JP2002275165A - Triazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine exhibiting strongly ameliorating effects both on immunoabnormality and chronic inflammation. SOLUTION: This triazole derivative is represented by a compound of the formula and its pharmacologically acceptable salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a triazole derivative which has excellent physical properties and is useful as a therapeutic agent for autoimmune diseases, inflammatory diseases and the like.

[0002]

2. Description of the Related Art Conventionally, acidic non-steroidal anti-inflammatory drugs or steroid drugs have been used as therapeutic agents for inflammatory diseases, but their use is limited in terms of side effects.
In addition, these treatment methods belong to symptomatic treatment and have no effect of improving the underlying cause of the disease.
As elucidation of the etiology and pathology of autoimmune diseases such as rheumatoid arthritis exhibiting a strong inflammation pattern, it is suggested that abnormalities of the immune system are deeply involved in the onset and chronicity of inflammation. From such a point, drugs that improve the disease state by acting on the immune system, such as gold preparations and D-penicillamine, have been attracting attention as causal treatments. However, it is not always in a satisfactory state due to side effects and lack of sustained effect. Under such circumstances, International Patent Publication No. 98/47880 (WO 98/47880) discloses that an autoimmune disease, an inflammatory disease having an excellent immunity improving effect and a chronic inflammation improving effect and having few side effects. There have been reported isoxazole derivatives substituted with a guanidino group, which are useful as therapeutic or prophylactic agents, etc., but compounds having further excellent pharmacological activity and physical properties have been desired.

[0003]

A therapeutic agent for an autoimmune disease requires a clear effect on chronic inflammation leading to tissue destruction. Furthermore, it is important for the radical therapy to also have an action of suppressing abnormalities of the immune system existing in the background of the disease. In addition, therapeutic agents for these diseases often require long-term administration, and are therefore required to have few side effects. The present invention provides compounds having excellent immunity abnormal improving action and chronic inflammation improving action, useful as a therapeutic or preventive agent for autoimmune diseases, inflammatory diseases and the like with few side effects, and also excellent in physical properties. The purpose is to provide.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, the triazole derivative represented by the following general formula (1) has a strong effect on both the immunity-improving effect and the chronic inflammation-improving effect. The present invention was found to be effective and was found to be excellent in physical properties, and completed the present invention.

The outline of the present invention will be described below. [1] Equation (1): [Wherein, M is a single bond, -O-, -S-, -SO-, -S
O ₂ -, -CQ- (Q represents a 1,3-dioxane ring or a 1,3-dioxolane ring with the carbon atom.), -
^{CH (OR 21) -, -C} (OR 21) 2 -, - C (=
NOR ²¹ )-, -C (= NR ²¹ )-(R ²¹ represents a hydrogen atom or an alkyl group), -C (= NNR
^{22 R 23)} - ^{(R 22} and ^{R 23} represent independently a hydrogen atom or an alkyl group,), -. CO-, or an -CS-. Y ¹ and Y ² independently represent a halogen atom, an alkyl group, a haloalkyl group, a nitro group, a cyano group, —OR ²⁴ , or —COR ²⁴ (R ²⁴ represents a hydrogen atom, an alkyl group, or a haloalkyl group.) , -CO
^{_{2 R 25, -SO 2 R 25}} , (R 25 represents an alkyl group.) - ^CONR 26 ^{R 27,} and _-SO 2 NR
^{26 R 2 7} (R ²⁶ and ^{R 27} represents a hydrogen atom or an alkyl group independently. ^{Or, R 26} and ^{R 27}
May combine to form an aliphatic heterocyclic ring. ) And may be bonded to any position on the benzene ring. Y
¹ and Y ² may each be 0 to 3;
Each may be the same or different. Also,
When two or more Y ¹ or Y ² are present, they may together represent a methylenedioxy group or an ethylenedioxy group. R ⁸ and R ⁹ each independently represent a hydrogen atom or an alkyl group. Or R ⁸
And R ⁹ are bonded together with the carbon atoms to which they are attached, may form a hydrocarbon ring may be substituted. R ⁷ represents a substituent bonded to any nitrogen atom of the triazole ring, and represents a hydrogen atom, -R ²⁸ , -CO
R ²⁸ , —SO ₂ R ²⁸ , —COOR ²⁸ (R ²⁸ is
An alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted,
Represents an optionally substituted aryl group, an optionally substituted cycloalkyl group, an optionally substituted aliphatic heterocyclic group, or an optionally substituted aromatic heterocyclic group. ), An optionally substituted carbamoyl group, or an optionally substituted sulfamoyl group. L is
formula: [In the formula, two broken lines mean one with a solid line and a double bond, and the other with a solid line and a single bond. R ¹ is bonded to the nitrogen atom having a bond in which the broken line and the solid line represent a single bond. R ¹ , R ² , R ³ and R ⁴ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, —R ²⁹ , —OR
²⁹ , -COR ²⁹ , -COOR ²⁹ , -SOR ²⁹ ,
—SO ₂ R ²⁹ (R ²⁹ represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, or an optionally substituted cycloalkyl group. ), An optionally substituted amino group, an optionally substituted hydroxyamino group,
Represents a carbamoyl group which may be substituted, or a sulfamoyl group which may be substituted. Or R ¹ ,
Any two of R ² , R ³ and R ⁴ may combine to form an optionally substituted aliphatic heterocyclic ring. ]. Or L is the formula: In the formula, R ⁵ or R ⁶ is each independently a hydrogen atom,
Hydroxyl group, -R ²⁹ , -OR ²⁹ , -COR ²⁹ , -CO
OR ²⁹ , —SOR ²⁹ , or —SO ₂ R ²⁹ (R
²⁹ has the same meaning as described above. ). Alternatively, R ⁵ and R ⁶ may combine to form an optionally substituted aliphatic heterocycle. Represents｝. Or a pharmaceutically acceptable salt thereof.

[2] Equation (2): [Wherein, M, L, Y ¹ , Y ² , R ⁸ and R ⁹ are as defined above. R ¹⁸ is a hydrogen atom, —R ²⁸ , —COR ²⁸ ,
—SO ₂ R ²⁸ , —COOR ²⁸ (R ²⁸ is as defined above), a carbamoyl group which may be substituted,
Or a sulfamoyl group which may be substituted. Or a pharmaceutically acceptable salt thereof. [3] Equation (3) [Wherein, M, L, Y ¹ , Y ² , R ⁸ and R ⁹ are as defined above. R ¹⁹ is a hydrogen atom, —R ²⁸ , —COR ²⁸ ,
—SO ₂ R ²⁸ , —COOR ²⁸ (R ²⁸ has the same meaning as described above; R ²⁸ has the same meaning as described above), an optionally substituted carbamoyl group, or an optionally substituted sulfamoyl group Represents Or a pharmaceutically acceptable salt thereof.

[4] Equation (4): [Wherein, M, L, Y ¹ , Y ² , R ⁸ and R ⁹ are as defined above. R ²⁰ is a hydrogen atom, -R ²⁸ , -COR ²⁸ ,
—SO ₂ R ²⁸ , —COOR ²⁸ (R ²⁸ is as defined above), a carbamoyl group which may be substituted,
Or a sulfamoyl group which may be substituted. Or a pharmaceutically acceptable salt thereof. [5] M is a single bond, -O-, -S-, -SO-,-
The triazole derivative according to [1] to [4], which is SO ₂ — or —CO—, or a pharmaceutically acceptable salt thereof. [6] M is a single bond or -CO-, [1].
To [4], or a pharmaceutically acceptable salt thereof.

[7] Equation (6): (Wherein L, Y ¹ , Y ² , R ⁷ , R ⁸ , and R ⁹ are as defined above), or a pharmaceutically acceptable salt thereof. [8] Equation (7): (Wherein L, Y ¹ , Y ² , R ⁷ , R ⁸ , and R ⁹ are as defined above), or a pharmaceutically acceptable salt thereof.

[9] Y ¹ or Y ² is independently
Hydrogen atom, halogen atom, alkyl group having 1 to 6 carbon atoms, haloalkyl group having 1 to 4 carbon atoms, 1 to 6 carbon atoms
A triazole derivative or a pharmaceutically acceptable salt thereof according to [1] to [8], wherein 0 to 2 each of Y ¹ or Y ² may be present. Acceptable salt. [10] Y ¹ or Y ² is independently a hydrogen atom,
Or a triazole derivative or a pharmaceutically acceptable salt thereof according to [1] to [8], which represents a halogen atom and may have 0 to 2 Y ¹ or Y ² each. [11] [7] wherein Y ¹ and Y ² represent a hydrogen atom.
Or a pharmaceutically acceptable salt thereof.

[12] Equation (8): (Wherein, Y ⁴ and Y ⁵ independently represent a hydrogen atom or a halogen atom; L, R ⁷ , R ⁸ , and R ⁹ have the same meanings as described above) or A pharmaceutically acceptable salt thereof.

[13] R ⁸ and R ⁹ are independently
Represents a hydrogen atom or an alkyl group. Alternatively, R ⁸ and R ⁹ combine to form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or the like, [1] to [12].
Or a pharmaceutically acceptable salt thereof. [14] The triazole derivative according to [1] to [12], wherein R ⁸ and R ⁹ independently represent a hydrogen atom or an alkyl group, and a pharmaceutically acceptable salt thereof. [15] The triazole derivative according to [1] to [12], wherein R ⁸ and R ⁹ independently represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, or a pharmaceutically acceptable salt thereof. [16] R ⁸ represents a hydrogen atom, R ⁹ represents a hydrogen atom,
Or the triazole derivative according to [1] to [12], which represents an alkyl group having 1 to 4 carbon atoms, or a pharmaceutically acceptable salt thereof. [17] The triazole derivative according to [1] to [12], wherein R ⁸ and R ⁹ independently represent a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof. [18] R ⁸ is a hydrogen atom, R ⁹ is a hydrogen atom,
Or the triazole derivative according to [1] to [12], which represents a methyl group, or a pharmaceutically acceptable salt thereof.

[19] R⁷, R¹⁸, R¹⁹Or
R²⁰Is a hydrogen atom, an optionally substituted carbamoy
Or a sulfamoyl group which may be substituted,
-R ³⁰, -COR³⁰, -SO₂R³⁰Or -C
OOR³⁰(R³⁰Is an optionally substituted alkyl
Group, an optionally substituted alkenyl group,
An alkynyl group or an optionally substituted
Represents a chloroalkyl group. ) [1] to [18],
Or a pharmaceutically acceptable derivative thereof.
Salt. [20] M represents a single bond or -CO-,
Y¹Or Y²But independently a hydrogen atom, a halogen atom
Child, alkyl group, haloalkyl group, alkoxy group, halo
Represents an alkoxy group;⁸And R⁹But independently, water
Represents an element atom or an alkyl group,⁷Is a hydrogen atom, -R
³⁰, -COR³⁰, -SO₂R³⁰, -COOR³⁰
(R³⁰Is as defined above. ), Even if substituted
A good carbamoyl group or an optionally substituted sulfo group
The triazole derivative according to [1], which represents a famoyl group.
The body, or a pharmaceutically acceptable salt thereof. [21] R⁸And R⁹But independently a hydrogen atom or
Is a triazole derivative according to [20], which represents a methyl group;
Or a pharmaceutically acceptable salt thereof. [22] R⁷Is -R³⁰, -COR³⁰, -SO₂
R³⁰, -COOR^{3 0}(R³⁰Is as defined above.
You. ), An optionally substituted carbamoyl group, or
Represents a sulfamoyl group which may be substituted, [2
0] or the triazole derivative according to [21] or
Pharmaceutically acceptable salts of

[23] [20] or [21] wherein R ⁷ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted alkynyl group. Or a pharmaceutically acceptable salt thereof. [24] The triazole derivative according to [20] or [21], wherein R ⁷ represents an optionally substituted alkyl group, or a pharmaceutically acceptable salt thereof. [25] R ⁷ represents a hydrogen atom, or a hydroxyl group, a cyano group, a carboxy group, an alkoxy group, a haloalkoxy group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkoxycarbonyl group, an optionally substituted aryl group, An optionally substituted aromatic heterocyclic group, an optionally substituted amino group, an optionally substituted carbamoyl group, and an optionally substituted sulfamoyl group having 1 to 4 carbon atoms [20] or the triazole derivative according to [21], which represents an alkyl group, or a pharmaceutically acceptable salt thereof. [26] R ⁷ represents an optionally substituted alkyl group having 1 to 4 carbon atoms, and the substituent is a hydroxyl group, a cyano group,
Carboxy group, alkoxy group, haloalkoxy group, alkylcarbonyl group, alkylcarbonyloxy group, alkoxycarbonyl group, optionally substituted aryl group, optionally substituted aromatic heterocyclic group, optionally substituted The triazole derivative according to [20] or [21], which is an amino group, a carbamoyl group which may be substituted, or a sulfamoyl group which may be substituted, or a pharmaceutically acceptable salt thereof. [27] [1] to [1], wherein R ⁷ , R ¹⁸ , R ¹⁹ or R ²⁰ represents an alkyl group which may be substituted.
8] The triazole derivative according to the above, or a pharmaceutically acceptable salt thereof. [28] R ⁷ , R ¹⁸ , R ¹⁹ or R ²⁰ represents a substituted alkyl group, and the substituent is a hydroxyl group, a cyano group, a carboxy group, an alkoxy group, a haloalkoxy group,
Alkylcarbonyl group, alkylcarbonyloxy group,
An alkoxycarbonyl group, an optionally substituted aryl group, an optionally substituted aromatic heterocyclic group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted sulfamoyl The triazole derivative according to [1] to [18], or a pharmaceutically acceptable salt thereof.

[29] Equation (5): (In the formula, Y ³ represents a hydrogen atom or a halogen atom. R ¹¹ represents a hydrogen atom or a methyl group. R ¹⁰
Represents a hydrogen atom, or a hydroxyl group, a cyano group, a carboxy group, an alkoxy group, a haloalkoxy group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkoxycarbonyl group, an optionally substituted aryl group, Represents an aromatic heterocyclic group which may be substituted, an amino group which may be substituted, a carbamoyl group which may be substituted, or an alkyl group having 1 to 4 carbon atoms which may be substituted by an optionally substituted sulfamoyl group; . L has the same meaning as described above. Or a pharmaceutically acceptable salt thereof.

[30] Equation (9): (Wherein, Y ³ , R ¹¹ and L have the same meanings as described above.)
R ¹² represents a hydrogen atom, or a hydroxyl group, a cyano group,
Carboxy group, alkoxy group, haloalkoxy group, alkylcarbonyl group, alkylcarbonyloxy group, alkoxycarbonyl group, optionally substituted aryl group, optionally substituted aromatic heterocyclic group, optionally substituted Represents an alkyl group having 1 to 4 carbon atoms which may be substituted with an amino group, an optionally substituted carbamoyl group, or an optionally substituted sulfamoyl group. )
Or a pharmaceutically acceptable salt thereof. [31] Equation (11): (Wherein, Y ³ , R ¹¹ , and L have the same meanings as described above. R ¹³ represents a hydrogen atom, or represents a hydroxyl group, a cyano group, a carboxy group, an alkoxy group, a haloalkoxy group, an alkylcarbonyl group, or an alkyl group. Carbonyloxy group, alkoxycarbonyl group, aryl group which may be substituted, aromatic heterocyclic group which may be substituted, amino group which may be substituted, carbamoyl group which may be substituted, Represents an alkyl group having 1 to 4 carbon atoms which may be substituted with a sulfamoyl group which may be substituted, L is the same as defined above, or a pharmaceutically acceptable salt thereof.

[32] L is a formula: Wherein R ⁴² and R ⁴³ are independently a hydrogen atom,
Hydroxyl group, nitro group, cyano group, -R ²⁹ , -OR ²⁹ ,
-COR ²⁹ , -COOR ²⁹ , -SOR ²⁹ , -SO
₂ R ²⁹ (R ²⁹ is as defined above), an optionally substituted amino group, an optionally substituted hydroxyamino group, an optionally substituted carbamoyl group, or an optionally substituted carbamoyl group Represents a good sulfamoyl group. Alternatively, R ⁴² and R ⁴³ may combine to form an optionally substituted 4- or 7-membered aliphatic heterocyclic ring. X ¹ represents —CH ₂ —, —O—, —S—, —SO—,
Or -SO ₂ - represents a. R ⁴⁴ is an optionally substituted alkyl group, an optionally substituted alkoxy group,
An optionally substituted alkylcarbonyl group, an optionally substituted alkylcarbonyloxy group, an optionally substituted alkoxycarbonyl group, an optionally substituted alkylsulfonyl group, an optionally substituted amino group, Represents a carboxy group, an oxo group, or a hydroxyl group.
q represents an integer of 0 to 4. ] The triazole derivative according to [1] to [31], and a pharmaceutically acceptable salt thereof.

[33] L is a formula: [Wherein R ⁴² , R ⁴³ , R ⁴⁴ or q has the same meaning as described above. R ⁴¹ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 4 carbon atoms, an optionally substituted alkylcarbonyl group having 2 to 5 carbon atoms, an optionally substituted alkoxy group having 2 to 5 carbon atoms Represents a carbonyl group or an optionally substituted alkylsulfonyl group having 1 to 5 carbon atoms. ] The triazole derivative according to [1] to [31], or a pharmaceutically acceptable salt thereof.

[34] L is a formula: [Wherein q, R ⁴² , R ⁴³ or R ⁴⁴ are as defined above. X ² represents a single bond or —CH ₂ —. ] The triazole derivative according to [1] to [31], or a pharmaceutically acceptable salt thereof. [35] L is a formula: (Wherein R ⁴² , R ⁴³ , R ⁴⁴ , and q have the same meanings as described above, and n represents an integer of 2 to 5.) The triazole derivative according to any one of [1] to [31], Or a pharmaceutically acceptable salt thereof.

[36] R ⁴² is a hydrogen atom or -R
²⁹ , R ⁴³ is a hydrogen atom, -R ²⁹ , -COR
²⁹ , —COOR ²⁹ , or —SO ₂ R ²⁹ (R ²⁹
Is as defined above. ), [32] to [3]
5] The triazole derivative according to the above or a pharmaceutically acceptable salt thereof. [37] R ⁴² represents a hydrogen atom or an alkyl group, and R ⁴³ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkylcarbonyl group, or an optionally substituted alkylsulfonyl. The triazole derivative according to [32] to [35], which represents a group, or a pharmaceutically acceptable salt thereof.

[38] L is a formula: (Wherein, R ⁴² , R ⁴³ , R ⁴⁴ , n and q have the same meanings as described above), or the pharmaceutically acceptable salt thereof according to [1] to [31]. [39] The triazole derivative or the pharmaceutically acceptable salt thereof according to [38], wherein R ⁴² and R ⁴³ independently represent a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbon atoms. .

[40] L is a formula: (In the formula, R ⁴⁵ independently represents a hydrogen atom or an optionally substituted alkyl group. R ⁴² , R ⁴⁴ , n
And q are as defined above. ) The triazole derivative according to [1] to [31], or a pharmaceutically acceptable salt thereof. [41] R ⁴² represents a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbon atoms, and R ⁴⁵ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
[40] The triazole derivative according to the above or a pharmaceutically acceptable salt thereof.

[42] L is a formula: (Wherein, R ⁴² , R ⁴⁴ , n and q have the same meanings as described above), or the pharmaceutically acceptable salt thereof according to [1] to [31]. [43] The triazole derivative or the pharmaceutically acceptable salt thereof according to [42], wherein R ⁴² represents a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbon atoms.

