JP2002212169A - Five membered heteroaromatic ring compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicine manifesting a strong ameliorating effect to both of an immunopathy and chronic inflammation. SOLUTION: This compound is a five membered heteroaromatic ring compound or its salt expressed by formula (I). [E is a group expressed by formula (2), (in the formula M is a single bond, -O-, -S-, -SO-, -SO2- or the like), A is a five membered heteroaromatic ring compound or the like expressed as a divalent group selected from group (3), G is -NR5R6 (R5 and R6 are each the same as or different from each other and H or -R19. R19 is a (substituted) alkyl group, a (substituted) alkenyl group, a (substituted) alkynyl group, a (substituted) cycloalkyl group, a (substituted) cycloalkenyl group or an aralkyl group.), R8, R9, R10 and R11 are each independently H, or an alkyl group. R8 and R9, and/or R10 and R11 may bond to form a hydrocarbon ring together with their bonding C or a saturated heterocycle together with a hetero atom selected from O, N and S].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a 5-membered heteroaromatic compound having excellent physical properties and 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 these circumstances,
63-152368 reports aralkyl-5-membered heterocyclic compounds containing thiazole, oxazole, isoxazole derivatives and the like as therapeutic agents for autoimmune diseases, inflammation, allergy, asthma and the like. German Patent No. 2,847,792 reports quinolylguanidine derivatives, including isoxazole derivatives, as anti-inflammatory, analgesic and antipyretic agents. J. M
ed. Chem., 21 , 773 (1978) states that N-cyano-N'-
It has been reported that isoxazolylguanidine derivatives are effective as antihypertensive agents. International Patent Publication No.
No. 98/47880 (WO 98/47880), which has an excellent immunity improving effect and a chronic inflammation improving effect, with few side effects,
A guanidino group-substituted isoxazole derivative useful as a therapeutic or prophylactic agent for autoimmune diseases and inflammatory diseases has been reported. JP-A-9-59258 reports thiazole, oxazole and imidazole derivatives having a guanidino group as compounds having a Maillard reaction inhibitory action and an antioxidant action. JP-A-8-41008 discloses a thiazole derivative having a guanidino group as a compound having an NOS inhibitory action, and JP-A-7-149745 discloses a 2-aminothiazole derivative as a compound having an elastase inhibitory action. It has been reported.

[0003]

The present invention has excellent physical properties,
It is another object of the present invention to provide a compound useful as a therapeutic agent for autoimmune diseases, inflammatory diseases and the like.

[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, have found various new 5 types.
The present inventors have found that a membered heteroaromatic compound has excellent physical properties and shows a strong effect on both the amelioration of immunological abnormalities and the amelioration of chronic inflammation, thereby completing the present invention. That is, the present invention is as follows. [1] Equation (1):

Embedded image [Wherein E is the formula:

Embedded image Ｍwherein 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 12) -, -C} (OR 12) 2 -, - C (=
NOR ¹² )-, -C (= NR ¹² )-(R ¹² represents a hydrogen atom or an alkyl group), -C (= NNR
^{13 R 14) -, (R} 13 and R ¹⁴ represent independently a hydrogen atom or an alkyl group,), -. CO-, or an -CS-. ｝ Or the formula:

Embedded image(Wherein B is a single bond, -O-, -S-, -SO- or
-SO₂Represents-. ). E is a halogen source
Child, nitro, formyl, acetyl, cyano, alkyl
Group, haloalkyl group, -OR²²(R²²Is hydrogen field
, An alkyl group, or a haloalkyl group. ),-
CO₂R²³, -SO₂R²³(R²³Is an alkyl group
Represents ) -CONR²⁴R²⁵, And -SO₂NR
²⁴R²⁵(R^{2 4}And R²⁵Is, independently, a hydrogen source
Represents a child or an alkyl group. )
It may be substituted with 1 to 4 groups. A is
Thiazole, oxazole, imidazole, pyrrole,
Furan, thiophene, isothiazole, isoxazo
1,3,4-oxadiazole, 1,3,4-thia
Diazole, 1,2,4-oxadiazole, 1,2,
4-thiadiazole, pyrazole, 1,2,4-tria
Represents sol. R⁷Is a carbon atom of A and / or nitrogen
Represents a substituent bonded to an atom. r represents an integer of 0 to 2
You. Substituent R on the carbon atom of A⁷Is a halogen atom, hydroxyl
Group, nitro group, cyano group, carboxyl group, substituted
Optionally substituted amino group, optionally substituted hydroxy
Amino group, carbamoyl group which may be substituted, substitution
An optionally substituted sulfamoyl group, -R^Fifteen, -OR
^Fifteen, -COR^Fifteen, -CO_TwoR^Fifteen(Where R^FifteenIs
Alkyl group which may be substituted, which may be substituted
Alkenyl group, alkynyl group which may be substituted,
An optionally substituted cycloalkyl group,
A cycloalkenyl group, an optionally substituted ant
Or an aralkyl group which may be substituted,
Represents an optionally substituted heterocyclic group. ), -S
R¹⁶, -SO-R¹⁶, -SO₂-R ¹⁶, -C
(O) SR¹⁶, -C (S) OR¹⁶, Or -CS_Two
R¹⁶(R^{1 6}Is an optionally substituted alkyl group,
An aryl group which may be substituted, or
Represents an aralkyl group. ). A is imidazo
1,2,4-triazole, pyrrole, or pyra
When representing a sol, a substituent on the nitrogen atom, R⁷Ha
Toro group, cyano group, carbamoyl which may be substituted
Group, an optionally substituted sulfamoyl group, an NH group
Protecting group, -R^Fifteen, -OR^Fifteen, -COR^Fifteen, -CO_Two
R^Fifteen, -SR¹⁶, -SOR¹⁶, -SO₂R ¹⁶,
-(CO) SR¹⁶,-(CS) OR¹⁶Or -C
S₂R¹⁶(Where R^Fifteen, And R¹⁶Is as defined above
It is. ). X is an oxygen atom, a sulfur atom, or
 = NR¹⁷(Where R¹⁷Represents a hydrogen atom, a hydroxyl group,
Or an optionally substituted alkyl. ).
G is -NR⁵R⁶[R⁵Or R⁶Are the same or different
Becomes a hydrogen atom, -R¹⁹(Where R¹⁹Is replaced
Alkyl group which may be optionally substituted
Nyl group, an optionally substituted alkynyl group,
An optionally substituted cycloalkyl group, which may be substituted
A cycloalkenyl group or an optionally substituted
Represents an aralkyl group. ). Alternatively, R⁵And R
⁶May be substituted together with the nitrogen atom
May form a saturated heterocyclic ring. ] Or the formula:

Embedded image [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 are independently a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, an optionally substituted amino group, an optionally substituted hydroxy amino group, -R ^{19, -OR 19, -COR 19,} -COOR
_{^{19, -SOR 19, -SO 2 R}} 19 ( ^{wherein, R 19} is an alkyl group which may be substituted, an optionally substituted alkenyl group, an optionally substituted alkynyl group,
It represents a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted, an aralkyl group which may be substituted, and a heterocyclic group which may be substituted. ), An optionally substituted carbamoyl group, or an optionally substituted sulfamoyl group. R ¹ , R ² , R ³ and R
⁴ may have any two of them bonded to form a heterocyclic ring which may be substituted with one nitrogen atom or with two nitrogen atoms and one carbon atom. ]. R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ each independently represent a hydrogen atom or an alkyl group. In addition, R ⁸ and R ⁹ and / or R ¹⁰ and R ¹¹ are bonded to each other, and together with the carbon atom to which they are bonded, a hydrocarbon ring or an oxygen atom, a nitrogen atom, or a sulfur atom is selected. It may form a saturated heterocyclic ring with a hetero atom. Or a pharmaceutically acceptable salt thereof.

[2] In the equation (1), A is an equation:

Embedded image[In the formula, m represents 0 or 1. R¹⁸Is a nitrogen atom
Represents a substituent that combines ¹⁸Is a nitro group, a cyano group,
Optionally substituted carbamoyl group, optionally substituted
Good sulfamoyl group, protecting group for NH group, -R^Fifteen, −
OR^Fifteen, -COR^Fifteen, -CO_TwoR^Fifteen, -S
R¹⁶, -SOR¹⁶, -SO2R¹⁶,-(CO) S
R¹⁶,-(CS) OR¹⁶, -CS₂R¹⁶Or
−CS_TwoR¹⁶(Where R^Fifteen, And R¹⁶Is
It is synonymous. ). 5 members according to [1],
A heteroaromatic compound or a pharmaceutically acceptable salt thereof. [3] In the formula (1), A represents the following group:

Embedded image The 5-membered heteroaromatic compound according to [1], which is represented by a divalent group selected from the following: or a pharmaceutically acceptable salt thereof.

[4] The 5-membered heteroaromatic ring compound according to [1] to [3], wherein X is an oxygen atom or a sulfur atom in the formula (1) or a pharmaceutically acceptable salt thereof.

[5] In equation (1), E is an equation:

Embedded image[Where M¹Is a single bond, -CQ- (Q is
A 1,3-dioxane ring or a 1,3-dioxolane ring
Represent. ), -CH (OR¹²)-, -C (OR^{1 2})_Two
-, -C (= NOR¹²)-(R¹²Is as defined above
is there. ), -C (= NR¹²)-, -C (= NNR¹³
R¹⁴)-(R¹³And R¹⁴Is as defined above. ),
Represents -CO- or -CS-. E is a halogen
Atom, acetyl, nitro, formyl, cyano, alkyl
Group, haloalkyl group, -OR²²(R²²Is as defined above
It is. ), -CO₂R ²³, -SO₂R²³(R²³
Is as defined above. ), -CONR²⁴R^{2 5},
And -CONR²⁴R²⁵(R²⁴And R²⁵Is before
Synonymous with ) Arbitrarily selected from the group consisting of
And may be substituted with four groups. Is represented by
The 5-membered heteroaromatic ring compound according to [1] to [4] or a compound thereof.
Pharmaceutically acceptable salts of [6] In the formula (1), E is a formula:

Embedded image Wherein M ² represents a single bond or —CO—, wherein E is a halogen atom, a cyano, an alkyl group,
The 5-membered heteroaromatic compound according to [1] to [4], which may be substituted with 1 to 4 groups arbitrarily selected from the group consisting of a haloalkyl group, an alkoxy group, and a haloalkoxy group, or a pharmaceutical thereof. Above acceptable salts.

[7] Equation (2):

Embedded image [In the formula, X ² is an oxygen atom or a sulfur atom.
Y ¹ and Y ^{2 each} independently represent a halogen atom, or an alkyl group, a haloalkyl group, an alkoxy group, or a haloalkoxy group;
And three may be bonded. Also, Y ¹ or Y ²
When two or more are present, two may be bonded to each other to represent methylenedioxy or ethylenedioxy. A, G, M ² , r, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R
¹¹ and R ¹² are as defined above. Or a pharmaceutically acceptable salt thereof. [8] The 5-membered heteroaromatic ring compound or a pharmaceutically acceptable salt thereof according to [7], wherein G is —NR ⁵ R ⁶ (R ⁵ and R ⁶ are as defined above).

[9] The 5-membered heteroaromatic ring according to [7] or [8], wherein X ² is an oxygen atom, R ¹¹ is an alkyl group, and R ⁸ , R ⁹ , and R ¹⁰ are hydrogen atoms. A compound or a pharmaceutically acceptable salt thereof. [10] The 5-membered heteroaromatic ring according to [7] to [9], wherein Y ¹ and Y ² are each independently a halogen atom, and 0 to 2 identical or different groups may be bonded. A compound or a pharmaceutically acceptable salt thereof.

