. 2-thiazolylmethyl, 4-thiazolylmethyl) and the like.

In the present specification, the term “aromatic heterocyclic ring” includes 5- to 6-membered aromatic ring containing, in the ring, one or more atoms arbitrarily selected from oxygen atoms, sulfur atoms and nitrogen atoms, and these may be fused with cycloalkyl, aryl, a non-aromatic heterocyclic group, or other heteroaryl, and may be fused at all possible positions.

Examples are pyrrole, furan, thiophene, imidazole, pyrazole, isothiazole, isoxazole, oxazole, thiazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, oxadiazole, thiadiazole, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylidine, quinoxaline, quinazoline, cinnoline, pteridine, carbazol, phenanthridine, acridine, dibenzofuran, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzisothiazole, benzothiazole, benzofuran, benzothiophene and thienopyrimidine and the like.

As the “aromatic heterocycric ring” in D ring, pyrrole, furan, thiophene, benzofuran, pyridine, pyrimidine, indole, and the like are preferable.

In the present specification, the term “non-aromatic carbocyclic group” which is used alone or in combination with other terms includes “cycloalkyl”, “cycloalkenyl”, “cycloalkynyl”, and the fused ring which “cycloalkyl”, “cycloalkenyl”, or “cycloalkynyl” may be fused with the above “aryl”. For example, cyclobutyl, cyclopentyl, cyclohexyl, indanyl, tetrahydronaphthyl, and the like are exemplified.

As the “non-aromatic carbocyclic group” in Z, cyclobutyl is preferable.

As the “non-aromatic carbocyclic ring” in D ring, cyclopentane, cyclohexane, cycloheptane and cyclohexane and the like are preferable.

Examples of the “non-aromatic carbocyclic group” in which R³and R⁴are taken together with an adjacent carbon to form a 5- to 6-membered non-aromatic carbocyclic group, are cycloalkane, cycloalkene and cycloalkyne. Cyclopentane, cyclohexane and the like are preferable.

In the present specification, a term “non-aromatic heterocyclic group” which is used alone or in combination with other terms includes a non-aromatic 5- to 7-membered ring containing in the ring, one or more atoms, arbitrarily selected from oxygen atoms, suffer atoms and nitrogen atoms, and the ring group in which two or more of the above rings are fused, and the ring group in which the abovementioned “ring” is fused with the abovementioned “aryl”. For example, pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl), pyrrolinyl (e.g. 3-pyrrolinyl), imidazolidinyl (e.g. 2imidazolidinyl), imidazolinyl (e.g. imidazolinyl), pyrazolidinyl (e.g. 1-pyrazolidinyl, 2-pyrazolidinyl), pyrazolinyl (e.g. pyrazolinyl), piperidyl (e.g. piperidino, 2-piperidyl), piperazinyl (e.g. 1-piperazinyl), indolinyl (e.g. 1-indolinyl), isoindolinyl (e.g. isoindolinyl), morpholinyl (e.g. morpholino, 3-morpholinyl), dihydropyridyl, tetrahydropyridyl, tetrahydroquinolyl, tetrahydrofuryl, tetrahydropyranyl, 1,3-benzodioxolanyl, 1,4-benzodioxanyl, 1-benzoxolanyl, oxetanyl, azetidinyl, diazetidinyl, chromanyl and the like are exemplified.

As the “non-aromatic heterocyclic group” in R²⁹, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidyl, piperazinyl, and the like are preferable.

As the “non-aromatic heterocyclic group” in R²⁶, R²⁸, R³⁰and R³¹morpholinyl and the like are preferable.

As the “non-aromatic heterocyclic group” in Z, oxetanyl, azetidinyl, and diazetidinyl are preferable.

As the “non-aromatic heterocyclic ring” in D ring, pyrrolidine, 2H-pyran, dihydro-2H-oxazine, pyrroline, tetrahydropyran, tetrahydroxazepine, dihydropyran, dihydropyridine, dihydropyrimidine, tetrahydropyridine, tetrahydropyrimidine, tetrahydroxazepine, tetrahydrodiazepine and the like are preferable.

As the “non-aromatic heterocyclic ring” in which R³and R⁴are taken together with an adjacent carbon to form a 5- to 6-membered non-aromatic heterocyclic ring, tetrahydropyran and the like are preferable.