[44] L is a formula: Or the formula: [Wherein, R ⁴⁶ , R ⁴⁷ and R ⁴⁸ independently represent a hydrogen atom or -R ²⁹ (R ²⁹ has the same meaning as described above), and R ⁴⁹ represents a hydrogen atom, a hydroxyl group, a nitro group, Group, cyano group, -R ²⁹ , -OR ²⁹ , -COR ²⁹ ,
—COOR ²⁹ , —SOR ²⁹ , or —SO ₂ R ²⁹
(R ²⁹ has the same meaning as described above.) ] The triazole derivative according to [1] to [31], or a pharmaceutically acceptable salt thereof. [45] R ⁴⁶ , R ⁴⁷ , R ⁴⁸ and R ⁴⁹ are
The triazole derivative according to [44], which represents a hydrogen atom, or a pharmaceutically acceptable salt thereof.

[46] R ⁴⁶ , R ⁴⁷ , and R ⁴⁸
Independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R ⁴⁹ represents —R ²⁹ (where R ²⁹ has the same meaning as described above). Or a pharmaceutically acceptable salt thereof. [47] R ⁴⁶ , R ⁴⁷ and R ⁴⁸ are independently:
Represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,
R ⁴⁹ represents a hydroxyl group, a nitro group, a cyano group, —OR ²⁹ ,
-COR ^{29, -COOR 29,} -SOR ²⁹ or _-SO 2 ^{R 29, (R} 29 has the same meaning as defined above.) Represents a, [44] triazole derivative or a pharmaceutically acceptable salt thereof. [48] R ⁴⁶ and R ⁴⁷ independently represent a hydrogen atom or the same or different —R ²⁹ , and R ⁴⁸ and R ⁴⁹ independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. Or the pharmaceutically acceptable salt thereof. ^{[49] R 46} and ^{R 48} are, independently, represents a hydrogen atom or an alkyl group having a carbon number of 1, ^{3, R 47}
And the triazole derivative or the pharmaceutically acceptable salt thereof according to [44], wherein R ⁴⁹ and R ⁴⁹ independently represent -R ²⁹ (R ²⁹ has the same meaning as described above). [50] R ⁴⁶ and R ⁴⁸ independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R ⁴⁷
Is a hydroxyl group, a nitro group, a cyano group, -OR ²⁹ , -COR
²⁹ , -COOR ²⁹ , -SOR ²⁹ , or -SO ₂
R ²⁹ (R ²⁹ has the same meaning as described above);
The triazole derivative or the pharmaceutically acceptable salt thereof according to [44], wherein ⁴⁹ represents -R ²⁹ (R ²⁹ has the same meaning as described above). [51] R ⁴⁶ and R ⁴⁷ independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R ⁴⁸
But a hydroxyl group, a nitro group, a cyano ^group, -OR 29, -COR
²⁹ , -COOR ²⁹ , -SOR ²⁹ , or -SO ₂
R ²⁹ (R ²⁹ has the same meaning as described above);
The triazole derivative or the pharmaceutically acceptable salt thereof according to [44], wherein ⁴⁹ represents -R ²⁹ (R ²⁹ has the same meaning as described above).

[52] L is a formula: ^{Wherein, R 50,} and ^{R 51} are, independently, ^{hydrogen, -R 29, -COR 2 9,} -COOR 29, -SO
R ^{29 represents} —SO ₂ R ²⁹ (R ²⁹ has the same meaning as described above). ] The triazole derivative according to [1] to [31], or a pharmaceutically acceptable salt thereof. [53] R ⁵⁰ or R ⁵¹ is independently a hydrogen atom or —R ²⁹ (R ²⁹ has the same meaning as described above.)
Or the pharmaceutically acceptable salt thereof. [54] R ⁵⁰ is a hydrogen atom, or -R ²⁹ (R
²⁹ has the same meaning as described above. ) Wherein R ⁵¹ is -C
OR ²⁹ , -COOR ²⁹ , -SOR ²⁹ , or -S
O ₂ R ²⁹ (R ²⁹ has the same meaning as described above),
[52] The triazole derivative or a pharmaceutically acceptable salt thereof according to [52].

[55] L is a formula:[Where X³Is a single bond, -CH₂-,-(CH₂)₂
-, -OCH₂-, -SCH₂-,-(SO) CH
₂−, − (SO₂) CH₂-Or -NR⁴¹CH ₂
− (R⁴¹Is as defined above. ). R⁴⁴,
And q are as defined above. ] From [1]
[31] The triazole derivative according to the above or a pharmaceutically acceptable product thereof
Salt to be carried. [56] L is a formula:中 where R¹⁴And R^FifteenAre each independently a hydrogen source
May be substituted with a hydroxyl group or an oxo group
Represents an alkyl group having 1 to 4 carbon atoms. Represented by｝
The triazole derivative or the triazole derivative according to [1] to [31].
Pharmaceutically acceptable salts of

[57] A medicament comprising the triazole derivative according to any one of [1] to [56] or a pharmaceutically acceptable salt thereof. [58] A therapeutic or prophylactic agent for an autoimmune disease, comprising the triazole derivative according to any one of [1] to [56] or a pharmaceutically acceptable salt thereof. [59] A therapeutic or prophylactic agent for an inflammatory disease, comprising the triazole derivative according to any one of [1] to [56] or a pharmaceutically acceptable salt thereof. [60] An antirheumatic drug comprising the triazole derivative according to any one of [1] to [56] or a pharmaceutically acceptable salt thereof.

Although the names of the substituents and the like used in the present specification can be easily understood by those skilled in the art, the description of the above general formula and the definitions included in the scope of the present invention and their preferable Examples are described in detail below. The halogen atom is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. Examples of the aryl group include an aryl group having 6 to 14 carbon atoms, and specific examples include phenyl, 1-naphthyl, 2-naphthyl, azulenyl, phenanthryl, and anthryl. Preferably, phenyl, 1-naphthyl,
2-naphthyl is mentioned. More preferably, it is phenyl. Heterocyclic groups are classified into aromatic heterocyclic groups and aliphatic heterocyclic groups. Examples of the aromatic heterocyclic group include 1 to 3 5- to 14-membered aromatic heterocyclic ring composed of 1 to 4 nitrogen atoms, 0 to 1 oxygen atom, 0 to 1 sulfur atom, and carbon atom. A monovalent group. Specifically, furyl, thienyl, benzothienyl, isobenzofuranyl,
Pyrrolyl, benzofuryl, imidazolyl, pyrazolyl,
Examples include isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and carbazolyl.

As the aliphatic heterocyclic ring, 4 to 8 containing at least one heteroatom selected from 0 to 3 nitrogen atoms, 0 to 1 oxygen atom, or 0 to 1 sulfur atom.
Membered heterocyclic ring, which may contain a double bond. As the aliphatic heterocyclic ring, for example, azetidine, pyrrolidine, piperazine, piperidine, morpholine, thiomorpholine, 1-oxothiomorpholine, 1,1-dioxothiomorpholine, imidazolidine, 4,5-dihydro-1H-imidazole, thiazolidine, Hexahydropyrimidine, 1,4,5,6-tetrahydropyrimidine,
3,6-dihydro-2H-1,3,5-oxadiazine, 4,5,6,7-tetrahydro-1H- [1,3]
Diazepine, perhydro- [1,3] -diazepine,
Perhydro- [1,3] -diazocine, 1,4,5
6,7,8-hexahydro- [1,3] -diazocine,
Tetrahydrofuran and the like.

Examples of the substituent in the aryl group, the aromatic heterocyclic group, and the aliphatic heterocyclic ring include, for example, any group included in the following groups a) to c). A plurality may be replaced. a): halogen atom, cyano group, nitro group, hydroxyl group,
Mercapto group, carboxy group, oxo group, formyl group,
A sulfo group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted carbamoyloxy group, and an optionally substituted sulfamoyl group. b): a cycloalkyl group, a cycloalkyloxy group,
Cycloalkyloxycarbonyl group, cycloalkylcarbonyl group, cycloalkylcarbonyloxy group, alkenyl group, alkenyloxy group, alkenyloxycarbonyl group, alkenylcarbonyl group, alkenylcarbonyloxy group, alkynyl group, alkynyloxy group, alkynyloxycarbonyl group, Alkynylcarbonyl group, alkynylcarbonyloxy group; [Each group in this group includes a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted sulfamoyl group, an alkyl group, a haloalkyl Group, alkoxy group,
It may be substituted with 1 to 3 groups selected from a haloalkoxy group, an alkylsulfonyl group, an alkylcarbonyl group, an alkylcarbonyloxy group, and an alkoxycarbonyl group. C): alkyl group, alkoxy group, alkoxycarbonyl group, alkylthio group, alkylcarbonyl group, alkylcarbonyloxy group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group, alkylsulfonyloxy group. [Each group in this group is a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted sulfamoyl group, an alkoxy group, or It may be substituted with 1 to 3 groups selected from a haloalkoxy group, an alkoxycarbonyl group, an alkylcarbonyl group and an alkylcarbonyloxy group. ]

Examples of the alkyl group include a straight-chain or branched alkyl group having 1 to 10 carbon atoms. Specifically, methyl, ethyl, propyl, 1-methylethyl,
Butyl, 1-methylpropyl, 2-methyl-1-propyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-methylbutyl, 3-methylbutyl, hexyl, 2- Examples thereof include methylpentyl, 3,3-dimethylbutyl, heptyl, 1-ethylpentyl, 5-methylhexyl, octyl, 1,5-dimethylhexyl, 2-ethylhexyl, nonyl, and decyl. Preferably, a linear or branched alkyl group having 1 to 6 carbon atoms is used.

Examples of the substituent in the optionally substituted alkyl group include, for example, any of the following groups a) to d), which may be arbitrarily substituted one or more times. . a): a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, an optionally substituted amino group, an optionally substituted hydroxylamino group,
Optionally substituted alkoxyamino group, hydroxyl group, carboxy group, optionally substituted carbamoyl group, optionally substituted carbamoyloxy group, optionally substituted sulfamoyl group b): cycloalkyl group, cycloalkyl Alkyloxy group,
Cycloalkylcarbonyl group, cycloalkylcarbonyloxy group, cycloalkyloxycarbonyl group, cycloalkenyl group, cycloalkenyloxy group, cycloalkenylcarbonyl group, cycloalkenylcarbonyloxy group, cycloalkenyloxycarbonyl group [each group in this group is For example, a halogen atom, a nitro group, a cyano group,
Mercapto group, oxo group, thioxo group, alkyl group, haloalkyl group, optionally substituted amino group, hydroxyl group, alkoxy group, haloalkoxy group, alkylcarbonyl group, alkylcarbonyloxy group, alkoxycarbonyl group, alkylsulfonyl group, It may be substituted with one or more groups arbitrarily selected from the group of an alkylthio group, a carboxy group, an optionally substituted carbamoyl group and an optionally substituted sulfamoyl group. ]

C): alkoxy group, alkoxycarbo
Nyl group, alkoxy (thiocarbonyl) group, alkylthio
O group, (alkylthio) thiocarbonyl group, (alkyl
Thio) carbonyl group, alkylcarbonyl group, alkyl
Thioyl group, alkylsulfinyl group, alkylsulfo
Nyl group, alkylcarbonyloxy group, alkylthioyl
Group, alkylsulfonyloxy group [each of this group
Examples of the group include a halogen atom, a nitro group, a cyano group,
Capto group, oxo group, thioxo group, may be substituted
Amino group, hydroxyl group, alkylcarbonyl group, alkyl
Carbonyloxy group, carboxy group, even if substituted
Good carbamoyl group, carbamoy which may be substituted
Ruoxy group, a sulfamoyl group which may be substituted,
-R⁶¹, -OR⁶¹, -COR⁶¹, -OCO
R^{6 1}, -COOR⁶¹, -SR⁶¹, -OCH_TwoR
⁶¹, -SCH_TwoR⁶¹(Where R⁶¹Is a phenyl group
Or a monocyclic heterocyclic group. Phenyl or monocyclic
The heterocyclic group includes, for example, a halogen atom, an alkyl group,
Alkyl, cyano, nitro, azide, hydroxyl,
Alkoxy group, haloalkoxy group, may be substituted
Amino group, carbamoyl group which may be substituted,
Boxoxy group, alkylcarbonyl group, alkoxycarbonyl
Group, alkylcarbonyloxy group, alkylthio group,
Alkylsulfinyl and alkylsulfonyl groups
Substituted with one or more groups arbitrarily selected from the group of
It may be. ), Cycloalkyl group (cycloalkyl group)
Is, for example, a halogen atom, an alkyl group, a haloalkyl
Group, amino group which may be substituted, hydroxyl group, alkoxy
Arbitrarily selected from a group such as a silyl group and a haloalkoxy group
It may be substituted with one or more groups. ), Arco
Xy, alkoxycarbonyl and alkylthio groups
(Alkoxy group, alkoxycarbonyl group and alkyl
A luthio group is, for example, a halogen atom, a cycloalkyl group,
Monocyclic heterocyclic group, phenyl group, cyano group, nitro group, water
Acid groups, alkoxy groups, haloalkoxy groups, substituted
Amino group, carbamoyl which may be substituted
Group, carboxy group, alkylcarbonyl group, alkoxy
Carbonyl group, alkylcarbonyloxy group, alkyl
Thio, alkylsulfinyl and alkylsulfo
With one or more groups arbitrarily selected from the group of
It may be replaced. ))
Or may be substituted with a plurality of groups. D): -R⁶¹, -OR⁶¹, -SR⁶¹, -OC
H_TwoR⁶¹, -SCH_TwoR ⁶¹, -COR⁶¹, -COOR
⁶¹, -OCOR⁶¹, -SOR⁶¹, -SO_TwoR⁶¹,(formula
Medium, R⁶¹Is as defined above. )

Preferred substituents of the alkyl group which may be substituted include, for example, any of the following groups a ′) to c ′), which are optionally substituted by one or more substituents. You may. a ′): a halogen atom, a cyano group, a hydroxyl group, a carboxy group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted carbamoyloxy group, an optionally substituted sulfamoyl Base. Optionally substituted aryl group, optionally substituted aromatic heterocyclic group, optionally substituted aliphatic heterocyclic group, b '): cycloalkyl group, cycloalkyloxy group, cycloalkyloxycarbonyl Group, cycloalkylcarbonyl group, cycloalkylcarbonyloxy group.
[Each group in this group may be substituted with 1 to 3 groups selected from a halogen atom, a hydroxyl group, or a carboxy group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, and an alkoxycarbonyl group. C '): an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, an alkylthio group, an alkylcarbonyl group, an alkylcarbonyloxy group, and an alkylsulfonyl group. [Each group in this group may be substituted with one to three groups selected from a halogen atom, a hydroxyl group, a carboxy group, an alkoxy group, a haloalkoxy group, and an alkoxycarbonyl group. ]

The haloalkyl group represents an alkyl group substituted with 1 to 5 halogen atoms. Preferably, it represents an alkyl group substituted with 1 to 3 halogen atoms.
Specifically, trifluoromethyl, 2,2,2-trifluoroethyl, 2-chloroethyl and the like can be mentioned. The alkoxy group represents an oxy group to which an alkyl group is bonded. Specifically, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, 2-butoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 2-pentoxy, 3-pentoxy, 2-methylbutoxy, 1, 1
-Dimethylpropoxy, 1,2-dimethylpropoxy,
3-methylbutoxy, hexoxy, 2-hexoxy, 3
-Hexoxy, 2-methylpentoxy, 3,3-dimethylbutoxy and the like. Examples of the substituent in the substituted alkoxy group include the same substituents as those in the substituted alkyl group. An alkoxycarbonyl group represents a carbonyl group to which an alkoxy group is bonded. Specifically, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl, butoxycarbonyl, 2-butoxycarbonyl, 1,1-dimethylethoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl 3,3-dimethylbutoxycarbonyl And the like. Examples of the substituent in the substituted alkoxycarbonyl group include the same substituents as those in the substituted alkyl group. A haloalkoxy group represents an alkoxy group substituted with 1 to 5 halogen atoms. Preferably,
Represents an alkoxy group substituted with 1 to 3 halogen atoms. Specifically, trifluoromethoxy, 2,2,2
-Trifluoroethoxy, 2-chloroethoxy and the like.

The alkylcarbonyl group represents a carbonyl group to which an alkyl group is bonded. Specific examples include acetyl, propanoyl, 2-propanoyl, butanoyl, 2-butanoyl, pentanoyl, pivaloyl, hexanoyl and the like. Examples of the substituent in the substituted alkylcarbonyl group include the same substituents as those in the substituted alkyl group. The alkylsulfonyl group represents a sulfonyl group to which an alkyl group is bonded. Specific examples include methanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl, 2-propanesulfonyl and the like. Examples of the substituent in the substituted alkylsulfonyl group include the same substituents as those in the substituted alkyl group. Incidentally, an alkylthio group, an alkylcarbonyloxy group, an alkylsulfinyl group, an (alkylthio) thiocarbonyl group, an (alkylthio) carbonyl group, an alkylcarbonyl group, an alkylthioyl group, an alkylsulfinyl group, an alkylcarbonyloxy group, an alkylthioyloxy group, The alkyl in the sulfonyloxy group is the same as the above-mentioned alkyl group. Further, alkoxy in the alkoxy (thiocarbonyl) group is
Represents the same as the above alkyl group.

Examples of the alkenyl group include linear or branched alkenyl groups having 1 to 3 double bonds and having 2 to 10 carbon atoms. Specifically, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-
Butenyl, 2-butenyl, 3-butenyl, 2-methyl-
2-propenyl, 1-pentenyl, 2-pentenyl, 4
-Pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 1-heptenyl, 2-heptenyl, 1-octenyl, 2-octenyl, 1,3-octadienyl, 2-nonenyl, 1,3-nonadienyl , 2-
Decenyl and the like. Preferred alkenyl groups include alkenyl groups having 2 to 6 carbon atoms. For example, an ethenyl, 1-propenyl, 1-butenyl group is mentioned. Examples of the substituent of the substituted alkenyl group include a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, an amino group which may be substituted, a hydroxyl group, an alkoxy group, a haloalkoxy group, an alkylcarbonyl group, and an alkoxycarbonyl group. Group, alkylcarbonyloxy group, alkylthio group, carboxy group, carbamoyl group which may be substituted,-
R ⁶¹ , —OR ⁶¹ , —SR ⁶¹ , —OCH ₂ R ⁶¹ ,
-SCH ₂ R ⁶¹ , -COR ⁶¹ , -COOR ⁶¹ ,-
OCOR ⁶¹ , -SOR ⁶¹ , -SO ₂ R ⁶¹ (wherein,
R ⁶¹ has the same meaning as described above. ) And the like. Also,
An alkenyloxy group refers to an oxy group to which an alkenyl group is bonded.

Examples of the alkynyl group include a linear or branched alkynyl group having 2 to 10 carbon atoms having 1 to 3 triple bonds. Specifically, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,
3-butynyl, 1-pentynyl, 2-pentynyl, 4-
Pentynyl, 1-octynyl, 6-methyl-1-heptynyl, 2-decynyl and the like. Preferred alkynyl groups include alkynyl groups having 2 to 6 carbon atoms. For example, examples of the alkynyl group include 1-propynyl and 1-butynyl. Examples of the substituent of the substituted alkynyl group include a halogen atom, a nitro group,
Cyano group, mercapto group, oxo group, thioxo group, optionally substituted amino group, hydroxyl group, alkoxy group, haloalkoxy group, alkylthio group, carboxy group, optionally substituted carbamoyl group, alkylcarbonyl group, alkoxycarbonyl group, alkyl Carbonyloxy group, -R
⁶¹ , -OR ⁶¹ , -SR ⁶¹ , -OCH ₂ R ⁶¹ ,-
SCH ₂ R ⁶¹ , -COR ⁶¹ , -COOR ⁶¹ , -O
COR ⁶¹ , -SOR ⁶¹ , -SO ₂ R ⁶¹ (wherein, R
⁶¹ has the same meaning as described above. ) And the like. Further, an alkynyloxy group refers to an oxy group to which an alkynyl group is bonded.