[11] A is the following group:

Embedded image The 5-membered heteroaromatic compound according to [7] to [10], or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[12] Equation (3):

Embedded image Wherein Y ³ and Y ⁴ are independently a halogen atom,
Or a hydrogen atom, and G, M ² , X ² , m, R ⁸ , R
⁹ , R ¹⁰ , R ¹¹ and R ¹⁸ are as defined above. Or a pharmaceutically acceptable salt thereof. [13] The 5-membered heteroaromatic ring compound of [12], wherein Y ⁴ is a hydrogen atom and Y ³ is a fluorine atom, or a pharmaceutically acceptable salt thereof. [14] Equation (4):

Embedded image [Wherein, G, X ² , m, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R
¹¹ and R ¹⁸ are as defined above. Or a pharmaceutically acceptable salt thereof.

[15] G is a compound represented by the formula: —NR ⁵ R
⁶ (R ⁵ and R ⁶ are as defined above), or the 5-membered heteroaromatic compound according to [12] or [14], or a pharmaceutically acceptable salt thereof. [16] G is a formula:

Embedded image Wherein R ⁴² and R ⁴³ are independently a hydrogen atom,
Hydroxyl group, nitro group, cyano group, -R ¹⁹ , -OR ¹⁹ ,-
COR ¹⁹ , -COOR ¹⁹ , -SOR ¹⁹ , -SO ₂ R
¹⁹ (R ¹⁹ is as defined above), an optionally substituted amino group, an optionally substituted hydroxyamino group,
Represents an optionally substituted carbamoyl group or an optionally substituted sulfamoyl group. Or R ⁴² and R
⁴³ may combine to form a heterocyclic ring which may be substituted. X ¹ is a single _{bond, -CH 2 -, - (CH} 2)
_2- , -NR ⁴¹ -CH _2- (R ⁴¹ is 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, A good alkoxycarbonyl group having 2 to 5 carbon atoms,
Represents an alkylsulfonyl group having 2 to 5 carbon atoms which may be substituted. _{), - O-CH 2 -} , - S-CH 2 -, - S
O-CH ₂ -, or _-SO 2 -CH 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, Represents an alkylsulfonyl group, an optionally substituted amino group, a carboxy group, an oxo group, or a hydroxyl group.
q represents an integer of 0 to 4. ] The triazole derivative according to any one of [1] to [14] and a pharmaceutically acceptable salt thereof.

[17] G is a formula:

Embedded image (Wherein, s represents an integer of 2 to 5. R ⁴² , R ⁴³ ,
R ⁴⁴ and q are as defined above. ) The triazole derivative according to [1] to [14], or a pharmaceutically acceptable salt thereof.

[18] G is a formula:

Embedded image (Wherein R ⁴² , R ⁴³ , R ⁴⁴ , s, and q are as defined above), or the pharmaceutically acceptable salt thereof according to [1] to [14].

[19] G is a formula:

Embedded image (In the formula, R ⁴⁵ independently represents a hydrogen atom or an alkyl group which may be substituted. R ⁴² , R ⁴⁴ , s and q have the same meanings as described above.) ] To [14], or a pharmaceutically acceptable salt thereof.

[20] G is a formula:

Embedded image (Wherein R ⁴² , R ⁴⁴ , s and q have the same meanings as described above), or the pharmaceutically acceptable salt thereof according to [1] to [14].

[21] G is a formula:

Embedded image Or the formula:

Embedded image [Wherein, R ⁴⁶ , R ⁴⁷ and R ⁴⁸ independently represent a hydrogen atom or —R ¹⁹ (R ¹⁹ is as defined above), and R ⁴⁹ represents a hydrogen atom, a hydroxyl group, a nitro group, Group, cyano group, -R ¹⁹ , -OR ¹⁹ , -COR ¹⁹ ,
—COOR ¹⁹ , —SOR ¹⁹ , or —SO ₂ R ¹⁹
(R ¹⁹ has the same meaning as described above.) ] The triazole derivative according to [1] to [14], or a pharmaceutically acceptable salt thereof.

[22] G is a formula:

Embedded image [Wherein, R ⁴⁴ and X ¹ are as defined above. ] The triazole derivative according to [1] to [14], or a pharmaceutically acceptable salt thereof. [23] A medicament comprising the 5-membered heteroaromatic compound of any one of [1] to [22] or a pharmaceutically acceptable salt thereof. [24] A therapeutic or prophylactic agent for an autoimmune disease, comprising the 5-membered heteroaromatic compound or the pharmaceutically acceptable salt thereof according to any one of [1] to [22]. [25] A therapeutic or prophylactic agent for an inflammatory disease, comprising the 5-membered heteroaromatic ring compound of any one of [1] to [22] or a pharmaceutically acceptable salt thereof. [26] An anti-rheumatic drug comprising the 5-membered heteroaromatic ring compound of any one of [1] to [22] or a pharmaceutically acceptable salt thereof.

The names of the substituents used in the present specification are easily understood by those skilled in the art, and are exemplified in more detail below. The halogen atom represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and is preferably a fluorine atom or a chlorine atom. 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, anthranyl, and phenanthrantryl. Preferably, they are phenyl, 1-naphthyl, and 2-naphthyl.

The heterocyclic group is, for example, a 1-3-membered, 4- to 7-membered, saturated heterocyclic group containing 1 to 6 heteroatoms arbitrarily selected from a nitrogen atom, an oxygen atom and / or a sulfur atom. Or an unsaturated heterocyclic group. As such a saturated heterocyclic group, specifically, a 4-membered saturated heterocyclic group such as azetidine, tetrahydrofuryl, pyrrolidinyl,
1 to 3 ring 5 such as pyrazolidinyl, imidazolidinyl, etc.
1- to 3-membered 6-membered saturated heterocycle such as a membered saturated heterocyclic group, piperidyl, morpholinyl, thiamorpholinyl, piperazinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, hexahydropyrimidinyl, etc. And a 1- to 3-ring 7-membered saturated heterocyclic group such as azepanyl and the like. Examples of such unsaturated heterocyclic groups include furyl, thienyl, indolyl, isothiazolyl, benzothienyl, isobenzofuranyl, pyrrolyl, benzofuryl, imidazolyl, 4,5-dihydro-1H-imidazolyl, pyrazolyl, isoxazolyl, thiazolyl, 1 to 3 5-membered heterocyclic groups such as isothiazolyl, oxazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, carbazolyl, pyridyl, pyrazinyl,
Pyrimidinyl, 1,4,5,6-tetrahydro-pyrimidinyl, 3,6-dihydro-2H- [1,3,5] oxadiazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,
1 to 3 ring 6-membered heterocyclic groups such as chromenyl and 2,3-dihydro-benzo [1,4] dioxanyl;
Examples thereof include 1 to 3 ring 7-membered unsaturated heterocyclic groups such as 6,7-tetrahydro-1H- [1,3] diazepinyl.

In substituted aryl and substituted heterocyclic groups
Substituents include, for example, the following groups a) to g):
Included are any groups included, which are optionally 1 or
A plurality may be replaced. a): halogen atom, nitro group, cyano group, azide
Group, mercapto group, amino group which may be substituted,
An optionally substituted hydroxylamino group, substituted
An alkoxyamino group, a hydroxyl group, an oxo group,
Silyl, acyloxy, carboxyl, substituted
An optionally substituted carbamoyl group, an optionally substituted cal
Bamoyloxy group, optionally substituted sulfamoi
B): -R²⁰, -OR²⁰, -CO₂R²⁰, -S
O₂R²⁰, -SR²⁰, -OCH₂R²⁰, -SCH
₂R²⁰, -C (= NOH) R²⁰ [Where R
²⁰Represents a phenyl group or a monocyclic heterocyclic group. Fe
A nyl group or a monocyclic heterocyclic group is, for example, a halogen atom,
Alkyl group, haloalkyl group, cyano group, nitro group,
Zide group, hydroxyl group, alkoxy group, haloalkoxy group,
An optionally substituted amino group, an optionally substituted
Rubamoyl group, carboxy group, alkylcarbonyl 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): alkyl group, alkoxy group, alkoxycarbonyl group, alkoxy (thiocarbonyl)
Group, alkylthio group, (alkylthio) thiocarbonyl group, (alkylthio) carbonyl group, alkylcarbonyl group, alkylthioyl group, alkylsulfinyl group,
Alkylsulfonyl group, alkylcarbonyloxy group,
Alkylthioyloxy group, alkylsulfonyloxy group [each group in this group is, for example, 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 acyl group, An acyloxy group, a carboxy group, an optionally substituted carbamoyl group, an optionally substituted carbamoyloxy group,
An optionally substituted sulfamoyl group, -R ²⁰ ,
_{^{-OR 20, -SR 20, -OCH 2}} R 20, -SCH 2
R ²⁰ (wherein, R ²⁰ has the same meaning as described above), a cycloalkyl group (for example, a cycloalkyl group is a halogen atom, an alkyl group, a haloalkyl group, an optionally substituted amino group, a hydroxyl group, an alkoxy group, May be substituted with one or more groups arbitrarily selected from a group such as a haloalkoxy group, etc.), an alkoxy group, an alkoxycarbonyl group, and an alkylthio group (an alkoxy group, an alkoxycarbonyl group, and an alkylthio group include, for example, a halogen atom , Cycloalkyl group, monocyclic heterocyclic group, phenyl group, cyano group, nitro group, hydroxyl group, alkoxy group, haloalkoxy group, optionally substituted amino group, optionally substituted carbamoyl group, carboxy group , Alkylcarbonyl group, alkoxycarbonyl group, alkylthio group, alkyl May be substituted with one or a plurality of groups arbitrarily selected from a group such as a sulfinyl group and an alkylsulfonyl group.). ]

D): Alkenyl group [Alkenyl group includes, for example, halogen atom, nitro group, cyano group, mercapto group, oxo group, thioxo group, optionally substituted amino group, hydroxyl group, alkoxy group, haloalkoxy group, alkoxycarbonyl group, an alkylthio group, an acyl group, an acyloxy group, a carboxy group, a carbamoyl group which may be substituted, - R 2 ^0, -OR
_{^{20, -SR 20, -OCH 2 R}} 20 and -SCH ₂ R
²⁰ (wherein R ²⁰ has the same meaning as described above), and may be substituted with one or more groups arbitrarily selected from the group such as ]

E): alkynyl group [alkynyl group includes, for example, halogen atom, nitro group, cyano group, mercapto group, oxo group, thioxo group, optionally substituted amino group, hydroxyl group, alkoxy group, haloalkoxy group, alkoxycarbonyl group, an alkylthio group, an acyl group, an acyloxy group, a carboxy group, a carbamoyl group which may be substituted, - R 2 ^0, -OR
_{^{20, -SR 20, -OCH 2 R}} 20 and -SCH ₂ R
²⁰ (wherein R ²⁰ has the same meaning as described above), and may be substituted with one or more groups arbitrarily selected from the group such as F): alkenyloxy group, alkenyloxycarbonyl group, alkenylcarbonyl group, alkenylcarbonyloxy group, alkynyloxy group, alkynyloxycarbonyl group [each group in this group is, for example, a halogen atom, an oxo group, Good amino groups, hydroxyl groups, alkoxy groups,
A haloalkoxy group, an acyl group, an acyloxy group, an alkylthio group, a carboxy group, an optionally substituted carbamoyl group, an alkoxycarbonyl group, and a phenyl group; Good. ]

G): cycloalkyl group, cycloalkyloxy 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, a mercapto group, an oxo group, a thioxo group, an alkyl group, a haloalkyl group, an optionally substituted amino group, a hydroxyl group; , An alkoxy group, a haloalkoxy group, an acyl group, an acyloxy group, an alkylthio group, a carboxy group,
It may be substituted with one or more groups arbitrarily selected from a group such as an optionally substituted carbamoyl group and an alkoxycarbonyl group. ]