The “nitrogen-containing heterocyclic ring which is optionally contained a further nitrogen atom, an oxygen atom, and/or a sulfur atom in a ring” in the B ring means a nitrogen-containing heterocyclic ring optionally further containing a nitrogen atom in addition to a nitrogen atom on the B ring, an oxygen atom, and/or a sulfur atom in the ring. The “nitrogen-containing heterocyclic ring” includes monocyclic 5- to 8-membered nitrogen-containing heterocyclic ring, and bridged nitrogen-containing heterocyclic ring. Preferable are nitrogen-containing heterocyclic ring represented by the formula:

wherein X is a carbon atom or a nitrogen atom, C ring is a 5- to 8-membered nitrogen-containing heterocyclic ring or a bridged ring. Further preferable are nitrogen-containing heterocyclic ring represented by the formula:

Particularly preferable are nitrogen-containing heterocyclic ring represented the formula:

In the present specification, “halogen” means fluorine, chlorine, bromine and iodine. Preferable are fluorine, chlorine, and bromine.

In the present specification, examples of the “lower alkyloxy” are methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, s-butyloxy, tert-butyloxy, n-pentyloxy, n-hexyloxy and the like. Preferable is C1-C6 alkyloxy. Further preferable is C1-C3 alkyloxy.

In the present specification, “lower alkyloxy lower alkylcarbonyl” means the abovementioned “lower alkylcarbonyl” is substituted with the abovementioned “lower alkyl”. Examples of the “lower alkyloxy lower alkylcarbonyl” are methyloxymethylcarbonyl, ethyloxymethylcarbonyl, methyloxyethylcarbonyl, isopropyloxymethylcarbonyl, isopropyloxyethylcarbonyl and the like.

In the present specification, examples of the “lower alkenyloxy” are vinyloxy, allyloxy, propenyloxy, 3-butenyloxy, 2-butenyloxy (crotonyloxy, isocrotonyloxy), 1-butenyloxy, isopentenyloxy and the like. C2-C3 alkenyloxy is preferable.

In the present specification, examples of the “lower alkylthio” are methylthio, ethylthio, propylthio, isopropylthio, butylthio, s-butylthio, isobutylthio, t-butylthio and the like. C1-C3 alkylthio is preferable. Particularly preferable is methylthio.

In the present specification, the term “halo lower alkyl” which is used alone or in combination with other terms includes the abovementioned “lower alkyl”, 1 to 8 atoms, preferably 1 to 5 atoms of which are substituted with the abovementioned “halogen”. For example, trifluoromethyl, trichloromethyl, difluoroethyl, trifluoroethyl, dichloroethyl, trichloroethyl and the like are exemplified. Preferable examples are C1-C3 lower alkyl, 1 to 5 atoms of which are substituted with the abovementioned “halogen”. Particularly preferable example is trifluoromethyl.

In the present specification, as the “halo lower alkyloxy”, C1-C3 lower alkyloxy, 1 to 5 atoms of which are substituted with the above “halogen”, is preferable. Particularly preferable example is trifluoromethyloxy.

In the present specification, as the “halo lower alkylthio”; C1-C3 lower alkylthio, 1 to 5 atoms of which are substituted with the above “halogen”, is preferable. Particularly preferable example is trifluoromethylthio.

In the present specification, the term “hydroxy lower alkyl” includes the abovementioned “lower alkyl” substituted with a hydroxy group. For example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl and the like are exemplified. Preferable examples are hydroxymethyl, 1-hydroxyethyl, and 2-hydroxyethyl.

In the present specification, examples of the “lower alkyloxycarbonyl” are methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl and the like.

In the present specification, examples of the “lower alkylsulfonyl” are methylsulfonyl, ethylsulfonyl and the like. Preferable example is methylsulfonyl.

In the present specification, examples of the “lower alkylsulfinyl” are methylsulfinyl, ethylsulfinyl and the like. Preferable example is methylsulfinyl.

In the present specification, examples of the “lower alkyloxyimino” are methyloxyimino, ethyloxyimino, propyloxyimino, isopropyloxyimino butyloxyimino isobutyloxyimino and the like.

In the present specification, examples of the “aralkyloxy” are phenyl C1-C3 alkyloxy, naphthyl C1-C3 alkyloxy and the like. Preferable example is benzyloxy.

In the present specification, examples of the “aralkylthio” are phenyl C1-C3 alkylthio, naphthyl C1-C3 alkylthio and the like. Preferable example is benzylthio.

In the present specification, examples of the “aralkylsulfonyl” are phenyl C1-C3 alkylsulfonyl, naphthyl C1-C3 alkylsulfonyl and the like. Preferable example is benzylsulfonyl.