The hydrocarbon ring is, for example, a saturated hydrocarbon ring having 3 to 6 carbon atoms, such as a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring. Examples of the cycloalkyl group include a cycloalkyl group having 3 to 6 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Further, the cycloalkyloxy group represents an oxy group to which a cycloalkyl group is bonded, and the cycloalkyloxycarbonyl group represents a carbonyl group to which a cycloalkyloxy group is bonded.

The cycloalkenyl group includes, for example, those having 3 to 10 carbon atoms, and the preferred cycloalkenyl groups include cycloalkenyl groups having 3 to 6 carbon atoms. Specific examples include cyclopentenyl, cyclohexenyl and the like. Further, a cycloalkenyloxy group refers to an oxy group to which a cycloalkenyl group is bonded.
Examples of the substituent of the substituted cycloalkyl group and the substituted cycloalkenyl group include, for example, a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, an alkyl group, a haloalkyl group, an optionally substituted amino group,
Examples include a hydroxyl group, an alkoxy group, a haloalkoxy group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkoxycarbonyl group, an alkylthio group, a carboxy group, an optionally substituted carbamoyl group, and an optionally substituted sulfamoyl group.

Position at the optionally substituted amino group
Examples of the substituent include the following a) to c),
The same or different ones may be substituted independently.
No. a) alkyl group, alkylcarbonyl group, alkylsulfur
Honyl group, alkoxycarbonyl group. [Each group of this group
Represents a halogen atom, a cyano group, a hydroxyl group, a formyl group,
A amino group (an amino group is one or two alkyl groups,
Killcarbonyl group, alkoxycarbonyl group, alkyl
It may be substituted with a sulfonyl group. ), Alkoxy
Group, haloalkoxy group, cycloalkyl group, aliphatic hetero
May be substituted with 1 to 3 groups selected from ring groups and the like.
No. B) -R⁶², -COR⁶², -COOR⁶², -SO
R⁶², -SO_TwoR⁶² (Where R⁶²Is a phenyl group
Or a monocyclic heterocyclic group. Phenyl or monocyclic
The heterocyclic group includes, for example, a halogen atom, an alkyl group,
Alkyl group, cyano group, nitro group, hydroxyl group, alkoxy
Group, haloalkoxy group, amino group (the amino group
Is two alkyl groups, alkylcarbonyl groups, alkoxy
Substituted with a cyclocarbonyl group or an alkylsulfonyl group
You may. ), Carbamoyl group (one carbamoyl group
Or may be substituted with two alkyl groups. ),
Rufamoyl group (sulfamoyl group is one or two
It may be substituted with a alkyl group. ), Carboxy group,
Alkylcarbonyl group, alkylcarbonyloxy group,
Alkoxycarbonyl group, alkylthio group, alkyls
Selected from the group of rufinyl group and alkylsulfonyl group
May be substituted with one or more selected groups
No. C) amidino, formyl, carbamoyl; concrete
Acetamide, propiona
Amide, butylamide, 2-butylamide, methylamido
No, 2-methyl-1-propylamino, 2-hydroxy
Ethylamino, 2-aminoethylamino, dimethylami
No, diethylamino, methyl carbamate, ureido,
Methanesulfonylamino, guanidino and the like can be mentioned.
A carbamoyloxy group is an oxo group to which a carbamoyl group is bonded.
It is a group. An optionally substituted carbamoyl group,
Or an optionally substituted carbamoyloxy group
Alkyl group, alkylcarbonyl
Group, or alkylsulfonyl group, (a group of this group is
Halogen atom, hydroxyl group, alkoxy group, haloalkoxy
Group, carboxyl group or alkoxycarbonyl group
It may be. ) Are the same or different
Numbers may be independently substituted. Also, Carbamoy
Or two carbamoyloxy groups are bonded.
Together may form a 4- to 7-membered aliphatic heterocyclic ring
No. Specifically, azetidine ring, piperidine ring, pipera
Gin ring, pyrrolidine ring, morpholine ring, thiomorpholine
Ring, 1-oxothiomorpholine ring, 1,1-dioxochi
An morpholine ring or the like may be formed. Has been replaced
The substituent of the sulfamoyl group which may be
Alkyl group, (alkyl group is halogen atom, hydroxyl group,
Alkoxy group, haloalkoxy group, carboxyl group,
It may be substituted with a carbonyl group. )
Are the same or different and are independently substituted
You may. Or, two substituents of the sulfamoyl group are
Bond to form a 4- to 7-membered aliphatic heterocycle,
Good. Specifically, azetidine ring, piperidine ring, pipet
Razine ring, pyrrolidine ring, morpholine ring, thiomorpholy
Ring, 1-oxothiomorpholine ring, 1,1-dioxo
It may form a thiomorpholine ring or the like. Substituted carba
Specific examples of the moyl group include ethylcarbamoyl and dicarbamoyl.
Methylcarbamoyl, diethylcarbamoyl, N-meta
Sulfonylcarbamoyl, morpholinocarbonyl,
Peridinocarbonyl, 1-piperazinylcarbonyl, 1
-Pyrrolidinylcarbonyl, 1-azetidinylcarboni
And the like. Substituted sulfamoyl groups include
Physically, ethylsulfamoyl, dimethylsulfamoy
, Diethylsulfamoyl, morpholinosulfonyl,
Piperidinosulfonyl, 1-piperazinylsulfonyl,
1-pyrrolidinylsulfonyl and the like.

Y ¹ , Y ² , R ²¹ , R ²² , R ²³ , R
The alkyl group for ²⁴ , R ²⁵ , R ²⁶ , and / or R ²⁷ is preferably alkyl having 1 to 6 carbons. Specific examples include methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, and 1,1-dimethylethyl. The haloalkyl group for R ²⁴ is preferably a haloalkyl group having 1 to 4 carbon atoms and substituted with 1 to 5 halogen atoms, and more preferably a haloalkyl group having 1 to 3 carbon atoms and substituted with 1 to 3 halogen atoms. 3 haloalkyl group. Specifically, trifluoromethyl, 2,2
2-trifluoroethyl, 2-chloroethyl and the like.

The alkyl group represented by R ⁸ and R ⁹ is preferably an alkyl group having 1 to 6 carbon atoms, and more preferably an alkyl group having 1 to 4 carbon atoms. Specifically, methyl, ethyl, propyl, 1-methylethyl,
Butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl and the like. The hydrocarbon ring formed by the combination of R ⁸ and R ⁹ is preferably
A hydrocarbon ring having 3 to 6 carbon atoms, specifically, cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

R ²⁸ , R ²⁹ , R ³⁰ , R ⁷ , R ⁴⁴ ,
And the alkyl group for R ⁴⁵ , R ²⁸ , R ²⁹ , R
³⁰ and the alkenyl group for R ⁷ and R
The alkynyl group in ²⁸ , R ²⁹ , R ³⁰ and R ⁷ is preferably an alkyl group, alkenyl group and alkynyl group having 1 to 6 carbon atoms, respectively. More preferred are an alkyl group, an alkenyl group and an alkynyl group having 1 to 4 carbon atoms. Specifically, methyl,
An alkyl group such as ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl, ethenyl, 1-propenyl, 2-propenyl, 3-propenyl, 1-methylethenyl , 1-butenyl, 2-butenyl, 3-butenyl, 4
Alkenyl groups such as -butenyl or 2-methyl-2-propenyl; and alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl.

The alkoxy group, alkylcarbonyl group, alkoxycarbonyl group, alkylcarbonyloxy group and alkylsulfonyl group represented by R ⁴⁴ are preferably an alkoxy group having 1 to 5 carbon atoms, an alkoxy group having 2 to 5 carbon atoms.
, An alkoxycarbonyl group having 2 to 5 carbon atoms, an alkylcarbonyloxy group having 2 to 5 carbon atoms, and an alkylsulfonyl group having 1 to 5 carbon atoms.

The cycloalkyl group for R ²⁸ and R ²⁹ is preferably a 3- to 6-membered cycloalkyl group, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. R
The aryl group at ²⁸ is preferably a phenyl group. The aromatic heterocyclic group for R ²⁸ is preferably 1-
A 5- or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from two nitrogen atoms, one oxygen atom and one sulfur atom, specifically, pyridyl, thienyl , Furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl and the like. The aliphatic heterocycle of the aliphatic heterocyclic group for R ²⁸ is preferably 5 or 5 containing 1 to 4 heteroatoms selected from 1-2 nitrogen atoms, 1 oxygen atom, and 1 sulfur atom. It is a 6-membered aliphatic heterocyclic ring, which is substituted on any carbon atom or nitrogen atom. Specific examples include pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine and the like.

The substituent of the optionally substituted carbamoyl group and the optionally substituted sulfamoyl group for R ⁷ is preferably an alkyl group having 1 to 4 carbon atoms, specifically, methyl, ethyl, Propyl, 1-methylethyl and the like. Here, the alkyl group may be substituted with a halogen atom, a hydroxyl group, an alkoxy group, a carboxyl group, or an alkoxycarbonyl group.

R²⁸, R²⁹, R³⁰And R⁷Smell
Alkyl, alkenyl, and alkynyl groups
When substituted, preferred substituents are from a) below
f). a) hydroxyl group, oxo group, carboxy group, cyano group, halo
Gen atom. b) an alkoxy group having 1 to 4 carbon atoms and 2 to 5 carbon atoms;
Alkoxycarbonyl group, alkyl group having 1 to 4 carbon atoms
Rubonyl group, alkylcarbonyloxy having 1 to 4 carbon atoms
A silyl group, an alkylsulfonyl group having 1 to 4 carbon atoms; [this
The groups of a group may be one or more, identical or different,
Is substituted with a group selected from a ') to d')
Is also good. a ') halogen atom, cyano group, hydroxyl group, carboxy
Group, an alkoxy group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms
Alkoxycarbonyl group, alkyl group having 1 to 4 carbon atoms
Rubonyl group, alkylcarbonyloxy having 1 to 4 carbon atoms
B ') amino group (amino group is an alkyl group having 1 to 4 carbon atoms)
Kill group, alkylcarbonyl group having 2 to 5 carbon atoms, charcoal
An alkylsulfonyl group having a prime number of 1 to 4, or carbon number
Substituted with 2 to 5 alkoxycarbonyl groups,
Is also good. ) C ') -CONR⁶³R⁶⁴ (R⁶³, And R⁶⁴
Is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or
Represents an alkylsulfonyl group having a prime number of 1 to 4. Also
Is R⁶³And R⁶⁴Combine to form a 4- to 7-membered aliphatic complex
It may form a ring. ) D ') -SO₂NR⁶⁵R⁶⁶ (R⁶⁵And R⁶⁶
Represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
I forgot. Or R⁶⁵And R⁶⁶Are combined, 4 to 7 members
May form an aliphatic heterocycle. ) Replaced by
It may be. C) an aliphatic heterocyclic group; (An aliphatic heterocyclic group is a hydroxyl group,
A oxo group, a halogen atom, an alkyl group having 1 to 4 carbon atoms,
A haloalkyl group having 1 to 4 carbon atoms;
Alkoxy group, alkylcarbonyl group having 1 to 4 carbon atoms,
An alkoxycarbonyl group having 1 to 4 carbon atoms, 1 carbon atom
An alkylcarbonyloxy group having 4 to 4 carbon atoms;
It may be substituted with an alkylsulfonyl group. D) amino group (an amino group is an alkyl having 1 to 4 carbon atoms)
Group, alkylcarbonyl group having 2 to 5 carbon atoms, carbon
An alkylsulfonyl group having 1 to 4 carbon atoms or 2 carbon atoms
Even if substituted with 5 alkoxycarbonyl groups
Good. E) -CONR⁶³R⁶⁴ (R⁶³, And R
⁶⁴Is as defined above. ) F) -SO₂NR⁶⁵R⁶⁶ (R⁶⁵, And R⁶⁶
Represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
I forgot. Or R⁶⁵And R⁶⁶Are combined, 4 to 6 members
May form an aliphatic heterocycle. )

Here, R ⁶³ and R ⁶⁴ , or R ⁶⁵
And the 4- to 7-membered aliphatic heterocyclic ring formed by R ⁶⁶ and R ⁶⁶ is preferably a 4- to 6-membered aliphatic heterocyclic ring, specifically, azetidine, piperidine, piperazine, pyrrolidine, morpholine, Thiomorpholine, 1-oxothiomorpholine, 1,1-dioxothiomorpholine, and the like.

When the aryl group, cycloalkyl group, aromatic heterocycle and / or aliphatic heterocycle in R ²⁸ is substituted, or when the cycloalkyl group in R ²⁹ is substituted, the substituent Is preferably a halogen atom, a hydroxyl group, a cyano group, an alkoxy group,
Haloalkoxy group, carboxy group, alkylcarbonyl group, alkoxycarbonyl group, alkylcarbonyloxy group, alkylsulfonyl group, optionally substituted amino group, optionally substituted carbamoyl group, optionally substituted carbamoyloxy Or a sulfamoyl group which may be substituted. R ² and R ³ , R
^The aliphatic heterocyclic ring formed by bonding ¹ and R ⁴ , R ⁴² and R ⁴³ , and R ⁵ and R ⁶ , respectively, is preferably 1-3 nitrogen atoms, 1 oxygen atom, 1 A 4- to 6-membered aliphatic heterocycle containing 1 to 4 heteroatoms selected from sulfur atoms, and when substituted, substituted on any carbon atom or nitrogen atom. In particular,
Examples include azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine. The aliphatic heterocycle includes a hydroxyl group, an oxo group, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, and an alkylcarbonyl group having 1 to 4 carbon atoms. An alkoxycarbonyl group having 1 to 4 carbon atoms, an alkylcarbonyloxy group having 1 to 4 carbon atoms,
Alternatively, it may be substituted by an alkylsulfonyl group having 1 to 4 carbon atoms. The aliphatic heterocyclic ring formed by the combination of R ² and R ¹ , R ² and R ⁴ , R ³ and R ¹ , R ³ and R ⁴ , and R ¹ and R ⁴ is preferably two nitrogen atoms. It is a 5- to 8-membered aliphatic heterocycle containing an atom, and may contain a double bond in some cases. Further, it may contain 0 to 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Specifically, imidazolidine, 1
H-4,5-dihydroimidazole, hexahydropyrimidine, 1,4,5,6-tetrahydropyrimidine and the like can be mentioned. When the aliphatic heterocyclic ring is substituted, it is substituted on any carbon atom or nitrogen atom. As a substituent, a hydroxyl group, an oxo group, a halogen atom,
An alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an alkylcarbonyl group having 1 to 4 carbon atoms, an alkoxycarbonyl group having 1 to 4 carbon atoms, 1 carbon atom To 4 alkylcarbonyloxy groups or an alkylsulfonyl group having 1 to 4 carbon atoms.

When R ⁴¹ is substituted, preferred substituents include the following a) to c). a) Halogen atom, hydroxyl group, carboxy group, cyano group. b) alkoxy group, alkylcarbonyl group, alkoxycarbonyl group, alkylcarbonyloxy group. [Each group in this group may be substituted with one or more halogen atoms, hydroxyl groups, carboxy groups, alkoxy groups, haloalkoxy groups, alkoxycarbonyl groups, and the like. C) an amino group, a carbamoyl group, a sulfamoyl group,
(Each group in this group may be substituted with one or more alkyl groups having 1 to 4 carbon atoms.)

R⁴⁴When is substituted, the substituent is
Preferably, any one of the following a ') to c')
Or one or more of the same or different
You may. a ') halogen atom, cyano group, hydroxyl group, carboxy
Group, an alkoxy group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms
Alkoxycarbonyl group, alkyl group having 1 to 4 carbon atoms
Rubonyl group, alkylcarbonyloxy having 1 to 4 carbon atoms
B ') amino group (amino group is an alkyl group having 1 to 4 carbon atoms)
Kill group, alkylcarbonyl group having 2 to 5 carbon atoms, charcoal
An alkylsulfonyl group having a prime number of 1 to 4, or carbon number
Substituted with 2 to 5 alkoxycarbonyl groups,
Is also good. ) C ') -SO₂NR⁶⁵R⁶⁶, -CONR⁶⁵R
⁶⁶ (R⁶⁵, And R⁶⁶Is as defined above. )

When R ⁴⁴ represents an amino group which may be substituted, the substituent of the amino group may have 1 to 4 carbon atoms.
And an alkylcarbonyl group having 2 to 5 carbon atoms, an alkylsulfonyl group having 1 to 4 carbon atoms, or an alkoxycarbonyl group having 2 to 5 carbon atoms. A carbamoyl group wherein R ⁴⁴ is optionally substituted;
Alternatively, when representing a sulfamoyl group which may be substituted, a preferred substituent is an alkyl group having 1 to 4 carbon atoms.

R⁴⁵Preferred substitution of the alkyl group in
Examples of the group include the following a) to c). a) halogen atom, cyano group, hydroxyl group, carboxy group,
An alkoxy group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms
Coxycarbonyl group, alkyl carboxy having 1 to 4 carbon atoms
B) an amino group (an amino group is an alkyl group having 1 to 4 carbon atoms)
Group, alkylcarbonyl group having 2 to 5 carbon atoms, carbon
An alkylsulfonyl group having 1 to 4 carbon atoms or 2 carbon atoms
Even if substituted with 5 alkoxycarbonyl groups
Good. ) C) -SO₂NR⁶⁵R⁶⁶, -CONR⁶⁵R⁶⁶
(R⁶⁵, And R⁶⁶Is as defined above. )

Q preferably represents an integer of 0 to 2. n
Preferably represents 2 or 3.

The present invention includes all stereoisomers, optically active forms and tautomers of the claimed triazole derivative. The present invention also includes solvates such as hydrates of the triazole derivative or a pharmaceutically acceptable salt thereof described in the claims, and crystal forms of all aspects. Pharmaceutically acceptable salts of the triazole derivatives of the present invention include acid addition salts and base addition salts. Examples of the acid addition salt include inorganic salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate and phosphate, citrate, oxalate, acetate, formate, Organic acids such as propionate, benzoate, trifluoroacetate, fumarate, maleate, tartrate, aspartate, glutamate, methanesulfonate, benzenesulfonate, camphor-sulfonate, etc. Salts. As base addition salts, sodium salts,
Inorganic base salts such as potassium salt, calcium salt, magnesium salt and ammonium salt; and organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt and diisopropylammonium salt. When the triazole derivative of the present invention has one or more asymmetric points, it can be produced by using a raw material having the asymmetric point or by introducing it at an intermediate reaction step according to a usual method. it can. For example, in the case of an optical isomer, it can be obtained by using an optically active raw material or performing optical resolution or the like at an appropriate stage of the production process. As the optical resolution method, the triazole derivative of the present invention or an intermediate thereof is dissolved in an inert solvent (for example, an alcohol solvent such as methanol, ethanol, or 2-propanol, an ether solvent such as diethyl ether, or an ester solvent such as ethyl acetate). , Aromatic hydrocarbon solvents such as toluene, acetonitrile and the like and mixed solvents thereof), optically active acids (for example, mandelic acid, N-benzyloxyalanine,
Salts may be formed with monocarboxylic acids such as lactic acid, dicarboxylic acids such as tartaric acid, o-diisopropylidene tartaric acid, malic acid, and sulfonic acids such as camphorsulfonic acid and bromocamphorsulfonic acid.
When the triazole derivative of the present invention or an intermediate thereof has an acidic substituent such as a carboxyl group, a salt is formed with an optically active amine (for example, an organic amine such as α-phenethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine). It can also be done.