Specific examples of the substituent of the substituted aryl group and the substituted heterocyclic group include methyl, 2-methyl-1-propyl, hexyl, 2-methyl-2-propyl, 2-propyl, phenyl and trifluoromethyl. , 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, 6,6,6-trifluorohexyl, hydroxymethyl, hydroxyethyl, methoxymethyl, hexyloxymethyl, cyclopropyl Methoxymethyl, acetoxymethyl, N, N-dimethylcarbamoyloxymethyl, methanesulfonyloxymethyl, N, N-dimethylsulfamoyloxymethyl, 2- (1-pyrrolidinyl) ethoxymethyl, 2-methoxyethyl, carboxymethyl, methoxy Carbonylmethyl, carbamoylmethyl, amidinome Methyl, methylthiomethyl, cyanomethyl, aminomethyl, aminoethyl, N, N-dimethylaminoethyl, methanesulfonylaminoethyl, sulfamoylethyl, morpholinoethyl, N-methanesulfonylaminoethyl, N-acetylaminomethyl, ethenyl, 2 -Propenyl, ethynyl, 2-propynyl, 2-
Methoxycarbonylethenyl, fluoro, chloro, bromo, nitro, cyano, hydroxy, amino, N, N-dimethylamino, mercapto, sulfo, carboxy, amidino, methoxy, cyclopropylmethoxy, 2- (1-
Pyrrolidinyl) ethoxy, methoxycarbonylmethoxy, 2-acetoxyethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, 4,4,5,5,5-pentafluoropentoxy, 2-methanesulfinylethoxy, phenoxy, benzyloxy, -Methoxybenzyloxy, methoxycarbonyloxy, 1-pyrrolidinyl, 3-hydroxy-1-pyrrolidinyl, acetylamino, N-acetyl-N-methylamino, N-methanesulfonylamino, N-methanesulfonyl-N-methylamino, methoxy Carbonyl, 2-methyl-2-propyloxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, carbamoyl, N, N-dimethylcarbamoyl, 2-thiazolidinyl, 2-oxazolidinyl, 5-
Tetrazolyl, methanesulfinyl, sulfamoyl,
N, N-dimethylsulfamoyl, acetyl, benzoyl, pivaloyl, trifluoroacetyl, formyl, ethylenedioxymethyl, imino, methoxyimino and the like.

Preferred examples of the substituent include methyl, 2-methyl-1-propyl,
Hexyl, 2-methyl-2-propyl, 2-propyl,
Phenyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, cyclopropylmethoxymethyl, acetoxymethyl, N, N-dimethylcarbamoyloxymethyl, methanesulfonyloxymethyl, N, N -Dimethylsulfamoyloxymethyl, 2- (1-pyrrolidinyl) ethoxymethyl, 2-methoxyethyl, carboxymethyl, methoxycarbonylmethyl, carbamoylmethyl, amidinomethyl, methylthiomethyl, cyanomethyl, aminomethyl, aminoethyl, N-acetyl Aminomethyl, fluoro, chloro, bromo, nitro, cyano,
Hydroxy, amino, N, N-dimethylamino, methoxy, 2- (1-pyrrolidinyl) ethoxy, methoxycarbonylmethoxy, 2-acetoxyethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, 2-methanesulfinylethoxy, 1-pyrrolidinyl , 3-hydroxy-1-pyrrolidinyl, acetylamino, N-acetyl-
N-methylamino, N-methanesulfonylamino, N-
Methanesulfonyl-N-methylamino, methoxycarbonyl, 2-methyl-2-propyloxycarbonyl,
Examples include 2,2,2-trifluoroethoxycarbonyl, carbamoyl, N, N-dimethylcarbamoyl, methanesulfinyl, acetyl, benzoyl, pivaloyl, trifluoroacetyl and the like. The preferred number of substituents in the aryl group and the heterocyclic group is 1, 2 or 3. Further, the aryl group and the heterocyclic group are preferably unsubstituted.

Examples of the alkyl group include a linear 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. Preferred alkyl groups include alkyl groups having 1 to 6 carbon atoms. More preferred alkyl groups are alkyl groups having 1 to 4 carbon atoms.

The substituent in the substituted alkyl group includes
For example, any group included in each of the following groups a) to d) may be mentioned, and these groups 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, acyl group, acyloxy group, carboxy group, optionally substituted carbamoyl group, optionally substituted carbamoyloxy group, optionally substituted sulfamoyl group b) : Cycloalkyl group, cycloalkyloxy 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, nitro group, cyano group, mercapto group, oxo group, thioxo group, alkyl group, haloalkyl group, optionally substituted amino group, hydroxyl group, alkoxy group, haloalkoxy group, acyl group, acyloxy group, alkylthio Group, carboxy group,
It may be substituted with one or more groups arbitrarily selected from a group such as an optionally substituted carbamoyl group and an alkoxycarbonyl 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
Oxy group, alkylsulfonyloxy group [Each group in this group is, for example, a halogen atom, a nitro group,
Ano, mercapto, oxo, thioxo, substituted
Amino group, hydroxyl group, acyl group, acyl group
Xy group, carboxy group, carbamo which may be substituted
Yl group, carbamoyloxy group which may be substituted,
An optionally substituted sulfamoyl group, -R²⁰,
-OR²⁰, -SR²⁰, -OCH_TwoR²⁰, -SCH_Two
R²⁰(Where R²⁰Is as defined above. ), Shiku
A loalkyl group (a cycloalkyl group is, for example, a halogen atom)
, Alkyl group, haloalkyl group, may be substituted
Amino, hydroxyl, alkoxy and haloalkoxy
Substituted with one or more groups arbitrarily selected from the group of
It may be. ), Alkoxy group, alkoxycal
Bonyl group and alkylthio group (alkoxy group, alcohol
Xycarbonyl and alkylthio groups are, for example, halo
Gen atom, cycloalkyl group, monocyclic heterocyclic group, phenyl
Groups, cyano groups, nitro groups, hydroxyl groups, alkoxy groups,
Alkoxy group, amino group which may be substituted, substitution
Carbamoyl group, carboxy group,
Killcarbonyl group, alkoxycarbonyl 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): -R²⁰, -OR²⁰, -SR²⁰, -OC
H_TwoR²⁰, -SCH_TwoR ²⁰(Where R²⁰Is
It is synonymous. )

Specific examples of the substituted alkyl group include trifluoromethyl, 2-nitroethyl, 2-cyanopropyl, 4-mercaptobutyl, 3-oxobutyl, 2-morpholinoethyl, 2-piperidinoethyl, 2-hydroxyethyl, -Methoxypropyl, ethoxycarbonylmethyl, cyclopropylmethyl, cyclohexylmethyl, 6-cyclohexylhexyl, 3-cyclohexenylbutyl, 2-phenylbutyl, benzyl, 2-naphthylmethyl, phenethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-quinolylmethyl, 3-quinolylmethyl, 3-thienylpropyl, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, N, N-dimethylaminoethyl, carboxymethyl, ethoxycal Nirumechiru, sulfamoyl ethyl, carbamoylmethyl, and the like. A haloalkyl group is an alkyl group substituted with 1 to 5 halogen atoms. Specifically, trifluoromethyl, trifluoroethyl, 2-chloroethyl and the like can be mentioned.

An alkylcarbonyl group, an alkylthio group,
The alkyl in the alkylsulfinyl, alkylsulfonyl, (alkylthio) thiocarbonyl, (alkylthio) carbonyl, alkylthioyl, alkylcarbonyloxy, alkylthioyloxy, and alkylsulfonyloxy groups is the same as the alkyl group described above. Represents a thing.

The alkoxy group represents an oxy group to which an alkyl group is bonded. Specific examples include methoxy, ethoxy, propoxy, 2-propoxy, butoxy, 1,1-dimethylethoxy, pentoxy, hexoxy and the like.
Examples of the substituent of the substituted alkoxy group include the same as the substituent of the substituted alkyl group. As the substituted alkoxy group,
Specifically, cyclopropylmethoxy, trifluoromethoxy, 2-pyrrolidinoethoxy, benzyloxy,
-Pyridylmethoxy and the like. Preferred alkoxy groups include alkoxy groups having 1 to 6 carbon atoms. A haloalkoxy group represents an alkoxy group substituted with 1 to 5 halogen atoms. Specifically, trifluoromethoxy, 2-trifluoroethoxy, 2-chloroethoxy and the like can be mentioned. An alkoxycarbonyl group refers to a carbonyl group to which an alkoxy group is bonded. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl and the like. Examples of the substituent in the substituted alkoxycarbonyl group include the same substituents as those in the substituted alkyl group.

As the alkoxy in the alkoxy (thiocarbonyl) group and the alkoxyamino group, the same as the above-mentioned alkoxy groups can be mentioned.

Examples of the alkenyl group include a linear or branched alkenyl group having 2 to 10 carbon atoms and having 1 to 3 double bonds. 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, for example, ethenyl, 1-propenyl and 1-butenyl groups. Preferred alkenyl groups include alkenyl groups having 2 to 6 carbon atoms. 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 alkoxycarbonyl group, and an alkylthio group. , an acyl group, an acyloxy group, a carboxy group, which may be substituted carbamoyl ^{group, - R 20, -OR 20,} -SR
²⁰ , -OCH ₂ R ²⁰ , -SCH ₂ R ²⁰ (wherein, R
²⁰ has the same meaning as described above. ) And the like. An alkenyloxy group refers to an oxy group to which an alkenyl group is bonded. The alkenyl in the alkenyloxycarbonyl group, the alkenylcarbonyl group, and the alkenylcarbonyloxy group represents the same as the above alkenyl group.

Examples of the alkynyl group include a linear or branched alkynyl group having 2 to 10 carbon atoms and 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, such as 1-propynyl and 1-butynyl groups. Examples of the substituent of the substituted alkynyl 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 acyl group, and an acyloxy group. ,
Alkylthio group, a carboxy group, which may be substituted carbamoyl group, an alkoxycarbonyl group, ^- R 20, -O
_{^{R 20, -SR 20, -OCH 2}} R 20, -SCH 2 R
²⁰ (wherein, R ²⁰ has the same meaning as described above). An alkynyloxy group refers to an oxy group to which an alkynyl group is bonded. Alkynyl in the alkynyloxycarbonyl group is the same as the above-mentioned alkynyl group. Alkynyl in the alkynyloxycarbonyl group is the same as the above-mentioned alkynyl group.

The cycloalkyl group includes, for example, a cycloalkyl group having 3 to 10 carbon atoms.
Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Preferred cycloalkyl groups include cycloalkyl groups having 3 to 6 carbon atoms. Further, a cycloalkyloxy group refers to an oxy group to which a cycloalkyl group is bonded. The cycloalkylalkyl in the cycloalkylcarbonyl group, the cycloalkylcarbonyloxy group, and the cycloalkyloxycarbonyl group is the same as the above-mentioned cycloalkyl group.

The cycloalkenyl group includes, for example, those having 3 to 10 carbon atoms. 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 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 amino group which may be substituted, a hydroxyl group, Examples thereof include an alkoxy group, a haloalkoxy group, an acyl group, an acyloxy group, an alkylthio group, a carboxy group, a carbamoyl group which may be substituted, and an alkoxycarbonyl group. The cycloalkenyl in the cycloalkenyloxy group, the cycloalkenylcarbonyl group, the cycloalkenylcarbonyloxy group, and the cycloalkenyloxycarbonyl group is the same as the above-mentioned cycloalkenyl group.