In the present specification, examples of the “aralkylsulfinyl” are phenyl C1-C3 alkylsulfinyl, naphthyl C1-C3 alkylsulfinyl and the like. Preferable example is benzylsulfinyl.

In the present specification, a term “acyl” which is used alone or in combination with other terms includes alkylcarbonyl in which an alkyl moiety is the abovementioned “lower alkyl” or “haro lower alkyl”, arylcarbonyl in which an aryl moiety is the abovementioned “aryl”, heteroarylcarbonyl in which a heteroaryl moiety is the abovementioned “heteroaryl”, aralkylcarbonyl in which an aralkyl moiety is the abovementioned “aralkyl”, heteroarylalkylcarbonyl in which a heteroarylalkyl moiety is the abovementioned “heteroarylalkyl” and non-aromatic heterocyclic carbonyl in which a non-aromatic heterocyclic moiety is the abovementioned “non-aromatic heterocyclic group”. For example, acetyl, propionyl, benzoyl, pyridylcarbonyl (e.g. nicotinoyl, isonicotinoyl and the like), morpholinocarbonyl, benzyl carbonyl and the like are exemplified. The “lower alkyl”, the “aryl”, the “heteroaryl” and “non-aromatic heterocyclic group” may be substituted with a substituent described later.

In the present specification, a term “acyloxy” includes acyloxy in which an acyl moiety is the abovementioned “acyl”. For example, they are acetyloxy, propionyloxy, benzoyloxy and the like.

In the present specification, the “optionally substituted amino” which is used alone or in combination with other terms includes amino and amino, 1 or 2 atoms of which are substituted with the abovementioned “lower alkyl”, the abovementioned “aralkyl”, the abovementioned “heteroarylalkyl”, the abovementioned “lower alkyloxycarbonyl”, the abovementioned “lower alkylsulfonyl”, or the abovementioned “acyl”. Preferable examples are unsubstituted amino, and amino substituted with 1 or 2 substituents selected from the group consisting of C1-C6 alkyl, phenyl C1-C3 alkyl, pyridyl C1-C3 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylcarbonyl and arylcarbonyl. For example, amino, methylamino, dimethylamino, ethylmethylamino, diethylamino, benzylamino, pyridylmethylamino, tert-butoxycarbonylamino, methylsulfonylamino, acetylamino, benzoylamino and the like are exemplified. Preferable examples are amino, methylamino, dimethyl amino, ethylmethylamino, diethylamino, methylsulfonylamino and acetyl amino.