The temperature at which the salt is formed is in the range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. Before the precipitated salt is collected by filtration, the salt can be cooled, if necessary, to improve the yield. The amount of the optically active acid or amine used is about 0.5 to about 2.0 with respect to the substrate.
A range of equivalents, preferably a range of about 1 equivalent is appropriate. If necessary, the crystals are placed in an inert solvent (for example, alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as toluene, etc. Recrystallization with acetonitrile or the like and a mixed solvent thereof) to obtain a high-purity optically active salt. If necessary, the obtained salt can be treated with an acid or base by a usual method to obtain a free form.

The triazole derivative of the present invention is, for example,
It can be manufactured by the following method. [1] Method for producing compound represented by formula 1-3 [Wherein, R ¹¹² and R ¹¹³ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, -R ²⁹ , -OR
^{29, -COR 29, -COOR 29,} -SOR 2 9,
—SO ₂ R ²⁹ (R ²⁹ is as defined above), an optionally substituted amino group, an optionally substituted hydroxyamino group, an optionally substituted carbamoyl group, and an optionally substituted carbamoyl group. A sulfamoyl group, or N
Represents a protecting group for the H group. R ¹¹² and R ¹¹³ may be taken together with a nitrogen atom to form an optionally substituted aliphatic heterocycle. Ax is of the formula: (In the formula, Y ¹ , Y ² , M, R ⁷ , R ⁸ , or R ⁹ are as defined above.) A compound represented by Formula 1-1 and a cyanamide derivative (Formula 1-2)
With an inert solvent or in the absence of a solvent at a reaction temperature of 15 to 130 ° C. in the presence of a base or acid to obtain a compound of the formula 1
The compound of the present invention represented by -3 can be produced. The amount of the cyanamide derivative used is, for example, in the range of 1 to 20 equivalents relative to the compound of the formula 1-1, preferably
1.0 to 1.2 equivalents are included. As the base, for example, lithium hydride, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, lithium amide, sodium amide, potassium amide, butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, butyl Magnesium chloride, sec-butylmagnesium chloride, tert-butylmagnesium chloride, sodium methoxide, potassium methoxide,
Magnesium methoxide, sodium ethoxide, potassium ethoxide, magnesium ethoxide, lithium te
rt-butoxide, sodium tert-butoxide, potassium
tert-butoxide and the like, preferably lithium hydride, sodium hydride, potassium carbonate, lithium amide, sodium amide, lithium tert-butoxide, potassium tert-butoxide and the like. When an alkoxide is used as a base, the alkoxide can be prepared by allowing an appropriate base to act on an alcohol such as tert-butanol in the reaction system. In this case, the base to be acted on is preferably lithium hydride, sodium hydride, lithium amide, sodium amide, potassium amide or the like. When using amides such as lithium amide and sodium amide, the reaction temperature is preferably in the range of 50 to 80 ° C., nitrogen gas,
The reaction is preferably performed while introducing an inert gas such as an argon gas into the reaction solution. Examples of the acid include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, Lewis acid and the like, preferably hydrochloric acid,
Examples thereof include sulfuric acid, phosphoric acid, aluminum chloride, titanium trichloride, titanium tetrachloride, tin dichloride, and boron trifluoride ether complex. The amount of the base or acid used is, for example, in the range of 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to the compound of the formula 1-1. Preferred solvents include, for example, dimethylformamide, dimethylacetamide, tetrahydrofuran, toluene, acetonitrile,
tert-butanol, methylene chloride, chloroform, 1,
2-dichloroethane, chlorobenzene and the like can be mentioned.

In the compound of the formula 1-3, R ¹¹² or R ¹¹³
Is a NH-protecting group, deprotection can be carried out if desired. This deprotection is carried out in a general manner (for example,
TWGreene and PGMWuts, ”Protective Groups in
Organic Synthesis ”, 2nd Ed., John Wiley and Sons,
inc., New York (1991), p.315-362). As the protecting group for the NH group, various commonly used protecting groups can be used. Examples include amide-type protecting groups such as acetyl and N-benzoyl, benzyl, nitro, p-toluenesulfonyl, methanesulfonyl and the like. If necessary, a general amino group modification method (for example, RC Larock, “Comprehensive Organ Organism”) can be used for the NH group in the compound represented by the formula 1-3.
ic Transformations ”, VCH Publishers, Inc., p. 397-
398, 401-402 (1989), or TWGreene and P. GMWut
s, “Protective Groups in Organic Synthesis”, 2nd
Ed., John Wiley and Sons, inc., P.315-362 (1991))
, A substituent or a protecting group may be introduced.

[2] Method for producing compound represented by formula 2-3 [Wherein, R ¹²⁰ represents an alkyl group which may be substituted, and R ¹¹¹ and R ¹¹⁴ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, -R ²⁹ , -OR ²⁹ , -C
OR ²⁹ , -COOR ²⁹ , -SOR ²⁹ , -SO ₂ R
²⁹ (R ²⁹ has the same meaning as described above.), An optionally substituted amino group, an optionally substituted hydroxyamino group, an optionally substituted carbamoyl group, an optionally substituted sulfamoyl group Or a protecting group for an NH group. R ¹¹¹ and R ¹¹⁴ may combine to form an optionally substituted nitrogen-containing aliphatic heterocyclic ring.
Ax, R ¹¹² , R ¹¹³ and two broken lines are as defined above. The compound represented by the formula 2-1 and the amine derivative (formula 2-2) are reacted in the presence of a reaction auxiliary, if necessary, in an inert solvent, if necessary, at a reaction temperature of 0 to 140 ° C. and a reaction time of By reacting for 1 hour to 3 days, the compound of the present invention represented by Formula 2-3 can be produced. As a reaction aid, for example,
Silver nitrate, silver carbonate, mercury chloride, ammonium chloride, ammonium acetate, sodium acetate, acetic acid, oxalic acid, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, 1,
Examples thereof include 8-diazabicyclo [5.4.0] undec-7-ene, triethylamine, pyridine, and a mixture thereof. When the reaction auxiliary is a liquid, it can also serve as a solvent. Preferably, triethylamine, triethylamine-
Silver nitrate, ammonium chloride, ammonium acetate, or no reaction aid. Examples of the solvent include water, acetonitrile; methanol, ethanol,
Alcohols such as isopropanol; amides such as N, N-dimethylformamide; ethers such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and chlorobenzene; methylene chloride; Chlorinated hydrocarbons such as chloroform, carbon tetrachloride, 1,2-dichloroethane,
Or a mixed solvent thereof, and preferably, acetonitrile, a mixed system of acetonitrile-tetrahydrofuran, and alcohols.

The compound represented by the formula 2-3 is obtained by converting the compound represented by the formula 2-11 or 2-12 and the amine derivative (2-2)
It can also be produced by the method described above. [In the formula, J represents a chlorine atom, a bromine atom, or an iodine atom, and Ax, R ¹¹¹ , R ¹¹² , R ¹¹³ , R ¹¹⁴ , R ¹²⁰ and the two broken lines are as defined above. The compound of the formula 2-11 can be converted from the compound of the formula 2-1 by a known method. For example, it can be produced by using chlorine, sulfuryl chloride, bromine, and iodine in a solvent of chlorine-based hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane. Alternatively, compounds of formula 2-12 can be prepared by using a suitable oxidizing agent, preferably m-chloroperbenzoic acid.

Formula 2-14, which corresponds to Formula 2-11, can be prepared according to a known method (for example, Angew. Chem. Internat. Edit. 12, 806 (1973)). ) Can be produced by the following method. [Wherein, Ax, R ¹¹¹ and R ¹¹⁴ are as defined above. In the compound of the formula 2-3, R ¹¹¹ , R ¹¹² , R ¹¹³ or R ¹¹⁴
Is a protecting group for an NH group, if desired, deprotection can be carried out in the same manner as described above. When an NH group is present in the compound represented by the formula 2-3, a substituent or a protecting group can be introduced, if desired, in the same manner as in the above-mentioned general amino group modification method.

The compound represented by the formula 2-1 can be produced as follows. [Wherein, R ¹²² represents an alkyl group or an aryl group;
x, R ¹¹¹ , R ¹¹⁴ , R ¹²⁰ and two broken lines are as defined above. That is, a triazole derivative having an amino group (2-4)
First, an acyl isothiocyanate compound represented by the formula: R ¹²² C (O) N = C = S is reacted with a known method (for example, JP-A-63-152368), Compound (2-5) is synthesized, and this is hydrolyzed to synthesize a thioureido compound (Formula 2-6). Where, if desired,
-6 to the compound represented by the formula (1) by introducing a substituent or a protecting group in the same manner as in the general amino group modification method described above.
The compound represented by 2-7 can also be used. Then, the expression
For the compound represented by 2-6 or 2-7, according to a known S-alkylation method (for example, International Patent No. 9847880), JR
¹²⁰ (J is as defined above) to produce a compound represented by the formula 2-1.

The compound of the formula 2-1 ′ corresponding to the compound of the formula 2-1 can be synthesized according to a known method by the following method. Wherein Ax, R ¹¹² , R ¹¹³ , R ¹²⁰ and the two broken lines are as defined above. The compound represented by the formula 2-1 can also be synthesized by the following method according to a known method. A compound represented by Ax-NH ₂ is reacted with thiophosgene in the presence of an appropriate base to synthesize an isothiocyanate compound represented by the formula: Ax-N = C = S. After reacting the desired amine, the compound represented by the formula 2-1 can be produced by performing S-alkylation. It can also be synthesized via a compound represented by Formula 2-10. The compound of the formula 2-10 can be produced by reacting carbon disulfide with JR ¹²⁰ (J is as defined above) in the presence of a base. The compound of Formula 2-10, wherein; NHR ¹¹² R
^The compound represented by the formula 2-1 can be produced by reacting the amine represented by ¹¹³ . As the base, sodium hydroxide, potassium hydroxide, triethylamine,
Pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene, sodium hydride, potassium hydride, lithium hydride, and the like, and examples of the solvent include water, acetonitrile; methanol, ethanol, isopropanol, and the like. Alcohols; amides such as N, N-dimethylformamide; ethers such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane;
Aromatic hydrocarbons such as benzene, toluene and chlorobenzene; methylene chloride, chloroform, carbon tetrachloride, 1,2-
Examples thereof include chlorinated hydrocarbons such as dichloroethane, and a mixed solvent thereof. When the compound represented by the formula 2-1 has an NH group, a substituent or a protecting group can be introduced, if desired, in the same manner as in the general amino group modification method described above.

[3] Method for producing compound represented by formula 3-2 [Wherein, R ¹³⁰ , R ¹³¹ and R ¹³² each independently represent a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, -R ²⁹ , -OR
^{29, -COR 29, -COOR 29,} -SOR 2 9,
—SO ₂ R ²⁹ (R ²⁹ is as defined above), an optionally substituted amino group, an optionally substituted hydroxyamino group, an optionally substituted carbamoyl group, and an optionally substituted carbamoyl group. A sulfamoyl group, or N
Represents a protecting group for the H group. R ¹³⁰ , R ¹³¹ and R ¹³²
And any two of them may combine with each other to form an optionally substituted aliphatic heterocyclic ring together with the nitrogen atom. Ax, R ¹²⁰ and R ¹¹¹ are as defined above. A compound represented by the formula 2-4 and a compound represented by the formula 3-1:
The compound of the present invention represented by the formula 3-2 can be produced by reacting at a reaction temperature of 0 to 140 ° C. in the presence of a reaction aid if necessary and in an inert solvent if necessary. As reaction aids, for example, silver nitrate, silver carbonate, mercury chloride, ammonium chloride, ammonium acetate, sodium acetate, acetic acid, oxalic acid, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, 1,8-diazabicyclo
[5.4.0] Undec-7-ene, triethylamine, pyridine, or a mixture thereof. When the reaction auxiliary is a liquid, it can also serve as a solvent. Preferably, triethylamine, triethylamine-silver nitrate, ammonium chloride, ammonium acetate, pyridine, or no reaction aid is used. As the solvent, for example,
Water; acetonitrile; alcohols such as methanol, ethanol, isopropanol; amides such as N, N-dimethylformamide; ethers such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane; benzene, toluene, Aromatic hydrocarbons such as chlorobenzene; chlorinated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane; and mixed solvents thereof, and the like, preferably acetonitrile, acetonitrile-tetrahydrofuran. Mixed systems, N, N-dimethylformamide, alcohols and the like can be mentioned. When R ¹¹¹ , R ¹³⁰ , R ¹³¹ or R ¹³² in the compound of the formula 3-2 is a protecting group for an NH group, deprotection can be carried out in the same manner as described above, if desired. Equation 3-
When the compound represented by 2 has an NH group, a substituent or a protecting group can be introduced, if desired, in the same manner as in the above-mentioned general amino group modification method.

[4] Method for producing compound represented by formula 4-3 [Wherein, R ¹⁴⁰ is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, and an optionally substituted Represents a cycloalkenyl group, an optionally substituted aryl group or an optionally substituted aromatic heterocyclic group. R ¹⁴¹ and R ¹⁴² each independently represent a halogen atom or a methylthio group. Ax, R ¹¹² , R ¹¹³ and R ¹¹¹ are as defined above. In an inert solvent at a reaction temperature of -20 to 80 ° C, a compound represented by the formula 2-4 and a methylene sulfonamide derivative represented by the formula 4-1 or a methylene sulfonamide derivative (for example, Che
m. Ber., 99 , 2900 (1966))
By reacting with the amine represented by the formula
The compound of the present invention represented by 3 can be produced. Examples of the solvent include acetonitrile; ethers such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran and 1,4-dioxane; aromatic hydrocarbons such as benzene, toluene and chlorobenzene; methylene chloride, chloroform and carbon tetrachloride , Chlorinated hydrocarbons such as 1,2-dichloroethane; or a mixed solvent thereof, and the like. Preferred examples of the solvent include acetonitrile,
Examples include diethyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, methylene chloride, carbon tetrachloride and the like. Suitable expression 4-1 compound, Compound R ^{14 1} and R ¹⁴² are both chlorine atoms. Equation 4-
In the compound of 3, when R ¹¹² , R ¹¹³ or R ¹²¹ is a protecting group for an NH group, deprotection can be carried out in the same manner as described above, if desired. If desired, known methods (for example, TWGreene and PGMWuts, "Protective
Groups in Organic Synthesis ”, 2nd Ed., John Wiley
and Sons, inc., according _{p.379-385 (1991)), -SO 2} R 140
The elimination of the group represented by is also possible. Equation 4-3
When there is an NH group in the compound represented by
Substituents or protecting groups can be introduced in the same manner as in the general amino group modification method described above. Among the guanidinotriazole derivatives obtained by the above production method, when the compound has an NH group, if necessary, a substituent or a protecting group may be introduced in the same manner as in the general amino group modification method described above. it can.

[5] Method for producing compound represented by formula 20-2 [Wherein, Ax, R111, R114 and R120 are as defined above. The compound represented by the formula 2-10 and a diamine derivative known per se or can be produced by a known method (formula 20-1) can be prepared by reacting the compound in an inert solvent, if necessary, in the presence of a reaction auxiliary. ,
The compound of the present invention represented by Formula 20-2 can be produced by reacting at a reaction temperature of 0 to 140 ° C. for a reaction time of 1 hour to 3 days. As a reaction auxiliary, for example, silver nitrate,
Silver carbonate, mercury chloride, ammonium chloride, ammonium acetate, sodium acetate, acetic acid, oxalic acid, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, 1,8-diazabicyclo [5.4.0] undec-7-ene, triethylamine,
Pyridine or a mixture thereof is used. When the reaction auxiliary is a liquid, it can also serve as a solvent. Examples of the solvent include water, acetonitrile; alcohols such as methanol, ethanol, and isopropanol; amides such as N, N-dimethylformamide; diethyl ether;
ethers such as tert-butyl methyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and chlorobenzene; chlorinated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and 1,2-dichloroethane, or These solvents include, for example, acetonitrile, acetonitrile-tetrahydrofuran mixed system, and alcohols. When R111 or R114 in the compound of the formula 20-2 is a protecting group for an NH group, deprotection can be carried out in the same manner as described above, if desired. When an NH group is present in the compound represented by the formula 20-2, a substituent or a protecting group can be introduced, if desired, in the same manner as in the above-mentioned general amino group modification method.

[6] Method for producing compound represented by formula 5-3 [Wherein, R ²²⁰ represents an alkyl group, R ¹⁷¹ , and R
¹⁷² is independently a hydrogen atom, a hydroxyl group, -R ²⁹ , -O
R ²⁹ , -COR ²⁹ , -COOR ²⁹ , -SO
R ²⁹ , —SO ₂ R ²⁹ (R ²⁹ has the same meaning as described above), or a protective group for an NH group. Or R ¹⁷¹
And R ¹⁷² may combine to form an optionally substituted aliphatic heterocycle. M, Y ¹ , Y ² , R ⁸ ,
And R ⁹ are as defined above. The 3-amino-1,2,4-triazole derivative (5-3) is prepared according to a known method (for example, J. Med. Chem., 41 , 2985 (1998)).
It can be produced by reacting the ester (5-1) and the aminoguanidine (5-2) in the presence of a base in an inert solvent at a reaction temperature of 15 to 110 ° C. Examples of the base include sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide and the like. Examples of the solvent include alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran and 1,4-dioxane; water; and mixed solvents thereof.

[7] Method for producing compound represented by formula 6-4 [Wherein, R ²²¹ represents an alkyl group, and M, Y ¹ , Y ² , R
⁸ , R ⁹ , R ¹⁷¹ and R ¹⁷² are as defined above. ] Known methods (for example, J. Med. Chem., 28 , 1628 (198
According to 5)), the triazole (6-4) can be produced by condensing the acylhydrazine (6-1) with the S-alkylisothiourea derivative (6-2) and then cyclizing it by heating. it can. The compound of the formula (6-4) can also be produced by the method shown below. [Wherein, M, Y ¹ , Y ² , R ⁸ , R ⁹ , R ¹⁷¹ and R ¹⁷² have the same ^{meanings as} described above. The compound of the formula (6-6) and the compound of the formula (6-7) are mixed in an inert solvent such as toluene, and optionally Dean-S
While dehydrating the reaction mixture using a
By reacting at 0 to 150 ° C., a condensation reaction and then a dehydration cyclization reaction are performed to obtain a compound of the formula (6-4). The compound of the formula (6-6) can be produced by reacting the corresponding carboxylic acid with a chlorinating agent such as thionyl chloride in an inert solvent such as toluene or methylene chloride. The compound of the formula (6-6)
It can be used in the next step without isolation and purification.
Further, the compound of the formula (6-4) is converted to the compound of the formula (6-
It can also lead to the compound of 5). (Wherein, M, Y ¹ , Y ² , R ⁷ , R ⁸ , R ⁹ ,
R ¹⁷¹ and R ¹⁷² have the same ^meanings as described above. That is, the substituent R ⁷ is introduced into the triazole ring of a compound of the formula 6-4 having a functional group protected as necessary, using a known method or the method described in Examples of the present specification. can do. For example, in a solvent such as THF, methylene chloride, and methanol in the presence of a base such as sodium hydride, sodium methoxide, and triethylamine, at a temperature of -20 ° C to 150 ° C, R ⁷ -J (J is as defined above). )) Represented by an alkyl halide,
The compound represented by the formula 6-5 can be produced by reacting a sulfonyl halide, an acyl halide or the like.