Examples of the aralkyl group include an alkyl group substituted by the aryl group. Examples of the alkyl group include a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,
2-methyl-1-propyl, 1,1-dimethylethyl,
Examples include pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-methylbutyl, 3-methylbutyl, hexyl, 2-methylpentyl, and 3,3-dimethylbutyl. Examples of the substituent in the substituted aralkyl group include the same substituents as those in the substituted aryl group. The acyl group is represented by the formula: -ZR ²⁶ }, wherein Z represents -CO- or -CS-, and R ²⁶ represents the following a)
Or b). a) alkyl, alkenyl or alkynyl group, [group this group, a halogen atom, a cyano group, ^{-R 27,}
-OR ²⁷ , -SR ²⁷ , -OCH ₂ R ²⁷ , -SCH
₂ R ²⁷ (wherein, R ²⁷ represents a phenyl group or a monocyclic heterocyclic group. The phenyl group or the monocyclic heterocyclic group is
For example, a halogen atom, an alkyl group, a haloalkyl group, a cyano group, a nitro group, an azide group, a hydroxyl group, an alkoxy group,
Haloalkoxy group, amino group (alkylcarbonyl group,
It may be substituted with an alkylsulfonyl group, an alkoxycarbonyl group, or 1 to 2 alkyl groups. ), A carbamoyl group (which may be substituted by 1 to 2 alkyl groups), a sulfamoyl group (1 to 2
May be substituted with an alkyl group. ), A carboxy group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group and the like. ], A cycloalkyl group (the cycloalkyl group is, for example, one selected from the group consisting of a halogen atom, an alkyl group, a haloalkyl group, an amino group, a hydroxyl group, an alkoxy group, a haloalkoxy group, etc.)
Alternatively, it may be substituted with a plurality of groups. ), An alkoxy group, an alkoxycarbonyl group, an alkylthio group and the like. B) a cycloalkyl group, an aryl group, or a heterocyclic group [each group in this group is a halogen atom, a cyano group, a nitro group, an azide group, a hydroxyl group, a carboxy group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group; Group, alkylcarbonyl group, alkylcarbonyloxy group, or alkoxycarbonyl group, alkylthio group, alkylsulfinyl group and alkylsulfonyl group, amino group (alkylcarbonyl group, alkylsulfonyl group, alkoxycarbonyl group, or 1 to 2 May be substituted with an alkyl group), a carbamoyl group (may be substituted with 1 to 2 alkyl groups), and a sulfamoyl group (may be substituted with 1 to 2 alkyl groups). ), Etc. may be substituted with one or more groups arbitrarily selected from the group There]} Alternatively, as the acyl group,
Natural and non-natural α-amino acid residues are also included. Specific examples of the acyl group include formyl, acetyl, propanoyl, 2-propanoyl, pivaloyl, valeryl, pivaloyl, trifluoroacetyl, benzoyl, naphthoyl, nicotinoyl and the like. Preferred acyl groups include an acetyl group. An acyloxy group refers to an oxy group to which an acyl group is bonded.

The sulfonyl group is represented by —SO ₂ —R ²⁶ (R
²⁶ has the same meaning as described above. ). Specific examples of the sulfonyl group include methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, p-toluenesulfonyl, benzenesulfonyl and the like.

Examples of the substituent in the substituted carbamoyl group include the following a) or b), and a plurality of the same or different substituents may be independently substituted. a) an alkyl group, an alkenyl group, or an alkynyl group [each group in this group is a halogen atom, a cyano group,
^{R 27, -OR 27, -SR 2} 7, -OCH 2 R 27,
—SCH ₂ R ²⁷ (wherein, R ²⁷ has the same meaning as described above), a cycloalkyl group (for example, a cycloalkyl group is a halogen atom, an alkyl group, a haloalkyl group, an amino group, a hydroxyl group, an alkoxy group, or a haloalkoxy group) And the like, may be substituted with one or more groups arbitrarily selected from a group such as), an alkoxy group, an alkoxycarbonyl group, and an alkylthio group. Good. B) a cycloalkyl group, an aryl group, or a heterocyclic group [each group in this group is a halogen atom, a cyano group, a nitro group, an azide group, a hydroxyl group, a carboxy group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group; Group, alkylcarbonyl group, alkylcarbonyloxy group, or alkoxycarbonyl group, alkylthio group, alkylsulfinyl group and alkylsulfonyl group, amino group (alkylcarbonyl group, alkylsulfonyl group, alkoxycarbonyl group, or 1 to 2 May be substituted with an alkyl group), a carbamoyl group (may be substituted with 1 to 2 alkyl groups), and a sulfamoyl group (may be substituted with 1 to 2 alkyl groups). ), Etc. may be substituted with one or more groups arbitrarily selected from the group As Yes] substituted carbamoyl group, specifically, ethylcarbamoyl, dimethylcarbamoyl, phenylcarbamoyl, 2-pyridylcarbamoyl, benzylcarbamoyl, and (3-pyridylmethyl) carbamoyl and the like. Examples of the substituent in the substituted sulfamoyl group include the same substituents as those in the substituted carbamoyl group, and a plurality of the same or different substituents may be independently substituted.
Specific examples of the substituted sulfamoyl group include ethylsulfamoyl, dimethylsulfamoyl, phenylsulfamoyl, 2-pyridylsulfamoyl and the like.

Examples of the substituent in the substituted amino group include the following a) to c), and a plurality of the same or different ones may be independently substituted. a) an alkyl group, an alkenyl group, or an alkynyl group [each group in this group is a halogen atom, a cyano group,
^{R 27, -OR 27, -SR 2} 7, -OCH 2 R 27,
—SCH ₂ R ²⁷ (wherein, R ²⁷ has the same meaning as described above), a cycloalkyl group (for example, a cycloalkyl group is a halogen atom, an alkyl group, a haloalkyl group, an amino group, a hydroxyl group, an alkoxy group, or a haloalkoxy group) May be substituted with one or more groups arbitrarily selected from a group such as a group, etc.), an alkoxy group, an alkoxycarbonyl group, and an alkylthio group. Is also good. B) a cycloalkyl group, an aryl group, or a heterocyclic group [each group in this group is a halogen atom, a cyano group, a nitro group, an azide group, a hydroxyl group, a carboxy group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group; Group, alkylcarbonyl group, alkylcarbonyloxy group, or alkoxycarbonyl group, alkylthio group, alkylsulfinyl group and alkylsulfonyl group, amino group (alkylcarbonyl group, alkylsulfonyl group, alkoxycarbonyl group, or 1 to 2 May be substituted with an alkyl group), a carbamoyl group (may be substituted with 1 to 2 alkyl groups), and a sulfamoyl group (may be substituted with 1 to 2 alkyl groups). ), Etc. may be substituted with one or more groups arbitrarily selected from the group C) acyl group, sulfonyl group, or amidino group Specific examples of the substituted amino group include acetamido, propionamido, butylamido, 2-butylamido, methylamino, 2-methyl-1-propylamino, 2-hydroxyethylamino , 2-aminoethylamino, diethylamino, methylcarbamate, ureido, methanesulfonylamide, guanidino and the like. The substituent in the substituted hydroxylamino group may be substituted with any one of a nitrogen atom and an oxygen atom.
The same substituents as those in the substituted amino group can be mentioned.

As the protecting group for the NH group, various protecting groups commonly used (TW Greene and P. GM Wuts, “Pro
tective Groups in Organic Synthesis, 2nd Ed., ”Jo
hn Wiley & Sons, Inc. pp.315-405 (1991)). For example, carbamate-type protecting groups such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and benzyloxycarbonyl, amide-type protecting groups such as acetyl and benzoyl, benzyl, nitro, p-
Examples include toluenesulfonyl, benzenesulfonyl, methanesulfonyl and the like.

R ⁸ and R ⁹ , or R ¹⁰ and R
Examples of the optionally substituted hydrocarbon ring formed by bonding of ¹¹ and a carbon atom include an optionally substituted cycloalkane ring having 3 to 8 carbon atoms or an optionally substituted cycloalkane ring having 3 to 8 carbon atoms. And the like. As such a cycloalkane ring or cycloalkene ring, specifically, cyclopropane, cyclobutane,
Examples include cyclopentane, cyclohexane, cycloheptane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and the like. Examples of the substituent in the substituted hydrocarbon ring include the same substituents as those in the substituted cycloalkyl group. 5 formed by the combination of R ⁸ and R ⁹ , or R ¹⁰ and R ¹¹
Examples of the to 7-membered heterocycle include oxolane, oxane, piperidine, and pyrrolidine.

The alkyl group for R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ is preferably an alkyl group having 1 to 4 carbon atoms, specifically, methyl, ethyl, propyl,
-Methylethyl and the like.

In the substituent (A),-(R ⁷ ) _r , when r represents 2, the two substituents of A may be the same or different.

R⁵And R⁶Is preferably each
Same or different, hydrogen atom, optionally substituted
Represents an alkyl group having 1 to 4 carbon atoms;⁵
And R⁶Is a 4- to 7-membered fat which may be substituted
Form a heterocyclic ring. R^Fifteen, R¹⁶, And R¹⁹To
Alkyl, alkenyl, and alkynyl
Preferred substituents when the group is substituted include:
The following a) to e) may be mentioned, and the same or different
A plurality may be substituted. 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 c')
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,
2 to 5 alkylcarbonyl groups, 1 to 4 carbon atoms
An alkylsulfonyl group or an alkyl group having 2 to 5 carbon atoms
It may be substituted with a alkoxycarbonyl group. ) C ') -SO₂NR⁶³R⁶⁴, -CONR⁶³R
⁶⁴  (R⁶³, And R⁶⁴Is a hydrogen atom, having 1 to 4 carbon atoms
Represents an alkyl group. Or R⁶³And R⁶⁴Is combined
To form an optionally substituted 4- to 6-membered aliphatic heterocycle
May be formed. ) May be substituted. C) an aliphatic heterocyclic group; (An aliphatic heterocyclic group is a hydroxyl group, an oxo group, a halogen atom,
, An alkyl group having 1 to 4 carbon atoms, a halo having 1 to 4 carbon atoms.
Loalkyl group, alkoxy group having 1 to 4 carbon atoms, carbon number
An alkylcarbonyl group having 1 to 4 carbon atoms;
Lucoxy carbonyl group, C1 to C4 alkyl carb
Bonyloxy group, alkylsulfonyl having 1 to 4 carbon atoms
May be substituted with a group. D) amino group (amino group is an alkyl group having 1 to 4 carbon atoms,
2 to 5 alkylcarbonyl groups, 1 to 4 carbon atoms
An alkylsulfonyl group or an alkyl group having 2 to 5 carbon atoms
It may be substituted with a alkoxycarbonyl group. ) E) -SO₂NR⁶³R⁶⁴, -CONR⁶³R⁶⁴  (R⁶³, And R⁶⁴Is a hydrogen atom, having 1 to 4 carbon atoms
Represents an alkyl group. Or R⁶³And R⁶⁴Is combined
To form an optionally substituted 4- to 6-membered aliphatic heterocyclic ring
May be formed. )