In the present specification, as the “optionally substituted aminocarbonyl”, unsubstituted aminocarbonyl, arylaminocarbonyl optionally substituted with a substituent selected from Substituent group c, aralkylaminocarbonyl optionally substituted with a substituent selected from Substituent group c, heteroarylalkylaminocarbonyl optionally substituted with a substituent selected from Substituent group c, aryloxyaminocarbonyl optionally substituted with a substituent selected from Substituent group c, lower alkyloxyaminocarbonyl optionally substituted with a substituent selected from Substituent group c, lower alkylaminocarbonyl optionally substituted with a substituent selected from Substituent group c, lower alkenylaminocarbonyl optionally substituted with a substituent selected from Substituent group c, lower alkynylaminocarbonyl optionally substituted with a substituent selected from Substituent group c, lower alkylaminocarbonyl substituted with a cycloalkyl optionally substituted with a substituent selected from Substituent group c, lower alkylaminocarbonyl substituted with a non-aromatic heterocyclic group optionally substituted with a substituent selected from Substituent group c, aminocarbonyl wherein nitrogen atom forms a non-aromatic heterocyclic group, aminocarbonyl optionally substituted with 1 or 2 non-aromatic heterocyclic group(s) substituted with a substituent selected from Substituent group c, or aminocarbonyl optionally substituted with 1 or 2 cycloalkyl substituted with a substituent selected from Substituent group c are preferable. For example, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylmethylaminocarbonyl, diethylaminocarbonyl, isobutylaminocarbonyl, isopropylaminocarbonyl, aminoethylaminocarbonyl, 2-(tert-butoxycarbonylamino)-ethylaminocarbonyl, 2-(tert-butoxycarbonyl(methyl)amino)ethylaminocarbonyl, 2-methylamino-ethylcarbonyl, 3-prop-2-ylaminocarbonyl, cyanomethylaminocarbonyl, cyanoethylaminocarbonyl, phenyloxyamino, benzylaminocarbonyl, 4-chlorobenzylaminocarbonyl, 3-chlorobenzylaminocarbonyl, 2-chlorobenzylaminocarbonyl, 4-fluorobenzylaminocarbonyl, 3-fluorobenzylaminocarbonyl, 4-bromobenzylaminocarbonyl, 4-methoxybenzylaminocarbonyl, 3-methoxybenzylaminocarbonyl, 4-tert-butylbenzylaminocarbonyl, phenylaminocarbonyl, pyridylmethylaminocarbonyl, 4-chlorophenylaminocarbonyl, 4-trifluoromethylbenzylaminocarbonyl, 3-trifluoromethylbenzylaminocarbonyl, 3-methylbenzylaminocarbonyl, 4-trifluoromethoylbenzylaminocarbonyl, 3-trifluoromethoylbenzylaminocarbonyl, 3,4-dimethoylbenzylaminocarbonyl, 3,4-dichlorobenzylaminocarbonyl, 3,4-difluorobenzylaminocarbonyl, 3,5-difluorobenzylaminocarbonyl, 2,5-dichlorobenzylaminocarbonyl, 4-dimethylaminobenzylaminocarbonyl, 3-dimethylaminomethyl-4-fluorobenzylaminocarbonyl, chloropyridylmethylaminocarbonyl, 2-methanesulfonylaminoethylaminocarbonyl, 3-methanesulfonylaminopropylaminocarbonyl, 4-methanesulfonylaminobutylaminocarbonyl, 1-(methanesulfonylpiperidin-4-ylmethyl)aminocarbonyl, 4-methanesulfonylbenzylaminocarbonyl, 4-piperidin-1-ylbenzylaminocarbonyl, 4-(2-oxopyrrolidin-1-yl)-benzylaminocarbonyl, 4-methylaminocarbonylbenzylaminocarbonyl, 4-isopropylcarbamoylbenzylaminocarbonyl, 3-isopropylcarbamoylbenzylaminocarbonyl, 4-acetylaminobenzylaminocarbonyl, (thiophen-2-ylmethyl)-aminocarbonyl, isopropylaminocarbonylaminopropylaminocarbonyl, ethoxycarbonylaminopropylaminocarbonyl, isopropylsulfonylaminopropylaminosulfonyl, 4-sulfamoylbenzylaminocarbonyl, 3-chloro-4-fluorobenzylaminocarbonyl, 4-dimethylaminocarbonylbenzyl, 4-fluoro-3-methylbenzylaminocarbonyl, (furan-2-ylmethyl)-aminocarbonyl, (1-methyl-1H-pyrazol-3-ylmethyl)-aminocarbonyl, 4-fluoro-3-methoxymethylbenzylaminocarbonyl, 4-methylbenzylaminocarbonyl, 4-isopropylbenzylaminocarbonyl, (benzo[1,3]dioxol-5-ylmethyl)-aminocarbonyl, (2,3-dihydrobenzofuran-5-ylmethyl)-aminocarbonyl, 4-sulfamoylbenzylaminocarbonyl, (5-methylisoxazol-3-ylmethyl)-aminocarbonyl, 4-methylfurazan-3-ylmethyl) -aminocarbonyl, 4-fluoro-3-trifluoromethylbenzylaminocarbonyl, (2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)aminocarbonyl, 4-morpholin-4-ylbenzylaminocarbonyl, (5-methyl-[1,2,4]oxadiazol-3-ylmethyl)aminocarbonyl, 3-(3-methoxyphenoxy)-benzylaminocarbonyl, 3-bromo-4-fluorobenzylaminocarbonyl, 4-fluoro-3-methoxybenzylaminocarbonyl, (1,5-dimethyl-1H-pyrazol-3-ylmethyl)-aminocarbonyl, 4-pyrazol-1-ylbenzylaminocarbonyl, (2,5-dimethyloxazol-4-ylmethyl)-aminocarbonyl, 4-pyrrol-1-ylbenzylaminocarbonyl, (biphenyl-4-ylmethyl)-aminocarbonyl, 3-hydroxy-4-methoxybenzylaminocarbonyl, 4-phenoxybenzylaminocarbonyl, 4-trifluoromethylsulfanylbenzylaminocarbonyl, 4-(tert-butoxycarbonylaminomethyl)-benzylaminocarbonyl, 3-(tert-butoxycarbonylaminomethyl)-benzylaminocarbonyl, 4-fluoro-2-methoxymethylbenzylaminocarbonyl, 3-iodobenzylaminocarbonyl, 4-fluoro-2-methoxybenzylaminocarbonyl, 4-aminocarbonylbenzylaminocarbonyl, 4-fluoro-2-methanesulfonylaminobenzylaminocarbonyl, 3-fluoro-4-methoxybenzylaminocarbonyl, [5-(4-chlorophenyl)-thiophen-2-ylmethyl]-aminocarbonyl, 2-dimethylcarbamoyl-4-fluorobenzylaminocarbonyl, 2-fluoro-ethylaminocarbonyl, 2-oxo-propylaminocarbonyl, cyclopropylaminocarbonyl, cyclohexylmethylaminocarbonyl, 3,4-dichlorobenzylaminocarbonyl, 3,5-dichlorobenzylaminocarbonyl and the like are exemplified.