[8] Method for producing compound represented by formula 7-3 [Wherein R ¹⁸⁰ represents an alkyl group. M, Y ¹ ,
Y ² , R ⁷ , R ⁸ , and R ⁹ have the same meaning as described above. ] Known methods (for example, J. Org. Chem. 39 , 1522 (1974))
To produce a triazole. N-cyanoimidate can be obtained by reacting imidate hydrochloride with cyanamide in an inert solvent at room temperature to 50 ° C. As the solvent, methanol, ethanol and the like are preferable. In N-cyanoimidate and inert solvent, 0
The desired 3-amino-1,2,4-triazole derivative can be produced by reacting with substituted hydrazine at a boiling point of the solvent used from a temperature of ° C. Preferred solvents include methanol and ethanol. Acad. Sci., Se
In the production method described in r C 287 , 121 (1978), the step of reacting the cyanamide and the step of reacting the hydrazine derivative can be performed in a different order.

The compound represented by the formula 7-3 can also be produced by the following method. (Wherein, M, Y ¹ , Y ² , R ⁷ , R ⁸ , and R ⁹ are
It is the same as the above. Using the method shown in the reference example of the present specification, the formula (6)
The compound of the formula (8-2) can also be produced by reacting the compound of the formula (6) with cyanamide and condensing it with hydrazine. The compound of the formula (6-6) can be synthesized by a known method by reacting a carboxylic acid with a halogenating agent such as thionyl chloride. The method for synthesizing 1,2,4-triazole shown above is not limited to the method described, but may be a general method (for example, ARK
atritzky et al., “Comprehensive Heterocyclic Chem
istry vol.5 ", p.761-784 (1984)).

[9] Method for producing compound represented by formula 9-6 or 9-7 [Wherein, Y ¹ , Y ² , R ⁸ and R ⁹ are as defined above. R ¹⁵⁰ represents an alkyl group. Among the raw materials for the compound of the present invention, the ester represented by the formula 9-6 or the carboxylic acid represented by the formula 9-7 can also be produced by the following method. That is, a benzene derivative having a carboxyl group and a bromine atom (formula 9-1) is used as a raw material, and is converted into an acid chloride according to a known acid chloride synthesis method.
C. Larock, “Comprehensive Organic Transformation
s ”, VCH Publishers, Inc., p. 703-708 (1989))
By reacting with a benzene derivative represented by the formula (9-2), a benzophenone derivative (formula 9-3) is synthesized. Subsequently, a known cyano substitution method (for example, Synthstic Communication, 19
97, 27, 1199.), a compound represented by the formula 9-4 is synthesized, and the compound is hydrolyzed to synthesize a carboxylic acid (formula 9-5). Subsequently, according to a known acid chloride synthesis method,
Acid chloride is synthesized and a known Arndt-Eistert synthesis method (for example, RCLarock, “Comprehensive Organic Transform
ations ", VCH Publishers, Inc., in accordance p.933 (1989)), by reaction with diazomethane or trimethylsilyldiazomethane, carboxylic acids (formula 9-7, R ⁸
= R ⁹ = H) or an ester (Formula 9-6). Further, by a known C-alkylation method, the compound represented by the formula: J-
After introducing an alkyl group into an ester (formula 9-6) using R ⁸ , JR ⁹ or JR ⁸ -R ⁹ -J (J, R ⁸ and R ⁹ are as defined above), The compound represented by the formula 9-7 can also be produced by hydrolysis.

The triazole derivative and the intermediate obtained by the above-mentioned production method may be introduced with a substituent or a protective group to the NH group in the compound, if desired, in the same manner as in a general amino group modification method. it can. In the case where the intermediate of the above production method contains a carbonyl group, a protecting group can be introduced as necessary. As the protecting group, for example, “Protective Groups in Organic Synthesi
s ”, 2nd Ed. (TW Greene and PGM Wuts, JohnW
Various protecting groups described in iley and Sons, inc., p. 175-223 (1991)) can be used. Preferably, an acyclic acetal such as dimethyl acetal; 1,3-dioxane or 1,3-dioxane
Cyclic acetal such as 3-dioxolane; thioacetal such as 1,3-dithiane; oxime. Deprotection can also be performed, for example, by the method described in the same document. In addition, even when a functional group such as an amino group, a hydroxyl group, or a carboxy group is present in the triazole derivative of the present invention or the intermediate of the above-mentioned production method, introduction and deprotection of a protecting group are performed as necessary. And a protecting group,
For more information on how to deprotect, see “Protective G
roups in Organic Synthesis ”, 2nd Ed. (TW Greene
and PGM Wuts, John Wiley and Sons, inc. (199
Those described in 1)) can be used.

The triazole derivative and the intermediate thereof produced by the above-mentioned method can be further converted to a functional group according to a known method, if necessary. For example, oxidation (conversion of sulfide to sulfoxide or sulfone), reduction (conversion of formyl to alcohol), solvolysis (conversion of ester to alcohol or carboxylic acid, conversion of nitrile to carboxylic acid), addition, deprotection Release,
Examples include condensation, alkylation, and acylation. For example, “Comprehensive Organic Transformations” Richa
rd C. Lalock, the method described in VCH Publications, Inc., and the like.

The triazole derivative of the present invention or a pharmaceutically acceptable salt thereof may be used orally or parenterally (for example, by intravenous, subcutaneous or intramuscular injection, topical, rectal) , Transdermal, or nasal). Forms for oral administration include, for example, tablets, capsules, pills, granules, powders, solutions, syrups and suspensions, and forms for parenteral administration include, for example, injection Aqueous or oily agents, ointments, creams, lotions, aerosols, suppositories, patches and the like.
These preparations are prepared using a conventionally known technique, and can contain an acceptable usual carrier, excipient, binder, stabilizer and the like. When the composition is used in the form of an injection, an acceptable buffer, solubilizing agent, isotonic agent and the like can be added. The dose and frequency of administration of the triazole derivative or a pharmaceutically acceptable salt thereof of the present invention vary depending on symptoms, age, body weight, and administration form. About 1-2 per day
000 mg, preferably 10 to 500 mg, can be administered once or in several divided doses.

Specific examples of the compounds included in the present invention include the following compounds. However, these compounds are for the purpose of illustration, and the present invention is not limited only to these. Me: methyl Et: ethyl Pr: propyl Bu: butyl Ph: phenyl Ac: acetyl Ms: methanesulfonyl

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The present invention will be described below with reference to examples and reference examples, but the present invention is not limited to these examples. In the examples and the like, the meanings of the abbreviations used are as follows. THF: tetrahydrofuran DMSO: dimethyl sulfoxide DMF: dimethylformamide IPA: isopropyl alcohol TFA: trifluoroacetic acid Et: ethyl Me: methyl Bu-t: tert-butyl Bz: benzoyl Boc: tert-butoxycarbonyl Pr: propyl Bu: butyl Ph: Phenyl Ac: acetyl Ms: methanesulfonyl

Example 1 3- [1- (2-fluoro-1,1'-biphenyl-4-yl) ethyl] -1H
-1,2,4-triazol-5-amine Sodium (6.8 g) was added to ethanol (200 ml) to prepare a sodium ethoxide solution. At 0 ° C., aminoguanidine hydrochloride (32 g) was added, and subsequently, a solution of flurbiprofen ethyl ester (20 g) dissolved in ethanol (200 ml) was added dropwise to the above reaction solution. After the addition, the reaction solution was refluxed for 13 hours. After cooling to room temperature, the ethanol was concentrated. Water was added to the residue, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried, and the residue obtained by concentrating the solvent was purified by column chromatography (chloroform: methanol = 10: 1) to obtain the desired product (4.0 g). ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.69 (d, 3H, J = 7.2H
z), 4.15 (q, 1H, J = 7.2Hz), 7.07-7.17 (m, 2H), 7.32-
7.56 (m, 6H)

Example 2 2- (3-benzoylphenyl) propanamide To ketoprofen (50 g), toluene (500 ml), thionyl chloride (15 ml) and dimethylformamide (1 drop) were added, and 90
Stirred at C for 1 hour. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. 25.5 g was taken from the obtained residue, and toluene (2
50 ml). Blow ammonia gas at room temperature,
After completion of the reaction, water and ethyl acetate were added, and the mixture was separated and extracted. The organic layer was washed with water, dried and concentrated to obtain the desired product (22.5 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.56 (d, 3H, J = 7.2H
z), 3.69 (q, 1H, J = 7.2Hz), 5.45 (br-s, 1H), 5.52
(br-s, 1H), 7.44-7.84 (m, 9H)

Example 3 2- (3-benzoylphenyl) propanenitrile The compound (86 g) obtained in Example 2 was dissolved in toluene (1000 ml), phosphorus oxychloride (35 ml) was added, and the reaction solution was refluxed. One hour later, the reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and stirred for a while. After extracting the toluene layer,
Washing with water, drying and concentration of the solvent gave the desired product (80 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.69 (d, 3H, J = 7.2H
z), 3.99 (q, 1H, J = 7.2Hz), 7.47-7.67 (m, 5H), 7.72-
7.83 (m, 4H)

Example 4 2- [1,1′-biphenyl] -4-ylpropanenitrile 4-acetylbiphenyl (100 g) in chloroform (400 m
l) / Methanol (200 ml) in NaBH4
(5.8 g) was added slowly, and the mixture was stirred at room temperature for 13 hours. A saturated ammonium chloride solution was added to the reaction mixture, and after stirring, the organic layer was separated. The aqueous layer was extracted with chloroform. The combined organic layers were dried over sodium sulfate, filtered, concentrated and concentrated to give the alcohol (101 g). This was used for the next reaction without purification. Phosphorus oxychloride (19.0 m) was added to a chloroform (100 ml) solution of DMF (15.8 ml).
l) was added and stirred for 30 minutes. Here the alcohol body (1
01g) in chloroform (400 ml) was added dropwise. The reaction mixture was stirred at 50 ° C. for 2 hours and then left at room temperature overnight.
Saturated aqueous sodium bicarbonate and water were added to the reaction mixture, and the organic layer was separated, washed with saturated saline, dried over sodium sulfate, and filtered.
Concentrated. The residue was dissolved in ethyl acetate, washed with saturated saline, dried over sodium sulfate, filtered, and concentrated to obtain a chlorinated compound (117 g). This was used for the next reaction without purification. Sodium cyanide (30.0 g) was added to a solution of the chlorinated compound (117 g) in DMSO (220 ml), and the mixture was stirred at 80 ° C. for 4 hours. After cooling, aqueous saturated sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. During the extraction, insoluble solids were removed by celite filtration. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain the desired product (82 g) as a yellow solid. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.69 (d, 3 H, J = 7.
2 Hz), 3.95 (q, 1 H, J = 7.2 Hz), 7.33-7.39 (m, 1
H), 7.40-7.47 (m, 4 H), 7.55-7.63 (m, 4 H)

Example 5 2- (4-bromophenyl) propanenitrile The desired product was obtained in the same manner as in Example 4. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.63 (d, 3H, J = 7.3H
z), 3.87 (q, 1H, J = 7.3Hz), 7.20-7.26 (m, 2H), 7.48-
7.56 (m, 2H)

Example 6 2- [4 '-(methylthio) -1,1'-biphenyl-4-yl] propane
Nitrile Toluene solution (100 ml) of the compound (8.3 g) obtained in Example 5
To the mixture, 4- (methylthio) phenylboronic acid (6.1 g), potassium carbonate (15 g) were added, degassing was performed under reduced pressure, and after nitrogen substitution, tetrakis (triphenylphosphine) palladium (0) was added to the reaction solution. (2.1 g) was added, and the mixture was heated under reflux for 4 hours. After allowing the reaction solution to cool to room temperature, it was filtered through Celite.
Water was added to the filtrate, and toluene extraction was performed. The organic layer was washed with saturated saline. After drying over sodium sulfate, the mixture was concentrated under reduced pressure. The obtained residue was recrystallized from toluene to obtain the desired product. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.68 (d, 3H, J = 7.3H
z), 2.53 (s, 3H), 3.94 (q, 1H, J = 7.3Hz), 7.33 (d, 2
H, J = 8.4Hz), 7.42 (d, 2H, J = 8.3Hz), 7.51 (d, 2H, J =
8.4Hz), 7.59 (d, 2H, J = 8.3Hz).

Example 7 2- [4 '-(methylsulfonyl) -1,1'-biphenyl-4-yl] p
Lopinitrile Methanol solution (100 ml) of the compound (4.5 g) obtained in Example 6
Then, water (50 ml) and OXONE (16.4 g) were added under ice-cooling and stirred. After 10 minutes, the temperature was returned to room temperature and stirred for 1.5 hours. The reaction solution was concentrated in half under reduced pressure, and water (100 ml) and chloroform (100 ml) were added for extraction. The organic layer was washed with saturated saline,
After drying over sodium sulfate, the mixture was concentrated under reduced pressure to give the desired product (4.6 g).
I got ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.70 (d, 3H, 7.3 Hz),
3.10 (s, 3H), 3.98 (q, 1H, J = 7.3Hz), 7.49 (d, 2H,
J = 8.2Hz), 7.64 (d, 2H, J = 8.2Hz), 7.77 (d, 2H, J =
8.5Hz), 8.03 (d, 2H, J = 8.5Hz).

Example 8 1- (1,1′-biphenyl-3-yl) ethanone The desired product was obtained in the same manner as in Example 6. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 2.66 (s, 3H), and 7.
38-8.38 (m, 9H)

Example 9 2- (1,1'-biphenyl-3-yl) propanenitrile The desired product was obtained in the same manner as in Example 4. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.69 (d, 3H, J = 6.8
Hz), 3.96 (q, 1H, J = 6.8 Hz), and 7.34-7.60 (m, 9
H)

Example 10 Methyl 2- (3-benzoylphenyl) propanimidoe
G hydrochloride The compound (80 g) obtained in Example 3 was dissolved in toluene (600 ml), and methanol (13.8 ml) was added. After cooling to 0 ° C,
Hydrogen chloride gas was blown into the reaction solution. The mixture was allowed to stand at 0 ° C. for 2 days, the reaction solution was concentrated, and the obtained crystals were dried under reduced pressure to obtain the desired product (100 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.70 (d, 3H, J = 7.3H
z), 4.30 (s, 3H), 4.65 (q, 1H, J = 7.3Hz), 7.45-7.54 (m,
3H), 7.57-7.73 (m, 2H), 7.77-7.90 (m, 4H)

Example 11 Methyl (1Z) -2- (3-benzoylphenyl) -N-cyanopro
Panimidate Compound (30 g) obtained in Example 10 was converted to methanol (300 ml).
, And cyanamide (13 g) was added thereto, followed by stirring at 50 ° C. for 2 hours. Methanol was concentrated, chloroform and water were added to the residue, and the mixture was separated and extracted. The organic layer was dried and concentrated to obtain the desired product (36 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.60 (d, 3H, J = 7.2H
z), 3.88 (s, 3H), 4.49 (q, 1H, J = 7.2Hz), 7.43-7.52 (m,
3H), 7.56-7.73 (m, 2H), 7.71 (m, 1H), 7.76-7.82 (m,
3H)

Example 12 (3- [1- (5-amino-1H-1,2,4-triazol-3-yl) ethyl)
[Phenyl] (phenyl) methanone Example 11 (36 g) was dissolved in ethanol (300 ml), hydrazine monohydrate (4.8 ml) was added, and the mixture was stirred at 0 ° C. for 10 minutes and at room temperature for 20 minutes. Water was added to the reaction solution, and ethanol was concentrated, followed by extraction with chloroform. The organic layer was dried and concentrated, and the residue was subjected to column chromatography (ethyl acetate / hexane = 3:
Purification with 1 to chloroform: methanol = 10: 1) gave the desired product (20.9 g). ¹ H-NMR (400 MHz, DMSO-d6) δ ppm: 1.58 (d, 3H, J = 7.0H
z), 4.11 (q, 1H, J = 7.0Hz), 5.94 (br, 2H), 7.51-7.83
(m, 10H)

Example 13 {3- [1- (5-amino-1-methyl-1H-1,2,4-triazole-3-
Yl) ethyl] phenyl} (phenyl) methanone Example 11 (31.5 g) was dissolved in ethanol (300 ml),
Add methyl hydrazine (4.8 ml) and add 10 minutes at 0 ° C and room temperature.
Stir for 30 minutes. After adding water to the reaction solution and concentrating the ethanol,
Extracted with chloroform. The organic layer is dried and concentrated, and the residue is subjected to column chromatography (ethyl acetate only to chloroform:
Purification with methanol = 5: 1) gave the desired product (18.8 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.66 (d, 3H, J = 7.2H
z), 3.60 (s, 3H), 4.12 (q, 1H, J = 7.2Hz), 5.38 (br, 2
H), 7.34-7.62 (m, 6H), 7.77-7.82 (m, 3H)

Example 14 2- {5-amino-3- [1- (2-fluoro-1,1'-biphenyl-4-i
Ru) ethyl] -1H-1,2,4-triazol-1-yl} ethanol A compound (1.0 g) obtained from flurbiprofen in the same manner as in Examples 2, 3, 10, and 11 was added to ethanol (20 m
l) and dissolved in 2-hydroxyethylhydrazine (0.29m
l) was added and stirred at room temperature for 2 hours. Water was added to the reaction solution, and ethanol was concentrated, followed by extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated, and the resulting crystals were revalvated with ethanol to give the desired product (0.8 g). ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.66 (d, 3H, J = 7.2H
z), 3.99-4.05 (m, 4H), 4.10 (q, 1H, J = 7.2Hz), 4.63 (b
r, 2H), 7.10-7.20 (m, 2H), 7.31-7.46 (m, 4H), 7.49-
7.55 (m, 2H)

Example 15 [4- (Bromomethyl) phenyl] (phenyl) methanone 4-methylbenzophenone (25 g) to carbon tetrachloride (250 ml)
And dissolved in AIBN (0.2 g) and N-bromosuccinimide (2
2.7 g) was added. After refluxing the reaction solution for 2 hours, the resulting succinimide was removed by filtration, and the filtrate was concentrated. The residue was recrystallized from ethanol to obtain the desired product (19.6 g). ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.58 (s, 3H), 4.54 (s,
2H), 7.46-7.54 (m, 4H), 7.60 (m, 1H), 7.76-7.83 (m,
4H)

Example 16 (4-benzoylphenyl) acetonitrile The compound (16.3 g) obtained in Example 15 was dissolved in dimethylformamide (200 ml), and sodium cyanide (3.2 g) was dissolved.
Was added and stirred at room temperature for 1 hour. The reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was washed with water and dried. The solvent was concentrated, and the obtained residue was purified by column chromatography.
The desired product (6.1 g) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.57 (s, 3H), 3.86 (s,
2H), 7.45-7.54 (m, 4H), 7.61 (m, 1H), 7.77-7.86 (m,
4H)

Example 17 (3-Bromo-4-methylphenyl) (phenyl) methanone 3-bromo-4-methylbenzoic acid (10 g) in thionyl chloride (50 m
l) and DMF (0.1 ml) were sequentially added dropwise, and then a calcium chloride tube was attached, and the mixture was heated under reflux for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain 3-bromo-4-methylbenzoyl chloride. Under a nitrogen atmosphere, aluminum chloride (7.4 g) was added to a solution of the residue obtained in benzene (100 ml) at room temperature, and the mixture was heated under reflux for 6 hours. After cooling to room temperature, the reaction solution was diluted with 10% aqueous hydrochloric acid (300 ml)
And extracted twice with toluene (200 ml). The obtained organic layer was washed with a 10% aqueous sodium hydroxide solution (200 ml) and saturated saline (200 ml), dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 10) to obtain the desired product (8.8 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 2.49 (s, 3H), 7.35 (d,
1H, J = 10.5 Hz), 7.50 (dd, 1H, J = 11.0 Hz), 7.51 (d,
1H, J = 10.5 Hz), 7.58-7.66 (m, 2H), 7.76-7.80 (m,
2H), 7.98 (s, 1H, J = 2.0 Hz).