The 4- to 7-membered nitrogen-containing aliphatic heterocyclic ring formed by the bonding of R ⁵ and R ⁶ is preferably 1-3 nitrogen atoms, 0-1 oxygen atoms, or 0-1 oxygen atoms. Is a saturated heterocyclic ring having 1 to 3 heteroatoms selected from sulfur atoms. Specific examples include azetidine, piperazine, piperidine, morpholine, thiomorpholine, thiomorpholine-1-oxide, thiomorpholine-1,1-dioxide, pyrrolidine, perhydroazepine and the like.
Examples of the substituent in these heterocycles include the same substituents as those in the substituted heterocycle. Preferred substituents on the 4- to 7-membered nitrogen-containing aliphatic heterocyclic ring formed by the bonding of R ⁵ and R ⁶ include the following a) to d). Is also good. In addition, R ⁴⁴ is also preferable as a)
To d). a) oxo group, hydroxyl group, carboxy group, cyano group, halogen atom. b) an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkylcarbonyl group having 1 to 4 carbon atoms, and 1 carbon atom
To 4 alkylcarbonyloxy groups, 1 to 4 carbon atoms
Alkylsulfonyl group. [The group of this group may be substituted with one or more groups which are the same or different and are selected from the following a ′) to c ′). a ') halogen atom, cyano group, hydroxyl group, carboxy group, alkoxy group having 1 to 4 carbon atoms, alkoxycarbonyl group having 1 to 4 carbon atoms, alkylcarbonyl group having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms Carbonyloxy group b ′) amino group (the amino group is an alkyl group having 1 to 4 carbon atoms, an alkylcarbonyl group having 2 to 5 carbon atoms, an alkylsulfonyl group having 1 to 4 carbon atoms, or C ') carbamoyl group, sulfamoyl group (each group in this group may be substituted with an alkyl group having 1 to 4 carbon atoms). It may be. C) amino group, (amino group is an alkyl group having 1 to 4 carbon atoms, an alkylcarbonyl group having 2 to 5 carbon atoms, an alkylsulfonyl group having 1 to 4 carbon atoms, or 2 to 5 carbon atoms) D) a carbamoyl group or a sulfamoyl group (each group in this group may be substituted with an alkyl group having 1 to 4 carbon atoms)

R preferably represents 0 or 1. s preferably represents an integer from 2 to 4. q is preferably
Represents an integer of 0 to 2. The present invention includes all stereoisomers, optically active isomers, tautomers and the like of the 5-membered heteroaromatic ring compound described in the claims. The present invention also encompasses solvates such as hydrates of the five-membered heteroaromatic ring compound or the pharmaceutically acceptable salt thereof described in the claims and crystalline forms of all aspects. In the case where R ⁹ or R ¹¹ in the formula (1) is a hydrogen atom, the 5-membered heteroaromatic compound of the present invention has the following formula:

Embedded image The tautomers represented by are represented by the following. In this specification, all of these tautomers are included even if not specified.

The pharmaceutically acceptable salts of the 5-membered heteroaromatic compounds 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, Propionate, benzoate, trifluoroacetate, fumarate, maleate, tartrate, aspartate,
Organic acid salts such as glutamate, methanesulfonate, benzenesulfonate, camphor-sulfonate and the like can be mentioned. Examples of the base addition salt include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt and ammonium salt, and organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt and diisopropylammonium salt. .

The compound of the present invention can be produced, for example, by the following method. [1] Method for producing compound represented by formula 1-4

Embedded image[Wherein -COR^b1Is the activated carboxyl group
And R¹⁰⁶Is a hydrogen atom, an optionally substituted
Represents a alkyl group. R¹⁰¹Is the R⁷Or R ¹⁸When
Synonymous or R in any suitable known manner⁷Or R¹⁸To
It is a group that can be converted. R¹⁰², R¹⁰⁴, And R
¹⁰⁵Is the above R⁸, R¹⁰, And R ¹¹When
Synonymous or R in any suitable known manner⁸, R¹⁰Or
R¹¹Is a group that can be converted into A, E, G, and r are as described above.
Is synonymous with A compound represented by the formula 1-1 and a compound represented by the formula 1-2
In an inert solvent or without solvent in the presence of a base or acid
By reacting at a reaction temperature of -100 ° C to 130 ° C,
The compound represented by Formula 1-3 can be produced. S
The amount of the ter derivative used is, for example,
The range is 1 to 20 equivalents, preferably 1.0 to 1.
2 equivalents. As the base, for example, hydrogenated lithium
, Sodium hydride, potassium hydride, sodium carbonate
, Potassium carbonate, lithium amide, sodium amide
, Potassium amide, butyllithium, sec-butyllithium
, Tert-butyllithium, lithium diisopropyl
Amide, butylmagnesium chloride, sec-butylmag
Nesium chloride, tert-butyl magnesium chloride
, Sodium methoxide, potassium methoxide, mug
Nesium methoxide, sodium ethoxide, potassium
Ethoxide, magnesium ethoxide, lithium tert-
Butoxide, sodium tert-butoxide, potassium ter
t-butoxide and the like, preferably lithium hydride
System, sodium hydride, potassium carbonate, lithium
, Sodium amide, lithium tert-butoxide, potassium
Lium tert-butoxide and the like. Alkoxide
When using as a base, tert-butanol is used in the reaction system.
Prepared by reacting a suitable base with alcohol such as
Can be. In this case, the base to be acted on is hydrogen
Lithium chloride, sodium hydride, lithium amide, nato
Lium amide, potassium amide and the like are preferred. lithium
When using amides such as amides and sodium amides,
The reaction temperature is preferably in the range of 50 to 80 ° C., nitrogen gas,
While introducing an inert gas such as argon gas into the reaction solution,
It is preferable to respond. Acids include hydrochloric acid, sulfuric acid, nitric acid
Acid, phosphoric acid, Lewis acid and the like, preferably hydrochloric acid,
Sulfuric acid, phosphoric acid, aluminum chloride, titanium trichloride, tetrasalt
Titanium fluoride, tin dichloride, boron trifluoride ether complex, etc.
Is mentioned. As the amount of the base or acid used, for example,
The range of 1-3 equivalents to the compound of the formula 1-1 is mentioned,
Preferred is 1-2 equivalents. Compound represented by Formula 1-3
The product is reacted in the presence of an acid in an inert solvent or without solvent.
By reacting at a temperature of 0 to 180 ° C, it is represented by the formula 1-4.
The compound of the present invention can be produced. Manufacture compound
can do. Acids include hydrochloric acid, sulfuric acid, nitric acid,
Acid, trifluoroacetic acid, methanesulfonic acid, Lewis acid
And the like, preferably hydrochloric acid, sulfuric acid, phosphoric acid,
Examples include fluoroacetic acid and methanesulfonic acid. Use of acid
The dose is, for example, 1 to 20 equivalents to the compound of the formula 1-3.
And preferably 2 to 5 equivalents.
Preferred solvents include, for example, tetrahydrofuran,
Ruene, acetonitrile, 1,4-dioxane, diethyl
Ether and the like. Or expressed by equation 1-3
The compound is prepared in the presence of a base in a suitable solvent or without solvent,
The reaction is carried out at a reaction temperature of 0 to 180 ° C. to convert the ester with a carboxylic acid.
After the reaction, in an inert solvent or without solvent, the reaction temperature 0 ~ 180
The reaction of the present invention represented by Formula 1-4
Light compounds can be prepared. Hydroxyl as base
Sodium chloride, potassium hydroxide, sodium hydroxide aqueous solution
Liquid and the like. The amount of the base used is, for example,
A range of 1 to 20 equivalents for 3 compounds is preferred,
Or 1 to 5 equivalents. Preferred solvents include, for example,
For example, methanol, ethanol, tetrahydrofuran,
Ruene, 1,4-dioxane, diethyl ether, etc.
And these mixed solvents, or these solvents and water
Can also be used. After converting to carboxylic acid, use
More preferred solvents include, for example, dimethylsulfoxy
Dimethylformamide, dimethylacetamide,
Trahydrofuran, toluene, acetonitrile, tert-
Butanol, 1,2-dichloroethane, chlorobenzene
And the like.

[2] Method for producing compound represented by formula 1-8

Embedded image In the formula, —CO ^{b 2} represents an activated carboxyl group, R ¹⁰⁷ represents a hydrogen atom or an optionally substituted alkyl group. R ¹⁰³ has the same meaning as R ⁹ described above or a group that can be converted to R ⁹ by an appropriate known method. R
^{101, R 102, R 1 04} , A, E, G, and r are as defined above. From the compound represented by the formula 1-5 and the compound represented by the formula 1-6, the compound represented by the formula 1 is prepared in the same manner as the compound represented by the formula 1-3.
The compound represented by -7 can be produced. Further, the compound represented by the formula 1-8 can be produced from the compound represented by the formula 1-7 in the same manner as the compound represented by the above formula 1-4.

The compound represented by the formula 1-1 or the formula 1-6 can be converted into the carboxylic acid derivative represented by the formula 1-9 or the formula 1-10 by a known activation method by the following reaction route. On the other hand, it can be prepared by reacting an activating agent in an inert solvent in the presence of an additive, if necessary.

Embedded image(Where R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, R
¹⁰⁵, R¹⁰⁶, R^1a, R ^1b, A, E, G, and r
Is as defined above. Activators, additives and reaction conditions are usually used.
Are available, for example, Reactivity and S
tructure Concepts in Organic ChemistryVol. 21: The
 Practice of Peptide Synthesis, M. Bodanszky and
A. Bodanszky, Springer-Verlag, Berlin (1984), p.87-
150. Preferred activator
For example, 1,1'-carbonyldiimidazole, chloroform
Isobutyl acid, isopropyl chloroformate, n-chloroformate
-Butyl and the like. Preferred solvents include, for example,
For example, dimethylformamide, dimethylacetamide, tet
Lahydrofuran, toluene, acetonitrile, tert-butyl
Tanol, methylene chloride, chloroform, 1,2-dic
Loroethane, chlorobenzene and the like can be mentioned.

The compound represented by the formula 1-2 or the formula 1-5 can be converted into the carboxylic acid derivative represented by the formula 1-11 or the formula 1-12 by a known activation method by the following reaction route. On the other hand, if necessary, in the presence of an additive, activated in the above manner in an inert solvent and then reacted with alcohol, or in the presence of an additive, if necessary, in an inert solvent, the condensing agent It can be prepared by reacting with an alcohol, or in the presence of a base and reacting with an alkylating agent.

Embedded image (Where R ¹⁰¹ , R ¹⁰² , R ¹⁰⁴ , R ¹⁰⁵ , R
¹⁰⁶ , R ¹⁰⁷ , A, E, G, and r are as defined above. ) For example, a halide represented by the carboxylic acid derivative and ^{R 106} of Formula 1-11 or formula 1-12 -X ^a or ^{R 107} -X ^a (X ^a represents a halogen atom.), The base By reacting in the presence of an inert solvent such as methylene chloride or tetrahydrofuran at a reaction temperature of −10 ° C. to 130 ° C., the compound of the formula 1-2 or the formula 1-5 can be produced. The amount of the halide to be used is, for example, in the range of 1 to 20 equivalents, preferably 1.0 to 3 equivalents, relative to the compound of the formula 1-5 or 1-6. As the base, for example, sodium hydroxide, sodium carbonate,
Potassium carbonate, sodium hydrogen carbonate, triethylamine, diisopropylethylamine and the like can be mentioned.

The compound of the formula 1-9 or 1-11 can be produced by a method described in International Patent Publication No. 98/47880 (WO98 / 47880). Compounds of Formula 1-10 or Formula 1-12 are known or can be prepared by the methods described in the Examples herein or described below. For example, when A is imidazole, J. Med. Chem., 30 , 222
The method described in 2-2227 (1987) can be used. When A is isothiazole, JP-A-56-1
42290 and the like can be used. Alternatively, when A is oxazole, J. Med.
Chem., 41 , The method described in 22-2227 (1987) and the like can be used. Alternatively, when A is thiazole, a method described in JP-A-56-86187 or the like can be used.