Preferable examples are aminocarbonyl, dimethylaminocarbonyl. dichlorobenzylaminocarbonyl, 4-chlorobenzylaminocarbonyl, 3-chlorobenzylaminocarbonyl, 4-methoxybenzylaminocarbonyl, 4-fluorobenzylaminocarbonyl, 4-tert-butylbenzylaminocarbonyl, (3-methyl-2-oxo-2,3-dihydrobenzoxazol-6-ylmethyl)-aminocarbonyl, pyridin-4-ylmethylaminocarbonyl, 4-cyanobenzylaminocarbonyl, and piperidinecarbonyl.

Substituent group c: halogen; hydroxy; cyano; acyl; lower alkyloxy; lower alkyloxycarbonyl; lower alkylthio; lower alkyl substituted with lower alkyloxy; lower alkylsulfonyl; aminosulfonyl; lower alkyl; halo lower alkyl; halo lower alkyloxy; halo lower alkylthio; amino optionally substituted with 1 or 2 lower alkyl and/or lower alkyloxycarbonyl; amino substituted with lower alkylcarbonyl; lower alkylaminocarbonyl optionally substituted with cyano; amino substituted with aminocarbonyl; amino substituted with lower alkylaminocarbonyl; sulfonylamino substituted with lower alkyl; aminoalkyl optionally substituted with 1 or 2 lower alkyl and/or lower alkyloxycarbonyl; optionally substituted aryloxy wherein the substituent is selected from the group consisting of halogen, lower alkyl, lower alkyloxy, hydroxy, lower alkyl substituted with hydroxy, halo lower alkyl, lower alkylsulfonyl, lower alkyloxycarbonyl, carboxy, aminocarbonyl, lower alkylaminocarbonyl, and the like; cycloalkyl; a non-aromatic heterocyclic group; cycloalkyl in which hydrogen atom on the ring is substituted with oxo; a non-aromatic heterocyclic group in which hydrogen atom on the ring is substituted with oxo; lower alkylsulfoneamide; optionally substituted heteroaryl; oxo; amino optionally substituted with 1 or 2 optionally substituted aryl and/or lower alkyloxycarbonyl;

a group represented by the following formula:

and aryl optionally substituted with the group represented by the formula:

In the present specification, as the “optionally substituted hydrazino”, unsubstituted hydrazino, lower alkyl hydrazino wherein the lower alkyl is abovementioned “lower alkyl”, aryl hydrazino optionally substituted with a substituent selected from Substituent group c and heteroaryl hydrazino optionally substituted with a substituent selected from Substituent group c are preferable. Examples are hydrazino, methyhydrazino, ethyhydrazino, phenylhydrazino, pyridylhydrazino and the like.

In the present specification, as the “optionally substituted aminoxalyl”, unsubstituted aminoxalyl or aminoxalyl substituted with 1 or 2 C1-C6 alkyl are preferable. For example, aminoxalyl, methylaminoxalyl, dimethylaminooxalyl, ethylmethylaminoxalyl, diethylaminoxalyl, isopropylaminoxalyl and the like are exemplified. Preferable examples are aminocarbonyl and dimethylaminoxalyl.

In the present specification, as the “optionally substituted aminosulfonyl”, unsubstituted aminosulfonyl or aminosulfonyl substituted with 1 or 2 C1-C6 alkyl are preferable. For example, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, ethylmethylaminosulfonyl, diethylaminosulfonyl, isopropylaminosulfonyl and the like are exemplified. Preferable examples are aminosulfonyl, dimethylaminosulfonyl and the like.

In the present specification, a term “lower alkylsulfonamide” includes the sulfonamide substituted with the abovementioned “lower alkyl”. For example, methylsulfonamide, ethylsulfonamide and isopropylsulfonamide and the like are exemplified.