Example 18 5-benzoyl-2-methylbenzonitrile The compound (5.0 g) obtained in Example 17 was dissolved in N-methyl-2-pyrrolidinone (10 ml), copper (I) cyanide (2.0 g) was added at room temperature, and the mixture was heated at 180 ° C. for 4 hours. After cooling to room temperature, the reaction mixture was poured into a 10% aqueous solution of ethylenediamine (200 ml) and extracted three times with ethyl acetate (100 ml). The obtained organic layer was washed with water (200 ml) and saturated saline (200 ml), dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 6) to obtain the desired product (3.4 g). ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 2.66 (s, 3H), 7.47 (d,
1H, J = 8.0 Hz), 7.52 (dd, 2H, J = 7.5 Hz), 7.64 (dd,
1H, J = 7.5 Hz), 7.77 (d, 2H, J = 7.0 Hz), 7.95 (d, 1
H, J = 2.0, 8.0 Hz), 8.03 (s, 1H, J = 2.0 Hz).

Example 19 5-bromo-2-methylbenzoic acid The compound (1.4 g) obtained in Example 18 was dissolved in ethanol (20 ml), a 4N-NaOH aqueous solution (5 ml) was added at room temperature, and the mixture was heated under reflux for 3 hours. After cooling to room temperature, the reaction solution was poured into water (100 ml) and extracted with ethyl acetate (100 ml). The obtained organic layer was washed with saturated saline (100 ml), dried over sodium sulfate, and concentrated under reduced pressure to obtain 5-benzoyl-2-methylbenzamide. An aqueous solution of sodium nitrite (1.7 g) (10 ml) was slowly added dropwise to a 75% aqueous solution of sulfuric acid (50 ml) of the obtained residue under ice-cooling. After 30 minutes, the reaction solution was returned to room temperature and stirred for 6 hours. The reaction solution was poured into ice water (200 ml), and chloroform (100 m
Extracted in l). 5% aqueous sodium bicarbonate (50 ml) was added to the obtained organic layer.
Was added, and the aqueous layer was extracted. Chloroform (100ml) in aqueous layer
And then acidify with a 10% aqueous hydrochloric acid solution.
Extracted times. The organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to obtain the desired product (1.3 g). ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 2.75 (s, 3H), 7.43 (d,
1H, J = 8.0 Hz), 7.51 (dd, 2H, J = 7.5 Hz), 7.62 (dd,
1H, J = 7.0 Hz), 7.80 (d, 2H, J = 7.0 Hz), 7.94 (d, 1
H, J = 2.0, 8.0 Hz), 8.49 (s, 1H, J = 2.0 Hz).

Example 20 (5-benzoyl-2-methylphenyl) acetic acid Oxalyl chloride (3.3m) was added to a solution of the compound obtained in Example 19 (3.0g) in methylene chloride (30ml) at room temperature under a nitrogen atmosphere.
l) was added and stirred for 12 hours. After concentrating the reaction solution under reduced pressure,
The toluene azeotrope was performed twice. Diazomethane gas generated by slowly adding potassium hydroxide (4.2 g) aqueous solution (14 ml) to a mixed solution of 2- (2-ethoxy) ethoxyethanol (40 ml), diethyl ether (80 ml), and diazald (13 g) at room temperature In a nitrogen stream, and the resulting residue is tetrahydrofuran
(25 ml) and diethyl ether (25 ml) were mixed and stirred. After stirring for 1 hour, the mixture was left under a nitrogen stream for 1 hour, and concentrated under reduced pressure. Subsequently, silver oxide (2.9 g) was added to an aqueous solution (50 g) of sodium thiosulfate (5.3 g) at room temperature, and the mixture was heated at 65 ° C., and the resulting residue was diluted with 1,4-dioxane (25 ml). ) The solution was added dropwise. After 2 hours, the precipitate was washed with water (5
0 ml) and chloroform (50 ml), and the filtrate was washed with water (100 ml).
ml) and extracted with chloroform (100 ml). The obtained organic layer was washed with saturated saline (100 ml), dried over sodium sulfate, and concentrated under reduced pressure. Chloroform (100 ml) and 5% aqueous sodium hydroxide solution (100 ml) were added to the obtained residue, and the aqueous layer was extracted. Chloroform (100 ml) was added to the obtained aqueous layer.
After the addition, the aqueous layer was made acidic with a 10% aqueous hydrochloric acid solution, and the organic layer was extracted twice. The obtained organic layer was washed with a saturated saline solution (100 m
After washing in l), drying over sodium sulfate and concentration under reduced pressure gave the desired product (2.9 g). ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 2.41 (s, 3H), 3.75 (s,
2H), 7.38 (d, 1H, J = 8.0 Hz), 7.49 (dd, 2H, J = 8.0
Hz), 7.58 (dd, 1H, J = 8.0 Hz), 7.64 (d, 1H, J = 1.5,
8.0 Hz), 7.70 (s, 1H, J = 1.5 Hz), 7.78 (d, 2H, J = 1.
5, 8.0 Hz).

Example 21 2- (5-benzoyl-2-methylphenyl) acetohydrazide Compound (1.0 g) obtained in Example 20 was treated with methylene chloride (20 ml).
Oxalyl chloride (2 ml) at room temperature, and add 6
Stirred for hours. The reaction solution was concentrated under reduced pressure, and the toluene azeotrope was
This was repeated twice to obtain (5-benzoyl-2-methylphenyl) acetyl chloride. Under a nitrogen atmosphere and under ice-cooling, chloride (5-benzoyl-
2-methylphenyl) acetyl in tetrahydrone solution (20m
l) hydrazine monohydrate (3.8ml) in tetrahydrofuran
(20 ml) solution was slowly added dropwise. After 30 minutes, the reaction solution was poured into water (50 ml) and extracted with ethyl acetate (50 ml). The organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: methanol = 20: 1) to obtain the desired product (0.60 g). ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 2.40 (s, 3H), 3.66 (s,
2H), 3.88 (brs, 2H), 6.63 (brs, 1H), 7.32 (d, 1H,
J = 8.0 Hz), 7.49 (dd, 2H, J = 8.0 Hz), 7.60 (dd, 1H,
J = 1.5, 8.0 Hz), 7.64 (d, 1H, J = 1.5, 8.0 Hz), 7.68
(s, 1H, J = 1.5 Hz), 7.78 (d, 2H, J = 1.5, 8.0 Hz).

Example 22 2- (2-Fluoro [1,1'-biphenyl] -4-yl) -2-methylp
Lopanoic acid To a suspension of 60% sodium hydride (11.3 g) in DMF (300 ml) was added 0
A solution of flurbiprofen (30 g) in DMF (300 ml) was added dropwise at 30 ° C. over 30 minutes. After returning to room temperature and stirring for 1 hour, methyl iodide (18.4 ml) was added, and the mixture was stirred overnight. The reaction solution was poured into ice, extracted with ethyl acetate, the organic layer was washed with water, dried, concentrated under reduced pressure, the residue was dissolved in ethanol (300 ml), a 6N-potassium hydroxide aqueous solution was added, and the reaction solution was heated to 50 ° C. And heated. 30
After a minute, water was added and ethanol was distilled off under reduced pressure. The obtained aqueous solution was extracted with ethyl acetate / hexane (v / v = 1/1). The aqueous layer was made acidic with 1N hydrochloric acid, extracted with ethyl acetate, and separated. The organic layer was washed with water, dried and concentrated under reduced pressure to give the desired product (24 g).
I got ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.63 (s, 6H), 7.19-7.5
6 (m, 8H)

Example 23 2- (3-benzoylphenyl) -2-methylpropanohydrazide
Do Using a compound obtained from ketoprofen in the same manner as in Example 22, the desired product was obtained in the same manner as in Example 21. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.63 (s, 6H), 3.83 (b
rs, 2H), 6.51 (brs, 1H), 7.33-7.85 (m, 9H)

Example 24 {3- [1- (5-Amino-1H-1,2,4-tria)
Zol-3-yl) -1-methylethyl] phenyl
(Phenyl) methanone N, N-dimethylformamide of the compound obtained in Example 23
(20 ml) solution, water (20 ml), methylthiourea 1 at room temperature
/ 2 sulfate (1.07 g) was added, and the mixture was heated under reflux. 48 hours later, the reaction solution was poured into saturated aqueous sodium hydrogen carbonate (100 ml), and ethyl acetate (100 ml) was added.
Extracted three times. The obtained organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue obtained is chromatographed on silica gel (chloroform:
Purification was performed with methanol = 20: 1) to obtain the desired product. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.77 (s, 6H), 4.2
7 (brs, 2H), 7.41-7.83 (m, 9H).

Example 25 2- [1,1′-biphenyl] -4-yl-N-cyano-2-methylpropa
Namide A compound (2.40 g) obtained from biphenylacetic acid in the same manner as in Example 22 was suspended in toluene (50 mL), and DMF was added.
After adding 5 drops, thionyl chloride (1.60 mL) was added, and
Stir for hours. After removing excess thionyl chloride and the solvent by an evaporator, the residue was dissolved in acetone (25 mL). Cyanamide monohydrate (631 mg) was dissolved in a 2M aqueous solution of sodium hydroxide (8 mL), and the acetone solution was added dropwise thereto,
Stir at room temperature for 3 hours. The reaction solution was diluted with water, extracted with ethyl acetate, dried over magnesium sulfate, and then concentrated with an evaporator to obtain the desired product quantitatively. ¹ H-NMR (300MHz, CDCl ₃ ) δ ppm: 1.65 (s, 6H), 7.34-7.4
8 (m, 5H), 7.56-7.64 (m, 4H)

Example 26 3- (1- [1,1′-biphenyl] -4-yl-1-methylethyl) -1H-
1,2,4-triazol-5-amine The target compound was obtained from the compound obtained in Example 25 by the same operation as in Example 12. ¹ H-NMR (400MHz, CDCl ₃ ) δ ppm: 1.71 (s, 6H), 4.45
(br s, 2H), 7.32-7.43 (m, 5H), 7.50-7.55 (m, 4H)

Example 27 1- (3-Benzoylphenyl) cyclobutanecarbonitrile Under a nitrogen atmosphere, 9.78 g of sodium hydride (60%
in Mineral Oil) dimethyl sulfoxide 100ml
To the suspension, a solution of 24.6 g of 3-benzoylacetonitrile and 50 ml of 1,3-dibromopropane in 50 ml of diethyl ether were added dropwise at room temperature while stirring with a mechanical stirrer. Five hours later, ice water was added under ice cooling, liquid separation was performed, and the water bath was extracted with diethyl ether. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 4), and the desired fraction was concentrated to give the title compound (16.4 g) as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 2.07-2.21 (m, 1H),
2.39-2.54 (m, 1H), 2.61-2.72 (m, 2H), 2.82-2.92
(m, 2H), and 7.48-7.87 (m, 9H).

Example 28 (3- {1- [5-amino-1- (phenylsulfonyl) -1H-1,2,4-
Triazol-3-yl] ethyl} phenyl) (phenyl) meta
Non To a suspension of 60% sodium hydride (0.75 g) in THF (30 ml),
Compound (5.0 g) obtained in Example 12 in THF (20 ml), D
An MF (10 ml) solution was added dropwise at 0 ° C. After 30 minutes, benzenesulfonyl chloride (2.4 ml) was added. After 30 minutes,
Water and ethyl acetate were added, and the mixture was separated and extracted. The organic layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography (ethyl acetate / hexane = 1: 3) to obtain the desired product (6.6 g). ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.50 (d, 3H, J = 7.2
Hz), 3.98 (q, 1H, J = 7.2Hz), 5.83 (br, 2H), 7.25-7.93
(m, 14H)

Example 29 Dimethyl 3- [1- (3-benzoylphenyl) ethyl] -1- (f
(Enylsulfonyl) -1H-1,2,4-triazol-5-yldi
Thioimide carbonate The compound (6.6 g) obtained in Example 28 was dissolved in THF (100 ml), and 60% sodium hydride (0.67 g) was added at 0 ° C. 30
One minute later, carbon disulfide was added, and 50 minutes later, 60% sodium hydride (0.67 g) was added. 1.5 hours later, methyl iodide (3.8m
l) was added dropwise and stirred for 1 hour at 0 ° C. Water and ethyl acetate were added, and the mixture was separated and extracted. The organic layer is washed with water, dried and concentrated,
The residue was purified by silica gel chromatography (ethyl acetate / hexane = 1: 1).
Purification in 2) gave the desired product (6.2 g). ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.64 (d, 3H, J = 7.3
Hz), 2.58 (s, 6H), 4.24 (q, 1H, J = 7.3Hz), 7.31-7.64
(m, 9H), 7.73-7.84 (m, 3H), 7.96-8.02 (m, 2H)

Example 30 Dimethyl 3- [1- (3-benzoylphenyl) ethyl] -1-methyl
-1H-1,2,4-triazol-5-yldithioimidocarbo
Nate The compound (1.5 g) obtained in Example 13 was dissolved in DMF (5 ml) and cooled to 0 ° C. 20N sodium hydroxide aqueous solution (0.
3 ml) and stirred for 30 minutes, and then carbon disulfide (0.61 ml) was added. After 30 minutes, the mixture was brought to room temperature, and a 20N aqueous sodium hydroxide solution (0.3 ml) was added. After stirring for 2 hours, methyl iodide (0.69
ml) was added dropwise. Two hours later, ethyl acetate and water were added to the reaction solution, and the mixture was separated and extracted. The organic layer is washed with water, dried and concentrated,
The residue was purified by silica gel chromatography to obtain the desired product. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.70 (d, 3H, J = 7.2
Hz), 2.55 (brs, 6H), 3.75 (s, 3H), 4.27 (q, 1H, J = 7.2
Hz), 7.36-7.52 (m, 3H), 7.54-7.67 (m, 3H), 7.77-7.90
(m, 3H)

Example 31 Methyl N '-{3- [1- (2-fluoro [1,1'-biphenyl] -4-i
Ru) ethyl] -1-methyl-1H-1,2,4-triazol-5-yl}
Imidothiocarbamate Examples 2, 3, 10, 11, 1 from flurbiprofen
Compound (1.2 g) obtained by the same operation as in 3, 30;
Mix dioxane (12 ml) and aqueous ammonia (3 ml) and add 7
Heated at 0 ° C. for 2 hours. Ethyl acetate and water were added to the reaction solution,
Separated and extracted. The organic layer was washed with water, dried and concentrated to obtain the desired product (1.2 g).

Example 32 Methyl N '-{3- [1- (3-benzoylphenyl) ethyl] -1-me
Tyl-1H-1,2,4-triazol-5-yl} imidothiocarb
Mate From the compound obtained in Example 30, the desired product was obtained in the same manner as in Example 31. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.67 (d, 3H, J = 7.3
Hz), 2.49 (s, 3H), 3.74 (s, 3H), 4.21 (q, 1H, J = 7.3H
z), 7.35-7.50 (m, 3H), 7.53-7.64 (m, 3H), 7.76-7.86
(m, 3H)

Example 33 3- [1- (3-Benzoylphenyl) ethyl] -5-{[(Z)-[(tert-
[Butoxycarbonyl) amino] (methylsulfanyl) methyl
Ridene] amino} -1-methyl-1H-1,2,4-triazole To a suspension of 60% sodium hydride (0.50 g) in THF (20 ml) was added dropwise a solution of the compound (1.9 g) obtained in Example 32 in THF (20 ml) at 0 ° C. Five minutes later, Boc2O (2.19 g) was added dropwise,
Stir for 45 minutes. The temperature was raised to room temperature, and the mixture was further stirred for 3 hours.
Water and ethyl acetate were added, and the mixture was separated and extracted. The organic layer was washed with water, dried and concentrated. The residue was purified by silica gel chromatography (ethyl acetate / hexane = 1: 2) to obtain the desired product (2.1 g). ¹ H-NMR (300MHz, CDCl ₃ ) δ ppm: 1.49 (s, 9H), 1.70
(d, 3H, J = 7.3Hz), 2.43 (s, 3H), 3.77 (s, 3H), 4.24
(q, 1H, J = 7.3Hz), 7.38-7.50 (m, 3H), 7.54-7.65 (m, 3
H), 7.76-7.81 (m, 3H), 12.35 (br, 1H)

Example 34 N-benzoyl-N ′-{3- [1- (2-fluoro [1,1′-biphenyl]
-4-yl) ethyl] -1H-1,2,4-triazol-5-yl} thio
Urea The compound (1.0 g) obtained in Example 1 was added to 1,2-dichloroethane (15 m
l), benzoyl isothiocyanate (0.53 ml) was added, and the reaction solution was refluxed. After 5 hours, the reaction was concentrated,
The residue was purified by a silica gel column (ethyl acetate / hexane = 1/2) to obtain the desired product (0.8 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.72 (d, 3H, J = 7.2 Hz),
4.26 (q, 1H, J = 7.2Hz), 7.08-7.19 (m, 2H), 7.30-7.68
(m, 9H), 7.85-7.92 (m, 2H)

Example 35 N- {3- [1- (2-Fluoro [1,1′-biphenyl] -4-yl) ethyl
Ru] -1H-1,2,4-triazol-5-yl} thiourea Compound (0.7 g) obtained in Example 34 was treated with THF (5 ml) and methanol.
(5 ml), and potassium carbonate (0.33 g) was added. At 70 ° C
After stirring for 2 hours, the temperature was returned to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure.
The residue was purified on a silica gel column (ethyl acetate / hexane = 1/1 to 3 /
Purification in 1) gave the desired product (0.3 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.61 (d, 3H, J = 7.2 Hz),
4.34 (q, 1H, J = 7.2Hz), 7.16-7.28 (m, 2H), 7.35-7.54
(m, 6H), 8.69 (br-s, 1H), 9.06 (br-s, 1H)

Example 36 Methyl N '-{5- [1- (2-fluoro [1,1'-biphenyl] -4-i
Ru) ethyl] -1H-1,2,4-triazol-3-yl} imidothio
Carbamate Acetone (100 ml) was obtained from the compound (4.2 g) obtained in Example 35.
And potassium carbonate (1.86 g) and methyl iodide (0.84 ml) were added at room temperature. After 1.5 hours, water was added to the reaction solution, acetone was concentrated, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was purified by silica gel chromatography (ethyl acetate / hexane = 1: 2) to give the desired product (4.0
g) was obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.70 (d, 3H, J = 7.3 Hz),
2.48 (s, 3H), 4.23 (q, 1H, J = 7.3Hz), 7.11-7.20 (m, 2
H), 7.30-7.55 (m, 6H)

Example 37 Methyl N '-{5- [1- (2-fluoro-1,1'-biphenyl-4-i
Ru) ethyl] -1-methyl-1H-1,2,4-triazol-3-yl}
Imidothiocarbamate To a suspension of 60% sodium hydride (0.25 g) in THF (30 ml) was added at 0 ° C. the compound (2.0 g) obtained in Example 36 in THF (15 ml).
l) The solution was added dropwise. 30 minutes later, methyl iodide (0.39ml)
After 1 hour, the temperature was raised to room temperature, and the mixture was left overnight. Water and ethyl acetate were added to the reaction solution, and the mixture was separated and extracted. The organic layer was washed with water, dried and concentrated. The residue was purified by a silica gel column to obtain the desired product (1.6 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.75 (d, 3H, J = 7.2H
z), 2.56 (s, 3H), 3.60 (s, 3H), 4.18 (q, 1H, J = 7.2Hz),
6.99-7.08 (m, 2H), 7.33-7.54 (m, 6H)

Example 38 tert-butyl (E)-({5- [1- (2-fluoro-1,1′-biphenyl)
-4-yl) ethyl] -1-methyl-1H-1,2,4-triazole-3-
Ill} imino) (methylthio) methyl carbamate The target compound was obtained from the compound obtained in Example 37 in the same manner as in Example 33. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.53 (s, 9H), 1.76 (d,
3H, J = 7.1Hz), 2.49 (s, 3H), 3.65 (s, 3H), 4.21 (q, 1
H, J = 7.1Hz), 7.00-7.07 (m, 2H), 7.34-7.55 (m, 6H)

Example 39 N '-[3- [1- (2-Fluoro-1,1'-biphenyl-4-yl) ethyl
L] -1- (Phenylsulfonyl) -1H-1,2,4-triazole-5
-Yl] morpholine-4-carboximidamide A compound (1.2 g) obtained from the compound obtained in Example 1 by the same operation as in Examples 28 and 29, ethanol (20 m
l) and morpholine (0.21 ml) were mixed and heated at 70 ° C. Two
After a period of time, the reaction solution was separated and extracted with ethyl acetate and water. The organic layer was washed with water, dried and concentrated, and the residue was crystallized by adding ethanol to obtain a crude product. Dissolved in dioxane (15 ml), added aqueous ammonia (3 ml) and heated at 80 ° C. for 3 hours. After cooling, ethyl acetate and water were added, and the mixture was separated and extracted. After washing the organic layer with water, drying and concentration,
The residue was purified by a silica gel column to obtain the desired product (0.85 g).