[3] Method for producing compound represented by formula 1-13

Embedded image [Where A, E, G, R ¹⁰¹ , R ¹⁰² , R ¹⁰⁴ , R
¹⁰⁵ and r are as defined above. The compound represented by the formula 1-13 can be produced by reacting the compound represented by the formula 1-4 in an inert solvent or in the absence of a solvent in the presence of a sulfurizing agent. Examples of the sulfurizing agent to be used include Lawson's reagent, hydrogen sulfide, thioacetic acid, thioacetic acid amide, sulfur, carbon disulfide, diphosphorus pentasulfide, sodium sulfide and the like. The amount of the sulphiding agent varies considerably depending on the reagent solvent used, but is usually about 1 to 50 times the mol of the compound of the formula 1-4. Suitable solvents include organic basic solvents such as pyridine, diethylamine and triethylamine; polar solvents such as dimethylformamide, acetonitrile and dimethylsulfoxide; ethers such as diethyl ether, tetrahydrofuran and dioxane; fatty acids such as acetic acid and propionic acid; and methanol. , Ethanol, propanol, butanol, 3-methoxy-1
-Alcohols such as butanol, aromatic hydrocarbons such as benzene, hydrocarbons such as hexane, ethyl acetate, acetone, water and the like. The reaction is completed in about 1 to 60 hours.

[4] Method for producing compound represented by formula 1-14

Embedded image [Wherein, R ¹⁰⁸ has the same meaning as R ¹⁷ described above, or is a group that can be converted to R ¹⁷ by an appropriate known method. A, E,
G, R ¹⁰¹ , R ¹⁰² , R ¹⁰⁴ , R ¹⁰⁵ and r are as defined above. The compound represented by the formula 1-4 is reacted in an inert solvent or in the absence of a solvent, optionally in the presence of an acid catalyst, at a reaction temperature of 0 ° C to 130 ° C.
By reacting at ° C., the compound represented by Formula 1-14 can be produced. 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 acid used is, for example, in the range of 1 to 3 equivalents to the compound of the formula 1-1, preferably 1 to 3.
~ 2 equivalents. Preferred solvents include, for example, dimethylformamide, dimethylacetamide, tetrahydrofuran, toluene, acetonitrile, tert-butanol, methylene chloride, chloroform, 1,2-dichloroethane, chlorobenzene and the like.

[5] Method for producing compound represented by formula 2-3

Embedded image [Wherein, E, G, R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , R ¹⁰⁴
Is as defined above. A compound represented by the formula 2-1 which can be produced according to a known method (for example, JP-A-54-3062) and a cyanamide which is known or can be produced by a known method, for example, from an amine derivative and bromocyanide By reacting the derivative (Formula 2-2) with a base or acid in an inert solvent or without solvent at a reaction temperature of 15 to 130 ° C., the compound of the present invention represented by Formula 2-3 is obtained. Can be manufactured. The amount of the cyanoamide derivative to be used is, for example, in the range of 1 to 20 equivalents, preferably 1.0 to 1.2 equivalents, relative to the compound of the formula 2-1. 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 tert-
Butoxide, sodium tert-butoxide, potassium ter
Examples include t-butoxide and the like, and 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 to be used is, for example, in the range of 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to the compound of the formula 2-1. 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.

[6] Method for producing compound represented by formula 2-5

Embedded image[Where R¹¹⁰Is an optionally substituted alkyl group
It is. E, R¹⁰², R ¹⁰⁴, R¹⁰⁵Is as defined above
It is. A compound represented by the formula 2-1 and a known or known method
For example, an alkyl halide derivative and potassium isothio
Isothiocyanate derivatives that can be produced from cyanates
(Formula 2-4) in an inert solvent or without a solvent,
And then react at a reaction temperature of 15 to 180 ° C.
Thus, it is possible to produce the compound of the present invention represented by Formula 2-5
it can. As the amount of the isothiocyanate derivative used,
For example, the range of 1 to 20 equivalents to the compound of the formula 2-1 may be mentioned.
And preferably 1.0 to 1.2 equivalents. As a base
Is sodium hydroxide, triethylamine, diisopro
Pyrethylamine and the like. As a preferred solvent
Is, for example, dimethyl sulfoxide, methanol, ethanol
, Acetonitrile, acetone, pyridine, diphenyl
Ether, cyclohexane, tetrahydrofuran, salt
Methylene chloride, benzene, toluene, diethyl ether,
And carbon tetrachloride.

[7] Method for producing compound represented by formula 3-2

Embedded image[Where R¹¹¹, R¹¹²Is the above R⁵, R⁶
Is synonymous with, or R⁵Or R⁶Strange
It is an interchangeable group. E, R¹⁰², R¹⁰⁴,
R ¹⁰⁵Has the same meaning as described above. The formula which can be produced by the method described in Examples of the present specification and the like.
In the presence of an acid catalyst, the compound represented by 3-1
Reaction in a solvent at a reaction temperature of 0 ° C to 130 ° C
Thus, the compound represented by the formula 3-2 can be produced.
Acids include hydrochloric, acetic, sulfuric, nitric, phosphoric, citric
Acids, Lewis acids and the like, preferably phosphoric acid, acetic acid,
Titanium trichloride, titanium tetrachloride and the like can be mentioned. Use of acids
The amount is, for example, 1-3 equivalents to the compound of formula 1-1
Range, and preferably 1 to 2 equivalents. Good
Preferred solvents include, for example, dimethylformamide,
Methylacetamide, tetrahydrofuran, acetonitrile
Ryl, tert-butanol and the like.

[8] Method for producing compound represented by formula 4-2

Embedded image [In the formula, X ¹⁰ has the same meaning as X, or represents a group which can be converted to X by an appropriate known method. R ¹²¹ , R ¹²² , R ¹²³ , R ¹²⁴
Each represents a group that is converted to ^{R 1, R 2, R 3} , R 4 and whether the same meanings, R ¹ in a suitable known ^{manner, R 2, R 3, R} 4.
R ¹⁰¹ , R ¹⁰² , R ¹⁰³ and R ¹⁰⁴ are as defined above. The compound represented by the formula (4-1), which can be produced by the method described in [1] to [7], is described in International Patent Publication No. 9
8/47880 (WO98 / 47880) and the like, using the formula (4-
It can be converted to the 5-membered heteroaromatic compound of the present invention represented by 2). here,

In the production of the above-mentioned 5-membered heteroaromatic ring compound, the starting materials used in this case include an amino group, a guanidino group,
When a highly reactive functional group such as a hydroxyl group, a ketone, or a carboxylic acid is present, it may be protected with an appropriate protecting group, reacted if necessary, and then deprotected. Protection and deprotection can be performed by a general method. For example, "Protective Groups in Organic Synthesi
s "2nd Edition, TWGreene and PGM Wuts, Joh
n Wiley and Sons, Inc. The functional group of the 5-membered heteroaromatic ring compound produced by the above method can be further converted according to a known method. 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 Separation, condensation, alkylation, acylation and the like. For example, “Comprehensive Organic Transformation
s "Richard C. Lalock, VCH Publications, Inc.

The 5-membered heteroaromatic ring derivative of the present invention can be converted into a pharmaceutically acceptable salt according to a known method.
When one or more asymmetric points are present in the 5-membered heteroaromatic ring compound of the formula (1), a raw material having the asymmetric point may be used according to a usual method, or introduced at an intermediate stage. , Can be manufactured. For example, in the case of an optical isomer, it can be obtained by using an optically active raw material or performing optical resolution at an appropriate stage of the production process. When one or more asymmetric points are present in the 5-membered heteroaromatic ring compound of the present invention, a raw material having the asymmetric point is used according to an ordinary method, or is introduced at an intermediate reaction step. Can be manufactured. 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 5-membered heteroaromatic compound 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 ethyl acetate. Ester solvents, aromatic hydrocarbon solvents such as toluene, acetonitrile and the like and mixed solvents thereof), optically active acids (for example, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, lactic acid, tartaric acid, o -Dicarboxylic acids such as diisopropylidene tartaric acid and malic acid, and sulfonic acids such as camphorsulfonic acid and bromocamphorsulfonic acid). When the 5-membered heteroaromatic compound of the present invention or an intermediate thereof has an acidic substituent such as a carboxyl group, an optically active amine (for example, α-phenethylamine, quinine, quinidine,
Salts with organic amines such as cinchonidine, cinchonine, strychnine, etc.).

The temperature at which the salt is formed may be 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 5-membered heteroaromatic compound of the present invention or a pharmaceutically acceptable salt thereof is used as an isoxazole derivative of the present invention or a pharmaceutically acceptable salt thereof. Orally (for example,
(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 of the isoxazole derivative of the present invention or a pharmaceutically acceptable salt thereof, the number of administrations varies depending on symptoms, age, body weight, dosage form,
Usually, as an active ingredient amount of the compound of the present invention for adults,
About 1 to 2000 mg, preferably 10 to 50 mg per day
0 mg may 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 thereto. In the specific examples, the meanings of the abbreviations used are as follows. Me: methyl Et: ethyl iPr: isopropyl

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EXAMPLES The present invention will be described below with reference to examples and reference examples, but the present invention is not limited to these examples. The meanings of the abbreviations used in the examples are as follows. tBu: tert-butyl

Example 1 3- (2-fluoro-1,1'-biphenyl-4-yl) -1- [3- (4-morpholinyl) -1,2,4-oxadiazol-5-yl] 2-butanone

Embedded image Reference Example 1 (2.81 g) compound and trifluoroacetic acid (10m
The mixture of l) was stirred at room temperature for 2 hours. After concentrating the reaction mixture with an evaporator, it was poured into saturated sodium bicarbonate water and extracted with ethyl acetate. The organic layer was collected, dried over magnesium sulfate, concentrated with an evaporator, and the residue was subjected to silica gel chromatography (hexane / ethyl acetate =
The product was purified by 2/1) to obtain the desired product (2.02 g) as a pale gray white powder. ¹ H-NMR (300MHz, CDCl ₃ ) δ ppm: 1.48 (d, 3H, J = 7.0Hz),
3.39-3.43 (m, 4H), 3.74-3.77 (m, 4H), 3.83 (d, 1H, J
= 16.7Hz), 3.91 (d, 1H, J = 16.7Hz), 3.97 (q, 1H, 6.9Hz
), 7.01-7.09 (m, 2H), 7.35-7.56 (m, 6H)

Example 2 3- (2-Fluoro-1,1'-biphenyl-4-yl) -1- [5- (4-morpholinyl) -1H-1,2,4-triazol-3-yl] 2-butanone

Embedded image 5- [1- (2-fluoro-1,1′-biphenyl-4-yl) ethyl] -3-isoxazolamine (2 g) which can be produced according to a known method (for example, JP-A-54-3062). ) In tetrahydrofuran (40 ml) in 60% sodium hydride.
57 g was added, and the mixture was stirred at 40 ° C for 30 minutes. After the temperature of the reaction solution was returned to room temperature, cyanomorpholine (1.00 ml) was added, and the mixture was stirred for 40 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, extracted with ethyl acetate, and washed with saturated saline. After drying and concentrating the organic layer, the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/3) to obtain the desired product (2.48 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.48 (d, 3H, J = 7.0 Hz), 3.3
5 (t, 4H, J = 4.8Hz), 3.78 (t, 4H, J = 4.8Hz), 3.89 (s, 2H), 3.95
(q, 1H, J = 7.0Hz), 7.01-7.09 (m, 2H), 7.37-7.54 (m, 6H)

Example 3 3- (2-Fluoro-1,1'-biphenyl-4-yl) -1- [5- (4-morpholinyl) -1H-1,2,4-triazol-3-yl] 2-butanone hydrochloride

Embedded image The compound of Example 2 (OD-01769) (2.48 g) was dissolved in diethyl ether (40 ml), and a 4N hydrochloric acid-dioxane solution was added to perform hydrochlorination. After evaporating the solvent, the residue was recrystallized from ethyl acetate to obtain the desired product (1.59 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.42 (d, 3H, J = 6.8 Hz), 3.
66 (brs, 4H), 3.71 (brs, 4H), 4.00-4.20 (1H, m), 4.02 (s,
2H), 7.00-7.09 (m, 2H), 7.30-7.52 (m, 6H)

Example 4 3- (2-Fluoro-1,1'-biphenyl-4-yl) -1- [3- (4-morpholinyl) -1,2,4-oxadiazol-5-yl] 2-butanone oxime