In the present specification, examples of a substituent of the “optionally substituted lower alkyl”, “optionally substituted lower alkenyl”and “optionally substituted lower alkyloxy” are lower alkylthio, cycloalkyl, carboxy, lower alkyloxy, hydroxy, mercapto, halogen, nitro, cyano, lower alkyloxycarbonyl, halo lower alkyl, halo lower alkyloxy, optionally substituted amino, optionally substituted aminocarbonyl, acyl, acyloxy, aryl optionally substituted with a substituent selected from Substituent group b, heteroaryl optionally substituted with a substituent selected from Substituent group b, a non-aromatic heterocyclic group optionally substituted with a substituent selected from Substituent group b, lower alkyloxyimino, aryloxy, aralkyloxy, lower alkylsulfonyl, guanidino, an azo group, ureido optionally substituted with a substituent selected from Substituent group b, carbamoyl and the like. These may substitute at one or more of all possible positions.

Substituent group b: lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, lower alkenyloxy, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo lower alkyl, halo lower alkyloxy, halo lower alkylthio, optionally substituted amino, optionally substituted aminocarbonyl, acyl, acyloxy, aryl, heteroaryl, a non-aromatic heterocyclic group, aralkyl, lower alkylsulfonyl, guanidino, an azo group, and ureido.

As a substituent of the “optionally substituted lower alkyl”, “optionally substituted lower alkenyl” and “optionally substituted lower alkyloxy” in R²⁶, R²⁸, R³⁰and R³¹, cycloalkyl, carboxy, lower alkyloxy, lower alkyloxycarbonyl, hydroxy, halogen, cyano, amino optionally substituted with 1 or 2 lower alkyl, aminocarbonyl optionally substituted with 1 or 2 lower alkyl, tetrazolyl, aminocarbonyl optionally substituted with a substituent selected from the abovementioned Substituent group b, aryl optionally substituted with a substituent selected from the abovementioned Substituent group b, heteroaryl optionally substituted with a substituent selected from the abovementioned Substituent group b, a non-aromatic heterocyclic group optionally substituted with a substituent selected from the abovementioned Substituent group b, or lower alkyloxyimino are preferable.

As a substituent of the “optionally substituted lower alkenyl” in R²⁹, halogen, cyano, carboxy, lower alkyloxycarbonyl, optionally substituted aminocarbonyl, tetrazolyl and the like are preferable.

As a substituent of the “optionally substituted lower alkyl” and “optionally substituted alkyl” in R², hydroxy, lower alkyloxy, a non-aromatic heterocyclic group optionally substituted with a substituent selected from the abovementioned Substituent group b and the like are preferable.

As a substituent of the “optionally substituted lower alkyl” in R³, lower alkyloxy, lower alkylthio, cycloalkyl, carboxy, halogen, hydroxy, carbamoyl and mercapto are preferable.

As a substituent of the “optionally substituted lower alkyloxyimino” in R³¹, halogen, hydroxy, aryl optionally substituted with lower alkyloxy, cyano, aminocarbonyl, amino optionally substituted with 1 or 2 lower alkyl or lower alkyloxycarbonyl and the like are preferable.

In the present specification, examples of the substituents in the “optionally substituted aryl”, the “optionally substituted heteroaryl”, the “optionally substituted aralkyl”, and the “optionally substituted heteroarylalkyl” in R²and R³are lower alkyl optionally substituted with a substituent selected from abovementioned Substituent group b, cycloalkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, lower alkenyloxy, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo lower alkyl, halo lower alkyloxy, halo lower alkylthio, optionally substituted amino, optionally substituted aminocarbonyl, acyl, acyloxy, aryl optionally substituted with a substituent selected from abovementioned Substituent group b, heteroaryl optionally substituted with a substituent selected from abovementioned Substituent group b, a non-aromatic heterocyclic group optionally substituted with a substituent selected from abovementioned Substituent group b, aralkyl optionally substituted with a substituent selected from abovementioned Substituent group b, lower alkylsulfonyl, guanidino, an azo group, ureido optionally substituted with a substituent selected from abovementioned Substituent group b and the like. These can substitute at one or more of all possible positions.

As a substituent of the “optionally substituted aryl” in R², hydroxy, lower alkyloxy, halogen, and halo lower alkyl are preferable.

As a substituent of the “optionally substituted aryl” in R³, hydroxy is preferable.