Example 40 N '-{3- [1- (2-Fluoro-1,1'-biphenyl-4-yl) ethyl
Ru] -1H-1,2,4-triazol-5-yl} morpholine-4-cal
Boxyimidamide Compound (0.85 g) obtained in Example 39 was treated with dioxane (15 m
l), 2N aqueous sodium hydroxide solution (5 ml) was added, and the mixture was heated at 70 ° C for 1 hour. Ethyl acetate and water were added to the reaction solution, and the mixture was separated and extracted. The organic layer is washed with water, dried and concentrated, and the residue is purified by a silica gel column to give the desired product (0.48
g) was obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.68 (d, 3H, J = 7.3H
z), 3.45-3.52 (m, 4H), 3.70-3.76 (m, 4H), 4.18 (q, 1
H, J = 7.3Hz), 7.07 (brs, 2H), 7.11-7.20 (m, 2H), 7.30-
7.55 (m, 6H)

Example 41 N '-[3- [1- (3-benzoylphenyl) -1-methylethyl] -1-
(Phenylsulfonyl) -1H-1,2,4-triazol-5-yl]
-N, N-dimethylmorpholine-4-carboximidamide A compound (1.8 g) obtained from the compound obtained in Example 24 in the same manner as in Examples 28 and 29, ethanol (30 m
l) and morpholine (0.34 ml) were mixed and heated at 70 ° C. for 2 hours. After concentrating the ethanol, water and ethyl acetate were added, and the mixture was separated and extracted. The organic layer was washed with water, dried and concentrated, and the residue was dissolved in methylene chloride (30 ml). Sulfuryl chloride (0.66 ml) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour.
After adding dimethylamine (6 ml) and stirring for 1 hour, chloroform and water were added, and the mixture was separated and extracted. The organic layer is dried and concentrated, and the residue is purified by a silica gel column to give the target compound (1.7
g) was obtained. ¹ H-NMR (400MHz, CDCl ₃ ) δ ppm: 1.70 (s, 6H), 2.76
(s, 6H), 3.10-3.16 (m, 4H), 3.57-3.65 (m, 4H), 7.30
(m, 1H), 7.41-7.64 (m, 8H), 7.73-7.80 (m, 3H), 7.98-
8.03 (m, 2H)

Example 42 N '-{3- [1- (3-benzoylphenyl) -1-methylethyl] -1H
-1,2,4-triazol-5-yl} -N, N-dimethylmorpholine
-4-carboximidamide The target compound was obtained from the compound obtained in Example 41 by the same operation as in Example 40. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.78 (s, 6H), 2.74
(s, 6H), 3.11-3.20 (m, 4H), 3.60-3.68 (m, 4H), 7.34-
7.49 (m, 3H), 7.52-7.63 (m, 3H), 7.75-7.80 (m, 2H),
7.86 (t, 1H, J = 1.7Hz)

Example 43 N '-{3- [1- (2-Fluoro-1,1'-biphenyl-4-yl) ethyl
L] -1-Methyl-1H-1,2,4-triazol-5-yl} thiomol
Holin-4-carboximidamide 1,1-dioxide The target compound was obtained from the starting compound of Example 31 by the same operation as in Example 39 using thiomorpholine dioxide and aqueous ammonia. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.67 (d, 3H, J = 7.2
Hz), 3.07-3.14 (m, 4H), 3.67 (s, 3H), 3.97-4.06 (m, 4
H), 4.16 (q, 1H, J = 7.2Hz), 7.12 (br, 2H), 7.12-7.21
(m, 2H), 7.31-7.46 (m, 4H), 7.48-7.54 (m, 2H)

Example 44 N ''-{3- [1- (3-benzoylphenyl) ethyl] -1-methyl-1
H-1,2,4-triazol-5 -yl} -N- [2- (4-morpholinyl)
Ethyl] guanidine hydrochloride Compound (1.33 g) obtained in Example 33 was treated with acetonitrile (1
5ml), and triethylamine (0.46ml) and aminoethylmorpholine (0.84ml) were added. After cooling to 0 ° C., a solution of silver nitrate (0.82 g) in acetonitrile (5 ml) was added dropwise. After 5 minutes, the temperature was raised to room temperature, and the mixture was stirred for 6 hours. The reaction solution was filtered through celite, concentrated, and ethyl acetate and water were added to the residue, followed by separation and extraction. The organic layer is saturated aqueous ammonium chloride,
After washing with water, drying and concentration, a contaminated product (1.4 g) was obtained.
This was dissolved in methylene chloride (10 ml), and TFA (3 m
l) was added dropwise. After standing overnight, the reaction solution was concentrated, chloroform and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was separated and extracted. The organic layer is dried and concentrated, and the residue is subjected to silica gel chromatography (chloroform: methanol = 20: 1 to 10:
Purification was performed in 1) to obtain a target product (1.12 g). Treatment with a 1N hydrogen chloride / ether solution gave the desired product (1.13 g). ¹ H-NMR (300 MHz, DMSO-d6) δ ppm: 1.59 (d, 3H, J = 7.2H
z), 3.00-4.00 (m, 15H), 4.28 (brq, 1H, J = 7.2Hz), 7.46
-7.75 (m, 9H)

Example 45 N '-{5- [1- (2-Fluoro-1,1'-biphenyl-4-yl) ethyl
Ru] -1-Methyl-1H-1,2,4-triazol-3-yl} -4-hydr
Roxypiperidine-1-carboximidamide The target compound was obtained from the compound obtained in Example 38 by the same operation as in Example 44 using 4-hydroxypiperidine. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.52-1.64 (m, 2H), 1.
74 (d, 3H, J = 7.1Hz), 1.90-2.00 (m, 2H), 3.21 (m, 2H),
3.56 (s, 3H), 3.91 (m, 1H), 4.01 (m, 2H), 4.15 (q, 1
H, J = 7.1Hz), 6.59 (br, 2H), 7.00-7.09 (m, 2H), 7.32-
7.55 (m, 6H)

Example 46 2-((2E) -2-{[3- [1- (1,1'-biphenyl-4-yl) ethyl] -1
-(Phenylsulfonyl) -1H-1,2,4-triazole-5-i
[Imino] imidazolidine-1-yl) ethanol Examples 10, 11, 12, 2 from the compound obtained in Example 4
Compound obtained by the same operation as in 8, 29 (2.0 g)
To a suspension of ethanol (20 ml) was added hydroxyethylethylenediamine (521 mg), and the mixture was heated under reflux for 2 hours.
The obtained reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound as a pale yellow oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.63 (d, 3H, J = 7.2
Hz), 3.61-3.76 (m, 4H), 4.14 (q, 1H, J = 7.2 Hz),
7.34-7.66 (m, 12H), and 8.09 (m, 2H)

Example 47 3- [1- (1,1′-biphenyl-4-yl) ethyl] -N-[(2E) -1- (2-
{[tert-butyl (dimethyl) silyl] oxy} ethyl) -3-me
Tylimidazolidine-2-ylidene] -1- (phenylsulfoni
) -1H-1,2,4-triazol-5-amine The compound (2.5 g) obtained in Example 46 was dissolved in DMF, imidazole (408 mg) and t-butyldimethylsilyl chloride (753 mg) were added, and the mixture was allowed to stand overnight. Water is added to the reaction mixture, and hexane: ethyl acetate = 1: 1 solvent is added to add 3
It was extracted once, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained oily product was dissolved in DMF (20 ml), and sodium hydride (120 mg) was added. One hour later, methyl iodide (0.187 ml) was added, and the mixture was further left overnight. Water is added to the reaction mixture, and hexane: ethyl acetate = 1: 1
The mixture was extracted three times with the addition of a solvent, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was subjected to silica gel column chromatography, and the desired fraction was concentrated to give the title compound (1.6 g). ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 0.02 (s, 6H), 0.86
(s, 9H), 1.63 (d, 3H, J = 7.2 Hz), 2.56 (s, 3H), 3.
20-3.22 (m, 2H), 3.42-3.45 (m, 2H), 3.57-3.66 (m,
4H), 4.12 (q, 1H, J = 7.2 Hz), 7.33-7.56 (m, 12H),
and 8.05-8.07 (m, 2H)

Example 48 2-[(2E) -2-({3- [1- (1,1'-biphenyl-4-yl) ethyl] -1
H-1,2,4-triazol-5-yl} imino) -3-methylimida
Zolidin-1-yl] ethanol The compound (1.6 g) obtained in Example 47 was added to 4N hydrochloric acid-dioxane (20 ml), and the mixture was allowed to stand overnight. The solvent was concentrated under reduced pressure, and the residue was washed three times with diethyl ether. Then, chloroform and a saturated aqueous solution of sodium hydrogen carbonate were added, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was subjected to silica gel column chromatography, and the desired fraction was concentrated to give the title compound (1.0 g). ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.69 (d, 3H, J = 7.2
Hz), 2.67 (s, 3H), 3.45-3.58 (m, 6H), 3.69-3.72
(m, 2H), 4.18 (q, 1H, J = 7.2 Hz), and 7.28-7.57
(m, 9H)

Example 49 1-((2E) -2-{[3- [1- (1,1′-biphenyl-4-yl) ethyl] -1
-(Phenylsulfonyl) -1H-1,2,4-triazole-5-i
[Imino] imidazolidine-1-yl) propan-2-ol Using 2-hydroxypropylethylenediamine, the desired product was obtained in the same manner as in Example 46. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.26 (d, 3H, J = 6.3
Hz), 1.63 (d, 3H, J = 7.2 Hz), 3.30-3.34 (m, 1H),
3.42-3.47 (m, 1H), 3.58-3.71 (m, 5H), 4.14 (q, 1H,
J = 7.2 Hz), 7.31-7.59 (m, 12H), 8.02 (s, 1H), and
8.09 (m, 2H)

Example 50 1-((2E) -2-{[3- [1- (1,1'-biphenyl-4-yl) ethyl] -1
-(Phenylsulfonyl) -1H-1,2,4-triazole-5-i
Le] imino} imidazolidine-1-yl) acetone Under a nitrogen atmosphere, add dimethyl sulfoxide to a solution of oxalyl chloride (0.74 ml) in dichloromethane (3 ml) at -30 ° C.
(1.26 ml) in dichloromethane (3 ml) was slowly added dropwise. After 15 minutes, a solution of the compound obtained in Example 49 (1.96 g) in dichloromethane (10 ml) was slowly added dropwise at the same temperature, and after 5 minutes, triethylamine (2.6 ml) was added, and the mixture was slowly returned to room temperature. After water was added to the reaction mixture and the layers were separated, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was subjected to silica gel column chromatography, and the desired fraction was concentrated to give the title compound (1.7 g). ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.62 (d, 3H, J =
7.2 Hz), 2.24 (s, 3H), 3.57-3.70 (m, 4H), 4.13 (q,
1H, J = 7.2 Hz), 4.72 (s, 2H), 7.31-7.57 (m, 12H),
and 7.96-7.99 (m, 2H)

Example 51 1-[(2E) -2-({3- [1- (1,1'-biphenyl-4-yl) ethyl] -1
H-1,2,4-triazol-5-yl} imino) imidazolidine-
1-yl] acetone From the compound obtained in Example 50, the desired product was obtained in the same manner as in Example 48. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.69 (d, 3H, J = 7.
2), 2.09 (s, 3H), 3.52-3.57 (m, 2H), 3.65-3.70 (m,
2H), 4.18 (q, 1H, J = 7.2 Hz), 4.28 (s, 2H), 7.29-
7.57 (m, 9H), and 8.49 (bs, 1H)

Example 52 1-[(2E) -2-({3- [1- (1,1'-biphenyl-4-yl) ethyl] -1
H-1,2,4-triazol-5-yl} imino) imidazolidine-
1-yl] -2-methylpropan-2-ol In a nitrogen atmosphere, the compound (1.05 g) obtained in Example 50 was treated with T
To the HF (10 ml) solution was added a 1.0 M methylmagnesium bromide THF solution (20 ml) at -40 ° C, and the temperature was raised to room temperature over 2 hours. Water and ethyl acetate were added, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was dissolved in dioxane, an aqueous sodium hydroxide solution was added, and the mixture was heated to 60 ° C for 2 hours. Ethyl acetate was added to the resulting mixture, liquid separation was performed, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was subjected to silica gel column chromatography, and the desired fraction was concentrated to give the title compound (0.6 g). ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.25 (s, 6H), 1.69
(d, 3H, J = 7.2 Hz), 3.29 (s, 2H), 3.59-3.70 (m, 4
H), 4.18 (q, 1H, J = 7.2 Hz), 7.31-7.58 (m, 9H), a
nd 8.36 (m, 1H)

Example 53 Ethyl [(2E) -2-({3- [1- (3-benzoylphenyl) ethyl ]
Ru] -1H-1,2,4-triazol-5-yl} imino) imidazoli
Gin-1-yl] acetate After cooling a suspension of 60% -sodium hydride (0.28 g) in THF (30 ml) to 0 ° C., a compound (3.2 g) obtained from the compound obtained in Example 29 and ethylenediamine in the same manner as in Example 46 (3.2 g) Was added in THF (30 ml). After 15 minutes, ethyl bromoacetate (0.74 ml) was added, and the mixture was stirred for 1 hour.
Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with water, dried and concentrated. Dissolve the residue in THF (50 ml),
Tetrabutylammonium fluoride (1MTHF solution,
12 ml) and heated under reflux for 3 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated, and the residue is purified by a silica gel column to give the desired product (1.6
g) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.26 (t, 3H, J = 7.1H
z), 1.68 (d, 3H, J = 7.2Hz), 3.57-3.70 (m, 4H), 4.13
(s, 2H), 4.19 (q, 2H, J = 7.1Hz), 4.20 (q, 3H, J = 7.2H
z), 7.36-7.50 (m, 3H), 7.52-7.65 (m, 3H), 7.76-7.88
(m, 3H), 8.22 (s, 1H)

Example 54 Methyl N- [3- [1- (3-benzoylphenyl) ethyl] -1- (f
Enylsulfonyl) -1H-1,2,4-triazol-5-yl]-
4-morpholinecarbimidothioate Compound (14.5 g) obtained in Example 29 was added to ethanol (270 m
l), morpholine (2.82 ml) was added, and the mixture was heated under reflux for 1 hour. After cooling to room temperature, the solvent was distilled off with an evaporator, the residue was poured into water, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and then concentrated with an evaporator to obtain a colorless powdery product (14.9 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.63 (d, 3H, J = 7.3 Hz),
1.97 (s, 3H), 3.67 (s, 8H), 4.19 (q, 1H, J = 7.3Hz), 7.
31-7.64 (m, 9H), 7.73-7.78 (m, 3H), 7.95-8.01 (m, 2H)

Example 55 (3- {1- [5- (2- (4-morpholinyl) -5,6-dihydro-1 (4H) -pi
Limidinyl) -1H-1,2,4-triazol-3-yl] ethyl} f
(Enyl) (phenyl) methanone Compound (1.0 g) obtained in Example 54 was converted into dioxane (10 ml).
And add 3-amino-1-propanol (1 ml), add 70
The mixture was heated and stirred at ℃ for 1 hour. After cooling to room temperature, ethyl acetate,
Water was added, and the mixture was separated and extracted. The organic layer was washed with water, dried and concentrated, and the residue was dissolved in dichloromethane (20 ml). 0 ℃
After cooling, triethylamine (0.41 ml) and methanesulfonyl chloride (0.24 ml) were added, and the mixture was stirred for 2 hours. The reaction solution was poured into a saturated aqueous solution of ammonium chloride, ethyl acetate and water were added, and the mixture was separated and extracted. The organic layer was washed with water, dried and concentrated. The obtained residue was dissolved in dioxane (40 ml), and a 2N aqueous sodium hydroxide solution (10 ml) was added.
For 1 hour. After cooling to room temperature, water and ethyl acetate were added and the layers were separated. The aqueous layer was extracted five times with chloroform,
After drying over sodium sulfate and concentration, 0.62 g of the desired product was obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.69 (d, 3H, J = 7.2 Hz),
1.84 (m, 2H), 3.01-3.09 (m, 4H), 3.38-3.47 (m, 2H),
3.58-3.72 (m, 4H), 3.77-3.85 (m, 2H), 4.24 (q, 1H, J =
7.2Hz), 7.38-7.51 (m, 3H), 7.56-7.66 (m, 3H), 7.77-
7.83 (m, 3H)

Example 56 5- [1- (2-Fluoro-1,1′-biphenyl-4-yl) ethyl] -1-
Methyl-1H-1,2,4-triazol-3-amine Sodium hydride (60%) in ice-cooled methanol (10 ml)
, 0.14 g) and stirred for 10 minutes to give the compound obtained in Example 1.
(1.0 g) was added to the reaction solution. After dissolving the raw materials, methyl iodide (0.53 ml) was added, and the mixture was heated and stirred at 60 ° C. Two hours later, the resulting crystals were filtered and washed to obtain the desired product (0.2 g). The filtrate is concentrated, the residue is purified by a silica gel column, and the desired product (0.1 g) and 3- [1- (2-fluoro-1,1′-biphenyl-4-yl) ethyl] -1-methyl-1H -1,2,4-Triazol-5-amine (0.6 g) was obtained. ¹ H-NMR (300 MHz, d ₆ -DMSO) δ ppm: 1.54 (d, 3H, J = 7.0H
z), 3.49 (s, 3H), 4.36 (q, 1H, J = 7.0Hz), 5.18 (brs, 2
H), 7.17-7.26 (m, 2H), 7.34-7.54 (m, 6H)