Embedded image Example 1 Compound (4 mg) of (OD-2819) and ethanol (0.2 mL)
To this mixture was added hydroxylamine hydrochloride (1.1 mg) and pyridine (0.04 ml). After heating at 60 ° C. for 18 hours, the solvent was distilled off, and water and ethyl acetate were added for extraction. The organic layer was washed with water, washed with saturated saline, dried over sodium sulfate, evaporated, and dried under reduced pressure to give the desired product (5 mg, white crystals). ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: E / Z mixture (major / mi
nor = 8/2 (1H-NMR)): 1.47-1.53 (m, total 3H), 3.35-3.4
0 (m, total 4H), 3.47-3.60 (m, total 1.2H), 3.70-3.7
6 (m, total 4H), 3.82-3.89 (m, total 1H), 3.90 (d, 0.
8H, J = 15.8Hz), 7.02-7.12 (m, total 2H), 7.34-7.55
(m, total 6H)

Example 5 3- (2-Fluoro-1,1'-biphenyl-4-yl) -1- [3- (4-morpholinyl) -1,2,4-oxadiazol-5-yl] -1-butene-
2-amine

Embedded image At 0 ° C., titanium tetrachloride (0.2 mL) was added to a solution of the compound of Example 1 (OD-2819) (100 mg) in benzene (30 mL), and the mixture was stirred for 50 minutes. Ammonia gas was blown at 0 ° C for 1 hour, and then stirred at room temperature for 3 days. After the reaction mixture was concentrated with an evaporator, the residue was purified by silica gel chromatography (hexane / ethyl acetate = 2/1) to obtain the desired product (88 mg) as a pale gray white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.58 (d, 3H, J = 7.1 Hz),
3.42-3.45 (m, 4H), 3.70 (q, 1H, J = 7.2Hz), 3.76-3.79
(m, 4H), 5.19 (s, 1H), 7.08-7.16 (m, 2H), 7.35-7.61
(m, 6H)

Example 6 N-benzyl-3- (2-fluoro-1,1'-biphenyl-4-yl) -1
-[3- (4-morpholinyl) -1,2,4-oxadiazol-5-yl] -1-buten-2-amine

Embedded image Example 1 (OD-2819) compound (8 mg) in benzene (0.5 m
l) / ether (0.1 ml) solution at 0 ° C in titanium tetrachloride (0.02
5 ml) and stirred for 1 hour. Benzylamine (0.05
0 ml) and stirred at room temperature overnight. After the reaction mixture was concentrated by an evaporator, the residue was purified by silica gel preparative thin-layer chromatography (hexane / ethyl acetate = 1/1) to obtain the desired product (4 mg) as a pale yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.50 (d, J = 7.1 Hz), 1.6
1 (d, J = 7.3Hz) (total 3H, 4: 1), 3.33-3.36 (m), 3.42-
3.45 (m) (total 4H, 4: 1), 3.72-3.75 (m), 3.77-3.80
(m) (total 4H, 4: 1), 3.91 (q, J = 7.0Hz), 5.62 (q, J =
7.0Hz) (total 1H, 4: 1), 4.21-4.46 (m, 2H), 5.13 (s),
5.19 (s) (total 1H, 1: 4), 7.03-7.55 (m, 13H), 8.65
(br t, 1H, J = 5.8Hz)

Example 7 3- (2-Fluoro-1,1'-biphenyl-4-yl) -1- [3- (4-morpholinyl) -1,2,4-oxadiazol-5-yl] -N-propyl-1-buten-2-amine

Embedded image The target compound (2 mg) was obtained from the compound of Example 1 (OD-2819) (15 mg) and n-propylamine (0.050 ml) in the same manner as in Example 6. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 0.94 (t, 3H, J = 7.4 Hz),
1.47-1.56 (m, 2H), 1.52 (d, 3H, J = 7.1Hz), 2.98-3.04
(m, 1H), 3.19-3.25 (m, 1H), 3.42-3.45 (m, 4H), 3.78-
3.81 (m, 4H), 3.93 (q, 1H, J = 7.1Hz), 5.07 (s, 1H), 7.
05-7.14 (m, 2H), 7.34-7.47 (m, 4H), 7.53-7.55 (m, 2H),
8.19 (br s, 1H)

Example 8 3- (2-Fluoro-1,1'-biphenyl-4-yl) -1- [3- (4-morpholinyl) -1,2,4-thiadiazol-5-yl] -2 -Butanone

Embedded image The compound of Reference Example 3 (SL-4689) (4.19
g) in tetrahydrofuran (14 ml) with stirring
60% sodium hydride (1.12 g) was added little by little, and after warming to room temperature, cyanomorpholine (2.06 ml) was added dropwise.
Stir at room temperature for 1 hour. The reaction mixture was poured into saturated saline, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated with an evaporator. The residue was purified by silica gel flash chromatography (chloroform) to give a mixture of the desired product as a pale yellow oil and cyanomorpholine.
(5.57 g) was obtained. This mixture (5.57 g) was added to 2-propanol
(80 ml) and heated to reflux until the solid dissolved. Stop heating and stir with phosphoric acid (85%, 1.56 g).
A solution of -propanol (8 ml) was added dropwise, and the mixture was gradually cooled to room temperature. The precipitated solid was collected by filtration and 2-propanol (8 ml)
And dried at 50 ° C. under reduced pressure to obtain pale yellow crystals (1.84 g). A mixture of this compound (3.80 g), dioxane (100 mL) and a phosphate / citrate buffer (pH 2.5, 100 mL) was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was collected, dried over magnesium sulfate, concentrated by an evaporator, and the residue was purified by flash chromatography (hexane / ethyl acetate = 2/1) to give the target compound as a dark brown oil (2.33
g) was obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.53 (d, 7.0 Hz), 1.59
(d, 7.1Hz) (total 3H, keto / enol = 4/1, -Me), 3.60-3.
64 (m, 4H, -CH2N), 3.71-3.79 (m, 4H, -CH2O, 0.2H, m
ethyne [enol]), 3.96 (q, J = 7.0Hz, 0.8H, methyne- [ket
o]), 4.17 (s, 1.6H, -CH2- [keto]), 5.74 (s, 0.2H, -C
H = [enol]), 6.91-7.20 (m, 2H), 7.35-7.61 (m, 6H), 12.
48 (br s, 0.2H, OH [enol])

Example 9 3- (2-Fluoro-1,1'-biphenyl-4-yl) -1- [3- (4-morpholinyl) -1,2,4-thiadiazol-5-yl] -2 -Butanone
Hydrochloride

Embedded image The compound of Example 8 (SM-156133) (1.18 g) was treated with a 4N-hydrochloric acid / dioxane solution to give the desired product (542 mg) as a pale yellow powder.
I got ¹ H-NMR (300 MHz, DMSO-d6) δ ppm: 1.44 (d, 3H, J = 7.0H)
Z), 3.45-3.47 (m, 4H), 3.62-3.63 (m, 4H), 3.89 (q, J =
7.1Hz), 4.19 (q, J = 7.1Hz), (total 1H, 6: 4), 4.40 (d,
0.4H, J = 19.8Hz), 4.60 (d, 0.4H, J = 19.8Hz), 6.04 (s,
0.6H), 7.20-7.30 (m, 2H), 7.38-7.51 (m, 6H)

Example 10 3- (2-Fluoro-1,1'-biphenyl-4-yl) -1- [5- (methylamino) -1,2,4-thiadiazol-3-yl] -2- Butanone

[Of 75] 5- [1- (2-fluoro-1,1'-biphenyl-4-yl) ethyl] -3-isoxazolamine hydrochloride which can be produced according to a known method (for example, JP-A-54-3062) (1.0g)
To a solution of methyl isothiocyanate (1.45) in pyridine (10 ml).
g) was added and the mixture was stirred at 70 ° C. for 9 hours. Toluene was added to the reaction solution, and the solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with toluene. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate =
The product was purified by 2/1 → 1/1) and then recrystallized from a mixed solvent of ether and hexane to obtain the desired product (0.54 g). ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.44 (d, 3H, J = 6.9 Hz), 2.
96 (d, 3H, J = 5.0Hz), 3.74-3.88 (m, 2H), 4.01 (q, 1H, J = 6.9H
z), 6.23 (s, 1H), 7.00-7.08 (m, 2H), 7.36-7.41 (m, 2H), 7.41
-7.48 (m, 2H), 7.48-7.53 (m, 2H)

Examples 11 to 15 In addition to the above examples, the following compounds shown in Table 1 were synthesized by the same operation as in Example 2 or Example 10. Each compound is isolated as a trifluoroacetate salt,
High-performance liquid chromatography retention time (column: Waters
Puresil C18, eluent: 10mM-AcONH ₄ / H ₂ O (pH 4): CH ₃ CN = 8
0: 20 → 20: 80 (30 min)) and LC / MS spectrum.

Embedded image

[Table 1]

Reference Example 1 (4S) -4- (2-Fluoro-1,1'-biphenyl-4-yl) -3-hydroxy-2- [3- (4-morpholinyl) -1,2,4- Oxadiazol-5-yl] tert-butyl-2-pentenoate

Embedded image At 0 ° C., a solution of isopropyl chlorocarbonate (1.09 g) in tetrahydrofuran (5 ml) was added to a mixture of flurbiprofen (1.98 g), N-methylmorpholine (0.98 ml) and tetrahydrofuran (8 ml), and the mixture was stirred for 30 minutes. The generated salt was removed with a filter paper to obtain a mixed acid anhydride solution. To this, a solution of the compound of Reference Example 4 (4.79 g) in a suspension of sodium hydride (60% in oil, 712 mg) in tetrahydrofuran (12 ml) at 0 ° C. and stirring for 30 minutes was added at 0 ° C.
Stir for hours. The reaction mixture was poured into a saturated saline solution and extracted with ethyl acetate. The organic layer was collected, dried over magnesium sulfate, concentrated with an evaporator, and the residue was subjected to silica gel chromatography (chloroform / methanol = 99/1).
To give the desired product (2.81 g) as a pale yellow oil. ¹ H-NMR (300MHz, CDCl ₃ ) δ ppm: 1.48 (s), 1.58 (s) (tot
al 9H, 5: 1), 1.57 (d, J = 6.75Hz), 1.62 (d, J = 7.1Hz)
(total 3H, 5: 1), 4.00-4.44 (m), 3.48-3.51 (m) (totsl
4H, 1: 5), 3.75-3.79 (m), 3.81-3.84 (m) (totsl 4H,
1: 5), 4.09 (q, J = 6.8Hz), 4.95 (q, J = 6.9Hz) (total 1
H, 5: 1), 7.20-7.24 (m, 2H), 7.32-7.54 (m, 6H), 13.37
(s), 14.21 (s) (total 1H, 1: 5)

Reference Example 2 [3- (4-morpholinyl) -1,2,4-oxadiazol-5-yl]
Ethyl acetate

Embedded image 4-morpholinecarbonitrile (11.2 g), diethyl malonate (61.0 ml), hydroxylamine hydrochloride (14.0 g)
g), sodium acetate (16.4 g) and dimethyl sulfoxide (100 ml) were stirred with heating at 120 ° C. for 24 hours. The reaction mixture was poured into 5% saline and extracted with ethyl acetate. The organic layer was collected, washed with saturated saline, dried over magnesium sulfate, and concentrated with an evaporator. The residue was purified by silica gel flash chromatography (hexane / ethyl acetate = 2/1) to give the target compound as a colorless oil (4.51 g).
I got ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.29 (t, 3H, J = 7.1 Hz),
3.43-3.47 (m, 4H), 3.76-3.80 (m, 4H), 3.83 (s, 2H),
4.26 (q, 2H, J = 6.8Hz)