As a substituent of the “optionally substituted heteroaryl” in R², hydroxy, lower alkyloxy, halogen, and halo lower alkyl are preferable.

As a substituent of the “optionally substituted heteroaryl” in R³, hydroxy and halogen are preferable.

As a substituent of the “optionally substituted aralkyl” in R², hydroxy, lower alkyloxy, halogen, halo lower alkyl, and nitro are preferable.

As a substituent of the “optionally substituted aralkyl” in R³, hydroxy, halogen, nitro, lower alkyloxy, halo lower alkyl, and carboxy lower alkyloxy are preferable.

As a substituent of “optionally substituted heteroarylalkyl” in R², hydroxy, lower alkyloxy, halogen, and halo lower alkyl are preferable.

As a substituent of the “optionally substituted heteroarylalkyl” in R³, a halogen, hydroxy, and carboxy are preferable.

In the present specification, as a substituent of “optionally substituted heteroaryl” and “optionally substituted non-aromatic heterocyclic group” in R²⁶and R²⁸, halogen, lower alkyl, lower alkyloxy, hydroxy, lower alkyl substituted with hydroxy, halo lower alkyl, lower alkylsulfonyl, lower alkyloxycarbonyl and the like.

In the present specification, examples of the substituent of the “optionally substituted aryl”, the “optionally substituted heteroaryl”, the “optionally substituted non-aromatic heterocyclic group”, the “optionally substituted aralkyl”, and the “optionally substituted heteroarylalkyl” in R³⁰and R³¹are halogen, lower alkyl, lower alkyloxy, hydroxy, lower alkyl substituted with hydroxy, halo lower alkyl, lower alkylsulfonyl, lower alkyloxycarbonyl and the like.

In the present specification, examples of the substituent of the “optionally substituted aryl”, the “optionally substituted heteroaryl”, the “optionally substituted non-aromatic carbocyclic group” and the “optionally substituted non-aromatic heterocyclic group” in R²⁹are halogen; optionally substituted lower alkyl; hydroxy; lower alkyl substituted with hydroxy; halo lower alkyl; lower alkyloxy; halo lower alkyloxy; optionally substituted amino; optionally substituted aminocarbonyl; optionally substituted aryl wherein the substituent is selected from the group consisting of halogen, lower alkyl, lower alkyloxy, hydroxy, lower alkyl substituted with hydroxy, halo lower alkyl, lower alkylsulfonyl, lower alkyloxycarbonyl, carboxy, aminocarbonyl, lower alkylaminocarbonyl and the like; optionally substituted aryloxy wherein the substituent is selected from the group consisting of halogen, lower alkyl, lower alkyloxy, hydroxy, lower alkyl substituted with hydroxy, halo lower alkyl, lower alkylsulfonyl, lower alkyloxycarbonyl, carboxy, aminocarbonyl, lower alkylaminocarbonyl and the like; optionally substituted aralkyl wherein the substituent is selected from the group consisting of halogen, lower alkyl, lower alkyloxy, hydroxy, lower alkyl substituted with hydroxy, halo lower alkyl, lower alkylsulfonyl, lower alkyloxycarbonyl, carboxy, aminocarbonyl, lower alkylaminocarbonyl and the like; optionally substituted aralkyloxy wherein the substituent is selected from the group consisting of halogen, lower alkyl, lower alkyloxy, hydroxy, lower alkyl substituted with hydroxy, halo lower alkyl, lower alkylsulfonyl, lower alkyloxycarbonyl, carboxy, aminocarbonyl, lower alkylaminocarbonyl and the like.

In the present specification, as a substituent of the “optionally substituted aryloxy” in R³⁰, halogen, lower alkyl, lower alkyloxy, hydroxy, lower alkyl substituted with hydroxy, halo lower alkyl, lower alkylsulfonyl, lower alkyloxycarbonyl and the like.

In the present specification, examples of a substituent of the “optionally substituted aralkyloxy” in R³¹, halogen, lower alkyl, lower alkyloxy, hydroxy, lower alkyl substituted with hydroxy, halo lower alkyl, lower alkylsulfonyl, lower alkyloxycarbonyl and the like.

As the present compound, particularly, a compound represented by the following A) to AB) is preferable.