Example 57 1- (2-{[tert-butyl (diphenyl) silyl] oxy} ethyl
) -3- [1- (2-Fluoro-1,1'-biphenyl-4-yl) ethyl
Ru] -1H-1,2,4-triazol-5-amine The compound (12.9 g) obtained in Example 14 was dissolved in DMF (200 ml), imidazole (6.8 g) and t-butyldiphenylsilyl chloride (12.3 ml) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated, and the residue is purified by a silica gel column.
g) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.03 (s, 9H), 1.67 (d,
3H, J = 7.2Hz), 3.95 (t, 2H, J = 4.8Hz), 4.09 (t, 2H, J =
4.8Hz), 4.12 (q, 1H, J = 7.2Hz), 4.63 (brs, 2H), 7.13-
7.23 (m, 2H), 7.29-7.46 (m, 10H), 7.50-7.57 (m, 6H)

Example 58 N '-[3- [1- (2-Fluoro-1,1'-biphenyl-4-yl) ethyl
L] -1- (2-Hydroxyethyl) -1H-1,2,4-triazole-5
-Yl] morpholine-4-carboximidamide To a solution of the compound (500 mg) obtained in Example 57 and triethylamine (0.75 mL) in dichloromethane (10 mL) was added 4- (dichloromethylene) morpholinium chloride (362 mg), and the mixture was stirred for 15 minutes. Aqueous ammonia (10 mL) and dioxane (10 mL) were added thereto, and the mixture was stirred for 2 hours. The solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with chloroform. The organic layers were combined, dried over sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain a guanidine compound. The silyl protecting group was removed by adding a tetrabutylammonium fluoride solution in a THF solvent and purified by column chromatography to obtain the desired product. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.67 (d, 3H, J = 7.2H
z), 3.46-3.49 (m, 4H), 3.73-3.76 (m, 4H), 3.93-3.95
(m, 2H), 4.14 (q, 1H, J = 7.2Hz), 4.23-4.25 (m, 2H),
4.72 (br.s, 1H), 7.00-7.18 (m, 4H), 7.32-7.36 (m, 2
H), 7.40-7.44 (m, 2H), 7.51-7.53 (m, 2H)

Example 59 N- [3- [1- (2-Fluoro-1,1′-biphenyl-4-yl) ethyl]
-1- (2-hydroxyethyl) -1H-1,2,4-triazole-5-a
[] Methanesulfonamide The compound (2.0 g) obtained in Example 57 was dissolved in THF (30 ml), and triethylamine (2.0 ml) and methanesulfonyl chloride (1.2 ml) were added at 0 ° C. 20 minutes later, water,
Ethyl acetate was added, and the mixture was separated and extracted. The organic layer was washed with water, dried and concentrated, and the residue was dissolved in THF (30 ml). 2 at 0 ° C
An N aqueous sodium hydroxide solution was added, and the mixture was stirred for 40 minutes. Water and ethyl acetate were added to the reaction solution, and the mixture was separated and extracted. The organic layer was washed with 1N hydrochloric acid, water and saturated saline, dried and concentrated, and the residue was dissolved in THF (30 ml). At room temperature, tetrabutylammonium fluoride (1 MTHF solution, 4.3 ml) was added and 9
Stirred for hours. Water and ethyl acetate were added to the reaction solution, and the mixture was separated and extracted. The organic layer was washed with water, dried and concentrated, and the residue was purified by a silica gel column to obtain the desired product (1.0 g). ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.68 (d, 3H, J = 7.2H
z), 2.99 (s, 3H), 3.99 (t, 2H, J = 5.0Hz), 4.05-4.16 (m,
3H), 7.01-7.11 (m, 2H), 7.35-7.55 (m, 6H)

Example 60 3- [1- (2-Fluoro-1,1′-biphenyl-4-yl) ethyl] -1-
[2- (azido) ethyl] -1H-1,2,4-triazol-5-amine Compound (5.0 g) obtained in Example 14 was treated with methylene chloride (100 g).
ml) and triethylamine (3.2 m
l), methanesulfonyl chloride (1.7 ml) was added. Four hours later, water and ethyl acetate were added, and the mixture was separated and extracted. The organic layer is washed with water, dried and concentrated, and the residue is DMF (150m
l). Add sodium azide (1.5 g) and add 8
Heated at 0 ° C. for 1 hour. Water and ethyl acetate were added to the reaction solution,
Separated and extracted. The organic layer was washed with water, dried and concentrated, and the residue was purified by a silica gel column to obtain the desired product (3.6 g). ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.66 (d, 3H, J = 7.2H
z), 3.75-3.81 (m, 2H), 3.95-4.02 (m, 2H), 4.10 (q, 1
H, J = 7.2Hz), 4.60 (brs, 2H), 7.10-7.20 (m, 2H), 7.31
-7.45 (m, 4H), 7.49-7.55 (m, 2H)

Example 61 1- (2-Aminoethyl) -3- [1- (2-fluoro-1,1′-biphenyl
Ru-4-yl) ethyl] -1H-1,2,4-triazol-5-amine The compound (3.6 g) obtained in Example 60 was added to ethanol (50 m
l), 10% Pd-C (0.5 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction solution was filtered through celite,
The filtrate was concentrated. The residue was crystallized from toluene-hexane to obtain the desired product (1.5 g). ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.59 (d, 3H, J = 7.2H
z), 3.11 (br, 2H), 4.01 (q, 1H, J = 7.2Hz), 4.06 (br, 2
H), 5.64 (br, 2H), 7.07-7.16 (m, 2H), 7.30-7.44 (m, 4
H), 7.47-7.53 (m, 2H)

Example 62 N- (2- {5-amino-3- [1- (2-fluoro-1,1'-biphenyl-4-)
Yl) ethyl] -1H-1,2,4-triazol-1-yl} ethyl)
Methanesulfonamide Compound (1.0 g) obtained in Example 61 was treated with methylene chloride (20 g).
ml), and triethylamine (0.51 ml) and methanesulfonyl chloride (0.28 ml) were added at 0 ° C. 2
After an hour, water and ethyl acetate were added to the reaction solution, and the mixture was separated and extracted. The organic layer was washed with water, dried and concentrated, and the residue was purified by a silica gel column to obtain the desired product (1.2 g). ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.62 (d, 3H, J = 7.1H
z), 2.77 (s, 3H), 3.36-3.50 (m, 2H), 3.91 (q, 1H, J =
7.1Hz), 3.94-4.07 (m, 2H), 5.08 (s, 2H), 6.98-7.09
(m, 2H), 7.32-7.53 (m, 6H), 8.51 (br, 1H)

Example 63 3- [1- (2-Fluoro-1,1′-biphenyl-4-yl) ethyl] -1-
(2-Fluoroethyl) -1H-1,2,4-triazol-5-amine A mesyl compound (3.0 g) as an intermediate of Example 60 was dissolved in acetonitrile (30 ml), tetrabutylammonium fluoride (1 MTHF solution, 11 ml) was added, and the mixture was heated at 80 ° C. After 1.5 hours, the reaction solution was concentrated, water and ethyl acetate were added, and the mixture was separated and extracted. The organic layer was washed with water, dried and concentrated, and the residue was purified on a silica gel column to obtain the desired product. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.65 (d, 3H, J = 7.2H
z), 4.10 (t, 1H, J = 4.4Hz), 4.17 (t, 1H, J = 4.4Hz), 4.
46 (br, 2H), 4.71 (t, 1H, J = 4.4Hz), 4.83 (t, 1H, J = 4.4
Hz), 7.11-7.20 (m, 2H), 7.31-7.45 (m, 4H), 7.50-7.55
(m, 2H)

Example 64 1- (2-ethoxyethyl) -3- [1- (2-fluoro-1,1′-biphe
Nyl-4-yl) ethyl] -1H-1,2,4-triazol-5-amine The compound (0.10 g) obtained in Example 14 was dissolved in THF (2 ml), cooled to 0 ° C., and 60% sodium hydride (14 mg) was added. After 30 minutes, ethyl iodide (0.04 ml) was added. After 5 hours, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated, and the residue was purified on a silica gel column to obtain the desired product. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.19 (t, 3H, J = 7.0H
z), 1.65 (d, 3H, J = 7.2Hz), 3.51 (q, 2H, J = 7.0Hz), 3.
73 (t, 2H, J = 4.5Hz), 4.06-4.13 (m, 3H), 4.86 (br, 2H),
7.11-7.21 (m, 2H), 7.29-7.46 (m, 4H), 7.49-7.55 (m,
2H)

Example 65 N ′-{3- [1- (3-Benzoylphenyl) ethyl] -1H-1,2,4-to
Riazol-5-yl} -N-propyl-4-morpholinecarbox
Simidamide trifluoroacetate Compound (288 mg) obtained in Example 54 was converted into dioxane (2 mL).
, And n-propylamine (0.082 mL) was added, followed by stirring at room temperature for 4 hours. After confirming the disappearance of the raw materials by TLC, 2
An N-sodium hydroxide aqueous solution (1 mL) was added, and the mixture was refluxed under heating for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated by an evaporator to obtain a crude product (244 mg). High performance liquid chromatography (column: YM)
C CombiPrep ODS-A 75xφ30mm, Solvent: 0.05% trifluoroacetic acid / water: 0.035% trifluoroacetic acid / acetonitrile =
95: 5 to 5:95) to give the desired product as an oil (43 mg). HPLC rt 13.48 min (column: Waters Puresil C18, e
luent: 10mM-AcONH ₄ / H ₂ O (pH 4): CH ₃ CN = 80: 20 → 20: 80 (3
0min)) LC / MS (m / e) 447.4 ¹ H-NMR (300MHz, CDCl ₃ ) δ ppm: 0.92 (t, 3H, J = 7.4Hz),
1.64 (sext, 2H, J = 7.2Hz), 1.75 (d, 3H, J = 7.3Hz), 3.
20-3.30 (m, 2H), 3.55-3.60 (m, 4H), 3.75-3.80 (m, 4
H), 4.40 (q, 1H, J = 7.0Hz), 7.40-7.65 (m, 6H), 7.76-
7.79 (m, 3H), 9.21 (br s, 1H)

Examples 77 to 716 The following compounds were synthesized in the same manner as in the above Examples. Each compound has a retention time of high performance liquid chromatography (column: Waters Puresil C18, eluent: 1
(0 mM-AcONH ₄ / H ₂ O (pH 4): CH ₃ CN = 80: 20 → 20: 80 (30 min)) and LC / MS spectrum.

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

Examples 800 to 1005 By the same operation as in the above Examples, the following compounds were synthesized.

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

Test Example 1Suppress adjuvant arthritis  Male SD rats were used as experimental animals. Mycobacteriu
The dead cells of m butyricum should be fluidized to a concentration of 0.5%.
Inject the suspension in raffin subcutaneously into the right hind footpad of the rat.
Entered. 17 days later, clear secondary inflammation on the left hind limb
Select recognized animals and suspend in 0.5% methylcellulose solution.
The turbidized compound of the present invention was orally administered for 5 consecutive days.
Volume of hind limb 5 hours after completion of administration
The swelling inhibitory effect was evaluated based on this difference. So
Table 1 shows the results.

[0261]

Industrial Applicability According to the present invention, it has become possible to provide a drug which is excellent in physical properties and has a strong improvement effect on both immune abnormality and chronic inflammation.

Continuation of the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) A61K 31/5355 A61K 31/5355 31/541 31/541 A61P 29/00 A61P 29/00 37/00 37/00 C07D 403 / 12 C07D 403/12 (72) Inventor Toshio Kanai 3-1-198, Kasuganaka, Konohana-ku, Osaka City Within Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Norihisa Fukuda 3-chome, Kasuganaka, Konohana-ku, Osaka-shi No. 98 Sumitomo Pharmaceutical Co., Ltd. F-term (reference) 4C063 AA01 BB08 BB09 CC41 DD10 DD26 DD29 EE01 4C086 AA02 AA03 BC60 GA07 GA12 MA04 MA52 MA55 NA14 ZB07 ZB11

Claims (12)

[Claims] 1. Equation (1): [Wherein, M is a single bond, -O-, -S-, -SO-, -S
O _2- , -CQ- (Q represents a 1,3-dioxane ring or a 1,3-dioxolane ring together with a carbon atom),-
^{CH (OR 21) -, -C} (OR 21) 2 -, - C (=
NOR ²¹ )-, -C (= NR ²¹ )-(R ²¹ represents a hydrogen atom or an alkyl group), -C (= NNR
^{22 R 23)} - ^{(R 22} and ^{R 23} represent independently a hydrogen atom or an alkyl group,), -. CO-, or an -CS-. Y ¹ and Y ² are independently a hydrogen atom,
Halogen atom, alkyl group, haloalkyl group, nitro group, cyano group, -OR ²⁴ , -COR ²⁴ (R ²⁴ represents a hydrogen atom or an alkyl group or a haloalkyl group), -CO ₂ R ²⁵ , -SO ₂ R ^{2 5, (R 25} represents an alkyl group.) - ^CONR 26 ^{R 27} and -
SO ₂ NR ²⁶ R ²⁷ (R ²⁶ and R ^{27 each} independently represent a hydrogen atom or an alkyl group, or R ²⁶ and R ²⁷ may combine to form an aliphatic heterocyclic ring.) And may be bonded to any position on the benzene ring. Each of Y ¹ and Y ² may be 0 to 3 and may be the same or different.
When two or more Y ¹ or Y ² are present, they may together represent a methylenedioxy group or an ethylenedioxy group. R ⁸ and R ⁹ are
Each independently represents a hydrogen atom or an alkyl group. Alternatively, R ⁸ and R ⁹ may combine to form an optionally substituted hydrocarbon ring together with the carbon atom to which they are attached. R ⁷ represents a substituent bonded to any nitrogen atom of the triazole ring, and represents a hydrogen atom, -R ²⁸ , -C
^{_{OR 28, -SO 2 R 28,}} -COOR 28 (R
²⁸ is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, an optionally substituted cycloalkyl group, Represents an aliphatic heterocyclic group which may be substituted, or an aromatic heterocyclic group which may be substituted. ), An optionally substituted carbamoyl group, or an optionally substituted sulfamoyl group. L is the formula: [In the formula, two broken lines mean one with a solid line and a double bond, and the other with a solid line and a single bond. R ¹ is bonded to the nitrogen atom having a bond in which the broken line and the solid line represent a single bond. R ¹ , R ² , R ³ and R ⁴ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, —R ²⁹ , —OR
²⁹ , -COR ²⁹ , -COOR ²⁹ , -SOR ²⁹ ,
—SO ₂ R ²⁹ (R ²⁹ represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, or an optionally substituted cycloalkyl group. ), An optionally substituted amino group, an optionally substituted hydroxyamino group,
Represents a carbamoyl group which may be substituted, or a sulfamoyl group which may be substituted. Or R ¹ ,
Any two of R ² , R ³ and R ⁴ may combine to form an optionally substituted aliphatic heterocyclic ring. ]. Or L is the formula: In the formula, R ⁵ or R ⁶ is each independently a hydrogen atom,
Hydroxyl group, -R ²⁹ , -OR ²⁹ , -COR ²⁹ , -CO
OR ²⁹ , —SOR ²⁹ , or —SO ₂ R ²⁹ (R
²⁹ has the same meaning as described above. ). Alternatively, R ⁵ and R ⁶ may combine to form an optionally substituted aliphatic heterocycle. Represents｝. Or a pharmaceutically acceptable salt thereof. 2. Equation (2):[Where M, L, Y¹, Y², R⁸, R⁹Is in claim 1
This is synonymous with significance. R¹⁸Is a hydrogen atom, -R
²⁸, -COR²⁸, -SO₂R²⁸, -COOR ²⁸
(R²⁸Has the same meaning as in claim 1. ),
An optionally substituted carbamoyl group, or
Represents an optionally substituted sulfamoyl group. ]
A lyazole derivative or a pharmaceutically acceptable salt thereof. 3. Equation (3): [Wherein, M, L, Y ¹ , Y ² , R ⁸ , and R ⁹ have the same meanings as in claim 1]. R ¹⁹ is a hydrogen atom,-
^{_{R 28, -COR 28, -SO 2}} R 28, -COOR 2
⁸ (R ²⁸ has the same meaning as in claim 1), represents an optionally substituted carbamoyl group, or an optionally substituted sulfamoyl group. Or a pharmaceutically acceptable salt thereof. Equation (4): [Wherein, M, L, Y ¹ , Y ² , R ⁸ , and R ⁹ have the same meanings as in claim 1]. R ²⁰ is a hydrogen atom,-
^{_{R 28, -COR 28, -SO 2}} R 28, -COOR 2
⁸ (R ²⁸ has the same meaning as in claim 1), represents an optionally substituted carbamoyl group, or an optionally substituted sulfamoyl group. Or a pharmaceutically acceptable salt thereof. 5. M is a single bond, -O-, -S-, -SO
—, —SO ₂ —, or —CO—, wherein Y ¹ or Y ² independently represents a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, or a haloalkoxy group. 5. The triazole derivative or the pharmaceutically acceptable salt thereof according to any of 4. 6. The triazole derivative according to claim 1, wherein R ⁸ and R ⁹ independently represent a hydrogen atom or an alkyl group, or a pharmaceutically acceptable salt thereof. 7. M represents a single bond or —CO—,
Y ¹ or Y ² independently represents a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, or a haloalkoxy group, and R ⁸ and R ⁹ independently represent a hydrogen atom or an alkyl group R ⁷ is a hydrogen atom, —R ³⁰ , —COR ³⁰ , —SO ₂ R ³⁰ , COO
R ³⁰ (R ³⁰ is an optionally substituted alkyl group,
Represents an optionally substituted alkenyl group, an optionally substituted alkynyl group, or an optionally substituted cycloalkyl group. 3. The triazole derivative according to claim 1, which represents an optionally substituted carbamoyl group or an optionally substituted sulfamoyl group, or a pharmaceutically acceptable salt thereof. 8. R ⁷ is a hydrogen atom, —R ³⁰ , —COR
^{_{30, -SO 2 R 3 0,}} -COOR 30 (R 30 has the same meaning and significance in claim 7.), Wherein representing the optionally substituted carbamoyl group or an optionally substituted sulfamoyl group, Item 7. The triazole derivative according to item 7, or a pharmaceutically acceptable salt thereof. 9. Do R ⁷ represents a hydrogen atom, or a hydroxyl group, a cyano group, a carboxy group, an alkoxy group, a haloalkoxy group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkoxycarbonyl group, aryl which may be substituted Group, an optionally substituted aromatic heterocyclic group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted sulfamoyl group, The triazole derivative or a pharmaceutically acceptable salt thereof according to claim 7, which represents an alkyl group of (1) to (4). 10. Formula (5): (In the formula, Y ³ represents a hydrogen atom or a halogen atom. R ¹¹ represents a hydrogen atom or a methyl group. R ¹⁰
Represents a hydrogen atom, or a hydroxyl group, a cyano group, a carboxy group, an alkoxy group, a haloalkoxy group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkoxycarbonyl group, an optionally substituted aryl group, Represents an aromatic heterocyclic group which may be substituted, an amino group which may be substituted, a carbamoyl group which may be substituted, or an alkyl group having 1 to 4 carbon atoms which may be substituted by an optionally substituted sulfamoyl group; . L has the same meaning as in claim 1. Or a pharmaceutically acceptable salt thereof. 11. The triazole derivative or the pharmaceutically acceptable salt thereof according to claim 10, wherein Y ³ represents a fluorine atom or a hydrogen atom, and R ¹¹ represents a methyl group. 12. L is a formula: In the formula, R ¹⁴ and R ¹⁵ each independently represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms which may be substituted with a hydroxyl group or an oxo group. The triazole derivative according to claim 10, which is represented by｝, or a pharmaceutically acceptable salt thereof.