Reference Example 3 3- [1- (2-Fluoro-1,1'-biphenyl-4-yl) ethyl] -5-
Isothiazolamine

Embedded image Known methods (for example, WO 98/47880)
4- (2-fluoro-1,1'-biphenyl-4-yl) -3-oxopentanenitrile (5.0 g) that can be produced according to
And stirred at 170 ° C. for 16 hours in a sealed tube. After cooling, the solvent was distilled off to obtain the desired product (4.9 g). To this, sodium sulfide 9 hydrate (220 mg), tetrabutyl ammonium bromide
(140 mg) and dissolved in benzene (10 ml) and water (10 ml). The mixture was stirred at about 70 ° C. for 24 hours under a hydrogen sulfide atmosphere. After adding water thereto, the mixture was extracted with benzene. The organic layer was concentrated and used for the next reaction. This residue was dissolved in diethyl ether (150 ml), potassium carbonate (4.4 g) was added, and the mixture was heated under reflux. To this, iodine (3.8 g) in diethyl ether (4
0 ml) solution was added dropwise. Eight hours later, water was added, extracted with diethyl ether, and washed with a 5% aqueous sodium thiosulfate solution. After drying and concentrating the organic layer, the residue was purified by silica gel column chromatography (benzene: ethyl acetate = 30: 1) to obtain the desired product (850 mg). ^{1 H-NMR (270MHz, CDCl} 3) δ ppm: 1.62 (t, 3H, J = 7Hz),
4.14 (q, 1H, J = 7Hz), 4.42 (brs, 2H), 6.07 (s, 1H), 6.98-
7.70 (m, 8H)

Reference Example 4 [3- (4-morpholinyl) -1,2,4-oxadiazol-5-yl]
Tert-butyl acetate

Embedded image 4-morpholinecarbonitrile (5.20 g), hydroxylamine hydrochloride (6.45 g) and di-tert-butyl malonate (2
From 5.0 g), a colorless oily target product (1.04 g) was obtained in the same manner as in Reference Example 2. ¹ H-NMR (300 MHz, CDCl ₃ ) δ ppm: 1.48 (s, 9H), 3.43-3.4
6 (m, 4H), 3.74 (s, 2H), 3.76-3.78 (m, 4H)

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 turbid compound of the present invention was orally administered for 5 consecutive days, and the administration was terminated.
Volume of hind limbs 5 hours after completion of administration
The swelling inhibitory effect was evaluated based on this difference. So
Table 2 shows the results.

[Table 2] Compound administered Oral dose Number of animals Increase in edema (ml) (mg / kg) Injectable foot Non-injectable foot ―――――――――――――――――――――― ―――――――――――― − − 10 0.45 0.03 Compound of Example 3 50 10 -0.49 -0.41 Indomethacin 0.5 10 -0.32 -0.36

[0110]

According to the present invention, immune abnormalities and chronic inflammation
In each case, it was possible to provide a drug showing a strong improvement effect.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 37/02 A61P 37/02 C07D 271/06 C07D 271/06 285/08 285/08 (72) Inventor Shogo Nakatani 3-1-1, Kasuganaka, Konohana-ku, Osaka Sumitomo Pharmaceutical Co., Ltd. ZB07 ZB11

Claims (7)

[Claims] (1) Formula (1):[Wherein E is a formula:Ｍwherein M is a single bond, -O-, -S-, -SO-, -S
O₂-, -CQ- (Q is 1,3-dithione together with carbon atoms
Represents a xanth ring or a 1,3-dioxolane ring. ),-
CH (OR¹²)-, -C (OR¹²)_Two-, -C (=
NOR¹²)-, -C (= NR¹²)-(R¹²Is water
Represents an atom or an alkyl group. ), -C (= NNR
¹³R¹⁴)-, (R¹³And R¹⁴Is independently water
Represents an atom or an alkyl group. ), -CO-, or
Represents -CS-. ｝ Or the formula:(Wherein B is a single bond, -O-, -S-, -SO- or
-SO₂Represents-. ). E is a halogen source
Child, nitro, formyl, acetyl, cyano, alkyl
Group, haloalkyl group, -OR²²(R²²Is hydrogen field
, An alkyl group, or a haloalkyl group. ),-
CO₂R²³, -SO₂R²³(R²³Is an alkyl group
Represents ), -CONR²⁴R²⁵, And -SO₂N
R²⁴R²⁵(R ²⁴And R²⁵Is, independently, hydrogen
Represents an atom or an alkyl group. )
It may be substituted with 1 to 4 selected groups. A
Is thiazole, oxazole, imidazole, pillow
Le, furan, thiophene, isothiazole, isoxazo
, 1,3,4-oxadiazole, 1,3,4-thiol
Asiazole, 1,2,4-oxadiazole, 1,
2,4-thiadiazole, pyrazole, 1,2,4-to
Represents liazole. R⁷Is a carbon atom of A and / or
Represents a substituent bonded to a nitrogen atom. r is an integer of 0 to 2
Represent. Substituent R on the carbon atom of A⁷Is a halogen atom, water
Acid group, nitro group, cyano group, carboxyl group, substituted
Optionally substituted amino group, optionally substituted hydroxy
Cyamino group, carbamoyl group which may be substituted,
An optionally substituted sulfamoyl group, -R^Fifteen, -O
R^Fifteen, -COR^Fifteen, -CO_TwoR^Fifteen(Where R^FifteenIs
Alkyl group which may be substituted, which may be substituted
Alkenyl group, alkynyl group which may be substituted,
An optionally substituted cycloalkyl group,
An optionally substituted cycloalkenyl group, an optionally substituted
A reel group, an aralkyl group which may be substituted, or
Represents an optionally substituted heterocyclic group. ),-SR
¹⁶, -SO-R¹⁶, -SO₂-R ¹⁶, -C (O)
SR¹⁶, -C (S) OR¹⁶, Or -CS_TwoR¹⁶
(R^{1 6}Is an optionally substituted alkyl group,
An optionally substituted aryl group, or an optionally substituted
Represents an aralkyl group. ). A is imidazole,
1,2,4-triazole, pyrrole or pyrazole
A substituent on the nitrogen atom, R⁷Is nitro
Group, cyano group, carbamoyl group which may be substituted,
Protection of optionally substituted sulfamoyl and NH groups
Group, -R^Fifteen, -OR^Fifteen, -COR^Fifteen, -CO_TwoR
^Fifteen, -SR¹⁶, -SOR¹⁶, -SO₂R ¹⁶, −
(CO) SR¹⁶,-(CS) OR¹⁶, Or -CS
₂R¹⁶(Where R^Fifteen, And R¹⁶Is as defined above
is there. ). X is an oxygen atom, a sulfur atom, or
= NR¹⁷(Where R¹⁷Represents a hydrogen atom, a hydroxyl group,
Represents an alkyl which may be substituted. ). G
Is -NR⁵R⁶[R⁵Or R⁶Are the same or different
Is a hydrogen atom, -R¹⁹(Where R¹⁹Is replaced
Alkyl group, alkenyl which may be substituted
Group, an optionally substituted alkynyl group,
An optionally substituted cycloalkyl group, an optionally substituted
A chloroalkenyl group or an optionally substituted ara
Represents a alkyl group. ). Alternatively, R⁵And R⁶
May be substituted together with the nitrogen atom
A saturated heterocycle may be formed. Or the formula:[Where the two dashed lines indicate double bonds with the solid line.
Taste, the other means a single bond with the solid line. R¹Is a broken line
Is bonded to a nitrogen atom having a bond that represents a single bond with the solid line
I do. R¹, R^Two, R^ThreeAnd R^FourIs each independently hydrogen
Atom, hydroxyl, nitro, cyano, substituted
Good amino group, hydroxyamino which may be substituted
Group, -R¹⁹, -OR¹⁹, -COR¹⁹, -COOR
¹⁹, -SOR¹⁹, -SO₂R¹⁹(Where R¹⁹Is
Alkyl group which may be substituted, which may be substituted
Alkenyl group, alkynyl group which may be substituted,
An optionally substituted cycloalkyl group,
An optionally substituted cycloalkenyl group, an optionally substituted
Reel group, aralkyl group which may be substituted,
Represents an optionally substituted heterocyclic group. ), Even if substituted
A good carbamoyl group or an optionally substituted sulfo group
Represents a famoyl group. Also, R¹, R^Two, R^ThreeAnd R
^FourMeans that any two of these combine to form one nitrogen source
With two nitrogen atoms and one carbon atom
May form a heterocyclic ring which may be substituted with
No. ]. R⁸, R⁹, R¹⁰And R¹¹Is each
Each independently represents a hydrogen atom or an alkyl group. Ma
R⁸And R⁹And / or R¹⁰And R¹¹Tied
Together with the carbon atoms to which they are attached,
Or select from oxygen, nitrogen, and sulfur atoms.
May form a saturated heterocyclic ring with the heteroatom
No. Or a pharmacy thereof.
Above acceptable salts. 2. In the formula (1), A represents the formula:[In the formula, m represents 0 or 1. R¹⁸Is a nitrogen atom
Represents a substituent that combines ¹⁸Is a nitro group, a cyano group,
Optionally substituted carbamoyl group, optionally substituted
Good sulfamoyl group, protecting group for NH group, -R^Fifteen, −
OR^Fifteen, -COR^Fifteen, -CO_TwoR^Fifteen, -S
R¹⁶, -SOR¹⁶, -SO2R¹⁶,-(CO) S
R¹⁶,-(CS) OR¹⁶, -CS₂R¹⁶Or
−CS_TwoR¹⁶(Where R^Fifteen, And R¹⁶Is
It is synonymous. ). 5. The method according to claim 1, wherein
A membered heteroaromatic compound or a pharmaceutically acceptable salt thereof. 3. In the formula (1), A is a group represented by the following formula: The 5-membered heteroaromatic ring compound or a pharmaceutically acceptable salt thereof according to claim 1, which is represented by a divalent group selected from: 4. The 5-membered heteroaromatic compound according to claim 1, wherein X is an oxygen atom or a sulfur atom in the formula (1) or a pharmaceutically acceptable salt thereof. 5. In the formula (1), E is a formula:[Where M¹Is a single bond, -CQ- (Q is
A 1,3-dioxane ring or a 1,3-dioxolane ring
Represent. ), -CH (OR¹²)-, -C (OR^{1 2})_Two
-, -C (= NOR¹²)-(R¹²Is as defined above
is there. ), -C (= NR¹²)-, -C (= NNR¹³
R¹⁴)-(R¹³And R¹⁴Is as defined above. ),
Represents -CO- or -CS-. E is a halogen
Atom, acetyl, nitro, formyl, cyano, alkyl
Group, haloalkyl group, -OR²²(R²²Is as defined above
It is. ), -CO₂R ²³, -SO₂R²³(R²³
Is as defined above. ), -CONR²⁴R^{2 5},
And -CONR²⁴R²⁵(R²⁴And R²⁵Is before
Synonymous with ) Arbitrarily selected from the group consisting of
And may be substituted with four groups. Request represented by]
Item 5. The 5-membered heteroaromatic compound according to items 1 to 4, or a pharmaceutical thereof.
Above acceptable salts. 6. In the formula (1), E is represented by the following formula: Wherein M ² represents a single bond or —CO—, wherein E is a halogen atom, a cyano, an alkyl group,
The 5-membered heteroaromatic compound according to claims 1 to 4, which may be substituted with 1 to 4 groups arbitrarily selected from the group consisting of a haloalkyl group, an alkoxy group, and a haloalkoxy group, or a pharmaceutically acceptable one thereof. Salt. 7. A medicament comprising the 5-membered heteroaromatic ring compound according to claim 1 or a pharmaceutically acceptable salt thereof.