A) A compound represented by the general formula (IV):

wherein R¹¹is

a) a group of the formula:

wherein R³⁶and R³⁷are each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkyloxy, lower alkylthio, aralkylthio, optionally substituted amino, carboxy, hydroxy, cyano, lower alkyloxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminoxaryl, acyl, lower alkylsulfonyl, lower alkylsulfinyl, aralkylsulfonyl, aralkylsulfinyl, optionally substituted aminosulfonyl, optionally substituted heteroaryl or an optionally substituted non-aromatic heterocyclic group;

n⁵is an integer of 0 to 3, and
R³⁷may be substituted on all substitutable atoms on the ring;
b) a group of the formula:

wherein F ring is benzene, pyridine, 2-pyridone, thiazole, tetrahydrothienopyrimidine or oxazole;

R³⁸is halogen, acyl, optionally substituted lower alkyl, optionally substituted lower alkyloxy, optionally substituted lower alkenyl, optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted non-aromatic heterocyclic group, optionally substituted aminocarbonyl or optionally substituted amino;
R³⁹is each independently halogen, hydroxy, nitro, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkyloxy, optionally substituted aryloxy, optionally substituted aralkyl, optionally substituted heteroarylalkyl, lower alkylthio, aralkylthio, optionally substituted amino, carboxy, cyano, lower alkyloxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminoxaryl, acyl, lower alkylsulfonyl, lower alkylsulfinyl, aralkylsulfonyl, aralkylsulfinyl, optionally substituted aminosulfonyl, optionally substituted aryl, optionally substituted heteroaryl or an optionally substituted non-aromatic heterocyclic group;
n⁶is an integer of 0 to 2, and
R³⁸and R³⁹may be substituted on all substitutable atoms on the ring, or
c) a group of the formula:

wherein G ring is a non-aromatic carbocyclic ring, a non-aromatic heterocyclic ring or an aromatic heterocyclic ring;

R⁴⁰is each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkyloxy, lower alkylthio, aralkylthio, optionally substituted amino, carboxy, cyano, oxo, lower alkyloxycarbonyl, lower alkyloxy lower alkylcarbonyl, optionally substituted aminocarbonyl, optionally substituted aminoxaryl, acyl, lower alkylsulfonyl, lower alkylsulfinyl, aralkylsulfonyl, aralkylsulfinyl, optionally substituted aminosulfonyl, imino, hydroxyimino, lower alkyloxyimino, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted aralkyloxy, optionally substituted aryl or an optionally substituted non-aromatic heterocyclic group;
n⁷is an integer of 0 to 4, and
all substitutable atoms of the benzene ring and all substitutable atoms of G ring may be bonded to Z¹,
R⁴⁰may be substituted on all substitutable atoms of the benzene ring and and all substitutable atoms of the G ring;
provided that when n⁷is an integer of 0, G ring is not unsubstituted indole;
Z is —C(R⁸)(R⁹)—C(R⁸)(R⁹)—, —C(R⁸)═C(R⁹)—, —C≡C—, —O—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—O—, —S—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—S—, —SO—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—SO—, —SO₂—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—SO₂—, —N(R¹⁰)—C(R⁸)(R⁹)—, —C(R⁸)(R⁹)—N(R¹⁰)—, —N(R¹⁰)—C(═O)—, —C(═O)—N(R¹⁰)—, —N(R¹⁰)—SO₂—, —SO₂—N(R¹⁰)—, —C(R⁸)(R⁹)—C(═O)—, —C(═O)—C(R⁸)(R⁹)—, or —C(═O)C(═O)—, wherein R⁸, R⁹and R¹⁰are each independently a hydrogen atom or lower alkyl;
R¹²is a hydrogen atom or lower alkyl;
R¹³is a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, tert-butyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxymethyl, carboxyethyl, methyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenyl, 4-hydroxyphenyl, 4-fluorophenyl, 4-methyloxyphenyl, benzyl, 4-hydroxybenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-methoxybenzyl, indol-3-ylmethyl, 1-carboxymethylindol-3-ylmethyl, thiazol-4-ylmethyl, carboxymethyloxybenzyl, or cyclopropylmethyl,
R¹⁴is a hydrogen atom; or
R¹³and R¹⁴may be taken together with an adjacent carbon to form the ring represented by the formula:

R¹⁵is hydroxy or lower alkyloxy;

R¹⁶and R¹⁷are each independently halogen, lower alkyl, lower alkyloxy, or hydroxy;

x and y are each independently an integer of 0 to 3,

an optically active isomer, a pharmaceutically acceptable salt, or a solvate thereof.

B) A compound represented by the general formula (V):

wherein, R¹¹, Z¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, x, and y are as defined in A),

an optically active isomer, a pharmaceutically acceptable salt or a solvate thereof.
C) A compound represented by the general formula (VI):